MX2008009543A - Indole sulfonamide modulators of progesterone receptors - Google Patents

Abstract

Compounds of Formula (I), wherein n is 1 or 2, and R1, R2, R3, R4, R5, R6, R7, and R8 are as defined herein, their preparation, pharmaceutical compositions, and methods of use are disclosed.

Description

SULFONAMIDE INDOL MODULATORS OF PROGESTERONE RECEPTORS FIELD OF THE INVENTION The current invention refers to the fields of organic medicinal chemistry, pharmacology and medicine. In addition, the current invention relates to new compounds and methods useful for the treatment of tumors, gynecological disorders and symptoms and related sequelae.

BACKGROUND OF THE INVENTION Leiomyomas are the most common non-cancerous tumors in women of childbearing age. Uterine leiomyomas (or fibroids) are considered benign tumors of muscle and connective tissue that develop within or are attached to the uterine wall. It is estimated from ultrasound examination that more than 70% of women will develop fibroids by the time they reach menopause (Baird et al., Am J. Qbstet, Gynecol., 2005; 188: 100-107; and Cramer et al. Am. J. Clin Pathol, 1990; 90: 435-438). While not all women are symptomatic to justify therapy, a significant number of women experience moderate to severe symptoms that include abnormal uterine bleeding, pelvic pressure and pain, and reproductive dysfunction. Current treatment therapies include surgical intervention, such as hysterectomies and myomectomies. Less invasive procedures include: uterine artery embolization and thermoablative coagulation. Medical therapies include hormonal treatment. Currently, the only hormone treatment approved by the FDA is the use of a GnRH agonist (gonadotropin releasing hormone), preoperatively with iron. (Walker and Stewart, Science, 2005; 308 / 1589-1592.). GnRH agonist therapy is often limited to 1-3 months due to measurable bone loss which leads to osteoporosis with long term use. In addition, myomas treated with GnRH agonist often return to pre-treatment size within weeks of cessation of therapy. As a result, this treatment is often used to reduce the size of the myoma and allow the woman to prepare for her eventual surgical removal. (Stewart, Lancet, 2001; 357; 293-298.). These options have undesirable consequences for women who want to conceive some time later. Obviously, a hysterectomy could prohibit subsequent conception, and the other surgical options also present risks, which include recurrent uterine rupture and fibroids. Medical treatment can also cause significant side effects. For example, GnRH agonists produce an environment in the body that is very similar to that of menopause, with associated side effects such as hot flashes, vaginal drying, and as noted earlier, loss of bone density. These and other problems highlight the continuing need to treat and alleviate gynecological disorders such as myomas in general, more specifically but not exclusively, leiomyomas, and endometriosis, and their attendant symptoms. As an additional background, the following references describe structures of indole or indoline and their therapeutic use. Merce et al. in document O 2005/013976 describe indole-6 sulfonamide derivatives of the following formula substituted as described herein: which are declared to be used as modulators of 5-HT-6. Hsieh et al. in US 6,933,316 discloses indole compounds of the following formula and substituted as described herein: which are declared to exhibit anti-cancer activities and work by focusing microtubule polymerization / depolymerization. The above references either do not disclose effective treatment of abnormal tissue growth or compounds used as ligands of the progesterone receptor. In addition, the disclosed compounds exhibit one or more undesirable characteristics including, low bioavailability, low binding affinity of progesterone, non-specific binding to hormone receptors in general, ie, absence of specific binding of the progesterone receptor (PR), and none or under effective treatment of tumors, in general, and more specifically none or under effective treatment of fibroids, leiomyomas and endometriosis. Consequently, a significant need remains for effective compounds and methods of treatment for tumors, gynecological disorders and related sequelae. The present invention addresses these needs.

BRIEF DESCRIPTION OF THE INVENTION Unless otherwise specified, the following numbering system for the indole core illustrated below will be used in the present application: present invention provides a compound Formula I (i) wherein n is 1 or 2 and R1-R8 are described herein. For selected applications, preferred compounds of the present invention are selective progesterone receptor modulators (SPRMs). In another form, the present invention also provides a pharmaceutical composition comprising a compound according to Formula I as defined above, and one or more of the following: a carrier, a diluent, and an excipient. The present invention also provides a method to prepare a compound of Formula I above. In one form, the method includes combining a compound of Formula II (ID with a base and R6SO2CI. This method can also include reducing the nitro group in a compound of Formula IIA below with the amine.

IIA In another form, the method includes replacing geno (X) in the 3 indole position in Formula III below III with an optionally substituted aryl group, optionally substituted heteroaryl, or bicyclic aryl optionally substituted or bicyclic heteroaryl. This method may further include first replacing the halogen with a more reactive leaving group such as the dioxoborolane group formed of bis (pinacolato) diborus, for example. In another form, the present invention provides a method for modulating the activity of the progesterone receptor and / or treating diseases mediated by the modulation of progesterone receptor activity in a mammal that includes, non-human and human (more specifically females). The method comprises administering a therapeutically effective composition comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, to a patient. In a preferred embodiment, the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, which exhibits a high degree of binding selectivity of the progesterone receptor (PR). . In a more preferred embodiment, the administered compounds exhibit a progesterone receptor binding selectivity greater than or equal to about 5 times that for the androgen receptor (AR), glucocorticoid receptor (GR), and mineralcorticoid receptor (MR), as is determined by comparing the individual IC50 values or the Ki values from the respective binding tests. In another preferred embodiment, the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers thereof, capable of, or selected to elicit a PR agonist effect, an antagonistic effect. PR, a partial PR agonist effect, or a partial PR antagonist effect or a mixture of these effects. In still another form, the present invention provides a method for treating or alleviating the effects of one or more of: tumors; neoplasms; myomas (myomata); leiomyomas (uterine fibroids); endometriosis (adenomyosis); post-operative peritoneal adhesions; endometrial hyperplasia; polycystic ovary syndrome; carcinomas and adenocarcinomas of the uterus, ovary, breast, colon and prostate; infertility; fertility control; female sexual function; other menstrual or gynecological syndromes, such as dysfunctional or abnormal bleeding, amenorrhea, menorrhagia, hypermenorrhea, and dysmenorrhea; or pathological sequelae due to previous disorders / syndromes in a mammal that include, non-human and human (more specifically, female). In still another form, the present invention provides a method for treating endometriosis or symptoms and pathological sequelae due to endometriosis. In another form, the present invention provides a method for treating or alleviating the effects of menstrual or gynecological disorders in a mammal by administering a therapeutically effective dose of a compound of Formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture of diastereomers to said mammal. In still yet another form, the present invention provides the use of a compound for the manufacture of a medicament for treating or alleviating the effects of one or more of: leiomyomas, endometriosis and dysfunctional bleeding. The present invention also provides a combination therapy, administered either as a concurrent, sequential or intermittent treatment regimen, which involves a compound of Formula I and one or more selective estrogen receptor modulators (SERMs), estrogen, agonist ER , ER antagonists, selective androgen receptor modulators (SARMs), gonadotrophin releasing hormone (GnRH) agonists, progesterone (P) / progestins and other PR agonists and modulators.

DETAILED DESCRIPTION OF THE INVENTION In one form, the present invention provides novel compounds of Formula I (I) where n is 1 or 2; R1 is selected from: Ci-C alkyl, C2-C6 alkenyl, alkynyl 02-06, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkylaryl, C1-C6 alkyl heteroaryl, C3-C8 cycloalkyl, alkylcycloalkyl Ci-C, alkyldicycloalkyl Ci-C6, alkylheterocyclyl-i-Ce, heterocyclyl, aryl, heteroaryl, alkyl Ci-C6-0-R9, alkyl C0-C6 C (S) R9, alkylCo-C6 C02R9, -SOnRll, where each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl listed either individually or in combination with an alkyl portion, are optionally substituted, from one to three individually selected groups of: halo, -CN, -OH, oxo, C1-alkyl C3, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl N02, -O C1-C3 alkyl, C1-C3 hydroxyalkyl, C0-C3 alkyl NR12R13, C0-C3 alkyl (0) R12 , C0-C3 alkyl C (0) OR12, C (0) NR12R13, C (S) NR12R13, CH2ORI 2, -SR12, S (0) nR12, -S (0) nNR12R13, -N (R9) C (0 ) R12R13, -N (R12) C (0) OR13, -N (R12) S (0) nR13, -N (R12) S (O) nNR1 2R13, -C = N-OR10, and -NC4R9 cycle; provided that aryl and heteroaryl are not individually di- or tri-substituted with alkoxy substituents; R2 is selected from H, halo, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl; R3 is selected from an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted bicyclic heteroaryl; wherein the substituted aryl, substituted heteroaryl and bicyclic heteroaryl are substituted with one to three groups individually selected from: halo, -CN, -OH, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2 alkenyl C5, C2-C6 alkynyl, C0-C3 alkyl N02, -O C1-C3 alkyl, -O haloalkyl C1-C3, hydroxyalkyl C1-C3, alkyl C0-C3 NR12R13, alkyl C0-C3 C (0) R12, alkyl C0 -C3 C (0) OR12, -C (0) NR12R13, -C (S) NR12R13, -CH2OR12, -SR12, -S (0) nR12, -S (0) nNR12R13, - (R9) C (O) R12R13, -N (R12) C (0) 0R13, -N (R12) S (O) nR13, - (R12) S (O) nNR12R13, -C = N-OR10 and -cyclo CN4R9; R4, R5, and R7 are each independently selected from: H, halo, -OH, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -O Ci-C alkyl, -O-C1-C4 haloalkyl; R6 is selected from: Ci-C6 alkyl, Ci ~ C6 haloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, heterocyclyl, C1-C3 alkylheterocyclyl, phenyl, C1-C3 alkylheteroaryl, C0-C3 alkyl NR9R10, and -N (H) C (0) R9, in wherein each of cycloalkyl, heterocyclyl, phenyl, and heteroaryl listed either singly or in combination with an alkyl portion, are optionally substituted from one to three groups individually selected from halo, -CN, -OH, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl N02, -O C1-C3 alkyl, and Ci-C3 hydroxyalkyl; R8 is selected from: H, Ci-C4 alkyl; R9 is individually selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C0-C6 alkylheterocyclyl, C1-C6 alkylcycloalkyl; C1-C6 alkylaryl, C0-C6 alkylheteroaryl, Ci-C6 hydroxyalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl; RIO is selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Rll is selected from: Ci-C6 alkyl, -NR9R9, C0-C6 alkylcycloalkyl, aryl, heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with 1 to 3 groups individually selected from halo, -CN, and -O alkyl C1 -C3; R12 and R13 are individually selected from: H, C1-C6 alkyl, Ci-C6 haloalkyl, C-Ce alkylcycloalkyl; alkylaryl Ci-C6 alkylheteroaryl Co-C6, hydroxyalkyl Ci-C6, alkenyl C2-C6, and cycloalkyl C3-C8; or a pharmaceutically acceptable salt thereof. In one form, more preferred groups for R1 include: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, aryl, Ci-C6 alkylaryl, heteroaryl, C1-C6 alkyl heteroaryl, Ci-C6 alkylheterocyclyl, -SOnRll, and C1-C6 alkyl -S-R9, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl, listed either singly or in combination with an alkyl portion, is optionally substituted with 1 to 3 groups individually selected from halo, -CN, OH, -N02, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. In another preferred form, Rl group include: heterocyclyl, C1-C6 alkylheterocyclyl, aryl, Ci-C6 alkylaryl, heteroaryl, and Ci-C6 alkylheteroaryl, wherein each is optionally substituted with 1 to 3 individually selected halo groups, -CN , -OH, -N02, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. More preferred groups for R3 include: benzo [1, 3] dioxol, benzofuranyl, benzo [1, 2, 5] thiadiazolyl, benzothiophenyl, chromen-2-onyl, 2,3-dihydro-benzo [1,4] dioxinyl, 2 , 3-dihydro-benzofuranyl, 2,3- dihydro-lly-indolyl, 1,3-dihydro-benzoimidazol-2-onyl, 1, 3, -dihydro-indole-2-onyl, furanyl, indan-l-onyl, indazolyl, isobenzofuran-l-onyl, isoxazolyl, naphthalenyl, phenyl, pyrazolyl, pyridinyl, pyrimidyl, pyrrolyl, quinolinyl, 1, 2, 3 , 4-tetrahydro-quinolinyl, thiophenyl, thiazolyl, tetrahydrofuranyl, and tetrahydropyranyl, each optionally substituted with 1 to 3 groups selected individually from: halo, -CN, -OH, -NO2, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyalkyl C1-C3, -0 C1-C3 alkyl, -C (S) NR9R9, -C = N-OH, -C = N-0R11, and C (0) R11. More preferred R6 groups include: Ci-C6 alkyl, Ci-C6 haloalkyl, C1-C6 alkylheterocyclyl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, C2-C6 alkenyl, heterocyclyl, and C0-C6 alkyl NR9R10. Still further, R6 groups include C1-C6 alkyl, Ci-C6 alkylcycloalkyl, and heterocyclyl. The present invention also contemplates within its field, the treatment and alleviation of non-malignant conditions such as myomas, leiomyomas (uterine fibroids), endometriosis (adenomyosis), postoperative peritoneal adhesions and endometrial hyperplasia or pathological sequelae due to the above conditions. The present invention also includes the treatment and / or relief of infertility; control of fertility; sexual dysfunction; and menstrual or gynecological disorders or syndromes; such as, abnormal or dysfunctional bleeding, amenorrhea, menorrhagia, hypermenorrhea, and dysmenorrhea or pathological sequelae due to diseases, treatments and / or previous syndromes. The present invention also includes the treatment and / or alleviation of malignant conditions such as, carcinomas and adenocarcinomas of the uterus, ovary, breast, colon and prostate or pathological sequelae due to diseases, treatments and / or previous syndromes. The term "modulation" could include, but is not limited to, ascending regulation, down regulation, inhibition, agonism, receptor antagonism as appropriate to achieve gene expression and the biological sequelae resulting from such interventions. The phrase "diseases related to receptor modulation" or "diseases mediated by receptor activity" refer to any physiological disorder of any origin, response to administration of a modulator of. receptor either as an agonist, antagonist, partial agonist or partial antagonist, and mixtures thereof. In the structures illustrated herein, the following indicates the atom or point of attachment of the group illustrated to the remaining portion of the molecule: The general chemical terms used in the description of compounds described in this document, carry their usual meanings. For example, the term "Ci-6 alkyl" or "(Ci-C6) alkyl" or "Ci-C6 alkyl" refers to a straight or branched aliphatic chain of 1 to 6 carbon atoms. Unless stated otherwise, the term "alkyl" means Ci-C6 alkyl. Unless specifically denoted otherwise, the carbon atom of alkyl groups is attached to the remainder of the reference molecule. When used in conjunction with a substituent, the alkyl group may be an alkylene group bonded to the substituent on the remainder of the reference molecule. The term "Co-Ce alkyl" implies an alkyl group as indicated above, however, when the C0 term applies, the alkyl group is not present. In this embodiment, the remaining groups are directly linked to the rest of the referenced molecule without the intermediation of the alkylene, linker group. The terms alkenyl and alkynyl, for example, a C2-C6 alkenyl group (or a C2-C6 alkynyl group), as used herein, means that the respective groups may include 1, 2 or 3 double bonds (or triple bonds). If more than one double or triple bond is present in the group, the double or triple bonds can be conjugated or unconjugated.

