CN101405280B

CN101405280B - Carbocyclic and heterocyclic arylsulfones as gamma secretase inhibitors

Info

Publication number: CN101405280B
Application number: CN2007800097448A
Authority: CN
Inventors: T·亚斯班洛; T·贝拉; C·E·班尼特; D·A·伯奈特; M·A·盖普兰; J·W·克拉德; D·J·柯尔; M·S·度玛斯基; H·B·乔西恩; C·E·纳森; 李虹美; M·D·麦布莱尔; D·A·彼萨尼斯基; 强莉; M·拉加戈帕兰; T·K·沙西库玛; 苏菁; 唐汉君; 吴文连; 古若
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2006-01-20
Filing date: 2007-01-18
Publication date: 2012-11-14
Anticipated expiration: 2027-01-18
Also published as: CN101405280A; ZA200806294B

Abstract

This invention discloses novel gamma secretase inhibitors of the formula: R<2 >and R<3>, or R<2> and R<4>, or R<3> and R<4>, together with the atoms to which they are bound, can form a fused cycloalkyl or fused heterocycloalkyl ring. The cycloalkyl ring or the heterocycloalkyl ring can be optionally substituted with one or more substituents. One or more compounds of formula (I), or formulations comprising such compounds, may be useful, e.g. in treating Alzheimer's Disease.

Description

Carbocyclic ring and heterocyclic arylsulfones as gamma-secretase inhibitors

Background

The WO00/50391 that announced on August 13rd, 2000 openly has the compound of sulphonamide part, and it is used for treatment and prevention of Alzheimer's disease and other and amyloid beta deposition diseases associated.

McCombie etc., Tetrahedron Letters, Vol.34, No.50, pp.8033-8036 (1993) has described the method for preparing chroman and thiochroman.Yet the chroman that this article is described is different fully with The compounds of this invention with thiochroman.

In view of the existing interests of treatment or prevention neurodegenerative disease (like Alzheimer), the contribution to the worth welcome of this area should be the compound that is used for such treatment or prevention.The present invention provides a kind of like this contribution.

Summary of the invention

The present invention is provided as gamma-Secretases (being also referred to as " gamma-secretase ") suppressor factor (like antagonist) and has the compound of formula (I):

Or its pharmacy acceptable salt, solvate or ester, wherein L ¹, m, n, Ar, X, R ², R ³And R ³Definition following.

The present invention also provides pure and formula unpack format (I) compound.

The present invention also provides formula (I) compound of pure form.

The present invention also provides formula (I) compound of unpack format.

The present invention also provides the final compound of embodiment 1,1A-1V, 2,3,3A-3H, 4,5,5A-5C, 6,6A, 7,7A-7E, 8,8A-8Z, 9,9A-9D, 10,10A-10E, 11,11A-11E, 12,13,13A, 14,14A, 15,15A, 16,17,18,19,20,20D-20K, 21,22,23,24,24C, 25,26,27A, 27B, 28-400 and 403-447.

The present invention also provides the final compound of embodiment 13A, 14A, 15A, 16,17,18,19,20,20D-20K, 21,22,23,24,24C, 25,26,27A, 27B and 28.

The present invention also provides the compound in the table 93.

The present invention also provides the compound in the table 94.

The present invention also provides medicinal compsns, and it comprises one or more formulas (I) compound and at least a pharmaceutically acceptable carrier of significant quantity.

The present invention also provides medicinal compsns, and it comprises formula (I) compound and at least a pharmaceutically acceptable carrier of significant quantity.

The present invention also provides the method that suppresses gamma-secretase, and it comprises that the patient who needs treatment effectively (that is, treats effectively) one or more formulas (I) compound of amount.

The present invention also provides the method that suppresses gamma-secretase, and it comprises that the patient who needs treatment effectively (that is, treats effectively) formula (I) compound of amount.

The present invention also provides the method for one or more neurodegenerative diseases of treatment, and it comprises that the patient who needs treatment effectively (that is, treats effectively) one or more formulas (I) compound of amount.

The present invention also provides the method for one or more neurodegenerative diseases of treatment, and it comprises that the patient who needs treatment effectively (that is, treats effectively) formula (I) compound of amount.

The present invention also is provided among the nervous tissue (like, brain), on or suppress the amyloid beta deposition method of (like, amyloid beta protein) on every side, it comprises effective one or more formulas (I) compound of (that is, treatment is effectively) amount of patient that needs treatment.

The present invention also is provided among the nervous tissue (like, brain), on or suppress the amyloid beta deposition method of (like, amyloid beta protein) on every side, it comprises effective formula (I) compound of (that is, treatment is effectively) amount of patient that needs treatment.

The present invention also provides the method for treatment Alzheimer, and it comprises that the patient who needs treatment effectively (that is, treats effectively) one or more formulas (I) compound of amount.

The present invention also provides the method for treatment Alzheimer, and it comprises that the patient who needs treatment effectively (that is, treats effectively) formula (I) compound of amount.

The present invention also provides the method for treatment Alzheimer; It comprises uniting needs the patient who treats effective (promptly; Treatment is effectively) one or more formulas (I) compound of amount and effectively (i.e. treatment effectively) amount one or more anticholinesterases (for example; (±)-2; 3-dihydro-5; 6-dimethoxy-2-[[1-(phenyl methyl)-4-piperidyl] methyl]-1H-1-Indanone hydrochloride, i.e. E2020 hydrochloride,

trade(brand)name that can be used as the E2020 hydrochloride obtains).

The present invention also provides the method for treatment Alzheimer; It comprises uniting needs the patient who treats effective (promptly; Treatment is effectively) formula (I) compound of amount and effectively (promptly; Treatment is effectively) one or more (as a kind of) of amount, anticholinesterase was (for example; (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenyl methyl)-4-piperidyl] methyl]-1H-1-Indanone hydrochloride; Be the E2020 hydrochloride,

trade(brand)name that can be used as the E2020 hydrochloride obtains).

The present invention also provides any described treat-ment, and its Chinese style I compound is selected from the compound that comprises in the table 93.

The present invention also provides any described treat-ment, and its Chinese style I compound is selected from the compound that comprises in the table 94.

The present invention also provides any described treat-ment, and its Chinese style I compound is selected from the final compound of embodiment 1,1A-1V, 2,3,3A-3H, 4,5,5A-5C, 6,6A, 7,7A-7E, 8,8A-8Z, 9,9A-9D, 10,10A-10E, 11,11A-11E, 12,13,13A, 14,14A, 15,15A, 16,17,18,19,20,20D-20K, 21,22,23,24,24C, 25,26,27A, 27B, 28-400 and 403-447.

The present invention also provides any described treat-ment, and its Chinese style I compound is selected from the final compound of embodiment 13A, 14A, 15A, 16,17,18,19,20,20D-20K, 21,22,23,24,24C, 25,26,27A, 27B and 28.

Detailed Description Of The Invention

Or its pharmacy acceptable salt, solvate or ester, wherein:

X is selected from-C (R ¹) ₂-,-O-,-S-,-S (O ₂)-,-NR ¹-with-N (C (O) R ¹)-;

Each R ¹Independently be selected from H and alkyl;

R ², R ³And R ⁴Independently be selected from separately: (1) H, (2) alkyl, (3)-OR ⁵, (4) alkylidene group-OR ⁵, (5)-alkylidene group-R ⁶, (6)-C (O)-alkyl, (7)-alkylidene group-C (O)-alkyl, (8)-C (O)-R ⁶, (9)-alkylidene group-C (O)-R ⁶, (10)-C (O) O-alkyl, (11)-alkylidene group-C (O) O-alkyl, (12)-C (O) NH-alkyl, (13)-alkylidene group-C (O) NH-alkyl, (14)-C (O) N (alkyl) ₂, (15)-alkylidene group-C (O) N (alkyl) ₂, (16)-R ⁸, (17)-alkylidene group-R ⁸, (18)-NHR ⁵, (19)-N (R ⁵) ₂, (20)-alkylidene group-NHR ⁵, (21)-alkylidene group-N (R ⁵) ₂, (22) alkenyl, (23)-NH-R ⁸(as ,-NH-(dihydro-furan-2-ketone), (24)

-NH-CH (C (O) O (C ₁-C ₆) alkyl)-alkylidene group-O-alkylidene group-R ⁶(as ,-NHCH (C (O) OCH ₃) CH ₂CH ₂OCH ₂Phenyl), (25)-NHCH (C (O) O (C ₁-C ₆) alkyl)-alkylidene group-OH (as ,-NHCH (C (O) OCH ₃) CH ₂CH ₂OH), (26)-NH-C (O)-alkenyl (as ,-NHC (O) CH=CH ₂) and (27)-N (C ₁-C ₆Alkyl) C (O)-alkenyl is (like ,-N (CH ₃) C (O) CH=CH ₂) (instance of wherein said alkyl (comprises said R ², R ³And R ⁴Substituent moieties) comprises C ₁-C ₆Alkyl, and wherein said R ², R ³And R ⁴The instance of the said alkylene moiety of substituting group comprises C ₁-C ₆Alkylidene group, and wherein said R ², R ³And R ⁴Substituent said non-limiting examples of alkenyls comprises C ₂-C ₆Alkylidene group); Or

R ²And R ³, or R ²And R ⁴, or R ³And R ⁴, forming condensed naphthenic base or heterocycloalkyl ring with the atom that connects shown in them, wherein said condensed naphthenic base or heterocycloalkyl ring are unsubstituted or by one or more L ³(instance of wherein said condensed naphthenic base comprises C in the group replacement ₃-C ₁₀Ring (comprising two carbon atoms that ring is total), and the instance of said condensed heterocycle alkyl ring comprises 4-8 unit ring (comprising two carbon atoms that ring is total), it contains 1-3 and independently is selected from following heteroatoms: O, N, S, SO ₂, SO, Si and P, and the said heteroatomic instance of said heterocycloalkyl ring independently is selected from: O, N, S, SO ₂, SO and P, and the said heteroatomic instance of said heterocycloalkyl ring independently is selected from: O, N and S); And those skilled in the art will appreciate that wherein substituted condensed ring can be able to be selected from following L on the substituted atom ³Group replaces: ring carbon (the total carbon atom that comprises two condensed ring) and heteroatoms (as, N or S); With

Prerequisite is when X is 1 for-O-and m, then R ², R ³Or R ⁴At least one be not H;

R ⁶Be selected from: unsubstituted (C ₆-C ₁₄) aryl, by one or more L ¹Substituted (the C of group ₆-C ₁₄) aryl, unsubstituted (C ₅-C ₁₄) heteroaryl and one or more L ¹Substituted (the C of group ₅-C ₁₄) heteroaryl;

R ⁷Be selected from unsubstituted Heterocyclylalkyl and by one or more L ²The substituted Heterocyclylalkyl of group (instance of wherein said heterocycloalkyl ring (unsubstituted or substituted) comprises 4-8 unit ring, its contain 1-3 independently be selected from following heteroatoms: O, N, S ,-S (O) ₂,-S (O)-, Si and P, and in other embodiments, the heteroatoms of said heterocycloalkyl ring independently is selected from: O, N, S ,-S (O) ₂,-S (O)-and P, and in other embodiments, the heteroatoms of said heterocycloalkyl ring independently is selected from: O, N and S);

R ⁸Be selected from unsubstituted naphthenic base and by one or more L ³The substituted naphthenic base of group (instance of wherein said naphthenic base (unsubstituted or substituted) comprises the C3-C10 cycloalkyl ring);

Ar is selected from: (a) unsubstituted aryl, and (b) by one or more L ¹The substituted aryl of group, (c) unsubstituted heteroaryl (like, pyridyl) and (d) by one or more L ¹The substituted heteroaryl of group (as, substituted pyridyl);

R ⁹For bridge joint encircles heterocycloalkyl ring (like, bridged bicyclic heterocycloalkyl ring), wherein said R more ⁹Part is unsubstituted or said R ⁹Part is by one or more L ²Group replaces, and wherein said heterocycloalkyl ring comprises 4-8 unit ring, its contain 1-3 independently be selected from following heteroatoms: O, N, S, Si and P (with in one embodiment, said heteroatoms is N), said R ⁹The instance of part includes but not limited to:

Each L ¹Independently be selected from: halogen, alkyl (as, C ₁-C ₆Alkyl) ,-CN ,-CF ₃,-O-(C ₁-C6) alkyl is (like ,-OCH ₃) ,-O-(halo (C ₁-C ₆) alkyl) (as ,-OCF ₃) ,-C (O)-O-(C ₁-C ₆) alkyl (as ,-C (O) OCH ₃) ,-alkylidene group-OH (CH ₂OH), halo (C ₁-C ₆) alkyl (as ,-CF ₃), the hydroxy alkoxy base-(as, HOCH ₂CH ₂O-) and the alkoxyl group alkoxyl group-(as, CH ₃OCH ₂CH ₂O-);

Each L ²Independently be selected from: (a)-OH, (b) alkyl is (like, C ₁-C ₆Alkyl), (c) alkyl (like, C ₁-C ₆Alkyl), replace by one or more-OH group, (d) halo, (e) haloalkyl is (like, halo (C ₁-C ₆) alkyl); (f) (comprise unsubstituted or substituted 4-8 unit heterocycloalkyl ring like, said heterocycloalkyl ring, it contains 1-3 and independently is selected from following heteroatoms: O, N, S Heterocyclylalkyl; And in other embodiments; The heteroatoms of said heterocycloalkyl ring independently is selected from: O, N, S and P, and in other embodiments, the heteroatoms of said heterocycloalkyl ring independently is selected from: O, N and S and P);

Each L ³Independently be selected from :-CN ,=O, R ⁵,-OR ⁵=N-R ⁵With-N (R ⁵) ₂(as ,-NHR ⁵); (L in one embodiment ³Be selected from :-CH ₂OH ,-CH ₂NH ₂,-CH ₂The NH alkyl (for example ,-CH ₂NH (C ₁-C ₆) alkyl) and-C (O) OH and in another embodiment, L ³Be selected from :-alkylidene group-C (O) NH (C ₁-C ₆) alkyl ,-alkylidene group-C (O) N ((C ₁-C ₆) alkyl) ₂, wherein each alkyl be independent select ,-alkylidene group-C (O) NH (C ₁-C ₆) haloalkyl and-alkylidene group-C (O) N ((C ₁-C ₆) haloalkyl) ₂, wherein each alkyl is independent the selection);

N is 0,1,2 or 3; With

M is 0,1,2 or 3; With

Prerequisite is for substituting group-OR ⁵, R ⁵The connected Sauerstoffatom of part do not form-and the O-O-group is (that is, for substituting group-OR ⁵, R ⁵Part is not passed through R ⁵The Sauerstoffatom of part is connected in-OR ⁵Substituent Sauerstoffatom); And

Prerequisite is for substituting group-OR ⁵,=N-R ⁵With-NHR ⁵, R ⁵Be not-CH ₂OH ,-CH ₂NH ₂,-CH ₂The NH alkyl ,-CH ₂The NH aryl or-C (O) OH.

In first embodiment, the present invention relates to aforesaid formula (I) compound, or its pharmacy acceptable salt, solvate or ester.

Another embodiment of the invention relates to formula (I) compound.

Another embodiment of the invention relates to the pharmacy acceptable salt of formula (I) compound.

Another embodiment of the invention relates to the solvate of formula (I) compound.

Another embodiment of the invention relates to the pharmaceutically acceptable ester of formula (I) compound.

In an embodiment of formula (I) compound, Ar is unsubstituted aryl (like, unsubstituted phenyl).

In another embodiment of formula (I) compound, Ar is substituted aryl (like, substituted phenyl).

In another embodiment of formula (I) compound, Ar is unsubstituted heteroaryl (like, unsubstituted pyridine base).

In another embodiment of formula (I) compound, Ar is substituted heteroaryl (like, substituted pyridyl).

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IA) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IA) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IA) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IA) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IB) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IB) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IB) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IB) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IC) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IC) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IC) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IC) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (ID) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (ID) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (ID) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (ID) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IE) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IE) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IE) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IE) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IF) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IF) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IF) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IF) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IF.1A) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IF.1A) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IF.1A) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IF.1A) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IG) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IG) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IG) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IG) compound.

In an embodiment of formula (I) compound, Ar is that unsubstituted aryl (like, unsubstituted phenyl) and said formula (I) compound are formula (IH) compound.

In another embodiment of formula (I) compound, Ar is that substituted aryl (like, substituted phenyl) and said formula (I) compound are formula (IH) compound.

In another embodiment of formula (I) compound, Ar is that unsubstituted heteroaryl (like, unsubstituted pyridine base) and said formula (I) compound are formula (IH) compound.

In another embodiment of formula (I) compound, Ar is that substituted heteroaryl (like, substituted pyridyl) and said formula (I) compound are formula (IH) compound.

In an embodiment of formula (I) compound, one or more L ³Group is-N (R ⁵) ₂Substituting group, one of them R ⁵Group is H, promptly one or more L ³Group is-NHR ⁵Therefore, in an embodiment of formula (I) compound, each L ³Independently be selected from :=O, R ⁵,-OR ⁵-NHR ⁵With-N (R ⁵) ₂

In a preferred embodiment of formula (I) compound, each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷With-S (O) ₂R ⁸

In another preferred embodiment of formula (I) compound, each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

In another preferred embodiment of formula (I) compound, each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Therefore, another embodiment of the invention relates to formula (I) compound, or its pharmacy acceptable salt, solvate or ester, wherein each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷With-S (O) ₂R ⁸

Another embodiment of the invention relates to formula (I) compound, wherein each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷With-S (O) ₂R ⁸

Another embodiment of the invention relates to the pharmacy acceptable salt of formula (I) compound, wherein each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶With-S (O) ₂R ⁷With-S (O) ₂R ⁸

Another embodiment of the invention relates to the solvate of formula (I) compound, wherein each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶With-S (O) ₂R ⁷With-S (O) ₂R ⁸

Another embodiment of the invention relates to the pharmaceutically acceptable ester of formula (I) compound, wherein each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶With-S (O) ₂R ⁷With-S (O) ₂R ⁸

Another embodiment of the invention relates to formula (I) compound, or its pharmacy acceptable salt, solvate or ester, wherein each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to formula (I) compound, wherein each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to the pharmacy acceptable salt of formula (I) compound, wherein each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to the solvate of formula (I) compound, wherein each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to the pharmaceutically acceptable ester of formula (I) compound, wherein each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to formula (I) compound, or its pharmacy acceptable salt, solvate or ester, wherein each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶, S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to formula (I) compound, wherein each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷,-S (O) ₂] R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to the pharmacy acceptable salt of formula (I) compound, wherein each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to the solvate of formula (I) compound, wherein each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶, S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Another embodiment of the invention relates to the pharmaceutically acceptable ester of formula (I) compound, wherein each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

At formula (I) compound, or in another embodiment of its pharmacy acceptable salt, solvate and/or ester

R ¹Be selected from H and (C ₁-C ₆) alkyl;

R ²Be selected from H ,-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-OR ⁵,-(C ₁-C ₆) alkylidene group-R ⁶,-(C ₁-C ₆) alkylidene group-C (O) O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-R ⁸,-C (O) O-(C ₁-C ₆) alkyl and-(C ₂-C ₆) alkenyl;

R ³Be selected from H ,-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-OR ⁵,-(C ₂-C ₆) alkenyl ,-C (O) O-(C ₁-C ₆) alkyl and-(C ₁-C ₆) alkylidene group-C (O) O-(C ₁-C ₆) alkyl; Or

R ²And R ³, or R ²And R ⁴, or R ³And R ⁴, form condensed (C with the atom that connects shown in them ₃-C ₁₀) cycloalkyl ring, wherein said condensed (C ₃-C ₁₀) cycloalkyl ring is unsubstituted or by one or more L ³Group replaces;

Each R ⁴Independently be selected from H ,-(C ₁-C ₆) alkyl and-(C ₁-C ₆) alkylidene group-R ⁶With

Prerequisite is when X is 1 for-O-and m, R ², R ³Or R ⁴At least one be not H;

Each R ⁵Independently be selected from H, (C ₁-C ₆) alkyl, R ⁶,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-R ⁶With-C (O)-R ⁷

R ⁶Be selected from unsubstituted (C ₆-C ₁₄) aryl and by one or more L ¹Substituted (the C of group ₆-C ₁₄) aryl;

R ⁷Be selected from unsubstituted (C ₃-C ₁₀) Heterocyclylalkyl and by one or more L ²Substituted (the C of group ₃-C ₁₀) Heterocyclylalkyl;

R ⁸Be selected from unsubstituted (C ₃-C ₁₀) naphthenic base and by one or more L ³Substituted (the C of group ₃-C ₁₀) naphthenic base;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, (C ₁-C ₆) alkyl ,-CN and-CF ₃With

Each L ²Independently be selected from-OH, (C ₁-C ₆) alkyl, by one or more-substituted (C of OH group ₁-C ₆) alkyl and (C ₃-C ₁₀) Heterocyclylalkyl.

In another embodiment, formula (I) compound, or its pharmacy acceptable salt, solvate and/or ester have following formula (IA):

In another embodiment, formula (I) compound, or its pharmacy acceptable salt, solvate and/or ester have following formula (IB):

In another embodiment, formula (I) compound, or its pharmacy acceptable salt, solvate and/or ester have following formula (IC):

In another embodiment, formula (I) compound, or its pharmacy acceptable salt, solvate and/or ester have following formula (ID):

In another embodiment, formula (I) compound, or its pharmacy acceptable salt, solvate and/or ester have following formula (IE):

Wherein:

R ¹Be H or alkyl;

R ²Be selected from H, alkyl, alkylidene group-OR ⁵,-alkylidene group-R ⁶,-alkylidene group-C (O) O-alkyl ,-C (O) O-alkyl and alkenyl;

R ³Be selected from H, alkyl, alkylidene group-OR ⁵With-alkylidene group-C (O) O-alkyl;

R ⁴Independent is H or alkyl;

Each R ⁵Independent be H or-C (O)-R ⁷

R ⁶Be selected from unsubstituted aryl and by one or more L ¹The substituted aryl of group;

R ⁷Be selected from unsubstituted Heterocyclylalkyl and by one or more L ²The substituted Heterocyclylalkyl of group;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independent is halogen or alkyl;

Each L ²Independently be-OH or Heterocyclylalkyl; With

N is 0,1 or 2.

Wherein:

R ¹For H or-CH ₃

R ²Be selected from H ,-CH (CH ₃) ₂,-CH ₃,-CH ₂CH ₃,-(CH ₂) ₃CH ₃,-CH ₂-R ⁶,-CH ₂CH ₂-OH ,-CH ₂-C (O) O-CH ₂CH ₃,-C (O) O-CH ₂CH ₃, by one or more L ²Group is substituted-CH ₂CH ₂-O-C (O)-pyrrolidyl, by one or more L ²Group is substituted-CH ₂CH ₂-O-C (O)-piperidyl ,-CH ₂CH=CH ₂,

R ³Be selected from H ,-CH ₃,-CH ₂CH ₃,-CH ₂-OH, by one or more L ²Group is substituted-CH ₂-O-C (O)-piperidyl, by one or more L ²Group is substituted-CH ₂-O-C (O)-pyrrolidyl ,-CH ₂-C (O) O-CH ₃,-CH ₂-C (O) O-CH ₂CH ₃

R ⁴For H or-CH ₃

R ⁶Be selected from unsubstituted phenyl and by one or more L ¹The substituted phenyl of group;

Ar is a unsubstituted phenyl or by one or more L ¹The substituted phenyl of group;

Each L ¹Independent be F, Cl or-CH ₃

Each L ²Independently be-OH or piperidyl; With

N is 0,1 or 2.

Wherein:

R ²Be selected from H, alkyl, alkylidene group-OR ⁵,-alkylidene group-R ⁶,-alkylidene group-C (O) O-alkyl ,-alkylidene group-R ⁸, and alkenyl;

R ³Be selected from H, alkyl and alkylidene group-OR ⁵Or

R ²And R ³, or R ²And R ⁴, or R ³And R ⁴, forming condensed naphthenic base or heterocycloalkyl ring with the atom that connects shown in them, wherein said condensed naphthenic base or heterocycloalkyl ring are unsubstituted or by one or more L ³Group replaces;

R ⁴Be selected from H, alkyl and-alkylidene group-R ⁶

Each R ⁵Independently be selected from H, alkyl and-C (O)-R ⁷

R ⁸Be selected from unsubstituted naphthenic base and by one or more L ³The substituted naphthenic base of group;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independent is halogen or alkyl;

Each L ²Independently be selected from-OH, alkyl, by one or more-substituted alkyl of OH group, and Heterocyclylalkyl;

Each L ³For-OR ⁵With

N is the integer of 0-3.

Wherein:

R ²Be selected from H ,-CH ₂-C (O) O-CH ₃,-CH ₃,-CH ₂CH ₃,-CH (CH ₃) ₂,-CH ₂-R ⁶,-CH ₂-R ⁸,-CH ₂CH ₂-OR ⁵,-CH ₂CH=CH ₂With-CH (CH ₃) CH ₂CH ₂-OH;

R ³Be selected from H ,-CH ₃,-CH ₂-OH and-CH ₂-O-CH ₃Or

R ⁴Be selected from H ,-CH ₃,-CH ₂CH ₃With-CH ₂-R ⁶

Each R ⁵Independently be selected from H or-C (O)-R ⁷

R ⁷Be selected from unsubstituted piperidyl, by one or more L ²The substituted piperidyl of group, unsubstituted piperazinyl, by one or more L ²The substituted piperazinyl of group, unsubstituted pyrrolidyl, by one or more L ²The substituted pyrrolidyl of group;

R ⁸Be selected from unsubstituted cyclopropyl and by one or more L ³The substituted cyclopropyl of group;

Each L ¹Independent be F, Cl or-CH ₃

Each L ²Independently be selected from-OH ,-CH ₂CH ₂-OH, piperidyl and-C (CH ₃) ₃

Each L ³Independent be-OH or-C (O)-R ⁷With

N is 0,1,2 or 3.

Wherein:

R ¹Be selected from H and alkyl;

R ²Be H;

R ³Be H;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃With

N is 0,1 or 2.

Wherein:

R ¹Be selected from H and-CH ₃

R ²Be H;

R ³Be H;

Each L ¹Independent is F or Cl; With

N is 0,1 or 2.

Wherein:

R ¹Be H;

R ²Be selected from H, alkyl and alkenyl;

R ³Be selected from H, alkyl and alkenyl;

Each R ⁴Be H;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃With

N is 0,1,2 or 3.

Wherein:

R ¹Be H;

R ²Be selected from H ,-CH ₃,-CH (CH ₃) ₂With-CH ₂CH=CH ₂

R ³Be selected from H ,-CH ₃With-CH ₂CH=CH ₂

Each R ⁴Be H;

Each L ¹Independent is F or Cl; With

N is 0,1 or 2.

Wherein:

R ²Be H or alkyl;

R ³Be H or alkyl;

Each R ⁴Be H;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃With

N is 0,1,2 or 3.

Wherein:

R ²For H or-CH ₃

R ³For H or-CH ₃

Each R ⁴Be H;

Each L ¹Independent is F or C1; With

N is 0,1 or 2.

In another embodiment of formula (I) compound, or its pharmacy acceptable salt, solvate and/or ester, R ²And R ³, or R ²And R ⁴, or R ³And R ⁴, forming condensed naphthenic base or heterocycloalkyl ring with the atom that connects shown in them, wherein said condensed naphthenic base or heterocycloalkyl ring are unsubstituted or by one or more L ³Group replaces.

For example, formula (I) compound comprises such compound, wherein R ²And R ³Form condensed ring (Q) with the carbon atom that connects shown in them, such compound has formula (IF) or (IF.1A):

or

Wherein Q is selected from following condensed ring: unsubstituted naphthenic base, by one or more L that independently are selected from ³The substituted naphthenic base of group, unsubstituted Heterocyclylalkyl and by one or more L that independently are selected from ³The substituted Heterocyclylalkyl of group, and wherein Y is connected in two condensed ring total carbon atom and Y and is selected from :-NHR ⁵,-OH and-OR ⁵In one embodiment, the substituent R of Y ⁵Be selected from :-O-alkylidene group-S (O) ₂NHC (O)-(C ₁-C ₆) alkyl ,-O-alkylidene group-S (O) ₂NHC (O)-haloalkyl alkyl ,-O-alkylidene group-S (O) ₂NHC (O)-R ⁶,-O-alkylidene group-S (O) ₂NHC (O)-R ⁷,-O-alkylidene group-C (O) NH-S (O) ₂-(C ₁-C ₆) alkyl ,-O-alkylidene group-C (O) NH-S (O) ₂-haloalkyl ,-O-alkylidene group-C (O) NH-S (O) ₂-(C ₁-C ₆) alkyl ,-O-alkylidene group-C (O) NH-S (O) ₂-R ⁶With-O-alkylidene group-C (O) NH-S (O) ₂-R ⁷

In one embodiment of the invention, formula I compound is formula (IF) compound.

In another embodiment of the invention, formula I compound is formula (IF.1A) compound.

Relate to formula (IF.1A) compound in other embodiment of the present invention, wherein Y as above defines, and remaining substituting group such as in arbitrary embodiment of hereinafter formula (IF) compound being described definition.

In an embodiment preferred of formula (IF) compound, each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷And-S (O) ₂R ⁸

In another embodiment preferred of formula (IF) compound, each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

In another embodiment preferred of formula (IF) compound, each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶, S (O) ₂R ⁷,-S (O) ₂R ⁸.-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Preferred formula (I) compound is formula (IF) compound, wherein each L ³Be identical or different-NHR ⁵Group, and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷With-S (O) ₂R ⁸

Preferred formula (I) compound also comprises formula (IF) compound, wherein each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Preferred formula (I) compound also comprises formula (IF) compound, wherein each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷, S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R ⁶,-S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

In another embodiment of formula (IF) compound, " Q " is the condensed cycloalkyl ring.

In an embodiment of formula (IF) compound, m is 1.

In another embodiment of formula (IF) compound, R ⁴Be H.

In another embodiment of formula (IF) compound, X is O.

In another embodiment of formula (IF) compound, L ¹Be halogen.

In another embodiment of formula (IF) compound, L ¹Be halogen, wherein each halogen independently is selected from: Cl and F.

In another embodiment of formula (IF) compound, substituent A r is by one or more L ¹The substituted aryl moiety of group.

In another embodiment of formula (IF) compound, substituent A r is by one or more L ¹The substituted phenyl of group.

In another embodiment of formula (IF) compound, substituent A r is by L ¹The substituted phenyl of group, wherein said L ¹Group is a halogen.

In another embodiment of formula (IF) compound, substituent A r is by L ¹The substituted phenyl of group, wherein said L ¹Group be Cl (as, Ar is right-Cl-phenyl).

In another embodiment of formula (IF) compound, n is 1 or 2.

In another embodiment of formula (IF) compound, n is 1.

In another embodiment of formula (IF) compound, n is 2.

In another embodiment of formula (IF) compound, L ¹Be halogen, wherein independently to be selected from Cl and Br and n be 2 to each halogen.

In another embodiment of formula (IF) compound, L ¹For F and n are 2.

In another embodiment of formula (IF) compound, m be 1 and X be O.

In another embodiment of formula (IF) compound, m is 1, and X is O and R ⁴Be H.

In another embodiment of formula (IF) compound, m is 1, and X is O and R ⁴Be H, n is 2, and L ¹Be selected from Cl and F.

In another embodiment of formula (IF) compound, m is 1, and X is O and R ⁴Be H, n is 2, L ¹Being selected from Cl and F and Ar is by the substituted phenyl of Cl.

In another embodiment of formula (IF) compound, m is 1, and X is O and R ⁴Be H, n is 2, and L ¹Be F.

In another embodiment of formula (IF) compound, m is 1, and X is O and R ⁴Be H, n is 2, L ¹For F and Ar are by the substituted phenyl of Cl.

Another embodiment of formula (IF) compound relates to formula (IF.1) compound:

Other embodiment of formula (IF) compound relates to preceding text to the described arbitrary embodiment of formula (IF), describes respectively equally as each embodiment, and its Chinese style (IF) compound is formula (IF.1) compound.

Other embodiment of formula (IF) compound as what in arbitrary above-mentioned embodiment, describe, relates to such compound, and wherein Q is described in arbitrary embodiment hereinafter.

In another embodiment of formula (IF) compound, Q is unsubstituted cyclohexyl ring:

as; For example,

In another embodiment of formula (IF) compound, Q is substituted cyclohexyl ring:

as; For example,

In one embodiment, cyclohexyl ring Q:

Cyclohexyl ring for following formula:

In another embodiment, cyclohexyl ring Q:

Cyclohexyl ring for following formula:

L wherein ³Be selected from :=O ,-OR ⁵,-NHR ⁵,-SO ₂R ⁶,-SO ₂R ⁷With-SO ₂R ⁸, R wherein ⁵Be selected from :-SO ₂-(C ₁-C ₆) haloalkyl (as ,-SO ₂CF ₃) ,-C (O)-(C ₁-C ₆) alkyl (as ,-C (O) CH ₃) ,-C (O) NH (C ₁-C ₆) alkyl (as, C (O) NHC ₂H ₅) ,-SO ₂-(C ₁-C ₆) alkyl (as ,-SO ₂CH ₃,-SO ₂C ₂H ₅With-SO ₂C ₃H ₇) and-(C ₁-C ₆) alkyl (like, methyl), and R wherein ⁶For unsubstituted heteroaryl (as, thienyl and pyridyl), and R wherein ⁷Be unsubstituted heterocycloalkyl ring (like, azetidinyl), and R wherein ⁸Be unsubstituted cycloalkyl ring (like, cyclopropyl).

L wherein ³Be selected from :=O ,-OH ,-NH ₂,-NHSO ₂CF ₃,-NHC (O) CH ₃,-NHC (O) NHCH ₂CH ₃,-NHSO ₂CH ₃,-NHSO ₂CH ₂CH ₃,-NHSO ₂CH ₂CH ₂CH ₃,-OCH ₃,

and

L wherein ³Be selected from :-alkylidene group-C (O) NH (C ₁-C ₆) alkyl (as,

-CH ₂C (O) NHC ₂H ₅With-CH ₂C (O) NHCH ₃) ,-alkylidene group-C (O) N ((C ₁-C ₆) alkyl) ₂, wherein each alkyl be independent select ,-alkylidene group-C (O) NH (C ₁-C ₆) haloalkyl (as ,-CH ₂C (O) NHCH ₂CF ₃) and-alkylidene group-C (O) N ((C ₁-C ₆) haloalkyl) ₂, wherein each alkyl is independent the selection.

as; For example,

L wherein ³Be selected from :-CH ₂C (O) NHC ₂H ₅,-CH ₂C (O) NHCH ₃With-CH ₂C (O) NHCH ₂CF ₃

L wherein ³Be selected from :-alkylidene group-NHS (O) ₂-(C ₁-C ₆) alkyl (as ,-CH ₂NHS (O) ₂CH ₂CH ₃) and-alkylidene group-NHS (O) ₂-(C ₁-C ₆) haloalkyl (as ,-CH ₂NHS (O) ₂CF ₃).

L wherein ³Be selected from: the substituted alkyl of hydroxyl (for example, by the substituted alkyl of at least one OH group, for example, by the 1-3-substituted (C of OH group ₁-C ₆) alkyl and in one embodiment, for by the substituted (C of 1 or 2-OH group ₁-C ₆) alkyl and in another embodiment, for by the substituted (C of 2-OH group ₁-C ₆) alkyl and be-CH in another embodiment ₂CH (OH) CH ₂CH ₃And be-CH in another embodiment ₂CH ₂CH (OH) CH ₂OH).

L wherein ³Be selected from: L wherein ³Be selected from :-alkylidene group-S (O) ₂-(C ₁-C ₆) alkyl (as, for-CH ₂CH ₂SO ₂CH ₂CH ₃Or-CH ₂CH ₂SO ₂CH ₃).

L wherein ³Be selected from: :-alkylidene group-C (O)-(C ₁-C ₆) alkyl (as ,-CH ₂CH ₂-C (O)-CH ₃).

In another embodiment of formula (IF) compound, Q is unsubstituted suberyl ring:

In another embodiment of formula (IF) compound, Q is substituted suberyl ring:

as; For example,

In another embodiment of formula (IF) compound, Q is substituted suberyl ring:

In another embodiment of formula (IF) compound, Q is substituted suberyl ring:

L wherein ³Be selected from :-OR ⁵(wherein, for example, R ⁵Be H) and-NHR ⁵(wherein, for example, R ⁵For-SO ₂-(C ₁-C ₆) haloalkyl (for example ,-SO ₂CF ₃)).

In another embodiment of formula (IF) compound, Q is substituted suberyl ring:

L wherein ³Be selected from :-OH and-NHSO ₂CF ₃.

In another embodiment of formula (IF) compound, Q is unsubstituted heterocycloalkyl ring, and contains one and is selected from-heteroatoms of O-and-NH-.

In another embodiment of formula (IF) compound, Q is by one or more L ³The group replacement (as, a L ³Group) heterocycloalkyl ring, said heterocycloalkyl ring contain at least one be selected from following heteroatoms :-O-,-NH-and-N (L ³)-(is like, the L on the wherein said N ³Be for example R ⁵Group-C (O)-(C ₁-C ₆) alkyl, for example ,-C (O) CH ₃).When for example said heterocycloalkyl ring comprise-O-is during as heteroatoms, said L ³Examples of groups comprises methyl and butyl.

In another embodiment of formula (IF) compound, Q is unsubstituted heterocycloalkyl ring:

as; For example,

In another embodiment of formula (IF) compound, Q is substituted heterocycloalkyl ring:

as; For example,

as; For example,

L ³Instance comprise alkyl, for example, methyl and butyl.Therefore, these Q examples of groups comprise:

and

L wherein ³Be selected from :-alkylidene group-C (O) NH (C ₁-C ₆) alkyl (as ,-CH ₂C (O) NHC ₂H ₅With-CH ₂C (O) NHCH ₃) ,-alkylidene group-C (O) N ((C ₁-C ₆) alkyl) ₂, wherein each alkyl be independent select ,-alkylidene group-C (O) NH (C ₁-C ₆) haloalkyl (as ,-CH ₂C (O) NHCH ₂CF ₃) and-alkylidene group-C (O) N ((C ₁-C ₆) haloalkyl) ₂, wherein each alkyl is independent the selection.

L wherein ³Be selected from: the substituted alkyl of hydroxyl (for example, by the substituted alkyl of at least one OH group, for example, by the 1-3-substituted (C of OH group ₁-C ₆) alkyl and in one embodiment, by the substituted (C of 1 or 2-OH group ₁-C ₆) alkyl and in another embodiment, by the substituted (C of 2-OH group ₁-C ₆) alkyl and in another embodiment, for-CH ₂CH (OH) CH ₂CH ₃With another embodiment be-CH ₂CH ₂CH (OH) CH ₂OH).

L wherein ³Be selected from: 3-hydroxybutyl (CH ₂CH (OH) CH ₂CH ₃) and 2,3-dihydroxyl butyl (CH ₂CH ₂CH (OH) CH ₂OH).

L wherein ³Be selected from :-alkylidene group-S (O) ₂-(C ₁-C ₆) alkyl.

L wherein ³For-CH ₂CH ₂SO ₂CH ₂CH ₃Or-CH ₂CH ₂SO ₂CH ₃.

L wherein ³Be selected from :-alkylidene group-C (O)-(C ₁-C ₆) alkyl.

L wherein ³For-CH ₂CH ₂-C (O)-CH ₃

as; For example,

as; For example,

Wherein be connected in the L of N ³Group and the L that is connected in ring carbon ³Group is identical or different.

L in one embodiment ³For-C (O)-alkyl, for example ,-C (O) CH ₃

In addition, for example, formula (I) compound comprises such compound, and wherein m is 1 and R ²And R ⁴Form condensed ring (Q) with the carbon atom that connects shown in them, such compound has formula (IG):

Wherein Q is selected from following condensed ring: unsubstituted naphthenic base, by one or more L that independently are selected from ³The substituted naphthenic base of group, unsubstituted Heterocyclylalkyl and by one or more L that independently are selected from ³The substituted Heterocyclylalkyl of group.

In an embodiment preferred of formula (IG) compound, each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R6 ,-S (O) ₂R ⁷With-S (O) ₂R ⁸

In another embodiment preferred of formula (IG) compound, each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

In another embodiment preferred of formula (IG) compound, each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷, S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl, S (O) ₂R ⁶, S (O) ₂R ⁷,-S (O) ₂R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷.

In another embodiment of formula (IG) compound, ring " Q " is the condensed cycloalkyl ring.

In addition, for example, formula (I) compound comprises such compound, and wherein m is 1 and R ³And R ⁴Form condensed ring (Q) with the carbon atom that connects shown in them, such compound has formula (IH):

In an embodiment preferred of formula (IH) compound, each L ³Be identical or different-NHR ⁵Group and each R ⁵Independently be selected from :-S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl ,-S (O) ₂R6, S (O) ₂R ⁷With-S (O) ₂R ⁸

In another embodiment preferred of formula (IH) compound, each L ³Be identical or different OR ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

In another embodiment preferred of formula (IH) compound, each L ³Be identical or different R ⁵Group and each R ⁵Independently be selected from: H, (C ₁-C ₆) alkyl, R ⁶, R ⁷, S (O) ₂-(C ₁-C ₆) alkyl ,-S (O) ₂-(C ₁-C ₆) haloalkyl, S (O) ₂R ⁶, S (O) ₂R ⁷,-S (O) ₂R ⁸,-C (O)-(C ₁-C ₆) alkyl ,-C (O)-(C ₁-C ₆) haloalkyl ,-C (O)-R ⁶With-C (O)-R ⁷

In another embodiment of formula (IH) compound, ring " Q " is the condensed cycloalkyl ring.

At formula (I) compound, or in another embodiment of its pharmacy acceptable salt, solvate and/or ester, said compound can have formula (1F):

Wherein:

X is-O-;

R ³Be selected from H, alkyl, alkylidene group-OR ⁵, alkenyl ,-C (O) O-alkyl and-alkylidene group-C (O) O-alkyl; Or

R ²And R ³, or R ²And R ⁴, forming the condensed cycloalkyl ring with the atom that connects shown in them, wherein said condensed cycloalkyl ring is unsubstituted or by one or more L ³Group replaces;

Each R ⁴Independently be selected from H, alkyl and-alkylidene group-R ⁶With

Each R ⁵Independently be selected from H, alkyl, R ⁶,-C (O)-alkyl ,-C (O)-R ⁶With-C (O)-R ⁷

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃

L ³For-OR ⁵

N is 0,1,2 or 3; With

M is 1.

At formula (I) compound, or in another embodiment of its pharmacy acceptable salt, solvate and/or ester, said compound can have formula (1G):

Wherein

X is-O-;

R ³Be selected from H, alkyl, alkylidene group-OR ⁵Alkenyl ,-C (O) O-alkyl and-alkylidene group-C (O) O-alkyl; Or

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃

L ³For-OR ⁵

N is 0,1,2 or 3; With

M is 1.

At formula (I) compound, or in another embodiment of its pharmacy acceptable salt, solvate and/or ester, said compound can have formula (1H):

Wherein

X is-O-;

R ²And R ³, or R ²And R ⁴, forming the condensed cycloalkyl ring with the carbon atom that connects shown in them, wherein said condensed cycloalkyl ring is unsubstituted or by one or more L ³Group replaces;

Ar is a unsubstituted aryl or by one or more L ¹The substituted aryl of group;

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃

L ³For-OR ⁵

N is 0,1,2 or 3; With

M is 1.

Relate to preceding text to the described arbitrary embodiment of formula (IF) compound in other embodiment of the present invention, wherein said compound is free acid or free alkali.

Relate to preceding text to the described arbitrary embodiment of formula (IF) compound in other embodiment of the present invention, wherein said compound is a pharmacy acceptable salt.

Relate to preceding text to the described arbitrary embodiment of formula (IF) compound in other embodiment of the present invention, wherein said compound is pharmaceutically acceptable ester.

Relate to preceding text to the described arbitrary embodiment of formula (IF) compound in other embodiment of the present invention, wherein said compound is a solvate.

Relate to preceding text to the described arbitrary embodiment of formula (IG) compound in other embodiment of the present invention, wherein said compound is free acid or free alkali.

Relate to preceding text to the described arbitrary embodiment of formula (IG) compound in other embodiment of the present invention, wherein said compound is a pharmacy acceptable salt.

Relate to preceding text to the described arbitrary embodiment of formula (IG) compound in other embodiment of the present invention, wherein said compound is pharmaceutically acceptable ester.

Relate to preceding text to the described arbitrary embodiment of formula (IG) compound in other embodiment of the present invention, wherein said compound is a solvate.

Relate to preceding text to the described arbitrary embodiment of formula (IH) compound in other embodiment of the present invention, wherein said compound is free acid or free alkali.

Relate to preceding text to the described arbitrary embodiment of formula (IH) compound in other embodiment of the present invention, wherein said compound is a pharmacy acceptable salt.

Relate to preceding text to the described arbitrary embodiment of formula (IH) compound in other embodiment of the present invention, wherein said compound is pharmaceutically acceptable ester.

Relate to preceding text to the described arbitrary embodiment of formula (IH) compound in other embodiment of the present invention, wherein said compound is a solvate.

The X of formula (I) compound is selected from-C (R ¹) ₂,-O-,-NR ¹-with-N (C (O) R ¹), prerequisite is when X is 1 for-O-and m, R ², R ³Or R ⁴In at least one for being not the group of H.-C (R ¹) ₂,-NR ¹-with-N (C (O) R ¹) limiting examples comprise wherein R ¹Those groups like this paper definition.

Each R of formula (I) compound ¹Independent is H and alkyl, and wherein term " alkyl " comprises, for example, and-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH (CH ₃) ₂,-CH ₂CH ₂CH ₂CH ₃,-C (CH ₃) ₃,-C (CH ₃) CH ₂CH ₃,-CH ₂CH (CH ₃) ₂Deng.

In an embodiment of formula (I) compound, R ²Be selected from H, alkyl, alkylidene group-OR ⁵,-alkylidene group-R ⁶,-alkylidene group-C (O) O-alkyl ,-alkylidene group-R ⁸,-C (O) O-alkyl and alkenyl.Work as R ²During for " alkyl ", the limiting examples of said " alkyl " comprises, for example, reaches those alkyl of other local definition above this paper.Equally, work as R ²For-C (O) O-alkyl or-during alkylidene group-C (O) O-alkyl, the moieties of these groups for example can comprise above this paper and " alkyl " group of other local definition.Work as R ²For-alkylidene group-OR ⁵The time ,-alkylidene group-OR ⁵Limiting examples comprise wherein R ⁵Partly those groups and " alkylidene group " part like this paper definition comprises, as ,-CH ₂-,-CH ₂CH ₂-,-CH ₂CH ₂CH ₂-, wherein each above-mentioned alkylidene group can be chosen wantonly by low alkyl group and replace, and forms branched alkylidene thus.Such branched alkylidene comprises, for example-and CH (CH ₃)-,-C (CH ₃) ₂-,-CH (CH ₃) CH ₂-,-CH ₂CH (CH ₃)-etc.Equally, work as R ²For-alkylidene group-R ⁶,-alkylidene group-C (O) O-alkyl and-alkylidene group-R ⁸The time, " alkylidene group " part of these groups can comprise non-side chain or the branched alkylidene that defines like above this paper and other place.Work as R ²During for " alkenyl ", the limiting examples of " alkenyl " comprises those groups described herein, comprises-CH=CH ₂,-C (CH ₃)=CH ₂,-CH=CH (CH ₃) ,-CH ₂CH=CH ₂,-CH ₂CH ₂CH=CH ₂Deng.

In an embodiment of formula (I) compound, R ³Be selected from H, alkyl, alkylidene group-OR ⁵, alkenyl ,-C (O) O-alkyl and-alkylidene group-C (O) O-alkyl.Work as R ³During for alkyl, the limiting examples of alkyl comprises those alkyl that define like above this paper and other place.Work as R ³For-C (O) O-alkyl or-during alkylidene group-C (O) O-alkyl, limiting examples comprises that wherein its moieties can comprise, for example, as above this paper and the group of other local alkyl of describing.Equally, work as R ³Be alkylidene group-OR ⁵Or-during alkylidene group-C (O) O-alkyl, its limiting examples comprises that wherein alkylene moiety comprises above this paper and other local those groups of describing.

In an embodiment of formula (I) compound, R ⁴Independently be selected from H, alkyl and-alkylidene group-R ⁶Work as R ⁴During for alkyl, the limiting examples of such group comprises alkyl of describing like above this paper and other place.Equally, work as R ⁴For-alkylidene group-R ⁶The time, the limiting examples of such group comprises wherein R ⁶Part is like this paper definition, and alkylene moiety comprises those groups of those alkylidene groups of describing like above this paper and other place.

Radicals R ²And R ³, or R ²And R ⁴, or R ³And R ⁴, can form the condensed cycloalkyl ring with the atom that connects shown in them, wherein said condensed cycloalkyl ring is unsubstituted or by one or more L ³Group replaces.It will be understood by those skilled in the art that and work as R ²And R ⁴, or R ³And R ⁴When forming the condensed cycloalkyl ring, only form a condensed cycloalkyl ring.Therefore, when m is 2 or 2 when above, has only a R ⁴Form the part of condensed cycloalkyl ring, and other R ⁴Group independently is that this paper is to R ⁴One of group of definition.

In an embodiment of formula (I) compound, each R ⁵Independently be selected from H, alkyl, R ⁶,-C (O)-alkyl ,-C (O)-R ⁶With-C (O)-R ⁷The limiting examples of such group comprises wherein alkyl, or R ⁶, R ⁷And moieties such as above this paper and other local those groups of definition.

When formula (I) compound comprises radicals R ⁶, or a substituting group of said compound comprises R ⁶During part, then in an embodiment of formula (I) compound, said R ⁶Comprise any chemically stable, optional substituted aryl.The limiting examples of such aromatic yl group comprises phenyl, naphthyl, xenyl, anthryl (anthacenyl) etc.

When formula (I) compound comprises radicals R ⁷, or a substituting group of said compound comprises R ⁷During part, then said R ⁷Comprise any chemically stable, optional substituted Heterocyclylalkyl.Such Heterocyclylalkyl limiting examples comprises piperidyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, parathiazan base, thiazolidyl, 1; 4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, thiazolinyl, 2; 3-dihydrofuran-base, 2,3-dihydro-thiophene base etc.

When formula (I) compound comprises radicals R ⁸, or a substituting group of said compound comprises R ⁸During part, then said R ⁸Comprise any chemically stable, optional substituted naphthenic base.Its limiting examples comprises, for example, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl etc.

Ar comprises any chemically stable, optional substituted aryl.The limiting examples of such aromatic yl group comprises phenyl, naphthyl, xenyl, anthryl (anthacenyl) etc.

Each L ¹Independently be selected from halogen, alkyl ,-CN and-CF ₃Work as L ¹During for halogen, each halogen independently is F, Cl, Br or I.Work as L ¹During for alkyl, the limiting examples of said alkyl comprises those alkyl that define like above this paper and other place.

In an embodiment of formula (I) compound, each L ²Independently be selected from-OH, alkyl, by the substituted alkyl of one or more OH groups, and Heterocyclylalkyl.Work as L ²Be alkyl or Heterocyclylalkyl, the limiting examples of said alkyl or Heterocyclylalkyl comprises those groups that define like above this paper and other place.Work as L ²For by the substituted alkyl of one or more OH groups, the limiting examples of such group comprises-CH ₂ ^-OH ,-CH ₂CH ₂-OH ,-CH (OH) CH ₃,-CH ₂CH ₂CH ₂-OH ,-CH ₂CH (OH) CH ₃Deng.

