TW201121978A - Substituted para-biphenyloxymethyl dihydro oxazolopyrimidinones, preparation and use thereof - Google Patents

Abstract

The present invention relates to a series of substituted para-biphenyloxymethyl dihydro oxazolopyrimidinones of formula (I): Wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein. This invention also relates to methods of making these compounds including novel intermediates. The compounds of this invention are modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2 receptor. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic neurodegenerative conditions, psychoses, cognition deficit disorders, convulsions, anxiety, depression, migraine, pain, sleep disorders and emesis.

Description

201121978 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to a series of substituted dihydrophenyloxymethyl ketones. More specifically, the present invention relates to a series of substituted 2 -biphenyl ice = methyl-2,3-hydrogen tau and [3,2_a] shots. The present invention (4) relates to a method of preparing the two compounds. The compounds of the present invention are metabolic profiles; (iv) viscera, especially the allosteric modulators of mG1. Thus, the present invention = a compound can be used as a medicament, especially for the treatment and/or prevention of various diseases, including diseases associated with the central nervous system. [Prior Art] Recently, there have been quite a lot of studies involving L-face Xiao Chun. L♦ Amine is the most abundant neurotransmitter in the midlined nervous system (CNS). More specifically, L- faceamine mediates a major excitatory pathway in mammals' and is therefore referred to as excitatory amino acid (EAA). Therefore, a receptor that responds to glutamate is called an excitatory amino acid receptor (EAA receptor). Based on recent extensive research, it is easy to see that 'Eaa is of great physiological importance. In particular, EAA is known to play a role in certain physiological processes, including long-term enhancement (learning and memory), synaptic plasticity development, motor control, respiration, cardiovascular regulation, and sensory perception, to name a few. See, for example, Watkins & Evans, Annual Reviews in Pharmacology and Toxicology, 21: 165 (1981); Monaghan,

Bridges, and Coltman, Annual Reviews in Pharmacology and Toxicology, 29:365 (1989); Watkins, Krogsgaard-Larsen and

Honore, Transactions in Pharmaceutical Science, 11:25 (1990) 0 4 201121978 Broadly speaking, 'the EAA receptors are divided into two types: i) "ionophilic" - they are directly coupled to the cation opening of the neuronal cell membrane; 2) "metabolic" - they are G-protein coupled receptors (GPCRs). Excessive stimulation or inappropriate stimulation of EAA receptors leads to destruction or loss of neuronal cells through a mechanism known as excitotoxicity. This process is thought to mediate neuronal degeneration in various symptoms. Therefore, there has been renewed interest in the development of new drugs for small molecules to alleviate these symptoms. Metabotropic glutamate receptors (mGluR) are a class of highly heterologous glutamate receptors that are linked to multiple second messenger pathways. One function of these receptors is to regulate presynaptic release of glutamate and post-synaptic sensitivity of neuronal cells to facial acid stimulation. Therefore, it is widely reported in the literature that agonists and antagonists of these receptors can be used to treat various diseases including acute and chronic neurodegenerative diseases, psychosis, paralysis, anxiety, depression, migraine, pain, sleep disorders and Region vomitosis 0 Based on receptor homology and signaling mechanism, the metabotropic glutamate receptor (mGluR) is further divided into three groups. Among them, recent pharmacological and histochemical studies suggest that Group II mGluR (mGluR2 and mGluR3) play a crucial role in the control of emotional state. For example, a selective π-group mGluR antagonist, MGS0039', has been shown to be dependent on the anti-suppression effect of Agent 1C in certain animal models. See, for example, Kawashima, et al., Neurosci. Lett., 2005, 378(3): 131-4. Recently, there have been reports that glutamic acid/N-methyl-D-aspartate-willine receptor (NMDAR) is associated with schizophrenia. Indeed, the following observations support the conclusion that administration of NMDAR blockers to volunteers can lead to psychosis, which can exacerbate the original symptoms in patients with mental schizophrenia 201121978. For example, systemic administration of a π-group mGluR agonist inhibits the behavioral effects of phencyclidine (PCP) and the increase in glutamate excretion. It has also been observed that activation of the third group mGluR (mGluR2 and mGlUR3) reduces the release of presynaptic nerve endings from the facial acid, suggesting that the third group mGluR agonist may be beneficial for the treatment of schizophrenia. See also 'for example Chavez-Noriega et al' Current Drug

Targets - CNS & Neurological Disorders, 2002, 1,261-281. Although there is great interest in the development of small molecule drugs that are effective at the mGluR site, researchers are faced with a lack of effective and selective molecules. Despite this, there are countless reports that show a great interest in people around these potential treatment goals. See, for example, Sabbatini and

Micheli, Expert Opin. Ther. Patents (2004) 14(11): 1593-1604. However, there is still a need to develop certain compounds that are more specific for one subtype than the other metabotropic face amine receptor site. A recently developed strategy involves the development of certain allosteric modulators that are not bound by the facial acid binding site. The allosteric modulator / will act in the presence of the agonist (face amine gt) at the orthotopic binding site 'so' (iv) the modulator will only enhance or block the effect due to the presence of the agonist 'But it is not active in itself. It is believed that this strategy will enable the desired drug to be used with a greater 'specificity' because they affect the normal aging of the agonist's large η to improve the efficacy and regulation of mGluR2 and change: the sophomore: Interesting, small molecule "drug-like" compounds are still pure, interesting. Typical and atypical antipsychotic compounds show some typical side effects of 201121978, including, for example, tardive dyskinesia, weight gain, etc. Extrapyramidal symptoms. There is also interest in the development of mGiuR2 modulators that do not have such side effects at all. It is also expected that improved sub-regulators will have improved pharmacological safety characteristics. Further, it is believed that careful selective modulators will also show no effect in cognitive dysfunction in patients with schizophrenia, thus improving memory and positive symptoms. WO 2008/112483 discloses a series of 2_substituted 2,3-dihydro-decane and [3'2-small terminal 7, and 2-substituted 2,3,5,6-tetradecyl. They are metabotropic glutamate receptors (mGluR) open 3[' = 7 allosteric modulators. In particular, 疋mGluR2 not only displays the desired allosteric regulation properties, such as various "drug-like" characteristics, including but not limited to the taste and excretion (ADME) characteristics and the good adsorption, distribution, and metabolism of the drug. Cytochrome P450 enzyme or CYP action ' ^, , · Tian et al. In general, it is suitable as a diprotein transduction, reductase, dehydrogenase, etc. The activity characteristics of the enzymes are more, and the minimum CYP embroidering effect and the 疋 'observation' are observed. Generally, WTJL Gu Gan “ 化合物 The best CYP-influencing compounds are recognized and have favorable “drug-like” properties. In addition to other CYP isoforms w.± CYP2D6 > CYP2C9 # 〇 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 、 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别 特别_ Dihydro Evil Butterfly... Chestnut Na is only a valid 201121978 mGluR2 synergist, and also _; +, I don't know the improved "drug-like" properties as described herein. SUMMARY OF THE INVENTION Accordingly, in accordance with the present invention, a compound of the formula ι is provided:

Wherein: Ri is far from the following group of groups and propyl; R2 is selected from the group consisting of the following groups: (I) hydrogen, fluorenyl, fluoroindolyl, ethyl, 2-fluoroethylhydromethyl, fluoromethyl, Ethyl, 2-fluoroethylpropyl, 1,1-difluoropropyl, methoxymethyl, ethoxymethyl fluoroethoxymethyl, ethoxy-fluoroethyl, isopropoxy The methyl group has no methyl group, ethyl group, morphinyl group, and VI ratio P each group: a group, a tetrahydrofuranyl methoxy fluorenyl group, a cyclopropyl group and a cyclopentyloxymethyl group; and R3 4 R5 And R6, R? and R8 are the same or different and independently of each other, from the group consisting of hydrogen, halogen, CF3, (CVC4) alkyl, (Ci, C4) alkoxy; or R6 R?? And two groups in r8 are on adjacent carbon atoms and form a naphthalene ring together with the benzene ring; or 8 201121978 R6, R7# r8 such that two groups are on adjacent carbon atoms and with carbon atoms - Forming a five-membered or six-membered ring; or a group of R6, R7^R8 bonded to an adjacent benzene ring to form a first base ring; or a salt thereof. In addition, 'the present invention', including the pharmaceutical compositions containing various subjects of the present invention, and their use in the treatment of various disorders and/or diseases disclosed herein are also part of the present invention, all of which are Both will be described in detail below. DETAILED DESCRIPTION OF THE INVENTION The terms used herein have the following meanings: As used herein, the term "(CrC:4)alkyl" includes fluorenyl and ethyl, as well as straight or branched propyl and butyl. Preferred alkyl groups are decyl, ethyl, n-propyl, isopropyl and tert-butyl. In particular, it should be noted that any possible branched (C1-C4) alkyl groups known in the art are included in this expression. Derived expressions such as "(Crc4) alkoxy", "(q-CO thioalkyl), "(CVC4) alkoxy (CrC4) alkyl" or "hydroxyl (crc4) alkyl", "(CVQ "Alkylcarbonyl", "(CrC4) alkoxycarbonyl (CrC4) alkyl", "(CrC4) alkoxycarbonyl", "amino (CVC4) alkyl", "(crc4) alkylamino" , "(CVC4)alkylamino decanoic acid (CrC4) alkyl", "(Crc4) dialkylamino fluorenyl (CrC4) alkyl", "mono or di(CrC4) alkylamino" Cvcoalkyl", "amino(CrC4)alkylcarbonyl", "diphenyl(crc4)alkyl", "phenyl (crc4)alkyl", benzyl (CrC4) alkyl, "benzene" The oxy group (C^-Cd alkyl group) and "(C]-201121978 c〇alkylsulfonyl group" should also be understood accordingly. Similarly, other derived expressions such as (CrC4) alkoxy ethoxylate The base should also be understood accordingly. Another derivative of the expressed di-mono- or di-fluoro(crc4)alkyl means that one or two deuterium atoms are said to be substituted. Representative examples of monofluoro (CVC4) alkyl groups include gas. Methyl, 2_glycolyl or 1-fluoroethyl-1-yl, 1-nitro-1-methylethyl-1-yl, 2^"methyl Small groups, alan-1-yl', etc. Representative examples of difluoro(QQ) alkyl groups include dimethylmethyl, 2,2-difluoroethyl-1-yl, 1,2-difluoroethyl Or u difluoroethyl+yl, fluoro-1-indenylethyl, 2,2-difluoromethylethyl, difluoropropanyl, etc. As used herein, "( The expression C3_c7) cycloalkyl or "(C3_C7) carbocycle" includes all known cyclic groups. Representative examples of "cyclofilament" or "carbocyclyl" include 'but without any limitation, cyclopropyl a group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. a derivative such as "cycloalkoxy" or "cycloalkyloxy", "lyoxyethoxy", "ring" The base of the base, the "ring-burning aryl group" and the "ring-ring base" should also be understood accordingly. It should be noted that the expression "(CVC8) carbon sulfhydryl" should have The meaning of C5_C8)cycloalkyl". "Halogen" (or "halogen") means gas, fluorine, desert, and iodine. "Work" as used herein. "Patient" means a warm-blooded animal, such as a rat. Mice, dogs, cats, guinea pigs, and primates As used herein, the expression "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is admixed with a compound of the present invention. The composition, that is, the form of the drug 201121978 which is suitable for administration to a patient. One example of such a carrier is a pharmaceutically acceptable oil, usually for parenteral administration. "Pharmaceutically acceptable salt" as used herein. This term means that the salts of the compounds of the invention are useful in the preparation of a medicament. However, some other salts may also be used in the preparation of the compounds of the present invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be prepared by admixture of a solution of a compound of the invention and a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonate Acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2- Phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Acid addition metal salts such as sodium hydrogen phosphate and potassium hydrogen sulfate can also be formed. Moreover, the salt thus formed may be present as a monoacid salt or a diacid salt form, or as a substantially anhydrous salt or a hydrated salt. Further, when the compound of the present invention itself contains an acidic group, the pharmaceutically acceptable salt may include a metal salt such as a sodium salt or a potassium salt; a soil metal salt such as ! a salt of a bow or a magnesium salt; and a salt formed with a suitable organic ligand, such as a quaternary ammonium salt. The term "prodrug" as used herein shall have the meaning commonly accepted in the art. Such definitions include pharmacologically inert chemical entities which can be converted to a pharmacologically active substance when biological systems such as mammalian systems cause their metabolism or chemical conversion. The expression "stereoisomer" is the only general term for all isomers of various molecules differing only in the orientation of the atoms in space. Typically, it includes mirror image isomers (enantiomers) which are often formed by the presence of at least one asymmetric center. When 201121978 =::=== one, they can also: = the same but fast; two or two of the equilibrium state ^ ^ 1 it ii tTm ^ ^ ^ ^ # 11 ; the isomer, imine - the enamine 2 = the isomer and its various ratios (4) mixtures are all encompassed by the present invention. The term "solvate" as used herein means a solute ion containing one or more solvents: An aggregate composed of molecules. Similarly, a "hydrate" is a solute ion or molecule that contains one or more water molecules. Broadly speaking, the term "substituted" is intended to include substituents for all acceptable organic compounds. In some specific embodiments disclosed herein, unless otherwise indicated, the term "substituted" means substituted by one or more substituents independently selected from the group consisting of: (Ci-Cm) alkyl, (C2-C6)alkenyl, (cr C6)perfluoroalkyl, phenyl, thiol, -C〇2H, ester, guanylamino, (Ci_c6) alkoxy, (C1-C6) thio Alkyl, (CrC6) all-I alkoxy, _Nh2, c-Br, IF, CN, SF5, -NH-lower courtyard, and -N (lower alkyl)2. However, any other suitable substituent known to those skilled in the art can be used in these specific embodiments. By "effective therapeutic amount" is meant a dose of a compound that is effective in the treatment of a particular condition, disorder or condition. The term "treatment" refers to: 12 201121978 (Preventing a disease, disorder or symptom that occurs in a patient who is prone to suffering but has not been diagnosed as having the disease, disorder and/or symptom; (ii) inhibiting the disease A disease, disorder or symptom, ie inhibiting its development; and (iii) mitigating the disease, disorder or symptom', thereby causing the regression of the disease, disorder and/or symptom. Thus, in accordance with the practice of the present invention, a phantom compound is provided:

Hydrogen, sulfhydryl, fluoromethyl, ethyl, 2-fluoroethyl

Ri is selected from the group consisting of the following groups and propyl groups; the core is selected from the group consisting of hydrogen, sulfhydryl, fluoroindolyl, ethyl, 2·fluoroethyl, propyl, 1 difluoropropyl, Methoxyfluorenyl, ethoxylated ethoxyethoxy fluorenyl, ethoxyoxyethyl, isopropoxy carbyl, fluorenyl, ethyl, morphinyl, slightly bite a fluorenyl bh- yl methoxymethyl group, a cyclopropyl group and a cyclodecyl group; and R 3 ft 4 R5 R6, r7 and R8 are the same or different and are independently selected from the group consisting of: hydrogen , dentate, CF3, (CrC4) alkyl, (Cr C6) cycloalkyl, (CrC4) alkoxy; or 13 201121978 and & Yin two groups on adjacent carbon atoms and together with the benzene ring Forming a naphthalene ring; or n = r8 t two groups on the phase _ carbon atom and with their attached stone anti-atoms form a five-membered or six-membered ring, or R6, if R8 makes a group and phase The adjacent benzene rings combine to form a middle-in particular embodiment. 'The compound of formula (1) of the present invention T substituents R1 to K have the following definitions: & selected from the following group of groups: hydrogen, methyl and Ethyl; R2 A group of groups from τ: hydrogen, methyl, methicone, dimethyl methoxymethyl, ethoxylated fluorenyl, 2- ethoxyethoxymethyl, isopropyl-methyl, benzene a group, a methyl group, an ethyl group, a methyl group, a methyl group, a molar ratio of a methyl group, a cyclopropyl group and a cyclopentyloxymethyl group; and R4, R5, R6, r7 and R8 are the same or different, and Independently selected from the group consisting of hydrogen, gas, chlorine, methyl, ethyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, Cyclopropyl and ethoxy. Again, this is present in the form of any possible salt of the invention. In a particular embodiment, the compound of formula (I) may be part of the present invention. 201121978 In another embodiment of the invention, the compound of formula (i) has the following substituents:

Ri is hydrogen or ethyl; R 2 is hydrogen; R 3 ' R 4 , Rs, R 6 , R 7 are the same or different and are independently selected from the group consisting of hydrogen, fluorine, methyl, ethyl, n-propyl. , isopropyl, n-butyl, isobutyl, tert-butyl, methoxy and ethoxy. Further, as mentioned above, all of the compounds of this embodiment may also be present in the form of a salt in any possible b state, and these salts are also part of the invention. As another specific embodiment of the present invention, the compound of the formula (1) represents a substituent:

Ri is selected from the group consisting of hydrogen, methyl and ethyl; I is hydrogen; R3, r4, r5 are hydrogen; and two of R6, K and R8 are on adjacent carbon atoms and with benzene The rings together form a naphthalene ring; or two of R6, R7 and r8 are on adjacent carbon atoms and together with the carbon atom to which they are attached form a five-membered or six-membered ring. All possible salts of this particular embodiment are also part of the present invention. Specific examples of the compound without any (1) can be exemplified by bis(S)-2-(biphenyl-4-yloxymethyl)_2,3-dihydronfzo[3,2-a]pyrimidinone; 201121978 (8)-2-(biphenyl-4-yloxyindenyl)-6-ethyl-2,3-dihydrooxazolo[3,2^]pyrimidin-7-one; (S -2-(biphenyl-4-yloxyindenyl)-5-pyridyl-2,3-dihydrooxazolo[3,2-a] 0-den-7-one; (S )_2_(biphenyl-4-yloxymethyl)_5_(2-ethylidene)-2,3-dihydroanthracene σ sit and [3,2-3.]03⁄4-7-> (S -2-(biphenyl-4-yloxymethyl)-5-ethoxyindolyl-2,3-dihydro σ-n-n-[3,2-a]pyrimidin-7-one; S)-2-(biphenyl-4-yloxymethyl)-5-isopropoxycarbonyl 2,3-dihydro 0-α-[3,2-a]pyrimidin-7-one (S)_2-(Biphenyl-4-yloxyindenyl)-5-cyclopentyloxy 2,3-dihydrocarbazo[3,2-&] mocking -7_ ,,, (S)-2-(biphenyl-4-yloxymethyl)-5-(tetrahydrofuran-2-yloxycarbonyl)_ 2,3-dihydro-4 spit[ 3,2-&]°Bite-7-_; (8)-2-(Biphenyloxyindenyl)-5-(2-fluoroethoxyindolyl)_2,3-dihydrooxazole And [3,2-a]pyrimidin-7-one; and (S)-2-(biphenyl-4-yloxyindenyl)_5-fluoroindolizine Pyrimidin-7-one. ' As a further specific example of the compound of the formula (I), there is no limitation: (S)_2-(3'-azinobiphenyl-4-yloxymethyl)-2,3-di can be exemplified by the following compounds Pyridin-7-one; dihydrocarbazo[3,2-a]pyrimidin-7-one; dihydrocarbazo[3,2-a]pyrimidine 16 201121978 (S)_2-(2-methyl linkage Benzene-4-yloxymethyl)_2,3_diaza-dead[m]-triacyl-7-one; '(S)-2-(2·-methylbiphenyl_4_yloxy)曱,), 2,3-dihydrocarbazolo[3,2 oxazolidine _7_ 酉; (S)-2-(3·-fluorenylbiphenyl _4_yloxy fluorenyl) _2,3_Dihydrocarbazole[a·小密°定-7_@同; (S)-6-ethyl-2-(2-mercaptobiphenyl-4-yloxymethyl)_2, 3_dihydrocarbazo[3,2-a]pyrimidin-7-one; (S)-6-ethylmethylbiphenyl-4-yloxymethyl)_2,3·dihydrooxazole And [3,2-a]pyrimidin-7-one; (sy-e-methylbiphenyl_4_yloxymethyl)_6_methyl-2,3_dihydro-decaine[3,2 -a]pyrimidin-7-one; (S)-2-(3'-methylbiphenyl-4-yloxymethyl)methyl-2,3-dihydro[3,2-a]pyrimidine -7-ketone; &(S)_2-(2·-ethylbiphenyl_4_yloxyindenyl)_2,3-dihydro-α-azolo[3,2_a]pyrimidin-7-one; ' ^ (S)-2-(2-ethylbiphenyl_4_yloxy) Methyl)_2,3_dihydrooxazolo[3,2_a]pyrimidin-7-one; ' & (S)-2-(4'-ethylbiphenyl_4_yloxymethyl)_2 , 3_dihydroindolozoloxazin-7-one; 'Mountain (S)-2-(3'-ethylbiphenyl-4-yloxyindenyl)_2,3-dihydrocarbazole Pyridin-7-one; ' & (S)-6-ethyl-2-(2,-ethylbiphenyl-4-yloxymethyl)_2,3_dihydrooxazol[3,2 -a]pyrimidin-7-one; 17 201121978 (S)-2-(2'-ethylbiphenyl_4-yloxyindenyl)_6-fluorenyl-2,3_dihydroπ-azolo[ 3,2-a]pyrimidin-7-one; (S)-2-(2-ethylbiphenyl-4-yloxyindenyl)-6-indenyl 2,3-dihydrocarbazol[3 , 2-a]pyrimidin-7-one; (S)-2-(4'-ethylbiphenyl·'-yloxyindenyl)·5-hydroxyindoleyl-2,3-dihydroindole [3,2-a]pyrimidin-7-one; (S)-2-(4··ethylbiphenyl·4-yloxyindenyl)_5_(2-hydroxyethyl)_2,3-dihydrogen (Z)-5-ethoxyindolyl-2_(4i-ethylbiphenyloxyindenyl)·2,3_dihydrogen 0 Isooxa[3,2-a]pyrimidin-7-one; (S)-2-(4'-ethylbiphenyl-4-yloxyindenyl)isopropoxyfluorenyl_2,3_ Dihydrocarbazo[3,2-a]pyrimidin-7-one; (S)-2-(4'-ethylbiphenyl-4-yloxymethyl) Phenyi-3_dihydroindole[3,2-a]pyrimidin-7-one; (S)-5-cyclopentyloxyindol-2-(4'-ethylbiphenyl_4-yloxy) Methyl)_2 y dihydrogen 0 oxa[3,2-a]pyrimidin-7-one; (S)-2-(4·-ethylbiphenyl_4_yloxyindenyl)_5_(four Hydrogen thiophene-2-yloxymethyl)-2,3-dihydro oxazolo[3,2-a]« pyridine-7,; (S)-2-(4'_ethyl Benzene-4-yloxymethyl)_5_(2_fluoroethoxymethyl)_2 3_dihydrooxazolo[3,2-a]pyrimidin-7-one; '(8)-2-(3'- Propylbiphenyl_4_yloxyindenyl)_2,3_dihydro-decane[3 唆-7-one; '(8)·2-(2'·isopropylbiphenyl_4_yloxy Methyl)_2,3 dihydro-pyrimidin-7-one; ' 18 201121978 (S) 2-(3-isopropylbiphenyl-4-yloxymethyl)_2,3-dihydrooxazolopyrene , 2_a] pyrimidine-7-one; (S) 5 (2-fluoroethoxyindenyl)_2_(3L isopropylbiphenyl_4_yloxymethyl)_dihydrocarbazo[3,2_a Mouth bite _7_ketone; (8)-5-gasmethyl-2-(3'-isopropylbiphenyl-4-yloxyindenyl)_2,3_diaza sigma squat [3,2 -a]pyrimidin-7-one; (s)-2-(3,-butylbiphenyl_4_yloxymethyl^,^Nitride and sita[3,2·smallidin-7-one ; (S)-2-(3'-isobutylbiphenyl_4_yl曱, _, _, _, _, _, _ , 3_dihydrocarbazolo[3,2_a]pyrimidine-7-_ ; '(S)_2-(3'-trifluoromethylidene phenyl-4-yloxymethyl)_2,3_2 Hydroquinone oxazole and a]. dense. (7)-2((2'-trifluorodecylbiphenyl-4-yloxyindenyl)-2,3-dihydrocarbazolyl [3,2_ a>-ketone;(S)_2-(3'-cyclopropylbiphenyl-4-yloxymethyl)_2,3-dihydrocarbazo[3,2_a]pyrimidine; ()2 (2 ring Hexylbiphenyl-4-yloxyindenyl)-2,3-dihydro-salt and [3,2-a] mouth-densified -7-酉; (δ)-2-(3'-- Oxybiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2_a] lysylose -7-oxime; (S)-5-isopropoxy fluorenyl _2_(4,_曱-oxybiphenyl_4_yloxyindenyl)_2,3_monohydrogen °°[3,2-a]n-biti-7-one; and 201121978 (8)-2 -(2'-Ethylbiphenyl-4-yloxymethyl)_2,3-dihydrocarbazo[3,2_a] σ疋-7 _ g. Further enumerated below are specific examples of the present invention: (S) 2 (2,3-mono-biphenyl-4-yloxyindenyl)-2,3-diaza. Salivary [3 2-a] pyrimidin-7-one; (8) stomach 2-(2\3'-difluorobiphenyl-4-yloxymethyl)_5_decyloxymethyl-2,3_ Dihydrocarbazol [3,2-a]pyrimidin-7-one; (8)-2-(3',4·-difluorobiphenyl-4-yloxyindenyl)_2,3-dihydroboxide And [3,2 a]pyrimidin-7-one; '(S)-2-(2',3'-dichlorobiphenyl_4_yloxymethyl)_2,3_dihydrocarbazolo[ 3,2_a] pyrimidine-7-one; 厶(2',3L di-biphenylbi-4-yloxyindenyl)_5_methoxymethyl-2,3-dihydrocarbazole P,2 -a]pyrimidin-7-one; '(S)-2-(2,4'_di-biphenylbi-4-yloxyindenyl-2,3-dihydroindole[3,2_a] Pyrimidine-7-one; '(S)-2^2',3'-di-biphenyl-4-yloxymethyl)·5-methyl'indole dihydrocarbazo[3,2-a ] pyrimidine-7-ketone; (8) 5-cyclopropane H (2',3·-di-biphenylbi-4-yloxymethyl)_2,3-diazinium and other salivary [3,2-a]pyrimidine -7-ketone; (S)-2-(2,,3,_di-biphenylbiylyloxyf-yl)_5_fluoroindolyl-2,3d# 11 sitting and [3,2-a] mouth Bite-7-keto; (S)-2-(2J-dioxbiphenyloxyindolyl)_5_morpholine_4_ylindenyl 1,3-dihydroazolo[3,2_a]pyrimidine_7· Ketone; 20 201121978 (S)-2-(2 3'-Dichlorobiphenyl-4-yloxymethyl ) _5_. Biha. _2,3_dihydrooxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2',3'-di-biphenyl-4-yloxy (8)-2-(2',3|-dichlorobiphenyl _ _5_hydroxyindole 2,3_2氡呤σ sitting and [3,2-a] mouth bite-7-ketone; (8)-2-(2',3|-dichlorobiphenyl 4-yloxyindenyl)_5_(2_ethylidene)_2,3_dioxaxo[3,2-a]pyrimidin-7-one; (S)-2-(2', 3'c chlorobiphenyl oxycarbonyl group >5_ethoxy fluorenyl 2,3_dihydro σ-oxazolo[3,2-a]pyrimidin-7-one; (S)_2- (2j|-dichlorobiphenyl_4_yloxyindenyl)_5_isopropoxycarbonyl group 2,3_ a squat and [3,2-3]° sessile-7-one; (S -2-0,3'_di-biphenylbi-4-yloxyindenyl)-5-phenyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one; S)-5: cyclopentyloxy 2,2-(2,,3,-dichlorobiphenyl_4-yloxyindenyl dihydro-sigma 坐[3,2-a]pyrimidin-7-one (S)-2-(2,3'-dichlorobiphenyl_4_yloxymethyl)_5_(tetrahydrofuran-2-ylmethoxymethyl)-2,3-dihydro 0 [3,2-a] bite _7-酉; (S)-2-(2',3L=glycol _4_yloxymethyl)_5_(2_fluoroethoxy fluorenyl) _ 2,3-Dihydrooxazolo[3,2_&] σ-melidine _7-ketone; (S)-2-(3',5i-dibromobiphenyl-4-yloxy Base)_2,3_dihydrocarbazino 2_ a] ° 密-7-鲷; '(S)-2-(4'_fluoro_3 methylbiphenyl_4_yloxymethyl) _2,3-dihydrocarbazo[3,2-a]pyrimidin-7-one; (S)-2-(3·-fluoro-4'-fluorenylbiphenylyloxymethyl)_2, 3_Dihydrooxazolo[3,2-a]^n-dec-7-one; 21 201121978 (S)-2-(2'-Fluoro-4'-fluorenylbiphenyl-4-yloxyindole (2) 2-(2,6-dimethylbiphenyl-4-yloxymethyl)_2,3-dihydrogen Oxazolo[3,2_a]pyrimidin-7-one; '(S)-2-(3',5'-dimethylbiphenyl_4_yloxymethyl)_2,3_dihydrob Zoxa[3,2_a]pyrimidin-7-one; '(S)-2-(2',3 dimethylbiphenyl-4-yloxymethyl)_2,3-dihydroindole, etc. [3,2-a]pyrimidin-7-one; (S)-2j2,3-methylbiphenyl-4-yloxymethyl)_5-methoxy-2,3·dihydrooxazole And [3,2-a]pyrimidine-7-one; (S)-2-(2',3'-dimethylbiphenyloxymethyl)_5_methyl_2,3_dioxane嗤 and P,2-a] squirting 7-ketone; (S)-5-cyclopropyl-2-(2,3,-dimethylbiphenyl yloxymethyl)·2,3 _Dihydro 11th oxazolo[3,2-a]pyrimidine _7_鲷; (S)-2-(2',3'-dimethylbiphenyl_4 _ yloxymethyl)fluorophenyl 2,3-dihydrooxazolo[3,2-a]pyrimidinone; (S)-2-(2',3'-dimethylbiphenyl_4 _ yloxymethylmethyl_ 2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one, · (S)-2-(2i,3·-dimethylbiphenyl冬基oxymethyl)_5♦ each bite-buylmethyl _ 2,3-dihydrooxazolo[3,2_a]pyrimidine _7-one; (S)-2-(2',4,_ : f-biphenyl-4-yloxyfyl-[3,2-a]pyrimidine_7-one; into 7 main open (8)_2_f j3L dimethylbiphenyl yloxymethyl) , 3-dihydroanthracene 弁[3,2-a] squeezing-7-one; 22 201121978 (S)-2-(2)3,-dimethylbiphenyl _4_yloxymethyl )_6_Methyl-2,3_Diazakiα sits and [3,2-a] is sprayed with 7-ketone; (8) Winter (2,1'-dimethylbiphenyl-4-yloxymethyl) -2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one; '(S)-2j2,2'-dimethylbiphenyl-4-yloxyindenyl) Methyl force-dihydro-decane and [3,2-a]pyrimidine-7-g are the same; (S)-2j2', 3k methyl phenyl group _4_yloxy fluorenyl)_5_ via methyl _ 2,3_Dihydroσ number α sits and [3,2-a] is sprayed with 7-ketone; (S)-2-(2,3'-dimethylbiphenyl_4_yloxymethyl )_5_(2_hydroxyhydrol oxazolo[3,1-a]pyrimidine _7-one; soil) _一(8)_2_一(21,3,1 dimethylbiphenyl_4_yloxyindenyl)-5-ethoxy T-based 2,3-dihydrooxazolo[3,2-a]pyrimidine -7-ketone; (S)_2_(2',3'? T-phenylbiphenyloxymethyl)-5-isopropylisomethyl- 2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one; (S) 2 (2'3 - monodecylbiphenyl-4-yloxymethyl)_5_phenyl-2,3-dinitrogen. Isozo[3,2-a]pyrimidine_7-one; (8)~pentyloxymethyl 2_(2,3,3-dimethylbiphenyl-butenyloxymethyl)_2,3_ monohydrogen σ |Saliva and [3,2-a]p-Bite-7-嗣; (S)-2-j2',3·-Dimethylbiphenyl_4_yloxyf-yl)_5_(tetrazole ^•Methoxymethoxyindenyl)-2,3-dihydro-decane[3,2-a]D-densified _7_嗣; (S)_2_(2',3'-dimethylene Benzene-4-yloxymethyl)-5-(2-fluoroethoxymethyl)_2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one; (S)-5 -(l,l-difluoro-propyl)_2_(21,31-dif-biphenylbiyloxymethyl)_ 23 1 ,3-dihydrooxazolo[3,2-a]pyrimidine_ 7_ketone; 201121978 (S)-2-(2-indolyl-3·-propylbiphenyl-4-yloxymethyl)_2,3-dihydrocarbazo[3,2-a> dense Biting a 7-keto; and (S)-2-(2',3'-dimethoxybiphenyloxymethyl)_2,3-dihydrocarbazo[3,2-a]%, 11 定-7- Same as. As a further example of the specific compound, the following compounds can be exemplified without any limitation: (8) 2-(2,3,5-difluorobiphenyl-4-yloxymethyl)_2,3_dihydroπ-α And [3,2_a]pyrimidin-7-one; (S)-2-(2',3',4'-trifluorobiphenyl-4-yloxyindenyl)-2,3-dihydrol ;4*1 sits and [3,2_a]pyrimidin-7-one; (S)-5-methyl-2-(2·,3',5'-trifluorobiphenyl·4-yloxyanthracene (2)-dihydrocarbazo[3,2-a]pyrimidin-7-one; (S)-5-hydroxyindenyl-2-(2',3',5'-trifluoro Benz-4-yloxyindenyl) 2,3-dihydro σ-oxazolo[3,2-a]pyrimidin-7-one; (S)-5-nonyloxyindolyl-2_(2', 3,5,-trifluorobiphenyl_4_yloxyindenyl)_2,3·dihydrooxazolo[3,2-a]pyrimidin-7-one; (S)-5-(2- Hydroxyethyl group>2_(2,3,5,5-trifluorobiphenyl_4-yloxymethyl)_2,3•dihydro-oxo-[3,2-a]pyrimidine-7- Ketone; (S)-5-ethoxymethyl-2-(2,3,5,3-trifluorobiphenyl-4-yloxymethyl)_2,3·dihydrocarbazol[3 , 2-a]pyrimidin-7-one; (S)-5·isopropoxypurinyl-2-(2,3,5,-trifluorobiphenyloxyindenyl)_ 2,3- Dihydroindolo[3,2-a]pyrimidine-7-one; (S)-5 -cyclopentyloxymethyl-2-(2,3,5,3-trifluorobiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2-a]pyrimidine- 7-keto; 24 201121978 (8)-5-(tetrachloro cough _2 _ methoxymethoxy yl)_2_(2|,3,5, _trifluorobiphenyl I yloxymethyl group > 2, 3. Dihydrocarbazo[3,2-a]pyrimidin-7-one; (S)-5-(2-fluoroethoxymethyl)·2_(2,,3,,5L-trifluorobiphenyl · 4_yloxytihyl)-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one; (8) gas methyl-2-(2',3,,5,-three Fluorobiphenyl-4-yloxymethyl)-2,3-di-yl and the like oxazo[3,2-a]pyrimidine-7-one; milk (S)-2-(2',3', 5'-trichlorobiphenyl_4_yloxymethyl)_2,3-dihydrocarbazole [3,2-a] spray π -7-g with; (S)-5-fluorof group _2-(2,,3',5'-three, oxobi-4-yloxymethyl) hydrogen σ 唾 并 [3,2-a> 密-7- ketone; (S )-2-(2',4',5'-trimethylbiphenylwhenyloxymethyl)_2,3-dihydroπ-azo[3,2-a]pyrimidin-7-one; S)_2-(2,2',3|-trimethylbiphenyl_4_yloxymethyl)_2,3_dihydrogen. Nozolo[3,2-a]pyrimidin-7-one; (S)-2_〇ethyl-2',3'-dimercaptobiphenyl_4·yloxyindenyl)_2,3_ Dihydro# oxazolo[3,2-a]pyrimidin-7-one; derivative (S)-2-(2-ethyl 2',3'-di-biphenylbiphenyl-4-yloxymethyl )_6_Methyl 3 Dihydro 11 No. [3,2-a] Pain -7-@同; (S)-2-(2-decyloxy-2',3'-dimethyl Benzene-4-yloxyindenyl)_2,3_two-luxioxazo[3,2-a]pyrimidin-7-one; and Λ 2',3'-dimethylidyl ((8)-7-keto) _2,3_Dihydro_7Η_〇Zolo[3,2_a 2-yloxy)-biphenyl-2-acetonitrile. Compounds of & Finally, the following compounds are listed as other specific examples of the formula (D) of the present invention: 25 201121978 (S)-2-(4-naphthalen-1-ylphenoxymethyl)_2,3-dihydrogen σ oxazo[3,2 a]pyrimidine _7 ketone; (S)-2-(4-dihydroindol-5-yl)-phenoxyindenyl)_2,3_two gas ten sitting and [3, 2_a] 〇^ pyridine-7-one; (S)-2-(4-dihydro-4-yl)-phenoxy-T-yl)_2,3_dihydro-decane[3,2_a]pyrimidine-7 -ketone; (s)-2-[4_(5,6,7,8-®hydro-naphthyl)-phenoxymethyl)_2,3_dihydro-benzazolo[3,2-a] Pyrimidine-7-one; (8)-state-(10) rhythm-hydrogen-naphthalene small phenoxymethyl from ^: hydrocarbazo[3,2-a]pyrimidin-7-one; and 7-ketone (S -2-(9H-indolyl-2-yloxymethyl)_2,3-dihydropyridazolo[3,2a]pyrimidine_η The compounds of the invention may be known to those skilled in the art. Any step of synthesis. In particular, several starting materials for the preparation of the compounds of the invention are known, or are commercially available per se. The compounds of the invention, as well as the precursor compounds, can also be prepared by methods known in the literature and for the preparation of analogous compounds as further described herein. More specifically, the compounds disclosed herein can be synthesized according to the procedures shown in Schemes 1-5 below, unless otherwise indicated. Scheme 6-8 illustrates the various steps that can be used to prepare the intermediate biphenyl of formula (VI). Biphenyl fluorene can be used to prepare compounds of formula (^). Figure 9 It-step illustrates a synthetic route for the preparation of a meta-phenoxy compound. As further detailed below, the meta-phenoxy compound has a much lower biological activity than the para- analog. 26 201121978 Scheme 1 illustrates the synthesis of several compounds of formula (i) of the invention wherein Ri is hydrogen. However, for other compounds of the invention of formula (I) wherein the core is not hydrogen as defined herein, a similar synthetic scheme can be employed. Schematic 1

