TW201000461A - New compounds useful in pain therapy - Google Patents

Abstract

Compounds of formula I are claimed, wherein R1 is hydrogen, C1-3alkyl, C1-3alkoxy, cyano, hydroxy or halo; wherein C1-3alkyl may optionally be substituted by one or more substituents independently selected from hydroxy, C1-3alkoxy or fluoro; and wherein C1-3alkoxy may optionally be substituted by one or more fluoro; m is 1 or 2; R2 and R3 is each and independently selected from hydrogen, C1-4haloalkyl, C1-4aloalkoxy, halo, C1-4alkoxy, C1-4alkyl and C3-7cycloalkyloxy; and wherein said C3-7cycoalkyloxy may optionally be substituted by one or more fluoro; and whereas both R2 and R3 can not be hydrogen; Het is selected from any one of pyridinyl, pyrazinyl, isoxazolyl, pyrazolyl, indolyl, triazolyl and pyrimidinyl, wherein each such heteroaryl may optionally be substituted by one or more X4; X4 is halo, C1-3alkyl, C1-3alkylOC1-3alkyl, -CH(CH3)-O-C(CH3)3, C1-4alkoxy, cyano, or hydroxyl, or C1-2hydroxyalkyl; ; and wherein said C1-3alkyl, C1-3alkylOC1-3alkyl, -CH(CH3)-O-C(CH3)3, or C1-4alkoxy may each optionally be substituted by one or more fluoro; L1 is C1-4alkylene, which may optionally be fluorinated or hydroxylated; and L2 is C1-3alkylene; with the exception of the compounds: 2-[1-(1, 5-dimethyl-1H-pyrazol-4-yl)ethyl]-5, 7-dimethoxy-3-oxo-N-[2-(trifluoromethyl)benzyl]isoindoline-1-carboxamide; N-(4-fluorobenzyl)-3-oxo-2-(2-pyridin-4-ylethyl)isoindoline-1-carboxamide; and N-(2-chlorobenzyl)-2-[2-(1 H-indol-3-yl)-1-methylethyl]-3-oxoisoindoline-1-carboxamide; The invention further relates to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.

Description

201000461 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds, methods of containing such compounds, and compounds such as the lysine combinations of such compounds. t. The present invention is also directed to the preparation of such [prior art] pain conditions for the current treatment of the use of compounds in the field of dexamethasone. -Classification of human 1 very limited (four) physical mechanism σ substance opioid (opioid) stimulate endogenous endorphins, first, the category - Ϋ ^ Jt Jliv / a case of morphine base (m〇rphine). Opioids have several drawbacks that limit their use, for example. Area spit and constipation

And the negative impact on breathing ability. The second major class of painkillers, cox. UcL type 2, non-steroidal anti-inflammatory analgesics also have the following disadvantages, such as insufficient efficacy in severe pain conditions, and mucosal ulceration when long-term use of Coy j+ with COX-1 inhibitors. The mechanisms of analgesic effects of other currently used drugs have not been fully characterized' and/or have limited therapeutic potential. Local anesthetics known to block most of the sodium channel types in the nerve are suitable for relieving pain in a small area of the body and are suitable for blocking the conduction of nerves from the peripheral nervous system to the central nervous system. It can also be used in the last mentioned method of blocking sensory signal transduction by instilling a local anesthetic solution at the spinal cord. However, due to its high toxicity (especially cardiotoxicity), it cannot be used as a generally useful analgesic for systemic administration. Therefore, there is still a need for more selective sodium channel modulators involved in pain signal transduction. To date, nine colony subtypes have been selected and functionally represented (Wood JN, Baker M.. Current 〇pini〇n in Pharmac〇l〇gy 140345.doc 201000461, 1, 1 7-2 1). It exhibits differential performance throughout the muscle and nerve tissue and exhibits different biophysical properties. All voltage-gated sodium channels are characterized by a high selectivity to sodium compared to other ions and their voltage-dependent gating. It has been shown by the application of genetic analysis that a mutation in the gene encoding the sodium channel NaVl_7, which causes the protein to lose its function, makes humans almost insensitive to pain (Cox jj et al., 2, 6, 44, 894- 898). It is well known that the voltage-controlled sodium channel in the nerve plays a key role in neuralgia (Baker MD and Wood JN_rre oil to ^ hall c〇 / kiss heart 2001, 22, 27-31). Peripheral nervous system damage usually causes long-lasting neuralgia after the initial damage has subsided. Examples of neuralgia include, but are not limited to, post-herpetic neuralgia, tri- and neuralgia, urinary neuropathy, chronic lower back pain, limb pain, pain caused by cancer and chemotherapy. Chronic pelvic pain, complex Regional pain syndrome and related neuralgia. It has been shown in human patients and animal models of neuralgia that damage to primary afferent sensory neurons can cause neuroma formation and spontaneous activity as well as evoked activity in response to generally innocuous stimuli. NaV 1 ·7 is expressed in human neuromas, which are swelling and allergic nerves and nerve endings that are normally present in chronic pain states (乂c’a 2002, 144, 803-810). In a rat model of peripheral nerve injury, ectopic activity in the injured nerve corresponds to behavioral signs of pain. In these models, intravenous administration of nanochannel blockade (IV) beta and local anesthetic lidocaine (Hd〇caine) can inhibit ectopic activity and reverse tactile allodynia without affecting the general behavioral and motor function concentrations (Mao J and Chen LL, Ρίπ>, 2000, 87, 7-17). 140345.doc 201000461 In addition to neuralgia, sodium channel blockers have clinical utility in the treatment of epilepsy and arrhythmia. Recent evidence from animal models suggests that sodium channel blockers can also be used for neuroprotection in ischemic conditions caused by stroke or neurological trauma and for patients with multiple sclerosis (MS). • SUMMARY OF THE INVENTION According to the present invention, there is provided a compound of formula I: R3

Wherein R is hydrogen, Cw alkyl, c!.3 alkoxy, cyano, hydroxy or halo; wherein the alkyl group is optionally independently selected from one or more selected from the group consisting of hydroxyl groups, Cy

Substituted with a substituent of a methoxy or fluoro group; and wherein the oxy group is optionally substituted with one or more fluoro groups; m is 1 or 2; and R3 are each and independently selected from hydrogen, Ci'alkyl, c] hydranyl, C. 4 alkoxy 'C丨-4 alkyl and C3_7 cycloalkoxy; and wherein the C3_7% alkoxy group may be optionally substituted with - or a plurality of fluoro groups; and wherein R2 And R3 may not be hydrogen at the same time; 糸 is recognized by any of the following: pyridyl, pyrazinyl, isoxazolyl, pyrazolyl, fluorenyl, triazolyl and pyrimidinyl, and the heteroaryl may be each 140345.doc 201000461 Alternately substituted by one or more χ4 · x is i-based, (^-based, k-alkyl qC) 3 alkyl, _CH(CH3)_〇_(3)3 Cl'4 alkoxy a cyano group, a hydroxy group or a Cu hydroxyalkyl group; and wherein the Cm alkyl group, the Ci 3 alkyl group 〇Ci 3 alkyl group, the _ch(ch+〇_(3)3 and 忒Cl-4 alkoxy groups may each be regarded as The situation is replaced by one or more fluoro groups;

Ll is a Cl-4 extended alkyl group which is fluorinated or hydroxylated as the case may be; and 1^2 is a Ci_3 stretching group; wherein the following compounds are excluded: 2-[1-(1,5-dimethyl-1H_ Pyrazole-4-yl)ethyl]_5,7-dimethoxy-% flavonyl-N-[2-(trifluoromethyl)benzyl]isoporphyrin-indole-amine; N -(4.fluorobenzyl)_3-oxo-2-(2-acridyl-4-ylethyl)isoindol-1 -cartoamine; and N-(2-p-benzophenanthryl) ) 2_[2_(1吲哚吲哚_3_yl) decylethyl]_3_ pendant oxy-iso- 丨ϋ 琳 琳 _ 1 1 甲 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Or a salt of the isomer. An embodiment of the invention is directed to a compound of formula I, wherein: 1 R is hydrogen, Cm alkoxy, Cl.3 alkyl, carbyl, fluoro, cyano or hydroxy; m is 1 or 2; r2 and r3 Each is independently and independently selected from the group consisting of hydrogen, alkyl, Cl_4li alkoxy halide, C!-4 alkoxy, and C", and wherein R2 and R3 are not simultaneously hydrogen;

Het is selected from any one of the following: D-pyridyl, pyrazinyl, isoxazolyl, 140345.doc 201000461 pyrazolyl, fluorenyl, triazolyl and pyrimidinyl, wherein the heteroaryl can be viewed separately The case is substituted by one or more X4; X4 is Cw alkyl, CN3 alkoxy or fluoro;

Li is a Ci-3 extension base; and L2 is a Ci-3 extension base. An embodiment of the invention is directed to a compound of formula I, wherein R1 is hydrogen. Another embodiment of the invention is directed to a compound of formula I, wherein R1 is methoxy. Another embodiment of the invention is directed to a compound of formula I, wherein R1 is thiol. Another embodiment of the invention is directed to a compound of formula I, wherein R1 is cyano. Another embodiment of the invention is directed to a compound of formula I, wherein R1 is hydroxy. Another embodiment of the invention is directed to a compound of formula I, wherein R1 is a gas group. Another embodiment of the invention is directed to a compound of formula I, wherein R1 is fluoro. Another embodiment of the invention is directed to a compound of formula I, wherein R2 is selected from the group consisting of chloro, fluoro and > odor. An embodiment of the invention is a compound of formula I, wherein R2 is-0-CF3. Another embodiment of the invention is a compound of formula I, wherein R2 is -0-CH2-cf3. Another embodiment of the invention is a compound of formula I, wherein R2 is CF3. Another embodiment of the invention is a compound of formula I wherein R2 is -ch2-cf3 exemplified by the formula - an embodiment is a compound of formula I wherein R2 is methoxy. This month's example is a compound of formula I wherein R2 is hydrogen. Another embodiment of the invention is a compound of formula I wherein R2 is isopropyl. Another embodiment of the invention is a compound of formula I wherein R3 is hydrogen. Another embodiment of the invention is a compound of formula I wherein R3 is a fluoro group. Another embodiment of the invention is a compound of formula I wherein R3 is chloro. Another embodiment of the invention is a compound of formula I wherein R3 is bromo. A consistent example of the present invention is a compound of formula I wherein R3 is a fluorenyl group. Another embodiment of the invention is a compound of formula I wherein R3 is CF3. Another embodiment of the invention is a compound of formula I, wherein R3 is -〇cf3. An embodiment of the invention is a compound of formula I wherein is a methylene group. Another embodiment of the invention is a compound of formula I wherein hydrazine is an ethylidene group. Another embodiment of the invention is a compound of formula I wherein k is a propyl group. An embodiment of the invention is a compound of formula I, wherein CH2-. An embodiment of the invention is a compound of the formula wherein Li*_ch_(cH3)_. Another embodiment of the invention is a compound of formula I wherein 1 is 彳(() 2_CH2-. Another example is a compound of formula I, wherein L! is -CH2_ch(ch3) An example is a compound of formula I, wherein -CH2-C-(ch3)2-. Another embodiment of the invention is a compound of formula I, wherein, is *·ί*. 140345.doc -10- 201000461 - Silver is only a compound of formula I wherein L2 is methylene. The g ^ embodiment of the invention is a compound of formula I wherein L2 is _CH-(CH3)-. The compound of the formula I wherein L2 is a -cyclopropyl propyl group. The present invention is a compound of the formula j wherein X4 is a decyloxy group. The present invention> A compound of formula I, wherein X4 is methyl. • Another embodiment of the invention is a compound of formula I wherein X4 is cyano. Inventive oxime H^Sl - only a compound of formula I wherein X4 is CF3. Another embodiment of the invention is a compound of formula I wherein X4 is a fluoro group. A compound of formula I wherein X4 is _〇_CH2-cf3. Another embodiment of the invention is a compound of formula I, wherein X4 for- CH2〇H. Another example of this Maoyue is a compound of formula I, where \4 is _ch(ch3)_oc(ch3)3. The consistent application of the present invention is a compound selected from any one of the following formulas. : N-[(4_气phenyl)indolyl]-3-oxo-2-(2-D-pyridin-2-ylethyl)-iH-isoindole-1 -carboxamide; : 3-Phenoxy-2-(2"2唆(唆)2-ylethyl)_Ν_[[4·(trimethylmethoxy)phenyl]indolyl]-1Η-isoindole-1-carboquinone Amine; 3-sided oxy, 2-(2-bite. 2-ylethyl)_ν_[[4_(trimethylmethyl)phenyl]methyl]-1Η-isoindole-1 -decylamine ; 3-sided oxy-2 decapyridyl _3· fluorenyl) Ν [ [[4_(三敦methoxy)phenyl]methyl]-1 Η-isoindole-1-nonanamine; N- [l-(4-Chlorophenyl)ethyl]_3_sideoxy-2_(2_.pyridin-2-ylethyl)_ 1Η-isoindole-1-carboxamide; 140345.doc 201000461 3 -Phenoxy-2-(2-pyridazine-2-ylethyl) fluoromethyloxy)phenyl] fluorenyl]-1 Η-iso- ̄ ° °-1 - guanamine; 2- [ (2-methoxypyridin-3-yl)methyl]_3_sideoxy_N_[[4_(trifluoromethoxy)phenyl]methyl]-1Η-isoindole-i-decylamine 3- 3-oxo-2-(°pyrazine-2-ylmethyl(trifluorodecyloxy) Methyl]-1 Η-isoindole-1 - decylamine; 3-sided oxy-2-(2-pyridin-2-ylethyl·trifluoroethoxy)phenyl]ethyl] -1H-isoindole-1 _ guanamine; 2-[(5-methyl-1,2-oxazol-3-yl)indolyl]-oxyl_N_[[4_(trifluoromethoxy) )phenyl]methyl]-1H-iso.引》朵-1_甲甲胺; Ν-[(4-chlorophenyl)indolyl]-3-sideoxy-2-(2-D-pyrazin-2-ylethyl)-ll·l- Isoindole-l-oxime; N-[1-(4-chlorophenyl)ethyl]-3-oxo-2-(2-pyridazin-2-ylethyl)-1H-iso吲哚-1-carbamamine; N-[l-(4-chlorophenyl)ethyl]-3-indolyl-2-7-pyridyl_3_ylindenyl)_1H-isoindole-1- Indoleamine; N-[(4-fluorophenyl)indolyl]-3-oxooxy-2-(2-acridin-2-ylethyl)-1Η-isoindole-1 -indole 3-trioxy-2-(2-.pyridin-2-ylethyl)-N-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]-1 H-isoindole-1 · decylamine; 2-[3-(3-indolyl-1Η-indazol-1-yl)propyl]_3_sideoxy_Ν_[4_(trifluoroanthracene Benzophenyl]-isoindole.朵琳-1 - 曱-amine; 2-(1-mercapto-2-pyridin-2-ylethyl)·3_sideoxy_Ν_μ-(trifluorodecyloxy) benzyl]isoindole Lin-1 - guanamine; 140345.doc -12- 201000461 4-methoxy-3-indolyl-2-(2-α-pyridin-2-ylethyl)-jin-[4-(three Fluoromethoxy)phenylhydrazinyl]isoindoline-1-carboxamide; 3-sided oxy-2-(2-pyridin-4-ylethyl)_'[4_(tri-methoxy) Benzyl]isoindoline-1 -decylamine; 3-tertiaryoxy-2-(2-pyridin-3-ylethyl)-'[4_(trifluoromethoxy) alum Isoindoline-1 -carbenamide; 2-(1-indolyl-2-acridin-2-ylethyl)-3_sideoxy-[4-(trifluoromethyl)benzoquinone Isoindolin-1-ylidene; #-(4-chlorobenzyl)-2-(1-methyl-2-°pyridin-2-ylethyl)_3_sideoxy吲哚琳-1-carbamamine; 2-[2-(1/ί-indol-3-yl)ethyl]-3-oxo-[[4-(trifluoromethoxy)benzyl) Isoindoline-1 -carboxamide; ,(4-decyloxyphenyl)-3-oxo-2-(2_〇比〇定-2-ylethyl)isoindole Lin-1 - guanamine; 4-methoxy-2-(1-methyl-2-pyridin-2-ylethyl)_3. pendant oxy-W-[4-(trifluoromethoxy) Phenyl sulfonyl isoindolin-1-carboxamide; #-(4-isopropylphenylhydrazino)_2-(1-methylpyridin-2-ylethyl)-3-oxooxy Isoline-1 - guanamine; #-[4.fluoro-3-(trifluoromethyl)benzyl]-2-(1-methyl-2-pyridin-2-ylethyl)- 3-sided oxyisoporphyrin-indoleamine; fluoro-4-(trifluoromethyl)benzyl]-2-(1-methyl-2-pyridin-2-ylethyl)- 3-sided oxyisoindoline formamide; 2 (1indol-2-pyridin-2-ylethyl)_3_sideoxy (trifluoromethoxy)benzyl]isoporphyrin- 1-carbamamine; 140345.doc -13- 201000461 iV- [1-(3-phenylphenyl)ethyl]-3-sideoxy-2-(2-° ratio!7定_2_基乙))isoporphyrin-1·decylamine; ', (4-(trifluoromethoxy) 2-(2-(5-fluoropyrimidin-2-yl)ethyl)-3-yloxy- N-phenylhydrazino)iso-n-pyroline-carbendazim; 2-(2-(4-methyl succinyl-2-yl)ethyl)_3_sideoxy, &Phenylhydrazinyl)isoindoline-1-decylamine; 3-tertiaryoxy-2-(2-(pyrimidin-2-yl)ethyl)_N_(4-(trifluoromethoxy)benzoinyl Isoindoline-1 -decylamine; 2-(2-(2-mercaptopyrimidin-5-yl)ethyl)_3_ Group, & ,, two both methoxy) benzyl) isoindoline-1-acyl-amine;

2-((6-Cyanopyridine-3-yl)indolyl)_3_sideoxy_N lean field n, chaotic methoxy) methyl)isoporphyrin-1 -decylamine; 3- alkoxy-N-(4-(trifluoromethoxy)benzyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-1-decylamine; Soil ratio 3-sideoxy.N_(4_(trifluoromethoxy)phenylmethyl)_2pe (trimethyl)methylpyridin-3-yl)indolyl)isoporphyrin_丨_甲醯Amine; 3-oxo-oxy-2-((6-(2,2,2-trisethoxy))-yl)methyl(4-(difluoromethoxy)benzoinyl) Small indoleamine; -N-(4-(trifluoromethoxy) 2-(1-(5-fluoropyridin-2-yl)ethyl)_3_sideoxybenzyl)isoindole Porphyrin, carbamazepine; 7-chloro-3- oxo oxime, acetophene) ethyl) phenylmethyl, light + formamide; gas methoxydicyano oxy 2, 2 X(tetra)_2_yl)ethyl)·ν_(4•(三敦基) 甲基methyl)isoporphyrin_丨_carbamamine; 140345.doc -14· 201000461 2-(2-hydroxy-2-(吼) Pyridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide; 2-(2,2- Difluoro-2-indolyl-2-yl)B --3-Alkyloxy-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-carboxamide; 2-(2,2-difluoro-2-(° ratio) Pyridin-2-yl)ethyl)-7-mercapto-3-oxo-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-decylamine; 3- 2-oxo-2-(3-(pyridin-2-yl)propyl)-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-indolyl; 7 -Methoxy-3-o-oxy-2-(2-(acridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1 -carbamamine; 7-hydroxy-3-oxo-2-(2-(acridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)phenyl) hydrazino Porphyrin-1-carboxamide; 2-(2-methyl-1 -(.pyridin-2-yl)propan-2-yl)-3-sideoxy-N-(4-(dimur) Methoxy)benzoyl)isoindoline-1-decylamine; 7-methyl-3-o-oxy-2-(2-(.pyridin-2-yl)ethyl)-N- (4-(Trifluoromethoxy)phenyl)-isoindoline-1-carboxamide; '2-(2-indolyl-2-(.pyridin-3-yl)propyl)-3 - pendant oxy-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-carboxamide; 2-(2-mercapto-2-(.pyridin-2-yl) )propyl)-3-oxo-N-(4-(trifluoromethyl) Oxylyl)benzyl)isoindoline-1-indoleamine; 3-tertiaryoxy-2-((1-(. Bis-2-yl)cyclopropyl)methyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-decylamine; 3-sided oxy-2- (2-(Acridine-2-yl)ethyl)-indole-(1-(4-(trifluoromethoxy)phenyl)ethyl)isoindoline-1-carboxamide, isomer 4; 140345.doc -15 - 201000461 2-(2-(6-Methylacridin-2-yl)ethyl)-3-oxo-N-(4-(trifluorodecyloxy)benzene Isoindolin-1-ylidene; 2-(2-(6-(hydroxyindenyl)acridin-2-yl)ethyl)-3-oxo-N-(4-(three Fluoromethoxy)benzyl)isoindoline-1 -decylamine; 2-(2-(4-(1-tert-butoxyethyl 2,3-triazol-1-yl)) 3-) 3-oxo-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-decylamine; 4-fluoro-3-indolyl-2-(2) -(°bipyridin-2-yl)ethyl)-N-(4-(trifluorodecyloxy)phenylhydrazolyl)isoindoline-1-carboxamide; 7-fluoro-3-oxirane -2-(2-(°-pyridin-2-yl)ethyl)-N-(4-(trifluorodecyloxy)phenylindenyl)isoindoline-1-carboxamide; 2- (2 -(3-Fluorooxaridin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)phenyl)indoline/anthranamine; 4 -hydroxy-3- side Oxy-2-(1-(pyridin-2-yl)propan-2-yl)-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-decylamine; 4 -hydroxy-3-oxooxy-2-(2-(.pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)phenylhydrazino)isoindoline-1- Methionamine; 3-oxo-2-(2-(acridin-2-yl)ethyl)-N-(3-(trifluorodecyloxy)phenylhydrazolyl)isoindoline-1- Indoleamine; N-(2-mercapto-4-(trifluoromethoxy)benzoinyl)-3-yloxy-2-(2-(acridin-2-yl)ethyl)isoindole Porphyrin-1-carbamide; N-(3-bromophenylhydrazone)-3-oxo-2-(2-(acridin-2-yl)ethyl)isoindoline-1 - A Indoleamine; N - (4 - > odorant phenyl)-3 - flavonyl-2 - (2 - (° ratio σ-2-1 -yl)ethyl) ° ϋ ϋ ϋ -1 -1 -1 -曱Indoleamine; 140345.doc -16- 201000461 N-(4-bromobenzyl)_3_sideoxy-2(2_(β-pyridyl-2-yl)ethyl)isoindoline-1 Amine, isomer 1; N (3'4·monomethyl)-3-oxo-2-(2-(°biti-2-yl)ethyl)isoindoline-1-pyrene Indoleamine; 3-oxo-2-(2-(acridin-3-yl)ethyl)-indole-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)iso-α嗓琳_ 1-carboxylic acid amine; and 3-sided oxy-2-(2-(pyridin-2-yl)ethyl)-indole-(4-(2,2,2-trifluoroethyl)benzoyl) Porphyrin _ 1 -decylamine. For the avoidance of doubt, it should be understood that in the present specification, "Cw" means a carbon-containing group having 1, 2, 3, 4, 5 or ό one carbon atom. Unless otherwise stated, in the present specification, the term "alkyl" includes straight and branched alkyl ' and may be, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl. , isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or isohexyl. The term C 1-4 hospital system as used herein is defined as a linear chain having from 1 to 4 carbon atoms, a ring-shaped ring (in which a ring of at least three carbon atoms is present), and may be ( However, it is not limited to fluorenyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or tert-butyl. The term Cw alkyl as used herein is defined as a straight, branched or cyclic alkyl chain having 1 to 3 carbon atoms (a ring having three carbon atoms)', ie methyl, ethyl, positive Propyl, isopropyl or cyclopropyl. As used herein for L, the term Cl-4 alkyl may be straight-chain, branched or cyclic alkyl, and includes, but is not limited to, methylene, ethyl, propyl, isopropyl, Cyclopropyl, n-butyl, isobutyl, tert-butyl and cyclobutyl chains. > 140345.doc 201000461 The term Ci3 alkyl group for L2 may be straight chain, branched or alkylene and includes, but is not limited to, anthracene, ethyl, and isopropyl. Base and extended propyl hydrocarbon chain. Unless otherwise stated, the term "alkoxy" refers to the beauty of the formula 〇_R, wherein R is selected from a hydrocarbon group. The term "Ci 6 alkoxy" may, however, be limited to: decyloxy, ethoxy, propoxy, isopropoxy, oxy, 1,4-butoxy, isobutoxy, cyclopropyl methoxy Base, dipropyl propyloxy. The term "Ci3 alkoxy" as used herein may include, but is not limited to, methoxy, ethoxy or propoxy. The term "1-4"oxy group as used herein may include, but is not limited to, methoxy, ethoxy, propoxy A, propoxy, butoxy, tert-butoxy, isobutyl). In one embodiment of the present invention, the "C1·3 alkoxy group" may be substituted with - or a plurality of fluorine atoms, whereby one or more hydrogen atoms in the alkoxy group are replaced by - or a plurality of fluorine atoms, such as -〇-CH2-CF3, -0-CH2-CH2-CF3, -〇_CH F. Unless otherwise stated, the term "C1·3 alkyl ocl.3 alkyl" means an ether group having the formula R-0-R wherein R is selected from a hydrocarbon group. The C13 alkyl group may include, but is not limited to, dioxins, mercaptoethyl ether, methyl propyl ketone, ethyl ketone, dipropyl ether or methyl isopropyl squaring. In the present specification, unless otherwise stated, the term "dental base", which is a base as defined above, is replaced by a Nanfu as defined above.技 吾 "C"-4函炫•基" may include (but is not limited to) fluoromethyl _ M sulfhydryl, difluoromethyl, hydroxymethyl, monomethyl, trimethyl sulfhydryl or fluoromethyl . 140345.doc 18- 201000461 In this specification, unless otherwise stated, the term "toothed alkoxy" means the oxy group as defined above, which is substituted by the south group as defined above. The term "Ci_4" Oxygen όΤ 4 an / 虱 虱 」 may include, but is not limited to, fluoromethyl, difluoromethoxy, trifluoromethyl sulfonate, w ^ aryl 1 ethoxy or difluoro ethoxy. The term "cycloalkoxy" refers to a ring (tetra) attached to the remainder via an oxime atom of the oxy group. As used herein, but not limited to -0-cyclohexyl, 〇-cyclopropyl , 〇 _ cyclobutyl and ring ^ base. 乂

