TWI322807B - Novel deazapurines and uses thereof - Google Patents

Description

1322807 玖 发明 发明 发明 发明 发明 发明 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346 346优先权 The priority of the case in the international application for the application of the case is recommended; the contents of each of these requests are hereby incorporated by reference. TECHNICAL FIELD OF THE INVENTION The present invention provides physicochemicals, pharmaceutical compositions, and uses thereof for treating inflammatory or autoimmune and proliferative disorders, and generally acts as a cell adhesion molecule and inflammatory cell activity. Inhibitor of the message transduction. [Prior Art] Inflammation is a process caused by an enlargement of blood vessels at a damaged or infected site and an increase in permeability. The chemical cytokines and cytokines released at this site increase the performance of cell surface proteins on endothelial cells, allowing white blood cells to circulate to adhere to the vessel wall and to migrate to the site of injury/infection within the tissue. These cell surface proteins are called "cell adhesion molecules" that allow the interaction between white blood cells and endothelial cells, and the mediators of white blood cells migrate into tissues. In addition, in inflammatory and immune responses, many cell-to-cell interactions require cell adhesion molecules. There are three types of adhesion molecules: selectin, integrin, and immunoglobulin-related proteins, which can be expressed on white blood cells and endothelial cells. Several adhesion molecules, including E-selectin and ICAM, are cytokines. IL-1 is caused by TNF, and its expression is mediated by the transcription factor NF-/cB. Sustained or inappropriate performance of adhesion molecules can lead to inflammatory or autoimmune disorders 85762 -9- 1322807 . Excessively increased performance of E-selectin and/or ICAM can cause chronic inflammation and is associated with several inflammatory-like or autoimmune disorders. Therefore, inhibitors of cell adhesion molecules can be used to treat such diseases. The Yan Yansheng and Autoimmune Disease Codes are handled well by current therapies, so the pursuit of better drug development is widely pursued. For example, rheumatoid arthritis is a chronic inflammatory state within the joint characterized by cartilage and bone destruction. Traditional therapeutic agents for inflammatory or autoimmune diseases such as rheumatoid arthritis, including non-steroidal anti-inflammatory drugs and salicylate, gold compounds, hydroxyquine, sulfasalazine, corticosteroids, oral penicillamine and cells Toxic or immunosuppressive drugs. However, many such therapeutic agents are not necessarily sufficiently effective and have caused serious side effects. Recently, injectable forms of neutralizing proteins have been successfully marketed for the treatment of rheumatoid arthritis and Crohn's disease; however, effective oral inhibitors have not been developed for such inflammatory or self Immune disease. Obviously, there is still a need to identify novel therapeutic agents for the treatment of inflammatory or autoimmune and neoplastic diseases. The agent is preferably orally effective, and there is no serious use of a new class of therapeutic agents, generally Treatment of inflammatory or autoimmune and proliferative disorders. SUMMARY OF THE INVENTION As is still the case, there is still a need to develop novel therapeutic agents useful for the treatment of inflammatory or autoimmune and proliferative diseases.纟纟明系 provides novel formula 1 compound 85762 丄 W2807

R2 (I) Generally and in the context of the invention and its pharmaceutical compositions, such as those described, as well as methods of making and using such compounds. Description of Certain Preferred Embodiments of the Invention for Cognition and Defining Novel Therapeutic Agent Types for Treating Rheumatic Joints

Under the need of inflammation and other conditions (in some neoplastic conditions), the novel denitrifying and metastatic or autoimmune and hypoplastic compounds can be used to treat diseases and conditions, 35 colitis/Clone's disease, such as multiple Sclerosing, systemic lupus erythematosus, asthma, allograft rejection / graft versus host disease (GVHD), psoriasis, atopic dermatitis, eczema, fungus, allergic rhinitis, myasthenia gravis, diabetes, spontaneous Thrombocytopenic purpura, spheroid nephritis, heart and vascular disease, and cancer. The compounds of the invention have also been found to be useful in the prevention of restenosis of blood vessels that are susceptible to damage such as angioplasty and stent placement. 1) General description of the compounds of the invention The compounds of the invention include the compounds of the formula (I) (and their tautomers) as further defined below: 85762 -11 - 1322807

Ri is hydrogen, -NH2, -NHMe, -NHAc, -oh NH(C=0)〇Et; where η is an integer 〇_4 ; -CN or · F ' -OMe R2 is hydrogen, -NRaRb, -0Ra , aliphatic, heteroaliphatic, aryl or heteroaryl moiety "wherein ~ and ~ are each independently hydrogen or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; The system is independently hydrogen, arginyl, cyano, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety ' or a group _G_K, wherein the 0 system is absent, or is -CH2-' - NRD...〇_ or (〇>〇), and its center is a chloroform, a _srf, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, = RD, RF and R 〇 each independently hydrogen, xRy, aliphatic, cycloaliphatic, heterozygous, annual heteroaliphatic, aryl or heteroaryl moiety #, an aliphatic, heteroaliphatic, aryl or heteroaryl a thiol moiety based on a partial group substitution, or a cyclic lipid substituted or unsubstituted with 3 or 4, 4 or 5 a group or a heterocyclic aliphatic moiety; wherein each of the three parts of the heart is hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, a heteroaliphatic, aryl or heteroaryl moiety, a thiol moiety substituted by an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a center thereof 4_, 5_ or 6-membered substituted or unsubstituted saturated or unsaturated cycloaliphatic or cycloaliphatic 85762 •12· I3228〇7 partial group; and each of the aforementioned aliphatic or heteroaliphatic moieties The group may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and wherein each of the aforementioned aryl or heteroaryl moiety may be independently substituted or Unsubstituted* In certain embodiments, the invention defines certain classes of compounds of particular interest. For example, a class of compounds of particular interest includes compounds substituted by the presence of two of the compounds, wherein the compound has the following structure:

Wherein the ruthenium and the ruthenium are each independently hydrogen, halogen, cyano, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a group-called, wherein G4 is absent, -CH2-, -NRD-, _〇_ or (〇=〇), and its center is hydrogen-called core, -SRf, or aliphatic, heteroaliphatic, aryl or heteroaryl moiety, its center, ~ And !^ each independently hydrogen, as an aliphatic, cycloaliphatic, heteroaliphatic, cycloaliphatic, aryl or heteroaryl moiety, is aliphatic, heteroaliphatic, aryl or hetero The aryl moiety replaces the (iv) moiety, or the moiety or the or the heart and R〇, together with a 3-, 4-, 5-, 6-, 7- or 8-member substituted or not Substituted cycloaliphatic or cycloaliphatic partial base ring; wherein each of ~ and ~ is independently hydrogen 'aliphatic, cycloaliphatic, heteroaliphatic, cycloaliphatic, aryl or heteroaryl The radical, group, heteroaliphatic, aryl or heteroaryl moiety of the group, 85762 -13 - 1322807 is substituted for the thiol moiety, or the center thereof is taken together with the core as 4_, 5_ or 6_membered substituted or unsubstituted, saturated or unsaturated cycloaliphatic or cycloaliphatic moiety And wherein each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; and wherein each of the foregoing aryl groups Or a heteroaryl moiety can be independently substituted or unsubstituted. Another class of compounds of particular interest includes compounds having the following structure:

Wherein la and lb are each independently hydrogen, a cycline, a cyano group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or a group wherein G is absent, -CH2-, -NRD -, -0_ or (〇〇) ' and its center is hydrogen, _Call,,, -SRF, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, of which Rc is independently hydrogen, -NRxRy, aliphatic, cycloaliphatic, heteroaliphatic, cyclo-Autumn, aryl or heteroaryl moiety "is aliphatic, heteroaliphatic, aryl or heteroaryl a thiol moiety substituted with a thiol moiety, or a conjugated or a heart or a R, together with a 3-, 4-, 5-, 6-, 7- or 8-member substituted or not a substituted cycloaliphatic or cycloaliphatic moiety; wherein each of the oxime and the heart is independently hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloaliphatic, aryl or heteroaryl a radical moiety, an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, 85762 -14-1322807, substituted thiol moiety, substituted or unsubstituted, group; Wherein Rx and Ry are used as 4_, 5_ or 6_ members are saturated or unsaturated, cycloaliphatic Or a cycloaliphatic moiety wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; Each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. Another class of compounds of particular interest includes a compound having the structure of formula 1, wherein -CH2NRfRg, and Rn is hydrogen, and the compound has the structure:

Wherein Ri, R2, RF and Rg are as defined above generally and in the categories and subgroups herein. Another particularly interesting compound, i1], includes a compound having the structure of formula 1, wherein R3b is -CH2NRF Rq' and R3a is hydrogen, and the compound has the following structure:

Wherein Ri, R2, RF and Rg are as defined above in general and in the categories 85762 -15-1322807 and subgroups herein. Another class of compounds of particular interest is those comprising a compound of formula 1 wherein R_3 c is -CH2 NRF R<3' and R;jd is hydrogen, and the compound has the structure:

Wherein Ri, rf and Rq are as defined above generally and in the categories and subgroups herein. Another class of compounds of particular interest is those comprising a structure of formula 1, wherein R3a is -(CH=CH)qCH2(CH2)rNRFRc and & is hydrogen' and the compound has the structure:

Wherein q and r are each independently 0 or 1; and the ruler, heart, ~ and heart are as defined above and in the categories and subgroups herein. Another class of compounds of particular interest is those having the formula (!) structure wherein R3a is hydrogen and R3b is (CKH^t^qCHdCHANRpRQ' and the far compound has the following structure: 85762 1322807

Wherein 9 and 1* are each independently 〇 or 1; and R!, R2, RF and R〇 are as defined above generally and in the categories and subgroups herein. Another class of compounds of particular interest is those comprising a compound of formula (0, wherein R3a is _(C=〇)NRfRg, and & is hydrogen, and the compound has the structure:

Wherein Ri, R2, Rf and are as defined above generally and in the categories and subgroups herein. Another class of compounds of particular interest is those comprising a structure of formula (I) wherein R3b is -(OCONRfI^ and R3a is hydrogen and the compound has the structure:

The centers, R2, Rf and Rg are as defined above generally and in the categories and subgroups herein. 85762 -17- 1322807 Another class of compounds of particular interest is a compound having the structure of formula 1, which is _CH2S(=〇)raNRFRG and is hydrogen, and the compound has the following structure:

Wherein R! and & are as defined above generally and in the categories and subgroups herein; m is 0, 1 or 2; and RF is an aliphatic 'cycloaliphatic, heteroaliphatic, heterocyclic An aliphatic, aryl or heteroaryl moiety; wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched , saturated or unsaturated; and wherein each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted, another class of particularly interesting compounds, including compounds having the structure of formula 1, Wherein R3a*_CH2〇RF and is hydrogen, and the compound has the following structure:

Wherein 1^ and 112 are as defined above generally and in the categories and subgroups of the text 85762 -18-1322807;

Rf is hydrogen, a protecting group, or an aliphatic, cycloaliphatic, heteroaliphatic 'cycloaliphatic, aryl or heteroaryl moiety; and wherein each of the aforementioned aliphatic or heteroaliphatic moiety is Independently substituted or unsubstituted, cyclic or acyclic, linear biting, saturated or unsaturated; and wherein each of the aforementioned aryl or heteroaryl moiety can be independently substituted or unsubstituted . Many important subgroups of each of the foregoing categories are worthy of individual reference; such subgroups include subgroups of the foregoing species, where: i) Ri is NH2; ii) Ri is hydrogen; iii) Ri ANHMe; iv) is NHAc; v) Rz Is NH2, OH, q-C6 alkyl or q-C6 fluorenyl, the alkyl and alkenyl are optionally substituted by dentate or hydroxy; vi) R_2 is Ci-C2 alkyl; vii) R2 is methyl; Viii) R2 is hydrogen; : ix) one of RF or R〇 is hydrogen or lower alkyl; and the other is alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl or alkyl heteroaryl Substituent, for each occurrence, optionally substituted by one or more elements, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl, or Wherein RF#R〇 is a 6-membered substituted or unsubstituted heterocyclic moiety; x) one of RFaR〇 is hydrogen or lower alkyl; and the other is aryl, heteroaryl a group of 85762 -19- 1322807, an alkylaryl or an alkylheteroaryl group, in the presence of p-quinone, optionally as a mono- or poly(tetra), alkoxy, thioalkyl or Substituted or unsubstituted alkyl, hetero Substituted by an aryl or aryl group, or wherein ~ and: are substituted or unsubstituted cyclic or heterocyclic moiety; XI) one of RF or % is hydrogen or low carbon Alkyl; and another - sentence suspension, p than bite, (alkyl) phenyl or (fluorenyl radical H-replacement by one or more of the fangs 'trifluoromethoxy, A Oxygen, S gas methyl, methylthio:

Substituted or unsubstituted lower alkyl, lower heteroalkyl, aryl substituted; & square XH) RF or % one is hydrogen or lower alkyl; and the other is cyclic or acyclic a linear, branched or branched aliphatic moiety, optionally substituted or unsubstituted aryl, heteroaryl, decylamine, alkoxy, hydroxy, thiol substrate, thiol , fluorenyl or amine substituted; xiii) RF is alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, fluorenylaryl hydroxy, heteroaryl, for each occurrence, Optionally substituted with one or more aryl, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl groups; and/or xiv) RF is hydrogen , protecting group, or alkyl, cycloalkyl, heteroalkyl, cycloheteroalkylaryl, heteroaryl 'alkylaryl or alkylheteroaryl, independently or in each case Monoterpenes, alkoxy groups, thioalkyl groups or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl groups. As will be appreciated by the reader, compounds of particular interest include, among others, one or more of the aforementioned subgroups. Some of these subcombinations are illustrated by the following compound classes: 85762 • 20-1322807 i) Compounds of the formula (and their pharmaceutically acceptable derivatives):

Wherein r#r2 is as defined in the general sense and in the species and subgroups herein; 〇 is 〇12 or _(〇〇), and ^ or one of the cores is chlorine or a low carbon group; ^: Is an alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, optionally in the presence of one or more teeth*, alkoxy a thioalkyl group or a substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl group, or a center thereof, taken together with the core, is a 3 to 8 member = substituted or unsubstituted ring or A heterocyclic moiety. In certain embodiments, one of the RF or the core is hydrogen or a lower alkyl group; and the other is an aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, each present Optionally, independently substituted by one or more of an alkyl, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl group or wherein rf and R are A 5 or 8-membered substituted or unsubstituted 5 singular or heterocyclic moiety is used together. In certain other embodiments, '^ or one of the cores is hydrogen or lower alkyl; the other is phenyl, pyridyl, (alkyl)phenyl or (alkyl)pyridyl, depending on One or more of the presence of a halogen, trifluoromethoxy, decyloxy, trimethylmethyl, methylthio or substituted or unsubstituted lower alkyl, lower aryl, aryl or Heteroaryl substitution. In still other embodiments, one of Rf or R is hydrogen or lower alkyl; and -85762 - 21· 1322807 is another cyclic or acyclic, linear or branched aliphatic moiety , optionally substituted by one or more substituted or unsubstituted aryl, heteroaryl, decylamine, enteric, thiol, thiol, thiol, thiol, aryl or amine groups. II) a compound of the formula (and its pharmaceutically acceptable derivatives):

R2

Where R! and % are as defined generally and in the categories and subgroups herein; G is CH2 or -(00), and X is 〇, s, c=〇, s=〇, C=CR4R5, call

Or CR4R5; wherein each of Rs is independently hydrogen, hydroxy, halogen 'cyano, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or is aliphatic, heteroaliphatic, aromatic a thiol moiety substituted with a aryl or heteroaryl moiety; wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be independently substituted or unsubstituted, cyclic or acyclic, linear Or branched, and wherein each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. m) a compound of the formula (and pharmaceutically acceptable derivatives thereof)

Wherein, as defined generally, and in the categories and subgroups herein, G is CH2 or -(〇〇), and one of the heart or heart is hydrogen or lower alkyl, and the other is alkyl or hetero An alkyl group, an aryl group, a heteroaryl group, a aryl group or a aryl group 85762 -22- 丄^2807 aryl group, independently of each occurrence, or optionally a halogen, alkoxy or thio group An alkyl or a substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl group, or a center thereof, taken together with the core, is a substituted or unsubstituted cyclic or heterocyclic group of 3 to 8 members. Part of the group. In some embodiments, one of the cores is hydrogen or a lower alkyl group; and the other is an aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, Wherever appropriate, substituted by one or more porins, alkoxy groups, thioalkyl groups or substituted or unsubstituted alkyl 'heteroalkyl, aryl or heteroaryl groups, or where RF is used together It is a 3- to 8-membered substituted or unsubstituted cyclic or heterocyclic moiety. In certain other embodiments, one of the cores or hearts is hydrogen or a lower alkyl group; and the other is a phenyl group, a pyridyl group, an (alkyl)phenyl group or an (alkyl)pyridyl group, as the case may be Or a plurality of halogens, trifluoromethoxy groups, methoxy groups, trifluoromethyl groups, methylthio groups or substituted or unsubstituted lower alkyl groups, low carbon heterocycles, 10,000 or hetero Aryl substitution. In still other embodiments, one or the % is hydrogen or a lower alkyl group; and the other is a cyclic or acyclic, linear or branched aliphatic moiety, optionally taken by one or A plurality of substituted or unsubstituted aryl, heteroaryl, decylamine, alkoxy, hydroxy, thioalkyl, thiol, decyl or amine groups are substituted. m compound of the formula (and its pharmaceutically acceptable derivative plant)

85762 • 23· 1322807 The center seems to be 2 as general and in the categories and subgroups of this paper; gach2 or - (〇 = 〇), and 乂 〇, s, c = 0, s = 〇, C=CR4R5, or CR4R5; each of 丨中~和^ is independently a hydrogen, a thiol, a sulfhydryl, a cyano, an aliphatic, a heteroaliphatic, an aryl or a heteroaryl moiety, or a thiol moiety substituted with an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be independently substituted or unsubstituted , cyclic or acyclic, linear or branched, and wherein each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. V) a compound of the formula (and its pharmaceutically acceptable derivatives)

White 2; where Ri and R2 are as defined generally and in the categories and subgroups herein, 'G is CH2 or -(C=0)' and the heart or! One of them is hydrogen or a lower alkyl group; and the other one is a tiger group, a heteroalkyl group, an aryl group, a heteroaryl 'alkylaryl group or an alkylheteroaryl group, which is optionally present for each One or more dentate, alkoxy, thiol groups or substituted or unsubstituted fluorenyl, heteroalkyl, aryl or heteroaryl groups, or wherein Rf and R 〇 are employed as 3 to 8-membered substituted or unsubstituted cyclic or heterocyclic moiety. In certain embodiments, one of RF or R is hydrogen or lower alkyl; and the other is an aryl, heteroaryl, alkylaryl or alkylheteroaryl group, Where present, optionally substituted by one or more of the commercially available, oxy, thio-85762 -24-1322807 pit or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl Or wherein the long F is taken together with the core as a 3 to 8 member substituted or unsubstituted cyclic or heterocyclic moiety. In certain other specific embodiments, one of the heart or heart is hydrogen or lower alkyl; and the other is phenyl, pyridyl, (alkyl)phenyl or (alkyl) aridinyl, as appropriate One or more halogen, trifluoromethoxy, methoxy, trimethyl, sulfonyl or substituted or unsubstituted lower alkyl, lower carbon, aryl or hetero Aryl substitution. In still other embodiments, one or the heart is hydrogen or a lower alkyl group; and the other is a cyclic or acyclic, linear or branched aliphatic moiety, optionally taken by one or A plurality of substituted or unsubstituted aryl, heteroaryl, decylamine, alkoxy, hydroxy, thioalkyl, thiol, decyl or amine groups are substituted. VI) a compound of the formula (and pharmaceutically acceptable derivatives thereof)

Wherein RjR2 is as defined in the general sense and in the categories and subgroups herein; 0 is 012 or -(00), and X is 〇, S, c=〇, s=〇, c=c^R5, Called or CR4R5; its center and heart are independent of hydrogen, hydroxyl, arginine, cyano 'aliphatic, heteroaliphatic, aryl or heteroaryl partial groups, or are aliphatic, heterolipid a thiol moiety substituted with a group, aryl or heteroaryl moiety; wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be independently substituted or not substituted: 85762 • 25· 1322807, Cyclic or acyclic, linear or branched, and wherein each of the aforementioned aryl or heteroaryl moiety can be independently substituted or unsubstituted. VII) a compound of the formula (and pharmaceutically acceptable derivatives thereof)··

Where RF, R]# R2 are the general terms of σ and are defined in the categories and subgroups herein; Ρ is an integer 0-3; s is an integer 〇_4; a, β 'd, £ and Each existence is independent of 不, 〇, s, c=〇, s=〇, C=CR4R5, or CR4R5, where each of R4 and & is a hydrogen, a few, a dentate, a base , -ORx, -SRX, -NRxRy 'aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or substituted with an aliphatic, heteroaliphatic, aryl or heteroaryl moiety Base group; and wherein A and b, b and d, _e, @k

And any two adjacent K groups 'when the valence bond allows, can be independent of the hydrogen iron protecting group by a single or double, wherein each of Rx and Ry exists, or a lipid, a heteroaliphatic 'aryl group, a heteroaryl, aliphatic aryl, heteroaliphatic aryl, lipoaryl or heteroaliphatic heteroaryl moiety, wherein each of the aforementioned aliphatic or aliphatic moiety can be independently substituted or Unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated, and wherein each of the foregoing aryl, arylaliphatic aryl, heteroaliphatic aryl, aliphatic heteroaryl or heteroaliphatic The heteroaryl moiety can be independently substituted or unsubstituted.

In certain exemplary embodiments, . represents a substituted or unsubstituted phenyl, pyridyl or furyl moiety of 85762 -26- 1322807. In some other specific embodiments

;:) V P represents a substituted or unsubstituted, saturated or unsaturated 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl or cycloheteroalkyl moiety. In some specific embodiments

I represents a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group. Some of the bicyclic aliphatic moiety groups in the specific examples are listed. Indicates substituted or unsubstituted

In certain exemplary embodiments, the heart is hydrogen or a lower alkyl group. In some embodiments, 'rf is hydrogen or methyl. It should also be understood that a variety of other subgroups are of particular interest for each of the above subgroups, including but not limited to the species described above, as well as the species, subgroups described above and in the examples herein. And species.

Some of the foregoing compounds may contain - or more asymmetric centers and thus may exist in various isomeric forms such as stereoisomers and 7 or diastereomers. Thus, the compounds of the present invention and pharmaceutical compositions thereof may be in the form of individual palmomers, non-isomers or geometric isomers, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are in the form of palms and sputum. In certain other specific embodiments, stereoisomers or mixtures of diastereomers are provided. Furthermore, the aforementioned compounds + & , ^ , _ 疋 any and all tautomeric systems are encompassed by the present invention and in particular the tautomeric structures depicted herein as τ pi. 85762 -27· 2807 is just an example, described and described as the following compounds: -

It can also be described and depicted as:

Further, certain compounds, as described herein, may have, which may be, if present, z-isomers, unless otherwise indicated, otherwise encompassing such compounds, becoming substantially free of other isomers. Isomers and/or mixtures of various isomers, such as stereoisomers. In addition to the compounds mentioned above, the invention also encompasses pharmaceutically acceptable derivatives of such compounds, and combinations comprising - or more of a compound of the invention and/or a plurality of pharmaceutically acceptable agents or additives Things. v The compound of the present invention can be prepared by crystallization of a compound of formula 1 in different <, s, and one of the polymorphs of the compound of formula 1 can be a part of the present invention. For example, different polymorphs;: identified and/or prepared in the manner described, using different solvents or different mixtures of solvents 7 for recrystallization; by crystallization at different temperatures; ^ 85762 -28- 1322807 : Various cold section modes are used to cover the range from very fast to very slow cooling during crystallization. Polymorphs can also be obtained by heating or dissolving the compound followed by slow or rapid cooling. Multi-materials, body detectors earned (4) Xue 1 spectroscopy, differential scanning card method ^ end ray diffraction diagram and / or other technical determination 1 This invention covers the compounds, their derivatives, their mutual variation a form, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable composition thereof, and a pharmaceutically acceptable composition containing the same. DEFINITIONS As discussed above, the present invention provides novel compounds having a range of biological properties. The compounds of the invention have biological activities associated with the treatment of inflammatory or autoimmune disorders and/or proliferative disorders. Specifically = In the case of the compound, the compound of the present invention can be used for the treatment of rheumatoid arthritis, ulcerative colitis/Clone's disease, central nervous system disease (CNS), such as multiple sclerosis, systemic lupus erythematosus, asthma, allograft rejection/ Grafts for sputum disease (GVHD), psoriasis, atopic dermatitis, moist therapy, urticaria, allergic rhinitis, myasthenia gravis, diabetes 'spontaneous thrombocytopenic purpura, spheroid Inflammatory, cardiac and vascular diseases and cancer. In certain other specific embodiments, the compounds of the invention are also found to be useful in the prevention of restenosis of blood vessels susceptible to damage such as angioplasty and stent placement. And the invention is described above and is described in part by the different classes, subspecies and species disclosed elsewhere herein. Further, the invention provides a pharmaceutically acceptable derivative of the compound of the invention 85762 -29- 1322807, and a method of using the same, a pharmaceutical composition thereof, or any one of them in combination with one or more other therapeutic agents to treat a patient. "Pharmaceutically acceptable derivative" as used herein. The wording means any pharmaceutically acceptable salt, ester or salt of such an ester, or any other adduct or derivative thereof, which is capable of providing (directly or indirectly) when administered to a patient. a compound as described in other aspects herein, or a metabolic product or residue thereof. Thus, a pharmaceutically acceptable derivative includes, inter alia, a prodrug Prodrugs are derivatives of compounds that generally have significantly reduced pharmacological activity and contain another moiety which is readily removed in vivo to produce a parent molecule as a pharmacologically active species. An example of this is an ester which is cleaved in vivo to produce a compound of interest to us. Prodrugs of various compounds, and materials and methods for derivatizing the parent compound to produce a prodrug are known and suitable for the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives are discussed in more detail below. The definitions of certain compounds and specific functional groups of the invention are also described in more detail below. In terms of chemical elements, the chemical elements are identified according to the CAS Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th edition, and the specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as the specific functional group and reactivity, are described in • 'Organic Chemistry', Thomas Sorrell, University of Science Books (Sausalito): 1999, all of which are included in this article. For reference, it should be understood that those skilled in the art should understand that the synthetic methods as described herein utilize a variety of protecting groups. The term "protecting group" as used herein refers to a specific official. 85762 -30- 1322807 The moiety of the energy moiety 'such as hydrazine, S or N, which is temporarily blocked, so that the reaction can be selectively carried out at another reactive position in the polyfunctional compound. In the examples, the 'protective group selectively reacts in good yield' to obtain a protected substrate which is stable to the intended reaction; the protecting group must be readily available, preferably non-toxic, and An agent that does not attack other functional groups, is selectively removed in good yield; the protective group forms a derivative that can be easily separated (more preferably, does not produce a new stereogenic center); and the protective substrate The minimum of additional functional groups, the reaction in order to avoid other locations. As described herein in detail, 'oxygen, sulfur' nitrogen and carbon protecting groups can be utilized. For example, in some embodiments, as exemplified herein, certain exemplary oxygen protecting groups are utilized. Such oxygen protecting groups include, but are not limited to, methyl ethers, substituted methyl mysteries (eg, MOM (methoxymethyl ether), MTM (methylthioether), BOM (methoxymethyl) Ether), PMBM or MPM (p-methoxymethoxymethyl ether), only a small part of which is referred to), substituted ethyl ethers, substituted decyl ethers, decyl ethers ( For example, TMS (trimethyl decyl ether), TES (triethyl decyl ether), TIPS (triisopropyl decyl ether), TBDMS (tri-butyl dimethyl decyl ether): , tribenzyl decyl ether, TBDPS (tris-butyldiphenyl decyl ether), only a small part of it, esters (such as formate, cousate, benzoate (Bz) ), trifluoroacetate, dichloroacetate, only a small part of which is referred to), carbonates, cyclic acetals and ketals. In some other specific embodiments, a nitrogen protecting group is utilized. Such nitrogen protecting groups include, but are not limited to, urethanes (including methyl, ethyl, and substituted ethylamino phthalates (eg, Troc), only a small portion of which are referred to), guanamines. , cyclic imine derivatives, N-alkyl and N-85762 -31- χ 322807 arylamines, imine derivatives and enamine derivatives, only a small part. Certain other exemplary protecting groups are described in detail herein, however, it should be understood that 'the invention is not intended to be limited to such protecting groups; rather, various other equivalent protecting groups can be readily identified using the above criteria, It is also used in the present invention. In addition, a variety of protection systems are described in "Protective Groups for Organic Synthesis", Third Edition, Greene Τ·W· and Wuts, RG. ed., J〇hn 岭岭 & s〇ns, commits % : 1999, the entire contents of which are hereby incorporated by reference. It will be appreciated that a compound as described herein may be substituted with any number of substituent or functional moiety groups. In general, the term "substituted", whether or not preceded by the term "as appropriate", and a substituent included in the formula of the invention, refers to a hydrogen radical in a particular structure. It is replaced by a substituent of the indicated. When more than one position in any particular structure may be substituted by more than one substituent from the specified group, the substituent may be the same or different at each position. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, the substituents are allowed to include acyclic and cyclic, branched, and undivided organic compounds. Branches, carbocyclic and heterocyclic, aromatic and non-aromatic substituents. For the purposes of the present invention, a hetero atom, such as nitrogen, may have a nitrogen substituent and/or any of the organic compounds described herein. Further, the present invention is not intended to be limited in any way to the permissible substituents of the organic compound. The combination of substituents and variables contemplated by the present invention is preferably It can cause the formation of stable compounds, and can be used to treat, for example, inflammatory and neoplastic conditions, including but not limited to rheumatoid arthritis, psoriasis, asthma and cancer. As used herein, "Standing 85762-32-1322807 " Preferably, the compound has a stability sufficient to permit manufacture, and it maintains the integrity of the compound, after a sufficient period of time to be detected, and preferably a period of time Sufficient time for the purposes detailed herein. The term "aliphatic" as used herein includes saturated and unsaturated, straight-chain (ie unbranched), branched, cyclic or more. Cycloaliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be apparent to those skilled in the art, "aliphatic" is intended to include, but is not limited to, alkyl groups, Alkenyl, blocked, cycloalkyl, cycloalkenyl and cyclic block radical groups. Thus, the term "alkyl" as used herein includes straight chain, branched and cyclic alkyl groups. Similar idioms apply to other general terms, such as "base", "block", and so on. Further, the terms "alkyl", "alkenyl", "alkynyl", etc., as used herein, are meant to include substituted and unsubstituted groups. In certain embodiments, As used herein, "low carbon alkyl" is used to denote an alkyl group having 1 to 6 carbon atoms (cyclic, acyclic, substituted, unsubstituted, branched or unbranched). In certain embodiments, the alkyl 'mercapto and alkynyl groups employed in the present invention contain from 1 to 20 aliphatic carbon atoms. In certain other specific embodiments, the alkyl, alkenyl and alkynyl groups employed in the present invention contain 丨_1〇 aliphatic carbon atoms. In still other embodiments, the thiol, alkenyl, and block groups employed in the present invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl and alkynyl groups employed in the present invention contain one aliphatic carbon atom. In still other embodiments, the alkyl group employed in the present invention, Alkenyl and alkynyl groups containing from 1 to 4 carbon atoms. Thus, illustrative aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isoendyl 'allyl, n-butyl, second butyl butyl, isobutyl, third Butyl, 85762 -33- 1322807 n-pentyl, second pentyl, isopentyl, tert-pentyl, n-hexyl, second-hexyl partial ring: etc. Or multiple substituents. The alkenyl group includes, but is not limited to, for example, a vinyl group, a propyl group, a butenyl group, a fluorenyl group, a methyl group, a butyl group, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like. As used herein, the term "alkoxy" (or "alkyloxy" or "thioalkyl" refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. Part of a particular embodiment, the alkyl group contains 20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains mo aliphatic carbon atoms. In still other embodiments, The 4-alkyl, alkenyl and alkynyl groups in the present invention contain 丨8 aliphatic carbon atoms. In still other embodiments, the 'alkyl group contains 丨6 aliphatic carbon atoms. In yet other embodiments In the examples, the fluorenyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, third- Butyloxy, neopentyloxy and n-hexyloxy. Examples of thioalkyl include, but are not limited to, methylthio 'ethylthio' propylthio, isopropylthio, n-butylthio, and the like. • • Amidino" refers to a group having the structure -NHri, wherein R1 is a thiol group as defined herein. "Aminoalkyl" Refers to a group having the structure NH2RL 'wherein R' is an alkyl group as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkane The group contains 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, sulfhydryl and alkynyl groups employed in the present invention contain 丨8 aliphatic carbon atoms. Still other embodiments Wherein the alkyl group contains 1-6 aliphatic carbon atoms. In its further embodiment 85762 • 34-^2807, in an embodiment, the alkyl group contains M aliphatic carbon atoms. The alkylalkylamine group includes, but is not limited to, methylamine. Base, ethylamine, isopropylamine, and the like.

