CN1334811A - Tricyclic farnesyl protein transferase inhibitors - Google Patents

Abstract

The present invention discloses a compound of formula (1.0), wherein ^R13 represents an imidazole ring; ^R14 represents a carbamate, urea, amide, or sulfonamide group; ^R8 represents H when the alkyl chain between the amide group and the ^R13 imidazole group is substituted, otherwise ^R8 represents a substituent such as an aralkyl or heteroarylalkyl group; the remaining substituents are as defined in the specification. The present invention also discloses compounds in which ^R8 is H and the alkyl chain between the amide group and the ^R13 imidazole group is not substituted, and discloses methods for treating cancer and methods for inhibiting farnesyltransferase using the disclosed compounds.

Description

Tricyclic farnesyl protein transferase inhibitors

Background of invention

April 20 nineteen ninety-five disclosed WO95/10516, on October 10th, 1996, the patent application serial numbers 09/094687 (submission on June 15th, 1998) of disclosed WO96/31478 and common pending trial all disclosed the tricyclic compounds that is used to suppress farnesyl-protein transferase.

In view of farnesyl protein transferase inhibitors has great importance, therefore, should provide the compound that a class is used to suppress farnesyl-protein transferase for the significant contribution in this field, and the present invention is just providing such contribution.

Summary of the invention

The invention provides the compound that is used to suppress farnesyl-protein transferase (FPT).Compound of the present invention or its pharmacy acceptable salt or solvate can be represented with following formula:

Wherein:

One of a, b, c and d represent N or N ⁺O ^-, remaining a, b, c and d group are represented CR ¹Or CR ²Perhaps

Each a, b, c and d independently are selected from CR ¹Or CR ²

When the optional key by the dotted line representative did not exist, X represented N or CH, and when having this optional key, X represents C;

The optional key of dotted line between the carbon atom 5 and 6 representative is so that when having pair key, A and B independently represent-R ¹⁵, halo ,-OR ¹⁶,-OCO ₂R ¹⁶Or-OC (O) R ¹⁵, when not having two key between carbon atom 5 and 6, the independent respectively H that represents of A and B ₂,-(OR ¹⁶) ₂, H and halo, dihalo, alkyl and H, (alkyl) ₂,-H and-OC (O) R ¹⁵, H and-OR ¹⁵,=O, aryl and H ,=NOR ¹⁵Or-O-(CH ₂) _p-O-, wherein p is 2,3 or 4;

Each R ¹With each R ²Independently be selected from H, halo ,-CF ₃,-OR ¹⁵(as-OCH ₃) ,-COR ¹⁵,-SR ¹⁵(as-SCH ₃With-SCH ₂C ₆H ₅) ,-S (O) _tR ¹⁶(wherein t is 0,1 or 2, as-SOCH ₃With-SO ₂CH ₃) ,-N (R ¹⁵) ₂,-NO ₂,-OC (O) R ¹⁵,-CO ₂R ¹⁵,-OCO ₂R ¹⁶,-CN ,-NR ¹⁵COOR ¹⁶,-SR ¹⁶C (O) OR ¹⁶(as-SCH ₂CO ₂CH ₃) ,-SR ¹⁶N (R ¹⁷) ₂(prerequisite is-SR ¹⁶N (R ¹⁷) ₂In R ¹⁶Be not-CH ₂-), each R wherein ¹⁷Independently be selected from H or-C (O) OR ¹⁶(as-S (CH ₂) ₂NHC (O) the O-tertiary butyl and-S (CH ₂) ₂NH ₂), tetrazolium-5-base sulfo-of benzotriazole-1-base oxygen base, tetrazolium-5-base sulfo-and replacement (tetrazolium-5-base sulfo-that replaces as alkyl is as 1-methyl-tetrazolium-5-base sulfo-), alkynyl, alkenyl and alkyl, described alkyl or alkenyl optional by halo ,-OR ¹⁵Or-CO ₂R ¹⁵Replace;

R ³And R ⁴Identical or different, the independent respectively H, R of representing ¹And R ²Or R ³And R ⁴In any substituting group represent saturated or undersaturated together and phenyl ring (ring III) condensed C ₅-C ₇Ring;

R ⁵, R ⁶And R ⁷Respectively independent represent H ,-CF ₃,-COR ¹⁵, alkyl or aryl, described alkyl or aryl is chosen quilt-OR wantonly ¹⁵,-SR ¹⁵,-S (O) _tR ¹⁶,-NR ¹⁵COOR ¹⁶,-N (R ¹⁵) ₂,-NO ₂,-COR ¹⁵,-OCOR ¹⁵,-OCO ₂R ¹⁶,-CO ₂R ¹⁵,-OPO ₃R ¹⁵Perhaps R ⁵With R ⁶Together representative=O or=S;

R ⁸Be selected from H, C ₃-C ₄Alkyl (preferred branched-chain alkyl, more preferably C ₄-C ₇Branched-chain alkyl), the cycloalkylalkyl of the cycloalkyl of the heteroarylalkyl of the heteroaryl of the aralkyl of the aryl of the alkyl of aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, replacement, replacement, replacement, replacement, replacement, replacement, replacement;

R ⁸Substituting group be selected from alkyl, aryl, aralkyl, cycloalkyl ,-N (R ¹⁸) ₂,-OR ¹⁸, cycloalkylalkyl, halo, CN ,-C (O) N (R ¹⁸) ₂,-SO ₂N (R ¹⁸) ₂Or-CO ₂R ¹⁸Prerequisite is-OR ¹⁸With-N (R ¹⁸) ₂Substituting group is not attached to and-C (O) NR ⁸On the carbon that the N of part links to each other;

Each R ¹⁸Independently be selected from H, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl;

R ⁹And R ¹⁰Independently be selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl or-CON (R ¹⁸) ₂(R wherein ¹⁸Identical with above-mentioned definition); And substituent R ⁹And R ¹⁰Optional be selected from following substituting group by one or more (as 1-3) and replace: alkyl (as methyl, ethyl, sec.-propyl etc.), cycloalkyl, aralkyl or heteroarylalkyl (are R ⁹And/or R ¹⁰Group can be unsubstituted or can be replaced by 1-3 above-mentioned substituting group, but work as R ⁹And/or R ¹⁰Except during for H); Perhaps

R ⁹And R ¹⁰Form C with the carbon atom that they connected ₃-C ₆Cycloalkyl ring;

R ¹¹And R ¹²Independently be selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl ,-CON (R ¹⁸) ₂,-OR ¹⁸Or-N (R ¹⁸) ₂, R wherein ¹⁸Identical with above-mentioned definition; Prerequisite is-OR ¹⁸With-N (R ¹⁸) ₂Be not attached on the carbon atom adjacent with nitrogen-atoms; And wherein said substituent R ¹¹And R ¹²Optional be selected from following substituting group by one or more (as 1-3) and replace: alkyl (as methyl, ethyl and sec.-propyl etc.), cycloalkyl, aralkyl or heteroarylalkyl; Perhaps

R ¹¹And R ¹²Form C with the carbon atom that they connected ₃-C ₆Cycloalkyl ring;

R ¹³For being selected from following imidazoles basic ring:

Or

R wherein ¹⁹Be selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) aralkyl, the aralkyl that (6) replace, wherein said substituting group is selected from halo (as F and Cl) and CN, (7)-C (aryl) ₃(as-C (phenyl) ₃, i.e. trityl) or (8) cycloalkyl;

Described imidazoles basic ring 2.0 or 2.1 is chosen wantonly and is replaced by one or two substituting group, and described imidazoles basic ring 4.0 is chosen wantonly by 1-3 substituting group and is replaced, described imidazoles basic ring 4.1 is optional to be replaced by a substituting group, wherein encircles on the carbon atom that 2.0,2.1,4.0 and 4.1 described optional substituting group is connected in described imidazoles basic ring and described optional substituting group independently is selected from :-NHC (O) R ¹⁸,-C (R ³⁴) ₂OR ³⁵,-OR ¹⁸,-SR ¹⁸, F, Cl, Br, alkyl, aryl, aralkyl, cycloalkyl or-N (R ¹⁸) ₂(each R wherein ¹⁸Separate); R wherein ¹⁸Identical with above-mentioned definition; Each R ³⁴Independently be selected from H or alkyl (preferable methyl), preferred H; R ³⁵Independently be selected from H ,-C (O) OR ²⁰Or-C (O) NHR ²⁰, R ²⁰The following definition (preferred R ²⁰Be alkyl or cycloalkyl, most preferably be cyclopentyl or cyclohexyl); Q represents aryl rings (as phenyl), cycloalkyl ring (as cyclopentyl or cyclohexyl) or heteroaryl ring (as furyl, pyrryl, thienyl, oxazolyl or thiazolyl), and described Q is optional independently to be selected from following substituting group by 1-4 and to replace: halo (as F or Cl), alkyl, aryl ,-OR ¹⁸,-N (R ¹⁸) ₂(each R wherein ¹⁸Be independent the selection) ,-OC (O) R ¹⁸Or-C (O) N (R ¹⁸) ₂(each R wherein ¹⁸Be independent the selection), and R ¹⁸Identical with above-mentioned definition; (C (R ³⁴) ₂OR ³⁵The example of group comprises-CH ₂OH ,-CH ₂OC (O) OR ²⁰With-CH ₂OC (O) NHR ²⁰)

R ¹⁴Independently be selected from:

Or

R ¹⁵Be selected from H, alkyl, aryl or aralkyl;

R ¹⁶Be selected from alkyl or aryl;

R ²⁰Be selected from H, alkyl, alkoxyl group, aryl, aralkyl, cycloalkyl, heteroaryl, heteroarylalkyl or Heterocyclylalkyl, prerequisite is to work as R ¹⁴Be group 5.0 or at 8.0 o'clock, so R ²⁰Not H;

Work as R ²⁰When being not H, so described R ²⁰Group is optional to be selected from following substituting group by one or more (as 1-3) and to replace: halo, alkyl, aryl ,-OC (O) R ¹⁸(as-OC (O) CH ₃) ,-OR ¹⁸Or-N (R ¹⁸) ₂, each R wherein ¹⁸Identical or different and R wherein ¹⁸Identical with above-mentioned definition, prerequisite is that described optional substituting group is not attached on the carbon atom adjacent with oxygen or nitrogen-atoms;

R ²¹Be selected from H, alkyl, aryl, aralkyl, cycloalkyl, heteroaryl, heteroarylalkyl or Heterocyclylalkyl;

Work as R ²¹When being not H, so described R ²¹Group is optional to be selected from following substituting group by one or more (as 1-3) and to replace: halo, alkyl, aryl ,-OR ¹⁸Or-N (R ¹⁸) ₂, each R wherein ¹⁸Identical or different and R wherein ¹⁸Identical with above-mentioned definition, prerequisite is that described optional substituting group is not attached on the carbon atom adjacent with oxygen or nitrogen-atoms;

N is 0-5;

For different n (be each-C (R ³²) (R ³³)-group), each R ³²And R ³³Independently be selected from: H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl ,-CON (R ¹⁸) ₂,-OR ¹⁸Or-N (R ¹⁸) ₂, R wherein ¹⁸Identical with above-mentioned definition, and wherein said substituent R ³²And R ³³Optional be selected from following substituting group and replace: alkyl (as methyl, ethyl and sec.-propyl etc.), cycloalkyl, aralkyl or heteroarylalkyl by one or more; Perhaps

R ³²And R ³³Form C with the carbon atom that they connected ₃-C ₆Cycloalkyl ring;

R ³⁶Be selected from branched-chain alkyl, straight chained alkyl, cycloalkyl, Heterocyclylalkyl or aryl (as phenyl); And

Prerequisite is:

(l) work as R ¹⁴Be selected from: group 6.0,7.0,7.1 and 8.0, when X is N, R so ⁸Be selected from C ₃-C ₁₀The C of alkyl, replacement ₃-C ₁₀The cycloalkylalkyl of the heteroarylalkyl of the aralkyl of alkyl, aralkyl, replacement, heteroarylalkyl, replacement, cycloalkylalkyl or replacement; With

(2) work as R ¹⁴Be selected from: group 6.0,7.0,7.1 and 8.0, X are N, R ⁸During for H, R so ¹³(being imidazole ring 2.0,4.0 or 4.1) and amide moieties (promptly-C (O) NR ¹⁸) between alkyl chain be substituted i.e. (a) R ⁹, R ¹⁰, R ¹¹, R ¹², R ³²And R ³³In have at least one not to be H, and/or (b) R ⁹And R ¹⁰, and/or R ¹¹And R ¹²Form cycloalkyl ring together.

The present invention also provides the compound of above-mentioned formula 1.0, wherein works as R ¹⁴Be group 5.0, X is N and R ⁸During for H, R so ¹³(being imidazole ring 2.0,4.0 or 4.1) and amide moieties (promptly-C (O) NR ¹⁸) between alkyl chain be substituted i.e. (a) R ⁹, R ¹⁰, R ¹¹, R ¹², R ³²And R ³³In at least one is not H, and/or (b) R ⁹And R ¹⁰, and/or R ¹¹And R ¹²Form cycloalkyl ring together.

Compound of the present invention has following effect: (i) externally can effectively suppress farnesyl-protein transferase, but not suppress geranyl geranyl protein transferase I; (ii) block by the farnesyl acceptor and transform Ras type inductive phenotypic alternation, rather than transform Ras type inductive phenotypic alternation by the geranyl geranyl acceptor that makes up; The (iii) interior processing of the cell of blocked method Thessaloniki acceptor Ras, and interior the processing and the (iv) misgrowth of blocking-up conversion Ras inductive cells in culture of cell of not blocking the geranyl geranyl acceptor Ras of structure.

Compound of the present invention suppresses the farnesylation of farnesyl-protein transferase and oncogene protein Ras.Therefore, the present invention also provides above-mentioned tricyclic compounds by giving significant quantity to suppress the method for farnesyl-protein transferase (as the ras farnesyl-protein transferase) in the Mammals (particularly people).Give patient's compound of the present invention with the inhibition farnesyl-protein transferase, thereby can be used for the treatment of following cancer.

The invention provides and suppress or the excrescent method of treatment cell (comprising transformant), this method comprises the compound of the present invention that gives significant quantity.The growth of abnormal growth of cells phalangeal cell does not rely on normal regulating mechanism (as the forfeiture contact inhibition).This comprises following abnormal growth of cells: (1) expresses the tumour cell (tumour) of activated Ras oncogene; (2) tumour cell that is activated owing to the Cancer-causing mutation of another kind of gene of Ras albumen and (3) optimum and malignant cell that unusual other proliferative diseases of Ras activated take place wherein.

The present invention also provides the method that suppresses or treat tumor growth by the tricyclic compounds described herein of the Mammals that needs this kind treatment (as the people) significant quantity.Particularly, the invention provides the method that suppresses or treat the tumor growth of expressing activated Ras oncogene by the above-claimed cpd that gives significant quantity, the example of the tumour that can be suppressed or treat includes, but is not limited to: lung cancer (as adenocarcinoma of lung), carcinoma of the pancreas (as carcinoma of the pancreas as the exocrine pancreas cancer), colorectal carcinoma (as colorectal carcinoma such as adenocarcinoma of colon and adenoma of colon), myeloid leukemia (as acute myeloid leukemia (AML)), thyroid follcular carcinoma, myelodysplastic syndromes (MDS), bladder cancer, epidermal carcinoma, melanoma, mammary cancer and prostate cancer.

Believe that the present invention also provides inhibition or treats optimum and the method neoplasm disease, Ras albumen in these diseases is because other gene carinogenicity sudden change and by abnormal activation, be that Ras gene itself is not activated owing to sporting the oncogene form, described inhibition or treatment are to realize by the tricyclic compounds described herein of the Mammals that needs this type of treatment (as the people) significant quantity.For example, give described tricyclic compounds and can suppress or treat the benign proliferative diseases neurofibroma, perhaps the tumour that is activated owing to (as neu, src, abl, lck and the fyn) sudden change of Tyrosylprotein kinase oncogene or overexpression of Ras wherein.

The tricyclic compounds that adopts in the inventive method can suppress or treat abnormal growth of cells.Be not bound by any theory although do not wish, but, we think that these compounds are to suppress the proteic function of G-by blocking-up G-albumen prenylization (isoprenylation), function as ras p2l works, thereby makes these compounds can be used for the treatment of proliferative disease such as tumor growth and cancer.Although do not wish to be bound by any theory,, we think that also these compounds can suppress the ras farnesyl-protein transferase, therefore the ras transformant are shown anti-proliferative activity.

Detailed Description Of The Invention

Except that indicating in addition, following term has following meaning as used herein:

MH ⁺: the molion hydrogenation of mass spectrum middle finger molecule;

BOC: tert-butoxycarbonyl;

CBZ:-C (O) OCH ₂C ₆H ₅(being benzyloxycarbonyl);

CH ₂Cl ₂: methylene dichloride;

CIMS: chemical ioni zation mass spectrum;

DEAD: diethyl azodiformate;

DEC: represent EDCI, i.e. 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride;

DMF:N, dinethylformamide;

Et: ethyl;

EtOAc: ethyl acetate;

EtOH: ethanol;

The HOBT:1-hydroxy benzotriazole hydrate;

IPA: Virahol;

IPrOH: Virahol;

Me: methyl;

MeOH: methyl alcohol;

MS: mass spectrum;

The NMM:N-methylmorpholine;

Ph: phenyl;

Pr: propyl group;

TBDMS: t-butyldimethylsilyl;

TEA: triethylamine;

TFA: trichoroacetic acid(TCA);

THF: tetrahydrofuran (THF);

Tr: trityl;

Alkyl: represent straight shape and ramose and contain the carbochain of 1-20 carbon atom, preferred 1-6 carbon atom;

Acyl group: expression G-C (O)-group, wherein G represent alkyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl ,-the O-alkyl ,-O-aryl or NR ²⁵R ²⁶, R wherein ²⁵And R ²⁶Independently be selected from alkyl or aryl;

Aralkyl: the alkyl of the above-mentioned definition that the aryl of quilt as following definition replaces, so that another substituent key is connected with moieties;

Aryl: the aryl that comprises aralkyl moiety, contain 6-15 carbon atom and have the carbocyclic ring (is phenyl ring as aryl) of at least one aromatic ring, all can all can be all possible tie point by substituted carbon atom isocyclic, and described carbocyclic ring is optional to be selected from following group by one or more (as 1-3) and to replace: halo, alkyl, hydroxyl, alkoxyl group, phenoxy group, trifluoromethyl ,-C (O) N (R ¹⁸) ₂,-SO ₂R ¹⁸,-SO ₂N (R ¹⁸) ₂, amino, alkylamino, dialkylamino ,-COOR ²³With-NO ₂, R wherein ²³Represent alkyl or aryl; With

Cycloalkyl: saturated carbon ring with 3-20 carbon atom, preferred 3-7 carbon atom, described cycloalkyl ring is optional to be replaced by one or more (as 1,2 or 3) alkyl (as methyl or ethyl), when existing more than 1 alkyl, each alkyl is independent the selection;

Cycloalkylalkyl: by the cycloalkyl of the above-mentioned definition of the alkyl of above-mentioned definition replacement, so that another substituent key is connected with moieties;

Halo: fluoro, chloro, bromo and iodo;

Heteroaralkyl: by the alkyl of the above-mentioned definition of the heteroaryl of above-mentioned definition replacement, so that another substituent key is connected with moieties;

Heteroaryl: have at least one and be selected from the heteroatomic optional of O, S and N by R ³And R ⁴The cyclic group that replaces, described heteroatoms is spaced apart with the carbocyclic ring ring texture, and has the delocalization pi electronics of enough numbers so that this aromatic heterocyclic group has the character of aromatic group, described aromatic heterocycle preferably contains 2-14 carbon atom, as 2-or 3-furyl, 2-or 3-thienyl, 2-, 4-or 5-thiazolyl, 2-, 4-or 5-imidazolyl, 2-, 4-or 5-pyrimidyl, the 2-pyrazinyl, 3-or 4-pyridazinyl, 3-, 5-or 6-[1,2,4-triazinyl], 3-or 5-[1,2, the 4-thiadiazolyl group], 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-indyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, triazolyl, 2-, 3-or 4-pyridyl or pyridyl N-oxide compound are (optional by R ³And R ⁴Replace), wherein pyridyl N-oxide compound can be represented with following formula: Or

With

Heterocyclylalkyl: contain saturated, the side chain or the unbranched carbocyclic ring of 3-15 carbon atom, preferred 4-6 carbon atom, wherein carbocyclic ring can by 1-3 is individual is selected from-O-,-S-or-NR ²⁴Heteroatoms at interval, R wherein ²⁴Represent alkyl, aryl ,-C (O) N (R ¹⁸) ₂(R wherein ¹⁸Identical with above-mentioned definition, as-C (O) NH ₂) or acyl group (suitable Heterocyclylalkyl comprises 2-or 3-tetrahydrofuran base, 2-or 3-tetrahydro-thienyl, THP trtrahydropyranyl, 2-, 3-or 4-piperidyl, 2-or 3-pyrrolidyl, 2-or 3-piperazinyl, 2-or 4-dioxane base, morpholinyl etc.).

The numbering of three ring ring systems is as follows:

Formula 1.0 compounds comprise 2R shown in following and 2S isomer (preferred 2R isomer):

R ⁸Substituent example comprises: benzyl ,-CH ₂C (CH ₃) ₂,-CH ₂-cyclohexyl ,-CH ₂-cyclopropyl ,-(CH ₂) ₂CH ₃,

With

R ⁹And R ¹⁰Examples of groups comprises H and benzyl.

R ¹¹And R ¹²Examples of groups comprise H ,-CH ₃,-CH ₂CH (CH ₃) ₂,-(CH ₂) ₃CH ₃, benzyl, ethyl, right-chloro-phenyl-and hydroxyl.

Cyclopropyl is R ¹¹And R ¹²Group forms the example of cycloalkyl ring with the carbon atom that they connected.

R ¹³The optional substituent example of part comprises-CH ₃,-CH ₂OH ,-CH ₂OC (O) O-cyclohexyl ,-CH ₂OC (O) O-cyclopentyl, ethyl, sec.-propyl, amino and-NHC (O) CF ₃

R ¹⁹Example comprise-C (O) NH-cyclohexyl ,-C (phenyl) ₃, H, methyl or ethyl.

R in the group 5.0 ²⁰Example comprise the tertiary butyl, ethyl, benzyl ,-CH (CH ₃) ₂,-CH ₂CH (CH ₃) ₂,-(CH ₂) ₂CH ₃, normal-butyl, n-hexyl, n-octyl, right-chloro-phenyl-, cyclohexyl, cyclopentyl, Or

R in the group 5.0 ²⁰Another example comprise:

6.0 in R ²⁰And R ²¹Example comprise cyclohexyl, the tertiary butyl, H ,-CH (CH ₃) ₂, ethyl ,-(CH ₂) ₂CH ₃, phenyl, benzyl, (CH ₂) ₂Phenyl and-CH ₃

7.0 in R ²⁰Example comprise 4-pyridyl NO ,-OCH ₃,-CH (CH ₃) ₂, the tertiary butyl, H, propyl group, cyclohexyl and

7.1 in R ³⁶Example comprise cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl and With

8.0 in R ²⁰Example comprise methyl, sec.-propyl and cyclohexyl methyl.

R ³²And R ³³Example comprise H, phenyl, hydroxyl and benzyl.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be selected from 6.0,7.0,7.1 and 8.0, when X is C or CH (preferred CH), R so ⁸Be selected from C ₃-C ₁₀The C of alkyl, replacement ₃-C ₁₀The cycloalkylalkyl of the heteroarylalkyl of the aralkyl of alkyl, aralkyl, replacement, heteroarylalkyl, replacement, cycloalkylalkyl and replacement.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be selected from 6.0,7.0,7.1 and 8.0, X is C or CH (preferred CH) and R ⁸During for H, R so ¹³(being imidazole ring 2.0,4.0 or 4.1) and amide moieties (promptly-C (O) NR ¹⁸Group) alkyl chain between is substituted, i.e. (a) R ⁹, R ¹⁰, R ¹¹, R ¹², R ³²Or R ³³In have at least one not to be H, and/or (b) R ⁹And R ¹⁰And/or R ¹¹And R ¹²Form cycloalkyl ring together.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be 5.0, X is C or CH (preferred CH) and R ⁸During for H, R so ¹³(being imidazole ring 2.0,4.0 or 4.1) and amide moieties (promptly-C (O) NR ¹⁸Group) alkyl chain between is substituted, i.e. (a) R ⁹, R ¹⁰, R ¹¹, R ¹², R ³²Or R ³³In have at least one not to be H, and/or (b) R ⁹And R ¹⁰And/or R ¹¹And R ¹²Form cycloalkyl ring together.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be selected from 6.0,7.0,7.1 or 8.0, when X is C or CH (preferred CH), R so ⁸Be selected from the cycloalkylalkyl of heteroarylalkyl, cycloalkylalkyl and replacement of aralkyl, heteroarylalkyl, the replacement of aralkyl, replacement.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be group 5.0, when X is C or CH (preferred CH), R so ⁸Be selected from the cycloalkylalkyl of heteroarylalkyl, cycloalkylalkyl and replacement of aralkyl, heteroarylalkyl, the replacement of aralkyl, replacement.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be selected from 6.0,7.0,7.1 and 8.0, when X is N, R so ⁸Be selected from the cycloalkylalkyl of heteroarylalkyl, cycloalkylalkyl and replacement of aralkyl, heteroarylalkyl, the replacement of aralkyl, replacement.

Compound of the present invention comprises formula 1.0 compounds, wherein works as R ¹⁴Be 5.0, when X is N, R so ⁸Be selected from the cycloalkylalkyl of heteroarylalkyl, cycloalkylalkyl and replacement of aralkyl, heteroarylalkyl, the replacement of aralkyl, replacement.

Therefore, one embodiment of the invention relate to such compound, wherein R ¹⁴Be carbamate groups 5.0, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is N, and remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is C or CH (preferred CH), and remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is N, R ⁸Be the aralkyl (preferred aralkyl) of aralkyl or replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is N, R ⁸Be the heteroarylalkyl (preferred heteroarylalkyl) of heteroarylalkyl or replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is N, R ⁸Be the cycloalkylalkyl (preferred cycloalkylalkyl) of cycloalkylalkyl or replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is C or CH (preferred CH), R ⁸Be the aralkyl (preferred aralkyl) of aralkyl or replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is C or CH (preferred CH), R ⁸Be the heteroarylalkyl (preferred heteroarylalkyl) of heteroarylalkyl or replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴Be carbamate groups 5.0, X is C or CH (preferred CH), R ⁸Be the cycloalkylalkyl (preferred cycloalkylalkyl) of cycloalkylalkyl or replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein works as R ¹⁴Be group 5.0, X is C or CH (preferred CH) and R ⁸During for H, R so ¹³(being imidazole ring 2.0,4.0 or 4.1) and amide moieties (promptly-C (O) NR ¹⁸Group) alkyl chain between is substituted, i.e. (a) R ⁹, R ¹⁰, R ¹¹, R ¹², R ³²And R ³³In have at least one not to be H, and/or (b) R ⁹And R ¹⁰And/or R ¹¹And R ¹²Form cycloalkyl ring together, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein works as R ¹⁴Be group 5.0, X is N and R ⁸During for H, R so ¹³(being imidazole ring 2.0,4.0 or 4.1) and amide moieties (promptly-C (O) NR ¹⁸Group) alkyl chain between is substituted, i.e. (a) R ⁹, R ¹⁰, R ¹¹, R ¹², R ³²And R ³³In have at least one not to be H, and/or (b) R ⁹And R ¹⁰And/or R ¹¹And R ¹²Form cycloalkyl ring together, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴For being selected from 6.0,7.0,7.1 and 8.0 group, X is N, R ⁸Be the aralkyl (preferred aralkyl) of aralkyl and replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴For being selected from 6.0,7.0,7.1 and 8.0 group, X is N, R ⁸Be the heteroarylalkyl (preferred heteroarylalkyl) of heteroarylalkyl and replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴For being selected from 6.0,7.0,7.1 and 8.0 group, X is N, R ⁸Be the cycloalkylalkyl (preferred cycloalkylalkyl) of cycloalkylalkyl and replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴For being selected from 6.0,7.0,7.1 and 8.0 group, X is C or CH (preferred CH), R ⁸Be the aralkyl (preferred aralkyl) of aralkyl and replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴For being selected from 6.0,7.0,7.1 and 8.0 group, X is C or CH (preferred CH), R ⁸Be the heteroarylalkyl (preferred heteroarylalkyl) of heteroarylalkyl and replacement, remaining substituting group is identical with definition in the formula 1.0.

Another embodiment of the invention relates to such compound, wherein R ¹⁴For being selected from 6.0,7.0,7.1 and 8.0 group, X is C or CH (preferred CH), R ⁸Be the cycloalkylalkyl (preferred cycloalkylalkyl) of cycloalkylalkyl and replacement, remaining substituting group is identical with definition in the formula 1.0.

R ¹, R ², R ³And R ⁴Be preferably selected from H and halo, more preferably be selected from H, Br, F and Cl, most preferably be selected from H, Br and Cl.The representative compounds of formula 1.0 comprises three halos, dihalo and a halogenated compound, as (1) 3, and 8,10-three halos; (2) 3,7,8-three halos; (3) 3,8-dihalos; (4) 8-halo and (5) 10-halogenated compound; Wherein each halo all is independent selections.Preferred formula 1.0 compounds comprise: (1) 3-Br, 8-Cl, the compound that 10-Br-replaces; (2) 3-Br, 7-Br, the compound that 8-Cl-replaces; (3) 3-Br, the compound that 8-Cl-replaces; (4) compound of 8-Cl-replacement; (5) compound of 10-Cl-replacement.More preferably 3,8-dihalo compound, most preferably 8-halogenated compound.Therefore, more preferably 3-Br for example, the compound that 8-Cl replaces, the most preferably compound that replaces of 8-Cl.

Substituting group a is preferably N or N ⁺O ^-, and preferred N.

A and B are preferably H ₂, promptly Ren Xuan key does not exist, and the bridge between the C5-C6 is not substituted.

R ⁵, R ⁶And R ⁷Be H.

X is preferably N or CH (promptly Ren Xuan key does not exist), and more preferably X is N.

Preferred R ⁸Be selected from the cycloalkylalkyl of heteroarylalkyl, cycloalkylalkyl and replacement of aralkyl, heteroarylalkyl, the replacement of aralkyl, replacement.R most preferably ⁸Be selected from aryl-(C ₁-C ₄) the aryl-(C of alkyl, replacement ₁-C ₄) alkyl, heteroaryl-(C ₁-C ₄) the heteroaryl-(C of alkyl, replacement ₁-C ₄) alkyl, cycloalkyl-(C ₁-C ₄) the cycloalkyl-(C of alkyl and replacement ₁-C ₄) alkyl.More preferably R ⁸Be selected from aryl-CH ₂-, aryl-CH of replacing ₂-, heteroaryl-CH ₂-, heteroaryl-CH of replacing ₂-, cycloalkyl-CH ₂-and cycloalkyl-CH of replacing ₂-.More preferably R also ⁸Be selected from benzyl, 3-pyridylmethyl, 4-fluoro-benzyl and cyclopropyl methyl, more preferably R ⁸Be benzyl.

Preferred R ¹³For encircling 2.0 or 4.0.When carbon atom commutable on the imidazole ring was substituted, this substituting group was selected from usually :-N (R ¹⁸) ₂,-NHC (O) R ¹⁸,-C (R ³⁴) ₂OR ³⁵And alkyl, as-CH ₃,-CH ₂OH ,-CH ₂OC (O) O-cyclohexyl ,-CH ₂OC (O) O-cyclopentyl, ethyl, sec.-propyl, amino and-NHC (O) CF ₃

Preferred R ¹⁹Be H or alkyl, most preferably be H, methyl or ethyl, more preferably methyl.

Preferred R ¹⁴Carbamate groups for above-mentioned substituting group 5.0 representatives.The substituent R of preferred group 5.0 ²⁰Be selected from the cycloalkyl of alkyl, aryl, cycloalkyl and the hydroxyl replacement of alkyl, replacement, prerequisite is that described hydroxyl substituent is not attached on the carbon atom adjacent with Sauerstoffatom.The more preferably substituent R of group 5.0 ²⁰Be selected from C ₁-C ₄Alkyl and C ₅-C ₇Cycloalkyl.The substituent R of group 5.0 most preferably ²⁰Be selected from the tertiary butyl, sec.-propyl and cyclohexyl, more preferably sec.-propyl and cyclohexyl, also more preferably cyclohexyl.

Preferred 6.0 substituent R ²⁰Be selected from alkyl and cycloalkyl, most preferably the tertiary butyl, sec.-propyl and cyclohexyl, more preferably cyclohexyl.Preferred R ²¹Be selected from H and alkyl, most preferably H, methyl and sec.-propyl, more preferably H.

Preferred 7.0 substituent R ²⁰Be selected from cycloalkyl and alkyl, most preferably cyclohexyl, cyclopentyl, sec.-propyl, more preferably cyclohexyl.

Preferred 7.1 substituent R ³⁶Be selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Or Most preferably be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Preferred 8.0 substituent R ²⁰Be selected from alkyl and cycloalkylalkyl, most preferable, sec.-propyl and cyclohexyl methyl, more preferably methyl and sec.-propyl, also more preferably methyl.

Preferred R ⁹, R ¹⁰, R ¹¹And R ¹²Be selected from H, C ₁-C ₄Alkyl (as methyl and sec.-propyl) ,-CON (R ¹⁸) ₂(as-CONH ₂), perhaps R ⁹And R ¹⁰, and/or R ¹¹And R ¹²Form cycloalkyl ring together, preferred described ring is cyclopropyl, cyclopentyl or cyclohexyl.

Work as R ¹⁴Be carbamate substituting group 5.0 and R ⁸When being not H, preferred R ⁹, R ¹⁰, R ¹¹And R ¹²Be H.

Work as R ¹⁴Be selected from substituting group 6.0,7.0,7.1 and 8.0, R ⁹, R ¹⁰, R ¹¹And R ¹²In at least one when being not H, R so ⁹, R ¹⁰, R ¹¹And R ¹²In at least one is:

(I) be preferably selected from: (1) C ₁-C ₄Alkyl, (2)-CON (R ¹⁸) ₂(3) work as R ⁹And R ¹⁰, and/or R ¹¹And R ¹²Form cycloalkyl ring with the carbon atom that they connected;

(II) most preferably be selected from (1) methyl, (2) sec.-propyl, (3)-CONH ₂(4) cyclopropyl; With

(III) more preferably: (1) R ⁹And R ¹⁰Be H, R ¹¹And R ¹²One of be selected from alkyl (preferable methyl and sec.-propyl), and another is selected from H and alkyl (preferable methyl); (2) R ⁹And R ¹⁰Be H, R ¹¹And R ¹²Form cycloalkyl ring (preferred cyclopropyl) together; Perhaps (3) R ⁹And R ¹⁰Be H, R ¹¹And R ¹²One of be-CONH ₂, another is H.

Work as R ⁹, R ¹⁰, R ¹¹And R ¹²One of when being not H, preferred compound also comprises such compound, wherein R ⁹And R ¹⁰Be H, R ¹¹And R ¹²Be identical or different alkyl, preferably they are identical, and wherein more preferably described alkyl is a methyl.

In compound of the present invention, preferred n is 0-4, and more preferably 0-2 most preferably is 0 or 1.

Preferred each R ³²And R ³³Independently be selected from H ,-OR ¹⁸, aryl and aralkyl (as benzyl), most preferably H ,-OH or phenyl, more preferably H.

Wherein X is that formula 1.0 compounds of N or CH comprise with respect to the R-of C-11 key and the isomer of S-:

Formula 1.0 compounds also comprise having the stereochemical compound of 2S stereochemistry and C-11R-or C-11S-.

Compound of the present invention comprises:

Compound of the present invention also comprises corresponding to 13.0-15.0,15.1,16.0,16.1,17.0-19.0,19.1,20.0,20.1,21.0-23.0,23.1,24.0 and the compound of 24.1-24.7, but has except the stereochemical compound of 2S.

Compound of the present invention also comprises corresponding to 13.0-15.0,15.1,16.0,16.1,17.0-19.0,19.1,20.0,20.1,21.0-23.0,23.1,24.0 and the compound of 24.1-24.7, but encircle I be phenyl rather than pyridyl except.

Compound of the present invention also comprises corresponding to 13.0-15.0,15.1,16.0,16.1,17.0-19.0,19.1,20.0,20.1,21.0-23.0,23.1,24.0 and the compound of 24.1-24.7, but encircle I be phenyl rather than pyridyl and have 2S stereochemical except.

Preferred formula 1.0 compounds comprise the compound of following formula:

(i.e. R wherein ¹⁴Be carbamate groups 5.0), wherein all substituting groups are identical with above-mentioned definition.