In step 1 of Scheme 1, the (S)-(S)-glycidyl sulfonate is reacted with a suitable cyanamide compound to form the oxazolidine of formula (III) in a suitable solvent. Any known compound that can react with an epoxide to form a carbazole amine can be used in this reaction. Suitable cyanamides for this purpose include, but are not limited to, any of the limitations, sodium cyanamide, hydrogen cyanamide, potassium cyanamide, hydrogen cyanamide, and the like. For example, the schematic diagram 1 shows that sodium cyanamide can be used as a suitable cyanamide compound. This reaction can usually be carried out in an alcohol solvent such as methanol, ethanol, isopropanol or the like or a mixture thereof. Moreover, the reaction is carried out at a suitable temperature, for example, from about ambient to above ambient. r in: in step 2 of the intention 2, the formula (ΠΙ)-decane amine and Rc are (C丨-heart) stupyl or benzyl group (ιν) α,β-unsaturated acetylate reacts to form, V) compound. Again, this reaction can be carried out using any procedure known to those skilled in the art. Typically, such an addition reaction is carried out in a suitable alcohol 27 201121978 solvent such as methanol, ethanol or isopropanol or a mixture thereof. Such an addition reaction can also be carried out using the formula (IV) 〇c, p-unsaturated acetyl vinegar itself as a solvent. This reaction is usually carried out at ambient temperature to above ambient temperature. More commonly, this reaction is carried out at the reflux temperature of the solvent. That is, an ambient temperature including a microwave oven having a temperature range of about 100 ° C to about 200 ° C can also be used for this reaction. In the step 3 of Scheme 1, the compound of the formula (v) obtained in the step 2 is reacted with a biphenol of the formula (VI). The biphenol can be prepared according to any known procedure', e.g., using the procedures described below without regard to Figures 6-9. Such substitution reactions are usually carried out in an aprotic polar solvent such as DMF or acetonitrile and in the presence of a suitable base such as an alkali metal carbonate such as a carbonic acid planer or an organic base such as triethylamine. Alternatively, the compound of formula (V) dissolved in an aprotic solvent (e.g., DMF or acetonitrile/dimethylacetal/DMSO) may be treated with a mixture of a suitable solvent such as acetonitrile or DMF containing a compound of the formula (vi). The reaction temperature may be from ambient temperature to ambient temperature to above ambient temperature, but usually the reaction is between 30 and 60. (: ambient temperature to a temperature range slightly above ambient temperature. Various other compounds of formula (〗) can be similarly prepared using appropriate starting materials. Figure 2 illustrates the preparation & Another method of inventing a compound of formula (I). In this method, a biphenyl group of formula (VI) is first subjected to an addition reaction with a compound of formula (ΙΠ)carbazolamide to obtain formula (VII) in step 1 of Scheme 2. Compound. In step 2 of Scheme 2, a compound of formula (VII) is reacted with a block acid of formula (IV) to obtain a compound of formula (I). Again, this schematic method can be used to prepare a formula in which Ri is not hydrogen. (I) Compounds 28 201121978 Not intended 2

2~<G>_ch: In the step 1 of Scheme 2, the carbazole amine of the formula (III) is reacted with the biphenylphenol of the formula (VI). As stated above, the biphenol can be prepared according to any known procedure, for example using the procedure outlined in Schemes 6-9 below. For example, such substitution reactions are generally carried out in the same manner as described in Step 3 of Scheme 1 above. Such substitution reactions are usually carried out in an aprotic polar solvent such as DMF or acetonitrile, and in the presence of a suitable test (such as a metal carbonate such as cesium carbonate) or an organic test (such as triethylamine). Go on. Alternatively, the compound of formula (III) in an aprotic solvent such as DMF or acetonitrile / dioxane / DMSO may be treated with a mixture of sodium hydride and a suitable solvent of the compound of formula (VI), such as acetonitrile or DMF. The reaction temperature may be lower than the ambient temperature to the ambient temperature to above the ambient temperature, but usually the reaction is carried out at a temperature below 30 to 60 ° C to a slightly higher temperature. In step 2 of Scheme 2, the compound of formula (VII) obtained in step 1 is reacted with an alpha, beta-unsaturated acetylenic acid ester of formula (IV) wherein Rc is (CrC4)alkyl, phenyl or benzyl to form a compound of formula (V). Again, this reaction can be carried out by any procedure known to those skilled in the art, such as the steps described in step 2, 2011 21978, step 2 of Scheme 1 above. Typically, such addition reactions are carried out in a suitable alcoholic solvent such as decyl alcohol, ethanol or isopropanol or mixtures thereof. Such an addition reaction can also be carried out using the α,β-unsaturated acetylenic acid ester of the formula (IV) as a solvent. This reaction is usually carried out at ambient temperature to above ambient temperature. More often, the reaction is carried out at the reflux temperature of the solvent. However, a microwave oven having a temperature range of from about 100 ° C to about 200 ° C above ambient temperature can also be used for this reaction. Various other compounds of formula (I) can be prepared analogously to Scheme 2 using the appropriate initials. Scheme 3 illustrates another method of preparing a compound of formula (I) wherein a phenoxy-substituted pyrimidinone of formula (XI) is first prepared and then converted to the formula by a suitable phenylation reaction in a subsequent step (I) a compound. In step 1 of Scheme 3, an appropriately substituted bromophenol of formula (VIII) is reacted with R-epichlorohydrin in an organic solvent to form a substituted bromophenoxy oxirane of formula (IX). Such substitution reactions can be carried out using any of the procedures known in the art. For example, such reactions are usually carried out in a suitable organic solvent in the presence of a suitable base and at ambient to elevated temperatures. The solvent which can be used in this step can be any solvent commonly used in such reactions. For example, suitable solvents are ketones such as acetone, acetophenone (MEK) and the like. Bases suitable for this reaction include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate, and the like. Usually, potassium carbonate is used. However, depending on the type of bromophenol of the formula (VIII) used, conditions below ambient temperature can also be used. It has been observed that the temperature at which the reaction proceeds can control the stereoselectivity of the reaction. For example, a reaction temperature below 50 °C favors higher stereoselectivity. More specifically, 201121978, depending on the solvent used and the substituents on the compound of formula (VII), a temperature range of from about 4 ° C to about 5 ° C can be employed. The oxirane δ of the formula (IX) produced in the step 2 of Scheme 3 is reacted with a cyanamide compound to form a carbazolamide of the formula (X). This reaction can be carried out using a similar procedure to that described in the first step of Scheme 1 above, for example, using sodium cyanamide as described in Unknown 3. Schematic 3

(I), in step 3 of Scheme 3, a compound of the formula (χ)carbazolamide is reacted with an Rc*(Ci_c4)alkyl group, a phenyl group or a benzyl group (Ιν) α,β_unsaturated acetylenic acid ester to form a compound of formula (V). Again, this reaction can be carried out using any procedure known to those skilled in the art, such as step 2 of Scheme 1 above or step 2 of Scheme 2. 31 201121978 In step 4 of Scheme 3, the formula (χι) is further subjected to a mesogenic reaction by substituting a siloxypyrimidinone to form a compound of formula (I) of the present invention. A variant of the known arylation and/or phenylation reactions can also be used for this purpose. For example, a compound of formula (XI) is reacted with a substituted phenylboronic acid of formula (XII) under appropriate reaction conditions to obtain a compound of formula (I). Figure 4 illustrates another variant of the intent 3, which is used to prepare the formula jl). The order of the acid addition and the phenylation is reversed, so that the phenylation is carried out first and then _§ The purpose of the addition reaction. Schematic 4 η〇, β.οη

R2^=-co2r〇 __(|V)__ Step 2

In step 1 of Scheme 4, the phenylation of the compound of formula (8) can be carried out using procedures analogous to those described in Step 4 of Scheme 3 above. In step 2 of Scheme 4, the addition reaction of the formula (IV) α,β-unsaturated alkyne, where 'Re is (Cl-C4), silly or fluorenyl, is used in step 2 of the above schematic diagram i. Or a similar procedure as described in Step 2' of Step 2 or Step 3 of Scheme 3. 32 201121978 Scheme 5 illustrates another method of preparing a compound of formula (I) wherein R2 is hydrogen. However, various modifications can be made to this method to prepare the various compounds of formula (I) disclosed herein. Not intended 5

Ra——s〇H^CH3 In step 1 of Scheme 5, the formula (XIV) p_fluorenyl group of the formula (ΠΙ)carbazolamide and an R is (qc:4)alkyl, phenyl or benzyl Alkynyl ester reaction. This step is typically carried out using various recognized reaction conditions in the art. For example, it can be carried out in an organic solvent in the presence of a suitable base to form a compound of the formula (XV). In step 2, which is not intended to be 5, the compound of formula (xv) is then reacted with a compound of formula (=). This type of substitution reaction is carried out by a similar procedure as used in the third step of the above-mentioned step 1 to obtain the compound of the formula (1). ^ Figure 6_9 (d) A variety of different materials that can be used to prepare compounds of the formula (νι) for biphenyl. The compound of formula (1) is prepared by a compound of Lai. 33 201121978 Schematic 6

(νι) f ^No, 5 Figure 6 Chinese formula (Vm) peak generation and the formula (ΧΙΟ 取 = = base boronic acid, with (4) formula (VI) substituted for this reaction can be recognized in the field of reaction Condition is carried out. Not intended 7

Scheme 7 illustrates another method of preparing a substituted biphenyl compound of formula (VI) wherein a substituted bromo group is substituted with a substituted (XVII)-substituted p-hydroxydecanoic acid to form a compound of formula (VI). . Again, such reactions can be carried out using art recognized procedures. Schematic 8 34 201121978

In the first step of Scheme 8, a substituted phenylbenzene ester of the formula (XVIII) is reacted with a substituted boronic acid of the formula (XII) to obtain a substituted biphenyl ester of the formula (XIX). Such reactions can be carried out using any procedure known in the art. In the step 2 of Fig. 8, the acetate of the formula (XIX) is subjected to a hydrolysis reaction to form a subgroup of the formula (VI). Any acid catalyzed, catalytically catalyzed and/or neutral reaction conditions can be used to carry out the hydrolysis reaction. Scheme 9 illustrates a procedure that can be used to prepare a biphenylpyrimidinone of formula (XXII). The bis-pyridylpyrimidinone is closely related to the compound of the formula (I) of the present invention. 0 In the step 1 of Scheme 9, the carbazole amine of the formula (III) is reacted with the substituted meta-iodophenol of the formula (XIX) to form a formula. (XX) oxazolamide. Such substitutions can be carried out using any known procedure, such as the similar procedure used in Step 1 of Scheme 2. In step 2, which is not intended to be 9, the oxazolidine of formula (XIV) is reacted with the formula (XIV) β-methanoyl alkynyl ester wherein R is (C1-C4)alkyl:phenyl or a benzyl group. This step is carried out by using various reaction conditions recognized in the art, for example, it can be used in various conditions of light riding to form a 35 201121978. In the step 3 of the schematic diagram 9, the compound of the formula (ΧΧΪ) is finally combined with the formula (XII). The reaction is carried out by substituting phenylboronic acid to form a self-identification of a biphenyloxymercaptopyrimidine of the formula (XXII). Schematic 9

</ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; More specifically, 'the biological characteristics that have been discovered, even the temples are slanting; the singularity of the singularity is not surprising 36 201121978

Method preparation. For example, a compound of the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with one or more pharmaceutical agents, dilute agents or carriers to form such a drug. In a further embodiment, the invention relates to a method of treating a particular disease, disorder or condition using an effective formula (D) of the invention, a specific disease treatable using a compound of formula (I) of the invention Including but not limited to neurological or psychiatric diseases. The compounds of the invention not only show superiority showing ideal metabolic stability, but also from the "mental diseases" used in this article and Diagnostic and Statistical

Manual of Mental Disorders, 4th Ed” (DSM-IV) The definition of “mental illness” in the American Psychiatric Association, 1995 has the same meaning. This manual is incorporated herein by reference. A fundamental feature of transient psychiatric illness is an abnormal state involving the sudden onset of at least one of the following positive psychotic symptoms: delusions, hallucinations, incoherence (such as frequent digression or inconsistency), or severely disordered or tense behavior (Standard A). An abnormal state lasts for at least one day but less than one month, and the patient eventually returns to full functional level before the onset (standard B). This abnormal state cannot be better explained by emotional disorders with psychosis, affective schizophrenia, or schizophrenia, nor by a substance (such as hallucinogens) or general health conditions (such as subdural hematoma). ) The direct physiological effects (Standard C) caused by 37 201121978. It should be further noted that those skilled in the art will recognize that there are other terms available for the term "menopausal and psychiatric disorders", disease taxonomy, and sub-systems, and that this (4) is the return of medical science. And development. It will also be appreciated that those skilled in the art will be able to treat these diseases by using an effective amount of a compound of formula (1) of the present invention to treat patients currently suffering from neurological and psychiatric disorders or to prophylactically treat such diseases. Therefore, the term "treatment", whether a noun or a verb, is intended to cover all steps. In the developmental steps of neurological and psychiatric disorders described herein, there may be a slowing, interruption, suspension, control or cessation. The stage, but does not necessarily mean a thorough treatment of all disease symptoms, and is intended to include prophylactic treatment of the disease and mental illness. In a further embodiment of the invention, specific diseases which can be treated using the compounds of formula (I) of the invention include, but are not limited to, anxiety, migraine, schizophrenia, epilepsy, and pain. It will be readily understood by those skilled in the art that the pathologies and conditions explicitly recited herein are not intended to be limiting, but rather to exemplify the utility of the compounds of the present invention. Thus, it should be understood that the compounds of the present invention are useful in the treatment of any disease involving the action of a metabotropic glutamate. In other words, the compound of the present invention is a metabotropic type of face amine receptor (mGluR), especially mGluR2, which is effective for improving any disease mediated entirely or partially by mGluR2. All of the specific embodiments of the compounds disclosed herein for use in the methods of the invention can be used in the treatment of various diseases described herein. As described herein, the compounds used in the methods of the present invention are capable of modulating the action of mGluR2, thereby reducing the effects and/or symptoms caused by the activity of mGluR2. In another embodiment of the method 38 201121978 of the present invention, the compound of the present invention can be administered by any method known in the art. In particular, the compounds of the invention may be administered via the oral, intramuscular, subcutaneous, rectal, tracheal, nasal, intraperitoneal, intraventricular (icv) or topical routes. Finally, in still another embodiment of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula (1) of the present invention, including a pharmaceutically acceptable salt thereof, a solvent A compound or derivative, and the compound has the structural formula shown in Structural Formula I as described herein. As described herein, the pharmaceutical composition of the present invention is characterized by its mG1UR2 modulating activity, and thus can be used for any disease, symptom or disorder involving the treatment of I. Likewise, as described above, all of the preferred embodiments of the compounds of the invention disclosed herein are used to prepare the pharmaceutical compositions described herein. Thus, in accordance with the present invention, the various compounds of formula (1) described herein can be used in the preparation of a pharmaceutical formulation that modulates the action of mGluR2 and can be used to treat all of the diseases disclosed herein. These pharmaceutical compositions are preferably in the form of tablets, pills, capsules, powders, granules, sterile injectable solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, automatic injection devices Or suppository; for intracavitary, parenteral, intranasal, sublingual or rectal administration, or for inhalation or insufflation. Alternatively, the drug composition may be administered in a suitable form weekly-time or monthly-time; for example, an insoluble salt of the active compound (such as citrate) may be changed to form an accumulation of intramuscular injection preparation. It is conceivable to use an easily recordable polymer containing an effective pharmaceutical ingredient. When preparing a solid 1 drug composition such as a tablet, the main active ingredient is mixed with a drug carrier, such as the commonly used tablet ingredient, Corn Palace 39 201121978 powder, lactose, sugar, sorbitol, talc, stearic acid , a mixture of stearic calcium, gums, and pre-formed pharmaceutical compositions in combination with other pharmaceutical diluents (e.g., water) in solid state, comprising the formula of the invention to form a homogeneous mixture of ~. When we say that these pre-formulated pharmaceutical composition compounds are uniformly dispersed in the pharmaceutical composition, the '5 $ di-component can be easily divided into equally effective unit dosage forms, such as; Music agents and capsules, etc. This solid pre-formulated pharmaceutical composition is then divided into the above unit dosage forms containing from 0.1 to about 500 mg of the active ingredient of the present invention. The flavored unit dosage form contains from 1 to 100 mg of the active ingredient, such as 1, 2, 5, 10, 25, 50 or 100 mg. The tablets or pills of the novel pharmaceutical composition may be coated or compounded with other ingredients to provide a dosage form having the advantage of a time delay. For example, a tablet or pill can comprise an inner dosage portion and an outer dosage portion, the outer dosage portion being a layer of outer shell that is disposed outside of the inner dosage portion. The two parts can be separated by a layer of casing so that the inner dose portion is not dissociated in the stomach&apos; to enter the duodenum intact or to be delayed in release. Many materials can be used to make this casing or coating, including many polymeric acids and mixtures of polymeric acids with shellac, green wax alcohol and cellulose acetate. A liquid form which may comprise the novel pharmaceutical composition of the present invention for administration by buccal or injection includes an aqueous solution, a slurry of a suitable taste, an aqueous suspension or an oil suspension, and an edible oil such as cottonseed oil, sesame oil, coconut oil or peanut oil. Flavored emulsions, as well as tinctures and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, sulfhydryl cellulose, polyvinyl Carbofuran or gelatin. 201121978 The pharmaceutical compositions of the present invention can be administered by any method known in the art. In general, the pharmaceutical compositions of this invention may be administered via the oral cavity, muscle, subcutaneous, 'rectal, tracheal, nasal, intraperitoneal, intraventricular (icv) or topical routes. The preferred mode of administration of the g-drug composition of the present invention is via the oral cavity and the nasal cavity & a &lt; a drug. Any known method of administering a pharmaceutical composition via the oral or nasal route can be used for the administration of the pharmaceutical composition of the present invention. In the treatment of the various diseases described herein, a suitable dosage level is from about 0.01 to 250 mg/kg per day, most preferably from about 0 05 to = mg/kg per day, especially about daily. 05 to 20 mg/kg. The compound can be taken 1 to 4 times a day. The invention is further illustrated by the following examples which are not intended to limit the scope of the invention in any way. ‘Examples】 Example (Overview) Tongfeng, the reaction enthalpy was carried out in a nitrogen atmosphere. The solvent was dried over sodium sulphate or magnesium sulphate and was subjected to vacuum in a rotary evaporator. The analysis was carried out on EM Science's Shijiao 60 F254 plate and developed in uv irradiation in any possible field. Flash chromatography was carried out using Isc〇's prefilled Shijiao column. The '4 NMR spectrum analysis was performed on a GeminiSOOi Varian VXR3 (10) spectrometer, unless otherwise stated, and was determined in an insolvent such as DMSO-d6 or CDC13. Chemical shift values are expressed in parts per million (ppm) and tetramethyl decane (TMS) is used as an internal standard. The lc/ms is performed on a Micromass Platform LCZ. 201121978 In the following examples and preparation methods, the terms used therein will have the following meanings: &quot;kg" means kilograms, "g" means gram, &quot;mg" means milligrams, means micrograms, &quot;pgn Refers to picograms, &quot;lb&quot; refers to pounds, "oz" means ounces, &quot;mol&quot; means Mohr, &quot;mmol1' means millimoles, &gt;mole&quot; means micro-mole,&quot; "nmole" means Nymole, means liter, &quot;mL" or &quot;ml&quot; means ML, &gt;L&quot; means microliter, "gal" means gallon, "°Cn means Celsius, &quot; Rf" means retention factor, "mp" or &quot;mp" means dazzling, "dec" is decomposed, &quot;bp&quot; or &quot;bp&quot; means boiling point, nmm Hg&quot; means millimeters of mercury The pressure of the gauge, &quot;cmM means centimeter, &quot;nm&quot; means nano, "abs." means absolute, "cone." means concentrated, "c&quot; means the concentration in g/mL, &quot;THF&quot; means tetrahydrofuran, &quot;DMF&quot; means dimercaptodecylamine, &quot;NMP·1 means 1-methyl-2-pyrrolidone, and "EtOH" means B "MeOH" means decyl alcohol, "EtOAc" means ethyl acetate; &quot;concentrated brine means saturated aqueous sodium chloride, ''M' means mol/liter, &quot;mMn means millim Ear/liter, "μΜ" means micromolecule/liter, "ηΜ" means Nemo/L, "Ν" means equivalent, &quot;TLC&quot; means thin layer chromatography, nHPLCM means high performance liquid Chromatography, &quot;ip&quot; means intraperitoneal, means intravenous, anhyd = anhydrous; aq = aqueous; min = minutes; mins = minutes; h or hr = hours; d = days; psi = broken / Square inch; atm = atmospheric pressure; sat. = saturated; s = single ridge, d = doublet; t = triplet; q = quadruple; m = multiple *%; dd = double overlap; br = broad LC = liquid chromatography; MS = mass spectrometry; ESI = electrospray ionization; CI = chemical ionization; RT = retention time; Μ = molecular ion. Photometric [ot]D25 was measured using a Perkin Elmer Model 341 polarimeter with sodium lamp, D line (589 nm), optical path length 100 mm, temperature 25 ° C, concentration (g/100 ml) and The solvents are as specified in the examples below. 42 201121978 Example 1 (S)-2-(4-Bromophenoxymethyl)_[3,2-a]pyrimidin-7-one

Step 1: (S)-2-(4-Bromo oxohydrazyl)oxirane Δ/0-〇-ΒΓ 4-bromophenol (9.34 g, 54 mmol), stirred at 45 ° C, A mixture of (R)-(+)-epichlorohydrin (10.04 g, i 〇 8 mmol) and cesium carbonate (7.46 g, 54 mmol) in acetone (70 ml) was heated for 4 days. The mixture was filtered and the filtrate was concentrated. The title compound was obtained as an oil (4.5 g, 37%). Step 2: (S)-5-(4-indolyloxymethyl)_4,5-dihydro-sigma number. Addition of 2-ethylamine H2NV-0 to a mixture of decyl alcohol (10 mi) containing sodium cyanamide (1.15 g, 18 mm 〇l) containing (S)-2-(4-oxaphenoxy) Ethylene oxide (4) g, 17 9 == A I' (2 G ml) solution was taken for 5 minutes. Mixing at room temperature Step 3: (8)-2-(4-bromophenoxymethyl H3, 2 externally bite

&gt;'Ό&gt;~βγ 43 201121978 will contain (8)-5♦ phenoxymethyl K5_diazepine asparagine (4) H.76 mmol) and ethyl propiolate (147 g, i5 claws) ethanol (2) =1) The mixture was heated under reflux for 6 hours. Concentrate the solution and use 〇ι〇% methanol/di, methane, and finally 2% triethylamine/10% methanol/two gas to be used as an eluent to purify the residue by flash chromatography. An oil of m-acid was triturated and the insoluble material was collected to give the title compound, </RTI> </RTI> <RTIgt; Example 2 (S)-2-(2',3·-di-biphenylphenoxymethyl)_2,3•dihydro$oxazolo[3,2_小密 °定-7-@同

(S)-2-(4-bromophenoxyindenyl)-[3,2-a]pyrimidin-7-one (0.22 g, 2.72 mmol), 2-oxopic acid (0.52 g ' 2.72 mmol) , tetrakis(triphenylphosphine)_ a mixture of (〇) (0.18 g, 0.16 mmol) and sodium carbonate (0.29 g, 2.72 mmol) in anhydrous ethylene glycol dimethyl ether (25 ml) was heated under reflux for 3 hours. The mixture was diluted with 1 mL of methanol and filtered over celite. The filtrate was concentrated and the residue was purified by flash chromatography eluting with EtOAc EtOAc /EtOAc The product fractions were combined and concentrated to give the title compound as a solid, m.p. [a] D25 = -37.8 0 (c = 0.36, DMSO) C19H14C12N203 ( 389.24), LCMS (ESI): 389.06 (M+H) NMR (DMSO_d6, 300 MHz) δ: 7.79 ( d,1H ), 7.65 (d 'lH), 7.37-7.40 (m, 4H), 7.06 (d'2H), 5.84 (d, 201121978 1H), 5.36-5.38 (m, lH), 4.38-4.45 (m, 3H), 4 u_416 (m , 1H). Example 3 (S)-7-keto-2,3-dihydro-7H-s-oxazolo[3,2-a] mouth of indole-4-sulfonic acid.定_2_基甲

Methanol, 112 mm 〇1) of methanol, which is added to the suspension of sodium cyanamide (7.16 g, ml) at room temperature Add W+, ester (25 1120C (8.0 g, 27%) 〇 Step 2 · Benzene-4-transacid (S)-7-mercapto-2 3 2-yl decyl ester

The g' 110 mmol) sterol (1 〇〇 ml) solution was taken for 3 〇 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated, extracted with water (1 〇〇mi) = residue and extracted with ethyl acetate (2 mL). The organic layer was washed twice with water, dried over magnesium sulfate and filtered. The deserted sputum is treated with jumping acetic acid B (f). The precipitate formed was collected to give the title compound as a solid, and the residue was H-dihydro-7H-4 oxa[3,2-a]. set-

45 201121978 Toxic benzene-4-sulfonic acid (S)-2-amino-4,5-dihydrooxazolo-5-yl decyl ester (8.0 g '29.6 mmol) and propiolate B The 50 ml ethanol mixture of the ester (2.8 g, 29.6 mmol) was heated under reflux for 4 hours. The solution was cooled and the precipitate was collected to give the title compound as a solid (4.6 g, 48%). Example 4 (S) 2 (3-methoxybiphenyl_4_yloxyindenyl)_2,.3_diazo alpha alpha benzo[3,2-a] dense

The solution will contain toluene-4-sulfonic acid (S)-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-ylindole (0.16 g, hydrazine) .5 mmol), 3'-nonyloxybiphenyl-4-ol (prepared from 4-bromophenol and 3-decyloxyphenylboronic acid) (ο·〗g, 〇.5 mmol) and carbonic acid ( 0.16 g, 0.5 mmol) of 20 ml of ethylene glycol dioxime ether mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (0.028 g, 16%). </ RTI> </ RTI> <RTIgt; 7.17-7.19 ( m,2H ), 7.02-7.05(m,2H), 6.88 (d,lH),5.82 (d,lH),5.35- 46 201121978 5.37 ( m ' 1H ) , 4.36-4.42 ( m,3H ), 4.12-4.16 (m, 1H), 3.81 (s, 3H). Example 5 (8)-2-(2-Methylbiphenyl-4-yloxymethyl)-2,3-dihydro-11. Sit and [3, 2-3]. dense.定-7 酉同

(S)-7-keto-2,3-dihydro-7H-indolo[3,2-a]-cyano-2-yl decyl ester (0.32 g, 1.0) Ment), 2-mercaptobiphenyl-4-ol (prepared from 4-&gt; odor-3-mercaptobenzene g and phenyl tartaric acid) (〇·18 g, 1.0 mmol) and carbonic acid planer (0.32) The mixture in 20 ml of dry acetonitrile, g, 1.0 mmol) was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated, and the residue was stirred with 20 ml of hot ethyl acetate for 5 min. The insoluble material was collected to give the title compound, m.p. C20H18N2O3 ( 334.37), LCMS (ESI) · 335.17 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.80 (d,1H) , 7.35-7.46 (m,5H ) , 7.08 ( d,1H ) , 6.82-6.92 ( m,2H ) , 5.82 (d,1H ) ' 5.25-5.40 ( m,1H ), 4.30-4.40 ( m,3H ), 4.10-4.20 (m,1H),2.20 (s,3H) . Example 6 47 201121978 (S)-2-(2,6-Dimethylbiphenyl-4-yloxyindenyl)-2,3-dihydro 0-pyrano[3,2-a]ff-melidine -7-ketone

(S)-7-keto-2,3-dihydro-7H-indazole-[3,2-a]pyrimidine-1-yl decyl ester (1.44 g) , 4.4 mmol), 2,6-dimethylbiphenyl-4-ol (prepared from 4-bromo-3,5-dinonylphenol and phenylboronic acid) (0.87 g, 4.4 mmol) and carbonic acid planing ( 1.43 g, 4.4 mmol) of 40 ml of anhydrous acetonitrile mixture was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjjjjj The organic layer was dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with EtOAc EtOAc (EtOAc (EtOAc) %) C2iH2〇N203 (348.40), LCMS (ESI): 349.17 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.80 (d, 1H), 7.41-7.44 (m, 2H), 7.31 7.34 ( m,1H ), 7.09-7.12 ( m,2H ), 6.72 (s,2H) , 5.85 (d,1H) , 5.34-5.35 (m,1H) ,4.31-4.41 (m,3H),4.09- 4.15 (m, 1H), 1.93 (s, 6H). Example 7 (8)-2-(2'-ethylbiphenyl-4-yloxyindenyl)-2,3-dihydrocarbazolyl [3, 2-a]pyrimidin-7-one 48 201121978

The indole-containing benzene-4-heteroic acid (S)-7, yl 2,3-dihydro·7H_10 sits and _[3,2_a]pyrimose&lt;_2_yl 曱g aims (0·48 g '1·5 mm〇1), 2·_ethylbiphenyl pentyl alcohol (prepared from benzene age and 2-ethylphenyl phenolic acid) (G 3 g, 15 mm 〇 1) and carbonic acid ( A mixture of 0 to 48 g '1.5 mmol) of 30 ml of anhydrous acetonitrile was heated under reflux for 1 hour. ? The residue was treated with aq. sodium bicarbonate and extracted with dioxane (75 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with EtOAc (EtOAc) (EtOAc) </ RTI> <RTIgt; , 2H), 6.99-7.02 (d, 1H), 5.84 (d ' 1H) ' 5.34-5.36 ( m,1H ), 4.36-4.42 ( m,3H ), 4.11-4.17(m,lH), 2.50 (q '2H), 1.02 (t, 3H). Example 8 (S)-2-(2',3'-Dioxaoxybiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2_a]pyrazine-7 -ketone

The indole benzene-4-transester (S)-7-keto-2,3-dihydro-7H-present. Sit and [3,2-a]. Dimer-2-yl decyl ester (0.6 g, 1.86 mmol), 2',3'-dimethoxyoxybiphenyl-4-ol 49 201121978 (from 4-bromophenol and 2,3-dimethoxy A mixture of phenylboronic acid (〇·43 g, j 86 mmol) and a carbonic acid planer (0.6 g ' 1.86 mmol) of 3 〇mi anhydrous acetonitrile was heated under reflux for 1 hour. The mixture was concentrated, and the residue was treated with aqueous sodium hydrogen carbonate and extracted with EtOAc (100 ml). The organic layer was dried over magnesium sulfate and dried. The concentrated filtrate was purified by EtOAc EtOAc (EtOAc) elute [a]D25 = _32.4. ( c = 0 63,

MeOH). </ RTI> <RTIgt; </ RTI> <RTIgt; 6.83 (d ' 1H), 5.83 (d, 1H) ' 5.36-5.38 (m ' 1H), 4.36-4.42 (m, 3H), 4.14 - 4.17 (m, 1H), 3.83 (s, 6H). Example 9 (S)-2-(2',3'-Difluorobiphenyl-4-yloxyindenyl)-2,3-dihydroπ-indene[3,2_a] mouth bite_7-ketone

Step 1: 2',3'-Difluorobiphenyl-4-ol will contain 4-bromobenzene (1.7 g, 10 mmol), 2,3-difluoro 1phenylboronic acid (3.1 g, 20 mmol) A mixture of tetrakis(triphenylphosphine)! bar (〇) (1.0 g, 0.86 mmol) and 2M sodium carbonate solution (6 ml) in 40 ml of 1,2-dimethoxyethanol was heated under reflux for 4 hours. The mixture was cooled and poured into an aqueous solution of ammonium sulfate. The mixture (10 ml) was extracted with ethyl acetate 50 201121978. The organic layer was washed with water and dried over sulfuric acid and filtered. The concentrated filtrate was purified by EtOAc (EtOAc) elute Step 2: (S)-2-(2',3'-Difluorobiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2-a]n-densified -7-ketone will contain toluene-4-sulfonic acid (S)-7-keto-2,3-dihydro-7Η-oxazolo-[3,2-a]pyrimidin-2-ylindole (0_85) A mixture of g ' 2.67 mmol), 2',3'-difluorobiphenyl-4-ol (0.55 g, 2.67 mmol) and 30 ml of anhydrous acetonitrile (1000 g, 2.67 mmol) was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was washed with water and dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was taken up in ethyl acetate (50 ml). The insoluble material was collected to give the title compound (yield: 46 g &apos; 48%), m.p. C19H14F2N203 ( 356.33) ' LCMS (ESI) : 357.13 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.76 (d,1H), 7.52 (d,2H) '7.26-7.39 (m,3H), 7.08 (d, 2H), 5.84 (d, 1H) '5.35-5.38 (m, lH), 4.39-4.44 (m, 3H), 4.10-4.16 (m, 1H), 3.83 (s, 6H). Example 10 (S)-2-(3i,5i-dimercaptobiphenyl-4-yloxyindenyl)_2,3 dihydro-oro-oxazolo[3,2-denidin-7-one 51 201121978

(S)-7-keto-2,3-dihydro-7H-indazolo-[3,2-a]pyrimidin-2-yl decyl ester (0.48 g, 1.5) Ment) dimercaptobiphenyl-4-ol (prepared from 4-bromophenol and 3,5-dianonylphenylboronic acid) (0.3 g, 1.5 mmol) and cesium carbonate (0.48 g, 1.5 mmol) The ml anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (0.06 g, 12%). C2iH2〇N2〇3 ( 348.40) &gt;LCMS (ESI): 349.15 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.79 (d, 1H), 7.57 (d, 2H), 7.21. (s, 2H ) , 7.00 ( d,2H ) , 6.94 ( s, 1H) '5.07 (d,lH), 5.36-5.38 (m,lH),4.39-4.42 (m, 3H) ,4.11-4.17 (m,lH) , 2.32 (s, 6H). Example 11 (S)-2-(4-naphthalen-1-ylphenoxyindenyl)-2,3-dihydroantho[3,2-a]-n--7-one

The sulphur-[3,2-a]c-amidino-2-ylmethyl ester (0.58) containing guanidine-4-acid (S)-7-mercapto-2,3-diqi-7Η-α g, 1.8 mmol), 4-naphthalen-1-ylphenol (prepared from 4-indiylbenzene 52 201121978 and naphthalene small succinic acid) (04 g, 18 〇1) and carbonic acid planing (〇·58 g, 1.8 A mixture of 30 mmol of anhydrous acetonitrile was heated under reflux for one hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse-phase HPLC (20 min), eluted with EtOAc (EtOAc (EtOAc) %). C23H18N203 (370.41), LCMS (ESI): 371.14 (M+H) NMR: NMR (DMSO-d6, 300 MHz) δ: 7·98 (d, 1H), 7.92 (d, 1H), 7.80 ( d,2H),7.32-7.57 (m,6H),7.10 (d, 2H) '5.85 (d,lH) '5.40-5.42 (m,lH),4.42-4.48 (m, 3H),4.15-4.20 ( m,1H). Example 12 (S)_2-(2',3'-di-biphenyl-4-yloxyindenyl)-5-decyloxyindenyl-2,3-dihydro$azole [3,2-a]pyrimidin-7-one

Step 1: Toluene-4-sulfonic acid (S)-5-decyloxymethyl-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-yl Methyl ester 53 201121978

Stirring benzenesulfonyl-4-sulfonic acid (S)-2-amino-4,5-dihydrooxazolo-5-ylmethyl ester (0.9 g '3.33 mmol) and 4-decyloxybutyrate A mixture of ethyl acetyl-2-carboxylate (prepared from the reaction of methylpropargyl ether and decyl chloroformate) (0.46 g, 3.6 mmol) in 15 ml of ethanol was heated under reflux for 3 hours. The solution was concentrated and the residue was purified by flash chromatography eluting with EtOAc (yield: EtOAc). Step 2. (S)-2-(2',3'-Diacetophen-4-yloxyindenyl)-5-decyloxymethyl-2,3_一虱°亏α sits and [3 ,2-a]啦β定-7-酉同

曱[3,2-a] pyrimidine-2, which is a pyridinium-containing benzoic acid (S)-5-nonyloxyindol-7-one-2,3-dihydro-7Η-» - hydrazinyl ester (0.6 g, 1.6 mmol), 2',3'-di-biphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,3-dichlorophenylboronic acid) (0.38 g) A mixture of '1.6 mmol) and 20 ml of anhydrous acetonitrile (0.52 g, 1.6 mmol) was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse-phase HPLC EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) ). </ RTI> <RTIgt; , 5.86 ( s, 1H ) , 5.37-5.39 (m, 1H), 4.34 - 4.44 ( m, 5H), 4.16 - 4.21 ( m, 1H ), 3.33 (s, 3H). Example 13 (S)-2-(2·,Dimethylbiphenyl-4-yloxyindenyl)-5-decyloxy-2,3-dihydro gazolo[3,2-a] Mouth Bite-7-ketone

Step 1: 2',3'-Dimethylbiphenyl-4-ol

4-iodophenyl acetate (prepared from 4-iodophenol and acetamidine) (2.6 g, 10 mmol) '2,3-monomethylphenyl spharigic acid (3.0 g, 20 mmol), four (three) Phenylphosphine) A mixture of (0) (1.0 g '0.86 mmol) and 2M sodium carbonate solution (6 ml) in 5 mL of 1,2-methoxyethanol was heated under reflux for 6 hours. The mixture was cooled and poured into an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and 55 201121978 domain residue (1 Gml), material soluble. Concentrate the residue and purify the residue. . The acid acesulfame (1.Gg) was used as an eluent, and the compound was subjected to fast-cutting gel chromatography (20 ml), and 9-8 of this compound in an ethanol solution (1 〇 ml) of 1% sodium hydroxide. The solution was heated, and the solution was stirred and stirred at room temperature for 30 minutes, poured into water (4 〇 (6)), and acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted (5 〇 〇 〇, and the organic layer was dried over magnesium sulfate and the filtrate was recrystallized from heptane to give the title compound, m.p. , 4§, 5()%). Step 2: - © # μ片 „ , J 2&lt;2,3-Methyl phenyl-4-yloxycarbonyl)-5-decyloxy-2, 3-dihydro alpha-azolo[3,2-a]pyrimidin-7-one

, will contain benzyl 4-sulfonic acid (S)-5-methoxyindol-7-keto-2,3-dihydro-7H-indole = and [3,2-a] chlorinated _2曱 曱 曱 ester (〇6 g, 16 mm〇1), 2,, 3'-dimethyl benzylidene 4 alcohol (〇3 g '1.6 mmol) and cesium carbonate (0.52 g, 1.6 mmol) in 20 ml The anhydrous acetonitrile mixture was heated under reflux for 15 hours. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was washed with water to dry with magnesium silicate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (〇.26 g, 42〇/〇). C23H24N2O4 (392.46) » LCMS (ESI): 393.18 (M+H) 56 201121978 NMR (DMSO-d6,300 MHz) δ: 7.20 (d,1H), 7.02-7.13 (m,3H),6.99-7.01 (m , 2H) , 5.86 (s, lH), 5.34 - 5.38 (m, 1H), 4.34 - 4.44 (m, 5H), 4.16 - 4.22 (m, 2H), 3.32 (s ' 3H), 2.28 (s' 3H ), 2.09 (s' 3H). Example 14 (S)-2-(4'-Ethylbiphenyl-4-yloxymethyl)-2,3-dihydro-11. Sit and [3,2_a]° close bite-7_ ketone

The sulphur-containing 4-pyroic acid (S)-7-mercapto-2,3-dimur-7Η-σ number π sits and compacts π-decan-2-yl decyl ester (0.55 g ' 1.71 mmol), 4'-Ethylbiphenyl-4-ol (prepared from 1-bromo-4-ethylbenzene and 4-hydroxyphenylboronic acid) (0.34 g, 1.71 mmol) and carbonic acid planer (0.55 g, 1.71) Methyl) 20 ml of anhydrous B. mixture was heated under reflux for 1.5 hours. The mixture was concentrated and the residue was taken &lt;RTI ID=0.0&gt;&gt; The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluting with 10-100% (EtOAc-EtOAc) elute (0.2 g, 34%). </ RTI> <RTIgt; ), 7.01 ( d, 2H ), 5.82 ( d, 1H), 5.35-5.37 (m, 1H), 4.35-4.41 ( m, 3H) , 4.10.4.15 (m, lH), 2.61 (q, 2H), 1.20 (t, 3H). 57 201121978 Example 15 (3)_2-[4-(5,6,7,8-Tetrahydro-naphthalene-2-yl)-phenoxymethyl)_2,3_dihydro-decaine[3,2- ^ Cancer bite-7-ketone

Step 1: 2-Bromo-5,6,7,8-tetrahydronaphthalene Tetrahydronaphthalene (1.06 g' 8 mm Gl) was added to alumina (neutral, Brockman grade 1) (8 g). The mixture was stirred into a homogeneous mixture'. A mixture of Moisture (1.44 g, 9 duty 1) and Oxidation (8 g) was added to the mixture over 5 minutes. After stirring for an additional 5 minutes, the mixture was loaded onto a silica gel column and eluted with dioxane (200 ml). The filtrate was concentrated and the residue was purified by flash chromatography eluting eluting eluting eluting eluting Step 2: 4-[5,6,7,8-Tetrahydro-naphthalen-2-yl]phenol in 1,2-dimethoxyethanol (2 〇) containing 2M sodium carbonate (6 ml) 2-Bromo-5,6,7,8-tetraaronaphthalene (1.3 g '6·16 mm〇1), 4-phenylphosphinic acid (1.27 g, 9.2 mmol) and tetrakis(triphenylphosphine) The mixture of bar (9) (〇8 g, 〇2 mmol) was heated under reflux for 4 hours. The mixture was added to chlorinated water, and then filtered and ethyl acetate (150 ml). The organic layer was washed with water, dried with EtOAc (EtOAc) and filtered. The filtrate was concentrated and the residue was purified by flash chromatography, eluting with 10% ethyl acetate/heptane. The product was recrystallized from heptane. I7传不58 201121978 c16h160 hNMRCCDdSOOMHdSWAJMMdH),?-7.27 (m,2H) ' 7.09-7.12 (d,1H), 6.86-6.89 (d,2H), 4.69 (s,1H), 2.79-2.82 ( m ' 4H), 1.80-1.83 (m, 4H). Step 3: (S)-2-[4-(5,6,7,8-tetrahydro-naphthalen-2-yl)- oxalylhydrazyl) -2,3-dihydro-s-oxazo[3,2-a]pyrimidin-7-one will contain (S)-7-keto-2,3-dihydro-β-and- [3,2-a]°Midine-2-yl decyl ester (0.43 g, 1.33 mmol), 4-[5,6,7,8-tetrahydronaphthalen-2-yl]benzene (0.3 g ' 1.33 Methanol) and a mixture of 20 ml of anhydrous acetonitrile (0.43 g, 1.33 mmol), EtOAc (EtOAc) The layer was dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reversed-phase HPLC for 20 min, eluted with ι 〇 〇〇〇 〇〇〇 /0 ( acetonitrile 〇 1 1% trifluoroacetic acid) and lyophilized The product fractions were concentrated to give the title compound (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H), 7.55 (d, 2H), 7.29-7.32 (m, 2H), 7.08 (d, 1H), 7.02 (d, 2H) '5.83 (d, lH), 5.35-5.37 (m, lH), 4.35 -4.42 (m, 3H) ' 4.10-4.16 (m,1H), 2.49-2.51 (m,4H), 1.75 (s, 4H). Example 16 59 201121978 (S)-2-[4-(5,6 ,7,8-tetrahydro-naphthalene-i-yl)-phenoxy-yl)_2,3-dihydro-sulphate and [3,2-a] 11-dens.

