TW201130854A - Pyridinone derivatives and pharmaceutical compositions thereof - Google Patents

Abstract

Pyridinone derivatives, process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially sex-hormone-related conditions in both men and women, as well as a mammal in general (also referred to herein as a "subject"). For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, heavy menstrual bleeding, particularly menorrahagia and dysmenorrehea, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization). The present application relates in particular to pyridinone derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists.

Description

201130854 6. TECHNOLOGICAL FIELD OF THE INVENTION The present invention generally relates to a pyridone derivative as a gonadotropinreleasing hormone (GnRH) receptor antagonist, and a pharmaceutical composition containing the pyridone derivative of the present invention And a method of treating a condition by administering a pyridone derivative to a mammal in need, especially a human. [Prior Art] Gonadotropin-releasing hormone (GnRH) is a decapeptide released from the hypothalamus (pGlu-His, Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), which also It is called luteinizing hormone releasing hormone (LHrh). GnRH acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland regulates the production of gonadal steroids in both sexes and advanced follicular development and ovulation in female mammals. FSH regulates sperm production in males and early follicular development. Therefore GnRH plays a key role in human reproduction. Due to the biological importance of synthetic antagonists and agonists of GnRH, it has become the center of several research activities, especially in endometriosis, uterine leiomyoma (fibroids). ), prostate cancer, breast cancer, ovarian cancer, benign prostatic hyperplasia, assisted reproductive therapy and precocious puberty. For example, describe such as leuprorelin (pGlu-His-

Peptide of Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) GnRH agonist 152524.doc 201130854

I is used to treat these conditions (JTze 2001, 358, 1793-1803; Mo/.

Ce//. Five Wo. 2000, 9-14). These agonists initially induce synthesis and release of gonadotropins ("flare-up") by binding to the GnRH receptor on pituitary gonadotropins. However, long-term administration of GnRH agonists reduces the release of gonadotropins from the pituitary gland and leads to downregulation of the receptor, thereby inhibiting the production of steroid hormones after a certain treatment period. Conversely, it has been suggested that GnRH antagonists can inhibit the action of gonadotropins, providing several advantages from ^, in particular, without the side effects associated with triggering seen under the treatment of GnRH superagonist. Several peptide antagonists with low histamine release potential are known in the art. These peptide products show low oral bioavailability, which limits their clinical utility. Many non-peptide compounds have also been described as useful as GnRH receptor antagonists, for example: -thieno[2,3-b]pyridin-4-one (C/zo#乂,··. Mel 1998, • 41, 4190 -4195); - Substituted oxime (US 5,780,437, US 5,849,764 'WO 97/21704, WO 98/55479, WO 98/55470, WO 98/55116, WO 98/55119, WO 97/21707, WO 97/21703 And WO 97/21435); tricyclodiazepine (WO 96/38438) and phenyl substituted fused nitrogen-containing bicyclic compound WO 99/33831 ; - quinoline and thienopyridine derivatives (WO 97/14682 , WO 97/14697 and WO 99/09033); 152524.doc 5 201130854

- substituted quinolin-2-ones (WO 97/44037, WO 97/44041, WO 97/44321 and WO 97/44339); - anthracene derivatives and novel bicyclic and tricyclic pyrrolidines (WO 02/066459 and WO 02/11732). Other compounds having a heterocyclic structure and their use as GnRH antagonists are disclosed in WO 00/69859, WO 01/29044, WO 01/55119, WO 03/013528, WO 03/011870, WO 03/011841, WO 03/ 011839, WO 03/011293 and WO 05/007164. However, there remains a great need in the art for effective small molecule GnRH receptor antagonists and pharmaceutical compositions containing such GnRH receptor antagonists and for their use in the treatment of, for example, sex hormone related conditions, specifically for the treatment of leiomyoma method. The pyridone derivatives of the present invention meet these needs while providing other related advantages. Pyridone derivatives are known in the art as pharmaceutically active ingredients, but their activity as GnRH receptor antagonists has not been described in current state of the art, for example, WO 0136426 A1 is described as being effective in treating or preventing Gram Gram-negative bacterial infection of pyridone and its derivatives. Pyridone is stable and readily derivatized; methods for accomplishing such derivatization have been described. Two site-selective and functional group-tolerant methods for synthesizing novel pyridone are also provided. One such synthetic method involves reacting an imine with a Meldrum's acid derivative in a solution. Another synthetic method is solid phase synthesis of pyridone wherein an imine bound to a solid support is prepared and the Michael acid derivative is reacted with the imine 152524.doc 201130854. Novel imine intermediates suitable for solid phase and solution processes for the synthesis of pyridone are also described. WO 2008054290 A1 describes 1H-pyridin-2-one derivatives, inhibitors of pAI1, processes for their preparation, pharmaceutical compositions containing the same, and their use in therapy. The compounds of formulae I, II and III are useful in the treatment of, for example, thrombosis, coronary heart disease, renal fibrosis, atherosclerotic plaque formation, cancer, diabetes and obesity. SUMMARY OF THE INVENTION An object of the present invention is to provide a gonadotropin releasing hormone (GnRH) receptor antagonist, a preparation method and use thereof, and a pharmaceutical composition containing a gonadotropin releasing hormone receptor antagonist. In particular, the invention relates to compounds of the general formula (I):

(I) where

Rsa and independently of each other represent a hydrogen atom, a C^-Ce alkyl- or a C3-C6 ring-based group, or

Rh is bonded to the atom to which it is attached to form a C3-C6 cycloalkyl group; Κό represents a dentate atom, an aryl group, a heteroaryl group, a stupid [1,3] 152524.doc 201130854 dioxagen Cyclopentenyl- or 2,3-dihydro-1,4-benzodioxanyl wherein the group is substituted, in the same or different manner, with one or more substituents Rll selected from the group consisting of Secondary: hydrogen, halogen, hydroxy, cyano, nitro, Ci-C6 alkyl, halo-C丨-C6 alkyl, C丨-C6 alkoxy, halo-CVC: 6 alkoxy C 1- C6, C1-C6H2O-C1-C6, _-Ci_C6 alkoxy-CVC6 alkyl, c!-c6 alkyl-C(=〇)〇H, C3-C1G Cycloalkyl, 3 to 10 membered heterocycloalkyl, aryl, heteroaryl, aryloxy-, heteroaryloxy-, _-C(=〇)〇H, alkyl, -C(=〇) 〇-C3-c10 cycloalkyl, -N(H)C(=0)R9, -IsKCi-C^ alkyl)C(=〇)R9, -N(H)S(=0)2R9, -N (C!-C6 alkyl)s(=o)2r9, _c(=o)nr9r10, -〇C(=0)NR9R10, -N(H)C(=0)0R9, -NCCVQ alkyl)C( =〇)〇R9, N(H)C(=0)NR9R1(), -NCCi-Ce alkyl)C(=0)NR9R10, -SR9, -S(=0)R9, -S(=〇) 2R9, _s(=〇)2NR9R丨0, -NR9R 10; its towel · R9 and R1G independently of each other represent a hydrogen atom, (^-(: 6 alkyl-, halo-CrQ alkyl-, CVC6 alkoxy-CVC6 alkyl... halo-(VC6 alkoxy) -C--C6 alkyl-, C2-C6 alkenyl-, C2-C6 block-, C3-Ci-cyclohexene (radical, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl -, CVC6 Stretching-aryl-, CVCdt-alkyl-heteroaryl-, -CVCdt-based-C3-Ci-indole--, C"C6 extended alkyl-(3 to 10 membered heterocyclic alkyl) ); its 152524.doc -8 -

201130854

Wherein the C3-C10 cycloalkyl- and the 3 to 10 membered heterocycloalkyl- are optionally substituted one or more times: halogen atom, cyano group, -OH, alkyl group, dentate-Ci-Ce alkyl group a cvc6 alkoxy group, a C3-C10 cycloalkyl group, an aryl group or a heteroaryl group; or R9 and R1G together with the atom to which they are attached form a 3 to 1 member heterocycloalkyl group, which is the same as the case Alternatively or in combination with one or more substituents selected from the group consisting of: dentyl, hydroxy-, cyano-, nitro-, pendant oxy, Ci_C$alkyl-, halo-Ci_C6 ·,Ci-C6 Instituteoxy_,Halo-CVC6 alkoxy-'CVC6 alkoxy-CVC6 alkyl-,-yl-CVC6 alkoxy-CVC6 alkyl·, (:3-(:10 ring) Alkyl-, 3 to 10 membered heterocycloalkyl-, -C(=〇)〇H, -(:(=0)0-(^-(:6 alkyl, -c(=o)o-c3 -c1()cycloalkyl, -0C(=0)-Ci-C6 alkyl, -0C(=0)-C3-Cig cycloalkyl, alkyl, -N(CrC6 alkyl K^OXCVCd-alkyl , alkyl, alkyl) SpOMCi-D-alkyl, -ChCONUCrC^)-alkyl) (((^-(:6)-alkyl), OChC^NUCVCd-alkylalkyl), -:^( 11)(:(=0)0((^-(:6)-alkyl, -Ν((ν(:6 alkyl)(:(=0)0((^-(:6)-alkyl) -N^epcONKCVC^)-alkyl)((Ci-C6)-hospital), -N(C!-C6 alkyl)C(=〇)N((Ci_C6)-alkyl)(((^ -(:6)-alkyl), -s(cvc6)-alkyl, -spoxcvc^)-alkyl, -s(=o)2oh, 4(=0)2((^- 152524.doc -9 - 201130854

R7 w X C6)-alkyl, ·3(=〇)2Ν(((:1_(:6)alkyl)((Ci_C6) alkyl), -p(=o)(oh)2, -ρροχοΑΑ) -院()(CVC6)-alkyl), -N((Ci-C6)-alkyl)((Ci_c6)alkyl)' and wherein (C^c:6)-alkyl is one or more Substituted by a south atom; represents a hydrogen atom, C^C6 alkyl, halo-CrC6 alkyl or c3-c6 cycloalkyl; Ο, S, S=0 or S(=0)2;

Wherein one or more substituents independently selected from the group consisting of argon, halo, cyano, nitro, Cl-C6 alkyl _, halo-Ci-C6 alkyl-, alkoxy _ , (^-〇:6 alkoxy-Ci-C6 alkyl_, halo-Ci_C6 alkoxy_c]_c6 alkyl-, C2-C6 alkenyl, c2-C6 alkynyl _, _c ( = o) r9, -C(=0)0R9, -C(=〇)NR9R10, -SR9, -S(=0)R9, -S(=〇)2R9, -S(=0)2NR9R10 or -NR9R10; Wherein R9 and R1G are bonded to each other independently or together with the atom to which they are attached, having the meaning given above; Y 152524.doc •10· 201130854

c

* where Rla and Rib represent hydrogen atoms independently of each other

Ci alkyl-' Cl-

,Ci-Ce alkoxy-Ci-C6 phenotype _,, _, aryl aryl, -CVC6 alkylene-aryl '-CVC6 stretching heat π-based - (3 •Ci_C6 stretching base - C3 -Ci〇 bad base, p base·, to 10 member heterocyclic alkyl), _C(=〇), C/C C6 alkylene-C/1 c6 alkynyl-, c3-c8 cycloalkyl〇yc ( 55= 0)° c

-heteroaryl, -c(=o)o-cvC6 alkyl C6 extended alkyl-aryl, = group, _c(=o)nr9r1(), -S(=0)2R9; Substituting one or more times from 'JL, ·β, and alkaloids in the same or different ways: halo-, hydroxy gas. Alkoxy-, Ci-Cfi-d-yl-, halo-Ci-C6 alkyl-, C1, halo-C丨-C6 alkoxy-'CVC6 alkoxy-CrC6 dah-heteroaryl Base 0-poly-, halo-Ci_C6-oxime-Ci-Ce Hyun'yl, C3_Ci〇% alkyl-, aryl-, heteroaryl, 3- to 1-membered heterocycloalkyl-, C(=0)0H, -CpCOO-Ci-Ce, and -C(=0)0-C3-C!. Cycloalkyl, -0(3( = 0)-(1^-(^6 alkyl, _〇c( = 〇)_ C3-C1❶cycloalkyl, -N(H)C(=0)R9, c base) C(=0)R9, -N(H)S(=0)2R9, -N(Ci_C6 yard base)

S 152524.doc -11 - 201130854 S(=0)2R9, -C(=0)NR9R丨0, -〇c(=〇)NR9R10, -N(H)C(=0)OR9,-N^- Ce alkyl)C(=0)0R9, -N(H)C(=0)NR9R10 '-N(H)C(=NH)NR9R10 '-N(c)-c6alkyl)C(=0) NR9R10, -SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, '-s(=o)2nr9r10, -p(=o)(oh)2, _P (=0) (〇R9)(〇R10), _NR9R10, and wherein R9 and RW are bonded to each other independently or together with the atom to which they are attached, have the meaning given above; or Rla and Rib together with the atom to which they are attached Coupled together to form a 3 to 10 membered heterocycloalkyl- group, which is optionally substituted one or more times with substituents selected from the group consisting of halo-, hydroxy-, cyano-, nitro-, Sideoxy, CVC6 alkyl-, halo-Ci_C6 alkyl-, Ci-C6-energy-oxyl, halo-Ci-C6 alkoxy _, C 1 -C6 alkoxy-C1-C6 炫 I Base-, dentate group CVC6 alkoxy-CVC6 alkyl-, -C(=0)0H, -CpCOO-CVCe alkyl, -(:(=0)0-(33-(^.cycloalkyl, -0(:(=0)-(^-(36 alkyl, -0C(=0)-C3-C1Q cycloalkyl, -N(H)C(=0)R9, alkyl)C(=0 ) R9, -N(H)S(=0)2R9, alkyl)S(=0)2R9, -C(=0)NR9R10, -OC(=0)N R9R10, -N(H)C(=0)0R9, -NCCVC6 alkyl)C(=0)0R9, -N(H)C(=0)NR9R10, -N(H)C(=NH)NR9R10 ' -NCC^-Ce alkyl)C(=0) NR9R10, -SR9, -S(=0)R9, -S(=0)20H, -S(=0)2R9, -s(=o)2nr9r10, -p(=o)(oh)2, -p(=o)(or9)(or10), 152524.doc -12- 201130854 NR R , wherein R9 and R10 are bonded to each other independently or together with the atom to which they are attached Together with the meaning given above' or

Rla and Rib are bonded together with the atom to which they are attached to form a 3-membered heterocycloalkyl group which is substituted with a group selected from the group consisting of cycloalkyl, aryl, heteroaryl, _Ci C6 Alkyl-aryl, _Ci_C6 alkyl-heteroaryl, _Ci_C6 Φ alkyl-(VC, anthracenyl, 3 to 10 membered heterocycloalkyl, -CrC6 alkyl) - 'The groups are optionally substituted one or more times by substituents selected from the group consisting of halo, cyano, Ci_C6 alkyl and halo-C丨·c6 alkyl as the same or different;

Rlc represents a hydrogen atom, a hydroxyl group, a methoxy group or a CrC6 alkoxy group, a Cl-C6 alkyl group, a Ci-C6 alkoxyalkyl group, a c2-C6 alkenyl group, a c2-c6 alkynyl group, a C3_C8 ring. Alkyl-, aryl-•, heteroaryl-, -CVC6 alkyl-aryl ' _Cl_c6 alkyl-heteroaryl, -CVC6 alkylene _c3-C1()cycloalkyl, -CV C6 Relating - (3 to 10 membered heterocycloalkyl); wherein the groups are now substituted one or more times in the same or different manner via a substituent selected from the group consisting of halo-, hydroxy-, cyano- , nitro-, Cl_c6 alkyl, dentyl-C丨-c6 alkyl _, cvc6 alkoxy-, halo-C丨-C6 alkoxy...Ci_c6 alkoxy_C]_C6 alkyl _, Toothyl-CVC6 alkoxy_Ci_c6 alkyl-, c3_Ci-cycloalkyl-, 3 to 10 membered heterocycloalkyl-, -C(=0)0H, -C(=〇)〇-ci_C6 152524.doc 5 -13. 201130854 Alkyl, -(:(=0)0-(:3-(^.cycloalkyl, -OCpCO-CVC^alkyl, -OCpOHVC, cycloalkyl, -N(H)C (=0)R9, -NCCVCfi alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(Ci-C6 alkyl)s(=o)2r9, -c(= o) nr9r10, -OC(=0)NR9R10, -N(H)C(=0)0R9,...((^-(^alkyl)C(=0)0R9, -N(H)C(=0 )NR9R10, -N(H)C(=NH) NR9R10, -NA -Q alkyl)C(=0)NR9R10, -SR9, -S(=0)R9, -S(=0)2R9, -S(=〇)2NR9R10, -NR9R10, wherein R9 and R1Q are independent of each other or Along with the atoms to which they are attached, they have the meanings given above; R3a and R^b independently of each other represent a hydrogen atom, an alkyl group, a Ci-C6 alkoxy-C "C6 alkyl group", and a C2-C6 salt. Base, c2-c6 alkynyl-, C3-C8 ring-based, 3- to 10-membered heterocyclyl-, aryl-, heteroaryl-, -〇ν(:6-alkylene-aryl, Alkyl-heteroaryl, -cvc:6alkyl-c3-c1()cycloalkyl, -Ci-C6 extended alkyl-(3 to 10 membered heterocycloalkyl); wherein the group The situation is substituted one or more times in the same or different manner by a substituent selected from the group consisting of: dentyl-, thiol-, cyano-, nitro-, (:---: 6 alkyl-, halo-( ^-(^alkyl·, CV C6 alkoxy-, halo-C^-Ce methoxy-, Ci-C6-oxyl-Ci-C^alkyl-, halo-C-C6 oxy-C^-Ce, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl (=0)0-(^-06 炫基, -C(=0)0-C3-Ci〇环焼基,·〇(^(=〇)_(^1_(^6垸152524.doc -14 -

201130854 base, -0C(=0)-C3-C丨. Cycloalkyl, -N(H)C(=0)R9, -N(CVC6 alkyl)C(=0)R9, -N(H)S(=0)2R9, -NCCVQ alkyl)s(= o) 2R9, -c(=o)nr9r10, -OC(=〇)NR9R10 ' -N(H)C(=0)0R9 ' -N(C,-C6 alkyl)C(=0)0R9,- N(H)C(=0)NR9R1G, -N(H)C (=NH)NR9R10, alkyl)c(=o)nr9r10, •SR9, -S(=0)R9, -S(=0) 2R9, -S(=0)2NR9R10, ^-NR9R1G, wherein R9 and R1G are bonded to each other independently or together with the atom to which they are attached, have the meanings given above; or

Rla and R3a, or Rlb and R3a, or R3b and Rla, or R3b and

Rlb is bonded together with the atom to which it is attached to form a 4 to 1 member heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl group, which is optionally substituted in the same or different manner with a substituent selected from the group consisting of Or multiple times: • from base-, hydroxy-, cyano-, nitro-, CVC6-alkyl-, halo-C丨-c6 alkyl, Ci_c6 alkoxy-, halo-CVC6 alkoxy... Ci-C6 alkoxy-C丨-C6 alkyl-, from yl-cv C6 bis-oxy-C1-C6 alkyl-, c3-c1Q cycloalkyl-, 3 to 1 fluorene heterocycloalkyl- , _c(=〇)〇H, -CPCOO-CkQ alkyl '-c(=o)〇_c3_Ci()cycloalkyl,_0C(=0)-Ci_C6^ group, -〇C(=〇)_C3_Ci. Ring base, _N(H)c(=〇)R9, •N((VC6 alkyl)C(=〇)R9, -N(H)S( = 〇)2R9, _N(Ci-C6 alkyl) s( = 〇)2r9, _c( = 〇)NR9R10, 152524.doc •15- 201130854 -OC(=0)NR9R10, -N(H)C(=0)0R9, -NA-Ce alkyl)C( =0) 0R9, -N(H)C(=0)NR9R10, -N(H)C(=NH) NR9R10, -NCCVC^alkyl)C(=0)NR9R10, -SR9, -s(=o )r9, -s(=o)2oh, -s(=o)2r9, -s(=o)2 NR9R10, -p(=o)(oh)2, -p(=o)(or9)(or10 '-NR9R1G, wherein R9 and R1G are bonded to each other independently or together with the atom to which they are attached, and have the meaning given above, and all other substituents in Y have the meanings given above; Is -C(=0)H. The compound of the present invention is a solvate of a compound of the formula (I), and a salt, a solvate thereof and a salt thereof; a solvent which is encompassed by the formula (I) and which has a compound of the formulae mentioned below and a salt, a solvate thereof and a salt thereof And a solvate of a salt, a solvate thereof and a salt thereof, which are encompassed by the formula (I) and exemplified hereinafter as exemplary embodiments; wherein the compound encompassed by the formula (I) and mentioned below is not It has been a solvate of salts, solvates and salts. The hydrate of the compound of the present invention or a salt thereof is a stoichiometric composition of the compound with water, such as a hemihydrate, a monohydrate or a dihydrate. The solvate of the compound of the present invention or a salt thereof is a stoichiometric composition of the compound and a solvent. Preferred solvates for the purposes of the present invention are hydrates. The salt for the purpose of the present invention is preferably a pharmaceutically acceptable salt of the compound of the present invention (for example, see S. M_Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 19, 66, Ί-Ί9). . 152524.doc -16- 201130854 Pharmaceutically acceptable salts include acid addition salts of mineral acids, carboxylic acids and sulfonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, decanesulfonic acid, ethanesulfonic acid, Toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, maleic acid, methacrylic acid, benzoic acid, ascorbic acid, succinic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid , citric acid, gluconic acid, lactic acid, almond i, cinnamic acid, aspartic acid 'stearic acid, palmitic acid, glycolic acid and glutamic acid salt. The pharmaceutically acceptable salt also includes salts of conventional bases such as, and preferably, metal salts (e.g., sodium, hydrate, and potassium), soil metal salts (e.g., salt and magnesium salts), and Ammonia or an organic amine-derived ammonium salt, such as preferred examples are ethylamine, diethylamine, triethylamine 'ethyldiisopropylamine' monoethanolamine, diethanolamine, =ethanolamine, dicyclohexylamine, dimethylaminoethanol Benzylamine

(di also covers itself not suitable for medical use but can be used, for example, for separation or purification

The occurrence of its asymmetry center is (and) _, ((S)· _ 〆, Ί 股 八 仔 〇 〇 〇 〇 ^ ^ 槎 槎 槎 槎 槎 152524 .doc 17· 201130854 It should also be understood that when two or more asymmetric centers are present in a compound of the invention, several diastereomers and enantiomers of the exemplified structure will generally be possible, and pure Diastereomers and pure enantiomers represent preferred embodiments. It is intended that the pure stereoisomers, the pure diastereomers, the pure enantiomers and mixtures thereof are within the scope of the invention. Geometric isomers due to the nature of a substituent with respect to a double bond or ring may exist in the cis (=ζ·) or trans (=penta-) form, and both isomeric forms are encompassed within the scope of the invention . All isomers of the compounds of the invention, whether isolated, purified, partially purified or in the form of a racemic mixture, are encompassed within the scope of the invention. Purification of such isomers and separation of such isomeric mixtures can be accomplished by standard techniques known in the art. For example, t, a mixture of diastereomers can be separated into individual isomers by chromatography or crystallization, and the racemates can be separated into the palm phase by chromatography or by resolution. Other enantiomers. Where a compound of the invention may exist in tautomeric form, the invention encompasses all tautomeric forms unless otherwise stated. The following definitions apply to the substituents and residues used throughout the specification and the patent application. Particularly named chemical groups and atoms (e.g., fluorof-group, decyloxy, and the like) are considered to be specific forms of the examples of the respective groups in the compounds of the present invention. The term "dentate atom" or "family" is understood to mean a fluorine, chlorine, bromine or iodine atom. The term "c"-c6 alkyl" is understood to mean preferably a straight or branched chain saturated monovalent hydrocarbon radical of the formula 4, 2, 3, 152524.doc 201130854 4, 5 or 6 carbon atoms, such as methyl, B. Base, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, second butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1 -ethylpropyl, 1,2-di-f-propyl, neopentyl, u-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, anthracene _Methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-didecylbutyl, 2,2-dimethylbutyl, 1,1-didecylbutyl, 2,3-Dimethylbutyl, anthracene, 3-dimethylbutanyl or hydrazine 2-dimethylbutyl, or an isomer thereof. In particular, the groups have 1, 2 or 3 carbon atoms ("Cl-C3 alkyl"), methyl, ethyl, n-propyl- or isopropyl. The term "halo-CrC6 alkyl" is understood to preferably mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical, wherein the term "C丨_c6 alkyl" is as defined above, and wherein one or more hydrogen atoms are the same or Different ways (ie, one fang atom is independent of another halogen atom) are replaced by a halogen atom. Special. The halogen atom is! 7. The halo group 丨-匕 alkyl group is specifically -CF3, _CHF2, .CH#, _CF2Cf3, _CF2CH3 or even CF3. The "c! C6 alkoxy" a is understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical of the formula _〇·alkyl group, wherein the term "formyl" is as defined above, for example, methoxy, ethoxy. , a ^ ^ ^ propyl, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, second butoxy, pentyloxy, isopentyloxy or n-hexyloxy , or an isomer thereof. ". From the radical -(VC6-homoyloxy) is understood to preferably mean a straight-chain or branched-chain saturated monovalent Ci_c6 methoxyl group as defined above, wherein one or more of the I52524.doc 201130854 hydrogen atoms are halogenated in the same or different manner. Atomic substitution. In particular, the dentate atom is F. The aldentyl group -Ci_C6 alkoxy is, for example, -OCF3, -OCHF2, -〇CH2F, -〇CF2CF3 or -〇CH2Cf3. The term "Cj-Ce alkoxylate" -C丨, C<5"5"5" is understood to mean preferably a straight or branched chain saturated monovalent alkyl group as defined above, wherein one or more hydrogen atoms are in the same or different manner via an alkoxy group as defined above Substituent substitution, for example, decyloxyalkyl, ethoxyalkyl, propoxyalkyl, isopropoxyalkyl, butoxy-based, isobutoxyalkyl, third butoxy, a second butoxyalkyl group, a pentyloxyalkyl group, an isopentyloxyalkyl group, a hexyloxyalkyl group, wherein the term "C^-C6 alkyl" is as defined above, or an isomer thereof. The base-Ci-C6 alkoxy-Ci-C6 alkyl group is understood to preferably mean a linear or branched chain saturated monovalent alkoxy-Ci-Ce alkyl group as defined above. One or more hydrogen atoms are replaced by a halogen atom in the same or different manner. Specifically, the halogen atom is F. The halo-CrC^ alkoxy-C^-Ce alkyl group is, for example, -CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCF2CF3 or -CH2CH2OCH2CF3. In general, an alkylcarbonyl group means a straight or branched alkyl group having from 1 to 4 carbon atoms which is bonded to the remainder of the molecule via a carbonyl group. Non-limiting examples include Anthracenyl, n-propyl fluorenyl, n-butyl fluorenyl, isobutyl fluorenyl, tert-amyl. Alkoxycarbonylamino group illustratively and preferably represents decyloxycarbonylamino, ethoxy-carbonylamino, n-propoxy Alkylcarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino and tert-butoxycarbonylamino. 152524.doc 20· 201130854 Alkoxycarbonyl illustratively and preferably represents methoxy Carbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group and tert-butoxycarbonyl group. In general, alkylsulfonyl group means having 1 to 4 carbon atoms. Linear or branched alkyl group's via sulfonyl (_so2-) and The remainder of the bond is bonded. Non-limiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonate In general, 'S-alkylsulfonimide fluorenyl denotes a straight or branched alkyl group having 1 to 4 carbon atoms' via sulfonimide fluorenyl [_S(=〇)(=NH _] is bonded to the rest of the molecule and to the sulfur atom of the group. Non-limiting examples include S-methylsulfonimide sulfhydryl, S-ethylsulfonimide fluorenyl, S-positive Propylsulfonimide fluorenyl, S-isopropylsulfonimide fluorenyl, s-n-butylsulfonimide fluorenyl, S-t-butylsulfonimide fluorenyl. In general, a monoalkylamino group means an amine group having an alkyl residue attached to a nitrogen atom. Non-limiting examples include mercaptoamine, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino. The above also applies to groups such as monoalkyl-aminocarbonyl groups. In general, a dialkylamino group means an amine group having two independently selected thiol residues attached to a nitrogen atom. Non-limiting examples include dimethylamino, sulfhydryl diethylamino, diisopropylamino, wethyl·#•methylamino, ·/V-methyl-7V·n-propylamine Base, isopropyl-iV»n-propylamino group, iV-t-butyl-#.methylamino group. The above also applies to groups such as a di-alkylaminocarbonyl group. £152524.doc -2b 201130854 Monoalkylaminocarbonyl illustratively and preferably represents methylaminocarbonyl, ethyl-amino, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butyl An aminocarbonyl group and a tert-butylaminocarbonyl group. Dialkylaminocarbonyl is illustratively and preferably denotes ## dimethylaminocarbonyl, diethylaminocarbonyl, diisopropylaminocarbonyl, #_ethylmethylaminocarbonyl, methyl -iV-n-propylaminocarbonyl, isopropyl-n-propylaminocarbonyl and #·t-butyl-yl-yl-carbonyl. In general, a 'homoylcarbonylamino group means a straight or branched alkyl group having 1 to 4 carbon atoms bonded to the remainder of the molecule via a carbonylamino group (_(:(=〇)-ΝΙί-) And linked to a carbon atom of a thiol group. Non-limiting examples include an ethyl-amino group, a n-propyl decylamino group, a n-butyl decyl amide group, an isobutyl decyl amine group, a pentyl amide group. It is understood that it is preferably a straight-chain or branched-chain monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6 carbon atoms' specific 2 or 3 carbon atoms (" CrC3 alkenyl"), it is understood that in the case where the alkenyl group contains more than one double bond, the double bonds may be isolated or conjugated to each other. The base group is, for example, ethylidene, dilute propyl, (v)- 2-methylethyl bake, (z)-2-nonylvinyl, homoallyl, (pentabutin-2-alkenyl, (fantasy_but_2•wolk, (five)-butyl- 1-diyl, (Z)-but-1-yl, pent-4-enyl, (v)-pent-3-enyl, (Z)-pent-3-enyl, (v)-pentyl -2-alkenyl, (Z)-pent-2-yl, (penta)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-ene Base, (5)-hex-4-enyl, (Z)-hex-4-alkenyl, (6)hex-3-alkenyl, (Z)-hex-3-enyl, (v)·hex-2 - alkenyl, (z)-hex-2-enyl, (£)-hexyl-1, dilute, (fanta-hexa! olefin 152524.doc -22- 201130854 base, isopropenyl, 2_A Propionyl 2 - dilute, methyl propenyl, 2 -methylpropan-1 - alkenyl, (6) + mercaptopropenyl, (z) 1 mercaptopropyl, 3-mercapto 3_fluorenyl, 2_methylbutyl_3 dilute, butyl-butyl-diyl, 3-mercapto-butyl-2, alkenyl, (6)·2-methylbut-2-yl, (2 methyl) But-2-yl, (6)-1-methylbut-2-enyl, (ζ)1 methylbutan-2-alkenyl, (6)-3-mercaptobutyr-1- County, (7)_3·methylbutene+ Alkenyl (6)_2·methylbutyl-1-yl, (Ζ)·2-methylbutan+alkenyl, (5) 丨丨·曱yl yi•alkenyl,

(Z)-l-decylbuten-1-enyl, u. dimethylpropan-2-a bake, b-ethylpropenyl, 1-propylvinyl, 丨-isopropyl vinyl, 4_ Indolyl 4- 4-alkenyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, dimercapto-4-enyl, 4-methylpent-3-enyl, (5) _3_methylpenta-3-alkenyl, (z)-3-decylpent-3-enyl, (penta)-2-decylpent-3-enyl, (Z)-2-methyl Pent-3-enyl, (v)-1-methylpent-3-enyl, methylpent-3-enyl, (f)·4·decylpent-2-enyl, (Z)- 4-methylpent-2-enyl, (5)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (5)-2-mercapto _ 2-alkenyl, (z)_2-methylpent-2-enyl, (f)-1-decylpent-2-enyl, (z)-l-methylpent-2-enyl, (6) 4-methylpent-1-enyl, (z)-4-methylpenta-l-alkenyl, (f)·3-methylpent-1-enyl, (Ζ)-3-fluorenyl Pent-1-enyl, (5)-2-nonylpentenyl, (Ζ)-2-methylpent-1-enyl, (v)_ι·methylpentenyl, (ζ)β1•甲Pent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (penta)-3-ethyl -2·ene , (Ζ)-3-ethylbut-2-enyl, (5)-2-ethylbut-2-enyl, (Ζ)-2-ethylbut-2-enyl, (5) small Ethylbut-2-enyl, (Ζ)·1-ethylbut-2-enyl, (5)-3-ethylbut-1-enyl, (Z)-3-ethylbutan-1 - Women's base, 2-ethylbutan-1-yl, (5)-1_ethylbut_1_ 152524.doc -23- 201130854 Alkenyl, (Z)-l-ethylbuten-1-enyl 2-propylpropan-2-alkenyl, isopropylpropylpropan-2-alkenyl, 2-isopropylpropan-2-enyl, 1-isopropylpropan-2-yl, (6)·2· Propylprop-1-enyl, (Z)-2-propylpropionyl-alkenyl, (pentapropylpropionyl-fluorenyl), (Z)-l-propylpropan-1-enyl, (5) _2_isopropylpropyl·(alkenyl), (ζ)·2·isopropylpropyl-1·alkenyl, anthracenyl-1-isopropylidene-indenyl group, (z)_i Isopropylpropan-1·alkenyl, (f)-3,3-dimethylpropyl-i-alkenyl, (ζ)_3,3·dimethylprop-1-enyl, 1-(1, 1-Dimethylethyl)vinyl, 1,4-13-dienyl 'penta-1,4-tetramethyl, hex-1,5-monoalkenyl or methylhexyl bake. In particular, the group is a vinyl or allyl group. δ 吾 "C2_C6 alkynyl" is understood to mean preferably a straight or branched bond monovalent hydrocarbon group containing one or more reference bonds and containing 2, 3, 4, 5, 6 carbon atoms, in particular 2 Or 3 carbon atoms ("C2-C3_alkynyl"). The C2-C1()alkynyl group is, for example, ethynyl, propanyl-alkynyl, propan-2-yl, butyn-alkynyl, but-2-ynyl, but-3-ynyl, pent-propyne , pentyl-2-alkynyl, pent-3-ynyl, pent-4-ynyl, hexyl-alkynyl, hexa-2-ynyl, hexa-3-ynyl, hex-4-ynyl, Hex-5-alkynyl, 1·methylpropan-2-ynyl, 2-methylbut-3-ynyl' 1-methylbut-3-ynyl, 1-mercapto-2-enyl , 3·methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-mercapto-4·ynyl, 2-methylpent-4-ynyl, 1-methylpentyl · a 4-alkynyl group, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4·methylpent-2-ynyl, 1-mercapto-2-alkynyl, 4-methylpent-1-ynyl, 3-methylpentynyl, 2-ethylbut-3-ynyl, 1·ethylbut-3-yl, 1-ethylbut-2-enyne , 1-propylprop-2-ynyl, i-isopropylpropan-2-ynyl, 2,2-di-f-but-3-ynyl, 1,1-dimethylbutyr-3- Alkynyl, 1,1-dimethylbut-2-blockyl or 3,3-dimethylbut-1-ynyl. Specific words 152524.doc • 24· 201130854, the alkynyl group is ethynyl, prop-1-ynyl or propynyl. The term "C3-C46 group" is understood to mean preferably a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8, 9 or 1 carbon atoms, in particular 3, 4, 5 or 6 carbon atoms ("C3_c6 cycloalkyl"). The 〇3_0:1()cycloalkyl group is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclodecyl; A bicyclic hydrocarbon ring, such as a perhydroquinone-based cyclopentadienyl group (Perhydr〇Pentalenylene) or a decahydronaphthalene ring. The cycloalkyl ring may optionally contain - or a plurality of double bonds, such as a cyclyl group, such as a cyclopropyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexyl group, a cycloheptenyl group, a cyclooctyl group. A ring or a sulfhydryl group wherein a bond between the ring and the rest of the molecule can be attached to any carbon atom of the hydrazine, whether saturated or unsaturated. The term "3 to 1 G member heterocycloalkyl" is understood to preferably mean a saturated or partially unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 2, 3, 4, 5, 6, 7, 8 or 9 carbons. An atom and one or more hetero atom-containing groups selected from the group consisting of c(=〇), 〇, s, s(=(7), ru(s), NH, NR, wherein r represents Ci-Q, C3_C6 cycloalkyl, C3_c6 heterocycloalkyl, C(=〇)r9, C(=0)nr1qr", _S(,2R9, _s(=〇)2NRiVj group' should also be known r, represents a C3-C6 heterocycloalkyl group, and then the c3_c6 heterocycloalkyl group is only present - times. In particular, the ring may contain 2, 3, 4 or 5 carbon atoms and - or more a hetero atom-containing group ("3 to 6 membered heterocyclic group"), more specifically, the ring may contain 4 or 5 carbon atoms and one or more of the above-mentioned hetero atom-containing groups ("5 Non-limiting examples of the 6-membered heterocycloalkyl group include aziridine, azacyclohexyl, oxetane 152524.doc 201130854, thietane, thiophene, D ratio tJ bite Base 'tetrahydrofuranyl, thiolanyl, sulfonyl sulfonyl (suif〇ianyi). Rhodium dioxolanyl, 1'3 oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydro 0-decyl, tetrahydrothiopyranyl, 1,3-dioxo Heterocyclohexane, anthracene, 4·dioxaxhexanyl, morphinyl, thiomorphinyl, 1,1-dioxy-ionic thiophenanthyl, perhydro-azepinyl , all hydrogenated ι, 4- dioxin, gasification 1,4_0 perhydro-1,4-oxazepinyl, perhydroazocinyl, octahydropyrrolo-[3 4_b]pyrrole , octahydroisodecyl, octahydropyrrolo[3,4-b]pyridyl, octahydropyrrolo[l,2-a]pyridazinyl, decahydroisoquinolinyl 7 7-azabicyclo [2 2 ^heptyl, 3-azabicyclo[3.2.0]heptyl, 7-azabicyclo-[4.1.〇]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2-azabicyclo-[2-2.2]octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[ 3.2.1] Octyl, 8-oxo-3-azabicyclo[3.2.1]octyl, 3-oxo-9-azabicyclo[3.3.1]fluorenyl. Especially preferably having up to 2 Choose 5 to 7 members of the hetero atom of the group consisting of N, 〇 and S Cycloheterocycloalkyl, such as, for example, and preferably tetrahydrofuranyl '1,3-methoxypentayl, 吼p each, thiol, tetrahydrocarbyl, i,4-dioxanyl, Piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, perhydrazinyl, fully hydrogenated M-diazahryl and perhydroanthracene, 'nothinginyl group. The term "aryl" is understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, or bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 1 〇, 丨 J, specifically 6 12, 13 or 14 carbon atoms ("c6_Cl4 aryl 152524.doc • 26 · 201130854 ring of carbon atoms ^, # J 6 square") such as phenyl or biphenyl; or have 9 ', the jade clothing ("匸9 aryl"), such as the festival, the name of the seven-|" J w as the base or the base; or 10 rings of the atom ("Γ一# a (Cio side "", for example, a tetralinyl, a ring ("c丨4 aryl, feng, or naphthyl; or a ring having 13 carbon atoms ("CI3 aryl"), such as fluorenyl (flU0renyl) Or having an M carbon atom group "), such as anthranyl. "t-heteroaryl" is understood to mean preferably a monovalent aromatic monocyclic or bicyclic aromatic ring system having 5, 6 , 7, 8, 9, 1 η 11 〇 ' 8 y 10, U, 12, 13 or 14 ring atoms ("5 to 14 Changzai; human heteroaryl"), special rumor 5 or 6 or 9 Or 10 atoms and contain at least _ ones can be the same or The same hetero atom (the hetero atom is such as oxygen, nitrogen or sulfur) and may be monocyclic, bicyclic or tricyclic, and further benzo fused (benz〇c〇ndense) in each It. Preferred are 6-membered heteroaryl groups having up to 2 nitrogen atoms and 5 membered heteroaryl groups having up to 3 heteroatoms. In particular, the heteroaryl group is selected from the group consisting of thienyl, indolyl, pyrrolyl, Oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazole, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thio-4H-pyrazolyl, tetrazolyl and a benzo derivative such as a benzofuranyl group, a benzothienyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzimidazolyl group, a benzotriazolyl group, a carbazolyl group, a fluorenyl group, a different a mercapto group; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a diazinyl group, etc., and a benzo derivative thereof, such as a quinolyl group, a quinazolinyl group, an isoquinolyl group, etc.; or a cleavage group (az〇cinyl), pyridazinyl, fluorenyl and its benzo derivatives; or cinnolinyl, phthalazinyl, quinazoline, quinoxalinyl, naphthylpyridyl, acridine Base (pterid Inyl), carbazolyl, acridinyl, phenazinyl, 152524.doc .27- 201130854 phenothiazinyl, phenoxazinyl, P-xanthenyl or oxepinyl. More specifically, the heteroaryl group is selected from the group consisting of thienyl, oxazolyl, thiazolyl, 1//-tetrazol-5-yl, beta-pyridyl, Benzothiophenyl or furyl. The term "alkylene" is understood to mean preferably an optionally substituted hydrocarbon chain (or "tether") having 1, 2, 3, 4, 5 or 6 carbon atoms, ie as the case may be Substituted -CH2·("methylene" or "single member tether" or for example -C(Me)2-), -CH2-CH2- ("extended ethyl", "dimethylene" or" Two members are chained"), -CH2-CH2-CH2- ("Extended propyl"" "Sanya 曱" or "Two members"), _0: Η2-(:Η2-0:Ιί2-〇ίί2- ("Stretching butyl", "tetramethylene" or "four-membered tether"), _CH2_CH2_CH2_CH2_CH2_ ("Extension", "Methylene" or "five"), or _CH2_CH2_CH2_CHrCHrCH2 ("Extension", "hexamethylene or six-membered tether") group. In particular, the alkyl chain has 1, 2, 3, 4 or 5 carbon atoms' more specifically 1 Or 2 carbon atoms. The term "alkylenedioxy" is understood to mean preferably 〇_Ci_C6 alkylene _ 〇 _ 'specifically, as exemplified in the following structural formula, methylene dioxyl and Dioxyl:

As used throughout this document, for example, in the case of the definitions of "C", alkyl, "(: G. alkoxy), "G-C6 alkoxy" or "CrC6 haloalkoxy" S. "Ci-C6" is understood to mean that the alkyl group has a finite number of 1 to 152524.doc • 28. 201130854 6 carbon atoms, ie 1, 2, 3, 4, 5 or 6 carbon atoms. It is further understood that the term "CkC6" should be interpreted to include any subranges therein, such as CVC6, C2-C5, C3-C4, CVC2, CVC3, cvc4, kc5, CVC6; specifically (^-(:2) , Ci-C5, CV c6; more specifically, Cl-C4; in the case of "Cl_Cd alkyl" or "^^ alkoxy", even more specifically Cl-C2. Similarly, as used herein As used throughout this document, the term "C2_C6" as used, for example, in the context of the definition of "c2_C6 alkenyl" and "CrC6 alkynyl" is understood to mean that an alkenyl or alkynyl group has a finite number of 2 to 6 carbon atoms. , ie 2, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "c2_c:6" should be interpreted to include any subranges therein, such as C2_C6, C3_C5, C3-C4, C2-C3 , C2-C 4. c2-c5; specifically c2-C3. In addition, as used herein, the term "C3_Cl()" as used throughout this document, for example, in the context of the definition of ΓC3_Ci〇cycloalkyl, shall be understood to mean The cycloalkyl group has a finite number of 3 to 10 carbon atoms, that is, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, specifically 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C3_ClG" should be interpreted to include any subranges therein, such as c3_c1(), c4-c9, c5-c8, c6-c7; specifically C3-C6. Side oxy represents double bond Oxygen atom as used herein. For example, the term "one or more times" in the definition of a substituent of the compound of the formula of the present invention is understood to mean "i, 2, 3, 4 or 5 times, in particular 1 2, 3 or 4 times, more specifically i, 2 or 3 times, or even more specifically 1 or 2 times.) 5 152524.doc -29- 201130854 Throughout this document 'for the sake of simplicity' The use of the singular wording goes beyond the wording of the plural wording. 'But it is generally intended to include the plural wording unless otherwise stated. For example, the expression "a treatment, a patient's disease A method of treating, comprising administering to a patient an effective amount of a compound of formula (I) is intended to include the simultaneous treatment of more than one disease and the administration of more than one compound of formula (1). Indicates a non-specified sp2 or sp3 stereo bond (stere〇b) 〇 nd) or a mixture of stereoisomers, for example a group representing a penta- or Z-isomer, or a mixture thereof. * indicates the point of attachment of a given group (e.g., a ring) to the formula in which the group is reported. Specific forms of the examples of the compounds of the general formula (I) as described above will be explained. Along with the above or below definitions and examples, the compound of formula (1) specifically refers to a compound wherein X is: R8b. In another embodiment, in conjunction with any of the above or below embodiments, the compound of formula (1) is specifically Y below and wherein Ria, the ruler "connects to each other independently or together with the atoms to which they are attached, and R3a R3b, independently of one another, has a composition 152524.doc -30-201130854 as expressed in relation to any of the above or below examples or definitions:

R

R 1a\. In the other ^ 尬 Y ^ column ' Together with any of the above or below examples, the compound of formula (I) is specifically / is a compound of any of the following groups:

R

V

1a\Nz R. H7 wherein Rla Rlb are bonded to each other independently or together with the atom to which they are attached: Yes: with respect to any of the above or below examples or definitions. In the case of the surname - I, with any of the above or below examples, the formula (1) is 1 and the Γ s is a compound in which γ is any of the following groups and wherein 1^'R3b are unique to each other: The meanings given in the following examples and definitions

The composition is specific: in the sputum' together with any of the above or below Examples D. A compound wherein Y is any of the following groups: wherein Rla 152524.doc

Rlb is independent of each other or Rla

Rib, and R3a, R3b

S-31 - 201130854 This independently has the meaning as given with respect to any of the above or below embodiments and definitions. In conjunction with any of the above or below embodiments, another particular embodiment relates to Y being any of the following groups and ' Rib being linked to each other independently or Rla, Rlb together with the atom to which they are attached, and having as described above with respect to any above or below Examples and definitions give the meaning of a compound of formula (I) whose γ is not ·c( = 〇)H:

In conjunction with any of the above or below examples, another embodiment comprises a group R16 which is or has a 6-membered heteroaryl group having at least one nitrogen atom and wherein has a meaning as given for any of the above or below examples and definitions. One or more compounds of formula (I) are present in combination with any of the above or below examples, and R6 is in the same or different manner via the group -substituting j or below. Give the meaning. In this regard, f, specific facts - the following groups: 疋 Examples

a compound of the formula (1) wherein R is as defined in relation to: 152524.doc • 32-201130854. The meaning of the examples and definitions is given. Another specific embodiment relates to 116 having Rn as described above with respect to any of the above or below. Appear one or more times. Together with any of the above or below examples, the following compounds of formula (I):

A compound of formula (I), together with any of the following or any of the following examples: wherein the group R! i has one or more meanings as defined in relation to any. The above or below embodiments and definitions are given to another detailed embodiment in which the rule 6 is

R

R 11c

Wherein Rlla, Riib and Rile have the meanings given in the above or below and in the following examples. In conjunction with any of the above or below examples, another detailed embodiment relates to a mouse atom of the following and wherein R1Ia is a halogen', and Rllb is haloalkyl, -0-CVC6 alkyl or -O-CVc. * 1 alkyl, specifically -CF2, ch3, -och3 or -ocf3 of the compound of formula (I):

152524.doc • 33· % 201130854 In conjunction with any of the above or below embodiments, another detailed embodiment relates to the rule 6 being the following and wherein Rna is a dentate, specifically a fluorine atom, Rllb is hydrogen and Rllc is -0-C丨-C: 6-alkyl or 〇·(^-(: 6-dentate alkyl group) specifically _〇CH3 or -OCF3 of the compound of formula (1):

In another embodiment, in conjunction with any of the above or below examples, the compound of formula (1) is characterized in that R0 is a compound of any of the following groups:

Wherein the groups Ri 13 and R] 2 have the meanings given as for any of the above or below examples and definitions, and Ru occurs one or more times; or R ia, R 丨 "and feet" have as described above with respect to any The following examples and definitions are given. More particularly, 'in conjunction with any of the above or below examples, other forms of the examples involve the inclusion of any of the compounds of the invention having the following meanings t &

Rla and Rlb are each independently a hydrogen atom, a CiC6 alkyl group, a Ci_C6 alkoxy group, a ^^-<:6 alkyl group-, a -CVC6 group, a C3_C8 cyclodyl group, an aryl group, a heteroaryl group. , -cvc: 6 alkyl, aryl, _Ci_c6 alkyl, heteroaryl, -cpohCrG alkyl, _c(=〇)_Ci_C6 alkyl aryl, 152524.doc -34· 201130854 -C(= 0)-C "C6 alkylene-heteroaryl, -c(=〇)〇_Cl_c6 alkyl, -S(=0)2R9 'Substituted in the same or different manner by a substituent selected from the following Or multiple times: halo-, hydroxy-, cyano, (^-(:6-alkyl-, self-based-CVC6 alkyl-, -C(=〇)〇H, -C(=〇)NH2, - s(=o)2oh, -n(h)c(=0)nh2, -N(H)C(=NH)NH2, -CpCOO-CVC^alkyl, -NR9R10 'where r9 and r10 are independent of each other Hydrogen, hydroxyl, CrCa alkyl, halo-CVC6 alkyl, Ci

〇6 saponin, halo-C^-C6 methoxy or R9 and R10 together with the atom to which they are attached form a 5 to 6 membered heterocycloalkyl group, which is optionally selected in the same or different manner Substituted 1 or 2 times from the following substituents: pendant oxy, CVC6 alkyl-, aryl-, heteroaryl, _C1_C6 alkyl-aryl, -CrC: 6 alkyl-heteroaryl; specific Ria is hydrogen, decyl or n-propyl-C(=0)0H, n-butyl-C(=〇)〇HiRib is 虱, 2-methoxyethyl- or 2-«» ratio bite_ 2_base_ethyl_.

Rla and Rlb are bonded together with the atom to which they are attached to form a 5 to 6 membered heterocycloalkyl- group which is optionally substituted or substituted in the same or different manner by a substituent selected from the group consisting of pendant oxy, Cl_C6 alkane a di-, heteroaryl-, -Cl-c6-extension-aryl-, 6-alkyl-hetero-yl group substituted as appropriate, the 4 groups being substituted in the same or different manner Anthracene, cyano, cyano, C^-C: 6 alkyl- and halo-Ci_c0 alkyl...specifically, and Rlb is bonded together with the atom to which it is attached to form a piperidinyl group or a 4-unit- Niang 11 Qin-1-based.

Rla and Rib are bonded together with the atom to which they are attached to form a base. 152524.doc -35- 201130854 Azinyl, morpholinyl or thiomorpholinyl, optionally substituted one or more times.

Both Rh and Rn are a hydrogen atom or a methyl group. R3a and R3b are, independently of each other, a hydrogen atom, a CkC6 alkyl-, a c2_c6 alkenyl group, an arylheteroaryl group, wherein the groups are optionally substituted in the same or different manner by one or more substituents selected from the group consisting of Secondary: fluorenyl, -(3), Cl-C6 fluorenyl, functional group Ci_C6 alkyl, Ci_c6 alkoxy or halo-CVC6 morphoxy. In particular, R3a is chlorine and &

a phenyl group and a phenyl group substituted by a fluorine atom, a chlorine atom, a methyl group or a hydrazine. R7 is a deuterium atom, -CH3 ' and R8b are hydrogen atoms independently of each other? Self-priming atom, alkyl halide-CVC6 alkyl, or

Rsa and RSb are each a hydrogen atom; or R8a is a hydrogen atom and R8b is selected from the group consisting of H-, halo-CVC6 alkyl;

Rsa is selected from the group consisting of:

Guojing Cl_C6 alkyl-, halo-C丨-c6 group, and R8b is selected from the group consisting of: bismuth group. halogen, C]-C6 alkyl _ halo-C]-C6 alkyl, · ' And 4 are specifically independent of each other by a hydrogen atom, a fluorine atom or a gasification system, more specifically - CF3. R and R1C) are independently selected from the group consisting of hydrogen, hydroxy, cardamom: 6 alkyl, halo-C丨-C6 alkyl, CrCVp, glycoxylated k垸, Mercapto-C丨-c6 alkane R9 and together with the atom to which it is attached form a 5 to 6 member heterocyclic ring 152524.doc -36 - 201130854 alkyl-, which is optionally selected from the same or different Substituted- or multiple times: oxo-oxime-, arylaryl-, -Cl-c6-extension-aryl, _Ci_C6-extension-based heteroaryl. "Rn, Rlla," and Rllc are each independently hydrogen, dentate, thiol, aryl, schwitz, Cl-c6, dentate _Ci_C6, cation, Ci_C6 oxy, halo (4) Good gas atom).

Ru, Rua and Rm are hydrogen halogen atoms, preferably fluorine atoms. In another embodiment, in conjunction with any of the above or below examples, the compound of formula (1) is specifically a compound represented by the following formula (11):

Wherein R~2a and R2b are both hydrogen atoms or sulfhydryl groups,

Rsa and Rsb are independently selected from the group consisting of: &; 鲜 虱 南 南 南 南 南 南 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Teeth, m-based, cyano, exact, Cl-C6 alkyl, dentate,

Ci-C0 alkoxy, halo-C丨-C: 6 alkoxy, and the pot is composed of 6 /, R lb, R 3a,

Rn has the meaning as given for any of the above or below implementations of G4.

S 152524.doc -37- 201130854 In another embodiment, along with any of the above or below examples, the formula (i) is a compound represented by the following formula (IIa):

R2a and R2b are each a hydrogen atom or a methyl group, and RSa and Rsb are independently selected from the group consisting of hydrogen, halogen, ^6 alkyl-, halo-CVC6-fluorenyl

Rn appears one or more times and is independently selected from the group consisting of hydrogen, halogen via aryl, nitro, Cl_C6 alkyl, halo, CVC6 alkoxy, halo-(: broad-area a radical, and wherein R 3 b has the meaning given to any of the above or below examples or definitions. In another embodiment, together with any of the above or below examples, the compound of formula (1) is specifically according to the following formula ( Compound represented by IIb):

152524.doc •38· 201130854 where

Rh and Rzb are both hydrogen atoms or methyl groups, 6

Rsa and RSb are independently selected from the group consisting of hydrogen, thiol-, halo-based, Ci'C RU, one or more occurrences, and independently selected from the group consisting of: hydroxy, cyano, Nitro, CVC6 alkyl, dentate, milk, south

CrQ leuco oxy, dentate _Cl_C6 oxime, and wherein ^, heart = yl, 4 have the meaning given to any of the above or below examples or definitions: meaning. In another embodiment, in conjunction with any of the above or below examples, the compound of formula (1) is specifically a compound represented by the following formula (111): p

R.

Rh and R2b are each a hydrogen atom or a methyl group, and R8a and R8b are independently selected from the group consisting of: gas, a hydroxyl group, a Ci_C6^ group-, a halo-Ci-Cg alkyl group, and an s R" Independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, phenyl, Cl-c: 6 alkyl, dentyl-Ci_c6 alkyl, Ci_c$ alkoxy, i-based: 6 alkoxy Base, and its tRia, Ru, R3a, R3b have 152524.doc · 39 · 201130854 as expressed in relation to you ~, on another or the following examples or definitions. Is a compound represented by the following general formula (IV):

In a human case, together with any of the above or below examples, the compound of formula (I) is specifically

Both Rh and Rn are a hydrogen atom or a fluorenyl group, and R8a and R8b are independently selected from the group consisting of hydrogen, a hydroxyl group, and the like. ^^alkyl-, dentate-CVC6 alkyl, R·6 is any of the following groups:

Wherein Rn occurs 1 to 3 times and is independently selected from the group consisting of hydrogen, i, hydroxy, cyano, nitro, Ci_C6 alkyl, dentyl-Ci_C6 alkyl, CVC6 alkoxy, dentyl-CVC6 alkane Oxyl, and wherein Ria ' Rib, R3a,

Rn has the meaning as given with respect to any of the above or below examples or definitions.

In another embodiment, together with any of the above or below examples, the compound of formula (r) is specifically defined as Re according to any of the following groups and wherein R 152524.doc •40· 201130854 and ruler 11<: are independent of each other The ground is hydrogen, halogen, hydroxy, cyano, nitro, Cl-C6 alkyl, functional-CVC6 alkyl, Ci-Ce alkoxy, i-based-(VC6 alkoxy; and all other groups have Compounds of the formulae (II), (IIa) and (IIb) as expressed in relation to any of the above or the following examples or definitions:

In another embodiment, in conjunction with any of the above or below examples, the compound of formula (j) is specifically a compound represented by the following formulas (II), (Ila) and (lib):

Wherein RlU is a dentate atom, specifically a fluorine atom, and Rllb is selected from the group consisting of: ci-c6 _alkyl, _〇_Ci_C6 alkyl or _〇_Ci_C6 dent alkyl, specifically CF^CH3 , _0CH3, 〇CF2^ _〇CF3, and wherein all other base BUs have the meanings as given with respect to any of the above or below embodiments or definitions. In the actual example, together with any of the above or below examples, the compound of formula (I) is specific to the compound of the formula (II), (IIa) and (IIb), of which 152524.doc 201130854 R2a and Ru are both a gas atom, a halogen atom, R8a is a hydrogen atom, and R8b is selected from the group consisting of a group of alkyl-, halo-CrC:6 alkyl groups; or R8a is selected from the group consisting of: ^^^^ a ketone-, halo-Ci-C6 alkyl group and R8b is selected from the group consisting of halogen, c丨-C6 alkyl-, halo-

Crh alkyl, Y is any of the following groups:

Wherein Rlla is a functional element, specifically a fluorine atom, and Rllb is selected from the group consisting of: _Cl-C0 卣 alkyl, _0_CrC6 alkyl or _〇_Cl_c6 haloalkyl, specifically 2 CH3, -〇CH3 or - 〇CF3, and wherein Rla, Rlb, R3a, R3b / are as given with respect to any of the above or below examples or definitions. In another embodiment, together with any of the above or below examples, the formula (I) is a compound represented by the formulae (II), (Ila) and (nb), wherein

Rh and both are hydrogen atoms, R*a and Rsb are all halogen atoms, specifically fluorine atoms, or 152524.doc •42·201130854 and R8b is cvc6 alkyl-,

Rsa is a halogen atom, specifically a fluorine atom, or a halogen-C丨-C6 fluorenyl group, specifically _Cp3. Y is any of the following groups: Η

Wherein Rlla is a halogen, specifically a fluorine atom, and Riib is selected from the group consisting of: -CVC6-dentate alkyl, -0-CVC6 alkyl or _〇_Ci_C6|i alkyl, in particular -CF2-CH3 , -CH3 or -0CF3, and wherein R3a, R3b have the meanings as given for any of the above or below embodiments or definitions. The compounds of the present invention are: • 8-(2,6-difluoro-phenylindenyl)-6-(2-fluoro-3-indolyl-phenylindolyl-5-sideoxy-2,3- Di-argon-5Η-» plug. Sit and [3,2-a] pyridine bite 3-thiobenzoic acid S-phenyl ester 6-(2-fluoro-3-indolyl-phenyl)-8-( 2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-thio S-phenyl phthalate 6-(2-chloro-5-trifluorodecyloxy-phenyl)-8-(2-fluorotrifluoromethyl-adenyl)-7-fluorenyl-5-side oxygen Base-2,3-dihydro-5H-喧β sits and [3,2_a]° bites -3-thiodecanoic acid S-benzene, vinegar

S 152524.doc •43· 201130854 6-(2-Fluoro-acridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-adenyl)-7-methyl-5-side Oxy-2,3-dihydro-5H-thiazolo[3,2-a]. Bis-pyridine-3-thiodecanoic acid S-phenyl ester 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy_6_(3_trifluoromethoxy Benzyl-phenyl)-2,3-dihydro-5H-thiazolo[3 2_a]0 than bite ·3_ benzoic acid S-phenyl ester 6-(2-fluoro-5-decyloxy-phenyl) 8-(2-fluorotrifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3 2_a]pyridine_3_thiocarboxylic acid s-Phenyl 6-(4-fluoro-benzo[1,3]dioxol-5-yl)_8·(2_fluoro-6-trifluoromethyl-adenyl)-7 - mercapto-5-tertiaryoxy-2,3-dihydro-5 oxime-thiazolo[3,2-a]pyridine-3. thiol S-phenyl ester 6- (2,2-difluoro-benzene And [1,3]dioxole·5_yl)_8_(2fluoro-6-trifluorodecyl·benzyl)-7-methyl-5-sideoxy_2 3_2 Hydrogen_5H_thiazolo[3,2_a]pyridine-3-thiodecanoic acid S-phenyl ester 3·benzimidyl-8-(2,6-difluoro-stupylmethyl)_6_(2_fluorine _3_methoxyphenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]pyridine-5-one 8-(2,6-difluoro-benzoinyl) -3-(4-fluoro-mupcapto)_6_(2_fluoro_3_decyloxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridine_ 5•ketone 8-(2,6·difluoro-benzyl)·6_(2_fluoro_3·methoxy (3) (2,6-difluoro-benzyl) - 6-(2-Fluoro-3-methoxy-phenyl)·7·fluorenyl_3_(4_trifluoromethoxy-benzoamyl)-2,3·dihydro-thiazolo[3] , 2_a]pyridine_5-keto 8_(2,6-difluoro-stupylmethyl)_6-(2-fluoro-3-methoxy-phenyl)_7-methyl_3_(thiophene-3-carbonyl)- 2,3-dihydro-thiazolo[3,2_a]pyridine_5•ketone 152524.doc -44 - 201130854 3-(Benzo[b]thiophene-3-carbonyl)-8-(2,6-difluoro -Benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-fluorenyl- 2,3-di-rhoose-sitting and [3,2-a]D ratio bite-5 -嗣8-(2,6-Difluoro-phenylhydrazino)-6-(2-fluoro-3-methoxy-phenyl)-3-(β-fusyl-3-refenyl)-7- Alkyl-2,3-diaza-嗟0 sits and [3,2 - a ]11 is more than a bite -5-(2,6-difluoro-benzyl)-6-(2-fluoro- 3-methoxy-phenyl)-7-methyl-3-(3-methyl-phenylhydrazino)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 8-(2,6-Difluoro-phenylhydrazino)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(3-trifluoromethyl-benzoquinone -2,3-dihydro-thiazolo[3,2-ap-pyridin-5-one 8-(2,6-difluoro-phenylhydrazino)-6-(2-fluoro-3- Oxy-phenyl)-7-methyl-3-(2-indolyl-phenylhydrazino)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 8-(() 2,6-Difluoro-benzyl)-3-(2-fluoro-benzylidenyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-2,3 -Dihydro-thiazolo[3,2-a]pyridin-5-one 3-(2-gas-3-fluorobenzhydryl)-8-(2,6-difluoro-benzyl)-6 -(2-fluoro-3-indolyl-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(3,5-di Fluoro-benzylidenyl)-8-(2,6-difluoro-phenylindenyl)-6-(2-fluoro-3-indolyl-phenyl)-7-mercapto-2,3-dihydro -thiazolo[3,2-a]pyridin-5-one 3-(2,3-difluoro-phenylindenyl)-8-(2,6-difluoro-benzoinyl)-6-(2 -Fluoro-3-methoxy-phenyl)-7-mercapto- 2,3-diaza-deuterium 0 is 弁[3,2-a]0 is 0--5-嗣8-(2, 6-Difluoro-benzyl)-3-(3-fluoro-benzylidenyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-2,3-di Hydrogen-thiazolo[3,2-&]. Bis-5-keto 3-(2,5-difluorophenylindenyl)-8-(2,6-difluoro-benzoinyl)-6-(2-fluoro-3-methoxy-benzene -7-methyl-2,3-dihydro-thiazolo[3,2-a]°pyridin-5-one 3-(2-chloro-5-mercapto-benzylidene)-8 -(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridine-5-one 152524.doc -45- 201130854 3-(4-fluoro-phenylindenyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro -6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]"pyridin-5-one 6-(2-fluoro-3 -Methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-3-(4-trifluoromethoxy-benzylidene)- 2,3-Dihydro-thiazolo[3,2-a] mouth bite-5-keto 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(three Fluoromethyl)phenylhydrazino]-7-mercapto-3-[(2H5)phenylcarbonyl]-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridyl- 5--paid 3 - benzoquinone-based 6-(2- gas-5-dioxanoxy-phenyl)-8-(2- gas-6-dimethyl-benzyl)-7- Methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-benzylidene-6-(2-fluoro-pyridin-3-yl)-8-(2- Fluoro-6-trifluoromethyl-benzyl) 7-Methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(3,5-di-r-benzoyl)-6-(2- gas-3 -decyloxy-phenyl)-8-(2- gas-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridine - 5-keto 3-(3-fluoro-benzoquinone)-6-(2-aluminum-3-methoxy-phenyl)-8-(2-gas-6-trismethyl-phenylene) -7-mercapto-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(5-a-infrathen-2-yl)-6-(2- Gas-3-methoxy-phenyl)-8-(2- gas-6-difluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a] pyridine-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl- 3-(3-Trifluoromethyl-phenylhydrazino)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-benzylidene-6-(2-fluoro -3-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)·7·decyl-2,3-dihydro-thiazolo[3,2-a ]»Bipyridin-5-one 152524.doc -46- 201130854 3-Benzene aryl-8(2-murine-6-dioxamethyl-benzyl)-7-methyl-6- (3 - squirrel succinyl-phenyl)-2,3-diaza-O-septazin[3,2 - a ]σ ratio -5-5 -嗣3 -benzoquinone-6-(2-fluoro -5-A -phenyl)-8-(2-gas-6-difluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridine-5- Keto 3-phenylhydrazin-6-(4-fluoro-benzo[1,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzene Methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-benzylmercapto-6-(2,2-difluoro-benzo [1,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3.dihydro-thiazole And [3,2-a]° ratio biting 5-keto 6-(2-^-3-decyloxy-phenyl)-8-(2-^-6-di-indolyl-benzoinyl) -3-(bite 0 south-2 - dream carbon base)-7 -methyl-2,3 -diaza-嗟σ sit 弁[3,2 - a ] 0 ratio °-5 -嗣8·(2 ,6-dioxo-phenylhydrazino)-6-(2- gas-3-methyllacyl-phenyl)-3-(3-fluoro-11-precipitate-2-carbonyl)-7-methyl-2 ,3·Dihydro-thiazolo[3,2-a]pyridin-5-one 8-(2,6-dioxa-phenylmethyl)_6-(2- gas-3-methoxyphenyl) -7 - fluorenyl - 3 · (5_ methyl 嗟 ° sitting - 2 · spicy base) - 2, 3 - two mice _ ° 塞 弁 sitting [3, 2 - a ] ° than biting -5 - 嗣 6_ ( 2-fluoro-3-indolyl-phenyl)-3-(3-fluoro-acridin-2-ylcarbonyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7• Methyl-2,3 -Dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2- gas-3-oxooxy-phenyl)_8-(2- gas-6-difluoroindolyl-benzoic acid -7-methyl-3·(5-fluorenyl-thiazole-2.carbonyl)-2,3·di-argon-thiazolo[3,2-a]pyridin-5-one 3-benzyl ·8_(2,6-ditro-benzyl)-6-(2- gas-3-methoxy-phenyl)· 2,2,7-dimethyl- 2,3 _two-rat-〇 The scorpion sits and [3,2 - a ] ° is more than 5 - 嗣8_(2,6-digas·benzyl)-6-(2-^-3-methyllacyl-phenyl)-3 -(Technylene _ 152524.doc •47- 201130854 Phenyl-fluorenyl)-7-methyl-2,3_dihydro-thiazolo[Ha]pyridin-one 8-(6,6-di Fluoro-phenylhydrazino) winter (2-fluoro-3-3 methoxyphenyl)·3·[(4)fluorophenyl)-imido-methyl]-7-methyl-2,3-dihydrogen +Sit and [3,2_decabiidine_ 5-_ 8-(2'6-difluoro-benzyl)_6_(2_gas_3·methoxy-phenyl)_3·[imine (4-methoxy-phenyl)-methyl]_7-methyl-2 3 indanindole [3 2_small ratio - 5 - 83⁄4 8-(2,6-difluoro-benzyl) )_6-(2_敦_3methoxyphenyl)_3 sylideneamino group (4-trifluoromethoxy-phenyl)_fyl]_7_mercapto-2 3 dichloros. Sit and [3,2 ^ D than bite -5 - _thiophen-3-yl-methyl)_7_methyl-2,3·dihydro ♦ sit and [3,2♦ than bite _5-ketone 8- (2,6-difluoro-benzyl)_6_(2_fluoro_3.methoxyphenyl)3-df-am-3-yl_light imido-methyl)-7-methyl-2, 3-dihydro-oxime-[3,2_a]n-pyridyl-5-one 8_(2'6:difluoro-benzyl)_6_(2_gas_3methoxyphenyl)3-( Imino group, o-indolyl group, 7-methyl-2,3-dihydro-indole, and [3,2-a] η than biting _5-keto 8-(2,6-di Fluoro-phenylhydrazinyl) winter (2_fluoro-3 methoxy-phenyl)·3_(imidoamino-m-tolyl-methyl)_7.methyl-2,3_dihydro" And [3,2·唆唆_5嗣8-(2,6-difluoro-benzene f &)·6·(2·fluoro_3_methoxyphenyl)_3_(imine group_ben Basement) 2,2,7-dimethyl-2,3-dihydro-indole[3,2-mad]0 than bite-5-_ 6-(2·fluoro-3-methoxy -phenyl)_8_(2_fluoro_6_trifluoromethyl-phenylphenyl)_3 (hydroxyimino-phenyl-methyl)_7-methyl-2 3·dihydro-thiazolo[3 2 a]pyridine-5-one 6-(2-fluoro-3-indolyl-phenyl)_3_[(4-fluorophenyl)hydroxylamino-indenyl]_8_ 152524.doc 48- 201130854 ( 2-fluoro-6-trifluorof-phenylmethyl-7-methyl-2,3 _Dihydro-喧〇 并 and [3,2_a] 0 than bite-5 - _ 6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl _Benzyl)_3 [hydroxyimino-(4-trifluoromethoxy-phenyl)-indenyl]·7-methyl-2,3-dihydro-thiazolo[3,2-8] ° 淀-5-嗣6-(2-Fluoro-3-methoxyphenyl)-8·[2-Fluoro-6-(trifluoromethyl)benzyl]-3_ {(hydroxyimino) [(2Η5)phenyl]methyl}-7·methyl_2,3_dihydro_5Η_[13]嗟^ D sit and [3,2-a]e than bite-5-keto 6-(2 -fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_3_(furophen-2-yl-pyridinyl-methyl)-7 -methyl-2,3-dihydro-thiazolo[3,2_a]0pyridin-5-one 6-(2-chloro-5-difluorodecyloxy-phenyl)-8_(2_fluoro_ 6_Trifluoromethyl_stupylmethyl)_ 3-(hydroxyimino-p-styl-fluorenyl)-7•methyl-2,3-dihydro-thiazolo[3,2_&]-bite- 5-keto 6-(2-fluoro-n-bipyridyl_3_yl)_8_(2_fluoro-6-trifluoromethylbenzoyl)_3•(hydroxyimine•yl-phenyl-methyl) -7-decyl 2,3-dihydro-thiazolo[3,2-a]pyridine·5-keto 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- Methoxy·phenyl)_3_[hydroxyimino](3-difluoromethyl-phenyl)-methyl]-7-methyl-2,3 -di Hydrogen-thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluoro-benzyl)_6_(2-fluoro-3-methoxy-phenyl)_3_[(2_ Fluoro-phenyl)-hydroxyimino-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridine-5-one 3-[(2-gas·3-fluoro -phenyl)-hydroxyimino-indenyl]_8_(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2 , 3-dihydro-indole and [3,2-mad]° ratio 152524.doc • 49- 201130854 bite-5-辋8_(2,6-difluoro-benzyl)-6-(2-fluoro 3-methoxy-phenyl)·3·[(3·fluoro·pyridin-2-yl)-hydroxyimino-methyl]_7-methyl-2,3·dihydro-thiazolo[3 , 2 &]Pylazen-5-steel 8-(2,6-difluoro-stupylmethyl)·6_(2·fluoro_3_methoxyphenyl)3 [hydroxyimino] (5· Methyl-thiazol-2-yl)-methyl]_7-methyl-2 3_dihydro-thiazolo[3,2 a] 0 is more than bis-5·_ 3_(benzo[b]thiophene-3- -hydroxyiminoamino-methyl)_8_(2 6-difluorobenzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-indenyl-2,3-dihydrogen _thiazolo[3,2_a]pyrodo-5-鲷6-(2-fluoro-3-indolyl-phenyl)·8_(2·fluoro-6-trifluoromethylphenyl fluorenyl Amino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2_a Pyridine·5·ketone 8-(2-fluoro-6-difluoroindolyl-benzyl)_3_(nonoxyiminophenyl)indolyl-7-ylamino-6-(3-trifluoromethyl) Oxy-phenyl)_2,3-dihydrothiazolo[32a]pyridine-5-keto 6 (2 I 5 -decyloxy-benyl)·8·(2_fluoro-6-trimethyl fluorenyl- Benzoyl)_3_(methoxyimino-phenyl-methyl)-7-methyl·2,3-dihydro-thiazolo[3,2_a;jpyridine-5-one 6-(4-fluoro -benzo[1,3]dioxol-5-yl)_8_(2_fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl) Mercapto) 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2,2-difluoro-benzo[,3]dioxane Pentene _5 yl) 8 (2Fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl-fluorenyl)-7 hydrazino-2 3- 2 152524.doc -50 - 201130854 Hydrogen_thiazolo[3,2-a]pyridine-5-one 3-(propylpropylimino-phenyl-methyl) winter (2_fluoro·3_methoxy_phenyl)_8_ (2_Fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 8-benzyl-7 -mercapto-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-decanoic acid benzylamine amine 8-benzyl- 7-曱基-5 -Sideoxy-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methoxy-decylamine 8-(2,6-difluoro-benzene Methyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-oxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3 -pyridin-2-ylamine amine 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-5-side oxygen Benzyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid phenyl decylamine 8-(2,6-difluoro-benzyl)-6-(2-fluoro 3-methoxy-phenyl)-7-methyl-5-oxo-2,3·dihydro-5H-thiazolo[3,2-a]pyridine-3-decanoate decyloxy Indoleamine 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-5- oxo-2,3-di Hydrogen-5H-嗟" sit and [3,2-a]°rti bite-3-formic acid benzylamine 7-(2,6-difluoro-methane)-6-(2-fluoro-3 -decyloxy-phenyl)-7-methyl-5-o-oxy-2,3-dihydro-5H-oxime[3,2-a]. Specific bite-3-formic acid cyclopropyl decylamine 8-(2,6-difluoro-phenylhydrazino)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-5-side Oxy-2,3 - one 虱-5H-0 stopper. Sit and [3,2-a]. Specific bite 3-carboxylic acid methyl-(2-0 than 唆-2-yl-ethyl)-nonylamine 8-benzyl-3-(phenylhydrazinylamino-methyl)indolyl-6-benzene Base_2,3_dihydro_sigh. Sit and [3,2-a]° bite 5-keto 3-(benzylamino-fyl)_8-(2,6-difluoro-benzoinyl)·6_(2·fluoro_3 -Methoxy-51 - 152524.doc 201130854 phenyl-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]. Bipyridin-5-one 8-(2-a-phenylhydrazino)-6-(2-aza-3-indolyl-phenyl)-7-mercapto-3-(4-). -yl-slightly D-methyl-1 -ylmethyl)-2,3-diode-嗟0 并[3,2-a]0 than bite-5-嗣3- [4-(1-ethyl- Propyl)-Nymidine-1 -ylmercapto]-8-(2-murine-bensyl)-6-(2·fluoro-3-indolyl-phenyl)-7-methyl-2, 3-Dihydro-thiazolo[3,2-a]pyridin-5-one 8-(2-fluoro-phenylindenyl)-6-(2-fluoro-3-methoxy-styl)-7- Mercapto-3-(4-indolyl-nivine 0-methyl-1 -ylmethyl)-2,3-two-rat-0 sputum 弁[3,2 - a ] ° than bite -5 -嗣8- (2- gas-benzyl)-6-(2- gas-3-methoxy-phenyl)-7-mercapto-3-(0-bito-4-ylaminomethyl)-2, 3-Dihydro-thiazolo[3,2-a]pyridin-5-one 8-(2-a-benzyl)-6-(2-a-3-methoxy-phenyl)-7- Mercapto-3-(4-phenyl-slightly-doped-1 -ylmethyl)-2,3-di-r-O-ca. Sitting 弁[3,2 - a ]π than biting -5 -嗣3-azetidin-1-ylmethyl-8-(2-fluoro-phenylindenyl)-6-(2-fluoro-3- Methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 8-(2-fluoro-benzyl)-6-(2 -fluoro-3-methoxy-phenyl)-7-methyl-3-[(2-indole-4-yl-ethylamino)-methyl]-2,3-diaza-sold Sitting on the [3,2-a] ° ratio β -5 -酉 with 8-(2-fluoro-phenylhydrazino)-6-(2-fluoro-3-methoxy-stupyl)-7-oxime Alkyl-3-(4-phenyl-p-D-l-yl-1-ylmethyl)-2,3-diaza-O-[beta][sigma][3,2-a]0 is a bite--5-嗣8-( 2-fluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-3-{[(β-pyridin-2-ylmethyl)-amino] -methyl}-2,3-dihydro-thiazolo[3,2-a]° pyridine-5-one 8-(2- gas-benzyl)-6-(2- gas-3-methyl Oxy-styl)-7-mercapto-3 - slightly bite-1 · fluorenyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 2-(2-{ [8-(2-Fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5- 152524.doc -52- 201130854 Sideoxy-2, 3_Dihydro-5H-(tetra) and [3,2·small decylmethyl]•aminopiethyl)-piperidine-1-carboxylic acid tert-butyl ester 2-(2-{[8·(2-gas) -benzyl)·6_(2·fluoro·3_τ Benzyl)7-methyl-^ oxo-2,3-dihydro-5 oxime-thiazolo[3,2_a]0 is more than _3_ylmethyl]-amino}_ethyl)- ° than bite-1-carboxylic acid tert-butyl ester 3-[(cyclopropylmethyl-amino)-methyl]_8_(2·fluoro·stupylmethyl)·6-(2 gas_3 methoxy Phenyl)_7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridinone

3-[4-(3,5-Dimethyl-phenyl)-pyrene·i•ylmethyl]·8(2 gas benzyl (2-fluoro-3-methoxy-phenyl)_7 _Methyl-2,3_二气"塞嗤和[3,2是比 bit_5-keto 3-{[(3-didecylamino)-propyl)-fluorenyl-amino]_曱}8(2-fluoro-3-benzyl)-6-(2-fluoro-3-methoxy-styl)_7-fluorenyl-2,3-dihydro-thiazolo[3,2_a]0唆-5-ketone ugly-cavity--dimethylamino-ethyl-methyl-amino-based methyl bromide-^-fluoro-benzyl)-6-(2-fluoro_3_methoxy-phenyl )_7_methyl_2,3_dihydro-thiazolo[32_a]° ratio bit-5-keto 3-cyclopropylamino fluorenyl _8_(2_fluoro-benzyl)_6_(2_ Fluorine_3_methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridine-5-one 8-(2-fluoro-benzoinyl)_6_ (2_Fluoro_3_decyloxy_phenyl)_7_methyl_3_phenylaminomethyl-2,3-dihydro·Spiral [3,2-a] ° ratio bite-5 -keto 3-((R)-3-dimethylamino]n-pyridylhydrazino)_8_(2-fluorophenylindenyl (2-fluoro-3.nonyloxy-phenyl)_7_A Base 2,3_dihydro-thiazolo[3,2_a]pyridine-5-one ((S)-3·dimethylamino-0-pyrrolidine 4•ylmethyl)_8_(2_Fluorine_ Stupid methyl)_6 152524.doc •53· 201130854 (2-Fluoro-3-methoxy- Base)············································································ Methyl) 6 (2 • gas small methoxy-phenyl)-7-fluorenyl 2,3-dihydro-indolo[3,2_a]acridine_5-ketone 8·(2_fluoro- Benzyl)-6_(2_fluoro,3·methoxy-phenyl phenyl 2 oxyethyl)-methyl-amino]-methyl}·7·methyl-2,3-dihydro _ sold saliva and [3,2• pyridine 5-1 5-keto 3 [4-(3·monomethylamino]propyl) 〇 嗪 嗪 小 ] ]]]]_8_(2 gas benzyl) 6 ( 2-fluoro-3-methoxy-3-phenyl)-7-methyl-2,3-dihydro-carbazol[3,2.a]e is more than 5--[2--[2-fluoro -Benzyl)_6_〇翁# 彡〇(2-fluoro-3-methylindenyl-phenyl)_7_methyl_5_sideoxy-2,3·dihydroguanidine , 2_a] 0 than biting _3_ylmethyl]•methyl-amino}-N,N-dimethyl-ethylamine benzyl)_6_(2 methoxy 3-phenyl) _7 methyl·3_(吼唆·2-ylaminomethyl)_2,3_dihydro-(tetra) and [3,2_a]Dtb bite_5 steel 8-(2-fluoro-benzyl)_6·( 2• Weng* fluoro 3-indolyl-benzamine) _3_[(furan-2-ylindolyl-indenylamino)-methyl]methyl J thiol-2,3·-虱-thiazolo[ 3,2-a]pyridine-8-(2-fluoro-benzene Methyl)_6·(2 + fluoro·3_methoxy-benyl)_7-methyl-3-(4-pyridyl-4-ylmethyl-piperazine q•base T丞)-2, 3-anthracene-thiazolo[3,2_a]pyrodo_ 5-keto-6-benzopyrene, 3]dioxol-5_yl_8_(2-fluorobenzyl)?methyl _ 3-U methyl-(2" than biting 1 yl-ethyl) aminyl] methyl}·23 dihydrogen + sitting and [3,2-a] ° bite _5· 152524.doc •54 - 201130854 8-(2,6-Difluoro·stylmethyl)_3_[4_(1_Ethylpropyl)piperazine·indolyl]_6_(2-fluoro-3-indolyloxy)phenyl _7_Methyl-2,3_dihydrothiazolo[3,2_&]pyridine_ 5-keto 8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_methoxy- Phenyl)_7_methyl·3_phenylaminomethyl-2,3-dihydro-indole[3,2-3]pyrene _5__difluoro-benzyl)-6-( 2-fluoro-3-methoxy-phenyl)·2,2,7-trimethyl-3-(4-methyl-piperazin-ylhydrazino)_2,3-dihydrothiazolo[3 , 2_a]pyridine _ 5 - _ 8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_methoxy-phenyl)_2,2,7-trimethyl _ 3_{[ F-(2-pyridin-2-yl-ethyl)-amino]-methyl b 2,3-dihydro-thiazolo[3,2-a]°fc bite-5-keto 8-(2 ,6-difluoro-benzyl)_3_Η(2·dimethylaminoethyl) _, arylamino]_methyl}-6-(2-fluoro-3-methoxy-phenyl)_2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2 -a]"定-5-鲷8-(2,6-Difluoro-benzyl)_6_(2_fluoro_3_methoxy_phenyl)·2,2,7-trimethyl_# 3-(4 -pyridin-2-ylmethyl-piperazine "-ylmethyl"_2,3-dihydro-thiazole, 2_ a] ° ratio. D--5-keto 3-cyclopropylaminomethyl-8- (2,6-difluoro-benzyl)_6_(2_fluoro_3.methoxy-phenyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3, 2_a]pyridine_5-keto 8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_decyloxy-phenyl)_7-methyl[(methyl-phenethylamine) ))-methyl]_2,3_dihydro-oxazolo[Hap than pyridine I ketone 8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_methoxyphenyl) 7·曱基吗琳-4-yl·ethylamino))methyl]_2,3·二气_嗟嗟[[,2,2 比 _ 5-ketone 152524.doc •55· 201130854 8- (2,6-difluoro-benzenef-yl)_3 servant (3,5-di-f-phenyl)m-ylmethyl]-6-(2-fluoro-3-methoxy-styl)_7· Methyl _23_二气_叹唾 a]pyridine-5-one ' 8-(2,6-di- benzyl)_6_(2_fluoro_3_?oxyphenyl)_7·methyl Ten-by-bit-4-ylamino fluorenyl) 2,3-dihydro-sodium sulphate [3,2♦ than y-5-keto 8-(2,6-difluoro-benzyloxy-benzene) Base) _7 methyl ketone (phenethylamino group - A -2,3-Dihydro-indole and [3,2_a]e than pyridine·5·ketone 3-cyclopropylaminomethyl_8_(2,6•difluoro-phenylmethyl)_6_( 2_Fluoryl_3_decyloxyphenyl)-7-fluorenyl-2,3-dihydro-thiazolo[3,2_a]pyridin-5-one ketone 8-(2,6-difluoro-benzene Methyl)_6_(2_fluoro_3_methoxyphenyl)1methyl% piperidin-1-ylmethyl-2,3-dihydro-thiazolo[3,2_a]pyridine_5-one 8 -(2,6-diqi-benzenefyl)_6_(2_fluoro_3_?oxyphenylmethyl_3_(4_ fluorenyl) is a group of 2,3_dihydro-indole Sit and [Μ*biidine_5-keto 8-(2,6-difluoro-benzyl)_3_{[(2-dif-aminoethyl)methylamino]-methyl}-6 -(2-fluoro-3-indolyl-phenyl)_7-methyl-2 3·dithiathio-[3,2-a]pyridin-5-one 8-(2,6-difluoro- Stupid methyl)_6_(2·fluoro_3•methoxyphenyl)7曱yl_3_ {[indolyl-(2-morpholin-4-yl-ethyl)-amino]-indenyl}_2 , 3 dihydrothiazolo[3,2-a]pyridin-5-one 8-(2,6-difluoro-anthracene)_3_α(3-didecylamino)propyl) fluorenyl-amino Bimethyl}-6-(2-fluoro-3-indolyl-phenyl)-7-indolyl-2 3 dihydrothiazolo[3,2-a]pyridin-5-one 8-(2,6- Difluoro-benzyl)_3_[4·(3-dimethylamino-propyl)· Pyridazylmethyl]-6-(2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydro-thiazolidine 152524.doc •56· 201130854 [3,2-a Nfcb 3-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)_6_(2fluoro-3-yloxy-phenyl)-2,2,7- Trimethyl-2,3-dihydro-salt and [3,2_a]e ratio bite·5·ketone 3·[(cyclopropylmethylamino)-f group]·8·(2,6. Difluoro-phenylmethyl)_6_(2_? 3-methoxy-phenyl)-7-methyl-2,3-dihydro-oxazolo[3,2_a]e than pyridine-5-one 3-(Benzylamino-fyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-yl-phenyl)-7-methyl-2, 3-Dihydro-thiazolo[3,2_a]. Bisyl-5-ketone φ 8-(2,6·difluoro-methane)-3-((S)-3-didecylamino-pyrrolidine-fluorenylmethyl)-6-(2 -Fluoro-3-methoxy-phenyl)_7-methyl-2,3-dihydro-thiazolo[3,2·a]0 to 11-but-5-one 8_(2,6-difluoro-曱7·曱基·3-{[Methyl-(2-pyridin-2-yl-ethyl)-amino]-indenyl}-6-(3-trifluoromethoxy-phenyl ) 2,3_dihydro-thiazolo[3,2·a]e is more than 5-(2,6-difluoro-m-methyl)-6-(2-fluoro-3-indole Oxy-phenyl)·7-methyl_3_(4_pyridin-4-yl-piperazine· ;!_ylmethyl)_2,3_dihydro-thiazolo[3,2_a]pyridine_ • 5- Ketone 8-(2,6-difluoro-stanomethyl)_6_(2·fluoro-3-methoxy-3-phenyl)_7-methyl·3_[(曱基_〇比0定-4-基甲) -Amino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyrodo-5-嗣8-(2,6-difluoro-anthracene)-6-( 2-fluoro-3-methoxy-phenyl)-2,2,7-trimethyl-3-[(2-morphin-4-yl-ethylamino)-indenyl]_2,3_ Dihydro-thiazolo[3,2-a] 11 is more than 5-butan-5-(6-(5-chloro-thienyl)_8_(2,6-difluoro-benzoinyl)_7_mercapto_3_{[ Sulfhydryl _ (2_° ratio octyl-ethyl)-amino]-mercapto}-2,3-dihydro-thiazolo[3,2-a]pyrr 152524.doc • 57- 2011 30854 Bite-5 ·嗣8-(2,6-Difluoro-phenylhydrazino)·3_((κ)_3·Didecylamino-pyrrolidinyl-p-methyl)-6-(2-Fluoro- 3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]°tt - 5-83⁄4 8-(2,6-difluoro-benzoinyl) _6_(2_Fluoro-3-methoxy-phenyl)·3·η(2-methoxy-ethyl)-indolyl-amino]-methyl}·7_mercapto_2,3_ Dihydro-thiazolo[3,2_a] 0 is more than 唆-5 -嗣8-(2'6-dioxin-benzyl)-6-(2-fluoro-3_methoxy-phenyl)-3 -[(furan-2-ylmethyl-methyl-amino)-indenyl]_7_mercapto-2,3-dihydro-thiazolo[3,24]pyridyl-5-one 8-(() 2,6-difluoro-benzyl)_6_(2fluoro_3_decyloxy-phenylmethyl_3·(4·pyridin-4-ylmethyl-piperazinylfluorenyl)_2,3_ Dihydro-thiazolo[3,2_a]. Bite-5-嗣3-[(benzyl-fluorenyl-amino)-methyl]_8_(2,6ι_difluoro-phenylmethyl) 6_( 2_Fluorum_3_Methoxy-stupyl-7-indenyl-2,3-dihydro-thiazolo[3,2-indolepyridyl-5-one 8_(2,6-difluoro-stupid Methyl)-6-(2-fluoro-3-methoxy-phenyl)_7-methyl_3_ {[methyl-(2m-ylethyl)-amino]-methyl b 2,3 Hydrogen·嗟[3,2-a]pyridine-5-嗣3-[4-(3,5-dimethylphenyl)-pyrazine small group Base]_6_(2_gas_3·^phenyl)-8-(2-fluoro-6-trifluoromethyl·benzyl)·carba[3,2-a] bite_5-鲷One wind - 嗟 二 二 : 基 基 乙基 乙基 : : : : : : :甲美 2 Thiazolo[3,2-a]pyridine_5-keto-cement, -monohydro- 152524.doc

-58 · 201130854 6-(2-Fluoro-3-oxooxy-phenyl)-8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_7•methyl-3-(4-A Benzyl-piperazin-1-ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridine· 5-keto 6-(2-ran-3-methoxy-benyl)- 8-(2-Fluoro-6·trifluoroyl-benzyl)-7-methyl-3-[(2-oxalin-4-yl-ethylamino)-methyl]-2,3- Dihydro-hydrazino-[32-a]° ratio bit-5-keto 3-(benzylamino-methyl)-6-(2-fluoro-3-methoxy-phenyl)_8_(2 _Fluorine-trifluoromethyl-p-methyl)_7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridine-5-one 6-(2-fluoro-3-methoxy- Stupid)_8_(2_fluoro_6_trifluoromethyl-benzyl)_3_ {[(2_曱-oxy-ethyl)-methyl-amino]-methyl}_7_mercapto-2 , 3 · dihydro _.塞°[3,2-a]° ratio β--5-copper 3_((R)-3-dimethylamino]β-pyrrolidine-diyl-yl)_6_(2_fluoro_3 -decyloxy-phenyl)-8-(2-fluorotrifluoromethyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]»pyridinyl-5 · Ketone 6-(2-fluoro-3-methoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl_3-{[methyl-(2- Acridine-2-ylethyl)-amino]-methyl}-2,3-dihydro-synthesis σ[3,2-a]ntb bite-5_嗣6-(2·1· 3-methoxy-phenyl)_8_(2_fluoro.6_trifluoromethylphenyl)-3_ ({[2-(6-methoxy-0-pyridine-2-yl)-ethyl] _Methyl-amino}-mercapto)7-methyl-2,3·dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2_dun-3_decyloxy-benzene 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl_3_({methyl-[2-(3-trifluoromethyl). -ethyl]-amino}-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl -Fluoro-0-pyridyl·2^_Ethyl

S 152524.doc -59- 201130854 benzyl-amino}-mercapto)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl-2,3-one gas-嗟β Sit and [3,2-a]11 bite _5 -阙3-({[2-(5-chloro-pyridin-2-yl)-ethyl]-methyl-amino}}-yl)- 6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7·methyl-2,3_dihydro-indole [3,2-a]D-pyridin-5-one 6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-anthracene) 7_mercapto-3·({methyl-[2-(3-methyl-β-pyridin-2-yl)-ethyl]•amino}-indenyl)-2,3-dihydro-indole Salivino[3,2-a]°pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-3-({[2-(5-fluoropyridin-2-yl) )-ethyl]-mercapto-amino}-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-2,3-dichloroacetate And [3,2-a]°lt bit-5-keto 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl) ·3_({[2-(3-methoxy-n-Bit-2-yl)-ethyl]-methyl-amino}-indenyl)_7_mercapto-2,3-dihydro-sigh η sits and [3,2-a]D ratio bites-5-嗣6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoquinone Base)_7_曱基_3-({曱-[2-(6-methyl) Pyridin-2-yl)-ethyl]-aminomethyl)_2,3-dihydro-indole[3,2-a]°*bit-5-keto-3_({[2-(4•chlorine) - η比〇定_2_yl)-ethyl]-indolyl-amino}-methyl)_6_(2_fluoro-3-indolyl-phenyl)-8-(2-fluoro-6- Trifluoromethyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-styl )-3-({[2-(3-Fluoro-tung-2-yl)-ethyl]-methyl-amino-methyl)-8-(2-fluoro-6-trifluoromethyl-benzene Base)_7_曱基-2,3-一风-嗟° sits and [3,2-3]° bites 5-- 6-(6-fluoro-3-indolyl-phenyl)-8 -(2_fluoro-6-trifluoromethyl-benzyl)_7_甲152524.doc •60- 201130854 基-3-{[曱基-(2-喧琳-2_基-ethyl)- Amino]-indenyl 2,3-dihydro-snack and [3,2-a]nit bite-5-one 8-(2,6-difluoro-m-methyl)-6-(2- Fluoro-3-methoxyphenyl)-7-methyl(piperidin-1-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1,3]thiazolo[ 3,2-a]0 than bite-5-keto 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-mercapto-3- {[Methyl(prop-2-yn-1-yl)amino]methyl}-2,3-dihydro-511-[1,3]0 塞°[3,2- 8-(2 ,6-difluoro cumyl)-3-({[4-(two Yl) phenyl] amino} Yue-yl) _ 6- (2 gas -3-- Yue basic milk-yl) -7-methyl-2,3 - dinitrogen -5H- [1,3] sigh. Sit and [3,2-a]° bite 5-keto 3-({[2-(diethylamino)ethyl)(indenyl)amino}indenyl)_8_(2,6_two Fluorobenzyl)-6-(2-disorgan-3-methoxyphenyl)-7-mercapto-2,3-dihydro-5H-[1,3]^oxazolo[3,2-a] Pyridine-5-one 3-{[4-(3-indolyl)piperazinyl]methyl}_8_(2,6-difluorophenylindenyl)_6_ y (2_ methoxyphenyl)- 7-mercapto-2,3-dihydro-5 H-[l,3] ° sputum and [3,2·a]° than bite 5-keto 8-(2,6-difluoro cumyl) )_6_(2·Fluoro_3_曱oxyphenyl)_7_曱基_3 {[4_(Pyrazin-2-yl)piperazin-1-yl]methyl}·2,3_dihydrothiazole And [3,2_ a] η than bite-5-_ 8-(2,6-difluoro-m-methyl)_heart (2_fluoro_3_methoxyphenyl)_7•methyl·3 ({ [2_(1-methylindole-2-yl)ethyl]amino}indenyl)_2,3_dihydro^hw,3]thiazolo[3,2-a]pyridine-5-_ 3 -{[4-(1,3-phenyl-dioxole-5)-piperazine-indolyl]methyl b 8_ 152524.doc -61- 201130854 (2,6-difluorobenzene Methyl)_6_(2_fluoro_3_methoxyphenyl)·7·methyl·2,3 dihydro 51^-[1,3]嗟 并[3,2-3]" -5-keto 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_7-methyl_3 {[(2_ A -1,3-benzopyrene_5.yl)amino]methyl b 2 3_dihydro_5Η [ι, 小塞0坐和[3,2-a]»比 bit_5__ 8-( 2,6-difluorophenylindenyl)·6·(2-fluoro-3-ylmethoxyphenyl)_7·methyl[3-(indolyl-i-yl)propyl]piperazinemethyl) _2,3 dihydrogen sold 0 sitting and [3,2-a] °fc bite 5-keto 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxybenzene _7_methyl(difluoromethyl)phenylhydrazinyl]amino}methyl)_2,3_dihydro-5Η·[1,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-monofluorobenzyl)_6-(2-fluoro-3-hydroxyphenyl)_3-{[(4-methoxybenzyl)amino]methyl}-7-oxime Base-2,3-dihydrogen plug. Sit and [3,2-a] ° ratio π -5 - _ 3-[(t-butylamino)methyl]-8-(2,6-difluorobenzoinyl)-6-(2 -1-3-methoxyphenyl)-7-methyl-2,3-dihydro-5H-[l,3]嗟β sits and [3,2-a]° 唆_ 5-嗣8 -(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_7-methyl·3_{[(4·mercaptophenyl)amino]methyl }-2,3-Dihydro-5Η-[1,3]thiazolo[3,2-a]. Specific bite-5-keto 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-indolylphenyl)-7-mercapto-3-{[(3-benyl) Propyl)amino]methyl}-2,3-dihydro-511-[1,3] sigh <1 sit and [3,2-ugly] 0 to bite 5-keto-8·(2,6-difluorophenylindenyl)-3-({[2-(3,5-didecyloxybenzene) Ethyl]amino} 152524.doc -62- 201130854 methyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro-5Η·[ 1,3] ι ^ 0 圭 [3,2-a] ° bite 5-ketone 842,6-difluoro benzyl)-6-(2-fluoro-3-methoxyphenyl)_7 -methyl_3_({[1 (4)-indolylpiperidin-1-yl)propyl]amino}methyl)_2,3-dihydro_5^-[1,3] thiabend[3 ,2-a] η比咬-5-keto 4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl _5_ pendant oxy-2,3-dihydro-5 fluorene-[1,3]thiazolo[3,2-a]pyridin-3-yl]methyl hydrazine, hydrazine-dimethylpiperazine-1-pyrene Indoleamine 8-(2,6-difluoro cumyl)_3-({[3-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3-indole Oxyphenyl)7-mercapto-2,3-dihydrothiazolo[3,2-a]«pyridin-5-one 8-(2,6-difluoro cumyl)·6·(2 Fluorine_3_methoxyphenylisoquinoline_8_ylamino)methyl]-7-methyl-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a Pyridine-5-one 2-(4-{[8-(2,6-difluorobenzyl)-6-(2_fluoro-3-yloxyphenyl)_7-fluorenyl_ 5_side oxygen Base-2,3-dihydro_5H -[1,3]thiazolo[3,2-a]pyridin-3-yl]indolyl}pyrazine-1-yl)-N-(2-phenylethyl)acetamidamine 8J2,6-di Fluorobenzyl)_6_(2_fluoro_3methoxyphenylmethyl_3·^4· (° ratio -3-methylmethyl) oxazine ^·yl] methyl b 2,3-di Hydrothiazolo[3,2-a]e is more than keto-5-keto 3-(azetidin-1-ylmethyl)·8_(26·difluoromethanemethyl)·6(2fluoro·3曱Oxyphenyl)-7-methyl-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a]pyridin-5-one 8_(2,6·difluoro cumyl - 6-(2-Fluoro-3-methoxyphenyl)-7-methyl-3-({4-[4-(difluoroindolyl)phenyl]piperazin-1-yl}fluorenyl) -2,3-dihydro-5Η-[1,3]thia 152524.doc -63- 201130854 0 sit and [3,2-a]° bite-5-_ 2- (4-{[8-( 2,6-difluorobenzyl)_6_(2_fluoro_3_methoxyphenyl)·7_methyl_ 5-sidedoxy-2,3-dihydro-5Η-[1,3] Thiazolo[3,2-a]pyridine-3-yl]methyl}piperazin-1-yl)-N-(2-decyloxyethyl)acetamide 8-(2,6-difluorobenzene Methyl)·6·(2_fluoro_3_methoxyphenyl)7-methyl [2- oxo-2-(° ratio) each bit -1-yl) ethyl] 嗓 _ _ 丨_yl)methyl)·2^-dihydro-5Η-[1,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzene - 6-(2-Fluoro-3-oxooxyphenyl)_7-methyl_3_({[2_(pyrrolidin-1-yl)ethyl]amino}methyl)-2,3-di Hydrogen_5H-[1,3]thiazolo[3,2-a]pyridin-5-one 3-{[(2-chlorobenzyl)amino]methyl}_8-(2,6-difluoro Benzyl)_6_(2_fluoro-3-methoxyphenyl)-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2_a]. Specific bite-5-嗣8-(2,6-monophenylphenyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4-fluorophenyl)amino]- }}-7-mercapto-2,3-dihydro-5H-[1,3]^° sit and [3,2-a]" than bite _ 5-ketone 8-(2,6-difluoro Benzyl)-3-{[(3,5-dimethoxybenzyl)amino]methyl}·6-(2-fluoro-3-methoxyphenyl)-7-methyl- 2,3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzoinyl)-6-(2-fluoro-3 -Methoxyphenyl)-3-({[2-(2-fluoro-4-phenyl)hexyl]amino}indenyl)-7-methyl-2,3-dihydro-5 H- [1, 3]嗟" sit and [3,2_a]0 than bite-5-keto 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-indolyl) -Methylphenoxyethyl)amino]methyl}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]吼152524.doc -64- 201130854 Bite-5 -keto 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(morpholin-4-ylmethyl)-2, 3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methyl Oxyphenyl)_7_methyl_3_{[(pyridin-4-ylf-yl)amino]indenyl}-2,3-dihydro-5H-[1,3]嗟β sits and [3 2 a] Pyridin-5-one 8-(2,6- Fluoromethyl)_6-(2-fluoro-3-methoxyphenyl)_3_{[(4_曱oxylubenmethyl)amino]methyl b 7-mercapto-2,3-di Hydrogen-5 H-[l,3]»seda[3 2 a]e is better than bite-5-one 8-(2,6-difluorobenzyl)-3-{[(2,2-di Phenylethyl)amino]methyl}_6_(2·fluoro-3-indolyloxy)-7-mercapto-2,3-dihydro-5 H-[l,3]〇塞峻和[ 3 2-a] ° 唆-5-keto 3-{[(2-chlorobenzyl)(fluorenyl)amino]methyl b 8_(26-difluorobenzyl)_6_ (2-fluoro- 3-methoxyphenyl)_7-mercapto-2,3-dihydro-511-[1,3]° plug" sits and [3,2- 玨]° bites 5-ketone • 3_ (" [4 gas phenoxy)phenyl]amino}mercapto)-8-(2,6-difluorobenzyl)_6_(2-fluoro-3-methoxyphenyl)_7_methyl_ 2,3_Dihydrothiazolo[3,2-a ] ° ratio _ 5 -嗣4- [(4-{[8-(2,6-difluorobenzyl)_6_(2·fluoro-3-) Methoxyphenyl)_7_methyl_5-sideoxy-2,3-dihydro-5Η-oxime, 3]thiazolo[3,2_a]0-pyridyl-3-yl]methyl}piperazine -1 -yl)methyl]benzoquinone 8-(2,6-difluoromethyl)_3_{[(35-dimethoxyphenylhydrazinyl)amino]methyl}-6-( 2-say-3_methoxyphenyl)-7-methyl_23·dichloro_5Η[ι,3]嗔[3,2-a] bite-5·ketone 152524.doc •65· 201130854 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_7 _Methyl_3-({4-[(1-methylpiperidin-4-yl)methyl]piperazine-1_yl}indenyl)_2,3·dihydro·5Ι1-[1,3] Thiazolo[3,2-a]pyridin-5-one 4-{[8-(2,6-dioxabenzyl)·6-(2-fluoro-3-indolyloxyphenyl)-7- Methyl-5· oxo-2,3-dihydro-5 Η-[1,3]° stopper and [3,2-a]° ratio -3-yl]methyl} oxazin _ 1 -methyl formate 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(thiophen-3-yl) Amino]methyl bromide 23_dihydrothiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzoinyl)-6-(2-fluoro-3-methyl Oxyphenyl)_7_methyl_3 {[methyl(naphthalen-2-ylmethyl)amino]indolyl 2,3_dichloro_5H_[13]thiazolo[3 2· a]0 Than 5-keto-5-keto 8-(2,6-di-l-methylmethyloxyphenyl)3{[(2-hydroxyethyl Kmethyl)amino]indenyl a] ° 8-(2,6-Difluorobenzoinyl) winter (2-fluoro.3.methoxyphenyl)_7-fluorenyl_3_{phenylphenyl)amino]methyl}·2,3· The second gas is - (10) 嗟 并 and [3, 2 bucket than bite -5-嗣8-(2,6-difluorobenzyl) 6·(2-Fluoro+decyloxyphenyl)_3·(10) Benzyl)amino]mercapto}-7-methyl-23 _ " , 虱-5Η-[1,3]thiazole [3 2_ a]pyridine-5-one '3·{[4-〇,3·benzodioxol-5-ylmethyl^Qinxin}-8-(2,6·difluorobenzene Methyl)_6^3 methoxyphenyl)_7 乂2,3-diaza·5Η-[1,3]β-snake [3,2, &]% pyridine_5_ ketone soil ~ 152524.doc -66 - 201130854 3- ({[3-(Ethylamino)propyl)amino}indenyl)-8-(2,6-difluorobenzyl)·0-(2-fluoro^3 -decyloxyphenyl)_7-methyl-2,3-dihydrothiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2 -Fluoro-3_methoxyphenyl)_7-methyl_3-{[4_(1-methylpiperidin-4yl)piperazin-1-yl]methyl}_2,3-dihydro_ 5H-[1,3]thiazolo[3,2-a]β is more than 5-(8,6-difluoro cumyl)-6-(2-fluoro-3-methoxybenzene Base)_7_methyl_3_{[(3· φ methyl alum) amino] fluorenyl}·2,3-dihydro-5H-[1,3]carbazolo[3,2-a Pyridone-5-keto 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(thiophene-4-yl) Methyl)-2,3-dihydro-5H-[1,3] sold saliva[3,2-a]° than bite 5-keto 4- [2-({[ 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-[ 1,3]thiazolo[3,2-a]"Bist-3-yl]fluorenyl}amino)ethyl]benzene decylamine 8-(2,6-difluoro cumyl)-6 -(2-Fluoro-3-indolylphenyl)_7-fluorenyl_3-({-methyl group [2_(°-pyridyl)ethyl]amino}methyl)-2,3 -dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6--fluorobenzino)-6-(2-fluoro-3-oxime _7-mercapto_3-{[4_(2-phenoxyethyl) oxazin-1-yl]methyl b 2,3-dihydro-5H-[ 1,3]thiazolo[ 3,2 - a ] ° ratio bite _ - 5 嗣8-(2,6-difluoro cumyl)-3-({[2-(didecylamino))methyl]amino}methyl - 6-(2-Fluoro-3-methoxyphenyl)-7-mercapto-2,3-dihydro-5Η-[1,3]thiazolo[3,2 - a ]D ratio bite- 5 - Stuffed 1 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)·7-methyl_3j[4_ 152524.doc -67- 201130854 ( Methyl-decyl)piperazin-1-yl]fluorenyl}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine_5-one 2_(4_{[ 8-(2,6-Difluorobenzoinyl)-6-(2-fluoro-3-methoxyphenyl)-7-indenyl 5- 5-oxo-2,3-dihydro-5H-[ 1,3 Thiazolo[3,2-a]pyridin-3-yl]indolyl} 0-decyl-1-yl)methylacetamide 3_({[2-(4-ethinylpiperazine) Ethyl]amino}indenyl)_8·(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro ·5Η·[1,3] °°°[3,2-a]° than biting 5-keto 8-(2'6-difluoro cumyl)·6_(2_fluoro_3_曱Oxyphenyl)7-methylmethylbenzyl)amino]methyl}-2,3-dihydro-5Η·[1,3]thiazolo[3,2-a]pyrodo-5 -_ 8·(2,6·difluorobenzyl)_6_(2_fluoro_3_decyloxyphenyl)_7_fluorenyl_3_({4_[3-(difluoromethyl)phenyl) Piperazinyl hydrazinylmethyl)·2,3·dihydroindole°[3,2-a]bite-5-one 3-[(1,3-benzodioxole- 5_ylamino)indenyl]_8(2,6 difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl·2,3-dihydro-5Ιί -[1,3] ° plug. Sit and [3,2-a] ° bite 5-keto 8-(2,6-difluorobenzyl)_6_(2_fluoro_3_foxyphenyl)_7_methyl·3_{[( Thiophen-2-ylindenyl)amino]hydrazino 2,3-dihydro-5Η_Π,3]thiazolo[3,2_a] 0 than bite-5 -8-(2,6-difluorobenzene Base)_6_(2_fluoro_3_methoxyphenyl)_7_decyl·3·(pyrrolidin-1-ylindenyl)-2,3-dihydro-5Η-[1,3]carbazole And [3,2-a]n-pyridin-5-one 8-(2,6-difluorobenzyl)·6_(2-fluoro-3-indolyloxyphenyl)_3_({[3·( 1η_imidazol-1-yl)propyl]amino}methyl)_7_methyl-2,3-dihydro_5Η_[13]thiazol 152524.doc -68 - 201130854 [3,2-a]^ b ate 5-ketone 4-[({[8-(2,6-difluorobenzyl)_6_(2_fluoro_3_decyloxyphenyl)_7_fluorenyl_5_ oxo-2, 3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl]methyl}amino)methyl]benzonitrile 8-(2,6-difluorobenzoate 6-(2-fluoro-3-indolylphenyl)-7-methyl-3·({methyl[(1-indolyl-1Η-pyrazol-5-yl)methyl]amine)曱 曱 ) ) ) ) ) [ [ [ [ [ [ [ [ [ [ [ [ [ [ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 _6-(2-Fluoro-3-yloxyphenyl)_7-methyl_3·{[(thia-3-ylmethyl)amino]indenyl}_2, 3_Dihydro_5H-[1,3]d sedative [3,2-a] 11 than yt-5- -8-(2,6-difluoro-m-methyl)_6-(2_fluoro_ 3·decyloxyphenyl)_7_mercaptomethyl-1Η_imida-5-yl)methyl]amino}indenyl)-2,3-dihydro-5Η·[1,3]嗔0 Sit and [3,2-a]n than bite 5-keto 8-(2,6-difluoromethanemethyl)_6_(2-fluoro_3_methoxyphenyl)_7_mercapto_3_( {4_ [2-(Trifluoromethyl)phenyl]piperazine-i•yl}indenyl)_23_dihydro_5Η·[13]thiophene ° ° sit and [3,2-a]° bite- 5-keto-8·(2,6-difluoro cumyl)_6_(2·fluoro·3_methoxyphenyl)_7•methyl·3_({[2-(4-mercaptophenyl)) Amino]methyl}methyl)_2,3_dihydrothiazolo[3,2-a]° than bite-5-b-8-(2,6-difluorobenzoinyl)-6-(2-fluoro 3-methoxyphenyl)·3-{[(2·methoxybenzyl)amino]methyl}_7_mercapto-2,3-dihydro-5Η-[1,3]thiazole And [3 2_ a]11 than 唆-5-one 8-(2,6-difluoro cumyl)_6_(2_fluoro_3_decyloxyphenyl)_7-decylmethylpiperidine-1 ·Methyl]·2,3-dihydro-5H-[1,3]thiazolo[3,2_a]pyridine-s 152524.doc •69· 201130854 5-keto 8-(2,6-one parent Iphenylphenyl)-6-(2-fluoro-3-indolylphenyl)-7-indenyl·3 _({[3·(2-sideoxy) . Ratio u each bite-ΐ_yl)propyl]amino}methyl)_2,3·dihydro_5Η·[1 3]thiazolo[3,2-a]pyridin-5-one 8-(2, 6-Difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-fluorenyl_3-({[4·(arachid-4-yl)phenyl]amino) }Methyl)-2,3-dihydro-5H-[1,3]pyrene and [3 2_ a]0 bis--5-copper 8-(2,6-fluorobenzyl)-6- (2- gas-3-methoxyphenyl)_3-({[2_(3_fluoro 1phenyl)ethyl]amino}methyl)-7-methyl-2,3-dichloro-5H -[ 1,3] for sale. Sit and [3 2-a]°fcb ^ -5»S^| N-[4-({[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-oxime) Phenyl))-7-mercapto-5-sideoxy-2,3-dihydro-5 H-[l,3] sin and [3,2-a] ° ratio -3-yl]methyl }amino)phenyl]methanesulfonamide 3-{[4-(2- gasbenzyl)hamo-1-yl]fluorenyl}-8-(2,6-difluorobenzoinyl)_6_ (2-Fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2_a]0 is more than 5-ketone-ketone 8- (2,6-difluorophenylindenyl)-6-(2-fluoro-3-indolylphenyl)_7-fluorenyl_3_ {[(1Η-«比嗤-3·ylmethyl)amino group ]Methyl}-2,3-dihydro-5H-[1,3] sputum and [3,2-a]° ratio biting 5-keto 8-(2,6-difluorobenzoinyl)- 6-(2-Fluoro-3-methoxyphenyl)_7-methyl_3-({4_[2-(»-pyridin-2-yl)ethyl]piperazin-1-yl}methyl) _2,3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3 -Methoxyphenyl)_7.methyl_3_({4_[(1-mercaptopiperidin-3-yl)indolyl]piperazine-l-yl}indenyl)_2,3_dihydro_5H_ 152524.doc •70_ 201130854 [1,3]thiazolo[3,2-a]pyridin-5-one N-cyclopropyl-2-(4-{[8-(2,6-difluorobenzyl) )-6-(2-fluoro-3-methoxyphenyl)-7- 5-5-oxy 2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-yl]methyl}piperazin-1-yl)acetamide 6-(2-Fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]]7-methyl-3-({[3-(?琳-4- Phenyl]amino}methyl)-2,3-dihydro-511-[1,3] Mouth and sit [3,2-3]. Specific bite-5-keto•6-(2-fluoro-3-methoxyphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl-3-{[( 2-mercaptophenyl)amino]methyl}_2,3-dihydro-5H-[1,3]° sedative [3,2-a]» than 唆-5-one 3_{[( 3-Chlorobenzyl)amino]methyl}-6-(2-fluoro-3-yloxyphenyl)_8[2_fluoro-6-(trifluoromethyl)benzyl]-7_A Base 2,3_dihydro-5H_[13]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-indolyloxyphenyl)-8-[2-fluoro- 6-(Trifluoromethyl)phenylhydrazino] {[(2-hydroxyethyl)(methyl)amino]methyl}-7-methyl·2,3-dihydro φ thiazolo[3,2 -a]pyridine-5-one 6-(2-fluoro-3.methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl-3 (Mallin-4-ylmethyl)-2,3-dihydro-5Η·[1,3] sputum and [3,2-a] bis--5-one 6-(2-fluoro-3曱oxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7 methyl-3-{[(4-phenylbutyl)amino]methyl}-2 , 3-dihydro _5H_[13] 嗔 并[3,2-a]. Bipyridin-5-one 3-(1,4'-linked 11 bottom bite_1'-ylmethyl)_6-(2-fluoro-3-methoxyphenyl)_8_[2_ defeat 6-(two Gas sulfhydryl) benzyl]-7-methyl-2,3-dihydro-5H-[1,3]fluorene. Sit and [3 2 152524.doc -71- 201130854 a] ° bite 5-keto 6-(2-fluoro-3-indenyloxy)-8-[2-fluoro-6-(trifluoromethyl) Alum ]7][7] fluorenyl-3-{[decyl (prop-2-yn-1-yl)amino] hydrazino 2,3-dihydro _5H_[13] thiazolo[3,2 -a]pyridine-5-one 6-(2-fluoro-3-indolyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_3· {[(3 - Methoxy-hydroxymethyl)amino]methyl}-7-methyl-2,3-dihydro-5H-[1 3] 嗟0 sits and [3,2-8]° bites 5-ketone-3 -{[(4-chlorophenyl)(methyl)amino]methyl b 6-(2·fluoro-3-methoxyphenyl)_8_ [2-fluoro-6-(trifluoromethyl)benzene Mercapto]-7-methyl-2,3-dihydro_5Η-[ι,3]η塞和和[3,2-a]pyridine-5-one 3- {[4-(1,3 - Benzodioxol-5-ylmethyl)piperazinyl]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-( Trifluoromethyl(methyl)phenylhydrazinyl]-7-mercapto-2,3-dihydro-511-[1,3]'»嗤嗤[3,2-&]» than bite _5-ketone —mercaptoamino)propyl]amino}mercapto)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl ]_7_Methyl-2,3·Dihydro_5H_[1,3]thiazolo[3,2-a]pyridin-5-one 4- {2-[({6-(2-fluoro-3-) Oxyphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl-5. oxo-2,3-dihydro-5H-[1,3]thiazole And [3,24]0-pyridyl-3-yl}methyl)amino]ethyl}benzene continual amine 6-(2-fluoro-3-methoxyphenyl)-8·[2-fluoro- 6-(Trifluoromethyl)benzyl]-7-methyl-3-{[(3,4,5-dimethoxybenzyl)amino]methyl)_2,3-dihydro_ 5H_[1,3]thiazolo[3,2-a]pyridine-5-one 3-{[t-butyl(methyl)amino]methyl}_6_(2_fluoro_3-methoxy Base)_8_[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1,3]喔 "Sit 152524.doc -72- 201130854 And [3,2-&]° ratio bit-5-keto 6-(2·fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoquinone ]_7_Methyl-3_({[2-(acridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1,3] sold out [3, 2-a]° ratio to 5-keto 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7-methyl -3-{[(pyridin-2-ylf-yl)amino]methyl}-2,3-dihydro-5Η-Π,3]thiazolo[3,2-a]. Specific bite-5-嗣φ 6-(2-fluorosmoutoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_3_ {[(4-methoxy Amino]mercapto}-7-mercapto-2,3-dihydro-5-[1,3]-thazolo[3,2-a]pyridin-5-one 3-{[(2- Gas benzyl)amino]methyl}_6-(2-fluoro-3-indolylphenyl)_8_[2·fluoro-6-(trifluoromethyl)benzyl]-7-methyl- 2,3-Dihydro·5Η-[1,3] sold out and [3,2-a]»tb bite 5-keto-3-[(diphenylmethylamino)methyl]_6_(2_fluoro -3 -methoxyphenyl)fluoro-6, (difluoromethyl)benzyl]-7-fluorenyl-2,3-dihydro-5H-[1,3]嗟π sits [3 2_a φ pyridine-5-one 4-({6·(2-fluoro-3-methoxyphenyl)-8-[2·fluoro-6-(trifluoromethyl)benzyl]_methyl- 5-Phenoxy-2,3-dihydrothiazolo[3,2a]pyridine-3-yl}methyl)piperazine-1-decanoic acid ethyl ester 6-(2-fluoro-3-methoxyphenyl) )_3_{[(4-fluorophenyl)amino]methyl}_8_[2_fluoro_6_(trifluoromethyl)phenylindenyl]_7_mercapto-2,3_dihydro_5H_[13] Thiazolo[3 2· a]pyridine-5·_ 3_(azepan-1·ylindenyl)·6-(2-fluoro-3-indolylphenyl)_8_[2·fluoro_6· (Trifluoromethyl) benzyl]-7-mercapto-2,3-dihydro-5Η-[1,3]thiazolo[3,2_a] 15 2524.doc •73- 201130854 0 than bite-5-keto 6-(2-fluoro-3-methoxyphenyl)_8-[2-fluoro-6-(trimethylmethyl)benzoinyl]_7 Benzyl-3-[(4-methylpyro-indyl)methyl]·2,3·dihydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-one ' 1-({6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-side oxygen Benzyl-2,3-dihydro-5H-[1,3]thiazolo[3,2_a]pyridine-3-yl}methyl)piperidine-3-carboxamide 3-{[(1,3-benzo) M-dioxol-5-ylindenyl)amino]methylfluoro-3-methyllacylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7 _曱基·2,3-dihydro-511-[1,3] sighs and [3,2-3] he bites 5-membered 6-(2-fluoro-3-methoxyphenyl)- 8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-indolyl 3-[(prop-2-yn-1-ylamino)methyl]·2,3-dihydro _5H-[1,3]thiazolo[3,2-a]° ratio to 5-keto 3-(3,4-dihydroisoquinolin-2(1H)-ylmethyl)-6-( 2-fluoro-3-yloxyphenyl)_8-[2-fluoro-6-(difluoroindolyl) benzyl]-7-methyl-2,3-dihydro-5H-[1, 3]0°° sitting and [3,2-a]«nt bite 5-0 with 6-(2-fluoro-3-methoxybenyl)-8-[2-fluoro-6-(trifluoro-1 Benzo)benzene Base]_7_mercapto-3-{[(3,4,5-dimethoxyphenyl)amino]methyl b 2,3-dihydro-5H-[1,3]thiazolo[3, 2-a]e than bite-5-keto 4-[({6-(2-gas-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl) ]_ 7-Methyl-5-o-oxy-2,3-dihydro-5H-[1,3] sigh. Sit and [3,2_a] β is more than -3-yl}methyl)amino]-indole-phenylbenzamide {4-[({6-(2-fluoro-3-)-methylphenyl) )-8-[2-Fluoro-6-(tris-decyl)benzyl]-7-indolyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3] , 2_a]pyridine - 152524.doc •74· 201130854 3-yl}methyl)amino]phenyl}ethyl acetate 3-{[(4-chlorobenzyl)(methyl)amino] fluorenyl} -6·(2·fluoro_3_methoxyphenyl)·8·[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl-2,3-dihydro-5Η -[1,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) Benzyl]_7_fluorenyl·3·({[3-(1Η-tetrazol-5-yl)phenyl]amino}indenyl)_23_dihydro_5H_[1,3]" Salivation [3,2-&]° ratio 5-- 6-(6-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoquinone 1-7-methyl·3-({[3-(piperidin-1-yl)propyl]amino}methyl)-2,3-dihydro-5H-[1,3] 嗟0 Sit and [3,2-a]° bite 5-- 6-(6-fluoro-3-indolylphenyl)_8_[2_fluoro_6-(trifluoromethyl)benzoinyl]_7 _Methyl_3-({[2-(thiophen-2-yl)ethyl)amino}indenyl)_2 3_dihydro 0 stopper ° sit and [3,2-a] ° than bite-5- 6-(2-Fluoro-3-yloxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)phenylindenyl]·7·methyl-3-[(4-indolyl-indole, 4 -diazepan-yl)methyl]_2,3·dihydro-5Η_[1,3]thiazolo[3,2-a]pyridin-5-one M (4-ethylpiperazine_1 _yl)methyl]_6_(2_fluoro-3-methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-2,3-dihydrothiazole [3,2-a]. Specific bite 5-keto 6-(2-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzoinyl]_7_indolyl 3-({[2- (2-Sideoxyimidazolidine-indolyl)ethyl]aminoindenyl)_23_dihydro-5indole-[1,3]thiazolo[3,2-a]pyridin-5-one 3- {[Bis(pyridin-2-ylindenyl)amino]methyl}_6-(2-fluoro-3-indolylphenyl)-8·[2-fluoro-6-(trifluoromethyl)benzene Mercapto]_7_methyl-2,3·dihydrothia 152524.doc -75- 201130854 Zoxao[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl -8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-3-{[(2-phenylpropan-2-yl)amino]methyl}-2 ,3-dihydro-5H-[1,3]thiazolo[3,24]° than bite-5-_ 3-({4-[2·(didecylamino)ethyl]piperazine-b曱6)(6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-2,3-di Hydrogen-511-[1,3]thiazolo[3,2-&]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-( Trifluoromethyl)benzyl]-7-mercapto-3-({4-[2-(morphin-4-yl)ethyl)-l-yl}methyl)_2,3-di Hydrogen-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 3-{[(biphenyl-4-ylmethyl)amino]methylfluoro-3-indolyloxy 8-)[2-fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a ]^b bite-5-class 4-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] -7-Methyl-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-yl}methyl)piperazin-1-yl ] 笨-carbonitrile 2- [4-({6·(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6·(trifluoromethyl)phenyl)]-7-methyl Sideoxy-2,3-dihydro·5Η-[1,3]thiazolo[3,2-a]pyridine-3-yl}methyl)piperazine-i-yl]_n,N-dimethyl Acetamide 6-(2-fluoro-3-methoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-3-({4-[ 2·(〇比罗ridin-1-yl)ethyl]piperazineindolylmethyl)2,3_dihydro-5Η-[1,3]thiazolo[3,2-a]pyridine-5- Ketone 6-(2-fluoro-3.nonyloxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl b-7-methyl-3-({[3-(5-methyl) - lH-n-Bizozol-4-yl)propyl]amino}methyl)_2,3-di 152524.doc 201130854 Hydrogen-5H-[1,3]thiazolo[3,2-a]pyridine-5 -keto 6-(2-aero-3-oxooxyphenyl)_8·[2-fluoro-6-(trifluoromethyl)benzyl]_3_ ({[4-(1Η·imidazol-1-yl) Phenyl] }}methyl)_7_methyl_23_dihydro_5H_[1,3]thiazolo[3,2-a]pyridin-5-one 6-(2·fluoro-3-indolylphenyl) _8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(5-methylpyrazine-2-yl)indolyl]amino} fluorenyl) _2 3_Dihydro-5H_[1,3]thiazolo[3,24]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)_8_[2-fluoro_6_(trifluoro Methyl)benzyl]-7•methyl-3-[(quinolin-4-ylamino)methyl]-2,3-dihydro-5H-[1,3]thiazolo[3,2 - a]° ratio to 5-keto 6-(2-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]]7methyl_3-({ Mercapto[(1_methyl_1Η_Π比唑_4·yl)indolyl]amino}methyl)23_dihydro-5Η-[1,3]thiazolo[3,2-ahb 唆-5-one 6-(2-Fluoro-3-indolylphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzyl]7-methyl-3-{[(3-mercaptobenzyl)amine曱 曱 } } } } } } } } } } } } } 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 苯 苯 苯 苯 苯 苯 苯 苯 苯 苯 苯 苯 苯 苯Methyl}-6-(2-fluoro-3-indolylphenyl)·8_[2_fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-2,3-dihydro- 5Η-[1,3]嗟嗟[3,2-a]. Bipyridin-5-one 3_({phenylmethyl[2-(dimethylamino)ethyl]amino}methyl)_6-(2-dun_3_methoxyphenyl)-8-[ 2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-2,3-digas _ 5H-[1,3] oxazolo[3,2-a]e ratio bite- 5-keto 6 (2-fluoro-3-indolylphenyl)-8_[2- gas-6-(trifluoromethyl)phenylindenyl]_3_[(isoquinolin-5-ylamino) A 7-methyl-2,3-dihydro-5H-[1,3]嗟 and 152524.doc •77· 201130854 [3,2-a]pyridin-5-one 6-(2-fluoro -3_methoxyphenyl)·8_[2_fluoro·6·(trifluoromethyl) aluminyl]_7_methyl-3·({[4-(morpholine-4-yl)phenyl) ]amino}f))-2,3-dihydro_5Η_Π,3] 嗟β sits and [3,2-a]. Than 5-ketone 6-(2-rat-3-methyllacylphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzyl]·3_ ({[3-(1Η-) Imidazolium-hydrazinyl)propyl].amino}indenyl)_7-methyl-2,3-dihydro-5Η·[1,3]thiazolo[3,2-a]pyridin-5-one 3 ·{[(3,5-Dimethoxyphenylhydrazino)amino]methyl}_6_(2_fluoro_3·decyloxyphenyl)_8-[2-fluoro-6-(trifluoromethyl) Benzyl]·7·methyl-2,3_dihydro_5Η_[1,3]thiazolo[3,2-a]pyridin-5-one 3-[(4-ethylhydrazine piperazine a • base) fluorenyl]_6_(2_fluoro_3_decyloxyphenylfluoro-6-(trifluoromethyl)benzyl]]7-mercapto-2,3_dihydro_5H [1,3 Thiazolo[3,2-a]°^> 唆-5-keto 6-(2-fluoro-3-methoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl) Benzoyl]_3_[(isoindol-4-ylamino)methyl]-7-methyl-2,3.dihydro-5Η·[1,3]thiazolo[3,2-a]. Specific bite 5-keto 6-(2-fluoro-3-indolylphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl-3·{[4- (1-Phenylethyl) piperazine_ι_yl]methyl)_2,3-dihydro-5Η-[1,3] sigh. Sit and [3,2-a] ° bite 5-keto 6-(2-fluoro-3-indolylphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzyl] -7-Methyl-3-[({2-[3-(trifluoromethyl)phenyl]ethyl decylamino)methyl b 23-dihydro-5H-[1,3]thiazolo[3 ,2-a]pyridine-5-one 3-({[4-(dimethylamino)butyl]amino}indenyl)·6 (2fluoro·3曱oxyphenyl)·8·[ 2-Fluoro-6-(trifluoromethyl)benzoinyl]_7-methyl-2,3_dihydro_5Η_ 152524.doc •78· 201130854 [1,3].塞和和[3,2_&] 吨 _5_ ketone 3-[(l,3-benzothiazolyl-6-ylamino)indenyl]_6_(2_fluoro_3•methoxyphenyl) _ 8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3·dihydro·5h[i,3]thiaβ[3,2-a]e Specific bite-5-嗣3-{[(2,5-dichlorobenzyl)amino]methyl}_6_(2_fluoro_3methoxyphenyl)_ 8 [2Fluoro-6-(II Fluoromethyl)benzyl]_7_methyl_2,3_dihydro_5h_[i,3]嗟0 sits and [3,2-a]n is more than 5-ketone φ 6-(2 -fluoro-3-methoxyphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzyl]7-methyl-3-{[(2-phenyloxyethyl)amino]methyl Bu 2,3-dihydro-511-[1,3]'1 plug <»Sit and [3,2-a]° bite 5-- 6-(6-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl ]_7_methyl_3-({mercapto[2-0-pyridyl-3-yl)ethyl]amino}methyl)23 dihydro- 5Η· [1,3]° 塞 塞 [ [3, 2-&]"Bite-5-keto-3_({[4-(dimethylamino)phenyl)]amino}methyl)·6_(2_fluoro_3_methoxyphenyl )-8-[2-Fluoro-6-(trifluoromethyl)benzyl]_7_methyl_23 dihydro·5Η_ • [1,3]°〇〇[3,2-狂]° Specific bite-5-_ Ν-{4-[({6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]-7- 5-O-oxy-2,3-dihydro-511-[1,3]pyrene and [3,2-3]0 than biting-3-yl}methyl)amino]phenyl}indole Alkyl decylamine 6-(2-fluoro-3-indolylphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]]7methyl_3-{[4-(thieno[ 3,2-d]pyrimidin-4-yl)piperazinyl]methyl b 2,3-dihydro-5H-[1,3] sold saliva [3,24]° bite 5-ketone 6- (2-fluoro-3-indolylphenyl)_8-[2-fluoro-6-(trifluoromethyl)phenylhydrazino]-7-methyl-3-{[4-(2-phenoxy) Ethyl)piperazine-yl]methyl b 2,3_dihydro·5H_ •79· 152524.doc 201130854 [1,3]thiazolo[3,2-a]pyridine -5-keto 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)phenylmethyl-7-yl-3-{[4-(phenylcarbonyl) Piperazine 4-yl]methyl b 2,3 dihydro-511 [13] thia-[3,2-a]°Hi 唆-5-one 4-({6-(2·fluoro-3) -methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]-7methyl-5-sideoxy-2,3-dihydro-511-[1,3]〇吐 并 和 [3, 2-3] 0 ratio. D--3-yl}methyl)-N,N-dimethylpiperazine_1-decylamine 3-({[2-(4-benzene) (piperidinyl)ethyl]amino}methyl)-6-(2-fluoro-3-yloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7_ Methyl 2,3_dihydro- 511-[1,3]° plug "sit and [3,2-3] ° than bite-5-net 6-(2-fluoro-3-decyloxy) -8_[2_Gas·6-(Tris-decyl)phenylhydrazino]_7-methyl-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazine-丨-yl]indolyl 2 3_Dihydro·5Η_ [1,3]喧 "Sit and [3,2-&]° than bite 5-ketone 6-(2-1-3-decyloxybenyl)_8_[2_败_ 6-(Trifluoro(indenyl)phenylhydrazino]_7-mercapto-3-({[2-(3-methylphenyl)ethyl]amino)methyl)_2,3_dihydro_5 -[1,3].塞°[3,2-a]n ratio bite-5-keto 3-({[2-(-methylamino)phenyl)amino}methyl)_6_(2_fluoro_3_曱oxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]·7-methyl-2,3_dihydro_5Η· [1,3]嗟 并[ 3,2-a]° than bite-5·copper 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylindenyl]_7_ Mercapto-3·{[methyl(pyridine-4-yl)amino]methyl)_2,3·dihydro 5JJU]thiazolo[3,2-a]D than bite-5-嗣6-(2 -Fluoro-3-indolyl phenyl fluoride-6-(trifluoromethyl)phenylhydrazinyl 3_ [(isoquinoline-8 an amino)methyl]·7·methyl-2,3- Dihydro-5H-[1,3]thiazole 152524.doc •80· 201130854 [3,2-a]pyridin-5-one 4-({6-(2-fluoro-3-decyloxyphenyl)) -8_[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3, 2-a]pyridin-3-yl}methyl)-1-(2-phenylethyl) brig. Qin-2,6-dione 6-(2-fluoro-3-methoxyphenyl)- 8-[2-Fluoro-6-(trifluoromethyl) benzyl]-7-methyl-3-{[(2-methyl-1,3-benzothiazol-5-yl)amino] Methyl b 2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one φ 2-[4-({6-(2-fluoro-3-methoxy) Phenyl -8-[2·Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-yloxy-2,3-dihydro-5Η·[1,3]thiazolo[3 ,2-a]°pyridin-3-yl}methyl)methyl)-1-yl]-N-(2-phenylethyl)acetamidamine 6-(2•fluoro-3-methoxybenzene _8-[2-Fluoro-6·(trifluoromethyl)benzyl]-7-methyl-3-({[(l-methyl-1H-indazol-5-yl)indolyl] Amino}methyl)_2,3_dihydro_511-[1,3]嗟[[,2-&]'1 ratio bite-5-_ 6-(2·fluoro-3-antimony (8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-indolyl-3-({methyl[(1-mercapto-1H-®)-pyrazole-3- Methyl]amino}mercapto)-2,3-φ dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3- Methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]]7-methyl-3-{[(1Η-indazol-3-ylmethyl)amino]methyl }·2,3·Dihydro_5h-[i,3] 嗟.Sitting and [3,2 <]° ratio bit-5-keto 6 (2-fluoro-3-methoxyamino)trifluoromethyl)phenylhydrazino]_7-methyl-3-{[4-(3-phenylpropyl Piperazine•yl]indolyl 2,3_dihydro·5Η·[13] sigh and [3,24]" than bite-5-_ 6-(2- gas-3-decyloxybenzene _8_[2_Fluoro-6-(trifluoromethyl)phenylindolyl]-7-methyl-3·({[2-(4-mercaptopiperazinyl)ethyl]amino) Methyl)_2 3 · dihydro _ 152524.doc -81 - 201130854 5H-[1,3] 嗟 并 [3,2-a]D than bite 5-keto 3-{[4-({6- (2-Fluoro-3-methoxyphenyl)_8_[2-Fluoro-6-(trifluoromethyl)phenylindenyl]-7-methyl-5-oxo-2,3-dihydro- 5H-[1,3]嗟" sits and [3,2-a]. Bispin-3-yl}methyl) slightly indol-1-yl]methyl}benzonitrile 3_{[(3,5- Dimethoxyoxymethyl)(methyl)amino]methylfluoromethoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-fluorenyl dihydrogen -511-[1,3]thiazolo[3,24]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) Benzyl]_7-mercapto-3_({[2-(2-methylphenyl)ethyl]amino}indenyl)-2,3-dihydro_5h_[13] thiazolo[3,2 -a]pyridine-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoro Methyl)benzyl]-7 methyl-3-[(pyridazin-3-ylamino)methyl]-2,3·dihydro-5H-[1,3]thiazolo[3,2_a] ° ratio 5-keto 6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]_7_mercapto_3-{[ (thiophen-3-ylmethyl)amino]methyl}-2,3-dihydro-5Η-Π,3]thiazolo[3,2-a]» than bite-5-one 6-(2-fluoro- 3-methoxyoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzoinyl]_7methyl-3-({4·[2-(°pyridin-4-yl)) Piperazine-1 -yl}methyl)·2,3_dihydro- 511-[1,3]thiazolo[3,24]pyridine-5-one 3_{[4-(biphenyl_3_ Base) piperazine·buki]methyl}_6_(2_fluoro·3_decyloxyphenyl)·8-[2-fluoro-6-(trifluoromethyl)methyl]-7-fluorenyl -2,3-dihydro·5Η_Π,3]thiatino[3,2-a]«> than biting 5-keto 6-(2-fluoro-3-methoxyphenyl)_8·[ 2-fluoro-6-(trifluoromethyl)benzoinyl]·3_ {[4-(3·methoxypropyl)piperazine·diyl]methyl}_7-methyl·2,3 dihydrogen _5h_ 152524.doc -82- 201130854 [1'3] Smelling and [3,2-&]» than biting _5-ketone 6 (2-fluoro-3-indolyl stupid)_8_[2_Fluorine_ 6_(Trifluoromethyl)benzyl]_7-methyl_3-{[4-(pyridine-3-yl)indolyl)pyridinyl 23 dihydro_5h_[1,3]thiazolo[3,2-a] bite_5_ketone 6_(2ϋ曱oxyphenyl)_8-[2- gas-6-(trifluoromethyl)benzene曱基]·7·曱3 ({4-[(1_methylpiperidin-3-yl)methyl]piperazine d•yl}methyl)_2,3·dihydro-5Η-[1, 3]thiazolo[3,2_a]pyridine_5•one (2 gas 3 decyloxy) _8_[2_fluoro_6_(trifluoromethyl)benzyl]]7_mercapto-3-({4 -[(l-decylpiperidine-4-yl)methyl]piperazine-4-yl}methyl)2 3_dioxin-5H-[1,3] squat and [3,2-ap ratio bite -5-keto 6-(2·fluoro-3-methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]_7-methyl-3-({4-[2- (Trifluoromethyl)phenyl]piperazine-diyl}methyl)_2,3_dihydro-5H-[1,3]嗟" sits and [3,2_a]ti ratio. _5_keto 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]7-yl-3-({[(l-- -1H-pyrazole-4.yl)methyl]amino}methyl)_2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 6- (2-fluoro-3-indolylphenyl)-8_[2_fluoro-6-(trifluoromethyl)phenylindenyl]_7-methyl·3·{[methyl(naphthalen-2-ylmethyl) Amino]mercapto}-2,3-dihydro-5H-[1,3]thiadoquinone[3,2-a]n ratio bite 5-ketooxime-cyclopropyl-2·[4 -({6-(2-Fluoro-3-methoxyphenyl)-8.[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-5. pendantoxy- 2,3-Dihydro-5H-[1,3]thiazolo[3,2-a]0-pyridin-3-yl}methyl)piperazin-1-yl]acetamidamine 6-(2-fluoro -3-decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl·3·({methyl[2-( <*pyrrolidin-1-yl)ethyl]amino}indenyl)_2,3_dihydro-152524.doc -83- 201130854 511-[1,3]thiazolo[3,24]pyridine- 5-keto 3-({ [2-(4-ethinylpiperazinyl))ethyl]amino}methyl)-6-(2-fluoro-3-indolyl)--8 -[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-511-[1,3]thiazolo[3,24]pyridine-5-one N-(3-{[({6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenyl)]-7-fluorenyl- 5-Phenoxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}indenyl)amino]methyl}phenyl)acetamide 6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({methyl[2-( 4-methylpiperidin-1-yl)ethyl]amino}indenyl)_2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 8- (2,6-monofluoro-benzyl)-6-moth-7-methyl-3-{[methyl_(2_. than bite_2_yl_ethyl)-amino]-fluorenyl} -2,3-dihydro-indole and [3,2-a]e ratio bite-5-嗣6-(3-chloro-phenyl)-8-(2,6-difluoro-benzyl) -7-fluorenyl_3_{[indenyl-(2"pyridin-2-yl-ethyl)-amino]-fyl}-2,3-dihydro-thiazolo[3,2_a]pyridine_ 5-keto 6-benzo[1,3 Di-dioxole-5-yl-8-(2,6-difluoro-phenylidene)7-methyl-3-{[methyl-(2-"-pyridin-2-yl- Ethyl)-amino]-methyl-i-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-3-(amino-phenyl-methyl) _8_(2,6-Difluorobenzyl)6(2-fluoro-3-methylphenyl)-7-methyl-2,3-dihydro-thiaxo[3,2_a]pyridine· 5- Ketone {3S-[3oc(R*)]}-3-(Amino-phenyl-indenyl)-8-(2,6-di-gas^,6-(2-fluoro-3-indolyl)- Phenyl)-7-mercapto-2,3-dihydro-thiazolo[3 2-pyridyl 5-ketone 152524.doc -84. 201130854 {3R-[3a(S*)]}-3-(amino group -Phenyl-methyl)-8-(2,6-difluoro-benzyl)·6. (2-Fluoro-3-indolyl-phenyl)-7-methyl-2,3-di Hydrogen-»塞嗤和[3,2_a] β is more than 5-ketone {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2,6·2 Fluoro-benzyl (2-fluoro-3-indolyl-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2_3]pyrene than 5-ketone [3a(R* )]-3-[Amino-(4-fluoro-phenyl)-methyl]·8·(2,6·difluorobenzyl)_ φ 6-(2-fluoro-3-methoxy- Phenyl)_7_methyl-2,3_dihydrothiazolidine 2_a]吼0定-5 -酉同[3a(S*)]·3·[Amino-(4-fluoro-phenyl)_曱基]_8_(2 6_Difluoro- Methyl)·6-(2·fluoro-3_methoxy-phenyl)_7-methyl-2,3-dihydro-thiazolo[3 2_4〇 咬-5-one [3a(R*) ]-3-[Amino-(4-methoxy-phenyl)-methyl]_8_(2,6-difluorobenzyl)_6_(2•fluoro_3_methoxy-phenylmethyl_ 2,3_Dihydro-carbazole[3 2_ ugly]"Bite 5-ketone•[3a(S*)]-3-[Amino-(4-methoxy-phenyl)_A Base]_8_(2,6-difluorophenylindenyl)-6-(2-fluoro-3·decyloxy-phenyl)_7-fluorenyl-2,3-dihydro-oxazolo[3,2_a °°Bite-5-_ [3a(R*)]-3-[Amino-(4.trifluoromethoxy-phenyl)methyl]_8^2,6-difluoro- _ 曱 曱) -6·(2·•fluoro-3·decyloxy_phenyl)_7•fluorenyl_23_dihydrothiazolo[3,2-a]. Specific bite 5-ketone [3a(S*)]·3·[Amine gas 'trifluoromethoxyphenyl)-indenyl]_8^2,6_difluoro_stylmethyl)-6-( 2-fluoro-3-methoxy-phenyl)-7-methyl-2,3.dihydro-thiazolo[3,2-a]pyridine-5-one s 152524.doc -85 - 201130854 3-( Amino-phenyl-indenyl-8-(2,6-difluoro-benzyl)-6-(2-^-3-methoxy-phenyl)-2,2,7-triterpene -2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-3-(amino-phenyl-indenyl)-6- (2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3 , 2-a] ° than biting 5-keto {3S-[3a(R*)]}-3-(amino-phenyl-indenyl)-6-(2-fluoro-3-indolyl- Phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]. Than 5-ketone {3R-[3a(S*)]}-3-(amino-phenyl-indenyl)-6-(2-fluoro-3-indolyl-phenyl)-8- (2-Fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a]D ratio bite-5-one {3S-[3a (S*)]}-3-(Amino-phenyl-indenyl)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorodecyl -benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-[amino-(4-fluoro) -phenyl)-methyl]-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl- 2,3-Dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-[Amino-(4-fluoro-phenyl)-methyl]-6- (2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydro-thiazolo[3 ,2-a]11 than bite-5-keto[3a(R*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-6-(2-fluoro- 3-decyloxy-phenyl)-8-(2- gas-6-trimethylsulfonyl-stupylmethyl)-7-mercapto-2,3-diox_sigh 0 sit and [3,2- a]° ratio bit-5-keto[3a(S*)]-3-[amino-(4-trifluorodecyloxy-phenyl)-methyl]-6-(2-fluoro-3-indole 152524.doc -86- 201130854 Methyl-2,3-dihydro-oxy-phenyl)-8-(2-fluoro-6-trifluorofyl) ▼基)嗟嗤[3,2-a]*^Bite-5-keto(tetra)·3·{Amino[(3⁄4)phenyl]methyl}·6_(2|3_methoxyphenyl) 8_[2-Fluoro-6-(trifluorof-yl)benzyl]-7-methyl-2,3-dichloro-dish (10)oxazolo[3,2-a]pyridin-5-one

6-(2_Gas·3·methoxy·phenyl)~·Fluorine_6·Trifluoromethyl·benzyl)_3-(Bite-Nan-2-yl·isopropylamino fluorenyl) _7•Methyl-2,3_:hydrogen_^ and [3,2_&] ° than pyridine-5-one [3oc(R*)]-3-(amino-phenyl.methyl)_6_(2_ Chloro-5_trifluoromethoxy-stupyl)_

8-(2-Fluoro-6-trifluoromethyl-phenylmethyl)_7_indolyl-2,3.dihydrothiazolo[3,2_a] mouth bite-5-brown I

[3a(S*)]-3-(Amino-phenyl-methyl)_6_(2_chloro-5-trifluoromethoxy-phenyl 8-(2-fluoro-6-trifluoromethyl- Benzyl)_7_methyl-2,3-dihydro-thiazolo[3,2_a] ° than bite-5-keto[3a(R)]·3·(amino-phenyl-methyl) _6_(2_Fluor-0 pyridine-3-yl)_8_(2Fluoro-6-difluoromethyl-benzyl)_7-methyl·2,3·dihydro-thiazolo[3,2_called pyridine · [3a(S)]-3-(Amino-phenyl-methyl)_6_(2_Fluorum_.Bit_3_yl)_8_(2Fluoro-6-difluoroindolyl-benzyl) -7-mercapto-2,3_dihydro-thiazolo[3,2_a]npyridin-5-one [3a(R*)]-3-(amino-phenyl-methyl)_8_(2 _Fluoryl-6-trifluoromethyl-phenylmethyl)-7-methyl-6-(3-difluoromethoxy-phenyl)_2,3-dihydro-thiazolo[3,2_a]pyridine- 5-keto[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl adenyl)_

