MX2008007811A - Azepinoindole derivatives as pharmaceutical agents - Google Patents

Abstract

The present invention relates to compounds of formula I, which exhibit affinity for the farnesoid X receptor.

Description

DERIVATIVES OF AZEPINOINDOL AS PHARMACEUTICAL AGENTS REFERENCE TO RELATED PATENT APPLICATIONS This patent application claims priority of US Provisional Patent Application Number 60 / 750,634, filed on December 15, 2005, and of US Provisional Patent Application Number 60 / 750,679, filed on December 15, 2005, both are incorporated in the present as a reference in its entirety.

FIELD OF THE INVENTION Compounds, compositions and methods are provided for modulating the activity of receptors and for the treatment, prevention or amelioration of one or more symptoms of a disease or a disorder related to the activity of the receptors.

BACKGROUND OF THE INVENTION Nuclear receptors Nuclear receptors are a superfamily of regulatory proteins that are related by their structure and function and are receptors of, for example, spheroids, retinoids, vitamin D and thyroid hormones (see for example, Evans (1988) Science 240: 889-895 ). These proteins bind to the cis-acting elements in the promoters of their target genes and modulate the expression of the gene in response to ligands of the receptors.

Nuclear receptors can be classified based on their DNA binding properties (see, for example, Evans, supra and Glass (1994) Endocr. Rev. 15: 391-407). For example, a class of nuclear receptors includes the glucocorticoid, estrogen, androgen, progestin and corticoid mineral receptors that bind as homodimers to hormone response elements (HREs) organized as inverted repeats (see, for example, Glass, supra). A second class of receptors, including those activated by retinoid acid, thyroid hormone, vitamin D, peroxisome fats / proliferators (ie, the peroxisome proliferator-activated receptor (PPAR)) and ecodisome, come together to HRE as heterodimers with a common partner, retinoid X receptors (ie, RXR, also referred to as 9-cis retinoic acid receptors, see, eg, Levin et al. (1992) Na ture 355: 359-361 and Heyman et al. (1992) Cell 58: 397-406).

RXRs are unique among nuclear receptors because they bind to DNA as a homodimer and are needed as a heterodimeric partner for numerous additional nuclear receptors to bind to DNA (see, for example, Mangelsdorf et al. (1995) Cell 83: 841-850). The last receptors, called the subfamily of nuclear receptors of class II, include many that have been established or implied as important regulators of gene expression. There are three RXR genes (see for example, Mangelsdorf et al. (1992) Genes Dev. 5: 329-344), which encode RXRa, -β, and - ?, the totality of which can be heterodimerized with any of the receptors of class II, although there are apparently preferences for RXR subtypes by in vivo recipients (see, for example, Chiba et al., (1997) Mol Cell. Biol. 17: 3013-3020). In the liver of an adult, RXRa is the most abundant of the three RXRs (see, for example, Mangelsdorf et al. (1992) Genes Dev. 6: 329-344), suggesting that it would play a prominent role in functions hepatic cells that participate in regulation by nuclear receptors of class II. See also, Wan et al. (2000) Mol. Cell. Biol 20: 4436-4444.

Orphan Nuclear Receptors In the nuclear receptor superfamily of regulatory proteins are included the nuclear receptors for which the ligand is known and those that lack known ligands. Nuclear receptors that are not in this last category are called orphan nuclear receptors. The search for activators for orphan receptors has led to the discovery of previously unknown signaling pathways (see, for example, Levin et al., (1992), supra and Heyman et al., (1992), supra). For example, it has been reported that bile acids, which involve physiological processes such as cholesterol catabolism, are ligands of the farnesoid X receptor. { infra).

Since it is known that products of the metabolism of intermediates act as transcriptional regulators in bacteria and yeast, these molecules can perform similar functions in higher organisms (see, for example, Tomkins (1975) Science 189: 760-763 and O 'Malley (1989) Endocrinology 125: 1119-1120). For example, a biosynthetic pathway in higher eukaryotes is the mevalonate pathway, which results in the synthesis of cholesterol, bile acids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitamin D, spheroidal hormones and farnesylated proteins.

Receptor Farnesoide X The farnesoid X receptor (originally isolated as RIP14 (retinoid X receptor that interacts with protein 14), see, for example, Seol et al (1995) Mol Endocrinol 9: 12-85) is a member of the superfamily of receptors for nuclear hormones and is expressed mainly in the liver, kidney and intestine (see, for example, Seol et al., supra and Forman et al. (1995) Cell 81: 687-693). It functions as a heterodimer with the retinoid X receptor (RXR) and binds to the response elements in the promoters of the target genes to regulate the transcription of the genes. The farnesoid X-heterodimer receptor of RXR binds with the highest affinity to an inverted repeat response element 1 (IR-1), wherein the hexamers that bind to the consensus receptor are separated by a nucleotide. The farnesoid X receptor is part of an interrelated process, in which the receptor is activated by bile acids (the end product of cholesterol metabolism) (see, for example, Makishima et al. (1999) Science 284: 1362-1365, Parks et al (1999) Science 284: 1365-1368, Wang et al (1999) Mol Cell 3: 543-553), which serve to inhibit cholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem. 275: 39313-39317.

Nuclear Receptors and Disease The activity of nuclear receptors, which includes the activity of farnesoid X receptors and / or orphan receptors, has been implicated in a variety of diseases and disorders, including, but not limited to, hyperlipidemia and hypercholesterolemia, and complications of they, including but not limited to coronary artery disease, angina pectoris, carotid artery disease, seizures, cerebral arteriosclerosis and xanthoma (see, for example, International Patent Application Publication No. WO 00/57915 ), osteoporosis and lack of vitamins (see, for example, U.S. Patent No. 6,316,5103), hyperlipoproteinemia (see, for example, International Patent Application Publication No. WO 01/60818), hypertriglyceridemia, lipodystrophy, peripheral obstructive disease, ischemic attack, hyperglycemia and diabetes mellitus (see, for example, International Patent Application Publication No. WO 01/82917), t disorders related to insulin resistance that include the group of disease states, conditions or disorders that make up "Syndrome X" such as glucose intolerance, an increase in plasma triglycerides and a decrease in cholesterol concentrations of high-density lipoprotein, hypertension, hyperuricemia, denser, denser, smaller density lipoprotein particles, and higher circulation levels of plasminogen activator inhibitor-1, atherosclerosis, and gallstones (see, for example, Publication of the Application U.S. Patent No. WO 00/37077), skin and mucous membrane disorders (see, for example, U.S. Patent Nos. 6,184,215 and 6,187,814 and International Patent Application Publication No. WO 00/37077). 98/32444), obesity, acne (see, for example, International Patent Application Publication No. WO 00/49992), and cancer, cholestasis, disease Parkinson's disease and Alzheimer's disease (see, for example, International Patent Application Publication No. WO 00/17334).

The activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, has been implicated in physiological processes including, but not limited form, metabolism, catabolism, transport or absorption of triglycerides, metabolism, catabolism, transport, absorption, reabsorption of bile acid or composition of bile, metabolism, catabolism, transport, absorption or reabsorption of cholesterol. Modulation of the 7a-h? Drox? Lasa (CYP7A1) gene transcription of cholesterol (see, for example, Chiang et al. (2000) J. Biol. Chem. 275: 10918-10924), HDL metabolism ( see, for example, Upzar et al (2000) J. Biol Chem 275:... 39313-39317), hyperlipidemia, cholestasis, and increased cholesterol flow and increased protein expression cassette transport ATP (ABC1) ( see for example, International Patent Application Publication No. WO 00/78972) are also modulated or otherwise affected by the farnesoid X receptor.

Therefore, there is a need for compounds, compositions and methods to modulate the activity of nuclear receptors, which include farnesoid X receptors and / or orphan nuclear receptors. These compounds are useful for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders in which the activity of nuclear receptors is involved.

The US patent application of the same holder No. 60 / 383,574, entitled "Azepinoindole and pyridoindole modulators of nuclear receptors," [ "Azepinoindol and pyridoindole modulators of nuclear receptors"], filed 24 May 2002, Martin et al. , and U.S. Patent Application No. 10 / 447,302, filed May 27, 2003, Martin et al., entitled "Azepinoindole and pyridoindole modulators of nuclear receptors," [ "Azepinoindol and pyridoindole modulators of nuclear receptors"] that incorporated herein by reference in their entirety, disclose novel compounds that bind to the farnesoid X receptor. The present inventors have identified a novel class of compounds that exhibit a very high affinity for the farnesoid X receptor, and high potency in vivo. Unexpectedly, these compounds have the ability to reduce plasma triglyceride and cholesterol levels in normal and hyperlipidemic animal models.

EXTRACT OF THE INVENTION Compounds are provided for use in pharmaceutical compositions and methods for modulating the activity of nuclear receptors. Specifically, compounds are provided for use in compositions and methods for modulating the farnesoid X receptor, and / or orphan nuclear receptors. In one embodiment, the compounds provided herein are agonists of the farnesoid X receptor In another embodiment, the compounds provided herein are antagonists farnesoid X receptor In another embodiment, the compounds provided herein are agonists inverted, partial agonists or partial antagonists of the farnesoid receptor X. Agonists having low efficacy are, in certain embodiments, antagonists.

In one embodiment, the compounds for use in the compositions and methods provided herein have the formula (I): (i) or a pharmaceutically acceptable derivative thereof; wherein: R1 is -C (J) R, -C (J) ORn, or -C (J) NR ^ NR11; J is direct bond, 0 or -NR10; n is from 0 to 4; R3 is hydrogen, -C (0) R9, or CON (R11) (R12); R6 or R7 is independently optionally substituted a, optionally substituted cycloa or optionally substituted cycloaa; R8 is selected from the group consisting of hydroxy, a optionally substituted a, alkenyl optionally substituted ayl, optionally substituted, halo, haloa, haloalkoxy, cycloa optionally substituted cycloaa, optionally substituted heterocyclyl optionally substituted heterocyclyla optionally substituted aryl, optionally substituted ara optionally substituted , optionally substituted heteroaryl, optionally substituted heteroara, -OC (O) N (R15) (R16), OC (0) Rn, or -OR20; R9 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl , OR10 and N (R12) (R13); R10 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl; each R 11 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl optionally substituted heteroaralkyl, -OR14 and -N (R15) (R16); R12 and R13 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl; or R12 and R13, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R10, R11, R12 and R13 are selected as in (a) or (b) in the following manner: (a) R10, R11, R12 and R13 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R10, R11, R12 and R13 together with the atoms to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring; and the others of R10, R11, R12, and R13, are selected as in (a) above.

Each R14 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl , optionally substituted heteroaralkyl, -OR18, -SR18 and -N (R20) (R21); R15 and R16 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR18, -SR18 and -N (R20) (R21); or R15 and R16, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; R17 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; each R 18 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl , or optionally substituted heteroaralkyl; R19 is alkylene or direct bond; R20 and R21 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or R20 and R21, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; Each R22 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl , optionally substituted heteroaralkyl, -R19-OR23, -R19-N (R23) (R24), -R19-C (J) R23, -R19-C (J) OR23, and -R19-C (J) N (R23) ) (R24); Each R23 and R24 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, heteroaryl optionally substituted, optionally substituted heteroaralkyl, -R19-OR25, -R19-N (R25) (R26), -R19-C (J) R25, -R19-C (J) OR25, and -R19-C (J) N (R25) (R26); OR R23 and R24, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; Each R25 and R26 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, heteroaryl optionally substituted and optionally substituted heteroaralkyl; Each R1-R26, when substituted, is substituted with one or more substituents, each of which is independently selected from Q1; where Q1 is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, amino, hydroxyalkyl, hidroxialquilariloxi, hydroxyaryl, hydroxyalkyl-, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, diaryl, hydroxyaryl, alkylaryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, alquilaralquilo, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, I triarylsilyl , alkylidene, arylalkylidene, alkylcarbonyl, alkylarylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroarylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, heterocyclylcarbonylalkaryl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, minocarbonilo, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, haloalkoxy, alkoxyaryloxy, alkylaryloxy, diaryloxy, alquilariloxialquilo, alquildiariloxi, perfluoroalkoxy, alkenyloxy, alkynyloxy, ariloxialcaoxi, aralcoxiariloxi, alquilarilcicloalquiloxi, heterocycloxy, alkoxyalkyl, alkoxyalkoxyalkyl, alquilheteroariloxi, alkylcycloalkoxy, cycloalkyloxy, heterocyclyloxy, aralkoxy, haloaryloxy, heteroaryloxy, alquilheteroariloxi, alcoxicarbonilheterocicloxi, alquilcarbonilariloxi, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, alkoxyaryloxy, aralcoxicarboniloxi, ureido, alkylureido, arylureido, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alauilarilaminoalquilo, alkylamino, dialkylamino, haloalkylamino, haloalkylarylamino, arylamino, diarylamino, alkylarylamino, aralkylamino, alkylcarbon ylamino, aralkylcarbonylamino, haloalkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, ariloxicarbonilaminoalquilo, ino ariloxiarilcarbonila, aryloxycarbonylamino, alquilendioxialquilo, dialquilalquilendioxialquilo, alkylsulfonylamino, arylsulfonylamino, azido, dialquilfosfonilo, alquilarilfosfonilo, diarilfosfonilo, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyl , alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q1 groups, which substitute atoms in an arrangement of 1.2 or 1.3, together form alkylenedioxy (ie, -O- (CH2) z-0-), thioalkyleneoxy (ie, -S- (CH2) z-0-) or alkylenedithioxy (ie, -S- (CH2) ZS-) where z is 2; and Each Q1 is independently unsubstituted or substituted with one or more substituents, in one embodiment of one to three or four substituents, each independently selected from Q2, wherein Q2 is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, amino, hydroxyalkyl, hydroxyaryl, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, arylcarbonylalkyl, aminocarbonyl, alkoxy, aryloxy, aralkoxy, alkylenedioxy, amino, aminoalkyl, dialkylamino, arylamino, diarylamino, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, aralkylamino, alkoxycarbonylamino, arylcarbonylamino, alkylthio or arylthio.

These compounds can bind to the farnesoid X receptor with high affinity and modulate their activity. Generally these compounds have an EC5o or IC50 lower than 0.5 μM, and in certain embodiments, lower than 250 nM, 100 nM or 50 nM.

Also of interest are all the pharmaceutically acceptable derivatives, which include salts, esters and ethers, esters of enol, solvates, hydrates and prodrugs of the compounds described herein. Pharmaceutically acceptable salts include, but are not limited to, the amine salts, such as non-exhaustive form, α, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, 7-methylglucamine, procaine, N -benzylphenethylamine, l-para-chlorobenzyl-2-pyrrolidin-l '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts, such as in the non-limiting form lithium, potassium and sodium; alkaline earth metal salts such as in non-exhaustive form barium, calcium and magnesium; transition metal salts such as in the non-limiting form zinc, aluminum, and other metal salts, such as in non-limiting form sodium hydrogen phosphate and disodium phosphate; and which also include, but are not limited to, salts of mineral acids such as in the non-limiting form hydrochloride and sulfates; and salts of organic acids such as non-exhaustively acetates, lactates, maleates, tartrates, citrates, ascorbates, succinates, butyrates, valerate and fumarates.

Also provided are pharmaceutical compositions formulated for administration by an appropriate route and medium containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof, which provide effective amounts for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders that are modulated or otherwise affected by the activity of the nuclear receptors, which includes the activity of the farnesoid X receptor and / or the orphan nuclear receptors, or where the activity of the receptors is involved. nuclear receptors, which includes the activity of the farnesoid X receptor and / or orphan nuclear receptors. The effective amounts and concentrations are effective to improve any of the symptoms of any of the diseases or disorders.

Methods are provided for the treatment, prevention, inhibition or amelioration of one or more of the symptoms of diseases or disorders mediated by or in which the activity of the nuclear receptors is involved, including the activity of the farnesoid receptor X and / or of orphan nuclear receptors. These methods include methods of treatment, prevention and improvement of one or more symptoms of hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immune disorders, lipid disorders, obesity, conditions characterized by disturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral obstructive disease, ischemic attack, conditions of disturbed differentiation or excessive membrane proliferation epidermal or mucosal, or cardiovascular disorders, using one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof.

Methods of modulating the activity of nuclear receptors, including the activity of X-farnesoid receptors and / or orphan nuclear receptors, are also provided, using the compounds and compositions provided herein. The compounds and compositions provided herein are active in assays that measure the activity of nuclear receptors, including the activity of the farnesoid X receptors and / or the orphan nuclear receptors, which include the assays provided herein. These methods include inhibiting and upregulating the activity of nuclear receptors, which includes farnesoid X receptors and / or orphan nuclear receptors.

Methods of reducing cholesterol levels are provided in a subject in need thereof by administration of one or more compounds or compositions provided herein.

Methods of modulating cholesterol metabolism are provided using the compounds and compositions provided herein.

Methods of treating, preventing, inhibiting or improving one or more symptoms of diseases or disorders that are affected by cholesterol, triglyceride or bile acid levels are provided by administration of one or more of the compounds or compositions provided herein.

Methods of reducing plasma cholesterol levels and directly or indirectly modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion or excretion of cholesterol are provided by administration of the claimed compounds and compositions provided herein.

Methods of reducing plasma triglyceride levels and directly or indirectly modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion or excretion of triglycerides are provided by administration of the claimed compounds and compositions provided herein.

Methods of reducing bile acid levels and directly or indirectly modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion, non-excretion of bile acid by administration of the claimed compounds and compositions provided herein are provided.

Methods of treatment, prevention, inhibition or amelioration of one or more of the symptoms of a disease or disorder affecting the levels of cholesterol, triglycerides, or bile acid, or any combination thereof, are provided using the compounds and compositions provided herein.

Methods are provided for the treatment, prevention, inhibition or amelioration of one or more symptoms of, as well as to treat the complications of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia and lipodystrophy.

Methods for the treatment, prevention or amelioration of one or more symptoms of atherosclerosis, atherosclerotic disease, events of atherosclerotic disease and atherosclerotic cardiovascular diseases are also provided.

In addition, the present invention also provides a method for preventing, inhibiting or reducing the risk of a first onset or subsequent onset of an atherosclerotic disease event comprising the administration of a prophylactic effective amount of a compound or composition of the present invention to a patient at risk of that event. The patient may already have atherosclerotic disease at the time of administration or may be at risk of developing it.

In another aspect, the method of this invention also serves to remove cholesterol from tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifested by clinical signs such as angina, claudication, murmur, one who has suffered myocardial infarction or transient ischemic attack, or one who has been diagnosed by angiography, sonography or MRI.

Methods of treatment, prevention, inhibition or improvement of one or more of the symptoms of diabetes mellitus are provided, as well as treatment of the complications of diabetes mellitus, using the compounds and compositions provided herein.

Methods of treatment, prevention, inhibition or amelioration of one or more of the insensitivity or insulin resistance symptoms as well as treatment of the insensitivity or insulin resistance complications are provided using the compounds and compositions provided herein.

Methods of treatment, prevention, inhibition or amelioration of one or more of the symptoms of hyperglycemia as well as treatment as well as treatment of the complications of hyperglycemia are provided, using the compounds and compositions provided herein.

Methods of treating, preventing, inhibiting or ameliorating any disorder related to diabetes, hyperglycemia, or insulin resistance are included which include the group of disease states, conditions or disorders that constitute "Syndrome X".

In addition, the present invention also provides a method for preventing, inhibiting or improving the risk of developing hyperglycemia, insulin resistance or diabetes in a patient, comprising administering an effective prophylactic amount of a compound or composition of the present invention to a patient. patient at risk of that event.

Methods for the treatment, prevention, inhibition or amelioration of one or more symptoms of cholestasis, as well as for the treatment of cholestasis complications by administering a compound or composition provided herein are also provided herein.

Accordingly, the compounds and compositions provided herein can be used for the treatment, prevention, inhibition or amelioration of one or more symptoms of intrahepatic or extrahepatic cholestasis, including but not limited to, biliary atresia, obstetric cholestasis, neonatal cholestasis, cholestasis induced by drugs, cholestasis arising from infection with Hepatitis C, chronic cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

Methods for treating obesity, as well as for treating the complications of obesity, by administering a compound or composition of the present invention are also provided by this invention.

Also contemplated herein is combination therapy using one or more compounds or compositions provided herein, or a pharmaceutically acceptable derivative thereof, combined with one or more of the following: antihyperlipidemic agents, plasma HDL raising agents, antihypercholesterolemic agents, inhibitors of cholesterol biosynthesis (such as HMG CoA reductase inhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and pvastatin), inhibitors of acyl-coenzyme A: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (eg cholestyramine or colestipol)), inducers of the low density lipoprotein receptor, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B? 2, antioxidant vitamins, ß -blockers, antidiabetic agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, agonists, antagonists or partial agonists of LXR a or β, aspirin or fibric acid derivatives. The compound or compositions provided herein, or pharmaceutically acceptable derivatives thereof, are administered simultaneously or prior to or subsequent to the administration of one or more of the preceding agents. Pharmaceutical compositions containing a compound provided herein and one or more of the preceding agents are also provided.

In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds, which are formulated for systemic administration, including parenteral, oral or intravenous administration, or for local or topical application for the treatment of diseases or disorders mediated by nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptor, or diseases or disorders in which the activity of nuclear receptors is involved, including the activity of the farnesoid X receptor and / or orphan nuclear receptors, which include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immune disorders, lipid disorders, obesity, conditions characterized by a function of the disturbed epidermal barrier, hyperlipidemia, cholestasis, peripheral obstructive disease, ischemic attack, conditions of disturbed differentiation or excessive proliferation of the epidermal or mucosal membrane, or cardiovascular disorders, are administered to an individual exhibiting the symptoms of these diseases or disorders. The amounts are effective to improve or eliminate one or more symptoms of the diseases or disorders.

Manufacturing articles are provided which contain packaging material, a compound or composition, or a pharmaceutically acceptable derivative thereof, provided herein, which is effective in enhancing the activity of nuclear receptors, including the farnesoid X receptor and / or nuclear receptors. orphans, or for the treatment, prevention or amelioration of one or more nuclear receptor symptoms, including diseases or disorders mediated by the farnesoid X receptor and / or the orphan nuclear receptor, or diseases or disorders in which the activity of the nuclear receptors, which includes the activity of the farnesoid receptor X and / or orphan nuclear receptors, within the packaging material, and a label indicating that the compound or composition, or the pharmaceutically acceptable derivative thereof, is used for modulate the activity of nuclear receptors, which includes the activity of the farnesoid receptor X and / or receptors orphan nuclear weapons, or for the treatment, prevention or amelioration of one or more symptoms of diseases or conditions mediated by nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, or diseases or disorders in which it is involved the activity of nuclear receptors, which includes the activity of the farnesoid X receptor and / or orphan nuclear receptors.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Effects of the Compounds on normolipidemic mice. Figure 1 shows plasma triglyceride levels in male C57BL6 mice treated with Compound A (Figure 1A) or with Compound B (Figure IB) daily by oral gavage at doses of 0.1 mg / kg / day (triangles filled), 1.0 mg / kg / day (inverted full triangles) or 10 mg / kg / day (diamonds) for seven days (n = 6 / group) compared to vehicle alone (full squares).

Figure 2: Effects of Compounds in LDLR ~ / _ Hyperlipidemic Mice Induced by a Diet Figure 2A shows plasma triglyceride levels in male LDRLL_ / ~ mice fed a "Western" diet (21% fat, 0.2% cholesterol p / p) without limit, for two weeks before and during treatment with Compound C daily by oral gavage at a dose of 10 mg / kg / day for 7 days (n = 9-10 / group) (full triangles ) compared to vehicle-treated controls (full squares). Figure 2B shows plasma cholesterol levels in the same mice treated with Compound C (filled triangles) compared to vehicle-treated controls (filled squares). Figure 3: Long-Term Effects of Compound C in LDLR_ / ~ Hyperlipidemic Mice Induced by Diet Figure 3A shows plasma triglyceride levels in LDLR_ mice "fed a" Western "diet (21% fat, 0.02% cholesterol p / p) without limit, for eight weeks before and during treatment with Compound B by oral gavage at a dose of 10 mg / kg / day for 6 weeks (n = 12-16 / group) compared to treated controls with vehicle (filled squares) Figure 3B shows plasma cholesterol levels in the same mice treated with Compound B (full triangles) compared to vehicle-treated controls (filled squares).

DETAILED DESCRIPTION OF THE INVENTION A. Definitions Unless defined otherwise, all technical or scientific terms used herein have the same definition as commonly understood by one skilled in the art to which this invention pertains. All patents, patent applications, publications of patent applications and other publications are hereby incorporated by reference in their entirety. In case there is a plurality of definitions for a term mentioned here, those that appear in this section will prevail unless otherwise stated.

As used here, a nuclear receptor is a member of a superfa ilia of regulatory proteins that are receptors of, for example, spheroids, retinoids, vitamin D and thyroid hormones. These proteins bind to elements that act cis on the promoters of their target genes and modulate the expression of the genes in response to a ligand for them. Nuclear receptors are classified based on the binding properties of DNA. For example, the glucocorticoid, estrogen, androgen, progestin and mineral corticosteroid receptors bind as homodimers to hormone response elements (HREs) organized as inverted repeats. Another example is the receptors, which include those activated by retinoic acid, thyroid hormone, vitamin D3, peroxisome proliferated / fatty acids and ecdysone, which bind to HRE as heterodimers with a common partner, the retinoid receptor X (RXR). The farnesoid X receptor is among the last receptors.

As used herein, an orphan nuclear receptor is a gene product that realizes the structural characteristics of a nuclear receptor that was identified without any prior knowledge of its association with a putative ligand and / or for which the natural ligand is ignored. According to this definition, orphan nuclear receptors include, but are not limited to, farnesoid X receptors, hepatic X receptors (LRX a and β), retinoid X receptor (RXR a, β and β), and peroxisome proliferator activating receptors ( PPAR a, ß and?) (See, Giguere, Endocrine Reviews (1999), Vol. 20, No. 5: pp. 689-725).

As used herein, farnesoid X receptor refers to all mammalian forms of that receptor that include, for example, alternative splice isoforms and natural isoforms (see, eg, Huber et al, Gene (2002), Vol. 290 , pp.:35-43). Representative species of farnesoid X receptors include, but are not limited to rat forms (GenBank Access No. NM_021745), mouse (Genbank Access No. NM_009108), and human (Access GenBank No. NM_005123) of the recipient.

As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. These derivatives can be readily prepared by those skilled in the art using known methods for that derivation. The compounds produced can be administered to animals or humans without substantial toxic effects and are pharmaceutical active or are prodrugs. The pharmaceutically active salts include, but are not limited to, amine salts, such as non-exhaustively, N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, W- benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-methylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts such as, but not limited to, lithium, potassium and sodium; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc; and other metal salts, such as in non-limiting form, sodium hydrogen phosphate and disodium phosphate; and which also include, but are not limited to, salts of mineral acids, such as non-exhaustively, hydrochlorides and sulfates; and organic acid salts such as non-exhaustive form, acetates, lactates, maleates, tartrates, citrates, ascorbates, succinates, butyrates, valerate and furates. Pharmaceutically acceptable esters include, but are not limited to alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl esters of acid groups including non-limiting carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, acids sulphonic and boronic acids. The pharmaceutically acceptable enol ethers include, but are not limited to, the derivatives of the formula C = C (OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. The pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula C = C (0C (0) R) wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. The pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent molecules or water, or from 1 to 100, or from 1 to 10, or from one to 2, 3 or 4, solvent or water molecules.

The derivation of drugs containing carbonyl, carboxylic, amines, amidines is known to one skilled in the art. "Pra ctice of Medi cinal Chemistry" by Camille Georges Wermuth, Second Ed. (2003); Shan, D., Nicolau, M., Buchardt, R., Wang, B., J. Pharm. Sci, 86 (7): 765-767 (1997); Prodrug strategies based on Intramolecular Cyclization Reaction; Prodrugs are converted to active drugs by metabolic transíormation. Different mechanisms of drug activation such as prodrugs attached to the carrier for various functional groups, bipartite prodrugs attached to the carrier, or tripartite drugs are disclosed in DeClerq, E. et al., Anitviral Drugs-development of successful prodrug strategies for antiviral chemotherapy, Bri t. J. Pharm. , 147: 1-11 (2006); Silverman, R., Organi c Chemi s try of Drug Design and Drug Act, 2nd ed.

The compounds of this invention having a group -OH, NH-, -SH or -COOH may have linked thereto a prodrug forming group which is removed by metabolic processes to release the compounds of this invention having the group - OH, -NH-, -SH or -COOH released m alive. Prodrugs are useful for adjusting pharmacokinetic properties of the compounds of the invention or salts thereof, such as solubility, hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and clearance rate. The experts in the art have the knowledge and the means to do it without undue experimentation. Different forms of prodrugs are well known in art. For examples of such prodrugs, see for example, a) Design of Prodrugs, Bundgaard, A. Ed., Elsevier, 1985 and Method in Enzymology, Widder, K. et al., Ed .; Acade ic, 1985, vol. 42, p. 309 396.

As used herein, "treatment" means any form in which one or more of the symptoms of a disease or disorder are improved or altered in a beneficial manner. The treatment also comprises all pharmaceutical uses of the compositions herein, such as use for treating a disease or disorder mediated by nuclear receptors, or diseases or disorders in which the activity of nuclear receptors is involved, which includes the activity of X farnesoid receptor or orphan nuclear receptors.

As used herein, the improvement of the symptoms of a disorder determined by the administration of a particular compound or composition refers to any decrease, whether permanent or temporary, lasting or transient that may be attributed or associated with the administration of the composition .

As used herein IC50 refers to an amount, concentration or dosage of a test compound determined to achieve a 50% inhibition of a maximal response, such as modulation of the activity of nuclear receptors, including farnesoid X receptor, in an essay that measures that response.

As used herein, EC50 refers to a dosage, concentration or amount of a given test compound having a dose-dependent response at 50% of the maximum response of a given response that is induced, evoked or potentiated with a compound of determined trial.

As used herein, a prodrug is a compound that, when administered in vivo, is metabolized by one or more steps or processes or is otherwise converted to a biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound is regenerated by metabolic processes. The prodrug can be designed to alter the metabolic stability or transport characteristics of a drug, to mask collateral effects or toxicity, improve the taste of a drug or alter other characteristics or properties of the drug. By virtue of the knowledge of pharmacodynamic processes and the in vivo metabolism of the drug, those skilled in the art, once the pharmaceutically active compound is known, can design prodrugs of the compound (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemi cal Approa ch, Oxford University Press, New York, pages 388-392).

The term "prodrugs" as the term is used herein, includes all covalently linked carriers that release an active parent prodrug of the present invention in vivo when that prodrug is administered to a patient. Since it is known that prodrugs improve numerous desirable qualities of pharmaceutical products (ie, solubility, bioavailability, manufacture, etc.) the compounds of the present invention can be administered in the form of drugs. Therefore, those skilled in the art will appreciate that the present invention comprises prodrugs of the compounds claimed herein, methods of administering them, and compositions that contain them. The prodrugs of the present invention are prepared by modifying functional groups present in the compound such that the modifications are broken, in routine manipulation or in vivo, to form the parent compound. The transformation in vivo can be, for example, as a result of some metabolic process, such as the chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or the reduction or oxidation of a susceptible functionality. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is attached to any group which, when the prodrug of the present invention is administered to a patient breaks down to form a free hydroxyl, free amino or sulfhydryl group free, respectively. Functional groups that can be rapidly transformed, by metabolic disruption, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. These include, but are not limited to, groups such as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl). - and triethylsilyl), monoethers formed with dicarboxylic acids (such as succinyl), and the like. Due to the ease with which the metabolically metabolizable groups of the compounds useful according to this invention are broken in vivo, the compounds carrying those compounds can act as prodrugs. Compounds that carry groups that can break metabolically have the advantage that they can exhibit improved bioavailability as a result of the improved solubility and / or absorption rate conferred to the parent compound by virtue of the presence of the metabolically metabolizable group. A thorough discussion of the prodrugs is given in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p. 309 396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; "Design and Applications of Prodrugs" p. 113 191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p. 1 38, 1992; Journal of Pharma ceuti cal Sciences, 77, p. 285, 1988; Chem. Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A. C. S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987; Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1 38. and are incorporated herein by reference.

When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is desired that the compounds include geometric isomers E and Z. Similarly, it is desired that all tautomeric forms be included. .

