SA97180648A - Novel bisindolylmaleimides, methods for their preparation and use, intermedlates therefor and pharmaceutical compositions comprising them - Google Patents

Abstract

The present invention relates to new indoleyl malimidate, methods of preparation and intermediate compounds for this purpose and pharmaceutical compositions comprising new compounds and intermediate compounds.

Description

New diindolyl maleimides, methods for their preparation and use, intermediate compounds to achieve this purpose, and pharmaceutical formulations containing a full description

BACKGROUND THE INVENTION The present invention relates to new (Jud sain) maleimides, and methods for their preparation; And intermediate compounds to achieve that purpose and pharmaceutical formulations. Includes new compounds and intermediate compounds.

© is a proteolytic enzyme (PKC) that is a family of non-phospholipid-independent serine/threonine specific enzymes that play an important role in the control, regulation, and differentiation of cellular growth. Therefore, activation of PKC is the cause of numerous human disease processes, including various forms of cancer, various forms of inflammation and/or immune disorders.

0 In addition to some neurological disorders; The PKC clamp may have therapeutic value in treating these cases. Various classes of compounds are designated as 1160 inhibitors, for example the sulfonamides isoquitoline, sphingosine and related sphingolipids, and endo-locarbazoles.

Ao EP 31,0328026 discloses the use of diindolyl maleimides;, a class of compounds related to indolocarbazoles; in medicines to treat a variety of disorders. Patent 17182/95 WO (Eli Lilly & Co.) is intended to describe AUS indolyl maleimides that are protease inhibitors.

Yes, although APKC antagonists have been described in the previous field, there is Tale Tala due to the presence of specific anti-inflammatory and immunosuppressive compounds that are suitable for oral and inhalation.

v General description of the invention. PKC new indolyl maleimides that are entanglers (AUS) A group of compounds of the formula (1) have been discovered, pharmaceutically acceptable salts and stereoisomers, whether in pure form or in the form of racemates; or mixtures of stereoisomers of These compounds are effective topically, moreover, these compounds are characterized by 0 activity in the body when taken orally; some of them are characterized by an enhanced anti-inflammatory effect and / or susceptibility to PKC The compounds of the present invention have the characteristics An inhibitor of improved solubility and/or improved potency orally and/or possesses the ability to inhibit .. Reactive oxygen species in inflammatory cells 0 The aim of the present invention is to provide new diindolyl maleimides and methods for their preparation And the intermediate compounds used for their preparation.Another objective of the invention is preferably ley the use of new compounds to treat inflammation and immune disorders can be taken orally for the topical treatment of inflammation and immune disorders; for example, the topical or oral treatment of diseases transmitted by Airway No, including inflammatory conditions For example, asthma, bronchitis and atopic diseases (inappropriately) such as rhinitis, dermatitis, Crohen's disease, Jia's atopic disease, and psoriasis; and colitis diseases; And rheumatoid arthritis and malignant diseases (for example, skin cancer and lung cancer). With a pharmaceutically acceptable adjuvant, diluent, or carrier las, as an active ingredient Detailed description: (1) Compounds according to the present invention are available from the formula 0 0 8 0 : L 0 AH L

N N sell | 2

Since each of the : 1220 which may be similar or different, is hydrogen or halogen; RY is methyl or hydrogen or 1 « 15.000 is a group of formula (11): , (CH,)n Ry 1 _© RC R, H Rs where 2 is single or double bond; 1 be from 1 to yy 0 be [12 is a hydroxy ; hydroxymethyl, amino « (C5-Cp)) alkyl) amino; As Nal ((01-05)methylamine, 14,17-di(C5-Cp))alkyl)methylamine, (01-05)acyloxy or (C5-C1)) - N acyl) amino + and be 142 and R3 is hydrogen; And when 7 is a single bond, it is 164 and Rs which may be the same or different. Each one is a hydrogen or a hydroxyzo salts that are pharmaceutically acceptable, in addition to all possible stereoisomers, whether in a reliable form or in the form of racemes or LIMA of the stereoisomers of those salts. Preparation methods used Y. Compounds can be prepared from formula (1) and pharmaceutically acceptable salts, in addition to possible stereoisomers, whether in pure form or in the form of racemates or mixtures of stereoisomers from these compounds by: 0 a) producing a compound from the formula (1) in which Rp is a hydroxyl or a methyl landay hydroxy in which Z is a single bond; So Ry and 115 are each one of them

0 hydrogen; By deprotecting a similar compound of character (1) in which RY is a hydroxyl group protected or a methylene dala of a Lams hydroxyl group or (b) produces a compound of character (1) in which [14 is amino or methyl amino; And when 7 is a single bond; So Ry and 165 are each a hydrogen of ©° by: a) reducing a similar compound in which Rp is more or more methyl 0 or i) removing the protection of a similar compound of formula (1) in it Ry is a protected amino group of methylene carrier of a protected amino group; or c) produce a compound from phenotype (1) in which Rp is an amino, 17-((25-01)alkyl) (C5-C1) ) di-N,N, alkyl) methylamine (CC) = No amine; amino methyl 0

Rs is one of 184 and JS is an alkyl) an amino methylation «and when 7 is a single bond» then it is hydrogen; By reaction of an ammonia or a suitable amine with a corresponding compound of which is a good methylene group or a carrier methylene group Ry character (]) in it or 0 leaving successively good Ge sand -17 is an acyloxy (01 -p) or Ry d) produce a compound of formula (1) in which 0

Ry acyl) is an amino, and when 7 is a single bond, each of (C5-C1)) is a hydrogen, by an acyl treatment of a corresponding compound of Rs and it is a hydroxy or an amino successively; or Ry with the adjective (1) in which it is a hydroxy acid; Hydroxy Ry e) the production of a compound from the character (1) in it

Ry single bond; each of the Z is methyl 10 amino; amine methyl, and when Ys: (0111) and 145 it is hydrogen, by a complex reaction of the formula 0 0 0 <> and | | [ 1 : 8 8 20

R R'

where RY, 120, and 18 are specified as in the adverb (D), but where RY is a protected hydroxyl group of a methylene carrier of a protected hydroxyl group or a protected amino group; or a methylene carrier of a protected amino group protected aminos; with (i) ammonia; or ammonia followed by treatment with an appropriate deprotecting agent 0 or (i) 0 ammonium acetate followed by treatment with an appropriate deprotecting agent; or (ii) hexamethyldisilazane-methanol This is followed by treatment using an appropriate removal agent and) producing a compound of character (1) in which Ry and A is a hydroxyl” by hydroxyl treatment of a compound of character (1) in which 7 double bonds are formed in the presence of 0 A metal oxidizing agent such as JBL or g) convert (i) a compound of formula (1) into a pharmaceutically acceptable salt of that compound; or vice versa 0 or i) a pharmaceutically acceptable salt of a compound of formula (1 ) to a different pharmacologically acceptable \o salt. In a process a) the conditions for removal of the protection are well known for similar reactions. The preferred conditions are: a) The protecting group may be a silylether, for example JUL tribut AUS is methylsilyl oxy “and the removal agent is Y. fluoride ions or aaa such as acetic acid. The deprotection step can be carried out in a “lin” solvent such as JUAL mixture of tetrahydrofuran at a temperature of 0.5 to 0°C; (i) The protective group may be an acyl group, such as a chloroacetate ester, and the removal agent may be a base, for example, JUL, an ammonium hydrate (Yo 7 by volume) or ammonia in mechanol. The deprotection step is in a suitable solvent, such as formamide at a temperature of 0.01 to 0.1°C or in methanol at a temperature of approximately 0.01 to 0.0°C.

In process b (i), the conditions for reduction are known (Tun) for similar reactions. The preferred conditions are:

a) Hydrogenation process over palladium/carbon or leo Lindlar catalyst for example

at atmospheric pressure and at a temperature of 01 to ¥ 0 Tau C using a protec solvent; eg ethanol or a mixture of 0-ethanol and ethyl acetate;

b) a sulfide in a suitable solvent, for example hydrogen sulfide in a mixture of pyridine and water;

=( triphenyl phosphine in a suitable solvent; eg tetrahydrofuran

./ at a temperature of 01 to Te degrees Celsius, followed by treatment with sodium hydrate and oxide, such as molecular concentration 1; or ammonium hydroxide (eg Yo 7 by volume) at a temperature of 01 to .? °C, overnight for example CL UGB in process (ii) conditions and protection groups for removal of protection are well known 1 for similar reactions. The preferred conditions are:

i) The protecting group is a phthaloyl group and the protecting agent is a methylamine in ethanol. The removal step can be carried out in a suitable solvent, eg JUL; tetrahydrofuran at about 0°C to 0°C semen degree.

(oY.) The protecting group may be a trifluoroacetamide group and the deprotecting agent is base, eg potassium hydroxide or potassium carbonate. The deprotecting step may be carried out in a suitable solvent, such as

Methanol - water (eg in a ratio of 01 to 1) at a temperature of 01 to V

degrees Celsius approx. 0

T° c) the protecting group may be a ternary butoxycarbonyl group and the unprotecting agent is an acid; such as trifluoroacetic acid.

A

In process c) a good leaving group may be a sulfonate group or a methylene sage bearing a sulfonate group, for example trifluoromethane sulfonate The conversion is followed by a treatment procedure with an amine, such as ammonia, a methylamine, or a dimethylamine, The appropriate avoidance combinations are well known to those with experience in . Tanofils this field. The preferred leaving group is the 0-thla-fluoromethane group. A compound containing a good leaving group can be separated or hydrolyzed in situ as a hydroxyl Ry in a process d) The compound can be converted from formula (1) in which it is an or an amino to the corresponding amide or ester by the reaction with an agent Helps in acylation, for example, acetic anhydride, and in the presence of a base « such as triethylamine. (ii) defined above in a process and in b) a reaction with ammonia at elevated temperature, optionally followed by i (i ole) treatment with a deprotecting agent, eg acetic acid or \o reaction with ammonium acetate, eg at (i) elevated temperature (i) acetic acid (Jie) followed by treatment with an aqueous deprotector or reaction with hexamethyldisilazane-methanol in a polar solvent; (i to 01 eg 13,1-dimethylformamide; at a temperature of Y. °C followed by treatment with a deprotecting agent, such as acid Ve. aqueous acetic acid in the process f) the conditions are well known to those experienced in this field. The ~N hydroxylating agent may be nitrogen oxide; For example, methylmorpholine 17 = oxide monohydrate, and the hydroxylation process is carried out YO

Tom Ve as an example at a temperature of ele - in a suitable solvent mixture, such as acetone; And in the presence of a metallic oxidizing agent, for example, Lote tetroxide. osmium

In process g) and g) i, the conversion can be carried out by conventional processes known by itself, for example the reaction of the free base with an acid containing a desired ion or by the process of converting the salt into a base form with great care. The reaction can be carried out in a suitable solvent, such as ethanol or methylene chloride.

0 The starting materials for the previous processes can be manufactured by the methods presented in the examples, or 0 by similar methods to achieve this purpose. Other traditional methods of making starting materials will be shown. The interaction experienced in this field is a single bond, then the need to transform the Z bond appears in cases where

double to single bond sass. The conditions necessary for that conversion are well known to these

0 experts in this field. The preferred method for double bond reduction is catalytic hydrogenation over a palladium catalyst. Within the range of methods described in the examples, the following common intermediates have been discovered; Which is also an object of the present invention:

Ry, but in it “adel (1) The identifier as in the form (IA) is a compound of the form (i

\o It is a protected hydroxyl group « methylene hydroxyl carrier

protected azide «azide methyl group» protected amino group; Methylene Jala for an amino group, a good denatured group, or a Jala methylene group for a good leaving group. (id is a component of the adverb (TTA) Y 0 0 Y. -_ R @ z rg N N 20 Rr: 1 which is defined as the form (IID) above , but a is an oxygen or nitrogen substituted with a methyl group .