S 152524.doc 201130854 7-Methyl-6-(3-trifluoromethoxy-phenyl).2m sits and [3,2_small than bite-5-keto[3〇^)]-3-( Amino-phenyl-fluorenyl)·6·(2_fluoro-5-methoxyphenyl (2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl_2,3_ Dihydro-thiazolo[3,2_a] 0 is more than keto-5-keto[3a(S*)]-3-(amino-phenyl-fluorenyl)-6·(2_fluoro·5_decyloxy · Stupid base) 8(2_fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2_a]〇 咬-5-_ {3R- [3a(R*(1)-3-(Amino-phenyl-methyl)_6_(4-fluoro-benzo-π,3]-d-luro-oxol-5-yl)-8-(2- Fluoro-6-trifluorodecyl-benzoinyl)_7_fluorenyl 2.3-dihydro-indole "» sits and [3,2-3]° bites 5-ketone {3S-[3a(R* )]-3-(Amino-phenyl-indenyl)_6_(4•Fluorum_Bisto[L3]dioxol-5-yl)-8-(2-Fluoro-6-III Fluorodecyl-benzoinyl)_7_fluorenyl-2,3-dihydro-sold. Sit and [3,2-a]. Bite 5-ketone {311-[3(1(8*)] }-3-(Amino-styl-methyl)_6_(4-fluoro-benzo[1,3]dioxol-5-yl)-8-(2-fluoro-6-tri Fluorinyl-benzoinyl)·7_mercapto_2.3-dihydro-indole. Sit and [3,2-a]° than bite 5-ketolu (3s-[3a(S*)]}- 3-(Amino-p-styl-methyl)-6-(4-fluoro-benzo[ι,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoro曱-Benzyl)_7_fluorenyl _ 2'3--hydrogen sold η sit and [3,2-a] ° than bite 5-keto [3a(R"]_3_(amino stupyl-A _6_(2,2-difluoro-benzo[13]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_7- Base 2,3_dihydro-thiazolo[3,2_a]pyridine-5-one [3a(SS|S)]-3'(amino-phenyl-methyl)-6-(2,2-di Fluorine-stupid [1,3]diox 152524.doc •88· 201130854 Heteropentene-5-yl)-8-(2-fluoro-6-trifluoromethyl·benzoyl)·7_ Mercapto-2,3_dihydrothiazolo[3,2-a]pyridine-5-one 3-[amino-(2·gas_3_fluoro-phenyl)-indenyl]_8·(2, 6_Difluorobenzyl)_6(2_fluoro-3-methoxy-benyl)_7-methyl-2,3-dihydro-indole. Sit and [3,2_a]n ratio bite_ 5-ketone [3a (R)]_3-(Amino-m-methylidyl-methyl)·8-(2 6 difluoro-m-methyl)_6_(2-fluoro-3-methoxy-phenyl)-7-methyl_ 2,3_Dihydro-thiazole[3,2_ypyridine·

Amino-m-mentyl-methyl)_8_(2,6-di-phenylene)_6_(2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydro- Thiazolo[3,2 5-keto-a]n ratio bite 3-(amino-thiophen-3-yl-indenyl)-8-(2,6-difluoro-benzyl)·6-( 2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2_a]pyridine·5-one [3a(R*)]-3-[amine Base-(3-fluoro-phenyl)-methyl]_8_(2 6 difluorobenzyl)

6-(2-Fluoro-3-indolyloxyphenyl)-7. Pyridin-5-one [3a(S*)]-3-[Amino-(3-fluoro-phenyl)-methyl] _8_(2,6-difluoro-p-methyl) 6-(2-fluoro-3-methoxy-phenyl)_7-fluorenyl-2,3-dihydro- _-5-嗣嗟β sits and [3 ,2-a]»比[3a(R*)]-3-[Amino-(5-methyl-隹 -2-2-yl)-methyl]8(26二气曱基基)-6- (2-fluoro-3-indolyloxy)phenyl-7-indenyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3- [Amino-(5-methyl-thiazole-2-yl)-indenyl]_8·(2 6 difluorophenylindenyl)-6-(2-fluoro·3·decyloxyphenyl)-7 -Methyl-2 monogas·嗟β sits and 152524.doc • 89 - 201130854 [3,2-a]&quot;Bite-5-keto[3cx(R*)]-3-[Amino-(3- Fluoro-acridin-2-yl)-methyl]-8-(2,6.difluoro-m-methyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl -2,3-dihydro-thiazolo[3 2· a]pyridin-5-one [3a(S*)]-3-[amino-(3-fluoro·«pyridin-2-yl)indolyl ]-8-(2,6-Di-l-stylmethyl)-6-(2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydrothio. Sit and [3 2 a] pyridine 5-ketone 3-(amino-benzo[b] phenyl-3-yl-fluorenyl)-8_(2,6-difluoro-benzyl)_6_( 2Fluoro-3_decyloxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridine-5-one 3-[amino(phenyl)methyl]- 6-(2-Fluoro-3.methoxyphenyl)_8_[2_fluoro-6(trimethylmethyl)benzyl]-7-methyl-2,3-dihydro-5Η_Π,3]thiazole And [3 2_a] ton bite _5·嗣1-oxide [3a(R*)]-3·(amino-phenyl·methyl)*M2-gas-6·trifluoromethyl benzyl )_6_Iodine_7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridine-5-one [3a(S*)]-3-(amino-phenyl-methyl) _8_(2·Golden trifluoromethylbenzyl)·6-峨-7-methyl-2,3-dihydro-furazolo[3,2_a]|?pyridin-5-one 3-( Amino-phenyl-fluorenyl)_8_(2,6-di-i-methyl) winter broken methyldihydro-anthracene [3,2a]pyrene than bite-5-steel 3-(amine = base _Methyl)_8_(2,6•diqi·phenylhydrazolyl)_7_methyl_6^ phenyl]yl-2,3-dihydro-thiazolo[3,2_&amp;]pyridone-3·(amino group ·Phenyl·methyl)_6·(5·chlorom-yl)-8·(2,6_:ι-benzyl)-7·methyl<,3-dihydro-嗔嗔[3,2_啦Bite _5_嗣3-(Amino-phenyl-methyl)-6_(3·chlorophenyl hydrazine·(2, 6-difluoro-phenylmethyl"_ 152524.doc -90· 201130854 Methyl-2'3-dihydro-thiazolo[3,2_a]pyridine-5-one 3-(amino-phenyl-methyl )_6_(6_氯_„比基基)_8_(2,6-di-gas-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2_a]pyridine_5-ketone 3-(Amino-phenyl.methyl)_8·(2,6-difluorobenzyl)·6(2-oxyl ratio _3_yl)_7-methyl_2'3-dihydrogen _ carbazole [3,2 inch pyridine ketone 3-(amino-phenyl-methyl)_8_(2_fluoro_6•trifluoromethylbenzylmethyl methoxypyridinyl 3)- 7-Methyl-2,3-dihydro-indole-[3,2_small-bite_5_-trifluoro-f-yl)--6-(6-methoxy-嗟 并[3 ,2-a]n than 唆-5-steel

3-(Amino-phenyl-methyl)_8-(2-fluoro-6-yl-0-pyridin-2-yl)-7-methyl-2,3-dihydro-3-(amino-benzene Base·methyl)·6_(6chloroκ2_&amp;)_8·(2•Fluoryltris-methyl-benzyl)-7-methyl_2,3_dihydro-indole[3,2_a] 〇 _ _ 5 ketone 3- (aminophenyl methyl) · 6 ♦ chloro _ 5 _ methoxy phenyl (2 · gas winter trifluoromethyl - benzyl) 曱 ^ ^ two Hydrogen-(4) and bite [3〇1(尺*)]-3-(amino-phenyl-methyl)_6_(2_gas (2-fluoro-6-dimethyl-benzyl) )_7•Methyl·2 3 0 than bite-5-keto 3-methoxy-phenyl)-8-dihydro-thiazolo[3,2-a] gas-嗟° sit and [3,2- a] „ ratio (amino-styl-fluorenyl)_6_(2_fluoro-6-trifluorodecyl-phenylhydrazino)·7·methyl-2-bit-5-one 3-(amino stupyl) -Methyl)·6_benzo π,3]dioxacyclo(2-fluoro-6-trifluoromethyl-benzoinyl)_7_fluorenyl^^yl-8-° ratio bite-5 - Ketone, -two winds - sputum and [3,2 called [3a(R*)]-3-(amino-phenylindolyl)_6-(2_gas-3⁄4 salivation-fluoro-6-trifluoro曱基·曱曱基)-7-methyl-2,

152524.doc -91- S 201130854 Bite 5-ketone [3ot(S*)]-3-(Amino-phenyl-methyl)-6-(2-fluoro-3-methyl-phenyl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-indolyl-2,3-dihydro-thiazolo[3,2-a]indole-5-one 3-(amine -phenyl-indenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-6-(2-fluoro-3-trifluoromethyl-phenyl)-7-fluorenyl -2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl.methyl)-6-(2-chloro-phenyl)-8-(2 -Mouse-6-dimethyl-benzyl--7-methyl-2,3-dinitro-O-O-[0,2-a]0 than bite-5-嗣3-(amine Phenyl-phenyl-methyl)-6-(3- gas-phenyl)-8-(2- gas-6-di-mercapto-benzyl)-7-methyl-2,3-dihydro -thiazolo[3,2-a]pyridin-5-one [3ot(R*)]-3-[3-(amino-phenyl-indenyl)-8-(2-fluoro-6-trifluoro Mercapto-benzyl)-7-methyl-5-sideoxy-2,3-diaza-5H-° plug 0 sit 弁[3,2-a] ΰ比 bit-6_ base]-2 - Fluoro-benzoic acid [3a(S*)]-3-[3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7- Methyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-6-yl]-2-fluoro-benzoquinone 3-(amino-phenyl- Methyl)-8-(2-fluoro-6-trifluoromethyl -benzyl)-7-methyl-6-thiophen-2-yl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3·(amino-phenyl-indole -8-(2-Ga-6-dioxamethyl-phenylhydrazino)-7-methyl-6-(5.nonyl-thiophene-2-yl)-2,3-dihydro-thiazole And [3,2-a]pyridine-5 ketone 3-(amino-phenyl-methyl)-6-(5-a-thiophen-2-yl)-8-(2-fluoro-6-tri Fluorofluorenyl-benzyl)-7-methyl·2,3-diode 0 弁[3,2-a]ϋ比咬-5-晒 3-(amino-phenyl-fluorenyl) -6-(3- gas-D-cephen-2-yl)-8-(2-fluoro-6-tris-decyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazole [3,2-a]pyridine-5-one 152524.doc -92- 201130854 [3ot(R*)]-3-[amino(phenyl)(2h)indenyl]-8-(2,6- Difluoromethanemethyl)6(2-Alan-3-oxooxy)-7-methyl-2,3·dihydro-5H-[1,3]fluorene. Sit and [3 2 a] 0 than bite-5-ketone [3ot(S*)]-3-[amino(phenyl)(2H)methyl]·8_(26_difluorobenzyl)6·( 2·Fluoro-3-methoxybenzyl)-7-methyl-2,3-dihydro-5 Η-[1,3] sigh. Sit and [3 2_a] 0 bite _ - 5 - Stuffed | [3a(R*)]-3-[Amino (phenyl)(2H)methyl]_6_(2_Fluoro-3·decyloxybenzene Base)_ φ 8-[2-Fluoro-6-(trifluoromethyl)benzyl]_7_methyl-2,3_dihydro_5Η [ι,3]thiatino[3,2- a]°rti bite-5-steel [3ot(S*)]-3-[amino(phenyl)(2h)indenyl]-6_(2_fluoromethoxyphenyl)_ 8-[2- Fluoro-6-(trifluoromethyl)benzyl]]7-methyl-2,3·dihydro-5H[1,3]thiazolidine[3,2-a]° 唆-5-one 3-(1-Amino-1-phenyl-ethyl)_6_(2_fluoro_3_methoxy-phenyl)8 (2Fluoro-6-difluoroindolyl-benzoinyl)-7- Methyl-2,3-dihydro-thiazolo[3,2_a]pyridine 3-(1-amino-1-phenyl-but-3-indolyl)-6-(2-fluoro-3-oxime -phenyl)_8·(2_ • fluoro_6·trifluoromethyl-phenylhydrazino)-7-fluorenyl-2,3-dihydro-thiazolo[3,2_a]pyridin-5-one {3R-[3oc(R*)]}-3-(Amino-phenyl-fluorenyl)·6·[3_(11 difluoroethyl)-phenyl]-8·(2-fluoro-6- Trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]° ratio bite-5 -嗣{3S-[3a(R*)]}-3 -(Amino-phenyl-fluorenyl)_6_[3_(11 difluoro-ethyl)- phenyl]-8-(2-fluoro-6-trifluoromethyl-m-methyl)_7-methyl 23•Dihydrogen Thiazolo[3,2-a]°tb pyridine-5-one {3R-[3oc(S*)]}-3-(amino-phenyl-methyl)_6_[3_(11 difluoroethyl

S 152524.doc •93- 201130854 Phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydrothiazolo[3,2-a]pyridine 5-ketone {3S-[3ot(S*)]}-3-(amino-phenyl-methyl)-6-[3-(1,1-difluoro-ethyl)-phenyl]- 8-(2-Fluoro-6·trifluoromethyl-phenylmethyl)_7-methyl-2 3_dihydrothiazolo[3,2-a]e than bite-5-嗣{3R-[3oc( R*)]}_4_({[6-(2_fluoro_3_ 曱oxy-phenyl)_8_(2•Fluoro_6 trisyl)-methyl)-7-methyl-5-flavor - 2,3-digas - 5Η-π嗤嗤[3 2_ &amp;]° pyridine-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester {3S-[3ct( R*)]}_4-({[6-(2-fluoro-3-indolyl-phenyl)_8_(2_fluoro·6·tris-yl-methyl)-7-fluorenyl-5- Sideoxy-2,3-diaza-5 Η-reservative salino[3 2 _ a].pyridin-3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester {3R- [3oc(S*)]}-4-({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)- 7-mercapto-5-oxo-2,3-dihydro-5H-thiazolo[3,2_a]°pyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid Ethyl {3S-[3ot(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8·(2-fluoro-6-triptanyl)- Benzoyl)-7 - 5-yloxy-2,3-dihydro-5-indole-purified [3,2-a]pyridin-3-yl]•phenyl-methyl-amino)ethyl butyrate ( {[6-(2-Fluoro-3-oxooxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-5-sideoxy-2 3-Dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]•phenyl-methyl}-amino)-ethyl acetate 3-({[6-(2-fluoro-3) -decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-yloxy-2,3·dihydro-5H-thiazole [3,2-a]pyridin-3-yl]-phenyl-methylindole-amino)-propionic acid ethyl ester M{[6-(4-fluoro-benzo[1,3]dioxan Cyclopentene-5-yl)-8-(2-fluoro-6-tris 152524.doc -94- 201130854 fluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3- Dihydro-5H-thiazolo[3,2- a]°pyridin-3-yl]•phenyl·methyl}_amino)-butyric acid ethyl 5-({[6-(2_fluoro-) 3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl 7-methyl-5-oxo-2,3-dihydro-5H-indole [3,2-a]°Bite·3-Base]-Phenyl-fluorenyl}-amino)-pentanoic acid ethyl ester 4-({[6-(2-fluoro-5-decyloxy-phenyl) -8-(2-Fluoro-6-trifluoromethyl-stupylmethyl)_ 7-mercapto-5-sideoxy-2,3 - 虱-5H- [3,2-a]0 is more than -3-yl]-phenyl-indenyl}-amino)-butyric acid ethyl ester 4 ({[8-(2 · gas-6-di-standard 1 methyl-) Stupid methyl)-7-methyl_5-sideoxy_6_(3-trifluorodecyloxyphenyl)-2,3.dihydro-5H-thiazolo[3,2-a]pyridine- 3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester {3R-[3a(R*)]}-4-({[6-(2-fluoro-3-decyloxybenzene) 8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-indole sitting and [3 2_ ap Bispin-3-yl]-phenyl-fluorenyl}-amino)-butyric acid {3S-[3a(R*)]}-4-({[6-(2-fluoro-3-decyloxy) -Phenyl)-8-(2- gas·6·trifluoromethyl-benzoinyl)-7-methyl-5-oxooxy-2,3-dihydro-5Η-.塞和和[3,2_ a]&quot;Bipyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid {3R-[3a(S*)]}-4-({[6 -(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-sideoxy-2,3- Dihydro-5H-indazolo[3,2_a]«pyridin-3-yl]-phenylindolyl)butyric acid {3S-[3a(S*)]}-4-({ [6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-tris-decyl-stupylmethyl)-7-indolyl-5-sideoxy-2,3 -Dihydro-5H-thiazolo[3,2_a] ° ratio -3-yl]-styl-fluorenyl}-amino)-butyric acid ({[6-(2-fluoro-3-decyloxy) -phenyl)-8-(2-fluoro-6-trifluoromethyl-alum)_7_

S 152524.doc _&lt;κ 201130854 and [3,2-a]pyridine_3_yl]•benzyl-5·sideoxy-2,3-diaza-5H- sold fluorenyl-fluorenyl}- Amino)-acetic acid 3-({[6-(2_fluoro_3_methoxyphenyl)_8_(2· π difluoromethyl-benzoic acid 7-fluorenyl-5-sideoxy-2, 3-dihydro-5Η-η plug η whole ugly well [3,2-a]° 唆.3-1 1 lean base-methyl amidino)-propionic acid group]- Ben 4_({[6· (4-Fluoro-abido[1,3]dioxole, terpene-5-yl)-8-(2-fluoro.6-trifluoromethyl-benzyl)-7-decyl- 5-Alkyloxy_2 1 &gt; I, -I wind-5Η-η塞撒和"3 2 a]pyridin-3-yl]-phenyl-methyl}-amino)·butyric acid' _

5-({[6-(2-gas Imethoxy)phenyl)-8-(2.oxycyl tris-l-methyl-benzyl)-7-methyl-5-sideoxy-2, 3-dihydro-5H-sigh n sitting on its door 0 liter [3,2_a]° bite 3-yl]-phenyl-methyl}-amino)-pentanoic acid fluoride-5-methoxy-stupid )8·(2ϋ(trifluoromethyl-benzoyl 7-fluorenyl-5-yloxy-2,3-dihydro-5 fluorene-suppressor[3,2·l-triyl-methyl}-amine) Base)-butyric acid 1

4-(m-(2-Fluoro-6-trifluoromethyl-benzyl)·7-methyl·5_sideoxy·6_(3·trifluoromethoxy-phenyl)-2,3 -Dihydro-5Η-thiazolo[3,2_a]β ratio _3 yl-methyl}-amino)-butyric acid ruthenium {3R-[3a(R*)]M_m6_(2_gas_3_methoxy Phenyl) 8_[2 gas_6_(Denylmethyl)benzyl]-7-methyl_5_sideoxy·2 3_dihydro-5H VII, 3] sigh [3,2-a] Sodium pyridin-3-yl}(phenyl)methyl]aminobutyrate {3S-[3a(R*)]}-4-{[{6-(2-fluoro-3-methoxyphenyl) )_8·[2 Fluorine_6_(_fluoromethyl)benzyl]-7-methyl_5_sideoxy·2,3-dihydro·5Η_[13]喧喧[3,2-a ]pyridin-3-yl}(stupyl)methyl]aminosodium butyrate {3R-[3a(S*)]}-4-{[{6-(2-fluoro-3-methoxybenzene) Base)-8·[2_ fluorine 152524.doc -96·

V 201130854 fluoromethyl)benzyl]-7-methyl-5-oxo-2,3-dihydro-5H-[1,3]&quot; stopper. Sodium [3,2-a]pyridin-3-yl}(phenyl)methyl]amino}butyrate {3S-[3a(S*)]}-4-{[{6-(2· Fluoro-3-methoxyphenylfluoro-6-(trifluoromethyl)benzyl]-7.methyl-5-oxo-2,3-dihydro-5H-[1,3]pyrene And [3,2-a]° ratio -3-yl}(phenyl)methyl]amino} sodium butyrate 6-(2-fluoro-3-methoxy-phenyl)-8-(2 -Fluoro-6-trifluoromethyl-benzyl)methyl-3-(methylamino-phenyl-methyl)-2,3-dihydro-thiazolo[3,2-&amp;]. Bisidine_ • 5 - _ 3-(dimethylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)_8&lt;2_fluoro-6-trifluoromethyl -benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2_a]npyridin-5-one 3·(butylamino-phenyl-methyl)-6-( 2-fluoro-3-indolyl-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydro-thiazolo[3,2- a]pyridine·5-keto 6-(2-fluoro-3-methoxyphenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- [Stupid-(4,4,4-trifluoro-butylamino)-indenyl 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(allyl Amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)_8_(2·fluoro-6-difluoromethyl-ben Indenyl)-7-fluorenyl- 2,3-dihydro-sodium [3,2-a]D is more than 5-keto-3-(1-allylamino)-phenyl-butyl 3-alkenyl)-6-(2-fluoro-3-indolyloxyphenyl)-8-(2-fluoro-6-trifluoromethyl-stanomethyl)_7-mercapto-2,3 _Dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene Methyl)_7_甲

S 152524.doc •97· 201130854 -3-(2-phenyl-1,2,3,6-four wind-n ratio bite-2-base)-2,3 -two gas-sigh 0 sit and [ 3,2-a] ° than biting 5-keto-N-{[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzene 7-mercapto-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-indenyl}-acetamidamine 3 -Bromo-2,2-difluoro-N-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-Methyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-propanamide 2.2-difluoro -3-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl)-benzyl)-7-indolyl-5-side Oxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propionic acid ethyl ester 2.2-difluoro-3- ({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl)-7-methyl-5-oxirane-2 ,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-indenyl}-amino)-propionic acid 3-[(3,3-difluoro-2- Oxyloxy-azetidin-1-yl)-phenyl-indenyl]-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl) Base-benzyl)-7-methyl-2.3-dihydro - ° plug ° sit and [3,2-a] ° bite 5-ketone

6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-3-[(3-hydroxy-propylamino)- Phenyl-methyl]-7-mercapto-2,3-dihydro-thiazolo[3,2 - a ]π ratio - 5 -I 6-(2-fluoro-3-indolyl-phenyl -8-(2-Fluoro-6-trifluoromethyl-benzoinyl)-3-[(4-hydroxy-butylamino)-phenyl-indenyl]-7-indenyl-2,3 -Dihydro-thiazolo[3,2-a] ° ratio 5-but-5-keto 3-[(2,2-difluoro-3-hydroxy-propylamino)-phenyl-methyl]-6- (2-Fluoro-3-oxo 152524.doc -98- 201130854 base-stupyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-methyl_2,3-di Hydrogen-°-pyrazolo[3,2-a]pyridin-5-one {3R-[3ot(R*)]}-4-({[6-[3-(l,i-difluoro-ethyl) )_Phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5-sideoxy-2,3-dihydro-5H-thiazolo[3, 2-a]pyridin-3-yl]-phenyl-indolylamino)-butyric acid ethyl ester {3S_[3a(R*)]}-4-(U6-[3-(l,l_二Ethyl)-phenyl]-8-(2-fluoro-6-difluoroindolyl-stanomethyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[ 3,2-a]°pyridin-3-yl]-phenylmethylammonyl&gt;ethyl butyrate {311-[3〇^*)]}-4-({[6-[3 -(1,1_difluoro-ethyl)-phenyl]-8-(2_ Fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]- Phenyl-mercaptoamino)-butyric acid ethyl ester {3S-[3a(S*)]}-4-({[6-[3-(l,i-difluoro-ethyl)-phenyl) ]-8-(2-Fluoro-6-trifluoromethyl-adenyl)-7-fluorenyl_5_sideoxy-2,3-dihydro-5H-thiazolo[3,2-a] Pyridin-3-yl]-phenyl-indenylamino)-butyric acid ethyl ester {3 ft.-[3 〇〇(尺*)]}_4-({[6-[3-(1,1_) Difluoro-ethyl)-phenyl]-8-(2-fluoro-6-tris-methyl-benzyl)-7-indolyl-5-oxo- 2,3-dihydro-5H-thiazole [3,2-a]°pyridin-3-yl]-phenyl-decylamino)-butyric acid {3 8_[3〇1(1^)]}-4-({[6-[3 -(1,1-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-difluoromethyl-m-methyl)-7-methyl-5-oxirane-2,3 -Dihydro-5 H-indole[3,2-a]pyridin-3-yl]-phenyl-methyl-amino)butyric acid {3R-[3a(S*)]}_4-( {[6-[3-(l,l-Difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)·7-fluorenyl_5-side Oxy-2,3-dihydro-5H-thiazolo[3,2_a]° pyridine·3_yl]-phenyl-methyl}-amino)-butyric acid {3S-[3a(S*) ]}-4-({[6-[3-(l,l.difluoro-ethyl)-phenyl]-8-(2-fluoro-) 6-

S 152524.doc -99- 201130854 Trifluoromethyl-phenylhydrazino)-7-methyl-5. oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3 -yl]-phenyl-methyl}-amino)-butyric acid 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7- Base-3-({methyl[2-(pyridin-2-yl)ethyl]amino}methyl)_2,3_dihydro-5H-[1,3]thiazolo[3,2-a] Pyridine-5·ketone 1·oxide 6-(4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzyl)-7-methyl_3_ ( {methyl[2-(°-pyridin-2-yl)ethyl]amino}methyl)·2,3·dihydrothiazolo[3,2-a]pyridin-5·one 1-oxide 6 -(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_3•(hydroxy-phenyl-methyl)-7-methyl _2,3-dihydropyrazine [3 2 external ratio bite · 5 · ketone 6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxine_6_ Base)_8_(2_gas·6_trifluoromethyl-benzyl)-7·decyl-5-sideoxy-2,3·dihydro-5Ηthiazolo[3,2-a]pyridine-3 -S-phenyl thiodecanoate 6-(2-fluoro-3-isopropoxy-phenyl)-8-(2·fluorotrifluoromethylbenzyl) 7-methyl-5-sideoxy- 2,3·Dihydro-5H-thiazolo[3,2_a]pyridine_3•S-phenyl ester of thiodecanoic acid 6- (2-fluoro-3-dimethoxy-bensyl)-8-(2-defeno-6-trifluoromethyl-phenylmethyl) 7-fluorenyl-5-sideoxy-2,3- Dihydro-5H-thiazolo[3,2_a]pyridine_3•S-phenyl thioester 6-[3-(1,1-difluoro-ethyl)·2-fluoro-phenyl b 8_(2 _Fluoro-6(trifluoromethylphenylhydrazino)-7-fluorenyl-5-yloxy-2,3-diargon-5H-thiazolo[3,2_a]pyridine_3_thiodecanoic acid S- Phenyl 6-(2-fluoro-4-indolyl-yl)-8-(2-rat-6-trifluoromethyl-benzyl)-?-fluorenyl-5-oxo-2 , 3- wind _5H-°S0 sit and [3, 2-3].比唆_3-thiocarbamate 8- 152524.doc •100- 201130854 Phenyl ester 8-(2-fluoro-6-trifluorof-phenyl)_6_(3·hydroxy-phenyl)-7-f 5--5-mercapto-2,3-ethane·5H-嗟0 sit-[3,2-a]11-precipitate-thiocarbamate S-benzidine 6_(2-fluoro-4-phenoxy -phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-o-oxy-2,3-dihydro-5H-indole[3, 2-a]0 than bitten-3-thiocarbamic acid S-phenyl ester 6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl) -7-M-φ-yl-5-sideoxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-thiodecanoic acid S-phenyl ester 6-(4-fluoro- 2,2-Di-p-benzo[1,3]dioxol-5-yl)_8_(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5- Sideoxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-thiodecanoic acid S-phenyl ester 6-(3-difluoromethoxy-2-fluoro-stupid 8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl-5-sideoxy-2,3-dihydro-5H-thiazolo[3,2_a]pyridine ·3_Silyl phthalate S-phenyl ester # 6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-indoleyl)_7_曱5--5-oxy-2,3-dihydro-5H-thiazolo[3,2_a]pyridine-3-thiocarboxylic acid 3_ Benzene vinegar 3-(2-fluoro-phenylindenyl)_6_(2-fluoro-3-trifluoromethoxy-phenyl)·8_(2·fluoro·6_dimethyl-benzyl)_7_ Methyl-2,3-dihydro-thiazolo[3,2_a]D is more than _5-keto 3-(2-fluoro-abteromyl)_6_(2_fluoro_3_decyloxy-phenyl Fluorotrifluoromethyl-benzyl)_7·methyl-2,3·dihydro-snap[3,2_a]n is more than 6-(2-fluoro-3-indolyl-phenyl)_8_ (2-fluorotrifluoromethyl) _7_曱152524.doc -101 - 201130854 -3-(thiophene-3-carbonyl)-2,3-dihydro-thiazolo[3,2-a Pyridine·5-keto 6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-indolyl-3-(2-indole) -Benzyl hydrazino)_2,3·dihydro-thiazolo[3,2_a]pyridine-5 ketone 6 (2-n-methyl-3-methoxy-phenyl)_8_(2_fluoro_6_trifluoro曱-Benzyl phenyl)_7_fluorenyl_3_(3-indolyl-phenylhydrazino)_2,3-dihydro-thiazolo[3,2-a]pyridine_5_-- 3-(2- Gas-cracking base)_6_(2_fluoro_3methoxy-phenyl)_8_(2_fluoro_6•trifluoromethyl-benzyl)-7-methyl-2,3-dihydro -thiazolo[3,2-a]pyridin-5-one 3_(2,5-difluoro-abidomethyl)-6-(2-fluoro-3-indolyl-phenyl)-8-( 2-fluoro-6·trismethyl-benzyl)_ 7_Methyl_23 dihydrothiazolo[32a]pyridine_5·ketone 3-(2,3-digas-benzene f醯ylindole_(2-gas_3_methoxy-phenyl gas_6· Trifluoromethyl-benzyl)-7•methyl-2,3_dihydrogen is sitting and [3,2 external ratio η5-keto-3_(2-chloro-3-fluoro-benzonitrile) _6_(2_Fluor_3_methoxyphenyl)_8_(2_gas_6_trifluoromethyl·benzyl)_7·decyl_2,3_: hydrogen to sit and [3,2•small ratio Bite_ 5-keto 3-benzhydryl-Μ5•fluoro-2,3_dihydro-benzo[μ]dioxine·, yl)8 (2-fluoro-6-difluoromethyl- Benzyl)-7-mercapto-2,3-dihydro-indole[3,2-a]pyridine-5-one 3 1 methyl-based 6_fluoropropane_3·isopropoxy-benzene Base)_8_(2_Fluoryltrimethylenemethyl)-7-methyldihydro-K#[3 2_a]titb〇^5, 3_本奸甲甲·6-(2·气·3 _Trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethylbenzyl)·7-methyl·2,3_dihydro_°ie sits and [3,2- a]. Than the bite-5-ketone 3_ 本甲基基&quot;^例丨山:Fluorine-ethyl)_2_Fluoro-phenyl]·8·(2·Fluor-6_III152524.doc -102- 201130854 Fluorine Methyl-stupylmethyl)_7_methylmethylene dichloride such as [3,2 external ratio 3-phenylhydrazin-6_(2_fluoro |methoxy-phenyl)_8_(2•fluoro·6 benzene Methyl)-7-fluorenyl·2,3_二气_嗟〇坐[3,2_小比唆土3-笨甲甲基·8_(2_氟_6_三阿曱基·Benzene Methyl)_6_(3, phenyl·stupid 7-methyl-2,3·dihydro-oxazolo[3,2_a]pyridinium-5-ketone soil 3_benzamide·6-(3_ Bismuthoxy-phenyl)-8-(2-fluoro+tris-methyl)-7-methyl-2,3-dihydroindenyl[3,2_a]0 is more than _5, soil Benzene 3-cracked basal winter (3·difluorodecyloxy·2_gas-phenyl (7) core: benzyl)-7-methyl-2,3-dihydro 3,2-a]D than bite phase - Fluorine-3 - Stupid carbaryl · 6_(3_Ethoxy_2_gas_stupyl)·8_(2_"·Triphenylsulfonyl)-7-A Base-2,3-dihydro-thiazolo[3,2 pyridine _5, 3- 曱醢 曱醢 _6-(4-gas-2?;; ϊί·ί4Γΐ, ΐΒΒ &gt;., chaos 2 , 2- 讥-本Π, 3] dioxo (tetra)-gas saponin methyl _ phenylmethyl) _7Wnt [3,2-ap than bite-5-keto 3-cupidyl- 6-(2-fluoro· 4-phenyloxy_phenyl)_8_(2_fluoro.6•trifluoromethyl_#phenylhydrazino)-7-fluorenyl-2,3-dihydro-thiazolo[3,2-a]pyridine -5-keto 3-indoleyl-6-(2-fluoro_3_isopropoxy-phenyl)_8_(2_gas_6•tris-methyl-benzyl)-7-fluorenyl -2,3-dihydro-oxazole[3,2_a]pyridine_5•ketone 6-[3-(1,1-diI-ethyl)_2_fluoro_styl]_8_(2•fluorine Trifluoromethyl·alum-based)-3-(hydroxyimino-phenylindenyl)·7-methyl-2,3-dihydro-thiazolo[3,2_a]0 ratio bite-5 -keto 6-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)hydroxylamino-methyl]_8-(2-fluoro-6-trifluoro Methyl-benzyl)_7-methyl·2,3·dihydro-thiazolo[3,2_a] ° ratio to 5-ketone

S 152524.doc •103· 201130854 6-(2-Fluoro-3-methoxyphenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl)_3_(imine-based Benz-3-yl-methyl)-7-methyl-2,3-dihydro-sinter β sits and [3,2_a]nj^ bites-5-嗣6-(2-fluoro-3-indolyloxy -phenyl)-8-(2-1-6-trifluoromethyl-benzyl)_3_(imido-o-phenylphenyl-fluorenyl)-7-mercapto-2,3-dihydro -thiazolo[3,2_a]e than bite-5-嗣

6-(2-Fluoro-3-indolyl phenyl)-8-(2-fluoro-6-trimethoxymethyl-benzoinyl)_3_(imine-m-phenyl-methyl) -7-Methyl-2,3-dihydro-thiazolo[3,2_a]nfc 盐-5- Brewing I 3-[(2-mur-phenyl)-imido-methyl]-6- (2-Oxo-3-indolyl phenyl(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl-2,3-dihydro- η 塞. Sit and [3 2 -a] 0 than bite-5-keto 3-[(2,5-disorgano-phenyl)-imidomethyl]-6-(2-aluminum-3-methoxy-phenyl) 8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-[(2 ,3-difluoro-phenyl)-hydroxyimino-f-yl]_6_(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-alum Base)_7_methyl-2,3_dihydro-thiazolo[3,2-a]° ratio bit-5-keto 3-[(2-chloro-3-fluoro-phenyl)-imine Base]_6_(2·gas_3_methoxyphenyl)-8-(2-fluoro-6-trimethoxymethyl-phenylmethyl)_7-methyl·2,3-dihydro-carbazole And [3,2-a]β ratio bite-5-b-6-(2-fluoro-3-methoxyphenyl)_8_(2_fluoro_6•trifluoromethylbenzyl)_3 Imino-(5·methyl·嗟 ··2_yl)·methyl]_7_f-based...· 二气嗟峻和[3,2-a]^h bite-5· Same as 152524.doc •104- 201130854 6-(5-fluoro-2,3-dihydro-benzopyrene, 4]dioxanylene)·8_(2κ trifluoromethyl-benzyl) -3-(f-Ominoimido-phenyl.methyl)7.methyl-23 Dihydro-thiaxo[3,2-a]efc^-5-_trifluoromethyl-benzyl) _3_Dihydro-thiazolo[3,2-a]pyridin-6-(2-fluoro-3-isopropoxy-phenyl(methoxyimino-phenyl-methyl)-7-fyl·2, 3-0 fixed -5 - _

6-(2-Fluoro-3-difluoromethoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)- fluorenylmethoxyimido-phenyl-methyl)- 7-Methyl-2,3_n-Salt[3,2•狂] D-bite-5-keto 6-[3-(1,1-di-1ethyl)_2_fluoro_phenyl]_8_(2_ Gas_6_trisyl-yl-phenylmethyl)-3-(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a] n ratio. D--5-keto 6_(2_fluoro_4.methoxy-phenyl)_8_(2_?6-trifluoromethylbenzyl) 1(methoxyimino-phenyl-methyl)_7 _Methyl-2,3. Digas-嗟唆[3,2_小比咬_ 5-keto 3_[(2-fluoro-phenyl)_methoxyimido]methyl]_6_(2_ Fluorine_3_trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-72.0-methyl-2,3-dihydro-serazolo[3, 2-a]. Bite-5-form 8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_6_(3-hydroxyl-phenyl)_3_(methoxyimino-phenyl-f Base)-7-f-based 2,3·dihydro-indenyl[3,2♦ than biting·5-keto 6-(3-ethoxy-2-fluoro-phenyl)_8_(2_fluorine _6_三敦 methyl benzyl w (methoxyimino phenyl-methyl) _7_methyl _2 &gt; dihydro _ _ [3, 2 external ratio bite · fluoromethyl - benzo Base)_3_(methyl 6-(3-difluoromethoxyphenyl)_8_(2_fluoro_6三152524.doc -105- 201130854 .Ominoimido-styl-fluorenyl)_7-methyl _2,3_digas(tetra) and [3,2 a]e ratio bite_ 5-ketone 6-(4-fluoro-2'2-mono-2-benzo[μ]dioxol-5- Base)_8_(2 gas_6-trifluoroindolyl-stupylmethyl)·3_(nonoxyiminophenylindenyl) 7-mercapto- 2,3-dihydro-anthracene [3,2- Ap than bite 5-ketone 6-(2- Fluoro-4-phenoxy-phenyl)_8_(2_fluoro.6-trifluoromethyl·benzyl}(methoxyimino-p-styl-fluorenyl)-7-indenyl-2,3 ·Two gas sputum and [32a] 〇 bite · 5-ketone 6-(2-fluoro-3-methoxy-phenyl)_3_[(2·fluoro-phenyl)methoxyimino]methyl ]_ 8-(2-Fluoro-6-trifluoromethyl-benzyl)_7-methyl-2,3-dihydro-salzolo[3,2_a]° ratio bite-5-嗣3- [(3'5-Difluoro-phenyl)-methoxyimino]methyl]_6_(2_fluoro_3_methoxy-benzene

-8-(2-Fluoro-6·trifluoromethyl-benzoinyl)_7-fluorenyl-2,3-dihydro-thiazolo[3,2 - a ]pyrene ratio bite _ - 5 - I 6-(3-difluoromethoxy-2|phenyl)_8_(2_fluoro-6-trifluoromethyl-benzoinyl 3-(methoxyimino-phenyl·methyl)_7 _Methyl-2,3_dihydro-salt and [3,2_a] 0 ratio bite-5 - _ ό-(2-fluoro-3-isopropoxy-phenyl)_8_(2_fluoro_6_ Trifluoromethyl benzyl) 3 · (methoxyimino-phenyl fluorenyl)-7-fluorenyl 2,3-dihydro-carbazole [3,2_small ratio sigma-5 -嗣{3R-[3a(R*)]}-3-(Amino-phenyl-fluorenyl)_6·(2·Fluoryl-3-isopropoxyphenyl)-8-(2-Fluoro-6 -trifluoromethyl-phenylhydrazino)·7-methyl-2,3 dihydrothiazolo[3,2-a]. Bite-5-_ {3S-[3a(R*)]}-3 -(Amino-stupyl-methyl)_6_(2_Fluoro-3 isopropoxy-benzene 152524.doc •106·201130854)-8-(2-Fluoro-6-trifluoromethyl-benzene Base)-7_mercapto-2 3 dihydrothiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl·methyl) _6_(2_Fluor_3·isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl·phenylindenyl)-7-methyl-2,3-dihydro-thiazolo[3 ,2-a]pyridine-5-one {3S-[3cc(S*)]}-3-(amino-phenyl-indenyl)_6·(2• _3 • isopropoxybenzene

8-(2-fluoro-6-trifluoromethyl)-phenylmethyl-7-mercapto-2 3-dihydrothiazolo[3,2-a]pyridin-5-one 3-( Amino-phenyl-indenyl-6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-adenyl)-7-indolyl-2, 3-Dihydro-thiazolo[3,2_a]pyridine-5-keto 3-[Amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3.trifluoromethoxy - stupid base) (2-fluoro-6.trifluoromethyl-adolino)_7-methyl-2,3.dihydro-thiazolo[3,2_a]. Specific bite-5-keto[3a(R*)]-3-(amino-phenyl-methyl)_8_(2_fluoro_6•trifluoromethyl-benzoinyl)_ 6-(3·hydroxyl -phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2_a]pyridone [3a(S*)]-3-(amino-styl-methyl)_8_(2_ Fluorine_6-trifluoromethylphenylhydrazino)-6-(3-hydroxy-phenyl)-7-methyl-2,3.dihydro-thiazolo[3,2_a]pyridine_5-ketone {3R- [3a(R*)]}-3-(Amino-phenyl-methyl)·6_(3-difluoromethoxyphenyl)-8-(2-fluoro-6-trifluoromethyl-benzene曱7)_7_methyl_2,3_dihydro-thiazolo[3,2-a]nb sigma-5-one {3 3-[3〇1(11*)]}-3-(amine Base-stupyl-mercapto)_6_(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)·7-methyl_2,3_ Dihydro-thiazolo[3,2-a]e ratio bite-5-嗣{3R-[3a(S*)]}-3-(amino-phenyl-methyl)6 (3 difluoroantimony) Base benzene 152524.doc •107· 201130854 base)8 (2 gas·6-trifluoromethyl·phenylmethyl)_7_methyl-2,3-H salino[3,2-decidine Open! (2[Fluor)]M_(Aminophenyl-methyl)_6々m-phenyl)· 8-(2-Fluoro-6-difluorol | # a]pyridine-5·_ ... Dihydro-thiazolo[3,2_{3R-[3〇c(R*)]M_(aminophenyl)indolyl fluoride·2, (10) Dioxacyclononene _5-yl) fluorinated winter trifluoromethyl_benzyl 7-methyl-2,3·dihydro-thiazolo[3,2_a]pyridine·, ketone earth i3S_[3a (R*)]}_3-(Amino-phenyl-methyl)-6-(4-fluoro-2,2-difluorene-benzopyrene, 3]dioxo-like 5•yl)_8_ (2 preparation 6_trifluoromethyl benzyl) 7-methyl 2,3-dihydro-thiazolo[3,2-a]pyridine_5_alumina {3R_[3a(S*)卜3·(Amino-phenyl-methyl)-6-(4-fluoro_2,2_digas_benzo(10)dioxanthene·(4) o-pre-trifluorodecyl-benzene Methyl)_7_methyl·2,3-dihydro-thiazolo[Ha]pyridine_5-ketone {3S-[3a(S*)]}_3•(amino-phenyl-methyl)6 (4 _22_ digas benzo[1,3] dioxolane _5_yl)_8_(2_form winter trifluoromethyl·phenylmethyl)_ 7_methyl·2, 3-Dihydro-thiazolo[3,2_a]pyridine-5-one {3R-[3a(R*)]}_3_(amino-phenylmethyl)6 (3·ethoxy 1 gas-phenyl -8-(2-Fluoro-6·trifluoromethyl-phenylf-yl)_7-methyl-2,3-dihydro--oxazolo[3,2-a]pyridine-5-branched | {3S- [3a(R*)]M•(Amino-phenyl-methyl)·6 (3·ethoxyfluorophenyl)-8-(2-fluorotrifluoromethyl-phenylmethyl)_7methyl _2,3·Dihydrothiazole [3,2-a]pyridine-5·one {3R- [3a(S*)]}_3_(Amino-phenyl-indenyl)_M3ethoxyl|Gas benzene 152524.doc •108- 201130854 Base)-8-(2-Fluoro-6-trifluorodecyl- Alum-based)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-stupid Base-fluorenyl)·6·(3_ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl_2,3· Dihydrothiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-indenyl)-6-(2-fluoro-4-phenoxy-phenyl)-8-( 2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2_a]pyridine_5-ketone φ {3R-[3a(R*) ]3_[Amino-(2-fluoro-phenyl)-fluorenyl]-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl) -phenylhydrazino)_7_methyl-2,3_dihydro-thiazide-[3,2-a]ntb 唆-5-one {3S-[3ot(R*)]}-3-[amine -(2-Fluoro-phenyl)-indenyl]_6_(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-yl _2,3_Dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-[Amino-(2-fluoro-phenyl)_- Base]_6_(2_fluoro_3.methoxy-styl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thia °Sit and [3,2-a]° Bite 5-ketone {3S-[3cx(S*)]}-3-[amino-(2-fluoro-phenyl)-methyl]_6·(2 fluoro_3 decyloxy-phenyl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-[Amino- (3,5-diphenyl)-methyl]_6_(2_fluoro_3 methoxyphenyl (2-fluoro-6-trifluorof-phenyl)-7-fyl 2,3 _ Dihydro·嗟σ sits and [3,2_a] 0 is more than 5-ketone [3a(R*)]-3-(amino-thiophen-3-yl-methyl)·6·(2_fluorine ·3_Methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_7•methyl-2,3_dihydro-thiazole 152524.doc . j〇9 201130854 [3,2-&amp;]11 than bite-5-keto[3a(S*)]-3-(amino-thiophen-3-yl-methyl)-6-(2-fluoro-3- Methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) adenyl-7-methyl-2,3-dihydro-thiazolo[3,2-a]D ratio Bite-5-keto[3a(R*)]-3-(Amino-o-phenylphenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2- Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a]e is more than keto-5-one [3a(S*)]- 3-(Amino-o-phenylphenyl-fluorenyl)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl) -7-methyl-2,3-dihydro-thiazole [3,2-a]n ratio bit-5-keto[3a(R*)]-3-(amino-m-tolyl-fluorenyl)-6-(2-fluoro-3-methoxy-benzene 8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]0 than bite-5-one [3a(S*)]-3-(Amino-m-phenylphenyl-fluorenyl)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-three Fluorinyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-sigma-5-one [3a(R*)]-3-[amino-(2 -chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7- -2,3-dihydro-thiazolo[3,2 - a ]π ratio - 5 -嗣[3a(S*)]-3-[amino-(2-chloro-phenyl)-methyl] -6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-mercapto-2,3-dihydro-thiazole And [3,2-a]pyridin-5-one [3a(R*)]-3-[amino-(3-chloro-phenyl)-methyl]-6-(2-fluoro-3-methyl Oxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-adenyl)-7-mercapto-2,3-dihydro-thiazolidine 152524.doc -110- 201130854 [3, 2-a]°it bite-5-keto[3a(S*)]-3-[amino-(3-a-phenyl)-indenyl]-6-(2-fluoro-3-methoxy -phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro- Imidazo[3,2-a]° ratio bit-5-keto[3cx(R*)]-3-[amino-(2,5-difluoro-phenyl)-fluorenyl]-6-(2 -Fluoro-3-indolyl-phenyl)-8-(2-dis-6-disorganomethyl-phenylmethyl)-7-mercapto-2,3-di-mouse-α stopper. Sit and [3,2-a]D than bite-5-keto^[3ot(S*)]-3-[amino-(2,5-difluoro-phenyl)-indenyl]-6-( 2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydro-thiazolo[3, 2-&amp;]° ratio bit-5-keto[3a(R*)]-3-[amino-(2,3-difluoro-phenyl)-fluorenyl]-6-(2-fluoro-3 -decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-adolino)-7-mercapto-2,3-dihydro-thiazolo[3,2-&amp;] ° ratio of 5-ketone [3a(S*)]-3-[amino-(2,3-difluoro-phenyl)methyl]-6-(2-fluoro-3-methoxy- Phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazole_[3,2-a]D ratio bite-5 -ketone [3a(R*)]-3-[amino-(2-a-3-fluoro-phenyl)-indolyl]-6-(2-fluoro-3-methoxy-phenyl)- 8-(2-Fluoro-6-difluoromethyl-benzoinyl)-7-methyl-2,3-diaza-σ. Sit and [3,2-&amp;]° than bite 5-keto) [3a(S*)]-3-[Amino-(2-a-3-fluoro-phenyl)-indenyl]-6 -(2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-indolyl-2,3-di-mouse-sigh. Sit and [3.,2-a]° bite 5-keto [3a(R*)]-3-[amino-(5-fluorenyl-thiazol-2-yl)-methyl]-6- (2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indenyl-2,3-dihydro- 152524.doc - 111 - 201130854 嗟0 sit and [3,2-a]e than bite-5-嗣[3α(δ*)]-3·[Amino-(5-methyl-嗟 嗟 -2--2-yl)-A Base]·6_(2|3·methoxy-phenyl)·8·(2-fluoro·6·trifluoromethyl-benzyl)-7-fluorenyl·2,3 dihydroindole° 3,2-a]° than bite-5-keto[3a(R*)]-3-[amino-(5_gas-porphin-2-yl)indenyl]6(2 gas_3 methoxy Base-phenyl)-8_(2·gas·6·trifluoromethyl-phenylmethyl)_7 methylhydrazine·dihydro-indole 0 sits and [3,2-a]&quot;bits 5-ketone [3ot(S*)]-3·[Amino-(5_gas "cephen-2-yl)-methyl] winter (2 defeated _3 methoxy-phenyl)-8-(2-fluoro -6-trifluoromethyl-benzyl)_7_fluorenyl-2,3_dihydro-thiazolidine[3,2-a]° ratio biting 5-keto 3-(amino-phenyl) -Methyl)_6·(3·Difluorodecyloxy_2_say_stupyl)_8_(2_gas_6-trifluorodecyl·benzoyl)-7-fluorenyl_2,3_2 Hydrogen_thiazolo[3 2_a]pyridine_ 5-keto{3R-[3a(R*)]}-3-(amino-phenyl·methyl)_6_(2fluoro-3-isopropoxyphenyl) -8-(2-fluoro-6 -trifluoromethyl-stupylmethyl)_7•mercapto-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3 -(Amino-phenyl-methyl)_6_(2_fluoro_3_isopropoxyphenyl)-8-(2-fluoro-6.trifluoromethyl-benzoinyl;)_7-methyl _2,3_Dihydro-oxazole[3,2-a]^b Bite-5-one {3R-[3tx(S*)]}-3-(Amino-phenyl-indenyl)_6_ (2_Fluoro_3•isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)·7-methyl·2,3-dihydro-» And [3,2 - a ]σ ratio bite-5 - reward {3S-[3a(S*)]}-3-(amino-stupyl-fluorenyl)-6-(2-like-3-iso Propoxy-styl)-8-(2-fluoro&lt;-6-trifluoromethyl-adenyl)·7·decyl·2,3·dihydro- um. Sit and 152524.doc -112 - 201130854 [3,2-a]° 唆-5-ketone {3 R-[3a(R*)]}-3-(Amino-phenyl-fluorenyl)-8_(2·Fluoro-6- Trifluoromethyl-benzyl)-6-broken-2,2,7-trimethyl-2,3-dihydro-indole-[3,2-a]° than bite-5-one {3S -[3a(R*)]}-3-(Amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-indole-2,2, 7-tridecyl-2,3-dihydro-indole and [3,2-a]° ratio bit-5-keto {3R-[3oc(S*)]}-3-(aminophenyl) Methyl)-8-(2-fluoro-6·trifluoromethyl-benzoinyl)_6· Fill in-2,2,7-trisyl-2,3_dihydro·sigh and sit [3,2_a]n than bite_5_ketone • (3S_[3a(Ss|!)]}-3_( Amino-phenyl-indenyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-moth-2,2,7-trimercapto-2,3-dihydro- Squat and [3,24]» than bite-5-_amino-phenyl-methyl-difluoro-ethyl)-phenyl]_ 8-(2-fluoro-6-trifluoromethyl- Benzoyl)-7-mercapto-2,3-dihydro-thiazolo[3,2- a] ° than bite-5-one _[3a(S*)]-3-(amino-phenyl - mercapto-difluoro-ethyl)-phenyl]- 8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-mercapto-2,3-dihydro-thiazolo[3, 2- a] ° than 唆-5-ming

• {3R-[3a(R*)]}_3-(Amino-phenyl-indenyl)-6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxole Hexene-6-yl)-8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-2,3-dihydrogen. Sit and [3,2 -a]0 than bite -5-stuffed J {3S-[3ot(R*)]}-3-(amino-stupyl-methyl)_6_(5_ fluoro_2 3_2 Hydrobenzo[1,4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl- adenyl)-7-methyl-2,3-dihydrogen. Sit and [3,2-巳]° bite-5-_ {3R-[3a(S*)]}-3-(amino-phenyl-fluorenyl)_6_(5_fluoro_2,3_ Dihydro-p-benzo[1,4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzylmethyl-2,3_dihydro-sigh Spit and [3,2-a]° than bite-5-class 152524.doc •113- 201130854 〇S_[3〇t(S*)]}_3_(amino-phenyl-methyl)-6-( 5-fluoro-2,3-dihydro-benzo[1,4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7_ Mercapto·2,3-dihydro-deuterium sputum and [3,2-a]n ratio bit-5-keto 3-(amino-phenyl-methyl)-6-(2-fluoro-3 -trifluoromethoxy-phenyl)-8-(2-fluoro-6-difluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a Pyridine_ 5-ketone [3oc(R*)]-3-(amino-phenyl.methyl)-643-0 difluoro-ethyl)_2-fluoro-phenyl]-8-(2-fluoro -6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydrothiazolo[3,2-a]pyridin-5-one [3oc(S*)]-3·(amine -Phenyl-methyl)difluoro-ethyl)_2-fluorophenyl]-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-fluorenyl-2,3-dihydrogen _thiazolo[3,2-a]pyridin-5-one 6-(3-acetamido-2-fluoro-phenyl)-3-(amino-phenyl-indenyl)_8_(2-fluoro- 6-trifluoromethyl -benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)_6_(2·fluoro- 5_Trifluoromethoxy-phenyl)_8_(2_fluoro.6-difluoromethyl-benzoinyl)_7-fluorenyl·2,3-dihydro-thiazolo[3,2-a]pyridine _ 5-keto 3-(amino-phenyl-fluorenyl)_8_(2-fluoro-6-trifluoromethyl-m-methyl)·6·(6•methoxy-4-methyl-pyridine· 3_yl)_7_methyl-2,3_dihydro-thiazolo[3,2_a]pyridine· 5-keto 3-(amino-phenyl-methyl)_6_(2_fluoro_4_trifluoro Oxyloxyphenyl)8(2fluoro-6-trifluoromethyl-benzyl)·7-fluorenyl·2,3·dihydro-thiazolo[3,2a]pyridine·5-one 3-(( Amino-phenyl-indenyl-8-(2-fluoro-6-trifluoromethyl-stanomethyl)6(3-methoxy 152524.doc •114-201130854 phenyl-phenyl)-7-f- 2,3-Dihydro-thiazolo[3,2_a]pyridine-5-one 3-(amino-phenyl-methyl)_6_(2_fluoro·3_methoxyphenyl)_8_(2 gas winter Trifluoromethyl-benzyl)-7-methyl-2,3.dihydro-thiazolo[3,2_a]pyridine-5-one [3cx(R*)]-3-(amino-phenyl -Methyl)_6_(2_Gas_3曱oxyphenyl)·8_(2-Fluoro-6·trifluoromethyl-benzoinyl)·2,2,7-trimethyl_2,3_ Dihydrothiazolo[3,2-a]n ratio唆_5_ketone [3〇c(S*)]-3-(amino-phenyl·methyl)_6_(2_fluoro_3_methoxyphenyl)8(2_ • Fluorine_6_3 Fluoromethyl-benzyl)-2,2,7-tridecyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [30^))-3-(amine Phenyl-methyl)6(5 gas_2 3_dihydrobenzo(1)4]dioxe-6-yl)-8-(2-fluorotrifluoromethyl-benzoyl)_2, 2,7_三曱基-2,3 -一气-叹°[3,2-&amp;]° than bite _5-ketone [3〇c(S*)]-3-(aminophenyl) -曱基卜卜^"Dihydro-benzo(1)# oxacyclohexene-6-yl)-8-(2-fluoro-6-trifluorodecyl-phenylmethyl)_2,2,7_ Tridecyl·2,3·dihydro-thiazolo[3,2_a]pyridine_5-keto_[3a(R*)]_3_(aminophenyl-fluorenyl)-6-(2-fluoro-3 -trifluoromethoxyphenyl)_ 8-(2-fluoro-6-trifluorodecyl-adenyl)_2,2,7·trisyl 2,3-dihydro-thiazolo[3, 2-a]a than bite-5-keto[3a(S*)]-3-(amino-phenyl.methylfluorobutanyloxy- benzoic acid 8·(2-fluoro_6_three Fluoromethyl·mute methyl)_2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]^b bite-5-鲷3-(amino-phenyl- Methyl)-6_(2_fluoro-phenyl)|(2•Fluoro-trifluoromethyl-adenyl)-2,2,7-trimethyl-2,3-dihydro-thiazole And [3,2_a] pyridinone ketone 3·(amino-phenyl-methyl)-6_(2_fluoro_5·decyloxy_phenyl)_8_(2_fluoro_6_three 152524.doc -115- 201130854 gas methyl-benzyl)-2,2,7-trimethyl·2,3_dihydro-oxazolo[3,2_biting_ 5-ketone[3a(R*) ]-3-(Amino-styl-fluorenyl)_6_[3-(11-difluoroethyl) 2 gas phenyl]-8-(2-fluoro-6-trifluoromethyl-adenyl) · 2,2,7·trimethyl-2,3 dihydro-thiazolidine and [3,2-a] ° ratio biting 5-keto [3ot(S*)]-3-(amino-benzene Base-methyl)_6_[3_(11-difluoroethyl) 2 gas phenyl]-8-(2-fluoro-6-trifluoromethyl-adenyl)_2,2,7-tridecyl _ 2,3_Dihydro-thio. Sit and [3,2-a]° bite 5--5-ketoamine-phenyl-mercaptodifluoroethyl)phenyl]- 8-(2-fluoro-6-trifluoromethyl-paraben Base)_2,2,7-trimethyl-2,3-dihydrothiazolo[3,2-a]° ratio bite 5--[3a(S*)]-3-(amino-phenyl -mercaptofluoroethyl)phenyl]· 8-(2-fluoro-6·trifluoromethyl-benzyl)_2,2,7-tridecyl-2-, diahydrothiazolo[3,2- a ] ° ratio - 5 -copper {3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)_8_(2-fluoro_6- Trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-indole-[3 2- 3]° ratio. --Methylamino)-ethoxy]-acetic acid methyl ketone {3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl) )·8_(2_Fluoro-6-trifluorodecyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5Η-thiazolo[3,2- a]&quot;咬-3-yl]-phenyl-methyl}•Amino)-ethoxy]-acetic acid A series {3R-[3a(S*)]}-[2-({[6-(2- Fluoro-3_methoxy-phenyl)_8_(2·fluoro·6_triformyl-methyl)·7·methyl-5-sideoxy-2,3-dihydro-5 H-&quot ; stopper n sit and [3,2· a]&quot; than 唆-3-yl]-phenyl-methyl}•amino)_ethoxy]-acetic acid methyl ester {3S-[3a(S*) ]} -[2-({[6-(2-fluoro-3-methoxy-phenyl)-8_(2·fluoro_6•3 152524.doc -116- 201130854 fluoromethyl-benzyl)-7 -Methyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]&quot;bipyridin-3-yl]-phenyl-methyl}•amino)-B Oxy]-methyl acetate 6-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-) 5-O-oxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-indenyl}-amino)-hexanoic acid methyl ester 6- ({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy- 2,3-Dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenylindolyl}-amino)-hexanoic acid decylamine 4_({[6-(2-fluoro) 3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)-7-methyl-5-oxo-2,3-dihydro-5H- Thiazolo[3,2-a]pyridin-3-yl]-phenyl-indenyl}-amino)-3-hydroxy-butyric acid ethyl ester 2-tert-butoxycarbonylamino-4-({ [6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-sideoxy-2, 3-Dihydro-5 H-. Terzolo[3,2-a]pyridine-3-yl]-phenyl-methyl}-amino)-butyric acid tert-butyl 4-({[6-(2-fluoro-3-methoxy) -Phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-yloxy-2,3-dihydro-5H-thiazolo[3, 2-a]°Bite-3-yl]-phenyl-fluorenyl}•Amino)-Ding guess {3R-[3a(R*)]}-4-({[6-(4-Fluoro- Benzo[u]m-dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)&gt;7-mercapto_5_sideoxy-2,3 _Dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl-amino)butyronitrile {3S-[3tx(R*)]}-4-({ [6-(4-Fluoro-benzo[u]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl·5_ Sideoxy 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-styl-methyl}-amino)-butyronitrile {3Μ3α(δ*)]} ·4·(Π6-(4-fluoro-benzo[iso]dioxol_5_ 152524.doc •117· 201130854)-8-(2-fluoro-6-trifluorodecyl-benzene Sulfhydryl)_7•methyl_5_sideoxy·2,3-dihydro-5Η-thiazolo[3,2-a]acridin-3-yl]-phenylmethylammonyl)_ Butyronitrile {3S-[3ot(S*)]}-4-({[6-(4-fluoro-benzo[13]dioxol-5-yl)-8-(2-fluoro- 6-trifluoro曱基-曱曱基)_7·methyl·5_sideoxy·2,3·dihydro-5Η-thiazolo[3,2-a]acridine-3_yl]_stupyl·曱基卜Amino)-butyronitrile 4-({[8-(2-fluoro-6-difluoroindolyl- cumyl)_6_(3-methoxy-phenyl)-7-indolyl-5-sideoxy -2,3-dihydro-5H-thiazolo[3,2-a.]n-pyridyl_3_yl]-stylyl-fluorenyl}-amino)-butyric acid ethyl ester 4-({[6 -(2-fluoro-4-methoxy-styl)-8-(2-fluoro-6-trifluoromethyl-benzyl 7-methyl-oxo-2,3-dihydro-5H- Thiazolo[3,2_a]acridine_3_yl]-phenyl-indenyl}-amino)-butyric acid ethyl 4-({[6-(3-ethylindenyl-2-fluoro-phenyl) -8-(2-Fluoro-6-trifluoromethyl-adenyl)-7-methyl-5-yloxy-2,3-dihydro-5H-branches [3,2-a ] 〇 咬 -3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester 4-({[6-(2-fluoro-5-trifluoromethoxy-phenyl)-8) -(2-Fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5 H-0. Sit and [3,2-a 〇 _ _3_ yl]-phenyl-fluorenyl}-amino)-butyric acid B g {3R-[3a(R*)]}-4-({[6-(2-fluoro-3) -isopropoxy-phenyl)-8·(2·fluoro-6-trifluoromethyl-benzoyl)-7-fluorenyl-5-sideoxy-2,3-dihydro-5 Η-嗟η sit and [3,2-a] &quot;Bistidin-3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester {3S-[3cc(R*)]}-4-({[6-(2-fluoro-3) -isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)-7-methyl-5-oxo-2,3-dihydro-5H.thiazole [3,2-a]Dfcb^-3-yl]-phenyl-methyl}-amino)-butyric acid B. {3R-[3a(S*)]}-4-({[6- (2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro_6· • 118- 152524.doc 201130854 trifluoromethyl-benzyl)-7-fluorenyl-5-side Oxyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl-amino)-butyric acid ethyl ester {3S-[3a(S* )]]-4-({[6-(2·fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-Phenoxy-2,3-dihydro-5H-thiazolo[3,2-a]0-pyridin-3-yl]-phenyl-methyl-amino)-butyric acid ethyl ester {3R_[ 3a(R*)]}-[2-({[6_(2_fluoro_3_isopropoxy-phenyl)_8_(2_fluoro_6_trifluoromethyl-benzyl)-7-fluorenyl- 5-Phenoxy-2,3-dihydro-5H-thiazolo[3,2-a]indolepyridin-3-yl]-phenyl-fluorenyl}-amino)-ethoxy]-acetic acid Ethyl {35-[3α(Ι^)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) Base benzyl)·7-mercapto-5- Sideoxy-2,3-dihydro-5H-thiazolo[3,2-a].乙-3-yl]-phenyl-methyl}•amino)·ethoxy]-ethyl acetate {3R43a(S*)]}-[2-({[6-(2-fluoro-3) -isopropoxy-phenyl)-8-(2-fluoro-6-triptanyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazole And [3,2-a]»Bit-3-yl]-phenyl-decylamino)-ethoxy]-ethyl acetate {3S-[3a(S*)]}-[2-( {[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-sideoxy- 2,3-Dihydro-5H-thiazolo[3,2-a].Bis-3-yl]-phenyl-decylamino)-ethoxy bromide 4-({[6- (2-Fluoro-3-isopropoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl·5-sideoxy-2,3-dihydro -5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl-amido)-butyronitrile 4-({(2-fluoro-phenyl)_[6_(2_fluoro) _3_Trifluoromethoxyphenyl)_8 (2-fluoro-6-trifluoroindolyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5indole-thiazole And [3,2-a]° ratio -3-yl]-mercaptoamino)-butyronitrile 4_({[6-(2-fluoro-4-trifluorodecyloxy-phenyl)_8_(2 _Fluor_6•trifluoromethyl_benzoquinone 152524.doc -119· 201130854 base)-7-fluorenyl-5-sideoxy-2,3-dihydro-5 Η- Salivation of [3,2-a]0 to butyl-3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester 4_({[6-(2-fluoro·3·decyloxy)- Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)_ 2.2.7-trimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3 ,2-a]pyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid ethyl ester 4-({[6-(2-fluoro-3-trifluorodecyloxy-phenyl)) 8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-2,2,7-trimethyl-5-oxo-2,3-dihydro-5H-indole 3,2-a]0 is more than -3-yl]-styl-methyl}-amino)-butyric acid, 4-({[6-(2-fluoro-phenyl)-8-(2- Fluoro-6-trifluoromethyl-benzyl)-2,2,7-trimethyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]acridine -3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester 4·({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-) 6-trimethylmethyl-benzyl)_ 2.2.7-trimethyl_5_sideoxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine_3_yl]- Phenyl-fluorenyl}-amino)-butyric acid ethyl ester [2-({[6-[3-(1,1-difluoro-ethyl)-2-fluoro-phenyl]-8-(2 -fluoro-6-tris-methyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl ]-phenyl-mercapto}-amino)-ethoxy --Acetylacetate 4-({[6-[3-(1,1-difluoroethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl) Methyl)-7_fluorenyl_5_sideoxy-2,3-dihydro-5H-singing 0 sits and [3,2-a]0 is bite 3-yl]-phenyl-methyl b Amino)-butyric acid ethyl ester [2-({[6·[3-(1,1-difluoro-ethyl)-phenyl]-8·(2-fluoro-6-trifluorodecyl)benzene Methyl)-7-fluorenyl-5-sideoxy-2,3-dihydro-5Η-thiazolo[3,2-a]pyroxyl_3_yl]•phenyl-indenyl}-amino) -ethoxy]-acetic acid oxime 4·({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-milo-6-trifluoromethyl-adenyl)· 152524.doc •120- 201130854 7-Methyl-5-oxooxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]phenyl-methyl}-amine Ethyl butyrate {3R-[3a(R*)]}_4-({[6-(3-difluoromethoxyphenyl)-8-(2_fluoro-6·trifluoromethyl-) Benzomethyl)-7-methyl-5-o-oxo-2,3-dihydro-5-and-[3,2-a]thalylene-3-yl]-phenyl-methyl}-amino )-ethyl butyrate {3S-[3cx(R*)]}_4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) - Benthyl)-7-mercapto-5-sideoxy-2,3-dihydro-5 H-° plug. Sit and [3,2-a] ° pyridine]-phenyl-methyl}-amino)-butyric acid ethyl ester {3R-[3cx(S*)]}-4-({[6-( 3-difluorodecyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H -thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester {3S-[3a(S*)]}-4_({[6- (3-difluorodecyloxy-phenyl)-8-(2-fluoro-6-trifluoroindolylbenzoyl)-7-methyl-5-oxo-2,3-dihydro- 5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methylamino)-butyric acid ethyl ester {3R-[3a(R*)]}-[2-({ [ 6-(3-dimethoxymethoxy-phenyl)-8-(2-gas_6·trismethylmethyl-bensyl)_7-methyl-5-sideoxy-2,3-dichloride -5H-嗟 并 and [3,2_ ap-pyridin-3-yl]-phenyl-methyl-amino)-ethoxy]-ethyl acetate {3S-[3a(R*)]}-[ 2-({[6-(3-difluorodecyloxy-phenyl)-8-(2ϋ-tris---methyl-methyl)-7-methyl-5-oxo- 2,3-diazo - 5Η-0 stopper. Sit and [3,2_ a]&quot;bipyridin-3-yl]-phenyl-methyl-aminomethyl)-ethoxy]-ethyl acetate {3R-[3ot(S* )]-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6_trimethylmethyl)methyl-7-methyl-5- Side oxy - 2,3 - two Nitrogen - 5H - ° plug σ sit and [3 2. a] acridine-3-ylphenyl-methyl-aminoethyloxy]-ethyl acetate {3S-[3a(S*)]}- [2-({[6-(3-Difluoromethoxy)phenyl)-8-(2-fluorotris 152524.doc -121- 201130854 fluoromethyl-benzyl)-7-methyl_5 - sideoxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methylindole-amino)·ethoxy]-ethyl acetate{ 3Κ-[3α(Ι^)]Μ·({[6-(4-fluoro-benzo[u]-dioxol-5(yl))-8-(2-fluoro-6-trifluoro) Methyl-benzyl)_7_methyl_5_sideoxy-2,3_dihydro-5H-selling [3,2♦pyridyl_3_yl]-phenylindolylamine Base)_ethyl butyrate {3S-[3a(R*)]M-({[6-(4-fluoro-benzo π,3]=oxirane _5_yl)-8_(2 ·Fluorine_6·trifluoromethyl_alum-based)1methyl·5_sideoxy 2,3-dichloro·5Η·嗟 并[3,2_ pyridine:3_yl]-benzene Ethyl methylaminobutyric acid ethyl ester {31^30^) 14.-(4.Fluorobenzo[13]dioxol-5-yl)-8-(2-offual trifluoroethylene Methyl·stupylmethyl)_7_methyl$lateral oxime% dihydro-5H-sold out and [3,2-ap ratio bite_3_美1 incineration field j violence]-benyl-methyl }•Amino)-ethyl butyrate {3S_[3a(S*)]M_({[6-(4- Fluoro-benzopyrene, 3]dioxol-5 base)_8-(2-fluorofluorotrifluoromethyl-stanomethyl)-7-methyl-5-sideoxy-2 3 nitrogen- 5...and [3,2-a]... base]_stupyl_methyl-ammonyl), butyl: ethyl vinegar ^ Η2·({[6·(4· gas·benzo[丨,3]) Oxacyclopentanyl 5 yl) _8_(2_fluorodongtrifluoromethyl _ phenylmethyl) _7_methyl _5 · pendant oxy group - hydrogen-5H-嗟4 and [3,2-a] (tetra) _3_ ]]•Phenyl hydrazide, thio]-acetate, ethoxylate

' 5 J {3S-[3a(R*)]H2-(1) 6.(4| stupid and Π, 3]inter)-8-(2-fluoro-6-trifluoromethyl·stupylmethyl) I Methyl side oxy group 152524.doc •122- 201130854 gas-5H-嗟 并[3,2_a].pyridinyl I)]•phenylmethyl}amino)ethoxy]-acetic acid decyl ester {3R- [3oc(S*)]}-[2-({[6-(4-Fluoro-benzo[13]dioxol-5-yl)-8-(2-fluoro-6-trifluoro) Mercapto-phenylhydrazino)_7_mercapto_5_sideoxy-2,3_diaza-5H- sulphate and [3,2♦ than acetophenyl phenylmethylamino) ethoxylate ]]-acetic acid decyl ester {3S-[3oc(S*)]}-[2-({[6-(4-fluoro-benzo-π,3]-dioxole_5_ • base)_8 ·(2·Fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-5-sideoxy-2,3_dihydro-5H-thiazolo[3'2-a]acridine_ 3_yl]_phenyl-methyl-amino)-ethoxy]-acetic acid decyl {3R-[3a(R*)]}-4-{[[6-(2-fluoro-3-A) Oxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3 , 2_ a] ° pyridine-3-yl]-(2-fluoro-phenyl)-methyl]-aminobutyric acid ethyl ester {3S-[3a(R*)]}-4-{[[ 6-(2_Fluoro-3 methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-bensyl)-7-methyl-5-side Base 2,3-dihydro-5 H-11 saponin [3,2_ ru a]&quot;bipyridin-3-yl]-(2-fluoro-phenyl)-methyl]-aminopyridine Ethyl ester {3R-[3oc(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl) -benzyl)-7-methyl-5.oxy 2,3-dihydro-5H-thiazolo[3,2_appyridin-3-yl]-(2-fluoro-phenyl)- Methyl]-amino}-butyric acid ethyl ester {38-[3〇^*)]}-4-{[[6-(2_fluoro-3-methoxy-phenyl)-8-(2 -fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl] -(2-Fluoro-phenyl)-methyl]-amino}-butyric acid ethyl ester {3R-[3a(R*)]}-(2-{[[6-(2-fluoro-3-) Oxy-phenyl)-8-(2-fluoro-6.trifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3 , 2-1233 152524.doc 201130854 a] ° pyridine _3_yl]-(2-fluoro-phenyl)-methyl]-amino}-ethoxy)-ethyl acetate {3S-[ 3oc(R*)]}-(2-{[[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)- 7-Methyl-5-o-oxy-2,3-dihydro-5H-thiazolo[3,2·a]&quot;Bis-3-yl]-(2-fluoro-phenyl)·methyl ]•Amino}_ethoxy)·Ethyl acetate {3R-[3ot(S *)]}-(2-{[[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-- 5--5-oxy-2,3-dihydro-5H-thiazolo[3,2-magnesium ratio _3_yl]-(2•fluoro-phenyl)-methyl]-amino group }-ethoxy)-ethyl acetate {3S-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2- Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]. Bispin-3-yl]-(2-fluoro-phenyl)-methyl]-amino-ethyloxy)-ethyl acetate 4-({(3,5-difluoro-phenyl)·[6_ (2_Fluoro_3_methoxy-phenyl)-8_(2·fluoro·6•trifluoromethylbenylmethyl)-7-methyl-5-oxo-oxy-2,3-diaza- 5Η -0 stopper and [3,2_a]° pyridine-3-yl]-fluorenyl}•amino)-butyric acid ethyl ester {3R-[3a(R*)]}-4-({[6 -(5-Gas-2,3-dihydro-benzo[1,4]dioxan-6-yl)-8-(2-fluoro-6-trifluorodecyl-benzoinyl) -7-fluorenyl-5-sideoxy_2.3-dihydro-5H-carbazolo[3,2-a]npyridin-3-yl]-phenylindolyl)-butyric acid Ethyl {3S-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-abido[ι,4]dioxe-6-yl) -8-(2-Fluoro-6-trifluorodecyl-phenylhydrazino)·7-methyl-5-sideoxy-2,3-hydrogen-5 Η-嗟 并[3,2- a] 吼-3-yl]-phenyl-methyl-amino)-butyl butyrate {3R-[3a(S*)]}-4-({[6-(5-fluoro-2, 3-Dihydro-p-benzo[14]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)·7-methyl_5_side oxygen Base _ 2.3- dihydro-5 oxime-thiazolo[3,2-a]pyridin-3-yl]-phenyl-fluorenyl}-amino)_ 152524.doc • 124- 201130854 ethyl butyrate {3S- [3ct(S*)]}-4-({[6_(5_Fluoro23 dihydrobenzo(1)-dihydroxyhexa-6-yl)-8-(2-fluoro-6-trifluoro) Methyl.benzoyl)·7_mercapto_5_sideoxy_ 2,3-dihydro-5H.t sits and [3,2_leine]•phenyl-methyl-amino group) · Ethyl butyrate {3R-[3ot(R*)]}-[2-({[6_(5_fluoro-2,3 dihydrobenzo(1)dioxan-6-yl)-8- (2-Fluoro-6-trifluoromethyl)-benzyl)·7-methyl_5_sideoxy_2.3-Dihydro-5Ηϋ[3,2♦ than bite·3]]phenyl hydrazine Ketoamino) ethoxy]-ethyl acetate {3S-[3a(R*)]H2-({[6m3-dihydro.benzo[Μ]dioxanthene) _8·( 2 preparation 6_trifluoromethyl·benzyl)·7-methyl-5-sideoxy-2.3-dihydro-5Η-(tetra) and [3,2 咖 _3 base]_phenyl-methyl Ethyl)_ethoxy]-ethyl acetate {3R [3a(S )]} [2 ({[6-(5_ ι _2 3· dihydro-benzo(1)4) dioxetane) )_8_(2_Fluoro.6_trifluoromethyl_phenylmethyl)-7.methyl_5•Sideoxy-2.3-Hydrogen 5Η嗟Sitting and [3,2_小比咬_3·基] - stupyl-methyl-amino group)_ethoxy]-ethyl acetate {3S_[3a(SH({[6-(5·fluoro-2,3-dihydro· benzo[M]dioxine Cyclohexene 6-based)-8-(2-fluoro-6-difluoromethyl·benzene "Methyl_5_sideoxy" 2.3 虱_511_嗟君[3,2 a(tetra)-p-phenylphenylmethylamino)-ethoxy]-ethyl acetate 6 (2 Gas 3曱oxy-styl)_8_(2_fluoro_6_trifluoromethylbenzyl)_3_ [(2-carbylethylamino)-phenylmethyl]_7•methyl_ 2,3_diazepine. Sit and [3,2 - a ]. Than bite 5 - same

S 152524.doc -125- 201130854 3- ({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl)· 7 -Methyl-5-o-oxy-2,3_dihydro-5H-thiazolo[3,2-a]&quot;biter-3-yl]•stupyl-mercapto}-amino)·propane 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-fluorenyl) -5-Sideoxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-indenyl}-amino)butane-1-sulfonic acid 2-[2-({[6-(2-Fluoro-3-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)-7-indolyl-5 -Sideoxy-2,3-dihydro-511-thiophene[3,2-a] ° than bite-3·yl]-phenyl-methyl}-amino)-ethyl]吲哚-i,3-dione 2-[3-({[6·(2-fluoro-3-曱-oxy-phenyl)_8·(2-fluoro-6-trifluoromethyl-benzyl) )-7-mercapto-5-p-oxy-2,3-dihydro-5 oxime-thiazolo[3,2-a]0-pyridin-3-yl]-phenyl-indenyl}-amino)· Propyl]-isoindole 1,3-dione 2-[4-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorofluorene) Base-stupylmethyl)-7-fluorenyl-5-o-oxy-2,3-dihydro-5H-. 塞0 sits and [3,2-a]* is more than benzoyl-methyl }-Amino)-butyl]-吲哚-1,3-dione ketone {3R-[3oc(R*)]}_4-({[6-(2-fluoro-3-isopropoxy-phenyl)-M2-fluoro-6- Trifluoromethyl-adenyl)-7-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]&quot;bipyridin-3-yl]- Phenyl-methylamino)-butyric acid ethyl ester {3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-) (2-Fluoro-6-trifluoromethyl-benzyl)·7-methyl-5-oxo-2,3-diin-5Η-oxazolo[3,2-a] -3-yl]-phenyl-methylamino)-butyric acid ethyl ester {3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-) Phenyl)-8-(2-fluoro-6-trifluoromethyl-p-methyl)·7-methyl-5-oxo-2,3-dihydro-5H-1# oxazepine [3, 2-ap-pyridin-3-yl]•phenyl-decylamino)·butyrate ethyl ester 152524.doc •126· 201130854 {3S_[3a(S*)]}_4-({[6-(2 -fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)·7·decyl-5-oxo-2,3-dihydro -5H-oxazolo[3,2-a]. Than -3-yl]-stupyl-methylindole-amino)-butyric acid ethyl ester {3R-[3a(R*)]}_[2-({[6-(2-fluoro-3-) Isopropoxy-phenyl)-8-(2-fluoro-6.trifluoromethyl-benzyl)·7-fluorenyl_5_sideoxy-2,3·dihydro-5H-oxazole And [3,2-a]«Bite-3-yl]-phenyl-indolyl ethoxy]-ethyl acetate {3S_[3oc(R*)]}_[2_({[6_ (2_fluoro·3_isopropoxy phenyl)_8_(2_fluoro_6_trifluoromethyl-adenyl)_7-methyl-5-sideoxy-2,3-dihydro-5Η-caca Azolo[3,2-a]&quot;fcb -3-yl]-phenyl-indolyl ethoxy]-ethyl acetate {3R-[3a(S*)]}-[2_( {[6_(2u•isopropoxy-phenyl)_8_(2_fluoro-6(trifluoromethyl-phenyl)phenyl-7-methyl-5-yloxy-2,3-dihydro- 5H-oxazolo[3,2-ap-pyridin-3-yl]-phenyl-methylaminoethoxy]-acetate {3S-[3oc(S*)]}-[2-( {[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-5-sideoxy- 2,3-Dihydro-5H-oxazolo[3,2-a].pyridin-3-yl]-phenyl-indenylamino)-ethoxy]-ethyl acetate {3R-[ 3a(R*)]}-[2-({[6-(2-Fluoro-3.methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl)- 7-mercapto-5-side oxygen -2,3-dihydro-5H-thiazolo[3,2-a].pyridin-3-yl]-phenyl-indolyl ethoxy]-acetic acid {3 8-[3〇〇 (11*)]}-[2-({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl)-7 -mercapto-5-o-oxy-2,3-dihydro-5H-thiazolo[3,2-a]&quot;bipyridin-3-yl]-phenyl-methyl-amino)-ethoxy ]]-acetic acid {3R·[3(X(S*)]}-[2-({[6-(2-defeno-3-methoxy-phenyl)-8-(2-mil-6-) Trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-styl-曱 卜 胺 ) _ 152 152 152524.doc • 127· 201130854 {3S-[3oc(S*)]}-[2-({[6-(2-fluoro-3- methoxy) -phenyl)·8_(2_fluoro-6-trifluoromethyl-mutemethyl)-7-methyl-5-oxirane·2,3-dihydro-5Η-sigh and [3,2- a]D-pyridin-3-yl]-phenyl-methyl-amino)-ethoxy]acetic acid 6-({[6-(2-fluoro-3-indolyl-phenyl)-8-() 2-fluoro-6-trifluorodecyl-benzoinyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl ]-Phenyl-methyl}-amino)-hexanoic acid 4-({[6-(2-fluoro-3-]decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) -benzyl)7-mercapto-5-side oxygen Base-2,3-chloro- 5H-嗔0 sits and [3,2-a]. Σσ-3-yl]-phenyl-methyl}-amino)-3-trans-butyric acid 4-({[8-(2-fluoro-6-trifluorodecyl)benzyl) -6-(3-methoxy-phenyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]- Phenyl-methyl}-amino)-butyric acid 4-({[6-(2-fluoro-4-methoxy-yl))-8-(2-fluoro-6-trifluoromethyl) Benzyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine·3·yl]-phenyl·decylamino) -butyric acid 4-({[6-(3-acetamido-2-fluoro-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl 7-methyl-5- side) Oxydihydro-5H-thiazolo[3,2-a]&quot;bipyridin-3-yl]•phenyl-indenyl}-amino)-butyric acid 4·({[6-(2-fluoro) -5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-5-yloxy-2,3-dihydro-5H -thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl-amino)butyric acid {3R-[3a(R*)]}-4-({[6-(2 -fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl·5-sideoxy-2,3·dihydro ·5Η·thiazolo[3,2-a]acridin-3-yl]-phenyl-indenyl}-amino)-butyric acid 152524.doc •128· 201130854 {3S-[3a(R^)] } _4-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6.didonyl-benzyl)_7-mercapto-5-side oxygen Benzyl-2,3-dihydro-5Η-thiazolo[3,2-a]°pyridin-3-yl]-phenyl-methyl}amino-butyric acid {3R-[3a(S*) ]}-4-({[6-(2-Fluoro-3·isopropoxy)phenyl)-8-(2-fluoro-6·trifluoromethyl-benzyl)-7-methyl- 5-Phenoxy-2,3-dihydro-5H-thiazolo[3,2-a]° ratio thiol]-phenyl-decylamino)·butyric acid {3S-[3a(S*) ]}-4-({[6-(2-Fluoro-3-isopropoxy)phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)-7-methyl- 5-Phenoxy-2,3-dihydro-5H-thiazolo[3,2-a]&quot;bipyridin-3-yl]-phenyl-methyl}•amino)-butyric acid PR-[ 3a(R*)]}-[2-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)) -7-mercapto-5-p-oxy-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methylamino)·ethoxy ]_Acetic acid {3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoro) Methyl-benzyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]. Bipyridin-3-yl]-phenyl-decylaminoethoxy; acetic acid {3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy) -phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3, 2-a]°pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid {3S-[3oc(S*)]}-[2-({[6- (2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-sideoxy-2,3· Dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-mercaptoamino)-ethoxy]-acetic acid 4-({[6-(2-fluoro-4) -trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5. oxo-2,3-dihydro-5H- Thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid 152524.doc •129- 201130854 4-({[6-(2-fluoro-3-)曱oxy-phenyl)-8-(2-fluoro-6-triptanyl-benzyl)_ 2,2,7-trimethyl-5-oxo-2,3-dihydro- 511-°3⁄4 唾和[3,2-a] ο比咬_3_基]-stupyl-methyl}-amino)-butyric acid 4-({[6-(2-fluoro-3-IIIII) Methoxy-phenyl)-8-(2-dun-6-trifluoromethyl-benzoinyl)-2,2,7-tridecyl-5-sideoxy-2,3-dihydro- 5H-sigh. Sit and [3,2-a]° ratio 3-yl]-phenyl-fluorenyl}-amino)-butyric acid 4-({[6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluorodecyl)-stupid Methyl)_2,2,7-tridecyl-5-sideoxy-2,3-dihydro-511-嗟°[3,2-&amp;]«&gt; than bite_3_ base] _Phenyl-methyl}-amino)-butyric acid 4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-|t-6-tri-indenyl) -phenylhydrazinyl)- 2,2,7-trimethyl-5-oxo- 2,3-dihydro-5H-indole and [3,2_a]° ratio biting 3-yl]-benzene Base-methyl}-amino)-butyric acid [2_({[6-[3-(1,1-difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6) -trifluoromethyl-benzyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl- Mercapto}-amino)-ethoxy]-acetic acid 4-({[6-[3-(1,1-difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro) -6-trifluoromethyl_ 曱 ))-7-fluorenyl _5. oxo 2,3_dihydro-5H-thiazolo[3,2_a] pyridine-3-yl]-phenyl -Methyl}-amino)-butyric acid [2-({[6-[3-(1,1-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluorofluorene) -Benzylmethyl)-7-methyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-yl]-]phenyl-methyl}- Amino)-ethoxy]-acetic acid 4-({[6-(2-fluoro-4-benzene) Oxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-pentyloxy-2,3-dihydro-5H-thiazolo[3 ,2-a]pyridyl]-phenyl-indenyl}-amino)-butyric acid 152524.doc -130- 201130854 {3R-[3a(R*)]}-4-({[6-(3 -dimethoxymethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3·dihydro-5H- Thiazolo[3,2-a] 0-pyridin-3-yl]-styl-methyl}-amino)-butyric acid {3S-[3ot(R*)]}-4-({[6- (3-Difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro- 5H-thiazolo[3,2-a;| °pyridin-3-yl]-styl-decylaminobutyric acid {3R-[3a(S*)]}-4-({[6- (3-difluorodecyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl·5·sideoxy-2,3-dihydro- 5H-thiazolo[3,2-a] &quot;bipyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid {3S-[3a(S*)]}_4-({[ 6-(3-Difluoromethoxy-phenyl)-8-(2-fluoro-6-tris-methyl-phenylhydrazino)-7-indolyl-5-sideoxy-2,3-di Hydrogen-5H-thiazolo[3,2-a] ° than -3-yl]-phenyl-methyl-amino)butyric acid (3R-[3a(R*)]}-[2-( {[6-(3-Difluoromethoxy-phenyl)-8·(2-fluoro -6-三敦methyl·Benyl)-7-methyl-5-sideoxy-2,3-dihydro- 5Η-° η sit and [3,2· a]&quot; than bite- 3-yl]-phenyl-methylindole-amino)·ethoxy]-acetic acid {3S-[3a(R*)]}_[2_({[6_(3-difluoromethoxy-benzene) _8_(2_Fluoro-6 chlorotrifluoro-phenylphenyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2- a]° ratio Pyridin-3-yl]-phenyl-methylamino)-ethoxy acetic acid {3R-[3cx(S*)]}-[2_({[6-(3-difluoromethoxy-phenyl) -8-(2-Fluoro-6-trifluoromethyl-adenyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a] »Bistidin-3-yl]-phenyl-methylamino)-ethoxy ethoxyacetic acid {3S-[3a(S*)]}-[2-({[6-(3-difluoroantimony) -Phenyl)-8-(2-fluoro-6(trifluoromethyl-benzyl)_7-methyl-5-sideoxy-2,3-dihydro-5H-嗟&quot; 3,2· a]°pyridyl]-phenyl-methyl}-amino)-ethoxy]-acetic acid 152524.doc -131 - 201130854 {3R-[3a(R*)]}-4- ({[6-(4-Fluoro-benzo[u]dioxol-5-yl)-8-(2-oxa-6-trifluoromethyl·phenylmethyl)·7-methyl _5 pendant oxy 2,3·dihydro _5 Η·carbazolo[3,2_a]° pyridine I yl]-phenyl-methyl}-amino)·butyric acid {3 S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[13]dioxol-5-yl)-8-(2-fluoro-6-three) Fluoromethyl-benzenef-yl)_7-methyl·5_sideoxy-2,3_dihydro-5H+ sit-[3,2-a] 吼___ _ _ _ phenyl phenyl group • Amino) butyric acid {3R-[3ot(S*)]}-4-({[6-(4-fluoro·benzo-π,3]-dioxol-5)-) -(2-fluoro-6-trifluoromethyl·phenylmethyl)_7_methyl_5·sideoxy-2,3_dihydro-5H-indole[3,2♦ than bite_3_ ]{•phenyl-hydrazinyl)butyric acid {3S-[3a(S*)]M-({[6-(4 benzo[13]dioxol-5) -8-(2-Fluoro.6-trifluoromethyl-benzoinyl 7-methyl-5-sideoxy-2,3·dihydro-SH-thiazolo[3,2♦bipyridine] 34]_Phenylmethyl}-amino)-butyric acid nR-'pwmKuw·fluoro-benzo[13]dioxol-5-yl)-8-(2-fluoro-6-trifluoro Methyl-benzyl)_7_methyl_5_sideoxy-2,3_dihydro-5H-indazolo[3,2-a]bazinyl-3-yl]phenyl-methyl }•Amino)ethoxy]-acetic acid (10)_[3a(R*)]H2-({[6.(4·Fluorobenzoyl)-dioxol-5-yl)-8-(2 -Fluoro-6-trifluoromethyl-stanomethyl)_7_methyl_5_sideoxydihydro_5H_indazolo[3,2_a]. Than the base]•Phenylmethylammonyl)-ethoxy]-acetic acid {3R-[3a(S*)]H2-({[6-(4·敦-benzopyrene, 3]) Dioxolane _5 yl)_8_(2_fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3-dihydro-5H-thiazole [3,2-a] 啶 _ _ _ _ _ _ _ _ phenyl hydrazinyl ethoxy] 152524.doc • 132 · 201130854 fluoro-benzodioxol _5_ -8-(2-Fluoro-6-trifluoromethyl-benzyl)·7-methyl-5•sideoxy-2,3·dihydro-5Η-thiazolo[3,2-a Acridine-3-ylphenyl-methyl}-amino)-ethoxy]-acetic acid {3R-[3a(R*)]}-4-{[[6-(2-fluoro-3) - decyloxy _ phenyl) _8 · (2 _ _ _ _ _ _ 曱 曱 - 笨 笨 笨 笨 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Sit and [3,2_a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]-aminobutyric acid φ {3S-[3a(R*)]}-4- {[[6-(2-Fluoro-3-indolyl-phenyl)_8_(2_fluoro-6-trifluoromethyl-methyl)-7-indolyl-5-yloxy-2,3 -Dihydro-5 Η-sigh" sits and [3,2_a]° bites 3-yl]-(2-fluoro-phenyl)-indenyl]-aminobutyric acid {311-[3〇 1(8*)]}-4-{[[6-(2-fluoro-3-indolyl-phenyl)-8_(2_fluoro_6_trifluoromethyl)-methyl)-7 Methyl-5-o-oxy-2,3-dihydro-511-° plug-and-[3,2.a]0-indol-3-yl]-(2-fluoro-phenyl)-methyl ]-Aminobutyric acid {3S-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- Trifluoromethyl-phenylhydrazino)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a] φ 〇 ____ Η2-fluoro -phenyl)-methyl]-aminobutyric acid {3R-[3cx(R*)]}-(2_{[[6_(2_fluoro_3_methoxy_phenyl)_8_(2_fluoro _6•Trifluoromethyl-bensyl)-7-mercapto-5-sideoxy-2,3-dihydro-5 H-salt [3,2·a]&quot; than bite-3 -yl]-(2.fluoro-phenylmethyl)-aminoethoxy)-acetic acid {3S-[3a(R*)]}_(2_{[[6-(2-fluoro-3-) Oxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- -5-Sideoxy-2,3_dihydro-5H-thiazolo[3,2-a].Bism-3-yl]-(2-fluoro·styl)-indenyl]-aminopur Ethoxy)·acetic acid {3Κ·[3α(δ*)]}·(2-{[[6-(2_fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-three Fluorinyl-benzoinyl)·7_methyl_5·sideoxy-2,3·dihydro-5H_thiazolo[3,2_S- 152524.doc •133- 201130854 a]e bite- 3-yl]-(2-fluoro-phenyl)-methyl]-amino}-ethoxy)-acetic acid {3S_[3a(S*)]}-(2-{[[6-(2- Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl·benzyl)-7-fluorenyl-5-oxo-2,3-dihydro-5H -thiazolo[3,2-a].pyridin-3-yl]-(2-fluoro-phenyl)-methyl]-amino}_ethoxy)-acetic acid 4-({(3,5) -difluoro-phenyl)_[6_(2·fluoro-3-methoxy-styl)·8_(2·fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5- Sideoxy-2,3-dihydro-5Η-thiazolo[3,2-a]°pyridin-3-yl]-mercaptoamino)butyric acid {311-[3〇1(11* )]]-4-({[6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxe-6-yl)-8-(2-fluoro-6) -trifluoromethyl-phenylhydrazino)-7-mercapto-5-sideoxy-2.3-dihydro-5H-thiazolo[3,2-a]°pyridin-3-yl]-phenyl-methyl Butyryl)butyric acid {3S-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[M]dioxe-6-yl)-8-) (2-Fluoro-6-trifluoromethyl-adenyl)_7_fluorenyl_5_sideoxy_2.3-dihydro-5H-thiazolo[3,2_a]e than alkidine_3_yl]• Stupid base_methyl}•amino)·butyric acid {3R[3a(S)]}-4-({[6-(5-fluoro·2,3-dihydro. stupid [14] dioxa Cyclohexanyl _6_yl)_8_(2_Fluoryltris-methyl-benzyl)·7·methyl_5_sideoxy_ 2,3-dihydro-5Η-(tetra) and [3,2_a ]D ratio bite_3_yl]phenyl-mercapto-aminobutyric acid ps-wsM-Muwm: hydrogen benzo[14]dioxanthene fluorocarbon-6-trifluoromethyl.benzyl )_7•Methyl_5•Sideoxy-2,3-dihydro-5Ηϋ[3,2•中...3·yl]phenyl·methyl-amino)-butyric acid dihydro-benzo[ 1,4]dioxane 152524.doc -134- 201130854 hexene-6-yl)-8-(2-fluoro-6-trifluoromethyl-phenylene)_7•methyl·5_side oxygen Base _ 2.3- dihydro-5 Η-嗟 并 and [3,2_a] (four) _3 base] • stupid methyl bromide _ ethyl lactyl] • acetic acid diluted _6_ base) winter (2_ fluorine _6, Trifluoromethyl·benzyl)_7•methyl-tert-oxyl·2.3-^ethyllactyl]-acetic acid

Dihydro-benzo[1,4]

Hexene-6-yl)-8-(2·fluoro·6·trifluoromethyl) alkalyl-7-fluorenyl-5-sideoxy-methyl}-amino)- 2,3 -dihydro-5H-thiazolo[3,2_a]D-pyridyl_3_yl]-phenylethoxy]-acetic acid {3S-[3a(S*)]H2-({[6_(5u,3) _Dihydrobenzo[14]dioxine_6_yl)_8_(2_fluoro-6-trifluoromethyl-benzyl)_7_methyl_5_sideoxy_ 2,3 -monohydro-5H-thiazolo[3,2_a]pyridine·3_pybyl-methyl-amidopropylethoxy]-acetic acid

{3R_[3a(RH!)]}-4-(U6-(2-fluoro-3-isopropoxy-phenyl)_8·(2-fluoro-6-difluoromethyl-benzyl)- 7-Methyl_5_sideoxy-2,3-dihydro-5Η-oxazolo[3,2-a]acridin-3-yl]·stupyl·indenyl}-amino)·丁Acid {3S-[3a(R*)]}-4-({[6_(2_fluoro_3_isopropoxy-phenyl)_8_(2_fluoro_6·difluoroindolyl phenyl))-7 · mercapto _5-sideoxy-2,3_dihydro-5H oxazolo[3,2-a]&quot;bipyridin-3-yl]-phenylmethyl}amino) Acid (3R_[3 W)]}-4-({[6-(2_fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl) _7_methyl_5_sideoxy-2,3_dihydro-5H-oxazolo[3,2_a]pyridin-3-yl]-phenyl-decylaminobutyric acid 152524.doc •135 · 201130854 {3S-[3a(S*)]}-4-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) -N-methyl)-7-methyl-5-o-oxy-2,3-dihydro-5Η-β oxazeto[3,2·* a]acridin-3-yl]•phenyl-indole }}-amino)-butyric acid {3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro) -6- Dimethyl-methyl-methyl-7-methyl-5-oxo- 2,3-dihydro-5H-°-β-[3,2-a]&quot; 3-yl]-phenyl-methyl Amino)-ethoxy]-acetic acid {3 8-[3〇1(1^)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)_8- (2-fluoro-6-

Difluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5Η-»oxo[3,2-a]pyridine-3-yl]-phenyl -Methylamino)-ethoxy]acetic acid {3R-[3a(S*)][2-({[6-(2-fluoro-3-isopropoxy-phenyl)_8_(2 _Fluorine_6_trifluoromethyl-benzyl)-7-methyl_5·sideoxy-2,3·dihydro·5Η·oxazole[3,2-a]D than pyridine_3_ ]]•phenyl_methyl}_amino)-ethoxy]-acetic acid {3S [3a(S)]}-[2-({[6-(2-fluoro-3-isopropoxy-) Phenyl)_8-(2_fluoro_6·

Trifluoromethyl-benzyl)-7-methyl_5_sideoxy-2,3_dichloro_5H_唉sa[3,2-a]acridine_3_yl]-phenyl _Methyl}_amino)-ethoxy]-acetic acid 4·({[6-(2-fluorooxy-phenyl)·8·(2 66•三amethylbenzyl 7-A) 5--5-oxo-oxy 3_di-argon_5H•thiazolo-p,2_a]pyridinyl]-phenyl-methyl}-amino)-butanamine 6-(2-fluoro-3_曱Oxy-phenyl)_8 (2 preparation of trifluoromethyl-phenylhydrazino)·7-base-3_{phenyl-[3-(ΐΗ·tetrakis-5-yl)-propylaminopyrylene}_2 , 3_dithiazolo[3,2-a]pyridine_5-ketone M4·gas], 3·benzone: anthracene heterocycle (tetra)·5·yl) 1[2|6-(tri-I)benzene F-based M-methyl-3_(phenyl{[3_(1H_tetras-5-yl)propyl cation)-2,3·dihydro·5Η_Π,3](d) 叩 叩 比 · 152524.doc -136· 201130854 6-(4Fluoro-benzo[1,3]dioxol-5_yl)_8 (2-6-trimethyl-benzyl)-7 -曱基-3·{phenyl.[3·(1Η_四吐_5基)propylamino]_methyl}-2,3-dihydro-thiazolo[3,2_a]pyridine_5_ Keto 2-amino-4-({[6-(2•说-3_曱oxy_phenyl)_8_(2_gas_6_trifluoromethyl_phenylmethyl)-7-methyl_ 5-sided oxy-2,3_dihydrogen 5Η· oxazolo[3,2a]n is more than 唆-3-yl]-phenyl-methyl}-amino)·butyric acid 3-[(2-amino-ethylamino)-phenyl] Sulfhydryl]_6_(2_fluoro_3_decyloxy-stupyl) φ 8-(2-fluoro-6-trifluoromethyl-benzoinyl)·7-methyl-2,3-dihydrogen _thiazolo[3,2_a]°tfc ^ - 5-83⁄4 3-[(3-amino-propylamino)-phenyl-indenyl]_6_(2_fluoro-3-methoxyphenyl) _ 8-(2-Fluoro-6-trifluoromethyl-stanomethyl)_7-methyl-2,3-dihydro-thiazolo[3,2_a] 0 to π-but-5-one 3-[ (4-Amino-butylamino)-phenyl-indenyl]_6_(2-fluoro-3-indolyloxy)phenyl 8-(2-fluoro-6-trifluoromethyl-alum Base)_7_mercapto-2,3_dihydrothiazolo[3,2-a]0 than bite-5-ketolu N-[3-({ [6-(2-fluoro-3-methoxy) -phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl_5_sideoxy·2,3-dihydro-5Η-π嗤嗤[ 3,2-a]0 is more than -3-yl]-phenyl-methyl}-amino)-propyl]-pulse [l$,3R(R)]-4-{[{6-(2 -fluoro-3-methoxyphenyl)-8-[2-oxo-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxoyl-5-sideoxy-2 ,3-dihydro-5H-[1,3]°"Sit and [3,2-a]e is more than indole-3-yl}(phenyl)methyl]amino}butyrate ethyl ester [l$ ,3S(R)]-4-{[{ 6-(2- IL-3-methoxyphenyl)·8-[2-oxo-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxo-yl-5-side Ethoxy-2,3-dihydro-5H-indole, 3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indenyl]amino}butyric acid ethyl ester 152524.doc -137 - 201130854 [lg,3R(S)]-4-{[{6-(2-Fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]-7 -Methyl-1-oxo-yl-5-sideoxy-2,3-dihydro-5Η·[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)fluorenyl Amino) ethyl butyrate [U'3S(S)]-4-{[{6-(2-fluoro-3-decyloxyphenyl;)_8_[2_fluoro_6_(trifluoromethyl) Benzyl]-7-mercapto-1-oxylyl_5_sideoxy-2,3_dihydro-5H_[1,3]thiazolo[3,2-appyrid-3-yl }(phenyl)indenyl]amino phthalic acid ethyl ester 3- [Amino (2-fluorophenyl)methyl]_6_[2_fluoro_3 gas trifluoromethoxy)phenyl]_8_ [2 -fluoro-6-(trifluoromethyl)benzyl]-7(methyl)-2 dihydro-5h [13]thiazolo[3,2-a]pyridin-5-one 1-oxide 4- { [{6-(2-Fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylmethyl 7-methyl-1-oxo-yl-5- Sideoxy-2,3-dihydrothiazolo[3,24]pyridin-3-yl}(phenyl)methyl Amino}ethyl butyrate 4-{[(3,5-difluorophenyl){6-(2-fluoro-3-methoxyphenyl)-8_[2·fluoro·6_(trifluoroanthracene) Benzo)benzyl--7-methyl-1-oxo-yl-5-sideoxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3 -yl}methyl]amino}ethyl butyrate 4-{[{6-(2-fluoro-3_decyloxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzoinyl 7 -methyl-1-oxylyl_5-sideoxy-2,3-dihydrothiazolo[3,2-a]pyridine-3-yl}(2-fluorophenyl)methyl]amino} Ethyl butyrate 4-{[{6-[3-(difluoromethoxy)phenyl]_8_[2_fluoro_6_(trifluoromethyl)benzoinyl]-7-methyl-1.oxy Ionic group 5-sideoxy-2,3. dihydrothiazolo[3,2-a]pyridine-3-yl}(phenyl)methyl]amino}butyrate ethyl ester [U,3R(R )]-4-{[{6-(2-fluoro-3-methoxyphenyl)_8_[2·fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxo Base _5_sideoxy-2,3·dihydro_5h_[1'3]隹. Sit and [3,2-ugly]°bidin-3-yl}(phenyl)indolyl]amino)butyronitrile 152524.doc •138· 201130854 [lg,3S(R)]-4-{[{ 6-(2-Fluoro-3-indolylphenyl)-8-fluorenylfluoro-6-(trifluoromethyl)benzoinyl]-7-indolyl-buoxyl-5-sideoxy- 2,3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indenyl]amino}butyronitrile [1$, 31^)]- 4-{[{6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) adenyl]-7-fluorenyl-1-oxo 5-O-oxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]acridin-3-yl}(phenyl)methyl]amino}butyronitrile [l$,3S(S)]-4-{[{6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)]indolyl] -7-Methyl-1-oxoyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-appyrid-3-yl}(phenyl曱]amino]butyronitrile [l$,3R(R)]-4-{[{6-(4-fluoro-1,3·benzodioxol-5-yl)- 8-[2-Ethyl-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxo-yl-5-sideoxy·2.3-dihydro-5H-[1,3]thiazole And [3,2-a]pyridin-3-yl}(phenyl)indenyl]amino}butyronitrile [1 $,3S(R)]-4-{ [{6-(4-fluoro-1, 3-benzo-3-dioxan-5- -8-[2-Fluoro-6-(trifluoromethyl)phenylindolyl]-7-methyl-1-oxoyl-5-sideoxy_2.3-dihydro-5H-[1, 3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indenyl]amino}butyronitrile [1$,311(8)]-4-{[{6-(4-fluoro -1,3-benzodioxole-5-yl)_8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxo-based _ 5-Sideoxy_2.3-Dihydro-5H-[1,3]thiazolo[3,2-a]0 is more than -3-yl}(phenyl)indenyl]amino}butyronitrile [1$ ,38(8)]-4-{[{6-(4-fluoro-1,3-benzodioxole-5-yl)-8- [2-fluoro-6-(trifluoro) Mercapto)benzylidene-7-indenyl-1-oxoyl-5-sideoxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine- 3-yl}(phenyl)methyl]amine 152524.doc -139- 201130854 base} butyronitrile [1$,311(11)]-4-{[{6-(4_fluoro_1,3_benzene P-dioxole_5_yl)_8_[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl·anthracene-oxyl group _5_sideoxy _ 2, 3. Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino}ethyl butyrate [U,3S(R)]- 4-{[{6-(4-fluoro-1,3-benzodioxole-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] _ 7_曱基_ι_oxy ionyl_5_sideoxy_2.3-dihydro-5H-[1,3]thiazolo[3,2_a]pyridin-3-yl}(stupyl)methyl]amine Ethyl butyrate [1$, 3 ft (5)] -4-{[{6-(4-fluoro-1,3-benzodioxole-5-yl)-8- [2-fluoro-6-(trifluoromethyl) adenyl]_7-methyl-1-oxylyl_5_sideoxy_2.3-dihydro-511-[1,3]thiazolo[3 ,2-&amp;]pyridin-3-yl}(phenyl)indenyl]amino}ethyl butyrate [lg,3S(S)]-4-{[{6-(4-fluoro-l,3 -benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-buoxy-yl-5_side oxygen Base_2.3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino}ethyl butyrate [1$, 311 (1 〇]-(2-{[{6-(4-Fluoro-1,3-benzodioxole-5-yl)-8-[2-fluoro-6-(trifluoromethyl)) Stupid methyl 7-methyl-1-oxo-yl 5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]0-pyridin-3- (}Phenyl)methyl]amino}ethoxy}acetate M-dioxole-5-yl)-8-[2-fluoro-6-(trifluoro-T-yl) phenylene]_7-methyl-1_oxyl _5_ side Base-2,3-dihydro-5H-[1,3]thiazolo[3 2_a]indolepyridin-3-yl}(phenyl)methyl] 152524.doc •140· 201130854 Amino}ethoxylate ) oxime acetate oxime, 3 ΙΙ (δ) Η 2 · {[{6·(4_fluorobenzo: oxacyclopentene _5_yl)_ 8-[2- gas-6-(di-I fluorenyl) Benzyl bromide 7·methyloxy ionyl·5·sideoxy-2,3-dihydro-5Η-[1,3] sina π sitting and [3,2-a] pyridine _3_ group (( stupid) is comparable to] amino} ethoxy) methyl acetate to, 38(8)]-(2-{[{6-(4-fluoro-1,3-benzodioxane)戊妇_5_基)-8_ [2-Fluoro-6-(difluoroindolyl) benzyl] _7_methyl 丨 丨 氡 氡 _ _ _ _ _ _ _ _ _ _ 2,3_ dihydro _ 5Η_[1,3]°Sexy and [3,2-a]° than bitten 3-yl}(phenyl)methyl]amino}ethoxy}acetate methyl ester [lg, 3R(R)] -4-{[{8-[2-Fluoro-6-(trifluoromethyl)benzyl]]7-methyl"oxyl-5-yloxy-6-[3·(trifluoromethoxy) Ethyl]phenyl]_2,3_dihydro-5h_[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino}butyrate ethyl ester [l$ ,3S(R)]-4-{[{8_[2-fluoro.6-(trifluoromethyl)benzyl]]7-methyl"oxyl-yl-5-sideoxy-6-[3·( Trifluoromethoxy)phenyl]_2,3·two _5Η_ [1,3]thiazolo[3,2-appyridin-3-yl}(phenyl)indolyl]amino}butyrate ethyl ester # [lg,3R(S)]-4-{[{ 8-[2-Fluoro-6-(trifluoromethyl)benzylmethyl][7-fluorenyl]-oxaoxy-5-yloxy-6-[3-(trifluoromethoxy)phenyl b , 3_Dihydro-5H_[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino)butyric acid ethyl ester [lg,3S(S)]- 4-{[{8-[2-Fluoro-6-(trifluoromethyl)benzylidene-7-fluorenyl-1-oxo-yl-5-yloxytrifluoro)phenyl]_2 , 3_Dihydro·5H_[1,3]thiazolo[3,2-a]acridin-3-yl}(phenyl)indolyl]amino}butyrate ethyl ester [1$, 3 ft (! 1)]-4-{[{6-(5-fluoro-2,3-dihydro-1,4-benzodioxan-6-yl)-8-[2-fluoro-6- (Trifluoromethyl)benzyl]-7-methyl-buoxyl_5_ oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]° ratio Acridine-3-yl}(phenyl) 152524.doc -141- 201130854 methyl]amino}butyrate ethyl ester [l$,3S(R)]-4-{[{6-(5-fluoro-2) ,3-dihydro-1,4-benzodioxan-6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl Ionic group _5_ pendant oxy-2,3·dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl Ethyl]amino}ethyl butyrate [l$,3R(S)]-4-{[{6_(5-fluoro-2,3-dihydro-1,4-benzodioxanene) _ 6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]_7-fluorenyloxy-yl-5_ oxo-2,3-dihydro-5H-[1, 3] ° 嗤 嗤 [3,2-a]. Butyl-3-yl}(phenyl)indolyl]amino}butyrate ethyl ester [l$,3S(S)]-4-{[{6-(5-fluoro-2,3-dihydro- 1,4-benzodioxan-6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzylmethyl-(oxycarbonyl)_5_ pendantoxy-2 ,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indolyl]amino}butyrate ethyl ester [l$,3R(R) ]-(2-{[{6-[3-(Difluoromethoxy)phenyl]_8_[2_fluoro-6-(trifluoromethyl)phenyl)]-7-methyl-1-oxyl _5_Sideoxy_2,3_Dihydro_5H_[1,3]thiazolo[3,2-appyridin-3-yl}(phenyl)methyl]amino}ethoxy}acetic acid Ethyl ester [l$,3S(R)]-(2-{[{6-[3-(difluorodecyloxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)benzene Indenyl]-7-mercapto-1-oxylyl_5_sideoxy-2,3_dihydro-5H_[1'3]thiazolo[3,2-a]pyridin-3-yl}( Phenyl)methyl]amino}ethoxy}acetate [U'3R(S)]-(2-{[{6-[3-(difluorodecyloxy)phenyl]-8-[ 2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxoyl _5_sideoxy-2,3_dihydro-5H_ Π,3]thiazolo[3 ,2-a] oxaridin-3-yl}(phenyl)methyl]amino}ethoxy}ethyl 152524.doc -142- 201130854 acid ethyl ester n$ 3S(S)J-(2-{[{6-[3-(Difluoromethoxy)phenyl]_8_[2-fluoro-6((trifluoromethyl)benzyl]-7-methyl) -1-oxoyl-5-yloxy-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indenyl]amine Ethoxylate) [l$,3R(R)]-3-[amino(phenyl)indolyl]-6-(2-fluoro-3-methoxyphenyl)-8- [2-Fluoro-6-(trifluoromethyl)benzoinyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolium[3,2-a]D ratio bite- 5-嗣1-oxide [lg,3S(R)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-indolyl)-8-[2-fluoro- 6-(Trifluoromethyl) aluminyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2_a]pyridin-5-one 1-oxide [U , 3R(S)]-3-[Amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)_8_[2-fluoro-6-(trifluoromethyl)phenyl Mercapto]-7-methyl-2,3-dioxa-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 1-oxide [lg,3S(S)]- 3-[Amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) benzyl]_7-methyl -2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 1-oxide 3-[amino(3,5-difluorophenyl)fluorenyl ]_6_(2-Fluorine- 3-decyloxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]]7-mercapto-2,3_dihydro-5H-[1,3]thiazolo[3,2 -Omium]°ipyridin-5-one 1-oxide 3-[amino(2-fluorophenyl)indenyl]_6_(2_fluoro_3_decyloxyphenyl)_8_[2_say-6_ (trifluoromethyl) aluminyl]_7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2_a]pyridin-5-one 1-oxide (2-{[ {6-[3-(1,1_Difluoroethyl)_2·fluorophenyl]_8_[2·Fluor_6·(trifluoromethyl)

S 152524.doc • 143· 201130854 Benzyl]-7-methyl-1-oxoyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2 -a]Phenidin-3-yl}(phenyl)methyl]amino}ethoxy}acetic acid methyl ester (2-{[{6-[3-(1, difluoroethyl)phenyl)] 8-[2-fluoro-6-(trifluoromethyl)phenylhydrazinyl]-7-methyl-1-oxoyl-5-yloxy-2,3-dihydro-5H-[1, 3] Thiazolo[3,2-a]indolepyridin-3-yl}(phenyl)methyl]amino}ethoxy}acetic acid methyl ester 3- [Amino (phenyl) fluorenyl]-6 -[3-(dioxadecyloxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-2,3-dihydro-5H-[ 1,3]thiazolo[3,2-a]pyridin-5-one 1-oxide 4-{[{6-(2-fluoro-4-methoxyphenyl)-8-[2-fluoro -6-(trifluoromethylmethyl)benzyl]-7-mercapto-1-oxo-yl-5-sideoxy-2,3-dihydro-5H-[1,3]嗟β sits [3,2-a] acridine-3-yl}(phenyl)methyl]amino}butyric acid [l €,3R(R)]-4-{[{6-(2 - -3-曱oxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxo-yl-5-o-oxy-2,3-dihydro -5 H_ [1,3]°Sit and [3,2-ap ratio -3-yl}(phenyl)indolyl]amino}butyric acid [1 ξ, 3 S(R)] -4- {[{6-(2-1-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxo Ionic 5--5-oxy-2,3-dihydro-5H_[1,3]fluorene. Sit and [3, 2- ugly]. Butyl-3-yl}(phenyl)indenyl]amino}butyric acid [l$,3R(S)]-4-{[{6-(2-gas-3-decyloxyphenyl)- 8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxoyl-5-yloxy-2,3-dihydro-5 H· [1, 3]thiazolo[3,2-a]acridin-3-yl}(phenyl)indenyl]amino}butyric acid [l$,3S(S)]-4-{[{6-(2- Fluor-3-methoxyphenyl)-8-[2- gas-6-(trifluoromethyl)benzyl]-7-methyl-1-oxoyl-5-sideoxy-2, 3-dihydro-5H_[1,3]thiazolo[3,2-a]heptan-3-yl}(phenyl)indenyl]amino}butyric acid 4-{[(3,5-difluoro Phenyl){6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6_(three 152524.doc 201130854 fluoromethyl)benzyl]-7-fluorenyl_i_ Oxygen ion group _5_sideoxy-2,3_dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-yl}methyl]amino}butyric acid [lg, 3R(R)]-4-{[{6-(2-fluoro.3_methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzoinyl]-7-methyl-indole_ Oxygen ion group _5_sideoxy-2,3_dihydro _5Η_ [1,3]thiazolo[3,2-a]pyridine-3-yl}(2-fluorophenyl)methyl]amino group } Butyric acid [l$,3S(R)]-4-{[{6-(2-gas_3_decyloxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl] -7-methyl oxygen Ionic group _5_sideoxy-2,3 dihydro _5H_ φ [1,3]thiazolo[3,2-a]pyridin-3-yl}(2-fluorophenyl)methyl]amino} Butyric acid [l",3R(S)]-4-{[{6-(2-fluoro_3_decyloxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzoinyl]-7 -Methyl-i_oxy ionyl_5_sideoxy-2,3_dihydro-5H_[1,3]thiazolo[3,2-a]pyridine-3-yl}(2-fluorophenyl) Amidino]aminobutyric acid [l$,3S(S)]-4-{[{6-(2-fluoromethoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl) Benzyl]methyl-1-oxoinyl_5_sideoxy-2,3_dihydro-5H_[1,3]thiazolo[3,2-a]pyridine_3_yl}(2_ Fluorophenyl)indolyl]aminobutyric acid [U,3R(R)]-4-{[{6-[3-(difluoromethoxy)phenyl]_8_[2_fluoro_6_(three Fluorine·methyl)benzyl]_7_mercapto-1-oxoyl-5-yloxy-2,3-dihydro-5H_[1,3]thiazolo[3,2-a]pyridine_ 3_yl}(phenyl)methyl]amino}butyric acid [lg,3S(R)H-{[{6-[3-(difluorodecyloxy)phenyl]_8_[2_fluoro_6 (Trifluoromethyl)benzyl]-7-methyl-1-oxylyl_5_sideoxy-2,3_dihydro-5H_Π,3]thiazolo[3,2-a].比β_3_yl}(phenyl)indenyl]amino}butyric acid [M,3R(S)]-4-{[{6-[3-(difluoromethoxy)phenyl]_8_[ 2_fluoro·6·(trifluoromethyl)benzyl]-7-fluorenyl-1·oxy ionyl_5_sideoxy-2,3_dihydro_5Η_Π,3]thiazolo[3, 2-ap-pyridyl-3-ylphenyl)indolyl]aminobutyric acid [U,3S(S)]-4-{[{6-[3-(difluoromethoxy)phenyl]_8_ [2_Fluor_6_(trifluoroanthracene 152524.doc •145· 201130854 base) benzyl]-7-methyl-1-oxo ionyl_5_sideoxy-2,3_dihydro_5H_ [ 1,3]thiazolo[3,2-a]pyridin-3-yl}(stupyl)methyl]amino}butyric acid [1$,311(1〇]-4-{[{6-(4 -Fluoro-1,3-benzodioxan-5_yl)_8_[2-Fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxo _5_sideoxy_2.3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-yl}(phenyl;)indolyl]amino}butyric acid [U, 3S(R)]-4-{[{6-(4-fluoro-1,3-benzodioxole-5-yl)·8· [2-fluoro-6-(trifluoromethyl) Benzyl]-7-methyl-1-oxo-yl-5-oxyl-2.3-dihydro-511-[1,3]° plug. Sit and [3,2-3] 〇 bite -3-yl}(phenyl)indenyl]amino}butyric acid [l$,3R(S)]-4-{[{6-(4-fluoro-1,3-benzo) Dioxole_5_yl)_8_[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxylyl_5_sideoxy_2.3- Hydrogen-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indenyl]amino}butyric acid [U,3S(S)]-4-{[{ 6-(4-Fluoro-1,3-benzodioxole gastric 5_yl)_8_ [2-Fluoro-6-(disorder methyl) alum-based]_7_曱基_ι_ Oxygen ion group _5_sideoxy·2.3-dihydro-5H-[1,3]thiazolo[3,2-a]acridin-3-yl}(phenyl)methyl]amino}butyric acid [l$'3R(R)H2-{[{6-(4-fluoro-1,3-benzodioxole_5_yl)_ 8-[2-fluoro-6-(three Fluorofluorenyl) benzyl]_7_methyloxy yl _5 pendant oxy-2,3-dihydro-5H-[1,3]thiazolo[3,2_a]pyridine _3_yl} (benzene Amino) ethoxy}acetic acid [l$,3S(R)]-(2-{[{6_(4i],3_benzodioxole 5_yl] 8 -[2-Fluoro-6-(trifluoromethyl) adenyl]_7_indolyl 4 oxo group·5 side oxygen 152524.doc • 146· 201130854 基妙工氢-he (1) small sputum and small Heterocentric (6)methyl]amino}ethoxy)acetic acid [W,3R(S)H2-{[{6-(4·fluor{3.benzodioxole·5·yl) )_ 8-[2-Fluoro-6-(three Yue-yl) benzyl] _7_ oxygen ion-yl methyl + _5 • oxo-2,3-dihydro-side -5Η- [1,3] ridge. Sit and [3,2♦ than biting _3_yl}(phenyl)methyl]amino}ethoxy}acetic acid [lg,3S(S)H2_{[{6-(4-fluoro·1,3 _Benzo-trioxolane-5-amino)8_ φ [2_Aconite (trifluoromethyl)benzyl]methyl-1-oxo-yl-5-sideoxy-yl}ethoxy Acetate [U,3R(R)]-4-{[{8-[2-fluoro·6·(trifluoromethyl)phenylhydrazinyl]-7(indolyl)oxy) _5-sideoxy _6_[3_(Trifluoromethoxy)phenyl]_2,3_dihydro_5η_ [1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)indenyl]amine Butyl acid [l$,3S(R)]-4-{[{8-[2-fluoro.6.(trifluoromethyl)benzyl]]7-methyl"oxyl-5-side Oxy-6-[3-(trifluoromethoxy)phenyl]_2,3·dihydro_5H_ φ [I3]thiazolo[3,2_a]epyridin-3-yl}(phenyl)anthracene Amino]butyric acid [l$,3R(S)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-mercapto-yloxyl -5-Sideoxy-6-[3-(trifluoromethoxy)phenyl]·2,3_dihydro_5H_ [1,3] sold "Sit and [3, 2-Wang]. Butyl-3-yl}(phenyl)methyl]amino}butyric acid [l$,3S(S)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzene Mercapto]-7-methyl-(oxy)yl-5-yloxy-6-[3-(tri-I-oxy)phenyl]_2,3-dihydro-5H-[1,3]thiazole And [3,2-a]. Bispin-3-yl}(phenyl)methyl]amino}butyric acid [l$,3R(R)]-4-{[{6-(5-fluoro-2,3-dihydro-1, 4-benzodioxan-6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxo-yl-5- 152524 .doc -147- 201130854 a]pyridine~3_yl}(phenyl) pendant oxy-2,3-monohydro-5H-[1,3]indole[3 2 fluorenyl]amino}butyric acid Fluorine 2,3_dihydrogen j, this well, a heterocyclic hexene _ 6 · yl)-8-[2-fluoro-6d f phenyl) benzyl] _ 7 _ methyl small oxygen ion base _5 · Sideoxy-2,3-dihydro-5 is called 1,3]carbazolo[3,2_a]pyridine_3^(phenyl)indolyl]amino}butyrate Α [14,3R(S) ]-4-{[{6-(5-Fluoro-2 3-di 1 _ι 4-cage - ϋ he 虱i, 4-benzino-oxohexene-6-yl)-8-[ 2-fluoro-6-(trifluoromethyl) benzyl]_7_methyloxy ionic group·5_

Oxyloxy-2,3-dihydro-5Η-[1,3]thiazolo[3,2_a]pyridine·3 κ phenyl) fluorenyl]amino phthalic acid A fluoro-2,3_dihydrogen .14_Benzene#dioxacyclohexanyl-6-yl)·8-[2-fluorodong(trimethyl)benzyl]-7-methyloxy-oxyl-5-sideoxy-2, 3_Dihydro-5η-[ι,3]嗟[and,[3,2_a]m4}a*) methyl]amino}butyric acid [lg,3R(R)H2-{[{6-[3- (difluorodecyloxy)phenyl]8[2 gas-(trifluoromethyl)methyl]-7-fluorenyl-1_oxy ionyl_5_sideoxy-2,3 dihydro_5h_ [1,3]thiazolo[3,2-appyridyl-3-yl}(phenyl)indenyl]amino}ethoxy}acetic acid [U,3S(R)H2-{[{6-[ 3-merfluoromethoxy)phenyl]_8_[2 gas_6 (trifluoromethyl)phenylhydrazino]-7-fluorenyl-i_oxyl group_5•sideoxy-2,3_dihydrogen _5H_ [1,3]thiazolo[3,2-a]&quot;bipyridine-3-(yl)(phenyl)methyl;|amino)ethoxy)acetic acid [U,3R(S)]- (2-{[{6-[3-(Difluoromethoxy)phenyl]_8_[2_gas_6(trifluoromethyl)benzyl]-7-methyl·ι_oxy ion group_ 5_sideoxy-2,3_dihydro_5H_ 152524.doc 201130854 [1,3]thiazolo[3,2-a].pyridin-3-yl}(phenyl)indenyl]amine} Ethoxy)acetic acid [l$,3S(S)]-(2 -{[{6-[3-(Difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxyl -5-Sideoxy-2,3-dihydro-5H-[1,3]thiasino[3,2-a].Bism-3-yl}(phenyl)indenyl]amino}B Oxy) acetic acid [1$, 311*(11*)b (2-{[{6-[3-(1,1-difluoroethyl)-2-fluorophenyl]-8-[2-fluoro -6-(Trifluoromethyl)benzyl]-7-methyl-1-oxoyl-5-yloxy-2,3-dihydro·5Η-[1,3]thiazolo[3, 2-a]pyridin-3-yl}(phenyl)indenyl]amino}ethoxy}acetic acid [U,3R*(S*)]-(2-{[{6-[3_(l,l -difluoroethyl)-2-fluorophenyl]-8-[2-fluoro-6-(trifluoromethyl)phenylhydrazino]_7-fluorenyl_ι_oxy ionyl_5_sideoxy- 2,3-Dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino}ethoxy}acetic acid (2-{[{ 6-[3-(1,1_Difluoroethyl)phenyl]_8_[2-fluoro-6-(trifluoromethyl)phenylindenyl]-7-methyl-1-oxylyl_5_ The pendant oxy-2,3·dihydro-5H-[1,3]thiazolo[3,2-a]acridin-3-yl}(stupyl)methyl]amino}ethoxy}acetic acid. Another embodiment of the present invention provides a compound of the formula (I) and related specific embodiments' which are used as a medicament. In another embodiment, the invention provides a method of treating a GnRH-associated disorder in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of the invention as defined above. In another aspect, the invention provides the use of a compound of the invention as defined above for the manufacture of a pharmaceutical composition for the treatment or prevention of a GnRH related disorder.

S 152524.doc -149- 201130854 The term "treatment" as used throughout this document is used by convention, for example to manage or care for an individual to achieve resistance, alleviation, attenuation, alleviation, amelioration of a disease or condition (such as endometriosis). And the purpose of the condition of uterine fibroids. The term "seven" "*," or "patient" includes organisms that are capable of suffering from a disease or that may otherwise benefit from the administration of the compounds of the present invention, such as human and non-human animals. Humans include human patients with or suffering from diseases such as endometrium, uterine fibroids. The term "non-human animal" includes vertebrate animals such as squirting animals (such as non-human primate sheep cattle, dogs, cats and rodents such as mice) and non-mammals (such as chickens, amphibians, cockroaches). Wait). In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. In another aspect, the invention provides a method of preparing a pharmaceutical composition. The method comprises the step of combining at least one compound of the invention as defined above with at least one pharmaceutically acceptable carrier and bringing the resulting combination into a form suitable for administration. 'The compound of the formula (I) is used as a medicament. In particular, such compounds are useful in the treatment of sex hormone-related conditions in both males and females, and generally mammals (also referred to herein as individuals). For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, excessive menstrual blood (heavy bleeding) (special dysmenorrhea (men〇rrahagia) ) and menstrual difficulties (dysmenorrehea), hirsutism, precocious puberty (prec〇ci〇us 152524.doc -150 - 201130854 puberty), gonadal ster〇 id dependent neoplasia (such as Prostate cancer, breast and ovarian cancer, gonadotrope pituitary adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia (benign) Prostatic hypertrophy), contraception and infertility (eg assisted reproductive therapy, such as in vitro fertilization). The compounds of the invention are also useful as adjuvants for the treatment of growth hormone deficiency and short stature and systemic lupus erythematosus. According to another embodiment of the present invention, the compound of the formula (1) is also suitable and can be used in combination with androgens, estrogens, progestins, SERMs, antiestrogens and antiprogestins to treat the endometrium. Ectopic, fibroids, and for contraception 'and for the treatment of uterine fibroids in combination with angiotensin-inhibitors, sphingosine II receptor antagonists or renin inhibitors. Combination of a compound of formula (I) with a bisphosphonate and other agents for the treatment and/or prevention of disorders of dance, dish acid esters and bone metabolism, and for preventing or treating bone loss or hypogonad energy during therapy of ffiGnRH antagonists Combinations of estrogens, SERMs, progestins and/or androgens with symptoms such as hot flushes are also part of the invention. The methods of the invention comprise administering to a mammal in need thereof an effective amount of a GnRH receptor antagonist, preferably in the form of a pharmaceutical composition. Thus, in another embodiment, a pharmaceutical composition comprising one or more antagonists of the invention and a pharmaceutically acceptable carrier and/or diluent of 152524.doc-151 - 201130854 is disclosed. These and other aspects of the invention will become apparent after reference to the following <RTIgt; To this end, various references to certain prior art, procedures, compounds and/or compositions are described in more detail herein and are hereby incorporated by reference in their entirety. The compounds of the invention may generally be utilized in the form of the free acid or the free base. Alternatively, the compound of the present invention can be used in the form of an acid addition salt or a base addition salt. Accordingly, the term "pharmaceutically acceptable salt" of the compound of formula (I) is intended to cover any and all acceptable salt forms. In addition, prodrugs are also included in the context of the present invention. A prodrug is any covalently bonded carrier which, upon administration of a prodrug to a patient, releases the compound of formula (I) in vivo. Prodrugs are generally prepared by modifying a functional group in such a manner that the modified body is subjected to conventional manipulation or decomposition in vivo to produce a parent compound. Prodrugs include, for example, compounds of the invention wherein the trans-base, amine or sulfhydryl group is bonded to any group which upon decomposition upon administration to a patient to form a hydroxyl, amine or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetic acid and amine functional groups of the formula (1), acetic acid, and benzoic acid (tetra). Further, in the case of acid (-COOH), a purpose such as methyl vinegar, ethyl ester or the like can be used. With respect to stereoisomers, the compound of formula (1) may exist in the form of a palmitic center and may be in the form of a racemate, a racemic mixture, and individual enantiomers or diastereomers. All such isomeric forms are included within the invention, including mixtures thereof. Further, some of the crystalline forms of the compound of the formula (1) 152524.doc • 152·201130854 may be present in the form of a polymorph in the present invention. In addition, some of the compounds of formula (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of the invention. The utility of a compound as a GnRH receptor antagonist can be determined by a variety of assay techniques. Assay techniques well known in the art include the use of cultured pituitary cells to measure GnRH activity (Fa/e#乂, less 1972, P7, 562-572) and measurements with rat pituitary membrane #乂, Mo/. 1983, 23, 44-51) or a membrane-bound radioligand that exhibits cells of the selected receptor as described below. Other assay techniques include, but are not limited to, measuring the effect of GnRH receptor antagonists on GnRH-stimulated calcium flux, regulation of phosphoinositol hydrolysis, and circulating concentrations of gonadotropins in castrated animals. The following describes the utility of these techniques, synthetic radiolabeled ligands, the use of radiolabeled ligands in radioimmunoassays, and the measurement of compounds as GnRH receptor antagonists. In another embodiment of the invention, a pharmaceutical composition comprising one or more GnRH receptor antagonists is disclosed. For the purpose of administration, the compounds of the present invention can be formulated into pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a GnRH receptor antagonist of the invention and a pharmaceutically acceptable carrier and/or diluent. The GnRH receptor antagonist is present in the composition in an amount effective to treat a particular condition, i.e., in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably the amount is toxic to the patient. In general, the pharmaceutical compositions of the present invention may comprise a GnRH receptor antagonist in an amount of from 0.1 mg to 500 mg per day, and more usually from 0.5 mg to 150 mg per day, depending on the route of administration. Appropriate concentrations of 152524.doc -153- 201130854 degrees and doses can be readily determined by those skilled in the art. As with those skilled in the art, a physician or veterinarian ("therapist clinician") can readily determine a therapeutically effective amount or a prophylactically effective amount of a compound of the invention by using known techniques and by observing results obtained under similar circumstances. . The dosage may vary depending on the patient's needs as seen by the care clinician; the severity of the condition being treated and the particular compound employed. Therapeutic clinician considers a number of factors in determining a therapeutically effective amount or dose and a prophylactically effective amount or dose, including, but not limited to, the particular GnRH-mediated disorder involved; the pharmacodynamic profile of the particular agent and its mode of administration and Route; the time course to be treated; the mammalian species, its size, age and general health; the specific disease involved'. the extent or involvement or severity of the disease; the response of the individual; the specific compound being administered; the mode of administration; Bioavailability characteristics of the formulation administered; the selected dosage regimen; the type of concurrent treatment (i.e., the interaction of the compounds of the invention with other co-administered therapeutic agents); and other related circumstances. Treatment can be initiated with a smaller dose than the optimal dose of the compound. Thereafter, the dose can be increased in small increments until the best results in these situations are achieved. For convenience, the total daily dose may be divided as necessary and administered in several ways during the day. Those skilled in the art are familiar with pharmaceutically acceptable carriers and/or diluents. For compositions formulated into &amp; body solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats, and other common additives. The composition may also be formulated as a pill, capsule, granule or lozenge containing a diluent, a dispersing agent and a surfactant, a binder and a lubricant in addition to the GnRH receptor antagonist. 152524.doc • 154· 201130854 Those skilled in the art may, in appropriate ways and in accordance with recognized norms, such as

Remmgton’s Pharmaceutical Gennar〇, Mack

The specifications disclosed in Publishing Co., Easton, PA 1990 for additional deployment

GnRH Receptor Antagonist β In another embodiment, the invention provides a method of treating a sex hormone related condition as discussed above. Such methods comprise administering to a warm-blooded animal a compound of the invention in an amount sufficient to treat the condition. In this case, "treatment" includes preventive administration. Such methods include systemically administering a GnRH receptor antagonist of the invention, preferably in the form of a pharmaceutical composition as discussed above. As used in this article, all! Raw peony drugs include oral and parenteral administration methods. Suitable pharmaceutical compositions for oral administration of σ, GnRH body antagonists include powders, granules, pills, troches, and capsules, as well as liquids, syrups, suspensions, and lotions, which may also include flavoring agents, Preservatives, suspending agents, thickeners and emulsifiers, and other pharmaceutically acceptable additives. For parenteral administration, the compound of the present invention can be prepared in an aqueous solution for injection, which may contain, in addition to the GnRH receptor antagonist, a buffer, a sputum-resistant anti-bacterial agent, and usually Other additives used in these solutions. [Embodiment] The following examples are provided for purposes of illustration and not limitation. In summary, the GnRH receptor antagonists of the present invention can be assayed by the general methods disclosed above, while the following examples reveal the synthesis of representative compounds of the invention. Detailed details and general methods The following table lists the abbreviations used in this paragraph and the example chapters, which have not been described in the body of the text so far.

S 152524.doc -155- 201130854 Abbreviation Meaning Ac Acetyl br Wide peak Cl Chemical ionization d Double peak dd Repeat double peak ddd Double repeat double peak dt Repeat triplet dq Repeat quadruple peak DCM Dimethyl methane DIPEA N, N -Diisopropylethylamine DMF N,N-dimethylformamide DMSO Dioxane eq. Equivalent EI Electron Impact ESI Electrospray Ionization GP General Procedure HPLC Liquid Chromatography LCMS Liquid Chromatography Mass spectrometry LG delocalization m multiple peaks me concentrated multiple peaks (centred multiplet) MS mass spectrometry NMR NMR spectra: chemical shifts (δ) give PR protection groups in ppm Rj retention time rt or rt or room temp. room temperature s single peak Sept sevenfold t or tr triplet TBAF tetra-n-butylammonium fluoride TEA triethylamine TLC thin layer chromatography TFA trifluoroacetic acid 152524.doc -156- 201130854 THF tetrahydrofuran Ts to a subtle S-zone UPLC-MS super The high performance liquid chromatography mass spectrometry NMR peak shape is stated as its appearance in the spectrum, and the possible higher order effect has not been considered. Chemical shifts are given in ppm; all spectra are corrected relative to solvent residual peaks. Except for the case where atropisomerism is observed, the whole is given as an integer. Then use a non-integer; the signal is marked with an asterisk (*), for example (0.5H*). &gt; Ultra Performance Liquid Chromatography/Liquid Chromatography Mass Spectrometry: The term "UPLC-MS (ESI + )" refers to the following conditions: Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 5〇 Χ2·1 mm; dissolving agent A: water + 0.1% formic acid, dissolving agent B: acetonitrile; gradient: 0-1.6 minutes 1-99% B, 1.6-2.0 minutes 99% B; flow rate 0.8 ml/min; temperature: 60 °C; injection: 2 μΐ; DAD scan: 210-400 nm; or instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH Cl8 1.7 5〇χ2· 1 mm; dissolving agent A: water +0.2% Ammonia, dissolving agent B: acetonitrile; gradient: 0-1.6 minutes 1-99% B, 1.6-2.0 minutes 99% B; flow rate 0.8 ml/min; temperature: 60 ° C; injection: 2 μΐ; DAD scan: 210- The 400 nm term "UPLC_MS(ESI+)" refers to the following conditions:

Waters HPLC-MS · Micromass ZQ » PDA 2996 (210-350 nm), column: Waters XBridge 4.6x50 mm C18 3.5 μηι (20 ° C), gradient: 0-8 minutes. 1-99% acetonitrile in water (0.1% formic acid), flow rate 2 ml/min® 152524.doc -157- 201130854 according to IUPAC rules [ACD/Name Batch version 12_00] or use as MDL ISIS Draw [MDL Information Systems Inc (Elsevier MDL)] AutoNom2000 was executed to generate the chemical name. In some cases, the recognized name of a commercially available reagent is used in place of the IUPAC name or the name generated by AutoNom2000. A stereo descriptor is used according to a chemical abstract. The reaction using microwave radiation can be operated with a Biotage initiator (a microwave oven equipped with a robotic device as appropriate). The reported reaction time using microwave heating is intended to be understood as the fixed reaction time after the specified reaction temperature is reached. Compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to those skilled in the art and may have several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, the impurities may be stirred and precipitated using a suitable solvent (stirred outp, in some cases, the compound may be chromatographed, specifically by flash tube column chromatography, using, for example, pre-filled silica gel filtration from Separtis). Cartridges, such as Isolute® Jumbo Gel or Isolute® H2S, are combined with a Flashmaster II Auto Purifier (Argonaut/Biotage) and a dissolving agent such as hexane/ethyl acetate or DCM/ethanol to purify. In some cases The compound can be combined, for example, with a Waters automatic purifier equipped with a diode array detector and/or an on-line electrospray ionization mass spectrometer, in combination with a pre-filled reverse phase column and a leaching agent such as a gradient of water and acetonitrile (which can Containing additives such as trifluoroacetic acid or aqueous ammonia) 'purified by preparative HPlc 152524.doc •158· 201130854 0 In some cases, the purification method as described above can provide functional groups with sufficient verifyability or acidity. The compounds of the invention in the form of a salt, such as in the case of a compound of the invention having sufficient abundance, such as a tritonic acid acetate or formate, Or in the case of a compound of the invention having sufficient acidity, such as a money salt. Salts of this type may be converted to their free base or free acid form, respectively, by various methods known to those skilled in the art, or in subsequent biological assays. As a salt, it is understood that the particular form (e.g., salt, free base, etc.) of a compound of the invention in a form isolated as described herein is not necessarily the only form in which the article can be applied to a bioassay to quantify a particular biological activity. The following schemes and general procedures illustrate the general synthetic route of the compounds of formula (1) of the present invention and are not intended to be limiting. It will be apparent to those skilled in the art that the order of transformation as illustrated in Schemes 1 through 4 can be modified in various ways. The order of transformation exemplified in Schemes 1 to 4 is therefore not intended to be limiting. In addition, the mutual conversion of substituents, such as the conversion of residues Ru, Rib, R2a, ruthenium, Rh, R6, R7 and R8 This can be achieved before and/or after the exemplified conversion. Such modified forms can be, for example, introduction of a protecting group, decomposition of a protecting group, reduction or oxidation of a functional group, halogenation, gold Other reactions known to those skilled in the art are employed, substituted or familiar. Such transformations include the introduction of a conversion form that allows for further interconversion of the substituents. Suitable protecting groups and their introduction and decomposition are well known to those skilled in the art. (See, for example, Greene Λ PGM Wuts, Protective Groups in Organic, 3rd edition Wiley 1999). 152524.doc -159- 201130854 Process 1

The general procedure for the preparation of the compound of Formula 3 starting from the vinegar of Formula 1, W, Rla, Rb, R2a, R2b, R6, Ruler 7, and R8 are as defined in the description of the present invention and in the scope of the May patent. This procedure is suitable for the synthesis of compounds of the formula (I) wherein 丫C is _C( = 〇)NRlaRlb. The compound of formula 3 can be synthesized from the suitably functionalized carboxylic acid of formula 2 by reaction with the appropriate amine HNRlaRlb according to the procedure described in Scheme 1. However, for the formation of indoleamine, all methods known to those skilled in the art from peptide chemistry are available. The acid of formula 2 which can be obtained by saponification from the corresponding ester can be reacted via an activated acid derivative with an appropriate amine in an aprotic polar solvent such as DMF, which may be, for example, in the oxime. At a temperature between the boiling point of the ruthenium/valley, preferably at room temperature with a benzotrisamine and a carbodiimide (such as diisopropylcarbodiimide), or at a point in contact with the solvent At a temperature between them, it is preferred to use a preforming reagent such as 0-(7-azabenzotriazolyltetramethylene hexafluorophosphate (see, for example, Cowrn. 1994, 201-203), or at room temperature. Obtained by an activator such as bicyclohexylcarbodiimide/W-dimethylaminopyridine or #·ethyl·di-n-ylaminopropylcarbodiimide dimethylaminopyridine. 152524.doc -160- 201130854 It may be necessary to add suitable bases such as methylmorpholine, TEA, DIPEA. The entrained amine formation may also be via an acid halide which may be derived from a carboxylic acid with, for example, ethylene dichloride, sulphur chloride or sulphur a reaction of chlorine formed), a mixed acid anhydride (which may be formed by reaction of a retinoic acid with, for example, isobutyl chloroformate), an imidazolide (which may be formed by reaction of a carboxylic acid with, for example, carbonyldiimidazole) or an azide compound (which This can be achieved by the formation of a carboxylic acid by reaction with, for example, a diphenylphosphonium azide.

Furthermore, it is possible to use the method described in C/zem. 1995, (10), 8414-8416, in the presence of trimethylaluminum and in a suitable solvent such as toluene at a temperature from 〇〇C to the boiling point of the solvent. The appropriate amine is reacted with an appropriately functionalized ester of formula 1. Process 2

152524.doc -161- 201130854 Scheme 2 General procedure for the preparation of compounds of formula 6 starting from the ester of formula 1, W, Ria, Rib, R &gt; 2a, R2b, R6, R7 and ruler 8 are as described herein and As defined in the scope of patent application. This procedure is suitable for the synthesis of compounds of the formula (I) wherein Y is -CR3aR3b-NRlaRlt^R3a and R3b comprises hydrogen. The compound of formula 6 can be in the aprotic polar solvent (such as THF or DMF) at a temperature between 0 ° C and the boiling point of the solvent, preferably at 60 ° C, according to the procedure described in Scheme 2. Synthetic precursor 5, suitably functionalized, is synthesized with the appropriate amine HNRlaRlb, where LG is a suitable leaving group such as p-toluenesulfonyloxy (LG is OT) or gas (LG is C1). It may be necessary to chlorinate according to the standard Finkelstein program (51·D. lowers Jr., J. Μ. Sturtevant, J. Am. Chem. Soc. 1955, 77, 4903-4907; M. Γ 1984, 34-35) Precursor 5 (LG is Cl) undergoes further in situ activation. The appropriately functionalized alcohol 4 can be, for example, at a temperature between -20 ° C and the boiling point of the solvent, preferably at room temperature, in an aprotic polar solvent such as dichloromethane. Reacting with p-toluenesulfonic anhydride and dinonylaminopyridine or p-toluenesulfonic acid vapor, catalytic amount of dimethylaminopyridine and a suitable base such as Hiinig base or triethylamine to obtain an activated precursor 5 ° Alternatively, LG may comprise a wake-up portion of oxygen, i.e., a compound of formula 6 may be subjected to an appropriately functionalized aldehyde 5 (LG is hydrazine) with appropriate amine HNRlaRlb using all methods available to those skilled in the art. Amination to synthesize. For example, at a temperature between 0 ° C and the boiling point of the solvent, preferably at room temperature, in the presence of a reducing agent such as sodium triethoxy borohydride, at 152524.doc -162 - 201130854 The appropriately functionalized aldehyde 5 (LG is 0) is reacted with the appropriate amine in a solvent such as toluene. The desired functionalized aldehyde can be prepared according to standard oxidation procedures, such as Dess-Martin oxidation (乂C7^/w. 1996, 335, 588-590) or Swern oxidation ("Cai" 1981, 165-185) Obtained from an alcohol of the formula 4. The alcohol of the formula 4 can be in an aprotic polar solvent such as THF at a temperature between _2 〇r and the boiling point of the solvent, preferably at a temperature. It is obtained by reduction of the corresponding suitably functionalized ester j mentioned above (see Scheme 1) with a suitable reducing agent such as lithium aluminum hydride or lithium borohydride.

8 9 1〇 Scheme 3 The general procedure for the preparation of the compound of formula 10 is from the beginning of formula 1, w, as defined in the scope of the patent application. This procedure is suitable for the synthesis of compounds of formula (I) wherein Y is CR3aR3b_152524.doc-163·201130854 NRiaRlb. The compound of formula 1 can be synthesized from the appropriately functionalized imine and/or hydrazine 9 according to the procedure described in Scheme 3. Since the process disclosed in Scheme 3 can optionally provide a compound of the formula R1 in which Rla and Rib comprise hydrogen, and a compound of the formula 10 in which Rh and Rib comprise hydrogen can serve as a substituent for introducing other substituents Rla and/or Rb other than hydrogen. Precursor. The conversion of the primary amine (Rla and Rlb of formula 10 to hydrogen) to a secondary or tertiary amine, a captanamine, a decylamine, etc., can be accomplished by any of the transformations known to those skilled in the art. For example: reductive amination and/or sulphonation introduces other substituents 1 &amp; and/or Rib 0 of formula 10; Rla and Rib of formula 10 contain a class of formula 1 of hydrogen. The amine can be in a similar manner to that described by the ruler 1980, 695-697 by using a temperature between -78 ° C and room temperature and the boiling point of the solvent, preferably at 〇 C. (Lewis acid), in the presence of titanium tetra-carbide, in a polar aprotic solvent such as dimethoxyethane, with appropriate reducing agent 'such as lithium borohydride to reduce Rlc to hydroxy or 〇-methyl The functionalized ruthenium 9 is synthesized. The R of the formula 10, a &amp; Rlb &amp; hydrogen-containing and different from the hydrogen or the atmosphere of the formula of a certain amine can be used by; ^ (10) into the transaction (price hit &amp; 198 〇, 695·697) The method is similar to 'in a polar aprotic solvent, such as dimethoxy, at a temperature between _78 art and room temperature and the boiling point of the solvent, preferably at o°c. In the presence of a Lewis acid, such as titanium tetrachloride, a suitable Grignard reagent, such as methyl magnesium chloride, is added. Ric self contained by the O-methyl group or a functional group of the suitably be synthesized 9-oxime. 152524.doc • 164 - 201130854 Alternatively, Rla and Rnj of Formula 10 may comprise hydrogen and the first amine of Formula 10 different from hydrogen or hydrazine may be at a temperature between room temperature and the boiling point of the solvent, preferably De-allylation at 80 C in a protic solvent such as ethanol using a suitable catalyst such as palladium on charcoal is carried out from the appropriately functionalized secondary amine 〇 (Rla is a propyl group). In addition to the formation of primary amines (see above), Ru or Rib differs from hydrogen in that the monoamine of formula 10 can also be similar to that described by the ruler (registered at 198, 695-• 697). By being between _78. R and the temperature between the room temperature and the boiling point of the solvent 'preferably at room temperature in a polar aprotic solvent such as dimethoxy ethane, using a suitable reducing agent 'such as lithium borohydride to reduce Ric containing olefin The base is synthesized by appropriately functionalized imine 9 . The secondary amine of the formula 10 in which Rla and Rn of the formula 10 are bonded to form an N-heterocyclic ring may be similar to the method described by "ΖπΗ则# 乂 (乂C/zem. 2009, 74, 1304- 13 13) By using a suitable catalyst, such as Grubbs, at a temperature between room temperature and the solvent point, preferably at 40 ° C, in an aprotic solvent such as diluchloromethane. The catalyst is synthesized by ring closure metathesis (RCM) of a suitably functionalized aminodiene of Rla and R3b.