It should be understood that the compounds provided herein may contain chiral centers. Those chiral centers can have the (R) or (S) configuration, or they can be a mixture of them. Therefore, the compounds provided herein can be enantiomerically pure, or they can be stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, those residues may be of the L or D form. The configuration for natural amino acid residues is generally L. When the residue is not specified it is the L form. As used herein, the term "amino acid" refers to a-amino acids that are racemic, or of the D or L configuration. The designation "d" preceding an amino acid designation (e.g., dAla, dSer, dVal, etc.) refers to the isomer D of the amino acid. The designation "di" that precedes an amino acid designation (e.g., dlPip) refers to a mixture of the D and L isomers of the amino acid. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one skilled in the art will recognize that the administration of a compound in the form (R) is equivalent, for the compounds undergoing epimerization in vivo, to the administration of the compound in its (S) form.

Optically active (R) and (S) or (D) and (L), (+) and (-) isomers can be prepared using chiral reagents, or can be resolved using conventional techniques, such as inverted-phase HPLC. .

As used herein, substantially pure means sufficiently homogeneous to appear free of detectable impurities as determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and spectrometry of mass (MS), used by those skilled in the art to evaluate that purity, or sufficiently pure so that a new purification does not alter in a detectable way the physical and chemical properties, such as the enzymatic and biological activities, of the substance. Methods for purifying the compounds to produce substantially chemically pure compounds are known to those skilled in the art. A chemically substantially pure compound can, however, be a mixture of stereoisomers. In those cases, another purification would increase the specific activity of the compound.

As used herein, "alkyl", "alkenyl" and "alkynyl" are straight or branched hydrocarbon chains, and if unspecified, contain from 1 to 20 carbons or from 2 to 20 carbons, preferably from 1 to 16 carbons or from 2 to 16 carbons. Carbon chains of alkenyl having 2 to 20 carbons, in certain embodiments, contain from 1 to 8 double bonds and carbon chains of alkenyl having from 2 to 16 carbons, in certain embodiments, contain from 1 to 5 bonds double. The alkynyl carbon chains having from 2 to 20 carbons, in certain embodiments, contain from 1 to 8 triple bonds, and the alkynyl carbon chains having from 2 to 16 carbons, in certain embodiments contain from 1 to 5 bonds triples Examples of alkyl, alkenyl and alkynyl groups here include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tere-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, allyl (propenyl) and propargyl (propinyl). As used herein, lower alkyl, lower alkenyl, and lower alkynyl, refer to carbon chains having 1 or 2 carbons up to 6 carbons. As used herein, "alk (en) (in) yl" refers to an alkyl group containing at least one double bond and at least one triple bond.

As used herein, "alkylene" refers to a straight, branched or cyclic divalent aliphatic hydrocarbon group wherein the alkylene is attached to the remainder of the molecule through two different bonds in the alkylene. In one embodiment, the alkylene has from 1 to 20 carbon atoms, in another embodiment the alkylene has from 1 to 12 carbons. The term "lower alkylene" refers to alkylene groups having 1 to 6 carbons. In certain embodiments, the alkylene groups are lower alkylene, which include alkylene of 1 to 3 carbon atoms.

As used herein, "alkylidene" refers to a divalent group, such as = CRpRq, wherein the alkylidene is attached to an atom of another group through the same carbon in the alkylidene, forming a double bond. The alkylidene groups include, but are not limited to, methylidene (= CH2) and ethylidene (= CHCH3). The alkylidenes can be optionally substituted with halo, cyano, nitro, haloalkyl or pseudohalo substituents. As used herein, "arylalkylidene" refers to an alkylidene group in which Rp or Rq is an aryl group; "heteroaralkylidene" refers to an alkylidene group in which Rp or Rq is a heteroaryl group; "cycloalkylidene" refers to an alkylidene group wherein R p and R q, together with the carbon to which they are attached, form a cycloalkyl group, or wherein at least one of R p and R q is a cycloalkyl ring; and "heterocyclicidene" refers to an alkylidene group wherein Rp and Rq, together with the carbon to which they are attached, form a heterocyclyl group, or wherein at least one of Rp and Rq is a heterocyclyl ring.

As used herein, "amidino" refers to a radical having the formula -C (= NRm) N (Rn) R ° where Rm, Rn and R ° are each independently hydrogen or alkyl.

As used herein, "aralkyl" refers to a radical of the formula -RaRd where Ra is an alkyl radical as defined above, substituted by Rd, an aryl radical, defined herein, for example, benzyl. The alkyl and aryl radicals may be optionally substituted as described herein.

As used herein, "aryl" refers to a monocyclic or multicyclic aromatic ring system containing from 6 to 19 carbon atoms, where the ring system may be partially or fully saturated. Aryl groups include, but are not limited to, groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl.

As used herein, "cycloalkyl" refers to a saturated mono or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments 3 to 6 carbon atoms, cycloalkenyl and cycloalkynyl refer to systems of mono- or multicyclic ring, which respectively include at least one double bond and at least one triple bond. Cycloalkenylol and cycloalkynyl groups can, in certain embodiments, contain from 3 to 10 carbon atoms, cycloalkenyl groups, in other embodiments, contain from 4 to 7 carbon atoms and cycloalkynyl groups, in other embodiments, contain from 8 to 10. carbon atoms. The ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups can be composed of one ring or two or more rings that can be joined together in fused, bridged or spiro form. "Cycloalk (en) (in) yl" refers to a cycloalkyl group containing at least one double bond and at least one triple bond.

As used herein, "cycloalkylalkyl" refers to a radical of the formula -RaRb where Ra is an alkyl radical defined above and Rb is a cycloalkyl radical defined above. The alkyl radical and the cycloalkyl radical can be optionally substituted as defined above.

As used herein, "guanidino" refers to a radical having the formula -N (Rp) C (= NRq) NRrRs wherein Rp, Rq, Rr and Rs are each independently hydrogen or alkyl.

As used herein, "heteroaralkyl" refers to a radical of the formula -RaRe where Ra is an alkyl radical defined above and Re is a heteroaryl radical defined herein. The alkyl radical and the heteroaryl radical may be optionally substituted as defined herein.

As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic heterocyclyl, as defined herein, in certain embodiments, from 5 to 15 members where one or more, in one embodiment, from 1 to 3, of the The ring system is a heteroatom, that is, a different element of carbon, which includes, but is not limited to, nitrogen, oxygen or sulfur. The heteroaryl group can be optionally fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl.

As used herein, a "heteroaryl" group is a heteroaryl group that has a positive charge on one or more of the heteroatoms.

As used herein, "hetarocyclyl" refers to a ring radical of 3 to 18 members comprising carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of the present invention, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, oxygen or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom may optionally be quaternized; and the ring radical can be aromatic or partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzolyl, benzothiadiazolyl, benzonaphtofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl, benzotriazolyl, benzo [4,6]. ] imidazo [1,2- a] pyridinyl; carbazolyl, cinnolinyl, dioxolanyl, dibenzofuranyl, decahydroisoquinolyl, furanyl, furanonyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, triazinyl, tetrahydropyranyl, thiophenyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone.

As used herein, "heterocyclylalkyl" refers to a radical of the formula -RaRc where Ra is an alkyl radical defined above or Rc is a heterocyclyl radical defined above. The alkyl radical and the heterocyclyl radical can be optionally substituted as defined herein.

As used herein, "aralkyl" refers to a radical of the formula -RaRc where Ra is an alkyl group radical defined herein and Rc is an aryl radical defined herein. The alkyl radical and the aryl radical can optionally be substituted as defined herein.

As used herein, "halo", "halogen" or "halide" refers to F, Cl, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups that behave in a manner substantially similar to halides. These compounds can be used in the same way and treated in the same way as halides. The pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy and azide.

As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. These groups include, but are not limited to, chloromethyl, trifluoromethyl, and l-chloro-2-fluoroethyl.

As used herein, "hydrazone" refers to a divalent group such as a = NNRfc which is attached to a carbon atom of another group, forming a double bond, wherein Rfc is hydrogen or alkyl.

As used herein, "imino" refers to a group such as = NR, which is attached to a carbon atom of another group, forming a double bond, wherein R is hydrogen or alkyl.

"Optionally substituted alkyl" "optionally substituted alkenyl" and "optionally substituted alkynyl" refer to alkyl radicals, alkenyl radicals and alkynyl radicals, defined herein, respectively, which may be optionally substituted by one or more substituents independently selected from the group formed by nitro, halo, azido, cyano, cycloalkyl, heteroaryl, heterocyclyl, -ORx, -N (Ry) (Rz), -SRx, -C (J) Rx, -C (J) ORx, -C (J) N (Ry) (Rz), -C (J) SRx, -S (0) tRx (where t is 1 or 2), -OC (J) Rx, -OC (J) ORx, -OC (J) N (Ry) (Rz), -OC (J) SRx, -N (Rx) C (J) Rx, -N (Rx) C (J) ORx, -N (Rx) C (J) N (Ry) ( Rz), -N (Rx) C (J) SRx, -Si (Rw) 3, -N (Rx) S (O) 2Rw, -N (Rx) S (O) 2N (Ry) (Rz), - S (O) 2N (Ry) (Rz), -N (Rx) C (J) Rx, -P (0) (Rv) 2, -0P (0) (Rv) 2, -C (J) N ( Rx) S (0) 2Rx, -C (J) N (Rx) N (Rx) S (O) 2Rx, -C (Rx) = N (ORx), and -C (Rx) = NN (Ry) ( Rz), wherein each Rx is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; each Rw is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each Rv is independently alkyl, alkenyl, alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, -ORx or -N (Ry) (Rz); and each J is independently O, NRx or S.

"Optionally substituted aryl", "optionally substituted aralkyl", "optionally substituted cycloalkyl", "optionally substituted cycloalkylalkyl", "optionally substituted heteroaryl", "optionally substituted heteroaralkyl", "optionally substituted heterocyclyl" and "hetaocyclylalkyl-substituted alkyl" refer to aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, hetaroaryl and heteroaralkyl radicals, respectively, defined herein, which are optionally substituted by one or more substituents selected from the group consisting of nitro, halo, azido, cyano, alkyl, haloalkyl, alkenyl , alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -Ru-ORx, -Ru-N (Ry) (Rz), -Ru-SRx, -Ru-C (J) Rx, - Ru-C (J) 0Rx, -Ru-C (J) N (Ry) (Rz), -Ru-C (J) SRx, -Ru-S (0) tRx (dondoe t is 1 or 2), - Ru-0C (J) Rx, -Ru-OC (J) ORx, -Ru-OC (J) N (Ry) (Rz), -Ru-OC (J) SR x, -Ru-N (Rx) C (J) Rx, -Ru-N (Rx) C (J) ORx, -Ru-N (Rx) C (J) N (Ry) (Rz), -Ru N (Rx) C (J) SRx, -Ru-Si (Rw) 3, -Ru-N (Rx) S (O) 2Rw, -Ru-N (Rx) S (O) 2N (Ry) (Rz) , -Ru-S (O) 2N (Ry) (Rz), -Ru -N (Rx) C (J) Rx, -Ru-P (O) (Rv) 2, -Ru-OP (O) (Rv) ) 2, -Ru-C (J) N (Rx) S (0) 2Rx, -Ru-C (J) N (Rx) N (Rx) S (O) 2Rx, -Ru-C (Rx) = N (ORx), and -Ru-C (Rx) = NN (Ry) (Rz), wherein each Ru is independently alkylene or a direct bond; each Rv is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, -ORx or -N (Ry) (Rz); each Rw is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aplo, aralkyl, heteroaryl, or heteroaralkyl; each Rx is independently hydrogen, alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; and each J is O, NRx or S.

Unless specifically stated otherwise in the specification, it is understood that substitution may occur on any atom of the aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl groups.

Optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl may be optionally substituted with oxo, thioxo, imam, oxime or hydrazone, or a saturated carbon of their respective ring system.

As used herein, "oxime" refers to a divalent group such as = N-OH, which is attached to a carbon atom of another group, which forms a double bond.

As used herein, "oxo" refers to an oxygen atom with a double bond to a carbon.

As used herein, pseudohalides or pseudohalo groups are groups that behave in a manner substantially similar to halides. These compounds can be used in the same way and treated in the same way as halides. The pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, and azide.

As used herein, "thioxo" refers to a sulfur atom bonded with a double bond to a carbon.

When the number of any given substituent is not specified (eg, haloalkyl), there may be one or more substituents present. For example, a "haloalkyl" may include one or more of the same or different halogens. As another example, "Cl-3alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three carbons.

As used herein, abbreviations for all protecting groups, amino acids and other compounds, are, unless otherwise indicated, in accordance with their use, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see , 1972) Biochem. 11: 942-944).

If they are used here, the following terms have their accepted definition in the chemical bibliography: AcOH: DCI acetic acid: carbodiimide CHC13 chloroform Conc concentrated DBU 1, 8-diazbicyclo [5.4] undec-7-ene DCM dichloromethane DDQ 2, 3-dichloro-5,6-dicyano-l, -benzoquinone DIEA diisopropyl ethylamine DMAP 4 - (dimethylamino) pyridine DME 1, 2-dimethoxyethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide ELSO evaporative light diffusing detector EtOAc ethyl acetate EtOH ethanol (100%) Et20 diethyl ether HBTU 1-H-benzotriazolium 1- [bis (dimethylamino) methylene] -hexafluorophosphate (1-), 3-oxide 0- (benzotriazol-1-yl) -N, N, N ', N' tetramethyluronium hexafluorophosphate Hex hexane H2S04 sulfuric acid LDA lithium di (iso -propyl ) amide MeCN actonitrile MeOH methanol NaBH3CN sodium cyanoborohydride PdC palladium on activated carbon TEA triethylamine THF tetrahydrofuran TFA trifluoroacetic acid B. Formulation of pharmaceutical compositions The pharmaceutical compositions provided herein contain therapeutically effective amounts of modulators of nuclear receptor activity provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated with activity of the receptors. nuclear receptors, which include the farnesoid X receptor and / or the orphan nuclear receptors.

These diseases or disorders include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerotic disease events, gallstone disease, acne vulgaris, acneiform skin conditions, type II diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a disturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral obstructive disease, ischemic attack, conditions of disturbed differentiation or excessive proliferation of the epidermal or mucosal membrane, and cardiovascular disorders.

In addition the pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the modulators of nuclear receptor activity provided herein that are useful in the prevention, treatment and amelioration of one or more of the symptoms of diseases or disorders that they are not directly associated with nuclear receptors, but for which a complication of the disease or disorder can be treated with the claimed compounds and compositions. By way of example, in non-exhaustive form, Cystic Fibrosis is not generally associated with the activity of a nuclear receptor, but can result in cholestasis, which can be treated with the present compounds and compositions.

The compositions contain one or more compounds provided herein. The compounds are preferably formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, lozenges, capsules, powders, sustained-release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as the preparation of transdermal patches and dry powder inhalers. Generally the compounds described above are formulated in pharmaceutical compositions using techniques and procedures known in the art (see, for example, Ansel In troduction to Pharma ceuti ca l Dosage Forms, Fourth Edi tion 1985, 126).

In the compositions, effective concentrations of one or more pharmaceutically acceptable compounds or derivatives are mixed with a suitable carrier or pharmaceutical carrier. The compounds can then be obtained as the salts, esters, enol ethers or esters, acids, bases, solvates, hydrates or corresponding prodrugs before the formulation, as described above. The concentrations of the compounds in the compositions are effective for the delivery of an amount, after administration, which treats, prevents or ameliorates one or more of the symptoms of diseases or disorders associated with the activity of the nuclear receptors or in which the activity of nuclear receptors is involved. These diseases or disorders include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerotic disease events, gallstone disease, acne vulgaris, acneiform skin conditions, type II diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immune disorders, lipid disorders, obesity, conditions characterized by disturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral obstructive disease, ischemic attack, conditions of disturbed differentiation or excessive membrane proliferation epidermal or mucosal and cardiovascular disorders.

Generally, the compositions are formulated for a single-dose administration. To formulate a composition, the fraction of the weight of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is alleviated or improved. Suitable carriers or pharmaceutical carriers for the administration of the compounds provided herein include any such carriers known to those skilled in the art or that are suitable for the specific administration form.

In addition, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. Liposomal suspensions, which include liposomes with white tissue, such as liposomes with a white tumor, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multimeric vesicles (MLV) can be formed by drying egg phosphatidyl choline and cerebral phosphatidyl serine (molar ratio 7: 3) from the inside of a flask. A solution of a compound provided herein is added in saline with phosphate buffer having no divalent cations (PBS) and the flask is stirred until the lipid film is dispersed. The resulting vesicles are washed to remove the unencapsulated compound, pellets are formed by centrifugation, and then resuspended in PBS.

The active compound is incubated in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the treated patient. The therapeutically effective concentration can be determined empirically by testing the compounds in in vitro and in vivo systems described herein and International Patent Application Publication Nos. 99/217365 and 00/25134 and then extrapolated therefrom for human dosages.

The concentrations of the active compound in the pharmaceutical composition depend on the rates of absorption, inactivation and excretion of the active compound, the physiological characteristics of the compound, the dosage schedule, and the amount administered as well as other factors known to those skilled in the art. For example, the amount that is supplied is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with the activity of nuclear receptors or in which the activity of nuclear receptors is involved, as described herein.

Generally, a therapeutically effective dosage should produce a serum concentration of the active ingredient of 10.1 ng / ml at 50-100 μg / ml. The pharmaceutical compositions should generally provide a dosage of 0.001 mg to 2000 mg of the compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from 1 mg to 1000 mg and preferably from 10 to 500 mg of the essential active ingredient or a combination of essential active ingredients per unit dosage form.

The active ingredient can be administered at one time, or it can be divided into numerous smaller doses that must be administered at time intervals. It is understood that the precise dosage and duration of treatment are a function of the disease being treated and can be determined empirically using known assay protocols or by extrapolation from the in vivo or in vitro assay data. It should be noted that the concentrations and dosage values may also vary with the severity of the condition that must be alleviated. It should also be understood that for any particular subject, the specific dosage regimens should be adjusted over time according to the individual need and according to the professional judgment of the person administering or supervising the administration of the compositions, and that the ranges of The concentration discussed here are only examples and it is not desired to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include forms of acids, bases, ethers and esters of enol, salts, esters, hydrates, solvates and prodrugs. The derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.

Therefore, effective concentrations and amounts of one or more of the compounds described herein or the pharmaceutically acceptable derivatives thereof are mixed with a carrier or pharmaceutical carrier suitable for systemic, topical or local administration for pharmaceutical compositions. The compounds are included in an amount effective to ameliorate one or more symptoms or to treat or prevent diseases or disorders associated with the activity of nuclear receptors or in which the activity of nuclear receptors is involved, as described herein. The concentration of the active compound in the composition depends on the rates of absorption, inactivation, excretion of the active compound, the dosage schedule, the amount administered, the particular formulation as well as other factors known to those skilled in the art.

The compositions are to be administered by any route, including oral, parenteral, rectal, topical and local. For oral administration, capsules and tablets are currently preferred. The compositions are in liquid, semi-liquid or solid form and are formulated in a form suitable for each administration route. Preferred administration forms include parenteral and oral administration forms. Oral administration is currently the most preferred.

Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application can include any of the following components: a sterile diluent, such as water for injection, saline, fixed oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediamine tetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of toxicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, disposable syringes or single or multi-dose ampoules made of glass, plastic or other suitable material.

In cases where the compounds exhibit insufficient solubility, methods for solubilizing compounds can be used. These methods are known to those skilled in the art and include, but are not limited to, using cosolvents, such as dimethyl sulfoxide (DMSO), using surfactants, such as TWEEN® or aqueous sodium bicarbonate solution. Derivatives of the compounds, such as prodrugs of the compounds in the formulation of effective pharmaceutical compositions can also be used.

When mixing or adding the compound (s), the resulting mixture can be a solution, suspension, emulsion or the like. The shape of the resulting mixture depends on numerous factors, including the desired form of administration and the solubility of the compound in the carrier or vehicle selected. The effective concentration is sufficient to improve the symptoms of the disease, disorder or condition treated and can be determined empirically.

The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, lozenges, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil and water emulsions containing suitable amounts of the compounds or pharmaceutically acceptable derivatives thereof. Pharmaceutically and therapeutically active compounds and derivatives thereof are generally formulated and administered in unit dosage forms or in forms of various dosages. The unit dosage forms as used herein refer to physically discrete units suitable for humans or animals and individually packaged as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the carrier, vehicle or pharmaceutical diluent required. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets or capsules. Unit dosage forms can be administered in fractions or several of them. One form of several doses is a plurality of identical unit dosage forms packaged in a single container to be administered in a segregated unit dosage form.

Examples of multi-dose forms include ampoules, tablet vials or capsules or pints or gallons. Therefore, the form of several doses is a multiplicity of unit doses that do not segregate when packaged.

The composition may contain together with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as acacia gelatin gum, glucose, molasses, polyvinylpyrrolidone, celluloses and derivatives thereof, povidone, crospovidones and other binders known to those skilled in the art. Liquid compositions that can be administered pharmaceutically can, for example, prepared by dissolving, dispersing or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, eg, acetate, sodium citrate, derivatives of cyclodextrin, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents. The actual methods of preparing such dosage forms are known, or will be apparent to those skilled in the art.; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. , 15th Edition, 1975. The composition or formulation to be administered in any case contains an amount of the active compound in an amount sufficient to alleviate the symptoms of the subject treated.

Dosage forms or compositions containing the active ingredient in the range of 0.005% to 100% and the non-toxic carrier compound residue can be prepared. For oral administration, a non-toxic pharmaceutically acceptable composition is formed by the incorporation of any of the excipients that are normally employed, such as, for example, pharmaceutical levels of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate or sodium saccharin. These compositions include solutions, suspensions, tablets, capsules, powders and sustained-release formulations, such as non-exhaustively, implants and microencapsulated delivery systems and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, poly-hydrides, polyglycolic acid , polyorthoesters, polylactic acid and others. Methods for the preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001% -100% of ingredient, preferably 0.1% -85%, generally 75% -95%.

The active compounds or pharmaceutically acceptable derivatives thereof can be prepared with carriers that protect the compound against rapid elimination from the body, such as formulations or release coatings over time. The compositions may include other active compounds to obtain combinations of desired properties. The compounds provided herein, or the pharmaceutically acceptable derivatives thereof which are described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent which is known in the art in general to be of value in the treatment of one or more of the diseases or disorders mentioned above, such as diseases or disorders associated with the activity of nuclear receptors or in which the activity of nuclear receptors is involved. It should be understood that such combination therapy constitutes another aspect of the compositions and methods of treatment provided herein.

Compositions for oral administration Oral pharmaceutical dosage forms are solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulky powders. Types of oral tablets include capsules and compressed chewable tablets that may have an enteric coating, sugar coating or film coating. The capsules may be hard or soft gelatin, while the granules and powders may be provided in a non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. In certain embodiments, the formulations are solid dosage forms, preferably, capsules or tablets. Tablets, pills, capsules, chips and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, a diluent, or a disintegrating agent, a lubricant, a glidant, a sweetening agent and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorant agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof.; and water insoluble FD and C dyes suspended in hydrated alumina. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any amount of spray-dried flavors. Flavoring agents include natural plant flavorings such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laural ether. Emetic coatings include fatty acids, fats, waxes, varnish, varnish with ammonia and cellulose acetate phthalates. Film coatings include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound can be provided in a composition that protects it from the acid medium of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

When the unit dosage form is a capsule, it may contain, in addition to the material of the preceding type, a liquid carrier such as a fatty oil. In addition, the unit dosage forms may contain other different materials that modify the physical form of the dosage unit, for example, sugar coatings and other enteric agents. The compounds may also be administered as a component of an elixir, suspension, syrup, wafer, spray, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and sabotards.

The active materials can also be mixed with other active materials that do not prevent the desired action, or with materials that complement the desired action, such as antacids, H2 blockers and diuretics. The active ingredient is a compound or a pharmaceutically acceptable derivative thereof which is described herein. Higher concentrations, up to 98% by weight of the active ingredient may be included.

The pharmaceutically acceptable carriers included in the tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric-coated tablets, due to the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. The sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances were applied. The film coated tablets are compressed tablets that have been coated with a polymer or other suitable coating. Several compressed tablets are compressed tablets made by more than one compression cycle using the pharmaceutically acceptable substances mentioned above. Colorants can also be used in the preceding dosage forms. Flavoring and sweetening agents are used in compressed tablets, compressed tablets and multiple chews coated with sugar. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and capsules.

Oral liquid dosage forms include solutions, emulsions, aqueous suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are oil-in-water or water-in-oil emulsions.

The elixirs are transparent, sweetened, hydroalcoholic preparations. The pharmaceutically acceptable carriers used in the elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose and may contain a preservative. An emulsion is a two-phase system in which a liquid is dispersed in the form of small globules in every other liquid. The pharmaceutically acceptable carriers used in emulsions are non-aqueous liquid emulsifying agents and preservatives. Suspensions are pharmaceutically acceptable suspending agents and preservatives. The pharmaceutically acceptable substances used in non-effervescent granules, which are reconstituted in a liquid oral dosage form, include diluents, sweeteners and wetting agents. The pharmaceutically acceptable substances used in effervescent granules, which are reconstituted in a liquid oral dosage form, include organic salts and a source of carbon dioxide. The coloring and flavoring agents are used in all of the preceding dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene monooleate sorbitan. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Ve gum and acacia. The diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin, artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laupl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. The colorant agents include any of the approved certified water soluble FD and C coloers, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste sensation.

For the solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Those solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, for example, in polyethylene glycol, can be diluted with a sufficient amount of the pharmaceutically acceptable carrier, eg, water, to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (eg, propylene carbonate) and other carriers, and encapsulating these solutions or suspensions in capsules. of hard or soft gelatin. Other useful formulations include those set forth in U.S. Patent Nos. Re 28,819 and 4,358,603. In summary, these formulations include, but are not limited to, those containing a compound provided herein, a mono or dialkylated polyalkylene glycol, including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglim, polyethylene glycol-350- dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol and one or more antioxidants, such as butylated hydroxytoluene (BHT), hydroxyanisole butylated (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, melic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholic solutions that include a pharmaceutically acceptable acetal. The alcohols used in these formulations may be any pharmaceutically acceptable water-miscible solvent having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acétals include, but are not limited to, acetals of di (lower alkyl) of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

In all embodiments, the tablet and capsule formulations can be coated as known to those skilled in the art to modify or sustain the dissolution of the active ingredient. Thus, for example, they can be coated with a conventional enterically digestible coating, such as phenyl salicylate, waxes and cellulose acetate phthalate.

Injectables, solutions and emulsions Parenteral administration, generally characterized by injection, subcutaneous, intramuscular or intravenous is also contemplated here. Injectables can be prepared in a conventional manner, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

The implantation of a slow release or sustained release system, such that the dosage level is maintained (see, for example, US Patent No. 3,710,795) is also contemplated herein. In summary, a compound provided herein is dispersed in a solid inner matrix, for example, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene copolymers vinyl acetate, silicone gums, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as acrylic and methacrylic acid hydrogels, collagen, cross-linked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate, which is surrounded by an outer polymeric membrane, for example polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone gums, polydimethyl siloxanes, neoprene gum, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin gum, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer, which is insoluble in body fluids. The compound diffuses throughout the polymer membrane in a step of controlling the rate of release. The percentage of the active compound contained in these parenteral compositions depends very much on its specific nature, as well as on the activity of the compound and the needs of the subject.

Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile ready-for-injection solutions, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent immediately before use, including hypodermic tablets, sterile suspensions ready for injection, soluble products dry sterile ready to be combined with a vehicle immediately before use and sterile emulsions. The solutions can be aqueous or non-aqueous.

If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Ringers Dextrose and Lacteal Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations should be added to parenteral preparations pacin multi-dose containers that include phenols or cresols, mercurials, vencilic alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and sodium chloride. benzethonium Isotonic agents include sodium chloride and dextrose. The buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A metal ion chelating or sequestering agent includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for vehicles miscible with water and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted such that the injection provides an effective amount to produce the desired pharmacological effect, the exact dose depends on the age, weight and condition of the patient or animal as is known in the art. Parenteral unit dose preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective form of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

Injectables are designed for local and systemic administration. Generally, a therapeutically effective dosage is formulated to contain a concentration of at least 0.1% w / w at 90% w / w or more, preferably more than 1% of the active compound to the treated tissue (s). The active ingredient can be administered all at once, or it can be divided into numerous smaller doses that are administered at time intervals. It is understood that the precise dosage and duration of treatment are a function of the tissue being treated and can be determined empirically using known assay protocols or by extrapolation from in vivo or in vitro assay data. It should be noted that the concentrations and dosage values may also vary with the age of the individual being treated. It should be further understood that for any particular subject, the specific dosage regimens should be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the formulations, and that the ranges of concentration set forth herein are only examples and do not limit the scope or practice of the claimed formulations.

The compound can be suspended in a micronized or other suitable form or it can be derivatized to produce a more soluble active product or to produce a prodrug. The shape of the resulting mixture depends on numerous factors, including the desired form of administration and the solubility of the compound in the carrier or vehicle selected. The effective concentration is sufficient to improve the symptoms of the condition and can be determined empirically.

Freeze-dried powders Freeze-dried powders are also of interest here, and can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels. The sterile lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient that improves the stability or other pharmacological component of the reconstituted powder or solution prepared from the powder. The excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or any other such buffer known to those skilled in the art, generally at neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those skilled in the art provides the desired formulations. Generally, the resulting solution is divided into portions in ampoules for lyophilization. Each ampoule contains a single dosage (10-1000 mg, preferably 100-500 mg) or several dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as from 4 ° C to room temperature.

Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, 1-50 mg, preferably 5-35 mg, more preferably 9-30 mg of the lyophilized powder per mL of sterile water or other suitable carrier is added. The precise amount depends on the selected compound. That amount can be determined empirically.

Topical administration Topical mixtures are prepared as described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion or the like and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, dyes, pastes, foams, sprays, irrigations, sprays, suppositories, bandages, patches dermal or any other formulation suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof can be formulated as aerosols for topical application, such as by inhalation (see, for example, US Patent Nos. 4,044,126, 4,414,111,209 and 4,364,923, which describe aerosols for administration of a spheroid useful for the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract may be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In that case, the particles of the formulation generally have diameters less than 50 microns, preferably less than 10 microns.

The compounds can be formulated for local or topical application, for example for topical application to the skin or mucosal membranes, for example, in the eye, in the form of gels, creams and lotions and for application to the eye or for the intracisternal or intraspinal application. Topical administration is contemplated for transdermal administration and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound can also be administered alone or in combination with other pharmaceutically acceptable excipients.

These solutions, particularly those intended for ophthalmic use, can be formulated as isotonic solutions at 0.01% -10%, at a pH of 5-7, with appropriate salts.

Compositions for other administration routes Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein.

Transdermal patches, including iotrophoretic and electrophoretic devices, are known to those skilled in the art. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433, and 5,860,957.

The pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for the systemic effect. Rectal suppositories are used herein to mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. The pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents for raising the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbocera (polyoxyethylene glycol) and appropriate mixtures of mono, di and triglycerides of fatty acids. You can use combinations of different bases. Agents for raising the melting point of suppositories include whale sperm and wax. Rectal suppositories can be prepared by the compression or molding method. The typical weight of a rectal suppository is 2 to 3 grams.

The tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for the formulations for oral administration.

Formulations with white The compounds provided herein, or the pharmaceutically acceptable derivatives thereof, may be formulated to target a tissue, receptor or other specific area of the body of the subject to be treated. Many methods of white are known to those skilled in the art. All of these target methods are contemplated herein for use in the present compositions. For non-exhaustive examples of target methods, see, for example, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071. 495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

In one embodiment, liposome suspensions, including liposomes with tissue targets, such as liposomes with tumor targets, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. In summary, liposomes such as multimeric vesicles (MLV) can be formed by drying phosphatidyl choline from egg and cerebral phosphatidyl serine (molar ratio of 7: 3) inside a flask. A solution of the compound provided herein is added in saline with phosphate buffer having no divalent cations (PBS) and the flask is stirred until the lipid film is dispersed. The resulting vesicles are washed to remove the unencapsulated compound, pellets are formed by centrifugation, and then resuspended in PBS.