.\ 0 X 0 Reo N R where O I Rog is hydrogen or halogen 0 p is a dey halogen atom preferably © be as defined above in the array ( IID) (iv is a component of J of form A) 0 LI Rye N R O | LINEN 0 20 is hydrogen or halogen; R is as defined above in the (IID) character. The preferred protecting groups are for each of 6, (if, (ii) just mentioned above, as previously defined under Glas processes a) and b) (i) above. It is possible to prepare compounds of (111) by means of a reaction compound of adjective (IV) with VO compound of adjective (71) : 0 OH 0 > Ryo N \ R,

AR) and m is defined as Rp as it was defined previously and RY or R is Ry where

Laan is a hydroxyl group Rp Lod Be Lady in formula (1) of a protected hydroxyl group “protected amino group; or methylene Jala methylene carrying a protected amino group “and in the presence of an amino base; For example, triethyl. Lamine | 0 by means of a reaction from (ITD) compound. It is also possible to prepare certain compounds from the formula: (VII) the formula a, b, cap, 0 \ / voy

H R" that LINEN each of the 1220 that may be the same or different, is a hydrogen or 0 halogen;

Y is a methyl group or a tertiary butoxycarbonyl group, and it is RY and it will be a 9 compound of | The affix L’ is an oxygen or nitrogen that carries a methyl group: (VII)

Q

n(CH,) 7

R, \o to ? 1 is the n of the group | Cytoxy + L-)-methylphenylsulfonyl) p-methyl Q, stoichiometric ic pana phenylsulfonamide + di-shea ethyl phosphate group or hydroxyl group Jala is a hydroxyl group protected i.e. methylene Ry .? It has a protected amino group. In Jala protected or amino group protected or methylene

\Y The presence of a metal catalyst for the conversion «and optionally the double bond» established can be converted into a single bond, by methods (VID) from a double bond in the compound of the formula. From similar reactions, Toa is known, it is possible to remove a group Tri-butoxycarbonyl by heating in a vacuum or: Trifluoroacetic acid JUL by treatment with acid, as 0 Maleimide nitrogen carrying a methyl group can be converted to oxygen by treatment using an aqueous base, such as sodium hydroxide This is followed by treatment with well-known (VID HCl). Jiao hydrochloric acid formula compounds are well known either from (VID) academic studies. The compounds of the class are considered studies or can be prepared by similar known methods. Which was established on transformation 0. It is also possible to prepare certain compounds of formula (111) by reacting an ion of (IX) with a compound of formula (VID, compound of formula

Q, one

R, where 0 ; (VIID) is as defined above in the adjective Ry pto and is , l) is a good declension group « eg methanesulfonyl . In a polar protic solvent iS compounds of formula (1) and pharmaceutically acceptable salts are prepared, in addition to stereoisomers, whether pure or in the form of racemes or mixtures of isomers |. The malformations of these compounds are useful because they demonstrate pharmacological activity; in particular, as is JUL, for example, PRC, these compounds show activity as inhibitors demonstrated for their potency in the test titrations described in Grant; arr. Eh et al., and in Olson; H. CEN to E0A from p. 1117 No. VAAV Analyt; Biochem, Chakrakarzi, EN; pp. 4.0 to 1 Issue VAR et al.; Cell Signal YO

1. 001 to 11 of VA p. VA issue VARY BR et al.; to topically «Moreover, it is characterized by systemic effectiveness. The compounds of the invention are

0 when taken orally; Some of them have an enhanced anti-inflammatory effect. . The compounds of the present invention are indicated for use in the treatment of inflammation and immune disorders; For example, the topical or physical treatment of airborne diseases, including inflammatory conditions, such as asthma, bronchitis, atopic diseases (i.e. out of place) jie, rhinitis, atopic dermatitis, psoriasis, and

Inflammation of the intestines, such as Crohn's disease, colitis, rheumatoid arthritis, malignant diseases (Jia), skin cancer, and cancer (A). 01 milligrams per day, whether as a single dose or in the form of two divided doses four times per day, thus including unit doses of Dur?

,. milligrams of a compound according to the invention 01 μg to No and/or members of Goll's transmission the compounds may be administered topically; For example, dry powder formulations; HFA air, and in the form of solutions, suspensions, and aerosols; or in an organized manner; Turbhaler® oral formulations in the form of tablets, pills, capsules, syrups, powders or

,. granules; Or rectally in the form of suppositories 0 And the compounds of the invention are taken as is or as a pharmaceutical composition that includes an acceptable carrier compound of an auxiliary substance of the invention in combination with a pharmaceutical adsorbent. In particular, the preferred formulations are formulations that do not contain a potent substance. To cause adverse reactions, for example an allergic reaction (allergic).

0? The dry powder and pressurized arerosol formulations (HFA) of the compounds of the invention may be ingested orally or inhaled through the nose; inhalation; The compound is finely divided in a desirable manner. preferably; The finely divided compound has a mean USS diameter of less than 10 micrometers; and may be suspended in a propellant mixture with the aid of a dispersing agent; For example stearic acid 020-08 or a salt of

YL is that acid; (as oleic acid), bile salt; a phospholipid; a sugar compound of

VE

Alkyl « and a treated surfactant reducer . with perflurane or a biological agent; ethoxylates; Or with the help of another pharmaceutically acceptable dispersing agent. It is also possible to ingest the compounds of the invention by means of dry powder inhalation, and the means of inhalation may be in a single dose or in multiple doses, and it may be a means of inhalation. Inhalation of the dry powder is actuated by breathing ° The possibilities are to mix the finely divided compound with a carrier; sal polyols sf Suu is alcohol oi « or poly ALS monosaccharide or JUL For example lactose JUL other. The suitable carriers are sugars, for example, glucose, leucine (a slightly sweet sugar extracted from beetroot and cottonseed), millilisitos, lactose, maltitol, trehalose (crystalline sugar), sucrose, mannitol, starch, and alternatively; The divided compound is carefully coated with another material, and the powder mixture can be distributed in hard gelatin capsules; Each one of them contains Lal. On a desired dose of the active compound, another possibility is to perform the process of forming the finely divided powder into pellets that are broken during the inhalation process. The formed powder is filled on Tia 0 multi-dose inhaler; For example, Un) pellets in the drug tank of aa and in which the dose-measuring unit Turbuhaler® measures the well-known inhalation device JU for the required dose, which is then inhaled by the patient. By using this system, the active compound is dispensed, with or without the use of a carrier, to the patient.? The pharmaceutical composition comprising the compound of the invention may suitably be in the form of tablets, pills, capsules, syrups, powders or granules for administration by or in the form of sterile solutions, non-enteric, suspensions for administration non-enterally or intramuscularly. The form of suppositories for rectal dehydration. Oral administration. The active compound can be mixed with an auxiliary substance or al, oY, tomato, Las Jie, as a carrier, such as lactose, sucrose, betaol, mannitol, Yo pectin starches, cellulose derivatives, A material that helps cohesion such as maize shoal or Las, gelatin or polyvinyl pyrrolidone, and a material that helps sliding such as amphetamine stearate, calcium stearate, polyethylene glycol, wax materials and paraffin

Tilia, then compressed into tablets; And if it is required to take GLA tablets using a concentrated sugar solution that [code] is prepared as described lll, 0.

A contains gum arabic, gelatin, talc, titanium dioxide and the like. Optionally, the tablets can be coated with a suitable polymer that has been dissolved in an easily volatile organic solvent. For the preparation of soft gelatin capsules; The compound can be mixed with, for example; 0 vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using either of the aforementioned formulations to make pal) such as lactose; sucrose;, sur betol; matnitol, starches, cellulose derivatives or gelatin. Blas may also offer liquid or semi-liquid formulations of the drug in hard gelatin capsules. Preparations for oral use may be in syrup or suspension form; 0 For example, solutions containing SOL and the remainder is sugar and a mixture of ethanol, water, glycerol and propylene glycol. optionally; These liquid preparations may contain Gola agents, flavorings, saccharin, carboxymethyl cellulose as a thickening agent, or other formulations known to experts in this field. 1 It is also possible to take the compounds of the invention in combination with other compounds used to treat the cases mentioned above. The preferred compounds of formula (I) are those, where Ry is hydroxy, hydroxymethyl, amino, or methylamine. Particularly favored compounds of Tall (1) are those of SL where YL is <1 or a capacitance of Rp is hydroxy or amyta and the most favored compounds of formula (1) are those Where is his expression for 1 or ? Ry is an amino. The most favorable compounds of the invention are the following compounds: (1S, 38) - 1[ = ¥ - 7-amino-1-cyclopentyl) - ¥ = indolyl] = 4 - Jude - 1[ - 7 ?- indolyl] - pyrrole Y= 9 - dione 0 (IR, 3R)) = [ = F - 7 = amino = 1-cyclopentyl) - ¥ = indolyl] - 4 - 1[ = instance [dad gail = ¥ - - pyrrol = ? 0, -dion; 0 trans) - 11-7 YL - 4-amino-1-cyclohexyl) - ?-indolyl]-4 - 1[-methyl-SV indolyl] - yyrol Y= 9 - dayon;

(IR, 4R) - 11-7 - (+) - 4 -1mini - ? -cyclopentene = (Jo - 1 = ¥ = indolyl] 1[ - - -methyl - ? - indolyl] pyrrole = 0. - dione; 1[ - * - ((45, 15) -4-amino-?-cyclohexene (-1-yl) Y= = indolyl]-;-[= methyl-?-indolyl]pyrrole-?,0-dione;

(IR, 25,38 ,48((-1-7-8-1-amino-7-dihydroxy-1-cycloentyl)-7-indolyl]-4-1[-methyl- 3 = indolyl]-pyrrole (Y= 00 -dione; (1S, 3R)) - 1[ = ¥ - ¥ - amino - 1 = cyclopentyl) - ?-indolyl] - 4 - A] -methyl 1 - -indolyl] -pyrol - ? 0 - Dione; 1[ = ¥ - ((35, 18) - 7 - amino - 1 - cyclopentyl) - ¥ = endo 1[ = 4 - [Jad - methyl

[dust - 7-0 - pyrol 0 Y = - dione; ¥ = ]\ = ((45, 38 , 18,28) - 4-amino Y= 3-dihydroxy-1-cyclopentyl) - = indolyl] - 4 - 1[ -methyl - =F indolyl] - pyrrole = 0. -dione; 1[ - ¥ - ((45, 18) - 4 - amino - ? - cyclopentene - (Jo - 1 - ?- indolyl] - 4 - -1[methyl - ? - indolele] - pyrrole - ?, 0 - dione;

SL - yl) -1- (hydroxymethyl;- ?-cyclopentene - SN (NEN) - 11-9 0 -dione; - 1[ = 6 = [od endo - yl) - ? - indolyl] - 1 - (aminomethyl) - ? - Cyclopentene - 4 - (18 4R)) - 1[-"-dione; Hydrochloride and chloride salts are among those compounds

: The most preferred compound of the invention is 0-methyl-1[-4-cyclopentyl)-¥ = indolyl]-1-amino-7-(1S,38)-11-* Dione; - 0, “--indolyl] - pyrrole - ?. And pharmaceutically acceptable salts », and in particular the hydrochloride salts of the aforementioned compound on (1) Gall hydrochlorides. The pharmaceutically acceptable salts of compounds include

0?*, hydrobromides, phosphates, nitrates, acetates, bezoates and sulfonates, and also includes all possible stereoisomers, whether pure or in the form of racemates or in the form of mixtures of stereoisomers. Optical isomers can be prepared by specific stereosynthesis or by hydrolysis of mixtures, eg racemic mixtures; containing them. can be forced

,. Decomposition using self-defined processes Y.

The invention is described in the following examples, but they do not in any way limit the scope of the invention. All reactions are carried out in glass vessels under Toa of argon or nitrogen at a temperature of about 01 to Ye degrees Celsius; If not stated otherwise. Tetrahydrofuran is distilled from sodium/benzophenone. “NN 0” dimethyl formamide and dichloromethane are distilled from calcium hydride; or dried over. molecular intersex. The ammonium hydroxide used is characterized by a concentration of 75 / volume / volume. If indicated otherwise, all commercial reagents are used as received. The chromatography is carried out using a chromatotron* (0 thin film chromatography c accelerated centrifugation, radiocatalytic); The plates used are prepared using Merck silica gel type 171254 that includes gypsum (aqueous calcium sulphate). The NMR spectra of hydrogen 1 are recorded on two sides - Varian XL 0 or + 500 - Unity and the peaks are used for the central solvent of chloroform (d = Bg Vo 1.14 ppm) and methanol - 3H) dg 4 “t? ppm) and DMSO - dg Yo.

