TW201130815A - Cyclohexyl amide derivatives as CRF receptor antagonists - Google Patents

Abstract

There are described cyclohexyl amide derivatives useful as corticotropin releasing factor (CRF) receptor antagonists.

Description

201130815 VI. Description of the Invention: [Technical Field] The present invention relates to a cyclohexylamine derivative, its preparation, its use as a medicine, and a pharmaceutical composition containing the same. More specifically, the invention relates to its use as a corticotropin releasing factor (CRF) receptor antagonist. SUMMARY OF THE INVENTION In a first aspect of the invention, there is provided a compound of formula I,

Wherein R is phenyl or 6 membered heteroaryl, each optionally substituted by one or more substituents selected from the group consisting of ci-ioalkyl, C1-10 alkoxy, halogen and C1_10-alkyl; X1 is a bond or -CR2R3_, _NR4·, _〇 or _cr5r6cr7r8_ ; X is a key or -CR9R10- or -CRnR〗 2CR13R14-; The restriction is that when χι is ·CR5R6CR7R8_, then χ2 is not -CRUrUcrHr', and 乂Only one of 丨 and ^ can be a bond; A is -N- or CR15; A2 is CR16; A is -N- or CR17; A is -N- or CR18, and the restrictions are a1, A3, and a4. Not more than two; or

R2, R3, R5, R6, R7, R8, r9, Rl〇' R", r12, and RH 153611.doc 201130815 may be the same or different and each is hydrogen, Cl-ioalkyl or halogen, or R2 and R3, R5 and R6, R7 and R8, R9 and R1. , R11 and R12, and one of the dentities 13 and Rl4 together form a 3 to 6 membered saturated carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms; R4 is hydrogen or C1-10 alkyl; R15, R16, R17 And R.sup.18 may be the same or different and each are hydrogen, €1_1 alkyl, C1-10 alkoxy, halogen or ci-i〇halo alkoxy; and isomers thereof; in free form or in the form of a salt. For the purpose of interpreting this specification, the following definitions shall apply, and the terms used in the singular will also include the plural, and vice versa, as appropriate. The term "alkyl" as used herein refers to a fully saturated branched or unbranched hydrocarbon moiety, ie, a first, second or third alkyl group, or, if appropriate, a cycloalkyl or naphthenic ring. Alkyl substituted alkyl which may also be a saturated or unsaturated alkyl group. If not otherwise defined, the alkyl group preferably contains from 丨 to 2 carbon atoms, more preferably from 1 to 16 carbon atoms, from 1 to 1 carbon atoms, from 1 to 7 carbon atoms, or from 1 to 4 carbons. atom. Representative examples of alkyl include, but are not limited to, methyl 'ethyl, n-propyl, isopropyl, n-butyl t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-decyl, n-decyl and Its similar group. The term "g-based" as used herein, refers to a radical as defined herein- or a plurality of (10) substitutions as defined herein. Preferably, the g-group may be a single-toothed base, a bidentate base or a poly- fluorenyl group, including a full-dentate base. Monodentate burning 153611.doc 201130815 The group may have an iodine group, a bromo group, a gas group or a fluoranthene group in the alkyl group. The dihaloalkyl and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups in the alkyl group. The polyhalogenated group preferably contains up to 12, or 1 Å, or 8, or 6, or 4, or 3, or 2 halogen groups. Non-limiting examples of haloalkyl groups include dimethyl, difluoroindenyl, trifluoromethyl, methoxymethyl, di-methylmethyl, dichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoro gas. Sulfhydryl, difluorofluoroanthryl mono-oxyethyl, monofluoropropyl, mono-ethyl and di-propyl. A fully halogenated system refers to an alkyl group in which all hydrogen atoms are replaced by a halogen atom. The term "alkoxy" as used herein refers to alkyl 〇 其中 ... wherein the primordium is as defined above. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclo Propyl-, cyclohexyloxy and the like. The alkoxy group preferably has from about 1 to about 7, more preferably from about 1 to about 4 carbons.

The term "heterocyclyl" or "heterocycle" further refers to a heterocyclic group as defined herein which is substituted by 1, 2 or 3 substituents selected from the group consisting of: (a) alkyl; b) hydroxy (or protected hydroxy); (c) halo; (d) haloalkyl; 0) pendant oxy, ie = hydrazine; (f) amine, alkylamino or dialkylamine (g) alkoxy; (h) cycloalkyl; 153611.doc 201130815 (1) a carboxyl group; (j) a heterocyclic oxy group, wherein the heterocyclic oxy group represents a heterocyclic group bonded via an oxygen bridge; (k) alkyl-fluorene-C(0)--; (1) sulfhydryl; (m) nitro; (η) cyano; (fluorene) sulfonyl or sulfonylamino; (fluorene) aryl; (q) Alkyl-C(0)-0--; (7) aryl-C(0)-0--; (s) aryl-S--; (t) aryloxy; (u) alkyl-S (v) methyl sulfhydryl, ie HC(O)--; (w) amine carbaryl; (X) aryl group; and (y) pyrolyzed, cycloalkyl, oxygenated An aryl group substituted with a thiol group, an amino group, an alkyl group, a C-(0)-NH--, an alkylamino group, a dialkylamino group or a halogen. The term "cycloalkyl" as used herein refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group having from 3 to 12 carbon atoms, preferably from 3 to 9, or from 3 to 7 carbon atoms. Each may be substituted with one, or two, or three, or three or more substituents such as alkyl, halo, pendant oxy, hydroxy 'alkoxy, alkyl-C(0)-- , amidino group, amine mercapto, 1536Il.doc • 6 - 201130815 院基侧·_, (hospital) 2N—, thiol group, alkyl group _s__, nitro group, aryl group carboxyl group, alkyl group-0 -c(0)·-, sulfonyl, sulfonylamino, sulfonate, and the like I group.丫 Listed monocyclic nicotyl groups include, but are not limited to, 1⁄4 propyl, cyclobutyl, cyclopentyl, cyclopentenylcyclohexyl, cyclohexyl and the like. Exemplary bicyclic hydrocarbyl groups include scopolamine, decyl, octafluoroindole, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2 1 1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2 ·1·1] heptyl, M. dimercaptobicyclo[3.U]heptyl, 2,6,6-dimethylbicyclo[31heptyl, bicyclo[2 2 2]octyl and the like group. Exemplary bicyclic hydrocarbon groups include adamantyl groups and the like. The term "aryl" as used herein refers to an aromatic carbocyclic ring system containing from 6 to 14 ring carbon atoms which may be unsubstituted or substituted as defined. The term "aryloxy" as used herein means _〇_aryl and _〇_heteroaryl, wherein aryl and heteroaryl are as defined herein. The term "heteroaryl" as used herein refers to a 5 to 14 membered monocyclic or bicyclic or polycyclic aromatic ring system having from 丨 to 8 heteroatoms selected from ruthenium, osmium or S. The heteroaryl group is preferably a 5 to 1 member or a 5 to 7 membered ring system. Typical heteroaryl groups include 2-thienyl or 3-thienyl, 2-furyl or 3-furanyl, 2-»pyrrolyl or 3-»pyrrolyl, 2-imidazolyl, 4-imidazolyl or 5 - imidazolyl, 3-n-bisazolyl, 4-pyrazolyl or 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl, 2-oxosino, 4-oxazolyl or 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl, 3-1, 2 , 4-triazolyl or 5-1,2,4-triazolyl, 4-1,2,3-triazolyl or 5- 1,2,3-triazolyl, tetrazolyl, 2-pyridine Base, 3-pyridyl or 4-pyridine 153611.doc 201130815 base, 3-oxazinyl or 4_哒, 3♦ Qin, 4" than fluorenyl or 5_fluorenyl 2 than Qin, 2_ Mouth bite base, 4_唆 bite base or 5_ shout bite. The term "heteroaryl" also refers to a heteroaromatic ring and - or a plurality of aryl, cycloaliphatic or fluorenyl groups, The linking group or point of attachment is on the heteroaromatic ring. Non-limiting examples include, but are not limited to, 1-β-pyridazinyl, 2-indolinyl 3 5丨oxazinyl, 5-pyridazinyl, 6-pyridazinyl, 7-吲哚秦基或八弓丨木嗪基,丨_isoindolyl, 3 吲哚isoindolyl, 4_isoindolyl 5 isopropenyl, 6-isoindenyl or 7-isoindolyl, 2_mercapto, 3 丨 基 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 , 5-carbazolyl, 6-fluorene, or 7-oxazolyl, 2-indenyl, 4-hydrazino, 5-hydrazino, 6-fluorenyl, 7-fluorenyl or 8-decyl, 1 - quinazinyl, 2-quinazinyl, 3-quinazinyl, 4-quinazinyl, 6-quinazinyl, 7-quinazinyl, 8-quinazinyl or 9-quinazinyl, 2-quinolinyl, 3-quinolyl, 4-quinolinyl, 5-quinolinyl, 6•quinolinyl, 7-quinolinyl or 8-quinolinyl, indole-isoquinolyl, 3·isoquinolinyl, deduction Isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7 isoquinolyl or 8-isoquinolyl, 1-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-oxazinyl, 7-pyridazinyl or 8-pyridazinyl, 2-cyridinyl, 3-acridinyl, 4-acridinyl, 5-indole Dumb-yl or 6-bite, 2-quinazolinyl leaching, 3- noise. Spider-based, 5-oxazolyl, 6-quinazolinyl, 7-oxazolinyl or 8-quinazolinyl, 3- porphyrinyl, 4-porphyrinyl, 5-carbolinyl, 6-4 lysyl, 7-carbolinyl or 8.4-yl phenyl, 2-acridinyl, 4-acridinyl, 6-acridinyl or 7-acridinyl, i_4aH-carbazolyl, 2- 4aH-carbazolyl, 3-4aH-carbazolyl, 4-4aH-carbazolyl, 5-4aH. oxazolyl, 6-4aH-carbazolyl, 7-4aH-carbazolyl or 8-4aH- Carbazolyl, 1-flavor 153611.doc 201130815. Sit-base, 2-leaf-saltyl, 3-saki "sitting base, 4-° card<» sitting base, 5-leaf sitting base, 6-leaf sitting base, 7_oxazolyl or 8-inch Azyl, 1-carbolinyl, 3-carbolinyl, 4-mercapto, 5-carbolinyl, 6-carbolinyl, 7-carbolinyl, 8-porphyrinyl or 9-phenylene , l-pyridinyl, 2-cylinoyl, 3-cylinidyl, 4-cyridinyl, 6-brothyl, 7-cyridinyl, 8-cyridinyl, 9-cyridinyl or 1 〇 啡 啡 基 丨 丨 啡 啡 吖 吖 吖 吖 吖 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 啡 啡 啡 啡 啡 啡 啡 啡 啡 啡 啡 啡 啡Acridine or 9-acridinyl, 1-acridinyl, 2-indolyl, 4-dehexidyl, 5-acridinyl, 6-acridinyl, 7-acridinyl, 8-dec Stationary or 9-heptidyl, 2-phinyl, 3-phinyl, 4-morpholinyl, 5-«#-linyl, 6-phenanthryl, 8-cyanoyl, 9-morpholinyl Or 10-phenanthryl, hydrazine-cultivation, 2, phenyl sulfinyl, 3-cyanozinyl, 4-cyanoazinyl, 6-cyanoazinyl, 7-«# fluorenyl, 8-cylinazinyl or 9-Pyrazinyl, 1-morphothazinyl, 2-cyanoazinyl, 3-cyphthyzinyl, 4-morphothazinyl, 6-phutthiazinyl, 7-phutthiazinyl, 8-嗟 嗟 基, 9- 嗟 嗟 ♦ base or 1 〇 __ D Piperazinyl, Shu _ brown. Oxazinyl, Parkinyl 3-morphoxazinyl, 4-morphoxazinyl, 6-morphoxazinyl, 7-morphomethyl, 8-morphoxazinyl, 9-morphoxazinyl or 10-morphine Oxazinyl, 2-benzoisoindolyl, 3. stupid and heteromeric, 4•benzoxyl, 5·benzhydrazinyl, 6·benzhydrazinyl, or 丨· Benzoiso(tetra)yl, 3·benzoindole, 4.benzisoindolyl, 5-iso-(tetra)yl, &

3-thiophene 153611.doc and isoindolyl-b]furanyl or thieno[2 3_bj. Sodium, 3-7H-pyrazine[2,3<]咔a, 6-7H-pyrazino[2,3-c]咔201130815 0, and 7·7Η-β丨2 3 μ , 3^]carbazolyl, 8-7H-pyrazine[2,3_c1 azolyl, 9-7H-pyrazine[2 3-elout 咔L,...carbazolyl, 10-7H- Pyrazino[2,3_el oxazolyl or 11-7H-pyrazinoindole 2 ^ Ί J calls for L2'3-c]oxazolyl, 2_2H-furan[3 2 fluorenyl, 3_2Η-«Ή and [ 3,2_b]N. sylvestris, 5 2H "Fu 并 [ [3 2 卟 ° bottom ° South base, 6H South and [3,2-b]-(four) base or 7 orphan. Fu Yan '舁[3,2- b]-^^^, . 3-5Η-% bite and [2,34 o..oxazinyl H is more than bite [2,34 o-m-methyl, pyrazinyl or 8-5H" than bite [2 , 3 buckets ozonazine, ιΐΗ_.比 并 并 外 外 坐 坐 坐 、 3 3 3 3 3 3 3 、 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 Base, oxazole and [4,5-d] oxazolyl or 5_4 Η_β imizolo[45_d] 〇gzolyl, 3. Bisin and heart] d] violates the Qin group 5 tb azine and [2,3_d] 哒. Qin Ji or base '2-flavor. Sit and [2,! Shuai sputum, 3 sputum and [2 ι sedyl, 5 - imidazo[2'1-b]thiazolyl or 6-imidazo[2113]thiazolylfuran [3,4-c] , 3, 10, and [3,4-c]4, aryl, 6, 6, 3, 4, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 3,4_c]吟琳基 or furo[3,4-C]porphyrinyl, ι_4Η_pyridine[2,3<]carbazolyl, 2·4Η_pyridine[2,3 is carbazolyl, 3 -4Η-Acridine[2,3-c]oxazolyl, 4_4Η·pyrido[2'3_C]oxazolyl, 5_4Η-pyrido[2,3-c]oxazolyl, 6-4Η-pyridine [2,3-c]oxazolyl, 8.4 pyridine pyridine [23 oxazolyl n. Bis-[2,3-c]oxazolyl, 1〇·4Η·pyrido[2,3 c]oxazolyl or ί 4H-M and [2,3 is called (tetra), 2 ❹ and trisyl, 3-flavored and [Hbnu〆] three-calling base, divination. Sit and [仏咖纠三嘻153611.doc • 10·, 2-, 2-201130815 or 7-imidazo[l,2-b][l,2,4]triazinyl, 7-benzo[ b] thienylbenzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl, 2-benzimidazolyl, 4 - Benzimidazolyl, 5-phenylene. Sitrate, 6-benzimidazolyl or 7-benzimidazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazole Or 7-phenylthiazolyl, benz〇xapinyl, 2-benzoxanyl, 4-benzoxanyl, 5-benzoxanyl, 6-benzoxan , 7-benzoxanyl, 8-benzoxanyl or 9-benzoxanyl, 2- benzoxazinyl, 4-benzoxazinyl, 5-benzoxazinyl, 6 _ benzoxazinyl, 7-benzoxazinyl or 8-benzoxazinyl, ΜΗ_ηpyrho[nb][2]benzozinyl, 2-1Η-吼 并 [l, 2 -b][2]benzoazepine, 3- and [l,2-b][2]benzodiazepine, 5-lH-° ratio and [i,2_b][2]benzo Nitrogen hexyl, 6-1H-pyrrolo[l,2-b][2] oxazepine, 7_1H•pyrrolo[l,2-b][2]benzodiazepine, 8-lH- ^b 并[i,2-b][2]benzozinyl, 9-1H- ° piroxi[l,2-b][2]benzozinyl, „比π和[ l,2-b][2]benzoazepine or ΐΐ-ΐΗ-° ratio[i,2_b][2]benzilinyl. Typical fused heteroaryls include (but are not limited to) 2 _Quinolinyl, 3_啥琳基, 4 Quinolinyl, 5-quinolyl, 6-quinolyl, 7-quinolinyl or 8-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5 _isoquinolyl, 6-isoquinolyl, 7-isoquinolinyl or 8-isoquinolinyl, 2 _. fluorenyl, 3-decyl, 4-fluorenyl, 5-fluorenyl , 6_fluorenyl or 7-fluorenyl, 2_benzopyranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzoxanyl, 6-benzofuranyl, 7-benzofuranyl, 2-benzo[b]thienyl, (benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl or 7-153611.doc 201130815 Benzo[b]thienyl, 2-benzoxazolyl, 4-phenyloxazolyl, % benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl, 2_ Benzimidazolyl, 'benzimidazolyl' 5 benzimidazolyl, 6-benzimidazolyl or 7-benzimidazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzoyl Thiazolyl, 6-benzothiazolyl or 7-benzothiazolyl. Heteroaryl may be monocyclic, bicyclic, tricyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, more preferably monocyclic or Double ring. The term "halogen" as used herein. Or "dental" means fluorine, gas, and immiscible. The trans-arrangement of 1,4-cyclohexyl substituent and -CH2 (hydroxyindole) is preferably β. The term alkyl includes straight chain, branched chain or ring. The alkyl group includes the alkyl group which is monosubstituted and polysubstituted (for example, substituted by a monodentate group, substituted with a dii group or substituted with a trisyl group). Specific compounds of formula I which may be mentioned include: trans-2-gas-N-[4-(6-chloro-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclo Hexyl]-5-trifluoromethyl-benzoguanamine; trans-2-gas-N-[4-(2-o-oxy-2,3-dihydro-indol-1-ylindenyl)- Cyclohexyl]-5-trifluoromethyl-benzoguanamine; trans-5-gas-oxime-[4·(3,3-dimethyl-2-oxo-2,3-dihydro·anthracene Indole-1-ylmethyl)-cyclohexyl]-2-mercapto-nicotinamide; trans-2-gas-rhodium-[4-(6-gas-3,3-difluoro-2-sideoxy) Base-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-5-trifluorodecyl-benzamide; trans-2-gas-Ν-[4·(3,3 - Dimercapto-2-yloxy-2,3-dihydro-pyrrolo[2,3- 1536D.doc •12·201130815 b]0 ratio α-1,4-methyl)-cyclohexyl]- 5-trimethylsulfonyl-benzoquinone amine; anti-5-murine-N-[4-(3,3-dimethyl-2-oxo- 2,3-dinitro-D ratio 0 each And [2,3_b]pyridin-1-ylindenyl)-cyclohexyl]-2-mercapto-nicotinium amide; trans-2-gas-N-[4-(2- oxo-2, 3-dihydro-O-specific ratio of [2,3-b] ° ratio l-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-2-gas- Ν-{-4-((5^Fluoro-2·-sideoxyspiro[cyclopropane-1,3 porphyrin]-1·-yl) Methyl)cyclohexyl}-5-(trifluoromethyl)benzamide; trans-5-gas-oxime-[-4-((5·-fluoro-2'-sideoxy snail [cyclopropane- 1,3·-porphyrin]-1·-yl)methyl)cyclohexyl]-2-methylnicotinium amide; trans-2-chloro-indole-[4-(5-methoxy-3) ,3-dimethyl-2-oxooxy-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-5-trifluoromethyl-crackamine; Chloro-indole-[4-(6-decyloxy-3,3-dimethyl-2-oxo-2,3-dihydro-pyrrolo[3,2-c]acridin-1-yl Indenyl)-cyclohexyl]-5-trifluoromethyl-benzene. decylamine; trans-2 - gas-N-[4-((R)-3 - gas-3-mercapto-2-yloxy) Benzyl-2,3-diaza-0-derived D--ylmethyl)-cyclohexyl]-5-trifluoromethyl-co-carboxamide; anti-2 -murine-N-[4-((S -3 - oxa-3-mercapto-2-yloxy- 2,3-diaza-0 丨 0 -1-ylindenyl)-cyclohexyl]-5-trifluoromethyl-benzoquinone Indoleamine; trans-2 -murine-N-[4-(3,3-dimethyl-2-oxo- 2,3-diazepine-1-ylmethyl)-cyclohexyl]- 5-trifluoromethyl-benzoguanamine; trans-2 -murine-N-[4-(3,3-dimercapto-2-oxo-5-trifluoro-1-decyloxy-2,3 -dihydro-indol-1-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzoguanamine;

I trans-5-gas-1^-[4-(5-murine-3,3-dimercapto-2-yloxy-2,3-diaza-1?11-11-.

I-based fluorenyl)-cyclohexyl]-2-methyl-nicotinium amide; 153611.doc •13· 201130815 anti-5-gas·Ν-[4-(4-methoxy-3,3-di Methyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-2-methyl·nicotinium amide; anti-5_gas·Ν-[4 -(7-Gas-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-2-mercapto-nicotinamide ; anti-5-gas-N-[4-(3,3-difluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-2-yl -Nicotine decylamine; trans-2-gas-N-[4-(3,3-diH-2-oxooxy-2,3-dihydro-indol-1-ylmethyl)-cyclo Hexyl]-5·trifluoromethyl-benzamide; reverse_2-gas-N-[4-(7-decyloxy-3,3-dimethyl-2-oxo- 2,3 -dihydroindol-1-ylindenyl)-cyclohexyl]trifluoromethyl-benzoguanamine; anti-5-chloro-N-[4-((R)-3-fluoro-3-methyl -2-Sideoxy-2,3-dihydro-0 丨0丨-1 -ylindenyl)-cyclohexyl]-2-indenyl-nicotinium amide; anti-5-gas-N-[ 4-((S)-3-fluoro-3-indolyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-2.methyl-nicotine Indoleamine; trans-5-gas-2-methyl-N-(4-((2-oxospiro[porphyrin-3,4,-piperidinyl]-1-yl)methyl) Cyclohexyl)nicotinamide; reverse_2_gas-N-[4-(6-methoxy-3,3-dimethyl-2-oxoethoxy-2,3.dihydro-0-lead Indole-1-ylmethyl)-cyclohexyl]_5-trifluoromethyl-benzamide; trans-2-gas-5-trifluoromethyl-indole-[4-(3,3,7·3 Mercapto-2-yloxy-2,3-dihydro-indolylmethyl)-cyclohexyl]-crackamine; trans-2-chloro-5-trifluoromethyl^-[4-( 3,3,4-trimethyl-2-oxooxy-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]·stupylamine; anti-5-gas-1^ -[4-(4-Gas-3,3 Methyl-2-oxo-2,3-dihydro-β-derived.-_1-ylmethyl)-cyclohexyl]-2-methyl- to base Indoleamine; 153611.doc •14· 201130815 anti-5-gas-N-[4-(6-chloro-3,3-di-2-nonyloxy-2,3-diazide n-type-1_ -ylmethyl)-cyclohexyl]-2-mercapto-nicotinamide; trans-5-chloro-2-methyl-^[-[4-(3,3,4-trimethyl-2- Oleoxy-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-nicotinylamine; trans-5-chloro-N-[ 4-(6-methoxy-3, 3-dimethyl-2-oxo- 2,3-diaza-D-derived D-l-ylindenyl)-3⁄4-hexyl]-2-indenyl-------- -N-[4-(6-chloro-3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-ylindenyl)- Hexyl]-2-methyl-nicotinamide; trans-5-chloro-N-[4-(6-methoxy-3,3-dimethyl-2-oxo-2,3-di Hydrogen-pyrrolo[3,2-c]. Bipyridin-1-ylmethyl)-cyclohexyl]-2-methyl-nicotinium amide; trans-5-chloro-1^-[4-(3-fail-3,5-dimercapto-2 - side oxy-2,3-diaza-0 丨 11-11-1-ylindenyl)-cyclohexyl]-2 -fluorenyl-------------------- (3 - gas - 3,5-dimethyl-2 - oxo - 2,3 -diaza-0 - 0 -1 -1 - fluorenyl)-cyclohexyl]-2-indenyl-nicotine amine;