Step 1: 5,6,7,8-tetrahydro-indole-naphthylamine (294 g, 20 mmol) and 48 in bromo-5,6,7,8-tetrahydronaphthalene in 10 min. To a thick mixture of % tetrafluoroboric acid (20 ml) was added aqueous sodium nitrite (1.6 g, 23 mmol) (20 ml). The mixture was filtered and washed with cold 5% tetrafluoroboric acid (1 mL) and cold water (10 mL). A solution of copper bromide (5.6 g, 25 mm 〇1) in dimercaptopurine (50 ml) was added in batches to the filter cake. The mixture was stirred for 30 minutes and added to water (15 mL). The mixture (15 ml) was extracted with ethyl acetate and the organic layer was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography eluting elut elut elut elut Step 2: 4-[5,6,7,8-Tetrahydro-naphthalen-1-yl]phenol will contain 4-phenylphenylboronic acid (1.〇g, 7.1 mmol), 1-ML-5,6 , 7 8_ tetrahydro-naphthalene (1.0 g ' 4.7 mmol), tetrakis(triphenylphosphine)|bar (〇) (〇.8 g, 〇69 mmol) and 2M sodium carbonate solution (6 ml) of 20 ml The 1,2-dimethoxyethanol mixture was heated under reflux for 4 hours. The mixture was cooled and poured into an aqueous solution of ammonium sulfate. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut The sample was recrystallized to obtain the title compound, and the refining point was 1 Torr.匚 (I" Lu, 69%). Step 3: (S)-2-[4-(5,6,7,8-Tetrahydro-naphthalen-1-yl)-phenoxymethyl)_2,3_dihydrosoleazolo[3,2- a] pyrimidine-7-one will contain toluene-4-sulfonic acid (s)-7-keto-2,3-dihydro-7H-indazo[3-,2-a]pyrimidin-2-ylindole Ester (〇.43g, 1.33mmol), 4-[5,6,7,8-tetrahydro-naphthalen-1-yl]phenol (0.3 g, 1.33 mmol) and carbonic acid planing (0.43 g, 1.33 mmol) The ml anhydrous acetonitrile mixture was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLc for 20 minutes, eluted with 1〇-1〇〇〇/0 (acetonitrile-0.1% trifluoroacetic acid), and the product was obtained by cold and dry method. The title compound (0.055 g, 11%). </ RTI> <RTIgt; ), 5.87 ( d,1H), 5.37-5.41 (m,1H) ' 4.35-4.43 (m,3H),4.12-4.17 (m,1H), 2.76-2.80 ( m,2H ),2.49-2.53 ( m , 2H ) &gt; 1.61-1.74 ( m &gt; 4H). Example 17 61 201121978 (S)-2-(4·Dihydrogenate·5-yl)·phenoxymethyl)_2,3_dihydro-decane[3,2_a] σ密唆_7

Step 1: 4-bromoindane was added to a thick mixture of 4·aminodihydroindole (2 66 g, 2 mmol) and 48% tetrafluoroboric acid (20 ml) cooled in an ice bath over 10 min. A solution of sodium nitrite (1.6 g '23 nrniol) (20 ml) was added. The mixture was sifted in ice for 10 minutes and filtered, and the filter cake was washed with cold 5% tetrafluoroboric acid (10 ml) and cold water (10 ml). The filter cake was batchwise added to a solution containing copper bromide (η) (5 6 liters, 25 mmol) in dimethyl sulfoxide (50 ml). The mixture was stirred for 3 minutes and added to water (150 ml). The mixture was extracted with ethyl acetate (15 mL) and the organic layer was washed with water. The organic layer was dried over magnesium sulfate and dried. The filtrate was concentrated and the residue was purified eluted elut elut elut elut elut elut elut elut elut Step 2. (S)-2-(4-Dihydroindol-5-yl)-phenoxyindenyl)-2,3-dihydrosoco[3,2_a]pyrimidin-7-one will contain fluorene-benzene- 4-Supply acid (S)-7-keto-2,3-dihydro-7Η-π 嗤 and _[3,2_a]t&gt; pyridine-2-yl decyl ester (〇·38 g, 1.19 mmol , 4-dihydroindol-4-ylphenol (prepared from 4-bromoindane and 4-hydroxyphenylboronic acid) (0.25 g, 1.19 mm 〇i) and cesium carbonate (0.38 g, 1.19 mmol) 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and &lt;RTIgt;&lt;/RTI&gt; The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (0.17 g, 40%). C22H20N2〇3 (360.41) » LCMS (ESI): 361.15 (M+H) NMR (DMSO-d6 &gt; 300 MHz) δ: 7.77 (d &gt; 1H ), 7.39 (d'2H), 7.19 (d) , 2H) '7.12-7.16 (m, lH), 7.03 (d, 2H), 5.86 (d, 1H), 5.36-5.38 (m, 1H), 4.36-4.40 (m, 3H), 4.11-4.17 (m , 1H), 2.88-2.93 (m, 4H), 1.95-1.99 (m, 2H). Example 18 (S)-2-(4-Dihydroindol-4-yl)-phenoxyindenyl)_2,3_dihydro D-salt [3,2_a] squeezing-7_

Step 1: 5-Bybromoindoline 33%) Hydrazine Indoline (0.94 g '8 mmol) was added to alumina (neutral, Brockman grade 1) (8 g). The mixture was stirred into a homogeneous mixture. Bromine (1 44 g, 9 mm 〇 1) and alumina were added to the mixture over 3 minutes. a mixture of g). After stirring for an additional 3 minutes, the mixture was loaded onto a silica gel column and eluted with dioxane 6 (200 ml). The filtrate was concentrated and the residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut Hydroquinone-4-yl)-phenoxymethyl)-2,3-dihydroσ-salt[3 2-a] Mouth bit-7-one will contain toluene-4-protonic acid (S)-7 - Keto-2,3-dihydro-7H-indole. Sit and _[3,2_a]D-mididin-2-yl decyl ester (0.3 g, 0.95 mmol), 4-dihydroindole _5-ylbenzene (from 5 · bromoindane and 4-hydroxyphenyl) A mixture of 1 boric acid (0.2 g, ο. % mmol) and hydrazine carbonate (0.3 g, 0.95 mmol) in 20 ml of anhydrous acetonitrile was heated under reflux for 1.5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and extracted with dioxane. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated concentrate was purified by reverse phase HPLC for 20 minutes, eluted with 10-100% (acetonitrile - y.%% trifluoroacetic acid) and concentrated in a cold-drying method.

Compound. (0.055 g, 16%). </ RTI> <RTIgt; ( d,1H ), 7.25 ( d, 1H ) , 7.00 ( d,2H ) , 5.85 ( s,1H ) , 5.35-5.37 ( m, 1H), 4.31-4.42 (m,3H), 4.10-4.16 ( m , 1H), 2.84 - 2.93 (m, 4H), 2.01-2.09 (m, 2H). Example 19 (S)-5-Cyclopropyldi-diphenylbiphenylyloxyindenyl)-2,3-dihydroazolo[3,2-&amp;]°-dens-7-one 64 201121978

Step 1: Ethyl cyclopropylpropynoate 2.5 g of n-butyllithium solution was added dropwise to a solution containing cyclopropylacetylene (4 g, 60.0 mmol) in anhydrous diethyl ether (100 ml) cooled to -78 °C. (25.6 ml, 64 mmol) for 5 minutes. The mixture was stirred at this temperature for 30 minutes. To this mixture, vanadic acid B (9 ml, 94 mmol) was added dropwise for 15 minutes. The mixture was stirred for 30 minutes and allowed to warm to room temperature over 1 hour. The mixture was added to an aqueous solution of ammonium chloride and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by EtOAc (EtOAc) elute Step 2: Indole Benzene-4-sulfonic acid (S)-5-cyclopropyl-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-ylindole The ester will be agitated in the benzene-sulfonic acid containing (S)-2-amino-4,5-dihydrooxazolo-5-yl decyl ester (2_6 g, 9.6 mmol) and cyclopropyl propyl A mixture of ethyl acetate (1.4 g, 10.1 mmol) in 20 ml of ethanol was heated under reflux for 4 hours. The solution was concentrated and the residue was purified eluting elut elut elut elut elut eluting Step 3: (S)-5-Cyclopropyl-2-(2',3'-dichlorobiphenyl-4-yloxyindenyl)-2,3-dihydro suffix β sits and [3,2 -a]e-sigma-7-one 65 201121978 Toluene-4-sulfonic acid (S)-5-cyclopropyl-7-keto-2,3-dihydro-7H-indazole[3 , 2-a]pyrimidin-2-ylindole (0.18 g, 0.5 mmol), 2',3'-di-biphenyl-4-ol (from 4-iodophenyl acetate and 2,3-dialdehyde) A mixture of phenylboronic acid (0.12 g, 0.5 mmol) and hydrazine carbonate (0.16 g, 0.5 mmol) in 20 ml of anhydrous acetonitrile was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (0.08 g, 37%). </ RTI> <RTIgt; 5.57 ( s, 1H ), 5.40-5.42 (m, lH), 4.27-4.32 (m, 3H), 4.41-4.45 (t, 2H), 1.84-1.88 (m, lH), 0.00_1.02 (d, 2H), 0.82-0.87 (m, 2H). Example 20 (S)-5-Cyclopropyl-2-(2',3'-dimercaptobiphenyl-4-yloxyindenyl)-2,3-dihydrotetrazole

(S)-5-cyclopropyl-7-keto-2,3-dihydro-7H-indazole-containing [3,2-a]°-density-2-yl Vinegar (0.23 g, 0.63 mmol), 2',3'-dimercaptobiphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,3-dimethylphenylboronic acid) (0.12 g) , 0.63 mmol) and carbonic acid (0.20 g, 0.63 mmol) in 20 ml of anhydrous 66 2011 21978 acetonitrile mixture was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was treated with aqueous sodium hydrogen carbonate and extracted with methylene chloride (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc EtOAc EtOAc) (〇.1 g, 40%). </ RTI> <RTIgt; ), 5.57 ( s, 1H ), 5.36-5.41 (m, 1H) ' 4.58 (t, 1H), 4.30-4.42 (m, 3H), 2.28 (s ' 3H) ' 2.09 (s, 3H), 1.81 1.84 (m, 1H), 0.99-1.01 (m, 2H), 0.81-0.84 (m, 2H). Example 21 (3)-2-(2',3'-Difluorobiphenyl-4-yloxyindenyl)-5-decyloxyindenyl-2,3-dihydrocarbazo[3,2 -a]pyrimidin-7-one

(S)-5-decyloxyindol-7-keto-2,3-dihydro-7H-indole-[3,2-a]pyrimidin-2-yl Oxime ester (0.5 g, 1.36 mmol), 2',3,-difluorobiphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,3-difluorophenylboronic acid) (0.28 g ' 1.36 Methanol) and 20 ml of anhydrous acetonitrile mixture of cesium carbonate (0.44 g, 1.36 mmol) were heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjjjj The organic layer 67 201121978 layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (0.135 g, 25%). </ RTI> <RTIgt; 5.82 ( s,1H ) &gt; 5.38-5.40 (m,1H), 4.40-4.45 (m,5H), 4.35-4.36 (m,1H), 3.34 (s,3H). Example 22 (S)-2-(2',3',5'-di-biphenyl-4-yloxyindenyl)-2,3-dihydro 0-seat and [3,2_a] bite -7-ketone

F

(S)-7-keto-2,3-dihydro-7H-indazo[3-,2-a]-pyridin-2-ylmethyl ester (0.5 g, 1.55 mmol), 2,3,5,-trifluorobiphenyl-4-ol (prepared from 4-bromophenol and 2,3,5-trifluorophenylboronic acid according to Scheme A) (0.34 g, 1.55 Methyl) and a mixture of 30 rnl of anhydrous acetonitrile (0.5 g, 1.55 mmol) were heated under reflux for 1.5 hours. The mixture was concentrated, dried with EtOAc EtOAc m. The filtrate was concentrated and the residue was crystallised from EtOAc (mjjjjjjjjjjjjjjjjjjjjjjjjjjjj NMR ( DMSO-d6,300 MHz ) δ : 7.76 ( d,1H ), 7.56 (d,lH), 7.48-7.52 (m,2H), 7.26_7.30 (m,lH),7.08 (d'2H) , 5.82 (d, lH), 5.36_5.38 (m, lH), 4.39-4.45 (m, 3H), 4.10-4.15 (m, 1H). Example 23 Trifluorobiphenyl-4-yloxyindenyl)-2,3-dihydro$oxazolo[3,2-a]pyrimidine

Pyridin-7-one will contain (S)-5-decyloxyindol-7-one-2,3-dihydro-7H-indazolo[3,2-a] Pyrimidin-2-yl decyl ester (0.47 g, 1-47 mmol), 2',3,,4'-trifluorobiphenyl-4-ol (from 4-iodophenyl acetate and 2,3,4-trifluoroacetate) (Preparation of phenylboronic acid) (0.33 g, 1.47 mmol) and 20 ml of anhydrous acetonitrile mixture (0.48 g, 1.47 mmol) were heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse-phase HPLC for 2 min, eluted with 10-100% ( acetonitrile - s. </RTI> </RTI> trifluoroacetic acid), and the product fraction was concentrated by lyophilization to give the title compound (0.3 g , 54%). </ RTI> <RTIgt; ), 7.07 (d, lH), 5.35-5.40 (m, 1H), 4.39-4.46 (m, 4H), 4.11-4.16, (m, 2H). 69 201121978 Example 24 (S)-2-(2\4'-Di-biphenyl-4-yloxymethyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

The indole-containing benzoic acid (S)-7-mercapto-2,3-diaza β-s-[3,2-a]-cyano-2-yl decyl ester (〇·47 g, 1.46 Ment), 2,4,-dichlorobiphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,4-diphenylphenylboronic acid) (0.35 g, 1.46 mmol) and carbonic acid (0.48) The mixture of g, 1.46 mmol) in 20 ml of dry acetonitrile was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse-phase HPLC (20 min) eluting with 10-100% EtOAc (EtOAc) elute . C19H14C13N203 (389.24), LCMS (ESI): 389.09 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.78 (d,1H), 7.71 (s'lH), 7.47-7.51 (m,lH), 7.37-7.43 (m'3H), 7.03 (d, 2H), 5.84 (d, lH), 5.37-5.38, (m, lH), 4.38-4.42 (m, 3H), 4.11-4.17 (m, 1H) . Example 25 (S)-2-(2',3'-Dimercaptobiphenyl-4-yloxyindenyl)-5-mercapto-2,3-dihydrooxazolo[3,2-a ]°^ π定-7·纲201121978

Step 1. Toluene-4-acid (S)_5-mercapto-7-@isoyl-2,3-dihydro-7Η-4σ sita[3,2-a]pyrimidin-2-yl decyl ester (S)-2-Amino-4,5-dihydrooxazolo-5-yl decyl ester (2.7 g, 10 mmol) and ethyl 2-butynoate in a stirred state A mixture of (1.12 g, 10 mmol) in 20 ml of ethanol was heated under reflux for 4 hours. The solution was concentrated and the residue was purified eluting elut elut elut elut elut elut elut elut elut elut elut Step 2: (8)-2-(2',3'-Dimethylbiphenyl-4-yloxyindenyl)-5-mercapto-2,3-dihydro-sigma-[3,2 -a]pyrimidine-7-one will contain toluene-4-sulfonic acid (S)-5-mercapto-7-keto-2,3-dihydro-7H-indazolo[3,2-a]pyrimidine -2-yl decyl ester (0.5 g, 1.48 mmol), 2',3,-dimercaptophenylidene-4-ol (prepared from 4-iodophenyl acetate and 2,3-didecylphenylboronic acid) (0.29 g ' 1.48 mmol) and 20 ml of anhydrous acetonitrile mixture of cesium carbonate (0.5 g, 1.48 mmol) were heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjjjj The organic layer was washed with water and dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min' to 10-100. /. (Ethyl acetonitrile - 0.1% trifluoroacetic acid) was eluted and the product fraction was concentrated by lyophilization to give the title compound. (0.08 g, 15%). C22H22N2〇3 ( 362.43), LCMS (ESI): 363.15 (M+H) 71 201121978 ln NMR (DMSO-d6 &gt; 300 MHz) δ : 7.21 (d » 2H) , 7.11 - 7.13 (m, 2H ) , 7.00 ( d,3H ) , 5.73 ( s,1H ) , 5.34 - 5.36 (m,1H ) , 4.35-4.46 ( m,3H ) , 4.19-4.22, (m,1H ), 2.28 (s,3H) , 2.23 ( s, 3H), 2.09 (s, 3H). Example 26 (S)-2-(2',3'-Dichlorobiphenyl-4-yloxyindenyl)-5-mercapto-2,3-dihydrooxazolo[3,2-a] Pyrimidine-7-one

Toluene-4-sulfonic acid (S)-5-methyl-7-keto-2,3-diindole-7H-indazo[3-,2-a]pyrimidin-2-ylindole ( 0.5 g, 1.48 mmol), 2',3·-di-biphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,3-dichlorophenylboronic acid) (0.35 g, 1.48 mmol) and A mixture of 20 ml of anhydrous acetonitrile (0.5 g, 1.48 mmol) was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallisjjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by EtOAc EtOAc EtOAc (EtOAc) C2〇H16C12N2〇3 (403.26) »LCMS(ESI): 403.09 (M+H) NMR (DMSO-d6,300 MHz) δ: 7.62 (d,1H), 7.36-7-42 (m,4H ), 7.04 ( d, 2H ), 5.73 ( s, 1H ), 5.35-5.36 72 201121978 (m ' 1H), 4.37-4.42 (m ' 3H), 4.17-4.22, (m, 1H), 2.22 (s, 3H). Example 27 (8)-2-(2',4',5'-Trimethylbiphenyl-4-yloxyindenyl)_2,3-dihydrooxazolo[3,2^]pyrimidine-7 -ketone

The (S)-7-keto-2,3-dihydro-7H-4oxazo-[3,2-a]pentidine-2-yl decyl ester containing fluorene-benzene-4-sulfonic acid (〇. 5g' 1.55mmol), 2',4',5'-trimercaptobiphenyl-4-ol (prepared from 4-methyl benzene benzene and 2,4,5-trimethylphenyl phthalic acid) A mixture of (0.33 g, 1.55 mmol) and 20 ml of anhydrous acetonitrile (0.5 g, 1.55 mmol) was heated under reflux for 1.5 hours. The mixture was concentrated, and the residue was crystallised eluted with m. The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute (0.24 g, 42%). </ RTI> <RTIgt; 5.83 (d, lH), 5.36-5.37 (m, 1H), 4.35-4.42 (m, 3H), 4.11-4.17, (m, 1H) ' 2.20 (s, 6H), 214 (s, 3H). 73 201121978 Example 28 (S)-2-(3',4·-Difluorobiphenyl-4-yloxymethyl)_2,3-dihydrocarbazo[3,2_a]pyrimidine-7-嗣

Toluene-4-sulfonic acid (S)-7-keto-2,3-dioxazolo[3,2_a]pyrimidin-2-yl oxime ester (0.5 g, 1.55 mmol), 3', 4' -difluorobiphenyl-4-ol (prepared from acetic acid 4_ benzene vinegar and 3,4-difluorophenyl succinic acid) (〇, 4 g, 1.9 mmol) and carbonic acid planer (0.6 g, 1.9 mmol) 20 ml of anhydrous acetonitrile mixture was heated under reflux for 5 hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and extracted with EtOAc (EtOAc) The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated mash was purified by reverse-phase HPLC for 20 minutes, washed with 10-100% (By-1 - 1 A-disc acetic acid) and cooled to dryness. g, 32%). C19H14F2N203 ( 356.33 ), LCMS (ESI): 357.11 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.77 (d,1H), 7.72-7.76 (m,2H), 7.69 (d,1H) 7.45-7.50 ( m,2H ) , 7.03 (d,2H) , 5.83 (d,1H) , 5.36-5.37, (m,1H) ,4.33-4.42 (m,3H) ,4.10-4.16 ( m,1H) . Example 29 (S)-2-(2',3',5'-Trichlorobiphenyl-4-yloxymethyl)-2,3-dihydrooxazolo[3,2-a]pyrimidine -7-ketone 201121978

The indole-containing benzoic acid (S)-7-mercapto-2,3-di. Deficient σ sits and [3,2-a]° dense 11-demethyl phthalate (0.47 g, 1.46 mmol), 2,, 3', 5'-trichlorobiphenyl-4-ol (from acetic acid A mixture of 4-iodophenyl ester and 2,3,5-trichlorophenylboronic acid (0.4 g, 1.46 mmol) and EtOAc (0.5 g, 1.46 mmol) elute The mixture was concentrated, and the residue was evaporatedjjjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by EtOAc EtOAc EtOAc (EtOAc). </ RTI> <RTIgt; , 7.04 (d'lH), 5.83 (d, 1H), 5.37-5.38 (m, 1H), 4.36-4.46, (m, 3H), 4.11-4.16 (m, 1H). Example 30 (S)-2-(3',5'-Dibromobiphenyl-4-yloxyindenyl)_2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

75 201121978 will contain (S)-7-keto-2,3-diπ-salt[3,2-a]&gt;^2-yl decyl ester (0.29 g, 0.91 mmol), 3',5--dibromo-biphenyl-4-ol (prepared from acetic acid 4-molybdenum S and 3,5-di&gt; odor phenyl phenolic acid) (〇.3 g, 0.91 mmol) and 20 ml of anhydrous acetonitrile mixture of carbonic acid planer (0.3 g '0.91 mmol) were heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase EtOAc (EtOAc) EtOAc (EtOAc) </ RTI> <RTIgt; 2H ), 5.82 ( d,1H ) » 5.35-5.37 (m,lH), 4.36-4.45 (m,3H), 4.10-4.15 (m,lH). Example 31 (S)-2-(2,3-Methylbiphenyl-4-yloxymethyl)-5-azepine-2,3-digas a sitting and [3,2-a] Pyrimidine-7-one

Step 1: 4-Tetrahydropyran-2-yloxybutyne-2-acid ethyl ester

76 201121978 2.5N n-butyl was added dropwise to a solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (17.44 g, 124.4 mmol) in 400 ml of anhydrous ether cooled to -78 °C. Kili solution (52.3 ml, 130.7 mmol) for 10 minutes. The mixture was stirred at this temperature for 1.5 hours. To the mixture was added dropwise a solution of methylene formate (20.4 g, 188 mmol) in diethyl ether (25 ml) for 15 min. The mixture was stirred at this temperature for 2 hours and at room temperature for 18 hours. The mixture was added to aqueous ammonium chloride and extracted with ethyl acetate (50 ml). The organic layer was washed with water, dried with barium sulfate and filtered. The concentrated filtrate was purified by flash chromatography eluting elut elut elut elut elut elut elut Step 2: 4-hydroxybutyne-2-acid ethyl ester ^^^γ0^ 0 will contain 4 - 4 murine π-pyran-2-yloxybutan-2-carboxylic acid B at room temperature (8.2 g, 38.6 mmol) and a solution of p-toluenesulfonic acid monohydrate (0.1 g) in ethanol (30 ml) were disrupted for 24 hours. The solution was concentrated <RTI ID=0.0></RTI> to <RTI ID=0.0> The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated at room temperature and dried to a constant weight (4.4 g). Step 3: 4-Fluorobutyne-2-acid ethyl ester 77 201121978 Anhydrous di-methane containing 4-hydroxybutyne-2-acid ethyl ester (4.4 g, 34.3 mmol) cooled to -78 °C ( To a solution of 1 〇〇 ml), diethylamine trifluoride (DAST) (5.0 g, 31 mmol) was added dropwise for 5 minutes. At this temperature, the mixture was mixed for 1 hour and allowed to warm to room temperature within 4 hours. 15 ml of water was added to the mixture. The organic layer was dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on EtOAc (EtOAc) elute Step 4: p-Phenylhydrazinesulfonic acid (8)_5_fluoroindolyl-7-keto-2,3-diaza_7Η_σ-oxazole [3,2-a]pyrimidin-2-ylindole

Stirring oxazino-4-sulfonic acid (S)-2-amino-4,5-dihydro π, etc. oxazolo-5-yl methyl ester (0.94 g, 3.5 mmol) and 4-fluorobutyne A mixture of ethyl-2-acidate (〇·46 g, 3.6 mmol) in 20 ml of ethanol was heated under reflux for 4 hr. The solution was concentrated and the residue was purified eluting elut elut elut elut elut eluting Step 5: (S)-2-(2',3,2-Dimercaptobiphenylyloxyindenyl)-5-fluoroindolyl-2,3_dihydrooxazole #3,2- a] pyrimidine-7-one will contain indole benzene-4-sulfonic acid (S)-5-fluoromethyl-7-keto-2,3-dioxazolo[3,2-a]pyrimidine-2 -based oxime ester (〇, 4 g, 1.13 mmol), 2',3'-dimercaptobiphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,3-didecylphenylboronic acid) (0.23 g, 1.13 78 201121978 mmol) and a mixture of sulphuric acid hydrazine (〇·38 g, 1.13 mmol) in 20 ml of anhydrous acetonitrile were heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (acetonitrile-0.1% trifluoroacetic acid), and the product fractions were concentrated by lyophilization. The resulting material was stirred in an aqueous sodium hydrogencarbonate solution for 30 min. The title compound (〇.1 g, 31%) was obtained after the insoluble material was collected. C22H21FN203 (380.42), LCMS (ESI): 381.13 (M+H) ln NMR (DMSO-dg &gt; 300 MHz) δ: 7.21 (d &gt; 2H) &gt; 7.11-7.13 (m, 2H), 6.97-7.02 (m, 3H), 5.98 (s, lH), 5.40-5.41 (m, 1H), 4.37-4.43 (m, 3H), 4.20-4.24 (m, 1H), 3.32 (s, 2H), 2.28 (s , 3H), 2.09 (s, 3H). Example 32 (S)-2-(2',3'-Dichlorobiphenyl-4-yloxymethyl)-5-fluoromethyl-2,3-dihydrooxazolo[3,2-a Ming sigma-7-ketone

(S)-5-fluoroindol-7-keto-2,3-dioxazolo[3,2^]pyrimidin-2-yl decyl ester (0-5 g, 1.4 mmol) , 2',3'-Dichlorobiphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,3-dichlorophenylboronic acid) (0.34g '1.4mmol) and cesium carbonate (0.46g) , 1.4 mmol) of 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was taken &lt The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was dissolved in hot ethyl acetate and filtered. The filtrate was diluted with heptane until the solution became cloudy. The precipitate formed was collected to give the title compound as a solid, m.p., 138-140o (0.31 g, 53%). </ RTI> <RTIgt; ), 5.98 ( s, 1H ) '5.40-5.42 (m, 1H ), 4.39-4.46 ( m, 3H ), 4.18-4.23 ( m, 1H ), 3.32 (s, 2H). Example 33 (S)-2-(4'-Fluoro-3'-fluorenylbiphenyl-4-yloxyindenyl)-2,3-dihydroindole-[3,2-a]pyrimidine- 7-ketone

(S)-7-keto-2,3-di®-containing salino[3,2-a]e-butyl-2-yl decyl ester (0.71 g ' 2_2 mmol) , 4'-Fluoro-3'-fluorenylbiphenyl-4-ol (prepared from 4-iodophenyl acetate and 4-fluoro-3-indolylphenylboronic acid) (〇·45 g, 2.2 mmol) A mixture of 20 ml of anhydrous acetonitrile with cesium carbonate (0.72 g, 2.2 mmol) was heated under reflux for 1 hour. The mixture was concentrated and the residue was taken &lt The organic layer was washed with water, dried over sodium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (acetonitrile-0.1% trifluoroacetic acid), and the product fractions were concentrated by lyophilization. This material was stirred in aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with 201121978 water, dried over magnesium sulfate and filtered. The concentrated filtrate was dissolved in hot ethyl acetate (100 ml) and filtered. The filtrate (50 ml) was diluted with heptane. The insoluble material was collected to give the title compound as a solid, m.p.: 173- 175. (0.25 g, 32%). C20H17FN2O3 ( 352.36) » LCMS (ESI) : 353.12 (M+H) NMR (DMSO-d6, 300 MHz) δ: 7.76 (d,1Η), 7.53-7.60 (m ' 3H), 7.42_7.47 (m, 1H), 7.15-7.18 (m, 1H), 7.01-7.04 (d ' 2H) ' 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.42 (m ' 3H), 4.10-4.15 ( m, 1H), 2.29 (s, 3H). Example 34 (8)-2-(3'-Fluoro-4'-methylbiphenyl-4-yloxymethyl)-2,3-dihydrooxazolo[3,2_3]dine-7-one

Toluene-4-supply-containing (S)-7-keto-2,3-di-[J, and [3,2-3]-doped 2-methyl ester (0.39 g, 1.23 mmol), 3 ,-Fluoro-4,-fluorenylbiphenyl-4-ol (prepared from 4-iodophenyl acetate and 3-fluoro-4-mercaptophenylboronic acid) (〇25 g, 123 mmol) and cesium carbonate (0.39 g, 1.23 mmol) of 20 ml of anhydrous B. mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 1 - 100% (acetonitrile - 0.1% trifluoroacetic acid), and the product fractions were concentrated by lyophilization. The resulting material was stirred in an aqueous sodium hydrogencarbonate solution for 1 hour. The title compound was obtained as a solid, m.p., 223- 226 ° C (0.14 g, 32%). [oc]D25 = -18.2. (c = 0.74, DMSO). C2〇H17FN203 (352.36), LCMS (ESI):353.04 (M+H), NMR (DMSO-d6,300 MHz) δ: 7.76 (d,1H), 7.63 (d'2H) '7.30-7.39 (m, 3H) '7.01-7.04 (d,2H), 5.82 (d ' 1H ) , 5.35-5.36 ( m,1H ) , 4.36-4.41 ( m,3H ), 4.09-4.15 (m,1H) , 2.25(s, 3H). Example 35 (S)-2-(2·-Fluoro-4·-fluorenylbiphenyl-4-yloxyindenyl)-2,3-dihydroindole σ 并[3,2_a] π dense.定-7-嗣

The succinyl-4-(S)-7-keto-2,3-dioxime is contained in the form of salino[3,2-a]. Dec-2-yl decyl ester (0.5 g, 1.55 mmol), 2'-fluoro-4'-mercaptobiphenyl-4-ol (from 4-iodophenyl acetate and 2-fluoro-4-mercaptobenzene) The base boric acid preparation) (0.31 g, 1.55 mmol) and 20 ml of anhydrous acetonitrile mixture of carbonic acid (0.5 g, 1.55 mmol) were heated under reflux for 1 hour. The mixture was concentrated <RTI ID=0.0>: </RTI> </RTI> <RTIgt; The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was taken up in boiling ethyl acetate (20 mL). The insoluble material was collected to give the title compound as a solid, m.p. 215 - 218% (0.3 g &gt; 55%). 82 201121978 [a]D25 = -16.4 ° ( c = 0.68 ' DMSO ). C2〇H17FN203 (352.36), LCMS (ESI): 353.12 (M+H) NMR (DMSO-d6,300 MHz) δ: 7.76 ( d,1H) &gt; 7.45 (d,1H),7.34-7.40 (m , 2H), 7.03-7.09 (d, 4H), 5.82 (d, 1H), 5.35-5.37 (m, 1H), 4.36-4.41 (m, 3H), 4.10-4.15 (m, 1H), 2.34 (s , 3H). Example 36 (8)-5-Methoxymercapto-2-(2',3',5'-trifluorobiphenyl-4-yloxymethyl)-2,3-dihydro 0 And [3,2-a]^. D--7-ketone

Toluene-containing acid (S)-5-decyloxymethyl-7-keto-2,3-dihydro-7Η-σ-oxazolo[3,2-a]pyrimidin-2-yl Anthracene ester (0.28 g, 0.76 mmol), 2,3,5,-difluorobiphenyl-4-ol (according to Scheme A from 4-bromobenzene and 2,3,5-trifluorophenyl group (Acid preparation) (0.17 g '0.76 mmol) and 20 ml of anhydrous acetonitrile mixture of hexane (0.25 g, 0.76 mmol) were heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was treated with 1 mL of hot ethyl acetate. The resulting solution was cooled in ice to precipitate the title compound mp 183-185. (:( 0.14 g, 44%). [a] D25 = + 2.4 ◦ ( c = 0.68, DMSO ). C21H18F2N204 (400.38), LCMS (ESI): 401.14 (M+H) 83 201121978 !H NMR (DMSO- D6 &gt; 300 MHz) δ : 7.58 (d &gt; 2H) &gt; 7.53-7.56 (m, 1H), 7.26-7.31 (m, 1H) 7.08 (d, 2H), 5.85 (s, 1H), 5.37- 5.38 (m,1H), 4.34-4.46 (m,5H), 4.14-4.20 (m,1H), 3.33 (s,3H).