The invention also contemplates that the terms "Ci-C6 alkyl", "C2-C6 alkenyl", and similar terms also encompass the specified alkyl or alkenyl moiety or the like, which may be chiral, regio or stereoisomeric. Such chiral or regio or stereoisomeric portions as substituents are also included within the scope of the present invention. The term "cycloalkyl" as used herein refers to a cyclic C3-C8 moiety having only carbon atoms as ring elements and that each ring element of the carbon atom includes an appropriate number of hydrogen atoms, or is optionally substituted with one or more substituents as described herein. It will be understood that the term also contemplates that the ring may include one or more carbon-carbon double bonds. The term "heterocycle", "heterocyclyl" or "heterocyclic", refers to a mono- or fused bicyclic ring of 5-10 elements, which may be saturated or partially unsaturated, and may contain 1-5 heteroatoms. The term "heteroatom" as used herein means an atom selected from N, S or O. Heterocyclic, heterocyclic, or heterocyclic rings may be optionally substituted at the carbon, nitrogen or sulfur ring atoms, unless specified otherwise with one or more of the substituents listed below. The heterocyclic ring it is linked to the referenced compound or substructure. In one form, mono heterocyclic rings are preferred. In another form, preferred heterocyclic groups include, benzothiophene, dioxarane, hexamethyleneimino, indolyl, isoquinolyl, morpholino, piperidinyl, pyridinyl, pyrrolidinyl, quinolyl, tetrazolyl, and thiomorpholino. As a corollary, the term "alkylheterocyclic", or "alkylheterocycle", is understood to mean that the alkyl group is attached to the heterocycle and the point of attachment to the remainder of the referenced molecule or substructure is the alkyl group (or alkylene group). The term "haloalkyl" as used herein, refers to an alkyl group (as noted above), substituted with one or more halo atoms selected from F, Br, Cl and I. In selected forms of the present invention, difluoroalkyls are example, difluoromethyl groups, -CHF2, are preferred. The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with one or more hydroxyl groups wherein a carbon atom of the alkyl group is attached to the referenced molecule or portion thereof. The term "alkoxy" or "-OC-C6 alkyl" as used herein, refers to an alkyl group attached to the referenced molecule or portion thereof via an oxygen atom. The term "aryl" or "aryl optionally "substituted" refers to a cyclic aromatic moiety Illustrative aryl moieties include fused monocyclic or bicyclic rings, such as but not limited to: phenyl, naphthylene, phenanthrene, anthracene, and the like When substituted, the aryl moiety may be substituted with one or more substituents listed below The term "phenyl" or "optionally substituted phenyl" refers to an aromatic portion having 6 carbons in the ring with an appropriate number of hydrogen atoms.An optionally substituted phenyl portion may having one or more substituents as listed below, attached to the ring carbons The term "alkylaryl" refers to an alkyl portion substituted by an aryl group (as described above) For example, C1-C6 alkylaryl indicates that an aryl group is attached to a C1-C6 alkyl portion (or alkylene group) and that the resulting C1-C6 alkylaryl is attached to the rest of the molecule referenced via the alkyl (or alkylene group) moiety. Benzyl is a preferred alkylaryl moiety. The term "heteroaryl" or "heteroaromatic" refers to rings of 5 or 10 substituted or unsubstituted elements that is / are considered to exhibit aromatic character and have from 1 to 4 heteroatoms as ring elements. Heteroaryl rings or heteroaromatics as used here, include fused monocyclic or bicyclic rings. As used in the present invention, for fused bicyclic heteroaryl rings or heteroaromatics, both rings do not have to be aromatic. For example, benzofused bicyclic rings are included within the terms heteroaryl and heteroaromatic rings. Unless otherwise specified, the aromatic ring is directly linked to the indole compound or structure referred to. Examples of heteroatoms include: O, S and N. Illustrative examples of heteroaryls include but are not limited to: benzodioxolyl, benzimidazolyl, benzofuryl, benzothienyl, furyl, imidazolyl, imidazolidinon-yl, imidazolone-yl, imidazopyridinyl, indazolyl, indolyl, isothiazolyl, isobenzofuranyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, quinilo, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolyl, triazinyl, 1, 2, 3-tetrazolyl, 1, 2,4-triazolyl, triazolyl-yl, thienyl and isomers thereof. Unless otherwise specified, the heteroaryl or heteroaromatic portion, which includes the heteroatoms, may be substituted with one or more of the substituents listed below. Unless specifically indicated otherwise, the term "optionally substituted" or "substituted", when used with groups such as aryl, heteroaryl, cycloalkyl, and / or heterocyclyl, is proposed to refer to the groups if they are used individually or in conjunction with another group or portion and means that the group is substituted with one or more substituents listed herein-typically, but not exclusively, replacing one or more hydrogens. Substituents include: halo, -CN, -OH, oxo (= 0), C1-C3 alkyl, C1-C3 haloalkyl, Ci-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl N02 -0 C1-C3 alkyl ( or C1-C3 alkoxyalkyl), C1-C3 hydroxyalkyl, C0-C3 alkyl NR12R13, C0-C3 alkyl (0) R12, C0-C3 alkyl (0) 0R12, C (0) NR12R13, -C (S) NR12R13 , -CH2OR12, -SR12, -S (0) nR12, -S (0) nNR12R13, - (R9) C (0) R12R13, -N (R12) C (0) ORI3, -N (R12) S (0) nR13, -N (R12) S (0) nNR12R13, -C = N-0R12, -cyclo CN4RI2 (optionally substituted tetrazole), wherein n = 1 or 2 and wherein R12, and R13 are individually selected from: H, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkyl cycloalkyl; C1-C6 alkylaryl, C0-C6 alkylheteroaryl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, and C3-C8 cycloalkyl. Preferred substituents are selected from the group consisting of: F, Cl, -CN, -N02, CH3, Ci-C3 alkyl -CF3, -CHF2, -CH2CN, C2-C4 alkenyl, -C (0) R12, -C ( 0) 0R12, C (0) NR12R13, -C (0) H, -CH2OR12, -0R12, -SR12, -NR12R13, and -C = N-0R12. The term "prodrug" describes derivatives of the Compounds of the invention having chemically or metabolically unfoldable groups and becoming by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid-derived forms as the base, but the acid-derived form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives such as esters prepared by reaction of the parent acid compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic esters (for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl), or aromatic esters derived from pendant acid groups in the compounds of this invention, are preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy. In some cases, it is desirable to prepare prodrugs of the double ester type such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. As used herein, the term "protecting group" refers to a group used to mask the reactive sites in one molecule to improve the reactivity of another. group or allow the reaction at another desired site or sites after which the protective group can be removed. Protective groups are usually used to protect or mask groups that include but are not limited to -OH, -NH and -COOH. Suitable protecting groups are known from one of skill in the art and are described in, Organic Synthesis, 3rd edition, Greene, T. W .; Wuts, P.G.M. Eds. , John Wiley and Sons, New York, 1999. As used herein, the term "solvate" refers to a crystal (or crystals) of a compound of the invention, formed to include a stoichiometric or non-stoichiometric amount of the compound of Formula I and a solvent molecule. Typical solvating solvents include, for example, water, methanol, ether, ethanol, ethyl acetate, acetone, acetonitrile and dimethylformamide. When the solvent is water, the term "hydrate" for a stoichiometric or non-stoichiometric amount of the compound and water (or half-hydrate for half the stoichiometric amount of water) may optionally be used. In those cases where a compound of the invention possesses basic or acid functional groups, various salts can be formed, which are more water soluble and / or more physiologically suitable than the parent compound. The salts are conveniently prepared by methods known in the art for example, by treating a acidic compound with a base or by exposing the acid compound to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic organic and inorganic acid addition or base addition salts of compounds of the present invention (see for example, salts described in SM Berge, et al., "Pharmaceutical Salts, "J. Phar. Sci., 66: 1-19 (1977) and" A Handbook of Pharmaceutical Salts Properties, Selection, and Use ", Wermuth, CG and Stahl, PH (eds.) Verlag Helvtica Chimica Acta, 2002 , which are incorporated here). Common base addition salts include, for example, salts formed of: arginine, benetamine, benzathine, diethanolamine, diethylamine, ethylenediamine, meglumine, lysine, magnesium, piperazine, calcium, potassium, sodium, tromethamine and zinc, as well as salts of ammonium, quaternary ammonium and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of the invention. However, the basic groups of the compounds of the invention can be reacted with organic and inorganic acids to form salts. Common acid addition salts include, for example: acetate, adipate, benzenesulfonate, benzoate, citrate, ethanesulfonate, fumarate, D-gluconate, bromide, chloride, lactate, lactobionate, maleate, methanesulfonic acid, naphthalene-2-sulphonic, phosphoric , succinic, sulfuric, tartaric and p- toluenesulfonic. A compound as illustrated by Formula I can occur as any of its stereochemical isomers, positional isomers or regio-isomers, all of which are within the scope of the present invention of the invention. Certain compounds of the invention may possess one or more chiral centers, and thus, may exist in optically active forms. Additional asymmetric carbon atoms may be present in a substituent group such as an alkyl group. The R and S isomers and mixtures thereof, which include racemic mixtures, as well as mixtures of enantiomers or cis and trans isomers, are contemplated by this invention. In the same way, when the compounds contain an alkenyl, alkenylene, oximes and O-alkylated oxime group, there is a possibility of cis and trans isomeric forms of the compounds. All isomers, as well as mixtures thereof, are proposed to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art using stereo-specific reactions with starting materials that contain the asymmetric centers and are already resolved. Alternately desired stereoisomers can be prepared by methods that lead to mixtures of the stereoisomers and subsequent resolution by methods known. For example, a racemic mixture can be reacted with a single enantiomer of some other compound, i.e., a chiral resolving agent. Reference will now be made to preferred compounds of the invention, which are illustrated by Formula I wherein n is 1 or 2 and R1-R8 are as described herein, and pharmaceutically acceptable salts of Formula I. The compounds of the present invention that are specifically exemplified and / or described herein, are named and numbered using the " AUTONOM "for ISIS / Draw version 2.5 SP1 or CHEMDRAW ULTRA AUTONOM versions 7.0.1. Preferred compounds of the invention are listed in the following Tables included herein, and may also include pharmaceutically acceptable salts, solvates, enantiomers, racemates, diastereomers and mixtures of diastereomers thereof. The geometric isomers associated with the double bonds and the optical isomers associated with asymmetric carbon atoms of compounds of Formula I are also contemplated to be within the scope of the current invention as used for the treatment of diseases related to modulation of the PR receptor.

General Synthesis of Indole Intermediates for Use in the Present Invention The compounds of the present invention can be synthesized as exemplified in the following Reaction Schemes, Examples and General Procedures. However, the following discussion is not proposed to limit the scope of the present invention in any way, because one skilled in the art is able to extrapolate without undue experimentation, from the Reaction Schemes and examples here, to other specific compounds. within the field of the invention. Many of the starting materials and reagents can be easily obtained from commercial suppliers or are readily available by one of ordinary skill in the art. Other necessary reagents and starting materials can be made by methods which are selected from standard techniques of organic and heterocyclic chemistry, techniques which are analogous to the synthesis of known similar reagents or starting materials, and the methods described in the preparations and following examples, which include any of the new procedures. The designations R, Rl, R2, R3, R4, R5, R6, etc., used within the immediately preceding section, are for purposes of illustrating the various methods of synthesizing compounds of the invention and / or illustrating the variability of substituents in the pending position and are not necessarily synonymous in field or meaning with similar groups used in the generic structure for compounds of Formula I. However, groups in final compounds of the reaction schemes that occupy similar positions are co-extensive in the field and meaning compared with groups occupying similar positions, as defined for the generic structure of compounds of Formula I. Specific examples of each of the Methods listed in Reaction Schemes 1-5 are described. It will be understood that the conditions, i.e., specific temperature (ranges), solvents, reaction times and the like, can be modified by those skilled in the art to provide all specific compounds as described herein. Accordingly, the methods and examples provide general procedures that can be used to prepare compounds of the present invention. The following terms and abbreviations are used as defined herein. DAST diethylaminosulfur trifluoride DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DPDB (diphenylphosphino) -2 '- (N, -dimethylamino) biphenyl DFN, N-dimethylformamide DMSO dimethylsulfoxide DMAP N ', N' -dimethylaminopyridine Pd2 (dba) 3 Tris (dibenzylidene ketone) dipalladium PdCl2 (dppf) 2 palladium chloride bis (diphenylphosphino ferrocene) EtOAc ethyl acetate Et20 diethyl ether Resin FC-1032 polystyrene - (PPh2) Pd [P (t-Bu) 3] Cl2 anchored, a Pd catalyst from Johnson Mathey Catalysis and Chiral Technologies H NMR means that the observed H NMR is consistent with the illustrated structure HMDS hexamethyldisilazane KOAc potassium acetate EMBR low resolution mass spectrum LiHMDS lithium hexamethyldisilazide NaHMDS sodium hexamethyldisilazide NBS N- bromosuccinamide TA room temperature THF tetrahydrofuran TBAF tetrabutylammonium fluoride PCy3 tricyclohexyl phosphine tosylate (p-toluenesulfonyl) TsCl p-toluenesulfonyl chloride X as used herein, refers to halides, i.e.

I, Br, Cl, or F. Reaction Scheme I below illustrates general synthetic strategies for preparing certain indole intermediates, which can be used for the synthesis of sulfonamide compounds according to the present invention. Examples of preparations of specific compounds are given below, both in the written examples and in the Tables. The "Methods" listed in bold text used (in addition to the reagents) in the Reaction Schemes, are described in more detail in the written examples. The procedures described for these "Methods"; they can be used as general procedures for preparing the compounds exemplified herein.

Reaction Scheme I X = CI, Bro I 3-bromo-6-nitro-lH-indole (2) N-bromosuccinamide (NBS) was added to 6-nitroindole 1 (22.72 g, 140.12 mmol) dissolved in tetrahydrofuran (600 mL) and the resulting mixture was allowed to stir by 18 hours. The reaction mixture was quenched with saturated aqueous sodium thiosulfate solution (600 mL), diluted with ethyl acetate (EtOAc) (600 mL), and the layers were separated. Sequentially, the organic layer was washed with saturated aqueous sodium bisulfate (100 mL), saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The resulting organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to give a yellow solid. The solid was recrystallized from dichloromethane and hexane to give 29.21 g of the title compound (86%). LRMS (API ES +) = 263.0 (+ Na). 3-bromo-l-methyl-6-nitro-lH-indole (3, Rl = Me) Method A. Add 1M lithium hexamethyldisilazide in tetrahydrofuran (31.2 mL, 31.17 mmol) and methyl iodide (2.6 mL, 41.56 mmol) ) to a solution of 3-bromo-6-nitro-ltf-indole 2 (5.01 g, 20.78 mmol) in N, N-dimethylformamide (100 mL) at 0 ° C. The reaction mixture was warmed to room temperature and allowed to stir for 5 hr. Quench with saturated aqueous ammonium chloride (100mL), dilute with ethyl acetate (200mL), and separate the layers. Sequentially, The organic layer was washed with 10% aqueous lithium chloride (75 [mu] L), saturated aqueous sodium bicarbonate (75 mL), water (75 mL x2), and brine (75 mL). The resulting organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to provide a residue. The residue was adsorbed with the crude product on silica gel. The residue was chromatographed on a column of silica gel by levigating with dichloromethane in hexane (5-50 v / v%) to give 4.13 g of the title compound (78%). LRMS (API ES +) = 255.0 (M + H). 3-bromo-l-isopropyl-6-nitro-lH-indole (3 ', Rl = i- Pr) The above procedure was followed (Method A), for 3-bromo-l-methyl-6-nitro-lf- indole, 3, with the following modifications: Isopropyl iodide was used in place of methyl iodide and the reaction mixture was allowed to stir at room temperature for 18 hours. Subsequently, 1M lithium hexamethyldisilazide in tetrahydrofuran (15.5 mL, 15.5 mmol) and isopropyl iodide (2.1 mL, 20.74 mmol) was added. The resulting mixture was heated to 40 ° C and allowed to stir for 6 hours. The mixture was cooled to room temperature and the product was purified as above to give 4.37 g of the title compound (74%). LRMS (API ES +) = 285.0 (M + H). 3-bromo-l-isobutyl-6-nitro-lff-indole (3", Rl = i-Bu) Method B. NaH (1.2 eq) was added to a solution of 3-bromo-6-nitroindole 2 (15 g , 62 mmol) in 250 mL D F. The reaction mixture was allowed to stir for 1 hr and then isobutyl iodide (17.2 mL, 149 mmol, 2.4 eq) was added.This solution was allowed to stir at room temperature. the red color associated with the anion changed to brown, more NaH and isobutyl iodide were added until most of the starting material was consumed, 600 mL of 5 M NaOH was added and 2x200 mL of ether (Et20) was extracted. provides a three-layer solution with the product in the Et20 layer and the starting material in the DMF / aqueous layer, half. The Et20 extracts were combined and washed with 5 M NaOH, water (2x) and brine. The organic layers were dried over Na2SO4 filtered, and concentrated. It was recrystallized from CH2Cl2 / hexanes to give 15.73 g, 52.9 mmol, 85% of the title compound. XH NMR (CDC13) d 8.28 (d, 1H, J = 2.2 Hz), 8.04 (dd, 1H, J = 1.8, 8.8 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.35 (s, 1H) , 3.96 (d, 2 H, J = 8.8 Hz), 2.18 (m, 1H), 0.93 (d, 6H, J = 6.6 Hz).

Alternatively, the Rl substituent may be attached to the indole Ni position using Method L described below for 4- [1- (3-Methyl-butyl) -6-nitro-ltf-indol-3-yl] -benzonitrile (11). , Rl = i-Pr).

The following two methods still illustrate alternative synthetic procedures to provide the indole intermediate 3. 3-Bromo-l- [(S) -sec-butyl] -6-nitro-lH-indole (3"', Rl = (S) -sec-Bu) BB method. Triphenylphosphine (19.04 g, 72.60 mmol) and (R) -2-butanol (6.14 mL, 66.38 mmol) were added to a solution of dichloromethane (400 mL) containing 3-bromo-6-nitro-lH-indole (10.00 g. , 41.49 mmoles). This mixture was cooled to 0 ° C, and while stirring, diisopropyl azodicarboxylate (13.98 mL, 70.53 mmol) was added as a solution in dichloromethane (50 mL) over a period of 45 min. After the addition is complete, the ice bath is removed and the reaction is allowed to stir for 3.5-4 hr at room temperature. The crude reaction mixture is concentrated in vacuo and the resulting oil is purified via flash chromatography (silica gel, charge 30% CH2Cl2 / Hexane, run 15% -35% CH2C12 gradient in hexane). To obtain 8.83 g (72%) of product as a yellow crystalline solid. XH NMR (CDC13) d 8.34 (d, 1H, J = 2.0 Hz), 8.04 (dd, 1H, J = 8.8, 2.0 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.45 (s, 1H), 4.47 (sextet, 1H, J = 6.9 Hz), 1.89 ( quit, 2H, J = 6.9 Hz), 1.53 (d, 3H, J = 6.9 Hz), 0.84 (t, 3H, J = 7.5 Hz); MS (ES + API) m / e 297 (M + 1, 9Br), 299 (M + 1, 81 Br). 3-Bromo-l - [(R) -sec-butyl] -6-nitro-lH-indole (3iv, Rl = (R) -sec-Bu); BB method. Triphenylphosphine (20.64 g, 78.69 mmol and (S) -2-butanol (6.11 mL, 66.52 mmol) was added to a dichloromethane solution (400 mL) containing 3-Bromo-6-nitro-lH-indole (10.02 g, 41.57 mmoles) This mixture was cooled to 0 ° C, and while stirring, diisopropyl azodicarboxylate (10.71 mL, 54.02 mmol) was added as a solution in dichloromethane (20 mL) over a period of 15 min. The ice bath is removed and the reaction is allowed to stir for 3.5-4 hr at room temperature The crude reaction mixture is concentrated in vacuo and then the resulting oil is purified via flash chromatography (silica gel, 30% loading H2Cl2 / Hexane, run 15% -35% CH2C12 gradient in hexane) to obtain 8.46 g (68%) of product as a yellow crystalline solid. 1 H NMR (CDC13) d 8.34 (d, 1H, J = 2.0 Hz), 8.04 (dd, 1H, J = 8.8, 2.0 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.45 (s, 1H) , 4.47 (sextet, 1H, J = 6.9 Hz), 1.89 (quint, 2H, J = 6.9 Hz), 1.53 (d, 3H, J = 6.9 Hz), 0.84 (t, 3H, J = 7.5 Hz); E (API ES +) m / e 297 (M + 1, 79 Br), 299 (M + 1, 81 Br). l-Isopropyl-6-nitro-3- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -lH-indole (4, Rl = i Pr) Method DD. A 500 mL flask was charged with vacuum-dried potassium acetate (37.50 g, 382.00 mmol), 3-bromo-l-isopropyl-6-nitro-lH-indole, 3 '(32.40 g, 114.50 mmol), bis ( pinacolato) diboro (40.71 g, 160.00 mmol), PdCl2 (dppf) 2"CH2C12 (12.75g, 15.64 mmol), and anhydrous dimethylsulfoxide (430 mL) This mixture was heated with an oil bath at 85 ° C and the mixture was allowed to stir overnight. dark colored reaction mixture at room temperature, quenched with sufficient water and extracted the resulting aqueous mixture with dichloromethane.The combined extracts were washed with water and e.The resulting organic layer was dried over sodium sulfate, filtered and filtered The resulting impure oil was purified by flash chromatography (silica gel, loading CH 2 Cl 2 / Hexane, run 2.5% to 20% ethyl acetate gradient in hexanes) The material of this column it can be purified again by flash chromatography (silica gel, 30% -60% CH2C12 gradient in hexane) to give the product (22.7 g, 60%) as a yellow crystalline solid. XH NMR (CDC13) d 8.32 (app.s, 1H), 8.03-8.04 (m, 2H), 7.90 (s, 1H), 4.69-4.79 (m, 1H), 1.56 (d, 6H, J = 6.7 Hz ), 1.35 (br s, 12H); MS (API ES +) m / e 331 (M + 1). - (l-isopropyl-6-nitro-lH-indol-3-yl) -pyridine-2-carbonitrile (5, Rl = i-Pr, R3 = 2-cyanopyridine) This compound was prepared from 1-isopropyl -6-nitro-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indole (4, Rl = i-Pr) and 5-bromo-2 -cyanopyridine using Method D described below. E BR (API ES +) = 307.0 (+ H). Alternatively, the nitro group can be converted to the sulfonamide in the indole core to provide intermediates having the structures as compound 100 in Reaction Scheme 1 above, using either Method H and Method I for 6-amino-1 -isopropyl-3- (3,, 5-trifluoro-phenyl) -ltf-indole and N- [l-Isopropyl-3- (3,4,5-trifluoro-phenyl) -lH-indol-6-yl] - methanesulfonamide (6, R1 = i-Pr, R3 = 3,4,5-trifluoro-phenyl, R6 = Me), respectively, described below. 4- (l-isopropyl-6-nitro-lff-indol-3-yl) -benzonitrile (5, R1 = i-Pr, R3 = 4-benzonitrile) Method C. 3-bromo-l-isopropyl-6-nitro-lff-indole, 3 ', (350 mg, 1.24 mmol), tris- ( dibenzylidene ketone) di-palladium (0) (110 mg, 0.12 mmol), tri-t-butyl phosphonium tetrafluoroborate (70 mg, 0.24), 4-cyanophenylboronic acid (364 mg, 2.48 mmol), potassium fluoride (216 mg, 3.72 mmol) and tetrahydrofuran (6 mL) under a nitrogen atmosphere in a 50 mL flask. The reaction mixture was heated at 40 ° C for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The celite pad was washed with ethyl acetate (200 mL). Then the filtrates were collected and concentrated. It was purified by precipitation or crystallization from ethyl acetate to give 260.2 mg of the title compound (69%). LRMS (API ES +) = 306.0 (M + H).