I-trans-5-chloro-;^-[4-(6-chloro-3-fluoro-3-methyl-2-oxo-2,3-diar-inden-1-ylmethyl)- 3⁄4-hexyl]-2-methyl-in the amine; anti-5-gas-N-[4-(6-gas-3-gas-3-methyl-2-oxo- 2,3-di Nitrogen-0-derived D-1-1-ylindenyl-cyclohexyl]-2-mercapto-nicotinium amide; trans-2-chloro-N-[4-(5-methoxy-1-sideoxy) -3,4-dihydro-1H-isoquinolin-2-ylindenyl)-cyclohexyl]-5-trifluorodecyl-benzamide; trans-2-gas-N-[4-( 3-sided oxy-3,4-dihydro-1H-isoquinolin-2-ylpropenyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-5-chloro-2- Mercapto-N-[4-(3,5,6-trifluoro-3-methyl-2-oxo-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]- Nicotine amide; 153611.doc -15- 201130815 anti-5-chloro-2-methyl-N-[4-(3,5,6-difluoro-3-indolyl-2-oxoxy-2, 3_Dihydro-indol-1-ylindenyl)-cyclohexyl]-nicotine decylamine; trans-5-gas-2-methyl-N-[4-(2- oxo-oxazole[ 4,5-b]pyridine, 3-methylmethyl)-cyclohexyl]-nicotinium decylamine; trans-5-gas-2-methyl-indole-[4-(2·sideoxy-benz)唾 _ 3_ ylmethyl)cyclohexyl]-nicotine guanamine; anti-5-gas-Ν-[4-(3,6-dimethylcyloxy-2,3-di _ imidazo[4 5_ b]° bit -1-ylindenyl)-cyclohexyl]_2_fluorenyl-final amine; anti-5-gas-N-[4-(3-ethyl-2 - pendant oxy-2,3-dihydro-mi. Sodium and [4 $ c] indole-1-ylmethyl)-cyclohexyl]-2-methyl-nicotinium amide; gas-N-[4-(3,7-dimethyl-2-oxooxy-2,3_dihydro-imidazo[4% b]. than bit-1-ylmercapto)-cyclohexyl ]-2 - mercapto-final amine; anti-5-chloro-indole-[4-(3,5-dimethyl-2-oxo-2,3-dihydro-imidazo[4 5 b]0 butyl-1-ylmethyl)-cyclohexyl]-2-methyl-final amine; anti-5-, gas-N-[4-(l,5-dimethyl-2- Side oxy-oxime, 2·dihydro-imidazolium b]0 butyl-3-ylindenyl)-cyclohexyl]-2-methyl-final amine; anti-5-chloro-N-[ 4-(3-ethyl-2-oxo-2,3-dihydro-benzoic-saltylmethyl)-cyclohexyl]-2-methyl-nicotinamide; anti-5-gas- Ν-[4·(3-isobutyl-2-oxo-2,3-dihydro- phenylidino-sialylmethyl)-cyclohexyl]-2-methyl-nicotinium amide; 5-Chloro-indole-[4·(5-methoxy-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-b]° ratio biti-1-yl曱基)_cyclohexyl]·2_mercapto- acetonamine; anti-5-gas-2-methyl-Ν_[4-(3,3, 5-trimethyl-2-oxooxy 2 3 dihydrogen.丨哚-1-ylmethyl)-cyclohexyl]-nicotinium amide; 153611.doc -16 · 201130815 anti-5- ox-2-mercapto-N-[4-(3-methyl-2 -Sideoxy-2,3·dihydro- benzoxazol-1-ylindenyl)-cyclohexyl]-nicotine-lacquered amine; trans-5-chloro-2-methyl-N-[4-( L-Methyl-2_p-oxy-1,2-dihydro-flavored [4,5-1?]πΛ^-3-ylmethyl)-cyclohexyl]-in the case of decylamine; Ν-[4_(3,3-Dimethyl-2-epoxy-2,3-dihydro-indole-j•ylmethyl)cyclohexyl]-2-mercapto-5-trifluorodecyl - smoldering amine; trans-5-chloro-2-indolyl-indole-[4-(2-o-oxy-2,3-dihydro-benzoimidazolyl)-cyclohexyl]- Nicotine decylamine; anti-5·chloro-indole-[4-(3-fluoro-3,5,6-trimethyl-2-oxo-oxy-2,3_diox_〇-noise 1-based Enantiomer 1 of mercapto)-cyclohexyl]-2-mercapto-nicotine decylamine; trans-5-chloro-indole-[4·(3-fluoro·3,5,6-trimethyl Enantiomer 2 of 2-oxooxy-2,3-dihydro-indolyl-yl)-cyclohexyl]-2-mercapto-nicotinamide; anti-5-gas- Ν-[4-(7-Methoxy-3,5-dimethyl-2-oxo-2,3_digas_., oxazolo[4,5-b]pyridin-1-yl曱))cyclohexyl]_2·mercapto-nicotinamide ·, anti-5-chloro-N-[4-(3, 3-dimethyl-2-oxo-2,3-dihydro-. 〇[3 2 bp than pyridin-1-ylmethyl)-cyclohexyl]-2-methyl-nicotine 醯Amine; anti-5-gas-N-[4-(2-methoxy-9-fluorenyl-8-oxoethoxy·8,9·dihydro-indole_7-ylindenyl)-cyclohexyl] -2-mercapto-nicotinium amide; trans-5-chloro-indole-[4-(2- gas-9-mercapto-8-sideoxy_8,9-dihydro-indole_7_ Methyl)-cyclohexyl]-2-mercapto-nicotinamide; trans-2-gas-Ν-[4-(5-gas-2-oxo-2,3-dihydro-challoid Indolylcyclohexyl]-5-trifluorodecyl-benzoguanamine; trans-2-chloro-N-[4-(6-fluoro-2-oxo-2,3-dihydroinduct.朵基甲武)cyclohexyl]-5-trifluoromethyl-benzamide; 153611.doc •17- 201130815 anti-2-gas-N-[4-(5-fluoro-3,3-dimethyl Benzyl-2-oxo-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-5-trifluorodecyl-benzoguanamine; trans-2-gas-N-[ 4-(3-ethyl-2-oxo-2,3-diphos-benzo-3-m0-yl-1-ylmethyl)-cyclohexyl]-5-trifluorodecyl-benzamide ; trans-2-chloro-N-[4-(3-mercapto-2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-ylindenyl)-cycle Hexyl]-5-.trifluoromethyl-benzamide; trans-2-gas-N-[4-(l-mercapto-2- Sideoxy-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylindenyl)-cyclohexyl]-5-trifluorodecyl-benzamide; trans-2-chloro -N-[4-(2-Sideoxy-2,3-dihydro-benzoimidazol-1-ylindenyl) gastric cyclohexyl]-5-trifluorodecyl-benzamide; - gas-N-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexyl]-5-dioxadecyl-benzene Amine; anti-4-fluoro-N-[4-(3-mercapto-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexyl]-3 -trifluoromethyl-benzoguanamine trifluoroacetate; trans-2,5-digas-:^-[4-(3-mercapto-2-oxo-2,3-dihydro-benzene And imidazol-1-ylmethyl)-cyclohexyl]-benzoguanamine trifluoroacetate; anti-N-[4-(3,3-dimercapto-2-yloxy-2,3-di Nitrogen-0-oxo-1-ylmethyl)-cyclohexyl]-4-fluoro-3-trifluoromethyl-benzamide; anti-2,5-diox-Ν-[4-(3 ,3-dimethyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-benzamide; and anti-Ν-[4-(3, 3-dimercapto-2-yloxy-2,3-diode-0-doxo-1-ylmethyl)-cyclohexyl]-3-methoxy-benzoguanamine; a substance; it is in free form or in the form of a salt. 153611.doc • 18· 201130815 Thus, according to another aspect of the invention, there is provided a compound of formula I as described above for use as a medicament. More specifically, a compound of formula I as described above is provided as a corticotropin releasing factor (CRF) receptor antagonist. According to another aspect of the invention, there is provided the use of a compound of formula I as described above for the manufacture of a medicament. More specifically, it provides use as described above for the manufacture of a corticotropin releasing factor (CRF) receptor antagonist. Furthermore, it has now been found that a compound of formula I or a salt thereof can act as a CRF receptor antagonist. Representative compounds of the invention do not have significant potent or antagonistic activity against melanin-concentrating hormone receptor l (MCH-1) or MCH-2. Certain compounds of formula I exhibit antagonistic activity against both corticotropin releasing factor receptor 1 (CRF-1) and cortisol releasing factor receptor 2 (CRF-2), and thus are dual CRF-1 and CRF-2 antagonists Agent. The activity of the compounds of the present invention can be evaluated by the following in vitro and in vivo methods. The CRF-1 and CRF-2 receptor antagonistic activities of the agents of the present invention have been assayed in vitro in the following assays: To demonstrate human or rat recombinant CRF -1 or human CRF-2a Chinese hamster ovary (CHO) cells (Chen et al, Proc Natl Acad Sci USA 90, 8967-8971, 1993; Liaw et al, Endocrinology 137, 72-77, 1996) supplemented with 10 Breeding in Duchenne's modified It's medium of % fetal calf serum, non-essential amino acid, 100 U/ml penicillin, 100 mg/1 streptomycin and 1 gH geneticin. CH0 cells expressing rat CRF-2P receptor (Wu et 153611.doc -19- 201130815 human, Endocrinology 148, 1675-1687, 2007) supplemented with 10% fetal bovine serum, 100 IU/ml penicillin, 100 mg /1 streptomycin, 600 pg/ml hygromycin, 10 pg/ml blasticidin Ham's-F12 Glutamax were propagated and induced with 1 gg/ml tetracycline for 24 hours before the experiment. In the cyclic AMP assay, the homogenized time resolved fluorescence (HTRF) cAMP dynamic 2 kit (Cisbio International, France) was used according to the manufacturer's instructions. CHO cells (Catalog No. 12648-010, Invitrogen) previously stored at a cryopreservation of 3 x 106 viable cells per ml of cell recovery medium were unwound, centrifuged at 1200 rpm for 7 minutes, and resuspended in serum-free medium to obtain 0.5χ106. The concentration of cells/ml. Next, it will be formulated in DMSO and then diluted in assay buffer (lxHanks balanced salt solution, 0.2% (w/v) bovine serum albumin, 1.7 mM isobutylmethylxanthine and 10 mM Hepes, pH 7.4). The compound of the invention was added to a 384 well low volume black assay plate (Corning Inc, US, Cat. No. 3676). Next, add 2000 cells/well to the assay plate, further dilute the compound 2 times, and then incubate the plate for 15 minutes at room temperature. After incubation, add 5 times the final concentration of the agonist to the plate ( Typically r/h CRF) buffer and incubated for 30 minutes at room temperature. Finally, d2 dye-labeled cAMP and cryptate-labeled anti-cAMP antibody (both prepared in lysis buffer) were added to the plate, followed by allowing to stand at room temperature for 1 hour. During the resting period, cAMP produced by the cells competes with the d2-labeled cAMP for binding to the anti-cAMP cryptate. Read the plate readings on Pherastar (BMG, Germany). When the endogenous cAMP content produced by the cells increases, the FRET fluorescence signal will decrease, and vice versa. 153611.doc -20- 201130815 The value represented by the change in arbitrary fluorescent units is converted to cAMP concentration by using a standard curve 'where the reagent is supplied from the kit. The antagonist dose response curve (1 ηΜ-31.6 μΜ) was constructed and tested in the presence of EC5〇 concentration of receptor-associated CRF (hCRF-l=3 nM, hCRF-2a=2 nM, rCRF -1 = 1 nM) And rCRF-2p=〇· 1 nM). The percentage of inhibition of the cAMP response induced by CRF was fitted by increasing the concentration of the antagonist, thereby the iCs 〇 value of the a ten antagonist. Fit using the nonlinear 丨〇gistic function of the Activitybase suite software v 5.4.5.27 (IDBS, UK). In this test, the agent of the present invention exhibits CRF1 antagonistic activity, and its IC5 〇 CRF1 value is about 1 nM to 30 μΜ', preferably about 1 to 5 〇〇 nM. Specific information is provided in the Biological Data section. The compounds of the invention are useful in the treatment of any condition in which the level of endogenous CRF (corticotropin releasing factor) is increased or sputum (hypothalamic pituitary axis) is dysregulated, or in the treatment of various diseases induced or contributed by CRF. The compounds of the invention are especially useful for the treatment or prevention of gastrointestinal disorders, including large bowel dysfunction with or without abdominal filling, inflammatory bowel disease, post-operative ileus, reflux disease, and infectious abdominal filling. The compounds of the invention are also particularly useful for the treatment or prevention of major depression, including bipolar depression, unipolar depression, single or recurrent major depressive episodes (with or without psychotic features, stress characteristics, comorbid conditions) , atypical features or postpartum episodes; for the treatment of anxiety disorders and treatment of panic disorder. Other mood disorders covered in sf·severe depression include fatigue syndrome and mood disorders (early or late onset with or without 153611.doc •21 · 201130815 atypical features) 'functional depression syndrome Post-traumatic stress, post-operative stress and social phobia; early or late onset, Alzheimer's type dementia with depression; vascular dementia with depression' by alcohol 'amphetainine, cocaine, psychedelic, inhalant, hong hong, phenCyeiidine, sedatives, sleeping pills, anti-anxiety agents and other substances induced by emotional disorders; anti-inflammatory schizophrenia (schizoaffective disorder); and adjustment disorder with inhibitory mood. Severe depression can also be caused by general medical conditions including, but not limited to, myocardial infarction, diabetes, miscarriage/abortion, and the like. The compounds of the invention are also useful for the treatment or prevention of schizophrenia, including paranoid schizophrenia, disorganised schizophrenia, catartic schizophrenia, undifferentiated schizophrenia (undifferentiated schizophrenia), residual schizophrenia The compound of the invention is also suitable for the treatment or prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntingtonis disease, Alzheimer's type senile dementia, and multiple infarct dementia β The compounds of the present invention are useful as analgesics. In particular, it is suitable for the treatment of traumatic pain 'such as post-operative pain; traumatic tear pain, such as brachial plexus; chronic pain 'such as arthritis pain' such as occurs in osteoarthritis, rheumatoid arthritis or psoriasis Arthritis; neuralgia, such as after the treatment of the god 153611.doc -22- 201130815 menstrual pain, trigeminal neuralgia, joint or intercostal neuralgia, muscle fiber pain, burning pain, peripheral neuropathy, diabetic neuropathy, by chemotherapy Causes neurosis, AIDS-related neuropathy, occipital neuralgia, ear neuralgia, glossopharyngeal neuralgia, reflex Sympathetie dystrophy, phantom limb pain; various forms of headache , such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; toothache; cancer pain; visceral pain; gastrointestinal pain; nerve entrapment pain; Injury pain; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; lower back pain, such as spinal stenosis (spinal sten 〇sis); lumbar disc herniation (prolapsed disc); sciatica; angina pectoris; ankylosing spondylitis, gout; burns; crusting pain; itching; and thalamic pain such as posterior thalamic pain. The compounds of the present invention are also suitable for the treatment of dysfunction of appetite and food intake, and are suitable for use in situations such as anorexia, anorexia nervosa, bulimia, obesity and metabolic syndrome. The compounds of the invention are also useful in the treatment of sleep disorders, including dysomnia, insomnia, sleep apnea, narcolepsy, and circadian rhythm disorders. The compounds of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive conditions include dementia, amnestic dis〇rder, and cognitive disorders not otherwise listed. In addition, other compounds of the invention may also be used as memory and/or cognitive enhancers in healthy humans without cognitive and/or memory deficits. I5361l.doc -23- 201130815 The compounds of the invention are also suitable for the treatment of tolerance and dependence on many substances. For example, it is suitable for treating dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidines), or treating opiates (such as marijuana, heroin, morphine) or benzodiazepines. Tolerance and dependence; treatment of cocaine, sedative hypnotics, amphetamines or amphetamine-related drugs (eg, dextroamphetamine, methamphetamine) addiction; or a combination thereof. The compounds of the invention are also useful as anti-inflammatory agents. In particular, it is suitable for the treatment of snoring in asthma, influenza, chronic bronchitis and rheumatoid arthritis, and for the treatment of inflammatory gastrointestinal diseases such as Crohn's disease, Ulcerative colitis, postoperative gastrointestinal obstruction (pc) I), inflammatory bowel disease (IBD) and damage caused by non-steroidal anti-inflammatory drugs; inflammatory skin diseases such as herpes and eczema; inflammatory bladder disease, such as Cystitis and urge incontinence; and inflammation of the eyes and teeth. The compounds of the invention are also useful for the treatment of fertility problems, sexual dysfunction and preterm birth' as well as non-inflammatory genitourinary conditions such as overactive bladder and related urinary incontinence. The compounds of the invention are also suitable for the treatment of allergic conditions, especially skin allergic conditions (such as urticaria) and tracheal allergic conditions (such as rhinitis). The compounds of the invention are also useful in the treatment of mast cell activation disorders, such as mastocytosis. The compounds of the invention are also suitable for the treatment of Cushing's syndrome caused by drugs such as steroids or cancers such as pituitary adenomas. The compounds of the invention are also suitable for the treatment of vomiting, namely nausea, retching and 153611. Doc •24- 201130815 Vomiting. Vomiting includes acute vomiting, delayed vomiting, and expected vomiting. The compound of the present invention is suitable for treating β-zone spit caused by any cause

I syndrome. For example, vomiting may be caused by drugs such as cancer chemotherapeutic agents, such as alkylating agents such as cyclamate, carmustine, lomustine, and leucovorin (chlorambucil); cytotoxic antibiotics, such as dactinomycin, doxorubicin, mitomycin-C, and bleomycin; antimetabolites such as arabinose Cytarabine, methotrexate and 5-fluorouracil. Vinca alkaloid, such as etoposide, vinblastine, and vincristine; and by other substances or factors such as cisplatin, Dacarbazine, procarbazine and hydroxy glands, and combinations thereof; radiation sickness; radiation therapy, such as chest or abdominal irradiation, such as in the treatment of cancer; poisons; toxins, such as by metabolic disorders or infections ( Toxins produced by, for example, gastritis, or toxins released during bacterial or viral gastrointestinal infections; pregnancy; vestibular disorders such as motion sickness, dizziness, dizziness, and Meniere's disease; post-operative conditions Gastrointestinal obstruction; decreased gastrointestinal activity; visceral pain, such as myocardial infarction or peritonitis; migraine; increased intracranial pressure; decreased intracranial pressure (eg, high altitude disease); opioid analgesics, such as morphine base; and gastric-esophageal reflux Disease, spastic dyspepsia, overeating, acid stomach, sour stomach, nausea, heartburn (such as paroxysmal heartburn, nighttime heartburn and heartburn caused by meals) and indigestion. 1536Il.doc • 25- 201130815 The compounds of the present invention have specific use in the treatment of: gastrointestinal disorders such as colonic dysentery; skin wide disorders such as psoriasis, sputum and sunburn; vasospasm diseases such as angina pectoris , HR headaches and Reynaud's disease; cerebral ischemia, such as cerebral vasospasm caused by subarachnoid hemorrhage; fibrosis and collagen diseases such as scleroderma and eosinophilic hepatic stagnation, and immune enhancement Or inhibiting related conditions such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis; and coughing. The compound of the invention is suitable for treating nerves caused by stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, hypoxia, hypoxia, perinatal asphyxia, and sudden cardiac arrest Toxic damage. The utility of the agents of the invention in the diseases referred to above can be demonstrated in a series of standard tests. (1) The anxiolytic activity of the agent of the present invention can be confirmed in a mouse elevated plus maze [see, for example, R〇dgers RJ, Behavioural Pharmacology 8: 477-496 (1997), which is on page 486. The elevated cross maze is discussed; for methods, see Rodgers R. J. Deaf's Ethology and Psychopharmacology (edited by SJ Cooper and CA Hendrie), pp. 9-44 (1994), J. Wiley,

Chichester]. (2) The analgesic activity of the agent of the present invention can be confirmed in a rat model of visceral hyperalgesia after expansion of the colorectal [see, for example, Schwetz I, Am J

Physiology 286: G683-G691 (2004); for methods, see Ness JJ., Brain Research 450: 153-169 (1988)]. (3) The antidiarrheal activity of the agent of the present invention can be confirmed during a stress or CRF attack in a rat defecation model [see, for example, Maillot C., Gastroenterology 119: 1569-1579 153611.doc · 26·201130815 (2002)] In these tests, the agent of the present invention showed an anxiolytic-like effect, a visceral analgesic effect, and an antidiarrheal effect after oral administration of 〇·丨 to 3〇mg/kg. Furthermore, it has been surprisingly found that dual Crf receptor 1 and crF receptor 2 receptors can be used to successfully reverse crF-induced intestinal barrier dysfunction in vivo. Thus 'in another aspect' provides a dual cortisol releasing factor constitutive protein (CRF-1) and a cortitainin releasing factor receptor 2 (CRF_2) antagonist for the treatment, alleviation or prevention of mucosa A condition characterized by barrier dysfunction of the epithelium, epidermis, or endothelium. In another aspect, there is provided a method of treating, ameliorating or preventing a condition characterized by a barrier dysfunction of the epithelial epithelium of the mucosal epithelium, comprising administering to the mammal a therapeutically effective amount of a dual cortisol releasing factor Party l (CRF-1) and corticotropin releasing factor receptor 2 (CRF_2) antagonist. According to another aspect, there is provided a use of a dual cortisol releasing factor receptor 1 (CRF-1) and a corticotropin releasing factor receptor 2 (CRF_2) antagonist for use in the treatment, amelioration or A drug that prevents conditions characterized by barrier dysfunction of the mucosal epithelium, epidermis, or endothelium. In one embodiment, the condition is characterized by a barrier function of the mucosal epithelium. In a particular embodiment, the condition is characterized by barrier dysfunction of the gastrointestinal mucosal epithelium. Barrier dysfunction of the gastrointestinal mucosa may be caused by radiation therapy and drugs such as non-steroidal anti-inflammatory drugs, cancer chemotherapeutics, cytotoxic anti-153611.doc -27- 201130815, antimetabolites, vinca alkaloids, and cisplatin, Caused by dacarbazine, procarbazine and other drugs of hydroxyurea and combinations thereof. Barrier dysfunction of the gastrointestinal mucosal epithelium may also be caused by malnutrition, total parenteral nutrition, food allergens or toxins (such as toxins produced by metabolic disorders or liver diseases or infections or during bacterial or viral infections) Caused by the released toxin. More specifically, the dual cortisol releasing factor receptor UCRFd) and corticotropin releasing factor receptor 2 (CRF-2) antagonists may be suitable for conditions characterized by dysfunction of the gastrointestinal mucosal epithelium including (but Not limited to) Inflammatory bowel disease, large bowel syndrome with or without diarrhea, short bowel syndrome, chronic bowel disease (such as celiac disease), postoperative intestinal obstruction, cystic fibrosis, reflux disease, heartburn, infection Sexual diarrhea, intestinal fistula, intestinal adenocarcinoma, diabetes, sepsis, chronic heart failure and AIDS. In a particular embodiment, the condition is characterized by barrier dysfunction of the mucosal epithelium of the respiratory tract. Barrier dysfunction of the mucosal epithelium of a beer channel may be caused by an allergen or toxin (such as a toxin produced by an infection or a toxin released during a bacterial or viral infection). More specifically, the dual cortisol releasing factor receptor 1 (CRIM) and the pro-regulatory factor receptor 2 (CRF_2) antagonists may be characterized by a barrier function of the respiratory mucosal epithelium. These include, but are not limited to, asthma, chronic bronchitis, rhinitis, sinusitis, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, sepsis, chronic heart failure, and AIDS. In an implementation <column, the sigma condition is characterized by barrier dysfunction of the epidermis. Barrier dysfunction of the epidermis may be caused by allergens or toxins (such as toxins produced by the infection of 1536Jl.doc •28·201130815 or by bacterial toxins). More specifically, the dual cortisol releasing factor receptor (CRF 1) and cortisol releasing factor receptor 2 ((3) (4) antagonists released during sexual or viral infection may be characterized by epidermal dysfunction The conditions include, but are not limited to, dermatitis, ichthyosis, and psoriasis. In a common case, the condition is characterized by barrier dysfunction of the endothelium. Barrier dysfunction of the endothelium may be caused by allergens or toxins (such as by metabolism) Caused by a disorder or a toxin produced by a liver disease or infection or a toxin released during a bacterial or viral infection. More specifically, the dual cortisol releasing factor receptor KCRF-D and the dermal releasing factor are affected by Body 2 (crf 2) antagonists may be applicable to conditions characterized by endothelial barrier dysfunction including, but not limited to, ischemic injury, hypoxia, diabetes, sepsis, chronic heart failure, edema, acute lung injury, Acute respiratory distress syndrome, thrombosis, and cancer. In a particular embodiment, the condition is characterized by a barrier to cerebral blood barriers, more specifically. The conditions of dual corticotropin releasing factor receptor 1 (CRF-1) and corticotropin releasing factor receptor 2 (CRF_2) antagonists that may be suitable for dysfunction of the cerebral blood barrier include (but are not limited to) Ischemic stroke, migraine, multiple sclerosis, Alzheimer's disease, epilepsy, cancer brain metastasis and encephalopathy. Dual cortisol releasing factor receptor 1 (CRF-1) and cortisol releasing factor receptor 2 (CRF-2) antagonists may be characterized by mucosal epithelial, epidermal or endothelial barrier dysfunction including (but not limited to) hair, inflammatory bowel disease, large bowel syndrome, short bowel syndrome, post-surgery Intestinal obstruction, allergy, 153611.doc -29· 201130815 Dermatitis, sepsis, ischemic injury, multiple sclerosis and encephalopathy (Elias and Schmuth, Curr Opin Allergy Clin Immunol 9, 437-446, 2009; Lindsberg et al. J Cerebral Blood Flow & Metabolism 30, 689-702. 2010; Marchiando et al, Annu Rev Pathol Mech Dis 5, 119-144, 2010; 0hman and SimrSn, Nat Rev Gastroenterol Hepatol 7, 163-173, 2010). Adaptation above 'The appropriate dosage will of course vary depending, for example, on the compound employed, the host, the mode of administration, and the nature and severity of the condition being treated. However, in general, it is indicated to be from about 〇〇 to about 〇〇 mg/ A satisfactory dose per kilogram of animal body weight, preferably from about 1 to about 30 mg/kg of animal body weight, is obtained in the animal. In larger mammals (e.g., humans), the indicated daily dose is in the range of from about i to about 5 mg, preferably from about i to about 100 mg of the agent of the invention, preferably, for example, up to three times per day. The second dose is administered or in a sustained release form. The medicament of the present invention can be administered by any conventional means, especially for the enteral, preferably oral, such as in the form of a key or capsule; or parenterally, for example, in the form of an injectable solution or suspension. . According to the above, the invention also provides an agent of the invention for use as a medicament, for example, for the treatment of diseases induced or contributed by CRF, such as the diseases referred to above. Providing a compound of formula I g thus 'an additional salt according to the invention for use in the treatment or alleviation of any condition in which the endogenous crf content has a misalignment of the a leg (hypothalamic pituitary axis), or by c(d): Various diseases. 153611.doc -30- 201130815 The medicament of the present invention can be administered alone or in combination with other medical agents in vivo, and other pharmaceutical agents, for example, can effectively treat endogenous CRF content and play a role or involve endogenous CRF. An agent that increases the disease and condition of the disease. Suitable combinations consist of a compound of the invention and one or more compounds selected from the group consisting of dopamine D2 receptor antagonists, serotonin 5-HT4 receptor agonists, serotonin 5-HT3 receptor agonists, serum 5-HT3 receptor antagonist, CCK1 receptor antagonist, motilin receptor agonist, μ-opioid receptor antagonist, opioid receptor agonist and opiate, other CRF receptor antagonists , glutamate receptor antagonist, neurokinin receptor antagonist, histamine Η2 receptor antagonist, histamine Η4 receptor antagonist, proton pump inhibitor, chloride channel activator, ornithine cyclization Enzyme-c activator, muscarinic receptor antagonist, antispasmodic, stimulant laxative, osmotic laxative, stool softener, absorbent and fiber supplement, antacid, GI relaxant, bismuth compound, class Vanilloside receptor antagonists, anticonvulsants, NSAIDS, COX-2 inhibitors, GABAb receptor modulators, CB receptor ligands, calcium channel blockers, sodium channel blockers, tricyclic antidepressants Drug, serotonin and norepinephrine reuptake inhibitor, benzodiazepine Call, α-2 receptor agonists and ghrelin receptor agonists. More specifically, the compounds of the invention may be administered in combination with one or more compounds selected from the group consisting of dopamine D2 receptor antagonists, such as chlorpromazine, prochlorperazine. , IL 0 haloperidol, alizapride, domperidone, metoclopramide and itopride; serotonin 5-HT4 receptor agonist , such as cisapride 153611.doc • 31 - 201130815

(cisapride), cinitapride, mosapride, renzapride, prucalopride, tegaserod, velusetrag ), ATI-7505, and WO 2005068461 ' US 2005228014 > WO 2005080389 ' US 2006100426 , US 2006100236 , US 2006135764 , US

2005277671, WO 2005092882, WO 2005073222, JP 2005104896, JP 2005082508, WO 2005021539, JP 2004277319, JP 2004277318, WO 2004026869, EP 1362857, WO 2006108127, US 20060183901, WO 2006127815, US 20060276482, WO 2007005951, WO 2007010390, WO 2007005951, Compounds described in WO 2007048643, WO 2007096352, WO 2007068739 and WO 20070117796; serotonin 5-HT3 receptor agonists, such as compounds described in pumesotrap and WO 2007004041; serotonin 5-HT3 Receptor antagonists such as aosetron, cilansetron, ramosetron, azasetron, ondansetron, glastrix Granisetron), tropisetron, DDP225 and compounds described in WO 2006183769, WO 2006105117 and WO 2007004041; CCK1 receptor antagonists such as JNJ-17156516, devazepide, gasamine ( Loxiglumide) and dextroxiglumide; motilin receptor agonist, such as motilin, atemimo Tin), erythromycin, alemcinal, memitcinal, KOS-2187, 1-[4-(3- 15361 丨.doc -32- 201130815

Fluoro-phenylamino)-piperidin-1-yl]-2-[4-((S)-3-methyl-piperazin-1-ylindenyl)-phenyl]-ethanone and WO 2005060693 , compounds described in WO 2006127252, WO 2007007018, WO 2007012479 and WO 2008000729; m-opioid receptor antagonists such as naloxone, alvomopan, methylnaltrexone And compounds described in US 20050203123, US 2006063792, WO 2007050802, US 2007103187 'WO 2009029252, WO 2009029256, WO 2009029257 and WO 2009029253; opioid receptor agonists and opiates, such as morphine base, buprenorphine 0 Buprenorphine, diamorphine, dihydrocodeine, fentanyl, pethidine 'asimadoline, tromethamine (Loperamide) and codeine; CRF receptor antagonists, such as GSK876008, pexacerfont, and WO 2004069257, WO 99400 δ9, US 6844351, WO 2005013997, WO 2005014557, WO

Compounds described in WO 2005026126 > WO 2005028480 > WO 005044793, WO 2005051954, WO 2005051954, WO 20051 15399, WO 2005028480, WO 2005023806, WO 2006044958, WO 2006044821 and US 20060211710; glutamine receptor antagonism Agents, such as AZD9272, AZD2066, AFQ056, At) X-48621, and WO 9902497, WO 2000020001, WO 200304758, and WO 2005030723, WO 2005077345, US 2006009443, EP 1716152, WO 2005080397, US 2006019997, WO 2005066155, WO 2005082884, WO 153611 .doc -33- 201130815

2005044266, WO 2005077373, EP 1713791, EP 1720860, WO 2005080379, EP 1716130, US 2006235024, WO 2005080363, WO 2006114264, WO 2006114260, WO 2006089700 2005272779 2006009477 2006025414 2006074884 2006123255 2007023242

WO 2006114262, WO 2006123257, US WO 2006048771, WO 2006123249, US WO 2006014185, EP 1723144, US

US 2006004021, US 2006160857, WO WO 2006129199, WO 2006123244, WO WO 2007040982, WO 2007023290, WO WO 2007050050, WO 2007039781, WO

a compound described in 2007039782 and WO 2007023245; a neurokinin receptor antagonist, such as taletant, osanetant, cassopitant, nepadutent, Compounds described in saredutant, DNK-333, SLV-317, SLV321, SLV317, and EP 96-810237, WO 2006137790, WO 2006137791, WO 2006094934, WO 2007037742, and WO 2007037743; histamine H2 receptor Antagonists such as famotidine, cimetidine, ranitidine, and nizatidine; histamine H4 receptor antagonists such as JNJ7777120, JNJ10191584, and US 2006111416, WO 2006050965, WO 2005092066, WO 2005054239, US 2005070550, US 2005070527, EP 1505064, WO 2007090852, WO 2007090853 'WO 2007090854 ' US 20070232616 ' US 20070238771, WO 2007117399, WO 2007031529 and WO 153611.doc -34- 201130815 Compounds described in 2007072 163; proton pump inhibitors, such as omeprazole, lansoprazole, and thunder Bella 0 (rabeprazole), tentoprazole, pantoprazole, and Esomera. Esomeprazole, revaprazan, soraprazan, and AGN201904; chloride channel activators, such as lubiprostone; tobramycin cyclase-2c activator, such as Linaclotide, guanilib, guanylin, uroguanylin, and WO 2005087797 > WO 2005016244 ' WO 2007022531 > WO 2007101 158, WO 2007101161 and US 7041786 The compound described in the cockroach; receptor anti-reagents such as daifenacin, solifenacin, atropine, dicycloverine, Haikou Xingbian desert ( Hycosine butyl bromide), propantheline, oxybutinin, cimetropium bromide, and pinaverium bromide; antispasmodic agents, such as mebeverine, oltipin Octylonium bromide, trimebutine, tiropramide, alverine and peppermint oil; irritant laxatives such as bisacod l); osmotic laxatives, such as activated carbon containing sorbitol, lactulose, magnesium hydroxide and phosphate buffered saline; stool softeners, such as senna leaf concentrates, liquid paraffin and peanut oil; absorbents and fiber supplements Bulk fiber laxatives, such as sputum, sulfhydryl cellulose, ispaghula husk and sterculia; antacids, such as sputum, sputum and antacids, including cicada eve 611611 .doc -35- 201130815 Preparation of simeticone and alginate; GI relaxant, such as cholestyramine resin; compound, such as bismuth subsalicylate; vanilloid receptor antagonist, For example, SB-705498, ABT-102, AZD1386, GRC-6211, MK-2295, and WO 2002076946, WO 2004033435, WO 2005121116, WO 2005120510, WO 2006006740, WO 2006006741, WO 2006010445, WO 2006016218, US 2006058308, WO 2006033620, WO 2006038871, US 2006084640, US 2006089360, WO 2006058338, WO 2006063178, US 2006128689, WO 2006062981, WO 2006065646, WO 2006068618, WO 2006068592, WO 2006068593, WO 2 006076646, US 2006160872, WO 200608082, US 2006183745, WO 2006095263, WO 2006102645, WO 2006100520, US 2006241296, WO 2006122200, WO 2006120481, WO 2006122250, DE 102005044814, WO 2006122772, WO 2006122777, WO 2006124753, WO 2006122799, WO 2006122770, Compounds described in WO 2006122769, WO 2006136245, WO 2007030761, US 20070088072 ' US 20070088073 ' US 20070105920, WO 2007042906, WO 2007045462, WO 2007050732; anticonvulsants, such as carbemazepine, oxcarbemazepine , lamotrigine, gabapentin and pregabalin; NSAIDS, such as aspirin, acetometaphen, ibuprofen, diclofenac 153611 .doc •36- 201130815 (diclofenac), naproxen, flurbiprofen, indomethacin, "piroxicam, keproprofen, Sulindac and diflunisal; COX-2 inhibitors such as celecoxib (celecoxib), rofecoxib, lumiracoxib, valdecoxib,