In an embodiment of formula (I) compound, L ³For-OR ⁵Its limiting examples comprises-OH ,-the O-alkyl (wherein said moieties comprise as above this paper and other local alkyl of describing) ,-the O-aryl (wherein said aryl moiety comprise as above this paper and other local aryl of describing) ,-the O-acyl group ,-the O-aroyl ,-O-C (O)-R ⁷, wherein said acyl group, aroyl and R thereof ⁷Part defines like above this paper and other place.

Like preceding text, and the disclosure in full, used in following claims, except as otherwise noted, be interpreted as having following meaning:

" patient " comprise humans and animals both.

" Mammals " means people and other class of mammals animal.

" one or more " mean at least one, for example, and 1,2 or 3, or 1 or 2, or 1, therefore, for example, " one or more L ³Group " mean at least one L ³Group, and instance comprises 1-3L ³Group, 1 or 2L ³Group and a L ³Group.

" at least one " means and is at least one here, and instance comprises 1,2 or 3, or 1 or 2, or 1.

" alkyl " means aliphatic hydrocarbon group, and can be straight or branched and on chain, contain about 20 carbon atoms of the 1-that has an appointment.Preferred alkyl contains the about twelve carbon atom of the 1-that has an appointment on chain.More preferably alkyl contains about 6 carbon atoms of the 1-that has an appointment on chain.Side chain means one or more low alkyl groups such as methyl, ethyl or propyl group are connected in linear alkyl chain." low alkyl group " means a group and on chain, has about 6 carbon atoms of about 1-, and can be straight or branched.Term " substituted alkyl " means alkyl and can be replaced by one or more substituting groups; Said substituting group can be identical or different, each substituting group independently be selected from halo, alkyl, aryl, naphthenic base, cyanic acid, hydroxyl, alkoxyl group, alkylthio, amino ,-NH (alkyl) ,-NH (naphthenic base) ,-N (alkyl) ₂, carboxyl and-C (O) O-alkyl (only if in addition clearly limit).The limiting examples of suitable alkyl comprise methyl, ethyl, just-propyl group, sec.-propyl and tert-butyl.

" alkylidene group " means derived from the divalent aliphatic alkyl that as above defines alkyl.Two " open (open) " valencys can be at identical carbon atom, or on the different carbon atoms.The instance of alkylidene group comprises C ₁-C ₆Alkylidene group, for example, C ₁-C ₄Alkylidene group, and in another embodiment, be C ₁-C ₃Alkylidene group and in another embodiment is C ₁-C ₂Alkylidene group.The limiting examples of alkylidene group comprises-CH ₂-,-CH ₂-CH ₂-,-CH (CH ₃)-etc.

" alkynyl " mean the aliphatic hydrocarbyl that contains at least one carbon-to-carbon triple bond and its can be straight or branched and on chain, contain about 15 carbon atoms of the 2-that has an appointment.Preferred alkynyl group has about 12 carbon atoms of about 2-on chain; Reach more preferably about 4 carbon atoms of about 2-on chain.Side chain means one or more low alkyl groups such as methyl, ethyl or propyl group are connected on the linear alkynyl chain." low-grade alkynyl " means about 6 carbon atoms of the 2-that on chain, has an appointment, and can be straight or branched.The limiting examples of suitable alkynyl group comprises ethynyl, proyl, 2-butyne base and 3-methyl butynyl.Term " substituted alkynyl " means alkynyl group and can be replaced by one or more substituting groups, and said substituting group can be identical or different, and each substituting group independently is selected from alkyl, aryl and naphthenic base.

" aryl " means the aromatic monocyclic that contains about 14 carbon atoms of the 6-that has an appointment or encircles loop systems more, about 10 carbon atoms of preferably about 6-.Aryl can be by one or more " loop systems substituting groups " optional replacement, and said substituting group can be identical or different, and as defined herein.The limiting examples of suitable aromatic yl group comprises phenyl and naphthyl.

" heteroaryl " means aromatic monocyclic or encircles loop systems more and contain about 14 annular atomses of the 5-that has an appointment, about 10 annular atomses of preferably about 5-, and wherein one or more annular atomses are non-carbon, for example nitrogen, oxygen or sulphur (alone or in combination).Preferred heteroaryl contains about 6 annular atomses of the 5-that has an appointment." heteroaryl " can be by one or more " loop systems substituting groups " optional replacement, and said substituting group can be identical or different, and as defined herein.Prefix azepine, oxa-or thia before the heteroaryl root name refer to that respectively at least one nitrogen, oxygen or sulphur atom exist as annular atoms.The nitrogen-atoms of heteroaryl can be chosen wantonly and be oxidized to its corresponding N-oxide compound.The limiting examples of suitable heteroaryl comprises that pyridyl, pyrazinyl, furyl, thienyl, pyrimidyl, pyridone (comprise the substituted pyridone) of N-、 isoxazolyl, isothiazolyl 、 oxazolyl, thiazolyl, pyrazolyl, furazan base, pyrryl, pyrazolyl, triazolyl, 1; 2; 4-thiadiazolyl group, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindole base, imidazo [1; 2-a] pyridyl, imidazo [2; 1-b] thiazolyl, benzo furazan base, indyl, azaindolyl, benzimidazolyl-, benzothienyl, quinolyl, imidazolyl, thienopyridine base, quinazolyl, Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinolyl, benzo-aza indyl, 1; 2,4-triazinyl, benzothiazolyl etc.Term " heteroaryl " also finger divides saturated heteroaryl moieties, for example tetrahydro isoquinolyl, tetrahydric quinoline group etc.

" naphthenic base " means non-aromatics list-or polycyclic loop systems, comprises about 3 to about 10 carbon atoms, is preferably about 5 to about 10 carbon atoms.Preferred cycloalkyl ring contains has an appointment 5 to about 7 annular atomses.Naphthenic base can be chosen wantonly by one or more " loop systems substituting group " and replace, and said substituting group can be identical or different, and all defines like preceding text.The limiting examples of suitable saturated monocyclic cycloalkyl comprises that the limiting examples of the unsaturated monocyclic cycloalkyl of cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc. and non-aromatics comprises cyclopentenyl, cyclohexenyl etc.Suitably the limiting examples of polycyclic naphthene base comprise 1-decahydro naphthyl, norcamphyl, golden steel alkyl etc., and the group of fractional saturation for example, indanyl, tetralyl etc.

" halogen " or " halo " means fluorine, chlorine, bromine or iodine.Be preferably fluorine, chlorine and bromine.

" loop systems substituting group " means the substituting group that is connected to aromatics or non-aromatic ring system, and it is the available hydrogen in the D-loop system for example.The loop systems substituting group can be identical or different, be selected from independently of one another alkyl, thiazolinyl, alkynyl, aryl (substituted or unsubstituted), heteroaryl (substituted or unsubstituted), alkylidene group-aryl, heteroaryl alkenyl, heteroaryl alkynyl, hydroxyl, hydroxyalkyl, alkoxyl group, aryloxy, the substituted alkoxyl group of aryl, acyl group, aroyl, halo, nitro, cyanic acid, carboxyl, carbalkoxy, aryloxycarbonyl, aromatic alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl, heteroarylsulfonyl, alkylthio, artyl sulfo, heteroaryl sulfenyl, aromatic alkylthio, heteroaralkyl sulfenyl, naphthenic base, Heterocyclylalkyl ,-C (=N-CN)-NH ₂,-C (=NH)-NH ₂,-C (=NH)-NH (alkyl), Y ₁Y ₂N-, Y ₁Y ₂The N-alkyl-, Y ₁Y ₂NC (O)-, Y ₁Y ₂NSO ₂-with-SO ₂NY ₁Y ₂, Y wherein ₁With Y ₂Can be identical or different, and be independently selected from hydrogen, alkyl, aryl, naphthenic base and-alkylidene group-aryl (only if limiting clearly in addition).Term " loop systems substituting group " also can mean single part, and it on two adjacent carbonss of loop systems, replaces two available hydrogen (H on each carbon) simultaneously.The instance of this kind part be methylene-dioxy, ethylenedioxy ,-C (CH ₃) ₂-etc., it forms for example with the lower section:

" Heterocyclylalkyl " means the non-aromatic monocyclic shape or encircles loop systems more; It comprises about 3 to about 10 annular atomses; Preferred about 5 to about 10 annular atomses, and wherein one or more atom in this loop systems is the element beyond the carbon, for example nitrogen, oxygen or sulphur (separately or combine).There are not adjacent oxygen and/or sulphur atom to be present in this loop systems.Preferred Heterocyclylalkyl contains has an appointment 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before Heterocyclylalkyl root title mean and exist at least one nitrogen, oxygen or sulphur atom as annular atoms respectively.Any-NH in the heterocycloalkyl ring can by the protection precedent as-N (Boc) ,-N (CBz) ,-N (Tos) group etc. and existing; This kind protection also is regarded as a part of the present invention.Heterocyclylalkyl can be chosen wantonly by one or more " loop systems substituting group " and replace, and said substituting group can be identical or different, and all defines like this paper.The nitrogen of Heterocyclylalkyl or sulphur atom can be chosen wantonly and be oxidized to its corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.Suitably the limiting examples of monocyclic heterocycles alkyl ring comprises piperidyl, pyrrolidyl, piperazinyl, morpholinyl, parathiazan base, thiazolidyl, 1,4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, lactan, lactone etc.The limiting examples of the unsaturated monocyclic heterocycles alkyl of non-aromatics ring comprises thiazolinyl, 2,3 dihydro furan base, 2,3-dihydro-thiophene base etc.

It should be noted, contain in the heteroatomic loop systems do not have hydroxyl on the carbon atom of contiguous N, O or S, and do not have N or S group on contiguous another heteroatomic carbon in the present invention.Therefore, for example in following ring:

Do not have-OH is connected directly to and is denoted as on 2 and 5 the carbon.

Should also be noted that tautomeric form, for example with the lower section:

In certain embodiments of the invention, be considered to be equal to.

" hydroxyalkyl " means with hydroxyl (OH) the substituted alkyl of group, wherein alkyl such as above-mentioned definition.Preferred hydroxyalkyl comprises low alkyl group.The limiting examples of suitable hydroxyalkyl comprises hydroxymethyl and 2-hydroxyethyl.

" acyl group " mean H-C (O)-, alkyl-C (O)-or naphthenic base-C (O)-group, wherein various groups are all of preamble.Key tying-in to parent fraction is crossed carbonyl.Preferred acyl group contains low alkyl group.Suitably the limiting examples of acyl group comprises formyl radical, ethanoyl and propionyl group.

" aroyl " means aryl-C (O)-group, and wherein aryl such as preamble are said.Key tying-in to parent fraction is crossed carbonyl.Suitably the limiting examples of group comprises benzoyl-and 1-naphthoyl.

" alkoxyl group " means-the O-alkyl group, and wherein alkyl such as preamble are said.The suitable limiting examples of alkoxyl group, comprise methoxyl group, oxyethyl group, just-propoxy-, isopropoxy and just-butoxy.Key tying-in to parent fraction is crossed ether oxygen.

" aryloxy " means-the O-aromatic yl group, and wherein aryl such as preamble are said.Suitably the limiting examples of aryloxy comprises phenoxy and naphthyloxy.Key tying-in to parent fraction is crossed ether oxygen.

" alkylthio " means-the S-alkyl group, and wherein alkyl such as preamble are said.Suitably the limiting examples of alkylthio comprises methylthio group and ethylmercapto group.Key tying-in over cure to parent fraction.

" arylthio " means-the S-aromatic yl group, and wherein aryl such as preamble are said.Suitably the limiting examples of artyl sulfo comprises thiophenyl and naphthyl sulfenyl.Key tying-in over cure to parent fraction.

" alkylthio-aryl " means-S-alkylidene group-aromatic yl group, and wherein alkylidene group and aromatic yl group such as preamble are said.Suitably the limiting examples of aromatic alkylthio is a benzylthio-.Key tying-in over cure to parent fraction.

" carbalkoxy " means alkyl-O-CO-group.Suitably the limiting examples of carbalkoxy comprises methoxycarbonyl and ethoxycarbonyl.Key tying-in to parent fraction is crossed carbonyl.

" aryloxycarbonyl " means aryl-O-C (O)-group.Suitably the limiting examples of aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.Key tying-in to parent fraction is crossed carbonyl.

" aromatic alkoxy carbonyl " means-C (O)-O-alkylidene group-aromatic yl group.Suitably the limiting examples of aromatic alkoxy carbonyl is a carbobenzoxy-(Cbz).Key tying-in to parent fraction is crossed carbonyl.

" alkyl sulphonyl " means alkyl-S (O ₂)-group.Preferred group is those of low alkyl group for alkyl wherein.Key tying-in to parent fraction is crossed alkylsulfonyl.

" aryl sulfonyl " means aryl-S (O ₂)-group.Key tying-in to parent fraction is crossed alkylsulfonyl.

One or more hydrogen that term " substituted " means on specified atom is selected from specified group replacement, and its condition is can not surpass specified atom in the normal valence link that exists under the situation, and this to replace the stable compound of meeting generation.The combination of substituting group and/or variable only can generate under the stable compound in this kind combination and just can allow.It is enough strong and remain in the reaction mixture that so-called " stable compound " or " stable structure " means compound, is separated to useful purity and is deployed into effective therapeutical agent.

When a group was replaced by " one or more " substituting group, specified group can be by a substituting group, two replacements such as substituting group.Condition is that the substituting group that obtains forms aforesaid rock steady structure.

Term " optional substituted " means with special groups, atomic group or part are optional and replaces.For example, comprise unsubstituted aryl by the optional substituted aryl of specified substituting group group and by the substituted aryl of arbitrary specified substituting group.

Term " isolating " or " being isolating form " about compound refer to that this compound is in the physical condition after compound method or natural origin or its combination and separation.About term " purifying ", " form that is purifying " of compound refer to this compound derive from described in purification process or this paper or method that skilled technician is known after physical condition; It has abundant purity, can through described in this paper or the standard analytical techniques characteristic known of skilled technician identify.

Should also be noted that any carbon atom and any heteroatoms with unsaturation valence link all is assumed that the Wasserstoffatoms with enough numbers, to satisfy this valence link in content, flow process, embodiment and the form etc. at this paper.

When the functional group in the compound was called as " protection ", this meant the form that this group is modification, with when the compound acceptable response, removed by the undesired side reaction at protective position place.The due care base will be by those of ordinary skills and reference standard textbook and is understood, T.W.Greene etc. for example, the protection base (1991) of organic synthesis, Wiley, NewYork.

As any variable (for example aryl, heterocycle, R ²Deng) when in any composition or formula I, occurring surpassing one time, its definition and its definition irrelevant (only if clearly indicating in addition) when other place occurs at every turn when each time occurs.

The term that uses among this paper " compsn " is intended to contain the product of the special component that comprises specified quantitative, and directly or indirectly by the spawn that is combined to form of the special component of specified quantitative.

The prodrug of The compounds of this invention and solvate also are intended to be included among this paper.The term that in this paper, uses " prodrug " means the compound as prodrug, and it is giving the patient after the successive dynasties thank or the chemical conversion of chemical process and production (I) compound or its salt and/or solvate.The discussion of prodrug; By T.Higuchi and V.Stella, " prodrug is as new transfer system ", A.C.S. collection of thesis series the 14th volume (1987); With the biological reversible carrier in medicinal design; Edward B.Roche edits, and provides in American Medical Association and the Pergamon press (1987), and both all are attached among this paper by reference.

The physics that " solvate " means The compounds of this invention and one or more solvent molecule associates.This physics associates and relates to ion and covalent linkage knot in various degree, comprises hydrogen bond.In some situation, solvate can be separated, for example, and when one or more solvent molecule is incorporated in the lattice of crystalline solid." solvate " comprises solution and separable solvate.The limiting examples of appropriate solvent compound comprises ethoxy, methylate etc." hydrate " is H for solvent molecule wherein ₂The solvate of O.

" significant quantity " or " treatment significant quantity " is intended to describe The compounds of this invention or proteic formation of the effective prevention of amyloid of compsn and/or deposition, thereby produces the amount of required treatment, general introduction, inhibition or preventive effect.

Formula (I) compound can form salt, and it also within the scope of the invention.When this paper relates to formula (I) compound,, otherwise comprise the salt that it relates to only if it should be understood that in addition and point out.When in this paper, adopting, term " salt " representes by acid-salt inorganic and/or that organic acid forms, and by basic salt inorganic and/or that organic bases forms.In addition, when formula (I) compound contain basic moiety (such as but not limited to pyridine or imidazoles) and acidic moiety (such as but not limited to carboxylic acid) both the time, can form zwitter-ion (" inner salt "), and be comprised in as in the term " salt " that uses among this paper.The salt of pharmaceutically acceptable (meaning is can accept on nontoxicity, the physiology) is for preferred, but other salt also can use.The salt of formula (I) compound can be for example through making formula (I) compound and a certain amount of acid or alkali, and for example equivalent medium (for example salt can be deposited in medium wherein), or is reacted in aqueous medium, then lyophilize and forming.

Exemplary acid salt, comprise acetate, ascorbate salt, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphorate, camsilate, fumarate, hydrochloride, hydrobromate, hydriodate, lactic acid salt, maleic acid salt, methane sulfonates, naphthalenesulfonate, nitrate salt, oxalate, phosphoric acid salt, propionic salt, salicylate, SUMATRIPTAN SUCCINATE, vitriol, tartrate, thiocyanate-, tosylate (toluenesulfonate) (being also referred to as tosylate (tosylate)) etc.In addition, it is generally acknowledged to be applicable to, for example by P.Stahl etc., Camille G. (editor) pharmaceutical salts handbook from the pharmaceutically acid of acceptable salts of basic medicinally compound formation. character, selection and purposes. (2002) Zurich:Wiley-VCH; S.Berge etc., medical science periodical (1977) 66 (1)1-19; P.Gould, international pharmacopedics periodical (1986) 33201-217; Anderson etc., medical chemistry put into practice (1996), university press, New York; With discussed at Orange Book (D.C. is on its website for food and drug administration, Washington) those.These disclosures are incorporated into this paper by reference.

Exemplary basic salt comprises ammonium salt, an alkali metal salt; For example sodium, lithium and sylvite, alkaline earth salt, for example calcium and magnesium salts; Salt with organic bases (for example organic amine); Said alkali is for example dicyclohexylamine, tert-butylamine, and with the salt that is become with amino acid, said amino acid is for l-arginine for example, from propylhomoserin etc.The alkalescence nitrogen-containing group can be quaternized by reagent, and said reagent for example has elementary alkyl halide (the for example muriate of methyl, ethyl and butyl, bromide and iodide), sulfuric acid dialkyl (the for example sulfuric ester of dimethyl-, diethylammonium and dibutyl), long-chain halogenide (the for example muriate of decyl, lauryl and stearyl, bromide and iodide), aralkyl halide (the for example bromide of benzyl and styroyl) and other.

All these hydrochlorates and alkali salt are intended to be the pharmacy acceptable salt in the scope of the invention, and for the purposes of this invention, all acid and alkali salt all are considered to be equivalent to the free form of respective compound.

Formula (I) compound with and salt, solvate, ester and prodrug, can its tautomeric form have (for example as acid amides or imido ether).All these type of tautomeric forms are intended to covered among this paper, as a part of the present invention.

The compounds of this invention (salt, solvate, ester and the prodrug that comprise this compound; And the salt of this prodrug, solvate and ester) all steric isomers (for example geometrical isomer, optical isomer etc.); Those isomer that for example can exist owing to the asymmetric carbon on the different substituents; Comprise chirality isomeric form (itself even can under the situation of no asymmetric carbon, exist), rotational isomeric form, atropisomer and diastereomeric form; All be intended to covered in the scope of the present invention, for example positional isomers (for example 4-pyridyl and 3-pyridyl).Each steric isomer of The compounds of this invention can for example be substantially free of other isomer, or can be for example through being mixed into racemoid, or with all other or other mix through the steric isomer of selecting.Chiral centre of the present invention can have as advising defined S or R configurations by IUPAC 1974.The use of term " salt ", " solvate ", " prodrug " etc. is intended to likewise be applicable to salt, solvate and the prodrug of enantiomorph, steric isomer, rotational isomer, tautomer, positional isomers, racemoid or the prodrug of The compounds of this invention.

The polymorphic of formula (I) compound, and salt, solvate and the prodrug of formula (I) compound all are intended to comprise within the scope of the invention.

Can have pharmacological property according to compound of the present invention; Particularly, formula (I) compound can suppress gamma-secretase, thereby is used for treatment or prevention neurodegenerative disease, like Alzheimer.

Representative compound of the present invention includes but not limited to compound described herein and embodiment.

Medicinal compsns can comprise one or more formulas (I) compound.For from compound medicinal compsns of the present invention, no matter the pharmaceutically acceptable carrier of inertia is solid or liquid if can be.But the solid form preparation comprises powder, tablet discrete particles, capsule, cachet and suppository.Powder and tablet can comprise about 5 to about 95% active compound.Suitable solid carrier is known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum, sugar or lactose.Tablet, powder, cachet and capsule can be used as the solid dosage that is suitable for oral administration and use.The instance of pharmaceutically acceptable carrier and the method for making of various compsns can be consulted A.Gennaro (editor), the RemingtonShi medical science, the 18th edition (1990), and Mack publishing company, Easton, Pennsylvania, it is attached among this paper in full by reference.

Liquid form preparation comprises solution, suspension-s and emulsion.It is non-through the enteral administration agent to mention that as an example water or water-propylene glycol solution are used for, or adds sweetener and opalizer, is used for oral liquid, suspension-s and emulsion.Liquid form preparation also can comprise the solution that supplies intranasal administration.

The aerosol preparations that is applicable to suction can comprise solution and be the solid of powder type, its can and with pharmaceutically acceptable carrier, for example inertia pressurized gas, for example nitrogen.

Also comprise the solid form preparation, it was intended to before using to be converted to liquid form preparation soon, for oral or non-through enteral administration.This type of liquid form comprises solution, suspension-s and emulsion.

The compounds of this invention also can transmit through the skin mode.Transdermal composition can be taked the form of emulsifiable paste, lotion, aerosol and/or emulsion, and can be comprised in matrix or depot in the skin patch, be used for the mode of this purpose as this area routine.

Pharmaceutical prepn preferably is unit dosage.In this type of form, preparation is subdivided into the unitary dose of suitable size, contains the active compound of appropriate amount, for example reach institute's syllabus significant quantity.

The single dose unit that term " medicinal compsns " is also intended to comprise feedstock composition and (as two) pharmaceutically active agents is formed more than one; For example; The compounds of this invention and the other medicine that is selected from other medicine tabulation described here, and the vehicle of any pharmaceutically non-activity.Above-mentioned " the more than one pharmaceutically active agents " of fixed amount can be contained in feedstock composition and each single dose unit.Feedstock composition is not for form the raw material of single dose unit as yet.Exemplary dose unit is oral dosage list such as tablet, pill etc.Similarly, as herein described be also intended to comprise through the method that gives medicinal compsns of the present invention treatment patient give above-mentioned raw materials compsn and single dose unit.

The amount of reactive compound in unit dose formulations can change or adjust, from the about 1000mg of about 0.01mg-, and the about 750mg of preferably about 0.01mg-, the more preferably from about about 500mg of 0.01mg-and the most preferably from about about 250mg of 0.01mg-decide based on application-specific.The actual dose that is adopted can change according to patient's requirement and by sanatory seriousness.Mensuration is for the suitable dosage regimen of particular condition, in those skilled in the art's technical scope.For simplicity, can total day clothes dosage be separated, and gradation gives in when needed during one day.

The dosage of The compounds of this invention and/or its pharmacy acceptable salt and frequency are being considered some factors according to the attending doctor, and for example the judgement after the seriousness of patient's age, symptom and body weight and quilt treatment symptom is adjusted.To dosage instructions about how to take medicine every day that the typical case of oral dosage regimen recommends, can contain from about 0.04mg/ days-Yue 4000mg/ days, give by one to four divided dose.

Embodiment

The present invention disclosed herein gives an example with following preparation and embodiment, and it should not be interpreted as the scope of restriction present disclosure.Alternate mechanism pathway and similar structures will be conspicuous to those skilled in the art.

Proposing under the NMR data conditions, ¹H spectrum in Varian VXR-200 (200MHz, ¹H), Varian Gemini-300 (300MHz) or XL-400 (400MHz) go up and obtain, and with the ppm report apart from the downfield of Me4Si, wherein proton number, multiplicity and coupling constant (representing with hertz) are indicated with the bracket mode.Proposing under the LC/MS data conditions, analyzing and use AppliedBiosystems API-100 mass spectrograph and Shimadzu SCL-10A LC post to carry out: Altech platinum C18,3 microns, 33mmx7mm internal diameter; Gradient flow quantity: 0 minute-10%CH ₃CN, 5 minutes-95%CH ₃CN, 7 minutes-95%CH ₃CN, 7.5 minutes-10%CH ₃CN, 9 minutes-stop.Provide RT and the parent ion of being found.

Following solvent and reagent can be represented through its abbreviation in bracket:

Ethanoyl (Ac), that is, and CH ₃C (O)-

Butyl (Bu)

Cyclopropyl (Pr-c)

Ethylene dichloride (DCE)

Methylene dichloride (DCM)

Ether (Et ₂O)

Diisobutyl aluminium hydride (DIBAL-H)

N (DMF)

Ethanol (EtOH)

Ethyl (Et)

ETHYLE ACETATE (EtOAc)

High resolution mass spec (HRMS)

Di-isopropyl lithamide (LDA)

LC/mass spectrum (LCMS)

M-chloro benzoic acid (mCPBA)

Methylsulfonyl (Ms), promptly-S (O) ₂CH ₃

Methyl alcohol (MeOH)

Methyl (Me)

NMR spectrum (NMR)

Preparation type thin-layer chromatography (PTLC)

Pyridine (Pyr)

Room temperature (RT)

Tert-butyl dimetylsilyl (TBS)

Tetrabutyl ammonium fluoride (TBAF)

THF (THF)

Trifluoroacetic acid (TFA)

Trimethyl silyl (TMS)

Trimethylsilyl chloride (TMSCl)

Triethylamine (NEt ₃Or Et ₃N)

The whole bag of tricks that formula (I) compound can be known by one of skill in the art and through the preparation of following method.Following method is typical.

Formula (I) compound can be according to the method preparation of universal method 1 general introduction.

Universal method 1

In the presence of appropriate reductant such as borine, choose wantonly acid as in the presence of the trifluoroacetic acid, with the thiol treatment cyclic ketones like (i).According to known method, make the sulfide oxidation that obtains, for example use peracid or oxone, obtain sulfone (ii).Formula (I) compound, wherein R ³Be H and R ²Be not H, can through with suitable alkali such as LDA or just-butyllithium processing sulfone (ii), then use radicals R ²(wherein Z is that leavings group such as halogeno-group or sulfonate radical or other make R to Z ³Become electrophilic functional group) the alkylation preparation.R wherein ³Can then not use radicals R through handling compound (i) with suitable alkali such as LDA for the formula of H (I) compound ³(wherein Z is that leavings group such as halogeno-group or sulfonate radical or other make R to Z ³Become electrophilic functional group) the alkylation preparation.(iii) said according to being used to that (i) is converted into, the ketone that obtains (iv) is converted into sulfone (v).

Formula (I) compound, particularly when X be-O-, S ,-NR ¹-with-N (C (O) R ¹) time, can be according to universal method 2 preparations.

Universal method 2

Handle sulfone (vi) (Z wherein with suitable alkali such as sodium hydride or LDA ¹Like the definition of again) to Z.(vii) handle, wherein Z as above defines and P is optional blocking group such as trimethyl silyl, tert-butyl dimetylsilyl, uncle-butoxy carbonyl the negatively charged ion that obtains, or benzyloxycarbonyl with alkylating agent.After removing optional blocking group, choose wantonly at alkali such as sodium hydride, cyclisation is chosen wantonly under the existence of salt of wormwood or LDA, obtains compound (iv).As said, can compound (iv) be converted into other formula (I) compound in other place.

Formula (I) compound is particularly worked as R ³When being not H, also can be through universal method 3 preparations.

Universal method 3

Vinyl sulphone (ix) is used nucleophilic reagent R ³-M handles, and wherein M is metal such as sodium, lithium, potassium, magnesium, copper or zinc, the optional nucleophilic reagent R that then uses ²Z handles, and wherein Z as above defines.

Formula (1F) compound can pass through universal method 1,2 or 3, with two R ²And R ³Group combines and prepares.Perhaps, formula (IF) compound (wherein Q is substituted or unsubstituted cyclohexyl ring) can be according to universal method 4 preparations.

Universal method 4

Choose wantonly in the presence of acid catalyst such as zinc chloride or boron trifluoride, in solvent such as toluene or phenylfluoroform, handle vinyl sulphone (ix), obtain formula (1F) compound with diolefine (x).

In addition, formula (1F) compound, wherein Q is substituted or unsubstituted heterocycle, and particularly wherein said substituted or unsubstituted heterocycle is as at the pyranoid ring shown in the XI, can be according to universal method 5 preparations.

Universal method 5

Method 1-5 graphic extension is used to prepare the universal method of The compounds of this invention.Functional group through being described below handles, and some The compounds of this invention can be converted into other The compounds of this invention.

Embodiment 1 and 2:

1-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4-tetrahydrochysene-naphthalene and 1-(4-chloro-benzenesulfonyl)-5,8-difluoro 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-naphthalene

Flow process 1-A

Step 1

To the LiCl in ST (3.39g, 80mmol) and acid chloride (II) (450mg adds 2 in DMF 2.0mmol) (75mL) solution; 5-difluoro benzyl bromide (9.65mL; 75mmol), vinylformic acid tert-butyl ester (11.9mL, 82mmol) and Tributylamine (19.5mL, 82mmol).Then reactant was stirred 2 hours in 45 ℃, again in 120 ℃ of stirred overnight.Make refrigerative solution be dissolved in Et ₂O, water and brine wash, dry and concentrated.Residue obtains 9.26g (49%) alkene through flash chromatography on silica gel purifying (with hexane/DCM 75:25-DCM wash-out).

Step 2

(6.36g, hydrogenation is 90 minutes 25mmol) and under the mixture 25psi of 10%Pd/C (650mg) in EtOH (20mL) and EtOAc (20mL), filters and concentrates through CELITE then, obtains 6.34g (99%) tert-butyl ester with the olefin product of step 1.

Step 3

(5.00g, 19.5mmol) solution in DCM (10mL) and TFA (10 mL) stirred 1 hour under room temperature, concentrated then with the tert-butyl ester products that derives from step 2.Also (3.35mL 39mmol) handles with 1 DMF with oxalyl chloride to make crude product (3.95g) be dissolved in DCM (20mL).Under room temperature, stirred this reactant 30 minutes, concentrate then.(5.20g 39mmol) and under room temperature stirred this reactant 2 days in the DCM of this crude product (15mL) solution, to add AlCl3.Among the 0.1N HCl that the final mixture impouring is ice-cooled, extract with DCM, dry and concentrated.Residue obtains 3.17g (89%) ketone through flash chromatography on silica gel purifying (with hexane/DCM7:3-DCM wash-out).

Step 4

In 0 ℃, (67mg, 0.37mmol) (56mg adds TFA (0.5mL) in DCM 0.39mmol) (0.4mL) solution, after 10 minutes, adds pyridine borane complexes (40 μ L) with the 4-chlorothio-phenol to the ketone product that derives from step 3.Then this solution was stirred 40 minutes in 0 ℃, concentrate then.Make residue be dissolved in Et ₂O and IN NaOH use Et ₂O extracts, through dried over sodium sulfate and concentrated.Also (172mg 1.0mmol) handles with mCPBA57 to make residue be dissolved in DCM (1mL).After reaction was spent the night, crude product washed with sodium carbonate solution, dry and concentrate with residue through preparation of silica gel type chromatography purification (with hexane/DCM1:1 wash-out), obtain 45.5mg embodiment 1: ¹HNMR (CDCl ₃400MHz) δ 7.67 (d, J=8.7Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 6.97 (m, 1H), 6.72 (m, 1H), 4.61 (d, 1H), 3.92 (m, 1H), 2.65-2.75 (m, 2H), 2.43 (m, 1H), 1.90 (m, 1H), 1.78 (m, 1H); LCMS (MH ⁺)=343.2; RT=4.71 minute.

Step 5

In-78 ℃, (21.9mg, (30 μ L, the BuLi2.5N in 0.07mmol) adds methyl iodide (30 μ L) after 2 minutes, make reaction mixture be warmed to room temperature to be added in hexane in THF 0.064mmol) (0.3mL) solution to the embodiment that derives from step 41 product.After 10 minutes, with the saturated NH of reaction mixture impouring ₄Among the Cl, extract, through dried over sodium sulfate and concentrated with DCM.Residue obtains 12.6mg embodiment 2 through preparation of silica gel type chromatography purification (with hexane/EtOAc9:1 wash-out): ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, J=8.7Hz, 2H), 7.45 (d, J=8.7Hz, 2H), 6.98 (m, 1H), 6.76 (m, 1H), 2.90 (m, 1H), 2.55-2.70 (m, 2H), 2.44 (m, 1H), 1.75-1.85 (m, 2H), 1.80 (s, 3H); LCMS (2MH ⁺)=713.4; RT=4.90 minute.

According to those methods that are similar to the flow process 1-A that is used for preparing embodiment 1 and 2, replace suitable electrophilic reagent and also replace the ketone product in the step 4, the compound among the preparation table 1-A with the ketone that obtains easily

Table 1-A

Embodiment 1-T:

(3R)-3-hydroxyl-tetramethyleneimine-1-carboxylic acid 2-[1-(4-chloro-benzenesulfonyl)-7-fluoro-1,2,3,4-tetrahydrochysene-naphthalene-1-yl]-ethyl ester

Flow process 1-B

Step 1

In-78 ℃, (100mg, (0.12mL, 0.30mmol) solution and with the solution stirring that obtains 10 minutes makes to be warming up to room temperature 5 minutes, and then is cooled to-78 ℃ to add the hexane of n-BuLi2.5N in THF 0.30mmol) (2mL) solution to embodiment 1-I.With the bromoethanol of TBS protection (0.32mL, 1.50mmol) quencher it.Make reactant be warming up to room temperature 2 days.In final mixture impouring water, extract with DCM, dry and concentrated.Residue obtains the alcohol of 90mg TBS-protection through preparation of silica gel type chromatography purification (with hexane/EtOAc90:10 wash-out).

Step 2

The pure product of TBS-protection is derived from step 1 (90mg; 0.186mmol) THF (5mL) solution with the THF of TBAF 1N (0.20mL, 0.20mmol) solution-treated and stirring 2 hours.Then reactant is concentrated,, obtain 54mg alcohol through preparation of silica gel type chromatography purification (with hexane/EtOAc80:20 wash-out).

Step 3

To the pure product that derives from step 2 (55mg, add in THF 0.149mmol) (1mL) and acetonitrile (0.5mL) solution carbonochloridic acid 4-nitrophenyl ester (60mg, 0.298mmol) with pyridine (0.08mL) and under room temperature this reactant of stirring 2 hours.Final mixture 1N HCl washing is extracted with DCM then.After concentrating, bullion obtains 70mg carbonic acid nitrophenyl ester through preparation of silica gel type chromatography purification (with hexane/EtOAc80:20 wash-out).

Step 4

With the carbonic acid nitrophenyl ester products (15mg) that derives from step 3 and (S)-DCE (1mL) solution stirred overnight under room temperature of 3-hydroxyl pyrrolidine (15mg).Water washing reaction thing extracts and drying with DCM.After concentrating, bullion obtains 6.0mg embodiment 1-T through preparation of silica gel type chromatography purification (with hexane/EtOAc 50:50 wash-out): ¹H NMR (CDCl ₃400MHz) δ 7.48 (d, J=8.7Hz, 1H), 7.35 (brs, 4H), 6.95 (d, J=7.2,2H); 4.42 (brs, 1H), 4.10-4.25 (m, 1H), 3.90-4.05 (m, 1H), 3.10-3.50 (m, 3H); 2.90-3.00 (m, 1H), 2.40-2.60 (m, 2H), 2.15-2.35 (m, 2H), 2.00-2.15 (m; 1H), 1.75-1.95 (m, 2H), 1.40-1.70 (m, 3H), 1.25 (brs, 1H); LCMS (MH ⁺)=482.3; RT=3.98 minute.

According to those methods that are similar to the flow process 1-B that is used to prepare embodiment 1-T, the compound among the preparation table 1-3.

Table 1-B

Embodiment 3 and 4:

Cis-1-(4-chloro-benzenesulfonyl)-2-ethyl-5,8-two fluoro-1,2,3,4-tetrahydrochysene-naphthalene and anti-form-1-(4-chloro-benzenesulfonyl)-2-ethyl-5,8-two fluoro-1,2,3,4-tetrahydrochysene-naphthalene

Flow process 2-A

Step 1

In-78 ℃, to deriving from flow process 1-A, the ketone product of step 3 (398mg, hexane (1.20mL, 2.19mmol) solution of adding LDA1.8N in THF 2.18mmol) (2mL) solution.Make reactant be warming up to-30 ℃, be cooled to-78 ℃ once more, and slowly add EtI (175uL, 2.18mmol).Make reactant be warming up to ambient temperature overnight, then the saturated NH4Cl of impouring and extract with DCM.After concentrating, bullion makes ethyl ketone, then wash-out 314mg starting raw material ketone according to the wash-out 32.7mg of elution order elder generation through flash chromatography on silica gel purifying (with hexane/EtOAc95:5-7:3 wash-out).

Step 2

According to the condition described in the step 4 that is similar to flow process 1-A, make from the ethyl ketone product and the reaction of 4-chlorothio-phenol of step 1, after silica gel separates, obtain cis-compound, i.e. embodiment 3 and trans-compound embodiment 4.Embodiment 3: ¹H-NMR (CDCl ₃400MHz) δ 7.55 (d, J=8.7Hz, 2H), 7.39 (d, J=8.7Hz, 2H), 6.91 (m, 1H), 6.58 (m, 1H), 4.65 (brs, 1H), 3.10 (m, 1H), 2.88 (m, 1H), 2.57 (m, 1H), 1.80-2.15 (m, 4H), 1.07 (t, J=7.2Hz, 3H); LCMS (MH ⁺)=371.2; RT=5.27 minute.Embodiment 4: ¹H-NMR (CDCl ₃400Mhz) δ 7.61 (d, J=8.7Hz, 2H), 7.43 (d, J=8.7Hz, 2H), 6.95 (m, 1H), 6.67 (m, 1H), 4.39 (brs, 1H), 2.70-2.80 (m, 3H), 2.46 (m, 1H), 1.46 (m, 1H), 1.30-1.40 (m, 2H), 0.93 (t, J=7.2Hz, 3H); LCMS (MH ⁺)=371.2; RT=5.21 minute.

According to being similar to those methods of in flow process 1-A, 1-B and 2-A, describing, the compound among the preparation table 2-A.

Table 2-A

Embodiment 3-G:

(3R)-and 3-hydroxyl-tetramethyleneimine-1-carboxylic acid 1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydrochysene-naphthalene-2-base-methyl ester

Flow process 2-B

Step 1

(700mg, 17.5mmol) (0.665mL, 5.0mmol), (1.20mL 14.3mmol) also should react backflow and spend the night the adding of the mixture in THF (35mL) α-Tetralone an intermediate of Sertraline then to add methylcarbonate to NaHH60%.Concentrate then, make to be dissolved in Et2O and half the-salt solution, with half brine wash twice, dry and concentrated.Residue obtains 936mg ester ketone through flash chromatography on silica gel purifying (with hexane/DCM 80:20-DCM wash-out).

Step 2

Make from the ester ketone product of step 1 (408mg, 2.00mmol) with the 4-chlorothio-phenol according to the conditioned response described in the step 4 that is similar to flow process 1-A, after silica gel separates.Obtain 85mg ester sulfone.

Step 3

(100mg, (120mg 5.84mmol) and with reactant refluxed 3 hours to add lithium borohydride in THF 0.27mmol) (2.5mL) solution to the ester sulfone product that derives from step 2.Final mixture is used the saturated sodium bicarbonate quencher, extracts with EtOAc, and is dry and concentrated.Residue obtains 65mg alcohol through preparation of silica gel type chromatography purification (with hexane/EtOAc 60:40 wash-out): ¹H-NMR (CDCl ₃400MHz) δ 7.35-7.45 (m, 3H), 7.10-7.25 (m, 3H), 6.87 (m, 1H), 6.37 (d; 1H), 4.60 and 4.51 (d, 1H), 4.22 (m, 1H), 3.92 and 3.80 (m, 1H); 2.00-2.10 (m, 1H), 2.80-2.90 (m, 1H), 2.53 (m, 1H); 2.15-2.25 (m, 1H), 1.74 (m, 1H), 1.25 (brs, 1H); LCMS (MH ⁺)=337.2; RT=3.10 minute.

Step 4

Feasible pure product experience from step 3 is similar to those conditions of describing in the step 3 and 4 of flow process 1-B, after silica gel separates, obtains embodiment 3-G: ¹H-NMR (CDCl ₃400MHz) δ 7.35-7.45 (m, 3H), 7.00-7.30 (m, 3H), 6.94 (m, 1H); 6.58 (m, 1H), 4.65-4.75 (m, 1H), 4.35-4.55 (m, 2H); 3.30-3.60 (m, 3H), 2.80-3.05 (m, 2H), 2.50-2.60 (m, 1H); 2.20-2.35 (m, 1H), 1.55-2.10 (m, 5H), 1.25 (brs, 1H); LCMS (MH ⁺)=450.2; RT=3.87 minute.

According to being similar to those methods of describing among the flow process 2-B, the compound among the preparation table 2-B.

Table 2-B

Embodiment 5:

1-(4-chloro-benzenesulfonyl)-5,8--two fluoro-4-methyl isophthalic acids, 2,3,4-tetrahydrochysene-naphthalene

Flow process 3

Step 1

To 1,4-two fluorobenzene (9.75mL, 100mmol) and γ-Wu Neizhi (1.90mL 20mmol) slowly adds AlCl in the solution in acetone bath ₃(13.4g, 100mmol), reaction stirred is spent the night under refluxing then.Then that the slow impouring of this mixture is ice-cooled 1N HCl extracts with DCM, and water and saturated sodium bicarbonate washing through dried over sodium sulfate and concentrated, obtain 3.92g (100%) ketone.

Step 2

According to being similar to flow process 1-A, the method described in the step 4 makes from the ketone product and the reaction of 4-chlorothio-phenol of step 1, obtains embodiment 5, is about 65:35 cis: the mixture of trans diastereomer: ¹H-NMR (CDCl ₃400MHz) δ 7.71 (d, J=8.7Hz, 2H cis), 7.70 (2H is trans for d, J=8.7Hz), 7.51 (d; J=8.7Hz, the 2H cis+trans), 6.97 (m, 1H cis+trans), 6.72 (m, 1H cis+trans), 4.60 (brs; The 1H cis), 4.56 (d, 1H is trans), 3.37 (m, 1H is trans), 3.17 (1H cis), 2.55-2.75 (m; The 2H cis+trans), 2.00-2.20 (m, 1H cis+trans), 1.83 (m, 1H cis), 1.60 (brd, 1H is trans); (1.44 d, J=6.8Hz, 3H cis), 1.18 (3H is trans for d, J=7.2Hz); LCMS (MH ⁺)=357.2; RT=3.79 minute.

According to being similar to the method described in flow process 1-A and 3, use suitable nucleophilic reagent and lactone reaction agent, the compound in the preparation table 3.

Table 3

Embodiment 6:

1-(4-chloro-benzenesulfonyl)-5,8-two fluoro-3-methyl isophthalic acids, 2,3,4-tetrahydrochysene-naphthalene

Flow process 4

Step 1

To magnesium chips (7.0g; Et 290mmol) ₂Add in O (40mL) solution and contain the iodine of catalytic amount and the hexane solution of ethylene dibromide (1mL).With reaction mass heated to 40 ℃ and with adding 2 in 1 hour, 5-difluoro benzyl bromide (15.0g, Et 72.4mmol) ₂O (40mL) solution.Then in other 1 hour of 40 ℃ of stirred reaction mixtures, cool off then and use Et ₂O is diluted to 100mL, obtains benzyl Ge Shi (Grignard) reagent solution (16.7g).

To cuprous iodide (I) (4.6g adds N in THF 24.1mmol) (80mL) solution, N, N ', (4.0mL 26.6mmol), stirs reaction mixture 15 minutes under room temperature N '-Tetramethyl Ethylene Diamine.Then this mixture is cooled to-78 ℃, with benzyl Ge Shi (Grignard) reagent (5g, Et 21.6mmol) of above-prepared ₂O (30mL) solution joins in this mixture, then stirs 15 minutes.(6.0mL, 60.4mmol) (2.0mL, THF 21.7mmol) (30mL) solution make reaction mixture be warmed to-50 ℃ and in-50 ℃ of stirred overnight with trans-methyl crotonate to add TMSCl then.With the saturated NH of crude product impouring ₄OH and NH ₄In the Cl solution, use Et ₂O extracts, with water washing and through dried over sodium sulfate.The crude product that concentrates the back acquisition obtains 2.5g (45%) ester through silica gel column chromatography purifying (with hexane/EtOAc 95:5 wash-out).

Step 2

To the ester that derives from step 1 (200mg, add 1N NaOH (4mL) in MeOH 0.88mmol) (4mL) solution and under room temperature with the reactant stirred overnight.The dilute with water reactant with the EtOAc washing, is used 1N HCl acidifying then, extracts with EtOAc, through dried over sodium sulfate and concentrated, obtains 173mg (92%) acid.

Step 3

(170mg, (0.14mL 1.60mmol) with 1 DMF, stirs reaction mixture 30 minutes under room temperature, concentrates then to add oxalyl chloride in DCM 0.79mmol) (2mL) solution to the acid that derives from step 2.The residue that makes that obtains is dissolved in DCM (3mL), uses AlCl ₃(213mg 1.60mmol) handles, then stirred overnight under room temperature.In crude product impouring 0.1N HCl, extract with DCM and EtOAc, through dried over sodium sulfate and concentrated.Residue obtains 112mg (70) ketone through silica gel column chromatography purifying (hexane/DCM 1:1).

Step 4

According to being similar to flow process 1-A, the method described in the step 4 makes from the ketone product and the reaction of 4-chlorothio-phenol of step 3, obtains embodiment 6, is the mixture of 55:45 diastereomer 1 and 2: ¹H-NMR (CDCl ₃400MHz) δ 7.76 (d, J=8.7Hz, 2H diastereomer 1), 7.45-7.55 (m, 2H diastereomer 1 and 2), 7.42 (d, J=8.7Hz; Diastereomer 2), 6.90-7.00 (m, 1H diastereomer 1 and 2), 6.60-6.75 (m, 1H diastereomer 1 and 2), 4.81 (dd, 1H diastereomers 2); (4.60 brs, 1H diastereomer 1), 3.45-3.50 (m, 1H diastereomer 2), 3.15 (dd, 1H diastereomers 1), 2.87 (brd; 1H diastereomer 2), 2.60-2.80 (m), 2.38 (m, 1H diastereomers 2), 2.10-2.30 (m), 1.50-1.60 (m); (1.18 d, J=6.4Hz, 3H diastereomer 2), 1.11 (d, J=6.4Hz, 3H diastereomers 1); LCMS (2MH ⁺)=713.4; RT=5.00.

According to being similar to the method described in the flow process 1, the compound in the preparation table 4.

Table 4

Embodiment 7:

5-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene

Flow process 5

Step 1

In-40 ℃, to 2, (8.65g, (85mL, the vinyl bromination magnesium 1N in 85mmol) made reaction mixture be warmed to 0 ℃ with 45 minutes to the 5-difluorobenzaldehyde slowly to be added in THF in THF 60.9mmol) (150mL) solution.Use saturated NH then ₄The Cl quencher is extracted with DCM and EtOAc, through dried over sodium sulfate and concentrated.Residue obtains 5.37g (37%) alcohol through flash chromatography on silica gel purifying (with hexane/EtOAc 95:5-70:30 wash-out).

Step 2

In 180 ℃, with the pure product that derives from step 1 (5.35g, 31.4mmol), triethly orthoacetate (41.3mL, 220mmol) and the solution of propionic acid (155mg) stirred overnight under refluxing.Concentrated reaction mixture through flash chromatography on silica gel purifying (with hexane/EtOAc 95:5-70:30 wash-out), obtains 6.42g (85%) alkene.

Step 3

With the olefin product that derives from step 2 (6.42g, 26.7mmol) and the solution of 10%Pd/C (720mg) in EtOH (20mL) and EtOAc (20mL) in 30psi hydrogenation 60 minutes, filter and concentrate through CELITE then, obtain 6.19g (96%) ester.

Step 4

(5.35g, EtOH 31.4mmol) (50mL) solution handle with 1N NaOH (50mL) and in 50 ℃ of stirrings, concentrate organic solvent then with the ester products that derives from step 3.Use Et ₂After the O washing,, extract,, obtain 4.76g (87%) acid through dried over sodium sulfate and concentrated with EtOAc and DCM with 1N HCl acidifying waterbearing stratum.

Step 5

In 0 ℃, (3.05g, (2.45mL 28.4mmol), then adds 1 DMF to add oxalyl chloride in DCM 14.2mmol) (30mL) solution to the acid product that derives from step 4.Make reaction mixture be warming up to room temperature and stirred 30 minutes, concentrate then.Make residue be dissolved in DCE (8mL) immediately, use AlCl ₃(3.79g 28.4mmol) handles and in 60 ℃ of stirred overnight.With among the rare HCl of its impouring, extract then, through dried over sodium sulfate and concentrated with DCM.Residue obtains 1.20g (43%) ketone through flash chromatography on silica gel purifying (with hexane/EtOAc 95:5-EtOAc wash-out).

Step 6

According to being similar to flow process 1-A, the method described in the step 4 makes from the ketone product and the reaction of 4-chlorothio-phenol of step 5, obtains embodiment 7: ¹H-NMR (CDCl ₃400 MHz) δ 7.58 (d, J=8.7Hz, 2H), 7.40 (d, J=8.7Hz, 2H), 6.96 (m, 1H); 6.63 (m, 1H), 4.84 (m, 1H), 3.20-3.35 (m, 2H), 2.72 (m, 1H); 2.23 (m, 1H), 1.90-2.10 (m, 2H), 1.70 (m, 1H), 1.40 (m, 1H); LCMS (MHB ⁺)=357.2; RT=5.04 minute.

According to being similar to the method for describing among flow process 1-A, 1-B, 2-A, the 2-B and 5, the compound in the preparation table 5.