OH) ppm) as internal references. Low decay mass spectra and exact mass determinations are recorded on the Autospec 158008-0 - Nessos Analytical Corporation dual focus clip device equipped with the 181148 interface. Ex 1 Y = (IS, 3R) - NV = X . = oxyhydroxy - 1 -cyclopentyl) - ?-indolyl]-4 - -1[methyl - ¥ = indolyl] - Birol -? 00 - dione (4R) (a , 1-013 -0 - acetyl = 1 - 0 - (tert-butyldimethylsilyl)cyclopentene - 9,27 -diol is dissolved in (1S, 4R) - CES-4-Acetoxy-?-cyclopentene-1-Oil (Ye) 1 g (Allar 1 mmol) and imidazole (5 g (1 1.47 mmol) and tert-butyldimethylchlorosilane (SYA). grams and VAY mmol) in tetrahydrofuran (Gla)© ml) and then stirred overnight at room temperature. ALS ethyl ether (0 ml) was added.

The solution is filtered and then evaporated, and the chromatographic separation of the crude product (gram + EY) is carried out through a short silica column to produce the compound mentioned in the subtitle. as viscous oil) 4 "H-NMR (500 MHz, CDCL): 50.09 (3H, 5), 0.09 (3H, 5), 0.90 (9H, 5), 1.61 (2H, dit, ] 5.0,13.7 Hz), 2.05 (3H, 5) 2.81 (2H, dt, | 7.5, 13.9 Hz), 4.72 (1H, t, ] 6.2 Hz), 5.46 (1H, o t 76.6 Hz), 5.89 (1H, d, J 6.0 Hz), 5.98 (1H, d, ] 6.0 Hz). methyl - ?- indolyl] - pyrrole - 1[ - 4 - indolele] = Y = yl) - 1 - cyclic: dione

0 dissolve ¥ = 1( - machell - ¥ - indolyl) - 6 - ()¥ - indolyl)furan - ? 0.- Dione (..t.1 g THAT mmol) and lithium hydride (LEV) + g, 5.88 mmol) in ALS dry methylformamide (YO) ml) and stirred for ten minutes. The complex purple solution is degassed in a vacuum, then the resulting compound from step (a V0) is added. g, YAY, mmol) and followed by the addition of tetracycline triphenylpalladium

0 (zero) YT) grams 190 QR. mmol). Then the reaction was allowed to continue for four hours at a temperature of 1°C. and after cooling; Diethyl ether YO (ml) and acetic acid (with a gram molecular concentration of YO ml) were added, followed by filtration through Silite 13 », the phases were separated, then the AU phase was washed with an additional portion of ether (Ja YO). The combined organic phases are washed with water (two volumes of both (Ue Yo Login).

.| It was dried over 1,442,504 degrees and evaporated, then chromatographic separation took place through silica, and the compound was recovered. = (IR, 48) - 1[ - 6 - tert-butyldimethylsilyloxy - ?-pentene - cyclo - 1 - yl) - ?- indolyl] = £ - -1[methyl - ? - Indolyl] - Furan - OY 0 - Dione (VY) g) Crude, which is used without further purification. This compound is dissolved in di(date4mamed) 01 (ml) in a container with a sealing tube

10 ml) followed by heating to 10 degrees (to leakage). Yo hydrate and ammonium oxide are added at 1 degree Celsius for two hours. After cooling, the remaining ammonia is removed by stirring in a vacuum for ten minutes, and the remaining solution is extracted using ether ml). The collected etheric phases are washed with Ye diethyl water (two volumes of ml each). It is dried over 1,142,504 and evaporated, then 01 of them are separated by YS (two sizes

1 Chromatography through silica, then the subtitle product is obtained in the form of (AVE pla 1.7) red solid "H-NMR (500 MHz, CDCL): § 0.06 (3H, s), 0.10 (3H, 5), 0.87 (9H, 5), 1.77 (1H, dt, ] 5.6 Hz, 14.3), 2.89 (1H, dt, [77 Hz, 13.8), 3.82 (3H, 5), 4.84 (1H, brs), 5.28 (1H, brs), 5.82 (1H, d, J 5.6 Hz), 6.01 (1H, brs), 6.70 (1H, t, ] 7.8 Hz), 6.73 (1H, d, J ] 77 Hz), 6.83 ° ( 1H, t, J 7.7 Hz), 7.06-7.11 (2H, m), 7.17 (1H, d, ] 7.7 Hz), 7.25 (1H, d, ] 9.6 Hz), 7.41 (1H, brs), 7.46 (1H , d, ] 9.0 Hz), 7.59 (1H, 5), 7.70 (1H, 5).HRMS (FAB) calcd for

C,H,N,0,5i 537.2477, found 537.2447 [M+]. (.4/t.gr: 1.19 mmol) in a mixture of ethanol (b) the step product is dissolved (© / 001 ml). Palladium is added to coal (17 t. grams Ve) and ethyl acetate (Jo 01 (0 hours), the catalyst is filtered from palladium, then Yo palladium) and the solution is hydrogenated for a period, the solvent is removed in a vacuum, and the product is dissolved Crude in tetrahydrofuran (0 ml), acid (ml) and water (© ml). Heating to a temperature of 00 degrees Celsius (Vo) results in acetic hours, evaporation of the solvent, and the aforementioned compound chromatographic separation procedure for 0 hours. Gram 96 //) in the form of a red solid. JW) in mites 1 1/1g (500 MHz, CDCL): 1.70-1.83 (3H, m), 2.01-2.10 (1H, m), 2.15-2.23 (1H, mw), 2.41 (1H, dq, J 56,94, 14.6 Hz), 3.84 (3H, 5), 431 (1H, brs), 479-484 (1H, m), 670-676 (2H, m), 6.94 (1H, t, ] 7.5 Hz), 7.11 (1H, dg, ] 3.0, 5.3, 8.2 Hz), 7.15 (1H, ] 7.5 Hz), 729 (1H, d, J 8.1 Hz), 7.37 (1H, d,] 8.1 Hz), 7.41 (1H, d, ] 8.6 Fz), 7.50 (1H), 7.67 (1H, 5), 7.72 (1H, 5). HRMS (FAB) calcd for CpgHL,,N;O; 426.1818, found Y. 426.1809 [M+]. Example? methyl = 1[ - 4 = indolyl] = V = cyclopentyl) = 1 - yenema1 - 7 - (15 , 35() = 1[ = F 0 indolele] - pyrrole - ?,9 - hydrate and chloride dione -7 -

01 mmol) and triphenyl NOVY “pla (1 R.91). The title compound is dissolved in dry methyl chloromethane (.? ml). ALS phosphine (50) is added. grams, 1.58 mmol) in mmol) to this YA * t? Grammolecular in 07.1 de benzene (hydrogen azide: 48.1: ml + SY) solutions, followed by the addition of diethyl azodicarboxylate (mmol). The mixture was stirred for an hour at room temperature, followed by adding an amount of 0 minutes. It results from removing the solvent in a vacuum and chapter 01 methanol (1 tsp) and then stirred for a period of time.

CF-cyclopenthyl)-1- ?-azido-(15,38)-1[-¥ complex chromatography dione hydrochloride-0,7-indolyl]-;-[1-methyl- ?- Atdulil] - Birol. . (19 t. g) raw “H-NMR (500, MHz, CDCL): 3 1.77-1.85 (1H, m), 1.86-1.94 (1H, m), 198-214 @H, 0-0 m) , 2.23-2-29 (1H, m), 2.34-2.43 (1H, m), 3.86 (3H, 5), 3.99-4.04 (1H, m), 4.98 (1H, p, ] 7.2, 14.5 Hz), 6.70-6.76 (2H, m), 6.90 (1H, t, J 7.5 Hz), 7.10-7.18 (2H, m), 7.26-7.32 (2H, m), 7.35 (1H, d, ] 8.1 Hz), 7.49 (1H, s), 7.64 (1H, brs), 7.75 (1H, s. ml) and YO water) The crude azide, which is used without additional purification, is dissolved in pyridine and hydrogen sulfide is introduced in the form of bubbles through The solution until (Ja Yo) Ne exhausts all the amount of azide as it is monitored by thin-layer chromatography. The solvent is removed in a vacuum “and chromatographic separation is carried out, then treatment, and then freeze-drying provides eld gill compound using hydrogen chloride . mentioned in the heading (*? R. 090 gr /) in the form of a red solid “H-NMR (500 MHz, CD,0D): 8 1.76-1.85 (1H, m), 2.03-2.12 (1H, m), 227-250 (4H, 0 m), 3.76 (1H, dt, J 7.3), 3.89 (3H, s), 5.19 (1H, dt, J 7.5, 14.8 Hz), 6.64 (1H, t, ] 7.8 Hz), 6.68 (1H, d, J 7.8 Hz), 6.80 (1H, t, ] 7.8 Hz), 7.06-7.16 (3H, m), 7.40 (1H, d, ] 8.5 Hz), 7.47 (1H, d, J] 7.8 Hz), 7.64 (1H, s), 7.81 (1H, s). HRMS (FAB) calcd for HC 424.1899, found 424.1930 [M+]. -- eg ? Yo ?-indolele] = ; - [methyl - (ila pentyl -1- amino = 7 = (IR, 3R)) = \] - 7 pyrrole - ? ,9-hydrochloride dione-[lelodeta-1-].

wrap (a ?- =F - (IR, 38) - 11 hydroxy-pentyl-cyclo) - =F indolyl] - 4 - -1[ methyl - ? = ando [dad - pyrrol - ? , 0 = dione The compound mentioned in the subtitle is prepared as described in Example 1 starting with (1S, 4R) -1- 0 - cyclopentene diethyl phosphate 0- 0 4 - diol 0 0) The compound mentioned in the title is prepared from the product of step (a) as described in example ?. FAB-MS: m/z 425 [MH+] example ¢ ¥ = ]\ - )£ - qn - ua x - 1-cyclohexyl)-¥-indolyl]-4 - 1(-methyl-¥ = indolyl)-pyrrole 0 Y= -dione 0 This compound is prepared in a manner similar to that described in Example 1 ; starting from (IR, 4S) - ) -acetoxy - ? - Cyclohexinol previously known. (1H, d, ] 2.9 Hz), 1.71 (2H, t, ] 14.0 Hz), 1.84 (2H, 51.30 bits” H-NMR (500 MHz, brd, 12.6 Hz), 1.91 (2H, br d, J 12.6 Hz), 2.07 (2H, dq, J 2.9, 13.1 Hz), 3.83 (3H, 5), zrb (1H, brs), 4.21 (1H, tt, ] 3.7, 11.9 Hz), 6.68 (1H, dt, ] 0.8, 8.0 Hz), 6.73 (1H, 4.12 m Hz), 6.84 (1H, t, ] 7.5 Hz), 7.04-7.13 (2H, m), 7.21 (1H, d, 81 Hz), 7.25 (1H, d,] 7.9 Hz), 7.33 (1H, d, ] 8.1 Hz), 7.40 (1H, brs), 7.63 (1H, 5), 7.70 (1H, 5). 8.1 HRMS calcd.for C,H,N,O, 439.1882, found 439.1896 [MH+].0 Example o — trans - 1[ = ¥ - amino - 1 - cyclohexyl) - ¥ - indolyl]-6 - 1[-methyl-SY .| indolyl]-pyrrole-?0-dione hydrochloride The said compound is prepared in a manner similar to that described in example ?;Towa of 1[- 0 = 0 - 3n - hydroxy - 1 - cyclohexyl) -? - -1(- f= [Jed pail methyl - ¥ = etdolyl) - pyrrole - ?0, -dione

YY

H-NMR (500 MHz, CDCL): § 1.69-1.79 (2H, m), 1.79-1.90 (2H, m), 2.17 (4H, t, ] 13.9

Hz), 3.22 (1H, tt, ] 3.2, 11.7 Hz), 3.86 (3H, s), 4.44 (1H, tt, [ 32, 11.7 Hz), 6.63 (1H, t, 7.7 Hz), 6.67 (1H, d, | 7.7 Hz), 6.76 (1H, t, ] 7.7 Hz), 7.05-7.10 (2H, m), 7.11 (1H, t, 7.6 Hz), 7.37 (1H, d, ] 8.4 Hz), 7.48 ( 1H, d, ] 8.4 Hz), 7.65 (1H, 5), 7.76 (1H, 5). HRMS calcd. for C,H,N,O, 439.2056, found 439.2039 [MH-+]. ° + eg [ad sas) = ¥ - cyclopentyl) - 1 - acetylamine) = N) - 7 (18, 38)) - 1[ = ¥ methyl - ?- etdolyl] - Birol -? ,9-Dione-1[--)- The compound mentioned in the title is dissolved, for example? (15.R.Bram, 1 and 1 mmol) in acetic anhydride (Dr.Ml) and triethylamine (Dr.ML), then stirred for one night at 0 room temperature. It is removed, then chromatographic separation takes place, and the aforementioned compound is produced. Title (.176 g, part-equivalent) as a red solid "H-NMR (500 MHz, CDCL): § 1.46-1.54 (1H, m), 1.75-1.84 (1H, m), 1.94 (3H, 5(, - 2.00-2.30 (4H, m), 4.23 (1H, hex, ] 7.0 Hz), 4.85 (3H, 5), 5.75 (1H, br d, | 6.8 Hz), 6.66- 6.72 (2H, m), 6.86 (1H, t, ] 7.5 Hz), 7.04-7.12 (3H, m), 7.25 (1H, d, 72 Hz), 729 (1H, 01 d,] 8.4 Hz), 7.47 ( 1H, s), 7.69 (1H, s).HRMS (FAB) calcd for C,H,CIN,O, 5 found 466.2040 [MH+].