Preferred formula 25.0 compounds are:

And most preferred is the compound of formula 27.0:

Wherein all substituting groups are identical with above-mentioned definition.

The compound of formula 25.0 comprises:

With

Wherein all substituting groups are identical with above-mentioned definition.

Preferred formula 28.0 and 29.0 compounds are such compound, wherein to R ¹-R ⁴Thereby substituting group selects to obtain aforesaid three halos, dihalo and a halogenated compound.

Preferred formula 29.0 compounds.Most preferably such formula 29.0 compounds, i.e. R wherein ⁸Be selected from benzyl, 4-luorobenzyl, 3-pyridylmethyl and cyclopropyl methyl; R ²⁰Be cyclohexyl, sec.-propyl or the tertiary butyl (more preferably cyclohexyl), R ¹Be Br or H, R ³Be Cl, R ⁴Be H.More preferably such formula 29.0 compounds, i.e. R wherein ⁸Be benzyl; R ²⁰Be cyclohexyl, sec.-propyl or the tertiary butyl (more preferably cyclohexyl), R ¹Be H, R ³Be Cl, R ⁴Be H or Cl.

The preferred compound of the present invention comprises:

(11S, 2R isomer) (embodiment 16);

(embodiment 58);

(embodiment 78 step B); (embodiment 79 step B isomer A);

(embodiment 80 isomer A); (embodiment 88 isomer A); (embodiment 93 isomer D);

(embodiment 99);

(embodiment 100);

(embodiment 225); (embodiment 226); (embodiment 227);

(embodiment 228);

(embodiment 229);

(embodiment 232); (embodiment 326); (embodiment 330); (embodiment 327);

(embodiment 328);

(embodiment 243);

(embodiment 286A);

(embodiment 286B);

(embodiment 304);

(embodiment 306); (embodiment 307); Or

(embodiment 308) most preferred comprises:

Embodiment 58;

(embodiment 225);

(embodiment 226);

(embodiment 227);

(embodiment 228);

(embodiment 229);

(embodiment 232); (embodiment 326); With (embodiment 327)

Most preferred comprises the compound of embodiment 58,199,225,226,229,232 and 326.More preferred embodiment 58,199,225,229 and 326 compound.The compound of more preferred embodiment 225 also.Preferred per os gives the compound of embodiment 225,229 and 326.

The invention still further relates to embodiment 26,30,32,41-44,81,105,106,293 and 309 compound.The compound of preferred embodiment 309.

The invention still further relates to embodiment 31,34-40,67-70,73,75,263,282-284,287 and 289 compound.The compound of preferred embodiment 67-70.

The invention still further relates to the compound of embodiment 27-29,71,72,74,76,98,101,103,104,107,108,110,111,255-262,264-278,285,286,286A, 290-292,294-297,299-303.Preferred embodiment 101,103,71,72 step B, 72 step C and 259 compound.

The invention still further relates to the compound of embodiment 33,279-281.

The line that points in the ring system shows that the key of indication can be connected on any commutable carbon atom.

Part compound of the present invention can exist with different isomer (as enantiomorph, diastereomer, atropisomer form).The present invention includes all these type of isomer, comprise their pure product form and form of mixtures, comprise racemic mixture.Also comprise the enol form.

Some tricyclic compound is natural to be tart, has the compound of carboxyl or phenolic hydroxyl group as those.These compounds can form pharmacy acceptable salt.The example of this type of salt comprises sodium salt, sylvite, calcium salt, aluminium salt, golden salt and silver salt.The present invention also comprises the salt that forms with pharmaceutically acceptable amine such as ammonia, alkylamine, hydroxyalkyl amine, N-methylglucosamine etc.

Some alkaline tricyclic compound also can form pharmacy acceptable salt, as acid salt.For example, the pyridine nitrogen atom can form salt with strong acid, and the compound with alkali subtituent such as amino also can form salt with weak acid.The example that is fit to the salifiable acid of shape is hydrochloric acid, sulfuric acid, phosphoric acid, acetate, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, fumaric acid, succsinic acid, xitix, toxilic acid, methylsulfonic acid and other mineral acid known in the art and carboxylic acid.According to conventional methods by making free alkali can produce salt with required sour contact of capacity.By with suitable dilute alkaline aqueous solution as dilute sodium hydroxide, salt of wormwood, ammonia and sodium bicarbonate aqueous solution handle salt can regenerate as described in free alkali form.Free alkali form and they salt form is separately gone up different in some physical properties (as the solubleness in polar solvent), but for purpose of the present invention, acid-salt and basic salt and their corresponding compounds free alkali forms are equivalent.

All these type of pharmaceutically acceptable acid-salts and basic salt include within the scope of the present invention, and for purpose of the present invention, the free form of all acid-salts and basic salt and their corresponding compounds is equivalent.

Formula 1.0 compounds can exist with non-solvent form and solvation form, comprise hydrate forms, as hemihydrate form.Generally speaking, for purpose of the present invention, with the solvate form thereof and the non-solvent compound form of pharmaceutically acceptable solvent such as water and ethanol etc. be equivalent.

According to April 20 nineteen ninety-five disclosed WO95/10516, on October 10th, 1996 disclosed WO96/31478, on July 3rd, 1997 disclosed WO97/23478, US5719148 that on February 17th, 1998 authorized and the common pending trial submitted on June 15th, 1998 the method described of patent application serial numbers 09/094687 (also referring to disclosed WO98/57960 on December 23rd, 1998) and can prepare compound of the present invention according to the method that describes below, it is for referencial use to be incorporated herein above-mentioned document.

Can prepare compound of the present invention according to following reaction process.

Reaction process 1 (n is 1)

In flow process 1, (the R in formula 1.0 when H is connected with amide nitrogen ⁸During for H) as 41.0, then preferred R ¹¹And R ¹²Be methyl, and when amide nitrogen is substituted the (R in the formula 1.0 ⁸When being not H), as 41.1, then preferred R ¹¹And R ¹²Be H.It will be appreciated by those skilled in the art that and can replace NSC 87419 to obtain to have the not isoplastic compound that is connected with carbonyl with other acylating agent, described carbonyl be connected with piperazine nitrogen.Those skilled in the art also are appreciated that and can replace compound 31.0 to obtain to have the compound of different carbon chain between imidazole ring and C (O) NH-group with other ester.

Under in ethanol, refluxing with the acrylate 31.0 that suitably replaces by imidazoles (2-, 4-and/or 5-replace) or carry out conjugate addition in 90 ℃ in the presence of solvent-free and begin, prepare 41.0 compounds.Ester 32.0 is carried out standard LAH reduction obtain alcohol 33.0, be translated into phthalimide 35.0 by the Mitsunobu reaction.Remove the adjacent diformazan acylimino of benzene by in ethanol, refluxing, obtain amine 36.0 with hydrazine.This amine can easily be opened piperazine acid anhydrides 37.0, produces carbonic acid gas simultaneously, and subsequently with isocyanate reaction, one jar of conversion obtains urea 38.0.Remove the BOC group with 50%TFA under room temperature, obtain salt 39.0, this salt can be easily and tricyclic chloride 40.0 couplings, obtains required product 41.0.

In flow process 1 and flow process subsequently, Y represents C, N or N ⁺O ^-So that only exist 0-2 independently to be selected from N and N ⁺O ^-The Y substituting group.R ^ARepresent the optional substituting group on the imidazole ring, described substituting group is identical with definition in the above-mentioned imidazole ring 4.0.R ^BRepresent above-mentioned R ⁸The optional aryl or the heteroaryl substituting group of middle definition.

For example, behind reaction process 1, R wherein ¹¹And R ¹²Be methyl, and adopt compound 42.0 (referring to the preparation embodiment 40 among the April 20 nineteen ninety-five disclosed WO95/10516), can obtain compound 43.0: compound 42.0 and 43.0 structure are as follows:

Reaction process 2 (n is 0)

The synthetic sodium salt 44.0 and 45.0 one by imidazoles (or the imidazoles that replaces) of intermediate amine 51.0 arises from 90 ℃ of alkylations to begin.Ester 46.0 is carried out the LAH reduction of standard, obtain alcohol 47.0.To 47.0 carry out methylsulfonylization and with phthalimide potassium 49.0 in DMF in 90 ℃ of displacement methanesulfonates, obtain the adjacent diformazan acylimino of benzene derivative 50.0, in the ethanol that refluxes, it easily can be converted into amine 51.0 with hydrazine.Can prepare wherein R according to shown in the flow process 1 ⁸It or not the compound of H.

With with make method like 36.0 and 36.1 response class shown in the flow process 1, in flow process 2, make 51.0 and 51.1 reactions form formula 1.0 compounds.In flow process 2, (the R in formula 1.0 when H is connected with amide nitrogen ⁸During for H), then preferred R ¹¹And R ¹²Be methyl, and when amide nitrogen is substituted the (R in the formula 1.0 ⁸When being not H), then preferred R ¹¹And R ¹²Be H.

Reaction process 3-ring IV=piperidines

According to the similar method of method that on July 3rd, 1997, disclosed WO97/23478 introduced, can split compound (±) 52.0.

The reagent that adopts in the reaction process 3 comprises: reactions steps a: isatoic anhydride/methylene dichloride; Reactions steps b: Sodium Nitrite/hydrochloric acid/methyl alcohol/cuprous chloride; Reactions steps c:(i) aqueous hydrochloric acid/methyl alcohol/(ii) sodium hydroxide/sodium cyanide refluxes; Reactions steps d: concentrated hydrochloric acid/backflow; Reactions steps e: tert-Butyl dicarbonate/sodium hydroxide/tetrahydrofuran (THF).

Reaction process 4 (n is 1-5)

Reagent V and VI are

Reaction process 5

In reaction process 5, R ³⁰Representative

Or

Reaction process 6-n is 0

In reaction process 6, adopt the method for flow process 4, but use

Replace

Can obtain corresponding urea (C (O) NHR ²⁰), acid amides (C (O) CH ₂R ²⁰Or-C (O) R ²⁰), sulphonamide (SO ₂R ²⁰) or carbamate (C (O) OR ²⁰) product, wherein n is 0.Equally, in reaction process 4 and 5, use to obtain from XI according to the method for reaction process 4

Replace

Can produce corresponding urea, acid amides, sulphonamide and carbamate, wherein n is 0.

It will be appreciated by those skilled in the art that in flow process 1,2 and 4-6, can replace with other aldehyde

Obtain R ⁸Be other substituent formula 1.0 compounds.

Those skilled in the art it is also understood that and can use in flow process 4 and 5 Replace

And in flow process 6, can use

Replace

Obtain corresponding compounds, wherein imidazoles is connected with alkyl chain by ring carbon.

Reaction process 7 (R ⁹And R ¹⁰Not H)

In flow process 7, oxidation alcohol 33.0 obtains aldehyde under standard conditions.Add corresponding R ⁹Grignard obtain alcohol, react according to the method for flow process 1 and be translated into amine, it is reoxidized is ketone, carry out R subsequently ¹⁰The Grignard addition.R therein ⁹=R ¹⁰Situation under, can be with ester 32.0 (flow process 1) with the 2 normal suitable Grignard reagent that add as electrophilic reagent.

Reaction process 8 (R ⁹And R ¹⁰Not H, the imidazoles that C-connects)

In flow process 8, nitrile is reduced to aldehyde with DIBAL-H.With with flow process 7 similar methods, obtain alcohol with suitable this aldehyde of Griganrd agent treated then.Carry out an oxidation and Grignard addition circulation again, obtain R ⁹, R ¹⁰Dibasic derivative, wherein R ⁹=R ¹⁰Or R ⁹R ¹⁰According to method shown in flow process 1 or 2, the alcohol that obtains is converted into amine subsequently.

The compound that adopts among the present invention can be by the following example example, and these embodiment should not regard the restriction to open scope as.

Preparation embodiment 1

Steps A:

In 90 ℃, with 2, (50.0g, 2.0eq.) (13.28g 200mmol) stirred 48 hours the 2-dimethacrylate with imidazoles.The solution that cooling produces, water (150ml) dilutes with methylene dichloride (150ml) and separates.(2 * 75ml) washing water layers are through the organic extract that dried over sodium sulfate merges, vacuum concentration with methylene dichloride.Through flash chromatography purifying crude mixture, as eluent, obtain purified product (11.27g, 29% productive rate) into clarification oily matter with the dichloromethane solution of 10% methyl alcohol.CIMS：MH ⁺＝197。

Step B:

(51ml, 1M diethyl ether solution 1.0eq.) are handled target compound (10.0g, 50.96mmol) solution that derives from steps A with lithium aluminum hydride.Under room temperature, reaction mixture was stirred 1 hour, drip saturated sodium sulfate (about 3.0ml) quenching then.Through the dry slurry that produces of solid sodium sulfate,, pass through diatomite filtration with the dilution of 100ml ethyl acetate.Concentrated filtrate obtains yellow oil (6.87,87% productive rate), with it without being further purified use.CIMS：MH ⁺＝155。

Step C

In 0 ℃, with the target compound of 10 fens clockwise step B (6.85g, 44.42mmol), phthalimide (7.19g, 1.1eq.) and triphenyl phosphine (12.82g, add in tetrahydrofuran (THF) 1.1eq.) (200ml) solution DEAD (7.69ml, 1.1eq.).Make the solution of generation be warmed to room temperature and stirred 48 hours.The concentrating under reduced pressure reaction mixture through methylene dichloride/ether Crystallization Separation product, obtains white solid (10.03g, 79% productive rate).CIMS：MH ⁺＝284。

Step D

In the target compound of heating steps C that refluxes down (9.50g, 33.53mmol) and N ₂H ₄(1.25ml, ethanol 1.2eq.) (100ml) solution.The slurry that cooling produces filters and concentrating under reduced pressure filtrate.Through flash chromatography purifying crude product product, as eluent, obtain faint yellow oily thing (2.80g, 53% productive rate) with the dichloromethane solution of 15% (methanol solution of 10% ammonium hydroxide).LIMS：MH ⁺＝154。

Preparation embodiment 2-4

According to embodiment 1 described essentially identical method, by the amine on synthetic the 3rd hurdle of the ester on the 2nd hurdle in the table 1." No. " expression preparation embodiment numbering.

Table 1

Preparation embodiment 5

With piperazine acid anhydrides (preparation embodiment 44) (0.28g, 1.0eq.) portioning add to embodiment 1 target compound (0.17g, in methylene dichloride 1.2mmol) (5.0ml) solution, under room temperature with the solution stirring that produces 10 minutes, add then NSC 87419 (0.21ml, 1.5eq.).After stirring 15 minutes under the room temperature, add this reaction mixture of methyl alcohol (1ml) quenching, vacuum concentration through the flash chromatography purifying, as eluent, obtains white solid (0.46g, 85% productive rate) with the methylene dichloride of 10% methyl alcohol.FABMS：MH ⁺＝491。

Preparation embodiment 6

According to preparation embodiment 5 essentially identical methods, but replace NSC 87419 with N-(benzyloxycarbonyloxy base) succinimide (CBZ-OSuc), preparation target compound (0.16g, 84% productive rate).

Preparation embodiment 6.1

According to preparation embodiment 6 essentially identical methods, but amine The amine that is derived from preparation embodiment 2 replaces: Obtain:

Preparation embodiment 7

According to preparation embodiment 5 essentially identical methods, but adopt the target compound (table 1) of preparation embodiment 3, the preparation target compound.LCMS：MH ⁺＝573。

Preparation embodiment 7.1

According to preparation embodiment 5 essentially identical methods, but adopt the amine of preparation embodiment 2, obtain target compound.

Preparation embodiment 7.2

According to the method identical, but adopt the amine of preparation embodiment 4, obtain target compound with preparing embodiment 5.

Preparation embodiment 7.3

According to the method identical, but adopt the amine of preparation embodiment 10, obtain target compound with preparing embodiment 5.

Preparation embodiment 8

Steps A

Target compound (0.82g to preparation embodiment 1 step D, 5.35mmol) methylene dichloride (10ml) and triethylamine (0.75ml, 1.0eq) (1.65g, 1.2eq.) (according to preparation embodiment 44 preparations) stir the solution that produces under room temperature by part adding a piperazine acid anhydrides in the solution.After finishing through the TLC monitoring reaction, this solution of vacuum concentration, through flash chromatography purifying crude product product, the dichloromethane solution of using 20% (methanol solution of 10% ammonium hydroxide) is as eluent with the dichloromethane solution of 10% (methanol solution of 10% ammonium hydroxide), then.CIMS：MH ⁺＝366。

Step B

Under room temperature, the target compound of steps A was stirred 2 hours in methylene dichloride (25ml) solution of 50% trifluoroacetic acid.The solution that concentrating under reduced pressure produces.Remove residual trifluoroacetic acid with methylbenzene azeotropic, obtain the crude product product, with it without being further purified use.CIMS：MH ⁺＝266。

Step C

With the target compound of step B be dissolved in methylene dichloride (30ml) and TEA (7.62ml, 10eq.).Reaction mixture was stirred 5 minutes, add then muriate (0.908g, 0.5eq.).Under room temperature, with the solution stirring that produces 96 hours.With 50ml water diluted reaction mixture, separate and with methylene dichloride (2 * 200ml) aqueous layer extracted.Through the organism that dried over mgso merges, concentrating under reduced pressure.Through flash chromatography purifying crude product product, as eluent, obtain product (0.926g, 30% productive rate) with the dichloromethane solution of 5%, 7.5% and 10% (methanol solution of 10% ammonium hydroxide).CIMS：MH ⁺＝571。

Step D

(11R, 2R (-)-isomer)

(11S, 2R (-)-isomer)

Adopt ChiralPak AD post, the target compound of step C be separated into independent diastereomer through preparation property HPLC, with the hexane solution of the 20%IPA that contains 0.2% diethylamine as eluent:

Isomer A (11S, 2R (-)-isomer): retention time=18.2 minute; [α] ²⁰ _D=-31.7 (in 2.0ml methyl alcohol, containing 3.0mg)

Isomer B (11R, 2R (-)-isomer): retention time=30.3 minute; [α] ²⁰ _D=-6.2 (in 2.0ml methyl alcohol, containing 2.4mg)

Preparation embodiment 9

According to the basic method identical, but, prepare target compound with the target compound (table 1) for preparing embodiment 2 with prepare embodiment 8.

Adopt ChiralPak AD post,, separate 11 (S)-and 11 (R)-isomer as eluent with the hexane solution of the 30%IPA that contains 0.2% diethylamine through preparation property HPLC:

(11S, 2R (-)-isomer)

(11R, 2R (-)-isomer)

11S, 2R (-)-isomer: retention time=10.2 minute; MH ⁺=569; [α] ²⁰ _D=-32.7 (in 2.0ml methyl alcohol, containing 4.04mg)

11R, 2R (-)-isomer: retention time=22.8 minute; MH ⁺=569; [α] ²⁰ _D=-1.2 (in 2.0ml methyl alcohol, containing 3.40mg)

Preparation embodiment 9.1

According to embodiment 8 described methods, but in steps A, use amine

Replace And in step C, use the 10-Cl tricyclic chloride

Replace 3-Br-8-Cl-tricyclic chloride (compound 42.0), obtain following compounds:

With

According to following method, obtain the 10-Cl tricyclic chloride (10,11-two chloro-6,11-dihydro-5H-benzo [5,6] ring [1,2-B] pyridine in heptan:

According to Villani etc. at J.Het.Chem.8, method described in the 73-81 (1971), preparation ketone (raw material) 5,6-dihydro-10-chloro-11H-benzo [5,6] ring [1,2-c] pyridine in heptan-11-ketone.Replace 10H three rings and, prepare product with 10-Cl according to embodiment 169 described methods.

1H?NMR(CDCl ₃δ)2.97(m，2H)，3.55(m，1H)，4.03(m，1H)，7.11(s，1H)，7.13(d，1H)，7.22(m，2H)，7.31(d，1H)，7.53(d，1H)，8.49(d，1H)。

Preparation embodiment 10

Steps A

(2.73g 40.1mmol) is heated to backflow and spends the night in crotonitrile (10ml) with imidazoles.The solution that vacuum concentration produces, with ether (50ml) dilution residue, water (2 * 100ml) and salt solution (1 * 25ml) washs.Through the organism that dried over sodium sulfate merges, concentrating under reduced pressure.The crude product product is through the flash chromatography purifying, as eluent, obtains product (2.13g, 39% productive rate) with the dichloromethane solution of 15% methyl alcohol.FABMS：MH ⁺＝136。

Step B

With LAH (5.5ml, in the 1.0M diethyl ether solution, the 1.1eq.) target compound of treatment step A (0.50g, THF 0.0037mmol) (10ml) solution.Under room temperature, reaction mixture was stirred 3 hours, drip saturated metabisulfite solution quenching.Add the dry slurry that produces of solid sodium sulfate, pass through diatomite filtration.Concentrating under reduced pressure filtrate, crude product product as eluent, obtain product (0.03g, 6% productive rate) with 20% (methanol solution of 10% ammonium hydroxide) solution through the flash chromatography purifying.

Preparation embodiment 11

Steps A

In 0 ℃, (2.5ml, the hexane solution of 2.5M 2.1eq.) add to iPr with n-Butyl Lithium ₂(0.87ml is in THF 2.1eq.) (8.0ml) solution for NH.With the solution stirring that produces 45 minutes, add nitrile (1.0g, THF 2.97mmol) (7.0ml) solution then.In 0 ℃ reaction mixture was stirred 30 minutes, add then MeI (0.37ml, 2.0eq.).Make the solution of generation be warmed to room temperature and stirred 1 hour.Add 1NHCl quenching reactant to acid, with the dilution of 40ml water, with ethyl acetate (2 * 200ml) ethyl acetate extractions.Organism and concentrating under reduced pressure through the dried over sodium sulfate merging.The crude product product is through the flash chromatography purifying, as eluent, obtains product (0.37g, 33% productive rate) with the hexane solution of 40% ethyl acetate.MH ⁺＝378。

Step B

(2.7ml, the THF solution of 1.0M 1.5eq.) add to target compound (0.68g, THF 1.80mmol) (5.0ml) solution of steps A with lithium aluminum hydride.The solution that stirring produces under room temperature 1.5 hours drips saturated sodium sulfate (10ml) quenching.(2 * 200ml) extraction solutions, through the organism that dried over mgso merges, concentrating under reduced pressure obtains product (0.6g, 88% productive rate) with ether.

Step C

According to prepare the described identical method of embodiment 27 step C, the preparation target compound.

Preparation embodiment 12

Under room temperature, will be according to the piperazine carboxylic acid (0.29g of preparation embodiment 43 described preparations, 0.881mmol), L-group acid amides dihydrochloride (0.20g, 1.0eq.), DEC (0.25g, 1.5eq.), HOBT (0.18g, 1.5eq.) and NMM (0.48ml, DMF 1.5eq.) (5ml) solution stirring is spent the night.Water (25ml) and methylene dichloride (50ml) diluted reaction mixture separate, with methylene dichloride (2 * 50ml) aqueous layer extracted.Through the organism that dried over sodium sulfate merges, concentrating under reduced pressure.The crude product product is through the flash chromatography purifying, as eluent, obtains product (0.24g, 59% productive rate) with the dichloromethane solution of 15% methyl alcohol.FAB?MS：MH ⁺＝467。

Preparation embodiment 13-17

According to J.Chme.Soc.Perkin I (1979), the described method of 1341-1344 prepares the histamine that following N-replaces.

Preparation embodiment 13,

Preparation embodiment 14,

Preparation embodiment 15,

The preparation embodiment 16 and

Preparation embodiment 17.

Preparation embodiment 18-26

According to preparation embodiment 74 described essentially identical methods, adopt listed aldehyde and amine in the table 2, the midbody product shown in the preparation table 2.

Table 2

Preparation embodiment 27

Steps A

(1.5g 4.29mmol) is dissolved among the 10mlTHF, is cooled to-78 ℃ under nitrogen with nitrile.Add the 20ml1.5MLDA cyclohexane solution.Then with the 10mlTHF solution that dripped 790mg (4.293mmol) 2-methyl-propyl iodide in 2 hours.Be warmed to room temperature and stir and spend the night.Add 10ml water, then adding 1NHCl to pH is 10-11.With 100ml methylene dichloride and the saturated aqueous sodium persulfate solution dilution of 20ml.Adding sal epsom to solution clarifies.Separate organic layer, through dried over mgso.Vacuum concentration through flash chromatography on silica gel, with ethyl acetate-hexane (1-3) wash-out, obtains being the semisolid product of brown.

Step B

(0.5g 1.23mmol) is dissolved in in the saturated ethanol (10ml) of ammonia with the product of steps A.Be added in 8.8mg (0.017mmol) H in the water ₂PtCl ₆6H ₂O and lg Raney Ni spend the night in 54psi hydrogenation on the Parr vibrator.By diatomite filtration and vacuum concentration.

Step C

(0.165g 0.403mmol) is dissolved in 4ml 2M HCl and the 2ml methyl alcohol with the product of step B.Refluxed 100 minutes, then vacuum concentration.Grind residue with ether, obtain product hydrochloride into white solid.

Preparation embodiment 28-29,29.1 and 30

According to preparation embodiment 27 described methods, but replace 2-methyl-propyl iodide, the histamine of the replacement shown in preparation is following with alkyl or benzyl halogenide.

Preparation embodiment 28 Halogenide

The histamine that replaces

Preparation embodiment 29 Halogenide

The histamine that replaces

Preparation embodiment 29.1

Halogenide

The histamine that replaces

Preparation embodiment 30

Halogenide

The histamine that replaces

Preparation embodiment 31

(4.5g 27.24mmol) places the Parr bottle of 500ml, is dissolved in the dehydrated alcohol (70ml) with 4-pyridyl ethyl acetate.In this bottle, add 10% palladium carbon (1.0g).Described bottle is placed on the hydrogenator, under the 55psi hydrogen pressure, 25 ℃ of jolting contents 94 hours.Pass through Celite ^Filtering mixt is with 4 * 40ml absolute ethanol washing.Rotary evaporation filtrate, residue is through silica gel column chromatography, with the dichloromethane solution of 3% (methanol solution of 10% dense ammonium hydroxide) as eluent, obtain target compound (productive rate: 63%, 2.944g).FABMS：m/z172.2(MH ⁺)：δ _C(CDCl ₃)CH ₃，14.3；CH ₂，33.2，33.2，41.9，46.5，46.5，60.2；CH，33.4，C，172.7；δ _H(CDCl ₃)1.18(m，1H，H ₄)，1.26(t，3H，CH ₃)，1.71(2H)，1.90(1H)，1.96(1H)，2.22(d，2H)，2.63(2H)，3.07(2H)，4.13(q，2H，CH ₃CH ₂-)。

Preparation embodiment 32

(500mg 2.92mmol) is dissolved in the anhydrous methylene chloride (25ml) with deriving from the 4-piperidyl ethyl acetate for preparing embodiment 31.In the solution that stirs, add trimethylsilyl isocyanate (5.9ml, 43.8mmol), in 25 ℃ with this solution stirring 17 hours.Handle this solution with methylene dichloride-saturated sodium hydrogen carbonate solution, product is through silica gel column chromatography, with 2 → 3% (dense ammonium hydroxide methanol solution) dichloromethane solution as eluent, obtain target compound (productive rate: 99%, 622mg).FABMS：m/z172.2(MH ⁺)：δ _C(CDCL ₃)CH ₃，14.2；CH ₂，31.6，31.6，41.0，44.2，44.2，60.4；CH，32.9；C，158.2，172.4；δ _H(CDCl ₃)1.23(m，1H，H ₄)，1.27(t，3H，CH ₃)，1.75(d，2H)，1.98(m，1H)，2.26(d，2H)，2.85(t，2H)，3.94(d，2H)，4.15(q，2H，CH ₃CH ₂-)，4.56(bs，2H)。

Preparation embodiment 33

With the preparation embodiment 32 1-aminocarboxyl-4-piperidyl ethyl acetate (153.6mg 0.717mmol) is dissolved in anhydrous methylene chloride (3.58ml) and the ethanol (3.58ml).(1.73ml 1.73mmol), stirs mixture 5.5 hours in 50 ℃ to add 1.0M LiOH in this solution.Mixture is quickly cooled to 25 ℃, add 1.0N HCl (2.02ml 2.02mmol), stirs mixture 5 minutes, and rotary evaporation obtains target compound to doing then, with it without being further purified use.

Preparation embodiment 34

(11S, 2R (-)-isomer) (11R, 2R (-)-isomer)

Make the C of above-mentioned isomer (preparation embodiment 141 62% purity) ₁₁-racemoid is at Chiralpak AD ^(50 * 5cm) go up experience preparation property HPLC to post, as eluent, by elution order, obtain 11-S (-)-isomer and 11-R (-)-isomer with 75% hexane-25% Virahol-0.2% diethylamine.

11S, 2R (-)-isomer: productive rate 55%, 0.8756g; LCMS:m/z543.1 (MH ⁺): δ _C(CDCl ₃) CH ₂, 30.3,30.4,31.0,36.3,44.3,44.7,52.0,54.5; CH, 58.7,79.4,118.8,126.0,129.6,130.4,132.3,137.1,141.3,147.0; C, 120.0,134.0,135.4,136.7,140.9,155.4,172.2; δ _H(CDCl ₃) ₂.02 (2H, m, 2 " CH ₂), 3.32 (2H, m, 3 " CH ₂), 3.98 (2H, dd, 1 " CH ₂), 4.30 (1H, s, H ₁₁), 6.93 (1H, s, Im-H ₅), 6.97 (1H, t, CONHCH ₂), 7.06 (1H, s, Im-H ₄), 7.11 (1H, s, Ar-H), 7.13 (2H, s, Ar-H), 7.16 (1H, s, Ar-H), 7.49 (1H, s, Ar-H ₁₀), 7.57 (1H, d, Im-H ₂) and 8.33ppm (1H, s, Ar-H ₂); [α] _D ^{20 ℃}-45.0 ° (methyl alcohol, c=9.32mg/2ml).

11R, 2R (-)-isomer: productive rate 38%, 0.5979g; LCMS:m/z543.1 (MH ⁺): δ _C(CDCl ₃) CH ₂, 30.2,30.3,3 1.1,36.4,44.1,44.7,52.2,54.0; CH, 58.2,79.4,118.8,126.1,129.6,130.7,132.3,137.0,141.2,146.8; C, 119.9,134.0,135.2,136.9,140.7,155.7,172.1; δ _H(CDCl ₃) 3.34 (2H, m, 3 " CH ₂), 3.97 (2H, dd, 1 " CH ₂), 4.30 (1H, s, H11), 6.93 (1H, s, Im-H ₅), 7.06 (1H, s, Im-H ₄), 7.08 (1H, s, Ar-H), 7.11 (2H, s, Ar-H), 7.14 (1H, s, Ar-H), 7.15 (1H, t, CONHCH ₂), 7.50 (1H, s, Ar-H ₁₀), 7.58 (1H, d, Im-H ₂) and 8.35ppm (1H, s, Ar-H ₂); [α] _D ^{23.5 ℃}-12.0 ° (methyl alcohol, c=10.19mg/2ml).

Preparation embodiment 35

Steps A

With different piperidine carboxylic acid (10g, 77.42mmol) and sodium hydroxide (3.097g, 77.42mmol) be dissolved in THF-water (1: 1) (230ml) in, add tert-Butyl dicarbonate (18.59ml, 85.17mmol).In 25 ℃ with this solution stirring 90 hours.Use BioRad ^50W-X4 (H ⁺) ion exchange resin (86.6ml) treating mixture, leach resin, wash successively with THF and water.Filtrate is evaporated to dried, obtains target compound, it is used for next step without being further purified.FABMS:m/z229.9 (MH ⁺): δ _C(d ₆-DMSO) CH ₃, 28.0,28.0,28.0; CH ₂, 42.0-43.1 (broad peak signal); CH, unclear; C, 78.5,153.8,175.6.

Step B

(2g 8.72mmol) is dissolved in the dry DMF (40ml), stirs this solution in ar gas environment, 0 ℃ with the target compound of above-mentioned steps A.(2.07ml, 9.59mmol), (2.68ml 9.59mmol), stirred this mixture 1 hour in 0 ℃, stirred 19 hours in 25 ℃ then to add triethylamine with adding diphenyl phosphoryl azide in 10 minutes.Be evaporated to dried, then through silica gel column chromatography, with the dichloromethane solution wash-out of 5% → 7% methyl alcohol, obtain target compound (productive rate: 72%, 1.57g); δ _C(CDCl ₃) CH ₃, 28.5,28.5,28.5; CH ₂, 32.9 (broad peaks), 42.8 (broad peaks); CH, 47.3; C, 79.7,154.8,156.5.

Preparation embodiment 36

Steps A

Method 1:

With the 4-hydroxy piperidine (5g 49.43mmol) is dissolved in the anhydrous methylene chloride (50ml), add trimethylsilyl isocyanate (6.27g, 7.36ml, 54.38mmol).In ar gas environment, 25 ℃ this mixture was stirred 24 hours.Add entry (10ml), mixture is evaporated to dried.Residue is through silica gel column chromatography, with 10% (methanol solution of 10% dense ammonium hydroxide)-dichloromethane solution as eluent, obtain target compound (productive rate: 97%, 6.895g); CIMS:m/z145.1 (MH ⁺); δ _C(d ₆-DMSO) CH ₂, 34.2,34.2,41.3,41.3; CH, 66.1; C, 158.0; δ _H(d ₆-DMSO) 1.22 (2H, m, 3/5-CH ₂), 1.68 (2H, m, 3/5-CH ₂), 2.84 (2H, m, 2/6-CH ₂), 3.60 (1H, m, 4-CH), 3.68 (2H, m, 2/6-CH ₂), 4.67 (1H, d, OH) and 5.87ppm (2H s, NH ₂).

Method 2:

With the 4-hydroxy piperidine (10g, 98.86mmol) and urea (59.4g 988.6mmol) is dissolved in the distilled water (100ml), in 100 ℃ with this solution heating 67 hours.To doing, product as elutriant, obtains target compound (output: 8.3g, 58%) with 10% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride through purification by silica gel column chromatography with this solution evaporation.

Step B

With the target compound of above-mentioned steps A (1g, 6.94mmol) and 4-nitrophenyl carbonochloridic acid ester (1.54g 7.63mmol) is dissolved in the anhydrous pyridine (10ml), in 25 ℃ this mixture is stirred 24 hours.Evaporating mixture is to doing, with residue and methylbenzene azeotropic.The product that obtains as elutriant, obtains target compound (1.35g, 63%): CIMS:m/z 310.05 (MH with 3% methyl alcohol-methylene dichloride through silica gel column chromatography ⁺); δ _C(CDCl ₃) CH ₂, 29.9,29.9,40.7,40.7; CH, 74.9,121.7,121.7,125.2,125.2; C, 145.2,151.7,155.3,158.7; δ _H(CDCl ₃) 1.82 (2H, m, 3/5-CH ₂), 2.01 (2H, m, 3/5-CH ₂), 3.06 (2H, s, NH ₂), 3.31 (2H, m, 2/6-CH ₂), 3.68 (2H, m, 2/6-CH ₂), 4.98 (1H, m, 4-CH), 7.39 (2H, d, Ar-H1/6) and 8.28 ppm (2H d, Ar-H3/5).

Preparation embodiment 37

Steps A

With acid anhydrides (0.5088g, 1.99mmol) (according to preparation embodiment 44 described method preparations) and 1-(3-aminopropyl) imidazoles (0.260ml, 2.18mmol) be dissolved in the anhydrous methylene chloride (10ml), under 25 ℃, ar gas environment, this mixture was stirred 5 minutes.Dilute this mixture with methylene dichloride, with saturated sodium bicarbonate aqueous solution extraction.Through the dried over mgso dichloromethane layer, filter and be evaporated to dried.The product that produces as elutriant, obtains target compound (output: 0.4955g, 74%) with 10% (methanol solution of dense ammonium hydroxide)-methylene dichloride through purification by silica gel column chromatography.LCMS:m/z338.1 (MH ⁺); δ _C(CDCl ₃) CH ₃, 28.4,28.4,28.4; CH ₂, 31.1,36.5 ,～43.5 (broad peaks), 44.8 ,～46.5 (broad peaks); CH, 58.2 ,～119.0 (broad peaks) ,～129.7 (broad peaks) ,～137.3 (broad peaks); C, 80.2,154.7,171.5 δ _H(CDCl ₃) 1.47 (9H, s, CH ₃), 6.96 (1H, s, Im-H ₅), 7.08 (1H, s, Im-H ₄) and 7.52ppm (1H, s, Im-H ₂).