Table 5

Embodiment 8:

4-(4-chloro-benzenesulfonyl)-4-ethyl-5,8-two fluoro-chromans

Step 1:2-(4-chloro-phenyl sulfenyl methyl)-1.3.4-three fluoro-benzene

Make 2,3, (9.79g, 43.3mmol) (6.23g 43.3mmol) is dissolved in 300mL THF to 6-trifluoro-benzyl bromine with the 4-chlorothio-phenol.The adding triethylamine (4.59g, 45.4mmol).With this solution stirred overnight under room temperature.Add 300mL EtOAc and 300mL water.Organic layer is with 200mL 1N HCl solution washing, through Na ₂SO ₄Dry and concentrated.Residue is pure products (12.5g, a quantitative yield). ¹H?NMR(CDCl ₃400?MHz)δ7.30(d，J＝8.8Hz，2H)，7.24(d，J＝8.8Hz，2H)，7.03(m，1H)，6.77(m，1H)，4.08(s，2H)。

Step 2: 2-(4-chloro-benzenesulfonyl methyl)-1,3,4-three fluoro-benzene

Make 2-(4-chloro-phenyl sulfenyl methyl)-1,3,4-three fluoro-benzene (12.5g 43.3mmol) is dissolved in 600mL DCM, slowly add mCPBA (77%, 19.3g, 86.4mmol), with this reaction mixture stirred overnight under room temperature.Be used in the 10.2g Na in the 300mL water ₂SO ₃The mCPBA that quencher is excessive.Separate organic layer also with 1N NaOH (2x200mL), salt solution (200mL) washing, through Na ₂SO ₄Dry, filtration and concentrated.Residue need not be further purified and be used for next step (14.8g, quantitative yield). ¹H?NMR(CDCl ₃400MHz)δ7.70(d，J＝8.8Hz，2H)，7.50(d，J＝8.8Hz，2H)，7.17(m，1H)，6.87(m，1H)，4.49(s，2H)。

Step 3: tert-butyl-[3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-propoxy-]-dimethyl--silane

Make 2-(4-chloro-benzenesulfonyl methyl)-1,3, (4.0g 12.5mmol) is dissolved in the 40mL dry DMF 4-three fluoro-benzene.Add respectively (2-bromo-oxyethyl group)-tert-butyl-dimethylsilane (4.1g, 17.1mmol) and NaH (2.28g, 95.0mmol).With this solution stirred overnight under room temperature.Add 200mL water and 200mL EtOAc.Water layer washs with 100mL EtOAc.The organic layer that merges is with salt solution (100mL) washing, through Na ₂SO ₄Dry and concentrated.Product employing column chromatography purification (hexane/EtOAc 100/0-90/10 warp 45 (minute), 1.7g, 28%). ¹HNMR(CDCl ₃?400MHz)δ7.65(m，2H)，7.46(m，2H)，7.14(m，1H)，6.84(m，0.5)，6.73(m，0.5H)，4.87(m，1H)，4.79(m，1H)，4.37(m，1H)，2.55(m，2H)，2.04(s，9H)、-0.13(d，J＝22.7Hz，6H)。

Step 4: 3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-third-1-alcohol

Make tert-butyl-[3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-propoxy-]-dimethyl--silane (2.62g 5.47mmol) is dissolved in 80mL THF, under room temperature, add tetrabutyl ammonium fluoride (1.96g, 7.51mmol).With this solution stirred overnight under room temperature.Add 200mLEtOAc and 200mL water, separate organic layer.Organic layer is through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with hexane/EtOAc as elutriant (from the gradient of 0/100-75/25, through 45 minutes, 1.38g, 69%). ¹H?NMR(CDCl ₃400MHz)δ7.63(d，J＝8.8Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.12(m，1H)，6.82(m，0.5H)，6.71(m，0.5H)，4.91(m，1H)，3.89(m，1H)，4.44(m，1H)，2.60(m，2H)。

Step 5: 4-[(4-chlorophenyl) alkylsulfonyl]-5,8-two fluoro-3,4-dihydro-2H-1-chromene

SCH?791199

(1.28g 3.51mmol) is dissolved in 40mL THF, adds NaH (60% in oil, and 0.5g is excessive) to make 3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-third-1-alcohol.With this solution stirred overnight under room temperature.Reaction mixture water (40mL) dilution is extracted with ETHYLE ACETATE (3x50mL), merges organic layer, through Na ₂SO ₄Dry and concentrated.Adopt column chromatography purification product (hexane/EtOAc 100/0-85/15 is through 40 minutes, then to 70/30 through 60 minutes, 0.81g, 67%). ¹H?NMR(CDCl ₃?400MHz)δ7.73(d，J＝8.8Hz，2H)，7.51(d，J＝8.8Hz，2H)，7.01(m，1H)，6.39(m，1H)，4.85(m，1H)，4.51(m，2H)，2.80(m，1H)，2.17(m，1H)。

Step 6: 4-/(4-chlorophenyl) alkylsulfonyl]-4-ethyl-5,8-two fluoro-3,4-dihydro-2H-1-chromene

SCH?796492

Make 4-[(4-chlorophenyl) alkylsulfonyl]-5,8-two fluoro-3, (101.1mg 0.294mmol) is dissolved in 10mL THF to 4-dihydro-2H-1-chromene.Add monobromoethane (600mg, 4.88mmol), then add potassium tert.-butoxide (1M in THF, 3.05mL, 3.05mmol).With this solution stirred overnight under room temperature.The reaction mixture dilute with water extracts with ETHYLE ACETATE (3x50mL).Separate organic layer, with salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product adopts column chromatography purification (hexane/EtOAc100/0-70/30 through 60 minutes, 55 mg, 50%). ¹H?NMR(CDCl ₃?400MHz)δ7.63(d，J＝8.8Hz，2H)，7.47(d，J＝8.8Hz，2H)，7.03(m，1H)，6.38(m，1H)，4.91(m，1H)，4.39(m，1H)，2.55(m，2H)，2.30(m，1H)，1.89(m，1H)，0.74(t，J＝7.3Hz，3H)。Chirality

Be used to prepare embodiment 8 described methods according to being similar to, the compound in the preparation table 6.

Table 6:

Embodiment 9: 4-(4-chloro-benzenesulfonyl)-6-fluoro-chroman

Step 1: 4-[(4-chlorophenyl) alkylsulfonyl]-6-fluoro-3,4-dihydro-2H-1-chromene

(352mg, 2.12mmol) (320mg 2.2mmol) is dissolved in 5mL DCM with the 4-chlorothio-phenol to make 6-fluoro chroman-4-ketone.Make reaction mixture be cooled to 0 ℃ and add the 2.4mL trifluoroacetic acid.In 0 ℃ after 5 minutes, slowly add pyridine-borane complexes (0.20mL).In 0 ℃ this reaction mixture was stirred 1 hour.Add Et ₂O (100mL) and saturated NaHCO ₃Solution (100mL).Through Na ₂SO ₄Dry ether layer also concentrates.Residue is dissolved among the 10mL DCM, and adding mCPBA (77%, 1.01g, 4.50mmol), with reaction mixture stirred overnight under room temperature.Add 2g Na ₂SO ₃The 20mL aqueous solution, reactant was stirred 1 hour, filter then.Separate each layer, organic layer is with 1N NaOH solution (100mL) washing, through Na then ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with hexane/EtOAc as elutriant (from the gradient of 100/0-30/70 60 minutes, 0.37g, 53%). ¹H?NMR(CDCl ₃400MHz)7.67(d，J＝8.8Hz，2H)，7.49(d，J＝8.8Hz，2H)，6.92(m，2H)，6.77(m，1H)，4.24(m，2H)，4.10(m，1H)，2.36(m，1H)，2.18(m，1H)。

Preparing the method described in the embodiment 9 according to being similar to, the compound in the preparation table 7.

Table 7

Embodiment 10: 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-3-methyl-chromans

Step 1: 2-[hydroxyl-(2,3,6-three fluoro-phenyl)-methyl]-propanedioic acid two basic esters

Make 2,3, the 6-trifluro benzaldehyde (10.2g, 63.8mmol) and methyl-malonate (8.41g 63.8mmol) is dissolved in 50mL DMF.Add 3gK ₂CO ₃And with reaction mixture be heated to 80 ℃ 3 hours.Add 500mL EtOAc and 500mL water.Organic layer is used saturated NH ₄Cl solution (200mL) washing is through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with EtOAc/hex as elutriant (from the gradient of 0/100-40/60 40 minutes, 13g, 70%). ¹HNMR(CDCl ₃?400MHz)δ7.12(m，1H)，6.85(m，1H)，5.72(d，J＝9.5Hz，1H)，4.17(d，J＝9.5Hz，1H)，3.84(s，3H)，3.61(s，3H)。

Step 2: 2-(2,3,6-three fluoro-tolylenes)-propanedioic acid dimethyl esters

Make 2-[hydroxyl-(2,3,6-three fluoro-phenyl)-methyl]-propanedioic acid dimethyl esters (13g, 44.5mmol) and NEt ₃(9g 89mmol) is dissolved in 300mL CH ₂Cl ₂Add then MsCl (10.3g, 89mmol).This reaction mixture was stirred under room temperature 1 hour.Reaction mixture is with 1NHCl solution (200mLx2), salt solution (100mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-25/75 40 minutes, 6.5g, 53%). ¹H?NMR(CDCl ₃?400MHz)δ7.71(s，1H)，7.20(m，1H)，6.89(m，1H)，3.87(s，3H)，3.80(s，3H)。

Step 3: 2-[(4-chloro-phenyl sulfenyl)-(2,3,6-three fluoro-phenyl)-methyl]-propanedioic acid dimethyl esters

(6.5g, 23.7mmol) (5.1g 35.5mmol) is dissolved in 100mL THF with the 4-chlorothio-phenol to make 2-(2,3,6-three fluoro-tolylenes)-propanedioic acid dimethyl esters.Add K ₂CO ₃(5g, excessive) stirs reaction mixture 3 hours in 60 ℃.Add 300mL EtOAc and 300mL water.Separate organic layer, use water washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, uses the EtOAc/ hexane to be elutriant (from the gradient of 0/100-25/75 45 minutes, 7.1g, 72%). ¹HNMR(CDCl ₃?400MHz)δ7.26(m，4H)，7.03(m，1H)，6.75(m，1H)，5.08?(d，J＝11.7Hz，1H)，4.34(d，J＝12.4Hz，1H)，3.84(s，3H)，3.56(s，3H)。

Step 4: 2-[(4-chloro-benzenesulfonyl)-(2,3,6-three fluoro-phenyl)-methyl]-propane-1,3-glycol

(7.1g 17mmol) is dissolved in 50mL THF, and (1M is in hexane, 68mL) to add DIBAL-H to make 2-[(4-chloro-phenyl sulfenyl)-(2,3,6-three fluoro-phenyl)-methyl]-propanedioic acid dimethyl esters.Reaction stirred is spent the night under the room temperature.Add 100mL water and react, add 100mL EtOAc to extract product with quencher.Organic layer is with 1N HCl solution (2x50mL), salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Make residue be dissolved in 200mL DCM, add mCPBA (77%, 7.6g, 34 mmol).In stirring at room reactant 3 hours.Add the 8gNa in the 50mL water ₂SO ₃With the excessive mCPBA of quencher.Separate organic layer, with 1N NaOH solution, brine wash, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with EtOAc/hex as elutriant (from the gradient of 0/100-75/25 40 minutes, 2.7g, 40%). ¹HNMR (CDCl ₃400MHz) δ 7.59 (m, 2H), 7.36 (m, 2H), 7.06 (m, 1H), 6.81 (m, 0.5H); 6.57 (m, 0.5H), 5.26 (d, J=11.0Hz, 1H), 4.65 (m, 1H), 4.20 (dt; J=11.7 and 2.2Hz, 1H), 3.93 (m, 1H), 3.42 (m, 1H), 3.02 (m, 1H).

Step 5: trans-4-[(4-chlorophenyl) alkylsulfonyl)]-5,8-two fluoro-3,4-dihydro-2H-1-chromene-3-methyl alcohol

SCH?795753

Make 2-[(4-chloro-benzenesulfonyl)-(2,3,6-three fluoro-phenyl)-methyl]-propane-1, (2.7g 6.9mmol) is dissolved in 70mL THF to the 3-glycol, adds NaH (2g, excessive).With this reaction mixture stirred overnight under room temperature.Add 50 mL water and 50mL EtOAc.Organic layer is with salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with EtOAc/hex as elutriant (from the gradient of 0/100-50/50 40 minutes, 2.3g, 90%).From reaction mixture, only isolate trans-isomer(ide). ¹H MR (CDCl ₃400 MHz) 7.72 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.03 (m; 1H), 6.41 (m, 1H), 4.93 (dd, J=11.7 and 3.7Hz, 1H), 4.63 (s; 1H), 4.41 (d, J=11.7Hz, 1H), 3.69 (dd, J=11.0 and 6.6Hz; 1H), 3.43 (t, J=11.0Hz, 1H), 3.02 (m, 1H).

Step 6: methanesulfonic O-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-3,4-dihydro-2H-1-chromene-3-base-methyl] ester

With trans-4-[(4-chlorophenyl) alkylsulfonyl)]-5,8-two fluoro-3,4-dihydro-2H-1-chromene-3-methyl alcohol (1.0g, 2.54mmole), methylsulfonyl chloride (0.87g, 7.6mmole) and triethylamine (0.77g is 7.6mmole) at 50ml CH ₂Cl ₂In in stirring at room 2 hours.Add 50ml water.Organic layer is with 1N HCl solution (50mlx2), salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-50/50 40 minutes, 1.1g, 96%). ¹H NMR (400MHz, CDCl ₃) 7.75 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.43 (s, 1H); 7.07 (m, 1H), 7.47 (s, 1H), 4.98 (dd, J=12.4 and 2.9Hz, 1H), 4.52 (s; 1H), 4.44 (d, J=12.4Hz, 1H), 4.20 (dd, J=10.3 and 6.6Hz, 1H); 4.00 (dd, J=10.3 and 8.7Hz, 1H), 3.31 (m, 1H), 2.98 (s, 3H).

Step 7: trans-4-[(4-chlorophenyl) alkylsulfonyl)]-5,8-two fluoro-3,4-dihydro-3-methyl-2H-1-chromene

With methanesulfonic O-[4-(4-chloro-benzenesulfonyl)-5; 8-two fluoro-3,4-dihydro-2H-1-chromene-3-base-methyl] and ester (0.5g, 1.1mmole), NaI (0.83g; 5.5mmole) (0.71g's zinc powder 11mole) refluxed 6 hours in the 15mL glycol dimethyl ether with 0.1mL acetate.Filter this solid, make filtrate distribution in 100mL 0.1N Na ₂SO ₃Between solution and the 100mL EtOAc.Organic layer is with 0.5N NaOH solution (2x50ml), brine wash, through Na ₂SO ₄Dry and concentrated.Residue from the EtOAc/ hexane recrystallization with purified product (0.33g, 83%). ¹H NMR (400 MHz, CDCl ₃) 7.71 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.03 (m, 1H), 6.40 (m, 1H), 4.92 (dd, J=11.7 and 2.9Hz, 1H), 4.21 (m, 2H), 3.02 (m, 1H), 1.07 (d, J=7.3Hz, 3H).

Be used to prepare embodiment 10 described methods according to being similar to, the compound of preparation table 8.

Table 8

Embodiment 11: 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,4-dimethyl--chroman

Step 1: 4-(4-chloro-benzenesulfonyl)-4-(2,3,6-three fluoro-phenyl)-Ding-2-alcohol

Make 2-(4-chloro-benzenesulfonyl methyl)-1,3, and 4-three fluoro-benzene (embodiment 8, step 2, and 305mg 0.95mmol) is dissolved in 4mL THF.(2.5M is in hexane, 0.4mL) to make this solution be cooled to-78 ℃ of also slow adding butyllithiums.Stir these solution 2 hours in-78 ℃, be warmed to 0 ℃ and stirred 0.5 hour then.Make this solution be cooled to-78 ℃ once more then, and (178.0mg, 3.1mmol), stirred reaction mixture also is warmed to ambient temperature overnight slowly to be added in propylene oxide among the 3.25mL THF.Reaction mixture is used saturated NH ₄Cl solution (50mL) quencher.Reaction mixture extracts (each 50mL) 3 times with EtOAc, the organism water (100mL) of merging and salt solution (100mL) washing.Organic layer is through Na then ₂SO ₄Dry and concentrated.(hexane/EtOAc100/0-70/30 was through 60 minutes to adopt the column chromatography purification product.0.19g，52％)。 ¹HNMR(CDCl ₃?400MHz)δ7.59(m，2H)，7.42(m，2H)，7.10(m，1H)，6.81(m，0.5H)，6.66(m，0.5H)，4.83-4.99(m，1H)，4.06(m，0.5H)，3.51(m，0.5H)，2.50-2.74(m，1H)，2.26(m，1H)，1.03-2.24(m，3H)。Product is the mixture of diastereomer.

Step 2: trans-4-[(4-chlorophenyl) alkylsulfonyl]-5,8-two fluoro-3,4-dihydro-2-methyl-2H-1-chromene

Adopt embodiment 8, the method for step 5 prepares above midbody.From reactant, only obtain trans-isomer(ide). ¹H NMR (CDCl ₃400 MHz) 7.72 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 6.99 (m, 1H), 6.36 (m, 1H), 5.00 (m, 1H), 4.50 (m, 1H), 2.79 (dt, J=15.4 and 2.2Hz, 1H), 1.85 (m, 1H), 1.50 (d, J=6.6Hz, 3H).

Step 3: trans-4-[(4-chlorophenyl) alkylsulfonyl]-5,8-two fluoro-3,4-dihydro-2,4-dimethyl--2H-1-chromene

Make trans-4-[(4-chlorophenyl) alkylsulfonyl]-5,8-two fluoro-3, (57mg 0.16mmol) is dissolved in 10mL THF to 4-dihydro-2-methyl-2H-1-chromene.Add methyl iodide (720mg, 5.11mmol), then add potassium tert.-butoxide (1M in THF, 0.5mL, 0.5mmol).With this solution stirred overnight under room temperature.Add 50mL water, product extracts with ETHYLE ACETATE (3x50mL).Separate organic layer, with salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product adopts column chromatography purification (hexane/EtOAc 100/0-70/30 through 60 minutes, 39mg, 65%).From reaction mixture, only obtain trans-isomer(ide). ¹H NMR (CDCl ₃400MHz) δ 7.66 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.01 (m, 1H), 6.35 (m, 1H), 5.08 (m, 1H), 2.79 (dt, J=15.4 and 2.2Hz, 1H), 1.72-1.81 (m, 4H), 1.47 (d, J=6.6Hz, 3H).

Be used to prepare embodiment 11 described methods according to being similar to, the compound of preparation table 9.

Table 9

Embodiment 12: 5-(4-chloro-benzenesulfonyl)-6,9-two fluoro-4-methyl-2,3,4,5-tetrahydrochysene-benzo [b] oxepane alkene (oxepine)

Step 1: 4-(4-chloro-benzenesulfonyl)-3-methyl-4-(2,3,6-three fluoro-phenyl)-butyric acid methyl ester

Make 2-(4-chloro-phenyl sulfenyl methyl)-1,3,4-three fluoro-benzene (embodiment 8, step 2,1.0g, 3.1mmol) and methyl crotonate (1.55g 15.5mmol) is dissolved in 50mL THF, adds that uncle-(1M is in THF, 6.2mL) for butanols potassium.This reaction mixture was stirred under room temperature 5 hours.Add 100mL water and 100mL EtOAc.Organic layer is with salt solution (100mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-50/50 40 minutes, 0.79g, 60%).Product is the mixture of diastereomer. ¹H?NMR(CDCl ₃?400?MHz)δ7.60(m，2H)，7.37(m，2H)，7.07(m，1H)，6.83(m，0.5H)，6.63(m，0.5H)，5.03(t，J＝10.2Hz，0.5H)，4.80(d，J＝10.2Hz，0.5H)，3.71(s，1.5H)，3.60(s，1.5H)，3.33(m，1H)，3.10(m，0.5H)，2.89(m，0.5H)，2.42(m，0.5H)，2.15(m，0.5H)，1.49(t，J＝6.6Hz，1.5H)，0.95(dd，J＝8.8?and?7.3Hz，1.5H)。

Step 2: 4-(4-chloro-benzenesulfonyl)-3-methyl-4-(2,3,6-three fluoro-phenyl)-Ding-1-alcohol

(0.79g 1.88mmol) is dissolved in 10mL THF, adds lithium borohydride (0.5g, excessive) to make 4-(4-chloro-benzenesulfonyl)-3-methyl-4-(2,3,6-three fluoro-phenyl)-butyric acid methyl ester.With this reaction mixture stirred overnight under room temperature.Add 50mL water and 50mL EtOAc.Organic layer is with salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Residue need not be further purified and be used for next step (0.71g, 96%). ¹H?NMR(CDCl ₃?400MHz)δ7.61(m，2H)，7.36(m，2H)，7.06(m，1H)，6.82(m，0.5H)，6.60(m，0.5H)，4.79(m，0.5H)，4.56(m，0.5H)，3.85(m，1H)，3.68(m，1H)，3.12(m，1H)，2.39(m，0.5H)，1.95(m，0.5H)，1.57(m，0.5H)，1.46(dd，J＝4.4?and?5.9Hz，1.5H)，1.32(m，0.5H)，0.92(dd，J＝7.3?and?9.5Hz，1.5H)。

Step 3: trans-5-[(4-chlorophenyl) alkylsulfonyl]-6,9-two fluoro-2,3,4,5-tetrahydrochysene-4-methyl isophthalic acid-benzo oxepane alkene and cis-5-[(4-chlorophenyl) alkylsulfonyl]-6,9-two fluoro-2,3,4,5-tetrahydrochysene-4-methyl isophthalic acid-benzo oxepane alkene

(0.71g 1.8mmol) is dissolved in 50mL THF, adds sodium hydride (60% in oil, and 0.5g is excessive) to make 4-(4-chloro-benzenesulfonyl)-3-methyl-4-(2,3,6-three fluoro-phenyl)-Ding-1-alcohol.This is reacted under the room temperature stirred 2 hours.Add 50mL water and 50mL EtOAc.Organic layer is with saturated NaCl solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with EtOAc/hex as elutriant (from the gradient of 0/100-25/75 40 minutes).Isolate two products.Cis-isomeride (31mg, 4.6%). ¹HNMR(CDCl ₃?400MHz)δ7.57(d，J＝8.8Hz，2H)，7.34(d，J＝8.8Hz，2H)，6.95(m，1H)，6.44(m，1H)，4.74(bs，1H)，4.66(dt，J＝12.4?and?3.7Hz，1H)，3.81(m，1H)，3.07(m，1H)，2.39(m，1H)，1.85(m，1H)，1.65(d，J＝7.3Hz，3H)。Trans-isomer(ide) (0.46g, 68%). ¹H?NMR(CDCl ₃?400MHz)δ7.52(d，J＝8.8Hz，2H)，7.37(d，J＝8.8Hz，2H)，7.03(m，1H)，6.54(m，1H)，4.52(d，J＝3.7Hz，1H)，4.40(m，1H)，3.93(m，1H)，3.21(m，1H)，2.79(m，1H)，2.72(m，1H)，1.11(d，J＝7.3Hz，3H)。

Through

post; Use hexane/isopropyl alcohol (75/25) as moving phase, separate two enantiomorphs from trans-isomer(ide).

Embodiment 13-15

Step 1:/7-(4-chloro-benzenesulfonyl)-7-(2,3,6-three fluoro-phenyl)-1-heptane

Make 2-(4-chloro-benzenesulfonyl methyl)-1,3, (1.5g 6.3mmole) is dissolved in 20mL THF, and uncle-(1M is in THF, 6.2mL) for butanols potassium in adding for 4-three fluoro-benzene (1.0g, 3.1mmol derive from embodiment 8, step 2) and 6-bromo-1-hexene.This reaction mixture was stirred under room temperature 3 hours.Add 50mL water and 50mL EtOAc.Organic layer is with salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-25/75 40 minutes, 0.65g, 52%). ¹H?NMR(CDCl ₃，400MHz)δ7.63(d，j＝8.05Hz，2H)，7.45(d，j＝8.05Hz，2H)，7.14(m，1H)，?6.83(m，0.5)，6.74(m，0.5H)，5.70(m，1H)，4.93(m，2H)，4.58(d，j＝5.1and?6.5Hz，1H)，2.43(m，1H)，2.31(m，1H)，1.99(m，2H)，1.39(m，2H)，1.25(m，2H)。

Step 2: 2-[5-(4-chloro-benzenesulfonyl)-5-(2,3, the 6-trifluorophenyl)-amyl group]-oxyethane

Will [7-(4-chloro-benzenesulfonyl)-7-(2,3,6-three fluoro-phenyl)-1-heptane (0.65g, 1.6mmo1e) with mCPBA (77%, 0.71g, 3.2mmo1e) in 50mL DCM the stirring 5 hours.Be added in the 2g Na in the 100mL water ₂S ₂O ₃, with the excessive mCPBA of quencher.Separate organic layer, with 1NNaOH solution (50mL), salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-40/60 40 minutes, 0.52g, 77%). ¹H?NMR(CDCl ₃，400MHz)δ7.63(d，j＝8.05Hz，2H)，7.45(d，j＝8.05Hz，2H)，7.15(m，1H)，6.83(m，0.5)，6.74(m，0.5H)，4.58(dd，j＝5.1?and?6.5Hz，1H)，2.84(m，1H)，2.71(t，j＝4.4Hz，1H)，2.41(dd，j＝2.9?and?5.1Hz)，2.45(m，1H)，2.34(m，1H)，1.25-1.55(m，6H)。

Step 3: (6aR)-10aS-[(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9; 10,10a-six hydrogen-6H-dibenzo [b, d] pyrans (racemic) and 7 (S)-[(4-chloro-benzenesulfonyl)-8,11-two fluoro-2; 4,5,6,7-six hydrogen-2 (S), 7-methyl bridge-1-benzo oxepane alkene (racemic)

(0.52g 1.24mmole) is dissolved in 25mL THF, and uncle-(1M is in THF, 3.72mL) for butanols potassium in adding to make 2-[5-(4-chloro-benzenesulfonyl)-5-(2,3,6-three fluoro-phenyl)-amyl group]-oxyethane.This reaction mixture was stirred under room temperature 2 hours, be heated to then 50 ℃ 4 hours, add 50mL water and 50mL EtOAc.Organic layer is with salt solution (50mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-25/75 40 minutes).Isolate two primary products.Embodiment 13: (6aR)-and 10aS-[(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-dibenzo [b, d] pyrans (racemic, as to contain and have an appointment 13%14,31mg, 5.4%). ¹HNMR (CDCl ₃, 400MHz) δ 7.59 (d, j=8.05Hz, 2H), 7.47 (d, j=8.05Hz, 2H), 7.06 (m; 1H), 6.40 (m, 1H), 5.23 (dd, j=11.7 and 2.9Hz, 1H), 4.14 (d, j=11.7Hz; 1H), 2.61 (m, 2H), 1.90 (tt, j=13.9 and 2.9Hz, 1H), 1.65-1.81 (m; 3H), 1.42 (m, 2H), 1.02 (m, 1H). compound 15:7 (S)-[(4-chloro-benzenesulfonyl)-8,11-two fluoro-2,3; 4,5,6,7-six hydrogen-2 (S), 7-methyl bridge-1-benzo oxepane alkene (racemic, 112mg, 23%). ¹H?NMR(CDCl ₃，400MHz)δ7.53(d，j＝8.05Hz，2H)，7.39(d，j＝8.05Hz，2H)，7.02(m，1H)，6.60(m，1H)，4.85(m，1H)，3.12(d，j＝13.9Hz，1H)，2.81(m，1H)，2.36(m，1H)，2.29(dd，j＝14.6?and?1.5Hz，1H)，2.10(m，1H)，1.97(m，1H)，1.65(m，1H)，1.09-1.37(m，3H)。

Embodiment 13A, 14A and 15A

Be used to prepare the described method of embodiment 13-15 according to being similar to, the compound of preparation table 10.

Table 10

Embodiment 16:

Step 1: 2-[(4-chloro-thiophenyl)-(2,3,6-three fluoro-phenyl)-methyl]-third melts-1, the 3-glycol

Make 2-[(4-chloro-phenyl sulfenyl)-(2,3,6-three fluoro-phenyl)-methyl]-propanedioic acid dimethyl esters (embodiment 10, step 3,11g 26.3mmole) is dissolved in 200mL THF, (1M is in hexane, 105mL) to add DIBAL-H.This reactant was stirred under room temperature 5 hours.(1M 100mL), stirs this reactant 3 hours in 60 ℃ in hexane to add other DIBAL-H.Add 300mL water and 300mL EtOAc.Organic layer is with 1N HCl solution (2x100mL), salt solution (100mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50, through 45 minutes).Must measure: 6.2g, 65%. ¹H NMR (CDCl ₃400MHz) δ 7.28 (d, J=8.1Hz, 2H), 7.20 (d, J=8.1Hz, 2H), 7.00 (m, 1H); 6.75 (m, 1H), 4.85 (d, J=11.0Hz, 1H), 4.36 (dd, J=7.3 and 3.7Hz, 1H); 4.21 (dd, J=8.1 and 2.9Hz, 1H), 3.85 (dd, J=8.8 and 2.9Hz, 1H), 3.49 (m; 1H), 2.46 (m, 1H), 2.22 (br, 1H), 2.10 (br, 1H).

Step 2: trans-[4-(4-chloro-thiophenyl)-5,8-two fluoro-chroman-3-yl]-methyl alcohol

Make 2-[(4-chloro-phenyl sulfenyl)-(2,3,6-three fluoro-phenyl)-methyl]-propane-1, (6.2g 14.8mmole) is dissolved in 150mL THF to the 3-glycol, and (60% in oil, 2g) to add NaH.This reactant was stirred 4 hours in 60 ℃.Add 300mL water and 400mL EtOAc.Organic layer is with salt solution (100mL) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50, through 45 minutes).Must measure: 5.0g, 85%. ¹H NMR (CDCl ₃400MHz) δ 7.45 (d, J=8.1Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 6.97 (m; 1H), 6.58 (m, 1H), 4.62 (dd, J=11.7 and 2.2Hz, 1H), 4.50 (br; 1H), 4.43 (td, J=11.7 and 2.2Hz, 1H), 3.67 (m, 1H), 3.48 (m; 1H), 2.25 (m, 1H), 1.50 (t, J=5.1Hz, 1H).

Step 3: 3-(2-benzyloxy-ethoxyl methyl)-4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chromans

(0.6g, 1.65mmole) (0.71g 3.3mmole) is dissolved in 30mlTHF, adds NaHH (0.5g) with (2-bromo-ethoxyl methyl)-benzene to make trans-[4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-yl]-methyl alcohol.With this reactant stirred overnight under room temperature.(0.71g is 3.3mmole) with NaH (0.5g) and should react backflow and spend the night to add (2-bromo-ethoxyl methyl)-benzene.Add 50ml water and 50ml EtOAc.Organic layer is with saturated NaCl solution (50ml) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (EtOAc/ hexane, from 0/100-25/75 through 40 minutes).Must measure: 0.42g, 53%. ¹H NMR (CDCl ₃400MHz δ 7.42 (d, J=8.8Hz, 2H), 7.25-7.37 (m, 7H), 6.96 (m, 1H), 6.57 (m, 1H), 4.60 (dd, J=11.7 and 2.2Hz, 1H), 4.52 (bs, 3H), 4.40 (t, J=11.0,1H), 3.3-3.56 (m, 6H), 2.38 (m, 1H).

Step 4: 3-(2-benzyloxy-ethoxyl methyl)-4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chromans

Make 3-(2-benzyloxy-ethoxyl methyl)-4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chromans (0.42g 0.88mmole) is dissolved in 15ml DCM, and adding MCPBA (77%, 0.6g, 2.6mmole).This reactant was stirred under room temperature 30 minutes.Be added in the 0.5g Sulfothiorine among 50ml water and the 50ml EtOAc.Organic layer is with 1N NaOH solution (50ml), salt solution (50ml) washing, through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50, through 45 minutes).Must measure: 0.40g, 89%. ¹H NMR (CDCl ₃400MHz δ 7.73 (d, J=8.8Hz, 2H), 7.4 (d, J=8.1Hz, 2H), 7.25-7.37 (m, 5H); 7.02 (m, 1H), 6.42 (m, 1H), 4.90 (dd, J=11.7 and 2.9Hz, 1H); 4.63 (s, 1H), 4.50 (s, 2H), 4.38 (t, J=11.0,1H); 3.45-3.62 (m, 5H), 3.30 (t, J=9.5Hz, 1H), 3.13 (m, 1H).

Step 5: 2-[trans-4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-ylmethoxy]-ethanol

Make 3-(2-benzyloxy-ethoxyl methyl)-4-(4-chloro-benzenesulfonyl)-5, (0.4g 0.79mmole) is dissolved in 10ml EtOAc to 8-two fluoro-chromans, adds Pd (OH) ₂Introduce hydrogen through air bag.This reactant was stirred under room temperature 30 minutes.Filtering catalyst, residue need not purifying and are used for next step.Must measure: 0.32g, 97%. ¹HNMR (CDCl ₃400MHz δ 7.73 (d, J=8.1Hz, 2H), 7.51 (d, J=8.1Hz, 2H), 7.03 (m; 1H), 6.41 (m, 1H), 4.90 (dd, J=8.8 and 2.9Hz, 1H), 4.57 (s; 1H), 4.39 (td, J=11.7 and 1.5Hz, 1H), 3.68 (br, 2H), 3.41-3.54 (m; 3H), 2.30 (t, J=9.5Hz, 1H), 3.15 (m, 1H).

Step 6: anti-form-1 0b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene also

Like preceding disclosed method, synthetic this compound.

Use Chiral OJ post, as elutriant, racemic mixture can be separated into two pure enantiomorphs with ethanol.

First flow point: [α]=-138.4deg. (c=1.00 is in DCM)

Second flow point: [α]=137.2deg. (c=1.02 is in DCM)

Embodiment 17

Step 1: 5,8-two fluoro-2H-chromene oxide compounds

Make 5,8-two fluoro-2H-chromenes (35g 0.21mole) is dissolved in 500ml DCM, and adding MCPBA (77%, 93g, 0.42mole).This reactant was stirred under room temperature 30 minutes.Be added in the 50g Na in the 500ml water ₂S ₂O ₃, react with quencher.Organic layer is with 2N NaOH solution (2x500ml), salt solution (200ml) washing, through Na ₂SO ₄Dry and concentrated.Residue is recrystallization solution from the EtOAc/ hexane, obtains the 21.6g pure products.Residue in the mother liquor is through column chromatography purification (the EtOAc/ hexane from 0/100-25/75, through 55 minutes, obtains other 1.4g).Must measure: 23g, 60%. ¹H?NMR(CDCl ₃?400MHz δ7.00(m，1H)，6.63(m，1H)，4.67(d，J＝12.4Hz，1H)，4.27(m，2H)，3.84(d，J＝4.4Hz，1H)。

Step 2: 4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-alcohol

Make 5, (23g, 0.125mole) (18.1g 0.125mmole) is dissolved in 500ml DCM to 8-two fluoro-2H-chromene oxide compounds, adds InCl with 4-chloro-thiophenol ₃(2.9g, 0.013mole).With this reactant stirred overnight under room temperature.Add 200ml DCM and 200ml water.Organic layer is used salt solution, and washing is through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50, through 55 minutes).Must measure: 23.2g, 57%. ¹H?NMR(CDCl ₃400MHz?δ7.48(d，J＝8.8Hz，2H)，7.34(d，J＝8.8Hz，2H)，7.01(m，1H)，6.64(m，1H)，4.63(d，J＝11.7Hz，1H)，4.32-4.41(m，2H)，4.12(m，1H)。

Step 3: 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2H-chromenes

Make 4-(4-chloro-phenyl sulfenyl)-5, and 8-two fluoro-chroman-3-alcohol (23.2,71mmole) be dissolved in 200ml DCM, adding MCPBA (77%, 31.7g, 142mmole).This reactant was stirred under room temperature 3 hours.Be added in the 10g Na in the 50ml water ₂S ₂O ₃, react with quencher.Organic layer is with 1N NaOH solution (2x100ml), salt solution (100ml) washing, through Na ₂SO ₄Dry and concentrated.Make residue be dissolved in 200ml DCM, add methylsulfonyl chloride (16.1g, 142mmole) and triethylamine (14.3g, 142mmole).This reactant was stirred under room temperature 1 hour.Reaction soln is with salt solution (100ml) washing, through Na ₂SO ₄Dry and concentrated.Residue is recrystallization from the EtOAc/ hexane solution, obtains the 8.4g pure products.(the EtOAc/ hexane is from 0/100-25/75, through 55 minutes, 7.1g) through column chromatography purification for residue in the mother liquor.Must measure: 15.5g, 64%. ¹H NMR (CDCl ₃400MHz δ 7.84 (dd, J=8.8 and 2.2Hz, 2H), 7.51 (d, J=8.1Hz, 2H), 7.30 (t, J=4.4Hz, 1H), 7.00 (m, 1H), 6.54 (m, 1H), 4.99 (d, J=4.4Hz, 2H).

Step 4: 4-benzyloxy-1-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-Ding-2-ketone

(1.23g 12.2mmole) is dissolved in the anhydrous THF of 150ml and make reactant be cooled to 0 ℃ to make Diisopropylamine.Just add-(2.5ml is in hexane, and 4.5ml 11.2mmole), stirs this reactant 10 minutes in 0 ℃ for butyllithium.Make reactant be cooled to-100 ℃, add 4-benzyloxy-2-butanone (1.83g, 10.3mmole) solution in the anhydrous THF of 50ml (preparatory-as to be cooled to-78 ℃).In-78 ℃, this reactant was stirred 30 minutes.Add 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2H-chromenes (3.2g, 9.36mmole) solution in 20ml THF (preparatory-as to be cooled to-78 ℃).In-78 ℃ of reaction stirred 1 hour.Adding 20ml water in-78 ℃ reacts with quencher.After making reaction be warmed to room temperature, add 200ml EtOAc.Organic layer is with salt solution (2x100ml) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-40/60, through 45 minutes).Must measure: 2.6g, 53%. ¹H NMR (CDCl ₃400MHz δ 7.82 (d, J=8.8Hz, 2H), 7.54 (d, J=8.1Hz, 2H), 7.20-7.35 (m; 5H), 7.05 (m, 1H), 6.47 (m, 1H), 4.89 (dd, J=11.7 and 2.9Hz; 1H), 4.42 (s, 3H), 4.24 (dt, J=12.4 and 2.2Hz, 1H), 3.65 (t; J=5.9Hz, 2H), 3.31 (m, 1H), 2.33-2.67 (m, 4H).

Step 5: 3-[2-(2-benzyloxy-ethyl)-[1,3] dihydro penta ring-2-ylmethyl]-4-(4-chloro-benzene-alkylsulfonyl)-5,8-two fluoro-chromans

Make 4-benzyloxy-1-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-Ding-2-ketone (10g, 19.2mmole), terepthaloyl moietie (20ml) and toluenesulphonic acids (1g) be dissolved in 300ml toluene.With Dean-Stark water collector (Dean-Stark trap) reactant was refluxed 4 hours.Make reactant be cooled to room temperature, add 200ml water and 200ml EtOAc.Organic layer is with salt solution (2x50ml) washing, through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50, through 55 minutes).Must measure: 6.3g, 58%. ¹H NMR (CDCl ₃400MHz δ 7.74 (d, J=8.1Hz, 2H), 7.51 (d, J=8.8Hz, 2H), 7.20-7.39 (m, 5H), 7.02 (m; 1H), 6.42 (m, 1H), 4.89 (dd, J=11.0 and 2.9Hz, 1H), 4.84 (s, 1H), 4.40 (d; J=2.0Hz, 2H), 4.21 (d, J=11.7Hz, 1H), 3.85 (m, 4H), 3.46 (t, J=5.9Hz; 2H), 3.03 (d, J=8.1Hz, 1H), 1.75-1.90 (m, 3H), 1.54-1.61 (m, 1H).

Step 6: anti-form-1 0a-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene spiral shell [6H-dibenzo [b, d] pyrans-8 (7H), 2 '-[1,3] dioxolane]

Make 3-[2-(2-benzyloxy-ethyl)-[1,3] dioxolane-2-ylmethyl]-4-(4-chloro-benzenesulfonyl)-5, (6.3g 11.2mmole) is dissolved in 200ml EtOAc to 8-two fluoro-chromans, adds Pd (OH) ₂(0.5g).Introduce hydrogen through air bag.This reactant was stirred under room temperature 45 minutes.Filtering catalyst and concentrated filtrate.Make residue be dissolved in 200ml DCM, add MsCl (1.4g, 12mmole) and NEt ₃(1.7g, 17mmole).Under room temperature, stirred this mixture 10 minutes.Add 200ml water and 100ml DCM.Organic layer is with 1N HCl (100ml), water (100ml), salt solution (100ml) washing, through Na ₂SO ₄Dry and concentrated.Make residue be dissolved in 200ml THF, (1M is in THF, 14ml) to add KOt-Bu.Under room temperature, stirred this mixture 20 minutes.Add 200ml water and 200ml EtOAc.Organic layer is with salt solution (200ml) washing, through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-25/75, through 45 minutes).Must measure: 3.1g, 61%. ¹H NMR (CDCl ₃400 MHz δ 7.61 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.07 (m, 1H); 6.42 (m, 1H), 5.23 (dd, J=11.7 and 2.9Hz, 1H), 4.12 (d, J=11.0Hz, 1H); 3.88-4.01 (m, 4H), 2.97 (dt, J=13.2 and 2.9Hz, 1H), 2.53 (dt, J=13.1 and 2.9Hz, 1H); 2.33 (tt, J=13.2 and 2.9Hz, 1H), 1.62-1.81 (m, 3H), 1.23-1.35 (m, 1H).

Step 7: anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone

Make anti-form-1 0a-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene spiral shell [6H-dibenzo [b, d] pyrans-8 (7H), 2 '-[1,3] dioxolane] (3.1g 6.8mmole) is dissolved in 200ml acetone and 10ml water.Adding toluene sulfonyl chloride (1g) also spends the night this mixture backflow.Remove acetone.Add 100 water and 100ml EtOAc.Organic layer water (50ml) washing is through Na ₂SO ₄Dry and concentrated.Residue has enough purity and is used for next step.Must measure: 2.8g, 100%. ¹HNMR (CDCl ₃400MHz δ 7.63 (d, J=8.1Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.14 (m; 1H), 6.64 (m, 1H), 5.27 (dd, J=11.7 and 2.9Hz, 1H), 4.13 (d; J=11.7Hz, 1H), 3.18 (d, J=12.4Hz, 1H), 2.79 (dt; J=12.4 and 3.7Hz, 1H), 2.4-2.57 (m, 4H), 2.04-2.17 (m, 1H).

Embodiment 18:

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [a] chromene-8-alcohol.

Make anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10, (1.0g 2.4mmole) is dissolved in 50ml THF to 10a-six hydrogen-6H-benzo [c] chromene-8-alcohol, adds sodium hydride (0.3g).This reactant was stirred under room temperature 10 minutes.Add 100ml water and 100mlEtOAc.Organic layer water (50ml), salt solution (50ml) washing are through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (EtOAc/ hexane, from 0/100-50/50 through 35 minutes).Must measure: 0.81g18 ^aAnd 60mg18B

18A: ¹H NMR (CDCl ₃400MHz) δ 7.58 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.05 (m, 1H); 6.61 (m, 1H), 5.22 (dd, J=8.8 and 2.9Hz, 1H), 4.15 (d, J=11.0Hz, 1H); 3.78 (m, 1H), 2.78 (dt, J=13.2 and 2.9Hz, 1H), 2.60 (dt, J=13.2 and 2.9Hz; 1H), 1.90-2.06 (m, 3H), 1.42 (m, 1H), 0.96-1.08 (m, 1H).

18B： ¹H?NMR(CDCl ₃?400MHz)δ7.63(d，2H，J＝8.8Hz)，7.50(d，2H，J＝9.0Hz)，7.10-7.04(m，1H)，6.45-6.39(m，1H)，5.28(dd，1H，J＝2.8Hz)，4.10(d，1H，J＝11.6Hz)，4.04(dd，1H，J＝2.8Hz)，3.10-3.06(m，1H)，2.54-2.46(m，1H)，2.37-2.33(m，1H)，1.85-1.59(m，3H)，1.49(brs，1H)，1.33-1.26(m，1H)。

Embodiment 19:

Step 1: cis-8-azido--10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene

Make anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-(0.81g 2.0mmole) is dissolved in 10ml DCM to 8-alcohol.Add methylsulfonyl chloride (0.23g, 2.0mmole) and triethylamine (0.5ml).This reactant was stirred under room temperature 10 minutes.Add 50ml salt solution and 50ml DCM.Organic layer is with 1N HCl solution (50ml), water (50ml), salt solution (50ml) washing, through Na ₂SO ₄Dry and concentrated.Make residue be dissolved in 20mlDMF.(0.5g is 7.4mmole) with 50mg 18-hat-6 to add sodiumazide.It's weekend is past reaction mass heated to 80 ℃.Add 50ml EtOAc and 50ml hexane.Organic layer water (2x50ml) washing is through Na ₂SO ₄Dry and concentrated.Residue is that pure products and its can be further purified and be used for next step.Must measure: 0.68g, 79%. ¹H NMR (CDCl ₃400MHz δ 7.61 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.08 (m, 1H); 6.42 (m, 1H), 5.25 (dd, J=11.7 and 2.9Hz, 1H), 4.12 (d, J=11.0Hz; 1H), 3.87 (m, 1H), 2.96 (dt, J=11.7 and 2.9Hz, 1H), 2.27-2.42 (m; 2H), and 1.79-1.92 (m, 2H), 1.61-1.70 (m, 1H), 1.23-1.31 (m, 1H).

Step 2: (6aR)-and 10aS-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [b, d] pyrans-8 (R)-amine (racemic)

Make cis-8-azido--10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene (0.63g 1.43mmole) is dissolved in 25ml THF, and the adding triphenyl phosphine (0.45g, 1.72mmole).Add 2ml water and reactant was refluxed 4 hours.Make reaction cooled to room temperature.Add 10ml1N NaOH solution, with reactant stirred overnight under room temperature.Add 50ml water and 50ml EtOAc.Organic layer water (2x50ml) washing is through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (EtOAc/2.5N NH3 in MeOH, from 100/0-80/20 through 45 minutes).Must measure: 0.46g, 78%. ¹H NMR (CDCl ₃400 MHz δ 7.61 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.05 (m, 1H); 6.40 (m, 1H), 5.24 (dd, J=11.7 and 2.9Hz, 1H), 4.07 (d, J=11.0Hz, 1H); 3.24 (bs, 1H), 3.09 (m, 1H), 2.52 (tt, J=13.9 and 2.9Hz, 1H); 2.27 (d, J=13.9Hz, 1H), 1.49-1.31 (m, 3H), 1.30 (m, 1H).

Embodiment 20:

N-[(6aR)-and 10aS-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [b, d] pyrans-8 (R)-yl]-1,1,1-three fluoro-Toluidrins

Make (6aR)-10aS-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7; 8,9,10; (150mg 0.36mmole) is dissolved in 25ml DCM to 10a-six hydrogen-6H-benzo [b, d] pyrans-8 (R)-amine; (0.15g 0.54mmole), then adds triethylamine (0.2ml) to be added in trifluoromethanesulfchloride chloride among the 5ml DCM.This reactant was stirred under room temperature 10 minutes.Add 50ml water and 50mlDCM.Separate organic layer, through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (EtOAc/ hexane, from 0/100-25/75 through 35 minutes).Must measure: 0.18g, 91% racemic compound 20A. ¹H NMR (CDCl ₃400MHz δ 7.57 (d, J=8.1Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.10 (m, 1H), 6.42 (m; 1H), 6.07 (d, J=8.1Hz, 1H), 5.25 (dd, J=11.7 and 2.9Hz, 1H), 4.13 (d, J=12.4Hz; 1H), 3.90 (bs, 1H), 2.96 (dt, J=13.2 and 2.9Hz, 1H), 2.52 (dt, J=13.9 and 2.9Hz, 1H); 2.25 (tt, J=13.9 and 2.2Hz, 1H), 1.81-2.01 (m, 3H), 1.41 (tt, J=14.6 and 2.9Hz, 1H).

Using Chiral OJ post, as solvent, can be two pure enantiomorph 20B and 20C with hexane/isopropyl alcohol (65/35) with racemic mixture separation.

First flow point: [α]=-72.2deg. (c=0.90 is in DCM)-compound 20B.

Second flow point: [α]=67.2deg. (c=0.95 is in DCM)-compound 20C

Employing is similar to the method for embodiment 20 (that is, being similar to those methods that are used to prepare compound 20A) and replaces suitable acyl group or alkylsulfonyl halogenide, the compound in the preparation table 11.

Table 11

Embodiment 21:

Step 1: 3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base is amino]-third-1-alcohol

Make 4-(4-chloro-benzenesulfonyl)-5, (0.3g 0.88mmole) is dissolved in 15ml THF to 8-two fluoro-2H-chromenes, adds 3-aminopropanol (1ml).Under room temperature, stirred this mixture 30 minutes.Add 50 saturated Na ₂CO ₃Solution and 50ml EtOAc.Organic layer water (50ml), salt solution (50ml) washing are through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification (EtOAc/ hexane, from 50/50-100/0 through 45 minutes).Must measure: 0.31g, 84%. ¹H?NMR(CDCl ₃?400?MHz)δ7.69(d，J＝8.8Hz，2H)，7.48(d，J＝8.1Hz)，6.99(td，J＝9.5，5.1Hz，1H)，6.38(td，J＝9.5，3.7HZ，1H)，4.80(dd，J＝12.5，2.9Hz，1H)，4.53(s，1H)，4.43(d，J＝11.8Hz，1H)，3.78(s，1H)，3.61(t，J＝5.9Hz，2H)，2.86-2.71(m，2H)，2.25(bs，1H)，1.57(p，J＝5.9Hz，2H)。

Step 2: methanesulfonic 3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base is amino]-propyl diester

Make methanesulfonic 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-(0.29g 0.69mmol) is dissolved in the 50ml methylene dichloride to 3-base ester.Add respectively methylsulfonyl chloride (64 μ L, 0.83mmol) and triethylamine (117 μ L, stirred overnight 0.83mmol) and under room temperature.This solution with water (40ml) and methylene dichloride (40ml) quencher.Separate each layer, water layer is used washed with dichloromethane.The organism that merges is through Na ₂SO ₄Dry and concentrated under vacuum.Product need not be further purified and be used for next step.Bullion yield: 280mg, 81%. ¹H?NMR(CDCl ₃?400MHz)δ7.71(d，J＝8.8Hz，2H)，7.50(d，J＝8.8Hz，2H)，7.01(td，J＝10.3，5.1Hz)，6.41(td，8.8，3.7Hz，1H)，4.80(dd，J＝11.8，2.2Hz，1H)，4.53(s，1H)，4.48(d，J＝11.8Hz，1H)，4.22(t，5.9Hz，2H)，3.75(s，1H)，2.93(s，3H)，2.82-2.67(m，2H)，1.79(p，J＝5.9Hz，2H)。

Step 3: 4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei

Make methanesulfonic 3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base is amino]-propyl diester (0.28g 0.57mmol) is dissolved in the 25ml THF, add then 1M potassium tert.-butoxide solution (2.40ml, 2.40mmol).This reactant is stirred 3.5h under room temperature.Reaction is also washed with 50ml ETHYLE ACETATE with the quencher of 50ml water.Organic layer is through Na ₂SO ₄Dry and concentrated.Product is through prep TLC (EtOAc/ hexane 50/50) purifying.Must measure: 140mg, 60%. ¹H?NMR(CDCl ₃?400MHz)δ7.60(d，J＝8.1Hz，2H)，7.49(d，J＝8.8Hz，2H)，7.08(td，J＝9.5，4.4Hz，1H)，6.47-6.40(m，1H)，5.21(dd，J＝11.8，2.2Hz，1H)，4.33(d，J＝11.8Hz，1H)，3.70(s，1H)，3.00(d，J＝13.2Hz，1H)，2.76(td，J＝12.4Hz，2.9Hz，1H)，2.68(d，J＝13.2Hz，1H)，2.17(tt，J＝13.2，2.9Hz1H)，1.66-1.44(m，2H)，1.21-1.07(m，1H)。

Embodiment 22 and 23:

4a-(4-chloro-benzenesulfonyl)-1-ethyl-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei and 1-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-ethyl ketone

Make 4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei (73mg 0.18mmol) is dissolved in the 5ml THF, add then acetic anhydride (182mg, 1.78mmol).With this reactant stirred overnight under room temperature.(64mg 2.91mmol), stirs 3h with this reactant under room temperature to add lithium borohydride.Reaction is with the quencher of 25ml water, and 25ml adds ETHYLE ACETATE then.Organic layer is through Na ₂SO ₄Dry and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-50/50 40 minutes).Separate two kinds of compounds.