Vv ex. -etolyl]-pyrol-? R. grams R. 111 mmol) and chloracetic acid

Jan and then cooled on ice. Add (Je V0) “dr. mmol) in dry methylene chloride

TV 01 μl drops of diethyl azodicarboxylate (21 g mmol). The temperature is maintained at zero degrees Celsius for an hour, then YO

Nuff it up to reach the ambient temperature and stir for one night. The resulting chloroacetate ester, * - Y= (1S, 38))-1[-(chloroacetoxy)-1-pentyl (ila 1-endo [Jad p 1]) is purified. -methyl -Y - endo [Jad - pyrrol - 0,7 - dione by chapter I of Cromatogra V in order to produce "Je" gram VA VY) in the form of a red solid found 501.1459. 501.1455 04, 4011 112, 02 HRMS (FAB) calcd for Hydrogenation of the chloroacetate ester (° ET a g) 0 is carried out by treatment with ammonia in methanol (? ml) Bul 0 min. The solvent is evaporated and the remaining part is purified by chromatographic separation, resulting in .76 g of Atwan compound (7 80 with a total percentage of 0 YY/) in the form of a red solid.” H-NMR (500 MHz, DMSO-d) ): 5 1.54-1.63 (1H, m), 1.66-1.74 (1H, m), 1.86-1.98 (2H, m), 2.04-2.10 (1H, m), 2.26-2.34 (1H, m), 3.88 (1H, 5), 4.25 (1H, br 5), 4.74 (1H, d,J 4.0 Hz), 5.10 (1H, p,] 7.7, 15.3 Hz), 6.59 (1H, d, ] 82 Hz ), 6.65 (1H, t, 7.6 Hz), (1H, t, ] 7.6 Hz), 7.05-7.12 (1H, m), 7.45 (1H, d, ] 8.3 Hz), 7.52 (1H, d, ] 8.3 Hz), 6.79 Vo 425.1739 0 (1H, s), 7.88 (1H, s) , 10.93 (1H, s). HRMS (FD) calcd for CH, 7.62 ‎found 425.1759 [MH+]. Ai 11 -" - ((112,45)-) - hydroxy = ¥ — cyclopropane 1- - yl) - ?-indolyl] - 6 - -1[methyl = ¥ - indolyl]pyrrole - 0, - Dione XY. Uo and water 1 (ml). Material image J | yan Lilia of color Y 0 A : Lr . “H-NMR (500 MHz, CDCLy): 81.64 (1H, dt, [ 4.5, 14.5 Hz), 2.98 (1H, dt, 7.2,14.5 Hz), 3.82 (3H, 5), 4.79 (1H, brs), 5.33 (1H, brs), 5.92 (1H, d, ] 4.5 Hz), 6.10-6.14 (1H, m), 6.70-6.75 (2H, m), 6.89 (1H, t, ] 7.9 Hz), 7.07-7.13 (1H, m), 7.14 (1H, t,] 7.4 Hz), (2H, m) , 7.40 (1H, d, | 7.9 Hz), 7.49 (1H, 5), 7.59 (1H, brs), 7.71 (1H, s). 7.25-7.30 HRMS (FAB) calcd for C,H, N, 0, 423.1583 found 423.1611 [MH+].

Ye 01 Example - indolyl] - ; = Y = yl) 1 - hydroxy - ? - cyclohexane - 6 - (1S, 4R)) - 1[ = -dione 027 - methyl = ?-indolyl] - pyrrole -1[ . nisca methylsilyl xi) - ?- SBS (tert-butyl - -)15,48 ((-1[ - ?(a)

SPIE 7-indolyl]-pyrrole (SPE SE)-4-yl)-?-indolyl]-1-cyclo0-dione The subtitle compound is prepared in a manner similar to that described in the acetoxy example -? = cyclohexinol - £ - (IR, 48) starting at (0) ' H-NMR (500 MHz, CDCL): 50.09 (3H, 5), 0.11 (3H, 5), 092 (9H, 5) , 1.54-1.62 (1H, m), 1.71-1.78 (1H, m), 1.92-1.99 (1H, m), 2.14-2.22 (1H, m), 3.85 (3H, 5), 423 (IF, br \ .s), 4.87 (1H, brs), 5.70 (1H, dd, 2.9, 10.3 Hz), 5.97 (1H, dt, ] 2.7, 10.3 Hz), 6.70-6.76 (2H, m), 6.89 (1H, t , ] 7.7 Hz), 7.08-7.15 (2H, m), 7.27 (2H, m), 7.39 (1H, br s), 7.45 (1H, d, [ 8.4 Hz), 7.56 (1H, 5), 7.24 ( 1H, 5). HRMS calcd. for C,H,N,0,5i 551.767, found 551.767 [M+]. The compound mentioned in the title is prepared from the product of step 2 (in a similar way to this method) © 00 . 4 Described in Example “H-NMR (500 MHz, CDCL,): § 1.52-1.60 (1H, m), 1.74 (1H, br d, [ 6.0 Hz), 1.83-1.91 (1H, m), 1.97 -2.08 (2H, m), 3.86 (3H, s), 4.24 (1H, brs), 4.94 (1H, br s), 5.82 (1H, dd, 72.9,10.1 Hz), 6.09 (1H, dt, [ 2.1 , 10.1 Hz), 6.71-6.79 (2H, m), 6.91 (1H, t, [ ] 7.5 Hz), 7.12 (1H, t,] 7.5 Hz), 7.16 (1H, b ] 7.5 Hz), 7.29 ( 1H, d, J 81 Hz), 7.30 (1H, 4,781 Y-

Hz), 7.37 (1H, d,] 8.1 Hz), 7.57 (1H, 5), 7.74 (1H, 5). HRMS caled. for C,H,N;0, 437.1739, found 437.1710 [M+]. 01 Ex endolyl] = ¥ = (Jo - 1 - hydroxy - ? - cycloheptene - 4 - (IS, 4R)) - 1[ - ¥ -dione 0, methyl - ? - indolyl] - pyrrole - ? - [2-0 YO

Yo methylsilyloxy) - ? -heptene (ALS (tert-butyl-1(1S,4R)-1[-?(a-027-methyl-?-indolyl]-pyrrole-1[-f=cyclo-1- (b) The compound mentioned in the subtitle is prepared in a manner similar to that in the example of acetoxy-?-cycloheptenol-4- (IR, 45) starting from 0 H-NMR (500 MHz, CDCL): 0.09 (3H, 5), 0.09 (3H, 5), 0.90 (9H, 5), 1.59-1.78 (2H, m), 1.82-1.88 (1H, m), 1.90-1.96 (2H, m), 1.99-2.06 (1H, m), 3.84 (3H, s), 4.42 (1H, br d, 9.9 Hz), 4.94 (1H, brs), 5.63 (1H, dt, ] 3.0, 12.1 Hz), 5.82 (1H, dt, J 2.6, 12.0 Hz), 6.68 (1H, t, [ 8.0 Hz), 6.73 (1H, d, ] 8.0 Hz), 6.82 (1H, x ‎ 7.6 Hz), 7.057.11 (2H, m), 7.16 (1H, d, ] 8.0 Hz), 7.25 (1H, d,] 8.1 Hz), 7.30 (1H, d, ] 8.4 Hz), 7.45 (1H [M+].

CA The title compound is prepared from the product of step 2 (similar to that of an example) 0 "H-NMR (500 MHz, CDCL): § 1.64 (1H, [Roh 2.7, 12.3 Hz]), 1.71 (1H, d, J 48 Hz, 1

OH), 1.72-1.82 (1H, m), 1.90-1.99 (3H, m), 2.01-2.09 (1H, m), 3.84 (3H, 5), 4.49 (1H, 1 brd, 9.2 Hz), 495 ( 1H, brs), 5.69 (1H, dt, ] 2.9, 12.1 Hz), 5.84 (1H, br d, ] 11.9 Hz), 6.68 (1H, t, ] 7.7 Hz), 6.73 (1H, d, ] 7.7 Hz ), 6.82 (1H, t,] 7.4 Hz), 7.05-7.12 (2H, m), 7.15 (1H, d,] 8.5 Hz), 7.26 (1H, d,] 8.5 Hz), 7.29 (1H, d, ] 7.8 Hz), 7.46 (1H, brs,

NH), 7.59 (1H, s), 7.72 (1H, 5).

HRMS caled. for C,gH, NO, 451.1896, found 451.1915 [M+]. XY. 11 Examples: - ? - Endo Lil] - 1 = Amini - ? - Bintein Halki - 4 - (IRL4R)) - 1[ ?- - (+) Birol - ? ,9-dione hydrochloride [lilodna-1-lithium-1]-)-(J mLimo 0 J 0.gr 4] A Jd LA, From O f gral J with compound J with 714.R. mmol) in pla.

Yi added in the form of azodicarboxylate drops (Je 250) dry diethyl methylene chloride and allowed the reaction to continue for a night at room temperature. The solvent was removed in a vacuum, and then the remaining part was separated by chromatography. It is obtained yl)- ?-pentene -1- -dione Yo Y= (isoandol - 4 - (IR, 4R)) - \] vy compound - 00, 7- methyl - ?-indolyl]-pyrrole-1[-4-yl)-7-indolyl]-1-cyclo0 dione is impure as a red solid and without further purification; melts in. Tetrahydrofuran (*t.ml), followed by the addition of a methylamine in ethanol (dr.ml per hour; the solvent is removed in a vacuum and the separation is carried out by Yo and after stirring for a period of 0 “ 7 - 8 = (IR, 4R) ) = V] = ¥ Residual chromatography. The compound is obtained methyl = 3 = indolyl] - 11 - 4 = indolyl] = F - yl) -1- pentencyclic SY amino 0 dione in the form of a red solid that is treated Using - 00 Y = pyrol, and it is evaporated twice (da 1.1 01) ethanolic hydrogen chloride (molecular concentration) using absolute ethanol; then dissolved in water and freeze-dried to produce the aforementioned compound. In the form of a red solid. )/ 1/01 g .eA) with the title H-NMR (500 MHz, CD,0D): 52.31 (1H, ddd, [ 3.6, 7.6, 14.8 Hz), 2.56 (1H, ddd, ve 3.3,7.9,14.8 Hz), 3.89 (3H, 5), 433 (1H, brs), 5.95 (1H, brs), 6.20 (1H, brs), 6.32 (1H, br 5), 6.64-6.70 (2H , m), 6.83 (1H, t,] 7.9 Hz), 7.11 (1H, 1, ] 81 Hz), 7.15 (1H, t, ] 7.6 Hz), 7.19 (1H, d, ] 7.6 Hz), 7.39 (1H; 5), 7.41 (1H, d, ] 7.6 Hz), 748 (1H, 4, 78.6

Hz), 7.79 (1H, 5). HRMS calcd. for CHL, CIN,0,-HC1 422.1743, found 422.1763

Me Y. 11 Example - 6 - indolyl] = Y = yl) - 1 - amino - ? - cyclohexane - 6 - (18 ,48() - 1[-methyl-1-etdolyl] - pyrrole - ?, 5-hydrochloride dione - 1[ of?-des 11] This is prepared compound in a manner similar to that described in the example [Jd sual =F = yl) -1- cyclohexane - Y = hydroxy -4 = (48,15)( - \] Yo" -dione 0. methyl-?-indolyl]-pyrrole-?-1[ = 4 =

H-NMR (500 MHz, CDCL): § 1821.92 (1H, m), 1.93-2.02 (1H, m), 220-227 (1H,

m), 2.33-2.40 (1H, m), 3.89 (3H, 5), 4.02 (1H, brs), 527 (1H, br s), 6.00 (1H, br d, ]

103 Hz), 6.12 (1H, br d, ] 10.3 Hz), 6.65 (1H, t, ] 7.8 Hz), 6.69 (1H, d, ] 8.0 Hz), 6.79

(1H, 17.6 Hz), 7.06-7.14 (3H, m), 7.39 (1H, d, ] 8.4 Hz), 7.48 (1H, d, ] 8.4 Hz), 7.54

(1H, 5), 7.79 (1H, s). HRMS calcd. for C,,H,;N,O,-HC1 436.1899, found 436.1898 ©

[M+].