Step B

Target compound (0.3248g with above-mentioned steps A, 0.96mmol), 4-pyridyl acetate N1-oxide compound (0.1916g, 1.25mmol), 1-[3-(dimethylamino) propyl group)-3-ethyl-carbodiimide hydrochloride (0.24g, 1.25mmol), I-hydroxybenzotriazole (0.169g, 1.25mmol) and 4-methylmorpholine (0.1376ml, 1.25mmol) be dissolved in the dry DMF (11ml), under 25 ℃ of ar gas environments, this mixture was stirred 18 hours.Evaporating mixture is dissolved in residue in the methylene dichloride to doing, with saturated sodium bicarbonate aqueous solution washing.Through the dried over mgso organic layer, filter drag be evaporated to dried.The product that obtains as elutriant, obtains target compound (output: 0.4333g, 95%): LCMS:m/z473.1 (MH with 5% methyl alcohol (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride through silica gel column chromatography ⁺); δ _C(CDCl ₃) CH ₃, 28.3,28.3,28.3; CH ₂, 30.8,36.5,38.7,43.2 ,～43.5 (broad peaks), 44.5 (broad peaks); CH, 53.8 ,～119.2 (broad peaks) ,～127.4,127.6 ,～129.3 (broad peak) ,～137.5 (broad peaks), 138.7,138.9; C, 80.7,134.5,154.4,169.6,169.6; δ _H(CDCl ₃) 1.44 (9H, s, CH ₃), 6.97 (1H, broad peak s, Im-H ₅), 7.09 (1H, broad peak s, Im-H ₄), 7.20 (2H, m, Ar-H), 7.53 (1H, broad peak s, Im-H ₂) and 8.14ppm (2H, d, Ar-H).

Step C

Target compound (0.289g with above-mentioned steps B, 0.612mmol) be dissolved in anhydrous methylene chloride (7.8ml) and trifluoroacetic acid (2.026ml, 26.3mmoles) in, under 25 ℃ of ar gas environments, this mixture was stirred 1.25 hours, be evaporated to driedly then, product is through silica gel column chromatography, with 5 → 10% methyl alcohol (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride as elutriant, obtain target compound (output: 0.208g, 91%).LCMS:m/z373.1 (MH ⁺); δ _C(CDCl ₃CD ₃OD) CH ₂, 30.4,36.2,38.2,43.9,44.5,46.2,46.7; CH, 52.3 ,～119.2 (broad peaks), 127.7,127.7 ,～128.3 (broad peaks), 137.4 (broad peaks), 138.4,138.5,138.5; C, 137.3,169.8,170.6; δ _H(CDCl ₃-CD ₃OD) 6.90 (1H, broad peak s, Im-H ₅), 6.94 (1H, broad peak s, Im-H ₄), 7.22 (2H, m, Ar-H), 7.47 (1H, broad peak s, Im-H ₂) and 8.12ppm (2H, d, Ar-H); [α] _D ^{26.3 °}+ 81.1 ° (c=10.43mg/2ml, methyl alcohol).

Preparation embodiment 38

Steps A

Under 0 ℃, nitrogen environment, with 30 fens clockwise 3-bromo-8-chloro-5,6-dihydro-11H-benzo [5,6] encircle heptan [1,2-b] pyridine-11-ketone (2g, 6.2mmol) anhydrous methylene chloride (14ml) solution in drip 3-chlorine peroxybenzoic acid (1.76g, anhydrous methylene chloride 10.4mmol) (35ml) solution.Make this mixture be warmed to room temperature, after 18 hours, (0.88g, anhydrous methylene chloride 5.2mmol) (25ml) solution stir this mixture 42 hours totally to add 3-chlorine peroxybenzoic acid again.Dilute this mixture with methylene dichloride, with 1N sodium hydroxide (200ml) washing.(2 * 200ml) aqueous layer extracted, the organic layer with dried over mgso merges filters and is evaporated to dried with methylene dichloride.Product as eluent, obtains target compound (output: 1.386g, 66%) with 0.25%-0.5%-1% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography; ESIMS m/z338.1 (MH ⁺); δ _C(CDCl ₃) CH ₂, 30.5,34.0; CH, 126.9,127.6,130.3,132.5,140.4; C, 121.0,135.1,138.3,139.7,141.6,145.3,188.0ppm.

Step B

With the target compound of steps A (1.3422g 3.96mmol) is dissolved in methyl alcohol (18ml) and the methylene dichloride (20ml), add sodium borohydride (0.219g, 5.79mmol).Under 0 ℃, ar gas environment, this mixture was stirred 1 hour.Made with 1 hour then and be warmed to 25 ℃.(800ml) dilutes this mixture with methylene dichloride, with 1N sodium hydroxide (150ml) washing.(2 * 100ml) aqueous layer extracted, the organic layer with dried over mgso merges filters and is evaporated to dried with methylene dichloride.Product as eluent, obtains target compound (output: 1.24g, 92%) with 1% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography; ESIMS m/z340.1 (MH ⁺); δ _C(CDCl ₃) CH ₂, 31.2,32.0; CH, 69.1,126.8,129.5,131.7,131.7,136.7; C, 118.3,134.7,135.2,139.7,141.0,148.9ppm.

Step C

With the target compound of step B (0.552g, 1.62mmol) and triethylamine (1.19ml 8.52mmol) is dissolved in the anhydrous methylene chloride (8.5ml), and this solution is cooled to 0 ℃.(0.4ml 5.16mmol), stirs this mixture 1.25 hours in 0 ℃ totally to add methylsulfonyl chloride with 30 minutes.This solution evaporation to doing, is obtained 11-methylsulfonyl derivative, with it without being further purified use.Described derivative is dissolved in the anhydrous methylene chloride (40ml), stirs this solution in 0 ℃.Be dissolved in N-[3-(1H-imidazoles-1-yl) propyl group in anhydrous methylene chloride (20ml) and the dry DMF (20ml) in 0 ℃ of adding]-2 (R)-piperazine carboxamides (preparation embodiment 136) (0.5g, 2.11mmol), stir this solution and made this solution be warmed to 25 ℃ with 2 hours.In 25 ℃ this reactant was stirred 18 hours,,,, filter and be evaporated to dried through dried over mgso with saturated sodium bicarbonate aqueous solution washing then with the methylene dichloride dilution.Product as eluent, obtains racemic compound (output: 0.399g, 44%) with 4% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography; FABMS m/z559.3 (MH ⁺).

Step D

(11R, 2R (+)-isomer)

(11S, 2R (-)-isomer)

The target racemic compound of above-mentioned steps C through preparation property HPLC chromatography, is adopted CiralpakAD ^(50 * 5cm), as eluent, order obtains 11-R (+)-diastereomer of target compound and 11-S (-)-diastereomer of target compound to post with 65% hexane-3,5% Virahol-0.2% diethylamine.

11R, 2R (+)-diastereomer: output 0.1 854g; FABMS m/z559.2 (MH ⁺); δ _C(CDCl ₃) CH ₂, 30.1,30.3,31.2,36.4,43.9,44.7,51.6,52.8; CH, 57.8,64.3,118.9,126.3,129.6,130.6,130.7,133.4,137.3,138.4; C, 118.2,133.6,134.6,140.1,141.0,148.1,172.0; δ _H(CDCl ₃) 5.70 (1H, s, H ₁₁), 6.95 (1H, broad peak s, Im-H ₅), 7.04 (1H, broad peak s, Im-H ₄), 7.51 (1H, broad peak s, Im-H ₂) and 8.22 ppm (1H, s, Ar-H ₂); [α] ^{20 °} _D+ 41.2 ° (c=11.08mg/2ml, methyl alcohol).

11S, 2R (-)-diastereomer: (output 0.18g); FABMS m/z559.2 (MH ⁺); δ _C(CDCl ₃) CH ₂, 30.1,30.3,31.1,36.5,44.4,44.8,51.6,53.4; CH, 58.9,64.4 ,～119.2,126.3,129.5,130.6,130.7,133.4 ,～137.3,138.5; C, 118.3,133.7,134.6,139.9,141.0,148.1,172.1; δ _H(CDCl ₃) 5.69 (1H, s, H ₁₁), 6.94 (1H, broad peak s, Im-H ₅), 7.07 (1H, broad peak s, Im-H ₄), 7.51 (1H, broad peak s, Im-H ₂) and 8.26 ppm (1H, s, Ar-H ₂); [α] ^{19.9 °} _D-71.0 ° (c=10.32mg/2ml, methyl alcohol).

Preparation embodiment 39

Steps A

(4.5g 27.24mmol) places 500ml Parr bottle and be dissolved in dehydrated alcohol (70ml) with 4-pyridyl ethyl acetate.Add 10% palladium carbon (1.0g), content is 94 hours under the 55psi hydrogen pressure, in 25 ℃ of jolting bottles.Pass through Celite ^Filtering mixt is with 4 * 40ml absolute ethanol washing.Filtrate is evaporated to dried, residue as eluent, obtains target compound (output: 2.944g, 63%) with 3% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography; FABMS m/z172.2 (MH ⁺); δ _C(CDCl ₃) CH ₃, 14.3; CH ₂, 33.2,33.2,41.9,46.5,46.5,60.2; CH, 33.4; C, 172.7; δ _H(CDCl ₃) 1.18 (1H, m, H ₄), 1.26 (3H, t, CH ₃), 1.71 (2H), 1.90 (1H), 1.96 (1H), 2.22 (2H, d), 2.63 (2H), 3.07 (2H), 4.13 (2H, q, CH ₃CH ₂-).

Step B

(500mg 2.92mmol) is dissolved in the anhydrous methylene chloride (25ml) with the 4-piperidyl ethyl acetate of above-mentioned steps A.In the solution of this stirring, add the trimethyl silane based isocyanate (5.9ml, 43.8mmol), in 25 ℃ with this solution stirring 17 hours.With the methylene dichloride dilution,,, filter and be evaporated to dried through the dried over mgso dichloromethane layer with saturated sodium bicarbonate aqueous solution washing.Product as eluent, obtains target compound (output: 622mg, 99%) with 2% → 3% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography; CIMS m/z215.3 (MH ⁺); δ _C(CDCl ₃) CH ₃, 14.2; CH ₂, 31.6,31.6,41.0,44.2,44.2,60.4; CH:32.9; C, 158.2,172.4; δ _H(CDCl ₃) 1.23 (1H, m, H ₄), 1.27 (3H, t, CH ₃), 1.75 (2H, d), 1.98 (1H, m), 2.26 (2H, d), 2.85 (2H, t), 3.94 (2H, d), 4.15 (2H, q, CH ₃CH ₂-), 4.56 (2H, bs).

Step C

(153.6mg 0.717mmol) is dissolved in anhydrous methylene chloride (3.58ml) and the ethanol (3.58ml) with 1-aminocarboxyl-4-piperidyl ethyl acetate of above-mentioned steps B.(1.73ml 1.73mmol), stirs this mixture 5.5 hours in 50 ℃ to add the 1.0M lithium hydroxide in this solution.This mixture is quickly cooled to 25 ℃, add 1.0N hydrochloric acid (2.02ml 2.02mmol), stirs this mixture 5 minutes, is evaporated to driedly then, obtains target compound, with it without being further purified use.

Preparation embodiment 40

Steps A

Target compound (0.45g with above-mentioned preparation embodiment 37 steps A, 1.33mmol), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (0.332g, 1.73mmol), I-hydroxybenzotriazole (0.234g, 1.73mmol) and the 4-methylmorpholine (0.382ml 3.46mmol) is dissolved in the anhydrous dimethyl formamide (7ml).(0.3228g 1.73mmol), stirred this mixture 22 hours in 25 ℃ to add the target compound that is dissolved in the above-mentioned preparation embodiment 33 step C in the anhydrous dimethyl formamide (8ml).This solution evaporation to doing, is dissolved in residue in the methylene dichloride,,, filters and be evaporated to dried through dried over mgso with saturated sodium bicarbonate aqueous solution washing.Residue as eluent, obtains target compound (output: 0.3553g, 53%) with 5% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography.

Step B

(0.45g 0.9mmol) is dissolved in the methyl alcohol (5.625ml) with above-mentioned steps A target compound.The dioxane solution (13.5ml) that adds 10% (v/v) vitriol oil stirs this mixture 2 hours in 25 ℃.Add anhydrous methanol (200ml), then add BioRad ^AGl-X8 (OH ^-) resin is to being neutral through this solution of pH test paper.Leach resin, use methanol wash, the filtrate that evaporation merges is to doing.Residue as eluent, obtains target compound (output: 0.317g, 96%) with 5% → 6.5% (methanol solution of 10% dense ammonium hydroxide) dichloromethane solution through silica gel column chromatography; FABMS m/z406.2 (MH ⁺); δ _C(CDCl ₃～5%CD ₃OD) CH ₂, 30.8,31.9,31.9,36.2/36.3/36.6,39.1/39.3/39.5,44.1/44.2,44.4,44.4,44.8,44.8; CH, 51.2/56.3,119.0,128.8,137.0; C, 158.7,171.0/171.1,171.9/172.6; δ _H(CDCl ₃-2.86%CD ₃OD) 4.84 (1H, d, H ₂), 6.96 (1H, broad peak s, Im-H ₅), 7.04 (1H, broad peak s, Im-H ₄) and 7.53 ppm (1H, broad peak s, Im-H ₂).

Preparation embodiment 40A

Steps A

52.i (J.Med.Chem.4890-4902 (1988)) concentrated hydrochloric acid (1L) and water (100ml) solution (205g) was refluxed 18 hours, incline then to ice (3Kg).Adding 50% aqueous sodium hydroxide solution is 12 to pH, and then (3 * 4L) extractions, with salt water washing extract, dry and evaporation obtains 52.ii (166g) with ethyl acetate.

Step B

Under room temperature, with 2 hours, the toluene solution (908ml) of 1M DIBAL is dropped in the toluene solution (4L) of 52.ii (166g), then stirred 18 hours.This mixture is cooled to 0-5 ℃, stirred 1 hour, with 1N hydrochloric acid (2L) extraction.With 50% sodium hydroxide water extract is alkalized to pH10, with ethyl acetate (3 * 2L) extractions.The evaporation extract is through silica gel (1Kg) chromatography.With 10% ethanol/methylene wash-out, obtain target compound (±) 52.0 (104g); HRMS (FAB) C ₁₉H ₂₁N ₂ ⁷⁹The BrCl calculated value: 393.0556, measured value: 393.0554.

Step C

In 25 ℃, racemoid (±) 52.0 (96g) is split on 8 * 30cmCHIRALPAK AD post through HPLC, the UV detector is arranged at 290nm.With 0.05% diethylamine-methanol-eluted fractions, obtain peak 1 (-) 52.0 (40g): [α] ²⁰ _D-28.4 ° (c0.3, MeOH); With the further wash-out of solvent, obtain peak 2 (+) 52.0 (42g): [α] ²⁰ _D+ 27.5 ° (c0.3, MeOH).

Preparation embodiment 41

Steps A

Under room temperature, the dimethyl formamide solution (30ml) of (+) 52.0 (2.3g) and N-carboxyl o-amino benzoyl acid anhydrides (1.25g) reacts 3 hours under DMAP (0.1g), descend to evaporate in reducing pressure then, with residual dimethyl formamide and methylbenzene azeotropic.Residue is dissolved in the ethyl acetate (50ml), and (3 * 100ml) extract this solution with 10% yellow soda ash.Filter organic layer by silica gel (100ml), through eluent ethyl acetate.Reduction vaporization filtrate obtains the target compound 53.0 (3.68g) into amorphous solid.MS(FAB)：m/z510(MH) ⁺。

Step B

Under room temperature, nitrogen, the methanol solution (500ml) of 53.0 (3.1g) and Sodium Nitrite (0.8g) is stirred with cuprous chloride (0.15g), simultaneously with 10 minutes dropping 4M hydrochloric acid/dioxane solution (3.9ml).Reaction mixture was stirred 24 hours, and then adding 10% yellow soda ash is 8 to pH, concentrating under reduced pressure, and water (200ml) dilution is with methylene dichloride (4 * 100ml) extractions.The extract that reduction vaporization merges, the crude product reactant is through silica gel (400ml) flash chromatography.With 25% ethyl acetate-hexane wash-out, obtain target compound 54.0a and 54.0b after the evaporation, be canescence amorphous solid (2.97g). ¹H?NMR(CDCl ₃，300MHz)d3.30(s，3H)；MS(FAB)m/e525(MH) ⁺。

Step C-E

In refluxing down, 54.0a and 54.0b (17g) methanol solution (150ml) and 2N hydrochloric acid (170ml) and concentrated hydrochloric acid (60ml) were heated 17 hours, follow reduction vaporization.The amorphous solid that produces is dissolved in the methyl alcohol (160ml), under agitation adds sodium cyanide (15g) to reactant and be alkalescence (pH is 8).This reactant was stirred 2 hours, with methylene dichloride (300ml) dilution and filtration.Evaporated filtrate is dissolved in residue in the concentrated hydrochloric acid (150ml), heats this mixture 4 hours in oil bath (120 ℃), then reduction vaporization.Residue is dissolved in the tetrahydrofuran (THF) (100ml), adds 10% sodium hydroxide (30ml), then drip (BOC) to pH＞8 ₂The tetrahydrofuran solution (50ml) of O (9g), vigorous stirring is 24 hours simultaneously.Concentrate this solution to small volume, with hexane (2 * 120ml) and frozen water stir, then, use ethyl acetate extraction with citric acid acidifying water layer.The crude product product that evaporation obtains through the flash chromatography purifying, obtains the mixture (16g) into filbert solid 57.0 and 57.0b, and TLC is a single point. ¹H?NMR(CDCl ₃，300MHz)d1.40(s，9H)；MS(FAB)m/e535(MH) ⁺。

The material that TLC is single point is 4 mixture of isomers, embodiment 77 to 79 and 87 to 97 compound below being separated into after deriving.

(steps A-E), adopt compound (-)-52.0 (17g) obtains the mixture (17g) of 58.0a and 58.0b, is the light color solid, and TLC is a single point according to above-mentioned steps.MS(FAB)m/z535(MH) ⁺。

Preparation embodiment 42

In 60 ℃, add sylvite (565g, 3.35mol) solution of 2-carboxyl-piperazine in 2.5kg (R)-(-)-camphorsulfonic acid in the 1250ml distilled water that is stirring.Stir this mixture to dissolving fully in 95 ℃.Under room temperature with this solution stirring 48 hours.Filter the precipitation that generates, obtain wet solid 1444g.Then, this solid is dissolved in the 1200ml distilled water, in vapor bath, is heated to the solid dissolving.Placing this solution then slowly cooled off them 72 hours.The filtering for crystallizing solid obtains the pure product 2-R-of 362g enantiomorph product, is white crystalline solid.[α] _D＝-14.9°。

Preparation embodiment 43

(362g 0.608mol) is dissolved in 1.4L distilled water and the 1.4L methyl alcohol with 2-R-carboxyl-piperazine-two-(R)-(-)-camphorsulfonic acid (preparation embodiment 42).In the reaction mixture that stirs, drip 75ml 50% sodium hydroxide, obtain pH and be～9.5 solution.Adding solid tert-Butyl dicarbonate in this solution (336g, 1.54mol).The pH of solution is reduced to～and 7.0.With 50% sodium hydroxide the pH of this reaction mixture is remained on 9.5 (175ml altogether), this reaction mixture was stirred 2.5 hours, obtain white precipitate.With 9L ice/water diluted reaction mixture, then with the washing of 2L ether.Discard ether, transfer to 3.0 by part adding the pH of solid citric acid with water layer.Use methylene dichloride (3 * 2L) extraction acidifying water layers then.Merge organic layer, through dried over sodium sulfate, filter and evaporation, obtaining 201.6g is white glass shape solid target compound.FABMS(M＋1)＝331。

Preparation embodiment 44

Under nitrogen environment, with the 5 fens ice-cold Ns of clockwise in the 5L round-bottomed flask, thionyl chloride (46.7ml) in dinethylformamide (49.6ml) solution.This reaction mixture was stirred 5 minutes, remove ice bath, under room temperature, this reaction mixture was stirred 30 minutes.Reaction mixture on ice bath adds N by conduit in reaction mixture once more, N-two tert-butoxycarbonyls-2-R-carboxyl-piperazine (preparation embodiment 43) (201.6g, 51.7ml pyridine 0.61mmol) and 1.9L acetonitrile solution.Make this reaction mixture be warmed to room temperature, obtain little yellow turbid solution.Stirred 18 hours under room temperature, filter this reaction mixture, filtrate is inclined to frozen water (7L), (4 * 2L) extractions, through dried over sodium sulfate, filtering also, vacuum-evaporation obtains 115.6g (73%) and is the target product of white solid to doing to use ethyl acetate then.

Preparation embodiment 45

With 1N-right-cyano group benzyl histamine (0.34,1.5mmol) (according to the described methods preparation of preparation embodiment 163) add to Boc-acid anhydrides (preparation embodiment 44) (0.38g in 10ml dichloromethane solution 1.5mmol), stir down in nitrogen.After 1 hour, add 0.15g Boc-acid anhydrides again, finish through positive TLC monitoring reaction, with 10% ethanol/methylene as eluent.After (about 1 hour) is finished in reaction, in reaction mixture, add 0.25ml (2mmol) cyclohexyl isocyanate, stirred 1 hour.Reaction mixture is inclined to salt solution, with methylene dichloride (3 *) extraction.The combined dichloromethane layer through dried over mgso, filters and is evaporated to dried.Residue is through silica gel rapid column chromatography purifying, and with 5% ethanol/methylene wash-out, obtaining 0.714g is the solid pure product target compound.FABMS(M＋1)＝564。

Preparation embodiment 46

(2.3g 11.3mmol) is dissolved in N, and in the dinethylformamide, (1.53g 1.5eq.), stirs this reaction mixture 5 hours in 90 ℃ to add imidazoles with N-(2, the 3-epoxypropyl) phthalimide.Add salt solution, use the ethyl acetate extraction product, obtain target product (0.67g).

Preparation embodiment 47

The adjacent diformazan acylimino of 1-benzene-2-hydroxyl-3-1-H-imidazoles-propane (deriving from preparation embodiment 46) (0.6g) is dissolved in the ethanol, adds the 5ml hydrazine hydrate.With this reaction mixture refluxed 3 hours.Cool off this reaction mixture to room temperature, filter the precipitation that produces.Filtrate is evaporated to dried, obtains product, it is used without being further purified.

Preparation embodiment 48

1-amino-2-hydroxyl-3-1-H-imidazoles-propane (deriving from preparation embodiment 47) (2.2mmol) is added to Boc-acid anhydrides (preparation embodiment 44), and (0.57g stirs down in 10ml dichloromethane solution 2.2mmol) and in nitrogen.After 1 hour, add 0.15g Boc-acid anhydrides again, finish through positive TLC monitoring reaction, with 10% ethanol/methylene as eluent.After reaction is finished (about 1 hour), in reaction mixture, add 0.85ml (6.6mmol) NSC 87419, stirred reaction mixture 1 hour.Reaction mixture is inclined to salt solution, with methylene dichloride (3 *) extraction.The combined dichloromethane layer, through dried over mgso, filter and evaporation as for.Residue is through silica gel rapid column chromatography purifying, and with 5% ethanol/methylene wash-out, obtaining 0.487g is the solid pure product target compound.

Preparation embodiment 49

(17.85g 30mmol) is dissolved in the 180ml distilled water with 2-carboxyl-piperazine two camsilates (preparation embodiment 42).Add dioxane (180ml), pH is transferred to 11.0 with 50% sodium hydroxide.On ice-methanol bath reaction mixture is cooled to 0-5 ℃, (4.28ml, 80ml dioxane solution 30mmol) remain on 10.5-11.0 in 0-5 ℃ of stirring and with 50% sodium hydroxide with pH simultaneously to add benzyl chloroformate with 30-45 minute.After adding finishes, continue to stir 1 hour.Then reaction mixture is evaporated to and does the dioxane that is used to extract with removal.Residue is dissolved in the 180ml distilled water, pH is slowly transferred to 4.0 with 1N hydrochloric acid.With 3 * 180ml ethyl acetate wash water solution (through the dried over mgso ethyl acetate, filtration and evaporation obtain N, and N-two-CBZ-2-carboxyl-piperazine is stand-by).The pH that will contain the water layer of required product with 50% sodium hydroxide transfers to 10.5-11.0, and (7.86g 36mmol), stirs this mixture, with 50% sodium hydroxide pH is remained on 10.5-11.0 simultaneously to add the solid tert-Butyl dicarbonate.After 1 hour, pH is stable.After reaction is finished, with 2 * 180ml ether washing reaction mixture.On ice bath, cool off water layer, pH is slowly transferred to 2.0 with 1N hydrochloric acid.With ethyl acetate (3 * 200ml) extraction products.Through dried over mgso, filter and be evaporated to dried, obtain 9.68g (88%) and be the purified product of white solid.

Preparation embodiment 50

(9.6g 263mmol) is dissolved in the 100ml dehydrated alcohol in hydrogenation vessel with 4-N-CBZ-1N-Boc-2-carboxyl-piperazine (preparation embodiment 49).In described container, feed nitrogen, add 3g 10%Pd/C (50% weightaqueous solution).Under 55psi hydrogen with mixture hydrogenation 18 hours.After 18 hours, produce precipitation in the reaction mixture.Through the TLC monitoring, with 30% methyl alcohol/ammonia/methylene dichloride wash-out.Through the Celite pad filter reaction mixture, use ethanol and distilled water Rubbing pad for washing use successively.Evaporated filtrate adds 200ml distilled water to about 1/3 volume (removal ethanol).With water layer extraction three times, ethyl acetate layer contains pure product N with ethyl acetate, and N-two-Boc-2-carboxyl-piperazine is retained.Water layer is evaporated to dried, from methyl alcohol, evaporates twice again, obtain 3.98 purified products (17.37g, mmol).

Preparation embodiment 51

With tricyclic alcohol (the preparation embodiment 40 of WO95/10516)

(5.6gm 17.33mmol) is dissolved in the 56ml methylene dichloride, adds the 2.46ml thionyl chloride, stirs down in the drying nitrogen environment simultaneously.After 5 hours, TLC monitoring (1 part of reaction mixture is added in the 1N sodium hydroxide, with the methylene dichloride jolting, through TLC monitoring dichloromethane layer, with 50% ethyl acetate/hexane as eluent).Evaporating mixture obtains jelly, and it is evaporated twice from dry toluene, from methylene dichloride the evaporation once, obtain chlorine derivative into spumescence solid 11-, with it without being further purified use.The 11-chloro-tricyclic compound that produces is dissolved in the 100ml anhydrous dimethyl formamide, adds 1N-Boc-2-carboxyl-piperazine (preparation embodiment 50) and (3.98g), then add the 12.11ml triethylamine, stir this mixture down in room temperature, nitrogen.After 24 hours, the evaporative removal dimethyl formamide is dissolved in residue in the 200ml ethyl acetate, uses the salt water washing.With brine layer washed twice again, the combined ethyl acetate layer through dried over mgso, filters also evaporation, obtains the spumescence solid with ethyl acetate.This solid is through 11/2 " * 14 " silica gel column chromatography, with 2L0.4%7N methyl alcohol/ammonia/methylene dichloride, 6L0.5%7N methyl alcohol/ammonia/methylene dichloride, 2L0.65%7N methyl alcohol/ammonia/methylene dichloride, 2L0.8%7N methyl alcohol/ammonia/methylene dichloride, 4L1%7N methyl alcohol/ammonia/methylene dichloride, 2L3%2N methyl alcohol/ammonia/methylene dichloride, 2L5%2N methyl alcohol/ammonia/methylene dichloride, 2L10%2N methyl alcohol/ammonia/methylene dichloride, 2L15%2N methyl alcohol/ammonia/methylene dichloride.4L20%2N methyl alcohol/ammonia/methylene dichloride wash-out obtains the 4.63gm end product.

Preparation embodiment 52

Target compound (1g with preparation embodiment 51,1.86mmol) be dissolved in the 50ml dimethyl formamide, add 1-amino-3-propyl alcohol (0.214ml, 1.5eq.), DEC (0.71g, 2.eq.), HOBT (0.5g, 2eq.) and N-methylmorpholine (1.02ml, 5eq.), with this reactant stirring 18 hours.This reaction mixture is added in the salt solution, with product extraction three times, obtain crude product oily matter, through purification by silica gel column chromatography, use the 20%-50% ethyl acetate/hexane it as eluent with ethyl acetate.Merge the component that contains product, obtain the pure product target of 0.67g (60%) compound.

Preparation embodiment 53

(8g 60mmol) is dissolved in the 200ml dimethyl formamide, cools off on ice bath with the 2-aminooimidazole.(2.4g 60mmol), stirs this reaction mixture 1 hour by part adding sodium hydride 60% an oily dispersion liquid.(16g 74mmol), stirs this reaction mixture 1/2 hour in 0 ℃, in stirring at room 1 hour, stirs 1 hour in 85 ℃ then to add N-(3-bromopropyl)-phthalimide.Then reaction mixture is cooled to room temperature, adds in the salt solution, use ethyl acetate extraction, obtain the crude product product,,, obtain the 4.88g target compound with 2% ethanol/methylene wash-out through column chromatography purification.Preparation embodiment 54

The adjacent diformazan acylimino of 0.5gl-benzene-2-aminooimidazole (deriving from preparation embodiment 53) was refluxed 6 hours in 20ml6N hydrochloric acid.Use the ethyl acetate purging compound, water layer is evaporated to dried, obtain the 0.45g target product.

Preparation embodiment 55

With 1-aminopropyl-2-aminooimidazole (preparation embodiment 54) (0.25g) and N, N-dibutoxy carbonyl-2-R-carboxyl-piperazine (deriving from preparation embodiment 43) (0.32g) is dissolved in the 10ml dimethyl formamide.Add DEC (0.2g), I-hydroxybenzotriazole (0.135g) and N-methylmorpholine (0.54ml), this reaction mixture was stirred 5 hours.This reactant is inclined to salt solution, use dichloromethane extraction, obtain the 0.43g target product, through silica gel column chromatography, with 2%-10% ethanol/methylene wash-out.FABMS?M＋1＝453.3。

Preparation embodiment 56

With 1-aminopropyl-2-aminooimidazole base-N1, N4-di-t-butyl-1,2 (R)-piperazine diformamide (preparation embodiment 55) (0.38g) is dissolved in 20ml methylene dichloride and the 0.24ml triethylamine.Add benzyloxycarbonyl-N-hydroxy-succinamide (0.22g), under room temperature, this reaction mixture was stirred 18 hours.With salt solution washing reaction mixture,, as eluent, obtain the 0.39g target product with ethyl acetate through silica gel column chromatography.FABMS?M＋1=587.3。

Preparation embodiment 57

With 1-benzyloxycarbonyl aminopropyl-2-aminooimidazole base-N1, N4-di-t-butyl-1,2 (R)-piperazine diformamides (preparation embodiment 56) (0.4g) are dissolved in the 3ml methylene dichloride, add the 1ml trifluoroacetic acid, under room temperature this reaction mixture are stirred 3 hours.Then this reaction mixture is evaporated to driedly, obtains pure product target product.

Preparation embodiment 58

(preparation embodiment 57) is dissolved in 50ml DMF and the 0.46ml triethylamine with 1-benzyloxycarbonyl aminopropyl-2-aminooimidazole base-1,2 (R)-piperazine diformamide.Add 3-bromo-8,11-two chloro-6,11-dihydro-5H-benzo [5,6] ring [1,2-b] pyridine in heptan (171mg) stirs this reaction mixture 24 hours.Reaction mixture is added in the salt solution, use dichloromethane extraction,, as eluent, obtain the pure product target of 82mg product with ethanol/methylene through silica gel column chromatography.FABMSM＋1＝694。

Preparation embodiment 59

(0.991g 4.4mmol) is dissolved in the 25mol anhydrous tetrahydro furan, is cooled to-78 ℃ with 1-tert-butoxycarbonyl aminopropyl-imidazoles.(3.88ml, cyclohexane solution 9.68mmol) stir this reactant 1/2 hour to drip the 2.5M n-Butyl Lithium.(0.49ml 8.8mmol), stirs this reactant 1/2 hour to add acetaldehyde.Make reaction mixture be warmed to room temperature, dilute this reactant, use the salt water washing with ethyl acetate.The evaporation of acetic acid methacrylate layer obtains jelly, and it through silica gel column chromatography, is obtained the 0.54g target product.(MH ⁺＝170)。

Preparation embodiment 60

(preparation embodiment 59) (0.51g) is dissolved in the trifluoroacetic acid with 1-tert-butoxycarbonyl aminopropyl-2-hydroxyethyl-imidazoles, stirs 3-4 hour.Evaporating mixture obtains the pure product trifluoroacetate of target compound to doing.

Preparation embodiment 61

1-N-trityl-4-iodine imidazoles (1.91g) is dissolved in the 20ml methylene dichloride, stirs adding 1.46ml ethylmagnesium bromide down.After 15 minutes, add N-Boc-phenylalanine aldehyde (0.5gm), this reaction mixture was stirred 18 hours.Ammonium chloride washing reaction mixture with saturated through dried over mgso, through silica gel column chromatography, obtains the product of 0.8g intermediate protection.FABMS(M＋1)＝561。Then it was handled 18 hours with 4M HCl/ dioxane.This mixture is evaporated to dried, it is dissolved in the distilled water, wash with ethyl acetate.The evaporation water layer obtains pure product target product.MH ⁺＝218。

Preparation embodiment 62

Steps A

Under 25-70 ℃, nitrogen, with N-(3-bromopropyl) phthalimide (12.3g, 46mmol), 4-methylimidazole (3.78g, 46mmol), sodium hydride (60% mineral oil, 1.84g, 46mmol) and anhydrous dimethyl formamide (50ml) mixture stir and to spend the night.This mixture of vacuum concentration obtains residue, dilutes with methylene dichloride, filter and vacuum concentration, through rapid column chromatography (silica gel) purifying, with the saturated 1% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtain target compound (8.04g, 65%, MH for oily matter ⁺=270).

Step B

(8.02g 29.8mmol) adds a hydrazine hydrate (15ml) to the target compound of the steps A in being dissolved in dehydrated alcohol (150ml) in the solution, in nitrogen, backflow down, this mixture was stirred 12 hours.Dilute this mixture with methylene dichloride, filter and vacuum concentration.With residue silica gel rapid column chromatography purifying,, obtain target compound (2.95g, 71%, MH into oily matter with the saturated 5% methyl alcohol-methylene dichloride of ammonium hydroxide aqueous solution ⁺=140).

Preparation embodiment 63-67

According to preparation embodiment 62 described methods, the substituted imidazole of table 3 replaces the 4-methylimidazole of steps A below adopting, the listed amine (product) of preparation table 3.

Table 3

Preparation embodiment 67

If adopt preparation embodiment 62 described methods, but use the imidazoles of following formula The 4-methylimidazole that replaces steps A obtains the amine of following formula:

Preparation embodiment 67.1

If according to preparation embodiment 62 described methods, still use the imidazoles of following formula

The 4-methylimidazole that replaces steps A obtains the amine of following formula:

Preparation embodiment 68

In reflux, under the nitrogen, with the 2-chloroethyl amine hydrochloride (7.66g, 66mmol), 2,4-methylimidazole (5.88g, 61mmol), tetrabutyl ammonium sulfate (0.83g, 2.5mmol), solid sodium hydroxide (8.81g, 220mmol) and anhydrous acetonitrile (80ml) stirred 48 hours.Filter this mixture, vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (10.7g, 100%, MH into oily matter ⁺=140).

Preparation embodiment 69-73

According to preparation embodiment 68 described methods, the substituted imidazole of table 4 or triazole replace 2 below adopting, and the 4-methylimidazole obtains the listed amine of table 4 (product).

Table 4

Preparation embodiment 74

Under room temperature, nitrogen, with 1-(3-aminopropyl) imidazoles (37.1g, 297mmol), phenyl aldehyde (30g, 283mmol), 3 dust molecular sieves (50g), sodium acetate (24.1g, 283mmol) and anhydrous methanol (700ml) stir and spend the night.This mixture is cooled to 0 ℃, with 1 hour by part add a sodium borohydride (10.9g, 288mmol).Under room temperature, this mixture was stirred 3 hours.By this mixture of diatomite filtration, use methanol wash, vacuum concentration obtains residue, and it is diluted with methylene dichloride, washs with 10% aqueous sodium hydroxide washes.With salt water washing organic phase, through anhydrous magnesium sulfate drying, filter and vacuum concentration, obtain target compound (56.3g, 92%, MH into faint yellow oily thing ⁺=216).

Preparation embodiment 75-95

According to preparation embodiment 74 described methods, the aldehyde and the imidazolyl alkylamine of table 5 obtain the listed amine of table 5 (product) below adopting.

Table 5

Preparation embodiment 95.1

Steps A

In being cooled to 0 ℃ methylene dichloride (500ml) solution of preparation embodiment 62 steps A target compounds (65.7g), add trityl chloride (27.2g).The mixture that produces is warmed to room temperature and stirred vacuum concentration under the situation that stops then heating 1.5 hours.Through rapid column chromatography purifying (silica gel, 1: 1 acetone-ethyl acetate), obtain pure product 4-methyl isomer (35.02g, MH ⁺=270).

Step B

According to preparation embodiment 62 step B described essentially identical method, but with the pure product 4-methylimidazole product (35.02g) of preparation embodiment 95.1 steps A, obtain target compound (16.12g, MH ⁺=140).