The amine-based diene 10 wherein Rla and Rsb are alkenyl groups can be in an aprotic non-polar solvent, such as a stupid, at a temperature between -78 ° C and the boiling point of the solvent, preferably at 0 ° C. Wherein the suitably functionalized alkenylimine 9 is obtained by reaction with a suitable Grignard reagent or metallated alkane or alkene, which is commercially available or can be, for example, at between -1 〇 152 °c and the boiling point of the solvent at a temperature, preferably at a temperature of -20 ° C, in an aprotic solvent, use 152524.doc -165 - 201130854 such as butyl or lithium metal from the alkyl dentate Or an alkenyl halide is obtained via a self-metal exchange. The imine or oxime 9 may be suitably employed in a polar solvent such as glacial acetic acid, alcohol or toluene or a mixture thereof at a temperature between room temperature and the boiling point of the solvent, preferably at 60 ° C. The functionalized ketone 8 is obtained by reaction with the appropriate amine H2n_RLc' such as hydroxylamine hydrochloride or guanidinohydroxylamine or allylamine. It may be necessary to add a suitable test, such as a bite or triethylamine. Some reactions may require the use of a Dean_Stark apparatus and/or the addition of a suitable Lewis acid, such as a titanium alkoxide. Ketone 8 can be synthesized in three different ways starting from the appropriately functionalized ester 1 1.) can be at a temperature between room temperature and the boiling point of the solvent, preferably at 6 〇 &lt; In the appropriate catalytic system, such as the ginseng (乂Cb·W 2000, 122, 1 1260-11261; and (d) · Ze&quot;, 2000, 2, 3229-3231) the reference (dipyridinone acetone) _Two (〇)/2_n copper (I) salt of phenoxybenzoate / triethyl phosphite in the presence of an appropriately functionalized thioester 7 in an aprotic polar solvent such as THF ) Square base - acid reaction. In addition, as described recently, Org. Z. (2003, 5, 3033-3035), in the presence of a suitable catalytic system, the appropriate (hetero) aryl tin can be used in place of the self-acid. However, sulphuric acid 7 can be prepared by all of the methods known to those skilled in the art for the formation of thioesters from the acid 2 (see Scheme 1). The acid of formula 2 obtainable by saponification of the corresponding ester of formula 1 can be reacted, for example, via an activated acid derivative with thiophenol in an aprotic polar solvent such as DMF, which can be at 0 ° C with At a temperature between the boiling points of the solvent, preferably at 152524.doc _ 166 · 201130854 at room temperature, for example with hydroxybenzotriazole and carbodiimide, such as N_ethyl-Ν''Ν·-dimethyl Aminopropylcarbodiimide/n,n-dimethylaminopyridine is obtained. 2.) The appropriately functionalized ester j can be used in an aprotic non-polar solvent such as toluene at a temperature between -78 and its boiling point, preferably at room temperature. The metallated (hetero)aryl group is directly converted to the ketone 8, which is commercially available or can be at a temperature between _1 ° C and the boiling point of the solvent. Preferably, at a temperature of _2 Torr, in an aprotic solvent, for example, butyllithium or lithium metal, by direct metallization of _ _ metal exchange or (aro) aromatics (aromat) ) aryl halides are obtained. 3.) In addition, the appropriately functionalized thioester 7 can also serve as a suitable starting material for the transformation described above. Process 4

S, 152524.doc -167- 16 201130854 Scheme 4 The general procedure for the preparation of the vinegar of Formula 1 begins with the propionitrile of Formula 11

Rh Rh, R0, R7 and ruler 8 are as defined in the description of the invention and in the scope of the patent application. This procedure is suitable for the synthesis of a compound of formula (1) which is 5 . The ester of Formula 1 can be prepared from the appropriately functionalized 6-mercaptoidone 16 and suitably functionalized benzo(1)"dioxolane-, according to the procedure described in Scheme 4. , 3-dihydro-indole, 4-benzodioxanyl or (hetero)aryl oleic acid 17 (R is H) or an ester thereof for synthesis. However, for carbon-carbon bond formation and 5, All methods known to those skilled in the art for Suzuki coupling can be used, for example, in a suitable solvent, such as dioxane, between room temperature and boiling point and above the boiling point of the solvent. At a temperature, preferably at a temperature of 130 ° C (using a microwave reactor), in a suitable catalyst and a base, such as a digas (U,-bis(diphenylphosphino)ferrocene) palladium dichloromethane complex and In the presence of an aqueous solution of potassium carbonate, a suitably functionalized 6 iodine oxime ketone 16 (halo is I) with a suitably functionalized benzo[U]dioxolane, 2 , 3-dihydro·1,4·benzodioxanyl or (hetero)aryl carboxylic acid 17 reaction. Synthesis of 6-dentyl-pyridone 16 with 乂Og·C /zem· 2004,(5P,7 830-7835) In a similar manner starting from the corresponding suitably functionalized 6-Η-» than the bite 15 at a temperature between _2 ° ° c and the boiling point of the solvent 'better at room temperature 'In a polar protic solvent such as glacial acetic acid, N-iodobutadiene imide and bromine can be used to introduce the desired halide at the C-6 position of the pyridone core, respectively. It can be synthesized from the appropriately functionalized thiazoline 13 (W is S) and appropriately functionalized Mic acid derivative 14 according to the method developed by 乂2003, 7, 165-169). 13" 塞嗤琳(W is S) 152524.doc -168· 201130854 and monohydroxazole (w is hydrazine) can be obtained via appropriately functionalized imino ether 12 and cytosine Methyl ester hydrochloride, penicillamine methyl ester hydrochloride (乂Ckm·2001, Μ, 6756_6761) and its derivatives or lanyl myristate and its derivatives starting from an appropriately functionalized amidonitrile To synthesize. Process 5

The general procedure for the preparation of the Michleric acid of Formula 14 of Scheme 5 begins with Mickey 18 and R? is as defined in the description of the invention and in the scope of the patent application. Mie's derivative 14 can be purchased (Formula 14, Scheme 5, where Ruler 7 is methyl, ie 5-Ethyl-2,2-dimethyl-1,3-dioxin-4,6- Diketone, 〇8-8::^〇. 72324-3 9-1) or as described in Flow 5 according to Tamamoio ((:/^»2· Co/wmwi 1997, 359-360) at -20 °C between the °C and the boiling point of the solvent, preferably at room temperature, in an aprotic polar solvent, such as gas imitation 'from the commercial sale of misoic acid 18 (2,2-dimethyl-1, 3-Dioxane·4,6-dione, CAS-No. 2033-24-1) and a suitable brewing reagent such as ι_(trifluoroethenyl)-σmrine (R7 is trifluoromethyl) It is synthesized starting or via an activated acetic acid derivative obtainable from Prison Diimidazole, for example, according to the fact that {Bioorganic and Medicinal Chemistry 1997, 5, 749-764).

S 152524.doc -169- 201130854

The general procedure for the preparation of propionitrile of formula 11 of Scheme 6 begins with benzaldehyde of formula 19, and R.8 is as defined in the description of the invention and in the scope of the patent application. The propionitrile of the formula 11 can be purchased [for example, 3-phenylpropionitrile (CAS-No. 645-5 9-oxime); or 3-(2-chloro-6-fluorophenyl)propanenitrile from PARAGOS] or The synthesis is carried out starting from the appropriately functionalized benzaldehyde of formula 19 as described in Scheme 6. A suitable precursor for propionitrile 11 is a suitably functionalized cinnamonitrile 21, however, it can be reduced by all methods known to those skilled in the art for reducing cinnamonitrile, such as by using palladium and hydrogen in methanol or In the catalytic hydrogenation, it is reduced by the town. For the synthesis of low-carbon 2-fluoroalkyl-6-fluoro derivatives, the specific oxime is 6·monofluorodecyl-2-fluoro and 2-fluoro-6-fluoromethyl, 2-fluoro-6-tri Fluorinyl cinnamonitrile acts as a starting material. Reduction of magnesium by sterol must be carried out under more severe conditions, such as extended reaction times. The cinnamonitrile of the general formula 21 can be directly subjected to the appropriately functionalized benzaldehyde 19 via the Wittig-Homer-reaction according to the literature, Bioorganic &amp; Medicinal Chemistry Letters 2007 lj 6280-6285). Or by a two-step procedure using the Knoevenagel condensation/decarboxylation sequence as outlined in Scheme 6. For this purpose, 'the appropriately functionalized benzaldehyde 19 is condensed with 50% aqueous solution of sodium cyanoacetate (CAS-No. 1071-30-9) and the acid 20 is catalyzed by copper 152524.doc-170-201130854 QFairhurst et al. Man, Leii. 1975, 彳 ,, 3 843-3 844) 〇 Process 7

The general procedure for the preparation of the ester of Formula 1 from Scheme 7 begins with the benzaldehyde of Formula 19, and W, R2a, R2b, R6, R7 and Caliper 8 are as defined in the description of the invention and in the scope of the patent application. This procedure is suitable for the synthesis of the general formula (1) compound. The ester of Formula 1 can be synthesized according to the alternative procedure described in Scheme 7. The synthetic steps for introducing the halogen (15-16) and R6 portions are the same as those outlined in Scheme 4, 152524.doc _171 201130854. 6-H-0 is better than bite _15 can be done with οπ 2〇08, to, 9368-9376) similar to one pot program, or by using the /5/n/mra facts (Org. Ze&quot;. 2005, 7, 1971-1974; 7Wra/zec/row 2009, 65, 2 102-2 109) Development of key-catalyzed dehydration cyclization, with appropriate functionalization of serine and cysteine and its derivatives The brewing amine 26 separates the intermediate 13 for synthesis. °Ephedrine and Lysine 13 can be synthesized by dehydrating the respective indoleamine 26 by methods known to those skilled in the art. However, for the formation of indoleamine, all methods known to those skilled in the art from peptide chemistry are available. The appropriate propionic acid of the formula 24 which can be obtained by saponification from the corresponding ester of the formula 23 can be obtained by activating the acid derivative with serine and cysteine and its derivatives in an aprotic polar solvent such as DMF. In response, the activated acid derivative can be used, for example, at a temperature between 0 ° C and the boiling point of the solvent, preferably at room temperature with hydroxybenzotriazole and carbodiimide (such as diisopropylcarbodiimide). Amine), or at a temperature between 0 ° C and the boiling point of the solvent, preferably at room temperature with a pre-formed reagent such as ruthenium hexafluorophosphate (7-azabenzotriazole-1 -yl)_1 , 1,3,3-tetrazole (see for example c/zem. Comm. 1994, 201-203) 'or use such as bicyclohexylcarbodiimide / ## dimethylaminopyridine or ethyl Dimethylaminopropylcarbodiimide•dimethylamino. It is obtained by the activator of biting. It may be necessary to add a suitable base such as hydrazine, TEA, DIPEA. The indoleamine formation may also be via acid complex 25 (which may be formed by the reaction of a carboxylic acid with, for example, ethylene glycol, sulfoxide or sulfonium chloride), a mixed anhydride (which may be a mixture of acid retardant 24 and, for example, chloroformic acid). a reaction of a butyl ester, an imidazolide (which may be formed by the reaction of a dicarboxylic acid with, for example, carbonyldiimidazole) or azide 152524.doc-172·201130854 (which may be derived from a carboxylic acid by, for example, diphenylphosphonium) The reaction of the azide is formed). A suitable precursor for ester 23 is a suitably functionalized cinnamate 22, however, it can be reduced by all methods known to those skilled in the art for reducing cinnamic acid. Reduction by hydration in sterol or catalytic hydrogenation, for example, by the use of palladium and hydrogen (see /awi/io;?&quot;/owrwa/o/'Medicz'wa/ 2002, 45, 3549-3557). The cinnamate of the formula 22 can be used according to the literature by using WWW-tetramethylguanidine (see #乂Organic Letters 1999, 4, 579-582) 'Sodium hydride (see WO 2007/93963) ^ TM ( $- Etemad -Moghadam ψ X Tetrahedron 1984, buckle, 5153-5 166) as a base and suitable for phosphorous carboxyacetate, such as diethylphosphonium carboxyacetate (CAS 1067-74-9) by appropriate functionalization Benzaldehyde 19 was synthesized by the Wittig-Honard reaction. Compounds of formula (I) wherein W is s (=o) (ie, sulfoxide) and S (=0) 2 (ie, sulfone) can be synthesized by any method known to those skilled in the art at any stage of synthesis and according to the present invention. The general procedures and examples outlined in the invention were synthesized from the corresponding sulfides (W is S) and sulfoxides [W is S (=0)], respectively. As mentioned above, the order of transformation as illustrated in Schemes 1 through 3 can be modified in various ways. The order of transformations exemplified in Schemes 1 through 3 is therefore not intended to be limiting. 152524.doc -173- 201130854 Process 8

See Process 1 or See Process 2

See process 3

See Process 4 15-^16 27

The general procedure for the preparation of the compound of Formula 10 from Scheme 8 begins with the ester of Formula 15 'W, RU, Rib, Heart, 1 as defined in the description of the invention and the scope of the patent application. The compound of formula 10 can be initiated in the final stage of the synthesis by using the synthetic method outlined in Scheme 4 for the conversion of W-J, as described in Scheme 8, 'from the appropriately functionalized 6-functional pyridone 28 The benzo[1,3]dioxolyl- or (hetero)aryl moiety (116 is synthesized at (:6). The corresponding functionally functionalized 6-H-pyridone 27 is introduced. Acting as a precursor to 28, 27 is halogenated in the same manner as outlined for Conversions 15-16 in Scheme 4. By appropriately functionalizing 6-H by using the synthetic procedures and methods outlined in Schemes 1, 2 and 3. - Pyridone 27 is readily available from ester 15. 152524.doc • 174· 201130854 General Procedures In the following paragraphs, the general procedure for the synthesis of key intermediates and compounds of the invention is described in detail. General Procedure 1 (GP 1): Wittig - Horner reaction (19-21, Scheme 6) is similar to Garbaccio et al, Bioorganic &amp; Medicinal Chemistry Ze&quot; (10) 2007, /7, 6280-6285 ° at 0 ° C, so that the temperature is maintained substantially at 〇 ° Rate at C to individual aldehydes 19, lithium gasification (1-2 equivalents) and diethyl cyanoguanidine phosphonate The ester (1-2 equivalents) is added dropwise to a stirred solution of acetonitrile (about 1-5 ml per mM vol.) of 1,8-diazabicyclo[5,4,0]unda-7ene ( 1-2 equivalents. The mixture was allowed to warm to room temperature with continued stirring. The mixture was concentrated and poured into ice-cold water. After collecting and washing the crystals, the crude product was used in the subsequent reaction without further purification. GP 2): Knavenner Gail reaction (19-20, Scheme 6) with Lapworth and Baker, a-Cyano-β-phenylacrylic acid. Organic Synthesis', Wiley: New York, 1941; Collect. ^ 1 S- , 18 1-1 83 similar. Add the individual aldehyde 19 to sodium cyanoacetate (50% aqueous solution, 1-1.5 equivalents) and sodium hydroxide (0.5-1% aqueous solution, 0.1-0.2 equivalents) at 40 °C The solution is stirred vigorously. After 30-60 minutes, the heating bath is removed and the reaction is allowed to cool to room temperature. After TLC and/or LCMS indicates complete depletion of the starting material, the pH is adjusted to 1-4 (Concentrated aqueous hydrochloric acid), the precipitated acid 20 is filtered off, washed with cold water and dried in vacuo. The title compound is usually used without further purification. Subsequent reaction 152524.doc -175 - 201130854 General Procedure 3 (GP 3):.. Decarboxylation (20421, Scheme 6) Fairhurst Yu et al., Tetrahedron Lett similar 1975, 44, 3843-3844. The respective acid 20 is mixed with copper oxide (11) (0.01-0.2 equivalent) and stirred vigorously while heating to 120 ° C [some acids may require a higher reaction temperature (up to 200 ° C bath temperature)]. At about 120 ° C, decarboxylation started violently with concomitant fumes. After the carbon dioxide evolution ceases and TLC and/or LCMS indicates complete depletion of the starting material, the oily suspension is filtered through the silica gel. The target compound 21 is isolated by distillation and/or flash column chromatography and/or preparative HPLC purification. General Procedure 4a (GP 4a): Reduction of Cinnamonitrile (21-&gt;11, Scheme 6) (Condition A) is similar to Montgomery et al.' J. Med. Chem. 1993, 36, 55-69. Magnesium swarf (3.0-50.0 eq.) was added to a stirred solution of each cinnamonitrile 21 in decyl alcohol (about 2-10 ml per mmol of cinnamonitrile) at room temperature. Immediately after the start of the reaction (2-3 minutes), it was cooled to 0 ° C and stirred at this temperature until TLC and/or LCMS indicated complete depletion of the starting material (usually 2 hours). The reaction was quenched by the addition of aqueous 6 N aqueous solution and the solid was filtered and evaporated. The reaction mixture was partitioned between EtOAc and EtOAc. The target compound 11 is isolated by distillation and/or flash column chromatography and/or preparative HPLC purification or used in the subsequent reaction without further purification. General Procedure 4b (GP 4b): Reduction of Cinnamonitrile (21-&gt;11, Scheme 6) (Condition B). 152524.doc -176- 201130854 with Bellamy et al., Journal of the Chemical Society, Perkin Chong 2, 1982 161 -168 is similar. Palladium/charcoal (5-10% palladium, about 2-50% by weight) and hydrogen are used at room temperature under normal pressure or high pressure to make each cinnamonitrile 21 in ethyl acetate (about mM cinnamonitrile per milligram). The solution in 2-10 ml) and glacial acetic acid (5.0-10.0 equivalents) was hydrogenated. After TLC and/or LCMS indicated the completion of the reaction, the reaction mixture was filtered through celite®, washed with toluene, glacial acetic acid was stripped with benzene, and the crude Φ was chromatographed and/or distilled to provide the desired propionitrile 11 . General Procedure 5a (GP 5a): Preparation of Imino Ether (11-12, Scheme 4) (Condition A) is similar to 乂, // 〇, Rong·CTiew 2001, &lt;56,6756-6761. Anhydrous hydrochloric acid (&β) was passed through a solution of each of the respective propionitrile 11 in absolute ethanol (about 0.2-10 ml per millimolar) at 〇 °C for 0.5-4 hours. The mixture is concentrated to produce ethyl imino ether hydrochloride 12 in the form of a crystal or an oil. • The target compound is usually used in subsequent reactions without further purification steps. General Procedure 5b (GP 5b): Preparation of Imino Ether (11-12, Scheme 4) (Condition B) Anhydrous hydrochloric acid (&amp;j8) was passed through each of the propionitrile at 0 °C for 0.5-4 hours. 11 in a solution of absolute ethanol (about 0.25 ml per millimolar). Dry n2 was passed through the solution after LCMS indicated the reaction was completed. The resulting ethanol solution of the imino ether hydrochloride 12 was used directly in the subsequent reaction. General procedure 6a (GP 6a): Preparation of thiazoline - u, W is S, Scheme 4) (Condition A) 152524.doc • 177· 201130854 and affair, */· Org·. C/zew. 2001, (56 , 6756-6761. Add triethylamine (1.0-10.0 equivalents) to cysteine hydrochloride or penicillamine hydrochloride (1.0-5 equivalents) in anhydrous DCM at 〇 °C (in a suspension of about 0.5-10 ml per milligram of amino acid derivative), followed by addition of individual imido ether 12 salts in DCM (0.5-10 ml per milligram of iminoethanol) The acid salt was allowed to warm to room temperature while stirring until TLC and/or LCMS indicated the starting material was completely consumed. The reaction mixture was partitioned between DCM and water, and the aqueous layer was extracted with DCM and combined organic layers Washing, drying and concentrating in vacuo. The title compound 13 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. General procedure 6b (GP 6b): Preparation of thiazoline (12-&gt; W is S, Scheme 4) (Condition B) Add ethanol solution of imino ether hydrochloride 12 (see GP 5b) (about 0.2-10 ml per milligram of imino ether) at 0 °C Methyl cysteate hydrochloride or penicillamine methyl ester hydrochloride (1.0-5 equivalents) in a solution of absolute ethanol (about 0.5-10 ml per milligram of amino acid derivative). Amine (1.0-12 equivalents) until the pH of the mixture is basic. The mixture is allowed to warm to room temperature while stirring until TLC and/or LCMS indicates complete depletion of starting material. The reaction mixture is concentrated in vacuo and the residue obtained The mixture is partitioned between DCM and aq. The target compound 13 was isolated. General procedure 7a (GP 7a): Preparation of pyridone (13 - 15, W is S, Scheme 152524.doc -178 - 201130854 4) (Condition A) and 乂' Μσ/ecw/ar 2003, 7,165-169. Add 1,2-dichloroethane (about 0.05-2.0 ml per mM thiazoline) pre-saturated with hydrochloric acid (Aa) to each thiazoline i3 (at room temperature) w is S) and the derivative of Michael's acid 14 (1·〇-5·〇 equivalent) in 丨, 2· dichloroethane (per mM thiazole) In a solution of about 0.5-10 ml), the reaction mixture was heated to 140 in a Biotage initiator microwave oven. (:, for 120 seconds, after which TLC and/or LCMS analysis usually showed complete conversion (otherwise addition of Mic acid was added again) Event 14 and continue heating to 14 〇t: 'until TLC and/or LCMS analysis shows completion of the conversion). After removal of the solvent, the title compound is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. The reaction mixture is concentrated in vacuo and the residue obtained is dissolved in DCM. The organic layer was washed with aqueous sodium bicarbonate and brine, dried and evaporated. Purification of target compound by crystallization and/or flash column chromatography and/or preparative HPLC purification 15 ° General procedure 7b (GP 7b): Preparation of pyridone (13 - 15, bomb 3, Scheme 4) (Condition B) Trifluoroacetic acid (1 equivalent) is added to each of the thiazoline i3 (w is s) and the Michaelic acid derivative 14 (10_50 equivalents) at room temperature in 曱 或 or i 2 dichloroethane (per 毫In a solution of morthiazolidine about 55. 5 〇 ml). The reaction mixture was refluxed for 2 hours, after which time TLC and/or LCMS analysis generally showed complete conversion (otherwise the addition of the Michler acid derivative 14 and continued reflux until TLc and/or LCMS analysis showed completion of the conversion). After removal of the solvent, the target compound 15 is isolated by crystallization 152524.doc -179.201130854 and/or flash column chromatography and/or preparative HPLC purification. Alternatively, the reaction mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. The target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. General procedure 7c (GP 7c): Preparation of pyridone (13-&gt;15, W is S, Scheme 4) (Condition C) 1,2-dioxaethane pre-saturated with hydrochloric acid at room temperature (per Monomethylthiazoline (0.05-2.0 ml) is added to each of the thiazoline 13 (W is S) and the Michaelic acid derivative 14 (1.0-5.0 equivalent) to 1,2-dichloroethane (per millimole) In a solution of thiazoline in about 0.5-10 ml). The reaction mixture was refluxed for 2 hours, after which time TLC and/or LCMS analysis generally showed a complete conversion (otherwise the addition of the Michler acid derivative 14 and continued reflux until TLC and/or LCMS analysis showed the conversion was complete). After removal of the solvent, target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. Alternatively, the reaction mixture was concentrated in vacuo and the residue obtained was dissolved in DCM. The organic layer was washed with aqueous sodium bicarbonate and brine, dried and evaporated. The target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. General Procedure 8 (GP 8): Preparation of 6-iodo·pyridone (15-16, halide I, Scheme 4) is similar to Aimqvist et al., J. 〇rg. Chem. 2004, 69, 7830-7S35. N-iodobutylimine (1.5-5.0 equivalents) was added to each 152524.doc -180- 201130854 at room temperature in the pyridone 15 in acetic acid (about 2-6 ml per millimolarone) And in a stirred solution of TFA (about 0.1-0.25 ml per milligram of pyridone). After the TLC and/or LCMS indicated that the starting material was completely consumed, the reaction mixture was poured on ice water and the precipitate was washed with saturated aqueous sodium hydrogen carbonate. Alternatively, the reaction mixture was partitioned between DCM and aqueous sodium thiosulfate, the aqueous layer was extracted with DCM and the combined organic layers were washed, dried and concentrated in vacuo. The target compound 16 (halogen is I) is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. General Procedure 9 (GP 9): Preparation of 6-bromo-pyridone (15416, halide is Br, Scheme 4) Similar to ^, /, Org. 2004, (59, 7830-7835. at 10 ° C Bromine (0.85-2.0 equivalents) was added dropwise to a stirred solution of each of the pyridone 15 in acetic acid (about 2-10 ml per millimolar). The mixture was allowed to warm to room temperature and TLC and / After the LCMS indicates that the starting material is completely consumed, the reaction mixture is poured on ice water and the precipitate is washed with a saturated aqueous solution of sodium hydrogencarbonate. Alternatively, the mixture is partitioned between DCM and aqueous sodium thiosulfate. The combined organic layers are washed, dried and concentrated in vacuo. The title compound 16 (dentate is Br) is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. General procedure l〇a (GP 10a): Suzuki coupling (16-1, Scheme 4) (Conditional Α) Add each _acid (1.0-5.0 eq.) and aqueous potassium carbonate solution (0.8-5.0 eq, 1,5 M) at room temperature To a solution of 6-halo-pyridone 16 in dioxane (about 2-50 ml per milligram of pyridine) followed by several minutes

S 152524.doc • 181 - 201130854 argon is bubbled through the reaction mixture followed by the addition of dichloro(丨, 丨, bis(diphenylphosphino)ferrocene) palladium dichloromethane complex (Oi-0.5 equivalent) . The reaction mixture was heated to 13 (rc for 6 min in a 31 〇 "# initiator microwave oven, after which TLC and/or LCMS analysis usually showed complete conversion (otherwise adding the respective acid and/or catalyst again and continuing to heat to 3 〇 It is until TLc and/or LCMS analysis shows that the conversion is complete. After the reaction is completed, the mixture is filtered through a pad of celite, and the filtrate is diluted with ethyl acetate and washed with water and brine. Drying of organic layer, evaporation of solvent and flash Column chromatography and / or preparative HPLC yield the target compound 1. General procedure 10b (GP 10b): Suzuki coupling, flow sentence (condition B) at room temperature, each will be the same acid (1_〇_5. 〇 equivalent)) is added to a solution of 6_dentyl-pyridone 16 in dioxane (about 2-5 mM per milligram of pyridine). Then argon is bubbled through the reaction mixture for several minutes, followed by addition. An aqueous solution of potassium carbonate (0.8-5.0 eq., ι·5 M) and two gases (ι,ι, bis(diphenylphosphino)ferrocene) (0.1-0.5 eq.). The reaction mixture was placed in a preheated oil bath. (80 C) and then heated under reflux until tlc and / or LCMS indication The starting material is completely depleted. Further addition of each of the facial acid, aqueous potassium carbonate and monochloro (1, bis-bis(diphosphine) ferrocene) palladium may be necessary for complete conversion. After the reaction is completed, the mixture is celite The pad is filtered, and the filtrate is diluted with ethyl acetate and washed with water and brine. Drying of organic layer, evaporation of solvent and flash column chromatography and/or preparation of &lt;11&gt;] 1 (:: target compound formation. General procedure ll (GPll): saponification (1-2, Scheme 1) Add 'Liquid Lithium Hydroxide equivalent, 〇5_1 M) to each ester 1 in THF (about 1:1 ml per mM of lactone) and / at room temperature Or a mixture of sterols and / or 152524.doc • 182 · 201130854 alcohol (per millimolar solution) and stir until TLC and / or LCMS indicates complete depletion of the starting material (usually 2 hours) The pH is then adjusted to 3-4 (aqueous citric acid or 2 N aqueous hydrochloric acid). The aqueous layer is extracted with ethyl acetate and the organic layer is dried and concentrated in vacuo. / or methanol. Target compound 2 by flash column chromatography and / or preparative HPLC purification or use in the subsequent reaction without further purification step. General procedure 12 (GP 12): guanamine formation (2 ~ > 3, Scheme 1) at room temperature '1H- Base stray triazole (1.0-1.5 equivalents) and N-ethyl_N,N-methylamino-propylcarbodiimide (1·〇·ΐ·5 equivalents) added to each acid 2 In a stirred solution of DMF (about 1-1 liter per mmol of oleic acid). After 1 hour at room temperature, add the respective amines to DMF (about 1 _ i 〇 ml per millimole of acid). The solution was stirred and continued until TLC and/or LCMS indicated complete consumption of starting material. The reaction mixture was partitioned between EtOAc and EtOAc. The target compound 3 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization. Alternatively, the product can be isolated by pouring the reaction mixture into ice water and filtering the target compound 3. General Procedure 13 (GP 13): Reduction (1-4, Scheme 2) Add lithium borohydride (1.0-4.0 equivalent; 2 Μ solution in THF) to each ester 1 in THF at -20 °C In the mixing solution (about 1-1 ml per mmol of mole). After stirring at the temperature for 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched by the addition of water after TLC and/or LCMS indicated that the starting material was completely consumed. The reaction mixture was partitioned between EtOAc EtOAc EtOAc. The title compound 4 is isolated by flash column chromatography and/or preparative HPLC purification or used in the subsequent reaction without further purification. General Procedure 14 (GP 14): Formation of tosylate (4 -&gt; 5, LG is OT, Scheme 2) N,N-dimethylaminopyridinium (2.0-5.0) at 〇 °C Equivalent) and p-toluenesulfonic anhydride (1.0-2.5 equivalents) were added to a stirred solution of the respective alcohol 4 in DCM (about 1-20 ml per mmol of alcohol). The reaction mixture was maintained between 0 ° C and 1 ° C until TLC and/or LCMS indicated complete consumption of starting material. The reaction mixture was partitioned between DCM and water. The target compound 5 (LG is OT) is isolated by flash column chromatography and/or preparative HPLC purification or used in the subsequent reaction without further purification. General Procedure 15 (GP 15): Formation of vapors (4-5, LG is CM, Scheme 2) at 〇 ° C, Ν, Ν-dimethylamino-based pyridine (0.1-1.0 equivalents) P-toluenesulfonic acid vapor (1.0-2.5 equivalents) was added to a stirred solution of the respective alcohol 4 in DCM (about 1-10 ml per mmol of alcohol). The reaction mixture was allowed to warm to room temperature and was monitored until TLC and / or LCMS indicated the starting material was completely consumed. The reaction mixture was partitioned between EtOAc and EtOAc. The target compound 5 (LG is C1) is isolated by flash column chromatography and/or preparative HPLC purification or used in the subsequent reaction without further purification. 152524.doc _ 184· 201130854 General procedure 16a (GP 16a): Amine formation (5_&gt;6, LG is hydrazine, Scheme 2) (Condition Α) Add each amine (10_1() 〇 equivalent) at room temperature To a separate stirred solution of the respective tosylate 5 (LG is hydrazine, Scheme 2) in THF (about 1-50 ml per millimole of tosylate) and warmed to 5 (TC) until TLc and/or LCMS showed the starting material was completely consumed. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed, dried and concentrated in vacuo. Purification or crystallization of the target compound 6 by flash column chromatography and/or preparative HPLC. General procedure 16b (GP 16b): amine formation (5~&gt;6, LG is OT, Scheme 2) (Condition B; for parallel Synthesis) Each of the respective amines (1.0-10.0 equivalents) in DMF (about 0.5-25 ml per mmol of toluenesulfonate) is added to each of the different phthalic acid esters at room temperature (l〇 〇Τ 'Scheme 2) in a stirred solution of DMF (about 0.5-25 ml per millimole of tosylate) and warmed to 50 ° C for 15 hours. The reaction mixture φ was methanol ( Dilute benzenesulfonate (about 1-50 ml) was diluted and concentrated in vacuo. Purification by preparative HPLC and lyophilization of title compound 6. General procedure 17 (GP 17): amine formation (5-6, LG is C1, Scheme 2) Add each amine (1.0_3〇_〇 equivalent) to each chloride 5 (LG is C1 'Scheme 2), sodium carbonate (i.〇) at room temperature in several portions. -i (h〇 equivalent) and moth (1.0-10.0 equivalents) in a stirred solution of DMF (about 1.0-75 ml per milligram of chloride) and warmed to 80-150t: until TLC and / or LCMS indicated that the starting material was completely consumed. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed and dried 152524.doc-185-201130854 dried and dried. The target compound 6 is isolated by flash column chromatography and/or preparative hplc purification or crystallization. General procedure 18 (GP 18): Reductive amination [5~&gt;ό, LG is 〇, Scheme 2] Add to the respective aldehydes 5 (LG is hydrazine, Scheme 2) and the respective amines (1. 〇 _ 5. 〇 equivalent) in 数The stirred solution in benzene (about 1-5 ml per mM molar) is stirred at this /m·degree until TLC and/or LCMS indicates complete depletion of the starting material. Between water, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed, dried and concentrated in vacuo. The title compound 6 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization. General Procedure 19 (GP 19): Thioester Formation (2-7, Scheme 3) 1H-Hydroxybenzotriazole (1.0-1.5 equivalents) and ethyl_NN-monomethylamino group at room temperature Propylcarbodiimide (1_0-1_5 equivalent) was added to a stirred solution of the respective acid 2 in DMF (about 1-15 ml per mmol of moric acid). After 1 hour at room temperature, a solution of thiophenol in DMF (about 355 ml per mmol) was added and stirring was continued until TLC and/or LCMS indicated the starting material was completely consumed. The reaction mixture was partitioned between EtOAc EtOAc m. Alternatively, the reaction mixture was poured into a mixture of ice water and a saturated aqueous solution of sodium hydrogencarbonate. The formed precipitate was filtered off and washed thoroughly with toluene and water. The filtrate was separated and the aqueous layer was extracted with a pad. The combined organic layers were washed, dried and concentrated in vacuo. The target compound 7 is used in the subsequent reaction by flash column chromatography and/or preparative HPLC purification and/or crystallization separation or without further purification step 152524.doc •186-201130854. General procedure 20a (GP 20a): Liebeskind coupling (748, flow 3) (condition A) is similar to the case, j_CTzew. Soc. 2000, 722, 11260-11261. At room temperature, each thioester 7 in THF (about 1-5 ml per mM thioester, degassed with argon) is added to each _acid (1.0-1.5 eq.), 2-nonyl carboxylic acid Copper (1+) salt (1.0-1.5 equivalents) and ginseng (dibenzylideneacetone)-di-palladium (0) (0.05-0.5 equivalents). Triethyl phosphite (0 丨 丨〇 丨〇 equivalent) is then added and the reaction mixture is heated under reflux until TLC and/or LCMS indicates complete depletion of starting material. Further add each carduic acid, 2-. Copper (1 +) salt, ginseng (dibenzylideneacetone)-two (0) and triethyl phosphite may be necessary for complete conversion. The reaction mixture was partitioned between EtOAc EtOAc m. The target compound 8 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General procedure 20b (GP 20b): Liebeskind coupling (7-8, Scheme 3) (Condition B) is similar to 乂, (&gt;Zeii. 2003, 5, 3033-3035. At room temperature and in argon Under the atmosphere, add each tin-tin (1.〇_2 equivalent) to the search solution in the respective sulphur vinegar 7 in THF (about 1 - 25 ml per millimolar sulphuric acid). Then add diphenyl in sequence. Copper phosphinate (1) (1-2.5 equivalents), tris(2-furanyl)phosphine (0.04-0.8 equivalents) and ginseng (dibenzylideneacetone)·Diji (〇) (〇.〇〇5- 〇·1 equivalent) and heat the reaction mixture to 50 ° C until tlc and / or

S 152524.doc -187- 201130854 LCMS indicated that the starting material was completely consumed. Further addition of each of the tin-sinter, copper (I) diphenylphosphinate, tris(2-indolyl)phosphine and ginseng (dibenzylideneacetone) to the genomic (〇) may be necessary for complete conversion. The reaction mixture was transferred via ceiite® and the filtrate was concentrated in vacuo. The target compound 8 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General procedure 21a (GP 21a): hydrazine formation (8-9 '111&lt;: hydroxy or hydroxy fluorenyl; Scheme 3) (Condition A) 'Different hydroxylamine hydrochloride (1.0-10.0 eq.) at room temperature Add to the respective ketone 8 in a stirred solution of tributanol (about 0.25 ml per mM ketone) and ethanol (about 1-25 ml per millimole of steel). Titanium (IV) tert-butoxide (2.0-8.0 equivalents) was then added and the reaction mixture was heated to 8 Torr. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried and concentrated in vacuo. The target compound 9 is used in the subsequent reaction by flash column chromatography and/or preparative HPLC purification and/or crystallization separation or without further purification. General procedure 21b (GP 21b): hydrazine formation (8-9, Ru is hydroxy or hydroxymethyl; Scheme 3) (Condition B) Each hydroxylamine hydrochloride (1 〇 1 〇〇 equivalent) at room temperature Add to the respective ketone 8 in a stirred solution of t-butanol (about 0.25 ml per mM ketone) and toluene (about 1-25 ml per mM ketone). Pyridine (about 1-10 ml per mM ketone) was added and the reaction mixture was heated to EtOAc until LCMS indicated the starting material was completely consumed. The reaction mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The target compound 9 is used in the subsequent reaction by flash column chromatography and/or preparative HPLC purification and/or crystallization separation or without further purification. General Procedure 22 (GP22): Imine Formation (8-&gt;9, Scheme 3) Similar to Capretta et al. &gt; Tetrahedron Lett. 2002, 43, 7687-7690® At room temperature, the appropriate titanium (IV) Lewis The acid (1.0-8.0 equivalents) was added to a separate solution of the respective amines (1.0-10.0 equivalents) and the respective ketones 8 in toluene (about milliliters per milligram of gram). Depending on the nature of the amine, the reaction mixture is stirred or heated to elevated temperature or 100 ° C at ambient temperature until TLC and/or LCMS indicates complete depletion of the starting material. The reaction mixture was partitioned between EtOAc (EtOAc)EtOAc. The target compound 9 is used in the subsequent reaction by flash column chromatography and/or preparative HPLC purification and/or crystallization separation or without further purification. Alternatively, the reaction mixture is concentrated in vacuo and the crude title compound 9 is used in the subsequent reaction without further purification. General procedure 23a (GP 23a): Reduction of hydrazine (9_^1〇, Rie is hydroxy or hydroxymethyl; Scheme 3) (Condition A) Lithium borohydride (10-80 equivalents in THF) at 〇 °c 2 "Solution" is slowly added to the titanium chloride (IV) (1.0-4.0 equivalents) in 丨, 2 · dimethoxyethane (about 50 ml per millimolar) in a mixture of 10 minutes ^ Add J肟9 in 1,2-methoxyethane (about 1-20 ml per millimolar) and continue stirring for 丨 hours under 〇c. Then increase the reaction mixture by 152524.doc 201130854 warm to room Warm and stir until TLC and / or LCMS indicates complete depletion of the starting material. After cooling to 〇 ° C, the reaction was quenched by the addition of water and aqueous ammonia (33% by weight). The mixture was partitioned between DCM and water. The solid is decanted, the aqueous layer is extracted with DCM and the combined organic layers are dried and concentrated in vacuo. The title compound 10 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. (GP 23b): Reduction of hydrazine (9-10 'Rk is hydroxy or benzyl group; Scheme 3) (Condition B) and Ο/ζ/ζαα 乂, 2000, 556, 245-253 Similarly, slowly add sodium borohydride (1.0-25.0 equivalents) to chlorinated (IV) (l.〇-15.〇 equivalent) to i,2-dimethoxyethane at 〇°C In a stirred solution of about 15 ml), after 10 minutes, add to each of the 1&gt;2_dioxane (about 1-20 ml per millimolar) and The mixture was further stirred for 1 hour, then the reaction mixture was allowed to warm to room temperature and stirred until TLC and / or LCMS indicated that the starting material was completely consumed. After cooling to hydrazine. - by adding water and ammonia (33% by weight) quenching reaction. The mixture was partitioned between DCM and water, the solid was filtered, the aqueous layer was extracted with EtOAc, and the combined organic layer was dried and concentrated in vacuo. / or preparative HPLC purification and / or crystallization separation of the target compound 1 〇 General procedure 23c (GP 23c): reduction of hydrazine (9 - 10 'Ru is hydroxy or benzyl group; Scheme 3) (Condition C) (10) Anthrax, 1980, 695-697 is similar. Slowly add sodium borohydride (1.0-8.0 equivalents) to chlorinated (IV) to 1,2-dimethoxyethane at 〇 °C (莫 肟 肟 uo 毫升 152 152 152524.doc • 190· 201130854 liquid. After 10 minutes, add 1,2-dimethoxyethane (about 1-20 ml per millimolar) The mixture was stirred for 1 hour, and the reaction mixture was allowed to warm to room temperature and stirred until TLC and / or LCMS indicated that the starting material was completely consumed. Cool to 〇. After hydrazine, the reaction was quenched by the addition of water and aqueous ammonia (33% by weight). The mixture was partitioned between DCM and water, and the solid was filtered off. The aqueous layer was extracted with DCM and the combined organic layers were dried and concentrated in vacuo. . The target compound 1 oxime is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General Procedure 24a (GP 24a): Add c nucleophile (9-»1〇, Scheme 3) (Condition A) to Kano et al. Synthesis 1980, 695-69711. Titanium chloride (ΐν) (1·〇-ΐ〇.〇 equivalent, 1 Μ solution in CH2C12) was slowly added at -78 °C to each 肟9 in dimethoxyethane (per millimolar) The ear is in a stirred solution of about 1-50 ml). The respective Grignard reagent (1.0-10.0 eq.) was then added and stirring was continued while the reaction mixture was gradually warmed to 60 C ' until TLC and/or LCMS indicated the starting material was completely consumed. Subsequent addition of Lewis acid and/or Grignard reagents may be necessary to drive the reaction to completion. The reaction was quenched by the addition of water and aqueous sodium hydroxide (2 Μ). The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The target compound is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General procedure 24b (GP 24b): Addition reaction of imine with C nucleophile (9~&gt;1〇, Scheme 3) (Condition B); and 似,乂2009,74,1304-1313 Class 152524 .doc • 191 · 201130854 Similar. A solution of each of the Grignard reagents (1.0-10.0 equivalents) was slowly added to a stirred solution of each of the respective imines 9 toluene (about 1-25 ml per millimolar) at 〇 ° C, and Stirring was continued at 0 ° C or room temperature until TLC and/or LCMS indicated complete consumption of starting material. The reaction is quenched by the addition of π 7jc, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuo. Purified by flash column chromatography and/or preparative HPLC purification and/or crystallization. Target compound 10. General procedure 25a (GP 25a): - N-alkylation or N-deuteration of the amines [foot" and Rib is hydrogen 10 -&gt; RU and / or R丨b are different from hydrogen, process 3 (Condition A) Add a solution of 'suitable alkylation or deuteration reagent 0 0 equivalents at room temperature to 00 equivalents of each of the primary amine 10 and N-ethyldiisopropylamine. a stirred solution of acetonitrile or DMF (per millimolar primary amine _25 ml). Stir the reaction mixture at ambient temperature or if necessary at elevated temperature until TLC and/or LCMS indicates complete depletion of the starting material. Adding a hydrazine or a saccharifying agent and/or a base to drive the reaction to completion. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and evaporated. Concentration. The alkylated/deuterated compound 10 is used in subsequent reactions by flash column chromatography and/or preparative HPLC purification and/or crystallization or without further purification. Alternatively, the reaction mixture is Concentration in vacuo and the resulting alkylated/deuterated compound crude product 10 was used without further purification Subsequent reaction, or purified by flash column directly via and / or preparative HPLC chromatographic purification. 152524.doc

S -192- 201130854 General procedure 25b (GP 25b): - N-alkylation of the amine by reductive amination [Rla and Rib contain the mouse 1〇~^Rla and/or Rib is different from the mouse 10' Process 3]. (Condition B) Add sodium triethylsulfonium borohydride (1.0-10.0 equivalents) to a suitable solvent (such as toluene) containing the respective aldehydes (1.0-5.0 equivalents) and the respective primary amines 10 at room temperature. To a stirred solution of THF or decyl alcohol (about 1-50 ml per mmol of olamine) and stirring at this temperature until TLC and/or LCMS indicated complete depletion of starting material. The reaction mixture was partitioned between EtOAc and EtOAc. The alkylated compound 10 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization. General procedure 25c (GP 25c): - N-deuteration of the amine [Rla & Rlb is hydrogen 10 - Rla and / or Rlb is different from hydrogen 10, Scheme 3]. (Condition C for parallel synthesis) The amine (0.1-0.3 mmol in 0.2-0.6 mL DCM, THF or DMF) was cooled to 0 ° C under inert atmosphere and triethylamine (0.1-0.6 mmol) was added sequentially. In 0.1-0.4 mL of DCM, THF or DMF) and oximation agent (chlorinated carbon, Sf chlorine, isocyanate or isothiocyanate); 0.1-0.6 mmo 1 in 0.2-0.6 mL DCM, In THF or DMF). After further 1 minute at 0 ° C, the mixture was warmed to 20-80 ° C, stirred at this temperature for 2 to 24 hours and concentrated. The title compound 10 was isolated by preparative HPLC purification and lyophilization. General Procedure 26 (GP 26): ring closure metathesis of an amine diene [1113 comprising an alkenyl group and R3b comprising an alkenyl group - Rla and R3b are joined to form an N-heterocyclic ring 10, Scheme 3]. 152524.doc -193- 201130854 Add an appropriate RCM catalyst, such as Grubbs second generation catalyst (0.05-0.5 equivalents), to each of the respective aminodiene 10 in a suitable solvent, such as di-methane (per millimole) at room temperature. Deaze in about 1-50 ml of eramide diene and stir the solution and stir it at this temperature or heat it to 40 ° C until TLC and/or LCMS indicates complete depletion of the starting material. The N-heterocyclic compound 10 is isolated by flash column chromatography and/or preparative HPLC purification. General Procedure 27a (GP 2 &lt;7a): Sulfide (W is S) is oxidized to sulfoxide [W is S(=0)] or sulfone [W is S(=0)2] and sulfoxide [W is S ( =0)] oxidized to sulfone [W is S(=0)2] (Condition A): m-chloroperoxybenzene is preferably used in several portions at -20 ° C to room temperature under 〇 ° C Capric acid (mCPBA) (1.0-5.0 equivalents) is added to the respective sulfide or sulfoxide in a suitable solvent such as dichloromethane or gas (about 1-50 ml per millimole sulfide / sulfoxide). Stir in the solution and at this temperature until TLC and/or LCMS indicate complete depletion of the starting material. It may be necessary to add mCPBA and/or solid sodium bicarbonate. The reaction mixture was partitioned between EtOAc (EtOAc)EtOAc. The oxidized compound is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General Procedure 27b (GP 27b): Sulfide (W is S) is oxidized to sulfoxide [W is S(=0)] or 飒 [W is S(=0)2] and sulfoxide [W is S (= 0) )] oxidized to sulfone [W is S (= 〇) 2] (Condition B): at -20 ° C to 80 ° C, preferably at room temperature, the appropriate oxidant, such as hydrogen peroxide or hydrogen peroxide Tributyl (1.0-10.0 eq.) is added to the respective sulfide or sulfoxide in a polar protic solvent such as acetic acid (about 152,524.doc -194 - 201130854 per millimolar / about 1-50 ml of hydrazine) The stirred solution is stirred at this temperature until TLC and/or LCMS indicates complete depletion of the starting material. It may be necessary to continue to add oxidant and/or heat the reaction mixture. The reaction mixture was partitioned between EtOAc EtOAc EtOAc. The oxidized compound is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General procedure 27c (GP 27c): sulphide (W is S) oxidized to sulfoxide [W is s (=o)] or sulfone [W is S (=0) 2] and yttrium [W is S (=0) )] oxidized to hydrazine [W is S (= 〇) 2] (Condition C): At -20 ° C to 80 ° C, preferably at room temperature, the appropriate iodine agent, such as (partial) periodic acid Sodium or (original) periodate (1.0-7.0 equivalents) added to the respective sulfides or arsine in a polar solvent such as acetonitrile or alcohol (about 1-50 ml per millimole sulfide / hydrazine) Stir in the solution and at this temperature until TLC and/or LCMS indicates complete depletion of the starting material. It may be desirable to add a catalytic amount of a suitable metal salt, such as iron (III) chloride and/or to add an iodine agent and/or to heat the reaction mixture. The reaction mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The oxidized compound is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General procedure 28a (GP 28a): guanamine formation (24-26, W is Ο, Scheme 7) is similar to 乂/wgWW 2008, &lt;54, 9368-9376. 6-azabenzotriazole-1,6-azabenzoate, at room temperature -Base)-7V, iV, W, W-tetrakis(HATU) (0.5-4.0 equivalents) added to 1H-hydroxybenzotriazole (1.0-2.0 equivalents), each propionic acid 24 (2.0-4.0 equivalents) And 2,6-dimercaptopyridine (2.0-6.0 eq.) in a stirred solution of DMF (1-50 ml per mmol of amino acid). Then add methyl ceramide (W is hydrazine) or a mixture of individual amino acids or amine hydrochloride/triethylamine (1:1) in DMF or DCM (about 1-10 ml per mmol of amino acid) The solution in the solution was continued to stir until TLC and/or LCMS indicated complete elution of the starting material. Further addition of triethylamine may be required. The reaction mixture was partitioned between EtOAc and EtOAc. The target compound 26 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. Alternatively, the product can be isolated by pouring the reaction mixture into ice water and filtering the target compound 26. General Procedure 28b (GP 28b): Indoleamine Formation (24-&gt;26, W is hydrazine, Scheme 7) Appropriate 2-amino acid vinegar (10 mmol) was added to the 〇 ° C under nitrogen. Appropriate acid gasification (16 mmol) and 7V-ethyldiisopropylamine (2.7 mL, 16 mmol, 1.6 eq; in the case of the use of the amino acid ester hydrochloride, the amount of base must be adjusted accordingly) to acetonitrile Or in a stirred solution in DCM (150 mL). After stirring until TLC and/or LCMS indicated the starting material was completely consumed, the mixture was quenched with saturated aqueous ammonium chloride (150 mL). The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. General Procedure 29a (GP 29a): Pyridone Formation (26-15, W is Ο, Scheme 7) and ΤΆ/Ζζαγα Facts 2009, &lt;55, 2102-2109) and 152524.doc -196· 201130854 Event 2008 , to, 9368-9376) is similar. Ammonium molybdate [(ΝΗ4)2Μ〇04] (0.005-0·50 eq.) was added to a stirred solution of decylamine 26 in toluene (10-100 ml per mmol of melamine) at room temperature. The solution was heated to reflux while water was removed using a Soxhlet apparatus containing activated 3 Å molecular sieves. After the TLC and/or LCMS indicated complete elution of the starting material, the reaction mixture was cooled to room temperature. The Mie acid derivative 14 (1.0-3.0 equivalent) and TFA (1.0-10.0 equivalent) were sequentially added. The solution was heated to reflux until TLC and / or LCMS indicated the starting material was completely consumed. It may be necessary to further add the Michleric acid derivative 14 . The solution was allowed to cool to room temperature, filtered through celite and concentrated. The target compound 15 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. Alternatively, the reaction mixture was partitioned between EtOAc EtOAc m. The target compound 15 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General procedure 29b (GP 29b): Pyridone formation (13 - 15, W is 0, Scheme 7) Millitic acid derivative 14 (1.0-3.0 equivalents), TFA or pyridinium pyridinium (1.0-10.0 equivalents) It is added sequentially to a stirred solution of the appropriate oxazoline or thiazoline 13 in toluene. The solution was heated to reflux until TLC and / or LCMS indicated the starting material was completely consumed. It may be necessary to further add the Mitas acid derivative 14. The solution was allowed to cool to room temperature, filtered through celite and concentrated. The target compound 15 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. Alternatively, the reaction mixture is partitioned between ethyl acetate and aqueous sodium hydrogencarbonate 152524.doc-197-201130854, and the aqueous layer is extracted with ethyl acetate and combined to dryness and in vacuo. The target compound ls is isolated by flash column chromatography and/or preparative hpl=purification and/or crystallization. General Procedure 30 (GP 30): Synthesis of Acid 17 (Scheme 4) (not for commercial use) &quot;&quot; At -78C, third butyl lithium (1 9〇_2 5 〇 equivalent) added to each aryl-, heteroaryl-, benzo[丨'3]dioxolyl- or 2,3-dihydro-1,4-benzodioxane The hexenyl-transactate (preferably bromide) is stirred in a solution of diethyl ether (per millimolar halide ίο-loo ml). Stirring was continued for 30 minutes at _78C&gt;c. Next, triisopropyl borate (2. 〇〇 4 〇〇 equivalent) was added and the mixture was slowly warmed to room temperature. After the addition of hydrochloric acid (2 N), the precipitated citric acid 17 was filtered off. Alternatively, the mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuo. The acid is isolated and/or crystallized by flash column chromatography and/or preparative HpLC. Synthesis of key intermediates Intermediate A.1 Preparation of 2-cyano-3-(2-fluoro-phenyl)-acrylic acid F 0

According to the modified form of GP 2: at 4 (rc, commercially available 2-fluorobenzaldehyde (21·2 mL '25·0 g '201 was added to sodium cyanoacetate (50% aqueous solution ' 18.5 mL, 48.7 g) , 227 mmol, equivalent) and sodium hydroxide 152524.doc -198· 201130854 [1% aqueous solution ' 1.11 g, 28 mmol, 0.14 equivalents) in a vigorous search solution. After 60 minutes, remove the heating bath and allow the reactants After cooling to room temperature, after TLC indicated that the starting material was completely consumed, the pH was adjusted to 34 (concentrated aqueous hydrochloric acid), the precipitated acid was filtered off, washed with cold water and dried in vacuo. To produce a second crop which was washed with cold water and dried in vacuo. The title compound was used in the next reaction without further purification (yield: 21.8 g). H-NMR (d6-DMSO, 400 MHz) : 7.36-7.44 (m, 2H); 7.63- 7·70 (m, 1H); 8.11-8.17 (m, 1H); 8'33 (s, 1H). UPLC-MS (ESI+): [M+H ]+=191. Table 1: The following intermediate A.2 was prepared in a similar manner to the intermediate A·1, and GP 2 was started from commercially available 2,6-difluorobenzaldehyde.

: No.; Structure.\ «Seven seven... Analytical data A.2 Ν 2-Cyano-3-(2,6-difluoro-phenyl)-acrylic acid ^-NMR (d6-DMSO, 400 MHz): 7.25 -7.33 (m, 2H); 7.59-7.71 (m, 1H); 8.19 (m, 1H). UPLC-MS (ESI+): [M+H]+=210 〇Intermediate B.1 Preparation of 3-(2-fluoro-phenyl)-acrylonitrile according to the modified form of GP 3: 2_cyano_3_ (2-fluoro-phenyl)-acrylic acid (intermediate Al) (lg '5 mmol) mixed with copper oxide (11) (40 mg, 0.5 mmol; 〇. 1 equivalent) and stirred vigorously while robbing by heating ( Heating gun) for heating. The carbon dioxide precipitation stops and tlc indicates

S 152524.doc .199- 201130854 After the starting material has been completely consumed, the oily suspension is filtered through a pad of celite®. The target compound was isolated by flash column chromatography (yield: 638 mg). ^-NMR (CDCI3, 300 MHz): 5.56 (d, 1H); 7.08-7.19 (m, 1H); 7.20-7.30 (m, 1H); 7.38-7.50 (m, 2H); 8.16-8.26 (m, 1H) ° (Z-isomer) MS (EI+): M+=147. ^-NMR (CDCI3, 300 MHz): 6.04 (d, 1H); 7.08-7.23 (m, 2H); 7.37-7.46 (m, 2H); 7.49 (d, 1H). (five-isomer) MS (EI+): M+ = 147. Table 2: The following intermediates b.2 were prepared in a similar manner to the intermediate B.1, and GP 3 was derived from the intermediate a.2 starting number structure name analysis data B.2 3-(2,6-difluoro -phenyl)-acrylonitrile*H-NMR (CDCI3, 400 MHz): 5.79 (d, 0.55H); 6.26 (d, 0.45H); 6.91-7.05 (m, 2H); 7.10-7.51 (m, 2H) ). (5 and Z-isomer) UPLC-MS (ESI+): [M+H]+=166 » Intermediate B.3 Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propene Nitrile according to the modified form of GP 1 : 1 &gt; 8 diazabicyclo [5, 4, 〇] eleven _7 baked (79 78 g, at room temperature at a rate such that the temperature is maintained substantially at room temperature 524 mmol, 2·〇 equivalent) was added dropwise to commercially available 2 fluoro-6 (trifluoromethyl)benzene 152524.doc -200- 201130854 citric acid (50.34 g, 262 mmol), lithium chloride (21.75 g ' 513 Methyl ' 1.95 eq.) and diethyl cyanomethyl phosphonate (90.51 g '511 mmol, 1.95 eq.) in EtOAc (500 mL). After the TLC showed that the starting material was completely consumed, the mixture was concentrated, poured into ice-cold water (3 L) and stirred for 30 minutes. The precipitate was filtered off and washed with n-hexane. (Yield: 32 g). !H-NMR (CDC13, 400 MHz): 5.89 (d, 1H); 7.27-7.30 (m, 1H); 7.36-7.64 (m, 3H). (Z-isomer) e]H-NMR (CDCI3, 400 MHz): 6.21 (d, 1H); 7.36-7.64 (m, 4H). (E-isomer). UPLC-MS (ESI+): [M+H]+=216. Preparation of 3-(2-fluoro-phenyl)-propionitrile by intermediate C.l

Adapted to GP 4a: Add magnesium crumb (1.64 g, 67 mmol, 40 equivalents) to 3-(2-fluoro-phenyl)-acrylonitrile (intermediate B.1) at room temperature ( 248 mg, 1.69 mmol) in a stirred solution of methanol (1 mL). Immediately after the start of the reaction (2-3 minutes), it was cooled to 〇 ° C and stirred at this temperature until TLC indicated complete consumption of starting material. The reaction was quenched by the addition of aqueous 6 N hydrochloric acid. The mixture was partitioned between EtOAc and EtOAc. The target compound is subjected to no further purification steps.

S 152524.doc • 201 - 201130854 Used in subsequent reactions (yield: 169 mg). Table 3: The following intermediates C.2 to C.4 were prepared in a similar manner to the intermediate C.1 and GP 4a was derived from the intermediates B.2 and B.3 starting number structure name analysis data C.2 0C&quot; 3-(2,6-Difluoro-phenyl)·c-cause^-NMR (CDC13, 400 MHz): 2.64 (t, 2H); 3.07 (t, 2H); 6.86-6.96 (m, 2H); -7.30 (m, 1H). UPLC-MS (ESI+): [M+H]+=168. C.3 άτΝ F 3-(2-Difluoroindolyl-6-a-phenyl)-propion-^-NMR (CDCI3, 400 MHz): 2.65 (t, 2H); 3.18 (t, 2H); (t, 1H); 7.20-7.26 (m, 1H); 7.28-7.33 (m, 1H); 7.34-7.41 (m, 1H). 19F-NMR (CDCI3, 400 MHz): -115.75 (m, IF); -108.87 (d, 2F). C.4 όςΤΝ Η 3-(2-Fluoro-6-fluoroindolyl-phenyl)-propion-^-NMR (CDC13s 400 MHz): 2.65 (t, 2H); 3.11 (t, 2H); 5.47 (d , 1H); 7.10-7.20 (m, 2H); 7.26-7.33 (m, 1H). 19F-NMR (CDCI3, 400 MHz): -202.85 (t, IF); -116.77 (m, IF). Intermediate C.5 Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propanenitrile

According to the modified form of GP 4b: using palladium/charcoal (10% palladium, 5.4 g, 20% by weight) and helium to make 3-(2-fluoro-6-trifluoromethane at room temperature under normal pressure Base-phenyl) acrylonitrile (intermediate B.3) (27.1 g, 126 mmol) in acetonitrile (541 mL) and glacial acetic acid (54 mL, 939 mmol, 7.5 eq.) 152524.doc -202 - 201130854 Liquid hydrogenation for 4.5 hours. The title compound (yield: 20.9 g) was obtained after the mixture was filtered from Celite®, washed with ethyl acetate, EtOAc (EtOAc) !H NMR (CDC13, 400 MHz): 2.65 (t, 1H); 3.21 (t, 1H); 7,28-7.34 (m,1H); 7.38-7.44 (m,1H); 7.49-7.51 (m, 1H). UPLC-MS (ESI+): [M+H]+=218. Intermediate D.l

Preparation of 3-phenyl-propionimidate ethyl ester hydrochloride

According to the modified form of GP 5a: in the 〇. (:, a solution of the anhydrous salt ("«!)) through commercially available 3-phenyl-propionitrile (25.0 g, 191 mmol) in absolute ethanol (15 mL) over 2 hours. The title compound was crystallized after standing overnight. The title compound was used in the next reaction without further purification (yield: 43.4 g). 'H-NMR (DMSO-d6, 300 MHz): 1.32 (t, 3H); 2.95 (s, 4H), 4.37 (q, 2H); 7.21-7.37 (m, 5H); 10.80-12.06 (m, 2H) MS (EI+): M+ = 177 (free base) Table 4 : The following intermediates D.2 to D.4 were prepared in a similar manner to the intermediate D丨 and the starting number structure of GP 5a or 5b from C, 1, C.2 and C.5; Name analysis data D.2 The crude 3-(2-fluoro-phenyl)-propionium imidate hydrochloride salt was used in the subsequent reaction without further characterization.

S 152524.doc .2〇3- 201130854 D.3 3-(2,6-Difluoro-phenyl)-propionium imidate-----^ The crude product is not further characterized Used in subsequent reactions. H, +.H. 3-(2-Fluoro-6-trifluoroindole crude product used in D.4 phenyl-phenyl)-------- UPLC-MS (ESI+): [M+H]+=256. (M=free test) Intermediate E.l Preparation of 2-phenylethyl-4,5-diaza-α-sodium

According to the modified form of GP 6a: triethylamine (36 mL '26.4 g' 1.0 equivalent) was added to the decyl decanoate hydrochloride under 〇ec (commercially available or according to Baldwin # Λ Tetrahedron 1989, 岑_5, 4537-4550 Preparation) (44.8 g, 1.0 eq.) in a suspension in anhydrous DCM (300 mL). Then, 3-phenyl-propionimidate ethyl ester hydrochloride (Intermediate D-1) (41.3 g) suspended in DCM (100 mL) was added portionwise, and the mixture was warmed to room temperature while stirring. LCMS indicated complete consumption of starting material. The reaction mixture was cooled, partitioned between DCM and water. EtOAc (EtOAc)EtOAc. The title compound was isolated by flash column chromatography (yield: 44.1 g). ^-NMR (CDC13, 300 MHz): 2.82-2.91 (m, 2H); 2.94-3.04 (m, 2H); AB signal (δΑ=3.51, δΒ=3.61, 2xlH); 3.81 (s,3H); -5.11 (m, 1H); 7.17-7.33 (m, 5H). MS (EI+): M+=249. 152524.doc .204- 201130854 Table 5: The following intermediates E.2 to E.7 were prepared in a similar manner to the intermediate E.1 and GP 6a or 6b from the intermediates D.1 to D.4 and respectively half Initiation of cysteine hydrochloride and penicillamine methyl ester hydrochloride

No. • ·- . . . , Structure, Name. Analysis E.2 0-CH, 2-[2-(2-Fluoro-phenyl)-ethyl]-4,5-dihydro-carbazole·4 - decyl decanoate 'H-NMR (CDC13, 400 MHz): 2.82-2.89 (m, 2H); 2.99-3.06 (m, 2H); AB signal (δΑ=3·52, δΒ=3·61, 2χ1Η ); 3.81 (s, 3H); 5.04-5.10 (m, 1H); 6.98-7.08 (m, 2H); 7.16-7.24 (m, 2H). UPLC-MS (ESI+): [M+H]+=268 〇E.3 O-CH, 2-[2-(2,6-difluoro-phenyl)-ethyl]-4,5-dual _ Thiazole-4-decanoate ' ester 'H-NMR (CDC13, 400 MHz): 2.75-2.88 (m, 2H); 2.99-3.11 (m, 2H); AB signal (δΑ=3.53, δΒ=3·61 , 2χ1Η); 3.81 (s, 3H); 5.01-5.12 (m, 1H); 6.79-6.91 (m, 2H); 7.08-7.22 (m, 2H). UPLC-MS (ESI+): [M+H]+=286. E.4 O-CH, 0=/ F FVF 2-[2-(2-Fluoro-6-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-indole. -4 NMR (CDC13, 400 MHz): 2.72-2.87 (m, 2H); 3.18 (t, 2H); AB signal (δΑ=3·55, δΒ=3.64, 2χ1Η); 3.83 (s, 3H); 5.09-5.14 (m, 1H); 7.24 (t, 1H); 7.30-7.35 (m, 1H); 7.45 (d, 1H). UPLC-MS (ESI+): [M+H]+=336. 152524.doc -205 - 201130854 E.5 O-CH, 5,5-Dimethyl-2-phenylethyl-4,5-dihydro-sigh&lt;»sodium-4-decanoate•H- NMR (CDC13, 300 MHz): 1.35 (s, 3H); 1.69 (s, 3H); 2.80-2.90 (m, 2H); 2.94-3.03 (m, 2H); 3.79 (s, 3H); 4.62 (s , 1H); 7.16-7.34 (m,5H) e UPLC-MS (ESI+): [M+H]+=278 «* E.6 P-ch3 2-[2-(2,6-difluoro-benzene Base)-ethyl]-5,5-dimethyl-4,5-dihydro-indole § «Sit &gt; 4-methyl decanoate 'H-NMR (CDCI3, 300 MHz): 1.35 (s, 3H 1.70 (s, 3H); 2.76-2.85 (m, 2H); 2.99-3.08 (m, 2H); 3.79 (s, 3H); 4.63 (s, 1H); 6.79-6.90 (m, 2H); 7.10-7.22 (m, 1H). E.7 o-ch3 0=( F HSC VN F, ' 2-[2-(2-fluoro-6-trifluoromethyl)phenyl]-ethyl]-5,5-dimethyl-4, Methyl 5-dihydro-thiazole-4-furoate^-NMR (CDCb, 300 MHz): 1.37 (s5 3H); 1.70 (s, 3H); 2.65-2.86 (m, 2H); 3.05-3.20 (m , 2, H, H, H, H, H 364 〇Intermediate Ε·4 (alternative synthesis, see Scheme 7) Preparation of 2-[2-(2-fluoro-6-difluoroindolyl-phenyl)-ethyl]-4,5-diaza-indole Sitting -4_ methyl citrate

Similar to Org Ze&quot; 2000, 2, 3289: under 〇〇c, 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)-propylamino]-3 Base · methyl vinegar (intermediate Wl) (4.75 g ' 13.4 mmol) dissolved in dioxane (2 〇〇 mL) 152524.doc • 206- 201130854 and added 1 Μ titanium (IV) solution ( 40.32 m Bu 40.32 mmol). After 30 minutes, the mixture was poured into saturated sodium bicarbonate and extracted with DCM and the extract was dried over sodium sulfate, dried and concentrated. Flash column chromatography gave the desired thiazoline (yield: 2.35 g). Consistent with the above substances. Preparation of 2-[2-(2-fluoro-6-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazole-4-carboxylic acid formazan by intermediate E.8

Method A 'Diethylaminosulfur trifluoride (DAST) (0.32 mL, 394 mg, according to the modified form of Example 6.f of WO 2007/127173 under nitrogen at -70 ° C 2.45 mmol, 1.65 eq.) is added to 2-[3-(2-gas-6-dimethylmethyl)phenyl-propylamino]_3_trans-propyl-propionic acid methyl acetate (intermediate W.2) (0.5 g, 1.5 mmol) in a mixture of DCM (15 mL). After stirring for 1.5 hours, the mixture was warmed to -20 ° C and anhydrous potassium carbonate (204.9 mg &apos; The mixture was then allowed to warm to room temperature. The mixture was poured into saturated sodium bicarbonate, stirred for 1 hour and extracted several times with DCM. The combined extracts were dried over sodium sulfate, and then concentrated and concentrated to give the desired s. W-NMR (methanol-d4, 400 MHz): 2.57 (t, 2H); 3.12 (t, 2H); 3.75 (s, 3H); 4.44-4.55 (m, 2H); 4.75 (dd, 1H); (t, 1H);

S 152524.doc -207· 201130854 7.40-7.47 (m, 1H); 7.48-7.53 (m, 1H). MS (ESI+): [M+H]+=320. Method B, according to the modified form of Example 3 of WO 2006/69063, at room temperature, the (methoxycarbonylamine sulfonyl)triethylammonium hydroxide inner salt (Burgess reagent) (20.7 g, 86.7) Ment, 1.1 equivalents) was added to methyl 2-[3-(2-fluoro-6-trifluorodecyl-phenyl)-propionylamino]-3-hydroxy-propionate (intermediate W.2) ( 26.6 g, 78.8 mmol) in a stirred solution of THF (450 mL). The reaction mixture was heated to 70 ° C for 1 hour. The mixture was concentrated and subjected to flash chromatography to give the title compound (? The product was identical to the material obtained above. Intermediate F. 1 Preparation of 8-benzyl-7-fluorenyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-decanoate

According to the modified form of GP 7a: 丨, 2-dichloroethane (2 mL) pre-saturated with hydrochloric acid (&amp;β) was added to 2-phenethyl-4,5-dihydrogen at room temperature. - Thiazole-4-decanoate methyl ester (Intermediate El) (446 mg, 1.79 mmol) and commercially available ethionyl-Michleric acid (1 g, 5 mmol, 3.0 eq.) in 12-dichloroethane (13 In the solution in mL). The reaction mixture was heated to 140 C in a Biotage initiator microwave oven for 120 seconds. TLC analysis showed complete conversion. After removing the solvent, the crude product was filtered through a pad of silica gel, followed by flash column chromatography I52524.doc - 208 - 201130854 to isolate the target compound (yield: 500 mg). !H-NMR (CDCI3, 300 MHz): 2.03 (d, 3H); AB Ε (δΑ=3.54, δΒ=3.74, 2xlH); 3.75 (s, 2H); 3.82 (s, 3H); 5.66 (dd, 1H); 6.18 (d, 1H); 7.09-7.15 (m, 2H); 7.17-7.24 (m, 1H); 7.26-7.32 (m, 2H). MS (EI + ): M+ = 315.

S 152524.doc 209- 201130854 矽 矽 β β 平 7砩婳to chat ^-^Ι&gt;·3^(Ν·3#sBf-WJ^-Imi doM frame n-^^^w 荽黩Ξ^χϋ^ ζ.ΡΗ荽SS-0-b 3: &lt; Analysis data h-NMIUCDCb, 300 MHz): 2.03 (s, 3H); AB signal (δΑ=3.54, δΒ=3·73, 2χ1Η); 3.75 (m, 2H); 3.82 (s, 3H); 5.66 (dd, 1H); 6.19 (s, 1H); 6.89-6.99 (m, 1H); 7.00-7.10 (m, 2H); 7.15-7.25 (m, 1H) . UPLC-MS (ESI+): [M+H]+=334. !_ ^-NMR (CDC13, 400 MHz): 2.10 (s, 3H); 3.48-3.77 (m, 4H); 3.80 (s, 3H); 5.61 (dd, 1H); 6.14 (s, 1H); 6.81 -6.90 (m, 2H); 7.15-7.23 (m, 1H). UPLC-MS (ESI+): [M+H]+=352.屮NMR (CDC13, 400 MHz): 2.07 (s,3H); AB signal (δΑ=3.45, δΒ=3·62, 2xlH); 3.79 (s, 3H); 3.96 (s, 2H); 5.61 (dd, 1H); 6.18 (s, 1H); 7.21 (t, 1H); 7.38 (td, 1H); 7.51 (d, 1H). UPLC-MS (ESI+): [M+H]+=402. Name ^ f ^ i ^ ') t % ^ ? IP OO 8-(2,6-di-n-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazole And [3,2-a]° pyridine-3-carboxylate 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5-sideoxy-2,3 -Dinitro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid decyl ester structure I1 U. Eight number &lt;N m inch 152524.doc -210· 201130854

iH-NMR (methanol-d4, 300 MHz): 1.53 (s, 3H); 1.64 (s, 3H); 2.15 (s, 3H); 3.75 (s, 3H); AB signal (δΑ=3.77, δΒ=3 · 84, 2xlH); 5.13 (s, 1H); 6.12 (d, 1H); 6.86-6.97 (m, 2H); 7.22-7.34 (m, 1H). MS (EI+): M ten = 379. 'H-NMR (CDC13, 300 MHz): 1.49 (s, 3H); 1.60 (s, 3H); 1.99 (s, 3H); 3.77 (s, 3H); 3.92 (br. s, 2H); 5.11 ( s, 1H); 6.12 (d, 1H); 7.13-7.23 (m, 1H); 7.29-7.39 (m, 1H); 7.46-7.51 (m, 1H). UPLC-MS (ESI+): [M+H]+=430. 8-(2,6-diphenylmethyl)-2,2,7-trimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]° pyridine 3-O-carboxylate 8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-2,2,7-trimethyl-5-yloxy-2,3-dihydro-5H- Thiazolo[3,2-a]pyridine-3-carboxylate

s 152524.doc -211 · 201130854 Intermediate F.7 Preparation of 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydrogen -5H-oxazolo[3,2-a]pyridine-3-carboxylic acid decyl ester

Modified according to the general procedure 29b: acetamido acid (27.4 g, 147 mmol, 3 equivalents) and 2-[2·(2-fluoro-6-trifluoromethyl) in toluene (300 mL) Benzyl-phenyl)-ethyl]-4,5-dihydro-oxazole-4-carboxylic acid decyl ester (intermediate Ε·8) (15·6 g, 49·0 mmol) heated to reflux for 20 minutes . Then tris-acetic acid (18_9 mL, 27.9 g, 245 mmol, 5 eq.) was added and reflux was continued for one hour. The reaction mixture was partitioned between water and acetic acid. After the phase separation, the aqueous layer was extracted with EtOAc. W-NMR (methanol-d4, 300 MHz): 3.77 (s, 3H); 3.99 (s, 2H); 4.64 (dd, 1H); 4.75 (t, 1H); 5.23 (dd, 1H); 5.96 (s , 1H); 7.30 (m, 1H); 7.38-7.47 (m, 1H); 7.48-7.55 (m, 1H). MS (ESI+): [M+H]+=386. Intermediate G. 1 Preparation 8-Benzyl-6-fill-7-methyl-5-oxo-2,3-dihydro-5 H-° plug. Sit and [3,2-a]pyridine-3-decanoic acid methyl ester 152524.doc •212- 201130854

H3c according to the modified form of GP 8: N-iodobutyric imide (342 mg, 1.52 mmol, 2.4 equivalents) was added to the 8-stylmethyl-7-mercapto-5-side at room temperature Methyloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-indoleate (Intermediate Fl) (200 mg, 0.63 mmol) in acetic acid (2 mL) and TFA ( In a stirred solution of 1 00 μί). After the LCMS indicated that the starting material was completely consumed, the mixture was partitioned between DCM and aqueous sodium thiosulfate. The aqueous layer was extracted with DCM and the combined organic layer was washed with sodium bicarbonate, dried over sodium sulfate and evaporated concentrate. The title compound (yield: 185 mg) was isolated by crystallised from ethyl acetate/t-butyl decyl ether. iH-NMR (CDC13, 300 MHz): 2.35 (d, 3H); AB signal (δΑ=3.58, δΒ = 3.77, 2xlH); 3.88 (s, 3H); 3.91 (s, 2H); 5.74 (dd, 1H) ); 7.12-7.19 (m, 2H); 7.23-7.38 (m, 3H). MS (EI+): M+=441.

S 152524.doc 213 - 201130854 驾^sfe^rd 龚迗斗菡418 doΜ 筚鹖馁^拎W 黩黩1.0#葩夺硪^“0 named^0荽葩-5-1-^:9&lt; Analysis data: h -NMR (CDC13, 400 MHz): 2.29 (s, 3H); AB signal (δΑ=3·54, δΒ=3·76, 2χ1Η); 3.83 (s,3Η);ΑΒ signal (δΑ=3·84, δΒ=3·89, 2xlH); 5.69 (dd,1H); 6.88-6.94 (m,1H); 7.02-7.09 (m,2H); 7.18-7.25 (m,1H). UPLC-MS (ESI+): [M+H]+=460. H-NMR (CDC13, 400 MHz): 2.36 (s,3H); AB signal (δΑ=3·52, δΒ=3.72, 2xlH); 3.80 (s, 3H); 3.83 -3.87 (m, 2H); 5.64 (dd, 1H); 6.80-6.92 (m, 2H); 7.14-7.25 (m, 1H). UPLC-MS (ESI+): [M+H]+=478 ° 4 NMR (CDC13, 400 MHz): 2.35 (s, 3H); AB signal (δΑ=3.47, δΒ=3·66, 2xlH); 3.80 (s, 3H); 4.06 (s, 2H); 5.66 (dd5 1H) 7.20 (t, 1H); 7.36-7.41 (m, 1H); 7.52 (d, 1H) UPLC-MS (ESI+): [M+H]+=528. ·.-, : · 八-'· '.'?. ': Name: II.:._: 8-(2-Fluoro-benzyl)-6-iodo-7-methyl-5-o-oxo-2,3-dihydro-5H -thiazolo[3,2-a]pyridine-3-decanoate methyl 8-(2,6-difluoro-methane)-6-iodo-7-methyl-5-sideoxy-2, 3-dihydro-5H - thiazolo[3,2-a]pyridine-3-carboxylate 8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-6-iodo-7-indolyl-5-sideoxy -2,3-Dihydro-5H-thiazolo[3,2-a]pyridine-3-decanoate decyl ester structure °Y^m No. (NC? m C5 inch ΰ 152524.doc •214- 201130854 -ST+? (+IH)ss. (HrsHcnTrlr^ffir day) 86.9-98.9 "Hrs^t.siKx^^.eHCQtoJoo-eH^) 赖 ffflv XHew) sz/ε i(Hevr)oorCNi(Hew) ς9·二(ΗεΜ) 3 : (ZHH οοε. Inch p-is®-) ΉΝΝ-Η- Lithium ¢-Helmet s--e-穿宇[«ι-ζώ味寺咿-Ης_Ί M^CN-^^sK-fffi-M-卜&lt;N(Ns -9-(^&amp;-arm-Ί U-9CS-8

152524.doc -215- 201130854 Intermediate G.6 Preparation 8-(2-Gas-6-trishydrazide-poor: a:, r ji· 1 chaotic T-group-present methyl)-6-Moth-7 -Methyl-5. pendant oxy 2,3-monohydro-5H-oxazole[3,2-ap-pyridyl-3•capric acid methyl ester

According to the modified form of GP 8: N_iodobutylidene imide (7_01 g, 31_4 mmol, 2.4 equivalents) was added to 8_(2_fluoro-6-trifluorodecyl-benzene at (7) 艽 temperature Methyl)-7-fluorenyl-5-sideoxy-2,3_dihydro-5H-oxazole[3,2·μpyridine·3·carboxylate (intermediate f.7) (5 〇 g, 13 mm 〇 1) in a stirred solution of acetic acid (74 mL) and TFA (2.4 mL). The reaction was stirred overnight and then partitioned between aqueous saturated sodium sulphate and ethyl acetate. After the phase separation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sodium hydrogen sulfate and dried and concentrated in vacuo. The target compound was isolated by crystallization from diethyl ether (yield: 4.69 g). ^-NMR (DMS0-d6, 400 MHz): 2.36 (s, 3H); 3.70 (s, 3H); 4.00 (br. s, 2H); 4.69-4.78 (m, 1H); 5.27 (dd, 1H) ; 7.43-7.55 (m, 2H); 7.56-7.61 (m, 1H). MS (ESI+): [M+H].= 512. Intermediate H. 1 Preparation of 8-benzyl-6-bromo-7-methyl-5-oxooxy-2,3-dihydro-5H-° succinyl[3,2-a]pyridine-3 -methyl formate 152524.doc -216- 201130854 Ο o^y ο

According to the modified form of GP 9: bromine (35 pL, 107 mg, 0.67 mmol, 1.06 equivalent) was added dropwise to the 8-octyl-7-fluorenyl-5-sideoxy group at 10 ° C. Methyl 2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate (intermediate F.1) (200 mg, 0.63 mmol) in acetic acid (6 mL) . After the mixture was allowed to warm to room temperature and LCMS indicated that the starting material was completely consumed, the mixture was partitioned between DCM and aqueous sodium thiosulfate. Dry over sodium sulfate and concentrate in vacuo. The title compound was isolated by crystallization from ethyl acetate/t-butyl methyl ether (yield: 147 mg).. W-NMR (CDC13, 300 MHz): 2.22 (s, 3H); AB signal (5a=3.55, δΒ= 3.76, 2xlH); 3.83 (s, 5H); 5.70 (dd, 1H); 7.08-7.14 (m, 2H); 7.18-7.34 (m, 3H). MS (EI+): M+=393 / 395. (Br isotope form) Intermediate 1.1 Preparation 8-Benzenyl-7-fluorenyl-5-o-oxy-6-phenyl-2,3-dihydro-5 thiophene °[3,2-a Pyridine-3-furoate methyl ester

152524.doc •217 201130854 Modified according to GP l〇a: commercially available stearic acid (290 mg, 2.3 7 mmol '1.5 equivalents) and aqueous potassium carbonate solution (263 mg, 1.90) at room temperature Mmo Bu 1.2 equivalent '1,5 Μ aqueous solution) was added to 8-benzyl-6-iodo-7-indolyl-5-sideoxy-2,3-dihydro-5Η-嗟"[3, 2-a] ° is more than a solution of bite-3 - decanoic acid ( intermediate G. 1) (700 mg ' 1.59 mmol) in dioxin (7 mL). Argon gas was then bubbled through the reaction mixture for 10 minutes, followed by the addition of dioxane (1,1,-bis(diphenylphosphino)ferrocene) palladium dichloromethane complex (116 mg ' 0.16 mmol ' 0.1 equivalent). The reaction mixture was heated to 13 (TC for 30 min) in a Biotage initiator microwave oven, then TLC analysis showed complete conversion. The mixture was filtered over celite® pad and washed with DCM. The organic phase was washed with water and dried over sodium sulfate. Flash column chromatography' yielded the title compound (yield: 463 mg). H-NMR (CDC13, 400 MHz): 1.90 (s, 3H); AB signal (δΑ=3.53, δΒ=3.76, 2xlH); 3.83 (s, 5H); 5.67 (dd, 1H); 7.15-7.25 (m, 5H); 7.27-7.40 (m, 5H) MS (EI+): M+=391. 152524.doc -218· 201130854

. Driving meal 1;^^ςΌ 30荽Ls2.-B-fw?4«o!!qor-l^s IPHO 噢铋馁^柃W 荜黩rI#s«:-&amp;-^r&lt;TS .I^rI#s£-&amp;-i-ti:l-~^ Analytical data 'iH-NMR (sterol-d4, 300 MHz): 1.86 (m,3H); 3.64 (dd,1H); 3.78 -3.81 (m, 3H); 3.84-3.99 (m, 6H); 5.66-5.75 (m, 1H); 6.68-6.78 (m, 1H); 6.98-7.14 (m, 5H); 7.20-7.28 (m, 1H). UPLC-MS (ESI+): [M+H]+=458. *H-NMR (CDC13, 400 MHz): 1.96 (m, 3H); 3.45-3.58 (m, 1H); 3.65-3.85 (m, 6H); 3.88 (m, 3H); 5.56-5.68 (m, 1H) 6.74-6.97 (m, 4H); 7.03-7.11 (m, 1H); 7.12-7.24 (m, 1H). UPLC-MS (ESI+): [M+H]+=476. Towel NMR (CDC13, 300 MHz): 1.93-1.94 (m, 3H); AB signal (δΑ=3·46, δβ-3.66, 2xlH); 3.77-3.80 (m, 3H); 3.89 (s, 3H); 4.05 (s, 2H); 5.58-5.67 (m, 1H); 6.79-6.90 (m, 1H); 6.94 (td, 1H); 7.06-7.13 (m, 1H); 7.19-7.25 (m, 1H); 7.34-7.41 (m, 1H); 7.50-7.52 (m, 1H). UPLC-MS (ESI+): [M+H]+=526. Name ^ χ ^ ®~ ...丨1Λ Λ ®~ A 7 Today s 硪智入w # ^ w ^ ®- ιΛ (N ώ ^ l ^ (NN-✓ 1 1 00硪8-(2,6-two Fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2 -a]pyridine-3-indole oxime ester Ί ^ 'Ί cA B-na¢- 00荜 slave a 5 ^ 砌 a Bach i 螂 螂 A ψ ^ ^ ώ V ®- i!^ Structure: V: U;X &gt; S^f9 0 %? k: CN cn inch. s 152524.doc -219- 201130854

^-NMR (methanol-d4, 400 MHz): 1.54 (s, 3H); 1·69 (d, 3H); 1.93 (d, 3H); 3.75 (m, 3H); 3.82-3.91 (m, 5H) 5.16 (d, 1H); 6.66-6.71 (m, 1H); 6.89-6.97 (m, 2H); 7.02-7.13 (m, 2H); 7.23-7.33 (m, 1H). MS (EI+): M+=503. h-NMR (CDC13, 400 ΜΗζ): 1.91 (s, 3H); ΑΒ signal (δΑ=3.53, δΒ=3.75, 2xlH); 3.81-3.84 (m, 5H); 5.65 (dd, 1H); 5.95 (m , 2H); 6.65-6.74 (m, 2H); 6.80-6.84 (m, 1H); 6.93-7.11 (m, 4H); 7.18-7.24 (m, 1H); 7.60 (s, 1H); 7.77-7.81 (m, 1H). UPLC-MS (ESI+): [M+H]+=454. h-NMR (methanol-d4, 300 MHz): 2.16 (s, 3H); 3.59 (dd, 1H); 3.76 (s, 3H); 3.81-3.96 (m, 3H); 5.61-5.67 (m, 1H) ; 6.70-6.75 (m, 1H); 6.88-6.97 (m, 3H); 7.22-7.33 (m, 1H). MS (EI+): [M+H]+=467. ^-NMR (sterol-d4, 300 MHz): 1.99 (s, 3H); 3.60 (dd, 1H); 3.77 (s, 3H); 3.81-3.98 (m, 3H); 5.56 (dd, 1H); 6.88-6.99 (m, 2H); 7.05-7.11 (m, 1H); 7.13-7.20 (m, 1H); 7.20-7.35 (m, 2H); 7.43-7.52 (m, 1H). UPLC-MS (ESI+): [M+H]+=512. 4 m ί '} t 4 3 Λ Λ 4 B- V ? ^ δ- ®- ^ ^ n| ^ m ^ I r〇〇'J Γί ψ 00 +·4 Φ ΐ „ 〇〇\ 1 m Ί s ^ ^ ff 遨, to '1 ^ C-Γ ^ ^ Mechanical TS v〇^ ", Wen\\ ®~ νό, 1 de cn oo cn J ¥ ? ^ m (N f -« rjf t ¢- ϊ: Ο Ο Ιη v〇OO 152524.doc -220- 201130854

'H-NMR (CDCls, 400 MHz): 1.86 (s, 3H); 3.48 (ddd, 1H); 3.62-3.72 (m, 1H); 3.77 (s, 1.5H*); 3.80 (s, 1.5 H* 3.99-4.10 (m, 2H); 5.62-5.68 (m, 1H); 7.05-7.17 (m, 2H); 7.19-7.26 (m, 1H); 7.35-7.43 (m, 1H); 7.43-7.55 (m, 2H). MS (CI+): [M+H]+=596. ^-NMR (CDCI3, 300 MHz): 1.94 (s, 3H); 3.41-3.52 (m, 1H); 3.56-3.72 (m, 1H); 3.78 (s, 1.5H*); 3.81 (s, 1.5 H *); 4.05 (s, 2H); 5.55-5.67 (m, 1H); 7.15-7.26 (m, 1H); 7.32-7.42 (m, 1H); 7.46-7.55 (m, 1H); 7.69-7.85 ( m, 1H); 8.15-8.23 (m, 1H). h-NMR (methanol-d4, 300 MHz): 1.97 (s, 3H); 3.51 (dd, 1H); 3.71-3.82 (m, 4H); 4.10 (br. s, 2H); 5.58-5.64 (m, 1H); 7.10 (br. s, 1H); 7.15-7.27 (m, 2H); 7.28-7.38 (m, 1H); 7.43-7.60 (m, 3H). MS (ESI+): [M+H]+=562. <RTIgt; (H, 1H); 6.86-7.08 (m, 1H); 7.29-7.37 (m, 1H); 7.44-7.52 (m, 1H); 7.54- 7.59 (m, 1H). MS (ESI+): [M+H]+= 526. 1潜^ ^ &lt;N ί ^ f ¥ ^ ^ +*4 ®- (N ^ ® ^ ^ Ϊ f ^ ^ Λ 5,, combining 1 ¢- ^ jrn ,, J Γ 'Ί ^ ^ 2 7 : ^ ^ ^ % f 4 4 ^ ®- CT ^ Ψ Φ彳矣谇, 丨温一®- 4 ^ ^ ¢- « rn ^ ''J Ϊ 'Ί 〇^ ^ Ψ ^ ^ X cs V ^ w ^ ^ Ί ^ 'Ί rA s- ¢- (A οό 萃 4? «SI T ®- (N 灭士味^ ® 7 ^ ^ ^ ώ a硪^ ^ ^ small x- ^ OS 0 Η-ΐ &lt;N i -; £- 152524.doc -221 · 201130854 h-NMR (sterol-34,3001^!1^): 1.97 (£1,311); 3.47-3.54 (111,111); 3.71-3.92 (m, 4H); 4.09 (br. s, 2H); 5.56-5.65 (m, 1H); 6.01-6.05 (m, 2H); 6.50-6.74 (m, 2H); 7.27-7.37 (m, 1H); 7.42- 7.59 (m, 2H) MS (ESI+): [M+H]+= 540. NMR (Methanol - £14,3001^112): 1.99 (5, 3, 3.48-3.55 (111,111) ;3.72-3.83 (m, 4H); 4.04-4.13 (m, 2H); 5.59-5.65 (m, 1H); 6.92-6.99 (m, 1H); 7.02-7.08 (m,1H); 7.18-7.27 ( m,1H); 7.28-7.61 (m,3H). MS (ESI+): [M+H]+= 558. NMR (Methanol-d4, 300 MHz): 1.96 (s,3H); Dd,1H); 3.70-3.83 (m, 4H); 4.10 (s, 2H); 4.29 (s, 4H); 5.55-5.66 (m, 1H); 6.51-6.65 (m, 1H); 6.65-6.73 ( m,1H); 7.28-7.39 (m,1H); 7.43-7.61 (m,2H). UPLC-MS (ESI+): [M+H]+=554. H-NMR (Methanol-d4, 300 MHz): 1.95 (s) , 3H); 3.51 (dd, 1H); 3.71-3.84 (m, 4H); 4.11 (s, 2H); 4.52-4.65 (m, 1H); 5.57-5.67 (m, 1H); 6.68-6.81 (m , 1H); 7.02-7.15 (m, 2H); 7.29-7.40 (m, 1H); 7.43-7.61 (m, 2H). UPLC-MS (ESI+): [M+H]+=554. Yn A ϊ if ^ nri ®- ^ ®-π ^ ' 1 rn ^ 'Ί Λ ^ ^ ^ 1 2 d ^ 丫 I want l OO I ^ ^ V VO 2 3 f | ®- ^ , π '1 ^ ^ ^ Sfi ®- || ®- ^ ^ rA Zl, 'Ί ri ^ Λ f ^ ^ »k M ^ M 4 «Α - AS 4 CT B- v〇10 ^ ^ ^ •4tfL tjAi Ί 4 *? ®- $ ®- "盘盘--&gt; ' 1 ®- ^ Uj rn rn ^ " " ^ wear \ OA ^ ^ cA ώ ¥ ^ &lt;na &gt;9 d", $13⁄4 iA ^ ¢- : Install a '1' ^ v〇(N ' 4 t A ^ ? ώ ffs ^ ^ ^ ^ s ^ cA ^ S ^ ^ '1 %? Small ϊ: γ〇» Small %? m Η-ΐ For »n lH v〇 152524.doc -222- 201130854

h-NMR (methanol-d4, 300 MHz): 1.96 (s, 3H); 3.53 (dd, 1H); 3.72-3.84 (m, 4H); 4.11 (s, 2H); 5.61-5.67 (m, 1H) ; 7.19-7.60 (m, 6H). UPLC-MS (ESI+): [M+H]+=580. 々-NMR (sterol-d4, 300 MHz): 1.87-2.04 (m, 6H); 3.46 -3.55 (m, 1H); 3.71-3.83 (m, 4H); 4.11 (br. s, 2H); 5.58 -5.67 (m, 1H); 7.23-7.60 (m, 6H). iH-NMR (sterol-d4, 300 MHz): 1.94 (s, 3H); 3.50 (dd, 1H); 3.70-3.82 (m, 7H); 4.09 (br. s, 2H); 5.55-5.64 (m , (1,1H) UPLC-MS (ESI+): [M+H]+=526. 6-(2-Fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-tridecyl-benzoinyl)-7-decyl-5-sideoxy-2, 3-Dihydro-511-thiazolo[3,2-&amp;]pyridine-3-carboxylic acid oxime ester CN ^ cA &quot;f ®- ^ ilL 3 ^ f ^ ii - 6 'Ί cA rn v〇^ ^ ^ ^ Ί ^ 'Ί cA ®- ¥毛®- 4 f ^ f .®- &lt;N 嘁ά味^ T κ %? :;%X5 〇/° rV^*0 - 1.17 1.18 1.19 s 152524.doc - 223 - 201130854 ^-NMR (sterol-d4, 400 MHz): 1.95 (s,3H); 3.49 (dd,1H); 3.70-3.82 (m, 4H); 4.08 (br. s, 2H); 5.57- 5.62 (m, 1H); 6.57-6.64 (m, 1H); 6.70-6.82 (m, 1H); 6.96-7.04 (m, 1H); 7.09-7.22 (m, 2H); 7.29-7.36 (m, 1H) ); 7.44-7.52 (m, 1H); 7.53-7.58 (m, 1H). UPLC-MS (ESI+): [M+H]+=494. ^-NMR (sterol-d4, 300 MHz): 1.98 (s, 3H); 3.51 (dd, 1H); 3.72-3.81 (m, 4H); 4.11 (br. s, 2H); 5.59-5.65 (m , 1H); 6.83 (tr, 1H); 6.94-7.63 (m, 7H). UPLC-MS (ESI+): [M+H]+=544. ^-NMR (methanol-d4, 300 ΜΗζ): 1.97 (s, 3H); 3.51 (dd, 1H); 3.64-3.82 (m, 4H); 4.10 (br. s, 2H); 5.58-5.65 (m, 1H); 6.72 (m, 0.5H*); 6.75 (m, 0.5H*); 6.78-7.84 (m, 1H); 7.02-7.59 (m, 9H). UPLC-MS (ESI+): [M+H]+=588 〇^-NMR (sterol-d4, 300 MHz): 1.98 (s,3H); 3_51 (dd,1H); 3.70-3.85 (m, 4H) 4.10 (br. s, 2H); 5.55-5.68 (m, 1H); 6.55-6.78 (m, 2H); 7.26-7.39 (m, 1H); 7.43-7.64 (m, 2H). UPLC-MS (ESI+): [M+H]+=542. ^ ^ ^ C '1 ¢- 啐A Helmet ί ^ S ^ ^ « ¢- Cl '1' ^ ^ ^ d J κ ώ硇10 —, 1 Feed 'Ί rn &amp;- 哧!盘""1" ¢- fN γΛ 4 ¥ ^ 3 4 π ί 3$ a硪, ^ δ- ^ 5 ^韶^ B-CN 4? Shi (1) Zhi _ aa 4 J; do 2 ^ f 5 ^ 1 s 5 ¥ ^ ^ 3 ^ 4 s 4 § G Age Office X- y^05 &quot; 13⁄4 o &lt;N &lt;N (N &lt;N cn (N H-; 152524.doc •224- 201130854

^-NMR (sterol-d4, 300 MHz): 1.95 (s, 3H); 3.52 (dd, 1H); 3.72-3.81 (m, 4H); 4.11 (br. s, 2H); 5.58-5.64 (m , 1H); 6.89 (tr, 1H); 6.96-7.59 (m, 6H). UPLC-MS (ESI+): [M+H]+=562. h-NMR (sterol-d4, 300 MHz): 1.40 (m,3H); 1.95 (s, 3H); 3.52 (dd, 1H); 3.72-3.82 (m, 4H); 4.11 (m, 4H); 5.62 (m, 1H); 6.72 (m, 1H); 7.00- 7.61 (m, 5H). UPLC-MS (ESI+): [M+H]+=540. 6-(3-Difluoromethyl-2-yl)-8-(2-fluoro.6.trifluoromethyl-benzyl)-7-fluorenyl-5-sideoxy·253-II Hydrogen-5H-thiazolo[3,2-a]pyridine-3·decylcarboxylate 6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-difluoromethyl -Benzyl phenyl)-7-methyl-5- oxo-2,3-dihydro-5H-° plug 0 sits and [3,2-a]° is more than -3- 曱 曱% 缺 s 152524.doc -225 - 201130854 Intermediate 1.26 Preparation of 6·(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene Methyl)-7-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridine-3-decanoic acid methyl vinegar

Similar to Guram AS et al. le.leii 2006, 5, 1787: argon was bubbled through commercially available 2-fluoro-3-isopropoxyphenyl ruthenate (2.13 g, 10.7 mmol, for 5 minutes). 2.5 equivalents), 8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_6_iodo-7-indolyl-5-sideoxy-2,3-dihydro-5H-oxazole[3 , 2-a]pyridine-3·formic acid methyl vinegar (intermediate G.6) (2.2 g, 4_3 mmol), carbonic acid unloading (1.19 g, 8.61 mmol, 2.0 eq.) and bis(di-t-butyl) (4_didecylaminophenyl)

A solution of phosphine dipalladium (11) (60.9 mg, 〇.〇9 mmo 〇·02 equivalent) in hydrazine/water (mL). The mixture was then heated to reflux, and the mixture was subjected to flash chromatography to give the title compound (yield: 1.8 g).

1H-NMR ( ψ 33⁄4 λ A ΚΎ %-d4, 300 MHz): 1.30 (m5 6H); 1.95 (s, 3H; 3.76 (d, 3H)· δ 〇f: ' ·06 (br. s, 2H) 4.50-4.62 (m, 1H); 4.66 (dc 1H); 4.78 (dt 1Hx _ ^ ' H); 5.21-5.30 (m, 1H); 6.66-6.79 (m 1ΡΓ 7.00-7.12 (jn 〇it\ vm , 2H); 7.27-7.37 (m, 1H); 7.38-7.47 (m 1H^ 7.50-7.55 (m, 1H). 152524.doc s -226· 201130854 MS (ESI+): [M+H]+=538 Intermediate K. 1 Preparation of 8-benzyl-7-fluorenyl-5-yloxy-6-phenyl-2,3-dihydro-5Η-thiazolo[3,2-a]° pyridine 3-carboxylic acid

According to the modified form of GP 11 : at room temperature, lithium hydroxide 8 3 mg, 0.77 mmol, 1 〇 equivalent, 1 Μ aqueous solution) is added to 8-bromo-yl-7-methyl-5-sideoxy- 6-Phenyl-2,3-diaza- 5Η-° plug 0 sit and [3,2-a]0 than bite-3_ decylcarboxylate (intermediate 1.1) (30 mg, 0.08 mmol) in THF (1 The stirred solution in mL) was stirred until TLC indicated complete consumption of starting material (1 hour). The pH was then adjusted to 4 (2 N aqueous hydrochloric acid). The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and brine] dried over sodium sulfate and concentrated in vacuo. The title compound was used in the subsequent reaction without further purification (yield: 29.4 mg). W-NMR (CDC13, 300 MHz): 2.00 (s, 3H); AB signal (δΑ=3.67, δΒ=4·16, 2χ1Η); ΑΒ signal (δΑ=3·88, δΒ=3.95, 2xlH); 5.80 (d, 1H); 7.16-7.50 (m, 10Η). MS (ESI+): [M+H]+=378. 152524.doc -227- 201130854 sCN.I^rl 荽浞-5-虿砟|11 dOI*乐T私馁^拎W 萃Γβ 荽匪4-铼^0 ":3called^:3#迗- 5-Bu^: 8^ 152524.doc Analytical data • H-NMR (CDCIs, 400 MHz): 2.05 (s, 3H); 3.61-4.18 (m, 7H); 5.65-5.75 (m, 1H); 6.75- 7.30 (m, 6H). UPLC-MS (ESI+): [M+H]+= 462. NMR (CDC13,400 MHz): 2.01-2.10 (m, 3H); AB signal (δΑ=3·63, δΒ=4.00, 2χ1Η); 3.91-3.92 (m, 3H); 4.08 (s, 2H); 5.68-5.72 (m, 1H); 6.75-6.89 (m, 1H); 6.98-7.02 (m, 1H); 7.12-7.18 (m, 1H); 7.20-7.25 (m, 1H); 7.37-7.42 (m, 1H); 7.51-7.53 (m, 1H) UPLC-MS (ESI+): [M+H]+= 512. H-NMR (CDCIs, 400 MHz): 1.93 (s, 3H); 3.58-3.70 (m, 1H); 3.86-4.13 (m, 3H); 5.70 (d, 1H); 7.12-7.27 (m , 3H); 7.35-7.44 (m, 1H); 7.47-7.55 (m, 2H) MS (CI+): [M+H]+=596. . . . . . 8-(2 ,6-dioxa-phenylhydrazino)-6-(2-fluoro-3-indolyl-phenyl)-7-indolyl-5-yloxy-2,3-diaza-5H-thiazole [3,2-a]pyridine-3-carboxylic acid 6-(2-a-3-methoxy-phenyl)-8-(2-aero-6-trifluoromethyl-benzoinyl)-7- Mercapto-5-sideoxy-2,3-dihydro-5沁thiazolo[3,2- Bis-pyridine-3-decanoic acid 6-(2-chloro-5-triptanylmethoxyphenyl)-8-(2-fluoro-6-trifluoroindolylbenzoyl)-7-mercapto-5 -Sideoxy-2,3-two wind-511-13⁄4° sit and [3,2-a]° bite-3·formic acid • ' ' ·'. ' . . . . , . . . . . . .. -,'y. ',·. .,. .' ... · Structure OH F. f-〇广, No. K.2 1 K.4 -228- 201130854

0 &quot;6* Gallium 1 κ- 阳 m: &lt; To s 1 Xiang iH-NMR (sterol-d4, 400 MHz): 1.96 (s, 3H); 3.50-3.62 (m, 1H); 3.71-3.84 (m, 1H); 4.10 (br. s, 2H); 5.53-5.68 (m, 1H); 7.11 (br. s, 1H); 7.16-7.25 (m, 2H); 7.28-7.36 (m, 1H) ; 7.44-7.59 (m, 3H). ^-NMR (sterol-d4, 300 ΜΗζ): 1.94 (s, 3H); 3.49-3.56 (m, 1H); 3.70-3.82 (m, 4H); 4.09 (br. s, 2H); 5.54-5.63 (m, 1H); 6.67-6.79 (m, 1H); 6.84-6.92 (m, 1H); 6.99-7.08 (m, 1H); 7.27-7.36 (m, 1H); 7.42-7.52 (m, 1H) ; 7.52- 7.59 (m, 1H). ^-NMR (methanol-d4, 400 MHz): 1.96 (s, 3H); 3.48-3.61 (m, 1H); 3.71-3-85 (m, 1H); 4.01-4.15 (m, 2H); 5.68 (m, 1H); 5.98-6.06 (m, 2H); 6.54-6.74 (m, 2H); 7.28-7.35 (m, 1H); 7.43-7.52 (m, 1H); 7.53-7.59 (m, 1H) ). MS (ESI+): [M+H]+= 526. ®- \ 1 ” &gt;il 〇r ®- ^ z ^ cn 参外 AS寺•J _ f ¥ t4 | v flat man rA ¢-硪A s , t ¢- W †£ V ^ J ^ ^ s ^ v I u| ^ ® νό懑灭^ ί Λ Φ5 ά ΟΟ w\ .. VO ^ ^ ^ f * f | 5 ^ s 7, zii V ^ 2 _佥1 ^ 1 ϊ 4 ί, _ gentleman 1 ~im: ri3 2, ι 3 Cloud ^T1 v〇^ CN $4 “ 苎. ^ Φ 5 \〇SyO ^ %? 〇ν〇.^ 〇〇152524.doc •229- s. 201130854 ^-NMR (sterol-d4, 400 MHz): 1.97 (s, 3H); 3.49-3.64 (m, 1H); 3.71-3.87 (m, 1H); 4.02-4.15 (m, 2H); 5.53-5.71 (m, 1H); 6.88-7.60 (m, 6H) MS (ESI+): [M+H]+= 544. H-NMR (Methanol-d4, 300 MHz): 1.93 (s, 3H); 3.49-3.58 ( m,1H); 3.69-3.81 (m, 1H); AB signal (δΑ=4·05, δΒ=4·12, 2χ1Η); 4_28 (s, 4H); 5.50-5.59 (m, 1H); 6.50- 6.72 (m, 2H); 7.25-7.38 (m, 1H), 7.38-7.61 (m, 2H). UPLC-MS (ESI+): [M+H]+=540. h-NMR (methanol-d4, 300 ΜΗζ): 1.32 (d,6H); 1.94 (s, 3H); 3.50-3.58 (m, 1H); 3.72-3.84 (m, 1H); 4.10 (br. s, 2H); 4.57 (septett, 1H) ; 5.54-5.65 (m, 1H); 6.69-6.83 (m, 1H); 7.03-7.11 (m, 1H); 7.28- 7.38 (m, 2H), 7.43-7.60 (m, 2H). UPLC-MS (ESI+): [M+Hf=540. 6-(2,2-difluoro&lt;-benzo[1,3] Dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5H -thiazolo[3,2-a]pyridine-3-indole hydrazine®-蝌~,丨ϊ Λ ^ ^ ^ W Λ ,* ΟΟ i: ώ ^色紫AT〇^ 4 cA ^ ύ, wf 〇〇 In S ^ 4 5. ®- a 灭灭哈1 e ®7 i“ ,_1 ^ rn 言丨'丨~ 〇%? K.9 Κ.10 K.11 152524.doc •230- 201130854

'H-NMR (methanol-d4,400 MHz): 1.93 (s,3H); 3.53-3.60 (m,1H); 3.74-3.84 (m, 1H); 4.03-4.17 (m, 2H); 5.55-5.62 (m, 1H); 7.18-7.36 (m, 3H); 7.36-7.43 (m, 1H), 7.44-7.51 (m, 1H); 7.54-7.59 (m, 1H). UPLC-MS (ESI+): [M+H]+=566. h-NMR (sterol-d4, 400 MHz): 1.88-2.02 (m, 6H); 3.50-3.62 (m, 1H); 3.71-3.87 (m, 1H); 3.99-4.17 (m, 2H); -5.71 (m, 1H); 7.23-7.59 (m, 6H). iH-NMR (methanol-d4, 300 MHz): 1.92 (s,3H); 3.49-3.58 (m,1H); 3.71-3-85 (m, 4H); 4.00-4.16 (m, 2H); 5.66 (m, 1H); 6.67-6.81 (m, 2H); 7.02-7.11 (m, 1H); 7.26-7.36 (m, 1H), 7.42-7.59 (m, 2H). UPLC-MS (ESI+): [M+H]+=512. ^-NMR (methanol-d4, 300 MHz): 1.93 (s,3H); 3.44-3.58 (m,1H); 3.66-3.83 (m, 1H); 3.99-4.15 (m, 2H); 5.51-5.64 ( m, 1H); 6.57-6.66 (m, 2H); 6.70-6.81 (m, 2H); 7.04-7.23 (m, 2H); 7.25-7.38 (m, 1H), 7.41-7.51 (m, 1H); 7.52-7.59 (m, 1H). UPLC-MS (ESI+): [M+H]+=480 〇φ ¥ ϊ Λ ^ f ^ ^ ®- moth i κη cn ¢- ^ I ^ rA &lt;N &lt;N i -D ¥ « f S ^ ^ s Λ ':! ir v ^ ^ Ό己军 6-(2-Fluoro-4-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7 -mercapto-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid^ Ί ^ 々&lt;Λ ®- « 2 έ ^ ^ f I t2 _ beads UJ ri (N ^ :^%X5 υ %? (N m inch H 152524.doc -231 - 201130854 ^-NMR (methanol-&lt;34, 400 MHz): 1.96 (s,3H); 3.48-3.61 (m,1H); 3.71-3.85 (m, 1H); 4.01-4.15 (m, 2H); 5.53-5.68 (m, 1H); 6.54-6.74 (m, 2H); 7.28-7_35 (m, 1H) 7.43-7.52 (m,1H); 7.53-7.59 (m,1H) UPLC-MS (ESI+): [M+H]+=528 〇UPLC-MS (ESI+): [Μ+Η]+=530 UPLC-MS (ESI+): [M+H]+=574. ^-NMR (decanol-d4, 300 MHz): 1.94 (s,3H); 3.54 (dd,1H); 3.72-3.82 (m, 1H); 4.11 (br. s, 2H); 5.59 (m, 1H); 6.89 (tr, 1H); 6.95-7.59 (m, 6H). UPLC-MS (ESI+): [M+H]+=548 ^ 1!!^ , 丨 key ^ rA S-^ 'Ί (N fA s啐硇* Art 4 J rs ^ «1砩Γ涑ri I*1. Packing seven φ minus $ 士士土醏Β- W \\\ .. ^ ^ f ύ m f A ^ S ^ i $ ί 咿 ΐ ΐ ΐ ^ ί ^ « of U| | 1 φί I 5 ^ s ^ 5 1 &quot;- ^ ^ Λ d ? I 〇〇V&quot;) D ¥ s -fi ^ ^ Ϊ I HH Well » m ®~ 硪®~ , \ '1 ^ γΛ γΛ ''J r/ νό %%? &gt; 13⁄4 %? vd^木νο 00 〇\ 152524.doc -232- 201130854 . 9?+[H+s] :(+IS3) sw-oldD. (Η^εΙ^ζ,—οοκ一(Hrs) os.9—99.9 i(Hrs)^.ιοΚΗΓε)οοζ,.ε ((ΗΓΡΡ) κ·ε KHrnw) inch6·Ιί(Ηε巨)0 inchΊ :(ΝΗ-^οο^寸 P-鮏¢-) Ή^Ν-Η-潜®--硪®iff s-butter S--H4S----sf Γ-9-¥3)-8-( Ϋί4-¥3-^^ο- ε)-9

s. 152524.doc -233- 201130854 Intermediate Ll Preparation of 8-benzyl-3-hydroxymethyl-7-mercapto-6-phenyl-2,3-dihydro-rhizozo[3,2- a ] ° ratio - 5 -嗣

According to the modified form of GP 13 (using lithium aluminum hydride instead of lithium borohydride): At a temperature, hydrogenated aluminum (92.9 mg, 0.19 mmol, 1.5 equivalents) was added to 8-benzyl-7-methyl- Methyl 5-oxo-6-phenyl-2,3-diaza-[3,2-a]pyridine-3-indoleate (Intermediate 1.1) (50 mg, 0.13 mmol) in THF (2.5 In a stirred solution in mL). After 1.5 hours of mixing at the temperature, TLC indicated that the starting material was completely consumed. The reaction mixture was quenched by the addition of water and partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The title compound was used in the subsequent reaction without further purification (yield: 39.3 mg). W-NMR (CDC13, 300 MHz): 1.89 (s, 3H); AB signal (δΑ=3.20, δΒ=3.63, 2xlH); 3.80-3.06 (m, 3H); 4.17 (dd, 1H); 4.24-4.36 (m, 1H); 5.39 (m, 1H); 7.13-7, 43 (m, 10H). MS (ESI+): [M+H]+= 364. 152524.doc -234· 201130854

荸荸阳'?了裘^8.1^3.1荽迗-5-虿^|£1(^|9^没有&gt;鹖馁^柃》荽黩1.1荽迗-&amp;-铼^8.1^3.1荽浞+^^:6啭

Analytical data ^-NMR (methanol-d4, 300 MHz): 1·83 (s, 3H); 3.55 (dd, 1H); 3.69-3.90 (m, 7H); 5.18-5.28 (m, 1H); 6.67- 6.77 (m, 1H); 6.96-7.16 (m, 5H); 7.19-7.29 (m, 1H) 〇 UPLC-MS (ESI+): [M+H]+=430. iH-NMR (sterol-d4, 400 MHz): 1.91 (s, 3H); 3.52 (dd, 1H); 3.69-3.90 (m, 8H); 5.13-5.21 (m, 1H); 6.64-6.71 (m , 1H); 6.87-6.96 (m, 2H); 7.02-7.19 (m, 2H); 7.22-7.32 (m, 1H). UPLC-MS (ESI+): [M+H]+=448 〇hNMR (CDC13,400 MHz): 1.91 (s,3H); AB signal (δΑ=3. 17, δΒ=3·54, 2χ1Η); 3.78 -3.84 (m, 1H); 3.88-3.90 (m, 3H); 4.04 (s, 2H); 4.06-4.23 (m, 2H) 5.27-5.39 (m, 1H); 6.77-6.86 (m, 1H); 6.94-6.98 (m, 1H); 7.09-7.14 (m, 1H); 7.19-7.24 (m, 1H); 7.35-7.40 (m, 1H); 7.51 (d, 1H). UPLC-MS (ESI+): [M+H]+=498. /· ν-.,^νΝ. ί.·' _ ; - Λ&gt; ^ &gt;'.&gt;'·^ί;^·· ί·':·ίί;:: V·-·^·'· Name t?毳4砼,ffi- i fork 4 地 εα Β-砩味磔刳磔刳 5 =» $4 8-(2,6-diphenylmethyl)-6-(2-fluoro-3-methoxy- Phenyl)-3-ylhydrazino-7-mercapto-2,3-dihydro-indole σ[3,2-a]吼11-but-5-one 6-(2-fluoro-3-曱oxy-phenyl)-8-(2-aero-6-trifluoromethyl-benzyl)-3-hydroxyindol-7-fluorenyl-2,3-dihydro-°°° [3,2-a]° than bite-5-ketone i - .. ' ' · ^ ' »'.·,, ο %? 〇〇: No. J m J inch J 152524.doc •235 - 201130854

h-NMR (sterol-d4, 400 MHz): 1.57 (d, 3H); 1.63 (s, 3H); 1.90 (s, 3H); 3.73-3.81 (m, 1H); 3.83-3.88 (m, 5H) 3.98-4.04 (m, 1H); 4.63-4.70 (m, 1H); 6.65-6.74 (m, 1H); 6.86-6.97 (m, 2H); 7.02-7.14 (m; 2H); 7.20-7.33 (m, 1H). L MS (EI+): M+=503. ^-NMR (CDC13, 400 MHz): 1.84 (s, 3H); 3.52 (d, 1H); 3.66-3.89 (m, 6H); 5.16-5.25 (m, 1H); 5.93 (s, 2H); -6.68 (m, 2H); 6.79-6.86 (m, 1H); 6.94-7.11 (m,3H); 7.17-7.27 (m,1H) » UPLC-MS (ESI+): [M+H]+=426 . iH-NMR (sterol-d4, 300 MHz): 2.11 (s, 3H); 3.51 (dd, 1H); 3.61-3.97 (m, 5H); 5.12-5.21 (m, 1H); 6.69 (d, 1H) ); 6.83-6.95 (m, 3H); 7.21-7.33 (m, 1H). MS (EI+): [M+Hf=439. iH-NMR (sterol-d4, 300 MHz): 1.94 (s, 3H); 3.51 (dd, 1H); 3.62-3.99 (m, 5H); 5.13-5.22 (m, 1H); 6.87-6.98 (m , 2H); 7.04-7.08 (m, 1H); 7.11-7.17 (m, 1H); 7.19-7.33 (m, 2H); 7.43-7.51 (m, 1H). MS 〇 EI+): [M+H]+=483. ,®- ^ 卜jj Ml 'τ ^ ® mi, '1 3 ^ 5 ^ d ώ硪~ yn 1 ·_4 % ^ f 2 ¢- λ1 ;4 blow 3 towards 2 1 士 4 s?na speak 3 w ώ J t ^ 5 -1 哼4 A ^ d 佘砩味Ψ ^ ^ Shouting enough 1 ώ &lt;Λ 2 ^ ? 4 Λ 1 * % ^ ^ W CN s- ci 味味味7\ ά 00 00 I o广0 v〇J 卜J 00 J 152524.doc -236- 201130854 Intermediate Ml Preparation of toluene-4-sulfonic acid 8-benzofluorenyl-7-fluorenyl-5-oxo-6-phenyl-2, 3 hydrogen _5H-° sputum and [3,2-a] ° bite -3-methyl ester

• In accordance with the modified form of GP 14 (using p-toluenesulfonate chloride instead of p-toluenesulfonic anhydride): N,N-dimethylaminopyridine (8.9 mg, 0.07 mmol, 2·2) at 0 °C Equivalent) and p-toluenesulfonic acid chloride (69 mg, 〇〇4 mmol, 1.1 eq.) were added to benzoyl-3-hydroxymethyl-7 methyl-6 phenyl-2-yl-dihydro- A stirred solution of thiazolo[3,2-a]pyridine-5-one (Intermediate [1] (12 mg, 0.03 mmol) in DCM (1 mL). The reaction mixture was kept at 0 ° C for 1 to 5 hours and at room temperature for 5 hours, after which TLC indicated that the starting material was completely consumed. The reaction mixture was partitioned between hydrazine (:1) and water. EtOAc (EtOAc m. That is used in the subsequent reaction (yield: 17.9 mg) UPLC-MS (ESI+): [M+H]+=518. £ 152524.doc -237· 201130854 &amp;- 啮 蚪 ---wwf*

ΟΟ.Ί^Ζ.Ι#匪屮虿^孤寸 I doM_铋馁^拎W 荽黩rH#s£-B-^^oo.lAI^rlAI#SE+i-ti:OK Analysis data λ η 5 ρ ε Τ left two.美食g ος (N ^ ^ ε &lt; ώ s〇§ 5 giant s. 5 1 ^ gs 2 S ^ +1 cs vi« ^ ^ 5 g' ^ S r^im 3 v〇· · • · «\ » &lt; CO '", s I f ^ ^ I ? 4 g ? I ^ S i S ' 5^ § ssi Q x J — specifically for AS' Φ ^ ^ ^ g ^ ^ • H-NMRiCDCh, 400 MHz): 1.92 (s, 3H); 2.43 (d, 3H); 3.36-3.48 (m, 1H); 3.56-3.63 (m, 1H); 3.71-3.85 (m, 2H); 3.87 (s, 3H); 4.39 (m, 2H); 5.30-5.39 (m, 1H); 6.65-6.76 (m, 1H); 6.82-6.95 (m, 3H); 7.03-7.10 (m, 1H) 7.17-7.23 (m, 1H) ; 7.29-7.34 (m, 2H); 7.74-7.79 (m, 2H). UPLC-MS (ESI+): [M+H]+=602. :.: 参', d ^ f ^ f〒 ,Ϊ $ £ f st ^ v i4 ® ^ S ^ ώ智if &gt;1 4 B- ' i4 rA ^ t ώ ^ 曱 -4--4-sulfonic acid 8-(2,6-difluoro-benzoinyl)-6 -(2- gas-3-fluorenyl-phenyl)-7-methyl-5_ oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl Ester structure number M.2 M.3 152524.doc 238- 201130854

4 NMR (CDC13, 300 MHz): 1.89 (s,3H); 2.43-2.44 (m,3H); AB signal (δΑ=3. 35, δΒ=3·54, 2xlH); 3.88 (s,3H); 3.99-4.00 (m, 2H); 4.22-4.37 (m, 2H); 5.29-5.37 (m, 1H); 6.70-6.78 (m, 1H); 6.90-6.97 (m, 1H); 7.05-7.12 (m , 1H); 7.19-7.25 (m, 1H); 7.32-7.42 (m, 3H); 7.52 (d, 1H); 7.75-7.79 (m, 2H). UPLC-MS (ESI+): [M+H]+=652. h-NMR (sterol-d4, 300 MHz): 1.54 (d, 3H); 1.58 (s, 3H); 1.90 (d, 3H); 2.40 (s, 3H); 3.73-3.92 (m, 5H); 4.32 (ddd, 1H); 4.55 (ddd, 1H); 4.77-4.82 (m, 1H); 6.52-6.59 (m, 0.5H*); 6.60-6.67 (m, 0.5 H*); 6.86-6.97 (m , 2H); 7.00-7.13 (m; 2H); 7.18-7.32 (m, 1H); 7.32-7.37 (m, 2H); 7.62-7.69 (m, 2H). MS (EI+): 1^=629. b-NMR (sterol-d4, 300 MHz): 1.85 (s, 3H); 2.42 (s, 3H); 3.39 (dd, 1H); 3.72-3.95 (m, 3H); 4.31 (dd, 1H); 4.55 (dd, 1H); 5.30-5.38 (m, 1H); 5.94 (s, 2H); 6.51-6.56 (m, 1H); 6.79-6.85 (m, 1H); 7.03-7.27 (m, 5H); 7.36-7.41 (m, 2H); 7.70-7.76 (m, 2H).帑" ▼ ¥ ^ ^ f « Ύ ΟΊ 4 ά Λ ^ i ^ ^ ®- _ a A ®- ^ ''J ®- 4 m £ 11 ^ ^ ^ 4 itk% M f ^ Ύ f ...^ S' # S i 4 4 ® S 温 宕 安 ® · · f f f 赫 赫 赫 赫 赫 赫 赫 赫 赫 龄 龄 龄 龄 龄 龄 龄 152 152 152 152 152 524524.doc -239- 201130854 h-NMR (methanol - D4, 300 MHz): 2.14 (s, 3H); 2.39 (s, 3H); 3.38 (dd, 1H); 3_72 (dd, 1H); AB signal (δΑ=3.82, δΒ=3·89, 2xlH); AB signal (δΑ=4.29, δΒ=4.44, 2xlH); 5.24-5.33 (m, 1H); 6.68 (d, 1H); 6.89-7.00 (m, 3H); 7.24-7.38 (m, 3H); 7.64- 7.72 (m, 2H). 1.———— . cn ^ S S II II to v§,. S芝目' SO visit 5 s SS T3 X ^ § ^ ί g -d * 5 ^ 'Lj S' Ύ K t&gt;〇£- 漶二 Of q ^ ^ co S 3 p mine ffi S di 5 ^ S a ^ r -:ss N Λ | ac (N 丨家丨!》“ to 4 ^ 5 ¥ 7 &gt;,m (N Φ ^ £ ^ ^ 5 ® i S 〇m * S- ^ ά '1 t '1 r} B- Ci ^ anthraquinone-4-sulfonic acid 8-(2,6-dioxa-phenylhydrazino)-7-indolyl-5-oxo-6-(3-trifluoromethoxy- Stupid)-2,3-dihydro-5H-thiazolo[3,2-a]0 is more than -3-ylmethacetate~ M.7 _i M.8 152524.doc -240- 201130854 Intermediate Nl Preparation of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazole[3,2-a]π ratio bite-3 - road

Similar to the documents 1996, 335, 588-590. Add 戴, Dess-Martin high moth (77·0 mg, 0·165 mmol, 1-5 equivalents) to 8-benzyl-3-_hydroxyl-yl group in several ways. 7-Methyl-6-phenyl-2,3-dihydrogenin beta-[3,2-a]n ratio bit-5-one (intermediate L.1) (40.0 mg '0.110 mmol) in DCM (2 mL) in a stirred solution. After TLC indicated complete elution of the starting material, the reaction mixture was quenched by aqueous sodium bicarbonate / aqueous sodium thiosulfate (1:1). After the phase separation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine. The title compound was used in the subsequent reaction without further purification (yield: 4 〇. 4 mg). W-NMR (CDC13, 300 MHz): 1.93 (s, 3H); AB signal (δΑ=3 59 δΒ=3.67, 2xlH); 3.83 (s, 3H); 5.54-5.60 (m, 1H); 7.14.7 43 (m, 10H); 9·75 (s, 1H). UPLC-MS (ESI+): [M+H]+=362 〇 Table 11: Starting from intermediate L.3, the following intermediates were prepared in a similar manner to the intermediate N·1. N.2 152524.doc 241 - 201130854 . No. 楫ρ—--- Name. -- : .... Analytical data N.2 8-(2,6-Difluoro-benzyl)_6_ (2-fluoro-3-methoxy -phenyl)·7-fluorenyl-5. oxo-2,3·dihydro-5Η-thiazolo[3,2-a] ° pyridine-3-carboxylic acid — ^-NMR (CDC13, 300 MHz ): 2.01 (s, 3H); 3.51-3.71 (m, 2H); 3.89 (s, 3H); 5.43-5.49 (m, 0.5H*); 5.51-5.57 (m, 0.5H*); 6.92-7.00 (m, 1H); 7.05-7.14 (m, 2H); 7.15-7.24 (m, 2H); 7.39-7,52 (m, 1H); 9.65-9.72 (m, 1H). MS (EI+): M+=445. Intermediate ο.ι Preparation of 8-(2,6-difluoro-anthracenyl)_3_hydroxymethyl-7-indenyl-2,3_dihydro-thiazolidine[3,2-&amp;] ° ° ° fixed -5-_

According to the modified form of GP 13: at _78. (:, lithium borohydride (3 75 mL ' 2 ]V [7.5 mmol, 1.5 eq in THF) was added to 8-(2,6-difluoro-benzoinyl)-7-methyl·5 - alkoxy 2,3_dihydro-5H-thiazolo[3,2-a]pyridyl-3-indole methyl ester (intermediate *F3) (1 75 g, 5. 〇mm〇l) In a stirred solution of THF (10 mL). After stirring at room temperature for 2.5 hours, the reaction mixture was warmed to 〇 ° C. stirring was continued until TLC indicated that the starting material was completely consumed. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The procedure was used in the subsequent reaction (yield: 1 2 152524.doc -242- 201130854 g) 〇W-NMR (methanol-d4, 300 MHz): 2 14 (s, 3H); 3 45 3(10), 1H); 3.57 -3.91 (m, 5H); 5.08-5.19 (m, 1H); 6.08 (s, 1H); 6.85-6.98 (m, 2H); 7.21-7.34 (m, 1H). UPLC-MS (ESI+): [M+H].=324. Intermediate P. 1 Preparation of toluene-4-sulfonic acid 8_(2,6-difluoro-phenylindenyl)-7-indenyl-5-oxo- 2,3-dihydro-511-.塞〇圭和[3,2-玨]〇比甲-3-基甲

According to the modified form of GP 14 (using p-toluenesulfonic acid chloride instead of p-toluenesulfonic anhydride at 0 ° C, Ν, Ν-dimethylaminopyridine (997 4 mg, 8.16 mmol '2.2 equivalents) And p-toluenesulfonic acid chloride (778 3 mg, 4 〇 8 mmol, 1.1 equivalents) added to 8-(2,6-difluoro-benzyl)_3_hydroxyindenyl-7-methyl-2,3 -Dihydro-&lt;·Sit "Sit and [3,2-a]. More than a stirred solution of 5-keto-ketone (Intermediate 0.1) (1.2 g, 4 mmol) in DCM (33 mL). The reaction mixture was kept at 〇 ° C for 0.5 h and at room temperature for 2.5 h until TLC indicated complete depletion of starting material. The reaction mixture was partitioned between DCM, water and sulfuric acid (1% aqueous). The combined organic layers were washed with sodium bicarbonate, dried over sodium sulfate and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjj NMR (sterol-d4, 400 MHz): 2.11 (s' 3H); μ (s, 3H); 3.62-3.83 (m, 3H); 4.23 (dd, 1H); 4.38 (dd, lH); 5&gt; 18.5 25 (m, 1H); 5.90 (S) ih); 6.88-6.97 (m, 2H); 7.2 4-7 35 (m 3H); 7.63-7.69 (m, 2H). ' Intermediate Ql Preparation 8_(2,6-Difluoro-methane)-7-methyl-3-{[methyl-(2-pyridyl-ethyl)-amino]-indenyl} 2,3-Dihydro-thiazolo[3,2-a] «•Biidine-5-one

Modified according to GP 16a: methyl(2•pyridin-2-yl-ethyl)-amine (95 5 mg, 7.01 mmol '5.0 equivalent) was added to toluene_4_sulfonic acid 8-(() at room temperature 2,6-difluoro-benzyl)-7-methyl-5-oxo-2,3-dihydro-5Η-oxazolo[3,2-a]pyridin-3-ylmethyl ester (middle The substance ρ.ι) was mixed in a solution of THF (10 mL). The reaction mixture was warmed to 55 °C until TLC indicated the starting material was completely consumed (2 h). The reaction mixture was partitioned between EtOAc EtOAc m. The title compound was isolated by flash column chromatography (yield: 332 mg). W-NMR (methanol-d4, 300 MHz): 2.39 (s, 3H); 2.49-2.57 (m, 1H); 2.63-2.80 (m, 2H); 2.87-3.01 (m, 5H); 3.35-3.46 ( m, 1H); AB signal (δΑ=3·73, δΒ=3.86, 2xlH); 5.06-5.16 (m,1H); 152524.doc • 244· 201130854 6.07 (d, 1H); 6.86-6.97 (m, 2H); 7.19-7.38 (m, 3H); 7.67-7.79 (m; 1H); 8.39-8.43 (m, 1H). UPLC-MS (ESI+): [M+H]+=442. Intermediate R. 1 Preparation 8-(2-Fluoro-6-trifluoromethylbenzoyl)·7-fluorenyl-5-sideoxy-2,3-dihydro-5H-° plug. Sit and [3,2-a] ° bite · 3 · tannic acid

According to the modified form of GP 11: at room temperature, the gas oxidation clock (6) * g, 56" mm 〇 h 15 equivalents, dissolved in 8 〇 mL water) is added to 8 (2 gas _ 6-difluoromethyl - Benzyl)_7_fluorenyl _ sideoxy-2,3_dihydro _5h sold. Sit and stir in [3,2-small ratio -3-carboxylic acid methyl vinegar (intermediate red 4) 〇 5 g, 37 4 匪〇 1) in THF (370 mL) and stir until TL (: indicates The starting material was completely consumed (2 hours). Then the value was adjusted to 4 (2^^ aqueous hydrochloric acid). The THF was evaporated and the residue was diluted with water. The solid was filtered and washed with water to give the title compound (yield: </ RTI> <RTIgt; , 1H); 6.00 (s, lH), 7.40_7.60 (m, 3H) MS (ESI+): [M+H]+=388.

Table 12: The following intermediates r.2 and R.3 are similar to the intermediate R丨 I 152524.doc -245- 201130854 Starting from the intermediates F.3 and F.6 according to the modified form of GP 11 To prepare the number structure name analysis data R.2 〇^OH 0 8-(2,6-difluoro-phenylhydrazinyl-fluorenyl-5-sideoxy-2,3-dihydro-5H-thiazide And [3,2a]0 than bite-3-decanoic acid 'H-NMR (d6-DMSO, 300 MHz): 2.06 (s, 3H); 3.47 (dd, 1H), 3.68 (m, 2H), 3.75 ( Dd,lH), 5.35 (dd, 1H); 5.96 (s, 1H), 6.98-7.08 (m, 2H), 7.26-7.36 (m, 1H). UPLC-MS (ESI+): [M+H]+ =338. R.3 8-(2·Fluoro-6-trifluoromethyl-benzoinyl)-2,2,7-trimethyl-5-oxo-2,3-dihydro-5H- Oxazolo[3,2-a]pyridine-3-carboxylic acid 'H-NMR (d6-DMSO, 300 MHz): 1.39 (s, 3H); 1.45 (s, 3H); 2.01 (s, 3H); -3.95 (m, 2H); 4.84 (s, 1H); 6.00 (s, 1H); 7.40-7.61 (m, 3H), 13.28 (br. s, 1H). Intermediate S.1 Preparation 8-(2) -Fluoro-6-tri-IL-methylphenyl-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-thio S-phenyl formate

According to the modified form of GP 19: 1H-hydroxybenzotriazole (6.43 g, 42 mmol, 1.2 eq.) and !^_ethyl_Νι, Ν, 曱 dimethylamino group · C at room temperature A carbodiimide (8.05 g '42 mmol, 1.2 eq.) was added to 8_(2·fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3· Dihydro·5H-thiazolo[3,2-a]pyridine-3-decanoic acid (intermediate R l) (13 5 g, 35 mm〇1) in 152524.doc -246- 201130854 DMF (450 mL) Stir in the solution. After 1 hour at room temperature, thiophenol (4.63 g, 42 mmol '1.2 equivalents) was added dropwise and the mixture was stirred for 18 hours until LCMS indicated the starting material was completely consumed. The mixture was poured into an ice/saturated aqueous solution of sodium bicarbonate and stirred for additional 30 min. The precipitate was filtered, washed with water and dried under reduced pressure to give the desired compound (yield: 14-5 g). ^-NMR (DMSO-d6, 300 MHz): 2.10 (s, 3H); 3.50 (m, 1H), 3.75 (m, 1H), 3.92 (m, 2H), 5.69 (m, 1H); 6.08 (s , 1H), 7·30_7·60 (m, 8H). MS (ESI+): [M+H]+= 480. Table 13: The following intermediates S.2 and S3 were prepared in a similar manner to the intermediate S1 and in accordance with the modified form of GP 19 from the intermediates R.2 and R.3, respectively. #r: - . ...3⁄4, weigh ten': side data S.2 03⁄4 8-(2,6-difluoro-phenylindenyl)-7-methyl-5-sideoxy-2,3 - dihydro-5H-thiazolo[3,2a]° pyridine-3-thiocarbamic acid S-phenyl ester *H-NMR (d6-DMSO, 300 MHz): 2.09 (s, 3H); 3.61 (dd, 1H)5 3.72 (dd, 2H), 3.86 (dd, 1H), 5.73 (dd, 1H); 6.04 (s, 1H), 7.02 (m, 2H), 7.29-7.50 (m, 6H). UPLC-MS (ESI+): [M+H]+=430. S.3 8-(2-Fluoro-6-trifluoromethyl-phenylhydrazino)-2,2,7-trimethyl-5-yloxy-2,3-dihydro-5H-arzoxa [3,2-a] pyridine-3-thiocarboxylic acid S-phenyl ester h-NMR (sterol-d4, 300 MHz): 1.51 (s, 3H); 1.59 (s, 3H); 2.18 (s, 3H) ); 4.05 (s, 2H), 5.22 (s, 1H); 6.24 (d, 1H), 7.26-7.610 (m, 8H) *&gt; UPLC-MS (ESI+): [M+H]+=508. • 247· 152524.doc 201130854 Intermediate τ. 1 Preparation 3-Benzyl-based 8-(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl-2,3_dihydro-sigh Sit and [3,2-a]«^^-5-_

According to the modified form of GP 20b: 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro at room temperature - 5H-indole[3,2-a] acridine-3-thiodecanoic acid S-phenyl ester (Intermediate S.1) (2.5 g, 5.21 mmol) was dissolved in THF (70 mL). Add copper diphenylphosphinate (i) (i.95 g, 6.26 mmol '1.2 equivalents), tris(2-furyl)-phosphine (97 mg, 0-42 mmol, 0.08 篁), ginseng (two sub-sections) Glycerin_) quaternary (48 mg, 52 μηιοί, 〇.〇1 equivalent) and phenyltributyltin (2.68 g, 7.30 mmol, 1.4 eq.) and the resulting light green suspension was stirred at 50 °C. 1.5 hours. After cooling, the mixture was filtered through celite®, concentrated and purified by flash chromatography (e.c./hexane/ethyl acetate) to purify the starting material (0.5 g) and obtained the desired ketone (yield: 1.80) g). ^-NMR (CDC13j 300 MHz): 2.07 (s, 3H); 3.31 (dd, 1H), 3.78 (dd, 1H), 2.05 (dd, 2H), 6.16 (s, 1H); 6.47 (dd, 1H) , 7.15-7.25 (m, 1H), 7.36 (m, 1H), 7.48-7.52 (m, 3H), 7.62 (m, 1H), 8.01 (dd, 1H). MS (ESI+): [M+H]+=448. 152524.doc • 248- 201130854 Table 14: The following intermediates τ 2 and T3 are prepared in a similar manner to the intermediate S1 and in accordance with the modified form of GP 19 starting from the intermediates s 2 and 3.3 respectively to prepare the 'number structure name' .. : . Analytical data: T.2 % 3-phenylmercapto-8-(2,6-difluoro-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3, 2a]° ratio bite·5·ketone 'H-NMR (d6-DMSO, 300 MHz): 2.10 (s, 3H); 3.41 (dd, 1H), 3.72 (dd, 2H), 3.91 (dd, 2H), 5.97 (s, 1H); 6.56 (dd, 1H), 7.04 (m, 1H), 7.32 (m, 1H), 7.57 (m, 2H), 7.70 (m, 1H), 8.04 (m, 2H). UPLC-MS (ESI+): [M+H]+=398. T.3 Λ 3-Benzyl decyl-8-(2-trifluoromethyl phenylene)-2,2,7-trimethyl-2,3-dihydro-thiazolidine [3, 2-a]»比比-5-keto]H-NMR (methanol-d4,400 MHz): 1.19 (s, 3H); 1.69 (s, 3H); 2.13 (s,3H); AB signal (δΑ= 3.99, δΒ=4.07, 2xlH); 6.12 (d, 1H); 6.30 (s, 1H); 7.30-7.38 (m, 1H); 7.44-7.52 (m5 1H); 7.52-7.59 (m, 3H); 7.64 -7.70 (m, 1H); 8.04-8.10 (m, 2H) » UPLC-MS (ESI+): [M+H].=476. Intermediate U.1 Preparation of 3-(aminophenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydro- Oxazo[3,2-a]pyridin-5-one

a) A modified form according to GP 21a by reduction of hydrazine: 3-benzylidene-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl-2,3 -Dihydro-thiazolo[3,2-a]acridin-5-one (Intermediate T. 1) (1.8 g, 4.02 mmol) dissolved in toluene (65 mL) and tert-butanol 152524.doc •249 · 201130854 (65 mL) f »Add hydroxylamine hydrochloride (1 34 g, Η 3 mm 〇 1,4 8 equivalents) and pyridine (17 mL, 220 mmo b 50 equivalents) and stir the mixture under 〇 (TC) 2 hours. UPLC-MS indicates complete conversion. After cooling, the mixture was partitioned between water and ethyl acetate, the phases were separated, the organic layer was washed with water and brine, dried over sodium sulfate and concentrated to dryness. (2-Fluoro-6-trifluoromethyl-phenylhydrazino)_3_(hydroxyimino)-styl-indenyl-yl 2,3-anthracene-»塞峻和[3,2-a]° It is used without further purification. It is used according to the modified form of GP 23 a: in the 〇. under the ,, it is dissolved in the dioxane (2 mL) Add shed lithium hydride (1.04 mmo 4.8 equivalent, 2 Μ solution in THF) and stir with chlorinated chlorinated (50 mg, 0.26 mmol, 1.2 eq.) 10 minutes. Then add 5/Ζ-8-(2-fluoro-6-trifluoromethyl-benzyl)_3_(hydroxyimino-benzene) dissolved in dimethoxyethane (2 mL). Base-fluorenyl)_7_mercapto-2,3-dihydro-indole. Sit and [3,2-a]° to bite 5-ketone (1 〇〇mg) and stir the mixture at room temperature 16 The reaction was terminated by the addition of 4 mL of water and 1 mL of ammonia (25% in water). The mixture was partitioned between water and hexanes and extracted with dichloromethane. The solvent was removed in vacuo to give 3-(amino-phenyl-indenyl)-8-(2-fluoro-6-trifluoro) as a mixture of diastereomers (1:2.5 according to HPLC). Methyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (yield: 60 mg). W-NMR (CD3OD, 300 MHz): 2.10 And 2.16 (s, 3H); 3.30-3.45 (m, 2H), 3.85 &amp; 4.01 (m, 2H), 4.53 &amp; 4.66 (d, lH), 5.27 (m, 1H), 6.07 and 6.22 (s, 1H), 7.10-7.60 (m, 8H) MS (ESI+): [M+H]+=449. 152524.doc -250-201130854 For single-strand HPLC (Chiralpak AD-H 5 μπι 150x4.6 mm; Burning / ethanol 70:30 + 0.1% diethylamine; io ml / min : diastereomer 1 'enantiomer 1 : rt = 5 46 min (15·4 〇 / 〇) diastereomer 1, enantiomer 2: Rt = 7 48 min ( 13 2〇/〇) diastereomer 2, enantiomer 1 : rt=8 94 min (36 3%) diastereomer 2, enantiomer 2: rt= 13' 42 minutes (35.1%) b) reduction by thiol-肟

According to the modified form of GP 21&amp;: 3_Benzene oxime _8_(2_fluoro_6_trifluoromethyl-phenylhydrazino)-7-fluorenyl-2,3-dihydro-thiazolo[ 3,2_a]pyridine-5-one (Intermediate Tl) (1.1 g, 2.46 mmol) was dissolved in toluene (27 mL) and EtOAc (27 mL). 〇-Methylhydroxylamine hydrochloride (985 u 8 mmol, 4.8 eq.) and pyridine (10 mL, 123 mm 〇1,5 〇 equivalent) were added and the mixture was stirred for 3 hrs at 1 Torr. ?!^&lt;:-143 indicates complete conversion. After the cold portion, the mixture was partitioned between water and ethyl acetate, the phases were separated, the organic layer was washed with water and brine, dried over sodium sulfate and concentrated to dry. //Z-8-(2-Fluoro-6·trifluoromethyl benzoyl)·3·(methoxyimino phenyl-indenyl)-7-methyl 2,3-dihydro -thiazolo[3,2_a]pyridine-5-one (yt. 1.12 g) was used without further purification. Under oc, tetrachlorobenzene in &gt; dimethoxyethane (2 mL) Titanium hydride (5 〇 mg, 0·26 mmol '1.2 eq.) was added sodium borohydride (33, 〇88 mmol, 4.2 eq.) and stirred for 5 minutes, then added dropwise to dimethoxyethane (2 mL). E/Z-8-(2-fluoro-6-trifluoromethyl-benzyl)_3_(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro- Thiazolo[3,2_a]pyridin-5-one oxime 00 mg) and the mixture was stirred at room temperature for 3 hours. The reaction was terminated by adding 152524.doc •251 · 201130854 plus 4 mL of water and 1 mL of ammonia (25% in water). The mixture was partitioned between EtOAc and EtOAc (EtOAc). An amine phase column, hexane/ethyl acetate) was further purified to give 3-(amino-phenyl-indenyl)-8- as a mixture of diastereomers (9:1 according to HPLC). (2-Fluoro-6-trifluoromethyl-benzoinyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (yield: 34 mg). W-NMR (CD3OD, 300 MHz), major isomer: 2 16 (s, 3H); 3.25 (m, 1H), 3.44 (m, 1H), 3.85 (m, 2H), 4.54 (d, 1H) , 5.30 (m, 1H), 6.22 (s, 1H), 7.10-7.60 (m, 8H). MS (ESI+): [M+H]+=449. For palmar HPLC (Chiralpak AD-H 5 μιη 150 x 4.6 mm; hexane / ethanol 70:30 + 0.1% diethylamine; 1 · 〇 ml / min): diastereomer 1 'enantiomer 1 : Rt = 5.44 min (46 3 〇 / 〇) diastereomer 1, enantiomer 2: RT = 7.45 min (44%) diastereomer 2, enantiomer体 i : Rt = 8 97 min (5 〇 %) diastereomer 2, enantiomer 2: RT = 13.44 min (4 7%) c) 3-benzyl group by reductive amination Mercapto-8·(2·fluoro·6_trifluoromethyl-benzoinyl) 7-methyl·2,3·dihydro-thiazolo[3,2-a]pyridin-5-one (intermediate T1 (2〇5 mg, 56〇mm〇1) dissolved in methanol (10 mL) 'addition of ammonium acetate (52 〇 mail, to mmo b 12 equivalent) and sodium cyano hydride (14 〇, 2 匪〇 4 equivalents) and the mixture was heated to reflux for 4 days. Evaporation of the sterol, the residue was re-cooled in methylene chloride and aqueous sodium hydroxide solution, and the fraction 152524.doc - 252 · 201130854 was extracted from 'dichloromethane' washed with brine, dried over sodium sulfate and evaporated a solvent to give 3-(amino-phenyl-methyl)·8-(2-fluoro-6-trifluorodecyl-benzene as a mixture of diastereomers (1:3.6 according to HPLC) Methyl)_7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (yield: I57 mg) by chromatography (amine phase, hexane/acetic acid B) Ester) for further purification. i-NMR (CD3OD, 300 MHz), major isomer: 2.09 (s, 3H); 3.30-3.50 (m, 2H), 4.00 (m, 2H), 4.66 (d, 1H), 5.30 (m, out ), 6.06 (s, 1H), 7.10-7.60 (m, 8H). MS (ESI+): [M+H]+=449. For palmar HPLC (Chiralpak AD_H 5 μιη 150×4.6 mm; shanghai/ethanol 70:30+0.1% diethylamine; io ml/min): diastereomer 1, enantiomer i ·· Rt = 5.47 min (11 2%) diastereomer 1, enantiomer 2: rt = 7.47 min (1. 4%) diastereomer 2, enantiomer 1 : Rt = 8.91 min (38.1%) diastereomer 2, enantiomer 2: RT = 13.39 min (40.3 〇 / 〇) Table 15: The following intermediate U.2 is similar to the intermediate υ; This was prepared in the modified form of gP 23a starting from the intermediate τ. 2 via methyl hydrazine. The intermediates U.3a and U.3b are prepared in the same manner as the intermediate LU and in the modified form of Gp 23&amp; from the intermediate Τ·3 starting from the hydroxy group.