1 “Example

?-3R, 4R))-11 , 18,28)-4-amino-7 7-dihydroxy-1-cyclopentyl)-?-indolyl]- ; -1[- muqil-?-atdollil]- perol-?,0-

0 Dione hydrochloride The title compound of Example 11 (.74 g, .717 mmol) and triethylamine (01 μL, .; R. mmol) in dry methylene chloride (1 ml) and then cooled on ice. Trifluoroacetic anhydride (YA) (μl, 0.0 mmol) was added, then the Bul solution was stirred for an hour, and the thin-layer chromatographic separation indicated a complete reaction.

Vo, water (Ja 1) is added, the phases are separated, then the organic phase is dried over 1182504, filtered, and then evaporated. The chromatographic separation of the remaining part is carried out, producing the compound?- (IR, 48) - \] - 4 - amino - ?-cyclopentene-1-yl)-?-indolyl] 1 = --methyl-1-indolyl]pyrrole-9,7-trifluoroacetamide dione as a red solid for immediate use .

0 and melt? - 1[ - ((18,48) - 4 - amity - ? - Bentein 1 - Ala - yl) - ?- indolyl] -1[-)- methyl - 7 - indolyl] pyrol - ? 0,-trifluoroacetamide dione and N = methylmorpholine N = oxide monohydrate (.11 g AVC 5 mmol) in acetone - ela (by 0 1.01 da) :01 Then tetro-osmium (; 00 µL? // in 130011 1 7..R. mmol) is added and the reaction is allowed to continue overnight.

,. The reaction was suppressed by stirring with sodium aerosulfite for 1 hour, and ethyl acetate (¥ ml) was added, then the organic phase was washed with water (¥ volumes of both ml) and evaporated after that. The remaining part was dissolved in methanol - water (1 mmol of it) «then stirred at a temperature (VE 2 LEN) 122003 ml) and 0.000 was added

Ya

for protection. Ethyl acetate (¥ ml) is added and Tals washes the room for an hour to give removal. ml) and then evaporates 1 of them, MS (organic phase) with water (¥ volumes), the remaining part is purified by preparative high-performance liquid chromatography, and the title compound (10.R.g 3.0/) is obtained in Photograph of a red solid after treatment with ethanol and freeze-drying from © . Water “H-NMR (500MHz, :(B00) 5228-7 (1H, m), 2.47-2.55 (1H, m), 3.85-3.95 (4H, m), 423 (1H, t, 3.9) Hz), 4.44 (1H, dd, ] 8.1, 10.1 Hz), 6.67 (1H, t, ] 7.8 Hz), 6.74 (1H, t, 77.8 Hz), 6.78 (1H, d, ] 7.8 Hz), 6.99 ( 1H, d, ] 7.8 Hz), 7.08 (1H, t, ] 7.8 Hz), 7.10 (1H, t, J 7.8 Hz), 7.38 (1H, d, ] 8.9 Hz), 7.50 (1H, d, ] 8.1 Hz), 7.78 (1H, 5), 7.80 (1H, 01 5). HRMS (FAB) calcd for C,H, CIN,0,-HCl 456.1797 found 456.1827 [M+]. [ - 4 - [Jd gush = ¥ - cyclopentyl) - 1 - amino - V - (1S, 3R)) - 1[ - ¥ pyrrole - ?00 - dione hydrochloride - ]lelodna-17 - indolyl] = - yl] - 1 = acetoxy - ? = cyclopentene - £ - (IR, 4S)) - \] = ¥ (a 01 -dione 0, methyl - ?- indolyl]-pyrrole - ?- \] - 4-(tert-butyldimethylsilyloxy) - ?=pentene - 4 - (IR, 48) - 1[ - * dissolves - 0, Ym methyl - 7 - indolyl] - pyrrole - VM - 4 - yl) = - indolyl] - 1 = la mmol) in a mixture of acetic acid and quaternary (SY pla (STV) dione) 00 and the solution is heated at a temperature Jo 050, 07 (by ebay hydrofuran | minutes and after cooling; The solvent was removed in a vacuum and the remaining part, 0 Bul semen, was dried by means of an azeotropic remover of water with toluene. The precipitating solid was dissolved in ml) and pyridine (5? t. ml) and the stirring for a period (YO) resulted in acetic acid anhydride overnight, followed by removal of the solvent by forced chromatographic separation of the aforementioned compound. Solid red sub Bala (14 tsp, quantitative yield) as YO

Ya 1

H-NMR (500 MHz, CDCL,): 1.89 (1H, dt, ] 4.5, 15.0 Hz), 2.04 (3H, 5), 3.07 (1H, dt, 179,146 Hz), 3.85 (3H, 5) , 5.43 (1H, br s), 5.69 (1H, br 5), 6.10 (1H, br d, ] 5.6 Hz), 6.19 (1H, br d, ] 5.6 Hz), 6.72 (1H, t, ] 72 Hz ), 6.76 (1H, d, ] 8.0 Hz), 6.84 (1H, t, ] 7.6

Hz), 7.08-7.15 (3H, m), 7.28 (1H, d,] 8.3 Hz), 7.39 (1H, brs), 7.41 (1H, d, ] 8.7 Haz), 7.61 (1H, s), 7.74 ( 1H, 5). HRMS (FAB) calcd for CeHL,;N,0, 465.1689 found 0 465.1715 [M+]. - 6 - yl) - ?- Indolele] - 1 - Azidi - ? -cyclopentene -4 - (18,45() -11 - ?(b -dione 09, methyl - ¥ = indolyl] - pyrrole - ? - 1]

Je 3 £) mmol) and more | Sodium 0 JY 2 g 0 R 0 T ((a 134 b product is made from step . ml) YoYo 0 1 mmol) in tetrahydrofuran-water (at a ratio of ? to SV cpa 0 and removed The phase is removed from the solution in a vacuum, then tetracycline triphenylpalladium (zero) is added

J hour. Wisa V0 mmol). The reaction is allowed to continue for a period of (RETA IP' gram ET v4). | 0 ma 0 g 0 - 0 ma 0 0 0 nl ga - to separate | Chromatography for the production of the aforementioned compound, I, the solvent in a 2 μm stream. In the form of a red solid for color 0 A. 1 gram (1 Y) sub-discretion (500 MEz, CDCL): 8 1.80 (1H, dt, ] 5.3, 14.4 Hz), 3.00 (1H , dt, J 8.1, 14.4 ve

Hz), 3.86 (3H, 5), 4.49 (1H, br t, [ 6.2 Hz), 5.43 (1H, br t, ] 6.7 Hz), 6.03 (1H, brd,] 5.6 Hz), 6.09 (1H, dt , [ 2.1, 5.6 Hz), 6.70-6.76 (2, m), 6.92 (1H, t, J 7.2 Hz), 7.12 (1H, dq, 20.61 Hz), 7.16 (1H, t,] 7.6 Hz) , 7.30 (2H, &, ] 8.8 Hz), 7.39 (1H, d, ] 8.4 Haz), 7.47 (1H, 5), 7.74 (1H, 5). HRMS (FAB) calcd for C,(FL, NO, 448.1648 found 448.1667 [M+].v in ethyl acetate)50 . ml) and ethanol (50). ml) and (b) the product is dissolved from step (©) followed by the hydrogenation procedure for 0 hours at (/ 001 mg Yo) palladium on charcoal at the level of pressure and ambient temperature. The catalyst is removed by filtration through Silite 13 » and the solvent is removed in a vacuum; The chromatographic separation is carried out

Y. Treatment using ethanolic hydrogen chloride and freeze-drying compound. for color le | yan as a solid 0 YY. eg 77 grams (in weight O moth I "H-NMR (500 MHz, CDCl): 6 1.92-2.02 (2H, m), 2.15-2.23 (1H, m), 2.29-2.42 (2H m) ), 2.80 (1H, dt, J 7.2, 12.9 Hz), 3.81 (1H, pent, 4 Hz), 3.89 (3H, s), 5.07 (1H pent, [ 8.74 Hz), 6.63 (1H, t, ] 7.8 Hz), 6.71-6.76 (2H, m), 6.98 (1H, d, J 8.2 Hz), 7.06- 0 7.13 (2H, m), 7.39 (1H, d, J 8.2 Hz), 7.49 (1H, d, ] 8.2 Hz), 7.80 (1H, s), 7.82 (1H, s).

HRMS (FAB) calcd for C,H, .CIN,O, - HCI 424.1899 found 424.1912 [M+].

Vo is an example of - 1[ - 4 - ? = amino = -cyclopentyl) - ¥ - indolyl] - (IR, 35)) - \] = ¥ chloride dione - 09, Y = -?-etdolyl] - pyrrole VL The aforementioned compound is prepared by addressing in a manner similar to that described in the example diol - 4 01 = cyclopentene diethyl phosphate - 0 = 1- (IS, 4R); starting from 0 . previously known

Y1_NMR identical to that of the title compound of Example 14. HRMS (FAB) calcd for C,,H,,CIN, RH - HCI 424.1899 found 424.1891 [M+]. Ve 01 Example Pentyl-1-mini-7.- dihydroxy 0- - (112.25 , 31 ,45(( - 1[ -" - 0, Ym cyclic)- 1-indolyl]- ); 1-7 (a ¥.dione - 0 methyl-? = indolyl]-pyrrole - ?- 1[-)-cyclo)-?- indolyl]- mmol) and L.oY. gram co a. ,

1

YO ml VY) and osmium tetroxide (JaToT) is added to 01 (by mmol) and the reaction is allowed to continue for four hours. R.01 34 (de ¥) suppresses the reaction by stirring with sodium pyrosulfite overnight. Water is added, then the phases are separated, and the aqueous phase is washed using acetate (Ja©) and ethyl acetate (ml). The organic phases are dried over 1142504, evaporated, then 0 Login NS ethyl (two volumes of 0 grams; VY) chromatographic separation is carried out to produce the compound mentioned in the subtitle. As a red solid (7 VA "H-NMR (500 MHz, CDCL): 1.69 (1H, [Ra 69 Hz), 277 (1H, dt, ] 87, 142 Hz), 3.86-3.91 (4H, m), 3.93-3.99 (1H, m), 4.18 (1H, t, ] 5.9 Hz), 4.86 (1H, q, ] 7.6 Hz), 6.68-6.76 (2H, m), 6.81 (1H, t, ] 7.7 Hz), 7.07-7.16 (2H, m), 7.19 (1H, d, ] 8.3 Hz), 7.40 01 (1H, by ] 8.3 Hz), 7.53 (1H, d, ] 8.3 Hz), 7.66 (1H, 5), 7.76 (1H, 5). HRMS (FAB) calcd for C,H, N,0, 483.1703 found 483.1718 [M+]. mmol) in ethanol and substance (a) is added. The product is dissolved from step (0 (.74 t. grams). The hydrogenation process results in a Lindlar pressure level, a catalyst of the type of clock, evaporation of the solvent, then purification by separation 6A normal at normal temperature for 0 (IR, 25, 3R, 48))] - preparative high-performance liquid chromatography (HPLC) for the production of the compound ?-cyclopentyl)-?- indolyl] - ;- 1- dimer Hydroxy-PR amino-?-1-dione as trifluoro salt = 7 00-methyl-3-indolyl]-pyrrole-11 acetate It results from the treatment of the trifluoroacetate salt with hydrogen chloride in Etha Loom, evaporation and then freeze-drying of water, title compound (with weight. As a red solid (7 TY g; .11 ratio) H-NMR (500 MHz, CDCL): 1.35 (1H, dt, ] 10.2, 13.4 Hz), 2.79 ( 1H, dt, ] 7.8, 13.1

Hz), 3.64 (1H, dt, ] 7.4,9.1 Hz), 3.87 (3H, 5), 4.15 (1H, t, J 4.1 Hz), 431 (1H, t, J 6.1

Hz), 4.94 (1H, q, J 7.8 Hz), 6.65 (1H, t,] 7.2 Hz), 6.71 (1H, t, ] 75 Hz), 6.77 (1H, d, J 8.0 Hz), 6.93 (1H , d, J 8.0 Hz), 7.04-7.13 (2H, m), 7.37 (1H, d, ] 8 5 Hz), 7.55 (1H, d,] Yo 8.5 Hz), 7.78 (1H, 5), 7.82 ( 1H, 5). HRMS (FAB) calcd for C,,H,.CIN,0,-HCl 456.1797 found 456.1828 [M+].

