CN105294732B

CN105294732B - The macrocyclic compound of the limited complete synthesis of conformation

Info

Publication number: CN105294732B
Application number: CN201510344719.1A
Authority: CN
Inventors: D·奥伯莱希特; P·厄尔玛特; S·乌姆士; F·拉什; A·卢瑟尔; K·马克斯; K·默勒
Original assignee: Polyphor AG
Current assignee: Spexis AG
Priority date: 2009-08-05
Filing date: 2009-08-05
Publication date: 2018-09-25
Anticipated expiration: 2029-08-05
Also published as: CN105294732A

Abstract

12 30 yuan big ring ring system that the conformation of type (I) is limited, that space limits includes three different structural units：Aromatics template a, conformation instrumentality b and interval body portion c, as described in detail by description and claims.The big ring of type (I) is easily prepared by parallel projects or combinatorial chemistry.They are designed to interact with specific biological targets.Especially, they show to following excitements or antagonistic activity：Motilin receptor (MR receptors), 5 HT of hypotype_2B5 seretonine receptor 5s (5 HT_2BReceptor) and Prostaglandin F2α receptor (FP receptors).To which they are efficiently used for treatment reduced gastrointestinal mobility obstacle such as diabetic gastroparesis and constipation-predominant of irritable bowel syndrome；Disease such as migraine related with CNS, schizophrenia, mental disease or depression；Ocular hypertension ocular hypertension such as related with glaucoma and premature labor.

Description

The macrocyclic compound of the limited complete synthesis of conformation

The application is the divisional application that female case is Chinese invention patent application 200980160767.8.

Technical field

Big ring is naturally and the product of synthesis is in research and development novel drugs, and especially anti-infectious agent is (referring to Review:F.von Nussbaum,M.Brands,B.Hinzen,S.Weigand,D. Angew.Chem.Int.Ed.Engl.2006, 45,5072-5129；D.Obrecht,J.A. Robinson,F.Bernardini,C.Bisang,S.J.DeMarco, K.Moehle, F.O. Gombert, Curr.Med.Chem.2009,16,42-65), it is led as anticarcinogen and in other treatments Domain (C.E.Ballard, H.Yu, B.Wang, Curr.Med.Chem.2002,9,471-498；F.Sarabia,S.Chammaa, A.S.Ruiz, L.M.Ortiz, F.J.Herrera, Curr.Med.Chem.2004,11,1309-1332) in play a crucial role. They usually show significant biological activity, and many big rings or their derivative are drug (L. by successfully exploitation A.Wessjohann,E.Ruijter,D.Garcia-Rivera,W.Brandt,Mol.Divers. 2005,9,171-186； D.J.Newman,G.M.Gragg,K.M.Snader,J.Nat.Prod. 2003,66,1022-1037).Big ring natural prodcuts Chemical Diversity is huge, thus provides the huge Inspiration Sources of drug design.

Background technology

Big ring is naturally and the product of synthesis generally shows semi-rigid skeleton conformation, and appended substituent group is placed in and is well limited Spatial position.Certain ring sizes be it is preferred (L.A.Wessjohann, E. Ruijter, D.Garcia-Rivera, W.Brandt, Mol.Divers.2005,9,171-186), such as frequently find 16- membered rings in the such as poly- acetyl of oxygen-containing big ring (M.Q.Zhang,B. Wilkinson,Curr.Opin.Biotechnol.2007,18,478-488).People assume semi-rigid Skeleton can be with certain advantageous binding characteristics (entropy) of rigid molecule, but also maintain and taken in binding events suitable for structure It is sufficiently flexible as (induction adapt to).

Big ring is naturally generally classified according to the chemical property of skeleton such as cyclic peptide with the product of synthesis (Y.Hamady,T.Shioiri,Chem.Rev.2005,105,4441-4482；N.-H.Tan, J.Zhou, Chem.Rev.2006,106,840-895)；cyclic depsipeptides(F.Sarabia, S.Chammaa, A.S.Ruiz,L.M.Ortiz,F.J.Herrera,Curr.Med.Chem. 2004,11,1309-1332)；Macrolide is (big Annular lactone) and big ring type lactone；Macrocyclic lactams, big cyclammonium, big cyclic ethers, big ring urea and urethanes, etc..Big ring day So with the conformation of the compound of synthesis, physical chemistry, pharmacology and pharmacodynamic characteristics are approximately dependent on ring size, skeleton and appended base Group chemical property (L.A.Wessjohann, E.Ruijter, D.Garcia-Rivera, W. Brandt, Mol.Divers.2005,9,171-186).By modifying these three kinds of parameters, nature has generated substantially unlimited molecule Diversity library.Although there are unarguable significant biological characteristics, natural prodcuts to show certain in medicament research and development for they A little limitations, such as：

High structural complexity

It is metabolized unstability

Low oral administration biaavailability

Low membrane permeability；It is not obedient to intracellular target

Low tissue penetration

Short-half-life

Chemical synthesis is usually very complicated and tediously long

Usually it can only be obtained by fermentation or recombination method

High production cost

Complicated quality control and development technology.

Invention content

To sum up, the present invention describes the class natural prodcuts molecule of the big ring of the type I of new complete synthesis, being capable of example Such as closed by will be connected to linear precursor in a modular way suitable for structural unit A, B and C of protection and be then cyclized (scheme 1) At.

Scheme 1：Brief summary of the invention

Structural unit A serves as conformation-induction pattern plate and based on the (R suitably replaced¹) and protection phenol or thiophenol aromatics Carboxylic acid.

Structural unit B is the (R suitably replaced², R³) and protection tertiary amino alcohol, be preferably derived from amino acid and such as replace Proline, substituted pipecolinic acid or substituted piperazine-2-carboxylic acid.Structural unit B is via ether (X=O) or thioether (X=S) Key connection is keyed to structural unit A, and via secondary or teritary amide to structural unit C.The sulphur atom of thioether connection can hold It changes places and is selectively oxidized to corresponding sulfoxide (S=O) or sulfone (S (=O)₂), this forms the part of the present invention.Importantly, Amido bond between instrumentality B and interval body C can also be a part of extension connector part U.For example, in standard amide In the case of key, U corresponds to carbonyl (- C (=O) -).If U is defined as carbamoyl moieties (- NR⁴- C (=O) -) B with Function connection between C corresponds to urea part.Similarly, the ammonia between B and C is described as the carboxyl of U (- O-C (=O) -) Carbamate connects.In addition, U can represent oxalyl group (- C (=O)-C (=O) -) or corresponding acetal (- C (- OR²⁰)₂-C (=O) -).

Importantly, in the R of structural unit B²The case where constituting amine substituent group, via amine function outside ring to the alternative of big ring ring It is possible to be incorporated to：

The alternative binding pattern is also the part of the present invention.

Structural unit B influences big ring conformation to serve as conformation instrumentality by the cis/trans through amido bond-isomerization.

In class I molecules, structural unit A is connected with B via bridge C；Structure element C passes through secondary or teritary amide key It is connected to A.Bridge C can include one to three (R suitably and independently replaced⁴-R¹⁰；R^14-17) subunit c1-c3, derive From the precursor for suitably replacing and protecting, most by being derived from, but it is not limited to, amino acid derivativges suitably replace and protection Or suitable for substitution and protection amine derivative.

These subunits c1-c3 is independently connected with each other further through following：Amido bond (- C (=O) NR⁴), methylene- Hetero atom connects (- CHR³- Z-), alkene [1,2] diyl part (- CHR that olefin metathesis introduces¹²=CHR¹³), hydrogenation is multiple Alkane [1,2] diyl interval body (- CHR that analytical product obtains¹²-CHR¹³), oxalyl group (- C (=O)-C (=O) -) or two Sulfide bridge (- S-S-).

Substituent R in type Compound I¹-R¹³Spatial orientation pass through it is vertical in ring size and structural unit A, B and C Body chemical connectivity is adjusted.Big ring skeleton and substituent R¹-R¹³The biology that can aid in type Compound I is lived Property.

The skeleton of type Compound I includes aromatic oxide/thioether connection and one or more teritary amide keys；In certain situations Under, aliphatic ether connection, ethylidene or ethylene moieties can also be a part for skeleton as defined hereinabove.In macrocycle molecule Ether connection by advantageously influencing physical chemistry and pharmacological characteristics, such as water solubility, to proteolytic degradation Metabolic stability, cell permeability and oral absorption and show helpfulness (K.X.Chen et al., J.Med.Chem.2006, 49, 995-1005).In addition, compared with the parent molecule with secondary amide key, the big ring containing teritary amide shows increased egg Plain boiled water Numerical solution, cell permeability and oral administration biaavailability (E.Biron, J. Chatterjee, O.Ovadia, D.Langenegger,J.Brueggen,D.Hoyer,H.A. Schmid,R.Jelinek,C.Gilon,A.Hoffmann, H.Kessler,Angew.Chem. Int.Ed.2008,47,1-6；J.Chatterjee,O.Ovadia,G.Zahn, L.Marinelli,A. Hoffmann,C.Gilon,H.Kessler,J.Med.Chem.2007,50,5878-5881).For example, The 11 peptide ciclosporin A (INN of ring-type of immunosuppressor as organ transplant：Cyclosporine) ammonia that methylates containing seven N- Base acid and have in the case of appropriate prepare good oral administration biaavailability (P.R.Beauchesne, N.S.C.Chung,K.M.Wasan,Drug Develop.Ind.Pharm.2007,33,211-220).The proline that contains and The peptidyl cis/trans isomerization of pipecolinic acid polypeptide and albumen is the processes known in protein folding event.In vivo, should Process can be situated between by peptidyl prolyl cis/trans isomerase such as cyclophilin, FK506- binding proteins and parvuline It leads (A.Bell, P.Monaghan, A.P.Page, Int.J. Parasitol.2006,36,261-276).Except they are in albumen Matter is folded with except the effect in immune system, and peptidyl prolyl cis/trans isomerase has involved in cell cycle control In (P.E. Shaw, EMBO Reports 2002,3,521-526) and therefore constitute significant drug targets.Respectively in connection with FK506 and ciclosporin A to FK506- conjugated proteins and cyclophilin are big ring natural prodcuts, the former contains pipecolinic acid Nubbin.

For the biological targets in many existing and appearance, it is difficult to find as the small point classical of drug development starting point Son hit (J.A.Robinson, S.DeMarco, F.Gombert, K. Moehle, D.Obrecht, Drug Disc.Today 2008,13,944-951).Many in these extracellular and intracellular " difficult targets " involves protein-protein phase interaction With, such as receptor tyrosine kinase class, growth factor receptors, activator/transcription factor of transcription, molecular chaperones, etc..For it In it is several, described big ring naturally and synthesis compound as drug development programs good starting point (such as D.Obrecht,J.A.Robinson,F.Bernardini,C.Bisang,S.J. DeMarco,K.Moehle, F.O.Gombert,Curr.Med.Chem.2009,16, 42-65)。

New and complete synthesis the type I macrocyclic compound that the present invention describes by the specific characteristic of big ring natural prodcuts with The beneficial physical chemistry and pharmacological characteristics of traditional small molecule are combined, such as：

The structural complexity of class natural prodcuts

Good solubility

High metabolic stability

Improved oral administration biaavailability

Improved membrane permeability

It is obedient to extracellular and intracellular target

Improved tissue penetration

The pharmacokinetics of micromolecular

Modular chemical synthesis

Adapt to the synthesis technology of parallelization

Reasonable production cost

The quality control of micromolecular and development process

Particularly, the present invention provide general formula I macrocyclic compound (scheme 2) comprising hereafter scheme 2 describe general formula A, The structural unit of B and C.

Scheme 2：Type Compound I and structural unit A, B and C

About structural unit A, B and C, the c1-c3 in the b and C in a, B in encircled portion namely A will represent them Most basic skeleton suitably and is independently replaced as detailed below.The basic skeleton of a and b is described corresponding to Tables 1 and 2 Ring system.

Table 1：The ring system a1-a25 of structural unit A

Table 2：The ring system b1-b11 of structural unit B

Depending on the substitute mode of skeleton b, alternative binding pattern is feasible.For skeleton b3 and b4, via nitrogen outside ring The combination of atom is represented by following two kinds of structures, forms the part of the present invention：

The encircled portion of bridge subunit c1-c3 represents optionally substituted group.Being defined in table 3 for c1-c3 is illustrated It is bright, respectively since the ends N- of connector C to the ends C- are read.In simplest situation, connector C includes a subunit C1 namely c1-1 to c1-6.For the embodiment being made of two or three subunits, subunit c1-c3 and coupling part U, V With W may all combine all be the present invention a part.

Table 3：The range of the subunit c1-c3 of connector group C

It is connected directly to the substituent group namely R of the basic skeleton containing structural unit A, B and C¹-R¹⁷, it is defined as follows：

R¹：H；F；Cl；Br；I；CF₃；OCF₃；OCHF₂；NO₂；CN；Alkyl；Alkenyl；Alkynyl；Naphthenic base；Heterocyclylalkyl；Virtue Base；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；-(CR¹⁸R¹⁹)_qOR²⁰；-(CR¹⁸R¹⁹)_qSR²⁰；-(CR¹⁸R¹⁹)_qNR⁴R¹¹； - (CR¹⁸R¹⁹)_qOCONR⁴R¹¹；-(CR¹⁸R¹⁹)_qOCOOR²¹； -(CR¹⁸R¹⁹)_qNR⁴COOR²¹；-(CR¹⁸R¹⁹)_qNR⁴COR²²； - (CR¹⁸R¹⁹)_qNR⁴CONR⁴R¹¹；-(CR¹⁸R¹⁹)_qNR⁴SO₂R²³； -(CR¹⁸R¹⁹)_qNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹；- (CR¹⁸R¹⁹)_qCONR⁴R¹¹； -(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qPO(OR²¹)₂；-(CR¹⁸R¹⁹)_qOPO(OR²¹)₂； - (CR¹⁸R¹⁹)_qCOR²²；-(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qOSO₃R²¹； -(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or- (CR¹⁸R¹⁹)_qR²⁶。

R²：H；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；- (CR¹⁸R¹⁹)_qOR²⁰；-(CR¹⁸R¹⁹)_qSR²⁰； -(CR¹⁸R¹⁹)_qNR⁴R¹¹；-(CR¹⁸R¹⁹)_qOCONR⁴R¹¹；-(CR¹⁸R¹⁹)_qOCOOR²¹； -(CR¹⁸R¹⁹)_qNR⁴COOR²¹；-(CR¹⁸R¹⁹)_qNR⁴COR²²； -(CR¹⁸R¹⁹)_qNR⁴CONR⁴R¹¹；-(CR¹⁸R¹⁹)_qNR⁴SO₂R²³；-(CR¹⁸R¹⁹)_qNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹； -(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qPO(OR²¹)₂；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；- (CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R³：H；CF₃；Alkyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl.

R⁴：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Or it is suitable N-protected group.

R⁵, R⁷And R⁹It is defined independently as：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Virtue Base alkyl；Heteroaryl alkyl；-(CR¹⁸R¹⁹)_sOR²⁰； -(CR¹⁸R¹⁹)_sSR²⁰；-(CR¹⁸R¹⁹)_sNR⁴R¹¹；-(CR¹⁸R¹⁹)_sOCONR⁴R¹¹； -(CR¹⁸R¹⁹)_sOCOOR²¹；-(CR¹⁸R¹⁹)_sNR⁴COOR²¹；-(CR¹⁸R¹⁹)_sNR⁴COR²²； -(CR¹⁸R¹⁹)_sNR⁴CONR⁴R¹¹；-(CR¹⁸R¹⁹)_sNR⁴SO₂R²³； -(CR¹⁸R¹⁹)_sNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹； -(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qPO(OR²¹)₂；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R⁶, R⁸And R¹⁰It is defined independently as：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Virtue Base alkyl；Or heteroaryl alkyl.

R¹¹：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Suitable Blocking group；-(CR¹⁸R¹⁹)_rOR²⁰；-(CR¹⁸R¹⁹)_rSR²⁰； -(CR¹⁸R¹⁹)_rNR⁴R²⁷；-(CR¹⁸R¹⁹)_rOCONR⁴R²⁷；- (CR¹⁸R¹⁹)_rOCOOR²¹； -(CR¹⁸R¹⁹)_rNR⁴COOR²¹；-(CR¹⁸R¹⁹)_rNR⁴CONR⁴R²⁷； -(CR¹⁸R¹⁹)_rNR⁴SO₂R²³；- (CR¹⁸R¹⁹)_rNR⁴SO₂NR⁴R²⁷；-(CR¹⁸R¹⁹)_qCOOR²¹； -(CR¹⁸R¹⁹)_qCONR⁴R²⁷；-(CR¹⁸R¹⁹)_qCOR²²；- (CR¹⁸R¹⁹)_qSO₂R²³； -(CR¹⁸R¹⁹)_qSO₂NR⁴R²⁷；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_sR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R¹²And R¹³It is defined independently as H；Or alkyl.

R¹⁴And R¹⁶It is defined independently as：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl Alkyl；Heteroaryl alkyl；-(CR¹⁸R¹⁹)_sOR²⁰； -(CR¹⁸R¹⁹)_sNR⁴R¹¹；-(CR¹⁸R¹⁹)_sNR⁴COOR²¹；-(CR¹⁸R¹⁹)_sNR⁴COR²²； -(CR¹⁸R¹⁹)_sNR⁴CONR⁴R¹¹；-(CR¹⁸R¹⁹)_sNR⁴SO₂R²³； -(CR¹⁸R¹⁹)_sNR⁴SO₂NR⁴R¹¹；- (CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹； -(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOR²²。

R¹⁵And R¹⁷It is defined independently as：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl Alkyl；Or heteroaryl alkyl.

Introduced residue R¹-R¹⁷The substituent group of sub-definite is：

R¹⁸：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkane Base；-(CR²⁹R³⁰)_sOR³¹；-(CR²⁹R³⁰)_sSR³¹； -(CR²⁹R³⁰)_sNR²⁸R³¹；-(CR²⁹R³⁰)_sOCONR²⁸R³¹；-(CR²⁹R³⁰)_sOCOOR²¹； -(CR²⁹R³⁰)_sNR²⁸COOR²¹；-(CR²⁹R³⁰)_sNR²⁸COR³¹； -(CR²⁹R³⁰)_sNR²⁸CONR²⁸R³¹；- (CR²⁹R³⁰)_sNR²⁸SO₂R²³； -(CR²⁹R³⁰)_sNR²⁸SO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qCOOR²¹； -(CR²⁹R³⁰)_qCONR²⁸R³¹；- (CR²⁹R³⁰)_qSO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qPO(OR²¹)₂； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；-(CR²⁹R³⁰)_qR²⁴；-(CR²⁹R³⁰)_qR²⁵；Or-(CR²⁹R³⁰)_qR²⁶。

R¹⁹：H；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl.

R²⁰：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；- (CR²⁹R³⁰)_rOR³¹；-(CR²⁹R³⁰)_rSR³¹； -(CR²⁹R³⁰)_rNR²⁸R³¹；-(CR²⁹R³⁰)_rOCONR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸COOR²¹； -(CR²⁹R³⁰)_rNR²⁸COR³¹；-(CR²⁹R³⁰)_rNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_rNR²⁸SO₂R²³；- (CR²⁹R³⁰)_rNR²⁸SO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹； - (CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；-(CR²⁹R³⁰)_qR²⁴；-(CR²⁹R³⁰)_qR²⁵；Or-(CR²⁹R³⁰)_qR²⁶。

R²¹：Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Or it is suitable O- blocking groups.

R²²：Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；- (CR²⁹R³⁰)_sOR³¹；-(CR²⁹R³⁰)_sSR³¹；-(CR²⁹R³⁰)_sNR²⁸R³¹； -(CR²⁹R³⁰)_sOCONR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸COOR²¹； -(CR²⁹R³⁰)_sNR²⁸COR³¹；-(CR²⁹R³⁰)_sNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_sNR²⁸SO₂R²³；- (CR²⁹R³⁰)_sNR²⁸SO₂NR²⁸R³¹； -(CR²⁹R³⁰)_sCOOR²¹；-(CR²⁹R³⁰)_sCONR²⁸R³¹；-(CR²⁹R³⁰)_sSO₂NR²⁸R³¹； - (CR²⁹R³⁰)_tCOR³¹；-(CR²⁹R³⁰)_sSO₂R²³；-(CR²⁹R³⁰)_tR²⁴；-(CR²⁹R³⁰)_tR²⁵；Or-(CR²⁹R³⁰)_tR²⁶。

R²³：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；- (CR³²R³³)_tR²⁴。

R²⁴：Aryl, preferred type C₆H₂R³⁴R³⁵R³¹Optionally substituted phenyl；Or heteroaryl, preferred formula H1-H34's One of group (table 4).

Table 4：Formula H1-H34 groups

R²⁵：It is shown in one of the group of the formula H35-H41 of the following table 5.

Table 5：Formula H35-H41 residues

R²⁶：It is shown in one of the group of the formula H42-H50 of the following table 6.

Table 6：Formula H42-H50 groups

R²⁷：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Suitable Blocking group；Or-(CR²⁹R³⁰)_qR²⁴。

R²⁸：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Suitable N-protected group；-(CR³²R³³)_sOR²¹； -(CR³²R³³)_sNR⁴³R⁴²；-(CR³²R³³)_sNR⁴²CONR⁴³R⁴²；-(CR³²R³³)_sNR⁴²COR²¹； -(CR³²R³³)_sNR⁴²SO₂NR²¹；-(CR³²R³³)_qCOOR²¹；-(CR³²R³³)_qCOR²³； -(CR³²R³³)_qSO₂R²¹。

R²⁹：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkane Base；-(CR³²R³³)_sOR³¹；-(CR³²R³³)_sSR³¹； -(CR³²R³³)_sNR²⁸R³¹；-(CR³²R³³)_sOCONR²⁸R³¹；-(CR³²R³³)_sOCOOR²¹； -(CR³²R³³)_sNR²⁸COOR²¹；-(CR³²R³³)_sNR²⁸COR³¹； -(CR³²R³³)_sNR²⁸CONR²⁸R³¹；- (CR³²R³³)_sNR²⁸SO₂R²³； -(CR³²R³³)_sNR²⁸SO₂NR²⁸R³¹；-(CR³²R³³)_qCOOR²¹； -(CR³²R³³)_qCONR²⁸R³¹；- (CR³²R³³)_qSO₂NR²⁸R³¹；-(CR³²R³³)_qPO(OR²¹)₂； -(CR³²R³³)_qCOR³¹；-(CR³²R³³)_qSO₂R²³；-(CR³²R³³)_qR³¹。

R³⁰：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl.

R³¹：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Or it is shown in One of the group of the formula H51-H55 of the following table 7.

Table 7：Formula H51-H55 groups

R³²And R³³It is defined independently as H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl Alkyl；Heteroaryl alkyl.

R³⁴And R³⁵It is defined independently as H；F；Cl；CF₃；OCF₃；OCHF₂；NO₂；CN；Alkyl；Alkenyl；Alkynyl；Naphthenic base； Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；-(CR²⁹R³⁰)_qOR³¹；-(CR²⁹R³⁰)_qSR³¹；- (CR²⁹R³⁰)_qNR²⁸R³¹； -(CR²⁹R³⁰)_qOCONR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸COOR²¹； -(CR²⁹R³⁰)_qNR²⁸COR³¹；- (CR²⁹R³⁰)_qNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_qNR²⁸SO₂R²³；-(CR²⁹R³⁰)_qNR²⁸SO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³； Or-(CR²⁹R³⁰)_qR³¹。

R³⁶：H；Alkyl；Alkenyl；Alkynyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl； Or-NR²⁸R³¹。

R³⁷：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Suitable N-protected group；-(CR²⁹R³⁰)_rOR³¹； -(CR²⁹R³⁰)_rSR³¹；-(CR²⁹R³⁰)_rNR²⁸R³¹；-(CR²⁹R³⁰)_rOCONR²⁸R³¹； - (CR²⁹R³⁰)_rNR²⁸COOR²¹；-(CR²⁹R³⁰)_rNR²⁸COR³¹； -(CR²⁹R³⁰)_rNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸SO₂R²³； -(CR²⁹R³⁰)_rNR²⁸SO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qCOOR²¹； -(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_rSO₂NR²⁸R³¹；- (CR²⁹R³⁰)_qCOR³¹； -(CR²⁹R³⁰)_qSO₂R²³；Or-(CR²⁹R³⁰)_qR³¹。

R³⁸：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；- (CR²⁹R³⁰)_qOR³¹；-(CR²⁹R³⁰)_qSR³¹； -(CR²⁹R³⁰)_qNR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸COOR²¹；-(CR²⁹R³⁰)_qNR²⁸COR³¹； -(CR²⁹R³⁰)_qNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_qCOOR²¹； -(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qCOR³¹；Or-(CR²⁹R³⁰)_qR³¹。

R³⁹：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkane Base；-(CR³²R³³)_uOR²¹；-(CR³²R³³)_uNR²⁸R⁴³； -(CR³²R³³)_tCOOR²¹；Or-(CR³²R³³)_tCONR²⁸R⁴³。

R⁴⁰：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkane Base；-(CR³²R³³)_uOR²¹；-(CR³²R³³)_uNR²⁸R⁴³； -(CR³²R³³)_tCOOR²¹；Or-(CR³²R³³)_tCONR²⁸R⁴³。

R⁴¹：H；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；- OR²¹；-NR²⁸R⁴³；-NR²⁸COR²³；-NR²⁸COOR²¹；

-NR²⁸SO₂R²³；-NR²⁸CONR²⁸R⁴³；-COOR²¹；-CONR²⁸R⁴³；- C (=NR⁴³)NR²⁸N⁴³；

-NR²⁸C (=NR⁴³)NR²⁸N⁴³；Or it is shown in one of the group of the formula H56-H110 of the following table 8.

Table 8：Formula H56-H110 groups

R⁴²：H；Alkyl；Alkenyl；Naphthenic base；Cycloheteroalkyl；Aryl；Heteroaryl； -(CR²³R³³)_sOR²¹；-(CR²³R³³)_sNR²⁸R⁴³；-(CR²³R³³)_qCOOR²¹；Or-(CR²³R³³)_qCONR²¹R⁴³。

R⁴³：H；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；Or it is suitable N-protected group.

R⁴⁴, R⁴⁵And R⁴⁶It is defined independently as H；F；CF₃；OCF₃；OCHF₂；NO₂； CN；Alkyl；Alkenyl；Alkynyl；Cycloalkanes Base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkyl；-OR²³；-NR²⁸R⁴³；-NR²⁸COR²³；-NR²⁸SO₂R²³； -NR²⁸CONR²⁸R⁴³；-COR²³；-SO₂R²³；

R⁴⁷：H；CF₃；Alkyl；Alkenyl；Alkynyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl alkyl；Heteroaryl alkane Base；-COOR²¹；Or-CONR²⁸R⁴³。

R⁴⁸：H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Cycloheteroalkyl；Aryl；Heteroaryl；-(CR²³R³³)_tOR²¹；- (CR²³R³³)_tNR²⁸R⁴³；-(CR²³R³³)_tCOOR²¹； -(CR²³R³³)_tCONR²¹R⁴³

R⁴⁹And R⁵⁰It is defined independently as H；F；CF₃；Alkyl；Alkenyl；Naphthenic base；Heterocyclylalkyl；Aryl；Heteroaryl；Aryl Alkyl；Heteroaryl alkyl；-(CR³²R³³)_qOR²¹； -(CR³²R³³)_qNR²⁸R⁴³；-(CR³²R³³)_qCOOR²¹；Or-(CR³²R³³)_qCONR²⁸R⁴³。

It is following to cyclic structure component part can be limited together with the substituent group：

With (R⁴And R¹¹)；(R⁴And R²⁷)；(R⁵And R⁶)；(R⁵And R⁷)；(R⁵And R⁹)；(R⁵And R¹⁴)；(R⁵And R¹⁶)；(R⁷With R⁸)；(R⁷And R⁹)；(R⁷And R¹⁶)；(R⁹And R¹⁰)；(R¹⁴And R¹⁵)；(R¹⁶And R¹⁷)；(R¹⁸And R¹⁹)；(R²⁷And R²⁸)；(R²⁸With R³¹)；(R²⁸And R⁴³)； (R²⁹And R³⁰)；(R³²And R³³)；(R³⁴And R³⁵)；(R³⁷And R³⁸)；(R³⁹And R⁴⁰)；(R³⁹And R⁴¹)；(R³⁹ And R⁴⁹)；(R⁴²And R⁴³)；(R⁴⁴And R⁴⁵)；Or (R⁴⁴And R⁴⁶) optionally substituted naphthenic base or Heterocyclylalkyl can be formed together Part.

In addition, structure element-NR⁴R¹¹；-NR²⁷R²⁸；-NR²⁸R³¹Or-NR²⁸R⁴³The formula for being shown in the following table 9 can be formed One of group of H111-H118.

Table 9：By connecting disubstituted amido-NR⁴R¹¹；-NR²⁷R²⁸；-NR²⁸R³¹Or-NR²⁸R⁴³Nubbin limits miscellaneous Cyclic group.

Variable hetero atom and linking group in aforementioned structure are

Z：O；S；S (=O)；S (=O)₂；Or NR²⁸。

Y：O；S；Or NR³⁷。

X：O；S；S (=O)；Or S (=O)₂。

Q：O；S；Or NR²⁸。

U, V and W：As defined in Table 3.

T：CR⁴⁶Or N.In the case where T occurs for several times in identical ring structure, each T independently of other is defined.

And Index Definition is：Q=0-4；R=2-4；S=1-4；T=0-2；And u=1-2.

The pharmaceutically acceptable salt of salt especially compound of formula I.

The salt forms such as acid-addition salts, preferably is selected from the type Compound I and organic or inorganic acid of tool basic nitrogen atom Form acid-addition salts, especially pharmaceutically acceptable salt.Suitable inorganic acid is for example the sulfuric acid containing hydracid such as hydrochloric acid, or Phosphoric acid.Suitable organic acid is such as the acetic acid for example, carboxylic acid, phosphonic acids, sulfonic acid or sulfamic acid, propionic acid, octanoic acid, capric acid, 12 Alkanoic acid, hydroxyacetic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, lemon Lemon acid, amino acid, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, citraconic acid, cyclohexane-carboxylic acid, Buddha's warrior attendant Alkane carboxylic acid, benzoic acid, salicylic acid, 4- aminosalicylic acids, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or second Alkane-sulfonic acid, 2- ethylenehydrinsulfonic acids, ethane -1,2- disulfonic acid, benzene sulfonic acid, 2- naphthalene sulfonic acids, 1,5- naphthalene-disulfonic acid, 2-, 3- or 4- Toluenesulfonic acid, methylsulfuric acid, ethyl sulfuric acid, dodecyl sulphate, N- cyclohexylsulfamics, N- methyl-, N- ethyls-or N- propyl-aminos sulfonic acid or other organic protons acid, such as vitamin C.

As used in this specification, term " alkyl ", alone or in combination (namely the part as another group, than Such as " aryl alkyl ") indicate saturation, straight chain or it is branched there are up to 24, preferably up to 12, the hydrocarbon of carbon atom is residual Base.According to the preferred embodiment of the present invention, " alkyl " is " low alkyl group ", indicates the alkane with up to 6 carbon atoms Base.

Term " alkenyl " indicates straight chain or branched hydrocarbon residue alone or in combination, preferably more with up to 24 To 12, carbon atom and containing at least one or depend on chain length up to four ethylenic double bonds.The alkenyl part can be made Exist for E or Z configurations, is the part of the present invention.

Term " alkynyl " refers to aliphatic hydrocarbon chain and includes but not limited to, have 2 to 10 carbon originals alone or in combination Sub (unless expressly specified otherwise) and the straight chain containing at least one three key and branched chain.

Term " naphthenic base " refers to alone or in combination the cycloaliphatic moiety of the saturation with three to ten carbon atoms.

Term " Heterocyclylalkyl ", alone or in combination, description has three to seven ring carbon atoms and one or more rings are miscellaneous Atom be selected from nitrogen, oxygen and sulphur saturation or the undersaturated heterocyclic moiety in part.The term includes, for example, azetidinyl, Pyrrolidinyl, tetrahydrofuran base, piperidyl etc..

Term " aryl " indicates the aromatic carbocyclic hydrocarbon residue containing one or two hexatomic ring such as alone or in combination Phenyl or naphthyl, can be by up to three substituent groups such as Br, Cl, F, CF₃、NO₂, low alkyl group or low-grade alkenyl substitution.

Term " heteroaryl " indicates the aromatic heterocycle containing one or two five yuan and/or hexatomic ring alone or in combination Residue, wherein at least one contain up to three hetero atoms for being selected from O, S and N, thus heteroaryl residue or its tautomer Form can be connected by the atom of any suitable.The heteroaryl ring is optionally substituted, such as above to " aryl " It is signified.

No matter term " aryl alkyl " uses individually or as a part of of another group as used herein, refers to base Group-R^a-R^b, wherein R^aIt is by R^bThe alkyl as defined hereinabove of aryl substitution i.e. as defined hereinabove.Arylalkyl moieties Example include, but are not limited to benzyl, 1- phenylethyls, 2- phenylethyls, 3- phenyl propyls, 2- phenyl propyls etc..It is similar Ground, term " lower aryl alkyl " refer to above-mentioned part-R^a-R^b, but wherein R^aIt is " low alkyl group " group.

No matter term " heteroaryl alkyl " uses individually or as a part of of another group, refers to group-R^a-R^c, Middle R^aIt is by R^cThe alkyl as defined hereinabove of heteroaryl substitution i.e. as defined hereinabove.Similarly, term " lower heteroaryl Alkyl ", refer to above-mentioned part-R^a-R^cBut wherein R^aIt is " low alkyl group " group.

Term " alkoxy " and " aryloxy group " refer to alone or in combination group-O-R^a, wherein R^a, it is as determined above The alkyl or aryl of justice.

" amino " expression primary (namely-NH₂), secondary (namely-NRH) and uncle (namely-NRR') amine.Special secondary and tertiary aminess are Alkylamine, dialkylamine, arylamine, diaryl amine, aromatic yl alkyl amine and diaryl amine, wherein alkyl are as defined herein and appoint Choosing is substituted.

" optionally substituted " expectation of term means such group：It is such as but not limited to alkyl, alkenyl, alkynyl, cycloalkanes Base, aryl, heteroaryl, Heterocyclylalkyl, alkoxy and aryloxy group, can be with being independently selected from following one or more substituent groups Substitution：For example, halogen (F, Cl, Br, I), cyano (- CN), nitro (- NO₂) ,-SR^a,-S (O) R^a,-S (O)₂R^a,-R^a,-C (O) R^a,- C(O)OR^a,-C (O) NR^bR^c,-C (=NR^a)N^RbR^c,-OR^a,-OC (O) R^a,-OC (O) OR^a,-OC (O) NR^bR^c,-OS (O)R^a,-OS (O)₂R^a,-OS (O) NR^bR^c,-OS (O)₂NR^bR^c,-NR^bR^c,-NR^aC(O)R^b,-NR^aC(O)OR^b,-NR^aC(O) NR^bR^c,-NR^aC (=NR^d)NR^bR^c,-NR^aS(O)R^b,-NR^aS(O)₂R^b, wherein R^a, R^b, R^cAnd R^dIt is independently respectively, for example, Hydrogen, alkyl, alkenyl, alkynyl, naphthenic base, aryl, heteroaryl or Heterocyclylalkyl, as described herein；Or R^bAnd R^cIt can be with it The N atoms that are connected to form Heterocyclylalkyl or heteroaryl together.These groups can be replaced again with the arbitrary part through description： Including but not limited to it is selected from following one or more parts：Halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkyl amino (for example, an alkyl amino, dialkyl amido or trialkylamino), arylamino is (for example, an arylamino, ammonia diaryl Base or triaryl amino), hydroxyl, carboxyl, alkoxy, aryloxy group, nitro, cyano, sulfonic acid, sulfuric ester, phosphonic acids, phosphate, or Phosphonate ester.

The group, being especially but not limited to hydroxyl, amino and carboxyl (can be optionally unprotected or protection) is It is well known to those skilled in the art.The example of suitable blocking group such as Peter G.M.Wuts, Theodora W.Greene, Greene's Protective Groups in Organic Synthesis,John Wiley and Sons,4th Edition is described in detail in 2006.

As used herein, the whole groups that can replace in one embodiment mean " optionally substituted ", unless It is otherwise indicated.

As described above, " rudimentary " the expression residue of term and compound have up to 6 carbon atoms.To for example, art Language " low alkyl group " expression saturation, straight chain or the branched hydrocarbon residue with up to 6 carbon atoms, such as methyl, ethyl, just Propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tertiary butyl, etc..Similarly, term " low-grade cycloalkyl " indicates saturation Cyclic hydrocarbon residue with up to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..

The present invention includes " prodrug " of so-called the compounds of this invention within its scope.In general, the prodrug is compound Functional derivatives, the compound of needs can be converted easily into vivo.Select and prepare the normal of suitable prodrug derivatives Regulation sequence is described in such as Hans Bundgaard, Design of Prodrugs, Elsevier, 1985；And Valentino J.Stella et al., Prodrugs:Challenges and Rewards,Springer,1st ed., 2007。

Certain substituent groups above-mentioned can occur for several times in identical molecular entities, such as, but not limited to R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶And R⁵⁰.It is each described repeatedly to go out Existing substituent group independently of same type other residues and selected within the scope of each group definition.

All may stereoisomer, the also apparent rotational isomer and atropisomer for including the big rings of type I, is this hair A bright part.

The general range of the present invention passes through the additional substitution described in the group of selected structural unit A, B and C and the part Base is defined.

Structural unit A1-A626 (table 10) constitutes the subset of the possibility structural unit based on ring system a1-a25 (table 1).As Structure feature, type A groups carry a nucleophilic moiety XH (wherein X is O or S) and carboxylic acid C (O) OH function.Below Type-X-a-CO- residue of divalent be the big ring skeletons of type I component part, by by the XH and COOH group of respective raw material It is bonded in wherein with appropriate reaction is carried out suitable for reactant.

It is limited as it was noted above, type A structural units serve as template and carry out important conformation to type I products.Type A The effect structure of structural unit is approximately dependent on the sky between the relative orientation and these groups of connection medium-X- and-C (O)- Between distance.Molecule modeling disclose distance in A1-A626 (table 10) (usually 2.5 to) and-X- and-C (O)-medium Arrangement significantly changes, to consumingly influence the conformation of the big rings of type I.

The general range of the present invention passes through the additional substitution described in the group of selected structural unit A, B and C and the part Base limits.

Structural unit A1-A626 (table 10) constitutes the subset of the possibility structural unit based on ring system a1-a25 (table 1).As Structure feature, type A groups carry a nucleophilic moiety XH (wherein X is O or S) and carboxylic acid C (O) OH function.Below Type-X-a-CO- residue of divalent be the big ring skeletons of type I component part, by by XH and COOH with suitable for reactant into Row appropriate reaction is bonded in wherein.

As described above, type A structural units serve as template and carry out important conformation to type I products and limit.Type A The effect structure of structural unit is approximately dependent on the sky between the relative orientation and these groups of connection medium-X- and-C (O)- Between distance.Molecule modeling disclose distance in A1-A626 (table 10) (usually 2.5 to) and-X- and-C (O)-medium Arrangement significantly changes, to consumingly influence the conformation of the big rings of type I.

Table 10：Residue A 1 (a1)-A626 (a25)

Divalent structural unit B1-B21 (table 11, hereafter) constitutes the possibility structural unit based on ring system b1-b11 (upper table 2) Subset.They are based on optionally substituted carrying type-CHR³The cyclic secondary amine of the parts-LG, wherein LG are suitable leave away Group (such as, but not limited to,-OH, Mitsunobu react during be formed in situ suitable LG or halogen such as-Br or- I adapts to S_NReaction), being leaving group can be replaced with the nucleophilic group of structural unit A, to be formed in type A and B structures Make the ether (- O-) between unit or thioether (- S-) connection.In most of type I products, the secondary amine nitrogen of structural unit B is formed It is connect with the teritary amide of the carboxyl of Type C structural unit.Outside there are suitable ring in the case of amine function, can (not be Ring-nitrogen) involve in forming secondary amide to C or preferred teritary amide key.The alternative binding pattern is real with (but not limited to) B10 It is existing.

Due to induction peptidyl Sys-trans isomerism or cis- amido bond is stabilized, type B structural unit potentially acts as class Conformation instrumentality in type I products.

Table 11：Residue B 1-B21

Divalent moiety C can be made of the group of one to three subunit c1-c3, respectively be derived from suitable for protection and function The amine or amino acid derivativges of change.As a result, C portion directly affect the ring size of the big ring of gained and can be considered as interval body or Connector.The connector group C is attached to structural unit A via its end N- and is attached to structural unit via its end C- B, to the big ring ring of internus I.It is defined according to it, the connection in connector group namely V or W can pass through following realities It is existing：Amido bond (- NR⁴- C (=O) -), alkene [1,2] diyl (- CHR¹²=CHR¹³), alkane [1,2] diyl (- CHR¹²- CHR¹³) or methylene-heteroatom moiety (- CHR³- Z-), oxalyl unit (- C (=O)-C (=O) -) or disulphide bridges (- S-S-).About the big ring skeleton of I, then connector C contributes at least one amido bond.

Suitable connector C can be represented by the part of (but not limited to) shown in table 12.Such as C1 represents connector part By being constituted along one to three alpha-amino acid derivatives that its main chain connects, and C7-C10 is equal to the dipeptide moieties of beta-amino acids.It is logical The most simple embodiment for crossing at least one connection between the wherein subunit that non-amide group is realized is C2-C5.Finally, C58- C101 by describe wherein to involve in amido bond suitable for diamines or diacid it is longer (>3C- atoms) side chain connection the case where.

Table 12：The representative embodiment of connector C

According to foregoing explanation, type I products contain at least two amido bonds.As described in introductory section, contain teritary amide Product generally show the cis and trans amido bond conformations of various ratios in the solution；The advantage with normally only use trans- structure The secondary amide of elephant is antithesis.There are how on the books cis- and/or anti conformation is in big ring natural prodcuts containing teritary amide. In some cases, the Fast-Balance between the cis- key with trans amide is observed, it is so-called " isomerization of peptidyl cis/trans "；And In other situations, detect discrete cis and trans teritary amide key as two kinds of Stable conformations in the solution at room temperature Isomers.