Method R. Pd (PPh3) 4 (58 mg, 0.05 mmol) was added to a suspension of S-bromo-l-isopropyl-S-nitro-lii-indole (3 ', Rl = i-Pr) (194.5 mg, 0.5 mmol), arylboronic acid (0.75 mmol) and KF-2H20 (141 mg, 1.5 mmol) in 5 mL of [1,4] dioxane under N2. The reaction mixture was heated to 80 ° C and stirred at such a temperature overnight. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (10 mL), then it was washed with water (5 mL). Concentration of the organic layer and purification using column chromatography gave the desired compounds (50-80%). 2-Fluoro-4- (6-nitro-lH-indol-3-yl) -benzonitrile (9F) A. 2-Fluoro-4-bromobenzonitrile (200 g, 990 mmol, 1.00 eq.) And triisopropyl borate were dissolved. (228 g, 1188 mmol, 1.2 eq.) In 700 mL of THF and 1400 mL of toluene. The mixture was cooled with an acetone / dry ice bath to an internal temperature of -75 ° C. N-BuLi (396 mL of a 2.5 M solution in hexanes) was slowly added over a period of 2 hours. After the addition is complete, a thin, slightly red suspension occurs. The solution was allowed to stir at -74 ° C for 15 minutes, the solution was allowed to warm to -20 ° C and then quenched with 1500 mL of 2.5 M HC1. The solution was allowed to warm to RT. The layers were separated, the aqueous layer was extracted with EtOAc, the combined organic phases were dried with Na 2 SO 4, filtered and concentrated in vacuo to give a light brown solid. The solid was triturated with hexane and transferred to a sintered glass funnel. Rinse with hexane once again to obtain a pale yellow filtrate. The light brown solid was stirred with cold CH2Cl2 and filtered. Rinse with a volume small amount of CH2Cl2 to provide a whitish solid and brown filtrate. The solid was dried in a vacuum oven at 40 ° C and dried to provide 112g (679 mmol, 69%) of 3-fluoro-4-cyanophenylboronic acid as an off-white solid.

B. 4- (l-Benzylsulfonyl-6-nitro-lH-indol-3-yl) -2-fluoro-benzonitrile of 1-benzenesulfonyl-3-bromo-6-nitro-lino-indole, 7, and 3-acid fluoro-4-cyanophenylboronic using Method AA: Pd2 (dba) 3, [(t-Bu3) PH] BF4, K2C03, THF, H20. It was purified by precipitation from EtOAc / hexanes. The benzenesulfonyl protecting group was removed using TBAF and THF as described for 4- (6-nitro-ltf-indol-3-yl) -benzonitrile (9) below. LRMS (API ES-) = 280.0 (M-l). l-Isopropyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -lH-indol-6-ylamine Method P. A solution of l-isopropyl- 6-Nitro-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indole, (4, Rl = i-Pr) (14.48 g, 43.88 mmol ) in ethanol to a suspension of 5% palladium on carbon (1.44 g) and ethanol in a Parr reaction bottle. The contents of the reaction bottle were placed under a hydrogen atmosphere (60 psi) and shaken in a Parr shaker at room temperature for 18 hr. After 18 hr, the contents of the reaction vessel through a pad of Celite, and the resulting filtrate was concentrated in vacuo. The crystalline material, slightly pink, crude, resulting (11.84 g, 90%) can be used without further purification. 1ti NMR (DSMO-d6) d 7.39 (s, 1H), 7.39 (d, 1H, J = 8.3 Hz), 6.54 (d, 1H, J = 1.8 Hz), 6.41 (dd, 1H, J = 8.3 Hz, 1.8 Hz), 4.73 (br s, 2H), 4.37 (septete, 1H, J = 6.8 Hz), 1.37 (br, 12H), 1.37 (d, 6H, J = 6.8 Hz); MS (API ES +) m / e 301 (M + 1).

N- [l-Isopropyl-3- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -lH-indol-6-yl] -methanesulfonamide (4-A, Rl = i Pr, R6 = Me).; Method I. A round-bottomed flask is charged with l-isopropyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -lH-indol-6-ylamine ( 11.83 g, 39.43 mmol), dichloromethane (400 mL) and pyridine (6.40 mL, 78.87 mmol). The resulting solution was cooled to 0 ° C; While stirring slowly, methanesulfonyl chloride (12.20 mL, 157.73 mmol) is added. The reaction was allowed to stir overnight and reach room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate. The resulting aqueous layer was extracted with dichloromethane. The combined extracts were combined and the combined extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated in vacuo. HE purify the resulting solid by flash chromatography (silica gel: 65% -100% gradient dichloromethane in hexane then gradient to 2.5% ethyl acetate in dichloromethane) to provide 12.0 g (80%) of the product as a light pink solid foam. 1 H NMR (CDCl 3) d 7.96 (d, 1 H, J = 8.4 Hz), 7.69 (s, 1 H), 7.39 (d, 1 H, J = 1.9 Hz), 6.88 (dd, 1 H, J = 8.4 Hz, 1.9 Hz ), 6.38 (br s, 1H), 4.56 (septete, 1H, J = 6.8 Hz), 2.91 (s, 3H), 1.49 (d, 6H, J = 6.8 Hz), 1.34 (s, 12H); MS (IS-) m / e 377 (M-1). l-isopropyl-6-nitro-3- (3,4,5-trifluoro-phenyl) -1H-indole (5, Rl = i-Pr, R 3 = 3,4,5-trifluoro-phenyl) Method D. combined l-isopropyl-6-nitro-3- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -lff-indole (4, Rl = i-Pr) (328 mg, 0.98 mmol), lithium chloride (125 mg, 2.94 mmol), 3,4-trifluorobromobenzene (240 μ ??, 1.96 mmol), toluene (4 mL), ethanol (4 mL) and 2M sodium carbonate. aqueous (1.7 mL, 3.43 mmol) in a 50 mL flask fitted with a reflux condenser. The flask was placed under a nitrogen atmosphere and tetrakis (triphenylphosphine) palladium (O) (58 mg, 0.05 mmol) was added. The reaction mixture was heated at reflux for 4 hours, then cooled to room temperature. The solution was filtered through a pad of celite and the pad was washed with ethyl acetate (50 mL). The combined filtrates were washed with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), brine (20 mL). The resulting organic solution was dried over Na2SO and filtered. The filtrate was concentrated, and the resulting residue was adsorbed on silica gel. The residue was chromatographed on a column of silica gel by levigating with dichloromethane in hexane (2-50 v / v%) to give 140.7 mg of the title compound (43%). LRMS (API ES +) = 335.0 (M + H). 4- (l-isopropyl-6-nitro-lH-indol-3-yl) -f-alonitrile (5, Rl = i-Pr, R3 = talonitrile) Method O. L-isopropyl-6-nitro-3- (4,, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-il was placed. ) -ltf-indole 4 (107 mg, 0.324 mmol), 4-iodophthalonitrile (246 mg, 0.968 mmol), Pd (OAc) 2 (11 mg, 0.049 mmol) and tricyclohexylphosphine (22 mg, 0.078 mmol) at 50 mL under a nitrogen atmosphere. Acetonitrile (4 mL) was added and nitrogen was bubbled through the solution for 15 min. Cesium fluoride (446 mg, 2936 mmol) was added, the reaction vessel was placed in an oil bath which is pre-heated to 90 ° C and stirred for 30 min. The reaction was cooled to room temperature and poured into water (15 mL) and the aqueous extracted with CH2C12 (2 x 15 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was triturated with CH2C12 and hexanes to provide 102 mg of the title compound (95%) as a yellow solid. H NMR (DMSO-de) d 8.705 (s, 1H), 8.640 (d, 1H, J = 2.1 Hz), 8.506 (d, 1H, J = 1.8 Hz), 8.280 (dd, 1H, J = 1.8, 8.5 Hz), 8,191 (d, 1H, J = 9.1 Hz), 8,137 (d, 1H, J = 8.5 Hz), 8.015 (dd, 1H, J = 2.1, 9.1 Hz), 5.072 (quin., 1H, J = 6.7 Hz), 1.511 (d, 6H, J = 6.7 Hz). 4- (l-isopropyl-6-nitro-lff-indol-3-yl) -3-methyl-5-carbonitrile-thiophen-2-yl (5, Rl = i-Pr, R3 = 3-methyl-5- carbonitrile-thiophen-2-yl) Method AA. L-isopropyl-6-nitro-3- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -líí-indole (4, Rl = i-Pr) ( 1.1 g, 1.00 equiv, 3.5 mmol), 5-bromo-4-methyl-2-thiophene carbonitrile (0.7 g, 1.00 equiv, 3.5 mmol), and potassium carbonate (1.0 g, 2.2 equiv, 7.6 mmol) in THF ( 10 mL) and water (5 mL). The mixture was spread with N2 for 20 minutes with a constant sub-surface current of N2. Then tris (dibenzylidenacetone) dipalladium (0) (158 mg, 0.05 equiv; 170 μg) was added and tri-t-butyl phosphonium tetrafluoroborate (101 mg, 0.1 equiv, 350 mol) and the mixture was heated to a 40 ° C sealed under N2 The reaction was monitored using CCD (30% EtOAc / hex); when starting material does not remain, the mixture is cooled to room temperature and 10 mL ethyl acetate is added. The mixture was washed with water, then brine and dried over MgSO4. The MgSO4 was removed by filtration, and the filtrate was concentrated in vacuo to provide a solid. The solid was recrystallized from dichloromethane / hexanes. Providing 0.789 g (70%). E BR (API ES +) = 326.0 (M + H). l-Isopropyl-3- [5- (l-methyl-lH-tetrazol-5-yl) -thiophen-2-yl] -6-nitro-lH-indole Method CC. In a 50 mL flask fitted with a reflux condenser, l-isopropyl-6-nitro-3- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) was combined. ltf-indole (4, Rl-i-Pr) (700 mg, 2.1 mmol), 5- (5-Bromo-thiophen-2-yl) -1-methyl-β-tetrazole (466 mg, 1.9 mmol), tris- (dibenzylideneacetone) di-palladium (0) (17 mg, 0.019 mmol), and tricyclohexylphosphine (13 mg, 0.0047 mmol) in dioxane (5.5 mL). it was degassed under nitrogen atmosphere three times; then 1.3M aqueous potassium phosphate (2.5 mL, 3.2 mmol) was added in a 50 mL flask fitted with a reflux condenser. The reaction mixture was heated at 100 ° C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL); then the layers separated. The aqueous layer was extracted three times with ethyl acetate (10 mL). The organics were combined; dried over MgSO4; the solids were removed by filtration; and the filtrate was concentrated in vacuo. It was purified by silica gel column chromatography by levigating with ethyl acetate in hexanes to provide 0.3 g (39%) of the title material. XH NMR (CDC13) d 8.39 (s, 1H), 8.09 (d, 1H, J = 9.1 Hz), 8.02 (d, 1H, J = 9.1 Hz), 7.78 (d, 1H, J = 3.9 Hz), 7.75 (s, 1H), 7.28 (d, 1H, J = 3.9 Hz), 4.79 (quin., 1H, J = 6.5 Hz), 4.37 (s, 3H), 1.62 (d, 6H, J = 6.5 Hz).

General Synthesis of Intents for Use in the Present Invention Reaction Scheme 2 below illustrates additional synthetic strategies for preparing indoles 6 of the indole intermediates prepared above. Some of the methods listed in bold in the Reaction Scheme are described above; other methods are described below after the Reaction Scheme.

Reaction Scheme 2 1 . H2l Pt02, THF (Method E, or 1. H1, 10% Pd / C, THF (Method F), or 1. SnCl, -2H, 0, DF, 60 ° C (Method G), or 1. NaBH "NÍ (OAc) ,, MeOH, THF (Method H) 0; / M 2. R6-S02CI, pyridine, CH -CI2l (Method I) 4- (6-amino-l-isopropyl-lH-indol-3-yl) -benzonitrile Method E. 4- (l-isopropyl-6-nitro-lyl-indol-3-yl) -benzonitrile (4 , R1 = i-Pr, R3 = 4-benzonitrile) 250 mg, 0.82 mmol) in a 50 mL flask and added to a suspension of platinum (II) oxide (16 mg) in tetrahydrofuran (9 mL). The reaction was placed under 1 atmosphere of hydrogen and stirred until the starting material was consumed. It was filtered through a pad of celite and the pad washed with ethyl acetate (50 mL).

The combined filtrates were concentrated to give 225.0 mg of the title compound (99%). LRMS (API ES +) = 276.0 (M + H). - (6-Amino-l-isopropyl-lff-indol-3-yl) -pyridine-2-carbonitrile Method F. This compound can be prepared from 5- (l-isopropyl-6-nitro-l / - indole-3-yl) -pyridine-2-carbonitrile (4, R1 = i-Pr, R3 = 5- (2-cyanopyridine)) in a manner substantially similar to that described immediately above for 4- (6-amino-1) -isopropyl-lly-indol-3-yl) -benzonitrile except that palladium was used in 10% activated carbon W / NE Degussa type E101 instead of platinum (II) oxide in Method E. EMBR (API ES +) = 277.0 (M + H). - (6-amino-l-isopropyl-lH-indol-3-yl) -thiophen-2-carbonitrile Method 6. N, N-dimethylformamide (2 mL) and tin dichloride (II) dihydrate (992 mg) were added. , 4.40 mmol) was added to a 50 mL flask loaded with 5- (l-isopropyl-6-nitro-lH-indol-3-yl) -thiophen-2-carbonitrile (4, RI = i-Pr, R3 = 2- cyano thiophene), (136.3 mg, 0.44 mmol) under a nitrogen atmosphere. It was heated to 60 ° C and stirred for 45 minutes. It was cooled to room temperature and quenched with baking soda. saturated aqueous sodium (15 mL). It was filtered through a pad of celite and the pad was washed with ethyl acetate (100 mL). The combined filtrates were washed with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated to give 107.9 mg of the title compound (87%). LRMS (API ES +) = 282.0 (M + H). 6-amino-l-isopropyl-3- (3,4,5-trifluoro-phenyl) -1H-indole Method H. l-isopropyl-6-nitro-3- (3,4,5-trifluoro-phenyl) was combined ) -lH-indole (4, Rl = i-Pr, R3 = 3,4,5-trifluoro-benzene) (136.1 mg, 0.41 mmol), tetrahydrate nickel acetate (II) (204 mg, 0.82 mmol), tetrahydrofuran (2.5 mL) and methanol (2.5 mL) in a 50 mL flask. Sodium borohydride (62 mg, 1.64 mmol) was added in small portions. Once the gas evolution was complete, the reaction was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ethyl acetate (10 mL), and the layers separated. The organic layer was washed with saturated aqueous sodium bicarbonate (5 mL), water (5 mL), brine (5 mL), dried (a2SO4), filtered and concentrated. This material can be used without further purification in the following preparation.

N- [1-Isopropyl-3- (3,4,5-trifluoro-phenyl) -lff-indol-6-yl] -methanesulfonamide (6, R 1 = i-Pr, R 3 = 3, 4, 5-trifluoro- phenyl, R6 = Me) Method I. 6-Amino-l-isopropyl-3- (3,4,5-trifluoro-phenyl) -lt-indole (116.6 mg, 0.38 mmol) was prepared, prepared as described immediately above , dichloromethane (3.0 mL) and pyridine (62 L, 0.76 mmol) under a nitrogen atmosphere in a 25 mL flask. The reaction was cooled to 0 ° C and methan sulfonyl chloride (33 μm, 0.42 mmol) was added. The reaction was allowed to warm to RT while stirring for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (5 mL), diluted with ethyl acetate (10 mL) and the layers separated. The organic layer was washed with water (5 mL), brine (5 mL), dried (Na2SO4) and filtered. The filtrate was concentrated and the crude product was adsorbed on silica gel. Purified by silica gel chromatography by levigating with ethyl acetate in dichloromethane (0-5 v / v%) to give 95.1 mg of the title compound (61%). E BR (API ES +) = 383.0 (M + H).

N- [3- (5-Chloro-thiophen-2-yl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide (6, RI = i-Pr, R3 = 5-chloro-thiophene-2- il, and R6 = methyl) Method J. N- [1-isopropyl-3- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -lH-indole- 6-il] - methanesulfonamide (266 mg, 0.70 mmol), potassium carbonate (242 mg, 1.75 mmol), 2-bromo-5-chloro-thiophene (207 mg, 1.05 mmol), dioxane (6 mL) and water (1 mL), followed by addition of tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.018 mmol) in a sealed tube under nitrogen. The reaction mixture was heated at 100 ° C overnight, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate, and sequentially the resulting mixture was washed with water and brine. The organic layer was dried over MgSO4. The crude residue was chromatographed on a column of silica gel by levigating with hexane and ethyl acetate (gradient) to give 89 mg (34%) of the title compound. 1 H NMR (CDC13) d 7.79 (d, 1 H, J = 8.8 Hz), 7.42 (d, 1 H, J = 1.8 Hz), 7.35 (s, 1 H), 6.97 (dd, 1 H, J = 2.0, 8.6 Hz ), 6.93 (d, 1H, J = 4.0 Hz), 6.88 (d, 1H, J = 4.0 Hz), 4.50-4.67 (m, 1H), 2.97 (s, 3H), 1.52 (d, 6H, J = 6.6 Hz). Alternatively, the substituent R3 can be attached to the indole of position 3 using Method Q described below for N- [3- (2-Cyano-phenyl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide (6, R1 = i Pr, R3 = 2-cyano-phenyl, R6 = Me).

N- [3- (2-Cyano-phenyl) -l-isopropyl-lH-indol-6-yl] methanesulfonamide (6, R1 = i Pr, R3 = 2-cyano-phenyl, Me) Method Q. N- [l-isopropyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -lH-indol-6-yl] -methanesulfonamide ( 50.0 mg, 0.132 mraoles), 4-bromo-3-methyl-benzonitrile (51.8 mg, 0.264 mmol), Pd (OAc) 2 (4.25 mg, 0.018 mmol, 4.25 mg), 2- (diphenylphosphino) -2 '- ( N, -dimethylamino) biphenyl (11.5 mg, 0.030 mmol), potassium phosphate (84.2 mg, 0.396 mmol), and 1,4-dioxane (1.00 mL) in a 10 mL microwave vessel, equipped with a stir bar. The reaction mixture was purged with nitrogen, and then the container was sealed with a lid. The vessel was placed in a microwave reactor at 150 ° C for 15 minutes at 250 W of heating. The reaction was monitored using LC / MS. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was extracted into ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride, water and brine. The resulting solution was dried over sodium sulfate (granular) and concentrated in vacuo. The resulting solid was dissolved in dichloromethane and purified on a chromatotron (1MM plate of silica gel) 0-2% gradient of ethyl acetate in dichloromethane. A second purification may be necessary. This time the material was purified with 30-40% gradient of ethyl acetate in hexane to provide N- [3- (4-Cyano-2-methyl-phenyl) -1-isopropyl-1H-indol-6-yl] -metanesulfonamide, 35 mg (75%) as a whitish solid. 1 H NMR (CDC13) d 7.58 (s, 1 H), 7.45-7.52 (m, 3 H), 7.41 (d, 1 H, J = 8.4 Hz), 7.25 (s, 1 H), 6.9 (dd, 1 H, J = 8.4 , 1.7Hz), 6.52 (s, 1H), 4.65 (septete, 1H, J = 6.7Hz), 2.98 (s, 3H), 2.34 (s, 3H), 1.55 (d, 6H, J = 6.7Hz); MS (IS-) m / e 377 (M-1).