Example 37 (S)-5-Mercapto-2-(2',3·,5^difluorobiphenyl-4-yloxymethyl)-2,3-dihydro oxime[3,2- a] pyrimidine-7-one F

(S)-7-keto-2,3-dihydro-oxazolo-[3,2-a]pyrimidin-2-ylmethyl ester (0.5 g, 1.48 mmol), 2' , 3',5--difluorobiphenyl alcohol (prepared from 4-bromophenol and 2,3,5-trifluorophenylboronic acid) (0.33 g, 1.48 mmol) and carbonic acid (0.48 g, 1.48 mmol) The 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was applied tojjjjjjjjjjjjj The organic layer of the knee was washed with water and dried with magnesium sulfate. The concentrated solution was dissolved in 10 ml of hot ethyl acetate and dried. The filtrate and the solution were cooled in ice to precipitate the title compound, which had a melting point of 1 l 〇 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; 7.09 (d,2H), 5.70 (s, 84 201121978 1H) ' 5.33-5.35 ( m,1Η ), 4.38-4.44 ( m,3H ),4 14-4 20 (m,1H),2.21 (s,3H) ). Example 38 (S)-2-(2 3 -Methylbiphenyl-4-yloxymethyl)-5-morphine_4_ylmethyl-2,3_dihydrooxazole[3 ,2-a]pyrimidin-7-one

〇Step 1: 4-propan-2-yl hydrazide in a solution of 5 ml of decyl alcohol (7 g, 84 mmol) and potassium carbonate (6.4 g, 46 mmol) in an ice bath 100 ml) The mixture was added to a solution of 80% fast propyl bromide in benzene (9.34 w, 841 _ 〇 1). The mixture was stirred on ice for 30 minutes and then at room temperature for 5 hours. The mixture was passed through and the filtrate was concentrated. The residue was treated with m (10) ml) and filtered. The filtrate was concentrated, and the residue was applied mjjjjjjj The money was dried with sulfuric acid, and the residue was concentrated to give the title compound as an oil (5.9 g, 56%). Step 2: 4-morpholin-4-ylbutyne-2-acid vinegar

g '47 mmol) Add 2·5 Μ-n-butyl clock (Mg stir the mixture for 30 minutes, here • 5 g, 60 mmol) for 5 minutes 85 20 Π 21978 minutes. The mixture was run at _78 〇c for 30 minutes, then at 3 hours (sounding. The organic layer was washed with water, dried over magnesium sulfate and dried. _ = and the residue was purified by flash chromatography. The title compound (04 g, 4%) was obtained by elution with acetonitrile. _2 Opening [3,2-a]pyrimidin-2-ylmethyl ester The mixture of ethanol (20 ml) containing toluene glacial sulfonic acid (8) 2 -amino group _4,5::-) was stirred under reflux for 4 hours. The title compound (G.3 g, 37%) was obtained. Sub-gas pit wash k, =4 dimethylbiphenyl _4_ yloxy fluorenyl> 5 _ linalyl-2,3-dihydrooxazolo[3,2_a]pyrimidinone. Toluene·4-supply acid (S)-5·Mallinomethyl_7__yl 2,3_dihydro_7 as number;:[[巧啶-2-基甲略(〇3 g'〇 71. 1), 2,, 3, dimethyl 9 _4_ol (0.14 g ' 〇·7ι 匪〇1) and cesium carbonate (〇23 邑, m mmol) of anhydrous acetonitrile (2 〇 混合物 mixture The mixture was heated under reflux for a few hours. The mixture was concentrated and the residue was treated with aqueous sodium bicarbonate and extracted with hexanes (150 ml). The organic layer was washed with water and dried over magnesium sulfate and filtered. The concentrated liquid was purified by reverse phase HPLC for 20 min, eluted with 1 〇 〇〇 〇〇 ( 〇 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 The resulting material 86 201121978 was treated with aqueous sodium bicarbonate and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (0.05 g, 16%). [a]D25 = +11.9. (c = 0·48, MeOH). C26H29N304 (447.54), LCMS (ESI): 448.23 (M+H).H NMR (DMSO-d6 &gt; 300 MHz δ:.7.00-7.13 (d &gt; 3H), 7.11-7_13 (m, 2H), 7.20 (d,2H) 5.79 (s,lH) , 5.38-5.40 (m,1H) 5 4.52-4.55 ( t 5 1H), 4.35-4.39 ( m,3H), 3.38 (s,2H), 3.32 (s, 4H), 2.42 (s' 4H), 2.28 (s, 3H), 2.09 (s, 3H). Example 39 (S)-2-(2'3'_di-biphenyl-4-yloxyindenyl) )-5-Nuprin-4_ylmercapto-2,3-dihydro-oxime[3,2-a]pyrimidin-7-one

(S)-5-morpholinoindolyl-7-keto-2,3-dihydro-7H-oxazo[3,2-a]pyrimidin-2-yl Mixture of methyl ester (0.3 g, 0.71 mmol), 2,3,-di-biphenyl-4-ol (0.17 g, 0.71 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in anhydrous acetonitrile (20 ml) Heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) The resulting material was treated with aqueous sodium bicarbonate and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (0.075 g, 21%). [a]D25 = -10.2° (c = 0.65,

MeOH). </ RTI> <RTIgt; d, 2H) 5.79 (s, lH), 5.36-5.40 (m ' 1H), 4.52-4.55 (t, 1H), 4.35.4.41 (m, 3H), 3.50 (s, 4H), 3.39 (s, 2H) ), 2.42 (s, 4H). Example 40 (S)-2-(2 3 -monomethylbiphenyl-4-yloxyf-yl)pyrazine adiylmethyl-2 3 Dihydroindolo[3,2-a] spray Bite-7-ketone

Step 1. 4-propylidene-2-yl-α ratio η

Adding 80% propargyl bromide to a mixture of pyrrolidine (6 〇g, 84 3 mmol) and potassium carbonate (6.4 g, 46 mmol) in diethyl ether (25 〇 ml) cooled in an ice bath over 10 minutes. Toluene solution (9.3 m b 84.3 mmol). The mixture was stirred in ice for 20 minutes and then at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated in a non-heated rotary evaporator. Residues using b-diether 88 201121978 The filtrate was concentrated without heating to give the title compound 14%). · s, step 2: 4-pyridin-2-yl-pyrrolidine (2 2 g, 2 〇 mmol) cooled to -78 ° C in 4-pyrrolidine _4_ylbutyne-2-acid ethyl ester The solution of anhydrous diethyl ether (100 ml) was added dropwise (10).1, 2) for 5 minutes. The mixture was stirred: base: clock. A solution of ethyl formate (6 5 g, 6 〇mm〇i) in diethyl ether (15 ml) was added dropwise to the mixture for 5 minutes. The mixture was stirred at -78 ° C for 3 Torr and then warmed. To the end. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with diethyl ether (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified eluting elut elut elut elut elut elut elut elut elut Step 3: Indole Benzene-4-sulfonic acid (S)-5-pyrrolidinyl-7-keto-2,3_dihydro-7H·^oxazolo[3,2_a]pyrimidin-2-yl decyl ester It will contain (S)-2-amino-4,5-dihydro σ. Sit and _5_ ketone vinegar (1.49 g, 5.5 mmol) and 4-port specific mouth -4- butylbutyne-2-acid ethyl ester (ί ο g, 5.5 mmol) of ethanol (20 ml) The mixture was heated under reflux for 4 hours. The solution was concentrated, and the residue was purified eluting elut elut elut elut eluting Step 4: (S)-2-(2,3,-Dimercaptobiphenyl-4-yloxyindenyl)_5_πpyrrolidine-丨-ylindolyl-2,3-dihydrocarbazo[ 3,2-a]pyrimidin-7-one 89 201121978 will contain a pyridinium-4-sulfonic acid (5)-5-°pyrrolidinyl-7-keto-2,3-dihydro-7H-carbazole [3,2-a]pyrimidin-2-yldecyl ester (〇.5 g, 1.23 mmol), 2,3,-dimethylbiphenyl-4-ol (0.24 g, 1.23 mmol) and cesium carbonate Anhydrous acetonitrile (25 ml) mixture (〇4 g, 1.23 mmol) was evaporated. The mixture was concentrated, and the residue was purified mjjjjd The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by reverse phase HPLC for 20 min, eluted with 10-100% (acetonitrile-0.1% trifluoroacetic acid), and the product fractions were concentrated by lyophilization. The resulting material was treated with aqueous sodium bicarbonate and extracted with ethyl acetate (EtOAc). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a mp (0.03 g, 6%). [a] D25 = +15.0. (c = 0.32, MeOH). (:26Η29Ν303 ( 431.53 ) ' LCMS (ESI) : 432.22 (M+H) !H NMR (DMSO-d6,300 MHz), δ: 7.20-7.23 (d,2H), 7.11-7.13 (m'2H), 7.00(d,3H)5.78(s,lH),5.34-5.38 (m '1H) ,4.52-4.54 ( t,1H) ,4.32-4.40 ( m,3H), 3.48-3.49 ( d,2H),2.28 ( s, 3H ), 2.09 ( s, 3H ), 2.50 (s, 4H), 1.70 ( s, 4H). Example 41 (S)-2-(9H-gyl-2-yloxymethyl)_2 , 3-terpenoid, and [3,2-a]pyrimidin-7-one

90 201121978 will contain (s)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-yl decyl ester (0.5 g, 1.55 mmol), A mixture of 2-hydroxydiyl (0.28 g, J 55 mmol) and cesium carbonate (〇·5 g '155 mmol) in 25 mmol of anhydrous acetonitrile was heated under reflux for 1 hour. The mixture was cooled and added to water (100 ml). Insoluble materials were collected and dried in vacuo. This material was heated with ethyl acetate (3 〇〇 ml). The insoluble material was collected to give the title compound with a melting point of 227-30. (:(0.085 g, 16%). [a]D25 = -28.3 °(C = Q.68'DMSO) qC2{)Hi6N2〇3 ( 332 36), LCMS (ESI) :333.11 (M+H) NMR (DMSO-d6, 300 MHz), δ: 7.79-7.81 (m,3H), 7,55 (d ' 1H) ' 7.32-7,34 (m,1H) 57.20-7.26 (m,2H), 6.96 -6.99 (d,1H),5.82-5.85 (d,1H),5·36 (s,1H), 4.37-4.45 (m ' 3H) ' 4.14-4.17 (m ' 1H),3.88 (s,2H) . Example 42 (S)-2-(2,2,3 · Dimercaptobiphenyl-4-yloxyindenyl)_2,3_dihydro-a saliva[3,2_a] Carcinogen-7-ketone

Step 1: 4-bromo-3-methylacetate acetate in 4-bromo-3-indenyl group (1.87 g, 1 〇mm〇i) and triethylamine (J 2 g, 12 mmol) Ethylene gas (0.94 g, 12 mmol) was added dropwise to a solution of chloranil (40 ml) for 3 minutes. The mixture was stirred at room temperature for 3 minutes. This mixture was added to water (100 ml) and extracted with dioxane (100 91 2011 21978 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (1.5 g, 66%). Step 2: Mercapto, 2',3'-dimercaptobiphenyl-4-ol will contain 4-bromo-3-indolyl phenyl acetate (1.5 g, 6.57 mmol), 2,3-didecyl 60 ml 1,2-dimethoxyethanol of phenylboronic acid (1.38 g, 9.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.86 mmol) and 2M sodium carbonate solution (6 ml) The mixture was heated under reflux for 4 hours. The mixture was cooled and poured into an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with ethyl acetate (10 ml) and filtered and evaporated. The filtrate was concentrated and the residue was purified by flash gel chromatography eluting with EtOAc EtOAc. This compound was heated in a mixture of 10% sodium hydroxide (5 ml) in ethanol (15 ml) and water (10 ml) to give a solution. This solution was spoiled at room temperature for 30 minutes. This solution was poured into water and acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with EtOAc (EtOAc)EtOAc. The filtrate was concentrated to give the title compound (m. Step 3: (S)-2-(2,2',3'. Trimethylbiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2-a]pyrimidine -7-one will contain (S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-yl decyl ester (0.4 g, 1.24 mmol) 2-Mercaptosyl, 2',3'-dimethylbiphenyl-4-ol (0.26 g, 1.24 mmol) and a mixture of 20 ml of anhydrous acetonitrile of EtOAc (0.4 g, 1.24 mmol). The mixture was concentrated, and the residue was crystallisjjjjjjjjjjj The organic layer was washed with water and dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was dissolved in a small amount of hot ethyl acetate. This solution was diluted with heptane until it became cloudy to precipitate the title compound </ </ RTI> </ RTI> </ RTI> <RTIgt; [a]D25 = -8.9. (c =0.40 &gt; DMSO) C22H22N2O3 (362.43) &gt; LCMS (ESI): 363.13 (M+H))H NMR (DMSO-d6, 300 MHz), δ: 7.77-7.79 (d,1H), 7.10- 7.12 (m ' 2H), 6.95-6.98 (d, 1H), 6.80-6.89 (m, 3H) ' 5.82-5.84 (d, 1H), 5.33-5.37 (m, 1H), 4.33-4.38 (m, 3H ) ' 4.13-4.16 (m, 1H), 2.28 (s, 3H), 1.95 s, 3H), 1.89 (s, 3H). Example 43 (S)-2-(2,4-nonylbiphenyl-4-yloxyindenyl)-2,3-dihydroπ-a is sitting and [3,2_3]„密定定-7- ketone

The succinyl-(S)-7-mercapto-2,3-dipo-[3,2-a]e succinimide &lt;RTIgt; 1.55 mmol), 2,,4,-dimercaptobiphenyl-4-ol (prepared from 4-iodophenyl acetate and 2,4-dimethylphenylboronic acid) (0.3 g, 1.55 mm〇i) A mixture of 20 ml of anhydrous acetonitrile with carbonic acid (0.5 g '1 · 55 mmol) was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over sulfuric acid and filtered. The filtrate was concentrated and the residue was crystallisjjjjjjjj The title compound was obtained by the collection of 93 201121978 insolubles, melting point 233_35 〇C (0.22 g, 40%). [a]D25 = -13.3. (c = 0.54, DMSO) C21H20N2O3 ( 348.40), LCMS (ESI): 349.14 (M+H).H NMR (DMSO-d6 '300 MHz), δ: 7.76-7.79 (d,1H), 7.23-7.26 ( m, 2H), 6.98-7.04 (m, 6H), 5.82-5.84 (d, 1H), 5.33_5.37 (m, 1H), 4.35-4.42 (m, 3H), 4.11-4.16 (m ' 1H) ' 2.29 (s, 3H), 2.18 s, 3H). Example 44 (S)-2-(2'-Isopropylbiphenyl-4-yloxymethyl)-2,3-dihydroπ-π π-[3,2-a]»-Bite-7 - Same as

(8)-7--yl-2,3-diπ-pyrido[3,2-a]-p--2-yl decyl ester (0.7 g ' 2.17 mmol), 2'-Isopropylbiphenyl-4-ol (prepared from 4-methyl phenylbenzene and 2-isopropylphenyl phthalic acid) (0.7 g, 3.3 mmol) and cesium carbonate (lg, 3. mmol) The 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was applied tojjjjjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The condensed filtrate was subjected to reverse phase HPLC purification for 20 minutes to elute with 1 〇·1 〇〇〇 /0 (acetonitrile 〇 1 〇 / 〇 tri-acetic acid), and the product-containing fraction was concentrated by freeze-drying. The resulting material was treated with aqueous sodium hydrogencarbonate solution and taken with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was taken from heptane (25 mi) The insoluble material was collected to give the title compound, m.p., </ RTI> </ RTI> </ RTI> <RTIgt; [a]D25 = -22.0. (c = 0.56, MeOH) 〇C22H22N203 ( 362.43 ), LCMS (ESI): 363.16 (M+H) 4 NMR (DMSO-d6, 300 MHz), δ: 7.77-7.79 (d, ih), 7.33-7.46 ( m &gt; 4H ) , 7.19-7.22 ( d, 2H ) , 6.99-7.02 ( d, 1H) , 6.62 - 6.64 (d, 2H) , 5.82 - 5.84 (d, 1H) , 5.36-5, 38 (m ' 1H), 4.36-4.42 (m ' 3H), 4.13-4.14 (m, 1H), 1.09-1.11 (d, 6H). Example 45 (S)-2-(3'-trifluorodecylbiphenyl-4-yloxyindenyl)_2,3-dihydroindole[3,2-a]pyrimidine _7·酉with

Toluene-4-sulfonic acid (S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethylhydrazine (0.27 g, 0.84 mmol), 3·- Trifluorodecylbiphenyl-4-ol (prepared from 4-phenylidene acetate and 3-trifluorodecylphenylboronic acid) (〇.2 g, 0.84 mmol) and saponin (0.27 g, 0.84) A 20 ml portion of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was evaporatedjjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and dried. The residue was dissolved in hot ethyl acetate (10 mL) and filtered. The filtrate was cooled in ice 95 201121978 to precipitate the product, m.p. 133-60 C (0.08 g, 24%). [a] D25 = -40.70 (c = 0.74, MeOH) C20H15F3N2O3 ( 388.34), LCMS (ESI): 389.10 (M+H) NMR (DMSO-d6, 300 MHz), δ:.7.93-7.96 (m, 2H ), 7.67-7.92 ( m,5H) &gt; 7.06-7.09 ( d &gt; 2H ) , 5.82-5.89 ( d, 1H), 5.36-5.38 (m, 1H), 4.35-4.46 (m, 3H), 4.10 -4.16 (m, 1H). Example 46 (S)-2-(3-isopropylbiphenyl-4-yloxyindenyl)-2,3-dihydro-sigma n-sand[3,2-a]c close-bit-7-酉同

(S)-7-keto-2,3-diindole-containing [3,2-a]-containing 2-ylmethyl ester (0.6 g ' 1.86 mmol) , 3'-Isopropylbiphenyl-4-ol (prepared from 4-iron phenylacetate and 3-isopropylphenyl phloem) (0.5 g, 2.36 mmol) and carbonic acid (0.75 g, 2.36 mmol) The 20 ml anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was concentrated, and the residue was crystallised eluted eluted eluted The organic layer was washed with water, dried over sulfuric acid and filtered. The concentrated filtrate was purified by reverse-phase HPLC for 20 min, eluted with EtOAc (EtOAc/EtOAc) elute The mixture was extracted (100 ml). The strip was washed with water and dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with EtOAc EtOAc &lt The insoluble material was collected to give the title compound, m.p., 153-56 ° C (0.13 g, 19%). C22H22N203 ( 362.43), LCMS (ESI): 363.20 (M+H) ]H NMR (DMSO-d6 » 300 MHz), δ: 7.76-7.79 (d,1H), 7.59-7.62 ( d ' 2H ),7.32- 7.40 ( m,3H ),7.18-7.21 ( d, 1H) ' 7.02-7.05 ( d,2H ),5.82-5.84 ( d,1H ) ,5.35-5.37 (m,1H),4.36-4.42 (m,3H ), 4·14-4·16 (m, 1H), 2.93-2.97 (m, 1H), 1.23-1.26 (d, 6H). Example 47 (S)-2-(2'3'_Di-biphenyl-4-yloxymethyl)-5-σ ratio σ each σ-based fluorenyl 2,3_dihydro π-salt [ 3,2-a]^^-7-_

(S)-5-pyrrolidinyl-7-keto-2,3-dihydro-7H-4indole[3,2-a]pyrimidin-2-ylindole A mixture of ester (0.25 g, 0.61 mmol), 2,3,-di-biphenyl-4-ol (0.15 g, 0.61 mmol) and anhydrous (0.2 g, 0.61 mmol) anhydrous acetonitrile (15 ml) Heat for 1 hour. The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC for 20 min, eluted with 10-100% (EtOAc-EtOAc) elute The resulting material was treated with aqueous sodium bicarbonate and extracted with ethyl acetate (1 </ RTI> </ RTI> <RTIgt; The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with EtOAc (EtOAc) The insoluble material was collected to give the title compound mp 152-55. (:(〇.〇7 g, 24%). [a] D25 = + 11.40 (c = 0.68, MeOH). C24H23CI2N3O3 (472.37) &gt; LCMS (ESI): 472-474 (M+H) 4 NMR ( DMSO-d6 '300 MHz), δ: 7.62-7.65 (d,1H), 7.33- 7.44 (m,4H), 7.02-7.05 (d,2H) 5.78 (s,1H), 5.34- 5.35 (m ' 1H ), 4.28-4.55 (m, 4H), 3.32 (s, 3H), 2.50 (s, 4H), 1.70 (s ' 4H). Example 48 (S) -2- (3'_ indole biphenyl-4 -yloxyindenyl)-2,3-dihydron-n-indole[3,2-a]·1 dense π--7-

(S)-7-keto-2,3-diindolo[3,2-a] aceto-2-yl decyl ester (0.38 g '1.2 mmol), 3 ·-Mo-biphenyl-4-ol (prepared from 4-methyl vinegar acetate and 3-di-phenyl phenyl acid) (0.3 g, 1.2 mmol) and 20 ml of carbonic acid planer (0 38 g, 1.2 mmol) The anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with dioxane (15 〇mi). The organic layer was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was taken up in hot ethyl acetate (25 ml) and filtered. The insoluble material was the title compound and had a melting point of 173-6 〇C (0.13 g, 27%). [a]D25 = -19.0. (c = 0.68, DMSO). 98 201121978 C19H15Br2N203 (399.24), LCMS (ESI): 398,400 (M+H) NMR (DMSO-d6, 300 MHz), δ: 7.76-7.81 (m, 2H), 7.63-7.67 (m &gt; 3H ), 7.42 -7.45 ( d,1H ), 7.36-7.39 ( d, 1H) , 7.03-7.06 ( d,2H) ,5.82-5.84 ( d,1H ) &gt; 5.35-5.37 (m,1H) ,4.33-4.45 ( m , 3H), 4.1-4.15 (m, 1H). Example 49 (S)-2-(2'-Mercaptobiphenyl-4-yloxyindenyl)-2,3-dihydrot^-pyrano[3,2-a]. Methyl -7-ketone

(S)-7-keto-2,3-diindole-containing [3,2-a] lysyl-2-yl decyl ester (0-61 g, 1.9) Ment), 2'-fluorenylbiphenyl-4-ol (prepared from 4-iodoacetate acetate and 2-mercaptophenylphosphonic acid) (0.35 g, 1.9 mmol) and carbonic acid (0.6 g, 1.9) A 20 ml portion of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (150 ml). The organic layer was washed with water and dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC for 20 min and eluted with 1 〇 1 〇〇〇 /0 (acetonitrile - 0.1% trifluoroacetic acid). The product containing fractions were combined and added to aqueous sodium hydrogencarbonate, and the mixture was taken up with ethyl acetate (1 〇〇). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with heptane (50 ml). The insoluble material was collected to give the title compound, m.p. </RTI> </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

Ci9〇H18N2〇3 ( 334.37), LCMS (ESI): 335.19 (M+H) 99 201121978 lR NMR (DMSO-d6 &gt; 300 MHz), δ: 7.77-7.79 (d,1H), 7.15-7.29 ( m &gt; 6H) &gt; 7.00-7.02 ( d &gt; 2H ) &gt; 5.82-5.84 ( d , 1H) , 5.33-5.38 (m, 1H) , 4.36-4.45 ( m, 3H') , 4.11-4.17 (m , 1H), 2.22 (s, 3H). Example 50 (S)-2-(3'-Ethylbiphenyl-4-yloxymethyl)_2,3-di Wow [3,2-&amp;]°Bite_7_ Ketone

The pyridinium-containing [())-7-keto-2,3-dioxime is spit [3,2-a]. Ding-2-yl (0.5 g, 1.5 mmol), 3'-ethylbiphenyl-4·ol (prepared from 4-nonyl acetate and 3-ethylphenylboronic acid) (0.6 g ' 3.0 mmol) and 20 ml of anhydrous acetonitrile mixture of carbonic acid planing (〇.5 g, 1.5 mmol) were heated under reflux for 1 hour. The mixture was taken up in aqueous sodium hydrogencarbonate and extracted with dioxane (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC for 20 min and eluted with 10-100% (EtOAc-EtOAc). The product-containing aliquots were combined and added to aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was stirred with heptane. The insoluble material was collected to give the title compound (0.140 g, 28%). [a]D25 = -45.2. (c = 0.67, MeOH). C21H20N2〇3 ( 348.40 ) ' LCMS (ESI) : 349.11 (M+H) 100 201121978 lR NMR (DMSO-d6 &gt; 300 MHz), δ: 7.77-7.79 (d,1H), 7.60-7.62 (m,2H ), 7.34-7.45 (m,3H), 7.15-7.17 (d, 1H), 7.02-7.05 (d,2H), 5.82-5.84 (d,1H), 5.35-5.37 (m,1H),4.32-4.41 (m,3H), 4.10-4.16 (m,1H), 2.62-2.67 (q,2H), 1.20-1.25 (t,3H). Example 51 (S)-2-(3'-Methylbiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

(S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.47 g, 1.45 mmol), 3' - mercaptobiphenyl-4-ol (prepared from 4-acetic acid acetate and 3-mercaptophenyl phthalic acid) (0.6 g, 3.26 mmol) and carbonic acid (0.47 g, 1,45 mmol) 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with dioxane (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was shrunk. The residue was purified by reverse phase HPLC for 20 min and eluted with EtOAc (EtOAc) The product-containing fractions were combined and added to aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue dissolved in hot ethyl acetate and filtered. The filtrate was diluted with heptane and the precipitate was collected to give the title compound, which was 183 - 50 C (0.07 g, 14%). 101 201121978 [a]D25 = -18.5. (c = 0.72, DMSO). C20H18N2O3 ( 334.37 ), LCMS (ESI): 335.16 (M+H), NMR (DMSO-d6, 300 MHz), δ: 7.76-7.79 (d,1H), 7.59-7.62 (m,2H), 7.29- 7.43 ( m,3H ), 7.11-7.14 ( d, 1H) , 7.02-7.04 ( d,2H) , 5.82-5.84 ( d,1H ) , 5.32-5.37 (m,1H),4.32-4.45 (m,3H ), 4.10-4.16 (m, 1H), 2.36 (s, 3H). Example 52 (S)-2-(3'-Chlorobiphenyl-4-yloxyindenyl)-2,3-dihydroindole. Sit and [3,2-a] spray bite _ 7-ketone

(3)2-keto-2,3-disino[3,2-a]carcinoma-2-yl decyl ester (0.55 g, 1.7 mmol), 3' a mixture of -chlorobiphenyl-4-ol (prepared from 4-indolyl acetate and 3-chlorophenylboronic acid) (0.35 g, 1.7 mmol) and cesium carbonate (0.5 g, 1.7 mmol) in 20 ml of anhydrous acetonitrile Heated under reflux for 1 hour. The mixture was taken up in aqueous sodium hydrogencarbonate and extracted with dioxane (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC for 20 min and eluted with 10-100% (acetonitrile). The product-containing fractions were combined and added to aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue dissolved in EtOAc EtOAc (EtOAc) The filtrate was diluted with heptane (200 ml) and the precipitate was collected to give the title compound, </RTI> </RTI> </RTI> <RTIgt; [a] D25 = -22.4 ° (c = 0.67, DMSO). C19 H15C1N203 ( 354.79), LCMS (ESI): 335, 357 (M+H) 4 NMR (DMSO-d6, 300 MHz), δ: 7.76-7.79 (d,1H), 7.59-7.68 (m ' 4H), 7 36_7 48 , 2H), 7.03-7.06 (d, 2H), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.33-4.45 (m ' 3H), 4.10-4.15 (m, 1H) ). Example 53 (S)-2-(3 _Di-dibutylbiphenyl_4_yloxyindenyl)_2,3_dihydroσ-salt p,2_a]^ -7-ketone

(S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-yl decyl ester (0.21 g '0.66 mmol), 3' - tert-butylbiphenyl-4-ol (prepared from 4-hydroxyphenylboronic acid and 3-tert-butyl bromide) (0 15 g, 〇66 mm〇1) and carbonic acid planer (0.2 g, 0.66) A 20 ml portion of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with dioxane. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with B.sub.2 acetic acid (20 ml) and filtered. The insoluble material was the title compound' melting point 188-91 ° C (0.07 g, 28%). [a]D25 II-15.8. (c = 0.68, DMSO). 103 201121978 C23H24N2〇3 ( 376.45 ), LCMS (ESI) : 377.19 (M+H) !H NMR (DMSO-d6,300 MHz), δ: 7.76-7.79 (d,1H), 7.57-7.62 (m,3H ), 7.34-7.41 (m, 3H), 7.02-7.05 (d, 2H) ' 5.82-5.84 (d, 1H), 5.35-5.40 (m, 1H), 4.36-4.45 (m, 3H) '4.10-4.16 (m, lH), 1.53 (s, 9H). Example 54 (S)-2-(3·-propylbiphenyloxyindenyl)_2,3-dihydrooxo-oxazolo[3,2_a]n-mididine_7-one

To a mixture of 3M ethylmagnesium bromide diethyl ether solution (6.7 megbrane 2〇mmol) and anhydrous ethyl acetate (2) ml, which was cooled in ice, a mixture of 3·indibenzaldehyde δ 10 mmo1) was added dropwise (10 ml) ) The solution is for 5 minutes. The two were stirred in ice for an hour. Pour this mixture into hci and take it with =. The ether layer was washed with water, dried over magnesium sulfate and filtered. The title compound was obtained as an oil (1.9 g, 88%). Step 1: 1-(3-bromophenylpropanol step 2: 3-propyl bromide) 2 small odor base (3.3 g, 15.3 s. 1), triethyl hydrazine ^ ^ (2° ml) 3 „ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The title compound was treated with heptane (20 ml) and filtered. The filtrate was concentrated, (2.1 g, 70%) 〇 虱 。 。. [3,2- Step 3: (S)-2- (3'_propylbiphenyl-4-yloxyindenyl)_2,3-dia]pyrimidin-7-one will be δ曱本-4-石页酸(S)-7-keto-2 , 3- slogan. Sit and [3,2_a] mouth dense. Set _2_ base vinegar (0.45 g, 1.4 mmol), 3'-propylbiphenyl _4-alcohol (〇3 g, j 4 Methanol) and hydrazine carbonate (0.45 g, 1.4 mmol) in 20 ml of anhydrous acetonitrile mixture were heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate and filtered. The residue was concentrated and the residue was crystallized from ethyl acetate to give the title compound 138-420 C (0.13 g) , 25%). [a] D25 = -51.3 0 (c = 〇.6〇,

MeOH). </ RTI> <RTIgt; (m,3H),7.12-7.15 (m, 1H), 7.02-7.05 (d,2H),5.82-5.84 (d,1H),5.32-5.37 (m,1H),4.32-4.45 ( m,3H ) , 4.10-4.16 ( m ' 1H ), 2.58-2.63 ( t, 2H) , 1.57-1.67 ( m, 2H ) , 0.89-0.94 ( t, 3H). Example 55 105 201121978 (S)-2-(3'-butylbiphenyl I oxymethyl)_2,3_dihydro. Sodium [3,2_small pyridine-7-

(S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylindole (l.〇g, 3.0mm〇l) , 3,-butylbiphenyl-4-ol (prepared from 4-hydroxyphenylboronic acid and 3-butylbromobenzene) (〇7 g, 3.〇mm〇i) and cesium carbonate (丄〇g) , 3.0 mmol) of 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by reverse phase HPLC for 20 min to elute with 10-100% (acetonitrile··········· The product-containing fractions were combined and added to an aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was triturated with EtOAc (EtOAc). The insoluble material was collected to give the title compound, which had a melting point of 148-52. (:(0.130, 12%). [〇^25 = -40.9. (c = 0.70, MeOH). C23H24N2 〇3 (376.45), LCMS (ESI): 377.18 (M+H) NMR (DMSO-d6) , 300 MHz), δ: 7.76-7.79 (d, 1H), 7.59-7.62 (d ' 2H), 7.30-7.42 (m, 3H), 7.12-7.15 (d, 1H), 7.02-7.05 (d, 2H ), 5.82-5.84 (d, 1H), 5.32-5.37 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16 (m, 1H), 2.61-2.66 (t, 2H), 1.54-1.64 ( m, 2H ), 1.27-1.39 ( m, 2H) , 0.89-0.94 (t, 3H). 106 201121978 Example 56 Hydroazolo[3,2-a]pyrimidinium(S)-2-(3'- Butylbiphenyl_4_yloxymethyl)_2,3_diπ-7-one

Step 1: 1-0 phenyl phenyl) 2 - methacrylol to tetrahydrofuran (2 W, 20 leg 〇 1) containing 2M iso-dibasin magnesium hydride cooled in ice and anhydrous ethyl bond (7 〇 ml) of the mixture was added dropwise to a solution containing 3 曱铋 曱铋 (1.85 g '10 〇 〇 1) of Essence (1 〇 (8) for 3 minutes. The mixture won in ice! Hours. The mixture was poured into hydrochloric acid and extracted with diethyl ether. The layer was washed with water (4), and dried with sulfuric acid and reduced. The filtrate was concentrated and the residue was purified by flash (4) chromatography. The title compound (0.6 g, 26%) was obtained. Step 2: 3-isobutylbromobenzene will be called bromophenyl-2-methylpropanol (14 g, 65 mm 〇1), triethyl hydrazine矽 ( (4 ml) and boron trioxide (4 volts mixture was heated under reflux for 3 hours. Pour the mixture into H) % hydrochloric acid and extract with ether. Wash the suture layer with water, dry with magnesium and secrete The title compound (〇·8 g, 58%) was obtained. 107 201121978 Hydrogen α η sits and steps 3. (S)_2_(3'·iso-biphenyl-4-yloxyindenyl)_2,3 _bis[3,2-a]pyrimidine-7, 匕 will contain 曱 ··4· collar (s) _7 keto group _2,3 two (four) and [3,2,.1 曱酉曰 曱酉曰 (0.4 g ' 1.3 _〇1), 3, isobutylbiphenyl _4 alcohol (from 4 by the US Stupid Mine and 3_ Preparation of isobutyl benzene) (8) g, 1.3 and carbon hydrazine (0.4 g, U mm 〇l) 20 ml of anhydrous acetonitrile mixture was heated under reflux for J hr. The mixture was added to aqueous sodium hydroxide solution and extracted with m. The organic layer was washed with water and filtered, and the filtrate was concentrated. The residue was purified by reverse-phase HPLC for 20 min, eluted with 1 〇 1 〇〇% (acetonitrile 〇 1% trifluoroacetic acid). The mixture was extracted with EtOAc (EtOAc) (EtOAcEtOAcEtOAc. Compound (0.1 g, 20%) [a] D25 = -38.9 ° (c = 0.70, MeOH) °C23H24N203 (376.45), LCMS (ESI): 377.19 (M+H) )H NMR (DMSO_d6, 300 MHz) , δ : 7.76-7.79 (d,1H), 7.59-7.62 (d,2H), 7.31-7.44 (m,3H),7.09-7.12 (d, 2H), 7.02-7.05 (d,1H),5.82- 5.84 ( d,1H) , 5.35-5.37 (m,1H ) 4.32-4.45 (m, 3H) &gt; 4.10-4.16 (m 5 1H), 2.50-2.51 (s »2H), 1.86-1.93 (m, lH), 0.88-0.90 (d, 6H). Example 57 108 201121978 (S)-2-(2,3 Methylbiphenyl-4-yloxymethyl)ethyl 2,3-dihydrogen. Isozo[3,2-8]°Bite-7-酉同

Step 1: 2-Methylmercaptobutyrate ethyl ester was added dropwise to a solution of -78 C in monoisopropylamine (7.06 ml, 50 mmol) in anhydrous tetrahydrogen beta-beta (50 ml). n-Butyllithium (20 ml, 50 mmol) for 5 minutes. The mixture was warmed to hydrazine (3c and kept in ice for 3 min. This mixture was again cooled to _78. and ethyl butyrate (5 9 ml '44.6 mmol) was added dropwise for 5 minutes. After 30 minutes, ethyl decanoate (12. 2 ml '150 mmol) was added over 5 min. The cold bath was removed and the mixture was stirred at room temperature for 3 hr. The mixture was poured into aqueous sodium hydrogencarbonate and extracted with diethyl ether. EtOAc (EtOAc)EtOAc. The title compound is obtained as a mixture with the enol isomer (2.4 g, 37%). Step 2: (S)-5-(2',3'-didecylbiphenyl-4-yloxy (曱基基)_4,5_Dihydro. No. The amine will contain 曱本-4-石页酸(S)-7-mercapto-2,3-two sigma α and [3,2-a ] 〇 〇 _2 _2 _2 _2 _2 _2 _2 _2 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 (Phenylboronic acid preparation) (1. 〇g, 5.0 mm 〇i) and carbonate planer (1·6 g, 5.0 mmol) of anhydrous The mixture of nitrile (20 ml) was heated under reflux for 6 hours. The mixture was added to aq. aqueous solution of sodium carbonate and extracted with ethyl acetate acet. 109 201121978: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The residue was collected. 9°C (〇·6 g, 40〇/〇) 〇Step 3: (8)_2_(2',3,_Dimercaptobiphenyl·4_yloxymethyl)-6_ethyl_2,3_ Dihydrocarbazo[3,2-a]pyrimidin-7-one' will contain (S)-5-(2,3,3-dimethylbiphenylyloxymethyl)_4,5_2 Nitrogen 10 _ 2-amine, toluene-4• Detective (8)·7-keto 2,3·2 (4) and [3,2__唆_2_ ketone (〇.6g' 2.0mm〇l) and A mixture of 2% methylmercaptobutyrate (5 g, 3 47 匪〇1) in ethanol (20 ml) was heated under reflux for 2 hr. The solution was concentrated and the residue was taken from ethyl acetate (10 ml). Precipitation gave the title compound < mp 178-82 〇 C (0.145 g, 19%). [A]D25 = -4.8. (c = 0.66 &gt; MeOH). C23H24N2O3 (376.45) » LCMS (ESI): 377.18 (M+H) HNMR (DMSO-d6, 300 MHz), S: 7.63 (s, lH), 7.20-7.23 (d, 2H), 7.08-7.15 (m, 2H), 7.02-7.06 (m, 4H) , 5.33-5.35 (m ′ 1H) , 4.31-4.45 (m, 3H) , 4.13-4.16 (q, 2H), 2.28 (s ' 3H), 2.09 (s, 3H), 1.03-1.08 (t, 3H). Example 58 (S)-2-(Biphenyl-4-yloxyindenyl)-2,3-diazaindole a sits on the [3,2-a] mouth.定-7-嗣

110 201121978 Toluene-4-producing acid (S)-7-keto-2,3-di-sodium sulphate [3,2-&amp;] ° dimethyl-2-methyl ester (0.32 g, 1.0 Methyl), 4-phenylphenol (0.17 g, 1·〇mmol) and cesium carbonate (0.32 g, 1.0 mmol) in 20 ml of anhydrous acetonitrile mixture were heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. Collect insolubles. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was combined with a first portion of insoluble material and the combined material was taken from ethyl acetate (50 ml) and filtered. The insoluble material was the title compound, m.p. 247 - 50 C (0.18 g, 56%). [a]D25 = -22.7. (c = 0.75, DMSO) 〇Ci9H16N203 (320.35), LCMS (ESI): 321.14 (M+H) NMR (DMSO-d6, 300 MHz), δ: 7.7.7-7.79 (d,1H), 7.61-7.63 ( m » 4H ), 7.41=7.46 ( t,2H ), 7.29-7.34 ( m, 1H) , 7.03-7.06 (d,2H) ,5.82-5.84 (d,1H) ,5.32-5.37 (m,1H) ' 4.43-4.45 (m, 3H), 4.10-4.16 (m, 1H). Example 59 (S)-6-Ethyl-2-(2'-ethylbiphenyl-4-yloxyindenyl)-2,3-dihydroanthracene | Saliva[3,2_3] - Same as

Step 1: (S)-5-(2'-Ethylbiphenyl-4-yloxymethyl)-4,5-dihydro-a-salt-2-amine will contain toluene-4-sulfonic acid (S )-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (2.2 g ' 8.1 mmol), 2'-ethylbiphenyl-4-ol ( A mixture of acetic acid 4-iodobenzene 201121978 ester and 2-ethylphenylboronic acid (1.61 g, 8.1 mm 〇i) and carbonated (2.6 g, 8.1 mmol) in anhydrous acetonitrile (25 ml) was heated under reflux for 6 hours. The mixture was added to an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified with EtOAc EtOAc EtOAc:EtOAc Step 2. (S)-6-Ethyl-2-(2'-ethylbiphenyl-4-yloxyindenyl)_2,3-diaza π. Sodium(3,2-a)pyrimidin-7-one will contain (S)-5-(2'-ethylbiphenyl-4-yloxyindenyl)-4,5-dihydrocarbazole-2 -amine, anthraquinone (S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylindole (1.7 g ' 5.74 mmol ) and 2-A A mixture of acetylbutyric acid (1.3 g, 9.0 mmol) in ethanol (25 ml) was heated under reflux for 24 hours. The solution was concentrated and the residue was purified by flash chromatography eluting eluting The most polar spot was again purified by reverse phase HPLC for 20 minutes and eluted with 10-100% (acetonitrile-0.1% trifluoroacetic acid). The product-containing fractions were combined and added to aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with a small amount of diethyl ether. The insoluble material was collected to give the title compound mp 196-98. (:(0.023 g, 1%). C23H24N203 (376.45), LCMS (ESI): 377.17 (M+H) 4 NMR (DMSO-d6, 300 MHz), δ:. 7.63 (s,1H),7.11-7.32 (m, 6H), 7.02-7.05 (d, 2H), 5.32-5.38 (m, 1H), 4.32-4.45 (m, 3H), 4.10-4.16 (m, 1H), 2.50-2.58 (m, 2H) , 2.21-2.28 (q, 2H), 1.02-1.08 (m, 6H). 112 201121978 Example 60 (S)-2-(2-mercapto&gt;3'-propylbiphenyl_4_yloxymethyl Base)_2,3_dihydroπ-azolo[3,2 pyrimidin-7-one