Some examples of substituents for the aliphatic (and other) moiety of the above compounds of the invention include, but are not limited to, aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl, alkyl heteroaryl Alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; thiol group; arylthio; heteroalkylthio; heteroarylthio;

Cl ; Br ; I ; - oh ; -N 2 ; -CN ; -CF 3 ; -CH 2 CF 3 ; -CHC12 ; -CH 2 OH ; -CH 2 CH 2 OH ; -CH 2 NH 2 ; -CH 2 S 02 CH 3 ; -C(0)Rx ; -C02(Rx); CON(Rx)2; -0C(0)Rx ; -〇C02Rx ; -OCON(Rx)2 ; -N(Rx)2 ; -S(0)2Rx ' -NRx(CO)Rx 'where each of RX Where present, including but not limited to aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl, any of the aliphatic, heteroaliphatic groups described above and herein , alkylaryl or alkylheteroaryl substituents which may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and any of the aryl groups described above and herein Or a heteroaryl substituent 'may be substituted or unsubstituted. Other examples of substituents that may be generally employed are illustrated by the specific embodiments shown in the examples described herein. Generally speaking, the term "aryl" and "heteroaryl" are used in this article to refer to a private order or polycyclic, heterocyclic, polycyclic and polyheterocyclic unsaturated moiety. a moiety, preferably having from 3 to 14 carbon atoms, each of which may be substituted or unsubstituted. It should also be understood that the aryl and heteroaryl moiety, as defined herein, may Attached via an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkyl or heteroalkyl moiety, thus also including _(aliphatic) aryl, _(heteroaliphatic) 3⁄4. -(aliphatic)heteroaryl, -(heteroaliphatic)heteroaryl, _(alkyl)aryl 85,762-35- 1322807,heteroalkyl)aryl, ·(pure)aryl, and (heterozy) a heteroaryl moiety. Therefore, the phrase "aryl or heteroaryl" and "aryl, heteroaryl/aliphatic" aryl, - (heteroaliphatic) are used herein. Aryl, (aliphatic)heteroaryl, (heteroaliphatic)hetero, aryl, -(heteroalkyl)aryl, _(heteroalkyl)aryl and (heteroalkyl) Heteroaryl" is exchangeable 1 base including but not limited to any previously mentioned Substituent, that is, a substituent relating to an aliphatic moiety or a group of other moieties as disclosed herein, which results in the formation of a stable compound. In some embodiments of the invention' "aryl" means a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, anthracenyl, tetrahydronaphthyl, hydroquinone, anthracene In certain embodiments of the invention, the term "heteroaryl" as used herein, refers to a cyclic aromatic group having five to ten ring atoms, one of which is The group is selected from the group consisting of S, 0 and Ν; the zero, one or two ring atomic systems are other heteroatoms independently selected from the group consisting of S, fluorene and fluorene; and the remaining ring atoms are carbon, and the group is bonded via any ring atom. To the rest of the molecule, such as hydrazine, ρ, arginyl, pyrimidinylpyrrolyl, pyrazolyl, imidazolyl, pyrazolyl, oxazolyl, iso-succinyl, V» Drink · thiopurine, thiophenyl, fluorenyl, sulphonyl, iso- 4: phenyl group, etc. It should be understood that fluorene, aryl and heteroaryl (including double ring An aryl group may be unsubstituted or substituted 'wherein the substitution includes the substitution of one, two or three hydrogen atoms independently of any one or more of the following groups, including but not limited to : aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; arylheteroaryl, fe oxy, aryloxy; hetero alkoxy; heteroaryloxy; thio; Thiothio; heteroarylthio; F; Cl; Br; j 85762 • 36- 1322807 ; -OH; -N〇2 ; -CN; -CF3 ; -CH2CF3 ; -CHC12 ; CH2OH; -CH2CH2OH; -CH2NH2; -CH2S02CH3; -C(0)Rx; -C02(Rx); -CON(Rx)2; -0C(0)Rx; -0C02Rx; -OCON(Rx)2 ; -N (RX)2; -S(0)2Rx; -NRx(CO)Rx, wherein each of Rx is present, independently but not limited to aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl Or an alkylheteroaryl group, wherein any of the aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or Unbranched, cyclic or acyclic, and any of the above and described herein Heteroaryl or aryl substituents, can be substituted or unsubstituted. Other examples of substituents that are generally applicable are illustrated by the specific embodiments shown in the examples described herein. The term "cycloalkylalkyl" as used herein, particularly refers to a radical having from three to seven, preferably from three to ten carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, etc., when in the case of an aliphatic, heteroaliphatic or heterocyclic moiety, optionally substituted with a substituent including, but not limited to, aliphatic ; heteroaliphatic; aryl; heteroaryl; alkyl aryl; alkyl heteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio ; heteroalkylthio; heteroarylthio; F; Cl; Br; I; - ΟΗ; - Ν〇 2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2S02CH3 ; -C(0)Rx ; -C02(Rx) ;-con(rx)2 ; -oc(o)rx ; -oco2rx ; -ocon(rx)2 ; -n(rx)2 ; -s( o) 2rx; -NRx(CO)Rx, wherein each of Rx is present, independently but not limited to aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl, Any of the aliphatic, heteroaliphatic, alkylaryl or 85762-37-I3228〇7 alkyl alkane described above and herein The substituent may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and any of the aryl or heteroaryl substituents described above and herein may be substituted or Unsubstituted. Other examples of substituents that may be generally employed are illustrated by the specific embodiments shown in the examples described herein. The term "heterolipid" as used herein refers to a lipid. a moiety of a group containing one or more oxygen, sulfur, nitrogen, phosphorus or germanium atoms, for example, instead of a halogen atom. The heteroaliphatic moiety may be branched, unbranched, cyclic or acyclic. 'like, and includes saturated and unsaturated heterocyclic rings such as, for example, rufolyl, tetrahydro ρ, phenyl, and the like. In certain embodiments, the heteroaliphatic moiety is one or more partial groups. The group 'is independently substituted by one or more hydrogen atoms on it, including but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkyl heteroaryl Alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroaryl Sulfur; F • Cl; Br; I; -OH; -N〇2; -CN; -CF3; -CH2CF3; -CHC12; -CH2OH; -CH2CH2〇H; -CH2NH2; -CH2S02CH3; -C(0) Rx ; -co2(rx); -CON(Rx)2 ; -〇c(〇)Rx ; -0C02Rx ; -OCON(Rx)2 ; -N(Rx)2 ; -S(0)2Rx ;-nrx( Co)rx, wherein each of rx is present independently, but not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl, as described above and herein Any aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl substituent 'may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic' and Any of the aryl or heteroaryl substituents described herein may be substituted or unsubstituted. Other examples of generally applicable substituents are illustrated by the specific embodiment 85762 - 38-1322807 shown in the examples described herein. The atoms used in this article are "and"dentate", bromine and iodine. Line 4 is selected from the group consisting of: ''commercially-based'' - the word system means a group as defined above having one, two or one tooth atom attached thereto, and in fact r ^ ^ beryllium is such as fluorine A base group such as a tiary group, a bromoethyl group or a trifluoromethyl group. "Heterocycloalkyl" or "hetero.,^ „ groceries, as used herein, refers to a non-aromatic 5-, 6- or 7-nuclear or polycyclic group, including A 1 Limited to a bi- or bicyclic group, a ^., an inter-doped atom, independently selected from two: and nitrogen, wherein (1) each anthracene ring has (1) (four) bonds, and each member ring to two double bonds '(8) The nitrogen and sulfur heteroatoms may be oxidized as appropriate, (iv) the nitrogen arsenazo may be quaternized, and (ιν) any of the above heterocycles may be fused to a banon, but not limited to tetrahydropyrrolyl'. Carbazolyl, tetrahydropyrazolyl, -.u. -oxazolyl' tetrahydroimidazolyl, hexamidinepyridinyl, hexahydropyrrole, four per lm The basis of the loss, the base of the two, and the base of the four gas, and the base of the four gas. In some of the products, the money is replaced by the money, and it is replaced by _ _ 疋 疋 疋 疋An alkyl or heterocyclic group, which is substituted by independently replacing one, -+ _ ^ ^, or one or two hydrogen atoms thereon, the substituent being, but not limited to, an aliphatic hetero group, a square group Heteroaryl; alkyl valyl; alkylheteroaryl; alkoxy. Β-milk emulsifier oxy, heteroalkoxy; heteroaryl aryl; alkylthio; arylthio; hetero fluorenyl; heteroarylthio; F;

Cl ; Br ; I ; ·0Η ; ·Ν〇 ; c

, -CF3, -CH2CF3; _CHC12; -CH2OH * -CH2CH2〇H; -CH2NH2; .CH cn orr cH2S02CH3 ; -C(0)Rx ; -C02(Rx);- 85762 •39· 1322807 CON(Rx)2 ; -〇C(0)Rx ; -0C02Rx ; -OCON(Rx)2 ; -N(Rx)2 ; -S(0)2Rx , -NRX (CO)Rx,: where each of Rx exists, Independently including, but not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl, any of the aliphatic, heteroaliphatic, alkylaryl groups described above and herein. The aryl or heteroaryl group can be either substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and any of the aryl or heteroaryl groups described above and herein. The substituent may be substituted or unsubstituted. Other examples of generally applicable substituents are illustrated by the specific embodiments shown in the examples described herein. 3) Research Use, Formulation, and Administration According to the present invention, the compound of the present invention can be detected by any of the assays known in the art to confirm a compound having a predetermined biological activity. For example, the detection can be cellular or non-cellular, in vivo or in vitro, still- or low-through format, and the like. In certain exemplary embodiments, the compounds of the invention are tested in assays to confirm that such compounds have anti-tuberculosis/anticancer activity, inflammatory cytokine signaling pathway inhibitory activity, adhesion molecule expression inhibitory activity, and / or anti-inflammatory effect: ·. Thus, in one aspect, compounds of the invention that are of particular interest include: 7F, generally as an inhibitor of the expression of adhesion molecules on the surface of endothelial cells when stimulated with inflammatory cytokines; π is shown to be an inhibitor of the inflammatory cytokine signaling pathway; • exhibits anti-inflammatory effects in appropriate cell lines maintained in vitro, or in animal studies using scientifically acceptable models; Appropriate cell lines in vitro, or in the use of scientifically available 85762 / modulo 4 VIII in animal studies to show anti-proliferative and / or anti-cancer effects; and - ~, factory, have #] treatment forms (such as safety Sex, efficacy and stability). As discussed above, certain compounds, as described herein, are shown to be commonly used as cell adhesion molecules (E-selectin and ICAM) on endothelial cells, and are caused by messages from fire cytokines. The inhibition of transcriptional activation, j, is clearly stated as 'the compound of the present invention is implanted with immunomodulatory activity', and thus the present invention further provides a method for treating an inflammatory or autoimmune disorder or a proliferative disorder. A subject in need of treatment, including, but not limited to, a human or an animal, administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof. In certain embodiments, the compounds of the invention are used in the treatment Rheumatoid arthritis 'cancerous colitis / Crohn's disease, central nervous system disease (CNS), such as multiple sclerosis, systemic lupus erythematosus 'asthma' allograft rejection / graft versus host disease (GVH〇), cowhide Apes, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, diabetes, spontaneous thrombocytopenic purpura, spheroid nephritis, heart and vascular disease and Cancer. In certain embodiments, the method relates to administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a patient in need of treatment, including but not limited to a human or an animal. In some embodiments, a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable derivative thereof), a carrier or diluent, and optionally another therapeutic agent is provided. As discussed herein, the present invention provides novel compounds having biological properties useful for the treatment of inflammatory and 85762-41-1322807 proliferative disorders, including but not limited to rheumatoid arthritis, ulcerative colitis/Clone Disease, central disease (CNS) 'such as multiple sclerosis, systemic lupus treatment, asthma, allograft rejection / graft versus host disease (GVHD), psoriasis, ectopic dermatitis, eczema, urticaria, allergic rhinitis , myasthenia gravis, diabetes, spontaneous thrombocytopenic purpura, spheroid nephritis, heart and vascular disease, and cancer. The compounds of the invention are also found to be useful Preventing vascular restenosis susceptible to damage such as angioplasty and stent placement. Accordingly, in a further aspect of the invention there is provided a pharmaceutical composition comprising any of the compounds described herein (or preceding) a pharmaceutically acceptable salt, or a pharmaceutically acceptable derivative, and optionally a pharmaceutically acceptable carrier. In certain embodiments, such compositions may be as appropriate or Other therapeutic agents, for example, other therapeutic agents that are/or administered with the compound of the invention, or added to the pharmaceutical composition, may be anti-inflammatory agents (for example, agents for the treatment of rheumatoid arthritis or psoriasis) or cytotoxic agents or Licensed to treat cancer and anti-cancer, as more detailed in this article, or it may be in the Food and Drug Administration + Acceptance, and its "Winter will be recognized" to treat a variety of immune disorders or cancer It will also be apparent that any of the agents of the invention may be present in a free form for 'treatment' or, where appropriate, pharmaceutically acceptable derivatives thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, a salt of a scientifically acceptable salt, a salt of such an ester, or a prodrug or other adduct of a compound of the present invention, which is administered Compounds 85762 • 42-1322807 or other metabolic products or residues thereof as described in other aspects herein can be provided, directly or indirectly, to a patient in need thereof. The term "pharmaceutically acceptable salt" as used herein, (4) is intended to be safe and reliable in medical judgment and is suitable for contact with humans and tissues of lower animals without undue toxicity, irritation, or allergies. Sexual response, etc., and accompanied by a reasonable benefit W risk ratio <salt. The pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art. For example, smb or the like describes in detail the pharmaceutically acceptable salt in ##料, y, n-19 (1977) and is incorporated herein by reference. Such salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or individually by reacting a free state or free acid group with an appropriate reagent&apos; as described generally below. For example, a free state functional group can be reacted with a suitable acid. Further, in the case where the compound of the present invention has an acidic moiety, the pharmaceutically acceptable salt may include a metal salt such as a metal s, such as a sodium or a clock salt; and a soil metal salt such as a dance. Or magnesium salt. An example of a pharmaceutically acceptable non-toxic acid addition salt is a salt formed from an amine group such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with an organic acid such as acetic acid or oxalic acid. a salt formed from cis-dicarboxylic acid, tartaric acid, citric acid 'succinic acid (tetra) or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts, including adipate, sulphate, ascorbate, aspartate, besylate 'benzoate, acid sulfate, salt, butyrate, camphor Acid salt, camphor acid, citrate, % pentoxide propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate 'glucoheptose Acid salt, glycerol sulphate, gluconate, hemisulfate, heptanoate, hexanoate, hydrogen 85762 • 43· 1322807 phthalate, 2-amino-ethyl sulfonate, lactic acid bioacid salt, Lactate, laurate, laurel: basal sulfate, malate, cis-butane, malonate, methane sulfonate 2 - tea sulfonate, nicotinic acid, nitric acid =, oil Ζ salt, early acid salt, palmitate, hydroxamate, pectin ester, persulfate, 3-phenylpropionate, phosphate, picrate, trimethylacetate, propanol Good hard citrate, succinate, magnetic acid salt, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or soil test metal salts include sodium, hydrazine, unloading, _, money, and the like. Other pharmaceutically acceptable salts, including, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations, formed using counterions, such as complexes, hydroxides, carboxylates, sulfates, phosphates, nitric acid Salts, lower alkyl sulfonates and aryl sulphates. Furthermore, the term "pharmaceutically acceptable ester" as used herein refers to an ester which hydrolyzes in vivo and which includes decomposition of the human body or a salt thereof to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, guar acids, naphthenic acids and alkanoic acids, wherein each alkyl or alkenyl moiety may advantageously have Not more than 6 carbon atoms. Examples of specific esters include formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates. Furthermore, the term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of the present invention which is suitable for use in tissues with humans and lower animals within the scope of safe and reliable medical judgment. Exposure without undue toxicity, irritation, allergic response, etc., accompanied by a reasonable benefit/risk ratio' and for its intended use, and where possible, 85762 44-1322807 is a sex of the compound of the invention Ionic form. &quot;Prodrugs&quot; - Words refer to the rapid in vivo? Also converted, the compound that produces the parent compound of the above formula, for example, via the hydrolysis of β in the blood. The discussion is provided in the τ twist ratio 丨 and V_ Stella, the prodrug as a novel transport system, the 14th A of the AC S. seminar series Volume, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Medical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

As indicated above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which is used herein, and includes any and all solvents, diluents or other liquid vehicles, dispersions or suspension aids. Agent, surface active Qi = isotonic agent, thickening or emulsifier, preservative, solid binder, lubrication &amp; The specific dosage form desired. Remingt〇n's medical science 16th edition, E.W. Martin (Mack Publishing Company Tao Ru, pA), 198〇) reveals the use of ^

Various carriers for pharmaceutical compositions, and known techniques for their preparation. Unless: to the extent that any conventional carrier medium is incompatible with the compound of the invention to produce any undesirable biological effects or to interact in a deleterious manner with any other component of the drug, its use is intended to be Inside. A substance which can be used as a pharmaceutically acceptable carrier, one of which includes but is not limited to sugars, such as lactose, glucose and rutin, such as corn starch and horse starch starch; fiber "cell cellulose, ethyl cellulose" And acetic acid fiber two: shape ^ glue; - agent, such as two:;; olive oil: two = peanut oil, cotton # oil; safflower oil, sesame., oil and soybean oil 'dioxins, such as propylene glycol; 酉 quot 85762 -45· 1322807 '譬 Ethyl oleate and ethyl laurate; agar; buffer, such as magnesium hydroxide and barium hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; And phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents 'sweetening, flavoring and fragrances, preservatives And antioxidants may also be present in the compositions, as judged by the formulator. Uses and Formulations of the Compounds of the Invention As described in more detail herein, in general, the invention provides for the treatment of inflammatory or Autoimmune disorders and treatment Compounds of proliferative disorders. Without wishing to be bound by any particular theory, more generally, the compounds of the invention have been shown to inhibit adhesion molecules, such as E-selectin and ICAM_1, via stimulation with inflammatory cytokines. The surface of the endothelial cells is expressed on the surface. This cell surface molecule plays a key role in inflammatory cell infiltration and inflammatory and immune response, 'field cell X interaction'. These compounds also reduce transcription factors. Activation, and inhibition of transcriptional activation in the inflammatory cytokine signaling pathway, which regulates many genes involved in the pathology of several inflammatory diseases, such as a few-丨α and, more generally, NF /cB Confirmation of the key role in the pathogenesis of hairpins indicates that NF-/c B-targeted therapeutic agents are effective against inflammatory and immune disorders (generally refer to NP·cheng(10) calendars in defense and disease). Yangteng 2〇〇1, surgery, is. As described in the examples in this article, the ability to detect the adhesion of adhesion molecules induced by cytokine to endothelial cells is detected. , certain compounds of the invention (generally one of which is present as hydrogen, and the other of the ampule 3 is a partial group as described herein) 85762 1322807 No ICw value (E _ Selectin and ICAM_1} are lower than. In other specific examples, the exemplified compound shows 1 (: 5 〇 value is less than 1 〇 "Μ. As the above suggests, the compound of the present invention exhibits immunomodulatory activity, The activity of tumor cell growth inhibition. Therefore, the compound of the present invention can be used to treat diseases and conditions including, but not limited to, rheumatoid arthritis, 'colitis colitis/cloncosis, central nervous system disease coffee,': Multiple sclerosis, all green lupus erythematosus, asthma, allograft rejection/graft versus host disease (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, diabetes, spontaneous Small blood-reducing purple spot disease, spheroid nephritis, heart and vascular disease, and cancer. As discussed above, the compounds of the present invention have also been found to be useful in the prevention of restenosis of blood vessels that are susceptible to damage such as angioplasty and stent placement. For example, it is desirable that the compounds of the present invention will be useful as a coating for implanted medical devices such as tubing, bypasses, catheters, artificial implants, pins, electrical implants, such as pacemakers, and especially for arterial or venous stents, including Balloon expandable bracket. In certain embodiments, the compounds of the invention may be incorporated into an implantable medical device or may be passively adsorbed to the surface of the implantable device. In certain other specific embodiments, the compounds of the invention may be formulated to be included in, or adapted to be released into, a surgical or medical device or implant, such as a vascular stent, a suture, a catheter that remains, Make up things and so on. In certain embodiments of the invention, the compounds of the invention may be used as a coating for vascular stents. The vascular stent is typically an open tubular structure with a pattern of holes (or a plurality of patterns) extending 85762 - 47 · 1322807 from the outer surface of the stent to the lumen. It is not uncommon to use a laser machine to create a vascular stent of biocompatible metal material with a cut pattern on the surface of the surface. The vascular stent can be electropolished to minimize surface irregularities, as such irregularities can trigger adverse biological responses. However, vascular stents can still stimulate foreign body reactions, causing thrombosis or restenosis. To avoid such complications, a variety of stent coatings and compositions have been proposed in prior art literature to reduce the incidence of such complications or other complications, and to restore tissue function alone, or to deliver therapeutic compounds to the lumen via delivery. tube. For example, drugs with anti-proliferative and anti-inflammatory activity have been evaluated as stent coatings and have been shown to be promising to prevent restenosis (see, for example, Presbitero P. et al., &quot; Drug-dissolving stents to make it really different?&quot; , Mhemz 2002, 50(5): 431-442; Ruygrok Ρ·Ν, et al., &quot;Rapamycin &quot; in Heart and Vascular Medicine, Μ沈ί. ·/·,2003, 33(3 ): 103-109; and Marx SO et al., &quot;Workbench to Clinical: Development of rapamycin and its application to vascular stent restenosis&quot;, CzVcM/artw, 2〇01,1〇4(8) : 852-855, each of which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in the the the the the the the the the the the Stent coating and/or use in stent drug delivery devices, particularly to prevent restenosis or reduce restenosis rate. A variety of compositions and methods for preventing restenosis associated with stent coating and/or topical stent drug delivery. Known in this art (see, for example, the US patent case) No. 6,517,889; 6,273,913; 6,258,121; 6,251,136; 6,248,127; 6,231,600; 6,203,551; 6,153,252; 6,071,305; 5,891,507; 5,837,313; Example 85762 • 48- 1^22807 If 'the stent can be coated with a polymer-drug conjugate by immersing the stent in a polymer/drug solution or spraying the stent with this solution In a specific embodiment, suitable materials for the implantable device, including biocompatible and non-toxic materials, may be selected from metals such as nickel-titanium alloys, steel, or biocompatible polymers. , hydrogel, polyurethane urethane, polyethylene, ethylene acetate acetate copolymer, etc. In some embodiments, the present Moon S is applied to the stent to After angioplasty, it is inserted into an artery or vein.

In certain broad aspects, the invention may be described as a method of inhibiting I artery restenosis or arterial occlusion after vascular damage, comprising administering to a subject in need thereof a conjugated to a suitable polymer or polymeric material. a composition of the compound. In the practice of this method, the patient may be, for example, a coronary, vascular, organ transplant or coronary or any other arteriovascular disease, and the composition may be administered in a direct manner, intravenously, when witnessing a vascular injury It is even applied to the stent to be implanted.

In another aspect, the invention encompasses implants and surgical or medical devices, iliac vascular stents and grafts that have been coated or otherwise constructed to contain =/ or release any of the inventions disclosed herein. Compound. In some: physical examples, these compounds 1 #

The substance has anti-frozen and/or anti-proliferative activity. In some other specific embodiments, humanized knee Ip σ σ 会 inhibits smooth muscle cell proliferation. Inventive implants and surgical or medical painkillers, sputum medical devices &lt;representative examples, including cardiac and tube devices (eg, implantable veins),

Guide g, venous valve, tunnel venous lead 3, chronic perfusion line or gas nΛ venous catheter E] including hepatic artery infusion catheter, genus, implantable defibrillation w, help consultation), neuropathy / neurosurgery device ( Case 85762 • 49- 丄 322807 Ventricular peritoneal bypass, ventricular bypass, nerve stimulation device, dura patch and implant 'to prevent epidural fibrosis after laminectomy, for continuous spider Intragastric perfusion device; gastrointestinal device (eg chronic catheter, feeding tube, portal vein bypass, bypass for water abdomen, peritoneal implant for drug delivery, peritoneal dialysis catheter, prolapse Implantable mesh, suspension or solid implant to prevent surgical adhesion, including mesh); genital and urinary devices (eg uterine implants, including intrauterine devices (IUD), and to prevent endometrial Proliferative devices, fallopian tube implants, including reversible sterile devices, fallopian tube stents, artificial sphincters, and incontinence of urethral pericardial implants, ureteral stents, chronic catheters, bladder intensification Ophthalmic implants (eg multi-implants, and other implants for glaucoma, pterygium drugs) Dissolved contact lenses, splints for failed lacrimal sac nasal ostomy, drug for dissolving contact lenses for corneal neovascular status, implants for retinopathy of diabetic patients, high-risk corneal grafts ^ drug-dissolving contact lenses Otorhinolaryngology devices (eg small bone implants, Oste's splints for: ear or chronic otitis or stents, an alternative to suffocating dryness); plastic surgical implants (eg, Prevention fiber

Implants (eg, glued torso).

Fixing the composition or composition of the present invention directly to the implant is applied in a variety of ways (or with its &gt; 'including, for example: (4) by implantation into an implant or device (eg, 85762 - 50. 1322807 : spraying the polymer/drug film from either the implant or device, or by dipping the implant or device into the polymer/drug, ^, 'hard, or by JL Xian Covalently or non-covalently); (8) by implanting an implant or device with a gelatinous substance, which will sequentially absorb the compound or composition of the present invention; Applying a compound or composition of the invention to a thread (or polymerization:, = to::: or device; _ by inserting an implant or device: ... a sleeve or mesh that has been coated with a compound or composition of the invention The tablet construct itself has an implant or composition of the compound or composition of the invention adapted to adjust the implant or device to otherwise align the invention: Γ廄 In some embodiments, the composition is in a period of error And in the insert preferably also during storage, in the second: the substance or combination is warmed to body temperature (If this is required to be broadcast into the inside of the body, then Α, τ, will degrade. In addition, it is better to Ι Γ 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入 入Preferably, the :: implant or device, when it has been deployed, should provide ^, predictable, long-term release of the compound of the invention or the combined tissue. For vascular stents, in addition to the above Sexuality σ 物 不应 不应 不应 不应 不应 不应 不应 不应 不应 不应 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵 仵In the context of the condition, a wide variety of scaffolds can be developed to contain and/or release a compound or composition of the invention provided, which includes an esophageal stent, a gastrointestinal stent, a vascular stent, a bile duct stent, a colon stent, and a fistula: ^ 85762 • 51- 1322807 Ureter and urethral stents, lacrimal duct stents, Oste's stents, fallopian tube stents, and tracheal _/ branch tracheal stents (see, for example, US Patent: 65丨5(1)6, all of which are incorporated herein. for reference). The racks are readily available from commercial sources, or are constructed in accordance with conventional techniques. Representative examples of stents include those described in U.S. Patent No. 4,768,523, entitled: Gel Adhesives: U.S. Patent 4,776,337, Titled "Expandable intraluminal grafts, and methods and devices for implanting implants in expandable lumens"; U.S. Patent 5,041 '126, entitled &quot;In Vascular Stents and Delivery Systems; U.S. Patent 5,052,998 , entitled "Standing and use of the resident"; US Patent 5,064,435, entitled "Automatic Expansion Compensator with Stable Axis Length": US Patent 5,089,606, entitled "For Medical Applications" Water-insoluble multi-vinegar hydrogel foam"; Meishili 37G, titled "Hollow in the stent for catheters"; US patent irony, titled &quot;Residing in and inside (bracket&quot; U.S. Patent No. 5,213,58, entitled "Biodegradable Poly: Intracavity Sealing Method" and U.S. Patent 5,328,471, entitled, in, hollow tubular organs Other tissue diseases and lesions treatment means catching rabbits lumen. The present inventors' have been coated (or otherwise adapted to adjust the stent) to eliminate stop tube blockage and to prevent re-coating and low rate. In other aspects of the invention Wherein, a combination of the composition of the present invention is provided (or otherwise adjusted to release) ===: In other words, a stent having a substantially lunar compound or composition is inserted into the channel such that the channel 85762 • 52-1322807 = bulging. In some embodiments, it has been coated (or otherwise adjusted: 乂 released). The present invention: a stent for the composition can be used to exclude bile ducts, gastrointestinal 'esophageal oxygen tubes/ A tracheal, urethral or vascular occlusion. Thus, as described above, in another aspect of the invention, a method for treating an inflammatory or autoimmune and proliferative disorder, comprising administering a disease 1 as needed, A therapeutically effective amount of a compound of formula 1 as described herein. In certain 2-body examples, the compounds of the invention are useful in the treatment of rheumatoid arthritis, ulcerative colitis/ Crohn's disease, central nervous system disorders (cns) , such as multiple Sclerosing, systemic lupus erythematosus, asthma, allograft rejection / graft versus host disease (GVHD), psoriasis, atopic dermatitis, eczema, urticaria, allergic rhinitis, myasthenia gravis, diabetes, spontaneous thrombocytopenia Purple spot disease, spheroid nephritis, heart and vascular disease, and cancer. It should be understood that, in accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and in any route of administration effective to treat inflammatory or autoimmune and proliferative conditions. Therefore, the term "effective amount" as used herein refers to a sufficient amount of an agent to kill or inhibit the growth of a tumor cell, or a sufficient amount to reduce the effect of an inflammatory or autoimmune response or condition. It is true that the amount varies with the patient, depending on the species, age and general condition of the patient, the severity of the disease, the specific anticancer agent, the mode of administration, etc. The compound of the present invention is preferably formulated into a dosage unit form. For ease of administration and uniformity of dosage. The term "dosage unit form" as used in this context refers to the condition suitable for the patient to be treated. The physically discrete unit of the therapeutic agent. However, it should be understood that the total daily usage of the compound of the present invention and the composition is determined by the responsible physician within the scope of safe and reliable medical judgment. For any particular patient or organism 85762 -53- 1322807 The specific therapeutically effective dose level of a body depends on a number of factors, including the severity of the condition and condition being treated; the activity of the particular compound employed; the particular composition employed; the age of the patient , weight, general state of health, sex and diet; time of administration, route of administration and rate of excretion of the particular compound used; duration of treatment; drugs combined with or concurrent with the particular compound employed; and similar in medical practice Factors (see, for example, Goodman and Gilman, "The Pharmacological Foundation of Therapeutics", 10th edition, edited by A. Gilman, J. Hardman and L. Limbird, McGraw-Hill, 155-173, 2001, full text And for reference in this article). In certain other embodiments, methods are provided for using implants of the invention and other surgical or medical devices that have been coated (or otherwise adapted to release) the compounds and compositions of the invention. In certain embodiments, methods are provided to prevent restenosis, including insertion of a stent into a occluded blood vessel, the stent having a generally tubular structure with the surface of the structure coated (or otherwise adapted to release) The compound or composition of the invention is such that the blockage is excluded and the compound or composition of the invention is delivered in an amount effective to prevent restenosis. In other embodiments, a method is provided for preventing restenosis, comprising inserting a stent into a occluded blood vessel, the stent having a generally tubular structure, the surface of the structure being coated (or otherwise adjusted for release) The compounds or compositions of the invention are such that occlusion is excluded and the compounds or compositions of the invention are delivered in an amount effective to inhibit smooth muscle cell proliferation. In other aspects of the invention, methods are provided for inflating a lumen of a body passage, including inserting a stent into a channel having a generally tubular structure 85762-54-1322807 with the surface of the structure coated (or Other means are coordinated to liberate the compound or I and the compound of the invention such that the channel is swollen. In some embodiments, the lumen of the body passage is inflated to exclude bile ducts, gastrointestinal, esophageal, tracheal/branched trachea, urethra, and/or vascular occlusion. Methods of using a stent to exclude bile ducts 'gastrointestinal, esophagus, tracheal/branched trachea, urethra and/or vascular occlusion are known in the art. The skilled practitioner will know how to adapt these methods to practice the invention. For example, reference may be made to the teachings of U.S. Patent Application Serial No.:20030, the entire disclosure of which is incorporated herein by reference. Furthermore, the pharmaceutical composition of the present invention may be administered orally, rectally, parenterally, intracisterically, intravaginally, intraperitoneally, or locally after being formulated into a desired dose with a suitably pharmaceutically acceptable carrier (for example, by Powders, ointments, creams or drops), cheeks, oral or nasal sprays or the like, administered to humans and other animals, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be from about 1 mg/kg to about 50 mg/kg per day, from about 0.01 mg/kg to about mg/kg, or from about 1% to about gram per kg. Dosing at a dose of about 10 mg/kg of the patient's body weight, one or more times a day, to obtain the desired therapeutic effect. It should also be understood that the patient may be administered a dose of less than 〇.〇〇1 mg/kg or more than 50 mg/kg (e.g., 50-100 mg/kg). In certain embodiments, the compounds are administered orally or parenterally. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents such as water or other solvents, solubilizers and emulsifiers commonly used in the art of 85762-55. 1322807, such as ethanol, isopropanol, ethyl carbonate, acetic acid. Ethyl ester, decyl alcohol, decyl benzoate, propylene glycol, hydrazine, 3-butanediol, dimethylformamide, oils (especially cotton aphid, groundnut, corn, germ, olive, ramie and sesame oil glycerin, Tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of phytosan, and mixtures thereof. In addition to inert diluents, 'oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, Sweetened 'flavor and fragrance.