The big rings of type I all may stereoisomer, including atropisomer and different rotamers or rotation Isomers is the part of the present invention.

Preferred residue is in the general range of structural unit A：

Preferred residue is A1 (a1) in the general range of structural unit A；A2(a1)；A3(a1)； A4(a1)；A5 (a1)；A6(a1)；A7(a1)；A9(a1)；A10(a1)；A73(a2)；A170(a4)； A209(a7)；A240(a10)；A272 (a10)；A532(a18)；A609(a24)；A612 (a24) and A614 (a24) (table 13).

Table 13：The preferable configuration unit of type A

Preferred type B structural unit is B4 (b3)；B5(b3)；B6(b3)；B7(b3)；B8(b3)； B9(b3)；B10 (b3)；B12(b4)；B13(b4)；B14(b4)；B15(b4)；B16 (b4) and B17 (b5) (table 14).

Table 14：The preferable configuration unit of type B

The preferred embodiment shown in table 15 of connector C.

Table 15：The preferred connector of Type C

The preferred substituents of preferable configuration unit A, B and C are defined as：

R¹：H；F；Cl；Br；I；CF₃；OCF₃；OCHF₂；NO₂；CN；Low alkyl group；Low-grade alkenyl；Low-grade alkynyl；Rudimentary ring Alkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_qOR²⁰； - (CR¹⁸R¹⁹)_qNR⁴R¹¹；-(CR¹⁸R¹⁹)_qNR⁴COOR²¹；-(CR¹⁸R¹⁹)_qNR⁴COR²²； -(CR¹⁸R¹⁹)_qNR⁴CONR⁴R¹¹；- (CR¹⁸R¹⁹)_qNR⁴SO₂R²³； -(CR¹⁸R¹⁹)_qNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹； - (CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qPO(OR²¹)₂；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qOSO₃R²¹；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R²：H；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Rudimentary virtue Base alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_qOR²⁰； -(CR¹⁸R¹⁹)_qNR⁴R¹¹；-(CR¹⁸R¹⁹)_qNR⁴COOR²¹；- (CR¹⁸R¹⁹)_qNR⁴COR²²； -(CR¹⁸R¹⁹)_qNR⁴CONR⁴R¹¹；-(CR¹⁸R¹⁹)_qNR⁴SO₂R²³； -(CR¹⁸R¹⁹)_qNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹； -(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qPO (OR²¹)₂；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R³：As defined above.

R⁴：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Or suitable N-protected group.

R⁵, R⁷And R⁹It is defined independently as：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary heterocycle alkane Base；Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_sOR²⁰；-(CR¹⁸R¹⁹)_sNR⁴R¹¹；- (CR¹⁸R¹⁹)_sNR⁴COOR²¹； -(CR¹⁸R¹⁹)_sNR⁴COR²²；-(CR¹⁸R¹⁹)_sNR⁴CONR⁴R¹¹； -(CR¹⁸R¹⁹)_sNR⁴SO₂R²³；- (CR¹⁸R¹⁹)_sNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹； -(CR¹⁸R¹⁹)_qCONR⁴R¹¹；-(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；- (CR¹⁸R¹⁹)_qPO(OR²¹)₂； -(CR¹⁸R¹⁹)_qCOR²²；-(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or- (CR¹⁸R¹⁹)_qR²⁶。

R⁶, R⁸And R¹⁰It is defined independently as：H；CF₃；Or low alkyl group.

R¹¹：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；Suitable blocking group； -(CR¹⁸R¹⁹)_rOR²⁰；-(CR¹⁸R¹⁹)_rNR⁴R²⁷；-(CR¹⁸R¹⁹)_rNR⁴COOR²¹； -(CR¹⁸R¹⁹)_rNR⁴CONR⁴R²⁷；-(CR¹⁸R¹⁹)_rNR⁴SO₂R²³； -(CR¹⁸R¹⁹)_rNR⁴SO₂NR⁴R²⁷；- (CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R²⁷； -(CR¹⁸R¹⁹)_qCOR²²；-(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qSO₂NR⁴R²⁷； -(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_sR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R¹²And R¹³It is defined independently as H；Or low alkyl group.

R¹⁴And R¹⁶It is defined independently as：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl； Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_sOR²⁰；-(CR¹⁸R¹⁹)_sNR⁴R¹¹；- (CR¹⁸R¹⁹)_sNR⁴COOR²¹； -(CR¹⁸R¹⁹)_sNR⁴COR²²；-(CR¹⁸R¹⁹)_sNR⁴CONR⁴R¹¹； -(CR¹⁸R¹⁹)_sNR⁴SO₂R²³；- (CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹； -(CR¹⁸R¹⁹)_qCOR²²。

R¹⁵And R¹⁷It is defined independently as：H；CF₃；Low alkyl group.

R¹⁸：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；It is rudimentary Aryl alkyl；Lower heteroarylalkyl；-(CR²⁹R³⁰)_sOR³¹； -(CR²⁹R³⁰)_sNR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸COOR²¹；- (CR²⁹R³⁰)_sNR²⁸COR³¹； -(CR²⁹R³⁰)_sNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸SO₂R²³； -(CR²⁹R³⁰)_sNR²⁸SO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qCOOR²¹； -(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qPO(OR²¹)₂； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；-(CR²⁹R³⁰)_qR²⁴；-(CR²⁹R³⁰)_qR²⁵；Or-(CR²⁹R³⁰)_qR²⁶。

R¹⁹：H；CF₃；Or low alkyl group.

R²⁰：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；-(CR²⁹R³⁰)_rOR³¹； -(CR²⁹R³⁰)_rNR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸COOR²¹；-(CR²⁹R³⁰)_rNR²⁸COR³¹； -(CR²⁹R³⁰)_rNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸SO₂R²³； -(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；-(CR²⁹R³⁰)_qR²⁴；- (CR²⁹R³⁰)_qR²⁵；Or-(CR²⁹R³⁰)_qR²⁶。

R²¹And R²³：As defined above.

R²²：Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；-(CR²⁹R³⁰)_sOR³¹； -(CR²⁹R³⁰)_sNR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸COOR²¹；-(CR²⁹R³⁰)_sNR²⁸COR³¹； -(CR²⁹R³⁰)_sNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸SO₂R²³； -(CR²⁹R³⁰)_sCOOR²¹；-(CR²⁹R³⁰)_sCONR²⁸R³¹；-(CR²⁹R³⁰)_sSO₂NR²⁸R³¹； -(CR²⁹R³⁰)_tCOR³¹；-(CR²⁹R³⁰)_sSO₂R²³；-(CR²⁹R³⁰)_tR²⁴；- (CR²⁹R³⁰)_tR²⁵；Or-(CR²⁹R³⁰)_tR²⁶。

R²⁴, R²⁵And R²⁶：As defined above.

R²⁷And R²⁸：As defined above.

R²⁹：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；It is rudimentary Aryl alkyl；Lower heteroarylalkyl；-(CR³²R³³)_sOR³¹； -(CR³²R³³)_sNR²⁸R³¹；-(CR³²R³³)_sNR²⁸COOR²¹；- (CR³²R³³)_sNR²⁸COR³¹； -(CR³²R³³)_sNR²⁸CONR²⁸R³¹；-(CR³²R³³)_sNR²⁸SO₂R²³； -(CR³²R³³)_qCOOR²¹；- (CR³²R³³)_qCONR²⁸R³¹；-(CR³²R³³)_qSO₂NR²⁸R³¹； -(CR³²R³³)_qPO(OR²¹)₂；-(CR³²R³³)_qCOR³¹；- (CR³²R³³)_qSO₂R²³； -(CR³²R³³)_qR³¹。

R³⁰And R³³：H；CF₃；Low alkyl group.

R³¹And R³²：As defined above.

R³⁴And R³⁵It is defined independently as H；F；Cl；CF₃；OCF₃；OCHF₂；NO₂； CN；Low alkyl group；Low-grade alkenyl；It is rudimentary Alkynyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；- (CR²⁹R³⁰)_qOR³¹；-(CR²⁹R³⁰)_qNR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸COOR²¹；-(CR²⁹R³⁰)_qNR²⁸COR³¹； -(CR²⁹R³⁰)_qNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸SO₂R²³； -(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；Or-(CR²⁹R³⁰)_qR³¹。

R³⁶：As defined above.

R³⁷：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；Suitable N-protected group； -(CR²⁹R³⁰)_rOR³¹；-(CR²⁹R³⁰)_rNR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸COOR²¹； -(CR²⁹R³⁰)_rNR²⁸COR³¹；-(CR²⁹R³⁰)_rNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_rNR²⁸SO₂R²³；- (CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹； -(CR²⁹R³⁰)_rSO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；Or-(CR²⁹R³⁰)_qR³¹。

R³⁸：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；-(CR²⁹R³⁰)_qOR³¹； -(CR²⁹R³⁰)_qNR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸COOR²¹；-(CR²⁹R³⁰)_qNR²⁸COR³¹； -(CR²⁹R³⁰)_qNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_qCOOR²¹； -(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qCOR³¹；Or-(CR²⁹R³⁰)_qR³¹。

R³⁹；R⁴⁰；R⁴¹；R⁴²；R⁴³；R⁴⁴；R⁴⁵；R⁴⁶；R⁴⁷；R⁴⁸；R⁴⁹And R⁵⁰：As defined above.

In preferred structure above-mentioned, variable hetero atom Z and coupling part U is defined as：

Z：O；S (=O)；Or S (=O)₂。

U：- C (=O)-；-NR⁴- C (=O)-；- C (=O)-C (=O)-；Or-C (- OR²⁰)₂- C (=O)-.

As defined above is：

Pair-wise combination and the substituent group of optionally substituted naphthenic base or heterocycloalkyl portion can be formed.

The structure element of one of group of formula H111-H118 (table 9) can be formed.

Variable hetero atom Q, T, X and Y.

Index q-u.

Above-mentioned preferred structure include the big rings of type I all may stereoisomer, also obviously include rotational isomer And atropisomer.

A1 (a1) is particularly preferably in type A structural units；A2(a1)；A3(a1)； A4(a1)；A5(a1)；A6 (a1)；A7(a1)；A9(a1)；A10(a1)；A73(a2)；A170(a4)； A209(a7)；A240(a10)；A272(a10)； A532(a18)；A614(a24).For most of in these structural units, oxygen is preferred nucleophilic moiety.However, A170's In the case of, it is made of sulphur atom；And in the case of three structural unit A5-A7, oxygen and sulfur derivatives are of the invention A part of (table 16).

Table 16：The particularly preferred structural unit of type A

Shown in table 17 B7, B8, B9 and B-17 are particularly preferably in type B structural unit.

Table 17：The particularly preferred structural unit of type B

The particularly preferred embodiment of connector C is listed in table 18.

Table 18：The particularly preferred embodiment of connector C

Particularly preferred substituent group on particularly preferred structural unit A, B and C is defined as：

R¹：H；F；Cl；CF₃；OCF₃；OCHF₂；NO₂；CN；Low alkyl group；Low-grade alkenyl；Low-grade alkynyl；Low-grade cycloalkyl； Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_qOR²⁰；-(CR¹⁸R¹⁹)_qNR⁴R¹¹； -(CR¹⁸R¹⁹)_qNR⁴COR²²；-(CR¹⁸R¹⁹)_qNR⁴CONR⁴R¹¹； -(CR¹⁸R¹⁹)_qNR⁴SO₂R²³；-(CR¹⁸R¹⁹)_qNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹； -(CR¹⁸R¹⁹)_qCONR⁴R¹¹；-(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R²：H；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Rudimentary virtue Base alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_qOR²⁰； -(CR¹⁸R¹⁹)_qNR⁴R¹¹；-(CR¹⁸R¹⁹)_qNR⁴COR²²；- (CR¹⁸R¹⁹)_qNR⁴CONR⁴R¹¹； -(CR¹⁸R¹⁹)_qNR⁴SO₂R²³；-(CR¹⁸R¹⁹)_qNR⁴SO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOOR²¹； - (CR¹⁸R¹⁹)_qCONR⁴R¹¹；-(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R³：As defined above.

R⁴：H；Low alkyl group；Low-grade alkenyl；Or suitable N-protected group.

R⁵, R⁷And R⁹It is defined independently as：H；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl； Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_sOR²⁰；-(CR¹⁸R¹⁹)_sNR⁴R¹¹；- (CR¹⁸R¹⁹)_sNR⁴COR²²； -(CR¹⁸R¹⁹)_sNR⁴CONR⁴R¹¹；-(CR¹⁸R¹⁹)_sNR⁴SO₂R²³；-(CR¹⁸R¹⁹)_qCOOR²¹； - (CR¹⁸R¹⁹)_qCONR⁴R¹¹；-(CR¹⁸R¹⁹)_qSO₂NR⁴R¹¹；-(CR¹⁸R¹⁹)_qCOR²²； -(CR¹⁸R¹⁹)_qSO₂R²³；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_qR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R⁶, R⁸And R¹⁰It is defined independently as：H；CF₃；Or CH₃。

R¹¹：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；Suitable blocking group； -(CR¹⁸R¹⁹)_rOR²⁰；-(CR¹⁸R¹⁹)_rNR⁴R²⁷；-(CR¹⁸R¹⁹)_rNR⁴CONR⁴R²⁷； -(CR¹⁸R¹⁹)_rNR⁴SO₂R²³；-(CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R²⁷； -(CR¹⁸R¹⁹)_qCOR²²；-(CR¹⁸R¹⁹)_qR²⁴；-(CR¹⁸R¹⁹)_sR²⁵；Or-(CR¹⁸R¹⁹)_qR²⁶。

R¹²And R¹³It is defined independently as H；Or low alkyl group.

R¹⁴And R¹⁶It is defined independently as：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl； Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR¹⁸R¹⁹)_sOR²⁰；-(CR¹⁸R¹⁹)_sNR⁴R¹¹；- (CR¹⁸R¹⁹)_sNR⁴COR²²； -(CR¹⁸R¹⁹)_qCOOR²¹；-(CR¹⁸R¹⁹)_qCONR⁴R¹¹。

R¹⁵And R¹⁷It is defined independently as：H；CF₃；Or CH₃。

R¹⁸：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；It is rudimentary Aryl alkyl；Lower heteroarylalkyl；-(CR²⁹R³⁰)_sOR³¹； -(CR²⁹R³⁰)_sNR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸COR³¹；- (CR²⁹R³⁰)_sNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_sNR²⁸SO₂R²³；-(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹； - (CR²⁹R³⁰)_qSO₂NR²⁸R³¹；-(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³； -(CR²⁹R³⁰)_qR²⁴；-(CR²⁹R³⁰)_qR²⁵；Or- (CR²⁹R³⁰)_qR²⁶。

R¹⁹：H；CF₃；Or CH₃。

R²⁰：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；-(CR²⁹R³⁰)_rOR³¹； -(CR²⁹R³⁰)_rNR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸COR³¹； -(CR²⁹R³⁰)_rNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸SO₂R²³； -(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；-(CR²⁹R³⁰)_qR²⁴；-(CR²⁹R³⁰)_qR²⁵；Or- (CR²⁹R³⁰)_qR²⁶。

R²¹And R²³：As defined above

R²²：Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；-(CR²⁹R³⁰)_sOR³¹； -(CR²⁹R³⁰)_sNR²⁸R³¹；-(CR²⁹R³⁰)_sNR²⁸COR³¹；-(CR²⁹R³⁰)_sNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_sNR²⁸SO₂R²³；-(CR²⁹R³⁰)_sCOOR²¹；-(CR²⁹R³⁰)_sCONR²⁸R³¹； -(CR²⁹R³⁰)_sSO₂NR²⁸R³¹；-(CR²⁹R³⁰)_tCOR³¹；-(CR²⁹R³⁰)_sSO₂R²³； -(CR²⁹R³⁰)_tR²⁴；-(CR²⁹R³⁰)_tR²⁵；Or- (CR²⁹R³⁰)_tR²⁶。

R²⁴, R²⁵And R²⁶：As defined above.

R²⁷And R²⁸：As defined above.

R²⁹：H；F；CF₃；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；It is rudimentary Aryl alkyl；Lower heteroarylalkyl；-(CR³²R³³)_sOR³¹； -(CR³²R³³)_sNR²⁸R³¹；-(CR³²R³³)_sNR²⁸COR³¹；- (CR³²R³³)_sNR²⁸CONR²⁸R³¹； -(CR³²R³³)_qCOOR²¹；-(CR³²R³³)_qCONR²⁸R³¹；-(CR³²R³³)_qCOR³¹； - (CR³²R³³)_qR³¹。

R³⁰And R³³：H；CF₃；Or CH₃。

R³¹And R³²：As defined above

R³⁴And R³⁵It is defined independently as H；F；Cl；CF₃；OCF₃；OCHF₂；Low alkyl group；Low-grade alkenyl；Low-grade alkynyl；It is low Grade naphthenic base；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkyl；Lower heteroarylalkyl；-(CR²⁹R³⁰)_qOR³¹； -(CR²⁹R³⁰)_qNR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸COR³¹； -(CR²⁹R³⁰)_qNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸SO₂R²³； - (CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qSO₂NR²⁸R³¹； -(CR²⁹R³⁰)_qCOR³¹；-(CR²⁹R³⁰)_qSO₂R²³；Or-(CR²⁹R³⁰)_qR³¹。

R³⁶：As defined in part 3 " general range of the present invention ".

R³⁷：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；Suitable N-protected group； -(CR²⁹R³⁰)_rOR³¹；-(CR²⁹R³⁰)_rNR²⁸R³¹；-(CR²⁹R³⁰)_rNR²⁸COOR²¹； -(CR²⁹R³⁰)_rNR²⁸COR³¹；-(CR²⁹R³⁰)_rNR²⁸CONR²⁸R³¹； -(CR²⁹R³⁰)_qCOOR²¹；-(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qCOR³¹；Or-(CR²⁹R³⁰)_qR³¹。

R³⁸：H；Low alkyl group；Low-grade alkenyl；Low-grade cycloalkyl；Rudimentary Heterocyclylalkyl；Aryl；Heteroaryl；Lower aryl alkane Base；Lower heteroarylalkyl；-(CR²⁹R³⁰)_qOR³¹； -(CR²⁹R³⁰)_qNR²⁸R³¹；-(CR²⁹R³⁰)_qNR²⁸COR³¹； -(CR²⁹R³⁰)_qNR²⁸CONR²⁸R³¹；-(CR²⁹R³⁰)_qCOOR²¹； -(CR²⁹R³⁰)_qCONR²⁸R³¹；-(CR²⁹R³⁰)_qCOR³¹；Or-(CR²⁹R³⁰)_qR³¹。

In aforementioned structure, variable hetero atom Z and coupling part U is defined as：

Z：O；Or S (=O)₂。

U：- C (=O)-；-NR⁴- C (=O)-；Or-C (=O)-C (=O)-.

As defined above is：

Variable hetero atom Q, T, X and Y.

Index q-u.

Above-mentioned particularly preferred structure includes the possible stereoisomer of whole of the big rings of type I, also apparent rotational isomeric Body and atropisomer.

The example for limiting the readily available substance of the possible subunits of connector C is listed in (but not limited to) table 19.

Table 19：Represent subunit's substance of particularly preferred connector C

Particularly preferred big ring type Compound I is following embodiments：Embodiment 9, embodiment 11, embodiment 12, embodiment 16, embodiment 30, embodiment 49, embodiment 184, embodiment 200 and embodiment 213.

Synthesize structural unit

Structural unit C for synthesizing macrocyclic compound of the present invention is described in detail to showing structure level fully defining in upper table 19 And it can be easy to get.Instrumentality structural unit B, the possible route of synthesis for especially preparing template constructing unit A are retouched in detail It is set forth in hereafter.

Synthesize template constructing unit A

General conversion

Type A structural units carry carboxylic acid group and phenol (Ar/Hetar-OH) based on the substance being easy to get, the substance Or thiophenol part (Ar/Hetar-SH).COOH group can be connected to the identical rings of-OH/-SH groups or be connected to and ring Can be the undersaturated ring of aromatics or part again.

Usual amphyl describes more than corresponding phenyl-sulfhydrate in the literature.However, it is well to convert phenols to thiophenol Established.Therefore, phenol system system can be considered as the precursor of its thip-analogues.Alternatively, thiophenol may be derived from corresponding aryl halide Or diazol.

For converting Ar/Hetar-X → Ar/Hetar-SH (X=OH, F, Cl, Br, I, N₂ ⁺) general range it is selected Example reference is as follows：

T-I) program of extensive utilization is to use N, N- dimethyl thio carbamyl chlorides that phenol is converted thiocarbamic acid Ester, subsequent progress Newman-Kwart rearrangements and then hydrolysis (A. Gallardo-Godoy et al., J.Med.Chem.2005,48,2407-2419；P.Beaulieu et al.,Biorg.Med.Chem.Lett.2006,16, 4987-4993；H.Sugiyama et al., Chem.Pharm.Bull.2007,55,613-624；S.Lin et al., Org.Prep.Proced. Int.2000；547-556).

T-II) adjacent to-OH of pyridine nitrogen (being equivalent to pyridone tautomer) it is direct conversion can by with P₂S₅ (K.Hirai et al., Heterocycles 1994,38,277-280) is realized in heating.

T-III) as the alternative of phenols, substituted (the especially F or Cl) aromatics ring system of halogen-may serve as precursor. In the case that halogen is located at the position activated by electron-withdrawing group, the aromatics substitution reaction of nucleophilic can be passed through in a mild condition (S_NAr) the o- or parts contraposition introducing-SH or protection analog (G.J.Atwell et al., J.Med.Chem.1994, 37,371-380).Especially in field of heterocyclic compound, the case where wherein electrophilic effect is worked by pyridines nitrogen-atoms Under, such substitution is (the S.McCombie et al., Heterocycles, 1993,35,93-97) usually used.

T-IV) similarly, in Sandmeyer- type reactions, diazonium groups (- N₂ ⁺) be replaced (C.Mukherjee, E.Biehl,Heterocycles 2004,63,2309-2318)。

T-V) in inactive position, the substitution of halogen atom (especially Br or I) can be via corresponding organolithium or lattice Family name's reagent realizes (J.L.Kice, A.G.Kutateladze, J.Org.Chem. 1993,58,917-923；P.C.Kearney et al.,J.Am.Chem.Soc.1993,115, 9907-9919；K.-Y.Jen,M.P.Cava,Tetrahedron Lett.1982,23, 2001-2004).Alternatively, Transition metal-catalyzed conversion is feasible to the type reaction, such as The thiobenzoate substitution (N.Sawada et al., Tetrahedron Lett.2006,47,6595-6597) of Cu- catalysis, Or the KS-Si (iso- Pr) of Pd- catalysis₃Substitution, the subsequent desilyated-SSi (iso- Pr) introduced in this way₃Group (A.M.Rane et al.,Tetrahedron Lett.1994,35, 3225-3226)。

In addition, the hydroxyl for being connected to aromatic ring (Ar-OH or Hetar-OH) can if not commercially available material part It is introduced by following various methods：

H-I) with T-III) similarly, hydroxyl or surrogate can by electron-withdrawing substituent (W. Cantrell, Tetrahedron Lett.2006,47,4249-4251) or pyridine nitrogen atom (S.D. Taylor et al., J.Org.Chem.2006,71,9420-9430) the S of the halogen atom of ortho position or contraposition especially Cl or F_NAr reactions introduce.

H-II) Sandmeyer- types aromatic amine hydroxylating via intermediate diazonium salt (P. Madsen et al., J.Med.Chem.2002,45,5755-5775)。

H-III it) is not directed to S_NThe substitution of the halogen atom (especially Br and I) of Ar activation can be urged by transition metal- The C-O- couplings of change are realized；Dominant be Pd- catalyst (K.W. Anderson et al., J.Am.Chem.Soc.2006, 128,10694-10695；B.J.Gallon et al., Angew.Chem., Int.Ed.2007,46,7251-7254), still Other such as Cu- catalyst (J.E.Ellis, S.R.Lenger, Synth.Commun.1998,28,1517- can also be used 1524)。

What H-IV) wide scope used also has two step programs, converts halogen atom (Cl, Br and I) to substitution boron first Acid esters, then oxicracking carbon-boron bond be phenol (J.R.Vyvyan et al., J. Org.Chem.2004,69,2461- 2468)。

The carboxylic acid group of template constructing unit A can pass through mark if not being already present in commercially available structural unit Quasi-ordering introduces：

C-I) functional group such as hydroxymethyl (- CH₂- OH) or the oxidation of aldehyde (- C (=O) H) can be real in a mild condition Existing (G.V.M.Sharma et al., Synth.Commun.2000,30,397-406；C.Wiles et al., Tetrahedron Lett.2006,47,5261-5264).Methyl on phenyl ring can also be aoxidized；However, due to usually needing Harsh reaction condition, application is wanted to be restricted.In contrast, the relatively acid methyl of the ortho position of pyridine nitrogen or contraposition can It is aoxidized under the conditions of milder；So that this method it is special for many pyridine ring analogues (T.R.Kelly, F. Lang, J.Org.Chem.1996,61,4623-4633)。

C-II) halogen atom easily can use carboxyl or its surrogate to replace, for example, exchanged by halogen metal and with Afterwards carboxylated intermediate Grignard or organolithium type (C.G.Screttas, B. R.Steele, J.Org.Chem.1989, 54,1013-1017), or by with Mander reagents (cyano methyl formate) (A.Lepretre et al., Tetrahedron 2000,56,265-274)。

C-III) in the case where the ring position of acidification waits for carboxylic esterification, feasible method is to use highly basic (usual tertiary butyl Lithium) deprotonation, subsequent carboxylated intermediate organolithium type, similar C-II).

C-IV the hydrolysis of) ester, amide or nitrile group.In addition, CN groups can be held by handling organohalogen compounds with CuCN Change places introducing (Rosenmund-von Braun reaction:C.F. Koelsch,A.G.Whitney,J.Org.Chem., 1941,6,795-803)。

Applied to commercially available raw material, these general conversions provide the tool box for obtaining template A.Other documents Example is incorporated in following all kinds of embodiments.

A1-A59 phenyl derivatives

Very more hydroxybenzoic acids with various substitute modes are commercially available and can be directly incorporated into as template A Big ring skeleton.In the case that several other, the presence offer of optionally substituted base can pass through organic synthesis and parallel/combinatorial chemistry Standard method extends further to the suitable function of more complicated height change substituent group.

Even if can be by according to above-mentioned conventional method if less universal quaternary hydroxybenzoic acid (A53-A59) Program structure, for example, replaced by carboxylated five phenol derivatives (K.Sung, R.J.Lagow, J.Mater.Chem.1996,6,917-918；E.Marzi,M.Schlosser, Tetrahedron 2005,61,3393- 3402；K.C.Nicolaou et al.,Angew.Chem., Int.Ed.1999,38,3334-3339).It obtains quaternary The alternative approach of hydroxybenzoic acid involves, such as oxidation benzaldehyde is subsequently introduced substituent group to remaining free position, also feasible Be to construct polysubstituted benzoic acid (K.C.Nicolaou et al., Chem. from less substituted benzoic acid Eur.J.2000,6,3095-3115)。

A60-A143 pyridine derivates

In the case where above-mentioned classification compound is also used for pyridine derivate, high amount of substance is commercially available, energy It is enough directly incorporated into big ring, or suitable hydroxypyridinecarboxylic acid can be easily converted to by above-mentioned conventional method：It can use It is (M.Shimano et al.Tetrahedron Lett.1998,39 in converting the selected literature examples of Type C-III； 4363-4366；ibid., Tetrahedron 1998,54,12745-12774)；For H-II (L.Carpino et al., J.Org. Chem.2004,69；54-61)；With for C-I (T.R.Kelly, F.Lang, Tetrahedron Lett.1995, 36,5319-5322), or for C-IV (J.L.LaMattina, R.L.Taylor, J. Org.Chem.1981,46,4179- 4182)。

A144-A165 pyridyl derivatives

Similar to general conversion easy to perform, can will be oxidized to accordingly suitable for the methyl pyridazine of substitution with bichromate 3- or 4- carboxylic acids (M.Morishita et al., Chem.Pharm.Bull. 1994,42,371-372；M.Winn et al., J.Med.Chem.1993,36,2676-2688).Similar the wide scope, (hydroxide under electrochemical conditions； G.Heinisch, D.Lassnigg, Arch.Pharm. (Weinheim, Ger.) 1987,320,1222-1226) or in enzymatic Under conditions of (the nitrilase of Rhod (Rhodococcus sp.)；N.Klempier et al.,Tetrahedron Lett.1991,32,341-344 corresponding nitrile) is hydrolyzed.

A kind of possibility that heterocycle pyridazine core is built from non-annularity precursor initiates from 'beta '-ketoester, can make its progress Staudinger reacts, subsequent azepine-Wittig- cyclisation intermediate azide (S.V. Galiullina et al., Russ.J.Org.Chem.2007,43,607-614；M.Guillaume et al.,Synthesis 1995,8,920-922) Or directly cyclic condensation (E.E.Schweizer, K.-J.Lee, J.Org.Chem.1982,47,2768-2773) is carried out with a hydrazone.

A166-A189 pyrimidine derivatives

Similarly with pyridine derivate, many suitable configurations units are commercially available and can be directly incorporated into big ring, or They can be easily converted to target compound by above-mentioned standard program, and above-mentioned standard program includes for converting Type C- I(Y.Honma et al.,Chem.Pharm. Bull.1982,30,4314-4324)；With C-IV (I.V.Oleinik, O.A.Zagulyaeva, Chem.Heterocycl.Compd.1993,29,427-431) selected example.In addition, pyrimidine core The heart can by oxalyl based compound and the third two amidine derivative cyclic condensations (G.A.Howard et al., J.Chem.Soc.1944,476-477) or malonate and amidine derivative cyclic condensation (M.Otsuka et al., Chem.Pharm.Bull.1985,33,515-519 it) easily builds.

A190-A200 pyrazines derivatives

Pyrazine carboxylic acid is readily available by α, β-diaminopropionic acid and α, beta-dicarbonyl derivative cyclic condensation (J.Bostroem et al.,Bioorg.Med.Chem.2007,15,4077-4084).Standard scheme example is used for C-I (J.R.Young et al.,Bioorg.Med.Chem.Lett.2000,10, 1723-1728)；For C-III (N.Ple et al.,Tetrahedron 1998,54,9701-9710)；With for H-II (A.P.Krapcho et al., J.Heterocycl.Chem.1997,34,27-32).The high chemoselectivity oxidation of Type C-I can be achieved：With evil Smelly bacillus (Pseudomonas putida) carries out bioconversion (A.Kiener, Ang.Chem.1992,104,748-749).

A201-A206 pyrrolotriazine derivatives

The possible approaches for obtaining the suitable substituted precursor of two function triazines are amidrazone and α, beta-diketon or α, beta-diketon Ester cyclic condensation (M.Sagi et al., Heterocycles 1990,30,1009-1021).α, γ-two ketone ester are also described as fitting Suitable raw material, however, in this case, need via intermediate 4- nitroso pyrazoles multistep reaction program (R.Fusco, S.Rossi,Tetrahedron 1958,3, 209-224)。

A207-A228 furans, thiophene and azole derivatives

Furans A207 and A208 can pass through bromine from the 2- formoxyls-or 2- acetyl group -3- oxo-butynic acid esters of suitable substitution Change then cyclisation and is synthesized (A.Becker, Helv.Chim.Acta 1949,32,1114-1122；R.Richter, Helv.Chim.Acta 1949,32,1123-1136).Thiophene A207 and A208 can be prepared from (substituted) 3- methoxies Carbonyl-thiophane -4- ketone:It aoxidizes (M.R.Banks et al., J.Chem.Res. (M) 1984,369-389) or contracts with aldehyde Close subsequent isomerization (R.Jaunin, Helv.Chim.Acta 1980,63,1542-1553).Pyrroles A207 and A208 (X=O) The suitable substituted 3- amino-acrylonitrile acid esters of N-protected can be derived from this way：Subsequent alkali is reacted with (substituted) 2- chloracetyl chlorides Induction cyclisation (E.Benary, R.Konrad, Chem.Ber. 1923,56,44-52).Thip-analogues (X=S) can be done in this way It synthesizes from 3- methoxycarbonyl groups-furans：Dibrominated/methanol solution, then reacts with 3- mercapto-propionates and amine, then acid induction ring Change and S- is deprotected (F.Eiden, U.Grusdt, Arch.Pharm.1989,322,807-810).

Furans A209 and A210 (X=O) can derive from (substituted) acetyl group (methoxycarbonyl group) methylene in this way]-triphenyl Phosphorane：With the subsequent ozone decomposed of aldehyde reaction and acid induction isomerization (H.H. Wasserman, G.M.Lee, Tetrahedron Lett.1994,35,9783-9786).Thiophene A209 and A210 can be prepared from 2- mercaptoacetates and (substituted) acetylene carboxylic Acid esters (H. Fiesselmann, G.Pfeiffer, Chem.Ber.1954,87,848-856) or from acetyl acetate and 2- Mercaptoacetate, subsequent alkali induction cyclisation (H.Fiesselmann, F.Thoma, Chem. Ber.1956,89,1907-1912).

Pyrroles A209 and A210 can be achieved in that：It is condensed Beta-alanine ethyl ester and (substituted) 2,3- dioxos- Amyl- obtusilic acid ester (H.H.Wasserman et al., Tetrahedron Lett.1989,30,1721-1724) will be suitable Substituted 3- oxo-propionates react (A.Treibs, A.Ohorodnik, Liebigs with glycinate Ann.Chem.1958,611,139-149).Thip-analogues (X=S) can be synthesized in this way from (substituted) pyrrolidines -2- carboxylics Acid esters：It is then reacted with ditosyl diimino sulphur and trimethyl phosphite, subsequent demethylation (J.Monatsh. Chem.1986,117,269-274)。

Type A211 and A212 furans can synthesize the alkynes from diazonium phenyl malonic ester and suitable for substitution in this way：In two step journeys In sequence, (P.M ü ller, C. are catalyzed by rhodium acetate (II) Helv.Chim.Acta 1993,76,521- 534).Thip-analogues (X=S) can derive from suitable for substituted oxazoles in this way：Deprotonation, it is anti-with dimethyl disulphide It answers, then bromination, lithiumation and carboxylated, subsequent demethylation (S.M.Nolan, T.Cohen, J.Org.Chem.1981,46, 2473-2476).Thiophene A211 and A212 are available from (substituted) thiophene：By deprotonation or lithiumation carry out 5- alkylations and/ Or 3- carboxylated (J.Sic é, J.Am.Chem.Soc.1953,75,3697-3700).Thip-analogues (X=S) can be done in this way Derived from (substituted) 2- trimethyl silyls oxygroup-cyclopropanecarboxylcompound：(C.Br ü ckner, H.- are reacted with carbon disulfide U.Reissig, Liebigs Ann.Chem.1988,465-470)。

Pyrroles A211 and A212 can be prepared from 2- chlorethylidenes-malonate suitable for substitution：Replaced with sodium azide, (F.-P.Montforts et al., Liebigs Ann.Chem.1990,1037- is then cyclized in the presence of triphenylphosphine 1043).Thip-analogues (X=S) can derive from 2- oxoethyls-malonate suitable for substitution：It is reacted with isothiocyanates, Then acid induction cyclisation and decarboxylation (J.Fuentes et al., Tetrahedron:Asymm.1998,9,2517-2532).

Type A213 and A214 furans can be achieved in that：2- hydroxyls-furans of 5- lithiumations/carboxylated (substituted) O- protections Or 5- bromination furans -2- carboxylates are then replaced with methide, demethylation (D.G.Manly, E.D.Amstutz, J.Org.Chem.1956,21,516-519).Thip-analogues (X=S) can derive from (substituted) 1,1- after demethylation Two (methyl mercapto) propyl- 1- alkene -3- ketone and bromacetate (A.Datta et al., Tetrahedron 1989,45,7631- 7641).Thiophene A213 and A214 can with compound A211 and A212 (J.Sic é, J.Am.Chem.Soc. 1953,75, 3697-3700) it is similarly prepared.The thip-analogues of thiophene A213 and A214 (X=S) can be synthesized from the 2- suitable for substitution Chloro- thiophene：5- carboxylated and the subsequent substitution of one sodium of sulphur hydracid (K.Clarke et al., J.Chem.Soc., Perkin Trans.1 1980,1029-1037).Pyrroles A213 and A214 can derive from the glutamate of the N-protected suitable for substitution, will It is converted into two dehydrogenation derivatives, in LiCuMe₂In the presence of be cyclized (M.M.Paz., F.J.Sardina, J.Org. Chem.1993,58,6990-6995)。

Thiophene A215 and A216 (X=S) can be synthesized from the bromo- thiophene of (substituted) 3-：3- lithiumations/sulfation, 2- bromines Change, 4- lithiumations/carboxylated, 2- debrominates and 3- demethylations (E.C.Taylor, D. E.Vogel, J.Org.Chem.1985, 50,1002-1004)。

Pyrroles A215 and A216 can be prepared from amino oxoacetate ester and oxalyl chloride：Alcoholysis isocyanates, with (3- bromines third Ketone group) reaction of triphenyl phosphonium bromide, N- deprotections (J.P.Bazureau et al., Tetrahedron Lett.1988, 29,1921-1922)；Or prepare the 3- oxos-proline ester protected from (substituted) N-Pfp-：Then reacted with alkali and acid (F.-A.Marcotte,W.D. Lubell,Org.Lett.2002,4,2601-2603).Thip-analogues (X=S) can obtain From pyrroles's -2- carboxylates suitable for substitution：Then with dicyano disulphanes and zinc/acetic acidreaction (A.Berlin et al., J.Chem.Soc,Perkin Trans.21990,5,699-704)。

Furans A217 and A218 can derive from (substituted) acetylene carboxylic acid's ester：With the ethyoxyl ethenylidene-suitable for substitution Four carbonyls-Ferrocene containing complex reacts, subsequent O- deprotection (Atiq-ur-Rehman et al., J.Am.Chem.Soc.1993,115,9848-9849).Thip-analogues (X=S) can be synthesized from the furans -3- suitable for substitution Carboxylate：Subsequent 5- brominations, react with dimethyl disulphide and S- be deprotected (G.Majetich et al., Tetrahedron Lett. 1994,35,4887-4890).Thiophene A217 and A218 should be available from (substituted) formoxyl amber Acid esters：In methanol, it is cyclized in the presence of hydrogen chloride and hydrogen sulfide, subsequent demethylation (S.Mitra et al., J.Chem.Soc.1939,1116-1117)；Or derive from (substituted) 2,4- dibromo thiophenes：Then and methanol, butyl lithium and dioxy Change carbon reaction, subsequent demethylation (D.Spinelli et al., J.Chem. Res. (M) 1993,8,1873-1890).Pyrroles A217 and A218 (ketone-tautomer) can derive from the succinic acid aminomethylene ester suitable for substitution：Alkali induction cyclisation (C.A.Grob,P.Ankli, Helv.Chim.Acta 1949,32,2023-2038).Thip-analogues (X=S) can be in fluorine Synthesis from (substituted) (trimethyl silyl) methyl-imino-diacetic thiocarbonic acid dimethyl esters and (replaces in the presence of change silver ) acetylene carboxylic acid's ester (A.Padwa et al., J.Org.Chem.1987,52,1027-1035).

A229-A234 oxazoles, thiazole and imdazole derivatives

Type A229 oxazoles can be achieved in that：Acetyl isocyanate and diazo acid ester are reacted, are then cyclized (O.Tsuge et al., Tetrahedron 1973,29,1983-1990), and thiazole A229 can be synthesized from dibromomalonic acid ester With thioamides (F.A.J.Kerdesky et al., J. Med.Chem.1991,34,2158-2165).Imidazoles A229 can be obtained From amidomalonic acid ester is reacted with substituted ethylenemine acid esters (M.S.Poonian, E.F.Nowoswiat, J.Org.Chem. 1980,45,203-208)。

Type A230 oxazoles and thiazole, which are available from the presence of trifluoroacetic anhydride, is cyclized acetylamino monoethyl malonate ( Dao oxazoles；J.Morgan et al., J.Chem.Soc., Perkin Trans.1 1997,5,613-620), or in five vulcanizations It is cyclized acetylamino monoethyl malonate in the presence of two phosphorus and (obtains thiazole；A.G.Long,A.Tulley, J.Chem.Soc.1964,1190-1192).Thiazole A230 (X=S) can be synthesized from N- ethanethioyls-glycine：PCl₃- Cyclisation is mediated, is then reacted with Vilsmeyer reagents and hydrogen sulfide, oxidation intermediates aldehyde (obtains 5- sulfydryls-thiophene of 2- substitutions Azoles；I.Y.Kvitko et al.,Chem.Heterocycl.Comp.1980,16,28-31)；Or it synthesizes from (substituted) 3- Bromo- 2- oxo-propionic acids：Reacted with thiocarbamide, via diazotising 2- take off amination, 5- brominations, substitution and deprotection (obtain 2- without Substituted 5- mercapto-thiazoles；B.Blank et al.,J. Med.Chem.1977,20,572-576).Imidazoles A230 (X=O) Amidomalonic acid ester can be derived from：It is reacted with trimethyl orthoformate, (R.S.Hosmane, B. is then cyclized in the presence of ammonia or amine B.Lim,Tetrahedron Lett.1985,26,1915-1918)；Or for (X=S) in the case of：Then by 2- ammonia Base -2- cyano-acetic acid esters reacts A.K.Sen, A.K.Mukhopadhyay with (substituted) trimethyl orthoformate and hydrogen sulfide, Indian J.Chem.B.1981,20,275-278)。

Oxazole A231 (X=S) should be obtainable：Initiate from glycollic aldehyde dimer and potassium rhodanide, subsequent S- methyl Change, lithiumation/be acylated with chloro-formate and demethylation (C.M.Shafer, T. F.Molinski, J.Org.Chem.1998, 63,551-555).Corresponding thiazole A231 (X=S) can be synthesized from the 'beta '-ketoester suitable for substitution：Then with [hydroxyl (tosyl Base oxygroup) iodine] benzene and ammonium dithiocarbamate reaction (P.-F.Zhang, Z.-C.Chen, Synth.Comm.2001,31, 415-420).Imidazoles A231 (X=S) can prepare the glycine from N-protected：Successively with formic acid, methyl formate and potassium rhodanide It reacts (G.van Lommen et al., Bioorg.Med.Chem. Lett.2005,15,497-500)；Or it is taken with suitable The chloracetate in generation carrys out the glycine of C- alkylation N-protecteds, then reacted with potassium rhodanide (J.Singh et al., Tetrahedron Lett.1993, 34,211-214)。

Type A232 oxazoles can be prepared from the diazo acid ester suitable for substitution：Rhodium-catalysis with cyanoformate It reacts (G.Shi et al., J.Fluorine Chem.1991,52,149-157).