Manufacturing articles The pharmaceutically acceptable compounds or derivatives can be packaged as articles of manufacture containing a packaging material, a compound or a pharmaceutically acceptable derivative thereof provided herein, which is effective for modulating the activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, or for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders mediated by the nuclear receptor, which includes the farnesoid receptor X and / or the orphan nuclear receptor, or diseases or disorders in the which is involved in the activity of the nuclear receptor, which includes the farnesoid X receptor and / or the orphan nuclear receptor, within the packaging material, and a label indicating that the compound or composition, or the pharmaceutically acceptable derivative thereof, is used to modulate the activity of nuclear receptors, including the farnesoid X receptor and / or orphan nuclear receptors, or for treatment, the prevention or improvement of one or more symptoms of diseases or disorders mediated by the nuclear receptor, which includes the farnesoid X receptor and / or the orphan nuclear receptor, or diseases or disorders in which the activity of the nuclear receptors is involved, which include the farnesoid X receptor and / or the orphan nuclear receptor.

The articles of manufacture provided here contain packaging materials. Packaging materials for use in pharmaceutical packaging products are known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, ampoules, containers, syringes, bottles, and any other suitable packaging material for a selected formulation and a form of desired administration and treatment. Herein is contemplated a broad group of formulations of the compounds and compositions provided herein as well as a variety of treatments for any disease or disorder in which the activity of the nuclear receptors is involved, which includes the activity of the farnesoid receptor X and / or the Orphan nuclear receptor, as a modulator or contributor to symptoms causes it.

C. Evaluation of the activity of the compounds.

Standard physiological, pharmacological and biochemical procedures are available to test the compounds to identify those that possess biological activities that modulate the activity of nuclear receptors, including farnesoid X receptor and / or orphan nuclear receptors. Such assays include, for example, biochemical assays such as binding assays, fluorescence polarization assays, FRET-based coactivator recruitment assays (see generally Glickman et al., J. Biomolecular Screening, 1 No. 1 3-10 (2002)), as well as cell-based assays that include the co-transfection assay, the use of LBD-Gal 4 chimeras, and protein-protein interaction assays (see Lehmann, et al., J. Biol Chem. , 272 (6) 3137-3140 (1997).

High performance detection systems are commercially available (see, for example, Zymark Corp., Hopkinton, MA, Air Technical Industries, Mentor, OH, Beckman Instruments Inc., Fullerton, CA, Precision Systems, Inc., Natick, MA). that allow these tests to be performed in a high performance mode. These systems generally automate complete procedures, which include pipetting all samples and reagents, timed liquid discharge incubations, and final readings of the microplate at the appropriate detector (s) for the assay. These configurable systems provide high performance and fast startup as well as a high level of flexibility and customization. The manufacturers of these systems provide detailed protocols for different high performance systems. Thus, for example, Zymark Corp. provides technical bulletins describing detection systems for detecting the modulation of gene transcription, ligand binding, and the like.

Assays that do not require liquid washing or separation steps are preferred for such high throughput detection systems and include biochemical assays such as fluorescence polarization assays (see, eg, Owicki, J., Biomol Screen 2000 Oct; (5): 297), scintillation proximity assays (SPA) (see, eg, Carpenter et al., Methods Mol Biol 2002; 190: 31-49) and fluorescence resonance energy transfer (FRET) or assays of recruitment of FRET-based coactivators resolved over time (Mukherjee et al., J Steroid Biochem Mol Bi ol 2002 Jul; 81 (3): 217-25; (Zhou et al., Mol Endocrinol. 1998 Oct; 12 (10 ): 1594-604.) Generally, such assays can be performed using the full length receptor, or the isolated ligand binding domain (LBD). In the case of the farnesoid X receptor, the LBD comprises amino acids 244 to 472 of the full length sequence.

If the labeled ligand in fluorescent form is available, fluorescence polarization assays provide a way to detect binding of the compounds to the nuclear receptor of interest by measuring changes in fluorescence polarization that occur as a result of the displacement of a number of traces of the fluorescence. Ligand of the label for the compound. In addition this approach can also be used to monitor the ligand-dependent association of a coactivator peptide labeled fluorescently to the nuclear receptor of interest to detect the ligand that binds to the nuclear receptor of interest.

The ability of a compound to bind to a receptor, or complex of heterodimers with RXR, can also be measured in a homogeneous assay format by evaluating the level at which the compound can interact with a radiolabelled ligand with a known affinity to the receptor using an assay proximity of scintillation (SPA). In this approach, the radioactivity emitted by a radio-labeled compound generates an optical signal when it is closely approached to a scintillation apparatus, for example an account containing Ysi-copper, to which the nuclear receptor is attached. If the radio-labeled compound is displaced from the nuclear receptor the amount of light emitted from the nuclear receptor bound to the scintillation apparatus decreases, and this can be detected rapidly using standard liquid-crystal plate scintillation plate readers such as, for example, a reader Wallac MicroBeta.

Heterodimerization of the X-farnesoid receptor with RXRa can also be measured by fluorescence resonance energy transfer (FRET) or time-resolved FRET, to monitor the ability of the compounds provided herein to bind to the farnesoid X receptor or other nuclear receptors. Both approaches depend on the fact that the transfer of energy from a donor molecule to a receptor molecule occurs only when the donor and the receptor are closely together. Generally the LBD purified from the nuclear receptor of interest is labeled with biotin and then mixed with stoichiometric amounts of europium-labeled streptavidin (Wallac Inc.) and the purified RXRa LBD is labeled with a suitable fluorophore such as CY5®. Equimolar amounts of each modified LBD are mixed together and allowed to equilibrate for at least 1 hour before adding variable or constant concentrations of the sample for which affinity should be determined. After equilibration, the fluorescent signal resolved with time was quantified using a fluorescent plate reader. The affinity of the compound can then be estimated from a graph of fluorescence against concentration of the aggregate compound.

This approach can also be exploited to measure the ligand-dependent interaction of a coactivator peptide with a nuclear receptor to characterize the activity of the agonist or antagonist of the compounds disclosed herein. Generally, the assay in this case consists of using a binding domain fusion protein (LBD) of nuclear receptor ligand of Glutathione-S-transferase (GST) and a synthetic biotinylated peptide sequence derived from the receptor interaction domain of a coactivator peptide such as the spheroid 1 receptor coactivator (SRC-1). Generally, GST-LBD is labeled with a europium (donor) chelate through an anti-GST antibody labeled with europium, and the coactivator peptide is labeled with allophycocyanin via a streptavidin-biotin binding.

In the presence of an antagonist for the nuclear receptor, the peptide is recruited for the GST-LBD that closely approaches the europium and allophycocyanin to allow the transfer of energy from the europium chelate to the allophycocyanin. Upon excitation of the complex with light at 340 nm of excitation, the energy absorbed by the europium chelate is transmitted to the allophicocyanin group which results in the emission at 665 nm. If the europium chelate is not close to the allophycocyanin group there is little or no energy transfer and the excitation of the europium chelate results in the emission at 615 nm. Therefore, the intensity of the light emitted at 665 nm gives an indication of the resistance of the protein-protein interaction. The activity of a nuclear receptor antagonist can be measured by determining the ability of a compound to competitively inhibit (ie, IC50) the activity of an agonist for the nuclear receptor.

In addition, a variety of cell-based assay methodologies can be successfully used in screening assays to identify and determine the specificity profile of compounds of the present invention. These approaches include the co-transfection assay, translocation assays, complementation assays, and the use of gene activation technologies to overexpress endogenous nuclear receptors.

There are three basic variants of the co-transfection assay strategy, co-transfection assays that utilize the full-length nuclear receptor, cotransfection assays that utilize nuclear receptors that comprise the ligand-binding domain of the nuclear receptor of interest fused to a nuclear domain. binding to heterologous DNA, and assays based on the use of the two-hybrid mammalian assay system.

The basic cotransfection assay is based on the cotransfection in the cell of an expression plasmid to express the nuclear receptor of interest in the cell with a reporter plasmid comprising a reporter gene whose expression is under the control of the DNA sequence that is able to interact with that nuclear receptor. (See, for example, U.S. Patent Nos. 5,071,773, 5,298,429, 6,416,957, WO 00/76523). The treatment of cells transfected with an agonist for the nuclear receptor increases the transcription activity of that receptor reflected by an increase in the expression of the reporter gene, which can be measured by a variety of standard procedures.

For these receptors that function as heterodimers with RXR, such as the farnesoid X receptor, the cotransfection assay generally includes the use of expression plasmids for the nuclear receptor of interest and for RXR. Typical cotransfection assays require access to the full length nuclear receptor and appropriate response elements that provide sufficient detection sensitivity and specificity to the nuclear receptor of interest.

The genes encoding the following full-length proteins previously described, which are suitable for use in cotransfection studies and in the profile of the compounds described herein, include the farnesoid X receptor (GenBank Access No. NM_021745), farnesoid receptor Human X (Access of GenBank No. NM_005123), RXR to human (Access of GenBank No. NM_002957), Human RXR ß (Access of GenBank No. XM_042579), RXR? Human (GenBank Access No. XM 053680), Human LXR (GenBank Access No. NM_005693), Human LXR ß (Access of GenBank No. NM_007121), Human PPAR (GenBank access No. NM_005036) and Human PPAR d (Access from GenBank No. NM_006238).

Indicator plasmids can be constructed using standard molecular biological techniques by placing the cDNA encoding the downstream reporter gene from a suitable minimal promoter. For example, luciferase reporter plasmids can be constructed by placing the cDNA encoding luciferase immediately below the herpes virus thymidine kinase promoter (located in the nucleotide resections -105 to +51 of the thymidine kinase nucleotide sequence) which is joined in turn to the different elements of response.

Numerous methods of cotransfection of the expression and indicator plasmids are known to those skilled in the art and can be used for the cotransfection assay to introduce the plasmids into a suitable cell type. Generally, that cell does not endogenously express the nuclear receptors that interact with the response elements used in the indicator plasmid.

Numerous indicator gene systems are known in the art and include, for example, alkaline phosphatase Berger, J., et al. (1988) Gene 6_6 1-10; Kain, S.R. (1997) Methods. Mol. Biol. 63 49-60), β-galactosidase (See U.S. Patent No. 5,070,012, issued Dec. 3, 1991, by Nolan et al., And Bronstein, I., et al., (1989) J. Chemilum, Biolum. 4 99-111), chloramphenicol acetyltransferase (See Gorman et al., Mol Cell Biol. (1982) 2 1044-51), β-glucuronidase, peroxidase, β-lactamase (US Patent Nos. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (U.S. Patent Nos. 5,221,623; 5,683,888; 5,674,713; 5,650,289; 5,843,746) and naturally fluorescent proteins (Tsien, RY (1998) Annu., Rev. Biochem 67 509-44).

The use of chimeras that comprise the binding domain of the ligand (LBD) of the nuclear receptor of interest to a binding domain of Heterologous DNA (DBD) expands the versatility of cell-based assays by directing the activation of the nuclear receptor in question to defined DNA-binding elements recognized by the defined DNA-binding domain (see WO 95/18380). This assay expands the ability of cell-based cotransfection assays in cases in which the biological response or window of detection using the native DNA binding domain is not satisfactory.

In general, the methodology is similar to that used with the basic cotransfection assay, except that a chimeric construction is used instead of the full-length nuclear receptor. As with the full length nuclear receptor, treatment of cells transfected with an agonist for the LBD of nuclear receptor increases the transcription activity of the heterologous DNA binding domain which is reflected by an increase in the expression of the reporter gene described above. . Generally for those chimeric constructs, DNA binding domains of defined nuclear, or yeast or bacterially derived transcription regulators such as members of the GAL-4 and Lex A / Umud superfamilies are used.

A third cell-based assay useful for detecting compounds of the present invention is a two-hybrid mammalian assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand (See, for example, U.S. Patent Nos. 5,667,973, 5,283,173 and 5,468,614) 1. The basic approach is to create three plasmid constructs that allow the interaction of the nuclear receptor with the interacting protein that must be coupled to the reading of transcription within a living cell. The first construct is an expression plasmid for expressing a fusion protein comprising the interacting protein, or a portion of the protein containing the interaction domain, fused to a DNA binding domain of GAL4. The second expression plasmid comprises the DNA encoding the nuclear receptor of interest fused to a resistant transcription activation domain such as VP16, and the third construct comprises the reporter plasmid comprising a reporter gene with a minimal promoter and current activation sequences. above GAL4.

Once the three plasmids are introduced into a cell, the DNA binding domain of GAL4 encoded in the first construct allows specific binding of the fusion protein to GAL4 sites upstream of a minimal promoter. However, since the GAL4 DNA binding domain generally has no isolated resistant transcription activation property, expression of the reporter gene occurs only at a low level. In the presence of a ligand, the VP16 fusion protein of the nuclear receptor can bind to the protein fusion protein that interacts with GAL4 that binds VP16 of transcriptional activator resistant to the GAL4 binding sites and the promoter's minimal promoter region. indicator gene The interaction significantly improves the transcription of the reporter gene, which can be measured for different reporter genes as described above. The transcription of the indicator gene is therefore activated by the interaction of the interacting protein and the nuclear receptor of interest in the ligand-dependent fusion.

Any compound that is a candidate for activation of the farnesoid X receptor can be tested by these methods. Generally, the compounds are tested at different concentrations to optimize the chances that receptor activation will be detected and recognized if present. Generally, assays are carried out in triplicate and vary within the experimental error by less than 15%. Each experiment is usually repeated three or more times with similar results.

The activity of the reporter gene can be conveniently normalized to the internal control and the data can be plotted as folds activation in relation to the untreated cells. A positive control compound (agonist) can be included together with DMSO as high and low controls for the normalization of the test data. Similarly, the activity of the antagonist can be measured by determining the ability of a compound to competitively inhibit the activity of an agonist.

In addition, compounds and compositions can be evaluated for their ability to increase or decrease the expression of genes known to be modulated by the farnesoid X receptor and other nuclear receptors in vivo, using Northern blot analysis, RT PCR or microgroup analysis. oligonucleotides to analyze RNA levels. Western blot analysis can be used to measure the expression of proteins encoded by the farnesoid X receptor white genes. Genes known to be regulated by the farnesoid X receptor include 7 cholesterol a-hydroxylase (CYP7A1), the enzyme that limits the speed in the conversion of cholesterol into bile acids, the companion of small heterodimer 1 (SHP-1), the pump that exports bile salt (SEP, ABCB11), the protein that exports canalicular bile acid, the cotransport polypeptide of sodium taurocholate (NTCP, SLC10A1) and the intestinal bile acid binding protein (I-BABP).

There are established animal models for numerous diseases of direct relevance to the claimed compounds and these can be used to describe the profile and further characterize the claimed compounds. These model systems include diabetic dyslipidemia using rats (fa / fa) or mice (db / db) Zucker, spontaneous hyperlipidemia using mice with apolipoprotein E insufficiency (ApoE_ / ~), diet-induced hyperlipidemia, using mice with receptor insufficiency of low density lipoprotein (LDR "/ _) and atherosclerosis using mice with Apo E (~ / _) and LDL (~ / _) fed a western diet (21% fat, 0.05% cholesterol). use farnesoid X receptor and LXR animal models (eg, knockout mice) to further evaluate the present compounds and compositions in vivo (see, for example, Sinal, et al., Cell 1, 102: 731-744 (2000)) , Peet, et al., Cell, 93: 693-704 (1998)).

D. Methods of use of the compounds and compositions Methods of using the compounds and compositions provided herein are also provided. The methods consist of in vitro and in vivo uses of the compounds and comopsicones to alter the activity of the nuclear receptors, which includes the activity of the farnesoid X receptor and / or the orphan nuclear receptors, and for the treatment, prevention or improvement of one or more symptoms of diseases or disorders that are modulated by the activity of the nuclear receptors, which includes the activity of the farnesoid X receptor and / or the orphan nuclear receptors, or in which the activity of the nuclear receptors is involved which includes the activity of the farnesoid X receptor and / or the orphan nuclear receptors. These compounds or compositions generally exhibit agonist, partial agonist, partial antagonist or farnesoid X receptor antagonist activity in one of the in vitro assays described herein.

Methods of altering the activity of nuclear receptors, including the activity of the farnesoid X receptor and / or the orphan nuclear receptors, are provided by contacting the receptor with one or more compounds or compositions provided herein.

Methods of reducing plasma cholesterol levels and directly or indirectly modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion or excretion of cholesterol by administering the claimed compounds and compositions are provided. Methods of reducing the absorption of dietary cholesterol are provided (see, for example, Publication of International Patent Application No. 00/40965) using the compounds and compositions. Methods of increasing the expression of the ATP-binding Cassstte (ABCA1) are also provided thereby increasing the transport of inverted cholesterol in mammalian cells using the claimed compounds and compositions (see, for example, International Patent Application Publication No. 00/78972).

Methods of reducing triglyceride levels in the plasma and directly or indirectly modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion or excretion of the triglycerides are administered by administering the claimed compounds and compositions.

Methods of reducing bile acid levels and directly or indirectly modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion or excretion of bile acids by administering the claimed compounds and compositions are provided.

Bile acid chemodeoxycholic acid (CDCA) is a potent ligand for FXR, with EC50 in the range of biological levels of bile acid. Parks, D. J. et al., Bile acids: Natural ligands for an orphan nuclear receptor. Science. 284: 1365-1368 (1999); Makishima, M. et al., Identification of a nuclear receptor for bile acids. Science. 284: 1362-1365 (1999). Wang, H. Et al., Endogenous bile acids are ligands for the nuclear receptor FXR / BAR. Mol. Cell. 3: 543-553 (1999).

Human studies demonstrated that the administration of CDCA in humans significantly decreases plasma triglyceride levels in patients with hypertriglyceridemia. The identification of the FXR function as a bile acid sensor shows that the effect is mediated through the FXR receptor. Camarri II. et al., Hypotriglyceridemic effect of chenodeoxycholic acid after a short time of administration, Int J Cl in Pharmacol Biopharm. Nov: 16 (11): 527-8 (1978); Camarri E. et al., Influence of chenodeoxycholic acid on serum triglycerides in patients with primary hypertriglyceridemia, Int J Clin Pharmacol Biopharm. , Nov: 16 (11): 523-6 (1978); Camarri E. et al., The hypotriglyceridemic effect of chenodeoxycholic acid in type IV hyperlipidemia, The hypotriglyceridemic effect of chenodeoxycholic acid in type IV hyperlipemia. Biomedi cine, Oct: 29 (6): 193-8 (1978). The absence of the effect on plasma lipids from the treatment with UDCA bile acid coincides with the function of FXR in the modulation of lipids in the plasma mediated by CDCA, since UDCA is not a ligand for FXR. Carulli N. et al., Chenodeoxycholic acid and ursodeoxycholic acid effects in endogenous hypertriglyceridemias.

A controlled double-blind trial. J Cl in Pharmacol. , 0ct: 21 (10): 436-42 (1981); Tint et al., Effect of ursodeoxycholic acid chenodeoxycholic acid on cholesterol and bile acid metabolism. Gasteroen terology, 91: 1007-1018 (1986); Iser and Salí, Chenodeoxycholic acid: a review of its pharmacological properties and therapeutic use. Drugs, 21: 90-119 (1981); Angelin et al., Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J. of Lipid Research, 19: 1017-1023 (1978).

The function of FXR is to regulate the metabolism of lipids. For example, the FXR can up-regulate PPARa. It is known that the activation of PPARa decreases the lipids in the plasma and also improves the resistance to insulin and the metabolism of glucose. . Pineda Torra I. et al., Bile acids induces the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor., Mol Endocrinol. Feb; 17 (2): 259-72 (2003).

FXR knockout mice exhibit non-HDL cholesterol and increased plasma triglycerides, apoß-containing lipoprotein synthesis and intestinal cholesterol absorption indicating that the loss of FXR function is potentially atherogenic. Therefore, activation of the FXR with agonists has antiatherogenic effects. Lambert G. et al., The Farnesoid X-receptor is an essential regulator of homeostasis, J Biol Chem. Jan 24; 278 (4): 2563-70 (2003); Sinal CJ, Tohkin M. et al., Targeted disruption of the nuclear receptor FXR / BAR impairs bile acid and lipid homeostasis, Cel l, Sep 15; 102 (6): 731-44 (2000); Edwards P.A. et al., BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis, J Lipid Res. Jan: 43 (1): 2-12 (2002); Kast H.R. et al., Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levéis to bile acids, Mol. Endocrinol Oct; 15 (10): 1720-8 (2001).

Methods of treatment, prevention, or amelioration of one or more symptoms of a disease or disorder affecting the levels of cholesterol, triglycerides, or bile acids, or any combination thereof, are provided using the compounds and compositions provided herein.

Methods are provided for the treatment, prevention or amelioration of one or more symptoms and for the treatment of the complications of hyperlipidemia, hypercholesterolemia, dyslipidemia and lipodystrophy.

The term "hyperlipidemia" refers to the presence of an abnormally high level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, that is, an elevated level of LDL cholesterol (120 mg / dL and more), (2) hypertriglyceridemia, that is, an elevated level of triglycerides (150 mg / dL and more) and (3) combined hyperlipidemia, ie a combination of hypercholesterolemia and hypertriglyceridemia.

The term "dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma that include decreased and / or elevated levels of lipoproteins (e.g., high levels of Low Density Lipoprotein (LDL), Very Low Density Lipoprotein (VLDL) and levels). Decreased High Density Lipoprotein (HDL) (less than 40 mg / dL)).

Methods for the treatment, prevention, or amelioration of one or more symptoms of atherosclerosis, atherosclerotic disease, atherosclerotic disease events and atherosclerotic cardiovascular diseases are provided.

Atherosclerosis is the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium and other substances accumulate in the inner lining of an artery. This accumulation is called a plate. Initially it affects the large and medium sized arteries. Often hardening of the arteries occurs when people get older.

The plaques can grow enough to significantly reduce blood flow through an artery. However, significant damage to the body can also occur when the walls of the artery become brittle and break. Atherosclerotic plaques that rupture can cause blood clots to form that can block blood flow or dislodge and travel to another part of the body. If any of these things happen and the blood clot blocks a blood vessel that feeds the heart, it can lead to a heart attack. If the blood clot blocks a blood vessel that feeds the brain, it can cause an attack. And if the blood supply to the arms or legs is reduced, it can cause difficulty walking and finally gangrene.

Accordingly, atherosclerosis comprises a range of vascular diseases and conditions that arise as a result of the primary disease modality. Atherosclerotic cardiovascular diseases can be recognized and understood by physicians practicing in the relevant fields of medicine and include the following: restenosis after revascularization procedures, coronary heart disease (also called coronary artery disease or ischemic heart disease) , cerebrovascular disease that includes ischemic attack, dementia due to multiple infarctions, and peripheral vessel disease, which includes erectile dysfunction.

A compound or composition of the present invention can be administered to prevent or reduce the risk of occurrence, or recurrence when the potential exists, coronary heart disease event, cerebrovascular event and / or intermittent claudication.

Events of coronary heart disease (CHD) include death from CHD, myocardial infarction (ie, heart attack), and coronary revascularization procedures. Cerebrovascular events include ischemic or hemorrhagic attack (also called cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. People who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of these events exists.

Individuals to be treated with the present therapy include those at risk of developing atherosclerotic disease and having an atherosclerotic disease event. The risk factors of standard atherosclerotic disease are known to the average physician who practices in the relevant fields of medicine. These known risk factors include, but are not limited to, hypertension, smoking, diabetes, low levels of high density lipoprotein cholesterol, high levels of low density lipoprotein cholesterol, and a family history of atherosclerotic cardiovascular disease. You can find published guides to determine those people at risk of developing atherosclerotic disease and of having an atherosclerotic disease event in: Third Report of the National Cholesterol Education Program, Expert Panel on Detection, Evaluation, and Treatment of high Blood Cholesterol in Adults ( Adult Treatment Panel III), National Institutes of Health, National Heart Lung and Blood Institute, NIH Publication No. 01-3670, May 2001; National Cholesterol Education Program, Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), National Institute of Health, National Heart Lung and Blood Institute, NIH Publication No. 93-3095 , September 1993; abbreviated version: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Summary of the second report of the national education program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), JAMA, 1993, 269, pp. 3015-23. People who are identified as having one or more of the risk factors indicated above, as well as people who already have atherosclerosis, are included in the group of people considered to be at risk of having an atherosclerotic disease event.

Events of coronary heart disease include death from coronary heart disease, myocardial infarction, and coronary revascularization procedures. Cerebrovascular events include ischemic or hemorrhagic attack (also called cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease.

The term "atherosclerotic disease event" as used herein includes events of coronary heart disease, cerebrovascular events, and intermittent claudication. People who have already experienced one or more atherosclerotic disease events are those for whom the potential for recurrence of that event exists.

In addition, the present invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactic effective amount of a compound or composition of the present invention to a patient at risk. of that event. The patient may already have atherosclerotic disease at the time of administration or may be at risk of developing it.

Risk factors for developing atherosclerotic disease events include aging (65 years and older), male sex, family history of atherosclerotic disease events, high blood cholesterol level (especially LDL or "bad" cholesterol greater than 100 mg / dL). ), smoking and exposure to tobacco smoke, high blood pressure, diabetes mellitus, obesity and physical inactivity.

In another aspect, the method of this invention also serves to remove cholesterol from deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifested by clinical signs such as angina, claudication, murmur, a person who has suffered myocardial infarction or transient ischemic attack, or a person who was diagnosed by angiography, sonography or MRI.

Methods of treatment, prevention, or improvement of one or more of the symptoms of diabetes mellitus are provided, as well as treatment of diabetes mellitus complications (see, for example, International Patent Application Publication No. WO 01 / 82917), using the compounds and compositions provided herein.

Diabetes mellitus, commonly referred to as diabetes, refers to a disease or condition that is generally characterized by metabolic defects in the production and utilization of glucose that result in the inability to maintain appropriate levels of blood sugar in the body (see, for example, LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. USA 1996)).

In the case of type 2 diabetes, the disease is characterized by insulin resistance, where insulin loses its ability to exert its biological effects over a wide range of concentrations. This resistance to sensitivity of insulin results in the insufficient activation of insulin from the absorption, oxidation and storage of glucose in the muscles and in the insufficient repression of lipolysis in adipose tissue and the production and secretion of glucose in the body. liver (see, for example, Reaven, GM, J. Basic &Clin. Phys. &Pharm. (1998) 9: 387-406 and Flier, J. Ann Rev. Med. (1983) 34: 145-60 ). The resulting oxidation is elevated blood glucose, which is termed "hyperglycemia". Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk of microvascular and macrovascular diseases, including retinopathy (deterioration or loss of vision due to injury to the blood vessels in the eyes); neuropathy (nerve injury and foot problems due to injury to blood vessels to the nervous system); and nephropathy (kidney disease due to damage to the blood vessels in the kidneys), hypertension, cerebrovascular disease and coronary heart disease. Consequently, the control of glucose homeostasis is an important approach for the treatment of diabetes.

Methods of treatment, prevention, or amelioration of one or more of the insensitivity or insulin resistance symptoms as well as for the treatment of insensitivity or insulin resistance complications are also provided (see, for example, Publication of International Patent Application No. WO 01/82917), using the compounds and compositions provided herein.

Methods of treatment, prevention, or amelioration of one or more of the symptoms of hyperglycemia as well as for the treatment of complications of hyperglycemia are provided (see, for example, International Patent Application Publication No. WO 01/82917 ), using the compounds and compositions provided herein.

It has been hypothesized that insulin resistance unifies the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglycerides and reduced HDL cholesterol, and central and general obesity. The association of insulin resistance with glucose intolerance, an increase in triglycerides in plasma and a decrease in high density lipoprotein cholesterol concentrations, hypertension, hyperuricemia, denser low density lipoprotein particles more Small, and higher circulating levels of plasminogen activator inhibitor 1 have been termed "Syndrome X" (see, eg, Reaven, GM, Physiol. Rev. (1995) 75: 473-486). Accordingly, methods of treatment, prevention, or improvement of all disorders related to diabetes, hyperglycemia, or insulin resistance are provided which include the group of disease states, conditions, or disorders that constitute "Syndrome X".

In addition, the present invention also provides a method to prevent or reduce the risk of the development of hyperglycemiainsulin resistance or diabetes in a patient, comprising administering a prophylactic effective amount of a compound or composition of the present invention to a patient at risk of that event. The patient may already be obese (BMI of 30.0 or more), overweight (BMI of 25.0 to 30.0) or have other risk factors for developing diabetes that include age, family history and physical inactivity.

Also provided herein are methods for the treatment, prevention, or amelioration of one or more symptoms of cholestasis, as well as for the treatment of cholestasis complications by administering a compound or composition provided herein.

Cholestasis is usually caused by factors within the liver (intrahepatic) or outside the liver (extrahepatic) and results in the accumulation of bile salts, bile pigment bilirubin, and lipids in the blood stream instead of being eliminated normally.

Intrahepatic cholestasis is characterized by a wide blockage of small ducts or by disorders, such as hepatitis, that impair the body's ability to eliminate bile. Intrahepatic cholestasis can also be caused by alcoholic liver disease, primary biliary cirrhosis, cancer that has spread (metastasis) from another part of the body, primary sclerosing cholangitis, gallstones, biliary colic, and acute cholecystitis. It can also occur as a complication of surgery, severe injury, cystic fibrosis, infection, or intravenous feeding or drug induced. Cholestasis can also occur as a complication of pregnancy and often develops during the second and third trimesters.

Extrahepatic cholestasis is most commonly caused by choledocholithiasis (bile duct tracts), benign biliary strictures (noncancerous narrowing of the common duct), cholangiocarcinoma (ductal carcinoma), and pancreatic carcinoma. Extrahepatic cholestasis can occur as a side effect of many medications.

Accordingly, the compounds and compositions provided herein may be used for the treatment, prevention, or amelioration of one or more symptoms of intrahepatic or extrahepatic cholestasis, including but not limited to, biliary atresia, obstetric cholestasis, neonatal cholestasis, drug-induced cholestasis. , cholestasis arising from infection with Hepatitis C, chronic cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

In addition this invention provides methods to treat obesity, as well as to treat the complications of obesity, by administering a compound or composition of the present invention, the terms "obese" and "obesity" refer, according to the World Health Organization, at a Body Mass Index (BMI) greater than 27.8 kg / m2 for men and 27.3 kg / m2 for women (BMI is equivalent to weight (kg) / height (m2).) Obesity is linked to a a variety of medical conditions including diabetes and an atherosclerotic disease event (See, for example, Barrett-Conner, E., Epidemol, Rev. (1989) 11: 172-181; and Knowler, et al., Am. J Clin. Nutr. (1991) 53: 1543-1551) Accordingly, the claimed compounds and compositions can be used to treat obesity or its complications, and can be identified, formulated and administered as described above.

E. Combination Therapy Also contemplated herein is combination therapy using one or more compounds or compositions provided herein, or a pharmaceutically acceptable derivative thereof, combined with one or more of the following: antihyperlipidemic agents, plasma HDL raising agents, antihypercholesterolemic agents, inhibitors of cholesterol biosynthesis (such as inhibitors of HMG CoA reductase, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rivastatin), acyl-coenzyme A: cholesterol acitransferase (ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide, inhibitors of cholesterol absorption, bile acid sequestrants (such as anion exchange resins, or quaternary amines (eg cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrizol, vitamin B6, vitamin B? 2, antioxidant vitamins, beta-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, antagonists, receptor of fibrinogen, agonists, antagonists or partial agonists of LXR a or β, aspirin or derivatives of fibric acid. The compound or composition provided herein, or a pharmaceutically acceptable derivative thereof, is administered simultaneously, before or after the administration of one or more of the preceding agents. Pharmaceutical compositions containing a compound provided herein and one or more of the preceding agents are provided.