N- [3- (2-thioamide-phenyl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide (6, R1 = i Pr, R3 = 2-thioamide, R6 = Me) The cyano substituent (or nitrile) of N- [3- (2-cyano-phenyl) -l-isopropyl-1H-indol-6-yl] -methanesulfonamide, can be derivatized to a thioamide group using the Lawesson reagent in accordance with a modified procedure described in : Thomsen et al. Org. Synth 1984, 62, 158; K. Ciasen et al. J. Chem. Soc. Perkin Trans. I, 1984, 785; and Shabana, R.; Meyer, H.J .; and Lawesson, R.-O. Phosphorus and Sulfur, 1985, 25, 297.

Example 178 N- [3- (6-Cyano-5-fluoro-pyridin-3-yl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide Method X. N2 was bubbled through a mixture of N - [l-isopropyl-3- (4,4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -lH-indo-6-yl] -methanesulfonamide (0.186g, 0.493 mmol) , 5-bromo-2-cyano-3-fluoropyridine (0.090 g, 0.448 mmol), K3P04 (1.3 M) (0.60 ml), and dioxane (1.2 ml) for 5 minutes. Tricyclohexylphosphine (3.0 mg, 0.011 mmol) and Pd2 (dba) 3 were added (4.1 mg, 0.0045 mmol). The tube was sealed and stirred at 100 ° C for 18 h. After cooling to room temperature, it was extracted with EtOAc and washed with NaHCO3. The organic phase was dried with MgSO4. The crude residue was purified using silica gel chromatography to give 0.112g (67% yield) of the title compound, MS: 373.0 (M + H) N- [3- (3, 5-Difluoro-4-hydroxymethyl-phenyl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide Method S. N- (3-Bromo-l-isopropyl-ltf was weighed -indol-6-yl) -metanesulfonamide (100 mg, 0.302 mmol) and 2-fluoropyridin-4-boronic acid (42.5 mg, 0.302 mmol) in a 10 ml microwave vial. Ethanol (4 mL) and 1 N potassium carbonate solution (847.4 mg, 0.362 mL, 0.362 mmol) were added. FC-1032 resin (19.3 mg, 9.1 μ? T ??, 0.47 mmol / g) was added and the vial was capped. It was microwaved at 110 ° C for 15 minutes. The reaction was filtered, and concentrated in vacuo. It was purified by Isco on silica (0-50% EtOAc / hexanes). Concentrate to provide the title compound (127 mg, 55%). 1 H-NMR (DMSO) is consistent with the product. The synthesis of various substituents which can be attached to the 3-indole position or to the N-1 position, is described below.

Amide of 3-Amino-5-bromo-pyridin-2-acid carboxylic: NaBH4 (0.663g, 17.5 nunol) was added in small portions to a methanol solution (50 mL) of 5-bromo-2-cyano-3-nitropyridine (2.00g, 8.77 mmol) and nickel acetate tetrahydrate (II ) (4.37 g, 17.5 mmol) at 0 ° C. After stirring at room temperature for 20 min, water and EtOAc were added. The mixture was passed through a pad of celite. It was extracted with EtOAc. The combined extracts of EtOAc were dried over gS04. The crude product was purified using silica gel chromatography to give 0.75 g (40% yield) of 3-amino-5-bromo-pyridine-2-carboxylic acid amide. E 216.0 / 218.0 (M + H) -Bromo-3-fluoro-pyridine-2-carboxylic acid amide: A solution of 3-Amino-5-bromo-pyridine-2-carboxylic acid amide (0.75 g, 3.47 mmol) and nitrosonium tetrafluoroborate (0.487) was stirred. g, 4.16 mmol) in dichloromethane (50 ml) at 23 ° C for 18 hours. The solvent was evaporated. The residue was azeotroped with toluene. The residue was suspended in toluene (20 ml) and refluxed for 2 hours. The mixture was concentrated and the crude product was purified by chromatography on silica (10-100% EtOAc / Hexane) to give 5-bromo-3-fluoro-pyridine-2-carboxylic acid amide (0.378 g, 50%). MS: M + H = 221.0.

-Bromo-2-cyano-3-fluoro-pyridine: One was stirred mixture of 5-bromo-3-fluoro-pyridine-2-carboxylic acid amide (0.375 mg, 1.71 mmol) and NaCl (0.120 g, 2.05 mmol) in CH2Cl2 (20 mL). After 15 minutes, POCI3 (0.795 mL, 8.55 mmol) was added and the mixture was refluxed overnight. The mixture was cooled to room temperature, and diluted with CH2Cl2; it was washed with saturated NaHCO 3 solution, dried over (MgSO). The crude product was purified using silica chromatography (0-50% EtOAc / Hexane) to yield 0.25 g (73% yield) of 5-bromo-2-cyano-3-fluoro-pyridine.

-Bromo-2-cyano-3-methoxy-pyridine: Sodium methoxide (141 mg, 2.61 mmol) and 5-bromo-2-cyano-3-fluoro-pyridine (105 mg, 0.52 mmol) were mixed in THF ( 5 mL) and refluxed for 18 h. Phosphate buffer was added at pH 7 and extracted with EtOAc. The EtOAc extracts were dried over gS04. The drying agent was removed and the filtrate was evaporated. The crude product was purified using chromatography on silica gel and levigated with EtOAc / hexane (0 to 30%) to give 77 mg (69% yield) of 5-bromo-2-cyano-3-methoxy-pyridine.

-Bromo-2-cyano-3-chloro-pyridine: NaNC > 2 (83.0 mg, 1.20 mmol) to a suspension of 3-amino-5-bromo-2-cyanopyridine (198 mg, 1.00 mmol) in 37% HC1 (2.00 ml) and H20 (0.5 ml) at 0 ° C and stirred for 1 hour. Copper powder (15 mg) was added and the mixture refluxed for 30 minutes. The mixture was cooled and, quenched with ice, basified with 5N NaOH. It was extracted with EtOAc and the organic extract was washed with brine, dried over MgSO4. The crude product was purified using silica gel chromatography and levigated with (0-30% EtOAc / Hex) to yield 110 mg (50% yield) of 5-bromo-2-cyano-3-chloro-pyridine. 4-Bromo-naphthalene-l-carbonitrile: A suspension of 4-bromo-naphthalene-1-ylamine (0.974 g, 4.386 mmol) in water (6 mL) and concentrated HC1 (2 mL) was sonicated for 10 minutes. The resulting suspension was cooled to 0 ° C. Sodium nitrite (0.336 g, 4.869 mmol) in water (2 mL) was slowly added at a rate to maintain the temperature below 5 ° C. The resulting mixture was stirred for 30 minutes, and then neutralized with solid sodium bicarbonate. The resulting solution was added in portions to a solution of potassium cyanide (0.717 g, 11,010 mmol) and copper cyanide (0.464 g, 5.181 mmol) in water (10 mL). A precipitate forms. The reaction mixture was heated at 70 ° C for 30 minutes, then the aqueous reaction mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and washed sequentially with water (30 mL), saturated ammonium chloride (30 mL), and sodium bicarbonate (30 mL). The organic layers resulting with (Na2SO4); the solids were removed by filtration; and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography with a gradient of hexanes to 20% ethyl acetate in hexanes to provide 0.864 g (85%) of 4-bromo-naphthalene-1-carbonitrile as a light brown solid. XH NMR (CDC13) d 8.314 (dd, 1H, J = 2.4, 7.0 Hz), 8.235 (dd, 1H, J = 2.4, 7.0 Hz), 7.836 (d, 1H, J = 7.6 Hz), 7.728 (m, 3H). 4-Bromo-2-fluoro-benzamide: A flask was charged with acid alumina (AI2O3) (3.03 g, 29.718 mmol) and methanesulfonic acid (10 mL). The resulting solution was heated to 120 ° C, and 4-bromo-2-fluorobenzonitrile (2.00 g, 9999 mmol) was added in one portion. The resulting mixture was stirred for 30 minutes, then the reaction was cooled to room temperature and poured into water (50 mL). The aqueous mixture was extracted with dichloromethane (3 x 30 mL). The organic extracts were combined; dried over (Na2SO4); the solids were removed by filtration; and the filtrate was concentrated in vacuo to give 2.14 g (98%) 4-bromo-2-fluoro-benzamide as a white solid. 1tt NMR (DMSO-d6) d 7.706 (d, 2H, J = 21.1 Hz), 7.598 (dd, 1H, J = 1.9, 10.1 Hz), 7.557 (dd, 1H, J = 8.0, 8.0 Hz), 7.446 ( ddd, 1H, J = 0.4, 1.9, 8.1 Hz). - (4-Bromo-2-flouro-phenyl) -lH-tetrazole: A flask was charged with 4-bromo-2-fluoro-benzonitrile (3.0 g, 15.0 mmol) and azidotributyltin (lOg, 30.0 mmol). The mixture was heated at 80 ° C for 24 hours, then the reaction mixture was cooled and diluted with 15 mL of diethyl ether. The resulting solution was poured into 15 mL of diethyl ether saturated with gaseous hydrochloric acid. The resulting solid was removed by filtration and the solids were washed with hexanes to provide 3.1 g (85%) of the title material. LRMS (API ES +) = 243.0 (M + H). - (4-Bromo-2-flouro-phenyl) -1-methyl-1H-tetrazole: Dry DMF was added to sodium hydride (0.2 g, 4.8 mmol), which was previously washed three times with hexanes, cooled the resulting suspension at 0 ° C and 5- (-Bromo-2-flouro-phenyl) -lH-tetrazole (1.0 g, 4.4 mmol) was added in portions. The mixture was stirred for 30 minutes then methyl iodide (0.68 g, 4.8 mmol) was added, and the reaction continued to stir at room temperature; the reaction was monitored via CCD. When completed, the reaction was quenched with 10% NaHS04 (50 mL); it was diluted with ethyl acetate (50 mL); and the layers separated. The aqueous layer was extracted three times with ethyl acetate (25 mL). The organic layers were combined; and dried over MgSC > Four . The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue chromatographed on a column of silica gel by levigating with 20% ethyl acetate in hexanes to provide 0.68 g (65%) of the title material. LRMS (API ES +) = 239.0 (M + H).

-Bromo-4-methyl-2-thiophene carboxamide: Combined Methyl 5-bromo-4-methyl-2-thiophene carboxylate (5.0g, 1.0 equiv, 21.2 mmol) and 7N NH3 in MeOH (50 mL) in a flask. The mixture was heated in a sealed tube at 100 ° C for 18 hours. The residue was purified on silica gel using elution gradient of 30% EtOAc / hex at elution of 80% EtOAc / hex. 0.7 g (64%) were isolated. LRMS (API ES +) = 221.8 (M + H).

-Bromo-4-methyl-2-thiophene carbonitrile: 5-Bromo-4-methyl-2-thiophene carboxamide (1.2 g, 1.0 equiv, 5.4 mmol) and POC13 (30 mL) were combined in a flask. The mixture was stirred at room temperature for 18 hours. The residue was purified on silica gel using 30% EtOAc / hex elution to give the title compound (0.7 g, 64%). 1 H NMR (CDCl 3) d 7.27 (s, 1H), 2.17 (s, 3H). 4-Bromo-3-methyl-2-thiophene carboxamide: 4-Bromo-3-methyl-2-thiophene carboxylic acid (2.0 g, 1.0 equiv, 9.0 mmol) and thionyl chloride (30 mL) were combined in a flask. The mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated in vacuo and then The residue was suspended in 7N NH3 in MeOH (50 mL). It was stirred for 1 hour. Concentrate in vacuo to provide 1.9 g (100%) of the title compound. E BR (API ES +) = 221.8 (M + H). 4-Bromo-3-methyl-2-thiophene carbonitrile: Dissolved 4-bromo-3-methyl-2-thiophene carboxamide in 30 mL of P0C13 and the mixture was allowed to stir at room temperature for 18 hours. The reaction was then concentrated in vacuo; and the residue was purified by chromatography (silica gel, 5% ethyl acetate / hexane) to give the title compound (0.9g, 49%). 1 H-NMR (CDC13) d 9.44 (S, 1H), 4.40 (S, 3H). 4-Bromo-2-fluoro-6-methoxy-benzonitrile: Method DF1 4-Bromo-2,5-difluoro-benzonitrile (1.5 g, 6.9 mmol) was dissolved in THF (10 mL). NaOMe (1.9 g, 25% by weight solution in MeOH, (8.3 mmol) was added.The reaction mixture was stirred overnight at room temperature, concentrated in vacuo and purified by chromatography on silica gel (0-50). % gradient EtOAc / hexanes / 30 min) The selected fractions were concentrated in vacuo to give the title compound (1.5 g, 94%) as a white solid.1H-NMR is consistent with the structure CCD (20% EtOAc / hexanes) Rf = 0.28. 4-Bromo-2-fluoro-6-methoxy-benzaldehyde: Method DF2 4-Bromo-2-fluoro-6-methoxy-benzonitrile (1.15 g, 5.0 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 ° C. DIBAL (6.0 mL, 1.0 N in methylene chloride 1.2 mmol) was added. The reaction mixture was stirred for about 1 hour at 0 ° C. 5N HC1 (20 mL) was added and the resulting solution was stirred for approximately 10 min. It was extracted with dichloromethane, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purified by chromatography on silica gel (0-50% EtOAc / hexanes / 30 min gradient). The selected fractions were concentrated in vacuo without heating to provide the title compound (485 mg, 44%) as a white solid. 1H-N R is consistent with the structure.

-Bromo-2-difluoromethyl-1-fluoro-3-methoxy-benzene: (Method DF3). 4-Bromo-2-fluoro-6-methoxy-benzaldehyde (485 mg, 2.0 mmol) was dissolved in dichloromethane (5 mL); DAST (0.3 mL, 2.2 mmol) was added and refluxed overnight in a sealed tube. It was cooled to room temperature and transferred directly to a loaded cartridge for chromatography on silica gel. Purified by chromatography on silica gel (0-50% EtOAc / hexanes gradient / 30 min) and concentrated in vacuo to give the title compound (353 mg, 70% yield) as a colorless oil. CCD (20% EtOAc / hexanes) Rf = 0.50. 1H-NMR It is consistent with the structure. 2-Bromo-5-ethynyltrimethyl-silane-pyridine: A mixture of 2-bromo-5-iodo-pyridine (1 g, 3.5 mmol), ethynyl trimethyl-silane (360 mg, 3.67 mmol) was refluxed. , copper iodide (I) (20 mg, 0.1 mmol) and tetrakis (triphenylphosphine) palladium (0) (121 mg, 0.01 mmol) in triethylamine (10 mL) under N2 in a sealed tube for 3 days. The solvent was evaporated. Purification of the crude residue using chromatography on silica gel gave 800 mg (90%) of the desired product. 4-bromo-2-thiophenecarbonitrile: 4-Bromo-2-thiophenecarboxylic acid (960 mg, 4.63 mmol) in SOCI2 (5 mL) was refluxed per lh. The excess of SOCI2 was evaporated. THF (5 mL) was added to the residue. Slowly the resulting solution was poured into concentrated NH 4 OH (15 mL) in an ice bath. The mixture was stirred overnight. The mixture was concentrated, followed by the addition of EtOAc, washed with brine; and dried over MgSO4; it was filtered and concentrated in vacuo. NaCl (307 mg, 5.26 mmol) and dichloromethane (10 mL) were added to the residue and subjected to. reflux for 30 min. After the addition of POCI3 (3.36 g, 21.9 mmol), the mixture was refluxed for 1 h. The mixture was diluted with dichloromethane and washed with aqueous NaHC03 solution, brine and dried over gS04; filtered and concentrated in vacuo to provide 753 mg of the desired product. 4-Bromo-2, 6-dimethyl-benzonitrile: 4-Bromo-2,6-dimethyl-phenylamine (4.49 g, 22.4 mmol), water (25 mL) and concentrated hydrochloric acid (8.0 mL) were placed in a glass flask. three necks and sonic until a fine suspension results. The suspension was cooled to 0 ° C and a solution of sodium nitrite (1.67 g) was added., 24.2 mmol) in water (5 mL) per drop to maintain a reaction temperature below 5 ° C. The reaction was stirred at 0 ° C for 30 minutes after the addition was complete. The reaction is carefully neutralized with solid sodium bicarbonate. The neutralized reaction was added portionwise to a round bottom flask containing copper (I) cyanide (2.42 g, 27.0 mmol), potassium cyanide (3.65 g, 56.1 mmol) and water (25 mL) at 70 ° C. C. The resulting solution was stirred for 30 minutes at 70 ° C. The reaction was cooled to room temperature and extracted with toluene (75 mL x 3). The organic layers were combined and washed with water and brine. It was dried over sodium sulfate and concentrated in vacuo. Purified by flash chromatography (2 to 20% ethyl acetate in hexane) to give 4-Bromo-2,6-dimethyl-benzonitrile (3.36 g, 15.99 mmol, 71%). H NMR (CDC13) d 7.50 (s, 1H), 2.46 (s, 6H). 4-Bromo-2-chloro-6-methyl-benzonitrile: Prepared in substantially the same manner as 4-Bromo-2,6-dimethyl-benzonitrile from 4-bromo-2-chloro-6-methyl-phenyl-amine. H NMR (DMS0-d6) d 7.52 (s, 1H), 7.38 (s, 1H) 2.53 (s, 3H). 4-Bromo-2,6-dichloro-benzonitrile: Prepared in substantially the same manner as 4-Bromo-2,6-dimethyl-benzonitrile of phenyl amine. 1 H NMR (CDC13) d 7.59 (s, 2H). 4-Bromo-3-methoxy-benzonitrile: Prepared in substantially the same manner as 4-Bromo-2,6-dimethyl-benzonitrile of phenyl amine. XH NMR (CDC13) d 7.62 (d, 1H, J = 7.9 Hz), 7.09 (dd, 1H, J = 7.9 Hz, 1.8 Hz), 7.07 (d, 1H, J = 1.8 Hz), 3.91 (s, 3H) ). 4-Bromo-2-fluoro-5-methyl-benzonitrile: Prepared in substantially the same manner as 4-Bromo-2,6-dimethyl-benzonitrile. 1ti NMR (CDC13) d 7.46 (m, 2H), 2.40 (s, 3H).

The compounds listed below in Table 1 can be prepared from compounds having the general structure of an indole core structure as an intermediate 2 in accordance with the procedures listed above.

Table I Compounds Prepared from Intermediary 2 % Prep. Preparation method that refers to Reaction Schemes 1-6 and the accompanying experimental descriptions.

The compounds listed above in Table 2 can be prepared from compounds having the general structure of an indole core structure illustrated as Intermediary 3 in accordance with the procedures listed above.