The/injectable formulation&apos;, e.g., a sterile injectable aqueous or oily suspension, can be formulated in accordance with the prior art using a suitable dispersing or wetting agent. Sterile

The injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, in guanidine, 3 • butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally employed as a solvent or suspension medium. For the purposes of this project, any mild, fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables. The injectable preparation may be sterilized, for example, by sterilizing the bacteria, or by incorporating sterile sterilized solid compositions, which may be dissolved or dispersed in sterile water or other sterile form. Injected into the medium. In order to prolong the effect of the drug, it should be slowed down from the subcutaneous or intramuscular injection of drugs, such as liquid sputum, sputum, and gt; The body suspension is hard or has a water-free solubility of crystalline or amorphous material. At ^ a ± ^ 疋, the absorption rate of the music is determined by the rate of crystallization, which can be determined according to the size and crystal form of the crystal. In the form of parenteral administration, the delayed absorption of the form of αβ丁&lt;the form of music is dissolved or suspended in &amp; vehicle by the 85762 •56- substance to form an injectable drug. The biodegradable polymer is prepared, for example, from a microcapsule matrix in a polyether. Depending on the ratio of the drug to the polymer, and the nature of the specific polymer, the release rate of the drug beam can be clamped. Examples of other biodegradable polymers, I include poly(orthoesters) and poly(races). The infusion formulation is also made by immersing the drug in a viscous or microemulsion. a, and weaving

A composition for rectal or vaginal administration, preferably a suppository, which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene. An alcohol or a compound which is solid at ambient temperature 'but liquid at body temperature' and thus melts in the rectal or vaginal cavity and releases the active compound. β

Solid dosage forms for oral administration, including capsules, tablets, pills, powders, and granules. In such a solid form &lt; towel H compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or sulphate #5, and / or 3) filler or Dosing agents, such as powder, lactose, sucrose, glucose, mannitol acid, b) binders, such as methine cellulose hexanoate, gelatin, polyethylidene tetrachloro ρ than ha, recommended Sugar and gum arabic, c) humectants 'such as glycerin, d) disintegrants, such as agar-agar, calcium carbonate potato or tapioca starch, alginic acid, certain citrates and sodium carbonate, e) dissolution retarders, For example, paraffin wax, hydrazine absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and hydrazine) lubricants, such as Talc, calcium stearate, magnesium laurate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures 85762 • 57-1322807. In the case of capsules, tablets and pills, the dosage form may also contain a buffer. A solid composition of a similar type may also be employed as a filler in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be formulated with a coating and a shell, such as an enteric coating, and other coatings conventionally known in the art of pharmaceutical formulation. Visible situation

It contains an opacifying agent and may also be a composition which will only or preferentially release the active ingredient in a certain portion of the intestinal tract, as appropriate, in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes. Solid compositions of the same type may also be employed as fillers in soft and hard-filled gelatin capsules, such as excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

The active compound may also be in micro-coated form, using one or more of the above-mentioned agents. The solid dosage form of tablet #j, sugar-coated key, capsule, pill, and granules can be formulated to have a coating and a shell layer, such as an enteric coating, a release control layer, and other coatings conventionally known in the art of pharmaceutical formulation. In such a solid dosage form, the active compound may be mixed with at least one inert diluent such as sucrose, lactose and starch. In normal practice, such dosage forms also include materials other than inert diluents, such as lubricants for pharmaceutical tablets, and pharmaceutically acceptable granules, such as magnesium stearate and microcrystalline cellulose. In the case of tablets and pills, the dosage form may also comprise a buffering agent, optionally containing an opacifying agent, and may also be a composition which will only release or preferentially release the active ingredient in a certain intestinal tract, as the case may be. With a delay of 85762 -58· 1322807. Examples of embedding compositions that can be used include polymeric materials and waxes. Dosage forms for topical or transdermal administration of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, and patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as may be required. Ophthalmic formulations, ear drops, and eye drops are also intended to be encompassed within the scope of the invention. Further, the present invention is intended to encompass the use of transdermal patches, which have

Additional benefits of controlled transmission of the compound are provided. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling film by blood or by dispersing the compound in a polymer matrix: gel. It should also be understood that the compounds of the present invention and pharmaceutical compositions may be formulated and used in combination therapy φ, &gt; __ _ ', thinking, such compounds may be combined with a pharmaceutical or a plurality of other desired therapeutic agents or Medical procedures, — or at the same time, in +'+―* ρ

Specific to the law, and into the drug. Used in merger services. By licking (therapeutic agent or procedure), it will be considered that the desired therapeutic agent is compatible with the desired therapeutic effect to be achieved. It should also be clear that the present invention can be administered in combination with another immunomodulator, an anticancer agent, or a psoriasis, or it can achieve different effects (for example, controlling any adverse effects). j such as package: other therapies or anticancer agents used in combination with the invention compounds, including surgery, radiation therapy (in only a few examples, r•radiation ^ 85762 -59· 1322807 beam radiation therapy, electron beam radiation therapy, protons Therapy, brachytherapy, and systemic radioisotopes, only a small part of it, endocrine therapy, biological response modifiers (interferon, interleukocaptokinin, and tumor necrosis factor (TNF), only one of them is referred to Parts), hyperthermia and hypothermia, agents that attenuate any adverse effects (such as antiemetics), and other approved chemotherapeutic drugs, including but not limited to alkylating drugs (nitrogen, chlorambucil) ), cyclophosphamide, aziridine, ifosfamide, anti-metabolism (amine oxime), sputum antagonist and pyrimidine antagonist (6-base guanidine, 5-fluoro) Urine p-dense, cytarabile, gemcitabine, spindle poison (Changchun flower test, Changchun test, vinorelbine, paclitaxel), Podophyllin Etoposide, irinotecan, topotecan, antibiotics (droxorubicin, bleomycin, mitomycin), nitrosourea ( Nitrosourea mustard, cyclohexyl nitrosourea), inorganic ions (shunamine, carbochloramine), enzyme (aspartate) and hormones (tamoxifen, leucolide) (leuprolide), flutamide and megestrol acetate, only a small part of it. For a more comprehensive discussion of updating cancer therapeutics, see http//www.nci.nih.gov/, a list of FDA-approved oncology drugs at http://www.fda.gov/cder/cancer/ druglistframe.htm And the Merck Handbook, Seventeenth Edition, 1999, the entire contents of which are hereby incorporated by reference. In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and/or palliative). For the purposes of the present invention, the term "〃姑桌" refers to a treatment that focuses on the relief of side effects of the disease and/or treatment, rather than a cure. For example, 85762 -60-1322807, palliative medicine treatment covers painkillers, nausea removal and anti-disease drugs. In addition, cost-based therapy, radiation therapy, and surgery can be used in a palliative manner (meaning 'reducing symptoms' without treatment; for example, reducing tumors and reducing stress, bleeding, pain, and other signs of cancer). Therapeutic Kits In other embodiments, the present invention is directed to a kit that is suitable and effective for performing the method according to the present invention. In general, a pharmaceutical pack or kit&apos; contains or contains a plurality of containers filled with one or more of the ingredients of the pharmaceutical compositions of the present invention. This kit is particularly suitable for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably comprises a plurality of unit doses and may also comprise a card having an amount directed to the order in which it is intended to be used. If desired, a memory aid may be provided, such as in the form of a number, letter or other indicia, or a day-to-day insertion, specifying the number of days in which the treatment schedule for which the dose can be administered. Alternatively, the dose comprising a placebo or a foraging supplement, in a form similar or different to the dosage of the pharmaceutical composition, provides a kit in which the dosage is taken daily. If the container is accompanied by such a condition, it may be in the form of a notice that is issued by a government agency to control the manufacture, use or sale of a drug product. The notice reflects that the institution permits manufacture, use or sale. For humans to administer drugs. The following representative examples are intended to be illustrative of the invention and are not intended to limit the scope of the invention. In fact, the various modifications of the present invention and many of its further and indirect embodiments, in addition to the ones shown in this article, are all familiar to those who are familiar with this, and the 'farmers' and 5 will be the whole content. Ming 85762 • 61 - 1322807, including the following examples and references to scientific and patent documents cited herein. It should be noted that the contents of the cited references are incorporated herein by reference to help explain the current state of the art. The following examples contain other important information 'examples and guidelines' which may be suitable for the practice of the invention in its various embodiments and equivalents. EXAMPLES The compounds of the present invention and their preparation will be apparent from the examples which illustrate some methods by which such compounds can be prepared or used. However, it should be understood that such examples are not limiting of the invention. Modifications of the present invention, which are currently known or further developed, are within the scope of the invention as described herein and as claimed hereinafter. In accordance with the present invention, any of the techniques of the present invention can be used to make or prepare a compound of the present invention or a composition comprising the same. For example, a variety of solution phase synthesis methods can be used, as discussed in detail below. Alternatively or additionally, the compounds of the invention may be prepared using any of a variety of binding techniques, parallel synthesis and/or solid phase synthesis methods known in the art. It will be appreciated that a variety of compounds of the invention can be synthesized according to the methods described herein, as described below. Starting materials and reagents for the preparation of such compounds are available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St Louis, Mo). ), or by methods generally known to those skilled in the art, according to the procedures described in the references, such as Fieser and Fieser 1991, &quot;Reagents for Organic Synthesis&quot;, Volumes 1-17, John Wiley & Sons, New York, NY, 1991; Rodd 1989 "Chemicals of Carbon Compounds", Volumes 1-5 and Supplements, Elsevier Science Press, 1989, 85762-62-1322807 Machine Reactions &quot;, Section 1- Volume 40, John Wiley &amp; Sons, New York, ΝΥ, 1991; March 2001, &quot;Advanced Organic Northern Studies&quot;, 5th ed., John Wiley &amp; Sons, New York, NY; and Larock 1990, &quot;Comprehensive Organic Transformation: Guidelines for the Preparation of Functional Groups, 2nd Edition, VCH Press. These synthetic systems are merely illustrative of some of the methods that can be used to synthesize the compounds of the present invention, and various modifications can be made to these synthetic systems, and Will be concerned about this The general content of the present disclosure is recommended by the artist. The starting materials, intermediates and compounds of the present invention can be isolated and purified by conventional techniques, including filtration, evaporation, crystallization, chromatography, etc. Characterization, including physical constants and spectral data. [Embodiment] 1) Exemplary Compounds Some exemplary compound series of the present invention are shown below, and are referred to by the compound number as indicated. 85762 63- 1322807 85762

64- 1322807 85762

-65- 1322807 85762

·················································· Boq^ N-Boc tbso^o^ Boc Boc 25 806107 Bo, N-Boc H0X〇^n Boc Boc 26 806123 nh2 Η ΝγΝΗ 67- 1322807 85762 27 806136 vcr〇^:2 28 806181 nh2 HN^NH 29 806221 H 丫H 30 806220 - NH2 0 ΝΙγΝΗ 31 806224 J) H NysJH 32 806228 nh2 kJJ ΝγΝΗ 33 806276 nh2 丫h MeO 1 34 806275 ::Xprn〇^ MeO N 丫NH 35 806274 (T^O^H2 H Νγ^Η 68- 1322807 85762

-69- 1322807 85762

-70- 1322807 85762

-71 - 1322807 85762 63 806419 丫Η 64 806420 〇?: 65 806421 66 806432 〇Λ^α^Η2 Η ΝγΝΗ 67 806435 1 ΝΗ2 η 68 806437 = νη2 Η n^)jh 69 806569 U η〒νη 70 806609 σ :^α^Η 71 806610 νη2 ρτηα^Ν OMe Νγ,ΝΗ -72- 1322807 85762 72 806644 /JH2 73 806645 nh2 74 806646 NH2 75 806647 σ:^α^Η 76 806653 77 806671 H ΝγΝΗ 78 806781 MeO, 79 806790 Nh2 ό τ -73- 1322807 85762 80 806796 Η Ν^ΝΗ 81 806820 Η Η ΝγΝΗ 82 806839 CI 0 (ULJ Η Ν^,ΝΗ 83 806840 9 νη2 Η Ν^ΝΗ 84 806841 CI^Vv^: Η Ν^ΝΗ 85 806842 νη2 CUJ〇&gt;^ Η ΝγΝΗ 86 806843 Fi^OXcv^r Η Ν^,ΝΗ 87 806844 νη2 ΟΧπ&gt;^ Η Ν 丫ΝΗ 88 806860 Η 〇〇/ ΰΛ〇^: Η 丫Η -74- 1322807 85762 89 806874 Η Η ΝγΝΗ 90 806875 Η 1 1 Μ ΝγΝΗ 91 806878 〇〇&quot;〇^: Η Ν^ΝΗ 92 806899 9 νη2 fov〇^〇^n 5 Η〒Η 93 806900 νη2 C^nj〇CV^n 0 Η Ν 丫ΝΗ 94 806901 fX^OyCc^_^n 0 Η ΝγΝΗ 95 806902 νη2 1 Η 〜\ΝΗ 96 8 06903 ά^οο^2 Η ΝγΝΗ 97 806904 νη2 Η Ν 丫'ΝΗ -75- 1322807 85762

98 806905 nh2 HN^NH 99 806987 HN^NH 100 807014 HN^NH 101 807015 9 9 nh2 NHN^;NH 102 807139 OMe HN 丫NH 103 807140 nh2 HN^NH 104 807183 ΜβΟ 0 fclLI 2 · HN^NH T 105 807240 MeO Mu HN 丫, NH 106 807313 1 nh2 HN丫NH 76- 1322807 85762 107 807377 nh2 F3Cxrr-〇v^NHN^NH 108 807392 nh2 F3CO^^a&gt;~0 HN 丫'NH 109 807400 nh2 〇〇X〇- ^NHN 丫'NH 110 807401 H NH2 CD^O&gt;-^n HH nT^nh trans-racemic γ 111 807399 Η ΝΗ2 Η Η nC}nh cis-racemic γ 112 807447 (Π _Γ2 Η Ν^ΝΗ 113 807448 νη2 &quot;Ί Η ν?νη 114 807449 νη2 115 807450 νη2 OCF3 Η ΝγΝΗ -77- 1322807 85762

-78- 1322807 85762

125 807463 nh2 HN^NH 126 807464 nh2 HN^NH 127 807465 HN^NH 128 807466 nh2 HN 丫'NH 129 807467 nh2 HN 丫NIH 130 807469 nh2 〇rrxcv^NHN^NH 131 807496 HN^/NH 132 807497 nh2 prr- 〇v^N 1 H 133 807498 nh2 HN 丫'NH 79- 1322807 85762

134 807505 nh2 135 807506 nh2 136 807528 ^Ί〇ν^1Η2 UHN^NH 137 807531 nh2 C〇T'X〇-^NHN^NH 138 807532 nh2 0^ HN^NH 139 807543 nh2 kj H 丫(一) 140 807544 nh2 - kJ : H 丫H 141 807546 CH 〇rn〇&gt;^ HN^NH 142 807548 nh2 pr?^〇y^N CN HN 丫NH •80- 1322807 85762

143 807549 144 807550 HN^NH 145 807562 nh2 0 ΝτΝΗ 146 807571 nh2 NCiX'Xcv^NH n^nh 147 807573 nh2 HN 丫, NH 148 807584 HN 丫'NH 149 807585 0X)nXcv^n HN^NH 150 807586 °ΤΊ /nh^ HN^NH 151 807587 HN 丫'NH -81 - 1322807 85762

152 807636 nh2 HN 丫'NH 153 807649 〇L /NH2 H Νγ'ΝΗ 154 807660 /NH2 H n^nh 155 807662 nh2 H n^nh 156 807663 丄_T2 HN^NH 157 807703 nh2 H n^nh 158 807704 nh2 HN^NH 159 807748 nh2 crr〇&gt;^ HN^NH -82- 1322807 160 807749 nh2 HN^NH 161 807750 Η Ν^ΝΗ 162 807751 Η ν^νη 163 807754 Η 丫 丫, ΝΗ 164 807758 ar^〇v^ lH2 Η Ν^ΝΗ 165 807759 0Υ\ Η Ν^ΝΗ 166 807762 ΝΗ2 . '^〇cv^^ - Η ν^}νη 167 807779 ?Γ〇&gt;^Η2 Η ν^,νη 168 807787 '^Ocvq^ Η Ν^,ΝΗ 85762 -83- 1322807 85762 169 807788 °ΤΊ Η N^NH 170 807789 MeO^N':5|^^ ΝΗ2 Η 丫 丫, ΝΗ 171 807790 Η0^ι νη2 Η 丫 丫'ΝΗ 172 807794 νη2 HO 1 173 ΝΗ ΝΗ ΝΗ 173 173 173 173 173 173 173 173 Ν^ΝΗ -84- 1322807 85762 178 807876 nh2 HCi HN^NH 179 807892 nh2 HN^,NH 180 807920 nh2 HN 丫'NH 181 807930 nh2 HN^NH 182 807931 nh2 OH HN 丫NH 183 807952 Γ1 ”NH2 H N^NH 184 807956 H Ν^,ΝΗ 185 807962 Cl ”NH2 ” H n?nh -85- 1322807

186 807976 F 7NH2 HN 丫'NH 187 807977 HN^NH 188 807978 J) nh2 HN^NH 189 807980 a*Xcv^H2 H Ν^,ΝΗ 190 808009 αΓ〇^Ν HN^NH 191 808028 0^1 nh2 H n ^nh 丫192 808036 〇L ”H2 HN^NH 193 808039 nh2 〇^〇v^NHN 丫NH 85762 -86- 1322807

194 808040, NH H N^/NH 195 808041 HCI H N^NH T 196 808069 n ; NH2 H N^NH 197 808078 nh2 F H N 丫 NH 198 808079 nh2 丨 H N NH T 199 808080 nh2 丨 H n'nh T 200 808081 ,. :rrrxx^N 1 H N丫 NH 201 808082 Cl ”NH2 as r〇&gt;~^ H N 丫'NH 202 808083 H N 丫, NH

85762 -87- 1322807 85762

203 808084 α&gt;Χ^&quot; HN 丫NH 204 808085 HN 丫VlH 205 808086 F ”nh2 HN^NH 206 808101 nh2 H n^/NH 207 808102 CVl nh2 hXcv^n HN^NH 208 808103 〇L ,nh^ HN ^NH 209 808107 nh2 oCTh^Ov^n HN^NH 210 808128 Cl /nhz HN 丫, NH -88- 1322807 85762

211 808151 Λ ” HN^NH 212 808152 &quot;ΤΊ /NH2 HN^NH 213 808153 nh2 HN^NH 214 808160 HN^NH 215 808164 _ _/NH2 H Ν^,ΝΗ 216 808247 Cl ”NH2 HN 丫, NH 217 808254 , nh2 Ό HN丫NH 218 808255 NH2 kJ H 丫H -89- 1322807 85762

219 808256 Η N^NH 220 808257 HN NH, NH 221 808259 HN 丫 'NH 222 808260 ^nJC〇-^Pn HN 丫'NH 223 808261 〇nJ〇C^~^n HN 丫NH 224 808262 Q3J〇cy^NHH n^nh 225 808266 CF3C02H Η N 丫NH 226 808268 O-)...,,,? | • €0 X B 1 227 808269 /〇, H N-^NH 228 808281 HN 丫'NH -90- 1322807 85762 229 808283 cf3co2h hn^nh 230 808284 Cmj〇Q^Pn HN 丫NH 231 808285 . ~JH VNH 232 808286 〇nJ〇^Pn HN 丫VlH 233 808287 Η Ν^,ΝΗ 234 808288 ςτ°^Ν JH 丫^ 235 808289 J〇H 丫H 236 808290 HN 丫'NH 237 808291 H ΝγΝΗ -91 - 1322807 243 808 α 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 241 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243 245 808347 νη2 Η ΝγΝΗ 、,〇” 1 -92- 1322807 85762

246 808355 nh2 HN 丫NH 247 808356 nh2 Kj H ίγΝΗ 248 808361 H〇^ H ΝγΝΗ 249 808362 〇cv^NH nC/nh 250 808363 HN^NH 251 808364 〇Λ Η^Η2 H ΝγΝΗ 252 808365 M ΝγΝΗ 253 808370 H t ^NH 254 808371 nh2 HN 丫'NH -93- 1322807 85762 255 808372 Η N^NH 256 808385 Η Ν^ΝΗ 257 808386 Η Ν Ν^ΝΗ 258 808387 νη2 cf3co2h Η 259 808388 Η Ν^ΝΗ 260 808469 Η Ν 261 ΝΗ ΝΗ 261 808470 α&gt;-^Ν ΝΤΝΗ 262 262 808473 Η Ν^ΝΗ 263 808496 ^iJ〇CV^N Η ΝγΝΗ 264 808497 JJ〇Q^^n J Η ΝγΝΗ 94- 1322807 85762

95- 1322807 85762 274 808544 nh2 〇〇H Oh cf3co2h cf3co2h ] 275 808548 nh2 H n^nh 276 808571 HN^NH 111 808576 nh2 ij H NrNH 278 808600 /VnJ〇CV-^n UH γΗ 278 808617 〇nj〇cv^ n H n^nh 279 808620 \ Less 0^ HN 丫NH 280 808622 °hy&lt;^ HN^NH 281 808623 HCI H Νγ-ΝΗ -96- 1322807 85762 282 808624 Η N^NH 283 808627 νη2 ^ hci Η ΝγΝΗ 284 808628 ^ hci Η ΝγΝΗ 285 808629 Η Ν^ΝΗ 286 808631 Η Ν^ΝΗ 287 808635 /nJ〇CV^n Η ΝγΝΗ 288 808636 Η Ν^ΝΗ 289 808637 〇nJCcv^Pn HCI Η 丫Η 290 808658 NHAc Η Ν^ΝΗ 291 808660 Μ ν^νη -97- 1322807 85762

292 808661 HN NH 293 808663 HN^NH 294 808665 o, HN^NH 295 808672 o H ΝγΝΗ 296 808673 M Ν^ΝΗ 297 808675 /〇νΓΎ /NHz . HI. HN丫NH 298 808691 HN^NH 299 808692 /^NjCcy -&lt;pN HN 丫NH -98- 1322807 85762 300 808702 H Ν^,ΝΗ 301 808703 HN^NH cf3co2h Ding 302 808704 Η N^NH cf3co2h T 303 808705 H ν^,νη CF3C02H I 304 808711 H n^nh 305 808712 1 HN 丫NH 306 808713 〇^〇rv^NHN 丫NH 307 808714 OjCQ^^n HN 丫'NH 308 808717 HN 丫NH 309 808719 Pair of palm H ΝγΝΗ -99- 1322807 85762

-100- 1322807 85762

320 809189 nh2 HN^NH 321 809190 nh2 H nC&gt;h 322 809191 nh2 H Ά 323 809192 nh2 Μβ〇ΛΛ^Η 324 809193 nh2 HN^NH 325 809196 h〇^^〇v^n 2 CF3C02H N丫NH 326 809197 2 CF3CO2H ΝγΝΗ 327 809198 2 CF3C02H ΝγΝΗ 328 809199 3 CF3C02H ΝγΝΗ 329 809200 HO. 2 CF3C02H N丫NH -101 - 1322807 85762 330 809201 2 cf3co2h H nVnh 331 809202 2CF3C02H H nVnh 332 809203 3 CF3C02H ΝγΝΗ 333 809204 HO 2 CF3C02H ΝγΝΗ 334 809205 2CF3C02H H ΝγΝΗ 335 809206 person 2 CF3CO2H Ν·γΝΗ 336 809207 3 CF3C02H ΝγΝΗ 337 809208 3 CF3C02H Ν·γΝΗ 338 809209 2 CF3CO2H ΝγΝΗ -102- 1322807 85762 339 809210 2 CF3C02H Ν-γΝΗ 340 809211 2 CF3C02H N 丫NH 341 809212 3 CF3C02H N, VNH 342 809213 2 CF3C02H ΝγΝΗ 343 809214 I. A 2 CF3CO2H ΝγΝΗ 344 809215 2 CF3CO2H ΝγΝΗ 345 809216 2 CF3C02H Νγ·ΝΗ 346 809217 2 CF3CO2H Ν丫ΝΗ 347 809218 2 CF3C02H ΝγΝΗ 348 809219 2 CF3C02H Ν丫ΝΗ 103- 1322807 85762

349 809220 A 2CF3C〇2H H NVNH 350 809221 2 CF3C02H N 丫NH 351 809222 rNXTOc^N 3 CF3C02H NVNH 352 809223 \ 2 CF3CO2H NVNH 353 809224 〇N^NH cf3co2h Ding 354 809225 0 n^nh CF3CO2H 1 355 809226 ^ 0 N ^NH 2 CF3C02H I 356 809227 1 0 n^nh cf3co2h 1 357 809228 0 Ν^ν,ΝΗ CF3C〇2H Ding 358 809229 〇~ 2 CF3C02H I 104- 1322807 85762 359 809230 ο ΝγΝΗ i cf3co2h 1 360 809231 丨〇N^ NH CF3CO2H Ding 361 809232 1 〇n^nh cf3co2h Ding 362 809233 0 M n^nh 2 CF3CO2H 1 363 809234 〇n^nh 2 CF3CO2H 1 364 809235 y/^RH CF3CO2H 1 365 809236 &gt; Ο ΝψΝΗ CF3C02H Ding 366 809237 0 N^NH cf3co2h 1 367 809238 H. 〇 NVNH cf3co2h 1 368 809251 1 ΝγΝΗ -105· 1322807 85762

369 809252 H N 丫 NH 370 IC261 〇c^n M N^NH 371 IC375 nh2 M N^NH 372 IC380 nh2 a&gt;-^N H HN NH 373 IC395 HN^〇~\ 0^. M N^NH 374 IC396 N^: n^nh 375 IC400 nh2 H N NH 376 IC401 nh2 fXX)-^n hc, H N^NH -106-

J3228〇7

As described above, the present invention provides novel deazapurines having the formula (I) as described above and in certain classes and subgroups of the present invention. The synthesis of several exemplary compounds is described in detail below. It will be appreciated that the methods as described herein are applicable to the various compounds and their equivalents as disclosed herein. Further, certain reagents and starting materials are known to those skilled in the art. Although the following θ examples describe certain exemplary compounds, it should be understood that the use of materials will facilitate the generation of other types of 85762-107-1322807 covered by the present invention: unless otherwise specified, The reaction mixture was stirred using a magnetic drive to remove the rod. Inert atmosphere refers to either dry argon or dry nitrogen. The reaction system is either by thin layer chromatography or proton nuclear magnetic resonance monitoring of the appropriately treated sample of the reaction mixture. General deficiencies: Unless otherwise indicated, the reaction mixture is allowed to cool to room temperature or lower, and then, if necessary, the reaction is quenched with a saturated aqueous solution of either water or ammonium hydride or sodium bicarbonate. The desired product is extracted by liquid separation between water and a suitable water-immiscible solvent such as ethyl acetate, dichloromethane or diethyl ether. The extract containing the desired product is suitably washed with water followed by saturated brine. In the case where the product-containing extract is considered to contain residual oxidizing agent ι, the extract is washed with a 10% solution of sodium sulfite in a saturated aqueous solution of sodium hydrogencarbonate before the above-mentioned washing procedure. Where the extract containing product is considered to contain a residual acid, the extract is washed with a saturated aqueous solution of sodium bicarbonate prior to the washing procedure referred to above (unless the desired product itself has acidic character) except). Where the product-containing extract is considered to contain a residual base, the extract is washed with a 10% aqueous citric acid solution prior to the scrubbing procedure referred to above (unless the desired product itself has an inspective property) Except in the case). After the washing, the extract containing the desired product was dried over anhydrous magnesium sulfate and filtered. The crude product is then separated by solvent evaporation under reduced pressure and at a suitable temperature (usually below 45 ° C). General Purification Leap Year: 85762 •108· 1322807 Unless otherwise indicated, chromatographic purification refers to flash column chromatography on tannin using a mono- or solvent mixture as the eluent. The extracts containing the desired product which have been properly purified are combined and concentrated to a constant mass under reduced pressure and at a suitable temperature (usually below 45 ° C). Experiments on certain example compounds:

In certain embodiments, Compounds 1 and 2 are made according to the procedures of Temple, C.; Smithy, Β. Η.; Montgomery, J.A.; JOg 1973, 35, 613-5.