I conjugated to etoricoxib and WO 2004048314; GAB Ab receptor modulators, such as baclofen and (R)-chloroaniline butyric acid, AZD3355, XP19986 And compounds described in WO 2006001750 and WO 2004000856; CB receptor ligands such as dronabinol, nabilone, cannabidiol, rimonabant and WO Compounds as described in 2002042248 and WO 2003066603; calcium ion channel blockers, such as those described in ziconotide, AGI0-003, PD-217014, and WO 2006038594, WO 2006030211 and WO 2005068448; sodium ions Channel blockers such as lamotrigine and compounds described in WO 2006023757, WO 2005097136, JP 2005206590 and WO 2005047270; tricyclic antidepressants such as clomipramine, amoxapine , nortripyline, amitriptyline 'imipramine' desipramine, doxepin, trimethoprim pmi 0 (trimiprami Ne) and protripyline; serotonin and norepinephrine reuptake inhibitors, such as milnacipran, desvenlafaxine, sibutramine, degree Duloxetine, fluoxetine, paroxetine, 153611.doc -37- 201130815 citalopram, sertraline, and fluvoxamine; Stupid and diazepane, such as levotofosopam, diazepam, lorazepam, clonazepam, and apu. Alprazolam; alpha-2 receptor agonists, such as clonidine, tizanidine, and guanfacine; intragastric hormone receptor agonists, such as gastric hormones (ghrelin), ibutamoren, capromorelin, tabimorelin, ipamorelin, 2-mercaptopropylamine-N-[1(R -Methylamino-2-(1Η-indol-3-yl)ethyl]-D-tryptophanamine, TZP-101, TZP-102, LY-444711, EX-1314 and US 6525203, US 20050154043, WO 2005097788, WO 2006036932, WO 2006135860, US 20060079562, WO 2006010629, WO 2006009674, WO 2006009645, US 20070021331, WO 2007020013, US 20070037857 'WO 2007014258, WO 2007113202, WO 2007118852, US 20080194672, US 20080051383 and US 20080051383 The compound; corticosteroids, such as hydrocortisone, cortisone, dexamethasone, betamethasone, beclomethasone, dehydrocortisol (prednisolone) ), 6- 曱 尼龙 nylon ( 6-methylprednisolone), budesonide, mometasone furoate, ciclesonide, fluticasone propionate and fluticasone furoate; aminosalicylic acid Salts, such as mesalazine, ipsalazide, olsalazine 153611.doc -38-201130815 (olsalazine) and balsalazide; immunomodulators such as sulfur sputum (azathioprine) ), 6-mercaptopurine, methylamine D, sputum, mycophenolate mofetil, ciclosporin, and tacrolimus; PDE4 inhibitors, such as tetomilast (tetomilast), cilomilast, roflumilast, and arofylline; antibiotics such as metronidazole, ornidazole, and ciprofloxacin (ciprofloxacin); anti-adhesive molecular agents, such as natalizumab and MLN02; anti-IL-2 agents, such as daclizumab and basilixumab; anti-CD-3 agents , such as Sicilizumab; and anti-TNF agents such as infliximab, adalimumab, fontolizumab, and certolizumab pegol; psychosis The medicament comprises a compound selected from the group consisting of agomelatine, aza, azapirone, and apu. Alprazolam, amitriptyline, aniracetam, acetaminophen-L-meat test, Ari 0 bottom. Sit (aripiprazol), acetophenazine, benzodiazepine, barbiturate, buspirone, bupropione, gas nitrogen Chlordiazepoxide, chlorazepate, clonazepam, chlorpromazine, nitrozapine, CX614, CX516, chlorprothixene, diphenhydramine, Called (hydroxyzine), demoxepam, diazepam, droperidol, duloxetine 153611.doc -39- 201130815 (duloxetine), doneeone (donezepil), more Doxepine, desipramine, flurazepam, fluphenazine, fluoxetine, flu flupentixol, gabapentin, Melatonin, a compound derived from ginkgo, galantamine, fluoroethanol, Hydergine (dihydro ergot), huperzine, Isocarbobox (isocarboxazid), imipramine, labor Lorazepam, loxapine, amphetamine S, medazepam, moclobemide, molindone, maprotinline, mo Modafinil, memantine, methylphenicate, mesoridazine, mesotrimeprazine, nortriptyline, naproxil Naproxen, oxazepam, oxiracetam, olanzapine, prazepam, paroxetine, phenelzine ), pipotiazine, perphenazine, promazine, pimozide, PDE4 inhibitors quazepam, quetiapine, ribose Reboxetine, rivastigmine, prochlorperazine, risperidone, sertraline, sertindole, temazepam ,three. Triazolam, tranylcypromine, tomoxetine, thiotixene, triflurane. Trifluoperazine, thioridazine, zolpidem 153611.doc -40- 201130815 and ziprasidone. When X1 is a key, X2 is preferably _CR11R12CR13r14_. When X1 is -CR5R6CR7R8-, X2 is _CR" R12CR13R14- is preferred. When X1 is -CR2R3, X2 is a bond or _CR9RiQ- is preferred. When X1 is -NR4-, X2 is preferably a bond. When X1 is -0-, it is preferable that X2 is a bond. One group of compounds may be mentioned as a hydrazine compound, 0

C1 -10 halogen group, X1, X2, A1, A2, Α3 and Α4 each as described above; and isomers thereof; in free form or in the form of a salt. One group of compounds may be mentioned as a hydrazine compound, 0

Wherein 111113 and 1111115 may be the same or different and each is a Chio alkyl group, a halogen group or a C1-10 tooth alkyl group; 153611.doc •41·201130815 X1, X2, A1, A2, A3 and A4 are each as described above; Isomer thereof; it is in free form or in the form of a salt. One group of compounds may be mentioned as a compound,

Wherein R, R2, R3, R9, R10, A1, A2, VIII3 and A4 are each as described above; and isomers thereof; in free form or in the form of a salt. One group of compounds may be mentioned as a compound of formula V,

And its isomers; it is in free form or in the form of a salt. One group of compounds may be mentioned as a compound of formula VI, 153611.doc • 42· 201130815

It is in free form or in the form of a salt. : Acid addition salts are prepared from the free base in a known manner, and vice versa. A pharmaceutically acceptable salt is any salt of a parent compound suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt formed in vivo by administration of an acid, another salt, or a drug that can be converted to an acid or a salt. Salts comprise one or more compounds in ionic form, such as a conjugate acid or base associated with - or a plurality of corresponding: counter ions. The salt may be formed from one or more acidic groups from which protons have been removed (eg, (iv)), or a plurality of protonated test groups (eg, amines), or both (eg, zwitterions), or may be combined with one or more An acidic group (eg, a carboxylic acid) that removes protons, one or more protonated basic groups (eg, an amine), or both (eg, amphoteric ion, as used herein, the term "pharmaceutically acceptable salts" "" refers to a salt that retains the biological effectiveness and properties of the compounds of the invention and which is biologically or otherwise non-defective. In many cases, the compounds of the invention are present due to the presence of amine groups and/or carboxyl groups or the like. It can form a salt of an acid and/or a salt of a base. The pharmaceutically acceptable acid addition salt can be formed by an inorganic acid and an organic acid, for example, an acetate, an aspartate, a benzoate or a benzenesulfonic acid. Salt, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphor 153611.doc • 43- 201130815 sulfonate, citrate, ethanedisulfonate, ethanesulfonate, formate, Fumarate, glucoheptonic acid , gluconate, glucuronate, hexafluorophosphate, benzal salt, hydrochloride/vapor, hydrobromide/bromide, arsenate/iodide, isethionate, lactic acid Salt, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, orotate , oxalate, phthalate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, gluconate, stearate, succinate, tartrate, tosylate And trifluoroacetate. The inorganic acid from which the salt can be derived includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids which can be derived from salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid. , oxalic acid, cis-butyl diacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methyl acid, ethyl acid, p-toluene acid, Salicylic acid and its similar acids. Pharmaceutically acceptable base addition salts can be formed by inorganic and organic tests. The test includes, for example, sodium, potassium, lithium, sulphate, calcium, magnesium, iron, sulphur, copper, sulphur, aluminum and the like; particularly preferred are salt, salt, sodium, salt and lock salt. Salt-free organic bases include, for example, first amines, second amines and third amines, substituted amines (including naturally occurring substituted amines), cyclic amines, cation exchange resins, and the like, particularly such as Isopropylamine, tridecylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound (alkaline or acidic moiety) by conventional chemical methods. In general, 'these salts can be obtained by subjecting the free acid form of such compounds to a stoichiometric amount of a suitable base (such as Na, Ca, Mg* 艮 氢氧化 hydroxide 153611.doc -44 - 201130815, carbonate, The bicarbonate or its analogous base is reacted or prepared by reacting the free base form of such compounds with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or in an organic solvent or a mixture of the two. In general, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where practicable. A list of other suitable salts can be found, for example, in the following literature: "Remington's pharmaceutical

Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). A prodrug is a compound that can be converted to a therapeutically active compound upon administration. For example, transformation can occur by hydrolysis of an ester group or some other biologically labile group. Prodrug preparation is well known in the art. For example, Richa].d B. Silverman, Organic Chemistry of Drug Design and Drug ―, Agricultural 2, Elsevier Academic press: Amsterdam, 2004, pp. 496-557, “Prodrugs and Drug DeUvery Systems” provides information on this topic. More details. The term "isomer" as used herein refers to a different compound having the same molecular formula but differing in the arrangement and configuration of the atoms. Furthermore, the term "optical isomer" or "stereoisomer" as used herein refers to any of the various stereoisomeric configurations that may be present for a given compound of the invention, and includes geometric isomers. It will be appreciated that the substituent may be attached to the palm center of the carbon, sulfur or phosphorus atom. Thus, the invention includes enantiomers, diastereomers or racemates of the compounds. "Enantiomers" are a mixture of 153611.doc •45·201130815 non-reproducible #-pairs of stereoisomers...opposite η mixture A "racemic" mixture. This term is used to indicate a racemic mixture as appropriate. "Diastereomers" are stereoisomers having at least two asymmetric atoms but not mirror images of each other. Absolute stereochemistry was assigned according to the Cahn-lng〇1d-Prelog R_S system. When the character is a pure enantiomer, the stereochemistry of each pair of palmar carbon can be specified by the money ball. Analyzed compounds of unknown absolute configuration may be designated as (1) or (a) depending on the direction in which the plane polarized light is rotated (right * or left-handed) under the wavelength of the sodium D line. Certain of the compounds described herein contain a ❹(tetra) symmetry center, and thus may result in enantiomers, diastereomers, and other stereoisomeric forms that may be determined by absolute stereochemistry to be (R)- or (8). . The present invention is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (8)- and (7)-iso(4) can be prepared using a palm-forming synthetic component or a palmitic reagent, or optically active W- and (external isomers can be resolved using conventional techniques. The complex contains a double bond. The substituent may then be in the £ or 2 configuration. If the compound contains a disubstituted cycloalkyl group, the cyclofilament substituent may have a cis or trans configuration and is intended to include all tautomeric forms. The compound of formula (1) in optically pure form can be obtained from the corresponding racemate according to well-known procedures, for example with HpLC on a palm substrate. Alternatively, optically pure starting materials can be used. By means of suitable separation methods Separation of stereoisomeric complexes (for example mixtures of diastereomers) into their corresponding isomers in a manner known per se, for example, by means of fractional crystallization, chromatography, solvent partitioning and the like. 46- 201130815 The separation of diastereomeric mixtures into their individual diastereomers. This separation can occur at the level of the starting compound or against the compound itself. By forming diastereomeric salts, For example, by mapping with The structure is pure to form a salt for the palm, or by chromatography using a chromatography matrix and a palmitic ligand, for example by HPLC, to separate the enantiomers. Any asymmetric atom (e.g., carbon or analog thereof) may be in racemic or enantiomerically enriched form, e.g., in (8)-(7) or configuration. In some implementations, each asymmetric atom is in (8) configuration. Or () has at least 5 % enantiomeric excess, at least 6 〇 0 / ❶ enantiomeric excess, at least 70%. Enantiomeric excess 'at least 8 % enantiomeric excess , 90% enantiomeric excess to v, at least 95% enantiomeric excess or at least 99. Enantiomeric excess. If possible, the substituent at the atom with an unsaturated bond can be cis (Z Or in the form of trans (£). Thus, as used herein, the compounds of the invention may be in the form of one of the possible isomers, singular (tetra), arsine, one isomer or a mixture thereof, For example, a substantially pure geometric (cis or trans) isomer, a diastereomer, an optical isomer (enantiomer), a racemate or a mixture thereof. Any mixture of the resulting isomers may be separated into pure or solid I by, for example, chromatography and/or fractional crystallization based on the physicochemical differences of the components, ' Geometric or optical isomers, diastereomers, racemates of any of the resulting end products or intermediates. The racemates can be resolved into optical enantiomers by known methods, for example It is achieved by the separation of its diastereomeric salt obtained with an optically active acid or base, and the release of an optically active acidic or basic compound 1536 ll.doc • 47·201130815. In particular, the present invention can be employed with a basic moiety. The compound is resolved into its optical enantiomer, for example by reacting with an optically active acid (eg tartaric acid, diphenyl decyl tartaric acid, diterpene tartaric acid, bismuth, hydrazine, _p-toluamyl tartaric acid, mandelic acid) The salt formed by malic acid or camphor_1 〇 sulfonic acid is obtained by fractional crystallization. The racemic product can also be resolved by lip chromatography, for example by high pressure liquid chromatography (HPLC) on a palm adsorbent. According to another aspect of the present invention, there is provided a method of treating or ameliorating any condition in which an endogenous CRF content is increased or ΗΡΑ (hypothalamic pituitary axis) is disordered or various diseases induced or promoted by CRF, the method comprising administering A therapeutically effective amount of a mammal as described above is a chelate or a salt thereof. Furthermore, a pharmaceutical composition comprising a compound of formula 1 as described above in free form or in a pharmaceutically acceptable salt form in combination with a pharmaceutically acceptable adjuvant, diluent or carrier is provided. Pharmaceutical compositions suitable for separate administration of the combination partners and in a fixed combination according to the invention (i.e. a single herbal composition comprising at least two combination combinations) can be prepared in a manner known per se and suitable for enteral administration (such as enteral) and parenterally administered to a mammal comprising a human comprising a therapeutically effective amount of a combination of at least one pharmacological activity, alone or in combination with - or a plurality of pharmaceutically acceptable carrier groups, Particularly suitable compositions for enteral or non-pharmaceutical compositions contain, for example, from about 0.1% to about 99.9%, preferably from about 20% to about 60%, by weight of active ingredient. Combination therapies suitable for enteral or parenteral administration The pharmaceutical preparations are, for example, pharmaceutical preparations in unit dosage form, such as a key (4) emollient), capsules, suppositories and ampoules. These formulations are prepared by themselves in the manner of 153611.doc • 48·201130815, for example by means of conventional mixing granulation, sugar coating, dissolution or lyophilization processes. It is to be understood that the unit content of the combination conjugate contained in the individual doses of the respective dosage forms does not necessarily constitute an effective amount by itself, since the necessary effective amount can be achieved by administering a plurality of dosage units. The pharmaceutical composition can be formulated for a particular route of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be formulated in solid form, including capsules, troches, pills, granules, powders or suppositories, in liquid form, including solutions, suspensions or emulsions. The pharmaceutical compositions may be subjected to conventional medical procedures such as sterilization and/or may contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers. Wait). These pharmaceutical compositions are usually a squeezing agent and a gelatin capsule containing the active ingredient and the following: am releasing agents such as lactose, dextrose, vegetable sugar, mannitol, sorbitol, cellulose and/or glycine Acid; b) a lubricant, such as sulphur dioxide, talc, stearic acid, its sedative or (d) and/or polyethylene glycol; for the preparation of money, it also comprises: C) a binder, such as magnesium citrate Aluminum, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyethylene. Bilobidone; if necessary, comprises: d) a disintegrant such as starch, loam, balsamic acid or its sodium or effervescent mixture; and/or e) absorbents, colorants, flavorings and sweeteners Flavor. Tablets can be coated with a film or casing according to methods known in the art. 153611.doc -49· 201130815 Compositions suitable for oral administration include an effective amount of lozenges, buccal, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or A compound of the invention in the form of a granule. Compositions intended for oral use are prepared according to any method known in the art of making pharmaceutical compositions, and such compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Medicament to provide a pharmaceutically elegant and palatable preparation. The lozenge contains the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of lozenges. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or arabic Glue; and a lubricant such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The formulation suitable for oral use may be a mixture of the active ingredient and an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. The gelatin capsule form is present in the form of a soft gelatin capsule in which the active ingredient is mixed with water or oil (for example, peanut oil, liquid paraffin or eucalyptus oil). Some injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preservatives, elixirs, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure, and/or buffers. Alternatively, it may contain other therapeutically valuable substances f. The compositions are prepared according to conventional mixing 'granulation or coating methods' and contain about _ _ 7 7 %, preferably from about 153,611.doc -50 · 201130815, preferably from about 1 to about 50% of the active ingredient. Compositions suitable for application to the skin include an effective amount of a compound of the invention and a carrier vehicle comprising a pharmacologically acceptable absorbable solvent to aid passage through the skin of the host. For example, a transdermal device is in the form of an end band, the crucible comprising a bottom member, a reservoir containing a compound and optionally a carrier, optionally used to deliver to the host at a controlled and pre-emptive rate over a prolonged period of time. The rate at which the skin delivers the compound controls the barrier and the means for securing the device to the skin. Compositions suitable for topical administration (e. g., to the skin and the eye) include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, by spraying or the like. Such topical delivery systems will be particularly suitable for transdermal administration, for example for the treatment of skin cancer, for example in the form of sunscreens, lotions, sprays and the like for prophylactic use. It is thus particularly suitable for topical (including cosmetic) formulations well known in the art. These formulations may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives. Topical application as used herein may also be related to inhalation or intranasal administration. It is preferably in the form of a dry powder (either alone, in a mixture (for example as a dry blend with lactose) or in the form of a component particle (for example with a barrier lipid), in a dry powder inhaler, or in the form of an aerosol spray. Self-pressurizing containers, pumps, ejector, nebulizers or nebulizers are added with or without the use of a suitable propellant for delivery. For a subject of from about 50 to 70 kg 'the pharmaceutical composition or combination of the invention may have from about 1 to 1000 mg of active ingredient, or from about 1 to 500 mg, or from about 25 to 153,611.doc • 51 · 201130815 mg, or A unit dose of from about 1 to 150 mg, hydrazine, hydrazine, and about 0.5 to 100 mg, or about uomg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition, the condition being treated, or the severity of the disease. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient necessary to prevent, treat, or treat a disease or disease progression. It is preferred to use mammals (e.g., mice, rats, dogs, wolves) or isolated organs, tissues, and specimens thereof to demonstrate the above dosage characteristics in both in vitro and in vivo tests. The compounds of the present invention can be administered in vitro in the form of a solution (e.g., preferably an aqueous solution), and administered, for example, in the form of a suspension or an aqueous solution, enterally, parenterally, or intravenously. The extracorporeal dose may be between about 1 〇, ear concentration to 109 mM concentration. Depending on the route of administration, the therapeutically effective amount in vivo may be between about 1·1·5〇〇 mg/kg or between about 11〇〇. The term "pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives, as will be known to those of ordinary skill in the art. (eg antibacterial, antifungal), isotonic, absorption delay, salt, preservative, pharmaceutical, pharmaceutical stabilizer, binder, excipient, disintegrant, lubricant, sweetener, flavoring Agents, dyes, such similar materials, and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, pp. 1289-1329) unless any conventional carrier is incompatible with the active ingredient, Both are contemplated for use in therapeutic or pharmaceutical compositions. 153611.doc -52- 201130815 The term "therapeutically effective amount" of a compound of the invention means that the amount of the compound of the invention will cause an individual's biological or medical response (eg, reduce or inhibit enzyme or protein activity), or improve symptoms, reduce symptoms , delay or delay disease progression, or prevent disease. In one non-limiting embodiment, the term "therapeutically effective amount" means that the amount of the compound of the present invention may have the following effects when administered to an individual. (1) at least partially alleviate, inhibit, prevent, and/or ameliorate (1) by CRF Mediating, or (8) a condition or disorder or disease associated with CRF activity, or characterized by abnormal CRF activity; or (7) reducing or inhibiting CRF activity; or (3) reducing or inhibiting CRF performance. In another non-limiting embodiment, the term "therapeutically effective amount" means that the amount of the compound of the invention is effective to at least partially reduce or inhibit CRF activity when administered to a cell or tissue or non-cellular biological material or medium; Or at least partially reduce or inhibit the performance of C "RF. The meaning of the term "therapeutically effective amount" as explained above in the examples of CRF is also applied to any other relevant protein/peptide/enzyme in the same manner. - The term "individual" as used herein refers to an animal. The animal is preferably a feeding animal. An individual also refers to, for example, primates (e.g., humans) 'bovines, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, blacks and their likes. & Animals. In a preferred embodiment, the individual is a human. The use of the "inhibition" means reducing or inhibiting a given condition, symptom or condition or disease, or significantly reducing the baseline activity of a biological activity or process. The term "re the treatment of any disease or condition as used herein, in one embodiment, is a heart-improving disease or condition (ie, delaying or preventing or alleviating the development of a disease or at least one of its clinical symptoms) 153611.doc-53-201130815 ). In another embodiment, "treatment" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that are indistinguishable by the patient. In yet another embodiment, "treating" refers to modulating a disease or condition either physically (e.g., to stabilize a discernible symptom), physiologically (e.g., to stabilize a body parameter), or both. In yet another embodiment, "treatment" refers to preventing or delaying the onset or progression or progression of a disease or condition. The terms "a", "an" and the like, as used herein, are used in the context of the present invention, particularly in the context of the claims. Both singular and plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted. The use of any and all examples or illustrative language (such as "such as " The compounds of the invention are obtained, in free form, in the form of their salts, or in the form of their prodrug derivatives. When the test group and the acidic group are both present in the same molecule, the compound of the present invention may also form an internal salt such as a zwitterionic molecule. The present invention also provides a prodrug of the compound of the present invention which can be converted into a sigma sigma in vivo. Prodrugs are active or inactive compounds which, upon administration to an individual, chemically alter the compounds of the invention via live meat + in vivo physiological effects such as hydrolysis, metabolism and similar physiological effects. The suitability and techniques associated with the manufacture and use of prodrugs are familiar to those skilled in the art. 153611.doc •54- 201130815 The medicine can be conceptually divided into two categories that are not mutually exclusive, namely, biological precursor cutting and _ m medicine. See The Practice < Medicinc^

Chemistry^ ^ 3 1-32 ^ (Wermuth , Academic Press, San

Diego’ Calif·, 2001). In general, a bioprecursor prodrug is a compound that is inactive or has low activity compared to a corresponding active pharmaceutical compound, which contains one or more protecting groups and can be converted to an active form by metabolism or solvolysis. The active drug form and any released metabolites should have acceptable low toxicity. The carrier prodrug is a pharmaceutical compound containing a transport moiety which, for example, improves the mode of absorption and/or localization delivery to the site of action. For this carrier prodrug, it is desirable that the bond between the drug moiety and the transport moiety is a covalent bond, and the prodrug is not eight/tongue! • Life or activity is lower than that of the drug compound, and any released transport portion is consciously non-toxic. For a drug that is intended to transport a portion that enhances absorption, the release of the transport moiety should generally be rapid. In other situations, it is desirable to utilize portions that provide slow release, such as certain polymers or other moieties such as cyclodextrins. Carrier prodrugs can be used, for example, to modify one or more, under-fertilizer, increased lipophilicity, increased duration of pharmacological effects, increased site specificity, reduced toxicity and adverse effects, and/or drug formulation Improvement of the substance (such as stability, water solubility, inhibition of undesired sensation or biochemical properties). For example, by (a) a hydroxy group with a lipophilic carboxylic acid (eg, a carboxylic acid having at least one lipophilic moiety), or (b) a carboxylic acid group and a relative alkaloid (eg, having at least one lipophilicity) The esterification of a portion of an alcohol, such as an aliphatic alcohol, increases lipophilicity. Examples of prodrugs are, for example, esters of free m acids, and s-mercapto derivatives of thiol 153611.doc -55-201130815, and hydrazine-flavor derivatives of alcohols or phenols, wherein the thiol group has The meaning defined in this article. Preferred are pharmaceutically acceptable ester derivatives which can be converted to the parent carboxylic acid by solvolysis under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters. , a monosubstituted lower alkyl ester or a disubstituted low carbon alkyl group, such as α_(amino, mono or dicarbamoylamino, carboxyl, lower alkoxycarbonyl) _ lower alkyl ester , α-(lower alkyl alkoxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl vinegar such as p-pentyloxymethyl ester, and conventionally known Used in analogs in the art. In addition, the amine has been masked and is in the form of a derivative substituted with an arylcarbonyloxyindenyl group which is decomposed by an esterase in vivo to release free drug and formaldehyde (Bundgaard, /. Met/· C/zew. 2503 ( 1989)). Furthermore, 'acidic NH-containing drugs (such as u-salt, saccharide, sputum and their analogs) have been masked by N-glyoxymethyl (Bundgaard, Design of Prodmgs, Elsevier (1985)). Masked to form esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich base hydroxamic acid prodrugs, their preparation and use. Furthermore, the compounds of the invention (including salts thereof) may also be hydrated. The form obtains 'or includes other solvents for its crystallization. The invention includes all pharmaceutically acceptable isotope-labeled compounds of the invention, i.e., one or more atoms of the formula (1) are substituted with the same The number of orders but the atomic mass is different from the atomic mass or mass number usually found in nature, and/or (2) the isotope ratio of one or more atoms is different from the naturally occurring ratio. Suitable for inclusion in the present invention. Examples of isotopes in compounds include hydrogen with 153611.doc • 56 - 201130815, such as 2h and 3h; carbon isotopes such as hc, nc and 丨4 夂l, gas isotope 'such as 36C1; Positions such as; iodine isotopes such as 1231 and 251; nitrogen isotopes such as 13N and; oxygen isotopes such as 15〇, 170 and 18〇; phosphorus isotope such as 32p; and sulfur isotope such as 35s. The compound of formula (1) labeled (for example, a compound of formula (I) incorporating a radioisotope) is suitable for drug and/or matrix tissue distribution studies. Radioisotope 氚 (ie 3H) and carbon _14 (ie 4C) are easy to apply. Incorporation and detection means are simple and particularly suitable for this purpose. To heavier isotopic substitutions such as gas (i.e., H) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or dose requirements. Decreased, and thus may be preferred in some cases, and the purine analogs are included in the formula of the compounds of the invention. Substitution with positron-emitting isotopes such as llc, UF, ^, and 3 can be applied to positron emission. Tomography (PET) studies to examine the occupancy of matrix receptors. Compounds of formula (1), which are isotopically labeled, can generally be obtained by 'known to those skilled in the art. The accompanying examples and methods analogous to those described in the preparations are prepared by substituting an appropriate isotopically labeled reagent for the unlabeled reagent employed above. The pharmaceutically acceptable solvate of the present invention includes crystallization. The solvent may be a solvate of the isotope substitution (for example D20, d6-acetone, d6-DMS〇). The compound of the invention 'is also a donor capable of acting as a hydrogen bond and/or subject to 153611.doc • 57· 201130815 The compound of formula (i) of the group of the group may be capable of forming a co-crystal with a suitable eutectic former. These eutectic crystals can be prepared from the compound of formula (1) by a known eutectic formation procedure. Such procedures include grinding, heating, co-subliming, co-melting, or contacting a compound of formula I with a eutectic forming agent in solution under crystallization conditions and isolating the co-crystals thus formed. Suitable eutectic formers include the eutectic formers described in WO 2004/078163. Accordingly, the present invention further provides a cocrystal comprising a compound of formula (I). The invention further comprises any variant of the process of the invention, wherein an intermediate product obtainable at any stage is used as a starting material and the remaining step ' or wherein the starting materials are formed in situ under the reaction conditions, or wherein The reaction components are used in the form of their salts or optically pure enantiomers. The compound of the present invention and the intermediate may also be converted into each other according to a method generally known per se. Within the scope of this document, unless the context indicates otherwise, only a readily removable group that is not a component of a particular desired end product of a compound of the invention is designated a "protecting group." The protection of the protecting groups by such protecting groups, the protecting groups themselves and their decomposition reactions are described, for example, in standard reference works such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999; "The Peptides"; Volume 3 (E. Gross and J. Meienhofer), Academic Press, London and New York 1981 "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, 153611.doc -58- 201130815

Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and Η· Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A protective group is characterized in that it can be easily removed, for example, by solvolysis, reduction, photolysis, or under physiological conditions (for example, by enzymatic decomposition) (i.e., no undue secondary reaction occurs) . The hair having at least one salt-forming group can be prepared by a method known per se

A salt of a compound. By way of example, it may be by using a metal compound such as a suitable alkali metal salt of an organic carboxylic acid, such as a sodium salt of 2-ethylhexanoic acid, an organic metal or a soil metal compound such as a corresponding hydroxide, a carbonate or bicarbonate, such as an argon oxide, carbonate or bicarbonate of sodium or potassium, a corresponding compound or ammonia or a suitable organic amine treatment compound

I is a salt of the compound of the present invention having an acid group, preferably a stoichiometric amount or a small excess of a salt-forming agent. The acid addition salts of the compounds of the invention are obtained in a conventional manner, for example by treatment of the compound with an acid or a suitable anion exchange reagent. The acidic and basic salt-forming groups (for example, free carboxyl groups and free amine groups) can be formed, for example, by neutralizing a salt (such as an acid addition salt) with a weak base to an isoelectric point or by treating the east with an ion exchanger. An internal salt of a compound of the invention. The salt can be converted into the free compound by conventional means; the metal salt and the ammonium salt can be exemplified by the treatment with a suitable acid, and the acid addition salt can be treated, for example, by a suitable alkaline agent, as exemplified by 153611.doc-59·201130815. To convert. Mixtures of isomers obtainable according to the invention can be separated into individual isomers in a manner known per se; diastereomers can be separated, for example, by partitioning between heterogeneous solvent mixtures, recrystallization and/or chromatography. Separating on a reverse phase column (for example in a silicone gel) or by, for example, medium pressure liquid chromatography; and the racemate can be formed, for example, by means of an optically pure salt-forming reagent, for example by means of fractional crystallization Alternatively, the mixture of the diastereomers thus obtained is separated by chromatography on an optically active column material. The intermediates and final products can be treated and/or purified according to standard methods, for example, using chromatography, partitioning, (re)crystallization, and the like. The following are generally applicable to all of the processes mentioned above and below. All of the above process steps can be carried out in the reaction conditions known per se, including the reaction conditions specifically mentioned, in the absence or usual presence of a solvent or diluent (including, for example, a solvent which is inert to the reagents used and which dissolves the reagents used or In the case of a diluent, in the absence or presence of a catalyst, a condensing agent or a neutralizing agent (for example an ion exchanger such as a cation exchanger, for example in the form of a ruthenium depending on the nature of the reaction and/or reactant) In the case of low temperature, normal temperature or high temperature (for example, in the temperature range of about _ 1 〇〇〇c to about 19 〇. 包括, including, for example, about -80 ° C to about 15 ° t, for example, -801 to -60 ec At room temperature, at -20 (: to 4 (at TC or at reflux temperature), at atmospheric pressure or in a closed container (under pressure when appropriate) and / or in an inert atmosphere (for example in Under argon or nitrogen atmosphere. The mixture of isomers formed in all reaction stages can be separated into a 153611, doc • 60-201130815, a cockroach such as a diastereomer or enantiomer, Or any separation into isomers The present compound 'e.g., a racemate or a mixture of diastereomers' is, for example, similar to that described under "Other Process Steps". It is additionally indicated in the description of <>>, otherwise it may be suitable The refrigerants selected for the "special reaction include those solvents specifically mentioned, or for example, water; δ is intended to be 'such as lower halogenaneous-lower alkanoate, such as ethyl acetate; hydrazine, blocked Such as aliphatic scales, such as 7 such as diethyl ether, or cyclic ethers, such as tetrahydrofuran or one. wicking, liquid aromatic furnace, $ l on ^, such as Ben or A stupid; alcohols, such as decyl alcohol, ethanol or 1-prop Alcohol or 2-propanol, nitrile, such as acetonitrile; toothed hydrocarbons, such as chloramphenicol or trisole, or acid amides, such as dimethyl decylamine or Dimethyl hydrazine., check for 'such as heterocyclic ring gas test, such as n bite or N-methylpyrrolidine 2-one; carboxylic anhydride, such as lower alkanoic acid needle, such as acetate H, straight chain By or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methylcyclohexane; 哎 鳌 々 々 々 A A A A A A A A For example, aqueous solutions. The solvent mixtures can also be treated, for example, by chromatography or partitioning. Compounds (including salts thereof) can also be obtained in the form of hydrates, or crystals thereof may include, for example, for crystallization, cross-linking; Agents. There may be different crystal forms. The present invention also relates to the following formulas, "&>> Spearman's form · use of a person who can be obtained in the form of t in any process stage, and m & m & The compound is used as a starting material and the rest of the process steps are carried out, or the starting material is to the right; 5 ', formed under the reaction conditions or used as a derivative, for example in the form of a protected 4, κ, or in the form of a salt, Or, under the process conditions, a compound which can be obtained by the method of the present invention is produced and processed on site. All starting materials, building blocks for the synthesis of the compounds of the invention, test 153611.doc *61. 201130815 agents, acids, bases, dehydrating agents, solvents and catalysts are all commercially available or can be commonly used by the skilled artisan Known by organic synthesis methods (H〇uben·

Weyl 4th Edition 1952, Methods 〇f 0rganic Synthesis, TMeme, Volume 21). Certain intermediates used in the processes described above are novel per se. Therefore, according to another aspect of the present invention, there is provided a compound of the formula νπ, ΗΝ^^Χ1 ν„ J ll3

AVA wherein X1, X2, A1, A2, A3 and A4 are each as defined above; and isomers thereof; in free form or in the form of a salt. [Embodiment] Referring to the following examples, the compounds of the preferred embodiments were synthesized using the methods described herein or other methods known in the art. It will be appreciated that the organic compounds according to the preferred embodiments exhibit tautomerism. Since the chemical structures within this specification may represent only one of the possible tautomeric forms, it is to be understood that the preferred embodiments encompass any tautomeric form of the depicted structure. The following examples are intended to illustrate the invention and are not to be construed as limiting the invention. The temperature is in degrees Celsius. If not mentioned &, the #evaporation is carried out under reduced pressure, preferably between about 15 Hg and 100 mm Hg (= 20-133 mbar) into the i536H.doc -62-201130815 row. The structure of the final product, intermediate and starting material is confirmed by standard analytical methods such as microanalysis and spectral features such as MS, IR, NMR. Abbreviations used are abbreviations commonly known in the art. All starting materials, building blocks, reagents, acids, assays, dehydrating agents, solvents and catalysts useful in the synthesis of the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods generally known to those skilled in the art. (Houben-Weyl 4th Edition 1952, Methods of Organic Synthesis, Thieme, Vol. 21). Further, the compounds of the present invention can be prepared by organic synthesis methods generally known to those skilled in the art, as in the following examples. Show. In addition, a variety of commercially available reagents and materials have been utilized. Such reagents and materials include 1ST PE-AX/SCX-2 and SCX-2 columns and are readily available upon request from the supplier. General conditions: W-NMR: Spectroscopic detection was performed on a Bruker AVANCE 400 (400 MHz) spectrometer or on a Bruker AVANCE 500 (500 MHz) NMR spectrometer using ICON-NMR. The spectrum was measured at 298 K, and the solvent peak was used as a reference to report the chemical shift (δ value) in ppm. If included, the coupling constant (J) is in Hz, and the spectral split pattern is monomodal (s), double Peak (d), triplet (1), quadruple (q), multiplet or more overlapping signals (m), broad signal (br), apparent signal (app) are shown, and the solvent is indicated in parentheses. MS: This is an Agilent 1100 HPLC/Micromass Platform combo instrument, or a Waters Acquity UPLC plus SQD mass spectrometer, or a Waters Alliance HT HPLC system equipped with MS detector Waters·MicromassZQ or Waters Micromass Plattform LCZ system. Mass Spectrometry 153611.doc -63- 201130815 The detection system uses electrospray ionization on the LC-MS system for β [m+h] + refers to the monoisotopic molecular weight. The various starting materials, intermediates and compounds of the preferred embodiments can be isolated and purified, as appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, capture and release, and chromatography. All starting materials were obtained from commercial suppliers and used without further purification unless otherwise stated. Salts can be prepared from the compounds by known salt formation procedures. If a product mixture that cannot be separated by conventional techniques is obtained, these materials are separated using supercritical fluid chromatography (SFC). General conditions for SFC screening and preparative versus palm separation are as follows: Approximately 1.0 mg sample is dissolved in 1·〇 ml ethanol and screened on the Thar Minigram SFC system using the following chromatographic conditions: Column:

Chiralpak AD-H » 250x10 mm id » 5 μηι Chiralpak AS-H, 250x10 mm id, 5 μπι Chiralpak IC, 250x10 mm id, 5 μηι Chiralcel OD-H, 250x10 mm id, 5 μπι Chiralcel OJ-H, 250x10 mm id , 5 μπι Move phase A : Methanol (depending on the compound, add 0.1% v/vDEA or TFA) Mobile phase B: 2-propanol (depending on the compound, add 〇.i%v/vDEA or TFA) Mobile phase C : C02 Filter 1 Condition: 153611.doc • 64 - 201130815

Gradient: Time 0-3 min 10% A 90% C Time 3-10 min 10-50% A 90-50% C Time 10-13 min 50% A 50% C Time 13-14 min 50-10% A 50 -90% C time 14-15 min 10% A 90% C Screening 2 conditions: As for Screening 1, but using mobile phase B instead of mobile phase A Detection: UV, flow rate at 220 nm: l〇ml/min sample Concentration: 1.0 mg in 1 ml of ethanol Injection volume: 30 μΐ The resulting chromatogram was examined to obtain the best resolution of the sample. Identify the best column and regulator. The isocratic method is then optimized to find a suitable method for preparative separation. Preparative separation is carried out on one of the five columns listed above and in the presence of methanol or 2-propanol (for optimal separation, if necessary, DEA or TFA) and CO 2 . The entire amount of the sample was dissolved in ethanol and multiple injections were performed until all of the sample solutions had been used. Depending on the sample concentration and the loading limit of the column, the injection volume is between 50 μΐ and 200 μΐ. In the following examples and throughout this application, the following abbreviations have the following meanings. If not defined, the term has a generally accepted meaning. 153611.doc -65- 201130815 Abbreviation: aq. Aqueous solution DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide Et20 Ethyl ether EtOAc Eth HH HATU hexafluorophosphate 2-(1Η-7-azabenzotriazol-1-yl)-1,1,3,3-tetradecylfluorene LDA diisopropylamino lithium MeCN acetonitrile MeOH sterol min min ppt precipitation Rt retention Time RT room temperature sat. Saturated lBuOH Tert-butanol TFA Trifluoroacetic acid SEM-C1 2-(trimethyldecyl)ethoxy methane If not otherwise indicated, analytical HPLC conditions are as follows: Method LowpH_v002 Column Pyrenomenex Gemini C l 8 5〇x4.6 mm, 3.0 μπι 153611.doc ·66· 201130815 Column temperature dissolvant flow rate gradient

50 ° C

A : H20, B: methanol, both containing 0.1% TFA 1.0 ml/min 2.0 min, 5% to 95% B; 0.2 min, 95% B Method 2 min LC_v002 Column Waters BEH C 1 8 5〇χ2· 1 mm,1 ·7 μπι

Column temperature 50 ° C

Dissolving agent A : H20, B: methanol, both containing 0.1% TFA Flow rate 0·8 ml/min Gradient 0.20 min, 5% B; 1.30 min, 5% to 95%

B ; 0.25 min > 95% B Method 2minLC_30_v002 Column Waters BEH C1 8 5〇χ2· 1 mm, 1.7 μηι

Column temperature 50 ° C

Dissolving agent A : H20, B: methanol, both containing 0.1% TFA Flow rate 0.8 ml/min Gradient 0.25 min, 30% B; 1.00 min, 30 °/. To 95%

B; 0.25 min > 95% B Example Preparation Example 1.1 Trans-2-Gas-N-[4-(6-Gas-2-Sideoxy-2,3-Diazin-e-bow Bee-1 Methyl)-cyclohexyl]-5-trifluoromethyl-benzoguanamine

To a stirred solution of 6-chloro-2-hydroxyindole (commercially available) (34.2 mg, 0.204 mmol) in DMF (1 ml) was added NaH (8.16 mg, 0.204 mmol). The mixture was stirred at room temperature for 1.5 hours, followed by 4-(2-a-5-trifluoromethyl-phenylhydrazino)-cyclohexyl decyl phthalate ( intermediate 153611.doc) -67- 201130815 B) (50 mg, 0.102 mmol) in DMF (1 ml). After stirring at 50 ° C overnight, the reaction mixture was partitioned between Et EtOAc and water. The aqueous portion was separated and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water, brine, dried (MgSO4) and evaporated. The oil was purified by preparative LC-MS eluting with EtOAc (EtOAc) eluting eluting eluting . NMR NMR (400 MHz, CDC13) δ 7.90 (1H, s), 7.60 (1H, dd), 7.53 (1H, d), 7.17 (lHj d), 7.03 (lHj dd), 6.82 (1H, d), 5.99 (1H, d), 4.00 (1H, m), 3.56 (4H, m), 2.19 (2H, m), 1.81 (3H, m), 1.27 (2H, m). The following table shows examples (the compounds of Table D are prepared by a similar method, using the appropriate toluene vinegar and starting compound, the preparation of which is described below (see "Intermediate Partial. 153611.doc • 68 - 201130815 Table 1 Example 1.2 1.3 Structure

XT;

Name Reverse · 2-Gas-N-[4-(2-Sideoxy-2,3--Gasin-1-ylindenyl)-cyclohexyl]-5-trifluorodecyl·benzoquinone Amine anti-5·gas-N-[4-(3,3-dimercapto-2-yloxy-2,3·dihydro-indol-1-ylmethyl)-cyclohexyl]-2- Sulfhydryl-final amine retention time (min) lM+H]+ (method 2minLC_30_ v002)

Rt 1.3 minutes [M+H]+451.2

Rt 1.29 minutes [M+H]+ 426.2

'HNMR (400 MHz, CDC13) 5 7.90 (1H, d), 7.60 (1H, dd), 7.53 (1H, d), 7.38 (2H, m), 7.07 (1H, t), 6.85 (1H, d) , 5.98 (1H, d), 4.00 (1H, m), 3.60 (2H, m), 3.58 (2H, m), 2.19 (2H, m), 1.86 (3H, m), 1.26 (4H, m). (400 MHz, CDCI3) δ 8.5 (1H, s), 7.7 (1H, s), 7.2 (2H, m), 7.05 (1H, t), 6.85 (1H, d), 5.75 (1H, br), 3.9 (1H, m), 3.6 (2H, d), 2.65 (3H, s), 2.15(2H, br)5 1.8 (3H, m), 1.4 (6H, s), 1.25 (4H, m). Example 2.1 trans-2-gas-N-[4-(6-gas-3,3-difluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl)·cyclohexyl 】 5-Trifluoromethyl-benzamide amide treatment of 6-gas-3,3-difluoro-1,3-dihydro-oxime--2-one with NaH (22 mg '2 eq.) F) (108 mg, 2 eq.) in <RTI ID=0.0>> To this reaction was added 4-(2-a-5-tri-n-m «. ^ τ-based, benzhydryl-amino)-cyclohexylmethyl ester (intermediate C) (110 153611.doc) -69-201130815 mg, 0.265 mmol), and the reaction was heated to 50 ° C for 2 days. After cooling to room temperature, the mixture was diluted with EtOAc / H.sub.2 (20 mL) and transferred to a sep. The organic layer was separated and washed with brine, dried (MgSO4) and evaporated. The crude product was purified by EtOAc EtOAc EtOAc:EtOAc: Method LowpH_v002.1HNMR (400 MHz, DMSO) δ 8.48 (1Η, d), 7.80 (1H, dd), 7.72 (3H, d), 7.55 (1H, s), 7.3 (1H, d), 3.70 (1H, m), 3.58 (2H, d), 1.9 (2H, m), 1.65-1.8 (3H, m), 1.1-1.3 (4H, m). Example 2.2 trans-2-gas-N-[4-(3,3-dimethyl-2-oxooxy-2,3-dihydro-pyrrolo[2,3-b]"tb-pyridine-1 -ylmethyl)-cyclohexyl]_5_trifluoromethyl_benzamide

Treatment of 3,3-dimethyl-1,3-dihydro-pyrrolo[2,3-13]0 with NaH (37 mg '2 eq.) to bite 2-branche 1 (intermediate 〇) (15 〇) 1118, 2 equivalents) of a solution in anhydrous 〇]^ (2 ml) and rinsed with n2. To this reaction was added 4-(2-a-5-trifluoromethyl-benzhydrylaminocyclohexylmethyl ester (Intermediate C) (191 mg, 0·462 mmol), and The reaction was heated to 5 ° C overnight. After cooling to EtOAc EtOAc EtOAc EtOAc (EtOAc). Chromatography on ruthenium dioxide, purification of the crude product with 〇% to 3 〇% EtOAc / hexanes 161611.doc </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; H]+ 480.37. Method L〇wpH_v〇〇2. iH NMR (400 MHz, DMSO) δ 8.48 (1H,d),8_15 (1H,d), 7.80 (1H,d), 7.72 (3H,d), 7.05 (1H, t), 3.70 (1H, m), 3.58 (2H, d), 2-1: 8 (3H, m), 1.65 (2H, d), 1.3 (6H, s), 1.1-1.3 ( 4H, m). Example 2.3 Anti-5-gas-N-[4-(3,3-dimethyl-2-oxo-oxy-2,3-dihydro-pyrrolo[2,3·b]pyridine -1-ylmethyl)·cyclohexyl]_2·methyl_final amine

Treatment of 3,3-dimethyl-1&gt;3-dihydro-pyrrolo[2,3-b]pyridin-2-one (intermediate g) with NaH (12_5 mg, 1 eq.) (50 mg, 1 eq. A solution in anhydrous DMF (1 ml) and the vial was rinsed with N2. To this reaction was added 4-[(5-Gas-2-indolyl-pyridine-3-carboyl)-amino]-cyclohexylmethyl methanesulfonate (Intermediate D) (83 mg, 0.231 mmol) The reaction was heated to 50 ° C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and transferred to a sep. funnel. The organic layer was separated and washed with brine, dried (MgSO4) and evaporated. The crude product was purified by preparative EtOAc EtOAc EtOAc. Method LowpH_v002. Example 2.4 trans-2-gas·Ν·[4-(2-Sideoxy-2,3-dihydro-pyrrolo[2,3-b]pyridin-1-ylmethyl)-cyclohexyl]-5 -trifluoromethyl-benzamide 153611.doc • 71· 201130815

The 1,3-dihydro- was treated with NaH (48.5 mg, 2 eq.). A solution of [2,3-b]indolepyridin-2-one (Intermediate G, Step 2) (162 mg, 2 eq.) in dry DMF (2 mL), then rinsed with N2. To the reaction was then added 4-(2-a-5-trifluoromethyl-benzimidino)-cyclohexyldecyl methanesulfonate (Intermediate C) (250 mg, 0.362 mmol). The reaction was heated to 5 ° C overnight. After cooling to room temperature, the mixture was diluted with EtOAc / H.sub.2 (20 mL) and transferred to a sep. The organic layer was separated and washed with brine, dried (M EtOAc) and evaporated. The crude product was purified by chromatography on silica gel eluting with EtOAc/EtOAc EtOAc (EtOAc) ; [M+H]+ 452.4 Method LowpH-v002. NMR (400 MHz, DMSO) δ 8.45 (1 Η, d), 8.15 (1H, d), 7.8 (1H, d), 7.75 (2H, d), 7.6 (1H, d), 7.0 (1H, t), 3.70 (1H, m), 3.58 (2H, s), 3.55 (2H, d), 1.9 (2H, m), 1·8 (1H, m), 1.65 (2H, m), 1.1-1.3 (4H, m). Example 2.5 Trans-2-Gas-N-{-4-((5,-Fluoro-2'-Sideoxyspiro[cyclopropane·Porphyrin]-1'-yl)methyl)cyclohexyl}-5 -(trifluoromethyl)benzamide

153611.doc •72· 201130815

Treatment of 5'-fluorospiro[cyclopropane-1,3,-吲哚琳]-2'-one with NaH (60% in mineral oil) (15.12 mg, 0.378 mmol) under N2 (intermediate h (67 mg '0.3 78 mmol) in anhydrous DMF (3 ml) and the contents were stirred for about 10 minutes. After this time, 4-(2-a-5-trifluorodecyl-phenylhydrazino)-cyclohexyl decyl sulfonate (Intermediate C) (l 〇 5 mg, 0_253 mmol) was added. And the solution was heated to 70 ° C for 2.5 hours. After cooling to room temperature overnight, the mixture was diluted with EtOAc / H.sub.2 (40 ml) and transferred to a separating funnel. The organic layer was separated and washed with brine, dried (M s s 4) and concentrated in vacuo to give a pale brown oil. The crude oil was chromatographed on EtOAc EtOAc (EtOAc:EtOAc:EtOAc Rt = 1.36 min; [M+H] + 495.3; Method = 2 min LC 30_ν002 » NMR (400 MHz, CDC13). δ 7.90 (1H, s), 7.55 (1H, d), 7.50 (1H, d), 6.95 ( 1H,m), 6.80 (1H,m), 6.60 (1H, m), 5.95 (1H, d), 4.0 (1H, m), 3.65 (2H, d), 2.20 (2H, m), 1.85 (5H , m), 1.55 (2H, m), 1.25 (4H, m). The compounds of the following table (Table 2) are obtained by a method similar to that of Example 21 from the 4-(2-a-5-trifluorodecyl-benzoguanidino)-ring of m-sulfonic acid. . hexyl decyl ester (intermediate C) or trans-methanesulfonic acid 4-[(5-Ga-2-methyl-pyridine-3-ylcarbonyl)-amino]-cyclohexylmethyl ester (Intermediate D) and appropriate The hydroxy hydrazine/aza is prepared by the hydrazine, and the preparation of the hydroxy hydrazine/aza hydroxy hydrazine is described in the section "Preparation of Intermediates". Example 2.33 Reverse-5-Gas-Ν·[4-(6-Chloro-3-fluoro-3-methyl-2-oxo-2,3·Dihydro-吲哚_ 153611.doc -73- 201130815 1-ylmethyl)cyclohexyl]-2-methyl-nicotinamide

The enantiomer of 6-gas-3-fluoro-3-methyl-3-oxiline-2-yl (intermediate KF) (86 mg, 0.431 mmol) was dissolved in DMF (2.5 ml) and added One portion of NaH (18.97 mg, 0.474 mmol) was worked up. Stir the mixture for 1 ' ' and add a portion of 4-[(5-Gas-2-methyl-pyridin-3-yl)-amino]-cyclohexyl decyl sulfonate (Intermediate D) (140 mg, 0.388 mm 〇 1), and the mixture was heated at 50 ° C overnight. The solvent was removed in vacuo and the residue was partitioned between DCM and water / brine. The organic fraction was removed using a phase separator and concentrated in vacuo. Purified by reverse phase chromatography to obtain the title product

1H NMR (400 MHz, DMSO) δ 8.53 (1H, d), 8.38 (1H d), 7·78 (1H, d), 7.60 (1H, dd), 7.38 (1H, s), 7.18 (1H , dd) 3.61-3.77 (1H, m), 3.54 (2H, d), 2.46 (3H, s), 1.82-98 (2.H m), 1.6-1.8 (6H, m), 1.04-1.3 (4H , m). 19F NMR 148.76 ppm 〇 Example 2.46 Reverse-5-Gas-Ν·[4·(3·Ethyl-2·Sideoxy-2,3-dihydro-benzimidazole·i-methyl)-cyclohexyl] -2-methyl-nicotine amide

153611.doc -74· 201130815 Treatment of 1-ethyl-1,3-dihydro-benzimidazole-2·one with NaH (60% in oil) (13.30 mg, 0.333 mmol) at 1^2 The intermediate was re) (44.9 mg, 0.277 mmol) in EtOAc (EtOAc)EtOAc. Add trans-indolesulfonic acid 4-[(5-chloro-2-indolyl-pyridine-3-carbonyl)-amino]-cyclohexylmethyl ester (intermediate d) (100 mg, 0,277 mmol) at 80 ° The mixture was heated under EtOAc (3 mL) EtOAc (EtOAc) H]+ 427.25. Method LowpH__v002. 4 NMR (400 MHz, DMSO) δ 8.53 (1H, s), 8.38 (1Η, d), 7·78 (1Η, s), 7.21 (2Η, m), 7.06 (2Η, m), 3.88 (2H, m), 3.70 (3H, m), 2.46 (3H, s), 1.88 (2H, m), 1.76 (1H, m), 1.67 (2H, m), 1.20 (7H, m). Example 2.47 Reverse-5-Gas-N-[4-(3-Isobutyl-2-oxooxy-2,3-dihydrobenzimidazole_i-ylmethyl)-cyclohexyl]-2-A Nicotinamide