(S)-7-keto-2,3-dioxazolo[3,2_a]pyrimidine-2-ylmethyl ester (〇5 g, 1.56 mmol), 2- Mercapto-3,-propylbiphenyl-4-ol (prepared from bromo-3-methylphenyl acetate (prepared from 4-bromo-3-ylnonylphenol and acetamidine) and 3-propenyl-based acid Prepare) (0.49 g ' 2.17 mmol) and 20 ml of anhydrous acetonitrile mixture of cesium carbonate (〇·7 g, 2.17 mmol) were heated under reflux for a few hours. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified with EtOAc EtOAc (EtOAc)EtOAc. The product fractions were combined and added to aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with diethyl ether (15 ml), and the title compound (0.06 g, 10%). (c = 0.36, MeOH). C23H24N203 (376.45), LCMS (ESI): 377.19 (M+H)]H NMR (DMSO-d6, 300 MHz), δ: 7.66-7.79 (d,1H), 7.29-7.34 (t,1H) &gt; 7.08 -7.31 ( m &gt; 4H ), 6.82-6.89 ( m, 2H) , 5.82-5.84 ( d,1H) , 5.31-5.39 ( m,1H) , 4.29-4.45 113 201121978 (m,3H),4.03-4.15 (m, lH), 2.50-2.67 (t, 2H), 2.20 (s, 3H), 1.55-1.68 (m, 2H), 0.88-0.93 (t, 3H). Example 61 2',3^Dimercapto-4-((S)-7-keto-2,3-dihydro-7H-indazolo[3,2-a]pyrimidin-2-ylindoleoxy )-biphenyl-2-yi guess

Step 1 : 4-Methyl-3-nitrobenzene was added dropwise to a mixture of 3-cyanobenzene (3.2 g, 26,8 mmol) in glacial acetic acid (20 mL) containing bromine (4.2 g, 23.3 mmol). (5 ml) solution for 5 minutes. The mixture was stirred at room temperature for 8 hours. The mixture was filtered. The filtrate was added to water (1 ml) containing a few milligrams of sodium thiosulfate. Insoluble materials were collected and the filter cake was added to warm methanol (15 ml) and filtered over Celite. The filtrate was slowly diluted with water, and the precipitate was collected and dried to give the title compound, m.p. Step 2: 2-Cyanide-2',3'-dimethylbiphenyl-4-ol will contain 4-&gt;odor-3-cyanobenzene (1.〇g, 5 mmol), 2,3- Dimethylphenyl succinic acid (1.1 g, 8 mmol), tetrakis(triphenylphosphine)palladium (〇) (0.5 g, 0.43 mmol) and 2M sodium carbonate solution (5 ml) of 50 ml of 1,2- The dimethoxyethanol mixture was heated under reflux for 6 hours. The mixture was cooled and poured into an aqueous solution of ammonium sulfate. The mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate (d. The concentrated filtrate was purified by flash chromatography, and the title compound was obtained eluting with ethyl acetate/glycolic acid. The bright spot was 丨33_7. 〇: (0.33 g, 30%) 〇Step 3. 2,3-Methyl-4-((S)-7-keto-2,3-dihydro-7H-d η sits and [3, 2-a], °-2-yloxy)-biphenyl-2-acetonitrile will contain toluene-4-supply (S)-7-keto-2,3-dioxime and [3 , 2-ap-Bite-2-ylindole (0.47 g' 1.56 mmol), 2-cyano-2',3'-diindolyl-phenylidene-4-ol (0.33 g, 1.4 mmol) and carbonic acid planer (0.5 g, 1.5 mmol) of 20 ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. This mixture was added to a solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified with EtOAc EtOAc (EtOAc) The product containing product was combined and added to an aqueous solution of cesium carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The filtrate and liquid were concentrated. The residue was treated with EtOAc (yield: EtOAc). [a] D25 = -21.9 0 (c = 0.47, MeOH). C22H19N303 (373.41), LCMS (ESI): 374.15 (M+H).H NMR (DMSO-d6 » 300 MHz), δ: 7.76-7.79 (d,1H), 7.57 (s,1H), 7.35 (s, 2H), 7.15-7.32 (m, 2H), 7.01-7.03 (d, lH), 5.82-5.85 (d, 1H), 5.37-5.39 (m, 1H), 4.39-4.54 (m &gt; 3H), 4.10 -4.15 ( m,1H), 2.31 ( s,3H), 2.00 (s,3H). 115 201121978 Example 62 (S)-2-(2',3i-Dimercaptobiphenyloxymethyl)_6-methyl-2,3-dihydrooxazo [3,2-a]pyrimidine- 7-ketone opening

Step 1. 2-Mercaptopropionic acid ethyl vinegar was added dropwise to a solution of diisopropylamine (7.06 ml, 5〇mm〇1) in anhydrous tetrahydrofuran (50 ml), which was cooled to -78 °C. 2.5 M n-butyl clock (2 〇 mi, 5 〇 mmol) for 5 minutes. The mixture was warmed to 〇cC and kept in ice for a few minutes. The mixture was again cooled to _7yC and ethyl propionate (5·17 ml ' 44.6 mmol) was added dropwise for 5 minutes. After stirring for 3 minutes, ethyl decanoate (12.2 ml, 150 mmol) was added over a minute. The cold bath was removed and the mixture was stirred at room temperature for 3 hours. Acetic acid ($ ml) was added to the mixture. This mixture was poured into an aqueous sodium hydrogencarbonate solution and extracted with an yoke (2 (9) Claw 1). The ether layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated with EtOAc (EtOAc): . Step 2: (S)-2-(2',3'-Dimercaptobiphenyl-4-yloxyindenyl)_6_methyl_2,3_dihydro 0 σ sits [3,2 -a]*»Mis-β--7-one will contain (S)-5-(2',3'-dimethylbiphenyl-4-yloxymethyl)_4,5-dihydrocarbazole_ 2-Amine, anthraquinone-4-sulfonic acid (S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.75 g, 2.53 mmol) and A mixture of ethyl 2-mercaptopropionate (containing some enol isomers) (0.6 g, 4.6 mmol) in ethanol (20 ml) was heated at reflux for 18 &lt;RTIgt; The resulting precipitate was collected to give the title compound m.p. 251 -3 ° C (0.15 g, 16%). [o]D25 = _2.0 0 (c = 0.70, DMSO). (:22Η22Ν203 ( 362.43 ), LCMS (ESI): 363.18 (M+H) lR NMR (DMSO-d6 &gt; 300 MHz), δ: 7.68 (s, 1H), 7.20_ 7.23 (d ' 2H) ' 7.08- 7.15 (m ' 2H), 6.98-7.02 (d, 3H), 5.31-5.38 (m, 1H), 4.31-4.44 (m, 3H), 4.10-4.15 (m, 1H), 2.28 (s, 3H), 2.09 (s, 3H), 1.81 (s, 3H). Example 63: mercaptobiphenyl-4-yloxyindenyl)_2,3-dihydrooxazole (S)-2-(2-decyloxy) -2·,3'-di[3,2-a]pyrimidin-7-one

Step 1: 4-Bromo-3-indolyl phenol was added in a batch over 10 minutes in a solution containing 3-methoxybenzene (12.4 g, 1 〇〇 〇 1) in acetonitrile (400 ml). N_bromo-lysine (Μ g, 110 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated in a rotary evaporator and the residue was treated with ethyl acetate (7G). The insoluble material was washed with water (4 〇 ml), and the organic layer was dried with sulfuric acid and passed through the tears. The filtrate was concentrated and the residue was purified eluting elut elut elut elut elut elut elut elut曰117 201121978 Step 2: 2-Methoxy-2',3·-dimethylbiphenyl-4-ol will be 4-oxa-3-methoxybenzoquinone (2.2g, 1〇8nim〇1) , 2,3 dimercaptophenyl stearnic acid (2.4g, 16.2mmol), tetrakis(triphenyl sulfonate) (1〇g 〇1) and 2M sodium carbonate solution (6 ml) in u dimethylox Base ethanol (7 〇 (4) mixture _ heating for 4 hours. Cool the mixture into the human chlorinated aqueous solution. Extract the mixture with ethyl acetate. Wash the organic layer with water, dry it with sulfuric acid and dry it. The reduced sputum was purified by chromatography, eluting with EtOAc EtOAc (EtOAc) _田焚_ Gas ten sitting and [3,2-cafe^2,3-monomethylbiphenyl-4-yloxy called 2,3-dimethyl hydrazine 5 gen? 6 continued acid (8) Μ base二^(四)Μ妙定_2·基(〇4H _), 2_methoxyyi 3·-dimethylbiphenylbutanol g, 1.75 mm〇1) and carbonated 1W 〇Λ ^ Anhydrous acetonitrile mixture back Steam plus 刼彳丨 主 main. g 1.75 mmol) in 20 ml of solution and use acetic acid &amp; ',, and mixture to add sodium bicarbonate water to the transition. The residue was dried and purified by EtOAc (EtOAc) EtOAc (EtOAc) In the aqueous solution of human sodium hydrogencarbonate, the product was distilled to a sub-layer of ', dried over magnesium sulfate #, and the compound. Washing organic with water

Ml) Stir and not accept. Will consider the liquid roll 'end. The residue was combined with diethyl ether (20 (〇Ug, 22t), title compound, melting point: 204WC C22H22N2 〇4 ( 378 43 ^ D ... 35·7/0; 0.66, ·), 8.43) 'lcms(esi) ) : 379 17 (m+h) 118 201121978 W NMR (DMSO-d6,300 MHz), δ : 7.77-7.79 (d,1H), 7.04-7.11 ( m,2H) ' 6.96-6.99 ( d,1H ) , 6.88-6.90 (d, 1H), 6.58-6.65 (m ' 2H), 5.82-5.85 (d, 1H), 5.33-5.38 (m, 1H), 4.33-4.46 (m, 3H), 4.11-4.17 ( m,1H), 3.68 (s,3H) ' 2.26 (s ' 3H), 1.91 (s, 3H). Example 64 (S)-2-(2'-ethylbiphenyl-4-yloxyindenyl) )-6-mercapto-2,3-dihydro oxazolo[3,2^] 密'1 -7-ketone

Will contain (S)-5-(2-ethylbiphenyl-4-yloxyindenyl)_4,5_digas π η sit_2_amine, indole-4-sulfonic acid (S)-7 -keto-2,3-dioxazolo[3,2-a]°-t-pyridine-2-yl decyl ester (0.2 g, 0.67 mmol) and ethyl 2-mercaptopropionate (0.18 g ' A mixture of 13 mmol) of ethanol (20 ml) was heated under reflux for 18 hours. The solution was concentrated and the residue (1 mL) was taken from ethyl acetate. The precipitate formed was collected, i.e., the title compound had a melting point of 223-5. (:(0.020 g, 8%). [oc]D25 = -1.6. (c = 0.70, DMSO) 〇C22H22N203 (362.43), LCMS (ESI): 363.0 (Μ+Η) NMR (DMSO-d6,300 MHz ), δ : 7.69 (s, 1H), 7.19_ 7.32 (m'5H), 7.11 - 7.13 (d, lH) '6.99-7.10(d, 2H), 5.34-5.36 (m ' 1H), 4.31-4.44 (m, 3H), 4.10-4.15 (m, 119 201121978 1H) ' 2.50-2.58 (q, 2H), 1.81 (s, 3H), 0.99-1.04 (t, 3H). Example 65 (S)-2- (2-ethyl-2·,3'-dimercaptobiphenyl-4-yloxymethyl)_2,3-dihydro-σ-isoazolo[3,2-&amp;]°Bite-7-嗣

Step 1: 4-Bromo-3-ethylphenol To a solution containing 3-ethylbenzene (3.0 g, 24.6 mmol) in acetic acid (20 ml) was added dropwise (4 g, 22 mmol) of acetic acid (10) Ml) solution for 5 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate (1 mL). The organic layer was washed successively with aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified eluting elut elut elut elut elut elut eluting Step 2: 2-Ethyl-2,3·-dimercaptobiphenyl-4-ol will contain 4-bromo-3-ethylphenol (1.6 g, 7.96 mmol), 2,3-didecyl Stable base acid (1.2 g, 7.96 mmol), tetrakis(triphenylphosphine) (〇) (1.0 g, 0.86 mmol) and 2M sodium carbonate solution (6 ml) of 1,2-dimethoxyethanol ( The mixture was heated under reflux for 6 hours. The mixture was cooled and poured into an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (150 ml). The organic layer 120 201121978 was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut elut elut Step 3: (S)-2-(2-ethyl-2',3'-dimethylbiphenyl-4-yloxymethyl)_2,3_dihydro ο et σ sit and [3,2 -a] mouth bite-7-ketone will contain indole phenyl-4-transacid (S)-7-keto-2,3-diindole α and [3,2-a]° densely bit-2-yl Methyl ester (0.4 g ' 1.24 mmol), 2-ethyl-2',3,-dimercaptobiphenyl-4-enol (0.3 g, 1.3 mmol) and bismuth carbate (0.42 g, 1.3 mmol) The ml of anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC for 20 min to elute with 10-100% (acetonitrile - hexane. The product containing fractions were combined and added to aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was stirred with diethyl ether (50 mL) for 1 hr and then the residue was collected to give the title compound mp. (:(0·11 g, 23%). [a] D25 = -30.4 ° (c = 0.70, MeOH). C23H24N203 (376.45), LCMS (ESI): 377.19 (M+H) NMR (DMSO-d6) , 300 MHz), δ: 7.77-7.80 (d, 1H), 7.07-7.16 (m, 2H), 6.80-6.95 (m, 4H), 5.82-5.85 (d, 1H), 5.33-5.41 (m, lH ),4.31-4.46 (m,3H),4.12-4.18 (m'lH),3.33-3.42 (q,2H), 2.24(s,3H),1.88(s,3H),0.91-0.96 (t,3H) 121 201121978 Example 66 (S)-2-(2-Ethyl-2',3·-dimercaptobiphenyl-4-yloxyindenyl)_6-fluorenyl-2,3_dihydrogen 0 Quo β sit and [3,2-a] shout bite-7-ketone

Step 1: (S)-5-(2-Ethyl-2',3'-dimercaptobiphenyl-4-yloxyindenyl)-4,5-dihydroπ-oxazole-2-amine will contain Toluene-4-sulfonic acid (S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylindole (0.47 g' 1.74 mmol), 2 丨, 3,- Dimercapto-2-ethylbiphenyl-4-ol (prepared from 4-bromo-3-ethylbenzene and 2,3-didecylphenyl rotten acid according to Scheme 7) (0.4 g, 1.75 mmol A mixture of cesium carbonate (0.56 g, 1.75 mmol) in dry acetonitrile (20 ml) was evaporated and evaporated. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (1 mL). The organic layer was washed with water and dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified eluting eluting elut elut elut elut elut elut elut elut elut elut elut 53%). Step 2: (S)-2-(2-Ethyl-2,3,-dimercaptobiphenyl-4-yloxyindenyl)-6-methyl-2,3-dihydroindole. Sitting and [3,2-a] sputum-7-one will contain (S)-5-(2-ethyl-2',3'-dimercaptobiphenyl-4-yloxymethyl)_4 ,5-Dihydrocarbazol-2-amine (0.7 g, 2.16 mmol) and ethyl 2-mercaptopropionate (containing some hydroxy isomers) (0.45 g, 3.46 mmol) in ethanol (20 ml) HE 122 201121978 The material was heated under reflux for 18 hours. The filtrate was concentrated and the residue was purified with EtOAc EtOAc (EtOAc) The product fractions were combined and added to aqueous sodium hydrogen sulfate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was reduced. The residue was treated with ethyl acetate (20 ml) and the insoluble material was collected to give the title compound </ </ RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; </ RTI> <RTIgt; -6.95 ( m,4H ), 5.30-5.35 ( m , 1H) ' 4.29-4.44 (m ' 3H), 4.10-4.16 (m,1H), 2.17-2.51 (m'5H), 1.18 (s' 3H) '1.81 (S,3H) '0.91-0.96 (t, 3H). Example 67 (S)-2-(Biphenyl-4-yloxymethyl)-6-mercapto-2,3-dihydro σ 嗤[3,2-a]

Step 1. (S)-5-(Biphenyl-4-yloxyindenyl)-4,5-dihydro π seeking. The total _2_amine will contain (S)-7-keto-2,3-dioxazolo[3,2_a]pyrimidin-2-yl decyl ester (2.2 g ' 7.77 mmol). A mixture of 4-phenylphenol (1 28 g '7.5 mm 〇1) and cesium carbonate (2.5 g '7.6 mmol) in anhydrous acetonitrile (25 ml) was heated under reflux for 6 hours. This mixture was added to an aqueous solution of sodium hydrogencarbonate and extracted with acetic acid (2011: 978) (100 m!). The insoluble material was collected and dried to give a product. The machine layer was washed with water and dried with a sulfuric acid lock and filtered. The mash was concentrated and the residue was taken up in hot ethyl acetate (5 mL). The insoluble material (Q2g) was collected and combined with the first batch of insoluble material to give the title compound, m.p., mp. Step 2. (S)-2-(Biphenyl-4-yloxymethyl)_6-methyl-2,3-dihydrooxazolo[3,2- a]° sessile-7-one Containing (S)-5-(biphenyl-4-yloxymethyl)_4,5-dihydrocarbazole-2-amine (〇.8 g, 2.9 mmol) and 2-methylmercaptobutyrate A mixture of ethanol (20 ml) (containing some carbomer) (0.86 g, 5.9 mmol) was heated under reflux for 18 hours. The filtrate was concentrated and the residue was purified using reversed phase HPLC for 20 mins. (acetonitrile-0.1% trifluoroacetic acid) eluted. The product-containing fractions were combined and added to aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate (5 〇ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with EtOAc (EtOAc) (EtOAc) [a] D25 = +0.8 0 (c = 0.64, DMSO). C21H20N2O3 ( 348.40), LCMS (ESI): 349.15 (M+H) ]H NMR (DMSO-d6 » 300 MHz), δ: 7.57-7.60 (d,5H), 7.37-7.40 (t,2H), 7.25- 7.30 ( m,1H ) , 6.99-7.02 ( d, 2H) , 5.26-5.34 (m,1H) , 4.28-4.41 ( m,3H) , 4.00-4.11 (m,lH) ,2.17-2.25 (t,2H ), 1.00-1.04 (t, 3H). Example 68 124 201121978 (S)-6-Ethyl-2-(indenylbiphenyl-4-yloxymethyl)_2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

Step 1: (S)-5-(2-Mercaptobiphenyl-4-yloxymethyl)_4,5-dihydrooxazol-2-amine will contain hydrazine-4-sulfonic acid (S)- 7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylmethyl ester (1.1 g, 4.0 mmol), 2-mercaptobiphenyl-4-ol (according to Schematic 7 from 4 - Preparation of bromo-3-nonyl phenol and phenylboronic acid) (〇8 g, 4 3 mm 〇i) and a mixture of carbonic acid (1_4 g, 4.3 mmol) in anhydrous acetonitrile (20 ml) was heated under reflux for 6 hours. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified with EtOAc EtOAc EtOAc (EtOAc) The product containing fractions were combined and added to aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound mp. Step 2: (S)-6-Ethyl-2-(indenylbiphenyl-4-yloxyindenyl)_2,3-dihydro-α-Salo[3,2-a]pyrimidin-7-one Will contain (S)-5-(2-mercaptobiphenyl-4-yloxyindenyl)-4,5·diaroxazol-2-amine (0.6 g, 2.1 mmol) and 2-mercapto A mixture of ethyl butyrate (containing some hydroxy isomers) (0.6 g', 4.2 mmol) in ethanol (20 ml) was heated at reflux for 8 h. The solution was concentrated and the residue was purified using EtOAc EtOAc (EtOAc) The product containing fractions were combined and added to aqueous sodium argon carbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with EtOAc (EtOAc) (EtOAc) [a] D25 = -13.10 (c = 0.36, DMSO). C22H22N203 ( 362.43 ), LCMS (ESI): 363.18 (M+H) NMR (DMSO-d6, 300 MHz), δ: 7.59 (s, 1H), 7.24-7.41 (m '5H), 7.08-7.11 (d , 1H), 6.79-6.86 (m, 2H), 5.26-5.30 (m, 1H), 4.25-4.37 (m, 3H), 4.05-4.11 (m, 1H) '2.20-2.47 (q, 2H), 2.17 (s, 3H), 0.99-1.04 (t, 3H). Example 69 (S)-2-(2-Ethylbiphenyl-4-yloxymethyl)-2,3-dihydro σ-salt[3,2-&amp;] °定-7- ketone

(S)-7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-ylindole (0.48 g '1.5 mmol), 2- Ethylbiphenyl pentyl alcohol (prepared from 4-bromo-3-ethylbenzene and phenylboronic acid according to Scheme 7) (〇3 g, 1.5 mmol) and cesium carbonate (0.49 g '1.5 mmol) 20 ml The anhydrous acetonitrile mixture was heated under reflux for 1 hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in 126 201121978 and the residue was purified by reverse phase HPLC for 20 min, eluting with EtOAc EtOAc (EtOAc) The product-containing fractions were combined and the aqueous solution of hydrogencarbonate was added to the mixture, and the mixture was extracted with ethyl acetate (150 ml). Wash with water; an organic layer, dried over magnesium sulfate and filtered. The filtrate was concentrated. The title compound was obtained by substituting the residue with &lt;RTI ID=0.0&gt;&gt;&gt; C2iH2〇N203 ( 348.40) &gt;LCMS (ESI): 349.16 (M+H) NMR (DMSO-d6,300 MHz), δ: 7.73-7.75 (d, 1H), 7.21-7.41 ( m ' 5H ) ' 7.04 -7.07 ( d,1H ), 6.79-6.87 ( m, 2H) ' 5.82-5.87 (d ' 1H) ' 5.28-5.36 (m,1H), 4.27-4 41 (m ' 3H),4.07-4.12 ( m , 1H ), 2.44 - 2.49 ( q, 2H ), 0.96-1.01 (t, 3H). Example 70 (S)-6-Ethyl-2-(2'-fluorenylbiphenyl-4-yloxymethyl)_2,3_dihydro D No.[3,2_a]. D-az-7-one

Will contain (S)-5-(2-mercaptobiphenyl-4-yloxymethyl)_4,5-dihydro-sigma β-sodium-2-amine (0.6 g, 2.12 mmol) and 2-methylhydrazine A mixture of ethyl butyrate (containing some hydroxy isomers) (0.6 g, 4.25 mmol) in ethanol (20 ml) was heated under reflux for 18 hours. The solution was concentrated and the residue was purified with EtOAc EtOAc (EtOAc) The product-containing fractions were combined and added 127 201121978 to aqueous sodium argon carbonate, and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was treated with diethyl ether (30 ml), and the titled compound was obtained to give the title compound (yield: </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [a]D25 = -7.0 0 ( c = 0.52,

MeOH). C22H22N203 (362.43), LCMS (ESI): 363.17 (M+H) 7.36 (m'5H) '7.07-7.10 (m'lH), 7.00-7.03 (d'2H), 5.28-5.36 ( m &gt; 1H) » 4.28-4.42 ( m &gt; 3H ) , 4.14-4.20 ( m, 1H), 2.22-2.30 (q, 2H), 2.20 (s, 3H), 1.00-1.04 (t, 3H). Example 71 (S)-2-(2-Ethylbiphenyl-4-yloxyindenyl)-6-mercapto-2,3-dihydroindole Saliva[3,2-a] Biting - 7-ketone

Step 1. (S)-5-(2-Ethylbiphenyl-4-yloxymethyl)-4,5-dihydro-#wow-2-amine will contain toluene-4-carnitine (8 )-7-@同基-2,3-二嗤嗤[3,2-&amp;]11-Bitter-2-ylmethyl ester (1.6 g, 6.0 mmol), 2-ethylbiphenyl-4 - a mixture of alcohol (prepared from 4-bromo-3-ethylbenzal and benzyl bromide according to Scheme 7) (1.3 g, 6.9 mmol) and EtOAc (EtOAc) hour. The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The sputum 128 201121978 was concentrated and the residue was purified by reverse phase HPLC for 20 min, eluting with EtOAc EtOAc (EtOAc) The product-containing fractions were combined and added to aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (0.6 g, 77%). Step 2: (S)-2-(2-ethylbiphenyl-4-yloxyindenyl)-6-methyl_2,3-dihydro-α-Salo[3,2-a]pyrimidine- The 7-ketone will contain (S)-5-(2-ethylbiphenyl-4-yloxymethyl)-4,5-dihydrog π cis-amine (0.6 g '2.0 mmol) and 2-曱醯The mixture of ethyl propyl propionate (containing some hydroxy isomers) (0.5 g '4.0 mmol) in ethanol (25 ml) was heated under reflux for 18 hours. The solution was concentrated and the residue was treated with ethyl acetate (1 mL). The precipitate formed was collected to give the title compound m.p. 224-7. [a] D25 = -0.6 0 (c = 0.66, DMSO). C22H22N203 ( 362.43 ), LCMS (ESI): 363.17 (M+H) NMR (DMSO-d6, 300 MHz), δ: 7.64 (s, 1H) &gt; 7.38-7.41 (m, 2H), 7.30-7.33 (m , 1H), 7.24-7.28 (t, 2H), 7.06-7.09 (d, 1H), 6.88 (s, 1H), 6.80-6.82 (d, 1H), 5.29-5.37 (m, 1H), 4.36-4.40 (m, 2H), 4.30-4.34 (m, 1H), 4.07-4.11 (m, 1H), 2.42-2.48 (q, 2H), 2.41 (s, 3H), 0.98-1.01 (s, 3H). Example 72 129 201121978 (S)-2-(2-indenylbiphenyl-4-yloxyindenyl)-6-mercapto-2,3-diazaindole 〇[[,2-a] Pyrimidine-7-one

Step 1: (S)-5-(2'-Methylbiphenyl-4-yloxyindenyl)-4,5-dihydrooxazol-2-amine will contain anthraquinone-4-sulfonic acid (S - 7-keto-2,3-dioxazolo[3,2-a]pyrimidin-2-yldecyl ester (0.5 g, 1.85 mmol), 2'-mercaptobiphenyl-4-ol ( A mixture of (4-glyphenyl acetate and 2-nonylphenylboronic acid) (0.4 g, 2.1 mmol) and EtOAc (EtOAc) (EtOAc) The mixture was added to an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified with EtOAc EtOAc (EtOAc) The product-containing fractions were combined and added to a solution of sodium hydrogencarbonate and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound mp. Step 2: Mercaptobiphenyl-4-yloxymethyl)_6-methyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one will contain (S)-5- (2·-fluorenylbiphenyl-4-yloxymethyl)_4,5-dihydrocarbazole-2-amine (0.3 g, 1.1 mm〇l) and 2-methylmercaptopropionate (containing A mixture of some hydroxy isomers (0·27 g, 2.2 mmol) in ethanol (20 ml) was added with &quot;heat for 18 hours. The solution was concentrated and the residue was taken ethyl acetate (1 mL). Collection shape 130 201121978 Cheng Shen Dian 'that is the title compound' melting point is 226_9CC (〇 〇 34 g 9%). [a]D25 = _46.9. (c = 〇.48, ChC13). C2iH2gN2〇3 ( 348 4〇) LCMS (ESI): 349.16 (M+H) iHNMR (DMSO-d6, 300 MHz), δ: 7.70 (s, lH), 7] 7.36 (m ' 6H) ' 6.99- 7.03 (d, 2H), 5.32-5.40 (m, 1H) 4.38-4.45 (m, 3H), 4.10-4.18 (m, 1H), 2.52 (s, 3H) 1.80 (s, 3H). Example 73 (S)-2-(2,2'-Dimercaptobiphenyl-4-yloxyindenyl)_2,3-dihydrooxanthazo[3,2_a]pyrimidine-11--7-one

Step 1. Acetate-2-mercapto-2'-fluorenylbiphenyl-4-ol

C 4-Chloro-3-methylphenol acetate (4.2 g, 18.3 mmol), 2-methylphenylboronic acid (5.0 g, 36.8 mmol), tetrakis(triphenylphosphine) (〇) (2.0 g A mixture of 1,73 mmol) and 2M sodium carbonate solution (8 mi) of ι,2-dimethoxyethanol (7 mL) was heated under reflux for 7 hours. The mixture was cooled and poured into an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with water, dried over magnesium sulfate and filtered. The concentrated filtrate was purified by flash chromatography on silica gel eluting with EtOAc EtOAc (EtOAc) τ B Step 2: 2-Mercapto-2'-fluorenylbiphenyl-4-ol

The thioglycolate-containing 2,-mercaptobiphenylbutanol (2 〇υ, 〇 〇 / 〇 〇 ( (5ml), water (5mi) in B 10.4 ' 〇 〇 用 heating heating The solution was formed at room temperature. The mixture was poured into water and acidified with concentrated HCl. The mixture was mixed with acetic acid 7 (100 ml) 邗田丄 寸 寸. g (4) machine layer. (4) Dragon The organic layer of the money and the desired shrinkage, the title compound (2.1 g, 100%). Step 3: (S)-2-n π - m β , monomethyl phenyl-4-yloxy fluorenyl )-2,3-dihydropurine 0 sitting forest [3,2-a]pyrimidin-7-酉 the same milk can be opened to contain 曱 -4--4-sulfonic acid (s) _7-keto_2 3_ Dioxazolone oxime ester (0.48 g, μ m , , l, dj generation _2 _ base ^ mm 〇 1), 2-mercapto-2,-fluorenyl phenylidene _4-alcohol (〇I, , 曰人: 〇 1) and carbonic acid (〇.48 g 'U mm 〇 1) of 20 ml of anhydrous ethylene bismuth". The mixture is added to human sodium bicarbonate solution and dry and excessive. ml) m The organic layer was eluted with a dry clock of magnesium sulfate and purified by UM〇〇〇/r 7昧Λgo for 20 minutes (acetonitrile·°.1% tri-glycolic acid). The human was also added with carbon (tetra) sodium water. Towel with acetic acid The mixture was taken up in EtOAc (EtOAc: EtOAc (EtOAc) (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The melting point is 160-3 ° C (0.085 g, 16%). C2iH2 () N203 ( 348.40), LCMS (ESI): 349.17 (M+H) NMR (DMSO-d6, 300 MHz), δ: 7.78-7.80 ( d,1H), 7.20-7.36 (m,3H), 6.90-7.08 (m,2H), 6.80-6.88 (m, 2H), 5.82-5.84 (d,1H), 5.32-5.42 (m,1H), 4.30-4.42 (m, 3H), 4.08-4.20 (m, 1H, 1.90 (s, 3H), 1.94 (s, 3H). Example 74 (S)-2-(2,2'-dimercaptobiphenyl -4-yloxyindenyl)-6-mercapto-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

Step 1 · (S)-5-(2,2'-Dimercaptobiphenyl-4-yloxyindenyl)-4,5-diaza. number. Sitting on a _2-amine will contain 曱本-4-生酸(S)-7-酉同基-2,3-·一σ deficit α sit 弁[3,2-a]σ密0定-2-yl Methyl ester (1.1 g, 8.5 mmol), 2,2·-dimercaptobiphenyl-4-ol (prepared from 4-bromo-3-nonylphenol and 2-mercaptophenylboronic acid according to Scheme 7) I. 8g, 9.1mmol) and cesium carbonate (2.9 g, 9.1 mmol) in dry acetonitrile (40 mi). The mixture was added to aqueous sodium hydrogencarbonate and extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified using EtOAc EtOAc EtOAc EtOAc EtOAc The product-containing aliquots were combined and added to aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a foam (0.8 g, 32%). Step 2: (S)-2-(2,2'-Dimethylbiphenyloxyindenyl)-6-indenyl-2,3-dihydrooxazolo[3,2-a]pyrimidine-7 - The ketone will contain (S)-5-(2,2'-dimethylbiphenyl-4-yloxymethyl)_4,5-dihydrocarbazole-2-amine (0.8 g '2.7 mmol) and 2 Ethyl mercaptopropionate (containing some hydroxy isomers) (0.55 g '4.2 mmol) was heated under reflux in ethanol (2 〇mi) mixture for 18 h. The solution was concentrated and the residue was taken ethyl acetate (1 mL). The precipitate formed was collected to give the title compound m. (:(0.14 g, 14%). C22H22N2O3 ( 362.43 ) » LCMS (ESI) : 363.16 (M+H) ]H NMR (DMSO-d6 &gt; 300 MHz) . 6 : 7.65 (s &gt; 1H) &gt; 7.17- 7.30 (m ' 3H), 7.00-7.02 (d ' 1H), 6.96-6.98 (d, 1H), 6.90 (s ' 1H), 6.80-6.82 (d, 1H), 5.32-5.38 (m, 1H) ), 4.28-4.38 ( m ' 3H ) ' 4.10-4.14 ( m ' 1H ) ' 1.96-1.98 ( s, 3H), 1.92-1.94 (s' 3H), 1.76-1.78 (S, 3H). Example 75 ( S)-2-(biphenyl-4-yloxyindenyl)-5-hydroxymethyl-2,3-dihydro-sigma-[3,2_a] spray. D--7-ketone 134 201121978

Step 1. 曱4--4-sulfonic acid (s)-7-keto-5-(tetrahydropyran-2-yloxyindenyl)_ 2,3-dihydro-7H-indazolo[3 , 2_a:|pyrimidine_2_yl decyl ester in phenylbenzene-4-sulfonic acid (s)-2-amino-4,5-dihydrooxazolo-5-yl decyl ester (Example 3 'Step 1 (5.0 g ' 18.50 mmol) of ethanol (8 〇 ml) was added with 4_(tetrahydropyran-2-yloxy)-butyne-2-acid ethyl ester (Example 31, step 丄) (4 · 72 g ' 22.20 mm〇i). The reaction mixture was stirred at reflux temperature for 3 hours. The mixture was cooled to room temperature and flash column chromatography (矽K%)

Purification with MeOH/CH2C12) afforded 2.70 g of phenylene- 4-pyrene (S)-7-keto-5-(tetrahydropyran-2-yloxyindenyl)_2,3-dihydro- 7H-carbazolo[3,2-a]pyrimidin-2-yldecyl ester is a white solid. C20H24N2O7S '(436.13), LCMS (ESI): 437.09 (M++H) 4 NMR ( 300 MHz ' CDC13) : δ 7.76 (dd, 2H), 7.37 (d, 2H ) ' 5.94 ( s,1H ) ' 5.15 (m,1H),4.66 ( s,1H ), 4.46(m'2H) '4.43 (s,2H), 4.29 (m,2H),3.81 (m, 1H),3.53 (m,1H),2.46 ( s ' 3H), 1.78 (m, 2H), 1.58 (m, 4H) Step 2: Indole-4-sulfonic acid (S)-7-keto-5-(hydroxyindenyl)-2,3-di Hydrogen-7H-a, such as oxazolo[3,2-a]pyrimidin-2-yldecyl ester, terpene-4-sulfonic acid (S)-7-keto-5-(tetrahydropyran-2-yl) Oxymethyl)-2,3-dihydro-7H-moxazo[3,2-a]pyrimidin-2-yl decyl ester is treated with a solution of p-toluenesulfonic acid in ethanol (see Example 31). Title compound. 135 201121978 Step 3: (S)-2-(Biphenyl-4-yloxyindenyl)-5-(hydroxyindenyl)-2,3-dihydrooxazolo[3,2-a]pyrimidine- 7-ketone (3)-(3-)-(2-hydroxy-indolyl)-7-keto-2,3-dihydro-7Η-πβ[3,2-密 ° 定 -2- 曱 曱 曱 ( vinegar (150 mg, 0.43 mmol) was dissolved in DMF (6 ml) together with 1.0 equivalent of 4-phenylbenzene. Carbonic acid (200 mg '0.6 mmol) was added to the mixture. The reaction was isolated from air and heated at 35 °C for 2 hours. The reaction mixture was then quenched with water and quenched with EtOAc EtOAc (EtOAc) (EtOAcjjjjjjjjjjj The gas decane solution) was concentrated to give the title compound. [a] D25 = -0.4. (c = 0.70, DMSO). Calculated for C20H18N2O4 (350.12), LCMS (ESI): 351.12 (M++H). NMR ( (CD3) 2S 〇 300 ΜΗζ ) δ : 7.63 ( d, 4H) '7.44 (t, 2H) '7.32 (t, lH), 7.05 (d, 2H), 5.82 · 5.78 (m ' 2H) ' 5.38 -5.36 (m ' 1H), 4.48-4.31 (m, 4H), 4.19 (dd, lH), 011 was not observed. Or [〇1]〇 =-. Example 76 (S)-2-(4'-Ethylbiphenyl-4-yloxymethyl)_% hydroxydecyl-2,3-dihydrocarbazol [3,2-a]. D--7-ketone

The title compound was prepared according to the procedure described in Example 75 using the appropriate starting material. 136 201121978 C22H22N204 Calculated (378.43), LCMS (ESI): 379.15 (M++H). 'H NMR ((CD3)2SO 30GMHz) δ : 7.58 (d, 2H), 7.52 (d, 2H) ' 7·26 (d, 2H), 7.03 (d, 2H), 5·80 (s, 1H) , 5.72 (t, 1H), 5.37-5.35 (m, 1H), 4.47-4.27 (6H) &gt; 4.17 (dd'lH), 1.2〇 (t'3H), no OR was observed. Example 77 (S)-2-(2',3'-Dimercaptobiphenyl-4-yloxyindenyl)-5-hydroxyindoleyl-2,3-dihydrocarbazo[3,2-a Pyrimidine-7-one

The title compound was prepared according to the procedure described in Example 76 using the appropriate starting material. [oc]D25 = -1.7. (c = 0.70, DMSO). C22H22N2〇4 (378.43), LCMS (ESI): 379.14 (M++H).咕NMR ((CD3)2SO 300MHz) δ : 7.96 (s, 1H), 7.22 (d, 2H), 7·13 (s, 1H), 7.11 (s, 1H), 7.02 (d, 2H), 5.81 ( s ' 1H ),5,77-5.75 ( m ' 1H ), 5.38-5.37 ( m,1H ), 4.48-4.33 (m ' 4H), 4.20 (dd,1H) ' 2.28 (s,3H),2.09 ( s, 3H), 〇H was not observed. Example 78 137 201121978 (S)-2-(2,3'-Dichlorobiphenyl-4-yloxyindenyl)-5-hydroxymethyl·2,3-dihydrocarbazolyl [3,2- &amp;] pain ° -7-ketone