NHC02Et Under anhydrous HTC, anhydrous HC1 (gas) was bubbled through a mixture of nitrile (R2-CN) in diethyl ether containing 1 moles of ethanol in EtOAc. After stirring at room temperature for another hour to overnight, nitrogen was bubbled through to remove excess HCl gas and ether. The residual slurry or suspension is filtered, washed three times with ether and then dried under vacuum to give the corresponding ethyl phthalate hydrogen chloride. A mixture of 1 (1 mmol) and ethyl hydrazide hydrogen chloride (1.1 mmol) in 5 ml of ethanol was heated at 65-70 ° C until the reaction was completed (1.5 hours to overnight). The mixture was allowed to cool to room temperature, diluted with 20 mL of water, stirred 30 min. The filter cake was collected and dried under vacuum to give the desired product 3.

A solution of 3 (1 mmol) in 28 ml of 57% m (aqueous solution, 2 mmol) was heated under reflux until the reaction was completed (12-2 hrs). The mixture was cooled to 〇C, slowly diluted with 5 N NaOH solution (19 mmol), then diluted with 1 liter of saturated NaHC 〇3 to pH ～9 ^. The resulting mixture was either ethyl acetate or acetic acid. The ethyl ester/XHP mixture is extracted until the extraction is complete. The combined extracts were dried over Na2SO4, filtered, and concentrated to give the desired product 4 as free. In some cases, if necessary, the product is washed with ethyl acetate to give a better purity. The reaction mixture was cooled to room temperature, filtered, washed with water, and then dried and evaporated and evaporated.

A mixture of 1 (300 mg, L3 mmol) and tetraethyl orthocarbonate (2.6 mmol) in 10 mL of acetic acid was stirred at room temperature overnight and the reaction was completed. The reaction mixture was concentrated with EtOAc EtOAc EtOAc EtOAc. This solid was dissolved in 24 ml of a H20-MeOH (1: hydrazine) solution containing 1.2 g of KOH and heated under reflux for 2.5 hours. After cooling to room temperature, the mixture was extracted with EtOAc. The extract was washed with water, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

A solution of 1 (203 mg, 0.88 mmol) in trifluoroacetic acid (2 mL), EtOAc. ) diluted with EtOAc (10 mL). The separated aqueous phase was extracted with EtOAc (EtOAc)EtOAc. This yellow solid was mixed with 3 ml of polyphosphoric acid, heated at 200 ° C for 3 hours, and cooled to room temperature. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc The combined organic layers were dried with Na2SO4, filtered and concentrated to afford brown brown solid. This solid was dissolved in 5 ml of a 57% HI solution and heated at 110 ° C for 12 hours. After cooling to rt, EtOAc (EtOAc m. The combined organic layers were dried with EtOAc EtOAc (EtOAc m.j. ). 85762 -111 - 1322807

W哚-5-carboxylic acid methyl ester (27 g, 155 mmol) (or its corresponding 4-, 6- and 7-carboxylate), di-tertiary-butyl phthalate (40 g, A mixture of 1.2 eq., Et3N (26 mL, EtOAc, EtOAc) The reaction mixture was quenched by the addition of saturated NaHC03 (350 mL). The separated aqueous layer was extracted once with EtOAc. The combined organics were concentrated and purified EtOAc (EtOAc)

A solution of DIBAL-H in toluene (460 ml) was added at -78 °C over a period of 30 minutes in a solution of 7 (42 g, 152 mmol) in dichloromethane (400 mL). , 3.0 equivalents). The cooling bath was replaced at -40 °C, the reaction mixture was stirred and warmed to -30 °C, and TLC showed the reaction was completed. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. The resulting suspension mixture was filtered through celite and washed with EtOAc until no product was detected. The filtrate was concentrated and the product was purified by chromatography (15%EtOAc elute

85762 -112- 1322807 chloromethanesulfonate (10.1 ml, 1.2 eq.) was added to 8 (27.0 g, 109 mmol, 1.0 eq.) and diisopropyl at 5 °C over 5 min. A solution of ethylamine (57 mL, 3.0 eq.) in dichloromethane (250 mL). After stirring for another 15 minutes, morphine (14.3 ml, 1.5 equivalents, or cyclic or acyclic R'R&quot; NH) was added to the reaction mixture and stirred at room temperature overnight. The mixture was poured into saturated aqueous NaHCO.sub.3 (100 mL) and water (20 mL). The combined organic phases were dried with EtOAc (EtOAc)EtOAc.

Method A: n-BuLi (2.5 Μ, over a period of 15 minutes at -78 ° C in a solution of diisopropylamine (17.0 mL, 1.2 eq.) in THF (350 mL) In hexanes, 48.6 mL, 1.2 eq.), and the mixture was stirred and warmed to room temperature after removal of the cooling bath. The reaction mixture was cooled to -78 °C, and a solution of 9 (32 g, &lt;RTI ID=0.0&gt;&gt; The resulting mixture was stirred and warmed to -20 °C over 15 minutes, then Bu3 SnCl (31.5 liters, 1.15 eq.) was introduced. The mixture was stirred and warmed to room temperature and poured into aq. EtOAc EtOAc. The separated aqueous phase was extracted with 3 x 100 mL EtOAc. The combined organic phases were dried with EtOAc (EtOAc m. 85762 - 113 - 1322807 Method B: This reaction was also carried out in accordance with the same procedure as used for the preparation of 15 from 14.

SnBu3 Boc Compound 11 was prepared from the tri-butyl phthalate-1-carboxylate, 86%, according to the procedure for the preparation of 10 from.

SnBuq 12 Boc R3a R3b Compound 12 was prepared from a mono- or disubstituted 4丨p flower according to a similar procedure for Preparations 7 and 10.

4 (0.4 mmol, 1.0 equivalent, or 2 or 5 or 6), 10 (1.6 equivalents, or 11 or 12) and [(C6H5)3P]4Pd (0.1 equivalent) in degassed DMF (1 ml) The mixture was heated under nitrogen at 60 ° C for 18-28 hours with or without K2CO3 (1.0 eq.), cooled to room temperature and concentrated under high vacuum. The residue was diluted with EtOAc (10 mL)EtOAc. The separated aqueous phase was extracted several times with EtOAc until no product was detected. The combined organic phases were dried over Na2SO4, filtered and concentrated. The product was purified by chromatography (5 % or 10%MeOHEtOAc) 85762 114- 1322807 Compound # -(ER# or IC#) Structure 13 MS (ES) or / and JH NMR IC 400 nh2 HN^NH 'HNMR 806014 HN 丫NH 287.3 (MH)· 806006 nh2 H hn(^ cf3 316.3 (MH)' 805985 nh2 〇cv〇278.3 (M+H)+ 4 夕85762 115- 1322807

85762 -116- 1322807 805895 (IC 405) Η HN丫^ !hnmr 806007 nh2 H HN^N cf3 425.2 (M-Η)' 805976 nh2 H HN^N 'HNMR 805975 nh2 cn〇&gt;^NH 'HNMR 805999 nh2 XHNMR 806011 NH2 Cn〇^N Η HN 丫N 393.3 (M+H)+ 85762 -117 - 1322807

85762 -118- 1322807

8 (5-hydroxymethyl, indole-1-carboxylic acid tert-butyl ester as an example, 24.4 g, 98.8 mmol), Et3N (41 ml '3 equivalents) and DMAP (1.2 g '0.1 equivalents) In a mixture of dichloromethane (185 ml), TBSC1 (23.1 g, 1.5 eq.) was added at room temperature, and the resulting mixture was stirred overnight. The reaction was quenched by the addition of sat. NaHC.sub.3 (200 mL). The combined organics were dried with EtOAc (EtOAc)EtOAc. Methyl)-indole-1-teric acid tri-butyl ester), a colorless oil (33.9 g, 95%).

At 14 (5-tert-butyl-dimethyl-decyloxyindenyl hydrazine-1-carboxylic acid 85762-119-1322807 third-butyl ester as an example, 33.5 g, 92.7 mmol) In a solution of THF (650 ml), tBuLi (63 ml '1.7 Μ, 1.2 eq in pentane) was added dropwise over a period of 45 minutes at a low temperature of -72 ° C. 4 minutes. The resulting brown solution was briefly warmed to -60 °C and then cooled back to below -72 °C. Then, Bus SnCl (31.6 ml, 1.3 equivalents) was introduced into the reaction mixture' and mixed at -40 ° C for 15 minutes. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The combined organic phases were dried with EtOAc (EtOAc) (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Methyl)-2-tributyltinpyridinium-1-resine third-butyl ester) was a colorless oil (60.6 g, 100%).

At 110C and in the mouse atmosphere, '15' (5-(T-butyl-dimethyl-m-m- s- oxymethyl)-2-tributyl decyl hydrazine-1-carboxylic acid · Butyl ester as an example, 60.6 g of '3.0 equivalents' solution in DMF (100 ml), added to 4 (R2 = Me ' 8.51 g, 31.0 mmol), pd (ph3p) in 24 hours over a 24 hour period ) 4 (3 2 g '0.09 eq.) and Et3N (26 liters '3,0 eq.) in DMF (100 mL) with or without &amp; CO3 (1.0 eq.). The resulting mixture was stirred for 20 hours, cooled to room temperature, and concentrated. The residue was diluted with aq. EtOAc (EtOAc) (EtOAc) The aqueous phase 85762 • 120-1322807, which had been separated from the filtrate, was extracted with 6 x 200 ml of Et〇Ac until no desired product was detected by TLC. The combined organic phases were dried over Naz SO4, filtered, and concentrated. The residue was diluted with EtOAc (br.) and EtOAc (EtOAc) The filtrate was concentrated and the residue was purified by chromatography (EtOAc EtOAc EtOAc EtOAc) -Methyl-mercaptooxymethyl)-ih-u5丨嗓-2-yl]-2-methyl-3H-imidazo[4,5-bipyridin-5-ylamine) Green-gray solid (6 86 g, 54%).

A solution of tBuOK in THF (1.66 Μ, 96.3 mL, 9.5 eq.) was added to 16 (by 7-[5-(T-butyl-di-) Methyl-石夕娱乐: ethoxylated fluorenyl)-1Η-Η|11-2-yl]-2-methyl-3H-m oxa[4,5-b&gt;pyridin-5-ylamine As an example, 6.86 g of ' 16.8 mmoles) and a mixture of di-tert-butyl dicarbonate (39 ml, 10 equivalents) in THF (1.1 L). After stirring for 10 min, the reaction was quenched with EtOAc EtOAc (EtOAc) The separated aqueous layer was extracted with 3×150 mL EtOAc. The combined organic phases were dried <RTI ID=0.0>: </RTI> <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; The di-Boc-protected intermediate was then dissolved in THF containing Et3N (55 mL), DIB 〇C (22.5 g, 6.0 eq.) and DMAP (0.21 g, 0.1 eq.) at 65 ° C Heat for 5 hours. After cooling to room temperature, the mixture was concentrated <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> and the product was purified by vacuum chromatography (10% EtOAc-hexanes) to afford a tetra-Boc-protected intermediate. The tetra-Boc-protected intermediate is then dissolved in HF / pyridine in THF (0.89 Μ, 5.3 eq, HF / pyridine solution via 1 gram 70% HF / pyridine, 52.5 pyridine and 330 The mixture was stirred with EtOAc (3 mL EtOAc). The combined organics were washed with brine (5 mL) dried over Nat. -(Third-butoxycarbonyl)amino-tert-butoxycarbonyl-5-hydroxyindenyl-1H-indol-2-yl)-2-methyl-imidazo[4,5-b]pyridine- 3-carboxylic acid tert-butyl vinegar, 5.64 g '48% 'over three steps), as a pale yellow solid.

Gasification of fluorenylsulfonyl hydrazide (014 ml, 15 equivalents) was added to 17 (5-di-(tris-butoxycarbonyl)amino-7-(1_tri-butoxycarbonyl) at 〇 °c _5_hydroxymethyl_ 1H-M丨嗓-2-yl)_2·methyl-imidazo[4,5-b]pyridine_3_carboxylic acid third-butyl vinegar as an example, 830 mg '12 mmol With a mixture of diisopropylethylamine (2 〇 8 mL (1) eq.) in dichloromethane (10 mL), the mixture was stirred and warmed to room temperature. After stirring at room temperature for 7 hours, the mixture was kept at 0 C for two days, warmed to room temperature, and concentrated to one half of its volume. The product was then purified by chromatography (20% to 30% EtOAc / hexanes) to afford &lt;RTI ID=0.0&gt;&gt; (5---(Third-butoxy-oxo)amino-7-(1-tris-butoxy-based 55-methyl fluorenyl, 2-yl-2-yl)-2-methyl- Imidazo[4,5-b]pyridine-3-carboxylic acid tert-butyl ester is an example, 958 mg, 1.38 mmoles in ffiuOH (10 ml), and the resulting mixture is mixed. After 30 minutes, the mixture was diluted with EtOAc (EtOAc (EtOAc) (EtOAc). The separated aqueous phase was extracted with EtOAc (3 mL) EtOAc (EtOAc)EtOAc. 'Providing 20 (2-(3-tert-butylcarbonyl-5-di-(t-butylcarbonyl))amino}f- 3H-imidazo[4,5-b]pyridine-7-yl )-吲哚-1,5·carboxylic acid μ third-butyl ester, 6舛 mg, 69%) »

(mono- or di-) substituted benzyl chloride (or bromide) or bromomethyl hydrazine or chloromethyl pyridine hydrochloride (2 〇 millimolar) with methylamine (22) A mixture of 40% in water (10 equivalents) in Me0H (18 mL) was stirred for 1-5 days ' until the reaction was completed. After concentration, the reaction mixture was diluted with EtOAc EtOAc m. The combined extracts were dried over <RTIgt; 85762 •124· 1322807

The amines 22-26 are made in accordance with the amendments disclosed in the published PCT application WO 01/00610 A1.

Add decanesulfonium chloride (0.80 ml, 1.2 eq.) to 2-(ethyl-phenyl-amino)-ethanol (1.43 g, 8.65 mmol) and diisopropyl at 0 °C. A solution of the ethylamine (3.0 mL, 2.0 eq.) in dichloromethane (10 mL). Then, an ammonia solution (20 ml, 2 Torr in MeOH) was introduced, and the resulting mixture was stirred at room temperature for five days, and concentrated. The residue was diluted with EtOAc (7 mL, 1 N) andEtOAc. The aqueous phase was treated with NaOH (15 mL, 1 N) and extracted with EtOAc. The extract was dried over Na 2 SO 4 , filtered and concentrated to give the product 27 °

Add NaH (1.5) at 〇 ° C in a solution of 2-benzyloxy-propane-1,3-diol (5.0 g, 27.4 mmol) in 5:1 THF-DMF (200 mL) Gram, 2.3 equivalents), followed by methane iodide (5.1 mL, 3.0 eq.). The resulting white slurry 85762 - 125 - 1322807 liquid mixture was stirred at room temperature over the weekend. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. 1-methoxymethyl-2-ethoxymethyl)-benzene (5.6 g, 97%). a mixture of (2-methoxy-1-methoxymethyl-2-ethoxymethyl)-benzene (5.5 g) and Pd(0H)2 (0.4 g) Stir at room temperature under hydrogen until the reaction is complete. Filtration, reaction mixture, and concentration gave 1,3-dimethoxy-propan-2-ol (3.0 g, 96%). Methanesulfonate (0.61 ml, 2.0 eq.) was added to 1,3-dimethoxy-propan-2-ol (0.50 g, 4.14 mmol) and triethylamine at 〇 °C (2.3 ml, 4.0 eq.) in a solution of dioxane (2 mL) and the mixture was stirred for 15 min. The reaction was quenched with saturated NaHC03 and EtOAc was evaporated. The combined extracts were dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in DMSO (10 mL) with Na.sub.3 (0.80 g, 3.0 eq.) and heated at 90 ° C over the weekend. After cooling to room temperature, the mixture was diluted with saturated NaHC03 and extracted with diethyl ether. The combined extracts were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> A mixture of the azide intermediate (320 mg) and Pd(OH)2 in MeOH (15 mL) The reaction mixture was filtered and concentrated to give EtOAc (EtOAc).

29 85762 -126- 1322807 Ethyl-phenyl-amine (4.15 ml '33 mmol), 3-bromopropene (4.3 ml, 1.5 equivalents) and $2C03 (9.1 g '2.0 equivalent) in acetone ( The mixture in 50 ml) was heated under reflux overnight. The reaction mixture was diluted with water (50 mL) andEtOAc. The separated organic phase was dried over NazSO4, filtered and concentrated, and then purified by chromatography (1% EtOAc EtOAc) 100%). Add 〇s〇4 solution (7.8 ml, 0.1 Torr in water, 〇.〇3 equivalent) to allyl-ethyl-phenyl-amine (4.1 g, 25.3 mmol) at room temperature A mixture of hydrazine (5.92 g, 2.0 eq.) in 9:1 acetone-water (40 mL). The mixture was diluted with saturated NaHC 3 (8 mL), sat. Na.sub.2.sub.2.sub.3 (20 mL) and 1:1 Et.sub.2. The separated aqueous phase was extracted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjj -(Ethyl-phenyl-amino)-propane·ι,2-diol (4.25 g, 86%). Methanesulfonyl chloride (2.5 ml, 1.5 eq.) was added to 3-(ethyl-phenyl-amino)·propanone_ι,2·diol at -30 to -35 °C. 4.22 g, 21.6 mmol, and triethylamine (9.03 mL, 3.0 eq.) in dichloromethane (20 mL). The reaction was quenched with EtOAc (EtOAc)EtOAc. The residue was dissolved in MeOH (30 mL) EtOAc (EtOAc) After cooling to room temperature, the mixture was diluted with EtOAc EtOAc m. The combined extracts were dehydrated and dried <RTI ID=0.0>(Na2SO</RTI> <RTI ID=0.0> </RTI> </ RTI> </ RTI> and concentrated, and the product was purified by chromatography (10% Et EtOAc / hexane) - Stupid-amine (172 g, 45%). A solution of ethyl-oxiranylmethyl-phenyl-amine (1.72 g, 9.65 mmol) and NaOMe (1.04 g, 2.0 eq.) in MeOH (8 mL) Over the weekend. After cooling to rt, the mixture was diluted with EtOAc EtOAc EtOAc. The combined extracts were dried with EtOAc (EtOAc m. Oxy-propan-2-ol (1.95 g, 97%). 1-(Ethyl-phenylamino)-3-methoxy-propan-2-ol (1.95 g, 9.32 mmol) with NMO (2.18 g, 2.0 eq.) in dichloromethane (15 mL) The solution was treated with TPAP (150 mg, 0.05 eq.) at room temperature until the reaction was completed. The reaction mixture was diluted with EtOAc EtOAc (EtOAc) The combined extracts are dried over n^sO4, dried and concentrated, and then purified by chromatography (9) to 15% Et0Ac-hexanes to give ethyl <RTIgt; Oxy-propan-2-one (0.98 mg, 51%). '_(Ethyl-phenyl-amino)-3.methoxy-propan-2-one (17 mg '0·08 mmol), hydroxylamine hydrochloride (30 mg) and at room temperature A mixture of pyridine (0.3 mL) in MeOH (0.4 EtOAc) was stirred for 15 hr. The reaction mixture was diluted with aq. NaHC[sub.3] and extracted with EtOAc. The combined extracts were dehydrated &apos;filtered&apos; with Na2S.sub.4 and concentrated. The residue was dissolved in THF (EtOAc) (EtOAc)EtOAc. Work-up and purification by chromatography (2MNH3: CH.sub.2 C. 85762 1322807

30 Compound 30 is prepared according to the procedure for the preparation of 29 from the 3-(ethylphenyl-aminopropane_1&gt;2-diol; the same procedure, from 3-phenoxy-propane-1,2-diol, 21% Total yield.

31 32 Mixture of 3-(bromo-propyl)-benzene or bromomethyl-cyclohexane (1 μ, 1.0 eq.) in MeOH with 40% MeNH2 (60 eq.) in water at room temperature or 45 . (The stirring is carried out until the reaction is completed. After cooling to room temperature, the mixture is concentrated and the residue is diluted with saturated NaHC03 and extracted with 3x CH2C12 (and / or 3x EtOAc). 4 Dehydrated, filtered, and concentrated to give 31 or 32.

NH

I 33 chloromethanesulfonate (〇·8 ml, 1.0 eq.) was added to cyclopentyl-nonanol (1.1 ml '1.0 eq.) and ethyl diisopropylamine (39 ml, 10) Equivalent) in a mixture of (:3⁄43⁄4 (5 ml), and stir the resulting mixture' and warm to room temperature. After adding saturated NaHC03, the separated aqueous phase is extracted with (:3⁄43⁄4, and combined The organic layer was concentrated to give a crude methanesulfonate intermediate. This methanesulfonate was then treated with MeNH2 in the same procedure as for the preparation of 31/32 to obtain 33. 85762 -129 - 1322807

Add TiCU solution (1M, 156 millimolar) to 1,2-diphenyl-ethanone (307 mg, 1.56 mmol); Et3N (655 micron) at 〇 °C升) and a mixture of methylamine (1.02 liter) in THF (5 ml). After stirring for 15 h, a solution of NaBH4 (280 mg, 37.8 mmol) in Me 〇H (8 mL) The resulting mixture was stirred for 2 hours. Then, saturated Na.sub.2 c.sub.3' was added and the reaction mixture was stored in a cold-branched oven overnight. After unwinding, the organic layer was removed and the aqueous phase was extracted with 3xCH2Cl2. The combined organic phases were dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> In a similar manner, 35 and 36 were prepared individually from 2-methoxy-1-phenyl-ethanone and cycloheptanone.

TCA (10 mL) was added to a solution of Boc-de- snails (5 </ RTI> 2.2 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction mixture was stirred for 2 hours and then concentrated. After addition of EtOAc and saturated NaHC03, the reaction mixture was extracted with 3xEtOAc. The combined organic layers were dried with EtOAc EtOAc (EtOAc)

85762 .130- 1322807 phenyl 2,5-dihydro-pyrrole-1-carboxylic acid (2 g, 1 mmol, L〇 equivalent) in acetone/water (9: 1, 20-ml) Within the solution, 〇s〇4 (4% in water, 1 liter) and NMO (2.3 g, 2 〇 millimolar, 2 equivalents) were added. The mixture was stirred overnight at room temperature; smd to remove most of the acetone, which was poured to sat. NaHC. The combined organic layers were dried over <RTI ID=0.0>A2 </RTI> <RTI ID=0.0> The crude mixture was purified by chromatography (7% to EtOAc-hexane) to give phenyl 3,4-dihydroxy-tetrahydropyrroleic acid (2 〇 4 g, 88 % ) 0 , 4--N------------------------ And put it under the taste for 4 hours. The catalyst was filtered through diatomaceous earth and rinsed with Me〇H. Concentration (25 C ) of the mash gave 38 as a reddish oil (840 mg, 1%). /

39 In a suspension of NaH (8.99 g '0.225 mol, 4.6 eq.) in DME (70 mL), slowly add 1,4-dioxo-spiro[4.5]癸-8- at 〇 °C. A solution of the ketone (7.56 g, 0.048 mol, 1.0 eq.) in DME (24 mL). After stirring for 3 minutes, a solution of Mel (14 ml of '0.225 mol, 4.6 eq.) in DME (70 ml) was slowly introduced over 7 hours, and the resulting mixture was slowly warmed to room temperature. Stir overnight. The reaction was quenched by the slow addition of water until no more foaming was observed. The reaction mixture was poured onto ice water and extracted with 3x hexane. The organic layers were combined, dried over MgSO 4 , filtered and concentrated. The crude mixture was purified by chromatography (100% hexanes to remove oil, then 5:1 hexanes ssssssssssssssssssssssssssss 1-Methyl-1,4.dioxa-spiro[4.5]dec-8-one (4.16 g, 40%) 〇: on 7,7,9,9·tetramethyl-1,4-dioxo Snail [4 癸 8-ketone (4 15 g, 〇〇 19 mol, 1 〇 equivalent) in THF (6 mL), ΐΝΗα (3 mL) was added, and the resulting mixture was Stir at room temperature overnight and concentrate to remove most of the hits and extract by overnight AC. The organic layers were combined, dried with EtOAc EtOAc (EtOAc m. In a solution of 2,2,6,6-tetramethyl-cyclohexene], 4_diindole (〇·4〇g, 24 μmol, 里) in THF (8 mL), Add molecular sieves (4 Α, 8 〇 milligrams of 2 在 2 in 2 Μ solution (five) ml, 26 mM, u equivalent) and AC 〇 H (〇.17 ml '3.0 mmol, 12 equivalents). After giving up for $ minutes, add (4) grams of '3,33 millimoles, 14 equivalents) and mix the resulting mixture overnight at room temperature. The reaction was quenched by the addition of saturated NaHC.sub.3. The mixture was then concentrated and the aqueous layer was extracted with 3×EtOAc. The combined organic layers were washed once with saturated NaHC(R)3, dried over EtOAc (EtOAc), filtered, and concentrated to give a crude pale yellow oil which crystallised to give white crystals (yield 4 g, &gt;100%). 40 曱 二 二 & & 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 臭 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正 正In hexanes, 18 mL, 1.4 eq.) and the resulting mixture was stirred for 1 hour. Then, 85762 -132· 1322807 was introduced dropwise into the solution of 1,4-dioxospiro[4.5]decan-8-one (5.0 g, 32 mM '1.0 eq.) in THF (10 liter): The resulting mixture was allowed to warm to room temperature' and allowed to mix overnight. The reaction was quenched by the addition of saturated NaHC03 and the separated aqueous layer was extracted with 4x Et. The combined organic phases were dried over Na 2 SO 4 to &apos;filter&apos; and concentrated. The residue was purified by chromatography (5% to 10% EtOAc / hexanes) to afford &lt;RTIgt;&lt;/RTI&gt; In a solution of 8_methylene-1,4-dioxo-spiro[4.5]decane (2.0 g, 13 mmol, 1.0 eq.) in THF (10 mL), 9_ββν was added dropwise. 0 5 μ '1 〇 4 ml, 4 〇 equivalents in THF, and the resulting mixture was stirred for 15 minutes' then warmed to room temperature and stirred overnight. Next, under the fc, NaB〇4 was introduced in two portions (32 g, 16 equivalents), and the resulting mixture was allowed to warm to room temperature' and stirred overnight, diluted with hexane (3 mL). The separated aqueous phase was extracted with Et〇Ac. The combined organic phases were dried over Na2SO4, dried and concentrated. The residue was purified by silica gel chromatography (5 〇% to 1% 〇% 〇 _ _ hexane) to give (1,4-dioxo-spiro[4.5] 癸-8-yl)-methanol (1.5 g, 67%). (1,4-Dioxo-spiro[4.5]dec-8-yl)-methanol (1·g, 5'8 mmol, 1. 〇 equivalent) with ethyl diisopropylamine (17 ml) , 3.0 eq.) in a solution of dichloromethane (4 ml) (under TC, Msci (〇. 46 mL, 1.0 eq.) was added dropwise, and the resulting mixture was allowed to warm to room temperature. After stirring for 2 hours, the reaction was quenched by the addition of saturated NaHC EtOAc, and the separated aqueous phase was extracted with &lt;RTI ID=0.0&gt; Concentration to obtain crude methanesulfonate sulfonate, 4-dioxo-spiro[4.5]癸-8-yl broth. Under reflux, crude methanesulfonic acid 1,4-dioxos[4_5]癸-8- Base (4 〇〇 Φg) mixture of 85762 • 133- 1322807 in MeOH (2 mL) and MeNH 2 aqueous solution (40% w/w, 5 mL), heated (60 〇c oil) overnight. The reaction was quenched with saturated NaHc.sub.3, and the separated aqueous phase was extracted with 4x dichloromethane and 4x EtOAc. Brown oil.

In a solution of 4-keto-hexahydropyridine-1-carboxylic acid benzyl ester (〇·5 g, 214 mmol, 1 〇 equivalent) in THF (20 mL) at _3 〇 °c Dibromodifluorodecane (0.90 mL, 4.5 eq.) was added followed by HMPA (1.75 mL, 4.5 eq.). The cooling bath was removed and the reaction mixture was periodically vortexed. After 3 minutes, zinc powder (0.63 g, 4.5 equivalents) and HMPA (80 μL, 0.4 eq.) were added and the mixture was heated under reflux for 18 hours. After cooling to room temperature, the residue was washed several times with diethyl ether. The combined ethereal washings were washed successively with a saturated aqueous solution of copper (II) sulfate, brine, dried over Na 2 EtOAc and concentrated. The residue was purified by chromatography (20%EtOAcEtOAc) elute a mixture of 4-difluoromethylene-hexahydrop-Bin-1-Resin (269 mg) and Pearlman's catalyst in methanol (2.5 ml) in a hydrogen atmosphere (using hydrogen filling) Stirring at room temperature for 4 hours. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.

85762 • 134· = Preparation of 41 hearts in the same procedure, 4_difluoroindenyl-hexahydro (tetra) carboxylic acid ^ rhyme (10) mg) using 4 • fluorenyl-hexachloropyridinium acid ^• dimethyl -Propyl ester (500 mg). Liver 4 - benzylidene-hydrogen pyridine small carboxylic acid 2,2_di: propyl vinegar (368 mg) in dichloromethane (10 ml) at room temperature with difluoroacetic acid (TFA ' 〇 _5 ml) treated for u hours. After concentrating the reaction mixture, crude 42 was used directly without further purification.