Treatment of 1-isobutyl-1,3-dihydro-benzopyran-2-one (intermediate r) with NaH (600/〇' in oil) (13.30 mg, 0.333 mmol) (52.7 mg, A solution of 0.277 mmol) in DMF (3 ml) was stirred at room temperature for 1 min. Add trans-methanesulfonic acid 4-[(5-chloro-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexylmethyl ester (Intermediate D) (100 mg '0.277 mmol) at 75° Heat the mixture under C 153611.doc •75- 201130815 3 hours 30 minutes. The solvent was removed in vacuo and the reaction mixture was partitioned between EtOAc (~ 40 mL) and water The aqueous portion was separated and extracted with EtOAc (20 mL). The combined organic portions were washed with saturated brine and dried (MgSO4). The solvent was removed in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Method LowpH-v002. 4 NMR (400 MHz, DMSO) δ 8.53 (1 Η, d), 8.37 (1H, d), 7.78 (1H, s), 7.20 (2H, m), 7.05 (2H, m), 3.67 (5H, m), 2.46 (3H, s), 2.11 (1H, m), 1.88 (2H, m), 1.78 (1H, m), 1.67 (2H, m), 1·17 (4H, m), 0.88 (6H, d). Table 2 Example structure name retention time (method LowpH v002) (unless otherwise specified) NMR 2.6 F trans-5-chloro-N-[-4-((5i-fluoro-2W oxy snail [cyclopropanol- 1,3^&gt;引》朵淋]_ 1·-yl) fluorenyl)cyclohexyl]-2-methylnicotinium amide 1^1=5.08 min, [M+H]+ 442.2 Method 2minLC 30 v002 'H NMR (400 MHz, CDC13) 6 8.50 (lH, s), 7.65 (1H, s), 6.95 (1H, t), 6.80 (1H, m), 6.60 (1H, d), 5.60 (1H, d ), 3.95 (1H, m), 3.65 (2H, d), 2.65 (3H, s), 2.15 (2H, m), 1.85 (5H, m), 1.50 (2H, d), 1.25 (4H, m) ° 2.7 0 —trans-2-gas-N-[4-(5-methoxy-3,3-dimethyl-2-oxo-2,3-dihydroarcho-1-yl) Base)-cyclohexyl]_5_trifluoromethyl-benzamide Rt=1.12 min; [M+H]+509.4 Method 2 min LC 30 v002 NMR (400 MHz, CDC13) δ 7.9 (1H, s), 7.60 (lH,d), 7.50 (1H, d), 6.85 (1H, s), 6.75 (2H,m), 6.0 (1H, d), 3.95 (1H, m), 3.80 (3H, s), 3.55 ( 2H, d), 2.20 (2H, m), 1.85 (3H, m), 1.40 (6H, s), 1.25 (4H, m). 153611.doc -76- 201130815 2.8 at 0^—0 anti-2·gas-Ν-[4-(6-methoxy-3,3-dimethyl-2-oxo-2,3-di Hydrogen ratio of [3,2-c]° to bit-1-ylmercapto)-cyclohexyl]-5-trihydroxyl-phenylamine Rt 1.04 min; [M+H]+510.3 Method 2 min LC 30 v002 'HNMR (400 MHz, CDC13) δ 7.9 (2H, m), 7.60 (1H, d), 7.55 (1H, d), 6.20 (1H, s), 5.95 (lH, d), 3.95 (4H, m), 3.55 (2H, d), 2.20 (2H, m), 1.80 (3H, m), 1.40 (6H, s), 1.25 (4H, m). 2.9 trans-2-gas-N-[4-((R)-3-fluoro-3-indolyl-2-yloxy-2,3-diaza-σ-d-d-l-ylmethyl) -cyclohexyl]-5·tris-decyl-benzoguanamine Rt=2.55 min; [MF]+ 463.42 JHNMR (400 MHz, DMSO) δ 8.47 (1H,d), 7.81 (1H, dd), 7.73 (2H , app d), 7.56 (1H, d), 7.43 (1H, t), 7.08-7.25 (2H, m), 3.69 (1H, m), 3.53 (2H, d), 1.83-2.0 (2H, m) , 1.6-1.8 (6H, m), 1.05-1.3 (4H, m). 2.10 trans-2-chloro-N-[4-((S)-3-gas-3-methyl-2-oxo-2,3-dihydrobone| 哚-1-ylindenyl)-cyclic Hexyl]-5-trifluorodecyl-benzoguanamine Rt = 2.55 min; [M+H] + 483.4 'HNMR (400 MHz, DMSO) δ 8.47 (1H, d), 7.79 (1H, dd), 7.73 (2H, app d), 7.58 (1H, d), 7.43 (1H, t), 7.08-7.15 (2H, m), 3.69 (lH, app m), 3.53 (2H, d), 1.85-2.0 (2H , m), 1.60-1.8 (6H, m), 1.05-1.3 (4H, m). 2.11 trans-2-gas-N-[4-(3,3-dimethyl-2-oxooxy-2,3-diaza.dol-1-ylindenyl)-cyclohexyl]-5- Trifluoromethyl-co-carboxamide Rt = 1.38 min; [M+H] + 479.2 Method 2 min LC 30 v002 'HNMR (400 MHz, CDCI3) δ 7.9 (1H, s), 7.6 (1H, d), 7.5 ( 1H, d), 7.2 (2H, m), 7.1 (1H, d), 6.85 (1H, d), 5.95 (1H, d), 4.0 (1H, m), 3.6 (2H, d), 2.2 (2H , br), 1.85 (3H, m), 1.4 (6H, s), 1.25 (4H, m). 2.12 0 Ή trans-2-gas-N-[4-(3,3-dimercapto-2-oxo-5-trifluorodecyloxy-2,3-dihydro-D-branched B-1 - fluorenyl)-cyclohexyl]-5-trifluorodecyl-benzoguanamine Rt = 1.35 min; [M+H] + 563.3 Method 2 min LC 30 v002 'HNMR (400 MHz, CDCI3) δ 7.9 (1H, s), 7.4 (lH, d), 7.5 (lH, d), 7.1 (2H, m), 6.8 (1H, d), 5.95 (1H, d), 4.0 (lH, m), 3.6 (2H, d ), 2.2 (2H, m), 1.8 (3H, m), 1.4 (6H, s), 1.3 (4H, m). 153611.doc 77- 201130815 2.13 F-Con-5-Gas-Ν-[4·(5-Fluoro-3,3-dimercapto-2-yloxy-2,3-diaza-indole-1- Methyl)-cyclohexyl]-2-indolyl-base decylamine Rt = 1.29 min; [M+H]+ 444.3 Method 2 min LC 30 v 002 NMR (400 MHz, CDC13) δ 8.50 (1H, s), 7.65 (1H, s), 6.95 (2H, m), 6.75 (1H, m), 5.6 (1H, br), 3.95 (1H, m), 3.55 (2H, d), 2.60 (3H, s), 2.15 (2H, m), 1.80 (3H, m), 1.40 (6H, s), 1.20 (4H, m). 2.14 trans-5-gas-oxime-[4-(4-methoxy-3,3-diindol-2-yloxy-2,3-dihydro-D-indol-1-ylmethyl) -cyclohexyl]-2-mercapto-nicotine decylamine Rt = 2.66 min; [M+H]+ 456.44 NMR (400 MHz, CDCI3) 6 8.48 (1H, s), 7.75 (1H, s), 7.2 (1H, t), 6.65 (1H, d), 6.5 (lH, d), 5.9 (lH, br), 3.9 (lH, m), 3.85 (3H, s), 3.55 (2H, d), 2.70 ( 3H, s), 2.15 (2H, m), 1.80 (3H, m), 1.45 (6H, s), 1.25 (4H, m). 2.15 trans-5-chloro-N-[4-(7-chloro-3,3-dimercapto-2-yloxy-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl ]-2-mercapto-alkaline decylamine Rt=2.6 min; [M+H]+ 460.38 Ή NMR (400 MHz, TFA: TFA acid set to 12.00 ppm) δ 12.95 (1H, s), 12.75 (1H, s), 11.55 (lH,d), 11.45 (lH,d),11.4(lH,t), 8.35 (2H,d),8_25 (1H, m),7.15(3H,s),6.4 (2H, s ), 6.25 (2H, s), 6.15 (2H, s), 5.65 (8H, m), 5.3 (2H, s). 2.16 aX^°^F anti-5-gas-N-[4-(3,3-difluoro-2-oxo-2,3-dihydro-0-n-l-ylmethyl)- <RTIgt; 1H, d), 7.71 (lH, d) 7.62 (lH, t), 7.34 (lH, d), 7.24 (lH, t), 3.62-3.78 (lH, m), 3.58 (2H, d), 2.46 ( 3H, s), 1.8-2.0 (2H, m), 1.6-1.8 (3H, m), 1.05-1.3 (4H, m). 2.17 % V ° ^ F trans-2-chloro-indole-[4-(3,3-difluoro-2-indolyl-2,3-dinitro 51^-1-ylmethyl)-cyclohexyl] -5-trifluoromethyl-benzoguanamine Rt = 2.56 min; [M+H] + 487.3 NMR (400 MHz, DMSO) 6 8.48 (1H, d), 7.80 (1H, dd), 7.72 (3H ,appt), 7.62(lH, t), 7.33 (1H, d), 7.24 (lH,t), 3.70(lH,m), 3.58 (2H,d), 1.85-2.00 (2H, m), 1.65- 1.8 (3H, m), 1.1-1.3 (5H, m). | 153611.doc -78- 201130815 2.18 trans-2-gas-N-[4-(7-decyloxy-3,3-dimethyl-2-oxo-2,3·diaza-σ °1_1-ylmethyl)-cyclohexyl]-5·trifluoromethyl-benzoguanamine Rt=2.64 min; [M+H]+ 509.45 *HNMR (400 MHz, DMSO) 5 8.45 (lH, d), 7.79 (1H, dd), 7.70-7.78 (3H, m), 6.95-7.08 (3H, m), 3.85 (3H, s), 3.6-3.8 (3H, m), 1.85-2.0 (2H, m), 1.6-1.7 (3H,m), 1.0-1.3( 11H, m) ° 2.19 trans-5-chloro-N-[4-((R)-3-fluoro-3-methyl-2- side Oxy-2,3-dihydroindol-1-ylindolyl)-cyclohexyl]-2-methyl-in the amine (R) = 2.42 min; [M+H] + 430.5 *HNMR (400 MHz, DMSO) δ 8.53 (1H, d), 8.35 (1H, d), 7.78 (1H, d), 7.56 (1H, d), 7.43 (lH, t), 7.1-7.24 (2H, m), 3.69 (lH , m), 3.53 (2H, d), 2.46 (3H, s), 1.8-2.0 (2H, m), 1.6-1.8 (6H, m), 1.05-1.3 (4H, m). 2.20 trans-5-gas-N-[4-((S)-3-fluoro-3-indolyl-2-yloxy-2,3-diaza_π5|indol-1-ylmethyl)- <RTIgt; 1H, d), 7.56 (1H, d), 7.43 (lH, t), 7.10-7.23 (2H, m), 3.69 (lH, m), 2.46 (3H, s), 1.8-1.97 (2H, m) , 1.6-1.8 (6H, m), 1.05-1.3 (4H, m). 2.21*. , anti--5-gas-2-methyl-indole-(4-((2-oxospiro[41 porphyrin-3,4'-piperidin]-1-yl)methyl)cyclohexyl) Nicotine decylamine Rt = 1.99 min; [M+H] + 467.48 'H NMR (400 MHz, DMSO) δ 8.55 (1H, d), 8.38 (1H, d)5 7.78 (1H, d), 7.56 (1H, d ), 7.25 (lH, t), 7.0-7.1 (2H, m), 3.69 (lH, m), 3.55 pH, d), 3.1 (2H, m), 2.9 (2H, m), 2.45 (3H, s ), 1.9 (2H, m), 1.7 (6H, m), 1.5 (2H, m) 1.15 (4H, m). 2.22 0 / trans-2-chloro-indole-[4-(6-decyloxy-3,3-diindol-2-yloxy-2,3-diaza-σ丨丨°-1- Methyl)-cyclohexyl]-5-difluoromethyl-benzoguanamine Rt=1.15 min; [M+H]+ 509.2 Method 2 min LC 30 v002 *ΗΝΜΚ(400ΜΗζ, CDC13)5 7.90(IH, s) , 7.60 (1H, d), 7.50 (1H, d), 7.10 (lH,d), 6.55 (1H, d), 6.45 (1H, s), 5.95 (1H, d), 3.95 (lH, m), 3.80 (3H, s), 3.55 (2H, d), 2.15 (2H, d), 1.80 (3H, m), 1.35 (6H, s), 1.25 (4H, m). 153611.doc •79- 201130815 2.23 trans-2-gas-5-trifluoromethyl-N-[4-(3,3,7-trimethyl-2-oxo-ylmethyl)-cyclohexyl ]-benzamide Rt=2/71 min; [M+H]+493.26 'HNMR (400 MHz, CDC13) 5 7.9 (1H, s), 7.6 (1H, d), 7.5 (1H, d), 7.1 (lH,d), 6.95 (2H, m), 5.95 (1H, d), 4.0 (1H, m), 3.85 (2H, d), 2.55 (3H, s), 2.2 (2H, d), 1.8 ( 3H,m), 1.4 (6H, s), 1.25 (4H, m) · 2.24 trans-2-gas-5-trifluoromethyl-N-[4-(3,3,4-trimethyl-2 -Sideoxy-2,3-diaza-indole 4-(4-methyl)-cyclohexyl]-benzocarbamide Rt=2.71 min; [M+H]+ 493.32 *HNMR (400 MHz, DMSO) δ 8.45 (1H, d), 7.8 (1H, d), 7.7 (2H, d), 7.15 (lH, t), 6.9 (1H, d), 6.8 (lH, d), 3.7 (lH, m), 3.5 (2H, d), 2.35 (3H, s), 1.9 (2H, m), 1.7 (3H, m), 1.35 (6H, s), 1.15 (4H, m). 2.25 aT^^,Cr&amp;trans-5-氱-N-[4-(4-Gas-3,3-dimethyl-2-oxo-2,3-dihydro-inden-1-yl) <RTIgt; , 7.75 (1H, d), 7.3 (1H, t), 7.1 (1H, d), 7.05 (1H, d), 3.65 (1H, m), 3.55 (2H, d), 2.45 (3H, s), 1.9 (2H, m), 1.7 (3H, m), 1.4 (6H, s), 1.15 (4H, m). 2.26 Cl trans-5-gas-Ν·[4-(6_gas_3,3·digas-2·sideoxy-2,3-dihydro-indolylmethyl)-cyclohexyl]-2 -Methyl-final amine Rt=2.6 min; [M+H]+ 468.23 'HNMR (400 MHz, DMSO) 6 8.55 (1H, d), 8.4 (1H, d), 7.8 (1H, d), 7.75 (1H, d), 7.55 (1H, s), 7.3 (lH, d), 3.7 (lH, m), 3.55 (2H, d), 2.45 (3H, s), 1.9 (2H, m), 1.7 (3H,m), 1.15 (4H, m) ® 2.27 trans-5-gas-2-methyl-indole-[4-(3,3,4-trimethyl-2-oxo-2,3 -Dihydro-indol-1-ylmethyl)-cyclohexyl]-nicotine decylamine Rt=2.62 min; [M+H]+ 440.35 *HNMR (400 MHz, DMSO) 5 8.55 (1H, d), 8.35 (lH,d), 7.8 (1H, d), 7.25 (lH,t), 6.95 (lH,d), 6.8 (lH,d), 3.65 (1H, m), 3.55 (2H, d), 2.45 (3H, s), 2.35 (3H, s), 1.9 (2H, m), 1.7 (3H, m), 1.35 (6H, s), 1.15 (4H, m). 153611.doc ·80· 201130815 2.28 ——0 anti-5·gas·Ν·[4-(6-decyloxy-3,3-dimercapto-2-yloxy-2,3-diaza- π 弓 1σ多············································ 1H, s), 7.65 (1H, s), 7.10 (1H, d), 6.60 (1H, d), 6.45 (1H, s), 5.65 (1H, d), 3.95 (lH, m), 3.85 (3H , s), 3.55 (2H, d), 2.65 (3H, s), 2.15 (2H, m), 1.80 (3H, m), 1.35 (6H, s), 1.25 (4H, m). 2.29 α 反-5-Gas-Ν-[4-(6-Chloro-3,3-dimethyl-2-oxo-2,3-dihydro-**#11-1-ylindenyl) )-cyclohexyl]-2-methyl-nicotinium decylamine Rt = 1 min; [M+H] + 460.1 Method 2 min LC 30 v002 'H NMR (400 MHz, CDC13) δ 8.50 (1H, s), 7.65 ( lH, s), 7.15 (1H, d), 7.05 (1H, d), 6.85 (1H, s), 5.65 (1H, d), 3.95 (lH, m), 3.55 (2H, d), 2.65 (3H , m), 2.15 (2H, m), 1.80 (3H, m), 1.40 (6H, s), 1.25 (4H, ιη). 2.30 —0 Reverse-5-Gas-Ν-[4-(6-Methoxy-3,3-dimercapto-2-yloxy-2,3-dihydro-0-pyro[3,2 -c]0-pyridin-1-ylmethyl)-cyclohexyl]-2-mercapto-nicotinamide Rt = 0.87 min; [M+H] + 457.4 Method 2 min LC 30 v002 *HNMR (400 MHz, CDCI3 ) δ 8.50 (1H, s), 7.90 (1H, s), 7.60 (1H, s), 6.20 (1H, s), 5.55 (1H, d), 4.0 (4H, m), 3.50 (2H, d) , 2.60 (3H, s), 2.15 (2H, m), 1.80 (3H, m), 1.40 (6H, s), 1.25 (4H, m). 2.31 trans-5-gas-N-[4-(3-fluoro-3,5-dimercapto-2-yloxy-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl ]-2-Methyl-alkaline decylamine Rt=2.54 min; [MF]+ 424.4 Ή NMR (400 MHz, DMSO) 5 8.53 (1H, d), 8.37 (1H, d), 7.78 (1H, d) , 7.39 (1H, s), 7.23 (1H, d), 7.06 (1H, d), 3.6-3.76 (1H, m), 3.51 (2H, d), 2.46 (3H, s), 2.30 (3H, s ), 1.85-1.98 (2H, m), 1.6-1.8 (6H, m), 1.05-1.3 (4H, m). 2.32. '于反-5-气-N-[4-(3-Fluorum λ3,5-dimethyl-2-oxo-2,3-dihydro-α-u-l-yl fluorenyl)- <RTIgt; d), 7.39 (1H, s), 7.23 (lH, d), 7.06 (lH, d), 3.6-3.8 (3H, m), 2.46 (3H, s), 2.30 (3H, s), 1.82-1.98 (2H, m), 1.58-1.8 (6H, m), 1.04-1.3 (4H, m). 153611.doc -81 - 201130815 2.33 c,x^rCr^ α anti-5-gas-Ν-[4-(6·gas-3-gas-3-methyl-2-oxo-2,3- Dihydro-hydrazinylmethyl)·cyclohexyl]-2-methyl--prodecylamine for 56 min, [MF]+ 444.3 Ή NMR (400 MHz, DMSO) δ 8.53 (1H, d), 8.38 ( 1H, d), 7.78 (1H, d), 7.60 (1H, dd), 7.38 (lH, s), 7.18 (lH, dd), 3.61-3.77 (lH, m), 3.54 (2H, d), 2.46 (3H, s), 1.82-98 (2H5m), 1.6-1.8 (6H, m), 1.04-1.3 (4H, m). 2.34 Cl Reverse-5-Gas-Ν·[4-(6-Ga-3-ox-3-methyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)· Cyclohexyl]-2-methyl-in the arsenic amine Rt=2.56 min; [MF]+ 444.3 Ή NMR (400 MHz, DMSO) δ 8.53 (1H, d), 8.38 (1H, d), 7.78 (1H, d), 7.60 (1H, dd), 7.38 (1H, s), 7.18 (1H, dd), 3.61-3.77 (1H, m), 3.54 (2H, d), 2.46 (3H, s), 1.84-98 (2H, m), 1.6-1.8 (6H, m), 1.05-1.3 ' (4H, m). 2.35 trans-2-gas-oxime-[4-(5-methoxy-1-oxo-oxy-3,4-dihydro-1 fluorene-isoquinolin-2-ylindenyl)-cyclohexyl]_5_ Tri-(indolyl)-benzamide Rt = 1.33 min; [M+H] + 495.3 Method 2 min LC 30 v002T NMR (400 MHz, CDC13) δ 7.99 (1H, d), 7.68 (1H, d), 7.61 ( 1H, dd), 7.53 (lH,d), 7.31 (1H, t), 7.00 (1H, d), 6.04 (1H, d), 4.00 (1H, m), 3.87 (3H, s), 3.57 (2H , t), 3.44 (2H, d), 2.99 (2H, t), 2.19 (2H, m), 1.90 (2H, m), 1.83 (lH, m), 1.25 (4H, m). 2.36 trans-2-gas-N-[4-(3-o-oxy-3,4-diIl-IH-isoquinoline-2-ylmethyl)cyclohexyl]·5-trifluoromethyl-benzene Invitrogen Rt = 1.28 min; [M+H] + 465.3 Method 2 min LC 30 v002 *H NMR (400 MHz, CDCb) δ 7.9 (1H, s), 7.6 (1H, d), 7.55 (1H, d), 7.25 (3H, m), 7.2 (2H, m), 5.95 (lH, br), 4.5 (2H, s), 3.95 (1H, m), 3.65 (2H, s), 3.4 (2H, d), 2.15 (2H, br), 1.8 (3H, br), 1.2 (4H, m) 0 2.37 FF trans-5-gas-2-methyl-indole-[4-(3,5,6-trifluoro-3- Methyl-2. oxo-2,3-dihydro-c-indole-1-ylindenyl)-cyclohexyl]-base base amine----- Rt=2.49 min; [MF]+ 446.4 NMR NMR (400 MHz, DMSO) δ 8.53 (1H, d), 8.38 (lH,d), 7.86 (1H, app t), 7.78 (1H, d), 7.48 (1H, dd), 3.6-3.77 (1H , m), 3.51 (2H, d), 2.46 (3H, s), 1.82-1.97 (2H, m), 1.6-1.8 (6H, m), 1.03-1.32 (4H, m). 153611.doc -82- 201130815 2.38 FF trans-5-chloro-2-methyl-indole-[4-(3,5,6-trifluoro-3-indolyl-2-yloxy-2,3- Nitrogen-°bendo-1·ylmercapto)-cyclohexyl]-in the case of the decylamine Rt=2.49 min; [MF]+ 446.3 *H NMR (400 MHz, DMSO) 5 8.53 (lH,d), 8.38 (1H, d), 7.86 (1H, appt), 7.78 (lH,d), 7.48 (1H, dd), 3.6-3.75 (1H, m), 3.51 (2H, d), 2.46 (3H, s) , 1.84-1.96 (2H, m), 1.6-1.8 (6H, m), 1.03-1.3 (4H, m). 2*39 anti-5-gas-2-mercapto-N-[4-(2-o-oxy-oxazolo[4,5-b].pyridin-3-ylindenyl)-cyclohexyl] - Nicotine amine Rt = 2.37 min; [M+H] + 401.31 NMR (400 MHz, DMS0) 6 8.52 (1H, d), 8.39 (lH, d), 8.12 (1H, q), 7.79 (lH , d), 7.71 (1H, q), 7.19 (lH5q), 3.70 (3H, m), 2.47 (3H, s), 1.90 (3H, m), 1.72 (2H, m), 1.20 (4H, m) o 2.40 0 〇trans-5-gas-2-methyl-N-[4-(2-oxo-benzoxazol-3-ylmethyl)-cyclohexyl]-nicotinium amide Rt=2.47 [M+H]+400.34 Ή NMR (400 MHz, DMSO) 6 8.52 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 7.32 (2H, d), 7.21 (lH, t), 7.12 (lH,t), 3.70 (3H, m), 2.48 (3H, s), 1.90 (2H,m), 1.80 (lH,m), 1.71 (2H,m), 1.20 (4H, m ). 2.41 Reverse-5-Gas-N-[4-(3,6-Dimercapto-2-yloxy-2,3-dihydro-imidazo[4,5-b]pyridin-1-ylmethyl )-cyclohexyl]-2-mercapto-nicotinamide Rt=2.41 min; [M+H]+ 428.54 NMR (400 MHz, DMS0)5 8.52 (1H, d), 8.39 (1H, d), 7.81 (1H, s), 7,79 (1H, d), 7.42 (lH, s), 3.67 (3H, m), 3.31 (3H, s), 2.48 (3H, s), 2.31 (3H, s) , 1.90 (2H, m), 1.74 (1 H, m), 1.67 (2H, m), 1.18 (4H, m) ° 2.42 anti-5-chloro-N-[4-(3-ethyl-2- The pendant oxy-2,3-dihydro-imidazo[4,5-c] 0 is more than -1-ylmethyl)-cyclohexyl]-2-methyl-nicotinium amide Rt = 1.85 min; M+H]+428.33 Ή NMR (400 MHz, DMSO) 5 8.89 (1H, br), 8.59 (1H, br), 8.52 (lH,d), 8.40 (1H, d), 7.90 (lH,br), 7.79 (1H, d), 4.01 (2H, q), 3.88 (2H, d), 3.69 (lH, m), 2.48 (3H, s), 1.90 (2H, m), 1.79 (lH, m), 1.69 (2H, m), 1.29 (3H, t), 1.20 (4H, m). 153611.doc • 83 - 201130815 2.43 - trans-5-gas-N-[4-(3,7-dimethyl-2-oxo-2,3-dihydro-imidazo[4,5- b]pyridinyl hydrazinyl)-cyclohexyl]·2_mercapto-nicotine decylamine Rt=2.38 min; [M+H]+ 428.32 *HNMR (400 MHz, DMSO) δ 8.52 (1H, s), 8.39 (1H, d), 7.89 (1H, d), 7.79 (1H, s), 6.89 (1H, d), 3.85 (2H, d), 3.70 (lH, m), 3.31 (3H, s), 2.51 (3H, s), 2.48 (3H, s), 1.90 (2H, m), 1.68 (3H, m), 1.20 (4H, m). 22.44 - trans-5-gas-N-[4-(3,5-dimercapto-2-yloxy-2,3-diargon-»myzolo[4,5-b]pyridine-1-曱 ))-cyclohexyl]-2-methyl-nicotinium amide Rt = 2.41 min; [M+H]+ 428.33 *HNMR (400 MHz, DMSO) δ 8.52 (1H, s), 8.39 (1H, d), 7.79 (1H, d), 7.45 (1H, d), 6.91 (lH, d), 3.69 (3H, m), 3.31 (3H, s), 2.47 (3H, s), 2.42 (3H, s ), 1.89 (2H, m), 1.73 (lH, m), 1.68 (2H, m), 1.19 (4H, m) ° 2.45 0 anti-5-gas-N-[4-(l,5-dioxin Benzyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylindoleyl-cyclohexyl]-2-methyl-nicotinium decylamine Rt=2.43 min ; [M+H]+428.27 *HNMR(400 MHz, DMSO) δ 8.53 (1H, s), 8.37 (1H, d), 7.78 (1H, s), 7.38 (1H, d), 6.93 (1H, d ), 3.70 (3H, m), 3.33 (3H, s), 2.47 (3H, s), 2.45 (3H, s), 1.86 (3H, m), 1.66 (2H, m), 1.17 (4H, m) . 2.46 〇人) Reverse-5-gas-N-[4-(3-ethyl-2-oxo-2,3-dihydro-benzimidazol-1-ylindenyl)-cyclohexyl]-2 - mercapto-nicotine decylamine Rt = 2.53 min; [M+H]+427.25 NMR (400 MHz, DMSO) δ 8.53 (1H, s), 8.38 (1H,d), 7.78 (1H, s), 7.21 (2H, m), 7.86 (2H, m), 3.88 (2H, m), 3.70 (3H, m), 2.46 (3H, s), 1.88 (2H, m), 1.76 (lH, m), 1.67 (2H, m), 1.20 (7H, m). 2.47 0 c,X^rCr5 trans-5-gas·Ν-[4-(3-isobutyl-2-oxo-2,3-diargon-benzoimidazol-1-ylindenyl)-ring Benzyl]-2-methyl-in the amine (R)=2.64 min; [M+H]+455.33 NMR (400 MHz, DMSO) δ 8.53 (1H, d), 8.37 (lH,d), 7.78 (1H , s), 7.20 (2H, m), 7.05 (2H, m), 3.67 (5H, m), 2.46 (3H, s), 2.11 (1H, m), 1.88 (2H, m), 1.78 (1H, m), 1.67 (2H, m), 1.17 (4H, m), 0.88 (6H, d). 153611.doc -84- 201130815 2.48 0 0 \ 反-5-Gas-Ν-[4-(5-Methoxy-3-mercapto-2-yloxy-2,3-dihydro-MM 0 sit And [4,5-b]°tb biti-1-ylmethyl)-cyclohexyl]-2-mercapto-nicotinamide Rt=2.48 min; [M+H]+444.27 NMR (400 MHz, DMSO) δ 8.53 (1H, s), 8.38 (1H, d), 7.78 (1H, s), 7.56 (1H, d), 6.48 (lH, d), 3.86 (3H, s), 3.67 (3H, m ), 3.31 (3H, s, N-CH3 is assumed to be under water signal), 2.46 (3H, s), 1.89 (2H, m), 1.73 (1H, m), 1.66 (2H, m)? 1.17 (4H, m). 2.49 trans-5-gas-2-methyl-N-[4-(3,3,5-trimethyl-2-oxo-2,3-dihydro-indol-1-ylindenyl) -cyclohexyl]-nicotine decylamine Rt = 2.64 min; [M+H]+440.41 NMR (400 MHz, DMSO) 5 8.52 (1H, s), 8.39 (1H, d), 8.39 (1H, d) , 7.78 (lH, s), 7.18 (1H, s), 7.03 (1H, d), 6.96 (1H, d), 3.68 (1H, m), 3.51 (2H, cl), 2.48 (3H, s), 2.30 (3H, s), 1.90 (2H, m), 1.71 (1H, m), 1.68 (2H, m), 1.29 (6H, s), 1.14 (4H, m). 2.50 0 0 person / trans-5-gas-2-mercapto-N~ [4-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-ylindenyl) -cyclohexyl]-nicotine decylamine Rt = 2.47 min; [M+H]+413.33 NMR (400 MHz, DMSO) δ 8.53 (1H, s), 8.38 (1H, d), 7.78 (1H, s) , 7.21 (lH, m), 7.14 (1H, m), 7.06 (2H, m), 3.68 (3H, m), 3.32 (3H, s), 2.46 (3H, s), 1.89 (2H, m), 1.76 (1.H, m), 1.67 (2H,m), 1.18 (4H, m) 〇2.51 anti-5-gas-2-methyl-N-[4-(1-methyl-2- side oxygen Base-1,2-dihydrocarbazolo[4,5-b]»pyridin-3-ylindenyl)-cyclohexyl]-final amine Rt=2.5 min; [M+H]+414.4 Ή NMR (400 MHz, DMSO) δ 8.54 (1H, s), .8.38 (1H, d), 7.99 (1H, d), 7.79 (1H, s), 7.50 (1H, d), 7.08 (1H, t) , 3.74 (2H, d), 3.70 (1H, m), 3.36 (3H, s), 2.47 (3H, s) 1.88 (3H, m), 1.67 (2H, m), 1.17 (4H, m). 153611.doc 85- 201130815 2.52 trans-N-[4-(3,3-dimethyl-2-oxo-2,3-diaza-°0--1-ylindenyl)-cyclohexyl ]-2-mercapto-5·trifluoromethyl-nicotinamide Rt=2.64 min; [M+H]+460.38 'H NMR (400 MHz, CDC13) δ 8.90 (1H, d), 8.48 (1H , d), 8.01 (1H, d), 7.33 (1H, m), 7.27 (1H, m), 7.08 (2H, m), 3.70 (1H, m), 3.52 (2H, d), 2.59 (3H, s), 1.92 (2H, m), 1.72 (1H, m), 1.69 (2H, m), 1.30 (6H, s), 1.17 (4H, m). 2.53 0 human 〇NH trans-5-gas-2-mercapto-N-[4-(2-o-oxy-2,3-di-argon-benzimidazole·l-ylmethyl)-cyclohexyl]- Nicotine decylamine Rt = 2.43 min; [M+H] + 399.91 NMR (400 MHz, DMSO) δ 10.81 (1H, s), 8.53 (1H, s), 8.39 (lH, d), 7.79 (lH, s), 7.15 (1H, d), 6.99 (3H, m), 3.68 (3H, m), 2.47 (3H, s), 1.90 (2H, m), 1.75 (lH, m), 1.67 (2H, m ), 1.19 (4H, m). 2.54 trans-5-gas-N-[4-(3-fluoro-3,5,6-trimethyl-2-oxo-2,3-dihydro-indenyl-l-ylmethyl)- Enantiomer 1 of cyclohexyl]-2-methyl-nicotinium amide 1 Rt = 2.52 min; [M-F+] 438.38 NMR (400 MHz, CDCI3) 8.47 (1H, s), 7.74 (lH, s), 7.20 (1H, s), 6.64 (1H, s), 5.93 (1H, bs), 3.85-4.01 (lH, m), 3.44-3.63 (2H, m), 2.68 (3H, s), 2.32 (3H, s), 2.27 (3H, s), 2.08-2.19 (2H, m), 1.75-1.91 (3H, m), 1.59 (3H, s), 1.15-1.37 (4H, m)0 2.55 Anti- 5-Chloro-N-[4-(3-fluoro-3,5,6-trimethyl-2-oxo-2,3-dihydro-. 丨 朵 -1- 1-yl fluorenyl)- The enantiomer of cyclohexyl]-2-methyl-alkaline amide 2 1^==2.52 min, [M-F+J438.36 Ή NMR (400 MHz, CDCI3) 8.48 (1H, s), 7.67 (1H, s), 7.28 (1H, s), 6.64 (1H, s), 5.74 (1H, bs), 3.87-4.01 (1H, m), 3.45-3.63 (2H, m), 2.64 (3H, s), 2.32 (3H, s), 2.27 (3H, s), 2.08-2.19 (2H, m), 1.75-1.91 (3H, m), 1.59 (3H, s), 1.14-1.36 (4H, m) . 153611.doc 86- 201130815 2.56 trans-5-chloro-indole-[4-(7-methoxy-3,5-dimethyl-2-oxo-2,3-dihydro-imidazo[4] ,5-b]pyridin-1-ylindenyl)-cyclohexyl]-2-indenyl-base decylamine Rt=2.52 min; [M+Hf 458.44 *H NMR (400 MHz, DMS0)5 8.52 (1H , s), 8.38 (1H, d), 7.79 (1H, s), 6.82 (1H, s), 3.95 (3H, s), 3.78 (2H, d), 3.69 (lH, m), 3.31 (3H, s), 2.47 (3H, s), 2.40 (3H, s), 1.90 (2H, m), 1.70 (1H, m), 1.61 (2H, m), 1.18 (4H, m). 2.57 trans-5·chloro-N-[4-(3,3-dimercapto-2·sideoxy-2,3-diaza·σpiro[3,2-7]acridin-1-yl曱 ))-cyclohexyl]-2-methyl-alkaline amine Rt=2.33 min; [M+H]+427.39 Ή NMR (400 MHz, DMSO) δ 8.55 (1H, d), 8.40 (1H, d ), 8.21(1H, d), 7.81 (1H, cl), 7.64 (1H, d), 7.39 (1H, m), 3.68 (1H, m), 3.59 (2H, d), 2.47 (3H, s) , 1.89 (2H, m), 1.70 (3H, m), 1.34 (6H, s), 1.17 (4H, m). 2.58 /°trans-5-gas-oxime-[4-(2-decyloxy-9-fluorenyl-8-p-oxy-8,9-dihydro-indol-7-ylindenyl)-cyclo Benzyl]-2-mercapto-yttrium amine Rt=2.29 min; [M+H]+445.35 Ή NMR (400 MHz, DMSO) δ 8.53 (1H, s), 8.39 (1H, d), 8.21 (1H , s), 7.80 (1H, d), 3.90 (3H, 6), 3.69 (3H, m), 3.30 (3H, s), 2.48 (3H, s), 1.90 (2H, m), 1.75 (lH, m), 1.69 (2H, m), 1.19 (4H, m). 2.59 α-trans-5-chloro-indole-[4-(2-gas-9-fluorenyl-8-oxo-8,9-diaza-indol-7-ylmethyl)-cyclohexyl]_2 - mercapto-yield amine Rt = 2.37 min; [M+H] + 449.29 NMR (400 MHz, DMSO) δ 8.52 (1H, d), 8.41 (1H, s), 8.39 (1H, d), 7.79 (1H, d), 3.72 (2H, d), 3.69 (1H, m), 2.51 (3H, s), 2.47 (3H, s), 1.89 (2H, m), 1.78 (1H, m), 1.71 (2H, m), 1.19 (4H, m). * Prepared from 2-tertyloxyspiro[porphyrin-3,4·-piperidine]-indole-decanoic acid tert-butyl ester, followed by removal of the protecting group with TFA/DCM to afford Example 2.21. Example 3.1 Anti-2-gas-Ν·[4_(5-gas-2-oxo-2,3-diaza-°bend-1-ylmethyl)-cyclohexyl]_5·trifluoromethyl Benzobenzamide 153611.doc -87 - 201130815