The title compound was prepared according to the procedure described in Example 76 using the appropriate starting material. Calculated for C20H16Cl2N2O4 (418.04), LCMS (ESI): 419.04 (M++H). Ln NMR ((CD3)2SO 300MHz) δ : 7.63 ( dd &gt; 1Η), 7.45-7.33 (m,4H ) ' 7.05 ( d,2H ), 5.80 ( s,1H ), 5.72 ( t, 1H ) , 5.38 -5.36 ( m,1H ) &gt; 4.47-4.33 ( m » 4H ) &gt; 4.18 (dd ' 1H), 〇H was not observed. Example 79 (S)-5-Hydroxymethyl-2-(2f,3',5'-trifluorobiphenyl-4-yloxyindenyl)-2,3-dihydrocarbazo[3,2 -a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 76 using the appropriate starting material. [a]D25 = -2.5. (c = 0.55, DMS0). C2〇Hi5F3N2〇4 (4〇4 〇9), LCMS (ESI): 405.08 (M++H). 138 201121978 NMR ((CD3)2SO 300ΜΗζ) δ : 7.57 (dd, 2H), 7.54-7.48 (m, 1H), 7.31-7.26 ( m, 1H ), 7.09 ( d, 2H ), 5.80 (s, 1H) ' 5.73 (t ' 1H), 5.38-5.36 (m, 1H), 4.48-4.34 (m'4H), 4.18 (dd, lH), 〇H was not observed. Example 80 (8)-2-(Biphenyl-4-yloxyindenyl)-5-(2-ethyl)-2,3-dihydro-deca-[3,2-&amp;] Bite-7-ketone

k^OH Step 1: Indole-4-cyanate (S)-5-(2-(tetrahydron-pyran-2-yloxy)-ethyl)-7-keto-2,3-di氲-7Η-σ号0 sits and [3,2-a]0 密乙-2-基曱酉 曱 Benzene-4-linoleic acid (S)-2-amino-4,5-dihydrogen The β-pyrug-5-yl hydrazine (see Example 3, Step 1) (4.35 g, 16 mmol) was dissolved in 115 mL of ethanol. 5-(Tetrahydropyran-2-yloxy)-pentyn-2-carboxylic acid decyl ester (3.74 g, 17.7 mmol) was added and the reaction mixture was heated at <RTI ID=0.0></RTI> The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was directly purified by chromatography (120 g column; 40 mL/min; 10% decyl alcohol in dichloromethane) to give the title compound as a coloring foam (0.9 g, 12%) C21H26N207S Calculated (450.14), LCMS (ESI): 451.09 (M++H).H NMR (CDC13 300MHz) δ: 7.75 ( d &gt; 2Η ), 7.37 ( d, 2H), 5.85 (s, lH ), 5.15-5.14 (m, 1H), 4.57-4.56 (m, 1H), 4.51-4.44 (m, 1H), 4.33 (t, 2H), 4.28-4.19 (m, 139 201121978 1H), 4.04-3.97 (m, lH), 3.80-3.39 (m, 4H), 2.72 (t, 2H), 2.46 (s, 3H), 1.73-1.52 (m, 5H). Step 2: Indole-4-sulfonic acid (S) -5-(2. hydroxyethyl)-7-keto-2,3-dihydro-7H-indazolo[3,2-a]pyrimidin-2-yl decyl ester Acid (S)-5-(2-(tetrahydrofuran-2-yloxy)-ethyl)-7-keto-2,3-indan-7Η-σ-salt [3,2- a] The solution was dissolved in 20 mL of ethanol, 0.27 g of macroporous resin was added and the reaction mixture was heated at 60 ° C for 3 hours. The reaction mixture was filtered to remove Macroporous resin pellets, and the mother liquor is concentrated in vacuo to give the title compound as beige Solid (760 mg, yield 100%). Calculated for C16H18N206S (366.08), LCMS (ESI): 367.11 (M++H) NMR ((CD3)2SO 300 MHz) δ: 7.80 (d, 2H), 7.50 (d, 2H), 5.69 (s, lH), 5.16-5.15 (m, 1H), 4.42-4.32 (m, 3H), 3.96 (dd, 1H), 3.64 (t, 2H), 2.55 (t, 2H) ), 2.43 (s, 3H) 〇Step 3. (S)-2-(Biphenyl-4-yloxyindenyl)-5-(2-like ethyl)-2,3-diazo And [3,2-a]pyrimidin-7-one

曱本-4-石黄酸(S)-5-(2-|^ethyl)-7-mercapto-2,3-diaza-7Η-σ 嗤[3,2-a]pyrimidine 2-Gethyl decyl ester (150 mg, 0.41 mmol) was dissolved in 6 mL DMF. 140 201121978 Added 4-phenyl stupid (〇 41 mmol) and Cs2C03 (187 mg, 〇·57 mmol). The reaction mixture was heated at 35 CC for 5 hours and stirred at room temperature overnight. The reaction mixture was then quenched with water and brine to quenched with ethyl acetate (EtOAc). The combined organic layers were dried with EtOAc (EtOAc m. C2iH2 〇 N2 〇 4 calculated value (364 14 ), LCms (ESI): 365.14 (M++H). 4 NMR ((CD3)2SO 300MHz) δ : 7.63 (d, 4H), 7.43 (t ' 1H ) ' 7·31 ( t ' 1H ) ' 7.05 ( d,2H ), 5.72 ( s,1H ), 5.34- 5.32 (m, 1H), 4.95 (t, 1H), 4.51-4.30 (m, 3H), 4.21 (dd, 1H) ' 3.69 (q, 2H), 2.64 (t, 2H). Example 81 (S)-2-(4'-Ethylbiphenyl-4-yloxyindenyl)_5_(2-hydroxyethyl)_2,3-dihydrooxazolo[3,2-a]pyrimidine -7-ketone

The title compound was prepared according to the procedure described in Example 81 using the appropriate starting material. C23H24N204 calculated (392.17), LCMS (ESI): 393.17 (M++H). H NMR ((CD3)2SO 300ΜΗζ) δ : 7.59 (d, 2H), 7.52 (d, 2H), 7.26 (d, 2H), 7.03 (d, 2H), 5.72 (s, lH), 141 201121978 5.33- 5.32 (m,1H), 4.95 (t,1H) ' 4.51-4.29 (m,3H), 4.21 (dd,1H) ' 3.69 (q,2H),2.66-2.61 (m,4H),1.20 (t, 3H). Example 82 (S)-2-(2',3'-Dimercaptobiphenyl-4-yloxymethyl)_5_(2-hydroxyethyl)_2,3_dihydroindole[3,2 -a]e bite-7-ketone

The title compound was prepared according to the procedure described in Example 81 using the appropriate starting material. C23H24N204 calculated (392.17), LCMS (ESI): 393.16 (M++H). Ln NMR ((CD3)2SO 300MHz) δ : 7.22 (d &gt; 2Η) ^ 7.15-7.11 (m, 2Η), 7.02-6.98 (m, 3Η), 5.72 (s, 1Η), 5.34-5.33 (m ' 1H ) ' 4.95 ( t ' 1H ) ' 4.52-4.29 ( m,3H ), 4.22 ( dd ' 1H ), 3.69 ( q ' 2H ) ' 2.64 ( t,3H ), 2.28 ( s, 3H), 2.09 (s , 3H). Example 83 (S)-2-(2,3-Chloropipet-4-yloxymethyl)_5_(2_ethyl)·2,3_dihydro 0 et al.[3,2- a]pyrimidin-7-one

142 201121978 The title compound was prepared according to the procedure described in Example 81 using the appropriate starting material. C21H18C12N204 Calculated (432.06), LCMS c ESI: 4 &amp;06 (M++H). ]H NMR ((CD3)2SO 300MHz) δ : 7.64 (dd ΜΗ) &gt; 7.44-7.33 (m ' 4Η) ' 7.05 (d, 2Η), 5.73 (s, m), 5 35_534 (m ' 1Η), 4.96 (t,1Η) ' 4.52-4.32 (m,3Η), 4.23 (dd,1H), 3.70 (q ' 2H), 2.65 (t,3H). Example 84 (S)-5-(2-Hydroxyethyl)-2-(2',3',5'-trifluorobiphenyl-4-yloxyindenyl)_2,3-dihydrooxazolyl [3,2-a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 81 using the appropriate starting material. C2iH17F3N204 Calculated (418.11), LCMS (ESI): 419.11 (M++H). 4 NMR ( (CD3) 2SO 300MHz ) δ : 7.57 ( d, 2H), 7.52-7.49 (m ' 1H), 7.30-7.26 (m, 1H), 7.09 (d, 2H ) ' 5.72 ( s ' 1H ), 5.35_5.33 ( m,1H ), 4.95 ( t, 1H ), 4.52-4.33 ( m,3H ) ' 4.22 ( dd,1H ), 3.69 ( q, 2H) , 2.64 (t,3H). 143 201121978 Example 85 (S)-2-(biphenyl_4-yloxymethyl)_5_ethoxyindolyl-2,3-dihydro-sigmazo[3,2_a]pyrimidine-7-3⁄4

Step 1: Aspart-4-sulfonic acid (S)-5-ethoxymethyl-7-keto-2,3-dihydro-7H-s-oxazolo[3,2-a]pyrimidin-2- The methyl ester will be a pyridyl-4-n-acid (S)-2-amino-4,5-dihydroanthracene and a 5-methyl ester (see Example 3 'Step 1) ( 1.34 g ' 5 mmol ) Dissolved in 35 mL of ethanol. Methyl 4-ethoxybutyn-2-carboxylate (0.7 g '5 mmol) was added and the reaction mixture was heated at 85 ° C for 3 h. The reaction mixture was then cooled to room rt and concentrated in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc

Ci7H2〇N206S Calculated (398.09), LCMS (ESI): 399.10 (M++H). NMR (CDC13 300MHz) δ : 7.4 ( d, 2H ), 7.36 ( d, 2H ), 5.86 ( s, 1H ), 5.27-5.22 ( m,1H ) , 4_50 ( t , 1H), 4.36 (t, 2H) , 4.27 (dd, 2H), 4.23 (dd, 1H), 3.53 (q, 2H), 2.44 (s, 3H), 1.21 (t'3H). Step 2: (S)-2-(Biphenyl-4-yloxyindenyl)-5-ethoxyindolyl-2,3-dihydromalolo[3,2-a]pyrimidine-7- Ketone 144 201121978 Benzene-4-sulfonic acid (S)-5-ethoxyindol-7-keto-2,3-dihydro, 7Η_Π 唾[3,2-a]° 2-Ginyl ester (106 mg, 0.28 mmol) was dissolved in 4 mL DMF. The corresponding bifenyl g fraction (〇·28 mmol) and CS2CO3 (127 mg '0.39 mmol) were added successively. The reaction mixture was heated at 35 ° C for 5 hours and stirred at room temperature overnight. The reaction mixture was then quenched with water and brine to give &lt;RTI ID=0.0&gt; The combined organic layers were dried with Na.sub.4[sub.sub.sub.sub.sub.sub.sub.sub.sub. [a]D25 = +2.7. (c = 0.60, DMSO). C22H22N204 Calculated (378.15), LCMS (ESI): 379.14 (M++H). 4 Li R (CDC13 300MHz) δ : 7.53-7.48 (m, 4H), 7·40 (t ' 2Η ), 7.30 ( t, 1Η ), 6.92 ( d, 2Η ), 5.92 ( s, 1Η ), 5.34- 5.29 (m, 1H), 4.52 (t, 1H), 4.44_4.25 (m, 5H), 3.55 (q ' 2H), 1 · 2 〇 (t, 3H). Example 86 (S&gt;5-ethoxyindolyl-2·(4,_ethylbiphenyl_4_yloxyindenyldiaza(tetra)-[3,2-a]pyrimidin-7-one

The material = compound was the procedure described in Example 85 using the appropriate initial 145 201121978 C24H26N2 〇4 (406.18), LCMS (ESI): 407.19 (M++H). NMR (CDC13 300MHz) δ : 7.50 (d, 2H), 7.45 (d ' 2H) ' 7.25 (d ' 2H), 6.92 (d, 2H), 5.98 (s, 1H) ' 5.30-5.25 (m,1H) ' 4.52-4.26 (m,6H),3.56 (q, 2H) ' 2.68 (q ' 2H) ' 1.27 (t,3H), 1.23 (t,3H). Example 87 (S)-2-(2',3'-Dimercaptobiphenyl-4-yloxyindenyl)_5-ethoxyindolyl-2,3_dioxanthazole [3, 2-a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 85 using the appropriate starting material. C24H26N204 calculated (406.18), LCMS (ESI): 407.19 (M++H). A NMR ( CDC13 300MHz ) δ : 7.21 ( d,2H ), 7.16-7.14 (m ' 2H ), 7.09-7.02 ( m,1H ), 6.91 ( d,2H ), 5.96 (s ' 1H) ' 5.35-5.30 (m,1H), 4.56-4.27 (m,6H),3.57 (q ' 2H ),2.33 ( s ' 3H ) ' 2.13 ( s,3H ),1.23 ( t, 3H) 〇Example 88 (S)_2- (2y-dichlorobiphenyl-4-yloxymethyl)_5_ethoxymethyl-2,3-dihydroanthracene [3,2-a] mouth bite-7-one 146 201121978

The title compound was prepared according to the procedure described in Example 86 using the appropriate starting material.

Calculated value of CrHmCi^O4 (446·08), LCMS (ESI): 447 〇8 (M++H). NMR (CDC13 300MHz) δ: 7.43 (dd, 1H), 7.32 (d, 2H), 7.29-7.16 (m, 2H), 6.93 (d, 2H), 5.93 (s, 1H), 5.36-5.35 (m, 1H), 4.56 (t, ih), 4.46-4.27 (m, 5H), 3.56 (q, 2H), 1.22 (t, 3H). Example 89

Oxazolo[3,2-a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 86 using the appropriate starting material. ' LCMS ( ESI ) : 433.12 C22H19F3N204 Calculated (432.12 ) (Μ +H ). 5 : 7.45 ( d ' 2Η), 6·96 ( d, 5·94 (s, ih), 5.36-5.31 (m, ]H NMR (CDC13 300MHz ) δ : 2Η) , 6.91-6.84 (m, 3Η) » 5.9- 147 201121978 1H ),4·54 ( t,1H ), 4.46-4.27 ( m,5H ),3 57 ( q, 2H), 1.22 (t,3H). Example 90 (S)-2-(Biphenyl-4-yloxyindenyl)-5-isopropoxymethyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one

Step 1: Indole-4-pyrhoic acid (S)-5-isopropoxydecyl-7,keto-2,3-dihydro-7H-4oxazolo[3,2-a]pyrimidine- 2-Methyl ester The indolebenzene-4-sulfonic acid (S)-2-amino-4,5-dihydrobenzazolomethyl ester (1.08 g '4 mmol) was dissolved in 30 mL of ethanol. 4-Isopropoxybutyn-2-decanate (0.63 g, 4 mmol) was added and the reaction mixture was heated at <RTI ID=0.0> The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by EtOAc (EtOAc) eluting eluting eluting eluting (CDC13 300MHz) δ : 7.4 (d, 2H), 7.36 (d, 2H) ' 5.87 (s, 1H), 5.26-5.21 (m, 1H), 4.50 (t, lH), 4.50 (t, lH), 4.41 (t,lH) , 4.36 (t,2H), 4.32-4.20 (m,1H), 3.72 (t,1H), 2.45 (s,3H), 1.19 (d,ffl). 148 201121978 Step 2 : ( S)-2-(biphenyl-4-yloxyindenyl)-5-isopropoxydecyl-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one will be stupid -4-Retinoic acid (S)-5-isopropoxy fluorenyl-7-keto-2,3-dihydro sulphate and [3,2-a] °^ bite-2-yl hydrazine (1〇6 mg, 0.28 mmole) was dissolved in 4 mL of DMF. The corresponding 4-phenylphenol (0.28 mmol) and Cs2C03 (127 mg '0.39 mmol) were added successively. The reaction mixture was heated at 35 ° C for 5 hours. After stirring overnight at room temperature, the reaction mixture was quenched with EtOAc EtOAc (EtOAc m. (4 g column; δ : 7.53-7.48 ( m,4H ), 7.40 ( t, 2H) ' 7.30 (t ' 1H), 6.93 (d, 2H), 5.93 (s, 1H), 5.33-5.29 (m ' 1H) ' 4.52 (t ' 1H), 4.44 - 4.25 (m, 5H), 3.70 (sept, 1H), 1.19 (d, 6H). Example 91 oxazo[3,2_a]pyrimidin-7-one (S)-2-( 4·-ethylbiphenyl-4-yloxymethyl)_5_isopropoxycarbonyl 2,3_dihydrogen

Material prepared. The title compound was the procedure described in Example 9G and was applied using the appropriate initial 149 2011 21978 [a] D25 = +0.5. (c = 0.75, DMSO). C25H28N204 (420.20), LCMS (ESI): 421.19 (M++H). lU NMR ( CDC13 300MHz ) δ : 7.48 ( d &gt; 2H ), 7.44 ( d, 2H) '7.24 (d, 2H), 6.91 (d, 2H) , 5.94 (s, lH), 5.34-5.29 (m ' 1H), 4.52 (t, lH), 4.45-4.25 (m, 5H), 3.70 (sept, 1H), 2.67 (q, 2H), 1.26 (t, 3H), 1.19 (d, 6H). Example 92 (S)-2-(2',3·-Dimercaptobiphenyl-4-yloxyindenyl)-5-isopropoxycarbonyl-2,3-dihydrocarbazo[3 ,2-a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 90 using the appropriate starting material. [cc]D25 = +10.9. (c = 0.65, DMSO). c25H28N2〇4 (420.20), LCMS (ESI): 421.19 (M++H). NMR (CDC13 300MHz) δ: 7.22-7.19 (m, 2H), 7.16-7.11 (m, 2H), 7.08-7.01 (m ' 1H), 6.93-6.90 (m, 2H), 5.95 (s, lH), 5.38-5.33 (m, lH), 4.47 (t, lH), 4.43_ 4.26 ( m ' 5H ), 3.72 ( sept ' 1H ), 2.95 ( s, 3H ), 2.32 (s, 3H) , 1.19 (d, 6H). 150 201121978 Example 93 (S)-2-(2',3'-dichloro-biphenyl-4°° sitting and [3,2-3]11-biti-7-keto-chloro-like stupid 4-yloxy oxime Base)_5_isopropoxydecyl dinitrogen

The title compound was prepared according to the procedure described in Example 91 using the appropriate starting material. [〇c]D25 = +10.3. (c = 0.60, DMS〇). C23H22N2〇4Ci2 (460.09) 'LCMS (ESI): 461.09 (M++H). Towel NMR (CDC13 300MHz) δ : 7.43 (dd,1H),7·32 (d, 2Η ), 7.25-7.17 ( m,2Η ), 6.94 ( d,2Η ), 5.93 ( s, 1H) ' 5.38-5.33 (m, 1H), 4.56 (t, 1H), 4.46-4.27 (m, 5H), 3.72 (sept, 1H), 1.20 (d, 6H). Example 94 (S)-5-Isopropoxymethyl-2-(2',3',5'-trifluorobiphenyloxyindenyl)_2,3-dihydrocarbazolyl [3,2 -a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 91 using the appropriate starting material. [〇c]d25 = -14.3 0 (c = 0.65, DMSO). C23H2丨N2〇4F3 (446.14), LCMS (ESI): 447.11 (M++H). 151 201121978 4 NMR ( CDC13 300MHz ) δ : 7.74 ( d,1H ), 7.44 ( d, 2H), 7.35 (d,lH), 6.97 (d,2H), 5.93 (s,iH), 5.38-5.33 (m , 1H), 4.56 (t, lH), 4.47-4.23 (m, 5H), 3.71 (sept, 1H), 1.19 (d, 6H). Example 95 (S)-5-Isopropoxydecyl-2-(4,-methoxybiphenyl-4-yloxyindenyl)_2,3-dihydrochaxyzolo[3,2- a]pyrimidine _7-ketone

The title compound was prepared according to the procedure described in Example 91 using the appropriate material. ° C24H26N205 (422.18), LCMS (ESI): 423.16 (M++H). NMR (CDC13 300MHz) δ: 7.45 (d, 2H), 7 45 (d, 2H), 6.94 (d, 2H), 6.91 (d, 2H), 5.95 (S, 1H) '5.32-5 27 (m , 1H), 4.54-4.26 (m, 6H), 3.84 (s, 3H), 371 (sept ' 1H), 1.20 (d, 6H). Example 96 (8) Winter (4,ethylbiphenyl·4-yloxyindenyl)·5·phenyl-2,3-dihydro-decane[3,2_alpyrimidin-7-one]

152 201121978 Step 1: Indole-4-sulfonic acid (S)-7-keto·5·phenyl-2,3-dihydro-7H-. Search for oxazolo[3,2_a]pyrimidin-2-ylmethyl ester'. Indole Benzene-4-sulfonic acid (S)-2-amino-4,5-dihydrooxazolo-5-ylmethyl ester ( 116 g, 4.3 mmol) was dissolved in 33 mL of ethanol. Methyl 4-phenylpropyne-2-carboxylate (〇_82 g, 5.16 mmol) was added at 85. (: The reaction mixture was heated for 24 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified directly on silica gel column chromatography (40 g column; 35 mL/min; 5% methanol in hexanes Compound II is a white foam (0.121 g, 7%). C20H18N2O5S (398.09) 'LCMS (ESI): 399.10 (M++H). Η NMR (CDC13 300MHz) δ: 7.74 (d &gt ; 2Η ), 7.53-7.43 (m, 5Η ) , 7.35 ( d, 2H ) , 5.93 ( s, 1H ) , 5.21-5.16 (m ' 1H) ' 4.34-4.26 (m, 3H), 4.05 (dd, 1H ), 2.45 (s, 3H) Step 2. (S)-2-(4'-Ethylbiphenyl-4-yloxyindenyl)-5-phenyl-2,3-diaza σ. Sit and [3,2-a]pyrimidin-7-one

(S)-7-keto-5-phenyl-2,3-dihydro-7H-nfoxazolo[3,2-a]^^-2-ylcarbamate (4 〇 mg, 0.1 mmol) was dissolved in 1 mL DMF. 4-(4'-Ethyl)phenylbenzene (οι mmol) and Cs2C〇3 (46 mg, 0.14 mmol) were added. The reaction mixture was heated at 35 cc for 5 hours and stirred at 30 ° C overnight. The reaction mixture was then quenched with water and brine to quenched and extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) The combined organic layers were dried with EtOAc (EtOAc) (EtOAcjjjjjj [〇c] D25 = +66.0. (c = 〇.6〇, DMS0). (:2 from 2 to 2〇3 (424 17), LCMS (ESI): 425.24 (M++H). 'H NMR (CDC13 300MHz) δ: 7.57-7.42 ( m &gt; 9H ) , 7. (d '2H) '6.91 (d,2H),6.02 (s,m),534_5 29 (m 1H) '4.42-4.35 (m,2H) , 4.28-4.17 (m,2H) ,2.67 (q 2H),1.26 (t, 3H). Example 97 (S)-2-(2',3·-Dimercaptobiphenyl-4-yloxyindenyl)-5-phenyl-2,3-dihydrooxazole And [3,2-a]^n-dec-7-one

The title compound was prepared according to the procedure described in Example 96 using the appropriate starting material. C27H24N2〇3 (424.17), LCMS (ESI): 425.24 (M++H). 4 NMR (CDC13 300MHz) δ: 7.57-7.48 (m, 5H), 7.23 (d, 2H), 7.13 (d, 2H), 7.02 (dd, 1H), 6.90 (d, 2H) ' 6.03 (s, lH ), 5.34 - 5.33 (m, 1H), 4.44 - 4.37 (m, 2H) ' 4.30-4.19 (m, 2H), 2.32 (s, 3H), 2.12 (s' 3H). 154 201121978 Example 98 (S)-2-(2',3'-monochlorobiphenyl_4-yloxyindenyl)-5-phenyl-2,3-dihydrooxazolo[3,2-a ]^^-7-酉同

The title compound was prepared according to the procedure described in Example 96 using the appropriate starting material. [a]D25 = +64.0. ( c = 〇·55, DMs〇). c25Hi8Cl2N2〇3 (464.06), LCMS (ESI): 465.14 (M++H). Ln NMR (CDC13 300MHz) δ : 7.58-7.51 ( m &gt; 5H ) &gt; 7.43 (dd,1H ) ' 7.31 ( d,2H ), 7.28-7.16 ( m ' 2H ), 6.93 (d,2H) ' 6.01 (s ' 1H) ' 5.39-5.34 (m, 1H), 4.46-4.40 (m, 2H), 4.32-4.18 (m, 2H). Example 99 (S)-2-(Biphenyl-4-yloxyindenyl)-5-cycloindoleoxy 2,3-dihydrooxazolo[3,2_a] °密0定-7- 3 with

Step 1: Prop-2-ynyloxycyclopentane DMF (200 ml) was cooled to 〇QC and cyclopentanol (6 g, 7 〇mmo, 1 eq.) was added. Solid NaH (60% oil solution, 2 94 g, 155 201121978 73.5 mmol, 1.05 mmol) was added in batches, and the mixture was stirred for 10 minutes, then a solution of 80% fast propyl bromide in diphenylbenzene (7.77 mL, 70 mmol, 1 equivalent). The reaction mixture was allowed to warm to room temperature and stirred for additional 3 hours. The reaction mixture was then diluted with 800 mL of H20 and extracted with diethyl ether (2×100 mL). The combined organic layers were dried with EtOAc (EtOAc) (EtOAcjjjjjjj The compound is a pale yellow oil. ]H NMR (CDC13 300MHz) δ: 4.15-4.10 (m &gt; 1H ) , 4.12 (d, 2H), 2.40 (t, lH), 1.91-1.44 (m, 8H). Step 2: 4-cyclopentyloxybutyne-2-carboxylic acid decyl ester. Prop-2-ynyloxycyclopentane (1.62 g, 13 mmol, 1 eq.) was dissolved in 130 mL THF and dried. Cool to -78 ° C in an acetone bath. 2.5 M nBuLi in heptane (5.2 mL, 13 mmol, 1 eq.) was slowly added and the pale yellow solution turned dark dark. After 15 minutes, the hydrazinium chloroformate (1.03 mL, 13 mmol, 1 eq.) was added and the reaction mixture became light and allowed to warm to room temperature. The reaction mixture was then diluted with 200 mL H20 and extracted with diethyl ether (2 X 50 ml). The combined organic layer was dried with EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH A pale yellow oil. ]H NMR (CDCI3 300MHz) δ : 4.23 ( s &gt; 2Η ) , 4.13-4.11 (m, lH) , 3.78 (s, 3H), 1.77-1.53 (m, 8H). 156 201121978 Step 3: Toluene-4-sulfonic acid (S)-5-cyclopentyloxyindol-7-keto-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidine-2 -Based esters Toluene_4_sulfonic acid (S)-2-amino-4,5-dihydrooxazolo-5-ylmethyl ester (2.09 g, 7.7 mmol) was dissolved in 60 mL of ethanol. 4-cyclopentyloxybutyn-2-carboxylic acid decyl ester (1.4 g, 7.7 mmol) was added and the reaction mixture was heated to 85 ° C and kept for 2.5 h. The reaction mixture was then cooled to room rt and concentrated in vacuo. The title product (1.27 g, 39%) was obtained as a pale yellow half. solid. C2 〇 H24N206S calculated (420.13), LCMS (ESI): 421.20 (M++H). 'H NMR ( CDC13 300MHz ) δ : 7.74 ( d &gt; 2Η ), 7.36 ( d, 2H), 5.86 (s, 1H), 5.25-5.20 (m, 1H), 4.51-4.19 (m, 6H), 3.99 -3.97 (m, 1H), 2.45 (s, 3H), 1.68-1.55 (m, 8H). Step 4: (S)-2-(Biphenyl-4-yloxymethyl)_5-cyclopentyloxymethyl 2,3-dihydron-oxazolo[3,2-a]pyrimidine-7- Ketone toluene-4-sulfonic acid (S)-5-cyclopentyloxyindolyl-7-keto-2,3-dihydro-7Η-α-sodium [3,2-a] «Methylene-2 - The decyl ester (8 〇 mg, 0.19 mmol) was dissolved in 2 mL DMF. 4-Phenylphenol (0.22 μ〇i) and Cs2C03 (89 mg, 0.27 mmol) were added in succession. The reaction mixture was heated to 35 ° C for 5 hours and stirred at 30 ° C overnight. The reaction mixture was then quenched with water and brine to give &lt;RTI ID=0.0&gt; The combined layer of 157 201121978 was dried over Na 2 S 〇 4, vacuumed and purified by silica gel column chromatography (4 〇 g column; % mL/min · 6% MeOH in CH2C12) to give the title compound. [α] β 25 = +47 q 0 (c = 0.60, DMSO). JH NMR ( CDC13 300MHz ) δ : 7.43 ( t &gt; 4Η ) , 7 32 ( t , 2H ) ' 7.22 ( t,1H ), 6.84 ( d,2H ) ' 5.85 ( s,1H ), 5.27-5.21 ( m ' 1H) ' 4.43 (t ' 1H), 4.33-4.13 (m, 5H), 3.91 (m, 1H), 1.66-1.45 (m, 8H). Example 100 (S)-5-Cyclopentyloxymethyl-2-([ethylbiphenyl-4-yloxyindenyl)_2,3-dihydrooxazolo[3,2-a]n-density β定-7-酉同

The title compound was prepared according to the procedure described in Example 99 using the appropriate starting material. [a] D25 = +4.4 0 (c = 0.75, DMSO). H NMR (CDC13 300MHz) δ : 7.40 ( d, 2H), 7.36 ( d, 2H ), 7.16 ( d ' 2H ) ' 6.83 ( d, 2H ), 5.85 ( s ' 1H ), 5.25-5.20 (m, 1H) , 4.42 (t,1H) , 4.33-4.13 ( m,5H) ' 3.93-3.89 (m,1H) 2.63 ( q,2H) ' 1.67-1.46 ( m,8H ), 1.19 (t,3H). Example 101 158 201121978 (S)-5-cyclopentyloxymethyl 2_(2,,y-dimethylbiphenyl-4-yloxyindenyl)_2,3_dihydro σ-salt [3, 2-a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 99 using the appropriate starting material. [a] D25 = +3.3° (c = 〇.7〇, DMSO). NMR (CDC13 300MHz) δ : 7.14 (d, 2H), 7.08-7.01 (m ' 2H ) ' 6.97-6.94 ( m,1H ), 6.83 ( d,2H ), 5.88 (s ' 1H) ' 5.28-5.23 ( m ' 1H) 4,44 (t,1H), 4.36-4.16 (m'5H) '3.95-3.91 (m,lH), 2.25 (S,3H),2.05 (s, 3H) ' 1.67-1.47 (m , 8H). Example 102 (S)-5-cyclopentyloxymethyl 2 -(2',3'-dichlorobiphenyl-4-yloxyindenyl) 2,3-dihydroindole °[3,2 -a] ° dense.定-7-_

The title compound was prepared according to the procedure described in Example 99 using the appropriate starting material. [a] D25 = +5.6° (c = 0.50, DMSO). 159 201121978 ^ NMR (CDC13 300MHz) δ : 7.43 (dd,1H), 7.32 (d, 2H ) ' 7.25-7.13 ( m,2H ), 6.93 ( d,2H ),5.94 ( s, 1H) ' 5.37-5.32 (m, 1H) ' 4.53 (t, 1H), 4.42-4.23 (m, 5H), 4.02-4.00 (m, 1H), 1.75-1.54 (m, 8H). Example 103 (S)-5-cyclopentyloxyindol-2-(2·,3',5'-trifluorobiphenyl-4-yloxyindenyl)_2,3_dihydrogen [3,2-&amp;]° 密定-7-ketone

The title compound was prepared according to the procedure described in Example 99 using the appropriate starting material. [a] D25 = +4.2o (c = 0.65, DMSO). NMR ( CDC13 300MHz ) δ : 7.44 ( d,2H ), 6.96 ( d , 2H) '6.90-6.84 (m'2H), 5.94 (S,1H), 5.38_5.33(m, 5H ) , 4.00 ( m , 1H), 4.53 (t, 1H), 4.42-4.23 (m, 1H), 1.74-1.54. Example 104 (8)-2-(Biben-4-yloxyindenyl)-5-(tetrahydrofuran.South-2-yloxycarbonyl)_2 3·Dihydrocarbazino[3 ,2-a]pyrimidin-7-one

A 160 201121978 Step 1: 2-prop-2-ynyloxyindenyl-tetrahydrofuran DMF (200 ml) was cooled to 〇〇c and tetranitro sugar alcohol (6 7 ‘, 70 mmo b 1 equivalent) was added. Add solid NaH (6〇% oil solution, 2 94 g '73.5 mmoL·1.05 mmol) in batch, stir for 1 minute, then add 8〇% propargyl wide diphenylbenzene solution (7.77 mL, 7〇i equivalent) ). The reaction mixture was allowed to warm to room temperature and stirred for additional 3 hours. The reaction mixture was then diluted with 8 mL of H.sub.2 and extracted with diethyl ether (2.times. The combined organic layers were dried with EtOAc (EtOAc) (EtOAcjjjjjj %) The title compound is a pale yellow oil. bNMR (CDC13 300MHz) δ : 4.22 (t, 2H), 4.10-4.05 (m, 1H), 3.93-3.85 (m'lH), 3,81_3 73 (m, lH), 3.61-3.48 (m, 2H) , 2.43 (t'lH), 2.01-1.85 (m, 3H) '1.69-1.61 (m, 1H). Step 2: Methyl 4-(tetrahydrofuran-2-ylmethoxy)-butynoate 2-Ethyl-2-mercaptolacyl-tetrahydro. Furan (2.57 g, 18.4 mmol, 1 eq.) was dissolved in 184 mL THF and cooled to _78 ° C in dry ice acetone bath. Slowly add 2.5 M nBuLi in heptane (7.4 mL 18.4 mmo 1 liter) and the pale yellow solution turned dark black. After 15 minutes, decyl chloroformate (2. 9 mL, 36. 8 mmol. 2 eq.) was added and the reaction mixture became light and allowed to warm to room temperature. The reaction mixture was then diluted with 200 mL of H.sub.2 and extracted with diethyl ether (2 x 50 ml). The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by chromatography eluting eluting eluting eluting The title compound is a pale yellow oil. 161 201121978 NMR ( CDC13 300MHz ) δ : 4.35 ( d,2H ) , 41 (M 〇 3 (m,1H) , 3.92-3.85 (m,1H) ,3.81-3.74 (m,1H), 3.79 (s,3H ), 3.61 (dd, lH) '3.51 (dd, lH), 2.01-1.84 (m, 3H), 1.68-1.60 (m, 1H) Step 3: Toluene-4-carnitine (S)-7- Keto-5-(tetrahydrofuranylmethoxyindolyl)-2,3-dihydro-7H-indazolo[3,2-a]pyrimidin-2-yloxime ester - Sustained acid (S)-2-amino-4,5-dihydro alpha saliva _5_yl hydrazine (21 g, 7.7 mmol) dissolved in 60 mL of ethanol. Add 4-(tetrahydrofuran_2_ The oxime)-butyne-2-carboxylate (1.53 g, 7.7 mmol) was heated at 850 C for 2.5 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. Chromatography (80 g column; 35 mL/min; hexanes EtOAc EtOAc) , LCMS (ESI): 437.13 (M++H). NMR (CDC13 300MHz) δ: 7.76 ( dd &gt; 2Η ), 7.37 ( d, 2H), 5.93 (s, lH), 5.14-5.10 (m, lH ), 4.56-4.44 (m, 1H), 4.38-4.30 (m, 5H), 4.08-4.04 (m, 1H), 3.86-3.75 (m, 2H), 3.57 ( dd, 1H ) , 3.44 - 3.35 ( m, 1H ) , 2.46 (s'3H), 2.00-1.84 (m, 3H), 1.55-1.51 (m, lH). Step 4: (S)-2-(biphenyl-4-yloxymethyl)-5-(tetrahydrofuran-2-yloxime) (2)3-dihydrooxazolo[3,2-a]pyrimidin-7-one 162 201121978 terphenylbenzene-4-linoleic acid (S)-7-keto-5-( Tetrahydrofuran-2-ylmethoxymethyl)-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-ylmethyl ester (1 mg, 0.23 mmol) dissolved in 2 mL CH3CN. 4-Phenylphenol (0.23 mmol) and Cs2C03 (104 mg '0.32 mmol) were then weighed. The reaction mixture was heated to 40 ° C and stirred overnight. The reaction mixture was then quenched with water and brine to &lt;RTI ID=0.0&gt; The combined organic layer was dried with EtOAc (EtOAc m. [oc]d25 = +17.2o (c = 0.75, DMSO). C25H26N205 calculated (434.18), LCMS (ESI): 435.20 (M++H). !H NMR (CDC13 300MHz) δ : 7.51-7.46 (m &gt; 4H) &gt; 7.38 (t » 2H ) ' 7.33-7.28 ( m ' 1H ), 6.91 ( d,2H ), 5.90 ( s, 1H), 5.31-5.28 (m,1H),4.56-4.28 (m,6H),4.02-3.99 (m ' 1H) ' 3.79-3.67 (m,2H),3.56-3.51 (m,1H), 3.44-3.39 (m , 1H) ' 1.92-1.77 (m, 3H), 1.52-1.48 (m, 1H). Example 105 (S)-2-(4'-Ethylbiphenyl-4-yloxyindenyl)·5_(tetrahydrofuran-2-yloxycarbonyl)-2,3-dihydrocarbazolyl[ 3,2-a]pyrimidine _7-ketone

163 201121978 The title compound was prepared according to the procedure described in Example 104 using the appropriate starting material. [cc] D25 = +3.6 ° (c = 0.70, DMSO) qC27H3 〇N2 〇5 (462.21), LCMS (ESI): 463.26 (M++H). iH NMR (CDC13 300MHz) δ: 7.47 ( d , 2H ) , 7.42 ( d , 2H), 7.23 (d, 2H), 6.91 (d, 2H), 5.93 (s, lH), 5.31-5.30 (m * 1H » 4.57-4.28 ( m &gt; 6H ) &gt; 4.03-4.00 ( m » 1H) ' 3.81-3.68 (m,2H) ' 3.57-3.53 (m,1H), 3.46-3.40 (m,lH), 2.67 (q'2H), 1.92-l.78 (m, 3H), 152_149 (m, 1H), 1.26 (t, 3H). Example 106 (S)-2-(2',3'-monodecylbiphenyl-4-yloxyindenyl)_5_(tetrahydrofuran-2-yloxycarbonyl)-2,3- Dihydro σ 嗤 [ [3,2-a] 0 密β定-7-酉同

The title compound was prepared according to the procedure described in Example 104 using the appropriate starting material. [a] D25 = +10.8 ° (c = 0.65, DMSO) » C27H3 〇N2 〇5 ( 462 21 ), LCMS (ESI): 463.26 (M++H).