The combination therapy includes the administration of a pharmaceutical single-dose formulation containing a compound of the present invention and one or more additional active agents, as well as the administration of a compound of the present invention and each active agent in its own formulation of pharmaceutical dosage separately. For example, an agonist, partial agonist, partial antagonist or antagonist of the farnesoid X receptor of the present invention and an inhibitor of HMG-CoA reductase can be administered to the patient together with a single oral dosage composition such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations. When separate dosage formulations are used, the compounds described herein and one or more additional active agents can be administered essentially at the same time, ie concurrently or at staggered times separately, ie in sequence; It is understood that combination therapy includes all of these regimens. An example of combination therapy that modulates or prevents the onset of symptoms, or associated complications of atherosclerosis, is administered with one or more of the following active agents: an antihyperlipidemic agent, an agent that elevates HDL in plasma, an agent antihypercholesterolemic, such as an inhibitor of cholesterol biosynthesis, for example an inhibitor of hydroxymethylglutaryl (HMG) CoA reductase (also called statins, such as lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin), an inhibitor of HMG-CoA synthase, an scalene epoxidase inhibitor, or a scalene synthase inhibitor (also called scalene synthase inhibitor), an inhibitor of acyl-coenzyme A cholesterol acitransferase (ACAT), such as melinamide, probucol, nicotinic acid and salts thereof, and niacinamide, an inhibitor of cholesterol absorption, such as β-sitosterol, an anion exchange resin of bile acid sequestrant, such as cholestyramine, colestipol or dialkylaminoalkyl derivatives of a crosslinked dextran, an inducer of LDL receptor (low density lipoprotein), fibrates such as clofibrate, benzafibrate, fenofibrate and gemfibrizole, vitamin B6 (also called pyridoxine) and pharmaceutically acceptable salts of it, such as the HCl salt, vitamin B 2 (also called cyanocobalamin), vitamin B 3 (also called nicotinic acid and niacinamide, supra), antioxidant vitamins such as vitamin C and E and beta carotene, a β-blocker, agonists, antagonists or partial agonists of LXR a or β, an angiotensin II antagonist, an angiotensin-converting enzyme inhibitor and an inhibitor of platelet aggregation, such as a fibrinogen receptor antagonist (ie, receptor antagonist) of fibrinogen glycoprotein Iib / IIIa) and aspirin. A compound or composition of the present invention is preferably administered with an inhibitor of cholesterol biosynthesis, particularly an inhibitor of HMG-CoA reductase. The HMG-CoA reductase inhibitor includes all forms of salts, esters, free acids and lactone of compounds having HMG-CoA reductase inhibitory activity and consequently, the use of those forms of salts, esters, free acids and lactone is included within the scope of this invention. Other inhibitors of HMG-CoA reductase can be easily identified using assays known in the art. For example, suitable assays are disclosed or disclosed in U.S. Patent No. 4,231,938 and in WO 84/02131. Examples of HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (MEVACOR®, see U.S. Patent No. 4,231,938); simvastatin (ZOCOR®; see U.S. Patent No. 4,444,784); pravastatin sodium (PRAVACHOL®; see US Pat. No. 4,346,227); fluvastatin sodium (LESCOL®; see U.S. Patent No. 5,354,772); calcium of atorvastatin (LIPITOR®, see U.S. Patent No. 5,273,995) and rivastatin (also called cerivastatin; see U.S. Patent No. 5,177,080). The structural forms of these and other HMG-CoA reductase inhibitors that can be used in the methods of the present invention are described on page 87 of M. Yalpani, "Cholesterol Lowering Drugs," Chemis try & Industry, pp. 85-89 (February 5, 1996). In one embodiment, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin. Dosage information for HMG-CoA reductase inhibitors is known in the art, since several HMG-CoA reductase inhibitors are marketed in the United States. In particular, the dosage amounts of the HMG-CoA reductase inhibitor can be the same or similar to those amounts that are employed for the anti-hypercholesterolemic treatment and which are described in Physi cians' Desk Reference (PDR). For example, see the 5th Ed. Of the PDR, 1996 (Medical Economics Co); in particular, see 216 the title "Hypolipidemics," subtitle "HMG-CoA Reductase Inhibitors," and the reference pages cited there. Preferably, the oral dosage amount of the HMG-CoA reductase inhibitor is from 1 to 200 mg / day and more preferably from 5 to 160 mg / day. However, the dosage amounts vary according to the potency of the specific inhibitor of HMG-CoA reductase used as well as other factors indicated above. An HMG-CoA reductase inhibitor that has sufficiently high potency can be given in daily doses of less than one milligram.

For example, the daily dosage amount for simvastatin can be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosage amount for atorvastatin calico may be in the range of 1 mg to 160 mg and more preferably 5 mg to 80 mg. Oral administration may be in single or divided doses of two, three, or four times daily, although a single daily dose of the HMG-CoA reductase inhibitor is preferred.

Diabetic patients are likely to suffer premature development of atherosclerotic disease events and increased rate of cardiovascular and peripheral vascular diseases. Hyperlipidemia and dyslipidemia are important factors that precipitate these diseases. See, for example, Wilson, J. et al., (Ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W. B. Sanders Company, Philadelphia, Pa. U.S.A., 1998). Dyslipidemia is characterized by abnormal levels of lipoproteins in blood plasma (eg, high levels of LDL, VLDL, and reduced levels of HDL) and has been shown to be one of the major contributing factors to the increased incidence of coronary events and deaths among diabetic subjects (see, for example, Joslin, E. Ann. Chim. Med. (1927) 5: 1061-1079). Epidemiological studies since then have confirmed the association and have shown a multi-fold increase in coronary diseases among diabetic subjects compared with non-diabetic subjects (see, for example, Garcia, MJ et al., Diabetes (1974) 23: 105- 11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997) 5 (4): 294-315).

The methods of the present invention can be used effectively in combination with one or more additional active antidiabetes agents according to the desired target therapy (see, for example, Turner, N. et al. Prog. Drug Res. (1998) 51: 33- 94; Haffner, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al. (Eds.), Diabetes Reviews (1997) Vol. 5 No. 4).

Numerous studies have investigated the benefits of combination therapies with oral agents (see, for example, Mahler, R., J. Clin Endocrinol, Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, CW, (ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby-Year Book, Inc., St. Louis, Mo. 1997); , J. et al., Ann., Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin. Ther. (1997) 19: 16-26; Coniff, R. et al. , Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. et al, Diabet Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82 ( 12A): 3U-17U). These studies indicate that the modulation of hyperlipidemia associated with diabetes can further improve the outcome of the treatment of diabetes.

Accordingly, another combination therapy claimed herein is suitable for treating diabetes and its symptoms, complications, and related disorders, and includes the co-administration of the compounds or compositions provided herein with for example, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide). , glyburide, gliclazide, glinasa, glimepride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone); and related insulin sensitizers, such as selective and non-selective activators of PPARa PPARβ and PPARα; agonists, antagonists and partial agonists of LXR a or β, dehydroepiandrosterone (also called DHEA or its conjugated sulfate ester, DHEA-S04), antiglucocorticoids, TNFa inhibitors, a-glucosidase inhibitors (such as acarbose, miglitol and voglibose), pramlintide (a synthetic analog of the human amylin hormone), other secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as active agents discussed above to treat atherosclerosis.

Another example of combination therapy claimed herein is the co-administration of the claimed compounds or compositions provided herein with compounds or compositions for treating obesity and disorders related to obesity, wherein the claimed compounds can be used effectively in combination with, for example, phenylpropanolamine, phentermine, diethylpropion, mazindol; fenfluramine, dexfenfluramine, fentiramine, ß3 adrenoreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), agonists, antagonists and partial agonists of LXR a or ß, and leptins. Other agents used in the treatment of obesity or disorders related to it include neuropeptide Y, enterostatin, colecitocinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptors, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).

Another example of a claimed combination therapy is the coadministration of the claimed compound or composition provided herein with compounds or compositions for treating cholestasis and its symptoms, complications and related disorders. Those compounds administered together include for example, Actigall (Ursodeosxicolic acid - UDCA), corticosteroids, anti-infective agents (Rifampin, Rifadin, Rimactan), antiviral agents, Vitamin D, Vitamin A, phenobarbital, cholestyramine, UV light, antihistamines, antagonists of oral opiate receptor and bisphosphates, for the treatment, prevention, or improvement of one or more symptoms of intrahepatic or extrahepatic cholestasis. The dosage information for these agents is known in the art.

F. Preferred realizations In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the invention wherein R1 is C (J) ORn; J is 0; R3 is COR9; R9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; R6 or R7 is optionally substituted alkyl; n is 0-3; R8 is optionally substituted alkyl or halo, preferably fluoro, chloro or bromo.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein R9 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl. In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein R9 is optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein R9 is optionally substituted heteroaryl or optionally substituted heteroaralkyl.

In a preferred embodiment, the compound is a compound of formula (I) in the Summary of the Invention wherein R9 is optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein R1 is C (J) ORlx; J is O; R3 is CON (R11) (R12); R11 is hydrogen or optionally substituted alkyl; R 12 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; R6 or R7 is optionally substituted alkyl; and n is 0-3.

In a preferred embodiment, the compound is a compound of formula (I) in the Summary of the Invention, wherein R11 and R12 together with the atom to which they are attached form an optionally substituted heterocyclyl or heterocyclyl optionally substituted.

In a preferred embodiment, the compound is a compuessto of formula (I) in the Summary of the Invention, wherein R11 and R12 together with the atom to which they are attached form an optionally substituted heterocyclyl or heterocyclyl optionally substituted, optionally substituted with one or more Q1.

In a preferred embodiment, the compound is a compound of formula (I) in the Summary of the Invention where R3 is C0N (Ru) (R12); R11 is hydrogen and R12 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylamino, dimethylamino, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 2-morpholin-4-ylethyl, -morpholin-4-ylpropyl, 3-morpholin-4-ylpropyl) amino, and piperidinyl.

In a preferred embodiment, the compound is a compound of formula (I) in the Summary of the Invention, wherein R11 and R12 together with the atom to which they are attached form heterocyclyl optionally substituted or optionally substituted heterocyclylalkyl selected from the group consisting of pyrrolidin -1-yl, 4-pyrrolidin-l-yl yl 4-methylpiperazin-l-yl 4-ethylpiperazin-1-yl 4-propylpiperazin-l-, piperidin-1-yl, 4-piperazin-l-yl, , piperidin-3-yl, piperidinyl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl and azepanyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention, wherein R9 is optionally substituted aryl or aralkyl, optionally substituted with one or more Q1.

In a preferred embodiment, the compound is a compound of formula (I) in the Summary of the Invention wherein Q1 is selected from the group consisting of methyl, ethyl, propyl, diethylamino, dimethylamino, diethylaminomethyl, diethylaminoethyl, dimetilaminopropiloximetilo, phenyl, phenylmethyl , pyrrolidinyl, piperazinyl, piperidinyl, methylpiperidinyl, methylpiperazinyl, 2-oxo-2-pyrrolidinylethyl, and morpholino-4-methyl.

In one embodiment, the compound is a compound of formula (I) in the Summary of the Invention wherein Q 1 is selected from the group consisting of hydroxy, cyano, 2-methyl; 3-methyl; methylpiperazinyl, 3-chloromethyl, 3,4-difluoro; 3-methyl, 4-methyl; 2-methyloxy; 3-methyloxy; 4-methyloxy; 3-fluoro-4-methyl; 4-fluoro-3-methyl; 2-trifluoromethyloxy; 2-chloro; 3-chloro; 4-chloro; 2,4-dichloro; 2-chloro-3,6-difluoro, 3-chloro-2,6-difluoro, 2-fluoro; 3-fluoro; 2-bromine; 3-trifluoromethyl; 2, 3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6-difluoro; 3, 4-difluoro; 3, 6-difluoro; 3, 4-difluoro; 2,3-difluoro-4-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 2-fluoro-3-trifluoromethyl; 3-fluoro-5-trifluoromethyl; 2,5-bistrifluoromethyl; 3, 5-bistrifluoromethyl; 3-chloro-2-fluoro-4-trifluoromethyl 3-fluoro-4-trifluoromethyl; 4-fluoro-3-trifluoromethyl; 4-fluoro-2-trifluoromethyl; 2-chloro-4-fluoro; 3-chloro-4-fluoro; 2-trifluoromethyl; 4-trifluoromethyl; 2, 3, 4-trifluoro; 2, 4, 6-trifluoro; 2, 4, 5-trifluoro; 3,4-bis (methyloxy); 3-phenylmethyloxy; metiloxifenilmetiloxi, 4-piperidin-4-yl, 3-piperidin-4-yl, 3-piperidin-4-lmetilo, piperidin-4-ylmethyl, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, 4-methylsulfonylpiperazin-1-yl, 3-azepan-1-ylmethyl, 4-methyl-1, 4-diazepane-1-yl, 3-pyrrolidin-1-ylethyl, 4-methyl-piperazin-1-ylmethyl; 4-ethylpiperazin-1-ylmethyl; 3-piperazin-1-ylmethyl; morpholin-4-ylmethyl; 3-morpholin-4-ylmethyl; 2-morpholin-4-ylethyloxy; 2-piperidin-1-ylethyloxy; 3-morpholin-4-ylpropyloxy-1H-pyrazol-1-yl, 4-trifluoromethyl-1H-pyrazol-1-yl, 4-acetylpiperazin-1-ylmethyl; metilbenzotriazolilo, dimetiletiloxicarbonilpiperazin-1-ylmethyl, 4-fenilsulfonilpiperazin-1-ylmethyl, 4-fluorofenilsulfonilpiperazin-1-yl, 4-etilsulfonilpiperazin-1-ylmethyl, 4-cyclopropyl carbonilpiperazin-1-ylmethyl, 2-metilpropanoilpiperazin-1-ylmethyl, 4 phenylcarbonyl piperazin-1-ylmethyl, 3-azocan-l-ylmethyl, 4-acetyl-l, 4-diazepan-l-yl, 4-phenylaminocarbonylpiperazin-1-ylmethyl; 4-ethylaminocarbonylpiperazin-1-ylmethyl; 3-piperidin-1-ylpropyloxy, 2-pyrrolidin-1-ylethyloxy; 3-piperidin-1-ylpropyloxy; and 3-morpholin-4-ylpropyloxy.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein R9 is optionally substituted heteroaryl or optionally substituted heteroaralkyl, optionally substituted with one or more Q1.

In a preferred embodiment, the compound is a compound of the formula (I) in the Summary of the Invention wherein Q 1 is selected from the group consisting of optionally substituted alkyl, halo and haloalkyl.

In a preferred embodiment, the compound is a compound of formula (I) in the Summary of the invention wherein R9 is optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, optionally substituted with one or more Q1.

In a preferred embodiment, the compound is a compound of formula (I) in the summary of the invention, wherein Q 1 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted alkyl, optionally aralkyl. replaced.

In a preferred embodiment, the compound is a compound of formula (I) in the summary of the invention wherein R9 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, cycloheptyl; dimethyl ammopropyl, 4-methylpentyl; (3s, 5s, 7s) -trip. { 3.3.1.1-3, 7 ~] dec-1-? Lo; 1S, S) -5-met? L-2, 5-diazabicyclo [2.2.1] hept-2-? Lo]; phenyl, isoxazolyl, piperidinyl, piperazmyl, pyrrolidinyl, morpholinyl, benzodioxolyl, and benzotpazolyl.

In a preferred embodiment, the compound is a compound of formula (I) in the summary of the invention, wherein Q 1 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally cycloalkylalkyl substituted, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

In a preferred embodiment, the compound is a compound of formula (I) in the summary of the invention wherein R8 is hydroxy, halogen, optionally substituted alkyl, optionally substituted aplo, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl heterocyclylalkyl optionally substituted.

In a preferred embodiment, the compound is a compound of formula (I) in the summary of the invention wherein R8 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention wherein n is 0, 1, 2, 3 or 4.

In a preferred embodiment the compound is a compound of the formula (I) in the summary of the invention, wherein R6 or R7 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention wherein R 1 is -C (J) OR 1: L and R 11 is selected from the group consisting of 2,2-dimethyl-1, 3-dioxolan-4-yl; 2-piperidin-1-oleolaminocarbonyl; 2,3-dihydroxypropyl or 2-fluoro-l- (fluoromethyl) ethyl, hydroxyethyl, phenylmethyloxyethyl, 3,4-difluorophenylcarbonyloxy-1-methylethyl, and 2-hydroxy-1-methylethyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention wherein R1 is C (J) N (R10) (R11) and R11 is optionally substituted alkyl, selected from the group formed by isopropyl; beta-alanine, 2,3-dihydroxypropyl; and 2-hydroxy-1- (hydroxymethyl) tyl.

In a preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention, wherein Q 1 is selected from the group consisting of optionally substituted alkyl, and halogen, preferably methyl, chloro, bromo, fluoro, or , 4-difluoro.

In a preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention wherein R1 is -C (J) ORu and R11 is optionally substituted alkyl; preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; more preferably, isopropyl; J is O; Rd or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; n is 0; R3 is COR9 wherein R9 is optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, preferably piperidin-3-yl or piperidin-4-yl; wherein R9 is optionally substituted with one or more Q1; wherein Q1 is selected from the group consisting of optionally substituted alkyl, halo, and haloalkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or methylethyldiethyl amino; more preferably, isopropyl or methyldiethylamino.

In another preferred embodiment, the compound is a compound of formula (I) in the summary of the invention, wherein R1 is -C (J) ORu; R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; J is 0; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl; more preferably, methyl; and n is 0. R3 is COR9; R9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; more preferably, R9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, cycloheptyl; dimethylaminopropyl, 4-methylpentyl; or (3s, 5s, 7s) - tricyclo [3.3.1.1-3, 7 ~] dec-1-yl; more preferably, butyl, cyclohexyl or cycloheptyl. R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkylalkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably butyl, cyclohexyl or cycloheptyl. In another embodiment, the compound is a compound of the formula (I) in the summary of the invention, wherein R1 is -C (J) OR11; R11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; J is 0; R6 or R7 is independently selected from optionally substituted alkyl, preferably methyl; n is 0-3; R8 is optionally substituted alkyl or halo, preferably, fluoro, chloro or bromo; R3 is COINR11) (NR12); wherein R 11 is optionally substituted hydrogen or alkyl; preferably hydrogen, methyl, or ethyl; more preferably hydrogen; R12 is optionally substituted alkyl, optionally substituted ani, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dimethylammoethyl, dimethylammopropyl, diethylammoethyl, diethylamino, dimethylammon, 2-morpholm-4-? let? lo, 3-morpholine? 4-propyl, 3-morpholine? 4-? Lprop? L) amino, or piperidmyl. R11 and R12 together with the atom to which they are attached form optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; preferably pyrrolidone-1, 4-pyrrolidone, p-pepd-n-1, 4-metipolipar 4-et? L? Peraz? Nl?? Lo, 4-p? Peraz? Nl? It, 4-prop? L? Peraz? Nl? Him, p? Per? D? N-3-? , piperidmyl, (1S, 4S) -5-met? l-2, 5-d? azab? c? clo [2.2.1] hept-2-? lo or azepanyl; R11 and R12 together are optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, optionally substituted alkyl, optionally substituted heterocyclyl heterocyclylalkyl optionally substituted; preferably methyl, ethyl, propyl, diethylamino, dimethylamino, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyloxymethyl, phenyl, phenylmethyl, pyrrolidinyl, piperazyl, piperidinyl, methylpiperidinyl, methylpiperazinyl, 2-oxo-2-pyrrolidolone, or morph? no-4-met? lo.

In another preferred embodiment, the compound is a compound of formula (I) in the summary of the invention, wherein R1 is -C (J) 0R?: L; R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; J is O; R6 or R7 is independently optionally substituted alkyl, preferably methyl; n is 0-3; R8 is halo, preferably fluoro, chloro or bromo; each R10 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, isopropyl. R3 is C0 (NR1: L) (NR12); each R 11 is preferably hydrogen or optionally substituted alkyl; more preferably methyl, or ethyl; more preferably, hydrogen; R 12 is optionally substituted alkyl, preferably methyl, ethyl, propyl; optionally substituted cycloalkyl or optionally substituted cycloalkylalkyl, preferably, cyclopentyl, cyclohexyl, cyclopheptyl; or optionally substituted aryl or optionally substituted aralkyl, preferably phenylmethyl or phenyl.

In another preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention wherein R1 is C (J) 0Rn; R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; J is O; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl; and n is 0. R3 is COR9 wherein R9 is optionally substituted aryl or optionally substituted aralkyl; preferably phenyl; wherein R 9 is substituted with one or more Q 1 selected from the group consisting of hydroxy, halogen, haloalkyl, haloalkoxy, optionally substituted alkyl, alkoxy, cyano, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; Q1 is preferably hydroxy, cyano, 2-methyl; 3-methyl; methyl-piperazinyl 3-chloromethyl, 3,4-difluoro; 3-methyl, 4-methyl; 2-methyloxy; 3-methyloxy; 4-methyloxy; 3-fluoro-4-methyl; 4-fluoro-3-methyl; 2-trifluoromethyloxy; 2-chloro; 3-chloro; 4-chloro; 2,4-dichloro; 2-chloro-3,6-difluoro, 3-chloro-2,6-difluoro, 2-fluoro; 3-fluoro; 2-bromine; 3-trifluoromethyl; 2, 3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6-difluoro; 3, 4-difluoro; 3, 6-difluoro; 3, 4-difluoro; 2,3-difluoro-4-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 2-fluoro-3-trifluoromethyl; 3-fluoro-5-trifluoromethyl; 2,5-bistrifluoromethyl; 3, 5-bistrifluoromethyl; 3-chloro-2-fluoro-4-trifluoromethyl 3-fluoro-4-trifluoromethyl; 4-fluoro-3-trifluoromethyl; 4-fluoro-2-trifluoromethyl; 2-chloro-4-fluoro; 3-chloro-4-fluoro; 2-trifluoromethyl; 4-trifluoromethyl; 2,3,4-trifluoro; 2, 6-trifluoro; 2, 5-trifluoro; 3, 4-bis (methyloxy); 3-phenylmethyloxy; or methyloxyphenylmethyloxy.

In another preferred embodiment, the compound is a compound of the formula (I) in the summary of the invention, wherein R1 is -C (J) ORn; J is O; R11 is optionally substituted alkyl, preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; and n is 0. R3 is COR9 wherein R9 is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroalkyl; more preferably 1,3-benzod-oxo-5-? lo or meth? l -soxazol-3-? lo; wherein R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, halogen or haloalkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl, fluoro, chloro or bromo.

In another embodiment, the compound is a compound of Formula I in the summary of the invention wherein R1 is -C (J) OR1: L; J is O; R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; and n is 0. R3 is COR9 wherein R9 optionally substituted, or optionally substituted aralkyl, preferably, phenyl. R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, halogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; Q1 is preferably 3,4-d? Fluoro; 4-p? Per? D? N-4-? Lo, 3-p? Per? D? N-4-ílo, 3-p? Per? D? N-4-? Lmet? Lo, p? Per? d? n-4-? lmethyl, dimethylaminomethyl, diethylamomethyl, dimethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, 4-methylsulfonylpiperazin-1-yl, 3-azepane-1-ylmethyl, 4-methyl-l, 4-diazepane-1-yl , 3-pyrrolidin-1-ylethyl, 4-methylpiperazin-1-ylmethyl; 4-ethylpiperazin-1-limethyl; 3-piperazin-1-ylmethyl; morpholin-4-ylmethyl; 3-morpholin-4-ylmethyl; 2-morpholin-4-ylethyloxy; 2-piperidin-1-ylethyloxy; 3-morpholin-4-ylpropyloxy-1H-pyrazol-1-yl, 4-trifluoromethyl-1H-pyrazol-1-yl, 4-acetylpiperazin-1-ylmethyl; methylbenzotriazolyl, dimethylethyloxycarbonylpiperazin-1-ylmethyl, 4-phenylsulfonylpiperazin-1-ylmethyl, 4-fluorophenylsulfonylpiperazin-1-yl, 4-ethylsulphonylpiperazin-1-ylmethyl, 4-cyclopropylcarbonylpiperazin-1-ylmethyl, 2-methylpropanoylpiperazin-1-ylmethyl, phenylcarbonyl piperazin-1-ylmethyl, 3-azocan-1-ylmethyl, 4-acetyl-l, 4-diazepane-1-yl, 4-phenylamino-carbonylpiperazin-1-ylmethyl; 4-ethylaminocarbonylpiperazin-1-ylmethyl; 3-piperidin-1-ylpropyloxy, 2-pyrrolidin-1-ylethyloxy; 3-piperidin-1-ylpropyloxy; or 3-morpholin-4-ylpropyloxy.

In another preferred embodiment, the compound is a compound of Formula I in the summary of the invention, wherein R1 is -C (J) 0R11; J is O; R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; and n is 0. R3 is COR9 wherein R9 is optionally substituted aryl, or optionally substituted aralkyl, preferably, phenyl. R9 is optionally substituted with -O- (CH2) p-R28. p is 1-3; R28 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, preferably, R28 is phenyl, dimethylamino, diethylamino, N-ethyl, N-methyl amino, morpholinyl, piperidinyl, piperazinyl, pyrrolidinuki, morpholinyl, or 4-methyloxyphenyl.

In another preferred embodiment, the compound is a compound of Formula I in the summary of the invention, wherein R1 is -C (J) OR1:; J is O; R 11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; and n is 0. R3 is COR9 wherein R9 is optionally substituted aryl, optionally substituted aralkyl, preferably, phenyl. R9 is optionally substituted with one or more Q1. R9 is optionally substituted with - (CH2) P-R29; p is 1-3; R29 is halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; preferably, R29 is dimethylamino, diethylamino, N-ethyl, N-methyl amino, chloro, morpholinyl, piperidinyl, piperazinyl, piperazin-1-ylmethyl, piperazin-1-ylethyl, pyrrolidinyl, morpholinyl, methyloxyphenyl; 4-acetylpiperazin-1-yl; -methylsulfonylpiperazin-1-yl; azepanil; azocan-1-yl; 4-methyl-l, -diazepan-1-yl; 4-acetyl-l, -diazepan-1-yl; dimethylethyloxycarbonylpiperazin-1-yl; 4-phenylsulfonyl piperazin-1-yl; 4-fluorophenylsulphonylpiperazin-1-yl; Ethylsulfonyl piperazin-1-yl; cyclopropylcarbonyl piperazin-1-yl; 2-methylpropanoyl piperazin-1-yl; phenylcarbonyl piperazin-1-yl; 4-phenylaminocarbonylpiperazin-1-yl; or 4-ethylaminocarbonylpiperazin-1-yl; Q1 is halogen or optionally substituted alkyl, preferably methyl, chloro, fluoro or bromo; and m is 0-3.

In another preferred embodiment, the compound is a compound of Formula I in the summary of the invention, wherein R1 is -C (J) ORn; J is 0; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; and n is 0. R3 is COR9 wherein R9 is optionally substituted aryl, or optionally substituted aralkyl, preferably, phenyl. R9 is optionally substituted with one or more Q1. Each R 11 is independently optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl. Preferably, R 11 is 2,2-dimethyl-1,3-dioxolan-4-yl; 2-piperidin-1-ylethylaminocarbonyl; 2,3-dihydroxypropyl or 2-fluoro-l- (fluoromethyl) ethyl, hydroxyethyl, phenylmethyloxyethyl, 3,4-difluorophenylcarbonyloxy-1-methylethyl, 2-hydroxy-1-methylethyl; p is 1-3; Q1 is halogen or optionally substituted alkyl, preferably methyl, chloro, fluoro, bromo or 3,4-difluoro.

In another embodiment, the compound is a compound of Formula I in the summary of the invention, wherein R1 is -C (J) N (R10) (R11); J is O; R10 is independently hydrogen or optionally substituted alkyl, more preferably, hydrogen; R11 is independently optionally substituted alkyl, preferably isopropyl; beta-alanine, 2,3-dihydroxypropyl; or 2-hydroxy-1- (hydroxymethyl) ethyl; R6 or R7 is optionally substituted alkyl; preferably methyl, ethyl, or propyl, more preferably, methyl; and n is 0-3; R8 is optionally substituted alkyl or halo, preferably chloro, bromo or fluoro. R3 is COR9 wherein R9 is optionally substituted aryl, or optionally substituted aralkyl, preferably, phenyl. R9 is optionally substituted with one or more Q1 selected from the group consisting of halogen and optionally substituted alkyl, preferably methyl, chloro, fluoro, bromo or 3,4-difluoro.

In another embodiment, R1 is -C (J) OR?: L, J is 0; R11 is optionally substituted alkyl, preferably methyl, ethyl, propidyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, methyl; R6 or R7 is optionally substituted alky; preferably methyl, ethyl, or propyl, more preferably, methyl; R8 is OR wherein R is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Preferably, R is 2- (dimethylamino) ethylaminocarbonyl; 1,1-dimethylethyloxycarbonyl; 2-diethyl aminoethylaminocarbonyl; dimethylaminopropyl; dimethylaminoethyl; methylamino carbonyl; diethylaminoethylol; methyloxyethyl; dimethylaminopropylaminocarbonyl; phenylmethyl; hydroxy; 2-pyrrolidinyl-1-ylaminocarbonyl; and n is 1-3. R3 is COR9 wherein R9 is optionally substituted aryl or optionally substituted aralkyl, preferably, phenyl. R9 is optionally substituted with one or more Q1 selected from the group consisting of halogen and optionally substituted alkyl, preferably methyl, chloro, fluoro, bromo and 3,4-difluoro.

In Embodiment 1, the invention provides a compound of the formula la, wherein each R6 and R7 is independently optionally substituted alkyl; preferably methyl; n is 0; R11 is optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; more preferably, methyl. R9 is optionally substituted alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Preferably, R 9 is piperidin-3-yl or piperidin-4-yl. R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, halo, and haloalkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, or methylethyldiethylamino; more preferably, methyl or methylethyldiethylamino.

The preferred compounds of embodiment 1 are selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- [(1-methylpiperidin-3-yl) carbonyl] -l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(1-methylpiperidin-4-yl) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; and 1-methylethyl 3- [4- (dimethylamino) butanoyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate.

In embodiment 2, the invention provides a compound of the formula wherein each R6 and R7 is independently optionally substituted alkyl; preferably methyl; n is 0; R9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; preferably, R9 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, cycloheptyl; dimethylaminopropyl, 4-methylpentyl; (3s, 5s, 7s) -trikel [3.3.1.1-3, 7 ~] dec-1-yl; more preferably, butyl, cyclohexyl or cycloheptyl. R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl. Each R 10 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl.

Preferred compounds of Embodiment 2 are selected from the group consisting of: 1-methylethyl 3- (cyclohexylcarbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-acetyl-1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3-butanoyl-l, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-pentanoyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- (cyclopentylcarbonyl) -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- (2,2-dimethyl propanoyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- (2-ethylbutanoyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (3-methylbutanoyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- (cycloheptylcarbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-propanoyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3s, 5s, 7s) -tricyclo [3.3.1.1.-3, 7-] dec-1-ylcarbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; and 1-methylethyl 1, l-dimethyl-3- (4-methylpentanoyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; In Embodiment 3, the invention provides a compound of formula Ib wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl; n is 0; each R11 is hydrogen or optionally substituted alkyl; preferably hydrogen, methyl, or ethyl; more preferably hydrogen; R 12 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylamino, dimethylamino, 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-morpholin-4-ylpropyl) amino, or piperidinyl. R11 and R12 together with the atom to which they are attached form optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl; preferably pyrrolidin-1-yl, 4-pyrrolidin-1-yl, piperidin-1-yl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-piperazin-1-yl, 4-propyl-piperazin-1 -yl, piperidin-3-yl, piperidinyl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl or azepanyl.

R11 and R12 together are optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl, and heterocyclylalkyl; preferably methyl, ethyl, propyl, diethylamino, dimethylamino, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyloxymethyl, phenyl, phenylmethyl, pyrrolidinyl, piperazinyl, piperidinyl, methylpiperidinyl, methylpiperazinyl, 2-oxo-2-pyrrolidinylethyl, or morpholino-4-methyl.