In this section, the terms "base" and "_" may be fluorine, iodine, chlorine or bromine unless otherwise stated. It will be appreciated that throughout the specification, the numbering and nature of the substituents on the ring in the compounds of the invention are selected to avoid spatially inappropriate combinations. For the avoidance of doubt, it should be understood that in this specification the group is defined by the definitions above, which covers the most extensive and broadest definition and for each specific definition and all specific definitions of the group. . The present invention relates to a hydrazine compound as defined above and a pharmaceutically acceptable salt thereof. The salt used in the pharmaceutical formulation should be a pharmaceutically acceptable salt. Further examples of suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts, such as those formed with inorganic or organic acids. Another example of a suitable salt is an alkali metal salt such as an alkaline earth metal salt; or a salt formed with an organic base. Examples of suitable salts of the invention are acetates, fumarates, maleates, tartrates, citrates, hydrochlorides, hydrobromides, sulfates and phosphates. 140345.doc -19- 201000461 Other pharmaceutically acceptable salts suitable for use in accordance with the present invention and methods of preparing such salts can be found, for example, in Rerningt〇n's Pharmaceutical Sciences (18th Edition 'Mack Publishing Co.). The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The phrase "tautomerism" is a chemical equilibrium between a ketone type and a dilute alcohol type in which an enol type and a keto form are tautomers. The compound of the formula X may also contain one or more asymmetric carbon atoms and thus may exhibit optical isomerism such as one or more enantiomers and/or non-:-isomers. Diastereomers can be knifed off using conventional techniques such as chromatography or ^ day. The various stereoisomers can be isolated by racemization or by the use of conventional techniques (e.g., fractional crystallization or inhibition). Or 'can be reacted by conditions such that the appropriate optically active starting material is caused by external or epimerization or by derivatization of the palmitic acid, followed by conventional methods (eg, different) Structure cut chromatography) (iv) enantiomers s for the preparation of the required optical preparations. All stereoisomers are included in the present pharmaceutical composition + τ η according to the invention _ therapeutically effective amount as an activity" A pharmaceutical composition comprising an acceptable salt Ρ❾ I Ρ❾ of the compound of the present invention or a pharmaceutically acceptable agent thereof and/or an inert medicinal agent. The pharmaceutically acceptable diluent 'formation medicinal composition may be a suitable agent , syrup, powder, granules or glue 2: for example, ingot swords, pill sacs, suitable for parenteral injection (including intravenous I40345.doc •20-201000461 intrapulmonary, subcutaneous, intramuscular, intravascular or infusion), Such as a sterile solution, suspension or emulsion; a form suitable for topical administration, such as an ointment, patch or cream; or a form suitable for rectal administration, such as a suppository. In general, the above compositions may be in a conventional manner. Use one or more conventions to assign vd^ • A pharmaceutically acceptable diluent and/or an inert carrier. In the treatment of a mammal, including a human, a suitable daily dose of a compound of the invention is about 5 to 100 mg/kg body weight when administered orally and When administered parenterally, it is about 0. 01 to 250 mg/kg body weight. Typical daily doses of active ingredients vary widely and should depend on various factors such as the relevant indication, the severity of the condition being treated, and the route of administration. The patient's age, weight and sex and the particular compound used, and may be determined by a physician. Pharmaceutical Uses The compounds of the invention are contemplated for use in therapy. The compounds of formula I as described herein and claimed in comparison to other essential sodium channels or their medicinal properties The upper salt and its corresponding active metabolite exhibit high potency at the sodium channel NaV丨7 and also exhibit high selectivity to the channel. Thus, the compounds of the invention are expected to be suitable for treatment with NaV 1.7 and C fibers. Upregulation of other sodium channels present in the condition associated with it. The compounds of the invention are useful for inhibiting sodium channels in mammals, including humans. An embodiment of the invention relates to the use of a compound of the formula as defined above for the manufacture of a medicament for the treatment of a Navl7 mediated disorder. H0345.doc -21 - 201000461 The compounds of the formula i of the invention are intended to be useful in the treatment of pain disorders, such as: Urgency: pain; chronic pain "sore pain, such as diabetic neuropathy; inflammatory pain associated with immediate inflammation and rheumatoid diseases; lower back pain, postoperative pain; and including cancer, colic, renal colic or Biliary colic, menstruation, muscle fiber, '隹 pain, pain after month pain, cancer pain, visceral pain (such as k丨生月盆痛, cystitis, IBS, pancreatitis), ischemic pain or gout A variety of conditions associated with pain. Another aspect of the invention is the use of a compound of the formula for the treatment of vascular headaches, such as migraine. Another aspect of the invention is the use of a guanidine compound for the treatment of pain conditions associated with erythematous limb pain, psoriasis, vomiting, urinary incontinence and hyperactive bladder. Another embodiment of the present invention is the use of a compound of formula j for the treatment of epilepsy. An embodiment of the invention relates to a compound of formula I as defined above for use in the treatment of arthritis, muscle fiber pain, lower back pain, post-operative pain, cancer pain, visceral pain (such as chronic pelvic pain, cystitis, Use of ibs, pancreatitis) or painful conditions associated with ischemic pain. An embodiment of the invention relates to the use of a compound of the formula as defined above in therapy. Another embodiment of the invention relates to the use of a compound of formula j as defined above for the manufacture of a medicament for the treatment of pain disorders such as acute pain, recurrent pain, neuralgia, such as diabetic neuropathy; Inflammatory pain associated with rheumatoid diseases; lower back pain; postoperative pain; and 140345.doc •22· 201000461 including cancer, colic, renal colic or biliary colic, menstruation, muscle fiber pain, lower back pain, Postoperative pain, cancer pain, visceral pain (such as chronic pelvic pain, cystitis, IBS, pancreatitis), pain associated with multiple conditions of ischemic pain or gout. Another aspect of the invention is the formula! The use of a compound for the manufacture of a medicament for the treatment of vascular headaches, such as migraine. Another aspect of the invention is the use of a compound of formula 1 for the manufacture of a medicament for the treatment of & pain conditions associated with red f' spot pain, psoriasis, vomiting, urinary incontinence and overactive bladder. Another embodiment of the invention is the use of a compound of formula 1 for the manufacture of a medicament for the treatment of epilepsy. Another embodiment of the present invention is a method for treating the following pain conditions: such as acute pain; chronic pain; neuralgia, such as diabetic neuropathy; inflammatory pain associated with arthritis and rheumatoid diseases. Back pain; postoperative pain; and includes cancer, colic, renal colic or biliary colic, (3, muscle fiber pain, lower back pain, postoperative pain, cancer pain, visceral pain (such as chronic pelvic pain, Pain associated with multiple conditions of cystitis, IBS, adrenitis, ischemic pain or gout; thereby administering to the individual to be treated a compound of the formula as defined above. A method for treating a headache (such as a migraine), thereby administering to a subject in need of such treatment, such as a few people, _ ^ ^ ^ ^ J40345.doc -23* 201000461, the individual in need of the treatment Administration of a hydrazine compound as defined above. Another embodiment of the invention is a method of treating epilepsy whereby a subject in need of such treatment is administered a compound of the formula as defined above. Implementation a compound of formula I as defined above for the treatment of pain conditions such as acute pain; chronic pain; neuralgia, such as diabetic neuropathy; inflammatory pain associated with arthritis and rheumatoid diseases; back pain; Post-pain; including cancer, colic, renal colic or biliary colic, menstruation, muscle fiber pain, lower back pain, postoperative pain, cancer pain, visceral pain (such as chronic pelvic pain, cystitis, IBS, pancreatitis) Pain associated with various conditions of ischemic pain or gout. For treating vascular heads Another aspect of the invention is a compound of formula I as defined above, such as a migraine. Another compound of the formula I of the invention is a compound of the formula I of the invention. The combination sadness is as defined above for the treatment of erythematous vomiting, urinary incontinence and overactive bladder. Pain, she is only used to treat epilepsy as defined above, and flat/sigma therapy can be applied as a treatment only, or in addition to this compound, #Α# It can be treated with other analgesics or adjuvants. The treatment can be, for example, a slow-motion, a combination of the following compounds or a polythene relief pain component: a) an opioid painkiller, for example, a test, a message Totoketone (ketobemidone: 140345.doc -24- 201000461 or fentanyl; b) NSAID or COX-1/2 analgesics, such as ibuprofene, naproxene, stopper Celecoxib or acetylsalicylic acid, and analogs thereof containing a nitric oxide supply group; c) analgesic adjuvants such as amitriptyline, imipramine, dulo Duloxetine or mexiletine; d) NMDA antagonists, such as ketamine or demetorfanf; (dextrometorfan); e) sodium channel blockers, such as Lido Cain; f) anticonvulsants, such as carbamazepine, topiramate or lamotrigine; g) anticonvulsant/analgesic amino acids, such as gabapentin or Pregabalin; h) cannabinoid ° This group The active compounds can be administered simultaneously, separately or sequentially. I EXAMPLES PREPARATION METHOD One aspect of the invention provides a process for the preparation of a compound of formula I or a salt thereof. Throughout the description of the methods, it will be appreciated that appropriate protection groups will be added to the reactants and intermediates as appropriate, and such protections will be removed from the respective reactants and intermediates, as appropriate to those skilled in the art of organic synthesis. base. A conventional procedure for the use of such protecting groups and examples of suitable protecting groups is described in "Green's Protective Groups in Organic Synthesis" P.G.M. Wuts, T.W. Green, Wiley, New York, 2007. References and descriptions of other suitable reactions are described in textbooks of organic chemistry (e.g., "Advanced Organic Chemistry", March, 4th Edition, McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994)). Representative examples of heterocyclic chemistry are described, for example, in "Heterocyclic Chemistry", JA Joule, K. Mills, G. F. Smith, 3rd edition 'Chapman and Hall (1995), pp. 189-224 and "Heterocyclic Chemistry". , TL Gilchrist, 2nd ed., Longman Scientific and Technical (1992), pp. 248-282. Unless otherwise specified, the terms "room temperature" and "ambient temperature" shall mean temperatures between 16 ° C and 25 ° C. Abbreviation. DMF Ν, Ν-dimethyl decylamine

NaOH Sodium hydroxide HC1 Hydrochloride Hydrazine Molar Concentration PG Protection One of the basic embodiments is a method for preparing a compound of formula I according to the method hydrazine and hydrazine, wherein unless otherwise specified, R1, R2, R3, L1, L2, Het and m is as defined in formula I.

Method A can be carried out by a 3-component Ugi reaction (Journal of Organic Chemistry (1999), 64(3), 1074-1076) using an appropriately substituted 2_mercaptobenzoic acid 140345.doc -26 - 201000461 酉义&gt Amines and isonitriles are prepared at ambient temperature to prepare compounds of formula I. Anti-solvent (for example, methanol)

Method B can be carried out by (iv) coupling reaction to appropriately replace the "(tetra) acid" and the amine oxime and a suitable activator (such as 'but not limited to hexafluorophosphate _ n, n, n', n' _ tetramethyl hydrazine Rust, bismuth hexafluorophosphate _ stupotriazole small group _ n, n, n', n'-tetramethyl hydrazine or hexafluorophosphate 0_ (7-aza benzotriazole _ 丨 _ group) · N, N,N',N'-tetramethylene oxime) in the presence of an organic base such as triethylamine, N,N-isopropylamine or 4-(didecylamino)pyridine at 0_45t in aprotic The compound is prepared by reacting a solvent such as DMF, acetonitrile, tetrahydrofuran or dioxane:

Tannin II can be found in the literature (eg Othman, M. and Decroix, B., Synthetic communications 1996, 26 (15), 2803-2809; and 140345.doc -27- 201000461

Obtained by the procedure described in Othman, Μ· et al., Tetrahedron 1998, 54 (3fU, υ), 8737-8744), as shown below in ruthenium tetrachloride by, for example, Ν- and then at 0 - bromobutylenimine (NBS) deodorizes high phthalate, amine or 4-(dimercapto) at 25 ° C in organic tests (such as triethylamine ' ν, Ν-diisolactam Amine irj σ in a solvent such as acetonitrile in the presence of π)

Example General Method Mass spectra were recorded on one of the following instruments: Α) LC-MS consisting of Waters Alliance 2795 HPLC, ters PDA 2996 diode array detector, Sedex 85 ELS detector, and early quadrupole mass spectrometer system. The mass spectrometer is equipped with an electrospray ion source (ES) operating in a cationic or anionic mode. Set the capillary voltage to 3 2 W and the cone voltage to 30 V. The mass spectrometer was scanned between (7) and 100_700 with a scan time of 〇·3 s. A diode array detector scan is performed from 200-400 nm. Adjust the temperature of the ELS detector to 4 〇. (: and the pressure was set to i 9 bar. Separation was performed on x_Terra MS C8 (3.0 mm x 5 〇 mm, 3.5 pm (Waters)) running at a flow rate of 1 ml/min. Using a linear gradient 'started at 100% A (A: 10 mM ammonium acetate in 5% acetonitrile or 8 mM citric acid in 50/〇 acetonitrile), terminated at 1 〇〇% B (B: acetonitrile). Tube 140345.doc -28 - 201000461 Column oven temperature set to 40 ° C. B) Waters sample manager 2777C, Waters 1525 μ binary pump, Waters 15 00 column oven, Waters ZQ single quadrupole mass spectrometer, Waters PDA 2996 diode array detection And the LC-MS system consisting of the Sedex 85 ELS detector. The mass spectrometer was configured using an atmospheric pressure chemical ionization (APCI) ion source, which was additionally equipped with an atmospheric pressure photoionization (APPI) device. The mass spectrometer scans in a cationic mode with a transition between APCI and APPI mode. Set the mass range to w/z 120-800, use

, 〇·3 s scan time. The APPI reflector and APCI corona were set to 0.86 kV and 0.80 μΑ, respectively. In addition, for the APCI and APPI modes, the desolvation temperature (300 ° C), the desolvation gas (400 L/Hr), and the cone gas (5 L/Hr) were constant. Separation was performed using a Gemini column C18 (3_0 ηιηιαο mm ′ 3 pm (Phenomenex)) and running at a flow rate of 1 ml/min. A linear gradient was used starting at 100% A (A: 10 mM acetic acid in 5% methanol) and ending at 100% B (sterol). The column oven temperature was set to 40 °C. C) by Waters Alliance 2795 HPLC and operating at 120 °C / V:

LC-MS system consisting of Waters Micromass ZQ detectors. The mass spectrometer is equipped with an electrospray ion source (ES) operating in either cationic or anionic mode. The mass spectrometer scan was performed between m/z 100-1000 with a scan time of 0.3 s. The LC system used was 75% acetonitrile and 25% 0.1% citric acid solution in water. Preparative chromatography was performed on one of the following instruments: A) Automated Dissolve Collector (Waters 2767), Gradient Pump (Waters 2525), Column Switch (Waters Switch) in combination with an autosampler CFO) and PDA (Waters 2996) Waters FractionLynx 140345.doc · 29· 201000461 system. Column: XTerra® Prep MS C8 10 μηι OBDTM 19x300 mm or XTerra® Prep MS C8 10 μπι OBDTM 30x150 mm, both with a front catheter column XTerra® Prep MS C8 10 μηι 19x10 mm column. A gradient of 100% A (95% 0.1 M ammonium acetate in MilliQ water and 5% acetonitrile) to 100% B (100% acetonitrile) was used for LC separation at a flow rate of 20 ml/min. PDA scanning was performed from 210-35 0 nm. UV triggering determines the collection of dissolved fractions. B) Automated Dissolve Collector (Waters 2767), Gradient Pump (Waters 2525), Regeneration Pump (Waters 600), Replenishment Pump (Waters 515), Waters Active Splitter, Column Switching Valve (Waters) in combination with an autosampler CFO), PDA (Waters 2996) and Waters Fraction Lynx system of Waters ZQ mass spectrometer. Column: XBridgeTM Prep C8 5 μιη 〇BDTM 19x100 mm with front conduit column: XTerra® Prep MS C8 1 0 μιη 19 x 1 0 mm column. A gradient of 1 〇〇% A (95% 0.1 Μ ammonium acetate in MilliQ water and 5% acetonitrile) to 100% B (100% acetonitrile) was used for LC separation at a flow rate of 25 ml/min. A PDA scan was performed from 21 0-350 nm. The ZQ mass spectrometer was run in cation mode ESI. The capillary voltage is 3 kV and the cone voltage is 30 V. The mixing trigger (UV and MS signals) determines the fraction collection. Purity analysis was performed on one of the following instruments: A) G1379A micro vacuum deaerator, G1312A binary pump, G1367 well plate autosampler, G13 16A thermostat column chamber and G1 31 5C diode array 4贞The Agilent HP 11〇〇 system consists of a tester. The column used was a Gemini C18 (3.0 x 50, 3 μπι 140345.doc • 30-201000461 (Phenomenex)) operating at a flow rate of 1. 〇 ml/min. The purity method consists of three parts: first a 3 minute column wash, followed by a blank run and finally a sample analysis. A linear gradient was used for both blank and sample starting at 100% A (A: 10 mM ammonium acetate in 5% acetonitrile) and ending at 100% B (B: acetonitrile) after 3.5 minutes. The blank run was subtracted from the sample runs at wavelengths of 220 nm, 254 nm, and 290 nm. B) Water Acquity system with PDA (Waters 2996) and Waters ZQ mass spectrometer. Column: Acquity UPLCTM BEH C8 1.7 μιη 2.1x50 mm. The column temperature was set to 65 °C. Linearity of 100% Α (Α : 95% 0.01 Μ acetic acid in MilliQ water and 5% acetonitrile) to 1 〇〇〇 /0 B (5% of 0.01 Μ ammonium acetate in MilliQ water and 95% acetonitrile) A 2 minute 15 second gradient was used for LC separation at a flow rate of 1.0 ml/min. A PDA scan was performed from 210-350 nm and extraction was performed at 254 nm for purity determination. The ZQ mass spectrometer was run with ESI in pos/neg conversion mode. The capillary voltage is 3 kV and the cone voltage is 30 V. C) Waters 600 control system with Waters 717 Plus autosampler and Waters 2996 photodiode array detector. The column used was ACE C18, 5 μιη, 6 〇χ 150 mm. A linear gradient was used starting at 95% A (A: 0.1% H3P〇4 in water) and ending at 55% B (B: acetonitrile) in a 20 min run. The column is at ambient temperature with a flow rate of 1 〇 mL/min. A diode array detector scan is performed from 200-400 nm. NMR spectra were recorded on a Varian Mercury Plus 400 NMR spectrometer operating at 400 MHz with a varian 400 ATB PFG probe; or operating at 400 MHz (protons) and 1 〇〇 MHz (carbon 13) with 140345.doc • 31 - 201000461 Recording NMR spectra on a Varian Unity+ 400 NMR spectrometer with a 5 mm Z gradient BBO head; or operating at 400 MHz (protons) and 1 〇〇mHz (breaking 13) with 3 mm Z gradient flow injection SHl i/D-^C probe, NMR spectrum recorded on a Bruker av400 NMR spectrometer using a BEST 215 liquid processor for sample injection; or at 4 〇〇 MHz (proton) and 1 〇〇 MHz («C13) NMR spectra were recorded on a Bruker DPX4 〇0 NMR spectrometer equipped with a Z-gradient 4-core probe. The following reference signals are used: (unless otherwise indicated 'otherwise) TMS δ 〇·〇〇, or DMSO-A residual solvent signal δ 2·49, CD3OD δ 3_3 1 or CDC13 δ 7.25. Resonance symmetry of monosexual, doublet, triplet, quadruple, multiple and broad peaks is denoted as s, d, t, q, m and br, respectively. Depending on the simplicity of the spectroscopic description, diastereoisomers may or may not be indicated in the spectrum. Unless otherwise stated, the chemical shift is given in ppm using the solvent as an internal standard. Column chromatography is performed using a Merck Silicone 60 (0.040-0.063 mm) or a Combi Flash® CompanionTM system using a RediSepTM normal phase column. ACD/Name, version 8.0 or 9.0 software from Advanced Chemistry Development Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004, and ELN 2.1 from Cambridgesoft, www.cambridgesoft.com, 2008 have been used. The software of the invention is named for the compound of the invention. [Embodiment] Preparation of Intermediates The present invention will now be illustrated by the following non-limiting examples. 140345.doc -32- 201000461 Example i-i 3-sided oxy-2·(2-pyridin-2-ylethyl)_1H_isoindole 4 formic acid ethyl vinegar

° Intermediate 1 2-(1-Diethyl-2-ethoxy-2-oxoethyl)benzoic acid ethyl acetate (3i5 g, 10.0 mmo according to Othman et al., Synth c〇mm 1996, 26 2803 The solution in acetonitrile (25 mL) was cooled to hydrazine with an ice bath, and the atmosphere above the solution was exchanged. Add triethylamine (2 23 sites, 16.0 mmol) and 2 decabi-2-yl)ethylamine (1.8 〇mL, 15 〇 〇 1) in turn, and warm the reaction mixture to ambient temperature while stirring for the next day. . The reaction mixture was taken up in ethyl acetate (100 mL)EtOAc. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using EtOAc/MeOH/EtOAc (EtOAc/EtOAc) The product was isolated and concentrated in vacuo to give the title compound as a yellow oil, <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> NMR (400 MHz, CDC13) δ ppm 8.48-8.54 (m, 1 Η) , 7.83 (d, 1 Η), 7.61 (t, 1 Η), 7.46-7.56 (m, 3 Η), 7.25 (d, 1 Η), 7.12-7.19 (m, 1 Η), 5.09 (s, 1 Η), 4.40-4.50 (m, 1 Η), 4.17-4.32 (m, 2 Η), 3.73-3.83 (m, 1 Η), 3.17-3.29 (m, 2 Η), 1.30 (t, 3 Η) MS (ESI) m/z 311 [M+H], MS (ESI) m. Example I_2 140345.doc -33- 201000461 3-Sideoxy-2-(2-0 than -2-ylethyl)-1 Η-iso 11 丨嗓-1-carboxylic acid

Add 2 M to a stirred solution of 3-oxo-2-(2-pyridin-2-ylethyl)-1 Η-isoindole formate (1.09 g, 3.50 mmol) in methanol (10 mL) NaOH (3.5 mL '7_0 mmol). The reaction mixture was stirred at ambient temperature for 15 min and then neutralized with 2 M EtOAc and concentrated to dryness in vacuo. The obtained solid was dissolved in a decyl alcohol/acetone 1 / 1 mixture (25 mL), and the white solid formed was crystallised to give the title compound as a yellow solid. . H NMR (400 MHz, DMSO-i/6) δ ppm 8.44-8.48 (m, 1 Η), 7.58-7.70 (m, 3 Η), 7.51-7.57 (m, 1 Η), 7.45 (t, 1 Η ), 7.26 (d, 1 Η), 7.17-7.22 (m, 1 Η), 5.07 (s, 1 Η), 4.13-4.24 (m, 1 Η), 3.53-3.64 (m, 1 Η), 2.95- 3.14 (m, 2 Η); MS (ESI) m/z 283 [M+H]. Example 1-3 3-Phenoxy-2-(pyridin-3-ylmethyl)-iH-isoindole·1-carboxylate

Intermediate 3 140345.doc -34- 201000461 2-(1-Bromo-2-ethoxy-2-oxoethyl)phenylhydrazine in acetonitrile (25 mL) according to the procedure described for Intermediate 1 The title compound was synthesized as a yellow oil. EtOAc (EtOAc: EtOAc, EtOAc, EtOAc, EtOAc, EtOAc , 0.56 g (63 〇 / 〇) ° !H NMR (400 MHz, DMSO-J6) δ ppm 8.52-8.55 (m, 1 Η), 8.47-8.50 (m, 1 Η), 7.76-7.80 (m, 1 Η), 7.69-7.73 (m, 1 Η), 7.65-7.69 (m, 1 Η), 7.57-7.64 (m, 2 Η), 7.33-7.38 (m, 1 Η), 5.39 (s, 1 Η ), 5.02 (d, 1 Η), 4.51 (d, 1 Η), 4.07-4.18 (m, 2 Η), 1.14-1.20 (m, 3 Η); MS (ESI) m/z 297 [M+H ], MS (ESI) m/z 295 [MH]. Example 1-4 3-Phenoxy-2-(pyridin-3-ylmethyl)-1Η-isoindole-1-carboxylic acid