43. To a solution of 2-aminohexanol (3 50 g, 23 〇 mmol, 1 eq.) in c.sub.2Cl.sub.2 (1 mL), ethyl chloroacetate (2.65 mL, 1.2 eq.). It is an aqueous solution of the heart (: 〇3 (16,0 g, in 2 mL of H2). The mixture is stirred vigorously for 1 hour. The separated aqueous layer is extracted twice with CH2C12. 4 Dehydration and drying, filtration and concentration to give (2-hydroxy-cyclohexyl)-amine methyl acid ethyl ester (4·36 g, &gt; 1%). (2-amino-cyclohexyl) _ Aminoethyl methacrylate (2 〇 6 g, u 〇 mmol, 丄〇 equivalent) in THF (80 mL), LiA1H4 (1 〇 9 g, 28 7 mmol) 2.6 equivalents The mixture was heated at 65 ° C for 2 hours. The reaction mixture was cooled to 0 ° C, the reaction was quenched with water, and the separated aqueous phase was extracted with 3x EtOAc. MgS〇4 was dehydrated and dried, and the residue was subjected to 2-methylamino-cyclohexylase (1.19 g, 84%). 2-Amino-cyclohexanol (〇.204 g, 1.58 m) Mohr, 1.0 equivalent) and two carbon Add a solution of K2C03 in water (1.09 g in 14.0 ml H20) 85762 • 135· 1322807 'and a solution of di-tert-butyl ester (0.422 g, 1_2 eq.) in CH2C12 (7.0 mL) The resulting mixture was stirred vigorously for a few hours. The separated aqueous layer was extracted twice with CH2C12. The combined organic phases were dried with &lt;RTI ID=0.0&gt;&gt; Tri-butyl methacrylate (0.332 g, 92%) » Tris-butyl (2-hydroxy-cyclohexyl)-methyl-amine methyl acid (〇237 g, 1〇3 毫Mole '1.0 eq.) in CH2C12 (7.0 mL), (Molecular sieve (4A, 3 mL) was added under TC. The reaction was stirred for 5 min and then NMO (0.422 g, 3.5 eq.) was introduced. TPAP (0.025 g, 〇.〇7 eq.). The reaction mixture was stirred at 0 C for 5 minutes, then at room temperature for 40 minutes. After diluting with hexane, the reaction mixture was passed through a mixture of chlorhexidine and hexane. To remove %' and then use a 1:1 mixture of hexane-EtOAc to give the desired product. After the 'methyl-(2-keto-cyclohexyl)-amine methyl acid third-butyl ester was obtained as a white solid (0.235 g, 1%). Hexyl-aminomethyl acid tert-butyl ester (〇2〇2 g, 〇89 mM '1.0 eq.) was added to a solution of CH2C12 (3.0 mL). 〇 ml), and the reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated to give 43 (0-285 g, &gt; 〇〇%).

〇-N'H 44 in a solution of cyclopentylamine (5.8 ml, 59 mmol, i 〇 equivalent) in Ch 2 a (25 mL), at room temperature, add ethyl formate (7·3) ML, 13 equivalents), followed by an aqueous solution of Κ2〇〇3 (37 g in 5 mL of Η2〇). The mixture was stirred vigorously for 1 hour. The separated aqueous layer was extracted twice with CH2C12. The combined organic layers were dried with EtOAc EtOAc (EtOAc)EtOAc. UAIH4 (3.08 g, 2.5 equivalents) was added to a solution of cyclopentylamine T-acidic ethyl acetate (6.00 g '32.4 mmol, 1. 〇 equivalent) in thf (250 mL). The mixture was heated at 65 ° C for 2 hours. The reaction was then cooled to 0 ° C and quenched by the addition of water. The separated aqueous layer was extracted with 3x EtOAc. The combined organic phases were dried with EtOAc EtOAc (EtOAc)EtOAc.

46 47 48 Compound 45_58 was prepared according to the same procedure for the preparation of 44 from its corresponding one of the amines.

To a solution of cyclopentanone (25.0 mL &lt;RTI ID=0.0&gt;&gt;&gt;&gt; This reaction was carried out with Dean-Stark and heated under reflux overnight. The reaction mixture was allowed to cool to room temperature &&lt;&gt;&gt; and concentrated to give 1-cyclopentenyl-tetrahydropyrrole (45.8 g, &gt; 1%). Pd(OAc) 2 (0.06 g '〇·〇6 eq), pph3 (0.32 g, 0.24 eq.) and 2-ethoxycarbonyloxymethyl- propyl propyl carbonate (123 g, 53 〇 mmol) Ear, ι·〇 equivalent 'made according to 1998, 54 (49), 14885-14904) in a solution of CH3 CN (30 ml), adding 1·cyclopenta-indole-tetrahydropyrrole (1.01 g) , 1.4 85762 • 137· 1322807 eq.)' and the resulting mixture was heated at 45 ° C for 35 minutes. Then, water (15 ml) was added, and the reaction mixture was heated at 5 y for 1 hour, cooled to room temperature and diluted with EtOAc (30 mL). The separated aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (10% to 15% EtOAc-hexanes) to give 3-methylene-bicyclo[3 21] octane-8 ketone (14 g, 7 %) as pale yellow liquid. Adding ethylene glycol to a solution of 3-methylenebicycloindole and oxime _8-ketone (14 g, 丨〇4 mmol, L〇 equivalent) in benzene (10 mL) 65 g, 16 equivalents) with PTSA (0.01 g '〇〇6 equivalents) ^ This reaction was loaded with Dean_stark and heated under reflux overnight. After cooling to room temperature, Et3N (0.15 mL) was introduced and the resulting mixture was passed through &lt;RTIgt; The filter cake was washed with CH2C12 and the combined filtrate was concentrated to give &lt;RTIgt;3&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; In a solution of 3-indenylbicyclo[3,2,1]octyl ketone acetal ketal (0.21 g, 1.15 mmoles 1.0 equivalent) in CH2Cl2 (2 mL) at _78° At C, 〇3 was bubbled until the reaction remained blue (about 3: minutes). The 〇3 foaming was stopped and the reaction mixture was stirred at -78 °C for 5 minutes. The reaction was quenched by the addition of triphenylphosphine (0.43 g, 1.4 eq.) and stirred at -78 °C for 10 min. The reaction mixture was allowed to warm at room temperature &apos; stirred for 40 min and concentrated. The residue was purified by silica gel chromatography (10% to 15% EtOAc-hexanes) to afford to give the the the the the the the the the the the the the the (〇.〇8g, 40%).

In a solution of bicyclo[3,2,1]octyl-3,8-diethyl ketal (53.1 mg, 0.27 mmol) (1.0 eq.) in THF (1.0 mL). (:, Add Et3 N 85762 -138-1322807 (ol 1 liter, 2.9 eq.), followed by MeNH2 (2 〇M in THF, 〇21 ml '1.5 eq.) 5 after stirring at room temperature for 5 minutes , 11 (::14 (〇3〇爱升, 10.0 equivalents) was introduced dropwise, and the resulting mixture was stirred for 45 minutes under 〇〇c. Then 'NaBH4 (53.1 mg '51 equivalents) was introduced at Me〇 A solution of H (2.0 mL), and the resulting mixture was stirred and stirred for a few hours. The reaction was quenched with saturated NaHC EtOAc, and the separated aqueous layer was extracted with 3x Et EtOAc. The organic phase was dried over MgS(R) 4, filtered, and concentrated to give the crude product &quot; 3-methylamino-bicyclo[3,2,1] sin&lt;8&gt; 3-Methylamino-bis-glycol[3,2,1]oct-8-S with ethyl hydrazide (94.5, 0-48 mmoles 1.0 equivalent) in acetone (2.0 mL), 1N was added Hci (15 ml) and the reaction was taken up in A &gt;jbl overnight. The reaction mixture was neutralized with saturated NaHC03 until pH was above 7 and extracted with 3x Et0Ac. Water was dried, filtered, and concentrated to give 49 (4 〇 〇 mg, 54%).

(3,3-Methyl-1,5--oxo-spiro[5,5]H -9-| )-methyl-amine hydrochloride gram '4 mmol, 1.0 eq.) To a solution of THF (12 mL) was added di-tert-butyl dicarbonate (U mL 'L2 eq.), triethylamine (2 mL) and dmap (catalytic amount). The resulting mixture is at 90. (The mixture was heated for 6 hours, cooled to room temperature' was poured into saturated NaHC(R)3, and the separated aqueous layer was extracted with 3xEt?Ac. The combined organic layers were dried over Na2SO4, dried and concentrated. The residue was purified by silica gel chromatography (10%EtOAc /hexane) to afford (3 3 dimethyl-1,5-dioxo-spiro[5,5]undec-9-yl)-methyl-amine Methyl acid third vinegar (14 g, 85762 -139-1322807 91%), as a white solid. (3,3--methyl-1,5-dioxo-spiro[5,5] eleven- 9-yl)-methyl-aminomethyl acid third-butyl ester (1.27 g, 3.63 mmol, 1. 〇 equivalent) in a solution of acetone (4 〇 ml) and water (2 〇 ml), PPTS (228 mg, 〇 25 eq.) was added and the mp EtOAc was evaporated. EtOAc m. The organic layer was dried over NazSO4, filtered, and concentrated. EtOAc EtOAc Third acid butyl ester (735 mg, 88% , as a white solid. Methyl-(4-keto-cyclohexyl)-amine methyl acid tert-butyl ester (〇.69 g, 3 〇 4 mmol, 1.0 eq.) in THF (25 mL) In the solution, add CBi*2F2 (1_25 ml, 4.5 equivalents), then slowly add p(N(CH3)2)^ to warm the mixture to room temperature for 5 hours. And Zn was introduced. The resulting mixture was stirred under reflux for 16 hours, cooled to room temperature, and diluted with EkO. The organic phase was decanted, and the aqueous phase was extracted with 2 χΕ 2 。. The combined organic phases were saturated with CuS. The 〇4 solution was washed until it was kept in a blue color, dried over Na 2 S 〇 4, filtered, and concentrated. The residue was purified by chromatography (2 〇% Et 〇Ac hexane) to obtain (4-difluoromethylene) Methyl-cyclohexyl)methyl-amine methyl acid tert-butyl ester (475 mg '60%) as a white solid. (4-difluoromethylene-cyclohexyl)-methyl-amine methyl acid To a solution of the third butyl ester (15 mg, 0.57 mmol, U), EtOAc (EtOAc) The reaction mixture was stirred for 4 hours and then concentrated to give 50 (85 mg). The crude compound was taken to the next step without further purification. 85762 -140- ' 51 ' 511322807 Η .Ν.

χ HCI is added dropwise to the solution of cyclopropylamine (5.0 g, 87. 5 mmol) and triethylamine (30 ml) in dichloromethane (100 mL) at 0 ° C Ethyl formate (15.0 mL, 10.5 mmol) was added and the resulting mixture was stirred for 2 h. Additional benzyl chloroformate (1 mL) was added and the resulting mixture was stirred overnight. Then, the reaction was quenched by the addition of saturated NaHC03, and the separated aqueous phase was extracted with dichloromethane several times. The combined dichloromethane extracts were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (EtOAc EtOAc EtOAc EtOAc Add NaH (2.20 g) at 0 ° C in a solution of cyclopropyl-amine methyl decanoate (11.8 g) and methane iodide (excess) in THF (80 mL) and DMF (20 mL) , 91.6 mmol, and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by saturating NaHC03 at 〇 °C. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 20% EtOAc /hexane) A mixture of cyclopropyl-indolyl-amine methyl decanoate (10.7 g) and Pd(OH) 2 in MeOH (100 mL) was stirred at room temperature under H2 gas for 17 hr. (4.8 ml) was diluted, filtered through celite, and concentrated. The residue was azeotroped several times with toluene to give cyclopropyl-indolyl-amine hydrochloride (51, 5.75 g). This crude material was used without further purification. 85762 -141 - 1322807 r&gt;JNH'H, 52 (tetrahydro-indol-3-yl)-methanol (1.00 g, 9.79 mmol, io equivalent), PPh3 (3.85 g '1.5 equivalent) and imidazole ( 1.33 g '2.00 eq.) In a solution of CH2C12 (15 mL), 12 (3.73 g, 1.5 eq) was added at 0 ° C, and the resulting mixture was stirred at 0 ° C for 30 min. Then at room temperature for 30 minutes. The reaction mixture was diluted with aq. sat. Na.sub.2SO.sub.3. The combined extracts were dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Gram, 76%). 3-Iodomethyl-tetrahydro-furan (5 mg, 2.36 mmol, 1.0 eq.) with MeNH2 (40% in H.sub.2, 1.62 mL, 8.0 eq.) in MeOH (1 mL) The mixture was heated at 60X: for 3 hours. After cooling to room temperature, the reaction mixture was diluted with an excess of Et3N and concentrated. This method was repeated until it was impossible to detect MeNH2 by 1 H NMR. This residual yellow oil (52) was used directly without further purification. /NH HCI 53 In a solution of 1-methoxymethyl-propylamine (2.50 g, 24.3 mmol, 1.0 eq.) in dioxane (15 mL), aq. H2〇)) and allowed the mixture to cool to 0 °C. Then, CBZ-C1 (4.16 ml '1.2 eq.) was introduced, and the resulting mixture was warmed to room temperature, and stirred for 3 hr, and extracted with EtOAc. The combined organic phases were dried over Na 2 S.sub.4, filtered and evaporated. The residue was purified by chromatography (hexane to 40% EtOAc /HHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .

(i-methoxymethyl-propyl)-amine methyl decanoate (4.4 g, 18.5 mmol, 1.0 eq.) with Mel (6.9 mL, 1 Π mmol, ό equivalent) in THF/DMF In a solution of (4: 1 '50 ml), add NaH (1 35 g, 55 5 mmoles 3 equivalents) slowly under 〇〇c. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was carefully quenched by slowly adding water until no foaming (H2) was found. The reaction mixture was poured onto ice water and extracted with 3×EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (3% to 5% EtOAc-hexanes) to afford (l-methoxymethyl-propyl)- decyl-amine methyl benzyl ester (4 g , 94%) β (1-methoxymethyl-propyl)-methyl-amine methyl decanoate (4 4 g, 17 5 mmoles 1·0 eq.) in MeOH (30 mL) Palladium hydroxide was added to the solution, and the resulting mixture was stirred at room temperature under h 2 for 15 hours. Then, the mixture was filtered through celite and washed with Me 〇H. The filtrate was treated with EtOAc (1 mL), EtOAc (EtOAc) This compound was confirmed by 1H NMR. The crude compound was used in the next step without further purification.

Compound 54 was prepared from benzyl (1-nonyl-2-#i-ethyl)-amine methyl methacrylate according to the same procedure as for steps 2 and 3 of Preparation 53. 85762 • 143- 1322807

TFA 55, (Nitrate methyl 2 #工基·ethylmethyl-amine methyl decyl ester was prepared according to the same procedure as in Step 2 of Preparation 53 from (tetra)hexylf-yl-yl-ethyl)-amine Methyl acid Yu Yu. Then, A, Tian, and Mann were treated with (1 -cyclohexylmethyl 2 -hydroxy-yl)-methyl-amine methyl acid as an espresso: ^ for 4 hours. The mixture was then concentrated to obtain 55.

TFA 56 is in (R)-(-)· ketamine (2.0 g, 17 mmol, 1 〇 equivalent), Et3N (36 mL, 1.5 eq.) and DMAP (1 〇 mg) in the stomach (2 ml) In the solution, BOC2(R) (4.5 g, 1_2 equivalent) was added at room temperature. After stirring for 5 hours, the reaction was quenched by water and the separated aqueous phase was extracted with a 4x chain. The combined organic phases were dried over NaaSO4, dried and concentrated. The residue was purified by chromatography (20% to 30% EtOAc / hexanes) to afford (1 - decyl - 3 - methyl - butyl) amine methyl acid tri-butyl ester (1.9 g, 53 %). This compound was confirmed by iH NMR. Compound 56 was prepared from (丨-hydroxyindole-3-methyl-butyl)-amine methyl acid tert-butyl ester according to the same procedure as for the preparation of 55.

85762 -144- 1322807 Add methyl hydrazone (1M in THF) (120 mL, 3.5 eq.) to 4·yl-cyclohexanone (cis/reverse mixture) at -78 °C (5_00 g, 1 eq.) in THF (350 mL). After stirring at -78 °C for 45 minutes, the cooling bath was removed, and the resulting mixture was allowed to warm to room temperature and stirred overnight. After a total of 24 hours, the resulting reaction mixture was poured into ice/water (8 (8) mL). This mixture was stirred vigorously. The separated aqueous phase was extracted with MeOH / EtOAc (~ 1 / 20). The combined organic layers were dried over Naz S04, filtered and concentrated. The crude product was purified by chromatography (50% to 100%EtOAcEtOAc) elute 1-(4-Hydroxy-cyclohexyl)-ethanone (2.24 g, 1 equivalent), toluene (160 ml), neopentyl glycol (1.96 g, 1.2 eq.) and pTsOH (150 mg, 〇.〇 5 equivalents) The mixture was heated to reflux overnight in a flask equipped with a Dean-Stark apparatus. The mixture was allowed to cool to room temperature and concentrated. The crude product was purified by column chromatography (25% to 5% EtOAc / hexanes) to afford 4-(2,5,5-trimethyl-[1,3]dioxyindole-2- Base)-cyclohexanol (2.23 g, 62%). TPAP (161 mg, 0.05 eq.) was added to 4-(2,5,5-trimethyl-[1,3]dioxoindolin-2-yl)-cyclohexanol (2.22 g, 1 eq.) IsjMO (2.28 g, 2 equivalents) in a solution of MeCN (65 mL). The reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of Na S2O3 was added to the mixture, and the resulting mixture was stirred vigorously for 15 min. The separated aqueous phase was extracted with CH2C12. The combined organic layers were dehydrated and dried with Naz SO# filtered through Celite, and concentrated. The crude product was purified by column chromatography (25% to 50%EtOAc / hexane) to afford 4-(2,5,5-trimethyl-[1,3]dioxaindole-2-yl) - cyclohexanone (〖. π g, 85%). Compound 57 was prepared according to the procedure for the preparation of 34 from 1,2-diphenyl-ethanone from 4_85762 -145-1322807 (2,5,5-trimethyl-[1,3]dioxane-2 -yl)-cyclohexanone. -"){~!)~n, h or CF3C02h cf3co2h 58 59 in (3,3-dimethyl-1,5-dioxo-spiro[5,5]undec-9-yl)-methyl- Addition of amine hydrochloride (6.9 g, 27.6 mmol, 1.0 eq.), Et3N (15 mL, 4.0 eq.) and DMAP (catalytic) in THF-MDF (1:1,100 mL) Di-tertiary-butyl phthalate (7.6 ml, 1.2 eq.), and the resulting mixture was heated at 90 ° C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with saturated NaHC03. The separated aqueous layer was extracted with 2x EtOAc. EtOAc (EtOAc) (3,3-Dimethyl-1,5-dioxo-spiro[5,5]undec-9-yl)-methyl-amine methyl acid tert-butyl ester as a white solid ( 9.53 g, 99%). At 3 C, '(3,3-dimercapto-1,5-dioxo-spiro[5,5]undec-9-yl)-methylamine decanoic acid Tri-butyl ester (9.53 g ' 27.2 mmol> 1. 〇 equivalent) and ppTs (2.1 g, equivalent) in acetone-water (2: 1 '500 mL), heated 18 Hour 'cooled to room temperature, and concentrated to remove acetone. The residual aqueous solution was diluted with NaHC 〇 3 and extracted with 2x EtOAc. The combined organic layers were dried with EtOAc EtOAc EtOAc. The product was purified by chromatography (2% to 5% EtOAc / hexanes) to afford methyl-(4-g- yl-cyclohexyl)amine methyl acid as a white solid (5.38 g). , 87%). A solution of methyl-(4-keto-cyclohexyl)-amine methyl acid tert-butyl ester oxime 34 mg, 〇59 亳mol, 1.0 eq. in CH2C12 (0.5 mL) Inside, at room temperature 85762-146- 1322807, add (] \^0012012) 2? 3 (217 μl, 2.0 equivalents), followed by ethanol (1 〇 microliter '0.3 equivalent -). After that, the reaction was quenched by the addition of saturated NaHC 〇3, and the mixture was stirred until the gas evolution was stopped. The separated aqueous phase was extracted with CH 2 Cl 2 , and the combined organic extracts were dried over Na 2 S04, filtered, and Concentration. Purification of the crude mixture by chromatography (5% to 1% Et〇Ac / hexane) to give (4,4-difluoro-cyclohexyl)-methyl-amine methyl acid tert-butyl ester a mixture with (4-difluoro-cyclohex-3-enyl)-methyl-amine methyl acid tert-butyl ester. The mixture of this product in CHZCl2 (1.5 ml) at room temperature Trifluoroacetic acid (1.5 ml) was added, and the resulting mixture was stirred for 25 hours and concentrated to give a mixture of 58 and 59 (2:1 ratio by H1 - NMR).

In a solution of 3-chloro-2-yl-methyl-1-propene (2 〇. gram, 160 mmol, 1. 〇) in THF (40 mL). Under the arm, NaOMe (100 ml of 25% solution in methanol, 2.8 eq.) was added. After the cooling bath was removed, the reaction mixture was stirred at room temperature for 20 hours and at 35T: 20 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The filtrate was concentrated by distillation of the ether 'THF and EtOH' under atmospheric pressure to give a pale-yellow liquid residue, and the residue was obtained to give 3-methoxy-2-methoxymethyl-1-propene (8.9). Gram, 43%). Boiling point = 12 (M30 °C.

In a solution of 3-nonyloxy-2-methoxymethylpropene (3.5 g, 30 mmol, 1.0 equivalent) in THF (10 mL). (:, BH3 · THF (1M 85762 -147 - 1322807 'in THF '18 ml, 0.6 eq.) was added, and the resulting mixture was stirred for 4 Torr. With water, #过过硼硼(1〇 6 g, 2.3 eq.) The reaction was quenched and allowed to warm to rt overnight. EtOAc EtOAc EtOAc (EtOAc). The extract was dehydrated and dried with Na2S〇4, and filtered. The filtrate was evaporated under atmospheric pressure to obtain a pale yellow liquid residue. The residue was fractionated at 4 Torr to give 3-methoxy-2-methoxy Methyl propyl-1-alcohol (L93 g, 48%). Boiling point = 90-li 〇 ° C. In the alcohol 3-methoxy-2-methoxymethyl propyl hydrazine - 丨 _ 〇克, 6.7 mmol, 1: 0 eq.) In a solution of CH2C12 (10 mL), Et3N (19 mL '2·0 eq), then MsCl (0.63 mL, 1.2 eq. After stirring for 40 minutes, the reaction was quenched with decylamine (4% in water). After the reaction mixture was concentrated at room temperature, the residue was taken from methanol (2 ml) with methylamine (3) Dilute, 40% in water) diluted, heated at 5 ° C for 18 hours, cooled to room temperature, saturated with NaaCO 3 and extracted with ether. The combined extracts were dried over Na 2 S 〇 4 and filtered. The filtrate was distilled under atmospheric pressure to give a crude product 60 (0.78 g, &lt;

MeO&quot;&quot; < . CF3CO2H 61 in trans-4-amino-cyclohexanol hydrochloride (5·g, 32.9 mmol, 1.0 eq.) in water (80 ml) and THF (60 ml) In the solution, NaHC03 (6.4 g '2.3 equivalents) and (B〇c) 2 〇 (14.8 ml '2.0 equivalents) were added at room temperature. After stirring for 48 hours, most of the THF was removed from the reaction mixture by concentration and taken to 85762 -148 - 1322807

The aqueous residue was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and then poured. The crude product was crystallized from EtOAc-hexane (9:1) toield (4-di-hydroxy-cyclohexyl)-amine methyl acid tris-butyl ester (5.2 g, 75%). (4-trans-hydroxy-cyclohexyl)-amine methyl acid tert-butyl ester (3.0 g, 13.9 mmol, 1.0 eq.) and methane iodide (4.3 ml, 5.0 eq.) in N-fluorenyl 60% NaH (1.67 g, 3.0 eq.) in mineral oil was added to the solution in -2-tetrahydropyrrolidone (NMP) (50 ml) at 0 ° C in controlled fractions. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by silica gel chromatography (20% EtOAc / hexanes) to afford (4-trans-methoxy-cyclohexyl)-methyl-amine methyl acid tri-butyl ester (3-25 g, 96 %). a solution of trans-(4-methoxy-cyclohexyl)-methyl-amine methyl acid tert-butyl ester (445 mg, 1.83 mmol, 1.0 eq.) in CH.sub.2. Trifluoroacetic acid (2 mL) was added at room temperature. After stirring for 2 hours, the reaction mixture was concentrated to give 61 (685 mg, 145%, with residual TFA). 1 H NMR confirmed this structure and used this product without further purification. Alternatively, compound 61 can be made according to the following pattern:

CH2C12 90%

Thus, under appropriate conditions (e.g., TPAP, NM0), the oxidation of 4-methoxycyclohexanol in a suitable solvent (e.g., dichloromethane) affords its corresponding 85762 - 149 - 1322807. Reductive amination of 4-methoxycyclohexyl copper under suitable conditions (eg dimethylamine, NaBH (〇Ac) 3 , AcOH in THF), which results in good stereoselectivity (ie trans) The corresponding amine 61. ΗΟ~^~~^-ΝΗ· CF3C〇2H 62 in methyl-(4-keto-cyclohexyl)-amine hydrazinoic acid III_丁自((About preparation of the intermediate with 59, 580 gram) , 2.56 mmol, 1 〇 equivalent) in a suspension in THF (8 mL), at -78t:, LS-selective (M-solution in THF, 5.7 mL '2.2 eq) . After stirring for 2.5 hours, the reaction mixture was allowed to warm to 0 C and stirred for 30 min. The reaction was quenched with EtOAc (EtOAc) EtOAc (EtOAc:EtOAc) The crude mixture was purified by silica gel chromatography (33% to 50% EtOAc) eluted to afford s. Compound 62 was prepared according to the same procedure as that for the preparation of 61 from (4-trans-hydroxy-cyclohexyl)-amine methyl acid-tri-butyl ester from (4·cis-hydroxy-cyclohexyl)-methylamine A. Third acid butyl ester

MeO Οτ 63 a solution of (4-cis-hexyl*cyclohexyl)-methyl-amino hydrazinoic acid tert-butyl ester (1.95 g '8-52 mmol, 1.0 eq.) in DMF (2 mL) Then, under 〇t&gt;c, NaH (559 mg, 2.5 eq.) was added. After stirring for 1 Torr, cesium iodide (3.9 liters, 7, 6 eq.) was introduced, and the ice bath was removed. After stirring at room temperature for 5 hours, the reaction was quenched with methanol (1.5 liters), stirred for 15 min and diluted with &lt;RTI ID=0.0&gt;&gt; The mixture was extracted with Et0Ac_hexane (1: hydrazine). The combined organic extracts were dried over Naz sq4, filtered, and concentrated. The crude mixture was purified by crystallization (10% to 25% EtOAc/hexanes) to afford (4- cis-methoxy-cyclohexyl)-methyl-amine methyl acid tri-butyl ester (1.73 g) , 84%). In a solution of (4-cis-methoxy-cyclohexylmethyl-amine methyl acid tert-butyl phthalocyanine, 7.12 mmol, 1. 〇 equivalent) in ml) at room temperature Next, trifluoroacetic acid (4 ml) was added. After stirring for 3.5 hours, the reaction mixture was concentrated to give a crude material. This product was dissolved in CH2C12 (5 mL). The aqueous layer was back-extracted with 5xCH2C12. The combined organic extracts were dried with EtOAc EtOAc EtOAc (EtOAc).

18 (0.01-0.1 Μ '1.0 eq.), diisopropylethylamine (5·〇 equivalent) and any of the amines from 21-63 or other commercially available secondary or secondary alkyl amines ( 3_1 〇 equivalent) of the mixture in dichloromethane at room temperature or 4 (TC, stirring for several hours to five days until the reaction is completed. The reaction mixture is concentrated and the intermediate product, whether by or not Purified by chromatography (EtO Ac / hexanes) in 1:1 mixture (0.05 M) of dichloromethane and trifluoroacetic acid, with or without toluene ether (5-10 eq.) Stir for 3-4 hours until the reaction is complete. Then carefully quench the reaction with saturated NaHC03 and extract with EtOAc until no product is detected. The combined extracts are taken from Na2S04 to 85,762. Dry, filter, concentrate, and purify the product 64 by reverse phase HPLC (MeOH-water).: The following procedure has been used for aromatic amines (RF and / or Rg = At). N-ethylaminobenzene (47 μL, 6 equivalents) in a solution of THF (1 mL), at -78 ° C, n-BuLi (148 μL, 2.5 Μ, at In the alkane, 6 equivalents, followed by hydrazine (200 liters), and stirred for 10 minutes. A solution of 18 (44 mg, 0.062 mmol) in THF (0.7 mL) After stirring for 10 min, EtOAcqqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ The intermediate was obtained. This intermediate was dissolved in 1:1 (1 mL) of dichloromethane and trifluoroacetic acid (2 mL) and stirred at room temperature for 3 hr. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc.