4a-(4-chloro-benzenesulfonyl)-1-ethyl-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei (22): must measure: 20.8mg, 26%. ¹H?NMR(CDCl ₃?400MHz)δ7.60(d，J＝8.1Hz，2H)，7.48(d，J＝8.8Hz，2H)，7.07-6.99(m，1H)，6.43-6.35(m，1H)，5.16(dd，J＝13.2，1.5Hz，1H)，4.67(dd，J＝13.2，1.5Hz，1H)，3.34(s，1H)，3.15-3.04(m，1H)，2.84-2.67(m，2H)，2.61-2.51(m，2H)，2.04-1.94(m，1H)，1.66-1.58(m，1H)，1.39-1.27(m，1H)，1.00(t，J＝7.3Hz，3H)。

1-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-ethyl ketone (23): must measure: 36.6mg, 46%. ¹H?NMR(CDCl ₃400MHz)δ7.61(d，J＝8.8Hz，2H)，7.43(d，J＝8.8Hz，2H)，7.05(td，J＝9.5，4.4Hz，1H)，6.60-6.51(m，1H)，5.40(bs，1H)，4.50(dd，J＝11.8，3.7Hz，1H)，4.20(dd，J＝11.8，5.9Hz，1H)，3.62(bs，1H)，2.90(bs，1H)，2.70-2.60(m，1H)，2.50-2.40(m，1H)，2.22-2.03(m，4H)，1.52-1.41(m，1H)。

Embodiment 24:

Embodiment 244 and 24B:

Anti-form-1 0b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-cis-4-methyl isophthalic acid, 4a, 5; 10b-tetrahydrochysene-2H, 4H-pyrans o [3,4-c] chromene and anti-form-1 0b-(4-chloro-benzenesulfonyl)-7; 10-two fluoro-are trans-the 4-methyl isophthalic acid, and 4a, 5; 10b-tetrahydrochysene-2H, 4H-pyrans o [3,4-c] chromene

Step 1

(500mg, DCM 1.46mmol) (3mL) solution is crossed iodine alkane (periodinane) with Dess-Martin, and (732mg 1.72mmol) handles, and under room temperature, stirs 1 hour, adds excessive Sulfothiorine then with the product that derives from embodiment 16 steps 2.With EtOAc and half the-saturated this soup compound of NaHCO3 dilution, with half the-saturated NaHCO3 washing, through Na ₂SO ₄Dry and concentrated.The aldehyde that obtains (500mg) but former state is used for next step.

Step 2

(1.23g, THF 5.00mmol) (6mL) solution stirred under room temperature 90 minutes, then in 0 ℃ of Et that adds methyl-magnesium-bromide 3N with anhydrous cerium chloride ₂O (1.66mmol, 5.00 mmol) solution.Stirred this soup compound other 1 hour in 0 ℃, stirred 1 hour then with THF (3mL) solution-treated of the aldehyde (500mg) that derives from step 1, and in 0 ℃.In the saturated NH4Cl of final mixture impouring, extract with EtOAc, dry and concentrated.Residue obtains 217mg (42%) isomer A through flash chromatography on silica gel purifying (with hexane/AcOEt 99:1-AcOEt wash-out) by elution order, then is 140mg (27%) isomer B.

Step 3

Make that (217mg, 0.61mmol) experience is similar to the condition of describing among step 3 embodiment 16, obtains 153mg (51%) midbody from the isomer A of step 2 product.According to being similar among step 4 embodiment 16 condition of describing, with the MCPBA oxidation intermediates (153mg, 0.31mmol), then usefulness be stated from 20%Pd (OH) 2 on the charcoal in AcOEt in 1atm hydrogenation 1 hour, obtain the 116mg alcohol intermediate.Make alcohol intermediate (116mg, 0.27mmol) experience is similar to the condition of description in the step 6 and 7 of embodiment 16, obtains 64 mg embodiment 24A: ¹H-NMR (CDCl ₃400MHz) δ 7.64 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.08 (m, 1H), 6.45 (m; 1H), 5.17 (dd, 1H), 4.43 (d, 1H), 3.87 (m, 1H), 3.40 (m, 1H); 3.18 (t, 1H), 2.45-2.55 (m, 2H), 2.33 (m, 1H), 1.38 (d, J=6Hz, 3H); LCMS (MH ⁺)=415.2; RT=4.86 minute.

Make from the isomer B of step 2 product (140mg, 0.40mmol) experience is similar to the condition of above description, obtains 26.5mg embodiment 24B: ¹H-NMR (CDCl ₃400MHz) δ 7.50 (d, J=8.7Hz, 2H), 7.42 (d, J=8.7Hz, 2H), 7.01 (m, 1H); 6.42 (m, 1H), 4.88 (dd, 1H), 4.36 (m, 1H), 4.12 (dd; 1H), 3.88 (m, 1H), 3.63 (m, 1H), 2.97 (m, 1H); 2.76 (m, 1H), 2.53 (m, 1H), 1.17 (d, J=6.8Hz, 3H); LCMS (MH ⁺)=415.2; RT=4.73 minute.

Be used for preparing the method that embodiment 24A and 24B describe, the compound in the preparation table 12 according to being similar to.

Table 12

Embodiment 25:

Embodiment 254 and 25B:

Anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9; 10,10a-six hydrogen-6H-benzo [c] chromene-pure and mild anti-form-1 0a-of trans-7-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7; 8,9,10,10a-six hydrogen-6H-benzo [c] chromene-cis-7-alcohol

Step 1

With the product solution (7.0 that derives from embodiment 16 steps 2; 20.0mmol) experience is similar to the condition of description in the step 1 and 2 of embodiment 24a and 24b; But replace methyl-magnesium-bromide with allyl group bromination magnesium; Similarly flash chromatography and according to after the identical elution order obtains 1.40g (21%) isomer A, then obtains 850mg (11%) isomer B.

Step 2

To the isomer A product that derives from step 1 (1.62g, add in THF 4.23mmol) (50mL) solution NaH60% (540mg, 13.4mmol), then add bromotoluene (1.5mL, 13.4mmol), with reactant in 55 ℃ of stirred overnight.In cooling mixture impouring water, extract with EtOAc, through Na ₂SO ₄Dry and concentrated.Residue obtains 1.07g (53%) allyl group benzylic ether isomer A through flash chromatography on silica gel purifying (with hexane/AcOEt 99:1-50:50 wash-out).

Make that (950mg, 2.48mmol) experience is similar to the above-mentioned condition that is used to prepare allyl group benzylic ether isomer A, obtains 700mg (59%) allyl group benzylic ether isomer B from the isomer B of step 1 product.

Step 3

(900mg, (4.7mL, 9.4mmol) solution will react on and stir 90 minutes under the room temperature and stirred 30 minutes in 55 ℃ the THF of adding borine dimethylsulphide 2N in THF 1.90mmol) (2mL) solution to the allyl group benzylic ether isomer A product that derives from step 2.Then with reactant with 3N NaOH (4mL), then use 30%H ₂O ₂(4mL) quencher and stirring 1 hour.The final mixture dilute with water extracts with EtOAc, through Na ₂SO ₄Dry and concentrated, obtain 1.52g crude alcohol isomer A.

Make that (550mg, 1.16mmol) experience is similar to the above-mentioned condition that is used to prepare pure isomer A, obtains 800mg crude alcohol isomer B from the allyl group benzylic ether isomer B of step 2 product.

Step 4

According to being similar to the condition of describing in embodiment 16 steps 4; Derive from the crude alcohol isomer A product (1.52g) of step 3 with the MCPBA oxidation; The midbody experience that obtains then is similar to the condition of describing in the step 6 and 7 of embodiment 16, obtains the direct precursor embodiment 25A of 320mg O-benzyl isomer A: ¹H-NMR (CDCl ₃400MHz) δ 7.40-7.60 (m, 4H), 7.15-7.30 (m, 3H), 7.03 (d, J=8.7Hz, 2H); 6.95 (m, 1H), 6.24 (m, 1H), 5.18 (m, 1H), 4.39 (m; 2H), 4.27 (d, 1H), 3.94 (brs, 1H), 2.75 (m, 1H); 2.63 (m, 1H), 1.95-2.10 (m, 2H), 1.40-1.65 (m, 3H).

According to being similar to the condition of describing in embodiment 16 steps 4; Derive from the crude alcohol isomer B product (800mg) of step 3 with the MCPBA oxidation; The midbody experience that obtains then is similar to the condition of describing in the step 6 and 7 of embodiment 16, obtains the direct precursor embodiment 25B of 223mg O-benzyl isomer B: ¹H-NMR (CDCl ₃400MHz) δ 7.60 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.20-7.40 (m, 5H); 7.07 (m, 1H), 6.41 (m, 1H), 5.06 (m, 1H), 4.88 (d, 1H); 4.63 (d, 1H), 4.48 (d, 1H), 3.25 (m, 1H), 2.63 (brd, 1H); 2.55 (d, 1H), 2.16 (m, 1H), 1.70-1.95 (m, 2H), 1.00-1.45 (m, 2H); LCMS (MH ⁺)=505.3; RT=5.31 minute.

Step 5

The O-benzyl isomer A product (320mg) that derives from step 4 that will be in EtOAc filters and concentrates through CELITE then with being stated from 20%Pd (OH) 2 on charcoal hydrogenation 1 hour under 1atm, obtains 220mg embodiment 25A: ¹H-NMR (CDCl ₃400MHz) δ 7.40-7.55 (m, 4H), 7.02 (m, 1H), 6.83 (m, 1H), 5.28 (dd, 1H), 4.49 (d, 1H), 4.27 (brs, 1H), 2.60-2.70 (m, 2H), 1.90-2.15 (m, 2H), 1.77 (m, 1H), 1.40-1.70 (m, 3H); LCMS (MH ⁺)=415.2; RT=4.12 minute.

The O-benzyl isomer A product (223mg) that derives from step 4 that will be in EtOAc (5mL) filters and concentrates through CELITE then with being stated from 20%Pd (OH) 2 on the charcoal (30mg) hydrogenation 1 hour under 1atm, obtains 146mg embodiment 25B: ¹H-NMR (CDCl ₃400MHz) δ 7.60 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 7.05 (m, 1H); 6.40 (m, 1H), 5.07 (m, 1H), 4.86 (d, 1H), 3.43 (m, 1H); 2.59 (brd, 1H), 2.40 (d, 1H), 2.28 (m, 1H), 1.85-2.05 (m; 2H), 1.76 (m, 1H), 1.38 (m, 1H), 1.08 (m, 1H); LCMS (MH ⁺)=415.2; RT=4.13 minute.

Embodiment 26:

Anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-cis-7-methoxyl group-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene

Step 1

To embodiment 25A (15mg, add in THF 0.036mmol) (1mL) solution 60%NaH (3mg, 0.072mmol), then add MeI (22uL stirs this reactant 2h 0.36mmol) and under room temperature, then among water and the EtOAc through aftertreatment.Mixture experiences quick silica gel column chromatography (with hexane/EtOAc 99:1-50:50 wash-out), obtains 13.5mg embodiment 26: ¹H-NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.8Hz, 2H), 6.99 (d, J=8.8Hz, 2H), 7.07 (m, 1H); 6.41 (m, 1H), 5.05 (m, 1H), 4.81 (d, 1H), 2.97 (m, 1H); 2.62 (brd, 1H), 2.45 (d, 1H), 2.16 (m, 1H), 1.89 (m; 1H), 1.78 (m, 1H), 1.25 (m, 1H), 1.06 (m, 1H); LCMS (MH ⁺)=429.2; RT=5.15 minute.

Embodiment 27A and 27B:

Anti-form-1 1a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,6a, 7,8; 9,10,11,11a-octahydro-cyclohepta [c] chromene-cis-pure and mild anti-form-1 1a-of 8-(4-chloro-benzenesulfonyl)-1; 4-two fluoro-6,6a, 7,8; 9,10,11,11a-octahydro-cyclohepta [c] chromene-trans-8-alcohol

Step 1

(35.0g, THF 109mmol) (500mL) solution was cooled to-78 ℃, added hexane (45.3mL, 113.2mmol) solution of nBuLi2.5N through 5 minutes with the product that derives from embodiment 8 steps 2.In-78 ℃ reactant was stirred 10 minutes, and warp adding in 10 minutes 2 (5H) furanone (8.2mL, 120mmol).Made this mixture slowly be warmed to-45 ℃ through 2 hours, and under this temperature, kept other 1 hour.Final mixture is used saturated NH ₄The Cl quencher is extracted with EtOAc and DCM, through Na ₂SO ₄Dry and concentrated.Residue obtains ester products in 17.9g starting raw material and the 10.4g through flash chromatography on silica gel purifying (with hexane/EtOAc 90:10-EtOAc wash-out) according to elution order.

Step 2

To the interior ester products that derives from step 1 (17.5g, add in THF 43.2mmol) (500mL) solution lithium borohydride (3.74g, 172mmol) and under room temperature with the reactant stirred overnight.With the slow impouring 0.1N of final mixture HCl, extract with EtOAc and DCM, through Na ₂SO ₄Dry and concentrated.Residue obtains 18.0g (100%) glycol through flash chromatography on silica gel purifying (eluted uses the DCM/EtOAc99:1-EtOAc wash-out).

Step 3

With the diol product that derives from step 2 (18.0g, 43.2mmol) and imidazoles (7.5g, DMF 110mmol) (150mL) solution with TBDPSCl (11.4mL 44.0mmol) handles, with reactant in 45 ℃ of heated overnight.The mixture dilute with water is used Et ₂O extracts, through Na ₂SO ₄Dry and concentrated.Residue obtains the glycol of the single protection of 28.7g (100%) through flash chromatography on silica gel purifying (with hexane/EtOAc 99:1-50:50 wash-out), is isomer mixture.

Step 4

With the glycol of the single protection that derives from step 3 (5.5g, THF 8.5mmo1) (50mL) solution with NaH60% hexane (375mg, 9.4mmol) in processing, with reactant in 60 ℃ of heated overnight.In final mixture impouring 10% Hydrocerol A, extract with DCM, through Na ₂SO ₄Dry and concentrate with residue through flash chromatography on silica gel purifying (with hexane/EtOAc99:1-50:50 wash-out), obtain the chromene that 4.8g (90%) O-protects.

Step 5

The chromene product that the O-that derives from step 4 is protected (15.7g, (30mL, 30.0mmol) THF 25.0mmol) (100mL) solution stirs reactant 3 hours in 60 ℃ at THF with TBAF1N by middle the processing.Final mixture is carried out aftertreatment in the EtOAc of water solution, through Na ₂SO ₄Dry and concentrate with residue through flash chromatography on silica gel purifying (with hexane/EtOAc 99:1-EtOAc wash-out), obtain 9.91g (100%) alcohol.

Step 6

(3.0g adds Dess-Martin and crosses iodine alkane (6.5g 15.4mmol), stirred this reactant 2 hours under room temperature in DCM 7.7mmol) (50mL) solution to the pure product that derives from step 5., extract with EtOAc, with saturated NaHCO3 dilution with saturated sodium thiosulfate quencher reaction through Na ₂SO ₄Dry and concentrated, obtain 3.25g (100%) crude aldehyde.

Step 7

In-78 ℃; To the crude aldehyde product that derives from step 6 (3.25g, slow Et2O (12.6mL, 12.6mmol) solution that adds allyl group bromination magnesium 1N in THF 8.4mmol) (60mL) solution; This reactant was stirred 2 hours in-50 ℃, be warmed to then 0 ℃ other 2 hours.In the saturated NH4Cl of final mixture impouring, extract with EtOAc, through Na ₂SO ₄Dry and concentrated.Residue obtains 1.50g (50%) allyl alcohol through flash chromatography on silica gel purifying (with hexane/EtOAc 99:1-EtOAc wash-out), is the mixture of isomer A and B.

Step 8

Feasible allyl alcohol isomer mixture product experience from step 7 is similar to the condition of describing among the step 2-5 of embodiment 25A and 25B; After silica gel column chromatography (with hexane/EtOAc99:1-EtOAc wash-out) separates fast; Obtain embodiment 27A, then obtain embodiment 27B.Embodiment 27A: ¹H-NMR (CDCl ₃400MHz) δ 7.66 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.03 (m, 1H), 6.91 (m; 1H), 5.18 (dd, 1H), 4.15-4.25 (m, 2H), 3.65 (brd, 1H), 2.96 (m, 1H); 2.15 (m, 1H), 1.98 (m, 1H), 1.70-1.90 (m, 3H), 1.35-1.65 (m, 3H); LCMS (MH ⁺)=429.2; RT=4.19 minute.Embodiment 27B: ¹H-NMR (CDCl ₃400MHz) δ 7.63 (d, J=8.7Hz, 2H), 7.48 (d, J=8.7Hz, 2H), 7.04 (m; 1H), 6.90 (m, 1H), 5.10 (dd, 1H), 4.26 (d, 1H); 3.94 (m, 1H), 2.99 (brd, 1H), 2.88 (m, 1H), 2.18 (m; 1H), 1.80-2.00 (m, 3H), 1.60-1.80 (m, 3H), 1.16 (m, 1H); LCMS (MH ⁺)=429.2; RT=4.03 minute.

Embodiment 28:

Anti-form-1 1a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,6a, 7,8,9,10,11,11a-octahydro-cyclohepta [c] chromene-cis-8-fluoroform sulphonamide

Step 1

Make embodiment 27A experience be similar to the condition of describing among embodiment 19 and 20 SCH 1372731, embodiment 28 be provided: ¹H-NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.7Hz, 2H), 7.48 (d, J=8.7Hz, 2H), 7.05 (m, 1H); 6.92 (m, 1H), 5.64 (brs, 1H), 5.10 (dd, 1H), 4.19 (dd, 1H); 4.03 (brs, 1H), 3.49 (d, 1H), 3.27 (brd, 1H), 2.95 (m; 1H), and 2.05-2.25 (m, 2H), 1.80-2.00 (m, 3H), 1.65-1.75 (m, 1H); LCMS (MH ⁺)=560.3; RT=4.78 minute.

Embodiment 29:

4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-4,4a, 10,10a-tetrahydrochysene-1H, 3H-9-oxa--2-thia-Fei

Step 1

2-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-methylthiol]-ethanol

Make at embodiment 10; The methanesulfonic 4-(4-chloro-benzenesulfonyl)-5 that describes in the step 6; (230mg 0.51mmol) is dissolved in 7.0mL methyl alcohol and also handles with 992mg (12.7mmol) 2 mercapto ethanol and the 2.0mL 1MNaOH aqueous solution 8-two fluoro-chroman-3-ylmethyl ester.Mixture in the filter freezing device in 77 ℃ of heated overnight.Cool off this mixture and be allocated in water and DCM between.Containing water extracts with DCM.The organic phase that merges is through MgSO ₄Dry and concentrated.Product is through column chromatography purification, is used in 20%EtOAc in the hexane as elutriant (140mg, 63%)

Step 2

Methanesulfonic 2-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-ylmethyl sulfenyl]-ethyl ester

According to embodiment 10, the method for step 6 makes the product methylsulfonylization of step 1, but reacts at 0 ℃.

Step 3

(4aS)-and 10bS-[(4-chlorophenyl) alkylsulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-thiapyran be [3,4-c] [1] chromene (racemic) also

(140mg 0.273mmol) is dissolved in 2.7mL THF, is cooled to 0 ℃, with the THF solution-treated of 0.273mL (0.273mmol) 1M potassium tert.-butoxide to make the product of step 2.In 0 ℃ this mixture was stirred 10 minutes, the water quencher is extracted with DCM.Organic phase is through MgSO ₄Dry and concentrated.Product is through column chromatography purification, is used in 10%EtOAc in the hexane as elutriant (50mg, 44%). ¹H NMR (CDCl ₃400MHz) δ 7.59 (d, J=8.5Hz, 2H), 7.50 (d, J=8.5Hz, 2H), 7.11 (m, 1H); 6.46 (m, 1H), 5.32 (dd, J=2.8 and 11.7Hz, 1H), 4.21 (d, J=11.7Hz, 1H); 2.94-2.86 (m, 2H), 2.77 (2, J=12.0Hz, 1H), 2.6-2.28 (ser.m., 4H).

Embodiment 30-31

With the 0.38mL acetone soln of 30mg (0.072mmol) embodiment 29 with 0.095mL water and 48.7mg (0.079mmol) oxone ^TMHandle.Stir after 4 hours, mixture is allocated between water and the DCM.Organic phase is through MgSO ₄Dry and concentrated.Below three kinds of products separate through prep.TLC, use 30%EtOAc in hexane as elutriant.

Embodiment 30

(4aS)-and 10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-thiapyran be [3,4-c] [1] chromene also, 3-oxide compound (racemic) (sulfoxide diastereomer A)

LCMS m/z=433.2 (M+H) ⁺, RT 3.65 minutes, ¹H NMR (CDCl ₃400MHz) δ 7.68 (d, J=8.5Hz, 2H), 7.54 (d, J=8.5Hz, 2H), 7.14 (m, 1H), 6.53 (m, 1H); 5.44 (dd, J=2.7 and 12.0Hz, 1H), 4.14 (d, J=12.0Hz, 1 H), 3.57 (d, J=12.2Hz, 1H); 3.17 (tt, J=14.8 and 3.2Hz, 1H), 3.02 (dt, J=14.0 and 2.9Hz, 1H), 2.91 (dm, J=14.5Hz, 1H); 2.60 (dm, J=14.3Hz, 1H), 2.45 (dd, J=12.0 and 14.0Hz, 1H), 2.24 (td, J=14.0 and 2.0Hz, 1H).

Embodiment 31

(4aS)-and 10bS-[(4-oxo phenyl) alkylsulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-thiapyran be [3,4-c] [1] chromene also, 3-oxide compound (racemic) (sulfoxide diastereomer B)

LCMSm/z=433.2 (M+H) ⁺, RT 3.57 minutes, ¹HNMR (CDCl ₃400MHz) δ 7.58 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.17 (m, 1H), 6.52 (m; 1H), 5.31 (dd, J=3.1 and 9.0Hz, 1H), 4.22 (dd, J=11.9 and 1.5Hz, 1H), 3.49 (s, 1H); 3.39 (tt, J=13.0 and 3.0Hz, 1H), 3.34-3.28 (ser.m, 1H), 3.13 (dm, J=12.2Hz, 1H), 2.84 (dd; J=13.5 and 6.9Hz, 1H), 2.69 (t, J=13.0Hz, 1H), 2.37 (t, J=12.0Hz, 1H).

Embodiment 32

(4aS)-and 10bS-[(4-chlorophenyl) alkylsulfonyl)-7,10-two atmosphere-1,4a, 5,10b-tetrahydrochysene-2H, 4H-thiapyran be [3,4-c] [1] chromene also, and 3,3-dioxide (racemic)

LCMSm/z=449.1 (M+H) ⁺, RT 4.10 minutes, ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.20 (m; 1H), 6.56 (m, 1H), 5.38 (dd, J=2.7 and 12.2Hz, 1H), 4.18 (d; J=12.2Hz, 1H), 3.46 (dm, J=12.6Hz, 1H), 3.13-2.69 (ser.m., 6H).

Embodiment 33:

Step 1

Tert-butyl-(R)-3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base oxygen base]-butoxy }-dimethylsilane

In 0 ℃, to 1.80g (8.77mmol) (R)-be added dropwise to 0.28mL (0.96mmol) 2.5Mn-BuLi in hexane in THF (10mL) solution of 4-(tert-butyl-dimethyl--silicon alkoxyl group)-Ding-2-alcohol.Stir this mixture for several minute and add 300mg embodiment 17, the product of step 3.Continue to stir 30 minutes in 0 ℃.Water quencher reaction is extracted with EtOAc, and water and brine wash are through MgSO ₄Dry and concentrated.Product (550mg) separates through flash chromatography, uses from the gradient liquid of 0%-40%EtOAc hexane.

Step 2

(R)-3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base oxygen base]-Ding-1-alcohol

(95mg 0.174mmol) is dissolved in the DCM solution of 2.0mL3%TFA to make the product of step 1.This mixture was stirred 40 minutes.Water and brine wash reactant are through MgSO ₄Dry and concentrated.Product (60mg) separates through prep.TLC, and the 40%EtOAc of use in hexane is as elutriant.

Step 3

(4aR)-and 10bR-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,2,3,4a, 5,10b-six hydrogen-3 (R)-methyl pyrans o [2,3-c] [1] chromene

According to embodiment 10, the method for step 6 makes the product methylsulfonylization of step 2, and then according to embodiment 29, step 3 is carried out cyclisation.Through prep.TLC, the 15%EtOAc of use in hexane separates required compound as elutriant from non-enantiomer mixture.

¹H NMR (CDCl ₃400MHz) δ 7.60 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.05 (m, 1H), 6.38 (m; 1H), 5.05 (dd, J=12.2 and 2.0Hz, 1H), 4.58 (m, 1H), 4.40 (dd, J=12.2 and 1.6Hz; 1H), 4.12 (m, 1H), 2.58 (tt, J=13.0 and 3.1Hz, 1H), 2.44 (tt, J=13.7 and 4.0Hz; 1H), 1.71-1.62 (ser. m., 1H), 4.53-1.46 (ser.m., 1H), 1.37 (d, J=6.7Hz, 3H).

Embodiment 34:

Step 1

3-[4-(4-chloro-benzenesulfonyl)-5,8-=fluoro-chroman-3-base oxygen base]-third-1-alcohol

With 1, the 3-propane diol is similar to embodiment 33 these compounds of preparation as starting raw material.

Step 2

(4aS)-and 10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,2,3,4a, 5,10b-six hydrogen pyrans are [2,3-c] [1] chromene (racemic) also

According to embodiment 10, step 6 makes the product methylsulfonylization of step 1, and again according to embodiment 29, step 3 is carried out cyclisation. ¹H NMR (CDCl ₃400MHz) δ 7.59 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 2H), 7.07 (m, 1H), 6.39 (m; 1H), 5.07 (dd, J=12.2 and 1.8Hz, 1H), 4.48 (d, J=13.9Hz, 1H), 4.30 (s, 1H); 3.94 (dd, J=11.2 and 4.7Hz, 1H), 3.59 (td, J=11.9 and 2.5Hz, 1H), 3.49 (d, J=5.5Hz, 1H); 2.72 (dm, J=13.0 Hz, 1H), 2.30 (tt, J=13.0 and 3.3Hz, 1H), 1.53-1.40 (ser.m., 1H).

Embodiment 35:

Step 1

3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base sulfenyl]-third-1-alcohol

Be similar to embodiment 33, this compound of step 1 preparation, but with 3-sulfydryl-third-1-alcohol as reagent and with salt of wormwood as alkali.

Step 2

(4aS)-and 10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-difluoro 1,2,3,4a, 5,10b-six hydrogen thiapyrans are [2,3-c] [1] chromene (racemic) also

According to embodiment 10, step 6 makes the product methylsulfonylization of step 1, and again according to embodiment 29, step 3 is carried out cyclisation. ¹HNMR (CDCl ₃400MHz) δ 7.57 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 2H), 7.10 (m, 1H); 6.44 (m, 1H), 5.44 (dd, J=12.2 and 1.8Hz, 1H), 4.25 (d, J=12.5Hz, 1H); 4.01 (s, 1H), 2.86 (td, J=12.5 and 2.7Hz, 1H), 2.67 (d, J=11.2Hz, 1H); 2.46 (d, J=13.5Hz, 1H), 2.04-1.90 (ser.m., 2H), 1.53-1.40 (ser.m., 1H).

Embodiment 36 and 37:

Based on the method for describing among the embodiment 30-32, the product that obtains among the embodiment 35 is handled with oxone.Through prep.TLC, the 30%EtOAc of use in hexane separates two product sulfoxides (embodiment 36) and sulfone (embodiment 37) as elutriant.

Embodiment 36

(4aR)-and 10bR-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,2,3,4a, 5,10b-six hydrogen thiapyrans are [2,3-c] [1] chromene also, 4-oxide compound (racemic)

LCMSm/z=433.2 (M+H) ⁺, RT 3.65 minutes. ¹H NMR (CDCl ₃400MHz) δ 7.59 (d, J=8.7Hz, 2H), 7.52 (d, J=8.7Hz, 2H), 7.13 (m, 1H); 6.46 (m, 1H), 5.43 (d, J=13.0Hz, 1H), 5.16 (d, J=13.1Hz, 1H); 3.51 (s, 1H), 3.45 (d, J=13.1Hz, 1H), 2.83 (td, J=13.0 and 3.3Hz, 1H); 2.70 (d, J=11.0Hz, 1H), 2.23-2.08 (ser.m., 2H), 1.5-1.43 (ser.m., 1H).

Embodiment 37

(4aR)-and 10R-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,2,3,4a, 5,10b-six hydrogen thiapyrans are [2,3-c] [1] chromene also, and 4,4-dioxide (racemic)

LCMSm/z=449.2 (M+H) ⁺, RT 4.19 minutes. ¹HNMR(CDCl ₃400MHz)7.53-7.49(m，4H)，7.12(m，1H)，6.42(m，1H)，5.27(s，2H)，3.99(t，J＝2.9Hz，1H)，3.19-3.05(ser.m.，2H)，2.85(d，J＝13.4Hz，1H)，2.32-2.16(ser.m.，2H)，1.96(m，1H)。

Embodiment 38: 1,4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone O-methyl-oxime

To anti-form-1 0a-(4-trifluoromethyl-benzenesulfonyl)-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone (40mg, add in EtOH 0.10mmol) (2mL) solution O-methyl hydroxy amine hydrochloric acid salt (20mg, 0.23mmol) and NEt ₃(20uL, 0.14mmol).With the reaction mixture stirred overnight, add PS-dimethyl aminoethyl resin then, continue to stir 2H, then through removing by filter resin.At N ₂Flow down to remove and desolvate, residue is used in 25% eluent ethyl acetate (22mg, 47%) in the hexane through preparation type TLC purifying.

Table 14

Through with embodiment 38 similar methods, the compound of embodiment in the preparation table 15.

Table 15

Embodiment 39:

4-toluene sulfonic acide [(E) (6aR)-10aS-[(4-chlorophenyl) alkylsulfonyl]-14-two fluoro-6a, 9,10,10a-tetrahydrochysene-6H-dibenzo [b, d] pyrans-8 (7H)-subunit] hydrazides.

To anti-form-1 0a-(4-trifluoromethyl-benzenesulfonyl)-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone (160mg, and adding p-toluenesulfonyl hydrazine in THF 0.38mmol) (1.5mL) solution (80mg, 0.43mmol).This reaction mixture is stirred 2H under room temperature, concentrate then.Residue obtains white solid～1:1 mixture of isomers (205mg, 96%) through silica gel purification. ¹H NMR (CDCl ₃400MHz) δ 7.77 (dd, 2H), 7.57 (d, 2H), 7.49 (d, 1H), 7.38 (s, 1H; Isomer B) 7.34 (s, 1H, isomer A), 7.30 (dd, 2H), 7.10-7.04 (m, 1H), 6.46-6.4 (m; 2H), 5.23 (dd, 3H, isomer B), 5.15 (s, 3H, isomer A), 4.10 (dd; 1H), and 2.91-2.77 (m, 1H), 2.71-2.44 (m, 2H), 2.28-2.16 (m, 5H); LCMS (MH ⁺) 581 au.

Embodiment 40:

10a-(4-chloro-benzenesulfonyl)-1,4,7-three fluoro-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone

To anti-form-1 0a-(4-chloro-benzenesulfonyl)-1; 4-two fluoro-6a; 9; 10,10a-tetrahydrochysene-6H adds Selectfluor

in DMF (4mL) solution of 7H-benzo [c] chromene-8-ketone.This reaction mixture in 50 ℃ of heated overnight, is cooled to room temperature, water is added, to precipitate required product.Product is used water washing through filtering separation, and is dry under vacuum then, obtains colorless solid. ¹H?NMR?CDCl ₃400MHz)δ7.61(d，2H)，7.53(d，2H)，7.19-7.14(m，1H)，6.55-6.49(m，1H)，5.20(d，1H)，4.74(dd， ²J _H-F＝46.7?Hz， ³J _H-F＝11.8?Hz，1H)4.66(d，1H)，3.18(t，1H)，2.9(m，1H)，2.53(m，1H)，2.41(m，1H)，2.18(m，1H)；LCMS(MH ⁺)431。

Use similar method, the compound of preparation embodiment 40B:

¹H?NMR?CDCl ₃400?MHz)δ：7.84(s，4H)，7.22-7.16(m，1H)，6.56-6.50(dt1H)，4.75(dd， ²J _H-F＝45.7?Hz， ³J _H-F＝10.8?Hz，1H)，4.67?(d，1H)，3.23(t，1H)，2.88(dt，1H)，2.60-2.53(m，1H)，2.45(tt，1H)，2.18(td，1H)。

Embodiment 41A and 41B:

According to being used to prepare the scheme that embodiment 18 describes, the compound among preparation embodiment 41A and the 41B (table 16).

Table 16

Embodiment 42A, 42B and 42C:

According to the method for embodiment 20, the compound of preparation embodiment 42A, 42B and 42C.

Table 17

Embodiment 43A, 43B, 43C and 43D:

Embodiment 43A and 43B

In 0 ℃, to anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-6H, (100mg 0.24mmol) adds MeMgBr (500 μ L, 1M is in THF) to 7H-benzo [c] chromene-8-ketone in the solution.Stop body lotion, with the reaction mixture stirred overnight.Reaction mixture dilutes with ETHYLE ACETATE, handles with 1N HCl, then uses NH ₄Cl (sat.aq.) handles.With 2 parts of other ethyl acetate extraction aqueous fluid.Merge the exsiccant organism, through MgSO ₄Dry and concentrated.Product through the silica gel column chromatography purifying with separate, with the mixture wash-out of methylene chloride.

Table 18

Use and embodiment 43A and the similar method of 43B the compound of preparation embodiment 43C and 43D (table 19).

Table 19

Embodiment 44

10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-chromene be [3,4-c] pyridin-3-yl amine also

In 0.09g (0.22mmol) amine and the stirred solution of 0.035g (0.5mmol) Sodium Nitrite in 3mL water and 5mL THF, slowly add 0.024g (0.4mmol) acetate.This mixture was stirred under room temperature 3 hours.With the quencher of 15mL saturated sodium bicarbonate, with the dichloromethane extraction of two parts of each 40mL.The extract that concentrate to merge makes residue be dissolved in 5mL THF and is cooled to 0 ℃.In this solution, be added in 0.6mL (0.6mmol) lithium aluminium hydride among the THF.This mixture is stirred 1 hour also with the quencher of 15mL water under room temperature.With the dichloromethane extraction of two parts of each 40 mL, concentrate the organic extraction that merges, obtain the 0.089g title compound.

Table 20

Embodiment 45 and 46

Use the method for describing among the embodiment 20, as starting raw material, prepare the compound in the table 21 with hydrazine embodiment 44.

Table 21

Embodiment 47:

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-TMS-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-alcohol

In the THF solution of 0.06g (0.145mmol) ketone and 1mL (0.5mmol) trimethylsilyl trifluoroacetamide base silane, add 0.005g (cat.) CsF.This mixture is stirred 2h under room temperature, with 3mL 3N HCl quencher.With this mixture stirred overnight, dilute with the 40mL methylene dichloride then.Use the 20mL brine wash.The 20mL dichloromethane extraction is used in the waterbearing stratum.Concentrate the organic extraction that merges, obtain crude product, make it be dissolved in 5mL methyl alcohol.With the unreacted ketone of 0.01g (0.25mmol) sodium borohydride reduction.Concentrated reaction mixture, residue is used in 40% eluent ethyl acetate in the hexane through preparation type TLC purifying, obtains title compound, the embodiment 47 in the table 22.

Table 22

Embodiment 48:

10a-(4-chloro-benzenesulfonyl)-1,4,8-three fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene

In 0 ℃, in the 5mL toluene solution of the pure and mild 0.06g of 0.054g (0.13mmol) (0.4mmol) DBU, be added in 0.06g (0.2mmol) the perfluoro butane sulfonic acid fluoride in the 1mL toluene.In 0-5 ℃ this mixture is stirred 1 dilution and places refrigerator (4 ℃) to spend the night.Concentrate, residue is used in 20% eluent ethyl acetate in the hexane through preparation type TLC purifying, obtains the 0.036g product.

Table 23

Embodiment 49:

The alternative compound method of the product of embodiment 17

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone

With the vinyl sulphone product of the step 3 of 10.8g (31.5mmol) embodiment 17 and the mixture of 24g (165mmol) 3-trimethylsiloxy-1,3-butadiene in the 100mL phenylfluoroform in ST in 150 ℃ of heating 15 hours.Concentrate, make residue be dissolved in 50mLTHF.In this solution, add 3mL 1N HCl, this mixture was stirred under room temperature 30 minutes.With the dilution of 300mL methylene dichloride, with 50mL brine wash and concentrated.Residue is recrystallization from ETHYLE ACETATE, obtains 6.8g ketone.The chromatography mother liquor obtains other 3.4g ketone.

Embodiment 50

2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-oxo-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-yl]-ethanamide

In-78 ℃, in the stirred solution of 40mL THF, add 10mL (10mmol) LiHMDS to 3.0g (7.27mmol) ketone.After 45 minutes, add 1.83g (11mmol) iodo acetonitrile.In-78 ℃ this mixture was stirred 2 hours, then with being warmed to room temperature in 5 hours.With the quencher of 15mL water, with this mixture stirred overnight.With the dilution of 100mL water,, obtain title compound (table 24) through filtering the collecting precipitation thing.

Table 24

Embodiment 51

3-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-hydroxyl-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-yl]-propionitrile

Step 1

In the suspension-s of 0.41g (1mmol) ketone in 15mL t-BuOH, add 0.08g (1.5mmol) vinyl cyanide and 0.03g (0.265mmol) potassium tert.-butoxide.This mixture was stirred under room temperature 4 days, add other 0.03g potassium tert.-butoxide and 5mL THF.Stirred 2 hours, with the quencher of 30mL salt solution, with the dichloromethane extraction of three parts of each 40mL.Concentrate, obtain crude product.It can directly be used for next step.

Step 2

Make the product of step 1 be dissolved in 4mL THF.Make it and be cooled to-78 ℃, be added in 3mL (3mmol) L-Selectride among the THF.After 2 hours, with the quencher of 15mLog salt solution, with the dichloromethane extraction of three parts of each 40mL.Concentrate the extract that merges, residue is used in the 15%-50% eluent ethyl acetate in the hexane through chromatography purification, obtains title compound (embodiment 51 of table 25).

The similar approach of describing in use and the step 2, the compound of preparation embodiment 52 and 53 (tables 25).

Table 25

Embodiment 54 and 55:

The method that use is described embodiment 18, the compound of preparation embodiment 54 and 55 (tables 26).

Table 26

Embodiment 56:

4-(1,4-two fluoro-8-oxos-6,6a, 7,8,9,10-six hydrogen-benzo [c] chromene-10a-alkylsulfonyl)-cyanobenzene

In ST, with 1.5g (3.63mmol) chloro ketone, 0.19g (0.2mmol) Pd ₂(dba) ₃, 0.23g (0.4mmol) dppf, 0.3g (2.5mmol) zinc cyanide and the mixture of 0.065g (1mmol) zinc powder in 18mL DMA heated 1 hour in 150 ℃ of microwave ovens (Biotage).With the dilution of 100mL water, with three parts of 80mL ethyl acetate extraction.Concentrate the extract that merges, residue is used in the 10%-40% eluent ethyl acetate in the hexane through chromatography purification, obtains the 0.8g title compound.

Table 27

Embodiment 57:

Use prepares the compound of embodiment 57 (table 28) from the method for embodiment 19.

Table 28

Embodiment 58 and 59:

Use prepares the compound of embodiment 58 and 59 (tables 29) from the method for embodiment 20.

Table 29

Embodiment 60:

1,4-two fluoro-7,7-dimethyl--10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone.

Make 1,4-two fluoro-7-methyl isophthalic acid 0a-(4-trifluoromethyl-benzenesulfonyl)-6a, 9,10,10a-tetrahydrochysene-6H, (48mg 0.104mmol) is dissolved in THF (2mL) to 7H-benzo [c] chromene-8-ketone.This solution is cooled off in dry ice/acetone batch, add THF (0.16mL) solution of 1.0ML-Selectride then.Along with the intensification of cryostat, make sluggish warm.After 2 hours, acetone is joined in the reactant.Remove cryostat, add 10%NH then ₄The OH aqueous solution.Stir after 1 hour, (3x) extracts this mixture with methylene dichloride.The organic layer that merges is through Na ₂SO ₄Dry, filtration and concentrated.The thick residue that obtains with ethyl acetate/hexane (0/100-40/60 was through 20 minutes) wash-out, obtains embodiment 60 (32mg, 66%) through the silica gel column chromatography purifying.

Embodiment 60: ¹H NMR (CDCl ₃, 400 MHz) δ 7.86 (d, 2H), 7.78 (d, 2H), 7.10-7.04 (m, 1H), 6.47-6.41 (m; 1H), 5.18 (dd, 1H), 4.51 (d, 1H), 3.75 (brs, 1H), 2.78 (brd; 1H), 2.54 (dddd, 1H), 2.26 (brd, 1H), 1.79 (dq, 1H); 1.63-1.58 (m, 1H), 1.32 (brt, 1H), 1.18 (d, 3H). LCMS: (M+1)=463.3, RT=4.46 minute.

Embodiment 61:

2-[1,4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl]-ethylamine

Step 1

[1,4-fluoro-10a-(4-trifluoromethyl--benzenesulfonyl)-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-subunit]-acetonitrile.

In 0 ℃ the mixture of 60%NaH oil suspension (60mg) in THF (11mL), add cyano methyl phosphonic acids diethyl ester (0.235mL).In 0 ℃ stir 10 minutes after, with 1,4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 9,10,10a-tetrahydrochysene-6H, (0.50g 1.12mmol) joins in the clarification and colourless solution that obtains 7H-benzo [c] chromene-8-ketone.After 1 hour, with saturated NH ₄The Cl aqueous solution joins in the reaction soln.Use ETHYLE ACETATE (3x) to extract this mixture then.The organic layer that merges is through Na ₂SO ₄Dry, filtration and concentrated.The rough residue (0.574g) that obtains need not be further purified and use.

Step 2

[1,4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl]-acetonitrile

To-78 ℃ bullions [1; 4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 9,10; 10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-subunit]-add THF (1.8mL) solution of 1.0ML-Selectride in THF (22mL) solution of acetonitrile (0.574g).Along with the intensification of cryostat, make sluggish warm.1.5 after hour, with salt solution (1.8mL), the 1M NaOH aqueous solution (1.8 mL) and 30%H ₂O ₂The aqueous solution (0.75mL) successively joins in the reactant.After stirring other 0.5 hour, add 25%Na ₂SO ₃(5mL) aqueous solution.(3x) extracts this mixture with ETHYLE ACETATE.The organic layer that merges is through Na ₂SO ₄Dry, filter and be absorbed in the silica gel (5g).The thick material of this absorption with ethyl acetate/hexane (0/100-50/50 was through 25 minutes) wash-out, obtains embodiment 61A (0.330g, 62% liang of step) through the silica gel column chromatography purifying.

Embodiment 61A: ¹H NMR (CDCl ₃, 400MHz) δ 7.79 (brs, 4H), 7.13-7.08 (m, 1H), 6.45-6.39 (m, 1H); 5.26 (dd, 1H), 4.14 (d, 1H), 2.81 (ddd, 1H), 2.58 (d; 2H), 2.40 (ddd, 1H), 2.24 (m, 1H), 2.12 (dddd; 1H), 1.82-1.73 (m, 3H), 1.42 (dddd, 1H) .LCMS: (M+1)=472.3, RT=4.53 minute.

Step 3

[1,4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl]-acetonitrile (embodiment 61.1) under room temperature is (23mg) at 7M NH ₃MeOH (1mL) in mixture in add Raney nickel 2800.Use H then ₂Capsule is full of reaction vessel.After stirred overnight under the room temperature, reaction mixture is used MeOH/CH ₂Cl ₂(1:1) dilution is filtered through Celite.Concentrated filtrate.The thick material that obtains is used MeOH/NH through the silica gel column chromatography purifying ₄OH/CH ₂Cl ₂(0/0/100-10/1/89 was through 15 minutes) wash-out then through reversed-phase HPLC, uses the CH that contains 0.1% formic acid ₃CN/H ₂O (5/95-95/5 was through 10 minutes) obtains formate embodiment 61 (13.6mg).

Embodiment 61: ¹H NMR (CDCl ₃, 400MHz) δ 7.98 (brs, 2H), 7.77 (brs, 4H), 7.10-7.04 (m, 1H), 6.40-6.34 (m; 1H), 5.13 (d, 1H), 4.07 (d, 1H), 3.25-2.95 (m, 4H), 2.82 (brd; 1H), 2.30 (brd, 1H), 2.19 (brt, 1H), 1.93 (brs, 2H), 1.76 (brs; 1H), 1.70-1.61 (m, 2H), 1.51 (brd, 1H), 1.25 (brt, 1H) .LCMS: (M+1)=476.3, RT=3.12 minute.

Embodiment 62 and 63:

According to the method that is similar to embodiment 20, the compound in the preparation table 30.

Table 30

Embodiment 64:

According to the method for describing in the step 1 that is similar to embodiment 61 and 2, the compound among preparation embodiment 64A and the 64B (table 31).

Table 31

Embodiment 65-108

According to the method for embodiment 23, the compound of preparation table 32.

Table 32

Embodiment 109-116:

Use the method for describing in embodiment 21 steps 1, the compound of preparation table 33.

Table 33

Embodiment 117 and 118:

Use the method for describing among the embodiment 20, the compound in the preparation table 34.

Table 34

Embodiment 119:

(4aS)-and 10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,4a, 10b-tetrahydrochysene-2H-[1] chromene is [3,4-b] pyridines-3 (4H)-ketone (racemic) also

Make 4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10, (96.8mg 0.242mmol) is dissolved in 2.35ml water, 11.5mg acetonitrile and the 11.5ml ETHYLE ACETATE 10a-six hydrogen-1H-9-oxa--1-azepine-Fei.Add respectively then sodium periodate (399mg, 1.86mmol) and ruthenium dioxide (20.5mg, 0.154mmol) and stirred overnight.With 50ml water quencher reaction, wash with 75ml ETHYLE ACETATE.Organic layer is handled and was placed 2.5 hours with the 50ml Virahol.Through this solution of diatomite filtration, use brine wash, through dried over sodium sulfate.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 50/50-100/0 60 minutes).Must measure: 30.0mg, 30%. ¹H?NMR(CDCl ₃?400MHz)δ7.65(d，J＝8.8Hz，2H)，7.52(d，J＝8.1Hz，2H)，7.10(td，J＝9.5，5.1Hz，1H)，7.01(bs，1H)，6.50-6.41(m，1H)，5.10(d，J＝12.4Hz，1H)，4.50(s，1H)，4.32(d，J＝12.4Hz，1H)，2.80-2.70(m，1H)，2.60-2.41(m，1H)，2.06-1.93(m，1H)，1.68(bs，1H)。

Through with the similar approach of embodiment 119, the compound in the preparation table 35.

Table 35

Embodiment 122:

Trans-9-chloro-10b-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,3,4,4a, 5,10b-six hydrogen-2H-[1] chromene is [3,4-b] pyridines (racemic) also

6-chloro-4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei

Make 4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10, (1.0190g 2.5475mmol) is dissolved in 75ml methylene dichloride and be cooled to 0 ℃ to 10a-six hydrogen-1H-9-oxa--1-azepine-Fei, adds triethylamine (1.1mL) then.Stirred this solution 10 minutes in 0 ℃, slowly add then II and in 0 ℃ with this solution stirring 3 hours, make reactant be warmed to room temperature then and stirred 1 hour.React with the quencher of 50ml frozen water.Organic layer is with 50ml1N HCl solution washing, through dried over sodium sulfate.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-50/50 45 minutes).Must measure: 124.0mg, 11%. ¹H?NMR(CDCl ₃400MHz)δ7.57(d，J＝8.8Hz，2H)，7.52(d，J＝8.8Hz，2H)，7.23(dd，J＝9.5，6.6Hz，1H)，5.19(dd，J＝8.8，6.6Hz，1H)，4.32(d，J＝11.7Hz，1H)，3.69(s，1H)，2.99(d，J＝13.1Hz，1H)，2.74(td，J＝13.1，2.9Hz，1H)，2.64(d，J＝13.1Hz，1H)，2.20-2.11(m，1H)，1.62(d，J＝13.1Hz，2H)，1.19-1.06(m，1H)。

Table 36

Embodiment 123:

Step 1: { 2-[4a-(4-chloro-benzenesulfonyl)-5,8-=two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-2-oxo-ethyl }-carboxylamine tert-butyl ester

Make the BOC-glycocoll be dissolved in 150ml DMF.Add the 0.5ml Diisopropylamine, then add HATU (2.54g, 6.68mmol).This solution was stirred under room temperature 25 minutes, add 4a-(4-chloro-benzenesulfonyl)-5 then, 8-two fluoro-2,3,4,4a, 10, (541mg is 1.35mmol) and with the reactant stirred overnight for 10a-six hydrogen-1H-9-oxa--1-azepine-Fei.The quencher of reaction water is with the 1:1 mixed solution washing of ETHYLE ACETATE and hexane solution.Organic layer is through dried over sodium sulfate and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (0/100-25/75 was through 35 minutes).Must measure: 594.6mg, 79%. ¹H?NMR(CDCl ₃400MHz)δ7.57(d，J＝8.8Hz，2H)，7.41(d，J＝8.8Hz，2H)，7.03(td，J＝8.8，4.4Hz，1H)，6.57-6.49(m，1H)，5.60-5.55(m，1H)，5.35(bs，1H)，4.49(dd，J＝11.7，3.7Hz，1H)，4.18(dd，J＝11.7，5.9Hz，1H)，4.00(s，1H)，3.90(d，J＝5.1Hz，1H)，3.54(bs，1H)，2.95-2.80(m，1H)，2.65-2.56(m，1H)，2.52-2.41(m，1H)，2.13-1.98(m，1H)，1.51-1.40(m，1H)，1.40(s，9H)。

Step 2: 2-amino-1-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-ethyl ketone

(2mL 27.0mmol) is dissolved in the 16ml methylene dichloride to make trifluoroacetic acid.This solution is joined { 2-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-2-oxo-ethyl }-carboxylamine tert-butyl ester (260mg, 0.467mmol) in.With this solution stirred overnight under room temperature.Through reacting with saturated sodium carbonate solution washing quencher.Organic layer is through dried over sodium sulfate and concentrated.Obtain: 20.0mg, 9%. ¹H?NMR(CDCl ₃400MHz)δ7.62(d，J＝8.1Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.06(td，J＝8.8，4.4Hz，1H)，6.61-6.52(m，1H)，5.41(bs，1H)，4.52(dd，J＝11.0，3.7Hz，1H)，4.21(dd，J＝11.7，5.1Hz，1H)，3.53(bs，2H)，2.86(bs，1H)，2.70-2.61(m，1H)，2.55-2.45(m，1H)，2.15-2.03(m，1H)，1.75-1.44(m，4H)。

Step 3: N-{2-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa-1-azepine-Fei-1-yl]-2-oxygen gets ethyl }-C, C, C-three fluoro-Toluidrins

Make 2-amino-1-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4; 4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-ethyl ketone (40.0mg; 0.0875mmol) be dissolved in the 1ml methylene dichloride, add respectively triethylamine (1ml) and three fluorosulfonic anhydride (343mg, 1.54mmol).With this solution stirred overnight under room temperature.Add 50ml 1N HCl, use the 50ml washed with dichloromethane then.The waterbearing stratum is with other 50ml washed with dichloromethane.The organism that merges is through dried over sodium sulfate and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (0/100-100/0 was through 35 minutes).Must measure: 35.2mg, 68%. ¹H?NMR(CDCl ₃400MHz)δ7.60(d，J＝8.1Hz，2H)，7.47-7.41(m，1H)，7.07(td，J＝9.50，4.4Hz，1H)，6.62-6.53(m，2H)，5.40(bs，1H)，4.52(dd，J＝11.7，3.7Hz，1H)，4.26-4.12(m，2H)，3.44(bs，1H)，2.95(bs，1H)，2.71-2.59(m，1H)，2.61-2.50(m，1H)，2.20-2.06(m，1H)，1.70(bs，2H)，1.61-1.49(m，1H)。

According to the similar approach of the method for embodiment 123, the compound in the preparation table 37.