Table 2 Compounds Prepared from Intermediary 3 The compounds listed below in Table 3 can be prepared from compounds having the general structure of an indole core structure illustrated as an intermediate 4 in accordance with the procedures listed above.

Table 3 Compounds Prepared from Intermediary 4 † Unless otherwise noted, the analytical data refers to the mass spectrum data. t Prep. Preparation Method that refers to Schemes 1-6 and the accompanying experimental descriptions.

The compounds listed below in Table 4 can be prepared from compounds having the general structure of an indole nucleus illustrated as Intermediary 4-A in accordance with the procedures listed below.

Table 4 Compounds Prepared from Intermediary 4-A See Methods DF1 and DF2 above * Method Q without using the microwave.

† Unless otherwise noted, the analytical data refers to the mass spectrum data. F Prep. Preparation method that refers to Schemes 1-6 and the accompanying experimental descriptions. *** See the experiments below.

The compounds listed below in Table 5 can be prepared from compounds having the general structure of an indole nucleus illustrated as Intermediary 100 in accordance with the procedures listed below.

Table 5 Compounds Prepared from Intermediary 100 † Unless otherwise noted, the analytical data refers to the mass spectrum data. F Prep. Preparation method that refers to Schemes 1-6 and the accompanying experimental descriptions.

Alternative synthetic reaction schemes that can be used to prepare indoles described in the present invention, are illustrated below in Reaction Scheme 3, which can be accomplished by using a compound having the indole nucleus illustrated as intermediate 9, 9F or 9C. Some of these methods listed in bold in the Reaction Scheme are described above; other methods are described below after the Reaction Scheme.

Reaction scheme l-benzenesulfonyl-3-bromo-6-nitro-lH-indole (7) Triethyl amine (Et3N) (6.7 mL, 48 mmol, 4 eq) and DMAP (240 mg, 2.0 mmol, 0.1 eq) were added to a suspension of 3- Bromo-6-nitro indole, 2 (4.82 g, 20 mmol) in 100 mL of CH2C12. The solution was allowed to stir until the 3-bromo-6-nitro indole was dissolved and then benzenesulfonyl chloride (3.1 mL, 24 mmol, 1.2 eq) was added. The solution was allowed to stir overnight. The precipitate was filtered, which was formed, the precipitate was washed with CH2C12, and the filtrates were collected to provide 6.83 g of the title compound. The combined filtrates were sequentially washed with 1 M HC1, saturated sodium bicarbonate, and brine. The organic layer was dried over Na 2 SO 4, filtered, and then the filtrate was concentrated. The resulting solid was boiled in ~ 30 mL of CH2C12 and a little MeOH, 30 mL hexanes was added, it was allowed to cool, and then the precipitate was filtered to provide another 1.3 g of the title compound. XH NMR (DMSO-d6) d 8.74 (d, 1H, J = 2.2 Hz), 8.58 (s, 1H), 8.19 (dd, 1H, J = 2.2, 8.8 Hz), 8.08-8.05 (m, 2H), 7.75-7.68 (m, 2H), 7.63-7.59 (m, 2H). 4- (l-Benzenesulfonyl-6-nitro-lff-indol-3-yl) -benzonitrile (8) This compound was prepared from 1-benzenesulfonyl-3-bromo-6-nitro-ltf-indole, 7, and 4-cyanophenylboronic acid using Method C described above for 4- (l-isopropyl-6-nitro-1-yl-indol-3-yl) -benzonitrile 5. It was purified by precipitation from EtOAc / hexanes. 1 H NMR (DMSO-d 6) d 8.78 (d, 1 H, J = 1.8 Hz), 8.73 (s, 1 H), 8.17 (dd, 1H, J = 2.2, 8.8 Hz), 8.14-8.11 (m, 2H), 8.07 (d, 1H, J = 8.8 Hz), 7.97-7.92 (m, 4H), 7.72 (tt, 1H, J = 1.3, 7.5 Hz), 7.63-7.59 (m, 2H). 4- (6-Nitro-lH-indol-3-yl) -benzonitrile (9) 100 mL of 1 M TBAF in THF was added to a suspension of 4- (l-benzenesulfonyl-6-nitro-l / -indol- 3-yl) -benzonitrile 8 (14.3 g, 35 mmol) in 50 mL of THF. The reaction was monitored by CCD. If starting material remained, 1 M TBAF plus in THF was added until the reaction was complete. The reaction mixture was poured into 200 mL saturated aqueous sodium bicarbonate and then the resulting 3x solution was extracted with EtOAc. The organic extracts were combined and the extracts were washed with saturated aqueous bicarbonate, water (2x), brine. The resulting organic solution was dried over Na2SC > 4, filtered, and then the organic solvent was removed to provide a solid. The solid was redissolved in ~ 400 mL of acetone with heating and then ~ 100 mL hexanes were added until a precipitate formed. The solution was allowed to cool and then the precipitate was collected. The filtrate was concentrated and redissolved in ~ 300 mL of 50% acetone / hexanes with heating. The solution was allowed to cool and then placed in a freezer at -20 ° C overnight. The crystals that formed were collected. The performance The combined compound of the title is 6.71 g, 25.5 mmol, 72%. LRMS (API ES-) = 262.0 (M-l). 2-Fluoro-4- (6-nitro-lH-indol-3-yl) -benzonitrile (9F) A. 2-Fluoro-4-bromobenzonitrile (200 g, 990 mmol, 1.00 eq.) And triisopropyl borate ( 228 g, 1188 mmol, 1.2 eq.) In 700 mL of THF and 1400 mL of toluene. The mixture was cooled with a dry ice / acetone bath to an internal temperature of -75 ° C. Slowly n-BuLi (396 mL of a 2.5 M solution in hexanes) was added over a period of 2 hours. After the addition was complete, a thin, light red suspension resulted. The solution was allowed to stir at -74 ° C for 15 minutes, the solution was allowed to warm to -20 ° C and then quenched with 1500 mL of 2.5 M HC1. The solution was allowed to warm to RT. The layers were separated, the aqueous layer was extracted with EtOAc, the combined organic phases were dried with Na2SC > 4, filtered and concentrated in vacuo to give a light brown solid. The solid was triturated with hexane and transferred to a sintered glass funnel. Rinse with hexane once again to obtain a pale yellow filtrate. The light brown solid was stirred with CH2C12, cooled and filtered. It was rinsed with a small volume of CH2C12 to give an off white solid and brown filtrate. The solid was dried in a vacuum oven at 40 ° C and dried to provide 112g (679 mmol, 69%) of 3-fluoro-4-cyanophenylboronic acid as a whitish solid. B. 4- (l-Benzylsulfonyl-6-nitro-lH-indol-3-yl) -2-fluoro-benzonitrile from 1-benzenesulfonyl-3-bromo-6-nitro-lH-indole, 7, and acid 3-fluoro-4-cyanophenylboronic using Method AA: Pd2 (dba) 3, [(t-Bu3) PH] BF4, K2C03, THF, H20. It was purified by precipitation from EtOAc / hexanes. The benzenesulfonyl protecting group was removed using TBAF and THF as described for 4- (6-nitro-lido-indol-3-yl) -benzonitrile (9) above. LRMS (API ES-) = 280.0 (M-l). 4- (6-Nitro-l-pyridin-3-yl-lH-indol-3-yl) -benzonitrile (10, Rl = pyridine) Method K. 4- (6-nitro-ltf-indole-3- was combined il) -benzonitrile, 9 (265 mg, 1.0 mmol), tribasic potassium phosphate (513 mg, 2.4 mmol), copper (I) iodide (38 mg, 0.2 mmol), and 2 mL of DMF in a 4-vial. mL. 3-Bromopyridine (120 μ?, 1.2 mmol) and rac-trans-N, N '-dimethylcyclohexane-1,2-diamine (127 μL, 0.8 mmol) were added. The solution was heated to 110 ° C. The solution was allowed to stir overnight. The solution was allowed to cool to RT, the yellow precipitate was isolated by filtration, and the precipitate was washed sequentially with DMF, 1: 1 DMF: H20, H20, DMF, EtOAc, and then hexanes. The precipitate was dried under vacuum to provide 301 mg, 0.88 mmol, 88% of the title compound.

LRMS (API ES +) = 341.0 (M + H). 4- [1- (3-Methyl-butyl) -6-nitro-lH-indol-3-yl] -benzonitrile (11, R1 = i-Pr) Method L. CS2CO3 (1.0 g, 1.88 mmol) was added to a solution of 4- (6-Nitro-lH-indol-3-yl) -benzonitrile, 9, (100 mg, 0.37 mmol) and isopentyl bromide (0.1 mL, 0.75 mmol) in DMF (10 mL). It was stirred overnight at room temperature. The DMF solvent was removed to provide a solid and the solid was partitioned between EtOAc and H20. Sequentially the organic layer was washed with H20 and brine, then the organic layer was dried over MgSO4. It was filtered and the solvent was removed leaving a solid. Purified by silica gel column chromatography (gradient 0-100% EtOAc / hexanes) and concentrated to dryness to provide 180 mg (95%) of the title compound. LRMS (API ES +) = 334.3 (M + H). 4- [1- (Cyano-methyl-methyl) -6-nitro-lH-indol-3-yl] -2-fluoro-benzonitrile. LL method. 2-Fluoro-4- (6-nitro-lH-indol-3-yl) -benzonitrile (1.24 mmol, 350 mg), cesium carbonate (3.61 mmol, 1.18 g) and dimethylformamide (10 mL) were added to a vessel. of reaction equipped with a stir bar. This mixture was stirred for 10 minutes at room temperature, then cyano-ethyl-methyl-toluene-4-sulfonic acid ester (3.11 mmol, 701 mg) was added. The resulting mixture was stirred for 5 hours at 55 ° C. This material was diluted with water (25 mL), brine (50 mL) and ethyl acetate (50 mL). The organics were separated and the resulting aqueous mixture was extracted with ethyl acetate (2X) and dichloromethane containing 10% methanol (2x). The organics were combined and concentrated in vacuo at about 1/2 volume. The resulting mixture was washed with water and the solvent was evaporated in vacuo. The resulting yellow solids were triturated with hot dichloromethane. The solids were collected by vacuum filtration and rinsed with 50% dichloromethane / hexane to give the title compound (196 mg, 47%) yellow amorphous solid. MS (IS-) m / e 333.0 (M-1), 393.0 (M-1 + OAc). 4- (L-cyclopentyl-6-nitro-lff-indol-3-yl) -benzonitrile (11, Rl = cyclopentyl) Method M. KOH pellets (200 mg, 3.42 mmol) were added to a solution of 4- ( 6-Nitro-ltf-indol-3-yl) -benzonitrile, 9, (150 mg, 0.57 mmol) in DMSO (10 mL). After the KOH pellets were dissolved, cyclopentyl tosylate (210 mg, 0.85 mmol) in DMSO (3 mL) was added. The reaction mixture was allowed to stir overnight at room temperature. Cyclopentyl tosylate was further added (210 mg, 0.85) and the reaction mixture was allowed to stir for another 6 h. Further cyclopentyl tosylate (210 mg, 0.85 mmol) was added and the reaction mixture was allowed to stir overnight at room temperature. The resulting reaction mixture was quenched with 5N HCl / ice. The quenched reaction mixture was extracted with EtOAc. The EtOAc extracts were washed with brine. The organic layer was dried over MgSO4, filtered, and the solvent was removed from the filtrate to provide a solid. Purified by silica gel column chromatography (0-100% EtOAc / hexanes gradient) and the fractions were collected and the solvent removed to provide 110 mg (58%) of the title compound. E BR (API ES +) = 332.2 (M + H). 4- [6-Nitro-l- (pyridine-3-sulfonyl) -lH-indol-3-yl] -benzonitrile (14 Rl = pyridinyl 3-sulfonate) Method N. 4- (6-nitro-lino) -indol-3-yl) -benzonitrile, 9, (290 mg, 1.1 mmol), 4-dimethylaminopyridine (14 mg, 0.11 mmol), triethyl amine (740 pL, 5.3 mmol), methylene chloride (7.0 mL) and dimethylformamide (2.5 mL) in a 25 mL flask. 3-Pyridine sulfonyl chloride hydrochloride (283 mg, 1.32 mmol) was added. The solution was allowed to stir overnight. The precipitate was isolated by filtration and the 3x precipitated was washed with methylene chloride to provide 251 mg, 0.62 mmol, 56% of the title compound. EMBR (API ES +) = 405.0 (M + H). Once the functionalized intermediates 10, 11, and 14 were obtained using the general routes described above, the 6-nitro substituent can be reduced to the amine, using the general procedures listed above by Reaction Scheme 1, i.e. Methods EH, and then the amine can be converted to the alkyl sulfonamide using an appropriately selected alkyl sulfonyl chloride as described in Method I above, to provide desired 6-alkyl sulfonamides 12, 13, and 15. The compounds illustrated below in Table 6 can be prepared according to the above procedures starting from intermediates 9, 9F, or 9C in Reaction Scheme 2.

Table 6 Compound Prepared from Intermediates 9, 9C or 9F 3 † Unless otherwise noted, the analytical data refers to the mass spectrum data. Prep. Preparation method that refers to Schemes 1-6 and the accompanying experimental descriptions. F The tosylate reagent was prepared according to the procedure for 3-methyl-2- (-methylphenylsulphonyloxy) butane below in Example 224. * CLAR-A: Quiracel OJ-H; 30% IPA / C02; 10 ml / m CLAR-B: Quiracel AD-H; 30% MeOH / C02; 5 ml / m CLAR-C: Quiracel AD-H; 0.2% DMEA / 3A EtOH; 0.6 ml / m CLAR-D: Quiracel AD-H; 0.2% DMEA / 3A EtOH; 1 ml / m ** See Methods Z-1 and Z-2 below *** see Experimental Description below. In addition to the compounds prepared in accordance with the general procedures described above using the methods and routes in Reaction Schemes 1-4, the following examples may be prepared by the procedures described herein.

Example 289. N- [3- (5-Cyano-4-fluoro-thiophen-2-yl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide A mixture of N- [3- (4 Chloro-5-cyano-thiophen-2-yl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide (Example 118) (0.15g, 0.381 mmol) and CsF (0.324g, 2.13 mmol) in DMSO (5 ml) at 150 ° C for 6 hours under N2. The mixture was cooled to 21 ° C and diluted with EtOAc. The mixture was washed with water, brine, and dried over MgSO4. The material was filtered and concentrated to dryness. The crude product was purified by reverse phase chromatography to provide 5 mg of the title compound. MS: 378.0 (MH +) Example 290. 2-Fluoro-4- (l-isopropyl-6-methanesulfonylamino-lH-indol-3-yl) -thiobenzamide: One drop of di-isopropylethylamine and one drop of water were added to N- [3- (4 -Ciano-3-fluoro-phenyl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide (100 mg, 0.27 mmol) in 10 mL of dimethoxy ether. It was heated to reflux, followed by the addition of O, -diethyl ester of dithiophosphoric acid (151 mg, 0.81 mmol), and refluxed in a sealed tube overnight. The solvent was evaporated. Purification of the residue using silica gel chromatography eluted with EtOAc and hexane gradient to provide 99 mg (91%) of the desired product.

Example 211. N- [l-isopropyl-3- (5-ethynyl-pyridin-2-yl) -1H-indol-6-yl] -methanesulfonamide A. N- [l-isopropyl-3- (5-trimethylsilanylethynyl- pyridin-2-yl) -lH-indol-6-yl] -methanesulfonamide can be prepared using the CC method described above from 2-bromo-5-ethynyl trimethyl silane pyridine and N- [1-Isopropyl-3- ( 4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indol-6-yl] -methanesulfonamide. B. Potassium carbonate (208 mg, 1.5 mmol) was added to N- [l-isopropyl-3- (5-trimethylsilanylethynyl-pyridin-2-yl) -lH-indol-6-yl] -methanesulfonamide (63 mg, 0.15 mmol) in MeOH (5 mL) and stirred at room temperature for one hour. The solvent was evaporated. Purification of the crude residue using silica gel chromatography afforded 14 mg (27% yield) of the desired product.

Example 194. N- [3- (4-Ethinyl-phenyl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide N- [l-isopropyl-3- (4-trimethylsilanylethynyl-phenyl) -lH was added -indol-6-yl] -methanesulfonamide (0.223 mmol, 95.0 mg, similarly prepared to N- [l-isopropyl-3- (5-trimethylsilanylethynyl-pyridin-2-yl) -lH-indol-6-yl] -methanesulfonamide ), dichloromethane (4.0 mL), methanol (4.0 mL); followed by potassium carbonate (1119 mmol, 154.6 mg) in a round bottom flask equipped with a bar agitator. The resulting material was stirred for 2 hours at room temperature. The reaction was diluted with water and acidified to a pH of 6-7 with 1N HCl. The resulting aqueous mixture was diluted with brine and extracted with dichloromethane. The resulting mixture was concentrated in vacuo and then the resulting material was purified on a chromatotron (silica gel plate 2, CH2Cl2 was charged, gradient 30% -50% ethyl acetate in hexanes was run) to obtain the desired product as a light yellow crystalline solid, 50 mg (63%). MS (IS +) m / e 353.0 (M + 1).

Example 243. N- [3- (4-Cyano-phenyl) -6-methanesulfonylamino-indol-1-yl] -N-methyl-acetamide A. NaH (98 mg, 2.47 mmol) was added to 4- (6 -nitro-lH-indol-3-yl) -benzonitrile (500 mg, 1.9 mmol) in DMF (10 mL) at 0 ° C under N2 and stirred for an additional 30 min at room temperature. Excess of NH 2 Cl ether solution prepared according to the procedure described in J. Org. Chem. 2004, 69 (4), 1369, and stirred for one hour. 10% sodium bisulfite was added and extracted with EtOAc. The EtOAc extracts were washed with 10% sodium bisulfite twice and dried over MgSO4. The solvent was evaporated to provide 4- (l-amino-6-nitro-lH-indol-3-yl) -benzonitrile. B. Acetic anhydride (214 mg, 2.1 mmol) was added to a mixture of 4- (1-amino-6-nitro-1H-indol-3-yl) - benzonitrile (400 mg, 1.4 mmol) and di-isopropylethylamine (194 mg, 2.1 mmol) and N, N-dimethylaminopyridine (2 mg) in DMF (20 mL) and stirred for 3 h. Acetic anhydride (214 mg, 2.1 mmol) and diisopropylethylamine (194 mg, 2.1 mmol) were further added and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with water and brine, and dried over MgSO4. The crude residue was purified using silica gel chromatography to provide 170 mg (38% yield) of N- [3- (4-Cyano-phenyl) -6-nitro-indol-1-yl] -acetamide. C. NaH (26 mg, 0.64 mmol) was added to a solution of N- [3- (4-Cyano-phenyl) -6-nitro-indol-1-yl] -acetamide (170 mg, 0.53 mmol) in DMF. (30 mL) at 0 ° C. After stirring for 30 min, Mel (170 mg, 0.64 mmol) was added. NaH (26 mg, 0.64 mmol) was further added, stirred for 30 min, then Mel (170 mg, 0.64 mmol) was added and stirred for 1 h. Water was added and extracted with EtOAc. The extracts were washed with water and brine, and dried over MgSO4. Purification of the crude residue using silica gel chromatography afforded 108 mg (61% yield) of the desired product. D. The use of the general procedure of catalytic reduction (Method F) and mesylation (Method I) described above provided N- [3- (4-cyano-phenyl) -6-methanesulfonylamino-indol-1-yl] -N-methyl -acetamide.