Add NaH (8.55 mg, 0.214 mmol) to a stirred solution of 5_ chloropyridinium (commercial) (35.8 mg, 0.214 mmol) in DMF (2 mL). Next, using trifluoro-m-acid 4-(2- gas-5-trifluoromethyl) benzhydrylamino) cyclohexyl methyl ester (intermediate E) (5 〇 mg, 〇·107 mm〇l )deal with. After stirring at room temperature for 1 hour, dilute the mixture with water and 〇Ac (3x2G for extraction. Wash with water, brine, and organic extract, dry (MgS〇4) and concentrate in vacuo to give orange. The oil was purified by preparative LC-MS to give the title compound LC MS Rt 1.36 min; MS m/z 485·2 [M+H]+; method min LC-3 〇 ν 〇〇 。 。 。 4〇〇MHz, cdc13) δ 7 columns (out, )' · 61 (1H, dd), 7.53 (1H, d), 7.26 (2H, m), 6.77 (1H, d), (1H, d), 4.00 (1H, m), 3.56 (4H, m), 2.19 (2H, m), 1,82 (3H, m), 1.25 (2H, m). The compounds listed in the table (Table 3) are Similar to Example 31, using the appropriate difluoromethanesulfonate and hydroxyhydrazine starting compounds, the preparation of starting compounds such as 27 is described below (see the "Intermediate" section). 15361 l. Doc •88- 201130815 Table 3 I Example structure name retention time (min), [M+H]+ (method LowpH v002) (unless otherwise specified) HNMR 3.2 F trans-2-gas-N-[4-( 6-fluoro-2-indolyl-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-5-di Mercapto-benzoguanamine Rt 1.32 min [M+H]+469.2 (Method 2 min LC 30 v002) (400 MHz, CDC13) δ 7.90 (lH,d), 7.61 (1H, dd), 7.53 (1H, d) , 7.20 (1H, dd), 6.74 (1H, m), 6.58 (1H, dd), 6.02 (1H, d), 4.00 (1H, m), 3.54 (4H, m), 2.20 (2H, m), 1.83 (3H,m), 1.27 (4H, m) 3.3 F trans-2-chloro-indole-[4·(5-say-3,3·dimethyl-2-oxo-2,3·3· Dinitro-D-inducing σ-l-yl-yl)-cyclohexyl]-5-trifluorodecyl-benzoguanamine Rt 1.18 min [M+H]+497.4 (Method 2 min LC 30 v002) (400 MHz, CDC13) δ 7.9 (1H, s), 7.6 (1H, d), 7.5 (1H, d), 6.95 (2H, m), 6.75 (1H, m), 6.1 (lH, d), 3.95 (1H, m ), 3.55 (2H, d), 2.15 (2H, m), 1.8 (3H, m), 1.4 (6H, s), 1.35 (4H, m). 3.4 0 trans-2-gas-oxime-[4-(3-ethyl-2-oxo-2,3-dihydro-benzimidazol-1-ylmethyl)-cyclohexyl]-5-three Fluorinyl-benzoguanamine Rt 2.56 min [M+H]+ 480.36 (400 MHz, DMSO) δ 8.48 (1H, d), 7.81 (1H, m), 7.72 (2H, m), 7.22 (2H, m), 7.05 (2H, m), 3.88 (2H, q), 3.69 (3H, m), 1.90 (2H, m), 1.74 (1H, m), 1.65 (2H, m), 1.23 (7H, m ). 3.5 0 F 〇r〆trans-2-gas-Ν-[4-(3-mercapto-2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl曱))-cyclohexyl]-5-trifluoromethyl-benzamide Rt 2.47 min [M+H]+ 467.32 (400 MHz, DMSO) δ 8.49 (1H, d), 7.98 (1H, d), 7.81 (lH,m), 7.62 (2H, m), 7.55 (lH,d), 7.07 (1H, m), 3.72 (2H, d), 1.91 (2H, m), 1.75 (lH,m), 1.68 (2H, m), 1.18 (4H, m). 153611.doc 89- 201130815 3.6 trans-2-gas-Ν-[4-(1·methyl-2-oxooxy-1,2-dihydro-&quot;miazolo[4,5-b]. Bispin-3-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide Rt 2.47 min [M+H]+ 467.32 (400 MHz, DMSO) δ 8.46 (1H, d), 7.98 (1H, m), 7.80 (1H, m), 7.73 (2H, m), 7.49 (1H, m), 7.08 (1H, m), 3.73 (2H, d), 3.70 (1H, m), 3.35 ( 3H, s), 1.91 (2H, m), 1.86 (lH, m), 1.67 (2H, m), 1.17 (4H, m). 3.7* trans-2-gas-oxime-[4·(2-o-oxy-2,3-dihydro-benzimidazol-1-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzene Methionine Rt 2.51 min [M+H]+ 452.3 (400 MHz, DMSO) δ 10.80 (1H, s), 8.47 (1H, d), 7.79 (1H, m), 7.73 (2H, m), 7.14 ( lH,m), 6.99 (3H, m), 3.70 (1H, m), 3.65 (2H, d), 1.91 (2H, m), 1.75 (1H, m), 1.67 (2H,m), 1.18 (4H , m) o 3.8 trans-2-gas-Ν-[4-(3-mercapto-2-epoxy-2,3-diqi_stigmidazol-1-ylmethyl)-cyclohexyl]- 5-Trifluoromethyl-benzoguanamine Rt 2.55 min [M+H]+ 466.54 (400 MHz, DMSO) δ 8.48 (1H, d), 7.80 (1H, d), 7.73 (2H, d), 7.20 (lH,m), 7.14 (lH,m), 7.05 (2H, m), 3.32 (1H, s), 1.89 (4H, m), 1.77 (lH, m), 1.68 (4H, m). | * This compound is based on 4-(2-a-5-trifluoromethyl-benzylidenylamino)-cyclohexylmethyl ester of trifluoromethanesulfonate (Intermediate E) and 2-oxooxy Preparation of -2,3-dihydrobenzoimidazole-1-carboxylic acid tert-butyl ester (intermediate rF). The protecting group was then removed with 4 μl of HC1/dioxane/MeOH to give the final compound. Example 4.1 trans-4-fluoro-N-[4-(3-methyl-2-oxo-2,3-dihydrobenzimidazolylmethyl)-cyclohexyl]-3-trifluoromethyl -benzimidamide trifluoroacetate

Treatment of 4·fluoro-3-trifluoromethylbenzoic acid (〇1〇1 mm〇1) with DIPEA (81 μb 〇 461 mmol) and HATU (52.8 mg, 0.139 mmol) in 153611.doc •90 · 201130815

To a solution of oxazol-2-one hydrochloride (R.sub.r. r.r.) (15 mg. The solvent was removed in vacuo. The residue was dissolved in DCM (2 ml) and washed with water (2 ml). The organic portion was passed through a phase separation column and concentrated in vacuo. The residue was dissolved in DMSO and purified by preparative LC-EtOAc eluting with EtOAc (EtOAc (EtOAc) (EtOAc) /z 450.3 [M+H]+ ; Method 2minLC_v003. Example 4.2 trans-2,5-di-gas-N-[4-(3-methyl-2-oxo-2,3-dihydro-benzimidazole-l-ylmethyl)-cyclohexyl]- Phenylguanamine trifluoroacetate

This compound was prepared by substituting the appropriate acid for 4- fluoro-3-trifluoromethyl-benzoic acid as in Example 4.1; LC-MS Rt 1.18 min; MS m/z 432.2 [M+H]+; Method 2minLC_v003. Example S.1 trans-N-[4-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-4-fluoro -3·trifluoromethyl-benzamide 1536H.doc • 91- 201130815

F F

1-(4-Amino-cyclohexylmethyl)- 3,3-diindenyl-i,3-dihydro-indol-2-one (intermediate RQ) (20 mg, 0.073 mmol) in DMF A solution of 4-fluoro-3-trifluoromethyl-benzhydrazide (33.3 mg '0.147 mmol) in DCM (367 μM) was taken from a solution of 467 μM) and pyridine (29.7 μM). The reaction mixture was shaken overnight at room temperature. The mixture was filtered and purified by preparative LC-EtOAc eluting eluting eluting eluting eluting eluting eluting ]+ ;Method 2minLC v003 〇Example 5.2 Anti-2,5·Digas-Ν-[4·(3,3-Dimethyl-2-oxo-2,3-dihydro·吲哚·1- Methyl)-cyclohexyl]-benzamide

This compound was prepared analogously to Example 5.1 by substituting the appropriate acid gas for 4-fluoro-3-trifluoromethyl-benzhydrazide; LC-MS Rt 1.28 min; MS m/z 445.2 [M+H ]+ ; Method 2minLC_v003. Example 5.3 trans-N-[4-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-3-methoxy -benzamide 153611.doc •92· 201130815 This compound was prepared analogously to Example 5.1 by substituting the appropriate acid gas for 4-fluoro-3-trifluoromethyl-benzoquinone; LC-MS Rt 1.2 min; MS m/z 407.3 [M+H]+;

Preparation of intermediates Intermediate A trans-toluene-4-sulfonic acid 4-[(5-Ga-2-methyl-pyridine-3-carbonyl)-aminobicyclohexyl methyl ester

Step 1: 5 -Chloro-2-methyl final test gas 5 - gas-2-mercapto-nicotinic acid (4.15 g, 24.2 mmol) in DCM (100 ml) and ethylene dichloride ( 3.68 g, 29 mmol) in a flask. DMF (200 μM) was added, and the reaction mixture was stirred at room temperature for 1 hour (gas evolution). The mixture was filtered and the solvent was evaporated in vacuo tolululululululululululululu Carbonyl)-amino]-cyclohexanecarboxylic acid decyl ester The trans-4-amino-cyclohexane decanoate (commercially available) (2.14 g, 11.05 mmol) was suspended in THF (50 ml) and Et3N (2.79) g, 27.6 mmol), and cooled to 0 °C. 5-Ga-2-methylnicotinium helium (step l) (2.20 g, 11.05 mmol) was slowly added portionwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and 1 M EtOAc. Water and 153611.doc -93· 201130815

The organic phase was washed with brine, dried (MgSO.sub.4), filtered and evaporated in vacuo to afford the product, which was used in the next step of &lt;RTI ID=0.0&gt; , d), 7.42 (1H, 5), 7·80 (1Η, d), 3·7〇 (1Η, m), 3.60 (3Η, s), 2.49 (3Η, s), 2.29 (1H, m) , 1.95 (4H, m), 1.42 (2H, m), 1.29 (2H, m); [M+H]+ 311.26. Step 3: Reverse-5-gas·Ν-(4-hydroxyindolyl-ring Benzyl) 2 -indolyl-nicotine decylamine will be trans-4-[(5-Gas-2-methyl-pyridine-3-methylcarbonylaminocyclohexanecarboxylic acid methyl ester (Step 2) (2.20 g, 7.08 mmol The mixture was placed in a flask containing anhydrous THF (100 ml). The mixture was cooled to hydrazine, and lithium aluminum hydride (yield 37 g ' 14.16 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then with water (0.5 ml), 2 M NaOH (0.5 ml) was quenched and then quenched with water (1·5 ml). The solid was filtered from Celite® (filter material) and the filtrate was partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give Further purification was used in the next step. 1H NMR (400 MHz, DMSO-^6) δ 8.53 (1 Η, d), 8.38 *1H, d), 7.79 (1H, d), 4.40 (1H, t), 3.66 (1H, m), 3.21 (2H, t), 2.47 (3H, s), 1.92 (2H, m), 1.78 (2H, m), 1.31 (1H, m), 1.22 (2H, m), 0.98 (2H, m).[M+H]+ 283.30 〇Step 4: 4-[(5-Gas-2-methyl-pyridin-3-carbonyl)-amino]-cyclo---toluene-4-sulfonic acid Benzylmethyl ester to trans-5-gas-N-(4-hydroxymethyl-cyclohexyl)-2-mercapto-nicotinium amide (Step 3) (250 mg, 0.884 mmol) in DCM (4 ml) In a stirred solution 153611.doc •94- 201130815 Add 0 to bite (1 ml) 'then add toluene helium (253 mg, 1.326 mmol). Mix the reaction mixture overnight at room temperature, then dilute with dcm The mixture was washed with 1 M HCl, water, brine, dried (MgSO.sub.4) and concentrated in vacuo to afford a pale yellow solid. The solid was sonicated in 1:5 jgtOAc: aliquots and EtOAc was added until all solids became a solution. Isohexane was carefully added to obtain a cloudy suspension which was collected by filtration to give the title compound. MS m/z 437.2 [M+H] + ; *H NMR (400 MHz, CDC13) δ 8.50 (1H, d), 7.80 (2H, d), 7.63 (1H, d), 7.39 (2H, d), 5.70 (1H, d), 3.89 (1HS m) , 3.84

(2H, d), 2.63 (3H, s), 2.48 (3H, s), 2.13 (2H, m), 1.85 (2HS m), 1.71 (1H, m), 1.23 (2H, m), 1.11 (2H m) 〇Intermediate B trans-toluene-4-sulfonic acid 4-(2- gas-5-trifluoromethyl-phenylhydrazinoylcyclohexylmethyl ester Step 1: Reverse -4- (2-gas -5-trifluoromethyl-benzhydrylamino)-cyclohexanol tartrate

Triethylamine (12 ml, added to a stirred suspension of trans-4-amino-cyclohexylformic acid methyl acetate (6,7 g '34.7 mmol) in dry THF (90 ml) 86.8 mmol). The suspension was cooled to 〇〇c, and 2-chloro-5-(trifluoromethyl)benzoquinone (8.85 §, % 4 153611.doc -95-201130815 mmol) was added dropwise over 2 Torr. Solution in THF (40 ml). At 〇-5. (: The resulting colorless thick slurry was stirred for 30 minutes) and then allowed to warm to room temperature and stirred at room temperature for 1 hour. A solution of water (5 ml) in THF (45 ml) was added dropwise. Quenching the reaction to obtain a clear solution. Dilute the solution with water (100 ml) and ethyl acetate (300 mi). The biphasic mixture was stirred for 5 minutes, then the organic phase was separated and successively water (100 ml), sat. Wash 1 ml) and saturated brine (100 ml), dry (MgSO4), filtered and evaporated to give a colorless solid: [M+H]+ 364. Step 2: ·Hydroxymethyl-cyclohexyl)_5_trifluoromethyl-benzoquinone

To a solution of trans-4-(2-a-5-trifluoromethyl-benzohydrazino)-cyclohexanecarboxylate (step 1) (95.2 g) at 0 ° C under nitrogen for 3 h. , 0.26 mol) A solution of lithium aluminum hydride pellet (2 〇g, 0.53 mol) was added portionwise in a solution of anhydrous THF (1 L). The reaction mixture was stirred at 0 ° C for an additional 2 hours, followed by hydrazine. The crucible was carefully quenched by the addition of water (40 ml) in THF (60 mL) then THF (500 mL) to maintain a mobile suspension. Finally, 1 Μ sodium hydroxide solution (8 〇 ml) was added at 0 ° C to produce a yellow solution containing a colorless suspension. The reactants were filtered through Celite® (transition material) to remove inorganic salts. The Celite® pad/salt was washed sequentially with EtOAc (500 mL) and EtOAc: THF (1:1; 300 ml). The organics were combined and diluted with EtOAc (EtOAc) (EtOAc) The dried (NazSO4) organic layer was filtered and concentrated under reduced pressure until a slurry was obtained. EhO was added to the slurry of 153611.doc -96 - 201130815, followed by stirring for 5 minutes, followed by filtration to recover a colorless solid. The solid was washed with isohexane followed by 35. The underarm is dried under vacuum to obtain the desired product. Step 3: trans-2-chloro-N-(4-hydroxymethyl) 4-(2-chloro-5-trifluoromethyl)benzylamino-cyclohexyldecyl ester -cyclohexyl)-5-trifluoromethyl-benzamide (Step 2) (1§, 2.98 111111〇1) is added to a mixture of 〇0^(12 1111) and pyridine (3.〇0 ml) . Add hydrazine sulfonate (〇 852 g, 4 47 Stir the mixture at room temperature. After dilution with DCM 'wash the mixture with 1 M HCl, water, brine, dry (MgS 〇 4) and concentrate in vacuo to give Yellow solid. The solid was triturated with EtOAc EtOAc EtOAc (EtOAc:EtOAc) δ 8.49 (1H, d), 7.80 (3H, m), 7.74 (2H, m), 7.50 (2H, m), 3.85 (2H, d), 3.62 (1H, m), 2.43 (3H, s), 1.89 (2H, m), 1.66 (2H, m), 1.58 (1H, m), 1.21 (2H, m), 1·〇2 (2H, m).

Intermediate C trans-methanesulfonic acid 4-(2-a-5-trifluoromethyl·benzimidyl)-cyclohexyl decyl ester to give trans-2-chloro-N-(4-hydroxyindolyl-ring Hexyl) _5·trifluoromethyl _ benzomethamine (Intermediate B 'Step 2) (1 g ' 2.98 mmol) was suspended in DCM (25 ml). THF (6 ml) was added to dissolve the alcohol. It was cooled to and treated with triethylamine (0.623 m, 4.47 mmol), then methanesulfonate (0.255 m, 3.28 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight and diluted with DCM &lt; , water, brine wash mixture, 153611.doc • 97- 201130815. Dry (MgSCU) and EtOAc (EtOAc) , d), 7.45 (1Η, d), 5.91 (1H, d), 4.00 (2H, d), 3.90 (1H, m), 2.94 (3H, s), 2.14 (2H, m), 1.86 (2H, m), 1.71 (1H, m), 1.19 (4H, m).

Intermediate D-Methanesulfonic acid 4-[(5-Gas-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexylmethyl ester under nitrogen - using an ice water bath to reverse -5-gas - N-(4-Hydroxymethylcyclohexyl)-2-methyl-nicotinium decylamine (Intermediate A, Step 3) (100 mg, 0.354 mmol) and pyridine (3.6 ml) in anhydrous DCM (3.5 ml) The solution is cooled to about 〇 ° C. Methanesulfonate (0.030 nU, 0.389 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by the addition of saturated NKCl at room temperature then extracted with diethyl ether (3.times. The combined Et20 extracts were washed with aq. LC-MS m/z 361.2 / 363.2 [M+H]+. NMR (400 MHz, CDC13) δ 8.52 (1H, d), 7.65 (1H, d), 5.68 (1H, br d), 4.09 (2H, d), 3.96 (1H, m)5 3.04 (3H, s) , 2.65 (3H, s), 2.21 (2H, m), 1.96 (2H, m), 1.79 (1H, m), 1.27 (4H, m).

Intermediate E, trans-trifluoro-methanesulfonic acid, 4-(2-a-5-trifluoromethyl)benzhydrylaminocyclohexylmethyl ester, trans-2-gas-N-(4-hydroxymethyl) -cyclohexyl)-5-trifluoromethyl-benzamide (Intermediate B 'Step 2) (2.00 g, 5.96 mmol) was placed in DCM (50 ml) 1536 M.doc -98 - 201130815 (0.56 g, 7.15 mol) in a flask. The reaction mixture was cooled to 〇C' and then trifluoromethanesulfonic anhydride (185 g, 6.55 mmol) was added dropwise. The mixture was stirred at 〇C for 1 hour and partitioned. Between dcm and 1 M HCl. Dry (MgS 〇 4) organic phase, filter and remove solvent in vacuo on ice-cooled water bath to give a beige solid. Wet-milled crude product in isohexane: Et 2 〇 2: 'The title product was obtained. 1H NMR (d6-DMSO, 400 ΜΗζ) δ 8.52 (1 Η, d)5 7.81 (1H, m), 7.74 (2H, m), 4.11 (2H, d), 3.70 (1H, m) , 1.95 (2H, m), 1.79 (2H, m), 1.67 (1H, m), 1.28 (2H, m), l.ii (2Hj m) 〇

Intermediate F 6-gas-3,3-difluorofluorene-2_one

Treatment of 6-chloroporphyrin_2 3 -dione (25 〇 mg, 1.377 mmol) with Deox®-Fluro(R) (50% in toluene, 1.099 ml, 3.44 mmol) over 10 min.

Suspension in DCM (14 ml). After the addition, the suspension was dissolved, and the mixture was allowed to stand at room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of NaH.sub.3 (6 mL) and the organic portion was separated and concentrated in vacuo. Purification by chromatography on EtOAc (EtOAc:EtOAc) , 7.22 (1H, dd), 7.03 (1H, m) 氯 Prepare chloro-3,3-difluoroindol-2-one in a similar manner. 1H NMR (400 MHz, d6-DMSO) δ 11.32 (1H, s), 7.84 (1H, m), 7.58 (1H, m), 7.01 (1H, m) ° 153611.doc •99· 201130815

Intermediate G 3,3-dimethyl-I,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

Step 1: 3,3-two&gt;Smell-1,3-Diman-°Biluo[2,3-1)]«1 than 2-butan-2-one at 25 ° C, after 30 minutes 7-Azaindole (2.51 g, 21.25 mmol) In a solution of tributanol (150 ml), pyridine bromide bromide (23.03 g, 64.8 mmol) was added portionwise and stirred for 2.5 hours. The solvent was removed in vacuo, diluted with EtOAc (EtOAc) The aqueous phase was back-extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) The resulting solid was triturated with EtOAc (EtOAc)EtOAc. Step 2: 1,3-Dinitrogen-° ratio 嘻[2,3-b]° ratio η=-2-嗣 Under Ν2 to 3,3-dibromo-1,3-dihydro-. To a solution of pyridine-2-one (4.6 g, 15.76 mmol) in AcOH (80 ml) was added EtOAc (3 EtOAc). The mixture was stirred at room temperature for 30 minutes at room temperature, followed by filtration through Celite® (filter material) to remove Zn. AcOH was removed in vacuo and the mixture was diluted with EtOAc and washed with NaHC. The organic phase was separated, dried (MgSO4) elut elut elut elut elut elut elut elut elut elut elut elut elut (1H, t), 3.55 (2H, s). Step 3: 3,3-Dimethyl-1,3-dihydro-pyrrolo[2,3_b]pyridine_2-one 153611.doc •100· 201130815 N1,N1,N2,N2 under nitrogen gas - Tetramethyl ketone_ι,2-diamine (1.956 m Bu 13.05 mmol) treatment of 1,3-dihydro-pyrrolo[2,3_b]pyridin-2-one (500 mg ' 3.73 mmol) in anhydrous THF Solution in (40 ml). The mixture was cooled to -78 ° C in an acetone/dry ice bath. n-BuLi (1.6 Μ in hexanes) (8.15 m, 13.05 mmol) was added dropwise over 3 Torr. After the addition, the mixture was stirred for another 30 minutes, then treated dropwise with methyl iodide (0 816 ml, 13.05 mmol) and stirred overnight at room temperature. The reaction was quenched by EtOAc (2×EtOAc) The organic portion was separated and washed with EtOAc EtOAc (EtOAc) The methylation process was repeated twice to obtain a di-f-formation product. The resulting solid was purified by EtOAc EtOAc (EtOAc) elute (1Η, dd), 7.65 (1Η, dd), 6.95 (1Η, dd), 1.25 (6Η, s).

Intermediate GB 6-gas-3,3-dimethylindol-2-one

Similar to 3,3-dimercapto-1,3-dihydro-pyrrolo[2,3-bppyridin-2-one (Intermediate G, Step 3), from commercially available 6-chloro-1,3 - Dihydroinzetroin-2-yl to prepare the title compound; 1H NMR (400 MHz, CDC13) δ 7.50 (1 Η, br), 7.1 〇 (1 Η, d), 7.05 (1 Η, d), 6.90 (1 Η, s) , 1·40 (6Η, s).