Type A233 oxazoles can obtain：Heating is suitable for the acetylene carboxylic acid's ester and diazo acid ester of substitution, subsequent piptonychia Base (R.Huisgen, H.Blaschke, Chem.Ber.1965,98,2985-2997).S- analogs (the X=of oxazole A233 S) it is available from N- (dimethyl sulphur-based) glycinate：It is then sour to induce cyclisation and demethylation with DMF- aldolisations (R.Gompper,U. Heinemann,Angew.Chem.1981,93,297-298).Thiazole A233 (X=O) can be prepared certainly Suitable for the Ethitanin of substitution:It is reacted with surpalite, subsequent bromination/elimination (G. Serra et al., Heterocycles 1995,41,2701-2711)。

Oxazole A234 (X=O) can be prepared from the hydroxyacetonitrile and oxalyl chloride suitable for substitution：Subsequent methanol solution intermediate, Demethylation (K.van Aken, G.Hoornaert, J.Chem.Soc., Chem.Comm.1992,12,895-896).Thiazole A234 (X=O) is available from 2- mercaptoacetates and cyanoformate (G.Satzinger, Liebigs suitable for substitution Ann.Chem.1978, 473-511).Corresponding thip-analogues (X=S) can be prepared from (substituted) S- methyl 3- oxo sulphur For malonate and glycinate：The cyclisation then induced by thionyl chloride, demethylation (A. Rahman et al., Synthesis 1984,250-252)。

A235-A239 isoxazoles, isothiazole and pyrazole derivatives

Isoxazole A235 can synthesize (2- the methoxymethylenes)-malonate replaced from 2-：Then contain with azanol Water HCl reactions (K.Bowden et al., J.Chem.Soc.C 1968,172-185).Corresponding pyrazoles A235 can be similarly Prepare, but with hydrazine rather than azanol (T.M. Willson et al., Bioorg.Med.Chem.Lett.1996,6,1047- 1050)。

Isothiazole A236 can derive from the O- tosyloxy acetimidic acid esters suitable for substitution：With thio oxyacetate It reacts (B.Rezessy et al., Tetrahedron Lett.1992,33,6523-6526).Corresponding pyrazoles A236 can make The standby Acetylformic acid ester from suitable for substitution：It is reacted with diazanyl ethyl acetate, then carries out the cyclisation of methoxide-mediation (R.N.Comber et al., Carbohyd.Res.1992,216,441-452)；Or it prepares from the 3- oxopropanoic acids replaced Ester：2- diazotising, be then cyclized in the presence of sodium hydride (F.J.L.Herrera, C.U.Baelo, Carbohyd.Res.1985,143,161-174)。

Isoxazole A237 can be achieved in that：The chloro- 3- oxo-butynic acids esters of 4- and isopentyl nitrous acid ester that 4- are replaced are anti- It answers (G.Hesse, G.Krehbiel, Chem.Ber.1955,88,130-133).Pyrazoles A237 can derive from third suitable for substitution Two acid esters：(A.Bertho, H.N ü ssel, Liebigs Ann.Chem.1927,457,278- is reacted with diazo acid ester 307).Type A238 pyrazoles (ketone isomers) can be synthesized from the ketosuccinic acid suitable for substitution：In the presence of acetic acid with hydrazine reaction (K.J.Duffy et al.,J.Med.Chem.2001,44,3730-3745)。

Type A239 isoxazoles can derive from the 2- bromine maleic acids of 3- substitutions：Esterification, then reacts with hydroxycarbamide (C.Bennouna et al.,Bull.Soc.Chim.Fr.1980,2,478-480).Isothiazole A239 can be prepared and be taken from 3- The 2- amino fumaramides in generation：Then with hydrogen sulfide and bromine reaction, the amide then hydrolyzed to form (J.Lykkeberg, P.Krogsgaard-Larsen,Acta Chem.Scand.B 1976,30,781-785).Corresponding pyrazoles is available from (substitution ) maleate：With hydrazine reaction, then oxidation obtains pyrazole ring (G.P.Lahm et al., Bioorg.Med. Chem.Lett.2007,17,6274-6279)。

A240-A357 benzofurans, benzothiophene and indole derivatives

Benzothiophene A240 can be prepared with multi-step sequence：Originate in 2- hydroxyls-benzaldehyde suitable for substitution, by its turn 3- isopropoxy -2,3- dihydrobenzo thiophene -2- ketone is turned to, then further in 2- position functionals, and in the positions 3- carboxylate Change (A.V.Kalinin et al., J.Org.Chem. 2003,68,5992-5999).

Obtain the hexamethylene -1,3- diketone that the possible approaches of type A241-A243 benzofurans involve condensation suitable for substitution With the bromo- 2- oxo-propionic acids of 3-, subsequent Pd- catalysis dehydrogenation (G.Kneen, P. J.Maddocks, Synth.Comm.1986, 16,1635-1640).Indoles A244-A247 can derive from the bromo- 3- Nitro-benzoic acids esters of 2- suitable for substitution：Stille is coupled To corresponding 1- ethyoxyls-styrene, then Pd- catalyzed reductive cyclizations in the presence of CO, are then deprotected alcohol and acid (R.W. Clawson et al.,Tetrahedron 2006,62,10829-10834)。

Type A248-A251 benzofurans can be synthesized from 2,6- dihydroxy-benzoic ether suitable for substitution：With 2- chlorine ketone React (F.H.Curd, A.Robertson, J.Chem.Soc.1933,714-720) or in the presence of lewis acid and HCl with Chloroacetonitrile reacts, then 3- acetylations and reproducibility deoxygenated (W.Gruber, K.Horvath, Mh.Chem.1950,81, 828-836).Corresponding indoles A250 and A251 should be available from 6- hydroxy-3-methyl -2- Nitro-benzoic acids, by itself and dimethyl methyl Amide reacts, and then hydrogenates nitro, is cyclized, diazotising amine and hydroxylating (H.D.Hollis Showalter et al., J.Org.Chem.1996,61,1155-1158).Benzothiophene A250 and A251 can derive from the 2- (thiophene -3- suitable for substitution Base -) acetaldehyde：It is reacted with propargyl ethanol, alcohol is oxidized to acid, converts the iodo- compounds of 6- to alcohol by subsequent iodo- cyclisation (J.P.Waldo et al.,J.Org. Chem.2008,73,6679-6685)。

Type A252-A255 benzothiophenes are available from the 3- methyl-thiophene -2- carboxylate methyl esters suitable for substitution, first by it Be converted into 3- Toluenesulfinyl methyl compounds, then further in the presence of a base with suitable for substitution acrylate reactions, Obtain methyl ester (J.W. Terpstra, the A.M.van Leusen, J.Org.Chem.1986,51,230- of A252-A255 238).Indoles A252-A255 can be synthesized from 2- methoxyl group -4- methyl-benzoic acid methyl esters, then by it in 5- brominations, 3- nitrated in position, then reacts with dimethylformamide, is restored with Ra/Ni and hydrazine, this makes its cyclisation be 7- methoxyl group -6- methoxy carbonyls Base-indoles.Then, these intermediates can be deprotected to obtain indoles A252-A255 (P.L.Beaulieu et al., Bioorg.Med.Chem.Lett. 2006,16,4987-4993)。

The possibility precursor of benzofuran A256-A259 and A264-A267 are 2,4- dihydroxy-benzoic acid suitable for substitution Ester is subjected to 4- alkylations with bromoacetaldehyde diethyl acetal, then carries out the cyclisation of Amberlyst A15 mediations (M.Dixit et al.,Synlett 2006,10,1497-1502).Type A256-A259 (it is protected in 4- TMS-, if No other substituent groups) and A264-A267 indoles can derive from suitable for substitution 5- hydroxy-indoles：Form diethylamino formic acid Ester is rearranged to diethylamide through anion Fries after, is then hydrolyzed with aqueous NaOH or perchloric acid (E.J.Griffen et al.,J.Org.Chem.1995,60,1484-1485).Type A260 and A263 benzothiophene should can Derived from bis- bromo- benzene -1,3- formaldehyde of 4,6- (2- or 5- substitutions)：Then replace bromination with methoxide and with 2- mercaptoacetates Object, then be cyclized, decarboxylation, demethylation and oxidation aldehyde be acid (A.E.Jakobs et al., Tetrahedron 1994,50, 9315-9324)。

Type A268-A271 benzofurans can be synthesized from corresponding 4- hvdroxv-benzofurans：With two in the presence of methoxide Carbonoxide carboxylated (T.Reichstein, R.Hirt, Helv.Chim.Acta 1933,16,121-129) is synthesized from suitable Substituted 5- carbomethoxies -6- hydroxyls-salicyl aldehyde：It reacts with bromacetate, is cyclized with after saponification and in the presence of acetic anhydride (R.T.Foster,A.Robertson, J.Chem.Soc.1948,115-116).Corresponding benzothiophene A268-A271 should can make The standby 4- oXo-tetrahydro benzothiophenes from suitable for substitution：It is acylated with dimethyl carbonate, then uses DDQ aromatizations (P.P.Yadav et al.,Bioorg.Med.Chem.2005,13,1497-1505).Indoles A268-A271 can be similarly prepared from 4- oxygen Generation-tetrahydro indole, or alternatively prepare the 4- amino-salicylics from the N-protected suitable for substitution：Claisen resets O- allyls Ether then cracks double bond and cyclisation (T.Kakigami et al., Chem.Pharm.Bull.1988,46,42-52).Type A273-A275 benzofurans can derive from 4- hydroxyls-salicyl aldehyde of 4-O- protections：In the presence of tetrafluoro boric acid with diazoacetic acid Ethyl ester reacts, subsequent dewatering and deprotection (M.E.Dudley et al., Synthesis 2006,1711-1714).Benzo thiophene Pheno A272-A275 is available from the bromo- benzothiophenes of 5-, and (it can be prepared again from the bromo- thiophenols of 4- and bromoacetaldehyde diethyl suitable for substitution Base acetal)：Friedel-Crafts is acylated, and converts methyl ketone to carboxylate, and bromide is replaced and piptonychia with methoxide Base (S.Mitsumori et al., J.Med.Chem.2003,46,2446-2455).Corresponding indoles A272-A275 should be possible It synthesizes in this way：It is reacted Nenitzescu is carried out with substituted 2- amino acrylates suitable for the p- benzoquinones of substitution (E.A.Steck et al.,J.Org.Chem.1959, 24,1750-1752).Type A276-A279 benzofurans can obtain From 3- acetyl group -4- hydroxy-benzoic acid esters：Diethylaminoethyl ketone, the keto tautomer that subsequent alkali induction cyclisation is A276-A279 (G. Doria et al.,Farmaco 1980,35,674-680).The benzofuran A278 of 2- substitutions can be synthesized in this way：Alkane Base or acylation.Corresponding benzothiophene A276-A279 can prepare 4- fluorobenzoates and thio oxyacetic acid from suitable substitution Ester：AlCl is carried out to intermediate 4- alkoxy carbonyl groups-acetic acid thiophenyl ester₃The intermolecular Fridel-Crafts of induction is acylated (D.L.Gernert et al.,Bioorg. Med.Chem.Lett.2004,14,2759-2764)。

Type A284-A287 benzofurans and benzothiophene can be synthesized from the 3- furfurals or 3- formoxyls-suitable for substitution Thiophene：It is condensed with diethyl succinate, be then cyclized in the presence of acetic anhydride then alkali (D.Simoni et al., J.Med.Chem.2006,49,3143-3152).Type A284 and A287 indoles is available from 3- methoxyl group -4- amino-benzoic acids Ester：Subsequent 5- iodate carries out Sonogashira couplings with TMS- acetylene, carries out the cyclisation of CuI- mediations, subsequent demethylation (J. Ezquerra et al.,J.Org.Chem.1996,61,5804-5812).Type A288-A291 benzofurans and benzo Thiophene can derive from the 2- furfurals suitable for substitution, be similar to the description of A284-A287 (D.Simoni et al., J.Med.Chem.2006,49,3143-3152).Indoles A288-A291 can be similarly synthesized from pyrrole-2-aldehyde and amber Diethyl phthalate：Subsequent alkali induction cyclisation (C.Fuganti, S.Serra, J.Chem.Res. (M) 1998,10,2769-2782).

Type A292-A295 indoles can be prepared from the furans of N-protected simultaneously [3,2-b] pyrroles -5- carboxylic acid, ethyl esters：In quinoline Copper chromite decarboxylation is used in quinoline, then carrying out Diels-Alder with ethyl propiolate reacts, and is then deprotected (A.Krutosikova,M.Hanes,Collect.Czech.Chem. Comm.1992,57,1487-1494)。

Type A296-A299 benzofurans can derive from (p- acetoxyl group phenoxy group) chloroacetic chloride suitable for substitution：With cyanogen Compound is reacted, and cyclisation (the L.Crombie et mediated by zinc chloride (II) and hydrogen chloride are then carried out with 1,3- dihydroxy-benzene al.,J.Chem.Soc.,Perkin Trans.11987, 2783-2786).Corresponding benzothiophene A296-A299 can be closed At from the 3 bromo thiophene alcohol suitable for substitution, similar synthesis A272-A275 (S.Mitsumori et al., J.Med.Chem.2003,46, 2446-2455).Indoles A296-A299 can derive from the 6- oxyindoles of O- protections：Use trichlorine Chloroacetic chloride is acylated at 3-, methanol solution, be then deprotected (M.Fedouloff et al., Bioorg.Med. Chem.2001, 9,2119-2128)；Or：The acylated indoles suitable for substitution at 3-, then via Friedel-Crafts acylations/Baeyer- Villiger aoxidizes sequence 6- hydroxylatings (S.Nakatsuka et al., Heterocycles 1987,26,1471-1474).

Benzofuran A300-A303 can derive from 3- acetyl group-furans suitable for substitution：It is converted into silyl enol Ether, then progress Diels-Alder reactions, elimination and dehydrogenation (A.Benitez et al., J.Org.Chem.1996,61, 1487-1492)。

Benzofuran A304-A307 can synthesize 2- allyl -3- allyl oxygroup -4- methoxyl groups-benzene first from substitution Aldehyde：Isomerization/double decomposition then aoxidizes aldehyde and demethylation (W.A.L.van Otterlo et al., Tetrahedron 2005,61,7746-7755)；Or the bromo- benzaldehydes of 2- hydroxy-3-methoxies -6- that synthesis replaces certainly：Also carbinol, shape is at Phosphonium Salt is cyclized in the presence of acyl chlorides, subsequent lithiumation/carboxylated and demethylation (K.Hagihara et al., Bioorg.Med.Chem.Lett. 2007,17,1616-1621).Corresponding benzothiophene A304-A307 is available from suitable for substitution Methylthiophene -2- carboxylates：It is converted into 1- (2 '-thienyl)-Isosorbide-5-Nitrae-dioxo butane, then carries out BF₃The ring mediated Change, 4- carbonylations reacted by Vilsmeyer-Haack, aoxidize aldehyde and demethylation (S.S.Samanta et al., J.Chem.Soc.,Perkin Trans.1 1997,3673-3678)。

Indoles A304-A307 can be achieved in that：By the silyl enol compound of the 2- acetyl pyrroles of N-protected with Propiolate carries out Diels-Alder reactions, subsequent air oxidation (M.Ohno et al., Heterocycles 1991,32, 1199-1202)；Or it (is prepared with multistep sequence derived from 4- benzyloxies -2- methyl-3-nitros-benzoic ether suitable for substitution From 3- methyl phenols)：Then with dimethylformamide and zinc/acetic acidreaction, then deprotection (M.Tanaka et al., Eur.J.Med.Chem. 1996,31,187-198)。

A358-A372 pyrrolo-es [2,3-b] pyridine derivate

Pyrrolopyridine A365 and A366 can be synthesized from 7- azaindoles, first via pyridinyl-N-oxide by its The chloro- 7- azaindoles of 4- (X.Wang et al., J. Org.Chem.2006,71,4021-4023) of N-protected are converted into, with 5- lithiumations and carboxylated afterwards, hydrolyzable chloride and ester carry out N- deprotections (A.L ' Heureux et al., Tetrahedron Lett.2004,45, 2317-2320).Type A367 and A368 pyrrolopyridine can derive from the chloro- 3- first of 4- suitable for substitution Acyl group-pyridine：Reacted with triazoacetic acid ester, then carry out Hemetsberger-Knittel reactions (P.J.Roy et al., Synthesis 2005,2751-2757)。

Type A369 and A370 pyrrolopyridine can be available from the chloro- pyrrolopyridines of the 5- accordingly replaced：It is anti-in Duff Middle formylated is answered, is oxidized to acid, hydrolyzable chloride (R.H.Bahekar et al., Bioorg.Med.Chem.2007,15, 6782-6795).Pyrrolopyridine A371 and A372 can be synthesized from the chloro- 7- azaindoles of 4-：Pyridyl group-N- oxidations and-methyl Change, then replaced with cyanide, hydrolyzes nitrile and chloride (T.Storz et al., Synthesis 2008,201-214).

A373-A385 pyrrolo-es [2,3-c] pyridine derivate

Pyrrolopyridine A379 may derive from the iodo- 3- nitro-pyridines of 4- suitable for substitution：Sonogashira is coupled, will Alkynes ethyl alcohol solution restores nitro, carries out TiCl₄Mediate cyclisation (T. Sakamoto et al., Chem.Pharm.Bull.1986,34,2362-2368).Type A382 and A383 pyrrolopyridine can be prepared from 2- methoxies The iodo- 5- aminopyridines of base -4-：Sonogashira couplings are carried out with TMS- acetylene, the cyclisation of CuI- mediations are carried out, in 3- first Acylated (and oxidation) and demethylation (D.Mazeas et al., Heterocycles 1999,50,1065-1080).

Type A384 and A385 pyrrolopyridine is available from 4- methoxyl groups-pyrroles's -2- formaldehyde suitable for substitution：Use 3,3- Diethoxy -2- amino-propionic acid ester reduction aminations carry out TiCl₄The cyclisation mediated and demethylation (S.K.Singh et al.,Heterocycles 1997,44,379-392)。

A386-A398 pyrrolo-es [3,2-c] pyridine derivate

Pyrrolopyridine A387 and A388 can be achieved in that：Initiate from the alkylated 2- formoxyls-pyrroles of N- suitable for substitution It coughs up, via 2- pyranose propylene benzenesulfonyl azides, it is pyrrolopyridinone to be then cyclized.Then, via corresponding aldehyde by this A little intermediates are converted into 3- carboxyl compounds (J.S. New et al., J.Med.Chem.1989,32,1147-1156).Type A389 and A390 pyrrolopyridines can derive from the 2- methoxyl group -3- Formyl-pyridins suitable for substitution：It is anti-with triazoacetic acid ester Answer, then carry out Hemetsberger-Knittel reactions, be similar to synthesis A367 and A368 (P.J.Roy et al., Synthesis 2005,2751-2757)。

A399-A413 pyrrolo-es [3,2-b] pyridine derivate

Type A406 and A407 pyrrolopyridine can derive from the 2- (6- methoxyl group -3- nitro -2- pyridyl groups)-of substitution Acetic acid esters：Knoevenagel is carried out with formaldehyde to react, then Pd- catalytic cyclizations in the presence of hydrogen and CO (B.C.G.Soederberg et al.,Synthesis 2008,6,903-912)。

Pyrrolopyridine A410 and A413 can be synthesized from the chloro- 3- nicotinic acid nitriles of 2- suitable for substitution：It is carried out with TMS- acetylene Sonogashira is coupled, then by alkynes ethyl alcohol solution, nitrile of degrading, final acid induction cyclisation (T.Sakamoto et al., Chem.Pharm.Bull.1986,34,2362-2368).Alternatively, A410 and A413 can be synthesized in this way：It will be suitable for substitution 3- nitro-pyridines react (Z.Zhang et al., J.Org.Chem.2002,67,2345-2347) with vinyl magnesium bromide. Pyrrolopyridine A408 and A412 can derive from 2- alkynyl -3- amino-pyridines (A.M.Palmer et by CuI- catalytic cyclizations al.,Bioorg.Med.Chem.2008,16,1511-1530)。

A414-A449 benzoxazoles, benzothiazole and benzimidizole derivatives

Benzoxazole A415 and A416 can be prepared：The chloro- 4- anisidines of 3- for initiating from N- acylations, via benzyne- It is formed and carboxylated (D.R.Reavill, S.K.Richardson, Synth. Comm.1990,20,1423-1436).Corresponding benzene And imidazoles A415 and A416 be available from 2- amino -3- it is halogenated-benzoic ether：Amine is acylated, in 6- nitrated in position, alkylated amide and It is cyclized (K.Kubo et al., J.Med.Chem.1993,36,1772-1784) under reductive condition.

Type A417-A419 benzimidazoles can derive from 4- acetylaminohydroxyphenylarsonic acid 2- methoxy-benzoic acid esters：Then at 5- Chlorination, in 3- nitrated in position, then in the presence of carboxylic acid or formic acid reductive cyclization obtain 3- nitro -4- amino-benzoic acid esters (S.Bolgunas et al.,J.Med.Chem.2006, 49,4762-4766).The reductive cyclization program may be also suitable Synthesize other benzimidazoles.Benzimidazole A420-A422 is available from corresponding 5- methoxyl groups -6- methyl-benzoimidazoles：Demethylation Change and oxidation methyl is carboxylate/ester (B.D.Palmer et al., J.Med.Chem.1999,42,2373-2382).Type A423-A425 benzoxazoles can be achieved in that：It is condensed the 4- methylene -2- oxazoline -5- ketone and 4- dihalotriphenylphosphoranes of substitution Subunit -3- oxobutanoic acid esters, then carry out iodo- mediation aromatization (F.Clerici et al., Tetrahedron 1991, 47,8907-8916).Corresponding benzimidazole A423-A425 may should in this way be synthesized：Initiate from 4- amino -2- hydroxyl -5- nitros Then benzoic ether restores nitro and cyclisation, such as to the description of the chloro- benzoic ethers of 2- (A. Tanaka et via acylation al.,Chem.Pharm.Bull.1994,42,560-569).Type A426-A428 benzoxazoles can synthesize in this way：Starting From 2,5-dihydroxybenzoic acid ester, with multi-step sequence by it in 6- aminations, then acylated and cyclisation (D.Diez-Martin et al.,Tetrahedron 1992, 48,7899-7939)。

Benzimidazole A429-A431 should be available from 3, the 4- diamino -2- hydroxy-benzoic acid esters of O- protections, by one acyl Change, then in acid condition cyclisation (Y.Hirokawa et al., Chem. Pharm.Bull.2002,50,941-959； A.Viger,P.B.Dervan,Bioorg.Med. Chem.2006,14,8539-8549).Type A438-A440 benzothiazoles It can synthesize in this way：4- amino -3- methoxy-benzoic acids salt/the ester and sulphur suitable for substitution are heated in the presence of copper sulphate (II) Potassium cyanate, subsequent 2- take off amination and 3- demethylations (I.A.Ismail et al., J.Org.Chem. 1980,45,2243- 2246).Benzimidazole A441-A443 can be prepared with multi-step sequence：From 8- aminoquinolines via corresponding 5,6- dihydros -4H- miaows Azoles and quinoline (R.C.Elderfield, F.J. Kreysa, J.Am.Chem.Soc.1948,70,44-48).Benzimidazole A444 It can be achieved in that with A447：It will react with nitrile suitable for 3- amino-4-methoxyls-benzoic ether of substitution, then carry out The cyclisation of NaOCl- inductions and then deprotection (J.Reagn et al., Bioorg.Med. Chem.Lett.1998,8, 2737-2742)。

A450-A459 benzoisoxazoles, benzisothiazole and indazole derivative

Type A456 and A459 benzoisoxazole can synthesize in this way：Initiate from 2,6- dihydroxy -3- formoxyl -4- first Base-benzoic ether, with azanol reaction, subsequent thermal cyclization (D.H.R.Barton et al., J.Chem.Soc.C 1971,2166- 2174).It is also possible to be used to synthesize other benzoisoxazoles (A450-A455, A457 and A458) by this method.Prepare indazole A457 has been described：3- amino -2- methoxyl group -4- methyl benzoic acid esters are reacted with isopentyl nitrous acid ester, subsequent demethylation Change (S.Bolgunas et al., J.Med.Chem.2006,49,4762-4766)；For other indazoles (A450-A456 and A458) seem it is feasible.

A460-A515 naphthalene derivatives

The suitable substituted naphthalene derivatives of relatively large amount are commercially available.In addition, type A460-A465 and A496- A499 naphthalenes can derive from corresponding 2- hydroxyls-naphthalene (K.Takahashi et al., Tetrahedron via lithiumation and carboxylated 1994,50,1327-1340).Alternatively, the demethylation of 2- methoxynaphthalenes carboxylic acid have been described (Y.Gao et al., J.Med.Chem.2001,44, 2869-2878).Higher substituted compound can be with multi-step sequence via 2- tetralones- 1- carboxylates are prepared from the 2 bromo toluene suitable for substitution, and F.C.Goerth et al., Eur.J.Org. are similar to The method of Chem.2000,2605-2612 descriptions.

The naphthalene of type A478-A483 and A508-A511 can be prepared：Demethylation 3- methoxynaphthalene -1- carboxylates (R.E.Royer et al.,J.Med.Chem.1995,38,2427-2432)；Or diazotising and then hydrolyze corresponding 3- ammonia Base naphthalene -1- carboxylates (K.J.Duffy et al., J.Med. Chem.2001,44,3730-3745).

Type A484-A489 and A504-A507 naphthalene can be readily constructed by carrying out condensation reaction with succinate：Starting From benzaldehyde (A.M.El-Abbady et al., the J.Org. Chem.1961,26,4871-4873 suitable for substitution； M.Kitamura et al., Angew.Chem.Int.Ed. 1999,38,1229-1232) or from benzophenone (F.G.Baddar et al., J.Chem.Soc. 1955,1714-1718) depends on the substitute mode of desired product.

Type A490-A495 and A512-A515 naphthalene derivatives can derive from 2- methoxynaphthalenes：In 4- brominations, lithiumation bromine Compound, subsequent carboxylated and demethylation (J.A.O ' Meara et al., J. Med.Chem.2005,48,5580-5588)； Or derive from the chloro- naphthalenes of 2-：With phthalic anhydride, then carry out KOH- inductions cracking (G.Heller, Chem.Ber.1912,45, 674-679)。

A516-A548 quinolines

Type A516-A518 quinoline can synthesize in this way：It will be suitable for the isatin of substitution and substituted benzoyl first Bromide compound reacts (H.John, J.Prakt.Chem.1932,133,259-272；E.J.Cragoe et al., J.Org.Chem.1953,18,552-560)。

Type A522-A524 quinoline can be via modificationSynthesis easily derives from the 2- suitable for substitution Amino-benzaldehyde (D.L.Boger, J.-H.Chen, J.Org.Chem.1995,60,7369-7371).Similarly, quinoline spreads out Biological A527-A529 can by with malonic acid condensation derive from 2- aminobenzaldehydes (J.Troeger, C.Cohaus, J.Prakt.Chem.1927,117, 97-116)。

Quinoline A525 can by reset synthesis from corresponding 2- cyano quinolines -1- oxides (C. Kaneko, S.Yamada, Chem.Pharm.Bull.1967,15,663-669).Quinoline A526 (4- substituted) is available from substituted 2- ammonia in principle Benzoylformaldoxime (substituted on acetyl group part)：It is reacted with the chloro- 3- oxopropanoic acids esters of 3-, subsequent alkali induction cyclisation (A.Capelli et al.,Bioorg. Med.Chem.2002,10,779-802)。

Type A530-A533 quinoline can be constituted in this way：2- anisidines are initiated from, are reacted with 2- oxosuccinic acid esters, with Thermal cyclization afterwards, demethylation and via hydrogenate corresponding chloride remove 4- hydroxyls (L.Musajo, M.Minchilli, Chem.Ber.1941,74,1839-1843)。

Condensation has been described suitable for the isatin of substitution with malonic acid synthesis type A543-A545 quinoline (e.g.W.Borsche,W.Jacobs,Chem.Ber.1914,47,354-363；J.A. Aeschlimann, J.Chem.Soc.1926,2902-2911)。

A549-A564 isoquinilone derivatives

The 1- type A549-A553 isoquinolin with carboxylate can be prepared from the benzaldehyde suitable for substitution：By its turn Aminoethane is turned to, then with oxalate aldehyde or acyl chloride reaction, is cyclized, oxidizing aromatic and final saponification (M.Keizo et al.,Chem.Pharm.Bull.1982,30, 4170-4174；S.Naoki et al.,Chem.Pharm.Bull.1989, 37,1493-1499)。

Isoquinolin -3- carboxylates (A554-A556) are available from hydroxylated phenylalanine：Via Bischler- Napieralski reacts, subsequent oxidizing aromatic；Or alternatively derive from the 2- tolyl aldehydes of suitable substitution：By itself and nitrine Acetic acid methyl ester reacts, and is then cyclized under heat condition, subsequent aromatization (Y.Fukuda et al., J.Med.Chem.1999, 42,1448-1458；T.R. Burke et al.,Heterocycles 1992,34,757-764).

Type A557 and A558 compound can construct in this way：It will be suitable for the 2- ammonia of substitution in the presence of amyl nitrous acid ester Benzoic acid and the chloro- 3- carboxyls -1,2 of 5-, the reaction of 4- pyrazines, then hydrolyze (A.M. d ' A.Rocha Gonsalves, T.M.V.D.Pinho e Melo, Tetrahedron 1992,48,6821-6826), and isoquinolin A559 and A560 can this It is prepared by sample：It by 2- formylbenzoates and 2- Thioxothiazolidin -4- reactive ketones, is then cyclized, with ethyl alcohol ammonia by different thio chromone It is converted into isoquinolin (D.J.Dijksman, G.T.Newbold, J.Chem.Soc.1951,1213-1217).

Isoquinolin A561 and A562 may be achieved in that：It will be converted into corresponding Reissert chemical combination suitable for the isoquinolin of substitution Object, in 4- nitrated in position, hydrolysis nitrile (M.Sugiura et al., Chem. Pharm.Bull.1992,40,2262-2266) is then Nitro is hydrogenated, diazotising amine is converted into hydroxyl.

Type A563 and A564 isoquinolin is available from (2- methoxycarbonyl-phenyls -) acetic acid suitable for substitution：Via with formic acid Methyl esters reacts, the enol that then cyclisation is formed, the heterochromatic ketone of amination (H.E. Ungnade et al., J.Org.Chem.1945, 10,533-536)。

A565-A577 quinazoline derivants

The most universal approach of quinazoline is obtained using the phenyl derivatives that suitably replace, and to being cyclized pyrimido ring thereon, Such as cyclic condensation 2- aminobenzamides and oxalate (M.Suesse et al., Helv.Chim.Acta 1986,69, 1017-1024), the substitution of cyclic condensation o- carbonyl phenyl oxamate with ammonium formate (S.Ferrini et al., Org.Lett.2007,9,69-72) or cyclic condensation 2- aminobenzonitriles and carbonyl formyl imidoate or chloromethane amidine (A.McKillop et al.,Tetrahedron Lett.1982,23,3357-3360；N.Harris et al., J.Med.Chem.1990,33,434-444) or the o- oxalyl N- anilids of cyclic condensation and ammonia (M.T.Bogert, F.P. Nabenhauer,J.Am.Chem.Soc.1924,46,1702-1707)。

A578-A587 quinoxaline derivants

It is fully described (E. Lippmann et via their 2- formaldehyde synthesis type A578-581 quinoxalines al.,Zeitschr.Chem.1990,30,251-252).Other representatives of these groups A582-587 are achieved in that：By β-two Carbonyl derivative or 'beta '-ketoester and ortho-phenylene diamine cyclic condensation (S.Grivas the et al., Acta suitably replaced Chem.Scand.1993,47,521-528；A. Zychilinski,I.Ugi,Heterocycles 1998,49,29-32； D.Zhou et al.,Bioorg. Med.Chem.2008,16,6707-6723).Unique quinoxaline is by applying tobacco The enzyme catalyst bioconversion of arthrobacterium (Arthrobacter nicotianae) introduces the possibility of carboxyl at 2- (T.Yoshida et al.,Biosci.Biotech.Biochem.2002,66,2388-2394)。

A588-A601 pyridos [5,4-d] pyrimidine derivatives

Double loop core can be by obtaining through ring-closing condensation reaction and ring suitable for the pyridine of substitution.Feasible raw material includes pyridine- 2,3- dicarboxylic acids (A.Tikad et al., Synlett 2006,12,1938-1942), 3- aminopyridine -2- carboxylates (M.Hayakawa et al., Bioorg.Med.Chem.2006,14,6847-6858) or 3- aminopyridine -2- nitriles (J.B.Smaill et al.,J.Med.Chem.2000,43, 1380-1397)。

A602-A608 pyrimidos [5,4-d] pyrimidine derivatives

The pyrimido-pyrimidine group of template may be via (the G. Rewcastle et of 4,6- dichloro-derivatives known to document al.,J.Med.Chem.1997,40；12,1820-1826) or corresponding tetra- chlorine derivatives of 2,4,6,8- (J.Northen et Al., J.Chem.Soc., Perkin Trans.1,2002,108-115) it obtains, with above-mentioned conventional method and detach desired Heterogeneous mixture.

A609-A618 tetrahydronaphthalenderivatives derivatives

Cause many response procedures of tetrahydronaphthalenderivatives derivatives to involve intermolecular Friedel-Crafts to be acylated as crucial Step, and can be prepared from phenylacetonitrile as the cyclization precursor of prerequisite, 2- phenylmalonic acids ester (R.S.Natekar, S.D.Samant,Indian J.Chem.,Sect.B:Org. Chem.Incl.Med.Chem.2002,41,187-190； L.Gong,H.Parnes,J. Labelled Compd.Radiopharm.1996,38,425-434).Alternatively, intermolecular ring Change to react by Buchner and realizes (A.Cheung et al., Bioorg.Med.Chem.Lett. 2003,13,133- 138).Then, the carbonyl for the 1- or 2- tetralones being achieved in that can be easily converted to carboxy moiety (M.Meyer et al.,J.Med.Chem.1997,40,104-1062；F. Berardi et al.,J.Med.Chem.2004,47,2308- 2317)。

A619-A626 indan derivatives

At 1-, the indan derivative of the type A619-A623 with carboxyl is available from suitably replacing and being easy to get 3- cyano-indenes：Hydrogenation is indane core, subsequent hydrolysing carboxylic part (T. McLean et al., J.Med.Chem.2006, 49,4269-4274).Indan-1-one can be also converted to indane -1- carboxylic acids, such as via ethylene oxide (D.-I.Kato et Al., 2003,68,7234-7242 J.Org.Chem.), or via 1,3- dithiane in Corey-Seebach- type reactions (Y.-P.Pang et al.,J.Org.Chem.1991,56,4499-4508)。

At 2-, the indan derivative of the type A624-A626 with carboxyl can easily take derived from obtainable The indan-1-one in generation：Corresponding enolate is handled with dimethyl carbonate, the ester group of hydrogenized carbonyl and hydrolysis introducing (T.Tanaka et al.,Chem.Pharm.Bull.1994, 42,1756-1759；U.Hacksell et al.J.Med.Chem.1981,24,429-434).Alternatively, indane ring system can construct in this way：Ortho-xylene is initiated from, Two methyl nubbins of NBS brominations are alkylated-spirocyclization and final glutamic acid ring with the enolate of barbituric acid It is cracked into indan-2-carboxylic acids (G.A.Kraus et al., J.Org.Chem.2002,67,5857- 5859).

Synthesize the structural unit of instrumentality B

The instrumentality part B of big ring I is derived from the amino alcohol suitably replaced, wherein contributing to the amino and alcohol radical that ring connects Group is separated by 2-4 C- atom.

If be not present in commercial construction unit, can by by the nucleophilic addition of organometallic reagent standard extremely Carbonyl or carboxy derivatives introduce substituent R³.It is above-mentioned for not carrying the B18-B21 of additional C- substituent groups in its ring system Precursor is commercially available.Similarly, in the case of B9, B10, B16 and B17, diversified substituent group form can be easily It realizes：Standard conversion is carried out (namely in B9-NH to the business analog with unhindered amina function₂→-NR¹¹R²⁷And - NH →-NR under B10, B16 and B17¹¹)。

B1 aziridine derivatives

In general, the acquisition of hydroxymethyl aziridine relies on the response procedures for involving structure aziridine ring.Using widest original Material is 'beta '-ketoester：It is converted into beta-hydroxy imino analogs thereof, intermolecular cyclization is aziridine ring, and ester reduction is alcohol groups, is obtained 1 structural unit of type B (such as T.Sakai et al., J.Org.Chem.2005,70,1369-1375).Alternative approach uses α, β-dihalogenated ester are translated into 1 substance of type B (P.Davoli et via carrying out aziridine with ammonia and restore ester group al., Tetrahedron 2001,57,1801-1812)。

B2-B3 azetidine derivatives

The standard way for obtaining hydroxymethylazetidine include so that readily available O- protection glycidol according to It is secondary to carry out using azide epoxides-open loop, convert the OH groups for the alcohol being achieved in that suitable leaving group (example Such as tosylate or sulfuric ester), azide is reduced to amine, with intermolecular cyclization (F.Hosono et al., Tetrahedron 1994,50, 13335-13346；D.-G.Liu,G.-Q.Lin,Tetrahedron Lett.1999,40, 337-340)。

B4-B8 pyrrolidin derivatives and B11-B15 piperidine derivatives

The route of synthesis of pyrrolidines and piperidines structural unit B rely on same policy and therefore discuss together.It can will divide Cyclization prominent pathway is applied to the substrate of the different substitutions of wide quantity between son：The portions leaving group remnants are carried in ω-position Point amine by intramolecular nucleophilic substitution directly result in desirable saturation ring system (G.Ceulemans et al., Tetrahedron 1997,53, 14957-14974；S.H.Kang,D.H.Ryu,Tetrahedron Lett.1997,38, 607-610； J.L.Ruano et al.,Synthesis 2006,687-691).N- halogenated amines can also pass through Hofmann-- Freytag reactions are converted into desirable compound (M.E.Wolff, Chem.Rev.1963,63,55- 64).Alternatively, cyclization double decomposition (RCM) reaction can be carried out by carrying two kinds of substituent group amine of each tool alkene or acetylene bond (Y.Coquerel, J.Rodriguez, Eur.J. Org.Chem.2008,1125-1132), then restores the portion being achieved in that It is saturated heterocyclic to divide undersaturated ring.

The analog that five yuan of corresponding aromatics and hexa-member heterocycle are reduced to its saturation is also described in document.However, by In a large amount of commercially available pyridines, the approach be mainly used for synthesizing piperidines system (J. Bolos et al., J.Heterocycl.Chem.1994,31,1493-1496；A. Solladie-Cavallo et al.,Tetrahedron Lett.2003,44,8501-8504；R.Naef et al.,J.Agric.Food Chem.2005,53,9161-9164).

The program description for synthesizing general formula structure I macrocyclic compound library is as follows, but bright for a person skilled in the art Aobvious is, if it is desired to synthesize the big ring type Compound I of a list, can modify these programs.

Macrocyclic compound of the present invention is obtained by being cyclized suitable linear precursor, and above-mentioned linear precursor is derived from optionally through taking The hydroxyaryl in generation, hydroxyl heteroaryl, sulfydryl aryl or sulfydryl heteroaryl carboxylic acid A (" template ", a), substituted amino alcohol B (" Instrumentality ", b) and formed " bridge " one to three types C structural units, c.

Variable substituents introduce in this way：Derivatization one or more structural unit B and C and optional before cyclic or after cyclization The tie point (such as amino, carboxyl, hydroxyl) of orthogonal protection on A.Variable R- groups are also used as side chain die body and introduce structure Make unit C.

The big ring product of the present invention can be prepared in the solution or on solid support.

According to the present invention, ring-closure reaction may occur between arbitrary structural unit in principle.

The big rings of general formula structure I with the bridge c for forming structural unit c are achieved in that：

A) Macrocyclic lactams between c and B；Or

B) Macrocyclic lactams between A and c；Or

C) aryl ether or thioaryl ether are formed between A and B；Or, alternatively,

D) Ring-closing metathesis reaction is also possible in Type C structural unit.

The big ring of structure I of Huan Wai functional groups (derivatization tie point) with orthogonal protection passes through following processes in the solution It prepares, which includes：

a¹) protect the hydroxyl-of suitable protecting or sulfydryl-aryl/hetaryl carboxylic acid PG-A-OH and the suitably ends C- Suitably the structural unit H-c1-OPG of side chain protection is condensed to form PG-A-c1-OPG；

b¹) if desired, discharging aryl/hetaryl (phenol) OH groups or sulfydryl respectively；

c¹) with the amino alcohol HO-B-PG of suitably N-protected form aryl/hetaryl ether or thioether causes to protect completely Linear cyclization precursor PG-B-A-c1-OPG；

d¹) cracking " main chain " protectiveness group (PG) provide free amino acid H-B-A-c1-OH (still carry suitable protecting Side chain functionalities)；Then select a progress：

e¹) coupling of intermolecular amide provides the big rings of general formula I of protection and (generate ring-(B-A-c1), still carry orthogonal protection Side chain functionalities)；Or

f¹) N- protects again in step d¹) in obtain product；

g¹) the coupling amino acid H-c2-OPG that suitably C- is protected；

h¹) cracking " main chain " protectiveness group provide free amino acid H-B-A-c1-c2-OH (still carry suitable protecting Side chain functionalities)；

i¹) coupling of intermolecular amide provides the big rings of general formula I of protection and (generate ring-(B-A-c1-c2)；Still carry orthogonal guarantor The side chain functionalities of shield)；Or

j¹) N-protected is in step d¹) in obtain product；

k¹) the coupling amino acid H-c2-OPG that suitably C- is protected

l¹) crack C- end protectiveness groups or cracking N- and C- end main chain protectiveness groups and protect the ends N- again；

m¹) the coupling amino acid H-c3-OPG that suitably C- is protected；

n¹) release " main chain " protectiveness group, free amino acid H-B-A-c1-c2-c3-OH is provided and (still carries protection Side chain functionalities)；With

o¹) coupling of intermolecular amide, the big rings of general formula I for providing protection (generate ring-(B-A-c1-c2-c3), still carry guarantor The side chain functionalities of shield).