Ex 17 1[ - - ((45, 18) - 4 - amino - ?-cyclopentene = 1 - yl) Y= = indolyl] - 1 - 6 - methyl - ? = indolyl] - pyrol = ? 0 0 = Hydrochloride dione The by-product of Example VE 5 (14 R. g c 50 710 mmol) is hydrogenated according to the procedure described in Example b AV The title product is obtained after chromatographic separation and treatment with ethanolic hydrogen chloride in the form of Lila red (..4 t. g / 000) LT NMR (500 MHz, CD,0D): § 1.81 (1H, dt, J 7.1, 13.5) Hz), 3.29 (1H, 86 Hz), 3.88 (3H, 5), 4.44 (1H, t,] 8.0 Hz), 5.80 (1H, br t, ] 6.9 Hz), 6.22 (1,1, ] 2.0, 56 Hz), 6.29-6.32 (1H, m), 6.65 (1 H, t,] 7.6 Hz), 6.72-6.77 (2H, m), 6.98 (1H, d,] 8.4 \. Hz), 7.07-7.14 (2H, m), 7.39 (1 H, d,] 82 Hz), 7.55 (1 H, d,] 8.2 Hz), 7.70 (1H, 5), (1H, s) . HRMS (FAB) calcd for C, H,,CIN,O,-HCl1 422.1743 found 422.1763 7.80 M+ Ex. \A 01 1-9 - ((4, 18) - 4 - ( hydroxymethylated)-?-cyclopentene (-1-yl)-?*- endolyl]-4-A]-methyl-? = Ando Lil] - Birol - ? 0, -dione dissolves 7 - 1 (Michel - ? - Indolyl) - 4 - (Jud sus) =F) furan - ? 0, -dione (.77 g 1.51 mmol), lithium hydride (..7 t. SYA pla + mmol), 1-lithium chloride (..t. g + “SYA mmol) in dry dimethylformamide Y. (dr.ml) and the solution was stirred for ten minutes. And add N - [(48, 25) = 4 - (oxymethyl acetyl) cyclo-pentate - ? = anyl] N= = (© - methylphenylsulfonyl) - ; - Methylphenylsulfonamide, then the gas is removed from the solution in a vacuum before adding tetraphenylpalladium (TY) (daa) 50” grams 1 195.R. mmol). The solution is heated at a temperature of Ta ju C for a period of BE hours, then allowed to cool to room temperature. Yo and aqueous acetic acid (concentration 1 mo yo ml) and ethyl acetate are added

YY

Then the phases were separated, and the aqueous phase was extracted using ethyl acetate (Ja Y).

US (two volumes each? ml). The combined organic phases were washed with water (two volumes of ml); Y), the solvent was removed, and the remaining part was dissolved in dimethylformamide. (de of them? Add hydrate and ammonium oxide) ¥ ml) and the solution is heated in a sealed tube at 1 degree Celsius for two hours. After cooling, 11 ethyl acetate is added at a temperature of © 0, the phases are separated, and the organelle phase is washed with water. The removal of the solvent (Ja 7 ( ) / YY) and chromatographic separation result in the compound mentioned in the title (with a weight of .17 grams; with a ratio of . in the form of a red solid "H-NMR (500 MHz, CDCL): § 1.49 (1H, dt, [ 5.5, 14.1 Hz), 267 (1H, dt,] 9.2, 13.6

Hz), 2.93 (1H, brs), 341 (2H, s), 3.83 (3H, 5), 3.52 (1H, br t, [ 6.4 Hz), 5.80-5.83 (1H, \.m), 6.02-6.05 (1H, m), 6.70-6.76 (2H, m), 6.89 (1H, t, ] 8.4 Hz), 7.06-7.12 (1H, m), 7.13 (1H, t,] 7.8 Hz), 7.27 (2H, d, ] 8.6 Hz), 7.39 (1H, d, ] 8.6 Hz), 7.49 (1H, 5), 7.52 (1H, brs), 7.71 (1H, s). HRMS (FAB) calcd for C,,H,,N,O, 438.1818 found 438.1818 [M+].

VA Example 1 [dd gual yl) = ?- - 1 - (aminomethyl) - ? - cyclopentene - 4 - (1S, ((8L4 - 1) [-hydrochloride dione - 5 Y = 7"-indolyl]pyrol - lithium-1[-;-

Yo) (71 tgr 10 mmol) and 7607-Liothidine VA (the product is dissolved in e.g. ml); The solution is cooled to 1 ( 1 μl 10?r.mmol) in dry 10 μl methylene chloride? mmol)., Yo) on ice before adding thalifluoromethanesulfonic anhydride +. This is followed by the addition of Linda Yo ammonium anhydride and oxide, and the reaction is allowed to continue for an aqueous period (at a concentration of 79 07? ml). The two-phase mixture is stirred for one night. MS separates them from the phases, and the aqueous phase is extracted using methylene chloride (two volumes), and the accumulated organic phases are washed with water (¥ ml) and saline solution (? ml). (Jo ¥ ol saad) and dried over 1,122,504 degrees, then chromatographic separation was carried out, producing Yo compound in the form of a red solid after treatment with free amine) / £0 «pla. 5.V0). with ethanolic hydrogen chloride followed by lyophilization of water ve' H.NMR (500 MHz, CD,0D): 8 1.50 (1H, dt, J 6.4, 13.6 Hz), 2.83 (1H, dd, ] 84,122

Hz), 2.91 (2H, m), 3.15 (1H, br t, ] 7.2 Hz), 3.88 (3H, 5), 575 (1H, t,] 2162 Hz), 6.05 (1H, dt, J 2.1,5.6 Hz), 6.19 (1H, dt,] 2.1, 5.6 Hz), 6.68 (1H, t,] 83 Hz), 6.73 (1H, d,] 7.9 Hz), 6.78 (1H, t,] 7.9 Hz), 7.06 -7.14 (2H, m), 740 (1H, d,] 8.8 Hz), 752 (1H, d,] 8.8 Hz), 7.55 (1H, 5), 7.77 (1H, 5). HRMS (FAB) calcd for CyH,N;0; - 0 27 23 3 170 438.2056 found 438.2065 [M+]. Ex: ?-cyclopentyl)-6-fluoro-? -indolyl]-;-1-amine-7-(19 , 35()-1] =F chloride dione -0 Y= ?-indolyl]-pyrrole-ode -1[Ve YoY] tri-butoxycarbonyl - ?- aza dicycly -N-Y-(IS.4R) (a \. If dicyclo- (IR, 45) is dissolved in ml) and 1 (0 (r) gram m Ra mmol) is added in toluene (0) one (1) hietine 0 .ar. grams) Then the reaction is hydrogenated for sixty-six years at a level of 0) pot palladium at a pressure of ? bar . The catalyst was filtered and the solvent was removed in a vacuum. The compound Vo [Ve YX] tri-butoxycarbonyl = ? = aza dicycline - (48,15 - 17-7 gram ¢ quantitative yield) as a white solid (YA) one 1-heptane 1 H-NMR(200 MHz, CDCL): § 1.40 (1 H, d), 1.51 (9 H, 5), 1.95-1.70 (5 H, m), 22 3 H, s),2.85 (1H, m),45 (1 H, s) ). cyclic Oo (tri-butoxycarbutyl) | mini - hepta - N) - cetyl] 1 1S, 3R) 0 XY. , diethyl ether YOY added in the form of methyl lithium drops (molecular concentration

VAs (1 gram YoA) (a mL) into a cooled solution) = .? degrees Celsius) of step product 0 3, | da yu for a reaction for an hour in J J (0 ml) and allows for a continuity (0 2 mmol) in toluene

Yo ml). (V0) degrees Celsius, after which saturated aqueous ammonium chloride Ve is added, the temperature rises, and the organic layer is separated; It was dried over 1002504 and then evaporated to the point of drying. Recrystallization from diethyl ether/pentane (Mr? g; . from the subtitle compound)/4" H-NMR (200 MHz, CDCL): E 145 (9 H, 5), -2.0 1.5 (5 H, m), 2.10 (1 H, m), 22 (3 H, ° s), 3.0 (1H, m), 40 (1 H, m), 49 (1 H, brs). 17-9-thia butoxycarbonyl sulfonate - ?- - 0 = V = (IR, 3S) (c-cyclopentanol - 1-amino .r* g, .r.? mmol) to the product of 7 V2) 7 = memol chlorobenzoic acid is added in toluene (01.0 pla YN) step i) at a temperature of 0.4 °C 0 (9? ml) and the reaction is allowed to continue for 0 days, followed by extracted using 1 (at a concentration of NaHCO3) da 01 Login IS Molecular, two volumes of 1 (at a concentration of NaHSO3 ml). The organic solution was separated and cooled on a bath of 10 of them Molecular MS; two volumes (151) and followed by adding parts of sodium methoxide (do 150) ice, and methanol is added

Sole NaHSO3 mmol). After an hour, the reaction is suppressed by adding Ye gram Vo, the layer (Jo Vo) is separated, and ethyl acetate is added. Jo 001 (at ? gram molecular concentration).

US saturated (two volumes of Sle NaHCO3 water and the organic layer was extracted using ml). The organic layer concentrates to reach half of its volume. 10 of them are abruptly cooled to the remaining part to zero degrees Celsius, then a thiacylamine (.R?) is added.

CA) mmol) followed by addition in the form of 19-sulfonyl methane chloride drops. da Y.

NaHCO3 mmol) and after two hours, the reaction mixture was extracted using 100 ml. The organic phase is heated to reach 10 degrees, of which MS is saturated (two volumes of SAL, and the product is precipitated by adding heptane (00 ml). Lisa produces a temperature VO (CW Marg VA) from the filtration and recrystallization of the aforementioned compound with the subtitle “H-NMR (200 MHz, CDCL): 14 H (9H, s), 225-15 ( 5H, m), 2.4 (1H, m), 30 BH, 3), vo 4.1 (1H, m), 47(1H, m), 5.15 (1H, m).

Al) (thia-butoxycarbonylamine) cyclopentyl] == fluoro-3 - (IRL 38)] - (d indole - + sodium hydride (0 //) is added in 0 70 g oil 1.1 mmol) to ml. The mixture is stirred (V) dry dimethylformamide = NUN fluoroadol dissolved in

Vode a minute. The product from step T (1 R. g Ye at room temperature for 0 mmol) is added in the form of one part. Another part of sodium hydride (7.. t. grams) is added, and “abd 8? r. mmol” is added after three hours have passed. The reaction is allowed to continue for a period of ml) and ethyl acetate (0; ml), then the phases are separated, and the aqueous phase is washed (11) with water and the organic solvent is removed in a vacuum. It is evaporated again.