S 152524.doc -253 - 201130854 No. Structure Name Analysis data U.2 OvH2. 3-(Amino-phenyl-indenyl)-8-(2,6-difluoro-benzoinyl)-7-methyl-2,3-dihydro-thiazolo[3,2a]0 -5-keto-b-NMR (CD3OD, 300 MHz) major diastereomer: 2.23 (s, 3H); 3.31 (m, 1H), 3.50 (dd, 1H), 3.63 (dd, 2H), 4.55 (d, 1H), 5.32 (dd, 1H), 6.20 (s, 1H), 6.86 (m, 1H), 7.09-7.29 (m, 7H); UPLC-MS (ESI+): [M+H]+= 399 ° U.3a 〇YHX Λ 3-(Amino-phenyl-fluorenyl)-8-(2-gas-6-trifluoromethyl-adenyl)-2,2,7-trimethyl- 2,3-Dihydro-thiazolo[3,2-a]»pyridin-5-one (diastereomer 1) ^-NMR (methanol-d4, 400 MHz): 1.15 (s, 3H) ; 1.37 (s, 3H); 2.12 (s, 3H); AB signal (δΑ=3·99, δΒ=4·08, 2xlH); 4.30 (d,1H), 5.21 (d, 1H), 6.25 (s , 1H), 7.24 -7.59 (m, 8H). UPLC-MS (ESI+): [M+H]+=477 ° for palmitic HPLC (Chiralpak IA 5 μιη 15〇χ4·6mm; hexane: 3⁄4/ethanol 80:20+0.1% diethylamine; 1.0 ml/min ): Enantiomer 1 : Rt = 6.84 min Enantiomer 2 : Rt = 7.89 U.3b 〇VH2 〇Λ 3-(Amino-phenyl-indenyl)-8-(2-Fluoro- 6-trifluoromethyl-adenyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,Ια]pyridin-5-one (diastereomer 2) h-NMR (methanol-d4, 400 MHz): 1.44 (s, 3H); 1.62 (s, 3H); 2.00 (s, 3H); 3.84 (s, 2H); 4.52 (d, 1H), 5.90 (s , 1H), 7.10 - 7.20 (m, 5H); 7.25-7.33 (m, 1H); 7.42-7.50 (m, 1H); 7.50-7.55 (m, 1H). UPLC-MS (ESI+): [M+H]+=477 ° for palmar HPLC (Chiralpak IA 5 μιη 15〇χ4.6 mm; hexane/ethanol 50:50+0.1% diethylamine; 1.0 ml/min ): Enantiomer 1 : Rt = 4.29 min. Enantiomer 2: RT = 6.07 Intermediate v. 1 Preparation of [3-(1,1-difluoroethyl)phenyl] </RTI> acid 152524. -254- 201130854 HOv

OH

According to the modified form of GP 30: third butyl lithium (1 33 mL, 144.9 mg, 2.20 mmol, 2.0 equivalents) was slowly added to the commercially available /^-3-(1, at _78 °c). 1-Afluoroethyl)benzene (250 mg, 1 _ 13 mmol) in a stirred solution of EtOAc (2 mL). Stirring was continued for 20 minutes at -781:. Next, triisopropyl borate (531, 8 mg, 2.83 mmol, 2.5 eq.) was added and the mixture was warmed to room temperature overnight. After the addition of hydrochloric acid (2N) (pH 1), the mixture was partitioned between ethyl acetate and water. Boric acid was isolated by flash column chromatography (yield: 70 mg). W-NMR (CDC13, 400 MHz): 2.03 (t,3H); 7.57-7.66 (Melon, 1H); 7.73-7.81 (m,1H); 8.27-8.38 (m, 2H). Preparation of [3-(1,1-difluoroethyl)-2-fluorophenyl]g-p-acid by intermediate V.2

FvLch,

Preparation of intermediate-V.2a 1-oxa-3-(1,1-difluoro-ethyl)-2-fluoro-benzene

152524.doc -255 - 201130854 'Tri-(2-methoxyethyl)aminosulfur trifluoride (deoxyfluoride) at room temperature (51 mL, 50% in THF) 61.2 g , 13 8.2 mmo, 3.0 eq.) was added to a stirred solution of commercially available 3-bromo-2-fluoroacetophenone (10.0 g, 46.1 mmol) in toluene (60 mL). The reaction mixture was heated to 65 ° C and stirred for 24 hours. Then deoxyfluoride plus mL, 50% in THF, 1 8.0 g, 40·6 mmol, 0.9 eq.) was added and stirring was continued for a further 24 hours. After the second addition of deoxyfluoride (15 mL, 50% in THF, 18.0 g, 40.6 mmol &lt;RTI ID=0.0&gt; An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture; after phase separation, the aqueous layer was extracted three times with diethyl ether. The combined organic layers were washed with aqueous sodium bicarbonate and brine, filtered and evaporated. The crude product was filtered through a pad (EtOAc / pentane) and used as a solution in the next reaction step (with residual amount of toluene) (yield: 10.9 g). iH-NMR (methanol-d4, 300 MHz): 1.95 (td, 3H); 7.10 (m, 1H); 7.51 (m, 1H); 7.70 (m, 1H). Preparation of 2-[3-(l,l-fluoroethyl)-2-fluorophenyl]_4,4,5,5-tetramethyl-i,3,2-dioxaborazole by intermediate V.2b

Bis (pinacolyl) diboron (19.8 g, 77.9 mmol, 2.0 eq.), potassium acetate (11.5 g, 116.8 mmol, 3.0 eq.) and digas 152524.doc -256-201130854 (Ι) at room temperature , Γ-bis(diphenylphosphino)ferrocene)palladium dichloromethane complex (3.2 g, 3.89 mmol, 0.1 eq.) was added to 1-di-3-(1,1-difluoro-ethyl)_2 - Deficient Benzene (Intermediate V.2a) (9.3 g '38.9 mmol) in a search solution in Dioxan (1 mL). The reaction mixture was heated to 11 ° C for 2 hours. After cooling, the reaction was quenched by the addition of water and ethyl acetate. The organic layer was separated, the aqueous layer was evaporated, evaporated, evaporated, evaporated W-NMR (fermentation-d4, 300 MHz): 1.35 (s, 12H); 1.96 (td, 3H); 7.23 (m, 1H); 7.64 (m, 1H); 7.77 (m, 1H). Intermediate V.2 Preparation of [3-(1,1-difluoroethyl)_2-fluorophenyl]tanoic acid fXch3

OH 'Addition of ammonium acetate (6.1 g, 80.2 mmol, 3.0 eq.) and (meta) sodium periodate (17.1 g '80.2 mmol, 3.0 eq.) to 2-[3-G,1-difluoro at room temperature Ethyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-diboron (intermediate V.2b) (7.6 g, 26.7 mmol) In a solution of acetone/water (200 mL/100 mL). At 4 〇. (The reaction mixture was stirred for 4 hours. The acetone was then treated and the aqueous phase was extracted three times with ethyl acetate. Washed with brine, dried and evaporated to give the desired acid, which was used as crude product (yield: 5.6 g) 152524.doc s •257- 201130854 H-NMR (CDC13 400 MHzV 2 m ^ 2.01 (t,3H); 7.27 (m,1H) 7.72 (m,1H); 8.16 (m,1H) Intermediate V.3 Preparation (5-Fluoro-2,3-dihydro-indole·benzodifluorenyl) Lysine

HO

Preparation of 5-fluoro-6-(4,4,5,5-tetramethyldioxaboron-2-yl), bis-hydrogen-1,4·benzodioxan, intermediate V.3a

Bis (pinacolyl) diboron (1 丨g, 4 3 mm 〇 1, 2.0 eq.), potassium acetate (632 mg, 6.43 mm 〇 1, 3 〇 equivalent) and two gases (ι) at room temperature , ι·-bis(diphenylphosphino)ferrocene)palladium gas methane complex (175 2 mg, 0.22 mmol, 0.1 eq.) was added to 6-bromo-5-fluoro-2,3-dihydro_1 4-benzodioxine [obtained in the form of a two-step process starting from commercially available 3-fluoro-1,2-benzenediol, see WO 2008/128942 (Α1), Example 53, Step (a) Z (b)] (500 mg ' 2.15 mmol) in a mixed solution of dioxane (15 mL). The reaction mixture was heated to 110 ° C for 2 hours. After cooling, the reaction was quenched by the addition of water and ethyl acetate. The organic sound separation of the ethyl acetate extract water was washed with brine and the organic layer was washed with water, and the crude acid was produced from 152524.doc -258-201130854, which was obtained by flash chromatography of 辠盛+丹精甶Further purification (yield: 860 mg). H-NMR (methanol-(14,300; \1 edge): 6-61 (dd, 1H); 7.07 (dd, 1H) 〇 intermediate V.3 3 〇 (s, 12H); 4.26 (m, 4H) Preparation of (5-fluoro·2,3-dihydro-i,4-benzodioxan-6-yl)|Phenic acid

Add acetic acid (4.9 g, 63 mmol, 3.0 equivalents) and (partial) sodium periodate (13.6 g, 63.4 mmo 3.2 〇 equivalent) to 5_Fluid Winter (4'4,5) ,5-tetramethyl],3,2-dioxaboronic acid 2_yl) 2,3-dichloro.anthracene benzodioxine (intermediate V.3a) (5_9 g, 21 "mm〇1) in a stirred solution of acetone/water (6 〇 mL / 30 mL). At 4 〇. The reaction mixture was stirred for 4 hours under the arm. Ammonium acetate (4.9 g, 63 mmol, 3.0 eq.) and (partial) sodium perrhenate (13.6 g, 63.4 mmol, 3_0 equivalent) were added again and the mixture was further stirred at 50 ° C for 4 hours. Then acetone and water were evaporated. The reaction was treated with aqueous HCl (2 M) and EtOAc (EtOAc) After washing with brine, the solvent was filtered and evaporated to give the desired acid, which was used as crude product (yield: 2.6 g) after stripping of benzene. lH_NMR (sterol-d4, 400 MHz): 4.26 (m, 4H); 6.63 (d, 1H); 6.67 (m, 1H) 〇 intermediate V.4 Preparation 5-fluoro·6-(4,4,5 ,5·tetramethyl-H2-diboron-2-yl)-2,2-di

S 152524.doc -259- 201130854 氘-Benzo[1,3]dioxole h3c H3

Preparation of 4-fluoro-2,2·diindole-benzo[,3]dioxole from intermediate V.4a

3-Fluorobenzene-1,3-diol (5 g '39 mmol), cesium carbonate (19 g, 58 mmol) and dibromodecane_D2 (10 g '175 mmol) in dimethylformamide The mixture in (100 ml) was heated to i 〇 (rc for 2 hours. After cooling) the reaction was filtered and the filtrate was partitioned between n-hexane and water. Separation of the organic layer. The aqueous layer was extracted with n-hexane and evaporated. The organic layers were combined to give the product. 'H-NMR (CDC13, 300 MHz): 6.57-6.83 (m, 3H) ° Intermediate V, 4b Preparation 5-bromo-4-fluoro-2,2-diindole- Benzo[1,3]dioxole

Bromine (7 g, 159 mmol) was added to 4-fluoro-2,2-diindole-benzo[1,3]monooxol (intermediate v.4a) at 〇 °C ( 5.2 g, 36 mmol) in a 152524.doc 201130854 alcohol (95 mL) in a mixing solution, the reaction mixture was allowed to stand overnight at room temperature and poured into saturated sodium bicarbonate solution and crushed ice (1:1 , 5〇〇, such as). The product was collected by filtration. lH_NMR (methanol _d4, 400 MHZ): 6.60 and 6.63 (2xd, 1H); 7.01 and 7·04 (2xd, 1H). Intermediate V.4

Preparation of 5-fluoro-6-(4,4,5,5-tetramethyldioxaboron-2-yl)_2,2•diindole-benzo[1,3]dioxole

D at room temperature, bis (pinacolyl) diboron (33 5 g, m mm〇1),

Potassium acetate (19 g' 197 mmol) and dichloro (1, Γ-bis (diphenylphosphino) ferrocene) boat-chloranthene complex (4.8 g' 6.6 mmol) was added to 5 · desert-4 A stirred solution of fluoro-2,2-diindole-benzo[1,3]dioxole (intermediate V4b) (i4"g, 221 mmol) in dioxane (470 mL). The reaction mixture was heated to 110 C ' for 2 hours. After cooling, the reaction was quenched by the addition of water and acetic acid. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with brine and then transferred to yield crude vinegar, which was further purified by flash chromatography. H-NMR (sterol-d4, 300 MHz): 1.32 (s, 12H); 6_67 (d, 1H); 7.20 (m, 1H). Intermediate V.5 152524.doc s •261· 201130854 Preparation of 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-4 -difluoromethoxy-benzene

Preparation of bromo-3-difluorodecyloxy-2-fluoro-benzene by intermediate V.5a

Odor-3-fluorobenzene (1〇g, 52 mmol), cesium carbonate (51 g, 15 Ί mmol) and sodium difluoroacetate (24 g, 157 mmol) in dimethyl hydrazine (150 ml) The mixture was heated to i ° ° C for 2 hours. The reaction was filtered after cooling and the filtrate was partitioned between n-hexane and water. Separation of the layers will be carried out. The aqueous layer is extracted with n-hexane and the combined organics are evaporated to give a shoulder product. (m, 1H); • H-NMR (CDCI3, 300 MHz): 6.50 (t, 1H); 6.85 6.96 (dd, 1H); 7.54 (t, 1H). Preparation of 5-fluoro-6-(4,4,5,5·tetramethyl-1,3,2-methoxy-benzene 152524.doc by intermediate V.5 diboron-2-yl)_4_ -262· 201130854

F

'Double (pinacol) diboron (5〇g, 2〇〇mm〇1), potassium acetate (40 g, 4〇〇mm〇1) and dichloro (u, double (two) at room temperature Palladium-based ferrocene) palladium-gas methane complex (9/7 g, 1; 3 mm 〇 1) added to bromo 3 difluoromethoxy-2- benzene-benzene (intermediate v. 5a) (32 g, 132 mm 〇 1) in a stirred solution of dioxane (535 mL). The reaction mixture was heated to u〇t: for 2 hours. After cooling, the reaction was quenched by the addition of water and ethyl acetate. The organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with brine and then transferred to yield crude acid ester, which was further purified by flash chromatography. ^-NMR (CDC13, 300 MHz): 1.36 (s, 12H); 6.54 (t, ιΗ). 6·81 (dd, 1H); 6.89 (dd, 1H); 7.74 (t, 1H). Intermediate W. 1 Preparation of 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)-propionylamino]-3-indenyl-diacid methyl ester

Intermediate W. 1 a Preparation of (£)-3-(2-fluoro-6-trifluoromethyl-phenyl)-acrylic acid methyl 152524.doc • 263· 201130854

Adding phosphine carboxylate trimethyl s (355 under nitrogen, K95 m〇1 at room temperature) to 2-fluoro-6-trifluorodecyl-benzaldehyde (250 g, 丄3 mQl) and oxynitridation Bell monohydrate (82 g'1.95 mol) in tetrahydrogen. Stirred in a solution of methane (3 L). After stirring for 24 hours, the mixture was partitioned between ethyl acetate and water, the aqueous layer was extracted with ethyl acetate and the combined organic layers dried and concentrated in vacuo to give (5) 6-Trifluoromethyl-phenyl)-decyl acrylate (329 g). !H-NMR (CDC135 400 MHz): 3.82 (s, 3H); 6.57-6.66 (m 1H) 7.24-7.58 (m, 3H); 7.72-7.83 (m, 1H). UPLC-MS (ESI+): [M+H]+=249. Intermediate W. 1 b Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionic acid

(5)-3-(2-Fluoro-6-trifluoromethyl-phenyl)-acrylic acid using Pd/C catalyst (50 g, 10% Pd, 50% water) in ethanol (2,5 L) The oxime ester (intermediate W.la) (248 g, 1 mol) was hydrogenated until hydrogen uptake ceased (consuming about 24 [hydrogen). The catalyst was filtered off and the filtrate was evaporated to give 3-(2-fluoro-6-trifluorodecyl--264- 152524.doc 201130854 phenyl)-methyl propionate (240 g). *H-NMR (CDCI3, 400 MHz): 2.58 (m, 2H); 3.14 (m, 2H); 3.72 (s, 3H); 7.24 (m, 1H); 7.32 (m, 1H); 7.45 (m, 1H). Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionic acid from intermediate W.lc

OH

F Add lithium hydroxide monohydrate (83 g, 1.98 mol) to methyl 3-(2-fluoro-6-difluoromethyl-phenyl)-propionate (intermediate W. lb) (240 g, 0.96 M〇i) In a solution of a mixture of water (2 L) and tetrahydrofuran (2 L) at room temperature and overnight, evaporating tetrahydrofuran and acidifying the residue to pH 2' with concentrated hydrochloric acid and the product precipitated. The precipitate was filtered, washed with water and dried to give &lt;RTI ID=0.0&gt; 3.15 (m, 2H); 7·26 (m, 1H); 7.34 (m, 1H); 7.46 (m, 1H). Intermediate W. Id Preparation of 3-(2·fluoro·6-trifluoroanthracene) Base base) · propylene chloride

CI

0 Add ethylene dichloride (239 g, 1.88 mol) to 3-(2-fluoro-6-152524.doc £-265-201130854 trifluoromethyl-phenyl)-propionic acid (intermediate) at room temperature w lc) (222 g, 0 94 m 〇 1) in dichloromethane (2.2 L) and stirred overnight. The mixture was then evaporated to give 3-(2-fluoro-6-trifluoromethylphenyl)-propanyl chloride (231 g). H-NMR (CDC13, 400 MHz): 3.18 (m, 4H); 7.28 (m, 1H); 7.37 (m, 1H); 7.47 (m, 1H). Intermediate W. 1 Preparation of 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)-propanylamino]_3_mercapto-propionic acid

Add 2-amino-3-mercapto-propionic acid methyl ester hydrochloride (2.9 g, 17 mmol) to 3·(2-fluoro-6-trifluoromethyl- under -(TC) under nitrogen. A stirred solution of phenyl)-propionyl chloride (intermediate W. ld) (4 g, 16 mmol) and EtOAc-ethyldiisopropylamine (27 mL, 16 mmol) in acetonitrile (150 mL). After stirring for 3 minutes, the mixture was quenched with saturated aqueous ammonium chloride (15 mL). The mixture was partitioned between ethyl acetate and water. Concentration in vacuo to give 2_[3_(2____••1 methyl-phenyl)-propenylamino]-3-mercapto-propionic acid methyl vinegar (4.75 g). Ή-NMR (CDC13, 400 MHz): 2.54 (m, 2H); 3.16 (m, 2H). 4.71 (m, ih); 6.39 (m, 1H); 7.19-7.52 (m, 3H). ' UPLC-MS (ESI+): [ M+H]+=354. Table 15a: The following intermediate W.2 is in a similar manner to the intermediate W. 1 from the middle door 152524.doc •266· 201130854 W. 1 d and methyl methacrylate hydrochloride Salt starting to prepare the number: 刼 ...... _ Name analysis data W.2 o-ch3 2-[3-(2-Fluoro-6-trifluoromethyl] stupyl)-propyl umamino]-3 -transmethyl-propionic acid methyl b-NMR (sterol-(!4,30014112) 2.48-2.60 (m, 2H); 3.03-3.17 (m, 2H), 3.74 (s, 3H), 3.75-3.92 (m, 2H), 4.53 (t, 1H) , 7.31-7.55 (m, 3H); UPLC-MS ^SI+): [M+H]+=338 » Synthesis of Example Compounds 1.1 Preparation of 8-(2,6-difluoro-benzoinyl)_6_(2 _Fluoro-3-methoxy-phenyl)-7-indenyl 5- 5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-thiodecanoic acid S-phenyl ester oxime / CHj

According to the modified form of GP 19: at room temperature, 'ι Η hydroxybenzotriazole (12·6 mg, 〇_〇 8 mmol 1.2 equivalent) and N-ethyl-N', N,-dimethyl Amino-propylcarbodiimide (15.8 mg, 〇.〇8 mmol, 1.2 eq) was added to 8-(2,6-difluoro-benzoinyl)-6-(2-fluoro-3-methoxy) -Phenyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-indoleic acid (intermediate K.2) (38 Mg, 0·08 mmol, 1.2 eq.) in a solution of DMF (2.5 mL). After 1 hour at room temperature, add a solution of thiophenol (7 μιη, 7.6 mg, 68 μηηοΐ) in DMF (0.5 mL) and continue to stir until TLC indicates 152524.doc -267- 201130854 Do it. The reaction mixture was poured into a mixture of ice/saturated sodium bicarbonate. The title compound was filtered, washed with water and dried in vacuo (yield: 40 mg). 1H-NMR (methanol-d4, 400 MHz): 1.97 (d,3H); 3.54-3.68 (m, 1H); 3.78-4.01 (m,6H); 6.66-6.79 (m,1H); 6.86-6.98 ( m, 3H); 7.03-7.15 (m, 2H); 7.21-7.36 (m, 2H); 7.37-7.50 (m, 3H). UPLC-MS (ESI+): [M+H]+=554. 152524.doc 268· 201130854

..' .: .- . . . . ... Analysis data (H NMR (methanol-d4, 300 MHz): 2.00 (s, 3H); AB signal (δΑ=3·58, δβ-3.86 , 2χ1Η); 3.89 (s, 3H); 4.15 (br. s., 2H); 5.83 (ddd, 1H); 6.73-6.81 (m, 1H); 7.08-7.18 (m, 2H); 7.32-7.54 ( m, 7H); 7.58-7.61 (m, 1H). UPLC-MS (ESI+): [M+H]+=603. [H-NMR (Methanol-(14,300)\«^): 1.93 (1 , 3 printed; 3.54-3.63 (111, 1 printed; 3.80-3.92 (m, 1H); 4.08-4.20 (m, 2H); 5.76-5.88 (m, 1H); 7.13-7.18 (m, 1H); 7.26 -7.54 (m,8H); 7.55-7.63 (m,2H). UPLC-MS (ESI+): [M+H]+=674. ^-NMR (f, -d4, 300MHz): 2.01 (s, 3H) ); 3.55-3.64 (m, lH); 3.81- 3.92 (m, 1H); 4.10-4.23 (m, 2H); 5.80-5.89 (m, 1H); 7.30-7.62 (m, 9H); 7.77-7.88 (m,1H); 8.19-8.24 (m,1H) UPLC-MS (ESI+): [M+H]+=575. ' ' v . , . , . . . . . . . . R- :: '.name' .:':'::bis'6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene 7-mercapto-5-oxo-2,3-dihydro-5 oxathiazolo[3,2-&amp;]pyridine-3-thiodecanoic acid S-phenyl ester 6-(2- Gas-5-trifluorodecyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-oxime -5-Sideoxy-2,3-dihydro-5 H-thiazolo[3,2-a]pyridine-3-thiodecanoic acid S-phenyl ester 6-(2-fluoro-pyridine-3 -yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazole p,2-a Pyridine-3-thiocarbamic acid S-phenyl ester structure 83⁄4 No.&lt;Ν ΓΛ ^Η s 152524.doc - 269- 201130854

h-NMR (sterol-d4,400 MHz): 2.00 (s, 3H); 3.57 (dd, 1H); 3.84 (dd, 1H); 4.09-4.15 (m, 2H); 5.79-5.84 (m, 1H) 7.12 (br. s, 1H); 7.18-7.28 (m, 2H); 7.29-7.60 (m, 9H). MS (ESI+): [M+H]+= 640. iH-NMR (sterol-d4, 300 MHz): 1.99 (s, 3H); 3.54-3.60 (m, 1H); 3.76 (m, 3H); 3.79-3.89 (m, 1H); 4.11-4.15 (m , 2H); 5.78-5.85 (m, 1H); 6.71-6.77 (m, 1H); 6.88-6.94 (m, 1H); 7.02-7.10 (m, 1H); 7.30-7.53 (m, 7H); -7.60 (m, 1H). ^-NMR (sterol-£^, 4001^1^): 2.01 (5, 311); 3.53-3.61 (111, 1 imprint; 3.80-3.94 (m, 1H); 4.10-4.17 (m, 2H); 5.76- 5.86 (m, 1H); 6.05 (s, 2H); 6.59-6.77 (m, 2H); 7.29-7.61 (m, 8H) MS (CI+): [M+H]+=618 » ^-NMR ( Sterol-€14,400141^): 2.02(3,3}1); 3.54-3.60(111,111);3.80-3.87 (m, 1H); 4.07-4.18 (m, 2H); 5.79-5.84 ( m, 1H); 6.95-7.00 (m, 1H); 7.05-7.08 (m, 1H); 7.20-7.25 (m, 1H); 7.28-7.53 (m, 7H); 7.55-7.60 (m, 1H). MS (ESI+): [M+H]+=636. Λ ^ ¥ ¢-硪A ball « ^ 1 ¢- rn 'tt ¢/3 f ':! 5 ^ ^ ^ ^ 5 u| ^ K ^ ^ 2 ^ s ^ Φ 5 λ OO (N 'Ί ^ ^ rn Φ 5 | 〇〇\ji uto 3 SG v ^ Λ &lt;N ^ A洙蛘ί; ά a ^ ¢-Μ ®- Ί ^ s° ^ Λ \\\ ^ cn ^ \〇^ ψ ^ ml ^ 玮a ?〒 ^ ^ ^ n 4 砩 a v ^ ^ B- f ^ Save US Ϊ ^ s ^ ^ ^ ^ ^ ^ small r^ ; OO 152524.doc •270- 201130854

^-NMR (methanol-&lt;14,300]\«^): 1.99 (8,311); 3.51-3.59 (111,111); 3.77-3.90 (m, 1H); 4.12 (br. s, 2H); 4.28 (s , 4H); 5.75-5.84 (m, 1H); 6.54-6·73 (m, 2H); 7.28-7.53 (m, 7H); 7.54-7.60 (m, 1H). UPLC-MS (ESI+): [M+H]+=632. h-NMR (methanol-d4, 300 MHz): 1.32 (d, 6H); 1.98 (s, 3H); 3.53-3.60 (m, 1H); 3.78-3.90 (m, 1H); 4.13 (br. s, 2H); 4.52-4.64 (m, 1H); 5.76-5.85 (m, 1H); 6.70-6.81 (m, 1H); 7.03-7.14 (m, 2H); 7.29-7.53 (m, 7H); 7.55- 7.60 (m, 1H). </ RTI> <RTIgt; (br. s, 2H); 5.79-5.87 (m, 1H); 7.20-7.54 (m, 10H); 7.55-7.61 (m, 1H). UPLC-MS (ESI+): [M+H]+=658 ° 6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxan-6-yl)-8 -(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3 -S-phenyl thioformate--*7 d ¥ g 〇〇, 3 ^ ^ Mechanical t 5柃^ ^ tt ^ ^ ft ^ ^ Φ ^ λ 'Ί CN ^ ^ d ? is ^ f 哿Ϊ S彳^ f ψ ζ. ί +4 土&lt; \\\ ^ ^ Ί rA ^ ^ ^ ^ Λ (Ν 'Ί V vi 4 Γ%9 〇τγ^ Winter Os o 1.11 152524.doc -271 · s 201130854 ^- NMR (sterol-d4, 400 MHz): 1.91-2.02 (m, 6H); 3.56-3.61 (m, 1H); 3.79-3.91 (m, 1H); 4.14 (br. s, 2H); 5.79-5.86 (m, 1H); 7.27-7.53 (m, 9H); 7.54-7.60 (m, 2H) UPLC-MS (ESI+): [M+H]+=638. 1 _ _ . __ —. 1 iH- NMR (sterol-d4, 300 MHz): l·99 (s, 3H); 3·52-3.61 (m, lH); 3·76-3.90 (m, 4H); 4.13 (br. s, 2H); 5.76-5.86 (m, 1H); 6.70-6.85 (m, 2H); 7.05-7.18 (m, 1H); 7.29-7.54 (m, 7H); 7.55-7.61 (m, 1H). UPLC-MS (ESI+ ): [M+H]+=604. h-NMR (sterol-£14,3001^1^): 1.99 (5,311); 3.45-3.58 (111,11^3.76-3.88 (m, 1H); 4.11 (br. s, 2H); 5.76-5.83 (m, 1H); 6.57 -6.67 (m, 1H); 6.70-6.78 (m,1H); 7.09-7.62 (m,5H). UPLC-MS (ESI+): [M+H]+=572 〇士地宁砩蚪ώ £ ^ Ώπώ Λ iVf ^ ί ^ 5 ' 1 ^ 1 rn A, 丨丨3蜍V ^ ^ a ^β巳苳6-(2-Ga-4-methoxy-phenyl)-8-(2-gas- 6-trifluorodecyl-benzoyl)-7-methyl-5-yloxy-2,3-diaza·5Η-^°[3,2-a]atbn--3-thio S-phenyl formate 8-(2-Ga-6-dimethylmethyl- benzyl)-6-(3-carbyl-phenyl)-7-methyl-5-sideoxy·2,3 -Di-argon-sit and [3,2-a]0 ratio biting -3-thioformic acid S-phenyl ester X* 1.12 1.13 U4 1 152524.doc - 272- 201130854

</ RTI> <RTIgt; ; 6.75 (tr, 1H); 6.88-7.50 (m, 11H). UPLC-MS (ESI+): [M+H]+=622. iH-NMR (methanol-d4, 300 MHz): 2.01 (s,3H); 3.53-3.61 (m,1H); 4·13 (s br,2Η) 5.76-5.87 (m, 1H); 6.59-6.76 ( m, 2H); 7.28-7.61 (m, 8Η). UPLC-MS (ESI+): [M+H]+=620. 6-(2-Ga-4-phenoxyphenyl)-8-(2-Ga-6-difluoroindolyl-phenylhydrazino)-7-indolyl-5-sideoxy-2,3- Two rats - 511-03⁄411 sit and [3,2-a] ° ratio of 3-thiobenzoic acid S-phenyl ester 6-(3-difluoromethoxy-phenyl)-8-(2-| T-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-thio S-phenyl ester N-phenyl ester 6-(4-fluoro-2,2-dioxabenzo[1,3]dioxanthene-5-yl)-8-(2-fluoro-6-trifluoromethyl) Benzyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo P,2-a]pyridine-3-thiodecanoic acid S-phenyl ester%? % 1.15 1.16 1.17 152524.doc - 273 · 201130854 h-NMR (sterol-d4, 300 MHz): 1.91 (s, 3H); 3.50 (dd, 1H); 3.73-3.81 (m, 1H); 5.73 (m , 1H); 6.82 (tr, 1H); 6.90-7.50 (m, llH). </ RTI> <RTIgt; 3.84 (m, 1H); 5.81 (m, 1H); 6.70-6.79 (m, 1H); 7.02-7.62 (m, 10H) » UPLC-MS (ESI+): [M+H]+=618. ^ Φ f Ϊ 5 ^ f ¥佘|怒w SS —&amp;·,)00 11 ^ ^ cA Mt 3 VA _ 6-(3-ethoxy-2-fluorophenyl)-8-(2-fluoro -6-trifluoromethyl-phenylhydrazino)-7-methyl_5_sideoxy-| 2,3-dioxane[3,2-&amp;]° ratio bite-3·thiocarboxylic acid S-Phenyl ester 〇r々+ 00 〇\ 152524.doc -274 201130854 Example 2.1 Preparation of 3-benzylidenyl-8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_A Oxy-phenyl)-7-mercapto-2,3-dihydro-O-pyrano[3,2-a]° ratio biting 5-ketone

According to the modified form of GP 20a: 8-(2,6-difluoro-benzyl)-6-(2-) in thF (5 mL, degassed with argon before use) at room temperature Fluoro-3 -decyloxy-phenyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]. S-phenyl pyridine-3-thiodecanoate (Example ii) (i 〇〇 mg) was added to phenyl gamic acid (26_4 mg, 0·22 mmol, 1.2 eq), 2-sold Copper (1+) salt (41.3 mg, 0.22 mmol, 1.2 eq.) and bis(dibenzylideneacetone)-di-palladium (0) (16.5 mg, 18 μιηοΐ, 0.1 eq.). Triethyl phosphite (12.5 μί '12.0 mg '72 μηιοί, 0.4 eq.) was then added and the reaction mixture was heated under reflux until TLC indicated complete elution of starting material. The reaction mixture was partitioned between EtOAc EtOAc m. The title compound was isolated by flash column chromatography (yield: 32.1 mg). !H-NMR (CDC13, 400 MHz): 1.99 (mc, 3H); 3.33-3.42 (m, 1H); 3.78-3.92 (m, 6H); 6.45-6.57 (m, 1H); 6.75-6.84 (m , 1H); 6.85-6.93 (m, 3H); 7.0-7.08 (m, 1H); 7.16-7.25 (m, 152524.doc • 275-201130854 1H); 7.44-7.52 (m, 2H); 7.55-7.64 (m, 1H); 7.97-8.05 (m, 2H). UPLC-MS (ESI+): [M+H]+=522. 152524.doc -276- 201130854

Driving 1ί«?4^8·τ^ΓΙ¥驷fw?4l5z do-r frame铋馁^柃W 荽黩r&lt;Ni# 驷c39(N.3^r&lt;Ni4ikwd :|&gt;1&lt; Analysis Information] Η-ΝΜΙΙ (methanol-d4, 300 MHz): 1.99 (d, 3H); 3.43-3.50 (m, 1H); 3.82-3.88 (m, 4H); 3.92 (br. s, 2H); 3.96- 4.04 (m, 1H); 6.57-6.75 (m, 2H); 6.88-6.99 (m, 2H); 6.99-7.13 (m, 2H); 7.21-7.36 (m, 3H); 8.09- 8.19 (m, 2H) UPLC-MS (ESI+): [M+H]+=540. ^ X ΟΟ ^ 0 ^ έχ 〆〇&lt;Ν Κ ^ g ® δ ςτ SS ^ κ ^ £ g S Fen (Ν οο 1 ® ig寸 „ 3 ΟΝ 芩 S S 6 ^ ^ ύ ^ t ξ Μ Μ ^ ^ ig -ν〇^ ? ? i C^i ^sD 〇Q Κ π r-CO X 2 3 SS s • ✓ h-NMR (sterol-d4, 300 MHz): 2.00 (s, 3H); 3.45-3.53 (m, 1H); 3.84 (d, 3H); 3.93 (br. s, 2H); 3.97-4.07 (m, 1H) 6.58-6.74 (m, 2H); 6.90-7.00 (m, 2H); 7.00-7.13 (m, 2H); 7.25-7.36 (m, 1H); 7.39-7.48 (m, 2H); 8.13-8.23 ( m,2H). UPLC-MS (ESI+): [M+H]+=606. Name χ ^ f ^ Human t-base A Λ ψ B- ^ cn -iJ ά ΐ ' ' '» 3 ί - Ό ^ id ζ. ^ οο rA ^ A ^ ψ ^ ^ ^ E 3 4 5 ί 9 i &gt;1 ^ ^ ^ νό地士^ f t 00 ®- ® rA ^ ^ ", 'J minus" dv Ί f vi rA ^ Λ ^ 6- ^ f\ ^ ^ Ϊ οό S- ®~ v ' :· V.,.:广.'!乂二. ''一结梅·:::〜:a, 5妒IL 广, F-〇广, :飙: (Ν CN m (N inch 152524.doc -277- 201130854

• H-NMR (CDC13, 300 MHz): 1.99 (s, 3H); 3.35-3.48 (m, 1H); 3.86 (m, 3H); 6.20 (m, 0.4H); 6.30 (m, 0.6H); 6.86 (m,4H); 7.02 (m,lH); 7.21 (m, 1H); 7.33 (m,lH); 7.58 (m,lH); 8.11 (m, 0.4H*); 8.17 (m, 0.6H)氺). UPLC-MS (ESI+): [M+H]+=528. iH-NMR (sterol-d4, 300 MHz): 2.0 (s, 3H); 3.54 (m, 0.5H*); 3.57 (m, 0.5H*); 3.82 (m, 3H); 6.59-6.75 (m) (2, H), 6. -8.66 (m, lH); 8.91 (m, 0.4H*); 8.95 (m, 0.6H*). UPLC-MS (ESI+): [M+H]+=578. ^-NMR (CDCI3, 300 MHz): 1.99 (m, 3H); 3.34-3.49 (m, 1H); 3.86 (m, 3H); 5.86-5.94 (m, 0.4H*); 5.98-6.04 (m, 0.6H*); 6.73-7.23 (m, 8H); 7.42 (m, 0.4H*); 7.45 (m, 0.6H*); 7.92 (m, 0.4H*); 8.07 (m, 0.6H*); UPLC-MS (ESI+): [M+H]+=512. 'H-NMR (CDCI3, 300 MHz): 1.99 (m, 6H); 2.39 (m, 3H); 3.29-3.41 (m, 1H); 3.86 (m, 3H); 6.41-6.56 (m, 1H); 6.72-7.24 (m, 9H); UPLC-MS (ESI+): [M+H]+=536 〇« ^ 2 i ^ Τ τ ^ X ^ w ^ ^ Ί ,彳AA彳§ Ci- ^ 〇〇B - op B- ® ^ ^ f 虢¥2 舍兮2; £ ^ i4 ^ V — ί rA ^ ^ c? ¥ £ A f 寺 砩 确 _ S ' S 2 «') 1 ¢- 00 ¥ ^ s CS v ^ S 2 ^ ^ x A f '砩. π ά 婳 Ci ^ 6-〇〇 ®- i4 °γ^α ό &amp; O, X&quot; m cs cs 卜 (N oo (N 152524.doc -278- 201130854

^-NMR (sterol-d4, 300 MHz): 1.99 (s,3H); 3.46-3.54 (m, 1H); 3.83 (m,3H); 3.96-4.10 (m, 1H); 6.57-8.00 (m , 10H). </ RTI> <RTIgt; (m, 3H); 6.30-6.40 (m, 1H); 6.78 (m, 1H); 6.83-6.95 (m, 4H); 7.00-7.44 (m, 4H); 7.75-7.84 (m, 1H). UPLC-MS (ESI+): [M+H]+=536. iH-NMR (methanol-d4, 300 MHz): 1·99 (s, 3H); 3.55 (m, 0.45 Η*); 3.59 (m, 0.55H*); 3.84 (m, 3H); 6.33-6.43 ( m, 1H); 6.64-6.75 (m, 1H); 6.88-6.99 (m, 2H); 7.03-7.19 (m, 2H); 7.21-7.38 (m, 3H); 7.63-7.73 (m, 1H); 7.93-8.01 (m, 1H). UPLC-MS (ESI+): [M+H]+=540. ^-NMR (sterol-d4, 300 MHz): 1.98 (m, 3H); 3.44-3.55 (m, 1H); 3.85 (m, 3H); 6.28-6.33 (m, 0.4H*); 6.35-6.40 (m, 0.6H*); 6.63-6.70 (m, 1H); 6.90-6.99 (m, 2H); 7.02-7.13 (m, 2H); 7.24-7.34 (m, 1H); 7.38-7.47 (m, 2H); 7.50-7.60 (m, 1H). UPLC-MS (ESI+): M+=574. rA ^ dv ^ im? ^ Ί ,Λ « ^ ^ s ^ Ύ j _ 婳 1 &lt;n 〇〇¢- ®- rn dd $ 3 ^ ^ &gt;Λ 1 \ 1 机械二乂 s "砩.π Μ ^ 5 Α One meal cs ®-〇〇®- ilt V ^ f 1 person ten bases A A, _1 ★ B- ^ cA -ri d 3 ^ ^ n ')« ί ^ Sis 〇〇Ά ^ ^ w ^ ^ 〇〇5- ^1 * 1 tumor ¥, 丨S »- es fA ^ &gt;4 ^ £, X &amp;- CL · mechanical A d ^ ^ rA , 1 mechanical Ik °γΛ/&lt;Λ 5Ό X) Ik 〇\ &lt;N ο (N (N cn s: 152524.doc -279- 201130854 'H-NMR (methanol-d4, 300 MHz): 1.98 (m, 3H); 3.47 (m, 0.4H*); 3.51 (m, 0.6H*); 3.84 (m, 3H); 6.50-6.62 (m, 1H); 6.63-6.73 (m, 1H); 6.87 -6.99 (m, 2H); 7.02-7.13 (m, 2H) 7.25-7.36 (m, 2H); 7.62-7.75 (m, 2H). UPLC-MS (ESI+): [M+H]+=558 - 'H-NMR (methanol-d4, 300 MHz): 1.99 (s, 3H); 3.57-3.67 (m, 1H); 3.85 (s, 3H); 3.97-4.11 (m, 1H); 6.30-6.42 (m, 1H); 6.64-6.75 (m, 1H); 6.88 -7.00 (m, 2H); 7.00-7.14 (m, 2H); 7.23-7.37 (m, 2H); 7.52-7.64 (m, 1H): 7.70-7.80 (m, 1H). UPLC-MS (ESI+) : [M+H]+=558. ^-NMR (sterol-d4, 300 MHz): 1.99 (s,3H); 3.46 (m, 0.5Η*); 3.49 (m , 0.5H*); 3.83 (s, 3H); 3.96-4.06 (m, 1H); 6.55-6.73 (m, 2H); 6.90 -6.98 (m, 2H); 7.00-7.11 (m, 2H); -7.34 (m, 1H); 7.37-7.45 (m, 1H); 7.53-7.61 (m, 1H); 7.76-7.81 (m, 1H)); 7.88-7.93 (m, 1H). UPLC-MS (ESI+): [M+H]+=540. Ί it x ^ f E rn shout '/Ί ^ ^ ®- CN ^ ^ 2 S,3 cA — Ί 泠^ 5 VX ^ If E ®~ (Ν Α ^ «Ν ,^ ®- ώ Β- ι&gt; ^ ·μ4. ^ CS ^5 ^ V ^ f ^ ^ M in do &quot;? ,1 ♦ ¢- ^ cA tt? 铋ά弋旮' 4 Μ « t 〇^ m X οο li. UU 2.13 2.14 2.15 152524. Doc •280· 201130854

^-NMR (sterol-d4, 300 MHz): 1.99 (s,3H); 3.59 (m, 0.4H*); 3.61 (m, 0.6H*); 3.84 (s, 3H); 3.99-4.07 (m , 1H); 6.31-6.39 (m, 1H); 6.65 -6.74 (m, 1H); 6.82-6.98 (m, 3H); 7.01-7.12 (m, 2H); 7.24-7.49 (m, 3H); 7.63 -7.69 (m, 1H); 7.77-7.86 (m, 0.4H*); 8.07-8.13 (m, 0.6H*). UPLC-MS (ESI+): [M+H]+=558. 'H-NMR (DMSO-d6, 400 MHz): 1.92 (m, 3H); 2.30 (m, 3H); 3.30 (m, 3H); 3.34 (m, 0.5H*); 3.37 (m, 0.5H*) 4.26 (d, 2H); 6.27-6.37 (m, 1H); 6.59-6.67 (m, 1H); 7.02-7.12 (m, 4H); 7.25 -7.40 (m, 2H); 7.42-7.47 (m , 1H); 7.60-7.64 (m, lH). UPLC-MS (ESI+): M+=570. ^H-NMR (methanol-d4, 400 MHz): 1.96 (br. s, 3H); 3.36-3.41 (m, 1H); 3.84 (s, 3H); 3.89-3.98 (m, 1H); 4.09-4. (m, 2H); 6.56-6.64 (m, 1H); 6.66-6.76 (m, 1H); 7.01-7.13 (m, 2H); 7.22-7.30 (m, 2H); 7.32-7.39 (m, 1H) 7.45-7.52 (m, 1H); 7.54-7.59 (m, 1H); 8.10-8.17 (m, 2H) 〇 UPLC-MS (ESI+): [M+H]+=590. Ί i4 S ^ 5 v SX ^ f W mv〇 key ' Ή ®- cil ^ ^ Λ A ^ &lt;N ^ ^ ^ ro ¢- 3 5 3 , B- Ψ OO Sun is 3 11 婳da兮®7 vi ^ ^ X ^ s ^ T\ ^ ^ ^ d: &lt;7 "(5) Φ ':' Λ ; ^ 3⁄4 ¥ &quot;舍婳$硪〒 B- °? &quot;f 3 A £ ^ ^ &quot; 4 ώ »: 3 Tibetan 〇 Y^m 5妒A φ IL VO &lt;N o CN 00 CN s 152524.doc -281 - 201130854

h-NMR (sterol-d4, 400 MHz): 1.96 (br. s, 3H); 3.38-3.44 (m, 1H); 3.84 (s, 3H); 3.90-3.97 (m, 1H); 4.09-4.18 (m, 2H); 6.55-6.64 (m, 1H); 6.65-6.76 (m, 1H); 7.00-7.18 (m, 2H); 7.26-7.36 (m, 1H); 7.39-7.50 (m, 2H) ; 7.67-7.75 (m, 2H); 8.14-8.21 (m, 2H). UPLC-MS (ESI+): [M+H]+=656. ^-NMR (methanol-d4, 300 MHz): 1.95 (d, 3H); 3.35-3.41 (m, 0.5 Η*); 3.46-3.53 (m, 0.5H*); 3.71-3.80 (m, 0.5H*) ); 3.82-3.88 (m, 3H); 3.90-3.99 (m, 0.5H*); 5.55-5. 63 (m, 0.5H*); 6.58-6.77 (m, 1.5H*); 7.00-7.15 ( m, 2H); 7.27-7.40 (m, 1H); 7.43-7.53 (m, 1H); 7.53-7.59 (m, 1H) 〇UPLC-MS (ESI+): [M+H]+=577 〇h- NMR (methanol-d4, 300 MHz): 1.92 (s,3H); 3.37-3.45 (m,1H); 3.92-4.03 (m, 1H); 4.10-4.18 (m, 2H); 6.59-6.70 (m, 1H); 7.09-7.18 (m, 1H); 7.21-7.76 (m, 8H); 8.02-8.10 (m, 2H). UPLC-MS (ESI+): M+=642. ^ r〇cA ^ Φ碥i $ oo ®- tef $ « 5: ? Λ S- ^ ^ ^ 4 5 械 i 11 6-(2-1-3-曱oxyphenyl)-8-[2- Fluoro-6-(trifluoromethyl)benzenef-yl]-7-methyl-3-[(23⁄4)phenylcarbonyl]-2,3-dihydro-5 士[1,3]嗔[ 3,2-a] ° ratio °-5-ketone νφ 巳^ ¢ ¢ 办 办 ώ Ί f 'Ί , ι 'v ^ i ^ d ^ id ^ 4 4 SS 3 ri small φ V; Q On (Ν CN iN 152524, doc -282- 201130854

^-NMR (methanol-d4, 400 MHz): 1.99 (d,3H); 3.38-3.44 (m,1H); 3.93-4.02 (m, 1H); 4.08-4.20 (m, 2H); 6.62-6.69 ( m, 1H); 7.31-7.40 (m, 2H); 7.45-7.61 (m, 4H); 7.62-7.69 (m, 1H); 7.74-7.84 (m, 1H); 8.03-8.09 (m, 2H); 8.14-8.18 (m, 1H). MS (EI+): M+=542. iH-NMR (methanol-d4, 400 MHz): 1.96 (s, 3H); 3.38-3.45 (m, 1 H); 3.85 (s, 3H); 3.87-3.95 (m, 1H); 6.49-6.59 (m , 1H); 6.66-6.76 (m, 1H); 7.01-7.13 (m, 2H); 7.25-7.38 (m, 2H); 7.45-7.52 (m, 1H); 7.55-7.60 (m, 1H); -7.72 (m, 1 H). </ RTI> <RTIgt; (m, 1H); 6.53-6.64 (m, 1H); 6.65-6.77 (m, 1H); 7.00-7.13 (m, 2H); 7.30-7.61 (m, 7H); 7.73-7.81 (m, 1H) ; 7.86- 7.92 (m, 1H). UPLC-MS (ESI+): M+ = 589. ^-NMR (methanol-d4, 400 MHz): 1.95 (s, 3H); 3.44-3.50 (m, 1 H); 3.84 (s, 3H); 3.88-3.96 (m, 1H); 6.23-6.43 (m (1,6H); UPLC-MS (ESI+): M+ = 612. « i | &lt;7 fS ^ B- r^T ^ ^ ® cs ®- ^ ^ ^ ^ Mechanical Ci butterflyrA ^ ^ ^ sUs 1S s I " 5漦ϊ Λ ^ ψ i Moth 1 rn ®- 1 frr mm ^ ^ rn rn ®- *^1 ¥ ^ i ^ Ί1 Ί ^ 5 泞rA ^ 3 ¥ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Es UJ Ί f .$ A, ^ fit τ 〇ό ^ Α ^ (Ν φ into 5 ώ ^ 5; ^ «Λ ^, X ®- ^ small IL · 5 tear u. %? ο r4 (N oi Oi £ 152524.doc -283 - 201130854 .6e9&quot; +S:(+IS3) SIAI-Uldn .(Η(ΝΙ€) Νε.8-9Γ8 XHrg)s.8-rN6.^(H"s) OOO. ZTU.i(HrsI9.Z,4SK KHrs) inch sz417.^(Hrs)I1^-or^(H(N *s) 5ΓΖ,-ιο·^(Η^δ)α·9-6Γ9 i( Hrs) lo.'Ts.cnifficnco') soo.e KffiΓ6) erf.rn-oore i(HS Bu 6.1 :(NHH 00' inch p-鮏®-) βιΑΓΚ-ΗΙ 1ι5ι^·ΐ^ι(Νώ^1ί1 ^·^M-et-(4lse-t4-^a-*ue)-ε-^®--/--3»-^-砩Β-Ί M-9 Ί d-8-(^--- ^Β--ε-1 d-9

152524.doc -284- 201130854 Example 2.27 Preparation of 3-phenylmercapto-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene -7-methyl-2,3-dihydro-thiazolo[3,2-a]°pyridin-5-one

Modified according to GP 20b: Add tri-n-butyl-phenyl-tin ( (335 mg, 0.91 mmol, 1.1 eq) to 6-(2) at room temperature under an argon atmosphere -fluoro-3-methoxy-styl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro- a stirred solution of 5H-thiazolo[3,2-a]pyridine-3-thiodecanoic acid S-phenyl ester (Example 1.2) (500 mg, 0.83 mmol) in THF (12 mL). Copper diphenylphosphinate (1) (3 10 mg, 0.99 mmol, 1.2 equivalents), tris(2-furyl)phosphine (15.4 mg, 0.066 mmol '0.080 equivalent) and ginseng (diphenylideneacetone) - palladium (0) (7.6 mg ' 0.008 mmol, 〇·〇1 equivalent) and the reaction mixture was heated to 50 ° C until LCMS indicated complete depletion of starting material. The reaction mixture was filtered over ceiite® and filtered. Concentration in vacuo. Compound (yield: 369 mg) was obtained by flash column chromatography. NMR (CDC13, 400 MHz)·· 1.95-1.96 (m, 3H); AB signal (δΑ=3.31, δΒ= 3.79, 2xlH); 3.86-3.87 (m, 3H); 4.08-4.09 (m, 2H); 6.47-6.56 (m, 1H); 6.79-6.86 (m, 1H); 6.88- 6.93 (m, 1H); 7.03-7.08 (m, 1H); 7.23-7.25 (m, 1H); 7.35-7.40 (m, 152524.doc -285- 201130854 1H); 7.45-7.52 (m, 3H); 7.57-7.62 (m, 1H); 7.99-8.03 (m 2H) UPLC-MS (ESI+): [M+H]+=572. 152524.doc •286- 201130854

4^8.1WHrI^(k众4. qo(Ndo-r 藏^&lt;^w^ΜΙΖ^·ζ: ί4^^^9£.(Ν^8ΓΖ: ί4ίκι-3:8Ι&lt; 152524.doc Analytical data h-NMR (f, -d4, 300MHz): 1.99 (s, 3H); 3.35-3.42 (m, lH); 3.90-4.00 (m, 1H); 4.10-4.15 (m, 2H); 6.60-6.67 ( m, 1H); 7.06-7.11 (m, 1H); 7.15-7.24 (m, 2H); 7.30-7.40 (m, 1H); 7.42-7.60 (m, 5H); 7.61-7.69 (m, 1H); </ RTI> 8.02-8. m,1H); 3·74 (d, 3H); 3.91-4.00 (m, 1H); 4.07-4.18 (m, 2H); 6.60-6.67 (m, 1H); 6.67-6.76 (m, 1H); 6.84-6.90 (m,1H); 6.99-7.06 (m,1H); 7.31-7.39 (m,1H); 7.44-7.60 (m,4H); 7.61-7.68 (m,1H); 8.02-8.10 (m , 2H). UPLC-MS (ESI+): [M+H]+=572. h-NMR (sterol-(14,300^«^): 1.99 (3,3); 3.33-3.42 (111,1) ;3.89-4.00 (m, 1H); 4.09-4.14 (m, 2H); 5.98-6.03 (m, 2H); 6.56-6.72 (m, 3H); 7.29-7.39 (m,1H); 7.42-7.69 ( m,4H); 8.01-8.09 (m,2H). UPLC-MS (ESI+): [M+H]+=586. Name®~ ^ ^ w\ ^ V ^ f « 4 cA ^ CS ¢- rjf f cA ^ ®~ ^ ^ f ^ t ^ E η λ ^ 5 i ^ I 4 V ^ ^ ^ AS ^ ^ ^ 3-Benzenyl-6-(4-fluoro-benzo[1,3]dioxanthene-5-yl)-8-(2 -Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a]» than sigma-5-one, .:'. ' .. · .. s number: .· - ' ·. 2.28 2.29 2.30 -287. 201130854

<RTIgt; 6.66 (m, 1H); 6.91-6.97 (m, 1H); 7.01-7.04 (m, 1H); 7.16-7.21 (m, 1H); 7.30-7.39 (m, 1H); 7.43-7.60 (m, 4H) ); 7.60-7.69 (m, 1H); 8.02-8.09 (m, 2H). UPLC-MS (ESI+): [M+H]+ = 604 ° The product was used in the subsequent reaction without further characterization. UPLC-MS (ESI+): [M+H]+=562. ^-NMR (methanol-d4,400 MHz): 1.98 (s, 3H); 3.62-3.70 (m, 1H); 3.84 (s, 3H); 3.98-4.13 (m, 1H); 6.60-6.75 (m, (H, 2H); 6.99-7.13 (m, 2H); 7.20-7.35 (m, 1H); 7.65-7.84 (m, 2H); 8.48- 8.56 (m, lH). UPLC-MS (ESI+): [M+H]+=54 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3.83 (m, 3H); 3.98-4.13 (m, 1H); 6.58-6.74 (m, 2H); 6.86-6.99 (m, 2H); 6.99-7.14 (m, 2H); 7.76-7.83 (m , 1H). UPLC-MS (ESI+): [M+H]+=543. S3 S i ^ ^ t ^ Ί 2 S B- 5Z 3,3 'rA 2 d ®- d £ ^ ^ Μ ¥ ® 5 $ S cn ¢- S- A ci “,, 1 寺寺r, ^ ^ Ψ ^ ¥ ΐ 1 (N〇* S 1 fa Ί ^ B- ^ ^ ^ 'j ^ £ a alkali 硇 $ CS B- 00 rn cn ^ ^ ^ rn 1 1 ^ ^ 4 Λ 2 ^ B- ^ ^ ^ i « £ i-4 ^ ¥ c? ^ ^ 2 ώ il Ϊ ^ ^ Ψ 〇〇rn ®~ 小^0»小°γ^α&gt;&amp;&gt; ΓΛ (N eN ΓΛ oi m (N 152524.doc • 288· 201130854

iH-NMR (sterol-d4, 400 MHz): 1.96 (s, 3H); 3.53-3.62 (m, 1H); 3.84 (m, 3H); 3.90-4.03 (m, 1H); 6.65-6.85 (m , 2H); 6.99-7.13 (m, 2H); 7.29-7.39 (m, 1H); 7.43-7.59 (m, 2H); 7.65-7.80 (m, 2H); 8.48-8.55 (m, lH). UPLC-MS (ESI+): M+ = 590. h-NMR (sterol-d4, 400 MHz): 1.96 (s, 3H); 2.58 (m, 3H); 3.59-3.66 (m, 1H); 3.84 (m, 3H); 3.92-4.04 (m, 1H) 6.57-6.64 (m, 1H); 6.65-6.77 (m, 1H); 6.98-7.14 (m, 2H); 7.31-7.39 (m, 1H); 7.44-7.51 (m, 1H); 7.53-7.59 (m, 1H); 7.76-7.81 (m, 1H). UPLC-MS (ESI+): [M+H]+=593. 6-(2-Ga-3-indolyl-phenyl)-3-(3-gas-° ratio bite_2_Werki)-8-(2-disorder-6-difluorodecyl·benzoic acid ))-7-fluorenyl·2,3-dihydro-β-insulphonone Φ ^ i ^ 〇〇布毛 g AA 灭 ' SS 1 *jA. l-j ^ ώ Ά Z φ ^ ':1 v ^ ^ ^ &1y&gt; u/^u· οΛζ H m &lt;N m CN s 152524.doc -289- 201130854 Example 2.37 Preparation 3-Methylmercapto_8_(2,6-difluoro-benzyl ) winter (2_fluoro·yltrimethyldihydro^ sitting and [3,2♦ than 唆_5, gas-based-ben

At 〇 ° C, a stupid base (0.53 machine, l8 M in Bu2 〇 Nakagawa mg, 0.95 mmol, equivalent) was added to 8 (26 _ 2 gas benzo (A) (213-methoxy-phenyl). 2, 2,7•trimethyl_5_sideoxy-2,3_digas_zincazole-[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate 15) (4 〇〇, The mixture was stirred in toluene (7 mL). After 3 minutes at the temperature, the reaction mixture was allowed to warm to room temperature and stirring was continued for 8 hours. Then, after cooling to o ° C, benzene was added. Lithium (0.44 mL '丨8 M in Bu2〇, 344 mg, 0.79 mmol '1.0 eq.). After 3 5 hours at room temperature, the reaction was quenched by the addition of aqueous saturated ammonium chloride and ice. The title compound was isolated (yield: 332 mg) eluted with ethyl acetate. NMR (sterol-d4, 400 MHz): 1.60 (d, 6H); 1.93 (d, 3H); 3.75-3.91 (m, 5H); 5.16 (d, 1H); 6.24-6.29 (m, 1H); 6.17-6.94 (m, 4H); 6.97-7.09 (m, 1H); 7.13-7.24 (ms 1H); 7.40-7.51 (m, 2 H); 7.51-7.62 (m, 1H); 7.99-8.08 (m, 2H) MS (HPLC-ESI+): [M+H]+=550. 152524.doc • 290· 201130854

Driving quilt--^^&quot;Ι Γ Ιβ &quot;1¥驷|-令扣03&lt;19&quot;^鹓^^柃》荽1-&quot;驷铢^9 inch-called 8£-&quot;^ ^^:(卜1^憋)€1卜1&lt;. Real': You' 々-NMR (sterol-d4,400 MHz): 1.96-2.00 (m,3H); 3.48-3.55 (m,1 H 3.94-4.03 (m, 1H); 4.13 (s, 2H); 6.33-6.42 (m, 1H); 7.18-7.43 (m, 6H); 7.44-7.53 (m, 1H); 7.55-7.59 (m , 1H); 7.64-7.73 (m, 1H); 7.95-8.01 (m, 1H). UPLC-MS (ESI+): M+ = 644. <RTIgt; 8.01 (m, 9H). </ RTI> <RTIgt; -3.99 (m, 1H); 4.11 (m, 2H); 6.44 (m, 1H); 6.71 (m, 1H); 7.07 (m, 2H); 7.34 (m, 1H); 7.43-7.63 (m, 4H) ); 8.51 (m, 1H). UPLC-MS (ES+): [M+H]+=578 = - _ · · · Name, J gas " 3 ^ f Τ Λ ^ ^13⁄4 I As ^ ? 锺硪A ^ ¢- ^ ^ CN^ ¢ - ° ^ ^ ¢- ¢- ^ Φ T\ I 兮5 AA s ^ ^ fi V ^ T 飧娜! X £ A 4 ®~ (A 味^ tf « i ^ I ^ t ^ f ^ 3 S 7 _ S rA B- T a T Ul Φ \〇^ Structure: 3⁄4 No. 2.38 2.39 1 -1 2.40 -Is- 30ρ.κ:ς3- s 152524.doc -291 · 201130854 iH-NMR (sterol-d4, 300 MHz ): 1.96 (s, 3H); 2.42 (s, 3H); 3.84 (s, 3H); 3.95 (m, 1H); 4.12 (m, 2H); 6.46 (m, 1H); 6.72 (m, 1H) ; 7.08 (m, 2H); 7.27-7.88 (m, 7H). UPLC-MS (ES+): [M+H]+=586. b-NMR (sterol-d4, 300 ΜΗζ): 1.96 (s, 3H); 2.40 (s, 3H); 3·86 (m, 3H); 4.12 (m, 2H); 6.56-6.78 (m, 2H); 7.00-7.13 (m, 2H); 7.30-7.61 (m, 5H); 7.85 (m, 2H) » UPLC-MS (ES+): [M+H]+=586. ^-NMR (sterol-d4, 300 MHz): 1.96 (s,3H); 3·87 ( m, 3H); 4.12 (m, 2H); 6.39 (m, 1H); 6.72 (m, 1H); 7.03-7.79 (m, 9H). UPLC-MS (ES+): [M+H]+=606 ^-NMR (sterol-d4, 300 MHz): 1.97 (s, 3H); 3.53 (m, 1H); 3.86 (s, 3H); 4.12 (m, 2H); 6.33 (m, 1H) ; 6. 72 (m,1H); 7.01-7.70 (m, 8H). UPLC-MS (ES+): [M+H]+=608 - 〇〇®- 11-section “3 f Λ ®- ^ 3 ¥婳? ^ Τ Γ ^ ®- 5 ^ '褊嘁ft 'Ί 〇έ&gt; 丨1区ά ^ t ί rA B- T ^ &lt;Ν 'Ί X 2 ο fi ¢- ^ φ ':! T\ ϊ ^ ^ Λ Λ ^ S ν ^ 7 ®- °? τ ^ ^ +*4 CN ¢,3⁄4 ®7 χ S ^“ _minus Φ ^ f ^ ^ ^ s ^ 5 ί Ί ^ t ^ , m rf S- ^ l Sun fr>mm ίy&gt; u_ into it P 1 W ilT^XL I ^ U-^^U. inch (Ν OJ (N CS CN 152524.doc -292- _za_ SPSS- s 201130854

b-NMR (sterol-d4, 300 MHz): 1.98 (s,3H); 3.54 (m,1H); 3.86 (s, 3H); 4.13 (m, 2H); 6.34 (m,1H); 6.72 ( m, 1H); 7.01-7.79 (m, 8H). </ RTI> <RTIgt; 4.12 (m, 2H); 6.33 (m, 1H); 6.71 (m, 1H); 7.03-7.62 (m, 8H). UPLC-MS (ES+): [M+H]+=624. ^ « ί ♦ 〇lii 03⁄4 ζΐ ^ % A Λ ^ ro i Butterfly B- B i * mmm ^ ^ Φ f ^ QA ® ¥ 3 4? 5 cs i Zhao 1 f〇_ o s- °? T ^51 i -4 SX ^ ^ ^ ^ ^ Reduced weapon i A ®~ _ BX - ]_r ^ u. %ξ? IL· 2.45 2.46 -£6Z, uop.t7-3- s 152524.doc -293 201130854瓌fw?^e6rl^e. I¥ikfK?^«iinqo&lt;NdoΜ 孽铋馁W 聋5ΓΖ:?{k^v:ir(N^5.(Ni4{ki-^:(81c^^)q8I^ Analytical data h-NMR (sterol-d4, 300 MHz): 1.98 (s, 3H); 3.38 (dd, 1H); 3.89-4.01 (m, 1H); 4.12 (br. s, 2H); 4.27 (s , 4H); 6.50-6.71 (m, 3H); 7.30-7.41 (m, 1H); 7.43-7.61 (m, 4H); 7.61-7.71 (m, 1H); 8.02-8.10 (m, 2H). UPLC -MS (ESI+): [M+H]+=600. ^^1^11^.-(14,3001^112):1.25-1.33 (111,61^1.96(5,31^3.35-3.42 (m , 1H); 3.90-4.01 (m, 1H); 4.12 (br. s, 2H); 4.55 (septett, 1H); 6.59-6.80 (m, 2H); 6.99-7.11 (m, 2H); 7.30-7.40 (m, 1H); 7.43-7.59 (m, 4H); 7.61-7.69 (m, 1H); 8.02-8.09 (m, 2H). UPLC-MS (ESI+): [M+H]+=600. —:—Name '_ 3-Benzenyl-6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxan-6-yl)-8-(2 -Dong-6-trifluoromethyl-benzene Base)-7-mercapto-2,3-dihydro-thiazolo[3,2-3.]σΛα^.-5-@ΐ^ 灭4妒_ 5 5 ¥ ^ ^ Ϊ v ¥ ^ ^ ^ &lt ;N 〇〇ri ^ . i 4 ^ 1 ' ! Structure %? Small number 2.47 2.48 • Inch 63 U03KK1 152524.doc -294- 201130854

'H-NMR (f, -d4, 300MHz): 1.98 (s, 3H); 3.37-3.44 (m, lH); 3.92-4.03 (m, 1H); 4.13 (br. s, 2H); 6.61-6.70 (m, 1H); 7.16-7.30 (m, 2H); 7.30-7.43 (m, 2H); 7.43-7.60 (m, 4H); 7.62-7.69 (m, 1H); 8.02-8.09 (m, 丨2H ). UPLC-MS (ESI+): [M+H]+=626. h-NMR (sterol-d4, 400 MHz): 1.87-2.01 (m, 6H); 3.37-3.43 (m, 1H); 3.92-4.02 (m, 1H); 4.13 (br. s, 2H); 6.62 -6.69 (m, 1H); 7.22-7.40 (m, 3H); 7.45-7.60 (m, 5H); 7.62-7.69 (m, 1H); 8.03-8.09 (m, 2H). UPLC-MS (ESI+): [M+H]+=606. iH-NMR (sterol-d4, 400 MHz): 1.96 (s, 3H); 3.34-3.40 (m, 1H); 3.78 (s, 3H); 3.89-3.98 (m, 1H); 4.06-4.17 (m (2, H); -7.67 (m, 1H); 8.02-8.08 (m, 2H). UPLC-MS (ESI+): [M+H]+=572. h-NMR (methanol-d4, 400 MHz): 1.98 (m, 3H); 3.37 (d, 1H); 3.89-3.99 (m, 1H); 4.11 (br. s, 2H); 6.56-6.75 (m, 2H); 7.28-7.70 (m, 7H); 8.02- 8.09 (m, 2H). UPLC-MS (ESI+): [M+H]+=540. ϊ ί " mm ,ι ga ... ^ ^ ^ « mi dd ®- ? VO 〇〇r^- £2j ^ ^ ^ ^ i4 *9 fA ® ^ ^ ^ M沦硪f Λ ^ V £ v 4 ^ c? V 5 ^ ώ ^ Z ^ 5 ^ , ifk Ψ ,i·^ ^ |lm » ^ ^ Ψ J ^ ^ f ^ cA ^ ^ ^ ^ l ¥硇旮^ V ^ tumor AA ^ 械 ^^ &amp; ° 4 A 机械 frt i 晒 ^ ^ (N — _ d &gt; Ί ^ ^ ¥ ¥ f ^ op »1 f ^ S ^ ^ ϊ ^ S t ^ Ϊ a; (N (N m CN CN (N 152524.doc -295- 201130854

*H-NMR (CDC13, 300 MHz): 1.95 (s, 3H); 3.25-3.36 (m, 1H); 4.07 (br. s, 2H); 6.47-6.54 (m, 1H); 6.49 (t, 1H 6.95-7.12 (m, 3H); 7.22-7.65 (m, 6H); 7.97-8.03 (m, 2H). UPLC-MS (ESI+): [M+H]+=590. 1 'H-NMR (CDC13, 300 MHz): 1.97 (s, 3H); 3.36-3.43 (dd, 1H); 6.65 (m, 1H); 6.87 (t, 1H); 6.93-8.12 (m, 10H) . UPLC-MS (ESI+): [M+H]+=608. h-NMR (methanol-d4, 300 MHz): 1.38 (m,3H); 1.96 (m,3H); 3.37 (dd, 1H); 3.88-4.01 (m, 1H); 6.57-6.77 (m, 2H) ; 7.02-7.62 (m, 11H). UPLC-MS (ESI+): [M+H]+=586. iH-NMR (methanol-d4, 300 MHz): 1.99 (m,3H); 3_38 (m, 1H); 3.88-4.01 (m,1H); 6.55-6.71 (m,3H); 7.28-8.11 (m, 8H). UPLC-MS (ESI+): [M+H]+=588. Λ ψ ^ ψ ^ ^ f '1 Hi ^ 53 ^ £ Pu'er t s key 00 *&quot;7 士 ^ ^. ^ * \ | ^ ':! γΛ ^ (N ',1 _ 4 swallowing d ®- ? 1 S two 萣 5 $4 ¢- _ 2 ^ ^ A硇. ^ ®: 1 灭气\丨谇Φ 2碥1 4 ^ rf S i 5«I i4 i4 ί ψ » 1 έ έ... Bead '1 c\ S = ΠΓ 5 ώ &quot; ¥ 韹®1 ,1 A ^ Tf Ί1 Λ i ν〇Μ V£) (Ν Γ^ι ^ ^ (Ν ^^^^^ ώ S沄ί i %? CN 寸 CN m (N v〇CN 152524.doc -296- 201130854. Inch ε9=+[Η+1ΛΙ] :(+ ISH) SPM-uldn.(H9rs) 0Γ8-09.9 ((Η^ε)οον inch-/,〇·inchi(Hrs) 06·ε-68·ε ί(ΗΓΡΡ) 6ε·ε KHeco) 66·Ι : (NHsoo inch p-iss-)oisN-^ -63- 1-ς-^τ14?ζώ珠ti MM. ^ &gt;5 ^ ^ -硪&amp;-ίμ-9-ί-ζ)-8-(硪蚪-砩竑机械-·Kf -(N)-9-^lsffi-i4-e

Ls.zs 152524.doc -297- 201130854 Example 2.58 Preparation of 3-benzylidenyl-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene Methyl)-7-methyl-2,3-dihydro-oxazole[3,2_a]pyridine_5•one

Add phenylmagnesium bromide (3 M in diethyl ether, 7 5 , 4.12 g, 22.7 mmol, 2. 〇 equivalent) to 6-(2-fluoro-3-isopropoxyphenyl) at -78 °C _ 8-(2-Fluoro-6-trifluoromethyl-phenylmethyl)_7-methyl·5_sideoxy-2,3_dihydro-5H-oxazolo[3,2-a]pyridine -3-carboxylic acid τ g (Intermediate I 26) (61 g, 11.4 mm 〇 1) in a stirred solution in toluene (200 mL). After complete addition, the reaction mixture was stirred for 5 hours while maintaining the temperature below -7 Torr. Hey. The reaction was then quenched by the addition of a pre-cooled (_7 (rc) mixture of methanol and water (2 mL, methanol / water = 9 / 1). Water was added and the mixture was allowed to warm to room temperature. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were concentrated in vacuo. The crude product was dissolved in thf and mixed with aqueous sulfuric acid ((UM) for 2 hours at room temperature. Between water and ethyl acetate. After phase separation, the aqueous layer was extracted with ethyl acetate and the combined organic layer was concentrated in vacuo. The title compound was obtained by flash column chromatography (yield: 2.3 g). HNMR (methanol _d4, 400 MHz): 1.25-1.34 (m, 6H); 1.98 (s, 3H), 4.09 (S) 2H); 4.50-4.60 (m &gt;2H); 4.95 (t, 1H); - 152524.doc 201130854 6.38 (m, 1H); 6.73-6.79 (m, 1H); 6.99-7.12 (m, 2H); 7.29-7.37 (m, 1H); 7.39-7.47 (m, 1H); 7.49- 7.58 (m, 3H); 7.63- 7.70 (m, 1H); 8.00-8.05 (m, 2H) MS (ESI + ): [M+H]+= 584. Example 3.1 Preparation 8-(2,6- Difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)·3_(hydroxyimino-phenyl-methyl)-7-methyl-2 ,3-dihydro-thiazolo[3,2_a]pyridine_5-ketone

Modified according to GP 21b: Hydroxylamine hydrochloride (417 mg, 6 mmol '4.8 equivalent) was added to 3-benzylidene-yl-8-(2,6-difluoro-phenylmethyl) at room temperature -6-(2-Fluoro-3-methoxy-phenyl)-7-mercapto-2 3 dihydro-thiazolo[3,2-a]pyridin-5-one (Example 2.1) (650 mg, i 24 mm 〇 1) in a stirred solution of t-butanol (20 mL) and hydrazine (20 mL). Pyridine (5.5 mL) was then added and the reaction mixture was heated to <RTI ID=0.0>, </RTI> </RTI> <RTIgt; The reaction mixture was partitioned between EtOAc (EtOAc)EtOAc. The target compound was isolated by flash column chromatography (yield: 603 mg). H-NMR (methanol-d4, 300 MHz): 1.84 (d, 3H); 3.60-3.73 (m, 1H); 3.75-3.96 (m, 5H); 3.97-4.08 (m, 1H); 6.00-6.10 (m,

S 152524.doc -299- 201130854 0.5H*); 6.40-6.50 (m, 1H); 6.56-6.64 (m, 0.5H*); 6.87-7.40 (m, 11H). UPLC-MS (EI+): M+=536. 152524.doc -300- 201130854

绪澍^ArnTwlrtNlf# 驷fw?4llqICNdo 敦 敦敦 W 荽ΜΞ.ε f# 驷^^(Νζ.ε^Γε i#{Ki^: 6K Analytical data::c iH-NMR (methanol-d4, 300 MHz) : 1.88 (d,3H); 3.60-3.72 (m, 1H); 3.75-3.95 (m, 5H); 3.96-4.06 (m, 1H); 6.13-6.20 (m, 0.5H*); 6.40-6.49 ( m, 1H*); 6.59-6.66 (m, 0.5H*); 6.81-7.42 (m, 10H). UPLC-MS (ESI+): [M+H]+=555. ^-NMR (methanol-d4, 300 MHz): 1.87 (d,3H); 3.56-3.68 (m, 1H); 3.73-3.93 (m, 9H); 3.94-4.05 (m, 1H); 6.11-6.17 (m, 0.5H*); 6.39 -6.48 (m, 1H); 6.58-6.64 (m, 0.5H*); 6.87-7.39 (m, 10H). UPLC-MS (ESI+): [M+H]+=567. -d4, 400 MHz): 1.86 (d,3H); 3.63-3.73 (m, 1H); 3.77-3.95 (m, 6H); 3.97-4.05 (m, 1H); 6.01-6.09 (m, 1H); 6.39-6.48 (m, 1H); 6.52-6.64 (m, 0.5H*); 6.88-7.38 (m, 10H). UPLC-MS (ESI+): [M+H]+=62 Bu• · ί , Miscellaneous ' 8-(2,6-Difluoro-phenylhydrazino)-6-(2-a-3-methoxy-phenyl)-3-[(4-a-phenyl)-imido group曱 ]]-7-mercapto-2,3-dihydro-thiazolo[3,2-a] 11 than bite-5-one 呤 呤 " s εί, s Ί 蚪澍呤A " 7d '1 S ί 8-(2,6-di-phenyl-phenyl)- 6-(2-Fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(4-trifluoromethoxy-phenyl)-indenyl]-7-fluorenyl-2,3 -Dihydro-thiazolidine sits and [3,2-3] ° ° ° -ketone structure %? Test ^-〇rvCM Φ V; No. CN m inch i 152524.doc -301 - 201130854 ^-NMR ( DMSO-d6, 400 MHz): 1.88 (m, 3H); 3.78 (m, 3H); 3.36 (m, 0.5H*); 3·39 (m, 0.5H*); 6.10-7.45 (m, 11H) . UPLC-MS (ESI+): [M+H]+=543. h-NMR (methanol-d4, 300 MHz): 1.99 (m, 3H); 3.43-3.50 (m, 1H); 3.84 (m, 3H); 6.37-7.38 (m, 8H). UPLC-MS (ESI+): [M+H]+=527. h-NMR (sterol-d4, 300 MHz)·· 1.84 (d,3H); 2_26 (m, 3H); 3.77-3.84 (m, 3H); 3.92-4.06 (m, 1H); 6.19-6.26 ( m, 0.5H*); 6.49-6.55 (m, 0.5H*); 6.55-6.66 (m, 1H); 6.82-7.36 (m, 9H). </ RTI> <RTIgt; H*); 3.55 (m, 0.5H*); 6.10 (m, 1 H); 6.15-6.30 (m, 1 H); 6.88-7.17 (m, 11 H); 7.27-7.49 (m, 1 H) . UPLC-MS (ESI+): [M+H]+=55卜更^ Ά ^ ώ X ^ f E ®- '1 ώ 澈 A A g彳 — οό ^ two ^ three ^ ^ XT甾ώ ^ ty ϊ ά澍刳f E ¢- Ί ^ ί4 Λ ° $ i 3 5 7- Sye 6 〇〇^ ® into S·* more ^ Λ Ά i4 ώ * ®-bead d ^ ^ ® reading A g Λ ° V CN Ji, 'Ο 4jJ_ 1 ri Τ ^ 〇〇^ liSf ^ ^ X ¢ ¢ - beads ds» X ^ f E ¢ - '1 ^ 蚪 AV AV (N Ό 4.jA · rj: T ^ ΓζγΛ/Μ ό % 9 rzv-Cw 5Ό %9 cn cn oo 152524.doc 302· 201130854

^-NMR (methanol-d4, 400 MHz): 1.69-1.90 (m, 9H); 3.64-3.88 (m, 5H); 6.18-6.24 (m, 0.5H*); 6.39 (d, 1H); 6.63- 6.69 (m, 0.5H*); 6.84-7.35 (m, llH). UPLC-MS (ESI+): [M+H]+=565 〇iH-NMR (sterol-d4, 300 MHz): 1.82-1.85 (m,3H); 3.56-3.65 (m, 1H); 3.85-4.15 (m, 6H); 6.10-6.15 (m, 0.5H*); 6.45 (ddd, 1H); 6.62-6.69 (m, 0.5H*); 7.01-7.42 (m, 6H); 7.46-7.65 (m, 3H); 7.75-7.90 (m, 1H); 8.61 (br. s·, 1H). UPLC-MS (ESI+): [M+H]+=587. iH-NMR (methanol-d4, 400 MHz): 1.85 (d, 3H); 3.53-3.62 (m, 1H); 3.85 (d, 3H); 3.87-4.06 (m, 3H); 6.16-6.23 (m, 0.5H*); 6.36-6.45 (m, 1H); 6.61-6.67 (m, 0.5H*); 6.88-7.14 (m, 4H); 7-22-7.61 (m, 6H). MS (CI+): [M+H]+=605. ^-NMR (methanol-d4, 400 MHz): 1.82 (d, 3H); 3.55-3.65 (m, 1H); 3.84 (d, 3H); 3.87-4.05 (m, 3H); 6.07-6.13 (m, 0.5H*); 6.36-6.46 (m, 1H); 6.60-6.66 (m, 0.5H*); 6.96-7.20 (m, 4H); 7.23-7.61 (m, 6H). UPLC-MS (CI+): [M+H]+=67卜A. Ύ s-砩q ^ △ i4 ; T ^ rl ^ 柃s &quot;眷独ώ s $ s ^ X ^ ψ ^ ^ 'X Λ V ύ ^ ^ i-4 &amp;- d ^ « vi « B- 械—寺 4 ^ ^ ϊ 1 ^ λ, d Λ ^ ^ 〇f ^ ^ i4 s ^ i Λ ® 二 二 二 二 二 二 二 二 二 二 二宁ί ^ s ^ ϊ绪ί ϊ 3 a 5 d ^ 4 νό 8- '1' »1 '1 vo ^ "^^ A嘁碥"Λ V ^ s- A ^ 5 s 5 ? ^ A 〇i硪S 6 S 1 s ...it碥i &lt;N ®: &-^ ^ ^ ό... tk r=y〇〇小V; 〇\ cn o rn rn &lt;N rn s 152524.doc •303 - 201130854 ifi-NMR (sterol-d4, 300 MHz): 1.94 (s, 3H); 3.45-3.64 (m, 2H); 3.81-3.90 (m, 3H); 4.04-4.13 (m, 2H); 5. 65 (m, 1H); 6.04-6.12 (m, 0.5H*); 6.36-6.48 (m, 0.5H*); 6.58-6.77 (m, 1.5H*); 6.97-7.17 (m, 4.5H *) UPLC-MS (ESI+): [M+H]+=592 〇1 . . . . . . . . . . The crude product was used in the subsequent reaction without further characterization. UPLC-MS (ESI+) : [M+H]+=577. ^-NMR (nonol-d4, 300 MHz): 1.71-1.91 (m,3H); 3.52-3.71 (m, 1H); 3.93-4.18 (m, 3H); 5.98-6.10 (m, 0.3H*); 6.26-6.30 (m, 0.3H*); 6.36-6.47 (m, 0.7H*); 6.93-7.14 (m, 0.7 H*); 7.16-7.62 (m, 1 OH). UPLC-MS (ESI+): M+=657. ^-NMR (methanol-d4, 300 MHz): 1.81 -1.96 (m, 2H*); 2.04 (s , 1H*); 3.50-3.71 (m, 1H); 3.87-4.15 (m, 3H); 5.98-6.13 (m, 0.3H*); 6.32-6.48 (m, 1H); 7.07-7.16 (m, 0.3 H*); 7.16-7.74 (m, 11H); 8.06-8.24 (m, 1H). MS (CI+): [M+H]+=558. £L ^ Λ ψ ή&gt; ^ A f SS 2 ? 5 2 t £ ^ 5 ^ ^ ΓΠ ¢- 1—1 ^ 3 g 2 CS ®~ i4 V〇^ΐ $訾訾¥ ^ f ^ ^ ^ 1 ^ 5 ^ ^ 2 ^ f ' 4 十Φ5 ^ ν〇4 H ^ d ^ ^ ^ ie 砩人3 i〆ί ^ ^ 1 ^ $4 &lt;N »1 &lt;A ,®-na d '&gt;,1 4 v〇v〇,.1 ®- ^ ^ d OO ^ Im: 呤澍;ά ^ V . ι 智和 ι1 f S' _ t ^ &lt;3 . ®- 小ο %? r zv^Cm - 6 Rv^&lt;n ό &lt;Τ) rn inch cn CO Ό cn 152524.doc •304· 201130854

^-NMR (DMSO-d6, 300 MHz): 1.76 (m, 3 H); 3.51-3.61 (m, 1 H); 3.77 (m, 1H); 3.90-4.06 (m, 1H); 5.98-6.07 ( m, 0.55H*); 6.17-6.28 (m, 1 H); 6.52-6.59 (m, 0.45H*); 6.92-7.02 (m, 4 H); 7.23-7.49 (m, 4 H); 7.59- 7.72 (m, 1H). UPLC-MS (ESI+): [M+H]+=605. ^-NMR (methanol-d4, 300 MHz): 1.86 (m,3H); 3.55-3.83 (m, 3H); 3.84-3.89 (m, 3H); 3.92-4.07 (m, 1H); 6.27-6.34 ( m, 0.5H*); 6.46-6.59 (m, 1H); 6.61-6.68 (m, 0.5H*); 6.81-7.39 (m, 9H) UPLC-MS (ESI+): [M+H]+=555 h-NMR (methanol-d4, 300 MHz): 1.88 (m,3H); 3.56-3.74 (m, 2H); 3.86-3.91 (m, 3H); 6.50-6.57 (m, 0.4H*); 6.60- 6.72 (m, 1,6H*); 6.77-6.93 (m, 2H); 6.94-7.34 (m, 6H). UPLC-MS (ESI+): M+=689^-NMR (methanol-d4, 300 MHz): 1.86 (m,3H); 3.62-3.71 (m, 1H); 3.82 (m, 3H); 3.93-4.04 (m , 1H); 6.31 (m, 0.5H*); 6.46-6.64 (m, 1,5H*); 6.85-7.08 (m, 4H); 7.23-7.35 (m, 2H); 7.38-7.58 (m, 1H) ); 8.04-8.12 (m, 1H). UPLC-MS (ESI+): ^=555 ^碥s ^ sw\ ^ d ά ? ^商&amp;合〇i硇蚪f 4芝^ cT 1 cz^ Ϊ亚味d; Enough 1 Butterfly 10, 丨, 械3 e字',丨3 Ϊ 1 5 ^ ®- T lii ^ &gt;1 Ϊ ? ^ Λ w S ^ 3i £, ^ i ^ ¥ ώ X ^ _ vi weapon S ^ ^ 1 ΛΛ ί s beads ¥ ^ e &amp; S ? i 〇m /uj ^ f ^ ,dt A, ^ 〇S^ rV-C·0 X) δ%) u. r2v-Cw &amp; 〇m 〇〇m C\ ΓΛ § 152524.doc • 305 · 201130854 h-NMR (sterol-d4, 300 MHz): 1.95 (m, 3H); 2.35-2.53 (m, 3H); 3.46-3.58 (m, 1H); 3.83 (m, 3H); 6.38- 6.71 (m, 2H); 6.83-7.13 (m, 4H); 7.20-7.32 (m, 1.5H*); 7.64 (m, 0.5H*). </ RTI> <RTIgt; (m, 0.5*H); 6.48-7.97 (m, 11H). UPLC-MS (ESI+): [M+H]+=593 8-(2,6-di-n-phenylphenyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[ Hydroxyimido-(5-methyl-thiazol-2-yl)-indenyl]_7-methyl-2,3-dihydro-oxazolo[3,2-a]° bite 5-ketone j; f ^ ψ S Φ ^ ^ ^ ^ ^ ψ ^ ^ ?: @ at V °f 4 %? Η I* &amp; 3.21 3.22 152524.doc -306- 201130854 Example 3.23 Preparation of 6-(2-Fluoro-3 -Methoxy-phenyl)-8-(2 Weng-3_(methoxyimino-phenyl-methylmethylpolytrifluoromethyl-phenylmethyl)_. than bite. 5, ▲, 3 _ Dihydro-sigh and [3,2-a]

According to the modified form of GP 21a: in the chamber, m ns . . , , Α Λ 峨 峨 〇 〇 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 ) added to 3-benzylidene-6_(2-

Fluoro-3-methoxy-phenyl)-8-(2-fluoroU~fluoroindolyl- azaindyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a] Pyridine-5-one, Ming (Example 2.27) (65 mg, 〇 u mmol) in a stirred solution of tributanol (2 mL) and ethanol #νυ·5 mL).

Next, a third butanol oxime (Iv) was added (m this, 〇46_θι, 4 q when 4 to heat the reaction mixture to 8 ° C) for 5 hours until TLC indicated complete depletion of the starting material. Diluted with ethyl acetate and washed with water and brine.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ): 1.82 (br. s, 2H*); 1.92 (d 1H*); 3.41-3.51 (m, 0.6H*); 3.57-3.64 (m, 0.4H*); 3·7ι 4.09 (m, 8H) ; 6.00-6.07 (m, 0.3H*); 6.16-6.22 (m, 0.3H*)· 6.33-6.42 (m, 0.5H*); 6.68-6.76 (m, 0.4H*); 6.80-7.58 (m 10H). UPLC-MS (ESI+): [M+H]+=601 » 152524.doc -307· 201130854 4°^ιι^ιι^^^δ-_0^ζ,Γ&lt;Ν^Γ(Νί4^^ 4·®ΙβΙ(ΝίίοΜ^ιι·^^^ν^^ε(Ν·εί#^^ν:ίΓ£^々(Ν·ε^^^^:οζ&lt; 152524.doc / ' V. Analysis data* H-NMR (CDC13, 400 MHz): 1.83 &amp; 1.96 (2 xs, 1.8H* &amp;1.2H*); 3.20 (d, 0.4H*); 3.52-3.57 (m, 0.6H*); 3.67- 3.73 (m, 1.6H*); 3.89-4.17 (m, 4.8H*); 6.05 (d, 0.4H*); 6.26-6.32 (m, 0.6H *); 7.00-7.07 (m, 0.5H*); 7.12-7.61 (m, 10.5H*) UPLC-MS (ESI+): [M+H]+=637. •H-NMR (CDC13, 300 MHz ): 1.79-1.97 (m, 3H); 3.12-3.23 (m, 0.5H*); 3.45-3.58 (m, 1); 3.65-3.79 (m, 4.5H*); 3.84-4.13 (m, 4.5H) *); 5.91-6.09 (m, 0.5H*); 6.26-6.35 (m, 0.5H*); 6.57-6.65 (m, 0.5H*); 6.69-7.61 (m, 13.5H*). UPLC-MS (ESI+): [M+H]+=6(U. ν .Name. 匕Φ寺cA ^ ¥ ά ^ ^ ^ ^ \i ¥ 2 s ^ ^ -' Brick a ui ^ '淫才d ^ * οό 灭, 'l 6-(2-Fluoro-5-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(nonoxyimine Benzyl-methyl-methyl&gt;7-methyl-2,3-di-mouse-D. Sit and [3,2-a]n is smaller than the bite-5-ketone structure 1&quot;Gentry 编号 3.24 3.25 - 308- 201130854

'H-NMR (CDC13, 300 MHz): 1.82-1.98 (m, 3H); 3.12-3.21 (m, 0.3H*); 3.45-3.56 (m, 1H); 3.64-3.74 (m, 1.5H*) ; 3.80-4.07 (m, 5.5H*); 5.96-6.08 (m, 2.5H*); 6.26-6.34 (m, 0.5H*); 6.47-6.75 (m, 1.5H*); 7.18-7.60 (m , 10.5H*); 7.79-7.89 (m, 1H); 8.48-8.55 (m, 2H) » UPLC-MS (ESI+): [M+H]+=615. 'H-NMR (CDCIb, 300 MHz): 1.85 &amp; 1.97 (2 xs, 1.6H* &amp;1.4H*); 3.16-3.22 (m, 0.5H*); 3.50-3.57 (m, 0.6H*) ; 3.64-3.73 (m, 1.6H*); 3.88-4.13 (m, 5.5H*); 6.04 (d, 0.4H*); 6.25-6.31 (m, 0.6H*); 6.86-7.00 (m, 1H) ); 7.09-7.23 (m, 1H); 7.25-7.61 (m, 8H). UPLC-MS (ESI+): [H]+=632. ^ Z ^ ^ 4 , &lt;Ν " ds» '*1 i E n: ^ mf ^ l-l ^ CS M οό cA ¥ « is ^ ^ ά f .M " , Empty Si: u 耸5 i II As ,1 ^1 v ^ A v ^ ^ attack s-\〇^ 卜' r γΚ/11 rn rn 152524.doc -309- s 201130854 Example 3.28 Preparation of 3-(allylimidate- Stupid-fluorenyl)_6_(2_fluoro_3_methoxy_phenyl)_ 8-(2-Deng-6-trifluoromethyl-benzyl)_7-methyl_2,3_2 Hydrogen - 0 - 0 圭 [ [3,2- a ] ϋ _ _ 5 - 嗣

According to the modified form of GP 22: Titanium (IV) isopropoxide (62 〇 KL ' 2.11 mmo Bu 1_0 equivalent) was added to allylamine (474, 6.33 mmol, 3.0 equivalents) and 3- at room temperature. Benzyl hydrazino _6_(2_fluoroundoxoxyphenyl)_8_(2-fluoro-6-difluoromethyl-benzyl)-7-methyl-2,3-dihydrogen n 3,2-a] A stirred solution of the 5-butanone (Example 2.27) (1.21 g, 2.11 mmol) in toluene (1 mL). The reaction mixture was stirred for 2 days at room temperature and then heated to 4 Torr: for 6 hours until TLC indicated the starting material was completely consumed. The reaction mixture was concentrated in vacuo and the crude title compound was used in the next reaction without further purification (yield: 丨g). 152524.doc •310· 201130854

8ε.(Ν¥驷英4&gt;mqI(NCIO-r^鹓馁V 柃W ΜΞ.ΜΞ i#{kc^8rrnwi6(N.rni4iki-^:(6l^^)q6I&lt; • · ' ·,· ·Ί.....- , . . . , . , .: . . . Analytical data Λ丨^-NMR (methanol-d4, 300 MHz): 1.80-2.04 (m, 6H); 3.18-3.26, 0.5 *H); 3.54-3.65 (m, 1H); 3.65-3.76 (m, 0.5*H); 3.88-4.14 (m, 4.5*H); 6.01-6.10 (m, 0.5*H); 6.37-6.47 ( m, 1H); 6.60-6.68 (m, 0.5*H); 7.09-7.63 (m, 13H). UPLC-MS (ESI+): [M+H]+=621 h-NMR (sterol-d4, 300 MHz): 1_77 -1.92 (m,3H); 3.86 (m, 3H); 5.95-7.56 (m,11H) UPLC-MS (ES+): [M+H]+=605. •H-NMR (曱Alcohol-d4, 300 MHz): 1.90 (m, 3H); 3.48 (m, 1H); 3.84 (m, 3H); 6.28 (m, 0.5H*); 6.42 (m, 1H); 6.66 (m, 0.5 H*); 6.97-8.10 (m, 7H) UPLC-MS (ES+): [M+H]+=593. • . . . ' Λ : I:/. 1. ' . Name ^ t1 $ ns ^ ^ ^ «HI Μ ί | ώ ^ &quot;f ^ d ^ 6-(2-^-3-曱-oxy-phenyl)-3-[(2-fluoro-phenyl)-hydroxyimino-A -8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a]° ratio. Ketone ^ Φ s 'machine 1 inch S ί V ^ ^ ^ «1^5 fA娜«ν ®- ¢^1 ' - . ' · : Structure 0 &amp; VOT No. 3.29 3.30 3.31 s 152524.doc -311 - 201130854 h-NMR (sterol-d4, 300 MHz): 1.75-1.92 (m, 3H); 2.21-2.29 (m , 3H); 3.86 (m, 3H); 5.95-7.58 (m, 11H). UPLC-MS (ES+): [M+H]+=601 ° lH-NMR (sterol-d4, 300 MHz): 1.78 -1.92 (m, 3H); 2.22-2.34 (m, 3H); 3_84 (m, 3H); 5.96-7.59 (m, 11H). UPLC-MS (ES+): [M+H]+=601. ^-NMR (methanol-d4, 300 MHz): 1.80 -1.92 (m,3H); 3.88 (m,3H); 5.96-7.57 (m, 11H). UPLC-MS (ES+): [M+H]+=621. h-NMR (methanol-d4, 300 MHz): 1.82 - 1.94 (m, 3H); 3.87 (m, 3H); 5.94-7.58 (m, 10H). UPLC-MS (ES+): [M+H]+=623. 'Ί ^ vi ^ ^ f φ ώ ,,® illi ^ a ^ ^ S- ¢- fn ^ ¢^1 ®-d VJD * u| . ^ t ^ ^ td ^ L 〇〇^ i E ^ s ? I硪tc\ s- ¢- ^•巴 “ w ®~ ά \〇灭(N 6- ^ ^ ^ 5 5 i ά J, VA °? 2 1 «1 is ^ B- ®~ (N ^ ί '碥r-—iu| *6^1 ί 1 ^ \ \ titsf HU 今嘁硇 in “ ®- ®7 miso rA &quot;fs ¥ f A ^ ^ ^11- X ?^vC/w 1111· ^0r CN m rn mm 2 m rn 152524.doc -312- 201130854

H-NMR (methanol-d4, 300 MHz): 1.80 - 1.94 (m, 3H); 3.54 (m, 1H); 3.87 (m, 3H); 5.97-7.58 (m, 10H). UPLC-MS (ES+): [M+H]+=623 « iH-NMR (methanol-d4, 300 MHz): 1.79 -1.96 (m,3H); 3.89 (m, 3H); 5.98-7.58 (m, 1 OH). UPLC-MS (ES+): [M+H]+=639. b-NMR (sterol-d4, 300 MHz): 1.89 -1.98 (m,3H); 2.38-2.65 (m,3H); 3.83 (m,3H); 4.10 (m, 2H); 6.35-7.80 (m ,8H)» UPLC-MS (ES+): [M+H]+=608 〇3-[(2,3-Difluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro -3-decyloxy-phenyl)-8-(2·fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydro-thiazole[3,2 - ] 〇 -5 -5-keto 3-[(2-chloro-3-fluoro-phenyl)-hydroxyiminomethyl]·6-(2-^-3-decyloxy-benzene Base)-8-(2-Ga-6-difluoromethyl-phenylhydrazino)-7-mercapto-2,3-dihydro-α stopper. Sit and [3,2-a]. Ratio of sigma-5-keto 6-(2-ran-3-yloxy-phenyl)-8-(2-fluoro-6-difluoroindolyl-phenylhydrazinyl)-3-[hydroxyimino -(5-fluorenyl-thiazol-2-yl)-fluorenyl]-7-mercapto-2,3-dihydrogen s-[3,2-&amp;]° ratio ～-5-ketooxime : %? ά: Η» 3.36 3.37 3.38 i s. 152524.doc -313 - 201130854 f# 驷^^-iraeudo Μ #&gt;^^^^w 荽黩s.rnf 驷铼 κιειη.ε^6Γε 驷i-Kt: (0&lt;s&lt;憋)qs^ Analytical data ^-NMR (f,-d4,400MHz): l-82, 1.85 &amp; 1.95 (3xs, 3H); 3.13-3.20 (m, 0.5H* 3.45-3.55 (m5 0.5H*); 3.64-3.74 (m, 2.5H*); 3.84-4.03 (m, 3.5H*); 4.24, 2.26 &amp; 4.28 (3 xs, 4H); 5.94-6.08 (m, 1H); 6.27-6.34 (m, 0.5H*); 6.44-6.71 (m, 2H); 7.19-7.40 (m, 6H); 7.43-7.60 (m, 2H). UPLC-MS (ESI+): [M+H]+=629. h-NMR (methanol-d4, 300 MHz): 1.24-1.38 (m, 6H); 1.81, 1.84 &amp; 1.94 (3 xs, 3H); 3.13-3.21 (m, 0.5H*); 3.45-3.58 (m , 0.5H*); 3.64-3.78 (m, 2H); 3.84-4.14 (m, 3.5H*); 4.47-4.56 (m, 1H); 6.01-6.18 (m, 0.7H*); 6.27-6.36 ( m, 0.4H*); 6.60-6.78 (m, 0.7H·&quot;); 6.92-7.14 (m, 2H); 7.19-7.61 (m, 1 OH). UPLC-MS (ESI+): [M+H].=629. Name 6-(5-Fluoro-2,3-dihydro-benzo[1,4]dioxapyridin-6-yl)-8-(2- disorder-6-dioxmethyl_ awkward ))-3-(oximeimido-phenyl-fluorenyl)_7-fluorenyl-2,3-dihydro-thiazolo[3,2-a] 0 to 0-but-5-one ^ ' 1 Cr ^ V «Ν ^ X Λ ^ ^ ^ B- £ 々®7 b d,, J Saki structure%? Factory small number 3.39 3.40 152524.doc -314- 201130854

^-NMR (f, -d4, 300MHz): 1.83, 1.86 &amp; 1.96 (3xs, 3H); 3.15-3.23 (m, 0.5H*); 3.48-3.60 (m, 0.5H*); 3.66-3.78 ( m, 2H); 3.84-4.15 (m, 3.5H*); 6.04-6.11 (m, 0.4H*); 6.28-6.36 (m, 0.4H*); 6.53-6.62 (m, 0·3Η*); 7.09-7.63 (m, 11H). UPLC-MS (ESI+): [M+H]+=655. iH-NMR (methanol-d4, 300 MHz): 1.80-2.06 (m, 6H); 3.13-3.24 (m, 0.5H*); 3.48-3.59 (m, 0.5H*); 3.65-3.78 (m, 2H) 3.85-4.16 (m, 3.5H*); 6.04-6.10 (m, 0.4H*); 6.28-6.37 (m, 0.4H*); 6.62-6.71 (m, 0.2H*); 7.13-7.62 ( m, 10H). UPLC-MS (ESI+): [M+H]+=635. ^-NMR (f, -d4, 300MHz): 1.82, 1.85 &amp; 1.95 (3xs, 3H); 3.13 - 3.22 (m, 0.5H*); 3.45-3.58 (m, 0.5H*); 3.65-3.85 ( m, 5H); 3.88-4.13 (m, 3.5H*); 6.02-6.09 (m, 0.4H*); 6.27-6.37 (m, 0.5H*); 6.42-6.50 (m, 0.3H*); 6.61 -6.83 (m, 2H); 6.94-7.13 (m, 0.7H*); 7.18-7.62 (m, 8H). UPLC-MS (ESI+): [M+H]+=6(M. 00 ^ \\ As ¢- · cr ^ i ^ ; «ί S ί ^ — Let B- ^ ^ ^ ^ ώ u| S- ^ Μ,Μd谇4 ή&gt; ^- \\ 5 v ^ f *7 Λ »Λ ^ s ί ^ 今® word '} ':! ^ 1 4 x蜢淫_ ^ d ^ 啐4令^ ^ Ψ1 ά ^ ώ 〇〇® ^ t Λ 2 2 ά ^ f 硪 ¢ - 7 minus ® - A s - 铋 7d ^ ® - 1 A r r r ^ C &gt; / rn rn cn s 152524.doc - 315- 201130854 h-NMR (methanol-d4, 400 MHz): 1.92-1.96 (m, 3H); 3.48-3.57 (m, 1H); 3.70-3.80 (m, 4H); 4.86-4.16 (m, 5H) ;5. NMR (methanol-d4, 400 MHz): 1.81 &amp; 1.94 (2x s, 3H); 3.16 (dd, 0.4H*); 3.51 (dd, 0.6H*); 3.63-3.73 (m, 1H); 4.12 (m, 4H); 6.03 (d, 0.4H*); 6.29 (dd, 0.6H*); 6.56-6. 76 (m, 2H); 7.05-7.60 (m, 9H). UPLC-MS (ESI+ ): [M+H]+=569. h-NMR (decyl alcohol-d4, 300 MHz): 1.31 (m,3H); 1.82 &amp; 1.96 (2xm, 3H); 3.17 (dd, 0.4H*); 3.51 (m, 0.6H*); 3.68-3.72 (m, 1H); 6.01-6.13 (m, 0.6H*); 6.31 (m, 0.4H*); 6.57-6.75 (m, 0.6H*); 6.93 -7.82 (m, 11.4H*) UPLC-MS (ESI+): [M+H]+=615 〇•H-NMR (sterol-d4, 300 MHz): 1.83 &amp; 1.96 (2x s,3H); 3.19 (dd, 0.4H*); 3.53 (dd, 0.6H*); 6.05 (d, 0.4H*); 6.28 (dd, 0.6H*); 6.83 (tr, 1H); 7.05-7.60 (m, 12H) . UPLC-MS (ESI+): [M+H]+=619. 3 v 4 f for reading rf f s ί 令 ¢ - cN t Ϊ碥 s ^ i t t V 4 ^ ^ fi Do a wonderful ώ set f 璋 丨, 丨. ^ X 53⁄4 'Ψ' ^ ^ z ώ ^ ^ 兮4 f “ f Ci 亚〇〇〇〇 \ | ^ (N ®~ pi CS Λ i iO ¢-, ό ^ νά u| ^ 兮f ^ ^ Ψ &amp; Rent 1〇ό1丨3匕AS 2 rA ^ ^ .士硝# _ 娜®- 灭®7夂ή Ί 6-. c, ^ ^ ν〇\\\ ^4* rvO &quot;&quot; ur ^〇小&lt;tzy〇w - r^D» ^ cn $ rn Ό inch rn rn 152524.doc -316- 201130854

^-NMR (sterol-d4, 300 MHz): 1.82-1.96 (m, 3H); 3.17 (dd, 0.4H*); 3.51 (m, 0_6H*); 6.27-7.66 (m, 10H). UPLC-MS (ESI+): [M+H]+=617. h-NMR (sterol-d4, 300 MHz): 1.81-1.99 (m, 3H); 6.06 (m, 0.45H*); 6.32 (m, 0·55 Η*) 6.47-7.62 (m, 15H). UPLC-MS (ESI+): [M+H]+=663. UPLC-MS (ES+): [H]+=619. ^-NMR (sterol-d4, 300 MHz): 1_87 (m, 3H); 3.97 (m, 3H); 6.00 (m, 1H); 6.23-6.37 (m, 1.5H*); 6.60-6.76 (m , 1.5H*); 7.25-7.61 (m, 7H). UPLC-MS (ES+): [H]+=637. Ί ^ JE u丨1 sd "鍩 base? V ^ rA ^ ^ J ^ 1 ,1硪4 _宁^ its rj ^ 2 ^ ^ 6-(2-fluoro-4-phenoxy-phenyl)-8 -(2-fluoro-6-trifluoromethyl-benzoinyl)-3-(nonoxyimino-phenyl-indenyl)-7-methyl-2,3-dihydro-thiazolo[3 ,2-a]°°°-5-ketone d φ ^ f A 3 ®- ^ ώ ^ ^ ή 3 ^ ^ ^ ^ 6- ^ ^ -^ ^ ^ ^ ^ ^ ^ ν〇, Piece 4 B- ¢- (Ν ^ ώ ^ ^ ')d »i ^ 吖2 vi ,1 .g 5 ' ά %? %? %? rV^C·0 ".物ryO· Ί rn ο iTi cn rS s 152524.doc -317· 201130854 h-NMR (methanol-d4, 300 MHz): 1.8 (d,3H); 3.95 (d,3H); 6.05 (m, 1H); 6.31 (m, 1H); 6.53-6.65 (m, 10H) UPLC-MS (ES+): [H]+=637. h-NMR (sterol-d4, 400 MHz): 1.27-1.39 (m, 6H); 1.90, 1.92 &amp; 1.94 (3x s, 3H 3.76 (s, 1.5H*); 3.90-4.08 (m, 6.5H*); 4.49-4.79 (m, 4H); 4.89-5.00 (m, 1H); 5.61-5.70 (m, 0.5H*) ;5. UPLC-MS (ESI+): [M+H]+=613. ά d, m- \\ S v ^ ? ¢=3⁄4 ^ ώ 驴嘁 I?1 )| u| Ψ G- ^ v〇^ “绪f CN^ ^ ro i 砩Y 〇T, A fan ^ ^ ®- £, tx XA, 丨丨, Γ〇 ° 3.52 3.53 152524.doc -318- 201130854 Example 4.1 Preparation of 8-benzofluorenyl-7-fluorenyl-5-sideoxy_6_ stupid Base 2,3_dihydro-5H-indolyl[3,2-a] than biting-3-carboxylic acid benzylamine

According to the modified form of GP 12: at room temperature, 1Η-hydroxy stupid and trisal (16.8, 0.11 mmol '1.2 equivalent) and Ν-ethyl-Ν', Ν'-dimethylamino propyl A carbodiimide (21.0 mg 'O.li mmol, 1.2 eq.) was added to 8-benzyl-7-indenyl-5-oxo-6-phenyl-2,3-dihydro-5H-indole. Sit and [3 2_ a] 0 in a mixed solution of benzoic acid (intermediate K_l) (41.4 mg, 0.11 mmol, 1.2 eq.) in DMF (2 mL). After 1 hour at room temperature, a solution of the benzoguanamine (10 g, 91 μιηο) in DMF (0.5 mL) was added and stirring was continued until TLC indicated the starting material was completely consumed. The reaction mixture was poured into an ice/aqueous sodium hydrogen carbonate solution. The title compound was filtered and dried in vacuo (yield: 40.9 mg). W-NMR (DMSO-d6, 400 MHz): 1.78 (s, 3H); AB signal (δΑ=3.44, δΒ=3.90, 2xlH); 3.75 (s, 2H); 4.30 (d, 2H); 5.48-5.53 (m, 1H); 7.06-7.36 (m, 15H); 8.68-8.73 (m, 1H). UPLC-MS (ESI+): [M+H]+=467.

S 152524.doc -319- 201130854 Stupid is wrong fw?^^re^r:a 荽s£-B--i!n(NI doM frame 鹓兴^拎W 荽黩1. inch 苳驷 disc^8.寸叫^寸¥驷卜^:1~&lt; Analytical data • H-NMR (DMSO-d6, 300 MHz): 1.83 (s, 3H); 3.44 (dd, 1H); 3.62 (s, 3H); 3.80 (s, 2H); 3.92 (dd, 1H); 5.29 (dd, 1H); 7.10-7.41 (m, 10H); 11.49-11.60 (m, 1H). UPLC-MS (ESI+): [M+H] +=407. JH-NMR (CDC13, 400 MHz): 1.98 (s, 3H); 3.63-3.72 (m, 1H); 3.82-3.87 (m, 2H); 3.90 (d, 3H); 4.04-4.12 ( m, 1H); 5.88 (d, 1H); 6.80-6.91 (m, 3H); 6.91-7.04 (m, 2H); 7.05-7.24 (m, 2H); 7.60-7.70 (m, 1H); 8.04- 8.10 (m, 1H); 8.25-8.32 (m, 1H); 10.24-10.34 (m, 1H). UPLC-MS (ESI+): [M+H]+=538 &gt; 'H-NMR (DMSO-d6 , 300 MHz): 1.95 (d, 3H); 3.52-3.60 (m, 1H); 3.77-4.00 (m, 6H); 5.51-5.60 (m, 1H); 6.64-6.72 (m, 1H); 6.98- 7.16 (m, 5H); 7.25 -7.43 (m, 3H); 7.51-7.60 (m, 2H); 10.38- 10.45 (m, 1H) MS (EI+): M+=536. Name VO ώ π鍩ψ ψ ^ ,ώώ硪έ·· Β- * rf “ t 4 Ί ®- Γ0 ^ οό 4 6- cn ®-^ rA ^ ^ ik a base 1鍩^ Ύ 7婳« S 2 ^ ^ ^ ^ ^ m ο ό shout, 1 ®- cA ¢-rn ^ rA “ $涂 A ^ f 苫 f云错人丨 A 3 £ ^ ώ 1 S ^ s ^ *7 r- ^ c£ ^ m Structure Q ί 0 Strictly, 〇rt ZX dl%r °^0 zz d No.·. .' (Ν rn — 152524.doc •320- 201130854

*H-NMR (DMSO-d6, 400 MHz): 1.88 (s, 3H); 3.54 (s, 3H); 3.74-3.84 (m, 6H); 5.10-5.19 (m, 1H); 6.59-6.68 (m , 1H); 6.99-7.12 (m, 4H); 7.26 - 7.38 (m, 1H); 11.41-11.49 (m, 1H). UPLC-MS (ESI-): [2M-H]-=979. ^-NMR (DMSO-d6, 400 MHz): 1.88 (s, 3H); 3.39 (d, 1H); 3.74-3.86 (m, 6H); 4.26 (d, 2H); 5.39-5.46 (m, 1H) ;660-6.68 (m, 1H); 6.98-7.13 (m, 4H); 7.15 -7.38 (m, 6H); 8.62-8.70 (m, 1H). </ RTI> <RTIgt; 3H); 2.52-2.63 (m, 1H); 3.66-3.84 (m, 6H); 5.19-5.27 (m, 1H); 6.58-6.68 (m, 1H); 6.98-7.13 (m, 4H); 7.25 - 7.38 (m, 1H); 8.20-8.30 (m, 1H). UPLC-MS (ESI+): [M+H]+=501. ®- rA S-cA ^ cA “ $士士士士士绪¢- ^ ^ i-4 ^ ¢. ^ ^ f ^ c£ ^ ^ Λ ®- rn S-Γ0 ^ cA ^ ^ 芩? 7 | A ^ (N ® ®- §-妹:®- 'J $4 S ώ ώ '1 ¢- cn ®- cA ^ cA ^ ^ ψ &lt;N f ^ ft 2 砩碥 butterfly B- ^- miso if v if £ rvf ^ 〇〇^ Λ 严〇, '°%τ °^ό ότ^ ζζ &lt;ί — inch·s 152524.doc -321 - 201130854 .08 V+[H+W] :(+IS3) SN-υΊίίη (HI .s) os.8-0 inch ooKHrscs Bub-65. Divination (ΗΖ/ε) 6 "Bu_b6.9 XHrs" Bu 9.9-8S.9 KHrs) Iqs-sz/^xz/s) Inoo.es.exHrs8 inch.e-εε.ε i(H'pp) IrexHro s^usvs) 95ΧΗΓΪ) sst ί(*Ης·ΙΜ) inch Bu·ZKH^S) 881 :(NHN ooevo'p-oslAIe' asN-H, 锲锺-cf^-^-fs-^fd-^s-Helmet®--ε-^^?(ΝΣ2:#1ί&lt;¥-Ης-ΊΜ -e&lt;Nf (4)si^ffi--HW械-神碱^ &gt;2 d,^s

8. Inch 152524.doc • 322- s 201130854 Example 5.1 Preparation of 8-benzylmethyl_3_(benzylamino-indenyl)_7_methyl_6_phenyl-2,3-dihydro-嗟峻And [3,2_a]e than bite _5-ketone

φ according to the modified form of GP 18: sodium triethyloxyborohydride (46.7 mg, 0.22 mmol, 2.0 equivalents) was added to 8-benzoinyl-7-methyl- in several portions at room temperature. 5-Phenoxyphenyl-2,3-dihydro-5H-thiazolo[3,2-ap ratio -3-carbaldehyde (intermediate n.1) (40 mg, 0.11 mm 〇l) and phenylhydrazine The base amine (14. 5 pL, 14.2 mg, 〇 13 mmol, 1.2 eq.) was taken in a mixture of DCM (3 mL) and stirred at this temperature until TLC indicated the starting material was completely consumed. The reaction mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The target compound was isolated by chromatography (yield: 15 mg).

Starting from intermediates N.2 and benzylamine

S 152524.doc -323- 201130854 No. X * · J Λ Painting leakage 5.2 3-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-( 2-fluoro-3-yloxyphenyl)-7-fluorenyl-2,3-diaza-sodium s[H-NMR (DMSO-d6, 600 MHz): 1.85 (s, 3H); -2.79 (m, 2H); 3.55-3.64 (m, 2H); 3.65-3.77 (m, 3H); 3.80-3.88 (m, 5H); 5.06-5.13 (m, 1H); 6.64-6.69 (m, 1H); 7.02-7.16 (m, 5H); 7.19 - 7.24 (m, 1H); 7.25-7.32 (m 4H); 7.31-7.38 (m, 1H). MS (CI+): [M+H]+=537. Preparation of 8-phenylhydrazino-3-(phenylhydrazinoamino-methyl)-7-mercapto-6-phenyl-2,3-dihydro-°°° via the tosylate Example 5.1 [3,2-&amp;] bite _5-ketone

Modified according to GP 16a: Add benzylamine (7.2 pL, 7.1 mg, 66 μπιοί, 2.0 eq.) to indole-4-sulfonic acid 8-benzoinyl-7-methyl at room temperature -5-Phenoxy-6-phenyl-2,3-dihydro-5indole-thiazolo[3,2-a]pyridin-3-yldecyl ester (Intermediate M.1) in THF (1.5 mL) In the stirred solution. The reaction mixture was warmed to 50 °C until TLC indicated the starting material was completely consumed. The reaction mixture was analyzed by UPLC-MS to give the title compound which had been synthesized starting from the respective aldehydes as described above. 152524.doc 324- 201130854

垵 ί ί « « « « « « « « do 孤 do do do do do do do do do do do do do { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { ' ' . -. . ' l ' . . . ' '丨Λ: Analytical data....^.丄,&quot;;:-,.;:;. UPLC-MS (ESI+): RT=1.01 [M +H]+=589. UPLC-MS (ESI+): RT = 1.24 [M+H]+=568. UPLC-MS (ESI+): Rt-1.14 [M+H]+= 512. 'ΐ&gt;: :言称', ':二蒙^ S '1 1 ,字Λ ^ ¥ Φ义涂ν ^ ^ ^ 5毛®-百 S 5S Γη fH J—ir ψ Φ ^ f ^ OO m- ^ 3 · [4·( 1 ·Ethyl·propyl)-Lv. Qin-1 -ylmethyl]-8·(2·fluoro·benzyl)-6-(2·1-3-methoxy Benzyl-phenyl)-7-mercapto-2,3-dihydro-α-septo-[3,2-a]D ratio bit-5-keto 8-(2-fluoro-benzyl)-6 -(2-Fluoro-3-indolyl-phenyl)-7-methyl-3-(4-indolyl-piperazin-1-ylindenyl)-2,3-dihydro-thiophene [3,2-&amp;]° is better than bite-5-ketone structure%9 Q wide, .cyOX^ H,c f-〇5勒〇n 蟀m inch in s 152524.doc -325- 201130854

UPLC-MS (ESI+): Rf=1.05 [M+H]+=507. UPLC-MS (ESI+): Rt = 1.24 [M+H]+=574. UPLC-MS (ESI-): Rq^l .10 [M+HCOOH-H]=513. UPLC-MS (ESI+): Ri=0.99 [M+H]+=534. Cn ψ ^ ^ &amp; TE ? 4,_丨S « ^ ^ i 5 δ f尾οό叫娜3 4^? ά 4 cA £ s ^ s幸^ S- &lt;Ί, ^ 5 1 ^ ^ ^ ( N ^ t1 VS ^ ^ ¥ 2: ^ \\ v ¥ Λ 1 A ^ ^ t, ^ ±f A Christine® ^^ ά x4 ^ Λ 1 i e&gt; (S 1 , A 2 1 A &quot;? ®~ 字ί ^ rL ^ £2, .沣沣沣〇^ AJ ^ f A $ 4 alkali ώ ^ ^ '1 5 ΖΧ ό S%9 % Π V) &lt;Γ ΖΖ έ VO 'Ο 卜 in 〇〇in OS 152524.doc -326- 201130854

UPLC-MS (ESI+): Rt-1.26 [M+H]+=575. UPLC-MS (ESI+): RT = 1.11 [M+H]+=520. UPLC-MS (ESI+): RT = 1.17 [M+H]+= 497. UPLC-MS (ESI+): RT = 1.39 [M+H]+= 640. ¥ Φ M 5 ? S ^ Ϊ 5 3 t ®- ^ s-Mechanical (4) 5 ¥ ^ 5 ^ MS 8-(2-Any-Alkyl)-6-(2-Fluoro-3-indolyl-benzene Base)-7τ曱yl-3-{[(α ratio bit -2-ylmethyl)amino]-methyl}-2,3-dihydro-D-plug β sits and [3,2_a] ° bites _5-_ ®- CN cA ώ 4*5 t ^ 5 +4 rsf ^ ^ ^ 1=3⁄4 (N^ ¢^1 ®- + &amp; · enough 1 T 1,1 out Η j 1 ϊ A ^ ^ ^ ^ Q bb %9 o 5 勒O (N ί〇152524.doc 327. 201130854 UPLC-MS (ESI+): .41 [M+H]+=626. i L _ _________ _ UPLC-MS (ESI+): Rt=1.17 [M+H]+=483 〇UPLC-MS (ESI+): Rt=1.35 [M+H]+=602. i ^ &quot;I? ^ 3 ® 4 “ 7 s save £-- ^ 1 λ di ^ (N ^ (N ^ s ^ ^ 人' cA ^ 砩d β智^ ί ^ ®~ S- ^ cn £ '爷_ SA硇缈U-1 ^ rn oo ^ 3-[4-(3 ,5-diamidino-phenyl)-piperazin-1-ylindenyl]-8-(2-a-benzophenyl)-6- ί (2-|t-3-decyloxyphenyl) -7·曱基·2,3-Dihydro-°°°°[3,2-3]° ratio -5-5-ketone zz V 〇.CH, 1 X 5.14 5.15 5.16 152524.doc -328- 201130854

UPLC-MS (ESI+): Rr = 0.95 [M+H]+=528. UPLC-MS (ESI+): Rt-1.19 [M+H]+= 514. UPLC-MS (ESI+): Rx=1.12 [M+H]+=469. UPLC-MS (ESI+): Rt = 1.50 [M+H]+= 505. ¢-士士 c\? cs ^ ^ g ^ 4 ^ ^ S ' ^ cn \\ ^ ^ ΓΟ ',' s ά2 rn ^ i&gt; 6- 6~ ^ cn a蚪砩ώ j; d $ 客 1 ^ ^ ^ f &quot; Name one V ®~ 4 士 ^ ^ &lt;7 '1 ^ ®~ ®~ ^ cn Αι '! 3 d 2; cA 4 Office; ^ ^ Λ t1 f °? ¢. ^ i〇cA ,,丨碌®~ ^ f ^ v ^ ®- ci ^ 3 ^ t ®- S m ro £2j ^ t-4 ^ d ^ 4 ^ 2? 1 s mechanical rsf 7 ^ ^ 4 ®- 00 ^ on X z_〇〆%? zz A zz ό 卜 production HuS 00 »/S Os in 152524.doc •329- s 201130854

UPLC-MS (ESI+): RT = 1.12 [M+H]+= 526. UPLC-MS (ESI+): Rr=1.12 [M+H]+= 526. UPLC-MS (ESI+): Rt = 1.23 [M+H]+= 588. UPLC-MS (ESI+): Rt=1.16 [M+H]+=501 ° ψ ^ Λ Zeng 5 t # 4 ^ S =Φ Today $ ! dt “ g 5 3 x 5 d ^ ^ s ^ f B- ^ 4 3 3 ^ d fi ^ ®7 °® ¥ into®- , , 1 S硪_ ; rA 二 e ri ώ ^ ^ ϋ 1 W ti ί 1 ®- ^ S ^ ί ί &lt;t 1 Sw^ '- --- , rA 〇〇t ί ®~ , 砩A ? ^成丄^ ^ X ^ ®7 ;宁'智^ , ®~ cn (N ¢^1 ό ^ 3_砩;9 A 9, od %9 〆(N -330- 152524.doc 201130854

UPLC-MS (ESI+): Rt = 0.99 [M+H]+=583. UPLC-MS (ESI+): Rt=1.14 [M+H]+=528. UPLC-MS (ESI+): Rt=1.14 [M+H]+= 506. UPLC-MS (ESI+): Rt = 1.18 [M+H]+= 523 ° 3-[4-(3-dimethylamino-propyl)-pyr. Qin-1-ylindenyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydro- Thiazolo[3,2·8]° ratio °-5·ketone d ^ ^ 4Namics t〇^ cf f ^ 8-(2-fluoro-phenylhydrazinyl)-6-(2-fluoro-3 -decyloxy-phenyl)-7-methyl-3-(»bipyridin-2-ylaminomethyl). 2,3-di-aryl-oxime. And i 8-(2-fluoro-phenylindenyl)-6-(2-fluoro-3-indolyloxy-phenyl)-3-[(furan-2-ylindenyl-fluorenyl-amino) )-Methyl]-7-methyl_ 2,3-dihydro-thiazolo[3,2-&amp;]pyridine-5-_ 〇-CH· H' F-〇乂H, -M: at Fb Ζχ ό i&gt; 5.25 5.26 5.27 5.28 s: 152524.doc -331 - 201130854 UPLC-MS (ESI+): Rt=1.01 [M+H]+=589. ^-NMR (sterol-d4, 300 MHz): 1.85 (s, 3H); 2·42 (s, 3H); 2.65 (dd, 1H); 2.72-2.90 (m, 2H); 2.90-3.05 (m , 3H); 3.50 (ddd, 1H); AB signal (δΑ=3.80, δΒ=3.88, 2xlH); 5.15-5.25 (m, 1H); 5.94 (s, 2H); 6.51-6.67 (m, 2H); 6.77-6.87 (m, 1H); 6.92-7.12 (m, 3H); 7.15-7.29 (m, 2H); 7.30-7.39 (m,1H); 7.66-7.78 (m,1H); 8.37-8.45 (m , 1H). MS (CI+): [M+H]+=544. h-NMR (methanol-d4, 400 MHz): 0.89 (t, 6H); 1.21-1.39 (m, 4H); 1.45-1.58 (m 1H); 1.92 (s, 3H); 2.08-2.16 (m 1H) ; 2.40-2.80 (m, 10H); 3.51-3.68 (m 2H); 3.78-3. 99 (m, 5H); 5.22-5.30 (m, 1H); 6.64-6.71 (m, 1H); 6.88-6.97 (m, 2H); 7.03-7.14 (m, 2H); 7.22-7.32 (m, 1H). MS (CI+): [M+H]+=586. Ik Λ E r^ 义义々ά 4 相 a aaf 3 ^ ; S ® ® i 寺 d碥硇_ 〇ό ^ 4 M 1 ^ s $ 2 4 5 ^ ^ 5 S λ S n: ^ ^ ^ X v V 4 ^ 味°? B- ΐ4 = 4 . cA 络二死 S- f V ®- A ^ ^ ^ ί 2 ^ ^ ^ ^ ^ ^ Ί S Ϊ *.1 \〇i ^ m CN ^ ^ SS ^ Q d (0 2-0 AQ 〇mx &lt; ή m 152524.doc -332, 201130854

^-NMR (methanol-d4,400 MHz): 1.91 (d,3H); 3.37-3.56 (m,3H); 3.59-3.67 (m, 1H); 3.78-3.97 (m, 5H); 5.32- 5.41 (m, 1H); 6.52-6.58 (m, 1H); 6.66-6.80 (m, 3H); 6.88-6.97 (m, 2H); 7.01-7.16 (m, 4H); 7.23-7.33 (m, 1H) ). UPLC-MS (ESI+): [M+H]+=523. ^-NMR (sterol-d4,400 MHz): 1.55-1.61 (m,6H); 1.90 (s,3H); 2.25 (d, 3H); 2.27-2.55 (m 3H); 2.95 (ddd, 1H) ; 3.74-3.79 (m, 1H); 3.80-3.91 (m, 5H); 3.99-4.05 (m, 1H); 4.64-4.69 (m, 0.5H*); 4.70-4.75 (m, 0.5H*); 6.66-6.73 (m, 1H); 6.88-6.96 (m, 2H); 7.02-7.14 (m, 2H); 7.22-7.32 (m, 1H). MS (EI+): M+=557. ^-NMR (sterol-d4, 300 MHz): 1.51 (d, 3H); 1.58 (s, 3H); 1.99 (s, 3H); 2.55 (s, 3H); 2.68-2.82 (m 2H); -3.18 (m, 1H); 3.33-3.48 (m, 1H); 3.86 (s, 3H); 3.96 (m, 2H); 4.09 (ddd, 1H); 4.76 (ddd, 1H); 6.51-6.59 (m , 1H); 6.81-6.91 (m, 2H); 7.00-7.11 (m, 3H); 7.13-7.24 (m, 2H); 7.59-7.67 (m, 1H); 8.31-8.37 (m, 1H). MS (EI+): M+=593 = ^ B- « ' t-4 ^ ri ^ ,1 砩wd: ®- ^ 〇〇^ ¢- -ο V υΐ s- ^ 士士硪《Λ (N ^ rn 义#味1 Do run a temple A ® ® - Ά ' 4 '1 ^ ^ X ^ 〇〇 (A &lt; N ^ 4 a S ^ SJU 2 ¥ ^ 3 § i 'aki Φ 5 3 , j a 碥 &amp; Ά ^ -7 Ci e Cellar 4 4

s: 152524.doc -333· 201130854 h-NMR (sterol-d4, 300 MHz): 1.51 (d, 3H); 1.58 (s, 3H); 2.00 (s, 3H); 2.11 (s, 6H); 2.21-2.31 (m, 1H); 2.55 (s, 3H); 3.07-3.17 (m, 3H); 3.84-3.91 (m, 4H); 3.97 (s, 2H); 4.03-4.12 (m, 1H); 4.83-4.81 (m, 1H); 6.66-6.72 (m, 1H); 6.82-6.91 (m, 2H); 7.05-7.22 (m, 3H). MS (EI+): M+=559. ^-NMR (methanol-d4, 300 MHz): 1.50 (d, 3H); 1.57 (s, 3H); 2.04 (s, 3H); 2.24-2.32 (m, 4H); 2.94-3.02 (m, 4H) 3.13 (ddd, 1H); 3.54 (s, 2H); 3.87 (s, 3H); 3.98 (s, 2H); 4.07 (ddd, 1H); 4.72 (dd, 0.5H*); 4.76 (dd, 0.5 H*); 6.72-6.80 (m, 1H); 6.81-6.91 (m, 2H); 7.01-7.31 (m, 4H); 7.42-7.49 (m,1H); 7.72-7.81 (m,1H); 8.38 -8.43 (m, 1H). MS (EI+): M+=634. ^-NMR (sterol-d4; 400 MHz): 0.27-0.36 (m, 1H); 0.47-0.65 (m, 3H); 1.62 (d, 6H); 1.94-1.99 (m, 1H); , 3H); 3.90 (s, 3H); 3.90-4.14 (m, 4H); 5.30-5.34 (m, 1H); 6.80-6.85 (m, 1H); 6.92-7.00 (m, 2H); 7.18-7.25 (m, 2H); 7.28-7.37 (m, 1H). MS (EI+): M+=514. 8-(2,6-Difluororphenylphenyl)-3-{[(2-didecylamino-ethyl)-indolyl-amino]-indenyl}-6-(2-fluoro- 3-decyloxy-phenyl)-2,2,7-tridecyl-2,3-dihydro-thiazolidine sits [3,2_a]° ratio biting _5·ketone 1 8-(2,6 -difluoro-phenylhydrazino)-6-(2-1-3-decyloxy-phenyl)-2,2,7-trimethyl-3-(4-0 ratio.基-旅°秦-1-ylindenyl)-2,3-dihydro-thiazolo[Μα]0 than bite-5-ketooxime ^ CS ®- ^ ιΛ ^ ^ ^ ^ S- Β- ^ ^ ^ 'Ί ^ 4 (N Vi: 义寺灭械pw ^CH, ch3 ο&quot; 5 ¥ 〇-CH> 1 L— _____________ 5.35 5.36 5.37 152524.doc -334- 201130854

h-NMR (sterol-d4, 400 MHz): 1.90 (d,3H); 2.38 (s,3H); 2.50-2.66 (m,2H); 2.67-2.76 (m, 4H); 3.37-3.47 (m , 1H); AB signal (δΑ=3·81, δΒ=3.93, 2xlH); 3.85 (s, 3H); 5.07-5.17 (m, 1H); 6.63-6.69 (m, 1H); 6.88-6.96 (m , 2H); 7.02-7.32 (m, 8H). MS (ESI+): [M+H]+=565. ^-NMR (sterol-d4, 300 MHz): 1.93 (s, 3H); 2.40-2.51 (m, 6H); 2.67-2.84 (m, 2H); 2.89-3.07 (m, 2H); 3.46-3.53 (m, 1H); 3.60-3.72 (m 5H); 3.79-4.01 (m, 5H); 5.17-5.27 (m, 1H); 6.65-6.73 (m, 1H); 6.88-6.99 (m, 2H); 7.03-7.16 (m, 2H); 7.22-7.34 (m, 1H). MS (CI+): [M+H]+=560. H-NMR (methanol-d4, 300 MHz): 1.94 (s, 3H); 2.22 (s, 6H); 2.52-2.64 (m, 3H); 2.74-2.87 (m, 3H); 3.00-3.17 (m, 4H); 3.54-3.72 (m, 2H); 3.79-4.02 (m, 5H); 5.25-5.36 (m, 1H); 6.49 (s, 1H); 6.56 (s, 2H); 6.66-6.73 (m, 1H); 6.86-6.98 (m, 2H); 7.03-7.16 (m, 2H); 7.20-7.33 (m, 1H). MS (CI+): [M+H]+=620. 8-(2,6-Difluoro-phenylhydrazino)-6-(2-fluoro-3-indolyl-phenyl)-7-indolyl-3-[(methyl-phenethyl-amino) )-mercapto]-2,3-dihydro-嗟σ sits and [3,2-a] 0 is more than 5-butanone Φ 3 S ci ^ XA ? « Ϊ ^ 2 ^ i +·^· ΛΛ ^ $-4 1 T\ ^ ^ ^ ^ Λ. '1 φ ^ ^ 1 ,^ j [ « f ί ώ ^ i-4 ^ ^ f ®- a °° S Ζ-ϋ zz 0 &gt; 〇uw 〇〇m »〇OS m 〇152524.doc -335 · 201130854 UPLC-MS (ESI+): Rj=l .37 [M+H]+=524 〇^-NMR (methanol-d4, 400 MHz): 1.92 ( s,3H); 2.70-3.01 (m,7H); 3.40-3.54 (m, 1H); 3.56-3.67 (m, 1H); 3.77-4.00 (m, 5H); 5.15-5.26 (m, 1H); 6.63-6.71 (m, 1H); 6.87-6.97 (m, 2H); 7.02-7.32 (m, 10H). MS (CI+): [M+H]+=55 iH-NMR (methanol-d4, 400 MHz): 0.23-0.35 (m, 2H); 0.38-0.48 (m, 2H); 1.92 (s, 3H) 2.12-2.20 (m, 1H); 2.95-3.05 (m, 2H); 3.44-3.50 (m, 1H); 3.58-3.68 (m, 1H); 3.78-4.00 (m, 5H); 5.21-5.31 (m, 1H); 6.64-6.73 (m, 1H); 6.87-6.98 (m, 2H); 7.02-7.15 (m, 2H); 7.21-7.33 (m, 1H). UPLC-MS (ESI+): [M+H]+=487. 8-(2,6-Difluoro-phenylhydrazino)-6-(2-say-3-oximeoxy-phenyl)-7-methyl-3-(oxime.de-4-ylaminopurine) Base)-2,3-diaza·° plug 0 sits and [3,2-a]° bites 5-ketone+fd ^ ¥ ^ ί ώ S S- ^ A ^ ^ ? 赖1 〇〇&lt; Λ ^ Λ 4 .vi extinguished enough 1 ^ ^ ^ ? &lt;N CN ^ ^ ^ T ^ 〇6- °i M i4 «A — 机械 0 0ΖΙ ό J zz &lt;/ 1 &lt; inch in 152524.doc - 336- 201130854

b-NMR (sterol-d4, 400 MHz): 1.37-1.46 (m, 2H); 1.47-1.64 (m, 4H); 1.92 (s, 3H); 2.32-2.49 (m, 3H); 2.59-2.76 (m, 3H); 3.52-3.68 (m, 2H); 3.79-3.99 (m, 5H); 5.21-5.30 (m, 1H); 6.64-6.71 (m, 1H); 6.87-6.96 (m, 2H) ; 7.03-7.14 (m, 2H); 7.22-7.32 (m, 1H). MS (ESI+): [M+H]+= 515. ^-NMR (sterol-d4, 300 MHz): 1.93 (s, 3H); 2.25 (s, 3H); 2.40-2.83 (m, 8H); 3.49-3.56 (m, 1H); 3.59-3.70 (m , 1H); 3.78-4.00 (m, 5H); 5.20-5.31 (m, 1H); 6.64-6.73 (m, 1H); 6.87-6.98 (m, 2H); 7.02-7.15 (m, 2H); 7.22 -7.34 (m,1H) » UPLC-MS (ESI+): [M+H]+=530. h-NMR (sterol-d4, 300 MHz): 1.93 (s, 3H); 2.24 (s, 3H); 2.25 (s, 3H); 2.33 (d, 3H); 2.42-2.57 (m, 4H); 2.61-2.85 (m, 2H); 3.54-3.68 (m, 2H); 3.79-4.01 (m, 5H); 5.18-5.29 (m, 1H); 6.65-6.72 (m, 1H); 6.88-6.98 (m , 2H); 7.03-7.15 (m, 2H); 7.22-7.34 (m, 1H). MS (CI+): [M+H]+=532. h-NMR (methanol-d4, 300 MHz): 1.93 (s, 3H); 2.31 (d, 3H); 2.47-2.63 (m, 9H); 2.64-2.74 (m, 1H); 2.81-2.90 (m, 1H); 3.54-3.69 (m, 5H); 3.78-3.88 (m, 4H); 3.92-4.01 (m, 1H); 5.22-5.29 (m, 1H); 6.64-6.72 (m, 1H); 6.88- 6.97 (m, 2H); 7.03-7.15 (m, 2H); 7.23-7.33 (m, 1H). MS (CI+): [M+H]+=574. ' fs 人¢-减i ^ i ') ® 1械1 3 f ^ cn·' 4 minus 1 CN -H ^ S Ί 1 d ^ ^ &quot; «, ί ii; ^ ®- 7 ' + '味^ ^ \〇\ 〇〇m ^ d «^ s ^砩ά 3 words TO ^ ^ v s- ®- 4 00 ^ cA A 5 ^ Λ ^ ^ -9 ^ ^ f E 彳 Ϊ Ϊ 3 1 ^ ώ V rA 5 00 C '°%T ό Ό Q on ZO △ l 〇mz* l%rso 152524.doc •337· 201130854 ^-NMR (sterol-d4,400 MHz): 1.58-1.70 (m, 2H); 1.92 (s, 3H); 2.22 (s, 6H); 2.30 (s, 3H); 2.30-2.42 (m, 3H); 2.43-2.58 (m, 2H); 2.72-2.83 (m, 1H); 3- 50-3.56 (m, 1H); 3.59-3.68 (m, 1H); 3.78-3.88 (m, 4H); 3.90-3.99 (m, 1H); 5.18-5.28 (m, 1H); 6.64-6.71 (m , 1H); 6.88-6.97 (m, 2H); 7.03-7.13 (m, 2H); 7.23-7.33 (m, 1H). MS (CI+): [M+H]+=546. h-NMR (methanol-d4,400 MHz): 1.61-1.72 (m, 2H); 1.92 (s, 3H); 2.23 (s, 6H); 2.29-2.37 (m, 4H); 2.38-2.58 (m, 6H); 2.63-2.81 (m, 2H); 3.50-3.56 (m, 1H); 3.59-3.68 (m, 1H); 3.79-3.88 (m, 4H); 3.90-3.99 (m, 1H); 5.21- 5.30 (m, 1H); 6.64-6.72 (m, 1H); 6.88-6.97 (m, 2H); 7.02-7.14 (m, 2H); 7.22-7.32 (m, 1H). MS (CI+): [Μ+Η]+=6 (Π. iH-NMR (methanol-d4, 500 MHz): 1.53 (d, 3H); 3.57 (d, 3H); 1.72-1.79 (m, 1H) ; 3.71-3.78 (m, 1H); 3.79-3.90 (m, 6H); 3.94-3.99 (m, 1H); 4.03-4.08 (m, 1H); 5.07-5.13 (m, 1H); 6.71-6.78 ( m, 1H); 6.90-6.96 (m, 2H); 7.00-7.04 (m, 2H); 7.06-7.13 (m, 3H); 7.15-7.21 (m, 2H); 7.22-7.32 (m, 1H). MS (CI+): [M+H]+=565 〇8-(2,6-Difluoro-phenylhydrazino)-3-{[(3-didecylamino-propyl)-indenyl-amine ]]-mercapto}-6-(2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]° than bite-5 -keto-l-(2,6-difluoro-phenylhydrazino)-3-[4-(3-didecylamino-propyl)-succinyl-1-ylindenyl]-6-(2 -Fluoro-3-indolyl-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-&amp;]° ratio bite-5-one 1 1_______.. -___ . \〇' 1 ri ΪΒ- rn T ώ ^ S i V ul ? 1 i ^ 1 St HP wide, ϋ_ b 5.48 5.49 i 5.50 152524.doc • 338 - 201130854

^-NMR (sterol-d4, 400 MHz): 0.10-0.19 (m, 2H); 0.42-0.50 (m, 2H); 0.84-0.99 (m, 1H); 1.93 (s, 3H); , 2H); 2.95-3.07 (m, 2H); 3.46-3.53 (m, 1H); 3.62-3.72 (m, 1H); 3.79-3.89 (m, 4H); 3.91-4.01 (m, 1H); 5.20 - 5.29 (m, 1H); 6.64-6.73 (m, 1H); 6.87-6.97 (m, 2H); 7.03-7.14 (m, 2H); 7.22-7.33 (m, 1H). MS (CI+): [M+H]+=501. ^-NMR (sterol-d4, 300 MHz): 1.91 (s, 3H); 2.90-2.97 (m, 2H); 3.47-3.54 (m, 1H); 3.57-3.67 (m, 1H); 3.69-3.79 (m, 2H); 3.79-3.88 (m, 4H); 3.88-3.99 (m, 1H); 5.16-5.29 (m, 1H); 6.63-6.71 (m, 1H); 6.85-6.96 (m, 2H) ; 7.01-7.14 (m, 2H); 7.15-7.35 (m, 6H). UPLC-MS (ESI+): [M+H]+=537. ^-NMR (methanol-d4,400 MHz): 1.61-1.75 (m,1H); 1.90-2.01 (m, 4H); 2.19 (d, 6H); 2.41-3.08 (m, 7H); 3.51-3.58 ( m, 1H); 3.58-3.68 (m, 1H); 3.77-3.99 (m, 5H); 5.18-5.30 (m, 1H); 6.63-6.71 (m, 1H); 6.87-6.96 (m, 2H); 7.02-7.15 (m, 2H); 7.22-7.33 (m, 1H). MS (CI+): [M+H]+=544. 5 ^ «Λ f T s_ ? ^ Ί ^ v ®- ^ ^ 00 cA 3-(phenylhydrazino-indenyl)-8-(2,6-difluoro-benzoinyl)-6-(2 -Fluoro-3-methoxy-phenyl)-7-methyl-2,3-dimurine sputum and [3,2-a] ° ratio -5 - S with i ¢- d ^ mi 5 ^ ^ s« ^ W楼ώ,丨硪' 6 2Σ \&gt; °^ό ζζ b ^rzv x on vn yr^i (N m yn 152524.doc -339- 201130854 ^-NMR (methanol-d4, 400 MHz): 1.93 (s,3H); 2.38 (s,3H); 2.54-2.62 (m, 1H); 2.72-2.81 (m, 2H); 2.88-2.98 (m, 3H); 3.40-3.49 (m , 1H); AB signal (δΑ=3.81, δΒ=3·94, 2xlH); 5.11-5.20 (m,1H); 6.88-6.97 (m, 2H); 7.02-7.07 (m, 1H); 7.10-7.16 (m, 1H); 7.19-7.35 (m, 4H); 7.43-7.51 (m, 1H); 7.68-7.75 (m, 1H); 8.38-8.43 (m, 1H). MS (CI+): [M+ H]+=602. ^-NMR (sterol-d4, 300 MHz): 1.93 (d,3H); 2.11-2.17 (m,2H); 2.49-2.62 (m, 3H); 2.69-2.90 (m, 3H); 3.30-3.41 (m, 2H); 3.50-3.73 (m, 2H); 3.77-4.02 (m, 5H); 5.23-5.35 (m, 1H); 6.63-6.72 (m, 1H); 6.75- 6.83 (m, 2H); 6.84-6.96 (m, 2H); 7.01-7.15 (m, 2H); 7.18-7.32 (m, 1H); 8.01-8.13 (m, 2H). MS (CI+): [M +H]+=593. h-NMR (sterol-d 4, 300 MHz): 1.93 (s, 3H); 2·32 (s, 3H); 2.57-2.68 (m, 1H); 2.73-2.86 (m, 1H); 3.46-3.71 (m, 3H); 3.72 -3.99 (m, 6H); 5.25-5.37 (m,1H); 6:64-6.73 (m,1H); 6.86-6.98 (m,2H); 7.03-7.17 (m,2H); 7.22-7.35 ( m,1H); 7.37-7.45 (m,2H); 8.37-8.47 (m,2H) » MS (CI+): [M+H]+=552. 11娜减味 B- t〇i 4 1 f ¥ ®- ^ v Ί ^ “ d 硪a 3 'j ^ 硇τ v ^ 5 ^ system di A 厪味厪, 丨钟5 ώ ώ ώ Ί ^ ^ ^ ο οο m &lt;Ν ¥ ^ ^ f 13 1 S 2 ^ $ f :(1)本士Ί ^ Ψ '.l 窆XA s uu g 2-U ft 2_U bmm Ό 152524.doc •340· 201130854

iH-NMR (sterol-d4, 400 MHz): 1.54 (s, 3H); 1.58 (d, 3H); 1.74-1.82 (m, 1H); 2.20-2.48 (m, 8H); 2.69-2.81 (m , 2H); 3.50-3.59 (m, 4H); 3.64-3.70 (m, 1H); 3.81-3.97 (m, 6H); 4.03-4.10 (m, 1H); 5.02-5.11 (m, 1H); 6.69 - 6.78 (m, 1H); 6.86-6.96 (m, 2H); 7.10-7.19 (m, 2H); 7.22-7.335 (m, 1H). MS (CI+): [M+H].=588. lH-NMR (sterol-d4, 400 MHz): 2.10 (s, 3H); 2.38 (s, 3H); 2.52-2.60 (m, 1H); 2.70-2.81 (m, 2H); 2.87-3.00 (m , 3H); 3.40-3.48 (m, 1H); AB signal (δΑ=3·80, δΒ=3.93, 2xlH); 5.11-5.19 (m,1H); 6.66-6.71 (m, 1H); 6.88-6.97 (m, 3H); 7.19-7.37 (m, 3H); 7.69-7.75 (m, 1H); 8.38- 8.44 (m, 1H). MS (CI+): M+=558. iH-NMR (methanol-d4, 400 MHz): 1.60-1.75 (m, 1H); 1.89-2.03 (m, 4H); 2.20 (d, 6H); 2.41-3.08 (m, 7H); 3.51-3.58 ( m, 1H); 3.59-3.68 (m, 1H); 3.79-3.99 (m, 5H); 5.19-5.29 (ra, 1H); 6.64-6.71 (m, 1H); 6.88-6.97 (m, 2H); 7.02-7.14 (m, 2H); 7.22-7.33 (m, 1H). UPLC-MS (ESI+): [M+H]+=544. ^ ^ XA, ^ 'll 1 2 f ^ ^ ψ E ttlp Ί ^ t \i ώ XXS ^ ^ Ϊ S t 3豸硪砩砩^ 1 lO l〇^ S- ^ NwX 1 | m ^ ^ 1 Λ t "进" 士 i ^ ^ ^ v Ί Si ZX Χηχ o 2-0 r\ 卜 wS 00 in Os in s 152524.doc -341 - 201130854

^-NMR (methanol-d4, 400 MHz): 1.92 (d,3H); 2.36 (s,3H); 2.46-2.62 (m, 2H); 2.70-2.79 (m, 1H); 2.81-2.92 (m, 1H); 3.41-3.54 (m, 2H); 3.56-3.67 (m, 2H); 3.78-3.89 (m, 4H); 3.90-3.99 (m, 1H); 5.16-5.25 (m, 1H); 6.64- 6.71 (m, 1H); 6.88-6.97 (m, 2H); 7.02-7.14 (m, 2H); 7.23-7.33 (m, 1H). MS (CI+): [M+H]+=519. iH-NMR (methanol-d4, 400 MHz): 1.91 (s,3H); 2.34 (s,3H); 2.44-2.51 (m, 1H); 2.80-2.90 (m, 1H); 3.40-3.62 (m, (3, 1H) 6.71 (m, 1H); 6.88-6.97 (m, 2H); 7.02-7.14 (m, 2H); 7.23-7.33 (m, 1H); 7.39-7.43 (m, 1H). MS (CI+): [M+H]+=54, NMR (methanol-d4, 300 MHz): 1.93 (s, 3H); 2.15 (d, 2H); 2.38-2.59 (m, 6H); -2.83 (m, 2H); 3.49-3.70 (m, 4H); 3.78-4.01 (m, 5H); 5.20-5.32 (m, 1H); 6.64-6.73 (m, 1H); 6.87-6.99 (m, 2H); 7.02-7.16 (m, 2H); 7.21-7.35 (m, 1H); 7.37-7.45 (m, 2H); 8.39-8.49 (m, 2H). MS (CI+): [M+H]+=607.苫dt ί s ϊ ff 5 ^ SM ^ ^ (N ®- V ¢- ώ ^ ^ l&gt; '哼宇Φ S 5, ^ ^ ^ 4 ώ S έ: ®- ^ ^ i « | 5 '1 ^ ^ § ί » ώ a 砩^ s ®- 1, dj 鳟c? M5 &quot;T ό iB- # ^ =rf f fl f S ^ f ^ Μ ί 〇ό fA ^ ZO S o om X*. Furnace L· °^ό s in S 152524.doc -342- 201130854

h-NMR (methanol-d4, 300 MHz): 1.90 (s, 3H); 2_29 (s, 3H); 2.42-2,52 (m, 1H); 2.76-2.87 (m, 1H); 3.34-3.62 ( m, 3H); 3.66-3.94 (m, 6H); 5.19-5.31 (m, 1H); 6.63-6.72 (m, 1H); 6.85-6.96 (m, 2H); 7.02-7.14 (m, 2H); 7.17-7.33 (m, 6H). MS (CI+): [M+H]+=55 ν^-NMR (Methanol-d4, 400 MHz): 1.91 (s, 3H); 2.37 (s, 3H); 2.53-2.60 (m, 1H); 2.70-2.82 (m, 2H); 2.87-2.98 (m, 3H); 3.40-3.50 (m, 1H); 3.77-3.87 (m, 4H); 3.88-3.98 (m, 1H); 5.11-5.20 (m , 1H); 6.63-6.69 (m, 1H); 6.87-6.97 (m, 2H); 7.02-7.13 (m, 2H); 7.19-7.35 (m, 3H); 7.68-7.75 (m, 1H); 8.38 -8.43 (m, 1H). UPLC-MS (ESI+): [M+H]+=566. h-NMR (sterol-d4, 400 MHz): 1.89 (s,3H); 2.21 (s,6H); 2.52-2.61 (m, 2H); 2.72-2.84 (m, 3H); 3.01-3.16 (m , 4H); 3.42-3.66 (m, 2H); 3.86 (s, 3H); 4.02-4.16 (m, 2H); 5.23-5.35 (m, 1H); 6.45-6.62 (m, 3H); 6.66-6.75 (m, 1H); 7.03-7.15 (m, 2H); 7.27-7.37 (m, 1H); 7.43-7.52 (m, 1H); 7.54-7.60 (m, 1H). MS (CI+): [M+H]+=670. ¢- ri i i pan f ^ 5- i ^ λ ^ ^ Ί ^ j Ά 替 1 S ώ cA γΛ ^ ^ f ^ s- , V rA 5 〇〇 ^ ^ ^ ^ CN ^ ^ ^ S ά 1 ? '1 Γ-ί-, (N ®- ^ ^ ^ ci; B-人☆味 4砩硇砩 S 二# ®~

152524.doc • 343 · 5 201130854 ^-NMR (sterol-d4,400 MHz): 1.91 (d,3H); 1.96-2.04 (m, 2H); 2.25 (s, 1.5H*); 2.29 (s, 1.5H*); 2.33 (s, 3H); 2.42 (s, 3H); 2.55-2.80 (m, 6H); 3.51-3.65 (m, 2H); 3.87 (d, 3H); 4.03-4.15 (m, 2H); 5.19-5.30 (m, 1H); 6.67-6.76 (m, 1H); 7.03-7.17 (m, 2H); 7.28-7.37 (m, 1H); 7.43-7.53 (m, 1H); 7.54- 7.60 (m, 1H). MS (CI+): [M+H]+=582. iH-NMR (sterol-d4, 400 MHz): 1.88 (s, 3H); 2.24 (s, 3H); 2.35-2.56 (m, 6H); 2.62-2.77 (m, 2H); 3.42-3.48 (m , 1H); 3.51-3.60 (m, 1H); 3.86 (d, 3H); 4.01-4.14 (m, 2H); 5.19-5.28 (m, 1H); 6.65-6.74 (m, 1H); 7.03-7.15 (m, 2H); 7.29-7.37 (m, 1H); 7.44-7.51 (m, 1H); 7.53- 7.59 (m, 1H). UPLC-MS (ESI+): [M+H]+=580. ^-NMR (sterol-d4, 400 MHz): 1.90 (s, 3H); 2.40-2.55 (m, 5H); 2.71-2.86 (m, 1H); 2.94-3.01 (m, 1H); 3.37-3.44 (m, 1H); 3.54-3.70 (m, 5H); 3.87 (s, 3H); 4.01-4.15 (m, 2H); 5.18-5.26 (m, 1H); 6.66-6.75 (m, 1H); 7.03 -7.16 (m, 2H); 7.29-7.37 (m, 1H); 7.44-7.52 (m, 1H); 7.55-7.60 (m, 1H). MS (CI+): [M+H]+=610. 3-{[(2-Dimethylamino-ethyl)-indolyl-amino]•methyl}-6-(2·gas-3-methoxy-phenyl)-8-(2- Fluorine-6-trifluoro*indolyl-benzyl)-7-fluorenyl-2,3-dihydro-°e-seat and [3,2-a] ° ratio -5 - _ Φ ^ s ^ A t word e砩砩〒机械®; — s 5 f ϊ i “ 4 YA B- B- W enough i ^ ^ ^ d &quot;5 rA \〇 _ (NV ^ ^ ^ A t硇寺 nitrate 4 f zone i-4 碥哿4 ,, lg 钟 q ¢ ¢ ® ® ® ® ® ® ® ® ® ® ® ® ^ ^ γ γ γ % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % 〇n ZX so oo so 152524.doc •344· 201130854