Intermediate H 153611.doc -101- 201130815 5,-Fluorospirocyclopropane-1,3,-carboline-2,-ketone

5_Fluorine D-Dallin-2-one (5 〇〇 mg '3.3 1 mmol) was dissolved in anhydrous THF (30 ml). To this mixture was added tetramethrin-1,2-diamine (i_〇9i ml, 7.28 mmol) and the mixture was cooled to -78 °C. BuLi (1.6 Μ in hexanes) (4.14 ml, 6.62 mmol) was added dropwise and the contents were stirred for 2 min. 12 乙乙乙烧(0·342 nU' 3.97 mmo丨) was added dropwise and the mixture was stirred at _78 ° C for 3 〇 minutes and rised until overnight. The reaction was quenched by the addition of EtOAc (EtOAc)EtOAc. The solvent was removed in vacuo and purified by EtOAc (EtOAc) eluting with EtOAc (EtOAc). NMR (400 MHz, CDCh) δ 8.40 (1H, s), 6.90 (2H,

m), 6.60 (in, d), 1.80 (2H, m), 1.55 (2H, m) 中间 Intermediate I 5-methoxy-3,3·dimethyldihydro-indol-2-one

Step 1: 5_Methoxy-吲哚-丨-carboxylic acid terpene vinegar was added to a solution of 5-methoxyindole (4.11 g, 27.9 mmol) in MeCN in a solution of di-tert-butyl dicarbonate. (7.13 ml, 30.7 mmol) and 153611.doc -102-201130815 DMAP (0.102 g, 0.838 mmol) » The reaction mixture was stirred at room temperature for 64 hours. The reaction mixture was partitioned between EtOAc (EtOAc) (EtOAc). The organic portion was dried (Na.sub.2CO.sub.3), filtered and concentrated in vacuo to give a white solid. The solid was triturated with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 6.95 (1H, dd), 6.52 (1H, d), 3.88 (3H, s), 1.69 (9H, s). Step 2: 1-(Tertibutoxycarbonyl)·5-decyloxy-1H-indol-2-yl-acidic acid LDA solution: to diisopropylamine (3.82 ml, 26.8 mmol) in THF (3 ml) To the solution at -78 ° C was added butyl lithium (2.5 Torr in hexane) (10/73 ml '26.8 mmol). After 10 minutes, the solution was allowed to warm to 01 and stirred at this temperature for 10 minutes. To a solution of 3-butoxy-5-decanoic acid tert-butyl ester (5.53 g '22.36 mmol) and triisopropyl borate (7.79 ml, 33.5 mmol) in THF (17 ml) at 0 °C The LDA solution prepared above was added dropwise to the solution (added over 10 minutes). The reaction mixture was stirred for 1 hour and was quenched by addition of &lt;RTI ID=0.0&gt;&gt; The reaction was extracted with di-methane (3.times.50 mL), washed with brine (50 ml), dried (M.sup.4) and concentrated in vacuo. The obtained oil was dissolved in ΕηΟ:isohexane 1:1 and scraped to promote crystallization. The resulting solid was filtered to give crystals crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssssssssssssssssssssssss 6.55 (1H, s), 3.77 (3H, s), 1.59 (9H, s). ' Step 3 : 5-methoxy-2-oxooxy 2,3 · dihydro-indole-1-decanoic acid third butyl 153611.doc -103- 201130815 to 1-(third butoxy Water (16 ml) and THF (8 ml) were added to a suspension of carbonyl)-5-methoxy-111-indol-2-yl-acid (2.10 g, 7.21 mmol) in acetone (16.00 ml). Sodium hydroxide (〇 433 g, 82 mmol) &amp; sodium hydrogenate (4.85 g, 57.7 mmol) was then added to cool the reaction mixture to 〇 ° C, followed by potassium persulfate (4.43 g, fork 2! mm 〇i), and the reaction was stirred for 30 minutes at 〇C. The reaction was quenched by the addition of 1 μ Na 2 S 205 (1 mL) and then the mixture was partitioned between Et EtOAc (10 EtOAc) (EtOAc) Combined organic matter. The organic portion was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was crystallized from hot EtOAc. After cooling, isohexane was added to give the title compound as a white solid: 1H NMR (400 MHz, DMSO_d6) δ 7.60 (1H, d), 6.93 (1HS d), 6.86 (1H, dd), 3.74 (3H, s ), 3.71 (2H, s), 1.55 (9H, s). Step 4: 5-Methoxy-1,3-dihydro-»pyridin-2-one ester to 5-methoxy-2-oxirane-2,3-dihydro-oxime at 〇 °C Trifluoroacetic acid (0.234 ml '3.04 mmol) was added to a solution of tert-butyl phthalate (0.800 g, 3.04 mmol) in di-methane (6 ml). Here. The reaction mixture was stirred for 1 hour and was quenched by pouring into saturated NaHCO3 (50 mL). The aqueous layer was back extracted with EtOAc (3×35 mL). Washed with brine (1x50 ml)

The organic extract was dried (MgSOS 4) and concentrated in vacuo to yield a solid residue. The residue was crystallized from EtOAc EtOAc (EtOAc)

Rt = 0.54 min; MS m/z 164.0 [M+H]+; </ RTI> 2 min LC 30 153611.doc • 104·201130815 v002 ; 'H NMR (400 MHz, DMSO-d6) δ 10.20 (1H, br s), 6.86 (1H, s), 6.72 (2H, m), 3.69 (3H, s), 3.43 (2H, s). Step 5: 5-methoxy-3,3-dimethyl-1,3-dihydro-inden-2-one is similar to 3,3-dimethyl-1,3-dihydro-° ratio And [2,3-b]pyridin-2-one (Intermediate G, Step 3), the title compound was obtained from 5-methoxy-1,3-dihydro-indol-2-one. This step was repeated twice to obtain a dimethylated product. 4 NMR (400 MHz, CDC13) δ 7.80 (1 Η, br), 6.85 (2H, m), 6.70 (1H, d), 3.80 (3H, s), 1.40 (6H, s).

Intermediate IB 3,3,7-trimethylporphyrin-2-one

This compound was prepared analogously to Intermediate I by substituting 7-mercapto-1H-indole for 5-methoxyindole (Step 1); LC-MS Rt = 2.32 min; MS m/z 176.16 [M +H]+; method LowpH_v002.

Intermediate IC 3,3,4-trimethyl 0 bow 丨 琳 -2- ketone

This compound was prepared analogously to Intermediate I' by substituting 4-mercapto-1H-indole for 5-decyloxyhydrazine (Step 1); 1H NMR (400 MHz, DMSO-d6) δ 10.3 (1H, s), 7.05 (1H, t), 6.7 (1H, d), 6.65 (1H, d), 2.3 153611.doc -105- 201130815 (3H, s), 1.3 (6H, s).

Intermediate ID 7_gas-3,3-dimethyl-1,3-dihydro-indol-2-one

Similar to Intermediate I, this compound was prepared by substituting 7_gas oxime for 5 曱 oxime (Step 1); h NMR (400 MHz, DMS 〇〇 g 1 〇 75 (1H, s), 7.25 (2H, dd), 6.95 (1H, t), 1.25 (6H, s).

The intermediate J 6-methoxy-3,3-dimethyl-l,3-dihydro-pyrrolo[3,2-c]pyridine_2_oxime is similar to 3,3-dimercapto-1. 3_Dihydro-deindol and [2,3-b]. Specific bite -2- (intermediate G, step 3), from 6-methoxy-1H-pyrrolo[3,2-c]pyrr. The title compound was prepared as a 2(3H)-one (commercially available). This step was repeated twice to obtain a dithiolated product. 1H NMR (400 MHz, CDC13) δ 7.90 (1H, s), 6.30 (1 Η, s), 3.95 (3 Η, s), 1.45 (6 Η, s).

Intermediate KA and KB (R)-3-fluoro-3-methyl-1,3-diar-indol-2-one and (S)-3-fluoro-3-methyl-1,3-di Argon·(iv) Mouth-2-one Step 1: (R/S)-3-Hydroxy-3-methyl-1,3-dihydro-indol-2-one gives ruthenium (3 g' 20.39 mmol) to The solution in THF (90 ml) was cooled in an acetone/dry ice bath, and MeMSBr (3 Μ ' 20.39 ml) was slowly added over 15 minutes. The reaction mixture was vigorously stirred for 1 hour and 45 minutes, followed by C 153611.doc 106-201130815 The mixture was removed from the dry ice bath and saturated aqueous NKUC1 (5 ml) was added. The reaction mixture was mixed until all the gas had evolved and a saturated NH4C1 aqueous solution (15 ml) was added. Water was added to dissolve the solid, and the mixture was extracted with ]gt〇Ac (70 ml). The combined organic extracts were washed with brine (30 mL) dry To the obtained yellow solid was added (15 ml), and the solid was taken out and dried in a vacuum oven at 4 Torr for 5 hours to obtain the title compound. Step 2 · (R)-3-fluoro-3-methyl-1,3-dihydro-indole-2-ketone and (s)_3_fluoro_3·decyl_1,3-dihydro-π (b/s)_3_hydroxy_3_methyldihydro-indole-2-one (1 g, 6.13 mmol) in DCM at -78 ° C for 10 min. Add Deoxo-FluroWpoo/W f benzene to the suspension in 65 ml), 2 445 ml, 7 66 bribes 1), and allow the mixture to warm to room temperature overnight. The reaction was quenched by the addition of a saturated aqueous NaHC.sub.3 solution (6 ml), and the organic portion was separated and concentrated in vacuo. The title product is obtained as a mixture by chromatography on silica gel in the evening elution with 〇_4〇% Et〇Ac/isohexane. The following compounds were obtained by separating the mixture from the palm SFC: (R) -3·Fluoro-3-methyl-1,3_dihydro-〇 卜 卜 _2 _2 ketone information: NMR (_ MHz, d6 -DMSO) δ 10.65 (1H, s), 7.49, (1H, d), 7.34 (1H, t), 7.05 (1H, t), 6.89 (1H, d), 1.66 (3H, d); (S) 3-oxo-3-methyl-1,3-dihydro "bamboo-2" ketone: Nmr (Liu MHz, d6-DMSO) δ 10.64 (1H, s), 7·49, (1H, d ), 7.34 (1H, t), 7.05 (1H, t), 6.89 (1H, d), 1.66 (1H, d).

Intermediate KC and KD 153611.doc •107· 201130815 (R)-3-Fluoro-3,5,6-trimethyl-1,3-dihydroanthracene-2· and (s)-3 gas· 3.5.6- Trimethyl-1,3-dihydro-indol-2-one is similar to the intermediates KA and KB by using 5,6-dimethylhydrazine η Λ 暴 -1 -1 Η-吲0 - 2,3-dione in place of eosin to prepare the title compound; by isolation of the palm sfc, the following compound is obtained: Intermediate KC (enantiomer 1): *H NMR (400 MHz, CDC13) δ 8.07 (1Η, bs), 7.1〇(ΐΗ s), 6.64 (1Η,S), 2.19 (3Η, aPP-s), 2·17 (3Η, s), 168 (3Η,d)'. Intermediate KD (enantiomer 2): !H NMR (400 MHz, CDC13) δ 8·1 〇 (1H, bs), 7.1 〇 (1H, s),

6.65 (1H, s), 2.19 (3H, aPP-s), 2. Π (3H, s),! 68 (3H, d). Intermediate KE and KF (R)-6-gas_3-fluoro-3-methylindolino-2-one and (S)-6-gas_3_gas·3_methylporphyrin-2 - 鲷 Similar to the intermediates ΚΒ and ΚΒ, the title compound was prepared by replacing the reddish with 6-gas ruthenium. By separating the palmitic SFC, the following compounds were obtained: Intermediate ΚΕ (Enantiomer 1): [M-F] + ion 180.1, Rt 2.25 min Intermediate KF (enantiomer 2):

[River-?] + ion 180.1111/2, at 2.25 minutes intermediate KG 3.5.6-trifluoro-3-methyl porphyrin-2-amine similar to intermediate KA steps 1 and 2, commercially available 5,6-two defeat-1H-吲153611.doc -108- 201130815

The title compound was prepared from hydrazine-2,3-dione. No need to carry out palmar SFC » Intermediate L 3,3-dimethyl-5-trifluoromethoxy-1,3-dihydro-indol-2-one is similar to 3,3-dimethyl- 1,3-Dihydro-pyrrolo[2,3-b]pyridin-2-one (Intermediate G, Step 3) from 5-(trifluoromethoxy)indol-2-one (commercially available) The title compound was prepared; 4 NMR (400 MHz, CDC13) δ 8.3 (1H, br), 7.10 (2H, m), 6.90 (1H, d), 1.40 (6H, s). The intermediate M 5 -gas-3,3-dimethyl·1,3-diaza-anthracene peak-2 -net is similar to 3,3-dimercapto-1,3-dihydrogen [2,3-b] indole-2-one (Intermediate G, step 3), the title compound was obtained from 5-fluoropyridin-2-one (commercially available); 1H NMR (400 MHz, CDC13) δ 7.9 (1Η, br), 6.9 (2Η, m), 6.8 (1H, m), 1.4 (6H, s). Intermediate N 4-methoxy-3,3-monomethyl-1,3·dihydrofuran Step 1: 4·Methoxy-1,3-dihydro-indole_2-one is similar 5-methoxy-1,3-dihydroindole-2-ol ester (Intermediate 1, Step 4) 'by using 4-methoxy.丨哚 丨哚 ” 氧基 氧基 氧基 氧基 氧基 (Step 1} to prepare this compound; LC-MS Rt = 1.85 minutes; MS _ 164 16 [M + H] +, method LowpH_v002 〇 step at 〇 ° C down to 4_曱oxy], 3-dihydrodeca-2-one (1.556 g' 954 Leg 〇 1) in THF (1 〇 ml) in the order of the addition of 峨, ie, 8 ml, 3 equivalents) and NaH (839 mg, 2.2 eq.). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The mixture was extracted with EtOAc (2×10 mL). The crude residue was purified with EtOAc EtOAc EtOAc (EtOAc) 1Η, d), 6.45 (1Η, d), 3.8 (3Η, s), 1.3 (6Η, s).

The intermediate O 7-gas-3,3-dimethyl-1,3-di-argon-»丨嗓丨嗓_2-明 is similar to 4-methoxy-3,3-dimethyl·ι,3_ Dihydro-indole-2-ketone (Intermediate N), prepared by substituting 7-gas hydrazine for 4-methoxy hydrazine (step 丨);] H NMR ((400 MHz, DMS〇) -d6) δ 10,75 (1H, s), 7.25 (2Η, dd), 6.95 (1Η 1·25 (6Η, s).

The intermediate P 3,3-difluoro-1,3-dihydro-indole-2- is similar to 6-gas-3,3-difluorotetralin-2, (intermediate F), -2,3-dioxine to prepare the compound; 丨η NMR (_ MHz, δ 11.17 (1H, s), 7.64 (1H' dd), 7.52 (1H, t), 716 (1 6.99 (lH, m). ''The other 吲喵〇m^ used in the preparation of the example is similar to the intermediate household, 0, 11, 1, 1, 1 (: or > 1) , 1^士^; The formula is synthesized from a commercially available starting compound.

Intermediate Q 153611.doc •110· 201130815 5-Methoxy-3,4-dihydro-2H-isoquinolin-1-one to 5-hydroxy-3,4-dihydroisoquinoline-1 (2H C- 2C03 (599 mg, 1.839 mmol) was added to a stirred solution of ketone (200 g, 1.26 mmol) in DMF (8 ml). The reaction mixture was stirred at 50 ° C for 20 minutes and then treated with a methylene chloride (·········· After stirring at 50 ° C for 30 minutes, the mixture was diluted with EtOAc / water. The organic portion was separated, washed with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs

Intermediate RA 1-ethyl-1,3-dihydro-benzimidazol-2-one Step 1: N-ethyl-benzene-1,2-diamine N-ethyl-2-nitroaniline ( 1 g, 6.02 mmol) and ammonium citrate (1.897 g, 30.1 mmol) were dissolved in ethanol (2 〇mi). Pd/c (1 〇 0 / 〇 carbon / Pd ' 100 mg, 0.094 mmol) was added, and the reaction was heated under reflux for one hour. The mixture was filtered and washed with MeOH. Concentrate the liquid in vacuo to give the title compound: NMR (400 MHz, CDC13) δ 7.29 (1 s, s), 6.85 (1H, m), 6.75 (1H, m), 6.70 (2H, m), 3.45 (2H, s, broad peak), 3.18 (2H, q), 1.33 (3H, t). Step 2: 1-Ethyl-1,3-dihydro-benzopyrene 0 sitting _2. Ketone N-ethyl stupin_ι,2·diamine (〇_795 g, 5.84 mm〇i) Dissolved in THF (25 ml) and added CDI (〇 947 g, 5 mmol) to this solution. The resulting solution was stirred overnight at room temperature under a hydrazine atmosphere, followed by stirring at 50 ° C for 3 hours. The solvent was removed in vacuo and the obtained crude was purified eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) δ 10.89 (1H, s), 7.14 (1Η, m), 6.97 (3Η, m), 3.80 (2Η, q), 1.18 (3Η, t).

The intermediate RB-RF is similar to the intermediate RA, which is prepared by substituting the appropriate starting compound for Nethyl-2-nitroaniline, ie: 4-mercapto-1,3-monohydro- Imidazo[4,5-b]pyridine-2-ketone (intermediate rb),

3-dihydro-benzimidazole-2-((intermediate ruler,

0 1-Methyl-1,3-dihydro-benzopyrene. Sitting 2-ketone (intermediate RD),

&quot;Sitting '2-鲷 (intermediate RE), and 1-ethyl-1,3-dihydro-benzoim

〇

153611.doc •112. 201130815

Intermediate RF 2-sided oxy-2,3-dihydro-benzimidazolecarboxylic acid tert-butyl ester 1,3-dihydro-benzimidazole-2-ketone (intermediate rd) under nitrogen (1 g , 7.46 mmol) was dissolved in dry DMF (20 mL) eluting with NaH (0.328 g, 8.20 mmol). After 15 hours, a solution of di-tert-butyl dicarbonate (1.627 g, 7.46 mmol) in DMF (10 ml) was added dropwise and the mixture was stirred at room temperature for 4 hrs. The partition was between saturated NH4Cl (about 50 mL) and EtOAc (~1 mL). The aqueous portion was extracted with EtOAc (ca. 100 mL) and EtOAc (EtOAc) Obtained with ethyl acetate/isohexane, the title compound was obtained, 1H NMR (400 MHz, DMSO) δ 1 丨.21 (1H s), 7.65 (1H, m), 7.14 (1H, m), 7.06 (1H , m), 6.99 (1H, m), 1.59 (9H, s).

Intermediate RG 1-methyl-1,3-dihydro-imidazo[4,5-b]pyridine-2-one

Step 1: N-Methyl-2-nitropyridin-3-amine 3-methoxy-2-nitropyridine (2 g, 12.98 mmol) was dissolved in 2 decylamine in MeOH (30 m. The solution was heated at 120 ° C for 2 hours using microwave radiation. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic portion was separated and the aqueous portion was extracted with DCM. The combined organic extracts were washed with a saturated brine solution and dried 153611.doc •113·201130815

(MgSCU) and concentrated in vacuo. The crude residue was purified by EtOAc EtOAc EtOAc EtOAc. ), 7.82 (1H, d), 7.64 (1H, m), 7.56 (1H d), 2.94 (3H, d). Step 2: N3-Mercaptopyridine 2,3-diamine N-Mercapto-2-nitropyridin-3-amine (535 mg, 3.49 mmol) was dissolved in MeOH (50 ml) with Pd- C (100 mg, 〇.〇94 赖〇1) treatment. The solution was placed under positive pressure for 4 hours and then filtered. The filtrate was concentrated in vacuo to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6 (2 Η, s), 4.8 4 (1Η, m), 2.6 9 (3 H d ). Step 3: 1-Methyl-1,3-dihydro-imidazo[4,5-b]pyridine-2-one-2-one (intermediate rA), compound; 4 NMR (400 similar to 1 -ethyl-1,3-dihydro-benzimidazole_2, imprinted), 7.41 (1H, m), N3-methylpyridine-2,3-diamine to give the title compound: MH, DMSO) δ 11.49 ( 1H, s), 7.91 (1H imprint) 7.02 (1H, m), 3.30 (3H, s) »

Intermediate RH 3,6-dimethyl-1,3-dihydro-imidazo[4,5-b] pyridine bite 2_

g '5·79 mmol) was placed in a step-by-step 1: methyl-(5-methyl-3-stone-based-n-pyridyl-2-yl)-amine 2-gas-5-methyl-3 - Shi Xiaoji. More than a bite (l.oo g, $7〇153611.doc • 1]4·201130815 Amine (2 Μ in THF) (11.59 ml, 23.2 mmol) in a microwave vial, and using microwave radiation at l〇〇t The reaction mixture was heated for 30 minutes. The solvent was removed in vacuo and the residue was crystallised eluted from Et. Purification was used in the next step. 'H NMR (400 MHz, DMSO) δ 8.40 (1H, s), 8.33 (1H, br), 8.25 (1H, s), 3.02 (3H, d), 2.21. , s) Step 2: N2,5-dimercaptopyridine 2,3-diamine is similar to N-ethyl-benzene-1,2-diamine (intermediate ra, step 1), from methyl- (5-Methyl-3-nitro-pyridin-2-yl)-amine (Step 1) Prepared this compound. 'H NMR (400 MHz, DMSO) δ 8.40 (1 Η, s), 8.33 (1H, br) , 8.25 (1H, s), 3.02 (3H, d), 2.21 (3H, s). Step 3: 3,6-dimercapto-1,3-dihydro-miso-[4,5-1&gt;;]° than bite similar to 1-ethyl-1,3-dihydro-benzimidazol-2-one (intermediate RA, step 2) 'from N2,5-lutidine-2,3-di Amine (Step 2) This compound was prepared. 咕NMR (400 MHz, DMSO) δ 11.00 (1H, broad peak), 7:.78 (1H, d), 7.12 (1 Η, d), 3.28 (3 Η, s), 2.29 (3 Η, s ).

The intermediate RI 3-ethyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-indole is similar to 1-ethyl-1,3-dihydro-benzimidazol-2-one (Intermediate ra, step 2) 'This compound was prepared from N3-ethylpyridine-3,4-diamine (commercially available). LC_MS Rt = 1.74 min; MS m/z 164.1 [M+H]+;

Intermediate RJ 3,7-dimethyl-i,3-dihydro-imidazo[4,5-b]® lb bit -2- Ming 153611.doc .115· 201130815 Similar to 1-ethyl-1 , 3-dihydro-benzo- </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Compound. LC-MS Rt=l.59 min; MS m/z 164.06 [m+h]+.

LowpH_v002 〇Intermediate RK-RN is similar to 1-ethyl-1,3-dihydro-benzimidazol-2-one (Intermediate Ruler 8, Step 2) 'Prepare these intermediates from appropriate commercially available starting compounds , ie: 3,5-dimethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (intermediate anti-reverse),

1,5-dimethyl-i,3-dihydro-imidazo[4,5-b]pyridine-2-ketone (intermediate *RL),

1-ethyl-1,3-dihydro-benzoimidazole-2-yl (intermediate *RM),

5-methoxy-3-methyl-1,3-dihydro-imidazo[4,5-b]pyridine-2-ketone (Intermediate 153611.doc •116·201130815 ο

Intermediate RO 1-isobutyl-1,3-dihydro-benzo-salt salivary_2-emergence

Step 1: 3-isobutyl-2-indenyl·2,3·dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester 2-sided oxy-2,3-di Hydrogen-benzimidazole decyl citrate (intermediate RA) (200 mg '0.854 mmol) was dissolved in DMF (3 ml) and stirred at room temperature under A. Sodium hydride (6 〇〇 /. in mineral oil) (4i. 〇 mg, 1.025 mmol) was added and the mixture was stirred for 20 min. Io_iodo-2-mercaptopropene (0.147 m Bu 1.281 mmol) was added and the mixture was stirred at room temperature for 2 days. The mixture was heated to 50 °C. After 2 hours, 1 equivalent of NaH and 0.5 equivalent of 1-iodo-2-mercaptopropane were added sequentially, and stirring was continued for an additional 1 hour and 3 minutes. The solvent was removed in vacuo and the residue was partitioned between DCM (ca. 40 mL) and water (approximately 5). The organic portion was passed through a phase separator and solvent was removed in vacuo. Chromatography, eluting with EtOAc/EtOAc (EtOAc) EtOAc (EtOAc) (2H, d), 2.11 (1H, m), 1.60 (9H, s), 〇.9o I53611.doc 117 201130815 (6H,d) 〇 step 2. 2-isobutyl-1,3-dihydrogen -Benzyl u-methane. Treatment of 3-isobutyl-2. oxo-2,3-digester-1H-benzo with 4 M HC1/二 烧 (3 ml ' 12.00 mmol) (4) a solution of imidazole _ 1 -carboxylic acid tert-butyl ester (j 5 j mg, 0.520 mm 〇i) in Me〇H (4 ni), and the resulting mixture was stirred at room temperature for 2 hours and 45 minutes "in a vacuum The solvent was removed to give the title product as the hydrochloride salt;]H NMR (400 MHz, d6.DMSC 〇δ 10-79 (1 Η, s), 7.10 (1H, m), 6.98 (3H, m)s 3.58 (2H, d), 2·〇9 (1H, m), 0.87 (6H, d).

Intermediate RP 3,3,5-trimethylphosphonium-2-one

Step 1: N-(2-Bromo-4-methylphenyl)methacrylamide was treated dropwise with methyl propylene (1.33 g, 12.72 mmol) 2-di-n-pyridin-3-amine ( 2·00 g, u.56 mmol) A solution of DCM (50 ml) and triethylamine (L 75 g ' 17.34 mmol) and stirred at room temperature for hr. The mixture was partitioned between EtOAc and water. The organic phase was washed with water, brine, dried over MgSO4, filtered and evaporated. The product was purified by chromatography on cerium oxide and elution with isohexane (1). The resulting residue was dissolved in MeOH EtOAc (EtOAc m. ), 7.52 (1H d) 7.39 (1H, d), 7.20 (1H, d of d), 5.90 (1H, s), 5.51 (ih s) 2.30 (3H, s), 1.95 (3H, s). Step 2: N-(2-Bromo-4-indolyl)·Ν-((2_(trimethyldecyl)ethoxy)methyl)methacrylamide with NaH (60% 'in oil () (2,33 g, 5.78 mmol The solution was stirred and stirred at room temperature for 1 Torr. Add SEM_C1 (0.89 g, 5.4 mmol) and heat the mixture under reflux! hour. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between dCM and water. The organic phase was washed with water, brine, dried over MgSO.sub.s, and evaporated and evaporated. The title compound was obtained by chromatography on silica gel eluting with EtOAc/EtOAc. NMR (400 MHz d6-DMSO) δ 7.59 (1Η, s), 7.28 (2H, m), 5.41 (IH, br), 5.05 (1H, br), 4.90 (1H, br), 4.60 (1H, br) , 3.61 (2H, br), 2.32 (3H, s), 1.80 (3H, br), 0.89 (2H, m), 0. 〇〇 (9H, s). Step 3: 3,3,5-trimethyl-1-((2-(trimethyldecyl)ethoxy)methyl)indol-2-one was sequentially treated with dibutyltinhydride (508 mg, Treatment of N-(2-bromo-4-methylphenyl)·Ν-((2-(3) by 1.75 mmol) and 1,1,·Azobis(cyclohexanecarbonitrile) (19.4 mg, 0.08 mmol) A solution of methyl decyl)ethoxy)methyl)methacrylamide (Step 2) (610 mg ' 1.59 mmol) in toluene (20 mL). The resulting mixture was heated under reflux for 2 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic phase was washed with water, brine 153611.doc -119- 201130815 phase dried over MgS04, filtered and solvent removed in vacuo. Purification by chromatography on ruthenium chloride eluting with isohexane/EtOAc afforded the title compound. 4 NMR (400 MHz, d6-DMSO) δ 7.28 (1H, d), 7.13 (1H, m), 7.02 (1H, m), 5.17 (2H, s), 3.57 (2H, t), 2.39 (3H, s), 1.37 (6H, s), 0.91 (2H, t), 〇.〇〇 (9H, s). Step 4: 3,3,5-trimethyl. lead. Dolantin-2-one, using microwave radiation, will contain 3,3,5-trimethyl-1-((2-(tridecylsulfonyl)ethoxy) fluorenyl) porphyrin-2- A mixture of the ketone (Step 3) (360 mg, 1.18 mmol) and tetrabutylammonium fluoride (1 Torr in THF) (2.36 m, 2.36 mmol) was heated at 120 ° C for 1 hour, then at 140 ° C Heat for 1 hour. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between DCM and water. The organic phase was washed with water, brine, dried over MgSO4, filtered and evaporated. Purification was carried out by chromatography on silica gel in the evening with iso-isoter/EtOAc. The appropriate fractions were combined and subducted in vacuo. The product was crystallized and wet-purified with isohexane to give the title compound: lc_ms Rt 2.32 min; 1^111/:2176.12[]\4+11]+; Method 1^11^002. 4 NMR (400 MHz, d6- DMSO) δ 10.20 (1Η, s), 7.l〇(1H, d), 6.97 (1H,d),6·71 (1H,d), 2.25 (3H,s), 1.25 (6H,s).