By suitable protecting, preferably acyloxy-or acylmercapto-, most preferably acetoxyl group-or acetyl group sulfydryl-substitution Aryl/hetaryl carboxylic acid (PG¹- A-OH) it is converted into corresponding acyl chlorides and in auxiliary alkali (such as iso- Pr₂NEt, Et₃N, pyridine, three Picoline) in the presence of, in solvent such as CH₂Cl₂, CHCl₃, in THF with the amino-acid ester H-c1-OPG suitable for protection²Contracting It closes, (preferably ammonolysis) provides hydroxyl or sulfydryl aryl/hetaryl amide H-A-c1-OPG after deacylation²。

Ammonolysis is advantageously carried out in solvent such as THF with dialkyl aminoalkyl amine at 0-25 DEG C.It was reacting as a result, The acyl amine byproduct formed in journey can be removed by being extracted with acidic aqueous solution.

Alternatively, acyloxy or acylmercapto aryl/hetaryl carboxylic acid (PG¹- A-OH) it can be in coupling reagent (such as benzene And triazole derivative, such as HBTU, HCTU, PyBOP or their aza analogues such as HATU or carbodiimide such as EDC) In the presence of be coupled to amino-acid ester H-c1-OPG², phenol or thiophenol H-A-c1-OPG are provided after deacylation²。

Phenol H-A-c1-OPG²Hydroxyaryl/heteroaryl carboxylic acid H-A- can also be derived directly from the presence of coupling reagent OH and amino-acid ester H-c1-OPG²。

With the amino alcohol HO-B-PG of suitably N-protected³Come alkylating phenol or thiophenol H-A-C₁-OPG², obtain ether or sulphur Ether PG³-B-A-c1-OPG²It is achieved：At 0 DEG C to room temperature, in the presence of trialkyl or triaryl phosphine, in solvent such as benzene, first Benzene, CH₂Cl₂, CHCl₃Or in THF, azoformic acid derivative such as DEAD, DIAD or ADDP are used.As modification, the reaction It can be induced with CMBP in toluene in 20-110 DEG C of temperature.

As alternative, alcohol HO-B-PG³Corresponding sulphonic acid ester (such as methanesulfonates, tosylate, trifluoro can be converted into Methanesulfonates) or corresponding halide (such as chloride, bromide and iodide), then in auxiliary alkali such as NaH or K₂CO₃It deposits Phenol or thiophenol H-A-c1-OPG are used in solvent such as DMF, DMSO, NMP, HMPA, THF under²Processing, obtains ether or thioether PG³-B-A-c1-OPG²。

Simultaneously or substep cracks main chain protectiveness group, provides linear amino cyclization precursor H-B-A-c1-OH.Alloc (PG³) and allyl ester group (PG²) it is preferred blocking group and most preferably in the presence of 1,3- dimethyl barbituric acids, Solvent such as CH₂Cl₂Or by palladium catalyst such as Pd (PPh in or mixtures thereof EtOAc₃)₄It mediates and carries out while cracking.

In solvent such as CH₂Cl₂Or in DMF under high dilution condition and temperature be 20 to 100 DEG C with coupling reagent such as T3P or FDPP handles cyclization precursor H-B-A-c1-OH (if desired, in the such as iso- Pr of auxiliary alkali₂In the presence of NEt), occur big Cyclic lactam generates ring-(B-A-c1).

Such as the Macrocyclic lactams mediated by FDPP can be found in J.Dudash, J.Jiang, S.C. Mayer, M.M.Joullié,Synth.Commun.1993,23(3),349-356；R.Samy, H.Y.Kim,M.Brady,and P.L.Toogood,J.Org.Chem.1999,64,2711- 2728。

Known many other coupling reagents have been used for above-mentioned be cyclized end to end to prepare Macrocyclic lactams, and above-mentioned other idols The above-mentioned reaction that joint-trial agent may be participated in alternatively.Example includes benzotriazole derivatives such as HBTU, HCTU, PyBOP and its Aza analogues such as HATU and DPPA and carbodiimide such as EDC, DIPCDI；For example, see P.Li, P.P.Roller, Current Topics in Mecicinal Chemistry 2002,2,325-341；D.L.Boger,S. Miyazaki,S.H.Kim,J.H.Wu,S.L.Castle,O.Loiseleur,and Q.Jin,J. Am.Chem.Soc.1999, 121,10004-10011)。

The another selection for obtaining Macrocyclic lactams includes amino (the carbamate remove-insurance for carrying out active ester and discharging in situ Shield, azide reduction) intermolecular reaction, as example shown in synthetic peptide alkaloids and vancomycin model system (U.Schmidt,A.Lieberknecht,H. Griesser,J.Talbiersky,J.Org.Chem.1982,47,3261- 3264；K.C. Nicolaou,J.M.Ramanjulu,S.Natarajan,S.H.Li,C.N.C.Boddy, F.Rü bsam,Chem.Commun.1997,1899-1900.)

N- protects H-B-A-c1-OH standard amino acid protection scheme can be used to realize again.In solvent such as dioxane, such as Fruit needs in alkali such as K₂CO₃In the presence of aqueous solution, chloro-formate or N- hydroxy-succinimide base carbonate reactions obtain N- The amino acid PG of protection³-B-A-c1-OH。

Being coupled additional amino acid can be carried out with classical peptide coupling condition.

Structural unit c1-c3 can be derived from amino acid (such as the Dap, Dab, Orn, Lys, Asp, Glu of trifunctional Derivative), main chain or side chain functionalities can be a parts for big ring skeleton.

The amino acid structural unit of non-protein trifunctional can be obtained by various synthetic methods, especially form alkyl Change Ser, HomoSer, Thr pendant hydroxyl group or the sulfydryl with Ω-haloalkyl carboxyl esters' derivatization Cys, HomoCys..

The alternative approach of synthesis macrocyclic compound of the present invention includes

a²) H-A-c1-OPG is synthesized as described above²Segment；

b²) use the amino acid PG that suitably ends N- are protected⁴- c2-OH carrys out N- acylated amino group alcohol HO-B-H, provides amide groups Alcohol PG⁴-c2-B-OH；

c²) with condition as described above, initiate from H-A-c1-OPG²And PG⁴- c2-B-OH, synthesizing aryl or thioaryl Ether；

d²) release " main chain " protectiveness group obtain cyclization precursor H-c2-B-A-c1-OH；With

e²) Macrocyclic lactams are carried out as described above, the big rings of general formula I (ring-(c2-B-A-c1), the side chain of protection are provided Functional group still carries orthogonal protectiveness group).

Segment PG⁴- c3-B-OH can be prepared：The amino acid PG4-C3-OH protected with the suitable ends N- is come N- Acylated amino group alcohol HO-B-H.N- is deprotected and is coupled to the amino acid PG of the suitably ends N- protection⁵- c2-OH provides alcohol PG⁵- Then c2-c3-B-OH can be translated into and (carry out corresponding to c²), d²) and e²) the step of) and protection the big ring (rings of general formula I (c2-c3-B-A-c1), side chain functionalities still carry orthogonal protectiveness group).

As another alternative, cyclisation can be obtained by cyclization double decomposition.The big rings of general formula structure I of orthogonal protection are with following Process synthesizes comprising

a³) the optionally substituted alkenyl amine of the structural unit c1 (alkenyl) containing Type C is coupled to acyloxy or hydroxyl Base or acylmercapto aryl/hetaryl carboxylic acid PG¹-A-OH；

b³) if desired, discharging aryl/hetaryl (phenol) OH groups or sulfydryl respectively；

c³) with optionally suitable for the alkene-carboxylic acid PG of substitution⁶- c2 (alkenyl)-OH carrys out N- acylated amino group alcohol HO-B-H, provides Amide groups alcohol PG⁶- c2 (alkenyl)-B-OH；

d³) aryl or thioaryl ether are formed as described above, generate cyclization precursor PG⁶- c2 (alkenyl)-B-A-c1 (alkenyl)；

e³) Ring-closing metathesis；And

f³) optionally hydrogenated step e³) metathesis product newly generated ethylenic double bond.

Ring-closing metathesis with from ethylenic precursor formed macrocyclic compound be it is well known (for example, see A. F ü rstner, O.Guth,A.Duffels,G.Seidel,M.Liebl,B.Gabor,and R. Mynott,Chem.Eur.J.2001,7 (22),4811-4820)。

PG⁶The Ring-closing metathesis of-c2 (alkenyl)-B-A-c1 (alkenyl) easily carries out in this way：Suitable solvent such as CH₂Cl₂Include two chloro- (3- phenyl -1H- indenes -1- subunits) two in sub-indenyl-ruthenium complex in 20 to 100 DEG C or in toluene (tricyclohexyl phosphine)-ruthenium (II), [1,3- bis- (2,4,6- trimethylphenyl) -2- imidazolidines subunit]-two chloro- (3- phenyl -1H- Indenes -1- subunits (tricyclohexyl phosphine)-ruthenium (II), [1,3- bis- (2,4,6- trimethylphenyl) -2- imidazolidines subunit]-two are chloro- In the presence of (3- phenyl -1H- indenes -1- subunits) (pyridyl group) ruthenium (II), (referring to S.Monsaert, R.Drozdzak, V.Dragutan, I.Dragutan, and F.Verpoort, Eur.J.Inorg.Chem.2008,432-440 and its reference text It offers).

The big ring core structure that derivatization tool can be changed R- groups can carry out as described below.

The tie point (such as exocyclic amino group, carboxyl, hydroxyl) of orthogonal protection allows substep deprotection and derivatization.

Reaction can be carried out parallelly, generate the library of final products.Following general process can be used：

a⁴) the first protectiveness group of cracking；

b⁴) the free functional group of derivatization；

c⁴) the second protectiveness group of cracking, and

d⁴) the free functional group of derivatization.

The such as preferred Boc of amine protecting group group, Cbz, Teoc, Alloc, Fmoc are removed with standard conditions, referring to T.W.Greene,P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd edition,John Wiley&Sons,1999；P.J.Koncienski, Protecting Groups,3rd edition,Georg Thieme Verlag,2005。

Carboxylic acid protective group such as tertiary butyl, benzyl, allyl, methyl are removed with standard conditions.

Alcohol protection group group such as tertiary butyl, benzyl, allyl, acetyl group, benzoyl, valeryl are removed with standard conditions It goes.

Tie point amino can be converted into amide：The ester activated with phosgene, carboxylic acid anhydrides reacts or soluble or poly- It closes the coupling reagent such as HATU, T3P that object is supported or is handled with carboxylic acid in the presence of the carbodiimide that polymer is supported.

Standard reductive alkylation tie point amino or by itself and alkyl halide, alkyl sulfonic ester or Michael receptor responses carry For higher alkylated amine.

Tie point amino is reacted with isocyanates or equivalent such as carbamyl chloride or HOSu NHS base ester, Urea is provided.

Tie point amino is reacted with isothiocyanates, thiocarbamide is provided.

By tie point amino and chloro-formate or equivalent such as HOSu NHS base carbonate reaction, amino is provided Formic acid esters.

Tie point amino is reacted with sulfonic acid chloride, generates sulfonamides.

In the presence of auxiliary alkali, if necessary in the presence of Pd catalyst (such as Buchwald couplings), by tie point ammonia Base is reacted with the aromatics of suitable activation or heteroaromatic halide or sulphonic acid ester, provides corresponding N- aryl or N- heteroaryl derivatives.

By tie point converting carboxylate groups it is amide with amine and coupling reagent.

Tie point alcoholic extract hydroxyl group can use alkyl halide or alkyl sulfonic ester to be alkylated, and obtain alkyl ether.Spread out in azoformic acid It is reacted with phenols in the presence of biology and triaryl or trialkyl phosphine, and by itself and the aryl halide or heteroaryl that suitably activate Base halogen or sulphonic acid ester reaction, provide aryl or heteroaryl ether.

Tie point secondary hydroxyl group can be oxidized to corresponding ketone, and it can be gone back with amine and suitable reducing agent Former amination.

Tie point alcoholic extract hydroxyl group can be converted to ester.

The big ring general formula I chemical combination appropriate of the Huan Wai functional groups and free primary amino group of tool one or more (orthogonally) protection Object can be converted into the product of complete derivatization on solid support.

The process for allowing for effective parallel array derivatization includes

a⁵) in reduction amination step, big cyclammonium is connected to appropriate functionalized solid support；

b⁵) acylation, carbamoyl, phenoxyl carbonyl or sulfonylation be in step a⁵) in the secondary amine that is achieved in that；

c⁵) remove the protectiveness group of next tie point；

d⁵) derivatization second dissociates functional group, thus：

Amino can be converted into amide, urea, thiocarbamide, carbamate or sulfonamides, or can be alkylated；And carboxylic acid Amide can be converted into；

e⁵) if there is additional derivatization site, then repeatedly step c⁵) and d⁵)；With

f⁵) from solid support discharge final products.

In principle, big ring carbon naphthenic acid can be coupled to the amine of polymer support and by carrying out corresponding c⁵) to f⁵) the step of It is converted into final products.

Functionalized solid support is the derivative for the polystyrene for being crosslinked preferred 1-5% divinylbenzenes, and cladding is poly- Ethylene glycol (Tentagel^R) polystyrene derivative and polyacrylamide resin derivative (referring to D.Obrecht, J.-M.Villalgordo,"Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries",Tetrahedron Organic Chemistry Series,Vol.17, Pergamon,Elsevier Science,1998)。

Solid support is functionalized by connector, that is, bifunctional spacer's molecule, and connection is contained in above-mentioned spacer molecule one end To solid support fixed group and the other end contains the alternative cracking for being useful for subsequent chemical conversion and cracking program Functional group.For the purposes of the present invention, using such connector, it is designed to discharge N- acyl derivatives in acid condition Object (amide, urea, carbamate) or sulfonamide.Above-mentioned connector has been used for framework amide connector (BAL) strategy, is used for The end modified and cricoid peptides of progress synthesis in solid state C- (K.J.Jensen, J.Alsina, M.F. Songster, J.Vagner,F.Albericio,and G.Barnay,J.Am.Chem.Soc.1998, 120,5441-5452；J.Alsina, K.J.Jensen, F.Albericio, and G.Barany, Chem.Eur.J.1999,5 (10), 2787-2795) and synthesis Heterocyclic compound (T.F.Herpin, K.G.Van Kirk, J.M.Savino, S.T.Yu, and R.F.Labaudiniere, J.Comb. Chem.2000,2,513-521,M.del Fresno,J.Alsina,M.Royo,G.Barany, and F.Albericio,Tetrahedron Lett.1998,39,2639-2642；N.S.Gray, S.Kwon,P.G.Schultz, Tetrahedron Lett.1997,38(7),1161-1164)。

Include DFPE polystyrene (2- (3,5- dimethoxy-4 's-by the above-mentioned functionalized example of connector structural resin Formvlphenoxv) ethyl polystyrene), DFPEM polystyrene (2- (3,5- dimethoxy-4 's-formvlphenoxv) ethoxy Ylmethyl polystyrene), FMPB resins (4- (4- formoxyl -3- methoxyphenoxies) butyryl AM resins), FMPE polystyrene HL (2- (4- formoxyl -3- methoxyphenoxies) ethyl polystyrene HL), FMPB NovaGel^TM(4- (4- formoxyl -3- first Oxygroup phenoxy group) butyryl NovaGelTM；PEG PS resins).

Big ring primary amine preferably in 1,2 dichloroethanes in the presence of trimethyl orthoformate by using NaBH (OAc)₃Reduction Amination and be connected to above-mentioned solid support.

Amine coupling to the resin containing above-mentioned connector has been had been well documented with reduction amination；Such as it uses in DMF Or NaBH in methyl alcohol₃CN, or in DMF/ acetic acid or the NaBH (OAc) in dichloromethane/acetic acid₃(referring to K.J.Jensen,J.Alsina,M.F.Songster, J.Vagner,F.Albericio,and G.Barany, J.Am.Chem.Soc.1998,120, 5441-5452；J.Alsina,K.J.Jensen,F.Albericio,and G.Barnay,Chem. Eur.J.1999,5(10),2787-2795；T.F.Herpin,K.G.Van Kirk,J.M. Savino,S.T.Yu,and R.F.Labaudinière,J.Comb.Chem.2000,2,513- 521；A.L.Vergnon, R.S.Pottorf,M.R.Player,J.Comb.Chem.2004,6, 91-98.).These authors also describe use carboxylic acid and idol Joint-trial agent includes PyBOP, PyBroP, HATU and carboxylic acyl fluorides or carboxylic acid anhydrides to be acylated the various conditions of gained secondary amine.

Second functional group is Alloc or fmoc-protected amino or the carboxyl that protection is allyl ester.With standard conditions with Deprotection and these functional groups of derivatization.

Pass through organic solvent or H₂Acid in O removes final products from solid support.Using the TFA in dichloromethane, In capturing agent such as H₂In the presence of O or dimethyl sulfide or in TFA/H₂O and TFA/H₂Dichloro in the presence of O/ dimethyl sulfides TFA in methane has been described in above-mentioned bibliography.

The big ring compound of Formula I with alterable height amino acid side chain die body can be advantageously with parallel array in bridge c Synthesis is prepared on solid support.The synthesis includes immobilization suitable protecting and functionalized precursor, and above-mentioned precursor includes Structural unit A, B are then coupled one to three amino acid c1, c2 and c3, are then cyclized and discharge the product being achieved in that.

Respective process includes：

a⁶) it is condensed suitable hydroxyl or sulfydryl aryl/hetaryl carboxylate H-A-OPG in aforementioned manners⁷With suitably N- The amino alcohol HO-B-PG that the primary amino group with orthogonal protection of protection replaces⁸；

b⁶) remove primary amine protectiveness group；

c⁶) similar to the process described in advance, it will be in step b in standard reductive alkylation step⁶) in obtain product connection To solid support, the polymer support fragment PG that tool dissociates side chain secondary amino group is provided⁸-B-A-O-PG⁷；

d⁶) acylated, carbamoyl, phenoxyl carbonyl or sulfonylation are in step c⁶) in obtain secondary amine；

e⁶) cracking " main chain " amine protectiveness group (PG⁸)；

f⁶) the coupling amino acid PG that suitably ends N- are protected⁹-c3-OH；

g⁶) remove in step f⁶) in obtain product the ends N- protectiveness group (PG⁹)；

h⁶) then, it is coupled to introduce amino acid PG⁹- c1-OH (the targets of bridge of the tool comprising two kinds of amino acid structural units Mark compound), or be coupled/be deprotected cycle to introduce amino PG⁹- c2-OH then carries out corresponding to f⁶) and g⁶) Step coupling amino acid PG⁹- c1-OH (the target compound of bridge of the tool comprising three kinds of amino acid structural units)；

i⁶) cracking aryl/hetaryl ester group (PG⁷)；

j⁶) cracking N- end protectiveness group (PG⁹)；

k⁶) support the upper linear cyclization precursor of Macrocyclic lactamsization (for the example being cyclized on solid support in solid Reference can be made to synthesis is connected to the cyclic peptide of the solid support of tool side chain, it is described in C.Cabrele, M.Langer, and A.G.Beck-Sickinger,J.Org.Chem.1999,64, 4353-4361.)；With

l⁶) slough final products.

As alternative, in step j⁶) in the linear cyclization precursor that obtains can be released from solid support and in the solution It is cyclized by following：

k⁶') slough linear cyclization precursor；With

l⁶') Macrocyclic lactams in the solution.

In parallel array synthesis, the coupling of soluble coupling reagent and polymer support as described above can be used Reagent such as N- cyclohexyl-carbodiimide-N '-methylated polystyrene or N- alkyl -2- chloropyridine trifluoromethanesulfonic acid salt resins (S.Crosignani,J.Gonzales,D.Swinnen, Org.Lett.2004,6(24),4579-4582)。

Other alternative objects are included in closed loop between other positions, such as amino acid c1 and c2.

Therefore, being coupled to the tool of immobilization precursor can be prepared that (polymer is supported there are two types of the precursor of amino acid PG⁹-c2-c3-B-A-OPG⁷)：Carry out segment description corresponds to step a⁶) to h⁶) the step of.So, subsequent step includes

i⁶') cracking aryl/hetaryl ester group (PG⁷)；

j⁶') the coupling amino acid H-c1-OGP that suitably ends C- are protected⁷；

k⁶') cracking c- end protectiveness group (PG⁷)；

l⁶') cracking N- end protectiveness group (PG⁹) and

m⁶') after sloughing linear precursor from solid support, on solid support or in the solution Macrocyclic lactams Change.

The big rings of formula I interact with specific biological targets.Especially, they show to Motilin receptor (MR receptors), hypotype 5-HT_2B5-hydroxytryptamine receptor (5-HT_2BReceptor) and Prostaglandin F2α receptor (FP receptors) excitement or Antagonistic activity.Correspondingly, these compounds are for treating reduced gastrointestinal mobility obstacle such as diabetic gastroparesis and constipation Type irritable bowel syndrome；For treating the related diseases of CNS such as migraine, schizophrenia, mental disease or depression；For example it controls Treat ocular hypertension ocular hypertension such as related with glaucoma and treatment premature labor.

Big ring itself or after advanced optimizing, can individually give or can be used as preparaton appropriate and ability Carrier, diluent or excipient known to domain are applied together.

For treating or preventing above-mentioned disease, big ring can individually, as the mixture of several big rings, Or it combines and is given with the reagent of other pharmaceutical actives.Big ring can be given individually or as pharmaceutical composition.

Including the pharmaceutical composition of the big ring of the present invention can by it is conventional mix, dissolve, be granulated, coat, make piece, it is levigate, It is prepared by emulsification, encapsulating, embedding or freeze-drying process.Pharmaceutical composition can use one or more physiologically in a conventional manner Acceptable carrier, diluent, excipient or adjuvant are prepared, and are made convenient for being pharmaceutically available by active big ring processing Preparation.Suitable preparaton depends on selected medication.

For local administration, the big ring of the present invention can be formulated as solution well known in the art, gel, ointment, creme, hang Supernatant liquid etc..

Systemic preparaton include designed for those of by drug administration by injection, such as subcutaneously, it is intravenous, intramuscular, intrathecal Or intraperitoneal injection, and designed for those of transdermal, transmucosal, oral or pulmonary administration.

For injection, the big rings of type I can be formulated as solution appropriate, the preferably buffer solution of physiological compatible such as Hank solution, Ringer's solution or physiological saline buffer.Solution can contain preparation reagent such as suspending agent, stabilizer And/or dispersant.Alternatively, the big ring of the present invention can be in for before the use with convenient medium object such as aseptic apirogen water The powder type of combination.

Administration for transmucosal, and it is known in the art, will be suitable for the penetrating agent of permeability barrier in preparaton.

For oral medication, compound can pharmaceutically connect itself or by the big ring of activity of the invention with well known in the art The carrier received is combined and is easily prepared.Above-mentioned carrier allows to the big rings of type I being formulated as tablet, pill, pastille, glue Capsule, liquid, gel, syrup, slurry, suspension etc., for the oral edible of patient to be treated.Such as oral preparaton Powder, capsule and tablet, suitable excipient include filler such as carbohydrate, (such as lactose, sucrose, mannitol or sorbierite) or Such as cellulose preparation (such as cornstarch, wheaten starch, rice starch, potato starch, gelatin, bassora gum, Methyl cellulose Element, hydroxypropyl methyl cellulose, carmethose)；And/or granulating agent；And/or adhesive such as polyvinylpyrrolidone (PVP).If desired, disintegrant can be added, such as crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt ratio Such as mosanom.If desired, solid dosage forms can coat sugar or cladding intestines with standard technique.

For oral liquid such as suspension, elixir and solution, suitable carrier, excipient or diluent include Water, glycol, oil, alcohol etc..Furthermore, it is possible to corrigent is added, and preservative, colorant etc..

For Buccal administration, composition can be in the forms such as tablet, the lozenge being typically formulated.

For inhalation, the big ring of the present invention easily with self-pressurization packet or the Aerosol delivery of atomizer spray, uses Suitable propellants, such as hydrofluoroalkane (HFA) such as HFA 134a (1,1,1,2 ,-tetrafluoroethane)；Carbon dioxide is another suitable Suitable gas.In the case of a pressurized aerosol, dosage device can deliver the valve of metered amount to determine by offer.It can match The capsule and cylindrantherae for inhalator or such as gelatin in insufflator are made, the mixture of powders of ring greatly of the invention is contained and is fitted Suitable powder base such as lactose or starch.

Compound can also be formulated as rectum or vagina together with appropriate suppository base such as cupu oil or other glyceride With composition such as suppository.

Other than above-mentioned preparaton, the big ring of the present invention can also be formulated as depot formulation.Above-mentioned slow release long-acting preparaton It can be given by implantation (such as through subcutaneously or through intramuscular) or by intramuscular injection.In order to prepare above-mentioned depot formulation, this Inventing big ring can be with suitable macromolecule or hydrophobic substance (for example, lotion in acceptable oil) or ion exchange resin one It rises and prepares, or be formulated as slightly soluble salt.

In addition it is possible to use other medicines delivery system is than liposome as known in the art and lotion.It can also use Certain organic solvents such as dimethyl sulfoxide.Extraly, the big rings of type I can use sustained release system such as consolidating containing therapeutic agent The semipermeable matrix of body polymer delivers.Various sustained-release materials have been determined and have been that those skilled in the art are ripe Know.Depending on its chemical property, sustained-release capsule can discharge compound within a couple of days up to several months.Depending on therapeutic agent Chemical property and biological stability can use additional stabilisation strategy.

Since big ring of the invention can contain electrification nubbin, they can be as former state or as pharmaceutically acceptable salt It is included in any of the above-described preparaton.Compared to corresponding free alkali or sour form, pharmaceutically acceptable salt tend to more soluble in Aqueous and other proton solvents.

The big ring of the present invention or combinations thereof object generally it is expected to be intended to effectively to measure using to realize.It should be understood that dosage depends on Specific application.

For example, effective dosage can initially be estimated by external test in the treatment of systemic applications：It can Dosage is prepared in animal model to realize the big ring concentration range of cyclicity comprising determining IC in cell culture₅₀Or EC₅₀(namely show half maximum suppression concentration in antagonist, and show that half maximum has in agonist Imitate the test compound concentration of concentration).Above- mentioned information can be used for more accurately determining the useful dosage in the mankind.

Predose can also be determined from intra-body data such as animal model with technology well known in the art.This field is general Logical technical staff can be easily based on animal data optimization mankind's administration.

Dosage for such as gastroparesis or schizophrenia etc. can be adjusted individually is enough to keep treatment to imitate to provide The reactive compound blood plasma level of fruit.Effective serum levels can be realized by the way that multi-dose is given once daily in treatment.

In the case of local administration or selectivity intake, effective local concentration of the big ring of the present invention can not be related to blood plasma Concentration.Those of ordinary skill in the art can optimize the upper effective local dose for the treatment of and be not added with excessively experiment.

Certainly, the amount for the big ring given depends on subject to be treated, subject's weight, sufferer seriousness, administering mode With the judgement of prescribing physician.

In general, effective dosage will provide treatment benefit without leading to substantial toxicity in the treatment of big ring described herein.

The toxicity of the big ring of the present invention can be determining in cell culture or experimental animal by standard pharmaceutical procedures, such as By determining LD₅₀(lethal 50% population dose) or LD₁₀₀(dosage of lethal 100% group).Between toxic effect and therapeutic effect Dose ratio be therapeutic index.Show that the compound of high therapeutic index is preferred.Derived from cell culture test and zooscopy Data can be used in obtaining for avirulent dosage range in the mankind.The dosage of the big ring of the present invention preferably include almost without In the range of the circulation composition of toxicity or avirulent effective dose.Depending on dosage form used and administration route used, dosage can To change within this range.Exact preparaton, administration route and dosage can be selected by individual doctor in view of patient profiles (referring to E.Fingl et al., The Pharmacological Basis of Therapeutics, 5^thed.1975 (Ed.L.Goodman und A.Gilman),Ch.1,p.1)。

Another embodiment of the invention can also include the compound of compound of formula I of equal value, but one of them or it is more A atom is replaced with such atom, have be different from the atomic mass number of atomic mass number or quality existing for nature or Quality, such as be enriched with²H (D),³H,¹¹C,¹⁴C,¹²⁵The compound of I etc..These isotope analogs and its drug salts and preparaton Useful reagent in treatment and/or diagnosis, such as, but not limited to, wherein in trimming body half-life can obtain optimization to The case where prescription case.

Embodiment

The present invention is described in more detail in following embodiments, but does not expect to limit its range in any way.Following abbreviations are used In these embodiments：

ADDP:Azodicarbonyldipiperidine

All:Allyl

Alloc:Allyloxycarbonyl

AllocCl:Allyl chlorocarbonate

AllocOSu:Allyloxycarbonyl-n-hydroxysuccinimide

AM-resin:Aminomethyl resin

aq.:It is aqueous

arom.:Aromatics

BnBr:Benzyl bromide

Boc:Tert-butoxycarbonyl

br.:It is wide

Cbz:Benzyloxycarbonyl

CbzOSu:N- (benzyloxy carbonyloxy group) succinimide

Cl-HOBt:The chloro- I-hydroxybenzotriazoles of 6-

CMBP:Cyanomethylene tributyl-phosphorane

m-CPBA:3- chloroperoxybenzoic acids

d:It or doublet (spectrum)

DBU:1,8- diazabicylos [5.4.0] hendecane -7- alkene

DCE:1,2- dichloroethanes

DEAD:Diethylazodicarboxylate

DFPE polystyrene:2- (3,5- dimethoxy-4 's-formvlphenoxv) ethyl polystyrene

DIAD:Diisopropyl azo-2-carboxylic acid

DIC:N, N '-diisopropylcarbodiimide

DMF:Dimethylformamide

DMSO:Dimethyl sulfoxide

DPPA:Diphenylphosphoryl azide

DVB:Divinylbenzene

EDC:1- [3- (dimethylamino) propyl -3- ethyl carbodiimides

equiv.:Equivalent

Et₃N:Triethylamine

EtOAc:Ethyl acetate

FC:Flash chromatography

FDPP:Diphenyl phosphonic acid pentafluorophenyl group ester

Fmoc:9- fluorenylmethyloxycarbonyls

h:Hour

HATU:O- (7- azo benzos triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphates

HBTU:O- (benzotriazole -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphates

HCTU:O- (1H-6- chlorobenzotriazole -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphates

HOAt:1- hydroxyl -7- azepine benzotriazole

HOBt.H₂O:I-hydroxybenzotriazole hydrate

HMPA:Hexamethyl phosphoramide

i.v.:In a vacuum

m:Multiplet (spectrum)

MeOH:Methanol

NMP:1-Methyl-2-Pyrrolidone

Pd(PPh₃)₄:Tetrakis triphenylphosphine palladium (0)

PEG PS resins:Coated with polyethylene glycol polystyrene resin

PG:Protectiveness group

PPh₃:Triphenylphosphine

prep.:Preparative

i-Pr₂NEt:N- ethyls-N, N- diisopropylamine

PyBOP:(benzotriazole -1- bases oxygroup) tripyrrole Wan Ji Phosphonium hexafluorophosphates

PyBroP:Bromine tripyrrole Wan Ji Phosphonium hexafluorophosphates

q:Quartet (spectrum)

quant.:It is quantitative

sat.:Saturation

soln:Solution

t:Triplet (spectrum)

TBAF:Tetrabutylammonium

Teoc:2- (trimethyl silyl) ethoxy carbonyl

TeocONp:2- (trimethyl silyl) ethyl 4- nitrophenyl carbonates

TFA:Trifluoroacetic acid

THF:Tetrahydrofuran

tlc:Thin-layered chromatography

T3P^TM:Propyl phosphonous acid cyclic acid anhydride

p-TsOH:P- toluenesulfonic acid

Conventional method

TLC：Merck (silica gel 60 F254,0.25mm).

Flash chromatography (FC)：60 silicon of Fluka silica gel 60 (0.04-0.063mm) and Interchim Puriflash IR Glue (0.04-0.063mm).

I. HPLC-MS methods are analyzed：

R_tIt is indicated (in the purity % of 220nm) with point, m/z [M+H]⁺

Volume injected：5 μ L, all methods

Method 1a and 1b

Method 2

Method 3

Method 4a-4b

Method 5a-5b

Method 6

Method 7

Method 8

Method 9a-9c

Analyze HPLC (x%CH₃CN)：R_tIt is indicated (in the purity % of 220nm) with point

Column：5 μM of Develosil RPAq, 4.6x 50mm；

Flow velocity：1.5ml/ point

0.0-0.5 minutes (x%CH₃CN, 100-x%H₂O contains 0.1%TFA)；

0.5-5.0 minutes (x%CH₃CN, 100-x%H₂O contains 0.1%TFA to 100% CH₃CN)

5.0-6.2 minute (100%CH₃CN)

II. preparative HPLC method：

1. reverse phase-acid condition

Column：5 μm of XBridge C18,30x 150mm (Waters)

Mobile phase：

A：0.1%TFA/ water/acetonitrile 95/5v/v

B：0.1%TFA/ water/acetonitrile 5/95v/v

2. reverse phase-alkaline condition

Column：5 μm of XBridge C18,30x 150mm (Waters)

Mobile phase：

A：10/ acetonitrile 95/5v/v of 10mM ammonium hydrogen carbonate pH

B：Acetonitrile

3. positive

Column：100/21 NUCLEOSIL 50-10,21x 100mm (Macherey-Nagel) of VP

Mobile phase：

A：Hexane

B：Ethyl acetate

C：Methanol

NMR spectra：Bruker Avance 300,¹H-NMR (300MHz), signified solvent, environment temperature.Chemical shift δ It is indicated with ppm, coupling constant J is indicated with Hz.

Term " isomers " includes equivalent chemical formula, the type of construction and molecular mass in the present invention, such as It is limited to amide cis/trans isomers, rotational isomer, rotamer, diastereomer.

Embodiment

Raw material

Type A structural units (scheme 1)：

2- acetoxyl group -5- fluobenzoic acids (2) are prepared according to following methods：C.M.Suter and A.W. Weston, J.Am.Chem.Soc.1939,61,2317-2318.

3- acetoxy-benzoic acids (3) are commercially available.

4-ABA (4) is commercially available.

5- hydroxy niacins (5) are commercially available.

8- acetoxyl groups quinaldic acid (8) prepares according to following methods：R.W.Hay, C.R. Clark, J.Chem.Soc.Dalton 1977,1993-1998.

(S) -2- tertbutyloxycarbonylaminos -8- hydroxyls -1,2,3,4- tetrahydrochysenes-naphthalene -2- carboxylic acids (10) are according to following methods It prepares：M.M.Altorfer, DissertationZ ü rich, 1996.

3- mercaptobenzoic acids (11) are commercially available

Type B structural unit (scheme 2)：

(3S, 5S) -5- (hydroxymethyl) pyrrolidin-3-yl carbamates (13) and corresponding HCl salt (13HCl) is commercially available.

(3R, 5S) -5- (hydroxymethyl) pyrrolidin-3-yl carbamates (17) and corresponding HCl salt (17HCl) is commercially available.

3- (hydroxymethyl) piperazine -1- carboxylic acids (S)-t-butyl ester hydrochloride (21HCl) is commercially available.

3- (hydroxymethyl) piperazine -1- carboxylic acids (R)-t-butyl ester hydrochloride (83HCl) (scheme 5) is commercially available.

(2S, 4S)-allyl 2- (hydroxymethyl) -4- ((2- (trimethyl silyl) ethyoxyl) carbonylamino) pyrroles Alkane -1- carboxylates (16) are prepared in three steps that (1. in CH₂Cl₂It is middle to use allyloxycarbonyl-n-hydroxysuccinimide (AllocOSu) Alloc protects secondary amino group, 2. Yong dioxanes-HCl to crack Boc groups；

3. from amino alcohol 13, in CH₂Cl₂In in Et₃Standard conditions 2- (trimethyl silyl) second is used in the presence of N Base 4- nitrophenyl carbonates (Teoc-ONp) carry out Teoc protections to primary amino group；Leading reference can be found in

T.W.Greene,P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd edition,John Wiley&Sons,1999；

P.J.Kocienski,Protecting Groups,3rd edition,Georg Thieme Verlag,2005。

16 data：C₁₅H₂₈N₂O₅Si(344.5)：Flow injection MS (APCI)：689 ([2M+H]⁺), 345 ([M+H]⁺) 。¹H-NMR(DMSO-d₆)：7.28 (d, J=6.1,1H), 5.90 (m, 1H), 5.25 (qd, J=1.7,17.2,1H), 5.16 (qd, J=1.5,10.5,1H), 4.90 (wide t, 1H), 4.54-4.42 (m, 2H), 4.04-3.97 (m, 2H), 3.90 (q, J=6.8, 1H), 3.80-3.66 (wide m and dd, 2H), 3.57-3.43 (wide m, 2H), 2.96 (wide m, 1H), 2.19 (wide m, 1H), 1.78 (wide m, 1H), 0.89 (t, J about 8.3,2 H), 0.00 (s, 9H)

(2S, 4R)-allyl 2- (hydroxymethyl) -4- ((2- (trimethyl silyl) ethyoxyl) carbonylamino) pyrroles Alkane -1- carboxylates (20) are prepared from amino alcohol hydrochloride salt 17HCl：With with synthesis diastereomer 16 described by identical conversion, In addition to Alloc protects step in CH₂Cl₂In in NaHCO₃It is carried out with chloro-carbonic acid allyl ester in the presence of aqueous solution.

20 data：C₁₅H₂₈N₂O₅Si(344.5)：LC-MS (method 9a)：R_t=1.98,345 ([M+H]⁺)；317； 259。¹H-NMR(DMSO-d₆)：7.26 (d, J=6.6,1H), 5.89 (m, 1H), 5.25 (wide d, J=17.0,1H), 5.15 is (wide D, J=10.2,1H), 4.75 (m, 1H), 4.48 (m, 2H), 4.16-3.98 (m, 3H), 3.82 (wide m, 1H), 3.48-3.30 (m, 3H), 3.21 (m, 1H), 2.01 (m, 1H), 1.80 (m, 1H), 0.89 (t, J=8.3,2H), 0.00 (s, 9H).

(S) -1- allyls 4- tertiary butyls 2- (hydroxymethyl) piperazine -1,4- dicarboxylic esters (22) are in CH₂Cl₂In NaHCO₃It is prepared from amino alcohol hydrochloride salt 21HCl with chloro-carbonic acid allyl ester in the presence of aqueous solution；Leading reference can join See T.W.Greene, P.G.M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley&Sons, 1999；

P.J.Kocienski,Protecting Groups,3rd edition,Georg Thieme Verlag,2005。

22 data：C₁₄H₂₄N₂O₅(300.4)：LC-MS (method 9a)：R_t=1.70,201 ([M+H]⁺)。¹H-NMR (DMSO-d₆)：5.90 (m, 1H), 5.29 (qd, J=1.7,17.3,1H), 5.18 (qd, J=1.5,10.5,1H), 4.81 (t, J=4.9,1H), 4.53 (d classes m, J about 5.1,2H), 4.04-3.75 (wide m, 4H), 3.39 (m, 2H), 2.95-2.70 (wide m, 3H), 1.40 (s, 9H).

Type C structural unit (scheme 3)：

(S) -5- allyls 1- benzyls 2- (methylamino) glutarates hydrochloride (27HCl)

At room temperature, by Boc-L-Glu (OAll) OH (23；33g, 115mmol) and NaHCO₃(27g, 322mmol) exists Mixture in DMF (500mL) stirs 1 hour, the benzyl bromide (35mL, 299mmol) being then slowly added in DMF (15mL). Continue stirring 16 hours, then (diethyl ether is saturated NaHCO for aqueous post-processing₃Aqueous solution, saturation NaCl aqueous solutions), pass through FC Purify (CH₂Cl₂/MeOH 100:0 to 98:2) corresponding benzyl ester (34.4g, 79%) is obtained, dioxane (40mL) is dissolved in, It is handled 1 hour with 4M HCl- dioxanes (400mL).Evaporating volatile substances.Nubbin is crystallized from diethyl ether, provides 24HCl (23.8g, 83%).

At 0 DEG C, 4- nitrobenzene sulfonyl chlorides (39g, 178mmol) are added into 24HCl (46.5g, 148mmol) and pyridine The CH of (42mL, 519mmol)₂Cl₂(700mL) solution.Stir mixture 15 hours, subsequent aqueous post-processing (CH₂Cl₂, 1M's HCl/water solution), semifinished product (hexane/EtOAc 80 is purified by FC:20 to 75:25) 25 (55.54g, 81%), are generated.

Anhydrous DMF (200mL) solution of 25 (41.3g, 89mmol) is cooled to 0 DEG C.It is slowly added in DMF (100mL) Iodomethane (5.8mL, 94mmol), then be added DBU (14 mL, 94mmol) DMF (100mL) solution.It is stirred at room temperature Mixture 4 hours, subsequent aqueous post-processing (the HCl/water solution of EtOAc, 1M, H₂O is saturated NaHCO₃Aqueous solution is saturated NaCl water Solution), 26 (42.8g, 99%) are provided.

At room temperature, by 26 (17.4g, 37mmol) without water degasification CH₃CN (270mL) solution with benzenethiol (6.7mL, 66mmol) and Cs₂CO₃(39g, 121mmol) is handled 16 hours.Mixture is filtered, nubbin is washed with diethyl ether.Carefully Filtrate (20 DEG C of bath temperature) is concentrated, (hexane/EtOAc 80 is purified by FC immediately:20 to 50:50).Carefully concentration is through combined production Grade point uses 4M HCl- dioxanes (20mL) to handle 5 minutes, is concentrated to give 27HCl (8.62 g, 72%) immediately.

The data of 27.HCl：C₁₆H₂₁NO₄HCl (291.3, free alkali).LC-MS (method 9b)：R_t=1.44,292 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：9.57 (wide s, NH₂ ⁺), 7.45-7.34 (m, 5 fragrance H), 5.88 (M, 1H), 5.32- 5.19 (m, 4H), 4.53 (td, J=1.3,5.4,1H), 4.13 (wide t, J about 6.0,1H), 2.69-2.40 (m, 2H), 2.56 (s, 3H), 2.30-2.05 (m, 2H).