Step C

According to preparation embodiment 74 described essentially identical methods, but with pure product 4-methylimidazole propylamine product (16.12g) replacement 1-(3-aminopropyl) imidazoles of above-mentioned preparation embodiment 95.1 step B, obtain target compound (18.03g, MH ⁺=230).

Preparation embodiment 97

In 50 ℃, with the target compound of preparation embodiment 82 (0.50g, 2.0mmol), dehydrated alcohol (50ml), 30% aqueous hydrogen peroxide solution (0.45ml, 4.4mmol) and the 1M aqueous sodium hydroxide solution (4.4ml, 4.4mmol) mixed solution stirred 12 hours.Vacuum concentration through the flash chromatography on silica gel purifying, uses the saturated 10% methyl alcohol-dichloromethane solution of ammonium hydroxide aqueous solution as elutriant, obtains target compound (0.33g, 61% productive rate, MH into oily matter ⁺=259).

Preparation embodiment 98

1-(3-aminopropyl) imidazoles of the cooling in being dissolved in anhydrous methylene chloride (20ml) (0 ℃) (Aldrich, 1.9ml, 16mmol) and triethylamine (5.6ml, 40mmol) add in the solution phenyl Acetyl Chloride 98Min. (2.12ml, 16mmol).Mixture is warmed to room temperature and stirs spend the night.Wash mixture with the 1N aqueous sodium hydroxide washes, through anhydrous magnesium sulfate drying and filtration.Vacuum concentrated solution and through silica gel rapid column chromatography purifying with the saturated 2% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (1.8g, 45% productive rate, MH into oily matter ⁺=244).

Preparation embodiment 99

The target compound of preparation embodiment 98 in being dissolved in anhydrous tetrahydro furan (5ml) (0.51g, and adding borine methyl-sulfide mixture in reflux solution 2.1mmol) (6.3ml, the tetrahydrofuran solution of 2M, 13mmol).After 1 hour, this mixture is cooled to room temperature, stirring is spent the night.Dripping hydrochloric acid (1N) to reaction mixture is acid (pH test paper).With the 1N aqueous sodium hydroxide solution mixture is transferred to alkalescence, use dichloromethane extraction, through anhydrous magnesium sulfate drying and filtration.This solution of vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (0.25g, 52% productive rate, MH into oily matter ⁺=230).

Preparation embodiment 100

The target compound of the preparation embodiment 62 step B of the cooling in being dissolved in anhydrous methylene chloride (10ml) (0 ℃) (0.7g, 5mmol) and triethylamine (1.7ml, 12.5mmol) add in the solution phenyl Acetyl Chloride 98Min. (0.67ml, 5mmol).Mixture is warmed to room temperature and stirs spend the night.With 1M aqueous hydrochloric acid purging compound, water is transferred to alkalescence with the 1N aqueous sodium hydroxide solution.With this phase of dichloromethane extraction, through anhydrous magnesium sulfate drying and filtration.This solution of vacuum concentration obtains target compound (0.72g, 56% productive rate, MH into oily matter ⁺=258).

Preparation embodiment 101

The target compound of preparation embodiment 100 in being dissolved in anhydrous tetrahydro furan (15ml) (0.66g, and adding borine tetrahydrofuran (THF) mixture in reflux solution 2.5mmol) (5ml, the tetrahydrofuran solution of 1M, 5mmol).The mixture backflow after 12 hours, is cooled to room temperature and vacuum concentration.Residue with the dilution of 1M hydrochloric acid, is used washed with dichloromethane, with 50% aqueous sodium hydroxide solution alkalization water, use dichloromethane extraction then, through anhydrous magnesium sulfate drying and filtration.This solution of vacuum concentration through preparation property silica-gel plate chromatography purification, with the saturated 3% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (0.21g, 35%, MH into oily matter ⁺=244), with it through preparation property chirality chromatography purification (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 5-8%IPA-hexane+0.2% diethylamine).

Preparation embodiment 101.1

According to the method for preparing embodiment 100, still make the compound of following formula: Target compound reaction with preparation embodiment 62 step B can obtain product:

Preparation embodiment 101.2

According to the method for preparing embodiment 101, but adopt the product for preparing embodiment 101.1, can obtain product ` so:

Preparation embodiment 102

Steps A

1-(3-aminopropyl) imidazoles of the cooling in being dissolved in anhydrous methylene chloride (50ml) (0 ℃) (10g, 80mmol) and triethylamine (17.1ml, 120mmol) add in the solution trifluoroacetic anhydride (12.4ml, 88mmol).This mixture is warmed to room temperature and stirs spend the night.Wash this mixture with water,, filter and vacuum concentration, obtain target compound (15.7g, 88%, MH into oily matter through anhydrous magnesium sulfate drying ⁺=222).

Step B

(0.24g 1.1mmol) adds sodium hydride solid (85mg, 2.1mmol, 60% mineral oil suspension) to the target compound of the steps A in being dissolved in anhydrous dimethyl formamide (10ml) in the solution.After stopping to produce gas, (0.1ml 1.1mmol), stirs this mixture 40 minutes in 70 ℃ to add methyl-iodide.The mixture that produces is cooled to room temperature, and vacuum concentration with the methylene dichloride dilution, washes with water.Through this solution of anhydrous magnesium sulfate drying, filter and vacuum concentration, obtain oily matter (0.28g).Through preparation property silica-gel plate chromatography purification,, obtain target compound (78mg, 30%, MH into yellow oil with the saturated 2% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution ⁺=236).

Step C

Under room temperature, with the target compound of step B (74mg, 0.3mmol) and the mixed solution of the aqueous solution (0.6ml) of 20% potassium hydroxide stirred 15 minutes.The mixture that vacuum concentration produces through silica gel rapid column chromatography purifying, with the saturated 10% methyl alcohol-90% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (65mg, 100%, MH into oily matter ⁺=140).

Preparation embodiment 103

According to preparation embodiment 102 step B-C in the similar method of preparation target compound, but replace methyl-iodide with iodoethane, obtain ethylamine (893mg, 43%, MH into oily matter ⁺=154).

Preparation embodiment 104

According to preparation embodiment 102 step B-C in the similar method of preparation target compound, but replace methyl-iodide with propyl iodide, obtain propyl group amine (649mg, 29%, MH into oily matter ⁺=168).

Preparation embodiment 105

(the other method of preparation embodiment 74)

According to preparation embodiment 102 step B-C in the similar method of preparation target compound, but replace methyl-iodide with bromotoluene, obtain benzyl amine (1.64g, 56%, MH into oily matter ⁺=216).

Preparation embodiment 106

Under room temperature, with the target compound of preparation embodiment 74 (1.34g, 6.2mmol), the target compound of preparation embodiment 44 (1.6g, 6.2mmol), triethylamine (1.3ml, 9.3mmol) and anhydrous methylene chloride (10ml) stirring 48 hours.Add trifluoroacetic acid (10ml), with the mixture restir that produces 1.5 hours.Drip 1N aqueous sodium hydroxide solution neutralization reaction mixture, with the mixture of dichloromethane extraction generation.Through the anhydrous magnesium sulfate drying organic phase, filter and vacuum concentration, obtain residue, through silica gel rapid column chromatography purifying,, obtain target compound (520mg, 26%, MH into oily matter with the saturated 1% methyl alcohol-99% methylene dichloride wash-out of ammonium hydroxide aqueous solution ⁺=328).

Preparation embodiment 107

According to preparation embodiment 106 described essentially identical methods, but with the target compound of preparation embodiment 76, preparation target compound (0.16g, 10%, MH ⁺=346).

Preparation embodiment 108

According to preparation embodiment 110 (following) described essentially identical method, but with the target compound of preparation embodiment 107 (146mg, 0.55mmol) and 8-Cl-tricyclic chloride (referring to the preparation embodiment 7 of WO95/10516) (159mg, 0.46mmol):

The preparation target compound, through preparation property silica-gel plate chromatographic separation, with the saturated 2% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, diastereomer A (45,17.1%, MH ⁺=573), diastereomer B (43mg, 16.3%, MH ⁺=573).

Preparation embodiment 109

The target compound of embodiment 113 below in being dissolved in anhydrous methylene chloride (25ml) (4.90,6.7mmol) add TFA (15ml) in the solution.With this solution stirring 2 hours, vacuum concentration with the methylene dichloride dilution, washed with saturated sodium bicarbonate aqueous solution, through anhydrous magnesium sulfate drying then under room temperature, nitrogen.Filter this mixture, vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains the target compound (3.66g, quantitative) into non-enantiomer mixture.Separate diastereomer through preparation property chirality chromatography (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 99.8% methyl alcohol+0.2% diethylamine), obtain 1.62g 11S, 2R diastereomer A and 1.97g 11R, 2R diastereomer B.

11S, the physicochemical data of 2R diastereomer A: mp=109.3 ℃; MH ⁺=633; [α] ²⁰ _D=-66.2 ° (in 3.93mg/2ml methyl alcohol).

11R, the physicochemical data of 2R diastereomer B: mp=64.5 ℃; MH ⁺=633; [α] ²⁰ _D=-41.8 ° (in 4.69mg/2ml methyl alcohol).

Preparation embodiment 110

(the other method of preparation embodiment 109)

Under room temperature, with the target compound of preparation embodiment 106 (510mg, 1.6mmol), tricyclic chloride (compound 42.0) (534mg, 1.6mmol), triethylamine (1.1ml, 7.8mmol) and methylene dichloride (10ml) mixture stirring spend the night.This reaction mixture of vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (420mg, 42%, MH into faint yellow solid ⁺=633).Separate diastereomer through preparation property chirality chromatography (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 99.8% methyl alcohol+0.2% diethylamine), obtain 182mg diastereomer A and 126mg diastereomer B.

Preparation embodiment 111

Under room temperature, target compound (1.93g with preparation embodiment 106,5.9mmol), 8-chloro-tricyclic chloride (seeing the preparation embodiment 7 of WO95/10516) (1.56g, 5.9mmol), triethylamine (4.1ml, 29.5mmol) and methylene dichloride (10ml) mixture stirred 48 hours.This reaction mixture of vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (1.56g, 49%, MH into faint yellow solid ⁺=555).Separate diastereomer through preparation property chirality chromatography (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 30%IPA+70% hexane+0.2% diethylamine), obtain 0.72g 11S, 2R diastereomer A and 0.57g 11R, 2R diastereomer B.

Preparation embodiment 111.1

Adopt the method for preparing embodiment 111, but use the 10-chloro-tricyclic chloride of following formula:

Obtain

Preparation embodiment 112

Carboxylic acid (2g to preparation embodiment 43, add HOBT (0.82g 6mmol), 6.1mmol), DEC (1.2g, 6.0mmol), the target compound of preparation embodiment 85 (1.39g, 6.1mmol is through preparation property chirality chromatographic separation (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 8%IPA+92% hexane+0.2% diethylamine), NMM (1.7ml, 15.5mmol) and dry DMF (60ml).Under room temperature, nitrogen, this mixture stirring is spent the night, this mixture of vacuum concentration with the methylene dichloride dilution, is washed with aqueous sodium hydroxide washes.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.Through silica gel rapid column chromatography purifying,, obtain target compound (1.8g, 55%, MH with the saturated 2-15% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution ⁺=542).

Preparation embodiment 113

According to preparation embodiment 109 described methods, but the target compound of embodiment 126 below adopting, preparation and separate targets compound: 11S, 2R (-)-diastereomer A:25.4% productive rate, MH ⁺=619; [α] ²⁰ _D=-46.7 ° (in 1.86mg/2ml methyl alcohol).11R, 2R (-)-diastereomer B:21.1% productive rate, MH ⁺=619; [α] ²⁰ _D=-23.0 ° (in 2.6mg/2ml methyl alcohol).

Preparation embodiment 114

The target compound of preparation embodiment 112 in being dissolved in anhydrous methylene chloride (5ml) (1.8,3.33mmol) add TFA (5ml) in the solution.Under room temperature, nitrogen this solution stirring is spent the night, vacuum concentration dilutes with DMF (10ml) then.(562mg, 1.1mmol) and triethylamine (10ml), stirring is 48 hours under room temperature to add the 8-Cl-tricyclic chloride in this solution.This reaction mixture of vacuum concentration is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing, through anhydrous magnesium sulfate drying.Behind filtration and the vacuum concentration, residue with the saturated 3-10% methyl alcohol-98% methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (11S, 2R diastereomer A, 152mg, 27%, MH through silica gel rapid column chromatography (silica gel) purifying ⁺=569,11R, 2R diastereomer B, 316mg, 56%, MH ⁺=569.

Preparation embodiment 115

Target compound (2.64g to preparation embodiment 43,8.0mmol) in add HOBT (1.26g, 9.3mmol), DEC (1.79g, 9.3mmol), the target compound (1.44g of preparation embodiment 78,6.7mmol), NMM (1.5ml, 13.6mmol) and dry DMF (10ml).Under room temperature, nitrogen, the mixture stirring is spent the night.This mixture of vacuum concentration with the methylene dichloride dilution, is washed with aqueous sodium hydroxide washes.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.Residue with the saturated 1% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (0.94g, 27%, MH through rapid column chromatography (silica gel) purifying ⁺=529).

Preparation embodiment 116

Under room temperature, with the target compound of preparation embodiment 115 (0.73g, 1.38mmol) and anhydrous methylene chloride (5ml) stirring 48 hours.Add trifluoroacetic acid (2ml), with the mixture restir that produces 1.5 hours.Drip 1N aqueous sodium hydroxide solution neutralization reaction mixture, with the mixture of dichloromethane extraction generation.Through the anhydrous magnesium sulfate drying organic phase, filter and vacuum concentration, obtain residue, through rapid column chromatography (silica gel) purifying,, obtain being oily matter target compound (346mg, 76%, MH with the saturated 5-15% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution ⁺=329).

Preparation embodiment 117

Adopt method prepare embodiment 110, but with the target compound for preparing embodiment 116 (343mg, 1mmol) and tricyclic chloride (compound number 42.0,718mg, 2mmol), preparation and separate targets compound: 11S, 2R diastereomer A:135mg, 29%, MH ⁺=634; 11R, 2R diastereomer B:126mg, 27%, MH ⁺=634.

Preparation embodiment 118

Carboxylic acid (7.26g to preparation embodiment 43, add 22mmol) HOBt (3.92g, 29mmol), DEC (5.49g, 29mmol), the target compound (4.73g of preparation embodiment 74,22mmol), NMM (4.84ml, 44mmol) and dry DMF (35ml).Under room temperature, nitrogen, the mixture stirring is spent the night.This mixture of vacuum concentration with the methylene dichloride dilution, is washed with aqueous sodium hydroxide washes.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.Residue with the saturated 1% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (1.71g, 15%, MH through rapid column chromatography (silica gel) purifying ⁺=528).

Preparation embodiment 119

In 130 ℃, with the target compound of preparation embodiment 118 (1.4g, 2.7mmol) and paraformaldehyde (solid 2.8g) heated 12 hours in the test tube of sealing.Dilute this mixture and filtration with methylene dichloride.The vacuum concentration organic phase through rapid column chromatography (silica gel) purifying, with the saturated 1% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (0.89g, 59%, MH ⁺=558).

Preparation embodiment 120

Under room temperature, with the target compound of preparation embodiment 119 (0.88g, 1.6mmol), anhydrous methylene chloride (10ml) and trifluoroacetic acid (10ml) stirring 1.5 hours.Drip 1N aqueous sodium hydroxide solution neutralization reaction mixture, vacuum concentration through rapid column chromatography (silica gel) purifying, with the saturated 5-12% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (503mg, 88%, MH into oily matter subsequently ⁺=358).

Preparation embodiment 121

With the preparation embodiment 120 target compound (498mg 1.4mmol) is dissolved in the anhydrous methylene chloride (10ml).(370mg, 1.4mmol) and triethylamine (0.6ml), stirring is 24 hours under room temperature to add the 8-Cl-tricyclic chloride in this solution.This reaction mixture of vacuum concentration, dilute with methylene dichloride, residue is through silica gel rapid column chromatography purifying, with 3% saturated methyl alcohol of ammonium hydroxide aqueous solution-methylene dichloride wash-out, obtain target compound (yield 38%), through preparation property chirality chromatographic separation (Chiralpack AD post, 5cm * 50cm post for non-enantiomer mixture, flow velocity 80ml/min, 30%IPA-hexane+0.2% diethylamine).Diastereomer A, 178mg, MH ⁺=585, diastereomer B, 130mg, MH ⁺=585.

Preparation embodiment 122

To the carboxylic acid of preparation embodiment 43 (8.11g, add in 25mmol) HOBT (4.39g, 33mmol), DEC (6.33g, 33mmol), the target compound of preparation embodiment 88 (5.97g, 25mmol), NMM (5.5ml, 50mmol) and dry DMF (40ml).Under room temperature, nitrogen, mixture was stirred 48 hours.This mixture of vacuum concentration with the methylene dichloride dilution, is washed with aqueous sodium hydroxide washes.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.Residue with the saturated 1% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (5.24g, 38%, MH through rapid column chromatography (silica gel) purifying ⁺=556).

Preparation embodiment 123

With the target compound of preparation embodiment 122 (5.23g, 9.4mmol)/stirring of anhydrous methylene chloride (10ml) and trifluoroacetic acid (10ml) spends the night.Drip 1N sodium hydroxide neutralization reaction mixture, vacuum concentration through rapid column chromatography (silica gel) purifying, with the saturated 5-9% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains being buttery target compound (2.69mg, 81%, MH ⁺=356).

Preparation embodiment 124

With the preparation embodiment 123 target compound (2.67,7.5mmol) be dissolved in the anhydrous methylene chloride (40ml).(1.98g, 7.5mmol) and triethylamine (3.14ml), stirring is 12 hours under room temperature to add the 8-Cl-tricyclic chloride in this solution.This reaction mixture of vacuum concentration is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing, through anhydrous magnesium sulfate drying.Behind filtration and the vacuum concentration, residue with the saturated 1-2% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (diastereomer A, 1.2g, MH with 43% productive rate through silica gel rapid column chromatography purifying ⁺=583, diastereomer B, 681mg, MH ⁺=583).

Preparation embodiment 125

Under room temperature, with the target compound of preparation embodiment 106 (200mg, 0.61mmol), the chloro benzo suberane (140mg, 0.61mmol), triethylamine (0.43ml, 3.1mmol) and methylene dichloride (10ml) stirring spend the night.This reaction mixture of vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (63mg, 20%, MH into faint yellow solid ⁺=520).

Preparation embodiment 126

Adopt the method for preparing embodiment 114, but use 3 of following formula, 8-dichloro tricyclic compound:

Replace 8-chlorine tricyclic chloride, obtain target compound.

Preparation embodiment 127

Steps A

To piperazine carboxylic acid two camsilates of water-soluble (80ml) and dioxane (80ml) (preparation embodiment 42,14.63g, add in 24.6mmol) 50% aqueous sodium hydroxide solution to pH be 11.(6.65g 27.04mmol), is 11 in stirring at room 6.5 hours and with 50% sodium hydroxide maintenance pH simultaneously to add BOC-ON.With 10% aqueous hydrochloric acid pH is transferred to 9.5, (4.0g, 24.6mmol), slowly adding 50% aqueous sodium hydroxide solution simultaneously, to keep pH be 9.5, simultaneously in 25 ℃ of restir 12 hours to drip the carbonochloridic acid cyclohexyl.With this mixture of extracted with diethyl ether, with 6M aqueous hydrochloric acid acidifying water to pH be 3.Use the ethyl acetate extraction water,, filter and vacuum concentration,,, obtain target compound (6.65g, 76%, MH with 25-50% ethyl acetate-hexane wash-out through quick purification by silica gel column chromatography through the anhydrous magnesium sulfate drying organic phase ⁺=357).

Step B

Under room temperature, will be dissolved in the steps A in the anhydrous methylene chloride (50ml) target compound (6.65g, 18.7mmol) and trifluoroacetic acid (20ml) stirred 1 hour.The vacuum concentration organic phase obtains residue.

Step C

The target compound of step B is dissolved in anhydrous methylene chloride (50ml) and the dimethyl formamide (50ml).(8.42g 31.8mmol) and triethylamine (3ml), stirred 48 hours under room temperature to wherein adding the 8-Cl-tricyclic chloride.The vacuum concentration reaction mixture is with ethyl acetate dilution, with the washing of 3N sodium hydroxide, with in 50% citric acid and organic phase, through anhydrous sodium sulfate drying.Behind filtration and the vacuum concentration, residue with 2-5% methyl alcohol-methylene dichloride wash-out, obtains target compound (11S, 2R diastereomer A, 2.43g, 27%, MH through silica gel rapid column chromatography purifying ⁺=485; 11R, 2R diastereomer B, 2.5g, 30%, MH ⁺=484).

Preparation embodiment 128

Target compound (1.83g to preparation embodiment 43,5.6mmol) in add HOBT (0.88g, 6.5mmol), DEC (1.24g, 6.5mmol), the target compound (1g of preparation embodiment 95,4.6mmol), NMM (1.0ml, 9.25mmol) and dry DMF (10ml).Under room temperature, nitrogen, the mixture stirring is spent the night.This mixture of vacuum concentration with the methylene dichloride dilution, is washed with aqueous sodium hydroxide washes.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.Residue with the saturated 10% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (0.70g, 24%, MH through rapid column chromatography (silica gel) purifying ⁺=529).

Preparation embodiment 129

Under room temperature, with the target compound of preparation embodiment 128 (0.70g, 1.3mmol), anhydrous methylene chloride (10ml) and trifluoroacetic acid (10ml) stirring 12 hours, vacuum concentration then.Drip 1N sodium hydroxide neutralization reaction mixture, with the mixture of dichloromethane extraction generation.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.Residue with the saturated 10% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains being brown oil target compound (232mg, 53%, MH through rapid column chromatography (silica gel) purifying ⁺=329).

Preparation embodiment 130

With the preparation embodiment 129 target compound (0.20g 0.61mmol) is dissolved in the dry DMF (5ml).To wherein add tricyclic chloride (compound number 42.0) (0.2g, 0.58mmol) and triethylamine (0.43mg 3.0mmol), stirred under room temperature 12 hours.Reaction mixture is inclined to salt solution, use ethyl acetate extraction.Through the anhydrous sodium sulfate drying organic extract, filter and vacuum concentration.Residue with the saturated 10% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (100mg, 27%, MH through rapid column chromatography (silica gel) purifying ⁺=634).

Preparation embodiment 131

Steps A

To the target compound that is cooled to 0 ℃ of preparation embodiment 51 (1.4g, 70% purity, 1.8mmol) and add in the methylene dichloride (10ml) triethylamine (0.5ml, 3.6mmol) with the carbonochloridic acid isobutyl ester (0.25ml, 1.9mmol).In 0 ℃ stir 3 hours after, target compound (the 0.4g that adds preparation embodiment 95.1,1.7mmol, through preparation property chirality chromatographic separation (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 8%IPA-92% hexane+0.2% diethylamine), under room temperature, nitrogen, the compound stirring is spent the night.Wash this mixture with the 1M aqueous sodium hydroxide washes,, filter and vacuum concentration through the anhydrous sodium sulfate drying organic phase.Residue with the saturated 2-5% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (0.45g, 34%, MH into non-enantiomer mixture through rapid column chromatography (silica gel) purifying ⁺=747).

Step B

The target compound of the steps A in being dissolved in anhydrous methylene chloride (5ml) (0.45, add TFA (5ml) in solution 0.60mmol).Under room temperature, nitrogen this solution stirring is spent the night, vacuum concentration with the methylene dichloride dilution, is washed with the 1N aqueous sodium hydroxide washes, through anhydrous sodium sulfate drying then.Filter this mixture, vacuum concentration and through rapid column chromatography (silica gel) purifying with the saturated 2-5% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains the target compound into non-enantiomer mixture.Separate diastereomer through preparation property chirality chromatography (Chiralpack AD post, 5cm * 50cm post, flow velocity 80ml/min, 60%IPA+40% hexane+0.2% diethylamine), obtain 0.11g diastereomer A and 0.23g diastereomer B.

11S, the physicochemical data of 2R (-)-diastereomer A: MH ⁺=647; [α] ²⁰ _D=-45.4 ° (in 2.91mg/2ml methyl alcohol).

11R, the physicochemical data of 2R (-)-diastereomer B: MH ⁺=647; [α] ²⁰ _D=-23.5 ° (in 2.21mg/2ml methyl alcohol).

Preparation embodiment 132

Steps A

In 0 ℃, to 1-(trityl-1H-imidazol-4 yl)-3-hydroxy propane (the WO9629315) (5.04g that stirs, 13.68mmol), phthalimide (2g, 13.6mmol) and triphenyl phosphine (3.57g, 13.6mmol) THF (100ml) solution in drip the diethylazodicarboxylate (2.14ml, 13.6mmol).In 0 ℃ this reaction mixture was stirred 1 hour, then in stirring at room 16 hours.Filter, obtain target compound (4.6g, 100%), CIMS:m/z (MH ⁺)=498; δ _H(CDCl ₃) 1.72 (bs, 1H), 1.9 (m, 1H), 2.05 (m, 1H), 2.6 (m, 1H), 3.75 (m, 2H), 6.6-7.8 (m, 21H).

Step B

In refluxing down, with the target compound of steps A (2g, 4.02mmol) and hydrazine hydrate (3.89ml 80.39mmol) heated 16 hours in ethanol (80ml).Cross filter solid, evaporated filtrate obtains target compound (1.35g, 91%), m/z (CIMS:MH ⁺) 368; δ _H(CDCl ₃) 1.8-1.85 (m, 2H), 2.6-2.62 (m, 2H), 2.8-2.83 (m, 2H), 7.1 (s, 1H), 7.3 (s, 1H).

Step C The Ph=phenyl

To the target compound of the step B that stirs (1.5g, 4.08mmol) and phenyl aldehyde (0.433g, 4.08mmol) add in the solution sodium cyanoborohydride (0.256g, 4.08mmol).With acetate the pH of this solution is transferred to about 4.25.Then this reaction mixture was stirred 2 hours, with 50% sodium hydroxide pH is transferred to 11.5 subsequently, use ethyl acetate extraction.Water and salt water washing acetic acid ethyl ester extract are through dried over mgso.Evaporation obtains the crude product residue, and it through the silica gel column chromatography purifying, as elutriant, is obtained target compound (1.04g, 78%), CIMS:m/z (MH with 4% (methanol solution of 10% ammonium hydroxide)-methylene dichloride ⁺)=458; δ _H(CDCl ₃) 1.8-1.82 (m, 2H), 2.58-2.64 (m, 4H), 3.6 (s, 2H), 6.5 (s, 1H), 7.15-7.4 (m, 6H).

Preparation embodiment 133

Steps A

(0.75ml, 12.05mmol) (2g, (20ml) solution of methylene dichloride 4.1mmol) also stirred 16 hours the target compound of Processing of Preparation embodiment 132 steps A with methyl-iodide.Be evaporated to driedly, the residue that obtains gluing refluxes them 16 hours with 6N hydrochloric acid (25ml) then.Be evaporated to driedly, obtain semisolid, with the sodium bicarbonate aqueous solution neutralization, be evaporated to driedly once more, it is semi-solid to obtain white.Stir with methylene dichloride (100ml) and methyl alcohol (50ml), leach solid.Evaporated filtrate obtains target compound (0.3g), CIMS:m/z (MH ⁺) 140; δ _H(CDCl ₃) 1.8 (m, 2H), 2.6-2.8 (m, 4H), 3.6 (s, 3H), 6.68 (s, 1H), 7.4 (s, 1H).

Step B

With the target compound of steps A (1.97g, 14.14mmol), phenyl aldehyde (1.65g, 15.55mmol), sodium acetate (1.1g, 13.42mmol) and 3 dust molecular sieves (2g) in methyl alcohol, stirred 18 hours.(0.519g 13.72mmol), stirred 4 hours to wherein adding sodium borohydride.Leach solid, evaporated filtrate obtains residue, through chromatography, obtains target compound (0.59g, 18.5%), CIMS:m/z (MH ⁺) 230; δ _H(CDCl ₃) 1.8 (q, 2H), 2.6 (t, 2H), 2.65 (t, 2H), 3.25 (s, 3H), 3.8 (s, 2H), 7.2-7.4 (m, 7H).

Preparation embodiment 134

Steps A

In 60 ℃, with 1-(2-phenyl-2,3-epoxypropyl)-1H-imidazoles (GB2099818A) (2.15g, 10.85mmol) and sodiumazide (1.41g, 21.71mmol) in DMF (20ml) heating 16 hours.Be evaporated to driedly, use dichloromethane extraction, use the salt water washing, through dried over mgso.Evaporation obtains target compound (0.932g, 36%), CIMS:m/z (MH ⁺)=244; δ _H(CDCl ₃) 3.7 (q, 2H), 4.5 (dd, 2H), 6.6 (s, 1H), 6.95 (s, 1H), 7.3-7.45 (m, 5H), 8.2 (s, 1H).

Step B

Under 50psi, (0.8g 3.31mmol) spends the night with 10% palladium carbon (0.2g) hydrogenation in ethanol (15ml) with the target compound of steps A.Filtration catalizer, evaporation obtains target compound (0.71g, 98%), CIMS:m/z (MH ⁺)=218.

Preparation embodiment 135

Adopting the step of preparation embodiment 41a to e, by (+) isomer, obtain the mixture into filbert solid target compound A and B, is a point on TLC: ¹NMR (CDCl ₃, 300 MHz) δ 1.42 (s, 9H), 4.85 (m, 2H), 7.12 (s, 1H), 7.50 (s, 1H), 7.55 (s, 1H), 8.48 (m, 1H); HRMS (FAB) C ₂₅H ₂₈N ₂O ₄BrCl ⁸¹The Br calculated value: 615.0084, measured value: 615.0092.

Preparation embodiment 136

According to the method for preparing embodiment 123, but adopt the target compound for preparing embodiment 37 steps A, obtain target compound (quantitative yield; MH ⁺=338).

Preparation embodiment 137-138

According to preparation embodiment 106 described methods, adopt the listed piperazine of corresponding amine preparation following table 5A.

Table 5A

Preparation embodiment 139-141

Similarly, according to preparation embodiment 110 described methods, the listed piperazine of table 5B prepares corresponding Tricyclic amine below adopting.

Table 5B

Preparation embodiment 142

Under room temperature, with the target compound of embodiment 289 (0.39g, 0.51mmol), anhydrous methylene chloride (3ml) and trifluoroacetic acid (3ml) stirred 2 hours, vacuum concentration then.Drip 1N aqueous sodium hydroxide solution neutralization reaction mixture, with the mixture of dichloromethane extraction generation.Through the anhydrous magnesium sulfate drying organic phase, filter and vacuum concentration, obtain residue, it through silica gel rapid column chromatography purifying, with the saturated 5% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, is obtained the target compound (52mg into pale solid, 15%, mp=150 ℃, MH ⁺=768).

Preparation embodiment 143

Under room temperature, will be dissolved in the preparation embodiment 71 in the anhydrous methylene chloride (10ml) target compound (0.9g, 5.14mmol) and the acid anhydrides of preparation embodiment 44 (1.38g 1.05eq) stirs and to spend the night.Add acid anhydrides (0.105g) again, after 1 hour, in reaction mixture, add NSC 87419 (0.98ml, 7.71mmol), with its restir 1.5 hours.Vacuum concentration through silica gel rapid column chromatography purifying, with the saturated 1-3% methyl alcohol-methylene dichloride wash-out of ammonium hydroxide aqueous solution, obtains target compound (1.82g, 69%, mp=126.9-128.9 ℃, MH into white solid ⁺=513).

Preparation embodiment 144-149

According to preparation embodiment 143 described essentially identical methods, adopt corresponding amine, the piperazine of the listed BOC-protection of table 5C below the preparation.

Table 5C

Preparation embodiment 150

If adopt 143 described essentially identical methods, but use the amine of following formula with preparation embodiment: Replace the amine of preparation embodiment 71, can obtain target compound so.

Preparation embodiment 151

Under room temperature, will be dissolved in the preparation embodiment 68 in the anhydrous methylene chloride (30ml) target compound (2.12g, 15.2mmol), (3.89g 15.2mmol) stirs 30 minutes for the acid anhydrides of triethylamine (30.4mmol) and preparation embodiment 44.(4.17g 16.7mmol), spends the night the mixture stirring that produces under room temperature to add the benzyloxycarbonyl succinimide.Vacuum concentration through silica gel rapid column chromatography purifying, uses the saturated 2% methyl alcohol-methylene dichloride of ammonium hydroxide as elutriant, obtains target compound (2.57g, 35%).Through with PLC (Chiracel AD post) separated region isomer, with 5% Virahol-95% hexane-0.2% diethylamine, obtain 2,4-dimethyl isomer (mp=64.2 ℃, MH ⁺=486) and 2, and 5-dimethyl isomer (mp=71.5 ℃, MH ⁺=486).

Preparation embodiment 152

Under room temperature, with embodiment 293 target compound diastereomer A (0.386g, 0.56mmol), acetate (1ml) solution stirring of glacial acetic acid (3ml) and 33%HBr 2 hours.Add ether, leach precipitation, vacuum-drying obtains target compound (0.48g, 100%, MH ⁺=557).

Preparation embodiment 153

Under room temperature, with acetate (1ml) solution stirring of embodiment 293 target compound diastereomer B (0.372g), glacial acetic acid (3ml) and 33%HBr 2 hours.Add ether, leach precipitation, vacuum-drying obtains target compound (0.433g, 100%, MH ⁺=557).

Preparation embodiment 154

Steps A

Under room temperature, with the target compound of preparation embodiment 66 (1.0g, 7.2mmol), the acid anhydrides of preparation embodiment 44 (2.2g, 8.6mmol), triethylamine (1.5ml, 10.8mmol) and anhydrous methylene chloride (10ml) mixture stirring 12 hours.Vacuum concentrated mixture is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration.

Step B

With trifluoroacetic acid (10ml) add to the target compound that is dissolved in the above-mentioned steps A in the methylene dichloride (10ml) (1.0g, 7.2mmol) in, in 25 ℃ the mixtures that produce were stirred 5 hours.This mixture of vacuum concentration, with methylene dichloride (50ml) dilution, (2.7g 7.9mmol) and triethylamine (5-10ml) merging, stirs under room temperature and spends the night with tricyclic chloride (compound number 42.0).This mixture of vacuum concentration is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration, through silica gel rapid column chromatography purifying, use the saturated 5% methyl alcohol-methylene dichloride of ammonium hydroxide aqueous solution as elutriant, obtain target compound (1.9g, 47%, MH into non-enantiomer mixture ⁺=557).

Preparation embodiment 155

Steps A

Under room temperature, with 30 minutes with N-carbonyl oxyethyl group phthalimide (62.8g, 0.275mol, 1.1eq.) by part add to stirring a histamine dihydrochloric acid (46.7g, 0.250mol, 1.0eq.) and yellow soda ash (54.3g, 0.513mol, in distilled water 2.05eq.) (1250ml) solution.Under room temperature with the snowy white suspension vigorous stirring that produces 90 minutes.Leach solid, with ice-cold distilled water thorough washing (4 * 50ml).Collect solid, in 60 ℃, vacuum,, obtain target compound (59.2g, 0.245mol, 98%, MH with dry 12 hours of Vanadium Pentoxide in FLAKES ⁺=242).

Step B

Under 90 ℃, nitrogen environment, with 1 hour, with chloro methyl pivalate (18.5ml, 0.125mol, anhydrous N 1.2eq.), dinethylformamide (DMF, 100ml) drips of solution add to stirring above-mentioned steps A (25.0g, 0.104mol, 1.0eq.) and salt of wormwood (17.2g, 0.125mol dry DMF 1.2eq.) (500ml) mixes in the liquid.In 90 ℃ this mixture was stirred 12 hours.In 50 ℃, vacuum removal volatile matter, residue is dissolved in the salt solution (100ml), with ethyl acetate (4 * 25ml) extractions.Through the organic extract that dried over sodium sulfate merges, filter and under 30 ℃, vacuum, concentrate.Through the residual pale solid of flash chromatography on silica gel (hexane: acetone=6: 4v/v), obtain target compound (20g, 0.056mol, 54%, MH ⁺=356).

Step C

In reflux, under the nitrogen environment, (5g, 14.1mmol) (2.5g, solution 15.5mmol) stirred 48 hours in anhydrous acetonitrile (60ml) with the 4-chlorobenzyl chloride with the target compound of above-mentioned steps B.This mixture of vacuum concentration, recrystallization from ethyl acetate-hexane obtains being solid target compound (3.2g, 47%, MH ⁺=480), the concentrated filtrate product (3.6g, 53%) of getting back.