丨H NMR (CDC13 300MHz) δ : 7.21 ( d,2H), 7.14-7 U (m,2H ), 7.04-7.01 ( m ' 1H ), 6.91 ( d,2H ),5 (s,lH) ' 5.39-5.31 (m'lH), 4.61-4.31 (m,6H), 164 201121978 4.05-4.02 (m,1H) '3.82-3.72 (m,2H),3 6〇3 55 (m, 1H ) ' 3.48 -3.42 ( m,1H ), 2.33 ( s,3H ),2·ΐ3 ( s , 3H), 1.93-1.80 (m,3H) '1.59-1.51 (m,1H). Example 107 (S)-2-(2',3'-= gasbiphenyl-4-ylftylindole (tetrahydropurine_2_ylmethoxymethyl)-2,3-dihydrosuccinic σ Sit and [3,2-a]. dense β-den-7-one

The title compound was prepared according to the procedure described in Example 1 to 4 using the appropriate starting material. [oc]D25 = +5.2. (c = 0.60, DMs〇). C25H24Ci2N2〇5 (502.10), LCMS (ESI): 503.15 (M++H). 4 NMR (CDC13 300MHz) δ : 7.35 (dd,1H), 7.23 (d, 2H ) ' 7.17-7.09 ( m,2H ) ' 6.85 ( d,2H ), 5.85 ( s, 1H), 5.27-5.26 ( m ,1H ),4.53-4.25 ( m,6H),3.97-3.92 (m'lH) '3.74-3.61 (m,2H),3.52-3.47 (m,iH), 3.39-3.34 (m,1H) ' 1.87 -1.72 (m, 3H), 1.47-1.43 (m, 1H). Example 108 (S)-5-(tetrahydrofuran-2-ylmethoxyindenyl)_2_(2,3,5,-trifluoro-phenylene-4-yloxyindenyl)-2,3 - One hydrogen ° ° ° sit and [3,2-a] sound. Ding-7-ketone 165 201121978

The title compound was prepared according to the procedure described in Example 105 using the appropriate starting material. [a]D25 = +5.7. (c = 0.70, DMSO). C25H23F3N205 (488.15), LCMS (ESI): 489.20 (M++H). lU NMR (CDC13 300MHz) δ : 7.36 ( dd &gt; 2Η ) } 6.88 ( d » 2H), 6.82 - 6.78 (m, 2H), 5.85 (s, 1H), 5.27-5.26 (m, 1H), 4.54- 4.25 (m ' 6H), 3.97-3.93 (m, 1H), 3.74-3.61 (m, 2H), 3.51-3.47 (m, 1H), 3.39-3.34 (m, 1H), 1.86-1.72 ( m, 3H ), 1.51-1.39 (m, 1H). Example 109 (S)-5-(2-Fluoroethoxyindenyl)-2-(3'-isopropylbiphenyloxyindenyl)_2,3-dihydroindole °[3,2 -a]pyrimidine-7-ketone

Step 1: 3-(2-·Fluoroethoxy)-propyne DMF (200 ml) was cooled to hydrazine.匸 mL '70 mmo b 1 equivalent). Add 2.94 g, 73.5 mmo Bu 1.05 mmol) in batches, add to 0〇c and add 2-fluoroethanol (4.11 batch of solid NaH (60% oil solution)

A solution of 80% propargyl bromide in xylene (7 77 mL' was stirred for 10 minutes, then the reaction mixture was warmed to room temperature and then dropped (7.77 mL, 70 mmol, 1 eq.).

3 hours. The reaction mixture was then diluted with 800 mL 166 2011 21978 %0 and extracted with diethyl ether (2 χ 1 〇〇 〇〇). The combined organic layer was dried with EtOAc (EtOAc m. H NMR (CDC13 300MHz) δ : 4.67 (dd, 1H), 4.51 (dd, 1H) ' 4.23 (d ' 2H), 3·83 (dd, 1H), 3.76 (dd, 1H), 2.44 (t, 1H) ). Step 2. 4-(2-Fluoroethoxy)-butynoic acid decyl ester 3-(2-fluoroethoxy)·propan (1.65 g, 16.7 mmol, 1 eq.) was dissolved in 70 mL THF and Dry ice in acetone bath to _78 °C. Slowly add a heptane solution (6.8 mL 17.0 mmo, 1 equivalent) containing 2.5 M nBuLi, and the pale yellow/trol solution turned dark black. After 15 minutes, the gas glycolate (1.41 mL, 17.8 mmol, 1.1 eq.) was added and the reaction mixture became light and allowed to warm to room temperature. The reaction mixture was then diluted with 200 mL H20 and extracted with diethyl ether (2 X 50 ml). The combined organic layer was dried with EtOAc (EtOAc) (EtOAcjjjjjjj A pale yellow oil. !H NMR (CDC13 300MHz) δ : 4.67 ( dd &gt; 1Η) , 4.51 (dd, 1H ), 4.37 ( s, 2H ), 3.85 ( dd, 1H ), 3.79 ( s, 3H ), 3.76 ( dd, 1H ). Step 3: Toluene-4-sulfonic acid (S)-5-(2-fluoroethoxyindolyl)-7-keto-2,3-dihydro-7H-. Nozolo[3,2-a]pyrimidin-2-yldecyl ester 167 201121978 terphenylbenzene-4-sulfonic acid (S)-2-amino-4,5-dihydrotetrazolo-5-yl The ester (ι. 13 g, 4.16 mmol) was dissolved in 35 mL of ethanol. 4-(2-Fluoroethoxy)-butyne-2-carboxylic acid decyl ester (0.605 g, 3.78 mmol) was added, and the reaction mixture was heated at 85 ° C for 3 hr. The reaction mixture was then cooled to room rt and concentrated in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc C17H19FN206S ( 398.09 ), LCMS (ESI): 399.12 (M++H). !H NMR ( CDC13 300MHz ) δ : 7.73 ( d &gt; 2H ), 7.35 ( d ' 2H), 5.86 (s, 1H), 5.27-5.22 (m, 1H), 4.64-4.20 ( buckle, 8H) '3.80 -3.77 (m, 2H), 3.70-3.67 (m, 2H), 2.43 (s, 3H). Step 4: (S)-5-(2-Fluoroethoxydecylisopropylbiphenyloxymethyl)_2,3-dihydro-decapine[3,2-a]. Metformin-7-one The indole benzene-4-sulfonic acid (S)-5-(2-fluoroethoxyindolyl)-7-keto-2,3-dihydro s. Sit and [3,2-a] ° your 唆-2-yl group (1 〇〇 mg, 0.25 mmol) dissolved in 2 mL CH3CN. 4'-Phenylphenylphenol (0.275 mmol) and Cs2C〇3 (117 mg '0.36 mmol) were added in succession. The reaction mixture was heated to 3 ° C and stirred overnight. The reaction mixture was then quenched with water and brine to quenched with ethyl acetate (EtOAc). The combined organic layer was dried with EtOAc (EtOAc) (EtOAc) D25 = +2.8. (c = 0.50, DMSO) °C25H27FN204 (438.19), LCMS (ESI): 439.19 (M++H). !H NMR ( CDC13 300MHz ) δ : 7.41 ( d 5 2H ), 7.29 ( s, 1H ), 7·25 ( d,2H ) ' 7.10 ( dt,1H ), 6.84 ( d,2H ), 5.85 (s, 1H) ' 5.26-5.21 (m,1H), 4.55-4.16 (m,8H), 3.73-3.70 ( m ' 1H ) ' 3.63-3.60 ( ra,1H ), 2.87 ( septet ' 1H),1.20 (d, 6H). Example 110 (S)-2-(Biphenyl-4-yloxymethyl)-5-(2-fluoroethoxyindenyl)_2,3-dihydrooxazole [3,2-a] 11 密-7-酉同

The title compound was prepared according to the procedure described in Example 109 using the appropriate starting material. [a] D = +3.1° (c = 0.70'DMSO) °C22H21FN204 (396.14), LCMS (ESI): 397.16 (M++H) 〇H NMR (CDC13 300MHz) δ: 7.53-7.48 (m, 4H) , 7.40 (t, 2H ) ' 7.32-7.27 ( m ' 1H ), 6.92 ( d,2H ) ' 5.93 ( s, 1H), 5.33-5.28 (m,1H), 4.63-4.24 (m,8H),3.81 -3.78 (m, 2H), 3.71-3.68 (m, 2H). Example 111 169 201121978 (S)-2-(4·-Ethylbiphenyl-4-yloxyindenyl)-5-oxazolo[3,2-a]pyrimidin-7-one (2-F Oxymethyl)-2,3-di

The title compound was prepared according to the procedure described in Example 109 using the appropriate starting material.

Md25 = +3.9. (c = 0.70, DMSO). Γ 订 〜 a / , L24H25fn204 (424.17), LCMS (ESI) : 425.20 (M++H). ]H NMR ( CDC13 300MHz ) δ : 7 47 r ^ , '.4/ ( d ' 2H) , 7.43 ( d, 2H), 7.23 (d, 2H), 6.90 (d, 2H), 5 87 (s, Ih), mq, 2H), 1.26 5.33-5.28 (m ' 1H), 4.63-4.23 (m, 8H), 3 8l 3 78 2H ), 3.71-3.68 (m, 2H), 2.67 3H). Example 112 (S)-2-(2',3'-Dimercaptobiphenyl-4-yloxyindenyl)dihydroindolo[3,2-a]pyrimidin-7-one

The title compound was prepared according to the material of Example 109. The procedure described and using the appropriate initial ton me = G.6(), face 0) QC24H25FN2〇4 (424 i7) LCMS (ESI): 425.19 (M++H) 〇170 201121978 4 NMR (CDC13 300MHz ) δ : 7.21 ( d,2H ), 7.19-7.10 (m,2H ), 7.04-7.01 ( m ' 1H ), 6.90 ( d,2H ), 5.94 (s &gt; 1H ) &gt; 5.37-5.31 ( m &gt; 1H ), 4.67-4.26 ( m &gt; 8H ) &gt; 3,83-3.81 (m, 2H), 3.73-3.71 (m, 2H), 2 32 (s, 3H), 2.12 (s, 3H). Example 113 (S)-2-(2',3'-di-biphenyl-4-yloxyindenyl)-5-(2-fluoroethoxyindolyl)_2,3-dihydrocarbazolyl[ 3,2-a]pyrimidin-7-one

The title compound was prepared according to the procedure described in Example 109 using the appropriate starting material. C22H19Cl2FN2〇4 (464.07), LCMS (ESI): 465.08 (M++H). NMR (CDC13 300MHz) δ : 7.43 (dd,1H), 7.31 (d, 2H ) ' 7.28-7.16 ( m,2H ), 6.93 ( d,2H ), 5.93 ( s, out ) ' 5.37-5.32 (m, 1H) ' 4.65-4.28 (m, 8H), 3.83-3.81 (m ' 2H), 3.73-3.71 (m, 2H). Example 114 (S)-5-(2-Fluoroethoxymethyl)_2_(2',3,,51-trifluorobiphenyl-4-yloxyindenyl)_2,3-dihydrocarbazolyl[ 3,2-a]pyrimidin-7-one 171 201121978

The title compound was prepared according to the procedure described in Example 109 using the appropriate starting material. [a]D25 = +3.6. (c = 0.50 'DMSO). C22H18F4lSr2〇4 (450.12), LCMS (ESI): 451.14 (M++H). NMR (CDC13 300ΜΗζ) δ : 7.43 (dd, 2H), 6.95 (d, 2H) ' 6.93-6.82 (m ' 2H) ' 5.92 (s ' ih), 5.40-5.31 (m, 1H) ' 4.67-4.27 ( m ' 8H) ' 3.83-3.81 (m, 2H), 3.73-3.71 (m, 2H). Example 115 (S)-5-(l,l-Difluoro-propyl)-2-(2',3'-diindenylbiphenyl-4-yloxyindenyl)-2,3-dihydrogen π et al. [3,2-a]β-Bite-7-ketone

According to the procedure described in step 4 of Comparative Example 1, the valence of ____石素

20.6 mg (26%) of the title compound was obtained. C24H24F2N2〇3 (426.17) &gt;LCMS(ESI): 427.17 (M++H) 172 201121978 !H NMR ((CDC13) &gt; 300MHz) δ : Ί.25-1.22 (d &gt; 2H) » 7.16- 7.10 (m, 2H), 6.92-6.89 (d, lH), 6.25 (s, lH), 5.30-5.24 (m, lH), 4.54-4.50 (m, 2H), 4.44-4.39 (dd, 1H), 4.31 -4.27 ( dd ' 1 ) ' 2.33 ( s, 3H ) , 2.30-2.19 ( m, 2H ), 2.13 (s, 3H) , 1.20-1.18 (t, 3H). Example 116 (S)-5-Fluoromethyl-2-(3'-isopropylbiphenyl-4-yloxyindenyl)-2,3-dioxazolo[3,2-a]^ . D--7-ketone

In the case of indole-containing benzenesulfonic acid (S)-5-fluoroindol-7-keto-2,3-dihydro-7H-carbazolo[3,2-a]0^11 Add 3'-isopropylbiphenyl-4-ol (66 mg, 0.31 mmol' [4-iodobenzene from acetic acid) to a solution of vinegar (Example 32) (100 mg, 0.282 mmol) in acetonitrile (6 ml) Preparation of ester and 3-isopropylphenylboronic acid]), then cesium carbonate (128.4 mg '0.395 mmol) was added. The reaction mixture was stirred at 35-45 °C for 18 hours. The reaction mixture was cooled to room temperature and filtered over a pad of Celite. The filtrate was concentrated in vacuo and purified eluting with EtOAc EtOAc EtOAc EtOAc C23H23FN203 (394.16), LCMS (ESI): 395.14 (M++H). ]H NMR ((CDCI3) &gt; 300MHz) δ : 7.54-7.51 (d &gt; 2H) &gt; 7.38-7.35 ( m,3H ), 7.21-7.18 ( m,1H ), 6.96_ 6.93 ( d, 2H) , 6.02-6.01 (d,lH) '5.36-5.30 (m,2H),5.14 (s, 173 201121978 1H) ' 4.55-4.51 (t,1H),4.43-4.28 (m,3H),2.99-2.94 ( m ' 1H), 1.31-128 (d, 6H). Example 117 (S)-2-(biphenyl-4-yloxyindenyl)-5-fluoroindolyl-2,3-dihydrooxazolo[3,2_a]pyrimidine-7-one

Following the procedure described in Example 116, from toluene-4-sulfonic acid (s)-5-fluoromethyl-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidine- 5-6 mg (54%) of the title compound was obtained from 2-yl decyl ester (0.282 mmol) and 4-phenylphenol (0.31 mmol). [ot]D25 = -6.4. (c = 0.67, DMSO) C20H17FN2O3 (352.12), LCMS (ESI): 353.10 (M++H). lU NMR ((CDC13) 5 300 ΜΗζ) δ : 7.55-7.52 (d &gt; 4H) » 7.45-7.40 ( t ' 2H ), 7.35-7.32 ( t,1H ). 6.97-6.94 (d,2H), 6.08-6.07 (d ' 1H), 5.35- 5.27 (m, 2H), 5.14 (s, 1H), 4.49-4.29 (m, 4H). Example 118 (S)-5-fluoroindolyl-2-(2·,3',5'-trioxobiphenyl-4-yloxyindenyl)_2,3-dihydrocarbazolyl [3, 2-a]pyrimidin-7-one 174 201121978

Following the procedure described in Example 116, from toluene _4_sulfonic acid (s) _5-fluoroindolyl-7-keto-2,3-dihydro-7H-^ and [3,2_a] s. 816 mg (64%) of the title compound was obtained from the title ((). 282 awake (4) and 2,, 3,,5,-trichlorobiphenyl-4-ol (〇·31 mm〇1). ] D25 = -4.0. ( c = 〇.74, DMS 〇) (454.00) ' LCMS (ESI) : 454.99 (M++H). NMR ((CDC13) &gt; 300MHz) δ : 7.47-7.46 (d » 1H) « 7.34- 7.31 (d,2H) ' 7.21-7.20(d ' 1H), 6.97-6.94 (d,2H), 6.02-6.01 (d,1H),5.39-5.33 (m,1H),5.31 (s,1), 5.15 (s,lH) '4.58-4.51 (t,lH), 4.45-4.32 (m'3H). Example 119 (S)-5-fluoromethyl-2-(2',3 ',5'-trifluorobiphenyl-4-yloxyindenyl)_2,3_dihydro-decane and [3,2-a]β-bite-7-g

Following the procedure described in Example 116, (S)-5-fluoroindol-7-keto-2,3-dihydro-7H-4oxazolo[3,2-a] Pyrimidine-2-yl decyl ester (0.282 mmol) and 2',3',5'-trifluorobiphenyl-4-ol (0.31111111 〇1) gave 83.4 11 (73%). [a]D25 = -6.6. (c = 0.68 'DMSO). 175 201121978 C20H14F4N2O3 ( 406.09 ), LCMS (ESI): 407.06 (M++H). ]H NMR ((CDC13) &gt; 300MHz) δ : 7.47-7.45 (d » 2H) &gt;6.99-6.96 (d, 2H) , 6.95-6.85 (m, 2H), 6.01-6.00 (d, 1H), 5.39-5.32 (m,1H), 5.30 (s,1H), 5.15 (s,1H) » 4.57-4.51 (t,1H) , 4.44-4.30 (m,3H). Example 120 (S)-2-(2'-Trifluoromethylbiphenyl-4-yloxyindenyl)-2,3-dihydrooxazolo[3,2-a]pyrimidine.定-7 - The same

Follow the procedure described in Example 117, from the indole-4-sulfonic acid (S)-7-keto-2,3-dihydro-7Η-σ number and [3,2-a] shouting -2- Base brewing (0.31 mmol) and 2'-trifluorodecylbiphenyl-4-ol (0.34 mmol [from 4-iodophenol and 2-trifluorodecylphenylboronic acid]) to prepare 15.3 mg (13%) ) title compound. C20H15F3N2O3 ( 388.10), LCMS (ESI): 389.09 (M++H). !H NMR ((CDCI3) &gt; 300MHz) δ : 7.74-7.72 (d &gt; 1H) &gt; 7.57-7.52 (t ' 1H), 7.48-7.43 (t, 1H), 7.31 - 7.24 (m, 3H) , 6.92-6.89 (d, 1H), 6.08-6.05 (d, 1H), 5.37-5.31 (m, 1H), 4.44-4.30 (m, 4H). Example 121 176 201121978 (S)-2-(2'_Ethylbiphenyl-4-yloxymethyl)_2,3-dihydrooxazolo[3,2-a]pergend-7-one

According to the procedure described in Comparative Example 3, from the indole-4-ylsulfonic acid (S)-7-keto-2,3-dihydro-7H-oxazo[3,2-a]pyrimidin-2-yl 63.4 mg (57%) of the title compound were obtained from decyl ester (0.31 mmol) and 2,-ethyl-biphenylbiphenyl-4-ol (0.34 mmol [from 4-iodophenol and 2-ethylphenylphenylboronic acid]). . [a]D25 = -4·3. (c = 0.46 'DMSO). C21H18N204 ( 362.12), LCMS (ESI): 363.11 (M++H) 〇4 NMR ((CDC13), 300MHz) δ: 7.37-7.34 (m,2H), 7.32-7.25 (m,2H),7.22-7.11 (m,2H), 6.96-6.93 (d, 1H), 6.88-6.85 (d,1H), 6.84 (s,1H), 6.05-6.03 (d, 1H), 5.34-5.31 (m,1H), 4.47 -4.24 (m, 4H), 3.05-2.96 (m, 1H), 1.16-1.14 (d, 6H). Example 122 (S)-2-(3·-Methylbiphenyl-4-yloxyindenyl)_6-methyl-2,3-dihydro-sigma-azolo[3,2_^°密定定- 7-ketone

Will contain (S)-5-(3'-methylbiphenyl-4-yloxyindenyl)-4,5-dihydro alpha carbazole-2-amine (0.4 g '1.4 mmol) and 2-oxime The mixture of ethanol (20 ml) of 177 201121978 was heated under reflux for 18 hours. The solution was concentrated and the residue was taken ethyl acetate (10 ml). The precipitate formed was collected to give the title compound a melting point of 212-150 C (0.058 g, 6%). [a]D25 = -6.4. (c = 0.72, DMSO). C2iH2〇N2〇3 ( 348.40) » LCMS (ESI) : 349.12 (M+H) ]H NMR (DMSO-d6 &gt; 300 MHz) » 67.70 (s &gt; 1H) » 7.58- 7.62 (d, 2H), 7.28-7.46 (m,3H),7.15-7.18 (d,lH), 7.00-7.06 (d ' 2H) ' 5.32-5.40 (m,1H),4.32-4.45 (m, 3H ),4.10-4.18 ( m , 1H ), 2.52 ( s, 3H ), 1.80 ( s, 3H). Example 123 (S)_2-(3'-cyclopropylbiphenyl-4-yloxyindenyl)_2,3-dihydrotetrazolo[3,2-a]pyrimidine-7-anthracene

Step 1 · · 3'-bromo-biphenyl-4-yl acetate will be 4-iodophenyl acetate (prepared from 4-iodophenol and acetamidine) (2.6 g, 10 mmol), 3-bromophenyl Boric acid (4.0 g, 20 mmol), tetrakis(triphenylphosphine) 60 ml of 1,0-methoxyethanol of (0) (1.0 g, 0.86 mmol) and 2 碳酸 sodium carbonate solution (6 ml) The mixture was heated under reflux for 6 hours. The mixture was cooled and poured into an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified mjjjjjjjjjjj The product I-containing fractions were combined and evaporated. The residue was recrystallized from heptane to give the title compound (m. Step 2: 3'-cyclopropylbiphenyl-4-yl acetate will contain 3·-bromo-biphenyl-4-yl acetate (0.68 g, 2.33 mmol), cyclopropyl stearic acid (0.25 g, 2.9 Methyl), acetic acid, bar (〇.〇25g, 0·11 mm〇i), tricyclohexylphosphine (0.65 g '2.3 mmol) and saponin tris (1.7 g, 7.7 mmol) in water (2 ml) The toluene (60 ml) mixture was heated under reflux for 6 hours. The mixture was added to water and extracted with ethyl acetate (15 mL). The organic layer was washed with water and dried over magnesium sulfate. The filtrate was evaporated and the residue was purified eluting elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut Biphenyl-4-ol in 3°/〇 sodium hydroxide (4 ml) and water (3 ml) in ethanol (15 ml), 3,-cyclopropylbiphenyl-4-yl acetate ( 0.3 g, 1.2 mmol) of the mixture was heated to form a solution. The solution was stirred at room temperature for a few hours. The mixture was poured into water (50 ml) and acidified with concentrated hydrochloric acid. The mixture was extracted with EtOAc (1 mL). The filtrate was evaporated to give the title compound as an oil (2 g, 80%). Step 4: 0)-2-(31.cyclopropylbiphenyl-4-yloxymethyl)_2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one 179 201121978 Indole-4-sulfonic acid (S)-5 morpholinoindol-7-one-2,3-dihydro-7Η·唠β sits and [3,2-a]e-den-2-yl Mixture of vinegar (0.4 g, 1.2 mmol), 3'-cyclopropylbiphenyl-4-ol (0.3 g, 1.4 mmol) and cesium carbonate (0.45 g, 1.4 mmol) in dry acetonitrile (20 ml) 2 hours. The mixture was poured into aqueous sodium hydrogencarbonate and extracted with ethyl acetate (150 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was purified by reverse phase HPLC for 20 min' eluting with 10-100% (acetonitrile-0.1% trifluoroacetic acid). The product-containing fractions were combined, washed with aq. The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was crystallised eluted elute The title compound ( 014 g, 32%) was obtained. [a]D25 = -18.4 0 ( c = 0_73, DMSO) C22H20N2〇3 ( 360.41 ) » LCMS (ESI) : 361.16 (M+H) iHNMR (DMSO_d6,300 MHz), $7.76-7.79 (d,1H), 7.59-7.62 (d,2H), 7.26-7.37 (m,3H) 6.99-7.04 (m, 3H) ' 5.82-5.84 (d,1H), 5.35-5.37 (m,1H),4.32-4.45 (m, 3H) » 4.10-4.16 (m,lH) , 1.93-2.02 ( m,1H) &gt; 0.91-1.11 (m,2H) ' 0.71-0.80 (m, 2H). Example 124 (8)-2-(2,3-1,4-indenylbiphenyl-4-yloxyindenyl)_2,3_dihydropyrano[3,2_small. D--7-ketone

180 201121978 The title compound was obtained according to the procedure of Example 49 and using toluene_4_retinyl (S)-7-keto-2,3-dicarbazolo[3,2-a]pyrimidinylmethyl ester, Preparation of a mixture of 2,3,-diindenylbiphenyl-4-ol (prepared from 4-indolyl acetate and 2,3-dimethylphenylboronic acid) and cesium carbonate. Example 125 (S)-2-(2'-i^Hexylbiphenyl-4-yloxymethyl)_2,3-dihydrooxazolo[3,2-small oxime-7-one

〇···, / Step 1: 2'-Cyclohexylbiphenyl-4-ol will contain 2-bromocyclohexylbenzene (2.39 g '10 mmol), 4-hydroxyphenylboronic acid (2.4 g '18 mm〇) l), tetrakis(triphenylphosphine)palladium (0) (! 〇g, 〇% mm〇1) and 2M sodium carbonate solution (4 ml) of 60 ml 1,2-dimethoxyethanol mixture is heated under reflux 18 hour. The mixture was cooled and poured into an aqueous solution of ammonium sulfate. The mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified eluting eluting eluting eluting eluting The second portion of the product fractions were combined and evaporated to give the product (0.45 g, 18%). Step 2: (S)_2_(2,_cyclohexylbiphenyl_4_yloxyindenyl)_2,3-dihydrooxazolo[3,2-a]pyrimidine_7-one 181 201121978 4-sulfonic acid (S)-5 morpholinoindol-7-keto-2,3-dihydro-7H-obxazo[3,2-a]pyrimidin-2-ylindole (0.38 g) A mixture of 1.19 mmol), 2,-cyclohexylbiphenyl-4-ol (0.3 g, 1.19 mmol) and cesium carbonate (0.39 g, 1.19 mmol) in anhydrous acetonitrile (20 ml) The mixture was added to aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (1 mL). The organic layer was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was taken from ethyl acetate (10 ml). The insoluble material was collected to give the title compound (0.15 g, 31%). C25H26N203 (402.49), LCMS (ESI): 403.19 (M+H) 4 NMR (DMSO-d6 ' 300 MHz), $7.77-7.80 (d,1H), 7.30-7.38 (m ' 2H), 7.08_7.28 ( m,4H) 7.00-7.02 (d, 2H) ' 5.82-5.85 (d,1H) ' 5.36-5.38 (m,1H),4.33-4.46 (m'3H),4.12-4.18(m,lH), 2.50 -2.63 (m, lH), 1.63 - 1.72 ( m &gt; 4H ) &gt; 1.4M.49 ( m &gt; 2H ) &gt; 1.06-1.24 ( m &gt; 4H). Comparative Example 1 (S)-5-(l,l-difluoro-propyl)_2-(3'-isopropylbiphenyl-3-yloxyindenyl)_2,3_dihydroanthracene[ 3,2-a] mouth bite -7-g with

Step 1. 4-oxohexan-2-acid vinegar 182 201121978 In a solution of 4-hydroxyhexyne-2-acid broth (ug, 1 〇·55 mm 〇1) in dichloromethane (30 ml) Add Dess-Martin high iodine reagent (6.0 g, 14.14 mmol) and stir at room temperature for 18 hours. Additional high iodine reagent (4.5 g) was added to the reaction mixture and stirred at room temperature for 6 hours. An aqueous solution of NaHC〇3 was added to the reaction mixture, and the precipitate was filtered and washed with dioxane. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. C7H803 (140.04) NMR ((CDC13), 300MHz) δ: 3.84 (s, 3H), 2.70-2, 63 (q, 2Η), 1.19-1.14 (t, 3Η). Step 2: 4,4-difluorohexyne-2-oxoate was added to a solution of 4-oxohexan-2-acid vinegar (1.48 g, 10.55 mmol) in dioxane (100 ml). Diethylaminosulfur trifluoride (daST) (5.1 g, 31.7 mmol) was stirred at room temperature for 18 hours. The reaction mixture was poured into crushed ice and stirred for several hours. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. c7H8F202 (162.04) NMR ((CDC13), 300MHz) δ: 3.84 (s, 3H), 2.15-2.05 (m, 2Η), 1.14-1.09 (t, 3Η). Step 3: Indole-4-sulfonic acid (S)-5-(l,l-difluoro-propyl)-7-keto-2,3-dihydro-7H-indazolo[3,2- a]pyrimidin-2-yl decyl ester 183 201121978 In the presence of indole benzene-4·sulfonic acid (S)-2-amino-4,5-dihydrooxazolo-5-yl decyl ester (2.17 g, 8.02 mmol To a solution of ethanol (10 ml) was added methyl 4,4-difluorohex-2-carboxylate (1.30 g, 8.02 mmol). The reaction mixture was stirred at reflux temperature for 2.5 hours. The mixture was cooled to room temperature, concentrated in vacuo and purified eluting elut elut elut elut eluting C17H18F2N205S (400.09), LCMS (ESI): 401.10 (M++H). 'H NMR ((CDC13) &gt; 300 MHz) : δ 7.77-7.75 (d » 2H) »7.39-7.36(d'2H), 6.17(s,lH),5.16-5.09(m,lH),4.50- 4.44 (t'lH), 4.34 - 4.29 (m'3H), 2.47 (s, 3H), 2.29-2.12 (m, 2H), 1.7-1.12 (t, 3H). Step 4: (S)-5-(l,l-Difluoro-propyl)-2-(3'-isopropylbiphenyl-3-yloxyindenyl)-2,3-dihydrol sitting And [3,2-a]^a -7-酉 in the pyrene-containing 4-sulfonic acid (8)-5-(l,l-di-d-propyl)-7-keto-2,3-dihydro To a solution of -7H-carbazolo[3,2-a]pyrimidin-2-yl decyl ester (75 mg, 0.188 mmol) in acetonitrile (6 ml) was added 3 _ isopropylbiphenyl-3-ol ( 6 〇 mg, 〇281 mmol) cesium carbonate (1〇7 mg, 0.325 mmol). The reaction mixture was stirred at reflux temperature until the reaction was completed. The reaction mixture was cooled with EtOAc EtOAc m. The product was purified by silica gel column chromatography eluting eluting eluting eluting eluting eluting [a]D25 = +1 7. (c = 0.54, DMSO). 184 201121978 C25H26F2N203 (440.19) ' LCMS (ESI) : 441.19 (M++H). NMR ( (CDC13 ), 300MHz ) δ : 7.40-7.33 ( m,4H ), 7.24-7.23 (d,1H),7.07 (S,1H), 6.86-6.83 (d,lH), 6.23 (s,1H) , 5.32-5.26 (m, 1H), 4.54-4.41 (m, 3H), 4.33-4.29 ( d ' 1H ) ' 3.02-2.93 ( m ' 1H ), 2.37-2.20 ( m, 2H), 1.31-1.29 ( d, 6H), 1.16.10.10 (t, 3H). Comparative Example 2 (S)-5-(l,l-Difluoro-propyl)-2-(2',3,-dimercaptobiphenyl-3-yloxyindenyl)_ 2,3- Dihydrocarbazo[3,2-a]pyrimidin-7-one

According to the procedure described in Comparative Example 1, 'from pyrene- 4_sulfonic acid (S)-5-(l,l-di-(trimethyl-propyl)-7-keto-2,3-dihydro-7Η-α No. [3,2-a] ° 密-2-基曱酉(0.188 mmol) and 2',3'-dimethylbiphenyl-3-ol (0.34 mmob [from acetic acid 3- Iodophenyl ester and 2,3,didecylphenylboronic acid]) 32 9 mg (41%) of the title compound. C24H24F2N203 (426.17), LCMS (ESI): 427.17 (M++H). 7.11 (m,2H) ' 7.05-7.03 (d,1H), 6.97-6.94 (d,1H), 6.84-6.82 (d'lH)'6.80(s,iH),6.22(s,lH),5.29- 5.24 ( m,1H) &gt; 4.56-4.48 ( m &gt; 2H ) , 4.42-4.39 ( dd, 185 201121978 1H), 4.28-4.24 (dd,lH), 2.34 (s,3H),2.31-2.17 (m , 2H), 2.13(s, 3H), 1_18_1.13 (t, 3H). Comparative Example 3 (S)_2-(3'-Ethylbiphenyl-3-yloxyindenyl)-2,3-dihydro π. Sit and [3,2-a] mouth bite -7-ketone

Step 1. 1-(3·-Pentylbiphenyl-3-yl)-Ethene J

3-iodophenol (2.0 g, 9.1 mmol), 3-ethylmercaptophenylboronic acid (1.97 g, 12.0 mmol), dichloro[1,anthracene-bis(diphenylphosphino)ferrocene]palladium (II) To a mixture of a gas-fired adduct (0.743 g '0.91 mmol) and cesium carbonate (5.92 g ' 18.2 mmol) was added 1-4-dioxane (9 ml) and water (3 ml). The reaction mixture was heated in a microwave reactor at 1 ° C for 22 minutes. The mixture was cooled to room temperature&apos; ethyl acetate and water were added and the contents transferred to a sep. funnel. The organic phase was washed with water and brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -(3,-trans-phenylphenyl-3-yl)·ethanone. C14H1202 (212.25), LCMS (ESI): 213.08 (M++H). NMR ((CDC13), 300MHz) δ: 8.17 (s, 1H), 7.94-791 (d '1H), 7.78-7.75 (d, 1H), 7.54-7.51 (t, 1H), 7.35- 186 201121978 7.30 ( t, lH), 7.18-7.15 (d, lH), 7.13 (s, lH), 6.91 - 6.89 (d, lH), 6.17 (bs, lH), 2.66 (s, 3H). Step 2: (S)-2-(3'-Ethylbiphenyl-3-yloxyindenyl)-2,3-dihydro$oxazo[3,2-a]pyrimidin-7-one

In the case of indole-containing benzene-4-heteroic acid (S)-7-keto-2,3-diaza-7Η-π-pyrano[3,2-a]σ-denidine-2-yl vinegar ( 100 mg, 0·31 mmol) of B. (7 ml) was added 1-(3'-P-biphenyl-3-yl)-ethanone (73 mg, 0.34 mmol) cesium carbonate (142 mg) , 0.435 mmol). The reaction mixture was stirred at 35-45 ° C for 18 hours. The reaction mixture was cooled to room temperature and passed through a tear. The mixture was concentrated in vacuo and purified by EtOAc EtOAc elut elut elut elut elut elut C21H18N204 ( 362.38), LCMS (ESI): 363.08 (M++H). lR NMR ((CDC13), 300MHz) δ: 8.13 (s, 1H), 7.94-7.91 (d, lH), 7.76-7.74 (d, lH), 7.55-7.50 (t, lH), 7.40-7.23 (m , 3H), 7.11 (s, lH), 6.91-6.88 (d, lH), 6.04-6.02 (d, 1H), 5.39-5.31 (m, 1H), 4.47-4.43 (q, 1H), 4.40-4.30 (m, 3H), 2.65 (s, 3H). Comparative Example 4 (S)-2-(2',3'-Dimercaptobiphenyl-3-yloxyindenyl)-2,3-dihydrooxazolo[3,2-a]- 7-keto 187 201121978

According to the procedure described in Comparative Example 3, (S)-7-keto-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2- Base oxime ester (0.31 mmol) and 2,3,-dimercaptobiphenyl-3-ol (0.34 mmol, from 3-iodophenyl acetate and 2,3,didecylphenylboronic acid)) 44.5 mg (41%) of the title compound. [a] D25 = -3.1 0 (c = 0.65, DMSO). C21H2〇N203 (348.40), LCMS (ESI): 349.11 (M++H). lR NMR ( (CDC13 ) &gt; 300ΜΗζ) δ : 7.31-7.26 ( m &gt; 2H ) ' 7.15-7.09 (m ' 2H), 7.05-7.02 (d, 1H), 6.95-6.93 (d, 1H), 6.86 -6.83 (d,1H),6·79 (s,1H),6.03-6.00 (d, 1H) &gt; 5.35-5.28 ( m &gt; 1H) &gt; 4.47-4.41 (t » 1H), 4.38-4.24 (m, 3H), 2.33 (s, 3H), 2.12 (s, 3H). Comparative Example 5 (S)-2-(2',3'-di-biphenylbiphenyl-3-yloxymethyl)_2,3-dihydrotetrahydropyrano[3,2-a] 7-ketone

According to the procedure described in Comparative Example 3, from the indole-4-ylsulfonic acid (s)-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-yl Ethyl ester (0.31 mmol) and 2,3,-di-biphenyl-3-ol (0.34 mmol, from 3-iodophenol and 2,3-diphenylphenyl boron 188 201121978 acid) were prepared to obtain 68.3 mg ( 56%) title compound. [oc] D25 = -1.9 ° (c = 0.73, DMSO). C19H14C12N203 (388.03), LCMS (ESI): 389.04 (M++H). 1H NMR ((CDCl3), 300MHz) S: 7.47-7.44 (d, lH), 7.37-7.21 (m, 4H), 7.04-7.01 (d, 2H), 6.92-6.89 (d, 2H), 6.02-5.99 ( d, 1H), 5.37-5.30 (m, 1H), 4.51-4.45 (t, 1H), 4.40-4.25 (m, 3H). Comparative Example 6 (S)-2-(3'-Isopropylbiphenyl-3-yloxymethyl)-2,3-dihydrooxazolidine|; 3,2-a]pyrimidine-7- ketone

Follow the procedure described in Comparative Example 3 from toluene-4-sulfonic acid (S)-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-ylindole The ester (0.31 mmol) and 3,-isopropylbiphenyl-3-ol (0.34 mmol 'from 3-mothol and 3-isopropylbenzene boronic acid) afforded 48.0 mg (43%) of the title compound. [a]D25 = _6.5. (c = 0.46 'DMSO). C22H22N203 ( 362.16) ' LCMS (ESI): 363.16 (M++H). NMR ( (CDC13 ) , 300MHz ) δ : 7.40-7.34 ( m,3H ), 7.31-7.30 (d'lH) '7.26-7.21 (m,3H),7_07(s,lH), 6.85-6.82 ( d ' 1H ) ' 6.03-6.00 ( d,1H ), 5.34 - 5.29 ( m, 189 201121978 1H), 4.48-4.41 (t ' 1H) ' 4.40-4.30 (m,3H), 2.99-2.92 (m,1H), 1.28-1.26 (d,6H) 〇Comparative Example 7 3'-((S)-7-keto-2,3-dihydro-7H-oxazolo[3,2.4]pyrimidin-2-yloxyl Biphenyl-3-B guess

According to the procedure described in Comparative Example 3, from phenylene-4-sulfonic acid (s)-7-keto-2,3-dihydro-7H-indolo[3,2-a]pyrimidin-2-yl Ester (0.31 mmol) and 3,-hydroxybiphenyl-3-acetonitrile (0.34 mmol, from 3-iodophenol and 3-cyanophenylboronic acid) afforded 87.3 mg (82%) of the title compound. [a]D25 = _74. (c = 0.72, DMSO). C2〇H15N303 (345.11), LCMS (ESI): 346.11 (M++H). JH NMR ((CDC13), 300MHz) δ: 7.81-7.76 (m, 2H), 7.64-7.61 (d, 1H), 7.56-7.51 (t, 1H), 7.41-7.36 (t, 1H), 7.32-7 , (30, d, 1H) ), 4.52-4.31 (m, 4H). Comparative Example 8 (S)-2-(2',3i-Dimethylbiphenyl-3-yloxyindenyl)-6-ethyl-2,3-dihydrocarbazolyl [3,2- a] pyrimidine-7-one 190 201121978

Step 1: (S)-5-(3-nonylphenoxy)-anthracene, etc. NYJ&gt;...

I will contain toluene-4-sulfonic acid (8)-2-amino-4,5-dihydrocarbazolyl-5-yl decyl ester (1 〇 g, 3.69 〇 1), 3 _ benzene benzene ( A solution of 0·812 g, 3 69 〇1) and acetonitrile (1.74 g' 5.40 mmol) in acetonitrile (50 ml) was stirred at reflux temperature until 7 C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was transferred to a separatory funnel, and the organic fraction was separated, washed with water, dried with NaJO4, concentrated in vacuo, and purified by silica gel column chromatography to give (〇_1〇%) decyl alcohol in dichloromethane. The elution gave 0.40 g (34%) of the title compound.