(R) -5- allyls 1- benzyls 2- (methylamino) glutarates hydrochloride (29HCl) is prepared from Boc-D-Glu (OAll) OH (28) methods described in synthesis enantiomer (27HCl) above.

The data of 29.HCl：C₁₆H₂₁NO₄HCl (291.3, free alkali).LC-MS (method 9b)：R_t=1.44,292 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：9.92 (wide s, NH⁺), 9.54 (wide s, NH⁺), 7.45-7.34 (m, 5 fragrance H), 5.88 (M, 1H), 5.32-5.19 (m, 4H), 4.53 (td, J=1.3,5.4,1H), 4.13 (wide t, J about 6.0,1H), 2.69-2.40 (m, 2H), 2.56 (s, 3H), 2.30-2.05 (m, 2H).

(S)-allyl 2- (Benzyoxycarbonylamino) -3- (methylamino) propionate hydrochloride (32HCl)

Convert Cbz-L-SerOH (30) to amino acid 31：It forms β-lactone and uses HNCH₃Si(CH₃)₃Open (referring to J.Kim, S.G.Bott, D.M.Hoffman Inorg. Chem.1998,37,3835-3841), according to J.K.Kretsinger And J.P.Schneider, J. Am.Chem.Soc.2003,125,7907-7913 and E.S.Ratemi and The program of J.C.Vederas, Tetrahedron Lett.1994,35,7605-7608 carry out.

By allyl alcohol (55mL) solution of 31HCl (2.2g, 7.6mmol) with thionyl chloride (1.7 mL, 23mmol) It handles 15 minutes, is handled 1.5 hours at 70 DEG C at room temperature.Evaporating volatile substances.Coarse products are dissolved in CH₂Cl₂, use NaHCO₃Aqueous solution washs.Water layer CH₂Cl₂It is extracted with EtOAc.Drying is through combined organic phase (Na₂SO₄), it filters, concentration. Gained grease (2.18g) is dissolved in CH₂Cl₂(80mL) is handled with 4M HCl- dioxanes (20mL), is stirred 5 minutes, and concentration carries For 32HCl (2.5g, quantitative).

The data of 32.HCl：C₁₅H₂₀N₂O₄HCl (292.3, free alkali).LC-MS (method 9a)：R_t=1.26,293 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：

9.20 (wide s, NH⁺), 9.03 (wide s, NH⁺), 8.02 (d, J=8.2, NH), 7.38-7.30 (m, 5 fragrance H), 5.89 (m, 1H), 5.33 (d, J=17.3,1H), 5.23 (d, J=10.5,1H), 5.08 (s, 2H), 4.63 (d, J=5.3, 2H), 4.56 (m, 1H), 3.35 (wide m, 1H), 3.25 (wide m, 1H), 2.56 (wide s, 3H).

As alternative, 32HCl is prepared from Cbz-L-DapOH：With the side of synthesis enantiomer 36HCl being described as follows Method.

(R)-allyl 2- (Benzyoxycarbonylamino) -3- (methylamino) propionate hydrochloride (36HCl)

According to T.M.Kamenecka and S.J.Danishefsky, Chem.Eur.J.2001,7,41-63 descriptions are closed At the program of D-Thr allyl ester, it converts Cbz-D-DapOH to allyl ester-pTsOH salt 33pTsOH.

Pass through extraction (CH₂Cl₂, it is saturated NaHCO₃Aqueous solution) convert amino ester 33pTsOH to free alkali, in CH₂Cl₂ In in the presence of pyridine (3.0 equivalent) with 4- nitrobenzene sulfonyl chlorides (1.05 equivalent) handle, obtain p- nitrobenzophenone sulfonamide 34。

At 0 DEG C, DMF (80mL) solution of iodomethane (2.3mL, 37mmol) is added to the DMF of 34 (16.4g, 35mmol) (80mL) solution.In 2 hours, DMF (80mL) solution of DBU (5.6mL, 37mmol) is slowly added to.It is stirred at room temperature Mixture 1.5 hours then carries out aqueous post-processing (EtOAC, 1M HCl solution, H₂O is saturated NaHCO₃Aqueous solution, saturation NaCl aqueous solutions), 35 (17.07g, quantitative) are provided.

At 0 DEG C, by benzenethiol (3.02mL, 29.6mmol) be added (dropwise, quickly) 35 (7,85 g, 16.5mmol) and K₂CO₃The mixture of (7.95g, 57.5mmol) in DMF (78mL).Mixture is stirred at 0-10 DEG C 2.5 hours.Mixture is used EtOAc dilutes, and uses H₂O and saturation NaCl aqueous solutions washing.Organic layer is extracted with the ice-cold aqueous HCl solutions of 1M.By water phase (alkali Extraction) it is poured onto aqueous Na₂CO₃In solution, reach pH about 7；2M NaOH aqueous solutions are added, reach pH about 10, then use EtOAc is extracted.Dry (Na₂SO₄) organic phase and concentrate.Remaining grease (2.72g) is dissolved in CH₂Cl₂(30mL), uses 4M HCl- dioxanes (10 mL) processing, provides 36HCl (3.34g, 62%) after evaporating volatile substances.

The data of 36.HCl：C₁₅H₂₀N₂O₄HCl (292.3, free alkali).LC-MS (method 7)：R_t=0.88,293 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：9.06 (wide s, NH⁺), 8.94 (wide s, NH⁺), 8.00 (d, J=8.3, NH), 7.38- 7.30 (m, 5 fragrance H), 5.88 (m, 1H), 5.33 (d, J=17.3,1H), 5.23 (d, J=10.5,1H), 5.08 (s, 2 H), 4.63 (d, J=5.3,2H), 4.56 (m, 1H), 3.35 (wide m, 1H), 3.20 (wide m, 1H), 2.57 (wide s, 3H).

(S)-allyl 2- (Benzyoxycarbonylamino) -4- (methylamino) butyric acid ester hydrochlorides (40HCl)

According to T.M.Kamenecka and S.J.Danishefsky, Chem.Eur.J.2001,7,41-63 descriptions are closed At the program of D-Thr allyl ester, it converts Cbz-L-DabOH (37) to allyl ester-pTsOH salt 38pTsOH.

By 38pTsOH (45g, 97mmol) in CH₂Cl₂In the mixture of (600mL) be cooled to 0 DEG C.MeOH is added (60mL) is followed by Trifluoroacetic Acid Ethyl Ester (23mL, 194mmol).Et is added dropwise₃N (53mL, 387mmol).It is stirred at 0 DEG C Then object 15 minutes is stirred at room temperature 4 hours.Evaporating volatile substances.Nubbin is dissolved in EtOAc, washs (1M HCl water Solution is saturated Na₂CO₃Aqueous solution), dry (Na₂SO₄), filtering and concentration provide corresponding trifluoroacetamide (32g, 84%).It presses According to Chu-Biao Xue et al.J.Med.Chem.2001, the programs of 44,2636-2660 descriptions by acetamide (21.78g, 56mmol；Use CH₃I and K₂CO₃DMF solution) N- methylates, exception be carry out at room temperature conversion 4 hours-provide 39 (25g, About 90%).

At room temperature, with Pd (PPh₃)₄(0.2g) and morpholine (8.5mL, 98mmol) are by 39 (8.0 g's, about 18mmol) THF (80mL) solution treatment 3 hours provides corresponding trifluoroacetyl after aqueous post-processing (EtOAc, 1M HCl/water solution) Amino acid (7.3g), is used NH₃(25% H₂O solution；It 50mL) handles 2 hours, is concentrated to give corresponding amino acid (8g).It will The substance is dissolved in allyl alcohol (150mL), is handled with thionyl chloride (6.6mL, 91mmol) at 0 DEG C.Mixture is stirred at 0 DEG C It 15 minutes, is stirred at room temperature 3 hours, is concentrated to give 40HCl (7.6g is used for subsequent step, is not added with and is further purified)

The data of 40.HCl：C₁₆H₂₂N₂O₄HCl (306.3, free alkali).Flow injection MS (ESI, holotype)：307 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：8.97 (wide s, NH₂ ⁺), 7.92 (d, J=7.8, NH), 7.40-7.25 (m, 5 fragrance H), 5.88 (m, 1H), 5.32 (d, J=17.2,1H), 5.22 (d, J=10.5,1H), 5.05 (s, 2H), 4.60 (d, J=5.2, 2H), 4.22 (m, 1H), 2.94 (m, 2H), 2.50 (s, 3H are sheltered by DMSO-d signals), 2.10 (m, 1H), 2.00 (m, 1H).

(S)-allyl 2- (Benzyoxycarbonylamino) -5- (methylamino) valeric acid ester hydrochlorides (44HCl)

According to T.M.Kamenecka and S.J.Danishefsky, Chem.Eur.J.2001,7,41-63 descriptions are closed At the program of D-Thr allyl ester, it converts Cbz-L-OrnOH (41) to allyl ester-pTsOH salt 42pTsOH.

The condition described in synthesis 39, converts ester 42pTsOH (5.5g, 11mmol) to 43 (3.97g, 83%), Exception is to continue N- at room temperature to methylate 8 hours.

Then the condition described in processing 39 cracks allyl ester group.According to Chu-Biao Xue et Al.J.Med.Chem.2001,44,2636-2660 program carry out the saponification of the trifluoroacetamido acid of gained, and exception is to make With 2 equivalent LiOH.

At room temperature, by gained amino acid (3.80g contains LiCl, about 9mmol) allyl alcohol (100mL) and sulfurous Acyl chlorides (3.0mL, 41mmol) processing.Mixture is heated at 70 DEG C 2 hours.Continue stirring 17 hours at room temperature.Evaporation volatilization Object.Obtained solid CH₂Cl₂Washing, provides 44HCl (3.62g, about 75%w/w；Yield 83%, is not added with and is further purified ground Using).

The data of 44.HCl：C₁₇H₂₄N₂O₄HCl (320.4, free alkali).LC-MS (method 9b)：R_t=1.48,321 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：9.26 (wide s, NH₂ ⁺), 7.86 (d, J=7.7, NH), 7.39-7.13 (m, 5 fragrance H), 5.89 (m, 1H), 5.31 (wide d, J=17.3,1H), 5.20 (wide d, J=10.4,1H), 5.04 (s, 2H), 4.58 (d, J= 5.2,2H), 4.05 (wide m, 1H), 2.81 (wide m, 2H), 2.44 (s, 3H), 1.80-1.60 (wide m, 4H),

With T.M.Kamenecka and S.J.Danishefsky, Chem.Eur.J.2001,7,41-63 description synthesis Sarcosine allyl ester (46) is prepared as p- TsOH salt by the program of D-Thr allyl ester.

2- ((allyloxycarbonyl) (methyl) amino) acetic acid (47) is prepared according to following methods：M. Mori, A.Somada,S.Oida,Chem.Pharm.Bull.2000,48,716-728。

3- ((allyloxycarbonyl) (methyl) amino) propionic acid (49) is prepared：With M.Mori, A. Somada, The method of S.Oida, Chem.Pharm.Bull.2000,48,716-728 description synthesis N- allyloxycarbonyl sarcosines.

To be similar to D.R.Ijzendoorn, P.N.M.Botman, R.H.Blaauw, Org.Lett 2006,8,239- 242 program passes through N-protected (CBzOSu , dioxanes, aqueous Na from (S)-allylglycine₂CO₃) prepare (S) -2- (benzyls Epoxide carbonyl amino) amyl- obtusilic acid (51).

Acid 51 is also described in Z-Y Sun, C-H.Kwon, J.N.D.Wurpel, J.Med. Chem.1994,37,2841- 2845。

General procedure

Synthesize A-c1 segments

Program A

A.1：Form acyl chlorides

Acetoxyl group aryl carboxylic acid (Ac-A-OH) and anhydrous diethyl ether or CH is added in oxalyl chloride (3.5-5.0 equivalents)₂Cl₂ Mixture.Gained mixture is stirred at room temperature 15 minutes, few drops of (about 50-100 μ L) anhydrous DMFs are then added.Continue to stir It mixes 16 hours.Filter mixture.Filtrate is concentrated, nubbin vacuum drying provides crude acetyl oxygroup aryl carboxyl acyl chloride (Ac- A-Cl), it is immediately available for subsequent step.

A.2：Amide is coupled

By amino ester salt (H-c1-OAll.HCl), (Ac-A-Cl, 1.1-1.5 work as crude acetyl oxygroup aryl carboxyl acyl chloride Amount) and anhydrous CH₂Cl₂Or the mixture of THF is cooled to 0 DEG C.Auxiliary alkali (equal trimethylpyridine or iso- Pr is added dropwise₂NEt；3.0 working as Amount).Mixture is stirred at room temperature 16 hours.Mixture is distributed between EtOAc and 1M HCl/water solution.Wash organic phase (1M HCl aqueous solutions, are then saturated NaHCO₃Aqueous solution or saturation NaCl aqueous solutions), dry (Na₂SO₄), filtering and concentration. FC (hexane/EtOAc gradients) is carried out, acetoxyl group aryl amide (Ac-A-c1-OAll) is provided.

A.3：It is deacetylated

At 0 DEG C, by the anhydrous THF solution 3- dimethylaminos third of acetoxyl group aryl amide (Ac-A-c1-OAll) Amine (3.0-4.5 equivalents) processing.Solution is stirred at room temperature 1-5 hours.By mixture be distributed in EtOAc and ice-cold 0.1M or Between 1M HCl/water solution.Wash organic phase (0.1 or 1M HCl/water solution, saturation NaCl aqueous solutions), dry (Na₂SO₄), mistake Filter and concentration, provide hydroxyaryl amide (H-A-c1-OAll).

Synthesizing linear cyclization precursor H-B-A-c1-OH

Program B

B.1.1：Use PPh₃/ DEAD carries out Mitsunobu aryl ether synthesis

By hydroxyaryl amide (H-A-c1-OAll) and PPh₃The mixture of (1.5 equivalent) is dried in vacuo 15 minutes.In argon Under, the anhydrous benzole soln of alcohol (HO-B-Alloc, 1.2 equivalents) is added, acquired solution is cooled to 0 DEG C.It is slowly added to (pass through note Emitter pumps) benzole soln of DEAD (40%, in toluene, 1.2 equivalents).Mixture is stirred at room temperature 18 hours, concentrates.It carries out FC (hexane/EtOAc gradients) provides the amino acid (Alloc-B-A-c1-OAll, sometimes by by-product such as such as three of protection Phenylphosphine oxide pollute, however be for subsequent step be not added with purify it is acceptable).

B.1.2：Mitsunobu aryl ether synthesis is carried out with CMBP

Under reflux, by hydroxyaryl amide (HO-A-c1-OAll), alcohol (HO-B-Alloc, 1.2-1.3 equivalent) and The anhydrous toluene solution of CMBP (2 equivalent) heats 3-4 hours.Concentrate solution.FC (hexane/EtOAc gradients) provides the ammonia of protection Base acid (Alloc-B-A-c1-OAll).

B.2：Crack allyl/alloc protectiveness groups

By Pd (PPh₃)₄The amino acid (Alloc-B-A-c1-OAll) and 1,3- bis- of protection is added in (0.05-0.1 equivalents) Methylbarbituric acid (2.5 equivalent) is in degassing EtOAc/CH₂Cl₂(about 1:1) mixture in.Acquired solution is stirred at room temperature 1-3 hours, concentration.FC (EtOAC, CH₂Cl₂/ EtOH or CH₂Cl₂/ MeOH gradients) free amino acid (H-B-A-c1- is provided OH)

Synthesizing linear cyclization precursor H-B-A-c1-c2-OH

Program C

C.1：Form Alloc carbamates

At 0 DEG C, allyl chloroformate (1.1 equivalent) is added slowly to amino acid (H-B-A-c1-OH) and Na₂CO₃ (1.5-3 equivalent) dioxanes/H₂O 1:Mixture in 1.Mixture is stirred at room temperature 15 hours.Mixture EtOAc Dilution, with 1M HCl/water solution treatments, until pH reaches about 2.Organic phase is detached, washing (saturation NaCl aqueous solutions) is dry (Na₂SO₄), it filters, concentrates, vacuum drying provides the alloc amino acid (Alloc-B-A-c1-OH) of protection.

C.2：Amide is coupled

By iso- Pr₂NEt (5.0 equivalent) is added slowly to the amino acid (Alloc-B-A-c1-OH) of alloc protections, amino Acid esters salt (the p- TsOH of H-c2-OAll., 1.2 equivalents), the mixing of HOAt (1.5 equivalent) and HATU (1.5 equivalent) in DMF Object.Mixture is stirred at room temperature 20 hours, is then distributed between EtOAc and ice-cold 0.5M HCl/waters solution.It washs organic Phase (0.5M HCl/water solution, H₂O is saturated NaHCO₃Aqueous solution, saturation NaCl aqueous solutions), dry (Na₂SO₄), it filters, concentration. FC (hexane/EtOAc gradients), provides the amino acid (Alloc-B-A-c1-c2-OAll) of protection

C.3：Crack allyl/alloc protectiveness groups

By Pd (PPh₃)₄The amino acid (Alloc-B-A-c1-c2-OAll) and 1,3- diformazans of protection is added in (0.1 equivalent) Base barbituric acid (2.5 equivalent) is in degassing EtOAc/CH₂Cl₂1:Mixture in 1.It is small that acquired solution 1-2 is stirred at room temperature When, concentration.FC (EtOAC, CH₂Cl₂/ EtOH or CH₂Cl₂/ MeOH gradients), free amino acid (H-B-A-c1-c2- is provided OH)。

Synthesize c2-B segments

Program D

Two steps synthesize, via amide base ester and with after saponification

By iso- Pr₂NEt (5.0 equivalent) is added slowly to amino acid (Alloc-c2-OH, 2.2 equivalents), the amino of N-protected Alcohol hydrochloride (HO-B-H.HCl), the mixture of Cl-HOBt (0.25 equivalent) and HCTU (2.5 equivalent) in DMF.In room temperature Lower stirring acquired solution 17 hours is then distributed in EtOAc and saturation Na₂CO₃Between aqueous solution.Wash organic phase (1M HCl Aqueous solution, saturation NaCl aqueous solutions), dry (Na₂SO₄), it filters, concentration.FC (hexane/EtOAc or CH₂Cl₂/ MeOH ladders Degree), corresponding amides base ester is provided, THF/H is dissolved in₂O 4:1, lithium hydroxide monohydrate (3.0 equivalent) is used at room temperature Processing 2 hours.Mixture is concentrated into about the 50% of initial volume, is diluted with EtOAc, with 1M NaOH aqueous solution extractions.Washing Organic phase (H₂O, saturation NaCl aqueous solution), dry (Na₂SO₄), it filters, concentration provides amide groups alcohol (HO-B-c2-Alloc).

Synthesizing linear cyclization precursor H-c2-B-A-c1-OH

Program E

E.1.1：Use PPh₃/ DEAD carries out Mitsunobu aryl ether synthesis

By hydroxyaryl amide (HO-A-c1-OAll) and PPh₃The mixture of (1.5-4.5 equivalents) is dissolved in benzene.It concentrates molten Liquid, vacuum drying nubbin 15-30 minutes.Under argon, alcohol (HO-B-c2-Alloc, 1.2-2.3 equivalent) is added anhydrous And the solution in the benzene that deaerates, gained mixture is cooled to 0 DEG C.It is slowly added to DEAD (40%, in toluene, 1.2-4.5 equivalents) Solution.Mixture is stirred at room temperature 18 hours.In the case of not exclusively consumption hydroxyaryl amide, be added it is additional (if Confirmed according to tlc and consumed) triphenylphosphine (1.0-1.3 equivalents) and DEAD (40%, in toluene, 1.0 equivalents) and alcohol (1.0 work as Amount) and continue stirring 18 hours.Concentrate mixture.FC (hexane/EtOAc, CH₂Cl₂/ EtOH or CH₂Cl₂/ MeOH gradients), it carries For Alloc-c2-B-A-c1-OAll (may by by-product, such as example triphenylphosphine oxide pollutes, however be for follow-up Step be not added be further purified institute it is acceptable).

E.1.2：Mitsunobu aryl ether synthesis is carried out with CMBP

Hydroxyaryl amide (H-A-c1-OAll) and alcohol (HO-B-c2-Alloc, 1.2- is added in CMBP (2-3 equivalents) 2.2 equivalents) mixture in dry toluene.Heating mixture 16 hours under reflux, concentration.FC (hexanes/EtOAc ladders Degree), the amino acid (Alloc-c2-B-A-c1-OAll) of protection is provided.

E.2：Crack allyl/alloc protectiveness groups

By Pd (PPh₃)₄The amino acid (Alloc-c2-B-A-c1-OAll) and 1,3- of protection is added in (0.05-0.1 equivalents) Dimethyl barbituric acid (2.4 equivalent) is in degassing EtOAc/CH₂Cl₂1:Mixture in 1.Acquired solution 1- is stirred at room temperature 3 hours, concentration.FC (EtOAC, CH₂Cl₂/ EtOH or CH₂Cl₂/ MeOH gradients), free amino acid (H-c2-B-A- is provided c1-OH)。

Synthesize big ring ring-(B-A-c1) and ring-(c2-B-A-c1)

Program F

Macrocyclic lactamsization are generally carried out in the ultimate density of 0.01M to 0.001M

F.1.1：The lactams that T3P is mediated is formed

In 2 hours, by syringe pump by precursor (H-B-A-c1-OH or H-c2-B-A-c1-OH or H-B-A-c1- C2-OH, respectively) anhydrous CH₂Cl₂T3P (in 50%, EtOAc, 2 equivalents) and iso- Pr is added in solution₂The nothing of NEt (4 equivalent) Water CH₂Cl₂Solution.Solution is stirred at room temperature 20 hours, with saturation Na₂CO₃Aqueous solution and H₂O is extracted, dry (Na₂SO₄), Filtering, then concentrates.FC (hexane/EtOAc/MeOH or CH₂Cl₂/ MeOH gradients), macrocyclic compound (ring-(B- is provided respectively A-c1) or ring-(c2-B-A-c1)).

F.1.2：The lactams that FDPP is mediated is formed

In 2 hours, by precursor (H-B-A-c1-OH or H-c2-B-A-c1-OH or H-B-A-c1-c2-OH, respectively) The anhydrous DMF solution of FDPP (2.0 equivalent) is added in anhydrous DMF solution.Solution is stirred at room temperature 20 hours.Evaporating volatile substances, Nubbin is scattered in EtOAc, washing (saturation NaHCO₃Aqueous solution, H₂O, saturation NaCl aqueous solution).Dry organic phase (Na₂SO₄), it filters, concentration.FC (hexane/EtOAc/MeOH or CH₂Cl₂/ MeOH gradients), macrocyclic compound is provided respectively (ring-(B-A-c1) or ring-(c2-B-A-c1)).

Substituent group is connected to big ring core structure：Synthesize final products

Program H

At room temperature, under usual pressure, in palladium dydroxide/activated carbon (moistening to 50%H₂O；0.5g is per g raw materials) it deposits It is under, the MeOH or MeOH/THF (about 100 mL are per g raw materials) of big ring benzyl ester is 2 hours solution hydrogenated.It is filtered by celite pad Mixture.Wash nubbin (MeOH, MeOH/CH₂Cl₂1:1, THF).Washing obtains big ring through combined filtrate, concentration Acid.

Program I

I.1：Teoc deprotections are carried out Yong dioxane-HCl

By big ring Teoc- amine (at 1.5mmol) dioxanes (18mL) solution 4M HCl dioxanes (18mL) solution Reason, is stirred at room temperature 4-16 hours.Mixture is handled with diethyl ether, filtering.Solid is washed with diethyl ether, and vacuum drying obtains Big cyclammonium hydrochloride.

I.2：Teoc deprotections are carried out with the THF solution of TBAF

At 0 DEG C, TBAF (in 1M, THF, 3 equivalents) solution is added to the THF (34mL) of big ring Teoc- amine (1.3 mmol) Solution.Continue stirring 3 hours at 0 DEG C to room temperature.Solution is distributed in CH₂Cl₂And H₂Between O.Wash organic phase (H₂O), dry (Na₂SO₄), it filters, concentration provides big cyclammonium after FC.

Program J

By big ring Boc- amine dioxanes (10mL is per g raw materials) solution 4M HCl dioxanes (20mL is per g raw materials) solution Processing, is stirred at room temperature 2 hours.Filter mixture.Solid is washed with diethyl ether, and vacuum drying obtains big cyclammonium hydrochloride.

Program K

At room temperature, in usual pressure, in palladium dydroxide/activated carbon (moistening to 50%H₂O；It, will be big in the presence of 0.3g) Solution hydrogenated 4 hours of the MeOH (52mL) of ring Benzylcarbamate (0.9mmol).Mixture is filtered by celite pad.It washs residual Remaining part point (MeOH).Washing obtains big cyclammonium through combined filtrate, concentration.

Program L

Amide is coupled

L.1.1：With carboxylic acid anhydrides or acyl chlorides

At 0 DEG C, by amino big ring (unhindered amina or hydrochloride；CH 0.09mmol)₂Cl₂(1mL) solution is used respectively successively Pyridine (10 equivalent) and the processing of carboxylic acid anhydrides (1.05-5 equivalents) or carboxyl acyl chloride (1.05-2.0 equivalents).Solution 15 is stirred at room temperature Hour.After MeOH (0.1mL) is added, agitating solution 10 minutes, concentration.Gained coarse products are steamed altogether with toluene, pass through color Spectrometry purifying (FC, positive or Reverse phase preparative HPLC) obtains the big ring of N- acyl aminos.

L.1.2：The carbodiimide supported with carboxylic acid and polymer

By amino big ring (unhindered amina or hydrochloride；0.09mmol), carboxylic acid (1.2 equivalent), HOBt.H₂O (1.2 equivalent) CH₂Cl₂(1mL) solution N- cyclohexyl-carbodiimide-N '-methylated polystyrene (1.9mmol/g；1.5 equivalents) and it is iso- Pr₂NEt (3.0 equivalent) processing.Mixture is stirred at room temperature 15 hours.(polystyrylmethyl) trimethyl bicarbonate is added Ammonium (3.5 mmol/g；3 equivalents), continue stirring 1 hour.Mixture CH₂Cl₂/MeOH 9:1 (2mL) dilutes, filtering.Polymerization Object CH₂Cl₂/MeOH 8:2 (5mL) are washed twice.Concentration is through combined filtrate and cleaning solution.Crude production is purified by chromatography Product (FC, positive or Reverse phase preparative HPLC), provide N- acyl aminos big ring

L.1.3：With carboxylic acid and HATU

By amino big ring (unhindered amina or hydrochloride；0.145mmol), carboxylic acid (2.0 equivalent), HATU (2.0 equivalent), The iso- Pr of DMF (2mL) solution of HOAt (2.0 equivalent)₂NEt (4.0 equivalent) processing.It is small that mixture 15 is stirred at room temperature When.Remove solvent.Nubbin is distributed in CHCl₃With saturation NaHCO₃Between aqueous solution.Wash organic phase (H₂O), dry (Na₂SO₄), it filters, concentration.Coarse products (FC, positive or Reverse phase preparative HPLC) are purified by chromatography, N- acyl groups are provided The big ring of amino.

L.2：With amine and HATU

By big ring carboxylic acid (0.78mmol), amine (2.0 equivalent), HATU (2.0 equivalent), the DMF of HOAt (2.0 equivalent) The iso- Pr of (6mL) solution₂NEt (4.0 equivalent) processing.Mixture is stirred at room temperature 15 hours.Remove solvent.By remaining portion It is distributed in CHCl₃With saturation NaHCO₃Aqueous solution.Wash organic phase (H₂O), dry (Na₂SO₄), it filters, concentration.Pass through chromatography Method purifies coarse products (FC, positive or Reverse phase preparative HPLC), provides macrocyclic amide.

Program M

N, the big ring of N- diethylaminos are prepared by reduction amination

At 0 DEG C, by NaBH (OAc)₃Amino big ring (unhindered amina or hydrochloride is added in (5 equivalent) and acetaldehyde (1mL)； THF (1mL) solution 0.09mmol).At 0 DEG C to room temperature, stirring mixture 15 hours.Mixture CHCl₃Dilution, with saturation NaHCO₃Aqueous solution washs.Dry organic phase (Na₂SO₄), it filters, concentration.By chromatography purify coarse products (FC, positive or Reverse phase preparative HPLC), provide diethylamino big ring.

Program N

Methyl ester cracks

At room temperature, by the THF (1.5mL) and MeOH (0.5mL) solution H of methyl ester (57 μM of ol)₂O (0.5mL) and Lithium hydroxide monohydrate (3 equivalent) is handled 2 hours.Aqueous 1M HCl acidifying mixtures are added, concentrate.Pass through preparative HPLC Purify coarse products.

Synthesize A-c1 segments

1. synthesizing (S) -5- allyl 1- benzyls 2- (the fluoro- 2- hydroxy-N-methvls benzamidos of 5-) glutarate (54) (scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (50 μ L), in anhydrous CH₂Cl₂By 2- second in (516mL) Acyloxy -5- fluobenzoic acids (2,11.78g, 59mmol) and oxalyl chloride (18 mL, 206mmol) reaction, provide 2- acetoxyl groups - 5- fluorobenzoyl chlorides (52).

In iso- Pr₂In the presence of NEt (23mL, 137mmol), by acyl chlorides 52 and (S) -5- allyls in THF (260mL) 1- benzyls 2- (methylamino) glutarate hydrochlorides (27HCl, 15.0g, 46mmol) react, and generate acetic acid esters 53 (19.35g, 90%) is handled it with 3- dimethylamino -1- propylamine (23mL, 185mmol) in THF (200mL), in water Property post-processing after (EtOAc, 0.1M HCl/water solution, saturation NaCl aqueous solutions) and in FC (hexane/EtOAc 8:2 to 7: 3) phenol 54 (14.4g, 81%) is provided after.

54 data：C₂₃H₂₄FNO₆(429.4).HPLC (30%CH₃CN)：R_t=3.79 (87%).LC-MS (methods 9a)：R_t=2.09,430 ([M+H]⁺)。

2. synthesizing (R) -5- allyl 1- benzyls 2- (the fluoro- 2- hydroxy-N-methvls benzamidos of 5-) glutarate (56) (scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (50 μ L) by 2- acetoxyl group -5- fluobenzoic acids (2, 13.0g, 67mmol) and oxalyl chloride (20mL, 233mmol) in anhydrous CH₂Cl₂Reaction, provides 2- acetoxyl groups-in (585mL) 5- fluorobenzoyl chlorides (52).

In iso- Pr₂In the presence of NEt (27mL, 156mmol), by acyl chlorides 52 and (R) -5- allyl 1- benzyls 2- (methyl ammonia Base) glutarate hydrochloride (29HCl, 17.0g, 52mmol) reaction in THF (280mL), generation 55 (21.5g, 88%), processing in THF (200mL) with 3- dimethylamino -1- propylamine (26mL, 205mmol) by it, in aqueous post-processing After (EtOAc, 0.1 M HCl/water solution, saturation NaCl aqueous solutions) and in FC (hexane/EtOAc 8:2 to 7:3) it is carried after For phenol 56 (14.8g, 75%).

56 data：C₂₃H₂₄FNO₆(429.4).HPLC (30%CH₃CN)：R_t=3.79 (89).LC-MS (method 9c)： R_t=2.11,430 ([M+H]⁺)。

3. synthesizing (S)-allyl 2- (Benzyoxycarbonylamino) -3- (3- hydroxy-N-methvls benzamido) propionic ester (59) (scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (50 μ L) by 3- acetoxy-benzoic acids (3,6.0g, It 33mmol) is reacted in anhydrous diethyl ether (216 mL) with oxalyl chloride (14mL, 164mmol), 3- acetoxyl group benzoyls is provided Chlorine (57,7.0g, quantitative).

In the presence of 2,4,6- trimethylpyridines (12.8mL, 96mmol), by 57 (7.0g, 35 mmol) and (S)-allyl Base 2- (Benzyoxycarbonylamino) -3- (methylamino) propionate hydrochloride (32HCl, 10.5g, 32mmol) is in CH₂Cl₂In (285mL) reacts, and generates 58 (12.34g, 82%).

Acetic acid esters 58 (12.82g, 28.2mmol) is with 3- dimethylamino -1- propylamine (10.6mL, 84.6mmol) in THF Processing, provides phenol 59 (10.45g, 90%) in (114mL).

59 data：C₂₂H₂₄N₂O₆(412.4).HPLC (10%CH₃CN)：R_t=3.91 (96).LC-MS (method 9a)： R_t=1.77,413 ([M+H]⁺)。

4. synthesizing (R)-allyl 2- (Benzyoxycarbonylamino) -3- (3- hydroxy-N-methvls benzamido) propionic ester (61) (scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (50 μ L), by 3- acetoxy-benzoic acids (3,5.82g, It 32.3mmol) is reacted in anhydrous diethyl ether (210mL) with oxalyl chloride (11.1mL, 129mmol), 3- acetyloxy phenyl first is provided Acyl chlorides (57,6.5g, 100%).

In the presence of 2,4,6- trimethylpyridines (10.3mL, 77.6mmol), by 57 (6.5g, 32.3mmol) and (R)- Allyl 2- (Benzyoxycarbonylamino) -3- (methylamino) propionate hydrochloride (36HCl, 8.5g, 26mmol) exists CH₂Cl₂In (220mL) react, generate 60 (10.73g, 92%).

Acetic acid esters 60 (15.46g, 34mmol) is with 3- dimethylamino -1- propylamine (12.8mL, 102mmol) in THF Processing, provides phenol 61 (12.92g, 92%) in (140mL).

61 data：C₂₂H₂₄N₂O₆(412.4).LC-MS (method 2)：R_t=1.77 (98), 413 ([M+H]⁺)。

5. synthesizing (S)-allyl 2- (Benzyoxycarbonylamino) -4- (3- hydroxy-N-methvls benzamido) butyrate (63) (scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (300 μ L), by 3- acetoxy-benzoic acids (3,7.65g, 43mmol) and oxalyl chloride (18.2mL, 213mmol) is in anhydrous CH₂Cl₂Reaction in (140mL), carries after 3 hours at room temperature For 3- acetoxyl groups chlorobenzoyl chloride (57).

In iso- Pr₂In the presence of NEt (15mL, 85mmol), by be achieved in that 57 and (S)-allyl 2- (benzyloxy carbonyls Base amino) -5- (methylamino) butyric acid ester hydrochlorides (40HCl, 8.7g, 28mmol) reaction in THF (140mL), it generates 62 (8.1g, 61%).

Acetic acid esters 62 (4.85g, 10mmol) is with 3- dimethylamino -1- propylamine (3.8mL, 31 mmol) at THF (90mL) Middle processing provides phenol 63 (4.23g, 95%).

63 data：C₂₃H₂₆N₂O₆(426.5).LC-MS：(method 6)：R_t=1.06 (99), 427 ([M+H]⁺)。

6. synthesizing (S)-allyl 2- (Benzyoxycarbonylamino) -5- (3- hydroxy-N-methvls benzamido) valerate (65) (scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (500 μ L), by 3- acetoxy-benzoic acids (3,10g, 58mmol) and oxalyl chloride (19mL, 218mmol) is in anhydrous CH₂Cl₂Reaction, provides 3- acetoxyl group chlorobenzoyl chlorides in (450mL) (57)。

In iso- Pr₂In the presence of NEt (25mL, 145mmol), by be achieved in that 57 and (S)-allyl 2- (benzyloxies Carbonylamino) -5- (methylamino) valeric acid ester hydrochlorides (44HCl, 17.3g, 48mmol) reaction in THF (200mL), 64 (12.08g, 51%) are generated, it is located with 3- dimethylamino -1- propylamine (9.3mL, 75mmol) in THF (240mL) Reason, in aqueous post-processing, (EtOAc, 1M HCl/water solution are saturated NaHCO₃Aqueous solution, saturation NaCl aqueous solutions) benzene is provided later Phenol 65 (10.84g, 98%).

65 data：C₂₄H₂₈N₂O₆(440.5).LC-MS (method 6)：R_t=1.15 (91), 441 ([M+H]⁺)。

7. (S) -5- allyl 1- benzyls 2- (4- hydroxy-N-methvls benzamido) glutarate (the 68) (scheme of synthesis 4)

According to program A (step is A.1-A.3), in the presence of DMF (50 μ L), by 4-ABA (4,10.7g, 59.5mmol) and oxalyl chloride (17.7mL, 206mmol) is in anhydrous CH₂Cl₂Reaction, provides 4- acetyloxy phenyl first in (350mL) Acyl chlorides (66).

In iso- Pr₂In the presence of NEt (23.3mL, 137mmol), by 66 and (S) -5- allyl 1- benzyls 2- (methyl ammonia Base) glutarate hydrochloride (27HCl, 15.0g, 46mmol) reaction in THF (250mL), generation 67 (16.24g, 78%).

By 67 (15.2g, 33.5mmol) with 3- dimethylamino -1- propylamine (12.6mL, 101 mmol) in THF Processing in (140mL), providing phenol 68, (14.86g is quantified；Product is polluted by 9% EtOAc).

68 data：C₂₃H₂₅NO₆(411.4).LC-MS (method 9b)：R_t=1.96,412 ([M+H]⁺)。

8. synthesizing (S)-allyl 2- (Benzyoxycarbonylamino) -3- (5- hydroxy-N-methvl nicotinoyl amido) propionic ester (71) (scheme 4)

At 95 DEG C, the mixture of 5- hydroxy niacins (5,3.5g, 25.1mmol) and acetic anhydride (23mL, 243mmol) is added Heat 45 minutes, is cooled to room temperature.Filter mixture.Wash (H₂O, diethyl ether) solid, it is dried in vacuo and obtains 5- acetoxyl group cigarettes Acid (6；3.76g, 82%) (scheme 1)

By 5- acetoxyl groups niacin (6；5.7g, 31.5mmol) it is suspended in CHCl₃(being stabilized with amylene, 230mL).It is added Oxalyl chloride (9.0mL, 105mmol), subsequent DMF (about 50 μ L).Mixture is stirred at room temperature 15 hours, then concentrates, with nothing Water CH₂Cl₂It steams altogether, vacuum drying provides 5- acetoxyl groups nicotinoyl chlorine (69).(S)-allyl 2- (benzyloxycarbonyl ammonia is added Base) -3- (methylamino) propionate hydrochloride (32,8.6g, 26.2mmol) and THF (225mL).Mixture is cooled to 0 DEG C. It is slowly added to Et₃N (13mL, 92mmol).At 0 DEG C to mixture being stirred at room temperature 18 hours.3- dimethylamino -1- propylamine is added (9.9mL, 78.6mmol) continues stirring 2 hours at room temperature.Mixture is distributed in EtOAc and 1M NaH₂PO₄Aqueous solution it Between.Separate organic layer, washing (saturation NaCl aqueous solutions), dry (Na₂SO₄), it filters, concentration.FC(CH₂Cl₂/MeOH 19: 1) phenol 71 (8.81g, 81%), is provided.

71 data：C₂₁H₂₃N₃O₆(413.4).LC-MS (method 6)：R_t=0.94 (92), 414 ([M+H]⁺)。

Synthesis of allyl 9. (2S) -2- [(benzyloxy) carbonyl] amino -3- [((2S) -2- [(tert-butoxycarbonyl) ammonia Base] -8- hydroxyl -1,2,3,4- tetrahydrochysene -2- naphthyl carbonyls) (methyl) amino] propionic ester

(72) (scheme 4)

By 10 (3.0g, 9.76mmol), HATU (5.57g, 14.6mmol), HOAt (1.99 g, 14.6mmol) and 32 The mixture of HCl (6.4g, 19.5mmol) is dissolved in DMF (113mL).Iso- Pr is added₂NEt (8.36mL, 48.8mmol).In room The lower stirring mixture 3d of temperature.Mixture is distributed in H₂Between O and EtOAc.Dry organic phase (Na₂SO₄), it filters, concentration. FC (hexane/EtOAc 75:25 to 50:50) 72 (2.58g, 45%), are provided.

72 data：C₃₁H₃₉N₃O₈(581.3).LC-MS (method 7)：R_t=1.27 (97), 582 ([M+H]⁺)。

10. synthesizing 5- allyl 1- benzyls (2S) -2- [[(8- hydroxyl -2- quinolyls) carbonyl] (methyl) amino] glutaric acid Ester (75)

(scheme 4)

According to program A (step is A.1-A.3), by 8- acetoxyl groups quinaldic acid (8,2.22g 9.6 mmol) and grass Acyl chlorides (2.1mL, 24mmol) is in anhydrous CH₂Cl₂Reaction in (90mL) (being not added with DMF), provides acetyl at room temperature after 2 hours Phenoxyl quinoline -2- carboxyl acyl chlorides (73).

In iso- Pr₂In the presence of NEt (5.5mL, 32mmol), by 73 and (S) -5- allyl 1- benzyls 2- (methylamino) Glutarate hydrochloride (27HCl, 2.3g, 8.0mmol) is in CH₂Cl₂In (200mL) react, 2.5 hours and lead at room temperature It crosses FC (hexane/EtOAc gradients) purifying and generates 74 (3.03g, 74%) later, it is used into 3- dimethylamino -1- propylamine (2.3mL, 18 mmol) processing in THF (54mL), in aqueous post-processing, (EtOAc, 1M HCl/water solution are saturated NaHCO₃Water Solution, saturation NaCl aqueous solutions) phenol 75 (2.79g, 99%) is provided later.

75 data：C₂₆H₂₆N₂O₆(462.5).LC-MS (method 7)：R_t=1.29 (94), 463 ([M+H]⁺)。

11. synthesizing N- allyl -3- hydroxy-N-methvls benzamides (77)

(scheme 4)

According to program A (step is A.1-A.3), in the presence of DMF (100 μ L), by 3- acetoxy-benzoic acids (3,23.7g, It 132mmol) is reacted in anhydrous diethyl ether (800mL) with oxalyl chloride (45.3mL, 527mmol), 3- acetyloxy phenyl first is provided Acyl chlorides (57).

In the presence of 2,4,6- trimethylpyridines (42mL, 316mmol), by be achieved in that 57 and N- allyl methyl amines (10.1ml, 105mmol) is in CH₂Cl₂In (500mL) react, generate 76 (24g, 98%).

Acetic acid esters 76 (10.9g, 46.7mmol) is with 3- dimethylamino -1- propylamine (17.5mL, 140mmol) in THF Processing in (90mL) provides phenol 77 after aqueous post-processing (EtOAc, 1M HCl/water solution, saturation NaCl aqueous solutions) (9.0g, 100%).