Intermediate RQ l-(4.Amino-cyclohexylmethyl)_3,3_dimethyl-1,3_di-argon-like odor _2·嗣

153611.doc • 120 201130815 Step 1: Methyl trans-4-(t-butoxycarbonylamino)cyclohexanecarboxylate: Ethyl trans-4-aminocyclohexanecarboxylate (43 g, 222 mmol) Add to MeOH (500 ml) to give a colorless solution. The solution was cooled to a (7) core, and triethylamine (46.4 ml, 333 mmol) was added dropwise, followed by the addition of dibutane dicarbonate (53.3 g, 244 mmol) in MeOH (400 ml) over 20 min. Solution in the middle. The reaction was allowed to warm to rt and stirred overnight. The mixture was evaporated to dryness under reduced pressure. The resulting colorless solid was dissolved in EtOAc (1000

I ml) in 'and successively using ι〇〇/. The obtained solution was washed with a citric acid solution (1 ml), EtOAc (EtOAc) (EtOAc) Step 2: tert-butyl 4-(hydroxymethyl)cyclohexylcarbamate to give trans-4-(t-butoxycarbonylamino)cyclohexane decanoate (55.5 g, 216 mmol) It was suspended in ethanol (900 ml) and THF (100 ml), and the mixture was cooled to 5 C. Granular gasification (47.9 g, 431 mmol) was added portionwise to obtain a milky suspension. Sodium borohydride (3 2.6 g, 863 mmol) was added portionwise over 5 minutes at 5 ° (5 ° C. The reaction mixture was stirred at 5 ° C (white emulsion) for 1 hour to remove the water bath, then the reaction mixture was allowed to warm to room temperature , and stirred at room temperature overnight. The reaction mixture was cooled to 1 ° C, and 5% potassium carbonate (200 ml) was added dropwise until the pH of the solution was pH 11. The formed colorless precipitate was filtered off. Stir with ethyl acetate (2000 ml) and water (500 ml). The organic layer was separated and washed with EtOAc EtOAc EtOAc (EtOAc) The solution was dried over anhydrous MgSCU, filtered and evaporated to give a white solid. The solid was dried under high vacuum overnight to constant weight; [M+H]+ 230 » 153611.doc -121-201130815 Step 3: Reverse-Trifluoro-A 4-butoxycarbonylamino-cyclohexylmethyl sulfonate Placed tert-butyl 4-(hydroxyindenyl)cyclohexylamine decanoate (Step 1) (1.00 g, 4.36 mmol) In a flask containing DCM (50 ml) and pyridine (0.41 g, 5.23 mmol), the reaction mixture was cooled to hydrazine. Anhydride (1.35 g, 4.80 mmol). The reaction mixture was stirred for 1 h under Ot: then partitioned between DCM and saturated gas. The organic phase was dried <RTI ID=0.0> The solvent was obtained as a beige solid. EtOAc (EtOAc) 2H, d), 3.03 (1H, m), 1.80 (2H, m), 1.70 (2H, m), 1.59 (1H, m), 1.38 (9H, s), 1.12 (2H, m), 1.01 (2H , m) 〇Step 4: [4-(3,3-Dimethyl-2-oxooxy-2,3·dihydro-indole_i-ylmethyl)-cyclohexyl]-amino decanoic acid Third butyl ester treated with NaH (60% 'in oil) (80 mg ' 1.99 mmol) 3,3-dimercapto-1,3-hydro-indol-2-one (commercially available) (268 mg , 1.66 mmol) in

The solution in DMF (10 mL) was stirred at room temperature for 1 min. Add anti-trifluoro-indolesulfonic acid 4-t-butoxycarbonylamino-cyclohexylmethyl ester (6 mg, 1.66 mmol) at 80. (The reaction mixture is heated for 4 hours. The solvent is removed in vacuo and the residue is partitioned between DCM and water. The organic portion is passed through a phase separator and solvent is removed in vacuo ◎ by cerium oxide Chromatography, eluting with EtOAc/EtOAc (EtOAc:EtOAc: EtOAc: 7.03 (1H, m), 3.49 (2H, d), 3.12 (1H, m), 1.73 (2H, m), 1·60 (3H, m), 1.37 (9H, s), 1.23 (6H, s) , 1.02 (4H, m). Step 5: 1-(4-Amino-cyclohexylmethyl)_3,3-dimethyl·ι,3-dihydroguanidin-2-one with 4 M HC1/ ·1° (2 ml) treatment [4-(3,3-dimethyl-2-oxo- 2,3-dihydro-indol-1-ylmethyl)-cyclohexylamino A solution of the third butyl formate (Step 4) in MeOH (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was removed in vacuo and the residue was dissolved in Me 〇H and loaded to On a 10 g SCX column, EtOAc (EtOAc m. d), 7.22 (1H, t), 7.03 (2H, m), 3.50 (2H, d), 3.31 (1H, m), 1.72 (2H, m), 1.67 (1H, m), 1.59 (2H, m ), 1.27 (6H, s), l. oi (2H, m), 〇 91 (2H, m).

The intermediate RR 1-(4-aminocyclohexylmethyl)_3_methyl_1&gt;3-dihydrobenzimidazole-2-ketone hydrochloride is similar to the intermediate RQ by using 丨_曱· 1H_benzo (4) imidazole 2 (3H)-ketone (commercially available) instead of 3,3-dimethyl-1,3-dihydro "bend x 0 _2 ketone (commercially available) (step 4) To prepare the compound LCMS Rt 1,81 min; MS m/z 260.23 [M+H]+; Method LowpH_v002. H NMR (400 MHz, d6-DMSO) δ 7.92 (3H, br), 7.20 (1H, m )' 7.13 (1H, m), 7.07 (2H, m), 3.69 (2H, d), 3.32 (3H, s), 1536Il.doc -123- 201130815 2.92 (1H, m), 1.92 (2H, m) , 1.73 (1H, m), 1.68 (2H, m) 1.23 (2H, m), 1.12 (2H, m).

Intermediate RS 7-methoxy_3,5-dimethyl-^-dihydro-imidazolium 4,5_b]pyridin-2-one

Step 1: (4-Ga-6-fluorenyl-3-tri-pyridin-2-yl)-methyl-amine gives 2,4-digas-6-methyl-3-nitro-pyridine (1.00 The mixture of g, 4.83 mmol) in decylamine (2 EtOAc in THF) (9.66 ml, 19.3 mmol) was ice-cooled and the reaction mixture was stirred at room temperature for an hour (exothermic reaction). The solvent was removed in vacuo and the residue was dissolved in Et EtOAc. The resulting precipitate was filtered off and the solvent was removed in vacuo. Purification by chromatography on cerium chloride eluting with isohexane/EtOAc afforded 6% of the title product. This compound was used in the next step without further purification. Step 2: (4-methoxy-6-methyl-3-nitro-pyridin-2-yl)-methyl-amine (4- gas-6-mercapto-3-nitro-pyridine-2 Methylamine (6% pure) (7 mg, 0.28 mmol) was dissolved in MeOH (10 mL). Sodium methoxide (25% in MeOH) (1.35 g, 6.25 mmol) was. The resulting precipitate was purified by chromatography eluting EtOAc EtOAc (EtOAc) , 3.88 (3H, s), 2.85 (3H, d), 2.30 (3H, s). 153611.doc •124· 201130815 Steps 3 and 4: 7-Methoxy_3,5-dimethyl-1,3-dihydro-imidazo[4,5吒] is similar to the bite-2-one Substituting R for N-ethyl·2·nitro by using (4-methoxy-6-indenyl-3-indolyl η%-pyridin-2-yl)-mercapto-amine (step 2) Aniline is used to prepare the title compound. 1H NMR (400 MHz, DMSO) δ 6.07 ΠΗ “ e v 5.29

(1H,m), 3.79 (3H,s), 3.72 (2H,s), 2.72 (3H,d),2.20 (3H

s). Intermediate RT 2-gas-9-methyl-7,9-dihydro-indole_8-嗣

Similar to 1-ethyl-1,3-dihydro-bromidoimidazole-2-ketone (intermediate ra) by replacing N-B with 2-gas-N4-methylpyrimidine-4,5-diamine This compound is prepared by the base-benzene-i,2-diamine (intermediate RA 'Step 2). Nmr (400 MHz, DMSO) δ 1.59 (1H, broad peak), 8.11 (1H, s), 3.28 (3H, s).

Intermediate RU 2-methoxy-9-methyl-7,9-dihydro-indole-8-one

〇 is similar to (4-methoxy-6-methyl·3-nitro-pyridin-2-yl)-indenylamine (Intermediate RS, Step 2) by using 2-gas-9-A Substituted -7,9-dihydro-indol-8-one (intermediate RT) instead of (4-chloro-6-methyl_3_definite than bit-2-yl)-methylamine 153611.doc - 125-201130815 to prepare the title compound; 4 NMR (400 MHz, DMSO) δ ll.li (1 Η, broad peak), 7.95 (1 Η, s), 3.85 (3 Η, s), 3·21 (3 Η, s ).

The intermediate RV 3,3·dimethyl-I,3-dihydro-pyrrolo[3,2-b]pyridin-2-one is similar to 3,3,5-trimethylindol-2-one (Intermediate Rp), the titled character was prepared by substituting 2-bromopyridin-3-amine with 2-bromopyridine-3-amine (step 1). 1H NMR (400 MHz, d6-DMSO) δ 9.57 (1H s) 8 26 (1H, m), 7.96 (1H, m), 7.49 (1H, m), 5·95 (1H, s), 5 6〇 (lH s), 1.98 (3H, s). ' Biological data: Table 1: Example CRF-1ICS0 (micro tomb, 1.1 0.065 2.1 0.149 2.10 0.201 2.3 0.242 2.4 0.900 2.42 0.275 2.43 0.416 2.5 0.009 2.52 0.612 2.7 0.166 2.8 0.347 2.9 0.016 3.1 0.205 3.3 0.028 3.6 0.145 3.7 0.091 3.8 0.037 153611.doc -126* 201130815 4.2 0.118 5.2 0.126 Table 2: Example CRF-1 IC5〇 (micro-mole) CRF-2 ICs〇 (micro-mole) 1.3 0.048 3.795 2.6 0.012 0.811 2.15 0.017 0.936 2.18 0.050 1.685 2.20 0.062 4.587 2.23 0.057 2.137 2.26 0.157 3.124 2.27 0.157 4.810 2.28 0.038 3.045 2.29 0.014 4.620 2.33 0.044 0.876 2.46 0.044 0.256 2.47 0.018 0.296 2.50 0.086 3.560 2.54 0.059 4.760 2.55 0.060 4.529 3.2 0.047 3.874 3.4 0.018 1.948 127· 153611.doc

Claims (1)

0 0201130815 VII. Patent application scope: 1. A compound of formula I, Wherein R1 is a stupid or 6-membered heteroaryl group, each of which may be substituted or a plurality of substituents selected from the group consisting of ci-ioalkyl, cl_10 alkoxy, dentate and 〇_1〇 alkyl; X1 is One key is either -CR2R3-, -NR4-, -0_ or _CR5R6CR7R8_; X2 is a key or _CR9R10- or -CRUR12CR13R14·; the restriction is that when χΐ is _CR5R6CR7R8·, then X2 is not -CR R CR13R14-, and only one of X1 and χ2 may be a bond; Α is -Ν- or CR15; A2 is CR16; A3 is -N- or CR17; A4 is -N- or CRi*' No more than two of Ai, a3 and a4 are -N-, or R2, R3, R5, R6, R7, R8, R9, R丨. Rll, Rl2, rI3 and R may be the same or different and each is hydrogen, Cl-10 alkyl or halogen, or R2 and R3, R5 and R6, ... and ..., R&gt; , R&quot; and Rl2, and one of r13 and R together form a 3 to 6 membered saturated carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms; r4 is hydrogen or C1-10 alkyl; 153611.doc 201130815 W , R&quot; and R, which may be the same or different and each of which is a gas, a samarium base, a C1-10 alkoxy group, a halogen or a ci-i oxime alkoxy group and its isomers; it is in free form or in the form of a salt form. 2. The compound of claim 1 wherein the compound has sn, 0 Wherein Rlla and Rllb may be the same or different and each is a C-base, a dentate or a C 1 -1 caries; X, X, A, A2, A3 and A4 are each as defined in claim llfj; a construct; it is in free form or in the form of a salt. 3. A compound as claimed in claim 1, wherein the compound has sin, 0 Wherein R and R may be the same or different and each is a crypto, dentate or C1-10 functional group; III XX, A, A, A3 and A4 are each as defined in claim i; and isomers thereof; 153611 .doc 201130815 It is in free form or in the form of a salt. 4. The compound of claim 1, wherein the compound has the formula IV, Wherein R2, R3, R9, R10, A], A2, A and A are each as defined in claim 1; and isomers thereof; in free form or in the form of a salt. 5. The compound of claim 1, wherein the compound has the formula V' Wherein Ri, r11, R12, R13', Ai, A2, A3 and A4 are each as defined in claim 1; and isomers thereof; in free form or in the form of a salt. 6_ The compound of claim 1 wherein the compound has the formula VI' 153611.doc 201130815 wherein R1, R2, R3, A1 are defined; A2, A3 and A4 are each as defined in claim 1 and areomers thereof; they are in free form or in the form of a salt. The compound of claim 1, which is selected from the group consisting of: trans-2-gas-N-[4-(6-gas-2-oxo-2,3-dihydro-indole_丨_曱 ))) _ cyclohexyl]-5-trifluoromethyl benzoguanamine; trans-2-gas-N-[4-(2- oxo-2,3-dihydro-indole 丨_ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; anti-5-gas-Ν_[4_(3,3·didecyl·2·sideoxy_2,3_ Dihydro-(indolyl)-cyclohexyl]-2-mercapto-nicotinium amide; trans-2-gas-Ν-[4-(6-gas-3,3·difluoro-2-side Oxy 2,3·dihydro-indole 4·ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-2-gas-Ν-[4·(3,3 -didecyloxy 2,3-dihydro-pyrrolo[2,3-b]pyridin-1-ylmethyl)-cyclohexyl]-5-trifluoromethyl- phenylcarbamide; -5·Gas-Ν-[4·(3,3-Dinyl-whenyloxy-2,3-dihydro-pyrrolo[2,3-b]« than bite-i-ylmethyl)- Cyclohexyl]·2_methyl-nicotinium decylamine; trans-2-aero-indole-[4-(2-trioxy-2,3·dihydro"pyrolo[2,3_b]pyridine Methyl)cyclohexyl]-5-trifluoromethyl-benzylmamine. trans-2-gas-N-{-4-((5i-fluoro-2,-sideoxy snail [cyclopropene ten] Γ朴Γ-基)methyl) ring }--5-(trifluoromethyl) benzoate; anti-5-chloro-N-[-4-((5'-fluoro-21- pendant oxyspiro[cyclopropane^, 3·,哚#Γ-yl)methyl)cyclohexyl]·2-methylnicotinium amide; trans-2-chloro-indole-[4-(5-methoxy-3,3-dimethylcyloxy) _2,3_Dinitrogen- 153611.doc 201130815 吲哚-1-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-2-gas-N-[4-( 6-decyloxy-3,3-dimethyl-2-oxo-2,3-dihydro-pyrrolo[3,2-c].pyridin-1-ylindenyl)-cyclohexyl] -5-trifluorodecyl-benzamide; trans-2-chloro-N-[4-((R)-3-^-3-methyl-2-oxo-2,3-diazo -0 bow 朵. _ 1- mercapto)-cyclohexyl]-5-trifluorodecyl-crackamine; trans-2-gas-N-[4-((S)-3 - gas- 3-methyl-2-oxo-oxy-2,3-diaza-O-quinone 0-yl-1-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; - gas-N-[4-(3,3-dimethyl-2-oxo- 2,3 -di-n-oxo-oxo-1-ylindenyl)-cyclohexyl]-5-trifluorodecyl - albino amine; trans-2-gas-N-[4-(3,3-dimethyl-2-oxo-5-dioxyloxy-2,3-diaza-° lead D -1-ylmethyl)-cyclohexyl]-5-dimethylmethyl-benzoquinone; anti-5-chloro- N-[4-(5-fluoro-3,3-dimercapto-2-oxo-2,3-dihydro-indolyl-l-ylmethyl)-cyclohexyl]-2-indenyl- Nicotinamide; anti-5-gas-N-[4-(4-methoxy-3,3-dimethyl-2-oxo-2,3-di-argon-β-bend α- L-基曱基)- 哀 己 ] ] 曱 曱 曱 曱 曱 曱 曱 曱 曱 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反 反-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-2-methyl-nicotinium amide; anti-5-gas-:^-[4-(3,3- Difluoro-2-l-oxy-2,3-diindole-indol-1-ylmethyl)- 哀 己 yl]-2-methyl-in the amine; anti-2-gas-Ν-[ 4-(3,3-difluoro-2-oxo-2,3-diar-indol-1-ylindenyl)-cyclohexyl]-5-trifluorodecyl-benzamide; 2-Ga-indole-[4-(7-decyloxy-3,3-dimethyl-2-oxo-2,3-dihydro-indole-l-ylindenyl)-cyclohexyl ]-5-trifluoromethyl-benzoguanamine; 153611.doc 201130815 Reverse-5-gas-N-[4-((R)-3-fluoro-3-methyl-2-oxo-2 ,3-dihydro-°bendo-i•ylindenyl)-cyclohexyl]-2-methyl-nicotinium amide; anti-5_gas-N-[4-((S)-3- Fluor-3-mercapto-2-oxo-2,3-dihydro-β 哚-1·ylmethyl)-cyclohexyl]_2-methyl-nicotinium amide; anti-5_gas- 2 -methyl-indole-(4-((2-oxo oxime[0 oxoline-3,4'-piperidine]-l-yl)methyl)cyclohexyl) acetonide; anti-2 - gas-Ν-[4-(6-methoxy-3,3-dimethyl-2. oxo-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]_5 _Trifluoromethyl-benzoquinone; trans-2-gas-5-trifluoromethyl-N-[4-(3,3,7-trimethyl-2-oxo-2,3- Dihydro-indole-1_ylmethyl)-cyclohexyl]-benzamide; trans-2-gas-5-trifluoromethyl-N-[4-(3,3,4-trimethyl) -2-Sideoxy-2,3-dihydro-0-indole-1-ylindenyl)-cyclohexyl]-benzamide; trans-5-gas-N-[4-(4-chloro - 3,3-dimethyl-2-oxo-2,3-dihydro-β 丨β-l-ylindenyl)-cyclohexyl l·2-methyl-nicotinium amide; -5-gas-N-[4-(6-gas-3,3-difluoro-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-2 -methyl-nicotine decylamine; trans-5-gas-2-methyl-N-[4-(3,3,4-trimethyl-2-nonyloxy-2,3-dihydro-indole Indole-1-ylmethyl)-cyclohexyl]-nicotinium decylamine; trans-5-gas-N-[4-(6-decyloxy-3,3-dimercapto-2-oxo- 2,3-dihydro-indolyl-l-ylmethyl)-cyclohexyl]-2-methyl-nicotinium amide; anti-5-gas-N-[4-(6-gas-3,3 -dimethyl-2- Sideoxy-2,3-dihydro-indole-buylmethyl)-cyclohexyl]-2-methyl-nicotinium amide; anti-5-gas-N-[4-(6-methoxy 3-3,3-dimercapto-2-yloxy-2,3-dihydro-°pyrolo[3,2-c]bitidyl-l-ylmethyl)-cyclohexyl]-2- Mercapto-nicotine 醯153611.doc 201130815 amine; trans-5-chloro-N-[4-(3-fluoro-3,5-dimethyl-2-sideoxy-2,3-dihydro-indole哚_1-ylindenyl)-cyclohexyl]-2-methyl-nicotinium amide; trans-5-chloro-N-[4-(3-fluoro-3,5-dimethyl-2-one Oxy-2,3-dihydro·indolyl-1-ylindenyl)-cyclohexyl]-2-methyl-final amine II anti-5-gas-N-[4-(6-chloro- 3-fluoro-3-methyl-2-oxo-2,3-dihydro-indole D-l-ylindenyl)-cyclohexyl]-2-ylyl------ - gas-N-[4-(6-chloro-3-fluoro-3-methyl-2-oxo-2,3-dihydro-indol-1-ylmethyl)-cyclohexyl]-2 -methyl-to-alkaline amide; trans-2-gas-N-[4-(5-decyloxy-1-o-oxy-3,4-dinitro-1H-isoindole-2-yl) ))-cyclohexyl]-5-trifluoromethyl-benzoguanamine; anti-_2·gas-N-[4-(3-o-oxy-3,4-dihydro-1H-isoquinoline- 2-ylindenyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-5-gas·2-methyl-N-[4_(3,5,6 Trifluoro methyl _2_ _3_ oxo-2,3-dihydro - indazol. Wood-1·ylmethyl)-cyclohexyl-purine test guanamine; anti-5 gas 2-methyl-Ν-[4-(3,5,6-trifluoro_3_methyl_2·sideoxy -2,3-dihydroindolyl fluorenyl)-cyclohexyl l·nicotinium amide; anti-5-gas hydrazine base [4_(2_sideoxy-. 恶 并 [ [4,5 handsome ratio Biting small group methyl)·cyclohexyl]-nicotine decylamine; anti-5·gas-polymethyl-N_[4-(2_sideoxy·stupid 嗤_3_基甲奸环基基)- Final test amine; anti-5-gas, 4·(3,6-dimethyl·2_sideoxy-2,3_dihydro_·嗤[ddin+ylmethyl)_cyclohexyl] 2•Methyl-enriched amine; anti-5_chloro*[4·(3_ethyl_2_sideoxy·2,3_dihydro-decaine and [4,5_〇153611.doc 201130815 pyridine -1-ylmethyl)-cyclohexyl]-2-methyl-nicotinium amide; trans-5-gas-oxime [4-(3,7-dimethyl-2-pyrene-2) 3-dihydro-imidazo[4,5-b]° ratio nitr-1-ylmethyl)-cyclohexyl]-2-indolyl-prodecylamine; trans-5-chloro-N-[4- (3,5-Dimethyl-2-oxo-2,3·dihydro-imidazo[4,5-b]0-biti-1-ylmethyl)-cyclohexyl]-2-indenyl - final test guanamine; trans-5-gas-N-[4-(l,5-dimethyl-2-oxo-1,2-dihydro-imidazo[4,5-b]acridine -3-ylindenyl)-cyclohexyl]·2 ·Methyl-nicotine decylamine; trans-5-chloro-N-[4-(3-ethyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylindenyl)- Cyclohexyl]-2-mercapto-nicotinamide; trans-5-gas·Ν-[4-(3-isobutyl-2-oxo-2,3-dihydro-benzimidazole-i_ (n-(5-methoxy-3-methyl-2-oxo- 2, 3-Dinitromethane β sits and [4,5-b]°fc.-1-ylmethyl)-cyclohexyl]-2-methyl-in the amine; anti-5-gas-2-A -N-[4-(3,3,5-trimethylidene-2-yloxy-2,3-dihydro-indol-1-ylindenyl)-cyclohexyl]-nicotinium amide; -5-5-Ga-2·Methyl-N-[4-(3 - f-based 2-epoxy-2,3·dihydro-benzoimidazol-1-ylindenyl)-cyclohexyl]- Nicotinamide; anti-5-gas-2-methyl·Ν-[4-(1-methyl_2_sideoxy-1,2·dihydro-imiindole[4,5-b] 〇 咬 -3- 曱 ) ) ) ) ) ) ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ Small base methyl)-cyclohexyl]-2-methyl-5-trifluoromethyl-nicotinium amide; trans-5-gas-2-methyl-Ν-[4-(2- side oxygen Base 2,3-dihydro-benzoimidazol-1-ylmethyl)cyclohexyl]-nicotinium amide; -5-Gas-Ν-[4-(3-Fluoro-3,5,6-trimercapto-2-oxo-2,3-dihydro·吲153611.doc 201130815 哚_1_ylmethyl )-cyclohexyl]-2-indenyl--an enantiomer of the amine (1); anti-5-chloro-N-[4-(3-fluoro-3,5,6-trimethyl-2) _Sideoxy-2,3·dihydro--吲哚_1_ylindenyl)-cyclohexyl]-2-methyl-in the enantiomer of decylamine 2; trans-5-chloro- 1^-[4-(7-methoxy-3,5-diindolyl-2-ylidene-2,3-dihydro-imiline][4,5-b] ° 唆-1 -ylmethyl)-cyclohexyl]-2_fluorenyl-protonamine; trans-5-chloro- 4-(3,3-dimethyl-2-oxo-2,3-hydrogen Bis-[3,2 sec-but-1-ylmethyl)-cyclohexyl]methyl-in the amine; anti-5-gas-N-[4-(2-decyloxy-9-- Base I side oxy _8,9-monohydro π 7 7-ylmethyl)-cyclohexyl l·2-indenyl--------5-gas-Ν-[4-(2-chloro -9H8-trioxy-8,9-diox-valerium I-methyl)-cyclohexyl]-2-methyl-nicotinamide; anti-2-chloro-indole[4-(5- Chloro-2-oxo-2,3-dihydroindolyl-1-ylindenyl)cyclohexyl]-5-trifluoromethyl-benzamide; trans-2-chloro-indole-[4 -(6-fluoro-2-o-oxy-2,3-di&-bamboo-bu-methyl) cyclohexyl]-5- Fluoromethyl-codamine; trans- 2_chloro-indole-[4-(5-fluoro_3,3-dimethyl-2-oxo-2,3·dihydro-indole-1 _ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzoguanamine; trans-2-gas-Ν-[4-(3_ethyl·2_sideoxy-2,3-di Hydrogen-benzimid-1-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-2-gas-&gt;!-[4-(3-mercapto-2 - pendant oxy-2,3-dihydro-imiphthene [4,5^]. Bipyridyl-1 -ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; trans-2-chloro-N-[4-(l-methyl-2-yloxy·1 ,2·Dihydro-imidazo[4,5_b]»pyridin-3-ylmethyl)-cyclohexyl]-5-trifluoromethyl-benzamide; 153611.doc -9- 201130815 anti_2 · gas_N-[4-(2· sideoxy-2,3_dihydro-benzoimidazole** fluorenyl)* cyclohexyl]-5-trifluoromethyl-benzamide; counter-2 - gas-N-[4-(3-methyl.2. pendantoxy-2,3-dihydro-benzimidazolyl)-cyclohexyl]·5-difluoromethyl-benzoguanamine ; anti-HN-[4-(3-methyl_2_sideoxy-2,3-dihydro-benzo-salt-salt methyl)-cyclohexyl]-3-trifluoromethyl group Amine trifluoroacetate; soil trans-2,5-diqi-indole-[4·(3-methyl-2-oxooxy-2,3_dihydro-bromoindole-1-ylindenyl)- Cyclohexyl]-benzamide amine trifluoroacetate; 'anti-Ν-[4-(3,3-didecyloxy 2,3-dihydroanthracene) carbamide) cyclohexyl ]-4-fluoro-3-trifluoromethyl-benzoguanamine; trans-2,5-diqi-indole-[4-(3,3-dimethyl-2-oxooxy-2,3_ -Spectrum - 0 bow I 〇 · · 1- mercapto)-cyclohexyl]-benzamide; and anti-Ν-[4-(3,3-dimethyl-2_ side Oxy-2,3-dihydro-indolyl)cyclohexyl]-3-methoxy-benzamide; and isomers thereof; in free form or in the form of a salt. 8. A compound of formula I according to claim 1 which is for use as a medicament. 9. A compound of formula I according to claim 1 which is for use as a corticotropin releasing factor (CRF) receptor antagonist. 10. The use of a compound of the formula I as claimed in claim 1 for the manufacture of a medicament. U. A use of a compound of the formula I as claimed in claim 1 for the production of a corticotropin releasing factor (CRF) A drug for a body antagonist. 12. The use of a compound of the formula I as claimed in claim 1 for use in the manufacture of 15361 丨.doc • 10·201130815 or to reduce the increase in endogenous CRF content or ΗΡΑ (hypothalamic pituitary axis) dysregulation Any of the conditions or drugs of various diseases induced or promoted by CRF. 13. A composition comprising a compound of the formula I in the form of a free form, in a form of pharmaceutically acceptable &quot;&quot; In combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Also 14, the compound 'includes as a free form or in the form of a pharmaceutically pharmaceutically acceptable salt as claimed. The formula [combination of the compound with another therapeutic component] is optionally combined with a pharmaceutically acceptable adjuvant formulation. Further, an adjuvant, a diluent or a carrier. 15. A compound of the formula VII, Wherein X1, X2, A1, A2, a3; 5 A4 t 1 A and A are each as defined and their isomers; as defined in item 1; they are in free form or in the form of a salt. 153611.doc 201130815 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: person 153611.doc