The preferred compounds of embodiment 3 are selected from the group consisting of: 1-methylethyl 1, 1-dimethyl-3. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-pyrrolidin-1-yl) piperidin-1-yl) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 1, l-dimethyl-3- (piperidin-1-ylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { [3- (dimethylamino) propyl] amino.} Carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { [4- (4-methyl-piperazin-1-yl) -phenyl] -amino} -carbonyl) -1,2,3,6-tetrahydroazepine [4, 5] b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (pyrrolidin-1-ylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { [2- (dimethylamino) ethyl] amino.} Carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [(3-morpholin-4-ylpropyl) amino] carbonyl} -l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [(2-morpholin-4-ylethyl) amino] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4-ethylpiperazin-1-yl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- (3-piperazin-1-ylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- (([2- (diethylamino) ethyl] (ethyl) amino.} Carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate: 1-methylethyl 1, l-dimethyl-3- ((4- [(1-methylpiperidin-4-yl) methyl] piperazin-1-yl}. carbonyl) -1, 2, 3, 6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ([4- (1-methylethyl) piperidin-1-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5 -carboxylate: 1-methylethyl 1, l-dimethyl-3- [(4-propylpiperidin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 9-fluoro-l, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 3- { [4- (diethylamino) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-methylethyl 8-fluoro-l, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5- carboxylate; 1-methylethyl 3- [(4-ethylpiperazin-1-yl) carbonyl] -8-fluoro-1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5- carboxylate; 1-Methylethyl 1, l-dimethyl-3- ([4- (2-oxo-2-pyrrolidin-1-ylethyl) piperazin-1-yl] carbonyl] -1, 2, 3, 6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-methylethyl 3- (. {4- [2- (diethylamino) ethyl] piperazin-1-yl}. Carbonyl) -1, 1-dimethyl-2, , 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (dimethylamino) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- (azepin-1-ylcarbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-methyl-1,4-diazepan-1-yl) carbonyl] -l, 2,3,6-tetrahydroaze? Ino [4,5-b] indole 5-carboxylate; 1-methylethyl 1, l-dimethyl-3- (morpholin-4-ylcarbonyl) -1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(dimethylamino) methyl] piperidin-1-yl}. Carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole -5-carboxylate; 1-Methylethyl 3- ( { (3S) -3- [(dimethylamino) methyl] piperidin-1-yl}. Carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { (3R) -3- [(dimethylamino) methyl] piperidin-1-yl}. Carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(diethylamino) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ([3- (morpholin-4-ylmethyl) piperidin-1-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole -5-carboxylate; 1-methylethyl 1, l-dimethyl-3- ([(3S) -piperidin-3-ylamino] carbonyl} - 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole -5-carboxylate; 1-methylethyl 3- {[[3- (. {[[3- (dimethylamino) propyl] oxy} methyl) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- [(piperidin-3-ylamino) carbonyl] -l, 2,3,6- tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, 1-dimethyl-3 { [(3R) -3- (morpholin-4-ylmethyl) piperidin-1-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3 { [(3R) -3- (piperidin-1 ethyl-ethyl-piperidin-1-yl] -carbonyl, -l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl-1, l-dimethyl-3-. { . [4- (phenylmethyl) -1,4-diazepane-1-yl] carbonyl.] -1, 2, 3, 6-tetrahydroazepi no [4, 5-b] indole-5-carboxylate; and 1-methylethyl 3- [(3'R) -l, 3'-bipiperazin-l '-ilcarbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate.

In Embodiment 4, the invention provides a compound of Formula Ib wherein each Rd and R7 is independently optionally substituted alkyl, preferably methyl; n is 0; each R10 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, isopropyl. Each R 11 is preferably hydrogen or optionally substituted alkyl; preferably methyl, or ethyl; more preferably, hydrogen; R 12 is optionally substituted alkyl, preferably methyl, ethyl, propyl; optionally substituted cycloalkyl or optionally substituted cycloalkylalkyl, preferably, cyclopentyl, cyclohexyl, cyclopheptyl; optionally substituted aryl or optionally substituted aralkyl, preferably phenylmethyl or phenyl. Preferred compounds of embodiment 4 are selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- [(propylamino) carbonyl] -1,2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate; 1-methylethyl 3- [(cyclopentylamino) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(cyclohexylamino) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(cycloheptylamino) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; and 1-methylethyl 1, l-dimethyl-3-. { [(phenylmethyl) amino] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate.

In embodiment 5, the invention provides a compound of the formula le wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl; n is 0-3; R8 is optionally substituted alkyl or halo, preferably fluoro, chloro or bromo; each R 11 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, isopropyl. Q1 is independently hydroxy, halogen, haloalkyl, haloalkoxy, optionally substituted alkyl, alkoxy, cyano, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; Q1 is preferably hydroxy, cyano, 2-methyl; 3-methyl; methylpiperazinyl, 3-chloromethyl, 3,4-difluoro; 3-methyl, 4-ethyl; 2-methyloxy; 3-methyloxy; 4-methyloxy; 3-fluoro-4-methyl; 4-fluoro-3-methyl; 2-trifluoromethyloxy; 2-chloro; 3-chloro; 4-chloro; 2,4-dichloro; 2-chloro-3,6-difluoro, 3-chloro-2,6-difluoro, 2-fluoro; 3-fluoro; 2-bromine; 3-trifluoromethyl; 2, 3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6-difluoro; 3, -difluoro; 3, 6-difluoro; 3, 4-difluoro; 2,3-difluoro-4-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 2-fluoro-3-trifluoromethyl; 3-fluoro-5-trifluoromethyl; 2,5-bistrifluoromethyl; 3, 5-bistrifluoromethyl; 3-chloro-2-fluoro-4-trifluoromethyl 3-fluoro-4-trifluoromethyl; 4-fluoro-3-trifluoromethyl; 4-fluoro-2-trifluoromethyl; 2-chloro-4-fluoro; 3-chloro-4-fluoro; 2-trifluoromethyl; 4 -trifluoromethyl; 2, 3, 4-trifluoro; 2, 4, 6-trifluoro; 2, 4, 5-trifluoro; 3,4-bis (methyloxy); 3-phenylmethyloxy; or methyloxyphenylmethyloxy; m is 0-3. The preferred compounds of embodiment 5 are selected from the group consisting of: 1-methylethyl 3- [(2-chloro-3,6-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- (phenylcarbonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [2- (trifluoromethyl) phenyl] carbonyl} -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [4- (trifluoromethyl) phenyl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-chlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-bromophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2-methylphenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [2- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {2- 2- [(trifluoromethyl) oxy] phenyl] carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(3-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(2,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2, 3-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2,6-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(2, 5-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2,3,4-trifluorophenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2,6,6-trifluorophenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2,4,5-trifluorophenyl) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-chlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4-chlorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3-fluoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3-methylphenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-methylphenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [4- (methyloxy) phenyl] carbonyl} -l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-N- (1-methylethyl) -1,2,3,4,5,5,6-hexahydroazepino [4, 5-b] indole-5 -carboxylate; 1-methylethyl 3-. { [3,4-bis (methyloxy) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1- . { 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-i1} -etanone; 1-Methylethyl 1, l-dimethyl-3- [(5- (methylisoxazol-3-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- {[4-fluoro-2- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; -methylethyl 3- [(2-chloro-4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- {. [3- [Chloromethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 2-chloro-l- {.3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-yl.} Ethanone; - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, 1-dimethyl-3 - ( { 3- [(phenylmethyl) oxy] phenyl} carbonyl) -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, 1-dimethyl -3- { [3- (trifluoromethyl) phenyl] carbonyl.} - 1, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-fluoro-4-methylphenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-fluoro-4- (trifluoromethyl) phenyl] carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- {[[3-chloro-2-fluoro- (4-trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxylate; 1-Methylethyl 3- [(2-fluoro-3- (trifluoromethyl) phenyl] carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3-fluoro- (5-trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3,5-bis (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2,5-bis (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2, 3-difluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-hydroxyphenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(3-cyanophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(2,4-dichlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4-fluoro-3-methylphenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-chloro-2,6-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-chloro-4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(3,4-dichlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4-chloro-2,5-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(3-bromo-4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; and 1-methylethyl 3-. { [3,4-difluoro-5- ( { [4-methyloxy) phenyl] methyl} oxy) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate.

In embodiment 6, the invention provides a compound of the Formula wherein each R6 and R7 is independently optionally substituted alkyl; preferably methyl; n is 0; R9 is optionally substituted aryl, optionally substituted aralkyl, heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl. Preferably, R 9 is 1,3-benzodioxol-5-yl or methylisoxazol-3-yl. R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, halogen, and haloalkyl; preferably methyl or halogen, more preferably, methyl, F, Cl, or Br.

The preferred compounds of embodiment 6 are selected from the group consisting of: 1-methylethyl 3- (1,3-benzodioxol-5-ylcarbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxylate; 1-Methylethyl 3- [(2, 2-difluoro-1,3-benzodioxol-4-yl) carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate; 1-Methylethyl 3- [(2,2-difluoro-l, 3-benzodioxol-5-yl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate; and 1-methylethyl 1, l-dimethyl-3- [(5-methylisoxazol-3-yl-) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; In Embodiment 7, the invention provides a compound of Formula I, wherein each R6 and R7 is independently alkyl, preferably methyl; n is 0; each R 11 is independently substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, isopropyl. Q1 is independently optionally substituted alkyl, halogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; m is 0-3; Q1 is preferably 3, -difluoro; , 3-piperidin-4-yl, 3-piperidin-4-ylmethyl, piperidin-4-ylmethyl, dimethylaminomethyl, diethyl inometilo, dimethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, 4-methylsulfonylpiperazin-1-yl, 3-yl 4-piperidin-4 -azepan-1-ylmethyl, 4-methyl-1, 4-diazepane-1-yl, 3-pyrrolidin-1-ylethyl, 4-methyl-piperazin-1-ylmethyl; 4-ethylpiperazin-1-ylmethyl; 3-piperazin-1-ylmethyl; morpholin-4-ylmethyl; 3-morpholin-4-ylmethyl; 2-morpholin-4-ylethyloxy; 2-piperidin-1-ylethyloxy; 3-morpholin-4-ylpropyloxy-1H-pyrazol-1-yl, 4-trifluoromethyl-1H-pyrazol-1-yl, 4-acetylpiperazin-1-ylmethyl; methylbenzotriazolyl, dimethylethyloxycarbonylpiperazin-1-ylmethyl, 4-phenylsulfonylpiperazin-1-ylmethyl, 4-fluorophenylsulfonylpiperazin-1-yl, 4-ethylsulphonylpiperazin-1-ylmethyl, 4-cyclopropylcarbonylpiperazin-1-ylmethyl, 2-methylpropanoylpiperazin-1-ylmethyl, 4-acetyl-l, 4-diazepan-l-yl -fenilcarbonil piperazin-1-ylmethyl, 3-azocan-l-ylmethyl, 4-phenylamino-1-ylmethyl carbonilpiperazin; 4-ethylaminocarbonylpiperazin-1-ylmethyl; 3-piperidin-1-ylpropyloxy, 2-pyrrolidin-1-ylethyloxy; 3-piperidin-1-ylpropyloxy; or 3-morpholin-4-ylpropyloxy.

The preferred compounds of embodiment 7 are selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- [(4-piperidin-4-ylphenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3-piperidin-4-ylphenyl) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- ( { 4- [(dimethylamino) methyl] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 3- ( { 3- [(dimethylamino) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 3- ( { 3- [(diethylamino) methyl] phenyl} carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (pyrrolidin-1-ylmethyl) phenyl; carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (piperidin-4-ylmethyl) phenyl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ((3- [(4-methylpiperidin-1-yl) methyl] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indo1-5-carboxylate; 1-methylethyl 3- ((3- [(4-ethylpiperazin-l-yl) methyl] phenyl} carbonyl) - 1, 1-dimethyl-l, 2,3, 6-tetrahydroazepino [.. , 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(3- {[4- (dimethylamino) ethyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4, 5-b ] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [4- (lH-pyrazol-1-yl) phenyl] carbonyl} - 1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4-acetylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4, 5] b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (methylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (azepan-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {3- [3- (4-methyl-1,4-diazepane-1-yl) methyl] phenyl] carbonyl) -l, 2,3,6- tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-5- (morpholin-4-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(1-methyl-1 H-1, 2, 3-benzotriazol-5-yl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {4- [4- (trifluoromethyl) -lH-pyrazol-1-yl] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 1, 1-dimethyl-3- ((3- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [5-b] indole - 5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-5- (piperidin-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4. {[[(1, 1-dimethylethyl) oxy] carbonyl} piperazin-1-yl) methyl] phenyl} carbonyl) -1, 1 -dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (phenylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- ( { 4- [(4-fluorophenyl) sulfonyl] piperazin-1-yl}. Methyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[4- (ethylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[4- (cyclopropylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3. {[[4- (2-methylpropanoyl) piperazin-1-yl] methyl] phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5-b] indo-1-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (phenylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (Azocan-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4-acetyl-1,4-diazepan-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1,3,3,6- tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (piperazin-1-ylmethyl) phenyl] carbonyl} -l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ((3,4-difluoro-5- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate; 1-methylethyl 3- ( {3,4-difluoro-5- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- (. {4- [(2-morpholin-4 -ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indo-1-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 4- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1, 2, 3, 6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- ( { 4- [(phenylamino) carbonyl] piperazin-1-yl}. Methyl) phenyl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- ( { 4- [(ethylamino) carbonyl] piperazin-1-yl}. Methyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-Methylethyl 3- [(4- {[2- (dimethylamino) ethyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[3- (diethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4. {[[3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 4- [(2-pyrrolidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [5-b] ] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ((4- [(3-piperidin-1-yl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; and 1-methylethyl 1, 1-dimethyl-3- ( { - [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6- tetrahydroazepino [4, 5-b] indole-5-carboxylate.

In embodiment 8, the invention provides a compound of the formula Id wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl. Each R 11 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, isopropyl; p is 1-3; m is 0-3; Q1 is optionally substituted alkyl or halo; R28 is optionally substituted alkyl, aryl optionally substituted, aralkyl optionally substituted heterocyclyl optionally substituted, or heterocyclyl optionally substituted, preferably, R 28 is phenyl, dimethylamino, diethylamino, N-ethyl, N-methyl amino, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, or 4-methyloxyphenyl.

Preferred compounds of embodiment 8 are selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- (. {3- [(phenylmethyl) oxy] phenyl} carbonyl) -1,2,3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3- [(3. {[[2- (dimethylamino) ethyl] oxy} phenyl} carbonyl] -1.1 dimethyl-1, 2, 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3- [(3. {[[3- (dimethylamino) propyl] oxy} phenyl carbonyl] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- ((3- [(2) -piperidin-1-ylethyl) oxy] phenyl.} carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indo-1-5-carboxylate, 1-methylethyl 1, 1-dimethyl-3- ( { 3- [(2-morpholin-4-ylethyl) oxy] phenyl.}. carbonyl) -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3 - { [3, 4-difluoro-5- ( { [4- (methyloxy) phenyl] methyl.}. Oxy) phenyl] carbonyl] -1, 1-dimethyl-l, 2,3, 6-tetrahydroazepine [4, 5-b] indole-5- carboxylate, 1-methylethyl 3- (. { 3,4-difluoro-5- [(2-morpholin-ethyl) oxy] phenyl} carbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3- (. {3, 4-difluoro-5- [( 2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- ( { 4- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [5-b] indole-5- carboxylate, 1-methylethyl 1, l-dimethyl-3- ( { 4- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- (. {3- [3-morpholin-4-ylpropyl] oxy] phenyl] carbonyl) -1,2, 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- (. {3- [3-piperidin-1-ylpropyl] oxy] phenyl} carbonyl) -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3- [(- { [2- (dimethylamino) ethyl] oxy} phenyl ) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate, 1-methyl il 3- [(3-. { [3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3- [(4- {[3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3 - (. {-. [(2-1-ylethyl pirro1idin-) oxy] phenyl.} carbonyl.) -1,2,3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- ((4- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate, and 1-methylethyl 1, l-dimethyl-3- (. {4- [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1, 2, 3, 6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate.

In Embodiment 9, this invention provides a compound of the formula le wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl; n is 0; each R 11 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl; more preferably, isopropyl; p is 1-3; R29 is halogen, optionally substituted aryl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; preferably, R29 is dimethylamino, diethylamino, N-ethyl, N-methyl amino, chloro, morpholinyl, piperidinyl, piperazinyl, piperazin-1-ylmethyl, piperazin-1-ylethyl, pyrrolidinyl, morpholinyl, methyloxyphenyl; 4-acetylpiperazin-1-yl; 4-methylsulfonylpiperazin-1-yl; azepanil; azocan-1-yl; 4-methyl-l, 4-diazepan-1-yl; 4-acetyl-l, 4-diazepan-1-yl; dimethylethyloxycarbonylpiperazin-1-yl; 4-phenylsulfonyl piperazin-1-yl; 4-fluorophenylsulphonylpiperazin-1-yl; Ethylsulfonyl piperazin-1-yl; cyclopropylcarbonyl piperazin-1-yl; 2-methylpropanoyl piperazin-1-yl; phenylcarbonyl piperazin-1-yl; 4-phenylaminocarbonylpiperazin-1-yl; or 4-ethylaminocarbonylpiperazin-1-yl; Q1 is halogen or optionally substituted alkyl, preferably methyl, chloro, fluoro or bromo; m is 0-3.

Preferred compounds of embodiment 9 are selected from the group consisting of: 1-methylethyl 3- (. {3- [(dimethylamino) methyl] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3- (. {3- [3-diethylamino] methyl] phenyl}. carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, 1-dimethyl-3. { [3- (pyrrolidin-1-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- ([3- (piperidin-1-ylmethyl) phenyl] carbonyl.} .l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- (. {3- (4-methyl-piperazin-1-yl) ) methyl] phenyl} carbonyl) -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3- (. {3- [4-ethylpiperazin-1] -yl) methyl] phenyl} carbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3 - { [3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3- ( {3- [(4-acetylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate , 1-methylethyl 1, l-dimethyl-3- [(3. {[[4- (methylsulfonyl) piperazin-1-yl] methyl] phenyl) carbonyl] -l, 2,3,6-tetrahydroazepine [ 4,5-b] indole-5-carboxylate, 1-methylethyl 3- { [3- (azepan-1-ilmet il) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- (. {3- [4- methyl-l, 4-diazepan-l-yl) methyl] phenyl} carbonyl) -1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3-. { [2-fluoro-5- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3-. { [4-fluoro-3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3-. { [2-fluoro-5- (piperidin-1-ylmethyl) methyl] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3-. { [4-fluoro-3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3- (. {3- [(4- { [(1 , 1-dimethylethyl) oxy] carbonyl} piperazin-1-yl) methyl] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate, 1-methylethyl 1, l-dimethyl-3- [(3- {[[4- (phenylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6 -tetrahydroazepino [4, 5-b] indo1-5-carboxylate, 1-methylethyl 3-. { [3- ( { - [(4-fluorophenyl) sulfonyl] piperazin-1-yl}. Methyl) phenyl] carbonyl} -l, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 3- [(3 { [4- (ethylsulfonyl) piperazin- 1 -yl] methyl.}. phenyl) carbonyl] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate, 1-methylethyl 3- ([3-. { . [4- (cyclopropylcarbonyl) piperazin-1-yl] methyl] phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-Methylethyl 1, 1-dimethyl-3- [(3. {[[4- (2-methylpropanoyl) piperazin-1-methyl]} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [ 4, 5-b] indo1-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- [(3- {[[4- (phenylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate, 1-methylethyl 3-. { [3- (Azocan-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 3- ((3- [(4-acetyl-1,4-diazepam- 1-yl) methyl] phenyl.} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 1-methylethyl 1, 1-dimethyl- 3- { [3- (piperazin-1-ylmethyl) phenyl] carbonyl] -1, 2, 3, 6-tetrahydroazepino [4,5-b] indo-1-5-carboxylate, 1-methylethyl-1, -dimethyl-3- { [3- ( { 4- [(phenylamino) carbonyl] piperazin-1-yl}. methyl) phenyl] carbonyl.] - 1, 2,3,6-tetrahydroazepine [ 4,5-b] indole-5-carboxylate, and 1-methylethyl 3- {[[3- (. {4 - [(ethylamino) carbonyl] piperazin-1-yl} methyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate.

In Embodiment 10, the invention provides a compound of the formula wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl; n is 0. Each R 11 is independently optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl. Preferably, R 11 is 2,2-dimethyl-1,3-dioxolan-4-yl; 2-piperidin-1-ylethylaminocarbonyl; 2,3-dihydroxypropyl or 2-fluoro-1- (fluoromethyl) ethyl, hydroxyethyl, phenylmethyloxyethyl, 3,4-difluorophenylcarbonyloxy-1-methylethyl, 2-hydroxy-1-methylethyl; p is 1-3; Q1 is halogen or optionally substituted alkyl, preferably methyl, chloro, fluoro, bromo or 3, -difluoro; m is 0-3.

Preferred compounds of embodiment 10 are selected from the group consisting of: (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- [(3,4-difluorophenyl) carbonyl] -1,3-dimethyl -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 2,3-dihydroxypropyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-2, , 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, (2R) -2,3-dihydroxypropyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2 , 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 2-fluoro-1- (fluoromethyl) ethyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylmethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-8 ( { [(2 -piperidin-1-ylethyl) amino] carbonyl.} oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, (2S) -2,3-dihydroxypropyl 3- [ (3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 2-hydroxy-1-methylethyl 3- [(3 , 4-difluorofe nil) carbonyl] -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, 2-. { [(3,4-difluorophenyl) carbonyl] oxy} -1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 2- [(phenylmethyl ) oxy] ethyl 3- [(3, -difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, and 2-hydroxyethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate.

In embodiment 11, the invention provides a compound of the formula Ilb, wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl; n is 0-3; R is optionally substituted alkyl or halo, preferably chloro, bromo or fluoro. Each R 11 is independently optionally substituted alkyl, preferably isopropyl; beta-alanine, 2,3-dihydroxypropyl; or 2-hydroxy-1- (hydroxymethyl) ethyl; Q1 is halogen or optionally substituted alkyl, preferably methyl, chloro, fluoro, bromo or 3,4-difluoro; m is 0-3.

The preferred compounds of embodiment 11 are selected from the group consisting of: N- (. {3- [3-4-difluorophenyl] carbonyl] -l, 1-dimethyl-l, 2, 3,4,5,6 hexahydroazepino [4, 5-b] indol-5-i1.} carbonyl) -beta-alanine; N- ( { 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indol-5-yl.} Carbonyl ) -beta-alanine; 3- [(3,4-difluorophenyl) carbonyl] -N- [(2,3-dihydroxypropyl) oxy] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxamide; 3- [(3,4-difluorophenyl) carbonyl] -N- (2,3-dihydroxypropyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxamide; 3- [(3,4-difluorophenyl) carbonyl] -N- [2-hydroxy-1- (hydroxymethyl) ethyl] -1,1-dimethyl-1,2,6,6-tetrahydroazepine [4, 5-b] indole-5-carboxamide; and 5- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-N- (1-methylethyl) -1,2,3,4,5,6-hexahydroazepino [4,5-b] indole 5-carboxamide.

In Embodiment 12, the invention provides a compound of formula III, wherein each R6 and R7 is independently optionally substituted alkyl, preferably methyl; R9 is optionally substituted aryl, preferably 3,4-difluorophenyl; each R is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Preferably, R is 2- (dimethylamino) ethylaminocarbonyl; 1,1-di ethylethyloxycarbonyl; 2-diethyl aminoethylaminocarbonyl; dimethylaminopropyl; dimethylaminoethyl; methylamino carbonyl; diethylaminoethyl; methyloxyethyl; dimethylaminopropylaminocarbonyl; phenylmethyl; hydroxy; 2-pyrrolidinyl-1-ylaminocarbonyl. Each R 11 is independently optionally substituted alkyl, preferably methyl, ethyl, propyl, isopropyl; more preferably, isopropyl.

Preferred compounds of embodiment 12 are selected from the group consisting of: 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8- [( { [2- (dimethylamino) ethyl] amino} carbonyl ) oxy] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8- ( { [(1,1-dimethylethyl) oxy] carbonyl.] Oxy) -1,1-dimethyl-l, 2,3 , 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 8 - [( { [2- (Diethylamino) ethyl] amino.} Carbonyl) oxy] -3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8-. { [2- (dimethylamino) ethyl] oxy} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8-. { [3- (dimethylamino) propyl] oxy} -l, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8-. { [(methylamino) carbonyl] oxy} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 8-. { [2- (diethylamino) ethyl] oxy} -3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 8-. { [3- (diethylamino) propyl] oxy} -3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3, -difluorophenyl) carbonyl] -1, 1-dimethyl-8-. { [2- (methyloxy) ethyl] oxy} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 8 - [( { [3- (Diethylamino) propyl] amino.} Carbonyl) oxy] -3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2, 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3, -difluorophenyl) carbonyl] -1, l-dimethyl-8- [(phenylmethyl) oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -9-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; and 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- ( { [(2-pyrrolidin-1-ylethyl) amino] carbonyl.} oxy] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate.

In Embodiment 12, the invention provides a compound of the formula I, wherein R6 or R7 is optionally substituted alkyl, preferably methyl; R1 is C (J) R1: L; wherein J is 0 and R11 is optionally substituted alkyl, preferably methyl; n is 0 and R3 is hydrogen.

The compounds of Table 2 are specifically excluded from the scope of this invention.

Table 2 Ethyl 3- [(4-fluorophenyl) carbonyl] -8-furan-3-yl-1, 1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; ethyl 8-furan-3-yl-l, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(3,4-difluorophenyl) carbonyl] -8-furan-3-yl-l, 1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- [methyl (phenylmethyl) amino] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- [3- (methyloxy) phenyl] -1,2,3,6-tetrahydroazepino [4,5-b] indo-1-5-carboxylate; ethyl 3- [(3, -difluorophenyl) carbonyl] -1, l-dimethyl-8- [3- (methyloxy) phenyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -8-. { [(dimethylamino) carbonyl] (methyl) amino} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -9-. { [(4-fluorophenyl) carbonyl] amino} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 9- (acetyla ino) -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; ethyl 9- [bis (phenylmethyl) amino] -3 - [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 9-. { [(dimethylamino) carbonyl] amino} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9-. { [(methyloxy) acetyl] amino} -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(morpholin-4-ylcarbonyl) amino] -1,2,3,6-tetrahydroazepino [5-b] indole-5- carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -l, l-dimethyl-9 - [(2-thienylacetyl) amino] -1,2,3,6-tetrahydroazepino [4,5-b] indo-1-5-carboxylate; ethyl 9- (dimethylamino) -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(phenylmethyl) amino] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 9-amino-3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- [(phenylmethyl) (2-thienylacetyl) amino] -1,2,3,6-tetrahydroazepino [5-b] indole-5 -carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- (. {[[(1-methylethii; amino] carbonyl} amino) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate, ethyl 8-. {[[(Dimethylamino) carbonyl] (methyl) amino.} -1, 1-dimethyl-1,2,3,6-tetrahydro azepino [5] -b] indole-5-carboxylate, ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(methylsulfonyl) amino] -1,2,3,6-tetrahydroazepine [4, 5] b] indo1-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9-. { [(2,2,2-trifluoroethyl) sulfonyl] amino} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- (methyl { [(1-methylethyl) amino] carbonyl}. amino) -1,2,3,6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- [methyl (2-thienylacetyl) amino] -1,2,3,6-tetrahydroazepino [4, 5-b] indo1-5- carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9-. { [(phenylmethyl) sulfonyl] amino} -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(3-methylbutanoyl) amino] -1,2,3,6-tetrahydroazepino [4,5-b] indo-1-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(phenylacetyl) amino] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- ( { [(phenylmethyl) amino] carbonyl}. amino) -1,2,3,6-tetrahydroazepine [4, 5 -b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- ( { [timethylethyl) oxy] carbonyl} amino) -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- ( { [(phenylmethyl) oxy] carbonyl} amino) -1,2,3,6-tetrahydroazepine [4, 5 -b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- ( { [methyl (phenyl) amino] carbonyl} amino) -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 9 - [(2,2-dimethylpropanoyl) amino] -3 - [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5 -carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -l, l-dimethyl-9- [( { [(1S) -1-phenylethyl] amino.} carbonyl) amino] -1, 2, 3, 6 -tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 9-. { [(cyclopentylamino) carbonyl] amino} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 9- [acety1 (methyl) amino] -3 - [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8-. { methyl [(methylamino) carbonyl] amino} -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8- [methyl ( { [(1S) -1-phenylethyl] amino} carbonyl) amino] -1,2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- (methyl { [(phenylmethyl) amino] carbonothioyl}. amino) -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -8- [. { [(furan-2-ylmethyl) amino] carbonothioyl} (methyl) amino] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8- [bis (phenylmethyl) amino] -3 - [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; N-cyclobutyl-3- [(3,4-difluorophenyl) carbonyl] -1-methyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxamide; ethyl 8-. { [(dimethylamino) carbonyl] amino} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8-. { [(dimethylamino) carbonyl] (methyl) amino} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; N-Cyclobutyl-3- [(3, -difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxamide; ethyl 8 - [(2-chloroethyl) (methyl) amino] -3- [(4-fluorophenyl) carbonyl [1,1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole-5- carboxylate; ethyl 3- [(3,4-difluorophenyl) carbonyl] -1, l-dimethyl-8- [methyl (phenylmethyl) amino] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- [methyl (pyrrolidin-1-ylcarbonyl) amino] -1,2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- [methyl (morpholin-4-ylcarbonyl) amino] -1,2,3,6-tetrahydroazepino [4,5-b] indo1- 5-carboxylate; ethyl 9-. { [(dimethylamino) carbonyl] (phenylmethyl) amino} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 1,1,3,6-tetramethyl-1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8- (methyl { [(2-pyridin-2-ylethyl) amino] carbonyl} amino) -1,2,3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -8-. { [(4-fluorophenyl) carbonyl] (methyl) amino} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8-. { [(cyclopropylamino) carbonyl] (methyl) amino} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8- (methyl. {[[(pyridin-2-ylmethyl) amino] carbonyl} amino) -1,2,3,6- tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(3,4-difluorophenyl) carbonyl] -3,6-dihydro-2H-spiro [azepino [4,5-b] indole-1,1'-cyclopentane] -5-carboxylate; ethyl 1, l-dimethyl-3-. { [4- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3 - [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3 - [(4-fluorophenyl) carbonyl] -1- (phenylmethyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8-bromo-3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 9-fluoro-3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -9-fluoro-1, 1-dimethyl-1,2,3, β-tetrahydroazepino [5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -9-fluoro-l, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 9-fluoro-3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; _ Q ethyl 3- [(4-fluorophenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3 - [(4-chlorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; ethyl 2- [(4-fluorophenyl) carbonyl] -4,4-dimethyl-2, 3,4,9-tetrahydro-lH-beta-carboline-1-carboxylate; ethyl 2- [(3,4-difluorophenyl) carbonyl] -4,4-dimethyl-2, 3,4,9- 0 tetrahydro-1H-beta-carboline-1-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1,6-trimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- [(phenylmethyl) oxy] -1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -8-hydroxy-1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8 - [(2-morpholin-4-ylethyl) oxy] -l, 2,3,6-tetrahydroazepino [4,5-b] indole -5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8 - [(2-piperidin-1-ylethyl) oixi] -1,2,3,6-tetrahydroazepino [4, 5-b] indole -5-carboxylate; ethyl 8-. { [2- (ethyloxy) -2-oxoethyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 8 - [(2-amino-2-oxoethyl) oxy] -3- [(4-fluorophenyl) carbonyl; 1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl- ( { [methyl (phenyl) amino] carbonyl} oxy] -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; ethyl 8- [( { [2- (dimethylamino) ethyl] amino.} carbonyl) oxy] -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6- tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 9-. { [(dimethylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(morpholin-4-ylcarbonyl) oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indo1-5 -carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9 - [(pyrrolidin-1-ylcarbonyl) oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indo1-5 -carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, l-dimethyl-8- [(phenylmethyl) oxy] -1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -9-hydroxy-1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -8 - [(3-hydroxypropyl) oxy] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 8-. { [(cyclopropylamino) carbonyl] oxy} -3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8-. { [(methylamino) carbonyl] oxy} -1, 2, 3, 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- ( { [(pyridin-2-ylmethyl) amino] carbonyl.} oxy] -1,2, 3, 6 -tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- ( { [(2-thienylmethyl) amino] carbonyl} oxy) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-9- ( { [(pyridin-2-ylmethyl) amino] carbonyl} oxy) -1, 2, 3, 6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, l-dimethyl-8- ([(propylamino) carbonyl] oxy}. -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1,1-dimethyl- ( { [(phenylmethyl) araino] carbonyl} oxy) -l, 2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxylate; Ethyl 3- [(3,4-difluorophenyl) carbonyl] -1, l-dimethyl-8- ([(phenylamino) carbonyl] oxy}. -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; Ethyl 3- [(3, 4-difluorophenyl) carbonyl] -8- [( { [(4-fluorophenyl) methyl] amino} carbonyl) oxy] -1,1-dimethyl-l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- [( { [(IR) -1-phenylethyl] amino.} carbonyl) oxy] -1, 2, 3 , 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- [( { [(1S) -1-phenylethyl] amino.} carbonyl) oxy] -l, 2,3 , 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(phenylmethyl) amino] carbonyl} oxy) -l, 2,3,6-tetrahydroazepine [4, 5 -b] indole-5-carboxylate; 'Ethyl 3- [(3,4-difluorophenyl) carbonyl] -8- ( { [(1,1-dimethylethyl) amino] carbonyl.} oxy] -1,1-dimethyl-l, 2,3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8- ( { [(1, 1-dimethylethyl) amino] carbonyl.}. oxy) -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 'Ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8- [( { [(1S) -1-phenylethyl] amino.} carbonyl) oxy] -1, 2, 3, 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 8-. { [(2,3-dihydro-l-benzofuran-5-ylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8-. { [(dimethylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 8-. { [(diethylamino) carbonyl] oixi} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8 - [(morpholin-4-ylcarbonyl) oxy] -1,2,3,6-tetrahydroazepino [5-b] indole-5- carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8 - [(piperidin-1-ylcarbonyl) oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- [(pyrrolidin-1-ylcarbonyl) oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate; ethyl 8-. { [(ethyloxy) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8-. { [(phenyloxy) carbonyl] oxy} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(phenylmethyl) oxy] carbonyl} oxy) -1,2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8- (([methyl (phenyl) amino] carbonyl) oxy] -l, 2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; ethyl 8- [( { [2- (dimethylamino) ethyl] amino.} carbonyl) oxy] -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2, 3, 6 tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8- [( { [2- (dimethylamino) ethyl] oxy} carbonyl) oxy] -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6- tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(-fluorophenyl) carbonyl] -1, l-dimethyl-8- (. {[[(2-pyridin-2-ylethyl) amino] carbonyl} oxy] -1,2, 3,6- tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8- ( { [bis (1-methylethyl) amino] carbonyl}. oxy) -3 - [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [ 4,5-b] indole-5-carboxylate; 'Ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8-. { [(2-oxoimidazolidin-1-yl) carbonyl] oxy} -l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8-. { [(4-methylpiperazin-1-yl) carbonyl] oxy} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(pyridin-4-ylmethyl) amino] carbonyl} oxy) -1, 2, 3, 6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 8 - [(azetidin-1-ylcarbonyl) oxy] -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indolyl-5 -carboxilate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8-. { [(4-pyridin-2-ylpiperazin-1-yl) carbonyl] oxy} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 8-. { [(cyclopropylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8- ( { [ethyl (1-methylethyl) amino] carbonyl.] oxy] -3- [(-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(pyridin-2-ylmethyl) amino] carbonyl} oxy) -1, 2, 3, 6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(pyridin-3-ylmethyl) amino] carbonyl} oxy) -1, 2, 3, 6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- (. {[[(4-methyl-piperazin-1-yl) amino] carbonyl] .ii) -1,2, 3,6 -tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(2-phenylethyl) amino] carbonyl} oxy) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(2-thienylmethyl) amino] carbonyl} oxy) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -8- ( { [(furan-2-ylmethyl) amino] carbonyl}. oxy) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; ethyl 8-. { [(cyclobutylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; ethyl 8-. { [(cyclopentylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 8-. { [(cyclohexylamino) carbonyl] oxy} -3- [(4-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; Ethyl 3- [(4-fluorophenyl) carbonyl] -1, 1-dimethyl-8 - [( { [(5-Methylpyrazin-2-yl) methyl] amino.} carbonyl) oxy] -1, 2, 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8-. { [(methylamino) carbonyl] oxy} -l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- [(4-fluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(1-methylethyl) amino] carbonyl} oxy) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 3- [(3,4-difluorophenyl) carbonyl] -9-fluoro-l, 1-dimethyl-N- (1-methylethyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5 -carboxamide; 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-N- (1-methylethyl) -1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxamide; ethyl 3- (1,3-benzodioxol-5-ylcarbonyl) -1-methyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- (1,3-benzodioxol-5-ylcarbonyl) -1-ethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; ethyl 3- (1,3-benzodioxol-5-ylcarbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; ethyl 3- [(3,4-difluorophenyl) carbonyl] -3,6-dihydro-2H-spiro [azepino [4,5-b] indole-1,1 '-cyclobutane] -5-carboxylate; ethyl 3- [(3, 4-difluorophenyl) carbonyl] -3,6-dihydro-2H-spiro [azepino [4, 5-b] indole-1,1 '-cyclopropane] -5-carboxylate; 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -3,6-dihydro-2H-spiro [azepino [4,5-b] indole-1,1 '-cyclopropane] -5-carboxylate; or ethyl 3- [(3,4-difluorophenyl) carbonyl] -3,6-dihydro-2H-spiro [azepino [4,5-b] indole-1,1'-cyclopentane] -5-carboxylate.