Example 68. 3- (4-Cyano-phenyl) -6-methanesulfonylamino-indole-l-carboxylic acid methyl ester 4- (6-Nitro-ltf-indol-3-yl) -benzonitrile, 9, 4- dimethylaminopyridine, triethyl amine, methylene chloride and dimethylformamide. Methyl chloroformate was added. The solution was allowed to stir until the starting material was consumed overnight. The precipitate was isolated by filtration and the precipitate was washed with 10% DMF in methylene chloride and then methylene chloride to provide the title compound. Once the desired functionalized nitro intermediate was obtained, Method F can be used to reduce the amine and then the amine can be converted to methyl sulfonamide using methyl sulfonyl chloride as described in Method I above to provide desired 6-methyl sulfonamides. .

Example 247. 4- (1- (4-tetrahydropyranyl) -6-methanesulfonylamino-lH-indol-3-yl) -benzonitrile A. 4- (4-methylphenylsulfonyloxy) tetrahydropyran: TsCl (22.33 g, 117.1 mmol) was added and DMAP (0.55 g, 4.5 mmol) to a mixture of 4-hydroxytetrahydropyran (9.2 g, 90.08 mmol), pyridine (10.93 mL, 135.12 mmol), and methylene chloride (180 mL). The mixture was stirred for 7 days, then hexanes (360 ml) was added and filtered. The filtrate was collected and washed sequentially with 5N HC1, and brine. HE dried over MgSO4, the solids were removed by filtration and the filtrate was concentrated. Purified by silica gel chromatography (methylene chloride / 5-30% hex) to give the product as an oil (20.75 90%). 1 HNRM (CDC13): d 1.70-1.91 (m, 4H), 2.47 (s, 3H), 3.48 (m, 2H), 3.86 (m, 2H), 4.65 (m, 1H), 7.35 (d, 2H, 8.8 Hz), 7.80 (d, 2H, 8.8 Hz).

B. 4- (1- (4-tetrahydropyranyl) -6-nitro-lH-indol-3-yl) -benzonitrile: CS2CO3 (2.54 g, 7.8 mmol) was added to a mixture of 4- (6-nitro-lH) -indol-3-yl) -benzonitrile (1591 g, 6 mmol), 4- (4-methylphenylsulphonyloxy) tetrahydropyran (2 g, 7.8 mmol) in DMF (25 mL) and under N2 atmosphere; the resulting mixture was heated at 60 ° C for 14 hours. After cooling, the reaction was poured into ice / water (200 ml) and 5N HC1 (6 ml), sonicated, and filtered with Et20, washed to provide a 1: 1 mixture of the title compound: starting material as a red-brown solid (1,202 g).

C. Using the General Methods described above, the title compound is provided.

Example 244. 3-Fluoro-4- (1- (R-3-methylbutan-2-yl) -6-methanesulfonylamino-lH-indol-3-yl) -benzonitrile and Example 2453. Fluoro-4- (1- ( S-3-methylbutan-2-yl) -6-methanesulfonylamino- lH-indol-3-yl) -benzonitrile A. 3-Methyl-2- (4-methylphenylsulfonyloxy) butane.

Sequentially TsCl (12405 g, 65.07 mmol) and DMAP (0.305 g, 2.503 mmol) were added to a mixture of 3-methyl-2-butanol (4.412 g, 50 mmol), pyridine (8.1 mL, 100.19 mmol), and chloride of methylene (40 ml). The mixture was stirred for 20 h, hex (40 mL) was added, and it was filtered with washed methylene chloride. The combined filtrate was washed with 5N HC1 (15 mL) and brine; then it was dried over MgSO4. The filtrate was concentrated and purified by chromatography (50-70% methylene chloride / hex) to give the title compound as an oil (9.15 g, 75%). LC: R t = 4182 m (capillary C18, 80:20 MeOH / H20, 0.5 g / L NH4OAc, 300 nm, 1 ml / m). 1H NMR (DMSO-d6): d 0.75 (m, 6H), 1.10 (d, 3H, 7.8 Hz), 1.70 (m, 1H), 2.40 (s, 3H), 4.39 (m, 1H), 7.46 (d, 2H, 8.8 Hz), 7.77 (d, 2H, 8.8 Hz).

B. 4- (1- (3-methylbutan-2-yl) -6-nitro-lH-indol-3-yl) -benzonitrile: A mixture of 3-methyl-2- (4-methylphenylsulfonyloxy) butane (15.08 g, 62.226 mmol) and DF (50 ml) was added via a syringe pump at a rate of 20 mL / h for a total addition time of 2.5 h at 50 ° C a mixture of the intermediate 9, 3-bromo-6-nitro-l / í-indole, (10.00 g, 41.485 mmol), Cs2C03 (27.04 g, 82.991 mmol, 2.0 eq), and DMF (100 mi), under N2. The reaction was stirred for 24 hours at 50 ° C. After cooling, the reaction was diluted with EtOAc and 1N HC1, then washed with water (3X), brine, and then dried over MgSO4. The solids were removed by filtration and the filtrate was concentrated. Purified by chromatography to give the title compound as a yellow paste (9.83 g, 76%). LC-MS: 352.0 (M + H). C. Following General Methods G and I described above to provide the title compound. The isomers can be separated by chiral column: CLAR-D: Quiralcel AD-H; 0.2% DMEA / 3A EtOH; 1 ml / m.

Example 121. [3- (5-Cyano-2-methyl-2H-pyrazol-3-yl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide A. 5- (l-Isopropyl) ethyl ester -6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carboxylic acid: A stirred solution of 5-Tributylstannayl-2H-pyrazole-3-carboxylic acid ethyl ester (47.7 g, 111 mmol) was sprayed. , 3-Bromo-l-isopropyl-6-nitro-lH-indole (30.0 g, 106 mmol) and dichlorobis (triphenylphosphine) palladium (II) (3.72 g, 5.30 mmol) in DMF (400 mL) with argon for 20 minutes . After this time, the mixture was stirred at 150 ° C for 1.25 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate (2 L), filtered through diatomaceous earth and the filtered pad was washed with ethyl acetate. ethyl (1 L). The filtrate was washed with water (3 x 3 L) then brine (3 L) was dried over sodium sulfate; it was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica, 9:11 ethyl acetate / heptane to 1: 1 ethyl acetate / heptane) to give 5- (l-Isopropyl-6-nitro-lH-indole) ethyl ester. -3-yl) -2H-pyrazole-3-carboxylic acid (17.4 g, 48%) as an orange solid: XH RN (300 MHz, CDC13) d 11.25 (br s, 1 H), 8.41 (m, 1 H), 8.14 (d, J = 9.0 Hz, 1H), 8.09 (dd, J = 9.0, 1.8 Hz, 1H), 7.91 (s, 1H), 7.12 (s, 1H), 4.82 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.63 (d, J = 6.6 Hz, 6H), 1.44 (t, J = 6.9 Hz, 3H).

B. 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carboxylic acid amide: 5- (l-Isopropyl-6-nitro-) ethyl ester was treated lH-indol-3-yl) -2H-pyrazole-3-carboxylic acid (18.5 g, 54.0 mmol) with a 7 M solution of ammonia in methanol at 125 ° C for 20 h (5 batches, 3.18 g-5.30 g, 200 mL of ammonia solution each). All batches were combined and concentrated under reduced pressure. The residue obtained was dissolved by boiling THF (700 mL), treated with 1,2-dichloroethane (300 mL) and concentrated under reduced pressure to provide 5- (1-Isopropyl-6-nitro-1H-) amide. indol-3-yl) -2H-pyrazole-3-carboxylic acid (18.0,> 100%) as an orange solid: XH NMR (500 MHz, DMSO- of, observed as a mixture of rotamers at room temperature) d 13.46 (m, 1H), 8.65-8.60 (m, 1H), 8.40 (m, 0.5H, rotamer), 8.29 (s, 0.5H, rotamer), 8.25 (d, J = 8.5 Hz, 0.5H, rotamer), 8.06-8.01 (m, 1.5H, rotamer), 7.92 (brs, 0.5H, rotamer), 7.56-7.53 (m, 1H), 7.22 (s, 1H), 7.03 (s, 0.5H, rotamer), 5.08 (m, 1H), 1.54 (d, J = 6.5 Hz, 6H).

C. 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carbonitrile: A mixture of 5- (l-Isopropyl-6-nitro-lH-) amide is reacted indol-3-yl) -2H-pyrazole-3-carboxylic acid (18.0 g, 54.0 mmol) and phosphorous oxychloride (1 Kg) at 100 ° C for 30 min. After this time, the reaction was concentrated under reduced pressure, diluted with ethyl acetate (500 mL) and quenched carefully with a saturated aqueous sodium bicarbonate solution (1.5 L). The mixture was poured into ethyl acetate (1 L), filtered through diatomaceous earth and the pad rinsed with ethyl acetate (500 mL). The organic layer of the filtrate was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide 5- (1-Isopropyl-6-nitro-1H-indol-3-yl) -2H-pyrazole-3. -carbonitrile (16.0 g, 100%) as a yellow solid: 1 H NMR (300 MHz, DMS0-d 6) d 14.19 (s, 1 H), 8.67 (m, 1 H), 8.46 (s, 1 H), 8.09 (d, J = 9.0 Hz, 1H), 8.02 (dd, J = 9.0, 2.1 Hz, 1H), 7.42 (s, 1H), 5.11 (m, 1H), 1.54 (d, J = 6.6 Hz, 6H).

D. 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carbonitrile and 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -l- methyl-lH-pyrazole-3-carbonitrile: A stirred solution of 5- (l-isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carbonitrile (16.0 g, 54.0 mmol) was treated in THF (500 mL) at 0 ° C with a 1 M solution of lithium bis (trimethylsilyl) amide in THF (81.0 mL, 81.0 mmol) and the resulting mixture was stirred at 0 ° C for 10 min. After this time, the reaction was treated with iodomethane (15.3 g, 108 mmol) and the resulting mixture was stirred at room temperature for 2 d. After this time, the reaction was quenched with water (100 mL), diluted with ethyl acetate (1.5 L) and washed with brine (1.5 L). The aqueous layer was extracted with ethyl acetate (500 mL) and the combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purified by column chromatography (silica, 1: 3 ethyl acetate / hexanes to 1: 1 ethyl acetate / hexanes, then again, silica, 7: 3, methylene chloride / hexane to methylene chloride) to provide 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carbonitrile (2.77 g, 17%) as an orange solid: mp 244-246 ° C; XH NMR (300 MHz, CDC13) d 8.41 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.10 (dd, J = 9.0, 2.1 Hz, 1H), 7.83 (s) , 1H), 7.01 (s, 1H), 4.81 (m, 1H), 4.14 (s, 3H), 1.63 (d, J = 6.6 Hz, 6H); m / z 310 [M + H] + and 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -1-methyl-lH- pyrazole-3-carbonitrile (9.92 g, 59%) as a yellow solid: XH NMR (500 Hz, CDC13) d 8.47 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 9.0, 2.0 Hz, 1H ), 7.61 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 4.87 (m, 1H), 3.92 (s, 3H), 1.66 (d, J = 7.0 Hz , 6H).

E. 5- (6-Amino-l-isopropyl-lH-indol-3-yl) -1-methyl-lH-pyrazole-3-carbonitrile: Prepared using Method G Purified by pouring the reaction carefully into a stirred solution of bicarbonate saturated aqueous sodium (1 L), diluted with ethyl acetate (1 L) and stirred for 15 min. The resulting mixture was filtered through diatomaceous earth. The organic layer was separated from the filtrate and washed with water (3? 1 L) then brine (1 L). The resulting solution was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide 5- (6-Amino-l-isopropyl-lH-indol-3-yl) -l-methyl-lH-pyrazole- 3-carbonitrile (2.03 g, qty) as a yellow foam: 1 H NMR (300 MHz, CDCl 3) d 7.30 (d, J = 8.1 Hz, 1 H), 7.12 (s, 1 H), 6.72 (m, 2 H), 6.66 (dd, J = 8.4, 1.8 Hz, 1H), 4.58 (m, 1H), 3.93 (s, 3H), 3.75 (br s, 2H), 1.55 (d, J = 6.9 Hz, 6H).

F. [3- (5-Cyano-2-methyl-2H-pyrazol-3-yl) -1-isopropyl-1H-indol-6-yl] -methanesulfonamide. It was prepared using Method I. It was purified by chromatography (silica, 1: 1 ethyl acetate / hexanes to ethyl acetate) was then crystallized from methylene chloride / hexanes (* 2) to provide N- [3- (5-cyano-2-methyl-2H-pyrazol-3-yl) - 1-isopropyl-lH-indol-6-yl] -methanesulfonamide (1.96 g, 79%) as a white solid: mp 189-191 ° C; XH RN (500 MHz, SO-d6 d 9.60 (s, 1H), 7.92 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.16 (s, 1H), 7.06 (dd, J = 8.0, 1.5 Hz, 1H), 4.73 (m, 1H), 3.99 (s, 3H), 2.96 (s, 3H), 1.52 (d, J = 7.0 Hz, 6H); m / z 358 [M + H] +.

Example 124 N- [3- (5-Cyano-2-ethyl-2H-pyrazol-3-yl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide A. 2-Ethyl-5- (l- isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carbonitrile and l-Ethyl-5- (l-isopropyl-6-nitro-lH-indol-3-yl) -lH-pyrazole -3-carbonitrile A stirred solution of 5- (l-Isopropyl-6-nitro-lH-indol-3-yl) -2H-pyrazole-3-carbonitrile (0.400 g, 1.35 mmol) in DMF (10 mL) was treated. with a 60% dispersion of sodium hydride in mineral oil (0.065 g, 1.62 mmol) and the resulting mixture was stirred at room temperature for 5 min. After this time, the reaction was treated with iodomethane (0.295 g, 1.89 mmol) and the resulting mixture was stirred at room temperature for 3 h. After this time, the reaction was quenched carefully with water (5 mL), diluted with ethyl acetate (100 mL) and washed with water (3? 100 mL) then brine (100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica, 1: 9 ethyl acetate / hexanes to 1: 4 ethyl acetate / hexanes) to give 2-Ethyl-5- (1-isopropyl-6-nitro-1H-indole. -3-yl) -2H-pyrazole-3-carbonitrile (0.195 g, 45%) as an orange solid: XH NMR (300 MHz, CDC13) d 8.41 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.10 (dd, J = 9.0, 2.1 Hz, 1H), 7.83 (s, 1H), 7.01 (s, 1H), 4.82 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.63 (m, 9H) and l-Ethyl-5- (l-isopropyl-6-nitro-lH-indol-3-yl) -lH-pyrazole-3-carbonitrile (0.129 g, 30%) as a yellow solid: 1 H NMR (300 MHz, CDC13)? 8.47 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 9.0, 2.1 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.74 (s, 1H) ), 4.86 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.66 (d, J = 6.9 Hz, 6H), 1.44 (t, J = 7.2 Hz, 3H).

B. 5- (6-Amino-l-isopropyl-lH-indol-3-yl) -1-ethyl-lH-pyrazole-3-carbonitrile A solution of l-Ethyl-5- (l-isopropyl-6) was stirred -nitro-lH-indol-3-yl) -lH-pyrazole-3-carbonitrile (0.127 g, 0.393 mmol) and tin (II) chloride dihydrate (0.887 g, 3.93 mmol) in DMF (2.5 mL) at 70 ° C. C for 1 h. After this time, the reaction was carefully poured into a stirred solution of saturated aqueous sodium bicarbonate (50 mL), diluted with ethyl acetate (50 mL) and stirred for 15 min. The resulting mixture was filtered through diatomaceous earth. The organic layer was separated from the filtrate and washed with water (3 x 50 mL) then brine (50 mL). The resulting solution was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide 5- (6-Amino-l-isopropyl-1H-indol-3-yl) -l-ethyl-1H-pyrazole- 3-carbonitrile (0.126 g, cant.) As a yellow foam. The foam was used without further purification.

C. N- [3- (5-Cyano-2-ethyl-2H-pyrazol-3-yl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide. A solution of 5- (6-Amino-l-isopropyl-lH-indol-3-yl) -1-ethyl-lH-pyrazole-3-carbonitrile (0.126 g, 0.393 mmol), pyridine (0.062 g, 0.786) was stirred. mmol) and methanesulfonyl chloride (0.068 g, 0.590 mmol) in methylene chloride (3 mL) at room temperature for 2.5 h. After this time, the reaction was purified directly by chromatography (silica, methylene chloride to 1: 9 ethyl acetate / methylene chloride) then freeze-dried from acetonitrile / water to give N- [3- (5 -Ciano-2-ethyl-2H-pyrazol-3-yl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide (0.132 g, 90%) as a slightly purple solid: mp 144-145 ° C; 1ti RN (500 MHz, DMSO-d6 .. d .60 (s, 1H), 7.84 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H) , 7.11 (s, 1H), 7.04 (dd, J = 8.5, 1.5 Hz, 1H), 4.73 (m, 1H), 4.27 (q, J = 7.0 Hz, 2H), 2.96 (s, 3H), 1.52 (d, J = 6.5 Hz, 6H), 1.35 (t, J = 7.0 Hz, 3H); LC S (Method 4) > 99%, 6.96 min, m / z 372 [M + H] +.

Example 270 N- [3- (4-Formyl-phenyl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide Method Z-1. N- [3- (4-Cyano-phenyl) -1-isopropyl-1H-indol-6-yl] -methanesulfonamide (500 mg, 1.41 mmol), sodium hyposulfite hydrate (311 mg, 3.53 mmol) and nickel were placed. Raney (50% soln in water, 700 μL, 2.96 mmol) in a round bottom flask was added water (6 mL), glacial acetic acid (12 mL) and pyridine (12 mL). It was heated to 50 ° C, and stirred for 1.5 hours. It was cooled to room temperature; it was diluted with water (10 mL); and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, and washed with saturated sodium bicarbonate, water (x3) and brine. It was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica (2-50% ethyl acetate in hexanes) to give N- [3- (4-formyl-phenyl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide ( 413.1 mg, 82%). LRMS (API ES-) = 355.0 (M-H).

Example 94 N-. { 3- [4- (Hydroxyimino-methyl) -phenyl] -1-isopropyl-lH-indol-6-yl} -methanesulfonamide Method Z-2. N- [3- (4-Formyl-phenyl) -1-isopropyl-lH-indol-6-yl] -methanesulfonamide and hydroxyl amine hydrochloride were placed in a round bottom flask under nitrogen. Ethanol (10 mL), tetrahydrofuran (10 mL) and pyridine were added. It was heated to 60 ° C, and stirred for 2 hours. It was diluted with ethyl acetate (20 mL), and washed with 1N hydrochloric acid. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica (5-40% ethyl acetate in dichloromethane) to give N-. { 3- [4- (Hydroxyimino-methyl) -phenyl] -l-isopropyl-lH-indol-6-yl} -methansulfonamide (241.1 mg, 69%). E BR (API ES +) = 372.0 (M + H).