Diisopropylethylamine (1.6 eq.) was added to a solution of 20 (0.03-0.05 Μ, 1.0 eq.) and TOTU (1.5 eq.) in DMF at room temperature and stirred for 15 min. To the resulting mixture, any of the amines from 21 to 63 or other commercially available mono- or secondary amines (1.5 equivalents) are added. The reaction mixture is stirred for several hours to overnight until the reaction is complete. The reaction mixture was concentrated, 85762 - 152 - 1322 </ br> and the intermediate product, either purified by chromatography (EtOAc / hexanes), dissolved in 1:1 mixture of dichloromethane and trifluoroacetic acid (0.01- In 0.05 M), and stirring at room temperature with or without Phenylphenyl ether (5-10 equivalents) for 3-4 hours until the reaction is completed. The reaction was then quenched carefully with sat. NaHC.sub.3, and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated, and then purified from EtOAc. The compounds in the table below were prepared according to the preparation of 13 or 64 or 65. 85762 153- 1322807 Compound # · (ER# or ic.#) Structure 64 or 65 MS (ES) or / and JHNMR 806094 nh2 TBS0^C〇^n H ^ NMR 806095 nh2 H0^C0^n Η HN 丫N nmr 806123 nh2 o^o&gt;-^n H ΝγΝΗ 361.4 (M+H)+ 806136 404.3 (M+H)+ 806181 nh2 Η ΝγΝΗ 'HNMR 806221 HN^H 413.3 (M+H)+ 85762 -154- 1322807 806220 465.3 (Μ+Η)+ 806224 Jo H 丫Η 409.3 (Μ+Η)+ 806228 νη2 kj 丫Η 412.3 (Μ+Η)+ 806276 νη2 Μβ〇ν ΎΝΗ MeO 1 471.3 (Μ+Η)+ 806275 :^^α ^Η2 MeO Ν^ΝΗ 487.3 (Μ+Η)+ 806274 〇r^〇y^H2 Η ΝγΝΗ 397.3 (Μ+Η)+ 806273 νη2 kj 丫Η 411.3 (Μ+Η)+ 806317 νη2 kji 丫Η 398.2 (Μ +Η)+ 85762 -155- 1322807 85762

-156-

1322807 85762

-157- 1322807 806402- σΛ^^Η2 Η NyNH 411.2 (Μ+Η)+ 433.2 (M+Na)+ 806417 X /Η2 Η ΝγΝΗ 397.1 (Μ+Η)+ 806419 Ώ νη2 469.2 (Μ+Η)+ 806421 1.2 Η Η 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 〇??: 495.3 (Μ-Η)' 85762 -158- 1322807 85762

-159- 1322807 85762

-160- 1322807 806874 Η H νη L〇JH 'HNMR 806875 H ^V°〇NH 1 1 H 〜\ΝΗ lHNMR 806878 HN 丫NH ^NMR 806899 ΡΌν〇ΝΧ〇&gt;^:2 〇HN^NH T 丄HNMR 806900 nh2 〇HN 丫NH 'HNMR 806901 fJO^O^O^2 〇HN丫NH 497.1 (M+H)+ 806902 nh2 〇HN 丫NH 377.3 (M+H)+ 85762 161- 1322807 806903- Cl ML·! Η N^NH 431.1 (M+H)+ 806904 nh2 HN^NH 431.2 (M+H)+ 806905 nh2 H Ν^,ΝΗ 431.2(M+H) 十806987 HN^NH 441.3 (M+H)+ 463.2 ( M+Na)+ 807014 H ΝγΝΗ 343.3 (M+Na)+ 807139 OMe H Ν^,ΝΗ 'HNMR 807140 NH2 H ΝγΝΗ 427.3 (M+H)+ 807183 MeO 0 kju H ΝγΝΗ 463.3 (M+Na)+ 441.3 ( M+H)+ 85762 162- 1322807 85762

Me〇 nh2 427.2 (M+H)+ 807240' H N丫NH

807377 nh2 HN^NH 'Η NMR 807392 nh2 F3CTXr^〇v^^ HN 丫'NH 'Η NMR 807400 nh2 HN^NH 'HNMR 807401 H NH2 1 HH NVNH trans-racemic γ !hnmr 807399 Η ΝΗ2 CDX〇^ n Η Η ν7;νη cis-racemic γ 'Η NMR 807447 ar^〇v^NH2 Η Ν 丫ΝΗ 'Η NMR 807448 νη2 &quot;1 Η Ν^ΝΗ ιΗ NMR 807449 νη2 lHNMR -163- 1322807 807450 nh2 ocf3 h N 丫Vih 481.1 (M+H)+ 807451 nh2 HN^NH 481.1 (M+H)+ 807452 nh2 Cl HN 丫NH 465.1 (M+H)+ 807453 nh2 Η Ν^,ΝΗ 'HNMR 807454 nh2 FHN^NH 'HNMR 807457 HN^NH 'HNMR 807458 cf3 nh2 (X'XCV^NH n^nh T = aHNMR 807459 nh2 Cl HN 丫, NH 'HNMR 807460 ρ3〇〇nh2 HN^NH 481.1 (M+H)+ 85762 -164 - 1322807

807460 nh2 1 H ΝγΝΗ 'HNMR 807463 nh2 HN 丫, NH 'HNMR 807464 nh2 HN^NH {HNMR 807465 〇i Γ2 HN 丫NH !hnmr 807466 nh2 HN^NH 丄HNMR 807467 nh2 HN 丫NH 'HNMR 807469 nh2 HN^NH 'HNMR 807497 nh2 THN^NH 'HNMR 807498 nh2 HN 丫NH aHNMR 85762 -165- 1322807

807505 nh2 ]HNMR 807506 'H NMR 807528 ▲HNMR 807531 nh2 Η Ν^,ΝΗ ahnmr 807532 nh2 H ν^,νη ahnmr 807543 nh2 CrX〇v^N kj H 丫H 'HNMR 807544 nh2 kj H 丫'HNMR 807548 nh2 ( Τ&gt;Ό&gt;^ν CN HN 丫NH 'HNMR 807549 H n^nh XH NMR 85762 -166- 1322807

807550 Η Ν^ΝΗ 'HNMR 807562 νη2 〇Η ΝτΝΗ 'HNMR 807571 νη2 ncJX-Xcv^n Η Ν^ΝΗ 'HNMR 807573 νη2 CTr^Ov^N Η 丫 丫, ΝΗ 387.3 (Μ+Η)+ 807586 °ΤΊ / ΝΗ^ Η Ν^ΝΗ 'HNMR 807636 νη2 0^X0·^ Η Ν 丫ΝΗ 'HNMR 807649 C1 /ΝΗζ Η ν 丫ΝΗ 'HNMR 807660 Η Ν^ΝΗ 'HNMR 807662 νη2 Η Ν^ΝΗ lHNMR 85762 •167· 1322807

807663 丄"H Ν^,ΝΗ aHNMR 807703 nh2 HN^NH 'HNMR 807704 nh2 HN^NH [HNMR 807748 nh2 HN 丫, NH 'HNMR 807749 nh2 H nvnh T 'HNMR 807751 H n^nh 'HNMR 807754 ar〇&gt ;^2 H n^nh 'HNMR 807758 α'Ό&gt;^Ν&quot; H Ν^,ΝΗ 'HNMR 807762 HN 丫'NH 'H NMR 85762 -168· 1322807

HI 807 ^ ΝΗ ΝΗ ΝΗ H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H HNMR 807876 νη2 HCI Η Ν^ΝΗ Τ 丄HNMR 807892 νη2 F2HCxro&gt;^ Η Ν^ΝΗ 'HNMR 807920 ο人广1 ΝΗ2 -Xcv^N· Η 丫 丫,ΝΗ 'HNMR 807930 νη2 hojOXcv^n Η Ν^ΝΗ ^ NMR 807931 νη2 OH Η Ν 丫ΝΗ lHNMR 85762 -169- 1322807

807 NH 」 NH NH NH NH NH NH H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H 'HNMR 808028 0^1 ΝΗ2 Η ν^νη 'HNMR 808039 νη2 Μ Ν^ΝΗ 'HNMR 85762 •170· 1322807

HF 808 H H 'HNMR 808078 νη2 F Η ΝγΝΗ 'HNMR Η Ν^/ΝΗ 'HNMR 808102 Η Ν^ΝΗ 'HNMR 808107 νη2 Η Ν^ΝΗ 丄HNMR 85762 171 - 1322807

808151 Λ /ΝΗ2 Η Ν^ΝΗ 'HNMR 808153 νη2 CTr^〇&gt;^ Η Ν^ΝΗ 'HNMR 808164 Π /ΝΗ2 hXcv^n Η 丫ΝΗ 丫ΝΗ 'HNMR 808247 MeO/, η Η2 Η Νγ;ΝΗ 丄HNMR 808254 /〇νι νη2 U Η Ν丫ΝΗ 'HNMR 808255 νη2 kj Η ΝΙ 丫ΝΗ lH NMR 808283 CF3CO2H Η ν^νη 'HNMR 808290 °rV〇&gt;^ Η Ν 丫ΝΗ ^NMR 85762 -172- 1322807

85762 -173- 1322807

808371 nh2 HN^NH 'HNMR 808387 nh2 CF3C02H Η ΝγΝΗ 'HNMR 808548 nh2 ij〇Q-^0N HN^NH 'HNMR 808661 HN^NH 'HNMR 808663 σ w HN?NH !hnmr 808665 o, H Νγ,ΝΗ 'HNMR 808675 HI HN 丫'HNMR 808702 θθΓ0&gt;^Η2 H n^nh ^NMR 85762 -174- 1322807

Diethyl azodicarboxylate (9.1 μL, 2.0 eq.) was added at room temperature to 17 (20 mg, 0.03 mmol, 1.0 eq.), triphenylphosphine (15 mg '2.0 eq) and To a solution of phthalimin (8.5 mg, 2.0 eq.) in toluene (2 mL). The reaction mixture was concentrated and the title was purified eluting elut elut elut elut This intermediate was dissolved in a 1:1 mixture of dichloromethane and trifluoro succinic acid (2 mL) and stirred at room temperature for 2 hrs until the reaction was completed. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The combined extracts were dried <RTI ID=0.0>: </RTI> <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; MS(ES) 423.2(M+H)+. 85762 -175- 1322807

H NU/NH

T ER-806287 Compound ER-806287 was prepared from 4-trifluoromethylphenol according to the same procedure as for the preparation of ER-806286. MS (ES) 438.2 (M+H)+

τ ER-806311 a mixture of 18 (12.5 mg, 0.018 mmol), diisopropylethylamine (0.2 mL, 65 eq.) and thiophenol (10 μL, 5.5 eq.) in DMF (0.5 mL). Stir at room temperature for two days. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc EtOAc This intermediate and toluene (100 μL) were dissolved in a 1:1 mixture (2 mL) of dichloromethane and trifluoroacetic acid and stirred at room temperature for 40 min. The reaction was then quenched with EtOAc (EtOAc)EtOAc. The combined extracts were dried with EtOAc EtOAc (EtOAc) MS(ES) 386.2 (M+H)+.

r ER-806355 85762 -176· 1322807 Chlorosulfonium chloride (9 μL, 2 equivalents), added to 17 (40.5 mg '0.058 mmol) and diisopropylethylamine at 0 °C (1 〇〇 microliter, 1 〇 equivalent) in dichloromethane (1 mL) to medium solution and stirred for 30 min. 4-Hydroxypiperidine (30 mg, 5.0 eq.) and DMF (0.5 mL) were taken and the mixture was warmed to room temperature and stirred for 2.5 days. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic extracts were dried with EtOAc EtOAc (EtOAc) This intermediate was dissolved in dichloromethane (0.5 ml) and treated with EtOAc (5 mg) and nM EtOAc (20 mg) for 1 hr at room temperature. The reaction was quenched by the addition of water and Na.sub.2 EtOAc. The combined organic extracts were dried with EtOAc EtOAc (EtOAc)EtOAc. This intermediate was dissolved in toluene (1 mL) with toluene (10 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> and was treated with trifluoroacetic acid (1 mL) for 4 hours at room temperature. The reaction was then quenched with EtOAc (EtOAc)EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated and then purified and purified by EtOAc (EtOAc: EtOAc (EtOAc) . iHNMR(DMS0_d6;) 5 2_35 (t, J = 6Hz, 4H), 2.49 (s, 3H), 2.70 (t, J = 6 Hz, 4H), 3.67 (s, 2H), 5.74 (s, 2H), 6.73 (s, 1H), 7.16 (dd, J = 8.2 and 1.2 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.2, 1H), 7.55 (s, 1H) .

ER-806401 85762 -177- 1322807 Hydrogen peroxide (4 ml, 30% in water, 3.6 equivalents) was added to thiomorpholine (1.0 g, 9.7 mmol) in acetic acid at room temperature (12 Within the solution in ML). The resulting mixture was stirred at 100 ° C overnight, cooled to room temperature and concentrated. The thiomorpholine arsine from the residue is crystallized from ethanol as a dark solid. In accordance with the general procedure for the preparation of 64, compound ER-806401 was prepared from 18 and thiomorpholine. MS (ES) 417.2 (M+Na)+

r ER-806404 A mixture of 18 (5 mg) and decyl alcohol (100 μL) was treated with tBuOK (1 mL, 1.66 EtOAc in THF) overnight. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined extracts were dried over Na 2 S 〇 4, filtered, concentrated, and the crude intermediate and toluene (50 liters) were dissolved in dichloromethane (0.5 ml) and at room temperature Fluorineacetic acid (0.5 ml) was treated for 3 hours. The reaction was then quenched carefully with sat. NaHC03 andEtOAcEtOAc The combined extracts were dried with EtOAc (EtOAc)EtOAc. MS (ES) 384·2 (M+H)+.

τ ER-806644 85762 -178- ^22807 On 5-Moth ♦ stay (5·〇克, 20.6 mmol), stupid acetylene (34 ml, equivalent) and diethylamine (19 ml) in DMF (2 In a solution of 5%), add Pda% a (120 gram ' 〇〇〇 5 equivalents) and cui (39 mg, 0.01 eq.) in a nitrogen atmosphere and cooling water temperature, and form the mixture in the chamber. Stir for 3 hours under temperature. The reaction was diluted with saturated NaHC EtOAc (50 mL) and EtOAc EtOAc. The combined extracts were dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (4_41 grams, 98%). The compound 5-phenylethynylfluorene-1-carboxylic acid tert-butyl ester is prepared according to the 丨5-carboxylic acid oxime ester from the bow 7 (with 啕哚-1,5-dicarboxylic acid 丨_第The procedure of _ vinegar 5_ 醋 作为 as an example, was prepared from 5-phenylethynyl_1H_^. The compound 5-phenylethylidene-2-tributyltinyl group 丨嗓_ι_ oxic acid r r _ 酉 酉 is in accordance with the procedure for the preparation of 10 from 9, from 5-phenylethynyl w-l-1 - a few acid, butyl ester. Compound ER-806644 was prepared according to the procedure of Preparation 13 from &lt;RTI ID=0.0&gt;&gt; _ MS 364.2 (M+H)+.

ER-806645 A solution of ER-806644 (6.5 mg) and Lindlar catalyst (50 mg) in thp (2 mL) was stirred at room temperature under hydrogen for 1 hour. The resulting mixture was filtered through celite and the filtrate was concentrated. The residual solid was washed several times with Et.sub.Ac., s., s., s., s., s. MS (ES) 366.3 (Μ+Η)+·;

ER-806646 A solution of ER-806644 (5 mg) and EtOAc (EtOAc) (EtOAc) The resulting mixture was filtered through EtOAc (EtOAc)EtOAc. MS (ES) 368.3 (M+H)+.

T ER-806095 A solution of 16 (20 mg) in EtOAc (MeOH) (EtOAc) The reaction mixture was diluted with saturated NaHC03 and extracted with EtOAc. The combined extracts were dried with EtOAc (EtOAc)EtOAc. iHNMR.

ER-806420 85762-180- 1322807 A solution of ER-806393 (1.3 mg) in MeOH (0.5 mL) Then, the reaction mixture was neutralized to pH = 5 with an aqueous solution of &lt;EMI ID&gt; The residue was dissolved in 1:1 MeOH-EtOAc and filtered. The filtrate was concentrated and purified by reverse phase HPLC (MeOH-water) to afford ER-806420 (0.5 mg, 40%). MS (ES) 496.3 (M-H)·.

A mixture of 18 (15.5 mg, 0. 02 mmol) and methylamine (0.11 mL, EtOAc. It was diluted with saturated NaHC03 and extracted with 3x EtOAc. The combined extracts were dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in DMF (0.5 mL) as solution A. Diisopropylethylamine (5.3 μl, 1.4 eq.) was added at room temperature to a solution of benzoic acid (3.4 mg, 1.3 eq.) and TOTU (10 mg, 1.4 eq.) in DMF (0.3 mL) Inside and stir for 15 minutes. Then, the solution was introduced by rinsing with 3×0.5 ml of DMF, and the resulting mixture was stirred overnight, concentrated, diluted with saturated NaHC03 and extracted with 3×EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane (0.5 mL) and EtOAc (EtOAc) The reaction mixture was carefully quenched with sat. NaHC.sub.3 and EtOAc, and the separated aqueous phase was extracted with 3xEtOAc. The combined extracts 85762-181 - 1322807 were dehydrated and dried with NaaSO 4 'filtered, concentrated, and the product was obtained by reverse phase 111^(:purification (MeOH-water)' to give ER-806432 (1.4 mg, 16%, after three Steps). MS (ES) 411 · 2 (M+H)+.

The 5-nitrobutyral-1-carboxylic acid tert-butyl ester was prepared from 5-nitro-staple*1 according to the same procedure as for the preparation of 7 from hydrazine-5-carboxylic acid oxime ester. A solution of 5-nitroindole-1-carboxylic acid tert-butyl ester (〇5 gram) with a catalytic amount of pd(〇H) 2 in MeOH-EtOAc mixture at room temperature under hydrogen Mix for 1 hour. The reaction mixture was filtered through celite <RTI ID=0.0></RTI> and the filtrate was concentrated to afford &lt;RTI ID=0.0&gt;&gt; Benzoyl chloride (305 μl, 1.5 eq.) was added to 5-amino-2,3-dihydroindole-1-carboxylic acid tert-butyl ester (4 〇 7 mg, 1.74) under 〇ec. Milliol) was added to a solution of triethylamine (1.2 mL, 5.0 eq.) in dichloromethane (5 mL). The reaction was then quenched by the addition of sat. NaHC.sub.3 and the mixture was extracted with EtOAc. The combined extracts were dehydrated and dried <RTI ID=0.0>(</RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Dihydrogen thief small carboxylic acid third _ butyl ester (588 mg, 100%). Sodium hydride (60 mg '1.5 eq.) was added to (but TC to 5-benzoylamino-2,3-dihydroindole-1-carboxylic acid tert-butyl ester (570 mg, 丨68 mmol) And a mixture of methane iodide (0.42 mL, 4.0 eq.) in DMF (10 mL), and the mixture of 85,762, 182 - 1322807 was stirred for 20 minutes. After concentration, the residue from the reaction mixture was obtained. Diluted with hydrazine and NaHC03, and extracted with EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. Thiol-methyl-amino)-2,3-dihydro, indole-1-carboxylic acid, tert-butyl ester (547 mg, 93%). 5-(benzylidene-methyl-amino group) A mixture of -3,3-dihydro-indole-1-carboxylic acid, tert-butyl ester (500 mg) and Mn.sub.2 (5 g) in toluene (20 mL). An additional Μ 02 02 (5 g) was introduced, and the resulting mixture was stirred at 80 ° C for 1 hour. After cooling to room temperature, the mixture was filtered over celite, and the filtrate was concentrated. (30% EtOAc-hex ), 5-(benzimidyl-methyl-amino)-decanoic acid-1-tris-butyl ester (372 mg, 75%) was obtained. 5-(benzimidyl-methyl-amine Benzyl-2-butanstannyl, decyl-1-carboxylic acid, third-butyl ester, according to the procedure for the preparation of 10 from 9, from 5-(benzimidyl-methyl-amino)-oxime 1-carboxylic acid tert-butyl ester. Compound ER-807313 was prepared according to the procedure for Preparation 13 from 5-(benzimidyl-methyl-amino)-2-tributyltin. 1-acidic tri-butyl ester with 4 (I = Me). MS (ES) 397.2 (M+H)+ and 410.1 (M+Na)+.

ER-807015 Compound ER-807015 was prepared as a by-product during the preparation of the amine from the sterically hindered amine 65 and produced a satisfactory iH NMR spectrum. 85762 -183· 1322807

r ER-807586 will be 18 (51 mg, 1.0 eq), (3,3-dimethyl-1,5-dioxo-spiro[5,5]undec-9-yl)-methyl-amine A mixture of the hydrochloride salt (71 mg, 4.0 eq.), ethyldiisopropylamine (0-25 mL, 20 eq.) and EtOAc (EtOAc) After concentration, the residue was dissolved in EtOAc (EtOAc) (EtOAc) After cooling to rt, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The combined extracts were dried with EtOAc (EtOAc)EtOAc. 1 H NMR and MS (ES) 403.5 (M+H)+

ER-807759 ER-807759 was prepared according to the same procedure as in 13 (with ER-805639 as an example) in the Stille coupling reaction and ER-807586 in the ketal hydrolysis reaction. iHNMR and MS(ES) 389(M+H)+.

ER-807789 85762 -184- 1322807 in a suspension of ER-807586 (5 mg, 0.0124 mmol, 1.0 eq.) in water (0.5 ml): NH2OMe · HC1 (5.2 mg, 0.623 mmol, 50 equivalents). The solid became soluble and saturated NaHCO3 (0.3 mL) was slowly added and the mixture formed was stirred overnight. The reaction mixture was diluted with EtOAc and sat. NaHC. The organic layers were combined, dried over MgSO4, filtered and concentrated. The crude mixture was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H NMR and MS (ES) 432 (M+H)+.

ER-807790 In EtOAc-EtOAc (EtOAc (EtOAc) (EtOAc) extraction. The organic layers were combined, dried with MgSO4, dried and evaporated. The crude mixture was purified by reverse EtOAc (MeOH-H.sub.2) to afford ER- 807 790.1HNMR and MS (ES) 405.5 (M+H)+.

ER-807835 is added to a solution of n-BuLi (1.6M in hexane, 0.35 mL, 0.56 mmol, 31_3 eq.) in THF (2.0 mL). Brominated scale (0.20 g, 0.56 mmol) 31 equivalents. The reaction was allowed to warm to room 85762 - 185 - 1322807 and stirred for 40 minutes. A portion of the solution (0.6 mL) was transferred to another flask and ER-807586 (7.2 mg, 0.019 mmol, L0 equivalent) was added. The resulting mixture was stirred at room temperature for 18 hr and water was added and the mixture was extracted with 3xEtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The crude mixture was purified by reverse EtOAc (EtOAc (EtOAc) (EtOAc) 1H NMR and MS (ES) 401·5 (M+1 Η).

ER-807837 In a solution of ER-807586 (11.5 mg, 0.0286 mmol, 1.0 eq.) in THF (2.0 mL), MeOH MeOH (3.0 Μ, THF, 0.25 mL, 0.75 Millions, 26.3 equivalents). The reaction was allowed to warm and stirred at rt for 18 h. The reaction was quenched with saturated EtOAc (EtOAc)EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting mixture was purified by EtOAc (EtOAc:EtOAcEtOAcEtOAcEtOAc 1H NMR and MS (ES) 419.4 (M+1H).

ER-808036 5-Chlorodecyl-indole-1-carboxylic acid tert-butyl ester according to procedure 9 for preparation 9 85762 -186- 1322807, but without the addition of wheyrin, from 8. 3-Chloromethyl;-indole-1-carboxylic acid tert-butyl ester (0.82 g, 3.10 mmol, 1.0 eq.), cyclohexyl mercaptan (0.53 ml, 1.4 eq.) and K2C03 (0.90 g) A mixture of 2.0 equivalents in DMF (6 mL) was heated at 40 ° C until the reaction was completed. The reaction mixture was cooled to room temperature, diluted with aq. The organic extract was dried over MgS04, filtered, and concentrated. The resulting mixture was purified by chromatography (5% EtOAc / hexanes) toield: ER-808036 was prepared from 5-cyclohexylthiomethyl, indole-1-carboxylic acid tert-butyl ester according to the procedure for preparation 16 from 14.

ER-808082 ER-808083 in ER-808036 (60 mg, 0.15 mmol, 1.0 eq.) in THF (2.5 mL) MeOH (1.5 mL) Mg, ~70%, 1.6 equivalents) solution in THF. After stirring for 2 hours, the reaction was quenched by the addition of saturated Na.sub.2SO.sub.3 and saturated NaHC.sub.3. The separated aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The crude mixture was purified by chromatography (5% to 10% MeOH /EtOAc) to afford semi-purified product (18 mg and 32 mg each). After further purification (MeOH-water) by reverse phase HPLC, ER-808082 (3.2 mg) and ER-808083 (3.2 mg) were obtained. These two products were confirmed by iH NMR. 85762 • 187- 1322807

ER-808103 5-Chloromethyl, decyl-1-carboxylic acid tert-butyl ester (0.41 g, 1.55 mmol, 1.0 eq.), cyclohexanol (0.82 mL, 5.0 eq.) and Ag20 (1.80 g) , 5.0 eq.) A mixture of diethyl ether (5 mL) was stirred at 35 ° C over the weekend. After cooling to room temperature, the reaction mixture was filtered over Celite and washed with ether. The filtrate was concentrated and the residue was purified EtOAcjjjjjjjjjj This compound was confirmed by 1H NMR. ER-808103 was prepared from 3-cyclohexyloxymethylindole-1-carboxylic acid tert-butyl ester according to the procedure for the preparation of 16 from 14. Both MS (ES) and 1 H NMR confirmed this compound.

ER-808040 In a suspension of compound 3 (R = Me, 300 mg, 1.03 micromoles, 1.0 eq.) in THF (5 mL), EtOAc (1······· , 2.56 ml, 2.5 eq.), and the resulting mixture was heated at 65 ° C for 30 minutes. After cooling to 0&lt;0&gt;C, EtOAc (EtOAc (EtOAc)EtOAc. The filtrate was concentrated, and the residue was purified EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc并[4,5-b]p ratio, as a white solid (190 mg '94%) 〇ER-808040 according to the procedure for preparation 13, from 7-chloro-2-methyl-5-oxime Amino-3H-imidazo[4,5 heptacycline with 5-[(cyclohexyl-methyl-amino)-methyl]_2_tributylstannium hydrazide-1-carboxylic acid tert-butyl ester (according to The procedure for the preparation of 1 ' was prepared from 8 and cyclohexyl-methyl-amine. This compound was confirmed by iH NMR.

Add (MeOCH2CH2)2NSF3 (14 μL, 1.8 eq.) at 0 ° C in a solution of ER-807790 (17 mg, 0.042 mmol, 1.0 eq.) in CH2C12 (1 mL). The resulting mixture was stirred at ° C for 1 hour and at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc (EtOAc-EtOAc)

5-Mercaptopurine-1-carboxylic acid tert-butyl ester or 6-methylindolyl 1-acidic third-butyl ester at 8 (8.0 g, 32.4 mmol, 1 equivalent) at In a solution of 85762-189- 1322807 in CH2C12 (24 ml), add Dess-Martin reagent (17.9 g, 1.3 eq.) in portions at 0 ° C and slowly warm the mixture to the chamber. Warm and stir for a few minutes. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The filtrate was washed with saturated NaHC.sub.3, dried with Nad%, filtered and concentrated. The crude product was azeotroped with toluene to obtain 5-methylglycolyl W哚 small carboxylic acid tert-butyl ester (7_3 g, 95%), or a similar manner to obtain a ruthenium 7?丨嗓-1-acid Third, Ding Yu.

Make Mg (swarf) activated by washing with 1]^11 (:1 and shame, and dry overnight at high true 2. Ethyl bromide in EbO (4 ml) (〇8) ML 1 § amount), 'f· laugh added to Εί; 2 Ο (10 ml) activated] y [g (418 mg) in 'to maintain the internal temperature at 3 〇 _33 ° c. The resulting reaction mixture was heated at 34. (: for 1 hour, and cooled to hydrazine. 〇. Then, introduced 5-methyl 4-indole-1-carboxylic acid tert-butyl ester (9 〇〇 mg) in (15 ml) Solution in solution' and warm the mixture to room temperature at 30-32. (3 hours heating at 3 hours to cool to room temperature, then add saturation to quench the reaction. The separated aqueous phase is EtOAc was extracted and the combined organic layers were dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0> 85%) » 1.5 In a mixture of alcohol (513 mg, 1 equivalent) and Et3N (625 μl, 3 equivalents) in CH2C12 (15 mL), decanesulfonic anhydride (39 mg) , 85762 - 190- 1322807 Equivalent). The cooling bath was removed, and the resulting mixture was stirred for 2.5 h and diluted with saturated NaHC03. The separated aqueous layer was extracted with CH.sub.2C12. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (hexane to 10%EtOAc / hexanes) toield of 3-(2-cyclohexyl-vinyl)-indole-1-carboxylic acid tert-butyl ester (380 mg, 78%) ER-808281 was prepared from 3-(2-cyclohexyl-vinyl)-indole-1-carboxylic acid tert-butyl ester according to the procedure for preparation of 16 from MS. MS (ES) and 1 H NMR Confirm this compound.

ER-808281 (~10 mg, 1 eq.) in MeOH (5 mL) with 10% Pd/C (catalyst) solution was maintained overnight in H2 atmosphere and room temperature. The mixture was then taken up in EtOAc (EtOAc) elute MS (ES) and 1 H NMR confirmed this compound.

Boc 5-vinylindole-1-carboxylic acid tert-butyl ester or 6-vinylindole-1-carboxylic acid tert-butyl ester in decyltriphenyl bromide rust (8.1 g, 22.7 mmol) n-BuLi (1.6 Torr in hexane, 14.2 mL, 22.7 mmol) was added dropwise to the suspension in THF (140 mL) over 10 min. After stirring for 20 minutes, 'in the 20 85762 -191 - 1322807 minutes, slowly introduce 5 · formazan hydrazine ·• acid-producing third _ butyl ester (463 g, 148 house Moer) in THF (20 liters) The solution in solution was allowed to slowly warm to room temperature and stirred for 30 minutes. The reaction mixture was poured into a saturated gasification mixture, and the separated aqueous phase was extracted with ethyl acetate (3 x 100 liters). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (dichloromethane to 1% acetone-dichloromethane) to give 5------------- The way to get 6_vinyl 丨哚μ retinoic acid - third brewing.

Boc 5-(2-Alkyl-ethyl)-indole small carboxylic acid tert-butyl ester or 6-(2-hydroxyethyl)·吲哚_1-acid acid tert-butyl ester in 5-vinyl group丨哚-1-carboxylic acid tert-butyl ester (4.5 g, 18.5 mmol, 1. 〇 equivalent) in a solution of THF (46 ml), in a solution, within 1 min, add 9 -BBN (0.5 Μ ' in THF, 87 mL, 2.4 eq.). The resulting reaction mixture was stirred for 2.5 hours and diluted with THF (150 mL) and water (150 mL). Then, the mixture was stirred in NaB03 · 4 Η 20 (44 g), and the resulting reaction mixture was stirred and warmed to room temperature and stirred. The reaction mixture was diluted with dichloromethane (100 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated. The residue was purified by chromatography (dichloromethane to 5% EtOAc/dichloromethane) to afford EtOAc (3. Or, in a similar manner, 6-(2-hydroxy-ethyl) 4丨嗓_1·reactive acid tert-butyl ester is obtained. 85762 -192· 1322807

5-(2-fofolin-4-yl-ethyl)-indole_ylic acid tri-butyl or 5-[2-(cyclohexylmethyl-amino)-ethyl]anthracene 1-carboxylic acid tert-butyl ester or 6-(2-morpholino-4-yl-ethyl)-indole-1-teric acid third butyl ester or 6_[2_(cyclohexyl-methyl -Amino)-ethyldipyridin-1-carboxylic acid tert-butyl ester in 5-(2-hydroxy-ethyl)-indolecarboxylic acid tert-butyl ester (26 mg, 1 mmol) Ear '1.0 equivalents), triphenylphosphine (391 mg, ι·5 eq.) and imidazole (136 mg, 2 eq.) in dichloromethane (5 ml) in 20 min at room temperature Iodine (328 mg, 1.3 equivalents) was added in small portions. The reaction mixture was poured into water and extracted with 4×1 mL of di-methane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% EtOAc / hexanes) to afford semi-purified moth (6 mg). The resulting compound was then taken up in MeOH (10 mL) and EtOAc (EtOAc &lt;RTI ID=0.0&gt; Dihydromethane extraction: The combined organic layer was dehydrated and dried with sodium silicate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane to 15% acetone/dichloromethane) to obtain 5_(2) _ morpholine _4 yl · ethyl) hydrazine small carboxylic acid tert-butyl ester (290 mg, 88%), or similarly obtained 5_[2_(cyclohexyl-methyl-amino)-ethyl啕哚 第三 carboxylic acid third _ butyl ester, or 6 — (2 — morpholine 4-yl-ethyl)-hydrazine small carboxylic acid tert-butyl ester, or 6_[2-(cyclohexylmethyl) -Amino)-Ethyl]-Astringent·1_Resinized third-butyl ester. 85762 -193· 1322807

3-(2.methoxycarbonyl-vinyl)-indol-1-carboxylic acid tert-butyl ester or 6-(2-methoxycarbonyl·vinyl)-indole-1-carboxylic acid tert-butyl The ester was added to a solution of 5-methylmercaptoindole-1-carboxylic acid tert-butyl ester (3.4 g, 13.8 mmol, 1. 〇 equivalent) in toluene (35 mL) at room temperature Ph3P = CHC02Me (5.5 g, 1.2 eq.), and the resulting mixture was stirred overnight. After concentration, the crude product was purified by column chromatography on silica gel (dichloromethane to 1% acetonitrile - _ _ _ _ _ _ _ _ _) to give 5-(2-methoxy-ethyl---- *·?丨嗓-1-Resinic acid tert-butyl ester (5.03 g, 90%), or similarly obtained 6-(2-methoxycarbonyl-vinyl)-4丨哚-1-acid Tri-butyl ester.