Preparation of the Compounds of the invention The starting materials of the synthesis examples provided herein are available, either on the market or by methods found in the literature. { for example, March Advanced Organi c Chemistry: Rea ctíons, Meisms, and Structure, (1992) 4th Ed .; Wiley Interscience, New York). All the compounds available on the market were used without further purification, unless otherwise indicated. CDCI3 (99.8% D, Cambridge Isotope Laboratories) was used in all experiments as indicated. Nuclear magnetic resonance (NMR) spectra (XH) were recorded on a Bruker Avance 400 MHz NMR spectrometer. Significant peaks were tabulated and generally include: number of protons, and multiplicity (s, singlet; d, doublet t, triplet; q, quartet; m, multiplet; br s, broad singlet). The chemical shifts are expressed in parts per million (d) relative to tetramethylsilane. Low resolution mass spectra (MS) were obtained as mass spectra by ionization with electrodispersion (ESI), which were recorded in a Perkin-Elmer SCIEX HPLC / MS instrument under reverse phase conditions (acetonitrile / water, trifluoroacetic acid 0.05%). For the flash chromatography Merck Silica Gel 60 (230-400 mesh) was used following the standard protocol (Still et al (1978) J. Org. Chem. 43: 2923). It is understood that in the following description, combinations of the substituents and / or variables of the described formulas are allowed only if such interventions result in stable compounds under normal conditions.

Also, those skilled in the art will appreciate that in the process described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkysilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C (0) -R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl, trifly and the like. Suitable protecting groups for the carboxylic acid include alkyl, aryl or aralkyl esters.

The protecting groups can be added or deleted according to conventional techniques, which are well known to those skilled in the art and which are described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective groups in Organi c Syn thesis (1991), 2nd Ed., Wiley-Interscience.

In the following Schemes, unless otherwise indicated, the various substituents R1-26, and R32-34 are as defined above in the Synthesis of the Invention, X is halo and Y is 0, N or S, and A is S, 0 or NH. The groups R8 in the following schemes further correspond to the groups R8 of the Synthesis of the Invention, to which more specifically reference is made as R8a, R8b, R8c and R8d. The person skilled in the art will be able to easily determine which are the possible options for each substituent, according to the reaction conditions of each Scheme. Also, the substituents are selected from the components as indicated in the specification so far and can be attached to the starting materials, intermediates, and / or final products according to the schemes known to those skilled in the art.

It is also evident that several of the products can be present as one or more isomers, ie isomers, enantiomers and / or diastereomers E / Z.

Scheme 1 below describes the synthesis of the compounds of formula (I). In general, heteroar-3-yl-2-ethylamines (1) are condensed with haloketones (2) (or haloaldehydes) and subjected to rearrangements to provide azepines (3), which can then be reacted with electrophiles to provide the products (4) of formula I. In particular, the heteroar-3-yl-2-ethylamines (Rq-Ra described above) consist of optionally substituted triptamines (A = NH), benzofuran-3-yl (A = O) and benzo [b] thiophen-3-yl-2-ethylamines (A = S). For example, a haloketone 2 can be chloro- or bro-opyruvate (R1 = C02R and R2 = H) and the electrophiles can be acyl chlorides or sulfonyl chlorides, chloroformates, isocyanates or isothiocyanates (R3 = COR, S02R, C02R, CONRR ' and CSNRR ', respectively). SCHEME 1 Several haloketones 2 (for example, R 1 and R 2 = alkyl or aryl) are commercially available and can be easily prepared by common procedures found in the literature. In addition, as described in Scheme 2 below, several 3 -halopiruvates (6, R2 = H) can be prepared by esterification of the corresponding alcohols (Rx0H) with 3 -halopyrubic chloride (5) (Teague, et al, Bioorg. & Med. Chem. Lett. 1995, 5, 2341-2346). SCHEME 2 X = CI or Rr 5 6 As described in Scheme 3 below, the higher 3-halopyruvates 6b (eg, R2 = alkyl) can be synthesized by oxidative broadening of a-hydroxyesters (7) (Heterocycles 1991, 32, 693). While the non-hydrogen substituent R2 can be incorporated into the final azepine products of formula I (eg, 4), the Schemes below will describe examples that have been simplified by the omission of R2. SCHEME 3 Some substituted tryptamines (11, A = NH) are commercially available, although many of them can be prepared from indoles (8, A = NH) as described in Scheme 4 below. For example, indoles 8 can be formylated to provide aldehydes (9, A = NH) (Mor et al., J. Med. Chem. 1998, 41, 3831-3844). These 3-formylindoles 9 can be subjected to a Henry reaction (Rosini Comp.Org Syn. 1991, 2, 321-340) with 1-nitroalkanes to provide nitroalkenes (10, A = NH), which can be reduced (ie say, catalytic hydrogenation or lithium aluminum hydroxide) and then treat with HCl to obtain tryptamine hydrochlorides 11. Similarly, other substituted heteroar-3-yl-2-ethylamines 11 (A = 0 or S) can be synthesized from of its corresponding heterocycle 8, that is, benzofurans and benzothiophenes. A variety of indoles can also be prepared by the Fischer indole synthesis (Smith &March, March 's Advanced Organi c Chemis try, 5th Ed., John Wiley and Sons: NY, 2001, ppl453-24). SCHEME 4 S 10 eleven As described in Scheme 5 below, other substituted tryptamines (16) can also be prepared. The protection of 3-indolyl acetonitriles (14), for example, with Boc (tert-butoxycarbonyl) followed by mono- or dialkylation, and subsequent deprotection may provide substituted 3-indolyl acetonitriles (15). Reduction of 15, for example, with lithium aluminum hydride, followed by treatment with HCl provides tryptamine hydrochloride 16. Thus, for example, the monoalkyl species 15 (e.g. R2 = H, R6) can be Prepare by adding 1 equivalent of alkyl halide. The Gem-dialkyl 15 species (R = Rd = R7) can be prepared from 2 equivalents of alkyl halide and the hetero-dialkyl species 15 (R2 = R6, R7) can be prepared by the sequential addition of 1 equivalent each two alkyl halides. Intermediates 14 can be easily prepared from grains (13), which are available on the market or can be synthesized from indoles (12) (Brown and Carrison, J. Chem. Chem. Soc. 1955, 77, 3839-3842). In general, the gramines (13) can be treated with methyl iodide to form a quaternary ammonium salt, which can be displaced with cyanide to provide 3-indolyl acetonitriles 14. Benzofuran-3-yl and benzo [b] thiophen-3 -yl ethylamines 7 (A = O and S) can be prepared using similar methods, in which the protection and deprotection steps are not necessary. SCHEME 5 I 3) TFA 15 16 The preparation of spirocyclic analogues (18) of tryptamine can also be achieved as described in Scheme 6 below. For example, intermediate 14 can be protected with benzyl bromide followed by alkylation with an alkyl dihalide, for example, 1,4-dibromobutane, to provide the corresponding intermediate (17, n = 2). Subsequently, 17 can be reduced, deprotected (for example, with sodium metal in liquid ammonia) and can be treated with HCl to provide spiro-substituted tryptamine hydrochloride 18.

SCHEME 6 17 18 As described in Scheme 7 below, substituted tryptamines (21, A = NH) can also be prepared by Knoevenagel condensation of 3-indolyl acetonitrile (19, A = NH) with an aldehyde to provide acrylonitriles (20, A = NH). The subsequent reduction, for example, Raney nickel, and treatment with HCl can produce tryptamine hydrochlorides 21. Benzofuran-3-yl and benzo [b] thiophen-3-yl ethylamines 21 analogues can also be prepared (A = O and S ) using similar methods.

SCHEME 7 19 20 21 As described in Scheme 8 below, the azepine ring present in the compounds of formula I (for example, 23) can be achieved by the Pictet-Spengler reaction and its subsequent rearrangement. Thus, for example, tpptamines 1 (A = NH) can react with a ketone such as 3-halop? Ruvates 6 to provide β-carboline intermediates (22), which are then heated under basic conditions, i.e. with ASD or in pipdin, to provide azepines (23) (Kuehne et al (1985) J. Org. Chem. 50: 919-924). Subsequent treatment of 23 with electrophiles, i.e., acyl or sulfonyl chlorides, isocyanates and chloroformates, in the presence of a base, eg, TEA, provides the final products 24. Such intermediates 23 and products 24 can then be derivatized to provide additional compounds of formula I, as described in the subsequent Schemes. Likewise, azepine [4,5-b] benzofurans (24, A = 0) and azepino [4,5-b] benzothiophenes (24, A = S) can be prepared in a similar manner from heteroar-3 -? l-2-et? lam? nas 1 (A = 0 and S).

SCHEME 8 Similarly, other haloketones (eg, R1 = alkyl or aryl) can be subjected to a similar reaction sequence to provide the corresponding azepines (26), as described in Scheme 9 below. SCHEME 9 As described in Scheme 10 below, hexahydroazepine compounds (25) can be synthesized by the reduction of azepines 23. For example, tetrahydroazepino [4,5-b] indoles 23 can be reduced with NaBH 3 CN to provide hexahydroazepine [ 4, 5-b] indoles 25 (Kuehne et al. (1985) J. Org. Chem. 50: 919-924), which can be treated with an electrophilic, for example, acyl chloride, to provide the corresponding product of azepine (26). SCHEME 10 23 27 28 As described in Scheme 11 below, the 5-esters 27 can be converted to 5-amides (30) by a multi-step reaction sequence. The azepine 27 can be treated with several amines to provide the corresponding amides (29), which can then be reacted with an electrophile, for example, an acyl chloride to provide the corresponding amide (29b). Then the oxidation of 29b with tere-butyl hypochlorite (Kuehne et al (1985) J. Org.Chem.50: 919-924) can provide the azepine product (30).

SCHEME 11 29b 30 A more general approach to the modification of the 5-ester group is described in Scheme 12 below. The azepine 28 can be saponified to provide the respective acid (31). A nucleophile RYH (ie, alcohols, phenols, amines, thiols) can be coupled with 31, for example, using carbonyldiimidazole (CDI), and then by oxidation with tere-butyl hypochlorite to provide azepine (33).

Scheme 12 The heterocyclyl groups can be introduced at the 5-position of the acid 31. For example, as described in Scheme 13 below, the oxazolines are prepared by the formation of amides (34) from the respective aminoalcohols and acid. The resulting amides 34 can then be cyclized, example, by treatment with thionyl chloride and then by a strong base, to provide the corresponding heterocycle (36). Halogenation and subsequent dehydrohalogenation of the intermediate (35) (not isolated) can occur under reaction conditions. Similar reactions can be envisioned for other heterocycles, i.e., imidazolines and thiazolines. Likewise the subsequent oxidation could provide the corresponding heteroaromatic product, for example, oxazole.

SCHEME 13 The 5-ester group of 23 can be hydrolyzed to provide 5-carboxylic acid (38). However, direct hydrolysis provides 38 in low yield. Accordingly, as described in Scheme 14 below, azepine 23 was transformed into the 3-Boc-protected compound (37), which can be hydrolysed under normal basic conditions with the elimination of Boc to provide the acid 38 SCHEME 14 23 37 38 As described in Scheme 15 below, azepine 23 can be treated with Lawesson's reagent (Curphey, et al, J. Org. Chem. 2002, 61, 6461-6473) to provide the O-alkyl thioester (39 ), which, for example, can be acylated to provide the azepine product (40). SCHEME 15 39 40 Scheme 16 below describes the incorporation of the 3-alkyl / aryl groups. For example, azepine 23 can be treated with a base, for example, NaH, and then with an alkyl halide (R3X) to provide a 3-alkyl azepine (41). An aryl or heteroaryl group (R3) can be introduced by coupling 27 with boronic acids (Lam, et al, Tetrahedron Lett, 2001, 42, 3415-3418), and then by oxidation of the intermediate (42) to provide the corresponding azepine product (43). SCHEME 16 27 42 43 The derivatization of the 2-substituted azepines (44) is described in Scheme 17 below. The diester (44) can be partially hydrolyzed to provide the acid (45), which can be transformed into amides (46), for example, using CDI. Intermediates 46 can be subsequently substituted by the addition of an electrophile, for example, acyl chloride, to provide the corresponding diamides (47).

SCHEME 17 Four. Five 46 47 As described in Scheme 18 below, the alcohol (48) can be derivatized by the addition of an electrophile (i.e., acyl chloride, chloroformate or isocyanate). For example, 48 may be esterified in the presence of a base to provide the diester (49), although the above may result in a mixture containing diester-amide (50). SCHEME 18 48 49 50 As described in Scheme 19 below, the 1-oxoazepines (52) can be used as key intermediates for the introduction of other functional groups. For example, azepine (51) can be oxidized, for example, with DDQ, to provide 1-oxoazepine 52, which can be reduced to provide the corresponding alcohol (53). Treatment of 53 with trifluoromethanesulfonic anhydride followed by the addition of the nucleophiles RYH (alcohols, thiols, amines, hydroxylamines and hydrazines) can provide the corresponding azepine products (54). SCHEME 19 53 54 As described in Scheme 20 below, 1-oxoazepine 52 can be converted, for example, with dimethylphenylsilane to TFA, to the corresponding azepine (55). SCHEME 20 Similarly, as described in Scheme 21 below, 1-oxoazepine 52 can be treated with ethylene glycol by acid-catalysis to form cyclic acetal (56). In addition, 52 can be treated with amines, hydroxylamines and hydrazines to provide imines (57, YR = NR15), oximes (57, YR = ÑOR14) and hydrazones (57, YR = NNR15R16), respectively. Likewise, 52 can be subjected to an ittig or Horner-Wadsworth-Emmons reaction (Maercker (1965) Org Rea Rea 24: 270-490; adsworth, Jr. (1977) Org Rea Rea 25: 73-253 ) to provide exocyclic alkylidenes (57, for example, YR = CRR ').

SCHEME 21 As described in Scheme 22 below, substituents can be introduced into the indole ring, that is, through the aryl amination and cross-coupling reactions of Suzuki from the corresponding aryl bromides (59). The bromo-substituted characters 59 can be prepared by direct bromination of indoles (58) with NBS or from commercially available tryptamine. Such intermediates 59 can be used in the cross-coupling reactions of Suzuki (Miyaura, et al, Chem. Rev. 1995, 955, 2457-2483) with boronic acids to provide, for example, aryl-substituted products (60, R8 = aryl) and in the aryl amination reactions (Wolfe, et al, J. Org. Chem. 2000, 65, 1144-1157) to provide the amino-substituted products (60, R = NR 28nR29, SCHEME 22 c Aminsc-.cn de Arzlc 60 As described in Scheme 23 below, other transformations of the functional groups can be achieved, for example, in the indole ring of azepine (61). Protecting groups, such as the alkyl and aryl groups, in oxygen, sulfur or nitrogen containing azepine substituents 61 can be removed under appropriate conditions to provide azepine (62). The treatment of 62 with the electrophiles, such as carbamoyl chlorides, can produce the corresponding azepines (63), for which the substituent R8 is C (0) NR32R33 in this representative example.

SCHEME 23 ? lectrc f ilc (BU? = MR < m O (E2"T!) = Protective Group As described in Scheme 23 below, other transformations of the functional groups can be achieved, for example, in the indole ring of azepine (61). Protecting groups, such as the alkyl and aryl groups, in oxygen, sulfur or nitrogen containing azepine substituents 61 can be removed under appropriate conditions to provide the azepine (62). The treatment of 62 with the electrophiles, such as carbamoyl chlorides, can produce the corresponding azepines (63), for which the substituent R8 is C (0) NR32R33 in this representative example. As described in Scheme 24 below, 3-cyanomethyl-indole-1-carboxylic acid (64) was treated with BOC anhydride in the presence of DMAP / TEA to provide the tert-butyl ester of 3-cyanomethyl-indole l-carboxylic acid (65). This product was then dissolved in dimethyl acetamide and then in NaOH and iodomethane to obtain 3- (cyano-dimethylmethyl) -indole-1-carboxylic acid tert -butyl ester (66). An aqueous solution of ammonium hydroxide was added in the presence of nickel Raney. The catalyst was filtered off and rinsed with methanol to obtain the 3- (2-amino-1,1-dimethyl-ethyl) -indole-1-carboxylic acid tert -butyl ester (67). The product was treated with HCl / dioxane with dichloromethane to provide 2 (1-H-indol-3-yl) -2-methyl-propan-1-amine (68). Isopropyl-3-bromo-2-oxopropional (69a) and isopropyl-3-chloro-2-oxopropional were added (69b) to (68) to produce 1,1-dimethyl-1,2,3,6-tetrahydroazepine [4, 5-b] isopropyl indole-5-carboxylate.

Scheme 24 (ca. 2: 3 mixture) 71 As described in Scheme 25, 2 (1H-indol-3-yl) acetonitrile (72) was treated with Boc anhydride in the presence of TEA, DMAP and DCM to provide 3- (cyanomethyl) ) -1-H-indol-l-carboxylic acid tertiary butyl (73). The carboxylate was then reacted with sodium hydroxide, methyl iodide, water and DMA to obtain 3- (2-cyanopropan-2-yl) -lH-indole-1-carboxylic acid tertiary butyl ester. (74) which was then reacted with Raney nickel, ammonium hydroxide, methanol and tetrahydrofuran to obtain 3- (l-amino-2-methyl-propan-2-yl) -lH-indole-1-carboxylic acid tertiary butyl ester (75 ). The product was treated with 4M hydrochloric acid and dioxane to provide tertiary butyl 3- (2-cyanopropan-2-yl) -lH-indole-1-carboxylate (76). (2,2-dimethyl-1,3-dioxolan-4-yl) methyl-3-bromo-2-oxopropanoate was added to provide (2, 2-dimethyl-l, 3-dioxolan-4-yl) methyl 1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate (77). 1N Hydrochloric acid and tetrahydrofuran were added to provide 2,3-dihydroxypropyl 1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate (78). 3-Difluorobenzoyl chloride was added to the resulting product to provide 2,3-dihydroxypropyl-3- (3,4-difluorobenzoyl-1,1-dimethyl-1,3,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate (79).

Scheme 25 As described in Scheme 26, the preparation of 2,3-dihydroxypropyl-3- (3,4-difluorobenzoyl-1,1-dimethyl-1,2,3,6-tetrahydroazepine [4,5-b] indole-5- The carboxylate is as follows: 2, 2-dimethyl-1,3-dioxolan-4-yl methanol and bromopropionic acid were reacted in the presence of chlorodimethoxymethane to yield (2,2-dimethyl-1,3-dioxolan-4-yl) methyl-3 bromo-2-oxopropionate 2- (lH-indol-3? l) -2-met? l-propan-1-amine hydrochloride was treated with (2,2-dimethyl-1,3-dioxolan-4-yl) ) methyl 3 bromo-2-oxopropanoate to form (2-methyl-1,3-dioxolan-4-yl) methyl-1,1-dimethyl-1,2,3,6 tetrahydroazepino [4,5-b] indole 5-carboxylate, which was then treated with difluorobenzoyl chloride to produce (2,2-dimethyl-1,3-dioxolan-4-yl) methyl 3- (3,4-difluorobenzoyl) -1,1-dimethyl-2, 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate This product was treated with 1N hydrochloric acid and tetrahydrofuran to produce 2,3-dihydroxypropyl 3- (3,4-difluorobenzoyl) -1- dimet Il-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate.

Scheme 26 As described in Scheme 27, 2-hydroxy-1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,3,6,6-tetrahydroazepine was prepared [4, 5 b) indole-5-carboxylate in the following manner: 3-bromo-2-oxopropanoic acid was treated with tertiary butoxy propan-2-ol and chlorodimethoxymethane to produce butane propan-2-yl-3-bromo-2-oxopropanoate tertiary. This product was reacted with 2- (1H-indol-3-yl) -2-methyl-propan-1-amine hydrochloride to provide 1-hydroxy propan-2-yl 1,1-dimethyl-1, 2,3 , 6-tetrahydroazepino [4, 5-b] Indol-5-carboxylate. This product was then treated with difluorobenzoyl chloride in the presence of DIEA and DCM to produce l-hydroxypropan-2-yl 3- (3,4-difluorobenzoyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate.

Scheme 27 As described in Scheme 28, the preparation of 2- [(phenylmethyl) oxy] ethyl 3- [(3,4-d? Fluorophenyl) carbonyl] -1,1-d? Met? L-1, 2,3 , 6-tetrahydroazepmo [4,5-b]? Ndol-5-carboxylate was prepared in the following manner: 3-Bromo-2-oxoproponic acid was reacted with 2-benzyl-ethanol in presence of chlorodimethoxymethane to produce 2- (benzyloxy) ethyl 3-bromo-2-oxopropanoate. The product was reacted with 2- (lH-? Ndol-3? L) -2-met? L-propan-1-amine hydrochloride to provide 2- (benzyloxy) l, l-dimethyl-l, 2 , 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate. The product was treated with difluorobenzoyl chloride to produce 2- (benzyloxy) ethyl 3- (3,4-difluorobenzoyl) -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate. Scheme 28 As described in Scheme 29, 2-Fluoro-l- (Fluoromethyl) ethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5 -b] indole-5-carboxylate was prepared in the following manner: 3-bromo-2-oxopropionic acid was reacted with 1,3-difluoropropan-2-ol to produce 1,3-difluoropropan-2-yl-3 -chloro-2-oxopropanoate. The product was reacted with 2- (1H-indol-3-yl) -2-methyl-propan-1-amine hydrochloride to provide 1,3-difluoropropan-2-yl 1,1-dimethyl-1,2, 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate. The product was then treated with difluorobenzoyl chloride in the presence of DIEA and DCE to provide 1,3-difluoropropan-2-yl 3- (3,4-difluorobenzoyl) -1, dimethyl-1,2,3,6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate. Scheme 29 81 soa- 91 80 ° C As described in Scheme 30, l- was prepared. { 3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-yl} ethanone in the following manner: biacetyl was refluxed with sulfur dichloride and benzene to produce 1-chlorobutane 2,3-dione. This product was treated with 2- (lH-indol-3-yl) -2-methyl-propan-1-amine hydrochloride to provide 1- (1,1-dimethyl-1,2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxylate The product was then treated with difluorobenzoyl chloride to obtain 1- (3- (3,4-difluorobenzoyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate Scheme 30 DMAP 80 ° C The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

EXAMPLES EXAMPLE 1 PREPARATION OF 1-METHYLETHYL 1, 1-DIMETHYL-1, 2, 3, 6-TETRAHYDROAZEPINO [4,5-b] INDOL-5-CARBOXYLATE The title compound was prepared as described in the Scheme 24:? H NMR (400 MHz, CDC13): d 10.98 (s, 1H), 7.88 (d, J = 8.0) Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 6.8 Hz, 1H), 6.99 (td, J = 7.8, 1.2 Hz, 1H), 5.29 (br s, 1H), 5.16 (sept. J = 6.4 Hz, 1H), 3.27 (br s, 2H), 1.56 (s, 6H), 1.33 (s, 3H), 1.32 (s, 3H); MS (El) for C? 8H23N2? 2, 299.2 (MH +).

PREPARATION 1 3-Cyanomethyl-indole-l-carboxylic acid tert-butyl ester To a stirred and cooled solution (in ice water bath) of 3-indolyl acetonitrile (64) (53.4 g, 0.342 mol) in dichloromethane (800 mL), triethylamine (84 mL, 0.603 mol) and dimethylaminopyridine (2) were added. , 64 g, 0.0216 mol). BOC anhydride (88.4 g, 0.405 mol) was melted by heating it a little in a hot water bath, and then slowly added to the reaction mixture as a liquid. After the addition was complete, the ice bath was removed and continued at room temperature for 2 -3 hours, or until there was no more indole starting by TLC (eluted with 25% EtOAc in hexanes). The reaction was washed with 1N HCl (2 x 400 mL) and brine, then dried with Na 2 SO 4, filtered, and concentrated in vacuo to provide 3-cyanomethyl-indole-l-carboxylic acid tert-butyl ester (65) in the form of a pale yellow solid (87.2 g, 100%). XH-NMR (400MHz, CDC13): 8.18-8.16 (d, 1H), 7.64 (s, 1H), 7.53-7.51 (dd, 1H), 7.40-7, 36 (m, 1H), 7.32-7.26 (m, 1H), 3.78 (s, 2H), 1.68 (s, 9H).

PREPARATION 2 3- (Cyano-dimethyl-methyl) -indol-1-carboxylic acid tert-butyl ester The 3-cyanomethyl-indole-l-carboxylic acid tert-butyl ester (65; (40.0 g, 1.0 eq.) Dissolved in N, N-dimethylacetamide (400 mL) was cooled in an ice water bath at 0 ° C, then NaOH (18.728 g, 3.0 eq.) Dissolved in H20 (18.728 mL) was added dropwise to the solution mixture. After stirring for 10 minutes, Mel (66.46 g, 3.0 eq.) Was added slowly while the reaction mixture continued to cool to 0 ° C. After the addition, the mixture was slowly warmed to room temperature and stirred overnight (16 hours). The precipitate was observed and the reaction was considered complete by LC / MS and TLC (Rf = 0.37, 10:90 EtOAc / Hex). Water (250 mL) was added to the reaction mixture and the precipitate was collected by filtration, and then rinsed with H20 several times to remove the NaOH and DMA residues. More precipitate formed in the filtrate and again collected by filtration as mentioned above. The precipitate was then rinsed with a small amount of hexanes, dried overnight in vacuo to give the 3- (cyano-dimethyl-methyl) -indole-1-carboxylic acid tert -butyl ester (66) in the form of a whitish solid (31.8 g 71.7%). XH-NMR (400MHz, CDC13): 8.18-8.16 (br d, 1H), 7.83-7.81 (dd, 1H), 7.53 (s, 1H), 7.39-7 , 28 (m, 2H), 1.85 (s, 6H), 1.68 (s, 9H).

PREPARATION 3 3- (2-Amino-1, 1-dimethyl-ethyl) -indol-1-carboxylic acid tert-butyl ester In a 1 L Parr shaker flask, the 3- (cyano) tert-butyl ester was dissolved. -dimethyl-methyl) -indole-1-carboxylic acid (66) (19.1 g, 0.067 mol) in a 2: 1 solution of MeOH / THF (375 mL). An aqueous solution of ammonium hydroxide (28-30%) (9.8 mL, 0.067 mol) was added, followed by approximately 19 mL of Raney nickel (suspension in water). The reaction was carried out on a Parr apparatus with H2 at 45 psi (3.15 bar). at room temperature. The reaction was completed after 3 hours. The catalyst was filtered off and rinsed with MeOH, and the resulting filtrate was concentrated in vacuo. The residual crude oil was taken up in dichloromethane (400 mL), and washed with water (2 x 250 mL) and brine, then dried with anhydrous Na 2 SO 4, filtered, and concentrated in vacuo to provide the tert-butyl ester of the product. 3- (2-amino-1, 1-dimethyl-ethyl) -indole-1-carboxylic acid (67) in the form of a yellow oil. 1 H-NMR (400MHz, CDC13): 8.18 (br s, 1H), 7.72-7.70 (d, 1H), 7.36 (br s, 1H), 7.32-7.28 ( m, 1H), 7.23-7.19 (m, 1H), 3.00 (s, 2H), 1.67 (s, 9H), 1.40 (s, 6H), 1, 03 (br s, 2H).

PREPARATION 4 2- (lH-indol-3-yl) -2-methyl-propylamine hydrochloride The yellow oil resulting from 3- (2-amino-1, 1-dimethyl-ethyl) -indol- tert-butyl ester 1-carboxylic acid (67) from the previous step was immediately subjected to 4M HCl / dioxane (200 mL) and stirred at room temperature overnight (16 hours). After that period, a white precipitate was observed. A small amount of dichloromethane was added to soften the solid. The solid was then filtered, rinsed with dichloromethane and dried in vacuo overnight to give 2- (1H-indol-3-yl) -2-methyl-propylamine hydrochloride (68) as a white solid. (16.0 g,> 99%). HPLC Purity: 98.4% (D = 254 nM). XH-NMR XH-NMR (400MHz, d6-DMS0): 11.08 (s, 1H), 7.80 (br s, 3H), 7.73-7.71 (d, 1H), 7.40- 7.38 (d, 1H), 7.15-7.14 (d, 1H), 7.11-7.07 (m, 1H), 7.01-6.97 (m, 1H), 3, 13-3.12 (d, 2H), 1.44 (s, 6H). Elemental analysis: calculated for Cl2? H? 6N2. HCl .0.65H20: 60. 96% C, 7.80% H, 11.85% N, 14.99% Cl; Found: 61.13% C, 7.06% H, 11.37% N, 14.51% Cl.