Step D

In-20 ℃, (10ml, (3.2g is in the stirred solution with methyl alcohol (10ml) dilution 6.6mmol) 0.07mol) slowly to add to the target compound of above-mentioned steps C with the methanol solution of 7N ammonia.The mixture that produces is warmed to room temperature, restir 12 hours, vacuum concentration through silica gel rapid column chromatography purifying, uses the saturated 3% methyl alcohol-methylene dichloride of ammonium hydroxide aqueous solution as elutriant, the solid target compound (1.2g, 51%, the MH that obtain gluing then ⁺=366).

Step e

Under 50 ℃, nitrogen environment, with the target compound of above-mentioned steps D (1.21g, 3.3mmol) and hydrazine monohydrate (1.7ml, 0.033mol, dehydrated alcohol 10eq.) (20ml) solution stirring 20 minutes.Suspension with ethanol and methylene dichloride dilution produce filters.Vacuum concentrated filtrate obtains being yellow oil solid target compound (0.7g, 91%, MH ⁺=236).

Step F

Under room temperature, will be dissolved in the above-mentioned steps E in the anhydrous methylene chloride (10ml) target compound (0.695g, 2.94mmol) and the preparation embodiment 44 acid anhydrides (0.75g, 2.94mmol) solution stirring is spent the night.Add acid anhydrides (0.1g) again, after 1 hour, use the methylene dichloride diluted reaction mixture, with the extraction of 1M aqueous hydrochloric acid.With 1N aqueous sodium hydroxide solution alkalization water, use dichloromethane extraction, through the anhydrous magnesium sulfate drying organic phase.After the filtration, the vacuum concentration organic phase obtains white foam shape thing (0.744g, 57%, MH ⁺=448).

Preparation embodiment 156-157

According to the method for embodiment 155 step C-F, adopt corresponding arylalkyl halogenide, the listed piperazine of preparation following table 5D.

Table 5D

Preparation embodiment 158

Steps A

3-in water-soluble (200ml) and methyl alcohol (200ml) (1H-imidazoles-1-yl) propylamine (20ml, add in 167.6mmol) 50% aqueous sodium hydroxide solution to pH be 9.5.(41g, 187.9mmol), in stirring at room 4 hours, keeping pH with 50% sodium hydroxide was 9.5 simultaneously to add tert-Butyl dicarbonate.Vacuum concentrated mixture is removed most of methyl alcohol, uses dichloromethane extraction then.Through the anhydrous magnesium sulfate drying organic phase, filter and vacuum concentration, obtain target compound (23.7g, 63%, MH ⁺=226).

Step B

To being dissolved in anhydrous THF (15ml) and (0.50g 2.22mmol) adds n-Butyl Lithium (2.8ml, 1.75M hexane solution) in the solution, the reaction mixture that produces is heated to-20 ℃ and stirred 1.5 hours in the target compound of the above-mentioned steps A of-78 ℃ of stirrings.Reaction mixture is cooled to-78 ℃, and the adding dry DMF (0.35ml, 4.52mmol).Be heated to 25 ℃ and stir 2 hours after, add methyl alcohol (2ml) and sodium borohydride (171mg, 4.5mmol), in 25 ℃ with the mixtures stirring that produces 1 hour.This mixture of vacuum concentration with the methylene dichloride dilution, washes with water, through the anhydrous sodium sulfate drying organic phase, filters and vacuum concentration.Through silica gel rapid column chromatography purifying, use the saturated 5-10% methyl alcohol-methylene dichloride of ammonium hydroxide as elutriant, obtain target compound (0.32g, 56%, MH ⁺=256).

Step C

(0.31g adds the dioxane (5ml) of 4M HCl in 1.2mmol), stirs these mixtures 12 hours in 25 ℃ to the target compound of above-mentioned steps B.Vacuum concentration obtains residue, and it is directly used among the step D.

Step D

Under room temperature, (0.55g 2.15mmol) stirs and spends the night will to be dissolved in the target compound, triethylamine (4ml) of the above-mentioned steps C in the dry DMF (10ml) and the acid anhydrides of preparation embodiment 44.This mixture of vacuum concentration is with anhydrous methylene chloride (5ml), DMF (5ml) and trifluoroacetic acid (10ml) dilution.Under room temperature the mixture that produces was stirred 12 hours, vacuum concentration dilutes with anhydrous methylene chloride (5ml) and dimethyl formamide (5ml) then.Add tricyclic chloride (compound number 42.0) (0.75g, 2.17mmol) and triethylamine (3ml), in 25 ℃ with this mixture stirring 48 hours.This mixture of vacuum concentration is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing.Through anhydrous sodium sulphate washing organic phase, filter and vacuum concentration, through silica gel rapid column chromatography purifying, use the saturated 5-10% methyl alcohol-methylene dichloride of ammonium hydroxide aqueous solution as elutriant, obtain target compound (0.376g, 33%, MH into non-enantiomer mixture ⁺=573).

Preparation embodiment 159-160

Method according to described in the embodiment 158 step D adopts corresponding amine or amine hydrochlorate, the listed piperazine of preparation following table 5E.

Table 5E

Preparation embodiment 161

Steps A

Under room temperature, will be dissolved in 4-hydroxymethyl imidazoles in the anhydrous methylene chloride (20ml) (2g, 14.9mmol), (2.5g, mixture 16.6mmol) stir and spend the night for triethylamine (5ml) and TBDMS-Cl.Filter this mixture, wash and refilter with anhydrous diethyl ether.Vacuum concentrated filtrate is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing.Through the anhydrous sodium sulfate drying organic phase, filter and vacuum concentration, obtain target compound (2.22g, 71%, MH ⁺=213).

Step B

In refluxing down, (2.22g 10.5mmol) stirred 48 hours will to be dissolved in the target compound of the above-mentioned steps A in the vinyl cyanide (10ml).Vacuum concentration obtains target compound (2.09g, 75%, MH ⁺=266).

Step C

Under room temperature, in the Parr hydrogenator, with the target compound of above-mentioned steps B (2.08g, 7.85mmol), Raney nickel (230mg), methyl alcohol (20ml) and ammonium hydroxide (7.5ml) stirred 48 hours.By this mixture of diatomite filtration, vacuum concentration is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing.Through the anhydrous sodium sulfate drying organic phase, filtration, vacuum concentration through silica gel rapid column chromatography purifying, use the saturated 5% methyl alcohol-methylene dichloride of ammonium hydroxide aqueous solution as elutriant, obtain target compound [(isomer that 4-replaces, 465mg, 22%, MH ⁺=270) and (isomer that 5-replaces, 220mg, 10%, MH ⁺=270)].

Preparation embodiment 162

According to the described method of preparation embodiment 155 step C-E, but in preparation embodiment 155 step C, replace the 4-chlorobenzyl chloride with the 4-fluoro benzyl bromide, and the preparation target compound (52%, MH ⁺=220).

Preparation embodiment 163

According to the described method of preparation embodiment 155 step C-E, but in preparation embodiment 155 step C, replace the 4-chlorobenzyl chloride with the 4-cyano-benzyl bromide, and the preparation target compound (63%, MH ⁺=227).

Preparation embodiment 164

With tricyclic chloride (5.04g, 1.1eq.) add to the preparation embodiment 50 target compound (4.0g, 17.3mmol) and TEA (12.05ml is in DMF 5eq.) (60ml) solution.Under room temperature, with the solution stirring that produces 72 hours, the concentrating under reduced pressure reaction mixture.With 3M sodium hydroxide dilution residue, use ethyl acetate extraction.With in 50% citric acid and water layer, use ethyl acetate extraction.Organism through dried over sodium sulfate merges filters and vacuum concentration.The crude product product is through silica gel rapid column chromatography purifying, with the methylene dichloride of 12% (methanol solution of 10% ammonium hydroxide) as elutriant, obtain C-11 (S)-isomer (2.13g, 54%), the isomer of first wash-out, C-11 (R)-isomer (2.4g, 61%), the isomer of second wash-out.

11S, 2R (+)-isomer

11 (S), 2 (R) (+)-isomer (isomer of first wash-out): [α] ²⁰ _D=+84.9 (5.18mg is in the 5.0ml methyl alcohol); LCMS:MH ⁺=458.

11R, the 2R isomer

11 (R), 2 (R)-isomer (isomer of second wash-out): FABMS:MH ⁺=458.

Preparation embodiment 165

According to preparation embodiment 25 described methods, adopt the target compound of preparation embodiment 13 to replace the N-1-methylhistamine, the preparation target compound (33%, MH ⁺=195).

Preparation embodiment 166

Similarly,, adopt the target compound of the target compound replacement preparation embodiment 289 of preparation embodiment 305 according to preparation embodiment 142 described methods, and the preparation target compound (80%, MH ⁺=599).

Preparation embodiment 167

According to preparation embodiment 142 described methods, adopt the target compound of the target compound diastereomer B replacement preparation embodiment 289 of preparation embodiment 305, the preparation target compound (100%, MH ⁺=599).

Preparation embodiment 168

Steps A

(5g 12.8mmol) is dissolved in 2.7ml2, in the 4-dimethoxy benzaldehyde by being heated to 120 ℃ of target compounds (compound 52.ii) that will prepare embodiment 40A steps A.(1.3ml) drops in the reaction mixture with formic acid, stirs 45 minutes in 120 ℃ simultaneously.The solid that produces is dissolved in the methylene dichloride, uses dried over mgso, filter and be evaporated to dried, obtain solid, it through silica gel column chromatography, is obtained the 5.17g target product.FABMS(M＋1)＝463.4。

Step B

(1g 1.8mmol) is dissolved in 45ml 5% acetic acid/water, in 85 ℃ of stirrings with the target compound of steps A.Add mercuric acetate (2.3g), this reaction mixture was stirred 5 hours.After cooling on the ice bath, add potassium cyanide (1.25g), with reaction mixture vigorous stirring 18 hours.Add 1N sodium hydroxide (excessive), product is extracted three times with ethyl acetate.Through silica gel column chromatography, as elutriant, obtain the 0.747g target product with ethyl acetate.

Step C

The target product (0.2g) of step B is dissolved in 6ml trifluoroacetic acid and the 0.5ml methyl-phenoxide,,, as elutriant, obtains target methane amide product (72mg) with 2% ethanol/methylene through silica gel column chromatography in 60 ℃ of stirrings 1 hour.FABMS(M＋1)＝432。

Step D

The primary product (methane amide) of step C (0.19g) is dissolved in the 10ml6N hydrochloric acid, refluxed 24 hours.Vacuum is removed 6N hydrochloric acid, in residue water-soluble (5ml).Add tert-Butyl dicarbonate (0.13g), reaction mixture is transferred to pH9.0 with 1N sodium hydroxide.After stirring 2 hours under the room temperature, reaction mixture is added in the citric acid, use dichloromethane extraction, obtain the crude product product, it through silica gel column chromatography, is obtained target product 93mg.FABMS(M＋1)＝533。

Step e

With the target compound of step D (70mg, 0.13mmol) be dissolved in 2mlDMF and DEC (37mg, 0.19mmol) in, add HOBT (26mg, 0.19mmol) and N-methylmorpholine (42 μ l, 0.4mmol), under room temperature with reaction mixture stirring 7 hours.After adding in the water, use dichloromethane extraction, the crude product product obtains the 86mg target product through silica gel column chromatography.FABMS(M＋1)＝640。

Preparation embodiment 169

11-chloro-6,11-dihydro-5H-benzo [5,6] ring [1,2-B] pyridine in heptan

According to the described method of US3419565, preparation ketone (raw material) 5,6-dihydro-11H-benzo [5,6] ring [1,2-C] pyridine in heptan-11-ketone.

In 0 ℃, (2g, (3g in methyl alcohol 14.35mmol) (50ml) solution, stirred 2 hours under room temperature then 53.3mmol) to add to ketone with sodium borohydride.Add ice (10g) and 2N hydrochloric acid (10ml) quenching reactant, with 2N sodium hydroxide (13ml) alkalization, with dichloromethane extraction (2 * 50ml).Separate organic layer, through dried over mgso, excessive and evaporating solvent obtains alcohol (3g, 100%).

1H?NMR(DMSO，δ)3.0-3.4(m，4H)6.101(brs，2H)7.0-7.3(m，4H)7.5(m，2H)8.314(d，1H)。

Under room temperature, (3ml, (2.5g in methylene dichloride 11.84mmol) (50ml) solution, stirred 1 hour then 41.12mmol) to add to above-mentioned alcohol with thionyl chloride.Evaporating solvent adds entry (50ml) and 5% sodium hydroxide (10ml).Use MeCl ₂(100ml) extract compounds, through the dried over mgso organic layer, excessive and evaporating solvent obtains brown solid, grinds with ether, and concentrated filtrate obtains white solid 1.5g.

1H?NMR(CDCl ₃，δ)2.9-3.0(m，2H)，3.6(m，1H)，3.9(m，1H)，6.3(s，1H)，7.2(m，3H)，7.3(d，1H)，7.4(d，1H)，7.5(d，1H)，8.42(d，1H)。

The solid of dry filter, product 0.9g gets back.Overall yield 2.4g, 87%.

Preparation embodiment 170

Acetonitrile (5ml) is added to 10-chlorine tricyclic compound, and (0.5g, 1.90mmol) (0.78g is 1.90mmol) in the mixture for (preparation embodiment 9.1) and the piperazine of replacement.(1ml 7.18mmol), spends the night this mixture stirring under room temperature to add triethylamine.Add entry (50ml) and 5% sodium hydroxide, use MeCl ₂(2 * 100ml) extraction mixtures.Separate organic layer, through dried over mgso, evaporating solvent obtains required product (0.7g, 57%), is the mixture of 2 kinds of diastereomers, it is separated through silica gel column chromatography, with the 5%v/v ethanol/methylene wash-out that contains 2% ammonium hydroxide.Isomer A (isomer that polarity is less) is at first eluted.

Table 5F

Isomer	Mass spectrum (FABS, MH)	????[α] 20 D
			????A，B	????569.1	????----
????A	????569.2786	????-55.9℃＝0.1085
			????B	????569.2816	????-27.4℃＝0.1085

Preparation embodiment 171

Steps A

In 100 ℃, with the 2-chloro-acetophenone (25g, 0.16mol) and 4-methylimidazole (66.1g, 0.8mol) mixture heating up is 2 hours.Cooling, crude product product with saturated methylene dichloride/3% methanol-eluted fractions of ammonium hydroxide aqueous solution, obtain 4-and 5-methyl isophthalic acid H-imidazolyl methyl phenyl ketone product (23g, 73%), MS, MH through purification by silica gel column chromatography ⁺=201.

Step B

(7.28g 0.26mol) adds in methylene dichloride (200ml) solution of the product of steps A, stirs under room temperature and spends the night with trityl chloride.Mixture with ethyl acetate/acetone (3: 1) wash-out, obtains 4-methyl isophthalic acid H-imidazolyl methyl phenyl ketone (15.5g), FabMS, MH through purification by silica gel column chromatography ⁺=201.

Step C

(0.998g, 24.97mmol) (5.49g, the product (5g) of adding step B stirred 1.5 hours in DMSO 24.97mmol) (50ml) mixture with trimethylammonium sulfoxonium iodide to sodium hydride.Use the ethyl acetate extraction product, use the salt water washing, dry and evaporating solvent obtains 1-(2-phenyl-2,3-epoxypropyl)-1H-4-Methylimidazole (3.44g, 64%).FABMS，MH ⁺＝215。

Step D

In 60 ℃, with the product of step C (3.45g, 16.11mmol) and sodiumazide (2.093g, 32.21mmol) heating 12 hours in DMF (100ml).Be evaporated to driedly, use dichloromethane extraction, use the salt water washing, through dried over mgso.Be evaporated to driedly, obtain target compound (3.83g, 93%).FABMS，MH ⁺＝258。

Step e

Under 50psi, the target compound of step D is spent the night with 10% palladium carbon (1.2g) hydrogenation in ethanol (80ml).Filtration catalizer, evaporation obtain target compound (2.83g is the sticking oily matter of yellow).

Preparation embodiment 172-188

According to preparation embodiment 74 described methods, but adopt aldehyde and imidazolyl alkylamine (imidazoles) among the table 5G, obtain showing the amine (product) among the 5G.

Table 5G

Preparation embodiment 190-197

According to preparation embodiment 109 described methods, but adopt the target compound of showing the embodiment among the 5H.Preparation product amine.

Table 5H

Preparation embodiment 199

Steps A

In refluxing down, stir target compound (0.9g), benzylalcohol (0.68ml), solid potassium hydroxide (0.66g), 18-hat-6-ether (80mg) and the dry toluene (20ml) of preparation embodiment 175.Through preparation property plate layer chromatography purifying (silica gel, 4%MeOH-CH ₂Cl ₂, saturated with ammonium hydroxide), obtain benzyl oxide (0.73g, 68%, MH ⁺=371).

Step B

Target compound (0.72g) under 50psi hydrogen, with above-mentioned steps A, methyl alcohol (60ml) and 10% palladium carbon (300mg) stirred 3 days.By diatomite filtration, obtain filtrate, handle with TEA (3eq.) and methylene dichloride.Filter, through preparation property plate layer chromatography purifying (silica gel, 5%MeOH-CH ₂Cl ₂, saturated with ammonium hydroxide), obtain target compound (0.20g, 42%, MH ⁺=247).

Preparation embodiment 200

The preparation of three ring N-oxide compound parts

1 → 2: with 1 hour, under nitrogen environment, 0 ℃, with 3-benzoyl hydroperoxide (25g, 102.59mmol, 2.5eq.) anhydrous methylene chloride (250ml) drips of solution add to the 8-chloro-4-azepine-10 of stirring, 11-dihydro-5H-dibenzo [a, d] (10g, 41.04mmol is in anhydrous methylene chloride 1.0eq.) (100ml) solution for suberene-5-ketone 1.With this solution slowly (3h) be warmed to room temperature, and restir 12 hours.(5 * 100ml) these solution, (2 * 100ml) washings through dried over sodium sulfate, are filtered and are concentrated under 30 ℃ of vacuum, obtain being faint yellow solid 2 with salt solution with the extraction of 1M aqueous sodium hydroxide solution.Target compound 2 is directly used, needn't be further purified.

Output: 10g, 38.51mmol, 94%

[M＋H] ⁺：260

HRMS (FAB+): C ₁₄H ₁₁ClNO ₂[[M+H] ⁺]: calculated value: 260.0475

Measured value: 260.0478

2 → 3: under nitrogen environment, 0 ℃, with 15 minutes, (1.5eq.) (10g, 38.51mmol is in anhydrous methanol 1.0eq.) (500ml) solution by part adding to 2 for 2.21g, 57.76mmol with sodium borohydride.In 0 ℃ the suspension that produces was stirred 1 hour, restir is 1 hour under room temperature.Under 30 ℃ of vacuum, remove volatile matter, residue is dissolved in the 1M sodium hydroxide solution (250ml).With methylene dichloride (5 * 100ml) extraction water solution.The organic extract that merges with salt solution (100ml) washing through dried over sodium sulfate, filters and in 30 ℃ of vacuum concentration, obtains being lime green (lime-green) solid 3.Compound 3 is directly used, needn't purifying.

Output: 9g, 34.39mmol, 89%

[M＋H] ⁺：262

HRMS (FAB+): C ₁₄H ₁₃ClNO ₂([M+H] ⁺): calculated value: 262.0635

Measured value: 262.0636

3 → 4: under nitrogen environment, 0 ℃, with 10 minutes, with thionyl chloride (5ml, 68.78mmol, 2.0eq.) drop to stirring 3 (9g, 34.39mmol is 1.0eq.) and in the stirred suspension of dry toluene (150ml).Slow (3h) is warmed to room temperature, restir 12 hours with milky suspension.Remove volatile matter under 30 ℃ of vacuum, residue is dissolved in methylene dichloride (250ml), (5 * 100ml) washings are medium basic pH9 until washings with ice-cold, saturated sodium bicarbonate aqueous solution.The organic layer that merges with salt solution (100ml) washing through dried over sodium sulfate, filters and in 30 ℃ of vacuum concentration, and obtaining with the productive rate of basal ration is 4 of Off-white solid.Because compound 4 has hyperergy, therefore compound 4 is directly used, needn't purifying or evaluation (remove ¹HNMR is outer).

Output: 9.55g, 34.09mmol, 99%

4 → 6: under nitrogen environment, room temperature, with triethylamine (18ml, 126.65mmol 5.0eq.) drop to 5 (described in the prior art, 9.38g, 25.33mmol is in anhydrous methylene chloride 1.0eq.) (50ml) stirred solution.Under room temperature,, be cooled to 0 ℃ with this solution stirring 30 minutes.(8.52g, 30.39mmol is in anhydrous methylene chloride 1.2eq.) (50ml) solution to drip 4 with 25 minutes.With this mixture slowly (3h) be warmed to room temperature, and restir 12 hours.Under 30 ℃ of vacuum, remove volatile matter, residue is dissolved in the 50%m/v aqueous citric acid solution (100ml), with ethyl acetate (5 * 100ml) extractions.Merge organic extract,, filter and in 30 ℃ of vacuum concentration, (methylene dichloride: methyl alcohol 19: 1v/v), obtaining in trinucleated C-11 is diastereomer pure isomer 6a and 6b through the residual Off-white solid of flash chromatography through dried over sodium sulfate.

6a：

Output: 5.75g, 11.50mmol, 45%

Canescence foam: M.p.:78-83 ℃

[M＋H] ⁺：500

HRMS (FAB+): C ₂₆H ₃₁ClN ₃O ₅([M+H] ⁺): calculated value: 500.1953

Measured value: 500.1952

6b：

Output: 3.00g, 6.00mmol, 24%

Pale solid: M.p.:94-99 ℃

[M＋H] ⁺：500

HRMS (FAB+): C ₂₆H ₃₁ClN ₃O ₅([M+H] ⁺): calculated value: 500.1953

Measured value: 500.1952

Preparation embodiment 201

Steps A

According to US5,151,423 described methods, but use US3, the 8-H analogue replacement 8-chlorine tricyclic compound in 419,565 obtains 8-hydrogen tricyclic chloride.

Step B

According to the described method of preparation embodiment 127 step C, with the 8-hydrogen tricyclic chloride replacement 8-chlorine tricyclic chloride of preparation embodiment 201 steps A, separate targets compound.

Through column chromatography (silica gel) separating isomerism body, with 3% ethanol/methylene wash-out.

Isomer A:C (11)-(S): 38%, MH ⁺=450.

Isomer B:C (11)-(R): 31%, MH ⁺=450.

Preparation embodiment 202

Steps A

According to the described method of preparation embodiment 127 step C, use tricyclic chloride

Replace 8-chlorine tricyclic chloride, obtain following formula acid: Solid, 51% productive rate, mp=120.5-125.1 ℃.

Embodiment 202A

According to the amino essentially identical method of loratadine (J.Med.Chem. (1997), 40,4290) of described preparation 3-such as Njoroge, but replace loratadine with 3-H ketone (J.Het.Chem (1971) 8,73), the preparation target compound.

Preparation embodiment 203

In 0 ℃, (1.62g 6.26mmol) adds to NO by part will to prepare embodiment 202A ⁺BF ₄ ^-(0.81g is in toluene 1.1eq.) (10ml) solution.In 0 ℃ the slurry that produces was stirred 2.5 hours, be warmed to room temperature then.In refluxing down, with reaction mixture heating 2 hours, cooling was with the neutralization of 1N sodium hydroxide, with ethyl acetate (3 * 50ml) extractions.With 1N hydrochloric acid (2 * 25ml), saturated sodium bicarbonate (1 * 25ml) and water (organism that 1 * 15ml) washing merges through dried over sodium sulfate, filters, concentrating under reduced pressure.The crude product product is through the flash chromatography purifying, and with 70: 30 hexanes: the ethyl acetate mixed solution obtained yellow solid (0.68g, 42% productive rate) as elutriant.LCMS：MH ⁺＝262。

Preparation embodiment 204

According to preparation embodiment 201 steps A described essentially identical method, prepare target compound by the ketone of preparation embodiment 203, without being further purified (0.66g, 100% crude product productive rate).

Preparation embodiment 205

Will ⁺NH ₄HCO ₂ ^-(2.44g, (2.00g 7.74mmol) and in ethanol (100ml) solution of 5%Pd/C (0.50g), is heated to backflow 2 hours with the solution that produces 10eq.) to add to preparation embodiment 202A.Cool off this reaction mixture, by diatomite filtration, concentrating under reduced pressure.With residue water (100ml) dilution, with methylene dichloride (3 * 75ml) extractions.Through the organism that dried over sodium sulfate merges, vacuum concentration obtains yellow solid (1.22g, 70% productive rate), with its not purified use: FABMS:MH ⁺=225.

Preparation embodiment 206

In 0 ℃, with the preparation embodiment 205 target compound (1.22g, 5.44mmol) by part add to cupric chloride (0.88g, 1.2eq) and tBuONO (0.98ml is in acetonitrile 1.5eq) (25ml) solution.The solution that produces is warmed to room temperature, stirred 72 hours.Add 1M hydrochloric acid (10ml) quenching reaction mixture, with the neutralization of 15% ammonium hydroxide, with ethyl acetate (3 * 100ml) extractions.With 15% ammonium hydroxide (1 * 50ml), 1M hydrochloric acid (1 * 50ml) and the organism that merges of saturated sodium bicarbonate washing, through dried over sodium sulfate, filter also and concentrate.The crude product product is through the flash chromatography purifying, and with 50: 50 ethyl acetate: the hexane mixed solution obtained faint yellow solid (0.81g, 61% productive rate): CIMS:MH as elutriant ⁺=244.

Preparation embodiment 207

According to preparation embodiment 201 steps A essentially identical method, prepare target compound by the ketone of preparation embodiment 206, and without being further purified use.

Preparation embodiment 208

According to preparation embodiment 206 essentially identical methods, but use CuBr ₂Replaced C uCl ₂, preparation target compound (1.33g, 60% productive rate): FABMS:MH ⁺=244.

Preparation embodiment 209

According to preparation embodiment 201 steps A essentially identical method, but with the ketone of preparation embodiment 208, preparation target compound, and without being further purified use.

Preparation embodiment 210

According to preparation embodiment 203 essentially identical methods, but with the compound of preparation embodiment 205, preparation target compound.

Preparation embodiment 211

According to preparation embodiment 201 steps A essentially identical method, but with the ketone of preparation embodiment 210, preparation target compound.

Preparation embodiment 212

According to preparation embodiment 127 step C essentially identical method, but with the 3-Cl of preparation embodiment 207 preparations, the 8-H tricyclic chloride replaces 3-H, 8-Cl tricyclic chloride, preparation target compound (C-11 (S)-and (R)-isomer).FABMS：MH ⁺＝484。

Embodiment 1

Under room temperature, (0.44g 0.897mmol) is stirred to raw material consumption finish (TLC) in methylene dichloride (10ml) and THF (4ml) with the target compound of preparation embodiment 5.The concentrating under reduced pressure reaction mixture is dissolved in compound in the methylene dichloride (5ml) to remove excessive TFA again, with muriate (42.0) (0.37g, 1.2eq.) and triethylamine (2.5ml 10eq.) handles, and stirs 84 hours under room temperature.Also separate with saturated sodium bicarbonate (25ml), water (25ml) and methylene dichloride (25ml) diluted reaction mixture.Use the dichloromethane extraction water layer, through the organism that dried over sodium sulfate merges, concentrating under reduced pressure.The crude product product as elutriant, obtains brown solid (0.45g, 71% productive rate) with 5% (methanol solution of 10% ammonium hydroxide) dichloromethane solution through the flash chromatography purifying.mp142-144℃；FABMS：MH ⁺＝696。

Embodiment 2

Through preparation property HPLC chromatography, use the CHIRALPAKAD post, with the hexane solution of 12% Virahol that contains 0.2% diethylamine as elutriant, with the target compound of embodiment 1 be separated into 11 (S) (+)-with 11 (R) (+)-diastereomers:

11S, 2R (+)-isomer: retention time=29.21 minute; [α] ^23.5 _D=+19.1 (3.35mg is in the 2.0ml chloroforms); Mp=147-149 ℃; LCMS:MH ⁺=696.

11R, 2R (+)-isomer: retention time=39.8 minute; [α] ^24.1 _D=+73.0 (3.07mg is in the 2.0ml chloroforms); Mp=128-131 ℃; LCMS:MH ⁺=696.

Embodiment 3

According to embodiment 1 described essentially identical method, but with the preparation embodiment 6 target compound, the preparation target compound (0.085g, 45% productive rate).mp103-106℃；LCMS：MH ⁺＝705。

Embodiment 4

According to embodiment 3 described essentially identical methods, but with the preparation embodiment 6.1 target compound, the preparation target compound.mp＝111-115℃；MH ⁺＝703。

Embodiment 5

According to embodiment 1 described essentially identical method, but with the preparation embodiment 7 target compound, the preparation target compound).mp138-140℃；LCMS：MH ⁺＝778。

Embodiment 6

With 4-pyridylacetic acid(HPAC) N-oxide compound (0.039g, 1.5eq.), NMM (0.03ml, 1.5eq), DEC (0.049g, 1.5eq.) and HOBT (0.034g, 1.5eq.) target compound (0.10g of Processing of Preparation embodiment 8,0.17mmol) DMF (1.0ml) solution of (11S, 2R (-)-isomer), under room temperature, the solution stirring that produces is spent the night.Add saturated sodium bicarbonate (10ml) quenching reaction mixture, with methylene dichloride (4 * 50ml) extractions.Organism through dried over mgso merges filters and vacuum concentration.The crude product residue is through preparation property TLC purifying, as elutriant, obtains 11S, 2R isomer (0.044g, 39% productive rate) with the dichloromethane solution of 15% (methanol solution of 10% ammonium hydroxide).mp＝115-117℃；LCMS：MH ⁺＝706。

According to essentially identical method, but use racemoid or the 11R for preparing embodiment 8, the 2R isomer can obtain corresponding racemoid or 11R, the 2R isomer products.

Preparation embodiment 7-9

According to method substantially the same manner as Example 6, obtain the compound of following formula:

R wherein ¹⁴Identical with following table 6 definition.

Table 6

Embodiment 10

With t-BuNCO (0.080ml, 5.0eq) target compound of Processing of Preparation embodiment 8 (11S, 2R-isomer) (0.080g, methylene dichloride 0.14mmol) (2.0ml) solution.Under room temperature, the solution stirring that produces is spent the night and concentrating under reduced pressure.The crude product product is through preparation property TLC purifying, as elutriant, obtains target compound (0.045g, 48% productive rate) with the dichloromethane solution of 10% (methanol solution of 10% ammonium hydroxide).mp＝139-142℃；LCMS：MH ⁺＝670。

Embodiment 11

According to embodiment 10 described essentially identical methods, but with the preparation embodiment 8 11R, the 2R isomer, the preparation target compound.mp＝157-159℃；LCMS：MH ⁺＝670。

Embodiment 12-14

According to embodiment 10 described essentially identical methods, but with the preparation embodiment 9 target compound, the preparation following formula compound R wherein ¹⁴Identical with the definition in the following table 7.

Table 7

Embodiment 15

To the preparation embodiment 8 target compound (11-racemoid) (0.072g, 0.12mmol) and TEA (0.010ml adds MeSO in methylene dichloride 1.1eq.) (4ml) solution ₂(0.01ml's Cl 1.1eq.), spends the night the solution stirring that produces under room temperature.Add saturated sodium bicarbonate (5ml) quenching reaction mixture, separate and (2 * 50ml) extract with methylene dichloride.Organism through dried over sodium sulfate merges filters and vacuum concentration.The crude product residue is through preparation property TLC purifying, with the dichloromethane solution of 10% (methanol solution of 10% ammonium hydroxide) as elutriant (44mg, 63% productive rate).mp＝107-110℃；LCMS：MH ⁺＝649。

According to essentially identical method, still use the 11R of the target compound of preparation embodiment 8 respectively, 2R or 11S, the 2R isomer obtains 11R, 2R or 11S, 2R isomer.

Preparation embodiment 16-18

According to method substantially the same manner as Example 15, obtain the compound of following formula: R wherein ¹⁴Identical with following table 8 definition.

Table 8

Embodiment 19

According to embodiment 1 described essentially identical method, but adopt the target compound of preparation embodiment 7.3, obtain target compound.mp＝133-138℃；LCMS：MH ⁺＝682。

Embodiment 20

Target compound (0.211g with preparation embodiment 4 in the table 1,1.4eq.) add to preparation embodiment 51 acid (0.487g, 0.90mmol), DEC (0.201g, 1.2eq.), HOBT (0.73g, 6.0eq.) and NMM (0.60ml is in DMF 6.0eq.) (6.0ml) solution.Under room temperature, with the solution stirring that produces 3 days.Adding entry precipitates the crude product product and filters from reaction mixture.Through flash chromatography purifying residue, carry out wash-out in order to the dichloromethane solution gradient of the methanol solution of 10% ammonium hydroxide of 0.5% 0.5%-3% that increases, obtain target compound (0.411g, 67% productive rate).mp＝178-179℃；MH ⁺＝685。

Embodiment 21

According to embodiment 110 described essentially identical methods, but adopt the target compound of preparation embodiment 11 step C.mp＝150-154℃；MH ⁺＝682。

Embodiment 22

According to embodiment 110 described essentially identical methods, but adopt amine to replace the target compound of preparation embodiment 102 step C according to preparation embodiment 11 steps A-described method preparation of C, in preparation embodiment 11 steps A, replace methyl-iodide with ethylene dichloride.mp＝156-158℃；MH ⁺＝680。

Embodiment 24

Steps A

Under room temperature, with target compound (0.23g, methylene dichloride 0.49mmol) (5.0ml) and TFA (3.0ml) stirring 2 hours, the vacuum concentration of preparation embodiment 12.Residue is dissolved in the methylene dichloride (5.0ml), with TEA (0.45ml, 2.0eq.) and muriate (0.056g, 0.33eq.)

Handle, under room temperature, stirred 48 hours.With saturated sodium bicarbonate (5.0ml) and water (15ml) diluted reaction mixture, with methylene dichloride (2 * 50ml) extractions.Through the organism that dried over sodium sulfate merges, concentrating under reduced pressure.The crude product product is through the flash chromatography purifying, as eluent, obtains product (0.063g, 67% productive rate) with the dichloromethane solution of 15% (methanol solution of 10% ammonium hydroxide).Mp=157 ℃ (decomposition); FABMS:MH ⁺=572.

Step B

(0.058g, methylene dichloride 0.101mmol) (3ml) solution stirred 1 hour under room temperature with the target compound of excessive NSC 87419 treatment step A.The vacuum concentration reaction mixture through the flash chromatography purifying, as eluent, obtains target compound (0.062g, 75% productive rate) with the dichloromethane solution of 8% methyl alcohol.mp＝164-167℃；FABMS：MH ⁺＝822。

Embodiment 25

In dense ammonium hydroxide (3.0ml) and methyl alcohol (3.0ml) just the target compound of embodiment 24 (0.045g 0.0547mmol) stirs and spends the night.The solution that vacuum concentration produces, residue is through the flash chromatography purifying, as eluent, obtains target compound (0.022g, 58% productive rate) with the dichloromethane solution of 15% methyl alcohol.mp＝164-169℃；FABMS：MH ⁺＝697。

Embodiment 26

Steps A

2.99g (15.09mmol) 3-methylhistamine hydrochloride is dissolved in the 100ml methylene dichloride, then 3.21g (31.70mmol) triethylamine is dissolved in wherein.Stirred 30 minutes down in nitrogen, divide aliquot to add the acid anhydrides that 4.83g (18.87mmol) derives from preparation embodiment 44 then, stirred 30 minutes down in nitrogen.Adding 4.14g (16.60mmol) benzyl chloroformate also stirs and spends the night.With the dilution of 100ml methylene dichloride, wash with sodium bicarbonate aqueous solution.Through dried over mgso organic layer and vacuum concentration.Through the 650g flash chromatography on silica gel,, obtain product into white solid with 97% methylene dichloride (ammonium hydroxide)-3% methanol-eluted fractions.mp＝51.8-63.2℃。

Step B

The product of 4.9g steps A is dissolved in the 30ml methylene dichloride, adds the 13ml trifluoroacetic acid.Under nitrogen, stir and spend the night, then vacuum concentration.Grind residue with ether, vacuum-drying then obtains the product into clarification oily matter.

Step C

The product of 10.01g (11.04mmol) step B is dissolved in the dimethyl formamide that 50ml contains 5.6g (55.19mmol) triethylamine.Drip muriate

The 70ml dimethyl formamide solution, stir down in nitrogen and to spend the night.Vacuum concentration is dissolved in residue in the 50ml methylene dichloride.With the sodium bicarbonate aqueous solution washing, through dried over mgso organic layer and vacuum concentration.Through 640g flash chromatography on silica gel purifying residue, as elutriant, obtain product with 97% methylene dichloride (ammonium hydroxide)-3% methyl alcohol into brown solid, mp=111.8-114.5 ℃, MH ⁺=677 (FAB).