Ci〇HuIN2〇2 (317.98), LCMS (ESI): 319.0 (M++H). 'H NMR ( (CDC13 ) ' 300MHz ) δ : 7.33-7.27 ( m,2H ), 7.03-6.98 ( t,1Η ), 6.90-6.86 ( d,1H ), 4.95-4.87 ( m, 1H) '4.45- 4.40 (bs'2H), 4.09-3.88 (m, 3H), 3.64-3.57 (q, 1H). Step 2: (S)-6-Ethyl-2-(3-iodophenoxyindenyl)_2,3_dihydrooxazolo[3,2_a]pyrimidine-7-酉

191 201121978 Add ethyl 2-mercaptobutyrate in a mixture of (S)_5-(3-iodophenoxy)-oxazolin-2-amine (2.17 g, 6.82 mmol) in ethanol (20 ml) (1.47 g ' 10.2 mmol) 'The mixture was stirred at reflux temperature for 40 hours. The mixture was cooled to room temperature, concentrated in vacuo and purified eluting eluting eluting eluting eluting eluting eluting eluting with C15H15IN203 (398.02), LCMS (ESI): 398.98 (M++H). *H NMR ((CDC13) * 300MHz) δ : 7.36-7.34 (d &gt; 1Η) &gt; 7.24 (s ' 1H) ' 7.05 (s ' 1H), 7.04-6.99 (t, 1H), 6.87-6.84 ( d, lH), 5.29-5.22 (m'lH), 4.41-4.38 (t, lH), 4.33-4.21 (m, 3H) ' 2.48-2.40 (q, 2H), 1.18-1.15 (t, 3H). Step 3: (S)-2-(2',3*-dimercaptobiphenyl-3-yloxyindenyl)_6_ethyl_2,3_dihydro 0#w and [3,2 The -ap cleavage-7-one will contain (S)-6-ethyl-2-(3-benzophenoxymethyl)-2,3-dihydroindole [3,2-a]. Midine-7-one (0.063 g, 0.162 mmol), 2,3, dinonylphenylboronic acid (〇_036 g, 0.243 mmol), diox[1,1, bis(diphenylphosphino)di a mixture of ferrocene]palladium (π) chlorohydrazine calcined adduct (0.016 g '0.02 mmol) and cesium carbonate (0.132 g, 0.405 mmol) in 1,4-dioxane (6 ml) and water (1 ml) Stir at room temperature for 4 hours and then at 40 ° C for 3 hours. The mixture was cooled to room temperature, ethyl acetate and water were added and the contents transferred to a sep. funnel. The organic phase was washed with water and brine, dried over Na~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ) title compound. 192 201121978 C23H24N2O3 (376.17) ' LCMS (ESI) : 377.16 (M++H). NMR ((CDC13), 300MHz) δ: 7.34-7.29 (t,1H),7·18 7.10 (m'2H) '7.05-7.03 (m,2H),6.96-6.93 (d,lH), 6.86-6.83 (d ' 1H) ' 6.80 (s,1H), 5.27-5.23+ (m,1H), 4.42-4.24 (m,4H) , 2.47-2.40 ( q,2H) , 2.33 ( s,3H), 2.13 ( s, 3H), 1.16-1.12 (t, 3H). Comparative Example 9 (S)-6-Ethyl-2-(3'-isopropylbiphenyl-3-yloxyindenyl)-2,3-dihydro π. Sit and [3,2-a]pyrimidin-7-one

According to the procedure described in Comparative Example 8, from (s)-6-ethyl-2-(3-iodophenoxymethyl)-2,3-dihydrooxazolo[3,2-a]pyrimidine-7 - ketone (0.344 mmol) and 3-isopropylphenylboronic acid (0.52 mmol). [a] D25 = +7.8 0 (c = 0.65, DMSO). C24H26N203 (390.19), LCMS (ESI): 391.18 (M++H). !H NMR ( (CDCI3 ), 300MHz ) δ : 7.40-7.33 ( m,4H ), 7.25-7.23 (d ' 2H) ' 7.09-7.06 (d,2H),6.87-6.84 (d ' 1H), 5.29- 5.24 (m,1H),4.43-4.28 (m,4H),3.02-2.93 (m,lH),2.47-2.42 (q,2H),1.31-1.29(d,6H),1.17-1.12 (t,3H ). 193 201121978 Comparative Example ίο (S)-2-(Biphenyl-3-yloxymethyl)-2,3-dihydroindole[3,2-a&gt;

(S)-7-keto-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-yl decyl ester (1.5 g, 4.7 mmol) , a mixture of biphenyl-3-ol (prepared from 3-bromophenol and phenyl tartaric acid) (0.8 g, 4.7 mmol) and cesium carbonate (i.5 g, 4.7 mmol) in 30 ml of anhydrous acetonitrile, heated under reflux for 1 hour . The mixture was concentrated, and the residue was crystallisjjjjjjjjj The organic layer was dried over magnesium sulfate and filtered. The filtrate was purified by reverse-phase HPLC for 20 min, eluted with 1 〇 1 〇〇〇 /0 ( acetonitrile - 01% trifluoroacetic acid), and the product fraction was concentrated by lyophilization to give the title compound ( 35%). C19H16N2〇3 ( 320.35 ), LCMS (ESI): 321.12 (M+H) 4 NMR (DMSO-d6 ' 300 MHz) δ: 7.80 ( d,1H), 7.66 (d ' 2H) ' 7.37-7.46 (m, 4H), 7.21-7.25 (m, 2H), 6.83 (d ' 1H), 5.83 (d ' 1H) ' 5.34-5.38 (m, 1H), 4.42-4.49 (m, 3H) , 4.11-4.17 (m, 1H). Comparative Example 11 (S)-2-(2'-Methylbiphenyl-3-yloxyindenyl)_2,3-dihydrooxazolo[3,2-a]pyridin-7-one 194 201121978

The procedure described in Example 117 'from (S)-2-indolyl-4-sulfonic acid mercapto-2,3-dihydro alpha-azo[3,2-a]pyrimidin-7-one (0.31 mmol) And 2'-mercaptobiphenyl-3-ol (0.34 mmol, prepared from 3-indenebenzene and 2-mercaptophenyl acid) gave 40.3 mg of the title compound. C2〇H18N203 (334.13), LCMS (ESI): 335.12 (M++H). ]H NMR ((CDC13), 300MHz): δ 7.32-7.16 (m, 6H), 6.97-6_95 (d ' 1H), 6.87-6.81 (m, 2H), 6.03-6.01 (d, 1H), 5.35- 5.28 ( m,1H) , 4.44 - 4.4.3 ( t,1H ) 4.37-4.24 ( m, 3H), 2.24 ( s, 3H). Comparative Example 12 β密定定-7-酉(S) 2 (2-fluoroindolyl-3-yloxyindenyl)-2,3-dihydro-s-[3,2_a]

According to the example, the compound is acid methyl -23-- and TM soil, - 虱 11 azole and [3 _ ___ alcohol [from 3 iodine phenol and oxime: γ 疋钿肊 117 117 Said step, from (s)_2_曱benzene_4 dioxin and saliva[3,2_a]pyrimidine _7_ 酉 and mz-ard, - Ming and 2, _trifluoroindolyl stupid difluoroindolyl The preparation of the epirubic acid]]). Biological Examples Example 125 195 201121978 The Ion (Ca2+) shift assay was used to identify and assay the activity of allosteric modulators of the rat or human mGluR2 receptor. Two modes were used: (1) Observing the concentration/response curve of the compound at different apical oleic acid concentrations to test the glutamic acid __effect (IV) ability, and (1) observing the face acid concentration _ response curve at the highest brood concentration To observe the ability of the modulator to affect the performance of the face acid. In order to monitor the functional receptor response for _ ion mobility analysis, a mGluR2 receptor stably expressing the atmosphere or human is produced in a tetracycline-inducible vector (usually through an inhibitory G protein Gai and its intracellular effector). Coupling) and cell lines of Ga!6. By activating phospholipase cp, Gal6 can confuse &amp; and the coupled receptor with the inositol fat-filled signaling pathway to produce a Ca2+ signal (usually Gaq-mediated). Plate reader monitoring, such as FLIPR (Molecular Devices, Fluorescence Imaging Plate Reader) ' FDSS6000 ( Hamamatsu, Fluorescence Drug

Screening System ) ' or FlexStation ( Molecular Devices ) ° Ca2+ mobile assay is based on the detection of changes in intracellular calcium flux using a selective calcium chelate dye: Fluo-3, Fluo-4, or Calcium-3. A significant increase in fluorescence intensity was observed when calcium was combined with the dye. The dye is delivered with acetoxymethyl ester&apos; and then washed away. A disposable kit (Molecular Devices) can also be used. The glutamate-stimulated fluorescence signal was recorded and used to generate the following pharmacological parameters: (1) the potency (EC50) of the compound studied for rat and human mGluR2 receptors, respectively, when glutamic acid was approximately EC10, and (2) The fold change in glutamate EC50 due to the highest concentration of the compound studied. 196 201121978 In general, the compounds of the invention show a good mGluR2 enhancing effect (EC50). Broadly speaking, the compounds of the invention have an activity range of about _ 1000 nM, and some compounds show an increase in mGiuR2 of 1 _ 1 〇〇. The results of the compounds of formula (1) of the present invention which were tested in accordance with this procedure have been summarized in Table 1 and wherein mGluR2 enhancement (EC5〇) is listed. For the purpose of comparison, mGluR2 enhancement (EC50) obtained from the corresponding meta-phenoxymercapto compound described herein as a comparative example is also listed.

Table I Example mGluR2 Enhancement (nM) Comparative Example mGluR2 Enhancement (nM) 2 32 5 122 49 49 11 395 57 19 8 44 58 109 10 528 120 30 12 471 124 36 4 109 The compound of the formula (I) of the present invention is treated as herein The efficacy of the disclosed various diseases can be confirmed by any method known to those skilled in the art. For example, the efficacy of treating anxiety disorders can be confirmed by Vogel conflict experiments. See, for example, Tatarczynska et al., Psychopharmacology (Berl). 2001 Oct; 158(l): 94-9', which is incorporated herein by reference in its entirety. In the case of 197 201121978, Tatarczynska et al. showed an anti-anxiety-like effect of Group I antagonists and Group II agonists and Group III metabotropic glutamate receptors. Preclinical models of anxiety and psychosis also include stress hyperthermia, fear of increased fear, and hyperactivity caused by PCP. See R〇rick-Kehn et al., J. Pharmacol. Exp. Ther. 2006 Feb; 316(2): 905-13. Epub 2005 Oct 13. See also Johnson et al., Psychopharmacology (Berl). 2005 Apr;179(l):271-83. Epub 2005 Feb 17. Helton et al., J Pharmacol Exp Ther. 1998 Feb; 284(2): 651-660 used the fear-increasing scare model and the elevated plus maze model to show the anxiolytic effects and side effects of LY354740. LY354740 is a potent, highly selective, orally effective steroidal agonist of the metaphyseal glutamate receptor. Various anxiety models that show efficacy in human patients are also known in the art. See Kellner et al., Psychopharmacology (Berl). 2005 Apr;179(l):310-5. Epub 2004 Sep 30 &gt; This article reports metabotropic glutamate in healthy individuals (2/3 The effect of a receptor agonist on panic anxiety caused by cholecystokinin tetrapeptide. Further, the efficacy of the compound of the formula (I) of the present invention for treating schizophrenia can also be confirmed by various known models in the art. For example, hyperactivity caused by PCP, prepulse inhibition of PCP interruption, hyperthermia of stress, and elevated cross maze models have been used to demonstrate the efficacy of mGluR2 allosteric modulators. See, Galici et al., J Pharmacol Exp Ther. 2006 Jul; 318(1): 173-85. Epub 2006 Apr 11 'This article shows that a positive allosteric modulator of mGluR2, bifenosterone A', has Antipsychotic and anti-anxiety-like effects. 198 201121978 The efficacy of the compounds of formula (i) of the present invention in improving human working memory can be demonstrated by various methods known in the art. For example, Krystal et al., Psychopharmacology (Berl). 2005 Apr;179(l): 303-9. Epub 2004 Aug 10 reports pre-treatment with the π-group metabotropic glutamate receptor agonist LY354740, NMDA The glutamine receptor antagonist ketamine has a reduced damaging effect on working memory in healthy subjects. In another example, Patil et al., Nature Medicine. 2007 Sep; 13(9): l 102-7. Epub 2007 Sep 2. Reporting 'n-group metabotropic glutamate receptors compared to placebo The agonist LY2140023 showed a statistically significant improvement in both positive and negative symptoms of schizophrenia. The compounds of formula (I) of the present invention are also useful in the treatment of sleep disorders and depression. According to Feinberg et al., Pharmacol Biochem Behav. 2002, 73(2) 467-74, the selective mGluR2/3 receptor agonist LY379268 inhibits rapid eye movement (RJEM) sleep and rapid EEG in rats. Gewirtz et al., Pharmacol Biochem Behav. 2002 Sep;73(2):317,26 studied the expression of BDNF mRNA in the medial prefrontal cortex induced by mGluR2/3 agonists on hallucinogens and 5ht2a/2B/2C agonists Impact. See also Schechter et al., NeuroRx. 2005 Oct; 2(4): 590-611. Review, which provides an overview of innovative approaches to antidepressant drugs. The activity of the mGluR2 allosteric modulator in the pain model was also reported in the literature. See Jones et al., Neuropharmacology. 2005; 49 Suppl 1:206-18, in which the analgesic effect of a selective diterpene group (mGlu2/3) metabotropic alanine receptor agonist is disclosed. 199 201121978 The efficacy of the compounds of formula (i) of the present invention in the treatment of epilepsy can also be demonstrated by various methods used in the art. See, for example, Alexander et al., Epilepsy Res. 2006, 71(1), 1-22, for discussion of metabolic glutamate receptors as a strategic target for the treatment of epilepsy. See also Klodzinska et al., Pol J Pharmacol. 1999, 51(6), 543-5, which discloses the selective π-group metabotropic glutamate receptor agonist LY354740 to alleviate pentylenetetrazol and imprints. Seizures caused by anti-hexatoxin. Thomsen et al., Neuropharmacology, 1998, 37(12), 1465-73, disclose the role of the metabotropic glutamate receptor subtype in regulating seizures in mice induced by pentylenetetrazole. Finally, Thomsen et al., J Neurochem. 1994, 62(6), 2492-5 discloses (S)-4-carboxy-3-hydroxyphenylglycine, a metabotropic glutamate receptor (mGluR) An antagonist of la and an mGluR2 agonist prevent DBA/2 mice from hearing seizures. It has also been reported in the literature that regulation of the mGluR2 receptor also improves cognitive function. See, for example, Moghaddam, Psychopharmacology (2004) 174: 39-44. Accordingly, it has been further suggested that modulation of the mGluR2 receptor may also ameliorate cognitive deficits in patients with Parkinson's disease and Alzheimer's disease. For specific information on Alzheimer's, see Lee et al., Brain Research, 1249 (2009), 244-250; for Parkinson's disease, see Samadi et al., Neuropharmacology. ) 54 (2008) 258-268. Example 126 Stress hyperthermia (anxiety model) 200 201121978 Reflects mammals undergoing stress stimulation

Increased core body temperature after stress hyperthermia (SIIi). An improved rectal test procedure based on the Linqing paradigm, measured in mice. The mice that were individually maintained were subjected to two rectal temperature measurements at intervals of 10 minutes. The basal body temperature (Τ1) of the δ hai animal was paid in the first test, and the second temperature (T2) was the body temperature obtained after the mild stimuli caused by the first temperature measurement. The difference between the first temperature and the second temperature (T2 _ T1 or ΔΤ) is the SIH. The temperature was measured by inserting a lubricated thermistor probe into the rectum of each animal 2 cm, accurate to 〇.l〇C. The test compound was injected '60 minutes before the first temperature measurement so that any stress stimulating effects produced by the injection completely resolved. Although the present invention has been described with reference to a few embodiments thereof, it should be understood that the invention is not limited thereto, but it is understood that the present invention covers the general scope of the above disclosure. Various modifications and embodiments may be made without departing from the spirit and scope of the invention. 201

Claims (1)

201121978 VII. Patent application scope: 1 · A compound of formula I, Wherein: the core is selected from the group consisting of hydrogen, sulfhydryl, methoxymethyl, ethyl, 2-methylethyl and propyl; R2 is selected from the group consisting of hydrogen, sulfhydryl, fluoroindolyl, Ethyl, 2-fluoroethyl, propyl, l,l-difluoropropyl, decyloxydecyl, ethoxylated fluorenyl, 2-fluoroethoxyindenyl, ethoxy+fluoroethyl, Isopropoxy fluorenyl basic group, fluorenyl group, oxime ethyl group, hydrazinyl fluorenyl group, η ratio _ a decyl fluorenyl group, tetrahydrofuranyl fluorenyloxymethyl group, cyclopropyl group and cyclopentyloxy fluorenyl group; and R3, &amp;, R5, R6, R? and Rs may be the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF3, cardinyl, ((VC6)cycloalkyl, (crc4) Alkoxy; or two of R6, core and Rs on an adjacent carbon atom and together with a benzene ring form a naphthalene ring; or two of R6, R7 and R8 are on adjacent carbon atoms And together with the carbon atom to which they are attached form a five-membered or six-membered ring; or 202 201121978 R6, R7 and r8 one group and a phase ring; or a salt thereof. The adjacent benzene rings combine to form a 苐2 ·If Shen The compound of claim 1, wherein: Ri is selected from the group consisting of hydrogen, sulfhydryl and ethyl; and I is selected from the group consisting of hydrogen, sulfhydryl, oxymethyl, u_: , methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, isopropoxymethyl, phenyl, methyl, ethyl, morphinyl, pyrrolidinium a group, a cyclopropyl group and a cyclopentyloxy fluorenyl group; and 3 R4 R5 R6, R7 and R8 may be the same or different and are selected from the group consisting of nitrogen, gas, chlorine, desert, methyl radical: N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, cyclopropyl and ethoxy; or a salt thereof. The compound of claim 1, wherein: is hydrogen or ethyl; Han 2 is hydrogen; 3 ft 4, Rs, R6, R7 and R8 may be the same or different and are independently selected from each other A group of groups: hydrogen, fluorine, decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy and ethane groups; or a salt thereof. 203 201121978 4. The compound of claim 1, wherein: R1 is selected from the group consisting of hydrogen, sulfhydryl and ethyl; I is hydrogen; and ruler 3, R4, and R5 are hydrogen; 6. R? and two of the groups are on adjacent carbon atoms and form a naphthalene ring together with the benzene ring; or two groups of Han 6, R7 and &amp; on adjacent carbon atoms and with them The attached carbon atoms together form a five-membered or six-membered ring; or a salt thereof. The compound of claim 1, wherein the compound is selected from the group consisting of: '' (S)-2-(biphenyl-4-yloxyindenyl)_2,3-dihydrocarbazino[ 3,2_a]pyrimidin-7-one; (S)-2-(biphenyl-4-yloxyindenyl)·6·ethyl 2,3_dihydro-oxazolo[3,2_a]pyrimidine-7 -ketone; '(S)-2-(biphenyl-4-yloxyindenyl)_5_ fluorenyl 2,3-dihydrobenzo[3,2-a] ° dense. (-7)-2-(biphenylyloxycarbonylethyl)_2,3-dihydro:oxazolo[3,2-a]pyrimidin-7-one; (S) -2-(biphenyl-4-yloxyindenyl)-5-ethoxyindolyl-2,3-dihydro,oxazolo[3,2-a]pyrimidin-7-one; 204 201121978 (S) -2-(biphenyl-4-yloxymethyl)_5-iso[3,2-a]pyrimidin-7-one; propoxy fluorenyl hydrogen-σ 嗤(S)-2-(linked Benz-4-yloxymethyl)_5_cyclopentyloxymethyl-2-[3,2-a]pyrimidin-7-one; 'One wind-° can sit 0(S)-2-( Biphenyl-4-yloxyindenyl)-5-(tetrahydro-.furan-2-ylmethoxy 2,3-dihydro-oxazo[3,2-a]pyrimidin-7-yl; ^ ^ (S)-2-(Biphenyl-4-yloxyindenyl)-5-(2-fluoro-ethoxymethyl)_2,3_dioxin-π-azolo[3,2- a] pyrimidine-7-one; &gt; (S)-2-(biphenyl-4-yloxyindenyl)-5-fluoromethyl-2,3-dihydro-σ-oxazolo[3,2_a ] pyridin-7-one; '(S)-2-(3'_gas-terphenyl-4-yloxyindenyl)_2,3_dihydro-D-azolo[3 2_ Pyridin-7-one; ^(S)-2-(3i-indi-terphenyl-4-yloxyindenyl)_2,3-dihydro-afazo[3,2_a]pyrimidine-7- Ketone; (S)-2-(2-indolyl-biphenyl-4-yloxyindenyl)-2,3-dihydro-α-indole [3 2_a] (S)-2-(2-indolyl-biphenyl-4-yloxyindenyl)-2,3-dihydro-&lt;!αα[3 2_a]pyrimidine- 7-keto; (S)-2-(3'-mercapto-biphenyl-4-yloxyindenyl)-2,3-dihydro-α-wow [3 2_a] pyridin-7-one (S)-6-ethyl-2-(2-indolyl-biphenyl-4-yloxyindenyl)_2,3-dihydro-indole α-sodium[3,2-a]pyrimidine- 7-keto; (S)-6-ethyl-2-(2'-indolyl-biphenyl-4-yloxyindenyl)_2,3-dihydro-u. Sit and [3,2- a] pyrimidine-7-one; 205 201121978 (S)-2-(2·-indenyl-biphenyl-4-yloxyindenyl)·6-fluorenyl-2,3-dihydro-carbazole [3,2-a]pyrimidin-7-one; (S)-2-(3'-mercapto-biphenyl-4-yloxyindenyl)·6-methyl-2,3-dihydro- π 唾 并 [3,2-a] α α定-7-ketone; (S)-2-(2'-ethyl-biphenyl-4-yloxyindenyl)_2,3_dihydro- 11 find 11 sit and [3,2-a] mouth 唆-7-ketone; (S)-2-(2-ethyl-biphenyl-4-yloxyindenyl)_2,3_dihydro-11 Find 0 sitting and [3,2-a] 11 bite-7-ketone; (S)-2-(4'-ethyl-biphenyl-4-yloxyindenyl)_2,3_di I- 0 search wow and [3,2-a] pyrimidine-7-one; (S)-2-(3L ethyl-biphenyl-4-yloxymethyl)_2,3-dihydroazolo[3, 2_a] pyrimidine-7-one; (S)-6-ethyl-2 -(2'-ethyl-biphenyl-4-yloxymethyl)_2,3-dihydro-4-oxazolo[3,2-a]-mouth -7-one; (S)-2-( 2'-ethyl-biphenyl-4-yloxymethyl)_6_mercapto-2,3_dihydro:oxazolo[3,2-a]pyrimidin-7-one; (S)-2- (2-ethyl-biphenyl-4-yloxyindenyl)-6-methyl-2,3-dihydro-indeno[3,2-a]pyrimidin-7-one; (S)- 2-(4·-ethyl-biphenyl-4-yloxymethyl)_5-hydroxyindoleyl 2,3-dihydro-σ-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(4'-ethyl-biphenyl-4-yloxymethyl)_5_(2-hydroxy-ethyl)_2,3-dihydro-oxazolo[3,2-a] Pyrimidine-7-one; (S)-5-ethoxyindolyl-2_(4,_ethyl_linked stupidyl-4-yloxyindenyl)_2,3_diaza_oxazole [3] ,2-a]pyrimidin-7-one; 206 201121978 (S)-2-(4'-ethyl-biphenyl-4-yloxyindenyl)-5-isopropoxycarbonyl-2,3 - diar-argon + and [3,2-a]pyrimidin-7-one; (S)-2-(4'-ethyl-biphenyl-4-yloxyindenyl)_5_phenyl- 2,3-dicarbazo[3,2-a]pyrimidin-7-one; (S)-5-cyclopentyloxyindol-2-(4'-ethyl-biphenyl-4-yloxy) (2)3-dihydro-oxazolo P,2-a]pyrimidin-7-one; (S)-2-(4-ethyl-biphenyl-4-yloxyindenyl)- 5-(tetrahydro-η夫η南_2_基曱(indolyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(4'-ethyl-biphenyl-4-yloxy) Ethyloxymethyl 2.3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(3'-propyl-biphenyl-4-yloxyindole (2)2-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2'-isopropyl-biphenyl-4-yloxymethyl) _2,3_Dihydro-deca-[3,2_a]pyrimidin-7-one; (S)-2_(3'-isopropyl-biphenyl-4-yloxyindenyl)_2,3· Dihydro-π-azolo[3,2_a]pyrimidin-7-one; (S)-5-(2-fluoro-ethoxyindenyl)_2-(3,-isopropyl-biphenyl_4 _ yloxymethyl 2.3-dihydrogen σ sits and [3,2-a] singly -7-酉; (S)-5-fluoroindolyl-2-(3'-isopropyl-linked Benzene-4-yloxyindenyl)-2,3-dihydro-oxazo[3,2-a]pyrimidin-7-one; (S)-2-(3'-butyl-biphenyl- 4-yloxyindenyl)_2,3_dihydro-σ-oxazolo[3,2_a]pyrimidin-7-one; (S)-2-(3'-isobutylene-biphenyl_4_yl Oxyfluorenyl)_2,3_dihydro-π-[azolo[3,2_a]pyrimidin-7-one; 207 201121978 (S)-2-(3'-T-butyl-biphenyl-4- (S)-2-(3'-trifluorodecyl-biphenyl-4-) thio[3,2-a]pyrimidin-7-one; base (S)-2-(2'-trifluoromethyl-biphenyl-4-yl) oxo[3,2-a]pyrimidin-7-one; Oxymethyl)_2,3-dihydroπ-[3,2-a]pyrimidin-7-one; (S)-2-(3'-i- s-propyl-biphenyl-4-yloxy (S)-2-(2-cyclohexyl-biphenyl-4-yloxyindenyl)_2, (S)-2-(2-cyclohexyl-biphenyl-4-yloxyindenyl)_2, 3. Dihydro-σ-β-[3 2_ a]pyrimidin-7-one; (S)-2-(3-indolyl-biphenyl-4-yloxyindenyl)_2,3_2 Hydrogen-π number. Sit and [3 2_ a]pyrimidin-7-one; (S)-5-isopropoxymethyl_2_(4,_曱-oxy-biphenylyloxycarbonyl)_2,3_dihydro- Oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2'-Ethylbiphenyl-4-yloxymethyl)_2,3_dihydro-σ-azole And [3,2_a]pyrimidin-7-one; '(8)-2_(2',3'-difluoro-biphenylyloxycarbonyl)- 2,3-dihydro-indazolo[3, 2_ a]pyrimidin-7-one; (S)_2_(2,3-fluoro-biphenyl-4-yloxyindenyl)_5_decyloxyindenyl-2,3-dihydro-nfazole And [3,2-a]pyrimidin-7-one; (S)-2-(3',4'-difluoro-biphenyl-4-yloxyindenyl)_2,3_dihydro·10 And [3,2_a]pyrimidin-7-one; (S)-2-(2',3i-di-benzene-biphenyl-4-yloxymethyl&gt;2,3-dihydro-oxazole [3,2_a]pyrimidine-7-oxime; ' 208 201121978 (S)-2-(2',3'_di-biphenyl-4-yloxymethyl)_5_methoxyindolyl_ 2,3-Dihydro σ-salt [3,2-a]11-Bite-7-酉; (S)-2-(2,4i·Dichloro-biphenyl-4-yloxyfluorenyl) _2,3_Dihydro-π-azolo[3,2-a] dimethyl -7-one; (S)-2-(2',3'-di-biphenyl-4-yl Oxyfluorenyl)_5_mercapto-2,3-dihydro-oxazolo[3,2-a]^^-7-_; (S)-5·cyclopropyl-2_(2 , 3ι_二气_Biphenyl_4_yloxyindenyl)_2,3_dihydro-indoleazo[3,2-a]pyrimidin-7-one; (S)-2-(2' , 3'-diqi-biphenyl-4-yloxyindenyl)_5_fluoroindolyl-2,3_dihydro-. 寻 并[3,2-a]pyrimidin-7-one; (S )_2-(2 3'-di- gas-biphenyl-4-yloxyindenyl)_5_morphin-4-ylindenyl-2,3-dihydro-oxazolo[3,2-a] Pyrimidine-7-one; (S)-2-(2 3'-di-biphenyl-4-yloxymethyl)_5-»Bilo bite_1_ylmercapto_ 2,3-dihydro -α seeking saliva and [3,2-small bite _7_ ketone; (S)-2-(2,3'-diqi-biphenyl_4_yloxyindenyl)_5_ fluorenyl _ 2,3_Dihydro-oxime and P,2-a]pyrimidin-7-one; (S)-2-(2',3'-di-biphenyl-4-yloxymethyl) _5_(2_hydroxy-ethyl)_2,3_dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2',3'-di-halo-biphenyl_ 4_yloxymethyl)-5-ethoxyindolyl-2, indenyl dihydro-sodium [3,2-a]° sessile -7-@同; (8)-2·(2^ '-Di-gas-biphenyl_4_yloxymethyl)_5_isopropoxymethyl-2,3_dihydrosaphth[3,2-a] «Bense-7-one; (3) -2&lt;2',3'-dichloro-biphenyl_4_yloxymethyl)_5_phenyl_2,3-dihydro-adaron and [3,2-a]pyrimidin-7-one; 209 201121 978 (S)-5: cyclopentyloxymethyl 2 - (2,3,-dichloro-biphenyl-4-yloxymethyl)_2,3-dihydro-n-oxazolo[3,2 -a]pyrimidin-7-one; (S)-2-(2',3'-di-biphenyl-4-yloxymethyl)_5_(tetrahydrofuran-2-ylmethoxymethyl) (2)3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)_2-(2',3'-dichloro-biphenyl-4-yloxy Base)_5_(2_fluoro-ethoxymethyl)_ 2'3-dihydro-σ-salt and sputum-small-small-small stalks; qiao)-2-(3|,5'-dibromo- Biphenyl yloxymethyl)_2,3_dihydro-oxazolo[3,2_a] ° sessile-7-ketone; (S)-2-(4'-fluoro-3'-oxime (Z)2-(3'-fluoro-4); oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(3'-fluoro-4 ·-Methylbiphenyl_4·yloxymethyl)_2,3-dihydrooxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2f-fluoro-4' -methyl-biphenyl-4-yloxyindenyl)_2,3-dihydro-doxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2,6-di Methyl-biphenyl_4_yloxyindenyl)_2,3_dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(3',5' _Dimethyl-biphenyl_4·yloxyindenyl)_2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2',3 _Dimercapto-biphenyl_4_yloxyindenyl)_2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2',3 '-Dimercapto-biphenyl_4_yloxyindenyl)_5_methoxy-2,3_dihydro- σ-oxazolo[3,2-a]pyrimidin-7-one; (S) -2-(2',3'-didecyl-biphenyl-4-yloxyindenyl)_5_mercapto-2,3_dihydro-〇 唾[3,2-a]° Bite-7-ketone; 210 201121978 (8)-5-cyclopropyl_2_(2,3,-dimercapto-biphenyl-4-yloxyindenyl)_2,3-dihydro-indazolo[ 3,2-a]pyrimidin-7-one; (8) 1(2',3'-dimercapto-biphenyl-4-yloxyindenyl)_5-fluoromethyl-2,3-diaza-carbazole And [3,2-a]pyrimidin-7-one; dimercapto-biphenyl-4-yloxyindenyl)_5_morpholine_4_ylindenyl- 2,3-dihydro-呤[3,2-a] 嘲-7-ketone; (S) 2 (2,3-methyl-biphenyl-4-yloxyindenyl)_5- σ ratio σ each α _1 _ group Methyl 2,3-dihydro-4« sits and [3,2-a]° 密-7-酉; K2',4'-dimercapto- phenylene _4_yloxy oxime (2)2-dihydro,oxazolo[3,2-a]pyrimidin-7-one; (S)_2_(2',3|-dimercapto-biphenyl-4-yloxyindenyl) _6_ethyl_2,3_dihydrogen. Sit and [3,2-a]pyrimidin-7-one; dimercapto-biphenyl_4_yloxyindenyl)_6_mercapto-2,3_dihydro-. No. Saliva [3,2-a] pyrimidine. D--7-ketone; dimethyl-biphenyl_4_yloxyindenyl)_2-dihydro-oxazolo[3,2-a]n-densit-7-one; dimethyl-biphenyl _4_yloxyindenyl)·6_mercapto_2,3_dihydro-indole 11 sits and [3,2-a&gt; densely bit-7-one; 2j2,3 _diindenyl-biphenyl _4_ yloxymethyl)_5_hydroxyindole-2,3_dihydro- π-α α[3,2-a]pyrimidine-7-one; (outside 2_(2"3,' Dimethyl-biphenyl 1-yloxyindenyl)-H2-ethyl-ethyl 2,2-dihydro-oxazolo[3,2-a]pyrimidine-7-one; (8) 2^3 fluorenyl-biphenyl _4_yloxyindenyl)_5•ethoxy fluorenyl-,^dihydro-oxazolo[3,2-a]pyrimidin-7-one; 211 201121978 (S)-2-(2y- Dimethyl-biphenyl_4-yloxyindenyl)_5-isopropoxyfluorenyl_2.3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-2 -(2,3'-dimercapto-biphenyl-4-yloxyindenyl)_5_phenyl_2,3_dihydro-oxazolo[3,2-a]pyrimidin-7-one (S)-5-Cyclopentyloxy 2,2-(2',3'-dimethyl-biphenyloxyindenyl)_2,3_dihydro-sodium [3,24]°. (-7)-2-(2,3-dimethyl-biphenyl-4-yloxymethyl)_5_(tetrahydrofuran-2-yloxycarbonyl)-2 , 3-dihydro-sodium(3,2-a)° sessile-7-one; (S)-2-(2',3'-dimercapto-biphenyl-4-yloxyindenyl -5-(2-Fluoro-ethoxyindolyl)-2,3-dihydro-ί-α sits and [3,2-ap dense β定_7_@同; (S)-5-(l ,l-difluoro-propyl)-2-(2',3'-dimethyl-biphenyl-4-yloxymethyl)_2.3-dihydro-oxazolo[3,2-a] Pyrimidine-7-one; (S)-2-(2-mercapto-3'-propyl-biphenyl-4-yloxyindenyl)_2,3-dihydro-n-oxazolo[3,2- a]pyrimidin-7-one; (S)-2-(2,3-oxooxy-biphenyl-4-yloxyindenyl)_2,3_dihydro-indole oxime [3,2 -a]pyrimidin-7-one; (S)-2-(2,3,5'-difluoro-biphenyl-4-yloxyindenyl)-2,3-dihydro-α et al. 3,2-a]pyrimidin-7-one; (S)-2-(2',3',4'-trifluoro-biphenyl-4-yloxyindenyl)_2,3-dihydro-σ Wait. Sodium [3,2-a]pyrimidin-7-one; (S)-5-mercapto-2-(2,3,5,-trifluoro-biphenyl-4-yloxyindenyl) _2,3_Dihydro-ordinazolo[3,2-a]pyrimidin-7-one; (S)-5-hydroxyindenyl-2-(2',3',5'-trifluoro-biphenyl -4-yloxymethyl)_2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; 212 201121978 (S)-5-methoxyindolyl-2_(2' ,3,,5,_trifluoro-biphenyl_4_yloxyindenyl)_2,3_dihydro-«foxaz[3,2-a]pyrimidine_7-one; (S)-5- (2=hydroxyethyl)_2_(2',3',5,__trifluoro-biphenyl_4_yloxyindenyl)_2,3_dihydro-oxazolo[3,2-a]pyrimidine _7_ketone; (S)-5-ethoxyindolyl 2_(2',3^trifluoro-biphenyl-4-yloxyindenyl)_2,3_dihydro-indazolo[3, 2-a]pyrimidin-7-one; (S)-5-isopropoxycarbonyl 2_(2,3,5,-trifluoro-biphenyl-4-yloxyindenyl)_ 2, 3_Dihydro-oxazolo[3,2-a]pyrimidine_7-one; (s)-5-cyclopentyloxyindol_2_(2',3,5,-trifluoro-biphenyl_ 4_yloxyindolyl·dihydro-oxazolo[3,2-a]pyrimidin-7-one; (S)-5-(tetrahydro-furan·2_yloxycarbonyl)_2_ (2,,3,5,_trifluoro-biphenyl-4_yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidine_ 7-ketone; (S)-5-(2-fluoro-ethoxyindenyl)_2_(2,3,5,-trifluoro-biphenyl-4-yloxymethyl)-2,3 - a hydrogen sitting and [3,2_&amp;] bite _7_ketone; (S)-5-l-mercapto-2-(2',3|,5匕tris-biphenyl_4_yloxy f-)_2,3_dihydro- π-thin [3,2-a]pyrimidin-7-one; (S)-2-(2',3',5'_three-gas-biphenyl_4 • hydroxyoxyindenyl) 2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; (8)-5-fluorodecyltrichloro-biphenyl-4-yloxyindenyl _2,3_Dihydro-oxazolo[3,2-a]pyrimidine_7-one; (S)-2-(2',4',5'-trimethyl-biphenyl_4-yloxy Methyl)_2,3-dihydro-indolo[3,2-a]pyrimidine-7-one; (S)-2-(2,2',3'-trimethyl-biphenyl_ 4_yloxymethyl)_2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-yl; 213 201121978 (S)-2-(2-ethyl-2',3' -didecyl-biphenyl-4-yloxyindenyl)-2,3-diaza-11-oxazolo[3,2-a]pyrimidin-7-one; (S)-2-(2- Ethyl·2·,3′-dimercapto-biphenyl-4-yloxyindenyl) each fluorenyl group 2,3_one 虱-σ number 11 sits and [3,2—a] mouth. D--7-ketone; (S)-2-(2-decyloxy-2',3'-dimethyl-biphenyl-4-yloxyindenyl)_2,3_dihydro_ 0°° Sit and [3,24] pyrimidine-7-one; 2',3'-dimercapto-4-((S)-7-keto-2,3-dihydro-7H-doxazo[ 3,2-a]pyrimidine-2-yloxy)-biphenylacetonitrile; (S)-2-(4-naphthalen-1-ylphenoxyl)-2,3-dihydro-OR-Oxazole And [3,2 a]pyrimidine _7_ ketone; (S)-2-(4·dihydroindole_5_yl)-phenoxymethyl)_2,3_dihydro-indole oxazole [3,2_a ] pyrimidine-7-酉; (S)-2-(4-dihydroindenyl)-phenoxymethyl)_2,3_dihydro-σ and the like oxazo[3,2_a]pyrimidin-7-one ; 5 (8)-2_[4-(5,6,7,8_tetrahydro-naphthalene-2-yl)-phenoxymethyl)_2,3_dihydro-(1 oxazolo[3,2-a Pyrimidine-7-one; (8)_2-[4-(5,6,7,8-tetrahydro-naphthalenylphenoxymethyl)_2,3-dihydrobenzo[3,2-a]pyrimidine- 7-keto; and (S)-2-(9HH2_yloxymethyl)_2,3-dihydro-sodium and [3,2a] 7-one. A pharmaceutical composition containing the scope of the patent application The compound or compounds described in any one of items 1 to 5, or a pharmaceutically acceptable salt thereof, 214 201121978, in combination with one or more pharmaceutically acceptable carriers, diluents or forms 7. The use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition capable of modulating one or more metabotropic glutamic acids The use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition, The compound is capable of modulating one or more metabolic type of facial acid receptors for the treatment of anxiety, migraine, schizophrenia, cognitive impairment, epilepsy and pain. 0 215 201121978 IV. Designated representative map: (1) Representative of the case Pictured: None (2) The symbol of the symbol of this representative figure is simple: No. 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 3