PREPARATION 5 isopropyl ester of 3-bromo-2-oxo-propionic acid and 3-chloro-2-oxo-propionic acid isopropyl ester 3-bromo-2-oxo-propionic acid was dissolved (1.8 g, 88.6 mmol, 1 eq) in isopropyl alcohol (50ml) and then the mixture was cooled in an ice bath. Thionyl chloride (31.6g, 265 mmol, 19.4ml, 3 eq) was added dropwise while the reaction temperature was maintained below 5 ° C. The addition was completed within a period of 30 minutes. At the end of the addition of thionyl chloride, the reaction was removed from the ice bath and allowed to stir at room temperature for 3 hours. The reaction mixture was concentrated under rotary evaporation to remove excess isopropyl alcohol and thionyl chloride. The mixture of the crude product was then subjected to vacuum distillation. After distilling off a first fraction (30 ° C to 4.3 torr), products 69a and 69b (12.89g, 88%) were collected as a 3: 2 mixture at a temperature between 68-75 ° C ( 4.3 torr). XH NMR (400 MHz, CDC13): 5.21 (m, 1H), 4.59 (s, 2H, compound 69b), 4.32 (s, 2H, compound 69a), 1.37 (d, 6H) ppm.

PREPARATION 6 1, 1-Dimethyl-1,2,3,6-tetrahydro-azepino [4,5-b] indole-5-carboxylic acid isopropyl ester 2- (lH-) hydrochloride was added to a round bottom flask. indol-3-yl) -2-methyl-propylamine (68) (3.0 g, 13.4 mmol, 1 eq), isopropyl alcohol (30 ml), a 2: 3 mixture of 3-bromo isopropyl ester -2-oxo-propionic acid (69a) and 3-chloro-2-oxo-propionic acid isopropyl ester (69b) (3.2 g, 1.5 eq, based on MW (molecular weight) of 69b) and carbon (10% by weight, 0.3 g). The mixture was heated under a nitrogen atmosphere at reflux for 2 hours. The reaction was monitored by LCMS after the formation of the intermediates 1- (bromomethyl) -4,4-dimethyl-2, 3,4,9-tetrahydro-1H-pyrido [3, -b] indole-1-carboxylate. isopropyl (70a) and 1- (chloromethyl) -4,4-dimethyl-2,3,4-9-tetrahydro-lH-pyrido [3,4-b] indole-1-carboxylic acid isopropyl ester (70b) and depletion of the starting material (68). The reaction was then cooled to room temperature and pyridine (2.65 g, 2.68 ml, 33.4 mmol, 2.5 eq) was added along with DMAP (260 mg, 9% by weight) (Note: DMAP may be unnecessary, although in some cases it proved to shorten the reaction times). Then the reaction was refluxed overnight and upon completion, the reaction was cooled and filtered through celite. The celite was washed in 300 ml of DCM and the filtrate was evaporated until dried. TLC revealed an Rf = 0.85 in DCM without nearby impurities and in this instance a silica cartridge or a column can be used. In case of using a silica cartridge, a 50:50 mixture of DCM / hexane should be considered. The dark brown solid was subjected to column chromatography using a Biotage system and DCM as eluent, providing the product in the form of a first fraction collected from the column. After extraction of the solvents in vacuo, hexane was added to remove a small impurity, yielding the product (71) as a yellow solid (2.98 g, 75% yield). X H NMR (400 MHz, CDC13): 10.99 (bs, 1H), 7.85 (d, 1H), 7.78 (m, 1H), 7.32 (d, 1H), 7.03 (m , 1H), 6.99 (m, 1H), 5.28 (bs, 1H), 5.15 (m, 1H), 3.22 (bs, 2H), 1.53 (s, 6H), 1 , 32 (d, 6H); MS (El) for C? 8H22N202: 335.1 (MH +); Analysis calculated for C? 8H22N202 • 0.1H2O: C, 72.02; H, 7.45; N, 9.33. Found: C, 71.78; H, 7.64; N, 9.23.

EXAMPLE 1A Preparation of 1, 2, 3, 6-tetrahydroazepino [5-B] indol-5-ethyl carboxylate A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), ethyl 3-bromopyruvate (1.67 mL, 1.2 equivalent and decolorizing carbon (0.5 g) in absolute ethanol was heated to reflux under nitrogen. overnight, TEA was added and the reaction mixture was heated to reflux for another 7.5 hours.After cooling, the carbon was removed by filtration and washed with ethanol.The filtrate was concentrated under vacuum and diluted with water (20 mL) Then it was extracted by EtOAc (3x30 mL) and the combined organic layers were washed with brine and dried over MgSO.sub.2 The evaporation of the solvent and recrystallization from DCM-Hexane gave the title compound (1, 17 g) XH-NMR (CDC13): d 10.49 (1 H, br s), 7.79 (1 H, d), 7.43 (1 H, d), 7.43 (1 H, d) , 7.06 (2H, m), 5.27 (1H, br s), 4.29 (2H, q) 3.58 (2H, m), 3.17 (2H, m), 1.36 ( 3H, t); MS (ES): 257 (MH +).

EXAMPLE 2 Preparation of 1, 2, 3, 6-Tetrahydroazepino [4,5-b] indol-5-carboxylate of iso-Propyl A. A 3-bromopyruvic acid hydrate (3.34 g, 20 mmol) was placed in a flask and 1,1-dichloromethyl methyl ether (3.7 mL, 20 mmol) was added at 20 ° C. The mixture was heated to 50 ° C with stirring and a clear solution was obtained in 10 minutes. Heating was continued for 2 hours. The solvent was removed under high vacuum to provide 3-bromopyruvic chloride (6 g, 90% pure by XH NMR) and the compound was used without further purification. B. To iso-propanol, 3-bromopyruvic chloride (5 g) was added dropwise at -5 ° C and the solution was stirred overnight at 20 ° C. Evaporation of the solvent afforded iso-propyl 3-bromopyruvate (3.5 g), which was used in the next step without further purification. C. A mixture of tryptamine hydrochloride (1.96 g, 10 mmol), iso-propyl 3-bromopyruvate in iso-propanol (1.67 mL, 1.2 equiv) and decolorizing carbon (0.5 g) was added. heated to reflux under nitrogen overnight. TEA was added and the reaction mixture was heated to reflux for another 7.5 hours. After cooling, the carbon was removed by filtration and washed with ethanol. The filtrate was concentrated in vacuo and diluted with water (20 mL). This was then extracted by EtOAc (3x30 mL) and the combined organic layers were washed with brine and dried over MgSO4. Evaporation of the solvent and recrystallization from DCM-Hexane afforded the title compound; XH-NMR (DMSO): d 10.61 (1H, br s), 7.81 (1H, s), 7.67 (1H, m), 7.28 (2H, m), 6.83 (1H , m), 4.96 (1H, br s), 3.39 (2H, m), 3.27 (1H, m), 2.93 (2H, m), 1.20 (6H, d); MS (ES): 271 (MH +).

EXAMPLE 3 Preparation of Iso-Propyl 3-Benzoyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate A. To a solution of 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5-carboxylic acid iso-propyl ester (52 mg, 0.2 mmol) in DCM was added benzoyl chloride (36 μL 0.2 mmol) and TEA (56 μL, 0.4 mmol) and the mixture was stirred overnight at 20 ° C. Trisamine resin (50 mg) was added and the suspension was stirred for 2 hours at 20 ° C. The resin was removed by filtration through a Florisil® cartridge. Evaporation of the solvent afforded a crude product, which was purified by trituration with methanol to provide the title compound; XH-NMR (CDC13): d 10.48 (1H, br s), 7.98 (1H, s), 7.47 (2H, m), 7.41 (2H, m), 7.40 (2H , m), 7.30 (1H, m), 7.15 (1H, m), 6.99 (1H,), 5.04 (1H, m), 4.15 (2H, t), 3, 2 (2H, d), 1.10 (6H, d); MS (ES): 375 (MH +). Simila but replacing benzoyl chloride with appropriately substituted acyl chloride, chloroformate, isocyanate or sulfonyl chloride, the following compounds were prepared: 3- (4-fluorobenzoyl) -1,2,3,6-tetrahydroazepine [4, 5-b] iso-propyl indole-5-carboxylate; XH-NMR (CDC13): d 10.43 (1H, br s), 7.86 (1H, s), 7.50 (2H, m), 7.41 (1H, d)), 7.26 ( 1H, d), 6.98-7.15 (4H, m), 5.02 (1H, m), 4.10 (2H, t), 3.2 (2H, d), 1.09 (6H , m); MS (ES): 393 (MH +); Iso-propyl 3- (4-anisoyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; XH-NMR (CDC13): d 10.45 (1H, br s), 8.27 (1H, s), 7.47 (1H, d), 7.22 (1H, d), 7.03 (1H, m ), 6.90 (4H, m), 6.77 (2H, m), 5.07 (1H, m), 3.99 (2H, m), 3.11 (2H, d), 1.21 (6H, d); MS (ES): 421 (MH +); Iso-propyl 3-piperoniloyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; XH-NMR (CDC13): d 10.52 (1H, br s), 8.04 (1H, s), 7. 48 (1H, d), 7.33 (1H, d), 7.15 (1H, m), 7.08 (3H, m), 6.82 (1H, 8.5), 6.02 (2H , s), 5.17 (1H, m), 4.17 (2H, d), 3.11 (2H, d), 1.20 (6H, d); MS (ES): 419 (MH +); Iso-propyl 3-phenoxycarbonyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; XH-NMR (CDC13): d 10.47 (1H, br s), 8.29 (1H, s), 7.38 (1H, d), 7.23-7.31 (3H, m), 7 16 (1H, d), 7.06 (3H, m), 6.97 (1H, m), 5.10 (1H, m), 4.02 (2H, m), 3.13 (2H, d), 1.24 (6H, d); MS (ES): 391 (MH +); Iso-propyl 3- (2,4-dichlorophenylcarbamoyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; XH-NMR (CDC13): d 10.41 (1H, br s), 8.06 (1H, d), 7.92 (1H, s), 7.31 (1H, d), 7.07-7 , 21 (4H, m), 6.90 (1H, m), 6.97 (1H, m), 5.07 (1H, m), 3.89 (2H, t), 3.04 (2H, t), 1.18 (6H, d); MS (ES): 458 (MH +); Iso-propyl 3- (4-tert-butylbenzenesulfonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; XH-NMR (CDC13): d 10.52 (1H, br s), 8.43 (1H, d), 7.79 (2H, d), 7.56 (2H, d), 7.40 (1H , d), 7.33 (1H, d), 7.15 (1H, m), 7.05 (1H, m), 5.23 (1H, m), 3.84 (2H, t), 3.00 (2H, t), 1.41 (6H, d), 1.33 (9H, s); MS (ES): 467 (MH +); 3- (4-chlorobenzoyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 409 (MH +); 3-phenylcarbamoyl-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 390 (MH +); 3- (4-chlorophenylcarbamoyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 424 (MH +); 3-p-tolylcarbamoyl-l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 404 (MH +); 3-phenylacetyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 389 (MH +; 3- (4-methoxybenzoyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 405 (MH +); -? - ester ester of 3- (4-chlorophenyl) ester of acid 1, 6-d? h? dro-2H-azep? no [4, 5-b]? ndol-3, 5-d ? carboxyl? co; MS (ES): 425 (MH +); 3-p-tolyl ester of 5-? -propyl ester of the acid 1,6-d? h? d-2H-azep? no [4, 5-b]? ndol-3, 5- d? carboxyl? co MS (ES): 405 (MH +); 3- (4-methoxyphenylcarbamoyl) -1,2,3,6-tetrahydroazepino [4,5-b]? ndol-5-carboxylic acid isopropyl ester; MS (ES): 420 (MH +); isopropyl ester of 3-nonane-1-l, 2, 3, 6-tetrahydroazepino [4, 5-b]? ndol-5-carboxyl? co; MS (ES): 411 (MH +); 3- (2-methoxy-benzoyl) -1,2,3,6-tetrahydroazepino [4,5-b]? ndol-5-carboxylic acid isopropyl ester; MS (ES): 405 (MH +); 3- (3-phenylpropionyl) -1,2,3,6-tetrahydroazepmo [4, 5-b]? ndol-5-carboxylic acid isopropyl ester; MS (ES): 403 (MH +); 3- (toluene-4-sulfonyl) -1,2,3,6-tetrahydroazepino [4, 5-b]? ndol-5-carboxylic acid isopropyl ester; MS (ES): 425 (MH +); 3- (4-chlorobenzenesulfonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 445 (MH +); 3- (4-methoxybenzenesulfonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 441 (MH +); 3- (3,4-dimethoxybenzenesulfonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 471 (MH +); 3- (4-trifluoromethoxybenzenesulfonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 495 (MH +); 3- (2, -dichlorobenzoyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 443 (MH +); 3- (3-methoxybenzoyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 405 (MH +); and 3- (Benzo [1,3] dioxol-5-carbonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylic acid isopropyl ester; MS (ES): 419 (MH +).

EXAMPLE 4A Preparation of N-propyl 3-benzoyl-l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate A. In a manner similar to that described in Example 1A, but using n-propyl 3-bromopyruvate and n-propanol, the following compound was prepared: n-propyl 1, 2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; 1H-NMR (CDC13): d 10.41 (1H, br s), 7.74 (1H, d), 7.35 (1H, s), 7.56 (1H, d), 7.26 (1H, d), 7.09 (1H, m), 5.23 (1H, br s), 4.11 (2H, d), 3.54 (2H, br s), 3.12 (2H, br s), 1.68 (2H, m), 0.95 (3H, t); MS (ES): 271 (MH +) B. The title compound was prepared in a manner similar to that described in Example 2A using n-propyl 1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate (compound from step A) and benzoyl chloride; XH-NMR (CDC13): d 10.55 (1H, br s), 8.07 (1H, s), 7.52-7.58 (4H, m), 7.47 (2H, m), 7 , 33 (1H, d), 7.21 (1H, m), 7.12 (1H, m), 4.23 (2H, t), 4.13 (2H, m), 3.28 (2H, m), 1.56 (2H, m), 1.40 (3H, t); MS (ES): 375 (MH +). EXAMPLE 4 Preparation of 1, 2, 3, 6-tetrahydroazepino [4,5-B] indole-5-carboxylic acid A mixture of 1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylic acid methyl ester (1.21 g, 5 mmol), di-tert-butyl dicarbonate (1.69 g) , 1.5 eq.) And diisopropylethylamine (1.3 mL, 1.5 eq.) In benzene was heated to reflux with a Dean-Stark trap for 48 hours. After cooling, the solvent was removed and the crude product was redissolved in DCM and passed through a plug of silica gel, and eluted with DCM. Evaporation of the solvent gave a gummy product (5-methyl ester of 1,6-dihydro-2H-azepino [4,5-b] indol-3,5-dicarboxylic acid 3-tert-butyl ester; NMR (CDC13): d 10.52 (1H, br s), 8.40 (1H, s), 7.47 (2H, d), 7.34 (1H, m), 7.15 (1H, dd ), 7.07 (1H, dd), 3.97 (2H, t), 3.87 (3H, s), 3.14 (2H, t), 1.57 (9H, s), 1.52 (3H, t) To a solution of 5-methyl ester of 1,6-dihydro-2H-azepino [4,5-b] indole-3,5-dicarboxylic acid ester of 3-tert-butyl ester ( 293 g, 0.62 mmol) in MeOH (4 mL) was added 4 N NaOH (2 mL) and the mixture was heated for 5 hours under nitrogen.After cooling, the reaction mixture was diluted with water and extracted with EtOAc The aqueous layer was acidified with AcOH The precipitate was collected by filtration and washed with water and ether and dried under high vacuum to give the title compound (70 mg): 1 H-NMR (DMSO-d 6) : d 11.40 (1H, s), 10.73 (1H, br s), 7.83 (1H, m), 7.73 (2H, d), 7.38 (1H, m), 7, 25 (1H, m), 6.88 (2H, m), 3.45 (2H, t), 3.87 (3H, s), 2.98 (2H, t); MS (ES): 229 (MH +).

EXAMPLE 4A Preparation Diethyl -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-2, 5-dicarboxylate In a manner similar to that described in Example 1A, but replacing tryptamine hydrochloride with methyl ester HCl of tryptophan, the following compounds were prepared: Diethyl 1,2,3,6-tetrahydroazepino [4,5-b] indo1 -2, 5-dicarboxtylate: XH-NMR (CDC13): dd 10.44 (1H, br s), 7.86 (1H, d), 7.48 (1H, m), 7.33 (1H, d ), 7.09 (2H, m), 6.10 (1H, d), 4.29 (4H, m), 4.10 (1H, m), 3.84 (1H, d), 2.97 (1H, dd), 1.33 (6H, m); MS (ES): 329 : MH +); EXAMPLE 5 Preparation Isopropyl 3- (3,4-Difluorobenzoyl) -1, 1-Dimet i1- 1,2,3,6-tetrahydroazepin [4, 5-B] Indole-5-carboxylate Ethyl 3- (3,4-difluorobenzoyl) -1,1-dimethyl-1,2,3,5,5,6-hexahydro-azepine [4,5-b] indole-5-carboxylate was saponified, it became the corresponding isopropyl ester using CDI and isopropanol, and then oxidized to provide the title of the compound; XH-NMR (DMSO-d6): d 10.83 (1H, s), 7.76 (1H, d), 7.71 (1H, app t), 7.64 (1H, s), 7.52 -7.61 (2H, m), 7.40 (1H, m), 7.08 (1H, app t), 6.98 (1H, app t), 5.05 (1H, sept), 1, 52 (6H, s), 1.18 (6H, d); MS (ESI): 439 (MH +).

EXAMPLE 6 Preparation of Analogs of 1-methylethyl 1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-β] indole-5-carboxylate 71 72 Acyl chloride was added to a solution of 1-methylethyl-l, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-β] indole-5-carboxylate (1.0 equiv) in DCM The mixture was stirred for 1 hour until overnight from room temperature to 50 ° C. The reaction mixture was concentrated with a rotary evaporator and purified by flash chromatography and gave the corresponding product in moderate to good yields.