Intermediate 4 was isolated from 3-o-oxy-2-(pyridin-3-ylindenyl)-1H- according to the procedure described for Intermediate 2. The title compound was synthesized as a white solid (0.43 g). (84%). !H NMR (400 MHz, DMSO-J6) δ ppm 13.68 (br. s., 1 H), 8.51-8.55 (m, 1 H), 8.48 (dd, 1 H), 7.76 (d, 1 H), 7.68-7.72 140345.doc -35- 201000461 (m, 1 Η), 7.62-7.68 (m, 2 Η), 7.55-7.61 (m, 1 Η), 7.35 (dd,l Η), 5.24 (s, 1 Η), 5.10 (d, 1 Η), 4.44 (d, 1 Η); MS (ESI) m/z 267 [M+H], MS (ESI) w/z 269 [MH] 〇Example 1-5 2 -(1-Methyl-2-pyridin-2-ylethyl)-3-oxoisoisoindoline-1-furoate ethyl ester

Ethyl 2-(1-bromo-2-ethoxy-2-oxoethyl)benzoate (3.0 g, 9.5 mmol) from acetonitrile (25 mL) The title compound was synthesized to give the product, 1.9 g (yield: 1-methyl-2-y)-diethyl-2-ethylamine (1.95 g, 14.3 mol) and triethylamine (2·13 mL, 1 5.3 mmol). 62〇/〇). 'H NMR (400 MHz, CDC13) δ ppm 8.52, 8.38 (d+d, 1 H), 7.76-7.81 (m, 1 H), 7.46-7.57 (m, 4 H), 7.20, 7.13 (d+d , 1 H), 7.04-7.10 (m, 1H), 5.31, 4.72 (s + s, 1 H), 4.75-4.80, 4.09-4.30 (m+m, 3H), 3.63-3.69, 3.24-3.34, 3.10 (m+m + dd, 2 H), 1.67, 1.37 (d+d, 3 H), 1.29 (m, 3H); MS (ESI) m/z 325 [M+H]. Example 1-6 2-(1-indolyl-2-0-buty-2-ylethyl)-3-sideoxyisoindole tipping _ι·capric acid 140345.doc 36- 201000461

Intermediate 6 was prepared from ethyl 2-(1-methyl-2-pyridin-2-ylethyl)_3_oxoxyisoindoline-1-carboxylate (0.97 g, according to the procedure for Intermediate 2). The title compound was synthesized as a yellow solid (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; NMR (400 MHz, CD3OD) δ ppm 8.43-8.47, 8.34-8.38 (m+m, 1 H), 7.47-7.71 (m, 4 H), 7.37-7.46 (m, 1 H), 7.24-7.29 (m , 1 H), 7.15-7.24 (m, 1 H), 5.15, 4.55 (s+s, 1H), 4.75-4.83, 4.22-4.3 1 (m+m, 1 H), 3.65, 3.08 (dd+dd , 1 H), 3.19-3.28 (m, 1 H), 1.64, 1.44 (d+d, 3 H); MS (APCI/APPI) m/z 297 [M+H]. Example 1-7 Ethyl 2-(2-ethoxy-2-oxooxyethyl)-6-methoxybenzoate

.0 0 Intermediate 7 Step 1: A mixture of 3-glycol- ortho-dibenzoic acid (2.90 g, 12-8 mmol), concentrated sulfuric acid (3 ml) in ethanol (20 ml) and toluene (30 ml) Dean _ Deco-Starck under reflux conditions overnight. The reaction mixture was cooled to a temperature of 140345.doc -37 - 201000461 and neutralized with 1 M NaOH. . Evaporate ethanol in vacuum and use brine

A clear oil was produced, 0.56 mg (22%). Step 2: Mix the ester product from the first step (〇56 g, 2 2 mm〇1) &amp; potassium carbonate (〇·77 g, 5.6 mmol, 2-5 equivalents) in mDMF (1 mL) in % Stir at temperature for 15 min. Iododecane (283, 4 5 mmol mmol '2.0 equivalent) was added, the atmosphere was changed to argon and the reaction mixture was heated to 60 ° C overnight. The reaction mixture was allowed to reach ambient temperature, diluted with EtOAc EtOAc EtOAc. The organic layer was dried with EtOAc EtOAc EtOAc (EtOAc) 4 NMR (400 MHz, CDC13-c/) δ ppm 7.33 (t,1 H), 6.84-6.93 (m, 2 H), 4.39 (q, 2 H), 4.14 (q, 2 H), 3.84 (s , 3 H), 3.66 (s, 2 H), 1.38 (t, 3 H), 1.25 (t, 3 H); MS (ESI) m/z 267 [M+H]. Example 1-8 2-(1-Bromo-2-ethoxy-2-oxoethyl)-6-nonyloxyphenyl hydrazine c\r\ ^

Intermediate 8 140345.doc -38· 201000461 Ethyl 2-(2-ethoxy-2-oxoethyl)-6-methoxybenzoate (3.10 g, 〇1) (3.00 g, 16.9 mmol, 1.5 eq.) and 2,2'-azobis(2-mercaptopropionitrile) (377 mg, 2.30 mmol, 0.2 hr) in carbon tetrachloride (5 〇 mL) The mixture was refluxed for 1.5 h. The reaction mixture was cooled to ambient temperature & filtered and concentrated in vacuo. The crude product was purified by column chromatography eluting EtOAc (EtOAc) !H NMR (400 MHz, CDCl3-i/) δ ppm 7.38-7.43 (m, 2 Η), 6.90-6.95 (m, 1 Η), 4.44 (q, 2 Η), 4.17-4.31 (m, 2 Η ), 3.85 (s, 3 Η), 1.74 (s, 1 Η), 1.41 (t, 3 Η), 1.27 (t, 3 Η); MS (ESI) m/z 345, 347 [M+H]. Example 1-9 4-methoxy-3-indolyl-2-(2-pyridin-2-ylethyl)isoindoline-1-carboxylic acid ethyl ester

Intermediate 9 2-(1-bromo-2-ethoxy-2-oxoethoxyethyl)-6-methoxybenzoic acid in acetonitrile (30 mL) according to the procedure for Intermediate 1 Ethyl ester (2.50 g, 7.24 mmol), 2-° ratio of sigma-2-ethyl-ethylamine (1.50 g, 12-2 mol) and triethylamine (2.20 mL, 15.8 mmol). %) Product. 140345.doc -39- 201000461 H NMR (400 MHz, CDC13) δ ppm 8.51 (d,l Η), 7.58 (t, 1 H), 7.45 (t, H), 7.22 (d, 1 H), 7.06- 7.17 (m, 2 H), 6.92 (d, 1 H), 4.95 (s, 1 H), 4.38 (dt, 1 H), 4.10-4.32 (m, 2 H), 3.96 (s, 3 H), 3.68 (dt, 1 H), 3.08-3.28 (m, 2H), 1.28, (t, 3 H); MS (ESI) m/z 341 [M+H]. Example 1-10 4-methoxy-3-indolyl-2-(2-pyridin-2-ylethyl)isoindoline_i-formic acid

Intermediate 10 according to the procedure described for Intermediate 2, 4-(methoxy-2-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-indole-carboxylic acid ethyl ester (〇) 681 g, 2 〇〇 mmol) The title compound was crystalljjjjjjjjjjjjjjjjjjj H NMR (400 MHz, MeOH) δ ppm 8.39-8.45 (m, 1 H), 7.71 (td, 1 H), 7.46 (t, 1 H), 7.33 (d, 1 H), 7.21-7.26 (m , 2 H), 6.97 (d,1 H), 4.83 (s,1 h), 4.30-4.41 (m,1 H), 3.89 (s, 3 H), 3.54-3.68 (m, 1 H), 3.05 -3.23 (m, 2 H); MS (ESI) m/z 313 [M+H]. Example I-11 4-methoxy-2-(1-methyl-2-pyridyl-2-ylethyl)-3-oxoisoindoline-1-carboxylate 140345.doc -40- 201000461

Intermediate 11 according to the procedure described for Intermediate 1 from 2-(1-di-(2-ethoxy-2-ethyloxyethyl)-6-methoxybenzoic acid ethyl acetate in acetonitrile Ι_曱基_2_. ratio. The title compound was synthesized from EtOAc (m.p. 4 NMR (400 MHz, CDC13) δ ppm 8.51 (dd, 1H), 7.39-7 69 (m, 2 H), 7.23 (dd, 1 H), 6.97-7.16 (m, 2 H), 6.90 (d, l 4.62-4.79 (m, 2 H), 4.07-4.36 (m, 3 H), 3.89-4.04 (m, 3 h) 3.19-3.39 (m, 1 H), 1.59-1.70 (m, 1 H), 1.17-1.39 (m, 5 H) ; MS (ESI) m/z 355 [M+H]. Example 1-12 4-Methoxy-2-(1•indolyl-2-pyridin-2-yl Base)-3-sideoxyisoindole _ 1-carboxylic acid

Intermediate 12 according to the procedure described for Intermediate 2, 4-methoxy-2-(1-indolyl-2-pyridylethyl)-3-oxoxyisoindole-1-carboxylic acid The title compound was synthesized as a yellow solid (0.2 g, EtOAc). 140345.doc •41 · 201000461 lH NMR (400 MHz, DMSO-£/6) δ 8.41-8.51 (m, 1 H), 7.56-7.68 (m, 1 H), 7.29-7.37 (m, 1 H), 7.13-7.22 (m, 2 H), 7.06 (t, 1 H), 6.85 (d, 1 H), 4.73, 4.31 (s+s, 1 H), 4.39-4.51, 4.06-4.18 (m, 1 H ), 3.80, 3.79 (s+s, 3 H), 3.40-3.49, 3.05-3.26, 2.91-3.00 (m, 2 H), 1.37, 1.20 (d, 3 H) ; MS (ESI) m/z 327 [M+H]. Example 1-13 3-Phenoxy-2-(2-pyridin-4-ylethyl)isoindoline _i-carboxylic acid ethyl ester

Ethyl 2-(1-bromo-2-ethoxy-2-oxoethoxyethyl)benzoate (acetic acid ethyl ester) (2.50 g, 7.90 mmol) from EtOAc (25 mL) The title compound was synthesized from 2-pyridin-4-yl-ethylamine (2_00 g, 16.3 mmol) ]H NMR (400 MHz, CDC13) δ ppm 8.51 (d, 2 H), 7.85 (d, 1 H), 7.46-7.61 (m, 3 H), 7.18 (d, 2 H), 4.94 (s, 1 H), 4.11-4.41 (m, 3 H), 3.46-3.61 (m, 1 H), 2.91-3.14 (m, 2 H), 1.30 (t, 3 H) ; MS (ESI) m/z 311 [ M+H]. Example 1-14 3-Alkyloxy-2-(2-pyridin-4-ylethyl)isoindoline-1-decanoic acid 140345.doc -42· 201000461

Intermediate 14 from 3-oxooxy-2-(2-pyridin-4-ylethyl)isoindoline_1-decanoate (0.621 g, 2.00 mmol) according to the procedure described for Intermediate 2 The title compound was synthesized from EtOAc (EtOAc m. *H NMR (400 MHz, MeOH) δ ppm 8.39-8.41 (m, 2 Η), 7.68-7.73 (m, 2 Η), 7.56 (td, 1 Η), 7.46 (t, 1 Η), 7.34-7.39 (m, 2 Η), 5.00 (s, 1 Η), 4.26-4.35 (m, 1 Η), 3.57-3.66 (m, 1 Η), 3.00-3_17 (m, 2 Η); MS (ESI) m /z 283 [M+H]. Example 1-15 3-Ethyloxy-2-(2-pyridin-3-ylethyl)isoindoline-1-carboxylate

Intermediate 15 2-(1 -Bromo-2-ethoxy-2-oxoethyl)benzoic acid ethyl ester (2.10 g, acetonitrile (25 mL), m. 6.60 mmol), 2-α ratio. The title compound was synthesized to give 1-29 g (yield: 63%). !H NMR (400 MHz, CDC13) δ ppm 8.51 (d, 2 H), 7.85 (d, 1 140345.doc -43» 201000461 Η), 7.46-7.61 (m, 3 Η), 7.18 (d, 2 Η ), 4.94 (s, 1 Η), 4.12-4.42 (m, 3 Η), 3.47-3.60 (m, 1 Η), 2.91-3.14 (m, 2 Η), 1.30 (t, 3 Η); MS ( ESI) m/z 3 11 [Μ+Η]. Example 1-16 3-Phenoxy-2-(2-pyridin-3-ylethyl)isoindoline-1-carboxylic acid

Intermediate 16 is based on the procedure described for Intermediate 2 from 3-tertiaryoxy-2 - (2 - ° to π-1,3-ethylidene). .2 g, 2.00 mmol). 'H NMR (400 MHz, MeOH) δ ppm 8.41-8.44 (m, 1 H), 8.36 (dd, 1 H), 7.76-7.82 (m, 1 H), 7.66-7.74 (m, 2 H), 7.53 -7.58 (m, 1 H), 7.42-7.49 (m, 1 H), 7.31-7.38 (m, 1 H), 5.00 (s, 1 H), 4.23-4.32 (m, 1 H), 3.54-3.63 (m, 1 H), 2.98-3.17 (m, 2 H); MS (ESI) m/z 283 [M+H]. Example 1-17 2 -Methyl-1 - (°~2 -yl)propan-2-amine

Intermediate 17 140345.doc -44- 201000461 2 -Methyl-1-(η ratio. _2_ yl)propan-2-ol (197 mg, 1.3 mmol, according to European Journal 〇f Or ganic Chemistry 2QQQ, 15 , 2735 Preparation) mixed with trimethyl decane cyanide (0.347 mL, 2.60 mmol), placed under N2 atmosphere and cooled to -丨5' followed by slow addition of concentrated sulfuric acid (〇2 i

mL '3·90 mmol). The mixture was warmed to room temperature and stirred for 16 h then poured onto ice &lt;&gt; The organic layer was dried over anhydrous sulphuric acid steel and filtered. The crude product is a mixture of an amine amine intermediate and an olefin by-product. The crude product was diluted with 6 μ HCl solution (5 mL) and reflux for 16 h. The pH was set to 7 by the addition of 4 M NaOH solution and the mixture was purified by preparative HPLC. Colorless oil, 32 mg (16 〇 / 0). H NMR (400 MHz, CD3OD) δ (ppm) 8.49 (dd, 1 Η) 7.74 (5), 1 Η) 7.23-7.32 (m, 2 Η) 3.28 (s, 2 Η) 3.01 (s, 2 Η) 1.29 ( s, 6 H). MS (ESI) w/z 151 [M+H]. Example 1-18 N_(l-(4-(Trifluoromethoxy)phenyl)ethyl)carboxamide

1-(4-(Trifluoromethoxy)phenyl)ethylamine (0.352 g, i.72 mm 〇1) was dissolved in di-methane (4 mL), placed in Nz atmosphere and cooled to d Phenyl formate (0.187 mL, 1.72 mmol) was added dropwise and the mixture was stirred at room temperature for 6 h. The solvent was removed in vacuo and the residue was purified on a silica gel column using hexanes: ethyl acetate = 100:0 to 0:100 as a gradient. Colorless oil, 284 mg (71%). 'H NMR (500 MHz, CDC13) δ (ppm) 8.20 (s, 1 H) 7.36 (d, 2 H) 7.17-7.22 (m, 2 H) 5.77 (br. s.,1 H) 5.24 (t, 1 H) 1.53 (d, 3 H). MS (ESI) m/z 234 [M+H]. Example 1-19 1-(1-Isocyanoethyl)-4-(trifluoromethoxy)benzene

c intermediate 19 N-(1-(4-(trifluorodecyloxy)phenyl)ethyl)decylamine (〇·275 ru, 1.18 mmol) was dissolved in dioxane (4 mL). Cool to -15 C in an n2 atmosphere. Add hydrazine, hydrazine-diisopropylethylamine (〇 780 mL, 4.72 mmol), and add phosphorus oxychloride (〇·丨32 mL, 1.42 mmol) and allow the mixture to slowly reach room temperature (3 hours) . Methanol (1_5 mL) was then added to stop the reaction. The mixture was diluted with di-methane and washed twice with saturated NaHc. The combined organic extracts were washed with EtOAc (EtOAc m. H NMR (500 MHz, CDC13) δ (ppm) 7.41 (d, 2 H) 7.24-7.29 (m, 2 H) 4.85 (q, i H) 1.70 (d, 2 H) 0 MS (ESI) m/z 216 [M+H]. Example 1-20 140345.doc *46- 201000461 6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridinecarboxaldehyde ί.丫,.Ν.丫 〇, ',

HLJ / Intermediate 20 Slowly add 2.5 (4) of a butyl ring (5.0 mL ' ιι_9 mm 〇l) in diethyl ether to 2 bromo-6 under nitrogen at 78 C ((tetrahydrofuran-2-yl) Oxy)methyl)anthracene (3.〇g, u.〇mm〇l, according to 丄^(10)/〇/ Org(iv)/c C/z(iv) in π 1993, 别&quot; team 1993 prepared in anhydrous tetrahydrofuran (15 In the solution in ml). The reaction mixture was stirred for 1 hour then DMF (5 mL) was added. The mixture was warmed to room temperature over 2 hours, then quenched with saturated aqueous ammonium chloride and extracted with diethyl ether (2.times. The ether layer was dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by EtOAc EtOAc EtOAc (EtOAc) NMR (400 MHz, CDC13) δ (ppm) 10.06 (s, 1 h) 7_88 (s 2 Η) 7.74 (d, 1 Η) 4.99 (d, 1 Η) 4.82 (br. s., 1 Η) 4.73 ( Sj ι H) 3.92 (d, 1 H) 3.57 (d, 1 H) 1.66-1.96 (m, 6 H). Example 1-21 (E)-2-(2-Nitrovinyl)-6-((tetrahydro-2H•piperidin-2-yloxy)methyl) 0 ratio bite

Intermediate 21 140345.doc -47· 201000461 Dissolve sodium hydroxide (0.282 g, 7.0 mmol) in water (1.7 mL) and slowly add to the Nitrogen Institute (0.394 g, 6.47 mmol) at 〇 °C And 6-((tetrahydro-2H- η sulpho-2-yloxy)methyl) π is a solution of the formic acid (ug, 59 mmol) in methanol (8 mL). The reaction mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was diluted with water (1 mL) and extracted with dichloromethane (2.times. The organic extract was concentrated in vacuo to give 2-nitro-1-(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)ethanol (1-21 g' 4.3 mmol) 'Dissolve in anhydrous dichloromethane (5 mL). To the mixture was slowly added to a mixture of methanesulfonate (0.478 g '4.3 mmol) in anhydrous di-methane (5 mL), followed by stirring for 15 minutes. Thereafter, N,N-isopropylethylamine (0.58 g, 4.5 mmol) was added, and the reaction mixture was further stirred for 1 hour, diluted with dichloromethane (1 mL) and water (10 mL) and brine 10 mL) wash. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography using hexanes: ethyl acetate = 1 00:0 to 90:1 to elute to afford the desired product 750 mg (50%). H NMR (400 MHz, CDC13) δ (ppm) 8.02 (d, 1 Η) 7.91 (d, l H) 7.79 (t, 1 H) 7.58 (d, 1 H) 7.36 (d, 1 H) 4.91 (d , 1 H) 4.80 (t,1 H) 4.66 (d,1 H) 3.80-4.00 (m,1 h) 3.48-3.66 (m, 1 H) 1.77-1.93 (m, 6 H) = MS (ESI) m/z 265 [M+H] ° Example 1-22 2-(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridine-2-yl)ethylamine 140345.doc - 48- 201000461

H2n

Intermediate 22 '(E)-2-(2-Nitrovinyl)-6-((tetrahydro-2H-piperidin-2-ylindenyl)methyl)D ratio (750 mg, 2.8) at room temperature The mmol of tetrahydrofuran (mL) was added dropwise to lithium aluminum hydride (323, 8.5 mmol) in diethyl ether (6 mL). The reaction mixture was refluxed for 2 hrs, cooled to room temperature and stirred for 18 h. The reaction mixture was quenched with a 2% aqueous NaH solution and extracted with diethyl ether (3 x 20 mL). The combined ether layers were dried over anhydrous sodium sulfate, filtered and succinated to give the desired compound, 38 <RTIgt; MS (ESI) m/z 237 [M+H] 〇 Example 1-23 3- </ RTI> </ RTI> </ RTI> 2-(2-(6-((tetrahydro-2H-pyran-2-yloxy)methyl) Pyridine-2·yl)ethyl)isoindene_1_ post-ethyl vinegar

\Λ:.〇,.〆Intermediate 23 2-((bromo-2-ethoxy-2-oxoethyl)benzoic acid ethyl ester in acetonitrile (5 mL) according to the procedure described for intermediate i (5〇4 mg, [6, 2 (6-((tetrahydro-2H_pyran-2-yloxy)methyl)acridin-2-yl)ethylamine (w〇g 1.6 mmo1) and The title compound solid was synthesized from ethylamine ( 323 mg, 3.2 mmol), 210 mg (3 〇〇 / 0). Ms (ESI) 425 [M+H]. 140345.doc -49- 201000461 Example 1-24

Ethyl)isophthalic acid

Intermediate 24 A solution of lithium hydroxide (14 mg, 0 58 mm 〇1) in water (3 mL) was added to 3- oxo-2-(2-(6-((4) Hydrogen-2H-piperidin-2-yloxy)methyl)pyridin-2-yl)ethyl)isoindoline decanoic acid ethyl ester (〇21〇g '0.49 mmol) in tetrahydrofuran (10 mL) Stir the solution. The reaction mixture was stirred for 3 hours then concentrated under reduced pressure. The crude residue was redissolved in water (10 mL) andEtOAcEtOAcEtOAc The combined organic extracts were washed with EtOAc (EtOAc m. MS (ESI) w/z 397 [M+H]. Example 1-25 2-(2-(3-Fluoro*Bite-2-yl)ethyl)-3-lateral oxy-iso- 丨嗓 丨嗓 _1 _1_

Intermediate 25 140345.doc -50- 201000461 2-(1_bromo-2-ethoxy-2-oxoethyl)benzoic acid ethyl acetate from acetonitrile (5 mL) according to the procedure described for Intermediate 1 (492 mg, 1.6 mmol), 2-(3-fluoro-bito-2-yl)ethylamine (218 mg, 1.6 mmol) and triethylamine (323 mg &lt; Solid, 16 mg (33.8%). ]H NMR (400 MHz, CDC13) δ (ppm) 8.26 (d, 1 Η) 7.78 (d, 1 Η) 7.37-7.47 (m, 2 Η) 7.28-7.36 (m, 2 Η) 7.02-7.15 (m , 1 Η) 5.33 (s, 1 Η) 4.13-4.26 (q, 2 Η) 2.83-3.10 (m, 4 Η) 1.38 (t, 3 H). MS (ESI) w/z 329 [M+H]. Example 1-26 2-(2-(3-Fluoropyridin-2-yl)ethyl)-3-oxooxyisoindoline-1_carboxylic acid

Intermediate 26 Add a solution of hydrogen hydroxide (10 mg, 0-41 mmol) in water (3 mL) to 2-(2-(3-fluoropyridin-2-yl)ethyl)-3 at room temperature - a mixture of oxetyl isoindole-1-acetic acid ethyl acetate (0.125 g, 0.38 mmol) in tetrahydrofurfuran (1 mL). The reaction mixture was stirred for 3 hours and then reduced under reduced pressure. The crude residue was redissolved in water (1 mL) and was acidified with succinic acid and then extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were washed with EtOAc EtOAc EtOAc m. 140345.doc -51 · 201000461 丨H NMR (400 MHz, CDC13) δ (ppm) 8.24 (d,1 Η) 7.80 (d,1 H) 7.27-7.35 (m, 2 H) 7.22-7.31 (m, 2 H) 7.02-7.10 (m, 1 H) 5.28 (s, 1H) 2.92-3.12 (m, 4 H) ° MS (ESI) m/z 301 [M+H]. Example 1-27 N-(3-(Trifluoromethoxy)benzyl)carbamamine

Intermediate 27 The title compound was prepared according to the procedure described for Example 18 using (3-(trifluoromethoxy)phenyl) decylamine (0.2 g, 1.05 mmol) and EtOAc. Colorless oil, I20 mg (52%). NMR (500 MHz, CDC13) δ (ppm) 8.31 (s, 1 Η) 7.35-7.40 (m, 1 Η) 7.22-7.26 (m, 1 Η) 7.15 (br. s·, 2 Η) 5·92 ( Br· s·, 1 H) 4_53 (d, 2 H). MS (ESI) m/z 220 [M+H]. Example I_28 1-(Isocyanomethyl)-3-(trifluoromethoxy)benzene

Intermediate 28 140345.doc • 52- 201000461 According to the method described in Example 19, N_(3_(trifluoromethoxy)benzyl)carnitine (120 mg, 〇55 _〇1), N N_ was used. The title compound was prepared from diisopropylethylamine (EtOAc EtOAc: EtOAc: EtOAc:EtOAc: A fading oil < 110 mg (i 〇〇 %) which was used without further purification. H N1VIR (500 MHz, CDC13) δ (ppm) 7.43-7.49 (m,1 H) 7.31 (d,1 Η) 7.21-7.25 (m, 2 Η) 4.69 (s, 2 H). MS (ESI) m/z 202 [M+H]. Example 1-29 N-(2-Methyl-4-(trifluoromethoxy)benzyl)carbamamine 0