^-NMR (sterol-d4, 400 MHz): 1.88 (s, 3H); 2.86-2.95 (m, 2H); 3.41-3.48 (m, 1H); 3.50-3.49 (m, 1H); δΑ=3.72, δΒ=3.78, 2χ1Η); 3.87 (d, 3H); 4.01-4.13 (m, 2H); 5.16-5.26 (m, 1H); 6.66-6.73 (m, 1H); 7.04-7.15 (m , 2H); 7.17-7.39 (m, 6H); 7.43-7.51 (m, 1H); 7.53-7.58 (m, 1H). UPLC-MS (ESI+): [M+H]+=587 ° iH-NMR (Methanol-d4, 400 MHz): 1.88 (s,3H); 2.35 (s,3H); 2.46-2.59 (m, 2H) 2.69-2.78 (m, 2H); 3.40-3.68 (m, 3.5H*); 3.73-3.80 (m, 0.5H*); 3.86 (d, 3H); 4.02-4.15 (m, 2H); 5.12 -5.23 (in, 1H); 6.65-6.75 (m, 1H); 7.03-7.16 (m, 2H); 7.29-7.37 (m, 1H); 7.43-7.51 (m, 1H); 7.53-7.60 (m, 1H). UPLC-MS (ESI+): [M+H]+=569 ° iH-NMR (Methanol-d4, 400 MHz): 1.61-1.74 (m,1H); 1.88 (s,3H); 1.91-2.03 (m (1, H), 2. , 1H); 6.66-6.74 (m, 1H); 7.03-7.15 (m, 2H); 7.29-7.37 (m, 1H); 7.44-7.52 (m, 1H); 7.54-7.59 (m, 1H) » UPLC -MS (ESI+): [M+H]+=594. 3-(phenylhydrazinoamino-methyl)-6-(2-fluoro-3-indolylphenyl)-δ-(2-fluoro-6-trifluoromethyl-benzyl)-7- Mercapto-2,3-dihydro-indole[3,2-a] ° ratio bite-5-_ J ^ f ^ ^ i ^ Ϊ , 碥to砩 A A « 12, 3 2 ? ί S νώ —砩砩彳寺^ B- S- ^ « 蛐rA bat t丨1? m ^ ''1 Λ f 4 砩? '1 ^ rl ^ g ^ 5 5 ZZ b Ζ-ϋ S ο ow Ο yf\ 卜 in s 152524.doc -345 - 201130854 h-NMR (sterol-d4, 400 MHz): 1.87 (s, 3H); 2.37 (s,3H); 2.52-2.59 (m, 1H); 2.67-2.81 (m, 2H); 2.85-2.98 (m, 3H); 3.20 (dd, 1H); 3.33-3.43 (m, 1H); 3.86 (d, 3H); 4.00-4.13 (m, 2H); 5.09-5.18 (m, 1H); 6.65-6.73 (m, 1H); 7.02-7.15 (m, 2H); 7.18-7.24 (m, 1H) 7.28-7.38 (m, 2H); 7.44-7.52 (m, 1H); 7.54-7.60 (m, 1H); 7.67-7.75 (m, 1H); 8.36-8.43 (m, 1H). UPLC-MS (ESI+): [M+H]+=616. h-NMR (sterol-d4, 400 MHz): 1.88 (s,3H); 2.36 (s,3H); 2.53-2.56 (m, 1H); 2.70-2.82 (m, 4H); 2.95-3.00 (m , 1H); 3.20 (dd, 1H); 3.33-3.38 (m, 1H); 3.84 (s, 3H); 3.86 (d, 3H); 4.01-4.12 (m, 2H); 5.12-5.18 (m, 1H 6.55 (d, 1H); 6.66-6.72 (m, 1H); 6.78 (d, 1H); 7.04-7.13 (m, 2H); 7.31-7.35 (m, 1H); 7.44-7.52 (m, 2H) ); 7.55-7.58 (m, 1H). UPLC-MS (ESI+): [M+H]+=646. h-NMR (sterol-d4, 300 MHz): 1.91 (s,3H); 2.40 (s,3H); 2.56-2.61 (m, 1H); 2.74-2.83 (m, 2H); 2.98-3.15 (m , 3H); 3.35 (d, 1H); 3.43-3.52 (m, 1H); 3.88 (s, 3H); 4.03-4.17 (m, 2H); 5.19-5.27 (m, 1H); 6.68-6.76 (m , 1H); 7.06-7.16 (m, 2H); 7.32-7.43 (m, 2H); 7.47-7.53 (m, 1H); 7.58-7.60 (m, 1H); 8.07 (dd, 1H); 8.70 (d , 1H). UPLC-MS (ESI+): [M+H]+=684. S- O 4 i碥"匾5 3 ^ 'i ?柃¢-奴q奴^ ^ f ^ ί, X 5 ^ ϊ 2 , ¢13⁄4 2 4娜Φ cA ^ ^ £ J 3 4 Cl C7 tl ®- ^ Ί ^ VO φ Λ v " g 3 ^ d ^ A, A ^ i rt t-4 B- 'Ί τ ^ ^ ^ Φ 5 | I ° s # 硪ψ ζ-υ ¥ z-5 2-0 &lt ;Ν cn in 152524.doc -346- 201130854

iH-NMR (sterol-d4, 300 MHz): 1.90 (s, 3H); 2.37 (s, 3H); 2.54-2.59 (m, 1H); 2.70-2.79 (m, 2H); 2.87-3.01 (m , 3H); 3.27 (d, 1H); 3.38-3.47 (m, 1H); 3.88 (d, 3H); 4.03-4.16 (m, 2H); 5.14-5.24 (m, 1H); 6.68-6.75 (m , 1H); 6.85 (dd, 1H); 7.06-7.17 (m, 2H); 7.20 (dd, 1H); 7.32-7.39 (m, 1H); 7.47-7.54 (m, 1H); 7.58-7.60 (m , 1H); 7.77-7.85 (m, 1H). UPLC-MS (ESI+): [M+H]+=634. ^-NMR (sterol-d4, 300 MHz): 1.90 (s,3H); 2.37 (s,3H); 2.55-2.60 (m, 1H); 2.70-2.79 (m, 2H); 2.90-2.98 (m , 3H); 3.24 (dd, 1H); 3.38-3.46 (m, 1H); 3.88 (d, 3H); 4.03-4.16 (m, 2H); 5.12-5.21 (m, 1H); 6.69-6.74 (m , 1H); 7.06-7.17 (m, 2H); 7.32-7.39 (m, 2H); 7.47-7.54 (m, 1H); 7.58-7.60 (m, 1H); 7.71-7.75 (m, 1H); 8.42 (d, 1H). </ RTI> <RTIgt; -2.64 (m, 1H); 2.69-2.83 (m, 2H); 2.86-3.01 (m, 3H); 3.30-3.48 (m, 2H); 3.88 (d, 3H); 4.03-4.16 (m, 2H) ;;;;;;;;;;;;;;; m, 2H); 8.25 (d, 1H). UPLC-MS (ESI+): [M+H]+=630. 6-(2-1-3-methoxy-phenylhydrazine [2-(6-fluoro-oral ratio ̄-2-yl)-ethyl]-indolyl-amino}-indenyl)-8 -(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-i 2,3·dihydro-thiazolo[3,2-a]&quot;bipyridine-1 ketone^ Φ 5 ^ S Butterfly: a sound A ^ ^ ^ ό 3 ώ 1 i ^ ! _ ¥ώ势1 A 硪' 3 CS ®- ^ cA ^ Of f ^ ^ ^ ^ j 6- s- T 1, 4 5 ^ 硇 硇 CL 巴ba ^ ':! 5 ^ fd ^ S ^ ^ (N Ί % Z - 〇ζ - ο ο 2-0 r- vS 152524.doc .347. 201130854 ^• NMR (methanol-d4, 300 MHz): 1.90 (s,3H); 2.38 (s,3H); 2.55-2.60 (m, 1H); 2.70-2.82 (m, 2H); 2.89-2.98 (m, 3H); 3.25 (dd, 1H) 3.39-3.47 (m, 1H); 3.88 (d, 3H); 4.03-4.16 (m, 2H); 5.13 -5.21 (m, 1H); 6.68-6.75 (m, 1H); 7.06-7.17 (m , 2H); 7.32-7.39 (m, 2H); 7.47-7.55 (m, 2H); 7.58-7.60 (m, 1H); 8.32-8.33 (m, 1H). UPLC-MS (ESI+): [M+ H]+=634. 'H-NMR (sterol-d4, 300 MHz): 1.90 (s,3H); 2.39 (s,3H); 2.52-2.58 (m, 1H); 2.66-2.79 (m, 2H) 2.87-3.01 (m, 3H); 3.22-3.27 (m, 1H); 3.35-3.44 (m, 1H); 3.85 (s, 3H); 3.88 (d, 3H); 4.02-4.16 (m, 2H) ); 5.11-5.19 (m, 1H); 6.68-6.75 (m, 1H); 7.05-7.17 (m, 2H); 7.21-7.25 (m, 1H); 7.32-7.38 (m, 2H); 7.46-7.53 (m, 1H); 7.58-7.60 (m, 1H) ; 7.97-7.99 (m, lH). UPLC-MS (ESI+): [M+H]+=646 〇h-NMR (sterol-d4, 300 MHz): 1.90 (s, 3H); 2.39 (s, 3H); 2.48 (s, 3H); 2.54-2.59 (m, 1H); 2.69-2.80 (m, 2H); 2.85-2.94 (m, 3H); 3.22-3.27 (m, 1H); 3.35-3.45 ( m, 1H); 3.88 (d, 3H); 4.03-4.16 (m, 2H); 5.12-5.21 (m, 1H); 6.68-6.75 (m, 1H); 7.06-7.17 (m, 4H); 7.32- 7.38 (m, 1H); 7.47-7.54 (m, 1H); 7.57-7.62 (m, 2H). UPLC-MS (ESI+): [M+H]+=630. ^ ^ A ^ ^ ί S ^ X $ 5 4 i ϊ 4 t “ X缕^哼Φ s A 1 j -s ul ^ Φ cA ii 芬 i哼i 3 i ^ ^ a ul ¢- ^ '1 ^ Φ «Λ ξΝ ¢- ^ rA ^ ^ ^ $4 6-8-®· A, 硪ει pigeons X Ϊ ^ s $ ', 'J 3 fv〇' \ % z-5 u. zo zo 〇〇yn 152524. Doc -348- 201130854

iH-NMR (sterol-d4, 300 MHz): 1.90 (s, 3H); 2.38 (s, 3H); 2.55-2.60 (m, 1H); 2.70-2.83 (m, 2H); 2.91-2.98 (m , 3H); 3.23 (d, 1H); 3.38-3.46 (m, 1H); 3.88 (d, 3H); 4.03-4.16 (m, 2H); 5.12-5.21 (m, 1H); 6.71 (dtd, 1H ); 7.06-7.17 (m, 2H); 7.29-7.38 (m, 2H); 7.44 (d, 1H); 7.47-7.54 (m, 1H); 7.58-7.60 (m, 1H); 8.37 (d, 1H) ). </ RTI> <RTIgt; 2.69-2.80 (m, 2H); 2.95-3.05 (m, 3H); 3.19 (d, 1H); 3.33-3.40 (m, 1H); 3.88 (d, 3H); 4.03-4.14 (m, 2H); 5.14 (dtd, 1H); 6.68-6.74 (m, 1H); 7.06-7.16 (m, 2H); 7.28-7.37 (m, 2H); 7.47-7.56 (m, 2H); 7.58-7.60 (m, 1H) ); 8.28-8.30 (m, 1H). UPLC-MS (ESI+): [M+H]+=634. h-NMR (sterol-d4, 300 MHz): 1.88 (s,3H); 2.42 (s,3H); 2·60 (dd, 1H); 2.73-2.92 (m, 2H); 3.03-3.18 (m , 4H); 3.24-3.26 (m, 1H); 3.88 (d, 3H); 4.00-4.13 (m, 2H); 5.11-5.20 (m, 1H); 6.67-6.73 (m, 1H); 7.05-7.16 (m, 2H); 7.31-7.37 (m, 1H); 7.46-7.60 (m, 4H); 7.73 (ddd, 1H); 7.88 (dd, 1H); 7_96 (d, 1H); 8.24 (d, 1H) ). UPLC-MS (ESI+): [M+H]+=666. ^ Ψ 3 ^ | , ☆ &amp; t cloud (N ^ OO (N ^ ό 3 ώ 1 s ^ 5 1 5 _ _ ώ 妙 ^ ^ ^ ^ ^ 1 S 5 2 ... s 6-(2-Fluorine- 3-decyloxy-phenyl θα [2-(3-fluoro--pyridin-2-yl)-ethyl]-indolyl-amino}-indenyl-8-(2-fluoro-6- Trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydrogen-sodium([3,2-a] ° ratio 0--5-ketone cs ®- 〇t ^ ^ 4砩7 ',1... &gt;4 ώ 4 ^ f J £ ά ^ ^ ^ Β- ίπώ ΐ 4 味% zo ΰ ZO % Ζ-ϋ oo m 00 s 152524.doc •349- 201130854 Analytical data UPLC_MS (ESI+): RT =0.93 [M+Hf=558. UPLC_MS (ESI+): RT=1.12 [M+Hf=499. Name 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-indoleoxy) Phenyl)-7-mercapto-3-({[2-(piperidin-1-yl)ethyl]amino}indolyl)-2,3-dihydro-511-[1,3]thiazole And [3,2- mad]0 is more than 5-(8,6-difluorobenzoinyl)-6-(2-fluoro-3-indolylphenyl)-7-fluorenyl -3- {[indenyl (prop-2-yn-1-yl)amino]methyl}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a] -5-ketone structure text ' . . . . . . rt AX No. 5.84 5.85 -350- 152524.doc 201130854

UPLC_MS (ESI+): RT-1.08 [M+H]+=566. UPLC_MS (ESI+): RT=1.10 [M+H]+=560 〇 UPLC_MS (ESI+): RT=1.22 [M+H]+=627. 8-(2,6-Difluorophenylindenyl)-3-({[4-(dimethylamino)phenyl]amino}methyl)-6-(2-fluoro-3-methoxy Phenyl)-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]° ••定-5-西同3-({[2-(二Ethylamino)ethyl](methyl)amino}methyl)-8-(2,6-difluoro-1-benzyl)-6-(2-fluoro-3-indolylphenyl)- 7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]° ratio to 5-ketone 3-{[4-(3-phenylphenyl)per Pyrazin-1-yl]methyl}-8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-indolylphenyl)-7-mercapto-2,3-di Hydrogen-5H-[1,3]thiazolo[3,2-a]0 is less than 0--5-S with η Ζ vCr ο « ζ 1 JX 0 5.86 5.87 5.88 1 s' 152524.doc -351 - 201130854

UPLC_MS (ESI+): RT=1.07 [M+H]+=594. UPLC_MS (ESI+): RT = 0.79 [M+H]+=558. UPLC_MS (ESI+): RT=1.08 [M+H]+=636 » 5窆f Ψ d 3 5 Ϊ Ύ A Ψ v # 3 f A ^ v ^ ST ^ ',' B- ri ^ οό 硪®- HI tfd, ^ ί s ® ¥ 13⁄4 ^ ^ U^l ssg: ? =w i4 c0 a- ^ &amp; i φ K mantle $ ^ t4 S' 11碥 3 Ί ®- ? M 5 i 2 #寺" _办钟cn®~ ^ ί 5 X ^ 0 ό r^w xz V know 1 r^w 0 χΦ '-ο OS oo wS ON 152524.doc -352 - 201130854

UPLC_MS (ESI+): RT = 1.42 [M+H]+=594. UPLC_MS (ESI+): RT = 0.83 [M+H]+=627. UPLC_MS (ESI+): RT = 1.15 [M+H]+=605. 8-(2,6-Difluorobenzoinyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-3-{[(2-mercapto-1,3-benzene) And thiazol-5-yl)amino]mercapto}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]0 is more than 5-ketone 8-(2,6 -difluorophenylindenyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-3-({4-[3-(pyrrolidin-1-yl)propyl]piperidin Iso-l-yl}methyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]fl ratio bite-5-嗣8-(2,6-difluorobenzene Methyl)-6-(2-fluoro-3-indolylphenyl)-7-indolyl-3-({[3-(trifluoromethyl)phenyl)]amino}methyl)-2, 3-Dihydro-5H-[1,3]thiazolo[3,2-pressure]0 ratio °-5-ketone 1 ^ 0 1 ^ 5.92 5.93 5.94 152524.doc -353 - s 201130854 UPLC-MS (ESI+ ): RT=1.45 [M+H]+=553. UPLC_MS (ESI+): RT=1.06 [M+H]+=503. UPLC_MS (ESI+): RT=1.12 [M+H]+=551. 8-(2,6-Difluorobenzoinyl)-6-(2-fluoro-3-indolylphenyl)-3-{[(4-decyloxyphenyl)amino]methyl}- 7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 3-[(t-butylamino)methyl]-8- (2,6-difluorobenzoinyl)-6-(2-fluoro-3-indolyl)-7-fluorenyl-2,3-dihydro-5H-[1,3]thiazolo[ 3,2-a]. Bipyridin-5-one 8-(2,6-difluorophenylindolyl)-6-(2-fluoro-3-indolyloxyphenyl)-7-methyl-3-{ [(4-fluorenyl) Stupid methyl)amino]methyl}-2,3-dihydro-5沁[1,3]thiazolo[3,2-indole ratio 0-but-5-one 1 ZZ P on X r on ίΓ 5.95 5.96 5.97 152524.doc -354- 201130854

UPLC_MS (ESI+): RT = 1.14 [M+H]+=565. UPLC_MS (ESI+): RT=1.05 [Μ+Η]+=6Π. UPLC_MS (ESI+): RT = 0.78 [M+H]+= 586. 8-(2,6-Difluorobenzoinyl)-6-(2-fluoro-3-indolylphenyl)-7-indolyl-3-{[(3-phenylpropyl)amino] Mercapto}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]吼t^-5-嗣8-(2,6-difluorobenzyl)-3- ({ [2-(3,5-Dimethoxyphenyl)ethyl]amino}indenyl)-6-(2-fluoro-3-methoxyphenyl)-7-indenyl-2, 3-Dihydro-5H-[1,3]thiazolidine[3,2-a] ° ratio =5 - brewed] 8-(2,6-difluorobenzyl)-6-(2 -fluoro-3-methoxyphenyl)-7-mercapto-3-({ [3-(4-mercaptopiperidin-1-yl)propyl]amino}methyl)-2,3- Dihydro-inducing-[1,3]thiazolo[3,2-a] than biting ~5-酉同Λ&gt; ZZ V η X 5.98 5.99 5.100 £ 152524.doc - 355 - 201130854 1 UPLC_MS (ESI+): RT =0.96 [M+H]+=587. II accounted for. W - U i? PL, UPLC_MS (ESI+): RT = 0.96 [M+H]+=574. UPLC_MS (ESI+): RT=1.05 [Μ+Η]+=677. »- *2, ^ ^ 1 iSi' _ 吹 Blow 9彳5 meal W Ψ 兮旮杳 (N (| Σ2; S-νό r·!·珠' 1 ri A -fi 1 ττ ^ηλ ^ ^ ^ S- ®- ^ '1 ^ ^ E £ ^ ώ 5 VV 7, ^ Xi ^ g_ B- ^ (N ^ ώ ^ ', l S rf ώ 1 4 2 Visit®-二Ί? cA砩A ^ ^ 5 兮, 1 zone « ί 5 ^ &lt;Ν 丄^ ώ ^ ^ Bit 1 » ^ ^ Λ ' 1 ®~ ^ Drive 1 ι-1 Solid d 3 呤玟兮 ι $do ^ ii ^ ®- ^ ι? 5 机械,Α τ d ν ,1 t 芩ν芩 ^ -fl ^ « S t 兰 $ 3綦4 ^ ^ # i** r^w 9j ύ 知 r^m zz υ,Ζχυ x if W Λ&gt ; ifp r^w 0 v° V) &lt;ns S ιη g in 152524.doc 356 - 201130854

UPLC_MS (ESI+): RT=0.92 [M+H]+=607 〇 UPLC_MS (ESI+): RT=0.99 [M+H]+=487. UPLC-MS (ESI+): RT = 1.26 [M+H]+= 660. UPLC-MS (ESI+): RT = 0.95 [M+H]+= 631. For fsi 6- m 3 jf X fi ^ ^ ci, "Holiday B- ^ &lt;7 5 s«- Η ά f 2 '灭ί ¢ - ¥ —cA刁i ϊ 2 t ^ x硇,' ^ 3 S ^ ^ ^ ®— ^-ν ro cA ^ £ ¥ 5 s ? v 'Ί ^ text 4 , J ί CO 5nj^ u2j — one &amp; n? s two 碜 5 λ s ^ v 2, 5 « 5砩ώ &lt;〇« s I &- f ^ ^ &lt;N ®- ^ JIL (N Ί ^ 4 G t wear X 4 ^ 4 ^ f Ο 0 bf^w &lt;0&gt; ο r^w 0 ί u. nT 知Λ&gt; 0 v° xz 1 ? on I* S vri yn g in I: 152524.doc -357- 201130854 UPLC_MS (ESI+): RT=1.06 [M+H]+=627. UPLC_MS (ESI+) : RT=0.92 [M+H]+=544. UPLC_MS (ESI+): RT=1.12 [M+H]+=572 » 8-(2,6-difluorobenzyl)-6-(2-fluoro 3-methoxyphenyl)-7-methyl-3-({4-[2-o-oxy-2-(pyrrolidinyl-I-yl)ethyl]11-indenyl-l-yl} Base)-2,3-diaza _ 5Η·[1,3]thiazolo[3,2-a]acridin-5-one oxime S ώ 1-Η (―&gt; ¥ ^ ^ 9泠ώ α Α έ 1 ^ ^ Ί X Λ ^ ^ a Sit οό ^ 3-{[(2-chlorobenzyl)amino]methyl}-8-(2,6-difluorobenzoinyl)-6-(2 -fluoro-3-methoxyphenyl)-7-mercapto-2,3-dihydro-5H-[ 1,3]thiazolo[3,2-a].pyridin-5-one 0 v° 0 5.109 5.110 5.111 15252 4.doc -358· 201130854

UPLC_MS (ESI+): RT=1.48 [M+H]+=541 〇UPLC_MS (ESI+): Rt=1.〇4 [M+H]+=597 〇UPLC_MS (ESI+): RT=1.04 [M+H] +=569. 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4-fluorophenyl)amino]methyl}-7- Methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]&quot;bipyridin-5-one 8-(2,6-difluorobenzoinyl)-3- {[(3,5-Dimethoxybenzyl)amino]indolyl}-6-(2-fluoro-3-methoxyphenyl)-7-indenyl-2,3-dihydro- 5H-[1,3]thiazolo[3,2-a] 比-嗣8-(2,6-difluorobenzoinyl)-6-(2-fluoro-3-methoxyphenyl)- 3-({[2-(2-fluorophenyl)ethyl]amino}indolyl)-7-indolyl-2,3-dihydro-5H-[1,3]thiazolo[3,2- a] 0 to bite-5-keto J〇r η Λ: ^ 1 X ZZ 5.112 5.113 5.114 152524.doc -359- 201130854 UPLC_MS (ESI+): RT=1.05 [M+H]+=567. UPLC_MS (ESI+): RT=l.〇3 [M+H]+=517. UPLC_MS (ESI+): RT=0.97 [M+H]+=538 〇8-(2,6-difluorobenzyl)-6-(2-fluoro-3-decyloxyphenyl)-7- Base-3-{[(2-phenoxyethyl)amino]indolyl}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]« than bite-5 ·8-(2,6-Difluorobenzoinyl)-6-(2-fluoro-3-indolylphenyl)-7-mercapto-3-(morpholin-4-ylmethyl) -2,3-Dihydro-5H-[ 1,3] sold 11 and [3,2-a] ° ratio -5-酉 with 8-(2,6-difluorobenzyl)-6 -(2-fluoro-3-indolylphenyl)-7-methyl-3-{[(pyridin-4-ylindenyl)amino]indenyl}-2,3-dihydro-511-[ 1,3]thiazolo[3,2-中比比定-5-ketooxime 6 A 0 6 5.115 5.116 5.117 _ 152524.doc -360· 201130854

UPLC_MS (ESI+): RT=1.09 [M+H]+=567. UPLC_MS (ESI+): RT=1.17 [M+H]+=627. UPLC_MS (ESI+): RT=1.16 [M+H]+=586. 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_3-{[(4-decyloxybenzyl)amino]methyl}- 7-Methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]. Specific bite-5-813⁄4 ^ Z ^ ί ^ ^ .-fl ^ ^ S*✓ * 1—1 ^ m CO d: ^ ^ ^ ^ M » B- rA ')3 3 ώ硪, 3-{[( 2-phenanthrenyl)(fluorenyl)amino]methyl}-8-(2,6-di-anthionyl)-6-(2-fluoro-3-methylphenyl)-7- Methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]°itadine-5·ketone°·«„ ζΓ* 5.118 5.119 5.120 1 152524.doc -361 · 201130854 UPLC—MS (ESI+): Rr=1.55 [M+H]+=629. UPLC—MS (ESI+): RT=1.03 [M+H]+=631 〇UPLC—MS (ESI+): RT=1.06 [M +H]+=611. UPLC_MS (ESI+): RT=0.83 [M+H]+=627. A ^ Calling machine li ^ ^ ^ 3,vi ft 5 _ f «si ®-vd: # m 5-1 rA minus 硪', _i ^ d S ^ ^ M5 φώ ^ CN ®~ —4 ^ Μ ®~ Zhu 2 v 5 £ i 4 ^1 v 言灭 s ¢- ^ B- ^ ^ \\ AX ^ S i S M 〆rA B- cA ^ iiil «® A -fl tl X ^ ζί &- 00 i*4 i!^ 械 ® R ^ « 二^ 4 W ^ ^ 1 ^ ^ A ¥ 13⁄4 ', 1 智^ d 5 j« 5 B- ^ ^ $4 «Λ ^ ^ ^ ^ m Λ ψ ° A...# CN As ·—7 r^n Φ 6 if9 k ^&gt;» A oA^v5 (5^W b. i〇in 152524.doc -362- 201130854

UPLC_MS (ESI+): RT=1.04 [M+H]+=574 〇 UPLC_MS (ESI+): RT=1.02 [M+H]+=557. UPLC_MS (ESI+): Rt=1.13 [M+H]+=601 〇4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl) -7-Methyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]acridin-3-yl]methyl}piperazine-1- Ethyl decanoate 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-mercapto-3-{[methyl (porphin-3) -ylmethyl)amino]mercapto}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]° ratio 0¢-5-keto 8-(2,6- Difluorophenylhydrazino)-6-(2-fluoro-3-methoxyphenyl)-7-mercapto-3-{[indenyl(cain-2-ylindenyl)amino] fluorenyl}- 2,3·Dihydro-5H-[1,3]thiazolo[3,2-a]-bybita-5-one 2 un I 6 , 5.125 5.126 5.127 152524.doc -363 - 201130854 UPLC_MS (ESI+): RT=0.96 [M+H]+=505 〇UPLC_MS (ESI+): RT=1.15 [M+H].=579. UPLC_MS (ESI+): RT=1.09 [M+H]+=567 〇UPLC_MS (ESI+): RT=1.11 [M+H]+=650 七7 7 ^ ^ ct ^ ^ J fssd ^ ^ f ip § 3澈,·^ S 3 5 5^(N ¢- ^ ώ ^ hd ^ ^ 4n 5 « έ ^ &amp;- T ^ Λ ^ M . &lt;^i ^ X ^ V ^ 00 ^ ig Y ϊ ϊ; ώ rA砩塔''s ds ^ ^ ^ ffi- ^ ¥ s ^ ^ s i4 f ^ ^ rA '' \Q 1 1 W 2硇〇〇¢^1 ®~ 5 ^ ^ ? 1 MJ 1 5 〇〇i4 a 1 5 S cA π: !t V ^ V , _Γ ^ cs ^ 4 ^ ^ v ®, in /, r^a zz r^a xf on af OO (N vn O m T*^ in m 152524.doc -364- 201130854

UPLC_MS (ESI+): RT=0.86 [M+H]+=560 〇 UPLC_MS (ESI+): RT=0.87 [M+H]+=613. UPLC-MS (ESI+): RT = 1.05 [M+H]+=551. 3-({[3-(diethylamine:propyl)amino}indenyl)-8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-indolylbenzene -7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]n ratio °-5-keto 8-(2,6-difluorophenylhydrazine 6-(2-Fluoro-3-methoxyphenyl)-7-mercapto-3-{[4-(l-fluorenyl) benzo-4-yl) pi-azine-1-yl ] mercapto}-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a]°A °-5-keto 8-(2,6-difluoro cumyl)- 6-(2-Fluoro-3-indolylphenyl)-7-indolyl-3-{[(3-mercaptophenyl)amino]indolyl}-2,3-dihydro-5H- [1,3]thiazolo[3,2-中比咬-5-_ N^. 1暂^ /V 5.132 5.133 5.134 s 152524.doc -365- 201130854 UPLC_MS (ESI+): RT=1.00 [M+H ]+=533 〇UPLC_MS (ESI+): RT=0.94 [M+H]+=630. UPLC_MS (ESI+): RT=0.87 [M+H]+=566. UPLC_MS (ESI+): RT=1.08 [M+ H]+=636. 8-(2,6-Difluorobenzoinyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(thiomorpholine-4- Methyl)-2,3-dihydro-5H-[1,3]°嗤嗤[3,2-a]°fc^-5-keto 1_____ φ— 1 rA alkali 砩2 m 23⁄4 23⁄4 M ^ Yuma ^ ^ ig £ ^ ^ ^ V ^ 4 shouts S 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)-7-mercapto-3 -( {methyl[2 decapyridin-3-yl) )ethyl]amino}methyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]° than bite-5-one 4 ^^ m ®- ^ £ cA 〇^“办·τ·匾^ ^ ^ ί X ? 2 S 4 ¢13⁄4 娜»1 ®- B- 窆 "二ifp 0 zz β° 蜃"» 0 S Ό 5.135 5.136 5.137 5.138 152524.doc -366 · 201130854

UPLC_MS (ESI+): RT = 1.06 [M+H]+=580. UPLC_MS (ESI+): RT=1.13 [M+H]+=594 - UPLC—MS (ESI+): RT=0.94 [M+H]+=587 〇% ^ ^ ^ m s- ®- ^ ,1 ^ ^ s 4 ϊ 5 s砩,)) ta_ ®- ^ CN Si3〆^ Si 埏二A 砩4 bar it ^ )Λϊ £ ® γλ ^ f X ®- ^ '1 Ί51 $4兮犬^ S g_ 1 /-Λ -ν . alkali butterfly 3 'J t &amp; d ? ^ 2 幺 _ S 3 ¢ ^ 1 ^ -3⁄4 ^ f ^ ^ mechanical, A i; , 1 S_味哼νό讣 ridicule: Ba #q智4 ^ V &lt;ni household 0 〇ί« 〇^21 jT 5.139 5.140 5.141 s 152524.doc -367- 201130854 UPLC_MS (ESI+): RT=0.90 [M+H]+=601. UPLC_MS (ESI+): RT=1.10 [M+H]+=551. UPLC_MS (ESI+): RT=1.26 [M+H]+=660. s ^ s ^ z ^ 5 ί 〇 ct〇v ^ S ^ X ^ ^ Two do 1 丨 wear 4 ® 7 Λ £ i ^ Ins likl rA ^ 8-(2,6-difluorophenyl fluorenyl)-6- (2-Fluoro-3-indolylphenyl)-7-methyl-3-{[(2-mercaptobenzyl)amino]indolyl}-2,3-dihydro-5H-[1 , 3]thiazolo[3,2-a]bite-5-one 8-(2,6-difluoro cumyl)-6-(2-fluoro-3-methoxyphenyl)-7- Mercapto-3-({4-[3-(trifluoromethyl)phenyl]piperazine small group}methyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2 -a]° than bite-5-ketone nf* Qin 9 Γ ^-ZI €ό 0 U. 5.142 5.143 5.144 152524.doc -368-

s 201130854

UPLC_MS (ESI+): RT = 1.44 [M+H]+= 567 ° UPLC_MS (ESI+): RT = 1.07 [M+H]+=543. UPLC-MS (ESI+): RT = 1.03 [M+H]+= 501. 3-[(l,3-benzodioxol-5-ylamino)indolyl]-8-(2,6-difluorobenzoinyl)-6-(2-fluoro-3 -methoxyphenyl)-7-mercapto-2,3-dihydro 3]thiazolidine[3,2-&amp;]° than bite-5-8 with 8-(2,6-difluoro Benzyl)-6-(2-fluoro-3-methoxyphenyl&gt;7-methyl-3-{[(thiophen-2-ylindenyl)amino]methyl}-2,3- Dihydro-5H-[1,3]thiazolo[3,2-a]« than bite-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-indole Oxyphenyl)-7-mercapto-3-(pyrrolidin-1-ylmethyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]. -5-ketooxime 6: 0 5.145 5.146 5.147 s 152524.doc -369· 201130854 UPLC_MS (ESI+): RT=0.78 [M+H]+=555 〇UPLC_MS (ESI+): RT=1.00 [M+H]+ =562 〇UPLC_MS (ESI+): RT=1.03 [M+H]+=555 » 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-indolylphenyl)- 3-({[3_(1Η-imidazol-1-yl)propyl]amino}indolyl)-7-indolyl-2,3-dihydro-5H-[1,3]thiazolo[3,2 -&amp;]°Bite-5-嗣m ^ ^ Ί ^ CN Λ ^ ®-苳^械T ¢^1 ct ®- CL A fl ρό.地— cn1 4 ^ ^ 8-(2,6-II Fluorobenzyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-3-({methyl[(1-mercapto-1H-pyrazol-5-yl)) Amino group }Methyl)-2,3-dihydro-5沁[1,3]°°°[3,2-&amp;]1〇 ratio. 定-5-ketone C' s^Y^ch3F fz Λ&gt ; 5.148 5.149 5.150 152524.doc •370· 201130854

UPLC_MS (ESI+): RT=1.00 [M+H]+=543. UPLC-MS (ESI+): RT = 0.85 [M+H]+=541. UPLC_MS (ESI+): RT=1.17 [M+H]+=660. 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-mercapto-3-{[(thiophen-3-ylindenyl)amino group ] mercapto}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluoro cumyl)-6- (2-fluoro-3-indolylphenyl)-7-indolyl-3-({[(1-indolyl-1H-imidazol-5-yl)methyl]amino}indenyl)-2, 3-Dihydro-5H-[1,3]thiazolo[3,2-a]° ratio bite-5-ketone machine# miso ¥ cA W £ ¥ 5 ? I v 'Ί ^ ;S 'J i ¥ U??5. UPLC-MS (ESI+): RT=1_10 [M+H]+=567 〇 UPLC_MS (ESI+): RT=1.07 [M+H]+=529. UPLC_MS (ESI+): RT = 0.94 [M+H]+=572. ^ 3 ^ ^ Ψ ΡΊ ^ ^ X ^ d, E ^ ^ ώ ^ into s 2 {〆δ- 3 Ί 13⁄4 ^4* cn cn ^ M ®~ do § i ^ ^ 5 ? ¢- ^ rA硪朱" Pigeon S d « ^ ^ ^ ^ ¥ X i ^ l!^ i ' 1 MSA νό x 3 X ^ 〇0 City®~ 剑士&gt;Λ 砩硪A ®; i ^ &lt;7 ri (N (N Luo Taste ^ ^ tm ®- ^ Two-armor ώ 祯 * ? ? ? ? ? Μ ^ ^ ^ ^ ^ ^ Μ r r r r r r r r r r r r r r r r r r r r r r r r r r r r r ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^人云 « £ ί s '} ®· 5 5 ^ £ _^r&gt; Λ^° rt z ^Cw 〇η r^w JV uS IT) ir&gt; νο mi〇152524.doc -372- 201130854 UPLC-MS ( ESI+): RT=1.13 [M+H]+=608. UPLC_MS (ESI+): RT=1.05 [M+H]+=569. UPLC-MS (ESI+): RT=1.28 [M+H]+=616 UPLC_MS (ESI+): RT = 1.08 [M+H]+ = 641. 8-(2,6-difluorophenylmethyl)-6-(2-fluoro-3-decyloxyphenyl)-7- Mercapto-3-({[4-(morpholin-4-yl)phenyl]amino}indenyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a ]0 to 0定-5-8同¢4 ^ ^ 砩硪A base t D a it ' s - d 〇^ ft S ώ § —s A d into οό ^ A N-[4-({[8- (2,6-Difluorobenzyl)-6-(2-fluoro-3·decyloxyphenyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-[1 , 3] thiazole p,2-a]-Bistidin-3-yl]fluorenyl}amino)phenyl]indole-burning amine 3-{[4-(2-benzophenanthryl)piperazin-1-yl]- }}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-2,3-dihydro-5H-[1, 3] Thiazolo J: XZ Q zz V ZZ » ZX % 0 5.158 5.159 5.160 5.161 1 1 J _1 152524.doc -373 -

s 201130854 UPLC_MS (ESI+): RT=0.92 [M+H]+=527. UPLC_MS (ESI+): RT = 0.98 [M+H]+=621. UPLC_MS (ESI+): RT=0.83 [M+H]+=627 &gt; UPLC_MS (ESI+): RT=0.97 [M+H]+=613 〇^ ^ ¢- ®: ^ ^ Ψ A ^ d ^ ^ fx 2 X x 'Z ¥ ^ mf a- Ί ^ 铋, A 驴硪q , 丨Ϊ多 ^ « ^ 3 ^ ^«3 ^ ^ 5C ® Ιϊ3έ 'ΪI ^ rA CJ, A 7 〇C ^ ®机械®- R _ m »-U t ^ $ 1 ^ i ^ «λ ¥ ') ^ h 3 more 5 2 3 7 s ¥ ^ η r; s 5 Sw^ '1 B- ° 5 i | X Λ ^ 蚪兮? ¢13. ^ . j j ( N N N N N N N N 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 m 0 V. xzv S yn s τ·Η y/i J2 152524.doc -374- 201130854

.搫鹖兴驾矽锲虿砵^寸.w#s£夺碟戏柃 W 戥Q9I do^^u&lt;Ns^99rs¥iKi^:sz^ Analysis f material.:V - . UPLC_MS (ESI+): RT = 0.82 [M+H] + = 624. UPLC_MS (ESI+): RT=1.10 [M+H]+=6(H. A ':Must name.夂'丄.. 6-(2-Fluoro-3-methoxyphenyl)-8-[2 -fluoro-6-(trifluoromethyl)phenylhydrazino]-7-mercapto-3-({[3-(morpholin-4-yl)propyl]amino}indenyl)-2,3- Dihydro-5H-[1,3]thiazolo[3,2-a]Bt^-5-_ 6-(2-fluoro-3-methoxyphenyl)-8-[2- defeat-6- (Trifluoromethyl)benzyl]-7-fluorenyl-3-{[(2-mercaptophenyl)amino]methyl}-2,3-dihydro-5H-[1,3] Thiazolo[3,2-a]°rt^ding-5-ketone, knot 樽^ζχ / 0 1 ^ZZ g0 No. 5.166 5.167 is 152524.doc - 375 · 201130854 1 i UPLC-MS (ESI+): RT= 1.12 [M+H]+=622. UPLC_MS (ESI+): RT=0.97 [M+H]+=555. UPLC_MS (ESI+): RT=1.04 [M+H]+=567. 3-{[(3 -p-benzoyl)amino]mercapto}-6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7 -mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]a than bite-5-one 6-(2-fluoro-3-indolylphenyl)- 8-[2-Fluoro-6-(trifluoromethyl)phenylindenyl]-3-{[(2-hydroxyethyl X-yl)amino]methyl}-7-methyl-2,3- Dihydro-5H-[1,3]thiazolo[3,2-a]°pyridin-5-one 6-(2-fluoro-3-indolylphenyl)-8-[2-1-6 -(trifluoromethyl)benzyl]-7- 3-(morpholin-4-ylindenyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a] 〇定定-5-_ X 0 5.168 5.169 5.170 152524.doc •376- 201130854 UPLC_MS (ESI+): RT=1.14 [M+H]+=629. UPLC_MS (ESI+): RT=0.88 [M+H]+=648. UPLC_MS (ESI+): RT=1.15 [M+H]+=549. UPLC_MS (ESI+): RT=1.08 [M+H]+=617 〇6-(2-Fluoro-3-methoxyphenyl)-8-[2-^-6 -(Trifluoromethyl)phenylhydrazino]-7-mercapto-3-{[(4-phenylbutyl)amino]indolyl}-2,3-dihydro-5H-[1,3] Thiazolo[3,2-a]pyridin-5-one 3-(1,4·-bipiperidinyl-fluorenylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8_ [2_敦-6_(trifluoromethyl)benzyl]-7-fluorenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]a&°- 5-keto 6-(2-fluoro-3.methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-3-{[methyl (prop-2-yn-1-yl)amino]methyl}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]D ratio bite-5-one ^ ^ ^ ^ 死布,丨钐^ ά cA ^ 蚪S ci 7 ^ rA ^ ή ί 3 ^ Ϊ cA t ά it ^ &lt;N ^ ®~ 〇®~ XZ P 0 A 〇X ZZ &quot;9 Ov〇rt X 5.171 5.172 5.173 5.174 152524.doc -377- s 201130854 UPLC_MS (ESI+): RT=1.62 [ M+H]+=622. UPLC_MS (ESI+): RT = 1.11 [M+H]+=700. UPLC_MS (ESI+): RT = 0.82 [M+H]+=582. j 3-{[(4-Chlorophenyl)(indolyl)amino]methyl}-6-(2-helium-3-oxophenyl)-8-[2·fluoro-6-( Trifluoromethyl)benzylidene-7-indenyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-&amp;]° ratio °-5-keto 3-{ [4-(l,3-benzodioxol-5-ylindenyl)piperazin-1-yl]indolyl}-6-(2-fluoro-3-indolylphenyl) 8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine -5-keto 3-({[3-(dimethylamino)propyl)amino}indenyl)-6-(2-fluoro-3-indolyl)-8-[2-fluoro -6-(Trifluoromethyl)benzyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazino[3,2-a]°fc°--5- _ 々 Ο - Ο Z Z ΰ 0 5.175 5.176 i 5.177 1 152524.doc ·378· s 201130854 f 霈UPLC_MS (ESI+): RT=1.00 [M+H]+=680. UPLC_MS (ESI+): RT=1.07 [M+H]+=677. UPLC-MS (ESI+): Rt=1.04 [M+H]+=567. UPLC_MS (ESI+): RT=1.02 [M+H]+=602. '4 Today (N Issf ^ ώ ^ ^ 1 1 4 ^ s ί 5 ^ ^ cA ¢- ^ ^ d ^ ® ^ :B-一®· ^ Ή '-v-^ n^/ r^i 4 νό N ^ Hfif ^ U1 ^ ^ i,i安^ ^ «ί Ψ s ^ ^ i, ^ J ^ a ®~ 4銮 銮 ^ IX ^- cs硪 vi vi Vi Vi Vi CN S ^ tf, 5 1 5 S “ “钐1 ®- A r^fr^ 4瑷难ώ u ^ δ- 'Ί ^ ^ s ί s 3: - ^ 噼呤s , , 1 A 丰 i ^ ^ £1 S ^ ? 〇i ^ ^ ^ s 3 ') I 砩t: beads cA S- ¢^1 isk ^ cs do νό ®- n3 zz volume. z xz V VjCo- o;° ίΓ -&gt;〇 : zz zz oo in On gt—H 1—H 00 yr\ s 152524.doc -379- 201130854 UPLC—MS (ESI+): RT=1.04 [M+H]+=588. 1___ UPLC_MS (ESI+): RT= 1.47 [M+H]+=603. UPLC_MS (ESI+): RT=1.11 [M+H]+=622. 6-(2-1-3-decyloxyphenyl)-8-[2- gas-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(pyridine-2- Methyl)amino]mercapto}-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]n than bite-5-one 1_" _ beads h| m V ^ 4 £1 砩土1 〇〇iSf in ώ ^ ^ ^ X £ «Ubiquitous cA ®- Τ ^ ϊΐ ί: 钟钟地\〇®- ¢- 3-{[(2-chlorophenylindenyl)amino group ] mercapto}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3- Di-Il-5H-[1,3]thiazolo[3,2-a]° bite 5-ketone (5: ζύ 5.182 5.183 5.184 152524.doc -380· 201130854

UPLC-MS (ESI+): RT = 1.46 [M+H] + = 677 ° UPLC_MS (ESI+): RT = 1.16 [M+H]+=638. UPLC_MS (ESI+): RT=1.51 [M+H]+=591 ° rL·, 'S-Call 1 A cA ®- ώ tgs -蜍^ ^ 4-({6-(2-Fluoro-3-methoxy) Phenyl)-8-[2-fluoro-6-(trifluoromethyl) azainyl]-7-methyl-5-yloxy-2,3-dihydro-5-[1,3 Thiazolo[3,2-&amp;]pyridin-3-yl}methyl)piperazine-1-carboxylic acid ethyl ester 6-(2-fluoro-3-methoxyphenyl)-3-{[ (4-fluorophenyl)amino]methyl H-[2-fluoro-6-(trifluoromethyl)phenylindolyl]-7-methyl-2,3-dihydro-5H-[1,3 ] Thiazolo[3,2-3]° ratio -5-ketone sf* Λ&gt; ^ $. ( οη XZ 0 U. 5.185 \ 5.186 5.187 152524.doc -381 · 201130854 UPLC_MS (ESI+): RT=1.05 [M+H]+=579. UPLC_MS (ESI+): RT=1.05 [M+H]+=579 UPLC_MS (ESI+): RT = 0.97 [M+H] + = 608. 3-(azephhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh 8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]°tb °^-5-ketone^ &quot;7 CN n| ^ ώ SS ¥ ^ ^ (N ii~i ώ S 2 i 1 1 1-1 , 5 3 soil, Sip 砩3 rA ®- ^ d S 5 νό ¢ - ^ 2 ώ... V ?云绪^ ^ 5 ^ ώ Ϊ w ' ^ ^ « M n( cA —w of 0 P 〇n x&quot; vO $ 5.188 5.189 5.190 152524.doc -382- 201130854

UPLC_MS (ESI+): RT=1.07 [M+H]+=631 〇 UPLC_MS (ESI+): RT=1.01 [Μ+Η]+=535. UPLC_MS (ESI+): RT=1.12 [Μ+Η]+=613. $娜4^T^7砩纤7书&amp;· $ CL ^ A ^ »1 v &amp;- ^ ^ 'Z ^ : £ 硪川川 i 2 3 ' 1 5叟d 乂rA ώ ώ CN Α连Enough 1 ώ s ^ 1 U Η|Η 1 ΟΟ 1 ΜΗ l〇娜碥. Will ί4 &amp;- «1 X ^ r^ cA ? 竑Α 〇ί 3 °? +j^_ ¢- ^3⁄43⁄4 ^ ®- ^ d S \〇^t- Ψ it 2 _令安1 £ ¥ " 3 ^ ώ rA A, 孝士 W ? ^ ^ ^ ίΓ spider 'negative ^ ^ ^ ^ ri ^ \ 1 4 ®- ^ r*^ cA tfr^ \. Γ Ο (P Ον *—η ιη uS s »ri 152524. Doc -383 - s: 201130854

UPLC_MS (ESI+): RT = 1.44 [M+H]+=663. UPLC_MS (ESI+): RT=1.45 [Μ+Η]+=692 〇 UPLC_MS (ESI+): Rr=1.51 [Μ+Η]+=659. UPLC_MS (ESI+): RT=1.17 [M+H]+=636 〇^ ^ f, w\ ¢- ^ -1-: ^ 1 CL C. ^ »Λ °? T 'J ^ ^ S 2 1 4 i ^ s Alkali ^ $ rA S~ 筚B _ 5t two νό B~ λ ^ 3 巳蔘; meal ij ^ 5 ^ ^ 51 ®- P_ q ice | ... ί·4 v quot S S ® ®- ®~ ^ S S 5 ^ 5 错Y军旮1〇文七;(啮灭_巴tO kt^$ έ«|δ 3 1 ^1 a硪叩&amp;&gt; i ^ ά Φ 3 oath 5 s-enough' / -*-v ~l « Π, ^ ^ nr 绪1¥ ' S « Φ .1 | ffT 00 (O 1 1 C ri ? « 1 4 s :S ^ ^ T ®~砩&lt;A P-7 "χζ χζ ο ο ΧΖ ο ( οη 〇z ΟΝ Η home ι—&lt; OS 152524.doc -384· 201130854

UPLC-MS (ESI+): RT = 1.37 [M+H]+=641. UPLC-MS (ESI+): RT = 0.84 [M+H]+=622. UPLC_MS (ESI+): RT=1.08 [M+H]+=607. 6-(2-Fluoro-3-indolylphenyl)-8-[2- gas-6-(trifluoromethyl)phenylindolyl]-7-indolyl-3-( {[3-( 1 Η-tetrazol-5-yl)phenyl]amino}indenyl)-2,3-dihydro-511-[1,3] °···Sitting and [3,2-a]0 is determined by 0 -5-keto 6-(2-a-3-methoxyphenyl)-8-[2-say-6-(trifluoromethyl)benzyl]-7-methyl-3-({[ 3-(piperidin-1-yl)propyl]amino}mercapto)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]° ratio to 5-ketone 6-(2-Fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-indolyl-3-({[2-(thiophene) -2-yl)ethyl]amino}methyl)-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a]°it°-5-keto r “Strict: ΧΖ NO ΧΖ 5.198 5.199 5.200 152524.doc -385 - 201130854 UPLC MS(ESI+): RT=1.03 — , [M+H]+=594 〇UPLC—MS (ESI+): RT=1.03 [M+H]+= 594. UPLC_MS (ESI+): RT=0.96 [M+H]+=609. ^ Ί ^ VO V ^ ^ ^ t '1 ^ ri, 4 Λ ^ 4 Q ι-ί-1 L ®-硪越妒rA ®- ^ ^ i4 ^ xs M 2 \〇ID~ s- rA 1 Zhu a X B- Q crocodile V匾硪ul EC «Λ &amp;- V 7, ώ « 3 1 £ rH », 1 «J ^ ώ ^ S i ά ^ ^ φ 2 5 m ^ ^ ψ ί '.' 1 νό f , Λ ' Φ 5 ± &lt; Ν £± ^ 4 X ^ ? « 5懋S Ϊ叟ϊ 减 minus seven.*w ^ ^ 3 ^ ^ ^ 5 ώ 4 ®~ with 13⁄4 ΖΖ , (ί p x&quot; 0 L an &lt;N in S &lt;NS (Ν in 152524.doc - 386- 201130854

UPLC_MS (ESI+): RT = 1.07 [M+H]+= 679. UPLC_MS (ESI+): RT=1.12 [M+H]+=615. UPLC-MS (ESI+): RT=0.84 [M+H]+=637 〇3-{[bis(.pyridin-2-ylindenyl)amino]]yl}-6-(2-fluoro-3 -decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoyl]-7-methyl-2,3-dihydro-5H-[1,3]thiazolocarb | ;3,2-a]pyridin-5-one 6-(2-fluoro-3-indolyl)-8-[2-1-6-(trifluoromethyl)benzoinyl]-7- Mercapto-3-{[(2-phenylpropan-2-yl)amino]indolyl}-2,3-dihydro-5H-[1,3]thiazolo[3,24]° ratio -5-keto 3-({4_[2-(didecylamino)ethyl]piperazine-l-yl} fluorenyl)-6-(2-fluoro-3-methoxyphenyl)-8 -Ρ-fluoro-6-(trifluoromethyl)benzoinyl]-7-mercapto-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a]acridine-5 -ketone oxime 0 S 〇-zu X&quot; £ 5.204 5.205 5.206 152524.doc .387· 201130854 UPLC_MS (ESI+): RT=0.87 [M+H]+=679. UPLC_MS (ESI+): RT=1.17 [M+H]+=663. UPLC_MS (ESI+): RT=1.20 [M+H]+=667. 6-(2-Oxo-3-methoxyphenyl)-8-[2-say-6-(trifluoromethyl)benzoinyl]-7-mercapto-3-({4-[2- (morpholin-4-yl)ethyl]piperazine-l-yl}methyl)-2,3-dihydro-5H-[1,3] stagnation and [3,2-8]° ratio °定-5-ketone^^ ter-1 ΜΗ 1 &lt;41 ^ ^ ^ ^ ^ ^智I φ £ t8^ As (N CN 寸械&amp;~ $4砩A 香|fi=i B-丫rA ®~ CO 4-[4-({6·(2-Fluoro-3-methoxyphenyl)-8-[2_fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- Sideoxy-2,3-dihydro-5^1-[1,3]thiazolo[3,24].pyridin-3-yl}pinyl)piperazin-1-yl]benzonitrile 0 S 0 ^Gs ^ 5.207 5.208 5.209 152524.doc - 388 - 201130854

UPLC—MS (ESI+): RT=1.03 [M+H]+=651 〇 UPLC—MS (ESI+): RT=0.85 [Μ+Η]+=663. UPLC_MS (ESI+): RT = 0.98 [M+H]+= 619. UPLC_MS (ESI+): RT=1.00 [M+H]+=639. 4 $涂膳f « s « cA 3 — 15 μ ? 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-mercapto-3-({4-[2-(pyrrolidin-1-yl)ethyl]pyrhyl-1-yl}methyl)-2,3-diaza_ 5Η·[1,3 ]thiazolo[3,2-a]acridin-5-one^ 1 1 ul硇A匾s ten ί SA s lost 5 ^ E 5 mechanical ®~硇3 ^ t ®-inch d *?, +4 - Fi K d«15 Ό i—' “Mechanical 1 w ^ 蛉—Ψ Ψ ^ ^ '1 ^ έΐ ? I 213⁄43⁄4 ^ 5 5 4 _ 1~1 03⁄4 0 V 0 S 0 xz xz u Q ο 1—Η ( Ν CN CN CN 152524.doc •389· 201130854 UPLC_MS (ESI+): RT=1.02 [M+H]+=603 - UPLC_MS (ESI+): RT=l.〇3 [M+H]+=624. UPLC —MS (ESI+): RT=0.99 [M+H]+= 605. 6-(2·fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylhydrazine 7-mercapto-3-({[(5-fluorenyl)-p--2-yl)indolyl]amino}methyl)-2,3·dihydro-511-[1,3]嗔D sits and [3,2-a] ° ratio °-5-ketone 4 Ψ f ϊ t it i 4 ^ iiv ^ ί «λ T ¢- ^ 3 6-(2-fluoro-3-methoxy -8-[2-1-6-(trifluoromethyl)phenylhydrazino]-7-methyl-3-({mercapto[(1-methyl-1H-pyrazole-4-) Methyl]amino}methyl)-2,3-dihydro-5H-[1,3]° plug 0 sit and [3,2-a]°fc bite-5- f 5.214 1 |! 5.215 1__ 5.216 152524.doc • 390- 201130854

UPLC_MS (ESI+): RT=1.10 [M+H]+=601. UPLC_MS (ESI+): RT = 1.12 [M+H]+= 615. UPLC_MS (ESI+): RT = 1.15 [M+H]+=658. 6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl-3-{[(3-indolyl) Benzyl)amino]mercapto}-2,3-dihydro-5H-[1,3]thiazolo[352-3]αΛ°^-5-self with ^ Z &amp; ^ ψ ^ « 5 S Fn〇a, 3 ώ &lt;4 ^ &gt;7 3-({phenylmethyl[2-(didecylamino)ethyl]amino}methyl)-6-(2-fluoro-3-A Oxyphenyl)-8-P-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2 -a] ° pyridine-5-one XZ 〇rt Irt z 6 0 ^ 5.217 5.218 5.219 152524.doc 391 201130854 UPLC_MS (ESI+): RT=1.00 [M+H]+=624. UPLC_MS (ESI+): RT = 1.20 [M+H]+=658. UPLC_MS (ESI+): RT = 0.82 [M+H]+=605. 6-(2-Fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-3-[(isoquinolin-5-ylamino) Mercapto]-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]n than bite-5-_ ! 6-(2-fluoro-3-indole Oxyphenyl)-8-[2-mer-6-(trifluoromethyl)benzyl]-7-methyl-3-({[4-(morpholin-4-yl)phenyl)] Amino}methyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]acridin-5-one 6-(2-fluoro-3-methoxyphenyl )-8_[2_gas-6-(trifluoromethyl)benzyl]-3-({[3·(1Η-imidazol-1-yl)propyl]amino}indenyl)-7-oxime Base-2,3-dihydro-5Η-[1,3]°°°[3,2-玨]° ratio biting 5-ketone XZ XX 0 XZ ,Cr 5.220 5.221 5.222 152524.doc -392 201130854

UPLC-MS (ESI+): RT = 1.10 [M+H]+=647. UPLC-MS (ESI+): RT = 1.07 [M+H]+=608. UPLC_MS (ESI+): RT=1.02 [M+H]+=624. Ψ ^ ^ f ^'1 v 5 ^ ^ i _ heart iA 5 ^ 'J ^ X ^ 5 Λ ? ^ f ^ minus _ core 'J &amp;- β ιή cA S- 5: d ^ 3-[ (4-Ethylpiperazin-1-yl)methyl]-6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzamide -7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-3]° ratio to 5-keto 6-(2-fluoro-3-methoxy Phenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-4-ylamino)indolyl]-7-methyl-2,3 - dihydro-5H-[1,3]thiazolo[3,2-a]&lt;U°定-5-ketone fine χ£ r^〇ΧΛ ύ&quot; I* 0 &amp; 5.223 5.224 5.225 152524.doc - 393 · 201130854 UPLC_MS (ESI+): RT=1.13 [M+H]+=670. UPLC_MS (ESI+): RT = 1.15 [M+H]+= 669. UPLC_MS (ESI+): RT = 0.82 [M+H]+=596. UPLC_MS (ESI+): RT = 1.43 [M+H]+=630. ^ 〇cn* ¥ v ^ 5 1 mq S 4 λCloud B- «Ν rp ¢- ilL ί ^ ^ $ ^ ^ ts ®~ do ^ ®- K w\ ^ V ^ Ά f{ E cn i (N &lt ;N &lt;N ^ V ^ A fork 5 _旮*ιώ ®Γ &lt;N 灭v 2 but cA S- ^ d ^ ίέ νό ¢-办 4 B- ^ 5 ^ ^ ^ ϋ 锘 "alkaline a ΛΪ g «s ^ T\ti^ V &lt;7 ^ ^ HX d S d SG &amp; · Enough 1 «Is ^ ^ § v 'J ^ 2 A if 7 ί4 a, rA ®-w rn B- &lt;~ή Destroy 0 «»&gt; XZ XZ zo o: Irt CN (N uS 00 CN iri

152524.doc -394- s 201130854

UPLC_MS (ESI+): RT = 1.17 [M+H]+=656. UPLC_MS (ESI+): RT = 1.11 [M+H]+=617. UPLC_MS (ESI+): RT = 0.93 [M+H]. CN ? ' s /-Λ-, ΓΠ ^ \i| £ s 'S ^ 5 Meng S 1 士 ^ cA £ ®-七 K ? ^ ^ g_ ^ Μ ^ J ^ A alkali seven SJ ^ cA i*^· ^ 〇5 i ^ 2 ^s '哿S ώ S ii • '-W 1/^ 1 OO i i1 i〇* 3 ^ iii (N ί S ϊ ώ —5 ί ^ A硪锲^ ^ 4 6-( 2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(tridecyl)phenylhydrazino]-7-methyl-3-({mercapto[2-(〇比咬-- 3-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1,3]° sputum and [3,2-a]° ratio biting 5-ketone a xz S〇 O 〇R *〇(Ν

S 152524.doc -395 - 201130854 UPLC-MS (ESI+): RT=1.11 [M+H]+=630 〇 UPLC-MS (ESI+): RT=1.35 [M+H]+=666. Inch 1-H i. £g dn P 5 ^ ^ ^ 4 v 5 ^ ^ V N-{4-[({6-(2-Fluoro-3-decyloxyphenyl)-8-[2-|L- 6-(three Fluorinyl)benzyl]-7-indolyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]&quot;bipyridine-3- Amino]phenyl]methanesulfonamide 6-(2-a-3-methoxyphenyl)-8-[2-fluoro-6-(tris-decyl)benzyl] -7-Methyl-3-{[4-(thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl]indolyl}-2,3-dihydro-5H-[1 , 3] thiazolo[3,2-a]. Bipyridin-5-one ZZ or. 0 z6^ 5.233 5.234 _ 5.235 152524.doc 396- 201130854

UPLC_MS (ESI+): RT = 1.13 [M+H]+=686. UPLC-MS (ESI+): RT = 1.23 [M+H]+= 670. UPLC_MS (ESI+): RT=1.04 [M+H]+=637 〇 UPLC_MS (ESI+): Rt=1.14 [M+H]+=698. 3 V 21 Μ ώ °? -r γΛ i ^ ^ t 3 5 ΐ ^ 1 3 S 'Ί ^ ^ ί 1 ^ ί S3 | 士,丨妇 rl f +4 ¢- 〇r ^ 硪A 士A A硇Bayu-do &amp;-flavor rA ®; 3 _ Jt — 4 νό ®~ Lu? City 7 Pei Φ ¥丢t ^ ^!ϊ T1 5 ^ 5 | :a 命命®- ¢- ^} ; V 1 CL &amp; Alkali Butterfly ^ ^ ϊ 1 ®~ ^ ^ ^ a 2 ί ? jt § ssia S_ ail - cA ¢- w 0 S Ό 0 °&quot;o £ zz \〇s 〇〇On A s 152524.doc -397- 201130854

UPLC_MS (ESI+): RT = 1.07 [M+H]+=663 - UPLC_MS (ESI+): RT = 1.13 [M+H]+=615. UPLC_MS (ESI+): RT=1.12 [M+H]+=630. UPLC_MS (ESI+): RT = 0.98 [M+H]+= 588. Ul ^. ^ ^ ^ I ‘Art, _i ^ s cA ®- i S ®~砩 ^械 $ 砩: £ ^ ffi 5 无 乂 s t 硪. ®巴rA ®~芰蝌^ ^ S ®~砩S ^ ®- 4 i 5 1 | „ » Φ ',' S ^ 5 ^ i « 5 ^ ή ^ ^ ^ m s- f' 7Γ rA ¢- ¥ v ^ i4 S: d ^ X ^ ® - gas inch s 'Ί ^ 2 ^ fsi rn ^ 二ώ ώ ^ ώ 丫 a itH 嚆rf ” A Φ- '~' rA ^ ▲ ϊί 4 &amp;硪锲vi ® ~ Shouting 13⁄4 % xz ]pt set to o &lt;N iri &lt;N in &lt;N 152524.doc -398- 201130854

UPLC_MS (ESI+): Rr=1.02 [M+H]+=624. UPLC-MS (ESI+): RT = 1.52 [M+H]+=698. UPLC_MS (ESI+): RT=1.47 [M+H]+=644. 6-(2-Gas-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-3-[(isoquinolin-8-ylamino) Methyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]°it°-5-keto 4-({6-(2-fluoro) 3-methoxyphenyl)-8-[2- gas-6-(trifluoromethyl)phenylhydrazinyl]-7-methyl-5-yloxy-2,3-dihydro-5H- [1,3]thiazolo[3,2-a]pyridin-3-yl}indolyl-1-(2-phenylethyl)piperazine-2,6-dione 6-(2-fluoro- 3-decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylhydrazino]-7-methyl-3-{[(2-mercapto-1,3-benzo) Thiazol-5-yl)amino]mercapto}-2,3-dihydro-5H-[1,3] °°°[3,2-a] ° ratio is determined to be 5-ketooxime. 0 5.244 5.245 5.246 1_ 152524.doc -399- 201130854 UPLC_MS (ESI+): RT=1.11 [M+H]+=727. UPLC_MS (ESI+): RT=1.01 [M+H]+=591. UPLC-MS (ESI+): RT = 1.02 [M+H]+=605. 2-[4-({6-(2-Fluoro-3-decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenyl)]-7-fluorenyl-5- Sideoxy-2,3-di-aryl-511-[1,3]thiazolo[3,2-&amp;]pyridin-3-yl}indolyl)piperazin-1-yl]-N-(2- Stupidylethyl)ethyl siamine 6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylhydrazino]-7-methyl-3 -({[(l-fluorenyl-1H-pyrazol-5-yl)methyl]amino}indolyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2- a]»Bipyridin-5-one 1 ................ —1 1 1 6-(2-Fluoro-3-decyloxyphenyl)-8-[2 -fluoro-6-(trifluoromethyl)phenylhydrazino]-7-mercapto-3-({mercapto[(1-indolyl-1H-pyrazol-3-yl)methyl]amino}曱Base)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]acridin-5-one v° \) Li!&gt; / X 5.247 5.248 5.249 152524.doc -400 - 201130854

UPLC-MS (ESI+): RT = 0.98 [M+H]+=577. UPLC_MS (ESI+): RT = 1.14 [M+H]+=684. UPLC_MS (ESI+): RT = 0.82 [M+H]+=623. UPLC-MS (ESI+): RT = 1.09 [M+H]+= 681. 6-(2-Fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trihydroindolyl)benzyl]-7-methyl-3-{[(1Η-» ratio Zyridin-3-ylmethyl)amino]mercapto}-2,3-dihydro-5H-[1,3]thiazolo[3,24]°*β定-5-ketone^ffi ' Φ sf Φέ m S 机械 ® - ί s ? $ s ^ i ^ ^ i 6-(2-Fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl) alum ]-7-Methyl-3-({[2-(4-methylpiperazin-1-yl)ethyl]amino}indenyl)-2,3-dihydro-5H-[1,3] °Sample α sits and [3,2-a] °A ° determinate 5-keto 3-{[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2- gas -6-(trifluoromethyl)phenylhydrazino]-7-mercapto-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]-pyr Acridine-3-yl}methyl)° bottom 噃-buki]methyl}benzonitrile cf Z 0 ' ZZ 〇0 VZ 5.250 5.251 5.252 5.253

S 152524.doc •401 - 201130854 UPLC_MS (ESI+): RT=1.12 [M+H]+=661 〇UPLC_MS (ESI+): RT=1.12 [M+H]+=615 〇UPLC—MS (ESI+): RT =0.96 [M+H]+=575. 3-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro -6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one "Mechanical 5 ^ 苫® ώ ^ CS Λ « d ΐ χ 乂 S 3 碥 A Order $4 ® - ά ά ΐ ί ^ 6-(2-Fluoro-3-decyloxyphenyl)-8-[2-Fluorine 6-(Trifluoromethyl)phenylhydrazino]-7-methyl-3-[(健嗓-3-ylamino)methyl]·2,3-dihydro-5Η·[1,3]thiazole And [3,2_ a]11 than bite-5_ketone zz ΧΖ 0 5.254 5.255 5.256 152524.doc •402· 201130854

UPLC_MS (ESI+): RT = 1.06 [M+H]+=593. UPLC_MS (ESI+): RT = 0.92 [M+H]+=671. UPLC_MS (ESI+): RT=1.28 [M+H]+=718 » ^ ¢-^ ^ t ^ Φ 2- 1 〇ό T ^ Ά 3 2 ί &amp; 1 — ^ ^ i-1 /^T' f ~r\ ¢-纳诺1~1 rA ®- ^ ^ 地士砩铝^ ®- s 丨,丨涂2 I (Factory J &lt;1 i ^ S ^ ^ 1 X ^ ^ ^ ¢4 ®- &lt;; N ^ 5 t S d ^ νό &amp;-do d 寺 ό ό - - - - aff aff aff aff aff aff aff aff aff aff aff aff aff aff aff aff aff aff aff aff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ff ; 0 0 0 卜 to CN in 00 (S in OS in 152524.doc -403 - 201130854 UPLC_MS (ESI+): RT=1.05 [M+H]+=638. UPLC_MS (ESI+): RT=0.98 [M+H ]+=657 » UPLC_MS (ESI+): RT=0.87 [M+H]+=677 » UPLC-MS (ESI+): R corpse 0.87 [M+H]+=677. ^ ^ 4 s盂5 圮,nr A ^ \\ V ώ ^ cA ^ ^ cA c/ ^ 砩cA ^巴四士二·味cA ®7 ®- ^ ^ ^ Ψ ^ Φ^Ι . ^ ^ ψ ^ »1 ^ Φ Φ 5 1 ^ ^ ^ S iiSif Γ-ϊ-ι ri 砩▲咿cA ^ ^ ^ -d ^ s ^ ®- 碱鲁,丨^1 ^ cA f ^ ^ i 5 &lt;n 4 δ- s 5 ^ 11 ^ &gt;7 Ϊ, f S ^ ?n :r ^ 5 ^ ' 5t 呤S CN ^ Λ ^ vi ®- ^ 谠杳,丨A do rA f ^ ^ rf VA 4 ®-man t ? ^ ^ 3 rf mechanical! f S 5 ^ Ξ: ^ 5 ^ Φ ί 5 ^ 0 \ o on jT 0 b 0 b ow of 13⁄4 0 b S in S (N xn s (N &lt;n 152524.doc •404- 201130854

UPLC_MS (ESI+): RT = 1.21 [M+H]+= 710. UPLC_MS (ESI+): RT = 0.98 [M+H]+=591. UPLC_MS (ESI+): Rt-1.17 [M+H]+=651 = 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylhydrazine -7-methyl-3-({4-[2-(trifluoromethyl)phenyl]piperazine-l-yl}indenyl)-2,3-dihydro-511-[1,3 ° ° plug 11 and [3,2-a] ° ratio of 5-ketone 6-(2-a-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoroanthracene) Benzophenyl]-7-fluorenyl-3-({[(l-fluorenyl-1H-«pyrazol-4-yl)indolyl]amino}indenyl)-2,3-dihydro- 5H-[1,3]thiazolo[3,2-a]&quot;bipyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2·Ί6-(trifluoro 1 methyl)phenylhydrazino]_7_mercapto-3-{[methyl(naphthalen-2-ylindenyl)amino]indenyl}-2,3-dihydro-5H-[1,3]thiazole And [3,2-a]D is more than bite -5-S with 13⁄4 .0 5.264 5.265 5.266 s 152524.doc -405- 201130854 UPLC_MS (ESI+): RT=1.03 [M+H]+=663 ° L —— ————— II accounted for. 00 00 £ s 〇 UPLC_MS (ESI+): RT=0.96 [M+H]+=651.械 ¥ ? v ^ ^ ί T ί S ^ ^ ^ ^ ^ ^ ^ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ ⁄ 6-(Trifluoromethyl)phenylhydrazino]-7-fluorenyl-3-({mercapto[2-(indolyl-1-yl)ethyl]amino}methyl)-2,3- Dihydro-5H-[1,3]° sputum and [3,2-a]° ratio biting 5-keto 3-({[2_(4-ethinylpipen-1-yl)ethyl] Amino} fluorenyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl-2, 3-Dihydro-511-[1,3]嗟°[3,2-3]° ratio biting 5-ketone 13⁄4 0 v° Izv if* r〇« . 0 ZZ S % 5.267 5.268 5.269 152524. Doc -406· 201130854

UPLC_MS (ESI+): RT=1.01 [M+H]+=644. UPLC_MS (ESI+): RT=1.17 [M+H]+=636. N-(3-{[({6-(2-Fluoro-3-decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl))]-yl-- 5-Phenoxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}indenyl)amino]methyl}phenyl)acetamide 6-(2-Den-3-methoxyphenyl)·8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl-3-({methyl[2- (4-mercaptopiperidin-1-yl)ethyl]amino}mercapto)-2,3-dihydro-511-[1,3]thiazoloindole,24]acridin-5-one 13⁄4 AX 5.270 5.271 s 152524.doc 407· 201130854 Example 5.272 Preparation of 8-(2,6-difluoro-benzoinyl)_6_iodo_7-methyl_3-{[methyl·(2·pyridine-2-yl)- Ethyl)-amino]-methyl}_2,3-dihydro-thiazolo[3,2-a]n ratio bite-5__

Modified according to GP 8: N-iodobutylimine (410 mg, 1.97 mmol, 2.5 equivalents) was added to 8-(2,6-difluoro-benzyl) at room temperature 7-Methyl-3-{[indenyl-(2_.Bis-2-yl-ethyl)-amino]-indenyl}_2,3-dihydro-thiazolo[3,2-a]pyridine- 5-ketone (Intermediate Q_1) (331 mg, 〇·75 mmol) in a stirred solution of acetic acid (3 mL) and TFA (120 μm). After the LCMS indicated that the starting material was completely consumed, the mixture was partitioned between DCM and aqueous sodium thiosulfate. The aqueous layer was extracted with DCM and the combined organic layer was washed with sodium bicarbonate, dried over sodium sulfate and evaporated concentrate. The title compound was isolated by flash column chromatography (yield: 340 mg). *H-NMR (CDC13, 300 MHz): 2.36 (s, 3H); 2.39 (s, 3H); 2.50-2.58 (m, 1H); 2.71-2.80 (m, 2H); 2.86-3.01 (m, 3H) AB signal (3 VIII = 3.84, 58 = 3.97, 2 &gt;111); 5.11-5.21 (111, 111); 6.85 - 6.97 (m, 2H); 7.18-7.38 (m, 3H); 7.68- 7.78 (m, 1H); 8.38-8.44 (m, 1H). UPLC-MS (ESI+): [M+H]+=568. Example 5.273 152524.doc -408 - 201130854 Preparation of 6-(3- gas-phenyl)-8-(2,6-difluoro-anthracene)_7-fluorenyl [methyl_(2-° ratio bite- 2-yl-ethyl)-amino]-methyl}-2,3-dihydro-indole[3,2_&]0 is more than 唆-5-

CI

According to the modified form of GP 10a: 3 气 酉 酉 酉 ( ( (55.1 mg, 0.36 mmol, 2.0 eq.) and potassium carbonate aqueous solution (39 mg '0.28 mmol, 1.6 eq, 1 at room temperature) , 5 M) added to 8-(2,6-difluoro-phenylhydrazino)-6-iodo-7-methyl-3-{[indenyl-(2-pyridin-2-yl-ethyl)_ Amino]•methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (Example 5.272) (100 mg '0.18 mmol) in dioxane (2 mL) In the solution. An argon gas was then bubbled through the reaction mixture for 1 minute, followed by the addition of di- bis(diphenylphosphino)ferrocene)palladium-dichloromethane complex (16 8 mg, 〇〇 2 mm (&gt;i) The reaction mixture was heated to 130 C ' in a Biotage initiator microwave oven for 60 minutes. The TLC analysis showed complete conversion. The mixture was filtered over celite® pad and washed with DCM. The organic phase was washed with water and dried over sodium sulfate. The solvent was evaporated and subjected to flash column chromatography to give the title compound (yield: 17 mg). H-NMR (methanol-d4, 4 〇〇MHz): ! 93 (s, 3H); 2 42 (s, 3H) 2.61-2.69 (m, 1H); 2.77-3.01 (m, 4H); 3.42-3.51 (m, 1H); AB signal (δΑ=3.81, δΒ=3.94, 2xlH); 5.14-5.22 (m, 1H) 6.89- 152524.doc -409- 201130854 6.97 (m, 2H); 7.02-7.06 (m, 1H); 7.13-7.16 (m, 1H); 7.20- 7.39 (m, 6H); 7.68-7.76 (m , 1H); 8.36-8.42 (m, 1H) MS (CI+): M+ = 552 / 554 (C1 isotope form). Table 26: Example 5.274 below was prepared in a similar manner to Example 5.273 and GP 10a is self-contained. 5.272 and 1,3-benzodioxole _5_ base Acid Off Start Number Structure Name Analysis Data 6-Benzo[1,3]dioxol-5-yl-8-(2,6-difluoro-m-methyl)-7-fluorenyl- 'H-NMR (methanol-d4,400 MHz): 1.91 (s,3H); 2,37 (s,3H); 2.52-2.60 (m, 1H); 2.69-2.80 (m, 2H); 2.85-2.98 (m, 3H); 3·37-3·45 (m,1H); AB signal 5.274 CH* 3-{[methyl-(2-. than $-2-yl-ethyl)-amino] A }}-2,3-dihydro-and p,2-a] ° than pyridine-5-one (δΑ=3·77, δΒ=3·90, 2χ1Η); 5.09-5.18 (m, 1H); 5.91 (s, 2H); 6.49-6.55 (m, 1H); 6.55-6.60 (m, 1H); 6.76-6.83 (m, 1H); 6.85-6.95 (m, 2H); 7.17-7.36 (m, 3H) 7.66-7.74 (m, 1H); 8.36-8.42 (m,1H) « MS (CI+): [M+H]+=562. Example 6.la and 6.1b Preparation of 3-(Amino-phenyl-methyl)-8·(2,6-difluoro-phenylindenyl)-6-(2-fluoro-3-indolyl--- ))-7-methyl-2,3-dihydro-D-disindol [3,2_a]B is more than 唆·5· 1 (diastereomers 1 and 2) 152524.doc -410. 201130854

Slowly add the rotten hydrogenation chain (1.79 4_8 equivalents) according to the modified form of GP 23a: in hydrazine. Underarm, mL, 2 Μ solution in THF, 3.58 mm 〇1,

To a stirred solution of vaporized titanium (IV) (196 pL, 1.79 mmol, 2.4 eq.) in ι, 2 - dioxane (4 mL). After 1 min, 8·(2,6-difluoro-benzyl)6 (2fluoro-6-nonyloxy-phenyl)-3 was added to dimethoxyethane (4 mL). -(hydroxyimino-p-styl-methyl)_7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (400 mg, 0.75 mmol) (Example 3.1) And hey. Continue to stir for 1 hour. The reaction mixture was allowed to warm to room temperature over 3 hours and was dropped until TLC indicated the starting material was completely consumed. Cool to 〇. After the hydrazine, the reaction was quenched by the addition of water and aqueous ammonia (33% by weight). After stirring for 2 minutes, the mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The target compound (14 7 m g and 83 mg) was isolated by flash column chromatography. Diastereomer 1 (Example 6.1a): ^-NMR (nonanol-d4, 300 MHz): 1_91 (d, 3H); 3.38-3.63 (m, 2H); 3.76-4.00 (m, 5H) 4.62 (d, 0.5H*); 4.72 (d, 0.5H*); 5.27-5.38 (m, 1H); 6.46-6.53 (m, 0.5H*); 6.64-6.71 (m, 〇.5H*) ; 6.88-7.41 (m, 11H). 152524.doc -411 · 201130854 UPLC-MS (ESI+): [M+H]+=523. For palmar HPLC (Chiralpak IC 5 μιη 150 x 4.6 mm; hexanol/ethanol 50: 50 + 0.1% diethylamine; 1.0 ml/min): Enantiomer 1: Ruler 1 = 6.20 minutes and 14.57 minutes ( Two peaks were generated due to dynamic hemitropy. Enantiomer 2: RT = 0.66 min and 11.17 min (two peaks due to dynamic hemitropy) Diastereomer 2 (Example 6.1 b): W-NMR (methanol-d4, 300 MHz): 2.00 (s, 3H); 3.47-3.63 (m, 2H); 3.63-3.76 (m, 2H); 3.86-3.93 (m, 3H); 4.56 (d, 0.5H*); 4.61 (d, 0.5H*); 5.32-5.41 (m, 1H); 6.69-6.76 (m, 0.5H*); 6.80-6.92 (m, 2.5H*); 7.01- 7.33 (m, 9H). UPLC-MS (ESI+): [M+H]+=523.莩HPLC (Chiralpak IC 5 μιη 150×4.6 mm; hexane/ethanol 50: 50 + 0.1% diethylamine; io ml/min): enantiomer 1:1^=7.44 min and 8.74 min ( Two peaks were generated due to dynamic hemitropy. Enantiomer 2: RT = 11.42 min and 13.91 min (two peaks due to dynamic hemitropy) 152524.doc •412· 201130854

^3·ε ί4 驷ίκ?^·ίπΙ5(ΝίΙΟ Έ&quot;离&gt; 铋^w^w 荽黩ql.9^二.9 ί#ίκ^^εΓ9^3.9¥_κ-^:ζ,ζ^ 152524 .doc v 'y , meal ' • - ΐ··· ..--)&gt; · h-NMR (methanol-d4, 300 MHz): 1.92 (d, 3H); 3.41-3.51 (m, 1H); 3.54-3.68 (m, 1H); 3.73-4.01 (m, 5H); 4.56 (d, 0.5H*); 4.62 (d, 0.5H*); 5.32-5.37 (m, 1H); 6.43-6.51 (m , 0.5H*); 6.62-6.70 (m, 0.5H*); 6.80-7.37 (m, 1 OH). MS (CI+): [M+H]+=54, h-NMR (methanol-d4, 400 MHz): 2.01 (s,3H); 3.36-3.58 (m,2H); 3.59-3.75 (m, 2H) 3.87-3.93 (m, 3H); 4.61 (d, 0.5H*); 4.66 (d, 0.5H*); 5.31-5.37 (m, 1H); 6.70-7.27 (m, 11H). MS (CI+): [M+H]+=541. Ί ^ S ¥ A «Λ S 3 1 S 修言 袁4 ^ ^ ϊ 1 '1 S Mb 娜,®- ·±2观4 ^ « 2 SV "You are lonely, 丨嘁岢A d ^ ^ , ' , * * Structure u. LL No. 6.2a 6.2b 1 1 -413- 201130854 H-NMR (sterol-d4, 300 MHz): 1.91 (d, 3H); 3.40-3.65 (m, 2H); 3.71- 3.79 (m, 3H); 3.81-4.02 (m, 5H); 4.53 (d, 0.5H*); 4.62 (d, 0.5H*); 5.22-5.35 (m, 1H); 6.44-6.52 (m, 0.5 H6); 6.63-6.71 (m, 0.5H*); 6.76-6.84 (m, 2H); 6.86-7.01 (m, 2H); 7.02-7.13 (m, 2H); 7.15-7.37 (m, 3H) MS (CI+): [M+H]+= 554. h-NMR (methanol - £14,4001^1^): 1.99 (4 3 imprints; 3.37 ((1 £1, 0.511*); 3.51-3.60 (m, 1H); 3.65-3.80 (m, 5.5^); 3.86-3.92 (m, 3H); 4.56 (d, 0.5H*); 4.60 (d, 0.5H*); 5.33-5.41 (m, 1H) 6.62-7.29 (m,11H) MS (CI+): [M+H]+= 554. H-NMR (methanol-d4, 300 MHz): 1.90 (d,3H); 3.42-3.57 (m, 1H); 3.57-3.70 (m, 1H); 3.75-4.01 (m, 5H); 4.58 (d, 0.5H*); 4.67 (d, 0.5H*); 5.25-5.37 (m, 1H); 6.36- 6.45 (m, 0.5H*); 6.60-6.68 (m, 0.5H*); 6.87-7.46 (m, 10H) MS (CI+): [M+H]+=607. 3-[Amino-( 4-methoxy-phenyl)-methyl]-8-( 2,6-difluoro-benzyl)-6-(2-fluoror3-decyloxy-phenyl)-7-fluorenyl-2,3-dihydrocarbazino[3,2-a]° 00-ketone (diastereomer 1) V 4 ^ § « 善 善 a ^ SA Ϊ ^ "爷 s when ^ cS ^ ^ E _,, 丨 1 A ^ s ^ s ^ ώ ^ 埏 $埏味键碱_ A 蜱 蜱 乂ί 2 Box ^ Γ^-ι ^ cn ^ 迤难 A ... Ϊ 1 °'〇I&quot; r % V; m 2 vd 152524.doc -414- 201130854

h-NMR (methanol-d4, 400 MHz): 1.99 (s,3H); 3.37-3.80 (m, 4H); 3.86-3.94 (m, 3H); 4.65 (d, 0.5H*); 4.71 (d, 0.5H*); 5.33-5.40 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.80-6.90 (m, 2.5H*); 7.01-7.30 (m, 7H). MS (CI+): [M+H]+=607. [H-NMR (sterol-d4, 300 MHz): 1.24-1.29 (m, 3H); 1.49 (s, 3H); 1.96 (d, 3H); 3.81-4.00 (m, 5H); 4.40 (d, 1H); 5.30 (dd, 1H); 6.69-6.82 (m, 1H); 6.89-7.00 (m, 2H); 7.04-7.18 (m, 2H); 7.23-7.41 (m, 4H); 7.48-7.55 ( m, 2H). UPLC-MS (ESI+): [M+H]+=551. 3-[Amino-(4-trimethylsulfonyloxy-phenyl)-indenyl]-8-(2,6-di-n-benzyl)-6-(2-fail-3-methoxy - stupid base)_ 7-mercapto-2,3-dihydroxy-thiazolo[3,2-a] «pyridin-5-one (diastereomer 2) ^ \\ ^ w s- cA ιΛ rA ^ 娜七宇¢- (N ^ 崎" 3 5 4 ¢- ^ ^ g i4 3 f 'arm r V; & £ 6.4b so s 152524.doc -415- 201130854 (#^vfwi&quot; Learn €^«8! 蜱讳嫠 蜱讳嫠 矣 ) ) ) 御 御 御 御 御 御 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;鮏o/^to: letter 9·inch έςι siloS 刍CL, lBJ3u)crwH±i^^os=+w:(+m)ss .(ΗΟΓε) Ι97--ιο.^(*ΙΚΌ ~ε)&lt; Ν布·9-99.9rHSo*s) 9S.9 丨0S.9 ί(Η„ε)卜Γς.卜r^UIKo *ρ)ε卜·inchirHSOss·inch a(H(N*s) Η.寸丨〇〇·inchί(Ηε巨)CN6.£-e8.e !(H^S) ss.rn^reiffirnsoooo·! :(NH1AI 00' inch p-鮏®-) ΉΙΑΙΝ_Η1 (ΐϋ鹚邮¥0淑$1-ς-^τ1.·?(Νώ味tifD-fM rAt-fB--Hf^--ffi-Ί M,9-¥(N)-8-cfi4-砩^&amp;-_ε - ¥(N)-9-(4ffi--砩柃-砩避-ε

CS9.9 152524.doc -416- 201130854

g i a 〇 t i den, K &lt; 蛛 spider Ϊ ^ 5 έ δ ί | 4 ^ ^ S ·· S f % 'Q .衾 + + + + + + + + + + + + + + 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 ^ 5 ill I - i i i h-NMR (sterol-d4, 400 MHz): 1.88 (d, 3H); 3.34-3.58 (m, 2H); 3.83-3.92 (m, 3H); 3.98- 4.15 (m, 2H); 4.54 (d, 0.5H*); 4.62 (d, 0.5H*); 5.23-5.33 (m, 1H); 6.46-6.52 (m, 0.5H*); 6.64-6.69 (m , 0·5Η*); 6.94-7.61 (m,1 OH). MS (EI+): 1^=590. ',Ή f 5^Ia 砩00 6 7 环环ί 1 i4 J i4 S ί cn rn ^ 1 ± ^ ^ t ^ ^ 4 ^ c5 5 t two butterflies d: Li two 彳 5 S 5 ^ ^ ifsil § ^ ^ ^ ll. 6.6b 6.7a 1 1 s 152524.doc •417· 201130854

*H-NMR (sterol-d4, 400 MHz): 1.96 (d,3H); 3.31-3.54 (m,2H); 3.80-3.99 (m, 5H); 4.61 (d, 0.5H*); 4.66 ( d, 0.5H*); 5.28-5.34 (m, 1H); 6.71-6.78 (m, 0.5H*); 6.82-6.88 (m, 0.5H*); 6.88-7.51 (m, 9H) 〇MS (EI+ ): [M+H]+=590. ^-NMR (methanol-d4, 400 MHz): 1.88 (d,3H); 3.36-3.63 (m, 2H); 3.82-3.92 (m, 3H); 3.99-4.17 (m, 2H); 4.57 (d, 0.5H*); 4.66 (d, 0.5H*); 5.25-5.36 (m, 1H); 6.41-6.48 (m, 0.5H*); 6.64-6.71 (m, 0.5H*); 6.99-7.62 (m , 1 OH). UPLC-MS (ESI+): [M+H]+=657 〇b-NMR (methanol-d4, 400 MHz): 1·93 (s, 3H); 3.32-3.56 (m, 2H); 3.82-3.94 ( m, 5H); 4.65 (d, 0.5H*); 4.70 (d, 0.5H*); 5.30-5.37 (m, 1H); 6.71-6.77 (m, 0.5H*); 6.83-6.89 (m, 0.5 H*); 7.07-7.51 (m, 10H) ° UPLC-MS (ESI+): [M+H]+=657. ± ^ ^ 砩4义3 S t S硪ώ cones if 5 5 5 ί ί,ώ s $ 3(1) $ ί ^ 2 ^ Λ i4 ^ £ cA ^ M § itk, 'J «Λ 罕二' U| A 5 q锲锲w硪铋耸# ^ ss ^£^11 It S ^ I a 4(1)f total 硪硪3 rf 7 ^ f u. V; U. ^ v; eg VO I 152524.doc -418· 201130854

iH-NMR (sterol-d4, 300 MHz): 1·95 (s, 3H); 3.44-3.55 (m, 1.5H*); 3.84-3.97 (m, 5H); 4.00-4.10 (m, 0.5H) *); 4.58 (br. s, 3H); 4.64 (d, 1H); 5.31-5.44 (m, 1H); 6.69-6.79 (m, 0.5H*); 6.83-6.90 (m, 0.5H*); 7.04-7.61 (m, 6H). UPLC-MS (ESI+): [M+H]+=578. *H-NMR (CDC13, 400 MHz): 1.00-1.04 (m, 6H); 1.91 (s, 3H); 2.75-2.82 (m, 1H); 3.28-3.48 (m, 2H); 3.90-3.92 (m , 4H); 3.94-4.01 (m, 1H); 4.57 (dd, 1H); 5.36-5.42 (m, 1H); 5.98 (dd, 1H); 6.23 (ddd, 1H); 6.85 (dddd, 1H); 6.96 (td, 1H); 7.10-7.18 (m, 2H); 7.27-7.29 (m, 1H); 7.30-7.40 (m, 1H); 7.47 (dd, 1H). UPLC-MS (ESI+): [M+H]+=605 - H-NMR (methanol-d4,400 MHz): 1.80 (s, 1.5H*); 1.87 (d, 1.5H*); 3.32-3.60 ( m, 2H); 3.81-4.18 (m, 2H); 4.52-4.62 (m, 0.5H*); 4.73 (d, 0.5H*); 5.25-5.41 (m, 1H); 6.84 (d, 0.5H* ); 7.10-7.67 (m, 10.5H*). UPLC-MS (ESI+): Heart 643. 3-{Amino[(23⁄4) phenyl] fluorenyl}-6·(2-Oxo-3-indolylphenyl)-8-[2·Fluoro-1 6-(trifluoromethyl)benzoquinone ]]-7-methyl-2,3-dihydro-5Η-[1,3]thiazolo[3,2-a]0 ratio °-5-嗣d £ i 7 °° &lt;7 硪砩t beads s- ^ fl E 4 if wrong f... s-肊丨1乇...-call A 0 ", 'l-7 (N ^ ψ 灭 - do poor ± ± ± 1% ^ ^ ^ 1 1 »» m Ό (Ν 冷: 〇vw £ό 〇\ 6.10 6.11as 152524.doc •419- 201130854

b-NMR (methanol-d4,400 MHz): 1.86-1.94 (m,3H); 3.31-3.56 (m, 2H); 3.82-4.01 (m, 2H); 4.52-4.64 (m, 1H); 5.41 (m, 1H); 7.07-7.68 (m, 12H). UPLC-MS (ESI+): M+=643. 1 _ iH-NMR (methanol-d4, 300 MHz): 1.89 (s, 1.8H*), 1.21 (s, 1.2H*), 3.39-3.57 (m, 2H*), 4.10 (m, 2H), 4.60 (d, 0.6H*), 4.69 (d, 0.4H*), 5.30 (m, 1H), 7.19-7.39 (m, 7H), 7.45-7.60 (m, 2.6H*), 7.75 (m, 0.4H) *), 8.15 (m, 0.6H*), 8.19 (m, 0.4H*); UPLC-MS (ESI+): [M+H]+=544 °^-NMR (methanol-d4, 400 MHz): 1.97 (d,3H); 3.45-3.66 (m,2H); 3.81-3.96 (m, 2H); 4.56 (d, 0.5H*); 4.62 (d, 0.5H*); 5.23-5.29 (m, 1H) ; 7.03-7.53 (m, 9H); 7.78-7.85 (m, 1H); 8.19-8.25 (m, 1H). UPLC-MS (ESI+): [M+H]+=544 » 3-(Amino-phenyl-indenyl)-6-(2-chloro-5-difluorodecyloxyphenyl)-8-( 2-Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl. 2,3. dihydrogen plug. Sit and [3,2-a] bite - 5-ketone (diastereomer 2) 3-(amino-phenyl-methyl)-6-(2-gas-0 ratio bite-3- -8-(2-Fluoro-6-trimethylsulfonyl-benzyl)-7-mercapto-2,3-dihydro-indole" sits and [3,2-a] ° ratio - 5-keto (diastereomer 1) 3-(amino-phenyl-indenyl)-6-(2-gas-»pyridin-3-yl)-8-(2-fluoro-6- Trifluoromethylbenzyl)-7-mercapto-2,3-diaza thiazolo[3,2-a]»pyridin-5-one (diastereomer 2) Ά 1-H 152524.doc -420- 201130854

^-NMR (sterol-d4, 300 MHz): 1.90 (s,3H); 3.39-3.53 (m,1H); 4.01-4.18 (m, 2H); 4.56-4.62 (m, 1H); 5.25-5.33 (m, 1H); 6.87-7.62 (m, 13H). UPLC-MS (ESI+): [M+H]+=610. !H-NMR (methanol-d4, 300 MHz): 1.97 (s,3H); 3.43-3.53 (m,1H); 3.94 (br. s,2H); 4.53-4:57 (m,1H); -5.40 (m, 1H); 7.13-7.60 (m, 13H). UPLC-MS (ESI+): [M+H]+=610. For palmity! ^1^(〇1如1? 吐1八5 4111150&gt;&lt;4.6111111; hexane/ethanol 80: 20+0.1% diethylamine; 1_0 ml/min): Enantiomer 1 : Rt = 4.23 minutes enantiomer 2: Rt-7.58 min iH-NMR ( methanol-d4, 300 MHz): 1.87 &amp; 1.91 (2 xs, 3H); 3.36-3-54 (m, 2H); 3.75 (s, 3H); 4.04-3.13 (m, 2H); 4.58 (d, 0.6H*); 4.72 (d, 0.4H*); 5.23-5.37 (m, 1H); 6.40-6.46 (m, 0.6 H*); 6.66-6.71 (m, 0.4H*); 6.81-7.61 (m, 10H). UPLC-MS (ESI+): [M+H]+=573. 3-(Amino-p-styl-fluorenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazinyl)-7-methyl-6-(3-trifluoromethoxy-phenyl -2,3-dihydrohydrazide [3,2-&amp;] ° ratio -5-keto (diastereomer 1) 3-(amino-phenyl-indenyl)-8 -(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(3-trifluorodecyloxy-phenyl)-2,3-dihydrogen , 2-a]° ratio bit-5-keto (diastereomer 2) 3-(amino-p-styl-methyl)-6-(2-fluoro&gt;-5-decyloxy-benzene -8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydrohydrazide [3,2-a]° ratio to 5-ketone (diastereomer 1) m τ·*Η vd vd s 152524.doc •421 - 201130854 h-NMR (methanol-d4, 300 MHz): 1.96 (d,3H); 3.43-3.52 (m,1H 3.76-3.81 (m, 3H); 3.83-3.97 (m, 2H); 4.50-4.62 (m, 1H); 5.28-5.41 (m, 1H); 6.70-6.76 (m, 0.5H*); 6.83 -6.87 (m, 0.5H*); 6.89-6.97 (m, 1H); 7.03-7.52 (m, 9H). UPLC-MS (ESI+): [M+H]+=573. S' x p &quot; 运 X S 1 1 乐 ... 亘 4 ϋ Taste ro a β , · ® Ρ - 3 ° 铋 S S 4 g i0 pay ffi m ^ ^ 昙 昙 g S. +1 IJ ί S 〇1 g | t ^ j &lt;N Λ ^ ^ ^ O g g1^ t ^ ^ 乐^ si “ 5 ^ ^ | ' Ή fi (N m Hit% m ιΛ ^ ϊ 1 “its 苫S _ fi « i SU ^ ^ 'Ί Λ ^ 扁 ^ ^ 7云^ ^ d ^ ^ $ Ϊ tam Φ^Ι ^ ^ · 6.14b 6.15 152524.doc • 422· 201130854

々-NMR (sterol-d4, 300 MHz): 1.90 (s, 3H); 3.41-3.50 (m, 1H); 3.99-4.17 (m, 2H); 4.55-4.61 (m, 1H); 5.23-5.32 (m, 1H); 6.64-7.63 (m, 11H). </ RTI> <RTIgt; m, 1H); 3.92 (br. s, 2H); 4.50-4.60 (m, 1H); 5.30-5.30 (m, 1H); 6.92-7.61 (m, 11H). UPLC-MS (ESI+): [M+H]+=605. ^-NMR (sterol-d4, 400 MHz): 1.91 (d,3H); 3.82-3.86 (m,3H); 4.94 (d, 0.5H*); 5.01 (d, 0.5H*); 5.38 (m , 0.5H*); 5.48 (m, 0.5H*); 6.37 (m, 0.5H*); 6.60 (m, 0.5H*); 6.88-7.51 (m, 9H). UPLC-MS (ESI+): 575. Go to post ^ Μ Λ Ψ ^ ^ 1 5 ώ ί 地 地 f A A A A A A A d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d “ “ “ “ “ “ “ “ “ “ “ “ “ “ ^ 1机械®f υ| ; fr ®- Μ νό (N to fg A 5 4 coated t-4 Γ} d Ϊ, 碥ϊ ia 3 锘蚪硪硪d X ' A 3-3-[amine-( 2-ox-3-ran-phenyl)-methyl]-8-(2,6-di-n-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7- Mercapto-2,3-dihydro-°嗤嗤[3,2-&amp;]»比〇定-5-ketone r·^ vd fH \〇卜152524,doc .423 - 201130854 h-NMR (曱Alcohol-d4, 400 MHz): 1.91 (d,3H); 2.26 (m,3H); 3.86 (m, 3H); 4.56-4.70 (m, 1H); 5.26-5.41 (m, 1H); 6.47 (m , 0.5H*); 6.68 (m, 0.5H*); 6.78-7.39 (m, 11H). UPLC-MS (ESI+): [M+H]+=637. ^-NMR (sterol-d4, 300 MHz): 1.99 (d, 3H); 2.23 (d, 3H); 3.91 (m, 3Η); 4·53-4.65 (m, 1H); 5.40 (m, 1H); 6.78-7.39 (m, 12H) UPLC-MS (ESI+): [M+H]+=637 〇b-NMR (methanol-d4, 300 MHz): 1.93 (d,3H); 3.85 (m,3H);4.71-4.81 (m, 1H); 5.37 (m, 1H); 6.67 (m, 1H); 6.93 (m, 2H); 7.06 (m, 3H); 7.28 (m, 3H); UPLC-MS (ESI+): [M+H] +=529. 4 Today, 丨匾S ^ A戈蝶A q A 二ts砩S颧汶4 t幸f ^ t 3 ώ ^ i " I s cA 〇T 6- ^ ^ SS a ί it 1 i ^ f{ s V〇J_y ^ ^ ¢- « 4 ΐ 1 ^ ^ ^ Ϊ ,S Ϊ t ϊ SS HaC /CH3 o° 6.18a 6.18b 6.19 152524.doc • 424· 201130854

^-NMR (sterol-d4, 300 MHz): 1.91 (d,3H); 3.85 (m,3H); 4.58-4J1 (m,1H); 5.26-5.38 (m,1H); 6.50 (m,0.5 H*); 6.66 (m, 0.5H*); 6.80-7.36 (m, 10H). UPLC-MS (ESI+): [M+H]+=641. iH-NMR (sterol-d4, 300 MHz): 2.0 (s, 3H); 3.90 (m, 3 Η); 4.61-4.69 (m, 1H); 5.36 (m, 1H); 6.73 (m, 0.5H*) ); 6.80-7.36 (m, 10.5H*). UPLC-MS (ESI+): [M+H]+=641. ^-NMR (methanol-d4, 300 MHz): 1.93 (s, 3H); 2.42 (s, 3H); 3.85 (m, 3H); 5.57-5.67 (m, 1H); 6.62-6.72 (m, 1H) ; 6.87-6.99 (m, 2H); 7.00-7.15 (m, 2H); 7.21-7.37 (m, 2H). UPLC-MS (ESI+): [M+H]+=544. 3-[Amino-(3-fluoro-phenyl)-fluorenyl]-8_(2,6-di-phenyl-phenyl)-6-(2-fluoro-3-indolyl-phenyl)- 7-fluorenyl-2,3-dihydro-°°°[3,2-a] ° ratio-5-ketone (diastereomer 1) i 1 ') i nitrate “ q A 1 ^ f SXA ^ —+4 机械 1巴隹Φ i ^ 5 £ ^ Μ 4 ά 3 V 5 ί ^ ΓΠ 4 4 韬^ ^ 3 s ^ ^ _| * ^ 邮二,·ι懑寺 A隹: ά dt ^ dare H3 rA ^ S s do 4 A 1 1 #&gt; m B- cn -Ο AV jT (N (Ν a CN 152524.doc •425· 201130854 b-NMR (sterol-d4, 300 MHz): 1.99 (m,3H); 2.35-2.40 (m,3H); 3.88 (m,3H); 5.33-5.41 (m,1H); 6.68-7.31 (m,7H). UPLC-MS (ESI+) : [M+H]+=544. ^-NMR (methanol-d4, 300 MHz): 2.0 (m,3H); 3.90 (m,3H); 5.11 (m, 1H); 5.48 (m, 1H) 6.80 -7.34 (m,8H); 8.29 (m, 1H). UPLC-MS (ESI+): [M+H]+=542. iH-NMR (Methanol-d4, 300 MHz): 1.92 (s, 3H) ; 3.86 (m, 3H); 4.99 (m, 1H); 5.51 (m, 1H); 6.58 (m, 1H); 6.84-7.56 (m, 7H); 8.29 (m, 1H). UPLC-MS (ESI+ ): [M+H]+=542. i 3·[Amino-(5-fluorenyl-°°°?-2-yl)_methyl]-8-(2,6·difluoro-benzamide Base)-6·(2-fluoro-3-methoxy-benzene )-7-Methyl-2,3-dihydro-snack and [3,2-a]° ratio biting 5-keto (diastereomer 2) 3-[amino-(3- Than-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-indenyl 2 , 3-dihydrogenase 0 sits and [3,2-a]°fc dentate · 5-keto (diastereomer 1) 1 s over six s-sub-^ ^ ^ g human ^ 钐 钐 &lt;硪巴m ¥ ;ι ' 2 ...i 6 J ^ fi ^ S ^ SV af 5妒&amp;&amp; Xi (N vd (Ν (N vd 152524.doc -426- 201130854 ο 6 ZH+W) :( +3⁄4 ss-cndn. (HIrs6Γ8-0 inch·9 ((Hrs) 8S.9 XHCN^I) 6ς·ς-ΙΙ.ιη i(H^e) Aoo.ei(Hrs) 86·Ι-2·ι :(NH^oos inch P-鮏B-)^SN-H- (荽φ^ϋϋ畹銮畹銮) 5 d-9-(^fi-t4^M-9(N)-8-«fr--^-e- ^fs#i4-^si)-e

Rns 152524.doc -427- 201130854 Example 6.6b (by highly diastereoselective reduction) and Example 6 24 Preparation of 3-(amino-phenyl-methyl)_6_(2_fluoro-3-methoxy -phenyl)_8_(2_fluoro-6-difluoroindolyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (non-pair 2) and 3-[amino(phenyl)methyl]_6_(2_fluoro_3_methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenyl Methyl]_7_methyl-2,3_dihydro·5H-[1,3]° plug" sits and [3,2-a]° bites 5-1- 1 -oxide

Lithium hydrogen hydride (16 65 mL, 2 M solution in THF, 33.3 mm 〇 1 '4 equivalent) was slowly added to titanium chloride (IV) (33.3 mL, 1 in dichlorohydrazine) at 0C The hydrazine solution '33.3 mmol' 4 equivalents) was added to a stirred solution of 1,2-dimethoxyethane (90 mL). After 1 minute, 6_(2_fluoro-3-indolylphenyl)8[2fluoro-6(trifluoromethyl)benzene was added to hydrazine, 2 • dimethoxyethane (70 mL). Methyl]·3_[(oximeimido)(phenyl)indolyl]-7-methyl-2,3-hydrogen-5Η-[1,3]thiazolo[3,2-a]pyridine -5-ketone (Example 3.23) (5 g, 8.32 mmol) and stirring was continued at 5 °C until TLC indicated the starting material was completely consumed. The reaction was quenched by the addition of cesium carbonate (75 g) at room temperature. After stirring for 3 minutes, add water (0.3 mL in several portions) and continue stirring for 9 knives. The mixture was then passed through and the filtrate was evaporated. The residue was partitioned between EtOAc (EtOAc)EtOAc. Separation by flash column chromatography 3. I52524.doc 201130854 (amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6 -Trifluoromethyl-methicyl)-7-methyl-2,3-dipho-pyrene. Sit and [3,2-a]e than bite-5-steel (diastereomer 2) (yield: 3.5 g). Example 6.6b: i-NMR (methanol-d4, 400 MHz): 1_94 (d, 3H); 3.44-3.53 (m, 1H); 3.85-3.95 (m, 5H); 4.55 (d, 0.5H*); 4.60 (d, 0.5H*); 5.31-5.39 (m, 1H); 6.71-6.76 (m, 0.5H*); 6.82-6.88 (m, 0.5H*); 7.07-7.51 (m, 10H). MS (CI+): [M+H]+=573. For palmar HPLC (Chiralpak IB 5 μιη 150x4.6 mm; hexane/ethanol 80: 20+0.1% diethylamine; 1.0 ml/min broad enantiomer 1:1^=6.85 min and 7.43 min (due to Dynamic hemitropy produces two peaks. Enantiomer 2: 1^ = 9.01 min and 1 〇. 33 min (two peaks due to dynamic ligation of isomerism) Preparative HPLC (Chiralpak IB 5 μπι 250x30mm; calcined/ethanol 80:20+0.1% diethylamine; 50_0 ml/min enantiomer 1: RT=8.7-9.9 min and 9.9-10.9 min (two peaks due to dynamic hemitropy 'An optical rotation: [0^^0+298.50 (^ = 1, methanol); enantiomer 2: RT = 11.7-1.38 minutes and 13.8 minutes -16.5 minutes (two due to dynamic trans-isomerism) Peak), optical rotation: [α]^2〇_ 229.20 (C=bu methanol); Example 6.24: s 152524.doc •429- 201130854 Knife off 3 as a by-product of the above separation [Amine (Stupid) A Base] winter (2·fluoro-3-methoxyphenyl)_8·[2_gas(trifluoromethyl)phenylmethyl]·7·methyl_2.3-dihydro-5Η-[1,3] Thiazolo[3,2_a]pyridine ketone oxime oxide (yield 5 〇 mg). H-NMR (methanol I 400 MHz): 1.83 (s, 3H); 3.85-3.93 (m, 4H); 4.06-4.18 (m5 1H); 4.27-4.48 (m, 2H); 4.61 (d, 0.3H* 4.67 (d, 0.7H*); 5.53-5.60 (m, 1H); 6.70-6.78 (m, 1H); 7.04- 7.57 (m, 12H) MS (ESI+): [M+H]+= 589. Example 6.24: (direct oxidation by sulfur) Modified form according to GP 27c: Iron chloride (ΙΠ) (83 mg, 0.051 mmol) was added to 3·(amino-phenyl) at room temperature _曱))_6_(2Fluoro-3·decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indenyl 2,3·dihydro-thiazole And [3,2-a]pyridin-5-one (Example 6.6b) (250 mg, 0.437 mmol) in a stirred solution of acetonitrile (10 mL). After 5 min, add (original) periodate ( 110 mg '0.48 mmol) and stirring was continued overnight. The mixture was partitioned between ethyl acetate and aqueous sodium thiosulfate. Dry and concentrate in vacuo. The target compound was isolated by flash chromatography. The analytical data is consistent with the above analysis. Examples 6.25a and 6.25b Preparation of 3-(amino-phenyl-indenyl)-8-(2-fluoro-6.trimethyl-phenylphenyl) moth-7-mercapto-2,3-di Hydrogen-oxime sniffing. [3,2-a]n ratio bite-5-_ (diastereomers 1 and 2) 152524.doc -430- 201130854

According to the modified form of GP 8: 3-(Amino-based)-based in the acetic acid (14 mL) and trifluoroacetic acid (290 mg, 2·5 mmol, 2 equivalents) was added dropwise at room temperature. )--8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro _ 鲁 0 0 sit and [3,2-a] ° than 唆- 5-indole (intermediate U. 1 ) (557 mg, 1.24 mmol). After 1 minute, N_^_butanediamine (67 mg, 3.0 mmol '2.4 equivalent) was added. After 1 hour, the mixture was diluted with 3 mL of dichloromethane and 20 mL of water and a saturated aqueous solution of sodium thiosulfate was added until the color changed from brown to yellow. After stirring for an additional 10 minutes, the pH was adjusted to about pH 8 by the addition of triethylamine, then the phases were separated, extracted with dioxane, washed with water and brine and dried over sodium sulfate. The solvent is evaporated to give the crude 3_(amino-p-styl-methyl)_8_(2·® fluoro-6-difluoromethyl-benzyl)-6-iodo-7- as a mixture of stereoisomers. Methyl-2,3-dihydro-thiazolo[3,2·a]pyridin-5-one. The diastereomers were separated by flash chromatography (Si 2 , dichloromethane / 5% isopropyl alcohol) (yield: 524 &lt;RTI ID=0.0&gt;&gt; Diastereomer 1 (Example 6.25a): h-NMR (CD3OD, 300 MHz): 2.37 (s, 3H); 3.35 (dd, 1H), 3.46 (dd, 1H), 4.11 (dd, 2H) , 4.71 (br, 1H), 5.33 (m, 1H), 7.24 (m, 1H), 7 32 (m, 3H), 7.38 (m, 2H), 7.48 (m, 1H), 7 57 (m, 1H) ). MS (ESI+): [M+H]+=575 〇 diastereomer 2 (example 6 25b) : (CD3〇D,3(9) 152524.doc 201130854 MHz): 2.42 (s, 3H); 3.25 (m , 1H), 3.49 (m, 1H), 3.95 (dd, 2H), 4.56 (m, 1H), 5.39 (m, 1H), 7.15 (m, 2H), 7.20-7.56 (m, 6H). MS (ESI+): [M+H]+=575. Table 28: Example 6.26 below was prepared in a similar manner to Example 6.25 and starting from intermediate U.2 in a modified form of GP 8 to prepare the numbered structure name analysis data 6.26 3-(Amino-phenyl-methyl)- 8-(2,6-Difluoro-benzyl)-6-iodo-7-indolyl-2,3-dihydro-snake sits and [3,2a]° bites -5-brewed I 'H -NMR (CD3OD, 300 MHz) major diastereomers: 2.48 (s, 3H), 3.30 (m, 1H), 3.56 (dd, 1H), 3.80 (dd, 2H), 5.46 (m, 1H) , 6.85-7.30 (m, 8H); UPLC-MS (ESI+): [M+H]+=525. Example 6.6b (by changing the order of the synthesis steps) Modified according to GP 10a: in microwave radiation ( 3-(Amino-phenyl-methyl)-8-(2-gas-6-difluoro&gt; fluorenyl-phenylhydrazino)-6-disc- 7- at 130 ° C / 100 W) Methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (Example 6.25b) (155 mg, 270 mmol), 2-fluoro-3-methoxyphenyl-teric acid (116 mg, 683 mmol, 2.5 equivalents), two-degree calcination (2.3 mL), carbonic acid clock solution (0.23 mL, 1.5 Torr in water) and (1,1-bis(diphenyl-phosphino)ferrocene ) palladium dichloride (II) and methylene chloride complex (10 mg, 23 μηιοί, 0.085 equivalent) reaction 20 minutes . After cooling, the mixture was diluted with EtOAc (EtOAc)EtOAc. Chromatography (silica gel, DCM / MeOH 0-5%) afforded the desired compound (yield: 97 mg). The product was identical to the material obtained above. 152524.doc -432- 201130854

The drive is bitten [«?^^9Γ9^ςΓ9¥^ι5Ι&lt;ίοΜ^?ι#^^ν^Μ29·9¥_^^9κ9^ΙΓ9¥^Η-^:6ζ^ ;.· '.' - :-' . ' -VV Ί ..'vi . ·ν· ' 'V . &quot; -·,·· - •&quot;••f · ' &quot; ·. . · · ·' .:.., w .y. Analytical data... +- ... :.. h-NMR (sterol-d4, 300 MHz): 2.13 (s, 3H); 3·16 (dd, 1H), 3.54 (dd, 1H), 3.73 (dd, 2H), 4.59 (d, 1H), 5.40 (dd, 1H), 6.84-6.91 (m, 2H), 6.94 (dd, 1H), 7.10 (dd, 1H), 7.16-7.30 (m, 6H), 7.50 (dd, 1H); UPLC-MS (ESI+): [M+H]+=481. ^-NMR (sterol-d4, 300 MHz): 2.20 (s,3H); 3.30-3.35 (m,1H), 3.54 (m, 1H), 3.72 (dd, 2H), 4.56 (d, 1H), 5.38 (dd, 1H), 6.80 (d, 1H), 6.88 (m, 2H), 6.96 (d, 1H), 7.14-7.35 (m, 6H); UPLC-MS (ESI+): [M+H]+ =516. ^-NMR (methanol-d4, 300 MHz): 2.01 (s, 3H); 3.28 (m, 1H), 3.53 (dd, 1H), 3.74 (dd, 2H), 4.57 (d, 1H), 5.39 (dd , 1H), 6.88 (m, 2H), 7.16- 7.44 (m, 10H); UPLC-MS (ESI+): [M+H]+=510. · \ V ·· ....:. - 1 v-|C ; · · ;: . . :y ' . Name: Scale &gt; 丨^ Ϊ f Ci. Mi &lt;ns ^ :匾^ ^ ^ Zero 5 Γ 1 s X ^ ^ «f ^ 1 3-(Amino-phenyl-indenyl)-6-(3-a-phenyl)-8-(2,6-difluoro-benzoinyl)- 7-Mercapto-2,3-dihydro-thiazolo[3,2-a] 0-poor-5-ketone structure P No. 6.27 6.28 6.29

152524,0C -433 - S 201130854 ^-NMR (sterol-d4, 300 MHz): 2.13 (s,3H); 3.33 (m,1H), 3.54 (dd, 1H), 3.72 (dd, 2H), 4.56 (d, 1H), 5.38 (dd, 1H), 6.87 (m, 2H), 7.10-7.60 (m, 8H), 7.89 (t, 1H); UPLC-MS (ESI+): [M+H]+= 511. *H-NMR (CDC13, 300 MHz): 1.93 (s, 3H), 3.11 (dd, 1H), 3.44 (m, 1H), 3.70 (m, 2H), 3.92 (s, 3H), 4.58 (m, 1H), 5.41 (m, 1H), 6.85 (m, 2H), 6.96 (m, 1H), 7.14-7.35 (m, 6H), 7.43-7.57 (m, 1H), 8.18 (dd, 1H); UPLC -MS (ESI+): [M+H]+=506. H-NMR (sterol-d4, 300 MHz): 1.89 (s, 3H), 3.31 (m, 1H), 3.48 (m, 1H), 3.85 (dd, 2H), 3.93 (s, 3H), 4.59 ( Dd, 1H), 5.37 (m, 1H), 7.05 (ddd, 1H), 7.21-7.31 (m, 6H), 7.37-7.63 (m, 3H), 8.16 (dt, 1H); UPLC-MS (ESI+) : [M+H]+=556. iH-NMR (sterol-d4, 300 MHz): 1.96 (s, 3H), 3.20 (m, 1H), 3.48 (m, 1H), 3.89 (m, 3H), 3.94 (s, 2H), 4.56 ( d, 1H), 5.38 (m, 1H), 6.98 (d, 1H), 7.00 (d, 1H), 7.20-7.30 (m, 6H), 7.43 (m, 1H), 7.50 (m, 1H), 7.75 (dd, 1H); UPLC-MS (ESI+): [M+H]+=556. ί ^ Ψ ^ ^ f E ί 乂 1 5 ^ ^ Λ ^ 地6? 7合^ X ^ ^ 3-(Amino-stupyl-methyl)-8-(2,6-difluoro-benzyl - 6-(2-decyloxypyridin-3-yl)-7-methyl-2,3-dihydro-thiazolidine and [3,2-a]&quot; ratio 11--5-ketone ^ ®- Λ f ^ ^ ft s ^ i 7 Λ &quot;f T £2, avoid ll丨 reduce cn \〇\ | ^ ^ ^ f Φ § °? ¢- ^ f ±Ύ ^ S search u annihilate Subtract cn Ό \ | r ^^9 O m VO VO m vd m vd 152524.doc -434· 201130854

iH-NMR (sterol-d4, 300 MHz): 1.96 (s, 3H), 3.33 (m, 1H), 3.51 (dd, 1H), 3.95 (s, 2H), 4.58 (d, 1H), 5.39 ( m, 1H), 7.3 (m, 6H), 7.42-7.52 (m, 4H), 7.91 (m, 1H); UPLC-MS (ESI+): [M+H]+=561 〇^-NMR (methanol- D4, 300 MHz): 1.89 (s, 0.75H*), 1.91 (s, 2.25H*), 3.36 (m, 1H), 3.51 (m, 1H), 3.80 (s, 2.25H*), 3.82 (s , 0.75H*), 3.89 (s, 1.5H*), 3.94 (s5 0.5H*), 4.56 (d, 0.25H*); 4.60 (d, 0.75H*), 5.35 (m, 1H), 6.78 ( d, 0.75H*), 6.92 (d, 0.25H*), 7.20-7.32 (m, 6H), 7.35-7.55 (m, 3H); UPLC-MS (ESI+): [M+H]+=590. ^-NMR (sterol-d4, 300 MHz): 1.78 (s, 2.1Η*), 1.83 (s, 0.9Η*), 3.39-3.56 (m, 2H), 3.87 (s, 2.1H*), 3.90 (s, 0.9H*), 4.08 (m, 2H), 4.62 (d, 0.7H*), 4.75 (d, 0.3H*), 5.31 (m, 0.7H*), 5.39 (m, 0.3H*) , 5.59 (dd, 0.7H*), 6.75 (dd, 0.3H*), 7.04 (m, 1H), 7.21-7.35 (m, 6H), 7.39 (m, 1H), 7.48 (m, 1H), 7.56 (m, 1H); UPLC-MS (ESI+): [M+H]+=590. 3-(Amino-p-styl-methyl)-6-(6-chloro-pyridin-2-yl)-8-(2-fluoro-6-trifluoromethyl-adenyl)-7-methyl -2,3-dihydro-α-plug 0 sits and [3,2-a] ° bites 5-ketone-3·(amino-phenyl-fluorenyl)-6_(2-chloro-5-methoxy -Phenyl)-8-(2-fluoro.6.difluoroindolylbenzoyl)-7-mercapto-2,3-dihydro-σ嗤嗤[3,2-a] ° ratio °定-5 - _ ^ ί if ϊ ^ ' A 士二' «mi ^ 11 W ΓΛ ^ , 1 0-0 5 marriage 2 m VO 152524.doc • 435- s 201130854 h-NMR (methanol-d4, 300 MHz): 1.86 (s, 1.05H*), 1.88 (s, 1.95H*), 3.34 (m, 1H), 3.50 (m, 1H), 3.90-3.94 (m, 5H), 4.60 (m, 1H) , 5.35 (m, 1H), 6. 08 (dd, 0.65H*), 6.91 (dd, 0.35H*), 7.10 (m, 1H), 7.18- 7.55 (m, 9H); UPLC-MS (ESI+) : [M+H]+=590 « ^-NMR (sterol-d4, 300 MHz): 1.97 (s,3H),3_20 (m,1H), 3.48 (m, 1H), 3.93 (s, 2H) , 3.93 (s, 3H), 4.58 (d, 1H), 5.39 (m, 1H), 5.97 (s, 2H), 6.72 (m, 2H), 6.88 (d, 1H), 7.20-7.31 (m, 6H ), 7.38-7.52 (m, 2H); UPLC-MS (ESI+): [M+H]+=569 ° iH-NMR (nonol-d4, 300 MHz): 1.86 (s, 1.5H*), 1.89 (s, 1.5H*), 2.25 (d, 1.5H*), 2.29 (d, 1.5H*), 3.34-3.55 (m, 2 H), 4.07 (m, 2H), 4.63 (d, 0.5H*), 4.75 (d, 0.5H*), 5.30 (m, 0.5H), 5.36 (m, 0.5H*), 6.80 (dt, 0.5 H*), 6.96 (dt, 0.5H*), 7.04 (t, 0.5H*), 7.08 (t, 0.5H*), 7.17-7.41 (m, 7H), 7.48 (m, 1H), 7.57 (t , 1H); UPLC-MS (ESI+): [M+H]+=557. i I S nitrate; ?璋^ 1 S cold g_ minus rn rA ^ ' 1 3-(amino-p-styl-methyl)-6-benzo[1,3]dioxol-5-yl-8-(2 -Fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-S0-biti-5-one ketone W 1 V ^ ^ ^ ^ Ball II ' ^ ^ Ψ cA cA ^ 6.36b 6.37 6.38a 152524.doc -436- 201130854

^-NMR (methanol-d4, 300 MHz): 1.93 (s,1·5Η*), 1.94 (s, 1.5H*), 2.29 (d, 1.5H*), 2.33 (d, 1.5H*), 3.22 -3.33 (m, 1H), 3.45-3.55 (m, 1H), 3.89 (s, 1H*), 3.93 (s, 1H*), 4.57 (d, 0.5H*), 4.62 (d, 0.5H*) , 5.37 (m, 1H), 6.97-7.15 (m, 2H), 7.16-7.30 (m, 7H), 7.38-7.52 (m, 2H); UPLC-MS (ESI+): [M+H]+=557 . h-NMR (methanol-d4, 300 MHz): 1.95 (s, 1.5H*), 1.96 (s, 1.5H*), 3.24-3.37 (m,1H), 3.47-3.55 (m,1H), 3.90 ( s, 1H*), 3.95 (s, 1H*), 4.56 (d, 0.5H*), 4.62 (d, 0.5H*), 5.37 (m, 1H), 7.15-7.32 (m, 6H), 7.38- 7.55 (m, 4H), 7.62-7.75 (m, 1H); UPLC-MS (ESI+): [M+H]+=611 〇^-NMR (sterol-d4,300MHz): l_87(s, 1.05Η *), 1.89 (s, 1.95 Η *), 3.20-3.30 (m, 1H), 3.45-3.50 (m, 1H), 3.94 (s, 2H), 4.56 (d, 1H), 5.37 (m, 1H) , 7.21-7.51 (m, 12H); UPLC-MS (ESI+): [M+H]+=560. Ifrii V ^ ll 5 « έ S it ^ ¢. ^ cn ^ ''合f Φ Φ A § ^ ^ S- B- ^ S \ι| (il ^ -νώ »1 A #岢^ ^ ? 5 ^ « « λ ® fn i ^ CN ? ^ ? &lt;N ®- ^ g Two Offices cA 蚪®·7 Office 6.38b 6.39 6.40 152524.doc -437· 201130854 ^-NMR (methanol-d4, 300 MHz): 1_96 (s , 3H), 3.20-3.33 (m, 1H), 3.45-3.55 (m, 1H), 3.89 (s, 1.3H*), 3.95 (s, 0.7H*), 4.60 (d, 0.35H*), 4.63 (d, 0.65H*), 5.39 (m, 1H), 7.21-7.32 (m, 7H), 7.34- 7.56 (m, 5H); UPLC-MS (ESI+): [M+H]+=560. h -NMR (methanol-d4, 300 MHz): 1.89 (s, 1.8H*), 1.92 (s,1 ·2Η*), 3.39-3.58 (m, 2H), 4.09 (m, 2H), 4.58 (d, 0.6H*), 4.70 (d, 0.4H*), 5.30 (m, 0.6H*), 5.35 (m, 0.4H*), 7.20-7.40 (m, 7.6H*), 7.46-7.53 (m, 1.4 H*), 7.58 (t, 1H), 7.70-7.77 (m, 1H); UPLC-MS (ESI+): [M+H]+= 568. h-NMR (methanol-d4, 300 MHz): 1.97 ( s, 1.5H*), 1.98 (s, 1.5H*), 3.25-3.38 (m, 1H), 3.45-3.55 (m, 1H), 3.90 (s51H*), 3.95 (s, 1H*), 4.56 ( d, 0.5H*), 4.63 (d, 0.5H*), 5.37 (m, 1H), 7.16-7.31 (m, 6H), 7.39-7.52 (m, 3H), 7.58 (dt, 05H*), 7.71 (dt, 0.5H*), 7.79 (m, 1H); UPLC-MS (ESI+): [M+H]+=568 = 5f ε ^ ^ ¥ 七减1丨^ 砩llj rA=νό οί a ' 4 ? ^ d S °? X ^ rA 铋®· d ^ f ^ ^ 4 a氐 Today's ice making 1, minus shouting difficult s- ®7 &gt;1 νά ^ 4 +_ A wearing only '¢- ΤΤ ^ ^ (Ν ^ g uj ψ cn rn v〇ιΛ ^ rA &amp; 4 wearing d ^ ^ ^ °? a 3 3 $ ώ 5 ΐ ΐ $ $ ψ ψ ώ ώ ώ ... ... ... ... rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn rn

^-NMR (methanol-d4, 300 MHz): 2.07 (s, 3H), 3.22-3.35 (m, 1H), 3.45-3.53 (m, 1H), 3.92 (s, 2H), 4.57 (d, 1H) , 5.36 (m, 1H), 6.96 (dd, 1H), 7.11 (dd, 1H), 7.17-7.27 (m, 6H), 7.30-7.48 (m, 2H), 7.50 (dd, 1H); UPLC-MS (ESI+): [M+H]+=531. iH-NMR (sterol-d4, 300 MHz): 2.10 (s, 3H), 2.50 (s, 3H), 3.23 (m, 1H), 3.49 (dd, 1H), 3.93 (s, 2H), 4.59 ( d, 1H), 5.39 (m, 1H), 6.76 (m, 2H), 7.25 (m, 6H), 7.47 (m, 2H); UPLC-MS (ESI+): [M+H]+=545. 'H-NMR (sterol-d4, 300 MHz): 2.15 (s, 3H), 3.25-3.33 (m, 1H), 3.49 (dd, 1H), 3.92 (s, 2H), 4.56 (d, 1H) , 5.37 (m, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 7.17-7.52 (m, 10H); UPLC-MS (ESI+): [M+H]+=566. iH-NMR (methanol-d4, 300 MHz): 1.99 (s, 1.5H*), 2.00 (s, 1.5H*), 3.20-3.40 (m, 1H), 3.46-3.54 (m, 1H), 3.87 ( s, 1H*), 3.93 (s, 1H*), 4.59 (d, 0.5H*), 4.62 (d, 0.5H*), 5.37 (m, 1H), 7.04-7.59 (m, 10H); UPLC- MS (ESI+): [M+H]+=566. ^ ft ^ S Λ I ^ ^ t S 'ij ψ cA 3-(Amino-phenyl-methyl)-8-(2-aero-6-trifluoromethylbenzoyl)-7-fluorenyl -6-(5-methyl- porphin·2·yl)-2,3-dihydrohydrazino[3,2-a]11 ratio bite-5-one ^ ^ ^ ^ ^ Ί f ? ;l ^ § ^ ^ ^ f &lt;N S- &quot;rt1 哿娜4 ϊ ^ &lt;NA Ψ ^ 3-(Amino-phenyl-methyl)-6-(3-gas_°Cet-2- )--8-(2-Ga-6-trifluorodecyl-phenylhydrazino)-7-fluorenyl-2,3-dihydro-° plug 0 sits and P,2-a] ° ratio α 5-keto i K octagonal vd JT) vd 152524.doc -439· 201130854 Examples 6.47a and 6.47b Preparation of 3-[Amino (phenyl)(211)methyl]-8-(2,6-difluoro Benzyl)_6_(2-fluoro-3-indolyloxyphenyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2_a] 0-pyridin-5- Ketones (diastereomers 1 and 2)

According to the modified form of GP 23b: sodium borohydride (fully powdered '145 mg ' 3.46 mmo b 20.6 eq.) was slowly added to titanium (IV) chloride (191 μί ' 1.74 mmo) • 4 equivalents) in a mixture of ι, 2-dimethoxyethane (1 8 mL). After 1 minute, added to 8-[2,6-difluoro-benzoinyl)-6-(2-fluoro-3-methoxy-) in I]dimethoxyhydane (2 mL) Styrene)-3-(imido-bens-methyl)_7_methyl-2,3_dihydro·嗟σ sita[3,2_a]pyridin-5-one (90 mg, 0.17 Methyl) (Example 3_1) and stirring was continued for two hours at 〇〇C. The reaction mixture was then allowed to warm to room temperature and stirred until TLc indicated the starting material was completely consumed. Cool to 〇. After the hydrazine, the reaction was quenched by the addition of water and aqueous ammonia (33% by weight). After stirring for 2 minutes, the mixture was partitioned between EtOAc EtOAc. The target compound was isolated by flash column chromatography (yield: 12 mg and 6 mg). Diastereomer 1 (Example 6.47a): 】H-NMR (methanol _d4, 300 MHz): 1.91 (d,3H); 3.38-3.63 (m, 152524.doc •440· 201130854 2H); 3.75 -3.99 (m, 5H); 5.27-5.38 (m, 1H); 6.47-6.54 (m, 0.5H*); 6.64-6.71 (m, 0.5H*); 6.86-7.50 (m, 11H) » MS ( CI + ): [M+H]+=524. Diastereomer 2 (Example 6.47b): W-NMR (Methanol-d4, 300 MHz): 2.00 (s, 3H); 3.38 (dd, 1H); 3.49-3.59 (m, 1H); -3.77 (m, 2H); 3-89 (d, 3H); 5.33-5.41 (m, 1H); 6.69-6.76 (m, 0.5H*); 6.79-6.92 (m, 2.5H*); 7.05- 7.30 (m, 9H) ° MS (CI+): [M+H]+=524 » Table 30: Examples 6.48 a and 6.48 b below were prepared in a similar manner to Examples 6.47 a and 6.47 b and GP 23b was from Example 3.10 Start p '· number...:Ί: ί··;. Ertao' nickname analysis material '...&gt; : 6.48a ^ch3 3-[Amino (phenyl)(2Η)fluorenyl]-6-〇fluoro·3·decyloxyphenyl)-8-[ 2-fluoro-6-(trifluoromethyl)azinomethyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo-p,2-a]pyridin-5- Ketone (diastereomer 1) W-NMR (methanol-d4, 300 MHz): 1.89 (d, 3H); 3.34-3.57 (m, 2H); 3.87 (d, 3H); 3.99-4.18 (m , 2H); 5.26-5.37 (m, 1H); 6.50-6.58 (m, 0.5H*); 6.66-6.74 (m, 0.5H*); 7.00-7·61 (m,10H) » MS (CI+) : [M+H]+=574. 6.48b ccc 3-[Amino(phenyl)(2H)methyl]_6-(2-fluoro-3-methoxybenyl)·8·[2-fluoro-6-(trifluoromethyl) 7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one (diastereomer 2) W-NMR (曱Alcohol-d4,300 MHz): 1.94 (br. s, 3H); 3.43-3.54 (m, 1H); 3.83-3.95 (m, 5H); 5.31-5.38 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.82-6.89 (m, 0.5H*); 7.03-7.60 (m, 10H) 〇MS (CI+): [M+H]+=574.

S 152524.doc •441 - 201130854 Example 6.49

Fluor-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]. Bisidine-5-one

According to the modified form of GP 24a: at _78. Under the armpit, a solution of titanium (IV) chloride (1.66 mL '1 μ solution in CH2CI2, 1.66 mmol, 4_0 equivalent) was added to 6-(2-fluoro-3-indolyl-phenyl)_8_ ( 2_Fluoro-6·trifluoromethyl-benzyl)-3-(oxiranimido-p-styl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a] Pyridine-5-one (250 mg, 416 μιηοΐ) (Example 3.23) in a stirred solution of 1,2-dimethoxyethane (9 mL). Gasified methylmagnesium (1 39 mL, 3 Μ solution in THF) 4.16 mmol, 10.0 eq. was added and stirring was continued while the reaction mixture was gradually warmed to hydr. (3 ^ The reaction mixture was again cooled to -50 ° C and gradually added an additional amount of titanium (IV) (2.5 〇 mL, 1 Μ solution in CH 2 CI 2 ' 2.50 mmol, 6.0 eq.) and bismuth magnesium chloride (4.16 mL '3 Μ solution in THF, 12.5 mmol, 30.0 eq.). The reaction mixture was slowly warmed to 6 ° C and stirred at this temperature for 2 hours. The mixture was added with water and aqueous sodium hydroxide (2) M) The reaction was quenched and the mixture was partitioned between ethyl acetate and water. EtOAc EtOAc EtOAc EtOAc. Purification of the title compound (yield: 41 mg). W-NMR (decanol-d4, 300 MHz): 1.53 (s, 3H); 1.91-1.94 (m, 3H); 3.08 (dd, 1H); 3.56 (dt , 1H); 3.89-3.91 (m, 3H); 4.04 (br. s, 2H); 5.64-5.70 (m, 1H); 6.70-6.75 (m, 0.5H*); 6.80 (ddd, 0.5H*) ; 7.07-7.19 (m, 2H); 7.22-7.27 (m, 1H); 7.31-7.39 (m, 3H); 7.45-7.52 (m, 3H); 7.56-7.59 (m, 1H). UPLC-MS ( ESI+): [M+H]+=587 〇φ Example 6.50 Preparation of 3-(1-amino-1-phenyl-but-3-enyl)-6-(2-fluoro- 3-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-wang] ° bite 5-ketone

Palladium (21 mg, 20 μπιοί, 0.10 equivalent, 1% by weight on wood) was added to 3-(1-dilylpropyl-1-phenyl-but-3-yl) at room temperature -6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-dihydro-thiazole And [3,2-a]pyridin-5-one (130 mg, 198 μιηοΐ) (Example 7·21 'see page 218) in a solution of ethanol (2.5 mL). The reaction mixture was heated to reflux for 4 hours and stirring was continued at room temperature for 18 hours. Gradually add another amount of palladium (168 mg, 16 〇μιη〇ι, 〇.8〇当里 '10% on charcoal)' while heating the reaction mixture to reflux' 152524.doc -443- 201130854 continued 5 hour. The catalyst was decanted and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography to yield title compound (yield: 47mg). 1H-丽R (methanol_d4, 600 MHz): 1&gt;91] 93 (m,3H); 2 43_2 49 (m, 1H); 3.06-3.11 (m, 2H); 3.47-3.54 (m, 1H) ; 3.89-3.90 (m, 3H); 4.04 (br. s, 2H); 4.92-4.95 (m, iH); 5.00 (d, 1H); 5.29-5.39 (m, 1H); 5.71 (dd, 1H) 6.70-6.73 (m, 0.5^)^ 6.80-6.83 (m, 0.5H*); 7.09-7.18 (m&gt;2H); 7.24-7.26 IH); 7.32-7.36 (m, 3H); 7.46-7.52 ( m, 3H); 7.56 (d, IH) 〇 UPLC-MS (ESI+): [M+H]+=613. Example 6.51b Preparation of 3-(Amino-phenyl-indenyl)_6-[3-(l,l-difluoro-ethyl)-phenyl]_8_(2_ 乱-6-difluoromethyl-benzoquinone Base)-7-methyl-2,3-dihydro-«&gt; stopper η sit and [3,2-a] n ratio bite -5 -嗣

According to the modified form of GP 10a: 3-(amino-p-styl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-6-moth-7-methyl-2 , 3 - dihydrogen plug. Sit and [3,2-a]&lt;* to 0-but-5-ketone (Example 6-25b) (464 mg, 0.81 mmol), [3-(1,1-difluoroethyl)phenyl]phosphonate (Intermediate V. 1) (380 mg, 2.04 mmol, 2.53 equivalents), dioxane (7 mL), potassium carbonate solution (0.6 mL '1.5 Μ in water) and (1,1-double (di-phenyl) a complex of phosphino)ferrocene)dichloropalladium (ruthenium) with methylene chloride (112.1 mg, 137 μιηοΐ, 〇. 17 equivalent) degassed by argon for 10 minutes and 152524.doc -444 - 201130854 in the microwave The reaction was carried out for 20 minutes under irradiation (130 ° C / 200 W). After the reaction mixture was cooled, the solvent was evaporated. Repeated flash chromatography was carried out followed by HPLC purification to give the title compound (yield: 200 mg). W-NMR (methanol-d4, 300 MHz): 1.85-2.01 (m, 6H); 3.42-3.49 (m, 1H); 3.93 (br. s, 2H); 4.55 (d, 1H); 5.31-5.39 ( m, 1H); 7.17-7.56 (m, 12H). MS (ESI + ): [M+H]+=589

S 152524.doc 445- 201130854 Driving ^Γη5·ε^6(Ν·εί4 驷ί«?4«απ5ζ:ίΙαΜ^^^ν^Μ^Μ2Γ9^Μ·9ί#^1#ν:ίρ.9^3ς .9[4^1-^:ρζ&lt;^)ίζ^ Analytical data e-S . . . 藏旦寸· g旦〇铌έ 4 S .客黎 2 w ^ ^ ^ 铋 鞮 〆; S &lt;〆; 5 。. 10 .·馊| I έ S ε § ε i | f 旦 · ^ S g ji s Let S i ^ ^ ssi ^ f ΐ --1 * S g δ | ^ 2 g S 1 -ffi s ^ ^ 1 Name ^ Ci X ? ^ s J i | S ®- ?7 S- ^ i4 ^ ^ f ^ Ning wy mm (N Structure I No. 6.52a 152524.doc 446. 201130854

^ B 铋气 ^ i R 1 | ie 5^1 ^ S -: δ | s^iS | S ^ ^ S 2 J $ έ $ ^ Η E ^ 1 S 5 5 5 S 1 S 2 g S t 2 | $ ^ &quot; r ^ 111 t S ^5 P ^ &quot; ^ f 1 III li? I 1 i cn w Private-H-NMR (sterol-d4, 300 MHz): 1.92-1.96 (m, 3H) 3.43-3.52 (m, 1H); 3.83 (d, 3H); 3.85-3.94 (m, 2H); 4.53-4.61 (m, 1H); 5.30-5.38 (m, 1H); 6.72-6.87 (m, 2H); 7.05-7.32 (m, 7H); 7.36-7.52 (m, 2H). UPLC-MS (ESI+): [M+H]+=573. d¥^fgm ^ 1 ^ ? ί 11 r^i ¥ ^ ά | ^ ^ ^ d ^ ^ 砩;r ^ ? ^ &lt;±L 5- ·++- a Do 1 I want s- ®-min rA 4 ^ Ί %? i&quot;* 6.52b 6.53 s 152524.doc •447- 201130854 h-NMR (methanol-d4, 300 MHz): 1.93-1.98 (m,3H); 3.36 (d,1H); 3.50-3.61 (m, 1H); AB signal (δΑ=3.90, δΒ=3·97, 2xlH); 4.91 (d, 0.5H*); 4.96 (d, 0.5H*); 5.36-5.45 (m, 1H); 6.93 -7.03 (m, 1H); 7.05-7.14 (m, 1H); 7.20-7.57 (m, 8H). UPLC-MS (ESI+): [M+H]+=645. h-NMR (sterol-d4, 300 MHz): 1.88 (s, 3H); 3.33-3.49 (m, 1H); 4.00-4.15 (m, 2H); 4.65 (d, 1H); 5.25-5.33 (m , 1H); 6.46-6.80 (m, 3H); 7.13-7.61 (m, 10). UPLC-MS (ESI+): [M+H]+=542. ^-NMR (f, -d4, 300MHz): 1.94 (s, 3H); 3.23 (dd, lH); 3.41 - 3.50 (m, 1H); 3.91 (br. s, 2H); 4.55 (d, 1H) ; 5.31-5.38 (m, 1H); 6.60-6.80 (m, 3H); 7.17-7.52 (m, 10). UPLC-MS (ESI+): [M+H]+=542. 3-[Amino-(2-a-phenyl)-methyl]-6·(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) Benzo-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2-a] ° ratio bit-5-keto ii 3-(amino-phenyl-indenyl)-8 -(2-Oxo-6-trifluorodecyl-phenylhydrazino)-6-(3-hydroxy-phenyl)-7-methyl-2,3-diaza-sales 0 sits and [3,2- &amp;]° ratio lean-5-ketone (diastereomer 1) 3-(amino-p-styl-methyl)-8-(2-gas-6-trifluorodecyl-benzyl) -6-(3-Hydroxy-phenyl)-7-methyl-2,3-diaza-indole 0 sits and [3,2-a]° bites 5-ketone (diastereomer 2 ) %? &amp; 6.54 6.55a 6.55b 152524.doc -448 - 201130854

iH-NMR (sterol-d4, 300 MHz): 1.96 (s, 3H); 3.44-3.50 (m, 1H); 3.93 (m, 2H); 4.55 (d, 1H); 5.35 (m, 1H); 6.86 (tr, 1H); 7.00-7.56 (m, 12H). UPLC-MS (ESI+): [M+H]+=591. For palmity 1^B (:(〇1洫1? 吐八0 5 411125(^3〇111111; hexane/ethanol 80: 20+0.1% diethylamine; 40 ml/min): Enantiomer 1 : Rt = 6.60 minutes enantiomer 2 : RT = 12.2 minutes 〇 ^ &quot;i S 1 g ^ ^ 5 —e tO έ έ ί 螫 ^ ^ tO jun s 1 〇έ ϊ ί ^ 1 £ ^ κ +&quot; ! 1 $ s will go to St. zither and fig 殳 55 55 〇 〇 5 I 5 ^ λ —— 2) 2 ο &amp; 〇 5 S ^ + m Ί ^ 3 Β &lt;ν αί匕卜匕) .· Β- ^ J &lt;Ν ✓ inch CLh Township 1 S Chen ^ _ 3 " 5 -ffi ^ Section 1, _丨, lM ! v ^ W 5 硇 硇 i 5 d ^ °? a 碥3硪£ ί4 ®~ 5 1 1 -^L ^ «ι 3-(Amino-phenyl-indenyl)-6-(4-gas_ 2,2-digas-benzo[1,3] Dioxindole-5-yl)-8-(2-1-6-dimethyl-benzyl)-7-fluorenyl-2,3-dihydro-α-sodium , 2-a]° than bite-5-ketone

s: 152524.doc .449· 201130854 ^-NMR (sterol-d4, 300 MHz): 1.42 (m,3H); 1.95 (s,3H); 3.49 (m, 1H); 3.91 (d, 2H); 4.13 (m, 2H); 4.58 (dd, 1H); 5.36 (m, 1H); 6.74 (m, 0·6Η*); 6·86 (m, 0.4H*); 7.04-7.52 (m, 10H) . UPLC-MS (ESI+): [M+H]+=587. For palmar HPLC (Chiralpak IB 5 μιη 15〇χ4.6 mm; hexane:) 3⁄4/ethanol 80: 20+0.1% diethylamine; 1.0 ml/min): Enantiomer 1 : Rt = 5.39 min and 6.39 minutes (two peaks due to dynamic helicotropy) Enantiomer 2: Rt = 7.14 minutes and 7.97 minutes (two peaks due to dynamic helium isomerism) h-NMR (sterol-d4 , 300 MHz): 1.99 (m,3H); 3.48 (m,1H); 3.92 (d, 2H); 4.59 (dd, 1H); 5.37 (m, 1H); 6.74-6.93 (m, 2H); 7.05 -7.56 (m, 15H). UPLC-MS (ESI+): [M+H]+=635. ¥ • 1 ^ ^ ^ '•Ο ^ ^ \ 3 Φ t云®- °〇«Ν 碥2砩5 4 ^ ^ ft ^ Ί1 r} fi (N 癸' 4 — ^ f Λ S ^ 逡 Mechanical 匕' cA 4 ^ '1 &gt; 〇〇0's tn 152524.doc -450- 201130854

^-NMR (methanol-d4, 300 MHz): 1.93 (d,3H); 3.89 (m,3H); 4.93 (d, 0.5H*); 5.39 (m, 1H); 6.72 (m, 0.5H*) ; 6.82 (m, 0.5H*); 6.97 (m, 1H); 7.05-7.53 (m, 9H). UPLC-MS (ES+): [M+H]+=591 〇Purpose HPLC (Chiralpak IC 5 μιη 15〇χ4.6 mm; hexane/ethanol 50:50+0.1% diethylamine, 1.0 ml/min ): Enantiomer 1 : R · corpse 5.60 minutes and 7.80 minutes (two peaks due to dynamic ligation of isomerism) Enantiomer 2 : RT = 9.5 min h-NMR (methanol-d4, 300 MHz): 1.95 (m,3H); 3.91 (m,3H); 4.66 (d,0.5H*); 4.69 (d,0.5H*); 5.32 (m,1H); 6.71-7.53 (m,9H) . UPLC-MS (ES+): [M+H]+=609. iH-NMR (sterol-d4, 300 MHz): 1.87-1.91 (m, 3H); 3.87 (m, 3H); 4.73 (d, 0.5H*); 4.81 (d, 0.5H*); 5.32-5.41 (m, 1H); 6.65-6.73 (m, 1H); 7.03-7.61 (m, 8H). UPLC-MS (ES+): [M+H]+=579 ° ± d, ^ t ^ °f A ^ Υ 1 minus, 1 HU ^ ^ 4 t two 砩S' g ^ Ϊ gi 2 ^ ? ^ ^ rl 1, S? A forbearance 5 s do Bachu AS; ^ 5 TT $4 -fi -g 2 ^ ψ ^ ψ i % ή ^ % ^ '1' ^ X d SS ^ Λ IL· ά VO VO v〇VO 152524 .doc •451 · 201130854 h-NMR (sterol-d4, 300 MHz): 1.91 (s,3H); 3.90 (m,3H); 4.75 (d, 0.5H*); 4.80 (d, 0.5H*) ; 5.29-5.38 (m, 1H); 6.71-6.88 (m, 2H); 7.07-7.54 (m, 7H). UPLC-MS (ES+): [M+H].=579. ^-NMR (methanol-d4, 300 MHz): 1.89 (d, 3H); 2·39 (d, 3H); 3.87 (d, 3H); 4.09 (m, 2H); 4.96 (d, 0.5H*) ; 5.05 (d, 0.5H*); 5.31 (m, 1H); 6.61 (m, 0.5H*); 6.70 (m, 0.5H*); 7.01-7.60 (m, 9H). UPLC-MS (ES+): [M+H]+=587. h-NMR (sterol-d4, 300 MHz): 1.% (d, 3H); 2.18 (d, 3H); 3.89 (m, 3H); 5.47 (m, 1H); 6.74 (m, 0.5H* ); 6.80 (m, 0.5H*); 7.07-7.59 (m, 9H). UPLC-MS (ES+): [M+H]+=587. ΙΦί Is ^ ^ ^ j 5 J ^ φ ^ ^ ^ S ^ | ?3^| (7) 一成娜d ^ ώ M3 ^ ^ ^ ^ 3 ^ ^ ? δ 4 people q chicks mi t 2 ί | nn 5 X ώ Ir I 3 ^ ^ S d J t δ B- 雉 5 5 ί棠: l ^ ί s 1 5 ^ m &lt;n -Μ ό ,〇η3 Λ 6.62b 6.63a 6.63b 152524.doc -452- 201130854

h-NMR (sterol-d4, 300 MHz): 1.89 (d, 3H); 2.29 (d, 3H); 3.87 (d, 3H); 4.57 (d, 0.5H*); 4.69 (d, 0.5H* 5.31 (m, 1H); 6.53 (m, 0.5H*); 6.70 (m, 0.5H*); 7.00-7.62 (m, 9H). UPLC-MS (ES+): [M+H]+=587. h-NMR (methanol-d4, 300 MHz): 1.94 (s, 3H); 2.26 (d, 3H); 3.90 (d, 3H); 4.53 (d, 0.5H*); 4.59 (d, 0.5H*) ; 5.38 (m, 1H); 6.74 (m, 0.5H*); 6.86 (m, 0.5H*); 6.9 b 7.55 (m, 9H). UPLC-MS (ES+): [M+H]+=587. h-NMR (sterol-d4, 300 MHz): 1.87 (d,3H); 3_85 (d,3H); 4.98 (d, 0.5H*); 5.07 (d, 0.5H*); 5.41-5.55 (m , 1H); 6.42 (m, 0.5H*); 6.64 (m, 0.5H*); 6.98-7.61 (m, 9H). UPLC-MS (ES+): [M+H]+=607. y 3 ^ Ϊ ^ s Φ ^ ^ i 〇?人雉^ 5 萣S 4 4 l 1 ^ ^ ^ 1 1 ' ul 3 5 S Φ Ϊ 7 s 旷人π cone^ ί ^ 5 if Ϊ; 5 i 5 ί ϊ ^ f ^ m &lt;n ± ^ t ^ 〇〇A (3⁄4 S t4 d:璁« δ 5 5 5 % ύ ^ ^ ^ ^ f ^ ^ v ^ ^ Μ Ϊ 1 $ 2 ώ S f ά ^ 4 ^ y〇&gt; -f- Λ) y〇&gt; X 〇, H, 6.64a 6.64b 6.65ajs 152524.doc -453 - 201130854 々-NMR (sterol-d4, 300 MHz): 1_94 ( d, 3H); 3.89 (d, 3H); 5_08 (m, 1H); 5_39 (m, 1H); 6.69-6.81 (m, 1H); 7.00-7.69 (m, 9H). </ RTI> <RTIgt; (m, 0_5H*); 6.68 (m, 0.5H*); 7.00-7.60 (m, 9H). </ RTI> <RTIgt; (m, 1H); 6.73 (m, 0.5H*); 6.85 (m, 0.5H*); 7.05-7.51 (m, 9H). UPLC-MS (ESI+): [M+H]+=607. ± ^ ^ 硇H5 AS ^ s砩d: Le a ^ ^ 5 Ϊ ^ ^ ^ V ^ ^ Μ Ϊ 4 2 ul - ^ 3-[Amino-(3-chloro-phenyl)-methyl]-6 -(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydro-thiazolo[ 3,2-*pyridin-5-one (diastereomer 1) XA ^ t ^ 硇呤! X (5 S 5^11 A ^ reduction butterfly ^y〇&gt; 41*· &amp; 〇 U 6.65b 6.66a 6.66b 152524.doc -454. 201130854

^-NMR (methanol-d4, 300 MHz): 1.86 (d, 3H); 3·85 (d, 3H); 4.66 (d, 1 0.5H*); 4.77 (d, 0.5H*); 5.40 (m , 1H); 6.40 (m, 0.5H*); 6.62 (m, 0.5H*); 6.92-7.60 (m, 8H). UPLC-MS (ES+): [M+H]+=609 ° iH-NMR (methanol-d4, 300 MHz): 1.94 (d,3H); 3.89 (d,3H); 4.91 (d, 0.5H*) 4.98 (d, 0.5H*); 5.35 (m, 1H); 6.72 (m, 0.5H*); 6.80 (m, 0.5H*); 6.92-7.54 (m, 8H). UPLC-MS (ES+): [M+H]+=609 °^-NMR (methanol-d4, 300 MHz): 1.85 (m,3H); 3.84 (d,3H); 4.66 (d, 0.5H* 4.76 (d, 0.5H*); 5.42 (m, 1H); 6.35 (m, 0.5H*); 6.61 (m, 0.5H*); 6.96-7.59 (m, 8H). UPLC-MS (ES+): [M+H]+=609. 3-[Amino-(2,5·di|L-phenyl)-fluorenyl]-6-(2-fluoro-3-indoleoxy-phenyl)_ 8-(2-IL-6-III Fluoromethyl-phenylhydrazino)-7-mercapto-2,3-dihydrooxazolo[3,2-a]. Bipyridine-5-W (diastereomer 1) S 硇3 8 «mechanical ^ annihilation 4 f5 'you 砩f ί Μ ^ ^ ^ £ d: ^ UJ 1 fi 1 ss § &gt;-- &lt; r-!«i (N ® - 3-[Amino-(2,3-diphenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)· 8- (2-fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]«pyridin-5-one (diastereomer Construct 1), h3 6.67a 6.67b 6.68as 152524.doc -455 - 201130854 h-NMR (sterol-d4, 300 MHz): 1.93 (m, 3H); 3.89 (d, 3H); 4.93 (d, 0.5H*); 5.01 (d, 0.5H*); 5.37 (m, 1H); 6.73 (m, 0.5H*); 6.81 (m, 0.5H*); 6.97-7.56 (m, 8H). UPLC- MS (ES+): [M+H]+ = 609. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; 5.09 (d, 0.5H*); 5.41 (d, 0.5H*); 5.52 (d, 0.5H*); 6.44 (m, 0.5H*); 6.64 (m, 0.5H*); 6.99-7.58 (m , 8H). UPLC-MS (ES+): [M+H]+=625. iH-NMR (sterol-d4, 300 MHz): 1.94 (d,3H); 3.89 (d,3H); 5.13 (d , 1H); 5.35 (m, 1H); 6.64 (m, 1H); 7.06-7.54 (m, 8H). UPLC-MS (ES+): [M+H]+=625. f令5 , k ^ t «1 ^ ^ ^ c\ ^ Λ ^ bar ^ rA area ^ έ 5 s § S ^ ^ ffi- ^ ^ ^ ώ ^ ® - 人 7 - ®机械®: 珠杂令 ^ ^ ά ϋά &lt;7 , '1 w &lt;N ^ rn W Λ cs ^ ^ g 5 2 1 a 硪ώ a π 彳 4彳穿邮4 4 妙芝...®· $ ώ鳘叫今,,丨3 ^ ''J cn ψ 4 v ^ 2 g S | i^C&gt; 4-0C IL·0C IL·5 Office ^氺ά: δ U. I VQ VO Vsd 1 'Ο 152524.doc -456- 201130854

iH-NMR (sterol-d4, 300 MHz): 1·95 (s, 3H); 2.41 (m, 3H); 3.87 (m, 3H); 5.38 (m, 1H); 5.47 (m, 1H); 6.71 (m, 1H); 6.96-7.62 (m, 7H). 1 UPLC-MS (ES+): [M+H]+=594. [H-NMR (sterol-d4, 300 MHz): 1.88 (d, 3H); 2.42 (m, 3H); 3.86 (d, 3H); 5.52 (m, 1H); 5.64 (m, lH); (m, 1H); 7.02-7.59 (m, 7H). UPLC-MS (ES+): [M+H]+=594. h-NMR (sterol-d4, 300 MHz): 1.91 (d, 3H); 3.87 (d, 3H); 4.74 (d, 0.5H*); 4.82 (d, 0.5H*); 5.35 (m, 1H) ); 6.63-7.61 (m, 7H). UPLC-MS (ES+): [M+H]+=613 〇3-[Amino-(5-fluorenyl-thiazol-2-yl)-fluorenyl]-6-(2-gas-3-oxo -phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]«pyridinyl- 5-keto (diastereomer 1) «,^ S 1 ^ ^ ύ ^ ^ . ^ il TL ^ \l( ' ^ f? ^ f JS ^ ^ v ^ 4 J Φ ϋ 3 ^ 3 « a砩蚪味璁134 f? w A ^rA区Λ ^ ^ 念工,硪涂 S rA CN S- β Α硪ώ A云un &gt;〇^ ΰ dvd 卜'O a Bu\ό s 152524.doc -457- 201130854 ^-NMR (sterol-d4, 300 MHz): 1.98 (m,3H); 3.90 (d,3H); 4.90 (d, 1 0.5H*); 4.95 (d, 0.5H*); 5.29 (m, 1H); 6.39 (d, 0.5H*); 6.46 (d, 0.5H*); 6.70-7.54 (m, 7H) UPLC-MS (ES+): [M+H]+=613. ^-NMR (methanol-d4, 300 MHz): 1.95 (m,3H) 3.90 (d,3H); 4.55 (d, 0.5H*); 4.59 (d, 0.5H*); 5.35 (m, 1H); 6.92 (t, 1H); 6.98-7.53 (m, 11H) UPLC-MS (ES+): [M+H]+=609. t 5 3 2 SI 11 m WS r-1-! (N ¢- ' 1 ^ λ3 * c 1 m ϋ 6.71b 6.72 152524.doc -458- 201130854 (Life humiliation ^^^ ¥ί 漤 隶 隶 馊葙衾-B) Pier φ0ΓιηΙ¥_Η^9ΌΙ=·^ :&lt;Νϋ Post ¥0葙(#宁vf^_ ^¥ί 璁咻 鞮一·葙念-©) Side f&lt;^99·/^ Side f^oovol·^: One 韬璁蜱銮: (御令/古Pepper 0.1 : $ιίΝ3Μ%ΓΟ+ο(Νο8 igto/^ro* i 9. inch xosl sisoI even 32ixD)cndH±i4^ Qss=+[H+w]:(+ISH)sw-31dn (Hors) 85 ./,-66.9^1^0^0 9Z/9-89.9 ίΓίί50„β)S.9-S10.9 XHrsfNz.s^o.lniuffisosQq inch rffiloo 308·inch ί(Ηε巨)69&gt;os.^( Hrs 寸 inch inch inch inch inch inch inch inch Ν τ τ 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 )eisM-H- (δ乐蜱¥0葙毋)1-5 J -9-^-3)-8-3⁄4 械.^邮-e -1d-9-cfffi--砩机械-砩®0- e

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Qrns 152524.doc -460· 201130854 Table 28b (Continued Table 28): The following Examples 6_74a and 6.74b start from the intermediates U.3a and U.3b in a similar manner to Example 6.25 and in accordance with the modified form of GP 8 To prepare

Wound structure ~· . Name. Partition: Zike•,··· 6.74a 3-(Amino-phenyl-indenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl) -6-iodo-2,2,7-tridecyl-2,3-dihydro-°°°[3,2-a]°pyridin-5-one (diastereomer 1) iH-NMR (methanol-d4, 400 MHz): 1.13 (s, 3H); 1.40 (s, 3H); 1.95 (s, 3H); AB signal (δΑ=4·06, δΒ=4.22, 2χ1Η); 4.55 (d, 1H), 5.36 (d, 1H), 7.29-7.40 (m, 2H), 7.41 -7.53 (m, 3H); 7.57-7.63 (m, 3H). UPLC-MS (ESI+): [M+H]+=603 〇6.74b 3-(Amino-phenyl-indenyl)-8-(2-fluoro-6-trifluorodecyl-benzoinyl)- 6-峨_ 2,2,7-tridecyl-2,3-dihydro-thrazole [3,2-a]°pyridin-5-one (diastereomer 2) h-NMR (methanol-d4, 400 MHz): 1.50 (s, 3H); 1.67 (s, 3H); 2.29 (s, 3H); 3.94 (s, 2H); 4.66 (d, 1H), 4.99 (d, 1H) ; 7.11 -7.57 (m, 8H). UPLC-MS (ESI+): [M+H]+=603 for palmar HPLC (Chiralpak IA 5 μιη 15〇x4.6mm; hexhide/2-propanol 80:20 +0.1% diethylamine; 1.0 ml/min): Enantiomer 1 : Rt = 5.14 min; enantiomer 2: Rt = 8.36 min.