77 data：C₁₁H₁₃NO₂(191.2).LC-MS (method 2)：R_t=1.52 (99), 192 ([M+H]⁺)。

12. synthesizing (S) -5- allyl -1- benzyls 2- (3- mercapto-N-methyls benzamido) glutarate (80)

(scheme 4)

At 0 DEG C, 3- mercaptobenzoic acids (11,250 mg, 1.62mmol) are added in acetic anhydride (0.46mL, 4.86mmol) 1M NaOH aqueous solutions (5.0mL, 5.0mmol) solution.Mixture is stirred at 0 DEG C 1 hour.Form precipitation.It is molten that 1M HCl/waters are added Liquid acidifying mixture, filtering.It is dried in vacuo solid, 3- (sulphur acetyl group) benzoic acid (12 is provided；280mg, 88%).

12 (260mg, 1.33mmol) and CHCl are added in oxalyl chloride (0.34mL, 3.97mmol)₃It (is stabilized with amylene； Mixture 16mL).DMF (7 μ L) is added.Mixture is stirred at room temperature 2 hours.Evaporating volatile substances provide 3- (sulphur acetyl Base) chlorobenzoyl chloride (78).

Addition (S) -5- allyl 1- benzyls 2- (methylamino) glutarates hydrochloride (27HCl, 434 mg, 1.33mmol) and anhydrous THF (5mL).Mixture is cooled to 0 DEG C, iso- Pr is then added₂NEt (0.79mL, 4.6mmol). Mixture is stirred at room temperature 16 hours, is distributed between EtOAc and 1M HCl/water solution.Organic phase is detached, it is dry (Na₂SO₄), it filters, concentration.FC (hexane/EtOAc 2:1) acetic acid esters 79 (420mg, 67%), is provided.

At room temperature, by degassing THF (3.6mL) the solution 3- dimethylaminos -1- third of 79 (246mg, 0.52mmol) Amine (0.13mL, 1.05mmol) is handled 1 hour.Mixture is distributed between EtOAc and 1M HCl/water solution.It detaches organic Phase, dry (Na₂SO₄), it filters, concentration.FC (hexane/EtOAc 2:1) 80 (153mg, 68%), are provided.

80 data：C₂₃H₂₅NO₅S(427.5)：LC-MS (method 7)：R_t=1.39 (84), 428 ([M+H]⁺)。

Synthesize c2-B segments

1. synthesis of allyl N-2- [(2S, 4S) -4- [(tert-butoxycarbonyl) amino] -2- (hydroxymethyl) tetrahydrochysenes -1H- Pyrroles -1- bases] -2- oxoethyl-N- methyl carbamates (81) (scheme 5)

By (2- ((allyloxycarbonyl) (methyl) amino) acetic acid (47,8.0g, 46mmol) and amino alcohol 13 DMF (120mL) solution of (11.0g, 51mmol) is cooled to 0 DEG C.2,4,6- trimethylpyridines (11mL, 82mmol) are added, with HATU (22g, 58mmol) afterwards.Mixture is stirred at 0 DEG C 1 hour, be then stirred at room temperature 16 hours, be then distributed in EtOAc and saturation Na₂CO₃Between aqueous solution.Organic phase (1M HCl solutions, saturation NaCl aqueous solutions) is washed, it is dry (Na₂SO₄), it filters, concentration.FC(EtOAc/MeOH 100:0 to 95:5) amide groups alcohol 81 (14.7g, 86%), is provided.

81 data：C₁₇H₂₉N₃O₆(371.4).HPLC (20%CH₃CN)：R_t=2.94 (97).LC-MS (method 9c)： R_t=1.55；743([2M+H]⁺), 372 ([M+H]⁺)。

2. synthesis of allyl N-2- [(2S, 4R) -4- [(tert-butoxycarbonyl) amino] -2- (hydroxymethyl) tetrahydrochysenes -1H- Pyrroles -1- bases] -2- oxoethyl-N- methyl carbamates (82) (scheme 5)

According to program D, at HCTU (40.9g, 98.9mmol), Cl-HOBt (1.68g, 9.89mmol) and iso- Pr₂NEt In the presence of (33.6mL, 198mmol), by amino alcohol 17HCl (10.0g, 39.6mmol) and 2- ((allyloxycarbonyl) (methyl) amino) acetic acid (47,15.1g, 87mmol) reaction in DMF (100mL), in FC (hexane/EtOAc 20:80 to 0: 100) after provide corresponding amides base ester intermediate (13.7g), by its with lithium hydroxide monohydrate (3.28g, 78.1mmol) in THF (350mL) and H₂Saponification in O (90mL) generates amide groups alcohol 82 (8.89g, 61%).

82 data：C₁₇H₂₉N₃O₆(371.4).LC-MS (method 9b)：R_t=1.57；372 ([M+H]⁺), 316,272 ([M+H-Boc]⁺), 156.

3. synthesis

Tertiary butyl (3R) -4- { 2- [[(allyl oxygroup) carbonyl] (methyl) amino] acetyl group } -3- (hydroxymethyl) four Hydrogen -1 (2H)-pyrazine carboxylic acid ester (84) (scheme 5)

According to program D, at HCTU (81.0g, 195mmol), Cl-HOBt (3.3g, 19 mmol) and iso- Pr₂NEt In the presence of (67mL, 390mmol), by (R)-tertiary butyl 3- (hydroxymethyl) piperazine -1- carboxylate hydrochlorides (83HCl, 19.7g, 78mmol) and 3- ((allyloxycarbonyl) (methyl) amino) acetic acid (47,30g, 172mmol) at DMF (188mL) Middle reaction provides corresponding amides base ester intermediate (40g) after FC (EtOAc), is used lithium hydroxide monohydrate (9.5g, 228mmol) is in THF (1020mL) and H₂Saponification in O (245mL), FC (EtOAc) generate amide groups alcohol 84 later； 22.8g, 79%).

84 data：C₁₇H₂₉N₃O₆(371.4).LC-MS (method 7)：R_t=0.99 (93), 372 ([M+H]⁺)。

4. synthesizing benzyl N- ((1S) -1- [(2S, 4S) -4- [(tert-butoxycarbonyl) amino] -2- (hydroxymethyl) tetrahydrochysenes - 1H- pyrroles -1- bases] carbonyl -3- cyclobutenyls) carbamate (85) (scheme 5)

Amino alcohol-hydrochloride 13HCl (3.7g, 14.7mmol) is added to the DMF of 51 (5.22g, 14.7 mmol) of acid (80ml) solution.Mixture is cooled to 0 DEG C.HATU (7.0g, 18.4mmol) and 2,4,6- trimethylpyridines are added (3.51ml, 26.4mmol).Solution is stirred 17 hours at 0 DEG C to room temperature, is then distributed in EtOAc and saturation Na₂CO₃It is water-soluble Between liquid.Washing organic phase, (1M HCl/water solution is saturated NaHCO₃Aqueous solution, saturation NaCl aqueous solutions), dry (Na₂SO₄), Filtering, concentration.FC (hexane/EtOAc 30:70 to 20:80) amide groups alcohol (85,5.78g, 88%), is provided

85 data：C₂₃H₃₃N₃O₆(447.5).LC-MS (method 2)：R_t=1.92 (92), 448 ([M+H]⁺)。

5. synthesis of allyl N-3- [(2S, 4R) -4- [(tert-butoxycarbonyl) amino] -2- (hydroxymethyl) tetrahydrochysenes -1H- Pyrroles -1- bases] -3- oxopropyl-N- methyl carbamates (86) (scheme 5)

According to program D, at HCTU (31.0g, 75.0mmol), Cl-HOBt (1.27g, 7.5mmol) and iso- Pr₂NEt In the presence of (25.6mL, 150mmol), by amino alcohol 17HCl (7.5g, 30mmol) and 3- ((allyloxycarbonyl) (first Base) amino) propionic acid (49,12.3g, 66 mmol) reaction in DMF (77mL), in FC (CH₂Cl₂/MeOH 100:0 to 97:3) There is provided corresponding amides base ester intermediate (17.1g) later uses lithium hydroxide monohydrate (3.8g, 90 mmol) in THF it (388mL) and H₂Saponification in O (105mL) generates amide groups alcohol 86 (10.48 g, 86%).

86 data：C₁₈H₃₁N₃O₆(385.4).HPLC (10%CH₃CN)：R_t=3.49 (88).LC-MS (method 9a)： R_t=1.62；386([M+H]⁺), 330 ([M+H-tBu]⁺), 286 ([M+H-Boc]⁺)。

Core 01：Synthetic example 1 (scheme 6)

Synthesize Mitsunobu products 87

At 0 DEG C, in N₂Under atmosphere, to 54 (350mg, 0.82mmol), 16 (590mg, 1,7mmol) and PPh₃(1069mg, 4.08mmol) without water degasification CHCl₃ADDP (1028mg, 4.08mmol) is added in (11mL) solution a batch.It is stirred at room temperature Gained mixture 16 hours.Mixture is filtered, slurry is further washed with diethyl ether.It is concentrated in vacuo through combined filtrate.It is crude Nubbin passes through FC (CH₂Cl₂/EtOH 100:0 to 99:1) it purifies, providing 87, (1.05 g, contain triphenylphosphine oxide； It for subsequent step, is not added with and is further purified).

Synthesizing amino acid 88

B.2 according to program, by 87 (441mg polluted triphenylphosphine oxide, about 0.5 mmol), 1,3- dimethyl bar Than mud acid (219mg, 1.4mmol) and Pd (PPh₃)₄(34mg) is in EtOAc/CH₂Cl₂(55:45,10mL) reaction in, 1,5 Hour and subsequent FC (CH₂Cl₂/MeOH 100:0 to 80:20) amino acid 88 (267mg, 72%) is generated after.

88 data：C₃₁H₄₂FN₃O₈Si(631.7).LC-MS (method 9a)：

R_t=2.02,632 ([M+H]⁺).HPLC (30%CH₃CN)：R_t=3.41 (96).

Synthesize Macrocyclic lactams embodiment 1

F.1.1 according to program, by the anhydrous CH of amino acid 88 (75mg, 0.12mmol) in 4 hours₂Cl₂(6mL) solution T3P (in 50%, EtOAc, 0.21mL, 0.36mmol) and iso- Pr is added₂The anhydrous CH of NEt (0.1mL, 0.59mmol)₂Cl₂ (6mL) solution, in FC (CH₂Cl₂/MeOH 100:0 to 96:4) Macrocyclic lactams embodiment 1 (45mg, 61%) is obtained after.

The data of embodiment 1：C₃₁H₄₀FN₃O₇Si(613.7).LC-MS (method 7)：

R_t=1.45 (41), 614 ([M+H]⁺)；1.47 (44), 614 ([M+H]⁺)。

¹H-NMR(DMSO-d₆)：Complexity spectrum, several isomers；7.45-7.01 (m, 8H), 6,78-6.58 (2m, 1H), 5.42-5.06 (m, 3H), 4.50-3.50 (several m, 7H), 3.30-1.40 (several m, 7H), 2.84,2.70,2.66 (s, 3H), 0.97-0.82 (m, 2H), 0.03,0.02,0.00 (s 9H).

Core 02：Synthetic example 2 (scheme 11)

Synthesize the Macrocyclic lactams embodiment 2 through protection

In 2 hours, by T3P (in 50%, EtOAc, 0.75mL, 1.27mmol) and iso- Pr₂NEt (0.36mL, Anhydrous CH 2.2mmol)₂Cl₂The anhydrous CH of amino acid 98 (250mg, 0.43mmol) is added in (20mL) solution₂Cl₂(730mL) Solution.Solution is stirred at room temperature 20 hours, then with saturation Na₂CO₃Aqueous solution extraction.Dry organic phase (Na₂SO₄), mistake Filter, concentration.FC(CH₂Cl₂/MeOH 100:0 to 95:5) embodiment 2 (187mg, 77%), is provided.

The data of embodiment 2：C₃₀H₃₆FN₃O₇(569.6) LC-MS (method 7)：

R_t=1.35 (62), 570 ([M+H]⁺)；1.39 (15), 570 ([M+H]⁺)

¹H-NMR(DMSO-d₆)：Complexity spectrum, several isomers；7.46-7.30 (m, 5H), 7.27-7.06 (m, 2H), 6.98-6.67 (4dd, 1H), 5.54-5.06 (m, 3H), 4.68-3.48 (m, 6H), 3.05-1.98 (m 10H；S in 2.82, 2.69,2.64), 1.44-1.41 (3s, 9 H).

Core 03：Synthetic example 3, embodiment 4 and embodiment 5 (scheme 7)

Synthesize Mitsunobu products 89

E.1.1 according to program, by phenol 54 (7.8g, 18mmol), alcohol 81 (16g, 43mmol), DEAD (40%, toluene In, 37mL, 82mmol) and PPh₃(21g, 80mmol) reaction in anhydrous benzene (250mL), in FC (CH₂Cl₂/EtOH 100:0 To 95:5) amino acid 89 through protection is provided after, and (15.9g polluted about 30% triphenylphosphine oxide；For subsequently walking Suddenly, it is not added with and is further purified).

Synthesizing amino acid 90

E.2 according to program, by 89 (9.6g polluted triphenylphosphine oxide, about 9mmol), 1,3- dimethyl barbital Sour (5.0g, 32.0mmol) and Pd (PPh₃)₄(0.4g) is in EtOAc/CH₂Cl₂(55:45,266mL) reaction in, at 1,5 hour Later and in FC (CH₂Cl₂/MeOH 90:10 to 50:50) amino acid 90 (4.34g, 76%) is generated after.

90 data：C₃₃H₄₃FN₄O₉(658.7).HPLC (10%CH₃CN)：R_t=3.87 (99).LC-MS (method 9a)： R_t=1.77,659 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 3 through protection

F.1.2 according to program, by anhydrous DMF (50mL) the solution FDPP of amino acid 90 (2.5g, 3.80mmol) DMF (400mL) solution treatment of (2.51g, 6.53mmol), in FC (EtOAc/MeOH 100:0 to 95:5) it is provided after big Cyclic lactam embodiment 3 (2.29g, 94%).

The data of embodiment 3：C₃₃H₄₁FN₄O₈(640.7).HPLC (30%CH₃CN)： R_t=3.20 (96).(the sides LC-MS Method 9c)：R_t=2.06,641 ([M+H]⁺)。¹H-NMR (CDCl₃)：7.45-7.32 (m, 5H), 7.06 (m, 1H), 6.94-6.88 (m, 2H), 5.57 (dd, J=2.8,12.6,1H), 5.42 (wide m, 1H), 5.26 (d, J=12.2,1H), 5.15 (d, J= 12.2,1H), 4.90 (dd, J=2.5,11.0,1H), 4.34 (d, J=17.2,1H), 4.35-4.11 (m, 3H), 3.82 is (wide T, J about 8.5,1H), 3.65 (d, J=17.3,1H), 3.29 (t, J about 8.8,1H), 3.14 (s, 3H), 2.65 (s, 3H), 2.51-1.98 (several m, 5H), 1.76 (td, J=8.2,12.7,1H), 1.36 (s, 9H).

Synthesis acid embodiment 4：

According to program H, in the presence of catalyst (1g), by ester embodiment 3 (2.0g, 3.1mmol) MeOH (120mL)/ Hydrogenation 2 hours, provide embodiment 4 (1.68g, 97%) in THF (40mL).

The data of embodiment 4：C₂₆H₃₅FN₄O₈(550.6).HPLC (5%CH₃CN)：R_t=3.60 (86).LC-MS：(method 9c)：R_t=1.53；551([M+H]⁺), 451 ([M+H-Boc]⁺)。

Synthesize amine embodiment 5：

According to program J, by (100mg, 0.16mmol) dioxanes (3mL) solution the 4M HCl- bis- Evil of ester embodiment 3 Alkane (3mL) processing provides embodiment 5HCl (100mg, quantitative).

The data HCl of embodiment 5：C₂₈H₃₃FN₄O₆HCl (540.6, free alkali).LC-MS：(method 9c)：R_t= 1.44 541 ([M+H]⁺)。

Core 04：Synthetic example 56 and embodiment 57 (scheme 8)

Synthesize Mitsunobu products 91

E.1.1 according to program, by phenol 54 (8.0g, 19mmol), alcohol 82 (16.0g, 43 mmol), DEAD (40%, first In benzene, 38mL, 84mmol) and PPh₃(22g, 84mmol) reaction in anhydrous benzene (260mL), provides protection after FC (33.5g polluted triphenylphosphine oxide to amino acid 91.Substance is used for subsequent step, is not added with and is further purified).

Synthesizing amino acid 92

E.2 according to program, by 91 (33.5g, impurities), 1,3- dimethyl barbituric acid (16g, 102mmol) and Pd (PPh₃)₄(0.2g) is in EtOAc/CH₂Cl₂(45:55,340mL) reaction in, after 3 hours and in FC (CH₂Cl₂/EtOH 100:0 to 70:30 and then CH₂Cl₂/MeOH 90:10 to 70:30) amino acid 92 is generated after, and (4.8g, two steps totally 39%, is based on Phenol 54).

92 data：C₃₃H₄₃FN₄O₉(658.7).HPLC (10%CH₃CN)：R_t=3.80 (95).LC-MS (method 9c)： R_t=1.81,659 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 56 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 92 (3.8g, 5.80mmol)₂Cl₂(40 mL) solution T3P (in 50%, EtOAc, 6.8mL, 12mmol) and iso- Pr₂The anhydrous CH of NEt (4.0 mL, 23mmol)₂Cl₂At (510mL) solution Reason, in FC (EtOAc/MeOH 100:0 to 95:5) Macrocyclic lactams embodiment 56 (3.23g, 87%) is provided after.

The data of embodiment 56：C₃₃H₄₁FN₄O₈(640.7).HPLC (30%CH₃CN)： R_t=3.49 (88).(the sides LC-MS Method 9c)：R_t=2.02,641 ([M+H]⁺)。¹H-NMR (CDCl₃)：7.41-7.32 (m, 5H), 7.04 (m, 1H), 6.94-6.83 (m, 2H), 5.54 (dd, J=3.0,12.7,1H), 5.25 (d, J=12.2,1H), 5.14 (d, J=12.2,1H), 4.89 (dd, J=2.1,11.0,1H), 4.63 (wide m, 1H), 4.39-4.10 (m, 4H), 3.79-3.64 (m, 2H), 3.49 (wide m, 1H), 3.12 (s, 3H), 2.64 (s, 3 H), 2.51-2.36 (m, 2H), 2.23-1.98 (m, 4H), 1.44 (s, 9H).

Synthesis acid embodiment 57：

According to program H, in the presence of catalyst (1.1g), by ester embodiment 56 (2.25g, 3.5 mmol) in MeOH Hydrogenation 2 hours in (120mL)/THF (40mL), with warm (50 DEG C) MeOH/THF 3:1- washing filtering nubbin acid Embodiment 57 (1.9g, 98%) is provided afterwards.

The data of embodiment 57：C₂₆H₃₅FN₄O₈(550.6).HPLC LC-MS：(method 2)：R_t=1.54 (82), 551 ([M+H]⁺)。

Core 05：Synthetic example 85 and embodiment 86 (scheme 9)

Synthesize Mitsunobu products 93

E.1.1 according to program, by phenol 56 (6.6g, 15mmol), alcohol 81 (13g, 35mmol), DEAD (40%, toluene In, 32mL, 69mmol) and PPh₃(18g, 69mmol) reaction in anhydrous benzene (220mL), in FC (CH₂Cl₂/MeOH 100:0 To 94:6) (34.5g polluted triphenylphosphine oxide and diethyl hydrazine -1,2- dicarboxylic acids to the amino acid 93 of offer protection after Ester；It is not added with to be further purified for subsequent step and be acceptable).

Synthesizing amino acid 94

E.2 according to program, by 93 (34.5g, impurities), 1,3- dimethyl barbituric acid (17g, 106mmol) and Pd (PPh₃)₄(0.1g) is in EtOAc/CH₂Cl₂(55:45,350mL) reaction in, after 3 hours and in FC (CH₂Cl₂/EtOH 100:0 to 70:30 and then CH₂Cl₂/MeOH 90:10 to 70:30) amino acid 94 is generated after, and (5.6g, two steps totally 55%, is based on Phenol 56).

94 data：C₃₃H₄₃FN₄O₉(658.7).HPLC (10%CH₃CN)：R_t=3.79 (96).LC-MS (method 9c)： R_t=1.77,659 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 85 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 94 (2.75g, 4.2mmol)₂Cl₂(35 mL) solution T3P (in 50%, EtOAc, 4.9mL, 8.3mmol) and iso- Pr₂The anhydrous CH of NEt (2.9 mL, 17mmol)₂Cl₂(355mL) solution Processing, in FC (EtOAc/MeOH 100:0 to 95:5) Macrocyclic lactams embodiment 85 (2.47g, 92%) is generated after.

The data of embodiment 85：C₃₃H₄₁FN₄O₈(640.7).HPLC (30%CH₃CN)： R_t=3.52 (96).(the sides LC-MS Method 9c)：R_t=2.06；641([M+H]⁺), 541 ([M+H-Boc]⁺)。¹H-NMR(CDCl₃)：Two kinds of isomers, ratio 85:15, 7.42-7.31 (m, 5H), 7.08-6.77 (m, 3H), 5.33 (d, J=8.3,1H), 5.23 (d, J=12.2,1 H), 5.17 (d, J=12.1,1H), 4.84 (dd, J=2.9,8.9,1H), 4.37-4.25 (m, 3H), 4.11 (dd, J=4.2,12.0, 1H), 3.89 (t, J=8.3,1H), 3.80 (d, J=8.9,1H), 3.61 (d, J=17.1,1H), 3.16 (t, J=9.1, 1H), 3.13 (s, 2.55H, the NCH of main isomer₃), 3.03 (s, 0.45H, the NCH of secondary isomers₃), 2.98 (s, 2.55H, the NCH of main isomer₃), 2.87 (0.45H, the NCH of secondary isomers₃), 2.64-2.41 (m, 2H), 2.27- 2.09 (m, 1H), 1.98-1.83 (m, 2H), 1.79-1.66 (m, 2H), 1.45 (s, 7.65H, Boc, main isomers), 1.35 (s, 1.35H, Boc, secondary isomers).

Synthesis acid embodiment 86：

According to program H, in the presence of catalyst (1g) by ester embodiment 85 (2.0g, 3.1mmol) MeOH (120mL)/ Hydrogenation 2 hours in THF (40mL), with warm (50 DEG C) MeOH/TFH 3:It is real that acid is provided after 1 washing filtering nubbin Apply example 86 (1.67g, 97%).

The data of embodiment 86：C₂₆H₃₅FN₄O₈(550.6).LC-MS：(method 3)：R_t=1.10 (83), 551 ([M+H ]⁺)；1.17 (15), 551 ([M+H]⁺)。

Core 06：Synthetic example 104 and embodiment 105 (scheme 10)

Synthesize Mitsunobu products 95

E.1.2 according to program, by phenol 56 (13.1g, 30.5mmol), alcohol 82 (13.6g, 36.6mmol) and CMBP (14.7g, 61mmol) reaction in dry toluene (500mL), in FC (hexane/EtOAc 50:50 to 30:70) guarantor is provided after The amino acid 95 (16g, 67%) of shield.

Synthesizing amino acid 96

E.2 according to program, by 95 (16.0g, 20mmol), 1,3- dimethyl barbituric acid (8g, 49mmol) and Pd (PPh₃)₄(0.1g) is in EtOAc/CH₂Cl₂(55:45,220mL) reaction in, after 3 hours and in FC (CH₂Cl₂/EtOH 100:0 to 70:30 and then CH₂Cl₂/MeOH 90:10 to 70:30) amino acid 96 (11g, 81%) is generated after.

96 data：C₃₃H₄₃FN₄O₉(658.7).LC-MS (method 2)：R_t=1.63 (97), 659 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 104 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 96 (4.0g, 6.1mmol)₂Cl₂(40 mL) solution T3P (in 50%, EtOAc, 7.2mL, 12.1mmol) and iso- Pr₂The anhydrous CH of NEt (4.2 mL, 24.3mmol)₂Cl₂(1160mL) Solution treatment, in FC (CH₂Cl₂/MeOH 100:0 to 95:5) after obtain Macrocyclic lactams embodiment 104 (2.32g, 60%).

The data of embodiment 104：C₃₃H₄₁FN₄O₈(640.7).LC-MS (method 7)：R_t=1.21 (47), 641 ([M+H ]⁺)；1.24 (53), 641 ([M+H]).¹H-NMR(DMSO-d₆)：Complexity spectrum, isomer mixture, 7.44-6.65 (m, 9H), 5.32-5.05 (m, 2H), 4.70-3.30 (several m, 9H), 2.92 (s, the NCH of main isomer₃), 2.84 (s, major isomers The NCH of body₃), 2.30-1.70 (several m, 6H), 1.40,1.38 (2s, 9H).

Synthesis acid embodiment 105：

According to program H, in the presence of catalyst (1.07g), by ester embodiment 104 (2.15g, 3.3mmol) in MeOH Hydrogenation 4 hours, provide sour embodiment 105 (1.72g, 93%) in (215mL).

The data of embodiment 105：C₂₆H₃₅FN₄O₈(550.6).LC-MS：(method 7)：R_t=0.91 (45), 551 ([M+H ]⁺)；0.95 (38), 551 ([M+H]⁺)。

Core 07：Synthetic example 115 and embodiment 116 (scheme 11)

Synthesize Mitsunobu products 97

By phenol 54 (6.42g, 14.9mmol), alcohol 22 (4.04g, 13.5mmol) and PPh₃(9.73g, 37.1mmol) Mixture be dried in vacuo 15 minutes, be dissolved in no water degasification chloroform (130 mL).Solution is cooled to 0 DEG C.It is slowly added to ADDP Chloroform (20 mL) solution of (9.36g, 37.1mmol).Mixture is stirred at room temperature 3 hours, is then added more 22 (4.04g, 13.5 mmol) and PPh₃Chloroform (20mL) solution of (5.97g, 22.8mmol).Mixture is cooled to 0 DEG C.It is slow Slow chloroform (20mL) solution that ADDP (5.74g, 22.7mmol) is added.Solution is stirred at room temperature 16 hours, concentrates.Remaining portion Divide and be suspended in diethyl ether, filters.Solid is washed with diethyl ether.Concentration is through combined filtrate and cleaning solution.FC(CH₂Cl₂/EtOAc 10:1) 97 (7.73g, 73%), are provided.

Synthesizing amino acid 98

B.2 according to program, by 97 (7.72g, 11mmol), 1,3- dimethyl barbituric acid (4.1g, 26.0mmol) and Pd (PPh₃)₄(0.63g) is in EtOAc/CH₂Cl₂(53:47,190mL) in reaction, after 2 hr and FC (EtOAc, then CH₂Cl₂/MeOH 95:5 to 90:10) amino acid 98 (4.31g, 67%) is generated after.

98 data：C₃₀H₃₈FN₃O₈(587.6).HPLC (10%CH₃CN)：R_t=3.86 (84).LC-MS (method 9a)： R_t=1.76；588([M+H]⁺), 488 ([M+H-Boc]⁺)。

Synthesize the amino acid 99 of Alloc protections

C.1 according to program, by amino acid 98 (4.3g, 7.3mmol), chloro-carbonic acid allyl ester (0.86 mL, 8.0mmol) And Na₂CO₃(1.2g, 11mmol) dioxanes (62mL) and H₂Reaction, provides acid 99 (5.07g, 100%) in O (60 mL).

Synthesize the diamides 100 through protection

C.2 according to program, by 99 (4.9g, 7.3mmol) of acid, (46. is p- with the p- toluene fulfonate of sarcosine allyl ester TsOH, 2.6g, 8.8mmol), HOAt (1.5g, 11mmol), HATU (4.2g, 11mmol) and iso- Pr₂NEt (6.2mL, 36mmol) the reaction in DMF (75mL), provides the amino acid 1 00 (4.37g, 76%) of protection.

100 data：C₄₀H₅₁FN₄O₁₁(782.8).HPLC (50%CH₃CN)：R_t=3.56 (99).LC-MS (methods 9a)：R_t=2.45；783([M+H]⁺), 683 ([M+H-Boc]⁺)。

Synthesize the amino acid 1 01 of deprotection

C.3 according to program, by the amino acid 1 of protection 00 (4.36g, 5.6mmol), 1,3- dimethyl barbituric acid (2.1g, 13mmol) and Pd (PPh₃)₄(0.32g) is in EtOAc/CH₂Cl₂(45:55,106mL) reaction in, generates amino acid 1 01 (3.46g, 93%).

101 data：C₃₃H₄₃FN₄O₉(658.7).LC-MS (method 9b)：R_t=1.74； 659([M+H]⁺), 559 ([M+ H-Boc]⁺)。

Synthesize the Macrocyclic lactams embodiment 115 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 01 (3.44g, 5.2mmol)₂Cl₂(50 mL) solution T3P (in 50%, EtOAc, 6.2mL, 10mmol) and iso- Pr₂The anhydrous CH of NEt (3.6 mL, 21mmol)₂Cl₂At (470mL) solution Reason, in FC (CH₂Cl₂/MeOH 95:5) Macrocyclic lactams embodiment 115 (2.95g, 90%) is obtained after.

The data of embodiment 115：C₃₃H₄₁FN₄O₈(640.7).HPLC (20%CH₃CN)： R_t=4.05 (93).LC-MS (method 9c)：R_t=2.08；641([M+H]⁺)。¹H-NMR (DMSO-d₆)：Complexity spectrum, isomer mixture, 7.38 (s, 5H), 7.35-6.95 (several m, 2H), 6.81-6.72 (several m, 0.4H), 6.64 (dd, J=3.1,8.2,0.25H), 6.39 (dd, J=3.2,7.7,0.25H), 6.30 (dd, J=3.3,8.2,0.1H), 5.37-4.99 (m, 3H), 4.60-3.60 (number Kind m, 9H), 3.20-2.60 (several m and s, 8H), 2.40-1.70 (several m, 4H), 1.45,1.43,1.42,1.38 (4s, Boc)。

Synthesis acid embodiment 116：

According to program H, in the presence of catalyst (0.6g), by ester embodiment 115 (1.2g, 1.9 mmol) in MeOH Hydrogenation 2 hours, provide sour embodiment 116 (1.02g, 99%) in (120mL).

The data of embodiment 116：C₂₆H₃₅FN₄O₈(550.6).HPLC (10%CH₃CN)： R_t=3.47 (20), 3.55 (75).LC-MS：(method 9c)：R_t=1.53,1.58；551([M+H]⁺)。

Core 08：Synthetic example 132 and embodiment 133 (scheme 12)

Synthesize Mitsunobu products 102

E.1.2 according to program, by phenol 56 (2.0g, 4.7mmol), alcohol 84 (2.08g, 5.6 mmol) and CMBP (2.25g, 9.3mmol) reaction in dry toluene (80mL), after 3 hours and in FC (hexane/EtOAc 1:1 to 1:2) The amino acid 1 02 (2.06g, 56%) of protection is provided later.

Synthesizing amino acid 103

E.2 according to program, by 102 (2.05g, 2.6mmol), 1,3- dimethyl barbituric acid (1.0 g, 6.3mmol) and Pd(PPh₃)₄(0.15g) is in EtOAc/CH₂Cl₂(55:45；45mL) in reaction, after 2 hr and FC (EtOAc, then CH₂Cl₂/MeOH 95:5 to 70:30) amino acid 1 03 (1.45g, 85%) is generated after.

103 data：C₃₃H₄₃FN₄O₉(658.7).HPLC (5%CH₃CN)：R_t=4.04 (97).LC-MS (method 9c)： R_t=1.87,659 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 132 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 03 (1.44g, 2.19mmol)₂Cl₂(40mL) solution T3P (in 50%, EtOAc, 2.6mL, 4.37mmol) and iso- Pr₂The anhydrous CH of NEt (1.5mL, 8.74mmol)₂Cl₂(170mL) is molten Liquid processing, in FC (CH₂Cl₂/MeOH 95:5) Macrocyclic lactams embodiment 132 (1.36g, 96%) is obtained after.

The data of embodiment 132：C₃₃H₄₁FN₄O₈(640.7).LC-MS (method 2)：R_t=1.93 (100), 641 ([M+ H]⁺)；LC-MS (method 9c)：R_t=2.12,641 ([M+H]⁺)。¹H-NMR (DMSO-d₆)：Complexity spectrum, isomer mixture, 7.38 (s, 5H), 7.35-6.99 (several m, 2H), 6.85-6.73 (several m, 0.4H), 6.65 (dd, J=3.1,8.2, 0.25H), 6.39 (dd, J=3.1,7.9,0.25H), 6.30 (dd, J=3.3,8.1,0.1H), 5.37-4.99 (m, 3H), 4.6-3.6 (several m, 9H), 3.2-2.6 (several m and s, 8H), 2.4-1.7 (several m, 4H), 1.45,1.43,1.41,1.38 (4s, Boc).

Synthesis acid embodiment 133：

According to program H, in the presence of catalyst (0.56g), by ester embodiment 132 (1.13g, 1.7mmol) in MeOH Hydrogenation 4 hours, provide sour embodiment 133 (0.92g, 94%) in (110mL).

The data of embodiment 133：C₂₆H₃₅FN₄O₈(550.6).HPLC (5%CH₃CN)： R_t=3.65 (27), 3.72 (71).LC-MS：(method 9c)：R_t=1.53,551 ([M+H]⁺)；1.57,551 ([M+H]⁺)。

Core 09：Synthetic example 142 and embodiment 143 (scheme 13)

Synthesize Mitsunobu products 104

E.1.2 according to program, by phenol 54 (3.1g, 7.2mmol), alcohol 86 (3.34g, 8.7 mmol) and CMBP (3.49g, 14.4mmol) reaction in dry toluene (123mL), after 3 hours and in FC (hexane/EtOAc 1:1 to 1: 2) amino acid 1 04 (4.11g, 71%) of protection is provided after.

Synthesizing amino acid 105

E.2 according to program, by 104 (4.07g, 5.1mmol), 1,3- dimethyl barbituric acid (1.9 g, 12mmol) and Pd (PPh₃)₄(0.3g) is in EtOAc/CH₂Cl₂(45:55,90mL) in reaction, after 2 hr and FC (EtOAc, then CH₂Cl₂/MeOH 95:5 to 70:30) amino acid 1 05 (3.19g, 93%) is generated after.

105 data：C₃₄H₄₅FN₄O₉(672.7).HPLC (5%CH₃CN)：R_t=3.96 (88).LC-MS (method 9c)： R_t=1.83,673 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 142 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 05 (2.4g, 3.6mmol)₂Cl₂(40 mL) solution T3P (in 50%, EtOAc, 4.2mL, 7.1mmol) and iso- Pr₂The anhydrous CH of NEt (2.4 mL, 14.2mmol)₂Cl₂(300mL) is molten Liquid processing, in FC (CH₂Cl₂/MeOH 95:5) Macrocyclic lactams embodiment 142 (1.92g, 82%) is obtained after.

The data of embodiment 142：C₃₄H₄₃FN₄O₈(654.7).HPLC (30%CH₃CN)： R_t=3.50 (89).LC-MS (method 9b)：R_t=2.01；655([M+H]⁺), 599 ([M+H-tBu]⁺), 555 ([M+H-Boc]⁺)。¹H-NMR(DMSO-d₆)： Complexity spectrum, isomer mixture, 7.41-7.38 (m, 5H), 7.37-7.14 (m, 3H), 6.80-6.67 (m, 1 H), 5.45- 5.13 (m, 3H), 4.60-3.30 (several m, 8H), 3.10-2.50 (several m and s, 8H), 2.50-1.80 (several m, 6H), 1.39,1.38,1.36 (3s, Boc).

Synthesis acid embodiment 143：

According to program H, in the presence of catalyst (0.53g), by ester embodiment 142 (1.07g, 1.6mmol) in MeOH Hydrogenation 4 hours, provide sour embodiment 143 (0.92g, 99%) in (100mL).

The data of embodiment 143：C₂₇H₃₇FN₄O₈(564.6).LC-MS：(method 2)：R_t=1.54 (91), 565 ([M+ H]⁺)。

Core 10：Synthetic example 164 and embodiment 165 (scheme 14)

Synthesize Mitsunobu products 106

B.1.2 according to program, by phenol 63 (4.2g, 9.8mmol), alcohol 16 (4.4g, 13mmol) and CMBP (4.8g, 20mmol) the reaction in dry toluene (120mL), 4 hours and FC (hexane/EtOAc 50:50) ammonia of protection is provided after Base acid 106 (6.37g, 86%).

Synthesizing amino acid 107

B.2 according to program, by 106 (1.18g, 1.6mmol), 1,3- dimethyl barbituric acid (0.6 g, 3.8mmol) and Pd(PPh₃)₄(90mg) is in EtOAc/CH₂Cl₂(60:40,15mL) reaction in, after 3 hours and in FC (CH₂Cl₂/EtOH 100:0 to 80:20) amino acid 1 07 (0.86g, 87%) is generated after.

107 data：C₃₁H₄₄N₄O₈Si(628.8).LC-MS：(method 6)：R_t=1.08 (88), 629 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 164 through protection

F.1.2 according to program, by the anhydrous DMF of amino acid 1 07 (310mg, 0.49mmol) (5 mL) solution FDPP Anhydrous DMF (500mL) solution treatment of (379mg, 0.99mmol), in FC (hexane/EtOAc/MeOH 50:50:0 to 0:95: 5) Macrocyclic lactams embodiment 164 (131mg, 43%) is provided after.

The data of embodiment 164：C₃₁H₄₂N₄O₇Si(610.8).LC-MS：(method 7)：R_t=1.34 (98), 611 ([M+ H]⁺)。¹H-NMR(DMSO-d₆)：7.42-7.27 (m, 8H), 6.98 (dd, J=1.4,8.2,1H), 6.91 (d, J=7.5, 1H), 6.84 (s, 1H), 4.98 (s, 2H), 4.50 (d, J=11.9,1H), 4.35-4.15 (m, 3H), 4.06-3.96 (m, 4H), 3.21 (m, 1H), 3.10-2.95 (m, 2H), 2.87 (s, 3H), 2.30-1.80 (m, 4H), 0.91 (t, J=8.3,2H), 0.00 (s, 9H).

Synthesize amine embodiment 165

At 0 DEG C, embodiment 164 (1.2g, 1.96mmol) is added in THF (1M, 3.9mL, 3.9mmol) solution of TBAF THF (42mL) solution.At 0 DEG C to room temperature, agitating solution 15 hours, be then added more TBAF THF (1M, 1.18mL, 1.18mmol) solution.Continue stirring 2 hours.Solution is distributed in CH₂Cl₂And H₂Between O.Water phase CH₂Cl₂It extracts repeatedly. Drying is through combined organic phase (Na₂SO₄), it filters, concentration.FC (CH₂Cl₂/MeOH 100:0 to 90:10), embodiment is provided 165 (0.76g, 83%).

The data of embodiment 165：C₂₅H₃₀N₄O₅(466.52).LC-MS：(method 4a)： R_t=1.49 (99), 467 ([M+ H]⁺)。

Core 11：Synthetic example 181 and embodiment 182 (scheme 15)

Synthesize Mitsunobu products 108

B.1.2 according to program, by phenol 65 (10.7g, 24mmol), alcohol 16 (10.0g, 29 mmol) and CMBP (12.0g, 49mmol) reaction in dry toluene (362mL), in FC (hexane/EtOAc 50:50 to 70:30) it is provided after The amino acid 1 08 (14.55g, 78%) of protection.

Synthesizing amino acid 109

B.2 according to program, by 108 (14.50g, 19mmol), 1,3- dimethyl barbituric acid (7.0 g, 47.0mmol) and Pd(PPh₃)₄(0.1g) is in EtOAc/CH₂Cl₂(55:45,203mL) reaction in, after 3 hours and in FC (CH₂Cl₂/MeOH 99:1 to 90:10) amino acid 1 09 (11.26g, 92%) is generated after.

109 data：C₃₂H₄₆N₄O₈Si(642.8).LC-MS：(method 6)：R_t=1.13 (94), 643 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 181 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 09 (4.0g, 6.2mmol)₂Cl₂(100 mL) solution T3P (in 50%, EtOAc, 7.4mL, 12.4mmol) and iso- Pr₂The anhydrous CH of NEt (4.3 mL, 24.8mmol)₂Cl₂(560mL) is molten Liquid processing.Before aqueous post-processing, by CH₂Cl₂It is replaced with EtOAc.FC (hexane/EtOAc 50:50 to 0:100) it, provides big Cyclic lactam embodiment 181 (2.11g, 54%).

The data of embodiment 181：C₃₂H₄₄N₄O₇Si(624.8).LC-MS (method 7)：R_t=1.37 (99), 625 ([M+ H]⁺)。¹H-NMR(DMSO-d₆)：(7.46 d, J=8.0,1H), 7.42 (d, J=7.2,1H), 7.34-7.23 (m, 6H), 7.06 (d, J=8.2,1H), 6.82 (d, J=7.4,1H), 6.78 (s, 1H), 5.02-4.86 (m, 3H), 4.13 (t, J=8.5, 1H), 4.06-3.67 (m, 7H), 3.05 (wide m, 1H), 2.88 (wide m, 1H), 2.88 (s, 3H), 2.15 (m, 2H), 1.51 is (wide M, 2H), 1.33 (wide m, 1H), 1.12 (wide m, 1H), 0.91 (tertiary class m, J about 8.4,2H), 0.00 (s, 9H).

Synthesize amine embodiment 182

I.2 according to program, THF (34mL) solution of carbamate embodiment 181 (844mg, 1.3mmol) is used TBAF solution (4.1mL) processing, in FC (CH₂Cl₂/MeOH 90:10) amine embodiment 182 (620mg, 95%) is provided after

The data of embodiment 182：C₂₆H₃₂N₄O₅(480.5).LC-MS：(method 2)：R_t=1.35 (99), 481 ([M+H ]⁺)。

Core 12：Linear synthetic example 196 and embodiment 197 (scheme 16)

Synthesize Mitsunobu products 110

B.1.1 according to program, by phenol 59 (5.22g, 12.6mmol), alcohol 16 (5.2g, 15.2 mmol), PPh₃ The anhydrous benzene of anhydrous benzene (124mL) solution and DEAD (40%, in toluene, 7.0mL, 15.2mmol) of (5.0g, 19mmol) (36mL) solution reaction, in FC (hexane/EtOAc 60:40 to 40:60) after provide protection amino acid 1 10 (8.3g, 88%, it polluted certain triphenylphosphine oxides；Be be not added with for subsequent step be further purified it is acceptable).