Example 271 N- [3- (3-Formyl-phenyl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide Prepared according to Method Zl in substantially the same blanket as N- [3- (4 -formyl-phenyl) -l-isopropyl-lH-indol-6-yl] -methanesulfonamide. 1 H NMR (DMSO-d 6) d 10.05 (s, 1 H), 9.51 (s, 1 H) 8.17 (s, 1 H), 7.99 (d, 1 H, 7.5 Hz), 7.95 (s, 1 H), 7.84 (d, 1 H) , 8.4 Hz), 7.72 (d, 1H, 7.5 Hz), 7.59-7.63 (m, 1H), 7.38 (s, 1H), 7.03 (d, 1H, J = 8.8 Hz), 4.62-4.69 (m, 1H ), 3.27 (s, 3H), 2.92 (s, 3H), 1.48 (d, 6H, J = 6.6 Hz).

Example 272 N-. { 3- [3- (Hydroxyimino-methyl) -phenyl] -1-isopropyl-lH-indol-6-yl} -methanesulfonamide Prepared according to Method Z-2 in substantially the same mantera as N-. { 3- [4- (hydroxyimino-methyl) -phenyl] -l-isopropyl-lH-indol-6-yl} -metansulfonamide. LRMS (API ES +) = 372.0 (M + H).

Example 300 lN-hydroxyiminyl-2-fluoro-4- (1- (isopropyl) -6-methanesulfonylamino-lH-indol-3-yl) -benzene A. l-formyl-2-fluoro-4- (1- (isopropyl ) -6-methanesulfonylamino-lH-indol-3-yl) -benzene: Prepared according to Method Zl starting from 2-fluoro-4- (1- (isopropyl) -6-methanesulfonylamino-lH-indol-3-yl) ) -benzonitrile.

Purify using chromatography (5% methylene chloride EtOAc / methylene chloride) from the residue to provide the title compound as a yellow solid (156 mg, 78%).

LC-MS: 375.1 (M + H). B. It was prepared according to Method Z-2 starting from l-formyl-2-fluoro-4- (1- (isopropyl) -6-methanesulfonylamino-lH-indol-3-yl) -benzene. Purify by crystallizing from hex / MeOH / methylene chloride to give the title compound as a light yellow solid (106 mg, 71%).

Example 52 (S) -N- [l-sec-Butyl-3- (5-formyl-thiophen-2-yl) -1H- indol-6-yl] -metanesulfonamide Prepared according to the procedure for l-hydroxyiminyl-2-fluoro-4- (1- (isopropyl) -6-methanesulfonylamino-lH-indol-3-yl) -benzene using the reagents suitable to provide the title compound as a whitish solid (95%).

Example 275 [3- (4-cyano-3-fluoro-phenyl) -1-isopropyl-1H-indol-6-yl] -amide of Propan-2-sulfinic acid A. A mixture of isopropyl disulfide was cooled (3.77 g, 25.1 mmol) in acetic acid (2.90 mL) with brine / ice bath in a 50 mL round bottom flask fitted with a screen of 5 sodium hydroxide, and added dropwise over a period of 30 minutes. min sulfuryl chloride (10.5 g, 77.8 mmol). The resulting mixture was allowed to stir for 3 h. The cooling bath was removed and the reaction was stirred at room temperature for 2 hours thereafter at 35 ° C for additionally 1 hour. The system was purged with argon for 25 min and concentrated under reduced pressure at 45 ° C to provide isopropyl sulfinyl chloride (6.37 g, 100%) as a yellow oil: 1 H NMR (500 MHz, CDC13) 5 d 3.30 (m, 1H), 1.46 (d, J = 7.0 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H).

B. A mixture of l-Isopropyl-3- (-cyano-3-fluoro-phenyl) -lH-indol-6-ylamine (0.442 g, 1.51 mmol) was cooled and triethylamine (0.306 g, 3.02 mmol) in methylene chloride (10 mL) in brine / ice bath under argon and treated with a solution of isopropyl sulfonyl chloride (0.210 g, 1.66 mmol) in methylene chloride and the mixture The resultant was stirred in the cooling bath for 30 min. After this time, the reaction was diluted with methylene chloride (40 mL); it was washed with a saturated solution of aqueous sodium bicarbonate (50 mL), then water (50 mL), then brine (50 mL); and dried over sodium sulfate. The solids were removed by filtration; the filtrate was concentrated under reduced pressure. The residue was triturated with boiling with methylene chloride (? 3) then boiling acetonitrile to give the title compound (0.212 g, 37%) as a white solid: mp 173-175 ° C dec; 1 H NMR (500 MHz, DMSO-d 6) d 8.48 (s, 1 H), 8.15 (s, 1 H), 7.88 (m, 2 H), 7.81 (d, J = 12.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 6.98 (dd, J = 8.5, 1.5 Hz, 1H), 4.70 (m, 1H), 3.09 (m, 1H), 1.50 (d, J = 6.5 Hz, 6H), 1.28 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H); ESI MS m / z 382 [M + H] +; m / z 294 [+ H - C3H6OS] +; HPLC (Method 2) > 99% (AUC), tR = 17.1 min.

Example 276 2-Fluoro-6-methyl-4- (1- (isopropyl) -6-methanesulfonylamino-lH-indol-3-yl) -benzonitrile. A. 2-Hydroxy-3-fluoro-5-bromobenzyl alcohol. NaBH4 (4.042 g, 106.84 mmol) was added for 30 minutes to a mixture of 2-hydroxy-3-fluoro-5-bromobenzaldehyde (19.5 g, 89.037 mmol) and MeOH (445 mL) maintained at 0 ° C. The reaction was warmed to RT, and stirred for 14 h. Partially, the solvent was removed and diluted with EtOAc (500 mL). The resulting mixture was acidified with 1N HC1, and partitioned. The organic layer was washed with brine; dried over MgSO0 the solids were removed by filtration; and the filtrate was concentrated to provide a white solid. The solid was recrystallized from Et20 / methylene chloride / hexanes to give the title compound as a white solid (15.0 g, 76.2%). LC-MS: 218.9 (A + H), 220.9 (A + 2 + H).

B. 2-hydroxy-3-fluoro-5-bromotoluene. BF3-OEt2 (7.54 mL, 60 mmol) was added to a mixture of 2-hydroxy-3-fluoro-5-bromobenzyl alcohol (6.63 g, 30 mmol), Et3SiH (23.96 mL, 150 mmol), and methylene chloride ( 120 mi) maintained at 0 ° C. The reaction was stirred for 10 min, then warmed to room temperature and further stirred for 6 hours. Et3SiH (11.98 mL, 75 mmol) and BF3-OEt2 (1.88 mL, 15 mmol) were added and stirred for another 8 hours. It is repeated if necessary. When the reaction is complete, it is poured into ice / water. A minimum of Et20 was added to dissolve the solid and divided. The organic layer was washed with brine; dried over Na2SO4; the solids were removed by filtration; and the filtrate was concentrated. It crystallized to from methylene chloride / hexanes at -20 ° C, then chromatography (120 SiO 2, hexanes 30% methylene chloride / hex) to give the title compound as a white solid (3.71 g, 50.5%; Rf = 0.2 [30]). % / hex]).

C. 2-Hydroxy-3-fluoro-5-bromotoluene was treated using Method D above to provide the title compound. Rf = 0.43 (methylene chloride). AP-AP +: 328.1246 (M + H).

The following Reaction Scheme 4 illustrates a general synthetic route to provide the desired functionalization in the indole position C2. It will be understood that those skilled in the art can use alternative synthetic routes to provide the same or similar compounds.

Reaction Scheme 4 -Nitro-2-prop-1-ynyl-phenylamine (17, R2 = Me) A mixture of 2-bromo-5-nitroaniline 16 (2.81 g, 12.95 mmol), dichlorobis (triphenylphosphine) palladium (II) was stirred ( 0.45 g, 0.65 mmol), and copper iodide (I) (0.12 g, 0.65 mmol) in anhydrous acetonitrile (10 mL) under an inert atmosphere. The mixture was saturated with propyne gas, then triethyl amine (3.6 mL, 25.90 mmol) was added, the vessel sealed, and stirred at room temperature for 14 hours. The mixture was concentrated in vacuo, suspended in 100 mL diethyl ether, celite added, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel, levigating with hexanes / ethyl acetate (9: 1 v / v) to give the title compound, 1.75 g (76%). LRMS (API ES +) = 177.0 (M + H). 2-Methyl-6-nitro-lff-indole (18, R2 = CH3) A mixture of sodium hydride (60% dispersion in oil, 0.33 g, 8.19 mmol) in anhydrous DMF at 0 ° C under an inert atmosphere was cooled. . 5-Nitro-2-prop-1-ynyl-phenylamine 17 (1.31 g, 7.44 mmol) in 10 mL DMF was added and stirred for 5 minutes. Ethyl chloroformate (0.78 mL, 8.19 mmol) was added, warmed to room temperature, and stirred 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, ethyl acetate was added, and it was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. A solution of sodium ethoxide in ethanol (0.6 M, 50 mL, 0.30 mmol) was added to the residue and refluxed for 14 hours. It was cooled to room temperature and concentrated in vacuo. The residue was redissolved in diethyl ether and washed with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and the residue was chromatographed on silica gel, levigating with hexanes / ethyl acetate (9: 1) to give the title compound, 0.79 g (60 mL). %). LRMS (API ES-) = 175.0 (M-H). l-Ethyl-2-methyl-6-nitro-lff-indole (19, R1 = CH2CH3, R2 = CH3) A solution of 2-methyl-6-nitro-l # -indole, 18 (0.31 g, 1.76 g. mmol) in anhydrous DMF (5 mL) under inert atmosphere at 0 ° C. Sodium hexamethyldisilazide (1.0 M in THF, 1.9 mL, 1.9 mmol) was added and stirred for 5 minutes. Iodomethane was added (filtered through basic alumina) (0.43 mL, 5.28 mmol), warmed to room temperature, and stirred 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, ethyl acetate was added, and it was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographed on silica gel using hexanes / ethyl acetate (9: 1) to give the title compound, (0.36 g, 100%). X H NMR (CDCl 3, 300 MHz) d 2.47 (s, 3 H), 4.18 (q, J = 7.1 Hz, 2 H), 6.23 (s, 3 H), 7.48 (d, J = 8.8 Hz, 1 H), 7.95 (dd) , J = 1.9, 8.6 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H). 3-Bromo-l-ethyl-2-methyl-6-nitro-lff-indole (20, R1 = CH2CH3, R2 = CH3) A solution of l-ethyl-2-methyl-6-nitro-l- 'was stirred. -indole, 19 (0.36 g, 1.76 mmol) and N-bromosuccinamide (0.31 g, 1.76 mmol) in anhydrous THF (10 mL) under inert atmosphere at room temperature for 14 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, acetate was added ethyl, and washed with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographed on silica gel using hexanes / ethyl acetate (9: 1) to give the title compound and 1-ethyl-2-methyl-6-nitro-1H-indole (0.37 g) unreacted in a 4 mixture: 1 which can be used in the subsequent stage without further purification. LRMS (API ES +) =: 283, 285 (?, M + 2H). Alternatively desired Indoles functionalized at the C2 position, can be prepared in accordance with the general procedures in the following Reaction Scheme. It will be understood that those skilled in the art can use alternative synthetic routes to provide the same or similar compounds.

Reaction Scheme 5 Ethyl-3-iodo-6-nitro-lH-indole (24) (R2 = Et) A solution of 2-but-inyl-5-nitro-phenylamine (2.98 g, 15.68 mmol) in anhydrous THF (100 mL) was added. 2,6-di-t-butyl-4-methylpyridine followed by trifluoroacetic anhydride anhydride (2.7 mL, 19.61 mmol) and stirred at room temperature for 18 hours. The reaction was quenched with 1N HC1 and ethyl acetate was added. The organic layer was extracted 2x 1N HC1, lx brine. The organic layer was dried over sodium sulfate, concentrated in vacuo, and redissolved in anhydrous acetonitrile (150 mL). Potassium carbonate (6.49 g, 47.04 mmol) was added to the solution and cooled to 0 ° C. Iodine (11.94 g, 47.04 mmol) was added and stirred at 0 ° C for 30 min. The reaction was quenched with 1M sodium thiosulfate (100 mL) and water (250 mL) was added. The mixture was stirred 30 min., Then filtered and rinsed with water to provide 3.94 g (80%) of the title compound. 1, 2-Diethyl-3-iodo-6-nitro-lH-indole (25) (RI, R2 = Et) was added to a solution of 2-ethyl-3-iodo-6-nitro-lH-indole (0.30) g, 0.95 mmol) in anhydrous DMF (5 mL) sodium hexamethyldisilylamide (1.0M in THF, 1.0 mL, 1.00 mmol) per drop followed by ethyl iodide (0.23 mL, 2.85 mmol) and stirred 3 hours at room temperature. The reaction was quenched with 1N HC1 and ethyl acetate was added. The organic layer was washed 2x 1N HC1, lx brine. The organic layer is dried over sodium sulfate, concentrated in vacuo, and flash chromatography with 20% ethyl acetate hexane to provide 0.28 g (86%) of the title compound.

The compounds listed below in Table 7 can be prepared from compounds having the general structure of an indole nucleus illustrated as Intermediary 17 in accordance with the procedures listed above.

Table 7 Compounds Prepared from the Intermediary † Unless otherwise noted, analytical data refers to mass spectrum data.

Assays The following protocol of tests and results thereof, further demonstrate the usefulness and effectiveness of the compounds and / or methods of the present invention, given for purposes of illustration and do not mean to be limiting in any way. To demonstrate that the compounds included within the present invention exhibit affinity for progesterone receptors, binding assays were performed. Functional assays provide support that the compounds of the present invention exhibit the ability to modulate the activity of the progesterone receptor. All ligands, radiolabels, solvents, and reagents employed in the following assays are readily available from commercial sources, or can be readily synthesized by one of skill in the art.

Cell lysate binding assays of HEK293 cells that overexpress human GR (glucocorticoid receptor), AR (androgen receptor), MR (mineralcorticoid receptor), or PR (progesterone receptor), were used for competition assays to determine Ki values for compounds of interest. Briefly, the binding competition assays were run on a buffer containing 20 mM HEPES, pH 7.6, 0.2 mM EDTA, 75 mM NaCl, 1.5 mM MgCl2, 20% glycerol, mM sodium molybdate, 0.2 m DTT, 20 ug / ml aprotinin, and 20 ug / ml leupeptin, using either 0.3 nM 3H-dexamethasone for GR binding, 0.36 nM of 3H-methyltrienolone for AR binding, 0.25 nM of 3H- aldosterone for MR binding, or 0.29 nM of 3H-methyltrienolone for PR binding, and either 20 ug of 293-GR lysate, 22 ug of 293-AR lysate, 20 ug of 293-MR lysate or 40 ug of 293-PR lysate per cavity. Competing compounds are aggregated at various concentrations in increments of half log. The non-specific binding is determined in the presence of 500 nM of dexamethasone for GR binding, 500 nM of aldosterone for MR binding, or 500 nM of methyltrienolone for AR and PR binding. The binding reaction (140 μ?) Is incubated overnight at 4 ° C, then 70 μ? of cold carbon-dextran buffer (containing 50 ml of assay buffer, 0.75 g of carbon and 0.25 g of dextran), is added to each reaction. The plates are mixed 8 minutes in an orbital shaker at 4 ° C. The plates are then centrifuged at 3,000 rpm at 4 ° C for 10 minutes. An aliquot of 120 μ? of the mixture, transferred to another 96-well plate and added 175 μ? of Wallac Optiphase "Hisafe 3" scintillation fluid to each cavity. The plates are sealed and shaken vigorously on an orbital shaker. After a 2 hour incubation, the plates are read in a Wallac Microbeta counter. The data are used to calculate an IC5o and the% inhibition at 10 μ ?. Kd for 3H-dexamethasone for GR bond, 3H- methyltrienolone for AR bond, 3H-aldosterone for MR bond, or 3H-methyltrienolone for PR bond, to be determined by saturation bond. The IC5o values for compounds are converted to Ki using the Cheng-Prusoff equation and the Kd is determined by saturation binding assay. Preferred compounds of the present invention have a PR binding value of Ki of < ????? More preferably, the compounds of the present invention have a PR Ki binding value of < 10 nM. Particularly preferred compounds of the present invention exhibit a bond selectivity greater than or equal to about 10 times that for each of MR, GR, and AR as determined by comparing IC50 values or Ki values for the respective receptors.

TABLE 8 † Receptor Link Test Results fifteen twenty # Example number; † ++++: K¡ < 50nM; +++: 50 nM < Ki < 100 nM; ++: 100nM < i < 500 nM +: 500 nM < i < 1000 nM 0: > 1000 nM 25 Functional Assays PR CTF assay: Human embryonic kidney HEK293 cells are co-transfected using Fugene. Briefly, reporter plasmid pGL3 containing two copies of the GRE (glucocorticoid response element 5'TGTACAGGATGTTCT3) and the TK promoter upstream of the luciferase reporter DNA, is transfected with a plasmid that constitutively expresses the human progesterone receptor (PR), using the CMV viral promoter. The cells are transfected in T225 cm2 flasks in DMEM medium with 5% Fetal Bovine Serum (FBS) extracted from carbon. After overnight incubation, the transfected cells are trypsinized, plated on 96-well discs in DMEM medium containing 5% FBS extracted from charcoal, incubated for 4h and then exposed to various concentrations of the test compounds in increments of 1: 4 dilution. In the antagonist assays, low concentrations of agonist (0.05-0.08 nM of R5020) are also added to the medium. After 24 h of incubation with the compounds, the cells are lysed and the luciferase activity is determined. The data is adjusted to a 4-parameter adjusted logistic curve to determine EC50 and IC50 values. The% efficiency is determined against the maximum stimulation obtained with 30 nM R5020. In the antagonist mode, the% inhibition is determined against the effects of 30 nM R5020 only. The compounds selected in the present application exhibit an IC50 of less than 200 n. Example 48 exhibits an IC 50 of approximately 11.7 nM.

C3 Rat Uterine Test: This test measures the potential PR antagonist of compounds in rats, measuring a RAM endpoint of estrogenic stimulation in the uterus (increased 3 complement or C3), which is effectively blocked by a PR agonist (R5020, 17 alpha, 21-dimethyl-19-nor-pregn-4, 9-diene-3, 20-dione). The addition of a potential PR antagonist can then neutralize the blocking effect of the PR agonist, resulting in a measurable increase in the expression of uterine C3. Female immature Sprague Dawley rats (21 days of age, each approximately 50 g in weight), are first administered with the progestin R5020 subcutaneously in the same vehicle sesame oil at 0.1 mg / kg. The rats are then treated with estinyl estradiol at a dose of 50 ug / kg plus a compound of interest at doses ranging from 1-30 mg / kg made in 20% of β-hydroxycyclodextran in water for an oral forced feed volume of 0.3 mi. This dosage is made 3 times at 24 hour intervals. Control groups include rats treated with one of the following (administered and dosed as described above): 1) vehicle estrogen (E2) + vehicle R5020, 2) vehicle E2 + R5020, 3) E2 + R5020, and 4) E2 + R5020 + asoprisnil (comparator compound, 5 mg / kg). Rats are sacrificed by decapitation 2 hours after the final dose (total dosing time 50 hours). The uteri are removed and cleaned of adipose tissue, and ½ (1 uterine horn) is instantly frozen in liquid nitrogen. The tissue is homogenized in TRIzol reagent using lysis matrix pellets. The RNA is isolated by extraction of chloroform from the homogenized tissue, followed by precipitation of isopropanol from the aqueous layer. The RNA is further purified by binding to a membrane based on silica gel or magnetic perill with a nucleic acid binding surface, and then levigated with water. The RNA is converted to a single-stranded DNA via reverse transcriptase. These cDNA templates are analyzed by quantitative real-time PCR, which multiplexes the C3 primer / probe adjusted to an endogenous control gene. The resulting C3 data is normalized to the internal control. (Adapted from Lundeen, S.G. et al., J. Steroid Biochemistry and Molecular Biology, 2001, 78, 137-143). Table 9 below provides data for representative compounds prepared in accordance with the present invention.