S 152524.doc 461 - 201130854

Benzoquinone 1 i«?4eq inchΑ.9^β inchΖ/9^9Γ9 , qsr9e 5Γ9¥驷Idol doM frame铋馁w^w 荽MS9.9 苳^^^q06.9^qIr9i#{Kl- ^:(6z^^)q6K Analytical data h-NMR (methanol-d4, 300 MHz): 1.76-1.99 (m, 6 Η), 3.38-3.57 (m, 2 Η), 3.98-4.16 (m, 2H); 4.60 (d, 1H); 5.26-5.34 (m, 1H); 6.78-6.96 (m, 1H); 7.05-7.61 (m, 11H). UPLC-MS (ESI+): [M+H]+=590 〇^-NMR (sterol-&lt;14,4001^1^): 1.90 (〇1,311), 3.34-3.43 (1«,1 both , 3.49-3.58 (m, 1H), 3.93-4.13 (m, 2H), 4.28 (d, 4H), 4.63 (d, 0.5H*), 4.75 (d, 0.5H*); 5.29-5.41 (m, 1H), 6.38-6.44 (m, 0.5H*); 6.51-6.58 (m, 0.5H*); 6.62-6.72 (m, 1H); 7.21-7.40 (m, 6H); 7.42-7.52 (m, 1H) 7.52-7.59 (m, 1H) UPLC-MS (ESI+): [M+H]+=601. Name 3-(Amino-phenyl-fluorenyl)-6-[3-(l,l -diqi-ethyl)-phenyl]-8-(2-disorder-6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-a Pyridine-5-one (diastereomer 1) 3-(rhoen-yl-phenyl)-6-(5-dun 2,3-dihydro-benzo[1,4] Dioxohedo-6-yl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazinyl)-7-methyl-2,3-dione-° plug 0 sits and [3 , 2-a] ° ° ° -ketone (diastereomer 1) structure number 6.51b 6.75a 152524.doc •462· 201130854

h-NMR (methanol-(14,4001^112): 1.97 (£1,311), 3.26 (£1, 0.311*), 3.49-3.54 (m, 1H), 3.87-3.95 (m, 2H), 4.30 -4.35 (m, 4H), 4.56 (d, 0.3H*), 4.61 (d, 0.7H*); 5.33-5.39 (m, 1H), 6.57-6.63 (ms 0.7H*); 6.71-6.79 (m , 1.3H*); 7.17-7.32 (m, 6H); 7.38-7.53 (m, 2H) UPLC-MS (ESI+): [M+H]+=601. For palmar HPLC (Chiralpak IB 5 μιη 150x4 .6 mm; hexane/ethanol 80: 20+0.1% diethylamine; 1.0 ml/min): Enantiomer 1: Rt = 8.97 min and 11.36 min (two peaks due to dynamic isomerization Enantiomer 2 : Rt = 11.36 minutes and 13.24 minutes (two peaks due to dynamic helication) h-NMR (sterol-d4, 400 MHz): 1.95-1.98 (m, 3H), 3.22 (d,0·4Η*), 3.47-3.56 (m, 1H), 3.86-4.00 (m, 2H), 4.59 (d, 0.4H*), 4.64 (d, 0.6H*); 5.35-5.44 ( m,1H), 7.16-7.54 (m, 11H). UPLC-MS (ESI+): [M+H]+=627. ^ f ^ ^ ί | ν〇ι 1 '1 , Λ rv 砩 锰 锰韬®- ^1ι (N i&amp;- ^ 碥5 4 4 order 5 mechanical 彳33銮^ 5 fT'J *^· 1 β cA ri Ο嘁咿 ( ( ( ( ( ( ( -(2-fluoro-3-triimethoxy) - stupid)-8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-2,3-dihydrogenate sit and [3,2-a] ° fc ° -5-ketone I %? 卜'Ο 152524.doc .463 · 201130854 iH-NMR (sterol-d4, 300 MHz): 1.78-2.05 (m, 6H), 3.38-3.51 (m, 1H), 3.69- 3.96 (m, 3H), 5.48-5.60 (m, 1H), 7.08-7.59 (m, 11H). UPLC-MS (ESI+): [M+H]+=607 » 'H-NMR (methanol-d4, 300 MHz): 1.80-2.02 (m, 6H), 2_87 (d, 0.5H*); 3.04 (d, 0.5H*); 3.47-3.60 (m, 1H), 3.85-4.05 (m, 2H), 5.50 -5.66 (m, 1H), 7.17-7.58 (m, 11H) 〇 UPLC-MS (ESI+): [M+H]+=607. ^-NMR (sterol-d4, 300 MHz): 1.96-2.01 (m, 3H), 2.59-2.69 (m, 3H); 3.48-3.59 (m, 1H), 3.88-4.01 (m, 2H), 4.60 (d, 0.5H*); 4.66 (d, 0.5H*); 5.35-5.47 (m, 1H), 7.17-7.63 (m, 10H); 7.85-7.93 (m, 1H). UPLC-MS (ESI+): [M+H]+=585. A &lt;N »- f ^ v ώ ^ 7 g cn * N (N| 余V硪硪^璁mi! 4 ^ ':! 1 ? ^ ^ &lt;N ^ ^ ' 1 ^ ^ 9 4 ^ | g ^ ^ ss ^ ^ 5 $ S 3 ...5 fit Φ^Ι 9 '|l cA ^ ^ v〇〇r ^ ^ Λ ^ ^ $ 1') ? and j 3兮fNl ffi— 0 ^ 4 Ϊ ^ 3 j ί ^ 3 Μ I cA ^4- ^ λ X 4 . Alkali: Lion 6.77a 6.77b 6.78 152524.doc -464- 201130854

^-NMR (sterol-d4, 300 MHz): 1_95·1.99 (m, 3H), 3.44-3.54 (m, 1H), 3.84-3.98 (m, 2H), 4.54 (d, 0.5H*); (d, 0.5H*); 5.31-5.41 (m, 1H), 7.13-7.53 (m, 11H). UPLC-MS (ESI+): [M+H]+=627. ^-NMR (methanol-d4, 300 MHz): 1.83 &amp; 1.85 (2x s,3H); 1.95 &amp; 2.01 (2x s, 3H), 3.40-3.48 (m, 1H), 3.50-3.63 (m, 1H) ), 3.89 (d, 3H); 3.99-4.17 (m, 2H); 4.64 (d, 0.5H*); 4.68 (d, 0.5H*); 5.30-5.42 (m, 1H); 6.73 (d, 1H) 7.22-7.40 (m, 6H); 7.44-7.62 (m, 2.5H*); 7.66 (s, 0.5H*). UPLC-MS (ESI+): [M+H]+=570. ^-NMR (sterol-d4, 300 MHz): 1.89 &amp; 1.93 (2x s,3H); 3.39-3.48 (m, 1H), 3.56-3.67 (m, 1H), 3.92-4.13 (m, 2H) 4.64 (d, 0.5H*); 4.74 (d, 0.5H*); 5.31-5.46 (m, 1H); 6.92-7.23 (m, 3H); 7.24-7.38 (m, 6H); 7.41-7.60 ( s, 2H). UPLC-MS (ESI+): [M+H]+=627. 3-(Amino-phenyl-methyl)-6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-|iJ-6-trifluoromethyl-benzyl )-7-Methyl-2,3-dihydro-sodium [3,2-a]° bite- 5-keto 3-(amino-phenyl-indenyl)-8-(2-fluoro-6) -trifluoromethyl-phenylhydrazino)-6-(6-methoxy-4-methylbutylet-3-yl)-7-methyl-2,3-dihydro-thiazolo-p,2- a]° ratio bit-5-keto 4-trifluorodecyloxy-phenyl)-8-(2·Ιό-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydro- Thiazolo[3,2-a]. Bipyridin-5-one &gt; 0-0 i 6.79 6.80 6.81 s 152524.doc -465- 201130854 ^-NMR (methanol-d4, 300 MHz): 1.95 (s, 3H); 3.31 (m, 1H); 3.47 (m, 1H); 3.81 (s, 3H); 3.94 (s, 2H); 4.57 (d, 1H); 5.38 (dd, 1H); 6.79 (m br, 1H); 6.91 (ddd, 1H); 7.21 -7.36 (m, 8H); 7.43 (m, 1H); 7.50 m, 1H). UPLC-MS (ESI+): [M+H]+=555 〇1 1 1 ---- iH-NMR (sterol-d4, 300 MHz): 1.94 (s, 1.35H*); 1.95 (s, 1.65 H*); 3.30-3.53 (m, 2H); 3.89 (s, 0.90H*); 3.94 (s, 1.10H*); 4.57 (d, 0.45H*); 4_61 (d, 0.55H*); 5.36 (m, 1H); 7.15-7.51 (m, 12H). UPLC-MS (ESI+): [M+H]+=543. b-NMR (sterol-d4,400 MHz): U7 &amp; 1.19 (2x s,3H); 1.43 (s, 3H); 1.90 &amp; 1.93 (2x s, 3H); 3.87 (d, 3H), 4.01 -4.21 (m, 2H); 4.31-4.37 (m, 1H); 5.24-5.31 (m, 1H); 6.72-6.82 (m, 1H); 7.05-7.19 (m, 2H); 7.24-7.30 (m, 1H); 7.31-7.40 (m, 3H); 7.44-7.54 (m, 3H); 7.55-7.60 (m, 1H). UPLC-MS (ESI+): [M+H]+=627. ^ ^ 1 d M f i5 taste. cn ^ Λ fiv〇CN $ 3 ί 1 rn rn ^ ' 1 3-(Amino-phenyl-fluorenyl)-6-(2-oxo-3-methoxy- Phenyl)-8-(2- gas-6-difluoromethyl-adenyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a&gt; 〇定-5-嗣 (diastereomer 1) 6.82 6.83 6.84a 152524.doc -466 - 201130854

h-NMR (methanol-d4, 400 MHz): 1. 54 (s, 3H); 1.74 &amp; 1_77 (2x s, 3H); 1.83 &amp; 1.91 (2x s, 3H); 3.78-3.94 (m, 5H) ), 4.78 (d, 0.5H*); 4.93 (s, O.SH*); 4.98 (d, 0.5H*); 5.09 (s5 0.5H*); 6.51-6.57 (m, 0.5H*); 6.70 -6.76 (m, 0.5H*); 7.04-7.55 (m, 10H). UPLC-MS (ESI+): [M+H]+=627. H-NMR (methanol-d4, 400 MHz): 1.15 &amp; 1.18 (2xs, 3H); 1.43 (s, 3H); 1.92 &amp; 1.95 (2x s, 3H); 3.99-4.21 (m, 2H); 4.22 -4.32 (m, 5H); 4.36-4.44 (m, 1H); 5.26-5.33 (m, 1H); 6.56-6.67 (m, 3H); 7.26-7.43 (m, 4H); 7.45-7.61 (m, 4H). UPLC-MS (ESI+): [M+H]+=629. iH-NMR (methanol-d4, 400 MHz): 1.53-1.58 (m, 3H); 1.78-1.82 (m, 3H); 1.92-1.96 (m, 3H); 3.77-3.84 (m, 2H), 4.28- 4.37 (m, 4H); 5.02-5.13 (m, 2H); 6.57-6.82 (m, 2H); 7.14-7.34 (m, 5H); 7.36-7.51 (m, 3H). UPLC-MS (ESI+): [M+H]+=629. ‘UJ ‘ ΐ ^ 'Ί ? 澧? S 1 is 3-(amino-phenyl-indenyl)-6-(5-gas-2,3-di-benzo[1,4]dioxine-6-yl)- 8-(2-Fluoro-6-trifluoromethyl-adenyl)-2,2,7-trimethyl-2,3-dihydro-°°°[3,2-a]e ratio Bite-5-capsule (diastereomer 1) 3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1,4] Oxecyclohexene-6-yl)-8-(2-fluoro-6-trifluoromethyl-adenyl)-2,2,7-trimethyl-2,3-dihydro-° 嗤And [3,2-a]D is determined by -5 -嗣 (diastereomer 2) %? %? oo 00 00 152524.doc -467· 201130854

^-NMR (sterol-d4, 400 MHz): 1.17 &amp; 1.20 (2x s,3H); 1.44 (s,3H); 1.92 &amp; 1.95 (2x s, 3H); 4.01-4.23 (m, 2H) ; 4.33-4.39 (m, 1H); 5.24-5.32 (m, 1H); 7.21-7.61 (m, 11H). UPLC-MS (ESI+): [M+H]+=656. h-NMR (sterol-d4, 400 MHz): 1.51-1.56 (m, 3H); 1.69-1.75 (m, 3H); 1.80 &amp; 1.88 (2x s, 3H); 3.85 (s, 1H); , (s, 1H); 4.64 (d, 0.5H*); 4.78 (d, 0.5H*); 4.90 (d, 0.5H*); 5.03 (d, 0.5H*); 6.80-6.86 (d, 0.5 H*); 7.06-7.12 (d, 0.5H*); 7.16-7.58 (m, 10H). UPLC-MS (ESI+): [M+H]+=656 °^-NMR (Methanol-d4, 400 MHz): 1.17 &amp; 1.19 (2xs,3H); 1.41-1.46 (m, 3H); 1.91 &amp;; 1.93 (2x s, 3H); 4.01-4.23 (m, 2H); 4.31-4.39 (m, 1H); 5.24-5.31 (m, 1H); 7.11-7.61 (m, 12H). UPLC-MS (ESI+): [M+H]+=57 卜^u.' ? , i CN CS ^ Ci ώ _ ^ : again 5 ^ ^ ^ ^ 碥A if the finder Φί ? ^ isss S u | u| ^ cA φ Φ ώ ^ ? A bead S ® - ® 7 T ^ WK is 5 5 s SU| H| cA cA vi ®- 3-(月安基-phenyl-methyl)-6- (2-Gas_Phenyl)-8-(2-Dai-6·Tris-decyl-phenylhydrazino)-2,2,7-tridecyl-2,3-dihydro-° 塞 吐 [ 3,2^]°°°-5-ketone 00 vd VO OO VO 152524.doc •468- 201130854

^-NMR (sterol-d4,400 MHz): 1.16 &amp; 1.19 (2xs, 3H); 1.41-1.46 (m, 3H); 1.92 &amp; 1.95 (2x s, 3H); 3.75 &amp; 3.78 (2x s , 3H); 4.00-4.21 (m, 2H); 4.31-4.39 (m, 1H); 5.24-5.30 (m, 1H); 6.73-6.83 (m, 1H); 6.87-6_97 (m, 1H); 7.02 -7.11 (m,1H); 7.23-7.61 (m, 9H). UPLC-MS (ESI+): [M+H]+=601. iH-NMR (methanol-(14,400)^1^): 1.05-1.16 (111, 311); 1.42 (3, 3; 1.87-2.06 (m, 6H); 3.95-4.09 (m, 1H); 4.18- 4.31 (m, 1H); 4.99 (d, 1H); 5.47 (d, 1H); 7.26-7.76 (m, 11H). UPLC-MS (ESI+): [M+H]+=635. ^-NMR ( Methanol-d4, 400 MHz): 1.50-1.56 (m, 3H); 1.67-1.74 (m, 3H); 1.75-2.09 (m, 6H); 3.86 (s, 1H); 3.95, (s, 1H); 4.55-4.62 (m, 1H); 4.72 (d, 0.5H*); 5.02 (d, 0.5H*); 6.83-6.92 (d, 0.5H*); 7.15 -7.61 (m, 11.5H*). UPLC -MS (ESI+): [M+H]+=635. 3-(Amino-phenyl--yl)-6-(2-fluoro-5-methoxy-phenyltrifluoromethyl-benzene -2,2,7-trimercapto-2,3-dihydro-thiazolo[3,2-a] aceto-5-one 3-(amino-phenyl-indenyl)-6 -[3-(l,l-difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-2,2,7-triterpene Base-2,3-dihydro-thiazolo[3,2-3]0 ratio °-5-嗣 (diastereomer 1) i Φ έ s £ 芷ί ΐ ^ ^ ^ I i ^ ^ B- X ^ 'Ί I f\ 011 6.88 6.89a 6.89b 152524.doc -469· 201130854 ^-NMR (sterol-d4, 400 MHz): 1.17 (s,3H); 1.43 (s,3H); 1.83 -1.99 (m, 6H); 4.00-4.24 (m, 2H); 4.42 (d, 1H); 5.30 (d, 1H) ; 7.25-7.61 (m, 12H). UPLC-MS (ESI+): [M+H]+=617. h-NMR (methanol-d4, 400 MHz): 1.57 (s, 3H); 1.80 (s, 3H) ); 1.86-2.05 (m, 6H); 3.84 (s, 2H); 5.06 (s, 1H); 5.14 (s, 1H); 7.17 - 7.61 (m, 11H). UPLC-MS (ESI+): [M +H]+=617. 3-(Amino-p-styl-fluorenyl)-6-[3-(l,l-diethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzoinyl) -2,2,7-tridecyl-2,3-dihydro-thiazolo[3,2-&amp;]pyridin-5-ketone (diastereomer 1) Λ νά ^ fv ', 〒 1 2 ^ ^ ^ S ^ J ^ 1 ? | M illusion χ, 丨Ό 6.90a 6.90b 152524.doc -470- 201130854 Example 7.1 a Preparation of 4-({[6-(2-fluoro·3_τ oxy) -phenyl)_8_(2_fluoro+trifluoro-t-benzyl)-7-methyl-5-oxooxy-2,3-dihydro-5Η-thiazolo[3,2_a]pyridine-3· Ethyl]-phenyl-methyl-amino)-butyric acid ethyl ester (diastereomer

According to the modified form of GP 25a: N-ethyldiisopropylamine (24 pL, 18 mg, 14 〇μπιοί, 1 equivalent) was added to ethyl bromobutyrate at room temperature (60, 82 mg, 419 μπιο1, 3 equivalents) and 3-(aminophenylindenyl)-6-(2-fluoro-3-methoxy-phenyl)_8_(2_fluoro-6-trifluoromethyl)benzoquinone Methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer oxime) (Example 6.6a) (80 mg, 140 μηιοί) in acetonitrile (2 mL The stirred solution is heated to 80 ° C for 20 hours. Then a second portion of N-ethyldiisopropylamine (24 pL, 18 mg, 140 Hm) is added and Ethyl 4-bromobutyrate (60 μί '82 mg, 419 μηηοΐ, 3 eq.) and stirring was continued for 7 hours. The solvent was evaporated and subjected to flash chromatography to give the title compound (yield: 46, 5 mg). NMR (sterol-d4, 400 MHz): 1.18 (dt, 3H); 1.59-1.69 (m 2H); 1.88 &amp; 1.91 (2 xs, 3H); 1.95 (mc, 1H); 2.02-2.14 (m 1H 2.20-2.32 (m, 3H); 2.52-2.61 (m, 1H); 3.33-3.46 (m 2H); 3.83-3.92 (m, 4H); 3.99-4.16 (m, 5H); 4.38 (d, 〇.5 H*)· s 152524.doc •471 - 201130854 4.51 (d, 0.5H*); 5.21-5.31 (m, 1H); 6.50-6.56 (m, 0.5H*); 6.67-6.73 (m, 0.5H*) 7. (H-7.61 (m, 11H). MS (ESI+): [M+H]+=687. 152524.doc -472- s

201130854

Driving gambling ο ι s-ι^έ fw?4^or9^q9.9¥^fw?4-mI^(NIdolr 鹓鹓兴^^wrif 黩BI.匕4 铋铼χί·卜叫qlc^f冬X卜Xt : Ie&lt;

'&gt; K -v: -·, •';€f: iN; .'This ί: κ. 1 1.. } , ;vi . V- ^-NMR (sterol-d4, 300 MHz): 1.17 (dt,3H); 1.60-1.76 (m, 2H); 1.93 (s, 3H); 2.25-2.52 (m, 4H); 3.17-3.22 (m, 0.5H*); 3.41-3.50 (m, 1H) ; 3.85-3.98 (m, 5H); 4.04 (q, 2H); 4.21 (d, 0.5H*); 4.29 (d, 0.5H*); 5.37-5.44 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.81-6.87 (m, 0.5H*); 7.07-7.33 (m, 8H); 7.37-7.54 (m, 2H). MS (ESI+): [M+H]+= 687. Enantiomer 1: Optical rotation: [a] D2Q + 210.8 (C = 1, sterol). iH-NMR (methanol-d4, 300 MHz): 1.19 (t, 3H); 1.94 (s, 3H); 3.36-3.51 (m, 2H); 3.83-3.97 (m, 5H); 4.04-4.15 (m, 2H); 4.31 (d, 0.5H*); 4.41 (d, 0.5H*); 5.39-5.48 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.85-6.92 (m, 0.5H*) ); 7.05-7.54 (m, 1 OH). MS (ESI+): [M+H]+= 659. 'i? titf» W :, by 4-({ [6-(2-gas-3-methoxy-phenyl)-8-(2- gas-6-trifluoromethyl-benzyl)- 7-mercapto-5-p-oxy-2,3-dihydro-5H-thiazolo[3,2-a]11 butyl-3-yl]-phenyl-indenyl}-amino)-butyl Ethyl ester (diastereomer 2) ({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)) -7-Methyl-5-oxo-2,3-dihydro-5H-thiazole P,2-a]»bipyridin-3-yl]-phenyl-indenyl}-amino)-acetic acid Ethyl ester 琮rW ^ °^\&gt; κ) Scale CN s 152524.doc -473 - 201130854 ^-NMR (methanol-d4, 300 MHz): 1.19 (dt, 3H); 1·93 (d, 3H); 2.37-2.48 (m, 2H); 2.60-2.79 (m, 2H); 3.41-3.51 (m5 1H); 3.84-3.95 (m, 5H); 4.01-4.13 (m, 2H); 4.29 (d, 0.5H *); 4.36 (d, 0.5H*); 5.37-5.45 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.85-6.92 (m, 0.5H*); 7.06-7.54 (m, 10H ). MS (ESI+): [M+H]+= 673. iH-NMR (methanol-d4, 300 MHz): 1.17 (dt, 3H); 1.96 (s, 3H); 2.24-2.33 (m, 2H); 2.35-2.51 (m, 2H); 3.18 (d, 0.5H) *); 3.41-3.50 (m, 1H); 3.87-3.97 (m, 2H); 4.00-4.08 (m, 2H); 4.23 (d, 0.5H*); 4.31 (d, 0.5H*); 5.38- 5.46 (m, 1H); 6.06 (d, 2H); 6.59-6.64 (m, 0.5H*); 6.71-6.79 (m, 1.5H*); 7.17-7.53 (m, 7H). MS (ESI+): [M+H]+= 701. iH-NMR (methanol-d4, 300 MHz): 0.81-1.00 (m, 2H); 1.18 (dt, 3H); 1.93 (s, 3H); 2.19-2.27 (m, 2H); 2.34-2.51 (m, 2H); 3.34-3.50 (m, 1H); 3.83-3.97 (m, 6H); 4.00-4.10 (m, 2H); 4.24 (d, 0.5H*); 4.30 (d, 0.5H*); 5.37- 5.46 (m, 1H); 6.69-6.76 (m, 0.5H*); 6.79-6.86 (m, 0.5H*); 7.03-7.61 (m, 10H). MS (ESI+): [M+H]+= 701. 4 ^ J ^ ^ % ψ ^ ®- 1 ΓΤ71 4 ^ 3 T Year ¥ 5 ^ 5 ? 4 ά ^ ώ 4-({[6-(4-Fluoro-benzo[1,3]dioxane) Pentene-5-yl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5Η-α stopper Sit and [3,2-a] ° than biting 3-yl]-phenyl-indenyl}-amino)-butyric acid ethyl ester w 办 妙 办 B B B B B B B B B B B B B B B B B B .4 〇^ ^ ^ ^ ^ f 7\ ^ ^ S ^ J ? % 乂0 af .〇c\ r Λ 寸 l〇 Bu ^ 152524.doc -474- 201130854

h-NMR (sterol-d4, 300 MHz): 1.12-1.22 (m,3H); 1.62-1.76 (m, 2H); 1.96 (s, 3H); 2.30 (t, 2H); 2.34-2.51 (m , 2H); 3.16 (d, 0.5H*); 3.40-3.51 (m, 1H); 3.79 (d, 3H); 3.87-4.13 (m, 5H); 4.21 (d, 0.5H*); 4.29 (d , 0.5H*); 5.38-5.46 (m, 1H); 6.70-6.76 (m, 0.5H*); 6.80-6.86 (m, 0.5H*); 6.89-6.98 (m, 1H); 7.03-7.16 ( m, 1H); 7.17-7.35 (m, 6H); 7.38-7.56 (m, 2H). MS (CI+): [M+H]+=687. iH-NMR (methanol-d4, 300 MHz): 1.17 (t,3H); 1.59-1.75 (m,2H); 1.97 (s, 3H); 2.23-2.34 (m, 2H); 2.34-2.51 (m, 2H); 3.18 (d, 1H); 3.40-3.51 (m, 1H); 3.89-4.15 (m, 5H); 4.20 (d, 1H); 5.36-5.45 (m, 1H); 7.13-7.34 (m, 9H); 7.39-7.58 (m, 3H). MS (CI+): [M+H]+=723. 4-( {[6-(2-Fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoyl)-7-methyl-5-side oxygen Base-2,3-dihydro-5H-thiazolo[3,2-a].pyridin-3-yl]-styl-fluorenyl}-amino)-butyric acid ethyl r: ^ ^ into one # tO , '1 1丨士潜¥ ? i 3 5 G, f ^ 〇ό B- ° ? i 4 c? σ

s 152524.doc .475. 201130854 Example 7.8b Preparation of 4-({[6-(2-fluoro-3.nonyloxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzene) Benzyl-7-methyl-5-sideoxy-2,3-dihydro-5H-salt[3,2-a]0-biti-3-yl]-phenyl-methyl}-amine Base)_butyric acid (diastereomer 2)

Add a solution of sodium hydroxide (32 bL 3 2% aqueous solution, 33.7 mg, 843 μηηοΐ '2 equivalent) in water (30 μΐ) to 4-({[6-(2-fluoro-) at room temperature 3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-methyl_5_ pendant oxy-2,3-dihydro-5H-indole And [3,2-a]e is more than -3-yl]-phenyl-indenyl}-amino)-butyric acid ethyl ester (diastereomer 2) (Example 7.1b) (289 mg, 421 μιηοΐ) was stirred in THF (6 mL) and stirred at 45 ° C for 3 h. Then, sodium hydroxide (32 pL 32% aqueous solution, 33·7 mg, 843 μηηοΐ, 2 equivalents) in water (30 kL) was added again and stirring was continued for 48 hours at room temperature. The value of ]11 was adjusted to ρΗ 5_6 by adding a 10% aqueous citric acid solution and the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The target compound was isolated by flash column chromatography (yield: 215 mg). W-NMR (methanol _d4, 300 MHz): i 66 1 82 (m, 2H); i % (d, 3H); 2.26-2.40 (m, 2H); 2.59-2.82 (m, 2H); d, 0.5H*); 152524.doc •476· 201130854 3.35 (d, 0.5H*); 3.49-3.58 (m, 1H); 3.84-3.97 (m, 5H); 4.45 (d, 0.5H*); 4.53 (d, 0.5H*); 5.50-5.57 (m,1H); 6.70-6.76 (m, 0.5H*); 6.85-6.91 (m, 0.5H*); 7.07-7.35 (m, 8H); 7.38 -7.55 (m, 2H). MS (ESI+): [M+H]+= 659. Enantiomer 1 : Optical rotation: [a] D2Q + 204.5 ° (C = l, methanol).

S 152524.doc 477- 201130854 Analytical data • ' .......... . . + ^-NMR (sterol-d4, 300 MHz): 1.72-1.82 (m, 2H); 1.91 (s, 3H); 2.26-2.36 (m, 2H); 2.61-2.81 (m, 2H); 3.45-3.54 (m, 1H); 3.65-3.76 (m, 1H); 3.83-3.93 (m, 5H); 4.57 ( d, 1H); 5.47-5.57 (m, 1H); 6.64-6.73 (m, 1H); 7.04-7.58 (m, 11H). MS (ESI+): [M+H]+= 659. ^-NMR (sterol-d4, 300 MHz): 1.95 (s, 3H); 2.83-3.23 (m, 2.5H*); 3.38-3.55 (m, 1H); 3.82-3.98 (m, 5H); (d, 0.5H*); 4.51 (d, 0.5H*); 5.42-5.55 (m, 1H); 6.69-6.78 (m, 0.5H*); 6.80-6.89 (m, 0.5H*); 7.06- 7.54 (m, 11H). MS (ESI+): [M+H]+= 631. Name 4-({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl- amidino)-7-fluorenyl-5-side Oxy-2,3-dis-5H-thiazolo[3,2-3]° ratio -3-amino]-phenyl-fluorenyl}-amino)-butyric acid (diastereomer) 1) ({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-side oxygen Base-2,3-dihydro-5H-thiazolo[3,2-a]fl than -3-yl]•phenyl-methyl}&quot;•amino)-acetic acid structure 〇&lt;0 〇 number 7.8a Ο) -478 - 152524.doc 201130854

lH-NMR (sterol-d4, 300 MHz): 1.94 (d, 3H); 2.34-2.49 (m, 2H); 2.70-2.90 (m, 2H); 3.04 (d, 0.5H*); 3.47-3.58 (m, 1H); 3.84-3.94 (m, 4H); 4.01 (br. s, 1H); 4.51-4.59 (m, 1H); 5.50-5.66 (m, 1H); 6.70-6.78 (m, 0.5H) *); 6.96-7.03 (m, 0.51^); 7.05-7.57 (m, 10H). MS (ESI+): [M+H]+=645. __:_iH-NMR (methanol-d4, 400 ΜΗζ): 1.75-1 ·90 (m, 2H); 2.01 (d, 3H); 2.29-2.41 (m, 2H); 2.74-2.88 (m, 2H) ; 2.99-3.05 (m, 0.5H*); 3.12-3.22 (m, 0.5H*); 3.53-3.64 (m, 1H); 3.94-4.06 (m, 2H); 4.63-4.73 (m, 1H); 5.64-5.74 (m, 1H); 6.07 (d, 2H); 6.60-6.67 (m, 0.5H*); 6.74-6.82 (m, 1.5H*); 7.23-7.56 (m, 9H). MS (ESI+): [M+H]+= 673. 々-NMR (sterol-d4, 400 MHz): 1.44-1.63 (m, 4H); 1.94 (d, 3H); 2.17-2.26 (m, 2H); 2.48-2.60 (m, 2H); 3.18 (d , 0.5H*); 3.45-3.53 (m, 1H); 3.86-3.99 (m, 5H); 4.38 (d, 0.5H*); 4.45 (d, 0.5H*); 5.47-5.55 (m, 1H) ; 6.70-6.76 (m, 0.5H*); 6.82-6.87 (m, 0.5H*); 7.07-7.53 (m, 11H). MS (ESI+): [M+H]+= 673.地人发发1不约2 乂" 1 Φ-lll ^ ή ^ ¥ z 4 U·1 ^ ^ ^ will $苳〒砩ss ^ ^ Ϊ q '丨蝴蝶.m_ ^ ^ AA 士^ X ψ ^ 砩土®- 4 ί 3 ί 3 ¥ ^ ^ ^ € ir—η 5 ¥ ^ c? %? % Λ0 o Ο cs s 152524.doc -479- 201130854

iH-NMR (sterol-d4, 300 MHz): 1.67-1.84 (m, 2H); 1.97 (d, 3H); 2.26-2.39 (m, 2H); 2.58-2.81 (m, 2H); 3.15 (d , 0.5H*); 3.48-3.58 (m, 1H); 3.79 (d, 3H); 3.86-4.01 (m, 2H); 4.47 (d, 0.5H*); 4.52 (d, 0.5H*); 5.50 -5.59 (m, 1H); 6.71-6.77 (m, 0.5H*); 6.87-6.99 (m, 1.5H*); 7.03-7.17 (m,1H); 7.18-7.38 (m,6H); 7.38- 7.56 (m, 2H). MS (ESI+): [M+H]+= 659. h-NMR (methanol-d4, 300 MHz): 1.66-1.78 (m, 2H); 1.95 (s, 3H); 2.19 (t, 2H); 2.52 (t, 2H); 3.32 (br. s, 1H ); 3.42-3.52 (m, 1H); 3.91 (br. s, 2H); 4.37 (d, 1H); 5.41-5.49 (m, 1H); 7.11-7.33 (m, 9H); 7.37-7.57 (m , 3H). MS (ESI+): [M+H]+= 695. 4-({[6-(2-Fluoro-5-decyloxy-phenyl)-8-(2-morpho-6-trifluoromethyl-benzyl)-7-methyl-5-side oxygen Base-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methyl}-amino)-butyric acid ^ SS 5 ^ 'Ί φ ^ — Destroy key "1 off 1 丨 卜 ^ ^ Λ ^ id ^ 2 〇〇®- V noisy 3 Λ 0 Λ 0 7.13 7.14 I 152524.doc • 480· 201130854 Example 7.15 Preparation 4-{[{6·(2_ Fluorine·3_methoxyphenyl)_8_[2_fluoro_6•(3^f-yl-methyl-5-sideoxy-2,3-digas-called (3)嗟 并[3, Sodium pyridin-3-yl}(phenyl)methyl]amino)butyrate

曰 Add sodium hydride (32% aqueous solution, 6 6 (four). 卜 〇 〇) to 4-({[6-(2-fluoro-3-methoxy-phenyl)_8_(2) at room temperature _Fluorine_6-trifluoromethylphenyl fluorenyl)-7-fluorenyl 5-sideoxy-2,3-dihydro·5Η_嗟嗤[3,2_&amp;]0 is more than 唆3_yl]- Phenyl-methyl-ammonium butyric acid (diastereomer example 7.8b) (40_6 mg '61.6 μιηοΐ) in a mixture of third butanol (〇5 mL) and water (〇5 鲁mL) In solution, proceed to dryness to give the title compound (yield: 34.7 mg). W-NMR (decyl alcohol _d4, 4 〇〇MHz): 丄65 ι 83 (m, 2H); 丄9Ubr s, 3H) , 2.07-2.19 (m, 2H); 2.41-2.57 (m, 2H); 3.35-3.55 (m, 2H), 3.79-3.95 (m, 5H); 4.32 (d, 0.5H*); 4.42 (d, 0.5H*); 5.39-5.48 (m, 1H); 6.68-6.77 (m, 0.5H*); 6.83-6.91 (m, 〇.5H*); 7.05-7.33 (m,8H); 7.34-7.52 ( m, 2H). Enantiomer i: Optical rotation: [a] D2 〇 + 198 2C) (c = 1 'sterol). Examples 7.16 and 7.17 152524.doc

I-481 - 201130854 Preparation of 6-(2-fluoro-3-methoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl-7-indenyl-3-(decylamino)- Stupid base_曱)_23_dihydro-thiazolo[3,2_a]pyridin-5-indole and 3-(didecylamino-phenyl-methyl)_6_(2_fluoro_3_methoxy Base_phenyl)_8_(2_fluoro-6-difluoromethyl-benzoinyl)_7_mercapto-2,3-dihydrothiazolo[3,2a]pyridin-5-one

Modified according to GP 25a: DIPEA (44 mg, 348 μιηοΐ ' 2 equivalents) was added to iododecane (4 〇 mg, 283 μιηοΐ, 1.62 eq.) and 3-(amino group) at room temperature. ·Phenyl-fluorenyl)_6_(2_fluoro_3_methoxy_phenyl)_8_(2-fail-6-trifluoromethyl·benzoyl)·7·decyl_2,3_2 Hydrogen-thiazolo[3,2_a]° in a stirred solution of ketone (diastereomer 2) (Example 6.6b) (100 mg, 174 μιηοΐ) in B. (3 mL). The reaction mixture was heated to 50 C ' for 4 hours. The solvent is evaporated and subjected to flash chromatography to give the target compound. Example 7.16: 6-(2-Fluoro-3-methoxy-phenyl&gt;8_(2_fluoro-6-trifluoromethyl-benzyl)-7-methyl_3_(methylamino Phenylmethyl)_23 dihydrothiazolo[3,2-a]pyridin-5-one H-NMR (methanol-d4, 300 MHz): 1.93 (m,3H); 2.28 (d,3H); m, 3H); 4.23-4.30 (m, 1H); 5.41-5.49 (m, 1H); 6.70- 152524.doc 201130854 6.77 (m, 0.5Η*); 6·81-6·9〇(m,〇 ·5Η*); 7〇6·7 53 plus 11H). , UPLC-MS (ESI+): [M+H]+=587. Example 7.17: 3-(Dimethylaminophenyl)methyl-6-(2-fluoro-3-yloxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzene曱7)_7_methyl-2,3_dihydro-thiazolo[3,2 - a ] ° ratio bite-5 - Ming W-NMR (methanol-d4, 300 MHz): 1.87 (m, 3H); 2 25 (4) 6h) φ 3.89 (m, 3H); 5.67-5.77 (m, 1H); 6.67-6.74 (mj 〇.5h*); 6.78-6.85 (m, 0.5H*); 7.06-7.49 (m, 11H). ' UPLC-MS (ESI+): [M+H]+=601. Table 33: The following Examples 7·1 8 and 7.19 were prepared in a similar manner to Example 7.16 and GP 25a was derived from Example 6.6b and the respective alkyl bromide number--·· ” ..卞.... :Structure:.::: ' -Ί :- . . &gt;v Name Analysis DataΓ 7.18 3-( Butylamino-phenyl-methyl)-6-(2-fluoro-3-decyloxy- Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydro-indole[3,2-a]0 ratio bite- 5-嗣h-NMR (methanol-d4,300 MHz): 0.84 (t, 3H); 1.22-1.47 (m, 4H); 1.92 (s, 3H); 2.32-2.50 (m, 2H); 3.40-3.50 (m, 1H); 3.85-3.95 (m5 5H); 4.26 (d, 0.5H*); 4.32 (d, 0.5H*); 5.38-5.46 (m, 1H); 6.69-6.76 (m, 0.5H* 6.77-6.85 (m, 0.5H*); 7.06-7.32 (m, 8H); 7.36-7.53 (m, 2H) MS (ESI+): [M+H]+=629. 152524.doc -483 - 201130854 fl o-CH, fluoro-3-indolyl-phenyl)-8-(2- gas-6-trifluoromethyl-benzyl)&gt;7--iH-NMR (sterol-d4, 300 MHz): 1.51-1.71 (m, 2H); 1.93 (s, 3H); 2.03-2.21 (m, 2H); 2.33-2.56 (m, 2H); 3.13-3.27 (m, 1H); 3.40-3.51 7.19 base-3-[styl-(4,4,4-trifluoro-butylamino)-indenyl]-2,3-dihydro-thiazolo[352-a]〇ib,^-5* B^ (m, 1H); 3.85-4.01 (m, 5H); 4.20 (d, 0.5H*); 4.26 (d, 0.5H*); 5.37-5.45 (m, 1H); 6.70-6.84 (m, 1H) 7.06-7.35 (m, 8H); 7.38-7.56 (m, 2H) MS (ESI+): [M+H]+= 683. Example 7.20 Preparation 3·(Allylamino-phenyl·methyl 6(2-fluoro-3-indolyloxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)7-methyl-23 dihydrothiazolo[32a] ° than bite-5 · _

Lithium borohydride (0.59 mL, 2 Μ solution in THF, 1 '2 mmol ' 4.8 eq.) was slowly added to crude 3-(allylimidinyl-phenyl-methyl) at 0 C. 6-(2-Fluoro-3-cyclooxyphenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3, 2_a] η is a stirred solution of pyridine-5-one (Example 3.28) (151 mg '247 μπιοί) in 1,2,2-dioxane (2.6 mL). Continue to mix at 〇 ° C for 2 hours and at room temperature for 22 hours. Then add another amount of borohydride clock (1 〇 mL, 2 Μ solution in THF ' 2 · 0 mm 〇 l ' 8.1 equivalents ). The reaction mixture was heated to 5 ° C, 152524.doc • 484 · 201130854 for 2.5 hours and quenched by the addition of water. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The title compound was isolated by preparative HPLC purification (yield: 21 mg). H_NMR (methanol_d4, _ MHz): 1.96 (s, 3H); 2.98-3.06 (m, 1H); 3.10-3.16 (m5 1H); 3.25-3.34 (m} 1H); 3.48 (td, 1H); 3.91-3.96 (m, 5H); 4.33-4.40 (m, 1H); 5.02-5.05 (m, 1H); 5.08 (ddd, 1H); 5.45 (t, 1H); 5.78-5.86 (m, 1H); 6.74-6.76 (m, 0.55H*); 6.83-6.85 (m, 0.45H*); 7.11-7.31 (m, 8H); 7.42-7.47 (m, 1H); 7.50-7.53 (m, 1H). UPLC-MS (ESI+): [M+H]+=613 ° Example 7.21 Preparation of 3-(1-allylamino-indole-phenyl-but-3-enyl)_6_(2_Fluor_3_ Methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-dihydro-thia*[3,2-a] Pyridine-5-ketone

According to the modified form of GP 24b: gasified allyl magnesium (164 pL, 2M solution in THF, 0.33 mmol, 4.0 eq.) was slowly added to the crude 3-(propylpropylimido- Phenyl-methyl)-6-(2-fluoro-3-indolyloxyphenyl)-8-(2-aero-6-trifluoromethyl-benzyl)-7-methyl-2, 3-Dihydro-salt-[3,2-indolyl]pyridin-5-one (Example 3.28) (5〇111§, 82 0111〇1) in toluene (〇.5 152524.doc _ 4 tossed · 201130854 In a stirred solution in mL). Stirring was continued at 〇 ° C for 20 minutes and at room temperature for 2.5 hours, after which time the reaction mixture was again cooled to zero. (: Add another amount of allyl magnesium chloride (164 0, 2 Μ solution in THF, 〇 33 mmol '4.0 eq.) and quench the reaction by adding water. The aqueous layer was extracted with acetonitrile and The combined organic layers were washed with brine, dried and evaporated wmjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 3H); 2.60-2.68 (m 1H); 2.74-2.81 (m, 1H); 2.97-3.21 (m, 3H); 3.48-3.59 (m 1H); 3.76-3.93 (m, 5H); 4.90-5.02 (m, 1H); 5.12-5.35 (m 3H); 5.65-5.70 (m, 1H); 5.73-5.87 (m, 1H); 5.96-6.08 (m 1H); 6.67-6.73 (m, 0.4H*) ; 6.90 (ddd, 0.6H*); 7.08-7.2l (m, 5H); 7.28-7.34 (m, 1H); 7.39-7.50 (m, 4H). UPLC-MS (ESI+): [Μ+Η] +=653. Example 7.22 Preparation of 6-(2-Fluoro-3-indolyl-phenyl)_8_(2-fluoro-6-trifluoromethyl)benzyl-7-indolyl-3-(2) -phenyl-1,2,3,6·tetrahydro-pyridin-2-yl)·2,3-dihydro-thiazolo[3,2-a]»pyridin-5-one

According to the modified form of GP 26: at room temperature, add ~ 汕 to the second generation catalyst (34 mg '40 μιη0 〇 2 〇 equivalent) to 3 (buallylamino group 152524.doc 201130854 1- Phenyl-but-3-yl)-6-(2-fluoro-3-methoxy-styl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 2,3-Dihydro-selling [3,2-a]° degassing and scrambling in 5-oxane (2 mL) than 5-ketone (130 mg, 198 μηιοί) (Example 7.21) Drop the solution. The reaction mixture was heated to 40 °C until TLC and / or LCMS indicated the starting material was completely consumed. The solvent was evaporated and subjected to preparative HPLC purification to give the title compound (yield: 44 mg). W-NMR (methanol-d4, 300 MHz): 1.98-2.00 (m, 3H); 2.88-2.99 (m, 1H); 3.33-3.53 (m, 2H); 3.54-3.71 (m, 2H); 3.96 (m, 7H); 5.57-5.61 (m, 2H); 5.95-6.05 (m, 1H); 6.74-6.79 (m, 0.5H*); 6.99 (ddd, 0.5H*); 7.16-7.36 (m , 7H); 7.38-7.46 (m, 2H); 7.48-7.51 (m, 1H). UPLC-MS (ESI+): [M+H]+=625. Example 7.23 Preparation of N-{[6-(2-fluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl-5-sideoxy-2 ,3-dihydro-5Η-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-acetamide

According to the modified form of GP 25a: DlpEA (22 mg, 174 is called i equivalent) is added to acetamidine (153 post, i95 is called 〇1, i i2 equivalent) and 3-(amino group) at room temperature. - stupid base_methyl)_6_(2_gas·3_methoxy-phenyl)8 (2_

S 152524.doc -487- 201130854 Fluoro-6-trifluoromethyl-p-methyl)_7_mercapto-2,3-dihydro-thiazolo[3,2_&amp;]0 is more than 5-ketone The enantiomer 2) (Example 6.6b) (100 mg, 174 μπιοί) was stirred in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 4 hours. The solvent is evaporated and subjected to flash chromatography to give the target compound. W-NMR (sterol-d4, 300 MHz): 1.84 (m, 3H); 1.93 (m, 3 Η). 3.89 (m, 3H); 5.46-5.61 (m, 2H); 6.67-6.80 (m, 1H) ); 7.07. 7.21 (m, 2H); 7.29-7.60 (m, 8H). UPLC-MS (ESI+): [M+H]+=615. Examples 7.24 and 7.25 Preparation of 3-bromo-2,2-difluoro-N-{[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluorotrifluoromethyl-benzene) -7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-indenyl}-propanamide And 2,2-difluoro-3-({[6-(2-fluoro-3-methoxy)-benzyl)-8-(2-1-6-trifluoromethyl-phenylmethyl)-7 -Methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-yl]-phenyl-methyl}-amino)-propionic acid ethyl ester

According to the modified form of 〇?253: at room temperature, 〇1? £ (150 卩 [, 112 mg, 873 μιηοΐ, 1 equivalent) and 3 - desert _2, 2 _ bis - propionic acid (568 152524 .doc • 488 - 201130854 mg, 2·6 mmol, 3.0 eq.) added to 3-(amino-phenyl-indenyl) 6-(2-fluoro-3-indolyloxy-phenyl)-8-(2-fluoro -6-trifluorodecyl benzoyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridine_5&gt; ketone (diastereomer 2) (Example 6.6 b) (500 mg, 873 μπχοΐ) in a stirred solution of acetonitrile (5 mL). The reaction mixture was stirred at 80 ° for 7 hours, at room temperature for 1 hour and again at 80 ° for 7 hours. The solvent was evaporated and subjected to flash chromatography to give the title compound (yield: 473 mg &amp; 4 mg). • Example 7.24: 3_Bromo-2,2·difluoro·Ν_{[6-(2-fluoro-3-methoxy-phenyl)_8_(2-fluoro-6-trifluorof-phenylmethyl) _7_Methyl _ _ side oxy 2,3_ dihydro _5η_ oxazolo[3,2-a]pyridin-3-yl]-phenyl-methylpropanamide H-NMR (methanol- D4, 300 MHz): 1.95 (s, 3H); 2.92-3.02 (m, 1H); 3.47-3.60 (m, 1H); 3.61-3.81 (m, 2H); 3.85-3.93 (ms 3H); 4.06- 4.18 (m, 2H); 5.31-5.41 (m, 1H); 5.57-5.70 (m, 1H); 6.69-6.77 (m, 0.3H*); 6.83-6.91 (m, 0.7H*); 7.07-7.21 (m, 2H); 7.28-7.62 (m, 8H). • MS (ESI+): [M+H]+=745. Example of isotope form 7.25: 2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8_(2_fluoro-6-difluoromethyl-benzene) Base)-7-methyl-5-sideoxy-2,3_dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methyl-amino) Ethyl propionate (diastereomer 2) UPLC-MS (ESI+): RT = 1.64 min, [m+h]+=709. Examples 7.26 and 7.27 Preparation of 2,2-difluoro-3-({[6-(2-fluoro-3.methoxy-phenyl)_8_(2·fluoro-6-trifluoromethyl-benzyl) -7-Methyl-5-sideoxy-2,3_dihydro-5H thiazole [3,2_叼152524.doc •489· 201130854 ° ratio -3-yl]-phenyl-methyl} -amino)-propionic acid and 3-[(3,3-difluoro-2-oxo-azetidinium-yl)-phenyl-methyl]_6_(2_fluoro-3-oxo) -Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indenyl-2,3-dihydro-indole[3,2-3]«» -5-ketone

Sodium hydride (6〇〇/0 in mineral oil, 3〇7 mg, 769 μηηοΐ, 4.0 equivalent) was added portionwise to 3-bromo-2,2-difluoro-N-{[6 at room temperature -(2-Fluoro-3·decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl_5_sideoxy_ 2,3_2 Hydrogen-;5H-thiazolo[3,2_a;]pyridine-3-yl]-phenyl-mercaptopropanamide (Example 7.24) (143 mg, 192 μιηοΐ) in DCM (1.2 mL) and DMF (150 μM) After stirring for 22 hours at the temperature, the solvent was evaporated and the residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride. After phase separation, the aqueous layer was extracted with ethyl acetate and The combined organic layers were dried and concentrated in vacuo. title compound was purified by flash column chromatography (yield: 109 mg and 8 mg). Example 7, 26: 2,2-difluoro-3-({[6- (2-Fluoro-3-methoxy-styl)-8-(2-fluoro-6-trifluoromethyl-p-methyl)-7-methyl-5- oxo-2,3-di Hydrogen-5H-thiazolo[3,2-a]&quot;bite_3_yl]-phenylmethyl}amino)propionic acid lH_NMR (sterol-0,400 MHz): 1.92 (d,3H) ; 2.85-3.14 (m, 2H); 3.33-3.53 (m, 2H); 3.76-3.93 (m, 5H) 4.45 (d, 0.5H*); 152524.doc s -490· 201130854 4-53 (d, 0.5H*); 5.40-5.47 (m, 1H); 6 ? 6.86-6.93 (m, 0.5H*) ; 7.07-7.28 (m 76 (called 〇5H*); 2H). )' 7.33-7·49 (m, UPLC-MS (ESI+): [M+H]+=681. Ding Yi 1·)) Stupid-helium methyl·benzyl)·Example 7.27. 3-[(3,3-Difluoro-2-oxo-indenyl]-6-(2-fluoro-3-antimony) -phenyl)-8-(2-fluoro,6,=7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridinyl W-NMR (methanol _d4, 400 MHz) : 1.904 (°1,3H); 2 82 id 〇.7H*); 3.01 (d, 0.3H*); 3.57-3.66 (ln lt ( ' ' H); 3.83-3.92 (m 4H); 4.00-4 ,16 (m,3H); 5.44 (d,〇.3H*,. '

)&gt; 5.49 (d, 〇 7H*V 5.80-5.88 (m, 1H); 6.68-6.79 (m, lHv 7 Λ ’

a ^·〇4-7.15 (m 2HV 7.25-7.59 (m, 9H). UPLC-MS (ESI+): [M+H]+=663. Example 7.28 Preparation of 6-(2-fluoro- 3-decyloxy) _ _ _ _ 8 ♦ fluoro + trifluoromethyl benzyl _ 3-[(3 · thio-propylamino) phenylmethyl] _ 7 _ _ 2 Sputum and [3,2-a]. Specific bite 5-ketone

According to the modified form of GP 25a: DipEA (4) 吣34, 266 μΐΠ〇1' 1 equivalent) was added to 3-bromo-propanol-ol at room temperature (85吣152524.doc -491 · 201130854 131mg ' 798 μηιο 3 equivalents) and 3-(amino-phenyl-fluorenyl)·6_(2_say_3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoquinone )7_methyl_2 3_dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 2) (example 6.6b) (152 mg, 266 μιηοΐ) in acetonitrile In a stirred solution in 3 mL). The reaction mixture was heated to 80 ° C for 12 hours and stirring was continued for two days at room temperature. The solvent was evaporated and subjected to flash chromatography to give the title compound (yield: 148 mg). W-NMR (methanol-d4, 300 MHz): 1.68-1.76 (m, 2H); 1.97 (m 3H); 2.67-2.74 (m, 2H); 3.20-3.27 (m, 1H); 3.50-3.63 (m 3H); 3.91-4.01 (m, 5H); 4.49-4.54 (m, 1H); 5.53-5.59 (m 1H); 6.73-6.78 (m, 〇.5H*); 6.90 (ddd, 0.5H*); 7.10_7 21 (m, 3H); 7.27-7.38 (m, 5H); 7.41-7.56 (m, 2H). 〇 UPLC-MS (ESI+): [M+H]+=631 〇Example 7.29 Preparation 6-( 2-fluorodecyloxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)_3-[(4-hydroxy-butylamino)-phenyl-methyl]_7曱Base 2,3_dihydro-thiazolo[3,2-a]pyridin-5-one

Lithium borohydride (0.80 mL, 2 Μ solution in THF, 32·8 μιηοΐ, 1.5 eq.) was slowly added to 4_({[6_(2_fluoro_3_methoxy-stupid 152524) at room temperature .doc 201130854 base)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-methyl·5_sideoxy-2,3_diaza-5Η-嗟 并[3, 2-a].pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl acetate (diastereomer 2) (example 7.1b) (15 mg, 21.8 μπιοί) Stirred in THF (2 mL). The reaction mixture was stirred for 5 hours until TLC showed the starting material was completely consumed. Water (1 mL) was added and the pH was adjusted to 3 (1 N hydrochloric acid). The title compound (yield: 1 mg) was obtained from ethyl acetate. W-NMR (methanol-(14, 400 MHz): 1.42-1.54 (m, 4H); 1.85-1.94 (m, 3H); 2.32-2.57 (m, 2H); 3.43-3.55 (m, 4H); -3.91 (m, 3H); 3.98-4.13 (m, 2H); 4.38 (d, 0.6H*); 4.59 (s, 1H); 5.25-5.31 (m, 1H); 6.46-6.54 (m, 0.7H) *); 6.67-6.74 (m, 0.3H*); 7.01-7.16 (m, 2H); 7.21-7.39 (m, 6H); 7.45-7.60 (m, 2H). UPLC-MS (ESI+): [M +H]+=645. Table 34: Example 7.30 below. Preparation of numbered structure name analysis data from Example 7.25 in a manner similar to Example 7.29. 7.30 OH CF .ch3 3-[(2,2-II U-基-propylamino)-phenyl-indenyl-6-(2- gas-3-indolyl-phenyl)-8-(2-fluoro-6.trifluoromethyl-benzoinyl) )-7-mercapto-2,3-dihydro-thiazolo[3,2-a]° ratio bit-5-keto h-NMR (methanol-d4, 300 MHz): 1.94 (s, 3H); 2.60 -2.98 (m, 2H); 3.43-3.51 (m, 1H); 3.58-3.73 (m5 2H); 3.82-4.05 (m, 5H); 4.26 (d, 0.5H*); 4.35 (d, 0.5H* 5.37-5.45 (m,1H); 6.70-6.78 (m, 0.5H*); 6.81-6.87 (m, 0.5H*); 7.06-7.34 (m, 9H); 7.38-7.55 (m, 2H) · MS (ESI+): [M+H]+=667.

S 152524.doc •493- 201130854 Example 7.31 Preparation of 4-({[6-[3-(1,1--fluoro-ethyl)·phenyl]_8(2fluoro-6trifluoromethyl-benzyl) -7-Methyl-5-o-oxy-2,3-dihydro-5H-thiazolo[m]pyridine-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl vinegar

A modified form of N-ethyldiisopropyl according to GP 25a: at room temperature, an amine (174 pL '131 mg '1.02 mm〇3 equivalent) was added to 4 methyl butyrate (49 pL' 66 Mg, 340 is 〇 1,] equivalent) and 3 · (aminophenyl fluorenyl)-6-[3-(1,1-difluoroethyl)-phenyl]_8_(2_fluoro_6 trifluoro Methylphenylhydrazinomethyl 2,3-dihydro-thiazolo[Ha]pyridinone (Example 6.51) (200 mg, 340 μπιοί) in a stirred solution of acetonitrile (5 mL) Heat to 80 ° C 'overnight. Evaporate the solvent and carry out decantation' to give the title compound (yield: 38 mg). ^-NMR (methanol-d4, 400 MHz): 1.16 (t 1 ^ V, called, 160-1.74 (m, 2H); 1.87-2.00 (m, 6H); 2.28 (t, 2H); 2 33 9 4〇' z.49 (m, 2H); 3.18 (d, 1H); 3.40-3.48 (m, 1H); 3.90-4.08 (m, 4H); 4 2〇(d 1H); 5.37-5.44 (m,1H); 7.19-7.56 (m,12H). ' MS (ESI+): [M+H]+ = 703. Example 7.32 Preparation of 4-({[6-[3-(l,l-difluoro-ethyl)-phenyl]·8·(2_fluoro·heart trifluoromethane 152524.doc -494- 201130854 Benzyl)-7-mercapto-5-sidedoxy-2,3-diar-5H-thiazolo[3,2-a] Piperidin-3-yl] - phenyl - methyl} • amino) butanoic acid ·

Add a solution of sodium hydroxide (21 Torr in 32% aqueous solution, 284 mg ' 2.28 mmol, 1 〇 equivalent) to difluoro-ethyl)-phenyl]-8-(2-fluoro-6 at room temperature -trifluoromethyl-phenylhydrazino)_7_methyl_5_sideoxy-2,3-dihydro-5Η-thiazolo[3,2-a]°pyridin-3-yl]-phenyl Methyl-methylaminobutyrate (Example 7.3 1) (160 mg, 228 μηηο) was stirred in ethanol (5 mL) and stirred at room temperature overnight. The pH was adjusted to pH 7 by the addition of aqueous hydrochloric acid (2 N) and the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc (3 mL). The target compound was isolated by HPLC chromatography (yield: 32 mg). W-NMR (methanol _d4, 3 〇〇 MHz): i 62-1 81 (take, call; i 84 2 〇 3 (m, 6H); 2.26-2.36 (m, 2H); 2.58-2.68 (m, 2H); 3 19 (d, 1H); 3.46-3.57 (m, 1H); 3.88-4.02 (m, 2H); 4.44 (d, 1H); 5.48-5.56 (m, ih); 7.22-7.57 (m , 12H). MS (ESI+): [m+H]+=675. s 152524.doc -495 - 201130854 Driving by Gong, but catching the spine ^ feeding ¢ ¢ - 硪 / / 琰 琰 -3fw?^^06.9^ ι ·9 ί 驷 ^ ^ISCNdo-r l l^^^w 荽? Ι.λ f 驷 驷 sen^£ε·λ 驷 i-3: (ιε&lt;赞)qi£&lt; Analysis data iH- NMR (methanol-〇14,3001^1^): 1.94 (3,311); 2.61-2.75 (111,211); 3.37-3.61 (m, 4H); 3.67-3.71 (m, 3H); 3.83-3.94 (m , 5H); 4.05-4.10 (m, 2H); 4.36 (d, 0,5H*); 4.41 (d, 0.5H*); 5.40-5.49 (m, 1H); 6.71-6.77 (m, 0.5H* 6.83-6.90 (m, 0.5H*); 7.06-7.52 (m, 10H) UPLC-MS (ESI+): [M+H]+=689. 1 •H-NMR (sterol-d4, 500) MHz): 1.21-1.26 (m,3H); 1.29-1.35 (m, 2H); 1.41-1.51 (m, 2H); 1.54-1.62 (m, 2H); 1.98 (s, 3H); 2.25-2.31 ( m, 2H); 3.38-3.52 (m, 2H); 3.24-3.32 (m, 1H); 3.43-3.53 (m, 1H); 3.83-4.01 (m, 5H); 4.07-4.15 (m, 2H); 4.29 (d, 0,5Η*); 4.35 (d, 0.5H*); 5.44-5.49 (m, 1H); 6.75-6.80 (m, 0.5H*); 6.84-6.88 (m, 0.5H*); 7.12-7.35 ( m, 9H); 7.44-7.56 (m, 2H). UPLC-MS (ESI+): [M+H]+=715 〇Name|&gt;({ [6-(2-Fluoro-3-methoxy-) Phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2- a] 3-yl]-phenyl-methyl-amino)-ethoxy]-acetic acid decyl 6-({[6-(2-fluoro-3-methoxy-phenyl)-8_) (2-Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-exopyridin-3- Methyl]-phenyl-methyl}-amino)-hexanoic acid methyl ester structure I* human 5 number 7.33 7.34 152524.doc •496· 201130854

h-NMR (methanol-d4,400 MHz): 1.24-1.33 (m, 2H); 1.38-1.60 (m, 4H); 1.93 (s, 3H); 2.10-2.17 (m, 2H); 3.37-3.51 ( m, 2H); 3.41-3.51 (m, 1H); 3.84-3.95 (m, 5H); 4.28 (d, 0,5H*); 4.33 (d, 0.5H*); 5.40-5.46 (m, 1H) ; 6.70-6.76 (m, 0.5H*); 6.79-6.85 (m, 0.5H*); 7.07-7.32 (m, 8H); 7.38-7.52 (m, 2H). UPLC-MS (ESI+): [M+H]+=686 〇h-NMR (sterol-d4, 300 MHz): 1.00-1.09 (m,3H); 1.19-1.31 (m, 2H); 1.94 (s , 3H); 2.42-2.59 (m, 2H); 3.42-3.54 (m, 1H); 3.83-3.96 (m, 5H); 4.04-4.15 (m, 2H); 4.34 (d, 0, 5H*); 4.38 (d, 0.5H*); 5.40-5.48 (m, 1H); 6.71-6.77 (m, 0.5H*); 6.80-6.88 (m, 0.5H*); 7.07-7.57 (m, 10H). UPLC-MS (ESI+): [M+H]+=703. 々-NMR (sterol-d4, 300 MHz): 1-38 (s, 9H); 1.47 (s, 9H); 1.67-1.76 (m, 1H); 1.92 (s, 3H); 1.97-2.09 (m , 1H); 2.17-2.28 (m, 1H); 2.46-2.62 (m, 1H); 3.38-3.54 (m, 1H); 3.83-3.92 (m, 5H); 4.02-4.08 (m, 2H); 4.20 -4.38 (m, 3H); 5.36-5.54 (m, 1H); 6.59-6.67 (m, 0.5H*); 6.81-6.90 (m, 0.5H*); 7.05-7.56 (m, 10H). UPLC-MS (ESI+): [M+H]+=830. M_ ^ ^ 人A寺丄ton A wonderful office 1 ΓΤΓ ^ 3 yit\ ^ ^ C砩ώ 〇? S ^ person f ' ^ ^ Ψ ^ m mechanical 砩ώ ®- $ ^ ®7 Λ, ^ ^ Ql_ ' 1 r^-, 1 Λ ^ ' ^ ^ ii ^ s 3 令 4 γ 1 ^ (N ^ ^ ώ 4兮苎宇毽J ^ t ^ 5=3⁄4 Ί rA 'Ί ^ ^ cA ^ CS ui 4 ¥ X* °γό &lt;Jn q 〇Ο I* z* in cn Ό ΓΛ (&gt; 卜 s 152524.doc • 497· 201130854 ^-NMR (sterol 44,3001^«^): 1.60-1.78 ( 111,211); 1.94 (3,3 impressions; 2.37-2.59 (m, 4H); 3.14-3.25 (m, 1H); 3.39-3.51 (m, 1H); 3.84-4.03 (m, 5H); 4.16-4.25 ( m, 1H); 5.36-5.44 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.77-6.85 (m, 0.5H*); 7.05-7.35 (m, 8H); 7.37-7.56 (m , 2H). UPLC-MS (ESI+): [M+H]+=640. iH-NMR (sterol-£14,300]\«^): 1.58-1.77 (111,211); 1.97 (8,311); 2.39 -2.57 (m, 4H); 3.20 (m, 1H); 3.46 (m, 1H); 4.19 (d, 0.5H*); 4.23 (d, 0.5H*); 5.41 (m, 1H); 6.06 (d , 2H); 6.60-6.79 (m, 2H); 7.20-7.53 (m, 9H). UPLC-MS (ESI+): [M+H]+=654. ^-NMR (nonol-d4, 300 MHz) : 1.17 (t,3H); 1.68 (m,2H); 1.95 (s, 3H); 2.30 (t, 2H); 2.43 (m, 2H); 3.18 (m, 1H); 3.44 (m, 1H); 3 .81 (s, 3H); 3.96 (m, 2H); 4.05 (q, 3H); 4.22 (d, 1H); 5.42 (m, 1H); 6.79 (m br, 1H); 6.91 (m, 1H) ; 7.22-7.54 (m, 10H). UPLC-MS (ESI+): [M+H]+=669. 4 ^ 1 ¥ $4砩由®- mi J Λ Λ 5 A ^ ^ 5 V ^ ^ cs «1 H| ^ 1 H n, ^ ή ^ ϊ Φ ^ ϊ ά tn,ti ^ t ^ ^ 1 &lt;N /^su| if ^ tO vi office 4 潜 ^ ^ 'J 3 ^ A q T 21 v ^ ^ V ^ ^ i 砩苳 砩苳 π 乂ό 〇〇m ON CO Ο 152524.doc -498· 201130854

^-NMR (methanol-d4, 300 MHz): 1.13-1.21 (m,3H); 1.61-1.76 (m, 2H); 1.94 (s, 3H); 2.25-2.33 (m, 2H); 2.34-2.50 ( m, 2H); 3.18 (d, 0.5H*); 3.40-3.49 (m, 1H); 3.83 (s, 3H); 3.86-3.99 (m, 2H); 4.02-4.15 (m, 2H); 4.22 ( d, 0.5H*); 4.28 (d, 0.5H*); 5.37-5.44 (m, 1H); 6.72-6.87 (m, 2H); 7.05-7.32 (m, 6H); 7.38-7.55 (m, 2H) ). UPLC-MS (ESI+): [M+H]+=687. ^-NMR (methanol-d4, 400MHz): 1.13-1.19 (m, 3H); 1.63-1.76 (m, 2H); 1.97 (s, 3H); 2.25-2.37 (m, 2H); 2.37-2.53 (m , 2H); 2.58-2.67 (m, 3H); 3.21 (d, 0.5H*); 3.43-3.53 (m, 1H); 3.90-4.00 (m, 2H); 4.00-4.09 (m, 2H); 4.24 (d, 0.5H*); 4.30 (d, 0.5H*); 5.40-5.47 (m, 1H); 7.17-7.58 (m, 11H); 7.84-7.91 (m, 1H). UPLC-MS (ESI+): [M+H]+=699. ^•NMR (methanol-d4, 300 MHz): 1.13-1.19 (m,3H); 1.60-1.73 (m, 2H); 1.96 (d, 3H); 2.24-2.49 (m, 4H); 3.17 (d, 0.5H*); 3.42-3.51 (m, 1H); 3.88-4.00 (m, 2H); 4.00-4.08 (m, 2H); 4.19 (d, 0.5H*); 4.28 (d, 0.5H*); 5.38-5.44 (m, 1H); 7.14-7.55 (m, 11H). UPLC-MS (ESI+): [M+H]+=741. M_ ^ ^ person from t1丄®- J rii ^ 4 3呤卜ί ^ « 5 ^ ? ^ ^ ώ m_ ^ 人A寺丄5 ^ ^ ^ s 3 ¢. ^ ^ ® ^ ^ cA A *9 u丨4 A Office ί is ' 5 ? Y 1 々&lt;N ^ ^ d, 诚1 i4 ^ ^ 5 乂 乂辛爸III ^ ^ H ^ ''1 ^ f 3 ¥ 1 ί ^ ¥ cs ^ T ^ ^ ti %&lt;λ 0/° 乂1木 Xo X °^o Ci X* °^C ό X inch s 152524.doc •499_ 201130854 ^-NMR (methanol-d4, 300 MHz): 1.12-1.22 (m,3H 1.29-1.41 (m, 6H); 1.61-1.78 (m, 2H); 1.94 (s, 3H); 2.25-2.35 (m, 2H); 2.35-2.55 (m, 2H); 3.19 (d, 0.5 H*); 3.41-3.52 (m, 1H); 3.86-4.00 (m, 2H); 4.00-4.12 (m, 2H); 4.23 (d, 0.5H*); 4.32 (d, 0.5H*); 4.54 -4.68 (m, 1H); 5.38-5.47 (m, 1H); 6.71-6.79 (m, 0.5H*); 6.82-6.90 (m, 0.5H*); 7.05-7.55 (m, 10H). UPLC-MS (ESI+): [M+H]+=715. Γ [H-NMR (methanol _d4, 400 MHz): 1.22 (dt, 3H); 1 · 31-1.38 (m, 6H); 1.93 (s, 3H); 2.60-2.74 (m, 2H); 3.30- 3.52 (m, 2H); 3.53-3.61 (m, 2H); 3.80-3.95 (m, 2H); 4.00-4.07 (m, 2H); 4.11-4.19 (m, 2H); 4.35 (d, 0.5H* 4.40 (d, 0.5H*); 4.54-4.68 (m, 1H); 5.41-5.47 (m, 1H); 6.71-6.77 (m, 0.5H*); 6.84-6.90 (m, 0.5H*) ; 7.06-7.30 (m, 8H); 7.36-7.51 (m, 2H). UPLC-MS (ESI+): [M+H]+=731. iH-NMR (methanol-d4, 300 MHz): 1.31-1.39 (m, 6H); 1.59-1.79 (m, 2H); 1.95 (s, 3H); 2.37-2.63 (m, 4H); 3.15-3.26 ( m, 1H); 3.41-3.53 (m, 1H); 3.87-4.03 (m, 2H); 4.17-4.27 (m, 1H); 4.55-4.68 (m, 1H); 5.37-5.47 (m, 1H); 6.71-6.79 (m, 0.5H*); 6.79-6.87 (m, 0.5H*); 7.06- 7.58 (m, 10H). UPLC-MS (ESI+): [M+H]+=668. _ fa-昧鍩^ ^ 4 « 5 'ji S 呼iq硇^ d ^ ^ ± ^ t ^ —i 々&lt;N 4 ^ ^ ^ person e-涑鍩硪...ft丄^ 3 P 1 S 2 cA Δ- ro ¢^1 ¢¢1 f 1 S 5 〇$ i ^ 5 T ^ a »-^ v ^ ^ *te ^ Μ ih ϊ: Λ ^ ^ ^ ^ 3 ^ ^ d ^ ί ^ ^ ^ 5 7 —1 々fN Χό I 卜^ 152524.doc -500- 201130854

^-NMR (^, -d4, 300MHz): 1.57-1.80 (m, 2H); 1.96 (s, 3H); 2.36-2.63 (m, 4H); 3.14-3.27 (m, 1H); 3.47-3.60 ( m, 1H); 3.88-4.13 (m, 2H); 4.58 (d, 0.5H*); 4.65 (m, 0.5H*); 5.44-5.54 (m, 1H); 6.96-7.08 (m, 1H); 7.09-7.19 (m,1H); 7.20-7.38 (m,4H); 7.39-7.59 (m,4H). </ RTI> <RTIgt; 1.68-1.86 (m, 2H); 1.89-2.00 (m, 3H); 2.29-2.38 (m, 2H); 2.53-2.87 (m, 2H); 3.37-3.49 (m, 1H); 3.56-3.73 (m , 1H); 3.85-4.14 (m, 5H); 4.49 (d, 0.5H*); 4.62 (m, 0.5H*); 5.38-5.51 (m, 1H); 6.99-7.61 (m, 11H) 〇 UPLC -MS (ESI+): [M+H]+ = 742. H-NMR (Methanol-d4, 600 MHz): 1.04-1.11 (m, 6H); 1.33-1.42 (m, 4H); 1.45-1.54 ( m, 1H); 1.85 (d, 3H); 1.91 (s, 3H); 2.03-2.17 (m, 3H); 2.18-2.27 (m, 1H); 3.80 (d, 3H); 3.88-4.07 (m, 7H); 5.12-5.19 (m, 1H); 6.65-6.70 (m, 1H); 6.98-7.10 (m, 2H); 7.14-7.19 (m, 1H); 7.23-7.30 (m, 3H); 7.34- 7.44 (m,3H); 7.47-7.52 (m,1H) UPLC-MS (ESI+): [M+H]+=715. 3 nill? isiii ^ $4 ^ 4 4 '' Butterfly ώ ^ S ί ^ ¥ H 泞 铤纟窆 铤纟窆 铤纟窆 爱 爱 爱 爱 爱 C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C On inch 152524.doc -501 - 201130854 iH-NMR (methanol-d4,400 MHz): 1.11-1.20 (m,6H); 1.41-1.51 (m, 4H); 1.52-1.64 (m, 1H); 1.94 ( d, 3H) 2.11-2.24 (m, 3H); 2.25-2.37 (m, 1H); 3.96-4.18 (m, 5H); 5.21-5.29 (m, 1H); 7.22-7.54 (m, 10H); 7.56-7.61 ( m, 1H). UPLC-MS (ESI+): [M+H]+=769 ° b-NMR (Methanol-d4, 600 MHz): 1.04-1.12 (m,6H); 1.33-1.42 (m, 4H); 1.44-1.55 (m, 1H); 1.84 (d, 3H); 2.02-2.27 (m, 4H); 3.87-4.09 (m, 5H); 5.12-5.20 (m, 1H); 7.03-7.19 (m, 4H); 7.23 -7.33 (m, 4H); 7.34-7.44 (m, 3H); 7.47-7.51 (m, 1H). UPLC-MS (ESI+): [M+H]+=685. ^-NMR (methanol-d4, 600 MHz): 1.03-1.12 (m, 6H); 1.32-1.43 (m, 4H); 1.44-1.55 (m, 1H); 1.86 (d, 3H); 2.02-2.30 ( m, 4H); 3.69 (d, 3H); 3.88-4.08 (m, 5H); 5.13-5.20 (m, 1H); 6.64-6.69 (m, 1H); 6.81-6.86 (m, 1H); 6.94- 7.02 (m, 1H); 7.15-7.19 (m, 1H); 7.22-7.31 (m, 1H); 7.35-7.44 (m, 3H); 7.48-7.51 (m, 1H). UPLC-MS (ESI+): [M+H]+=715. 4-({[6-(2-Fluoro-3-trifluorodecyloxy-phenyl)-S-(2-fluoro-6-trifluoromethyl-benzoinyl)-2,2,7-three Methyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]&quot;biti-3-yl]-phenyl-indenyl}-amino)-butyric acid Ethyl 4-( {[6·(2_oxy-phenyl)-8-(2-fluoro-6-trifluoromethyl)benzyl-2,2,7-trimethyl-5-side oxygen Base-2,3-dihydro-5H-thiazolo[3,2-a]° butyl-3-yl]-phenyl-fluorenyl}-amino)-butyric acid ethyl ester 4_({[6- (2-fluoro-5-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2,7-tridecyl-5-sideoxy- 2,3-Dihydro-5H-thiazolo[3,2-a].pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester. i /xk ^ X* 7.50 7.51 1 7.52 152524.doc -502- 201130854

iH-NMR (sterol-d4, 300 MHz): 1.84-2.12 (m, 7H); 2.60-2.76 (m, 2H); 3.38-3.60 (m, 4H); 3.63-3.75 (m, 2H); -3.98 (m, 2H); 4.01-4.14 (m, 2H); 4.36 (d, 0.5H*); 4.41 (d, 0.5H*); 5.41-5.50 (m, 1H); 7.10-7.65 (m, 11H). UPLC-MS (ESI+): [M+H]+=715. ^-NMR (sterol-d4, 400 MHz): 1.13-1.20 (m,3H); 1.60-1.74 (m, 2H); 1.85-2.08 (m, 9H); 2.23-2.61 (m, 6H); (d5 0.5H*); 3.37-3.51 (m, 2H); 3.85-4.17 (m, 6H); 4.21 (d, 0.5H*); 4.28 (d, 0.5H*); 5.38-5.44 (m, 1H ); 7.16-7.62 (m, 11H). UPLC-MS (ESI+): [M+H]+=721 -^-NMR (Methanol-d4, 400 MHz): 1.94 (s,3H); 1·94 (t,3H); 2.57-2.73 (m , 2H); 3.40-3.60 (m, 4H); 3.67 (s, 3H); 3.91 (br. s, 2H); 4.05 (s, 2H); 4.35 (d, 1H); 5.40-5.47 (m, 1H ); 7.17-7.57 (m, 12H). UPLC-MS (ESI+): [M+H]+=705. [2-({[6-[3-(l,l-diethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trit-decyl)]- Indolyl-5-yloxy-2,3-diaza·5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl-amino)-ethoxy]-acetic acid Ethyl 4-( {[6-[3-( 1,1 -difluoro-ethyl)-2- gas-phenyl]-8-(2-fluoro-6-trifluoromethyl-adenyl) -7-Methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]»bipyridin-3-yl]-phenyl-indenyl}-amino)- Ethyl butyrate [2-({[6-[3-(l,l-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluorodecyl-benzyl)- 7-fluorenyl-5-o-oxy-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methyl}-amino)-ethoxy Methyl]-methyl acetate 〇/ό XV 0 X 7.53 7.54 7.55 s 152524.doc •503 - 201130854

h-NMR (sterol-d4, 300 MHz): 1.17 (m, 3H); 1.70 (m, 2H); 1.97 (m, 3H); 2.24-2.34 (m, 2H); 2.34-2.53 (m, 2H) 3.88-3.99 (m, 2H); 3.99-4.10 (m, 2H); 4.26 (dd, 1H); 5.43 (m, 1H); 6.74-6.90 (m, 2H); 7.05- 7.57 (m, 15H) ). UPLC-MS (ESI+): [M+H]+=749. ^-NMR (sterol-d4, 300 MHz): 1.16 (tr, 3H); 1.57-1.74 (m, 2H); 1.95 (s, 3H); 2.28 (m, 2H); 2.37 (m, 1H); 2.44 (m, 1H); 3.18 (d, 1H); 3.41-3.49 (m, 1H); 3.95 (m, 2H); 4.00-4.07 (m, 2H); 4.20 (d, 1H); 5.41 (m, 1H); 6.86 (tr, 1H); 6.98-7.53 (m, 12H). UPLC-MS (ESI+): [M+H]+=705. H-NMR (sterol-d4, 300 MHz): 1.21 (tr, 3H); 1.95 (s, 3H); 2.65 (m, 2H); 3.56 (m, 2H); 3.91 (m, 2H); m, 2H); 4.34 (d, 1H); 5.43 (m, 1H); 6.86 (tr, 1H); 6.99-7.52 (m, 12H). UPLC-MS (ESI+): [M+H]+=72卜^% ψ ^ ^ ^ ^ ® ^ ^ ή O Ϊ 乂 " h ¥ ^ 5 5 « s ^ j ? ^ ^ ^ 2 咿外咿心t ^ ^ ® ^ ^ ^ 5 λ 11 J ss 13 V 'Ί ^ A, stf tolerance 4 ^ ^ ^ ^ g 4 ^ ^ 4 ^ 彳鲜 to S' 4 ^ 士士减¢- q地硪cA u | ^ ψ ^ V ¥ ? 3 ^ ^ 4 ώ 〇ssC ό °^5 ν〇卜 OO 152524.doc •504· 201130854

b-NMR (methanol-d4, 300 MHz): 1.18 (tr, 3H); 1.59-1.77 (m, 2H); 1.97 (s, 3H); 2.30 (m, 2H); 2.44 (m, 2H); (m, 1H); 3.93 (m, 2H); 4.00-4.11 (m, 2H); 4.26 (dd, 1H); 5.42 (m, 1H); 6.07 (m, 2H); 6.62 (m, 0.5H* ); 6.75 (m, 1.5H*); 7.16-7.56 (m, 9H). UPLC-MS (ESI+): [M+H]+=701. iH-NMR (methanol-d4, 300 MHz): 1.95 (s, 3H); 2.60-2.73 (m, 2H); 3.57 (m, 2H); 3.87 (m, 2H); 4.06 (d, 2H); (d, 0.5H*); 4.40 (d, 0.5H*); 5.43 (m, 1H); 6.06 (m, 2H); 6.62 (m, 0.5H*); 6.75 (m, 1.5H*); 7.13 -7.52 (m, 9H). UPLC-MS (ESI+): [M+H]+=703. ^-NMR (sterol-d4, 300 MHz): 1.17 (m,3H); 1.60-1.74 (m,2H); 1.93 (m, 3H); 2.23-2.32 (m, 2H); 2.35-2.50 (m , 2H); 3.20 (m, 1H); 3.44-3.55 (m, 1H); 3.88 (m, 3H); 4.00-4.08 (m, 2H); 4.59 (d, 0.5H*); 4.63 (d, 0.5 H*); 5.47 (m, 1H); 6.69-6.74 (m, 0.5H*); 6.79-6.84 (m, 0.5H*); 6.95-7.53 (m, 9H). UPLC-MS (ESI+): [M+H]+=705. S i ^ Π ^ « Λ ^ 4 ':&gt; ^ 1 i 竺5军7 v 3, 硇^ ^ ^ ¥ ^ ^ X ψ 4 , 砩ώ ώ ^ i4 ^ 蛘碥, 丨 s 2 5 S ? Λ 7\ ^ ^ S ^ ^ t A Ϊ d 尝 宁 t bat t硪B~ j ΐ 2 ί ^ S ^ ^ 1 d蛱^ M硇〇〇»- 5 ^ si^ Λ ^ ^ 〇Ϊ ' J it ^ ^ ί ^ v J ί 1 « ^ ^ ^ ^ % 〇&lt;0 Γ I* 〇\ VO s 152524.doc • 505 · 201130854

^-NMR (sterol-d4, 300 MHz): 1.22 (tr, 3H); 1.92 (m, 3H); 2.67 (m, 2H); 3.56 (m, 2H); 3.89 (m, 3H); 4.15 ( m, 2H); 4.71 (d, 0.5H*); 4.77 (d, 0.5H*); 5.48 (m, 1H); 6.69-6.75 (m, 0.5H*); 6.80-6.85 (m, 0_5H*) ; 6.93-7.56 (m, 9H). UPLC-MS (ESI+): [M+H]+=721. ^-NMR (sterol-d4, 300 MHz): 1.19 (m, 3H); 1.66-1.80 (m, 2H); 1.95 (m, 3H); 2.28-2.40 (m, 2H); 2.41-2.53 (m , 2H); 3.90 (m, 3H); 4.01-4.11 (m, 2H); 4.33 (d, 0.5H*); 4.38 (d, 0.5H*); 5.40 (m, 1H); 6.70- 7.55 (m , 9H). UPLC-MS (ESI+): [M+H]+=723. <RTIgt; , 1H); 4.20 (d, 0.5H1&quot;); 4.28 (d, 0.5H*); 4.31 (d, 4H); 5.40 (m, 1H); 6.57 (m, 0.5H*); 6.71 (m, 1.5 H*); 7.15-7.54 (m, 8H). UPLC-MS (ESI+): [M+H]+=715 ° X % X ^ ί ^ I s 5 i ¥ ^ ^ S i V 2 S I Think Lan ‘? Order dd 3, 2 ^ d ^ ^ ^ ^ ^ V 4 .3⁄4 t ^ »- 5 x ^ A ¥ ^ sv $4 ^ ^ Ί1 ^ s, Ψ 三孓革V t ^ S s ^ 减叉®p令人M办^ ώ办赵Η 2 ° 亨τό机械蚪 £ I ^ λ ¥ ί ^ 5 S § V „ & °^5 u. %? 5&quot; 7 ' **8&gt;»· s S 152524 .doc -506- 201130854

^-NMR (methanol-d4, 300 MHz): 1.22 (m,3H); 1.94 (m,3H); 2.67 (m, 2H); 3.57 (m, 1H); 3.87 (m, 2H); 4.31 (d , 4H); 4.34 (d, 0.5H*); 4.40 (d, 0.5H*); 5.43 (m, 1H); 6.58 (m, 0.5H*); 6.72 (m, 1.5H*); 7.15- 7.51 (m, 8H). UPLC-MS (ESI+): [M+H]+=731. iH-NMR (sterol-d4, 300 MHz): 1.93 (s, 3H); 3.56 (m, 2H); 3.89 (m, 5H); 4.37 (d, 0.5H*); 4.42 (d, 0.5H* 5.46 (m, 1H); 6.70-6.77 (m, 0.5H*); 6.82-6.89 (m, 0.5H*); 6.93-7.56 (m, 10H). UPLC-MS (ESI+): [M+H]+=617. ^-NMR (sterol-d4, 300 MHz): 1.94 (s, 3H); 3.47 (m, 2H); 3.91 (m, 5H); 4.29 (d, 0.5H*); 4.40 (d, 0.5H* 5.45 (m, 1H); 6.71-6.78 (m, 0.5H*); 6.89-6.94 (m, 0.5H*); 7.06-7.54 (m, 10H). UPLC-MS (ESI+): [M+H]+=695. [2-({[6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxan-6-yl)-8-(2-gas-6-difluoro) Mercapto-benzyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a]» than -3-yl]-styl-anthracene Ethyl}-amino)-ethoxy]-ethyl acetate 6-(2-a-3-methoxy-phenyl)-8-(2-aero-6-trifluorodecyl phenylmethyl) 3 -[(2-carbyl-ethylamino)-phenyl-indenyl]·7·methyl-2,3-dihydro-β-indole[3,2-a]n&amp;°-5 -keto 3-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5- Oxyloxy-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-indenyl}-aminopropanone τ 1 -supply acid • 7.65 7.66 7.67 s 152524.doc -507· 201130854 ^-NMR (sterol-d4, 300 MHz): 2.00 (s, 3H); 3.90 (m, 3H); 5.80 (m, 1H); 6.71-6.79 (m, 0.5H) *); 6.86-6.93 (m, 0.5H*); 7.08-7.60 (m, 10H). UPLC-MS (ESI+): [M+H]+=709 » 1 b-NMR (sterol-d4, 300 MHz): 1.83 (d,3H); 3.87 (m,3H)·,4.33 (d, 0.5H*); 4.40 (d, 0.5H*); 5.38 (m, 1H); 6.71 (m, 1H); 7.03-7.87 (m, 14H) &gt; UPLC-MS (ESI+): [M+H]+=746 » h-NMR (Methanol-d4, 300 MHz): 1.77 (m 2H); 1.91 (s,3H); 2.48 (m, 2H); 3.87 (m, 3H); 4.26 (d, 0.5H*); 4.31 (d, 0.5H*); 5.40 (m, 1H); 6.72 (m, 0.5H*); 6.85 (m, 0.5H*); 7.01-7.85 (m, 14H) UPLC-MS (ESI+): [M+H]+=760. 4-({[6-( 2-fluoro-3-methoxy-phenyl)-8-(2-po-6-trifluoromethyl-benzyl)-7-fluorenyl-5-oxo-2,3-dihydro -5H-thiazolo[3,2-a]atb^-3-yl]•phenyl-methyl}-amino)-butylate-1·supply 2-[2-({[6-(2) -fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-adenyl)-7-methyl-5-oxo-2,3-dihydro- 5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methyl}-amino)-ethyl]• 异叫卜朵-1,3-二嗣人¢- ^ ^ ψ ^ χ ^ 1 si ¥ 5 ^ ί έ V Ί(Ι ^ ψ νό ^ ^ ϊ t « a work is ει ^5 % (^C 〇7.68 7.69 III 7.70 152524.doc -508- 201130854 ^-NMR (methanol-d4, 300 MHz): 1.47 (m, 2H); 1·94 (d, 3H); 2.38-2.58 (m, 2H); 3.66 (m, 2H); 3.92 (m, 3H); 4.26 ( d, 0.5H*); 4.34 (d, 0.5H*); 5.45 (m, 1H); 6.76 (m, 0.5H*); 6.85 (m, 0.5H*); 7.10-7.86 (m, 14H). UPLC-MS (ESI+): [M+H]+=774. h-NMR (sterol-d4, 400 MHz): 1.18 (dt, 3H); 1.30-1.37 (m, 6H); 1.56-1.69 (m, 2H); 1.93 (s, 3H); 2.14-2.35 (m , 3H); 2.54-2.66 (m, 1H); 3.95 &amp; 3.99 (2x s, 2H); 4.00-4.09 (m, 2H); 4.34-4.43 (m, 1H); 4.46 (d, 0.5H*) 4.51 (d, 0.5H*); 4.53-4.71 (m, 2H); 4.98-5.07 (m, 1H); 6.68-6.75 (m, 0.5H*); 6.78-6.84 (m, 0.5H*); 7.04-7.15 (m, 2H); 7.22-7.44 (m, 8H); 7.46-7.52 (m, 1H). UPLC-MS (ESI+): [M+H]+=699. iH-NMR (sterol-d4, 300 MHz): 1.23 (dt, 3H); 1.30-1.38 (m, 6H); 1.92 (br. s, 3H); 2.24-2.53 (m, 1H); 2.68-2.80 (m, 1H); 3.46-3.55 (m, 2H); 3.94-4.05 (m, 4H); 4.11-4.22 (m, 2H); 4.34-4.43 (m, 1H); 4.53-4.66 (m, 2H) ;469..78 (m, 1H); UPLC-MS (ESI+): [M+H]+=715. 2-[4-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoroindolyl)]-indenyl-5 -Sideoxy-2,3-dihydro-5H-thiazolo[3,2-a]*^a_^-3-yl]-phenyl-indenyl}-amino)-butyl]-isoindole哚·1,3_dione f ^ 'ii ^ S Ϊ 9 11 d 'ό ί ^ ^ ^ s 7 4 ^ ^ 1 [2-({[6-(2-fluoro-3-isopropoxy-) Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5H-oxazole[3,2 -a] 0 to 0 -3 -yl]-phenyl-fluorenyl}-amino)·ethoxy]-ethyl acetate% ^古乂ό%? Ο I 7.71 7.72 7.73

s 152524.doc -509- 201130854 ^^^^^εζ/ζ&lt;^εε·ι&gt;·^ίκ&lt;ΙΠν^Ν^Μ38·ί14ικ^πίΝ0Γι&gt;^17ζ/Δ^{κΗ-^:(ζε^1 ^)5ε^ Analytical data ^-NMR (f, -d4, 400MHz): 1.98 (d, 3H); 2.99-3.15 (m, lH); 3.19-3.30 (m, 1H); 3.48 (d, 0.5H* ); 3.59-3.80 (m, 3.5H*); 3.82-4.01 (m, 7H); 4.76-4.81 (m, 1H); 5.68-5.75 (m, 1H); 6.74-6.80 (m, 0.5H*) ; 6.86-6.92 (m, 0.5H*); 7.09-7.52 (m, 10H). MS (ESI+): [M+H]+= 675. ^-NMR (sterol-d4, 400 MHz): 1.24-1.35 (m, 2H); 1.40-1.62 (m, 4H); 1.94 (s, 3H); 2.14-2.26 (m, 2H); 2.38-2.60 (m, 2H); 3.15-3.26 (m, 1H); 3.43-3.54 (m, 1H); 3.84-4.02 (m, 4H); 4.37 (d, 0.5H*); 4.43 (d, 0.5H*) ;5..5. MS (ESI+): [M+H]+=687 〇1 _ Name 5? Ιέ ^ t ^ ^ 1 ^砩cA T and ^ ^ ^ 2 0 — 驴人驴 AU丨 alkali#砩S νφ 军1^ _ ώ d嘁杗6-({[6-(2-Fluoro-3-indolyl-phenyl)-8·(2-fluoro-6-trifluoromethyl)-benzyl)-7-methyl- 5-Phenoxy-2,3-dihydro-5H-thiazolo[3,2-a].pyridin-3-yl]-phenyl-fluorenyl}-amino)-hexanoic acid structure 'r - Λ %? 〇乂S No. 7.74 7.75 • 510- 152524.doc 201130854

^-NMR (sterol-d4, 400 MHz): 1.93 (s, 3H); 2.46-2·62 (m, 2H); 3·44-3.53 (m, 1H); 3.84-3.97 (m, 4H); 4.36 (d, 0.5H*); 4.41 (d, 0.5H*); 5.43-5.49 (m, 1H); 6.70-6.76 (m, 0.5H*); 6.80-6.86 (m, 0.5H*); 7.07 -7.33 (m, 8H); 7.37-7.53 (m, 2H). MS (ESI+): [M+H]+= 675. h-NMR (methanol-d4, 300 MHz): 1.73 (m, 2H); 1.94 (s, 3H); 2.31 (t, 2H); 2.64 (m, 2H); 3.52 (m, 2H); , 3H); 3.95 (m, 2H); 4.46 (d, 1H); 5.52 (m, 1H); 6.80 (m br, 1H); 6.90 (m, 1H); 7.25-7.52 (m, 1 OH). UPLC-MS (ESI+): [M+H]+=641. ^-NMR (methanol-(14,3001^〇2):1.67-1.94 (111,2 Ma; 1.95 ((1,311); 2.26-2.38 (m, 2H); 2.62-2.80 (m, 2H); 3.19 (d, 0.5H*); 3.48-3.59 (m, 1H); 3.84 (d, 3H); 3.87-3.99 (m, 2H); 4.47 (d, 0.5H*); 4.51 (d, 0.5H*) 5.49-5.57 (m, 1H); 6.72-6.88 (m, 2H); 7.06-7.14 (m, 0.5H*); 7.19-7.54 (m, 8.5H*) MS (ESI+): [M+ H]+=660. 1 ftt -&lt;ll V °° T f ^ , 4 helmets are Ϊ 械 t 成 into $, 丨i _ '硪六T澍cn ^ rn ^ ή &quot;S % i Φ ί 1S 4 CS 砩ϊ CN s Ϊ ^ 硪A Ϊ 2 ^ ^ a Ul, 毽 一 一 一 卜 卜 卜 卜 卜 卜 卜 卜 卜 卜 卜 卜 卜 π π π π 1 iif ^ j 5 _ 崎ί st 'bat 4i A f ύ m ^ %? j~C - o=Ts〇氺Λ0 υ 〇\0 00 r·^

S 152524.doc -511 - 201130854 ^-NMR (sterol &lt;14,300^«^): 1.67-1.82 (111, 2 imprints; 1.97 (5, 311); 2.16-2.29 (m, 2H); 2.52-2.70 (m , 5H); 3.35-3.54 (m, 2H); 3.82-3.99 (m, 2H); 4.38-4.49 (m, 1H); 5.44-5.55 (m, 1H); 7.16-7.62 (m, 10H); 7.83 -7.93 (m, 1H) MS (ESI+): [M+H]+=67 </RTI> NMR (methanol-(14,400^^112): 1.64-1.82 (111,211); 1.97 (1,311 2.25· 2.40 (m, 2H); 2.57-2.75 (m, 2H); 3.17 (d, 0.5H*); 3.36 (d, 0.5H*); 3.50-3.58 (m, 1H); 3.83-4.01 (m, 2H); 4.42-4.49 (m, 1H); 5.48-5.56 (m, 1H); 7.17-7.38 (m, 9H); 7.38-7.54 (m, 2H). MS (ESI+): [M+ H]+=713. ^-NMR (methanol-d4, 300 MHz): 1.31-1.37 (m,6H); 1.68-1.82 (m,2Η)·, 1.95 (d, 3H); 2.19-2.36 (m, 2H); 2.58-2.79 (m, 2H); 3.22 (d, 0.5H*); 3.36 (d, 0.5H*); 3.50-3.58 (m, 1H); 3.83-4.00 (m, 2H); 4.48 ( d, 0.5H*); 4.54 (d, 0.5H*); 4.55-4.67 (m, 1H); 5.51-5.57 (m, 1H); 6.72-6.77 (m, 0.5H*); 6.86-6.92 (m , 0.5H*); 7.07-7.34 (m,8H); 7.38-7.53 (m,2H) MS (ESI+): [M+H]+=687. 1 im vt| if ^ s ^ ¥ ^ ^ ^ 3 ^ ^ ® t ^ B- (N *? 〇^ ^ ^ ^三 ‘...s .0 ^ m A S~ , W 5 ί 乂 W ‘ 4 ί | ί 4 - f 3 硪 έ v ^ g ^微妙®· ή% ^ 1 1 l Ur 哫硪A rA 人琳. A硪 cA ^ i ^ = c!j _ beads 4 ώ ^ :&gt;%9 〇&lt;0 wood 〇&lt;0 〇4〇 On 〇〇 152524.doc -512- 201130854

h-NMR (sterol-d4, 400 MHz): 1.27-1.41 (m, 6H); 1.93-1.98 (m, 3H); 2.80-3.21 (m, 2H); 3.37-3.72 (m, 4H); -4.07 (m, 4H); 4.38 (br. s, 0.5H*); 4.51-4.72 (m, 1.5H*); 5.57-5.69 (m, 1H); 6.68-7.55 (m, 11H). UPLC-MS (ESI+): [M+H]+=703. ^-NMR (methanol-d4, 300MHz): l·68-l·83 (m, 2H); 1.94 (d, 3H); 2·24-2.38 (m, 2H); 2.58-2.90 (m, 2H) ; 3.42-3.51 (m, 1H); 3.61-3.76 (m, 1H); 3.85-4.09 (m, 2H); 4.53 (d, 0.5H*); 4.64 (d, 0.5H*); 5.46-5.62 ( m, 1H); 7.11-7.37 (m, 8H); 7.39-7.57 (m, 2H). MS (ESI+): [M+H]+= 713. iH-NMR (sterol-d4, 300 MHz): 1·17 (d, 3H); 1.45 (d, 3H); 1.45-1.70 (m, 2H); 1.94 (d, 3H); 2.14-2.41 (m , 4H); 3.88 (d, 3H); 3.99-4.21 (m, 3H); 5.22-5.33 (m, 1H); 6.71-6.85 (m, 1H); 7.04-7.19 (m, 2H); 7.23-7.42 (m, 4H); 7.43-7.54 (m, 3H); 7.54-7.61 (m, 1H). MS (ESI+): [M+H]+= 687. [2-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8·(2-fluoro-6-trifluoromethyl-)methyl]-7-fluorenyl-5-side Oxy-2,3-dihydro-5H-thiazolo P,2-a]acridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid 4-({[ 6-(2-Fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5-sideoxy-2 ,3-dihydro-5H-thiazide[3,2-a]etb°-3-yl]-phenyl-methyl}-amino)-butyric acid 4-({[6-(2- Fluoro-3-methoxy-phenyl)-8-(2-oxa-6-trifluoromethyl-benzyl)-2,2,7-diamidino-5-sideoxy-2,3 -二风-5H_thiazolo[3,2-a]°pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid%? y 0 Λ0 &gt; 7.82 7.83 j 7.84 152524.doc -513- 201130854 h-NMR (sterol-d4, 300 MHz): 1.17 (d,3H); 1.46 (d,3H); 1.46-1.68 (m, 2H); 1.95 (d, 3H); 2.14-2.41 (m, 4H); 4.01-4.21 (tn, 3H); 5.23-5.33 (m, 1H); 7.22-7.61 (m, 11H). MS (ESI+): [M+H]+=============================================================== , 3H); 2.13-2.40 (m, 4H); 4.01-4.20 (m, 3H); 5.23-5.31 (m, 1H); 7.12-7.42 (m, 8H); 7.45-7.52 (m, 3H); -7.60 (m, 1H) MS (ESI+): [M+H]+=657. H-NMR (Methanol-d4, 300 MHz): 1.17 (d,3H); 1.45 (s,3H); -1.68 (m, 2H); 1.96 (d, 3H); 2.13-2.42 (m, 4H); 3.77 (d, 3H); 4.01-4.21 (m, 3H); 5.24-5.33 (m, 1H); 6.73 -6.81 (m, 1H); 6.86-6.96 (m, 1H); 7.02-7.12 (m, 1H); 7.23-7.43 (m, 4H); 7.43-7.54 (m, 3H); 7.54-7.62 (m, 1H) MS (ESI+): [M+H]+= 687. 4-({6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- Trifluoromethyl-benzyl)-2,2,7-trimethyl-5-oxo-2,3-dihydro-5H-thiazolo-p,2-a]pyridin-3-yl]- Phenyl-fluorenyl}-amino)-butyric acid 4-({[6-(2-fluoro-phenyl)-8-(2-H-6-trifluorodecyl-benzyl)-2, 2,7-trimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]D ratio 1,4--3-yl]-phenyl-fluorenyl}-amine ))_ Butyric acid _ 1 ! 4-({[6-(2-Fluoro-5-decyloxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzoinyl)-2 ,2,7-: 三曱基- 5-Phenoxy-2,3-dihydro-5H-thiazolo-Pj-a]'-pyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid%? X ryV ^ ζ 7.85 7.86 7.87 152524.doc -514· 201130854

h-NMR (sterol-d4, 300 MHz): 1.90-2.09 (m, 6H); 2.95-3.26 (m, 2H); 3.44 (d, 1H); 3.58-3.82 (m5 3H); 3.84-3.98 ( m, 4H); 4.76-4.82 (m, 1H); 5.67-5.75 (m, 1H); 7.22-7.53 (m, 10); 7.55-7.64 (m, 1H). MS (ESI+): [M+H]+= 709. ^-NMR (methanol-d4, 300 MHz): 1.66-1.81 (m, 2H); 1.86-2.09 (m, 6H); 2.25-2.38 (m, 2H); 2.55-2.77 (m, 2H); d, 0.5H*); 3.35 (d, 0.5H*); 3.47-3.62 (m, 1H); 3.82-4.04 (m, 2H); 4.44 (d, 0.5H*); 4.50 (d, 0.5H* ); 5.48-5.57 (m, 1H); 7.17-7.64 (m, 11H). MS (ESI+): [M+H]+= 693. ^-NMR (sterol-d4, 300 MHz): 1.80-2.06 (m, 6H); 2.68-2.96 (m, 2H); 3.47-3.66 (m, 3H); 3.81-4.04 (m, 4H); 4.41 -4.54 (br. s, 1H); 5.57-5.66 (m, 1H); 7.23-7.57 (m, 12H). MS (ESI+): [M+H]+=69b [2-( {[6-[3 -(1,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2- Fluoro-6-trifluorodecyl-phenylhydrazino)-7-mercapto-5-flavoryl-2,3-dimur-5H-thiazepine[3,2-a]acridin-3-yl •Phenyl-fluorenyl}-amino)-ethoxy]-acetic acid 4-({[6-[3-(l,l-difluoro-ethyl)-2-fluoro-phenyl]-8 -(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]acridine- 3-yl]-phenyl-fluorenyl}**amino)-butyric acid P-({[643-(l,l-difluoro-ethyl)-phenyl]-' 8-(2-fluoro- 6-trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-5H-thiazolo[3,2-a].pyridin-3-yl]- Phenyl-fluorenyl}-amino)-ethoxy]-acetic acid y 0 X〇^9 - V 0 7.88 7.89 7.90 s 152524.doc -515- 201130854 iH-NMR (methanol-d4, 300 MHz): 1.68 -1.84 (m, 2H); 1.98 (m, 3H); 2.33 (m, 2H); 3.51-3.59 (m, 1H); 3.90-4.10 (m, 2H); 4.52 (dd, 1H); 5.57 (m , 1H); 6.74-6.90 (m, 2H); 7.04-7.55 (m, 15H). UPLC-MS (ESI+): [M+H]+=721. iH-NMR (methanol-d4, 300 MHz): 1.64-1.78 (m, 2H); 1.96 (m, 3H); 2.31 (m, 2H); 2.62 (m, 2H); 3.47-3.56 (m, 1H) 3.96 (m, 2H); 4.45 (d, 1H); 5.52 (m, 1H); 6.86 (tr, 1H); 7.00-7.57 (m, 12H). UPLC-MS (ESI+): [M+H]+=677 〇iH-NMR (methanol-d4, 300 MHz): 1.99 (d,3H); 3.41 (d,1H); 5.72 (m, 1H); 6_87 (tr, 1H); 7.00-7.55 (m, 12H). UPLC-MS (ESI+): [M+H]+=693. i JS two s Ϊ ^ ^ f . ^ ^ ^ 4 5 t 4 ®- (N $^l !Right 4 d砩ϊ 1 1 Qt_ -?&lt;t| ^ AT 6- 嗖5 4, sneak out T, 1 3 h ¢- ^ rA TA ^ ¢- &lt;N &lt;7 ^ 7\ ^ Λ ^ ^ rA 'Ί ^ s ^ ^ s 4 d ^ ^ 陶 l ^ ί Ί i 5 ^ s- &lt;N Left Ridge 苳〒铤ώ d ^ ^ °^o 0 winter y 0 O) 152524.doc -516- 201130854

H-NMR (sterol-d4, 300MHz): 1.66-1.81 (m, 2H); 1.98 (m, 3H); 2.31 (m, 2H); 3.49-3.56 (m, 1H); 3.92 (m, 2H) 4.44 (d, 0.5H*); 4.51 (d, 0.5H*); 5.52 (m, 1H); 6.06 (m, 2H); 6.62 (m, 0.5H*); 6.75 (m, 1.5H*) ); 7.19-7.55 (m, 9H). UPLC-MS (ESI+): [M+H]+=673. , ^-NMR (sterol-d4, 300 MHz): 2.00 (m, 3H); 5.72 (m, 1H); 6.07 (m, 2H); 6.64 (m, 0.5H*); 6.77 (m, 1.5H) *); 7.20-7.58 (m, 9H). UPLC-MS (ESI+): [M+H]+=689. iH-NMR (methanol-d4, 300 MHz): 1_93 (m, 3H); 2.30 (m, 2H); 3.53-3.64 (m, 2H); 3.54 (m, 1H); 3.86-4.02 (m, 5H) ; 4.72 (m, 1H); 5.53 (m, 1H); 6.72 (m, 0.5H*); 6.83 (m, 0.5H*); 6.98-7.54 (m, 9H). UPLC-MS (ESI+): [M+H]+=677. 4-({[6-(4-fluoro-benzo[1,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl) -7-mercapto-5-oxo-2,3-dihydro-5H-thiazolo-p,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyrate r r r r r r r r r r r r r r r r r r - ri ^ s/s £ ^ Ljii 5 'Ί ^ ^ ^ V vi ^ ^ 4 Ci硪完% 〇iS^〇ό % y 0 彳dr ss 152524.doc •517· 201130854 b-NMR (methanol-d4, 300 MHz): 1.97 (m, 3H); 3.90 (m, 3H); 5.08 (d, 0.5H*); 5.12 (d, 0.5H*); 5.72 (m, 1H); 6.75 (m, 0.5H*) ); 6.82 (m, 0.5H*); 7.04-7.73 (m, 9H). </ RTI> <RTIgt; ); 2.52 (m, 2H); 4.37 (m, 0.5H*); 4.43 (d, 0.5H*); 5.42 (m, 1H); 6.70-7.53 (m, 9H). UPLC-MS (ESI+): [M+H]+=695. ^-NMR (methanol-d4, 300 MHz): 1.73 (m, 2H); 1.95 (m, 3H); 2.32 (m, 2H); 3.53 (m, 1H); 3.91 (m, 2H); 4.31 (d , 4H); 4.44 (d, 0.5H*); 4.51 (d, 0.5H*); 5.52 (m, 1H); 6.58 (m, 0.5H*); 6.72 (m, 1.5H*); 7.19-7.56 (m, 8H) 〇UPLC-MS (ESI+): [M+H]+=687 〇彳砩S ' a ^ 5 ^ Φ ^ &amp;- 4 ^ ^ tO rn £B- &lt;N ^ ^ au\ ^ f ^ ± ff J ^ dd ^ Ϊ ί 兮 ^ ^ ^ Ink ^ . d &amp; ^ 虿π t ^ v 4 ϊ ^ T °? 3 丄 "S a Λ 硪 w ^ s 硇 4 ®~ 4' 5兮军3士1 ^ ή 3 S Η 1 π ^»1 ^ ^ ^ 4 Ί 'Ί ^ 氺r &amp; X U. as (&lt;

152524.doc -518- s 201130854

J ^-NMR (methanol-d4, 300 MHz): 1_98 (m, 3H); 4.31 (d, 4H); 5.72 (m, 1H); 6.60 (m, 0.5H*); 6.73 (m, 1.5H*) ); 7.21-7.54 (m, 8H). UPLC-MS (ESI+): [M+H]+=703. ^-NMR (methanol-d4, 400 MHz): 1.36-1.45 (m, 6H); 1.75-1.87 (m, 2H); 1.99 (s, 3H); 2.30-2.41 (m, 2H); 2.68-3.00 ( m, 2H); 3.81-4.01 (m, 2H); 4.58-4.75 (m, 3H); 5.30-5.36 (m, 0.5H*); 5.39-5.46 (m, 0.5H*); 6.74-6.81 (m , 0.5H*); 6.88-6.95 (m, 0.5H*); 7.11-7.54 (m, 1 OH). UPLC-MS (ESI+): [M+H]+=671. h-NMR (methanol-d4, 300 MHz): 1.31-1.48 (m, 6H); 1.84-2.09 (m, 4H); 2.36-2.81 (m, 1H); 3.67-4.10 (m, 5H); 4.29 (m, 1H); 4.34-4.48 (m, 1H); 5.82-6.08 (m, 1H); 6.64-7.58 (m, 11H). UPLC-MS (ESI+): [M+H]+=687. 5 t罕-义^ ^ « ώ ^ 褊tO ten, 1 2 base △ 蛘 4 a 3 ) 0. ^ ®~ (N rA = minus "sportsman (N Ί 'Ί ^ f 1 4-({[6 -(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-indolyl-5-sideoxy-2,3 -dihydro-5H-oxazolo[3,2-a]&quot;bipyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid [2-({[6-(2- Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro- 5H-oxazolo P,2-a]»bipyridin-3-yl]-phenyl-indenyl}-amino)-ethoxy]-acetic acid y° 〇&gt;&gt; 7.100 7.101 7.102 1 s. 152524.doc -519- 201130854 Example 7.103 Preparation of 4-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl) -7-Methyl-5-sideoxy-2,3_dihydro-5H_thiazolo[3,2-a]pyridine·3_yl]-styl-methyl}-amino)-butylamine

Add to the &gt; dish's Wind Oxidation (4·6 mg, 82 μιηοΐ, 1.5 equivalents) to 4·({[6-(2-fluoro-3-methoxy-phenyl)_8_(2_ Fluoro-6-trifluoromethyl-mutemethyl)-7-methyl-5-oxo-2,3-dihydro-5Η-thiazolo[3,2-a].pyridyl_3_yl] -Phenyl-fluorenyl}-amino)-butyronitrile (Example 7.38) (35 11^, 54 卩 111 〇 1) in a stirred solution of ethanol (0.63 mL). The reaction was stirred at room temperature for 3 days and at 4 (TC for 7 days. The reaction mixture was then partitioned between water and ethyl acetate and neutralized with citric acid (10% aqueous). After phase separation The aqueous layer was extracted with ethyl acetate and the combined organic layer was concentrated in vacuo. The title compound was isolated by HPLC chromatography (yield _ 8 W-NMR (methanol - &lt;14, 400 MHz): 1.66 -1 81 广ΟΤτ, .1 (m, 2H); 1.94 (d, 3H); 2.16-2.22 (m, 1H); 2.27-2.37 (m lm 0 , v 1H), 2.42-2.55 (m, 1H) 2.59-2.82 (m, 2H); 3.21 (d, 0.5H*V q ,, ' 3.36 (d, 〇.5H*); 3.45-3.58 (m, 1H); 3.83-3.99 (m, 5H)· 4 〇〇4 c. ' ^ 4.29-4.54 (m,1H); 5.40-5.56 (m, 1H); 6.70-6.77 (m, 0.5Η*Ί· λ ^ (m&gt; 152524.doc •520- 201130854 0.5 H6); 7.06-7.34 (m,8H); 7.37-7.53 (m,2H) MS (ESI+): [M+H]+= 659. Example 7.104 Preparation of 6-(2-fluoro-3-oxo -Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-{phenyl-[3-(1Η-tetrazol-5-yl)· Propylamino]-methyl}-2,3-dihydro-singing and sitting [3,2-a]e than biting 5-ketone

Add azide triterpene base (11,96.5 mg, .820 μιηοο 15 equivalent) and oxidized (dibutyl)tin (IV) (2〇8 mg, 82 pmo, 1.5 equivalents) at room temperature To 4-({[6-(2-Fluoro-3-methoxy-phenyl)·8_(2-fluoro-6-tri-φ fluoroindolyl)-yl)-7-fluorenyl-5-side oxygen Base 2,3-dihydro-5 oxime-thiazolo[3,2- a]0 is more than -3-yl]-phenyl-indenylamino)butyronitrile (Example 7 38) (35^, 54 μηιοί) in a stirred solution of toluene (2 mL). The reaction was allowed to stand overnight at 8 °c. The reaction mixture was then partitioned between water and ethyl acetate. After the phase separation, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sat. The target compound was isolated by HPLc chromatography (yield: 12 mg). W-NMR (sterol_d4, 300 MHz): 1.85-2.03 (m, 5H); 2.63-2.77 (m, 2H); 2.86-2.99 (m, 2H); 3.12-3.24 (m, 1H); -3.61

S 152524.doc -521 - 201130854 (m,1H); 3.89 (s, 3H); 3.91-4.04 (m, 2H); 4.52 (d, 1H); 5.51-5.62 (m, 1H); 6.70-6.83 ( m, 1H); 7.06-7.21 (m, 2H); 7.22-7.38 (m, 6H); 7.39-7.56 (m, 2H) ° MS (ESI+): [M+H]+= 683. Table 37: The following Examples 7·105 and 7.106 were prepared in the same manner as in Example 7.1 04 from the examples 8.10 and 7.39 to prepare the numbered structure name analysis data 7.105 6-(4-fluoro-1,3-benzodioxanthene Cyclopentene-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-3-(phenyl{[3-(1Η-tetrazole-5) -yl)propyl]amino}methyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-&amp;]° ratio bite-5-嗣1-oxide^- NMR (sterol-d4, 300 MHz): 1.87 (s, 3H); 2.68 (m, 2H); 3.01 (m, 2H); 5.70 (m, 1H); 6.07 (d, 2H); 6.64 (m, 1H); 6.76 (m, 1H); 7.04-7.58 (m, 9H). UPLC-MS (ESI+): [M+H]+=687. 7.106 Λ 6-(4-Fluoro-benzo[1,3]dioxol-5-yl)-8-(2-gas-6-dimethylmethyl-phenylphenyl)-7- Methyl-3-{phenyl-[3-(1Η-tetrazol-5-yl)-propylamino]-indenyl}-2,3-dihydro-sold squat and [3,2-a ] 〇 咬 -5 - Ming H-NMR (sterol-d4, 300 MHz): 1.99 (s, 3H); 2.71 (m, 2H); 2.93 (m, 2H); 3.97 (d, 2H); 4.53 (m, 1H); 5.58 (m, 1H); 6.07 (d, 2H); 6.65 (m, 1H); 6.74 (m, 1H); 7.20-7.56 (m, 9H). UPLC-MS (ESI+): [M+H]+=697. Example 7.107 Preparation of 2-Amino-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7 -methyl-5-o-oxy-2,3-dihydro-5H-thiazolo[3,2-a]pyridine 152524.doc -522- 201130854 pyridin-3-yl]-phenyl-methylamino )_butyric acid

Add a solution of hydrochloric acid (4 Torr in dioxane, 114 pL, 0-46 111111 〇 1 '2 equivalent) to 2-tributoxycarbonylamino group at room temperature _4-({[6 -(2-say-3-methoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-phenylmethyl)_7_methyl_ 5-sidedoxy-2,3-dihydro_ 5H-» plug. Sit and [3,2-a] ° bite 3-yl]-phenyl-methyl}-amino)-butyric acid tert-butyl ester (Example 7.37) (19 〇 mg, 〇 23 mm 〇 1) in a stirred solution of dioxin (5 mL). The reaction was stirred overnight at 4 °c. The solvent was evaporated and subjected to HPLC chromatography to give the title compound (yield: 34 mg). lH-NMR (sterol_d4, 400 MHz): 1.78-1.92 (m, 2H); 1.95 (d 3H); 1.96-2.08 (m, 1H); 2.64-2.79 (m, 2H); 3.17-3.27 ( m 1H); 3.44-3.62 (m, 2H); 3.86-4.00 (m, 5H); 4.32-4.40 (m? 1H); 5.42-5.49 (m, 1H); 6.71-6.78 (m, 0.5H*) ; 6.83-6.91 (m, 0.5H*); 7.09.7.33 (m, 8H); 7.38-7.52 (m, 2H). MS (ESI+): [M+H]+=674. Example 7.108 Preparation 3 [(2-Aminoethylamino)phenyl]methyl]oxime phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_7_ Methyl 2,3·dihydro-thiazole 152524.doc ... 201130854 and [3,2-a] bite-5-ketone

To 2-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-)methyl)- at room temperature 7-Methyl-5-o-oxy-2,3-dihydro-5H-thiazolo-p,2-a]»biidine-3-yl]-phenylindolyl}-amino)-ethyl To a solution of hydrazine in THF (1.24 ml, 1.2 mmol) and a solution of hydrazine in THF (5 ml). Search and mix overnight. The evaporated mixture was wet-milled with dioxane and filtered off. Water was added to the filtrate and the pH was adjusted to pH 14 with stirring. The organic layer was evaporated to give 3-[(2-amino-ethylpyranyl)-phenyl-methyl]_6_(2-fluoro-3-yloxy-phenyl)-8-(fluoro-6) -Trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3 2 a]0 is a bit of 5-ketone. W-NMR (methanol-d4, 400 MHz): 1.92 (m, 3H); 3 88 (m, 5H). 4.26 (m, 0.25H*); 4.36 (m, 0.75H*); 5.4i (m, 1H); 67' 0.5H*); 6.83 (m, 0.5H*); 7.02-7.57 (m, 1〇H).坊 ' UPLC-MS (ES+): [M+H]+=616.