Synthesizing amino acid 111

B.2 according to program, by 110 (4.15g, 5.62mmol), 1,3- dimethyl barbituric acid (2.19 g, 14.0mmol) With Pd (PPh₃)₄(0.71g) is in EtOAc/CH₂Cl₂1:Reaction in 1 (60mL), after 1 hour and in FC (CH₂Cl₂/EtOH 95:5 to 90:10 and then CH₂Cl₂/MeOH 90:10 to 70:30) amino acid 1 11 (2.75g, 80%) is generated after.

111 data：C₃₀H₄₂N₄O₈Si(614.8).HPLC (10%CH₃CN)：R_t=3.82 (99).LC-MS (methods 9a)：R_t=1.81；615([M+H]⁺)。

Synthesize the amino acid 1 12 of alloc protections

C.1 according to program, by amino acid 1 11 (1.5g, 2.4mmol), chloro-carbonic acid allyl ester (0.29mL, 2.68mmol) and Na₂CO₃(0.72g, 6.83mmol) dioxanes (40mL) and H₂Reaction in O (40mL), provides acid 112 (1.7g, 100%).

Synthesize the amino acid 1 13 through protection

C.2 according to program, by 112 (1.7g, 2.4mmol) of acid and the p- toluene fulfonate of sarcosine allyl ester (46. P- TsOH, 0.88g, 2.9mmol), HOAt (0.5g, 3.6mmol), HATU (1.4g, 3.6mmol) and iso- Pr₂NEt (2.1mL, 12mmol) reaction in DMF (25mL), provides the amino acid 1 13 (1.51g, 75%) of protection.

113 data：C₄₀H₅₅N₅O₁₁Si(809.9).HPLC (40%CH₃CN)：R_t=4.43 (91).LC-MS (methods 9c)：R_t=2.51,810 ([M+H]⁺)。

Deprotection is amino acid 1 14

C.3 according to program, by the amino acid 1 of protection 13 (1.5g, 1.85mmol), 1,3- dimethyl barbituric acid (0.72g, 4.6mmol) and Pd (PPh₃)₄(0.23g) is in EtOAc/CH₂Cl₂(1:1,25mL) reaction in, generates amino acid 1 14 (1.05g, 83%).

114 data：C₃₃H₄₇N₅O₉Si(685.8).HPLC (10%CH₃CN)：R_t=3.85 (95).LC-MS (methods 9c)：R_t=1.78,686 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 196 through protection

F.1.2 according to program, by the anhydrous DMF of amino acid 1 14 (1.0g, 1.46mmol) (20 mL) solution FDPP Anhydrous DMF (130mL) solution treatment of (1.12g, 2.92mmol) generates Macrocyclic lactams embodiment after FC (EtOAc) 196 (0.61g, 63%).

The data of embodiment 196：C₃₃H₄₅N₅O₈Si(667.8).LC-MS (method 1a)：R_t=2.66 (100), 668 ([M +H]⁺).LC-MS (method 9c)：R_t=2.12,668 ([M+H]⁺), 640.¹H-NMR(CDCl₃)：(7.34-7.26 m, 6H), 7.17 (d, J=7.6,1H), 7.02 (s, 1H), 6.91 (d, J=9.5,1H), 5.49 (d, J=9.5,2H), 5.10 (m, 1H), 5.06 (s, 2H), 4.39-4.13 (m, 5H), 4.00-3.95 (m, 2H), 3.65 (m, 1H), 3.36 (wide s, 2H), 3.14 (m, 2H), 3.09 (s, 3H), 2.74 (s, 3H), 2.45 (m, 1H), 2.08 (m, 1H), 0.98 (m, 2H), 0.00 (s, 9H).¹H- NMR (DMSO-d₆)：7.98 (d, J=9.9,1H), 7.52 (d, J=7.9,1H), 7.36-7.27 (m, 6H), 7.18 (s, 1H), 7.06 (dd, J=1.8,8.1,1H), 6.83 (d, J=7.5,1 H), 5.12 (d, J=12.5,1H), 5.04 (d, J= 12.5,1H), 4.87 (d, J=8.8,1H), 4.25-3.89 (m, 8H), 3.71-3.66 (m, 2H), 3.20 (m, 1H), 3.02 (m, 1H), 2.97 (s, 3H), 2.65 (s, 3H), 2.20 (m, 1H), 2.09 (m, 1H), 0.92 (t, J=8.2,2H), 0.00 (s, 9H).

Synthesize amine embodiment 197

I.1 according to program, by carbamate embodiment 196, (120mg, 0.18mmol) dioxanes (3mL) solution is used 4M HCl- dioxanes (3mL) processing, provides embodiment 197HCl (59 mg, 58%).

The data HCl of embodiment 197：C₂₇H₃₃N₅O₆HCl (523.5, free alkali).HPLC (5%CH₃CN)：R_t= 3.05(83).LC-MS (method 9c)：R_t=1.12,524 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：8.53 (wide s, NH₃ ⁺), 8.03 (d, J=9.9,1H), 7.41-7.31 (m, 7H), 7.15 (m, 1H), 6.85 (d, J=7.5,1H), 5.14 (d, J=12.5,1 H), 5.04 (d, J=12.5,1H), 4.86 (dd, J about 2.2,11.0,1H), 4.42-4.13 (m, 2H), 4.05 (t, J=8.5, 1H), 3.96 (d, J=17.8,1H), 3.85-3.75 (m, 2H), 3.65 (wide m, 1H), about 3.3-3.1 (m, 3H, by H₂O signals Shelter part), 2.97 (s, 3H), 2.67 (s, 3H), 2.42 (m, 1H), 2.18 (wide q, J about 11.1,1H).

Core 12：Collect synthetic example 197 and embodiment 198

(scheme 17)

Synthesize Mitsunobu products 115

E.1.1 according to program, by phenol 59 (4.6g, 11mmol) alcohol 81 (5.0g, 13 mmol), and DEAD (40%, first In benzene, 6.1mL, 13mmol) and PPh₃Processing 40 hours in anhydrous benzene (150mL) (4.4g, 17mmol).After 2 hr After 18 hours, more PPh are added₃The benzene (50mL) of (1.82g, 6.9mmol), alcohol 81 (2.04g, 5.5mmol) are molten Benzene (13mL) solution of liquid and DEAD (40%, in toluene, 2.55mL, 5.6mmol).FC (hexane/EtOAc 50:50 to 90: 10), the amino acid 1 15.1 (2.5g, 29%) of protection is provided.

E.1.2 according to program, by phenol 59 (2.9g, 7.0mmol), alcohol 81, (5.7g, 15mmol) and CMBP (5.1g, 21mmol) the reaction in dry toluene (121mL), in FC (hexane/EtOAc 20:80 to 90:10) ammonia of protection is provided after Base acid 115.2 (2.92g, 54%).

Synthesizing amino acid 116

E.2 according to program, by 115.1 (3.17g, 4.14mmol), 1,3- dimethyl barbituric acid (1.62g, 10.3mmol) and Pd (PPh₃)₄(0.53g) is in EtOAc/CH₂Cl₂(1:Isosorbide-5-Nitrae 6mL) in reaction, after 1 hour and in FC (CH₂Cl₂/MeOH 90:10 to 70:30) amino acid 1 16.1 (1.86g, 70%) is generated after.

116.1 data：C₃₂H₄₃N₅O₉(641.7).HPLC (5%CH₃CN)：R_t=3.65 (100).LC-MS (methods 9c)：R_t=1.60,642 ([M+H]⁺)。

E.2 according to program, by 115.2 (2.9g, 3.8mmol), 1,3- dimethyl barbituric acid (1.5 g, 9.5mmol) and Pd(PPh₃)₄(0.48g) is in EtOAc/CH₂Cl₂(1:Isosorbide-5-Nitrae 6mL) in reaction, after 1 hour and in FC (CH₂Cl₂/MeOH 90:10 to 70:30) amino acid 1 16.2 (2.0g, 83%) is generated after.

116.2 data：C₃₂H₄₃N₅O₉(641.7).HPLC (5%CH₃CN)：R_t=3.73 (98).LC-MS (methods 9c)：R_t=1.61,642 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 198 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 16.1 (1.0g, 1.6mmol)₂Cl₂(200mL) solution T3P (in 50%, EtOAc, 1.8mL, 3.1mmol) and iso- Pr₂The anhydrous CH of NEt (1.1mL, 6.2mmol)₂Cl₂(1400mL) is molten Liquid processing, in FC (EtOAc/MeOH 95:5 to 80:20) Macrocyclic lactams embodiment 198 is provided after and (contains 15% difference To isomers embodiment 231；0.38g, 39%).

The data of embodiment 198：C₃₂H₄₁N₅O₈(623.7).LC-MS：(method 2)：R_t=1.78 (84), 624 ([M+H ]⁺)；1.82(15).LC-MS (method 9c)：R_t=1.87,624 ([M+H]⁺)。

¹H-NMR(CDCl₃)：7.42-7.25 (m, 7H), 7.07 (s, 1H), 7.00 (d, J=8.2,1H), 5.59 (d, J= 9.5,1H), 5.38 (wide d, J about 7.9,1H), 5.18 (dd, J=2.5,12.2,1H), 5.13 (s, 2H), 4.43-4.01 (m, 5H), 3.73 (m, 1H), 3.47 (d, J=17.7,1H), 3.33 (d, J=17.7,1H), 3.20-3.11 (m, 2H), 3.17 (s, 3H), 2.81 (s, 3H), 2.50 (m, 1H), 2.15 (m, 1H), 1.51 (s, Boc, main isomers), 1.45 (s, Boc, it is secondary Want isomers)；¹H-NMR(DMSO-d₆)：7.97 (d, J=10.3,1H), 7.41-7.30 (m, 7H), 7.18 (s, 1H), 7.09 (d, J=8.2,1H), 6.85 (J=7.6,1H), 5.12 (d, J=12.5,1H), 5.05 (d, J=12.6,1H), 4.89 (J =9.6,1H), 4.30-3.55 (m, 6H), 3.40 (2H, by H₂O signals are sheltered), 3.25-3.00 (m, 2H), 2.99 (s, 3H), 2.65 (s, 3H), 2.22 (m, 1H), 2.05 (wide q, 1H), 1.41, (s, 9H).

F.1.1 according to program, by the anhydrous CH of amino acid 1 16.2 (0.85g, 1.3mmol)₂Cl₂(170mL) solution is used T3P (in 50%, EtOAc, 1.56mL, 2.6mmol) and iso- Pr₂The anhydrous CH of NEt (0.91mL, 5.3mmol)₂Cl₂ (1190mL) solution treatment, in FC (EtOAc/MeOH 95:5 to 80:20) provided after Macrocyclic lactams embodiment 198 and its Epimer embodiment 231 (about 1:1 mixture；0.61g, 73%).

The data of 198/ embodiment 231 of mixture embodiment：C₃₂H₄₁N₅O₈(623.7). LC-MS：(method 2)：R_t= 1.78 (44), 624 ([M+H]⁺)；1.82 (56), 624 ([M+H]⁺)。¹H-NMR(CDCl₃)：Complexity spectrum, epimer mixing Object, 7.41-7.20 (m, 6H), 7.07-6.92 (m, 3H) 5.8-4.8 (several m, 5H), 4.3-3.0 (several m, 10H), 3.16 (s, NCH₃), 2.81 (s, NCH₃), 2.58-2.45 (m, 1H), 2.19-2.03 (m, 1H), 1.51,1.41 (2s, 9H)

Synthesize amine embodiment 197

According to program J, by 198/ embodiment 231 (about 85 of carbamate embodiment:15,749 mg, 1.2mmol) two Oxane (7.5mL) solution is handled with 4M HCl- dioxanes (15mL), provides embodiment 197HCl/ embodiments 232HCl (607mg, 90%).

The data of embodiment 197HCl/ embodiments 232HCl：C₂₇H₃₃N₅O₆HCl (523.5, free alkali).LC-MS (method 2)：R_t=1.26 (75), 1.33 (14)；524([M+H]⁺)。

¹H-NMR(DMSO-d₆), key component embodiment 197HCl：Spectrum with above to COMPOUNDS EXAMPLE 197 HCl (referring to scheme 16) is described identical.

According to program J, by 198/ embodiment 231 (about 1 of carbamate embodiment:1,1.32g, 2.12mmol) two Oxane (13mL) solution with 4M HCl- dioxanes (26mL) handle, by preparative RP-HPLC (method 1) detach isomers it Embodiment 197.TFA (460 mg, 34%) and embodiment 232.TFA (470mg, 35%) is provided afterwards.

The data of embodiment 197.TFA：C₂₇H₃₃N₅O₆·C₂HF₃O₂(523.5, free alkali).LC-MS (method 2)：R_t= 1.25 (99), 524 ([M+H]⁺).LC-MS (method 7)：R_t=0.74 (97), 524 ([M+H]⁺)。¹H-NMR(DMSO-d₆)： 8.34 (wide s, NH₃ ⁺), 8.07 (d, J=9.9,1H), 7.43-7.33 (m, 6H), 7.20 (s, 1H), 7.10 (dd, J=1.5, 8.2,1H), 6.87 (d, J=7.4,1H), 5.17 (d, J=12.5,1H), 5.05 (d, J=12.5,1H), 4.87 (wide dd, 1H), 4.27-4.16 (m, 2H), 4.06 (t, J=8.6,1H), 4.01-3.91 (m, 2H), 3.82 (t classes dd, J about 8.1,1H), 3.70 (wide m, 1 H), 3.35-3.20 (m, 3H), 2.98 (s, 3H), 2.70 (s, 3H), 2.49 (m, 1H), 2.18 (wide q, J are about 11.0,1H).

The data of embodiment 232.TFA：It see below；Core 14.

Core 13：Synthetic example 215 and embodiment 216 (scheme 18)

Synthesize Mitsunobu products 117

B.1.1 according to program, by phenol 59 (2.1g, 5.1mmol), alcohol 20 (2.1g, 6.1 mmol), PPh₃(2.0g, Anhydrous benzene (14mL) solution of anhydrous benzene (50mL) solution 7.6mmol) and DEAD (40%, in toluene, 2.8mL, 6.1mmol) PPh is further being added in reaction₃(0.84g, 3.2mmol), benzene (21mL) solution of alcohol 20 (0.88g, 2.6mmol) and After benzene (6mL) solution of DEAD (40%, in toluene, 1.2mL, 2.6mmol) and in FC (hexane/EtOAc 50:50) after The amino acid 1 17 (3.8g, 100%) of protection is provided.

Synthesizing amino acid 118

B.2 according to program, by 117 (7.63g, 10.3mmol), 1,3- dimethyl barbituric acid (4.03 g, 25.8mmol) With Pd (PPh₃)₄(1.31g) is in EtOAc/CH₂Cl₂(1:1,110mL) reaction in, after 1 hour and in FC (CH₂Cl₂/MeOH 95:5 to 70:30) amino acid 1 18 (3.48g, 60%) is generated after.

118 data：C₃₀H₄₂N₄O₈Si(614.8).HPLC (10%CH₃CN)：R_t=3.88 (100).LC-MS (methods 9a)：R_t=1.80,615 ([M+H]⁺)。

Synthesize the amino acid 1 19 of alloc protections

C.1 according to program, by amino acid 1 18 (3.36g, 5.5mmol), chloro-carbonic acid allyl ester (0.64mL, 6.0mmol) and Na₂CO₃(0.87g, 8.2mmol) dioxanes (51mL) and H₂Reaction in O (51mL), provides acid 119 (3.51g, 92%).

Synthesize the amino acid 1 20 through protection

C.2 according to program, by 119 (3.47g, 5.0mmol) of acid, (46. is p- with sarcosine allyl ester tosilate TsOH, 1.8g, 6.0mmol), HOAt (1.0g, 7.4mmol), HATU (2.8g, 7.4mmol) and iso- Pr₂NEt (4.2mL, 25mmol) the reaction in DMF (108mL), provides the amino acid 1 20 (3.52g, 88%) of protection.

120 data：C₄₀H₅₅N₅O₁₁Si(809.9).LC-MS：(method 4b)：R_t=2.51 (95), 810 ([M+H]⁺)

Deprotection is amino acid 1 21

C.3 according to program, by the amino acid 1 of protection 20 (3.49g, 4.31mmol), 1,3- dimethyl barbituric acid (1.68g, 10.8mmol) and Pd (PPh₃)₄(0.55g) is in EtOAc/CH₂Cl₂(1:1；Reaction in 50mL), generates amino acid 121 (2.72g, 92%).

121 data：C₃₃H₄₇N₅O₉Si(685.8).LC-MS：(method 4b)：R_t=1.84 (94), 686 ([M+H]⁺)

Synthesize the Macrocyclic lactams embodiment 215 through protection

F.1.2 according to program, by the anhydrous DMF of amino acid 1 21 (1.33g, 1.94mmol) (27 mL) solution FDPP Anhydrous DMF (164mL) solution treatment of (1.49g, 3.88mmol), in FC (EtOAc/MeOH 95:5) it is generated in big ring after Amide examples 215 (0.89g, 68%).

The data of embodiment 215：C₃₃H₄₅N₅O₈Si(667.8).LC-MS：(method 1b)： R_t=2.60 (99), 668 ([M +H]⁺).LC-MS：(method 9c)：R_t=2.14,668 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：7.94 (d, J=9.8,1H), 7.39-7.27 (m, 7H), 7.11 (s, 1H), 6.97 (dd, J=1.5,8.2,1H), 6.82 (d, J=7.5,1H), 5.05 (s, 2H), 4.83 (wide d, 1H), 4.25 (wide m, 1H), 4.17-3.96 (m, 5H), 3.73 (wide q, J about 16.8,2H), 3.47 (m, 1H), 3.33 (m, 1H), 3.19 (m, 2H), 2.96 (s, 3H), 2.67 (s, 3H), 2.20 (m, 1H), 2.00 (m, 1H), 0.91 (t, J=8.4,2H), 0.00 (s, 9H).

Synthesize amine embodiment 216

I.1 according to program, by carbamate embodiment 215, (881mg, 1.3mmol) dioxanes (16mL) solution is used 4M HCl- dioxanes (16mL) processing, provides embodiment 216HCl (666mg, 90%).

The data HCl of embodiment 216：C₂₇H₃₃N₅O₆HCl (523.5, free alkali).HPLC (5%CH₃CN)：R_t= 3.11(91).LC-MS (method 9c)：R_t=1.19,524 ([M+H]⁺)。

Core 14：Synthetic example 231 and embodiment 232 (scheme 19)

Synthesize Mitsunobu products 122

By phenol 61 (4.6g, 11.2mmol) and PPh₃The mixture of (5.27g, 20.1mmol) is dissolved in benzene.Concentrate solution, Nubbin is dried in vacuo 20 minutes.Be added alcohol 81, (7.46g, 20.1mmol) without water degasification benzene (120mL) solution.Institute It obtains mixture and is cooled to 0 DEG C.It is slowly added to benzene (10mL) solution of DEAD (40%, in toluene, 11.5mL, 25.1mmol). Agitating solution 16 hours at room temperature.More PPh are added₃(1.46g, 5.6mmol), alcohol 81 (1.04g, 2.8mmol)；At 0 DEG C, Benzene (2mL) solution of DEAD (40%, in toluene, 2.6mL, 5.7mmol) is added, continues stirring 7 hours at room temperature.It is added more More PPh₃(1.46g, 5.6 mmol), alcohol 81 (1.04g, 2.8mmol), at 0 DEG C, be added DEAD (40%, in toluene, 2.6mL, 5.7mmol) benzene (2mL) solution.Continue stirring 16 hours at room temperature.Concentrate mixture.FC (hexanes/EtOAc 30:70 to 0:100), providing 122, (12.8g polluted about 40% triphenylphosphine oxide, and yield is about 90%).This substance is used It is not added with and is further purified in subsequent step)

Synthesizing amino acid 123

E.2 according to program, by the amino acid 1 of protection 22 (polluted about 40% triphenylphosphine oxide, 12.8g, about 10mmol), 1,3- dimethyl barbituric acid (3.91g, 25.1mmol) and Pd (PPh₃)₄(1.27g) is in EtOAc/CH₂Cl₂(1: 1,120mL) reaction in, after 1 hour and in FC (CH₂Cl₂/MeOH 100:0 to 70:30 and then CHCl₃/MeOH 70:30) Amino acid 1 23 (2.80g, 44%) is generated later.

123 data：C₃₂H₄₃N₅O₉(641.7).LC-MS：(method 2)：R_t=1.56 (94), 642 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 231 through protection

F.1.2 according to program, at 60 DEG C, by the anhydrous DMF of amino acid 1 23 (3.29g, 5.13 mmol) in 4 hours Anhydrous DMF (4980mL) solution of FDPP (3.94g, 10.3mmol) is added in (150mL) solution, 60 DEG C of processes 16 hours it Afterwards and in FC (EtOAc/MeOH 100:0 to 95:5) Macrocyclic lactams embodiment 231 is provided after, and (its containing about 15% is poor To isomers embodiment 198；2.5g, 78%).

The data of embodiment 231：C₃₂H₄₁N₅O₈(623.7).LC-MS：(method 2)：R_t=1.78 (12), 1.82 (83), 624([M+H]⁺).LC-MS：(method 7)：R_t=1.16 (18), 624 ([M+H]⁺)；1.18 (80), 624 ([M+H]⁺)。¹H-NMR (CDCl₃)：Complexity spectrum, two kinds of epimers；7.38-7.22 (m, 6H), 7.06-6.90 (m, 3H), 5.80-4.80 is (several M, 4H), 5.08,5.12 (2s, 2H), 4.43-2.80 (several width m, 15H), 2.51 (m, 1H), 2.19-2.03 (m, 1H), 1.50,1.42 (2s, 9H).

Synthesize amine embodiment 232

According to program J, carbamate embodiment 231 (is contained into 15% epimer embodiment 198；1.42g 2.3mmol) dioxanes (30mL) solution with 4M HCl- dioxanes (45 mL) handle, preparative RP-HPLC (method 1) it Embodiment 232.TFA (1.10g, 71%) and embodiment 197.TFA (0.27g, 17%) is provided afterwards.

The data of embodiment 232.TFA：C₂₇H₃₃N₅O₆·C₂HF₃O₂(523.5, free alkali).LC-MS (method 2)：R_t= 1.32 (99), 524 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：Complexity spectrum, isomer mixture；8.40 (wide s), 8.20 (wide s), 7.84 (d, J=7.1), 7.50-6.80 (several m), 5.25-3.40 (several m, by H₂O signal sections are sheltered), 3.30-2.80 (m), 3.04 (s, NCH₃), 2.98 (s, NCH₃), 2.67 (s, NCH₃), 2.64 (s, NCH₃), 2.6-1.9 (several m).

The data of embodiment 197.TFA：It sees above；Core 12.

Core 15 and core 16：

Synthetic example 238 and embodiment 239 (scheme 20)

Synthesize Mitsunobu products 124

E.1.1 according to program, by phenol 77 (1.63g, 8.5mmol), alcohol 85 (5.72g, 12.8 mmol) and PPh₃ Anhydrous benzene (80mL) solution of (4.02g, 15.3mmol) is small with DEAD (40%, in toluene, 8.79mL, 19.2mmol) processing 20 When.Pass through FC (hexane/EtOAc 20:80 to 100:0) then (hexane/EtOAc 50:50 to 20:80) it purifies, protection is provided Amino acid 1 24 (1.96g, 37%).

Synthesize big ring embodiment 238

Two chloro- [(mesitylene the base) -2- imidazolidines of 1,3- bis- subunit]-(3- phenyl -1H- indenes -1- subunits) (thricyclohexyls Phosphine) ruthenium (II)

By (Umicore M2 catalyst；88mg) be added 124 (1160mg, 1.29mmol) without water degasification CH₂Cl₂ (170mL) solution.At 40 DEG C in seal pipe, agitating solution 68 hours is then stirred at room temperature 45 hours.In the period The decile (total 350mg) of further catalyst is added in period after 20 hours, 28 hours, 44 hours and 52 hours.It is dense Contracting solution.FC (hexane/EtOAc 70:30 to 0:100), (mixing of 350mg, 46%, two kind of isomers of embodiment 238 is provided Object, ratio>9:1, be acceptable for subsequent step).Analysis sample (69 mg) is passed through into preparative RP-HPLC (method 2) It is further purified, pure 238 (main isomer of embodiment is provided；45mg).

The data (main isomer) of embodiment 238：C₃₂H₄₀N₄O₇(592.6).LC-MS：(method 4a)：R_t=2.23 (92), 593 ([M+H]⁺)。¹H-NMR(CDCl₃)：7.62-7.31 (m, 6H), 7.07 (d, J=7.6,1H), 6.99 (dd, J= 2.0,7.9,1H), 6.85 (s, 1 H), 5.69-5.61 (m, 2H), 5.48 (d, J=8.2,1H), 5.21 (m, 1H), 5.10 (s, 2H), 4.76 (d, J=10.1,1H), 4.54 (dt, J=3.5,7.9,1H), 4.41-4.25 (m, 2H), 4.13 (d, J= 10.7,1H), 3.97 (m, 1H), 3.62 (m, 2H), 3.48 (m, 1H), 3.10 (s, 3H), 2.73 (m, 1H), 2.60-2.45 (m, 2H), 2.02 (m, 1H), 1.46 (s, 9H).

Synthesize amine embodiment 239

At room temperature and under usual pressure, in palladium dydroxide/activated carbon (moistening to 50%H₂O；In the presence of 215mg), By the MeOH/THF 1 of embodiment 238 (430mg, 0.73mmol):3,36mL) solution hydrogenated 3.5 hours.It is logical to filter mixture Cross celite pad.Concentration filtrate obtains embodiment 239, and (355mg is quantified；It for subsequent step, is not added with and is further purified).

Analysis sample (68mg) is purified by preparative RP-HPLC (method 2), pure embodiment 239 (37mg) is provided.

The data of embodiment 239：C₂₄H₃₆N₄O₅(460.6)：LC-MS (method 7)：R_t=0.88 (97), 461 ([M+H ]⁺)。¹H-NMR(DMSO-d₆)：7.36 (t, J=7.8,1H), 7.25 (d, J=6.1,1H), 7.03 (dd, J=1.6,8.2, 1H), 6.88-6.65 (m, 2H), 4.51 (d, J=8.3,1H), 4.18 (t, J=10.3,2H), 4.09 (wide s, 1H), 3.96 (wide m, 2H), 3.19-2.72 (m, 3H), 2.92 (s, 3H), 2.34 (m, 2H), 2.05 (wide q, 1H), 1.82 (m, 1H), 1.60- 0.85 (m, 5H), 1.40 (s, 9H), 0.82 (m, 1H).

Core 17：Synthetic example 248 and embodiment 249 (scheme 21)

Synthesize Mitsunobu products 125

E.1.1 according to program, by phenol 68 (6.0g, 14.6mmol), alcohol 82 (9.75g, 26.2 mmol) and PPh₃ (6.88g, 26.2mmol) is in the anhydrous benzene (160mL) with DEAD (40%, in toluene, 15mL, 32.8mmol) processing 40 hours. After 18 hours and after 25 hours, more PPh are added₃(1.27g, 4.8mmol) and DEAD (40%, in toluene, 2.23 mL, 4.9mmol) benzene (2mL) solution.FC (hexane/EtOAc 30:70 to 20:80), the amino acid 1 25 of protection is provided (16.85g polluted about 40% triphenylphosphine oxide, and yield is about 85%).This substance is not added with further for subsequent step Purifying)

Synthesizing amino acid 126

E.2 according to program, by 125 (16.8g polluted about 40% triphenylphosphine oxide, about 12mmol), 1,3- bis- Methylbarbituric acid (4.80g, 30.8mmol) and Pd (PPh₃)₄(1.56 g) is in EtOAc/CH₂Cl₂(1:1,170mL) anti-in It answers, after 1 hour and in FC (CH₂Cl₂/MeOH 0:100 to 70:30, then CHCl₃/MeOH 70:30) ammonia is generated after Base acid 126 (4.15g, about 52%).

126 data：C₃₃H₄₄N₄O₉(640.7).HPLC (10%CH₃CN)：R_t=3.67 (69).LC-MS (method 9c)： R_t=1.75,641 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 248 through protection

F.1.1 according to program, in 3 hours, by the anhydrous CH of amino acid 1 26 (4.55g, 7.1mmol)₂Cl₂(120mL) T3P (in 50%, EtOAc, 8.37ml, 14.2mmol) and iso- Pr is added in solution₂NEt's (4.83ml, 28.4mmol) is anhydrous CH₂Cl₂(6660mL) solution.Before aqueous post-processing, by CH₂Cl₂It is replaced with EtOAc.FC(CH₂Cl₂/MeOH 100:0 to 95:5) Macrocyclic lactams embodiment 248 (2.38g, 54%), is generated.

The data of embodiment 248：C₃₃H₄₂N₄O₈(622.7).LC-MS：(method 2)：R_t=1.83 (100), 623 ([M+ H]⁺).LC-MS：(method 9c)：R_t=1.97,623 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：(7.45-7.34 m, 5H), 7.15- 6.78 (m, 5H), 5.25 (s, 2H), 5.08 (d, J=12.8,1H), 4.62 (d, J=13.5,2H), 4.29 (m, 1H), 4.09 (d, J=7.3,1H), 3.89 (d, J=12.4,1H), 3.54 (wide t, 1H), 3.27 (m, 1H), 3.07 (s, 3H), 2.80 (m, 1H), 2.71 (s, 3H), 2.28-2.06 (m, 4H), 1.94 (m, 1H), 1.71 (m, 1H), 1.39 (s, 9H).

Synthesis acid embodiment 249：

According to program H, in the presence of catalyst (1.09g), by ester embodiment 248 (2.16g, 3.5mmol) in MeOH Hydrogenation 2.5 hours, provide sour embodiment 249 (1.83g, 99%) in (130mL)/THF (40mL).

The data of embodiment 249：C₂₆H₃₆N₄O₈(532.6).LC-MS：(method 2)：R_t=1.42 (95), 533 ([M+H ]⁺)。

Core 18：Synthetic example 272, embodiment 273 and embodiment 274 (scheme 22)

Synthesize Mitsunobu products 127

E.1.1 according to program, by phenol 71 (6.47g, 15,7mmol), alcohol 81 (10.5g, 28.2mmol), DEAD (40%, in toluene, 26mL, 56.3mmol) and PPh₃(14.8 g, 56.3mmol) reaction in anhydrous benzene (380mL), in room (EtOAc is saturated Na after passing through 2 hours under temperature and in aqueous post-processing₂CO₃Aqueous solution, saturation NaCl aqueous solutions) after, it does Dry (Na₂SO₄), concentration of organic layers and FC (hexane/EtOAc 30:70,0:100, then CH₂Cl₂/MeOH 90:10) guarantor is provided The amino acid 1 27 (12.0g, 99%) of shield.

Synthesizing amino acid 128

E.2 according to program, by 127 (12.0g, 16mmol), 1,3- dimethyl barbituric acid (5.9 g, 38.0mmol) and Pd(PPh₃)₄(0.9g) is in EtOAc/CH₂Cl₂(55:45,275mL) in reaction, after 2 hr and FC (EtOAc, then CH₂Cl₂/MeOH 90:10 to 60:40) amino acid 1 28 (9.05g, 90%) is generated after.

128 data：C₃₁H₄₂N₆O₉(642.7).LC-MS：(method 7)：R_t=0.90 (94), 643 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 272 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 28 (5.04g, 7.8mmol)₂Cl₂(100mL) solution T3P (in 50%, EtOAc, 9.2mL, 16mmol) and iso- Pr₂The anhydrous CH of NEt (5.4mL, 31mmol)₂Cl₂At (700mL) solution Reason, in FC (CH₂Cl₂/MeOH 39:1 to 19:1) after provide epimerism Macrocyclic lactams embodiment 272 (1.90g, 38%).

The data of embodiment 272：C₃₁H₄₀N₆O₈(624.7).LC-MS：(method 2)：R_t=1.61 (99), 625 ([M+H ]⁺).LC-MS：(method 7)：R_t=1.01 (99), 625 ([M+H]⁺)。¹H-NMR(DMSO-d₆)：8.47 (d, J=2.6,1H), 8.12 (s, 1H), 7.95 (d, J=9.6,1H), 7.61 (s, 1H), 7.40-7.29 (m, 6H), 5.10 (d, J=12.6,1 H), 5.04 (d, J=12.6,1H), 4.98 (wide d, J=10.7,1H), 4.16 (wide d, J=11.8,1H), 4.10-3.90 (m, 4H), 3.71 (wide t, J about 8.4,1H), 3.65-3.40 (m, 2H), 3.23 (wide dd, J=11.1,15.2,1H), 3.04 (s, 3H), 2.92 (t, J=9.6,1H), 2.66 (s, 3H), 2.12 (m, 1H), 2.09 (wide q, 1H), 1.42 (s, 9H).

Synthesize amine embodiment 273

According to program J, by (3.12g, 5mmol) dioxane (31mL) the solution 4M of carbamate embodiment 272 HCl- dioxanes (62mL) processing, provides embodiment 273.2HCl (2.9 g, 97%)

The data HCl of embodiment 273.2：C₂₆H₃₂N₆O₆.2HCl (524.5, free alkali).LC-MS (method 2)：R_t= 1.31 (92), 525 ([M+H]⁺)。

Synthesize amine embodiment 274

According to program K, in the presence of catalyst (100mg), by carbamate embodiment 272 (200mg, 0.32mmol) the hydrogenation in MeOH (20mL), provides embodiment 274 (154mg, 97%).

The data of embodiment 274：C₂₃H₃₄N₆O₆.(490.5).LC-MS (method 2)：R_t=1.26 (98), (491 ([M+ H]⁺)。

Core 19：Synthetic example 297 and embodiment 298 (scheme 23)

Synthesize Mitsunobu products 129

E.1.2 according to program, by phenol 75 (4.58g, 9.9mmol), alcohol 81 (5.5g, 15 mmol) and CMBP (4.8g, 20mmol) the reaction in dry toluene (24mL), in FC (hexane/EtOAc 1:3) amino acid 1 29 of protection is provided after (5.54g, 68%).

Synthesizing amino acid 130

E.2 according to program, by 129 (5.53g, 6.8mmol), 1,3- dimethyl barbituric acid (2.5 g, 16mmol) and Pd (PPh₃)₄(0.39g) is in EtOAc/CH₂Cl₂55:Reaction in 45 (118mL), after 2 hr and in FC (CH₂Cl₂/MeOH 95:5 to 70:30) amino acid 1 30 (1.45g, 85%) is generated after.

130 data：C₃₆H₄₅N₅O₉(691.7).LC-MS (method 7)：R_t=1.09 (96), 692 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 297 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 30 (2.57g, 3.7mmol)₂Cl₂(40 mL) solution T3P (in 50%, EtOAc, 4.4mL, 7.4mmol) and iso- Pr₂The anhydrous CH of NEt (2.5 mL, 14.9mmol)₂Cl₂(330mL) is molten Liquid processing, in FC (CH₂Cl₂/MeOH 99:1 to 90:10) obtaining Macrocyclic lactams embodiment 297 after, (2.5g polluted about 20% iso- Pr₂NEt；Yield 80%).

The data of embodiment 297：C₃₆H₄₃N₅O₈(673.7).LC-MS：(method 7)：R_t=1.18 (93), 674 ([M+H ]⁺)。

Aqueous post-processing (EtOAc, 1M NaH₂PO₄Aqueous solution) analysis sample (100mg), pure embodiment 297 is provided (81mg)。

LC-MS：(method 2)：R_t=2.20 (93), 674 ([M+H]⁺)。¹H-NMR (DMSO-d₆)：Complexity spectrum, Shuo Zhongyi Structure body, 8.51 (d, J=8.5,0.2H), 8.47 (d, J=8.7,0.1H), 8.40 (d, J=8.5,0.55H), 8.32 (d, J= 8.5,0.15H), 7.68-7.10 (several m, 10H), 5.96 (wide s, 0.3H), 5.90 (wide s, 0.3H), 5.4-5.0 (m, 2.4H), 4.8-3.8 (several m, 8H), 3.3-2.5 (several m and s, 8H), 2.5-1.6 (several m, 4H), 1.42,1.41, 1.36,1.26 (4s, Boc).

Synthesis acid embodiment 298：

According to program H, in the presence of catalyst (1g), by ester embodiment 297, (2.0g polluted about 20% iso- Pr₂NEt 2.4mmol) hydrogenation 3 hours in MeOH (200mL).

Coarse products are suspended in diethyl ether (20mL), are stirred 20 minutes, filtering is washed (diethyl ether) and drying, carried For embodiment 298, (1.63g polluted 15% iso- Pr₂NEt, quantitative yield).

Aqueous post-processing (CH₂Cl₂, 1M NaH₂PO₄Aqueous solution) analysis sample (200mg), pure embodiment 298 is provided (135mg)。

The data of embodiment 298：C₂₉H₃₇N₅O₈(583.6).LC-MS：(method 4a)：R_t=1.78 (86), 584 ([M+ H]⁺)。

Core 20：Synthetic example 311 (scheme 24)

Synthesize Mitsunobu products 131

By phenol 72 (200mg, 0.34mmol), alcohol 16 (178mg, 0.52mmol) and PPh₃(180mg, 0.69mmol) Benzene (5mL) solution degassing.At 0 DEG C, DEAD (40%, in toluene, 0.32mL, 0.69mmol) is added.It is stirred at room temperature mixed Close object 15 hours.More alcohol 16 (178mg, 0.52mmol) and PPh is added₃(180mg, 0.69mmol).At 0 DEG C, it is added DEAD (40%, in toluene, 0.32mL, 0.69mmol).Stir mixture 20 hours, concentration.FC(CH₂Cl₂/EtOAc 100:0 To 80:20) 131, are provided and (contains about 20% diethyl hydrazine -1,2- dicarboxylic ester；It is not added with and uses with being further purified).

Synthesizing amino acid 132

B.2 according to program, by 131 (250mg, about 80%, 0.22mmol), 1.3- dimethyl barbituric acid (107mg, 0.69mmol) and Pd (PPh₃)₄(16mg) is in EtOAc/CH₂Cl₂(55:45,4.8mL) reaction in, after 3 hours and in FC (EtOAc/MeOH 100:0 to 90:10, then CH₂Cl₂/MeOH 90:10 to 80:20) 132 (177mg, two steps are generated after Yield is total：73%).

132 data：C₃₉H₅₇N₅O₁₀Si(784.0)：LC-MS：(method 7)：R_t=1.31,784.2 ([M+H]⁺)。

Synthesize the amino acid 1 33 of alloc protections

C.1 according to program, by 132 (150mg, 0.19mmol), chloro-carbonic acid allyl ester (23 μ L, 0.21mmol) and Na₂CO₃(61mg, 0.57mmol) dioxanes (1.5mL) and H₂Reaction in O (1.5 mL) carries after 0 DEG C of process 2 hours For 133 (154mg, 92%) of acid.

Synthesize the amino acid 1 34 through protection

C.2 according to program, by 133 (140mg, 0.16mmol) of acid and sarcosine allyl ester tosilate (46 PTsOH, 58mg, 0.194mmol), HOAt (33mg, 0.24 mmol), HATU (92mg, 0.24mmol) and iso- Pr₂NEt (0.138mL, 0.81mmol) reaction in DMF (2.4mL), provides the amino acid 1 34 (106mg, 67%) of protection.

134 data：C₄₉H₇₀N₆O₁₃Si(979.2).LC-MS：(method 7)：R_t=1.68,979.3 ([M+H]⁺)。

Synthesizing amino acid 135

C.3 according to program, by the amino acid 1 of protection 34 (100mg, 0.10mmol), 1.3- dimethyl barbituric acids (38mg, 0.25mmol) and Pd (PPh₃)₄(6mg) is in EtOAc/CH₂Cl₂(45:55,1.9mL) reaction in, after 16 hours With in FC (EtOAc, then CH₂Cl₂/MeOH 90:10) 135 (70mg, 80%) are generated after.

135 data：C₄₂H₆₂N₆O₁₁Si(855.1).LC-MS：(method 7)：R_t=1.30,855.5 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 311 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 35 (60mg, 0.07mmol) in 2 hours₂Cl₂(2mL) solution T3P is added (in 50%, EtOAc；84 μ L, 0.14mmol) and iso- Pr₂The CH of NEt (48 μ L, 0.28mmol)₂Cl₂(5mL) is molten Liquid.Then, saturation NaHCO is added₃Aqueous solution, mixture CH₂Cl₂Extraction.Dry organic phase (Na₂SO₄), it filters, concentration.FC (EtOAc), embodiment 311 (26mg, 44%) is provided.

The data of embodiment 311：(C₄₂H₆₀N₆O₁₀Si(837.0).LC-MS：(method 7)： R_t=1.51 (90), 837.4 ([M+H]⁺)。¹H-NMR(CDCl₃)：7.26 (s, 5H), 7.09 (t, J=8.4,1H), 6.78 (d classes m, 1H), 6.61 (d, J= 7.4,1H), 5.50-4.90 (several width m, 5H), 4.90-3.80 (several width m, 8H), 3.69 (wide t, J about 8.5,1H), 3.6-2.3 (several width m, 14H), 2.12 (m, 1H), 1.61 (m, 1H), 1.38 (s, 9H), 1.24 (s, 2H), 0.93 (wide t, J About 8.0,2H), 0.00, -0.03 (2s, 9H).

Core 21：Synthetic example 312 and embodiment 313 (scheme 25)

Synthesize Mitsunobu products 136

Alcohol 82 (217mg, 0.58mmol) and CMBP (212mg, 0.88mmol) are dissolved in anhydrous degassed toluene (7mL), 100 DEG C are heated 30 minutes.Toluene (2mL) solution of 80 (250mg, 0.58mmol) is added dropwise.Continue stirring 1 hour at 100 DEG C. Evaporating volatile substances.FC (hexane/EtOAc 2:1 to 1:1) 136 (290mg, 63%), are generated.