Table 37

Embodiment 133:

Step 1: 3-{ (3-benzyloxy-propyl group)-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-amino }-third-1-alcohol

(7.8475g 34.27mmol) is dissolved in 50ml THF, and (2.56g 34.13mmol), stirred this reactant 3 days under room temperature to add the 3-aminopropanol then to make benzyl 3-bromo propyl ether.With 100ml unsaturated carbonate potassium solution quencher reaction, with this solution of ETHYLE ACETATE washing.Organic layer is with unsaturated carbonate potassium solution (2x100mL) washing, then through dried over sodium sulfate and concentrated.This amine aqueous solution need not any being further purified and using.(3.91g 17.5mmol) is dissolved in 100ml THF to make this amine aqueous solution.Add 4-(4-chloro-benzenesulfonyl)-5, and 8-two fluoro-2H-chromenes (2.0486g, 5.97mmol), with this reactant stirred overnight under room temperature.Add triethylamine (3ml), this reactant is stirred 2h. under room temperature, (2.85g 12.8mmol), with this reactant stirred overnight under room temperature, is warmed to then and refluxes and stirred overnight to add other amine aqueous solution then.Reaction water quencher (100ml) and wash with ETHYLE ACETATE (100ml).Organic layer is through dried over sodium sulfate and concentrated.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-100/0 45 minutes).Must measure: 570mg, 17%. ¹H?NMR(CDCl ₃400MHz)δ7.64-7.59(m，2H)，7.45-7.40(m，2H)，7.36-7.25(m，5H)，7.00(td，J＝9.5，5.1Hz，1H)，6.42(td，J＝8.8，3.7Hz，1H)，4.74(dd，J＝12.4，5.1Hz，1H)，4.65(s，1H)，4.42(s，2H)，4.32-4.26(m，1H)，4.06-4.01(m，1H)，3.59(t，J＝5.4Hz，2H)，3.41(t，J＝5.9Hz，2H)，2.87(bs，1H)，2.71-2.53(m，3H)，2.50-2.42(m，1H)，1.74-1.62(m，3H)，1.60-1.50(m，1H)。

Step 2: 1-(3-benzyloxy-propyl group)-4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei

Make 3-{ (3-benzyloxy-propyl group)-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-amino }-third-1-alcohol (570mg 1.01mmol) is dissolved in 50ml DCM, add respectively methylsulfonyl chloride (439 μ L, 5.68mmol) and triethylamine (2ml).This reactant was stirred under room temperature 1 hour.Wash with 50ml water quencher reaction and with 50ml DCM.Organic layer is through dried over sodium sulfate and concentrated.Methanesulfonic 3-{ (3-benzyloxy-propyl group)-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-amino }-propyl diester need not be further purified and use.

Make methanesulfonic 3-{ (3-benzyloxy-propyl group)-[4-(4-chloro-benzenesulfonyl)-5; 8-two fluoro-chroman-3-yl]-amino }-propyl diester is dissolved in 60mL THF; (1M solution is in the trimethyl carbinol to add potassium tert.-butoxide then; 3.27ml, 3.27mmol), this reactant was stirred under room temperature 1 hour.With 100ml salt solution and 100ml ETHYLE ACETATE quencher reaction.Separate each layer and organic layer through dried over sodium sulfate, concentrate then.Product is through column chromatography purification, with the EtOAc/ hexane as elutriant (from the gradient of 0/100-100/0 35 minutes).Must measure: 438.8mg, 80. ¹H?NMR(CDCl ₃400MHz)b7.61(d，J＝8.1Hz，2H)，7.48(d，J＝8.8Hz，2H)，7.37-7.24(m，5H)，7.04(td，9.5，5.1Hz，1H)，6.43-6.36(m，1H)，5.14(d，J＝12.4Hz，1H)，4.72(d，J＝13.9Hz，1H)，4.47(dd，J＝28.5，11.7Hz，2H)，3.42(t，J＝6.2Hz，2H)，3.29(s，1H)，2.90-2.82(m，2H)，2.82-2.75(m，1H)，2.57(d，12.4Hz，1H)，2.45(td，J＝11.7，2.2Hz，1H)，2.03-1.93(m，1H)，1.83-1.64(m，2H)，1.63-1.59(m，1H)，1.36-1.23(m，1H)。

Step 3: 3-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-third-1-alcohol

Make 1-(3-benzyloxy-propyl group)-4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10, (399.1mg 0.728mmo1) is dissolved in 20ml ETHYLE ACETATE to 10a-six hydrogen-1H-9-oxa--1-azepine-Fei.(20% is stated from the carbon, 105mg) also uses the hydrogen purge and wash system to add palladium hydroxide.This reactant was stirred under room temperature 1.5 hours.Add and more be stated from the palladium hydroxide (203mg) on the carbon.This reactant was stirred under room temperature 3.5 hours.Add palladium hydroxide (307mg) again and stirred 1 hour.Through zeyssatite cake filtering reaction thing and concentrated.Product is through column chromatography purification, with hexane/EtOAc as elutriant (from the gradient of 100/0-50/50 35 minutes, then to 0/100), obtain three kinds of products like this: required product and two kinds of dechlorinationizations (dechloronation) product.

3-[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl]-third-1-alcohol: must measure: 14.8mg, 4.4%. ¹H?NMR(CDC1 ₃400MHz)δ7.62(d，J＝8.1Hz，2H)，7.50(d，J＝8.1Hz，2H)，7.06(td，9.5，4.4Hz，1H)，6.46-6.38(m，1H)，5.21(d，J＝13.2Hz，1H)，4.81(d，J＝13.2Hz，1H)，3.68-3.55(m，2H)，3.22(s，1H)，3.20-3.11(m，1H)，3.05(d，J＝11.0Hz，1H)，2.70(s，1H)，2.61-2.53(m，2H)，2.25(td，J＝11.7，2.9Hz，1H)，2.02(tt，J＝13.2，3.2Hz，1H)，1.85-1.74(m，1H)，1.69-1.56(m，2H)，?1.35-1.22(m，1H)。

4a-benzenesulfonyl-1-(3-benzyloxy-propyl group)-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-1H-9-oxa--1-azepine-Fei: must measure: 7.1mg, 1.9%. ¹H?NMR(CDCl ₃400MHz)δ7.68(t，J＝8.4Hz，3H)，7.69(t，J＝7.7Hz，2H)，7.37-7.25(m，5H)，7.02(td，J＝9.5，5.1Hz，1H)，6.42-6.34(m，1H)，5.19(d，J＝13.2Hz，1H)，4.72(d，J＝13.2Hz，1H)，4.47(dd，J＝28.6，11.7Hz，2H)，3.42(t，J＝6.2Hz，2H)，3.27(s，1H)，2.90-2.83(m，2H)，2.78(d，J＝5.9Hz，1H)，2.62(d，J＝5.9Hz，1H)，2.45(td，J＝11.7，2.2Hz，1H)，1.99(tt，J＝13.1，2.9Hz，1H)，1.82-1.64(m，2H)，1.62-1.56(m，1H)，1.36-1.23(m，1H)。

3-(4a-benzenesulfonyl-5,8-two fluoro-2,3,4,4a, 10,10a-six hydrogen-9-oxa--1-azepine-Fei-1-yl)-third-1-alcohol: must measure: 17.9mg, 1.9%. ¹HNMR(CDCl ₃400MHz)δ7.68(t，J＝8.8Hz，3H)，7.51(t，J＝7.7Hz，2H)，7.05(td，J＝9.5，5.1Hz，1H)，6.44-6.34(m，1H)，5.24(d，J＝13.2Hz，1H)，4.81(d，J＝13.9Hz，1H)，3.68-3.54(m，2H)，3.22(s，1H)，3.20-3.10(m，1H)，3.04(d，J＝10.9Hz，1H)，2.83(bs，1H)，2.64-2.53(m，2H)，2.25(td，J＝11.7，2.2Hz，1H)，2.02(tt，J＝13.1，3.3Hz，1H)，1.85-1.73(m，1H)，1.67-1.55(m，2H)，1.37-1.22(m，1H)。

Through with the similar method of the method for embodiment 133, the compound of preparation in the table 38.

Table 38

Embodiment 139:

Step 1: [4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4,4a, 9,10,10a-octahydro-Fei-1-yl]-methyl alcohol (+) and (-) enantiomorph

Make [4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3; 4,4a, 9,10; 10a-octahydro-Fei-1-yl]-(1.11g 2.59mmol) is dissolved in isolating Virahol on the OD post, uses hexane/isopropyl alcohol (80/20 ratio) as elutriant for the racemic mixture of methyl alcohol.

[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4,4a, 9,10,10a-octahydro-Fei-1-yl]-methyl alcohol (-): must measure: 470mg, 42%.[α]=-153.4 (c=1.035 is in DCM).Through analyzing 98.3% enantiomer-pure of OJ post.

[4a-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4,4a, 9,10,10a-hydrogen-Fei-1-yl]-methyl alcohol (+): must measure: 450mg, 41%.[α]=+ 158.6 (c=0.955 is in DCM).Through analyzing 97.9% enantiomer-pure of OJ post.

Table 39

Embodiment 140-148:

The similar method of method of use and embodiment 139, the compound in the preparation table 40.

Table 40

Embodiment 149:

4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-thiochromans

Step 1:

To 2,3,6-trifluro benzaldehyde (10g; 60.6mmol) add 1-triphenyl-Ya phosphoranyl (phosphoranylidene)-2-acetone (24.3g in the stirred solution in toluene (100mL); 72.7mmol, 1.2equiv.), this reaction mixture was stirred 3 hours in 50 ℃.The water quencher, (3x100mL) extracted with EtOAc in the waterbearing stratum, and the organic layer of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane: 10%, then 20%), obtain Wittig reaction product (11.47g, 85% yield). ¹H-NMR(CDCl ₃400MHz)δ：7.74(d，J＝16.84Hz，1H)，7.22-7.06(m，1H)，6.82-6.67(m，1H)，6.77(d，J＝16.84Hz，1H)，3.83(s，3H)。

Step 2:

To the alpha, beta-unsaturated ketone that derives from step 1 in THF (20mL) (1.948g, add in 9.01mmol) 4-chlorinated benzene thiophenol (1.303g, 9.01mmol, 1.0equiv.) and K ₂CO ₃(0.88equiv.), with this reaction mixture stirred overnight under room temperature, starting raw material is completely consumed not for 1.1g, 7.96mmol.Then add excessive 4-chlorothio-phenol (0.65g, 0.5equiv.) and K ₂CO ₃(0.6g 0.5equiv.), stirs reaction mixture 1 hour in 40 ℃ then. and make it be cooled to room temperature, with EtOAc (200mL) dilution, water, 1N NaOH and salt solution wash in proper order, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant .EtOAc/ hexane: 5%-50%), concentrate the product that contains certain thiophenol. ¹H-NMR(CDCl ₃400MHz)δ：7.31(d，J＝8.4Hz，2H)，7.26-7.20(2H)，7.03-6.98(m，1H)，6.75-6.73(m，1H)，4.95(t，J＝8.05Hz，1H)，3.65(s，3H)，3.13(d，J＝8.05Hz，2H)。

In the Michael adduct that derives from said step in DCM (150mL), add m-cpba, it was stirred under room temperature 2 hours, use saturated Na ₂S ₂O ₃Quencher is to reduce excessive m-cpba.Reaction mixture is used 1N NaOH and brine wash then, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=10%-100%), obtain sulfoxide (1.443g, 3.67mmol, 41% liang of step) ¹H-NMR (CDCl ₃400MHz) δ: 7.65 (d, J=7.6Hz, 2H), 7.47 (d, J=8.0Hz, 2H), 7.20-7.10 (m, 1H); 6.90-6.70 (wide s, 1H), 5.16 (t, J=7.4Hz, 1H), 3.66 (s, 3H), 3.52 (dd; J=6.0,17.6Hz, 1H), 3.32 (dd, J=8.8,17.6Hz, 1H).

Step 3:

In 0 ℃, (1.35g is added dropwise at Et in 3.44mmol) to the sulfoxide that derives from step 2 in THF (15mL) ₂(LAH in 2.0equiv.) stirred 1 hour under this temperature O for 1.0M, 6.9mL.Saturated NaHCO is used in reaction ₃Quencher is extracted (3X100mL) with EtOAc, and the organic layer of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Obtain crude reaction mixture (1.289g, quantitative). ¹H-NMR(CDCl ₃400MHz)δ：7.63(d，J＝8.4Hz，2H)，7.44(d，J＝8.4Hz，2H)，7.16-7.10(m，1H)，6.90-6.68(m，1H)，6.92(dd，J＝5.6，9.4Hz，1H)，3.87(m，1H)，3.47(m，1H)，2.70-2.50(m，2H)。

Step 4:

In the presence of molecular sieve, in 0 ℃, (0.849g adds Et respectively in 2.33mmol) to the alcohol that derives from step 3 in DCM (50mL) ₃N (0.65mL, 0.471g, 4.65mmol, 2.0equiv.) and MsCl (3.49mmol 1.5equiv.), stirs them 50 minutes in 0 ℃, uses 1.0mL CH for 0.27mL, 0.399g ₃The OH quencher.Filter through Celite pad, filtrating is used brine wash, through MgSO with DCM (100mL) dilution ₄Drying, filtration and evaporation.Obtain crude reaction mixture (1.215g, quantitative). ¹H-NMR(CDCl ₃400MHz)δ：7.63(d，J＝8.8Hz，2H)，7.46(d，J＝7.2Hz，2H)，7.22-7.15(m，1H)，6.96-6.67(m，1H)，4.81(dd，J＝5.6，9.6Hz，1H)，4.48(m，1H)，4.13(m，1H)，3.14-3.05(m，1H)，2.95(s，3H)，2.84-2.70(m，1H)。

(1.064g, 9.32mmol 4.0equiv.) stirred 30 minutes in 90 ℃ in DMF with the methanesulfonates that derives from preceding step (2.33mmol) and KSAc.Make it be cooled to room temperature,, use water washing with EtOAc (100mL) dilution.Water extracts (3x50mL) with EtOAc, and the organic phase water and the brine wash of merging are through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=5%-50%), obtain thioacetate (0.848g, 2.00mmol, 86% liang of step). ¹H-NMR(CDCl ₃400MHz)δ：7.62(d，J＝8.0Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.21-7.10(m，1H)，6.90-6.70(m，1H)，4.74-4.68(m，1H)，3.04-2.94(m，1H)，2.85-2.50(m，3H)，2.29(s，3H)。

In 0 ℃, at CH ₃Add 1NNaOH (10mL) in the thioacetate (0.542g) among the OH (10mL), make it slowly be warmed to room temperature and stirred overnight.Reaction mixture is with EtOAc (100mL) dilution, with 1N HCl (12 mL) acidifying.Water extracts (3x50mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Rough reaction residue can directly experience the cyclisation of next ring. ¹H-NMR(CDCl ₃400MHz)δ：7.62(d，J＝8.8Hz，2H)，7.45(d，J＝8.8Hz，2H)，7.25-7.10(m，1H)，6.90-6.70(m，1H)，4.85-4.76(m，1H)，2.86-2.64(m，3H)，2.55-2.40(m，1H)。

Step 5:

In the mercaptan that derives from step 4 (0.5g) in THF (30 mL), add NaH (0.2g, excessive), with it in 60 ℃ of stirred overnight.Make reactant be cooled to room temperature, use saturated NH ₄The Cl quencher is extracted with EtOAc.The organic layer that merges is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=2%-50%), obtain 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-thiochromans (0.176g, 0.49 mmol, 38% liang of step). ¹H-NMR(CDCl ₃400?MHz)δ：7.67(d，J＝8.0?Hz，?2H)，7.48(d，J＝7.2Hz，2H)，7.00-6.92(m，1H)，6.60-6.50(m，1H)，4.68(s，1H)，3.87(dt，J＝3.6，13.2Hz，1H)，3.17(d，J＝15.2Hz，1H)，3.04(d，J＝12.4Hz，1H)，2.04(t，J＝12.8Hz，1H)。

Embodiment 150:

4-(4-chloro-benzenesulfonyl)-4-ethyl-5,8-two fluoro-thiochromans

To the 4-in THF (20mL) (4-chloro-benzenesulfonyl)-5,8-two fluoro-thiochromans (0.246g, add respectively in 0.68mmol) K-tOBu (1.0M, 2mL, 3.0equiv.) and EtI (0.318g, 0.16mmol, 3.0equiv.).Stir after 20 minutes, TLC shows the reaction completion.Use saturated NH ₄The Cl quencher, with the EtOAc dilution, water layer extracts (3x20mL) with EtOAc, and the organic layer of merging is with water washing and salt solution, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=2%-50%), obtain ethylization thiochroman (0.143g, 0.37mmol, 54%). ¹H-NMR(CDCl3?400MHz)δ：7.60(d，J＝8.8Hz，2H)，7.46(d，J＝8.8Hz，2H)，7.00-6.95(m，1H)，6.60-6.52(m，1H)，3.93(t，J＝13.2Hz，1H)，2.92(dd，J＝4.2，12.6Hz，1H)，2.82(d，J＝15.2Hz，1H)，2.70-2.48(m，1H)，2.33(dt，J＝4.0，14.4Hz，1H)，1.92-1.80(m，1H)，0.775(t，J＝7.4Hz，3H)。

Embodiment 151:

4-(4-chloro-benzenesulfonyl)-4-ethyl-5,8-two fluoro-thiochroman 1-oxide compounds and 4-(4-chloro-benzenesulfonyl)-4-ethyl-5,8-two fluoro-thiochromans 1,1-dioxide

To the 4-in DCM (20mL) (4-chloro-benzenesulfonyl)-4-ethyl-5,8-two fluoro-thiochromans (0.119g, 0.31mmol) the middle m-cpba (0.137g that adds; 0.61mmol; 2.0equiv.), it was stirred under room temperature 1 hour, TLC shows starting raw material consumption.Use saturated Na _sS ₂O ₃The quencher reaction is with DCM (100mL) dilution, with 1N NaOH (20mL) and brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=25%-75%), obtain sulfone (0.063g, 0.15mmol, 48%) and sulfoxide (0.028g, 0.07mmol, 22%). ¹H-NMR (CDCl3 400MHz) for sulfone δ: 7.65 (d, J=8.8Hz, 2H), 7.53 (d, J=8.8Hz, 2H), 7.36-7.28 (m, 1H); 7.16-7.08 (m, 1H), 4.70 (td, J=2.9,14.3Hz, 1H), 3.40-3.32 (m; 1H), 3.10-3.00 (m, 1H), 2.87 (dt, J=4.1,8.2Hz, 1H); 2.70-2.58 (m, 1H), 1.90-1.76 (m, 1H), 0.83 (t, J=7.2Hz, 3H). ¹H-NMR (CDCl3 400MHz) is for sulfoxide δ: 7.65 (d, J=8.8Hz, 2H), 7.53 (d, J=8.0Hz, 2H), 7.35-7.25 (m; 1H), 7.20-7.10 (m, 1H), 4.05 (td, J=2.8,14.8Hz, 1H); 3.30-3.12 (m, 2H), 2.76-2.64 (m, 1H), 2.53 (d, J=16.4Hz; 1H), 1.89-1.77 (m, 1H), 0.85 (t, J=7.00Hz, 3H).

Embodiment 152:

11b-(4-chloro-benzenesulfonyl)-8,11-two fluoro-1,4,4a, 5,6,11b-six hydrogen-2H-3,7-dioxa-dibenzo [a, c] suberene

Step 1:

In-78 ℃, to the 2-in THF (100mL) (4-chloro-benzenesulfonyl methyl)-1,3,4-three fluoro-benzene (6.51g, be added dropwise in 20.3mmol) n-BuLi (2.0M in pentanem, 12.2mL, 24.4mmol, 1.2equiv.).It was stirred 30 minutes under this temperature, then add α, β-unsaturated methyl ester.This reactant slowly is warmed to ambient temperature overnight.The water quencher is extracted (3x150 mL) with EtOAc, and the organic layer of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.(elutriant: EtOAc/ hexane=5%-75%), obtain Michael adducts (2.637g, 4.78mmol, 24%) is the mixture (29%) of diastereomer and starting raw material to crude reaction mixture through column chromatography purification.(2.637g, 4.78mmol) (1.0M is at Et with LAH for ester that will be in THF ₂Among the O, 9.6mL 2.0equiv.) handles in 0 ℃, stirs 1 hour, uses saturated NaHC0 ₃Quencher.Water extracts (3x100mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture uses column chromatography that (elutriant: EtOAc/ hexane=10%-50%) obtains three different flow points (1.457g, 58%) and all has according to LCMS ([M+H] ⁺=523) correct quality.For first flow point ¹H-NMR (CDCl3 400MHz) δ: 7.81 (d, J=8.8Hz, 2H), 7.53 (d, J=7.6Hz, 2H), 7.01-6.95 (m, 1H), 6.86-6.80 (m; 1H), 4.77 (s, 1H), 4.48 (s, 1H), 4.18-4.04 (m, 1H), 3.96 (t, J=9.6Hz; 1H), 3.67 (dd, J=5.6,10.0Hz, 1H), 3.48 (dd, J=6.8,10.8Hz, 1H); 3.31-3.23 (m, 2H), 0.71 (s, 9H), 0.03 (s, 3H), 0.04 (s, 3H).For second flow point ¹H-NMR (CDCl3 400MHz) δ: 7.59 (dd, J=2.8,8.8Hz, 2H), 7.37 (d, J=8.0Hz, 2H), 7.12-6.98 (m; 1H), 6.90-6.48 (m, 1H), 4.87 (d, J=10.4Hz, 1H), 3.96-3.77 (m, 2H); 3.73 (t, J=10.2Hz, 1H), 3.31 (t, J=11.6Hz, 1H), 3.17-3.02 (m, 1H); 2.60-2.41 (m, 1H), 2.31-2.11 (m, 1H), 0.75 (s, 9H) ,-0.16 (s, 3H) ,-0.32 (s, 3H).For the 3rd flow point ¹H-NMR (CDCl3 400MHz) δ: 7.75-7.45 (m, 2H), 7.44-7.29 (m, 2H), 7.11-6.98 (m, 1H), 6.92-6.52 (m, 1H); 5.09 (t, J=8.2Hz, 1H), 4.28 (dt, J=3.6,10.8 Hz, 1H), 3.92-3.80 (m; 1H), and 3.72-3.48 (m, 2H), 3.19-3.06 (wide s, 1H), 1.60-1.48 (m, 2H), 0.90 (s; 9H), 0.13 (d, J=5.2Hz, 3H), 0.10 (d, J=3.2Hz, 3H).

Step 2:

All three flow points that derive from step 1 in THF are handled with NaH, with this reaction mixture in 60 ℃ of stirred overnight.Use saturated NH ₄The Cl quencher is extracted with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.(elutriant: the EtOAc/ hexane=5%-50%), all three reactions provide the cyclisation product of identical ring to crude reaction mixture through column chromatography purification. ¹H-NMR (CDCl3 400MHz) δ: 7.54 (d, J=8.8Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 7.06-7.00 (m, 1H); 6.60-6.54 (m, 1H), 4.93 (d, J=4.4Hz, 1H), 4.41-4.34 (m, 1H), 3.93-3.87 (m; 1H), 3.70-3.58 (m, 2H), 3.03 (wide s, 1H), 2.58-2.44 (m, 1H); 1.88-1.76 (m, 1H), 0.83 (s, 9H), 0.01 (s, 3H) ,-0.03 (s, 3H).

Step 3:

In 0 ℃, (0.552g, (1.0M is in THF, and 1.6mL 1.5equiv.), stirs it 1 hour under this temperature, uses saturated NH slowly to add TBAF in 1.10mmol) to the two ring products that derive from step 2 in THF (30mL) ₄The Cl quencher.Water extracts (3x50mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=5%-100%), obtain alcohol (0.394g, 1.01mmol, 92%). ¹H-NMR (CDCl3 400MHz) δ: 7.54 (d, J=8.8Hz, 2H), 7.39 (d, J=8.8Hz, 2H), 7.05 (dt, J=5.2,9.0Hz, 1H); 6.59 (dt, J=3.6,8.8Hz, 1H), 4.89 (d, J=4.4Hz, 1H), 4.40-4.30 (m, 1H); 3.95-3.85 (m, 1H), 3.75 (dd, J=6.2,10.6Hz, 1H), 3.66 (dd, J=7.6,9.2Hz; 1H), 3.09 (wide s, 1H), 2.48-2.36 (m, 1H), 2.00-1.86 (wide s, 1H ,-OH), and 1.86-1.74 (m, 1H).

Step 4:

To the alcohol (0.469g that derives from step 3 in THF (20mL); 1.20mmol) (0.096g 2.0equiv.), stirred it 30 minutes middle adding NaH under room temperature; Then add benzyl 2-bromoethyl ether (0.401g; 0.30mL, 1.5equiv.), with this reaction mixture stirred overnight under refluxing.Make it be cooled to room temperature, use saturated NH ₄The Cl quencher is extracted with EtOAc.The organic phase that merges is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=10%-75%), obtain alkylate (0.459g, 0.88mmol, 73% yield). ¹H-NMR(CDCl3?400MHz)δ：7.53(d，J＝8.0Hz，2H)，7.35(d，J＝8.8Hz，2H)，7.33-7.20(m，5H)，7.02(dt，J＝5.2，8.8Hz，1H)，6.55(dt，J＝4.0，8.8Hz，1H)，4.88(d，J＝4.4Hz，1H)，4.50(s，2H)，4.40-4.30(m，1H)，3.91-3.80(m，1H)，3.62-3.44(m，6H)，3.23-3.12(m，1H)，2.65-2.50(m，1H)，1.88-1.74(m，1H)。

Step 5:

According to the method for describing among the embodiment 16, the product of step 4 is converted into title compound. ¹H-NMR (CDCl3 400MHz) δ: 7.50 (d, J=8.0Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.10 (dt, J=4.4; 8.8Hz, 1H), 6.54 (ddd, J=4.4,9.2,13.2Hz, 1H), 4.50-4.33 (wide s; 1H), and 4.28-4.11 (wide s, 1H), 4.10-3.97 (m, 2H), 3.77 (dd, J=7.2; 12.0Hz, 1H), and 3.56-3.39 (wide s, 1H), 3.06-2.98 (m, 1H), 2.80-2.60 (wide s; 1H), and 2.57-2.35 (m, 2H), 2.14-2.00 (m, 1H). LCMS (M+1, RT)=415.2,4.24 minutes

Embodiment 153

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-7-hydroxymethyl-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-alcohol

Step 1:

In 0 ℃, in 30 minutes, (3.93g, 98.3mmol 1.06Equiv.) are added dropwise to methyl acetoacetate in the suspension-s in THF (100mL), and it was stirred under this temperature other 30 minutes to NaH through syringe pump.Make reaction mixture be cooled to-25 ℃ then, with 15 minutes, (2.0M was in pentane to be added dropwise to 51mL n-BuLi through tap funnel; 102mmol, 1.1Equiv.), after the adding; It was stirred under this temperature other 30 minutes, then slowly add BOMCl (14.2mL, 15.98g; 102.0mmol, 1.1Equiv.).In-25 ℃ of stirrings 1 hour, with the ice-cooled 1N HCl quencher reaction of 100mL.With 100mL EtOAc dilution, water extracts (3x100mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.(elutriant: EtOAc/ hexane=10%-40%) obtains pure products (9.14g, 38.7mmol, 41%) to crude reaction mixture through column chromatography purification. ¹H-NMR(CDCl3400MHz)δ：7.40-7.20(m，5H)，4.51(s，2H)，3.75(t，J＝6.0Hz，2H)，3.72(s，3H)，3.51(s，2H)，2.83(t，J＝6.0Hz，2H)。

Step 2:

In 0 ℃, to the beta-keto methyl ester in THF (100mL) (3.825g, 16.2mmol, 1.05Equiv.) the middle NaH (0.648g that adds; 16.2mmol, 1.05Equiv.), it was stirred 30 minutes under this temperature; Then add vinyl sulphone (5.285g, 15.4mmol, 1.0Equiv.).When starting raw material consumes, use saturated NH ₄The Cl quencher, water extracts (3x150mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture obtains Michael adducts (7.21g, 12.4mmol, 80%) through column chromatography purification, is diastereomer (ratio: 1/1). ¹H-NMR(CDCl3?400MHz)δ：7.85(d，J＝8.0Hz，2H)，7.80(d，J＝9.2Hz，2H)，7.56(d，J＝8.8Hz，2H)，7.49(d，J＝9.2Hz，2H)，7.38-7.22(m，8H)，7.18(d，J＝6.8Hz，2H)，7.12-6.97(m，2H)，6.55(dt，J＝3.66，8.78Hz，1H)，6.48(dt，J＝3.66，8.78Hz，1H)，4.91(d，J＝12.4Hz，1H)，4.81(d，J＝12.8Hz，1H)，4.51-4.28(m，7H)，4.25(d，J＝12.4Hz，1H)，3.74-3.65(m，5H)，3.61-3.53(m，5H)，3.53-3.47(m，4H)，2.89-2.75(m，2H)，2.72-2.55(m，2H)。

Step 3:

In 0 ℃, (1.0equiv.) (2.92g, 73.2mmol 4.0equiv.), stir them 2 hours under this temperature middle adding LAH, with 1N HCl (50mL) quencher for 10.59g, 18.3mmol to the Michael adducts in THF (200mL).Extract with EtOAc (3x100mL) and DCM (3x100mL), the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=30%-50%), obtain glycol (9.42g, 17.0mmol, 93%).To this glycol in acetone (200mL) (9.42g, add respectively in 17.1mmol) p-TsOH (0.324g, 1.7mmol, 10%cat.) with 2,2-dimethoxy-propane (1.774g, 2.1mL, 170mmol, 10equiv.), with its stirred overnight under room temperature.Reaction is used saturated NaHCO with EtOAc (500mL) dilution ₃Washing is extracted (2x100mL) with EtOAc.The organic phase that merges is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=10%-25%), obtain two flow points (5.66g, 9.54 mmol, 56% liang of step).

Step 4:

Through the standard closed-loop policy of embodiment 16, handle two flow points that derive from step 3.

Step 5:

Under room temperature, the mixture of three ring glycol in DCM of acetonide protection handled 1 hour with TFA (5%), use saturated NaHCO ₃Quencher is extracted with DCM, and the organic layer of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=35%-75%), obtain four kinds of isomer of title compound.For A's ¹H-NMR (CDCl3 400MHz) δ: 7.65 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.12-7.00 (m, 1H), 6.50-6.40 (m; 1H), 5.22 (d, J=12.8Hz, 1H), 4.55 (d, J=12.4Hz, 1H), 4.17-4.07 (m, 2H); 3.93 (d, J=11.2Hz, 1H), 3.28 (d, J=11.6Hz, 1H), 2.98-2.89 (wide s, 1H), 2.83-2.74 (wide s; 1H), 2.55 (t, J=13.6Hz, 1H), 2.32 (d, J=13.2Hz, 1H), 1.74 (dd, J=3.0; 14.4Hz, 1H), 1.52 (d, J=12.8 Hz, 1H), 1.30 (t, J=14.8Hz, 1H).For B's ¹H-NMR (CDCl3 400MHz) δ: 7.51 (d, J=9.2Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.08-7.00 (m, 1H); 6.48-6.37 (m, 1H), 5.04 (dd, J=4.0,11.6Hz, 1H), 4.17 (dd, J=3.6; 11.6Hz, 1H), 4.10-4.03 (m, 1H), 3.84 (dd, J=4.0,10.0Hz, 1H); 3.29 (dd, J=5.2,9.6Hz, 1H), 3.22 (t, J=9.8Hz, 1H), 2.80 (t; J=13.2Hz, 1H), 2.45-2.29 (m, 2H), 1.86-1.78m, 1H), 1.68-1.58 (m, 1H).For C's ¹H-NMR (CDCl3 400MHz) δ: 7.61 (d, J=8.4Hz, 2H), 7.50 (d, J=8.4Hz, 2H), 7.13-7.03 (m, 1H); 6.49-6.39 (m, 1H), 5.17 (dd, J=3.2,13.2Hz, 1H), 4.53 (d, J=12.4Hz; 1H), 4.22 (dd, J=2.92,10.25Hz, 1H), 3.89 (dd, J=6.0,10.8Hz; 1H), 3.78 (dt, J=4.4,10.4Hz, 1H), 2.74 (d, J=11.6Hz, 1H); 2.60-2.50 (m, 1H), 2.01-1.92 (m, 2H), 1.58-1.42 (m, 1H), 1.20-1.07 (m, 1H).For D's ¹H-NMR (CDCl3 400MHz) δ: 7.44 (d, J=8.8Hz, 2H), 7.39 (d, J=9.6Hz, 2H), 7.06-6.95 (m, 1H), 6.50-6.36 (m; 1H), 4.99 (dd, J=4.8,11.6Hz, 1H), 4.29 (dd, J=5.2,11.6Hz; 1H), 4.21-4.14 (m, 1H), 3.88 (dd, J=4.8,11.2Hz, 1H), 3.60 (dd; J=8.4,9.8Hz, 1H), 2.98 (dd, J=5.2,10.0Hz, 1H), 2.76-2.68 (m; 1H), 2.56 (t, J=5.8,2H), 2.04-1.98 (m, 1H), 1.72-1.60 (m, 1H).

Provide in table 41 in the LCMS of A, B, C and D data.

Table 41

Embodiment 154 and 155:

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-7-methoxymethyl-6a, 7,8,9; 10, the 10a-six hydrogen-pure and mild 10a-of 6H-benzo [c] chromene-8-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-methoxyl group-7-methoxymethyl-6a, 7; 8,9,10,10a-six hydrogen-6H-benzo [c] chromene

In 0 ℃, to the glycol in THF (5mL) (0.101g, add in 0.22mmol) NaH (0.014g, 0.34mmol 1.5equiv.), stir them 30 minutes, then add CH3I (16uL, 0.25mmol, 1.1equiv.).Make reaction mixture slowly be warmed to room temperature, use saturated NH ₄The Cl quencher.Water extracts (3x50mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification,, then through preparation type TLC, obtain title compound.For 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-7-methoxymethyl-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-alcohol ¹H-NMR: (CDCl3 400MHz) δ: 7.65 (d, J=8.8Hz, 2H), 7.49 (d, J=9.2Hz, 2H), 7.12-7.00 (m, 1H), 6.51-6.39 (m; 1H), 5.21 (d, J=12.8Hz, 1H), 4.45 (d, J=12.4Hz, 1H), 4.03 (s; 1H), 3.94-3.87 (m, 1H), 3.65-3.59 (m, 1H), 3.40 (s, 3H), 3.25 (d; J=12.4Hz, 1H), 2.58 (t, J=11.8Hz, 1H), 2.23 (d, J=13.2Hz, 1H); 1.86-1.75 (m, 1H), 1.56 (d, J=11.6Hz, 1H), 1.21 (t, J=13.6Hz, 1H).

Table 42

Embodiment 156

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-7-methyl-6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone,

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-7,7-dimethyl--6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone with

10a-(4-chloro-benzenesulfonyl)-1,4-fluoro-7,9-dimethyl--6a, 9,10,10a-tetrahydrochysene-6H, 7H-benzo [c] chromene-8-ketone.

In-78 ℃, to the tricycle kentones in THF (20mL) (0.484g, be added dropwise in 1.17mmol) LiHMDS (1.0M in THF, 1.3mL, 1.3mmol 1.1equiv.), stirred 30 minutes under this temperature, then slowly added CH ₃I.Make reactant slowly be warmed to room temperature, and under room temperature stirred overnight.The water quencher is extracted (3x50mL) with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=5%-50%), obtain three alkylation ketone (A, 41%; B, 4%; C, 3%).For A's ¹H-NMR (CDCl3 400MHz) δ: 7.64 (d, J=8.0Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.19-7.08 (m; 1H), 6.56-6.44 (m, 1H), 5.26 (d, J=12.4Hz, 1H); 4.50 (d, J=12.8Hz, 1H), 2.83-2.70 (m, 2H), 2.52-2.28 (m; 3H), 2.21-2.09 (m, 1H), 1.26 (d, J=6.4Hz, 3H).For B's ¹H-NMR (CDCl3 400MHz) δ: 7.58 (d, J=8.0Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.15-7.02 (m, 1H); 6.45-6.32 (m, 1H), 5.22 (dd, J=4.4,13.4Hz, 1H), 4.68 (d, J=12.4Hz; 1H), 2.96 (d, J=4.4Hz, 1H), 2.81-2.64 (m, 2H), 2.60-2.47 (m; 1H), 2.47-2.35 (m, 1H), 1.33 (s, 3H), 0.96 (s, 3H).For C's ¹H-NMR (CDCl3 400MHz) δ: 7.62d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.19-7.07 (m, 1H), 6.57-6.44 (m, 1H); 5.27 (d, J=12.4Hz, 1H), 4.49 (d, J=12.4Hz, 1H), 2.77 (dd, J=4.0,12.8Hz; 1H), 2.72 (d, J=11.6Hz, 1H), 2.44-2.32 (m, 1H), 2.26-2.14 (m, 1H), 2.09 (dd; J=2.8,13.2Hz, 1H), 1.24 (d, J=64Hz, 3H), 0.98 (d, J=6.8Hz, 3H).

Embodiment 157-161

The similar method of method of use and embodiment 156, the compound in the preparation table 43.

Table 43

Embodiment 162-165:

According to the method for embodiment 18, the compound in the preparation table 44.

Table 44

Embodiment 166:

Trimetylene sulfonic acid [10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-hydroxyl-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-ylmethyl]-acid amides

Step 1:

In 0 ℃, (1.0M 0.24mL), stirs them 1.5 hours in THF, dilutes with DCM (20mL) in the alcohol of the nitrile in THF (10mL) (0.052g, 0.12 mmol), to be added dropwise to LAH.Reaction mixture is with 4 saturated NaHCO ₃Neutralization, and stirred 15 minutes, then add Na ₂SO ₄(solid).Filter, use CH ₃OH/DCM (40%) washing is also evaporation for several times.Crude reaction mixture is through preparation type TLC purifying (elutriant: CH ₃OH/DCM=30%) obtain azanol (0.034g, 0.08mmol, 65%). ¹H-NMR(CD3OD?400?MHz)δ：7.69(d，J＝9.2Hz，2H)，7.63(d，J＝8.8Hz，2H)，7.23-7.14(m，1H)，6.61-6.51(m，1H)，5.15(d，J＝13.2Hz，1H)，4.51(d，J＝12.4Hz，1H)，3.98(s，1H)，3.57(s，1H)，3.34(s，1H)，3.16-2.96(m，1H)，2.91(d，J＝11.6Hz，1H)，2.53(t，J＝13.2Hz，1H)，2.36(d，J＝13.2Hz，1H)，1.77(d，J＝14.4Hz，1H)，1.63-1.47(m，2H)，1.36-1.20(m，1H)。

Step 2:

With the method for describing among the embodiment 20, the product of step 1 is converted into title compound.

Table 45

Embodiment 167 and 168:

Embodiment 167

N-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-7-methyl-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl]-C, C, C-three fluoro-Toluidrins

According to universal method from embodiment 19 and 20, the title compound of preparation embodiment 167.According to the method that is similar to embodiment 167, the compound of preparation embodiment 168 (table 46).

Table 46

Embodiment 169

N-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-ylmethyl]-Toluidrin

Step 1:

In 0 ℃, in the ester in THF (40mL), add earlier NH (i-Pr) ₂(4.0mL, 2.86g, 28.3mmol, 3.0Equiv.), then be added dropwise to n-BuLi (11.3mL, 28.3mmol, 3.0Equiv.).Under this temperature, stirred 10 minutes, be cooled to-78 ℃ then.Then in-78 ℃ of stirred reaction mixtures 1 hour, (3.226g 9.43mmol), stirs it other 1 hour under this temperature, water quencher (40mL), and slowly be warmed to room temperature then slowly to be added in vinyl sulphone among the THF (20mL).Extract (3x100mL) with EtOAc, the organic layer water of merging, brine wash are through MgSO ₄Drying, filtration and evaporation.Obtain rough reactant for the mixture of diastereomer (9.95g), and by directly reduction.

Make the Michael adduct be dissolved in EtOAc (100mL), and at H2 (1atm) and Pd (OH) ₂(10%, 3.0g) there is stirring down in catalyzer to/C.When reaction is accomplished, filter, with EtOAc washing and vacuum-evaporation through Celite pad.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=10%-75%), obtain alcohol (3.039g, 6.60mmol, 70% liang of step).

According to universal method from embodiment 16, make said ring cyclisation, make a pair of diastereomer epimerization turn to required ester.For methyl ester ¹H-NMR (CDCl3 400MHz) δ: 7.61 (d, J=8.8Hz, 2H), 7.49 (d, J=9.2HZ, 2H), 7.14-7.00 (m, 1H); 6.50-6.35 (m, 1H), 5.19 (dd, J=3.2,12.4Hz, 1H), 4.20 (d, J=11.6Hz; 1H), 3.72 (s, 3H), 2.98 (d, J=12.0Hz, 1H), 2.64 (d, J=13.2Hz; 1H), 2.45 (dt, J=4.4,12.8Hz, 1H), 1.98-1.87 (m, 2H), 1.82-1.73 (m; 1H), 1.54 (dd, J=4.0,12.8Hz, 1H), 1.18-1.02 (m, 1H).For the tert-butyl ester ¹H-NMR (CDCl3 400MHz) δ: 7.60 (d, J=8.4Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.14-7.01 (m, 1H), 6.48-6.35 (m, 1H); 5.18 (dd, J=2.8,12.0Hz, 1H), 4.23 (d, J=11.6Hz, 1H), 2.90 (d, J=11.6Hz; 1H), 2.65 (d, J=14.0Hz, 1H), 2.31 (dt, J=4.0,12.0Hz, 1H), 1.96-1.84 (m; 2H), 1.80-1.70 (m, 1H), 1.46 (s, 9H), 1.54-1.40 (m, 1H), 1.16-1.06 (m, 1H).

Step 2:

To the ester in THF/EtOH (10mL/50mL) (0.454g, 0.99mmol) the middle LiBH that adds ₄(0.433g, 19.88mmol, 20Equiv.), with its stirred overnight.Vacuum is removed most of solvents, makes residue water-soluble, extracts with EtOAc, and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=5%-75%), obtain alcohol (0.285g, 0.66mmol, 67%). ¹H-NMR(CDCl3?400MHz)δ：7.61(d，J＝9.2Hz，2H)，7.48(d，J＝8.8Hz，2H)，7.09-7.04(m，1H)，6.46-6.39(m，1H)，5.16(d，J＝12.4Hz，1H)，4.63(d，J＝12.4Hz，1H)，3.88(d，J＝4.4，10.8Hz，1H)，3.70(dd，J＝2.8，11.2Hz，1H)，2.69(d，J＝11.2Hz，1H)，2.56(d，J＝13.2Hz，1H)，1.94-1.83(m，1H)，1.80-1.36(m，6H)，1.16-1.02(m，1H)。

Step 3:

Universal method according to from embodiment 19 is converted into amine with alcohol.

Step 4:

According to the universal method from embodiment 20, synthesising title compound.

Table 47

Embodiment 170-182

The similar method of method of use and embodiment 169, the compound in the preparation table 48.

Table 48

Embodiment 183:

N-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-ylmethyl]-N-ethyl-Toluidrin

Step 1:

(0.431g, (0.10mmol, 10mol%) (0.363g, 1.10mmol 1.1Equiv.), stir it until reacting completion under room temperature with DIAB to add TEMPO in 1.00mmol) to the alcohol in DCM (10mL).With DCM (100mL) dilution, use saturated Na ₂S ₂O ₃Washing is extracted with DCM (3x50mL).The organic layer that merges is used saturated NaHCO ₃, brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=5%-75%), obtain aldehyde (0.311g, 0.73mmol, 73%). ¹H-NMR(CDCl3?400Mz)δ：9.66(s，1H)，7.61(d，J＝8.8Hz，2H)，7.49(d，J＝8.8Hz，2H)，7.11-7.03(m，1H)，6.47-6.40(m，1H)，5.16(dd，J＝2.8，12.6Hz，1H)，4.32(d，J＝12.8Hz，1H)，3.00(d，J＝11.2Hz，1H)，2.67(d，J＝12.4Hz，1H)，2.56-2.48(m，1H)，2.00-1.80(m，3H)，?1.78-1.65(m，1H)，1.20-1.06(m，1H)。

Step 2:

To at CH ₃OH/CH ₃Aldehyde among the OH (10mL/10mL) (0.271g, 0.63mmol) middle ethylamine (the 2.0Min CH that adds ₃OH, 0.48mL, 0.95mmol, 1.5Equiv.) and Ti (OiPr) ₄(0.95mmol 1.5Equiv.), after stirred overnight under the room temperature, adds NaBH (OAc) for 0.271g, 0.28mL ₃, it was stirred 4 hours.Reaction mixture is used 10mL H ₂The O quencher, and stirred 30 minutes, filter through Celite pad, use CH ₃OH washing, filtration also concentrate.Residue is used saturated NaHCO ₃Dilution is extracted (3x100mL) and DCM (100mL) with EtOAc, and the organic layer of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: DCM/CH ₃OH (0.7N NH ₃)=5%-50%) obtains amine embodiment 183A (0.169g, 0.37mmol, 59%). ¹H-NMR (CDCl3 400MHz) δ: 7.60 (d, J=8.4Hz, 2H), 7.47 (d, J=8.8Hz, 2H), 7.08-7.01 (m, 1H), 6.48-6.33 (m, 1H); 5.70-5.30 (wide s, 1H), 5.14 (d, J=12.4Hz, 1H), 4.60 (d, J=12.8Hz, 1H), 2.83 (d; J=12.8Hz, 1H), 2.71-2.63 (m, 3H), 2.55 (d, J=10.4Hz, 2H), 2.04-1.82 (m, 7H); 1.82-1.68 (m, 2H), 1.60-1.48 (m, 1H), 1.30-1.16 (m, 1H), 1.10 (t, J=7.0Hz, 3H).

Step 3:

According to universal method from embodiment 20, synthetic sulphonamide and acid amides. ¹H-NMR(CDCl3?400MHz)δ：7.62(d，J＝8.8Hz，2H)，7.49(d，J＝8.8Hz，2H)，7.11-7.04(m，1H)，6.49-6.42(m，1H)，5.18(d，J＝12.4Hz，1H)，4.56(d，J＝12.4Hz，1H)，3.40(dd，J＝4.0，13.6Hz，1H)，3.32-3.11(m，3H)，2.84(s，3H)，2.56(d，J＝13.2Hz，1H)，2.45(d，J＝11.2Hz，1H)，1.95(d，J＝13.2Hz，1H)，1.86(t，J＝13.2Hz，1H)，1.66(d，J＝9.6Hz，1H)，1.68-1.60(m，1H)，1.16(t，J＝7.2Hz，3H)，1.05-0.98(m，1H)。

Embodiment 184-188

The similar method of method of use and embodiment 183, the compound in the preparation table 49.

Table 49

Embodiment 189:

4-[10a-(4-oxygen-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-yl]-Ding-2-alcohol

Step 1:

To the aldehyde in toluene (10mL) (0.049g, add in 0.11mmol) ylide (0.055g, 0.17mmol, 1.5Equiv.), with it in 90 ℃ of stirred overnight.Remove and desolvate, thick residue is through preparation type TLC purifying (elutriant: EtOAc/ hexane=20%), obtain Wittig reaction product (0.039g, 0.08mmol, 76%). ¹H-NMR(CDCl3?400MHz)δ：7.60(d，J＝9.2Hz，2H)，7.49(d，J＝8.8Hz，2H)，7.08(dd，J＝9.4，6.0Hz，1H)，6.47-6.40(m，1H)，6.20(d，J＝16.0Hz，1H)，5.09(d，J＝9.2Hz，1H)，4.30(d，J＝12.0Hz，1H)，2.62(d，J＝13.2Hz，1H)，2.51(d，J＝10.8Hz，1H)，2.27(s，3H)，2.26-2.18(m，1H)，1.94(t，J＝13.2Hz，1H)，1.80-1.74(m，1H)，1.71-1.57(m，1H)，1.39(dq，J＝4.0，12.8，16.0Hz，1H)，1.12(q，J＝13.2，16.4Hz，1H)。

Step 2:

Alpha, beta-unsaturated ketone is used in the Pd (OH) among the EtOAc ₂Catalyzer hydrogenation is handled, through the Celite pad filtering catalyst, and dried filtrate under vacuum.EtOAc/ hexane=20%) and obtain reductive product (0.0188g, 0.04mmol, 54%) crude reaction mixture is through preparation type TLC purifying (elutriant:. ¹H-NMR(CDCl3?400MHz)δ：7.60(d，J＝8.0Hz，2H)，7.48(d，J＝8.0Hz，2H)，7.08-7.02(m，1H)，6.44-6.32(m，1H)，5.15(d，J＝12.4Hz，1H)，4.58(d，J＝12.4Hz，1H)，2.55(d，J＝10.8Hz，1H)，2.52-2.44(m，1H)，2.44-2.38(m，1H)，2.34(d，J＝11.2Hz，1H)，2.14(s，3H)，2.08-1.96(m，1H)，1.86(t，J＝12.8HZ，1H)，1.70(d，J＝10.4Hz，2H)，1.60-1.48(m，1H)，1.44-1.28(m，1H)，1.14-0.96(m，2H)。

Step 3:

Employing is from the universal method of embodiment 18, reduces said ketone and obtain a pair of diastereomer (1/1). ¹H-NMR(CDCl3?400MHz)δ：7.60(d，J＝8.8Hz，2H)，7.48(d，J＝8.8Hz，2H)，7.09-7.02(m，1H)，6.45-6.38(m，1H)，5.15(d，J＝11.6Hz，1H)，4.64-4.58(m，1H)，3.82-3.70(m，1H)，2.54(d，J＝11.6Hz，1H)，2.37(d，J＝10.8Hz，1H)，1.96-1.22(m，9H)，1.20(d，J＝6.4Hz，3H)，1.16-.98(m，1H)。

Embodiment 190:

1-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-yl]-ethanol

According to universal method, obtain two diastereomers (embodiment 190A and 190B) of title compound from embodiment 24 steps 2.For 190A's ¹H-NMR (CDCl3 400MHz) δ: 7.62 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.09-7.03 (m, 1H), 6.46-9.39 (m; 1H), 5.17 (d, J=12.4Hz, 1H), 4.73 (d, J=12.0Hz, 1H), 4.32-4.22 (m, 1H); 2.81 (d, J=10.4Hz, 1H), 1.87 (t, J=12.8Hz, 1H), 1.77 (d, J=13.6Hz, 1H); 1.70-1.60 (m, 1H), 1.40-1.22 (m, 3H), 1.19 (d, J=6.8Hz, 3H), 1.10-0.98 (m, 1H).For 190B's ¹H-NMR (CDCl3 400MHz) δ: 7.60 (d, J=8.0Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.10-7.03 (m, 1H); 6.48-6.39 (m, 1H), 5.16 (d, J=12.8Hz, 1H), 4.51 (d, J=12.4Hz, 1H); 4.36-4.24 (m, 1H), 2.56-2.42 (m, 2H), 1.92-1.84 (m, 2H), 1.84-1.72 (m, 1H); 1.72-1.52 (m, 2H), 1.20 (d, J=6.4Hz, 3H), 1.12-0.96 (m, 1H).