Table 38: The following Examples 7·Η) 9 and 7.110 were prepared starting from Examples 7.70 and 7.71 similar to Example 7丨(10). X 152524.doc -524. 201130854 Edited by *-· Structure;: Name, Analysis Data ; ..;; .....::twisted.' 7.109 3-[(3-Amino-propylamino)-phenyl-indenyl]-6-(2-ran-3-yloxy -phenyl)-8_(2-fluoro-6-trifluorodecyl-benzoinyl)-7-fluorenyl-2,3-dihydro-°Se and [3,2-a]0 ratio bite- 5-_ !H-NMR ( f S|-d4,400 MHz): 1.61 (m, 2H); 1.93 (s, 3H); 2.50 (m, 2H); 2.70 (m, 2H); 3.90 (m, 5H); 4.27 (d, 0.5H*); 4.30 (d, 0.5H*); 5.42 (m, 1H); 6.74 (m, 0.5H*); 6.83 (m, 0.5H*); 7.05-7.54 ( m, 10H). MS (CI+): [M+H]+=630. 7.110 0- 3-[(4-Amino-butylamino)-phenyl-methyl]-6-(2-fluoro-3-indolyl-phenyl)-8_ (2-fluoro-6- Trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydro-singer[3,2-a]0 ratio bite-5-ketone W-NMR (methanol-d4, 400 MHz) : 1.42 (m, 4H); 1.93 (s, 3H); 2.43 (m, 2H); 2.55 (m, 2H); 3.89 (m, 5H); 4.30 (d, 1H); 5.42 (m, 1H); 6.73 (m, 0.5H*); 6.82 (m, 0.5H*); 7.03-7.53 (m, 1 OH) 〇 UPLC-MS (ES+): [M+H]+=644. Example 7.111

Preparation of N-[3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl)-benzyl)-7-fluorenyl- 5-Phenoxy-2,3-dihydro-5H-thiazolo[3,2-a]acridin-3-yl]-phenyl-methyl}-amino)-propyl]-pulp HN ^nh2

Add at a room temperature to saliva-1-曱脒 (40 mg, 0.27 mmol)

S 152524.doc -525 - 201130854 to 3_[(3·Amino-propylamino)-phenyl-methyl]·6_(2_'_3 methoxyphenyl)-8-(2-fluoro-6 -difluoromethyl-phenylhydrazino)methyl-2,3 dihydrothiazolo[3,2-a]pyridine-5-one (Example 7 1〇9) (1 〇〇 mg, 〇16 in acetonitrile ( 5 mL) and a stirred solution of AT, #-diisopropylethylamine (〇〇83 m 〇 47 mm 〇 1). The reaction mixture was stirred for a few hours and evaporated. The title compound was obtained after chromatography. W-NMR (methanol-d4, 300 MHz): 1.65 (m, 2H); 195 (s, 3H); 2.46 (m, 2H); 3.89 (m, 3H); 4.22 (m, 1H); , 1H); 6.77 (m, 1H); 7.07-7.55 (m, 10H) MS (ES+): [M+H]+=672. Example 7,112 Preparation [3-({[6-(2-fluoro-) 3_decyloxy-phenyl)_8_(2_fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-yloxy-2,3-dihydro-5H-thiod And [3,2_a] ° than bit-3-yl]-benyl-mercapto-amino)-propyl]-gland

Add trimethylsulfonium isocyanate (13 mg, 0.095 mmol) to 3-[(3-amino-propylamino)-phenyl-methyl]·6-(2) at room temperature -fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-2,3-dihydro-oxazolo[3, 2-a]pyridin-5-one (Example 7.109) (60 mg, 0.095 mmol) was dissolved in a stirred solution of 152524. doc - 526 - 201130854 gas (5 mL). The reaction mixture was stirred for 1 hour and evaporated. The target compound is obtained after chromatography. h-NMR (methanol-d4, 300 MHz): 1.60 (m, 2H); 1_94 (s, 3H); 2·53 (m, 2H); 3.50 (m, 1H); 3.90 (d, 3H); 4.33 (d, 0.5H*); 4·38 (d, 0.5H*); 5.47 (m, 1H); 6.74 (m, 0.5H*); 6.84 (m, 〇-5H*); 7.06-7.54 (m , 10H). UPLC-MS (ESI+): [M+H]+=673. Examples 8.1 and 8.2 Preparation of 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl ({methyl[2]pyridin-2 -yl)ethyl]amino}indenyl)-2,3-dihydro-5Η·[1,3&gt;- oxazolo[3,2-a]pyridin-5-one 1·oxide and 6-( 4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzoinyl)-7-fluorenyl_3_({methyl[2-(acridin-2-) Ethyl]amino}indenyl)·2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 1-oxide

Adapted to GP 27c: Add ferric chloride (in 乂〇3 mg, 0.002 mmol, 0.03 eq.) to 8-(2,6-difluoro-benzyl)_6_ (2- at room temperature Fluoro-3-methoxy-phenyl)-7.methyl-3-{[methyl-(2-««pyridin-2-yl-ethyl)-amino]-methyl}-2, 3-Dihydro-pen-sit and [3,2-&amp;]0 is a scrambled solution in the acetonitrile (3 mL) than the 5-keto-ketone (Example 5.64) (3 5 mg, 0.062 mmol). After 5 minutes, (original) peracid (15.5 mg, 0.068 mmol, 1.1 152524.doc • 527 · 201130854 equivalent) was added and mixing was continued for 3-5 hours. Iron chloride (111) (0.3 mg, 0.002 mmol, 〇. 〇 3 eq.) and (original) periodic acid (15.5 mg, 〇. 〇 68 mmol s 1 _ 1 equivalent) were then added again and the mixture was stirred overnight. The reaction mixture was partitioned between EtOAc and EtOAc. The target compound was isolated by preparative HPLC purification (yield: 16 mg and 9 mg). Example 8.1: 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-indolyloxyphenyl)-7-mercapto-3-({mercapto[2-(&quot; Bipyridin-2-yl)ethyl]amino}methyl)_2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 1-oxide W- NMR (sterol-d4,400 MHz): 2.02-2.08 (m,3H); 2,98 (d, 1.5H*); 3.10 (d, 1.5H*); 3.36-3.70 (m, 4.5H*) ; 3.72-3.96 (m, 5H); 4.08-4.22 (m, 0.5H*); 4.26-4.46 (m, 2H); 5.76-5.93 (m, 1H); 6.60-6.79 (m, 1H); 6.90- 7.04 (m, 2H); 7.13- 7.43 (m, 5H); 7.74-7.86 (m, 1H); 8.16-8.31 (m, 1H). MS (CI+): [M+H]+=582. Example 8.2: 6-(4-Chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzoinyl)-7-methyl-3-({mercapto[2] -(«bipyridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-5-one 1- Oxide] H-NMR (methanol-d4, 300 MHz): 2.00-2.06 (m, 3H); 2.89-2.94 (m, 1H); 3.02-3.09 (m, 2H); 3.56-3.73 (m, 3H) 3.85-3.96 (m, 4H); 4.28-4.46 (m, 2H); 5.78-5.94 (m, 1H); 6.91-7.04 (m, 2H); 7.15-7.47 (m, 5H); 7.76-7.88 ( m, 1H); 8.26-8.36 (m 1H). MS (CI+): [M+H]+=616 〇152524.doc 201130854 Example 8.3 Preparation of 4-{[{6·(2-Fluoro-3-methoxyphenyl)-8-[2-Fluoro-6 -(Trifluoromethyl)phenylhydrazino]-7-fluorenyloxy ion-5·sideoxy-2,3_dihydro_5Η·[ι,3]thiazolo[3,2-a]« Ethylpyridin-3-yl}(phenyl)methyl]amino}butyrate

4-({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-5-side oxygen Ethyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-indenyl}-amino)-butyric acid ethyl ester 4_({[6·( 2_Fluor_3·decyloxy_phenyl)-8-(2-fluoro-6-trifluoromethyl·benzoinyl)·7_fluorenyl_5_sideoxy-2,3_dihydro- 5Η-thiazolo[3,2_a]pyridine_3_yl]•phenyl-methyl}-amino)-butyric acid ethyl ester (Example 7.1) (35 0 mg, 〇·5 mmol) was dissolved in acetonitrile ( Add 1 mg of gasified iron, 0.06 mmol) and phloem (128 mg, 0. 056 mmol) to 1 〇mL). An additional amount (once per hour io 28 mg '0.05 6 mmol) of periodic acid was added until complete reaction, followed by treatment of the mixture and flash chromatography to yield the title compound. lH-NMR (sterol _d4, 300 MHz): 1.18 (dt, 3H); 1.83 (m, 2H); 1-97 (s, 3H); 2.36 (m, 2H); 2.56 (m, 2H); 3.87 (d, 3H); 5.67 (m, 1H); 7.02-7.59 (m, 11H) ° UPLC-MS (ESI + ): [M+H]+=703. s 152524.doc -529- 201130854 Driving qr^_ Fu Gu 3 Bu 3 doM 鹓馁 鹓馁 v^w 荽 Γ 8 f 驷 驷 Zhu 3⁄4IrooWH inch · 8 ί杳驷κ-3: 6ε&lt; Analysis data ^- NMR (sterol-d4, 400 MHz): 1.87 (d, 3 Η), 3.05-3.16 (m, 1 Η), 3.93-4.01 (m, 1H); 4.37-4.71 (m, 6H); 5.37-5.41 (m , 1H); 5.64-5.70 (m, 1H); 7.01-7.73 (m, 1 OH). </ RTI> <RTIgt; , 2H), 2.52-2.63 (m, 2H); 3.83 (d, 3H); 4.01-4.19 (m, 4H); 4.25-4.37 (m, 2H); 4.40-4.53 (m, 1H); 5.63-5.72 (m, 1H); 6.71-6.87 (m, 2H); 7.01-7.60 (m, 11H). UPLC-MS (ESI+): [M+H]+=704. Name 3-[Amino(2-fluorophenyl)indolyl]-6-[2-fluoro-3-(trifluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) Benzyl]-7-mercapto-2,3-dihydro-5H-[1,3]thiazolo[3,2-&amp;]° than bite-5-ketophene oxide 4-{[ {6-(2-Fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) adenyl]-7-methyl-1-oxo-yl-5- Ethyloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]indolepyridin-3-yl}(phenyl)indenyl]amino}butyric acid ethyl ester structure Ό 5-〇X No. 00 yn οό -530- 152524.doc 201130854

^-NMR (methanol-d4, 300 MHz): 1.20 (m,3H); 1.75 (m,2H); 1.83 (s, 3H); 2.38 (m, 2H); 2.54 (m, 2H); 3.88 (d , 3H); 5.69 (m, 1H); 6.61- 7.62 (m, 9H). UPLC-MS (ESI+): [M+H]+=739. ^-NMR (methanol-d4, 300 MHz): 1.22 (m,3H); 1.78 (m, 2H); 1.85 (m, 3H); 2.39 (m, 2H); 2.60 (m, 2H); 3.90 (d , 3H); 4.10 (m, 2H); 4.26 (d, 2H); 5.81 (m, 1H); 6.67 (m, 1H); 6.99-7.64 (m, 9H). </ RTI> <RTIgt; (tr, 2H); 2.56 (tr, 2H); 4.06 (m, 2H); 4.10-4.48 (m, 4H); 5.67 (m, 1H); 6.84 (tr, 1H); 6.92-7.60 (m, 12H ). UPLC-MS (ESI+): [M+H]+=72 卜^^^ ώ 4 ¥ ^cA ^ ^ ^ f ^ 5 d ^ ir ? h i4 H5 An ^ S ig r ¢- B- rf £ Λ妙$ »0 ®- e- 7 ^ ^ ^ f7&gt; ^ ΐ C!, h ¥ ψ SSS 5 v ^ -r ^ ^ Ϊ έ ί ^ 1 5 5 Today S knot 5 temple t coffee ^ ^ ^ ^ Z 5 5 | S 4 is 幽^ 5 i ^ 4 MS ^ £1 &- cA A, III TO inch 00 卜CN uf °^X) xV/=\ VO 〇6 00 00 OO od s 152524.doc -531 - 201130854 lH-NMR (CDC13, 600 MHz): 1.71-1.84 (m, 5H); 2.35-2.47 (m, 2H); 2.62-2.76 (m, 2H); 3.22-3.28 (m, 1H); 3.89 (d, 3H); 4.17-4.27 (m, 3H); 4.39-4.47 (m, 1H); 5.51-5.58 (m, 1H); 6.92-6.97 (m, 1H); 7.11-7.24 (m, 4H) ); 7.30-7.38 (m, 4H); 7.46-7.51 (m, 1H). MS (ESI+): [M+H]+=656 〇i______ ... ...... ^-NMR (methanol-d4, 400 MHz): 1.73-1.84 (m, 2H); 1_85 (br. s, 3H); -2.58 (m, 2H); 2.63-2.71 (m, 2H); 3.89 & 3.92 (2x s, 3H); 4.07-4.19 (m, 1H); 4.27-4.42 (m, 2H); 4.46-4.55 ( m, 1H); 5.64-5.73 (m, 1H); 6.72-6.82 (m, 1H); 7.08-7.24 (m, 4H); 7.25-7.38 (m, 4H); 7Λ2-7.51 (m, 1H); 7.53-7.60 (m, 1H). MS (ESI+): [M+H]+= 656. ^NMR (sterol-d4, 300 MHz): 1.79 (m, 2H); 1.87 (s, 3H); 2.53 (m, 2H); 2.66 (m, 2H); 4.05-4.52 (m, 4H); (m, 1H); 6.07 (d, 2H); 6.65 (m, 1H); 6.76 (m, 1H); 7.05-7.58 (m, 8H). UPLC-MS (ESI+): [M+H]+=670 ° SJ 2 a 1 ^ Mechanical 1 lean γ荽®- &- Τ ΡΓ &lt;4 ^ 4 “ id έ ¥ ^ ® ^ ί CS &quot;ό 2* &lt;7 π· ά ^ &quot;t S ^ s S ^ S £ $ ui i ice 1 g 硪ϊί Ύ ¥ 荽ca ^ i 5 έ ¥ ^ SS ^ ί 133⁄4^3⁄43⁄4 4-{[{6 -(4-fluoro-1,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl- 1-oxoyl-5-yloxy-2,3-dihydro-5H-[1,3]thiazolo[3,2-appyridin-3-yl}(phenyl)indenyl]amine } Butyronitrile factory i οό s 〇00 152524.doc - 532 - 201130854

h-NMR (methanol-d4, 300 MHz): 1.19 (m,3H); 1.78 (m, 2H); 1.88 (m, 3H); 2.37 (m, 2H); 2.59 (m, 2H); (m, 1H); 6.07 (d, 2H); 6.58-7.59 (m, 10H). UPLC-MS (ESI+): [M+H]+=717. UPLC-MS (ESI+): [M+H]+=719. ^-NMR (methanol-d4, 300 MHz): 1.18 (tr, 3H); 1.75 (m, 2H); 1.85 (s, 3H); 2.35 (tr, 2H); 2.56 (tr, 2H); 4.01-4.48 (m, 5H); 5.67 (m, 1H); 7.03-7.59 (m, 12H). UPLC-MS (pong SI+): [M+H]+=739. Ί ^ ί ^ u , 昃SH 3 7 weapon ί ? i ^ 2 1 ^ — « _ S j When S “ A ® : f S ssffs 4 i “鏺S 4 'Ί iSif &lt;7 S ^ f \0涑T ' η π — rA °? A 3 淫 ®®_ -r S i J 5 ^ “ iA ® 7 δ» tO s iS ^ ^ ^ i ^ x i4 ιΑ H ^ ^ 3碥 two H 5; &amp;- ff irf An ¢^1 iinr "Lu &amp; II · 'machine ^ ul ^ v X ί t swallow P 〇〇pJL, $13⁄4 ^ An 4 ®~ leather office% / vc^. Ice yo I* 〇6 (N 00 cn 〇〇 152524.doc - 533 - 201130854 ^-NMR (sterol-d4, 300 MHz)·· U9 (m,3H); 1.77 (m,2H); 1.85 ( m, 3H); 2.37 (m, 2H); 2.57 (m, 2H); 4.31 (d, 4H); 5.67 (m, 1H); 6.59 (m, 1H); 6.73 (m, 1H); 7.03-7.60 (m,8H). UPLC-MS (ESI+): [M+H]+= 731 °^H-NMR (decanol-d4, 300 MHz): 1.25 (tr, 3H); 1.87 (s, 3H); 2.81 (m, 2H); 3.60 (m, 2H); 4.15-4.54 (m, 6H); 5.74 (m, 1H); 6.85 (tr, 1H); 6.94-7.62 (m, 12H). UPLC-MS ( ESI+): [M+H]+=737 ° h-NMR (sterol-d4, 300 MHz): 1.83 (s,3H); 3.89 (d,3H); 4.12 (m, 1H); 4.61 (d, 0.5H*); 4.68 (d, 0.5H*); 5.57 (m, 1H); 6.75 (m, 1H); 7.03-7.56 (m, 1 OH). UPLC-MS (ESI+): [M+H] +=589 〇cs £, H ώ 3 ^ ^ | Ί ^ ^ 7 tO懋相荽 ig ^ 灭龄$屮2 K ^ ^ ^ v ^ 3 to 4 Shouting 硇M wearing 1111S 3 S f 5 « Σ2 '砩1j f — i φ ^ ^ | s 5 « ,杗s ¥ ^ ^ 7 JS 2 s ^ ★+今械二, rn cn * \\ %$ / Vb% Winter°ώ〇. ^Λ〇^ όοό Όό v〇00 152524.doc -534 - 201130854

^-NMR (sterol-d4, 300 MHz): 1.83 (s,3H); 3.87 (d,3H); 4.62 (d, 0.5H*); 4.74 (d, 0.5H*); 5.61 (m,1H) ); 6.61-7.60 (m, 9H). UPLC-MS (ESI+): [M+H]+=625. h-NMR (methanol-d4, 300 MHz): 1.81 (s, 3H); 3.87 (d, 3H); 4.16 (d, 0.5H*); 4.22 (d, 0.5H*); 5.67 (m, 1H) ; 6.58-6.72 (m, 1H); 6.92- 7.61 (m, 9H). UPLC-MS (ESI+): [M+H]+=607. iH-NMR (methanol-d4, 300 MHz), mixture, slightly impure: 1.80-2.09 (m, 6H); 2.72-2.82 (m, 2H); 3.55-3.63 (m, 1H); 3.64-3.71 (m, 2H); 3.99-4.10 (m, 2H); 4.10-4.24 (m, 1H); 4.26-4.44 (m, 1H); 4.47-4.58 (m, 1H); 5.67-5.77 (m, 1H); 7.05- 7.13 (m, 1H); 7.23-7.65 (m, 10H) 〇 UPLC-MS (ESI+): [M+H]+=739 ·&gt; J ϊ ΓΙ i 湓4 more vf , Λ B- ^ ^ cn] (Λ ^ \ ι f forced ' rA Υ ^ d ^ ^ ^ 5 4 ' 硪 ^ &lt;N \A (N ^ ^ ^ ώ 砩 纤 纤 与 5 5 5 5 5 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘 咿哼蚪埘^ ^ ^ S Μ 1 ^ ^ ® 灭 a哼毛呤彡Μ ^ -r ^ ^ ^ 士-砩,|繁繁 (N ®~ cA 〇^ 丫4 ®7 s味娜 v〇.〇^ IL · ^γ^Ι.11•如r 〇 00 00 00 Os 00 s 152524.doc - 535 - 201130854 ^NMR (sterol-d4, 300 MHz): 1.84 (s, 3H); 1.91 (t , 3H); 2.75-2.82 (m, 2H); 3.53-3.63 (m, 1H); 3.68 (s, 3H); 4.04 (s, 2H); 4.14-4.52 (m, 4H); 5.69-5.75 (m , 1H); 7.07-7.14 (m, 2H); 7.20-7.60 (m, 10H). UPLC-MS (ESI+): [M+H]+=72 h-NMR (sterol-d4, 300 MHz) : 1.85 (s,3H); 4.61 (d,1H); 5.58 (m, 1H); 6.84 (t,1H); 6.95 -7.58 (m,11H). UPLC-MS (ESI+): [M+H]+=607 ° 军军刳旷骒硇A q蚪Helmet T\ ^ ^ X ^ i 4 ί 3 5 ^ V ^ 3 ι | Ϊ ^ ^ oo &quot; ί rrT S dj ^ ^ 3-[Amino (phenyl)methyl]-6-[3-(difluoromethoxy)phenyl]-8-[2-H-6 -(Trifluoromethyl)phenylhydrazino]-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]&quot; than bite-5-one 1- Oxide r 0 0 8.20 8.21 152524.doc •536· 201130854

乐铋馁^恤^搿锴, w^^-®lfcnr8^(Nr8¥(Ki^:0,&lt;,;:;;··-;; ' ·&gt;'·' -;s : .v . . . ...K -....7 «•ίΧΛίί'Κ'ί'.ϋϋ'.'....;.:. . .:·· &gt;···&gt;, ... ... &gt;·.:··;·.&lt;; -- · ·· •.'''-S*. , , . - * ;' ·. ' . ..·' .. . &gt;,*'·»; t · ..1' Analytical data ^-NMR (methanol-d4, 400 MHz): 1.70-1.81 (m, 2H), 1.84 (d, 3H); 2.26-2.36 (m, 2H) , 2.57-2.67 (m, 2H); 3.83 (d, 3H); 4.12 (t, 1H); 4.26-4.40 (m, 2H); 4.47 (t, 1H); 4.58 (br. s, 2H); 5.67 -5.73 (m, 1H); 6.72-6.86 (m, 2H); 7.07-7.58 (m, 9H). UPLC-MS (ESI+): [M+H]+=675. h-NMR (methanol-d4, 300 MHz): 1.79 (m, 2H); 1.84 (m, 3H); 2.36 (m, 2H); 2.64 (m, 2H); 3.89 (m, 3H); 4.05-4.53 (m, 4H); 5.71 ( m, 1H); 6.84-6.74 (m, 1H); 7.05-7.59 (m, 10H) UPLC-MS (ESI+): [M+H]+=675. Name 4-{[{6-(2- Fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxoyl-5-sideoxy-2, 3-dihydro-5沁[1,3]thiazolo[3,2-a]acridin-3-yl}(phenyl)methyl]amino}butyric acid 4-{[{ 6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)phenylindenyl]-7-methyl-1-oxo-yl-5-side Oxy-2,3-dihydro-5沁[1,3]thiazolo[3,2-exopyridin-3-yl}(phenyl)indenyl]amino}butyrate.; '.-二·:·;; . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NMR (sterol-d4, 300 MHz): 1.74 (m, 2H); 1.82 (m, 3H); 2.34 (m5 2H); 2.55 (m, 2H); 3.87 (d, 3H); 4.14-4.55 (m) , 4H); 5.70 (m, 1H); 6.61-6.78 (m, 3H); 6.82-6.90 (m, 1H); 7.07-7.17 (m, 2H); 7.26-7.36 (m, 1H); 7.42-7.51 (m, 1H); 7.53-7.60 (m, 1H). UPLC-MS (ESI+): [M+H]+=711. lH-NMR (methanol-d4, 300 MHz): 1.74 (m, 2H); 1.81 (m, 3H); 2.33 (m, 2H); 2.59 (m, 2H); 3.86 (d, 3H); 4.16-4.54 (m, 4H); 5.77 (m, 1H); 6.58-6.69 (m, 1H); 6.93-7.61 (m, 9H). UPLC-MS (ESI+): [M+H]+=693. iH-NMR (methanol-d4, 300 ΜΗζ): 1.76 (m, 2H); 1.85 (s, 3H); 2·34 (tr, 2H); 2.63 (m, 2H); 4.10-4.50 (m, 4H) ; 5.70 (m, 1H); 6.84 (tr, 1H); 6.95-7.59 (m, 12H). UPLC-MS (ESI+): [M+H]+=693. ^ »1 ^ ^ Art "硪, i丨Φ卜 S ώ $ 9 J 薙笆文死4 w错丁i ^ f 3 &quot;it 念事几 v S 5 Art 4, 丨智τ έ ί ό 1 5 S ^ 5 S t4 ®- S ^ ^ «ϊΐ 5 1 ®; 115 机械 p ^ 4 S « ^ S 4 4 1 Ϊ 宁竽十ά旮寸00 Bu Ik 2 $ οο 〇〇152524.doc _ 538 · 201130854

ί ^-NMR (sterol-d4, 300 MHz): 1.77 (m, 2H); 1·87 (s, 3H); 2.35 (m, 2H); 2.63 (m, 2H); 4.05-4.61 (m, 4H); 5.70 (m, 1H); 6.06 (d, 2H); 6.58-7.57 (m, 10H). UPLC-MS (ESI+): [M+H]+=689. h-NMR (sterol-d4, 300 MHz): 1.88 (m,3H); 4.66 (d, 0.5H*); 4.73 (d, 0.5H*); 5.88 (m,1H); 6.07 (d,2H) ); 7.07-7.63 (m, 1 OH). UPLC-MS (ESI+): [M+H]+=705. ^-NMR (methanol-d4, 300 MHz): 1.78 (m, 2H); 1.87 (s, 3H); 2.35 (tr, 2H); 2.69 (m, 2H); 4.11-4.47 (m, 4H); (m, 1H); 7.10-7.60 (m, 12H) ° UPLC-MS ^SI+): [M+H]+=71 足足'砩,•丨穿穿! z $ Φ ί ρ 1 ? a 5 ^ ^ Miscellaneous m ^ i 5 S f 1 5 in 'Ί ^ · &lt;7 S 2 1 ΐ 3 ^ ^ Λ 1 ^ ί(4) $ P Main i«漀5 reading crocodile氐砩B-屮灭二办1S S s $ ί v ^ ¢^1 ^ ¥ ί Φ ^ 5 1 ϊ i 5 Λ | 2 〇6 OO s 152524.doc -539- 201130854

iH-NMR (methanol-d4, 300 MHz): 1.71 (m, 2H); 1.78 (m, 3H); 2.29 (m, 2H); 2.58 (m, 2H); 4.23 (d, 4H); 4.27-4.43 (m, 2H); 5.63 (m, 1H); 6.67 (m, 1H); 6.99-7.51 (m, 8H). </ RTI> <RTIgt; ; 4.14-4.48 (m, 3H); 5.92 (m, 1H); 6.85 (tr, 1H); 7.01- 7.60 (m, 12H). UPLC-MS (ESI+): [M+H]+=709. h-NMR (sterol-d4, 300 MHz), slightly impure: 1.83-1.87 (m, 3H); 1.92-2.07 (m, 3H); 2.92-3.25 (m, 3H); 3.37-3.46 (m, 1H) ); 3.58-3.77 (m, 3H); 3.89-4.05 (m, 3H); 4.32-4.43 (m, 1H); 4.48-4.72 (m, 1H); 5.86-5.91 (m, 1H); 7.18-7.66 (m, 1 OH). UPLC-MS (ESI+): [M+H]+=725. ^ | ^ I ώ s 1111 ?—丨, ii CO ^ | ^ 4 ^ ti S ^ s S ^ s s 't °? a, ^ ώ ^ 3 J “味1 5 ϊ bow S s bat A k extraction哼S二M, alkali attack two „“ 4,.l驽殳鋈£堂ί 5 words 1 f 5 3 η 5 / y 〇t 〇om oo m oo Ά OO 152524.doc 540- 201130854

h-NMR (methanol-d4, 300 MHz), slightly impure: 1.85-2.06 (m, 6H); 2.72-2.83 (m, 1H); 2.96-3.09 (m, 2H); 3.18-3.26 (m, 1H) ; 3.60-3.80 (m, 3H); 3.91-4.17 (m, 3H); 4.43-4.60 (m, 2H); 5.20-5.27 (m, 1H); 6.06-6.14 (m, 1H); 7.21-7.67 ( m, 10H). UPLC-MS (ESI+): [M+H]+=725. ^-NMR (sterol-d4, 300 MHz): 1.84 (s,3H); 1.92 (t,3H); 2.86-3.10 (m,2H); 3.55-3.72 (m,2H); 3.92 (s,2H AB signal (δΑ=4·15, δΒ=4.39, 2xlH); 4.50-4.59 (m, 2H); 5.78-5.88 (m, 1H); 7.14-7.24 (m, 2H); 7.25-7.60 (m , 1 OH). UPLC-MS (ESI+): [M+H]+=707. ...4 ^ ^ two $ + 械 g 湓41 temple, 昱11 ^ ^ ^ ^ ca CN ®- cn ^ ^ ^ Φ ? i 2;^ 5 兰三证普 S1 V i-4 ®7 ^ ^ ^ ^ ^ ¢- 灭 t军 but tt〇砩*rtO 1 ί S 罟5 g ? S § ? ά @4珠r ό . γ v^.例 9.1 Preparation of 6-(2-fluoro-3-methoxyphenyl)-8-(2-fluoro-3-6-trifluoromethyl)methyl 3-(sayyl-phenyl·methyl)_7·methyl·2,3_dihydrosultaneous β sits and [3,2a]ij ratio bites_ 5-ketone

Sodium borohydride (51 mg, 1.338 mmol) was added to 3-phenylhydrazin-6-(2-fluoro-3-methoxy-phenyl)_8_(2_fluoro_6_3) at 〇C Fluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2_a]β is more than ketone-5-one (Example 2.27) (153 mg '0.268 mmol) in methanol ( 5 mL) in a stirred solution. After 1 hour, the pH was adjusted to 6 (1 N aqueous hydrochloric acid). The solution was extracted with EtOAc. The target compound was isolated by flash column chromatography (yield: 80 mg). ^-NMR (Me3〇D, 300 MHz): 1.94 (m, 3H); 3.90 (m, 3H); 5.28-5.44 (m, 2H); 6.74 (m, 0.5H*); 6.85 (m, 0.5H) *); 7.04-7.53 (m, 11H). UPLC-MS (ESI+): [M+H]+=574. Bioassay 1. Materials Buselelin for IP-One HTRF® assay was purchased from 152524.doc -542- 201130854

Welding (Frankfurt/Main, Germany) or USbiological (#B8995, Swampscott, USA) and LHRH was purchased from Sigma-Aldrich® (Munich, Germany). Labeled cells for Tag-lite® binding assay, Tag-Lite buffer, labeled and unlabeled GnRHR binding peptides were purchased from Cisbio Bioassays (Bagnols-sur-Ceze Cedex, France). [1251] Sodium Desulfurization (2000 Ci/mmol; PerkinElmer Life and Analytical Sciences, USA) was carried out by the Iodogen method at the Department of Isotope Chemistry of Bayer Schering Pharma AG (Berlin, Germany). Radiolabeling yields [1251] monoiodo-buserelin. The radiotracer was passed through a reverse phase HPLC on a Spherisorb ODS II column (25 〇 x 4 mm, particle size 3 μιη) with acetonitrile/water (34:66) containing 39 mM trifluoroacetic acid at 1 mL/min. Flow rate dissolution purification. [1251] The residence time of monoiodo-buserelin is about 17 minutes. All other chemicals are obtained from commercial sources at the highest available purity level. 2. Method 2.1 - Receptor binding assay using radiolabeled buserelin Binding studies for competition curves were performed in 96-well polypropylene microtiter plates (Nunc, New Jersey, USA), where sample 1 Three copies. One assay sample contains 70 μM of 300 μ000 CHO cells stably transfected with human GnRH receptor, 20 μΐ 1251 labeled buserelin (for competition curves, 100,000 cpm per sample) and 10 μΐ assay buffer or Test the compound solution. Test compounds were dissolved in DMSO. Cetrorelix is dissolved in 〇.1 Μ hydrochloric acid. Use assay buffer (DMEM or

S 152524.doc •543· 201130854 DMEM/Ham's F12 medium » 10 mM Hepes buffer (pH 7_5) '0.5% BSA) Preparation of serial dilutions (5xl (T6 M to 5χ10·12 M) Non-specific binding was determined in the presence of excess unlabeled buserelin (10·5 μ). Test samples were incubated for 60 minutes at room temperature. Binding and free ligands were applied by Unifilter GF by applying negative pressure. /C filter microtiter plates (PerkinElmer, CT, USA) were filtered and washed twice with 200 mL of 0_02 Μ Tris/hydrochloric acid (pH 7.4). The filter plates were incubated with 0.3% polyethylenimine (gerva; Heidelberg, Germany) soak for 30 minutes to reduce non-specific binding. The radioactivity retained by the filter was determined in a TopCount NXT HTS (PerkinElmer, CT, USA) using a 20 μl/well MicroScint40 scintillator cocktail (PerkinElmer, CT, USA). Activity. The competition curve was obtained by plotting the measured radioactivity relative to the concentration of each test compound using internal software. 2.2. TAG-LITE® Receptor Binding Assay This binding assay is based on fluorescent donor-labeled human GnRHR. And Fluorescence resonance energy transfer between color-labeled GnRHR-binding peptides. Compounds that interfere with the ligand-binding side of human GnRHR will displace the labeled peptide, thereby reducing the signal. The principle of verification is from €^1)丨〇6丨0 Wang 38 &amp; 丫 8 (83 吕11〇18-8111·-C0ze Cedex, France) is established and can be found on its homepage for more details. The assay procedure is further optimized for internal use at a reduced assay volume. Frozen Hek293 cells transiently transfected with human GnRHR and the receptor for this receptor, as well as Tag-Lite buffer and green-labeled GnRHR binding peptide, were supplied by Cisbio Bioassays. The cells were unloaded and transferred to cold Tag-Lite buffer. Add 8 μΐ volume of this cell suspension to pre-divided 152524.doc -544- 201130854 in a white low-volume 384-well microtiter plate (Greiner Bio-〇ne,

The compound was tested in a 100 nl 160-fold concentrated solution in DMSO in one well of Frickenhausen, Germany. The mixture was incubated for 5 minutes at room temperature. In the next step, 4 μM Tag-Lite buffer or 4 μΐ of the excess unlabeled binding peptide in the Tag-Lite buffer as a control was transferred to the mixture. The green labeled GnRHR binding peptide was added to the 4 μΐ volume of Tag-Lite buffer as EC50 in the final step. After incubation for 1 hour at room temperature for φ, the plates were measured in a microplate reader, such as PHERAstar (BMG Labtechnologies, Offenburg, Germany) using a specific optical module. Calculate the ratio of fluorescence emission from 520 nm (green fluorescence) to 490 nm (background signal of 铽-labeled GnRHR) and correct the data (reaction of no test compound = 〇% inhibition by binding of green-labeled peptide; Reaction without test compound but with excess unlabeled binding peptide = 100% inhibition of binding by green labeled peptide). 10 different concentrations in the range of 12.5 μΜ to 0.64 nM on the same microtiter plate (12.5 μΜ, 4.2 μΜ, 1.4 μΜ, 0.46 • μΜ ' 0.15 μΜ, 51 ηΜ, 17 ηΜ, 5.7 ηΜ, 1.9 ηΜ and 0.64 Μ Μ The compound was tested prior to assay by a dilution series prepared by serial dilution of 100% DMS0 with 1:3 on a 160-fold concentrated stock solution, with each concentration value in duplicate. The IC5G value was calculated using a 4-parameter fit by using internal software. 2.3. IP-ONE HTRF® Verification The generation of a component of the GnRH-R signaling cascade can be measured by using uniform time-lapse fluorescence resonance energy transfer (HTRF). CH0 152524.doc -545 - 201130854 cells stably stimulated by the EC80 ΘηΡίΉ agonist buserelin (established by Professor Thomas Gudermann currently at the University of Marburg, Germany; After being supplied as an aliquot of frozen cells by the Cell Culture Services (Hamburg, Germany), the Gq protein-coupled receptor signaling cascade is activated, resulting in PLC-dependent cleavage of PIP2. Inositol-1,4,5-triphosphate (1?3) and dimercaptoglycerol. The second messenger degrades into myo-inositol in 1?3 cells. The step of inhibiting the final degradation of inositol-1-phosphate (IP1) to inositol by the addition of a gasification chain can result in the accumulation of IP1 in the cells. In cell lysates, IP1 can be detected via antibody-based HTRF detection technology, in which IP1 replaces FRET recipient IP1-d2 with a trans-labeled anti-IP1 antibody as a donor, thereby reducing the signal. The ability of the compound to inhibit buserelin activation of GnRH-R was tested. For all IP-One HTRF® assays, reagents from Cisbio Bioassays (IP-One Tb Jumbo kit, #62IPAPEJ; Cisbio Bioassays,. Bagnols sur Ceze Cedex, France) were used. For the assay, frozen cell aliquots were thawed and a cell suspension containing ip b d2 (dilution 1:40) (3.33 x 106 cells per ml) was prepared and incubated at 37 °C. After 1 hour, 3 μM cell suspension was added to a well pre-dispensed in a white low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) to test the compound in 50 nl 100-fold concentrated solution in DMSO. in. The mixture was incubated at 22 °C for 20 minutes to pre-conjugate the test compound to GnRH-R. Stimulation buffer (1 mM Hepes 'pH 7.4, 1 mM CaCl2, 0.5 mM MgCl2, 4.2 mM KC 146 152524.doc) by adding 2 μΐ containing buserelin or LHRH (under EC5〇 or EC8〇) -546- 201130854 mM NaCl, 5.5 mM ct-D-glucose, 0.05% BSA, 125 mM LiCl (final assay concentration 50 mM) in distilled water) to stimulate the receptor signaling cascade. The plates were incubated for 1 hour at 37 ° C and 5% CO 2 and then made by adding 3 μΐ of the conjugated anti-ΙΡ1 antibody (1:40) diluted with the conjugate and the lysis buffer supplied with the kit. The cells are dissolved. Incubate at 22 ° C for 1 hour to allow complete cell lysis and antibody binding to free IP 1 or IP1 -d2, then to HTRF readers such as RUBYstar, PHERAstar (both from BMG Labtechnologies, Offenburg, Germany) Or measuring each plate in Viewlux (PerkinElmer LAS, Rodgau-Jiigesheim, Germany). Calculate the ratio according to glory emission at 665 nm (FRET) and 62 〇 nm (background signal of 铽-antibody) (665 nm) Emissions were divided by emission at 620 nm) and data were corrected (no test compound reaction = 0% inhibition; all other assay components except agonist = 100% inhibition). 10 different concentrations (20 μΜ, 6.7 μΜ '2.2 μΜ, 0.74 μΜ ' 0.25 μΜ ' 82 ηΜ, 27 ηΜ, 9.2 ηΜ, 3.1 ηΜ and 1 ηΜ in the range of 20 μΜ to 1 nM on the same microtiter plate Compounds were tested prior to assay by dilution series prepared by serial dilution of 1:3 with 100% DMS0 on a 1 liter stock solution level, with each concentration value in duplicate. The IC50 value was calculated using a 4-parameter fit by using internal software. 2.4. In vivo resection of ovarian cynomolgus monkeys (CYNOMOLGUS MONKEY)

The study of castrated animals provides a sensitive in vivo assay for the action of GnRH antagonists (1993, 25, 141-147). GnRH in the pituitary gland 152524.doc -547- 201130854 Receptor-mediated GnRH stimulates LH release into the circulation. Due to the decrease in negative feedback from gonadal steroids, castration increases circulating LH levels, resulting in enhanced LH release from GnRH stimulation. Therefore, measurement of inhibition of circulating LH content in castrated cynomolgus monkeys can be used as a sensitive in vivo measure of GnRH antagonism. Female macaques were castrated using surgery and allowed to recover for 4 weeks, at which time an elevated LH content was established. The test compound is then administered to the animal in an oral, subcutaneous, intraperitoneal or intravenous dosage form and a continuous blood sample is collected for measurement of LH. Ovariectomized cynomolgus macaques (body weight 3.5-6 kg) are treated intraperitoneally and/or orally with a single dose of a suitable vehicle, such as a physiological saline solution. The dose administered is 10 and / or 30 and / or 100 mg / kg. After the administration of 0; 0.5 hour; 1 hour; 2 hours; 4 hours; 7 hours; blood samples were taken 24 hours. Serum LH levels were monitored by RIA. The biologic reagent was provided by Dr. A.F. Parlow (Parlow@humc.edu) of the National Hormone &amp; Pituitary Program, HUMC, CA., U.S.A. The cynomolgus macaque LH was radioactively filled using the Chloramine-T method as described in the RIA immunoreactant manual. Results The data revealed that the compounds of the invention have antagonist activity at the human GnRH receptor. Within the meaning of the present invention, antagonist activity is reflected by the ability of the compounds of the invention in the IP-One HTRF® assay to antagonize human GnRH receptor stimulation by at least 3 standard deviations from background levels. 152524.doc - 548 - 201130854 Table 35: Efficacy of radiolabeled buserelin in receptor binding assays; potency is given by Ι(:50[μΜ] V ·. - ...丨μΜΓ / 1.2 &gt;10 3.18 2.1 4.8 7.1 5.64 0.081 5.78 0.24 5.136 2.5 6.14a 0.53 6.16b 0.20 7.10 1.5 7.28 0.04

Table 41: The efficacy obtained using the TAG-LITE technique in the receptor binding assay; the potency is given by IC50 [μΜ] 3 摩., ' ? Example '-', h Η:· ; ;νΐ f ^Μ{μΜ\ ^ 8.27 0.010 7.79 0.011 7.74 0.023 7.93 0.026 7.94 0.035 7.9 0.053 7.97 0.063 7.95 0.10 7.81 0.10 7.88 0.12 7.1 0.12

S 152524.doc -549- 201130854 Table 36: Efficacy obtained by using buserelin (under EC80) in the IP-One HTRF® assay; efficacy is given as IC50 [μΜ] Example 丨μΜ] 1.2 15.1 2.7 7.40 2.11 14.3 2.12 &gt;20.0 2.26 &gt;20.0 2.34 &gt;20.0 2.36 4.41 3.1 4.85 3.6 14.2 3.18 1.71 4.1 &gt;20.0 5.10 &gt;20.0 5.13 &gt;20.0 5.14 &gt;20.0 5.15 &gt;20.0 5.16 &gt;20.0 5.23 15.3 5.30 4.00 5.35 &gt;20.0 5.39 &gt;20.0 5.44 12.3 5.47 7.50 5.48 6.98 5.56 3.60 5.59 2.88 5.64 0.43 5.65 &gt;20.0 5.70 2.69 152524.doc -550* 201130854

. : 6 .:.Example ' ; Gentry 'Efficiency [μ]^;工,^ 5.71 1.87 5.72 0.83 5.74 2.95 5.77 0.22 5.78 0.86 5.82 1.36 5.86 17.0 5.89 7.54 5.9 &gt;20.0 5.94 16.5 5.96 8.57 5.105 2.80 5.109 4.74 5.110 7.84 5.111 7.34 5.114 9.77 5.115 14.5 5.122 3.76 5.142 14.0 5.145 &gt;20.0 5.148 15.4 5.152 8.51 5.156 7.94 5.159 12.9 5.165 4.59 5.168 &gt;20.0 5.169 14.5 5.170 11.0 5.175 &gt;20.0 5.178 5.54 5.180 6.76 152524.doc -551 - 201130854 Example performance 182μΜ] 5.182 2.21 5.190 8.86 5.206 8.77 5.212 1.91 5.213 0.27 5.214 1.58 5.215 0.33 5.220 1.40 5.225 0.88 5.228 1.38 5.229 9.45 5.230 11.6 5.237 18.0 5.238 6.54 5.243 7.02 5.252 13.8 5.259 &gt;20.0 5.260 6.34 5.270 9.53 6.12b 0.36 6.13a 1.69 6.13 b 0.42 6.14a 0.53 6.14b 0.27 6.15 0.039 6.16a 1.56 6.16b 0.35 6.18a 0.34 6.18b 0.11 6.19 0.72 6.1a 0.43 152524.doc -552· 201130854

• _ . ., _ ::: U ' -. .Examples.- ·· - · · Spider energy [μΜ] 6.1b 0.08 6.20a 0.31 6.20b 0.16 6.21b 0.29 6.22a 0.14 6.22b 0.58 6.23 0.25 6.24 0.003 6.27 2.54 6.2b 1.00 6.30 4.27 6.33 0.58 6.34 0.45 6.35 0.83 6.36 a 0.17 6.36b 0.022 6.37 0.18 6.38b 0.13 6.39 0.42 6.40 0.11 6.41 0.58 6.42b 0.14 6.43 0.51 6.44 0.28 6.45 0.99 6.46 0.26 6.47a 0.32 6.47b 0.12 6.48a 0.19 6.48b 0.021 6.49 0.13 s 152524.doc -553 - 201130854 Example Efficacy 丨μΜ] 6.4a 18.8 6.5 0.070 6.50 0.96 6.6a 0.15 6.6b 0.027 6.7a 0.95 6.7b 0.21 6.8a 18.7 6.9 0.043 7.10 0.68 7.11 0.056 7.12 0.19 7.13 0.050 7.14 0.095 7.15 0.019 7.16 0.021 7.17 0.59 7.18 1.94 7.1b 0.40 7.2 0.74 7.20 0.13 7.23 0.54 7.28 0.037 7.3 0.11 7.30 0.43 7.4 0.99 7.6 1.33 7.8b 0.031 7.9 0,79 8.1 1.88 9.1 0.25 152524.doc -554- 201130854 The table is used in (4) such as the town chest test using buserelin (in %. B) The efficacy of stimulation; the efficacy is given in IC50 [μΜ]. The new values given in this table may differ from the values given in Table 36 due to the fact that the measurements are repeated and provide an average. The value in the parentheses in parentheses refers to the efficacy of the single enantiomer, which in turn gives enantiomers 1 and 2 (ie, 6.6a: racemic mixture = 0.16, enantiomeric Construct 1 = 0.18, enantiomer = construct 2 = 1.67). The value marked with an asterisk refers to the potency of the enantiomer obtained from the most active enantiomer of the parent amine (see Example 6). Example; p----- 'Enable.[ΙιΜϊ: ΐ'ν * ..夂1. 1.1 &gt;20 1.2 16.3 — 1.9 &gt;20 1.16 ι&gt;20 1.17 &quot;--- &gt;20 1.18 - ------- &gt;20 1.19 &gt;20 2.1 3.7 2.10 &gt;20 2.11 14.25 2.12 &gt;20 2.13 &gt;20 2.14 &gt;20 2.15 19.11 2.16 &gt;20 2.17 -- &gt;20 2.23 2.38 2.24 1.39 2.25 &gt;20 ------------ 152524.doc Example: ! : 'Year: ίμΜ].:: ί. 十...h 2.26 &gt;20 2.3 &gt;20 2 33 17.06 JT: ----- 2.34 &gt;20 2.35 2.34 2 36 4.41 ------- 2.39 3.15 2.40 0.26 2.41 6.95 2.42 13.57 2.43 13.3 2 44 2.49 m a 2.45 5.75 2.46 13.33 2.47 2.58 2.5 4.31 2.53 3.53 2.54 &gt;20 2.55 3.48 - 555 - 201130854 Example performance [μΜ] Example performance [μΜ] 2.56 3.45 3.53 9.03 2.57 &gt;20 3.6 14.19 2.58 9.52 3.7 1.54 2.6 &gt;20 3.8 6.15 2.7 7.4 4.1 &gt;20 2.8 &gt;20 4.2 &gt;20 2.9 &gt;20 4.3 &gt;20 3.1 4.84 4.4 &gt;20 3.10 1.38 4.5 18.72 3.17 7.36 4.6 13.39 3.18 1.71 4.7 11.33 3.19 1.95 4.8 5.81 3.20 1.46 5.1 &gt;20 3.21 3.03 5.10 &g t;20 3.22 2.7 5.100 &gt;20 3.30 0.5 5.101 6.1 3.31 0.93 5.102 8.59 3.32 0.95 5.103 2.66 3.33 0.82 5.104 6.73 3.34 0.58 5.105 2.8 3.35 0.62 5.107 &gt;20 3.36 0.61 5.108 4.33 3.37 0.71 5.109 4.74 3.38 3.63 5.11 &gt;20 3.39 2.14 5.110 7.85 3.44 10.72 5.111 7.34 3.46 1.91 5.112 &gt;20 3.47 5.53 5.113 15.73 3.48 2.16 5.114 9.77 3.49 &gt;20 5.115 14.52 3.5 2.93 5.116 10.01 3.51 1.18 5.118 &gt;20 3.52 &gt;20 5.119 &gt;20 152524.doc -556 - 201130854

Greedy/efficiency [μΜ] ' ' 5.12 &gt;20 5.120 4.7 5.121 &gt;20 5.122 3.76 5.123 6.42 5.124 10.29 5.125 7.31 5.126 1.06 5.127 &gt;20 5.128 &gt;20 5.129 14.15 5.13 &gt;20 5.130 6.88 5.131 10.14 5.132 15.24 5.133 &gt;20 5.134 7 5.135 8.51 5.136 4.05 5.137 6.18 5.138 7.7 5.139 1.83 5.14 &gt;20 5.140 7.73 5.141 6.54 5.142 14.04 5.143 8.57 5.144 18.84 5.145 &gt;20 5.146 3 5.147 13.36 5.148 15.39 5.149 10.57 Example. Performance [μΜ]... 5.15 &gt;20 5.150 4.85 5.151 2.84 5.152 8.51 5.153 &gt;20 5.154 15.05 5.155 3.82 5.156 7.94 5.157 12.05 5.158 12.76 5.159 12.95 5.16 &gt;20 5.160 7.97 5.161 10.33 5.163 4.26 5.164 11.5 5.165 4.59 5.166 15.72 5.167 11.35 5.168 &gt;20 5.169 14.5 5.17 &gt;20 5.170 10.99 5.171 &gt;20 5.172 13.5 5.173 11.1 5.174 10.01 5.175 &gt;20 5.176 8.63 5.177 8.32 5.178 5.54 5.179 9.28 5.18 &gt;20 s 152524.doc -557- 201130854 Example performance [μΜ] Example ~ Efficacy [μΜ] 5.180 6.76 5.210 1.03 5.181 4.44 5.211 1.68 5.182 2.21 5.212 1.91 5.183 &gt;20 5.213 0.27 5.184 12.11 5.214 1.58 5.185 &gt;20 5.215 0.33 5.186 13.38 5.216 2.23 5.187 &gt;20 5.217 3.94 5.188 9.71 5.218 4.8 5.189 15.13 5.219 &gt;20 5.19 &gt;20 5.22 17.52 5.190 8.86 5.220 1.4 5.191 14.48 5.221 6.32 5.192 10.86 5.222 5.2 5.193 5.89 5.223 5.78 5.194 &gt;20 5.224 2.42 5.195 &gt;20 5.225 0.88 5.196 &gt;20 5.226 7.19 5.197 &gt;20 5.227 &gt ;20 5.199 9.77 5.228 1.38 5.2 4.97 5.229 9.45 5.20 &gt;20 5.23 15.34 5.200 13.13 5.230 11.57 5.201 8.68 5.231 7.16 5.202 6.73 5.232 4.21 5.203 4.95 5.233 15.27 5.204 4.65 5.234 15.45 5.205 10.86 5.235 13.39 5.206 8.77 5.236 10.9 5.207 8.05 5.237 18.03 5.208 &gt;20 5.238 6.54 5.209 14.64 5.239 15.53 5.21 18.11 5.24 14.53 152524.doc - 558 - 201130854

; example --- ... - ., - -- -, performance [history k 5.240 8.29 5.241 &gt; 20 5.242 5.17 5.243 7.02 5.244 1.21 5.245 5.15 5.246 &gt;20 5.247 9.8 5.248 8.96 5.249 5.59 5.25 14.18 5.250 12.42 5.251 &gt ;20 5.252 13.79 5.253 4.29 5.254 13.92 5.255 19.89 5.256 1.74 5.257 7.3 5.258 4.47 5.259 &gt;20 5.26 11.93 5.260 6.34 5.261 2.17 5.262 18.04 5.263 16.59 5.264 &gt;20 5.265 13.35 5.266 &gt;20 5.267 5.94 5.268 12.2 5.269 10.14 5.27 11.87 :Instance :: Performance [μΜ] . ' 5.270 9.53 5.271 10.49 5.273 5.28 5.274 1.27 5.28 11.19 5.29 4.39 5.30 4 5.31 16.35 5.32 18.97 5.33 &gt;20 5.34 &gt;20 5.35 &gt;20 5.36 &gt;20 5.37 &gt;20 5.38 &gt;20 5.39 &gt;20 5.40 &gt;20 5.41 19.35 5.42 13.16 5.43 13.15 5.44 12.29 5.45 11.27 5.46 10.38 5.47 7.5 5.48 6.98 5.49 6.04 5.50 5.3 5.51 5.27 5.52 2.78 5.53 4.1 5.54 4.09 5.55 3.64 5.56 3.6 s 152524.doc -559- 201130854 Example performance [μΜ] 5.57 3.41 5.58 3.07 5.59 2.88 5.6 &gt;20 5.60 2.67 5.61 1.73 5.62 1.52 5 .63 1.16 5.64 0.43 5.65 &gt;20 5.66 3.89 5.67 3.71 5.68 3.51 5.69 3.21 5.7 &gt;20 5.70 2.69 5.71 1.87 5.72 0.85 5.73 4.59 5.74 2.94 5.75 4.92 5.76 1.05 5.77 0.22 5.78 0.86 5.79 1.31 5.8 &gt;20 5.80 3.57 5.81 3.47 5.82 1.36 5.83 10.05 5.84 4.09 5.85 10.48 5.86 16.96 Example performance [μΜ] 5.87 14.28 5.88 16.17 5.89 7.54 5.9 &gt;20 5.90 6.59 5.91 &gt;20 5.92 &gt;20 5.93 14.22 5.94 16.53 5.95 &gt;20 5.96 8.57 5.97 12.69 5.98 19.88 5.99 5.71 6.10 1.05 6.11a 17.99 6.11b 12.47 6.12a 5.61 6.12b 0.36 6.13a 2.26 6.13b 0.42 6.14a 0.53 6.14b 0.27 6.15 0.04 (0.01,0.25) 6.16a 1.56 6.16b 0.35 6.17 1.81 6.18a 0.34 6.18b 0.12 6.19 0.72 6.1 a 0.43 6.1b 0.08 6.20a 0.31 152524.doc -560- 201130854

Example .fr performance [μΜ] ΐ !; v: 6.20b 0.21 6.21a 1.15 6.21b 0.29 6.22a 0.14 6.22b 0.58 6.23 0.25 6.24 0.00379 6.25a &gt;20 6.25b 7.67 6.27 2.54 6.28 2.19 6.29 2.06 6.2a 1.4 6.2b 1.01 6.30 4.27 6.31 11.11 6.32 1.52 6.33 0.58 6.34 0.45 6.35 0.82 6.36a 0.17 6.36b 0.02 6.37 0.18 6.38a 1.07 6.38b 0.12 6.39 0.42 6.3a 2.48 6.3b 3.11 6.40 0.11 6.41 0.58 6.42a 1.77 6.42b 0.14 6.43 0.51 :Example孓Efficacy [μΜ] -ί 6.44 0.28 6.45 0.99 6.46 0.26 6.47a 0.32 6.47b 0.12 6.48a 0.19 6.48b 0.02 6.49 0.13 6.4a 18.83 6.4b 18.75 6.5 0.07 6.50 0.96 6.51b 0.86 6.51a 2.51 6.52a 0.98 (0.59,&gt; 20) 6.52b 0.04 (0.06, 0.56) 6.53 0.7 6.54 0.12 6.55a 14.11 6.55b 1.54 6.56 0.09 (7.69, 0.17) 6.57 0.02 (0.02,0.69) 6.58 0.03 6.59 0.24 6.60 0.05 (0.02,0.55) 6.61 0.03 6.62a 0.6 6.62b 0.02 6.63a 0.23 6.63b 0.08 6.64a 0.11 6.64b 0.02 6.65a 0.8 152524.doc •561 - 201130854 Example performance [μΜ] 6.65b 0.13 6.66a 0.67 6.66b 0.04 6.67a 0.28 6.67b 0.05 6.68a 0 .42 6.68b 0.09 6.69a 0.39 6.69b 0.13 6.6a 0.16 (0.18, 1.67) 6.6b 0.03 (0.08, 0.27) 6.70a 1.52 6.70b 3.65 6.71a 0.52 6.71b 0.1 6.72 5.83 6.73a 0.37 6.73b 0.16 (0.18, 16) 6.74a (&gt;20,13) 6.74b (&gt;20,12.17) 6.75a 0.23 6.75b 0.04 (0.07,0.51) 6.76 0.07 6.77a 1.02 6.77b 0.14 6.78 0.11 6.79 2.51 6.7a 0.95 6.7b 0.21 6.80 1.69 6.81 17.63 6.82 0.17 6.83 0.27 Example performance [μΜ] 6.84a 0.02 6.84b 0.02 6.85a 0.04 6.85b 0.02 6.86a 0.18 6.86b 0.12 6.87 0.14 6.88 0.28 6.89a 0.21 6.89b 0.44 6.8a 18.74 6.8b 10.82 6.9 0.04 6.90a 0.32 6.90b 0.69 7.10 0.68 7.100 0.06 (0.05,0.62) 7.101 (0.59,&gt;20) 7.102 (0.42,&gt;20) 7.103 0.05 7.104 0.1 7.105 (0.07)* 7.106 (0.14)* 7.107 0.54 7.108 0.04 7.109 0.07 7.11 0.04 7.110 0.41 7.111 0.07 7.112 0.03 7.12 0.19 7.13 0.09 7.14 0.1

152524.doc -562- 201130854

:? Example performance [μΜ] f ( 7.15 0.02 7.16 0.03 7.17 0.59 7.18 1.94 7.19 3.57 7.1b 0.4 (0.11,1.86) 7.2 0.74 7.20 0.13 7.21 17.08 7.22 1.26 7.23 0.54 7.24 3.46 7.26 2.1 7.27 1.62 7.28 0.04 7.29 1.09 7.3 0.11 7.30 0.52 7.31 3.69 7.32 0.11 7.33 0.08 7.34 1.48 7.35 0.86 7.38 0.03 7.39 (0_05)* 7.4 0.99 7.41 3.27 7.43 &gt;20 7.44 2.01 7.45 (0.66)* 7.46 0.19 7.47 0.14 7.49 0.26 : Example V Effectiveness [μΜ];:'. '夂,.〆:,':':? 7.5 1.33 7.50 2.65 7.51 3.04 7.52 2.55 7.56 &gt;20 7.57 1.25 (15.4, 1.15) 7.58 (&gt;20,0.39) 7.59 (0.26)* 7.6 1.33 7.60 (0.06) * 7.61 (0.26)* 7.62 (0.16)* 7.63 0.15 7.64 (1.02)* 7.65 0.51 (0.4,1.66) 7.66 0.02 7.67 0.34 7.68 0.07 7.69 0.92 7.7 4.24 7.70 0.27 7.71 2.58 7.72 (1.21)* 7.73 (0.68)* 7.74 0.02 (0.02)* 7.75 1.25 7.76 0.03 7.78 0.19 7.79 0.04 7.80 0.38 7.81 0.05 7.82 (0.07)* 7.83 &gt;20 152524.doc - 563 - 201130854 Example performance [μΜ] 7.84 1.49 7.85 2.64 7.86 4.73 7.87 3.07 7.88 0.05 7.89 0.187.8b 0.03 (0.01,0.44) 7.9 0.79 7.90 0.06 7.91 0.27 7.92 0.03 (7.3,0.04) 7.93 (5.19,0.02) 7.94 0.04 (0.02)* 7.95 (0.02)* 7.96 0.03 (0.03,1.21) 7.97 (0.03,1.3 ) 7.98 0.05 7.99 (0.03,0.5) 8.1 1.88 8.10 (0'0064)* 8.13 2.1 (&gt;20,0.43) 8.14 (0.17,1.49) 8.15 (0.13)* 8.16 (0.00186)* 8.17 0.00353 Example performance [μΜ] 8.18 0.00547 8.2 18.85 8.21 0.02 8.22 0.1 8.23 0.009 (0.005,0.34) 8.24 0.01 8.25 0.02 8.26 0.03 (8.23,0.07) 8.27 (0.01)* 8.28 (0.00678)* 8.29 (11.3,0.09) 8.3 0.04 8.30 (0.02,0.39) 8.31 (5.62,0.01) 8.32a 0.08 8.32b 0.24 8.33 0.09 8.4 4.46 8.6 0.02 8.7 0.06 8.8 (0.37)* 8.9a 0.02 8.9b 0.66 9.1 0.25 152524.doc -564-

Claims (1)