Synthesizing amino acid 137

E.2 according to program, by 136 (250mg, 0.32mmol), 1,3- dimethyl barbituric acid (120mg, 0.77mmol) With Pd (PPh₃)₄(18mg) is in EtOAc/CH₂Cl₂(45:55,5.5 mL) in reaction, after 0.5h and in FC (CH₂Cl₂/ MeOH 95:5 to 70:30) amino acid 1 37 (164mg, 78%) is generated after.

137 data：C₃₃H₄₄N₄O₈S(656.8).LC-MS (method 7)：R_t=1.15 (95), 657 ([M+H]⁺)。

Synthesize the Macrocyclic lactams embodiment 312 through protection

F.1.1 according to program, by the anhydrous CH of amino acid 1 37 (100mg, 0.15mmol) in 2 hours₂Cl₂(2mL) is molten T3P (in 50%, EtOAc, 0.18mL, 0.31mmol) and iso- Pr is added in liquid₂NEt's (0.1mL, 0.61mmol) is anhydrous CH₂Cl₂(13mL) solution.Continue stirring 1 hour at room temperature, then (EtOAc is saturated NaHCO for aqueous post-processing₃Aqueous solution, Na₂SO₄) and FC (EtOAc), embodiment 312 (56mg, 57%) is provided.

The data of embodiment 312：C₃₃H₄₂N₄O₇S(638.7).LC-MS (method 7)：R_t=1.33 (95), 639 ([M+H ]⁺)。¹H-NMR(CDCl₃)：7.37-7.23 (m, 8H), 6.92 (wide s, 1H), 5.25 (m, 2H), 5.17 (s, 1H), 4.88 (d, J =16.2,1H), 4.62 (wide m, 1H), 4.46 (wide t classes m, 1H), 4.31 (wide m, 1H), 4.17 (dd, J=4.1,14.2, 1H), 3.72 (dd, J=4.8,10.7,1H), 3.50 (m, 1H), 3.30-2.80 (several m, 2H), 3.14 (s, 3H), 3.01 (s, 3H), 2.60-1.90 (several m, 6H), 1.46 (s, 9H).

Synthesize sulfone (sulfon) embodiment 313

At 0 DEG C, by m- CPBA (70%w/w；10mg, 41 μm of ol) embodiment 312 (20 mg, 31 μm of ol) is added CH₂Cl₂(0.5mL) solution.It stirs mixture 15 minutes, m- CPBA (9mg, 37 μm of ol) is then added.In 1 hour, it will mix It closes object to warm to room temperature, uses CH₂Cl₂Dilution, uses Na₂S₂O₃Aqueous solution simultaneously uses NaHCO₃Aqueous solution washs.Dry organic phase (Na₂SO₄), it filters, concentration.FC(EtOAc/MeOH 100:0 to 90:10) embodiment 313 (8mg, 38%), is provided.

The data of embodiment 313：C₃₃H₄₂N₄O₉S(670.7).LC-MS (method 6)：R_t=1.24 (95), 671 ([M+H ]⁺)。¹H-NMR(CDCl₃)：7.89 (td, J=1.7,7.3,1H), 7.71 (s, 1H), 7.43-7.28 (m, 7H), 5.17 (d, J =12.0,1H), 5.10 (d, J=12.0,1H), 5.01 (dd, J=5.9,9.1,1H), 4.96-4.85 (m, 2H), 4.71 (d, J=15.4,1H), 4.57 (wide m, 1H), 4.33 (wide m, 2H), 3.85 (dd, J=7.8,12.3,1H), 3.25 (s, 3H), 3.20 (m, 1H), 3.10 (m, 1H), 2,97 (s, 3H), 2.73-2.54 (m, 2H), 2.45-2.23 (m, 2H), 2.17 (m, 1H), 1.99 (m, 1H), 1.46 (s, 9H).

Synthesize final products

Advanced macrocyclic intermediate and final products described in table 21a-36a (scheme 26) initiate from the big ring of suitable precursor Acid or big cyclammonium are prepared with general procedure (H-N) described above.Difference with general procedure is pointed out in table 21a-36a.

The analysis data of these intermediates and final products are described in table 21b-36b.

The IUPAC names of whole embodiments are listed in table 20,21c-36c and 37.

Selected embodiment is described in detail：

Core 03：

The selected advanced intermediate of synthesis and final products (scheme 27)

Synthesizing amide embodiment 27

By embodiment 4 (432mg, 0.79mmol), HATU (597mg, 1.57mmol) and HOAt (214mg, 1.57mmol) Mixture be dissolved in DMF (6mL).N, N- dimethyl-ethylenediamines (173 μ L, 1.57mmol) and iso- Pr is added₂NEt (537 μ L, 3.14mmol).Solution is stirred at room temperature 15 hours, concentrates.Nubbin is dissolved in CHCl₃, with saturation NaHCO₃Aqueous solution and H₂O is washed.Dry organic phase (Na₂SO₄), it filters, concentration.FC (CH₂Cl₂The dense NH of/MeOH/₃Aqueous solution 100:0：0 to 90:10: 0.5) embodiment 27 (405 mg, 83%), is provided.

The data of embodiment 27：Referring to table 21b

Synthesize amine embodiment 28

By embodiment 27, (400mg, 0.64mmol) dioxanes (4mL) solution uses 4M HCl- dioxanes at room temperature (8mL) is handled 2 hours.Evaporating volatile substances.Nubbin is dissolved in CH₂Cl₂/ MeOH is concentrated, and vacuum drying provides embodiment 28HCl (343mg, 90%).

The data of embodiment 28：Referring to table 21b

Synthesizing amide embodiment 11

By embodiment 28HCl (75mg, 0.126mmol),¹H- indole-3-acetic acids (44mg, 0.253mmol), HATU The mixture of (96mg, 0.253mmol) and HOAt (34mg, 0.253mmol) are dissolved in DMF (2mL).Iso- Pr is added₂NEt(87μ L, 0.505mmol).Solution is stirred at room temperature 15 hours, concentrates.Nubbin is dissolved in CHCl₃, with saturation NaHCO₃It is water-soluble Liquid and H₂O is washed.Dry organic phase (Na₂SO₄), it filters, concentration.FC (CH₂Cl₂The dense NH of/MeOH/₃Aqueous solution 100:0：0 to 90:10:1) embodiment 11 (50 mg, 58%), is provided.

The data of embodiment 11：Referring to table 21b

¹H-NMR(DMSO-d₆)：10.81 (s, 1H), 8.26 (d, J=7.4,1H), 7.62 (t, J=5.5,1H), 7.46 (d, J=7.9,1H), 7.37-7.15 (m, 4H), 7.09 (d, J=2.2,1H), 7.04 (t, J=7.5,1H), 6.92 (t, J are about 7.4,1H), 5.08 (d, J about 12.5,1H), 4.74 (d, J=8.9,1H), 4.37 (d, J=11.0,1H), 4.25 (d, J= 17.7,1H), 4.22-4.13 (m, 2H), 3.97 (d, J=17.6,1H), 3.78 (t, J=8.3,1H), 3.41 (s, 2H), 3.24 (m, 1H), 3.15 (m, 1H), 2.98 (t, J=9.2,1H), 2.88 (s, 3H), 2.53 (s, 3H), 2.41-2.27 (m, 4H), 2.17 (s, 6H), 2.04 (m, 1H), 1.83 (t classes m, 2H), 1.69 (q classes m, 1H).

Synthesizing amide embodiment 49

By embodiment 28HCl (60mg, 0.101mmol), 1- naphthyl acetic acids (23mg, 0.121 mmol), and HOBt.H₂The mixture of O (19mg, 0.121mmol) is dissolved in CH₂Cl₂(1mL).N- cyclohexyl-carbodiimide-N '-methyl is added Polystyrene (1.9mmol/g；80mg, 0.152 mmol) and iso- Pr₂NEt (52 μ L, 0.303mmol).It is stirred at room temperature mixed Close object 15 hours.(polystyrylmethyl)-trimethyl ammonium hydrogen carbonate (3.5mmol/g is added；87mg, 0.303 mmol), after Continuous stirring 1 hour.Mixture CH₂Cl₂/MeOH 9:1 (2mL) dilutes, filtering.Polymer CH₂Cl₂/MeOH 8:2(5mL) It washes twice.Concentration is through combined filtrate and cleaning solution.Pass through FC (CH₂Cl₂The dense NH of/MeOH/₃Aqueous solution 100:0：0 to 90: 10:1) coarse products are purified, embodiment 49 (58mg, 83%) is provided.

The data of embodiment 49：Referring to table 21b

¹H-NMR(DMSO-d₆)：8.45 (d, J=7.3,1H), 8.00-7.87 (m, 2H), 7.79 (d, J=8.0,1H), 7.62 (t, J=5.5,1H), 7.53-7.25 (m, 6H), 7.19 (dd, J=3.0,8.4,1H), 5.10 (d, J=12.3,1H), 4.75 (d, J=8.9,1H), 4.39 (d, J=10.8,1H), 4.27 (d, J=17.8,1H), 4.28-4.08 (m, 2H), 3.95 (d, J=17.9,1H), 3.83 (m, 1H), 3.81 (s, 2H), 3.24 (m, 1H), 3.16 (m, 1H), 3.03 (t, J= 9.2,1H), 2.87 (s, 3H), 2.54 (s, 3H), 2.42-2.27 (m, 4H), 2.16 (s, 6H), 2.02 (m, 1H), 1.84 (t classes M, 2H), 1.71 (q, J about 9.4,1H).

Synthesizing amide embodiment 30

By embodiment 4 (400mg, 0.73mmol), HATU (552mg, 1.45mmol), HOAt (198mg, 1.45mmol) It is dissolved in DMF (6mL) with the mixture of tryptamines (233mg, 1.45mmol).Iso- Pr is added₂NEt (497 μ L, 2.91mmol). Agitating solution 15 hours at room temperature, subsequent aqueous post-processing (CHCl₃, it is saturated NaHCO₃Aqueous solution, H₂O).Dry organic phase (Na₂SO₄), it filters, concentration.FC(CH₂Cl₂/MeOH 100:0 to 95:5) embodiment 30 (410mg, 81%), is provided.

The data of embodiment 30：Referring to table 21b

¹H-NMR(DMSO-d₆)：10.80 (s, 1H), 7.91 (t, J=5.6,1H), 7.56 (d, J=7.7,1H), 7.32 (d, J=8.0,1H), 7.27-7.12 (m, 5H), 7.06 (t, J=7.5,1H), 6.97 (t, J=7.4,1H), 5.08 (d, J= 12.4,1H), 4.75 (d, J=9.3,1H), 4.34 (d, J=10.9,1H), 4.24 (d, J=17.8,1H), 4.10 (t class m, 1H), 3.97 (d, J=17.7,1H), 3.86 (m, 1H), 3.77 (m, 1H), 3.42-3.30 (m, 2H), 2.96-2.83 (m, 3H), 2.89 (s, 3H), 2.50 (s, 3H are sheltered by DMSO-d signals), 2.27 (m, 2H), 2.08 (m, 1H), 1.84 (t classes m, 2 H), 1.65 (q, J=10.8,1H), 1.34 (s, 9H).

Synthesize amine embodiment 55

At room temperature by (380mg, 0.55mmol) dioxanes (4mL) the solution 4M HCl- dioxanes of embodiment 30 (8mL) is handled 4 hours.Evaporating volatile substances.Nubbin is dissolved in dioxane (4mL), again with 4M HCl- dioxanes (8mL) Processing 2 hours.Evaporating volatile substances.Nubbin is washed with diethyl ether, passes through FC (CH₂Cl₂The dense NH of/MeOH/₃Aqueous solution 90: 10:0 to 90:10:1) it purifies, embodiment 55 (136mg, 42%) is provided.

The data of embodiment 55：Referring to table 21b

Synthesizing amide embodiment 12

By embodiment 55 (68mg, 0.092mmol), 1H- indole-3-acetic acids (32mg, 0.184 mmol), HATU (70mg, 0.184mmol) and the mixture of HOAt (25mg, 0.184mmol) is dissolved in DMF (2mL).Iso- Pr is added₂NEt (63 μ L, 0.367mmol).Solution is stirred at room temperature 15 hours, concentrates.Nubbin is dissolved in CHCl₃, with saturation NaHCO₃Aqueous solution And H₂O is washed.Dry organic phase (Na₂SO₄), it filters, concentration.It is purified by preparative HPLC method 1, embodiment 12 is provided (38mg, 55%).

The data of embodiment 12：Referring to table 21b

¹H-NMR(DMSO-d₆)：10.81 (s, 2H), 8.26 (d, J=7.2,1H), 7.93 (t, J=5.7,1H), 7.57 (d, J=7.8,1H), 7.46 (d, J=7.7,1H), 7.38-6.90 (m, 11H)；5.10 (d, J=12.1,1H), 4.76 (d, J =9.3,1H), 4.38 (d, J=10.8,1H), 4.26 (d, J=17.8,1H), 4.23-4.11 (m, 2H), 3.96 (d, J= 18.0,1H), 3.78 (t, J=8.3,1H), 3.7-3.25 (m, 3H), 3.60 (s, 2H), 3.01-2.81 (m, 2H), 2.88 (s, 3H), about 2.5 (s, 3H are sheltered by DMSO-d signals), 2.33 (m, 2H), 2.06 (m, 1H), 1.85 (t classes m, 2H), 1.63 (q, J About 10.7,1H).

Synthesizing amide embodiment 16

By embodiment 55 (68mg, 0.092mmol), n,N-Dimethylglycine (19mg, 0.184 mmol), HATU The mixture of (70mg, 0.184mmol) and HOAt (25mg, 0.184mmol) are dissolved in DMF (2mL).Iso- Pr is added₂NEt(63μ L, 0.367mmol).Solution is stirred at room temperature 15 hours, concentrates.Nubbin is dissolved in CHCl₃, with saturation NaHCO₃It is water-soluble Liquid and H₂O is washed.Dry organic phase (Na₂SO₄), it filters, concentration.It is purified by preparative HPLC method 1, embodiment is provided 16.TFA (40mg, 55%).

The data of embodiment 16.TFA：Referring to table 21b

¹H-NMR(DMSO-d₆)：10.81 (s, 1H), 9.66 (wide s, NH⁺), 8.75 (d, J=6.9,1H), 7.90 (t, J =5.6,1H), 7.56 (d, J=7.8,1H), 7.34-7.14 (m, 5H), 7.06 (t, J about 7.5,1H), 6.97 (t, J=7.4, 1H), 5.08 (d, J=12.3,1H), 4.78 (d, J=9.2,1H), 4.39 (d, J=10.7,1H), 4.24 (d, J=17.8, 1H), 4.24-4.14 (m, 2H), 4.00 (d, J=17.8,1H), 3.96-3.75 (m, 3H), 3.45-3.35 (m, 2H), 3.0- 2.67 (m, 3H), 2.90 (s, 3H), 2.75 (s, 6H), 2.50 (s, 3H are sheltered by DMSO-d signals), 2.5-2.27 (m, 2H), 2.08 (m, 1H), 1.85 (t classes m, 2H), 1.64 (q, J=10.8,1H).

Synthesizing amide embodiment 53

Embodiment 5 is added in pyridine (2mL) and acetic anhydride (0.14mL, 1.48mmol)^.HCl's (95 mg, 0.15mmol) Anhydrous CH₂Cl₂(2mL) solution.Solution is stirred at room temperature 20 hours.Solution is diluted with EtOAc, with 1M HCl/water solution, saturation NaCl aqueous solutions are saturated NaHCO₃Aqueous solution, and saturation NaCl aqueous solutions washing.Dry organic phase (Na₂SO₄), it filters, concentration. FC coarse products provide embodiment 53 (60mg, 70%).

The data of embodiment 53：Referring to table 21b

Synthesis acid embodiment 54

At room temperature under usual pressure, (moistened to 50%H in palladium dydroxide/activated carbon₂O；It will be real in the presence of 50mg) Apply the MeOH (5mL) of example 53 (58mg, 0.01mmol) solution hydrogenated 2 hours.Filtering mixture passes through celite pad.Wash the portions remnants Divide (MeOH).Concentration generates embodiment 54 (45mg, 92%) through combined filtrate and cleaning solution, vacuum drying.

The data of embodiment 54：Referring to table 21b

Synthesizing amide embodiment 9

By embodiment 54 (45mg, 0.091mmol), HATU (52mg, 0.137mmol) HOAt (19mg, 0.137mmol) It is dissolved in DMF (1mL) with the mixture of tryptamines (22mg, 0.137mmol).Iso- Pr is added₂NEt (47 μ L, 0.274mmol). Agitating solution 20 hours at room temperature, subsequent aqueous post-processing (CHCl₃, it is saturated NaHCO₃Aqueous solution, H₂O).Dry organic phase (Na₂SO₄), it filters, concentration.FC(CH₂Cl₂/MeOH 100:0 to 86:14) embodiment 9 (36mg, 62%), is provided.

The data of embodiment 9：Referring to table 21b

¹H-NMR(DMSO-d₆)：10.81 (s, 1H), 8.06 (d, J=7.0,1H), 7.93 (t, J=5.6,1H), 7.56 (d, J=7.8,1H), 7.34-7.14 (m, 5H), 7.05 (t, J about 7.5,1H), 6.97 (t, J about 7.4,1H), 5.09 (d, J= 12.4,1H), 4.75 (d, J=9.1,1H), 4.38 (d, J=10.8,1H), 4.26 (d, J=17.7,1H), 4.19-4.10 (m, 2H), 3.97 (d, J=17.9,1H), 3.78 (t, J=8.3,1H), 3.43-3.30 (m, 2H), 2.96-2.83 (m, 3H), 2.89 (s, 3H), 2.50 (s, 3H are sheltered by DMSO-d signals), 2.40-2.27 (m, 2H), 2.08 (m, 1H), 1.85 (m, 2H), 1.71 (s, 3H), 1.62 (q, J about 10.6,1H).

Core 11 and core 12：

The selected advanced intermediate of synthesis and final products (scheme 28)

Synthesizing amide embodiment 184

By embodiment 182 (500mg, 1.04mmol), 2- naphthyl acetic acids (232mg, 1.25 mmol), HATU (791mg, 2.08mmol) and the mixture of HOAt (283mg, 2.08mmol) is dissolved in DMF (15mL).Iso- Pr is added₂NEt (712 μ L, 4.16mmol).Solution is stirred at room temperature 20 hours, concentrates.Nubbin is dissolved in CHCl₃, with saturation NaHCO₃Aqueous solution and H₂O is washed.Dry organic phase (Na₂SO₄), it filters, concentration.FC (EtOAc, then CH₂Cl₂/MeOH 95:5), embodiment is provided 184 (637mg, 94%).

The data of embodiment 184：Referring to table 29b

¹H-NMR(DMSO-d₆)：8.41 (d, J=7.0,1H), 7.90-7.83 (m, 3H), 7.77 (s, 1H), 7.53-7.44 (m, 4H), 7.32-7.22 (m, 6H), 7.04 (d, J=8.4,1H), 6.86 (d, J=7.4,1H), 6.81 (s, 1H), 5.02- 4.90 (m, 3H), 4.19 (t, J about 8.6,1H), 4.14-3.96 (m, 2H), 3.83 (t classes m, 2H), 3.63 (s, 2H), about 3.3 (m, 1H, by H₂O signals are sheltered), 3.05 (m, 1H), 2.95 (m, 1H), 2.91 (s, 3H), 2.27 (m, 1H), 2.16 (wide q, J About 11.3,1H), 1.54 (m, 2H), 1.31 (m, 1H), 1.15 (m, 1H).

Synthesizing amide embodiment 200

By embodiment 197.TFA (60mg, 0.094mmol), 1H- indole-3-acetic acids (25mg, 0.14mmol), HATU The mixture of (54mg, 0.14mmol) and HOAt (19mg, 0.14mmol) are dissolved in DMF (1.5mL).Iso- Pr is added₂NEt(81μ L, 0.471mmol).Solution is stirred at room temperature 18 hours, concentrates.Nubbin is dissolved in CHCl₃, washing (saturation NaHCO₃ Aqueous solution, H₂O).Dry organic phase (Na₂SO₄), it filters, concentration, subsequent FC (EtOAc, then CH₂Cl₂/MeOH 95:5) it, carries For embodiment 200 (50mg, 78%).

The data of embodiment 200：Referring to table 30b

¹H-NMR(DMSO-d₆)：10.86 (s, 1H), 8.42 (d, J=7.8,1H), 8.01 (d, J=10.0,1H), 7.58 (d, J=7.8,1H), 7.36-7.19 (m, 9H), 7.07-7.02 (m, 2H), 6.97 (t, J=7.1,1H), 6.86 (d, J= 7.6,1H), 5.08 (s, 2H), 4.88 (d, J=8.7,1H), 4.30-4.10 (m, 2H), 4.13 (d, J=10.9,1H), 4.01 (t classes m, 1H), 3.95 (d, J=18.0,1H), 3.75-3.70 (m, 2H), 3.56 (s, 2H), 3.4-3.2 (m, 2H, quilt H₂O signal sections are sheltered), 3.04 (t, J=9.9,1H), 2.98 (s, 3H), 2.65 (s, 3H), 2.27 (m, 1H), 2.09 (q, J =11.7,1H).

Synthesize amine embodiment 202

In usual pressure and at room temperature, in palladium dydroxide/activated carbon (moistening to 50%H₂O；It will in the presence of 158mg) Solution hydrogenated 4 hours of the MeOH (28mL) of embodiment 200 (320mg, 0.47mmol).Filtering mixture passes through celite pad.It washs residual Remaining part point (MeOH).Concentration generates embodiment 202 (250mg, 97%) through combined filtrate and cleaning solution, vacuum drying.

The data of embodiment 202：Referring to table 30b

Synthesizing amide embodiment 213

By the anhydrous CH of embodiment 202 (60mg, 0.11mmol)₂Cl₂At (1mL) solution pyridine (89 μ L, 1.1mmol) Reason.Decanoyl chloride (46 μ L, 0.22mmol) is slowly added at 0 DEG C.At 0 DEG C to mixture being stirred at room temperature 18 hours, then it is added MeOH(0.1mL).Continue stirring 10 minutes.Evaporating volatile substances.Nubbin toluene is handled three times, evaporation.Pass through preparative HPLC methods 1 purify, subsequent FC (EtOAc/MeOH 90:10 to 80:20) embodiment 213 (27mg, 35%), is provided.

The data of embodiment 213：Referring to table 30b

¹H-NMR(DMSO-d₆)：10.86 (s, 1H), 8.53 (d, J=9.8,1H), 8.44 (d, J=7.7,1H), 7.57 (d, J=7.7,1H), 7.35-7.30 (m, 3H), 7.27 (s, 1H), 7.19-6.95 (m, 3H), 6.84 (d, J=7.5,1H), 4.86 (dd, J=2.4,11.2,1H), 4.60 (q, J=8.4,1H), 4.25 (q classes m, 1H), 4.14 (d, J=10.7,1H), 4.04-3.82 (m, 3H), 3.73 (t, J about 8.5,1H), 3.55 (s, 2H), 3.24 (d, J=7.8,2H), 3.09 (t, J= 9.5,1H), 2.99 (s, 3H), 2.67 (s, 3H), 2.26 (m, 1H), 2.15 (t, J=7.2,2H), 2.09 (m, 1H), 1.51 (t Class m, 2H), 1.24 (s, 12H), 0.85 (t, J=6.6,3H).

Core 11：

In solid support synthetic example 186 (scheme 29)

Synthesize amine 139

At room temperature under usual pressure, in palladium dydroxide/activated carbon, (15-20%Pd is moistened to 50%H₂O； By solution hydrogenated 3 hours of the MeOH of embodiment 181 (2.0g, 3.2mmol) (200 mL) in the presence of 400mg).It is logical to filter mixture Cross celite pad.Wash nubbin (MeOH).Concentration obtains corresponding amine through combined filtrate and cleaning solution, vacuum drying (1.57g), is dissolved in CH₂Cl₂(8mL), with saturation NaHCO₃Aqueous solution (2.9mL) and chloro-carbonic acid allyl ester (0.36 ML, 3.43mmol) processing.Mixture is stirred at room temperature 2 hours.Detach organic phase, concentration.It is purified by FC (EtOAc) residual Remaining part point, provides allyl carbamate 138 (1.65g, 92%).

At 0 DEG C, TBAF solution (in 1M, THF, 7mL, 7mmol) is added to the THF of 138 (1.29 g, 2.24mmol) (53mL) solution.At 0 DEG C to solution being stirred at room temperature 3 hours, concentrate.Nubbin is distributed in CH₂Cl₂With saturation NaHCO₃Water Between solution.Water phase is detached, CH is used₂Cl₂Extraction.Drying is through combined organic phase (Na₂SO₄), it filters, concentration.By nubbin It is dissolved in CH₂Cl₂(10mL) is handled 20 minutes with 25%HCl aqueous solutions (0.29mL).Evaporating volatile substances, the portions vacuum drying remnants Point, 139HCl (1.14g are provided；About 15% 4-butyl ammonium is polluted, is not added with and uses with being further purified；Yield is about 90%)

139 data HCl：C₂₂H₃₀N₄O₅HCl (430.5, free alkali).LC-MS (method 4a)：R_t=1.22 (92), 431.3 [M+H]⁺。

Synthetic resin 140

By DFPE polystyrene (1%DVB, 100-200 mesh, carrying capacity 0.89mmol/g；200 mg, 0.178mmol) in DCE (2mL) swelling 1 hour.Filter resin.By the DCE of amine hydrochlorate 139HCl (about 85%w/w, 166mg, 0.303mmol) (1.33mL) and orthoformic acid front three base ester (0.66mL, 6.02mmol) solution is added.Shaking resin 1 hour at room temperature, then Triacetoxy boron hydride object sodium (75mg, 0.356mmol) is added.It shakes mixture 15 hours, filters resin.Resin is respectively used DMF, 10% iso- Pr₂NEt/DMF, DMF, CH₂Cl₂It washs successively three times, vacuum drying provides resin 140 (293mg).

Synthetic resin 141

First sour coupling step：By (the carrying capacity 0.77mmol/g of resin 140；50mg, 0.038 mmol) in DMF (1mL) Swelling 30 minutes, filtering.Sequentially add CH₂Cl₂(0.5mL), DMF (0.5mL), 2- naphthyl acetic acids (65mg, 0.35mmol), Iso- Pr₂NEt (0.13mL, 0.76mmol) and HATU (144mg, 0.38mmol).Shake resin 1 hour, filtering is washed with DMF It washs.By CH₂Cl₂(0.5mL), DMF (0.5mL) 2- naphthyl acetic acids (65mg, 0.35 mmol), iso- Pr₂NEt (0.13mL, 0.76mmol) and then resin is added in HATU (144mg, 0.38mmol).Shake mixture 1 hour, filtering.Resin is washed with DMF Three times, CH is used₂Cl₂It washes twice.

Crack Alloc groups：By CH₂Cl₂(1mL), phenyl silane (41mg, 0.375mmol) and Pd (PPh₃)₄(9mg) Resin is added.Shake mixture 15 minutes, filtering.Resin CH₂Cl₂Washing, uses CH₂Cl₂(1mL), phenyl silane (41mg, 0.375mmol) and Pd (PPh₃)₄(9 mg) is handled 15 minutes again.Resin is filtered, CH is respectively used₂Cl₂, DMF wash three times, use MeOH and CH₂Cl₂It washes twice.

Second sour coupling step：By DMF (0.5mL), CH₂Cl₂(1mL), 2- naphthyl acetic acids (70mg, 0.375mmol), Iso- Pr₂Resin is added in NEt (0.13mL, 0.75mmol) and PyBOP (195 mg, 0.375mmol).Shake mixture 1 hour, Filtering.Resin respectively uses DMF and CH₂Cl₂Washing three times, provides resin 141, is immediately available for subsequent step.

Discharge amide examples 186

Resin 141 is used into 20%TFA/CH₂Cl₂(1mL) is handled 10 minutes, filters and use CH₂Cl₂Washing.Resin is used 20%TFA/CH₂Cl₂(1mL) is handled 10 minutes again, and CH is used in filtering₂Cl₂Washing is three times.Concentration is through combined filtrate and washing Liquid.Nubbin CH₃CN processing is evaporated, vacuum drying, is purified coarse products by preparative HPLC method 3, is provided reality Apply example 186 (11mg, yield：Totally 32%) based on 139.

The data of embodiment 186：C₄₂H₄₂N₄O₅(682.8).LC-MS (method 4a)：R_t=2.26 (98).¹H-NMR (DMSO-d₆)：8.38 (d, J=7.0,2H), 7.91-7.69 (m, 8H), 7.54-7.27 (m, 7H), 7.03 (dd, J=1.5, 8.2,1H), 6.86-6.82 (m, 2H), 4.94 (d, J=12.7,1H), 4.19 (t, J=8.6,1H), 4.11-3.94 (m, 3H), 3.71 (dd, J=9.2,16.5,1H), 3.62 (s, 2H), 3.58 (s, 2H), 3.08 (m, 1H), 2.89 (m, 1H), 2.89 (s, 3H), 2.5 (m, 1H are sheltered by DMSO-d signals), 2.30 (m, 1H), 2.14 (q classes m, 1H), 1.64-1.49 (m, 2H), 1.34 (m, 1H), 1.14 (m, 1H).

¹H-NMR spectrums are identical as the spectrum for the sample being prepared in solution, referring to table 29

Biological method

1. preparing embodiment compound

Embodiment compound is weighed on microbalance (Mettler MX5), is dissolved in 100%DMSO to for Ca²⁺It measures 2.5mM ultimate densities.

Embodiment compound is dissolved in DMSO/H₂O 90:10 to for plasma stability measurement and metabolic stability measure 10mM ultimate densities.

2.Ca²⁺It measures：GPCR is measured, and is used for Motilin receptor, prostaglandin F (FP) receptor and serotonine 2B (5- HT_2B) receptor

It is measured with FLIPR Tetra (Molecular Devices)；Data analysis and FLIPR Tetra operations are soft Part is ScreenWorks version 2s (Molecular Devices).

Measure dose dependent agonist and antagonist activities.Determine percentage activation value and percentage inhibiting value.

Percentage activation is measured after being initially added sample compound, is then incubated 10 minutes at 25 DEG C.In compound After incubation, with EC₈₀Reference agonist is added to determine that percentage inhibits.

The purchase of reference agonist is prepared from reputable commercial distributors and according to the certain illustrated of each ligand.Complete ligand Whole processing to ensure suitably to control in entire experiment.

Test compound is serially diluted with DMSO.It is that test buffers by diluted chemical compound once obtaining debita spissitudo Liquid.

GPCR assay buffers：

Assay buffer is the HBSS (Hank balanced salt solutions) of supplement.HBSS is supplemented with 20 mM HEPES (4- (2- hydroxyls Base ethyl)-piperazine -1- ethanesulfonic acids) and 2.5mM probenecid (Sigma P8761).

Test board is inoculated with：

GPCR is measured to carry out in this way：Use Ca²⁺The hematopoietic cell system (rat) of optimization, culture never exceed 90% and converge Degree.Harvest cell and with 50000 cells/wells inoculation (from the culture less than 90% degree of converging) in 96 orifice plates (12500 cells/ Hole is in 384 orifice plates).After inoculation, test board 45 (45) point kind is incubated at room temperature.After incubation at room temperature, surveying Before examination, in 37 DEG C of 5%CO₂Incubate test board 24 hours.

Calcium dyestuff carrying capacity：

Whole GPCR measurement Fluo-8Ca²⁺Dyestuff carries out.

Ca²⁺Dyestuff is prepared with 1x dye strengths in GPCR assay buffers.After incubating 24 hours, cell GPCR Assay buffer is washed, and Ca is then added²⁺Dyestuff (100 μ L/well).

Before FLIPR tests, in 30 DEG C of 5%CO₂Incubate plate 90 minutes.

Agonist is tested：

Prepare compound plate：50 holes μ L/ are added during agonist test pattern.During FLIPR is tested, it will come from and change 50 holes μ L/ for closing object plate dilute 3 times for the existing holes 100 μ L/ from dyestuff carrying capacity step.Therefore, whole compounds are all made The standby 3x for desired ultimate density in test.

After completing the test operation of single addition for the first time, test board is removed from FLIPR Tetra, it is tested in antagonist It is preposition to maintain for seven (7) minutes in 25 DEG C.

Antagonist is tested：

The EC measured during being tested used in agonist₈₀Value, whole precincubation sample compounds and reference antagonist are (if can Row) Kong Douyong EC₈₀Reference agonist (motilin；Dinoprost) it is stimulated.

After reference agonist is added, fluorescence is monitored 180 seconds with FLIPR Tetra.

Data analysis：

It from FLIPR data, is corrected using negative control, exports the maximum statistics in each hole, and calculate opposite E_maxThe hundred of control Divide than activation.

3. plasma stability

Human plasma (3-5 is contributed for people, Blutspendedienst SRK, Basel) and CD-1 mice plasmas (mixing gender library >50 animals, Innovative Research, CA, USA) all it is that sodium citrate is stabilized.To repeat to change at 10 μM three times It closes object concentration and 37 DEG C is tested.Sample was obtained in 0,15,60 and 240 minute, is precipitated with 2 volumes of acetonitrile to stop. Supernatant is collected, evaporation is reconstructed in 5% acetonitrile solution, analyzed by HPLC/MS/MS.Gained peak area counts are with 0 value hundred Divide than expression, and for measuring terminal stability (%) and half-life period T1/2 (dividing).In order to monitor the integrality of measurement, every time Experimental group all tests propanthaline degradation.

4. metabolic stability

It is contributed from the mankind 50 and mixes the microsome in gender library and microsome from the single gender library of CD-1 mouse for people 1:1 mixture is bought from Celsis (Belgium).Enzymatic reaction is under the having containing NADPH regenerative systems and microsome It states in the buffer solution of endpoint concentration and carries out：100 mM potassium phosphate buffer agents (all being from Sigma), 1mg/mL glucose -6- phosphorus Acid, 1 mg/mL β-nicotinamide-adenine dinucleotide phosphate (NADP), 0.65mg/mL magnesium chlorides, 0.8 unit/mL glucose- 6- phosphate dehydrogenases (use 5mM citric acid buffer agents beforehand dilution), 10 μM of compounds and 1mg/ml microsomal protein matter. 37 DEG C repeatedly incubate compound, and sample is obtained after 0,20 and 60 minute.In acetonitrile precipitation (2 volume) and HPLC/MS/ After MS analyses, metabolism overturning is expressed with initial 0 minute value %, calculates half-life period T1/2 (min).Verapamil is used as the mankind Reference and Propranolol are used as mouse reference, and are tested in each experimental group.

-F.P.Guengerich,Analysis and Characterization of Enzymes；in: Principles and Methods of Toxicology；A.W.Hayes(Ed.)Raven Press: New York, 1989,777-813.

-R.Singh et al.,In vitro metabolism of a potent HIV-protease inhibitor(141W94)using rat,monkey and human liver S9,Rapid Commun.Mass Spectrom.1996,10,1019-1026.

5. result

The result of the experiment (above-mentioned) of 1.-4. descriptions is shown in the following table 38 and table 39.

Claims

1. the compound of following formula：

Wherein

R²It is

R⁵⁰It is

R¹¹It is

X=S or SO₂；

Wherein

R²It is

R⁵It isWith

Wherein

R²It is

R⁵It isOr CH₃(CH₂)₈CONH。

2. compound according to claim 1, is selected from：

(2R, 11S, 19aS)-N- [2- (dimethylamino) the ethyls fluoro- N of -15-, 7,12- trimethyls -2- { [2- (1- naphthalenes) second Acyl group] amino } ten dihydro -1H, 5H- pyrrolo-es of -5,8,13- trioxy-s -2,3,6,7,8,9,10,11,12,13,19,19a- 15 carbon of [2,1-c] [1,4,7,12] three azacyclo- of benzo oxa-, seven alkene -11- formamides；

(2R, 11S, 19aS)-N- [the fluoro- 2- of 2- (dimethylamino) ethyl -15- { [2- (1H- indol-3-yls) acetyl group] ammonia Base } ten dihydro -1H, 5H- pyrroles of -7,12- dimethyl -5,8,13- trioxy-s -2,3,6,7,8,9,10,11,12,13,19,19a- Cough up simultaneously 15 carbon of [2,1-c] [1,4,7,12] three azacyclo- of benzo oxa-, seven alkene -11- formamides；

The fluoro- 12- of (12S, 20aS)-16- ({ [2- (1H- indol-3-yls) ethyl] amino } carbonyl) dimethyl-6,9-8,13-, Ten dihydro -6H- pyrazines of 14- trioxy-s -3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2,1-c] [1,4,7,12] benzene And -2 (1H)-t-butyl formate of three azacyclo- of oxa-, 15 carbon, seven alkene；

The fluoro- N- of (12S, 20aS) -2- acetyl group -16- [2- (1H- indol-3-yls) ethyl] -8,13- dimethyl -6,9,14- three Ten tetrahydrochysene -6H- pyrazines of oxo -1,2,3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2,1-c] [1,4,7,12] benzene And three azacyclo- of oxa-, 15 carbon, seven alkene -12- formamides；

(12S, 20aS)-N- [2- (dimethylamino) ethyl] fluoro- 2- of -16- [2- (1H- indol-3-yls) acetyl group] -8,13- Ten tetrahydrochysene -6H- pyrazines of dimethyl -6,9,14- trioxy-s -1,2,3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2, 1-c] three azacyclo- of [1,4,7,12] benzo oxa-, 15 carbon, seven alkene -12- formamides；

(12S, 20aS) -2- [2- (dimethylamino) acetyl group] fluoro- N- of -16- [2- (1H- indol-3-yls) ethyl] -8,13- Ten tetrahydrochysene -6H- pyrazines of dimethyl -6,9,14- trioxy-s -1,2,3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2, 1-c] three azacyclo- of [1,4,7,12] benzo oxa-, 15 carbon, seven alkene -12- formamides；

The fluoro- 2- of (12S, 20aS) -16- [2- (1H- indol-3-yls) acetyl group]-N- [2- (1H- indol-3-yls) ethyl] -8, Ten tetrahydrochysene -6H- pyrazines of 13- dimethyl -6,9,14- trioxy-s -1,2,3,4,7,8,9,10,11,12,13,14,20,20a- are simultaneously 15 carbon of [2,1-c] [1,4,7,12] three azacyclo- of benzo oxa-, seven alkene -12- formamides；

The fluoro- 12- of (12R, 20aR)-16- ({ [2- (1H- indol-3-yls) ethyl] amino } carbonyl) dimethyl-6,9-8,13-, Ten dihydro -6H- pyrazines of 14- trioxy-s -3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2,1-c] [1,4,7,12] benzene And -2 (1H)-t-butyl formate of three azacyclo- of oxa-, 15 carbon, seven alkene；

(12R, 20aR) -2- [2- (dimethylamino) acetyl group] fluoro- N- of -16- [2- (1H- indol-3-yls) ethyl] -8,13- Ten tetrahydrochysene -6H- pyrazines of dimethyl -6,9,14- trioxy-s -1,2,3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2, 1-c] three azacyclo- of [1,4,7,12] benzo oxa-, 15 carbon, seven alkene -12- formamides；

The fluoro- N- of (12R, 20aR) -2- acetyl group -16- [2- (1H- indol-3-yls) ethyl] -8,13- dimethyl -6,9,14- three Ten tetrahydrochysene -6H- pyrazines of oxo -1,2,3,4,7,8,9,10,11,12,13,14,20,20a- simultaneously [2,1-c] [1,4,7,12] benzene And three azacyclo- of oxa-, 15 carbon, seven alkene -12- formamides；

N- [(4S, 6S, 10S)-13- methyl-6- { [2- (2- naphthalenes) acetyl group] amino } oxa--8-9,14- dioxo-2-, 13- diaza tricyclics [13.3.1.0^4,8] ten nine -1 (19), 15,17- triolefin -10- bases] benzyq carbamate；

N- [three oxygen of (4S, 6R, 13S) -6- { [2- (1H- indol-3-yls) acetyl group] amino } -11,15- dimethyl -9,12,16- Three aza-tricycle [15.3.1.0 of generation -2- oxa-s -8,11,15-^4,8] 21-1 (21), 17,19- triolefin-13- bases] amino first Acid benzyl ester；

N- [three oxygen of (4S, 6S, 13R) -6- { [2- (1H- indol-3-yls) acetyl group] amino } -11,15- dimethyl -9,12,16- Three aza-tricycle [15.3.1.0 of generation -2- oxa-s -8,11,15-^4,8] 21-1 (21), 17,19- triolefin-13- bases] amino first Acid benzyl ester；

N- [three oxygen of (4S, 6S, 13S) -6- { [2- (1H- indol-3-yls) acetyl group] amino } -11,15- dimethyl -9,12,16- Four aza-tricycle [15.3.1.0 of generation -2- oxa-s -8,11,15,19-^4,8] 21-1 (21), 17,19- triolefin-13- bases] amino Benzyl formate.

3. according to the compound of claims 1 or 2, it is used as therapeutic active substance.

4. compound according to claim 3 is used as to Motilin receptor, hypotype 5-HT_2B5-hydroxytryptamine receptor and prostate Plain F2 α receptors have the therapeutic active substance of excitement or antagonistic activity.

5. pharmaceutical composition, the compound containing with good grounds claims 1 or 2 and the inert carrier for the treatment of.

6. composition according to claim 5, to Motilin receptor, hypotype 5-HT_2B5-hydroxytryptamine receptor and prostaglandin F2 α receptors have excitement or antagonistic activity.

7. according to the composition of claim 5 or 6, form is suitable for oral, local, transdermal, injection, cheek, transmucosal, lung Or inhalation.

8. composition according to claim 7, form is tablet, pastille, capsule, solution, liquid, gel, clay, creme, Ointment, syrup, slurry, suspension, spray, atomizer or suppository.

9. being used to prepare to Motilin receptor, hypotype 5-HT according to the compound of claims 1 or 2_2B5-hydroxytryptamine receptor and Prostaglandin F2α receptor has the purposes of the drug of excitement or antagonistic activity.

10. purposes according to claim 9, wherein the drug it is expected for treating reduced gastrointestinal mobility obstacle；Treatment with The related diseases of CNS；Treat ocular hypertension.

11. purposes according to claim 9, wherein drug expectation is easy for treating diabetic gastroparesis and constipation type intestines Bowel syndrome；Treat migraine, schizophrenia, mental disease or depression；Treatment ocular hypertension related with glaucoma and premature labor.

12. being used for the purposes that pharmaceutical lead is found according to the compound of claims 1 or 2.