Embodiment 191:

1-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-7-yl]-ethyl ketone

According to carrying out oxidation from the universal method of embodiment 24 steps 1. ¹H-NMR(CDCl3400MHz)forδ：7.61(d，J＝8.4Hz，2H)，7.49(d，J＝8.8Hz，2H)，7.12-7.05(m，1H)，6.48-6.42(m，1H)，5.13(dd，J＝2.8，12.4Hz，1H)，4.10(d，J＝12.8Hz，1H)，3.02(d，J＝10.8Hz，1H)，2.70-2.58(m，2H)，2.20(s，3H)，1.96-1.74(m，3H)，1.32-1.20(m，1H)，1.20-1.08(m，1H)。

Embodiment 192:

Methyl-carboxylamine 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzene [c] chromene-7-ylmethyl ester

Step 1:

To the alcohol in DCM (20mL) (0.147g, 0.34mmol) middle Py (0.28mL, 0.271g, the 3.43mmol of adding; 10Equiv.) (20% in toluene, 1.44mL, 1.356g, 2.74mmol for photoreactive gas; 8.0Equiv.), it was stirred 30 minutes water (10mL) quencher under room temperature.Water extracts with DCM (50mL), and the organic phase of merging is used brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through column chromatography purification (elutriant: EtOAc/ hexane=5%-35%), obtain carbonochloridic acid ester (0.073g, 0.15mmol, 43%). ¹H-NMR(CDCl3?400MHz)forδ：7.62(d，J＝8.4Hz，2H)，7.50(d，J＝8.0Hz，2H)，7.12-7.05(m，1H)，6.48-6.42(m，1H)，5.22(d，J＝12.8Hz，1H)，4.54(dd，J＝4.4，11.6Hz，1H)，4.49(d，J＝12.4Hz，1H)，4.38(dd，J＝3.0，11.8Hz，1H)，2.65(d，J＝11.6Hz，1H)，2.57(d，J＝12.8Hz，1H)，1.92(t，J＝13.2Hz，1H)，1.84-1.68(m，3H)，1.50-1.36(m，1H)，1.18-1.02(m，1H)。

Step 2:

(0.036g is added in THF (2.0M, 74uL, 0.15mmol, the CH in 2.0Equiv.) in 0.074mmol) to the carbonochloridic acid ester that derives from step 1 in DCM (4mL) ₃NH ₂, it was stirred under room temperature 20 minutes, with the DCM dilution, use brine wash, through MgSO ₄Drying, filtration and evaporation.Crude reaction mixture is through preparation type TLC purifying (elutriant: EtOAc/ hexane=35%), obtain carbamate (0.014g, 0.029mmol, 39%). ¹H-NMR(CDCl3?400MHz)forδ：7.60(d，J＝8.0Hz，2H)，7.48(d，J＝8.4Hz，2H)，7.10-6.98(m，1H)，6.50-6.38(m，1H)，5.15(d，J＝12.4Hz，1H)，4.71(s，1H)，4.60(d，J＝12.4Hz，1H)，4.35(d，J＝12.0Hz，1H)，4.07(d，J＝12.0Hz，1H)，2.82(d，J＝4.8Hz，3H)，2.62(d，J＝10.4Hz，1H)，2.54(d，J＝12.4Hz，1H)，1.88(t，J＝13.2Hz，1H)，1.80-1.50(m，4H)，1.48-1.32(m，1H)，1.16-1.00(m，1H)。

Embodiment 193:

The similar method of method of use and embodiment 192, the compound in the preparation table 50.

Embodiment 194-196

Based on the compound in the embodiment 20 preparation tables 51.

Table 51

Embodiment 197-199:

According to being similar to the method for describing among the embodiment 26, the compound in the preparation table 52.

Table 52

Embodiment 200

10b-(4-chloro-benzenesulfonyl 0-7,10-two fluoro-4,4-dimethyl--1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene also

Step 1

(400mg, DCM 1.12mmol) (5mL) solution is crossed iodine alkane with Dess-Martin, and (715mg 1.68mmol) handles and under room temperature, stirred 1 hour, adds excessive Sulfothiorine then with the isomer mixture A that derives from embodiment 24 steps 2 and B.With AcOEt and half-saturated NaHCO3 dilution soup compound, with saturated NaHCO3 washing, drying also concentrates.Bullion ketone (but～430mg) former state is used for next step.

Step 2

Make and the condition that is similar to description in embodiment 24 steps 2 and 3 from the bullion ketone experience of step 1 obtain embodiment HJ1: ¹H NMR (CDCl ₃400MHz) δ 7.55 (d, J=8.6Hz, 2H), 7.48 (d, J=8.6Hz, 2H), 7.18 (m, 1H), 6.40 (m, 1H); 5.18 (dd, 1H), 4.46 (m, 1H), 3.72 (m, 1H), 3.41 (t, 1H), 2.71 (d; 1H), 2.53 (brd, 1H), 2.37 (m, 1H), 1.40 (s, 3H), 0.98 (s, 3H); LCMS (MH ⁺)=429.2; RT=4.83 minute.

Embodiment 201:

1-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-Ding-2-alcohol

Step 1

In-78 ℃; With the product (20.0g that derives from embodiment 16 steps 2; 58.6mmol) DCM (25mL) solution with 1, the two trimethyl silyl glycol of 2-(18.7mL, 76.2mmol) and trimethylsilyl triflate (0.60mL; 3.5mmol) handle, reactant is warming up to ambient temperature overnight.Final mixture dilutes with saturated NaHCO3, extracts with DCM, and is dry and concentrated.Residue obtains 15.50g (70%) ketal through flash chromatography on silica gel purifying (with hexane/AcOEt 99:1-50:50 wash-out).

Step 2

To the ketal (13.72g that derives from step 1; 35.65mmol) DCM (200mL) solution in add allyl trimethyl silane (28.7mL 180mmol), then add boron trifluoride etherate (22.6mL; 180mmol) and with reactant in 38 ℃ of stirred overnight; In the impouring water, extract and AcOEt then with DCM, dry and concentrated.Residue obtains 7.11g (47%) allyl alcohol isomer A through flash chromatography on silica gel purifying (with hexane/AcOEt95:5-70:30 wash-out) according to elution order, then is allyl alcohol isomer B.

Step 3

With the allyl alcohol isomer A that derives from step 2 (7.11g, 16.65mmol) and oxone (30.75g, acetone 50.0mmol) (100mL) and water (25mL) solution stirred overnight under room temperature; Filter then; Water and AcOEt dilution are extracted with AcOEt, and be dry and concentrated.Residue obtains 5.50g (72%) allyl sulfone through flash chromatography on silica gel purifying (with hexane/AcOEt 99:1-60:40 wash-out).

Step 4

To the allyl sulfone that derives from step 3 (1.78g, 3.87mmol) add in the solution in DCM (40mL) methylsulfonyl chloride (480uL, 6.20mmol), then add triethylamine (730uL, 5.2mmol), with this reactant stirred overnight under room temperature.With rare HCl and DCM aftertreatment, obtain 2.46g methanesulfonates midbody.With methanesulfonates midbody (2.46g) in THF (40mL), be used in THF (10mL, the tBuOK1N in 10mmol) slowly handles, and this reactant was stirred under room temperature 35 minutes, dilute with water extracts and DCM with AcOEt then, and is dry and concentrate.Residue obtains 1.50g (88%) allyl group pyrans through flash chromatography on silica gel purifying (with hexane/AcOEt95:5-60:40 wash-out).

Step 5

In-78 ℃, (2.0g, bubbling feeds ozone in DCM 4.35mmol) (100mL) solution, and is constant until blueness to the allyl group pyrans that derives from step 4.Bubbling feeds nitrogen and becomes colourlessly until solution then, and (1.87g 7.12mmol), is placed to room temperature and 1 hour with this reactant to disposable adding triphenyl phosphine.After concentrating the residue that obtains,, obtain 2.6g (100%) aldehyde through flash chromatography on silica gel purifying (with hexane/AcOEt95:5-60:40 wash-out),

Step 6

In-78 ℃, (75mg, (120uL, 0.36mmol) solution made reactant be warmed to 0 ℃ with 30 minutes to the Et2O of adding EtMgBr3N then, used saturated NH in THF 0.17mmol) (1mL) solution to the aldehyde product that derives from step 5 ₄The Cl quencher is extracted with DCM and AcOEt, and is dry and concentrated.Residue obtains 65.8mg embodiment 201 through silica gel purification (with hexane/AcOEt7:3 wash-out), is the 1:1 non-enantiomer mixture: ¹HNMR (CDCl ₃400 MHz δ 7.63 (d, J=8.7Hz, 2H), 7.52 (d, J=8.7Hz, 2H), 7.11 (m, 1H), 6.46 (m; 1H), 5.14 (d, 1H), 4.41 (m, 1H), 3.92 (m, 1H), 3.65-3.85 (m, 1H); 3.45-3.60 (m, 1H), 3.18 (m, 1H), 2.62 (m, 1H), 2.53 (m, 1H), 2.33 (m; 1H), and 1.85-2.05 (m, 1H), 1.60-1.80 (m, 1H), 1.45-1.55 (m, 1H), 0.95-1.00 (m, 3H); LCMS (MH ⁺)=473.3; RT=4.51 minute.

Embodiment 202:

Step 1

With the product (433mg that derives from embodiment HJ2 step 4; 0.98mmol) THF (3 mL) solution with the THF (1.5mL of borine dimethylsulphide 2N; 1.50mmol) solution-treated and with this reactant stirred overnight under room temperature, slowly handle with 3NNaOH (9mL) and 30%H2O2 (9mL) in 10 ℃ then.After following 1 hour, the dilute with water final mixture also extracts with DCM and AcOEt in room temperature, and is dry and concentrated.Residue obtains 281mg (63%) alcohol through flash chromatography on silica gel purifying (with hexane/AcOEt 95:5-60:40 wash-out).

Step 2

(281mg, DCM 0.61mmol) (5mL) solution is crossed iodine alkane with Dess-Martin, and (320mg 0.75mmol) handles, and this reactant was stirred under room temperature 45 minutes, and then with the AcOEt dilution, with saturated NaHCO3 washing, drying also concentrates with the alcohol that derives from step 1.Residue dilutes with DCM, filters then and concentrates, and obtains the rough ketone of 391mg.

Step 3

In-78 ℃, THF (2mL) solution of the bullion ketone (178mg) that derives from step 2 is used in Et2O, and (350uL, the MeMgBr 3N in 1.05mmol) handles, then with making reactant be warmed to 0 ℃ also among the saturated NH4Cl of impouring in 45 minutes.After DCM and AcOEt extraction, then dry and concentrated through Na2SO4, the residue warp is silica gel column chromatography purifying (with hexane/AcOEt 95:5-60:40 wash-out) fast, obtains 95mg alcohol.

Step 4

Feasible alcohol from step 3 (95mg, the condition of 0.20mmol) describing in the experience step 2 behind the silica gel purification (with hexane/AcOEt 8:2 wash-out), obtains 69mg embodiment 202: ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, J=8.6Hz, 2H), 7.50 (d, J=8.6Hz, 2H), 7.09 (m, 1H); 6.44 (m, 1H), 5.14 (m, 1H), 4.48 (m, 1H), 3.86 (m, 1H); 3.23 (m, 1H), 3.10 (m, 1H), 2.60-2.70 (m, 1H), 2.45-2.55 (m; 3H), 2.10-2.35 (m, 2H), 2.12 (s, 3H), 1.78 (m, 1H); LCMS (MH ⁺)=471.3; RT=4.55 minute.

Embodiment 203:

4-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-1,1,1-three fluoro-fourth-2-alcohol

Step 1

(33.3mg adds trifluoromethyl trimethyl silane (200u) 0.072mmol) and in DMF (0.6mL) solution of tributylphosphine (20uL), then in water-bath, slowly adds TBAF 1N (65uL) to the product that derives from embodiment 202 steps 2.This reactant was stirred under room temperature 60 hours, and water and DCM aftertreatment are handled with AcOEt then then.Residue obtains 11mg embodiment HJ4 through silica gel purification (with hexane/AcOEt 8:2 wash-out), is the 1:1 non-enantiomer mixture: ¹H NMR (CDCl ₃400MHz) δ 7.53 (d, J=8.6Hz, 2H), 7.26 (d, J=8.6Hz, 2H), 7.11 (m; 1H), 6.46 (m, 1H), 5.17 (m, 1H), 4.44 (m, 1H); 3.83 (m, 2H), 3.31 (m, 1H), 3.10-3.20 (m, 1H), 2.50-2.65 (m; 2H), 2.33 (m, 1H), 2.14 (m, 1H), 1.65-1.95 (m, 3H); LCMS (MH ⁺)=527.3; RT=4.74 minute.

Embodiment 204:

(4S)-[10b (S)-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-Ding-(2S)-alcohol

Step 1

The ketone product of embodiment 202 is through Chiracel Column purification uses hexane/isopropyl alcohol (30/70) as moving phase, obtains (-) enantiomorph ([α] D according to elution order ²⁰=-1.17 ° (c=1, DCM)) then obtains (+) enantiomorph ([α] D ²⁰=+0.98 ° (c=1, DCM)).In 0 ℃; To (-) enantiomorph (10mg; 0.021mmol) THF (200uL) solution in add (R)-methyl-CBS-boron oxynitride heterocyclic pentene (oxazaborolidine) 1N toluene (15uL, 0.015mmol) solution is after 5 minutes; With the THF (30uL, 0.06mmol) solution that added borine dimethylsulphide 2N in 5 minutes.In 0 ℃ this reactant was stirred 45 minutes, then with the DCM dilution, (～0.5mL) quencher and stirring 5 minutes is diluted with saturated NaHCO3, with DCM extraction and AcOEt with MeOH.Residue obtains 8.4mg embodiment 204 through silica gel purification (with hexane/AcOEt6:4 wash-out): ¹HNMR (CDCl ₃400MHz) δ 7.63 (d, J=8.6Hz, 2H), 7.50 (d, J=8.6Hz, 2H), 7.08 (m, 1H); 6.45 (m, 1H), 5.17 (m, 1H), 4.46 (m, 1H), 3.89 (m, 1H); 3.77 (m, 1H), 3.26 (m, 1H), 3.14 (m, 1H), 2.50-2.60 (m, 2H); 2.30 (m, 1H), 2.00 (m, 1H), 1.45-1.70 (m, 3H), 1.19 (d, 3H); LCMS (MH ⁺)=473.3; RT=4.37 minute.

Embodiment 205-218

According to being similar to the method for describing among the embodiment 200-204, the compound in the preparation table 53.

Table 53

Embodiment 219:

Ethane sulfonic acid [10b-(4-chloro-benzenesulfonyl)-7,10-difluoro 1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-ylmethyl also]-acid amides

Step 1

With the ketal product that derives from embodiment 201 steps 1 (15.0g, acetone 39.0mmol) (480mL) and water (120mL) solution join oxone (51.0g, 82.0mmol) in and under room temperature, reactant was stirred 48 hours.Filter final mixture, with the DCM washing, dilute with water and extract then with DCM.After dry and concentrated, residue obtains 13.5g (70%) sulfone ketal through flash chromatography on silica gel purifying (with hexane/AcOEt 99:1-50:50 wash-out).

Step 2

In 0 ℃, (5.0g adds trimethylsilyl cyanide (2.40mL in DCM 12.0mmol) (100mL) solution to the sulfone ketal that derives from step 1; 18.0mmol); (1.50mL 12.0mmol), was warmed to room temperature with 1 hour with this reactant then to add the boron trifluoride etherate.(1.20mL, 9.0mmol) (0.75mL 6.0mmol) and with this mixture stirred 1 hour with the boron trifluoride etherate to add other trimethylsilyl cyanide.Final mixture extracts with DCM with DCM and water dilution, and is dry and concentrated.Residue obtains 2.20g (41%) cyanic acid alcohol isomer A (41%) through flash chromatography on silica gel purifying (using the easy gradient liquid of DCM/AcOEt 99:1-60:40), then obtains .8g (52%) cyanic acid alcohol isomer B.

Step 3

0 ℃, (2.70g adds THF (12.0mL, 12.0mmmol) solution and reactant stirred 1 hour of lithium aluminium hydride 1N under room temperature in THF 6.08mmol) (200mL) solution to the cyanic acid alcohol isomer A that derives from step 2.Final mixture dilutes with DCM, with the slow quencher of the saturated NaHCO3 of 3 mL, under room temperature, stirs 15 minutes, handles with Na2SO4 then, filters (using DCM/MeOH 9:1) through CELITE.After concentrating, obtain 2.60g (96%) amino alcohol.

Step 4

To the amino alcohol that derives from step 3 (2.60g, add in DCM 5.81mmol) (60mL) solution triethylamine (1.60mL, 12.0mmol), then add two carbonic acid tertiary butyl ester (1.50g, 6.88mmol), with this reactant stirred overnight under room temperature.Concentrate final mixture,, obtain 2.80g (88%) Boc-amino alcohol through flash chromatography on silica gel purifying (with hexane/AcOEt 80:20-20:80 wash-out).

Step 5

To the Boc-amino alcohol that derives from step 4 (2.80g, add in DCM 5.11mmol) (60mL) solution methylsulfonyl chloride (0.60mL, 7.60mmol), then add diisopropylethylamine (1.80mL, 10.2mmmol), with this reactant stirred overnight under room temperature.Concentrate final mixture,, obtain 3.0g (94%) methanesulfonates midbody through flash chromatography on silica gel purifying (with hexane/AcOEt80:20-AcOEt wash-out).In-30 ℃, (10mL, the tBuOK1N in 10mmol) handle the methanesulfonates midbody, and (dilute with water extracts with AcOEt and DCM then, and is dry also concentrated for 3.0g, THF 4.80mmol) (60mL) solution, and reactant stirred 30 minutes to be used in THF.Residue obtains the amino pyrans of 2.20g (90%) Boc-through flash chromatography on silica gel purifying (with hexane/AcOEt80:20-AcOEt wash-out).

Step 6

(900mg adds TFA (1mL) and under room temperature, reactant was stirred 1 hour in DCM 1.70mmol) (60mL) solution to the amino pyrans of the Boc-that derives from step 5.Carry out aftertreatment through adding 0.5NNaOH, then extract with DCM, drying also concentrates, and obtains the amino pyrans of 700mg (95%).

Step 7

With the amino pyrans (25mg that derives from step 6; 0.058mmol) DCM (1mL) solution handle with ethanesulfonyl chloride (50uL); Then add diisopropylethylamine (100uL) also with this reactant stirred overnight under room temperature; Through silica gel purification (with hexane/AcOEt50:50 wash-out), obtain 19.0mg embodiment 219 then: ¹HNMR (CDCl ₃400MHz) δ 7.64 (d, J=8.7Hz, 2H), 7.54 (d, J=8.7Hz, 2H), 7.11 (m, 1H); 6.49 (m, 1H), 5.17 (m, 1H), 4.56 (m, 1H), 4.43 (m, 1H); 3.90 (m, 1H), 3.35-3.50 (m, 3H), 3.20 (m, 1H), 3.00-3.10 (m, 2H); 2.88 (m, 1H), 2.61 (m, 1H), 2.15 (m, 1H), 1.37 (t, 3H); LCMS (MH ⁺)=522.3; RT=4.23 minute.

Comprise according to being similar in embodiment 20 and 219 method of describing, adopt subsequently identical method, the compound in the preparation table 54 the cyanic acid alcohol isomer A that derives from step 2.

Table 54

Embodiment 234:

10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-nitrile also

Step 1

In-40 ℃; To the cyanic acid alcohol isomer B product (50mg, THF (0.17ml, 0.17mmol) solution of adding tBuOK1N in THF 0.11mmol) (1mL) solution that derive from embodiment 219 steps 2; Under this temperature, this reactant was stirred 30 minutes, stirred 2 hours in 0 ℃ then.The final mixture dilute with water extracts with AcOEt, and is dry and concentrated.Residue obtains 5.7mg embodiment 234 through silica gel purification (with hexane/AcOEt 50:50 wash-out): ¹H NMR (CDCl ₃400MHz) δ 7.63 (d, J=8.7Hz, 2H), 7.53 (d, J=8.7Hz, 2H), 7.15 (m, 1H), 6.52 (m; 1H), 5.25 (m, 1H), 4.60 (m, 1H), 4.15 (m, 1H), 4.00 (m, 1H); 3.19 (m, 1H), 3.03 (m, 1H), 2.58 (m, 1H), 2.38 (m, 1H); LCMS (MH ⁺+ H2O)=443.3; RT=4.61 minute.

Embodiment 235 and 236

According to being similar to the method for describing among the embodiment 234, using the tBuOK/KOH mixture to replace pure tBuOK, and comprise the possible N-of adding subsequently alkylating agent, the compound in the preparation table 55.

Table 55

Embodiment 237:

N-{2-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-ethyl }-Toluidrin

Step 1

(1.50g, (160mg 4.23mmmol) and with reactant stirred under room temperature 2 hours slowly to add Peng Qinghuana in MeOH 3.39mmol) (50mL) solution to the aldehyde product that derives from embodiment 201 steps 5.With salt solution and this mixture of DCM dilution, extract then with DCM, dry and concentrated, obtain 1.54g (100%) alcohol.

Step 2

Make and the condition that is similar to description in embodiment 19 and 20 from the alcohol experience of step 1 obtain embodiment 237: ¹HNMR (CDCl ₃400MHz) δ 7.63 (d, J=8.7Hz, 2H), 7.52 (d, J=8.7Hz, 2H), 7.12 (m, 1H); 6.47 (m, 1H), 5.66 (m, 1H), 4.84 (m, 1H), 4.38 (m, 1H); 3.90 (m, 1H), 3.10-3.45 (m, 4H), 2.90 (s, 3H), 2.45-2.60 (m; 2H), 2.30 (m, 1H), 2.17 (m, 1H), 1.82 (m, 1H); LCMS (MH ⁺)=522.3; RT=4.02 minute.

Embodiment 238-243:

According to being similar in embodiment 20 and 237 method of describing, comprising and derive from method like the pure product type of step 1, the compound in the preparation table 56.

Table 56

Embodiment 244

3-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-ylmethyl also]-isoxazole

Step 1

(250mg adds hydroxy amine hydrochloric acid salt (150mg) and sodium acetate (300mg) in EtOH 0.56mmol) (5mL) solution to the aldehyde product that derives from embodiment 201 steps 5.With this reactant stirred overnight under room temperature, filter then and concentrate, residue obtains 209mg (82%) oxime (hydroxime) through flash chromatography on silica gel purifying (with hexane/AcOEt 99:1-AcOEt wash-out).

Step 2

To the oxime (35mg that derives from step 1; 0.076mmol) and the EtOH (1mL) of trimethyl silyl acetylene (25uL) and water (0.3mL) solution in add chloramine-T trihydrate (28.1mg; 0.10mmol), this reactant was stirred under room temperature 1 hour, then dilute with water; And with DCM and AcOE extraction, dry and concentrated.Residue obtains 15mg TMS isoxazole through silica gel purification (with hexane/AcOEt6:4 wash-out).

Step 3

The acetonitrile (2mL) of TMS isoxazole (15mg) that derives from step 2 and CsF (40mg) and EtOH (0.4mL) solution were refluxed 10 minutes, concentrate then and, obtain 8mg embodiment 244 through silica gel purification (with hexane/AcOEt7:3 wash-out): ¹H NMR (CDCl ₃400MHz) δ 8.32 (s, 1H), 7.62 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 2H); 7.11 (m, 1H), 6.48 (m, 1H), 6.30 (s, 1H), 5.14 (m, 1H); 4.56 (m, 1H), 3.91 (m, 1H), 3.52 (m, 1H), 3.10-3.20 (m, 2H); 2.70-2.85 (m, 1H), 2.56 (m, 1H), 2.46 (m, 1H), 2.21 (m, 1H); LCMS (MH ⁺)=482.3; RT=4.62 minute.

Embodiment 245

According to being similar to the method for describing among the embodiment 244, the compound in the preparation table 57.

Table 57

Embodiment 246:

2-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-ylmethyl also]-benzothiazole

Step 1

To the aldehyde product (35mg that derives from embodiment 201 steps 5; 0.08mmol) and 2-aminothiophenol (8uL; 0.10mmol) DCM (0.6mL) solution in add DDQ (23mg; 0.10mmol) and with this reactant stirred overnight under room temperature, through silica gel purification (with hexane/AcOEt 7:3 wash-out), obtain 17.9mg embodiment 24612 then: ¹H NMR (CDCl ₃400MHz) δ 7.98 (d, 1H), 7.83 (d, 1H), 7.62 (d, J=8.6Hz, 2H), 7.48 (t; 1H), 7.35-7.45 (m, 3H), 7.12 (m, 1H), 6.49 (m, 1H), 5.20 (m; 1H), 4.65 (m, 1H), 3.96 (m, 1H), 3.77 (m, 1H), 3.45-3.65 (m; 2H), 3.21 (m, 1H), 2.55-2.65 (m, 2H), 2.23 (m, 1H); LCMS (MH ⁺)=548.3; RT=5.16 minute.

Embodiment 247 and 248:

According to being similar to the method for describing among the embodiment 246, comprising and use or do not use oxygenant such as air, the compound in the preparation table 58.

Table 58

Embodiment 249:

1-{2-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-ethyl }-the 1H-imidazoles

Step 1

In the DCM (3mL) of the pure product (50mg) that derives from embodiment 237 steps 1 solution, add methylsulfonyl chloride (10uL), then add triethylamine (30uL), then this reactant was stirred under room temperature 30 minutes, filter and concentrate through silicagel pad.Make residue be dissolved in DMF (0.5mL), add Na2CO3 (24mg), then add imidazoles (12mg), with 60 ℃ of heating of this mixture 48 hours.The dilute with water reactant extracts with AcOEt, and is dry and concentrated, through silica gel purification (with hexane/AcOEt60:40 wash-out), obtains 6mg embodiment 249 then: ¹HNMR (CDCl ₃400MHz) δ 7.64 (d, J=8.7Hz, 2H), 7.52 (d, J=8.7Hz, 2H), 7.40 (brs, 1H), 7.12 (m; 1H), 7.03 (brs, 1H), 6.89 (brs, 1H), 6.47 (m, 1H), 5.17 (m; 1H), 4.38 (brd, 1H), 4.00-4.15 (m,, 2H), 3.93 (m, 1H); 3.05-3.15 (m, 2H), 2.50-2.60 (m, 2H), 2.25-2.40 (m, 2H), 1.97 (m, 1H); LCMS (MH ⁺)=495.3; RT=3.04 minute.

Embodiment 250:

According to being similar to the method for describing among the embodiment 249, the compound in the preparation table 59.

Table 59

Embodiment 251 and 252

Embodiment 251: 10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,10b-dihydro-2H-pyrans be [3,4-c] chromene-4a-alcohol also

Step 1

Under room temperature, (10.0g adds tetrahydrochysene-4H-pyrans-4-ketone (10.0g in THF 250mmol) (300mmL) mixture at hexane to NaH60%; 100mmol); Then add after 30 minutes methylcarbonate (21.0mL, 250mmol), then with this mixture in 45 ℃ of heated overnight.In final mixture impouring 0.01N HCl and Et2O, filter through CELITE, with the AcOEt dilution, with brine wash and concentrated.Lower liquid layer obtains the 1.30g keto esters through silica gel purification (with hexane/AcOEt 99:1-60:40 wash-out).

Step 2

In-78 ℃, to the keto esters product that derives from step 1 (2.22g, the THF (15.4mL of adding NaHMDS 1N in THF 14.0mmol) (60mL) solution; 15.4mmmol) solution; After 10 minutes, then be added in N-phenyl two (trifluoromethane sulphonamide) among the THF (20mL) (5.50g, 15.4mmol).This reactant is warming up to ambient temperature overnight, among the impouring 1N HCl, extracts with DCM and AcOEt, dry and concentrated.Residue obtains 6.76g enol triflate through silica gel purification (with hexane/AcOEt 99:1-60:40 wash-out).

Step 3

In 50 ℃, with the enol triflate that derives from step 2 (5.65g, 19.5mmol), 2,3; 6-trifluorophenyl boric acid (4.46g, 25.4mmol), sodium acetate (6.00g, 73mmol) with four (triphenyl phosphine) palladium (0) (1.75g; 1.50mmol) mixture stirred overnight in dioxane (75mL), stirred cooling then 3 hours in 85 ℃ then; With the AcOEt dilution, use brine wash, dry and concentrated.Residue obtains 4.80g aryl unsaturated ester through silica gel purification (with hexane/DCM80:20-DCM wash-out).

Step 4

In-78 ℃, (4.40g, (16.2mL, 16.2mmol) solution made reactant be warming up to room temperature through 45 minutes to the THF of slow adding LAH1N in the THF solution (40mL) 16.2mmol) to the aryl unsaturated ester that derives from step 3.Use saturated NaHCO3 quencher then, with the AcOEt dilution, add Na2SO4, mixture filters and concentrates through CELITE.Residue obtains the 2.42g unsaturated alcohol through silica gel purification (with hexane/AcOEt 99:1-AcOEt wash-out).

Step 5

In-20 ℃, (2.42g, (10.0mL, 10.0mmol) solution made reactant be warming up to room temperature through 30 minutes to the THF of adding t-BuOK 1N in THF 9.90mmol) (20mL) solution to the unsaturated alcohol that derives from step 4.Use saturated NH4Cl quencher then, extract with DCM, dry and concentrated, through silica gel purification (with hexane/AcOEt 99:1-60:40 wash-out), obtain the unsaturated pyrans of 1.03 g then.

Step 6

Make and the condition of in the unsaturated pyrans experience embodiment 284 step 6-8 of step 5, describing obtain embodiment 251: ¹H NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 2H), 7.12 (m, 1H), 6.45 (m, 1H); 5.13 (d, 1H), 4.23 (brs, 1H), 4.04 (d, 1H), 3.98 (m, 1H), 3.62 (m; 1H), 3.50 (m, 1H), 3.25 (m, 1H), 2.84 (m, 1H), 2.57 (m, 1H); LCMS (MH ⁺)=417.2; RT=3.94 minute.

According to being similar to the method for describing among the embodiment 251, the compound of the embodiment 252 of preparation table 60.

Table 60

Embodiment 253-255

According to being similar to the method for describing among flow process 1-A, 1-B and the 2-A, the compound in the preparation table 61.

Table 61

Embodiment 256-263

Be used to prepare embodiment 8 described methods according to being similar to, the compound in the preparation table 62.

Table 62

Embodiment 264:

According to the method for embodiment 16, the compound below the preparation.

(MS:435.2 (M+1); 4.69 minute).

Embodiment 265-282

Use is similar to those methods (promptly being similar to the method that is used to prepare compound 20A) of embodiment 20 and replaces suitable acyl group or alkylsulfonyl halogenide, the compound in the preparation table 63.

Table 63

Embodiment 283:

[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl]-pyridine-2-base-amine

In containing the bottle of amine that 18mg (0.043mmol) derives from embodiment 19, add 3.5mg (0.018mmol) three (dibenzalacetone) palladium (0), 5.4mg (0.004mmol) 2-(two-tert-butyl phosphine) biphenyl, the anhydrous THF of 0.5mL, 2-pyridine bromide (0.11mmol) and hexamethyl dimethyl silanyl Lithamide (0.11mmol).With this mixture with purging with nitrogen gas and be heated to 65 ℃ 14 hours.Rough thing uses and is containing 1%NH through prep TLC plate direct purification ₃DCM in the 3%MeOH wash-out. ¹H?NMR(CDCl ₃400MHz)δ1.40(m，1H)1.80(m，2H)2.00(m，2H)2.40(m，1H)3.00(m，1H)3.90(m，1H)4.15(d，J＝11.9Hz，1H)5.24(d，J＝11.9Hz，1H)6.41(m，2H)6.66(m，1H)7.10(m，1H)7.50-7.62(m，4H)8.10(m，1H)。

Embodiment 284:

10aR-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-6aR-hydroxyl-6H-dibenzo [b, d] pyrans-8 (7H)-ketone

Step 1

With hexane wash NaH (60% oil suspension, 24.36g, 2eq) 3 times.Under nitrogen, room temperature, with ketone (47.51g, THF 304.6mmol) (1.2L) solution joins among the NaH, with the solution stirring that obtains 30 minutes, then add methylcarbonate (54.82g, 2eq).This mixture was stirred 60 hours.The quencher of reaction water.Add 0.6LEtOAc, 0.6L hexane.Bullion is with 1.75N HCl (350mL, 2.01eq) washing.Through Na ₂SO ₄Drying, evaporating solvent obtains the 60g keto esters with 89% yield, is white solid. ¹H?NMR(CDCl ₃400MHz)δ1.80(m，2H)2.50(m，4H)3.70(s，3H)4.00(s，4H)12.15(s，1H)。

Step 2

Under 0 ℃, nitrogen, (60% oil suspension, 5g 1.1eq) join the keto esters (24.28g that derives from step 1 in THF (1L) with NaH; 113.5mmol).After 10 minutes, and adding N-phenyl-two (trifluoromethane sulphonamide) (44.59g, 1.1eq).The red solution that obtains was stirred under room temperature 24 hours.At this moment, add other 0.5g NaH and 2.4g N-phenyl-two (trifluoromethane sulphonamide), this mixture was further stirred 24 hours.Add saturated NH ₄Cl (100mL).After most of THF solvent evaporation, add 800mL EtOAc.Organic layer is with 1N HCl, saturated NaHCO ₃, water and brine wash, through Na ₂SO ₄Dry.Flash chromatography (hexane/EtOAc 90: 10) obtains triflate (35.3g) with 90% yield. ¹HNMR(CDCl ₃400MHz)δ1.90(m，2H)2.60-2.70(m，4H)3.80(s，3H)4.00(m，4H)。

Step 3

To the product that derives from step 2 (10.0g adds 2,3 in toluene 28.9mmol) (160mL) and EtOH (50 mL) solution, 6-trifluorophenyl boric acid (6.1g, 1.2eq), four (triphenyl phosphine) palladium (1.2g, 0.05eq), 2M Na ₂CO ₃(28.9mL, 2eq).Mixture with the argon gas purge and be heated to 48 ℃ 14 hours.Make this mixture be cooled to room temperature, filter through Celite.Except that after desolvating, add EtOAc.Behind water washing, salt solution, through Na ₂SO ₄Dry and concentrated, bullion obtains the 6.4gSuzuki coupling product through flash chromatography purifying (hexane/EtOAc 70: 30) with 68% yield. ¹HNMR(CDCl ₃400MHz)δ1.90(m，2H)2.60(m，2H)2.75(brs，2H)2.60-2.70(m，4H)3.58(s，3H)4.00(m，4H)6.80(m，1H)7.00(m，1H)。

Step 4

Under-78 ℃, nitrogen, with the product that derives from step 3 (10.0g, 30.49mmol)/300mLTHF uses LiAlH ₄(2.3N is in THF, and 13.25mL 0.9eq) handles.After in 2 hours, being warmed to 0 ℃, reaction water (1.2mL), 15%NaOH (3.6mL), water (1.2mL) quencher are stirred this mixture 10 minutes, and are passed through diatomite filtration.Except that after desolvating, add EtOAc.Water, brine wash are through Na ₂SO ₄Dry and concentrate, need not be further purified and obtain bullion (8.7g, 95% yield) into required product. ¹H?NMR(CDCl ₃400MHz)δ1.90(m，2H)2.42(m，2H)2.60(brs，2H)3.84(d，J＝5.9Hz，2H)4.06(m，4H)6.83(m，1H)7.10(m，1H)。

Step 5

In 0 ℃, with the product that derives from step 4 (11.8g, 39.33mmol)/(1N learns among the THFHF 400mL THF, 1eq) handles with KOtBu.1.5 after hour, add EtOAc, organic layer water, brine wash are through Na ₂SO ₄Dry.Except that after desolvating, bullion washs with cold diethyl ether, is collected as the white solid (5.8g, 53% yield) of required cyclisation product. ¹H?NMR(CDCl ₃400MHz)δ1.90(m，2H)2.30(brs，2H)2.80(m，2H)4.00(brs，4H)4.55(brs，2H)6.55(m，1H)6.84(m，1H)。

Step 6

Under room temperature, with the product that derives from step 5 (0.16g, 0.57mmol)/(70% purity, 0.28g 2eq) handle 5mL DCM with MCPBA.After 40 minutes, add 10mL10%Na ₂S ₂O ₃Organic layer is with 1N NaOH, saturated Na ₂HCO ₃, water, brine wash are through Na ₂SO ₄Dry.Except that after desolvating, obtain the 0.18g bullion, it is used for next step. ¹HNMR(CDCl ₃?400MHz)δ1.60(m，1H)1.80(m，1H)1.92(d，J＝14.1Hz，1H)2.17(d，J＝15.2Hz，1H)2.56(m，1H)2.82(m，1H)3.90(m，4H)4.05(d，J＝12.1Hz，1H)4.35(d，J＝12.1Hz，1H)6.59(m，1H)6.90(m，1H)。

Step 7

In 0 ℃, to the epoxide product that derives from step 6 (1.0g, 3.4mmol)/add in the 15mLDCM solution 4-chlorothio-phenol (1.03g, 2eq), Indium-111 chloride (80mg, 0.1eq).This mixture is stirred 14H and uses saturated Na under room temperature ₂CO ₃Quencher.After water, the brine wash, through Na ₂SO ₄Dry and concentrated, bullion is through flash chromatography purifying (hexane/EtOAc5:1), obtain 0.32g cis adducts (first eluate, 21% yield) and the trans adducts of 1.14g (second eluate, 76% yield).The cis adducts: ¹H NMR (CDCl ₃400MHz) δ 1.43 (dt, J=2.6,13.8Hz, 1H) 1.70 (m, 1H) 1.83 (dd, J=3.1; 14.2Hz, 1H) 2.06 (d, J=14.4Hz, 1H) 2.38 (m, 1H) 2.95 (brd, J=14.7Hz; 1H) 3.90 (m, 5H) 4.40 (s, 1H) 4.80 (d, J=11.1Hz, 1H) 6.21 (m, 1H) 6.82 (m; 1H) 7.13 (d, J=7.9Hz, 2H) 7.24 (d, J=7.9Hz, 2H).

Trans adducts: ¹H NMR (CDCl ₃400MHz) δ 1.84 (m, 2H) 2.20-2.40 (m, 2H) 2.58 (m, 1H) 2.65 (m, 1H) 4.00 (s, 4H) 4.06 (d; J=10.9Hz, 1H) 4.75 (d, J=11.0Hz, 1H) 5.00 (s, 1H) 6.19 (m, 1H) 6.80 (m; 1H) 7.13 (d, J=7.9Hz, 2H) 7.24 (d, J=7.9Hz, 2H).

Step 8

Under room temperature, to the cis adducts that derives from step 7 (0.32g, 0.73mmol)/(70% purity 2eq) and with mixture stirred 1 hour to add 0.36gMCPBA in the 6mLDCM solution.The 10%Na that adds 5mL ₂S ₂O ₃Organic layer is with 1N NaOH, saturated Na ₂HCO ₃, water, brine wash are through Na ₂SO ₄Dry.Except that after desolvating, obtain the 0.35g bullion and also be used for next step. ¹H?NMR(CDCl ₃400MHz)δ1.46(dt，J＝3.8，14.0Hz，1H)1.60(dd，J＝2.9，14.6Hz，1H)1.80(m，1H)1.95(d，J＝14.6Hz，1H)2.40(m，1H)2.99(brd，J＝15.2Hz，1H)3.90(m，5H)4.38(s，1H)5.28(d，J＝11.0Hz，1H)6.41(m，1H)7.05(m，1H)7.42(d，J＝8.0Hz，2H)7.70(d，J＝8.0Hz，2H)。

Step 9

Under room temperature, to the product that derives from step 8 (0.35g, 0.73mmol)/add in the 20mL acetone, the 5mL aqueous solution 0.12g right-toluenesulphonic acids, this mixture was stirred 14 hours in 70 ℃.Add other p-toluenesulphonic acids (60mg), this mixture was stirred 5 hours in 70 ℃.Except that desolvating and adding EtOAc.Organic layer is used saturated NaHCO ₃, water, brine wash, through Na ₂SO ₄Dry.Except that after desolvating, bullion obtains required ketone product (0.21g, 66% yield) through flash chromatography purifying (hexane/EtOAc 65: 35). ¹HNMR(CDCl ₃400MHz)δ2.10(m，1H)2.40-2.60(m，4H)3.01(m，1H)4.10(d，J＝11.0Hz)4.60(d，J＝2.8Hz，1H)5.15(d，J＝11.0Hz，1H)6.45(m，1H)7.10(m，1H)7.50(m，4H)。

Step 10

To product derive from step 9 product (70mg, 0.16mmol)/add 7.3mg NaBH4 in the 0.6mL THF/0.3mLEtOH solution.After stirring 3 hours under the room temperature, react with the MeOH quencher.Except that after desolvating, bullion obtains required cis glycol (16 mg, 23% yield) and trans glycol (40mg, 57% yield) through Prep TLC (hexane/EtOAc 2: 1) purifying.The cis glycol: ¹H NMR (CDCl ₃400 MHz) δ 1.43 (m, 1H) 1.80-1.99 (m, 3H) 2.50 (m, 1H) 2.82 (m, 1H) 3.40 (m; 1H) 4.00 (brs, 1H) 4.06 (d, J=11.1Hz, 1H) 5.10 (m, 1H) 5.12 (d; J=11.1Hz, 1H) 6.43 (m, 1H) 7.10 (m, 1H) 7.50 (d; J=8.6Hz, 2H) .7.62 (d, J=8.6Hz, 2H).

Trans glycol: ¹HNR (CDCl ₃400MHz) δ 1.18 (m, 1H) 1.60 (m, 2H) 2.00 (m, 2H) 2.42 (m, 1H) 2.70 (m, 1H) 4.07 (d, J=11.0Hz, 1H) 4.10 (m, 1H) 4.60 (s, 1H) 5.10 (d, J=11.0Hz, 1H) 6.40 (m, 1H) 7.10 (m, 1H) 7.50 (m, 4H).

Embodiment 285-88:

According to the similar method of the method for embodiment 284, the compound of preparation table 64.

Table 64

Embodiment 289-296:

Embodiment 289

N-[10aR-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6aS-hydroxyl-6H-dibenzo [b, d] pyrans-8 (R)-yl]-1,1,1-fluoroform sulphonamide (cis)

According to the similar method of the method for embodiment 19 and 20, compound and the compound of embodiment 290-296 (table 65) of preparation embodiment 289.

Table 65

Embodiment 297:

Use is similar to those methods (promptly being similar to the method that is used to prepare compound 20A) of embodiment 20 and replaces suitable acyl group or alkylsulfonyl halogenide, the compound in the preparation table 66.

Table 66

Embodiment 298:

N-{2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-oxos-8,9,10,10a-tetrahydrochysene-7H-benzo [c] chromene-6a-base oxygen base]-ethyl }-C, C, C-three fluoro-Toluidrins

Step 1

In under the room temperature, under the nitrogen, with the cis adducts that derives from embodiment 284 steps 7 (1.19g, 2.70mmol)/(1.2eq) handle by 60% oil suspension with 0.13g NaH for 20mL THF.After 30 minutes, add 0.83g monobromo-acetic acid methyl esters (0.83g, 2eq), with this mixture heating up to 80 ℃ 16 hours.Except that after desolvating, add EtOAc, organic layer water, brine wash are through Na ₂S0 ₄Dry.Initial alcohol (0.6g) that flash chromatography (hexane/EtOAc 5: 1) obtains reclaiming and required product (0.61g) are white solid, 44% yield. ¹HNMR(CDCl ₃400MHz)δ1.40(m，1H)1.70(m，1H)1.94(d，J＝15.9Hz，1H)2.13(m，1H)2.56(m，1H)2.67(m，1H)3.79(s，3H)3.83(m，2H)3.93(m，2H)4.01(d，J＝11.2Hz，1H)4.13(d，J＝15.3Hz，1H)4.36(d，J＝15.3Hz，1H)?4.85(d，J＝1011.2Hz，1H)6.35(m，1H)6.84(m，1H)7.12(d，J＝9.0Hz，2H)7.37(d，J＝9.0Hz，2H)。

Step 2

Under-78 ℃, nitrogen, make from the product of step 1 (0.45g, 0.88mmol)/30mLTHF uses LiAlH ₄(2.3M is in THF, and 0.38mL 1eq) handles.Make reactant slowly be warmed to ambient temperature overnight.After 5 salt solution quenchers, add EtOAc, bullion is through diatomite filtration.Flash chromatography (hexane/EtOAc1: 1), obtain required product (0.23g), be white solid with 54% yield. ¹HNMR(CDCl ₃400MHz)δ1.36(dt，J＝2.9，13.9Hz，1H)1.70(m，1H)1.92(d，J＝15.3Hz，1H)2.23(dt，J＝2.9，15.4Hz，1H)2.60(m，1H)2.80(m，1H)3.60-4.04(m，8H)4.16(d，J＝10.1Hz，1H)4.94(d，J＝10.9Hz，1H)6.24(m，1H)6.84(m，1H)7.12(d，J＝8.7Hz，2H)7.22(d，J＝8.7Hz，2H)。

Step 3-7

According to embodiment 19 and 20 similar methods, obtain required product. ¹H?NMR(CDCl ₃400MHz)δ1.31(m，1H)1.75(m，2H)2.10(m，1H)2.60(m，1H)2.80(m，2H)3.18(m，1H)3.35(m，1H)3.58(m，1H)3.70(m，1H)3.80(m，2H)3.90-4.03(m，2H)4.15(d，J＝12.2Hz，1H)5.36(d，J＝12.2Hz，1H)6.35(m，1H)7.08(m，1H)7.36(d，J＝7.8Hz，2H)7.54(d，J＝8.0Hz，2H)。

Step 8

Implement the similar method of method with step 9 embodiment 284.

¹H?NMR(CDCl ₃400MHz)δ 2.14(m，1H)2.42-2.60(m，2H)2.68(m，1H)2.95(m，1H)3.20(m，1H)3.42-3.60(m，2H)3.66(m，1H)3.78(m，1H)4.26(d，J＝10.3Hz，1H)5.60(d，J＝11.0Hz，1H)6.30(m，1H)6.70(m，1H)7.10(m，1H)7.40(m，4H)。

Embodiment 299:

According to the similar method of the method for embodiment 298, synthetic following compound.

¹HNMR (CDCl ₃400MHz, 1: 1 rotational isomer) δ 0.97 (t, J=7.4Hz, 1.5H, rotational isomer 1) 1.02 (t, J=7.4Hz, 1.5H; Rotational isomer 2) 2.30 (m, 1H) 2.40-2.60 (m, 2H) 2.65-2.90 (m, 5H) 2.90-3.10 (m, 1H) 3.20-3.39 (m, 2H) 3.95 (m, 1H) 4.13 (dt; J=3.6,13.1Hz, 1H) 4.26 (dd, J=5.8,10.9Hz, 1H) 5.50 (d; J=11.0Hz, 1H) 6.60 (m, 1H) 7.18 (m, 1H) 7.40 (m, and 2H) 7770 (m, 2H).

Embodiment 300

Phenylsulfonic acid (6As)-10Ar-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6A, 7,8,9,10,10A-six hydrogen-6h-dibenzo [B, D] pyrans-8 (s)-methyl alcohol, 4-methyl ester (racemic)

Step 1:

Under-78 ℃, nitrogen, to Ph ₃PCH ₂OCH ₃ ⁺Cl ^-(17.62g is added dropwise to LiHMDS (50.4mL, 1.0M is in THF) in THF 0.051mol) (100mL) solution.After the adding, make reactant be warming up to room temperature and stirred 1 hour.Reaction soln becomes orange.Make mixture be cooled to-78 ℃, with the anti-form-1 0A-[(4-chlorophenyl) alkylsulfonyl]-1 that drips, 4-two fluoro-6A, 9,10,10A-tetrahydrochysene-6h-dibenzo [B, D] pyrans-8 (7h)-ketone (racemic) (5.2g, THF 0.0126mol) (100mL) solution-treated.In-78 ℃, this reaction mixture was stirred 2 hours, be warming up to room temperature then, use the saturated ammonium chloride solution quencher.Use ETHYLE ACETATE (200mL) to extract this mixture then.Extract with ETHYLE ACETATE (200mL) in the waterbearing stratum.The organic layer that merges is with brine wash (200mL), through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-30/70).Obtain 4.74g, 85%. ¹H?NMR(CDCl ₃400MHz)δ7.60(d，2H)，7.49(d，2H)，7.08(m，1H)，6.44(m，1H)，5.80(s，1H)，5.24(d，1H)，4.22(m，1H)，3.53(s，1H)，2.64-2.84(m，1H)，2.58-2.63(m，2H)，1.62-2.10(m，4H)。

Step 2:

(2.0g 0.0045mol) adds trichoroacetic acid(TCA) and under room temperature, stirring 30 minutes in the solution to the vinyl ether product that derives from step 1.With saturated sodium bicarbonate solution quencher reaction, extract with methylene dichloride (100mLX2).The organic layer that merges is with brine wash (100mL), through dried over sodium sulfate and concentrated.Make residue be dissolved in THF and use NaBH in 0 ℃ ₄Handle.Make reaction mixture be warming up to room temperature and stirred water quencher then 30 minutes.Use ETHYLE ACETATE (100mL X2) to extract then.The organic layer that merges is used brine wash, through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50).Must measure 1.65g, 84.8%. ¹H?NMR(CDCl ₃?400MHz)δ7.58(d，2H)，7.49(d，2H)，7.07(m，1H)，6.39(m，1H)，5.22(m，1H)，4.17(m，1H)，3.75(m，1H)，3.38(t，1H)，2.63-2.72(m，2H)，1.74-1.89(m，3H)，1.35-1.47(m，1H)，0.65-1.17(m，1H)。

Step 3:

To the pure product that derives from step 2 (1.65g, add in DCM 0.0038mol) (100mL) solution triethylamine (1.1ml, 0.0079mol), the p-toluene sulfonyl chloride (1.1g, 0.0058mol), with its stirred overnight.Reaction mixture washs with saturated sodium bicarbonate solution, uses DCM (50mL X2) to extract then.The organic layer that merges is used brine wash, through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-40/60).Must measure: the merging amount of cis and trans-isomer(ide) is 1.82g, 82.1%.Required cis-isomer embodiment 3000.82g, yield 37%.