1.1 Ν〆, Ή 中间 Intermediate 29

The title was prepared according to the method described in Example 18 using (2-mercapto-4-(trifluoromethoxy)phenyl)methanamine (0.35 g ' 1.71 mmol) and phenyl formate (0.191 mL, 1 71 mmol) Compound. The crude product was used as a gradient on a ruthenium dioxide column using dioxane: (di-methane/methanol/ammonia 90:10:1) = 100:0 to 30:70. White solid, 252 mg (63%). NMR (500 MHz, CDC13) δ (ppm) 8.28 (s, 1 H) 7.27 ^ 5 1 Η) 7·06 (br. s., 2 Η) 5.68 (br. s.,1 Η) 4.49 (d, 2 Η) 2.36 ( 3 Η). MS (ESI) w/z 232 [Μ-Η]. 'Example 1-30 140345.doc -53 - 201000461 W isocyanomethyl)_2_methyl,trifluoromethoxy)benzene F丫,〇,\, intermediate 3 0 $ according to Example 19 The method uses ν·(2_methyl_4_(trimethylmethoxy)phenylhydrazine) to brew amine 25〇g,i. 7匪. , ΝΝdiisopropylethylamine (0.742 mL ' 4.29 mm〇i) and phosphorus oxychloride (〇12〇mL, 1.29 mmol); ^ compound compound. Brown oil, then (13%) It was used without further purification. MS (ESI) w/z 216 [M+H]. Example 1-31 4-(2,2,2-trifluoroethyl) benzonitrile

Intermediate 31 Add zinc cyanide (2 U) to a solution of 1-bromo-4-(2,2,2-trifluoroethyl)benzene (215 §, 〇〇111111〇1) in DMF (25 mL) g, 18 〇 mmol) and Pd(PPh3) 4 (0.828 g '0.720 mmol). The mixture was taken at 1 Torr. (: heating for 18 hours), then cooled to room temperature, diluted with ethyl acetate (5 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The ethyl acetate = 90:1 was used as the solvent to afford the title compound, mp (yield: EtOAc, EtOAc (EtOAc) , 2 Η) 7.43 (d, 2 Η) 3.44 (q, 2 H). 19F NMR (400 MHz, CDC13) δ (ppm) 140345.doc • 54· 201000461 -65.85, -65.88 and -65.91. MS (ESI m/z 186 [M+H]. Example 1-32 (4-(2,2,2-trifluoroethyl)phenyl)methylamine

Intermediate 32 was added to tetrahydrofuran in a solution of 4-(2,2,2-trifluoroethyl)benzonitrile (Quo g, 3.13 mmol) in tetrahydrofuran (9.40 mL, 9.40 mmol). (15 mL) in solution. The mixture was placed at 6 Torr. (: heating under 18 hours, cooling to room temperature and concentrating under reduced pressure. The residue was redissolved in decyl alcohol (1 5 mL), refluxed for 2 hr and concentrated under reduced pressure. The title compound was obtained as a pale yellow oil. EtOAc (EtOAc m. , 600 mg (; 1 00%). H NMR (400 MHz, CDC13) δ (ppm) 7.27-7.34 (m, 4 Η) 3.88 (s, 2 Η) 3.36 (q, 2H) (NH2 not shown) 19F NMR (400 MHz, CDCl3) S (ppm)-66.42, -66.45A-66.48 °MS (ESI) m/zl90 [M+H]. Example 1-33 N-(4-(2,2,2) -trifluoroethyl)benzidine)

Intermediate 33 140345.doc -55- 201000461 (4-(2,2,2-Trifluoroethyl)phenyl)methylamine (〇65〇g, 3 4〇〇1) to ethyl formate (5 The solution in mL) was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure and purified EtOAc EtOAc EtOAc EtOAc , 620 mg (84%). NMR (400 MHz, CDC13) δ (ppm) 8.30 (s, 1 H) 7.29 (s, 4 H) 5.77 (m, 1 H) 4.51 (d, 2 H) 3.36 (q, 2 H) 〇19F NMR ( 400 MHz, CDC13) δ (ppm) - 66.36, -66.39 and -66.41. MS (ESI) m/z 218 [M+H]. Example 1-34 1-Isocyanoindol-4-(2,2,2-trifluoroethyl)benzene

Add phosphorus oxychloride (0.320 mL, 3.43 mm 〇i) dropwise to N-(4-(2,2,2-difluoroethyl)phenylhydrazinyl) guanamine at -20 °C (〇62 〇笆, 2% mmol) and a solution of N,N-diisopropylethylamine (1.97 mL, 11.4 mmol) in dichloromethane (20 mL). The mixture was slowly warmed to room temperature and searched for 6 hours. Thereafter, the reaction mixture was concentrated, and the residue was dissolved in methanol (trim) and triethylamine (2 - 5 mL). The reaction mixture was stirred for 5 minutes and concentrated under reduced pressure. The crude compound was purified by hydrazine gel column chromatography using hexanes: EtOAc (EtOAc) to EtOAc (EtOAc: EtOAc)丨H NMR (400 MHz, CDC13) δ (ppm) 7.36 (s, 4 Η) 4.66 (s 2 140345.doc •56- 201000461 H) 3 39 (q, 2 H). 19F NMR (400 MHz, CDC13) δ (ppm) -66.31, _66 34 and _66 37. MS (ESI) w/z 200 [M+H]. Example 1 (general procedure 1) N-[(4-Phenylphenyl)methyl]_3_sideoxy-2-(2-»pyridin-2-ylethyl)-1Η-isoindole-1- Formamide

Add 2-(2-Aminoethyl)pyridine (24 μιη, 0.20 mmol) to a solution of methanol (2 mL) in MeOH (2 mL), followed by 1-chloro- 4-(isocyanomethyl)benzene (27 mg, 〇18 mm〇1). The reaction mixture was stirred overnight at ambient temperature, then filtered and purified using preparative liquid chromatography. The product-containing fractions were pooled and the acetonitrile was removed in vacuo. The aqueous solution was extracted with ethyl acetate. Dry the organic layer with magnesium sulfate

It was dried and concentrated in vacuo to give the title compound, m. 'H NMR (400 MHz, CDC13) δ ppm 8.95-9.04 (m, 1 H), 8.16 (d, 1 H), 7.64-7.72 (m, 3 H), 7.54-7.60 (m, i H), 7.44 -7.5〇(m, 1 H), 7.28 (s, 1 H), 7.11-7.21 (m, 3 H), 7.01-7.07 (m, 2 H), 5.04 (s, 1 H), 4.30-4.47 ( m, 2 H), 4.03-4.13 (m, 1 H), 3-82-3.91 (m, 1 H), 3.12-3.23 (m, ! H)} 3.01-3.10 (m, | H) ; MS ( ESI) w/z 406 [M+H]. 140345.doc -57- 201000461 Example 2 (general procedure 2) 3. Side oxy-2-(2-bite-2-ylethyl) good [[4_(trifluoromethoxy)phenyl]methyl 】-1H-isoindole-1-cartoamine

To a solution of 3-oxo-2-(2-pyridin-2-ylethyl)_1H-isoindole-indole-carboxylic acid (56 mg, 0.2 mm 〇l) in DMF (~. 5 mL) Triethylamine (84 pL, 0.6 mmol) and fluoro-N,N,N,N,4-tetramethylhydrazine (79 mg, 0.3 mmol) were added in that order. The reaction mixture was stirred at ambient temperature for 5 to 1 min. 4-Trifluoromethoxy-benzoguanamine (152 melon, i mm 〇 1) was added, and the mixture was stirred at 45 C for 2.5 h. The mixture was dried and purified using preparative liquid chromatography. The product-containing fractions were pooled and the acetonitrile was removed in vacuo. The aqueous solution was assayed with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried with EtOAc EtOAc EtOAc. H NMR (400 MHz, CDC13) δ ppm 9.11-9.19 (m,1 Η), 8 13 (d,1 H), 7.66-7.75 (m, 3 Η), 7.54-7.60 (m,1 H), 7.47 (tj H), 7.31 (d, 1 H), 7.11-7.21 (m, 3 H), 7.03-7.09 (m; 2 H) 5.09 (s, 1 H), 4.35-4.51 (m, 2 H) , 4.02-4.13 (m, 1 H), 3.83-

3.94 (m,1 H),3.13-3.24 (m,1 H), 3.03-3.13 (m,1 H); MS (ESI) w/z 456 [M+H], MS (ESI) m/z 454 [MH]. Example 3 140345.doc -58- 201000461 3_Sideoxy_2-(2·β-pyridin-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl b 111-isoindole-1-carbamamine, isomer 1

Isomer 1 a = unknown absolute configuration by using the LaPrep system (tube: Chiralpak AD; 50x300 mm ' 10 μηι; mobile phase: 4〇% ethanol / 6〇% heptane, followed by 9% after 9 min) Ethanol; flow rate: 120 mL/min, 170 mg/inj) separation of racemic compound 3-oxo-2-(2-pyridin-2-ylethyl)-N-[[4-( The trifluoromethoxy)phenyl]methyl]-1 fluorene-isoindol-1-amine affords the enantiomerically pure compound. The fractions were collected according to the residence time and produced as the first isomer of the isomer at 13·31! . The dissolved fraction was evaporated under 23-25 to avoid thermal racemization and treatment separately. Analytical Lc analysis was performed using a Gils(R) system (column: Α〇, 4.6 x 250 mm, 1 〇 μηι; mobile phase: 1% ethanol; flow rate: 1 mL/min). Isomer 1 (5.5 broad 134 mg. Enantiomeric purity 99%. !H NMR (400 MHz, DMSO-c/^^ δ ppm 9.19 (tj 1 Η), 8.43- 8.47 (m, 1 H), 7.66-7.71 (m,2 Η&quot; η, 7.57-7.63 (m, 1 H), 7.48- 7.56 (m, 2 H), 7.35-7.40 (m, 2 7 on 〇κ «), 7.29-7.34 (m , 2 H), 7.26 (d, 1 H), 7.19-7.24 (m, 1 H), 5 ,, ^-24 (s, 1 H), 4.36 (d, 2 H), J40345.doc -59· 201000461 4-15-4.25 (m, 1 Η), 3.37-3.45 (m, 1 Η), 3.04-3.14 (m, 1 Η), 2.95-3.05 (m,1 Η); MS (APCI/APPI) w /z 456 [M+H]. Example 4 3-Phenoxy-2-(2-»pyridin-2-ylethyl)-N-[[4-(trifluoromethyl)phenyl]methyl ]-1H-isoindole-i_hydamine

According to the general procedure 2 described in Example 2, from 3-oxo-2-(2-pyridin-2-ylethyl)-1 hydrazine-iso-indole-1-decanoic acid (56 mg, 0.2 mmol) The title compound was synthesized from 4-trifluoromethyl-benzamide (142 pL, 1 mmol). White solids '17 mg (19%). 1H NMR (400 MHz, CDCl3) δ ppm 9.28-9.35 (m, 1 Η), 8.10-8.14 (m, 1 Η), 7.66-7.73 (m, 3 Η), 7.55-7.61 (m, 1 Η), 7.44 -7.51 (m, 3 Η), 7.30 (d, 1 Η), 7.20 (d, 2 Η), 7.13-7.17 (m, 1 Η), 5.07 (s, 1 Η), 4.51-4.59 (m, 1 Η), 4.37-4.45 (m, 1 Η), 4.06-4.17 (m, 1 Η), 3.81-3.89 (m, 1 Η), 3.14-3.24 (m, 1 Η), 3.02-3.11 (m, 1 MS (ESI) m/z 440 [M+H], MS (ESI) m/z 438 [MH]. Example 5 3-Phenoxy-2-(»bipyridin-3-ylmethyl)-N-[[4-(trifluoromethoxy)phenyl]indolyl]-1H-isoindole-1- Formamide 140345.doc -60- 201000461

3 _ side oxy-2 is more than 2-3 amino-methyl)-1 Η-iso-t-- _ formic acid (268 mg, ! mmol) is dissolved in two gas burning and _ 叩 5 and 2 In the mixture. Add triethylamine (556 μί, 4 mm〇1), n, n,-dicyclohexylcarbodiimide (412 mg, 2 mm〇1) A1_transbenzotrisole (27 〇, 2 Methyl) and the mixture was stirred at ambient temperature for 5 min. The intrinsic trifluoromethoxy-benzylamine (152 pL, 1 mmol) was added and the mixture was stirred at ambient temperature for 24 h. The mixture was diluted with ethyl acetate (25 mL) and brine and then brine. The organic layer was collected and dried over magnesium sulfate and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc) !H NMR (400 MHz, CDC13) δ ppm 8.57 (br. s., 1 H), 8.54 (d, 1 H), 7.71 (d5 1 H), 7.62-7.67 (m, 1 H), 7.57-7.62 (m, 2 H), 7.46-7.51 (m, 1 H), 7.23-7.27 (m, 1 H), 7.09-7.16 (m, 4 H), 6.42-6.50 (m, 1 H), 5.28 (d , 1 H), 4.94 (s, 1 H), 4.36-

4.40 (m, 2 H), 4.28 (d, 1 H) ; MS (ESI) m/z 442 [M+H], MS (ESI) m/z 440 [MH] 0 Example 6 Ν_[1-(4 ·Phenyl phenyl)ethyl]_3_sideoxy-2_(2-°tb ate-2·ylethyl)-1Η-isoindole-1_carbamamine 140345.doc •61 · 201000461

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (30 mg, 0.20 mmol), 2-(2-aminoethyl) 0 ratio (24 μί, 0.20 mmol) and 1- The title compound was synthesized from chloro-4-(1-isocyanoethyl)benzene (30 mg, 0.18 mmol). White solid, 35 mg (41 ° / 〇). ]H NMR (400 MHz, CDC13) δ ppm 8.56-8.82 (m, 1 Η), 8.03- 8.30 (m, 1 Η), 7.57-7.65 (m, 2 Η), 7.45-7.51 (m, 1 Η) , 7.42- 7.45 (m, 1 Η), 7.35-7.41 (m, 1 Η), 7.20-7.26 (m, 1 Η), 7.15- 7.18 (m, 1 Η), 7.06-7.14 (m, 1 Η) , 7.01-7.05 (m, 1 Η), 6.77- 6.83 (m, 1 Η), 4.96-5.11 (m, 1 Η), 4.91 (d, 1 Η), 3.72-4.07 (m, 2 Η), 2.84 -3.29 (m, 2 Η), 1.27-1.40 (m, 3 Η); MS (ESI) w/z 420 [M+H]. Example 7 3-Phenoxy-2-(2-&quot;pyrazin-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]methyl]-1H-isoindole -1-carboxamide

The general procedure 1 as described in Example 1 was carried out from 2-mercaptobenzoic acid (75 140345.doc -62 - 201000461 mg '0.50 mmol), 2-σpyr-2-yl-ethylamine (61 mg, 0.50) The title compound was synthesized from EtOAc (m.). White solid, 116 mg (50%). !H NMR (400 MHz, CDC13) δ ppm 8.58 (s, 1 Η), 8.47 (s, 1 Η), 8.18 (s, 1 Η), 7.97-8.05 (m, 1 Η), 7.68 (d, 1 Η), 7.64 (d, 1 Η), 7.56-7.62 (m, 1 Η), 7.43-7.50 (m, 1 Η), 7.10-7.17 (m, 2 Η), 7.04-7.10 (m, 2 Η) , 5.10 (s, 1 Η), 4.37-4.45 (m, 2 Η), 3.91-4.08 (m, 2 Η), 3.09-3.23 (m, 2 Η), 1.90 (br. s., 1 H); f. % MS (ESI) m/z 457 [M+H], MS (ESI) w/z 455 [MH]. Example 8 2-[(2-Methoxy)pyridin-3-yl)methyl]-3-oxo-N-[[4-(trifluoromethoxy)phenyl]methyl]-1H -isoindole-1-carboxamide

According to the general procedure 1 described in Example 1, from 2-mercaptobenzoic acid (38 mg, 0.25 mmol), (2-decyloxy-0 to 0--3-yl)-methylamine (35 mg, The title compound was synthesized from 0.25 mmol (yield of EtOAc/EtOAc). White solid, 18 mg (15%). !H NMR (400 MHz, DMSO-c/6) δ ppm 9.13 (t, 1 H), 8.08-8.13 (m, 1 H), 7.74 (d, 1 H), 7.59-7.65 (m, 1 H) , 7.51-7.58 140345.doc •63 201000461 (m,2 H),7.44-7.50 (m,1 H),7·30·7·39 (m,4 Η),6·90_6·97

(m, 1 H), 5.09 (s, 1 H), 4·97 (d, 1 H), 4.30_4·41 (m, 2 H), 4.17 (d, 1 H), 3.84 (s, 3 H MS (ESI) m/z 472 [M+H], MS (ESI) m/z 470 [MH] 0 Example 9 3- 3-oxo-2-(&quot;by ♦ -2-ylmethyl) -N-[[4-(trifluoromethoxy)phenyl]methyl]-1H-isoindole-1-cartoamine

According to the general procedure 1 described in Example 1, bromobenzoic acid (75 mg, 0.50 mmol), 0-pyridyl-2-yl-methylamine (72 mg '0.50 mmol) and 1-(isocyanoguanidine) The title compound was synthesized from -4-(trifluoromethoxy)benzene (100 mg 〇·5 〇 mmol). White solid, 20 mg (9%). !H NMR (400 MHz, DMSO-^6) δ ppm 9.17-9.23 (m, 1 Η), 8.67-8.69 (m, 1 Η), 8.54-8.57 (m, 2 Η), 7.73-7.78 (m, 1 Η), 7.61-7.67 (m, 1 Η), 7.53-7.59 (m, 2 Η), 7.29-7.38 (m, 4 Η), 5.31 (s, 1 Η), 5.24 (d, 1 Η), 4.41 (d, 1 Η), 4.34 (d, 2 Η); MS (ESI) w/z 443 [M+H], MS (ESI) w/z 441 [MH]. Example 10 3-Phenoxy-2-(2-«pyridin-2-ylethyl)-N-[l-[4-(2,2,2-trifluoroethoxy)phenyl]ethyl 】-1H-isoindole-1·carbamamine 140345.doc •64· 201000461

General procedure 2 as described in Example 2 from 3_sideoxy-2_(2-pyridine-2-ylethyl)-1Η-isoindole small formic acid (56 mg, 〇2 mm〇1) &amp; 1- [4_(2,2,2-Difluoro-ethoxy)-phenyl]-ethylamine (prepared according to WO 2007/073303, 150 mg, 〇.60 mm 〇1e as the title compound. White solid, 13 mg ( l 3%).H NMR (400 MHz, CDC13) δ ppm 8.64, 8.47 (d+d, 1 Η), 8.36, 8.13 (d+d, 1 Η), 7.42-7.73 (m, 5 Η), 7.22-7.34 (m, 2 Η), 7.11-7.22 (m5 1 Η), 6.90-6.96 (m, 1 Η), 6.82-6.88 (m, 1 Η), 6.68-6.75 (m, 1 Η), 5.04 -5.17 (m, 1 Η), 5.03, 4.95 (s+s, 1 Η), 4.24-4.35 (m5 2 Η), 4.01-4.11, 3.90-4.00, 3.81-3.90 (m+m +m, 2 H ), 3.26-3.36, 3.03-3.14, 2.90-3.01 (m+m+m, 2 H), 1.47, 1.39 (d+d, 3 H) ; MS (ESI) w/z 484 [M+H], MS (ESI) w/z 482 [MH]. Example 11 2-[(5-Mercapto-1,2-Napi-3-yl)indolyl]-3-Sideoxy-N- [[4- (di-l-methyl) phenyl]methyl]-1H-isoindole-1-carboxamide

140345.doc -65 - 201000461 according to the general procedure 1 described in Example 1 from 2-mercaptobenzoic acid (38 mg, 0.25 mmol), 5-mercapto-isoxazol-3-yl-decylamine ( 29 mg, 0.25 mmol) and 1-(isooxalyl)-4-(trifluorodecyloxy)benzene (50 mg, 0. 25 mmol). White solid, 41 mg (3 70 / 〇). ]H NMR (400 MHz, DMSO-J6) δ ppm 9.21 (t, 1 Η), 7.73-7.78 (m, 1 Η), 7.61-7.67 (m, 1 Η), 7.53-7.59 (m, 2 Η) , 7.35-7.40 (m, 2 Η), 7.30-7.34 (m, 2 Η), 6.17-6.21 (m, 1 Η), 5.20 (s, 1 Η), 5.13 (d, 1 Η), 4.36 (d , 2 Η), 4.17 (d, 1 Η), 2.36 (s, 3 Η); MS (ESI) m/z 446 [M+H], MS (ESI) m/z 444 [MH]. Example 12 N-[(4-Phenylphenyl)methyl]-3-oxo-2-(2·&quot;pyrazin-2-ylethyl)-1Η-isoindole-1-carboxamide

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (30 mg '0.20 mmol), 2-(pyrazin-2-yl)ethylamine (25 mg, 0.20 mmol) and 1-gas 4-(Isocyanoindolyl)benzene (27 mg, 0.18 mmol). White solid, 36 g (44%). *H NMR (400 MHz, CDC13) δ ppm 8.55 (s, 1 H), 8.43-8.49 (m, 1 H), 8.18-8.23 (m, 1 H), 7.83-7.92 (m, 1 H), 7.62 -7.71 (m, 2 H), 7.56-7.61 (m, 1 H), 7.44-7.50 (m, 1 H), 7.16-7.22 140345.doc -66- 201000461 (m,2 Η), 7.00-7.05 ( m, 2 H), 5.07 (s, 1 H), 4.38 (d, 2 Η), 3.90-4.08 (m, 2 H), 3.07-3.22 (m, 2 H) ; MS (ESI) m/z 407 [M+H]. Example 13 N-[l-(4-Phenylphenyl)ethyl]_3_sideoxy-2_(2_wbiazine-2-ylethyl)-lH-isoindole-1-carboxamide

General Procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (30 mg '0.20 mmol), 2-(0-pyridin-2-yl)ethylamine (25 mg, 0.20 mmol) and 1-disorder 4-(1-Isocyanoethyl)benzene (3 mg, 0.18 mmol). White solid, 50 mg (59%). ]H NMR (400 MHz, CDC13) δ ppm 8.59 (d, 1 Η), 8.50 (br. s., 1 H), 8.27 (d, 1 H), 7.79 (d, 1 H), 7.65-7.71 ( m, 1 H), 7.58-7.63 (m, 1 H), 7.54-7.58 (m, 1 H), 7.44-7.51 (m, 1 H), 7.25-7.27 (m, 2 H), 7.10-7.15 ( m, 1 H), 6.84-6.90 (m, 1 H), 5.00-5.16 (m, 2 H), 3.82-4.13 (m, 2 H), 3.15-3.36 (m, 1 H), 3.03-3.13 ( m, 1 H), 1.33-1.47 (m, 3 H); MS (ESI) m/z 421 [M+H]. Example 14 N-[l-(4-Phenylphenyl)ethyl]-3-oxooxy-2-(&quot;bipyridin-3-ylmethyl)-1Η-isoindole-1-carboxamide 140345.doc -67- 201000461

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (30 mg '0-20 mmol), 3-(aminomercapto)pyridine (2〇pL, 0.20 mmol) and chloro-4-( The title compound was synthesized from 1-isocyanoethyl)benzene (33 g, 0.20 mmol). White solid, 35 mg (43 ° / 〇). 'Η NMR (400 MHz, DMSO-i/6) δ ppm 9.04-9.17 (m 1 Η) 8.49- 8.54 (m, 1 Η), 7.71-7.78 (m, 1 Η), 7.62-7.70 (m5 1 Η ), 7.49- 7.61 (m, 3 Η), 7.38-7.45 (m, 2 Η), 7.32-7.38 (m, 3 Η), 7.27-7.31 (m, 1 Η), 5.08-5.15 (m, 1 Η) ), 5.02-5.06 (m, 1 Η), 4.84-4.94 (m, 1 Η), 4.00-4.20 (m, 1 Η), 1.34-1.41 (m, 3 Η); MS (ESI) w/z 406 [M+H]. Example 15 N-[(4-Fluorophenyl)methyl]-3-oxo-2-(2-&gt;»pyridin-2-ylethyl)_1H-isoindole-1-cartoamine

General procedure 2 as described in Example 2 from 3_sideoxy-2_(2_pyrox_2_140345.doc-68-201000461 ethethyl)-1 Η-isoindole-1-carboxylic acid (56 mg The title compound was synthesized from the title compound (yield: 0.2 mmol) and 4-fluoro-phenylhydrazinamine (165 pL, 2 mmol). Yellow solid, 13 mg (16%). !H NMR (400 MHz, CDC13) δ ppm 8.76-8.85 (m5 1 Η), 8.16 (d, 1 Η), 7.70 (d, 2 Η), 7.63-7.68 (m, 1 Η), 7.54-7.59 ( m, 1 Η), 7.47 (t, 1 Η), 7.23-7.26 (m5 1 Η), 7.10-7.16 (m, 1 Η), 7.04-7.10 (m, 2 Η), 6.86-6.92 (m, 2 Η), 5.02 (s, 1 Η), 4.35-4.41 (m, 2 Η), 4.01-4.11 (m, 1 Η), 3.84-3.93 (m, 1 Η), 3.12-3.21 (m, 1 Η) , 3.00-3.08 (m, 1 Η); MS (ESI) m/z 390 [M+H], MS (ESI) w/z 388 [MH]. Example 16 3-Phenoxy-2-(2-&quot;bipyridin-2-ylethyl)-N-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl] -1H-isoindole-1-carboxamide