HNMR (500 MHz, CDCL,): § 1.46 (9H, s), 1.67-1.55 (1H, m), 1.98-1.85 (1H, m), 2.13-2.03 (aH, m), 2.40-1.24 (3H, m), 4.24 (1H, br d, ] 6.5 Hz), 4.71 (1H, brs), 4.81 (1H, p, J 7.3 Hz), 647 (1H, d,] 32 Hz), 6.86 (1H, t, ] 9.0 Hz), 7.02 (1H, d, ] 10.3 Hz), 7.14 (1H, d, ] 3.4 Hz), 7.50 (1H, dd, ] 5.5, 8.5 Hz). \o -7+- cyclopentyl) = F - tributoxyamine aminocarbonyl - 1 - (15,38) - 11 -* (e dione - 0 methyl = ¥ = indolyl] - pyrrole - ? -1[-4 = fluoro-?-indolyl] µL, .1 mmol) to an ice-cooled solution of AS) add oxalyl chloride (product step 0) (10 r.g; ?dr + mmol) dissolved in dry methylene chloride (ml). The solution was stirred at room temperature for 0.7 min; and vaporizes to £50) "0

EN) ?- - (18 ,39(( = 1 - drying, the compound 4 = fluorobutoxyamine amino (cyclopentyl) - 3 - indolyl] - crude geloxy chloride in . Photograph of an orange precipitate -17 This substance was dissolved in dry methylene chloride (* t 7 ml) and a solution of the powder was slowly added. garam; turn around mmol) and triethylamine (WA) methylindole acetic acid (YO ml). The solution was stirred at Y50 (mmol) to methiethylene chloride 1. R. ml;£)

Yv hours, followed by removal of the solvent in a vacuum, and the remaining part A irradiated at room temperature for (1S, 35)) = 1 [- caramel red in color through a short 5:02 column. Cyclopentyl) = - Fluoro = ? = etdolyl] - 1 = tributoxycarbonylamine - 0 - after evaporation of the solvent pla methyl- ?-indolyl]furan- ? 00 Dayun -1 [-;- . It is used without additional purification © - thalate butoxycarbonyl - amino - 3 - (IS, 38(() - 1 [ - connective compound dissolved? methyl - 1-indolyl] furan = N = -; [dad pus) = F - bentyl - cyclo) = = fluoro Hydroxide (Je) methylformamide SUS - 17,17 dione is added at - 0, - hours at Vid °C 001 ammonium (1 ml), then the solution is stirred at a temperature (ml) and then extracted (YO) from a leaky tube. After cooling, saline solution (0 ml) is added. Vo is removed in two volumes each, 1 solution with ethyl acetate - heptane (in a ratio of ? to the organic solvent in a vacuum, and the chromatographic separation of the remaining part is carried out, so you get .) / 17 R. grams; BY ratio of the compound cited in the subtitle (by weight "H-NMR (500 MHz, CDCL): 146 (9H, 5), 1.60-L51 (1H, m), 192-175 (2H, m), 2.22-2.08 (2H, m), 2.38-2.22 (1H, m), 3.84 (3H, 5), 4.02 (1H, sext., [ 6.8 Hz), 471 (1H, \o brs), 4.79 (1H, p,] 7.7 Hz), 6.61 (1H, t, ] 9.4 Hz), 6.74 (2H, m), 6.99 (1H, d, ] 9.9 Hz), 7.10 (1H, t, ] 7.3 Hz), 7.16 (1H , br t, ] 7.3 Hz), 7.27 (1H, 5), 7.50 (1H, 5), 7.74 (1H, 5), 8.07 (1H, 5).|] cyclopentyl) = -fluoro = ¥ = indolyl ] - 1-amino = ¥ - (1S, 38) - \ = ¥ (f .? --;-[1-methyl-?-indolyl]-pyrrole - ?,© -hydrochloride dione Pentyl =F = tert-butoxycarbonylamine - = (1S, 38((-1[ - ¥ -527-methyl-?-indolyl]-pyrrole-1[-)-cyclo) = - Fluoro-? Oxygen is removed from the solution in (Y) min. The cooled solution is divided into Yo in a vacuum and then heated to 0.9 °C for YO (Jo Yo) ml) and ethyl acetate 111 7 To a slight degree between hydrate and ammonium oxide (Dr?

Ya

The organic phase is evaporated to dryness. It is produced by chromatographic separation, followed by treatment with ethanolic hydrogen chloride and freeze-drying of Lilia red in the form of material (7 YA order. g; 0) mentioned in the title SUE. Water 1 "H-NMR (500 MHz, CD,0D): 5 7.86 (1H, s), 7.66 (1H, s), 7.42 (1H, d,J83 Hz), 7.23 (1H, dd, J2 .1,9.9 Hz), 7.11 (1H, t,] 7.3 Hz), 7.08 (1H, dd, J 4.6(5.5) Hz), 6.69-6.64 0 (2H, m), 6.58 (1H, t,] 9.3 Hz), 5.11 (1H, p, J-7.7 Hz), 3.93 (3H, (3.77 (1H, p,] 7.7)

Hz), 2.50-2.43 (1H, m), 2.41-2.27 (3H, m), 2.11-2.04 (1H, m), 1.80 (1H, sex.,] 7.0 Hz). 1 ex. 0 Y = pyrol - [Updos = Y= dasa =A 0. Jas! Starting | from 0 — Chloroy Y. J Gia as then described in O A compound is synthesized | cursed "H-NMR ( 500 MHz J7.1Hz),3.94 (3H,s), 5.17 (1H, p, J 7.4 Hz), 6.63-6.70 (2H, m), 7.08-7.14 (3H, m), 7.45 (2H,t,] 88Hz),7.68(1H,s), 7.83 1 H, s).i ve 1 eg methyl - 1[- 4 - [Jd endo = Y= cycloid) - 10 - mini |] - (1S , 35((-1[-1pyrol-?,9-hydrochloride dione -]lelodta-17 = mini 0-? - Jus gs —S b la ga triple Butoxy (1 S, 3S)) -1[ methyl - ?- - 1 ) 0 - 0, methyl - atdolil - ?- yl] - yrol - ? - 1[ - 4 - [Jad pus) = 3- Cyclopentyl) 0. dione —\Li solution of J mmol) \ Bp) 11.0 gm of potassium I added in tri-butoxide dione - ©, - Joo — Endo Lil) 1 - Endo Lil (p) \ —- Mithel - 79 1 - Mithel and turns ¢ (Js Yo 0) binary methylformamide _ N 0 N mmol) in \ J \ 3 g 0 JY)

Ya minutes at room temperature. The subtitle product of 01 was added to the mixture for 1 mmol) and then the reaction mixture was stirred for 2 hours at 1 degree. , (4 T. grams CR 1. Example saturated Ala 10011003 ml of fo ° C. The mixture is poured at 100 degrees Celsius and extracted using toluene (*.ml). The organic layer is washed with water, It was dried over 1,882,504 degrees, then evaporated to dryness, and purified on a silica gel column (© 00 grams /) in the form of a red solid (+L) of the compound mentioned in the subtitle. Color H-NMR (200 MHz, CDCL): 1.44 (9H, ,1.51 (1H, m), 1.82 (1H, m), 2.35-2.0 (4H, m), 3.16 (3H, 5), 3.83 (3H, 5), 4.01 (1H, m), 4.53 (1H, 5), 4.88 (1H, m), 6.69 (1H, t,] 7.6

Hz), 6.74 (1H, 4, 8.1 Hz), 6.85 (1H, ,] 8.1), 7.08 (1H, , ] 7.6 Hz), 7.11 (1H, , | 7.6 \

Hz), 7.24 (1H, 5), 7.26 (1H, d, ] 8.3 Hz), 7.30 (1H, d, ] 8.3 Hz), 7.50 (1H, 5), 7.70 (1H, 5) ?- 1 - thalibutoxycarbutyl-7 = aminocyclopentane (18,38) = 11-7)

SEE - methyl-indole-?-yl)-pyrol-1(-1-yl)-etdole-7-yl]-1-dione 0 (do Ys) mmol) dissolved in TV water g; + VA) potassium hydroxide is added then (do 0) to a solution of Mint step 2 (1 R. g 50 mmol) in ethanol The resulting mixture is heated at recession for two hours. Acid is added Hydrochloric at a molecular concentration to the cooled solution until the hydrogen number reaches - ?. The resulting red precipitate dimethyl-NON is filtered, washed with water, then re-dissolved in XY. (Jo £) formamide 2 hours.The reaction is divided between ethyl acetate and water.Bal conducts at 171 degrees Celsius, evaporation of the organic layer to reach the degree of dryness.The chromatographic separation of the aforementioned compound silica gel column gives Sub (4R. 0/57 g) in 0" . red solid image YO" H-NMR (200 MHz, CDCL): 1.4 (9H, 5), 2.3-1.4 (6H, m), 3.85 (3H, 5), 3.90 (1H, m), 5.0 (1H, m), 7.90-6.60 (10 H, m), 10.9 (1 H, s).

©) ?- 1[ - (-amine cyclopentane - 1 - yl) - etdol - 3 - yl] - 4 - -1(myl -

indole - ?-yl) - pyrrole - 0,7 - dione

The address complex is obtained by processing the product from bask using

acid as described in Example 67. 0 example yw

- yl) - ?- indolyl] - ; - 1 - hydroxy - ? - Cyclopentane - 4 - (1S, 4S) - 1[ = F

[© = indolyl] - Y= pyrrole = dione

(a - methyl - ?- 1[ = ((45, 18) - £ - (tert-butyl dimethylsilyl xi) - ?-

cyclopentane-1 yl)-?-indolyl]-4--1[(tributoxycarbonyl)-=0 indolyl]-pyrrole-09.7-dione

Dissolves 1 - 6 - INTEL - methyl - 1 - 3 ( - thalathi butoxycarbonyl - ?-

indolele) - pyrol = ? 0 0 - Dione (Flar.gr 1.Lar1 mmol) and Lithium Chloride

)°..t. grams R. 111 mmol) and lithium hydride (R. 11 grams, R. 1 mmol) in

Four Mamed Dimethyl Dry (WV ml) and then stirred for 10 minutes. The gas is removed from the dark purple solution 10 and then (1S, 4R) = 4 - 0 - acetyl = - 0 - (tert-butyl) is added

ALS methylsilyl)cyclopentane = 0 - diol HEE . grams; ./r1 mmol) and to follow

With the addition of tetracycline triphenylpalladium (0 LY) grams SW 1 mmol).

The reaction is allowed to continue for 10 minutes at a temperature of 10 °C. And yet

After cooling, diethyl ether (Ja V1) and aqueous acetic acid (at a concentration of 1 molecular) are added. (do YoY) and the phases are separated, then the aqueous phase is washed using an additional part of AUS ether.

acyl (.3 ml).

The combined organic phases were washed with water (two volumes of AS, of which (Ja Yo) and dried over

4; It evaporates and then undergoes chromatographic separation. The compound is obtained

mentioned in the subtitle as a red solid (CW pla VE).

1 Rosa (500 Mhz, CDCL): 5 0.04 (3H, 5), 0.07 (3H, 5), 0.86 (9H, 5), 1.73 (1H, dt, J 5.1, 13.8 Hz), 2.88 (1H, dt, ] 7.5, 13.6 Hz), 3.18 (3H, 5), 4.83 (1H, brs), 5.26 (1H, br Ba J 63 Hz), 5.78 (1H, d, ] 5.1 Hz), 6.00-6.04 (1H, m), 675-693 (21, m), 7.09 (1H, £J 78

Hz), 7.13-7.17 (2H, m), 7.20 (1H, d, ] 8.0 Hz), 7.45 (1H, d, ] 8.0 Hz), 7.66 (1H, s), 8.02 (1H, 5), -8.07 8.16 (1H, m). HRMS(FD) calcd for C,H,N,0,Si 637.2972, found 0 637.2989 [MH+]. tertetrahetyldibutyl - 4 = (IR, 45) - 1( (ALS - 4, ¥ - methyl - 1 - 0 2 yl) - ¥ = indolyl) - pyrrole - ? - 1- Cyclopentane = Y = methylsilyloxy). Dione as an important by-product 18. The title compound is obtained by heating the product of Step 8) in vacuum (bY.