Embodiment 300: ¹H NMR (CDCl ₃400MHz) δ 7.82 (d, 2H), 7.42-7.52 (m, 6H), 7.09 (m, 1H), 6.39 (m, 1H), 5.09 (dd; 1H), 4.12 (d, 1H), 3.96 (d, 1H), 2.49 (m, 4H), 2.33 (d, 1H); 2.06 (m, 1H), 1.92 (t, 1H), 1.67 (m, 2H), 1.58 (m, 1H) .LCMS (MH ⁺)=583.3; RT=5.10 minute.

Embodiment 301-320:

Embodiment 301-303:

Step 1:

To embodiment 300 (0.25g, add in DMF 0.43mmol) (4mL) solution thioacetic acid potassium and with this suspension-s be heated to 120 ℃ 2 hours.In reaction mixture, adding salt solution also extracts with ETHYLE ACETATE (50mL X2).The organic layer that merges is used brine wash, through dried over sodium sulfate and evaporation.Make residue be dissolved in methyl alcohol (20mL), handle and under room temperature, stirred 2 hours with the 1N NaOH aqueous solution.In reaction mixture, adding salt solution also extracts with ETHYLE ACETATE (50mLX3).The organic layer that merges is used brine wash, through dried over sodium sulfate and evaporation.Product embodiment 301 is through the reverse hplc purifying, and water and acetonitrile are as elutriant. ¹H?NMR(CDCl ₃400MHz)δ7.58(dd，2H)，7.49(d，2H)，7.08(m，1H)，6.43(m，1H)，5.24(d，1H)，4.13(dd，1H)，2.86(d，2H)，2.77(d，1H)，2.40(d，1H)，2.08(m，2H)，1.68-1.84(m，3H)，1.26-1.34(m，2H)。

Step 2:

In 0 ℃, (0.22g adds KNO in acetonitrile 0.49mmol) (20mL) solution to embodiment 301 ₃And SO ₂Cl ₂And in 0 ℃ of stirring 3 hours.Reaction mixture is used the saturated sodium bicarbonate solution quencher, uses ethyl acetate extraction.Organic layer washs with saturated sodium bicarbonate solution and salt solution once more, through dried over sodium sulfate and evaporation, obtains oily matter.This SULPHURYL CHLORIDE former state is used for next step.

Step 3:

(0.02g, (0.098mL, the 2N methylamine in 0.196mmol) is with its stirred overnight to be added in THF in DCM solution 0.039mmol) to the bullion SULPHURYL CHLORIDE that derives from step 2.The solvent of evaporation reaction mixture, product are through the reverse hplc purifying, and water and acetonitrile are as elutriant.From reaction mixture, separate two kinds of products.Embodiment 302: ¹H NMR (CDCl ₃400MHz) δ 7.56 (d, 2H), 7.50 (d, 2H), 7.11 (m, 1H), 6.41 (m, 1H), 5.25 (dd; 1H), 4.16 (m, 2H), 3.19 (d, 2H), 2.86 (d, 3H), 2.79 (d, 1H); 2.47 (m, 2H), 2.10 (t, 1H), 1.70-1.94 (m, 3H), 1.36 (m, 1H) .LCMS (MH+)=506.3; RT=4.28 minute.Embodiment 303: ¹H NMR (CDCl ₃400MHz) δ 7.57 (m, 4H), 7.25 (m, 1H), 5.24 (dd, 1H), 4.17 (m, 2H), 3.19 (m, 2H), 2.86 (d, 3H), 2.68 (d, 1H), 2.40-2.46 (m, 2H), 1.62-2.06 (m, 4H), 1.38 (m, 1H) .LCMS (MH ⁺)=542.3; RT=4.55 minute.

According to being similar to the method that embodiment 301-303 is described, the compound of the embodiment 304-320 in the preparation table 67.

Table 67

Embodiment 321-326

Embodiment 321:

According to being similar to the method for describing among the embodiment 337, the compound in the preparation table 68.

Table 68

Embodiment 327 and 328:

(6As)-and 10Ar-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6A, 7,8,9,10,10A-six hydrogen-8 (s)-(iodo-methyl) 6h-dibenzo [B, D] pyrans (racemic)

(0.016g, (0.02g 0.13mmol), is heated to and refluxed 12 hours to add NaI in 2mL acetone soln 0.027mmol) to embodiment 300.Vacuum is removed all solvents.This material obtains 0.013g product embodiment 327 through preparation of silica gel type TLC (with ethyl acetate/hexane 30/70 wash-out). ¹H?NMR(CDCl ₃400?MHz)δ7.57(d，2H)，7.50(d，2H)，7.10(m，1H)，6.43(m，1H)，5.25(dd，1H)，4.12(d，1H)，3.40(d，2H)，2.79(d，1H)，2.35(d，1H)，2.12(m，2H)，1.93(m，2H)，1.77(m，1H)，1.35(m，1H)。

According to the similar method of describing among the embodiment 327 of method, the compound among the preparation embodiment 328 (table 69).

Table 69

According to the method that is similar to description in the embodiment 301-303 step-1, but use potassium acetate, preparation embodiment 329 compounds as reagent.

Embodiment 329:

(6As)-and 10Ar-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6A, 7,8,9,10,10A-six hydrogen-6h-dibenzo [B, D] pyrans-8 (s)-methyl alcohol (racemic)

According to the method that is similar to description in the embodiment 301-303 step-1, but use potassium acetate, the compound of preparation embodiment 329 as reagent.

Embodiment 329. ¹H NMR (CDCl ₃400MHz) δ 7.57 (d, 2H), 7.49 (d, 2H), 7.08 (m, 1H), 6.41 (m, 1H), 5.19 (d, 1H), 4.12 (d, 1H), 3.75 (d, 2H), 2.79 (d, 1H), 2.38 (d, 1H), 2.11 (m, 1H), 1.58-1.88 (m, 3H), 1.24-1.37 (m, 3H), LCMS (MH ⁺)=429.2; RT=4.15 minute.

According to being similar to the method for describing in the flow process 1-B step 3.Preparation embodiment LQ-31/LQ-flow process-6.

Embodiment 330:

(6As)-and 10Ar-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6A, 7,8,9,10,10A-six hydrogen-6h-dibenzo [B, D] pyrans-8 (s)-methyl alcohol, methyl carbamate (racemic)

According to being similar to the method for describing in the flow process 1-B step 3.The compound of preparation embodiment 330.

According to being similar to the method for describing in the flow process 1-B step 3, the compound of preparation embodiment 330. ¹HNMR (CDCl ₃400MHz) δ 7.57 (d, 2H), 7.49 (d, 2H), 7.10 (m, 1H), 6.43 (m, 1H); 5.20 (d, 1H), 4.70 (m, 1H), 4.19-4.21 (m, 2H), 4.12 (d; 1H), 2.83 (d, 3H), 2.38 (m, 1H), 2.19 (m, 1H); 1.99 (m, 1H), 1.66-1.73 (m, 2H), 1.25 (m, 2H), LCMS (MH ⁺)=486.3; RT=4.44 minute.

Embodiment 331

2-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-ethanol

Step 1

In-78 ℃, with O ₃The air-flow bubbling feeds alkene, and (1,57g is in DCM 3.56mmol) (120mls) stirred solution.When being continuously blueness, stop to add O ₃Continue to stir 10 minutes in-78 ℃.Bubbling feeds N in reactant ₂Stream becomes colourless until it.Gradation adds PPh ₃(1.40g, 5.34mmol).Then reactant was stirred under room temperature 2.5 hours.Through anhydrous Na ₂SO ₄Dry this solution.Filter, then evaporation obtains oily matter (～1.58g aldehyde).But this aldehyde former state is used for next step.

Step 2

(～1.58g 3.56mmol) is dissolved in EtOH (50mls) and be cooled to 0 ℃ to make bullion aldehyde.Add NaBH in batches ₄(135mg, 3,56mmol).In 0 ℃ reactant is continued to stir 15 minutes, under room temperature, stirred 1 hour then.Be added dropwise to H ₂O (2mls) is with quencher NaBH ₄Vacuum-evaporation EtOH.Make residue be allocated in DCM (150mls) and H ₂Between the O (2x75mls).DCM is with brine wash (75mls) and through anhydrous Na ₂SO ₄Dry.Evaporation DCM obtains solid residue.This material obtains the product (1.58g, 100%) into the solid expectation through flash chromatography on silica gel purifying (with hexane/EtOAc95:5-50:50 wash-out).

Embodiment 332-335:

(wherein R indicates in table 70)

Step 1A

With alcohol (10mg, 0.0224mmol) and ethyl isocyanate (1.6mg 0.0224mmol) is containing 1 of 1m HCl/ ether (1), and the solution in the 2-ethylene dichloride (0.50mls) stirs under room temperature.After 2 hours, evaporating solvent.Residue obtains a solid (9.7mg, 84%) through preparation type TLC purifying (50%EtOAc/ hexane, 1000 microns silica gel G F).

Step 1B

With alcohol (10mg, 0.0224mmol), carbonochloridic acid 4-nitrophenyl ester (6.8mg, 0.0337mmol) and pyridine (2.7mg, 0.0337mmol) solution in THF (0.50mls) stirs under room temperature.The mixture that obtains was stirred under room temperature 1 hour.Be added in THF (1.4mg, the 1M MeNH in 0.0448mmol) ₂, with this reactant stirred overnight under room temperature.Solvent removed in vacuo, crude product obtains a solid (11mg, 98%) through preparation type TLC purifying (50%EtOAc/ hexane, 1000 microns silica gel G F).

Use the universal method of step 1A and 1B, the compound in the preparation table 70.

Table 70

Embodiment 336:

3-[10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H, 4H-pyrans be [3,4-c] chromene-4-yl also]-propionitrile

Step 1

Under room temperature, make alcohol (1.06g, 2.38mmol) and TosCl (907mg 4.76mmol) is dissolved in DCM (20mls).With Et ₃(482 mg 4.76mmol) are added dropwise in the solution of stirring N.With this reactant stirred overnight.With DCM (100mls) dilution, use saturated NaHCO ₃(50mls) and H ₂O (2x50mls) extracts.Through anhydrous Na ₂SO ₄Dry DCM solution also flashes to oily matter.Crude product flash chromatography on silica gel purifying (with EtOAc/ hexane 5:95-50:50 wash-out) obtains a solid (1.34g, 94%).

Step 2

With tosylate (100mg, 0.167mmol) and NaCN (25mg, the stirred solution of DMF 0.501mmol) (2mls) be heated to 110-120 ℃ 3 hours.With EtOAc (2mls)/hexane (2mls) this reactant of mixture diluted and use H ₂O (2x3mls) distributes.Organic phase is through anhydrous Na ₂SO ₄Dry also evaporation.Residue flash chromatography on silica gel purifying (with EtOAc/ hexane 5:95-100:0 wash-out) obtains a solid (62mg, 82%).

Table 71

Embodiment 337:

10b-(4-chloro-benzenesulfonyl)-7,10-two fluoro-4-[2-(propane 2-alkylsulfonyl)-ethyl]-1,4a, 5,10b-tetrahydrochysene-2H4H-pyrans is [3,4-c] chromene also

Step 1

With tosylate (96mg, 0.160mmol), isopropyl mercaptan (24mg, 0.32mmol) with 1M KOH in EtOH (13.5mg, 24mmol) mixture heating up in EtOH (3mls) to 70-75 ℃ 30 minutes.Evaporation reaction mixture.Absorb residue with DCM (15mls), use H ₂O (2x5mls) washing.DCM is through anhydrous Na ₂SO ₄Drying also is evaporated to solid (79mg).The product former state is used for subsequent reaction.

Step 2

Under room temperature, (73mg, 0.145mmol) (75mg 0.435mmol) handles the stirred solution in DCM (3mls) with mCPBA with sulfide.After 1 hour,, use saturated NaHCO with DCM (10mls) diluting reaction thing ₃(2x5mls) and H ₂O (5mls) extracts.Through anhydrous Na ₂SO ₄Dry DCM also concentrates.Residue flash chromatography on silica gel purifying (with EtOAc/ hexane 5:95-80:20 wash-out) obtains being solid expectation product (57mg, 73%).

Table 72

Embodiment 338:

Use the universal method of embodiment 337, the compound in the preparation table 73

Table 73

Embodiment 339 and 340:

Based on embodiment 24, the compound in the preparation table 74.

Table 74

Embodiment 341:

4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2-methyl isophthalic acids, 2,3,4-tetrahydrochysene-quinoline

With 2, (5.0g, (1M is at Et with HCl solution for ether 38.7mmol) (50mL) solution for the 5-difluoroaniline ₂Among the O, 39mL) handle also vacuum concentration.Make the powder that obtains be dissolved in EtOH (30mL) and be cooled to 0 ℃.(2.2mL 39mmol), makes solution be warmed to room temperature to be added dropwise to acetaldehyde.After 30 minutes, use H ₂O (6mL) diluted reaction mixture, add fast 4-chlorophenyl-sulfinic acid sodium (3.5g, 17.7mmol).After 4 hours, the vacuum concentration reaction mixture.Residue is used saturated NaHCO ₃CH is used in aqueous solution dilution ₂Cl ₂(2x) extract.The organic extraction that merges is through MgSO ₄Dry and concentrated.Flash chromatography (5 → 10%EtOAc/Hex) obtain embodiment 341 (1.23g, 19%): ¹H NMR (CDCl ₃400MHz) δ 7.70 (dd, J=8.8,2.2Hz, 2H), 7.49 (dd, J=8.8,2.2Hz, 2H); 6.84 (m, 1H), 6.00 (m, 1H), 4.53 (dd, J=5.1,2.2Hz, 1H); 4.35 (brs, 1H), 4.18 (m, 1H), 2.76 (m, 1H), 1.68 (ddd; J=14.6,12.4,5.1Hz, 1H), 1.33 (d, J=6.6Hz, 3H).

Embodiment 342:

4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4-tetrahydrochysene-quinoline

Step 1:

2N-[3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-propyl group]-4-methyl-benzsulfamide

In-78 ℃, with 2-(4-chloro-benzenesulfonyl methyl)-1,3,4-three fluoro-benzene (5.6g, [(5:1,180mL) EDA handles with n-BuLi (1.5M is in hexane for 12mL, 17.5mmol) THF/TM 17.5mmol) by solution.After 15 minutes, add N-ptoluene-sulfonyl ethylenimine THF (10mL) solution of (3.5g, 17.5mmol as at EurJ.Org.Chem2002, prepare described in 3004), this reaction mixture slowly is warming up to room temperature.After 4 hours, extract (2x) with 1N HCl quencher reaction mixture and with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (25 → 50%EtOAc/Hex) obtain title compound (4.9g, 54%): ¹H NMR (CDCl ₃400MHz) δ 7.64 (d, J=8.1Hz, 2H), 7.57 (d, J=8.1Hz, 2H), 7.43 (d, J=8.1Hz; 2H), 7.28 (d, J=8.1Hz, 2H), 7.14 (m, 1H), 6.75 (m, 1H); 4.81 (m, 1H), 3.17 (ddd, J=7.1,7.1,5.6Hz, 1H), 2.96 (m; 1H), 2.64 (m, 1H), 2.47 (m, 1H), 2.41 (s, 3H).

Step 2:

3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-propyl group amine

With 2N-[3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-propyl group]-4-methyl-benzsulfamide (500mg, 48%HBr/H 0.97mmol) ₂(282mg 3.0mmol) is heated to backflow and handles O (4mL) solution with phenol.After 7 hours, add another part 48%HBr/H ₂O (3mL).After other 36 hours, make reaction mixture be cooled to room temperature and be added dropwise to 1N NaOH and carry out quencher.Reaction mixture is used CH ₂Cl ₂(4x) extract, the organic layer of merging is through MgSO ₄Drying is filtered and vacuum concentration.Flash chromatography [1%MeOH/CH ₂Cl ₂→ 5%NH ₄OH/MeOH (1:9)/CH ₂Cl ₂) obtain title compound (240mg, 68%): ¹H NMR (CDCl ₃400MHz) δ 7.64 (d, J=8.1Hz, 2H), 7.43 (d, J=8.1Hz, 2H), 7.14 (m, 1H), 6.78 (m, 1H), 4.89 (dd, J=9.5,5.1Hz, 1H), 2.87 (m, 1H), 2.56-2.40 (m, 3H), 1.22 (s, 2H).

Step 3:

4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4-tetrahydrochysene-quinoline

With 3-(4-chloro-benzenesulfonyl)-3-(2,3,6-three fluoro-phenyl)-(100mg, DMF 0.27mmol) (3mL) solution is heated to 80 ℃ to propyl group amine.After 4 hours, make reaction mixture be cooled to room temperature, use saturated NaHCO ₃The aqueous solution and extract (2x) with EtOAc.The organic layer water (2x), the brine wash that merge are through MgSO ₄Dry also vacuum concentration.Flash chromatography (20%EtOAc/Hex) obtains embodiment 342 (78mg, 84%): ¹H NMR (CDCl ₃400MHz) δ 7.69 (dd, J=8.1,2.2Hz, 2H), 7.49 (dd, J=8.1,2.2Hz; 2H), 6.84 (m, 1H), 6.03 (m, 1H), 4.52 (d, J=5.1Hz; 1H), 4.50 (brs, 1H), 3.95 (ddd, J=12.4,12.4,4.4Hz; 1H), 3.48 (m, 1H), 2.81 (m, 1H), 2.00 (m, 1H).

Embodiment 343:

4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1-methyl isophthalic acids, 2,3,4-tetrahydrochysene-quinoline

With 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-1,2,3,4-tetrahydrochysene-quinoline (50mg, CH 0.145mmol) ₃CN (1mL) solution is used K ₂CO ₃(4mg, 0.16mmol), (10 μ L 0.16mmol) handle and be heated to 50 ℃ to MeI.After 6 hours, (10 μ L, 0.16mmol) reaction mixture and be heated to 80 ℃ after 12 hours, are transferred to this reaction mixture in the ST and dilute with propionitrile (2mL) with MeI.Add salt of wormwood (20mg) and MeI (50 μ L), this reaction mixture is heated to 80 ℃.After 48 hours, make reaction mixture be cooled to room temperature, use saturated NH ₄The Cl aqueous solution and extract (2x) with EtOAc.The organic layer that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Preparation type thin-layer chromatography (20%EtOAc/Hex) obtains embodiment 343 (25.6mg, 49%): ¹H NMR (CDCl ₃400MHz) δ 7.67 (dd, J=8.8,2.2Hz, 2H), 7.48 (dd, J=8.8,2.2Hz, 2H); 6.87 (m, 1H), 6.12 (m, 1H), 4.53 (d, J=5.1Hz, 1H); 3.69 (ddd, J=13.9,11.7,4.4Hz, 1H), 3.32 (m, 1H); 3.13 (d, J=4.4Hz, 3H), 2.82 (m, 1H), 2.07 (m, 1H).

Embodiment 344:

Step 1:

4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-3-(2-iodine ethyl)-chroman

In 0 ℃, with the product that derives from embodiment 27 steps 5 (2.7g, CH 6.94mmol) ₃(1:2,70mL) solution is used Ph to CN/tol ₃P (2.2g, 8.3mmol), imidazoles (0.61g, 9.0mmol), (2.1g 8.3mmol) handles and be warmed to room temperature to iodine.After 1 hour, this reaction mixture is used saturated NaHCO ₃The aqueous solution/Na ₂S ₂O ₃(1:1) dilute and use Et ₂O (2x) extracts.The organic extraction that merges is with 1N HCl, saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (2 → 10%EtOAc/Hex) obtain title compound (3.47g, 99%): ¹H NMR (CDCl ₃400MHz) δ 7.77 (dd, J=8.1,1.5Hz, 2H), 7.55 (dd, J=8.1,1.5Hz, 2H); 7.04 (m, 1H), 6.46 (m, 1H), 4.92 (dd, J=11.7,2.9Hz, 1H); 4.31 (dd, J=11.7,1.5Hz, 1H), 4.28 (s, 1H), 3.17-3.10 (m, 2H); 2.97 (t, J=6.6Hz, 1H), 1.89 (m, 1H), 1.74 (m, 1H).

Step 2:

3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-propionitrile

With 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-3-(2-iodo-ethyl)-chroman (3.47g, CH 6.94mmol) ₃CN (70mL) solution is used n-Bu ₄(2.2g 8.0mmol) handles NCN.After 12 hours,, use Et with 1N HCl diluted reaction mixture ₂O (3x) extracts.The organic extraction that merges is with 1N HCl (2x), saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration obtains title compound (2.6g, 94%): ¹HNMR (CDCl ₃400MHz) δ 7.74 (dd, J=8.8,2.2Hz, 2H), 7.55 (dd, J=8.8,2.2Hz, 2H); 7.07 (m, 1H), 6.46 (m, 1H), 4.99 (dd, J=12.4,2.9Hz, 1H); 4.34 (dd, J=12.4,2.2Hz, 1H), 4.32 (s, 1H), 2.99 (t, J=6.6Hz; 1H), 2.47 (t, J=7.3Hz, 2H), 1.76 (m, 1H), 1.65 (m, 1H).

Step 3:

3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-propionic aldehyde

In-78 ℃, with 3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-propionitrile (500mg, CH 1.26mmol) ₂Cl ₂(15mL) (1M is in hexane, and 1.5mL 1.5mmol) handles and warp was warmed to 0 ℃ in 1 hour with DIABAL for solution.After 1 hour, with 1N HCl quencher reaction mixture, vigorous stirring 30 minutes is used CH ₂Cl ₂(3x) extract.The organic extraction that merges is used H ₂The O washing is through MgSO ₄Dry also vacuum concentration.Flash chromatography (8 → 60%EtOAc/Hex) obtain title compound (455 mg, 90%): ¹HNMR (CDCl ₃400MHz) δ 9.75 (s, 1H), 7.73 (dd, J=8.8,2.2Hz, 2H), 7.51 (dd, J=8.8; 2.2Hz, 2H), 7.04 (m, 1H), 6.43 (m, 1H), 4.90 (dd, J=12.4; 2.2Hz, 1H), 4.32 (dd, J=12.4,2.2Hz, 1H), 4.31 (s, 1H); 2.83 (t, J=6.6Hz, 1H), 2.56 (m, 1H), 1.76-1.54 (m, 3H).

Step 4:

1-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-oneself-5-alkene-3-alcohol

In-78 ℃, (1.79g, (1M is at Et with allyl group bromination magnesium for THF 4.47mmol) (45mL) solution with 3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-propionic aldehyde ₂Among the O, 5.8mL 5.8mmol) handles and was warmed to 0 ℃ with 1 hour.Reaction mixture is used saturated NH ₄The quencher of the Cl aqueous solution is extracted (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (2 → 10%EtOAc/CH ₂Cl ₂) obtain title compound (1.3g, 66%): ¹H NMR (CDCl ₃400MHz) δ 7.71 (dd, J=8.1,1.5Hz, 2H), 7.53 (dd, J=8.1,1.5Hz, 2H), 7.03 (m; 1H), 6.41 (m, 1H), 5.76 (m, 1H), 5.16-5.08 (m, 2H), 4.93 (ddd, J=11.7; 2.9,2.9Hz, 1H), 4.32 (dd, J=12.4,2.2Hz, 1H), 4.31 (s, 1H); 3.59 (m, 1H), 2.85 (m, 1H), 2.29-2.10 (m, 2H), 1.68-1.43 (m, 4H).

Step 5:

Tert-butyl-(1-{2-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-ethyl }-Ding-3-thiazolinyl oxygen base)-dimethyl--silane

In 0 ℃; With 1-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-oneself-5-alkene-3-alcohol (1.30g, DMF 2.93mmol) (29mL) solution is with imidazoles (0.41g; 6.0mmol), (0.66g 4.4mmol) handles and is warmed to room temperature to TBSCl.After 36 hours, reaction mixture is used saturated NH ₄The quencher of the Cl aqueous solution is extracted (2x) with EtOAc.The organic extraction that merges is used H ₂O (3x), saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (1 → 10%EtOAc/Hex) obtains title compound (1.45g, 89%): ¹HNMR (CDCl ₃400MHz) δ 7.71 (dd, J=8.1,1.5Hz, 2H), 7.52 (dd, J=8.1,1.5Hz, 2H), 7.03 (m; 1H), 6.42 (m, 1H), 5.72 (m, 1H), 5.01-4.89 (m, 3H), 4.33 (dd, J=11.0; 2.2Hz, 1H), 4.27 (s, 1H), 3.62 (m, 1H), 2.74 (m, 1H), 2.12-2.10 (m; 2H), 1.55-1.24 (m, 4H), 0.78 (s, 4.5H), 0.76 (s, 4.5H) ,-0.01 (s, 3H) ,-0.08 (s, 3H).

Step 6:

3-(tert-butyl-dimethyl--silicon alkoxyl group)-5-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-penta-1-alcohol

In-78 ℃, with tert-butyl-(1-{2-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-ethyl }-Ding-3-thiazolinyl oxygen base)-dimethyl--silane (1.45g, 1:1 MeOH/CH 2.60mmol) ₂Cl ₂(25mL) solution is constant until blueness with the ozone purge.Use N then ₂Purge reaction mixture 5 minutes adds NaBH in batches ₄(300mg 7.8mmol) handles, and slowly is warmed to room temperature.Through 4.5 hours, add the outer NaBH of 2 shares again ₄(each 500mg) uses saturated NH ₄Cl aqueous solution quencher reaction mixture and vacuum concentration.Residue is used CH ₂Cl ₂(3x) extract.The organic extraction that merges is used saturated NaHCO ₃Solution washing is through MgSO ₄Dry also vacuum concentration.Flash chromatography (5 → 40%EtOAc/Hex) obtain title compound (730mg, 50%): ¹H NMR (CDCl ₃400MHz) δ 7.72 (dd, J=8.8,1.5Hz, 2H), 7.52 (dd, J=8.8,1.5Hz, 2H), 7.02 (m, 1H); 6.38 (m, 1H), 4.90 (dd, J=11.7,2.2Hz, 1H), 4.33 (d, J=12.4Hz, 1H), 4.28 (s; 1H), 3.85 (m, 1H), 3.73-3.64 (m, 2H), 2.76 (m, 1H), 1.91 (brs, 1H); 1.71-1.22 (m, 6H), 0.80 (s, 4.5H), 0.79 (s, 4.5H), 0.03 (s, 3H) ,-0.04 (s, 3H).

Step 7:

Tert-butyl-[11a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,6a, 7,8,9,10,11,11a-hydrogen-cyclohepta [c] chromene-9-base oxygen base]-dimethyl--silane

In 0 ℃, with 3-(tert-butyl-dimethyl--silicon alkoxyl group)-5-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-yl]-penta-1-alcohol (730mg, CH 1.30mmol) ₂Cl ₂(10mL) solution is used Et ₃(360 μ L 2.6mmol) handle N, and then (150 μ L 1.95mmol) handle with MsCl.After 30 minutes, use saturated NH ₄Cl aqueous solution quencher reaction mixture is also used CH ₂Cl ₂(2x) extract.The organic extraction that merges is used saturated NaHCO ₃Solution washing is through MgSO ₄Dry also vacuum concentration obtains crude product.Make residue be dissolved in THF (13mL), also (1M is in THF, and 3.0mL 3.0mmol) handles with KOt-Bu to be cooled to 0 ℃.After 1 hour, use saturated NH ₄Cl aqueous solution quencher reaction mixture extracts (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration obtains title compound (700mg, 99%, 2 steps of warp): ¹HNMR (CDCl ₃400MHz) δ 7.63 (dd, J=8.8,1.5Hz, 2H), 7.49 (dd, J=8.8,1.5Hz, 2H), 7.04 (m, 1H); 6.43 (m, 1H), 5.07 (dd, J=10.9,2.2Hz, 1H), 4.23 (m, 1H), 4.04 (m; 0.5H), 3.58 (m, 0.5H), 2.97 (m, 1H), 2.71-2.26 (m, 2H), 2.10 (m, 1H); 1.83-1.43 (m, 5H), 0.90 (s, 4.5H), 0.77 (s, 4.5H), 0.03 (s, 3H) ,-0.01 (s, 3H).

Step 8:

11a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,6a, 7,8,9,10,11,11a-hydrogen-cyclohepta [c] chromene-9-alcohol

In 0 ℃, with tert-butyl-[11a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,6a; 7,8,9; 10,11,11a-octahydro-cyclohepta [c] chromene-9-base oxygen base]-dimethyl--silane (700mg; 1.30mmol) THF (10mL) solution (1M is in THF, and 2.6mL 2.6mmol) handles and be warmed to room temperature with TBAF.After 12 hours, use saturated NH ₄Cl aqueous solution quencher reaction mixture also extracts (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (2 → 20%EtOAc/CH ₂Cl ₂) obtain embodiment 344A1 (200mg, Rf=0.49,10%EtOAc/CH ₂Cl ₂): ¹H NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 2H), 7.04 (m, 1H), 6.40 (m; 1H), 5.13 (dd, J=11.7,2.2Hz, 1H), 4.26 (dd, J=11.0,2.2Hz, 1H); 4.14 (m, 1H), 2.85 (d, J=6.6Hz, 1H), 2.52 (ddd, J=14.6,10.3; 2.2Hz, 1H), 2.34 (m, 1H), 2.22 (m, 1H), 1.87-1.62 (m, 5H); Then be embodiment 344B1 (130mg, Rf=0.33,10%EtOAc/CH ₂Cl ₂): ¹H NMR (CDCl ₃400MHz) δ 7.64 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.04 (m, 1H); 6.40 (m, 1H), 5.13 (dd, J=11.0,2.2Hz, 1H), 4.26 (dd, J=11.7; 2.2Hz, 1H), 3.67 (m, 1H), 2.96 (m, 1H), 2.75 (m; 1H), 2.19 (m, 1H), 2.02 (m, 1H), 1.81-1.49 (m, 5H).

Embodiment 345

N-[11a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6,6a, 7,8,9,10,11,11a-octahydro-cyclohepta [c] chromene-9-yl]-C, C, C-three fluoro-Toluidrins

Step 1:

Make the solution experience of embodiment 344A be similar to the condition of describing among the embodiment 20, obtain embodiment 345A: ¹HNMR (CDCl ₃400MHz) δ 7.60 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.04 (m, 1H); 6.41 (m, 1H), 5.15 (dt, J=11.7,9.5,2.2Hz, 1H), 4.28 (dd; J=11.7,1.5Hz, 1H), 3.46 (m, 1H), 2.97 (d, J=10.2Hz, 1H); 2.34-2.28 (m, 2H), 2.09-1.91 (m, 2H), 1.81 (m, 1H), 1.66-1.52 (m, 2H).

Use is similar to those methods among the embodiment 345, replaces suitable isocyanic ester, acyl group or alkylsulfonyl halogenide, the compound in the preparation table 75.

Table 75

Embodiment 354:

11a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,10,11,11a-six hydrogen-6H-5,9-dioxa-cyclohepta [a] naphthalene

Step 1:

3-(2-allyl group oxygen base-ethyl)-4-(4-chloro-benzenesulfonyl)-5,8-two chloro-chromans

In 0 ℃, with the product that derives from embodiment 27 steps 5 (268mg, THF 0.692mmol) (7mL) solution with 60%NaH (30mg, 0.76mmol) and allyl iodide (76 μ L 0.83mmol) handle and are warmed to room temperature.After 12 hours, this reaction mixture is heated to 60 ℃.After other 6 hours, make this reaction mixture be cooled to room temperature, use saturated NH ₄The quencher of the Cl aqueous solution is also extracted (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (5 → 30%EtOAc/Hex) obtain title compound (200mg, 67%): ¹H NMR (CDCl ₃400MHz) δ 7.74 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.02 (m, 1H), 6.44 (m; 1H), 5.80 (m, 1H), 5.23-5.18 (m, 2H), 4.94 (dd, J=11.7,2.9Hz, 1H); 4.57 (s, 1H), 4.33 (d, J=11.7Hz, 1H), 4.88-4.83 (m, 2H), 3.50-3.35 (m; 2H), 2.96 (t, J=6.6Hz, 1H), 1.68 (m, 1H), 1.50 (m, 1H).

Step 2:

Make 3-(2-allyl group oxygen base-ethyl)-4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman solution experience is similar to the condition of describing in embodiment 345 steps 6 and 7, obtains embodiment 354: ¹H NMR (CDCl ₃400MHz) 7.57 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.06 (m, 1H), 6.44 (m; 1H), 5.15 (dd, J=11.7,2.9Hz, 1H), 4.25 (dd, J=11.7,2.2Hz, 1H); 3.99-3.90 (m, 2H), 3.82 (dd, J=13.1,8.1Hz, 1H), 3.66 (m, 1H); 3.21 (m, 1H), 2.96 (m, 1H), 2.40 (m, 1H), 1.95-1.85 (m, 2H).

Embodiment 355 ((+)-isomer):

Acetate 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base ester

With cis-10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7; 8,9,10; 10a-six hydrogen-6H-benzo [c] chromene-8-alcohol (embodiment 18B) (50mg, pyridine 0.121mmol) (1mL) solution with Acetyl Chloride 98Min. (40 μ L, 0.54mmol), DMAP (10mg) handles and be heated to 80 ℃.After 12 hours, make this reaction mixture be cooled to room temperature and dilute with EtOAc.Organic layer is with 1N HCl, saturated NaHSO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Preparation type thin-layer chromatography (25%EtOAc/Hex) obtains title compound (embodiment 355) (24.9mg, 45%): ¹H NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.1Hz, 2H), 7.50 (d, J=8.1Hz, 2H), 7.05 (m, 1H); 6.41 (m, 1H), 5.28 (dd, J=11.7,2.9Hz, 1H), 4.96 (m, 1H); 4.12 (m, 1H), 3.02 (m, 1H), 2.41-2.37 (m, 2H), 2.11 (s; 3H), 1.97-1.85 (m, 2H), 1.67 (m, 1H), 1.31 (m, 1H).

Use is similar to those methods among the embodiment 355, replaces suitable acyl halide, the compound in the preparation table 76.

Table 76

Embodiment 358A:

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-8-methoxyl group-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene

In 0 ℃, with cis-10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a; 7,8,9; 10, and 10a-six hydrogen-6H-benzo [c] chromene-8-alcohol (embodiment 18B) (75mg, THF 0.180mmol) (1mL) solution is with 15-hat-5 (60 μ L; 0.30mmol) and NaH (60% in oil, and 12mg 0.27mmol) handles.After 30 minutes, (20 μ L 0.32mmol), make this reaction mixture be warmed to room temperature to add MeI.1.5 after hour, reaction mixture is through preparation type thin-layer chromatography (25%EtOAc/Hex) direct purification, obtain title compound (embodiment (-)-358A) (56.5mg, 73%): ¹H NMR (CDCl ₃400 MHz) δ δ 7.60 (d, J=8.8Hz, 2H), 7.49 (d, J=8.1Hz, 2H), 7.05 (m, 1H); 6.41 (m, 1H), 5.21 (dd, J=11.7,2.9Hz, 1H), 4.09 (d, J=11.7Hz; 1H), 3.40 (m, 1H), 3.31 (s, 3H), 3.00 (d, J=13.2Hz, 1H); 2.41-2.26 (m, 2H), 1.99-1.87 (m, 2H), 1.45 (m, 1H), 1.15 (m, 1H).

Use is similar to those methods among the embodiment (-)-358, replaces suitable alkyl halide, the compound in the preparation table 77.

Table 77

Embodiment 362:

N-{2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base oxygen base]-ethyl }-C, C, C-three fluoro-Toluidrins

Step 1:

8-allyl group Oxy-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene

With cis-10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8; 9,10,10a-six hydrogen-6H-benzo [c] chromene-8-alcohol (embodiment 18B) (1.00g; 2.41mmol) THF (20mL) solution (0.80mL is 4.00mmol) with 60%NaH (150mg, 3.80mmol) processing with 15-hat-5.After 20 minutes, (460 μ L 5.00mmol), are heated to backflow with this reaction mixture to add allyl iodide.After 18 hours, make this reaction mixture be cooled to room temperature, extract (2x) with 1N HCl quencher and with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (2 → 20%EtOAc/Hex) obtain title compound (990mg, 90%): ¹H NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.06 (m, 1H), 6.40 (m; 1H), 5.90 (m, 1H), 5.27-5.22 (m, 2H), 5.15 (d, J=10.2Hz, 1H), 4.12 (d; J=11.0Hz, 1H), 3.99-3.92 (m, 2H), 3.55 (m, 1H), 3.01 (m, 1H); 2.41-2.34 (m, 2H), 1.96-1.86 (m, 2H), 1.50 (m, 1H), 1.13 (m, 1H).

Step 2:

2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base oxygen base 7-ethanol

In-78 ℃, with 8-allyl group Oxy-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene (1.55g, 1:1MeOH/CH 3.41mmol) ₂Cl ₂(30mL) solution is used O ₃Purge is constant until blueness.Disappear until blueness with the purging with nitrogen gas reaction mixture then, add NaBH ₄(0.39g 10.2mmol), makes this reaction mixture slowly be warmed to room temperature.After 18 hours, use saturated NH ₄Cl aqueous solution quencher reaction mixture and vacuum concentration.The residue dilute with water is also used CH ₂Cl ₂(3x) extract.The organic extraction that merges is used saturated NaHCO ₃Solution washing is through MgSO ₄Dry also vacuum concentration obtains title compound (1.46g, 93%): ¹H NMR (CDCl ₃400MHz) δ 7.60 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.06 (m, 1H), 6.41 (m; 1H), 5.23 (dd, J=11.7,3.7Hz, 1H), 4.13 (d, J=11.7Hz, 1H), 3.76 (t; J=5.1Hz, 2H), 3.56-3.50 (m, 3H), 2.99 (m, 1H), 2.40-2.30 (m, 2H); 1.96-1.84 (m, 2H), 1.60 (brs, 1H), 1.54 (m, 1H), 1.16 (m, 1H).

Step 3:

Methanesulfonic 2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo (c] chromene-8-base oxygen base]-ethyl ester

In 0 ℃, with 2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base oxygen base]-ethanol (1.09g, CH 2.54mmol) ₂Cl ₂(25mL) solution is used Et ₃N (0.37mL) and MsCl (0.65mL) handle, and make this reaction mixture slowly be warming up to room temperature.After 14 hours, use saturated NH ₄Cl aqueous solution quencher reaction mixture also extracts (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃Solution washing is through MgSO ₄Dry also vacuum concentration obtains title compound (1.24g, 97%): ¹H NMR (CDCl ₃400MHz) δ 7.58 (d, J=8.1Hz, 2H), 7.47 (d, J=8.1Hz, 2H), 7.07 (m, 1H), 6.40 (m, 1H); 5.23 (dd, J=2.9,11.7Hz, 1H), 4.37 (dd, J=3.7,4.4Hz, 2H), 4.11 (d, J=11.7Hz; 1H), 3.72 (m, 2H), 3.58 (m, 1H), 3.13 (s, 1H), 3.01 (m, 1H), 2.40 (m; 2H), 1.87 (m, 2H), 1.56 (ddd, J=1.6,14.7,14.7Hz, 1H), 1.14 (m, 1H).

Step 4:

8-(2-azido--oxyethyl group)-10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene

[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base oxygen base]-(180mg, DMF 0.355mmol) (5mL) solution is used NaN to ethyl ester with methanesulfonic 2- ₃(46mg 0.707mmol) handles, this reaction mixture is heated to 80 ℃, 16 hours after, make this reaction mixture be cooled to room temperature and use saturated NH ₄The Cl aqueous solution dilutes and extracts (2x) with EtOAc.The organic extraction that merges is used H ₂O, saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration obtains title compound (153mg, 95%): ¹H NMR (CDCl ₃400MHz) δ 7.63 (d, J=8.1Hz, 2H), 7.49 (d, J=7.3Hz, 2H), 7.07 (m, 1H); 6.42 (m, 1H), 5.25 (dd, J=2.9,11.7Hz, 1H), 4.12 (d, J=11.7Hz); 3.60 (m, 2H), 3.36 (m, 2H), 3.02 (m, 1H), 2.37 (m; 2H), 1.94 (m, 2H), 1.56 (m, 2H), 1.16 (m, 2H).

Step 5:

2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base oxygen base]-ethylamine

With 8-(2-azido--oxyethyl group)-10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-(110mg is 0.242mmol) at 4:1THF/H for 6H-benzo [c] chromene ₂Solution among the O (5mL) is used Ph ₃(127mg 0.484mmol) handles and with reaction mass heated to 60 ℃ P.After 16 hours, make this reaction mixture be cooled to room temperature and vacuum concentration to remove THF.Reaction mixture is used saturated NH ₄The dilution of the Cl aqueous solution is also used CH ₂Cl ₂(3x) extract.The organic extraction that merges is through MgSO ₄Dry also vacuum concentration.Flash chromatography (10%MeOH/CH ₂Cl ₂) obtain title compound (52mg, 52%): ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.06 (m, 1H), 6.43 (m; 1H), 5.22 (dd, J=10.9,2.9Hz, 1H), 4.11 (d, J=11.7Hz, 1H), 3.51 (m; 1H), 3.41 (m, 2H), 2.98 (m, 1H), 2.88 (brs, 2H); 2.39 (m, 2H), 1.94 (m, 2H), 1.49 (m, 3H), 1.13 (m, 1H).

Step 6:

In-78 ℃, with 2-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base oxygen base]-ethylamine (71mg, CH 0.168mmol) ₂Cl ₂(5mL) solution is with 2, and the 6-lutidine (33 μ L, o.284mmol), Tf ₂(45 μ L 0.948mmol) handle, and slowly are warming up to room temperature O.After 17 hours, use saturated NH ₄Cl aqueous solution diluted reaction mixture is also used CH ₂Cl ₂(2x) extract.The organic extraction that merges is used saturated NaHCO ₃Solution washing is through MgSO ₄Dry also vacuum concentration.Residue obtains title compound (29mg, 30%) through preparation of silica gel type chromatography purification (with hexane/EtOAc1:1 wash-out): ¹H NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.08 (m, 1H); 6.44 (m, 1H), 5.22 (dd, J=11.7,2.9Hz, 1H), 4.12 (d, J=11.7Hz; 1H), 3.57 (m, 3H), 3.01 (m, 1H), 2.56 (m, 1H), 2.33 (m; 1H), 1.91 (m, 2H), 1.56 (m, 1H), 1.15 (m, 2H).

Use is similar to those methods among the embodiment 362, replaces suitable acyl halide, isocyanic ester or alkylsulfonyl halogenide, the compound in the preparation table 78.

Table 78

Embodiment 368 (A and B):

Cis and anti-form-1-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzene [c] chromene-8-alkylsulfonyl]-tetramethyleneimine

Step 1:

Thioacetic acid S-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl] ester

In 0 ℃, with anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a; 7,8,9; 10, and 10a-six hydrogen-6H-benzo [c] chromene-8-alcohol (embodiment 18A) (750mg, 1.81mmol) solution is with Et3N (750 μ L; 5.40mmol), MsCl (560 μ L, 7.20 mmol) handles and is warmed to room temperature.1.5 after hour, use saturated NH ₄Cl aqueous solution quencher reaction mixture also extracts (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃Solution washing is through MgSO ₄Dry also vacuum concentration obtains crude product.Make residue be dissolved in DMF (15mL), (270mg 2.30mmol) handles and is heated to 120 ℃ with KSAc.After 3 hours, make this reaction mixture be cooled to room temperature, with the quencher of the saturated NH4Cl aqueous solution, and with EtOAc extraction (2x).The organic extraction that merges is used H ₂O (3x), saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (2 → 20%EtOAc/Hex) obtain title compound (420mg, 61%, 2 steps of warp): ¹H NMR (CDCl ₃400MHz) δ 7.58 (d, J=8.1Hz, 2H), 7.49 (d, J=8.1Hz, 2H), 7.07 (m, 1H); 6.41 (m, 1H), 5.21 (dd, J=11.7,2.9Hz, 1H), 4.10 (d, J=10.3Hz; 1H), 3.88 (m, 1H), 2.83 (m, 1H), 2.50 (d, J=14.6Hz, 1H); 2.35 (s, 3H), 2.18 (m, 1H), 1.92-1.77 (m, 3H), 1.53 (m, 1H).

Step 2:

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-mercaptan)

(420mg, MeOH 0.888mmol) (8mL) solution then handle with THF (3mL) with 1N NaOH (2mL) with thioacetic acid S-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl] ester.After 4 hours, the vacuum concentration reaction mixture extracts (2x) with 1N HCl dilution and with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration.Flash chromatography (2 → 20%EtOAc/Hex) obtain the disulphide (133mg, 17%) of title compound: ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, J=8.8Hz, 4H), 7.51 (d, J=8.8Hz, 4H), 7.07 (m; 2H), 641 (m, 2H), 5.24 (dd, J=11.0,2.9Hz, 2H); 4.11 (d, J=11.0Hz, 2H), 3.48 (m, 2H), 3.14 (d, J=13.2Hz; 2H), 2.55 (m, 2H), 2.42 (m, 2H), 1.92-1.52 (m, 8H); Then obtain title compound (169mg, 44%): ¹H NMR (CDCl ₃400MHz) δ 7.60 (dd, J=8.8,1.5Hz, 2H), 7.48 (dd, J=8.8,1.5Hz, 2H); 7.08 (m, 1H), 6.42 (m, 1H), 5.25 (dd, J=11.7,2.2Hz, 1H); 4.11 (d, J=11.0Hz, 1H), 3.11 (m, 1H), 2.95 (d, J=12.5Hz; 1H), 2.40-2.38 (m, 2H), 2.04-1.82 (m, 3H), 1.49 (m, 1H).

Through following method, the disulphide of title compound is converted into title compound:

(380mg, THF 0.44mmol) (3mL) solution is used NaBH with the disulphide of title compound ₄(50 mg 1.30mmol) handle and are heated to 60 ℃.After 4 hours, make this reaction mixture be cooled to room temperature,, use Et with 1N HCl quencher ₂O (2x) extracts.The organic extraction that merges is through MgSO ₄Dry also vacuum concentration.(2 → 20%EtOAc/Hex) obtain title compound (370mg, 98%) to flash chromatography.

Step 3:

10a-(4-chloro-benzenesulfonyl)-1,4-difluoro 6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-SULPHURYL CHLORIDE

In-10 ℃, with 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-mercaptan (370mg, CH 0.860mmol) ₃CN (30mL) solution is used KNO ₃(191mg 1.89mmol) handles, and then is added dropwise to SO ₂Cl ₂(152 μ L 1.89mmol) handle.After 3 hours, reaction mixture is used saturated NaHCO ₃Aqueous solution quencher is also extracted (2x) with EtOAc.The organic extraction that merges is used saturated NaHCO ₃The aqueous solution, brine wash are through MgSO ₄Dry also vacuum concentration obtains title compound (380mg, 89%): ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.11 (m, 1H), 6.48 (m; 1H), 5.24 (dd, J=11.7,2.9Hz, 1H), 4.22 (d, J=11.7 Hz, 1H), 3.80 (m; 1H), 3.17 (d, J=12.4Hz, 1H), 2.64-2.48 (m, 5H), 1.67 (m, 1H).

Step 4:

Cis and anti-form-1-[10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-alkylsulfonyl]-tetramethyleneimine

With 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-SULPHURYL CHLORIDE (50mg, CH 0.10mmol) ₂Cl ₂(1.0mL) solution is used Et ₃(30 μ L, 0.20mmol), then (20 μ L 0.24mmol) handle N with tetramethyleneimine.After 12 hours, use saturated NH ₄Cl aqueous solution quencher reaction mixture is also used CH ₂Cl ₂(2x) extract.The organic extraction that merges is through MgSO ₄Dry also vacuum concentration.Preparation type thin-layer chromatography (33%EtOAc/Hex) obtains embodiment 368A (7.1mg, 13%): ¹H NMR (CDCl ₃400MHz) δ 7.63 (dd, J=8.8,2.2Hz, 2H), 7.50 (dd, J=8.8,2.2Hz, 2H), 7.10 (m, 1H); 6.46 (m, 1H), 5.22 (dd, J=11.7,2.9Hz, 1H), 4.17 (d, J=11.7Hz, 1H), 3.39-3.35 (m; 4H), 3.27 (d, J=12.4Hz, 1H), 3.12 (m, 1H), 2.71 (m, 1H), 2.46 (m; 1H), 2.31-2.27 (m, 2H), 1.96-1.93 (m, 4H), 1.82 (m, 1H), 1.50 (m, 1H); Then obtain embodiment 368B (12.0mg, 22%): ¹H NMR (CDCl ₃400MHz) δ 7.56 (dd, J=8.8,2.2Hz, 2H), 7.50 (dd, J=8.8,2.2Hz, 2H), 7.10 (m; 1H), 6.42 (m, 1H), 5.24 (dd, J=11.7,2.9Hz, 1H), 4.20 (d; J=11.7Hz, 1H), 3.34-3.30 (m, 4H), 3.13 (m, 1H), 2.78-2.74 (m, 2H); 2.13-2.02 (m, 3H), 1.90-1.87 (m, 4H), 1.78 (m, 1H), 1.38 (m, 1H).

Use is similar to those methods among the embodiment 368, replaces suitable amine, the compound in the preparation table 79.

Table 79

Embodiment 374:

8-amino methyl--10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base amine

With anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-tetrahydrochysene-6H, (2.50g is 6.06mmol) at dense NH for 7H-benzo [c] chromene-8-ketone (as at embodiment 17, described in the step 7) ₄OH/MeOH (1:1, the solution in 40mL) with KCN (0.51g, 7.9mmol) and NH ₄(0.42g 7.9mmol) handles Cl.After 12 hours, the vacuum concentration reaction mixture is used H ₂The O dilution is also used CH ₂Cl ₂(4x) extract.The organic extraction that merges is through MgSO ₄Dry also vacuum concentration.Make the bullion reaction mixture be dissolved in THF (20mL) and be added dropwise to LAH in 0 ℃ (0.41g is 10.9mmol) in the suspension-s in THF (40mL).After 1 hour, reaction mixture adds H through order ₂O (400 μ L), 1N NaOH (800 μ L), H ₂O (800 μ L) quencher, and stirred 15 minutes.Filtering suspension liquid is used CH ₂Cl ₂Washing, vacuum concentrated filtrate.Flash chromatography (1% → 15%NH ₄OH/MeOH (1:9), CH ₂Cl ₂) obtain embodiment 374 (950mg, 35%, through 2 the step): ¹HNMR (CDCl ₃400MHz) δ 7.54 (d, J=8.8Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 7.05 (m, 1H), 6.38 (m, 1H), 5.17 (dd; J=11.7,2.9Hz, 1H), 4.10 (d, J=11.0Hz, 1H), 2.80 (d, J=12.4Hz, 1H), 2.70 (m, 1H); 2.69 (d, J=12.4Hz, 1H), 2.40 (m, 1H), 2.04 (m, 1H), 1.77-1.68 (m, 2H), 1.34 (dd; J=13.9,13.2Hz, 1H), 1.13 (brs, 4H), 0.95 (ddd, J=13.9,13.9,2.9Hz, 1H).