Embodiment 27

Steps A

The product of 4.61g (6.8mmol) embodiment 26 step C is dissolved in the acetic acid solution of 6ml acetate, 9ml5.7M (33%) HBr.After 3 hours, finish through silica gel tlc (95% methylene dichloride (ammonium hydroxide)-5% methyl alcohol) assaying reaction.Add the 25ml ether and filter the precipitation that produces down, obtain the 5.8g brown solid in nitrogen.Through Chiralpack AD 5cm * 50cm post (Chiral Technologies) chromatography, with 25%2-propyl alcohol/hexane+0.2% diethylamine wash-out, flow velocity is 80ml/min, obtains two diastereomers.

Diastereomer A:Mp=122.2-130.2 ℃, MH ⁺=543 (FAB).

Diastereomer B:Mp=122.1-130.2 ℃, MH ⁺=543 (FAB).

Step B

The diastereomer A of 0.07g (0.129mmol) steps A is dissolved in the 2mL methylene dichloride, then adds 0.021g (0.155mmol) 4-fluorophenyl isocyanic ester, under nitrogen, stir and spend the night.With the dilution of 20ml methylene dichloride, with the sodium bicarbonate aqueous solution washing, through dried over mgso organic layer, vacuum concentration.Residue with 95% methylene dichloride (ammonium hydroxide)-5% methanol-eluted fractions, obtains the product that 0.0179g is a white solid through preparation property silica gel tlc chromatography.Diastereomer A:Mp=143.1-145.2 ℃, MH ⁺=680 (FAB).

With similar method, make the diastereomer B and the 4-fluorophenyl isocyanate reaction of 0.07g (0.129mmol) steps A, obtaining 0.018g is the diastereomer B product of white solid.Diastereomer B:Mp=140.1-149.4 ℃, MH ⁺=680 (FAB).

Embodiment 28

According to the method for embodiment 27, make the product and the tert-butyl isocyanate reaction of 0.07g (0.129mmol) embodiment 27 steps A, obtaining 0.065g is the diastereomer A product of white solid.Mp＝125.1-133.5℃，MH ⁺＝642(FAB)。

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtaining 0.052g is the diastereomer B product of white solid.Mp＝128.1-135.2℃，MH ⁺＝642(FAB)。

Embodiment 29

According to the method for embodiment 27, make the diastereomer A and the n-Isopropyl isocyanate reaction of 0.10g (0.184mmol) embodiment 27 steps A, obtain to such an extent that 0.041g is the diastereomer A product of white solid.Mp＝128.1-133.3℃，MH ⁺＝628(FAB)。

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtaining 0.040g is the diastereomer B product of white solid.Mp＝128.1-133.4℃，MH ⁺＝628(FAB)。

Embodiment 30

The diastereomer A of 0.116g (0.202mmol) embodiment 27 steps A is dissolved in the 2ml methylene dichloride, then dissolves in the toluene solution of 0.02g (0.202mmol) triethylamine and 0.24ml (0.24mmol) 1.0M carbonochloridic acid isopropyl ester, stir down in nitrogen and spend the night.With the dilution of 20ml methylene dichloride, with the sodium bicarbonate aqueous solution washing, through dried over mgso organic layer, vacuum concentration.Residue is through preparation property silica gel tlc chromatography, and with 95% methylene dichloride (ammonium hydroxide)-5% methanol solution wash-out, obtaining 0.044g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtaining 0.038g is the diastereomer B product of white solid.

Diastereomer A:Mp=120.5-125.5 ℃, MH ⁺=629 (FAB).

Diastereomer B:Mp=120.3-126.1 ℃, MH ⁺=629 (FAB).

Embodiment 31

Adopt the method for embodiment 30, make diastereomer A and 0.021g (0.142mmol) the 4-morpholine carbonyl chloride and the reaction of 0.035g (0.256mmol) triethylamine of 0.07g (0.128mmol) embodiment 27 steps A, obtaining 0.024g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtaining 0.019g is the diastereomer B product of white solid.

Diastereomer A:Mp=137.9-138.9 ℃, MH ⁺=656 (FAB).

Diastereomer B:Mp=136.4-138.6 ℃, MH ⁺=656 (FAB).

Embodiment 32

The diastereomer A of 0.07g (0.129mmol) embodiment 27 steps A is dissolved in the 0.5ml methylene dichloride, then dissolves in 0.033g (0.152mmol) tert-Butyl dicarbonate and and spend the night in following stirring of nitrogen.With the dilution of 20ml methylene dichloride, with the sodium bicarbonate aqueous solution washing, through dried over mgso organic layer, vacuum concentration.Residue is through preparation property silica gel tlc chromatography, and with 95% methylene dichloride (ammonium hydroxide)-5% methanol solution wash-out, obtaining 0.024g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtaining 0.026g is the diastereomer B product of white solid.

Diastereomer A:Mp=127.1-128.4 ℃, MH ⁺=643 (FAB).

Diastereomer B:Mp=134.9-137.5 ℃, MH ⁺=643 (FAB).

Embodiment 33

Adopt the method for embodiment 30, the diastereomer A of 0.05g (0.092mmol) embodiment 27 steps A and 1.1g (0.10mmol) methylsulfonyl chloride and 0.019g (0.183mmol) triethylamine are reacted in the 1.5ml methylene dichloride, and obtaining 0.011g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtaining 0.032g is the diastereomer B product of white solid.

Diastereomer A:Mp=138.1-144.6 ℃, MH ⁺=621 (FAB).

Diastereomer B:Mp=139-145.1 ℃, MH ⁺=621 (FAB).

Embodiment 34

The diastereomer A of 0.07g (0.129mmol) embodiment 27 steps A is dissolved in the 1.0ml dimethyl formamide, then dissolve in 0.023g (0.167mmol) 4-fluorobenzoic acid, 0.032g (0.167mmol) DEC, 0.0225g (0.167mmol) HOBT and 0.018ml (0.167mmol) N-methylmorpholine, stir down in nitrogen and spend the night.Vacuum concentration is dissolved in residue in the 20ml methylene dichloride, washs with the 1N aqueous sodium hydroxide washes, through dried over mgso organic layer, vacuum concentration.Through flash chromatography on silica gel, with 93% methylene dichloride (ammonium hydroxide)-7% methanol solution wash-out, obtaining 0.060g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 27 steps A, obtain diastereomer B product into white solid.

Diastereomer A:Mp=141.5-145.8 ℃, MH ⁺=665 (FAB).

Diastereomer B:Mp=144.9-148.7 ℃, MH ⁺=665 (FAB).

Embodiment 35

Adopt the method for embodiment 34, replace the 4-fluorobenzoic acid, obtain diastereomer A product into white solid with the 4-fluorophenylacetic acid.Mp＝132.8-140.1℃，MH ⁺＝679(FAB)。

Adopt aforesaid method, obtain diastereomer B product into white solid.Mp＝132.5-139.7℃，MH ⁺＝679(FAB)。

Embodiment 36

Adopt the method for embodiment 34, replace the 4-fluorobenzoic acid, obtain to the diastereomer A product of white solid and be the diastereomer B product of white solid with 4-pyridylacetic acid(HPAC) N-oxide compound.Diastereomer A:Mp=168.5-172.4 ℃, MH ⁺=678 (FAB).Diastereomer B:Mp=168.9-172.3 ℃, MH ⁺=678 (FAB).

Embodiment 37

Adopt the method for embodiment 34, replace the 4-fluorobenzoic acid, obtain to the diastereomer A product of white solid and be the diastereomer B product of white solid with N-tert.-butoxy-carbonyl-4-Piperidineacetic acid.Diastereomer A:Mp=135.1-142.1 ℃, MH ⁺=768 (FAB).Diastereomer B:Mp=141.7-143.2 ℃, MH ⁺=768 (FAB).

Embodiment 38

The diastereomer A product of 0.23g (0.31mmol) embodiment 37 is dissolved in 3ml methylene dichloride and the 3ml trifluoroacetic acid, stirred 3.5 hours down in nitrogen.Vacuum concentration is dissolved in residue in the 20ml methylene dichloride, washs with the 1.0N aqueous sodium hydroxide washes.The vacuum concentration organic layer, residue is through preparation property silica gel tlc chromatography, and with 80% methylene dichloride (ammonium hydroxide)-20% methanol solution wash-out, obtaining 0.113g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 37 steps A, obtain diastereomer B product into white solid.

Diastereomer A:Mp=136.1-139.5 ℃, MH ⁺=668 (FAB).

Diastereomer B:MH ⁺=6668 (FAB).

Embodiment 39

The diastereomer A product of 0.073g (0.11mmol) embodiment 38 is dissolved in the 3ml methylene dichloride that contains 0.013g (0.121mmol) trimethylsilyl isocyanate, stirs down in nitrogen and spend the night.With the dilution of 5ml methylene dichloride, with the saturated sodium bicarbonate aqueous solution washing of 10ml.Through dried over mgso organic layer, vacuum concentration.Residue is through preparation property silica gel tlc chromatography, and with 90% methylene dichloride (ammonium hydroxide)-10% methanol solution wash-out, obtaining 0.032g is the diastereomer A product of white solid.

Adopt aforesaid method, but use the diastereomer B of embodiment 38, obtain diastereomer B product into white solid.

Diastereomer A:Mp=148.2-151.3 ℃, MH ⁺=711 (FAB).

Diastereomer B:Mp=148.1-150.4 ℃, MH ⁺=711 (FAB).

Embodiment 40

Carboxylic acid (0.32g with preparation embodiment 51,0.596mmol), the product of preparation embodiment 13 (0.108g, 0.775mmol), DEC (0.149g, 0.775mmol), HOBT (0.105g, 0.775mmol) and the 0.13ml N-methylmorpholine be dissolved among the 5ml DMF, stirring is spent the night.Vacuum concentration is dissolved in residue in the 20ml methylene dichloride.With saturated sodium bicarbonate aqueous solution washing, through dried over mgso, through the flash chromatography on silica gel purifying, with 97% methylene dichloride (ammonium hydroxide)-3% methanol solution wash-out, obtaining 0.2g is white solid product.Adopt preparation property chirality chromatography (Chiralpack AD, 5cm * 50cm post, flow velocity 100ml/min, 15%2-propyl alcohol/hexane+0.2% diethylamine), separate diastereomer.

Diastereomer A:Mp=54-58 ℃, MH ⁺=657 (FAB).

Diastereomer B:Mp=64-58 ℃, MH ⁺=657 (FAB).

Embodiment 41

According to the method for embodiment 40, adopt the product of the product replacement preparation embodiment 13 of preparation embodiment 14, obtain product into white solid.Mp＝116-123℃，MH ⁺＝671(FAB)。

Embodiment 42

According to the method for embodiment 40, adopt the product of the product replacement preparation embodiment 13 of preparation embodiment 15, obtain product into white solid.

Diastereomer A:Mp=115-120 ℃, MH ⁺=671 (FAB).

Diastereomer B:Mp=98-101 ℃, MH ⁺=671 (FAB).

Embodiment 43

According to the method for embodiment 40, adopt the product of the product replacement preparation embodiment 13 of preparation embodiment 16, obtain product into white solid.Mp＝120-122℃，MH ⁺＝685(FAB)。

Embodiment 44

According to the method for embodiment 40, adopt the product of the product replacement preparation embodiment 13 of preparation embodiment 17, obtain product into white solid.Mp＝101-103℃，MH ⁺＝733(FAB)。

Embodiment 45-59

According to the method for embodiment 40, adopt the amine that derives from preparation embodiment 18-26 to replace the product of preparation embodiment 13, obtain following formula: compound: R wherein ²⁷Identical with definition in the table 9.

Table 9

Embodiment 60

Steps A

(0.148g 0.202mmol) is dissolved in the 0.78ml methylene dichloride, adds the 0.45ml trifluoroacetic acid, stirs 2 hours down in nitrogen with the product of embodiment 47.Vacuum concentration is dissolved in residue in the 20ml methylene dichloride, and with the sodium bicarbonate aqueous solution washing, through the dried over mgso organic layer, vacuum concentration obtains the amine into white solid.

Step B

(0.05g 0.078mmol) is dissolved in the 2ml methylene dichloride, adds 0.015g (0.118mmol) NSC 87419 with the product of steps A.Stirring is spent the night and vacuum concentration.Residue with 99% methylene dichloride (ammonium hydroxide)-1% methanol-eluted fractions, obtains the isomer A product into white solid through the flash chromatography on silica gel purifying.Mp＝138-142℃，MH ⁺＝758(FAB)。

According to aforesaid method, still replace the product of embodiment 47 steps A with the product of embodiment 48, obtain isomer B product into white solid.Mp＝130-139℃，MH ⁺＝758(FAB)。

Embodiment 61

Steps A

According to the method for embodiment 60, adopt the product of embodiment 47, and in step B, replace NSC 87419 with tert-butyl isocyanate, obtain isomer A product into white solid.Mp＝127-132℃，MH ⁺＝732(FAB)。

Step B

According to the method for embodiment 60, but in steps A, use the product of embodiment 48 to replace the product of embodiment 47, and in step B, replace NSC 87419, obtain isomer B product into white solid with tert-butyl isocyanate.Mp＝127-130℃，MH ⁺＝732(FAB)。

Embodiment 62

Steps A

Acid (0.37g with preparation embodiment 43,1.12mmol), the preparation embodiment 19 product (0.29g, 1.35mmol), DEC (0.289g, 1.46mmol), HOBT (0.197g, 1.46mmol) and N-methylmorpholine (0.25ml, 2.24mmol) be dissolved among the 20ml DMF, stir down in nitrogen and spend the night.Vacuum concentration is dissolved in residue in the 50ml methylene dichloride, with saturated sodium bicarbonate aqueous solution washing, through dried over mgso organic layer, vacuum concentration.Residue with 100% methylene dichloride (ammonium hydroxide) wash-out, obtains white solid through the flash chromatography on silica gel purifying.

Step B

(0.59g 1.048mmol) is dissolved in the 3ml methylene dichloride, adds the 2.5ml trifluoroacetic acid with the product of steps A.Stirring is spent the night and vacuum concentration.

Step C

With the product of step B (0.5g, 1.048mmol), the 8-Cl-tricyclic chloride (0.359g, 1.048mmol) and triethylamine (2.19ml 15.72mmol) is dissolved in the 5ml methylene dichloride, and stirring is spent the night.Vacuum concentration through the flash chromatography on silica gel purifying, with 95% methylene dichloride (ammonium hydroxide)-5% methyl alcohol, obtains white solid product.

Step D

(0.27g 0.486mmol) is dissolved in the 2ml methylene dichloride, and (0.125g 0.57mmol), stirred 2 hours to add tert-Butyl dicarbonate with the product of step C.Vacuum concentration through preparation property chirality chromatography (Chiralpack AD, 5cm * 50cm post, flow velocity 100ml/min, 5%2-propyl alcohol/hexane+0.2% diethylamine), separates diastereomer.Obtain product for white solid.

Diastereomer A:Mp=93.1-99.8 ℃, MH ⁺=655 (FAB).

Diastereomer B:Mp=93.1-99.8 ℃, MH ⁺=655 (FAB).

Embodiment 63

According to the method for embodiment 40, the product with the product replacement preparation embodiment 13 for preparing embodiment 27 obtains the product into white solid.

Isomer mixture 1:Mp=148-151 ℃, MH ⁺=687 (FAB).

Isomer mixture 2:Mp=110-114 ℃, MH ⁺=687 (FAB).

Embodiment 64

According to the method for embodiment 40, the product with the product replacement preparation embodiment 13 for preparing embodiment 28 obtains the product into white solid.Mp=131-138 ℃ of decomposition, MH ⁺=687 (FAB).

Embodiment 65

According to the method for embodiment 40, the product with the product replacement preparation embodiment 13 for preparing embodiment 29 obtains the product into white solid.

Isomer mixture 1:Mp=148-157 ℃, MH ⁺=721 (FAB).

Isomer mixture 2:Mp=120-126 ℃, MH ⁺=721 (FAB).

Embodiment 66

According to the method for embodiment 40, the product with the product replacement preparation embodiment 13 for preparing embodiment 30 obtains the product into white solid.

Isomer mixture 1:Mp=146-154 ℃, MH ⁺=657 (FAB).

Isomer mixture 2:Mp=122-127 ℃, MH ⁺=657 (FAB).

Embodiment 67

11R with preparation embodiment 34,2R (-)-diastereomer (0.25g, 0.46mmol), 4-pyridylacetic acid(HPAC) N1-oxide compound (0.0915g, 0.598mmol) (seeing the preparation embodiment 61 of the United States Patent (USP) 5719148 that on February 17th, 1998 authorized), DEC (0.1146g, 0.598mmol), HOBt (0.0807g, 0.598mmol) and the 4-methylmorpholine (0.0657ml 0.598mmol) is dissolved in the dry DMF (9ml), in argon gas, 25 ℃ this mixture is stirred 96 hours.According to the described method processing reaction of embodiment 40 steps A thing, through silica gel column chromatography, with 5% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride as eluent, obtain target compound (productive rate: 78%, 0.2434g); FABMS:m/z 678.0 (MH ⁺); δ _C(CDCl ₃) 30.1,30.3,30.9,36.5,38.5,44.1,44.3,50.7,52.5; CH, 53.4,78.3 ,～119.1,126.2,127.3,127.3 ,～129.1,130.6,132.3 ,～137.1,138.6,138.6,141.1,146.9; C, 120.1,134.2,134.6,134.8,137.1,140.8,155.1,169.2,169.8; δ _H(CDCl ₃) 4.31 (1H, s, H ₁₁), 4.97 (1H, broad peak s, CHCO), 6.74 (1H, broad peak s, Im-H ₅), 6.91 (1H, broad peak s, Im-H ₄), 7.02 (1H, broad peak s, Ar-H), 7.07-7.17 (5H, m, CONHCH ₂And Ar-H), 7.38 (1H, broad peak s, Im-H ₂), 7.56 (1H, s, Ar-H), 8.08 (1H, d, Ar-H), 8.10 (1H, d, Ar-H) and 8.35ppm (1H, s, Ar-H ₂); [α] _D ^{23.2 °}+ 44.4 ° (c=10.64mg/2ml, methyl alcohol).

Embodiment 68

11S with preparation embodiment 34,2R (-)-diastereomer (0.3g, 0.552mmol), 4-pyridyl acetate N1-oxide compound (0.110g, 0.718mmol) (seeing the United States Patent (USP) 5719148 on February 17th, 1998), DEC (0.1375g, 0.718mmol), HOBT (0.0969g, 0.718mol) and the 4-methylmorpholine (0.0788ml 0.718mmol) is dissolved in the dry DMF (9ml), in argon gas, 25 ℃ this mixture is stirred 19 hours.According to the described method processing reaction of embodiment 40 steps A thing, through silica gel column chromatography, with 6% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride as eluent, obtain target compound (productive rate: 80%, 0.2847g); FABMS:m/z 678.0 (MH ⁺); δ _C(CDCl ₃) 30.1,30.6,30.8,36.5,38.5,44.0,44.4,51.1,52.7; CH, 53.4,78.5 ,～119.0,126.2/126.3,127.2/127.3,127.2/127.3 ,～129.2,130.3,132.4/132.6 ,～137.1,138.7,138.7,141.2/141.5,147.0/147.2; C, 120.1,134.2/134.4,134.3,134.9,136.9,141.5,154.4/154.7,168.8/169.2,169.0/169.9; δ _H(CDCl ₃) 4.30 (1H, s, H ₁₁), 4.96 (1H, broad peak s, CHCO), 6.64 (1H, broad peak s, CONHCH ₂), (3H, broad peak is overlapping, Im-H for 6.89-7.02 ₅, Im-H ₄And Ar-H), and 7.10-7.18 (4H, m, Ar-H), 7.33 (1H, broad peak s, Im-H ₂), 7.59 (1H, s, Ar-H), 8.08 (1H, d, Ar-H), 8.10 (1H, d, Ar-H) and 8.37ppm (1H, s, Ar-H ₂); [α] _D ^{23.4 °}+ 6.9 ° (c=10.48mg/2ml, methyl alcohol).

Embodiment 69

The 11R of preparation embodiment 34 will be derived from, 2R (-)-diastereomer (0.3g, 0.552mmol), 1-aminocarboxyl-4-piperidyl acetate (0.1335g, 0.718mmol) (preparation embodiment 33), DEC (0.1375g, 0.718mmol), HOBt (0.0969g, 0.718mmol) and the 4-methylmorpholine (0.157ml 1.436mmol) is dissolved in the dry DMF (7ml), in argon gas, 25 ℃ this mixture is stirred 68 hours.Method according to the above-mentioned embodiment of preparation 40 steps A is handled this reactant, through purification by silica gel column chromatography, as eluent, obtains target compound: output: 0.3547g, 90% with 6% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride; LCMS:m/z 711.2 (MH ⁺); δ _C(CDCl ₃) 30.3,30.4,31.2,32.0,32.0,36.6/37.2,39.3/39.6,43.9,44.4,44.4,44.4,51.0,51.8; CH, 32.9,53.0,78.7,118.9,126.2,129.7,130.5/130.7,132.3,137.3,141.3,147.0; C, 120.3,134.3,135.1,137.3,141.1,155.1,157.9,170.0,171.9; δ _H(CDCl ₃) 4.30 (1H, s, H ₁₁), 4.89 (2H, s, NCONH ₂), 4.98 (1H, s, CHCO), 6.92 (1H, broad peak s, Im-H ₅), 6.99 (1H, broad peak s, Im-H ₄), 7.07-7.14 (3H, m, Ar-H), 7.41 (1H, broad peak s, Im-H ₂), 7.57 (1H, s, Ar-H), 7.59 (1H, broad peak s, CONHCH ₂) and 8.35ppm (1H, s, Ar-H ₂); [α] _D ^{20.0 °}+ 35.5 ° (c=9.40mg/2ml, methyl alcohol).

Embodiment 70

According to the method for embodiment 69, but use the 11S for preparing embodiment 34,2R (-)-diastereomer replaces 11R, 2R (-)-diastereomer, and under argon gas, stirred 96 hours rather than 68 hours, obtain target compound: output: 0.3241g, 83%; LCMS:m/z 711.2 (MH ⁺); δ _C(CDCl ₃) 30.2,30.6,31.1,32.0,32.0,36.5/36.8,39.6/39.7,43.8,44.4,44.4,44.4,51.3,51.6; CH, 32.9,53.0,78.8,119.0,126.3/126.4,129.4,130.4/130.6,132.5/132.6,137.1,141.5,147.1; C, 120.2,134.3,135.0,137.1,141.5,155.1,158.1,170.3,172.4; δ _H(CDCl ₃) 4.29 (1H, s, H ₁₁), 4.55 (2H, s, NCONH ₂), 4.98 (1H, s, CHCO), 6.23 (1H, t, CONHCH ₂), 6.92 (1H, broad peak s, Im-H ₅), 703 (1H, broad peak s, Im-H ₄), 7.10-7.17 (3H, m, Ar-H), 7.43 (1H, broad peak s, Im-H ₂), 7.59 (1H, s, Ar-H) and 8.37ppm (1H, s, Ar-H ₂); [α] _D ^{23.1 °}+ 1.0 ° (c=10.00mg/2ml, methyl alcohol).

Embodiment 71

With pyridine-4-acyl azide N1-oxide compound (J.Med.Chem., 1998,41,877-893) (0.346g 2.30mmol) is dissolved in the dry toluene (30ml), in argon gas, 110 ℃ with this vlil 1 hour.This solution is cooled to room temperature, adds the C of preparation embodiment 141 ₁₁-racemize target compound (0.250g, 0.46mmol).Stirred this mixture 22 hours in 25 ℃.To doing, residue as eluent, obtains target compound: output: 0.1265g, 32% with 4% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride through purification by silica gel column chromatography with solution evaporation; LCMS:m/z 679.2 (MH ⁺); δ _C(CDCl ₃) CH ₂: 30.3,30.6,31.0/31.1,36.7/36.8,42.6,44.6,51.0/51.3,52.4/52.6; CH, 55.1/55.2,78.8,115.8,115.8,119.2,126.3,129.1,130.5/130.6,132.7,137.2,138.6,138.6,141.4,147.0/147.2; C:120.2,134.2,134.3,134.9,136.9,136.9,141.3,155.0,155.2,170.4; δ _H(CDCl ₃) 4.34 (1H, s, H ₁₁), 4.67 (1H, s, CHCO), 6.89 (1H, d, Im-H ₅), 6.99 (1H, d, Im-H ₄), 7.10-7.15 (3H, m, Ar-H), 7.46 (2H, d, Ar-H), 7.59 (1H, broad peak s, Im-H ₂), 7.90 (2H, d, Ar-H), 8.39 (1H, s, Ar-H ₂) and 9.77 (1H, broad peak s, NCONH).

Embodiment 72

Steps A

With 1-N-tert-butoxycarbonyl piperidines-3-acyl azide (above-mentioned preparation embodiment 35 step B) (1.177g 4.63mmol) is dissolved in the dry toluene (150ml), in argon gas, 110 ℃ with this vlil 1 hour.This solution is cooled to room temperature, divides three parts (added 1.47mmol in 0 hour, added 2.21mmol in 69 hours and added 0.95mmol in 93 hours) to add the C of preparation embodiment 141 ₁₁(0.4g is in anhydrous methylene chloride 0.735mmol) (26ml) solution for-racemize target compound.Stirred this mixture 117 hours in 25 ℃.To doing, residue as eluent, obtains target compound: output: 0.1265g, 32% with 4% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride through purification by silica gel column chromatography with solution evaporation; LCMS:m/z 679.2 (MH ⁺); δ _C(CDCl ₃) CH ₃: 28.5,28.5,28.5; CH ₂: 30.5,30.6,31.2/31.3,32.5,32.5,36.6,41.8,42.7,42.7,44.6,50.9/51.1,51.9/52.2; CH, 48.2,54.9/55.0,78.9/79.0 ,-119.0,126.4/126.5 ,-129.6,130.5/130.6,132.8 ,-137.1,141.3/141.4,147.1/147.3; C:79.6,120.3,134.5,134.7,136.9,141.1,154.7,154.8,157.6,171.0; δ _H(CDCl ₃) 1.46 (9H, s, CH ₃), 4.33 (1H, s, H ₁₁), 4.41 (1H, broad peak s, CHCO), 5.18 (1H, d, NCONH), 6.55 (1H, broad peak m, CONHCH ₂), 6.92 (1H, broad peak s, Im-H ₅), 7.08 (1H, broad peak s, Im-H ₄), 7.10-7.15 (3H, m, Ar-H), 7.50 (1H, broad peak s, Im-H ₂), 7.59 (1H, d, Ar-H) and 8.40ppm (1H, s, Ar-H ₂).

Step B

(0.2361g 0.307mmol) is dissolved in methyl alcohol (1.61ml), adds dioxane (4.18ml) solution of 10% (v/v) vitriol oil with the target compound of above-mentioned steps A.In argon gas, 25 ℃ this mixture was stirred 1 hour.Through BioRad ^AG1-X8 (OH ^-) this mixture of resin filter, use methanol wash.The elutriant that merges is evaporated to dried, residue as eluent, obtains target compound: output: 0.1984g, 97% with 20% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride through silica gel column chromatography; LCMS:m/z 669.2 (MH ⁺); δ _C(CDCl ₃) CH ₂: 30.3,30.5,30.9,31.6,31.6,36.3/36.4,42.3,42.3,42.3,44.3,50.8/51.2,52.1/52.4; CH, 47.2/47.3,54.8,78.9,119.1,126.3,129.0,130.5/130.6,132.7,137.5,141.3,147.0/147.1; C:120.1,134.2/134.3,134.9,136.9,141.2,155.2,157.7/157.8,171.2; δ _H(CDCl ₃) 4.29 (1H, s, H ₁₁), 4.61 (1H, broad peak s, CHCO), 5.72 (1H, broad peak m, NCONH), 6.85 (1H, m, CONHCH ₂), 6.92 (1H, broad peak s, Im-H ₅), 6.99 (1H, broad peak s, Im-H ₄), 7.10-7.15 (3H, m, Ar-H), 7.57 (1H, s, Ar-H), 7.66 (1H, broad peak s, Im-H ₂) and 8.37ppm (1H, s, Ar-H ₂).

Step C

With the target compound of above-mentioned steps B (0.195g 0.291mmol) is dissolved in the anhydrous methylene chloride (10ml), add trimethylsilyl isocyanate (0.394ml, 2.91mmol).Stirred this mixture 20 hours in argon gas, 25 ℃.(0.188ml 0.873mmol), stirred this mixture 23 hours altogether to add trimethylsilyl isocyanate again.(900ml) dilutes this mixture with methylene dichloride, with saturated sodium bicarbonate aqueous solution washing, through dried over mgso, filters and be evaporated to dried.Residue as eluent, obtains target compound: output: 0.1325g, 64% with 4% (10% dense ammonium hydroxide methanol solution)-methylene dichloride through silica gel column chromatography; LCMS:m/z 712.2 (MH ⁺); δ _C(CDCl ₃) CH ₂: 30.3/30.4,30.6,31.0/31.1,32.4,32.4,36.5,42.0,43.4,43.4,44.4,50.9/51.2,52.4/52.6; CH, 48.1,54.9/55.0,78.9,119.0,126.3/126.4,129.4,130.5/130.6,132.7,137.3,141.3/141.4,147.1/147.2; C:120.2,134.2/134.3,135.1,136.9,141.2,155.1,157.8/157.9,158.1,171.4/171.5; δ _H(CDCl ₃) 4.31 (1H, s, H ₁₁), 4.53 (1H, broad peak s, CHCO), 4.75 (2H, broad peak s, NCONH ₂), 5.73 (1H, d, NCONH), 6.65 (1H, t, CONHCH ₂), 6.92 (1H, broad peak s, Im-H ₅), 7.04 (1H, broad peak s, Im-H ₄), 7.10-7.15 (3H, m, Ar-H), 7.46 (1H, s, Ar-H), 7.58 (1H, broad peak s, Im-H ₂) and 8.38ppm (1H, s, Ar-H ₂).

Embodiment 73

The 11R of above-mentioned preparation embodiment 38 step D will be derived from, 2R (+)-diastereomer (0.1647g, 0.294mmol), 4-pyridyl acetate N1-oxide compound (0.0586g, 0.382mmol), DEC (0.0733g, 0.382mmol), HOBt (0.0517g, 0.382mmol) and the 4-methylmorpholine (0.042ml 0.382mmol) is dissolved in the dry DMF (5ml), in argon gas, 25 ℃ this mixture is stirred 25 hours.Method according to the above-mentioned embodiment of preparation 40 steps A is handled this reactant, through purification by silica gel column chromatography, as eluent, obtains target compound with 2% → 6% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride: (output: 0.1048g, 51%); SIMS:m/z 694.5 (MH ⁺); δ _C(CDCl ₃) 30.0,30.4,31.0,36.7,38.5,44.1,44.5,50.5,51.3; CH, 53.6,63.6,119.1,126.4,127.4,127.4 ,-129.1,130.7,130.8,133.4 ,-137.2,138.4/138.6,138.7,138.7; C, 118.5,133.3,134.6,134.9,140.4,141.4,147.4,169.2,169.9; δ _H(CDCl ₃) 4.98 (1H, broad peak s, CHCO), 5.70 (1H, s, H ₁₁), 6.92/6.97 (1H, broad peak s, Im-H ₅), 7.01 (1H, broad peak s, Im-H ₄), 7.08-7.18 (5H, m, Ar-H), 7.43/7.51 (1H, broad peak s, Im-H ₂), 7.79 (1H, t, CONHCH ₂), 8.05 (1H, d, Ar-H), 8.09 (2H, d, Ar-H), 8.26/8.31ppm (1H, s, Ar-H ₂); [α] _D ^{20.0 °}+ 82.8 ° (c=9.11mg/2ml, methyl alcohol).

Embodiment 74

The 11S of above-mentioned preparation embodiment 38 step D will be derived from, 2R (-)-diastereomer (0.1576g, 0.281mmol), 4-pyridyl acetate N1-oxide compound (0.0560g, 0.366mmol), DEC (0.0702g, 0.366mmol), HOBt (0.0495g, 0.366mmol) and the 4-methylmorpholine (0.040ml 0.366mmol) is dissolved in the dry DMF (5ml), in argon gas, 25 ℃ this mixture is stirred 26 hours.Method according to the above-mentioned embodiment of preparation 40 steps A is handled this reactant, through purification by silica gel column chromatography, as eluent, obtains target compound with 2% → 6% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride: (output: 0.1017g, 50%); SIMS:m/z 694.5 (MH ⁺); δ _C(CDCl ₃) 29.7,30.5,30.8,36.5,38.4,44.2,44.3,50.1,52.3; CH, 53.4,63.6 ,-119.0,126.4,127.4,127.4 ,-129.1,130.3,130.9,133.3 ,-137.3,138.3/138.7,138.7,138.7; C, 118.4,133.3,134.6,134.8,140.1,141.6,147.4,169.2,169.9; δ _H(CDCl ₃) 4.97 (1H, broad peak s, CHCO), 5.71 (1H, s, H ₁₁), 6.58 (1H, t, CONHCH ₂), 6.88 (1H, broad peak s, Im-H ₅), 6.98/7.03 (1H, broad peak s, Im-H ₄), 7.09-7.21 (5H, m, Ar-H), 7.34/7.41 (1H, broad peak s, Im-H ₂), 8.09 (1H, d, Ar-H), 8.10 (2H, d, Ar-H), 8.27/8.28ppm (1H, s, Ar-H ₂); [α] _D ^{20.0 °}-12.7 ° (c=10.08mg/2ml, methyl alcohol).

Embodiment 75

With 3-bromo-8,11-two chloro-6,11-dihydro-5H-benzo [5,5] encircle heptan [1,2-b] pyridine N1-oxide compound (preparation embodiment 38 step C) (0.2656g, 0.74mmol) be dissolved in the anhydrous methylene chloride (3.8ml), add to 1-[2-[N-[3-1H-imidazoles-1-yl) propyl group]-2 (R)-piperazine carboxamides]-2-oxoethyl-1-piperidyl urea (above-mentioned preparation embodiment 40 step B) (0.3g, 0.74mmol) and triethylamine (1.0316ml, 7.40mmol) anhydrous methylene chloride (6ml) solution in, stirred this mixture 19 hours in ar gas environment, 25 ℃.This solution as eluent, obtains target compound with 3.5% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride directly through purification by silica gel column chromatography.Output: 0.3727g, 69%; LCMS:m/z 727.2 (MH ⁺); δ _C(CDCl ₃) CH ₂: 29.9/30.1,30.4/30.5,31.1/31.2,32.0,32.0,36.5/36.6,39.6,44.0/44.4,44.0/44.4,44.4,44.4,50.5/50.7/51.1,52.1; CH, 32.9,53.0/53.1,63.8 ,-119.2,126.4/126.5 ,-129.4,130.5/130.7,130.9,133.4 ,-137.2,138.4; C, 118.5,133.3/133.4,134.8/134.9,140.2/140.5,141.4/141.6,147.6/147.8,158.1,169.3/170.2,171.4/172.0; δ _H(CDCl ₃) 4.60 (2H, s, NCONH ₂), 4.98 (1H, broad peak s, CHCO), 5.69 (1H, s, H ₁₁), 6.29/6.53 (1H, t, CONHCH ₂, be respectively the C of S (-) and R (+) isomer ₁₁), 6.92 (1H, broad peak s, Im-H ₅), 7.05 (1H, broad peak s, Im-H ₄), 7.14 (2H, m, Ar-H), 7.18 (1H, m, Ar-H), 7.20 (1H, m, Ar-H), 7.56 (1H, broad peak s, Im-H ₂) and 8.27ppm (1H, s, Ar-H ₂).

Embodiment 76

Method 1

With 3-bromo-8,11-two chloro-6,11-dihydro-5H-benzo [5,5] encircle heptan [1,2-b] pyridine N1-oxide compound (preparation embodiment 38 step C) (0.2818g, 0.785mmol) be dissolved in the anhydrous methylene chloride (4ml), add to N1-cyclohexyl-N2-[3-1H-imidazoles-1-yl) propyl group]-1,2 (R)-piperazine diformamides] (as follows) (0.2844g, 0.785mmol) and triethylamine (1.094ml, 7.85mmol) anhydrous methylene chloride (4.5ml) solution in, stirred this mixture 67 hours in ar gas environment, 25 ℃.This solution as eluent, obtains the racemic mixture of target compound with 3% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride directly through purification by silica gel column chromatography.Output: 0.4664g, 87%.This mixture is through Chiralpak AD ^(50 * 5cm) preparation property HPLC purifying, as eluent, order obtains 11S, 2R (-)-diastereomer and 11R, the elutriant of 2R (+)-diastereomer to post with 65% hexane-35% Virahol-0.2% diethylamine.