201130854 VII. Patent application scope: 1. A compound having the following structure X (I) Wherein the ruler and the ruler independently of each other represent a hydrogen atom, a Ci_C6 alkyl group or a ruthenium &lt;6 cycloalkyl group or a and a ring together with the atom to which they are attached form a C3-C6 cycloalkyl group; Re represents a dentate atom, an aryl-, a heteroaryl-, a benzo[13] dicyclopentenyl- or a 2,3-dihydro-i,4-indigo-dihydrohexenyl Wherein the group is optionally substituted 1 to 3 times with the substituent Rn selected from the following in the same or non-identical manner: wind halogen, thiol, chaotic, nitro, C!-C6 alkyl, dentate- CVC6 alkyl, C丨-C6 alkoxy, _yl-(: 丨-(:6 alkoxy, CVC6 hydroxy, CVC6 alkoxy-CVC6 alkyl, self-based-Ci-Ce alkoxy-C" C6 yard base, 0 〗 - (!! 6 rod base - C (= 〇) 〇 H, (: 3- (: 10 cycloalkyl, 3 to 10 members heterocycloalkyl, aryl, heteroaryl, aromatic Oxy-, heteroaryloxy-, -C(=〇)〇h, -CpCOCVC^alkyl, -&lt;:(=〇)〇-〇:,· C6 alkyl, _C(=0)0_C3- Cl. cycloalkyl, -N(H)C(=〇)R9, 152524.doc .,. 201130854 -NCCi-Cg alkyl)C(=0)R9, -N(H)S(=0)2R9 , -NCCVCs alkyl)S(=0)2R9, -c(=o)nr9r10, -OC(=0)NR9R10 ' -N (H)C(=0)0R9 '-N(C!-C6 alkyl)C(=0)0R9, -N(H)C(=0)NR9R1(}, -Νγ]-C6 alkyl)C (=0) NR9R1 (&gt;, -SR9, -S(=0)R9, -s(=o)2r9, -S(=0)2NR9R10, -NR9R10; wherein R9 and R1Q independently represent a hydrogen atom, Cl-C6 alkyl- , halo-(VC6 alkyl-'CVQ alkoxyalkyl-, halo-CVC6 alkoxy-CVC6 leuco-, c2-C6 alkenyl-, (VC6 alkynyl-, C3-C1G cycloalkyl) _, 3 to 1 杂环 heterocycloalkyl _, aryl-, heteroaryl-, CVC6 alkylene group _ aryl _, c 丨 _ c6 alkyl-heteroaryl-, -C ^ C6 alkyl a group of -C3_Ci()cycloalkyl-, Ci-C6alkylene-(3 to 10 membered heterocycloalkyl); wherein the c3-c10 ring-based group - and the 3 to 1 member heterocyclic alkyl group are optionally Substituted 1 or 2 times by: dentate atom, cyano group, -〇h, cvc6 炫, from _Ci_C6 alkyl cathoxy, C3-Cl. cycloalkyl, aryl or heteroaryl; or V Atoms attached to the group (4) are bonded together to form a 3 to 10 membered heterocyclic group, and the spectroscopy, month/brother is substituted in the same or different manner by a substituent selected from the group consisting of the following: t β group Sub-dentyl-, thiol-, yl-based, nitro-, pendant oxy, Ci-C6 alkyl-, halo-cc^, 6-alkyl...CVC6 alkoxy-, halo-CVC6 Alkoxy-, c ^ ^ , alkoxy-CVC6 alkyl-HCl-C6 alkoxy-Ci-C _, c3_Ci 〇 152524.doc -2- 201130854 R7 w X cycloalkyl-, 3 to 10 membered heterocycloalkyl _, · ί: (=〇)〇Η, -C(=0)0-C丨-C6 alkyl, -CpCOO-CVC!. Cycloalkyl, -OCpCO-CVCe alkyl, _〇(:(=〇)-(:3-(:10cyclodecyl, alkyl, alkyl) (:(=0)((^-(:6) )-alkyl, -:^(11)8(=0)2((:,-(:6)-alkyl, -N(Ci-C6 alkyl)S(=0)2(Ci-C6) -alkyl, -CpCONUCi-Cd-alkyl)((Cl_c6)·alkyl), -0(:(=0)1^(((^-(:6)-alkyl)(((^-( ^)-alkyl group, -:^(11)0(=0)0((^-(:6)-alkyl, -NA-Ce alkyl) ¢:(=0)0((^-( :6)-Alkyl, -1^(11)(:(=0)1^(((^-(:6)-alkyl)(((^-(:6)-alkyl), _n( Ci-C6 alkyl)C(=0)N ((CVC6)·alkyl)((〇ν(:6)-alkyl), -SKi-CO-alkyl, -SpOKCrCfi)-alkyl, _s( =〇)2〇H, -S(=〇)2(C1-C6)-, -S(=0)2N((Ci-C6)-alkyl)((&lt;^·(:6)·alkane Base), -p(=〇)(〇h)2, -P(=0) (0(CVC6)-alkyl KCrCe)-alkyl), -Ν((〇ν(:6)-alkyl XCCVCe )-alkyl), and wherein (CrQ)-alkyl is optionally substituted with 1 to 3 _ atoms; represents a hydrogen atom, a CrG alkyl group, a halo-Cl_C6 alkyl group or a €3-&lt;6 Cycloalkane ;, S, s=o or s(=o)2; is .__ R 〇 152524.doc S 201130854 where R8 represents 1 to 3 independently selected from the following Substituents for the group: hydrogen, #素, cyano, nitro, C1_Q alkyl _, halo-C--C6 alkyl _, C] _C6 alkoxy, Ci^ alkoxy-C丨- C6 alkyl-, dentate-C丨-C0 alkoxy-C丨-(: 6 alkyl, C2-C6 alkenyl, c2_c6 alkynyl, c(=〇)r9, -C(~〇 〇R9, _C(=〇)NR9R1〇, _sr9, s(=〇)r9 '〇)2r, _s(=〇)2NR9R104_NR9R10; wherein R and R1G are bonded to each other independently or together with the atom to which they are attached The meaning given above; Y is R 01a\ J R1b/ 3a Wherein Rla and Rib independently of each other represent a hydrogen atom, C._C6 alkyl. C6 alkynyl-, C3_C8 cycloalkyl-, aryl, heteroaryl-, decyl-heteroaryl CVC6 alkyl-C3- C1Q cycloalkyl, _Ci_C6 alkyl to 10 member heterocyclic fluorenyl), {(=〇)々'alkyl, -C(-〇)-CrC6 alkyl-aryl, -C(=〇)_Ci -C6 alkylene-heteroaryl, _C(=0)0_C1_C6 alkyl, _c(=0)0_ • 4- 152524.doc S Ci-Ce extended alkyl-aryl, -C(=0)〇-Ci-C6 extended alkyl-heteroaryl, -C(=0)NR9R10, -S(=〇)2R9 group Wherein the groups are substituted 1 to 3 times in the same or different manner via substituents selected from the group consisting of halo-, hydroxy-, cyano-, nitro-, CVCe-alkyl-, halo-CVC6 Alkyl, Ci-C6 alkoxy-, _*-d-C6 alkoxy-'Ci-Ce alkoxy-CVC6 alkyl-, functional group-CVC6 alkoxy-CrC^alkyl-, c3 -c10 cycloalkyl, aryl-, heteroaryl-, 3 to 10 membered heterocycloalkyl-, -C(=0)0H, -(:(=0)0-01-(:6 alkyl , -c(=o)o-c3-c丨〇cycloalkyl, -oc(=o)-c丨-c6 alkyl,-0(:(=0)-(:3-(:1() Cycloalkyl, -N(H)C(=0)R9, n(Ci-C6 alkyl)C(=0)R9, -N(H)S(=0)2R9, -Nd-Q alkyl) S(=0)2R9, -C(=0)NR9R10, -〇C(=〇)NR9R10 &gt; -N(H)C(=0)0R9 ' -N(Ci-C6 system base)C(=0 ) 0R9 , -N(H)C(=0)NR9R10 , -N(H)C(=NH)NR9R10, alkyl)c(=o) NR9R10, _SR9, _S(=0)R9, -S(= 0) 20H, -s(=o)2r9, _s(=0)2NR9R10, -P(=〇)(〇H)2, -p(=o)(or9)(or10), -NR9R10, and R9 And r1() are independent of each other or together with the atom to which they are attached Linked together has the meaning given above; or Rla and Rlb are bonded together with the atom to which they are attached to form a 3 to 1 member heterocycloalkyl-, which may optionally be substituted or otherwise selected from the following substituents Substituted to 3 times: halo-201130854, hydroxy-, cyano-, nitro-, pendant oxy, (VCfi alkyl _, functional group - Ci-C6 alkyl group, Ci_C6 alkoxy-, functional group -Ci-匸6 alkoxy _, C1-C6 decyloxy-C1-C6-homo-, dentate-Ci-Cs alkoxy-CrCfi alkyl-, -C(=0)0H '-C( =0) 0-Ci_C6 alkyl, -C(=0)0-C3-Ci〇cycloalkyl, -0C(=0)-Ci_C6 alkyl, -OC(=〇)-C3-Ci〇cycloalkyl , -N(H)C(=0)R9, alkyl)C(=0)R9, -N(H)S(=0)2R9, -NCCVCe alkyl)S(=0)2R9, -C( =0) NR9R10, -〇C(=0)NR9R10, -N(H)C(=0)0R9, -N(CrC6 alkyl)C(=0)0R9, -N(H)C(=0) NR9R10, -N(H)C(=NH)NR9R1Q, -N(CrC6 alkyl)c(=o)nr9r10, -SR9, -S(=〇)R9, -S(=〇)2〇H,- S(=0)2R9, -S(=0)2NR9R10, -P(=〇)(〇h)2, -P(=〇)(〇R9)(〇R10), -NR9R1() 'where R9 and Rigs are linked to each other independently or together with the atoms to which they are attached Meaning, or Ria and Rib, together with the atom to which they are attached, form a 3 to 10 membered heterocycloalkyl group, which is substituted with a group selected from the group consisting of C3-C10 cycloalkyl-, aryl-, hetero Aryl-, _Cl_c6 alkylene/aryl, -alkyl-heteroaryl, -(:"(:6-extension-C3-C1G cycloalkyl, 3 to 10 membered heterocycloalkyl-, - CV C6 Stretching Group Heterocycloalkyl-'These groups are optionally substituted 1 to 3 times in the same or different manner via substituents selected from the group consisting of: dentate, cyano, CVC6 alkyl- and dentate- CVC6 alkane 152524.doc S -6- 201130854 base; Rlc represents a hydrogen atom, a hydroxyl group, a decyloxy group or an alkoxy group, a Crc6 alkyl group, a CVC6 alkoxy group - a CVC6 alkyl group, a c2-c6 alkenyl group , c2-c6 alkynyl-, c3-c8 cycloalkyl-, aryl-, heteroaryl-, -CVC6 alkyl-aryl, -CVC6 extended alkyl-heteroaryl' _.C 1 - C 6 Stretching base _ C 3 _ C 1 〇 ring cyclyl, -CrC^ stretching group - (3 to 1 member heterocyclic alkyl group); wherein the groups are optionally selected from the following or different ways The substituent is substituted 1 to 3 times: a base group, a thiol group, a cyano group, a schlossyl group, a C!-C6 alkyl group, and a base group - C 1 -C6 alkyl group. C 1 -C6 alkoxy-, halo-cvg alkoxy-, (ν(:6 alkoxy-CVC6 alkyl-, from ke-C^-Ce alkoxy-CVC6 alkyl-, C3- Ci〇i sputum-, 3 to 10 member heterocycloalkyl-, -C(=0)0H, -(:(=0)0-(^-(:6 alkyl, -C(=0) 0· Cs-Ct. Cycloalkyl, -00:(=0)-(^-(:6 alkyl, -0C(=0)-C3-Ch)cycloalkyl, -N(H)C(=0)R9, -TsKCVQ Alkyl)C(=0)R9, -N(H)S(=0)2R9, -n(c)-c6 alkyl)s(=o)2r9, -c(=o)nr9r10, -0C( =0) NR9R1(), _N(H)C(=0)0R9, -NiCVQ alkyl)C(=0)0R9, -N(H)C(=0)NR9R1(), -N(H)C (=NH)NR9R10 ' -N(C!-C6 ^ 1. )C(=0)NR9R1〇, -SR9 ' -S(=0)R9 ' -S(=0)2R9 ' -S(=0) 2NR9R1〇n -NR9R1(), wherein R9 and R10 are bonded to each other independently or together with the atom to which they are attached, having the meaning given above, 152524.doc 201130854; Rh and Rm independently of each other represent a hydrogen atom, a CrQ alkyl group _ , Cj-Ce 々 々 - (^院基-, C2-C6 dilute-, C2-C6 alkynyl-, C3-C8 cycloalkyl, 3 to 1 杂环 heterocycloalkyl-, aromatic Base-, heteroaryl-, alkylene-aryl, -CVCe-extension-heteroaryl, -〇^-(:6-alkyl-C3-C1()cycloalkyl, -CrC6 alkylene - (3 to 1 member heterocycloalkyl); wherein the groups are optionally substituted 1 to 3 times in the same or different manner via a substituent selected from the group consisting of: dentyl group, hydroxy group, cyano group, and nitrate Base-, C--C6 alkyl-, haloalkyl-, Ci-C6 alkoxy ·, haloalkoxy-, (VC6 alkoxy-CVC6 alkyl-, halo-C, -C6 alkoxy-C^-Ce-formyl-, aryl-, heteroaryl-, C3- C1()cycloalkyl-, 3 to 10 membered heterocycloalkyl-, -C(=0)〇H, -C(=0)0-Ci-C6 alkyl, -(:(=0)0- 03-(^.cycloalkyl, -OCpCO-Ci-Ce alkyl, -oc(=o)-c3-c1Q cycloalkyl, -n(h)c(=o)r9, -NCCrC^ alkyl) C(=0)R9, -N(H)S(=0)2R9, alkyl)s(=o)2R9, -c(=o)NR9R10, -OC(=0)NR9R10 ' ^N(H) C(=0)0R9 ^ -N(C,-C6 alkyl)C(=0)OR9, -N(H)C(=0)NR9R1G, -N(H)C (=NH)NR9R10, -N (CVC6 alkyl)c(=o)nr9r10, -SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR9R10, -NR9R1G, wherein R9 and R1Q are independent of each other or Together with the atoms to which it is attached, it has the meaning given above, 152524.doc S 201130854; or Ru and R3a, or Rlb and R3a, or R3b and Ria, or R3b and Rlb, together with the atoms to which they are attached Forming 4 to 10 membered heterocycloalkyl- or 4 to 10 membered heterocycloalkenyl-, optionally substituted 1 to 3 times with substituents selected from the group consisting of: i-, hydroxy-, cyanide, in the same or different manner Base - 'nitro-, Cl-C6 alkyl- • _S-Ci-C6 alkyl-, CVC6 alkoxy-, dentyl-(^-(^ alkoxy-'CVC6 alkoxy-CVC6 alkyl-, dentate-CVC6 alkoxy-CVC6 alkane Base-, C3-C1G cycloalkyl-, 3 to 10 membered heterocycloalkyl-, -C(=〇)〇H, -CpCOO-Ci-Ce alkyl, -C(=0)0-C3-C1 ()cycloalkyl, -〇c(=〇)-C丨-c6 alkyl, -OCpC^-CrC,. Cycloalkyl, -N(H)C(=0)R9, -NCCVCe alkyl)C(=0)R9, -N(H)S(=0)2R9, •Ν((ν(:6 alkyl) )s(=o)2R9, -c(=o)nr9r10, • -〇C(=〇)NR9R1Q, -N(H)C(=0)OR9, -NCCVCs alkyl)C(=0)0R9, -N(H)C(=0)NR9R1(), -N(H)C (=NH)NR9R10, -NCCVCe alkyl)C(=0)NR9R10, -SR9, _s(=〇)R9, _s( =0) 2〇H, -s(=o)2r9, -S(=〇)2NR9R10, -P(=〇)(〇h)2, -P(=〇)(〇R9)(〇R10), -NR9R1G, wherein R9 and R1G are bonded to each other independently or together with the atom to which they are attached, and have the meanings given above, and all other substituents in γ have the meanings given above; S 152524.doc 201130854 Y is not _C(=〇)H. 2. A compound according to claim 1 wherein X is R R, 8b, and "are independently of each other are a hydrogen atom, a halogen atom or a dentate group - CVC6 alkyl group. 3. The compound of claim 1, wherein γ is G-C6 alkyl #, Ru, R, lb are bonded to each other independently or together with the atom to which they are attached, and Rh, R〇b are independently of each other. As stated in the request item. 4. The compound of claim 1, wherein Y is or Η wherein Ru, Rlb are bonded to each other independently or together with the atom to which they are attached, having the meaning as given in claim 1. 5. The compound of claim 1, wherein γ is V3b y* or h2n/\152524.doc 201130854 wherein Rh, Rm has the meaning as given in claim 1. 6. The compound of claim 1 wherein γ is R 1a\ R w 1a\ Or 1a\ R ) The connection is at the beginning - M3a, R3b has the meaning given in the request item. 7-A compound of claim 1, wherein γ is Wherein Rla, Rlb are independently of each other or Rla and Rib together with the atom to which they are attached Its =Ru, Rlb are independent of each other or Rla, Rlb, together with the atom to which they are attached, have the meaning given as in claim 1 t. 8. The compound of claim 1, wherein R6 is , or a 6-membered heteroaryl group of a nitrogen atom, wherein the ruler 11 has the meaning as given in claim 1. 9. The compound of claim 1, wherein the pyridine ring is substituted 1 to 3 times in the same or different manner by a substituent selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, (^-C6). An alkyl group, a halo-CVC6 alkyl group, a CVC6 alkoxy group, a halo-CVC6 alkoxy group 152524.doc 201130854 ίο. A compound according to claim ,, wherein R6 is J where R11 has the meaning given as the request item. 11. A compound according to any one of clauses 8 or 10, wherein R&quot; is hydrogen, halogen, benzyl, cyano, nitro, Cl_C6 alkyl, halo-Cl_C6 alkyl, Cl_C6 alkoxy, Alkoxy group, _c(= 〇)Ci_C6 alkyl group. 12. The compound of claim 1 wherein 1 la 丨b and Rile are independently nitrogen, element, base, and atmosphere. Nitroso, C丨-C6 alkyl, halo-c _c6 alkyl, fluorenyl-decyloxy, halo-c--c6 alkoxy, ·c(=0)c丨_C6 alkyl . 13. The compound of claim 1 wherein Wherein Riu is hydrogen or dentate, specifically a fluorine atom, and the ruler is _〇_C1-C6 alkyl or -0-CVC6-dentate alkyl, specifically _0Ch3, 152524.doc S • 12· 201130854 -〇CF2H or -OCF3. 14. A compound according to claim i, wherein Κ·6 is 0 Wherein Rlla is hydrogen, halogen, hydroxy, cyano, nitro, Ci_c6 alkyl, halo-c丨-C6 alkyl, c丨-a alkoxy, halo-Ci_Ce alkoxy, preferably a fluorine atom And R!2 is hydrogen or a fluorine atom. 15. The compound of claim 1, wherein R7 is a hydrogen atom, -CH3, -CF3, -CH2CH3, -CH2CF3. 16. The compound of claim i, which has the formula (ιι): Wherein and Rn are each a hydrogen atom or a methyl group, and RSb is independently selected from the group consisting of: gas C6 alkyl-, halo 丨-c6 alkyl, s-N, 丨Rn appear 1 to 3 times and independently Selected from the following group: gas 152524.doc -13· 201130854 素, thiol, cyano 'nitro, CVC6 alkyl, halo CVC6 alkoxy, halo _Cl_C6 alkoxy, = alkyl, hydrazine A dimethyloxy group or an ethylidene dioxy group, and wherein 6 is the meaning of the group. Rla, Rib, R3a, R3b have the compound as given in claim 1, 17. The compound of claim 1, which has the formula (IIa): Wherein Rh and R2b are each a hydrogen atom or a methyl group, and hydrogen, halogen, C Rea and R.sb are independently selected from the group consisting of C6 alkyl-, halo-c, -C6 alkyl, R1丨 appears 1 to 3 times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CVC6 alkyl, halo-CVC6 alkyl, C]-C6 alkoxy, halo _c"c6 alkoxy, -CpCOCVCe alkyl, methyleneoxy- or ethylidene, and wherein Ria, Rib, R3a, R3b have the meanings given in claim 1. A compound of claim 1, which has the formula (IIb): 152524.doc • 14-S 201130854 among them R2a and R2b are each a nitrogen atom or a methyl group, and Rsa and Rsb are independently selected from the group consisting of &amp; C6 alkyl group, haloalkyl group, gas halogen, C, Ru appearing 1 to 3 times and independently selected. Free group consisting of qi, hydroxy, cyano, nitro, Cl_C6 alkyl, dentyl-Ci_C6 alkyl, Ci-c6 alkoxy, halo-Ci_c6 alkoxy, -c(=〇) Ci_C6 alkyl, methylene monooxy- or exoethyldioxy, and wherein Rla, Rib'R3a, R3b have the meanings given in claim 1. 19. The compound of claim 1, which has the formula (III): Wherein R2a and R2b are each a hydrogen atom or a sulfhydryl group, 152524.doc •15·201130854 Halogen, C!-Rsa and Rsb are independently selected from the group consisting of: gas, Ce-based, and insect-based Ci-Cs. R11 is present once and independently selected from the group consisting of oxime, oxime, halogen, 11⁄2 base, murine, decyl, C!-C6 alkyl, halo and Ci-C6 alkoxy And halo-(^-0:6 alkoxy, and wherein Rla, Rlb, R3a, R3b have the octyl group as given in claim 1 20. The compound of claim 1, which has the formula (IV): Wherein Rh and Rh are each a hydrogen atom or a methyl group, and halogen, q RSa and RSb are independently selected from the group consisting of hydrogen C6 alkyl-, fluorenyl-c丨-C6 alkyl, and Re is any of the following groups. group· Wherein Rii appears 1 to 3 times and dentate, hydroxy, cyano, nitro, C丨-C6 alkyl* As. 虱, 1-C6 alkane I52524.doc 201130854, CrCe alkoxy, halo-CVC6 alkane Alkyl, and wherein Rla, Rlb, R3a, R3b have the meanings given in claim i. The compound according to any one of claims 1 to 16, wherein R 2a and R 2b are each a hydrogen atom or a methyl group. The compound of any one of claims 2 or 16 to 20, wherein R_8a and Rsb are each a hydrogen atom; or • R8a is a hydrogen atom and R8b is selected from the group consisting of a halogen atom, a Ci-C6 alkyl group- a halo-C^-C^alkyl group; or Rh is selected from the group consisting of dentate, Ci_C6 alkyl group, dentate group _CrC: 6 alkyl group, and Ru is selected from the group consisting of halogen, ^ A compound of any one of claims 2 or 16 to 20, wherein Rsa and R8b are each independently a hydrogen atom, a fluorine atom or a fluorine kCi_C6 alkane. The compound of any one of claims 16 to 20, wherein R3a, R3b are all hydrogen atoms Rla, R]b are bonded to each other independently or together with the atom to which they are attached Together, has the meaning as given in claim 1. 25. The compound of claim 16 to 2, wherein Rla, Rib are each a hydrogen atom, and R3a, R3b have the meanings as given in claim 1. The compound of any one of claims 16 to 2, wherein at least one of the substituents RIA, R]b, R3a, R3b is a gas atom, 152524.doc 201130854 and all other substituents have the meanings given in the claim 27. 27. The compound of any of claims i, 3 to 4, 6 to 7 or 25 to 26, wherein Rla, Rlb are independently of each other Hydrogen atom, CrQ ndyl group, Cl-C6 alkoxy group-CVC^alkyl group, dilute group, aryl group, heteroaryl group, -Ci-C6 alkylene group-aryl group, -CVC6 alkylene group -heteroaryl, _C(^0)-Cl_C6 alkyl" is optionally substituted 1 or 3 times with the substituent selected from the following in the same or different manner. Halo-, thio-, cyano-, Ci_c6 leuko -, _ base_Ci~ c6 alkyl-, -C(=0)〇H, -C(=〇)NH2, -s(=0)2〇H, -N(H)C(=〇)NH2 , -N(H)C(=NH)NH2, -C(=0)0-Cl-C6 alkyl, -NH2 0 28 · as in claim 1, 3, 5 to 7 or 25 to 26 a compound wherein R3a, R3b are each independently a hydrogen atom, CVC6 alkyl group, C2_C6 dilute group, aryl group, heteroaryl group, wherein the groups are optionally substituted or otherwise selected from the group consisting of the following substituents Substituting 丨 to] times: halo-, cyano-, Ci-C6 alkyl, halo-Ci-Cs leucoyl, CVC6 morpho- or halo-Ci-Cg alkoxy-. The compound of claim 27, Wherein Ria is hydrogen and Rlb is -CH2-CH2-CH2-C(=0)0-CH2-CH3, -ch2-ch2-o_ch2-c(=o)o-ch3, -ch2-ch2-o-ch2- c(=o)o-ch2-ch3, -ch2-ch2-ch2-c(=o)oh, -ch2-ch2-o-ch2-C(_〇)〇H, four° sit-5-group. 30. The compound of any one of claim 28, wherein 152524.doc -18- 201130854 R·3 a is wind and R^b is phenyl, succinyl, benzoxenyl, butyl, thiazole The base or pyridyl group is optionally substituted 1 to 3 times by halogen atom, cyano group, CVC6 alkyl group, halo-CVC6 alkyl group, CVC6 alkoxy group or halo-CVC6 alkoxy group. 31. 8-(2,6-Fluoro-fluorenyl)-6-(2- gas-3-methoxy-phenyl)-7-methyl- 5· oxo-2,3-di Hydrogen-5 ugly-thiazolo[3,2-&lt;a]° pyridine-3-thiocarbamic acid S-phenyl ester 6-(2-fluoro-3-methoxy-phenyl)-8-(2 -Fluoro-6-trifluoromethyl-benzyl)- 7-methyl-: 5-oxo-oxy-2,3-dihydro-:5//-thiazolo[3,2·α]pyridine- S-phenyl 3-thiocarbamate 6-(2-chloro-5-trifluorodecyloxy-phenyl)_8·(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl -5-Sideoxy-2,3-dihydro-5if-thiazolo[3,2-α]pyridine-3-thiodecanoic acid S-phenyl ester 6-(2-fluoro-acridin-3-yl -8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-5/ί-thiazolo[3,2-α Pyridine-3-thiodecanoic acid S-phenyl ester 8-(2-fluoro-6-trifluoroindolyl-phenylhydrazino)-7-methyl-5-oxo-6-(3-trifluoroanthracene Oxy-phenyl)-2,3-dihydro-5//-thiazolo[3,2-α]° pyridine-3-thiocarbamic acid S-phenyl ester 6-(2-fluoro-5-A Oxy-styl)_8_(2_fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-5-yloxy-2,3-dihydro-5 oxetazole[3, 2-α]β-pyridyl-3-thiocarbamic acid S-phenyl ester 6-(4-fluoro-benzo[1,3]dioxol-5-yl)-8-(2-1 · 6-trimethylsulfonyl-phenylhydrazino)-7-mercapto-5-sideoxy-2,3-dihydro-5-sodium-sodium 152524.doc •19· 201130854 [3,2-α ]0 比交'3-thiodecanoic acid S-stupid vinegar 6-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-8-(2- Fluoro-6-trifluorodecyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5open-thiazolo[3,2_α]0 is more than -3-thio S-phenyl benzoate 3-benzylidene _8_(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)·7·methyl-2, 3-Dihydro-thiazolo[3,2-α]pyridone 8-(2,6-difluoro-phenylhydrazinyl)-3-(4-fluoro-somantyl)-6-(2-fluoro 3-methoxy-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 8-(2,6-difluoro-benzoinyl) - 6-(2-Fluoro-3-methoxy-phenyl)_3_(4-methoxy- oxalyl)-7-methyl-2,3-dihydro-thiazolo[3,2 -ω]pyridine_5-_ 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)_7-methyl·3_(4-digas曱oxy-benzylidene)-2,3-dihydro-«» plug. Sit and [3,2_α]0& bite-5-keto 8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_methoxy-phenyl)-7-mercapto-3 -(sinter-3-carbonyl)·2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 3-(benzo[b]thiophene-3-ylcarbonyl)_8_(26_two Fluorobenzoyl)6(2fluoro-3-methoxy-phenyl)-7(indolyl) 2,3-dihydro-thiazolo[3,2α]pyridine ketone (2'6 one gas-ben Indole)-6-(2-fluoro-3-methoxy-phenyl)-3_(coopsonium-3-phenyl)-7-methyl-2,3-dihydro-thiazolo[3, 2-α]pyridin-5-one 8·(2,6-difluoro-benzyl)_6_(2_fluoro_3_methoxyphenyl)_7-methyl· 3-(3-methyl -benzimidyl) 2 3 dihydrothiazolo[3,2 β]pyridine-5-one 1 (2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy Phenyl)_7_mercapto-3-(3-difluoromethyl·benzhydryl)-2,3-dihydro-thiazolo[3,2·α]pyridine_ 5-ketone 152524.doc 201130854 8 -(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-3-(2-methyl-benzylidene)- 2,3-Dihydro-thiazolo[3,2-α]pyridin-5-one 8-(2,6-dioxa-phenylhydrazinyl)-3-(2- gas-benzoquinone)-6 -(2-gas-3-methyllacyl-phenyl)-7-methyl-2,3-di Wind-° plug β sits and [3,2 - fl ]. Specific bite-5-嗣3-(2-chloro-3-fluoro-benzimidyl)-8-(2,6-difluoro-phenylindenyl)-6-(2-fluoro-3-methoxy - stupid)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 3-(3,5-digas-benzoquinone)-8-( 2,6-dioxa-phenylhydrazino)-6-(2- gas-3_nonyloxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]. Bipyridin-5-one 3 - (2,3 -digas-benzoquinone)-8 _ (2,6-di-phenyl-phenyl)-6 - (2-oxo-3 · methoxy- Phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 8-(2,6-difluoro-benzyl)-3 - (3 - Gas-benzoic acid)-6 - (2 -1 - 3 -decyloxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]°-pyridyl- 5-keto 3-(2,5-diqi-benzoquinone)-8-(2,6-di-phenyl-phenyl)-6-(2-a-3-methoxy-phenyl) -7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 3-(2- gas-5-methyl-benzoquinone)-8-(2, 6-disorder-benzyl-)-6-(2-fluoro-3-methoxy-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]acridine · 5-keto 3-(4-fluoro-benzylidenyl)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzoquinone -7-mercapto-2,3-dihydro-thiazolo[3,2-β]pyridin-5-one 6-(2-rat-3-methyllacyl-phenyl)-8-(2 -murine-6-di-mercapto-benzyl)-7-fluorenyl-3-(4-trifluorodecyloxy-adolino)·2,3·dihydro-thiazolo[3,2 -α]α ratio bit-5-keto 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]- 152524.doc - twenty one - 201130854 7-Methyl-3-[(2H5)phenylcarbonyl]-2,3-dihydro-5//-[l,3]thiazolo[3,2-specific bite-5-keto-3-benzamide Styrene-6-(2- gas-5-disorganooxy-phenyl)-8-(2- gas-6-difluoroindolyl-benzyl)-7-methyl-2,3- Dihydro-thiazolo[3,2-α]pyridin-5-one 3-phenylhydrazin-6-(2-fluoro-acridin-3-yl)-8-(2-fluoro-6-trifluoro Mercapto-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 3-(3,5-digas-benzyl)- 6-(2- gas-3-oxooxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazole [3,2-α]. 00--5-keto 3-(3-fluoro-benzylidene)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl -phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2^]pyridine-5-one 3-(5-a-non-phenan-2-yl)-6-( 2-oxo-3-methoxy-phenyl)-8-(2- gas-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3, 2-α]吼® D--5-keto 6-(2- gas-3-decyloxy-phenyl)-8-(2-N--6-di-methyl-phenylindenyl)_ 7- 曱Benzyl-3-(3-trifluoromethyl-benzylidene)-2,3-dihydro-thiazolo[3,2-α] ° than 5-butanone 3-benzylidene-6- (2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3 ,2-α]pyridin-5-one 3-benzylmercapto-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-indolyl-6-(3-trifluoroanthracene -Phenyl)-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 3-benzylidene-6-(2-fluoro-5-decyloxy-phenyl) 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-di-series-supplement β[3,2 - α ] ° than bite-5 - Ming 152524.doc •22- 201130854 3-Benzene ai·6_(4_fluoro·benzo π,3]dioxole 8-(2-fluoro-6- Fluoromethyl·benzyl)_7_methyl·&quot; 5 一虱···塞哇和[3,2-α]° pyridine-5·clear 3-benzoic m(2,2_二气-Benzo-π,3]dioxol-j-yl)-(2-fluorotrifluoromethyl-benzyl)-7-methyl-2,3-dihydro- oxazolo[3,2 -α].pyridyl 5-ketone, - muscle ν - tendon • stupid methyl) 3·(Bite-2-yl) _7·methyl-2,3_dihydro-嗟 并[3,2_biten 5-keto-8_(2,6-di-Iphenylmethyl)-6- (2-Dun-3-methoxy-phenyl)_3·(3·ι 口 bit -2-carbyl)-7-methyl·2,3_dihydro-carbazolo[3,2_啦 _ _ 5-ketone 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(5-fluorenyl- Thiazole-2-carbonyl)·2,3-dihydro-thiazolo[3,2·α]pyridine_5•ketone 6-(2-1-3-methoxy-phenyl)_3_(3_气_ 〇比 bit_2_罗炭基)_8_(2·ΐ-ό-trifluoromethyl-benzyl)_7-methyl_2,3_dihydro-thiazolo[3,2_port] 〇 π定-5-keto 6-(2·fluoro_3_decyloxy-phenyl)_8_(2_fluoro_6_trifluoromethyl-benzyl)-7-fluorenyl-3-(5- Methyl-thiazole_2•carbonyl)·2,3-dihydro-thiazolo[3,2 ^ ° ratio biting-5-keto 3-benzoinyl-8-(2,6-difluoro-benzamide _6_(2·Fluoro-3-methoxy-phenyl)-2,2,7·dimethyl-2,3-dihydro-thiazolo[3,2_β]pyridine_5-ketone 8_(2 ,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-3-(hydroxyimino-phenyl-methyl)-7-methyl-2,3 _Dihydro-thiazolo[3,2_β]pyridine_ 5-ketone 152524.doc •23- 201130854 8-(2, 6-Difluoro-phenylhydrazino)-6-(2-fluoro-3-indolyl-phenyl)-3-[(4-fluoro-phenyl)-hydroxyimino-methyl]-7- Mercapto-2,3-dihydro-thiazolo[3,2-α]° ratio 5--(8,8-difluoro-benzoinyl)-6-(2-fluoro-3- Methoxy-phenyl)-3-[subimino-(4-decyloxy-phenyl)-methyl]-7-mercapto-2,3-dihydro-thiazolo[3,2- α]pyridin-5-one 8-(2,6-dioxa-benzyl)-6-(2-defo- 3-methyllacyl-phenyl)-3-[iminyl-(4) -trifluoromethoxy-phenyl)-methyl]-7-mercapto-2,3-dihydro-thiazolo[3,2-iz]D than bite-5-one 8-(2,6- Difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(imido-decanophen-3-yl-indenyl)-7-methyl- 2,3-di-mouse-α-saliva[3,2-α]π ratio sigma-5-keto 8-(2,6-difluoro-1-phenylmethyl)-6-(2-gas-3 - oxime-phenyl)-3-(°f--3-yl-imido-indenyl)-7-mercapto-2,3-didam. Sitting on 弁[3,2-β]. Than 5-keto 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-o-tolyl- Mercapto)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pylot-5-one 8-(2,6-difluorophenylindenyl)-6-(2- Fluoro-3-methoxy-phenyl)-3-(imido-m-tolyl-methyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridyl Bite 5-keto 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-3-(hydroxyimino-phenyl-methyl )-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-α]pyrodo-5-嗣152524.doc -24- 201130854 6-(2-fluoro-3- Methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-3-(imido-phenyl-methyl)-7-methyl-2,3 ·Dihydro-indole "Sitting and [3,2-α] °tb - 5 - 33⁄4 6-(2-fluoro-3-methoxy-phenyl)·3-[(4-fluoro-phenyl)- Hydroxyimido-methyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-salt[3,2-α]比 咬-5-keto 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6.trifluoromethyl-benzyl)_ 3-hydroxylamino -(4-Trifluoromethoxy-phenyl)-methyl]_7-methyl·2,3-dihydro-thiazolo[3,2-α]pyridine-5- 6-(2-defo-3-methoxyphenyl)-8-[2-1-6-(trimethylene)phenylindolyl]-3-{(hydroxyimino)[(2H5)benzene基]曱基}-7-mercapto-2,3-dihydro-5/^ [1,3] violates "» sit and [3,2-〇]° bite -5-_ 6-(2 - Fluoro-3-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(°f-amyl-2-yl-imido-methyl) -7-mercapto-2,3-digas- η σ 坐[3,2-&lt;3]° ratio bite 5-- 6-(2- gas-5-trifluoromethoxy-benzene -8-(2- gas-6-trifluoromethyl-benzyl)-3-(hydroxyimino-phenyl-indenyl)-7-fluorenyl-2,3-dihydro· Thiazolo[3,2-α]° ratio to 5-keto 6-(2-fluoropyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-adenyl)·3 ·(Hydroxyimino-phenyl-indenyl)-7-mercapto-2,3-dihydro-supplemental β[3,2-α]π ratio biting-5-keto 8-(2,6 -difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)_3_[hydroxyimino-(3-trifluoromethyl-phenyl)-methyl]-7- Mercapto-2,3·dihydro-thiazolo[3,2-α]pyridin-5-one S 152524.doc -25- 201130854 8·(2,6-difluoro-benzoinyl)-6-( 2-fluoro-3-methoxy-styl)_3_[(2-fluoro-phenyl)-hydroxyimino-methyl]-7-methyl-2,3-dihydro-thiazolo[3, 2_ ]Pyridine-5- _ 3_[U-chloro-3-fluoro-phenyl)-hydroxyimino-indenyl]_8_(2,6-di-image-stupylmethyl)-6-(2-fluoro- 3-methoxy-phenyl)-7-mercapto-2,3-dihydro-indole[3,2-α]pyridin-5-one 8-(2,6-difluoro-benzyl) - 6-(2-Fluoro-3-indolyloxyphenyl)_3_[(3·Fluorine ratio bite--)-hydroxyimino-methyl]_7_methyl_2,3 _Dihydro-嗟 并[3,2_α]pyridine-5-one 8-(2,6-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl) , 3 [hydroxyimino, (5-methyl-thiazol-2-yl)-methyl]_7_fyl-2,3-dihydrothiazolo[3,2-α]pyridine-5-one 3-( Benzo[b]thiophen-3-yl-hydroxyimino-methyl)_8·(2,6 difluorobenzyl)-6_(2_fluoro_3_decyloxy-phenyl)_7_A Base 2,3_dihydro-thiazolo[3,2-α]η ratio biting _5·ketofluoromethyl-benzyl)_dihydroserzo[3,2_6·(2-fluoro- 3-decyloxy-phenyl)-8-(2-fluoro.6-tris 3-(methoxyimino-phenyl-methyl)-7-methyl-2,3-α]° bite -5-keto 8-U-fluorodongsan said methylbenzyl) winter (methoxyimino-phenyl-methyl)-7-methyl 叩difluoromethoxy-phenyl)_2, 3_Dihydro "serazolo[32_ &lt;3]° than bite-5-ketone 6·(2 -fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl adenyl) (methoxyimino-phenyl-fluorenyl)-7-fluorenyl-2 , 3-dihydro sito[=2 α]pyridin-5-one 152524.doc -26- 201130854 6-(4-fluoro-benzo[ι,3]dioxol-5-yl) _8_(2_Fluorotrifluoromethyl-phenylhydrazino)_3_(nonoxyimino-phenyl-methyl)-7-methyl_2 3·Dihydro-indolo[3,2-α] ° ratio _5·ketone 6-(2,2-difluoro-benzopyrene, 3) dioxole_5_yl b 8_(2_fluoro-6-difluoromethyl-benzoquinone ))-3-(methoxyiminophenyl-methylindolyl 2,3-dihydro-β sputum and [3,2-α]β ratio bite_5-_ 3-(allyl Iminoamino-phenyl-methyl)_6_(2•fluoro_3_decyloxyphenyl)_ • 8-(2·fluorodongtrifluoromethyl-phenylh-indole-indenyl-2, 3-dihydro-carbazolo[3,2-a]°it bite-5-_ 8-benzoinyl-7-fluorenyl_5_sideoxy_6_stupyl_2,3_two gas _ 嗟 嗟 并 [3,2-α]pyridin-3-quinic acid albino decylamine 8-phenylfluorenyl 7-fluorenyl _5_side oxy group 6 _ phenyl group 2,3 _ Hydrogen·5仏喧〇 sitting and [3,2-α]pyridine-3-carboxylic acid decyloxy-decylamine 8-(2,6-difluoro-benzyl)_6_(2nfoxyphenyl)7_ Methyl 5-sideoxy-2,3- Dihydro_5-open thiazol[3,2_啦变_3-formic acid bite_2_ φ decylamine 8-(2,6-monophenylmethyl)_6_(2_gas_3·decyloxy Phenyl p_methyl_ 5-sidedoxy-2,3-dihydro·5H_thiazolo[3,2_β]β ratio biting_3_carboxylic acid phenyl decylamine 8-(2,6-I-- Benzyl)_6_(2_说3_曱oxyphenyl)methyl 5-pentyloxy-2,3·2L-salt[3,2__biting_3_carboxylic acid methoxy _ 醯Amine 8-(2,6-fluoroindolyl)_6_(2-fluoro-3-indolyloxyphenyl)_7methyl_ 5-epoxy-2,3-dihydro-5 good thiazole And [3,2_ small ratio bite_3 carboxylic acid benzyl S 152524.doc -27- 201130854 octaamine 8-(2,6-difluoro-benzoinyl)-6-(2-fluoro-3_A Oxy-phenyl)_7-methyl-5-sideoxy-2,3-dihydro-5//-嗔"Sitting and [3,2-α] than biting 3-carboxylic acid cyclopropyl decylamine 8-(2,6-Difluoro-benzoinyl)-6-(2-fluoro-3-methoxy-phenyl)-7-indolyl 5- 5-oxo-2,3-dihydro-5i/ -thiazolo[3,2-α] ° ratio -3- 曱 曱 - - (2- ° than bit -2-yl-ethyl) · octa-amine 8-benzyl 3- (clum) Amino-mercaptopurine _6_phenyl-2,3_dihydro-03⁄4 ° sit and [3,2-&lt;3]β ratio bit-5-keto 3-(benzylamino) 曱Base)-8-(2,6-difluoro-benzoinyl)-6-(2 -Fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-&lt;3]. Bipyridin-5-one 8-(2-fluoro-methane)-6-(2-fluoro-3-methoxy-phenyl)-7-indolyl_3_(4-pyridin-4-yl-pyrazine -1-ylmethyl)_2,3-dihydro-oxazolo[3,2-α]pyridine· 5- _ 3-[4-(1-ethyl-propyl)-piperazinylmethyl ]_8 (2fluorophenylindenyl)_ 6-(2-fluoro-3-methoxy-phenyl)-7-indolyl 2,3-dihydro-η-azolo[3,2-α] Pyridine-5-one 8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl_3_(4-methyl-piperazin-1-yl Indenyl)-2,3-dihydro-thiazolo[3,2_α]pyridine-5-keto 8-(2-fluoro-benzyl)-6-(;2-fluoro-3-methoxy-benzene Base)_7_methyl_3_(„bipyridin-4-ylaminomethyl)-2,3-dihydro-thiazolo[3,2_ypyridine·5-one 8-(2·fluoro-benzyl) - 6-(2-Fluoro-3-methoxyphenyl)·7·methyl_3_(4-phenyl-piperidin-1-ylmethyl)-2,3·dihydro-thiazolo[ Nypyridine _5•ketone 3-azetidin-1-ylmethyl-8-(2-fluoro-stanomethyl)_6_(2_fluoro_3_曱oxy 152524.doc -28· 201130854 base-benzene 7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridine-5-one 8-(2-fluoro-benzyl)-6-(2-fluoro-3-曱oxy-stupyl)_7-methyl-3-[(2-° ratio -4-yl-ethylamine) )·Methyl]_2,3_Dihydro-Oxazo[3,2_α]pyridin-5-one 8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy- Phenyl)-7-mercapto-3-(4-pyl-piperazin-1-ylindenyl)-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 8-(() 2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-mercapto-3-{[(&quot;pyridin-2-ylindenyl)-amino group ]-mercapto}-2,3·dihydro-thiazolo[3,2α] 0 than bite-5 - _ 8-(2-fluoro-phenylhydrazino)-6-(2-fluoro-3-antimony oxide Benzyl)-7-mercapto-3-piperidin-1-ylindolyl-2,3-dihydrogenase β sita[3,2-β]pyrene than bite-5-one 2-(2 -{[8-(2-Fluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-indolyl-5-yloxy-2,3-dihydro- 57/-thiazolo[3,2-α]pyridin-3-ylindenyl]-amino}-ethyl)-piperidine-hydrazine-f acid tert-butyl ester 2- (2-{[8-( 2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-indolyl-5-oxo-2,3-dihydro-5 ugly-thiazolo[ 3,2-α]°pyridin-3-ylmethyl]-amino}-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 3- [(cyclopropylindenyl-amino)-hydrazine 8-(2-fluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2 -α]pyridine-5-one 3-[ 4-(3,5-Dimethyl-phenyl)-t-Chloro-l-ylmethyl]-8-(2-(-)-indolyl-6-(2-fluoro-3-methoxy) -phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]efcb ate-5-one 3-{[(3-didecylamino-propyl)- -Amino]-methyl}-8-(2-fluoro-methane)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro -thiazolidine 152524.doc •29 201130854 [3,2-α]«比唆·5-keto 3-{[(2-dimethylamino]ethyl)methyl]amino]_methyl} 8_(2_Fluorobenzoyl)-6·(2-fluoro-3.methoxy-phenyl)-7-indenyl-2,3-dihydro-thiazolo[3,2-α]&quot ; ratio to 5-keto 3-cyclopropylaminomethyl-M2-fluoro-benzyl <6_(2_fluoro_3_decyloxy) stannyl-7-methyl-2,3 -Dihydrogen plugs sit and [3,2-α]η ratio bite_5-keto 8-(2-fluoro-benzyl)-6-(2-fluoro-3-indolyl_phenyl)_7 _曱基_3_Phenylaminomethyl-2,3·dihydro-thiazolo[3,2-α]pyridine_5•one 3-(0)-3-dimethylamino-pyrrolidine Methyl)8(2fluorobenzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-23 dihydrothiazolo[3,2-&lt;2]» Than 5-ketone 3-((5&gt;3-dimethylamino)-p-pyrrolidine-diyl)8 (2fluorobenzamide) -6-(2-Fluoro-3.methoxy-phenyl)_7-methyl-2,3-dihydro-thiazolo[3,2-&lt;3]° ratio bite-5-_ 3 -(4·phenylindole-aminazine small group f)_8_(2_gasbenzyl)_6_(2_gas_3-methoxy-phenyl)-7-methyl-2,3·2 Hydrogen "plug-and-salt [3,2_bite_5_steel 8-(2-fluoro· alum)]_6_(2-fluoro_3_methoxyphenylphenyloxy-ethyl)-A Amino-amino]-methyl}-7-methyl-2,3-dihydro- oxazolo[3,2_α]0 is more than a 5-keto-3·[4_(3·dimethylamino) -propyl)·0 azine pyridylmethyl]_8(2 gas benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3 dihydrothiazolidine [3,2-α]β ratio bite-5-keto-2·{[8-(2-fluoro-methane)_6_(2_fluoro_3_methoxyphenylmethyl_ 5-epoxy -2,3-dihydro·5/ί_thiazolo[3,2·α]pyridine-3-ylindenyl]- 152524.doc -30- 201130854 base-amino}dimethyl-ethanoamine 8- (2-Fluoro-benzoinyl)_6-[2-. ))·3·3-methoxy-phenyl)-7-methyl-3-(pyridin-2-ylaminomethyl)_2,3·dihydro·0 塞 并[3,2_啦 bit_ 5. Copper 8 (2 phenylphenyl)- 6-(2-fluoro'3-methoxyphenyl)-3-[(indol-2-ylindenyl-methyl-amino)·methyl 77_Methyl·2,3•Dihydroindole[3,2·^° than biting 5-ketone 8-(2-Fluoro-phenylmethyl)-6-(2-1 ° ratio _4_ yl-based - oxazol-1 -yl 0-buty-5-ketone '3-decyloxy-phenyl )-7-Methyl-3-(4-indolyl)-2,3-dihydro-»塞" sits and [3,2-α] 6-benzo[1'3]m-oxirane _5_基_8_(2_Fluoro-benzyl)-7 [Methyl-(2_° ratio bit _2chunethyl)-amino]-methyl}-2,3-dihydro-嗟° And [3,2-α]pyridine_5-_ 8-(2,6-bis-phenylethylethyl-propyl ruthenium-1-ylmethyl)M2 fluoro-3-indolyloxy _Stupyl)·7-methyl-2,3-dihydro-oxazolo[3,2-α]acridin-5-one 8-(2,6-monofluoro-benzyl)_6_(2_nmethoxy-phenyl)-7 methyl-3-phenylamino-indenyl 2,3-dihydro-sodium [3,2_α ]π ratio bite_5·ketone 8_(2,6-monofluoro-benzyl)-6-(2·fluoro-3-indolyl-phenyl)-2,2,7-trimethyl-3 -(4-methyl-piperazine small group methyl) 2,3·di tthiazolo[3,2-y 0 ratio bite-5 -copper 8·(2,6·difluoro-adolyl)- 6-(2-Fluoro-3-indolyl-phenyl)-2,2,7·trisyl-3-({[indenyl](2-pyridine-2-ylethyl)amino]-A Base} 2,3_dihydro-nuclear sit and [3,2-α]pyrene than bite 5-ketone 8-(2,6-difluoro-stupylmethyl)·3·{[(2_two Methylamino-ethyl)-methylamine 152524.doc S .31 - 201130854 】]methyl}-6-(2-fluoro-3-methoxy-phenyl)_2,2,7· Trimethyl-2,3-dihydro-s-zolo[3,2-α].pyridin-5-one 8-(2,6·difluoro-benzoinyl)_6_(2_fluoro_3_ Methoxy-phenyl)_2,2,7-trimethyl-3-(4-pyridin-2-ylmethyl-piperazine a.ylmethyl)·2,3-dihydro-thiazolo[3 , 2-α]. 咬-5-keto 3-cyclopropylaminomethyl·8_(2,6-difluoro-stanomethyl)_6_(2_fluoro_3_methoxy-phenyl) -2,2,7-trimethyl-2,3-dihydro-thiazolo[3 2_α]0-pyridyl-5-one 8-(6,6-di - Benzyl) _6_(2_fluoro_3·decyloxyphenyl)_7-methyl·3-[(methyl-phenethyl-amino)-indenyl]_2,3-dihydro-thiazole And [32^]pyridine-5-one 8-(2,6-difluoro-benzyl)_6_(2_fluoro_3_methoxy-phenyl)_7_mercapto-3--[(2- Morpholin-4-yl-ethylamino)-indenyl]_2,3-dihydro-thiazolo[3,2_α] ° ratio biting 5-keto 8-(2,6-difluoro-benzoquinone ))·3·[4_(3,5-didecylphenyl)piperazine-indolyl]-6-(2-fluoro-3-methoxy-phenyl)-7-indenyl-2, 3-Dihydro-indole[3,2-α]pyridin-5-one 8-(2,6-difluoro-benzoinyl)_6·(2_fluoro_3_decyloxyphenyl)_7 _曱基_ 3-(° than biti-4-ylamino fluorenyl)_2,3_dihydro-sighs sit and [3,2-α]β than bite 5-keto 8-(2,6 -difluoro-phenylhydrazino)_6_(2_fluoro_3_methoxyphenyl)7曱yl_3·(phenethylamino-methyl)-2,3-dihydro-thiazolo[3 ,2-α]pyridin-5-one 3-cyclopropylamino fluorenyl-8-(2,6-difluoro-methane)-6-(2-fluoro-3-methoxy-phenyl )-7-Methyl-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 8-(2,6-difluoro-benzoinyl)_6_(2_fluoro_3_曱oxy_phenyl)_7_mercapto_ 152524.doc •32· 201130854 3-piperidin-1-ylmethyl- 2,3-Dihydro-thiazolo[3,2-fl]pyridin-5-one 8-(2,6-difluoro-benzyl)_6_(2-fluoro-3-methoxy-phenyl) _7_Methyl_ 3-(4-methyl-piperazin-1-ylmethyl)_2,3_dioxothiazolo[3,2-indolyl]pyridin-5-one 8-(2,6- Difluoro-benzoinyl)_3_U(2-didecylamino-ethyl)-fluorenyl-amino]-mercapto}-6-(2-fluoro-3-methoxy-phenyl)-7 -methyl-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-indolyloxy -phenyl)_7_fluorenyl_ 3-{[methyl-(2-morphin-4-yl-ethyl)-amino]-methyl}-2,3-dichloro-«samerin 3,2-α]pyridin-5-one 8-(2,6-disorgano-benzyl)-3-{[(3-dimethylamino-propyl)-indolyl-amino]- Mercapto}-6-(2-fluoro-3-indolyl-phenyl)-7-mercapto-2,3-dihydro-supplemented β[3,2-〇]&quot; 5-keto 8-(2,6-dioxo-benzyl)-3-[4-(3-dimethylamino-propyl)_旅嗓_ 1-ylmethyl]-6-(2 -Fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-indole®»Shen[3,2-α]pyridin-5-one 3·(benzoylamino group -mercapto)-8-(2,6-difluoro-benzyl)-6·(2-a-3-methoxy-phenyl)-2,2,7-trimethyl-2,3 -dihydro-thiazolo[3,2 -α]Pyridine _ 5-keto 3-[(cyclopropylmethyl-amino)-methyl]-8-(2,6-difluoro-phenylindenyl)_6_ (2-fluoro*-3 - Methoxy-stupyl)_7-methyl-2,3-hydrogen-sodium([3,2-[alpha]]. Than-5-branched I 3-(benzylaminomethyl-methyloxy-phenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridine·5 · Ketone 152524.doc •33· 201130854 8·(2,6-di-r-phenylmethyl)-3-((iS*)_3-dimethylamino-11-Bilobit-1-ylmethyl) -6-(2- gas-3-methoxy-phenyl)-7-mercapto-2,3-diox-°°°[3,2-α]pyridin-5-one 8-(() 2,6-Difluoro-benzyl)-7-methyl-3-{[indenyl-(2-acridin-2-yl-ethyl)-amino]-methyl}_6-(3- Trifluoromethoxy-phenyl)-2,3-diazo- 03⁄4° sits and [3,2-α]° bites 5--- 8-(2,6-di-t-benzyl)- 6-(2-Fluoro-3-methoxy-phenyl)-7-mercapto-3-(4-0 ratio bit-4-yl-pyryo-methyl-1-ylmethyl)-2,3- Two mouse-D plugs sit and [3,2-α] utb - 5 - 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl) -7-methyl_ 3-[(methyl 唆-4-ylindolyl-amino)-indenyl]-^^-two mice-sigh 弁[3,2- &lt;3]° ratio bit-5-keto 8-(2,6-dioxa-benzyl)-6-(2•gas-3-methoxy-phenyl)-2,2,7-di Mercapto-3-[(2-Olin-4-yl-ethylamino)-indenyl]-2,3-diphos·°ϋϋ[3,2-α]pyridin-5-one 6-(5-Gas-Phenylphen-2-yl)-8-(2,6-di- benzyl)-7-decyl-3_{[methyl-(2-0 ratio. -yl-ethyl)-amino]-mercapto}-2,3-two wind-°°°[3,2-α] ° than pent-5·ketone 8-(2,6-disorder -phenylhydrazinyl)-3 - ((7?)-3-dimethylamino-σpyrazole-1-ylindenyl)-6-(2-fluoro-3.methoxy-phenyl) 7-Mercapto-2,3-dihydro-thiazolo[3,2-α].唆-5-keto 8·(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-{[(2-methoxy-B Base)-mercapto-amino]-mercapto}-7-mercapto-2,3-two-rat-嗟^ sit and [3,2- &lt;2]° ratio biting 5-ketone 152524.doc -34- 201130854 8-(2,6-difluoro-anthracene)·6_(2_fluoro_3_methoxy_phenyl)_3_[ (furan·2-ylmethyl-methyl-amino)·methyl]_7_methyl-2,3-dihydro-thiazolo[3,2_α]pyridin-5-one 8-(2,6 -difluoro-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-3-(4-pyridin-4-ylmethyl-piperazine-oxime-yl Base)_2,3_dihydro-thiazolo[3,2-α]°pyridin-5-one 3-[(stupyl-subyl-amino)-methyl]-8-(2,6 -difluoro_alum-based)_6_^(2-fluorooxy-phenyl)-7-methyl-2,3-dihydro-indole[3,2_α] &lt;Bite-5 -嗣8-(2,6-difluoro-phenylhydrazino)_6-(2-fluoro-3-methoxy-styl)_7_mercapto_ 3-{[曱基-( 2-«Bistidin-2-yl-ethyl)-aminomercapto 2,3-dihydrothiazolo[3,2-α]pyridyl-5-one 3-[4-(3,5- A thiol-phenyl) 〇 〇 bottom. __ι_基曱基]_6_(2Fluoromethoxy-benyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)indolyl 2 3 -hydrogen hydrazino[3 ,2- &lt;3]° ratio bite-5-_ #3 gas [(2-dimethylamino-ethyl)-indolyl-amino]-methyl}-6-(2-fluoro-3-methoxy -Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl_2 3_dihydroindolizine [3,2-α]β than 唆-5 -keto 6-(2-fluoro-3-methoxy-phenyl)_8_(2·fluoro·6-trifluoromethyl- adenyl)-7-methyl-3-(4-methyl-piperidin Oxazine_ι_ylmethyl)_2,3_dihydro-thiazolo[3,2_α] 0 than bite-5·ketone 6-(2-fluoro-3-methoxy-phenyl)_8-(2 -fluoro-6-trifluoromethyl-benzyl) 7-methyl-3-[(2-morpholin-4-yl-ethylamino)-indenyl]_2,3-dihydro-thiazole And [3,2-^?]° than bite-5-discipline S 152524.doc •35- 201130854 3-(benzylamino-methyl)-6-(2-fluoro-3-methoxy- Phenyl)-8-(2-fluoro-6-difluoroindolyl-benylmethyl)-7-mercapto-2,3-dihydro-»seda[3,2-α] 5-keto 6-(2-fluoro-3-methoxy-phenyl)_8-(2-fluoro-6-trifluoromethyl-phenylmethyl 3-{[(2-methoxy-ethyl) -Methyl-amino phenyl hydrazino 7-mercapto 2,3 dihydro _ 嗟 0 sits and [3,2-α] «比唆-5-one 3-((/?)-3-dimethyl Amino group is slightly smaller than succinyl) _6_(2·gas-3_decyloxy-phenyl)-8-(2-fluoro-6-three Fluoromethyl-benzyl)-7-mercapto-2 3-dihydro-thiazolo[3,2-α]»pyridin-5-one 6-(2-fluoro-3-methoxyphenyl) )_8_(2_Fluoro-6-trifluoromethyl-phenylmethyl)_ 7-methyl-3-{[indolyl-(2-pyridin-2-yl-ethyl)-amino]-indenyl 2,3_Dihydro-嗟β sits and [3,2-(3].pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)_8_(2_fluoro_6 _Trifluoromethyl-phenylhydrazino)_ 3-({[2-(6-methoxybipyridin-2-yl)-ethyl]-indenyl-amino}}indolyl)_7_methyl- 2,3-Dihydro-thiazolo[3,2-α]pyridine-5-keto 6-(2-fluoro-3-indolyl-phenyl)_8_(2_fluoro_6•trifluoromethylbenzene曱)) 7-methyl-3-({mercapto-[2-(3-tris-methyl-methyl-0))-ethyl]-aminopurinyl)-2,3-dihydro- Thiazolo[3,2·α]pyridine_5-keto 6-(2-fluoro-3-indolyloxyphenyl)·3·({[2 (6-fluoro-indolyl)-yl)·B ]]-mercapto-amino}methyl)·8·(2-dispulsed trifluoromethyl-phenylhydrazino) 7-fluorenyl 2,3_dihydro-sold °[3,2- α]η ratio bite 5-ketone 3-({[2·(5-chloro-Μ·2-yl)-ethyl]•methylamino}}methyl)·6·(2_fluoro-3- Methoxy-phenyl)-8-(2-fail-6-trifluorof-phenylmethyl) 7-methyl· 2,3-dihydro- Zoxao[3,2-fl]pyridine·5__ 152524.doc -36 - 201130854 6-(2-Fluoro-3-methoxy-styl)-8-(2-fluoro-6-trifluoromethyl- Benzyl)·7-mercapto-3-({methyl-[2-(3-indolyl-). Bis-2-yl)-ethyl]-amino}-indenyl-2,3-dihydro-indole[3,2-α]*»pyr-5-one 6-(2- Fluoro-3-methoxy-phenyl)-3-({[2-(5-fluorobiridin-2-yl)-ethyl]-methyl-amino}-methyl)-8-(2) -Fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-sigh 弁[3,2-£2]«1 than bite-5-copper 6-( 2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-3-({ [2-(3-methoxy-acridine)- 2-yl)-ethyl]-methyl-amino}-mercapto)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 6-(2 -fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-p-methyl)-7-methyl-3- ({mercapto-[2-(6- Mercapto-indolyl-2-yl)-ethyl]-amino}-indenyl-2,3-diaza-indole[3,2-ίζ]β is more than 5-ketone 3-keto-3 ({[2-(4-Chloropyridin-2-yl)-ethyl]-methyl-amino}-indenyl)-6-(2-fluoro-3-methoxy-phenyl)-8 -(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 6-(2-fluoro -3-decyloxy-phenyl)·3-({[2-(3 - say-0-bito-2-yl)-ethyl]-indenylamino}} fluorenyl)-8-( 2-fluoro-6-trifluoromethyl-benzoyl)-7-fluorenyl- 2,3-di Argon-°°°°[3,2-α]β ratio bite 5-gram 6-(2-fluoro-3.methoxy-phenyl)-8-(2-fluoro-6-trifluoroanthracene -Benzyl hydrazino)-7-methyl-3-{[indolyl-(2-quinolin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-carbazole And [3,2-α]β ratio bit-5-keto 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl- 3-({[2-(piperidin-1-yl)ethyl]amino}indenyl)-2,3-dihydro-5//-[1,3]thiazolo[3,2 - ίζ ] ° ratio - 5 -嗣152524.doc -37- 201130854 8-(2,6-difluorophenylindenyl)_6_(2-fluoro-3-methoxyphenyl)-7-methyl·3_ {[A (propyl-2-yn-1-yl)amino]methyl b 2,3-dihydro-5i/-[l,3]thiazolo[3,2-α]β ratio bite_5__ 8-( 2,6-difluorobenzyl)_3-({[4-(dimethylamino)phenyl]amino}indolyl)-6-(2-fluoro-3-indolylphenyl)- 7·Methyl-2,3-dihydro-5/f-[l,3]thiaphetine[3,2-α]° ratio biting 5-keto 3-({[2-(diethyl) Amino)ethyl](methyl)amino}methyl)_8-(2,6-difluoro cumyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl- 2,3-Dihydro-5/ί-[1,3]嗟嗤[3,2-〇]«» than bite _5-嗣3_{[4-(3-chlorophenyl)piperazine·b Base]methyl}_8_(26_ Difluorobenzyl 6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydrothiazolo[3,2-α]® is more than ketone-5-one 8-( 2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3_ {[4-(pyrazin-2-yl)piperazine_丨_ Methyl bromide 23_dihydro_5 ugly _[13]thiazolo[3,2-α]&quot; than bite _5_鲷8_(2,6-difluoro cumyl)-6-(2 -Fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(1-decylpyrrolidin-2-yl)ethyl]aminopurine methyl)_23 dihydro·5 Ugly [1,3]嗔嗤[3,2- &lt;3] &lt;7 ratio bite_5-keto 3-{[4-(1,3-benzodioxol-5-yl)piperazine 1_yl]indenyl}-8-(2,6 -difluorobenzyl)_6_(2_fluoro_3_methoxyphenyl)7曱yl_ 2,3-dihydro-5/ί-[1,3]thiazolo[3,2-α] Pyridine-5-one 8_(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-mercapto-3-{[(2-mercapto-1) , 3-phenylidene thiazole _5_yl)amino] hydrazino 2,3_dihydro _5 ugly _ [1,3] ° plug β sit and [3,2-α]. Specific bite-5-class 152524.doc •38· 201130854 8·(2,6-difluorobenzyl)_6_(2-fluoro_3_methoxyphenyl)_7_fluorenyl ({4-[3 -(pyrrolidinyl)propyl]piperazine-hydrazinylmethyl)_2 3·dihydro_5&quot;· [1,3]thiazolo[3,2-α]pyridin-5-one 8-(() 2,6·difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl_3&gt;&gt; ({[3-(trifluoromethyl)phenyl) ]amino}indenyl)_2,3_dihydro_5-open-[1,3] sigh 0 sitting and [3,2-α] ° than biting 5-keto 8-(2,6-difluorobenzene Methyl)-6-(2-fluoro-3-indolylphenyl)-3-{[(4.methyl oxyphenyl)amino]methyl}-7-methyl-2,3· Dihydro-5 ugly-[1,3]thiazolo[3,2-α]° bite 5-keto 3-[(t-butylamino)methyl]_8·(2,6-difluoro Benzoyl)_6_(2_fluoro-3-methoxyphenyl)-7-mercapto-2,3-dihydro-5/indole[1,3]thiazolo[3,2-α]pyridine -5- Brewed I 8-(2,6-monofluoro*bensyl)-6-(2-1-3-methoxyphenyl)-7-methyl-3_ {[(4-mercaptobenzene) Mercapto)amino]methyl}·2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-β]η ratio bite-5-_ • 8-(2,6-di Fluoroquinone)-6-(2-fluoro-3-indolylphenyl)-7-methyl-3-{[(3-phenylpropyl)amine Methyl}_2,3_dihydro-5//.-[1,3]thiazolo[3,2-α]° ratio bit-5-keto 8-(2,6-difluoromethyl )·3·({[2·(3,5-Dimethoxyphenyl)ethyl]amino}indenyl)-6-(2-fluoro-3-methoxyphenyl)-7·A Base 2,3-dihydro-5//-[1,3] bite and [3,2-〇]° bite 5-keto 8-(2,6-difluoromethanemethyl)-6 -(2-Fluoro-3-methoxyphenyl)-7-methyl-3-({[3-(4-methylpiperidin-1-yl)propyl]amino}indenyl)_2, 3_Dihydro-5//-[1,3] sold η sit and [3,2-α] ° than bite 5-ketone 152524.doc 201130854 4·{[8-(2,6-difluorobenzene Methyl 6-(2-fluoro-3-methylphenyl)-7 methyl-5-yloxy-2,3-dihydrothiazolo[3 2_β]pyridine-3-yl]methyl} Methylpiperazine 丨 醯-carbamamine 8-(2'6·difluorobenzyl)_3_({[3_(dimethylamino)phenyl)]amino}methyl)-6-(2 -Fluoro-3-methoxyphenyl)·7·fluorenyl 2,3_dihydro_5/f[1,3] 0-spin-sit and [3,2-β]η ratio bite-5- Ketone 8-(2,6-difluorobenzyl)·6_(2·fluoro·3methoxyphenyl)_3_κ isoquinolin-8-ylamino)methyl]methyl_2,3_2 Hydrogen is opened," Thiazolo[3 2· α]pyridine-5-one 2-(4-{[8-(2,6-difluorophenylindenyl)_6_(2_fluoro_3_ Oxyphenylmethyl-5-sideoxy-2,3-dihydro-5 open-[13]oxazolo[3,2 a]ijpyridin-%yl]methyl}piperazine-1- Base)·ΛΓ-(2-phenylethyl)acetamamine 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)_7-methyl_ 3_ {[4 decapyridin-3-ylindenyl)pyrazine small group]methyl} 2 3 二气_5仏[13] 0 plug 0 sit and [3,2-α]η ratio bite·5- Ketone 3-(azetidinyl-h-methyl)_8_(2,6-difluorobenzyl)6(2fluoro-indolyloxyphenyl)-7-indenyl-2,3-dihydrogen ·57Η1,3] sigh and [32_啦 bit-5-keto 8-(2,6-difluoro cumyl)-6-(2-fluoro-3-methoxyphenyl)methyl_3_ ({4_[4-(Trifluoromethyl)phenyl)pyrazine-1_yl}methyl)-2,3-dihydro_5open_[1,3]喧. Sit and [3,2- &lt;2]»比唆_5_网2-(4·{[8-(2,6·difluorophenylindenyl)_6_(2·gas_3_τ oxyphenyl)·7·methyl- 5-sided oxy-2,3_dihydro_5/μ1,3]thiazolo[3,2_ypyridine-3-yl]indolyl}piperazin-1-yl)-lip (2-methoxyethyl) Ethylamine I52524.doc 201130854 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-3-({4-[ 2-Phenoxy-2-0-pyrrolidin-1-yl)ethyl]piperazine-oxime-yl}methyl)· 2,3-digas-5//&quot;-[1,3]&quot ; plug ° sit and [3,2- &lt;3].唆-5-_ 8-(2,6-Difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl·3-({[2-(. Bilobidine-1-yl)ethyl]amino}indenyl)_2,3-dihydro-5//-[1,3]thiazolo[3,2-α]pyridin-5-one 3-{ [(2-Chlorobenzyl)amino]methyl}-8-(2,6-difluorobenzyl)-6-(2-•fluoro-3-methoxyphenyl)-7-A Benzyl-2,3-dihydro-5/f-[l,3]thiazolo[3,2-bite-5-keto-8·(2,6-difluoro cumyl)-6-(2- Fluoro-3-methoxyphenyl)-3-{[(4-terphenyl)amino]methyl}-7-methyl-2,3-dihydro-5 ugly-[1,3]thiazole And [3,2-α] ° ratio of 5-(8,6-difluorobenzyl)-3-{[(3,5-dimethoxy adenyl)amino] }--6-(2-fluoro-3-indolyl)-7-methyl-2,3-dihydro-5//-[1,3]carbazolo[3,2-α] Pyridine-5-one φ 8-(2,6·difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[2-(2-fluorophenyl)) Ethyl]amino}methyl)-7-methyl-2,3-dihydro-5-[1,3]thiasino[3,2-a]etb ate-5-one 8-(2 ,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_7-fluorenyl_3_ {[(2-phenoxyethyl)amino]methyl}·2 , 3-dihydro-5-good-[1,3]thiazolo[3,2-α]» than bite -5-keto 8_(2,6·difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-fluorenyl·3_(morpholin-4ylmethyl)- 2,3-Dihydro-5Η-[1,3]thiazolo[3,2-a]pyridine-5-_ 152524.doc •41 · 201130854 8-(2,6-difluorobenzyl)_6_( 2_fluoro_3_methoxyphenyl)_7_mercapto-3· {[(pyridin-4-ylmethyl)amino]methyl}·2,3·dihydro_5open·π , 3] thiazolo[3,2-〇]° ratio bit-5-keto 8-(2,6-difluorophenylindenyl)_6_(2_fluoro_3.methoxyphenyl)·3_{[ (4-methoxyphenylhydrazino)amino]methyl b 7-mercapto-2,3_dioxathiazolo[3,2-α]° ratio biting_5_ketone 8-(2,6- Difluorobenzyl)_3_{[(2,2-diphenylethyl)amino]indenyl}·6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3 -Dihydro-5//-[1,3]thiazolo[3,2-α]吼 bit-5-keto 3_{[(2-phenethyl)(methyl)amino]methyl b 8_ (2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)_7•methyl-2,3_dihydro_5/^π,3]thiazolo[ 3,2-α]bite-5-one 3-({[4-(stupyloxy)phenyl]amino}indenyl)-8-(2,6-difluorobenzyl)-6-( 2-fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro·57/-[1,3]thiophene[3,2 -β]«比唆_5_keto 4-[(4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_7_ fluorenyl) -5-Sideoxy-2,3_dihydro_5//_[1,3]thiazolo[3,2_synyl-3-yl]methyl}piperazine-1·yl)methyl]benzene N-carbonitrile 8-(2'6-difluorophenylindenyl)-indole (3,5-dimethoxybenzoinyl)(fluorenyl)amino]methyl b-6-(2-fluoro-3-methoxy Phenyl)-7-methyl-2,3·dihydro_5 ugly _ [1,3]thiazolo[3,2-βρ-pyridin-5-one 8-(2,6-difluorobenzene f _6_(2_Fluoro-3·f-oxyphenyl)·7-methyl_3_({4-[(1-methylpiperidin-4-yl)methyl]piperazine·丨_yl} Methyl)_2,3_dihydro-5-dan-[1,3] stagnation β and [3,2-β]π ratio bite-5-嗣152524.doc -42- 201130854 4-{[8-( 2,6-difluorophenylindenyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-5-yloxy-2,3-dihydro-5孖-[1, 3] Thiazolo[3,2-α]pyridin-3-yl]methyl}piperazine-1-decanoate methyl 8-(2,6-fluoroindolyl)-6-(2-fluoro- 3-decyloxyphenyl)-7-methyl-3_ {[indolyl(thiophen-3-ylmethyl)amino]indolyl 2,3-dihydro-5//-[1,3] Thiazolo[3,2-α]pyridin-5-one 8-(2,6-fluorobenzino)-6-(2-fluoro-3-indolylphenyl)-7 -mercapto-3_ • {[indenyl(naphthalen-2-ylmethyl)amino]indolyl}-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-^7 ]° than bite-5-_ 8-(2,6 -1 IL thiol)-6-(2-fluoro-3-methoxyphenyl)-3-{[(2-propylethyl) (Meth)amino]methyl}-7-methyl-2,3-dihydro-5//-[1,3]thiazolo[3,2 - a ] ** ratio - 5 - 83⁄4 8 -(2,6-difluoro cumyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl-3-{[(4-phenylbutyl)amino]- }}_2,3-di-argon-5//-[1,3]嗟嗤[3,2-α]0 ratio °-5-keto•8(2,6-difluoro cumyl) -6-(2-fluoro-3-indolylphenyl)-3-{[(3-decyloxybenzyl)amino]fluorenyl}-7-methyl-2,3-dihydro- 5孖-[1,3]thiazolo[3,2- &lt;3]° ratio bit-5-keto 3-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl] fluorenyl]·_8 -(2,6 - a 'gas thiol)-6-(2-aero-3-oxooxyphenyl)-7-methyl-2,3-dihydro-5//_-[1, 3] sigh and [3,2-^1] ° bite 5-ketone 3_({[3-(--ethylamino)propyl]amino} fluorenyl)-8-(2,6 -dioxabenzoyl)-6-(2-fluoro-3-indolylphenyl)_7-methyl-2,3-dihydro-5/ί-[1,3]嗟0 sits and [3 , 2-〇]° ratio bite-5-嗣152524.doc -43- 201130854 8·(2,6-difluorobenzyl)-6-(2-fluoro-3_decyloxyphenyl)_7- Methyl-3-{[4-(1·methylpiperidin-4-yl)piperazine_ι_yl]methyl b 2,3_dihydro·5&quot;_ [1,3] oxazo[ 3,2-α]pyridyl-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[ (3-Methylmethyl)amino]methyl}_2,3-dihydro-5-[1,3]thiazolo[3,2-α]. Than 5-keto 8-(2,6-difluorophenylindolyl)-6-(2-fluoro-3-indolyloxyphenyl)-7-methyl-3-(thiomorphin-4-yl) Methyl)-2,3-dihydro-57/-[1,3] sigh and sit [3,2- &lt;3]0 than 5-keto-5-keto 4-[2-( {[8-(2,6-difluorobenzoinyl)-6-(2-fluoro-3-methoxyphenyl)-7 -Methyl-5-o-oxy-2,3-dihydro-5//-[1,3]&quot;plug" sits and [3,2-α]0 is more than -3-yl]methyl} Amino)ethyl]benzenesulfonamide 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-indolylphenyl)-7-fluorenyl-3-({methyl [2-(pyridin-3-yl)ethyl]amino}methyl)_2,3-dihydro-5//-[1,3] 0 plug 0 sit and [3,2-fl]e ratio bite -5-keto 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(2-phenoxy) Ethyl)piperazin-1-yl]methyl b 2,3_dihydro-5 good-[1,3] thio. Sit and [3,2-β]β ratio bit-5-keto 8-(2,6-difluorobenzyl)·3·({[2-(dimethylamino)phenyl)]amino group } methyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro-5//· [ 1,3] thiazolo[3,2-α Pyridine-5-one 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4_(mercaptosulfonate) Mercapto)piperazin-1-yl]methyl}·2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-α]pyridin-5-one 152524.doc -44- 201130854 2-(4-{[8-(2,6-Difluorobenzyl)_6_(2_fluoro_3_methoxyphenyl)_7_methyl-5- oxo-2,3-dihydro -5/f-[l,3]thiazolo[3,2-α]pyridin-3-yl]indolyl}°endazin-1-yl)mercaptoacetamide 3- ({[2-(4) -Ethyl Piperazine 4•yl)ethyl]aminopurine methyl)_8_(2 6 difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)_7_fluorenyl 2,3_Dihydro_5 is good _ [1,3]°°°[3,2-α]β than biting 5-keto 8-(2,6-difluorobenzyl)_6_(2 _Fluorine_3_methoxyphenyl)_7_methyl_3 stomach φ {[(2_methyl benzyl)amino]methyl}_2,3_dihydro-5 ugly-[1,3 Thiazolo[3,2-α]» than bite-5-copper 8-(2,6-difluorophenylindenyl)·6_(2·fluoro·3_decyloxybenzene Base)_7 methyl-3_({4-[3-(difluoromethyl)phenyl]0-piperazine-1_yl}indenyl)_2,3 dihydro-_5 good_[1,3]嗟哇And [3,2-〇]** than bite-5-keto 3-[(1,3-benzodioxol-5-ylamino)indolyl]8_(2,6-difluoro Benzyl)-6-(2-fluoro-3-methoxyphenyl)_7-methyl-2,3_dihydro-5-p-[1,3]嗔η[[,2-β η 比 咬 · · · -2-ylmethyl)amino]methyl}-2,3_dihydro_5 ugly [13]thiazolo[3,2-α]»pyridyl_5_明8-(2,6- Difluorobenzyl)_6_(2_fluoro_3_methoxyphenyl)·7·methyl-3_(pyrrolidin-1-ylmethyl)-2,3-dihydro·5//-[ 1,3]thiazolo[3,2_β]pyridine_ 5-net 8 (2,6--fluorobenzyl)·6-(2-fluoro-3-methoxyphenyl)_3_({ρ_ (1 Imidazolyl-1-yl)propyl]amino}indenyl)-7-fluorenyl_23dihydro_5//·[1,3]thiazolo[3,2_α]pyridine·5-ketone S 152524. Doc •45- 201130854 4_[({[8·(2,6-Difluoro]methyl)_6·(2_fluoro_3_methoxyphenyl)_7 methyl 5-oxo-2,3- Dihydro_5//-[1,3]carbazolo[3,2-α]ηpyridyl-3-yl]methyl}amino)f-group] Benzoonitrile nitrile 8 (2'6·fluoroindolyl)-6-(2-fluoro-3-indolyloxyphenyl)_7-methyl_3_ ({methyl[(1-methyl_1) Good-„bazole_5_yl)methyl]amino}methyl)23_dihydro-5//-[1,3]thiazolo[3,2_λ]pyridine_5-ketone 8-(2, 6-difluorobenzyl)_6_(2_fluoro_3_decyloxyphenyl)7-methyl-% {[(thiophen-3-ylmethyl)amino]methyl}_2 3_dihydro_ 5 good · [13] thiazolo[3,2 - ^2 ] ° ratio.定-5 - Stuffed J 8_(2'6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl ({[(1-methyl·1/) Ί-imidazole-5-yl)methyl]amino}methyl)·2,3_dihydro_5//· [1,3]嗟 并[3,2-〇]° than bite-5- Ketone 8-(2,6-difluorobenzyl)_6-(2-fluoro-3-methoxyphenyl)-7-methyl_3_({4-[2-(trifluoromethyl)phenyl) ] piperazine-yl)mercapto)_2,3·dihydro_5孖_ [1,3] sigh and [3,2-α]π ratio bite _5_嗣8-(2,6 - one Fluorobenzoyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl_3_({[2-(4-methylphenyl)ethyl]amino}methyl) _2,3_Dihydro_5孖_[13] sigh and sit [3,2-〇]. Specific bite 5-keto 8-(2,6-difluoro cumyl)·6_(2_fluoro-3-indolylphenyl)_3·{[(2·methoxybenzyl)amino group ]methyl b-7-methyl-2,3-dihydro-5-[1,3]thiazolo[3,2-fl]&quot; than bite-5-one 8-(2,6-difluoro Benzyl)_6·(2·fluoro-3-methoxyphenyl)-7-methyl_3_[(3-methylpiperidin-1-yl)indolyl]_2,3·dihydro-5 Open-[1,3]thiazolo[3,2·α]. Specific bite _ 5 - _ 152524.doc -46- 201130854 8 · (2,6-difluoromethyl)-6-(2-fluoro-3-indolylphenyl)-7-methyl_3· ({[3-(2-Axyloxypyrrolidine-bu)propyl]amino}indenyl)_2,3_dihydro-5-open-[1,3]thiazolo[3,2-£ ζ]pyridine-5-one 8-(2,6-difluorophenylindenyl)-6-(2-fluoro·3·methoxyphenyl)-7-fluorenyl_3_ ({[4-(? Phenyl-4-yl)phenyl]amino}methyl)_2,3-dihydro-5-[1,3]thiazolo[3,2-α]η than bite-5-one 8-(2) ,6-difluorobenzoinyl)-6-(2-fluoro-3-yloxyphenyl)_3_({[2_(3_ φ fluorophenyl)ethyl]amino}methyl)-7-fluorenyl -2,3-Dihydro-5/ί-[1,3] thiophene. Sit and [3,2-α]° than bite 5-ketone #_[4-({[8-(2,6·difluorophenylhydrazino)-6-(2-fluoro-3-indolyloxy) Styrene) fluorenyl-5-yloxy-2,3-dihydro-5//-[1,3]thiazolo[3,2-α]pyridine-3-yl]hydrazino}amino)phenyl ] decanesulfonamide 3·{[4-(2-oxacyl)piperazine-1_yl]methyl}_8·(2,6-difluorophenylindenyl)-6-(2-fluoro -3-decyloxyphenyl)_7-methyl-2,3-diar-argon-5 ugly-[1,3]thiadoquinone[3,2-ap than precipitation-5-class•8(2) ,6-difluorobenzoinyl)-6·(2_fluoro_3_methoxyphenyl)·7·methyl·3_ {[(17/-0-pyrazole-3-ylmethyl)amino group ]methyl}-2,3-dihydro-5//-[1,3]thiazolo[3,2-α]° ratio 5-- 8-(2,6-difluorobenzyl) _6_(2_Fluoro_3_methoxyphenyl)_7_fluorenyl ({4-[2-(.pyridin-2-yl)ethyl)piperazine-1_yl}methyl)_2,3 _Dihydro[1,3] sold °[3,2-α]° than bite 5-keto 8-(2,6-difluorophenylindenyl)-6-(2-fluoro-3-indole Oxyphenyl)-7-fluorenyl ({4-[(1-mercaptopiperidin-3-yl)indolyl]piperazine-1_yl}indenyl)_2,3_dihydro-5// *[1,3]嗟°[3,2-α]η ratio bite-5-ketone S 152524.doc 201130854 Cyclopropyl-2_(4-{[8-(2,6-difluorobenzene) Base)-6-(2-fluoro_3_methoxy Phenyl)-7-methyl-5. oxo- 2,3·dihydro-577413]thiazolo[3 2_β]pyridin-3-yl]indolyl}piperazine-indole-yl)acetamide 6 -(2-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]-7-indolyl-3-({[3-(morpholine_4_) Propyl)amino}methyl)_23·diar argon _5 ugly _ [1,3] 嗟 并 and [3,2-α] π than bite _5-keto 6-(2-fluoro-3-曱oxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]_ 7-methyl-3-{[(2-methylbenzyl)amino]methyl}_2 , 3_ dihydroindole 0 sits and [3,2-α]» than bite _5-keto 3_{[(3-chlorobenzyl)amino]methyl}_6_(2_fluoro_3_methoxy Phenyl)) 8-[2-Fluoro-6-(trifluoromethyl)benzyl]_7_methyl_2,3_dihydro_5// [13] 0 塞 ° sits and [3, 2-α]π ratio bite-5-steel 6-(2-fluoro.3·decyloxyphenyl)·8-[2·fluoro-6-(trifluoromethyl)benzyl]_ 3-{ [(2-hydroxyethyl)(methyl)amino]mercapto 7-methyl-2,3_dihydro_5 ugly [1,3]thiazolo[3,2-α]pyridine-5 -keto 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7methyl-3-(morphin-4-yl) Methyl)-2,3-diaza-5// [ 1,3 ] 嗔〇 and [3 2~ α]0 than bite-5-keto 6-(2-^- 3-methoxyoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzylidene-7-methyl-3-{[(4-phenylbutyl)amino]fyl }-2,3-Dihydro-5-[1,3]嗔°[3,2-α]°ϋ Bite-5-鲷3-(1,4'-bipiperidin-1·-曱-)-6-(2-fluoro-3-indolylphenyl)_8· [2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro _5 open seven, 3] 嗟β sit and [3,2-α] ° bite-5-steel 152524.doc •48· 201130854 6-(2-fluoro-3 -decyloxyphenyl)·8_[ 2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[f-based (propan-2-yl-1-yl)amino]yyl 2,3 dihydrogen $好·[1,3]thiazolo[3,2-α]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl) Benzyl]_ 3-{[(3-methoxybenzyl)amino]methyl}_7_methyl_23 dihydro_5i/_ [1,3]嗓 并[3,2- α]η ratio bite-5-keto 3-{[(4-乱本基)(fluorenyl)amino]methyl}_6_(2_fluoro_3_methoxybenzeneφ)-8-[2 _Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/f-[1,3]嗟σ sits and [3,2-"] Bite-5·嗣3-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-buyl]methyl}-6-(2-fluoro 3-methoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl-2,3-dihydro-5 ugly-[1,3]thiazole And [3,2-α]pyr.定·5_ketone 3·({[3-(monodecylamino)propyl]amino}methyl)_6_(2_fluoro_3_decyloxyphenyl)-8-[2-fluoro- 6-(Trifluoromethyl)benzyl]_7·methyl-2,3-dihydro-5//-[1,3]thiazolo[3,2-4pyridine-5-one• 4-{ 2-[({6-(2-Fluoro-3_methoxyphenyl)_8-[2-fluoro-6.(trifluoromethyl) oxalyl]-7-methyl-5-sideoxy- 2,3-dihydro-5 ugly-[1,3]thiazolo[3,2_α]β-predative-3-yl}indenyl)amino]ethyl}benzamide 6-(2-fluoro 3-methoxyphenyl)-8-[2·fluoro-6-(trifluoromethyl)ethyl]-7-fluorenyl-3-{[(3,4,5-trimethoxybenzene Indenyl)amino]indolyl 23_dihydro-5 ugly-[1,3]thiaphthyl][3,2-α]. Than 5-ketone 3-{[t-butyl(methyl)amino]methyl}_6_(2·fluoro·3 -decyloxy)-8-[2-氤-6-(three Fluoromethyl)benzyl]-7-mercapto-2,3-dihydro-5//-[1,3]thiazolo[3,2-α]pyridin-5-one 152524.doc •49- 201130854 6_(2-Fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(pyridine-2) -yl)ethyl]amino}indenyl)-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-α]pyridin-5-one 6-(2-fluoro-3 -decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(»-pyridin-2-ylmethyl)amino ]methyl}-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-α]acridin-5-one 6-(2-fluoro-3-methoxyphenyl) -8-[2·Fluoro-6-(trifluoromethyl)benzyl]_ 3-{[(4-methoxyphenyl)amino]methyl}-7-fluorenyl-2,3· Dihydro-5//-[1,3]thiazolo[3,2-a]pyridin-5-one 3-{[(2-phenethyl)amino]methylfluoro-3-indolyloxy Phenyl)- 8-[2-fluoro-6-(trifluoromethyl)benzyl]_7-methyl-2,3.dihydro·5 ug[_]thiazolo[3,2-α] Pyridine-5-one 3-[(diphenylmethylamino)methyl]_6_(2_fluoro_3_methoxyphenyl)8 [2_fluoro-6-(difluoromethyl) Benzyl]-7-methyl-2,3-dihydro-5//-[1,3]indole[3,2-α]吼 bit-5-one 4- ({6- (2-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]-7-fluorenyl-5-yloxy-2,3-dihydro_5&quot ;_[1,3]thiazolo[3,2-α]pyridin-3-yl}methyl)π-decanoic acid ethyl ester 6-(2-fluoro-3.methoxyphenylphenyl) Amino]methyl b-8_[2-fluoro-6-(difluoromethyl)benzoinyl]_7_methyl_23 dihydro_5 ugly-Η,]]thiazolo[3,2-α]〇 Bipyridine _5·ketone 3-(azetidin-1-ylmethyl)·6_(2·fluoro·3曱oxyphenyl)8 [2_fluoro_6_(difluoroindolyl)benzoinyl] · 7-Methyl-2,3-dihydro·5-[1,3]thiazolo[3,2-"]° ratio bit-5-ketone 152524.doc 201130854 6-(2-Fluoro-3-曱oxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl 7-indolyl-3-[(4-methylpyridinyl)methyl]_2,3-dihydroindole 0 sits and [3,2-α]βΛ 唆-5-_ ^({6-(2-fluoro-3-oxooxyphenyl)_8_[2_fluoro·6_(trifluoromethyl)benzyl ]-7-mercapto-5-sideoxy·2,3_dihydro_5open_[13]carbazole[3 2 rushing than -3-yl} fluorenyl) 唆-3 - formazan Amine 3_{[(1,3-benzodioxole·5-yl-f-group) Amino]methyl b. 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]7-methyl-2,3-dihydro -5 ft -[1,3]thiazolo[3,2-α]&quot; than bite-5-keto 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_( Trifluoromethyl)benzyl]-7-methyl-3-[(prop-2-yn-1-ylamino)methyl]_2,3_dihydro ugly _[13] thia [3,2-α]β is more than 5-keto 5-(3,4·dihydroisoquinoline-2-(1 ugly)-ylmethyl)_6_(2_fluoro_3·methoxyphenyl) )-8-[2-Fluoro-6-(trifluoromethyl)benzoinyl]_7_mercapto-2 3 dihydro_5 ugly _ [1,3] sigh ° sit and [3,2-α] ° ratio of 5- to 9- 6-(2-fluoro-3-methoxyphenyl)·8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3 -{[(3,4,5-trimethoxyphenyl)amino] hydrazino 2,3·dihydro·5-[1,3]° stopper. Sit and [3,2-〇]. Specific bite-5-嗣4-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-oxime 5-O-oxy-2,3-dihydro-5//-[1,3]thiazolo[3,2-0]acridin-3-yl}methyl)amino]-indole-benzene Benzobenzamide {4-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-) 5-yloxy-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2·α] 0-pyridin-3-yl}methyl)amino]phenyl}acetic acid Ethyl ester 152524.doc •51 - 201130854 3-{[(4-Phenylphenyl)-(indenyl)amino]methyl}-6-(2·fluoro-3-indolylphenyl)-8- [2-Fluoro-6-(trifluoromethyl)phenylindolyl]-7-indolyl-2,3-dihydro-5i/-[1,3]嗟[S,[[,2-[alpha]]pyrr Bite 5-keto 6-(2-fluoro-3-indolyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-indolyl-3-({ [3-(1//-tetrazol-5-yl)phenyl]amino}indenyl)-2,3-dihydro-5 ugly-[1,3]carbazolo[3,2-α] &quot;Bipyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3 -({[3-(piperidin-1-yl)propyl]amino}methyl)_2,3_dihydro_5开_[1,3]嗟"Sitting and [3,2-〇]» Than 5-ketone 6-(2-fluoro-3-indole Oxyphenyl)8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(嗟-phen-2-yl)ethyl); }}methyl)_2,3_dihydro_5 ugly_[1,3]thiazolo[3,2-α]pyridin-5-one 6-(2-fluoro-3-decyloxyphenyl)_8_ [2_Fluoro_6_(trifluoromethyl)benzyl]-7-indolyl-3-[(4-indolyl-1,4-diazepanyl)methyl]_2,3 · Dihydro _ 5 open _[1,3] sing β sitting and [3,2-α] η than biting _5-keto 3-[(4·ethylpiperazine ΐ ΐ yl) methyl]•6_ (2_Fluoro_3_methoxyphenyl)·8_[2-Fluoro-6-(trifluoromethyl)phenylhydrazinyl 7methyl_23 dihydro_5 ugly _[13] thia [3,2- &lt;a]n than bite 5-keto 6-(2-fluoro-3-yloxyphenyl)_8_[2•fluoro·6_(trifluoromethyl)benzyl 7-indolyl-3-( {[2-(2-Sideoxyimidazolidinyl)ethyl]amino}methyl)_ 2,3-dihydro-5//[1,3]thiazolo[3,2_α]pyridine_5 -keto 3-{[bis(pyridin-2-ylmethyl)amino]methyl b 6-(2.fluoro-3-ylmethoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) Benzo)]benzylidene]_7_methyl-2,3_dihydro_5//· [1,3]° stoppered [3,2-α]. Specific bite - 5-_ 152524.doc •52- 201130854 6-(2-Fluoro-3_methoxyphenyl)_8_[2_Fluoryl_6_(trifluoromethyl) alkalyl]_ 7-methyl -3-{[(2-phenylpropan-2-yl)amino] fluorenyl}·2,3_dihydro_5 _ [1,3] sings β and [3,2_α]β ratio bite _5_keto 3-({4-[2-(didecylamino)ethyl]piperazine-ylindenyl)_6 (2Fluoro-3-phenyloxyphenyl)-8_[2- Fluoro-6-(trifluoromethyl)benzyl]-7-methyl_2,3·dihydro-5//-[1,3]thiazolo[3,2-α]pyrodo-5- Ketone 6-(2-fluoro-3-hydroxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzoinyl]-7 methyl-3-({4-[2-(? -4-yl)ethyl]decene n-methyl-l-yl}indenyl)_2,3_dihydro-5-[1,3]thiazolo[3,2-ίζ]pyridin-5-one 3- {[(Biphenyl-4-ylmethyl)amino]mercapto}_6_(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzene Base]_7_methyl_2 3_dihydro_5 good_ [1,3]嗟°[3,2-(2]〇 _5-_ 4- [4-({6-( 2-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzoinyl]-7-indolyl-5-yloxy-2,3-dihydro-5/ Ί-[1,3]thiazolo[3,2-α] ° than -3-yl}methyl) 唤 _ι_基]benzonitrile • 2-[4-G6_(2-Fluoro-3 _甲Oxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-5-yloxy-2,3-dihydro-5i/-[l,3 Thiazolo[3,2w] 0 is more than -3-yl} fluorenyl) n base _ι_yl] dimethyl ethanoamine 6-(2-fluoro-3-methoxyphenyl)-8 [2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2-(»-byridine-1-yl)ethyl]piperazine_1 _基}Methyl)_2.3-Dihydro-5//-[1,3] gar and [3,2- &lt;2]° ratio 5-- 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-A Base-3-({[3-(5-methyl-1//-carbazol-4-yl)propyl]amino}indenyl)_2.3-dihydro-1,3]嗟"» sit and [3,2-α] ° ratio bite-5-_ 152524.doc -53· 201130854 6-(2-fluoro-3-methoxybenyl)_8_[2-fluoro-6-(trifluoromethyl)benzene Methyl]_ 3-({[4-(1/Γ-imidazolyl)phenyl]amino}fyl)_7_methyl_2,3_dihydro_ 5/ί-[ 1,3]嗟·"Sit and [3,2-α] ° bite 5-keto 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl] _ 7-Methyl-3-({[(5-methylpyridazine-2-yl)indolyl]amino}methyl)_2,3 dihydro-5i/-[l,3]thiazolo[3 ,2-α]pyridin-5-one 6-(2-fluoro-3-methoxybenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3- [(quinolin-4-ylamino)methyl]_2,3_dihydro_5 good_[13]thiazolo[3,2-α]° ratio bite-5-branched I 6-(2-fluoro -3-methoxybenyl)_8_[2_fluoro &lt;_6-(Trifluoromethyl)benzyl]] 7-methyl-3-({mercapto[(ι-methyl-pyrazole-4-yl)indolyl]amino]indenyl) -2,3-dihydro-5 ugly-[1,3]thiazolo[3,2_β]pyroxyl-5-one 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_ 6 (trifluoromethyl)benzyl] 7-mercapto-3-{[(3-mercaptophenyl)amino]methyl} 2 3 dihydro _5// [13] 0 plug 0 Sit and [3,2-α]biting 唆-5-keto 3_{[phenylhydrazinyl(ethyl)amino]indenyl}_6·(2fluoro-3-methoxyphenyl)_ 8- [2- Fluoro-6-(difluoromethyl)benzoinyl]_7_methyl_2 3_dihydro_5 ugly [13] thiazolo[3,2-α]pyridine·5-one 3-({benzene Mercapto[2-(didecylamino)ethyl]amino}methyl)_6(2fluoro-3-methoxy-phenyl)-8-[2-fluoro-6-(trifluoromethyl) Awkward base]_7_mercapto-2,3_dihydro-5-[1,3]thiazolo[3,2·α]pyridine·5-ketofluoro-3-methoxyphenyl)_8_[2 _Fluoryl_6_(trifluoromethyl)benzyl]_ 3-[(isoquinolin-5-ylamino)indolyl]_7•indenyl_2 3 dihydro_5 ugly ["3] thiophene 0 Sit and [3,2-ί3] bite ·5_ketone 152524.doc S • 54 - 201130854 6-(2-Fluoro-3_methoxyphenyl)_8_[2-Fluoro-6-(trifluoromethyl) Phenylmethyl]_mercapto_3-({[4-(morpholine-4) _ yl)phenyl]amino}indenyl)_2,3_dihydro_5//_ [1,3]嗟 并[3,2- &lt;3]° ratio of 5-keto-6-(2-fluoro-3-methoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)benzyl]_ 3-({ [3-(1//-imidazole-i•yl)propyl]amino}indenyl)_7·methyl-2,3_dihydro-5open-[1,3]thiazolo[3,2· α]pyridine-5-one 3-{[(3,5-dimethoxybenzohydrazyl)amino] fluorenyl}_6_(2_fluoro_3-methoxy xyphenyl)_8·[2- Fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-2,3-dihydro-5i/-[l,3]thiazolo[3,2-α]pyridin-5-one 3 -[(4-Ethylpiperazine)i-methylmethyl6-(2-fluoro-3-indolylphenyl)-8-U-fluoro-6-(trifluoromethyl)benzyl]_7 _Methyl 2,3_dihydro·5//·[ι,3] 0 塞0 sits and [3,2·α]η ratio bites _5_ketone 6-(2-fluoro-3-oxime Phenyl))_8_[2- gas-6-(trifluoromethyl)benzyl]-3-[(isoindol-4-ylamino)methyl]_7-methyl-2,3-di Hydrogen-5//-[1,3] sighs β and sits [3,2-α]° than bite 5-keto-6-(2-disorder-3-methoxyphenyl)_8-[2 - Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(1-ptynyethyl)piperazine-1_yl]methyl}_2,3-dihydrogen _5//_ [1,3] sold and [3,2-α]° ratio bite-5-steel 6-(2_fluoro-3_methoxyphenyl)_8·[2·Fluor-6 -(trifluoromethyl)benzyl]- 7-mercapto-3-[({2-[3-(trifluoromethyl)phenyl]ethyl decyl) fluorenyl] 2,3-dihydro-5i/-[l,3] azole And [3,2-α]pyridin-5-one 3-({[4-(dimethylamino)butyl]amino}methyl)_6_(2_fluoro_3_methoxyphenyl) -8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/^-[1,3]thiaside[3,2- &lt;3]° ratio biting 5-ketone 152524.doc -55- 201130854 3-[(l,3 -benzo-pyrene-sodium-6-ylamino)methyl]-6-(2-fluoro- 3-methoxyphenyl)-8-[2-fluoro-6.(trifluoromethyl)benzoinyl]-7-fluorenyl-2,3-dihydro-5//--[1,3 ]嗟1»Sit and [3,2-(3]. than bite-5-keto 3-{[(2,5-dibenzophenyl)amino]] yl}-6-(2-fluoro- 3-decyloxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5ϋ/~ [1,3] Olfactory [3,2-α]° ratio bite 5-- 6-(2-fluoro-3-indolylphenyl)-8-[2_fluoro-6-(trifluoromethyl)benzyl ]_7-Methyl-3-{[(2-phenoxyethyl)amino]methyl}-2,3-dihydro-5-[1,3]thiazolo[3,2-α Pyridine-5-one 6-(2-fluoro-3-indolyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-( {曱[[((pyridin-3-yl)ethyl]amino}methyl)_2,3-dihydro-5//-[1,3]° plug '1 sits and [3,2 -(3]° than bite-5-_ 3-({[4-(dimethylamino)benzyl)amino}indenyl)_6_(2_fluoro_3_decyloxyphenyl)- 8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-2,3-dihydro-5//-[1,3]嗟°[3,2- &lt;2]° 唆-5-ketone#-{4-[({6-(2-fluoro-3-methoxyphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzophenone) ]]-7-methyl-5-sideoxy-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2_ &lt;3]° ratio -3-yl}methyl)amino]phenyl}methyl burned amine 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(three Fluoromethyl)benzoyl]_ 7-methyl-3-{[4·(sales benzo[3,2-d] 咬-4-yl)°底嗓-1_基]曱基卜2 ,3-dihydro-5i/-[l,3]thiazolo[3,2-α]pyridin-5-one 6-(2-fluoro-3-indolyloxyphenyl)_8_[2_fluoro_6_ (Trifluoromethyl) benzyl] 7-mercapto-3-{[4-(2- phenoxyethyl)piperazine 丨 基 yl] methyl b 2 3_ dihydro _ 5// -[1,3] sold "Sit and [3,2-"]. Bite 5-ketone 152524.doc S -56· 201130854 6-(2-Fluoro-3-methoxyphenyl)_8-[ 2-_Fluoro_6_(trifluoromethyl)phenylindenyl]-7-fluorenyl-3-{[4-(phenylcarbonyl)piperazin-1-yl]methyl}_2,3_dihydro-5 _ [1,3]thiazolo[3,2-α]pyridin-5-one 4-({6-(2·fluoro-3-indolyloxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)phenylhydrazino]-7-fluorenyl-5-sideoxy-2,3·dihydro-5 ugly-[1,3]thiazolo[3,2-α]吼 bit-3 -基}曱基)-#,#-Dimethylpiperazine-ΐ-carbamamine 3-({[2-(4-phenylhydrazinopiperidinyl)ethyl]amino}methyl)_6_ (2_gas_φ 3-methoxyphenyl)_8-[2-fluoro-6.(trifluoromethyl)benzyl]-7-methyl-2,3- Hydrogen, 3]«&gt; stopper, sit and [3,2-a]^b bite-5-_ 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (Trifluoromethyl)phenylhydrazino]-7-fluorenyl-3-{[4-(pyrrolidin-1-ylcarbonyl)piperazine·buki]methyl b 2 3_dihydro-5--[ 1,3]. Plug "sit and [3,2-〇] ° than the mouth -5-keto 6-(2-fluoro-3-methoxyoxyphenyl)-8-[2-fluoro-6- (three Fluorinyl)benzyl]-7-mercapto-3-({[2-(3-methylphenyl)ethyl]amino}methyl)_23·dihydro-5/f-[l, 3]°嗤嗤[3,2-α]π ratio biting-5-ketoφ 3 _({[2-(dimethylamino)phenyl)]amino}methyl)-6-(2 -gas-3-methoxyphenyl)-8-[2-say-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5-[1,3 Thiazolo[3,2-α]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] -7-mercapto-3-{[decyl(pyridin-4-yl)amino]indolyl)-2,3-dihydro-5//-[1,3] mouth and [3,2- α]«比咬-5-keto 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(different Salicyl-8-ylamino)indolyl]-7-mercapto-2,3-dihydro,3]-thazolo[3,2-α]pyridin-5-one S 152524.doc -57- 201130854 4-({6-(2- -3-decyloxyphenyltrifluoromethyl)phenylhydrazinyl]-7-methyl-5-yloxy-2,3-dihydro-5/ί-[1,3]pyrene[3 , 2-α] 〇 is more than -3-yl} fluorenyl)-1-(2-phenylethyl) chen. Qin-2,6-dione 6-(2-fluoro-3-methoxyphenyl)_8_[2_say-6-(trifluoromethyl)benzyl]-7-methyl-3-{ [(2-Mercapto-1,3- benzothiazol-5-yl)amino] fluorenyl}·2,3_ dihydro-5 ugly-[1,3]thiazolo[3,2-α]pyridine -5-keto 2-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-oxime 5-O-oxy-2,3-dihydro-57/-[1,3]thiazolo[3,2-α]pyridin-3-yl}methyl)piperazine-oxime-based]_# -(2-phenylethyl)acetamide 6-(2-fluoro-3-methoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)phenylindenyl]-7-fluorenyl -3-({[(1-methyl·ι//_ carbazole _5_yl) fluorenyl]amino) fluorenyl) 2,3_ dihydro-5 ugly-[1,3]thiazolo[3 ,2-α]pyridine-5-one 6-(2-fluoro-3-indolyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3- ({曱基[(1_曱基-丨开·吼azole_3_yl)methyl]amino} fluorenyl)-2,3-·一气-5// [1,3]π塞t» Sit and [3,2- &lt;3]° ratio bite-5-嗣. 6-(2-Fluoro-3-methoxyphenyl)&gt;8_[2-fluoro-6-(trifluoromethyl)benzoinyl]-7- Base-3-{[(l/f-pyrazole-3-ylmethyl)amino]methyl}-2,3-dihydro-5//-[1,3] sigh and sit [3, 2-〇]° ratio bite_5-keto 6-(2-fluoro-3-indolyl phenyl fluoride-6-(trifluoromethyl)benzoinyl]-7-methyl-3-{[4 · (3-Phenylpropyl)piperazin-1-yl]methyl}-2,3-dihydro[1,3]pyrene[3,2-α]° than 唆-5-one 6- (2·fluoro-3-methoxyphenyl)_8_[2·fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(4-mercapto) Pyrazin-1-yl)ethyl]amino}mercapto)-2,3-dihydro-5-[1,3]thiazolo[3,2-α]pyridin-5-one 152524.doc S - 58- 201130854 3-{[4-({6-(2-Fluoro-3·methoxyphenyl)·8·[2_fluoro-6(trifluoromethyl)benzyl]-7-methyl -5-Sideoxy-2,3-dihydro-5-[1,3]thiazolo[3,2-bipyridin-3-yl}methyl)piperazin-1-yl]fyl}benzene 3-carbonitrile 3-{[(3,5-dimethoxymethyl)(methyl)amino]methyl}6(2fluoro-3-yloxyphenyl)-8-[2·fluoro-6 -(Trifluoromethyl)benzyl]]7-mercapto-2,3_diindole-5/f-[l,3]« sputum and [3,2-α]β ratio bite _5-keto 6_ (2_Fluor_3_methoxybenzene -8-[2-Fluoro-6-(trifluoromethyl)benzyl]-φ 7-mercapto-3-(indolyl 2)(2-indolyl)ethyl]amino}methyl) _23_Dihydro·5//-[1,3]°Sawa and [3,2-α] ton bit-5-keto 6-(2-fluoro-3-methoxyphenyl)_8_[2_ Fluorine_6·(trifluoromethyl)benzyl]] 7-fluorenyl-3-[(pyridazine-3-ylamino)indolyl]·2,3·dihydro-thiazolo[3,2 -α]bite·5-keto 6 (2-gas-3-anthraceneoxy)_8_[2_fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-3-{[( Thiophene _3_ylmethyl)amino]methyl}_2,3_dihydro_5//· [1,3] sigh "Sit and [3,2-〇]° bite 5-ketone # 6 -(2-fluoro-3-indolylphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl]-7-indolyl-3·({4-[2-(pyridine-4) -yl)ethyl]piperazine-l-yl}methyl)-2,3-diin-5-[1,3]thiazolo[3,2-α]pyridin-5-one 3-{[ 4-(biphenyl-3-yl)piperazine_ι_yl]methyl}-6-(2-fluoro-3-indolylphenyl)-8-[2-fluoro-6-(trifluoromethyl) Phenylhydrazino]_7_mercapto-2,3-dihydro-5//-[1,3]° stoppered [3,2- &lt;3]. Than 5-keto 6-(2-fluoro-3-indolylphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzyl]_ 3-{[4-(3-曱Oxypropyl) piperazine q•yl]methyl}_7_methyl-2,3_dihydro-5//-[1,3]thiaside[3, than bite_5·ketone 152524.doc -59- 201130854 6-(2-Fluoro-3.methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4 -(»Bipyridin-3-ylmethyl)piperazin-1-yl]methyl b 2,3-dihydro-5 ugly-[1,3] 嗟 并 [3,2-α]β ratio bite -5-_ 6-(2-Fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4 -[(l-methylpiperidin-3-yl)indolyl]piperazine-i-yl}methyl)-2.3-dihydro-5孖-[1,3]thiazolo[3,2-α] Pyridine-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-mercapto-3-({ 4-[(l-methylpiperidin-4-yl)indolyl]piperazine_1-yl}methyl)-2.3-dihydro-5//-[1,3]° 塞 并 [3, 2- &lt;2]&quot;Bite-5-keto 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- Methyl-3-({4-[2-(trifluoromethyl)phenyl)piperazine-bupyridinylmethyl)_2,3_dihydro-5//~[1,3] sigh and [ 3,2-α]β ratio bite-5-嗣6-(2-fluoro-3-indolyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7 - mercapto-3-({[(l-methylpyrazole-4-yl)methyl]amino}methyl)_23_dihydro-5//-[1,3]° stopper. Sit and [3,2-〇]° than 唆-5-_ 6-(2-fluoro-3-methoxyphenyl)-8_[2_fluoro_6_(trifluoromethyl)benzoinyl]_ 7-Methyl-3-{[methyl(naphthalen-2-ylmethyl)amino]methyl b 2,3_dihydro_5 ugly _ [1,3]°°°°[3,2 -α]β is more than 5--3⁄4 cyclopropyl-2-[4-({6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)) Methyl]-7-fluorenyl-5-sideoxy-2,3_dihydro-5i/-[l,3] sigh. Sodium [3,2-α]pyridin-3-yl}methyl) Piperazine·buki]acetamide 6-(2-fluoro-3-methoxyphenyl)_8-[2·fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-3 -({曱[2-(pyrrolidinyl]-yl)ethyl]amino}methyl)_2,3_dihydro-5//-[ 1,3] oxime [3,2-α ]&quot;Bite_5_ketone 152524.doc,6〇, S 201130854 3·({[2-(4-Ethylpiperazine)-ethyl)amino}methyl)-6-( 2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5β-[1, 3]thiazolo[3,2-α]pyridine-5-one #-(3-{[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-) (trifluoromethyl) benzyl]-7-methyl-5-oxooxy-2,3-dihydro-5/ί-[1,3]thiazolo[3,2-pyridin-3- Base} methyl) Ethyl]methyl}phenyl)acetamide 6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)methyl]-7-fluorenyl-3 -({methyl[2-(4-methylpiperidin-1-yl)ethyl]amino}methyl)_2.3-dihydro-5//-[1,3]嗟嗤[3, 2-£1]° ratio bit-5-keto 8-(2,6-difluoro-benzyl)-6-iodo-7-methyl_3-{[methyl-(2-pyridin-2-yl) -ethyl)-amino]methyl}-2,3-dihydro-thiazolo[3,2_α]pyridine-5-one 6-(3- gas-phenyl)-8-(2,6-di Fluoro-phenylmethyl)_7_methyl_3_([methyl-(2-n-bipyridin-2-yl-ethyl)-amino]-indenyl}_2 3_dihydrothiazolo[3 2_α] ° ratio biting-5-keto 6-stupid [1,3] dioxolane-5_yl_8·(2,6-difluoro-stupyl)-7-methyl-3- {[曱基-(2-η比丁_2_基·ethyl)·aminomethyl b.2.3-diaza-嗔°[3,2-(2]° ratio bite-5-class { 37?-[3〇1(and*)]}-3-(Amino-phenyl-methyl)_8_(2,6-difluoro-stylmethyl)-6-(2-fluoro-3-A Oxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2 - λ]β ratio bite-5 -copper {3孓[3α(Λ*)] }-3-( Amino-phenyl-methyl)_8_(2,6-difluoro-mupcapto)-6-(2-fluoro-3-indolyloxyphenyl)-7-methyl·2,3_2 -thiazolo[3,2-〇]° ratio bit-5-keto {3 and -[3 W)]}-3-(amino-styl-methyl)·8_(2 6_difluoro 152524.doc • 61 · 201130854 base)-6-(2-fluoro-3-methoxyphenyl)_7-methyl-2,3-dihydro-thiazolo[3,2 - a ] ° ratio - 5 - ah {3义[3〇^*)]}-3-(Amino-phenyl-methyl)-8·(2,6-di-phenyl-phenyl)-6-(2-fluoro- 3-decyloxy-styl)_7-methyl-2,3-dihydro-oxazolo[3,2-α]° ratio bite-5-net [3α(π*)]-3-[amine -(4-Fluoro-phenyl)-indenyl]_8_(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2 , 3_Dihydro-thiazolo[3,2-β]π ratio bit-5-keto[3α(π)]-3-[amino-(4-fluoro-phenyl)-indenyl]·8_( 2,6-Difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydrothiazolo[3,2-α]° ratio Bite-5-net [3α(Λ*)]-3·[Amino-(4-methoxyphenyl)-methyl]_8_(2,6-difluoro-phenylmethyl)-6-( 2-fluoro-3,methoxy-phenyl)_7-methyl-2,3-dihydro-thiazolo[3,2-α]° ratio -5-3⁄4 [3a〇S*)]-3 ·[Amino-(4-methoxy-phenyl)-methyl]·8(26 dioxo-benzyl) winter (2-fluoro-3-methoxy-phenyl)_7·methyl_ 2,3 - dihydro- _ oxazole [3,2- &lt;2]d ratio bit-5-keto[3a(巧]-3-[amino-(4-trifluoromethoxy-phenyl)methyl"(Μ·difluoro-benzyl)-6 -(2-(3)-methoxyl-phenyl)_7_f-based 2,3_two-gas 嗟 嗟 并[3,2-a] «Because bite _5_ketone [^] -3-[ Amino-(4-trifluoromethoxy-phenyl)-methyl^•__difluoro-benzyl)-6-(2-fluoro-3.methoxy-phenyl)·7_A Base 2,3_dihydro- 嗟0 sits and [3,2-β]η ratio bites 5--' ' 3-(aminophenyl)-(2,6-difluoro-benzoic acid) Base) 仰气·3•甲152524.doc •62· 201130854 oxy-stupyl)-2,2,7-trimethyl-2,3-dihydro-indole and [3,2-£7 ] &lt;1 ratio biting_ 5-ketone {3/?-[3α(Λ*)]}-3-(amino-phenyl-indenyl)-6-(2-fluoro-3-indolyl_benzene -8-(2-fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-indenyl[3,2-α]β ratio bite-5 -_ {3 &lt;5-[3〇1(;?*)]}_3-(Amino-phenylindenyl)·6·(2-Fluoro-3_decyloxyphenyl)-8-(2-fluoro -6-Trifluoro 1 fluorenyl-benzyl)-7-fluorenyl-2,3-dihydro-嗟u sits [3,2-α]. Than 5-ketone {3i?-[3a(S*)]}-3-(Amino-phenyl-methyl)-6-(2-fluoro-3-indolyl_phenyl)-8 -(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-2,3-dihydro-indole[3,2-a]pyridin-5-one pS-PaOS *)] }-3-(Amino-phenyl-methyl)-6-(2-fluoro-3-methoxyphenyl)-8-(2-fluoro-6-trifluorodecyl-benzene Methyl)-7-fluorenyl-2,3-dihydrogen plug. Sit and [3,2-α]pyridine-5-one [3a(i?*)]-3-[amino-(4-fluoro-phenyl)-methyl]-6-(2-1^ 3-methoxyphenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro·· violates β and [3,2 -α]° than bite-5-嗣[3a(iS*)]-3-[amino-(4-fluoro-phenyl)-indenyl]-6-(2-fluoro-3-indolyl) Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydro-indole. Sit and [3,2-α]β ratio bite-5-嗣[3a〇R*)]-3-[amino-(4-trifluoromethoxyphenyl)-fluorenyl]-heart (7) fluoro^ 3-decyloxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-adenyl)_7-fluorenyl-2,3-dihydro-thiazolo[3,2-a]pyridine_ 5-ketone [3〇^*)]-3-[Amino-(4trifluoromethoxyphenyl)-methyl]·6_(2_^· 152524.doc -63- 201130854 3-:oxy -phenyl)·8_(2_fluoro·6_trifluorof-benzylmethylhydrazine) a wind 嗟β sits and [3,2-α]η ratio bites _5-ketoamine [(3⁄4) benzene Base]f base}·6·(2Fluoro-3 methoxyphenyl)-fluorene 2-fluoro-6-(trimethyl)benzyl]7-methyl·2,3_digas [1,3] sigh. Sit and [3,2- &lt;2] 吼唆_5-keto 6-(2-fluoro-3-methoxyphenyl)|(2-fluorodongtrifluoromethylbenzyl)_ 3-(furan-2-yl-iso Propylamino-mercapto)_7_methyl_23 dihydrothiazolo[3,2-α]° bite 5-keto [3α(Λ*)]-3-(amino-phenyl-methyl Base)_6_(2_chloro_5trifluoromethoxy-phenyl)-8-(2-|1-6-trifluoromethylphenyl)_7-fluorenyl·2,3·:hydrogen_mouth Azolo[3,2- &lt;2]° ratio bit-5-keto[3a(*S*)]-3-(amino group·styl-fluorenyl)_6_(2_chloro-5 pentafluoro-phenyl)-8 -(2-Fluoro-6-trifluoromethyl·phenylmethyl)·7-methyl-2,3-dihydro-thiazolo[3,2-α]. Specific bite-5-keto [3α(Λ*)]-3-(amino-phenyl-methyl)_6_(2_fluoro_„biidine_3 base)8_(2·Fluoro-6-difluoromethyl -Benzyl hydrazino)·7-methyl-2,3-dihydro-thiazolo[3,2_α] D is more than 唆-5-one [301(5^)1-3-(amino-stupyl- Methyl)_6-(2_fluoro_0biidine_3_yl)_8_(2_fluoro-6-trifluoromethyl-benzoinyl)_7-methyl-2,3-dihydro-thiazolo[3, 2 0 than bite-5-keto [3α(Λ*)]-3·(amino-phenyl-methyl)_8-(2-fluoro-6-trifluoromethyl-stupylmethyl)-7- -6-(3-trifluoromethoxyphenyl)_2,3-dihydro-indole. Sit and [3,2_α]β is more than 唆5-ketone [3a( &lt;S*)]-3-(Amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-alum 152524.doc •64·201130854)-7-methyl -6-(3-trifluorodecyloxy-phenyl)-2,3-dihydro-sold*sand[3,2·α]〇 ratio bite 5-- [3α(/?*)]- 3-(Amino-phenyl-methyl)-6-(2-fluoro-5-decyloxyphenyl)-8-(2-^-6-trifluoromethyl·phenylmethyl)-7 -Methyl-2,3-dihydro-sigh, and [3,2-α]acridin-5-one [3a〇S*)]-3·(Amino-phenyl-indenyl)-6 -(2-fluoro-5.methoxy-phenyl)· 8-(2-fluoro-6-trifluoromethyl-phenylfyl)·7-methyl-2,3-dihydro-thiazolo[ 3,2-a]° than biting 5-ketone {3i?-[3a(i?*)]}-3-(amino-styl-methyl)-6-(4-fluoro·stup [ 13] m-dioxolan-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzoquinone tomb)_7_mercapto-2,3-dihydro-sale" 3,2-a]° than bite-5-keto {3 51-[3 α(Λ*)]}-3-(amino-phenyl-fluorenyl)-6-(4-fluoro-benzo[ 1 3] m-oxocyclo-5-yl)-8-(2-fluoro-6-trifluoromethyl·stupylmethyl)methyl-2,3-dihydro-嗟η sits [3 ,2-a]»比比-5-ketone {3^[3α(π)]}-3·(amino-phenyl-methyl)·6·(4_fluorobenzo[13]dioxan Cyclopentene-5-yl)-8 -(2-fluoro-6-trifluoromethyl-adenyl)-7-yl- 2,3-dihydro-sigh "» sit and [3,2-a]D than bite-5-ketone {3 ^[3α(π)]}_3·(Amino-phenyl-indenyl)_6_(4fluorobenzo[13]m-oxo-5-yl)-8-(2-gas-6 -trimethylsulfonyl-phenylmethyl)_7_mercapto-2,3-dihydro-thiazolo[3,2_a]pyridine-5-one [3a(and)]-3-(amino-styl- Methyl)_6-(2,2-difluoro-benzo[i,3]dioxol-5-yl)-8-(2-fluoro-6-trifluorodecyl-stupylmethyl )_7_mercapto-2,3-dihydro-indole[3,2-a]» than bite-5-one [3a(«S)]·3-(amino-stupyl-fluorenyl) _6_(2,2_Difluoro cumin [^3] S 152524.doc 201130854 dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazine)- 7_曱基-2,3 - 二风-嗟β坐弁[3,2 - &lt;3 ] ° ratio biting -5 -嗣3-[amino-(2-a-3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6 -(2-Dun-3-methoxy-phenyl)-7-methyl-2,3-di-r-O-plug. Sitting well [3,2-α] ° than biting 5-keto [3oc(i?*)]-3-(amino-m-phenylphenyl-fluorenyl)-8-(2,6-difluoro- Benzyl)-6-(2-fluoro-3-indolyl-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]°lt bite-5-one [3〇1(5&gt;*)]-3-(Amino-m-tolyl-methyl)-8-(2,6-difluoro-benzoinyl)-6-(2-^-3-曱Oxy-phenyl)-7-methyl-2,3-diaza plug. Sitting 弁 [3,2- &lt;3]° ratio 5-ketone 3-(aminosept-3-yl-fluorenyl)-8-(2,6-di-phenylphenyl)-6-(2-disorganized-3 _甲乳基_Phenyl)-7-Methyl_ 2,3 -Dinitro-violation of 弁[3,2 - a ] 0 than bite-5 -嗣[3a〇R*)]-3-[ Amino-(3-fluoro-phenyl)-indolyl]-8-(2,6-difluoro-benzyl)-6-(2-a-3-methoxy-phenyl)-7- Methyl-2,3- diazepine 0 sits and [3,2-a]. Specific bite-5-keto[3α(5·*)]-3-[amino-(3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6 -(2-ox-3-oxooxy-phenyl)-7-methyl-2,3-diaza-sales[3,2-a]° than bite-5-ketone [3a(i ?*)]-3-[Amino-(5-methyl-thiazol-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro- 3-decyloxy-phenyl)-7-mercapto-2,3-dihydro-thiazolidine[3,2-α]° ratio biting 5-keto [3〇1(1^*)] -3-[Amino-(5-fluorenyl-thiazol-2-yl)-methyl]-8-(2,6-difluoro-phenylhydrazino)-6-(2-fluoro-3-oxime Base-phenyl)-7-mercapto-2,3-dihydro-thio 152524.doc -66- 201130854 °Sit and [3,2-α] 唆_5__ [3α(Λ*)]-3- [Amino-(3-fluoropyridin-2-yl)-methyl J-8-(2,6-difluoro-benzyl)-6-(2-fluoro.1 2 3 -decyloxy-benzene Methyl-2,1_dihydrothiazolo[3,2-α]pyridine_5·ketone[3a〇S*)]-3_[amino-(3_fluoro-pyridin-2-yl)methyl ]_8_(2 6•Difluoro-benzyl)-6-(2-fluoro_3_methoxy-phenyl)_7_fyl-2,3-dihydro-thiazolo[3,2-a]pyridine ketone 3-(Amino-benzo[b]thiophene-3-yl-methyl)_8_(2 6 difluorobenzyl)_(2fluoro-3-decyloxy-benyl)_7-methyl-2,3 _Dihydro-oxo-[3,2·α]pyridin-5-one 3-[amino(phenyl)indenyl]_6_(2_fluoro_3_indolyloxyphenyl)-8 [2 Gas-^(trifluoromethyl)benzyl;|-7_methyl_2,3_dihydro·5//_π,3]嗟η sits and ma]pyridin-5-one 1-oxide [3咐*)]-3-(Amino-phenyl-methyl)_8_(2_Fluoro-6•trifluoromethylbenzyl)-6·颂-7-methyl-2,3·2 Hydrogen "plug and saliva [3,2 · bite _5_嗣[3α(巧卜3-(amino-phenyl. fluorenyl)_8_(2•fluorotrifluoromethyl)H7_methyl_ 2'3_Dihydro·(4) and [3,2_Bite·5_嗣3_(Amino-phenyl-methyl)-8_(2,4 5-difluoro-benzyl)-6-iodine -7·Methyl 2,3-dihydrohydrazide[3,2a] η ratio. _5_ketone 152524.doc •67- 1 -(Amino-phenyl-methyl oxime, 4·2 Gas·benzyl)-7-methyl(1)-2-phen-2-yl-2,3-dihydro-thiazolo[3,2_a]〇th pyridine-5·_ 3 3-(amino-phenyl-曱))-6_(5_chloro- sin. 2 base) 8_(2,6 di-gas 4 fluorenyl)-7-mercapto-2,3-diaza + sito[3,2_α]ηbipyridine -5__ 5 3-(Amino-phenylmethyl)-6_(3 _气·笨基)8_(2 6-Difluoro 甲甲 201130854 基)-7·曱基_2,3·Dihydro-嗟 并[3 2_ 啶 _ 5 5 ketone 3 _ (amino-phenyl -曱基)_6·(6.Gas "thans bite_2 base-like-diqi-stupylmethyl)-7-mercapto-2m sit-[3,2_ lysyl-5-one 3_(amino group -Phenyl.methyl)_8•(Anodic phenylene)·6 servomethoxy-pyridin-3-yl)-7-methyl-2,3-dihydro-oroxazole Acridine_5, soil 3-(amino-phenyl.methyl)_8_(2_gas_6_trifluoromethylbenzyl)_methoxy-...-yl)-7-methyl-2, 3_Dihydro-.塞和和[3,2物_ 5-ketoamino-phenyl-methyl)-8-(2_气_6_三imethyl-benzyl)6_(6_methoxy-terminal 2- Base)··································································· Methyl·benzyl)-7-methyl-2,3_digas _. plug. Sit and [3,2·small ratio. 3 -(aminophenyl)methyl)-M2_ Gas I 曱 oxy _ phenyl) _ 8 _ (2 _ _ 6 fluoroquinone basic methyl) _ 7 - methyl - 2, 3 dihydro sulphide [Ha]. Than the bite -5--methoxyphenyl)_ '-gas·π plug and [3α(Λ*)]-3-(amino-p-styl-methyl) 6(2-chloro-8-(2) -fluoro-6-trifluoromethyl-benzyl)-7-methyl-2 [3,2-a]pyridin-5-one [3α(5**)]·3-(Amino-stupyl· Methyl)·6·(2_chloro·3methoxy·phenylene)_ 8-(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl·2,3-dihydrothiazole And [3,2·α]pyridin-5-one 3-(amino-phenyl-methyl)benzo[1,3]dioxine $8-(2-fluoro-6-three Fluoromethyl-benzyl)-7-methyl-2, indole dihydrothiazolidine 152524.doc -68 · 201130854 [3,2-α]pyridin-5-one [3a(i?*)]- 3-(Amino-phenyl-methyl)_6_(2-fluoro-3-(nonyl-6-trifluoromethyl-benzoinyl)-7-methyl·2,3- Dihydrothiazolo[3,2_a]0 is more than 5--[3α(π)]_3-(amino-phenyl.methyl)_6_(2_fluoro_3_methyl_phenyl) ;8·(2-Fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydro-thiazolo[32_β] 0 ratio biting-5-keto 3-(amino group -phenyl-indenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(2-fluoro-3-trifluoromethyl-phenyl)-7-methyl-2,3 ·Dihydro-thiazolo[3,2·β]pyridine-5-one 3-(amino- -methyl)-6-(2-chloro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dioxime-thiazolo[ 3 2_a]pyridine_5-keto 3-(amino-phenyl-indenyl)-6-(3-chloro-phenyl)_8_(2_fluoro-6-trifluoromethyl-stupyl)-7 -Methyl-2,3-dihydro-thiazolo[3,2-a]n ratio bite_5-keto[3αβ*)]-3-[3-(amino-phenyl-fluorenyl)_8_( 2_Fluoro-6-trifluoromethyl_phenylhydrazino)-7-methyl-5-oxirane-2,3·dihydro·5//·thiazolo[3,2_〇]pyridine bite- 6-yl]-2-fluoro·cracked nitrile [3a〇S*)]-3-[3-(amino-phenyl-fluorenyl)_8_(2_fluoro-6-trifluoromethyl)-benzoic acid Benzyl)-7-methyl-5-o-oxy-2,3-dihydro-5//-thiazolo[3,2_s0-pyridin-6-yl]_2·fluoro-benzoquinonitrile 3- (amino-phenyl-fluorenyl)-8-(2-fluoro-6-trifluoromethyl-p-methyl)_7-methyl-6-thiophen-2-yl-2,3-dihydro-thiazole [3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)_8-(2-fluoro-6-trifluoromethyl-stanomethyl)7-ylyl_6_(5·曱-thiophen-2-yl)-2,3-dihydro-thiazolo[3,2·α]pyridine·152524.doc -69- 201130854 5-keto 3-(amino-phenyl-indenyl)_6_ (5-chloro-thiophen-2-yl)-8-(2-fluoro-6(trifluoromethyl-benzyl)-7-methyl- 2,3-Dihydro-thiazolo[3,2-α]pyridone 3-(amino-phenyl-indenyl)-6-(3-chloro-indol-2-yl)-8-(2 -^ -6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one [3α(Λ*)]-3 [Amino (phenyl) (2 fluorene) fluorenyl]-8-(2,6-difluoro cumyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-2 ,3_Dihydro-5-[1,3]thiazolo[3,2-α]&quot;Bite-5-keto[3α(Ρ)]·3-[Amino(phenyl)(2η) Methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro-5//-[ 1,3]thiazolo[3,2-α]pyridin-5-one [3α(/?*)]-3-[amino(phenyl)(2η)methyl]-6-(2-fluoro- 3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl-2,3-dihydro- 5 good_[1,3]* . Sit and [3,2-"]° bite -5-阙[3αθ*)]"-[Amino (phenyl)(2h)methyl]-6-(2-fluoro-3-methoxybenzene Base)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyl-2,3 dihydro-_5 ugly [1,3] sigh "Sit and [3,2- ]]° ratio bite 5-- 3-(1-amino-1-phenyl-ethyl)_6_(2-fluoro-3-methoxyphenyl&gt;8_(2_fluoro-6·trifluoromethyl) -benzyl)7-mercapto-2,3-dihydro-thiazolo[3,2·α]pyridin-5-one 3-(1-amino-1-phenyl-butenyl)_6_( 2fluoro·3methoxy-phenyl b- 8-(2-fluoro-6-trifluoromethyl·benzoinyl)&gt;7•methyl·2,3•dihydro-thiazolo[3,2-α .. than bite -5-嗣{3 called 3〇^*)]}_3_(amino-phenyl-methyl) winter [3 (ιι二气乙152524.doc 70· 201130854 基)-phenyl]- 8-(2-Fluoro-6·trifluoromethyl-m-methyl)methyl-2,3•dihydro-pyrazole[3,2-α]» than bite-5-one {3孓[3 (1(/?*)]}-3-(Amino-phenyl-methyl)_6_[3_(11-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoro曱基-曱曱基)methyl·2 3_dihydro 0. Sit and [3,2-&lt;3]% bite 5-ketone {3 and -[3ot〇S*)]}-3· (Amino-phenylindenyl)·6_[3·(11 •Difluoro-ethyl)-phenyl]-8_(2-Fluoro-6- Fluorinyl-benzyl)·7_mercapto_2,3·dihydro- φ 嗟嗤[3,2-α]» than bite-5-ketoamino-phenyl-methyl)_6_[ 3_(1,difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-adenyl)_7-methyl-2,3-dihydro- 0 And [3,2-α]. Bite-5-_ {3 and -[3〇^*)]}-4-({[6-(2-fluoro-3-曱-oxy-phenyl)_8_ (2_Fluor_6_disorder methyl-present methyl)-7-methyl-5-sideoxy-2,3-dihydro-5 ° plug β sit and [3,2-λ]0 bite -3-yl]-benyl-methyl-amino)-butyric acid acetonitrile {3][3α(/?*)]}-4-({[6-(2-fluoro-3-methoxy) -phenyl)-8-(2-fluoro-6-di-methyl-n-decyl)-7-indolyl-5-yloxy-2,3-dihydro-5 //-α-sa-[ 3,2-α]«Bistidin-3-yl]-phenyl-methyl}•Aminobutyric acid ethyl ester {37^301(5^)^-4-0 [6-(2-Fluoro-3) -Methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-p-methyl)-7-indolyl-5-yloxy-2,3-dihydro-5/f- Thiazolo[3,2-α]&quot;bipyridin-3-yl]-phenyl-decylamino)butyric acid {3S-[3a(V)]}-4-({[6 -(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-indolyl-5-sideoxy-2,3- Dihydro-5i/-thiazolo[3,2-α]pyridine-3- Ethyl p-butyrate ethyl ester ({[6-(2-fluoro-3-decyloxy-phenyl)-8-(2-fluoro-6-trifluorodecyl) -benzoquinone 152524.doc -71 · 201130854 base)-7-methyl_5·sideoxy-2,3-dihydro-5/oxathiazolo[3,2-α]pyridine_3_yl]-benzene Ethyl-fluorenyl}-amino)-ethyl acetate 3-({[6-(2-fluoro-3-methyl-kilo-phenyl)-8-(2-fluoro-6-trifluoro)-yl- Phenylhydrazinyl)-7-methyl-5-oxooxy-2,3-dihydro-5F-thiazolo[3,2-«]pyridine-3-yl]]phenyl-indenyl}-amino )-ethyl propionate 4-({[6-(4-fluoro-benzo[u]dioxol-5_yl)_8_(2fluoro-6-trifluorodecyl-benzoinyl) )_7_mercapto-5-sideoxy-2,3-dihydro·5//-thiazolo[3,2-α]ηpyridin-3-yl]-phenyl-methyl}-amino group )-ethyl butyrate 5-({[6-(2-fluoro-3-methoxy-benyl)-8-(2-gas-6-tris-methyl-benzyl)-7-oxime) 5-yloxy-2,3-dihydro-5//-thiazolo[3,2-α]pyr. _3_yl]-phenyl-methyl}-amino)-pentanoic acid ethyl ester 4-({[6-(2-fluoro-5-decyloxy-phenyl)-8-(2-fluoro-) 6-trimethylmethyl-phenylhydrazino)-7-methyl-5-oxooxy-2,3·dihydro-5 ugly-thiazolo[3,2-α]pyroxyl_3_ ·yl]- Phenyl-methyl}-amino)-butyric acid ethyl 4-({[8-(2.fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- pendantoxy group _ 6_(3-Trifluoromethoxy-phenyl)-2,3-dihydro-5 ugly-thiazolo[3,2-α]pyridine-3(yl)-phenyl-methyl}-amino) _ ethyl butyrate {3i?-[3a(i?*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-) Trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a].pyridin-3-yl]-phenyl- Methyl}-amino)-butyric acid {3][3〇1(/?*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-( 2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5 ugly thiazolo[3,2-ap-pyridin-3- ]]-phenyl-methyl}-amino)-butyric acid {3i?-[3a〇S*)]}-4-({[6-(2·fluoro-3-methoxy-phenyl)) 8-(2-fluoro-6- ' 152524.doc • 72· 201130854 difluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5 ugly-thiazole And [3,2-α]0 ratio -3-yl]-phenyl-methyl-amino-)butyric acid {35^3a(5·*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl) -8-(2-Fluoro-6-difluoromethyl-m-methyl)-7-indolyl-5. oxo-2,3-dihydro-5 ugly-thiazolo[3,2-α ]pyridin-3-yl]-styl-methyl}-amino)-butyric acid ({[6-(2-fluoro-3-indolyloxy)phenyl)_8_(2_fluoro_6_trifluoro Methyl-benzyl)-7-fluorenyl-5- side fluorenyl 2,3_dihydro-5//-thiazolo[3,2α]pyridine_3_yl]-phenyl-fluorenyl} -amino)-acetic acid 3-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl- 5-Sideoxy·2,3·Dihydro-5-thiazo[3,2_β]pyridine·3_yl]-benyl-methyl-amino)-propionic acid 4- ({[6·(4 -Fluoro-benzodioxole_5_yl)_8·(2•Fluor-6-difluoroindolyl- alum)-7-methyl-5-sideoxy-2,3- Dihydro-5if-indazolo[3,2~p-pyridin-3-yl]-phenyl-indolyl)-butyric acid 5-({[6-(2-fluoro-3-methoxy) -Phenyl)_8_(2_Fluoro-6(trifluoromethyl)-benzyl)-7-methyl-5- side fluorenyl 2,3_dihydro·5πthiazolo[3,2_β]pyridine _3_yl]-phenyl-methyl}-amino)-pentanoic acid 4-({[6-(2-fluoro-5-decyloxy)phenyl)_8 _(2_Fluoro.6•Trifluoromethyl group·stupylmethyl)-7-fluorenyl_5_sideoxy-2,3-dihydro_5 ugly-thiazolo[3,2_small pyridine] 3_基]•Phenyl-methyl}•Amino)-butyric acid 4-({[Μ2-Fluoro-6-tri-Iinyl- alum)-7•indenyl·5·sideoxy_6_ ( 3-difluoromethoxy-styl)_2,3-dihydro-5 open-thiazolo[3,2_α]pyridine·3·yl]-phenyl-methyl}-amino)-butyric acid {3Λ_ [3α(Λ*)]}_4_{[{6_(2_fluoro·3_methoxyphenyl)-8-[2-fluoro-6- 152524.doc -73- 201130854 (trifluoromethyl)benzyl ]_7·Indolyl-5-sideoxy-2,3-dihydro-5i/-[l,3]thiazolo[3,2-α]pyridin-3-yl}(stupyl)indolyl]amine Sodium butyrate {3 heart [3〇1 (and *)]}-4-{[{6-(2-fluoro-3-indolyloxyphenyl)-8-[2-fluoro-6-( Trifluoromethyl) adenyl]-7-fluorenyl-5-sideoxy-2,3-dihydro-5 if-[1,3]thiazolo[3,2-α]pyridin-3-yl }(phenyl)methyl]amino} sodium butyrate {3i?-[3a(S*)]}-4-{[{6-(2-fluoro-3-methoxyphenyl)-8- [2-Fluoro-6-(trifluoromethyl)benzyl]-7-indolyl-5-yloxy-2,3-dihydro-5i/-[l,3] °-pyrazole[3 ,2-a]&quot;Bistidin-3-yl}(phenyl)methyl]amino} Butyrate sodium fluoride-3-methoxyphenyl)_8-[2- -6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-a]pyridine -3-yl}(phenyl)methyl]amino}butyrate sodium 6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzene Methyl)_7-methyl-3-(decylamino-phenyl-methyl)_2,3-dihydro-thiazolo[3,2-a] 0 ratio bite-5-_ 3_(dimethyl Amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)_8_(2-fluoro-6-diImethyl-phenylindenyl)-7-methyl-2 ,3-di-argon-嗔u sitting and [3,2· &lt;3]0 ratio bit-5-keto 3_(butylamino-phenyl·methyl)_6_(2_fluoro_3_methoxy ·Phenyl)_8·(2·Fluoro-6-difluoromethyl-benzyl)·7-fluorenyl-2,3-dihydro-thiazolo[3,2-α] ° ratio bite · 5 - _ 6 (2-Fluoro-3-methoxy-phenyl)_8_(2_fluoro-6-trifluoromethylbenzyl)_ 7-methyl·3-[phenyl-(4,4,4 -Trifluoro-butylamino)_methyl]_2,3_dihydro-.唾[3,2-α]pyridine-5-one 3 (allylamino-p-styl-methyl)_6_(2_fluoro_3methoxy-phenyl)8_ 152524.doc 201130854 (2 -6·3-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2_α]pyridine 3-(i-allylamino-1-phenyl -but-3-enyl)-6-(2-fluoro-3-indolyloxy)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl_ 2,3_Dihydro-thiazolo[3,2-α]&quot; than biting _5-keto 6_(2-fluoro-3-methoxyphenyl)_8·(2_fluoro-6_trifluoro Methyl·stylmethyl)_7-methyl-3-(2-phenyl-1,2,3,6-tetrahydro-pyridin-2-yl)-2,3-dihydro-thiazolo[3 ,2-α]pyridine_5-keto#·〇6-(2·fluoro-3-methoxy-phenylfluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-side Oxy-2,3-dihydro-5/ί-thiazolo[3,2-α]pyridin-3-yl]-phenyl-methyl}-acetamide 3-bromo-2,2-difluoro _#-{[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoroindolyl-phenylhydrazino)-7-methyl-5. _2,3-Dihydro-5//-thiazolo[3,2α]pyridine_3_yl]-phenyl-methylpropiamine 2,2-difluoro-3-({[6-(2- Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5-side Oxy-2,3-dihydro-5if-thiazolo[3,2-α]pyridine-3-yl]-phenyl-indenyl}-amino)-propionic acid ethyl ester 2,2·difluoro 3-({[6·(2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-stanomethyl)-7-indolyl-5-side oxygen 2-[(3,3-difluoro-2-oxooxy) 2-(3-dihydropyrano[3,2-α]pyridin-3-yl]-phenyl-methylamino)propanoic acid ·azetidin-1-yl)-phenylindenyl]·6_(2-fluoro-3-indolyloxyphenyl)_8_(2_fluoro-6-trifluoromethyl-benzoinyl) _7_Methyl-2,3_Dihydro-indole D sits and [3,2-α]η is more than 唆_5__ 6-(2·fluoro-3-methoxy-stupyl)-8-(2- Fluoro-6·trifluoromethyl-benzoyl)_S 152524.doc -75. 201130854 3-[(3-Hydroxy-propylamino)-phenyl-methyl]_7_mercapto-2 3 Hydrothiazolo[3,2-α]吼 bit-5·ketone 6-(2·fluoro-3-methoxy-phenyl)_8_(2_fluoro_6_trifluoromethyl-benzyl)_ 3-[(4. hydroxy-butylamino)-phenyl-indenyl]_7-mercapto-2,3 dihydrothiazolo[3,2-α]-specific bite-5-one 3-[( 2,2-Difluoro-3-hydroxy-propylamino)-p-styl-methyl]_6_(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoro曱-stupylmethyl)_7-methyl·2,3-dihydro-°°°[[,2-α]. Than the bite-5-net {3i?-[3a(i?*)]}-4-({[6-[3-(1,1-difluoro-ethyl)-phenyl]_8-(2- Fluoro-6-trifluorodecyl-stupylmethyl)_7_mercapto_5, pendant oxy-2,3_dihydro_5 ugly thiazolo[3,2-α]pyridin-3-yl]- Phenyl-mercaptoamino)-butyric acid ethyl ester {35&lt;-[3ίχ(Λ*)]}-4-({[6-[3-(1,1-difluoro-ethyl)) benzene Base]_8_(2_fluoro-6-trifluoromethyl-benzyl)_7·fluorenyl_5_sideoxy-2,3-dihydro-5i/-thiazolo[3,2-α]» ratio Acridine-3-yl]-phenyl}}-amino)-butyric acid ethyl ester {3i?-[3a(&lt;S*)]}-4-({[6-[3-(l, l· Difluoro-ethyl)·phenyl]_8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-sideoxy-2,3-dihydro-5 ugly- Thiazolo[3,2a]pyridin-3-yl]-phenyl-methylamino)-butyric acid ethyl ester difluoroethyl)-phenyl]·8-(2-fluoro-6-trifluoromethyl) -Benzylmethyl)-7-methyl-5-yloxy-2,3-dihydro-5/ί-thiazolo[3,2-α]npyridin-3-yl]-phenyl- Methylamino)-butyric acid ethyl ester {3/?-[3α(/?*)]}-4-({[6-[3-(1,1-difluoro-ethyl)-phenyl] _8_(2_Fluoro-6-trifluoromethyl-stupylmethyl)_7-methyl-5- oxo-2,3-dihydro-577-indazolo[3,2-a]° pyridine- 3-yl]-phenyl-indenylamino)_ Butyl difluoroethyl)butyl]_8_(2_ 152524.doc •76· 201130854 Fluoro-6-trifluoromethyl·benzyl)-7-methyl-5-sideoxy-2,3 - Dihydro-5//· thiophene. Sit and [3,2-αρ-pyridyl, yl]-phenyl-methylamino)-butyric acid {3t[3a〇S*)]}-4-({[6-[3-(l, L-Difluoro-ethyl) phenyl fluorotrifluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3·dihydro-5/ί-sigh and [3, 2-α]η比pyridine_3_yl]•phenyl-methyl}_amino)_butyric acid {3^[3α〇5*)]}-4-({[6·[3-(1 ,1-difluoro-ethyl)-styl]8_(2_fluoro-6-difluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3_dihydro- plug Zoxa[3,2%]pyridine_3_yl]-phenyl-indolyl i-amino)-butyric acid 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-indole Oxyphenyl)_7-fluorenyl_3-({mercapto[2-(acridin-2-yl)ethyl]amino}indenyl)_2,3_dihydro_5 ugly [13] thiazole And [3,2-α]ηpyridin-5-one 1-oxide 6-(4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorophenylhydrazine Base)_7_mercapto-3-({methyl[2-(barridin-2-yl)ethyl]amino}methyl)_2 3_dihydro_5open_[1,3]thiazolo[ 3,2-α]pyridin-5-one 1-oxide 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl) _ 3-(Pentyl-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2_^pyridyl-5-keto-6-(5-fluoro-2,3- Dihydro-benzo[1 4]dioxine_6_yl)8-(2_fluoro-6-trifluoromethyl-benzyl)-7.methyl-5-sideoxy-2,3_dihydro_5 _ oxazolo[3,2-α]pyridine-3-thiocarbamic acid S-phenyl ester 6-(2-^-3-isopropoxy-benyl)-8-(2-^-6-three Air fluorenyl-benzyl)-7-fluorenyl-5-sideoxy-2,3-dihydro-5//-. Sit and [3,2-^2]1» than bite_3. S-phenyl thiodecanoate 6-(2-fluoro-3-trifluorodecyloxy-yl)-8-(2-fluoro Trifluoropyranyl-benzoic acid S 152524.doc -77· 201130854 its)-7-methyl-5_ side-milk base_2,3_a' gas_5 square~ sale 0 sit and [3,2_α] Beta ratio bite-3_ thioformic acid S-benzene vinegar 6-[3-(1, 卜二说_ethyl)-2_气-本基]-8-(2- gas-6-trifluoromethyl) Benzyl)_7-methyl_5_sideoxy-2,3-dihydro-5//-thiazolo[3,2·α]pyridin-3-deuteroic acid S_benzene vinegar 6- (2-Fluoro-4-methoxyphenyl)_8_(2_--6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3-diindole- 5/f-嗟〇 sitting and [3,2-&lt;a]0 is a bit of S-phenyl benzoate benzoate 8-(2-fluoro-6-trifluoromethyl-benzoinyl)- 6-(3-carbyl-phenyl)-7-fluorenyl 5- 5-oxo-2,3-dihydro-5//-° stopper and [3,2-α] ratio -3- S-phenyl thioformate 6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-7-yl-5- Sideoxy-2,3-dihydro-5-thiazole[3,2_α]pyridine_3_thiobenzoic acid S-phenyl ester 6-(3-dimethoxymethoxy-phenyl)-8-( 2-fluoro-6·trifluoromethyl-benzoinyl)-7-fluorenyl-5-oxo-2,3-dihydro-5/ί-thiazole [3,2-λ]pyridine-3-thiocarboxylic acid S-phenyl ester 6-(4-fluoro-2,2-dioxabenzo[1,3]dioxol-5-yl) _8_(2-fluoro-6-difluoromethyl-benzyl)_7·methyl_5-sideoxy-2,3_dihydrocotentan-thiazolidine[3,2-α]pyridine- S-phenyl 3-thiocarbamate 6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluorof-phenyl)-7- 5-O-oxy-2,3-dihydro-5/indole-thiazolo[3,2_α]pyridine_3_ S-phenyl thioformate 6-(3-ethoxy-2-fluoro-benzene -8-(2-Fluoro-6-trifluoromethyl- phenylmethyl)· 152524.doc -78- 201130854 7-Methyl-5-sideoxy-2,3-dihydro-5// -thiazolo[3,2-α]pyridine-3-thiodecanoic acid S-phenyl ester 3-(2- gas-benzoquinone)-6-(2-fluoro-3-difluoromethoxy- Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α].唆-5-keto 3-(2-fluoro-benzylidene)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl- Phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]pyridine-5-one 6-(2- gas-3-oxooxy-phenyl)-8- (2-Gas-6-difluoromethyl-benzoinyl)-7-methyl-3-(thiophene-3-carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridine -5-keto 6-(2-defo-3-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-3-(2- Indole-stupyl)-2,3-dihydro-thiazolo[3,2-α]pyrodo-5-嗣6-(2-fluoro-3-indolyl-phenyl)-8- (2-Gas-6-trifluoromethyl-phenylmethyl)_7-methyl-3-(3-indolyl- albino)-2,3-dihydro-thiazolo[3,2- α]Pyridine-5-one 3-(2-Gas-phenylhydrazino)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoroanthracene -Benzyl phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-β]α-pyridin-5-one 3-(2,5-disorder-benzyl) -6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-mercapto-2,3-dihydro-thiazole And [3,2-^] ° is more than 5-ketone 3-(2,3-digas-benzyl)-6-(2-fluoro-3-indolyl-phenyl)-8- (2-fluoro-6-trifluorodecyl-benzene Base)-7-mercapto-2,3-dihydro-thiazolo[3,2-α] 152524.doc -79- 201130854 0 than bite-5 - brewed i 3-(2-chloro-3·fluoro- Benzyl hydrazino)_6_(2_fluoro-3-methoxyphenyl) 8-(2_ 齓·6·trifluoromethyl-benzyl)·7·methyl-2,3·dihydro-thiazole [3, 2 evenly. Specific bite-5 -嗣^benzene^yl+...fluorodihydro-benzo(10)dioxan-6-yl)·Μ2·fluoro·6·trifluoromethyl_phenylmethyl)-7_ Methyl 2 3 -diamino-oxazolo[3,2-α] gnache-5-one 3-phenylhydrazin-6-(2-fluoro-3-isopropoxy phenyl)_8_ (2•Fluoro-6trifluoromethyl: phenylmethyl)_7_methyl-2,3_dihydro-thiazolo[3,2-exopyridyl-5-one 3-benzimidyl-6-( 2-fluoro-3-trifluoromethoxy-phenyl)_8_(2_fluoro_6•trifluoromethyl·stupylmethyl)·7·methyl-2,3_dihydro-嗟嗟[3 , 2 唆 唆 唆 3- 3- 3- 3- 3- 3- - - - - - - - - - - - - - - - - - - - - - - - -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 Base)_7_methyl-2,3_dihydro" plug. Sit and [3,2_sm-pyridin-5-one 3-benzimidyl-6-(2-fluoro-4-methoxy- Phenyl)-8·(2·fluoro·6_trifluoromethyl-m-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridine-5-one 3 -benzimidyl-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_6-(3hydroxyphenyl)-7-methyl-2,3-dihydro-thiazolo[3,2 -α]pyridine-5-鲷3-benzoinyl-6_(3-difluorodecyloxy-phenyl)_8_(2_fluoro·6•trifluoromethyl-phenylhydrazino)-7-methyl -2,3-dihydro-thiazolo[3,2-α]pyridine- % benzylidene-6-(3-difluoromethoxy-2-fluoro-phenyl)_8_(2•fluoro·6·trifluoromethyl-phenylhydrazinomethyl-2,3_dihydro- Thiazolo[3,2·α]pyridine_5-ketononylphenyl-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl Phenylhydrazino)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridine-5one 152524.doc -80 - 201130854 3-phenylmercapto-6-(4- Fluorin-2,2-diindole-benzo[1,3]dioxanthene-5-yl)-8-(2-fluoro-6-trifluorodecyl-phenylindoleyl)_7_A 2·3_Dihydro-thiazolo[3,2-β]pyridin-5-one 3-benzoinyl-6-(2-fluoro-4-phenoxy-phenyl)-8-( 2-fluorotrifluoromethyl-n-decyl)-7-methyl- 2,3-dihydro-indole α-[3,2-β]pyrene ratio bite_5-keto 3-benzoinyl- 6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)-7-methyl-2,3-dihydro-oxazole [3,2_α]pyridine_5-keto 6-[3-(1,1-difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl·benzoquinone 3-(hydroxyimino-p-styl-fluorenyl)-7-fluorenyl-2,3-dihydro-thiazolo[3,2-a]nit. D--5-keto 6-(2-fluoro-3-indolyl-phenyl)-3-[(2-fluoro-phenyl)-hydroxyimino-indenyl]-8-(2-fluoro- 6-trifluoromethyl-p-methyl)-7-fluorenyl-2,3-dihydro-thiazolo[3,2-α]π ratio bite_5-keto 6-(2-fluoro-3-methyl Oxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-stanomethyl)_3·(hydroxyimino-thiophen-3-yl-indenyl)-7-methyl-2, 3_Dihydro-thiazole[3,2-&lt;2]° ratio biting 5-keto 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6_3 Fluoromethyl-benzyl)-3-(hydroxyimino-o-phenylphenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-&lt;2]° ratio Bite-5-嗣6-(2-fluoro-3-methoxy-styl)-8-(2-fluoro-6-trifluoromethylbenzyl)_ 3-(hydroxyimino-m-toluene Base_methyl)_7_methyl-2,3-dihydro-thiazolo[3,2-α]° ratio bite 5-- 3-[(2-chloro-phenyl)-hydroxyimino] Methyl]_6_(2_fluoro_3_methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzenef-yl)-7-methyl-2,3-dihydro-thiazole And s 152524.doc -81 - 201130854 [3,2-α]. Bipyridin-5-one 3-[(2,5-difluoro-phenyl)-hydroxyimino-methyl]_6_(2-fluoro-3-methoxy-3-phenyl)-8-(2-fluoro -6-trifluoromethyl-benzyl)_7-methyl-2 3_dihydro-thiazolo[3,2-α]β ratio bit-5-keto 3-[(2,3-difluoro) Stylosyl)-hydroxyimino-methyl]_6_(2_fluoro_3_methoxyphenyl)-8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_7_fluorenyl _2,3_Dihydro-thiazolo[3,2-α]β is more than 唆-5-one 3-[(2-chloro-3-fluoro-phenyl)-hydroxyimino-methyl]_6_( 2-fluoro?3methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl gastric 2,3-dihydro-thiazolo[3,2- α]pyridine-5-one 6-(2-fluoro-3-indolyl-phenyl)_8-(2-fluoro-6-trifluoromethyl-benzyl)_ 3-[hydroxyimino]- (5-Methyl-thiazol-2-yl)-indenyl]-7-mercapto-2,3-dihydro-indole[3,2-〇]° than 唆-5-ketooxime-(5 -fluoro-2,3-dihydro-benzo[1,4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3- (Methoxyimido-phenyl-methyl)-7-mercapto-2,3-dihydropyrano[3,2-α]. Specific bite-5-copper M2-fluoro-3-isopropoxy-phenyl)·8·(2-fluoro-6-trifluoromethyl-benzoinyl)_3·(nonoxyimino-phenyl) -methyl)_7_methyl-2,3-dihydro-thiazolo[3,2-α]° ratio _5·ketone 6-(2-fluoro-3-trifluorodecyloxy-phenyl) _8_(2_Fluoro-6-trifluoromethyl benzoyl)-3-(anthoxyimino-p-styl-methyl)·7-methyl-2,3-dihydro-thiazolo[3, 2-α]pyridone 6 [3 (1,1--fluoro-ethyl)·2_gas·phenyl]_8_(2_gas_6·trifluoroindolyl_benzyl)-3-( Methoxyimido-phenyl-methyl)-7-mercapto-2,3•dihydro-thia 152524.doc 201130854 Zoledolo[3,2-α]pyridin-5-one 6-(2-fluoro 4-methoxy-phenyl)_8_(2_fluoro_6_trifluoromethylidenemethyl)_ 3_(methoxyimino-phenyl-methyl)_7_methyl_2,3_ Dihydro-thiazolo[3,2_α]° ratio biting 5-keto-3_[(2-fluoro-phenyl)-methoxyimino-methyl]_6-(2-fluoro-3-trifluoromethyl) Oxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-dihydro-thiazolo[3,2-α]pyridine-5- Ketone φ 8-(2-fluoro-6-trifluoromethyl-benzyl)_6_(3-hydroxy-phenyl)3 (methoxyimino-phenyl-methyl)-7-methyl-2 , 3-dihydro-thiazolo[ 3,2_α]pyridine_ 5-keto 6 (3-ethoxy-2-ran-benzyl)-8-(2-fluoro-6-trifluoromethyl-m-methyl)_ 3_(methoxyimine Benzyl-phenyl-methyl)·7-methyl·2,3-dihydro-thiazolo[32_α]° than bite-5-keto 6 (3-monoxanthoxy-phenyl)-8-( 2-fluoro-6-trifluoromethyl-benzoinyl) 3-(oxiranimidophenyl-indenyl)-7-methyl-2,3-dihydro-thiazolo[3,2_lu α]° ratio biting 5-keto 6-(4-fluoro-2,2-diindole-stupidin,3]dioxol-5-yl)·8_(2-fluoro-6- Trifluoromethyl-benzyl)_3_(oximeimido-phenylmethylmercapto-2,3-dihydro-thiazolo[3,2-α]pyridin-5-one 6 (2- -4 - the present gas group - the base) _8_(2_fluoro_6_trifluoromethyl-benzyl)_ 3_(nonoxyimino-phenyl-fluorenyl)_7_mercapto-2,3 _Dihydro-thiazolo[3,2·α]° ratio bite 5-ketone 6 (2-fluoro-3-methoxy-phenyl)_3-[(2-fluoro-phenyl)-methoxy Imino-alumina 8-(2-fluoro-6-difluoromethyl-benzyl)·7_mercapto-2,3_dihydro-sigh. Sit and S 152524.doc -83- 201130854 [3,2-α]° ratio to 5-keto 3-[(3,5-difluoro-phenyl)-methoxyiminomethyl]_6 (2_fluoro_3_methoxy- Phenyl)-8-(2-fluoro-6-trifluoro _-Benzyl)_7_曱基·2 _hydrothiazolo[3,2-cz]pyridin-5-one 6-(3-fluorofluorooxy-2-fluoro-phenyl)·8_(2 _Fluoryl·6·Trifluoromethane _ laughing base)-3-(methoxyimino-stupyl-fluorenyl)_7•indenyl-2,3-diazolo[3,2-α]pyridine -5-keto 6-(2-fluoro_3_isopropoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino) -曱基)_7•曱基_2,3_dihydro-oxazole[3,2-α]°pyridin-5-one {3iM3ae*)]}-3-(Amino-phenyl.曱)6_(2·Fluoro-3isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl'thiazolo[3,2-a] Pyridin-5·one {35·-[3α(π)]}-3-(amino-phenyl-methyl)_6 (2fluoro-3-isopropoxy-phenyl)_8_(2_fluoro-6 -Trifluoromethyl-benzyl)_7_fluorenyl-2,3_dihydro 0. Sit and [3,2-α]η ratio bite-5·ketone {3^[3α(π)]}_3·(aminophenyl-methyl)·6·(2fluoroisopropoxy-benzene Base)-8-(2-Fluoro-6-trifluoromethyl·benzyl)·7-methyl-2 3-dihydroindole. Sit and [3,2-&lt;a]n than bite-5-keto {3 meaning [3〇1(5·*)]}-3·(amino-phenyl-fluorenyl)_6_(2F3 Isopropoxy-benyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl' 嗟0 sits and [3,2-〇]° bites 5-ketone 3-(Amino-phenyl-methyl)-6-(2-fluoro-4-hydroxy-phenyl)8(2fluoro-6-trifluoromethyl-benzyl)-7-methyl -2,3-Dihydro-thiazolo[3,2_y. Ratio 152524.doc -84- 201130854 bite 5-keto 3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-trifluorodecyloxy-phenyl) 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3·dihydro-thiazolo[3,2-&lt;3]° ratio bite-5-_ [3a(i?*)]-3-(Amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl) -7·methyl-2,3_dihydro-thiazolo[3,2_^]0 is more than 5-ketone [301(5^)1-3-(Amino-phenyl-indenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl) -7-Methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3i?-[3〇t(i?*)]}-3-(Amino- Stupid base _6_(3 difluorodecyloxy _ phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)methyl _2 3 dihydrothiazole [3,2 - a ] ^ ratio ° 5 - brewing I {3 meaning [3〇〇(and *)]}-3-(amino-phenyl-methyl)·6_(3_difluoromethoxy-benzene )--8-(2-fluoro-6-trifluoromethyl) _7-mercapto-2,3-dihydro-thiazolo[3,2- &lt;3]° ratio biting 5-aminol-phenyl-methyl)_6_(3 difluoromethoxyphenyl)-8-(2-gas-6-trimethyl)· alum )_7• Mercapto-2,3_dihydro-oxazole-[3,2-β]° ratio bite 5-genus {3叩a(m3_(amino.phenyl.indenyl)·6_( 3•Difluoromethoxy-phenyl)-8-(2-fluoroitrimethylmethyl·stupylmethyl)_7_methyl_2,3_dichloro-hydrazine. Sit and [3,2-a ]° than bite-5-_ (10)·[3α(我]}·3_(amino-stupyl-methyl)-6-(4-fluoro·2,2-digas-stupid and π,3] Dioxole_5_yl)_8_(2_gastrotrixol-benzene S 152524.doc -85· 201130854 fluorenyl)-7-mercapto-2,3-dihydro- oxazolidine [3,2_α]ιί pyridine _5• ketone {3 meaning [3a(m3_(amino-phenyl-indenyl)6 (4 gas_2 2·digas·benzo[1'3]) Heterocyclic pentylene·5·yl)_8_(2···Three gas fluorenyl dimethane)-7-fluorenyl-2,3, dihydro-oxazolo[3,2 succinyl _5- Ketone {3iK3a〇S*)]H(Amino-stupyl-methyl)-6-(4-say-2,2-dioxin·benzo[1,3]dioxetene_5 -yl)_8_(2·版·6_trifluoromethyl: alum-based)-7-fluorenyldihydro-thiazolo[3,2-a]pyridine_5-one {3S-[3a〇S* )]}_3_(Amino-phenyl-methyl ) 6 (4 fluoro 2,2 di-halogen _ benzo[1,3]dioxol _5_yl)_8_(2_fluoro_6_trifluoroindolylphenylphenyl)-7 -methyl-2,3-dihydro-thiazolo[3,2_β]pyridine·5-ketooxime 3〇^*)]}_3·(amino-phenyl-indenyl)6 (3·ethoxyl) 2-fluorophenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-methyl_23_dihydro-indole. Sit and [3,2- &lt;3]° ratio bite-5-_ {35&gt;-[3 Zhuo*)] 3-(Amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro]phenyl )-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7•mercapto-2 3_dihydro-thiazolo[3,2-a]«* bite- 5-i^j {3Λ-[3α('}_3·(Aminophenyl-methyl)6·(3ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenyl Base)_7_methyl-2,3_dihydro-thiazolo[3,2_"]° ratio bite-5 -嗣{3S-[3a(V)] }_3_(amino-styl-yl) _6·(3_ethoxy·2_fluoro·phenyl)-8-(2-fluoro-6-trifluorodecyl-adenyl)·7-methyl·2,3-dihydro-thiazole [3,2-α].Bite·5-steel 3-(amino-phenyl-methyl)-6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro -6-trifluoromethyl-benzoinyl)_7_mercapto-2,3-dihydro-thiazolo[3,2-a]pyridine 152524.doc • 86 - 201130854 Bite 5-ketone {3/? -[3(χ(Λ*)]}-3-[Amino-(2-fluoro-phenyl)-indolyl]-6-(2-fluoro-3-indolyl-phenyl)-8- (2-Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-2,3-dihydro-sell β-sit[3,2-α]° than bite-5-ketone {35· -[3(χ(/?*)]}-3-[Amino-(2-fluoro-phenyl)-indolyl]-6-(2-fluoro-3-methoxy-phenyl)-8 -(2-fluoro-6-difluoromethyl- Methyl)-7-mercapto-2,3-dihydrocarbazide {3π-[3α(5·*)]}-3·[amino-(2-fluoro-phenyl)-methyl]-6 -(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-dimethyl-benzyl)-7-fluorenyl-2,3-dihydro-indole [3,2-α]° than bite-5-keto ps-pae*)]}-]-[Amino-(2-fluoro-phenyl)-indenyl]-6-(2-fluoro-3-曱oxy-phenyl)-8-(2- gas-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2,3-dihydrocarbazino[3,2-a]° ratio Bite 5-keto 3-[Amino-(3,5-difluoro-phenyl)-indolyl]-6-(2-fluoro-3-indolyloxy-phenyl)-8-(2-fluoro -6-trifluorodecyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]° ratio bit-5-keto[3oc(/?*)]- 3-(Amino-a-cephen-3-yl-methyl)-6-(2-carb-3-anthracene-phenyl)-8-(2- gas-6-dioxanyl-benzene Sulfhydryl)-7-methyl-2,3-dichloro-indole. Sit and [3,2-a] ° than bite 5-keto [306(5^))-3-(amino thiophene- 3-yl-methyl)-6-(2-ran-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-2 ,3-dihydro-thiazolo[3,2- &lt;3]° ratio to 5-keto [3a(i?*)]-3-(amino-o-phenylphenylmethyl)-6-(2-fluoro-3-indolyl-phenyl)- 8-(2-^-6-Dimethyl fluorenylbenzoyl)-7-methyl-2,3-diaza- 03⁄411 sit s 152524.doc • 87 - 201130854 and [3,2-〇]° Than 5-ketone [3a(*S*)]_3-(Amino-o-phenylphenyl fluorenyl)-6-(2-fluoro-3-indolyl-phenyl)-8-(2- Gas-6-dimethyl-benzyl)-7-methyl-2,3-digas-嗟[S,[3,2-a]pyridin-5-one [3a〇R*)]- 3-(Amino-m-phenylphenyl-methyl)-6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl) -7-mercapto-2,3-di-argon-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-m-phenylphenyl-fluorenyl)- 6-(2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-difluorene-thiazole [3,2-a]°it. 5-butanone [3a(i?*)]-3-[amino-(2-a-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)- 8-(2-disorder-6-dimur methyl-benzyl)-7-methyl-yl-2,3-di-r-D-a sata and [3,2-a] ° than bite-5- Ketone [3a(*S*)]-3-[Amino-(2-chloro-phenyl)-indolyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2 - gas-6-disorganomethyl-phenylhydrazino)-7-methyl-2,3-dimur-D stopper. And[3,2-a]pyridin-5-one [3a(i?*)]-3-[amino-(3-chloro-phenyl)-indenyl]-6-(2-fluoro-3 -methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-dihydro-thiazole.弁[3,2 - a ] ° ratio bite-5 -嗣[3α(5·*)]-3-[amino-(3-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl -8-(2-Fluoro-6-trifluorodecyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2- &lt;3 ] ° than bite -5 [嗣[3a(i?*)]-3-[amino-(2,5-difluoro-phenyl)-fluorenyl]-6-(2-fluoro-3 -decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-di 152524.doc -88 - 201130854 Hydrogen-° And [3,2-α]ρ ratio bite-5-keto[3a(S*)]-3-[amino-(2,5-difluoro-phenyl)-methyl]-6-(2- Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazinyl)-7-methyl-2,3-dihydro-purine β sits [3, 2-〇]° ratio bit-5-keto[3a(i?*)]-3-[amino-(2,3-difluoro-phenyl)indolyl]-6-(2-fluoro-3 -decyloxy-phenyl)-8-(2-oxa-6-difluoromethyl-benzyl)-7-methyl-2,3-dihydrogen &lt;7 sits and [3,2-a]. Than 5-ketone [301(5^)1-3-[Amino-(2,3-difluoro-phenyl)-methyl]-6-(2-fluoro-3-indolyl-benzene) -8-(2-fluoro-6-trimethyl-methyl-phenylhydrazino)-7-mercapto-2,3-dihydropyrano[3,2-a]° than bite-5-ketone [3α(Λ*)]-3-[Amino-(2-chloro-3-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-salt-[3,2- &lt;3]° ratio bit-5-keto) [3α(5**)]-3-[amino-(2-chloro-3-fluoro-phenyl)-indenyl]-6-(2-fluoro 3-methoxy-phenyl)-8-(2-fluoro-6-dioxamethyl-benzyl)-7-methyl-2,3-dihydro-indole.圭和[3,2-a]° ratio bit-5-ketone [3〇1 (and *)]-3-[amino-(5-fluorenyl-sodium-sodium-2-yl)-indenyl] -6-(2-disorder-3-methoxy-styl)-8-(2-fluoro-6-trimethylsulfonyl-phenylhydrazino)-7-methyl-2,3-dihydro-° Plug D sits and [3,2-a]° bites 5-keto [3α(Ρ)]-3-[amino-(5-fluorenyl-thiazol-2-yl)-fluorenyl]-6- (2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-2,3-dihydro-sold.圭和[3,2-a]°Bite - 5-13⁄4 [3a(i?*)]-3-[Amino-(5-chloro-thiophen-2-yl)-indenyl]-6-( 2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-dioxamethyl-benzyl)-7-fluorenyl-2,3-di S 152524.doc -89- 201130854 Hydrogen-deutero[3,2-α]. Ratio to 5-keto [3α(π)]-3-[amino](5.chloro-thiophen-2-yl)-methyl]-6-(2-fluoro-3.methoxy-phenyl -8-(2-Fluoro-6-trifluoromethyl-phenylmethyl)_7-methyl-2 3-dihydro-indole[3,2-β]npyridin-5-one 3 -(Amino-phenyl-fluorenyl)_6_(3-difluoromethoxy-2-fluorophenyl)8_(2_fluoro-6-difluoromethyl-adenyl)-7-fluorenyl_2 , 3-dihydro-嗟 坐 坐 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ (2_Fluoro_3·isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indenyl 2,3-dihydro _ ° And [3,2-α]° ratio biting 5-keto-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)_7-methyl-2,3-dihydrogen _ ° 恶 ° sit and [3,2-α]β than bite 5-keto {3Λ-[3α(5*)]}-3-(amino-phenyl-methyl)_6_(2_fluoro· 3·Isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indenyl-2,3-dihydro-oxazolo[3,2-α °°pyridin-5-one {35-[3〇^*)]}-3-(amino-phenyl-fluorenyl)_6·(2-fluoro-3_isopropoxy-phenyl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-α]pyridin-5-one {3 and-[ 3〇1 (/?* )]-3-(Amino-phenyl-fluorenyl)_8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-2,2,7·trimethyl·2, 3-Dihydro-thiazolo[3,2-α]pyridyl-5-one {3*?-[3〇1(and*)]}-3-(amino-phenyl-fluorenyl)_8_( 2_Fluoro-6-trifluoromethyl-benzyl)-6-filled-2,2,7-trimethyl-2,3-dihydro-selling "Sit and [3,2-α]pyridine 152524 .doc • 90· 201130854 Bite 5-ketone {3iH3oc(^*)]}-3-(Amino-phenyl-indenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl - 6-iodo-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-α]pyrodo-5-ketoamino-phenyl-methyl)-8- (2-Fluoro-6-trifluoromethyl-benzyl)-6-iodo-2,2,7-trimercapto-2,3-dihydro-thiazolo[3,2-α]pyrr-5 - 93⁄4 [3oc(i?*)]-3-(Amino-phenyl-methyl)-6-[3-(1,1-difluoro-ethyl)-phenyl]-8-(2- Fluoro-6-trifluoromethyl-adenyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-α]. Than bite 5-ketone [3a( &lt;S*)]-3-(Amino-styl-fluorenyl)-6-[3-(1,1-difluoro-ethyl)-phenyl]-8-(2-fluoro-6- Trifluoromethyl-p-methyl)-7-mercapto-2,3-dihydro-thiazolo[3,2-a]elt 唆-5-one {3i?-[3a(i?*)]} -3_(Amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxan-6-yl)-8-(2 -Fluoro-6-trifluoromethyl-benzoyl)_ 7 _ fluorenyl _ 2,3 -diaza-** plug 弁[3,2 - a ]0 ratio °-5 -嗣{3 ^[3α(Λ*)]}-3-(Amino-phenyl-indenyl)-6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxine -6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridine-5- Ketoamino-p-styl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxine-6-yl)-8-(2-fluoro -6-trifluorodecyl-benzyl)· 7-methyl-2,3 -two wind-° plug σ sit and [3,2 - &lt;3]. Specific bite-5 -嗣{3^[3α(5*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1, 4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzene 152524.doc -91 - 201130854 base)-7-methyl-2,3-di Hydrogen-thiazolo[3,2·α]^idine_5-one 3-(amino-phenyl-methyl)-6-(2-1_3·trismethoxy-phenyl)_8_(2_fluoro -6_difluoromethyl-adenyl)·7·methyl-2,3_dihydro-thiazolo[3,2·α] ° than bite-5-keto[3〇^*)]-3 -(Amino-phenyl-methyl)_6_[3_(11 difluoroethyl)2_fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_7•曱Base 2,3 dihydrogen _ ° plug ° sit and [3,2-α]» than bite-5-keto [3a〇S*)]-3-(amino-phenyl-fluorenyl)_6_[3_ (1, difluoroethyl) 2_fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl·phenylmethyl)_7-methyl-2,3-dihydro-[## [3,2-α]. Bis-5-keto 6-(3-acetamido-2-fluoro-phenyl)-3-(amino-phenyl-methyl)_8_(2_fluoro-6-difluoroindolyl-benzol Base)-7-methyl-2,3-dihydro-indole and [3,2_ &lt;3]0 ratio - 5 -嗣3-(amino-phenyl·indenyl)-6-(2-fluoro-5-trifluoromethoxy-phenyl)_8_(2_fluoro*·6 - Amphiphilic *methyl-n-decyl)-7-mercapto-2,3-diaza-pyrene η sita[3 2 Q] 0 than bite-5-keto 3-(amino-phenyl-methyl 8-(2-fluoro-6-trifluoromethyl-stanomethyl)_6_(6-methoxy-4-indolyl-pyridin-3-yl)-7-methyl-2,3-di Hydrogen-thiazolo[3孓α]0 is more than 5-keto-5-one 3-(amino-phenyl-methyl)-6-(2-fluoro-4-trifluorodecyloxy-phenyl)_8_(2_ milk -6_difluoroindolyl-presentyl)-7-mercapto-2,3-diaza-indenyl[3 2 α] 0 is more than 5-ketone 3-(amino-phenyl-methyl) -8-(2-Fluoro-6-trifluoromethyl-benzyl)·6·(3_methoxy-yl)-7-fluorenyl-2,3-dihydro-嗟0 sits and [ 3,2-α]0 is more than 唆5-ketone 152524.doc -92- 201130854 3·(Amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-indenyl-2,3-dihydro-thiazolo[3,2-α]pyrazine-5-brown I [3a( i?*)]-3-(Amino-stylylmethyl)_6_(2_Fluoro-3_decyloxy-phenyl 8-(2-fluoro-6-trifluorodecyl-stupylmethyl) _2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-^(]«»pyridin-5-one [3a(*S *)]-3-(Amino-phenyl-fluorenyl)_6_(2_fluoro_3_methoxy_phenyl)_ • 8-(2-fluoro-6-trifluorodecyl-benzyl) ) 2,2,7-tridecyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3α(/?*)]-3-(amino-phenyl- Methyl)·6_(5·fluoro_2 3_dihydrobenzo[1,4]dioxine-6-yl)·8-(2·fluoro-6-trifluoromethyl-benzene Base)_ 2,2,7·dimethyl- 2,3--wind-嗟0 sits and [3,2-α]β is more than 5-ketone [3 W)]-3-(amino group- Phenyl-methyl)_6_(5-fluoro-2,3-dihydrobenzo[1,4]dioxine-6-yl)-8-(2-fluoro-6-trifluorodecyl) -benzoyl)_ 2,2,7-dimethyl-2,3--虱-嗟嗤[3,2- &lt;3] 〇比咬-5-_ • [3α(Λ*)]-3-(aminophenyl-methyl)-6-(2-fluoro-3·trifluoromethoxy·stupyl) 8-(2-fluoro-6-trifluoromethyl-mutemethyl)_2,2,7-trimethyl-2 3-hydrogen·嗟β sits and [3,2-α]βΛβ定- 5-keto[3α(π)]-3-(amino-phenyl-indenyl)_6_(2-fluoro-3-trifluoromethoxyphenyl)-8-(2-fluoro-6-trifluoro Methyl-benzyl)_2,2,7-tridecyl_2 3 sold in 0 and [3,2-a]elt bite-5-one 3-(amino-phenyl-methyl)-6 -(2) _8_(2 gas _6 trifluoromethyl- phenylmethyl)-2,2,7-trimethyl-2,3-dihydro s-[3,2_ab-pyridinium · 5-_ 152524.doc •93- S 201130854 3-(Amino-phenyl-methyl)-6-(2-fluoro-5.methoxy-phenyl)-8-(2_fluoro-6 -difluoromethyl-adenyl)-2,2,7-trimethyl-2,3-dihydro-sold °[3,2~ &lt;3]° ratio bite-5-鲷[3a(i?*)]-3-(amino-phenyl-fluorenyl)_6_[3_(11•difluoro-ethyl)_2_fluoro-phenyl] 8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_2,2,7-tridecyl_2,3_dihydro-snip-[3,2-α]吼 bit-5- Ketone [3a〇S*)]-3-(Amino-phenyl-methyl)_6_[3_(1,difluoroethyl)2_fluoro-phenyl]-8-(2-fluoro-6- Trifluoromethyl-stupylmethyl)_2,2,7-trimethyl-2,3_dihydro-sigh" sits and [3,2-a] ° is more than 5-ketone [3a(i?*) ]-3-(Amino-phenyl-methyl)_6_[3_(1,difluoro-ethyl)phenyl]-8-(2-fluoro-6-trifluorodecyl benzoyl)_2 ,2,7_tridecyl·2,3-dihydro-thiazolo[3,2-α]pyridin-5-one [3a(*S*)]-3-(amino-phenyl-methyl ), difluoro-ethyl)phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)_2,2,7-trimethyl-2,3-dihydro-thiazole [3,2-a]pyridine-5-one {3Λ-[3α(Λ*)]}_[2-({[6-(2-fluoro-3-]decyloxy-phenyl)-8-( 2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5//-thiazolo[3,2-fl]pyridine-3 -yl]-styl-decylamino)-ethoxy]-acetate {35*-[3α(β*)]}-[2-({[6-(2-fluoro-3-)曱oxy-phenyl)-8-(2-fluoro-6 -trifluoromethyl-phenylhydrazino)_7-methyl-5-yloxy-2,3-dihydro-5//- oxazolo[3,2-a]&quot;bipyridin-3-yl ]-Phenyl-methyl}-amino)-ethoxy]-acetic acid oxime {3Λ-[3α(5·*)]}-[2-({[6-(2-fluoro-3-曱) Oxy-phenyl)·8_(2_fluoro-6-trifluorodecyl-adenyl)-7-indolyl-5-yloxy-2,3-dihydro-5//-thiazolo[3 , 2-α]° 咬-3-yl]-phenyl-fluorenyl}-amino)-ethoxy]acetic acid vinegar 152524.doc •94- 201130854 {3义[3 W)]H2-( {[6-(2-Fluoro-3_methoxy-phenyl)_8_(2_fluoro, 6-difluoroindolyl-benzyl)-7-indolyl-5-yloxy-2,3-di Hydrogen _5 ugly _ 嗔. Sit and [3,2-α]. Bite _3-yl]-stupyl-mercapto}-amino)-ethoxy]•acetate formazan 6-({[ 6-(2-Fluoro-3-oxooxy-phenyl)-8-(2-fluoro-6-tris-methyl-benzyl)-7-indolyl-5-sideoxy-2,3 -Dihydro-5//-thiazolo[3,2_β]pyridyl]-phenyl-fyl}• amino decanoate 6-({[6-(2-fluoro-3-methoxy)- Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-yloxy-2,3-dihydro-5-thiazole[3,2 -α]pyridyl]-phenyl-fluorenyl}-amino)-hexanoic acid decylamine 4-({[6-(2-fluoro-3-methoxy-) 8-(2-fluoro-6-trifluoromethyl-benzyl)·7-mercapto-5-sideoxy·2,3-dihydro-5 ugly-thiazolo[3,2- α]Pyridine]-phenyl-f-yl}-amino)-3-hydroxy-butyric acid ethyl ester 2-secondoxy-oxyamino--4-({ [6-(2-fluoro-) 3-methoxy-phenyl)_ 8-(2_^-6-difluoromethyl-bensyl)_7_methyl_5_sideoxy-2,3_dihydro·5/ί-thiazole And [3,2-α]ηpyridin-3-yl]-phenyl-methyl}-aminobutyric acid tert-butyl 4-({[6-(2·fluoro-3-methoxy)- Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-5//-indole. Sit and [3,2-£7]«»Bite-3~yl]-phenyl}}-amino)-butyronitrile {3^[3α(Λ*)]}-4-({[6- (4.Fluoro-benzo[1,3]dioxole, 5-yl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5 _Sideoxy_2,3_Dihydro-5//-thiazolo[3,2-ap-pyridyl_3_yl]-phenyl-methyl}-amino)_butyronitrile {3义[3α( Λ*)]}-4-({[6-(4-fluoro-benzo[1,3]dioxole·152524.doc •95- 201130854 5-base)-8-(2- Fluoro-6-trifluoromethyl-mutemethyl)-7-methyl-5-oxooxy-2,3-dihydro-5β-thiazolo[3,2 &lt;]° pyridine _3· kib phenyl-decyl butylaminobutyronitrile benzo[L3]dioxol-5-yl)-8-(2-fluoro-6-three Fluoromethyl-adenyl)-7_fluorenyl-% pendant oxy-2 3_dihydro-5π-thiazolo[3,2-α]acridin-3-ylphenyl-methylbupro Butyronitrile {3义[3α(π)]}-4-({[6-(4-good-benzodioxol-5-yl)-8-(2-fluoro-6-) Trifluoromethyl-methyl)-7-methyl-5-oxoxime-2 3 dihydro-5//-thiazolo[3,2-α]&quot;bipyridine_3_yl]-benzene 4-methyl-butamine-butyronitrile 4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-7-methyl -5-Sideoxy-2,3-dihydro-5//-thiazolo[3,2_α]pyridine-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl 4-( {[6-(2-Fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethylbenzyl)-7-methyl-5-sideoxy-2, 3-diindole-5/f-嗔π-sitting and [3n ratio / 3 yl]-phenyl-methyl}-amino)-butyric acid ethyl ester 4_({[6-(3-ethyl fluorenyl-2-) _Fluoro-phenyl)-8-(2•fluoro-6-trifluoromethyl-phenylmethyl)_7·methyl_5_sideoxy-2,3-dihydro-5仏thiazole [3, 2]pyridyl]-phenyl-intermediate}-amino)·ethyl butyrate' ({[6-(2_fluorine) _5-Trifluoromethoxy-phenyl)-8·(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5β -thiazolo[3 2 β]pyridin-3-yl]-phenyl-methylamino)-butyric acid ethyl ester {3Λ_[3αα*)]}-4_({[6_(2·Fluor_3_isopropyl) Oxy-phenyl 152524.doc • 96- 201130854 Fluoro-6-difluoromethyl-benzene-t-yl)_7-methyl_5_sideoxy-2,3_dihydro_5 ugly _ thiophene. [3,2-α]ηpyridyl_3_yl]-phenyl-decylamino)-butyric acid ethyl ester {35-(30^ and *)]}-4-({[6-(2 -Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-difluoromethyl) agglomerate _7_fluorenyl_5_sideoxy-2,3_dihydro_ 5/f_thiazolo[3,2-appyridin-3-yl]-phenyl-indolyl)-butyric acid ethyl ester {3 and -[3α(*^)]}_4-({ [6-(2•Fluoro-3·isopropoxyphenyl)-8-(2-fluoro-6-difluoromethyl-phenylhydrazino)_7_methyl-oxyl-2,3_2 Hydrogen_5&quot;_thiazole•[3,2_α]pyridine-3-yl]-phenyl-indenyl}-amino)-butyric acid ethyl ester {35·_[3α(5·*)]}-4 ·({[6_(2_ι_3 isopropyloxyphenyl) 8(2 fluoro-6-difluoroindolyl) _7_fluorenyl-5-sideoxy-2,3-dihydrothiazolo[ 3,2-α]pyridin-3-yl]-phenylindolylamino) Ethyl acetate {3Λ_[3α(and*)]Η2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-difluoroindolyl-benzene) Methyl)-7-mercapto-5-yloxy-2,3-dihydro-5/f-thiazolo[3,2-fl]n-pyridyl_3_yl]-phenyl-methyl b Aminoethoxy]-ethyl acetate • {35_[3a(m[2-({[6-(2-fluoro-3-isopropoxy)phenyl)-8-(2-gas-6-) Difluoro(indenyl-benzyl)·? _Methyl_5_sideoxy-2,3_dichloro_5-danoxazol[3,2~ρ-pyridyl_3_yl]-phenyl-methyl}•amino)ethoxy ]_Ethyl acetate {3i?-[3a(m|;2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) -Benzyl hydrazino)_7·fluorenyl_5_sideoxy-2,3_dihydro-5 good-thiazolo[3,2-a]acridine_3_yl]-phenylindenyl}amine Ethyl ethoxy]ethyl acetate {35·[3α(5*)]}·[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2- 152524.doc -97· 201130854 Fluoro-6·trifluoromethyl-benzoinyl)·7·methyl·5_sideoxy-2,3_dihydro_5 is good _ sulphate [3,2· α]° pyridine-3-yl]-phenyl-fluorenyl}-amino)-ethoxy]-acetic acid acetamidine 4 ({[6-(2- gas-3-isopropoxyphenyl) Gas methyl-benzyl)-7-fluorenyl-5. oxo-2,3-dihydro-5i7-thiazolo[3,2-α]pyridin-3-yl]-phenyl-methyl }_Amino)_butyronitrile 4_({(2-fluoro-phenyl)-[6-(2-fluoro-3-trifluoromethoxyphenyl)-8-(2-fluoro-6_three Fluorinyl-benzyl)-7-methyl-5-o-oxy-2,3·dihydro-5//-thiazolo[3,2-α]acridin-3-yl]-methyl }•Amino)_butyronitrile core ({[6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2- -6-trifluorodecyl phenyl phenyl)-7-methyl-5-oxo-2,3-dihydro-577-thiazolo[3,2-α] π ratio -3-yl] -Phenyl-fluorenyl}-amino)-butyric acid ethyl ester 4_({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorodecyl) - alkalyl)-2,2,7-trimethyl-5-oxo-2,3-diindole-5/f-thiazolo[3,2-α]pyridin-3-yl]- Phenyl-methyl-ammonyl)-butyric acid ethyl 4-({[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6.trifluoromethyl) Base — benzyl”-2,2,7-trimethyl-5-oxo-2,3-dihydro-5β-thiazolo[3,2_α]»pyridin-3-yl]- stupid Ethyl-methyl}-amino)-butyric acid ethyl ester 4_({[6·(2-fluoro-phenyl)-8-(2-fluoro-6-trifluorodecyl-benzoinyl)-2, 2,7-Trimethyl-5-oxo-2,3-dihydro-5//-thiazolo[3,2-α]pyridine-3-yl]-phenyl-methyl}-amino )-ethyl butyrate 4-({[6-(2-fluoro-5-decyloxy-phenyl)-8-(2-fluoro-6-trifluoromethyl)benzyl)-2,2 ,7-trimethyl-5-sideoxy-2,3-dihydro-5 ugly-thiazolo[3,2-a]〇fc -3-yl]-phenyl-methyl-amino group) _ ethyl butyrate 152524.doc -98· 201130854 [2-({[6-[3-(1,1-difluoro-ethyl)-2-fluoro-phenyl]_8-(2-fluoro-6) -trifluoromethyl- Benzyl)_7_methyl_5_sideoxy·2,3-dihydrothiazolo[3,2-situ ratio -3-yl]-phenyl-methyl}-amino)-B Ethyl]-ethyl acetate 4-({[6-[3-(1,1-difluoro-ethyl)-2.fluoro-phenyl]-8-(2-fluoro-6-trifluorodecyl) · alkalyl)-7-methyl-5-o-oxy-2,3-dihydro-5 ugly-thiazolo[3,2-α]0-pyridin-3-yl]-phenyl-methyl }·Amino)-ethyl butyrate [2-({[6-[3-(1,1-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl) -φ phenyl fluorenyl fluorenyl side oxy 2,3 · dihydro _ 5 good - thiazolo[3,2-^]pyridin-3-yl]-phenyl-methyl}-amino)-B Oxy]-acetic acid decyl 4-({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- Mercapto-5-sideoxy-2,3-dihydro-5//-thiazolo[3,2-α]pyridine·3-yl]-phenyl-methyl}•amino)-butyric acid B Ester {3Λ-[3α(Λ*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl) )-7-mercapto-5-o-oxy-2,3-dihydro-5 ugly-thiazolo[3,2-β]»pyridin-3-yl]-phenyl-decylaminobutyric acid Ethyl ester φ {35Ι-[3α(Λ*)]Μ-({ [6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl) )-7-曱-5-Sideoxy-2,3-dihydro-5/ί-thiazolo[3,2-α]acridin-3-yl]-phenyl-methylaminobutyric acid ethyl ester {3i?- [3a(kS )]}-4-({[6-(3-difluoro-1-methoxy-phenyl)-8-(2-gas-6_dioxamethyl-benyl)-7-曱5-yloxy- 2,3-di-milk-5 7/-a sputum and [3,2^]° pyridine-3-yl]-styl-indenyl hydrazine Ethyl ester {3»?-[3〇1(5^)]}-4-({[6-(3·difluoromethoxy-phenyl)-8-(2-fluoro-6_ 2 gas) --Benyl)-7-fluorenyl-5-sideoxy-2,3-two wind-5 ° sputum and [3,2-〇!]'1 pyridine-3-yl]-benzene Ethyl-fluorenyl}-amino)-butyric acid ethyl ester 152524.doc -99- 201130854 {3Λ·[3α〇?^)]}·[2-({[6-(3·difluoromethoxy) Phenyl)-8-(2-fluoro-6-trifluorodecyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5-thiazole[3,2 - 比 啶 -3- -3-yl]-phenyl-hydrazinyl)·ethoxy]-ethyl acetate {3 heart [3〇1(/^)]}-[2-({[6- (3·Difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-fluorenyl-5-oxo-2,3-dihydro- 5//-thiazolo[3,2-α]°pyridin-3-yl]-phenyl-methylamino)-ethoxy]-ethyl acetate {31[3〇〇(6^)] }-[2-({[6-(3 -difluoromethoxy-phenyl)_8-(2-fluoro-6.trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-57/-thiazole And [3,2-α]pyridin-3-yl]-phenyl-methylamino)-ethoxy]-ethyl acetate {35-[3α(5*)]}-[2-({[ 6_(3_Difluoromethoxy-phenyl)_8_(2 gas_6_difluoromethyl-benzyl)_7-methyl-5-oxo-2,3-dihydro-5-thiazole And [3,2-α]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-ethyl acetate {37?-[3α(/?*)]}-4- ({[6·(4-fluoro-benzo[υ]m-dioxol-5-1-yl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_7_fluorenyl _5_Sideoxy_2,3_Dihydro-5 ugly-嗟Shen[3,2-microbiidine_3_yl]-phenyl-methyl}-amino)-butyric acid ethyl ester {3 ^[3α(π)]}-4-({[6_(4-Fluorobenzoxanthene)-dioxanthene-5-1-yl)-8-(2-fluoro-6-trifluorodecyl) __曱基基)_7_曱基_5_Sideoxy_2,3_Dihydro-5//-thiazolo[3,2_α]npyridin-3-yl]phenylmethylamino)butyric acid Ethyl ester {3Λ_[3α(5*)] Bu 4_({[6_(4·Fluorobenzo[1,3]dioxol-5-yl)-8-(2-fluoro-6) -trifluoromethyl_phenylmethyl)_7_methyl·% pendantoxy·2,3· Dihydrogen H and [3,2·α ]0 pyridine _3 yl] phenyl hydrazinyl ethyl butyrate 152524.doc -100- 201130854 {3义[3W)]M_({[6-(4-fluoro.benzo[13] Di-dioxacyclohexane _ 5-yl)-8-(2-prepared 6-trifluoromethyl-benzene-f-yl)_7-mercapto-5-oxyl_23_ 二气摆喧°坐#[3, 2-&quot;]° 唆-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester {3Μ3α(Λ*)]}-[2-({[6-(4-fluoro) Benzo[13]dioxol-5-yl)-8-(2-prepared 6-trifluoromethyl-benzenef-yl)7-methyl-5-oxyl_2.3-dihydro-H . Sit and [3,2♦ than pyridine·3,_phenylmethyl}-amino)_ethoxy]-acetic acid methyl ester {3^3α(π)]Η2_({[6_(4_ fluorine_ stupid [13] m-dioxole-5-yl)-8-(2-oxa-6-trimethylmethyl-benzyl)-7-methyl_5_sideoxy_^dihydrogen- Selling scent and 义 比 比 丄 丄 卜 苯基 苯基 苯基 苯基 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 从 {{ U]m-dioxole-5-yl)-8-(2-indol-6-trifluoromethyl-benzoinyl)-7-indenyl_5_sideoxy_2.3-dihydro-5 //-.嗤 嗤 [3, 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -(4_ i _benzo π,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl_5_ side Oxy _ 2.3- dihydro-5i7-thiazolo[3,2^]pyridinyl-3-yl]•phenylmethyl}•amino)_ethoxy]-acetic acid decyl ester {3t[3a( i?*)]}-4-{[[6-(2-Fluoro-3_decyloxy-phenyl)·8·(2•Fluoryl_6_difluoroindolyl-phenylhydrazyl)-7-fluorenyl -5-Sideoxy-2,3_Dihydro_5 ugly thiazolo[3,2-α]ηpyridin-3-yl]-(2-fluoro-phenyl)indenyl]-amino Ethyl butyrate {3义[3〇1(;2*)]}-4-{[[6-(2-fluoro-3-indolyloxyphenyl)-8-(2-fluoro_6 · S 152524.doc -101- 201130854 Dimorphic quinone basic methyl)-7·methyl-5-sideoxy-2,3-diaza//salt[3,2-α]acridine-3 -yl]-(2-fluoro-phenyl)-methyl]-aminobutyric acid ethyl ester {3Λ-[3αβ*)]}-4-{[[6-(2-fluoro-3-methoxy) -phenyl)-8-(2-fluoro-6-trifluoromethyl- adenyl)-7-indolyl-5-yloxy-2,3-dihydro-5 ugly thiazolo[3 ,2-α]Acridine-3-yl]-(2-fluoro-phenyl)-methyl]-amino}-butyric acid ethyl ester {35>-[3〇1(5* )]-4-{[[6-(2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-stanomethyl)·7-fluorenyl- 5-Phenoxy 2,3_dihydro-5 ugly-thiazolo[3,2-β]&quot;bipyridin-3-yl]-(2-fluoro-phenyl)-methyl]-amino }_ethyl butyrate {3/Μ3α(π)]}·(2-{[[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoro) Methyl-benzyl)-7-fluorenyl-5-oxo-2,3-dihydro-5 ugly-thiazolo[3,2-α].pyridin-3-yl]-(2- Fluoro-phenyl)-methyl]-amino}-ethoxy)-ethyl acetate {3 &lt;S-[3a(i^)]}-(2-{[[6-(2-A-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene) Methyl)-7-mercapto-5-o-oxy-2,3-dihydro-5i/-thiazolo[3,2-a]«•bipyridin-3-yl]-(2-fluoro-benzene Ethyl)-methyl]-amino}-ethoxy)-ethyl acetate {3π-[3α(5^)]}-(2-{[[6-(2-fluoro-3·decyloxy)- Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-indolyl-5-yloxy-2,3-dihydro-5//-thiazolo[3, 2w] °Bitter-3-yl]-(2-fluoro-phenyl)-indolyl]-aminopurine·ethoxy)_ethyl acetate {35>-[3α(ν)]}-(2 -{[[6-(2·fluoro-3·decyloxy-phenyl)-8-(2-fluoro-6-di-preparative) methyl-n-decyl)-7-fluorenyl-5-side oxygen Benzyl-2,3-diaza-5. sulphate [3,2-aPpyridin-3-yl]-(2-fluoro-phenyl)-indolyl ethoxy) acetate 152524.doc -102· 201130854 4-({(3'5-Difluoro-phenyl)_[6_(2_fluoro_3_ methoxyl_phenyl)_8_(2_fluoro-6-trifluorodecyl) -phenylhydrazino)-7-methyl_5_sideoxy-2,3_dihydro_5 ugly-thiazolo[3,2-α]pyridin-3-yl]-methyl-amino)) Ethyl butyrate {3/Η3α(Λ*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxine-6- Base)-8-(2- -6-trifluoromethyl-adenyl)·7_mercapto_5_sideoxy-2,3-dihydro-5-thi-[3,2_β]π-pyridyl_3_yl]• Phenyl-methyl-ammonium)·ethyl butyrate φ {3iS-[3a(/?*)]}_4_({[6-(5-fluoro-2,3-dihydro-benzo[μ]] Dioxepan-6-yl)-8-(2-fluoro-6·trifluoromethyl-adenyl)_7-fluorenyl_5_sideoxy-2,3-dihydro-5/ /-thiazolo[3,2_a]pyridine_3_yl]-phenyl-methyl-amino)-butyric acid ethyl ester {3iM3W)]}-4-({[6-(5_ fluoro_2,3) _Dihydro-benzo π,4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-fluorenyl--oxyl- 2,3-Dihydro-5//-thiazolo[3,2-a]pyridine-3-yl]-styl-decylamino)-butyric acid ethyl ester • {3义[3α(ν) ]}·4-({[6-(5-fluoro-2,3-diindole- benzo[M]dioxe-6-yl)-8-(2-fluoro-6-trifluoro) Methyl-phenylhydrazino)_7_methyl_5_sideoxy-2,3-dihydro-5/f-thiazolo[3,2-a]pyridine-3-yl]•phenyl-methyl Ethyl)-butyric acid ethyl ester {3^(3^7^)^42-(^6-(5-fluoro-2,3-dihydro-benzo[M]dioxine-6 -yl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)_7-methyl-5_ pendant oxy-2,3-dihydro-5i/- 0 stopper β sits and [ 3,2-〇] 〇 _ _ _ _ _ _ ] - - _ _ 卜 卜 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 {[6-(5-Fluoro-2,3-dihydro-benzo[Μ]dioxane 152524.doc - 103- 201130854 cyclohexene-6-yl)-8-(2-fluoro-6-three Fluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/f-thiazolo[3,2-α]pyridin-3-yl; μphenyl-methyl} _ Amino)-ethoxy]-ethyl acetate {3/?-[3α(5*)]}-[2-({[6·(5-fluoro-2,3-diindole-benzo[ 1,4]dioxacyclohexan-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3- Dihydro-5;/-thiazolo[3,2-α]0-pyridin-3-yl]-phenyl-fluorenyl}-amino)-ethoxy]-ethyl acetate {35 &lt;-[3〇6(51*)]}-[2-({[6-(5-Gas-2,3 -) 虱-benzo[1,4]dioxacyclo-6- 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-sideoxy-2,3-dihydro-5//-thiazole[3,2- α]pyridin-3-yl]-phenyl-methyl-amino)-ethoxy]-ethyl acetate 6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro -6-trifluoromethyl-benzyl)_3-[(2-hydroxy-ethylamino)-phenyl-methyl]_7-methyl·2,3-dihydro-thiazolo[3, 2-α]pyridyl-5-one 3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)) -7-Methyl-5-yloxy-2,3-dihydro-5/f-thiazolo[3,2_β]^^_3·yl]-benyl•methyl}-amino)-propan 4-(1-[2-fluoro-3-methylindolyl-phenyl)-8-(2-aero-6-trifluoroindolylphenyl)-7-fluorenyl -5-Sideoxy-2,3-dihydro-5//-thiazolo[3,2_α]pyridine_3_yl]-phenyl-methyl}-amino)-butane_丨_sulfonic acid 2 -[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2·gas_6_trifluoromethyl]phenylphenyl)-7-methyl_5_ Oxyloxy-2,3-dihydro-5/f-thiazolo[3,2α]pyridine-3-yl]phenyl-indenylamino)_ethyl]-isoindole_i, 3_dione 2-P-({[6- (2-fluoro-3-indolyloxy)phenyl)_8_(2_fluoro_6•trifluoromethyl-152524.doc -104- 201130854 benzyl)-7-fluorenyl-5-sideoxy- 2,3-Dihydro-5-homo-thiazolo[3,2-β]pyridin-3-yl]-phenyl-indenyl}-amino)-propyl]-isoindole 4,3-dione 2-[4-({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6·trifluoromethyl)-phenyl)-7-methyl-5 -Sideoxy-2,3-dihydro-5//-carbazo[3,2-fl]0-pyridin-3-yl]-phenyl-indenyl}-amino)-butyl]_ Isoindole d,3_dione {3β-[3α(Λ*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2- mess -6-amphiphilic 1 methyl-benzyl)-7-methyl-5-sideoxy-2,3 -di-negative 1_5 ° carbazino[3,2-α]pyridin-3-yl]-benzene Ethyl-fluorenyl}-amino)-butyric acid ethyl ester {35ί-[3α(Λ*)]Μ-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-( 2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-5-oxo-2,3-dihydro-5 ugly-oxazole[3,2-ap ratio -3- Ethyl]-phenyl-methyl}-amino)·ethyl butyrate {37?-[3οι(π)]}-4-({[6_(2-fluoro-3-isopropoxy-phenyl) -8-(2-Fluoro-6-trifluoromethyl-p-methyl)_7-mercapto-5-p-oxy-2,3-dihydro-5-oxo[3,2-α ]«&gt;Bipyridine -3-yl]-phenyl-mercaptoamino)-butyric acid ethyl ester {35^30^5^)0-4-(^6-(2-fluoro-3-isopropoxy-phenyl) -8-(2-Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl_5.Sideoxy-2,3·dihydro·5 ugly oxazolo[3,2- α]&quot;Acridine-3-yl]-phenyl-methyl-amido)·Ethyl butyrate {3 and -[3oc(i?*)]}_[2-Q[6_(2_ Fluorine_ 3_Isopropoxyphenyl)_8 (2_fluoro-6-trifluoromethyl-benzyl)_7_methyl_5_sideoxy-2,3-dihydroazolo[3,2-fl] ° pyridine-3·yl]-phenyl-mercaptoamino)-ethoxy]-ethyl acetate {35> _[3〇1(and *)]}-[2-({[6- (2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluorofyl-benzyl)-7-indolyl_5_sideoxy-2,3-di Hydrogen_5//^oxazolo[3,2-fl]°pyridin-3-yl]-phenyl-methyl-amino)-ethoxy]-acetic acid 152524.doc •105· 201130854 ethyl ester {3/?-[3α(5^)]}-[2-({[6-(2-Fluoro-3-isopropoxy)phenyl)_8_(2_fluoro-6-difluoromethyl-benzene) Indenyl)-7-fluorenyl-5-yloxy-2,3-dihydro-5//-oxazolo[3,2-α]. Bispin-3-yl]-phenyl-fluorenylamino)·ethoxy]-ethyl acetate fluoride-3-isopropoxy-phenyl)·8-(2-fluoro-6-trifluoromethyl - stupid methyl)-7-mercapto-5-o-oxy-2,3-dihydro-57/- oxazolo[3,2-α] °pyridin-3-yl]phenyl- Benzylamino)-ethoxy]-ethyl acetate {3i?-[3a(i?*)]}-[2-({[6-(2-fluoro-3-indolyloxy)phenyl) 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5 ugly-thiazolo[3,2-α] °pyridin-3-yl]-phenyl-decylamino)-ethoxy]-acetic acid {3*S-[3a(i?*)]}-[2-({[6-(2- Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-difluoromethyl-benylmethyl)-7-methyl-5-sideoxy-2,3-dihydro-5 //-°Sapy and [3,2a] acridine-3-yl]-phenyl-indenylamino)-ethoxy]-acetic acid {37?_[3α(*^)]}-[ 2-({[6-(2-fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-side oxygen Benzyl-2,3-dihydro-5//-thiazolo[3,2-fl]« ratio. -3-amino]-phenyl-methyl-amino)-ethoxy]-acetic acid {351 -[3〇1(*^)]}-[2-({[6-(2-fluoro_3_ methoxy)phenyl)-8-(2-fluoro-6-trifluoromethyl-benzene) Base)_7_methyl_5•sideoxy·2,3_ Hydrogen_5 ugly_thiazolo[3,2-fl]&quot;bipyridin-3-yl]-phenyl-methyl-amino)-ethoxy]-acetic acid 6-({[6-(2- Fluoro-3-indolyl-phenyl)_8_(2_fluoro.6-trifluoromethyl-benzyl)-7-methyl_5_sideoxy·2,3·dihydro_5&quot;- Thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-hexanoic acid 152524.doc 201130854 4_({[6-(2-fluoro-3-decyloxy) Phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydrothiazolo[3,2-α]pyridine -3-yl]-phenyl-methyl}-amino)-3-hydroxy-butyric acid 4-({[8-(2·fluoro·6-trifluoromethyl- stupidyl)·6-( 3_曱oxy-styl)_7-methyl-5-oxooxy-2,3-dihydrothiazolopyridine-3-yl]-phenyl-methyl}-amino)-butyric acid 4 -({[6-(2-Fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoquinone)-7-methyl-oxy-2, 3-Dihydrogen argon and [3,2-α] ° ratio biting _3_ yl]-phenyl-methyl}-amino)-butyric acid 4-({[6-(3-ethyl fluorenyl)- 2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5 oxime-thiazole [3,2-α]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid 4-({[6-(2- -5-trifluoromethoxy-phenyl)·8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5 //-thiazolo[3,2-α]pyridin-3-yl]-styl-fluorenyl}•amino)·butyric acid φ {3Λ·[3α(Α*)]}-4-({[ 6-(2-Fluoro-3-isopropoxy-phenyl)-8·(2_fluoro-6-trifluoromethyl-benzyl)_7_fluorenyl_5_sideoxy·2,3_ Dihydro _5 ugly _ thiazole [3, 2 &lt;P-pyridin-3-yl]•phenyl-decylamino)butyric acid {3][3(1(/^)]}-4-({[6-(2-fluoro-3) -isopropoxy-phenyl)-8-(2-fluoro-6-difluoroindolyl- azainyl)_7-mercapto-5-sideoxy-2,3-dihydroserazo[3 ,2-ii]°fcL pyridine-3-yl]-phenyl-decylamino)butyric acid {3/^4301(5^)1)-4-((16-(2-fluoro-3) -isopropoxy-phenyl)_8_(2_fluoro-6-difluoromethyl-benzoinyl)·7-fluorenyl-5-oxo-2,3-dihydro-5/f-thiazole And [3,2w].pyridin-3-yl]-phenylmethylamino)butyric acid S I52524.doc -107- 201130854 {3^[3α(·^)]}·4-({ [6-(2-Fluoro-3-isopropoxy-phenyl)_8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl·5-sideoxy-2, 3-Dihydro-5/ί-thiazolo[3,2-flp-pyridin-3-yl]-phenyl-methyl-amino)butyric acid {3π-[3α(π*)]}-[ 2-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7-methyl_5_ side oxygen Base 2,3_dihydro-5/f-thiazolo[3,2-α].pyridin-3-yl]-phenyl-decylamino)-ethoxy]-acetic acid {3 &lt;S-[3a(i^)]}-[2-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) -benzyl)7-methyl_5•sideoxy-2,3_dihydro_5 ugly thiazolo[3,2-α].pyridin-3-yl]-phenyl-fluorenyl丨·Aminoethoxy]-acetic acid {3Α-[3α〇^)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2- Fluoro-6-trifluoromethyl-benzylmethyl_5_sideoxy-2,3_dihydro_5 ugly thiazolo[3,2-a]°pyridin-3-yl]-benzene Methyl-methylamino)-ethoxy]-fluoro-3-isopropoxy-phenyl)-8-(2-say-6-trifluoromethyl-benzyl)-7-yl _5_Sideoxy_2,3_Dihydro_5 ugly thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid 4-({[6-(2-Fluoro-4_trifluoromethoxy-phenyl)_8_(2-fluoro-6-trifluoromethyl]benzoyl)-7-methyl-5-sideoxy -2,3-dihydro-5 ugly-thiazolo[3,2-a]indole butyl-3-yl]-phenyl-fluorenyl}-amino)-butyric acid 4_({[6-(2 -fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-p-methyl)-2,2,7-trimethyl-oxy 2,3_2 Hydrogen-5/f-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid 4-({[6-(2-fluoro-3-) Trifluoromethoxy-styl 8-(2-fluoro-6.trifluoromethyl-benzyl)-2,2,7-trimethyl-5-yloxy-2,3-diargon-5i/-thiazolo[3 , 2-Λ]°pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid 152524.doc •108- 201130854 4-({[6-(2-fluoro-phenyl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)·2 2 7_ tridecyl-5·sideoxy-2,3-dihydro-5/ί-thiazolo[3,2- α]pyridine-3-yl]·phenyl-mercapto}-amino)-butyric acid 4-({[6·(2-fluoro-5-decyloxy-phenyl)-8-(2-fluoro) -6-trifluorodecyl-stupylmethyl)-2,2,7-trimethylidene-5-o-oxy-2,3-dihydro-5 oxime-thiazolo[3,2-α]pyridine -3-yl]-phenyl-fluorenyl}-amino)-butyric acid [2-({[6-[3-(1,1-difluoroethyl)-2-fluorophenyl]]- 8-(2-Fluoro-6-trifluoromethyl)-benzino)-7-indolyl-5-yloxy-2,3-diaza-5//-11 plug&gt;»Sitting and [3 ,2_α]&quot;Bistidin-3-yl]-styl-fluorenyl}-amino)-ethoxy]-acetic acid 4-({[6-[3-(1,1-difluoro-B) Base)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-indolyl-5-yloxy-2,3-dihydro-5 ugly -thiazolo[3,2_α]»pyridin-3-yl]-phenyl-methyl-aminobutyric acid [2 ({[6-[3-(1,1-mono-ethyl)-benzene) Base]_g_(2 - gas_6 - triseocarbazyl phenyl phenyl)-7-methyl-5-sideoxy-2,3-dihydro-5 ugly-thiazolo[3,2-α]pyridin-3-yl]-benzene Base-fluorenylamino)-ethoxy]-acetic acid φ 4-({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6.trifluoromethyl) Benzyl)-7-methyl-5-sideoxy-2,3-dihydro-5 ugly-thiazolo[3,2-α]pyridine·3·yl]-phenyl-methyl}- Amino)-butyric acid {3Λ_[3α^^)]]-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-) Benzyl)-7-fluorenyl-5. oxo-2,3-dihydro-5//-thiazolo[3,2-α]acridin-3-yl]-phenyl-indole Amino)·butyric acid {3 孓[3α(Λ*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl) -benzyl)7-fluorenyl-5-yloxy-2,3-dihydro-5//-thiazolo[3,2-4indolepyridin-3-yl]-phenyl-methyl }-Amino)-butyric acid S 152524.doc -109- 201130854 Bu 4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-difluoromethyl) - stupid methyl)-7-methyl-5-yloxy-2,3-dihydro-5//- oxazolo[3,2·α]0 is more than -3-yl]•phenyl Methylamino)butyric acid {3ι5_[3α(*^)]Bu 4_({[6_(3-difluorodecyloxy-phenyl)-8-(2-fluoro-6-difluorofluorene) -Benzyl)-7-fluorenyl-5-o-oxy-2,3-dihydro-57/-thiazolo[3,2-α]»pyridin-3-yl]•phenyl·A (amino)butyric acid {3/Η3α(Λ*)]}-[2-({[6_(3·difluoromethoxy)phenyl)_8_(2_fluoro-6-difluoromethyl- Benzyl)_7-methyl-5-o-oxy-2,3-dihydro-5-thiazole[3,2-α]»pyridin-3-yl]•phenyl-methylbuamine Ethyl]acetic acid]-[2-({[6-(3-difluoromethyl)-styl]8(2-fluoro-6-trifluoromethyl-benzoinyl)-7- Mercapto-5-sideoxy-2,3-dihydro-5//-thiazolo[3,2-α]acridin-3-yl]-phenylmethyl}amino) ethoxylate ]]-acetic acid {3/Η3α(5·*)]}-[2-({[6_(3_difluoromethoxy)phenyl)8-(2 fluoro-6-trifluoromethyl-benzyl) _7_曱基_5_Sideoxy_2,3_Dihydro·5 ft. thiazolo[3,2 core] acridine-3-yl]-phenyl-methyl-amino) ethoxylate ]•Acetic acid {3义[3〇1(巧]}-[2-({[6_(3_二气曱oxyphenyl)8(2 gastrotrifluoromethyl-benzyl)-7- Methyl_5_sideoxy-2,3-dihydrothiazolo[3,2-α]acridin-3-yl]-phenyl-fluorenyl}-amino)ethoxy]-acetic acid {3i ?-[3a(/n]M-({[6_(4_fluoro·benzo-π,3]dioxol-5-yl) 8-(2-fluoro.6-trifluoromethyl-m-methyl)_7•fluorenyl_5_sideoxy-2,3_dihydro-5 ugly-thiazolo[3,2_α]β-pyridyl· 3_基]_phenylhydrazinylbutyric acid {3义[3〇^*)]}-4_({[6_(4_fluoro-benzo[13]dioxanthene _ 5 -yl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)_7_fluorenyl_5_sideoxy-2,3_152524.doc •110- 201130854 Dihydrogen H嗤[3 , 2·10 bite _3_ base]_phenyl-methyl-aminobutyric acid {3/?-[琴*)]}-4-({[6_(4_fluoro_benzo[1, 3] m-dioxol-5-1-yl)-8-(2-gas-6-trifluorofyl-stupyl)_7-methyl_5-oxy 2,3-dihydro-5 //-Sell saliva and [3,2 punch than bite _3_base]_phenylmethyl amidino)_butyric acid sand [qin*)]}·4-({[6·(4·Fluorine- Benzopyrene, 3]dioxole _ • 5_yl) 1(2-fluoro-6-trifluoromethyl-benzyl)_7•methyl_5_sideoxy_2,3_ Dihydro-5H-finch. Sit and [3, 2 today than bite _3_ base]_phenyl-methyl}_amino)_butyric acid [3α(Ρ)]}·[2·({[6·(4-gas-stupid And [1,3]trioxol-5-yl)-8-(2-fluoro-6·trisylmethyl-phenylmethyl)_7-methyl_5_sideoxy_2.3- Dihydrogen sputum and sputum [3,2. bite _3_yl]_phenyl _ decylamino> ethoxy]-acetic acid {3 heart [3 W)] H2_({[6_(4_ a _ benzo π,3]dioxol ene-5-yl) winter (2_fluoro_6_tris-amply-phenyl-phenyl)-7-fluorenyl-5-sideoxy _ 2.3- Dihydro-5-indole and [3,2_bite_3yl]phenylmethyl}•amino)_ethoxy]-acetic acid {3/Κ3α〇5*)]}- [2-({[6·(4_fluoro-benzo[13]dioxol-5-yl)-8-(2-fluoro-6_triainyl)-phenylmethyl) 7曱Base _5 side oxy _ 2.3- dihydro H saliva [3, 2 ♦ _ _ 3 _ yl] phenyl _ methyl oximino) · ethoxy] - acetic acid (10) - (10) (four) Bu (10) for fluorine -benzo[13]dioxol-5-yl)-8-(2fluoro-6-trisinyl-phenylhydrazino)_7_fluorenyl_5_sideoxy_ 152524.doc 201130854 2,3-Dihydro-5//-thiazolo[3,2-α]pyridine-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid {3 and-[ 3〇1(7?*)]}-4-{[[6_ (2-Fluoro-3-methoxy-3-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-fluorenyl-5-sideoxy-2,3_2 Hydrogen-5/f-thiazolo[3,2-α]. Bipyridin-3-yl]-(2-fluoro-phenylmethyl]-amino}-butyric acid "35&gt;_[3a(m4_U[6-(2-fluoro-3-decyloxy-phenyl)) 8-(2-fluoro-6-difluoroindolyl-phenylhydrazinyl)-7-fluorenyl_5_sideoxy-2,3-dihydro-5//-thiazolo[3,2-aP Bipyridin-3-yl]-(2-fluoro-phenyl)methyl]-amino}-butyric acid {3Α-[3α(π)]}-4-{[[6·(2·fluoro· 3_methoxyphenyl)_8_(2·fluoro_6_difluoromethyl-phenylhydrazino)-7-methyl_5_sideoxy-2,3_dihydro_5 ugly thiazol[3, 2-exo-butyl-3-yl]-(2-fluoro-phenyl)-methyl]-aminobutyric acid {35_[3α(5*)]}·4·{[[6-(2· Fluoro-3-indolyl-phenyl)-8-(2-like-6-tris-methyl-benzyl)·7-methyl_5_sideoxy·2,3_dihydro_5&quot ;_thiazolo[3,2-exo-butyl-3-yl]-(2-a-phenyl)-methyl]amino}butyric acid {3i?-[3a(/?*)]}-( 2-{[[6_(2_fluoro-3_methoxy-phenyl) winter (2_fluoro-6-trifluoromethyl-benzyl)_7_fluorenyl_5•sideoxy-2,3 dihydrogen _5 ugly _ thiazolo[3,2ap than -3-yl]-(2·fluoro·phenyl)_methyl]-aminophenyl ethoxy)_acetic acid {3义[3〇^*)] Bu(2"[[6-(2-fluoro-3-indolyl-phenyl)-8-(2-Deng-6-difluoromethyl) methyl)_7_methyl_5_ side oxygen Base_2, 3_Dihydro_5 ugly _thiazolo[3'2-flp ratio bite base]_(2•fluorophenyl)methyl]-aminophenylethoxy)·acetic acid {3/K3a〇S*)] }-(2•川6_(2-Fluoro_3_methoxyphenyl)_8_(2_fluoro-6-dioxamethyl-benzyl)_7-methyl·5_sideoxy_2,3_ Diterpene _5i^thiazole 152524.doc -112- 201130854 and [3,2-aPtt pyridine-3-yl]-(2-fluoro-phenyl)-methyl]-amino}_ethoxy)-acetic acid {3f[3(x(P)]}-(2-{[[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-石-三气methyl-本本Methyl bromide-fluorenyl^-l-oxyl-^-diaza^/^-嗟pyrano[3,2-α]npyridin-3-yl]-(2-fluoro-phenyl)- Methyl]-amino}-ethoxy)-acetic acid 4-({(3,5-difluoro-phenyl)-[6·(2-fluoro-3-indolyl-phenyl)-8- (2-Fluoro-6-disorderyl-n-decyl)-7-fluorenyl-5-sideoxy-2,3-dioxane-5. Plug. Sit and [3,2-α]. Acridine-3-yl]-fluorenyl}-amino)-butyric acid {3/?-[3〇1(and*)]}-4-({[6-(5-fluoro-2,3-di) Hydrogen-benzo[1,4]dioxan-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-5-sideoxy- 2,3-Dihydro-5//-thiazolo[3,2-α]pyridin-3-yl]-phenyl-methyl}-amino)·butyric acid {3·5-[3 α(Λ*)]}-4-({[6-(5_fluoro-2,3-dihydro-benzo[1,4]dioxine·6-yl)-8-(2- Fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-oxo-2,3-dihydro-5//-carbazolo[3,2-α]° ratio. Ding-3-yl]-phenyl-methyl}_amino)-butyric acid {37^-1:3 01(5^)^-4-((1:6-(5-fluoro-2,3) -Dihydro-benzo[ι,4]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-stanomethyl)indolyl-5-sideoxy- 2,3-Dihydro-5//-thiazolo[3,2-α]pyridin-3-yl]•phenyl·indenyl}_amino)-butyric acid {35^301(^^):1 )-4-((1:6-(5-fluoro-2,3-dihydro- benzo[14]dioxan-6-yl)-8-(2-fluoro-6·trifluoro Methyl-stupylmethyl)_7_mercapto_5_sideoxy-2,3-dihydro-5//-thiazolo[3,2-β]°pyridin-3-yl]-phenyl· Methyl}_S 152524.doc -113· 201130854 Amino)-butyric acid {3/Μ3〇^*)]Η2·({[6-(5-fluoro-2,3·dihydro-benzo[M] Dioxecyclohexyl-6-yl)-8-(2-fluoro-6-trifluoromethyl) benzylene-7-methyl-% oxo-2,3-dihydro-5 ugly -thiazolo[3,2-α]pyridine-3-yl]phenylmethyl}-amino)-ethoxy]•acetic acid {3 heart·2,3_dihydro-stupid [14]diox Heterocyclohexene-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)·7-fluorenyl_5_sideoxy-2,3-dihydro-5// -thiazolo[3,2-α]ηpyridyl_3_pybyl-decylamino)-ethoxy]-acetic acid {3/Μ3α(π)]Η2-({[6- (5-1·2,3_Dihydro-benzo[indenyl]dioxine-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzoyl)-7-yl _5 pendant oxy-2,3-dihydro-5//-thiazolo[3,2-α]pyridine _3_ phenylphenyl hydrazinyl)-ethoxy]-acetic acid {3 Heart [3α(5·*)]}-[2·({[6-(5-fluoro-2,3-dihydro-benzo[1,4]dioxe-6-yl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5β-thiazolo[3,2-α]pyridinium _3_yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid {3i?-[3a(i?*)]}-4-({[6-(2-fluoro-3) -isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl_5_sideoxy-2,3_dihydro_5// _ 恶0 sits and [3,2-a]n is more than -3-yl]•phenyl-methyl-ammonyl)-butyric acid {35·-[3α(/?*)]··4-( {[6-(2·Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-5-sideoxy- 2,3-Dihydro-57/-oxazolo[3,2-a]»pyridin-3-yl]-phenyl-methyl}•amino)·butyric acid {3/?-[3α( 5·*)]}-4-({[6-(2·Fluoro-3·isopropoxy-phenyl)-8-(2-fluoro- 152524.doc •114· 201130854 6-trifluoromethyl) -benzyl)-7-methyl-5-sideoxy- 2,3-Dihydro-5i/-oxazolo[3,2-a]&quot;tb -3-yl]-styl-methyl}•aminobutyric acid {3^[3W)]}- 4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- side Oxy-2,3-dihydro-5//-oxazolo[3,2-α]. Bispin-3-yl]-phenyl-methyl}•amino)-butyric acid {3/Μ3α(Λ*)]}-[2·({[6-(2-fluoro-3-isopropoxy) -Phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylhydrazino)-7-methyl-5-yloxy-2,3-dihydro-5//- oxa^. Sit and [3,2_α]° than bite base]-phenyl-methyl-amino-ethoxy]-acetic acid {35-[3α(Λ*)]}-[2-({[6-( 2-fluoro-3-isopropoxyphenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxooxy-2,3·dihydrogen -5 ugly-oxazolo[3,2-α]»pyridin-3-yl]-phenyl-methyl-amino)-ethoxy]-acetic acid {3/?-[3〇^*) ]}-[2-({[6-(2-Fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7-methyl) -5-Sideoxy-2,3-dihydro-5//-oxazolo[3,2-β]&quot;bipyridin-3-yl]-phenyl-methyl-amino)-ethoxy ]]-acetic acid {35-[3(χ(5*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2- • fluorotri Fluorinyl-benzyl)-7-methyl·5-sideoxy-2,3-dihydro-5-ugly-oxazolo[3,2-α]»pyridin-3-yl]-benzene 4-Methylaminoethoxyacetic acid 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-phenylmethyl)-7 -methyl-5-sideoxy-2,3-dihydro-5//^ Ββ sits and [3,2-α]0 is more than -3-yl]-phenyl-methyl}-amino)-butylamine 6-(2-fluoro-3-indolyl-phenyl) 8-(2-fluorotrifluoromethyl phenyl)- 7-fluorenyl-3-{phenyl-[3-(1//-tetrazol-5-yl)-propylamino]_ Methyl b 2 3_ dihydro-sigh &quot;sit and [3,2-α]β ratio bite 5-- 6-(4-fluoro-1,3-benzodioxole_5_ Base)_8_[2·Fluor_6_(three 152524.doc -115- 201130854 fluoromethyl)benzyl]]7-mercapto-3-(phenyl{[3-(1//-tetrazole-5-) Propyl]amino}indenyl)-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-α]pyridine^oxide 6-(4-fluoro·stup [ ι,3]dioxol-5_yl)_8_(2·fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-{phenyl-[3-( 177 -tetrazol-5-yl)-propylamino]-mercapto}-2,3-dihydro-thiazolo[3,2-β]pyridin-5-one 2-amino-4-({[ 6-(2-Fluoro-3-indolyl-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzoinyl)-7-methyl-5-oxirane-2,3 -Dihydro-5//-thiazolo[3 2_α] ° ratio -3-yl]-phenyl-fluorenyl}-amino)-butyric acid 3-[(2-amino-ethylamino) Phenyl-methyl]_6_(2_fluoro_3_methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-alum )_7-mercapto-2,3·dihydro-thiazolo[3,2-α]pyridin-5-one 3·[(3-amino-propylamino)·phenyl-fluorenyl]_6_( 2_fluoro_3_decyloxy-phenyl)-8-(2-fluoro-6-trifluorodecyl-phenylhydrazino)-7-mercapto-2,3-dihydro-thiazolo[3,2 - &lt;3]«»Bite 5-ketone 3-[(4.Amino-butylamino)-phenyl-indenyl]_6-(2-fluoro-3-methoxy-phenyl)- 8-(2-Fluoro-6-trifluoromethyl-benzyl)-7-indolyl-2,3-dihydro-β-sar sitting and [3,2-a]nt biting-5-ketone# -[3-({[6-(2-fluoro-3-indolyl-phenyl)_8_(2-fluoro-6-trifluoromethyl)-phenylmethyl)-7-methyl-5-side oxygen Base-2,3-dihydro-5//-thiazolo[3,2-α]pyridin-3-yl]-phenyl-indenyl}-amino)-propyl]_胍[1ξ,3 /^)]-Μ[{6-(2-Fluoro-3-methoxyphenyl)-8·[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -Oxygenyl-5-sideoxy-2,3-dihydro-5 ft-[1,3]thiazolo[3,2-fl]. Bispin-3-yl}(stupyl)indolyl]amino}butyric acid 152524.doc •116- 201130854 Ethyl ester [1ξ,3 &lt;5(;〇]-4-{[{6-(2-Fluoro-3-methoxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)phenylindenyl]-7-fluorenyl -1-Oxygenyl-5-sideoxy-2,3-dihydro-5open-[1,3]thiazolo[3,2-α]ηpyridin-3-yl}(phenyl)indole Ethyl]ethyl}butyrate ethyl ester [1 €, 3 and (phantom)_4-{[{6-(2-fluoro-3-methoxyphenyl)_8-[2-def-6-(trifluoro) Mercapto)phenylhydrazino]-7-methyl-1-oxo-yl-5-sideoxy-2,3·dihydro-5-[1,3]thiazolo[3,2-α]η Ethylpyridin-3-yl}(phenyl)methyl]amino}butyrate [^,35(^)-4-(^6-(2-fluoro-3-methoxyphenyl)_8_[ 2_fluoro_6_(trifluoromethyl)phenylhydrazino]-7-methyl-buoxyl group_5_sideoxy-2,3-dihydro-5 ugly-[1,3]thiazolo[3 ,2-α]ηpyridin-3-yl}(phenyl)methyl]amino}ethyl butyrate 3- [Amino (2-fluorophenyl)methyl]•6_[2_Fluor_3 Xingtrifluoromethoxy)phenyl]_8-[2-fluoro-6-(trifluoromethyl)benzyl]_7-methyl·2 3·dihydro_5 ugly [13] thiazolo[ 3,2-α]pyridine_5-ketone oxide 4-{[{6-(2·fluoro-4-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)benzyl] -7-Methyl-1-oxo-based _5_sideoxy-2,3-dihydrothiazolo[3,2-α]° ratio bite-3_ }(phenyl)methyl]amino}ethyl butyrate 4-{[(3,5-difluorophenyl){6_(2_fluoro-3-methoxyphenyl)_8_[2 fluoro_6_ (three gas sulfhydryl) stupid methyl]_7_methyl_丨_oxy ionyl_5_sideoxy-2,3_dihydro-5 ugly-[1,3]thiazolo[3,2_α]pyridine _3_yl}methyl]amino}ethyl butyrate 4-{[{6-(2-fluoro-3-methoxyphenyl)_8_[2-fluoro-6-(trifluoromethyl)benzene Methyl]-7-methyl-1-oxoinyl_5_sideoxy-2,3 dihydroindolyl,"thiazole S 152524.doc -117- 201130854 and [3,2-α]pyridine -3-yl}(2-fluorophenyl)methyl]amino}butyrate ethyl ester 4_{[{6-[3-(difluoromethoxy)phenyl]_8_[2_fluoro_6•( Trifluoromethyl)benzyl]-7-fluorenyl-1-oxoyl_5_sideoxy-2 3 dihydro is &quot;^,"thiazolo[3,2*^]. Ethyl 3-yl}(phenyl)methyl]amino}butanoate [1ξ,3Λ(/?)]-4-{[{6-(2-fluoro-3-]decyloxyphenyl)_8· [2_ fluoro.6_(trifluoromethyl)phenylhydrazinyl]-7-methyl-1.oxy ionyl_5_sideoxy-2,3_dihydro-5//-[1,3]thiazole And [3,2- &lt;h-pyridyl_3_yl}(phenyl)indenyl]amino}butyronitrile [1ξ,35(/?)]-4-{[{6-(2-fluoro-3-decyloxy) Base)_8_[2_fluoro_6(trifluoromethyl)benzyl]]7-methyl_1_oxy ionyl_5_sideoxy-2,3_dihydro-5open-[1,3] Oxazolo[3,2-acridin-3-yl}(phenyl)indenyl]amino}butyronitrile [1ξ,37?(^]-4-{[{6-(2-fluoro-3-)曱oxyphenyl)_8_[2 fluoro_6_(trifluoromethyl)benzyl]-7-methyloxyoxyl group|sideoxy-2,3_dihydrogen-5-anthracene, 3]嗟君和[3,2-小比咬-3_基}(phenyl)methyl]amino}butyronitrile [1ξ,3;)]-4-{[{6-(2- H -3-曱oxyphenyl)8 [2 -6 -6(trifluoromethyl)benzyl]_7-methyl-1-oxyl _5_ side he[1,3]嗟 并[3,2 ♦ than biting -3_yl}(phenyl)methyl]amino}butyl nitrile '3 · benzodioxol _5 · yl)-8-[2-fluoro-6-(three Fluoromethyl)benzyl]_7•methyloxy ion·% sideoxy-2,3-dihydro·5/ί-[1,3]thiazolo[3,2_port]pyridine_3• κPhenylphenyl) fluorenyl]amino}butyronitrile Πξ,3(10))]_4·(1)6·(4_say-1,3-benzodioxole_5_yl)-8-[2 -Fluoro-6-(trifluoromethyl)benzyl]7-methyl 4 oxygen Subunit·5_ sideoxy-2,3-dihydro-5//-[1,3]thiazolo[3,2_α]pyridine·3•yl phenyl)methyl]amino}butyronitrile 152524 .doc -118· 201130854 Fluoro-l,3-benzodioxole·5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7-methyl_丨·Oxygen ion group _5_ side oxy-2,3-dihydro-5//-[1,3]thiazolo[3,2_β]indole pyridine-3-yl}(phenyl)methyl]amine Benzene nitrile [1ξ,35^)]-4-{[{6-(4-fluoro-indene, 3-phenyl-dioxole-5-yl)-8-[2-fluoro-6 ·(Trifluoromethyl)benzyl]-7-methyl-oxime-oxyl-% pendant oxy-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-α Pyridin-3-yl}(phenyl)fluorenyl]amino}butyronitrile [1ξ,3Λ(β)]-4-{[{6-(4-fluoro-indole, 3-benzodioxanthene) Cyclopentene _5_ yl)-8-[2-fluoro-6-(trifluoromethyl)phenyl fluorenyl]_7-fluorenyloxy ion-5-sideoxy-2,3-anthene-5// -[1,3]嗟β sits and [3,2-α]β is more than -3-yl}(stupyl)methyl]amino}butyrate ethyl ester [l$,3*S(i〇] -4-{[{6-(4-fluoro_ι,3·benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] _7_methyloxy ion group _5_ side oxy-2,3-di Hydrogen-5-[1,3]thiazolo[3,2-indolyl]pyridin-3-yl}(phenyl)methyl]amino}butyrate ethyl ester [1ξ,3Λ(^]-4-{ [{6-(4-Fluoro-i,3_benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7_methyl_ι _Oxygen group _5_ oxo-2,3-dihydro-5i/-[l,3]thiazolo[3,2-α]pyridin-3-yl}(stupyl)methyl]amino} Ethyl butyrate [1ξ,35(^]-4-{[{6-(4-fluoro-indole, 3-benzo-dioxy-cyclohexyl)-5-[2-fluoro- 6-(Trifluoromethyl)benzyl]_7-methyl-buoxyl_5_ oxo-2,3-dihydro-5/f-[l,3]嗔. Sit and [3,2-α]β is more than -3-yl}(stupyl) fluorenyl]amino}ethyl butyrate S 152524.doc -119- 201130854 [1ξ,3/^)]·(2 -{[{6-(4-fluoro-u-benzodioxol-5_yl)-8-[2-fluoro-6-(trifluoromethyl)phenylindenyl]_7-methyl 4 oxygen ion group _5_ side oxy-2,3-dihydro-5i/-[l,3]thiazolo[3,2-α]pyridine-3-ylphenyl)methyl]amino}ethoxy Methyl acetate [1ξ,35(Λ)Η2-{[{6-(4-fluoro13-benzodioxanthene-5-yl)-8-[2-fluoro_6_(trifluoro Methyl) alkaloid]_7_methyl d-oxyl group % pendant oxy-2,3-dihydro-5//-[1,3]thiazolo[3,2-α]pyridine·3_ Methylphenyl)methyl]amino}ethoxy)acetate methyl ester, 3 and (fluorinated fluorine '3-benzodioxolane 5 ·yl)-8-[2·fluoro-6 -(trifluoromethyl)phenylindenyl]_7_methyl-hydrazino-yl-% pendant oxy-2,3-dihydro-5/f-[l,3]thiazolo[3,2-α Pyridine_3_ylindole (phenyl) fluorenyl]amino}ethoxy}acetic acid methyl ester [1ξ,3·5〇5)]-(2-{[{6-(4-fluoro-1, 3_ benzodioxole_5_yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7-methyloxy ionyl_5_ oxo-2,3 -Dihydro-5// -[1,3]thiazolo[3,2-αρpyridin-3-yl}(phenyl)methyl]amino}ethoxy}acetic acid methyl ester [1$,3/?(and)]- 4-{[{8-[2-Fluoro-6-(trifluoromethyl)benzyl]]7-methyl-1-methoxy-yl-5-yloxy-6_[3_(trifluoromethoxy Phenyl]_2,3·dihydro-5 ugly-[1'3]thiazolo[3,2_α]pyridine_3_yl}(stupyl)methyl]amino}ethyl butyrate [1ξ, 35 ·(Λ)]-4-{[{8-[2-Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-methoxy-yl-5-yloxy-6- [3-(Trifluorofoxy)phenyl]_2,3_dihydro-5 ugly-[1,3]thiazolo[3,2·αρpyridyl_3_ylindole(phenyl)methyl] Amino}ethyl butyrate 152524.doc -120· 201130854 [1ξ,3Λ(^)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]_7_methyl _ 1-Oxygenyl-5-sideoxy·6-[3-(trifluorodecyloxy)phenyl]_2,3-dihydro-5 ugly-[1,3]thiazolo[3,2- 〇]&quot;Bistidin-3-yl}(phenyl)methyl]amino}butyrate ethyl ester [1ξ,35Ό)]-4-{[{8-[2-fluoro-6-(trifluoroanthracene) Benzo)benzyl-7-methyl-1-phenyloxy-5-yloxy-6-[3-(trifluoromethoxy)phenyl]_2,3_dihydro-5&quot;-[1 , 3]thiazolo[3,2-α]pyridine-3-yl}(phenyl)- Amino} ethyl butyrate [1ξ,3Λ(;〇]·4-{[{6·(5-fluoro·2,3-dihydro-1,4·benzodioxan-6 -yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7_methyl_丨_oxy ionyl_5_sideoxy-2,3-dihydro_5 ugly- [ι,3]thiazolo[3,2_β]pyridine-3·yl}(phenyl)▼-yl]amino}butyrate ethyl ester [1ξ'35(7?)]-4-{[{6-( 5-fluoro-2,3-dihydro-1,4-benzodioxan-6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7_ Methyl_丨_oxy ionyl-5-sideoxy-2,3-dihydro-5孖-[1,3]thiazolo[3,2-α]. Bis pyridyl·3_yl}(phenyl)methyl]amino}butyrate ethyl ester fluoride-2,3-dihydro-1,4-benzodioxanthene-6-yl)-8·[ 2-fluoro-6-(trifluoromethyl)benzyl]-7-methyloxyindol-5-yloxy-2,3-dihydro-5扒[1,3]thiazolo[3, 2-a] D is more than 唆3 alkyl}(phenyl)f-yl]amino}ethyl butyrate [1ξ,3«5(^)]-4-{[{6-(5-fluoro-2, 3-Dihydro-1,4-benzodioxine-6-yl)-8-[2-fluoro-6-(trifluoromethyl)phenyl]-7-methyllacyl -5-Sideoxy-2,3-dihydro-5//-[1,3]thiazolo[3,2-β] 疋 疋 3 _ yl}(phenyl)f-yl]amino} Ethyl butyrate £ 152524.doc -121- 201130854 [1ξ,3Λ(π)]-(2-{[{6-[3-(difluorodecyloxy)phenyl]-8-[2-fluoro- 6·(Trifluoromethyl)benzyl]-7-fluorenyl-1-oxoyl-5-yloxy-2,3-dihydro·57/-[1,3]thiazolo[3, 2-αρpyridin-3-yl}(phenyl)methyl]amino}ethoxy}ethyl acetate [1ξ,35^)]-(2-{[{6-[3-(difluoro-) Oxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxo-yl-5-yloxy-2,3-dihydro -5//-[1,3]thiazolo[3,2-indene]«pyridin-3-yl}(phenyl)methyl]amino}} Ethyloxyacetate difluoromethoxyoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxo-yl-5-side Ethyloxy-2,3-dihydro, 3]° plug" and [3,2-α]° ratio 0--3-yl}(phenyl)methyl]amino}ethoxy}ethyl acetate [1ξ,35^)]-(2-{[{6-[3-(Difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)phenyl)]- 7-Methyl-1-oxoyl-5-sideoxy-2,3-dihydro-5//-[1,3]thiazolo[3,2-α]α-pyridylpyryl}(benzene Ethyl)methyl]amino}ethoxy}acetate [1ξ,3π(_/?)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-oxime Phenyl)-8_[2_fluoro_6_(trifluoromethyl)benzyl]]7-methyl-2,3-dihydro-5/ί· [1,3]° stopper. Sit and [3,2-α] bite 5-ketone 1-oxide [1ξ,3«5(/?)]-3-[amino(phenyl)indenyl]-6-(2-fluoro -3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]_7·decyl-2,3-diindole-5//_ [1,3] Thiazolo[3,2-α]pyridine_5·ketone oxide [1ξ,37?(5)]_3-[amino(phenyl)methyl]_6_(2-fluoro-3-methoxybenzene Base)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-decyl-2,3·dihydro 201130854 [1,3]嗟"»Sitting and [3,2_£ 3!]11 than bite_5-_1-oxide [ΙξΜ(7)]-3-[amino(phenyl)indenyl]-6-(2-fluoro.3.methoxyphenyl)·8[2 -Fluoro-6-(trifluoromethyl)benzyl]]7-methyl-2,3_dihydro_5/f [i,3] 0 plug 0 sits and [3,2·α]pyridine_5 _ ketone 1-oxide 3 · [amino (3,5-difluorophenyl) fluorenyl]_6_(2_fluoro_3_decyloxyphenyl)_8_ [2- gas-6-(trifluorof) Benzyl]_7_methyl_2 3_dihydro_5 ugly [Μ] oxazolo[3,2-α]pyridine_5-ketooxime_oxide 3-[amino group (2-fluoro Phenyl)fluorenyl]_6_(2_fluoro_3_decyloxyphenyl)_8_[2_fluoro-6-(trifluoromethyl)benzoinyl]-7-fluorenyl-2,3-dihydro-5 Ugly-[13]thiazolo[3,2-α]pyridine·5__丨_oxide (2-{[{6-[3·(1,ΐ_) Difluoroethyl)_2_fluorophenyl]_8_[2_fluoro-6(trifluoromethyl)benzyl]-7-decyl-1-oxo-yl-5-sideoxy-2,3_2 Hydrogen_5//_[1,3]thiazolo[3,2-indole]]pyridine-3-yl}(phenyl)indolyl]amino}ethoxy}methyl acetate (2-{[{ 6-[3·(1,ΐ-difluoroethyl)phenyl]_8_[2_fluoro_6_(trifluoromethyl)benzhydryl]-7-fluorenyl-hydrazine-oxygen group_5-side Oxy 2,3_dihydro,3]thiazolo[3,2-αρpyridinyl-3-yl}(phenyl)methyl]aminopurine ethoxy)acetate methyl 3-[amino group Styyl)methyl]_6_[3_(difluorodecyloxy)phenyl]_8·[2_fluoro·6·(trifluoromethyl) benzyl]_7-methyl-2,3-dihydro- 5//·[1,3] thiapyrano[3,2-α]pyridine-5-one 1-oxide 4_{[{6-(2-fluoro-4-methoxyphenyl)-8- [2·Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxoyl-5-sideoxy-2,3-dihydro-5&quot;-[1,3] Thiazolo[3,2-appyridin-3-yl}(phenyl)indenyl]amino}butyric acid S 152524.doc •123- 201130854 [1ξ,3/2(;?)]-4-{ [{6·(2·fluoro-3-methoxyphenyl)_8-[2-fluoro-6-(trifluoromethyl)phenylhydrazinomethyl-1-oxylyloxy-2,3 - dihydro-5 ugly-[1,3]thiazolo[3, 2-α]pyridin-3-yl}(phenyl)indenyl;|amino}butyric acid [H,3 &lt;S(i?)]-4-{[{6-(2--3-methoxyphenyl)_8-[2- 1 -6-(trifluoromethyl)benzyl]-7- Methyl-1_oxy ionyl_5_sideoxy-2,3_dihydro-5 ugly-[1,3]thiazolo[3,2-α]pyridin-3-yl}(phenyl)indole Amino]butyric acid [15,3^(^)1-4-(1:(6-(2-fluoro-3-methoxyphenyl)_8_[2_fluoro_6_(trifluoromethyl)) Benzyl]-7-methyl_i-oxylyl_5_sideoxy-2,3_dihydro-5//-[1,3]thiazolo[3,2-α]ηbipyridine -3-yl}(phenyl)indenyl]amino}butyric acid [^,35(5))-4-(1:(6-(2-fluoro-3-decyloxyphenyl)·8· [2_ fluoro_6_(trifluoromethyl) benzyl]-7-methyl-1-oxoyl_5_ oxo-2,3-dihydro-5-p-[1'3]thiazole [3,2-α]pyridin-3-yl}(phenyl)indenyl]amino)butyric acid 4-{[(3,5-fluorophenyl){6-(2-fluoro_3_A Oxyphenyl)8-[2-fluoro-6-(difluoromethyl)benzyl]-7-methyl-1_oxylyl_5_sideoxy-2,3_dihydro-5 Ugly-[1,3]thiazolo[3,2 &lt;] acridine-3_yl}mercapto]amino}butyric acid [U,3i?(^]-4-{[{6-(2-fluoro-3-methoxyphenyl)_8.[ 2•Fluoro-6(trifluoromethyl)benzyl]-7-methyl_1_oxylyl_5_sideoxy-2,3_dihydro-5i/-[l,3]thiazole [3,2_α]ηpyridyl_3_yl}(2fluorophenyl)indolyl]amino}butyric acid [1ξ'3(10))]-4-{[{6-(2-)-3-oxo Phenyl)-8_[2_gas_6_(trifluoromethyl)benzyl]-7-methyl-1-oxylyl_5•sideoxy-2,3_dihydro_ 5 open_[ 1,3]thiazolo[3,2-α]. Bisyl}}(2-fluorophenyl)methyl]amino}butyric acid [1ξ,3Λ(5·)]·4·{[{6-(2-fluoro-3-methoxyphenyl)_8_ [2_ 氟_6•(三152524.doc -124· 201130854 fluoromethyl)phenylhydrazino]-7-methyl-buoxyl-5-sideoxy-2,3·dihydro-5 ugly- [1,3]thiazolo[3,2-β]pyridin-3-yl}(2-fluorophenyl)methyl]amino}butyrate fluoride-3-methoxyphenyl)-8-[2 -Fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxoyl-5-yloxy-2,3-dihydro-5-[1,3]thiazole [3,2-α]pyridin-3-yl}(2-fluorophenyl)methyl]amino}butyric acid [1ξ,3Λ(Λ)]-4-{[{6-[3-(difluoro Methoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)azinomethyl]-7-indolyl-buoxyl-5-yloxy-2,3-dihydro -5 ugly-[1,3]thiazolo[3,2-α]αpyridin-3-yl}(phenyl)indolyl]amino}butyric acid [1€,3*5(7?)] -4-{[{6-[3-(Difluoromethoxy)phenyl]_8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxo ion 5--5-oxy-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-β]pyridin-3-yl}(phenyl)methyl]aminoindolinoic acid Difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl)phenylindenyl]·7·曱-1-Oxygenyl-5-sideoxy-2,3_dihydro-5//·[1,3]嗟[3,2-α]η&amp;唆-3-yl}(phenyl曱]amino]amino)butyric acid difluoromethoxy)phenyl]_8_[2.fluoro-6_(trifluoromethyl)phenylhydrazino]-7-fluorenyl-1-oxyl group _5_ side Oxy-2,3_dihydro-5 ugly-[1,3]thiazolo[3,2-αρpyridin-3-yl}(phenyl)indenyl]amino}butyrate,3Λ(7 ?)]-4-{[{6-(4-Fluoro-1,3-benzodioxole-5_yl)-8-[2-fluoro-6-(trifluoromethyl)benzene曱]]-7-fluorenyl-hydrazine-oxyl group _5· pendant oxy-2,3-dihydro-5//-[1,3]thiazolo[3,2-ίφ than pyridine_3_ Base}(笨基) 曱基]amino}butyric acid [14,35(;?)]-4-{[{6-(4-fluoro-1,3-benzodioxanthene) 5_ S 152524.doc -125* 201130854 base)-8-[2·fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1-oxoyl-5-sideoxy-2 ,3-dihydro-5i/-[l,3]thiazolo[3,2-α]βpyridin-3-yl}(phenyl)indolyl]amino}butyric acid [1ξ,3Λ(^) ]-4-{[{6-(4-Fluoro-,3-benzodioxole-5-yl)-8-[2-fluoro-6.(trifluoromethyl)benzene ]-7-methyl-1-oxo-yl 5- 5-oxo-2,3-dihydro-5//-[1,3]thiazolo[ 3,2-α]β-pyridin-3-yl}(phenyl)indolyl]amino}butyric acid [1ξ,3^5*)]-4-{[{6-(4-fluoro-13- Benzodioxol-5_yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]7-methyl-1-oxo-yl-5-sideoxy- 2,3-Dihydro-5//-[1,3]嗟β sits and [3,2- &lt;3]°°°-3-yl}(phenyl)fluorenyl]amino}butyric acid [1ξ,3Λ(8)]-(2-{[{6-(4-fluoro_ι,3-benzo) M-dioxanthene_5_yl)-8-[2-fluoro-6-(trifluoromethyl)phenylhydrazino]_7-methyl_1_oxylyl-5_ oxo-2,3 -Dihydro-5/f-[l,3]thiazolo[3,2-α]°pyridin-3-yl}(phenyl)indolyl]amino}ethoxy}acetic acid [1ξ, 35^ )]-(2-{[{6-(4-fluoro-ι,3-benzodioxole-5-yl)-8-[2-fluoro-6-(difluoromethyl)benzene Methyl]methyl-1_oxy ionyl_5_ pendant oxy-2,3-dihydro-5 ugly-[1,3]thiazolo[3,2-α]pyridin-3-ylphenyl)indole Amino]ethoxy}acetic acid [1ξ,3Μ^]-(2-{[{6·(4-fluoro-L3-benzodioxol-5_yl)-8-[2 -Fluoro-6-(trifluoromethyl)phenylhydrazino]·7-methyloxyl-yl---oxyl-2,3-dihydro-5/ί-[1,3]thiazolo[3, 2-α]pyridine_3·yl}(phenyl)methyl]amino}ethoxy}acetic acid [1$,35(5)]-(2-{[{6-(4-fluoro- ΐ, 3-benzo-3-dioxole_5_ 152524.doc -126 · 201130854 base)-8-[2-fluoro-6-(trifluoromethyl)benzyl]_7_mercapto-p-oxygen Base _5· side oxy-2,3-dihydro-5//-[1 3]thiazolo[3,2-α]pyridin-3-yl}(stupyl)methyl]amino}ethinyl)acetic acid [1ξ,3Λ(Λ)]-4-{[{8-[2 -fluoro-6-(trifluoromethyl)benzyl]-7-methyl· 1-oxo-yl-5-oxo-6-[3-(trifluorodecyloxy)phenyl b. 3-Dihydro-5 ugly-[1,3]thiazolo[3,2-indolyl]pyridin-3-yl}(phenyl)methyl]amino}butyric acid [15,35(/^-4- (1: (8-1:2-fluoro-6.(trifluoromethyl)benzyl]-7-methyl_ φ 1_oxy ionyl_5_sideoxy-6·[3·(three Fluoromethoxy)phenyl]-2,3·dihydro-5/f-[l,3]thiazolo[3,2π]pyridin-3-yl}(phenyl)methyl]amino}butyric acid [1ξ,3Λ(^)]-4-{[{8-[2-Fluoro-6-(trifluoromethyl)phenylmethyl]7_methyl_ 1-oxoionyl-5-sideoxy-6 -[3.(Trifluoromethoxy)phenyl]·2,3-dihydro·5//-[1,3]thiazolo[3,2-α]pyridin-3-yl}(phenyl) Methyl]aminobutyric acid [1ξ,35(^)]-4-{[{8-[2·fluoro-6-(trifluoromethyl)benzyl]]7-indenyl-1-oxygen -5-Sideoxy-6-[3-(trifluoromethoxy)phenyl]_2,3-dihydro-5-dan-[1,3]thiazolo[3,2-α]pyridine-3 -yl}(phenyl)indenyl]amino}butyric acid • Fluorin-2,3-dihydrobenzodioxan-6-yl)-8 -[2-Fluoro-6-(trifluoromethyl)benzoinyl]_7•methyl_丨_oxy ion-5-sideoxy-2,3-dihydro-5孖-[1,3] Thiazolo[3,2·α]pyridine_% base}(phenyl)f-yl]amino}butyric acid [1$,3 external/?)]-4-{[{6-(5-fluoro-2) ,3-dihydro-1,4-benzodioxan-6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]]7_methyl_丨_ Oxygenyl-5-yloxy-2,3-dihydro-5孖-[1,3]thiazolo[3 2 α]pyridine·3 -yl}(stupyl)methyl]amino}butyric acid [1ξ,37?(^]-4-{[{6-(5-fluoro-2,3-dihydro-14. benzodioxan 152524.doc -127- 201130854 ene-6-yl) -8-[2-Fluoro-6-(trifluoromethyl)benzyl]7-methyl-phenoxy-yl-5-sideoxy-2,3-dihydro-5 ugly-[1,3 Thiazolo[3,2-pyridyl-3-yl}(phenyl)methyl]amino}butyric acid [16,35(5)]-4-{[{6-(5-fluoro-2,3) -dihydro-1,4-benzodioxan-6-yl)-8-[2-fluoro-6-(trifluoromethyl)benzoinyl]-7-methyl_ι_oxygen Ionic group - 5' pendant oxy-2,3 -hydrogen-5i/-[ 1,3] sputum β sitting and [3,2-〇]° ratio biting -3_yl}(phenyl)fluorenyl] Amino}butyric acid [1ξ,3/?(/2)Η2-{[{6·[3-(difluorodecyloxy)phenyl]_8_[2_fluoro-6_ ( Fluoromethyl)benzyl]-7-mercapto-1-oxylyl_5_sideoxy-2,3_dihydro-5//-[1,3]thiazolo[3,2-ω ° 啶 -3--3-yl}(phenyl)methyl]amino}ethoxy}acetic acid [1ξ,35(8)]-(2-{[{6-[3-(difluorodecyloxy)phenyl) ]_8_[2_Fluoryl-6-(trifluoromethyl)benzyl]-7-fluorenyl-1-oxylyl_5•sideoxy-2,3·dihydro-5 ugly-[1,3] Thiazolo[3,2-α]ηpyridyl_3_yl}(phenyl)indenyl]amino)ethoxy)acetic acid [1ξ,3Λ(5)Η2-{[{6-[3-( Difluoromethoxy)phenyl]_8_[2_fluoro_6_(difluoromethyl)benzyl]-7-fluorenyl-1-oxoyl_5_sideoxy-2,3-dihydro- 5 ugly - [1,3] thiazolo[3,2-«]. Bispin-3-yl}(phenyl)indenyl]amino}ethoxy}acetic acid [14,35(5)1-(2-^(6-1:3-(difluoromethoxy)benzene) Base]_8-[2-fluoro-6-(difluoromethyl)benzyl]-7-fluorenyl-1-oxylyl_5_sideoxy-2,3-dihydro-5 ugly-[ 1,3]thiazolo[3,2-α]pyridin-3-yl}(phenyl)indenyl]amino}ethoxy}acetic acid [1ξ,3Λ*(Λ*)]-(2-{[ {6-[3-(1,1-Difluoroethyl)_2-fluorophenyl]·8- 152524.doc -128- 201130854 [2-Fluoro-6-(trifluorof-yl)benzyl]- 7-Methyl-1-oxo-yl_5_sideoxy-2,3- one wind 1,3] °ββ[3,2-α]0 than bit-3-yl}(phenyl )methyl]amino}ethoxy)acetic acid [1$,3 and *(*^*)]-(2-{[{6-[3-(1,1-difluoroethyl)-2- Fluorophenyl]_8_[2-fluoro-6-(trifluoromethyl)benzyl]_7-methyl-buoxyl_5_sideoxy·2'3-dihydro-5i/-[l , 3] every. Sit and [3,2-α].0 than indole-3-yl}(phenyl)methyl]amino}ethoxy}acetic acid (2-{[{6-[3-( 1,1_difluoroethyl)phenyl]-8_[2_fluoro_6·(trifluoromethyl)benyl]-7-methyl-1-oxoyl-5-sideoxy-2 ,3-dihydro-5i/-[l,3] ° succinyl[3,2-s-azino-3-yl}(phenyl)methyl]amino}ethoxy The compound of any one of claims 1 to 31, which is used for the treatment of endometriosis. , uterine fibroids, polycystic ovarian disease, excessive menstrual bleeding (specifically, dysmenorrhea and menstrual difficulties), hirsutism, precocious puberty, gonadal steroid-dependent neoplasia (such as prostate cancer, breast cancer and ovarian cancer), gonad pituitary gland Tumor, sleep apnea, large intestine irritability, menstrual syndrome, benign prostatic hypertrophy, contraception, infertility, assisted reproductive therapy such as in vitro fertilization, treatment of growth hormone deficiency and short stature, and treatment of systemic lupus erythematosus. 34. A pharmaceutical composition comprising a compound as claimed in claims 1 to 31. S 152524.doc • 129-201130854 IV. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) A brief description of the component symbols: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: X (|) S 152524.doc