Embodiment 375:

In 0 ℃, with 8-aminomethyl-1,2 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base amine (embodiment 374) (50mg, CH 0.113mmol) ₂Cl ₂(1mL) solution is used Et ₃N (31 μ L, 0.22mmol), (20 μ L 0.14mmol) handle, and are warmed to room temperature the cyclopropyl SULPHURYL CHLORIDE.After 12 hours, reaction mixture is used saturated NaHCO ₃CH is used in aqueous solution dilution ₂Cl ₂(2x) extract.The organic extraction that merges is through MgSO ₄Dry also vacuum concentration.Preparation type thin-layer chromatography (5%NH ₄OH/MeOH (1:9), 95%CH ₂Cl ₂) obtain embodiment 375 (8.4mg, 14%): ¹H NMR (CDCl ₃400MHz) δ 7.59 (d, J=8.1Hz, 2H), 7.48 (d, J=8.1Hz, 2H), 7.09 (m, 1H), 6.43 (m, 1H); 5.21 (dd, J=11.7,2.2Hz, 1H), 5.01 (brs, 1H), 4.12 (d, J=11.7Hz, 1H), 3.19 (d; J=13.2Hz, 1H), 3.15 (d, J=12.4Hz, 1H), 2.78 (d, J=12.4Hz, 1H), 2.55 (m, 1H); 2.42 (m, 1H), 2.10 (m, 1H), 1.86-1.79 (m, 2H), 1.45-1.18 (m, 6H), 1.04-1.00 (m, 2H).

Embodiment 376 ((-)-376 and (+)-376):

10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-alcohol.

Racemic mixture according to the method among the embodiment 20 preparation can use Chiral OD post, as solvent, and is separated into two pure enantiomorphs with hexane/isopropyl alcohol (75/25).

First flow point ((-)-isomer): [α]=-162.3deg. (c=1.095 is in DCM).

And individual flow point ((+)-isomer): [α]=137.deg. (c=0.95 is in DCM).

, and use and be similar to those methods among the embodiment 20 as starting raw material with (-)-isomer of embodiment 376, replace suitable acyl group or alkylsulfonyl halogenide, the compound in the preparation table 80.

Table 80

Embodiment 380:

Step 1

Carbonochloridic acid 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base ester

Make 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-(0.46g 1.11mmole) is dissolved in 30ml DCM to 8-alcohol.(20%in toluene 4ml) and pyridine (1ml), stirred this reactant 10 minutes under room temperature to add phosgene.Add 20mlDCM, slowly add 10ml water quencher reaction.Organic layer is with 50ml1N HCl solution washing, through dried over sodium sulfate.Remove desolvate after, through the column chromatography purification residue, with the EtOAc/ hexane as solvent (from the gradient of 0/100-25/75 25 minutes).Must measure: 0.37g, 70%. ¹H NMR (CDCl ₃400MHz) δ 7.62 (d, 2H, J=8.8Hz), 7.50 (d, 2H, J=8.8Hz), 7.06-7.13 (m, 1H); 6.40-6.47 (m, 1H), 5.28 (dd, 1H, J=11.7 and 2.9Hz), 5.05 (s, 1H); 4.14 (d, 1H, J=11.7Hz), 3.02 (dt, J=13.2 and 2.9Hz, 1H), 2.31-2.49 (m; 2H), and 2.01-2.16 (m, 2H), 1.66-1.75 (m, 1H), 1.30-1.40 (m, 1H).

Step 2

(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-hydroxyl-1-pyrroline carboxylicesters (racemic).

Make carbonochloridic acid 10a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-base ester (40mg) is dissolved in 5ml DCM.Add 2 (R)-hydroxyl pyrrolines (40ul) and diisopropylethylamine (50ul), this reactant was stirred under room temperature 1 hour.Add 20ml DCM, with 50ml saturated sodium carbonate solution washing reaction thing, through dried over sodium sulfate and concentrated.Residue is through column chromatography purification, with the EtOAc/ hexane as solvent (from the gradient of 25/75-100/0 25 minutes).Must measure: 42mg, 95%. ¹H?NMR(CDCl ₃400MHz)δ7.60(m，2H)，7.49(m，2H)，7.03-7.11(m，1H)，6.37-6.46(m，1H)，5.21-5-28(m，1H)，4.87(s，1H，)，4.49(d，J＝15.3Hz，1H)，4.10(m，1H)，3.33-3.55(m，4H)，2.89(dJ＝12.4Hz，1H)，2.48(m，2H)，2.32(m，1H)，1.95(m，3H)，1.61(m，1H)，1.26(m，1H)。

Use is similar to those methods among the embodiment 380, replaces suitable amine, the compound in the preparation table 81.

Table 81

Embodiment 387:

N-[[(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-yl] Toluidrin (racemic)

Step 1

(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-nitrile (racemic)

Make anti-form-1 0a-(4-chloro-benzenesulfonyl)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-(1.3g 3.1mmole) is dissolved in 10ml DCM to 8-alcohol.Add methylsulfonyl chloride (0.53g, 4.7mmole) and triethylamine (1ml).This reactant was stirred under room temperature 10 minutes.Add 100ml salt solution and 50ml DCM.Organic layer is with 1N HCl solution (50ml), water (50ml), salt solution (50ml) washing, through Na ₂SO ₄Dry and concentrated.Make residue be dissolved in 50ml toluene.Adding tetrabutyl ammonium cyanide (1.6g, 6.1mmole).Reaction mass heated to 80 ℃ is spent the night.Make reactant be cooled to room temperature and add 100ml EtOAc.Organic layer is with brine wash (2x100ml), through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (EtOAc/ hexane, from the gradient of 0/100-50/50 35 minutes).Must measure: 0.70g, 53%. ¹H NMR (CDCl ₃400MHz δ 7.64 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.06-7.13 (m, 1H); 6.42-6.49 (m, 1H), 5.29 (dd, J=11.7 and 2.9Hz, 1H), 4.17 (d, J=11.7Hz, 1H); 2.94-3.02 (m, 2H), 2.62 (d, J=13.9Hz, 1H), 2.34 (tt, J=13.8 and 2.9Hz; 1H), and 1.94-2.09 (m, 2H), 1.66-1.75 (m, 1H), 1.30-1.40 (m, 1H).

Step 2

(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-difluoro 6a, 7,8,9,10,10a-six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-Ji-aminomethane (racemic)

Make (6aR)-10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10, (0.34g 0.80mmole) is dissolved in 50mlTHF to 10a-six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-nitrile, and reactant is cooled to 0 ℃.(1M in ether 1.6ml), stirred this reactant 1 hour under room temperature to add LAH.Add 100ml1N NaOH solution and 100ml EtOAc.Organic layer is with brine wash (2x100ml), through dried over sodium sulfate and concentrated.Residue is through column chromatography purification (among the EtOAc/2.5N NH3 MeOH, from 100/0-80/20.Through 35 minutes).Must measure: 0.24g, 70%. ¹HNMR (CDCl ₃400MHz δ 7.57 (d, J=8.8Hz, 2H), 7.47 (d, J=8.8Hz, 2H), 7.02-7.09 (m; 1H), 6.35-6.43 (m, 1H), 5.19 (dd, J=11.7 and 2.9Hz, 1H), 4.10 (d; J=11.7 Hz, 1H), 2.70-2.85 (m, 3H), 2.33 (tt, J=13.2 and 2.9Hz, 1H); 2.08 (m, 1H), 1.58-1.80 (m, 4H), 1.20-1.30 (m, 1H).

Step 3

N-[[(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-

Six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-yl] Toluidrin (racemic)

Make (6aR)-10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10, (50mg 0.12mmole) is dissolved in 5mlDCM to 10a-six hydrogen-6h-dibenzo [b, d] pyrans-8 (R)-Ji-aminomethane, and methylsulfonyl chloride (50ul) adds triethylamine (30ul).This reactant was stirred under room temperature 2 o'clock.Add ml saturated sodium carbonate solution and 50ml EtOAc.Organic layer water (50ml), salt solution (50ml) wash through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (the EtOAc/ hexane is from/100-100/0, through 5 minutes).Obtain: 38mg, 64%. ¹HNMR (CDCl ₃400MHz δ 7.57 (d, J=8.8Hz, 2H), 7.47 (d, J=8.8Hz, 2H), 7.03-7.09 (m, 1H), 6.36-6.43 (m; 1H), 5.17 (dd, J=11.0 and 2.9Hz, 1H), 4.81 (t, J=6.6Hz, 1H) 4.09 (m, 1H), 3.22 (t; J=7.3,2H), 2.98 (s, 3H), 2.75 (d, J=12.5Hz, 1H), 2.36 (d, J=13.9Hz; 1H), 2.08 (t, J=13.9Hz, 1H), 1.59-1.90 (m, 4H), 1.20-1.30 (m, 1H).

Use is similar to those methods among the embodiment 387, replaces suitable acyl group or alkylsulfonyl halogenide, the compound in the preparation table 82.

Table 82

Embodiment 395:

Step 1:

[3-benzyloxy-1 (R)-cyano methyl-propyl group]-carboxylamine tert-butyl ester

(7.4g 25mmole) is dissolved in 100ml DCM to make (3-benzyloxy-1-hydroxymethyl-propyl group)-carboxylamine tert-butyl ester.Add methylsulfonyl chloride (4.3g, 37.5mmole) and triethylamine (5.0g, 50mmole).This reactant was stirred under room temperature 20 minutes.Add 100ml DCM and 100ml water.Organic layer is with brine wash (100ml), through dried over sodium sulfate and concentrated.Residue is dissolved in 200ml toluene.Adding cyaniding four ammoniums (10g, 37.5mmole), with this reactant stirred overnight under room temperature.Organic layer water (2x100ml), salt solution (100ml) washing are through dried over sodium sulfate and concentrated.Residue is through column chromatography purification (the EtOAc/ hexane is from 100/0-30/70, through 45 minutes).Obtain 6.4g, 84%. ¹H?NMR(CDCl ₃400?MHzδ7.29-7.38(m，5H)，5.20(d，J＝5.9Hz，1H)，4.50(m，2H)，3.91(m，1H)，3.54-3.66(m，2H)，2.60-2.77(m，2H)，1.89-1.99(m，2H)，1.44(s，9H)。

Step 2:

5-benzyloxy-3 (R)-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base is amino]-pentane nitrile

(6.4g 21mmole) is dissolved in 20ml DCM to make [3-benzyloxy-1 (R)-cyano methyl-propyl group]-carboxylamine tert-butyl ester.Add 4N HCl in dioxane (20ml), this reactant was stirred under room temperature 1 hour.Remove and to desolvate, make residue be dissolved in 200ml THF and add 4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-2H-chromenes.Add diisopropylethylamine (10ml),, refluxed then 5 hours this reactant stirred overnight under room temperature.Make reactant be cooled to room temperature, add 100ml EtOAc.Organic layer is with brine wash (100ml), through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (the EtOAc/ hexane is from 100/0-30/70, through 45 minutes).6.0g, 58%, it is the mixture of two diastereomers.

Step 3:

3-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base-(R)-amino]-5-hydroxyl-pentane nitrile.

Make that 5-benzyloxy-3 (R)-[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base is amino]-(0.9g 1.64mmole) is dissolved in 20ml DCM to the pentane nitrile, and this reactant is cooled to-78 ℃.(1M 8.2ml), stirs this reactant 30 minutes in hexane to add boron trichloride then.Through adding the saturated NaHCO of 50ml ₃Solution quencher reaction adds 100mlDCM.Organic layer is with brine wash (100ml), through dried over sodium sulfate and concentrated.Residue is through column chromatography purification (the EtOAc/ hexane is from 0/100-75/25, through 40 minutes).Must measure: 0.64g, 88%.It is the mixture of diastereomer.

Step 4:

(4aR)-and 10bR-[(4-chlorophenyl alkylsulfonyl)-7,10-two fluoro-1,3,4,4a, 5,10b-six hydrogen-2H-[1] chromene is [3,4-b] pyridines-3 (S)-acetonitrile also

[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-base-(R)-amino]-(1.7g 3.7mmole) is dissolved in 50ml DCM to 5-hydroxyl-pentane nitrile to make 3-.Add methylsulfonyl chloride (1ml) and triethylamine (2ml).This reactant was stirred under room temperature 5 minutes.Add 500mlDCM and 50ml water.Organic layer is with 1N HCl solution (2x100ml), salt solution (100ml) washing, through dried over sodium sulfate and concentrated.Make residue be dissolved in the anhydrous THF of 100ml and add KOt-Bu (1M is in t-BuOH, 4.5ml).This reactant was stirred under room temperature 10 minutes.Add 100ml EtOAc.Organic layer is with brine wash (2x100ml), through Na ₂SO ₄Dry and concentrated.Residue is through column chromatography purification (the EtOAc/ hexane is from 100/0-40/60, through 45 minutes).Must measure: 0.72g, 44% (the 0.51g trans-compound also separates from reactant). ¹H NMR (CDCl ₃400MHz δ 7.59 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.06-7.13 (m, 1H); 6.40-6.47 (m, 1H), 5.18 (dd, J=11.7 and 2.9Hz, 1H), 4.29 (dd, J=11.7 and 1.5Hz; 1H), 3.82 (d, J=7.3Hz, 1H), 3.36 (bs, 1H), 2.62-2.82 (m; 2H), 2.32-2.52 (m, 2H), 2.70-2.86 (m, 2H), 1.52 (m, 1H).

Step 5:

(4aR)-and 10bR-[(chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,3,4,4a, 5,10b-six hydrogen-2H-[1] chromene [3,4-b] pyridines 3 (S)-ethylamine (pure enantiomorph)

Make (4aR)-10bR-[(4-chlorophenyl alkylsulfonyl)-7,10-two fluoro-1,3,4; 4a, 5,10b-six hydrogen-2H-[1] chromene also [3; 4-b] (0.47g 1.1mmole) is dissolved in 100ml THF and add boron trichloride (2M is in THF, 5.4ml) to pyridine-3 (S)-acetonitrile.With reaction mass heated to 60 ℃ 3 hours.Make reactant be cooled to room temperature and be added dropwise to 100ml water and react with quencher.Add 100ml2N NaOH solution and 200ml EtOAc.Organic layer is with brine wash (100ml), through dried over sodium sulfate and concentrated.Make residue be dissolved in 100ml methyl alcohol.Add the ethereal solution of 10ml1N HCl, this reactant was stirred one hour under room temperature.Remove and desolvate, residue is allocated between 100ml1N NaOH solution and the 100ml EtOAc.Organic layer is with brine wash (100ml), through dried over sodium sulfate and concentrated.Product is through column chromatography purification (DCM/0.7N NH3 is in MeOH, from 0/100-50/50, through 45 minutes).Must measure: 0.40g, 84%. ¹H NMR (CDCl ₃400MHz δ 7.59 (d, J=8.8Hz, 2H), 7.47 (d, J=8.8Hz, 2H), 7.02-7.10 (m, 1H); 6.37-6.45 (m, 1H), 5.15 (dd, J=11.7 and 2.2Hz, 1H), 4.25 (dd, J=11.7 and 1.5Hz, 1H); 3.86 (s, 1H), 2.95-3.03 (m, 1H), 2.82 (t, J=5.8Hz, 2H), 2.38-2.45 (m; 2H), and 1.94-2.05 (m, 1H), 1.45-2.55 (m, 2H), 1.32-1.44 (m, 1H).

According to those methods that are similar to embodiment 395, the compound in the preparation table 83.

Table 83

Embodiment 403-410:

(wherein R specifies in table 84)

Step 1:

Trans-4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-formaldehyde

Make trans-[4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-yl]-methyl alcohol (embodiment 16 steps 2) (2.8g 8.8mmole) is dissolved in 15ml DCM, add then Dess-Martin reagent (4.1g, 9.7mmole).This reactant was stirred under room temperature 3 hours.Add 40ml EtOAc and 30ml saturated sodium thiosulfate solution.Organic layer washs with saturated sodium bicarbonate solution, through dried over sodium sulfate and concentrated.Residue need not be further purified and be used for next step).Must measure: 2.8g, 100%. ¹H NMR (CDCl ₃400MHz) δ 9.70 (s, 1H), 7.45 (d, J=8.8Hz, 2H), 7.34 (d, J=8.8Hz, 2H); 6.93-7.00 (m, 1H), 6.59-6.65 (m, 1H), 4.92 (dt, J=11.7 and 2.2Hz, 1H); 4.89 (br, 1H), 4.74 (dd, J=11.7 and 2.9Hz, 1H), 2.83 (m, 1H).

Step 2:

2-{ [4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-ylmethyl]-amino }-ethanol.

Make trans-4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-formaldehyde (2.2g, 5.9mmole) and thanomin (1.1g 18mmole) is dissolved in 20ml THF.With this reactant stirred overnight under room temperature.Add 2g Peng Qinghuana and 10ml MeOH, this reactant was stirred 3 hours.Add 100ml water and 100ml EtOAc.Organic layer is used water washing, through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 25/75-100/0, through 45 minutes).Obtain 0.40g, 17.5%. ¹H NMR (CDCl ₃400MHz) δ 7.45 (d, J=8.1Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 6.92-7.00 (m, 1H); 6.54-6.60 (m, 1H), 4.62 (dd, J=8.8 and 2.2Hz, 1H), 4.48 (br, 1H), 4.38 (dt; J=11.7 and 2.2Hz, 1H), 3.55 (t, J=5.1Hz, 2H), 2.67 (dd, J=12.4 and 7.3Hz, 1H); 2.62 (t, J=5.1Hz, 2H), 2.48 (dd, J=12.4 and 8.1Hz, 1H), 2.09 (m, 1H).

Step 3:

[4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-ylmethyl]-(2-hydroxyl-ethyl)-carboxylamine tert-butyl ester

Make 2-{ [4-(4-chloro-phenyl sulfenyl)-5,8-two fluoro-chroman-3-ylmethyl]-amino }-(0.4g 1.0mmole) is dissolved in 20ml DCM to ethanol, adds Boc ₂O (0.24g, 1.2mmole).This reactant was stirred under room temperature 3 hours.(77%, 0.8g 3.6mmole), stirred this reactant 2 hours under room temperature to add MCPBA then.Be added in the 2g Sulfothiorine in the 50ml water,, add 100ml EtOAc to extract product with the quencher reaction.Organic layer is with 1N NaOH solution (50ml), salt solution (50ml) washing, through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-50/50, through 45 minutes).Must measure: 0.44g, 85%. ¹H?NMR(CDCl ₃400MHz)δ7.71(d，J＝8.1Hz，2H)，7.49(d，J＝8.1Hz，2H)，6.98-7.05(m，1H)，6.36-6.44(m，1H)，4.90(d，J＝11.7Hz，1H)，4.40(br，1H)，4.28(d，J＝11.7Hz，1H)，3.70(br，2H)，3.15-3.40(m，5H)，1.26(s，9H)。

Step 4:

(4aR)-and 10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H-[1] chromene is [3,4-c] pyridines-3 (4H)-carboxylic acid 1 also, 1-dimethyl ethyl ester (racemic)

Make that [4-(4-chloro-benzenesulfonyl)-5,8-two fluoro-chroman-3-ylmethyl]-(0.44g 0.85mmole) is dissolved in 5ml DCM to (2-hydroxyl-ethyl)-carboxylamine tert-butyl ester.Add methylsulfonyl chloride (0.11g, 1.0mmole) and triethylamine (0.86g, 8.5mmole).This mixture was stirred under room temperature 2 hours.Add 50ml water and 50ml EtOAc.Organic layer water (50ml) salt solution (50ml) washing is through dried over sodium sulfate and concentrated.Make residue be dissolved in 5ml THF, and adding KOt-Bu (1M inTHF, 2ml).This mixture was stirred under room temperature 2 hours.Add 50ml water and 50ml EtOAc.Organic layer is with brine wash (50ml), through dried over sodium sulfate and concentrated.Product is through column chromatography purification (the EtOAc/ hexane is from 0/100-25/75, through 45 minutes).Must measure: 0.23g, 54%. ¹H NMR (CDCl ₃400MHz) δ 7.60 (d, J=8.8Hz, 2H), 7.50 (d, J=8.8Hz, 2H), 7.06-7.13 (m, 1H); 6.40-6.47 (m, 1H), 5.20 (dd, J=11.7 and 2.2Hz, 1H), 4.23 (d, J=11.7Hz; 1H), 4.10 (br, 2H), 2.76 (br, 2H), 2.57 (d, J=12.7Hz; 1H), 2.43 (br, 1H), 2.11 (m, 1H), 1.44 (s, 9H).

Step 5:

(4aR)-and 10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,3,4,4a, 5,10b-six hydrogen-2H-[1] chromene is [3,4-c] pyridines (racemic) also

Make (4aR)-10bS-[(4-chlorophenyl) alkylsulfonyl]-7,10-two fluoro-1,4a, 5,10b-tetrahydrochysene-2H-[1] chromene is [3,4-c] pyridines-3 (4H)-carboxylic acid 1 also, and (0.21g 0.42mmole) is dissolved in 20ml DCM and II5ml TFA to 1-dimethyl ethyl ester.This mixture was stirred one hour under room temperature.Add 100ml saturated sodium carbonate solution and 100ml EtOAc.Organic layer is with saturated sodium carbonate solution (50ml) washing, through dried over sodium sulfate and concentrated.Residue is recrystallization from the EtOAc/ hexane.Must measure: 0.16g, 100%. ¹H NMR (CDCl ₃400MHz) δ 7.61 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.05-7.12 (m, 1H); 6.39-6.46 (m, 1H), 5.18 (dd, J=11.7 and 2.2Hz, 1H), 4.26 (d, J=11.7Hz, 1H); 3.08 (d, J=9.5Hz, 1H), 301 (dt, J=13.2 and 2.9Hz, 1H), 2.58-2.73 (m; 3H), 2.35 (td, J=12.4 and 1.5Hz, 1H), 2.09 (dt, J=12.4 and 2.9Hz, 1H).

Use the method for describing among the embodiment 20, the product of step 5 is converted into the compound in the table 84.

Table 84

Embodiment 411:

The alternative route of compound 18B among the synthetic embodiment 18

Step 1

In-78 ℃, (2.0g slowly adds nBuLi (2.8mL, 6.9mmol, 2.5M hexane) in THF 6.2mmol) (30mL) solution to I.Stir after 15 minutes, (1.3g 7.0mmol), through 16 hours, makes this reaction mixture be warmed to room temperature gradually to disposable adding Eschenmoser salt.Reaction mixture is used saturated NH ₄The quencher of Cl solution is extracted with EtOAc.Organic phase is used brine wash, through Na ₂SO ₄Dry, filtration and concentrated.Residue obtains the 1.11g title compound through flash chromatography on silica gel purifying (with hexane/EtOAc75:25 wash-out). ¹HNMR(CDCl ₃?400MHz)δ7.68-7.65(m，2H)，7.48-7.44(m，2H)7.21-7.09(m，1H)，5.29(s，1H)，4.79(d，J＝4.2，4.2Hz，，1H)，3.44-3.33m，1H)，3.14-3.10，m，1H)，2.19(s，6H)。

Step 2

With the amine product that derives from step 1 (4.57g, 12.1mmol) solution, acetic anhydride (3.6mL, 38.0mmol) and toluene (40mL) reflux 2 hours.After being cooled to room temperature, concentrated reaction mixture, residue obtains the 2.57g title compound through quick silica gel column chromatography purifying (with hexane/EtOAc75:25 wash-out), is white solid. ¹H?NMR(CDCl ₃?400MHz)δ7.62(d，J＝6.6Hz，2H)，7.49(d，J＝6.3Hz，2H)7.10-7.04(m，1H)，6.93(s，1H)，6.83-6.72(m，1H)，6.10(s，1H)。

Step 3

With the olefin product that derives from step 2 (7.8g, 23.8mmol), (E)-1,4-two (t-butyldimethylsilyloxy base)-2,4-pentadiene [Frey, B.; Schnaubelt, J.; Hans-Ulrich, R.; Eur.J.0rg.Chem. 1999, (6), 1377-1384] and (3.95g is 11.9mmol) with the solution of o-YLENE (10mL) reflux 16 hours in ST.After being cooled to room temperature, concentrated solvent is dissolved in the ice-cooled solution of the DCM (140mL) of 1N HCl residue.This reaction mixture was kept 1 hour in 0 ℃, carefully be neutralized to PH8 with saturated NaHCO3 then.Separate each layer, extract water with DCM, the organic phase of merging is used brine wash, through Na ₂SO ₄Dry and concentrated.Residue obtains 1.26g isomer A and 1.08g isomer B through quick silica gel column chromatography purifying (with hexane/EtOAc75:25 wash-out).

Isomer A: ¹H NMR (CDCl ₃400MHz) δ 7.71-7.35 (m, 4H), 7.26-7.17 (m, 1H), 7.90-6.53 (m, 1H); 3.94 (s, br, 1H), 3.77-3.75 (m, 1H), 3.62-3.55 (m; 2H), and 3.27-3.20 (m, 2H), 3.00-2.80 (m, 1H), 2.53-2.45 (m; 2H), 0.72 (s, 9H) ,-1.00 (s, 3H) ,-1.10 (s, 3H).

Isomer B: ¹H NMR (CDCl ₃400M [Hz) 7.41 (d, J=7.2Hz, 2H), 7.33 (d, J=8.4Hz, 2H), 7.22-7.14 (m, 1H), 7.00-6.45 (m; 1H), 4.71 (ddJ=2.4,11.2Hz, 1H), 4.10 (dd, J=4.4,11.0Hz, 1H), 3.97 (s; Br, 1H), 3.30-3.26 (m, 1H), 2.98-2.95 (m, 1H), 2.68-2.59 (m, 2H); 2.25-2.09 (m, 2H), 0.92 (s, 9H), 0.15 (s, 3H), 0.1. (s, 3H).

Step 4

In 0 ℃, (1.26g adds CeCl in THF 2.3mmol) (60mL) solution to the isomer A that derives from step 3 ₃.7H ₂O (2.0g, 5.3mmol), then add BaBH4 (0.575g, 15.2mmol).After stirring 16 hours under the room temperature, make this reaction mixture be cooled to 0 ℃ and water quencher.Extract with EtOAc then, organic phase is used brine wash, through Na ₂SO ₄Dry and concentrated.Residue obtains the 1.19g title product through quick silica gel column chromatography purifying (with hexane/EtOAc1:1 wash-out). ¹HNMR(CDCl ₃?400MHz)δ7.40-7.30(m，4H)，7.20-7.06(m，1H)，6.85-6.50(m，1H)，4.23-4.10(m，1H)，3.70-3.50(m，2H)，3.05-2.10(m，4H)，2.90-2.30(m，3H)，0.95-0.85(m，1H)，0.80(s，9H)、-1.00(s，3H)、-2.05(s，3H)。

Step 5

In 0 ℃, (1.19g adds TBAF in THF 2.17mmol) (40mL) solution to the pure product that derives from step 4.Remove cryostat.This reaction mixture was stirred under room temperature 2 hours.Concentrated solvent, residue obtains the 403mg title product through quick silica gel column chromatography purifying (with hexane/EtOAc1:1 wash-out). ¹H?NMR(CDCl ₃400MHz)δ7.63(d，J＝6.0Hz，2H)，7.49(d，J＝6.0Hz，2H)，7.10-7.94(m，1H)，6.45-6.39(m，1H)，5.26(d，J＝12.9Hz，1H)，4.10(d，J＝8.7Hz，1H)，4.05(s，br，1H)，3.07(d，J＝9.9Hz，1H)，2.51-2.48(m，1H)，2.37-2.34(m，1H)，1.85-1.26(m，5H)。

Embodiment 412: 1378579

(3aR)-and 9bS-[(4-chlorophenyl) alkylsulfonyl]-6,9-two fluoro-1,2,3,3a, 4,9b-six hydrogen-2-(phenyl methyl) [1] chromene is [3,4-c] pyrroles (racemic) also

In 0 ℃, (50mg, 0.145mmol) (100mg adds TFA (10mg) and under room temperature, stirred 2 hours in CHCl3 0.42mmol) (2mL) solution, in water and EtOAc, carry out aftertreatment then with dipole precursor (dipoleprecursor) to vinyl sulphone.Mixture experience preparation of silica gel type TLC (with hexane/EtOAc80:20 wash-out) obtains 50mg embodiment 412: ¹H-NMR (CDCl ₃400MHz) δ 7.47 (d, 2H), 7.38 (d, 2H), 7.21 (m, 5H), 7.03 (m, 1H), 6.60 (m, 1H), 4.40 (m, 1H), 3.67 (m, 4H), 3.41 (m, 2H), 2.95 (m, 1H), 2.43 (m, 1H) LCMS (MH ⁺)=476.3; RT=3.29 minute.

Embodiment 413:

(3aR)-and 9bS-[(4-chlorophenyl) alkylsulfonyl]-6,9-two fluoro-1,2,3,3a, 4,9b-six hydrogen-2-methylene radical benzo [b] cyclopenta-[d] pyrans (racemic)

Under room temperature, (100mg, 0.29mmol) (70mg adds dppf (10mg) in THF 0.37mmol) (4mL) solution, and (20mg 0.017mmol), heats this reaction mixture 12 hours in 80 ℃ then to add Pd (PPh3) 4 with the dipole precursor to vinyl sulphone.Make reaction mixture pass through short Celite pad.Mixture experience preparation of silica gel type TLC (with hexane/EtOAc 80:20 wash-out) obtains 20 mg embodiment 413: ¹H-NMR (CDCl ₃400MHz) δ 7.59 (d, 2H), 7.48 (d, 2H), 7.0 (m, 1H), 6.41 (m, 1H), 4.90 (s, 1H), 4.85 (s, 1H), 4.74 (d, 1H), 4.14 (d, 1H), 3.41 (m, 2H), 3.15 (d, 2H), 2.76 (m, 1H), 2.33 (m, 1H).

Embodiment 414to416:

According to the method for describing among the method embodiment 61, the compound in the preparation table 85.

Table 85

Embodiment 417 and 418:

(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-8 (r)-hydroxyl-6h-dibenzo [b, d] pyrans-8-methyl alcohol (racemic)

Under room temperature, to alkene (10mg, add in DCM 0.024mmol) (2mL) solution mCPBA (10mg, 2eq) and stirred 2 hours.Add Sulfothiorine (200mg is at 0.5mL water) and extract with DCM.Solvent removed in vacuo makes to be dissolved in THF (2mL), handles and under room temperature, stirs 30 minutes with 2 dense H2SO4.Add the saturated NaHCO3 aqueous solution (2mL), extract with DCM.Mixture experience preparation of silica gel type TLC (using the DCM/MeOH95:5 wash-out) obtains 4mg embodiment 417 and 4mg418.

Embodiment 417: ¹H-NMR (CDCl ₃400MHz) δ 7.62 (d, 2H), 7.49 (d, 2H), 7.0 (m, 1H), 6.41 (m, 1H), 5.30 (d, 1H), 4.12 (d, 1H), 3.61 (s, 1H), 3.44 (m, 3H), 3.05 (m, 2H), 2.48 (m, 2H), 1.78 (m, 1H), 1.25 (m, 2H).

Table 86

Embodiment 419 and 420:

(6aR)-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-8 (S)-hydroxyl-10aS-[[4-(trifluoromethyl) phenyl] alkylsulfonyl]-6h-dibenzo [b,, d] pyrans-7 (R)-methyl alcohol (racemic)

In-78 ℃, to tricycle kentones (5g, add in THF 0.0112mol) (50mL) solution LHMDS (1M in THF, 13.44mL, 1.2eq) and stirred 30 minutes.In the flask of opening in a minute, make SEM-Cl (2.24g, 0.0134mol) and NaI (2g 0.0133mol) is dissolved in THF (50mL) and be cooled to-78 ℃.The ketone of the enolization that obtains is transferred to the SEM-Cl/NaI mixture through conduit and stirred 6 hours in-78 ℃.Make this reaction mixture slowly be warming up to room temperature and stirred overnight, then the saturated NH of impouring ₄Extract among the Cl and with EtOAc.Residue obtains 1.7g (26%) product through flash chromatography on silica gel purifying (with hexane/EtOAc 0-20%EtOAc wash-out).

(1.6g 0.0027mol) is dissolved in DCM (50mL), handles and stirs 3 hours with BF3:OEt2 (0.3mL) in 0 ℃ to make top product.(5mL 2.5M), extracts with EtOAc to add aqueous sodium hydroxide solution.Solvent removed in vacuo makes to be dissolved in THF (10mL) and to handle with NaBH4 (500mg) in 0 ℃.This reaction mixture stirred 2 hours and be warmed to room temperature, other 2 hours of restir in 0 ℃.With aqueous solution aftertreatment, then extract and silica gel column chromatography through EtOAc, obtain the compound of embodiment 419 and 420.

Embodiment 420: ¹H-NMR (CDCl ₃400MHz) δ 7.77 (s, 4H), 7.06 (m, 1H), 6.39 (m, 1H), 5.16 (d, 1H), 4.12 (d, 1H), 3.74 (m, 1H), 2.74 (d, 1H), 2.56 (d, 1H), 2.01 (m, 6H), 1.36 (m, 1H), 0.98 (m, 1H).

Embodiment 421-426

Embodiment 421 and 422

(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6a, 7,8,9,10,10a-six hydrogen-7 (R)-[[2-(trimethyl silyl) oxyethyl group] methyl]-6h-dibenzo [b, d] pyrans-8 (s)-alcohol (racemic)

In-78 ℃, to tricycle kentones (100mg, add in THF 0.24mmol) (3mL) solution LHMDS (1M in THF, 0.29mL, 1.2eq) and stirred 30 minutes.In the flask of opening in a minute, make SEM-Cl (200 mg, 1.1mol) and NaI (50mg) be dissolved in THF (2mL) and be cooled to-78 ℃.The ketone of the enolization that obtains is transferred in the SEM-Cl/NaI mixture and in-78 ℃ through conduit stirred 2 hours.Make this reaction mixture slowly be warming up to room temperature and stirred 4 hours, the saturated NH4Cl of impouring and extract with EtOAc makes mixture through preparation of silica gel type TLC (with hexane/EtOAc 80:20 wash-out) then, obtains the 18mg product.Also (5mg 5eq) handles and stirred 1 hour in-40 ℃ with NaBH4 to make this product be dissolved in Virahol (1mL).Make this reaction mixture be warmed to room temperature and stirred overnight.Adding citric acid solution (contains 8% water, 1mL), extracts with EtOAc.Mixture obtains the product of 2mg embodiment 421 through preparation of silica gel type TLC (with hexane/EtOAc80:20 wash-out). ¹H-NMR(CDCl ₃400MHz)δ7.60(d，2H)，7.50(d，2H)，7.06(m，1H)，6.43(m，?1H)，5.17(d，1H)，4.48(d，1H)，3.89(d，1H)，3.60(m，3H)，3.17(s，1H)，2.68(d，1H)，2.51(d，1H)，1.97(m，2H)，1.15(m，1H)，1.12(m，1H)，0.94(m，3H)，0.02s，9H)。Also isolate compound TKS-11.

According to the method for embodiment 421 and 422, the embodiment 423-426 compound in the preparation table 88.

Table 88

Embodiment 427:

(6aR)-and 10aS-[(4-chlorophenyl) alkylsulfonyl]-1,4-two fluoro-6A, 7,8,9,10,10A-six hydrogen-6h-dibenzo [B, D] pyrans-8 (R)-acetonitrile (racemic)

(20mg, (5mg 0.102mmol), in 120 ℃ of heating 2 hours, carries out aftertreatment with this reaction mixture then in water and EtOAc to add NaCN in DMF 0.034mmol) (2mL) solution to tosylate.Mixture obtains 11mg embodiment 427 through preparation of silica gel type TLC (with hexane/EtOAc50:50 wash-out). ¹H-NMR (CDCl ₃400MHz) δ 7.58 (d, 2H), 7.48 (d, 2H), 7.08 (m, 1H), 6.43 (m, 1H), 5.24 (d, 1H); 4.12 (d, 1H), 2.76 (m, 1H), 2.55 (d, 2H), 2.44 (d, 1H), 2.22 (m; 1H), 2.07 (m, 1H), 1.76 (m, 3H), 1.56 (s, 1H), 1.41 (m, 1H) LCMS (MH ⁺)=83.2; RT=4.43 minute.

Embodiment 428 and 429:

Embodiment 428

(6aR)-1,4-two fluoro-6a, 9,10,10a-tetrahydrochysene-7 (S)-[2-(phenyl sulfonyl) ethyl]-10aS-[[4-(trifluoromethyl) phenyl] alkylsulfonyl]-6h-dibenzo [b, d] pyrans-8 (7h)-ketone (racemic)

Under room temperature, (115mg is 0.25mmol) with phenyl vinyl sulfone (50mg to tricycle kentones; 0.29mmol) tBuOH/THF (3+1 mL) solution in add KtBuO solution (1M be in THF; 0.025mL, 10mol%) and stirred 4 hours, in water and EtOAc, carry out aftertreatment then.Mixture obtains 25mg embodiment 428 through preparation of silica gel type TLC (with hexane/EtOAc 80:20 wash-out): ¹H-NMR (CDCl ₃400MHz) δ 7.91 (d, 2H), 7.82-7.59 (m, 7H), 7.19 (m, 1H), 6.52 (m, 1H), 5.21 (d, 1H), 4.40 (d, 1H), 3.25 (m, 2H), 2.86 (d, 1H), 2.72 (m, 1H), 2.44 (m, 3H), 2.11 (m, 3H).

Use similar method, the compound in the preparation table 89.

Table 89

Embodiment 430:

Based on the method that embodiment 19 is described, the compound in the preparation table 90.

Table 90

Embodiment 431-436

Based on the method that embodiment 20 is described, the compound in the preparation table 91.

Table 91

Embodiment 437-439:

Step 1:

2-((6a, 8,10a)-1, and 4-two fluoro-10a-(4-(trifluoromethyl) phenyl sulfonyl)-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl) the acetate ethyl ester

In the 0 ℃ mixture of 60%NaH oil suspension (0.12g) in THF (22mL), add phosphine acyl acetic acid triethyl ester (0.58mL).After 0.5 hour, add 1 in 0 ℃ of stirring, 4-two fluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a, 9,10,10a-tetrahydrochysene-6H, (1.0g 2.24mmol), obtains clarifying and colourless solution 7H-benzo [c] chromene-8-ketone.0.5 after hour, with saturated NH ₄The Cl aqueous solution joins in this reaction soln.Use ETHYLE ACETATE (3x) to extract this mixture then.The organic layer that merges is through Na ₂SO ₄Dry, filtration, and be absorbed in the silica gel (5g).The thick material of this absorption with ethyl acetate/hexane (0/100-30/70 was through 30 minutes) wash-out, obtains 0.89g white foam thing through the silica gel column chromatography purifying.

Make this white foam thing (0.62g) of a part be dissolved in THF (22mL).This solution is cooled to-78 ℃, is added in the 1.0ML-Selectride in the THF (1.8mL) then.Then cryostat was remained between-55 ℃ and-25 ℃ 4.5 hours.4.5 after hour, with salt solution (1.8mL), the 1 MNaOH aqueous solution (1.8mL), and 30%H ₂O ₂The aqueous solution (0.7mL) joins in this reactant.After stirring other 0.5 hour, add 25%Na ₂SO ₃The aqueous solution (6mL).Mixture extracts with ETHYLE ACETATE (3x).The organic layer that merges is through Na ₂SO ₄Dry, filter and be absorbed in the silica gel (5g).The thick material of this absorption with ethyl acetate/hexane (0/100-40/60 was through 40 minutes) wash-out, obtains embodiment 437 (0.236g) through the silica gel column chromatography purifying, is the white foam thing.

Embodiment 437:LCMS: (M+1)=519.3, RT=5.11 minute.

Step 2:

2-((6a, 8,10a)-1,4-two fluoro-10a-(4-(trifluoromethyl) phenyl sulfonyl)-6a, 7,8,9,10, the acetate of 10a-six hydrogen-6H-benzo [c] chromene-8-)

With 2-((6a, 8,10a)-1; 4-two fluoro-10a-(4-(trifluoromethyl) phenyl sulfonyl)-6a, 7,8; 9; 10,10a-six hydrogen-6H-benzo [c] chromene-8-yl) (embodiment 437,0.23g), the mixture of Lithium Hydroxide MonoHydrate (93mg), water (3mL) and THF (9mL) places 65 ℃ of oil baths for the acetate ethyl ester.After 2.5 hours, the reaction mixture dilute with water also is acidified to pH1-2 in 65 ℃ of stirrings.Use ETHYLE ACETATE (3x) to extract this mixture then.The organic layer that merges is through Na ₂S0 ₄Dry, filtration and concentrated obtain embodiment 438 (0.202g, 94%), are white solid.

Embodiment 438:LCMS: (M+1)=491.3, RT=4.30 minute.

Step 3:

2-((6a, 8,10a)-1,4-two fluoro-10a-(4-(trifluoromethyl) phenyl sulfonyl)-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl)-the N-ethyl acetamide

Add THF (0.1mL) solution of 2M ethamine in the mixture of EDCI under room temperature (39mg) in THF, then add HOBT (28mg).((6a, 8,10a)-1,4-two fluoro-10a-(4-(trifluoromethyl) phenyl sulfonyl)-6a, 7,8,9,10,10a-six hydrogen-6H-benzo [c] chromene-8-yl) (embodiment 438, THF 67mg) (3mL) solution for acetate in the mixture that this obtains, to add 2-.After stirring 16 hours under the room temperature, reaction mixture is absorbed in the silica gel, through the silica gel column chromatography purifying,, obtain embodiment 439 (66.5mg, 94%) with ethyl acetate/hexane (45/65-100/0 was through 20 minutes) wash-out, be clarification and colorless oil.

Embodiment 439:LCMS: (M+1)=518.3, RT=4.29 minute.

According to being similar to the method that embodiment 439 is described, the compound in the preparation table 92.

Table 92

Measure

The pharmacological characteristics of The compounds of this invention can be measured through a series of pharmacology and estimate.The pharmacology that hereinafter is described is measured and is adopted The compounds of this invention and salt thereof to carry out.

Gamma-secretase is active in (Biochemistry, 40 (16), 5049-5055,2001) said mensuration such as Zhang, and the document is attached among this paper by reference.Activity is expressed as percent inhibition or is expressed as and produces the compound concentrations that 50% enzymic activity suppresses.

Reagent

Antibody W02, G2-10 and G2-11 obtain from Dr.Konrad Beyreuther (University ofHeidelberg, Heidelberg, Germany).The residue 5-8 of W02 identification A β peptide, and G2-10 and G2-11 discern specific C-end structure of A β 40 and A β 42 respectively.Vitamin H-4G8 available from Senetec (St.Louis, MO).All tissue culture reagent that are used for this work are from Life Technologies, Inc., except as otherwise noted.Pepstatin A is available from RocheMolecular Biochemicals; DFK167 available from Enzyme Systems Products (Livermore, CA).

CDNA member, tissue culture and clone make up

The existing description of member SPC99-Ion (it contains initial 18 residues and terminal 99 amino acid of C-of the APP that carries out the London sudden change) (zhang, L., Song, L., and Parker, E. (1999) J.Biol.Chem.274,8966-8972).After inserting film, 17 amino acid signal peptides are processed, stay the extra leucine on the N-end of AB.With SPC99-lon be cloned in the pcDNA4/TO carrier (Invitrogen) and transfection in 293 cells with the pcDNA6/TR stable transfection, pcDNA6/TR is provided by T-REx system (Invitrogen).Cells transfected is selected from Dulbecco ' s improvement Eagle ' s substratum (DMEM), and this culture medium supplemented has 10% foetal calf serum, 100 units/mL penicillium mould, 100g/mL Streptomycin sulphate, 250g/mL zeocin and 5g/mL blasticidin (Invitrogen).Screening produces the bacterium colony of A β, and the generation of A β is expressed 16-20 hour also with interlayer (sandwich) immunoassay (seeing below) analysis condition substratum through induce C99 with the 0.1g/mL tsiklomitsin.A clone who is called pTRE.15 is used to these research.

Membrane prepare.

Induce the expression 20h of C99 in cell with the 0.1g/mL tsiklomitsin.Before the results, in 37 ℃ with 1M phorbol 12-myristinate 13-acetic ester (PMA) and this cell of 1M brefeldin A (BFA) pre-treatment 5-6 hour.With cold phosphoric acid salt-BS (PBS) washed cell 3 times, and in the buffer A that contains 20mM Hepes (pH7.5), 250mM sucrose, 50mMKCl, 2mM EDTA, 2mM EGTA and adequate proteins enzyme inhibitors (Roche MolecularBiochemicals), gather in the crops.With cell precipitation thing quick freezing and before use in-70 ℃ of storages in liquid nitrogen.

Be the preparation film, make in the cell suspending liquid buffer A and molten born of the same parents in 600 psi liquid nitrogen bottles.Cellular lysate centrifugal 10 minutes through 1500g is to remove karyon and big cell debris.With supernatant centrifugal 1 hour with 100000g.Make the film throw out be suspended in buffer A once more and add among the 0.5MNaCl, and pass through with centrifugal 1 hour collection membrane of 200000g.The film of brine wash deposition is washed with buffer A and with 100000g centrifugal 1 hour once more.With Teflon-glass homogenizer, final film deposition is suspended in a small amount of buffer A once more.Measure protein concentration, film aliquots containig quick freezing and in-70 ℃ of storages in liquid nitrogen.

Gamma-secretase reaction and A β analyze.

Active for measuring gamma-secretase, in 37 ℃, in containing the 50 μ L damping fluids of 20mM Hepes (pH7.0) and 2mM EDTA, film was cultivated 1 hour.When cultivate finishing, use electrochemistry fluorescence (electrochemiluminesescence) (ECL)-the Ji immunoassay measures A β 40 and A β 42.A β 40 usefulness antibody are identified TAG-G2-10 and vitamin H-W02, and A β 42 usefulness TAG-G2-11 and vitamin H-4G8 identifies.The ECL signal is according to the specification sheets of manufacturers, and (IGEN International Inc.) measures to use the ECL-M8 instrument.The average that the data that obtain are measured for twice or three times for each sample.The active characteristic use of the gamma-secretase of describing surpasses 5 parts, and independently the membrane prepare material evidence is real.

The compound of embodiment 1-A, 1-B, 1-C, 1-D, 1-E, 1-I, 1-P, 1-Q, 1-U, 3G, 5-B, 7-A, 7-B, 8-A, 8-I, 8-L, 8-M, 8-P, 8-U, 8-Y, 8-Z, 9-B and 11-C has the IC greater than about 10 μ M ₅₀

Derive from the IC of all other compounds of other embodiment ₅₀The value scope is at the about 10 μ M of about 10nM-.

Embodiment 1,2,1-J, 1-K, 1-O, 1-R, 1-S, 1-T, 3,4,3-A, 3-B, 3-C, 3-E, 3-F, 3-H, 5,6,6-A, 7,7-C, 7-E, 8,8-B, 8-D, 8-J, 8-K, 8-O, 8-T, 8-V, 8-W, 10,10-A, 10-B, 10-C, 10-D, 11,11-B, 12,13,13A, 15,15A, 16,17,18A, 18B, 19A, 20A-20L, the IC of 21-23,24A-C, 25A, 25B, 26,27A, 27B and 28 compound ₅₀The value scope is at the about 3000nM of about 10nM-.

Compound in the table 93 has the film IC in the 1nM-100nM scope ₅₀

Table 93

The IC of embodiment 20A, 141,144,180,202,208,292,379,338 and 442 compounds ₅₀Data provide in table 94.

Table 94

Though the present invention has combined above-mentioned specific embodiments to describe, many kinds substitute, modify and other changes to those skilled in the art, are conspicuous.What all were such substitutes, modifies and change all in spirit of the present invention and scope.

Claims

1. formula (IA) compound:

Or its pharmacy acceptable salt, wherein:

Each R ¹Independently be selected from H and (C ₁-C ₆) alkyl;

R ², R ³And R ⁴Independently be selected from separately: (1) H, (2) (C ₁-C ₆) alkyl, (4) (C ₁-C ₆) alkylidene group-OR ⁵, (5)-(C ₁-C ₆) alkylidene group-R ⁶, (10)-C (O) O-(C ₁-C ₆) alkyl and (11)-(C ₁-C ₆) alkylidene group-C (O) O-(C ₁-C ₆) alkyl; With

Each R ⁵Independently be selected from: (1) H and (9)-C (O)-R ⁷

R ⁶Be selected from: unsubstituted (C ₆-C ₁₀) aryl and by one or more L ¹Substituted (the C of group ₆-C ₁₀) aryl;

R ⁷Be selected from by one or more L ²The substituted Heterocyclylalkyl of group;

Ar is selected from: (a) unsubstituted (C ₆-C ₁₀) aryl with (b) by one or more L ¹Substituted (the C of group ₆-C ₁₀) aryl;

Each L ¹Independently be selected from: halogen and (C ₁-C ₆) alkyl;

Each L ²Independently be selected from: (a)-OH and (f) Heterocyclylalkyl;

N is 0,1 or 2; With

Wherein said Heterocyclylalkyl is meant the non-aromatic monocyclic system, and it comprises 5 to 10 annular atomses, and wherein one or more atom in this loop systems is a nitrogen.

2. the compound of claim 1, or its pharmacy acceptable salt, wherein:

R ¹Be H or (C ₁-C ₆) alkyl;

R ²Be selected from H, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylidene group-OR ⁵,-(C ₁-C ₆) alkylidene group-R ⁶,-(C ₁-C ₆) alkylidene group-C (O) O-(C ₁-C ₆) alkyl and-C (O) O-(C ₁-C ₆) alkyl;

R ³Be selected from H, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylidene group-OR ⁵With-(C ₁-C ₆) alkylidene group-C (O) O-(C ₁-C ₆) alkyl;

R ⁴Independent is H or (C ₁-C ₆) alkyl;

Each R ⁵Independent be H or-C (O)-R ⁷

R ⁶Be selected from unsubstituted (C ₆-C ₁₀) aryl and by one or more L ¹Substituted (the C of group ₆-C ₁₀) aryl;

Ar is unsubstituted (C ₆-C ₁₀) aryl or by one or more L ¹Substituted (the C of group ₆-C ₁₀) aryl;

Each L ¹Independent is halogen or (C ₁-C ₆) alkyl;

Each L ²Independently be-OH or Heterocyclylalkyl; With

N is 0,1 or 2,

3. the compound of claim 1, or its pharmacy acceptable salt, wherein:

R ¹For H or-CH ₃

R ²Be selected from H ,-CH (CH ₃) ₂,-CH ₃,-CH ₂CH ₃,-(CH ₂) ₃CH ₃,-CH ₂-R ⁶,-CH ₂CH ₂-OH ,-CH ₂-C (O) O-CH ₂CH ₃,-C (O) O-CH ₂CH ₃, by one or more L ²Group is substituted-CH ₂CH ₂-O-C (O)-pyrrolidyl, by one or more L ²Group is substituted-CH ₂CH ₂-O-C (O)-piperidyl,

R ⁴For H or-CH ₃

Each L ¹Independent be F, Cl or-CH ₃

Each L ²Independently be-OH or piperidyl; With

N is 0,1 or 2.

4. be selected from following compound, or its pharmacy acceptable salt:

5. medicinal compsns, it contains among the claim 1-4 each at least a compound and at least a pharmaceutically acceptable carrier.

6. each compound is used for suppressing the purposes of the medicine of gamma-secretase among the claim 1-4 in preparation.

7. each compound is used for treating the purposes of the medicine of one or more neurodegenerative diseases through suppressing gamma-secretase in preparation among the claim 1-4.

8. each compound is used for suppressing the purposes of the sedimentary medicine of amyloid beta among the claim 1-4 in preparation.

9. each compound is used for treating the purposes of the medicine of Alzheimer through suppressing gamma-secretase in preparation among the claim 1-4.