General procedure 2 as described in Example 2 from 3-oxo-2-(2-pyridin-2-ylethyl)-1 Η-isoindole-1-carboxylic acid (67 mg, 0.24 mmol) (4-(2,2,2-Trifluoroethoxy)phenyl)decylamine (73 mg, 0.36 mmol). Yellow solid, 11 mg (10%). !H NMR (400 MHz, DMSO-i/6) δ ppm 9.11 (t, 1 H), 8.43-8.49 (m, 1 H), 7.62-7.72 (m, 2 H), 7.54-7.63 (m, 1 H), 7.47- 140345.doc • 69- 201000461 7.55 (m, 2 Η), 7.17-7.26 (m, 4 Η), 6.95-7.03 (m, 2 Η), 5.22 (s, 1 Η), 4.72 ( q, 2 Η), 4.28 (d, 2 Η), 4.14-4.25 (m, 1 Η), 3.35-3.46 (m, 1 Η), 2.93-3.12 (m, 2 Η); MS (ESI) m/ z 470 [M+H], MS (ESI) m/z 468 [MH]. Example 17 2-[3-(3-Mercapto-1H-&quot;Biazol-1-yl)propyl]-3-oxacyl-N-[4-(trifluoromethoxy)benzyl] Isoindoline-1-decylamine

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (30 mg, 0.20 mmol), 3-(3-indolyl-1-yl)propan-1-amine (28 mg, 0.20 mmol) The title compound was synthesized from 1-(isocyanomethyl)-4-(trifluoromethoxy)benzene (40 mg, 0.20 mmol). Solid, 44 mg (470/〇). 'H NMR (400 MHz, DMSO-c/6) δ ppm 9.14-9.22 (m, 1 Η), 7.67-7.73 (m, 1 Η), 7.58-7.65 (m, 1 Η), 7.49-7.58 (m , 3 Η), 7.29-7.38 (m, 4 Η), 5.95 (d, 1 Η), 5.32 (s, 1 Η), 4.34 (d, 2 Η), 3.99-4.06 (m, 2 Η), 3.73 -3.84 (m, 1 Η), 2.97-3.08 (m, 1 Η), 2.10 (s, 3 Η), 1.94-2.08 (m, 2 Η) ; MS (ESI) m/z 473 [M+H] , MS (ESI) m/z 471 [MH]. Example 18 2-(1-Methyl-2-»pyridin-2-ylethyl)-3-oxooxyindole-[4-(trifluoromethoxy) 140345.doc -70- 201000461 Benzyl Isophthalene-1-carboamine

The general procedure 2 as described in Example 2 was carried out from 2-(1-indolyl-2-pyridin-2-ylethyl)-3-oxooxy. The title compound was prepared from the title compound (89 mg, 0.30 mmol) and (4-(trifluoromethoxy)phenyl) decylamine (172 mg, 0.90 mmol). Solid, 77 mg (55%). ]H NMR (400 MHz, DMSO-i/6) δ ppm 9.32, 9.25 (t+t„ 1 Η), 8.45-8.48, 8.32-8.36 (m+m, 1 Η), 7.54-7.70 (m, 3 Η), 7.43-7.54 (m, 2 Η), 7.41 (dd, 2 Η), 7.28-7.36 (m, 2 Η), 7.12-7.24 (m, 2 Η), 5.41, 5.04 (s + s, 1 Η), 4.62-4.72, 4.26-4.44, 4.07-4.15 (m+m+m, 3 Η), 3.26-3.33, 2.88 (m+dd, 2 Η), 3.12 (d, 1 Η), 1.33, 1.14 (d+d, 3 Η); MS (APCI/APPI) m/z 470 [M+H]. Example 19 2-(1-methyl-2-&quot;bipyridin-2-ylethyl)-3 -Sideoxy-N-[4-(trifluoromethoxy)phenylindenyl]isoindoline-1-decylamine, isomer 3

140345.doc -71 - 201000461 Isomer 3 f = Unknown absolute configuration e = Unknown absolute configuration by using the SFC Berger Multigram II system (tube: Chiralpak AD, 20x250 mm, 10 μιη; mobile phase: 25%) Propyl alcohol + diethylamine C 〇 2 'flow rate: 50 mL / min, 15 mg / inj) separation of the racemic compound 2-( 1 -methyl 2 - acridine 2 - yl ethyl) _3_Sideoxy_n_[4_(trifluoromethoxy)phenylindenyl]isoindoline-indole-guanamine to give the enantiomerically pure compound. The dissolved fraction was collected according to the residence time, and the isomer 3 as the third fraction was produced at 6.1 min. The dissolved fraction was evaporated at 2 3 - 25 ° C to avoid thermal exotropy and treated separately. Analytical LC was performed using a Berger SFC Analytix (column: Chiralpak AD, 4.6x25 0 mm, 10 μηι; mobile phase: 3〇% isopropanol + diethylamine/70% C02; flow rate: 2 mL/min) Analysis: Isomer 3 (5.43 min), 13 mg, enantiomeric purity: 99%. Η NMR (400 MHz, CDC13-J) δ ppm 8.66-8.75 (m 1 H) 8.02 (d, 1 H), 7.74 (d, 1 H), 7.67 (d, 1 H), 7.58-7.64 (m , 1 H), 7.55 (td, 1 H), 7.45 (t, 1 H), 7.32 (d, 1 H), 7.12-7.17 (m, 2 H), 7.06-7.10 (m, 2 H), 6.98 -7.05 (m,1 H), 5 2〇(sj H), 4.45-4.51 (m, 1 H), 4.39-4.45 (m, 1 H), 4.31-4.39 (m, 1 H), 4.09 (dd , 1 H), 3.20 (dd, 1 H), 1.44 (d, 3 H); MS (ESI) w/z 470 [M+H], MS (ESI) m/z 468 [MH]. Example 20 2-(1-Methyl-2-0-Bitter-2-ylethyl)-3-oxo-N-indol-4-(trifluoromethoxy)benzyl]isoporphyrin- 1. Brewing amines, isomers 4 140345.doc -72- 201000461

h=unknown absolute configuration g=unknown absolute configuration by using the square in the previous example ^ ί %

("基-...ylethyl"_3, oxymethyl]iso-xanthene + guanamine and earth (di-halomethoxy) stupid enantiomerically pure compound. Separate the fraction according to the retention time The isomer 4 as the fourth dissolving fraction was produced at 6.5 min. Analytical Lc analysis was carried out as above: Isomer 4 (6 〇 9 _), μ mg, enantiomeric purity: 98%. H NMR (400 MHz, CDCl3-i/) δ ppm 10.72 (t, 1 Η), 7.82-7.88 (m, 1 Η), 7.70-7.73 (m, 1 Η), 7.65-7.70 (m, 1 Η), 7.61- 7.65 (m, 1 H), 7.56 (td, 1 H), 7.46 (t, 1 H), 7.29-7.33 (m, 1 H), 7.04-7.11 (m, 3 H), 6.98-7.04 (m, 2 H), 5.19 (s, 1 H), 4.64-4.74 (m, 1 H), 4.53 (dd, 1 H), 4.31 (dd, 1 H), 3.02 (dd, 1 H), 2.86 (dd, 1 H), 1.50 (d, 3 H); MS (ESI) m/z 467 [M+H], MS (ESI) m/z 468 [MH]. -2-(2-Acridine-2-ylethyl)-N-[4-(trifluoromethoxy)benzoinyl]isoindoline-1-carboxamide I40345.doc 73- 201000461

According to the general procedure 2 described in the shell example 2, 4-methoxyl_3_sideoxy (2 ratio. 疋_2_ylethyl)isoindoline-1·decanoic acid (0.468 g, 1.50 mmc) ^ and (4_(trifluoromethoxy)phenyl)methanamine (〇.7丨7 g, 3·75 mmol) to prepare the title compound, but stirred at ambient temperature for 4 〇 min. Chromatography or column chromatography was carried out using a gradient (〇-1%) of chloroform/methanol/methanol (7 M in methanol) in chloroform to yield a solid, 〇 491 § (67%). 'H NMR (400 MHz, DMSO-^6) δ ppm 9.13 (t, 1 Η), 8.42-8-47 (m, 1 Η), 7.69 (td, 1 Η), 7.51 (t, 1 Η), 7.33-7.39 (m, 2 H), 7.27-7.33 (m, 2 H), 7.18-7.26 (m, 2 H), 7.05 (d, 2 H) 5.11 (s, 1 H), 4.34 (d, 2 H),4·08_4·18 (m, 1 H), 3.83 (s,3 H), 3.27-3.36 (m, 1 H), 3.00-3.09 (m, 1 H), 2.88-2.99 (mj H) MS (ESI) m/z 486 [M+H], MS (ESI) m/z 484 [MH] 〇 Example 22 3 </ RTI> ·Ν-[4-(Trifluoromethoxy)benzyl]isoindoline-1-carboxamide

201000461 according to the general procedure 2 described in Example 2 from 3_sideoxy-2_(2_pyridin-4-ylethyl)isoindoline-1 -carboxylic acid (56 mg, 〇2〇mm〇1)&amp; (4,4-trifluoro-methoxy)phenyl)decylamine (76 mg, EtOAc, EtOAc) *H NMR (400 MHz, DMSO-^6) δ ppm 9.17 (t, 1 Η), 8.37-8.47 (m, 2 Η), 7.67 (d, 1 Η), 7.58-7.63 (m, 1 Η), 7.49-7.56 (m, 2 Η), 7.30-7.40 (m, 4 Η), 7.20-7.24 (m, 2 Η), 5.19 (s, 1 Η), 4.36 (d, 2 Η), 4.09-4.19 ( m, 1 Η), 3.22-3.32 (m, 1 Η), 2.92-3.01 (m, 1 Η), 2.82-2.91 (m, 1 Η); MS (ESI) m/z 456 [M+H], MS (ESI) m/z 454 [MH]. Example 23 3-Sideoxypyridin-3-ylethyl)-N-[4-(trifluoromethoxy)benzyl]isoindolin-1-ylidene

General procedure 2 as described in Example 2 from 3-tert-oxy-2-(2-pyridin-3-ylethyl)iso- 0-indolyl-1-carboxylic acid (56 mg, 0.20 mmol) and (4) - (Tris-methoxy)phenyl)methanamine (76 mg, 0.40 mmol). iHNMRGOOMHz'DMSOOSppmg.lSG'lHLSW-8.45 (m, 2 Η), 7.66 (d, 1 Η), 7.58-7.64 (m, 2 Η), 7.48-7.56 140345.doc -75- 201000461 (m, 2 Η) , 7.31-7.41 (m, 4 Η), 7.28 (dd, 1 Η), 5.22 (s, 1 Η), 4.30-4.42 (m, 2 Η), 4.07-4.17 (m, 1 Η), 3.20-3.29 (m, 1 Η), 2.92-3.01 (m, 1 Η), 2.80-2.91 (m, 1 Η); MS (ESI) m/z 456 [M+H], MS (ESI) m/z 454 [ MH]. Example 24 2-(1-Methyl-2-indazin-2-ylethyl)-3-oxo-N-[4-(trifluoromethyl)benzoinyl]isoindoline-1 -Procarbamide

The general procedure 2 as described in Example 2 was carried out from 2-(1-mercapto-2-pyridin-2-ylethyl)-3-oxooxy. Lead b. The title compound was prepared to give 14 mg (30%) of EtOAc (3 EtOAc, EtOAc, EtOAc) !H NMR (600 MHz, OMSO-d6) δ ppm 9.34, 9.27 (t+t, 1 Η), 8.46, 8.33 (dd+dd, 1 Η), 7.67-7.70 (m, 2 Η), 7.56-7.67 (m, 3 Η), 7.43-7.53 (m, 4 Η), 7.18-7.23 (m, 1 Η), 7.11-7.16 (m, 1 Η), 5.41, 5.04 (s+s, 1 Η), 4.63 -4.70, 4.29-4.36 (m+m, 1 Η), 4.40-4.47 (m, 2 Η), 3.26-3.30, 3.12, 2.86 (m+d+dd, 2 H),1_33, 1.15 (d+d , 3 Η) ; MS (ESI) m/z 454 [M+H]. Example 25 140345.doc 76· 201000461 -2-»Bipyridin-2-ylethyl)_3•trioxyisoindole N-(4-chlorobenzyl)-2-(1-methylindene-1 - 甲甲胺

General procedure 2 as described in Example 2 from ethyl)_3_sideoxyisoindole_ 1 Procedure 2 from 2-(1-methyl-2-pyridin-2-yl-carboxylic acid (30 mg, hydrazine) · ι〇mmol) and (4-chlorophenyl)methanamine (35 mg, 0.25 mmol) to give the title compound to give 1 mg (23%) °H NMR (600 MHz, DMSO-^6) δ ppm 9.27 , 9.21 (t+t, 1 Η), 8.46, 8.34 (dd+dd, 1 Η), 7.54-7.68 (m, 3 Η), 7.40-7.52 (m, 2 Η), 7.36-7.40 (m, 2 Η), 7.27-7.32 (m, 2 Η), 7.17-7.21 (m, 1 Η), 7.12-7.16 (m, 1 Η), 5.39, 5.02 (s+s, 1 Η), 4.63-4.69, 4.28 -4.38 (m, 3 Η), 3.26-3.30, 3.11, 2.87 (m+d+dd, 1H),1_33, 1.14 (d+d, 3 Η) ; MS (ESI) w/z 420 [M+H Example 26 2-丨2-(1Η-β丨丨-3-yl)ethyl]-3-yloxy-N-[4-(trifluoromethoxy)benzyl]isoindole Phenyl-1-carboxamide

140345.doc 77· 201000461 According to the general procedure 1 described in Example 1, from 2-mercaptobenzoic acid (35 mg, 0.23 mmol), 2-(1Η-indol-3-yl)ethylamine (3 7 The title compound was synthesized to give 41 mg (35%). ]H NMR (600 MHz, DMSO-J6) δ ppm 9.16 (t, 1 Η), 7.71 (d, 1 Η), 7.59-7.62 (m, 1 Η), 7.50-7.56 (m, 3 Η), 7.32 -7.37 (m, 3 Η), 7.26-7.30 (m, 2 Η), 7.14 (d, 1 Η), 7.05-7.09 (m, 1 Η), 6.93-6.97 (m, 1 Η), 5.29 (s , 1 Η), 4.32-4.39 (m, 2 Η), 4.13-4.19 (m, 1 Η), 3.25-3.30 (m, 1 Η), 3.03-3.09 (m, 1 Η), 2.92-3·00 (m, 1 Η); MS (ESI) m/z 494 [M+H]. Example 27 N_(4-Methoxyphenyl)-3-oxo-2-(2-pyridin-2-ylethyl)isoindoline-1-carboxamide

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (35 mg, 0.23 mmc^), 2-(2-aminoethyl) ° bit (28 mg, 0.23 mmol) and 1 -(Isocyanoindolyl)-4-decyloxybenzene (31 mg, 0.21 mmol). NMR (600 MHz, DMSO-i/6) δ ppm 9_〇8 (t, 1 H), 8.45- 140345.doc •78- 201000461 8.47 (m, 1 Η), 7.64-7.71 (m, 2 Η) , 7.59 (td, 1 Η), 7.48-7.53 (m, 2 Η), 7.24 (d, 1 Η), 7.19-7.23 (m, 1 Η), 7.16-7.20 (m, 2 Η), 6.85-6.89 (m, 2 Η), 5.22 (s, 1 Η), 4.26 (d5 2 Η), 4.17-4.23 (m, 1 Η), 3.72 (s, 3 Η), 3.37-3.43 (m, 1 Η), 3.06-3.12 (m,1 Η), 2.96-3.02 (m,1 Η); MS (ESI) m/z 402 [M+H]. Example 28 4-Methoxy-2-(1-methyl-2-»*hept-2-ylethyl)-3-oxooxy_n_[4-(trifluoromethoxy)benzyl 1 -isoindoline-1-carboxamide

The general procedure 2 as described in Example 2 was carried out from 4-methoxy-2-(1-methyl-2-[rho]pyridin-2-ylethyl)-3-oxooxy. The title compound was prepared to give the title compound (yield: 38 mg, 0.25 mmol). H NMR (400 MHz, DMSO-ci6) δ ppm 9.22, 9.15 (t+t, 1 Η), 8.44-8.50, 8.35-8.38 (m, 1 Η), 7.65 (tt, 1 Η), 7.45-7.51 ( m, 1 Η), 7.36-7.40 (m, 2 Η), 7.27-7.34 (m, 2 Η), 7.12-7.22 (m, 2 Η), 7.03 (t, 1 Η), 6.96 (dd, 1 Η ), 5.27, 4.93 (s+s, 1 Η), 4.56-4.65, 4.25-4.41 (m+m, 3 Η), 3.84, 3.81 (s+s, 3 Η), 3.23, 2.80 (dd+dd, 1 Η), 3.06 (d, 1 Η), 1.26, 1.08 (d+d, 3 Η); MS (ESI) m/z 500 [M+H]. 140345.doc -79- 201000461 Example 29 N-(4-isopropylbasinhydrazino)-2-(1-methyl_2-t» than 2-butyl-2-ylethyl)_3 ethoxylated isoindole -1 - guanamine

According to the general procedure 2 described in Example 2, from 2_(1_indolyl-2-pyridin-2-ylethyl)-3-oxo-isoindolinecarboxylic acid (3 〇 mg, 〇l〇mm〇i The title compound was prepared as (4_ isopropylphenyl) decylamine (37 mg, EtOAc) H NMR (600 MHz, DMSO-&lt;i6) δ ppm 9.20, 9.14 (t+t, 1 Η) 8.44-8.47, 8.33-8.36 (m+m, 1 Η), 7.59-7.67 (m, 2 H) , 7.57 (td, 1 H), 7.41-7.52 (m, 2 H), 7.17-7.22 (m, 5 H), 7.13-7.16 (m,1 H), 5.39,5.04 (s+s, 1 H) , 4.64-4.70, 4.24-4.36 (m,3 H), 3.27-3.30, 3.1 1, 2.82-2.91 (m+d+m, 3 H), 1.31-1.36, 1.15-1.20 (m+m, 9 H MS (ESI) w/z 428 [M+H]. Example 30 N-[4-Fluoro-3-(trifluoromethyl)benzyl-methyl-2-wtb-2-ylethyl)-3-oxo-isoindoline "Metformamide 140345. Doc -80- 201000461

F

According to the general procedure 2 described in Example 2, from 2-(1-mercapto-2-pyridin-2-ylethyl)_3-sideoxyiso-introduction, η1 曱1 -decanoic acid (3〇mg, 0.10 mmol) and (4-

The title compound was prepared from fluoro-3-(trifluoromethyl)phenyl)methanamine (48 mg, EtOAc. !H NMR (600 MHz, DMSO-i/6) δ ppm 9.31, 9.24 (t+t ,1 H), 8.44-8.46, 8-31-8.33 (m+m, 1 H), 7.58-7.68 (m , 4 H), 7 53 7 57 (m, 1 H), 7.40-7.52 (m, 3 H), 7.17-7.21 (m, 1 H), 7.12, 7 ... (m, 1 H), 5.40, 5.03 (s+s, 1 H), 4.64-4.71, 4.27-4 .34 (m+ n,1 H), 4.36-4.45 (m, 2 H), 3.26-3.30, 3.09, 2.86 (m+d+dd, 2,. J,i · 3 2, 1.12 (d+d, 3 H) ; MS (ESI) m/z 472 [M+H]. Example 31 N-[3-fluoro-4-(trifluoromethyl) Benzoyl bromide 2-(1-indolyl-2 -. 比 之 基 基 ) ) ) ) ) 氧基 氧基 氧基 氧基 -1- -1- -1- -1- -1- -1- -1-

〇140345.doc -81 - 201000461 according to the general procedure 2 described in Example 2 from 2-(1-methyl-2-pyridin-2-ylethyl) 3- oxetyl isoindole citrate (3) The title compound was prepared to give 10 mg (20%). JH NMR (600 MHz, DMSO-J6) δ ppm 9.35, 9.27 (t+t, 1 Η), 8.45-8.48, 8.32-8.34 (m+m, 1 Η), 7.74 (t, 1 Η), 7.56- 7.69 (m, 3 Η), 7.44-7.53 (m, 2 Η), 7.28-7.34 (m, 2 Η), 7.18-7.23 (m, 1 Η), 7.13-7.17 (m, 1 Η), 5.42, 5.05 (s + s, 1 Η), 4.63-4.70, 4.29-4.37 (m+m, 1 Η), 4.39-4.46 (m, 2 Η), 3.27-3.30, 3.13, 2.87 (m+d+dd, 2 Η), 1.33, 1.16 (d+d, 3 Η); MS (£81^ w/z 472 [M+H]. Example 32 2-(1-methyl~bito_2_ylethyl) _3_Sideoxy_N_[3(trifluoromethoxy)benzyl)iso-β丨嗓琳_1-nonylamine

F

, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The benzylamine (48 mg, Λ g 0.25 _ 〇 1) was prepared to give the title compound 140345.doc •82- 201000461 to give 13 mg (28%). lU NMR (600 MHz, DMSO-J6) δ ppm 9.34, 9.26 (t+t, 1 H), 8.41-8.48, 8.30-8.35 (m+m, 1 H), 7.58-7.68 (m, 2 H), 7.53-7.58 (m, 1 H), 7.41-7.52 ( m, 3 H), 7.28-7.32 (m, 1 H), 7.22-7.26 (m, 1 H), 7.17-7.22 (m, 2 H), 7.12-7.17 (m, 1 H), 5.41, 5.04 ( s+s, 1 H), 4.65-4.71, 4.27-4.35 (m, 01 H), 4.36-4.43 (m, 2 H), 3.27-3.30, 3.10, 2.90 (m+d+dd, 2 H), 1.34, 1.14 (d+d, 3H); MS (ESI) m/z 467 [M+H]. Example 33 N-[l-(3-phenylphenyl)ethyl 2-(2-»pyridin-2-ylethyl)isoindole_1_nonylamine

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (35 mg, 0.23 mmol), 2-(0-but-2-yl)ethylamine (28 mg, 0.23 mmol) and 1- The title compound was synthesized as chloro-3-(1-isocyanoethyl)benzene (3 5 mg, 0.21 mmol) to yield 33 mg (34%). NMR (600 MHz, DMS0-4) δ ppm 9.17, 9.16 (s+s5 1 H), 8.46-8.48, 8.44-8.46 (m, 1 H), 7.46-7.72 (m, 5 H), 7.19-7.40 ( m, 6 H), 5.25, 5.24 (s+s, 1 H), 4.91-4.97 (m, 1 H), 4.12-4.23 (m, 1 H), 3.37-3.44, 3.28-3.30, 2.95-3.13 ( m+m+m, 3 H), 1.43, 1.42 (d+d, 3 H); MS (ESI) m/z 420 [M+H]. 140345.doc -83- 201000461 Example 34 2-(2-(5-fluoropyrimidin-2-yl)ethyl)_3_sideoxy_n_(4(trifluoromethoxy)benzoinyl)isoindole Lin-1-carbamamine

2-(5-Fluoropyrimidin-2-yl)ethylamine hydrochloride (59.2 mg, 0.33 mm 〇G,, 5 in decyl alcohol (2 mL) and added triethylamine (0.093 mL, 〇67 claws) Claw (1) / and the mixture was stirred at room temperature for 45 minutes, followed by the addition of 2-methylpyrrolidinoic acid (50 mg, 0.33 mmol) &amp;1_(isocyanomethyl)·4_(trifluoromethoxy ^ (0.067 mL, 0.33 mmol), and the mixture was stirred at <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The aqueous layer was extracted with EtOAc. EtOAc (EtOAc m.jjjjjjjjjjj H) 8.16 (br. s., l H) 7.69 (d, 1 H) 7.51-7.63 (m, 2 H) 7.43 (t, 1 H) 7.14 (m, 2 H) 7.07 (m, 2 H) 5.10 (s&gt; l H) 4.36-4.48 (m, 2 H) 3.91-4.16 (m, 2 H) 3.15-3.39 (m, 2 H). MS (ESI) m/z 475 [M+H]. 2-(2-(4-Methylpyrimidin-2-yl)ethyl)_3_sideoxy_N_(4(trifluoromethoxy)benzyl)isoindoline-1-carboxamide 140345 .doc -84 - 201000461

r°Y

U

[N- According to the method described in Example 34, 2-(4-pyrypyrimidin-2-yl)ethylamine salt (121 mg '〇·7〇mm〇1), triethylamine (〇195 ^) , ι·4〇_〇1) and 2-mercaptobenzoic acid hydrazine 5 mg, 〇7 _〇1) and 1 (isocyanomethyl) 4-(difluoromethoxy)benzene 141 The title compound was prepared from 〇 (4). Orange oil, 8 〇 mg (24%). H NMR (500 MHz CDCl Λ r / \ , team 13) δ (PPm) 8.85 (br. s·, 1 H) 8.31 (d, 1 H) 7.70 (dd 2 m 7 "./ , ) 7·58 ( T5 l H) 7.48 (t, 1 H) 7.07-7.14 (m, 2 H) 7.02-7.07 (rn 0 „, (,2 H) 7.00 (d,1 h) 5.11 (s,1 H) 4.43-4.58 (m,1 H) 4 3i_4 4,, ,TT,,42 (m, 1 H) 4.20 (d, 1 H) 3.87 (d, 1 H) 3.14-3.29 (m, 2 H) 2.28 ( · (Ss 3 H) 〇MS (ESI) m/z 471 [M+H]. </RTI> <RTI ID=0.0>################################################################ -(trifluoromethoxy)benzene