5-(3-carboxy-propenyl)-indole-1-teric acid tri-butyl acrylate or 6-(3-polypropylpropenyl)-4 丨哚-1-carboxylic acid tert-butyl ester in methyl 5-(2-methoxycarbonyl-vinyl)_4 hydrazinoic acid tert-butyl ester (4.64 g ' 15.3 mmol, ΐ·〇 equivalent) in THF (87 mL) in _ 3〇&lt;t下', add UA1H4 (1 N in ΤΗρ, μ 6 ml '1.2 eq) in a syringe pump over 20 minutes, and stir the resulting mixture' and warm to _5&gt;&gt;c . After cooling back to -3 (TC, the reaction was then quenched by slowly adding acetone (1 mL), keeping the temperature below _15 &lt; t, poured into the Lothel salt under 〇〇c, stirring 1 The separated aqueous layer was extracted with Et0Ac. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (2 m. Alkane), which gives 5·(3 propylpropyl 85762-194- 丄W2807 dilute base)-bow 丨哚-1-3⁄4 acid third-butyl ester (2.89 g, 70%) 'or obtain 6_( in a similar manner) 3-Hydroxy-propenyl)-inden-1-decaylic acid tert-butyl ester.

5-(3-morpholine-4-yl-propenyl)-inden-1-recodactic acid tert-butyl ester or 6-(3-norfosolin-4-yl-propenyl)-indole 5丨哚-1-carboxylic acid tert-butyl ester in 5-(3-hydroxy-propenyl)-hydrazinecarboxylic acid tert-butyl ester (ο % mg, 3.48 mmol [1.0 eq.) and Et3N (1.8 ML, 3.0 eq. in a solution of dichloromethane (1 mL), EtOAc (0.40 mL, 1.5 eq.). And stirring for an additional hour. Then introduce cyclohexyl-amine (83 ml, 18 equivalents), and the resulting mixture was stirred over the weekend, diluted with saturated NaHC〇3, and taken. The phase was dehydrated with Na2S〇4 and the residue was purified by silica gel chromatography (50% EtOAc &lt;RTI ID=0.0&gt;

The separated aqueous phase was extracted with 3x EtOAc. The combined 4 was dried &apos;filtered&apos; and concentrated. Let the residue borrow from the quinques of the genus of the genus 5-(3-fofo-4-yl-propanyl, or a similar manner to obtain 6-(3-morpholin-4-yl-- Butyl ester.

ER-808501 ER-808514 85762 • 195- 1322807 - "NH2 NH: 0O^J〇&gt;-^N Η Ν^ΝΗ 〇α HN^NH 2CF3C02H I 2CF3C〇2H T ER-8085042 ER-808544 Analog ER- 808501, ER-808514, ER-8085042 and ER-808544, according to the same procedure for the preparation of 16 from 14 from 5-(2-hofolin-4-yl-ethyl丨嗓-1-decanoate Di-S-, 5-(3-fosolin-4-yl-propyl-homolyl)-p5丨ρ-l-decanoic acid second-butan S, 6-(3-? -4-yl-propyl-associated)-ρ5|ρ朵-1- 叛 酸 弟 二 二 二 酉 及 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 · ^ Private brother II - Ding Yu.

A solution of 20 (51 mg) in dichloromethane (1 mL)EtOAc. The solid residue was washed with EtOAc (EtOAc) (EtOAc) MS (ES), 19F and 1H NMR confirmed this structure.

7-Chloro-3H-microbial and [4,5-b]p ratio at 120 ° C (J. CTzem. 1982, /9, 513) (250 mg, containing 25% 5-chloro -3H-imidazo[4,5-b]pyridine) 85762 -196- 1322807, 2-tributylstannylhydrazine carboxylic acid tert-butyl ester (11,822 mg) and hydrazine (triphenylphosphine) palladium (〇) (1 mg) of a mixture in DMF (10 mL). The reaction mixture was extracted with AcOEt and washed with water and brine. The organic layer was dehydrated and dried with MgS 4 and evaporated. The residue was purified by chromatography (Ac EtOAc / hexane) to give 7-(1 Η- 吲哚 -2- yl)-3 Η imidazo[4,5-b&gt; pyridine IC-261 (28 mg ), as a light brown solid. This structure was confirmed by iH NMR.

2 (1.66 g, 6 when Mo), 2-tributyltin ketone·Ρ5 丨 小 小 第三 第三 第三 第三 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( A mixture of 6 mmoles and hydrazine (triphenylphosphine) palladium (0) (600 mg '1 mol%) in DMF (1 ml) was heated at 130 ° C for 6 hours. During the reaction, u (1〇1 g X 2) was added in two portions. The reaction mixture was extracted with ethyl acetate and washed with water and dried over anhydrous magnesium sulfate. After filtration, 1 gum (4 mesh) was added to the residue and concentrated. The residue was purified by chromatography (EtOAc/MeOH) to afford 10395 (240 mg) This structure was confirmed by iH NMR.

(7-Chloro-2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5yl)-amine methyl acid ethyl ester in 4-chloro-5- To a solution of diethyl nitro-2,6-pyridinedicarboxylate (for the preparation of 85762-197· 1322807 intermediate) (500 mg) in EtOH (50 mL), EtOAc (1 g) Stir for 12 hours under hydrogen atmosphere and room temperature. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was dissolved in 2-propanol (10 mL) and stirred under reflux for 60 hr. The reaction mixture was allowed to cool to room temperature and the precipitate was filtered. The filtrate was concentrated to give 25 mg (7·chloro-2- 2-keto-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-amine methyl acid B Ester, a gray solid. 1H NMR confirmed this structure. Nh2

0 IC-380 (7-Chloro-2-keto-2,3-dihydro-1H-imipo[4,5-b] -5-5-yl)-amine at 120 ° C Ethyl thioglycolate (240 mg), 2-tributyltinidyl β丨嗓-1-carboxylic acid tert-butyl ester (11 ' 472 mg) and hydrazine (triphenylphosphine) palladium (9) (54 mg) in hydrazine The mixture in 1 ^ (1 mL) was heated for 4 hours. Introduce another 2-tributylstannyl hydrazine-1-carboxylic acid, the third-buty (11,472 mg) and the hydrazine (triphenylphosphine), (9) (54 g), and form The mixture was heated at 120 ° C for an additional 12 hours. The reaction mixture was concentrated under reduced pressure and purified (EtOAc) (EtOAc) 1H NMR confirmed this structure. NHCOOEt Ν'γΝΗ ΝΗ2 85762 -198- 1322807 (2-Amino-7-carbyl-3H-imidazolium 4,5-potential pyridin-5-yl)-amine methyl acid ethyl ester at room temperature, Chiang Cyanogen bromide (0.55 g, 5.2 mmol) was added to ethyl 5,6-diamino-4-chloro-2-pyridylcarbamate (for intermediate 1 of Preparation 1 丨. (8) g, 4 3 Millol) in a stirred solution in 20 ml of ethanol. The solution was stirred for 3 hours and then at 60 C for 3 hours. The precipitate was filtered and washed with acetonitrile to give (2-amino-7-chloro-3H-mimidol[4,5-b&gt;pyram-5-yl)-amine methyl acid ethyl ester (〇55 g, 38%), yellow powder. This structure was confirmed by iH NMR.

IC-416 is obtained from (2_Amino-7-chloro-3H-imidazolium [;4,5-b]pyridin-5-yl)-amine methyl acid B using the typical procedure described for IC_380 The ester was confirmed by 11.1 η NMR.

7-picyl-2-alkyl-3H-imidazo[4,5-b]pyridine compound 7-iodo-2-alkyl-3Η-imidazo[4,5-b]pyridine (7-iodoyl) · 3 Η _ 吐 并 [4,5-b] pyridine, 7 · moth 2 / methyl Γ 3 Η - imidazo[4,5-b] pyridine, 7-iodoethyl 3H-imidazo[4, 5-b]pyridine) and/or its HI salt are prepared from 4-chloro-p-pyridyl 2,3-diamine according to the same procedure for the preparation of 2 and 4 from 1 (Recueil, 1969, 55, 1274) 〇85762 -199- ^22807

5-Fluoro-7-mothyl-2-methyl-3H-imidazo[4,5-b]pyridine at 4 (RfMe, HI mono-salt, 300 mg, 0.75 mmol, 1.0 eq.) in hbF4 ( Add NaN〇2 (1.0 g '19 equivalents) in a solution of 48-51% in water, 3 ml) at 0 ° C for 1 hour, and keep the reaction temperature at 4 °C. under. The resulting mixture was stirred at 〇 ° C for 40 minutes and at room temperature for 3 minutes. The reaction was quenched with saturated NaHC(R)3, and the resulting mixture was extracted with 5xEtOAc. The combined organic phases were dried over NaaSO4, filtered, and concentrated to give a 5-[sup. Solid (170 mg, 86%). 19 F NMR, 1H NMR and MS confirmed this structure

R2 66

Ri = H, F = H, Me, Et Compound 66 was prepared from 7········· Its m mono-salt) or 5-fluoro--7-pyridyl-2·methyl-3H-imidazo[4,5b]pyridine and 15. 85762 -200- rI322807 r\

Compound 67 was prepared from 7-iodo-2-fyl-3H-imidazo[4,5-b]pyridine and 15 according to the same procedure as for the preparation of 65.

ER-# 1· Structure 66 or 67 'H NMR and / or MS 807496 Η ΝγΝΗ [HNMR

85762 201 - 1322807 85762

807584 :· Η Ν 丫ΝΗ ^NMR 807585 Η ν^νη !hnmr 807587 FiX'Xc^N Η ΝγΝΗ ^NMR 807750 Η Ν^ΝΗ. 'HNMR 807787 七h Η Ν 丫,ΝΗ aHNMR 807788 Η N^NH 'HNMR 807865 HN^/NH 'HNMR 808009 H NyNH 'HNMR 808081 ^°Χ'ΎΧν^Ν 1 HN^NH 'HNMR 202- 1322807

808085 Η Ν^ΝΗ 'HNMR 808160 Η Ν^ΝΗ !hnmr 808256 Η 丫 丫, ΝΗ 'HNMR 808257 Η Ν 丫ΝΗ 'HNMR 808259 Me0/o Η ΝνΝΗ -Τ 'HNMR 808260 Η Ν 丫ΝΗ 'HNMR 808261 〇nJ〇 Q&gt;~^n Η ΝνΝΗ Τ 'HNMR 808262 Cbj〇C>~^N Η Η Ν 丫'νη 'HNMR 808266 V〇^ cf3co2h η ν 丫νη 'HNMR 85762 203 - 1322807

808268 - kJ H ΝγΝΗ ]HNMR 808269 八HN^NH 'HNMR 808284 CXjj〇Q~^n HN 丫VlH 'HNMR 808285 ^nJ〇CV^n HN^NH 丫'HNMR 808286 〇j〇cy-^NH Νγ,ΝΗ 'HNMR 808287 H -N^nh ^NMR 808288 ςτ〇τ^ J〇H 丫H ^NMR 808289 'HNMR 808291 kJ HN^NH 'HNMR 808310 a HN 丫NH ^NMR 85762 -204- 1322807 85762

808311 -Ο - Η ΝγΝΗ 'HNMR 808319 a&gt;Xcv^N Η Ν 丫ΝΗ 'HNMR 808322 Η ν 丫ΝΗ 'HNMR 808361 Η〇Τ 丫Η 丫Η 'HNMR 808362 Η Ν^ΝΗ - 'Η NMR 808363 Η Ν^ΝΗ 'Η NMR 808370 〇Ν^α&gt;-ςΝ Η Ν 丫, ΝΗ 'HNMR 808372 Η Ν^ΝΗ 'HNMR 808385 Η Ν^ΝΗ 'HNMR -205 - 1322807 85762

808386 -HHN^NH 'HNMR 808388 HN^NH ^NMR 808469 HN^NH 'HNMR 808470 〇v^N iy' NrNH 'HNMR 808473 HN^NH 'HNMR 808496 H ΝγΝΗ 'HNMR 808497 ^j〇cy-^NHN 丫NH ▲HNMR 808498 :· UH 'HNMR 808499 .nJ〇CV^Pn V h NyNH lHNMR 808500 cf3co2h cf3co2h hn^nh 'HNMR 206- 1322807 85762

808513 cf3co2h —On^O&gt;~Q -cf3c〇2h h N'yNH 'HNMR 808541 〇N^j〇cy^NH n^nh cf3co2h CF3C02H I 'HNMR 808543 〇〇H n^nh cf3co2h cf3co2h j 'HNMR 808571 HN丫NH 'HNMR 808600 rrNjCCV^NUH n?h 'HNMR 808617 〇nJ〇CV^n HN^/NH 'HNMR 808620 HN^NH T : 'HNMR 808622 HN 丫NH aHNMR 808623 HCI H 丫H 'HNMR 808624 HN^NH ^NMR -207- 1322807 85762

808628 -^ HCI H 丫H 'HNMR 808629 HN^NH 'HNMR 808631 H n^nh ^NMR 808635 /^J〇CV^Pn HN 丫NH 'HNMR 808636 ^nJ〇CV^n H n^nh ^NMR 808637 〇 nJCcv^n hci H NyNH lHNMR 808660 H ΝγΝΗ 丄HNMR 808672 O UCV^NHN 丫NH 'HNMR 808673 HN^NH ^NMR 808691 r〇^ HN^/NH *HNMR -208· 1322807 85762

808692 - HN^NH 'HNMR 808703 H n^nh cf3co2h T 'HNMR 808704 HN^NH CF3C02H [ 'HNMR 808705 HN^NH cf3co2h T *HNMR 808711 HN 丫NH [HNMR 808712 1 HN^NH 'HNMR 808713 HN 丫NH ^ HNMR 808714 OnJCcv-Qn HN 丫NH ^ NMR 808717 H n^nh aHNMR 808719 Pair of palmitic H ΝγΝΗ ^NMR • 209- 1322807 85762

808720 〇Νχτα^ VJ Η Ν^ΝΗ 'HNMR 808834 MeO^^ H ΝγΝΗ !hnmr 808835 HN 丫'NH ^NMR 808849 V〇&gt;·^ HN^NH 'HNMR 809187 • HI HN NH 'HNMR 809196 2 cf3co2h nVnh MS 809197 2 CF3C02H HN VNH MS 809198 2CF3C02H H ΝγΝΗ MS 809199 〇Ν'^α&gt;^ 3CF3C02H H ΝγΝΗ MS 210-

1322807 85762

602200 HO. 2CF3C02H H nVnh MS 809201 乂2CF3C02H H nVnh MS 809202 2cf3co2h H nVnh MS 809203 3CF3co2h H nVnh MS 809204 HO. 2CF3C02H H NVNH MS 809205 2CF3C02H H nVnh MS 809206 Person 2CF3C02H H ΝγΝΗ MS 809207 3 CF3C02H N 丫NH MS • 211 · 1322807

809208 3cf3co2h Η nVnh MS 809209 2CF3C02h H nVnh MS 809210 2CF3C02H H nVnh MS 809211 2 CF3C02H N丫NH MS 809212 3CF3C02H H NVNH MS 809213 a 2 CF3C02H N丫NH MS 809214 2CF3C02H H NVNH MS 809215 A 2CF3co2H H nVnh MS 809216 2 CF3C02H ΝγΝΗ MS 809217 αιΓΧ5&gt;^ 2 CF3C02H N丫NH MS 85762 -212- 1322807 85762

809218 2 CF3C02H NVNH MS 809219 2 cf3co2h NvNH MS 809220 2 CF3C02H n丫nh MS 809221 2CF3C02H H nVnh MS 809222 3 CF3CO2H N丫NH MS 809223 2CF3co2H H nVnh MS 809224 〇ΝγΝΗ cf3co2h T MS 809225 〇N^NH CF3CO2H Ding MS 809226 J On^nh 2 CF3C02H 1 MS -213- 1322807 85762

809227 1 〇Ν- ΝΗ cf3co2h Τ MS 809228 0 Ν^ΝΗ cf3co2h I MS 809229 〇~ 2 CF3C02H I MS 809230 1 cf3co2h Ding MS 809231 1 〇Ν-, ΝΗ cf3co2h I MS 809232 1 0 Ν^ν,ΝΗ cf3co2h I MS 809233 o nvnh 2 CF3C02H Ding MS 809234 o... 〇N&lt;s/NH 2 CF3C02H I MS 809235 y/»^H /J 〇N^NH cf3co2h I MS 809236 , cf3c〇2h Ding MS -214- 1322807

7-Mothyl-2-methyl-1,4-dihydro-imidazo[4,5-b]pyridin-5-one in compound 4 (R=Me, 160 mg, 0.59 mmol) in 10 ml Sodium nitrite (1.54 mmol) was added in small portions at 〇 ° C in a solution of 20% H 2 S 〇 4 aqueous solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was neutralized to pH 7-8 with a saturated aqueous NH3 solution, and the formed precipitate was collected to give a yellow solid. Then 'the solid was crystallized in water to give 140 mg of the product 7-iodo-2-mercapto-1,4-dihydro-imidazo[4,5-pyridin-5-one (87%) with Satisfactory MS and 1H NMR.

ER-807546 ER-807546 was prepared according to the same procedure as for Preparation 13 from 7-iodo-2-methyl-1,4-dihydro-imidazo[4,5-b]pyridin-5-one and 10 (R'=PhCH2, R&quot;=Me). Satisfactory MS and 1H NMR for ER-807546 were obtained. 85762 -215· 1322807

The analogs ER-809251 and ER-809252 were prepared individually from 7-iodo-2-methyl-3H-imidazo[4,5-b]pyridine, and 6-[in the same procedure as for the preparation of 16 from 14. 3-(cyclohexyl-fluorenyl-amino)-ethyl]indole-1-carboxylic acid tert-butyl ester with 5-[2-(cyclohexyl-methyl-amino)-ethyl]-indole 1-carboxylic acid third-butyl ester. 3) Biological assay HUVEC assay: The pooled human umbilical vein endothelial cells (HLTVEC, Clonetics) were seeded on 96 well plates at 5 X 104 cells/ml and cultured at 37 °C. On the next day, 20 microliters of each compound dilution was added to the cells and incubated for 30 minutes, followed by stimulation with TNFα (1 ng/ml) for four hours at 37 °C. After TNF stimulation, the plates were washed with PBS containing 0.5% BSA, fixed with 0.025% glutaraldehyde, and stained with primary and secondary antibodies to detect sputum-selectin and ICAM performance. The plates were incubated with 100 μl of primary mouse anti-human sputum-selectin and anti-human ICAM antibody (R&amp;D Systems, Minneapolis, ΜΝ) diluted 1:500 in PBS containing 0.5% BSA and 5% FBS. For one hour, the plates were then washed and 100 μl of secondary peroxidase conjugated goat anti-mouse IgG antibody (Pierce, Rockford, IL) diluted 1: 10,000 in PBS/0.5% BSA/5% FBS was used. , culture for 30 minutes. The plates were then washed and 100 microliters of TMB substrate was added and the color reaction developed for 15-20 minutes. The reaction was stopped by adding 50 μl of 1NH2S04 85762 -216-1322807, and the optical density (OD) was measured: r : % inhibition = 1 - and on a microplate spectrophotometer, at 450 nm, read ^ The IC5 threshold is based on the percentage of inhibition calculated by the following formula (average compound OD-average blank test OD)]]*1〇〇

J (mean TNF OD _ average blank test OD) ^

85762 -217·

Claims (1)