McPhail trial The effects of progesterone receptor modulators on uterine endometrial transformation are evaluated in New Zealand White Rabbits (Harán, 800-900g) using the McPhail adapted test of McPhail, MK. J Physiol, 1934: 145-156. To evaluate the antagonist effects of compounds, rabbits are treated with 17-p-estradiol encapsulated in cyclodextrin (Sigma, 10.52 ug / kg / day in 1 ml of saline) on days 1-6. The rabbits are then treated with progesterone (Sigma, 1.0 mg / kd / day in 1 ml of corn oil) in combination with the compound of the present invention (in 15% of Povidone K12, 10% Pluronic F68 (poloxamer 188) in deionized water (DIW): probe sonicated at the mean <2 micron, 3 ml dose volume) on days 7-12. To evaluate the agonist effects of the compound, rabbits are treated with either a compound of interest or progesterone alone on days 7-12. On day 13, the animals are sacrificed, the uterus removed and fixed in zinc formalin (Richard-Alian Scientific). The fixed uteri are sectioned in transverse slices of 2-3 mm and stained with hematoxylin and eosin. A total of six slices (a proximal, middle and distal section of each uterine horn) are evaluated histologically and the progestational effect is recorded using the McPhail index. The McPhail test can be used to identify the SPRM. Table 9 below, provides data for representative compounds prepared in accordance with the present invention.

Table 9 Index McPhail +++ > 3 ++ 2 - 3 + < 2 Method of Treatment As used herein, the term "effective amount" means an amount of the compound of the present invention, ie, Formula I, which is capable of or effectively treating or alleviating the symptoms of the various pathological conditions described in this document. A specific dose of a compound administered in accordance with this invention, of course, will be determined by the particular circumstances surrounding the case, including, for example, but not limited to: the compound administered, the route of administration, the welfare state of patient, and the pathological condition to be treated. A typical daily dose will contain a non-toxic dosage level from about 0.01 mg to about 1000 mg / day of a compound of the present invention. Preferred daily doses in general will be from about 1 mg to about 250 mg / day. The compounds of this invention can be administered by a variety of routes including, oral, rectal, intravaginal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are preferably formulated before administration, the selection of which will be decided by the attending specialist. Thus, another aspect of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate, prodrug, enantiomer or prodrug thereof, and a carrier, diluent or pharmaceutically acceptable excipient. The total ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. The term "pharmaceutically acceptable", as used herein, means that the carrier, diluents, excipients and salt are compatible with the other ingredients of the formulation and are not deleterious to the container thereof. The pharmaceutical formulations of the present invention can be prepared by methods known in the art using well known and readily available ingredients. For example, the compounds of Formula I can be formulated with common excipients, diluents or carriers, and formed into tablets, capsules, suspensions, powders and the like. Non-limiting examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene glycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suitable for formulation as sustained dosage forms and the like. The formulations may also be constituted that release the active ingredient only or preferably at a particular physiological location, possibly over a period of time. The coatings, envelopes, and protective matrices can be made, for example, of polymeric substances or waxes. The compounds of Formula I, in general, will be administered in a convenient formulation as determined by the attending specialist. The compounds of the present invention can be administered with another active agent such as one or more of: SER s, estrogen, ER agonist, ER antagonists, SARMs, GnRH agonists or antagonists, P4 (progesterone), progestins and other PR agonists or modulators. When used in combination with another active agent, a compound of the present invention and the active agent, can be administered concurrently or sequentially. For example, a compound of the present invention can be administered concurrently with a SERM or a progestin to control fertility. When administered concurrently, it is understood that the two or more active agents can be administered in an individual formulation, i.e., a single tablet, elixir, injection or patch, or in separate formulations, i.e. in tablets, elixirs, patches or injections prepared separately. Alternatively, a compound of the present invention and another active agent can be administered sequentially. For example, a compound of the present invention can be administered sequentially to treat no or more gynecological disorders. A compound of the present invention can be administered during a first dosage period. Subsequently, another active agent such as a P4, progestin or other PR agonist, can be administered in a second dosage period. A period without treatment may or may not be instituted between the first and second dosing periods. It will be understood that the order of administration can be reversed, that is, a compound of the present invention can be administered during a second dosage period after the other active agent has been administered during the first dosage period. Still in another alternative treatment regimen, a compound of the present invention and another active agent can be administered intermittently. For example, a first agent, such as a compound of the present invention, can be administered for a period of dosage ie, via a tablet, injection, elixir taken twice a day, daily or weekly (or via a patch), while a second agent, such as one of the active agents listed above, is administered at one or more times or intervals selected during the dosing period. The times or intervals for administering the second agent may be selected by a specialist and may be based on the menstrual cycle, related physical indications, hormonal levels, or disease status, as considered medically prudent or necessary. As noted above for the sequential administration regimen, the administration of a compound of the present invention as the first agent and the other active agent as the second agent can be reversed. As described herein, the compounds of the present invention provide advantageous use for treating and alleviating one or more of the following: tumors; neoplasms; neoplasms; myomas; leiomyomas (uterine fibroids); endometriosis (adenomyosis); post-operative peritoneal adhesions; endometrial hyperplasia; polycystic ovary syndrome; carcinomas and adenocarcinomas of the uterus, ovary, breast, colon and prostate; infertility; fertility control; female sexual function; other menstrual or gynecological syndromes, such as dysfunctional or abnormal bleeding, amenorrhea, menorrhagia, hypermenorrhea, and dysmenorrhea; or pathological sequelae due to previous disorders / syndromes.

Claims (20)

1. An indole of Formula I characterized in that n is 1 or 2; R1 is selected from: Ci-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 hydroxyalkyl, Ci-C6 haloalkyl, Ci-C6 cyanoalkyl, Ci-C6 alkylaryl, Ci-C6 alkylheteroaryl, C3-C8 cycloalkyl, Ci-C6 alkylcycloalkyl, Ci-C6 alkyldicycloalkyl, C1-C6 alkylheterocyclyl, heterocyclyl, aryl, heteroaryl, Ci-C6-0-R9 alkyl, C0-C6 alkyl (S) R9, CoC6 alkylC02R9, -SOnRll, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl listed either individually or in combination with an alkyl portion, are optionally substituted, from one to three individually selected groups of: halo, -CN, -OH, oxo, C1-alkyl C3, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl N02, -O C1-C3 alkyl, hydroxyalkyl C1-C3, alkyl C0-C3 NR12R13, alkyl C0-C3 C (0) R12, alkyl C0-C3 C (0) 0R12, C (0) NR12R13, C (S) NR12R13, CH2ORI2, -SR12, S ( 0) nR12, -S (0) nNR12R13, -N (R9) C (0) NR12R13, -N (R12) C (0) OR13, -N (R12) S (0) nR13, -N (R12) S (0) nNR12R13, -C = N-OR10, and -NC4R9 cycle; provided that aryl and heteroaryl are not individually di- or tri-substituted with alkoxy substituents; R 2 is selected from H, halo, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl; R3 is selected from an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted bicyclic heteroaryl; wherein the substituted aryl, substituted heteroaryl and bicyclic heteroaryl are substituted with one to three individually selected groups of: halo, -CN, -OH, oxo, Ci-C3 alkyl, Ci-C3 haloalkyl, Ci-C3 cyanoalkyl, C2 alkenyl C5, C2-C6 alkynyl, C0-C3 alkyl N02, -0 Ci-C3 alkyl, -0 C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C0-C3 alkyl NR12R13, C0-C3 alkyl (0) R12, C0 alkyl -C3 C (0) 0R12, -C (0) NR12R13, -C (S) R12R13, -CH2OR12, -SR12, -S (0) nR12, -S (0) nNR12R13, -N (R9) C (0) ) R12R13, -N (R12) C (0) 0R13, - (R12) S (0) nR13, -N (R12) S (0) nNR12R13, -C = N-OR10 and -NCR9 cycle; R4, R5, and R7 are each selected independently of: H, halo, -OH, -CN, C -C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -0 C1-C4 alkyl, -0 Ci-C4 haloalkyl; R6 is selected from: Ci-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, heterocyclyl, C1-C3 alkylheterocyclyl, phenyl, C1-C3 alkylheteroaryl, C0-C3 alkyl NR9R10, and -N (H) C (0) R9, wherein each of cycloalkyl, heterocyclyl, phenyl, and heteroaryl listed either singly or in combination with an alkyl portion, are optionally substituted from one to three groups individually selected from halo, -CN, -OH, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl, NO2, -0 C1-C3 alkyl, and C1-C3 hydroxyalkyl; R8 is selected from: H, C1-C4 alkyl; R9 is individually selected from: H, C1-C6 alkyl, Ci-C6 haloalkyl, C0-C6 alkylheterocyclyl, C1-C6 alkylcycloalkyl; C 1 -C 6 alkylaryl, C 0 -C 6 alkylheteroaryl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl; RIO is selected from H, CI-CQ alkyl, and C3-C8 cycloalkyl; Rll is selected from: C1-C6 alkyl, -NR9R9, C0-C6 alkylcycloalkyl, aryl, heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with 1 to 3 groups individually selected from halo, -CN, and -0 C 1 -C 3 alkyl; R12 and R13 are individually selected from: H, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkylcycloalkyl; Ci-C6 alkylaryl, C0-C6 alkylheteroaryl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, and C3-C8 cycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that R1 is selected from the group consisting of: Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 haloalkyl, Ci-C6-0-R9 alkyl , C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, -SOnRll, C 1 -C 6 alkyl -S-R 9, and tetrahydrofuranyl, and tetrahydropyranyl, wherein each of cycloalkyl, heterocyclyl, aryl, heteroaryl, tetrahydrofuranyl, and tetrahydropyranyl, listed either singly or in combination with an alkyl portion is optionally substituted with 1 to 3 groups individually selected from halo, -CN, -OH, -N02, Ci-C3 alkyl, C1-C3 haloalkyl, Ci-C3 hydroxyalkyl.

3. The compound according to claim 1, characterized in that R1 is selected from the group consisting of: heterocyclyl, C1-C6 alkylheterocyclyl, aryl, C1-C6 alkylaryl, heteroaryl, and Ci-C6 alkylheteroaryl, wherein each optionally substituted with from 1 to 3 groups individually selected from halo, -CN, -OH, -N02, C1-C3 alkyl, Ci-C3 haloalkyl, C1-C3 hydroxyalkyl.

4. The compound according to any of claims 1-3, characterized in that R3 is selected from the group consisting of: benzo [1, 3] dioxol, benzofuranyl, benzo [1, 2, 5] thiadiazolyl, benzothiophenyl, chromium 2-onyl, 2, 3-dihydro-benzo [1,4] dioxinyl, 2,3-dihydro-benzofuranyl, 2,3-dihydro-ltf-indolyl, 1,3-dihydro-benzoimidazol-2-onyl, 1, 3, -dihydro-indole-2-onyl, furanyl, indan-l-onyl, indazolyl, isobenzofuran-1-onyl, isoxazolyl, naphthalenyl, phenyl, pyrazolyl, pyridinyl, pyrimidyl, pyrrolyl, quinolinyl, 1,2,3,4 -tetrahydro-quinolinyl, thiophenyl, thiazolyl each optionally substituted with 1 to 3 groups individually selected from: halo, -CN, -OH, -N02, C1-C3 alkyl, haloalkyl Ci-C3 hydroxyalkyl Ci ~ C3, -O alkyl Ci-C3, -C (S) NR9R9, -C = N-OR10, and C (0) R12.

5. The compound according to any of claims 1-4, characterized in that R6 is selected from the group consisting of: Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkylheterocyclyl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl , C2-C6 alkenyl, heterocyclyl, and C0-C6 alkyl NR9R10.

6. The indole of Formula I according to claim 1, characterized in that: R1 is selected from C1-C6 alkyl, Ci-C6 haloalkyl, C3-Cs cycloalkyl, C0-C6 alkylcycloalkyl, Ci-C4-0 alkyl-Ci-C4 alkyl; R2 is selected from H, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C8 cycloalkyl; R3 is selected from a phenyl, naphthyl, or heteroaryl selected from thiophenyl, pyridinyl, pyrazolyl, pyrrolyl, furanyl, thiazole, benzothiophene, benzofuran, benzo [1, 2, 5] thiadiazole, benzo [1, 3] dioxol, quinoline, indan -canvas; each optionally substituted with from one to three individually selected groups of: halo, -CN, -OH, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, -N02, -C1-C3 alkyl, hydroxyalkyl C1 -C3, -NR12R13, -C (0) R12, C0-C3C (O) alkyl OR12, C (0) NR12R13, -CH2OR12, C (S) NR12R13, and -C = N-OR12; R4, R5 and R7 are each individually H, halo, C1-C6 alkyl or C1-C6 haloalkyl; R6 is C1-C3 alkyl, Ci-C3 haloalkyl, C0-C6 alkylcycloalkyl; R8 is H; R12 and R13 are each individually selected from: H, C -C6 alkyl, C1-C6 haloalkyl, Ci-C6 alkylcycloalkyl, and C3-C8 cycloalkyl; or a pharmaceutically acceptable salt thereof.

7. A compound characterized in that it is selected:

8. A compound, characterized in that it is selected from the following:

9. A compound, characterized in that it is selected from the following:

10. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-9 and at least one of: a carrier, a diluent, and an excipient.

11. An indole compound of Formula I, according to any of claims 1-9, for use as a medicament.

12. A method for preparing an indole of formula II, or a pharmaceutically acceptable salt thereof, characterized in that n is 1 or 2; R1 is selected from: Ci-Cs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6 hydroxyalkyl, C1-C6 haloalkyl, Ci-C6 cyanoalkyl, Ci-C6 alkylaryl, C1-C6 alkylheteroaryl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, C1-C6 alkyldicycloalkyl, Ci-C6 alkylheterocyclyl, heterocyclyl, aryl, heteroaryl, Ci-C6-0-R9 alkyl, C0-C6 alkyl C (S) R9, CoC6 alkylC02R9, -SOnRll, wherein each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl listed either individually or in combination with an alkyl portion, are optionally substituted, from one to three individually selected groups of: halo, -CN, -OH, oxo, C1-alkyl C3, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl N02, -0 C1-C3 alkyl, C1-C3 hydroxyalkyl, C0-C3 alkyl NR12R13, C0-C3 alkyl (0) R12 , C0-C3 alkyl C (0) 0R12, C (0) NR12R13, C (S) NR12R13, CH20R12, -SR12, S (0) nR12, -S (0) nNR12R13, -N (R9) C (0) R12R13, -N (R12) C (0) OR13, - (R12) S (0) nR13, -N (R12) S (0) nNR12R13, -C = N-OR10, and -NC4R9 cycle; provided that aryl and heteroaryl are not individually di- or tri-substituted with alkoxy substituents; R2 is selected from H, halo, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl; R3 is selected from an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted bicyclic heteroaryl; wherein the substituted aryl, substituted heteroaryl and bicyclic heteroaryl are substituted with one to three groups individually selected from: halo, -CN, -OH, oxo, Ci-C3 alkyl, Ci-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl , C2-C6 alkynyl, C0-C3 alkyl N02, -0 C1-C3 alkyl, -0 C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C0-C3 alkyl NR12R

13, C0-C3 alkyl (0) R12, C0- alkyl C3 C (0) 0R12, -C (0) NR12R13, -C (S) R12R13, -CH2OR12, -SR12, -S (0) nRl2, -S (0) nNR12R13, -N (R9) C (0) NR12R13, -N (R12) C (0) OR13, -N (R12) S (0) nR13, -N (R12) S (0) nNR12R13, -C = N-OR10 and -cycle CN4R9; R4, R5, and R7 are each independently selected from: H, halo, -OH, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -0 alkyl C1-C4, -O haloalkyl Ci-C4; R8 is selected from: H, Ci-C4 alkyl; R9 is individually selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C0-C6 alkylheterocyclyl, Ci-C6 alkylcycloalkyl; Ci-C6 alkylaryl, C0-C6 alkylheteroaryl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl; RIO is selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; Rll is selected from: Ci-C6 alkyl, -NR9R9, C0-C6 alkylcycloalkyl, aryl, heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with 1 to 3 groups individually selected from halo, -CN, and -O alkyl C1 -C3; R 12 and R 13 are individually selected from: H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylcycloalkyl; C 1 -C 6 alkylaryl, C 1 -C 6 alkylheteroaryl, hydroxyalkyl Ci-C6, C2-C6 alkenyl, and C3-C8 cycloalkyl; or a pharmaceutically acceptable salt thereof; said method comprises combining a compound of Formula II with a base and R6SO2CI, wherein R6 is selected from: C1-C6 alkyl, Ci-C6 haloalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkylcycloalkyl, heterocyclyl, C1-C3 alkylheterocyclyl, phenyl, C1-6 alkylheteroaryl C3, C0-C3 alkyl NR9R10, and -N (H) C (0) R9, wherein each of cycloalkyl, heterocyclyl, phenyl, and heteroaryl listed either singly or in combination with an alkyl portion, are optionally substituted from one to three individually selected halo groups, -CN, -OH, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 cyanoalkyl, C2-C5 alkenyl, C0-C3 alkyl N02, -O C1-C3 alkyl, and hydroxyalkyl C1-C3. A method for modulating the activity of the progesterone receptor, characterized in that it comprises administering a therapeutically effective composition comprising a compound of Formula I as claimed in any of claims 1-9, or a pharmaceutically acceptable salt thereof, to a patient.

14. A method for treating or alleviating the effects of leiomyomas, characterized in that it comprises administering a therapeutically effective composition comprising an indole of Formula I according to any of claims 1-9, or a pharmaceutically acceptable salt thereof to a patient.

A method for treating or alleviating the effects of endometriosis, characterized in that it comprises administering a therapeutically effective composition comprising a compound of Formula I according to any of claims 1-9, or a pharmaceutically acceptable salt thereof of a patient.

16. A method for treating or preventing pathological sequelae due to leiomyomas, endometriosis, or breast cancer in a mammal, characterized in that it comprises administering a therapeutically effective dose of a compound of Formula I according to any of claims 1-9, a pharmaceutically acceptable salt thereof to said mammal.

17. A method for treating gynecological or menstrual disorders in a mammal, characterized in that it comprises administering a therapeutically effective dose of a compound of Formula I according to any of claims 1-9, a pharmaceutically acceptable salt thereof to said mammal.

18. Use of a compound for the manufacture of a medicament for treating and / or preventing leiomyomas in a mammal, comprising administering an effective dose of a compound of Formula I according to any of claims 1-9, a pharmaceutically acceptable salt thereof to said mammal.

19. Use of a compound for the manufacture of a medicament for treating and / or preventing endometriosis, whcomprises administering an effective dose of a compound of Formula I according to any of claims 1-9, a pharmaceutically acceptable salt thereof to said mammal.

20. A pharmaceutical composition, characterized in that it comprises a compound of Formula I according to any of claims 1-9, for treating leiomyomas or endometriosis.