Use 2-(pyrimidin-2-yl)ethylammonium chloride 140345.doc -85· 201000461 (0.106 g, 0.67 mmol), triethylamine (〇186 mL, 1.33 mmol), 2- The title compound was prepared from the methylmercaptobenzoic acid (0.10 g, 〇·67 mm 〇1) &amp;1_(isocyanoindolyl)-4 (trifluoromethoxy)benzene (〇.134§, 0.67111111〇1). The mixture was stirred at room temperature for 2 days. The solvent was evaporated in vacuo and EtOAc mjjjjjjjjjjjj Alkane: (di-hydrogen methane/methanol 90··10) = 100··0 to 60:40 as a gradient to purify the crude product. Yellow solid, 87 mg (28 ° / 〇) °

m/z 457 [M+H]. Example 37 140345.doc -N-(4-(trifluorodecyloxy)

According to the method described in Example 34, ethylammonium (0.035 g, 〇.2〇mmol), mmol), 2-methyl-bromobenzoic acid (〇〇3() g 1 0.20 with chlorinated 2- (2-mercaptopyrimidine-5-triethylamine (0.056 mL, 0.40 g '〇20 mmol) and 1-(isocyano-86 - 201000461 methyl)-4-(trifluoromethoxy)benzene ( The title compound was prepared in EtOAc EtOAc (EtOAc: EtOAc (EtOAc) (s, 2 Η) 7.59-7.65 (m, 1 Η) 7.52-7.59 (m, 1 Η) 7.32 (t, 1 Η) 7.23-7.28 (m, 1 Η) 7.11-7.18 (m, 2 Η) 7.05 -7.11 (m, 3 Η) 5.06 (s, 1 Η) 4.31-4.49 (m5 2 Η) 4.11-4.26 (m, 1 Η) 3.36 (ddd, 1 Η) 2.76-3.00 (m, 2 Η) 2.69 ( s, 3 H). MS (ESI) w/z 471 [M+H]. Example 38 2-((6-Cyano &quot;tb </RTI> <RTIgt; -(4-(Trifluoromethoxy)benzyl)isoindoline-1-carboxamide

The general procedure 1 as described in Example 1 was carried out from 2-mercaptobenzoic acid (0.030 g, 0-20 mm oi), 5-(aminomercapto) ruthenium ratio. The title compound was synthesized from carbonitrile (0.027 g. s. 20 mmol) and 1-(isocyanoindolyl)-4-(trifluoromethoxy)benzene (0.040 g. Yellow oil, 3.7 mg (4 ° / 〇). *H NMR (500 MHz, CDC13) δ (ppm) 8.65 (d, 1 H) 7.76 (dd, 1 H) 7.61-7.66 (m, 2 H) 7.57-7.61 (m, 2 H) 7.48 (t, 1 H) 7.10-7.17 (m, 4 H) 6.49 (t, 1 H) 5.32 (d, 1 H) 4.92 (s, 1 H) 4.31-4.46 (m, 3 H). MS (ESI) m/z 467 [M+H]. 140345.doc -87 - 201000461 Example 39 3-Phenoxy-N-(4-(trifluoromethoxy)benzyl)-2-((5-(trifluoromethyl))-2-yl )methyl)isoindole-1-methyl amide

According to the method described in Example 34, (5-(trifluoromethyl)pyrrole-2-yl)guanamine hydrochloride (42_5 mg '0.20 mmol), triethylamine (0.084 mi, 0.60 mmol), 2- The compound was prepared by the use of mercaptobenzoic acid (30 mg, 0.20 mmol) and 1_(isosylhydrazino)-4-(trifluoromethyloxy)benzene (0.040 ml, 0.20 mmol). The solution was stirred at ambient temperature for 2 hours and then heated to 50 °C for 16 hours. Brown semi-solid, 12.8 mg (12-6%). ]H NMR (400 MHz, CDC13) δ (ppm) 9.49 (t, 1 Η) 8.16 (sj H) 7.94 (d, 1 H) 7.87 (d, 1 H) 7.79 (d, 1 H) 7.61-7.69 ( m; j H) 7.47-7.61 (m, 2 H) 7.12-7.20 (m, 2 H) 7.04-7.12 (m? 2 H) 5.27 (s, 1 H) 4.91 (d, 1 H) 4.66-4.81 ( m, 1 H) 4.3l-4.52 (m, 2 H). MS (ESI) m/z 510 [M+H]. Example 40 3-Phenoxy-N-(4-(trifluoromethoxy)benzyl)_2-((6-(trifluoromethyl)heptan-3-yl)methyl)isoindoline-1 -carbamamine 140345.doc -88· 201000461

The general procedure described in Example 1 was carried out from 2-methylmercaptobenzoic acid (3 〇 mg, 0.20 〇1), (6-(trimethoxymethyl) 0 pyridine-3-yl)methylamine (45). 3 Oh,

0.26 faces. 1) and W isocyanomethyl...trifluoromethoxy)benzene (mL, 0-20 mmol) were synthesized as the title compound. The crude product was purified by silica gel chromatography using hexanes: EtOAc = EtOAc: EtOAc: EtOAc: , 25 mg (24.6%). !H NMR (500 MHz, CDC13) sr (PPm) 8.66-8.73 (m, 1 H) 7.80-7.93 (m, 2 H) 7.49-7.67 (m 4 , m, 4 H) 7.12 (m, 4 H) 6_01 (t, 1 H) 5.35 (d, 1 H) 4.92 (s, 1 m ^

W) 4.29-4.45 (m, 3 H). MS (ESI) m/z 510 [M+H]. Example 41 3-Phenoxy-2-((6-(2,2,2-trifluoroethoxy)K-pyridyl)pyridin-3-yl)indenyl)-N-(4-(trifluoromethoxy) ) benzyl)isoporphyrin, JSc

140345.doc -89- 201000461 according to the general procedure 1 described in Example 1 from 2-methylmercaptobenzoic acid (30 mg '0·20 mmol), (6-(2,2,2-trifluoroethoxy) The title compound was synthesized from D-pyridyl-3-yl)guanamine (45.3 mg '0.22 mmol) and 1-(isocyanohydrazide &gt; 4_(trifluoromethoxy)benzene (0.040 mL '0.20 mmol). The title compound was obtained as a white solid (45% (yield: 42%)). (500 MHz, DMSO-£/6) δ (ppm) 9.13 (t, 1 Η) 8 04-8.17 (m, 1 Η) 7.73-7.80 (m, 1 Η) 7.67 (dd, 1 Η) 7 59- 7 65 (m, 1 Η) 7.52-7.59 (m, 1 Η) 7.46-7.52 (m, 1 Η) 7 35 (s 4 Η) 6.95 (d, 1 Η) 5.02-5.11 (m, 2 Η) 4.97 (q, 2 Η) 4.24-4.41 (m, 2 Η) 4.16 (d, 1 H). MS (ESI) w/z 540 [M+H]. Example 42 2-(1-(5-1° ratio) Bite-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy)benzoinyl)isoindole-1-carbamide

General procedure 1 as described in Example 1 from 2_mercaptobenzoic acid (3 〇 mg, 0-20 mmol), i_(5-fluoropyridin-2-yl)ethylamine mg, 0.2 mm 〇l) and 1- (Isocyanomethyl)-4-(trifluoromethoxy)benzene (0.036 mL, 0.18 mmol). White solid, 27 mg (29%), diastereomer. 140345.doc -90- 201000461 1.1 This product corresponds to one proton of one diastereomer and the integral is set to 1 proton. H NMR (400 MHz, DMSO-c/6) δ (ppm) 9.24 (t, 2 Η) 8.39 (d, 1 Η) 8.29 (d, 1 Η) 7.49-7.71 (m, 12 Η) 7.29-7.40 ( m, 8 Η) 5.44 (d, 1 Η) 5.39 (s, 2 Η) 5.23 (d, 1 Η) 4.33 (dd, 2 Η) 4.17 (dd, 2 Η) 1.66 (d,3 Η) 1.53 (d , 3 H). MS (ESI) m/z 474 [M+H]. Example 43 7-Ga-3-oxo-2-(2-(»pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoporphyrin -1-carboxamide

General Procedure 1 as described in Example 1 from 4-chloro-3-hydroxyisobenzofuran-1(3H)-one (220 mg, 1.19 mmol, prepared according to Jowwa/2003, 2030), 2-(. The title compound was synthesized from EtOAc (m.p.), EtOAc (EtOAc: EtOAc, EtOAc The product was subjected to gelatinization chromatography using a hexane yield: acetonitrile: 100:0 to 0:100 as a gradient to yield a product as a white solid 355 mg (61%) ° NMR (500 MHz, DMSO 〇 δ (ppm) ) 9.57 (t, 1 H) 8.47 (m, 1 H) 7.62-7.76 (m, 3 H) 7.56 (t, 1 H) 7.42-7.50 (m, 2 H) 140345.doc -91 - 201000461 7.27-7.35 (m, 2 Η) 7.15-7.27 (m, 2 Η) 5.40 (s, 1 Η) 4.31-4.50 (m, 2 Η) 4.04-4.21 (m, 1 Η) 3.26-3.33 (m, 1 Η) 3.05 -3.22 (m,1 Η) 2.89-3.05 (m, 1 H). MS (ESI) m/z 491, 493 [M+H]. 2-(tacyl-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide

7-Chloro-3-oxooxy-2-(2-(.Bis-2-yl)ethyl)-N-(4-(tris-methoxy)benzyl)isoporphyrin- 1-Protonamine (83 mg, 0.17 mmol), diphenylindolyl Ibar (7·76 mg, 0.0085 mmol), 2-dicyclohexylphosphino _ 2',6'-dimethoxy linkage Benzene (6.96 mg, 0.02 mmol) and zinc cyanide (0.012 mL '0_19 mmol) were combined in DMF (2.5 mL) and water (0 1 mL). Change the air father to nitrogen and then heat it to 13 〇 in a microwave for 7 5 minutes. The mixture was filtered through celite and washed with ethyl acetate. Add 6°/ to the fluid. NaOH (10 mL) and brine (5 mL). The organic phase was separated, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by preparative EtOAc EtOAc EtOAc. NMR (500 MHz, CDC13) δ (ppm) 8.36 (br. s., 1 H) 8.27 (dt, 1 H) 7.98-8.06 (m, 1 H) 7.83 (dd, 1 H) 7.70-7.80 (m, 1 140345.doc •92- 201000461 Η) 7.61 (t, 1 Η) 7.37-7.44 (m, 2 Η) 7.30-7.36 (m, 1 Η) 7.21- 7.26 (m, 1 Η) 7.11-7.19 (m, 2 Η) 5.32 (br. s., 1 Η) 4.47- 4.67 (m, 2 Η) 4.23-4.35 (m, 1 Η) 3.82 (ddd5 1 Η) 3.23 (t, 2 H). MS (ESI) /2 480 [M+H]. Example 45 2-(2-Hydroxy-2-(acridin-2-yl)ethyl)_3·trioxy-N (4 (trifluoromethoxy)phenyl)-isoindole-1-A Guanamine

〇 r〇 X

\-NH F Ί i Ο HO \~ According to the general procedure described in Example 1, from 2_mercaptobenzoic acid (45 mg '0.30 _〇1), 2-amino group small (η-pyridine _2 The title compound was synthesized from ethanol (42, 〇3〇_〇1) and i(isocyanomethyl)-4_(trifluoromethoxy)benzene (6 〇 3 〇, 〇 3 〇 mm 〇 1). The crude product was purified by column chromatography using a second gas: methanol = 0 to 95:5 as a dissolving agent. White solid 74 mg (52%), a mixture of diastereomers: a mixture, i protons corresponding to one diastereomer, the integral is set to one proton. lH NMR (4〇° MHZ^ C〇C13) δ (ppm) 8.64 (m, 1 Η) 8.55 (d, 1 Η) 8.33 (d, 1 Η) 7.46-7.80 (m, n H) 7.39 (d, 1 H) 7.20- 7.29 (m, 4 H) 7.04-7.18 (m, 6 H) 6.76 (m, l H) 5.55 (m, 1 H)5.43(S,1H)5.11(d,lH)51〇( siH) 4 98 (miH) 4.82 (d, 1 H) 4.53 (dd, 1 H) 4.40 (d, 2 H) 4.38 (dd, 1 H) 140345.doc -93- 201000461 4.16 (dd, 1 Η) 3.94 (dd, 1 Η) 3.69 (dd, 1 Η), 3.57 (dd, 1 H). 19F NMR (400 MHz, CDC13) δ (ppm) - 58.30 and -58.35. MS (ESI) m/z 472 [M+H]. Example 46 2-(2,2-Difluoro-2-(acridin-2-yl)ethyl)-3-yloxy-]^-(4-(trifluoromethoxy)phenylmethyl) Porphyrin-1-carboxamide

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (30 mg '0.20 mmol), 2,2-difluoro-2-(. butyl-2-yl)ethylamine (3 1.6 mg The title compound was synthesized from EtOAc (EtOAc m. The mixture was given μ at 50 ° C. Yellow oil, 54 mg (55%). ]H NMR (400 MHz, CDC13) δ (ppm) 8.28 (d, 1 H) 8.13 /t (t,1 H) 7.83 (td? 1 H) 7.68 (dd? 2 H) 7.52-7.62 (m? 1 H) 7 43 7.50 (m,1 H) 7.3 Bu 7.42 (m,2 H) 7.17 (d,2 H) 7.06 (d, 2 H) 5·26 (s, 1 H) 4.43-4.58 (m, 2 H) 4.36 (dd, 1 H) 4.17_4 3l (m, 1 H). MS (ESI) m/z 492 [M+H]. Example 47 2-(2,2-Difluoro-2-((pyridin-2-yl)ethyl)-7-indolyl-3-yloxy.v_(4·(=fluoromethoxy)phenylmethyl) Isoporphyrin-1-carbamamine 140345.doc -94- 201000461

According to the general procedure 1 described in Example 1, from 3-amino- 4-methylisobenzopyran-1 (3H)-one (30 mg, 0.18 mmol, according to 2002, 43, 73 1 5 for Prepared by the procedure described for the substituted analog), 2,2-difluoro-2-(acridin-2-yl)ethylamine (28.9 mg, 〇.18 mm〇1) and 1-(isocyanomethyl) The title compound was synthesized from -4-(trifluorodecyloxy)benzene (36.8 mg, 〇·18 mm 〇1). The mixture was stirred at 5 (TC) for 60 hours. EtOAc (m.p.), mp (1, s, </ s) NMR (500 MHz, CDC13) δ (ppm) 8.47 (d,1 (1) 7.85 (t,1 Η ) 7.69 (d, 1 Η) 7.55 (br. s., 1 Η) 7.35-7.42 (1115 3 H) 7·19 (m, 2 Η) 7.10 (m, 2 Η) 6.95 (br. s_, 1 Η 5.32 (s,1 H) 4·61~ 4.78 (m, 1 H) 4.50 (dd,1 H) 4.37 (dd,1 H) 3.98-4.14 (m,i H) 2.41 (s,3 H). MS (ESI) w/z 506 [M+H]. </RTI> <RTI ID=0.0>########################################################## Methyl)isoindoline-1-carboxamide

140345.doc -95- 201000461

-(3-ammoniopropyl) outer oxime 2-indole benzoic acid (30 mg, 〇·2〇ram〇1) &amp;1_(difluoromethoxy) stupid (40.2 111 £, 〇 2〇 111111〇1) Preparation—The title compound was prepared as a female (yield: EtOAc (0.070 mL, 0.50 mmol), ??? 2 〇 〇 〇 )) and 1-(isocyanomethyl)-4-indole. Brown CDC13) δ (ppm) 8.41 (d, 1 η) 7.58-7.64 color oil, 43 mg (46%). ]H NMR (400 MHz, CDC1 (m, 1 H) 7.49-7.57 (m, 2 H) 7.29-7.40 (m, 3 H) 7.13-7.18 (m,2 H) 7.11 (d,1 H) 7.02- 7.09 (m, 3 H) 5.16 (s, 1 H) 4.32-4.50 (m, 2 H) 4.04 (ddd, 1 H) 3.17-3.28 (m, 1 H) 2.71-2.87 (m, 2 H) 2.04- 2.16 (m, 2 H) = MS (ESI) m/z 470 [M+H]. Example 49 7-Methoxy-3-oxooxy-2-(2-(«» 比乙-2-基Ethyl)-]\-(4-(trimethylmethoxy)benzyl)isoindolin-1-ylidene

General procedure 1 as described in Example 1 from 3-hydroxy-4-decyloxyisobenzopyran-1(3H)-one (60 mg, 0.33 mmol' according to Jowma/ of (10)k 2007, 72, 3419 ), 2-(pyridin-2-yl)B

The title compound was synthesized from the amine (5 7 mg, 0.47 mmol) and 1-(iso <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was stirred at 50 ° C under 140345.doc 96· 201000461 for 4 hours. White solid, 119 mg (73%). NMR (500 MHz, DMSO-i/6) δ (ppm) 9.24-9.41 (m, 1 Η) 8.37-8.53 (m, 1 Η) 7.68 (td, 1 Η) 7.39-7.52 (m, 3 Η) 7.28 -7.39 (m, 2 Η) 7.09-7.28 (m, 4 Η) 5.28 (s, 1 Η) 4.52 (dd, 1 Η) 4.31 (dd, 1 Η) 4.05-4.20 (m, 1 Η) 3.80 (s , 3 Η) 3.20-3.32 (m,1 Η) 3.10 (ddd,1 Η) 2_88-3·04 (m,1 H). MS (ESI) w/z 484 [M+H]. Example 50 7-Hydroxy-3-oxo-2-(2-(»pyridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoporphyrin -1-carboxamide

7-Methoxy-3-o-oxo-2-(2-(°-But-2-yl)ethyl)-N-(4-(trifluorodecyloxy)benzyl)isoindole The atmosphere above the solution of oxo-L-amine (136 mg, 〇.28 mm 〇i) in dichloromethane (5 mL) was exchanged for nitrogen. The mixture was cooled to -78 ° C. and boron tribromide (0.105 mL, 1.11 mmol) was added via syringe. The mixture was stirred at -78 °C for 2 hours and then gradually warmed to 10 ° C overnight. The crude product was cooled to hydrazine with ice, and the reaction was quenched with water (about 1 mL) dropwise. The reaction mixture was diluted with dichloromethane (ml) and extracted with brine. The aqueous phase was extracted with EtOAc and EtOAc (EtOAc)EtOAc. Purification by preparative HPLC 140345.doc -97- 201000461 crude product. The dissolved fractions containing the compound are combined and the acetonitrile is removed in vacuo. The aqueous solution was taken up with acetic acid. The organic layer was dried over anhydrous sodium sulfate, EtOAc (EtOAc) H NMR (500 MHz, DMSO 〇 δ (ppm) 1 〇 27 (s, 丄H) 9 3 〇 (t, lH) 8.57 (d, lH) 7.26-7.50 (m59H) 7.06-7. i 2 (m, 1 H) 6.95-7.04 (m, 1 H) 5.29 (s, 1 H) 4.42-4.49 (m, i H) 4.33- 4.42 (m, 1 H) 4.12 (ddd, 1 H) 3.09-3.23 (m, 2 H) 3.06 (d, 1 H). MS (ESI) w/z 472 [M+H]. Example 51 2-(2-methyl-1-(pyridin-2-yl)propan-2-yl) -3-Sideoxy_N_(4_(trifluoromethoxy)benzyl)isoindoline-1-carboxamide

通用 from the general procedure 1 described in Example 1 from 2-mercaptobenzoic acid (3 〇 mg '0.20 mmol), 2-mercapto-1-(pyridin-2-yl)propan-2-amine (3) The title compound was synthesized from EtOAc (m.p., EtOAc, EtOAc) Brown oil, 5 mg (5%). !H NMR (400 MHz, CDC13) δ (ppm) 8.52 (t, 1 Η) 8.02-8.10 (m, 1 Η) 7.71 (d, 1 Η) 7.61-7.64 (m, 1 Η) 7.51-7.58 (m , 2 Η) 7.47 (t, 1 Η) 7.21 (d, 1 Η) 6.99-7.05 (m, 3 Η) 6.92-6.99 (m, 2 Η) 5.08 (s, 1 Η) 4.40 (dd, 1 Η) 4.13 (dd, 1 Η) 3.71 (d, 140345.doc •98- 201000461 1 Η) 3.22 (d, 1 H) L59 (d, 6 H). MS (ESI) 484 [M+H]. Example 52 7-Indolyl-3-side gas group-2_(2·(π ratio)ethyl)-N-(4-(trifluoromethoxy)methanemethyl)isoindoline_1_ Formamide

According to the general procedure 1 described in Example 1, from 3-carbyl-4-methylisobenzofuran-l(3H)-g with (220 mg' 1.34 mmol) root Tetrahedron Letters 2002, 43, 7315 Prepared by the procedure described for the unsubstituted analog), 2-(. butyl-2-yl)ethylamine (164 111 §, 1.34 111111〇1) and 1-(isocyanoindolyl)-4 -(Trifluoromethoxy)benzene (0.270 mL, 1.34 mmol). The solution was stirred at 45 ° C for 60 hours. The crude product was subjected to silica gel chromatography using EtOAc (EtOAc): EtOAc: EtOAc (EtOAc) 'H NMR (500 MHz, OMSO-d6) δ (ppm) 9.39 (t, 1 H) 8.44-8.53 (m, 1 H) 7.69 (td, 1 H) 7.48 (ddd, 1 H) 7.34-7.45 (m , 4 H) 7.27-7.34 (m, 2 H) 7.19-7.26 (m, 2 H) 5.31 (s, 1 H) 4.32-4.47 (m, 2 H) 4.10-4.21 (m, 1 H) 3.27 (ddd , 1 H) 3.12 (ddd, 1 H) 2.92-3.03 (m, 1 H) 2.24 (s, 3 H) ° MS (ESI) m/z 470 [M+H]. 140345.doc 99· 201000461 Example 53 2-(2-Methyl-2-(β-But-3-yl)propyl)-3-yloxy-N-(4-(trifluoromethoxy)benzene Methyl)isoindoline-1-decylamine

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (44 mg, 0.29 mmol), 2-methyl-2-(0-but-3-yl)propan-1-amine (44) The title compound was synthesized from mg, 0.29 mmol, and 1-(iso-lactyl)-4-(difluoromethoxy)benzene (58.9 mg, 0.29 mmol). Colorless oil, 84 mg (59%). !H NMR (400 MHz, CDC13) δ (ppm) 8.51 (d, 1 Η) 8.41 (d, 1 Η) 7.59 (ddd, 1 Η) 7.46-7.53 (m, 1 Η) 7.37-7.44 (m, 2 Η) 7.30-7.36 (m, 1 Η) 7.08-7.24 (m, 6 Η) 4.44 (s, 1 Η) 4.28-4.43 (m, 2 Η) 4.25 (d,1 Η) 3.26 (d, 1 Η) 1·35 (d, 6 H). MS (ESI) w/z 484 [M+H]. Example 54 2-(2-Mercapto-2-(acridin-2-yl)propyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoporphyrin -1-carboxamide

140345.doc -100- 201000461 According to the general procedure described in Example 1, 2 from 2-methylmercaptobenzoic acid (3 〇 mg, 0.20 mmol), 2-mercapto-2-(.pyridyl-2-yl) The title compound was synthesized from propylamine (3 mg, 〇2 mmol) and 1-(isocyanoindolyl)-4-(trifluoromethoxy)benzene (4 〇 2 mg, 〇 2 〇 mmol). Brown oil, 22 mg (22%). NMR (400 MHz, CDC13) δ (ppm) 8.52-8.58 (m, 1 Η) 7.64 (td, 1 Η) 7.53 (d, 1 Η) 7.42-7.50 (m, 2 Η) 7.33-7.40 (m, 1 Η) 7.26-7.30 (m, 2 Η) 7.24 (d, 1 Η) 7.19 (ddd, 1 Η) 7.13 (d, 2 Η) 6.86 (t, 1 Η) 4.50 (dd, 1 Η) 4.32 (dd, 1 Η) 4.05-4.21 (m, 3 Η) 1.32 (s, 6 H). MS (ESI) w/z 484 [M+H]. Example 55 3-Phenoxy-2-((1-(acridin-2-yl)cyclopropyl)methyl)-N-(4-(trifluoromethoxy)phenylmethyl)isoindoline- 1-methylamine

General procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (30 mg, 0.20 mmol), (1-(°biti-2-yl)cyclopropyl)methanamine (29.6 mg, 0.20 mmol) The title compound was synthesized from 1-(isocyanoindolyl)-4-(trifluoromethoxy)benzene (4 mmol·2 mg, 0.20 mmol). Yellow solid, 36 mg (37%). ]H NMR (400 MHz, CDC13) δ (ppm) 8.54 (t, 1 H) 8.08-8.14 (m, 1 H) 7.65 (dd, 2 H) 7.59 (td, 1 H) 7.55 (td, 1 H) 7.43 (t, 1 H) 7.30 (d, 1 H) 7.02-7.14 (m5 5 H) 5.06 (s, 1 H) 4.51 (dd, 1 H) 4.30 (d, 1 H) 4.25 (dd, 1 H) 3.54 (d, 1 H) 1.19- 140345.doc • 101 - 201000461 1.25 (m,! η) 0.94-1.03 (m, 3 Η). MS (ESI) w/z 482 [M+H] </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Oxy)phenyl)ethyl)isoindoline-1-carboxamide, isomer 4

p = unknown absolute configuration isomer 4 was converted from 2-mercaptobenzoic acid (〇. 105 g, 0.70 mmol), 2-(2-aminoethyl) ruthenium according to the general procedure 1 described in Example 1. The title compound was synthesized according to EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) With the LaPrep system! (column: chiralpak AD, 50x300 mm ' 10 μιη; mobile phase: 〇_23 min: 5/5/9 sterol: ethanol: heptane, 23-35 min: 1 〇/1 〇/80 sterol: Ethanol: heptane, 35_45 min: 15/1 5/70 sterol: ethanol: heptane; flow rate: 12 〇 ml/min) Opposite chromatography of the lamp on a white solid (〇112 g, 34) Enzymatic separation was carried out in % yield. Isolation of four separations at π minutes (isomer enthalpy), 26 minutes (isomer 2), 32 minutes (isomer 3), and 38 minutes (isomer 4) 140345.doc •102· 201000461 Structure. The separated isomers are collected, transferred and separately processed. GILSON HPLC system was used with HpLC (column · Repr〇sil AM (AD), 4.6 x 250 mm, 5 μπι; mobile phase: 7/3/9 〇 methanol: ethanol: heptane; dynamic rate. 0.83⁄4 liter/min The sample was analyzed for isomer 4 (22 minutes), 2 1 mg, enantiomeric purity: 99%. H NMR (500 MHz, DMSO-c/6) δ (ppm) 9.21 (d, 1 Η), 8.47 (d, 1 Η), 7.70 (td, 1 Η), 7.63 (d, 1 Η), 7.55 ( m, 1 Η), 7.48 (m, 4 Η), 7.30 (m, 3 Η), 7.22 (dd, 1 Η), 5.23 (s, 1 Η), 4.97 (m,1 Η), 4.20 (ddd, 1 H), 3·1〇 (m, 1 h), 3.01 (m, 1 H), 1.43 (d, 3 H). MS (ESI) m/z 470 [M+H]. Example 57 2-(2_(6-Methyl)-Bite-:2-yl)ethyl)_3-tertiaryoxyfluoromethoxy)phenylphenyl)isoindoline-1-carboxamide

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (1 〇〇 mg, 0.67 mmol), 2-(6-decylpyridin-2-yl)ethylamine (90.5 mg, 0.67 mmol) The title compound was synthesized from 1-(1-isocyanoethyl)-4-(trifluoromethoxy)benzene (134 mg, 0.67 mmol). Solid, 200 mg (64.5%). lU NMR (400 MHz, CDC13) δ (ppm) 9.33 (br. s., 1 H) 7.67 (d, 1 H) 7.46-7.60 (m,3 H) 7.40 (t,1 H) 7.06-7.17 (m , 2 H) 140345.doc • 103- 201000461 6.88-7.06 (m, 4 Η) 5.04 (s5 1 Η) 4.29-4.54 (m, 2 Η) 3.92-4.12 (m, 1 Η) 3.84 (dt, 1 Η ) 2.99-3.20 (m, 1 Η) 2.93 (dt, 1 Η) 2.13 (s, 3 H). MS (ESI) m/z 470 [M+H]. Example 58 2-(2-(6-(Hydroxymethyl)&quot;bipyridin-2-yl)ethyl)-3-o-oxy-N-(4-(trifluoromethoxy)phenylmethyl) Porphyrin-1-nonylamine

Step 1: 1 -(3-didecylaminopropyl)-3-ethyl; ε-carbodiimide hydrochloride (1 30 mg '0.67 mmol) and 1-hydroxybenzotriazole hydrate ( 8〇mg, 〇59 mmol) was added to 3-tert-oxy-2-(2-(6-((tetrahydro-2H-pyran-2-yloxy)) fluorenyl)) Isoindolin-1 - decanoic acid (1 80 mg, 〇. 45 mmol) in tetrahydrofuran (1 mL). After 1 min, (4·(monooxy)oxy)methylamine (160 mg, 0.9 mmol) was added. The reaction mixture was stirred at room temperature for 16 hr then concentrated EtOAc. The ethyl sulphate layer was extracted with water (2 〇 匕) and brine (2 〇 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated and evaporated. The product was obtained as a solid, 110 mg (430/0). 140345.doc •104- 201000461 MS (ESI) m/z 570 [M+H]. Step 2: Add pyridinium p-toluenesulfonate (44 mg, 〇177 mm〇1) to 3-oxo-2-(2-(6-((tetrahydro-2H-pyran-2-yloxy)) Base) fluorenyl) acridine·2_yl)ethyl)-N-(4-(difluoromethoxy)benzoinyl)isoindole_丨_carbamamine (84, 〇· 148 mmol) The mixture was stirred with EtOAc (2 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by hydrazine gel column chromatography using hexane:ethyl acetate = 100:0 to 40:60 as a solvent. White solid, 42 mg (60%) °, H NMR (4 〇 MH^ CDC13) δ (Ppm) 8.00 (br. s., ! H) 7.47-7.71 (m, 3 H) 7.21-7.39 (mj 2 H) 6.93-7.21 (m, 6 H) 5.01 (s, 1 H) 4.53 (s, 2 H) 4.43 (m? 2 H) 4.15-4.31 (m, 1 H) 3.84 (dt, 1 H) 3.66 ( Br. s., 1 H) 2.92-3.16 (m, 2 H) = MS (ESI) 486 [M+H]. Example 59 2-(2-(4-(1-Terti-butoxyethyl)1H l 2 3 triamyl)diethyloxy-N-(4-(difluorodecyloxy)benzene Isoporphyrin

140345.doc -105· 201000461 Step 1: According to the method described in Example 34, using gas-purified 2-gas ethylammonium (3〇9 mg, 2.66 mmol), triethylamine (0.334 mL, 2 4 (Ί) • υ mmol), 2-曱醯

2-(2^-虱乙) Preparation of 2-phenylene phthalic acid (400 mg, 2.66 mmol) and 1-(Iso I, sulphonium)_4_(trifluoromethoxy)benzene (0.482 mL, 2.40 mmol) ))-3-Sideoxy-N-(4-(trifluoromethoxy)benzyl)isoindole_丨-methylguanamine. Use heptane to purify the crude product by gel chromatography using ethyl acetate: ethyl acetate = 90:10 to 50.50 to provide a dry film-like chloride μ, 250 mg (23%) ° 1H NMR (400 MHz, CDC13) δ (ppm) 7.65 (d, 1 H) 7 6 〇 (dl H) 7.50 (d, 1 H) 7.41 (t, 1 H) 7.16 (d, 2 H) 7.10 (d , 2 H) 6.83 (br.s., 1 H) 5.32 (s, 1 H) 4.42 (d, 2 H) 4.22-4.29 (dt, 1 H) 3.78 (t, 2 H) 3.55-3.60 (dt, 1 H) 〇MS (ESI) m/z 413, 415 [M+H]. Step 2:

2-(2-Chloroethyl)-3-oxo-N-(4-(trifluoromethoxy)benzoinyl)iso. Leptoline-1-carbamide (100 mg, 0.24 mmol) was dissolved in anhydrous dMF. Azide (20 mg, 0.3 1 mmol) was added and the resulting solution was stirred at 6 ° C for 48 hours. The solution was cooled to room temperature, then water (2 mL), ethyl acetate (2 mL) and toluene (2 mL) were added and the mixture was stirred vigorously for 10 min. The layers were separated and the organic phase was washed with water (2 mL) and concentrated (to ~2 mL) & </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2-(2-azidoethyl)_3_sideoxy_N_(4_(difluoromethoxy)benzyl)isoporphyrin-indoleamine (5〇mg, ( Add 3_3 -butoxybutyne (〇〇23, 〇l8 mm〇1) and cuprous iodide (15 mg, 0.08 mmol) to M2 mmol). Mix the mixture vigorously for 60 hours at room temperature. Thereafter, decyl alcohol (〇.丨〇mL) was added and 3 -3 -butoxybut-1-yne (0.023 mL, 0·18 mmol) was further added, and the temperature was increased to 55 C and stirred for 24 hours. Ethyl acetate (3 mL) and water (2 mL) were then added and the phases were separated. The organic layer was concentrated and the residue was purified by preparative hplc. The fractions containing compound were combined and acetonitrile was removed in vacuo. The aqueous solution was extracted with EtOAc. EtOAc (EtOAc m. The number of protons in one diastereomer is set to 1 proton. !H NMR (400 MHz, CDC13) δ (ppm) 7.55 (t, 2 Η) 7.52 (d, 6 Η) 7.38-7.48 (m, 4 Η) 7.20 (d, 4 Η) 7.09 (d, 4 Η) 4.86 (s, 1 Η) 4.79-4.86 (m, 2 Η) 4.76 (s, 1 Η) 4.57-4.70 (m, 4 Η) 4.35-4.49 (m, 4 Η) 4.18-4.26 (m, 2 Η) 3.82-3.89 (m, 2 Η)

1.40 (d, 3 Η) 1.36 (d, 3 Η) 1.16 (s, 9 Η) 1.09 (s, 9 H). MS (ESI) w/z 546 [M+H]. Example 60 4-Fluoro-3-oxooxy-2-(2-(acridin-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzyl)isoindoline- 1-methylamine 140345.doc -107- 201000461

General procedure 1 as described in Example 1 from 7-fluoro-3-hydroxyisobenzofuran-1(3H)-one (35 mg, 21 mmol), 2-(pyridin-2-yl)ethylamine (0.025 mL, 0.21 mmol) and 1-(isocyanoindolyl)-4-(trifluoromethoxy)benzene (0.042 mL, 0.21 mmol) White solid, 36 mg (3 6%) ° NMR (400 MHz, CDC13) δ (ppm) 9.22 (br.s., 1 H) 8.17 (d, 1 H) 7.68 (t, 1 H) 7.50-7.55 ( m, 1 H) 7.45 (d, 1 H) 7.26 (d, 1 H) 7.17 (m, 2 H) 7.08 (m, 2 H) 5.07 (s, 1 H) 4.37-4.49 (m, 2 H) 3.97 -4.07 (m, 1 H) 3.80-3.91 (m, 1 H) 3. 〇〇-3.2 〇 (m, 2 H). MS (ESI) A 474 [M+H]. Example 61 7-Fluoro-3-oxooxy-2-(2-(indolyl-2-yl)ethyl)-N-(4-(trifluoromethoxy)benzoyl)isoindolinecarboxylic acid amine

According to the general private sequence 1 described in Example 1, from 4-fluoro-3-3-iso-isobenzo. -108- 】40345.doc 201000461 -1-1(3H)-one (40 mg, 0.24 mmol), 2-(pyridin-2-yl)ethylamine (0.029 mL, 0.24 mmol) and 1-(isocyano) The title compound was synthesized from methyl)-4-(trifluoromethoxy)benzene (0.048 mL, 0.24 mmol). White solid, % mg (32%) ° lU NMR (400 MHz, CDC13) δ (ppm) 8.29 (d, 1 Η) 8.06 (d, 1 Η) 7.67 (dt, 1 Η) 7.50 (d, 1 Η) 7.43 (m, i H) 7.12-7.28 (m, 7 H) 5.22 (s, 1 H) 4.49 (d, 2 H) 4.14-4.22 (m, 1 H) 3.80- 3.91 (m,1 H) 3.11- 3.20 (m, 2 H). MS (ESI) w/z 474 [M+H]. Example 62 2-(2-(3-Fluoroacridin-2-yl)ethyl)·3·trioxy_N_(4•(trifluoromethoxy)benzyl)isoindolin-1- Formamide

1-(3-Dimercaptoaminopropyl)_3·ethylcarbodiimide hydrochloride (76

The ethyl acetate layer was extracted with 140345.doc -109- 201000461 mL) and brine (20 mL). The organic layer was dried over anhydrous sulfuric acid, filtered and dried. The residue was purified by silica gel column chromatography using hexanes: EtOAc: EtOAc: EtOAc. The title compound was obtained as a solid, 51 mg (40%). *H NMR (400 MHz, CDC13) δ (ppm) 8.77 (br. s., 1 H) 7.92 (d,1 H) 7.68 (d,1 H) 7.47-7.61 (m,3 H) 7.32-7.47 ( m, 3 H) 7.09-7.23 (m, 2 H) 6.97-7.09 (m, 1 H) 5.09 (s, 1 H) 4.31-4.57 (m, 2 H) 3.98-4.13 (m, 1 H) 3.90 ( Dt, 1 H) 3.16-3.34 (m,1 H) 3.06 (dt, 1 H). MS (ESI) w/z 474 [M+H]. Example 63 4-Terazine-3-Sideoxy-Bite-2-yl)propan-2-yl)trisyloxy)phenyl)isophthalide-1-carboxamide

According to the method described in Example 50, 4-methoxyl_3_sideoxy-2_(1-(σ-pyridin-2-yl)propan-2-yl)-N-(4-(trifluoromethyl) was used. Oxy)phenylphenyl)iso). The title compound was prepared from oxoline-1-carbamide (50 mg, EtOAc) and boron tribromide. White solid, π mg (35%). !H NMR (400 MHz, DMSO-J6) δ (ppm) 9.67 (br. s., 1 H) 9.21(t,lH)8.43-8.51(m,lH) 7.62-7.69 (m,iH) 7 35_ 7.41 (m, 2 H) 7.29-7.34 (m, 3 H) 7.17-7.22 (m, 1 H) 7 15 140345.doc -110- 201000461 (d,lH) 6.79-6.85 (m, 2 H) 4.94 (s , 1 H) 4.35 (d, 2 H) 4.22-4.31 (m, l H) 3.22-3.29 (m, 1 H) 2.79-2.88 (m, 1 H) 1-29 (d, 3 H). MS (ESI) m/: 486 [M+H]. Example 64 Hydroxy_3-sideoxy-2_(2_(0-bito)ethyl)_N_(4_(difluoromethoxy)benzyl)iso-β-lead-leaved 1-methylamine

According to the method described in Example 50, 4-methoxy_3_sideoxy-2_(2-(acridin-2-yl)ethyl)-indole-(4-(trifluorodecyloxy)benzene was used. The title compound was prepared as the title compound, m.p. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; White solid, 56. 4 NMR (400 MHz, CDC13) δ (ppm) 9.32-9.39 (m,1 H) 8 16 (s, 1 H) 8.10 (d, 1 H) 7.64-7.73 (m, 1 H) 7.40-7.48 (m , 1 H) 7.27-7.31 (m,1 H) 7.11-7.21 (m, 4 H) 7.04-7.09 (m 2 H) 6.88 (d, 1 H) 5.05 (s,1 H) 4.32-4.54 (m, 2 H) 4. 〇 CM 12 (m 1 H) 3.70-3.81 (m, 1 H) 3.09-3.20 (m, 1 H) 2.97-3.07 (m 1 H). MS (ESI) m/z 472 [M+H]. Example 65 3-Phenoxy-2-(2-(&quot;bipyridin-2-yl)ethyl)-N-(3-(trifluoromethoxy)phenylmethyl)isoindoline-1- Formamide 140345.doc -111 - 201000461

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (〇·446 g, 2.97 mmol), 2-(2-aminoethyl)pyridine (〇355 mL, 2.97 mmol) and 1-( The title compound was synthesized from isocyanoindenyl)-3-(trifluoromethoxy)benzene (0 597 g, 2.97 mmol). White solid, 450 mg (33 ° / 〇). 'H NMR (500 MHz, DMSO-J6) δ (ppm) 9.22 (t, 1 H) 8.45 (d,1 H) 7.72-7.65 (m,2 H) 7.59 (dt,1 H) 7.56-7.50 O, 2 H) 7.44 (t, 1 H) 7.31-7.19 (m, 4 H) 7.17 (s, 1 H) 5.25 (s, 1 H) 4.38 (d, 2 H) 4.22 (m,1 H) 3.41 (m , 1 H) 3.14-3.06 (m, 1 H) 3.06-2.97 (m, 1 H) 〇MS (ESI) m/z 456 [M+H] 〇 Example 66 N-(2-methyl_4_(3) Fluoromethoxy)benzyl)3 oxo-2 (2 (acridin-2-yl)ethyl)isoindoline-1-carboxamide

General procedure 1 as described in Example 1 from 2-mercaptopurine (37.5 mg '0.25 mmol), 2-(2'-aminoethyl)pyridine (0.030 mL, 0.25 κ (isocyanomethyl) The title compound was synthesized as a white solid (1.6 g (1.3%). ) δ (ppm) 7.79 (d, 1 Η), 7.62 (m, 1 Η), 7.56 (t, 1 Η), 7.49 (d, 1 Η), 7.30 (d, 1 Η), 7.13 (s, 1 Η), 7.06 (d, 1 Η), 5.30 (s, 1 Η), 4.44 (m, 2 Η), 4.29 (m, 1 Η), 4.00 (dd, 1 Η), 3.93 (m, 1 Η) , 3.49 (m, 2 Η), 2.38 (s, 3 Η), 1.97 (qd, 1 H), 1.82 (m, 3 H). MS (ESI) m/z 470 [M+H]. Example 67 N -(3-xitylmethyl)-3-oxo-2-(2-(«Λ乙-2-yl)ethyl)iso-bend 琳 琳 -1- -1- 醯 -1-

General procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (35 mg '0.23 mmol), 2-(pyridin-2-yl)ethylamine (28.5 mg, 0.23 mmol) and 1-di-3 The title compound was synthesized from -(isocyanoindolyl)benzene (0.041 mL, 0.21 mmol). White solid, 53 mg (50%). iH NMR (500 MHz, CDC13) δ (ppm) 9.04 (t, 1 H) 8-18 (ddd, 1 H) 7.62-7.75 (m, 3 H) 7.58 (tt, 1 H) 7.46 (t, 1 H ) 7.28-7.36 (m, 2 H) 7.20 (t, 1 H) 7.11-7.17 (m, 1 H) 6.95-7.11 (m, 2 H) 5.06 (s, 1 H) 4.48 (dd, 1 H) 4.31 (dd, 1 H) 4.01-4.14 (m, 1 H) 3.81-3.98 (m, 1 H) 3.13-3.27 (m, 1 H) 2.96-3.13 (m, 1 H). MS (ESI) m/z 451 [M+H]. 140345.doc -113- 201000461 Example 68 N-(tetra)benzyl)_3 sideoxy-2_(2_(ton bite_2_yl)ethyl)iso(tetra)

The general procedure 1 described in Example 1 is from 2-mercaptobenzoic acid (0.113 g, mm〇1), 2_(° bit _2_yl) ethylamine (0.090 mL, 0.75 mmol), 卜4-(Isocyanoindenyl)benzene (0,140 g, 〇71 mm 〇1). White solid, 151 mg (45%). H NMR (400 MHz, DMSO-J^) δ (ppm) 9.19 (t, 1 Η) 8.44-8.48 (m, 1 Η) 7.64-7.72 (m, 2 Η) 7.57-7.63 (m, 1 Η) 7.47 -7.55 (m, 4 Η) 7.25 (d, 1 Η) 7.18-7.23 (m, 3 Η) 5.23 (s, 1 Η) 4.30 (d, 2 Η) 4.14-4.25 (m, 1 Η) 3.35-3.44 (m, 1 Η) 3.04-3.14 (m, 1 Η) 2.93-3.04 (m, 1 H). MS (ESI) m/z 451 [M+H]. Example 69 N-(4-Bromobenzyl)-3-oxo-2-(2-(nb)-2-yl)ethyl)isoindoline-1-carboxamide, isomer 1

201000461 Isomer 1 a = unknown absolute configuration on the Berger Multigram II system (column: Chiralpak AD, 21.2x250 mm, mobile phase: 40% ethanol and 60% C〇2; flow rate. 50 liters per minute) Execution of n-(4-bromobenzyl)-3-oxo-2,2-(2-(^ π-but-2-yl)ethyl)isoindoline small formamide (151 mg, 0.34 mmol) The preparative separation provided two isolated isomers which were dissolved at 5.4 minutes (isomer 1) and at 8.7 minutes (isomer 2). The separated isomers are collected, evaporated and separately treated. Perform analysis by HPLC using SFC Berger Anaiytix (column: Repr〇Sil-AM(AD) ' 4.6x250 5 μηι; mobile phase: 4% ethanol and 60% C〇2, flow rate: 2 ml/min) Thus, the separation of the two isomers was the first isomer/isomer 1 at 5-9 minutes and the second isomer/isomer 2 at 8.4 minutes. Isomer i: white solid, 46 mg, enantiomeric purity: 99%. H NMR _ MHz, DMS〇〇 s (ppm) 9 i9 (t,! h) 8

8.48 (m, 1H) 7.64-7.72 (m, 2 H) 7.57-7.63 (m, 1 H) 7 47-7.55 (m, 4H) 7.25 (d, 1H) 7.18.7.23 (m, 3 H) 5.23 ( s, 1 H) 4.30 (d, 2 H) 4.14-4.25 (m, 1 H) 3.35-3.44 (m, 1 H) 3.04- 3.14 (m, 1 H) 2.93-3.04 (m, ! H) 〇MS (ESI) m/z 451 [M+H] 0 Example 70 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Entrained amine 140345.doc -115- 201000461

General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (35 mg, 0.23 mmol), 2-(pyridin-2-yl)ethylamine (28.5 mg, 0.23 mmol) and 1,2- - Milk_4-(isolacyl fluorenyl) this (0,039 mL, 0.21 mmol). White solid, 36 mg (35%). NMR (500 MHz, CDC13) δ (ppm) 9.42 (t, 1 Ji) 8.17 (dd, 1 H) 7.64-7.86 (m, 3 H) 7.53-7.64 (m, 1 H) 7.44-7.53 (m, 1 H) 7.34 (d, 1 H) 7.13-7.24 (m, 2 H) 6.83-7.02 (m, 1 H) 5.31 (s, 1 H) 5.09 (br. s.; 1 H) 4.46 (dd, 1 H ) 4.29 (dd, 1 H) 4.12 (br. s·,1 H) 3.84 (d,1 H) 3.13-3.29 (m,1 H) 3.09 (d,1 H). MS (ESI) m/z 440, 442 [M+H] </RTI> &lt;&quot;&&&&&&&&&&&&&&&&& -(trifluoromethyl)phenyl)cyclopropyl)isoindoline-1-decylamine

1-(3-Dimercaptoaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.78 mmol) and 1-hydroxybenzotriazole hydrate (100 mg, hydrazine) 74 mmol) added to 3-oxooxy-2-(2-pyridin-3-ylethyl)isoindole_ι_曱140345.doc •116- 201000461 acid (0.125 g, 0.443 mmol) in tetrahydrofuran ( 1 〇 溶液 溶液 solution, and after 10 minutes, add trifluoromethyl-phenyl)-cyclopropylamine (1〇6 9 mg, 0.527 mmol). The reaction mixture was stirred at rt EtOAc EtOAc (EtOAc)EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. mjjjjjjjjjjjjjj Compound, 45 mg (24.7%). !H NMR (400 MHz, CDC13) 6 (ppm) 8.30-8.50 (m, 2 Η) 7.83 (s, 1 Η) 7.52-7.69 (m, 2 Η) 7.32- 7.52 (m, 5 Η) 7.17 (dd, 1 Η) 7.06 (d, 2 Η) 5.00 (s, 1 Η) 4.12-4.36 (m, 1 Η) 3.26-3.45 (m, 1 Η) 2.78-3.04 ( m, 2 Η) 1.27-1.46 (m, 2 Η) 1.13-1.27 (m, 2 H). MS (ESI) m/z 466 [M+H]. -(®tbbit-2-yl)ethyl)-N-(4-(2,2,2-trifluoroethyl)phenylhydrazolyl)isoindoline-1-decylamine

General Procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (30 mg, 0.20 mmol), 2-(pyridin-2-yl)ethylamine (24.4 mg, 0.20 mmol) and 1-isocyano Methyl-4-(2,2,2-trifluoroethyl)benzene (40 mg, 0.20 mmol) 140345.doc -117· 201000461 The title compound was synthesized. Light yellow solid, 5 8 mg (64%). 'H NMR (400 MHz, CDC13) δ (ppm) 8.90 (m, 1 Η) 8.06 (d, 1 Η) 7.67-7.72 (m, 2 Η) 7.53-7.66 (m, 2 Η) 7.46 (dd, 1 Η) 7.23 (d, 1 Η) 7.04-7.15 (m, 5 Η) 5.02 (s, 1 Η) 4.32-4.49 (m, 2 Η) 4.02-4.12 (m, 1 Η) 3.83-3.91 (m, 1 Η) 3.23-3.34 (m, 2 Η) 3.11-3.21 (m,1 Η) 2.98-3.06 (m,1 H). 19F NMR (400 MHz, CDCl3) 5 (ppm) - 66.35, - 66.37 &amp; - 66.40 ° MS (ESI) w/z 454 [M+H]. Biological Testing The performance of voltage-gated sodium channels in cell lines: As is well known in the art, the gene encoding the full-length protein of the desired voltage-gated sodium channel is selected under a suitable promoter and expressed in a suitable cell line. Screening assays were performed using such constructed stable cell lines to identify suitable compounds active against the voltage-gated sodium channel. A suitable screening assay is as follows.