11S, 2R (-)-diastereomer, output 0155.5g, LCMS:m/z 684.2 (MH ⁺); δ _C(CDCl ₃) 25.0,25.1,25.6,30.1,30.5,31.1,33.7,33.7,36.4,42.4,44.5,50.2,51.5; CH, 49.9,54.8,64.1,119.1,126.5,129.3,130.5,130.8,133.5,137.2,138.4; C, 118.4,133.1,134.9,140.2,141.4,147.8,157.6,171.2; δ _H(CDCl ₃) 4.53 (1H, broad peak s, CHCO), 4.91 (1H, d, NCONH), 5.68 (1H, s, H ₁₁), 6.62 (1H, t, CONHCH ₂), 6.94 (1H, broad peak s, Im-H ₅), 7.08 (1H, broad peak s, Im-H ₄), 7.15 (1H, m, Ar-H), 7.17 (1H, s, Ar-H), 7.21 (1H, s, Ar-H), 7.23 (1H, m, Ar-H), 7.55 (1H, broad peak s, Im-H ₂) and 8.27ppm (1H, s, Ar-H ₂); [α] _D ^{20.0 °}-33.1 ° (c=8.76mg/2ml, methyl alcohol).

11R, 2R (+)-diastereomer, output 0.1890g; LCMS:m/z 684.2 (MH ⁺); δ _C(CDCl ₃) 25.1,25.1,25.6,30.3,30.7,31.1,33.7,33.7,36.5,42.3,44.7,50.2,50.7; CH, 50.0,55.0,64.2,119.1,126.3,128.8,130.6,130.9,133.5,137.2,138.5; C, 118.5,133.1,134.7,140.4,141.4,147.5,157.5,171.1; δ _H(CDCl ₃) 4.52 (1H, broad peak s, CHCO), 4.95 (1H, d, NCONH), 5.69 (1H, s, H ₁₁), 6.97 (1H, t, NCONHCH ₂), 6.97 (1H, broad peak s, Im-H ₅), 7.10 (1H, broad peak s, Im-H ₄), 7.13 (1H, m, Ar-H), 7.18 (2H, s, Ar-H), 7.21 (1H, m, Ar-H), 7.69 (1H, broad peak s, Im-H ₂) and 8.27 ppm (1H, s, Ar-H ₂); [α] _D ^{20.0 °}+ 49.9 ° (c=10.23mg/2ml, methyl alcohol).

Raw material reaction agent N1-cyclohexyl-N2-[3-1H-imidazoles-1-yl) propyl group]-1,2 (R)-piperazine diformamide obtains according to the method for preparing embodiment 5, but usefulness

Replace

With TFA the compound that the BOC that obtains protects is gone protection according to the method for preparing embodiment 8 step B.

Method 2

With 11S, 2R (-)-diastereomer (above preparation embodiment 38 step D) (1mg 0.00179mmol) is dissolved in the anhydrous methylene chloride (0.05ml), and the adding NSC 87419 (0.0023ml, 0.0179mmol).Under 25 ℃, ar gas environment, this mixture was stirred 0.5 hour.Solution evaporation to doing, is obtained target compound, and through the 11S of chirality HPLC proof with aforesaid method 1 preparation, 2R (-)-diastereomer is identical.

Embodiment 77

In room temperature (20 ℃), imidazoles (reagent 2) (250mg with preparation embodiment 74,1.16mmol) add to BOC-acid (reagent 1, see preparation embodiment 41) (0.45g, 0.842mmol), EDCI (200mg, 1.043mmol), HOBT (130mg, 0.962mmol) and N-methylmorpholine (0.2ml, 1.81mmol) DMF (anhydrous, 2ml) in the solution.In 20 ℃ the solution stirring that obtains is spent the night, evaporating solvent adds entry (70ml) and ethyl acetate (120ml).Separate organic layer, with 10% sodium carbonate solution (50ml) washing, then through dried over mgso, filter and evaporating solvent, obtain oily matter, with it through silica gel column chromatography, using 100% eluent ethyl acetate, obtain the product (300mg) into white solid, is the miscellany of 4 kinds of isomer A, B, C and D.

Mass spectrum: high resolving power (ES) theoretical value (MH ⁺): 732.2316, measured value: 732.2332.

Embodiment 78

Steps A

(150mg, 50% trifluoroacetic acid 0.205mmol)-dichloromethane solution stirred 3 hours in 20 ℃ with the target compound (isomer A, B, C and D) of embodiment 77.Evaporating solvent adds entry (25ml) and 10% sodium hydroxide (4ml), uses methylene dichloride (2 * 100ml) extractions then.Separate organic layer, through dried over mgso, evaporating solvent obtains solid, and through the silica gel column chromatography purifying, the 3% sodium hydroxide-methylene dichloride wash-out with containing 2% ammonium hydroxide obtains the product (70mg, 54% productive rate) into white solid with it.

Obtaining is the product (product 1) of 2 kinds of isomer (C and D) mixture.Mass spectrum FABS (MH) 632.

Further wash-out obtains white solid (25mg, 20% productive rate).This product is the product (product 2) of 2 kinds of isomer (A and B) mixture.Mass spectrum FABS (MH ⁺) 632.

Adopt Chiralcell AD post that product 2 is separated into single isomer,, obtain isomer A, FABS (MH into white solid with 40% Virahol-hexane wash-out ⁺) 632.Further wash-out obtains the isomer B into white solid, FABS (MH ⁺) 632.

Shown in following step B, product 1 is derived and be separated into isomer C and D composition.

Step B

In 0 ℃, (65mg, methylene dichloride 0.29mmol) (2ml) solution add to product 1 (steps A, isomer C and D), and (150mg in methylene dichloride 0.237mmol) (10ml) solution, stirred 10 minutes in 20 ℃ then with tert-Butyl dicarbonate.This reactant is cooled to 0 ℃, adds entry (5ml), 10% sodium hydroxide (2ml) and methylene dichloride (10ml).Separate organic layer, use dried over mgso, filter and evaporating solvent, obtain oily matter, with it through silica gel column chromatography, use 3%v/v methyl alcohol: the methylene dichloride wash-out, obtaining the product (150mg) for white solid, is 2 kinds of mixture of isomers, separates through Chiralcell AD post, with 30% Virahol-hexane/0.2% diethylamine wash-out, obtain isomer C 60mg.Mass spectrum (FABS, MH ⁺) C ₃₈H ₄₄N ₅O ₃BrCl: calculated value: 734.2296; Measured value: 734.2304.Further wash-out obtains isomer D70mg.Mass spectrum (FABS, MH ⁺) calculated value: 734.2296; Measured value: 734.2305.

Embodiment 79

Steps A

According to the method for embodiment 78 steps A, remove the BOC group of the isomer C product of step B, obtain isomer C target product (mass spectrum, MH into white solid ⁺) FABS632.

Step B

In 0 ℃, (0.025ml, (25mg in methylene dichloride 0.039mmol) (3ml) solution, stirred 30 minutes in 20 ℃ then 0.19mmol) to add to isomer A (embodiment 78 steps A) with NSC 87419.Add methylene dichloride (20ml) and water (20ml).Separate organic layer, through dried over mgso, filter and evaporating solvent, obtain residue, it through silica gel column chromatography, is used 2%v/v methyl alcohol: the methylene dichloride wash-out obtains the product (isomer A) into white solid: high resolution mass spec (ES) C ₄₀H ₄₇O ₂N ₆ClBr calculated value: 757.2632 (Br=79), measured value: 757.2643.

According to aforesaid method, but replace isomer A, obtain target product (isomer B) with the isomer B (embodiment 78 steps A) of equivalent.Mass spectrum (FABS, HRMS) calculated value: 759.2612 (Br=81), measured value: 759.2626.

According to aforesaid method, but replace isomer A, obtain the target product isomer C with the isomer C (embodiment 79 steps A) of equivalent.Mass spectrum (ES, MH ⁺) 757 (Br=79).

According to aforesaid method, still, obtain isomer mixture into target compound C and D with the mixture (deriving from the product 1 of embodiment 78 steps A) of isomer C and D.Mass spectrum (ES, MH ⁺) 757.

Embodiment 80

In 20 ℃, (0.1ml, (20mg is in methylene dichloride 0.03mmol) (2ml) solution 1.04mmol) to add to isomer A (embodiment 78 steps A) with chloro ethyl formate.Add triethylamine (0.1ml, 0.7mmol), in 20 ℃ with this solution stirring 30 minutes.Evaporating solvent, residue are through silica gel column chromatography, and use the 3%v/v methyl alcohol that contains 2% ammonium hydroxide: the methylene dichloride wash-out obtains the isomer A product (20mg) into white solid.Mass spectrum (ES, MH ⁺) 704.

According to aforesaid method, but replace isomer A, obtain target product isomer B with the isomer B (embodiment 78 steps A) of equivalent.Mass spectrum (ES, MH ⁺) 704; HRMS (ES) calculated value: 704.2003 (Br=79), measured value: 704.2012.

Embodiment 81-85

According to the method for embodiment 127 and 80, but adopt the target compound of preparation embodiment 9.1 or 111.1 and suitable isocyanic ester or carbonochloridic acid ester, obtain the compound of following formula:

R wherein ⁸And R ¹⁴Identical with table 10 definition.

Table 10

The compound that separates embodiment 83 and 84 through Chiralcell AD post.

Embodiment 86

According to the method for embodiment 77-79, but 1-(3-aminopropyl) imidazoles with a great deal of replaces preparing the imidazoles that the N-benzyl among the embodiment 74 replaces in embodiment 77, obtains target compound.

11S-isomer: mass spectrum (FABS, MH ⁺) 667 (Br=79) HRMS (MH) C ₃₃H ₄₁N ₆O ₂Cl (81) Br calculated value: 669.2142: measured value: 669.2151.

11R-isomer: FABS (MH ⁺) 667.

Embodiment 86A

Adopt the imidazoles of preparation embodiment 1 step D, and, obtain following compounds according to the method for embodiment 77 and embodiment 79 steps A:

Method according to embodiment 79 step B makes this compound and NSC 87419 reaction then.Mass spectrum (FABS, MH) 695 (Br=79) 669.2142.

Embodiment 87-97

According to embodiment 77-80 method, but adopt 11 (R)-isomer, obtain following formula: compound: R wherein ¹⁴Identical with definition in the table 11.

Table 11

Embodiment 98

The product (0.6g) of preparation embodiment 45 is dissolved in the 6ml methylene dichloride, adds the 6ml trifluoroacetic acid, reaction mixture was stirred 2 hours.After 2 hours,, obtain oily matter with the reaction mixture evaporation.This oily matter is dissolved in N, in the dinethylformamide, the adding triethylamine (0.445ml 3eq.), adds 3-bromo-8,11-two chloro-6, and (0.39g 113mmol), stirs this reaction mixture 24 hours 11-dihydro-5H-benzo [5,6] ring [1,2-b] pyridine in heptan.Reaction mixture is added in the salt solution, with product extraction 3 times, obtains crude product oily matter after the solvent evaporated under reduced pressure with ethyl acetate, with it through purification by silica gel column chromatography, with 2% → 4% ethanol/methylene as eluent.Merge the component that contains product, obtain the pure product target of 0.34g compound.Is pure product enantiomeric form through ChiralTechnologies AD post HPLC with compound separation, with 20% isopropanol/hexane wash-out.Isomer 1:mp=148.3-157.5 ℃; Isomer 2:mp=148.3-157.5 ℃.

Embodiment 99

The product (0.487g) of preparation embodiment 48 is dissolved in the 3ml methylene dichloride, adds the 3ml trifluoroacetic acid, reaction mixture was stirred 2 hours.Reaction mixture is evaporated to dried, be dissolved in 10ml N, in the dinethylformamide, add triethylamine (1.42ml, 10eq.), add 3-bromo-8,11-two chloro-6,11-dihydro-5H-benzo [5,6] encircle heptan [1,2-b] (0.45g 1.2eq), stirs this reaction mixture 24 hours pyridine (compound number 42.0).Reaction mixture is added in the salt solution, with product extraction 3 times, obtains crude product oily matter after the solvent evaporated under reduced pressure with ethyl acetate, with it through purification by silica gel column chromatography, with 2% → 4% ethanol/methylene as eluent.Merge the component that contains product, obtain the pure product target of 0.26g compound, be mixture of isomers.With isomer separation, use 20%-30% isopropanol/hexane wash-out through Chiral Technologies AD post HPLC.Isomer 1:mp=192.7-194.3 ℃; Isomer 2:mp=189.2-190.7 ℃.

Embodiment 100

The target compound of stirring preparation embodiment 52 in the mixture of 10ml methylene dichloride and 15 μ l water (0.3g, 0.5mmol), adding Dess-Martin Periodinane (0.32g, 1.5eq), stirred reaction mixture under room temperature.After 24 hours, with 20% hypo solution and sodium hydrogen carbonate solution washing reaction mixture successively, vacuum-evaporation is to doing.Compound is dissolved in the methylene dichloride, in reaction mixture, adds premixed 4-iodo-1-trityl-imidazoles (89mg) and ethylmagnesium bromide (3M diethyl ether solution, 66 μ l) solution, under room temperature, stirred 4 hours.Reaction mixture is inclined to saturated ammonium chloride solution, use the dichloromethane extraction product, obtain the crude product product, through preparation property TLC purifying, through going protection with TFA and with (BOC) ₂O obtains the 52mg target compound after introducing the Boc group.

Embodiment 101-102

According to the described similar method of embodiment 98-100, obtain following compounds:

The target compound of preparation embodiment 58 is dissolved in the 1ml methylene dichloride, adds 68 μ l tertiary butyl isocyanic ester, stir this reaction mixture.Evaporation reaction mixture obtains the crude product product, stirs in 33%HBr/HOAc, adds in the ether, is collected as the product of brown solid and behind the preparation of lamina chromatography, obtains the 20mg target product.FABMS?M＋1＝659。

Embodiment 104

The target compound (50mg) of embodiment 103 is dissolved in the 5ml methylene dichloride, adds the 0.5ml diacetyl oxide.After 18 hours reaction mixture is evaporated to driedly,, obtains the pure product target of 39mg product through preparation property TLC chromatography.FABMS?MH ⁺＝699。

Embodiment 105

According to preparation embodiment 52 described essentially identical methods, but replace 1-amino-3-propyl alcohol with 1-(3-aminopropyl)-2-aminooimidazole, the preparation target compound, the productive rate with 65% obtains target product.FABMS?MH ⁺＝660。

Embodiment 106

According to embodiment 104 described methods, still replace the target compound of embodiment 103, and replace diacetyl oxide with trifluoroacetic anhydride with the target compound of preparation embodiment 105, the preparation target compound obtains pure product target product.FABMS?MH ⁺＝756。

Embodiment 107

According to embodiment 104 described methods, but replace diacetyl oxide, obtain pure product target product with trifluoroacetic anhydride.FABMS?MH ⁺＝755。

Embodiment 108

According to embodiment 110 described methods, but replace the target compound of preparation embodiment 102 step C and replace NSC 87419 with tert-butyl isocyanate with the target compound of preparation embodiment 60, the preparation target compound obtains pure product target product.FABMS?MH ⁺＝688。

Embodiment 109

According to preparation embodiment 52 described methods, but use 2-S-benzyl-3-R, S-hydroxyl-histamine replaces 1-amino-3-propyl alcohol, the preparation target compound.FABMS?MH ⁺＝737。

Embodiment 110

With the target compound of preparation embodiment 102 step C (0.28g, 2mmol), the target compound of preparation embodiment 44 (0.5g, 2mmol) and the mixture of anhydrous methylene chloride (5ml) under room temperature, stirred 15 minutes.(0.51ml 4mmol), stirs this reaction mixture 48 hours under room temperature to add NSC 87419.The vacuum concentration reaction mixture, (10ml dilutes residue, stirs under room temperature and spends the night to use methylene dichloride (10ml) and trifluoroacetic acid.The mixture that vacuum concentration produces, with dry DMF (5ml) dilution, to wherein add N-methylmorpholine (2.2ml, 20mmol) and tricyclic chloride (compound number 42.0) (0.83g, 2mmol).Under room temperature the reaction mixture stirring is spent the night, vacuum concentration is through silica gel rapid column chromatography purifying, with the saturated 5% methyl alcohol-95% dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtain target compound (brown solid, 95mg into non-enantiomer mixture, 7%, MH ⁺=682, mp=118.4 ℃).

Embodiment 111

According to preparing similar method,, obtain target compound (brown, sticking solid, 28.7mg, 2%, MH into non-enantiomer mixture still with the target compound of preparation embodiment 103 with the target compound that is used for embodiment 110 ⁺=696, mp=79.3 ℃).

Embodiment 112

According to preparing similar method, still, obtain target compound (brown solid, 18.5mg, 1%, MH into non-enantiomer mixture with the target compound of preparation embodiment 104 with the target compound that is used for embodiment 110 ⁺=710, mp=63.8-67.4 ℃).

Embodiment 113

Target compound (10.04g to preparation embodiment 51, add 19mmol) HOBT (3.34g, 25mmol), DEC (4.79g, 25mmol), the target compound (4.32g of preparation embodiment 74,20mmol), NMM (5.5ml, 50mmol) and dry DMF (20ml).Under room temperature, nitrogen this mixture stirring is spent the night, this mixture of vacuum concentration is with the methylene dichloride dilution, with saturated sodium bicarbonate aqueous solution washing.Through the anhydrous magnesium sulfate drying organic phase, separate and vacuum concentration.Residue with the saturated 2% methyl alcohol-98% dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtains target compound (4.92g, 36%, MH into non-enantiomer mixture through silica gel rapid column chromatography purifying ⁺=733).

Embodiment 114

Adopt embodiment 113 described methods, but, can obtain required compound with the imidazolyl alkylamine that following N-replaces.

Embodiment 115-126

Adopt embodiment 113 described methods, but use the imidazolyl alkylamine (imidazoles) of the N-replacement in the table 12 and the carboxylic acid of preparation embodiment 51, can obtain the product of table 12.

Table 12

Embodiment 127

To the target compound of preparation embodiment 109 (11R, 2R diastereomer B, 1.7g, add in anhydrous methylene chloride 2.7mmol) (10ml) solution NSC 87419 (0.38ml, 2.9mmol), under room temperature, nitrogen with the solution stirring that obtains 1.5 hours.Vacuum concentrated solution through silica gel rapid column chromatography purifying, with the saturated 2% methyl alcohol-98% dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtains target compound (1.98g, 84%, MH into faint yellow solid ⁺=758).

Embodiment 128-148

Adopt embodiment 127 described methods, but, obtain the product in the table 13 with the compound of the isocyanic ester in the table 13 with preparation embodiment.

Table 13

Embodiment 149

Target compound (11S, 2R diastereomer A, 50mg to preparation embodiment 109,0.08mmol) anhydrous methylene chloride (1ml) solution in add Benzoyl chloride (0.02ml, 0.16mmol) and triethylamine (0.03ml 0.2mmol), spends the night the solution stirring that obtains under room temperature, nitrogen.Dilute this solution with methylene dichloride, wash with the 1N aqueous sodium hydroxide washes, through anhydrous magnesium sulfate drying.Filter and vacuum concentration, obtain residue, it through preparation property silica-gel plate chromatography purification, with the saturated 5% methyl alcohol-95% dichloromethane solution wash-out of ammonium hydroxide aqueous solution, is obtained target compound (54.4mg, 93%, MH into pale solid ⁺=737).SCH

Embodiment 150-217

Adopt and embodiment 149 described similar methods, with the target compound (diastereomer A or B) of the preparation embodiment in the corresponding acyl chlorides that provides in the table 14, carbonochloridic acid ester, urea chloride, two carbonic ethers, acid anhydrides or SULPHURYL CHLORIDE (electrophilic reagent hurdle) processing list 14, obtain listing in aralkyl or heteroarylalkyl product that the N-in the table 14 replaces.

Table 14

Embodiment 218

According to embodiment 149 described methods, make the preparation embodiment 109 target compound (diastereomer A) with

Reaction obtains compound

Embodiment 219

According to the method for embodiment 149, make the preparation embodiment 109 target compound (diastereomer A) with Reaction obtains compound

Embodiment 220

According to the method for preparing embodiment 51, but with 3,8-dichloro tricyclic alcohol Replace the 3-Br-8-Cl tricyclic alcohol, can prepare following compound

If adopt the method for embodiment 113, above-claimed cpd and the target compound of preparation embodiment 95.1 are reacted, then obtain following compound:

If adopt the method for preparing embodiment 109, use above-claimed cpd, can obtain following compound:

If adopt the method for embodiment 149, use above-claimed cpd and compound: , can obtain following compound:

Embodiment 220A

If adopt the method for embodiment 220, but in the step of embodiment 113, replace the target compound of preparation embodiment 95.1, then can obtain following compound with the target compound for preparing embodiment 90:

Embodiment 221

Target compound (11S to preparation embodiment 109,2R diastereomer A, 75mg, 0.12mmol) be dissolved in the solution in the dry DMF (1ml) and add HOBT (32mg, 0.24mmol), DEC (45.4mg, 0.24mmol) and isovaleric acid (0.026ml 0.24mmol), will obtain solution stirring and spend the night under room temperature, nitrogen.This solution of vacuum concentration with the methylene dichloride dilution, is washed with the 1N aqueous sodium hydroxide washes, through anhydrous magnesium sulfate drying.Filter and vacuum concentration, obtain residue,,, obtain target compound (81.5mg, 96%, MH into pale solid with the saturated 5% methyl alcohol-95% dichloromethane solution wash-out of ammonium hydroxide aqueous solution through preparation property silica-gel plate chromatography purification ⁺=717).

Embodiment 222-224

According to embodiment 221 described methods, the target compound (diastereomer A or B) with the carboxylic acid Processing of Preparation embodiment 109 in the table 15 obtains the N-benzyl product in the table 15.

Table 15

Embodiment 225

Target compound (11S to preparation embodiment 127 step C, 2R diastereomer A, 1.73g, 3.57mmol) the middle HOBT (0.689g that adds, 5.1mmol), DEC (0.98g, 5.1mmol), the target compound of preparation embodiment 95.1 (0.9g, 3.9mmol), NMM (0.87ml, 7.9mmol) and dry DMF (20ml).Under room temperature, nitrogen, the mixture stirring that obtains is spent the night.This mixture of vacuum concentration, with the methylene dichloride dilution, the sodium bicarbonate aqueous solution washing with saturated separates organic phase, through anhydrous magnesium sulfate drying.Filter and vacuum concentration, residue with the saturated 2% methyl alcohol-98% dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtains target compound (1.7g, 69%, MH through silica gel rapid column chromatography purifying ⁺=695).

Embodiment 226-232

According to embodiment 225 described methods, imidazolyl alkylamine with the carboxylic acid (diastereomer A) of preparation embodiment 127 step C and suitable N-replacement, through preparation property chirality chromatography (Chiralpack AD, 5cm * 50cm post, flow velocity 80ml/min, 5-13% IPA-hexane+0.2% diethylamine), obtain product listed in the following table 16.

Table 16

Embodiment 234B

According to the method for embodiment 225, but adopt the amine for preparing embodiment 101.2, obtain following compound:

Embodiment 235

Target compound (0.184g with preparation embodiment 51,0.35mmol) add to the target compound (0.2g of preparation embodiment 132 step C, 0.437mmol), DEC (0.168g, 0.87mmol), HOBT (0.118g, 0.87mmol) and NMM (0.22g is in DMF 2.19mmol) (10ml) solution.Under room temperature, will obtain solution stirring 24 hours.Dilute with water reaction mixture to precipitation stops, and filters slurry.With methylene dichloride dilution precipitation, use the salt water washing, through dried over sodium sulfate and concentrated.The crude product product is through chromatography purification, as eluent, obtains target compound (0.18g, 42% productive rate) with the dichloromethane solution of 5% (methanol solution of 10% ammonium hydroxide).

Embodiment 236-238

According to embodiment 235 described essentially identical methods, but with the amine in the table 18, obtain the compound of following formula:

Wherein Z is identical with definition in the table 18:

Table 18

Embodiment 239

Steps A

Under room temperature, (0.5g, methylene dichloride 0.517mmol) (50ml) solution stir with trifluoroacetic acid (6ml) and spend the night with the target compound of embodiment 235.Evaporation reaction mixture obtains the target compound (0.743g) into trifluoroacetate, uses it in the following reaction.

Step B

To the target compound of the steps A that stirs (0.102g, 0.0936mmol), triethylamine (0.0798g, (0.0515g, 0.236mmol), spend the night to add tert-Butyl dicarbonate in dichloromethane solution 0.798mmol) by stirring.Evaporation obtains residue, spends the night stirring in its methanol solution at 2N ammonia (2ml), is evaporated to dried.Residue with 5% (methanol solution of 10% dense ammonium hydroxide) wash-out, obtains target compound (0.043g) through silica gel column chromatography.

Embodiment 240-243

According to the described essentially identical method of embodiment 239 step B, but with the carbonochloridic acid ester in the following table 19, obtain following formula: compound: R wherein ¹⁴Identical with definition in the table 19.

Table 19

Embodiment 244

To the target compound of embodiment 239 steps A (0.126g, 0.126mmol), triethylamine (0.071g, add in methylene dichloride 0.726mmol) (5ml) solution tert-butyl isocyanate (0.018g, 0.189mmol).To obtain solution stirring under room temperature spends the night.Be evaporated to driedly, in the methanol solution (3ml) of 2N ammonia, residue stirred then and spend the night.Be evaporated to driedly, residue with 5% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride wash-out, obtains target compound (0.046g) through silica gel column chromatography.CIMS：m/z(MH ⁺)732。

Embodiment 245-254

According to embodiment 77-79 and 86 described methods, but adopt diastereomer A and the mixture of B and the suitable amido imidazoles for preparing embodiment 135, obtain following compound:

Embodiment 255-278

According to embodiment 127 described methods, the target compound (diastereomer A or B or A+B) with the preparation embodiment in the corresponding isocyanate processing following table 20 obtains the listed urea product of table 20.

Table 20

Embodiment 279-286

According to embodiment 149 described methods, target compound (diastereomer A or B or A+B) with the preparation embodiment in corresponding acyl chlorides, carbonochloridic acid ester, urea chloride, two carbonic ethers, acid anhydrides or the SULPHURYL CHLORIDE processing list 21 obtains the listed product of table 21.

Table 21

Embodiment 287-289

According to embodiment 221 described methods, the target compound (diastereomer A or B or A+B) with preparation embodiment listed in the corresponding carboxylic acid processing following table 22 obtains the listed product of table 22.

Table 22

Embodiment 290

Under room temperature, will be dissolved in target compound (0.59g, solution stirring 1.15mmol) 3 hours of the preparation embodiment 143 in anhydrous methylene chloride (10ml) and the trifluoroacetic acid (2ml).The solution that vacuum concentration obtains, with residue and anhydrous methylene chloride (10ml), tricyclic chloride (compound number 42.0) (0.474g, 1.38mmol) and triethylamine (1.61ml 11.5mmol) mixes, and stirs 12 hours in 25-40 ℃.The vacuum concentration reaction mixture through quick post of silica gel and preparation property plate layer chromatography purifying, with the saturated 1-4% methyl alcohol-dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtains target compound (457mg, 55%, MH ⁺=718).

Embodiment 291-297

According to preparation embodiment 290 described methods, the piperazine of the BOC-protection below adopting in the table 23 is prepared as the tricyclic compound in the table 23 of non-enantiomer mixture.Separate diastereomer, separate, obtain diastereomer A and diastereomer B through preparation property chirality chromatography (Chiralpack AD, 5cm * 50cm post, flow velocity 80ml/min, 7-12% Virahol-hexane+0.2% diethylamine).

Table 23

Embodiment 299

Steps A

(0.30g, (0.09ml 0.7mmol), will obtain solution stirring 30 minutes, then vacuum concentration to preparation embodiment 155 step F in being dissolved in anhydrous methylene chloride (3ml) under room temperature 0.67mmol) to add NSC 87419 in the solution.Dilute the residue that obtains with methylene dichloride (3ml) and trifluoroacetic acid (3ml).Under room temperature solution stirring is spent the night, vacuum concentration with the methylene dichloride dilution, washs with 1N hydrogen sodium hydride aqueous solution then.Through the anhydrous magnesium sulfate drying organic phase, filter and vacuum concentration, obtain yellow foam (0.319g, 100%, MH ⁺=473).

Step B

Target compound (the 0.212g of above-mentioned steps A in being dissolved in anhydrous methylene chloride (10ml), 0.45mmol) add tricyclic chloride (compound number 42.0) (0.154g in the solution, 0.45mmol) and triethylamine (0.32ml, 2.25mmol), in 25 ℃ of stirrings 48 hours.The vacuum concentration reaction mixture through preparation property silica-gel plate chromatography purification, with the saturated 5% methyl alcohol-dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtains target compound (125mg, 35%, mp=114.8 ℃, MH ⁺=778).

Embodiment 300

According to the method described in embodiment 299 steps A-B, prepare product listed in the following table 24 with corresponding piperazine among the specified preparation embodiment.

Table 24

Embodiment 302

Steps A

In 25 ℃, with the target compound of preparation embodiment 162 (400mg, 1.86mmol), the acid anhydrides of preparation embodiment 44 (561mg, 2.19mmol) and anhydrous methylene chloride (10ml) stirring 3 hours, add then tert-butyl isocyanate (0.26ml, 2.19mmol).After 12 hours, this mixture of vacuum concentration with the methylene dichloride dilution, washes with water.Through the anhydrous sodium sulfate drying organic phase, separation also concentrates.Foam with anhydrous methylene chloride (10ml) and trifluoroacetic acid (10ml) dilution produce stirred 3 hours.Vacuum concentration with methylene dichloride dilution, with 1N sodium hydroxide (the 0.5M aqueous solution) washing, obtains organic solution, through anhydrous sodium sulfate drying, filters, and concentrates and without being further purified use (181mg, 27%, MH ⁺=431.5).

Step B

The target compound of the steps A in being dissolved in anhydrous methylene chloride (10ml) (170mg, 0.39mmol) add in the solution tricyclic chloride (compound number 42.0) (175mg, 0.51mmol) and triethylamine (71 μ l 0.51mmol), stirred 48 hours in 25 ℃.The vacuum concentration reaction mixture through preparation property silica-gel plate chromatography purification, with the saturated 5% methyl alcohol-dichloromethane solution wash-out of ammonium hydroxide aqueous solution, obtains target compound (oily matter, 24mg, 8%, MH ⁺=736).

Embodiment 303

If according to the method for embodiment 302, and in steps A, adopt the target compound for preparing embodiment 162, then can obtain following compound:

Embodiment 304

According to the method described in the embodiment 58, but replace preparing the target compound of embodiment 25 with the target compound of this embodiment 165, can prepare target compound (51%, MH ⁺=711, mp=103.7-107.5).

Embodiment 305

Through HPLC (Chiracel AD post) target compound of embodiment 58 is separated into two diastereomers, with 10% Virahol-90% hexane-0.2% diethylamine wash-out, obtains 11 (R), 2 (R) and 11 (S), 2 (R) isomer.

Diastereomer A:MH+=697; Mp=103-108 ℃.

Diastereomer B:MH+=697; Mp=101-107 ℃.

Embodiment 306

According to embodiment 58 described methods, but adopt 11 (S) of preparation embodiment 164,2 (R) diastereomer replaces the target compound of preparation embodiment 51, obtain target compound (59%, MH ⁺=619, mp=100-114 ℃).

Embodiment 307

According to embodiment 306 described methods, but adopt the target compound of preparation embodiment 165 to replace the target compound of preparation embodiment 25, obtain target compound (73%, MH ⁺=633, mp=89.1-96.5 ℃).

Embodiment 308

According to embodiment 58 described methods, but adopt 11 (R) of preparation embodiment 164,2 (R) diastereomer replaces the target compound of preparation embodiment 51, replaces the target compound of preparation embodiment 25 with the target compound of preparation embodiment 165, obtain target compound (65%, MH ⁺=633, mp=89.1-96.5).

Embodiment 309

Add the racemic product (0.2g of hot preparation embodiment 141 down in refluxing, 0.368mmol), 4-(4-nitrophenoxy carbonyl) piperidines-1-methane amide (0.1706g, 0.552mmol) (preparation embodiment 36 step B) and Virahol (10ml), and heated 24 hours down in 87 ℃, ar gas environment.Solution evaporation to doing, is diluted residue with methylene dichloride,,, filter and be evaporated to dried through dried over mgso with saturated sodium bicarbonate aqueous solution and water washing.Residue as eluent, obtains target compound (0.057g, 22%) with 3%-6%-10% (methanol solution of 10% dense ammonium hydroxide)-methylene dichloride through silica gel column chromatography; FABMS:m/z 712.9 (MH ⁺); δ _C(CDCl ₃) CH ₂: 30.3,30.5,30.6,30.6,31.1,36.7,41.3,41.3,42.2,44.5,50.7/51.1,52.3; CH, 55.4,71.0,78.8 ,-118.9,126.3,129.4,130.5,132.5,137.0,141.4,147.1; C:120.2,134.3,135.0,137.0,141.3,155.2,155.2,158.0,170.2; δ _H(CDCl ₃) 4.31/4.32 (1H, s, H ₁₁), 4.56 (2H, broad peak s, NCONH ₂), 6.93 (1H, broad peak s, Im-H ₅), 7.07 (1H, broad peak s, Im-H ₄), 7.10-7.16 (3H, m, Ar-H), 7.48 (1H, m, Ar-H), 7.60 (1H, broad peak s, Im-H ₂) and 830ppm (1H, s, Ar-H ₂).

Embodiment 310-342

According to embodiment 225 described methods, adopt the carboxylic acid (diastereomer A or B) of preparation embodiment 127 step C and the imidazolyl alkylamine that suitable N-replaces, product in the preparation table 25.

Table 25

Embodiment 343-361

According to embodiment 40 described methods, the imidazolyl alkylamine that the mixture of the carboxylic acid of employing preparation embodiment 51 or pure product isomer (diastereomer A and/or B) and suitable N-replace replaces the amine of preparation embodiment 13, prepares listed product in the table 26.Through HPLC (Chiracel, AD post, 85/15 hexane/isopropyl alcohol) separated product.

Table 26

Embodiment 362-366

According to embodiment 225 described methods, but adopt the 11S of preparation embodiment 164,2R (+)-carboxylic acid replaces the product of preparation embodiment 127 step C and adopts the amine of the amine replacement preparation embodiment 95.1 of the replacement of indicated preparation embodiment in the table 27, the product of preparation table 27.

Table 27

Embodiment 367-374

According to embodiment 225 described methods, but adopt carboxylic acid listed in the following table 28 (diastereomer A or B) to replace deriving from the carboxylic acid of preparation embodiment 127 step C and suitable imidazolyl alkylamine (amine), listed product in the preparation table 28.

Table 28

Embodiment 375-382

Similarly, according to embodiment 149 described methods, with the target compound (diastereomer A or B) of the preparation embodiment in the carbonochloridic acid cyclohexyl processing list 29, the product of preparation table 29.

Table 29

Embodiment 383-392

According to embodiment 149 described essentially identical methods; with the target compound (diastereomer A or B) of suitable acylating agent (being carbonochloridic acid cyclohexyl or Boc two carbonic ethers, NSC 87419, tert-butyl isocyanate or carbonochloridic acid isobutyl ester) Processing of Preparation embodiment 170, obtain the compound of following formula: R wherein ¹Definition in table 30 hurdle 2 is identical.

Table 30

Embodiment 393

Steps A

If the acetoxyl group hexalin with light gas disposal market obtains can obtain the carbonochloridic acid ester.

Step B

If according to embodiment 149 described methods, the carbonochloridic acid ester of steps A is combined with the piperazine amine shown in top, can obtain acetic ester so.

Step C

If, obtain target compound so with the product of salt of wormwood treatment step B in methyl alcohol.

Embodiment 394

Steps A

If the hexalin with light gas disposal market obtains can obtain the carbonochloridic acid ester.

Step B

If according to embodiment 149 described methods, the carbonochloridic acid ester of steps A is combined with the piperazine amine shown in top, can obtain ketal so.

Step C

If handle the product of described step B with aqueous acid, obtain ketone so.

Step D

If the product with MeMgBr or MeLi treatment step C obtains target product so.

Embodiment 395

According to embodiment 225 described essentially identical methods (coupling), but only replace the acid of preparation embodiment 127 step C with the target compound of preparation embodiment 212, obtain target compound.Mp91-107℃，LCMS?MH ⁺＝695。

Embodiment 397

Steps A

If the muriate with the 3-bromo tricyclic chloride replacement preparation embodiment 127 step C that prepare embodiment 209 then can obtain carboxylic acid:

Step B

If basis and embodiment 225 used essentially identical methods, the carboxylic acid of employing steps A then can prepare target compound.With chirality HPLC (AD post), use Virahol-hexane as eluent, separable isomer.

Embodiment 398

Steps A

As adopt the 3-fluoro tricyclic chloride for preparing embodiment 211 to replace the muriate of preparation embodiment 127 step C, then will obtain carboxylic acid:

Step B

If basis and embodiment 225 described essentially identical methods, the carboxylic acid of employing steps A then can prepare target compound.With chirality HPLC (AD post), use Virahol-hexane as eluent, separable isomer.