SEVER °C for 49 minutes. And the chromatographic separation results in the compound -1- (tert-butyldimethylsilyloxy)-? - Cyclopentane - £ - (45,18)((a small part is dissolved.)/ Ve 0 g EA) dione - 0, yl) - = indolyl] - pyrrole - ? ml) and hydrate and aqueous sodium oxide (1) of the product (.11 grams, mmol) in ethanol, and the solution is regressed for 1.8 hours; Convert the solution to an acidic form using Jo 1 (of which SIS is hydrochloric acid), then extract the product ethyl acetate (two volumes -1- hydroxy -? The intermediate compound is produced? Formamide Jute binary NN.? The product is in Celsius for two hours in a tubular vessel sealed (Taya Yo) and results from heating to the point of leakage; extraction and then evaporation from the solvent the product mentioned in the title (weighed in the form of a solid red color after separation) / VY gram, ratio yet. Chromatographic “H-NMR (500 MHz, CDCL): 1.61 (1H, dt, 747, 13.9 Hz), 1.75 (1H, br d, J 62 Hz, Yo

Za OH), 2.95(1H,dt, ] 7.9, 14.3 Hz), 4.79 (1 H, brs), 5.33 (1 H, brs), 591(1H,d,J52 Hz), 6.09 (1H, dt, J 1.9, 5.6 Hz), 6.76 (1 H, t, ] 7.4 Hz), 6.83 (1 H, d,] 8.1 Hz), 6.88 (1 Ht ] 7.4Hz), 7.07 (1H, ] 7.7 Hz), 7.14 (1H, t,] 7.7 Hz), 7.26 (1H, d,] 8.1 Hz), | (IH, d,] 8.1Hz), 740 (1H, d,] 84 Hz), 7.52 (1 H, s), 7.67 (1 H, s), 770 1 H,d, 731 Hz), 8.62 (1 H, s). HRMS(FAB) calcd for C,H,N,O, 409.1426, found 409.1436 ° 17.5 M+]. |Example Ye a 7-di(IR, ,48((-1(-4-hydroxy-?-cyclopentane-1-yl)-SY indolyl)-pyrrole 0 Y = - Dione 0 The primary by-product of Dimethyl YF 2 ( (.01 g 0.0/1.0 mmol) is dissolved in ethanol (; ml) and potassium hydroxide Sle ( At a concentration * R. molecular weight (Yi ml).The solution is heated to the point of recession for an hour.The resulting cooling to room temperature followed by conversion of the solution to an acidic form using hydrochloric acid and then extraction of the product using ethyl acetate (two volumes of which 1 SIS mL) intermediate ELT 0 di(1-(-(48, 18)-4-hydroxy-?-cyclopentane 1--yl)-SY endolyl)-furan Y= 5. Dione The aforementioned product is dissolved in N,N dimethylformamide (? ml) and ammonium hydroxide (? ml), and it results from heating to the VY degree. Then the solvent for the product mentioned in the title (with a weight of .. 4 grams; with a percentage of EE /) was evaporated in the form of Talay, red in color, after chromatographic separation H-NMR (500 MHz, CDCL): § 1.72 (2H, dt, J 5.3, 1 3.5 Hz), 3.08 (2H, dt, ] 7.8, 13.8 Hz), 4.87 (2H, brs), 5.51 (2H, brs), 5.99 (2H, d, ] 53 Hz), 6.19 (2H, d, ] 5.3 Hz), 6.73 Hz), 82 hrs (2H +, ] 7.6 Hz), 6.91 (2H, d, ] 8.0 Hz), 7.08 (2H, t, ] 7.7 Hz), 7.55 (2H, ‎H, s). HRMS(FAB) calcd for C, HNO, 491.1845, found 491.1854 [M+]. 2( 7.72

Claims (1)

iY (1) is a compound of the suffix — 1 5 . N 0 0 B A A Ben Fao N N Ra 0 1 0 8 0 A Whereas it is hydrogen or Talia each of the 1220 that may be similar i.e. 3 halogen; hydrogen or +1; of Jade R for Le R' 1 : (ID) to be a group of the adjective R, A (CH, ? 2 ' R; Rs H Ry (m) where 9 0 is for a single or double bond sy lee 7 \ 0 XY to 1 consist of < 11 amino; ((01-05)alkyl)amino; 1 form 16 hydroxy;hydroxymethyl 1"mini, 17.17-di ((01-05) Methel) 1 Methel) Methil (01-05(( Ne as Amity NY “M KK ©-and) Aseel) | Mini )) -N siloxy or (Cs-C 1 ) « Mitty | A} Ry and Ry are single bonds, and Z is hydrogen, and when Ry is 4 Ry is 0 1 which may be the same or different. Each one is hydrogen or 10-hydroxy and VA are pharmaceutically acceptable salts in addition to all the stereoisomers (Bal) whether 4 in pure form or in the form of racemes or mixtures of the stereoisomers of these 0 salts. 1 7 ?- is a compound according to era 1, where Ry is a hydroxy or hydroxymethyl Y or an amino or aminomethyl . 1 ?- Compound according to the element ¥ where “ is 1 or 7 ; And Rp is a Y-hydroxy or an amino. 1 4 - compound according to the element? ; Is it about 1 or ? , and 181 is an amino. 1 *- Compounds: 11-7 - " - ((38, 15) - 3 = amino = - cyclobutyl) - ?- indolyl] - 4 - 11 - methylYY indolyl] - pyrrole 0 Y = - dione; Y = (IR, BR) = \] = F 4 = amino - 1-cyclopentyl) - ¥ = indolyl] - 4 - 1[ - methyl 0 -7 -indolyl]-pyrrole-?.©-dione; SRO RTE SE -amino-1-cyclohexyl)-7-indolyl]-4-1[-methyl-SL V indolyl] - pyrrole 0 Y = -dione; - 18, 4(( - 1 = F = (+) A - amino Y = = cyclopentene - 1 = yl) - ?- indolyl] 4 4 -0 - 11-methyl-?-indolyl]pyrrole 0 Ym-dione; 11-7 0 - ((48, 19) - 4-amino-7-cyclohexene - (J - 1 - ? -indolyl]-;-1[11-methyl-9-etdolyl]pyrrole-?; 9-dione; 11-90" - ((4, 38 , 28,18) - 4-amino- 17 7-dihydroxy-1-pentyl (1"cyclo)-=F indolyl]-4-1[-methyl-=F indolyl]-pyrrole-?Cosham 0 (IS, 3R)) = 11-7 014 - 7-amino = 1-cyclopentyl) - ¥ = indolyl] = 4 = 1[ = methylVo -?- etdolyl] - pyrrole - ?; 0”-dione; n 11-7 AX - ((18,39) - ? = amino-1-cyclopentyl ) =? = indolyl] - 4 - -1[methyl AY - ?- indolyl] - pyrrole - ? 0 - Dione; β-Penticyl-1-amino-3 7-dihydroxy-4- (IR, 2S, 3R ,48)((-11-37 04 methyl-7 = indolyl]-pyrrole-?00 dione;- 1[ - 4 - cyclic) - ?- indolyl] 4 SA) - 4 - [dad yl) - 3 - endo - 1 - amino - ? - Cyclopentene - 4 - (18,45) - 7-11 dione; yl) -?- - 1 - (48,18) - 1-7 YY -dione; yl) - ?- indolyl] - 1 - cyclopentene - Y = (aminomethyl) - £ - (ISR) - 1-7 YE -dione;0 methyl-?-indolyl] Pyrrole -? ] = 1 - Ynim1 - Y = (1S, 38)) - 11 - 7 ¥ . dayon; And pharmaceutically acceptable salts - 0c Y = -7-indolyl] = pyrrole ¥ . 6 to 1 hydrochloride salt of a compound according to any of the elements from 7-1: ; It includes 1 process for preparing a compound according to the element -4 + 1 is a hydroxyl or hydroxyl Rp in which D is a compound product of 1 Y, one of which is JS and 1615 is Ry lic methyl; and when 7 is a VF mono bond of hydrogen, by removing protection for a similar compound of formula (1) in which 81 is; a methylene carrier of a protected hydroxyl group; or of a protected hydroxyl group 0 0 is an amino or methyl amine RY (b) producing a compound from character (1) in which 1 is each hydrogen; Rs and Ry plac and when there are 27 single bonds V and that by: 4 is more or more methylation; or Rp is a reduction of an identical compound in which (A) is an amino group Ry deprotection of an analogous compound of formula (1) in which (i \. is protected or Methylene is a carrier of a protected amino group; or 11 is an amine; 17-((01-and-2)alkyl)Ry c) production of a compound from phenotype (1) in which MY (C5-C1)) alkyl)methylamine , 11,17 - Binary (05-01)) = No Amino; Aminomethyl VY supported VE | alkyl) methylamine and when 7 is a single bond, O La. Each of R4 and 5 p 0 is hydrogen, by the reaction of an ammonia or an appropriate amine with a corresponding compound of 1 A (I) Lal in which Le Ri for a good alia group or a methylene group carrying a successively good leaving group ' or a compound product of | Lasifa (0) in which Le Ry is from | siloxy) (Cs -Cy) or 1 - (C5-Cp)) 01 acyl) amino, and when 7 is a single bond, each of the Ry Y. and Rs are hydrogen, by acylation of a corresponding compound of 1 of formula (0) in which B is a hydroxyl or an amino respectively, or YY e) producing a compound of The phenotype (D) in which Ry is hydroxy; rugen ¢ by a complex reaction of | of the formula (IID): 0 0 0 TI, 0 a N N 20 . a R' 000 TA in which 1820, 88 and 18 are specified as in the adjective ( D , but in which Ry is a VV hydroxyl group that has been protected by a methylene carrier of a protected hydroxyl group or a YA protected amino group; or a methylene carrier of a protected amino group;, using YA 0 amo ¢ or ammonia, followed by treatment with an appropriately protective Aza agent ¢ or Sun 0 acetate pois! followed by treatment with a deprotecting agent lia or (iii YA) hexamethyldisilazane-methanol, followed by treatment with a deprotecting agent YY Protection of asta YY and rd asd is a composite of a matrix (D) in which Rg and Rs are defective from hyd doxyl boa S Taha?? Hydroxylation of a compound of formula (1) in which a 2 double bond is formed in the presence, for example, of Yeo, a metal oxidant, or 1g) convert (i Yv compound of formula (1) into a pharmaceutically acceptable salt of that compound; or vice versa YA) or (i Ya a pharmaceutically acceptable salt of formula compound (D) into a salt Pharmaceutically acceptable 2 different. 1-1 compounded according to any of items 1 to 6 for use in treatment. 1 01 - compounded according to category 4, for use in treating inflammation or immune disorders. The use of a compound according to any phase of elements 1 to 6 for the purpose of manufacturing a drug to treat "inflammation and immune disorders". ast of a mammal in Tala for that "treatment. 17 1 - Pharmaceutical composition wherein the active ingredient is a compound according to any of the" elements 1 to 6. VE - a compound of formula (IA) : H N 0 0 7 R] ] to Ryo N N Ro R R' 0 A) 3] B 8 Each of the 1220 which may be the same or different, is a hydrogen 8 or La ligne ¢ 11 250 is a methylation of hydrogen or R R 7 is a defect of a group of | Lasifa (1D): H over A (CH,)n R, (2) ] R; R, H Rs where A ¢ is a single or double bond 7 / 0 to ?. 1 is “© 11 of a Jala hydroxyl group protected hydroxyl group; methylene Ry b11 , protected ,; increase; azidomethyl group, protected amino group; Methylene is a VY carrier of a protected amino group;, a good cyclic group or a methylene group that is a carrier of [0] KX group is a good \o Rs and Ry single bond. Z is hydrogen; and when R35 is 162 7 hydrogens; OR 1: (IIA) compound of the adjective VA Y 0 0 - \4 R © | | @1 N N Ry, R R' 94 using a methyl group Jd ested Ca 9 a0 e from oxygen or J Le Y n ! Sian Y. Rp are as previously defined in the claims; but is 0 2,8,8,820 Y) £4 YY is a hydroxyl group Liana methylene carrier of a protected hydroxyl group YY ; a protected amino group of methylene Jala is a protected amino group; and YE d tho R3 is a hydr and a gene; And when it is 7 single bonds, Rs 9R4 YO is hydrogen 0 or 0 X and F, 0 Ryo N: R YA, where YA Kr is a halogen atom , and 1220 is hydrogen or halogen ;, and R is as it was done 0. Define it above in the adjective oe (ID) YY compound of (VA): Gall LD R N YY * R Ea YY that Rpg ve is It is hydrogen or ha-logine ¢ and is R as defined above in Yo summer (111). 7