1322807 Patent Application No. 092114905 (Replacement of Patent Application Scope (September 1998) ------" Pickup, Patent Application Scope: 吐"月ψ曰修(羡)本本''-___ 1. A Compound with structure 1: Ri, errone or a salt of such an ester -NHAc, -oh, f, -OMe, -CN and pharmaceutically acceptable salts thereof wherein η is an integer 〇_4; Ri is hydrogen, -NH2, _NHMe, or - NH(C=〇)〇Et ; Ma Feng-, _0Ra, aliphatic, heteroaliphatic moiety, where r, Rb, or hetero-, 芸m-gan is 虱' or aliphatic, miscellaneous Aliphatic or heteroaryl group; each of the presences of &amp; is independently hydrogen, ^ from Gan, hamster' or aliphatic, heterozygous, aryl or heteroaryl a group, ^ Λ 4 violent group - G.Rc, where G is absent, or -CH2-, -NRD_, ·〇, n Ο) ' and wherein Rc is hydrogen-NRfRc, -〇RF, _SRf, or Aliphatic m # , n , 知族, aryl or heteroaryl group, wherein Rd and &amp; independently are hydrogen, oxime, di t = group, % heteroaliphatic, aryl or heteroaryl a group -c(9)Rz (wherein Rz is an aliphatic, heteroaliphatic, aryl group): or wherein the ring is taken as a 3::4 2: or 8-capped substituted or unsubstituted cycloaliphatic Group .^ , ^ t A miscellaneous aliphatic group 'two: ~ each of the existence of the system, independent of hydrogen, aliphatic, Aliphatic, hetero said known month, cyclic heteroaliphatic, aryl or heteroaryl group U S side. ^partition group, -C(0)Rz( 85762'980904.doc 1322807 wherein Rz is an aliphatic, heterocyclic φκ 9 *, aryl or heteroaryl moiety), or its center and And or unsaturated cycloaliphatic or cyclic: two: substituted or unsubstituted, saturated heteroaliphatic moiety; and wherein each of the foregoing aliphatic or unsubstituted, cyclic #heteroaliphatic moiety Independently substituted (tetra), cyclic, H-divided, saturated or unsaturated, and each of the foregoing substituted or unsubstituted. The earth or hetero-based group may be independently as follows. 2. According to the scope of the patent application, the structure of the first item: the compound of the first item, wherein the compound has the following R2 wherein R3a and R3b are each independently hydrogen, (iv) an aliphatic, aryl or heteroaryl moiety, or Does not exist, or even _, tear or earthen called, where G is, -NRFR&lt;3, kiss '_SRf, or ~ Κ is a hydrogen group ^ where Rd, Rf and ~ are each independently hydrogen. Ton: = % 曰 曰 、, heteroaliphatic, cycloaliphatic, aryl-y, -C(0)RZ (where Rz4 month sect, hetero-p Ί ” 方 square base group), or Its ~ with base = or 8-membered substituted or unsubstituted,; its "existence of its existence is unique: == group part of the group Yuelu, cycloaliphatic, 85762-980904.doc - 2 - 1322807 Heteroaliphatic, cycloaliphatic, ^ ^ , aryl or heteroaryl moiety, -C(0)Rz( ✓, middle Rz is aliphatic, miscellaneous furnace. D ώ 如知,芳a base or a heteroaryl moiety), or a yttrium or a heterocyclic aliphatic or cycloaliphatic moiety thereof, which is substituted or unsubstituted by 4,5 or 6_members. And each of the above-mentioned aliphatic χ4雑月曰 private part can be independently substituted or unsubstituted, cyclic or non-μ,. The development is linear or branched, saturated or not. And wherein each of the aforementioned aryl, aryl or heteroaryl moiety may be independently substituted or Unsubstituted. 3. According to the scope of the patent application 丨 Structure: The compound of the compound, wherein the compound has the following Wherein R3a and R3b are each independently a gas, a sulphate, an aryl or a heteroaryl moiety λ* or an aliphatic, ϋ not present, or an even _, a second =: or a group called ..., -NRfRo, - ORF, -SRF, or (C-〇), and its center is the base part of the residue, wherein RD, R4: base or hetero-group 'cycloaliphatic, heteroaliphatic, cycloaliphatic, aromatic A is ^^为为,族, -C((四)其&quot;Z is an aliphatic, heterodish group: = base group group), or the knowledge and &amp; or heart and ^ from the use of soil or miscellaneous The aryl moiety or the 8-membered substituted or unsubstituted: ·, ' 5 ·, 6_, 7_ fly % heteroaliphatic moiety 85762-980904.doc 1322807 'where ~ and Ry exist in each Independently a hydrogen, aliphatic, cycloaliphatic, heteroaliphatic, cycloaliphatic, aryl or heteroaryl moiety, _c(o)kz (wherein Rz is aliphatic, heteroaliphatic, aryl or a heteroaryl moiety is broadly defined as a 4- or 5- or 6-membered substituted or unsubstituted saturated or unsaturated cycloaliphatic or cycloaliphatic moiety; Each of the aforementioned aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, Or acyclic, linear or branched, saturated or unsaturated; and wherein the aforementioned aryl or heteroaryl moiety may be substituted or unsubstituted. % 4. According to the scope of the patent application a compound in which the compound has a structure: Φ wherein Rl, R2, Rf and are as defined in the first paragraph of the patent application. 5. The compound according to claim 1, wherein the compound has the following structure: 85762-980904.doc IS where Ri, R2, RF and % are as defined in the 丨 丨 丨 〇 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据馆&gt; A , , 寸 干 化合物 第 第 第 第 第 第 第 第 第 第 第 - 中R! R2, RA% are as defined in item i of the patent application scope 〇 7. According to the scope of patent application 】 Top Structure: . 祀固弟1 compound, of which the compound has the following R2 . R2 'RF and Rq, as applied for, wherein the compound has the following wherein q and r are each independently 1 or 1; and &amp; 丨, as defined in the first item of the patent scope. 8. According to the compound of the scope of patent application i, structure: 85762-980904.doc ^2 ; 1322807. Where q and r are each independently 〇 or 1; and the heart, R2, RF and % are as defined in item 1 of the scope of the patent application. 9. A compound according to claim 1 wherein the compound has the structure: R2 RqRfN wherein &amp;, R2, and R〇 are as defined in claim 1 of the patent application. 10. The compound according to claim 1, wherein the compound has the following structure: RGRfN Wherein 1, R2, Rf and R〇 are as defined in the first paragraph of the patent application. 11. According to the compound of claim 1, wherein the compound has the following structure: R2; its center and R2 are as defined in the first paragraph of the patent application; 85762-980904.doc -6- 1322807 m is 〇, 1 or 2; and the cycloaliphatic aryl or heteroaryl RF is aliphatic, a group of heterocyclic aliphatic or heteroaliphatic groups; and each of the armor is aliphatic or heteroaliphatic or unsubstituted, cyclic or acyclic/cluster, independently substituted; and each of the foregoing Aromatic = dimorphic or branched, saturated or unsubstituted or unsubstituted. The heterocyclic group moiety may independently be a compound of which the compound has the following C according to the scope of the patent application: R2 · wherein Rl and R2 are as defined in the first paragraph of the patent application; and Rf is a mouse 'protective group, or a lipid, a bright, a soil, a heteroaliphatic, a heteroaliphatic a aryl or heteroaryl moiety; wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be substituted or unsubstituted, cyclic or acyclic, linear or branched, It is saturated or unsaturated, and each of the aforementioned aryl or heteroaryl moiety groups may be independently substituted or unsubstituted. 13. According to the scope of the patent application! A compound of the formula wherein the compound has the structure: ^ 85762-980904.doc 丄 JZr厶OV7 f Where RjR2 is as defined in the patent _1; G is CH2 or -(C=〇); and 〇s C~〇, S=〇, C=CR4R5, or (8)匕; where WR5 Each existing system, independently hydrogen, thiol, cyano, alicyclic, heterocyclic, aryl or heteroaryl moiety ' or 'C(0)RZ (where k is H) An aliphatic, aryl or heteroaryl moiety; wherein each of the oxime or heteroaliphatic moiety can be independently substituted, cyclic or acyclic, linear or branched. , the aforementioned aryl or heteroaryl part of the United States can think of - & _ 14_ root ❹ 财 ( (4) filth or unsubstituted. Structure. The compound of the first item, wherein the compound has the following H 〇 2 ; where R 丨 and R 2 are as defined in item 1 of the patent scope when applying for the gamma gamma; G is CH2 or -(c=〇); and X is Ο, S, c=〇, r , R4 and the existence of the heart, independent ^CR4 or CR4 R5; where 浐^ horse 虱, hydroxy, halogen, cyano, alicyclic, heteroaliphatic, aryl or 哞 一 * a group, or -C(0)Rz (in the pot 85762-980904.doc m Rz is an aliphatic, heteroaliphatic, aryl or heteroaryl group); and wherein each of the aforementioned aliphatic Ge is lacking# Or the heterozygous part of the group may independently be substituted by A, substituted by ring or this f # ^ times non-%, linear or branched, and each 15::::= base part of J1 The group can be independently substituted or unsubstituted. Structure: β &quot; Compound of the first item, wherein the compound has the following '中Rl和尺2岣 as defined in the first paragraph of the patent application scope; G is CH2 or -(c=〇); and 'S 'C=&lt;), S==0 'C=CR4R5, NR4 or CH Wherein each of ~ and R5 is independently hydrogen, thiol, dentate, cyano, aliphatic mm-aryl moiety, or -c(〇)Rz (wherein Rz is aliphatic, heterolipid) Wide range of group, aryl or heteroaryl groups And the aliphatic or heteroaliphatic moiety of each of the eight intermediates may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched, and each of the aforementioned aryl or heteroaryl portions The moiety may be independently substituted or unsubstituted. 16. The compound of claim 1, wherein the compound has the following structure: 85762-9S0904.doc -9- 1322807. R2 . where R! and R2 are as defined in item 1 of the patent application, P is an integer 0-3; s is an integer 0-4; l π k &amp; 合 隹慝 独 _ _ 句 句 句 句 句, s So C CR4R5, -NR4 or _CR4r5, the center and the heart are independent of each other 1, the base ' _ prime, the base 'wind', _SRX, xRy 'aliphatic, heteroaliphatic, aryl or hetero An aryl moiety, or x is -C(0)RZ (wherein Rz is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety); and wherein A and B, B and D, _ , K, and any of the K-rings of the soil, when the valence bond allows, can be linked by a single or double bond; wherein r and ^ exist independently of hydrogen, protecting groups, or aliphatic, hetero (4) Or a heteroaliphatic heteroaryl moiety; two: 'aryl, aliphatic aryl, heteroaliphatic aryl, aliphatic heteroaryl and wherein each of the aforementioned aliphatic or heteroaliphatic moiety is independently Or unsubstituted, j sorrow or acyclic, linear or branched, saturated, and each of its precursors, "aliphatic aryl, aryl, aliphatic heteroaryl or heterozygous or not Replaced. Inquiries 17. According to the scope of patent application No. 1.16 The compound of any one of the compounds is a substituted or a non-stirring group. The &amp; 85762-980904.doc 1322807 18_ is hydrogen according to the scope of the patent application. A compound according to any one of the preceding claims, wherein Rl 19. is substituted by a halogen or a hydroxy group, depending on the scope of the patent application, u 6 ^ or CVQ alkenyl. 20. According to Article _16 of the scope of application for the patent (4). Any of the compounds in the item, of which R2 21. According to the scope of the patent application! Item 1-6, wherein R is a methyl group. 22. According to the scope of patent application, item i_16 is hydrogen. The compound of the item, the center of which is 23. The compound according to any one of the claims of the invention, wherein the medium- or R-- is hydrogen or a low-carbon sulphonic group; and the other is a burnt base or miscellaneous a aryl group, an aryl group, a heteroaryl group, a aryl group or a aryl group, which is independently substituted by ❹(tetra), thiol, thiol or substituted or unsubstituted Substituted, heteroalkyl, aryl or heteroaryl substituted, or the center thereof is used together with ~ as a 3_, 4_, 5_, 6, 7 or 8_ member substituted or unsubstituted, saturated or unsaturated ring or A heterocyclic moiety. 24. A compound according to any one of the items in paragraph 4.1() of the scope of the patent, wherein one of &amp; or R〇 is hydrogen or lower alkyl; and the other is arylheteroaryl, alkylaryl Or an alkylheteroaryl moiety, independently of each occurrence - or a plurality of i, alkoxy, thiol or substituted or unsubstituted fen, rhodamine, aryl Substituted or heteroaryl substituted, or wherein RF and R 〇 are employed as 3-, 4-, 5-, 6-, 7- or 8-member substituted or unsubstituted 85762-980904.doc • 11 - , A saturated or unsaturated cyclic or heterocyclic moiety. 25. The compound of the 24th patent of the patent application is known as nitrogen or low carbon alkyl; the other is phenyl, ton, phenyl or (calcining base) A biting group, optionally in the presence of one or more halogens, a methoxy group, a methoxy group, a trifluoromethyl group, a methylthio group or a substituted or unsubstituted lower alkyl group or a lower alkane. A compound according to any one of claims 4 to 11, wherein one of ~ or R is hydrogen or lower alkyl; and the other is cyclic or Acyclic, linear or branched, saturated or unsaturated aliphatic moiety, optionally substituted with one or more substituted or unsubstituted aryl, heteroaryl, decylamine, alkoxy, hydroxy , a thioalkyl group, a thiol group, a thiol group or an amine group. 27. A compound according to item U of the patent application, wherein ~ is an alkyl group, a cycloalkyl group, a heteroalkyl 'cycloalkyl group, an aryl group, Heteroaryl, alkylaryl or alkylheteroaryl, as the case may be, independently, by one or more halogen, alkoxy, thioalkyl or substituted or unsubstituted a substituted alkyl, heteroalkyl, aryl or heteroaryl group. 28. A compound according to claim 12, wherein the center is hydrogen, a protecting group, or a decyl group, a cycloalkyl group, a heteroalkyl group, a ring a compound, an aryl group, a heteroaryl hydroxy group or an alkyl group, optionally substituted by one or more elements, alkoxy, thioalkyl or substituted or Substituted unsubstituted alkyl, miscible, aryl or heteroaryl. 29. According to the compound of claim 1, the compound has the following formula: 85762-980904.doi •12· 1322807 85762-980904.doc -13- 1322807 ; or σ Or a pharmaceutically acceptable salt, ester or salt thereof. 30. A compound according to claim 1 wherein the compound has the formula: -14- 85762-980904.doc [S 1322807 and pharmaceutically acceptable salts thereof. 31. The compound according to claim 1 wherein the compound is selected from the group consisting of: 85762-980904.doc 15- 1322807 85762-980904.doc 16- 1322807 11 H HN^N 12 ◦cr〇&gt;^ H ΗΝγΝ cf3 13 O^O^2 H HN^N 14 cro>^H2 H HNsj^N 15 cn〇h^ 16 OXQ^ H2 H HN^ 85762-980904.doc -17- 1322807 85762-980904.doc •18- 1322807 85762-980904.doc -19- 1322807 85762-980904.doc •20- 1322807 40 41 Ν 丫ΝΗ 42 9°ΝΗ2 νηζ , s Η ν′丫'ΝΗ 43 9〇2Me νη2 45 〇CT〇&gt;^H2 Η Ν丫ΝΗ 46 χηα^2 ΝγΝΗ 47 48 〇τη〇&gt;^Η2 Η Ν 丫ΝΗ 85762-980904.doc -21 · 1322807 85762-980904.doc -22- IS ] 1322807 85762-980904.doc •23 · 1322807. 85762-980904.doc -24- 1322807 74 /JH2 75 76 77 Η ΝγΝΗ 78 MeO, Λ αΝ^Λα^Η 79 nh2 〇 H ΝγΝΗ ό 80 . NH H Ν'丫 NH 85762-980904.doc -25- 1322807. 85762-980904.doc 26- 1322807 85762-980904.doc •27- 1322807 97 nh2 H ΝγΝΗ 98 nh2 H ΝγΝΗ 99 Me〇^^:2 HN^NH 100 H Ν'丫, NH 101 Q 9 nh2 ^〇Υ'〇Λαν^Ν NH 丫, NH 102 c^a^H2 OMe HN^ NH 103 nh2 Meoir^xcv^NHN^NH 104 MeO 0 mu 6V〇^2 H ΝγΝΗ 105 MeO k|Li ώ^α&gt;·^2 H ΝγΝΗ 85762-980904.doc 28 · 1322807 106 Η Ν'丫'NH 107 F3Cxrr〇^: H Ν^ΝΗ 108 nh2 F3C^Xcv^n HN 丫NH 109 nh2 oxo&gt;^ HN 丫NH 110 H NH2 CD^O&gt;^n Η HN^NH Trans racemic [ 111 H NH2 HHN^NH Cis racemic T 112 『NH2 广HN^NH 113 NHZ &quot;TH ym 114 nh2 85762-980904.doc -29- 1322807 85762-980904.doc -30- 1322807 124 nh2 1 H ΝγΝΗ 125 nh2 Η ΝγΝΗ 126 nh2 HN 丫'NH 127 Cl ”nh2 HN 丫'NH 128 nh2 Crr〇h^ HN 丫, NH 129 nh2 HN 丫NH 130 nh2 0 ^0)^ H ΝγΝΗ 131 H Ν^,ΝΗ 85762-980904.doc •31 - 1322807, 132 nh2 THN?H 133 nh2 HN 丫NH 134 nh2 Kj HN丫NH 135 β~λ nh2 136 〇^calling: 137 nh2 ox^xcv^^ HN 丫'NH 138 nh2 (X^'Xcv^n H n^nh 139 nh2 140 nh2 ΝγΝΗ 85762-980904.doc -32- 1322807 141 Η N 丫NH 142 nh2 CN HN^NH T 143 144 HN 丫'NH 145 nh2 〇H NrNH 146 nh2 NCiXa^NHN 丫NH 147 nh2 crr〇&gt; ^ Η ΝγΝΗ 148 HN^NH has 85762-980904.doc -33- 1322807 85762-980904.doc •34- 1322807 157 nh2 HN 丫NH 158 nh2 Η N 丫NH 159 nh2 HN^NH 160 nh2 HN 丫NH 161 HN^NH 162 HN^NH 163 H n^nh 164 HN^NH 85762-980904 .doc -35- 1322807 165 Η Ν^ΝΗ 166 tenνη2 ^XCV^N Η Ν 167 167 α^α&gt;~^:2 Η ΝγΝΗ 168 &lt;ΤΙ Η ΝγΝΗ 169 Τΐ ^rXcv^N Η ΝγΝΗ 170 MeO&quot;N^f^ ΝΗ2 Η NyNH 171 Η〇Υ^1 ΝΗ2 Η Ν下'ΝΗ 172 νη2 ηο^Χ〇-^ ΗΟ Η ΝγΝΗ 85762-980904.doc -36- 1322807 173 Η Ν^ΝΗ 174 &lt; ^ ”Η2 Η Ν 丫'ΝΗ 175 ΗΟ〆Η Ν 丫'ΝΗ 176 νη2 Η Ν^ΝΗ 177 0^X0·^ Η ΝγΝΗ 178 νη2 Ν 179 179 νη2 .0〇^〇ν^Ν Η Ν^ΝΗ 180 νη2 Η Ν 丫ΝΗ 85762-980904. Doc •37- 1322807, 181 NH2 H HyUH 182 nh2 OH HN 丫NH 183 n ”nhz H NyNH 184 HN^NH 185 aj^XH^2 1 HN丫NH 186 HN 丫'NH 187 &lt;n /nhz HN 丫'NH 85762-980904.doc -38 - 1322807 188 Λ ν η 189 189 ΝΗ ΝΗ 189 189 ΝΗ ΝΗ ΝΗ ΝΗ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 192 192 192 192 C C C C C C C C C C C C C C C 194 194 194 194 194 194 194 194 194 194 194 194 194 194 194 194 194 Η Ν^ΝΗ 85762-980904.doc 39- 1322807 195 Η ΝγΝΗ 196 n , NH^ H N^NH 197 nh2 F H N^/NH 198 nh2 1 H N^NH 199 nh2 , . : 1 H N^NH 200 ,. : 1 Η Ν^,ΝΗ 201 Γΐ ”NH2 H n^nh 202 ^sC〇cv^H2 H n^nh 85762-980904.doc -40- 1322807 203 Η ΝγΝΗ 204 Η Ν^ΝΗ 205 F&quot;V^L JH2 Η Ν 丫, ΝΗ 206 νη2 Η Ν^ΝΗ 207 CVi νη2 'Ν,Γι〇&gt;^ Η Ν^ΝΗ 208 (ΤΙ ΝΗ2 Η Ν^ΝΗ 209 νη2 〇rn〇h^ Η Ν 丫, ΝΗ 210 Cl ” ΗζΗζ -Χ0-^ν Η Ν^,ΝΗ Γ Γ 1 85762-980904.doc •41 - 1322807 85762-980904.doc -42- 1322807 219 Η N^NH 220 H n^nh 221 MeO*#/.a^ HN 丫NH 222 HN 丫NH 223 OjCO^n HN^NH 224 cbxcv^ HH Ν'丫'NH 225 HN 丫NH 226 kjl H n^nh 227 A- /iXcv^ HN 丫NH 85762-980904.doc -43 - 1322807 228 HN 丫'NH 229 HN 丫NH 230 cx.tj〇cyHPN HN丫NH 231 s^JH n^nh 232 H n^nh 233 H n^nh 234 Jo H 丫H 235 236 HN^NH 85762-980904.doc 44- 1322807 237 h 丫h 238 On H NyNH 239 o H nT; NH 240 MN 丫NH 241 a, HN^NH 242 HN^NH 243 Η ΝγΝΗ 85762-980904.doc • 45- 1322807 85762-980904.doc 46- 1322807 252 r 253 H ΝγΝΗ 254 NHZ Η Η, 255 V N V ( H NH r 256 〇&gt; N 丫 NH 257 八八八 a cvr YV\ &gt;=( H H N^.NH 258 259 N~NH 260 85762-980904.doc 47- 1322807 261 丫Η 262 α&gt;^ Η Ν^ΝΗ 263 ^j〇v^N 〇上JT Η Ν^ΝΗ 264 .nJ〇Q^Pn L! Η Ν 丫ΝΗ 265 ^ij〇CV^PN 〇rJ Η ν? 266 266 tjCcv-^N ν η NyNH 267 °^〇ν^ Η ΝγΝΗ 268 νη2 Η ΝγΝΗ 269 〇O^Xcv^N Η 丫ΝΗ 丫ΝΗ 85762-980904.doc -48- 1322807 270 nh2 HN 丫NH 271 H ΝγΝΗ 272 NH2 Η ΝγΝΗ 273 N 丫NH 274 nh2 ΝγΝΗ 275 nh2 JJCC)-^n JHN 丫NH 276 HN^NH 277 nh2 χχΗ NrNH 278 Cj HN?NH 85762-980904.doc -49- 1322807 278 OnJCcv^P&quot; Η ΝγΝΗ 279 Η ν^νη 280 〇Cr&amp;v^N Η Ν^ΝΗ 281 Η ΝγΝΗ 282 Η Ν 丫ΝΗ 283 aiXc^H 284 crij:^ 285 cr〇^N Η Ν 丫NH 286 Η ^yHH 85762-980904.doc -50- 1322807 85762-980904.doc -51 - 1322807, 295 Ο Ν ΝΗ^ΝΗ 296 Η 297 297 、 Η Ν ΝΗ 298 298 Η UyHH 299 ^njCcv^n Η ΝγΝΗ 300 σ6^2 Η ΝγΝΗ 301 Η ΝγΝΗ 302 Η ΝγΝΗ 85762-980904.doc -52· 1322807 303 Η ΝγΝΗ 304 311 ΝΗ ΝΗ 305 305 305 305 305 305 305 305 305 305 305 305 305 308 308 308 308 308 308 308 308 308 308 309 308 308 308 308 ΝΗ ΝΗ ΝΗ ο ο ο ο ο ο 311 ο ο ο ο ο 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 311 r c 1 85762-980904.doc -53 - ' 1322807 313 Ur〇cy^ Η Ν^ΝΗ 314 Un〇h^2 Η 丫 丫'ΝΗ 315 Η Ν^ΝΗ 316 ΗΟ^ Η Ν^,ΝΗ 317 νη2 OnJ〇CV-^n Η Ν 丫ΝΗ 318 Λχ&gt;^: 2 Η ΝγΝΗ 319 α Ν Ν^ΝΗ 320 321 Η NyNl·Sr 85762-980904.doc 54 · 1322807 322 nh2 Me0Ocv^N Η N 丫NH 323 nh2 N^NH 324 nh2 N 丫NH 325 . HN 丫NH 326 HN 丫NH 327 HN 丫NH 328 HN 丫NH 329 HO^ HN 丫NH 85762-980904.doc 55 · 1322807. 330 H ΝγΝΗ 331 HN 丫NH 332 HN 丫NH 333 HO^ HN 丫NH 334 H ΝγΝΗ 335 HN 丫NH 336 HN 丫NH 337 HN 丫NH 85762-980904.doc 56 · 1322807 338 Η ΝΙ 丫ΝΗ 339 Η Ν 丫ΝΗ 344 Η 343 342 342 342 344 343 343 343 345 345 344 344 344 345 345 345 345 345 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 762 347 HN 丫NH 348 cro^ N 丫NH 349 -HN 丫NH 350 HN 丫NH 351 ΝγΝΗ 352 NyNH 353 〇N 丫NH 354 〇HN 丫NH 355 1 ～ ^ 0 ΝγΝΗ 85762-980904.doc -58- 1322807 356 1 0 Ν 357 357 ο Η ΝγΝΗ 358 〇~ 359 斗^ 〇ΝγΝΗ 360 1 ο ΝγΝΗ 361 丫一362 ΝγΝΗ 363 O^j〇v^ 〇Η ΝγΝΗ 364 &gt; 〇ΝγΝΗ 365 &gt; 0 Ν 丫ΝΗ 85762-980904 .doc -59- 1322807. 85762-980904.doc -60- 1322807 32. A compound of the formula: -61 - 85762-980904.doc 丄d厶厶ovj / o and its pharmaceutically acceptable salts. 33. A pharmaceutical composition comprising a compound having structure 1: R2 (I) and a pharmaceutically acceptable salt, ester or salt thereof; wherein η is an integer 〇_4; heart is chlorine, -NH2, -NHMe, -NHAe, -OH'F, _〇 Me, or -NH(C=〇)〇Et; R2 is hydrogen, -nrarb, _ORa, aliphatic, hetero, aryl or heteroaryl a base group in which R^RB is independently a hydrogen or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; R; each of the radicals is independently hydrogen, a cycline, or a cyano group, or An aliphatic, heteroaliphatic, aryl or heteroaryl moiety K' or a group of groups, wherein G is absent, or is even, _m((9)), and its core is gas, -NRfRg, - 〇rf, _SRf, or an aliphatic, heteroaliphatic aryl or heteroaryl moiety, which gives R, R and each individual mf as hydrazine, wind%, aliphatic mm, cycloaliphatic, aromatic a hetero or heteroaryl moiety '-C(〇)RZ (wherein Rz is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety 85762-980904.doc • 62-1322807 money)' or its W And (4) called, - or 8 - bead replaced or not, '5,, .% of the gas of the month or ring heteroaliphatic part of the base circle. The existence of each of MRy is independent % ^ ^ 勹虱知私, cycloaliphatic, heterozygous, bad heteroaliphatic, aryl or 卩&amp; base®, &lt;(〇)Κζ( φ'= Is a H heteroaliphatic, aryl or heteroaryl moiety (Fig. 5), or its p, Ry- is taken as 4, 5 or 6. Substituted or unsubstituted: saturated or unsaturated cycloaliphatic Or a cycloaliphatic moiety; wherein each of the aliphatic or heteroaliphatic moiety can be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or Unsaturated' and wherein each of the preceding or heteroaryl moiety can be independently substituted or unsubstituted; and a learned carrier or diluent; and optionally another therapeutic agent. 34. A pharmaceutical composition according to claim 33, wherein the compound is present in an amount effective to inhibit the inflammatory cytokine pathway. 35. The pharmaceutical composition according to claim 33, wherein the compound is present in an amount effective to inhibit cell proliferation. 36. The pharmaceutical composition according to item 33 of the scope of the patent application, wherein the compound is present in an amount effective to exhibit an anti-inflammatory effect. 37. The pharmaceutical composition according to claim 33, wherein the compound has the structure: 85762-980904.doc -63- wherein R3a and R3b are each independently a dentate, aliphatic, aryl or heteroaryl moiety, Rat soil 'or aliphatic, miscellaneous, group ' or group -G-Rc ' J: medium G is absent, -CH2-, -NRd_, _〇~八中〇, -〇RF,- SRF, or aliphatic, ground) and wherein Rc is hydrogen, -nrfRg, wherein RR „\ , , also aliphatic, aryl or heteroaryl moiety, RD, heart and heart, and heterotrophic Family, ring heterolipids; ^" xRy, aliphatic, cycloaliphatic wherein rz is rr $ or heteroaryl moiety kappa (〇)ΙΙζ (r κζ is aliphatic, heterolipid brigade, - center and RC or And the %, / or heteroaryl group), or the % thereof, is a ring substituted by 3-, 4-, 5-, 6-, 7- or 8_ An aliphatic or cycloaliphatic moiety; wherein Rx and 'where present are independently hydrogen' aliphatic, cycloaliphatic, heteroaliphatic, cyclic 1, aryl or heteroaryl moiety, _c (0) Rz (wherein Rz is a lipid, a heterozygous "vector of a sagittal, aryl or heteroaryl moiety" ), or a saturated or unsaturated cycloaliphatic or cycloaliphatic moiety which is employed as a 4- 5- or 6-g π, , '-a-, ic-substituted or unsubstituted, together with ^ a group; and / or each of the aliphatic or heteroaliphatic moiety may be independently substituted or unsubstituted, bad or acyclic, linear or branched, or not saturable' Each of the aforementioned aryl or heteroaryl moiety may be independently substituted or unsubstituted. 38. The pharmaceutical composition according to the scope of the patent application, wherein the compound has 85762-980904.doc IS 1 -64-1322807 Has the following structure: Wherein RSa and Ru are each independently a hydrogen, hydrazine &amp; aliphatic, aryl or heteroaryl moiety, or a group: a base 'or aliphatic,: absent or even-, -NRD-,-0- Or (c = ^ G heart, wherein G - NRA, - 〇 RF, _SR Ge ', and wherein Rc is a hydrogen group, one of which: mono-, cycloaliphatic, heteroaliphatic, cycloaliphatic, aromatic义xRy月曰族-C(9)Rz (where Rz is an aliphatic, heteroaliphatic group: a radical group, a soil or a heteroaryl moiety) Correction/heart and heart or heart and ^, starting from 3,4- , 5-6-: or 8-beta substituted or unsubstituted s ': where each is represented by a cycloheteroaliphatic moiety 3 heteroaliphatic, cycloaliphatic, aryl or kiln Is an aliphatic, heteroaliphatic, aryl λ: group: P group '-C(〇)Rz in W- using ...::= part of the group), or its member! Substituted or unsubstituted And or unsaturated cycloaliphatic or cycloaliphatic moiety _ ; 2: Γ The aforementioned aliphatic or heteroaliphatic moiety can be independently substituted =::, cyclic or acyclic, linear or fractional Branched, saturated or not "medium" or (4) radical moiety can be independently substituted or unsubstituted According to the scope of patent County pharmaceutical composition of item 33, wherein the compound has the following structure Shang 85762-980904.doc -65-: R2 义 where Ri, R2, % and the scope of claim 3 of the patent scope 40. According to the scope of patent application No. 3 3 $ &lt; Xile composition, wherein the compound has the following structure: 〃 RqRpN Wherein Rl, R2, h and R are all pharmaceutical compositions of claim 33 in the scope of claim 3, wherein the compound has Righteousness. Scope of Article 3 3 42. According to the scope of application 坌 The pharmaceutical composition of Group 33 has the following structure: r compound with 85762-980904.doc -66 - 1322807 43. The pharmaceutical composition according to the third aspect of the Chinese patent, wherein the compound has the following structure: Where q and r are each independently 〇 or 1; and the heart, heart, knowledge, and mind are as defined in claim 33 of the main patent scope. Month 44. The pharmaceutical composition according to item 33 of the patent scope, which has the following structure: /, R2 where Ri, R2, heart and !^ are as defined in item 33 of the patent application.疋 45· According to the third paragraph of the patent scope of the Chinese patent, the following structure: The medical composition of the compound wherein the compound has 85762-980904.doc -67- 1322807 The heart and the uniform are as follows. Please refer to the patent range 33 where &amp;, r2, meaning. 46. According to the patent application model, the following structure: The pharmaceutical composition of Section 33 of the formula MR2 is as defined in the second paragraph of the patent application scope. m is 0, 1 or 2; and 疋 I'RF is aliphatic, cycloaliphatic, heterozygous steroids, nuclear heteroaliphatic, aryl base Group; Wanhao A miscellaneous Further, each of the scorpion or heteroaliphatic moiety may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, saturated or unsaturated; and each of the foregoing The aryl or heteroaryl moiety can be independently substituted or unsubstituted. Wherein the compound has 47. The pharmaceutical composition according to Item 3 of the patent application has the following structure: 85762-980904.doc -68- It is as defined in Article 33 and is known as the second, protecting group, or wax, ring wax, miscellaneous, cycloaliphatic, aryl or heteroaryl a base circle; wherein each of the aforementioned aliphatic or heteroaliphatic moiety groups may independently be substituted 2, (4) (4), (4) or branched 1 and or unequal, and each of the foregoing aryl or Hetero-substituted or unsubstituted. (4) The square group # group can be independently as the pharmaceutical composition according to Article 33 of the patent application scope, and has the following structure: R2, 〇 where rar2 are as defined in Article 33 of the patent application scope; G is CH or -(C=〇); and X is the existence of each of the reference w is hydrogen, meridine, acetyl, cyanide a fatty, heteroaliphatic, aryl or heteroaryl moiety, or _c(〇)Rz (in the middle, Rz is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety) The alicyclic or heteroaliphatic moiety of each of the sylvestris may be independently substituted or unsubstituted, cyclic or acyclic, linear or branched, and each of the foregoing aryl or heteroaryl The binder group can be independently substituted or unsubstituted. 49. The medical compound according to item 33 of the scope of the patent application, wherein the compound has the following structure: 85762-980904.doc -69-1022m/ Where R! and R2 are as defined in Clause 29 of the patent application; G is CH2 or -(C=〇); and X is 〇, S, c=0, s=0 ' C=CR4R5, NR4 or CR4R5 Wherein each of WR5 is independently hydrogen, a meridine, an imine, a cyano group, an aliphatic, a heteroaliphatic, an aryl or a heteroaryl moiety, or a _c(〇)Rz (wherein Rz is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; wherein each of the aforementioned aliphatic or heteroaliphatic moiety can be independently substituted or unsubstituted, disubstituted, cyclic or Acyclic 'linear or branched, and wherein each aryl or heteroaryl moiety of each month can be independently substituted or unsubstituted. 50. The pharmaceutical composition according to claim 33, wherein the compound has the following structure: Where &amp;&amp; are as defined in Section 3 of the patent application; G is CH2 or -(c=〇); and X is 〇, S, C=〇, S=〇, C=CR4R5, NR4 Or CR4R5; wherein each of R4 and R5 is independently hydrogen, hydroxy, (tetra), cyano, aliphatic, heteroaliphatic, aryl or heteroaryl moiety, or -C(0) RZ (where 85762-980904.doc iS-70-, aryl or heteroaryl moiety); =, each of the aliphatic or heteroaliphatic moiety can be independently substituted = substituted, ring Or a non-cyclic, linear or branched form, and wherein each of the groups or heteroaryl moiety can be independently substituted or unsubstituted == the scope of the pharmaceutical composition of item 33, wherein the compound has the following structure : R2; where R] and heart%% of the patent application scope of the third paragraph of the definition of P is an integer 0-3; s is an integer (M; A, B, D, E' and κ are independent of each other Existence, 〇S, -C=0, -S=〇, _C=CR4R5, Na or CR4R5 are independent of hydrogen, thiol, cyano, and -NRxRy a group, a heteroaliphatic, aryl or heteroaryl moiety, or a -C(9)Rz (wherein Rz is an aliphatic, heteroaliphatic, aryl or heteroaryl moiety); and its tA and &quot; And ... coffee ^ and any two ^ neighboring groups, when the valence bond allows 'can be connected by single or double bonds; wherein, with each of them exist independently hydrogen, protecting groups, or aliphatic, fatty a Group X, an aryl, a heteroaryl, an aryl, a heteroaliphatic aryl, an aliphatic heteroaryl or a heteroaliphatic heteroaryl moiety; the earth wherein each of the aforementioned aliphatic or heteroaliphatic moiety The group may independently be substituted 85762-980904.doc • 71 · ^ unsubstituted, cyclic or non-relative, linear or branched, saturated or different, and each of the foregoing aryl, heteroaryl aliphatic aryl , heteroaliphatic aromatic earth, aliphatic The aryl or heteroaliphatic heteroaryl moiety may be independently substituted or unsubstituted. 52_ According to the scope of the patent application, 3 3 _ R is NH 2 . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Or a dilute group, the alkyl group and the dilute base are optionally substituted by a dentate or a hydroxy group. The pharmaceutical composition according to any one of claims 33 to 51, wherein the rule 2 is a Q-C2 alkyl group. The pharmaceutical composition according to any one of the preceding claims, wherein the second aspect of the invention is the pharmaceutical composition of any one of the inventions, wherein R2 is hydrogen. The pharmaceutical composition according to any one of items 39 to 45, wherein ～ or ～ is hydrogen or a low hydroxy group; and the other _ is (4), (4) aryl aryl #aryl, alkyl aryl or alkyl aryl Each being' is optionally independently- or poly(tetra), silk-based, thio-based, or substituted or unsubstituted Mercapto, (tetra), aryl or heteroaryl substituted, or a saturated or unsaturated ring which is substituted or unsubstituted by 3_, 4_, 5_, 6_, 7_ or 8_ The pharmaceutical composition according to any one of claims 39 to 45, wherein one of rf or a heart is hydrogen or a low carbon burn group; And the other is an arylheteroaryl, alkylaryl or alkylheteroaryl moiety, independently of one or more halo, alkoxy, thioalkyl or Substituted by a substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl group, or a mixture thereof which is substituted or unsubstituted by 3,4_,5_,6_,7_ or 8_ Unsaturated cyclic or heterocyclic moiety. 60. The pharmaceutical composition according to claim 59, wherein one of the centers or centers is hydrogen or a lower alkyl group; and the other is a phenyl group, a pyridyl group, an (alkyl) phenyl group or a (alkyl) pyridine. Base, optionally in the presence of one or more halogens, trifluoromethoxy, methoxy, trifluoromethyl, f-thio or substituted or unsubstituted lower alkyl, lower carbon Alkylaryl or heteroaryl substituted. The pharmaceutical composition according to any one of claims 3-9 to 45, wherein one of RF or R〇 is hydrogen or a lower alkyl group; and the other is cyclic or acyclic, linear or a branched, saturated or unsaturated aliphatic moiety, optionally substituted with one or more substituted or unsubstituted aryl, heteroaryl, decylamine, alkoxy, hydroxy, thioalkyl, Mercaptothio or amino group substitution. 62. The pharmaceutical composition according to claim 46, wherein the center is a burnt group, a cycloalkyl group, a heteroalkyl group, a cycloheteroalkyl group, an aryl group, a heteroaryl group, an alkylaryl group or an alkyl heteroaryl group. The base, for each occurrence, is optionally substituted with one or more halogen, alkoxy, thioalkyl or substituted or unsubstituted alkyl, heteroalkyl, aryl or heteroaryl groups. 63. The pharmaceutical composition according to claim 47, wherein the gas protecting group is a thiol group, a thiol group, a methacrylic group, a miscible group, a cyclodextrin group, and a scented 85762-980904.doc-73· 1322807 Alkyl, arylaryl-heteroaryl, for each occurrence, as the case may be independently - or a plurality of self-priming, alkoxy 'thioalkyl or substituted ^ unsubstituted alkyl heteroalkyl Aryl or heteroaryl substituted. A pharmaceutical composition according to claim 33, which comprises a compound having the formula: •74- 85762-980904.doc IS 1322807 : or σ Ν c 1 85762-980904.doc •75 - 65. or a pharmaceutically acceptable salt, ester or salt thereof. Kind for 〆. A pharmaceutical composition for treating an inflammatory or autoimmune disorder or a proliferative disorder, comprising: a therapeutically effective compound (4) or a diluent according to any one of claims U 9 of the patent application; Further, another therapeutic agent is included as the case may be. 66. The pharmaceutical composition according to claim 65, wherein the pharmaceutical composition is for treating rheumatoid arthritis, ulcerative colitis/Clone's disease, central nervous system disease (CNS), such as multiple sclerosis, Systemic erythema: sore, asthma, allograft rejection/graft versus host disease (gvhd) cutaneous fistula, atopic dermatitis, eczema, urticaria, allergic rhinitis, = weakness, diabetes, spontaneous thrombocytopenic purpura , silky nephritis, heart and vascular disease or cancer. Wherein the pharmaceutical group 67. The pharmaceutical composition according to the scope of the patent application is for the treatment of rheumatoid arthritis. The pharmaceutical group 68. The pharmaceutical composition according to the scope of the patent application, the compound system For the treatment of ulcerative colitis/Clone's disease, wherein the pharmaceutical composition is used according to the patent application of claim 65, for the treatment of multiple sclerosis. Among them, the pharmaceutical group 70. The pharmaceutical composition according to the scope of the patent application is used to treat asthma. 65 pharmaceutical compositions, ιΑ». 6 of the pharmaceutical compositions 'where the pharmaceutical group' is the pharmaceutical group 71. According to the patent application range, the first compound is used to treat cowhide 72. According to the patent application scope 85762-980904.doc system for treating allografts Rejection / GVHD. 2 The pharmaceutical composition according to claim 65, wherein the pharmaceutical group %° is used for treating spontaneous thrombocytopenic puricolor. 2 The pharmaceutical composition according to claim 65, wherein the medical group is for treating allergic rhinitis. 75. The pharmaceutical composition according to claim 65, wherein the pharmaceutical group &amp; system is for treating atopic dermatitis. 76. The pharmaceutical composition according to claim 65, wherein the pharmaceutical group &amp; system is for treating systemic lupus erythematosus. The pharmaceutical composition according to claim 65, wherein the pharmaceutical composition is for treating spheroid nephritis. 78. The pharmaceutical composition according to claim 65, wherein the pharmaceutical composition is for treating diabetes. 79. The pharmaceutical composition according to claim 3, wherein the compound has the formula: And pharmaceutically acceptable salts thereof. 80. Use of a compound according to any one of claims 1 to 29 for the preparation of a medicament for the treatment of an inflammatory or autoimmune or proliferative disorder. 81. —The intermediate with the following formula, 85762-980904.doc -77- 1322807 〇Ο&quot;ΧΪ0^8ηΒυ3 Boc 85762-980904.doc -78-