Embodiment 399

Steps A

As adopt 3-fluoro-8-chloro tricyclic chloride replacement of preparation embodiment 204 to prepare the muriate of embodiment 127 step C, then will obtain carboxylic acid:

Step B

If basis and embodiment 225 described essentially identical methods, the carboxylic acid of employing steps A then can prepare target compound.With chirality HPLC (AD post), use Virahol-hexane as eluent, the separating isomerism body.

Measure

According to the described measuring method of nineteen ninety-five disclosed WO95/10516 on April 20, measure FPT IC ₅₀(restraining effect of farnesyl-protein transferase, vitro enzyme is measured) and COS cell IC ₅₀(based on the mensuration of cell).Measure GGPT IC according to the described method of WO95/10516 ₅₀(restraining effect of geranyl geranyl protein transferase, vitro enzyme is measured), cell Mat measures and anti-tumor activity (anti-tumor in vivo research).It is for referencial use to be incorporated herein the WO95/10516 disclosure.

According to carrying out other mensuration, still replace the T24-BAG cell with other indication tumor cell line with top described essentially identical method.Adopt to express the DLD-1-BAG human colon cancer cell of activated K-ras gene or express activated K-ras gene or SW620-BAG human colon cancer cell is measured.With other tumor cell lines known in the art, can prove that compound of the present invention suppresses the activity of the tumour cell of other types.

Soft agar is measured:

Fixedly the dependency growth is a feature of tumor cell line.Human tumor cells is suspended in the growth medium that contains 0.3% agarose and appointment farnesyl transferase inhibitor concentration.Described solution is laid on the 0.6% agarose solidified growth medium of using the farnesyl transferase inhibitor that contains same concentrations as the upper strata.After solidify on the upper strata, culture plate was hatched 10-16 days under 37 ℃, 5% carbon dioxide environment, make the colony growth.After hatching, be laid on the agar colony is dyeed with MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-phenylbenzene tetrazolium bromination, Thiazolyl blue) (in the 1mg/mlPBS solution) solution.Colony is counted, determined IC ₅₀Value.

Embodiment 1-19,21-25,67-71,72 step B, 72 step C, 73-77,78 step B (isomer C), 78 step B (isomer D), 79 step B (isomer A, B and C), 80 isomer A and B), 81-86,86A, 87,88,93-104,106,108,110-113,115-211,214-217,221-228,236-238,236-238,241-244,255-286,286A, 286B, 287-297,299 step B, 300,302 step B, the FPT IC of 305 and 309 compound ₅₀Value 20% during for＜0.05nm to 170nM.

Embodiment 1,2,6-13,15-17,19,78 step B (isomer D), 80 (isomer A), 67-71,72 step B, 72 step C, 73,76,81-86,87,88,93,95-101,103,106,108,110,111,113,115-118,121,122,124,125 (isomer A), 127-134,137,142,144-146,148,151-153,155-157,161-162,164,166,168,173-175,177,180-187,189-192,195-196,198-208,210-211,216-217,221,222,225,237,238,242-245,247-263,265,268-286,286A, 286B, 288-289,292,295-296,299 step B, 300,302 step B, 305,309,310-342, the FPT IC of the compound of 342-373 and 375-382 ₅₀Value is＜0.04nM to 6.7nM.

The FPT IC of embodiment 11,16,78 step B (isomer C and D), 79 step B (isomer A), 80 (isomer A), 88 (isomer A), 93 (isomer D), 99,100,225,243,367 and 368 compound ₅₀Value is＜0.04nM to 2.7nM.The FPT IC of the compound of embodiment 225 ₅₀Value is 0.36nM.

The Cos cell IC of embodiment 1,2,8,25,86,100 compounds ₅₀Value is in＜10-920nM scope.The Cos cell IC of embodiment 98,101,103,104,106,108,258,259,261 and 262 compounds ₅₀Value is＜5 to＞500nM.The Cos cell IC of embodiment 245-250 compound ₅₀Value is 100% when 0.01-0.087 μ M.The Cos cell IC of embodiment 100,101,103 and 259 compounds ₅₀Value is＜5nM-35nM.

The soft agar IC of embodiment 1,2,3,7,8,10-16,21,25,67-69,70,81,82,86 (11R, 2R isomer), 88-95,97,110,111-113,115-119,121-176,178-184,186-200,202-204,206-211,214-217,221-225,256,258,259,261,262,268-271,273-274,276,278,280-286,289,292,295-296,299 step B, 305,309-346,351-373 and 375-382 compound ₅₀Value is＜5-＞500nM.

The soft agar IC of embodiment 116,117,160,170,184,186-188,196-200,202-204,206-208,217,225,305 (11s, 2R isomer), 316,316,322,324,325,335,339,365,364,372,373,375 and 382 compounds ₅₀Value is 2-10nM.

The soft agar IC of embodiment 11,16,79 step B (isomer A), 80 (isomer A), 88 (isomer A), 93 (isomer D) and 225 compounds ₅₀Value is 2-300nM.The soft agar IC of embodiment 225 compounds ₅₀Value is 2nM.

When adopting compound pharmaceutical composition of the present invention, inertia, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, discrete particles, capsule, cachet and suppository.Powder and tablet can contain about 95% active ingredient of the 5-that has an appointment.Suitable solid carrier is known in the art, as magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar or lactose.Tablet, powder, cachet and capsule can be as being fit to oral solid dosage.The example of pharmaceutically acceptable carrier and various composition manufacturing method are at the Remington ' s of A.Gennaro (editor) Pharmaceutical Sciences, 18 editions (1990), Mack Publishing Co., Easton can find among the Pennsylvania.

Liquid absorption member comprises solution, suspension and emulsion.The example that can mention comprises water or water-propylene glycol solution that is used for the parenteral injection or oral liquid, suspension and the emulsion that adds sweeting agent and opalizer.Liquid absorption member also can comprise the solution of intranasal administration.

The aerosol formulation that is fit to suck comprises the solid of solution and powder type, it can be mixed as nitrogen with pharmaceutically acceptable carrier such as inertia pressurized gas.

Also be included in the preparation that is converted into the solid form that is used for oral or parenteral admin of liquid form at once with preceding.This type of liquid absorption member comprises solution, suspension and emulsion.

Compound of the present invention also can discharge through skin.Transdermal composition can be creme, lotion, aerosol and/or emulsion, it can be contained in this area and be usually used in the matrix or depot transdermal patch of this purpose.

Best described medicinal preparations is a unit dosage form.When being this type of form, described preparation can be further divided into the unitary dose of the suitable size of the active ingredient that contains an amount of (as obtaining the significant quantity of required purpose).

According to concrete application method, the amount of active compound can be at about 0.01mg between about 1000mg in the unit dose formulations, preferred about 0.01mg is between about 750mg, and more preferably from about 0.01mg is between about 500mg, and most preferably from about 0.01mg changes between about 250mg.

The actual dosage that adopts is decided with the severity of the disease of being treated with patient's needs.Those skilled in the art can easily determine dosage suitable under the particular case.For simplicity, per daily dose can be divided into several parts and administration as required in a day.

The dosage of The compounds of this invention and/or its pharmacy acceptable salt and administration frequency can be adjusted according to following factors by the attending doctor: the severity of age, patient's body situation and body weight and the disease for the treatment of.The recommended of oral administration is about 0.04mg/ days to about 4000mg/ days, divides 2-4 administration.

Although invention has been described in conjunction with specific embodiment, many additive methods, improvement and variation will be apparent to those skilled in the art.All these class methods, improvement and variation include within the scope of the present invention.

Claims (36)

1. A compound of the following formula or a pharmaceutically acceptable salt or solvate thereof: in: One of a, b, c and d represents N or N ⁺ O ⁻ , and the remaining a, b, c and d groups represent CR ¹ or CR ² ; or each a, b, c and d are independently selected from CR ¹ and CR ² ; X represents N or CH when the optional bond represented by the dashed line is absent, and X represents C when the optional bond is present; The dashed line between carbon atoms 5 and 6 represents an optional bond such that when a double bond is present, A and B independently represent -R ¹⁵ , halo, -OR ¹⁶ , -OCO ₂ R ¹⁶ or -OC(O) R ¹⁵ , when there is no double bond between carbon atoms 5 and 6, A and B independently represent H ₂ , -(OR ¹⁶ ) ₂ , H and halogenated, dihalogenated, alkyl and H, (alkyl ) ₂ , -H and -OC(O)R ¹⁵ , H and -OR ¹⁵ , =O, aryl and H, =NOR ¹⁵ or -O-(CH ₂ ) _p -O-, where p is 2, 3 or 4; Each R ¹ and each R ² is independently selected from H, halo, -CF ₃ , -OR ¹⁵ , -COR ¹⁵ , -SR ¹⁵ , -S(O) _t R ¹⁶ (where t is 0, 1 or 2 ), -N(R ¹⁵ ) ₂ , -NO ₂ , -OC(O)R ¹⁵ , -CO ₂ R ¹⁵ , -OCO ₂ R ¹⁶ , -CN, -NR ¹⁵ COOR ¹⁶ , -SR ¹⁶ C(O) OR ¹⁶ , -SR ¹⁶ N(R ¹⁷ ) ₂ (provided that R 16 in -SR ¹⁶ N ⁽ R ¹⁷ ) ₂ is not -CH ₂ -), wherein each R ¹⁷ is independently selected from H or -C(O )OR ¹⁶ , benzotriazol-1-yloxy, tetrazol-5-ylthio and substituted tetrazol-5-ylthio, alkynyl, alkenyl and alkyl, said alkyl or Alkenyl is optionally substituted by halo, -OR ¹⁵ or -CO ₂ R ¹⁵ ; R ³ and R ⁴ are the same or different, each independently represents H, R ¹ and R ² or any substituent in R ³ and R ⁴ together represent a saturated or unsaturated C ₅ -C fused to a benzene ring (ring III) ₇ rings; R ⁵ , R ⁶ and R ⁷ independently represent H, -CF ₃ , -COR ¹⁵ , alkyl or aryl, and the alkyl or aryl is optionally replaced by -OR ¹⁵ , -SR ¹⁵ , -S(O) _or ^{R _ _ _} _{_ _} ^{_ _} _{_} ^_ _{_} ^_ _{_} ^{_ 5} and R together represent = ^O or =S; ^R is selected from H, C ₃ -C ₄ alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl , substituted aralkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; The substituent of R ⁸ is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, -N(R ¹⁸ ) ₂ , -OR ¹⁸ , cycloalkylalkyl, halo, CN, -C(O)N (R ¹⁸ ) ₂ , -SO ₂ N(R ¹⁸ ) ₂ and -CO ₂ R ¹⁸ ; provided that the -OR ¹⁸ and -N(R ¹⁸ ) ₂ substituents are not attached to the -C(O)NR ⁸ moiety On the N-linked carbon; each R ^is independently selected from H, alkyl, aryl, aralkyl, heteroaryl, and cycloalkyl; R ⁹ and R ¹⁰ are independently selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and -CON(R ¹⁸ ) ₂ (wherein R ¹⁸ is as defined above) and the substituents ^R and ^R are optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aralkyl, and heteroarylalkyl; or R ⁹ and R ¹⁰ form a C ₃ -C ₆ cycloalkyl ring together with the carbon atoms they are connected to; R ¹¹ and R ¹² are independently selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R ¹⁸ ) ₂ , -OR ¹⁸ and -N(R ¹⁸ ) ₂ , wherein R ¹⁸ is the same as defined above; the premise is that -OR ¹⁸ and -N(R ¹⁸ ) ₂ are not connected to the carbon atom adjacent to the nitrogen atom; and wherein the substitutable R ¹¹ and R ¹² The group is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, aralkyl and heteroarylalkyl; or R ¹¹ and R ¹² form a C ₃ -C ₆ cycloalkyl ring together with the carbon atoms they are connected to; R ¹³ is an imidazolyl ring selected from the group consisting of:

or

Wherein R ^is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) aralkyl, (6) substituted aralkyl, wherein the substituent selected from halo and CN, (7)-C(aryl) ₃ and (8)cycloalkyl; The imidazolyl ring 2.0 is optionally substituted by one or two substituents, and the imidazolyl ring 4.0 is optionally substituted by 1-3 substituents, and the imidazolyl ring 4.1 is optionally substituted by one substituent, wherein The optional substituents of the rings 2.0, 4.0 and 4.1 are independently selected from: -NHC(O)R ¹⁸ , -C(R ³⁴ ) ₂ OR ³⁵ , -OR ¹⁸ , -SR ¹⁸ , F, Cl, Br, Alkyl, aryl, aralkyl, cycloalkyl, and -N(R ¹⁸ ) ₂ (wherein each R ¹⁸ is independently selected); wherein R ¹⁸ is the same as defined above; wherein R ³⁴ is independently selected from H and alkane group, R ³⁵ is selected from H, -C(O)OR ²⁰ and -C(O)NHR ²⁰ , R ²⁰ is as defined below; Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, and any of the Q is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, alkyl, aryl, -OR ¹⁸ , -N(R ¹⁸ ) ₂ (wherein each R ¹⁸ is independently selected), -OC (O)R ¹⁸ and -C(O)N(R ¹⁸ ) ₂ (wherein each R ¹⁸ is independently selected), and R ¹⁸ is the same as defined above; R ¹⁴ is selected from:

or ^R is selected from H, alkyl, aryl and aralkyl; R ¹⁶ is selected from alkyl and aryl; ^R is selected from H, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, heteroaryl, heteroarylalkyl and heterocycloalkyl, provided that when ^R is a group 5.0 or 8.0 , then R ²⁰ is not H; When R ²⁰ is not H, then said R ²⁰ group is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, -OC(O)R ¹⁸ , -OR ¹⁸ and -N(R ¹⁸ ) ₂ , wherein each R ¹⁸ is the same or different, and wherein R ¹⁸ is as defined above, provided that the optional substituent is not attached to a carbon atom adjacent to an oxygen or nitrogen atom superior; R ^is selected from H, alkyl, aryl, aralkyl, cycloalkyl, heteroaryl, heteroarylalkyl and heterocycloalkyl; When R ²¹ is not H, then said R ²¹ group is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, -OR ¹⁸ and -N(R ¹⁸ ) ₂ , wherein each R ¹⁸ is the same or different, and wherein R ¹⁸ is as defined above, provided that the optional substituent is not attached to a carbon atom adjacent to the oxygen or nitrogen atom; n is 0-5; For different n, each R ³² and R ³³ are independently selected from: H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R ¹⁸ ) ₂ , -OR ¹⁸ and =-N(R ¹⁸ ) ₂ , wherein R ¹⁸ is as defined above, and wherein the substituents R ³² and R ³³ are optionally substituted by one or more substituents selected from the group consisting of: alkyl radical, cycloalkyl, aralkyl and heteroarylalkyl; or R ³² and R ³³ form a C ₃ -C ₆ cycloalkyl ring together with the carbon atoms they are connected to; ^R is selected from branched chain alkyl, straight chain alkyl, cycloalkyl, heterocycloalkyl and aryl; and The premise is: (1) When R ¹⁴ is selected from: groups 6.0, 7.0, 7.1 and 8.0, and X is N, then R ⁸ is selected from C ₃ -C ₁₀ alkyl, substituted C ₃ -C ₁₀ alkyl, arane radical, substituted aralkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, and substituted cycloalkylalkyl; and (2) When ^R14 is selected from: groups 6.0, 7.0, 7.1 and 8.0, and X is N and ^R8 is H, then the alkyl chain between ^R13 and the amide moiety is substituted. 2. The compound of claim 1 having the following structure:

or

3. The compound of claim 1, wherein R ¹ -R ⁴ are independently selected from H, Br and Cl, R ⁵ -R ⁷ are H, a is N, and the remaining b, c and d substituents are carbon; or a, b, c and d are carbon, A and B are H ₂ , n is 0 or 1, R ¹³ is a group 2.0 or 4.0. 4. The compound of claim 1, wherein (a) ^R is selected from aralkyl, substituted aralkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl and substituted heteroarylalkyl; (b) R ⁹ and R ¹⁰ are independently selected from H, alkyl, -C(O)N(R ¹⁸ ) ₂ and aralkyl; (c) R ¹¹ and R ¹² are independently selected from H, alkyl, substituted aryl, -OR ¹⁸ , or R ¹¹ and R ¹² form a cycloalkyl ring together with the carbon atoms to which they are attached; (d) R ³² and R ³³ are independently selected from H, -OR ¹⁸ , aralkyl and aryl; (e) R ¹⁹ is selected from -C(O)N(R ¹⁸ ) ₂ , alkyl, aralkyl and -C(aryl) ₃ ; and (f) said optional R ¹³ substituent is selected from -N(R ¹⁸ ) ₂ , -NHC(O)R ¹⁸ , -C(R ³⁴ ) ₂ OR ³⁵ , alkyl and hydroxyl substituted cycloalkyl, Provided that the hydroxy substituent is not attached to a carbon atom adjacent to the oxygen atom. 5. The compound of claim 1, wherein R ¹⁴ is (a) 5.0, R ^is selected from alkyl, aralkyl, heterocycloalkyl, aryl, haloaryl, cycloalkyl and alkyl-substituted cycloalkyl; (b) 6.0, wherein R and ^R are independently selected from H, cycloalkyl, alkyl, aryl ^and aralkyl; (c) 7.0, wherein R ²⁰ is selected from heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkyl substituted by -C(O)N(R ¹⁸ ) ₂ ; (d) 7.1, wherein R is selected from ^cycloalkyl and heterocycloalkyl; or (e) 8.0, wherein R ²⁰ is selected from alkyl and cycloalkyl. 6. The compound of claim 1, wherein (a) R ¹ -R ⁴ are independently selected from H, Br and Cl; (b) ^R5 - ^R7 is H; (c) a is N and the remaining b, c and d substituents are carbon; (d) A and B are _H2 ; (e) n is 0 or 1; (f) R ¹³ is group 2.0 or 4.0, and said optional R ¹³ substituent is selected from -N(R ¹⁸ ) ₂ , -NHC(O)R ¹⁸ , -C(R ³⁴ ) ₂ OR ³⁵ and alkyl; (g) R is selected from ^aralkyl , substituted aralkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl and substituted heteroarylalkyl; (a) R ⁹ and R ¹⁰ are independently selected from H, alkyl, -C(O)N(R ¹⁸ ) ₂ and aralkyl; (h) R ¹¹ and R ¹² are independently selected from H, alkyl, substituted aryl, -OR ¹⁸ , or R ¹¹ and R ¹² form a cycloalkyl ring together with the carbon atoms to which they are attached; (i) R ¹¹ and R ¹² are independently selected from H, alkyl, substituted aryl, -OR ¹⁸ , or R ¹¹ and R ¹² form a cycloalkyl ring together with the carbon atoms to which they are attached; (j) X is CH or N; (k) R ¹⁹ is selected from -C(O)N(R ¹⁸ ) ₂ , alkyl, aralkyl and -C(aryl) ₃ ; (1) R in ^5.0 is selected from (1) alkyl, (2) aralkyl, (3) heterocycloalkyl, (4) aryl, (5) halogenated aryl, (6) ring Alkyl, (7) alkyl-substituted cycloalkyl and (8)-OC(O)R ¹⁸ or hydroxyl-substituted cycloalkyl, provided that the hydroxyl group is not attached to a carbon atom adjacent to the oxygen atom; (m) for ^6.0 , R and ^R are independently selected from H, cycloalkyl, alkyl, aryl and aralkyl; (n) R ²⁰ in 7.0 is selected from heteroaryl, cycloalkyl, alkoxy, heterocycloalkyl substituted by -C(O)N(R ¹⁸ ) ₂ ; (o) R in 7.1 is selected from ^{heterocycloalkyl} and cycloalkyl; R in (p) ^8.0 is selected from alkyl and cycloalkyl; and (q) R ³² and R ³³ are independently selected from H, -OR ¹⁸ , aralkyl and aryl. 7. The compound of claim 6, wherein (a) R ^is selected from aralkyl, cycloalkylalkyl and heteroarylalkyl; (b) R ^{and R} are independently selected from H and benzyl; (c) R ¹¹ and R ¹² are independently selected from H, -CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -(CH ₂ ) ₃ CH ₃ , benzyl, ethyl, p-chlorophenyl, hydroxyl, Or R ¹¹ and R ¹² form a cyclopropyl ring together with the carbon atoms to which they are attached; (d) R and ^R are independently selected from H, phenyl, ^hydroxy and benzyl; (e) R ¹⁹ is selected from -C(O)NH-cyclohexyl, -C(phenyl) ₃ , H, methyl and ethyl; (f) The optional R ¹³ substituent is selected from -CH ₃ , -CH ₂ OH, -CH ₂ OC(O)O-cyclohexyl, -CH ₂ OC(O)O-cyclopentyl, ethyl , isopropyl, amino and -NHC(O)CF ₃ ; (g) R ²⁰ in group 5.0 is selected from tert-butyl, ethyl, benzyl, -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -(CH ₂ ) ₂ CH ₃ , n- Butyl, n-hexyl, n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl,

or

(h) R ²⁰ and R ²¹ in 6.0 are selected from cyclohexyl, tert-butyl, H, -CH(CH ₃ ) ₂ , ethyl, -(CH ₂ ) ₂ CH ₃ , phenyl, benzyl, (CH ₂ ) ₂ phenyl and -CH ₃ ; (i) R ²⁰ in 7.0 is selected from 4-pyridyl NO, -OCH ₃ , -CH(CH ₃ ) ₂ , tert-butyl, H, propyl, cyclohexyl and

(j) R in 7.1 is selected from ^cyclohexyl , cyclopentyl, cyclobutyl, cyclopropyl and or

and R in (k) ^8.0 is selected from methyl, isopropyl and cyclohexylmethyl. 8. The compound of claim 7, wherein R ⁸ is selected from benzyl, -CH ₂ C(CH ₃ ) ₂ , -CH ₂ -cyclohexyl, -CH ₂ -cyclopropyl, -(CH ₂ ) ₂ CH ₃ ,

or

9. The compound of claim 8, wherein (a) R ⁸ is selected from benzyl and -CH ₂ -cyclopropyl; (b) R in 5.0 is ^cyclohexyl ; (c) R in 6.0 ²⁰ is selected from tert-butyl, isopropyl and cyclohexyl; R ²¹ is selected from H, methyl and isopropyl; (d) R in 7.0 is selected from ^cyclohexyl , cyclopentyl and isopropyl; (e) R in 7.1 is selected from ^cyclopropyl , cyclobutyl, cyclopentyl and cyclohexyl; and (d) R ²⁰ in 80 is methyl. 10. The compound of claim 9, wherein said compound is the 2R isomer. 11. The compound of claim 1, wherein R ⁸ is H, and the alkyl chain between the amide substituent -C(O)NR ⁸ and R ¹³ is substituted. 12. The compound of claim 1, wherein when ^R is a group 5.0, X is N, and R is ^H , then (a) the alkyl chain between R ^and the amide moiety is substituted and/or (b ) R ⁹ and R ¹⁰ and/or R ¹¹ and R ¹² together form a cycloalkyl ring. 13. A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof:

in One of a, b, c and d represents N or N ⁺ O ⁻ , and the remaining a, b, c and d groups represent CR ¹ or CR ² ; or each a, b, c and d are independently selected from CR ¹ and CR ² ; X represents N or CH when the optional bond represented by the dashed line is absent, and X represents C when the optional bond is present; The dashed line between carbon atoms 5 and 6 represents an optional bond such that when a double bond is present, A and B independently represent -R ¹⁵ , halo, -OR ¹⁶ , -OCO ₂ R ¹⁶ or -OC(O) R ¹⁵ , when there is no double bond between carbon atoms 5 and 6, A and B independently represent H ₂ , -(OR ¹⁶ ) ₂ , H and halogenated, dihalogenated, alkyl and H, (alkyl ) ₂ , -H and -OC(O)R ¹⁵ , H and -OR ¹⁵ , =O, aryl and H, =NOR ¹⁵ or -O-(CH ₂ ) _p -O-, where p is 2, 3 or 4; Each R ¹ and each R ² is independently selected from H, halo, -CF ₃ , -OR ¹⁵ , -COR ¹⁵ , -SR ¹⁵ , -S(O) _t R ¹⁶ (where t is 0, 1 or 2 ), -N(R ¹⁵ ) ₂ , -NO ₂ , -OC(O)R ¹⁵ , -CO ₂ R ¹⁵ , -OCO ₂ R ¹⁶ , -CN, -NR ¹⁵ COOR ¹⁶ , -SR ¹⁶ C(O) OR ¹⁶ , -SR ¹⁶ N(R ¹⁷ ) ₂ (provided that R 16 in -SR ¹⁶ N ⁽ R ¹⁷ ) ₂ is not -CH ₂ -), wherein each R ¹⁷ is independently selected from H and -C(O )OR ¹⁶ , benzotriazol-1-yloxy, tetrazol-5-ylthio and substituted tetrazol-5-ylthio, alkynyl, alkenyl and alkyl, said alkyl or Alkenyl is optionally substituted by halo, -OR ¹⁵ or -CO ₂ R ¹⁵ ; R ³ and R ⁴ are the same or different, each independently represents H, R ¹ and R ² or any substituent in R ³ and R ⁴ together represent a saturated or unsaturated C ₅ -C fused to a benzene ring (ring III) ₇ rings; R ⁵ , R ⁶ and R ⁷ independently represent H, -CF ₃ , -COR ¹⁵ , alkyl or aryl, and the alkyl or aryl is optionally replaced by -OR ¹⁵ , -SR ¹⁵ , -S(O) _or ^{R _ _ _} _{_ _} ^{_ _} _{_} ^_ _{_} ^_ _{_} ^{_ 5} and R together represent = ^O or =S; ^R is selected from H, C ₃ -C ₄ alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl , substituted aralkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; The substituent of R ⁸ is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, -N(R ¹⁸ ) ₂ , -OR ¹⁸ , cycloalkylalkyl, halo, CN, -C(O)N (R ¹⁸ ) ₂ , -SO ₂ N(R ¹⁸ ) ₂ and -CO ₂ R ¹⁸ ; provided that the -OR ¹⁸ and -N(R ¹⁸ ) ₂ substituents are not attached to the -C(O)NR ⁸ moiety On the N-linked carbon; each R ^is independently selected from H, alkyl, aryl, aralkyl, heteroaryl, and cycloalkyl; R ⁹ and R ¹⁰ are independently selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and -CON(R ¹⁸ ) ₂ (wherein R ¹⁸ is as defined above) and wherein the substitutable R ^{and R} groups are optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aralkyl, and heteroarylalkyl; or R ⁹ and R ¹⁰ form a C ₃ -C ₆ cycloalkyl ring together with the carbon atoms they are connected to; R ¹¹ and R ¹² are independently selected from H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R ¹⁸ ) ₂ , -OR ¹⁸ and -N(R ¹⁸ ) ₂ , wherein R ¹⁸ is the same as defined above; provided that -OR ¹⁸ and -N(R ¹⁸ ) ₂ groups are not attached to the carbon atom adjacent to the nitrogen atom; and wherein the substitutable R ¹¹ and The ^R group is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, aralkyl, and heteroarylalkyl; or R ¹¹ and R ¹² form a C ₃ -C ₆ cycloalkyl ring together with the carbon atoms they are connected to; R ¹³ is an imidazolyl ring selected from the group consisting of:

or Wherein R ^is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) aralkyl, (6) substituted aralkyl, wherein the substituent selected from halo and CN, (7)-C(aryl) ₃ and (8)cycloalkyl; The imidazole ring 2.0 is optionally substituted by one or two substituents, and the imidazole ring 4.0 is optionally substituted by 1-3 substituents, and the imidazole ring 4.1 is optionally substituted by one substituent, wherein the Optional substituents for rings 2.0, 4.0 and 4.1 are independently selected from: -NHC(O)R ¹⁸ , -C(R ³⁴ ) ₂ OR ³⁵ , -OR ¹⁸ , -SR ¹⁸ , F, Cl, Br, alkyl , aryl, aralkyl, cycloalkyl and -N(R ¹⁸ ) ₂ , wherein R ¹⁸ is the same as defined above; wherein R ³⁴ is independently selected from H and alkyl, and R ³⁵ is selected from H, -C(O) OR ²⁰ and -C(O)NHR ²⁰ , R ²⁰ is as defined below; Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, and the Q is optionally 1-4 substituents independently selected from the following Substituted by: halo, alkyl, aryl, -OR ¹⁸ , -N(R ¹⁸ ) ₂ (wherein each R ¹⁸ is independently selected), -OC(O)R ¹⁸ and -C(O)N( R ¹⁸ ) ₂ (wherein each R ¹⁸ is independently selected), and R ¹⁸ is the same as defined above; ^R is selected from H, alkyl, aryl and aralkyl; R ¹⁶ is selected from alkyl and aryl; ^R is selected from the group consisting of alkyl, alkoxy, aryl, aralkyl, cycloalkyl, heteroaryl, heteroarylalkyl and heterocycloalkyl; The R ²⁰ group is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, -OC(O)R ¹⁸ , -OR ¹⁸ and -N(R ¹⁸ ) ₂ , wherein each R ¹⁸ is the same or different and as defined above, provided that the optional substituent is not attached to a carbon atom adjacent to an oxygen or nitrogen atom; n is 0-5; For different n, each R ³² and R ³³ are independently selected from: H, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R ¹⁸ ) ₂ , -OR ¹⁸ and =-N(R ¹⁸ ) ₂ , wherein R ¹⁸ is as defined above, and wherein the substitutable R ³² and R ³³ groups are optionally replaced by one or more substituents selected from Substituted: alkyl, cycloalkyl, aralkyl, and heteroarylalkyl; or R ³² and R ³³ form a C ₃ -C ₆ cycloalkyl ring together with the carbon atoms they are connected to; The premise is: When X is N ^and R is H, then R ^and the alkyl chain of the amide moiety are substituted. 14. The compound of claim 13 having the following structure:

or

15. The compound 25.0B of claim 14, wherein R ⁸ is H, and the alkyl chain between the amide substituent -C(O)NR ⁸ and R ¹³ is substituted. 16. The compound 25.0B of claim 14, wherein (a) R ¹ -R ⁴ are independently selected from H, Br and Cl; (b) R ⁵ -R ⁷ are H; (c) (1) a, b, c and d are carbon, and R is ^selected from alkyl, alkoxy, aryl, aralkyl, cycloalkyl, heteroaryl, heteroarylalkyl and heterocycloalkyl; The R ²⁰ group is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, -OC(O)R ¹⁸ , -OR ¹⁸ and -N(R ¹⁸ ) ₂ , wherein each ^R is the same or different and as defined above, provided that the optional substituent is not attached to a carbon atom adjacent to the oxygen or nitrogen atom; or (2) a is N, the remaining b, c and d substituents are carbon, and R ^is selected from alkyl, aralkyl, heterocycloalkyl, aryl, halo-substituted aryl, cycloalkyl, alkane Cycloalkyl substituted by radical and cycloalkyl substituted by hydroxy, provided that the hydroxy substituent is not attached to a carbon atom adjacent to the oxygen atom; (d) A and B are _H2 ; (e) n is 0 or 1; (f) R ¹³ is group 2.0 or 4.0; (g) R is selected from ^aralkyl , substituted aralkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl and substituted heteroarylalkyl; (h) X is CH or N; (i) R ⁹ and R ¹⁰ are independently selected from H, alkyl, -C(O)N(R ¹⁸ ) ₂ and aralkyl; (j) R ¹¹ and R ¹² are independently selected from H, alkyl, substituted aryl and -OR ¹⁸ , or R ¹¹ and R ¹² form a cycloalkyl ring together with the carbon atoms to which they are attached; (k) R ³² and R ³³ are independently selected from H, -OR ¹⁸ , aralkyl and aryl; (l) R ¹⁹ is selected from -C(O)N(R ¹⁸ ) ₂ , alkyl, aralkyl and -C(aryl) ₃ ; and (m) The optional R ¹³ substituent is selected from -N(R ¹⁸ ) ₂ , -NHC(O)R ¹⁸ , -C(R ³⁴ ) ₂ OR ³⁵ and alkyl. 17. The compound of claim 16, wherein a is N, and the remaining b, c and d substituents are carbon, and (a) R ^is selected from aralkyl, cycloalkylalkyl and heteroarylalkyl; (b) R ^{and R} are independently selected from H and benzyl; (c) R ¹¹ and R ¹² are independently selected from H, -CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -(CH ₂ ) ₃ CH ₃ , benzyl, ethyl, p-chlorophenyl, hydroxyl, Or R ¹¹ and R ¹² form a cyclopropyl ring together with the carbon atoms to which they are attached; (d) R and ^R are independently selected from H, phenyl, ^hydroxy and benzyl; (e) R ¹⁹ is selected from -C(O)NH-cyclohexyl, -C(phenyl) ₃ , H, methyl and ethyl; (f) The optional R ¹³ substituent is selected from -CH ₃ , -CH ₂ OH, -CH ₂ OC(O)O-cyclohexyl, -CH ₂ OC(O)O-cyclopentyl, ethyl , isopropyl, amino, and -NHC(O)CF ₃ ; and (g) R ²⁰ is selected from tert-butyl, ethyl, benzyl, -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -(CH ₂ ) ₂ CH ₃ , n-butyl, n-hexyl , n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl,

or 18. The compound of claim 17, wherein ^R9 , ^R10 , ^R11 , ^R12 , ^R32 and ^R33 are H. 19. The compound of claim 17, wherein R ⁸ is selected from benzyl, -CH ₂ C(CH ₃ ) ₂ , -CH ₂ -cyclohexyl, -CH ₂ -cyclopropyl, -(CH ₂ ) ₂ CH ₃ ,

or

20. The compound of claim 19, wherein (a) R ⁸ is selected from benzyl and -CH ₂ -cyclopropyl; and (b) R ²⁰ is cyclohexyl. 21. The compound of claim 20, which is (1) 3-Br-8-Cl-compound, 8-Cl-compound or 10-Cl-compound, or (2) 3-Br-8-Cl-compound, 8-Cl-compound or 10-Cl-compound, wherein R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ³² and R ³³ are H. 22. The compound of claim 1 selected from the group consisting of:

(11R, 2R isomer) (Example 11);

(11S, 2R isomer) (Example 16);

(Example 58);

(embodiment 78 step B);

(Example 79 Isomer A); (Example 80 Isomer A);

(Example 88 Isomer A); (Example 93 Isomer D);

(Example 99);

(Example 100); (Example 225); (Example 226);

(Example 227);

(Example 228);

(Example 229); (Example 232); (Example 326); (Example 330); (Example 327);

(Example 243); (Example 286A);

(Example 286B);

(Example 304);

(Example 306);

(Example 307); or (Example 308). 23. The compound of claim 1 selected from the group consisting of:

Example 58; (Example 226);

(Example 227);

(Example 228); (Example 229);

(Example 232); (Example 326);

(Example 330); or (Example 327). 24. A compound having the formula (Example 225); 25. A compound having the formula (Example 393) (Example 394). 26. The compound of claim 1 selected from the following Example compounds: Examples 1-22, 25, 45-66, 77, 78 Step B, 79, 80, 82-85, 86, 86A, 87-97, 99 , 100, 102, 112-208, 208A, 209, 209A, 210, 210A, 210B, 211-220, 220A, 221-232, 234B, 234C, 234E, 235-254, 286A, 286B, 304-308, 310 -342, 343-366, 367-373 and 375-382. 27. A compound selected from the compounds of the following Examples: Examples 26-44, 67-76, 81, 98, 101, 103-108, 110, 111, 255-287, 289-297, 299-303 and 309. 28. A method of treating tumor cells comprising administering an effective amount of a compound according to any one of claims 1-27. 29. The method of claim 28, wherein said treated tumor cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, bone marrow dysplasia tumor cells, epidermal cancer cells, bladder cancer cells, colon cancer cells cells, melanoma cells, breast cancer cells and prostate cancer cells. 30. A method of treating tumor cells, wherein the Ras protein is activated due to an oncogenic mutation in a gene other than the Ras gene, said method comprising administering an effective amount of a compound according to any one of claims 1-27. 31. A method of inhibiting farnesyl protein transferase comprising administering an effective amount of a compound according to any one of claims 1-27. 32. A pharmaceutical composition for inhibiting farnesyl protein transferase, comprising an effective amount of the compound of any one of claims 1-27 and a pharmaceutically acceptable carrier. 33. Use of a compound according to any one of claims 1-27 for the manufacture of a medicament for the inhibition of farnesyl protein transferase. 34. Use of a compound according to any one of claims 1-27 in the production of a medicament for the treatment of pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myeloid dysplasia tumor cells, epidermal carcinoma cells, bladder cancer cells, colon cancer cells, melanoma cells, breast cancer cells, and prostate cancer cells. 35. Use of a compound according to any one of claims 1-27 for the inhibition of farnesyl protein transferase. 36. Use of a compound according to any one of claims 1-27 in the treatment of the following cells: pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, bone marrow dysplasia tumor cells, epidermal cancer cells, bladder cancer cells Cancer cells, colon cancer cells, melanoma cells, breast cancer cells and prostate cancer cells.