Li+ Influx Assay A cell line expressing the desired voltage-gated sodium channel is applied to a conventional 96 or 384-well tissue culture dish at a suitable cell density (cell density, for example, 40,000 cells/well in a 96-well culture dish or at 20,000 cells/well in a 384-well culture plate). The cells are then 'repelled repeatedly' with a suitable commercially available scrubber (e.g., El_405 scrubber) using a suitable Na-free buffer until all tissue culture groups are removed from the wells. A suitable sodium-free buffer may have the following composition OM): gasification test 137, KC1 5 4, MgS〇4 〇81, CaCl2 〇%, glucose 5.5 5 and HEPES 25 (pH 7.4), but it may have other Suitable composition. After all washing steps have been completed, the cells are incubated for 15 min in a suitable sodium-free buffer at 140345.doc • 118· 201000461. Subsequently, the sodium-free buffer was removed and the cells were incubated with LiCl-rich buffer for 60 min at 37 C. LiCl buffer is also rich in potassium ions, which produces depolarizing stimulation of the cells. This buffer can have the following! And (mM): LiCl 100, KC1 50, MgS04 0.81, CaCl2 0.95, glucose 5.55 and HEPES 25 (pH 7.4), but it may have other suitable, and can be formed. To enhance the signal-to-noise ratio, an effective concentration (eg, 100 μΜ) of voltage-gated sodium channel opener veratridine or any other suitable voltage-gated sodium channel opener can be added to the medium to enhance the signal. Detection. In addition, in order to enhance the signal-to-noise ratio, an appropriate concentration of scorpion venom (e.g., 10 pg/ml) may be added to the medium to delay channel inactivation. In order to find the regulator of the required voltage-gated sodium channel, the compound from the compound library can be supplemented in the assay. The desired compound is added to the U-rich solution with one compound per well. At the end of the incubation period, the cells were washed repeatedly with sodium-free buffer until all cells were removed 々UC1. The lysate is obtained by incubating the cells with triton (丨%) for 5 min or any other suitable method. Subsequently, the obtained lysate is introduced into an atomic absorption spectrophotometric juice, thereby quantifying the amount of enthalpy inflow during the above-mentioned procedure. The assay can be carried out using any atomic absorption spectrophotometer using a 96 well format, 3 84 well format plate or any other conventional culture plate format. The assay can be used to represent any of the "one voltage gated control channel" alpha subunits and a cell line that combines a voltage-gated "subunit" with any given one or more beta subunits. If necessary, the appropriate potassium leakage ion channel (eg, TREK_丨) can be expressed by transient co-transfection or by establishing a stable co-transfected cell line, thereby allowing the selected cell line to be over 140345.doc -119- 201000461 polarization. Traditional intracellular electrophysiology can be used in whole cell patch clamps, perforated patch clamps or conventional two-electrode voltage clamps to confirm the successful performance of the leaky κ current. As described above, selected cell lines modified to successfully represent the desired voltage-gated sodium channel and the appropriate potassium-leakage channel transfected can be used for screening using atomic absorption spectroscopy. Whole-Cell Voltage Clamp Electrophysiological Assays Electrophysiological recordings of sodium currents in cells that stably exhibit the required voltage-gated sodium channels demonstrate valid and provide functional measures that specifically affect the efficacy of the compounds of the channels. Electrophysiological studies can be performed using an automated patch clamp electrophysiology platform (such as IonWorks HT, IonWorks Quattro, PatchXpress) or any other suitable platform. The cell line expressing the desired voltage-gated sodium channel is applied to a suitable well tissue culture dish as supplied by the manufacturer of the automated patch clamp platform. The appropriate extracellular and intracellular buffers for these experiments were used according to the instructions provided by the manufacturer of the automated patch clamp platform. Cells expressing the desired voltage-gated sodium channel protein are exposed to the drug via a micropipetting system integrated into the platform. A suitable voltage stimulation protocol is used to activate the desired voltage-gated sodium channel protein. A suitable stimulation scheme consists of eight voltage pulses, each of -20 mV and a length of 50 ms, separated by a 330 ms interval at a potential of -90 mV or -65 mV, but it may also have Other suitable parameters. Electrophysiological studies can also be performed as described in the literature using a whole cell configuration of standard patch clamp techniques. In this assay, cells displaying the desired human voltage-gated sodium channel protein are exposed to the drug by a conventional micro-perfusion system and the voltage-suppressed sodium channel is activated using a suitable voltage stimulation protocol 140345.doc-120-201000461. In Vivo Experiments When a compound of the present invention is administered to a mouse or a rat by systemic injection, the compound of 6H can specifically reduce the pain behavior in the f〇rmalin test. This test is an accepted model of clinical pain in humans, including members of pain receptor activation, inflammation, peripheral sensitization, and sensitization of the sputum (A Tj0lsen et al., corpse 5 1,5). Therefore, it can be inferred that the compounds of the present invention are useful as therapeutic agents for relieving pain from various sources. The compound of formula I can be tested in rat intraarticular FCA (Freund, s complete adjuvant) (inflamed pain model et al, 79, 2〇5_72) and rat Chung nerve injury test (neural pain model) And C/z (iv) g. households exhibit analgesic activity in „7 columns 2, 5 sense 355.” Analgesic effects can be obtained in animal models after administration, which do not produce tissue concentrations that block conduction in nerve fibers. ,

The local anesthetic properties of the compounds mentioned in the Thio publication do not account for analgesic effects. Systemic administration (4) Analgesic effect is not the general characteristic price of a drug with local anesthesia (10), etc., fine ^ (10) ^

Anaesthesia 1988, 61, 165-8). In general, the compounds of the invention are active in the above whole cell voltage clamp electrophysiological assay, wherein 1 (: 5 〇 is less than 1 〇 μΜ. In the present invention - the IC50 value is less than 1 μΜ. The title compound of the above example was tested in the above-mentioned whole-cell voltage clamp electrophysiological assay. The ICSG value indicates the concentration of the compound required for 50% inhibition. The test results are shown in the table below as pIC50 values (i.e., cut IC50). Because 140345. doc -121 - 201000461 Therefore, the larger the pIC5Q value, the more effective the compound. For example, a pIC50 value of 6.6 indicates an IC5 of 10_6·6 Μ. value. Example No. NaV1.7 pIC5〇 Example No. NaV1.7 pICso Example No. NaV1.7 pIC5〇1 6.6 25 6.4 49 6.8 2 6.8 26 6.2 50 6.4 3 7.3 27 5.8 51 7.0 4 6.8 28 5.6 52 7.3 5 6.4 29 7.2 53 6.1 6 6.4 30 7.3 54 5.8 7 6.4 31 7.0 55 5.5 8 6.3 32 7.0 56 7.2 9 6.3 33 6.4 57 7.1 10 6.2 34 6.6 58 5.8 11 6.2 35 6.3 59 5.7 12 5.9 36 6.3 60 6.5 13 5.7 37 5.7 61 7.1 14 5.7 38 6.0 62 7.1 15 5.5 39 6.4 63 6.8 16 6.4 40 6.6 64 7.2 17 6.2 41 6.4 65 7.3 18 6.9 42 5.7 66 6.5 19 7.1 43 6.8 67 6.5 20 7.4 44 6.0 68 6.5 21 5.5 45 6.0 69 6.9 22 6.5 46 7.3 70 6.7 23 6.7 47 7.3 71 6.2 24 6.9 48 6.9 72 6.6 140345.doc -122-

Claims (1)

201000461 VII. Patent application scope: 1. A compound of formula I: Ο R2 wherein R1 is hydrogen, Ci.3 alkyl, Ci_3 alkoxy, cyano, via 戍. Some of the C!·3 alkyl groups may be independently selected from the group consisting of a trans group and a Ci_3. Substituted by a substituent of an oxy or IL group; and wherein c13;j^oxy is optionally substituted with one or more fluoro groups; m is 1 or 2; R and R are each independently and independently selected from hydrogen, CK4 halogenated a group, a Cl_4 halogen-oxyl group, a halogen group, a Cw alkoxy group, a Cw alkyl group, and a c3_7 cycloalkoxy group; and wherein the C:3·7 cycloalkoxy group may be optionally substituted with one or more fluorine groups; Wherein R 2 and R 3 are not simultaneously hydrogen; Het is selected from the group consisting of pyridyl, pyrazinyl, isoxazolyl, and °. Sitylene, fluorenyl, triazolyl and pyrimidinyl, wherein the heteroaryl can be optionally substituted by one or more X4; X4 is dentate, Cl-3 alkyl, Cl-3 alkyl OCw alkyl , -CH(CH3)-〇-c(ch3)3, Cl 4 alkoxy, cyano, hydroxy or Cl 2 hydroxyalkyl; and wherein the lenyl group, the Ci-3 alkyl OCl-3 Alkyl, the -ch(ch3)-140345.doc 201000461 〇-C(CH3)3 and the c.4 oxy group can be substituted by one or more fluorines according to the case of the sample J; An alkyl group which may be fluorinated or hydroxylated as appropriate; and L*2 is a Ci_3 alkyl group; wherein the following compounds are excluded: 2-[1-(1,5-dimercapto-indole-carbazole_4 _ yl)ethyl]_5,7-dimethoxy_3_ oxo-oxime-[2-(difluoromethyl)benzoinyl]isoindole 丨 曱醯 曱醯 曱醯; Ν (4- Fluorobenzyl)-3-oxo-oxy-2_(2-acridyl-4-ylethyl)isoindoline-1-carboxamide; and, N-(2-p-benzophenyl)_2_[ 2_(1h•吲哚_3_yl)methylethyl] oxoisoindol-1 -decylamine; and a pharmaceutically acceptable salt or isomer thereof or a salt thereof 0 2 · The compound of claim 1 which : R1 is chloro, Cw, oxy, Cl3, chloro, fluoro, chloro or hydroxy; m is 1 or 2; R and R3 are each and independently selected from hydrogen, Ci-4 haloalkyl, Cl 4 a haloalkoxy halo group, a Cl-4 decyl group, and a (4) alkyl group, wherein R2 and R3 are not simultaneously hydrogen; Het is selected from any one of the following: pyridyl, pyrazinyl, isoxazole Comparing: a sitting group, a fluorenyl group, a tris-based group, and a pyrimidine group, wherein the heteroaryl group may be optionally substituted by one or more X4; χ4 is a C]_3 alkyl group, an alkoxy group or a fluoro group; H0345.doc 201000461 Li is CK3 alkyl; and [2 is CK3 alkyl. 3. The compound of claim 1 or 2, wherein Ri is hydrogen. 4. The compound of claim 1 or 2, wherein R1 is The compound of claim 1 or 2, wherein R1 is a decyl group. 6. The compound of claim 1 or 2, wherein R1 is cyano. 7. The compound of claim 1 or 2, Wherein Ri is a hydroxy group. 8. A compound according to claim i or 2, wherein Ri is a chloro group. 9. The compound of claim 1 or 2, wherein R1 is a fluoro group. The compound of any one of claims 1 to 9, wherein R2 is a gas group, a fluorine group or a bromo group. The compound of any one of claims 1 to 9, wherein R2 is _〇cF3 or 〇-CH2-CF3. The compound of any one of claims 1 to 9, wherein ... is a compound of any one of claims 1 to 9, wherein R2 is oxime. The compound of any one of claims 1 to 9, wherein R2 is chlorine. The compound according to any one of claims 1 to 9, wherein R2 is isopropyl. The compound of any one of claims 1 to 5, wherein R3 is a gas. The compound according to any one of claims 1 to 15, wherein R3 is a gas, a chloro group or a bromo group. The compound of any one of claims 1 to 5, wherein R3 is a compound of any one of claims 1 to 15, wherein R3 is. The compound of any one of claims 1 to 5, wherein R3 is a compound of any one of claims 1 to 20, wherein the compound is selected from the group consisting of an anthracene group and an ethyl group. Prolonged propyl. The compound according to any one of claims 1 to 20, wherein Li is selected from the group consisting of -CH-(CH3)-CH2-; -CH-(CH3)-; -C(CH3)2-CH2-; -CH2 - ch(ch3) ; -ch2-c-(ch3)2-; and. The compound of any one of claims 1 to 22, wherein L2 is an anthracenylene group. The compound of any one of claims 1 to 22, wherein L^_ch_(CH3)_. The compound of any one of claims 1 to 22, wherein L2 is a -cyclopropyl propyl group. The compound of any one of claims 1 to 25, wherein X4 is a methoxy group. 27. The compound of any one of claims 1 to 25, wherein X4 is methyl. 28. The compound of any one of claims 1 to 25, wherein X4 is cyano. 29. As requested! The compound of any one of 25' wherein χ4 is cF3. The compound of any one of claims 1 to 25, wherein X4 is an i group. The compound of any one of claims 1 to 25, wherein χ4 is _〇_CH2_CF3. The compound of any one of claims 1 to 25, wherein X4 is a fluorenyl group. 33. The compound of any one of claims 1 to 25, wherein χ4 is _cH2〇h. The compound of any one of claims 1 to 25, wherein π is 〇-c(ch3)3. The compound according to any one of the claims, which is selected from the group consisting of N-[(4-chlorophenyl)methyl]_3_sideoxy-2_(2_pyridinyl) Ethyl)·1H_isoindole-1-carboxamide; 3_p-oxy-2-(2-indenyl ethylfluoromethoxy)phenyl]methyl]-1H-isoindole- 1 -decylamine; 140345.doc 201000461 3-Phenoxy-2-(2-oxaridin-2-ylethyl)-N-[[4-(trimethyl)phenyl]indolyl]- 1H-isoindole-p-carbamamine; 3-sided oxy-2-C-pyridin-3-ylindenyl)-N-[[4-(trifluorodecyloxy)phenyl]methyl]- 1H-isoindole-: 1 -carbamamine; N-[l-(4-phenylphenyl)ethyl]_3-tertiaryoxy-2_(2-°pyridin-2-ylethyl)-1H -isoindole-1-carboxamide; 3-oxo-2-(2-pyrazine-2-ylethyl)-N-[[4-(trifluoromethoxy)phenyl]indole -1H-isoindole-1-carboxamide; (2-[(2-methoxypyridin-3-yl)indolyl]-3-yloxytrimethoxy)phenyl]- ]]-Η-isoindole _ carbamide; 3- oxo-2-(pyridazin-2-ylindenyl)-indole-[[4-(trifluoromethoxy)phenyl] fluorene Base]-1Η-isoindole-1 -decylamine; 3-sided oxy-2-(2-°pyridin-2-ylethyl)-indole-[1-[4-(2,2 , 2_: gas ethoxy) phenyl] ethyl]-1 Η-isoindole-1-decylamine; 2_[(5-methyl-1,2-oxazol-3-yl)indolyl]- 3-Alkyloxy_ν_[[4_(三气史曱oxy)phenyl]indolyl]-1Η-isoindol-1-amine; ^ Ν-[(4-chlorophenyl)fluorenyl ]_3-Sideoxy-2-(2-.pyrazine_2-yl-ethylamine) 1Η-isoindole-1-carbamimid; Ν·Π-(4-phenylphenyl)ethyl]-3 - oxo-2-(2-pyridazine-2-enyl) 1 Η-isoindole-1 - decylamine; N-[l-(4-chlorophenyl)ethyl]-3- Sideoxy-2-(acridinylmethyl&gt;1H-isoindole]-formamide; N_[(4-fluorophenyl)indolyl]-3-oxo-2-(2-oxime) Than bite_2_ its lane 'Ethyl)-1H-isoindole_丨_carbamamine; 140345.doc 201000461 3- Sideoxy-2-(2-D ratio σ-but-2-ylethyl) -N-[[4-(2,2,2-dioxaethoxy)phenyl]indolyl]-1H-isoindol-1-amine; 2-[3-(3-methyl- 1H-carbazol-1-yl)propyl]-3-yloxy-N-[4-(trifluoromethoxy)benzyl]-isoindoline-1-decylamine; 2- ( 1-mercapto-2-(pyridin-2-ylethyl)-3-oxo-N-[4-(trifluorodecyloxy)benzyl]isoindoline-1-decylamine ; 4- 曱oxy-3-side oxygen 2- (2. Bis-2-ylethyl)-7V-[4-(trifluoromethoxy)phenylindenyl]isoindoline-1-indolyl; 3-oxo-2-(2-acridine) 4--4-ethyl)-[4-(trifluorodecyloxy)benzyl]isoindoline-1-carboxamide; 3-sided oxy-2-(2-° pyridine-3 -ylethyl)-7V-[4-(trifluoromethoxy)phenylindenyl]isoindoline-1-carboxamide; 2-(1-indolyl-2-.pyridin-2-yl) Ethyl)-3-oxooxy-7V-[4-(trifluoromethyl)benzoinyl]isoindoline-1-decylamine; #-(4-chlorobenzyl)-2-( 1-mercapto-2-acridin-2-ylethyl)-3-oxo-isoindoline-: 1 -decylamine; 2-[2-(1//- 丨哚 丨哚-3 -yl)ethyl]-3-oxooxy-7V-[4-(trifluoromethoxy)phenylindenyl]isoindoline-1-decylamine; 7V-(4-decyloxyphenylhydrazine) 3-)-3-oxo-2-(2-.pyridin-2-ylethyl)isoindoline-1 -carboxamide; 4 -decyloxy-2 - (1-indolyl-2 -α ratio 0-but-2-ylethyl)-3-sideoxy-N-[4 _(trifluoromethoxy)benzyl]-isoindoline-1-decylamine; Ν-( 4-isopropylbenzyl)-2-(1-indolyl-2-pyridin-2-ylethyl)-3-oxoisoindoline-1 -decylamine; 140345.doc -6 - 201000461 N-[4-Oxo~3_(trifluoromethyl)benzyl]-2-(1-indolyl-2-pyridin-2-ylethyl)_3-trioxyisoindoline guanamine; N_ [3_Gas~4-(Trifluoromethyl)benzyl]-2-(1-methyl-2-pyridyl-2-ylethyl)-3-oxooxyisoporphyrin_丨_曱Indoleamine; 2-(1-methyl-2-acridin-2-ylethyl)_3_sideoxy_Ν·[3·(trifluoromethoxy)benzoinyl]isoindoline-1 - guanamine; Ν-ΠΚ3-chlorophenyl)ethyl]_3_sideoxy-2_(2_acridin-2-ylethyl) iso-°°° nozzle 1-amine; 2_( 2-((5-fluoropyrimidin-2-yl)ethyl)-3-oxo-N-(4-(trifluoromethoxy) adenyl)isoindol-1 -cartoamine; 2- (2-(4-Mercaprypyrimidin-2-yl)ethyl)_3_sideoxy_N_(4_(trifluoromethoxy)phenylindenyl)isoindoline-1 -decylamine; 3_ 2-oxo-2-(2-(pyrimidin-2-yl)ethyl)-N-(4-(trifluoromethoxy))phenylhydrazinyl)isoindol-1 -nonylamine; 2-( 2-(2-amidinopyrimidin-5-yl)ethyl)_3_sideoxy_Ν·(4_(trifluoromethoxy)phenylindenyl)isoindoline-1 -decylamine; 2- ((6-Cyano-n-pyridyl_3_yl)methyl)_3_sideoxy_Ν_(4_(trifluorodecyloxy) benzyl Isophthalene _ i _ guanamine; 3- oxo-N-(4-(trifluorodecyloxy)phenyl fluorenyl)_2_((5-(trifluoromethyl)pyridin-2-yl)indole (iso) porphyrin 丨 醯 醯 醯 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Porphyrin-1-carboxamide; 3_p-oxy-2-((6-(2,2,2-trifluoroethoxy)acridine_3_yl)methyl)_N_ (4 (― Oxymethoxy))methyl)iso-α-indole-dopamine; 140345.doc 201000461 Fluoromethoxyfluoromethoxy+((5fluoropyridin-2-yl)ethyl)_3_sideoxy_ N_(4_(yl)benzyl)isoindoline-1 -carboxamide; 7: chaotic-3. sideoxy_2_(2_(. Specific bite _2_yl)ethyl)j(heart (benzyl) benzyl)isoporphyrin _ 丨 醯 醯 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Base)_N cases of tris-methoxy)benzyl)isoindoline-1-carboxamide; , 2_(2·trans-base_2 decyl-2-yl)ethyl)-3-side oxygen -N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide; monofluoro 2 (ratio π疋-2-yl)ethyl)_3_sideoxy_ N-(4-(Trifluoromethoxy)benzyl)isoindoline-1-carboxamide; 2 (2'2-fluoro-2-(p-pyridin-2-yl)ethyl) _7_methyl_3_sideoxy_N_((-fluoromethoxy)phenylmethyl)isoindene_丨_carbamamine; 3-sideoxy-2_(3_(π-pyridine) _ yl) propyl) _ Ν _ (4 · (trifluoromethoxy) benzyl) isoindolin-1-carboxamide; 7 _ methoxy-3- oxo 2 - (2- ( 〇 啶 _2 - - - - - _2 _2 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 2_(2_(η比啶_2_yl)ethyl)_Ν_(4_(trifluoromethoxy) alumheptyl)isoindoline-1-decylamine; 2-(2-indenyl (pyridine) 2_yl)propan-2-yl)_3_sideoxy_Ν_(4_(trifluoroanthracene) Phenylhydrazinyl)isoindoline _ i _ decylamine; 7-mercapto-3-yloxy-2-(2-(acridin-2-yl)ethyl)-N-(4-( Trifluoromethoxy)phenylhydrazino)isoindoline-1 -decylamine; 2-(2-methyl-2-(pyridin-3-yl)propyl)_3_sideoxy-N-( 4-(trifluorodecyloxy) benzyl)isoindoline-1 -decylamine; 140345.doc 201000461 methyl 2 (.pyridin-2-yl)propyl)·3-sideoxy- N-(4-(trifluoromethoxy)benzyl)iso.嗓嗓琳+甲含胺; ",oxy 2 ((1-(°-pyridin-2-yl)cyclopropyl)methyl)-N-(4-(trifluoromethyl)phenyl)) 。 嗓 嗓 小 小 小 酿 ;; # 1 2 2 (2 _ (° than bite '2' base) ethyl) _N-0-(4-(trifluoromethoxy) soil based) Mouth _ j _ ketoamine, isomer*; e (methyl ratio. 疋_2-yl)ethyl)_3_sideoxy-N-(4-(trifluoromethoxy)benyl) (4); ^ 基 甲基 甲基 。 。 。 。 定 ) ) 。 。 。 乙基 乙基 乙基 乙基 乙基 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。.弓布朵琳·bwedoxime; 2-(2-(4-(1-second and yl)-3-yloxy~♦(Ethylethyl).111·1,2,3·three m Ethylamine; 虱 methoxy) benzyl) isoporphyrin- ΐ _ 4- 4- -3- oxo- 2 _ (2 比 咬 基 戊 戊 甲基 嗓 小 小 小 小 小 小Amine; ((-----------------) () 异 卜 卜 琳 曱 曱 曱 ;; ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( _ methoxy) benzyl is the spider 1 • ketoamine; (“rat L-yl-3- flavonyl 2 — (2 pyridine) benzyl) (four) ^ (four); 3_sideoxy-2 to the ratio. Benz-2-yl)hexyl)-(trifluoromethoxy)benzene 140345.doc 201000461 fluorenyl)isoindoline-1-decylamine; N-(2 -mercapto-4_(trifluoromethoxy)benzyl)-3-oxo-2-(2-(pyridin-2-yl)ethyl)isoindole η 嘴 _ 1 _曱Acid amine; Ν-(3-bromomethyl)_3_sideoxy_2_(2_(π-pyridyl-2-yl)ethyl)isoindole °-linyl-1 -carboxamide; Ν-(4-bromobenzoinyl)_3_sideoxy_2_(2_(acridin-2-yl)ethyl)isoindole·-1-carbamamine; Ν-(4- desert benzene Sulfhydryl)_3_sideoxy-2_(2 octyl _2-yl)ethyl)isoindoline-1_decylamine, isomer]; Ν-(3,4-dichlorobenzene曱))_3_sideoxy_2_(2_(π-pyridine-2-yl)ethyl) iso-sigma-inducible-1 -cartoamine; 3: sideoxy-2-(2 dec. _3_yl)ethyl)good (1♦(trifluoromethyl)phenyl)cyclopropyl)isoindoline_丨_carbamidamine; and 3-sided oxy-2-(2 ten bite _2_yl)ethyl)_N_(4_(2,2,2-trifluoroethyl)benzyl)isoindoline-1 -decylamine. 36. A compound according to any of the preceding claims, which is for use in therapy. 37. Use of a compound according to any one of the claims, for use in the manufacture of a medicament for the treatment of a pain condition. 38. A method of treating a pain condition, whereby the individual in need of the pain treatment is in combination with the compound of any one of items i to 35. A compound according to any one of claims 1 to 3, which is for use in the treatment of a pain condition. 40. A medicinal composition comprising a compound according to any one of claims 1 to 35 in combination with a pharmaceutically and pharmacologically acceptable compound. 140345.doc -10· 201000461 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 140345.doc -4-