Using identical or analogous synthetic techniques and / or substituting alternative reagents, the following compounds of the invention were prepared: 1-Methylethyl 3- [(2-chloro-3,6-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.63 (s, 1H), 7.85 (d, 1H), 7.60 (s, 1H), 7.37 (d, 1H), 7.18 (t, 1H), 7.08 (m, 3H), 5.05 (m, 1H), 4.11 (bs, 1H), 1.67 (d, 6H), 1.17 (t, 6H); MS (El) for C 25 H 23 ClF 2 N 2? 3: 473.1 (MH +). 1-Methylethyl 1, l-dimethyl-3- (f-enylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10, 73 (bs, 1H), 8.12-7.06 (m, 10H), 5.11 (m, 1H), 4.05 (bs, 2H), 1.64 (s, 6H), 1.17 (d, J = 6.0 Hz, 6H); MS (El) for C25H26N2? 3: 403.3 (MH +). 1-Methylethyl 3- [(2-fluoro-phenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro-azepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.71 (bs, 1H), 7.84-7.05 (m, 9H), 5.08 (m 1H), 4.06 (bs, 1H), 1.64 (s, 6H ), 1.16 (d, J = 6.0 Hz, 6H); MS (El) for C 25 H 26 FN 203: 421.3 (MH +). 1-Met ileethyl 1, l-dimethyl-3-. { [2- (trifluoromethyl) phenyl] carbonyl} - 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxtilate: 1H NMR (400 MHz, CDC13): d 10.65 (s, 1H), 7.92 (s, 1H), 7.82 (m, 3H), 7.68 (s, 1H), 7.58 (t, 1H), 7.40 (d, 1H), 7.20 (t, 1H), 7.10 (t, 1H), .15 (m, 1H), 4.10 (bs, 2H), 1.64 (s, 6H), 1.21 (s, J = 6.26 Hz, 6H); MS (El) for C 26 H 25 F 3 N 2? 3: 471.2 (MH +). 1-Methylethyl 1, l-dimethyl-3-. { [4- (trifluoromethyl) phenyl] carbonyl} - 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate:? H NMR (400 MHz, CDCl 3): d 10.68 (s, 1H), 8.28 (d, 1H ), 7.82 (m, 2H), 7.71 (m, 3H), 7.40 (d, 1H), 7.19 (t, 1H), 7.09 (t, 1H), 5.11 (m, 1H), 4.11 (bs, 1H), 1.64 (s, 6H), 1.17 (d, J = 6.26 Hz, 6H); MS (El) for C 26 H 25 F 3 N 2? 3: 471.2 (MH +). 1-Methylethyl 3- [(2-chlorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO ): d 10.81 .bs, 1H), 7.84-7.45 (m, 7H), 7.05-6.95 (m 2H), 4.96 (m, 1H), 1.64 ( s, 6H), 1.09 (d, J = 6.0Hz, 6H); MS (El) for C 25 H 26 ClN 2? 3: 437.3 (MH +). l-Methylethyl 3 - [(2-bromofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate:? H NMR (400 MHz, DMSO ): d 10.83 (bs, 1H), 7.83-7.07 (m, 9H), 4.96 (m, 1H), 1.70 (s, 6H), 1.10 (d, J = 6.0Hz, 6H); MS (El) for C 25 H 26 BrN 2? 3: 482.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(2-methylf-enyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, DMSO ): d 10.69 (bs, 1H), 7.76-6.97 (m, 9H), 4.95 (bs, 1H), 4.00 (bs, 2H), 2.22 (s, 3H) ), 1.54 (s, 6H), 1.11 (bs, 6H); MS (El) for C 26 H 28 N 203: 417, 3 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [2- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, DMSO): d 10.83 (bs, 1H), 7.75-6.92 ( m, 9H), 4.93 (bs, 1H), 3.67 (s, 3H), (s, 3H), 1.52 (s, 6H), 1, 06 (s, 6H); MS (El) for C 26 H 28 N 2? 4: 433.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- (. {2- 2- [(trifluoromethyl) oxy] phenyl} carbonyl) -l, 2,3,6-tetrahydroazepino [4,5-b] indole -carboxylate of: XH NMR (400 MHz, DMSO): d 10.82 (bs, 1H), 7.74-7.42 (m, 7H), 7.05-6.95 (m, 2H), 4 , 92 (bs, 1H), 3.98 (bs, 2H), 1.54 (s, 6H), 1.52 (s, 6H), I, 04 (s, 6H); MS (El) for C26H25F3N204: 487.4 (MH +), 1-methylethyl 3-. { [4-fluoro-3- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [, 5-b] indol-5-carboxy lat: 1H NMR (400 MHz, CDC13): d 10.65 (bs, 1H), 7.92-7.82 (m, 3H), 7.73 (s, 1H), 7.41-7.08 (m, 4H), 5.16 (m, 1H), 4.05 (bs, 2H), 1.64 (s, 6H), 1.21 (d, J = 6.4 Hz, 6H); MS (El) for C 26 H 24 F 4 N 2? 3: 489.4 (MH +). 1-methylethyl 3-. { [3-fluoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.65 (bs, 1H), 7.84-7.07 (m, 8H), 5.12 (m, 1H), 4.08 (bs, 2H), 1.64 (s, 6H), 1.20 (d, J = 6.4 Hz, 6H); MS (El) for C 26 H 24 F 4 N 2? 3: 489.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(4-piperidin-4-ylf-enyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR ( 400 MHz, DMSO-d6): d 10.85 (bs, 1H), 8.74 (bs, 1H), 8.50 (bs, 1H), 7.76-6.98 (m, 9H), 5 , 02 (m, 1H), 3.98 (bs, 2H), 2.99 (m, 4H), 2.09-1.84 (m, 4H), 1.53 (s, 6H), 1, 14 (d, J = 6.4Hz, 6H); MS (El) for C 25 H 33 N 3 O 3: 487.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(3-piperidin-4-ylphenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, DMSO-d6): d 10.85 (bs, 1H), 8.76 (bs, 1H), 8.48 (bs, 1H), 7.78-6.97 (m, 9H), 5, 03 (m, 1H), 3.98 (bs, 2H), 3.71 (m, 1H), 2.95 (m, 4H), 1.99-1.78 (m, 4H), 1.53 (s, 6H), 1.13 (d, J = 6.4Hz, 6H); MS (El) for C 25 H 33 N 303: 487.2 (MH +). 1-Methylethyl 3- ( { 4- [(dimethylamine) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate:? H NMR (400 MHz, DMSO-d6): d 10.86 (bs, 1H), 7.76-6.98 (m, 9H), 5.02 (m, 1H), 3.98 ( bs, 2H), 3.45 (s, 2H), 2.15 (s, 6H), 1.53 (s, 6H), 1, 13 (d, J = 6.4Hz, 6H); MS (El) for C28H33N3? 3: 460.4 (MH +). 1-Methylethyl 3- ( { 3- [(dimethylamine) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.85 (bs, 1H), 7.74-6.96 (m, 9H), 4.98 (m, 1H), 3.96 (bs, 2H), 3.40 (s, 2H), 2.09 (s, 6H), 1.57 (s, 6H), 1.10 (d, J = 6.4 Hz, 6H); MS (El) for C2SH33N3O3: 425.4 (MH +). 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1, l-dimethyl-9 - [(phenylmethyl) oxy] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate: H NMR (400 MHz, CDC13): d 10.57 (s, 1H), 7.73 (s, 1H), 7.49 (d, 2H), 7.39 (t, 1H), 7 , 32 (m, 7H), 7.21 (t, 1H), 6.96 (m, 1H), 5.13 (m, 1H), 4.06 (bs, 2H), 1.57 (s, 6H), 1.22 (d, 6H); MS (El) for C32H3oE2N204: 545.4 (MH +). 1-Methylethyl 3- [(3,4-difluorofenyl) carbonyl] -9-hydroxy-1, 1-dimet i 1-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole -5- carboxy lat o: 1H NMR (400 MHz, CDC13): d 10.56 (s, 1H), 7.74 (s, 1H), 7.51 (m, 1H), 7.34 (m, 1H), 7.25 (m , 2H), 7.22 (m, 1H), 6.78 (dd, 1H), 5.14 (m, 1H), 4.47 (s, 1H), 4.05 (bs, 2H), 1 , 57 (d, J = 11.5 Hz, 6H), 1.22 (d, J = 6.25 Hz, 6H); MS (El) for C25H24F2N204: 455.2 (MH +). 1-Methylethyl 1, l-dimethyl-3-. { [3- (trifluoromethyl) phenyl] carbonyl} - 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.68 (s, 1H), 7.80 (m, 5H) , 7.60 (t, lH), 7.39 (d, 1H), 7.20 (t, 1H), 7.09 (t, 1H), 5.13 (m, 1H), 4.09 ( bs, 2H), 1.65 (s, 6H), 1.17 (d, 6H); MS (El) for C 26 H 25 F 3 N 2 O 3: 471.1 (MH +). 1-Met ileethyl 1, l-dimethyl-3-. { [4- (lH-pyrazol-1-yl) phenyl] carbonyl} - 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10.72 (s, 1H), 8.00 (d, 1H) , 7.85 (m, 2H), 7.82 (d, 1H), 7.78 (m, 2H), 7.72 (m, 2H), 7.40 (d, 1H), 7.19 ( t, 1H), 7.09 (t, 1H), 5.13 (m, 1H), 4.11 (bs, 2H), 1.64 (s, 6H), 1.20 (d, J = 5 86 Hz, 6H); MS (El) for C28H28N403: 469.3 (MH +). 1-Met ileethyl 3- [(3-cyanophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDC13 ): d 10.65 (s, 1H), 7.92 (s, 1H), 7.82 (m, 3H), 7.69 (s, 1H), 7.58 (t, 1H), 7, 40 (d, 1H), 7.21 (t, 1H), 7.10 (t, 1H), 5.15 (m, 1H), 4.12 (bs, 2H), 1.64 (s, 1H) ), 1.21 (d, 6H); MS (El) for C 26 H 25 N 3? 3: 428.3 (MH +). 1-Met ileethyl 3- [(2, -dichlorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz , CDCl 3): d 10.65 (s, 1H), 7.84 (d, 1H), 7.51 (d, 2H), 7.37 (q, 3H), 7.17 (t, 1H), 5.06 (m, 1H), 4.07 (bs, 1H), 1.67 (s, 6H), 1.17 (s, 6H); MS (El) for C 25 H 24 C 12 N 203: 471.0 (M +), 473.1 (M + 2). 1 - . 1-Methethyl 3- [(3,4-di chloro phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1H NMR ( 400 MHz, CDCl 3): d 10.67 (s, 1H), 7.82 (d, 1H), 7.74 (m, 2H), 7.52 (d, 1H), 7.41 (m, 2H ), 7.20 (t, 1H), 7.09 (t, 1H), 5.16 (m, 1H), 4.11 (bs, 2H), 1.62 (s, 6H), 1.23 (d, 6H); MS (El) for C 25 H 24 Cl 2 N 2 O 3: 471.2 (M +), 473.3 (M + 2). 1-Methylethyl 3- [(4-chloro-2,5-difluorofenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: X H NMR (400 MHz, CDCl 3): d 10.65 (s, 1 H), 7.82 (d, 1 H), 7.63 (m, 1 H), 7.37 (m, 1 H), 7.34 ( m, 2H), 7.18 (t, 1H), 7.07 (t, 1H), 5.13 (m, 1H), 4.10 (bs, 2H), 1.62 (s, 6H), 1.22 (s, 6H); MS (El) for C25H23C1F2N203: 473.3 (MH +). 1-Met ileethyl 1, l-dimethyl-3- [(1-methyl-lH-1, 2,3-benzotriazol-5-yl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5-b] ] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s, 1H), 8.32 (s, 1H), 7.81 (m, 3H), 7.58 (d , 1H), 7.41 (d, 1H), 7.20 (t, 1H), 7.09 (t, 1H), 5.09 (m, 1H), 4.35 (s, 3H), 4 , 13 (bs, 2H), 1.66 (s, 6H), 1.12 (d, 6H); MS (El) for C 26 H 27 N 503: 458.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- (. {4- [4- (trifluoromethyl) -lH-pyrazol-1-yl] phenyl} carbonyl) -1,3,6-tetrahydroazepine [ 4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.72 (s, 1H), 7.82 (m, 2H), 7.74 (m, 3H), 7 , 60 (dd, 2H), 7.40 (dd, 1H), 7.20 (t, 1H), 7.09 (t, 1H), 6.87 (s, 1H), 5.12 (m, 1H), 1.66 (s, 6H), 1.20 (d, 6H); MS (El) for C 29 H 27 F 3 N 4? 3: 458.2 (MH +). 1-Methylethyl 3- [(3-f luorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDCI3): d 10.82 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.41 (m, 3H), 7.33 (m, 3H), 7.19 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 5.13 (sept, J = 6.4) Hz, 1H), 4.11 (br s, 2H), 1.63 (s, 6H), 1.20 (s, 3H), 1.19 (s, 3H); MS (El) for C25H25FN203: 421.2 (MH +). 1-Methylethyl 3- [(2,4-difluorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.62 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.69 (br s, 1H), 7.52 (q, J = 7 , 2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.17 (td, J = 6.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.02 (t, J = 1.6 Hz, 1H), 6.90 (t, J = 2.4 Hz, 1H), 5.11 (m, 1H), 4.06 ( br s, 2H), 1.62 (s, 6H), 1.20 (s, 3H), 1.19 (s, 3H); MS (El) for C25H25F2N203: 439.2 (MH +). 1-Methylethyl 3- [(2,3-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCI3): d 10.69 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.68 (br s, 1H), 7.37 (d, J = 8.0) Hz, 1H), 7.33 (m, 1H), 7.23 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.07 (t, J = 7.2) Hz, 1H), 5.10 (br s, 1H), 4.07 (br s, 2H,) 1.63 (s, 6H), 1.18 (s, 6H); MS (El) for C 25 H 25 F 2 N 2 O 3: 439.2 (MH +). 1-Methylethyl 3- [(2,6-difluorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate: XH NMR (400 MHz , CDCl 3): d 10.66 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.47 (m, 1H), 7, 36 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.04 (m, 3H), 7.02 (t, J = 1.6 Hz, 1H), 5.06 (sept, J = 6.4, 1H), 4.13 (brs, 2H), 1.66 (s, 6H), 1.16 (s, 3H), 1 , 14 (s, 3H); MS (El) for C 25 H 25 F 2 N 2 O 3: 439.2 (MH +). 1-Methylethyl 3- [(2,5-dif luorofenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate: XH NMR (400 MHz , CDCl 3): d 10.69 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.68 (br s, 1H), 7.37 (d, J = 8, 0 Hz, 1H), 7.17 (m, 4H), 7.07 (t, J = 7.2 Hz, 1H), 5.10 (br s, 1H), 4.06 (br s, 2H) , 1.64 (s, 6H), 1.19 (s, 6H); MS (El) for C 25 H 25 F 2 N 2 O 3: 439.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(2,3,4-trifluorofenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.66 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.64 (br s, 1H), 7.37 (m, 1H ), 7.18 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 7.08 (t, J = 7.2, 1H), 5 , 13 (m, 1H), 4.06 (br s, 2H), 1.63 (s, 6H), 1.23 (s, 3H), 1.21 (s, 3H); MS (El) for C 25 H 24 F 3 N 203, 457.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(2,4,6-trifluorophenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.64 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.37 (d, J = 8, 0 Hz, 1H), 7.66 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.79 (t, J = 8.0 Hz, 2H), 5.09 (Sept.J = 6.0 Hz, 1H), 4.09 ( br s, 2H), 1.65 (s, 6H), 1.20 (s, 3H), 1.19 (s, 3H); MS (El) for C 25 H 24 F 3 N 2? 3, 457.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(2,4,5-trif luorofenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.67 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.65 (br s, 1H), 7.40 (m, 2H ), 7.18 (t, J = 6.8 Hz, 1H), 7.08 (t, J = 6.8 Hz, 1H), 7.01 (m, 1H), 5.14 (Sept. J = 5.6 Hz, 1H), 4.05 (br s, 2H), 1.62 (s, 6H), 1.23 (s, 3H), 1.22 (s, 3H); MS (El) for C 25 H 24 F 3 N 2? 3, 457.2 (MH +). 1-Methylethyl 3- (1,3-benzodioxol-5-ylcarbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400MHz, CDCI3): d 10.71 (s, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz , 1H), 7.14 (m, 4H), 6.81 (d, J = 8.0 Hz, 1H), 6.04 (s, 2H), 5.16 (sept, J = 6.0) Hz, 1H), 4.06 (br s, 2H), 1.61 (s, 6H), 1.25 (s, 3H), 1.23 (s, 3H). 1-Methylethyl 3- [(3-chlorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3 ): d 10.70 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.51 ( d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.38 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 5.14 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 1.63 ( s, 6H), 1.21 (s, 3H), 1.20 (s, 3H); MS (El) for C 25 H 26 Cl 1 N 2 O 3, 437.2 (MH +). 1-Methylethyl 3- [(4-chlorofenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDCl 3 ): d 10.69 (s, 1H), 7.82 (dd, J = 8.0, 0.8 Hz, 1H), 7.76 (s, 1H), 7.54 (m, 2H), 7.41 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 5.14 (sept, J = 6.4 Hz, 1H), 4.07 (br s, 2H), 1.62 (s, 6H), 1.22 (s, 3H), 1.21 (s, 3H); MS (El) for C 25 H 26 Cl 1 N 2 O 3, 437.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(3-methyl phenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3 ): d 10.73 (s, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.35 (m, 5H), 7.18 ( t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 5.12 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 2.38 (s, 3H), 1.64 (s, 6H), 1.19 (s, 3H), 1.17 (s, 3H); MS (El) for C 26 H 29 N 2 O 3, 417.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(4-methylfenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCI3): d 10.72 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz , 2H), 7.39 (dt, J = 8.0, 1.2 Hz, 1H), 7.23 (dt, J = 7.6, 0.8 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 5.12 (sept, J = 6.4 Hz, 1H), 4.09 (br s, 2H), 2.41 (s, 3H), 1.63 (s, 6H), 1.20 (s, 3H), 1.19 (s, 3H); MS (El) for C 26 H 29 2 O 3, 417.2 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [3- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10.72 (s, 1H), 7.86 (s, 1H) , 7.83 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.8, Hz, 1H), 7.17 (m, 2H), 7.08 (m, 3H), 5.12 (sept, J = 6.4 Hz, 1H), 4.01 (br s, 2H), 3.83 (s) , 3H), 1.64 (s, 6H), 1.20 (s, 3H), 1.18 (s, 3H); MS (El) for C 26 H 29 N,204, 433.2 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [4- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.73 (s, 1H), 7.89 (s, 1H) , 7.82 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.0, Hz, 2H), 7.18 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 7.08 (ddd, J = 7.6, 7.2, 1.2 Hz, 1H), 6, 92 (d, J = 9.2 Hz, 2H), 5.12 (sept, J = 6.4 Hz, 1H), 4.09 (br s, 2H), 3.82 (s, 3H), 1.62 (s, 6H), 1.22 (s, 3H), 1.21 (s, 3H); MS (El) for C 6 H 29 N,204, 433.2 (MH +). 1-Methylethyl 3- [(2,2-difluoro-l, 3-benzodioxol-4-yl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole - 5 -carboxi lat o: lH NMR (400 MHz, CDC13): d 10.71 (s, 1H), 7.84 (dd, J = 8.0, 0.8 Hz, 1H), 7.74 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31 (dd J = 7.4, 1.6 Hz, 1H), 7.21 (m, 3H), 7.08 (t, J = 7 , 6 Hz, 1H), 5.15 (sept,, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 1.64 (s, 6H), 1.19 (s, 3H ), 1.17 (s, 3H); MS (El) for C26H25F2N205, 483.2 (MH +). 1-Methylethyl 3- [(2, 2-difluoro-1,3-benzodioxol-5-yl) carbonyl] -1, 1-dimethyl-1, 2, 3, 6-tetrahydroazepine [4, 5-b] Indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.67 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.39 (m, 2H), 7.36 (dd J = 8.2, 2.0 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.09 (m, 2H), 5.16 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 1.62 (s, 6H), 1.24 (s, 3H), 1.22 (s, 3H); MS (El) for C26H25F2N205, 483.2 (MH +). 1-methylethyl 3-. { [3,4-bis (methyloxy) phenyl] carbonyl} -1,1 -dimet i 1- 1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.71 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 2 , 0, Hz, 1H), 7.18 (m, 2H), 7.08 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5 , 15 (sept, J = 6.0 Hz, 1H), 4.09 (br s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 1.63 (s, 6H), 1.23 (s, 3H), 1.21 (s, 3H); MS (El) for C27H3? N205, 463.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(5-methylisoxazol-3-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.73 (s, 1H), 8.48 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8, 4, 0.8 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.8, Hz, 1H), 6.46 (s, 1H) ), 5.22 (sept, J = 6.0 Hz, 1H), 4.13 (brs, 2H), 2.52 (s, 3H), 1.57 (s, 6H), 1.36 (s, 3H), 1.35 (s, 3H); MS (El) for C23H26N3? 4, 408.2 (MH +). 1-methylethyl 3-. { [4-fluoro-2- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.63 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.48 (s, lH), 7.37 (s, 1H), 7.34 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.08 (t, J) = 7.6, Hz, 1H), 5.03 (sept, J = 6.0 Hz, 1H), 4.01 (br s, 2H), 1.66 (s, 6H), 1.14 ( s, 3H), 1.13 (s, 3H); MS (El) for C 26 H 25 F 4 N 2 O 3, 489.1 (MH +). 1-Methylethyl 3- [(2-chloro-4-f luorofenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.67 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.40 (t, J = 6.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.14 (m, 4H), 5.06 (m, 1H), 4.09 (br s, 2H ), 1.67 (s, 6H), 1.17 (s, 3H), 1.15 (s, 3H); MS (El) for C25H25C1FN203, 455.1 (MH +). 1-Methylethyl 1, l-dimethyl-3- (4-methylpentanoyl) -1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s, 1H), 8.11 (br s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H) , 7.16 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 5.25 (sept, J = 6.4, 1H), 3 , 89 (br s, 2H), 2.61 (t, J = 8.4 Hz, 2H), 1.62 (m, 1H), 1.58 (s, 3H), 1.55 (s, 3H) ), 1.40 (s, 3H), 1.38 (s, 3H), 1.35 (m, 1H), 0.94 (s, 3H), 0.93 (s, 3H); MS (El) for C 24 H 33 N 2 O 3, 397.1 (MH +). 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.73 (s, 1H), , 83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.42 (m, 2H) , 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 5.11 (sept,, J = 6.0, 1H), 4 , 58 (s, 2H), 4.10 (br s, 2H), 1.64 (s, 6H), 1.19 (s, 3H), 1.18 (s, 3H); MS (El) for C 26 H 28 CIN 2 O 3, 451.1 (MH +). 1-Methylethyl 3- [(3-f-luoro-4-methylf-enyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.82 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.25 (m, 2H), 7.18 (t, J = 6.8 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 5 , 14 (sept,, J = 6.4, 1H), 4.09 (br s, 2H), 2.34 (s, 3H), 1.62 (s, 6H), 1.22 (s, 3H) ), 1.20 (s, 3H); MS (El) for C 26 H 28 FN 203: 435.2 (MH +). 1-Methylethyl 3- ([2-f luoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxi lato:? NMR (400 MHz, CDCl 3): d 10.66 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.60 (m, 3H), 7.44 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 6.8 Hz, 1H), 7.08 (t, J = 7) , 2, Hz, 1H), 5.07 (m, 1H), 4.10 (br s, 2H), 1.66 (s, 6H), 1.14 (s, 3H), 1.13 (s) , 3H); MS (El) for C 26 H 25 F 4 N 203: 489.2 (MH +). 1-methylethyl 3-. { [3-chloro-2-f luoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate:? H NMR (400 MHz, CDC13): d 10.64 (s, 1H), , 85 (m, 2H), 7.70 (s, 1H), 7.57 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 6.8 Hz, 1H), 7.08 (t, J = 7.2, Hz, 1H), 5.11 (m, 1H), 4.10 (br s, 2H), 1.66 (s, 6H), 1.18 (s, 3H), 1.17 (s, 3H); MS (El) for C26H24C1F4N203: 523.1 (MH +). 1-methylethyl 3-. { [2-fluoro-3- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.68 (s, 1H), 7.81 (m, 2H), 7.72 (t, J = 6.4 Hz, 1H), 7.62 (s, 1H) ), 7.40 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.6, Hz, 1H), 5.09 (m, 1H), 4.11 (br s, 2H), 1.66 (s, 6H), 1.14 (s, 3H), 1.13 (s, 3H); MS (El) for C 26 H 25 F 4 N 203: 489.2 (MH +). 1-methylethyl 3-. { [3-f luoro-5- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.65 (s, 1H), 7.83 (d, J = 8.0, 1H), 7.71 (s, 1H), 7.63 (s, 1H) , 7.52 (t, J = 9.6 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7 , 10 (t, J = 8.0, Hz, 1H), 5.15 (sept, J = 6.4 Hz, 1H), 4.09 (br s, 2H), 1.65 (s, 6H) ), 1.21 (s, 3H), 1.19 (s, 3H); MS (El) for C 26 H 25 F 4 N 203: 489.2 (MH +). 1-methylethyl 3-. { [3, 5-bis (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] i ndol -5-car box i lat o: 1H NMR (400 MHz, CDC13): d 10.64 (s, 1H), 8.06 (s, 2H), 8.05 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H ), 7.68 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.10 (t, J) = 8.0, Hz, 1H), 5.15 (sept, J = 6.4 Hz, 1H), 4.11 (br s, 2H), 1.66 (s, 6H), 1.18 ( s, 3H), 1.17 (s, 3H); MS (El) for C 27 H 25 F 6 N 203: 539.2 (MH +). 1-methylethyl 3-. { [2,5-bis (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.63 (s, 1H), 7.91 (m, 3H), 7.62 (s, 1H), 7.45 (s, 1H), 7.37 (d , J = 8.4 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 5.15 (Sept. J = 6.4 Hz, 1H), 4.10 (br s, 2H), 1.69 (s, 6H), 1.09 (s, 3H), 1.07 (s, 3H); MS (El) for C 27 H 25 F 6 N 2 O 3: 539.1 (MH +). 1-methylethyl 3-. { [2,3-difluoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxy lat: lH NMR (400 MHz, CDC13): d 10.63 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.53 (m, 2H), 7.37 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 5.09 (m, 1H), 4.10 (br s, 2H), 1.66 (s, 6H), 1.18 (s, 3H), 1.16 (s, 3H); MS (El) for C 26 H 24 F 5 N 2 3 3: 507.0 (MH +). 1-Methylethyl 3- [(4-f-luoro-3-methylf-enyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDCl 3): d 10.70 (s, 1H), 7.83 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.49 (dd, J = 7.2, 1.6 Hz, 1H), 7.40 (m, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 9.2 Hz, 1H), 5.15 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 2.30 (s) , 3H), 1.63 (s, 6H), 1.22 (s, 3H), 1.20 (s, 3H); MS (El) for C 26 H 28 FN 203: 435.3 (MH +). 1-Methylethyl 3- [(3-chloro-2,6-difluorofenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: ? H NMR (400 MHz, CDC13): d 10.64 (s, 1H), 7.84 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (s) , 1H), 7.53 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t , J = 7.8 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 5.08 (sept, J = 6.0 Hz, 1H), 4.11 (br s , 2H), 1.66 (s, 6H), 1.18 (s, 6H); MS (El) for C25H24C1F2N203: 473.2 (MH +). 1-Methylethyl 3- [(3-chloro-4-f luorofenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.67 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.72 (dd, J = 6.8, 2.0 Hz, 1H), 7.50 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7. 09 (t, J = 8.2 Hz, 1H), 5.16 (sept, J = 6.4 Hz, 1H), 4.07 (br s, 2H), 1.63 (s, 6H), 1.24 (s, 3H), 1.22 (s, 3H); MS (El) for C 25 H 25 ClFN 2 O 3: 455.2 (MH +). 1-Methylethyl 3- [(3-bromo-4-f luorofenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.68 (s, 1H), 7.86 (dd, J = 6.6, 2.4 Hz, 1H), 8. 10 (m, 1H), 7.84 (m, 1H), 7.77 (s, 1H), 7.56 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.34 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.16 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 1.63 (s, 6H), 1.24 (s, 3H), 1.23 (s, 3H); MS (El) for C25H25BrFN2? 3: 499.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- (. {3, 3- [(phenylmethyl) oxy] phenyl} carbonyl) -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5- carboxylate: XH NMR (400 MHz, CDC13): d 10.72 (bs, 1H), 7.84-7.00 (m, 14H), 5.12 (m, 1H), 5.08 (s, 1H) ), 4.11 (bs, 2H), 1.57 (s, 6H), 1.19 (d, J = 6.4Hz, 6H); MS (El) for C 32 H 32 N 2 O 4: 509.3 (MH +). l-Methylethyl-3- (cyclohexylcarbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10, 67 (s, 1H), 8.18 (s, 1H), 7.78 (d, 1H), 7.36 (d, 2H), 7.20 (t, 1H), 7.12 (t, 1H) ), 5.22 (m, 1H), 3.85 (bs, 2H, 2.68 (m, 1H), 1.84 (s, 2H), 1.47 (m, 9H), 1.39 ( d, 6H), 1.22 (m, 5H); MS (El) for C25H32N203: 409.2 (MH +). 1-methylethyl-l, l-dimethyl-3- [(1-methylpiperidin-3-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR ( 400 MHz, DMSO): d 8.01 (bs, 1H), 7.96 (s, 1H), 7.77-6.98 (m, 4H), 5.25 (m, 1H), 3.80 -3.40 (m, 4H), 3.40-3.08 (m, 2H), 2.98 (m, 1H), 2.88 (s, 3H), 2.10-1.60 (m , 4H), 1.52 (m, 6H), 1.40 (m, 6H); MS (El) for C25H33N3? 3: 509.3 (MH +). 1-Methylethyl 3-acetyl-1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s , 1H), 8.03 (br s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.0, 0.8 Hz, 1H), 7.16 (t, J = 8.2 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 5.24 (sept., J = 6.4 Hz, 1H), 3 , 88 (br s, 2H), 2.39 (s, 3H), 1.56 (s, 6H), 1.40 (s, 3H), 1.38 (s, 3H); MS (El) for C2oH25N203: 314.2 (MH +). 1-Methylethyl-3-butanoyl-1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s) , 1H), 8.10 (br s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.15 ( d, J = 7.6 Hz, 1H), 5.24 (sept., J = 6.4 Hz, 1H), 3.90 (br s, 2H), 2.59 (t, J = 7.2) Hz, 2H), 1.76 (app.sext., J = 7.6, 2H), 1.55 (s, 6H), 1.40 (s, 3H), 1.38 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); MS (El) for C22H29N203: 369.2 (MH +). 1-Methylethyl 1-, 1- dimethyl-3-pen tand i 1-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10 , 70 (s, 1H), 8.10 (br s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.0, 0.8 Hz , 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 5.24 (sept., J = 6.4 Hz, 1H), 3.90 (br s, 2H), 2.59 (t, J = 7.2 Hz, 2H), 1.76 (app.sext., J = 7.6, 2H), 1.55 (s, 6H), 1.39 (m, 8H), 1.00 (t, J = 7.2 Hz, 3H); MS (El) for C23H3? N203: 383.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(1-methylpiperidin-4-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, DMSO-d6): d 10.91 (bs, 1H), 9.42 (bs, 1H), 7.97 (bs, 1H), 7.72-6.97 (m, 4H), 5, 15 (m, 1H), 3.82 (bs, 2H), 3.44 (m, 1H), 2.76 (m, 3H), 2.0-1.75 (m, 4H), 1.44. (s, 6H), 1.37 (d, J = 6, 4 Hz, 6H); MS (El) for C 25 H 33 N 303: 424.2 (MH +). 1-Methylethyl 3- (cyclopentyl carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10, 69 (s, 1H), 8.20 (br s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7 , 15 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 5.23 (m, 1H), 3.92 (br s, 2H), 3.14 (m, 1H), 1.90 (br m, 4H), 1.77 (br m, 2H), 1.64 (br m, 2H), 1.58-1.54 (m, 6H) ), 1.40 (s, 3H), 1.38 (s, 3H); MS (El) for C24H3oN3? 3: 395.2 (MH +). 1-Methylethyl 3- (2,2-dimethylpropanoyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10.66 (s, 1H), 8.36 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H) , 7.15 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 5.24 (m, 1H), 3.95 (br s, 2H ), 1.60-1.30 (m, 21H); MS (El) for C23H3oN303: 383.2 (MH +). 1-Methylethyl 3- (2-ethylbutanoyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate:? NMR (400 MHz, CDC13): d 10.69 (s, 1H), 8.18 (br s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 5.24 (Sept., J) = 6.0 Hz, 1H), 3.93 (br s, 2H), 2.69 (br s, 1H), 1.76 (m, 2H), 1.58 (m, 2H), 1.55 (s, 6H), 1.40 (s, 3H), 1.39 (s, 3H), 0.93 (d, J = 7.6 Hz, 6H); MS (El) for C 24 H 33 N 2 O 3: 397.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- (2-methylbutanoyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10 , 69 (s, 1H), 8.09 (br s, 1H), 7.79 (dd, J = 8.4, 0.8 Hz, 1H), 7.36 (d, J = 8.0 Hz , 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 5.24 (sept., J = 6.4 Hz, 1H), 3.93 (br s, 2H), 2.49 (d, J = 7.2 Hz, 2H), 2.22 (sept., J = 6.8 Hz, 1H), 1.55 ( s, 6H), 1.40 (s, 3H), 1.38 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H); MS (El) for C23H31N2? 3: 383.2 (MH +). 1-Methylethyl 3- (cycloheptylcarbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.70 (s, 1H), 8.14 (br s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7, 15 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 5.25 (sept., J = 6.0 Hz, 1H), 3.89 (br s, 2H), 2.88 (m, 1H), 1.81 (m, 6H), 1.60 (m, 6H), 1.54 (s, 6H), 1.40 (s, 3H) ), 1.38 (s, 3H); MS (El) for C 26 H 35 N 203: 423.3 (MH +). 1-Methylethyl 1, l-dimethyl-3-propanoyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDC13): d 10.70 (s , 1H), 8.11 (br s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.16 ( t, J = 7.6 Hz, 1H), 7.05 (t, J = 6.8 Hz, 1H), 5.24 (sept., J = 6.4 Hz, 1H), 3.90 (br s, 2H), 2.64 (q, J = 7.2 Hz, 2H), 1.55 (s, 6H), 1.40 (s, 3H), 1.39 (s, 3H), 1, 25 (t, J = 7.2, 3H); MS (El) for C2? H27N203: 385.3 (MH +). 1-Methylethyl 3- [4- (dimethylamino) butanoyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3) : d 10.67 (s, 1H), 7.97 (br s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 5.24 (sept., J = 6.4 Hz, 1H) ), 3.90 (br s, 2H), 2.93 (t, J = 7.2 Hz, 2H), 2.77 (m, 2H), 2.68 (s, 6H), 2.06 ( app. quint., J = 6.8, 2H) 1.55 (s, 6H), 1.41 (s, 3H), 1.39 (s, 3H); MS (El) for C 24 H 34 N 303: 412.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(3s, 5s, 7s) -tricyclo [3.3.1.1 3, 7] dec-1-ylcarbonyl] -1,2,3,6-tetrahydroazepine [4, 5] b) Indole-5-carboxylated lat: XH NMR (400 MHz, CDC13): d 10.66 (s, 1H), 8.50 (s, 1H), 7.77 (d, J = 8.0 Hz , 1H), 7.36 (dd, J = 8.0, 0.8 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 8, 4 Hz, 1H), 5.27 (sept., J = 6.0 Hz, 1H), 3.94 (brs, 2H), 2.06 (m, 5H), 1.93 (m, 2H) , 1.73 (m, 8H), 1.50 (s, 6H), 1.40 (s, 3H), 1.39 (s, 3H); MS (El) for C29H37N203: 461.3 (MH +).

EXAMPLE 7 PREPARATION OF 1-Methylethyl 3- [(3-Hydroxyphenyl) Carbonyl] -1, 1-Dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] Indole-5-carboxylate OH • O Pd (OH) 2 / C, cyclohexyldiene N MeOH N H H O O O 1-Methylethyl 3- [(3-hydroxyphenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: To the solution of 1-methylethyl 1 , l-dimethyl-3- ( { 3- [(phenylmethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate (1.075 g, 2, llmmol) in methanol was added cyclohexyl diene (1.69 g, 21.1 mmol) and Pd (0H) / C in a sealed tube. The reaction mixture was heated at 64 ° C overnight. After completion, the reaction mixture was filtered and the solvent was evaporated to provide the desired product (0.82 g, 93% yield): XH NMR (400 MHz, CDC13): d 10.71 (bs, 1H) , 7.83-6.99 (m, 9H), 5.92 (s, 1H), 5.13 (m, 1H), 4.05 (bs, 2H), 1.63 (s, 6H), 1.20 (d, J = 6.4 Hz, 6H); MS (El) for C25H26N2? 4: 419.3 (MH +.

EXAMPLE 8 PREPARATION OF 1-Methylethyl 3- [(3- {[2- (Dimethylamine) Ethyl] Oxi.}. Phenyl) Carbonyl] -1,1-Dimeti1-1,2,3,6-tetrahydroazepine [4 , 5- b] Indole-5-carboxylate 1-Methylethyl 3- [(3- {[2- (dimethylamine) ethyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4, 5-b ] indole-5-carboxylate: To the solution of 1-methylethyl 3- [(3-hydroxyphenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole 5-carboxylate (150 mg, 0.36 mmol) in TF was added 2-dimethylamineethanol (35.14 mg, 0.39 mmol), diisopropyl azodicarboxylate (80 mg, 0.39 mmol), triphenylphosphine polystyrene (358 mg , 0.39 mmol) subsequently. The reaction mixture was stirred at room temperature overnight. After filtering, the solvent was evaporated in vacuo and the residue was purified by liquid chromatography using gradient 10% -90% ACN / H20 with 0.05% TFA for 11 minutes. The desired fractions were combined and neutralized by saturated NaHCO 3 and ethyl acetate. The organic layer was dried over Na2SO4 and filtered. Extraction of the product in a rotary evaporator provides the desired product (26.4 mg, 15% yield): 1 H NMR (400 MHz, CDC13): d 10.72 (bs, 1H), 7.84-7.06 ( m, 9H), 5.12 (m, 1H), 4.11 (bs, 2H), 4.08 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.32 (s, 6H), 1.63 (s, 6H), l, 19 (d, J = 6.4Hz, 6H); MS (El) for C29H35N3O4: 490.2 (MH +.

Using the same or analogous synthetic techniques and / or substituting alternative reagents, the following compounds of the invention were prepared: 1-methylethyl 3- [(3- {[[3- (dimethylamine) propyl] oxy} phenyl) carbonyl] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.72 (bs, 1H), 7.86-7.05 (m, 9H), 5.12 (m, 1H), 4.06 (bs, 2H), 4.03 (t, J = 6.4 Hz, 2H), 2.43. (t, J = 7.2 Hz, 2H), 2.24 (s, 6H), 1.95 (m, 2H), 1.63 (s, 6H), 1.19 (d, J = 6, 0Hz, 6H); MS (El) for C 30 H 37 N 3 O 4: 504.4 (MH +. 1-Methylethyl 1, l-dimethyl-3- (. {3- [3- (2-piperidin-1-ylethyl) oxy] phenyl] carbonyl) -1,3,3,6-tetrahydroazepine [4, 5] b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.72 (bs, 1H), 7.84-7.08 (m, 9H), 5.12 (m, 1H), 4 , 11 (t, J = 6.0 Hz, 2H) 4.09 (bs, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.48 (bs, 4H), 1, 63 (s, 6H), 1.58 (m, 4H), 1.43 (m, 2H), 1.19 (d, J = 6.0 Hz, 6H); MS (El) for C 32 H 39 N 3 O 4: 530.4 (MH +. 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboXylate: XH NMR (400 MHz, CDC13): d 10.71 (bs, 1H), 7.84-7.06 (m, 9H), 5.11 (m, 1H), 4 , 12 (t, J = 5.6 Hz, 2H) 4.09 (bs, 2H), 3.72 (t, J = 4.8 Hz, 4H), 2.80 (t, J = 5.6 Hz, 2H), 2.57 (m, 4H), 1.63 (s, 6H), 1.19 (d, J = 6.0Hz, 6H); MS (El) for C 31 H 37 N 3 O 5: 532.4 (MH +). 1-methylethyl 3-. { [3, 4-difluoro-5- ( { [4- (methyloxy) phenyl] methyl.}. Oxy) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.68 (bs, 1H), 7.82-6.68 (m, 11H), 5.17 (m, 1H), 5.04 (s, 2H), 4.04 (bs, 2H), 3.69 (s, 3H), 1 , 58 (s, 6H), l, 25 (d, J = 6.0Hz, 6H); MS (El) for C 33 H 32 F 2 N 2? 5: 575.4 (MH +). 1-Methylethyl 3- ( {3,4-difluoro-5- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,1-dimethyl-l, 2,3, 6- tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.64 (bs, 1H), 7.83-7.03 (m, 7H), 5, 17 (m, 1H), 4.17 (bs, 2H), 4.07 (bs, 2H), 3.69 (bs, 4H), 2.82 (bs, 2H), 2.56 (bs, 4H) ), 1.56 (s, 6H), 1.25 (d, J = 5.6Hz, 6H); MS (El) for C 31 H 35 F 2 N 3 O 5: 568.4 (MH +). 1-Methylethyl 3- ((3,4-difluoro-5- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepine [ , 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.65 (bs, 1H), 7.83-7.00 (na, 7H), 5.17 (m, 1H ), 4.16 (t, J = 5.6 Hz, 2H), 4.10 (bs, 2H) 2.78 (t, J = 5.6 Hz, 2H), 2.47 (m, 4H) , 1.62 (s, 6H), 1.55 (m, 4H), 1.42 (m, 2H), 1.25 (d, J = 6.0Hz, 6H); MS (El) for C32H37F2N3O4: 566, 4 (MH +). 1-methylethyl, l-dimethyl-3- ((4- [(2-morpholin-ethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole -5 -carboxylate: 1H NMR (400 MHz, CDC13): d 10.72 (bs, 1H), 7.88-6.93 (m, 9H), 5.15 (m, 1H), 4.16 (t, J = 5.6 Hz, 2H), 4.10 (bs, 2H) 3.74 (m, 4H), 2.82 (t, J = 5.6 Hz, 2H), 2.58 ( m, 4H), 1.62 (s, 6H), 1.22 (d, J = 6.0Hz, 6H); MS (El) for C31H37N3O5: 532.4 (MH +). 1-methylethyl, l-dimethyl-3- ({4- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate: 1TI NMR (400 MHz, CDC13): d 10.73 (bs, 1H), 7.89-6.93 (m, 9H), 5.14 (m, 1H), 4, 14 (t, J = 5.6 Hz, 2H), 4.13 (bs, 2H) 3.74 (m, 4H), 2.78 (t, J = 5.6 Hz, 2H), 2.50 (bs, 4H), 1.62 (m, 10H), 1.46 (m, 2H), I, 21 (d, J = 6.0Hz, 6H); MS (El) for C 32 H 39 N 3 O 4: 530.4 (MH +). 1-Methylethyl 3- [(4- {[2- (dimethylamine) ethyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4,5-b ] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.73 (bs, 1H), 7.89-6.93 (m, 9H), 5.14 (m, 1H), 4.11 (t, J = 5, 6 Hz, 2H), 4.10 (bs, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.36 (s, 6H), 1.62 (s, 6H), 1 , 22 (d, J = 6.0 Hz, 6H); MS (El) for C 29 H 35 N 3 O 4: 490.2 (MH +). 1-Methylethyl 3- [(4. {[[3- (dimethylamine) propyl] oxy} phenyl) carbonyl] 1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate: H NMR (400 MHz, CDC13): d 10.73 (bs, 1H), 7.90-6.92 (m, 9H), 5.14 (m, 1H), 4 , 10 (bs, 2H), 4.06 (t, J = 6.40 Hz, 2H), 2.45 (t, J = 6.8 Hz, 2H), 2.25 (s, 5H), 1 , 97 (dt, J = 6.4, 6.8 Hz, 2H), 1.62 (s, 6H), I, 22 (d, J = 6.0Hz, 6H); MS (El) for C 30 H 37 N 3 O 4: 504.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { 4- [(2-pyrrolidin-1-ylethyl) oxy] phenyl} carbonyl) -1,3,3,6-tetrahydroazepino [5-b] ] i ndol -5-car box i lat: 1H NMR (400 MHz, CDC13): d 10.73 (bs, 1H), 7.89-6.93 (m, 9H), 5.14 (m, 1H), 4.15 (t, J = 5.8 Hz, 2H), 4.15 (bs, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.63 (m, 4H), 1.82 (m, 4H), 1.62 (s, 6H), 1.22 (d, J = 6.40Hz, 6H); MS (El) for C 30 H 37 N 3 O 4: 516.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { 4- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate:? H NMR (400 MHz, CDC13): d 10.73 (bs, 1H), 7.90-6.92 (m, 9H), 5.14 (m, 1H), 4.10 (bs, 2H), 4.05 (t, J = 6.4 Hz, 2H), 2.47 (t, J = 7.4 Hz, 2H), 2.39 (m, 4H), 1.99 (dt, J = 6.4, 7.4 Hz, 2H), 1.62 (s, 6H), 1.59 (m, 4H), 1.44 (m, 2H), 1.22 (d, J = 6.40Hz, 6H); MS (El) for C33H41N3O4: 544.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { 4- [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.72 (bs, 1H), 7.89-6.90 (m, 9H), 5.15 (m, 1H), 4 , 09 (bs, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.72 (m, 4H), 2.52 (t, J = 7.4 Hz, 2H), 2 , 47 (m, 4H), 1.99 (dt, J = 6.2, 7.4 Hz, 2H), 1.62 (s, 6H), 1.22 (d, J = 6.00 Hz, 6H); MS (El) for C 32 H 39 N 3? 5: 546.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b) indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (s) , 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.14 (m, 1H), 7.08 (m , 2H), 6.98 (t, J = 7.2 Hz, 1H), 5.03 (sept, J = 6.0 Hz, 1H), 4.03 (t, J = 6.0 Hz, 2H ), 3.97 (bs, 2H), 3.53 (bt, J = 4.4 Hz, 4H), 2.39 (bt, J = 7.2 Hz, 2H), 2.33 (bs, 4H) ), 1.86 (quint, J = 7.2 Hz, 2H), 1.52 (s, 6H), 1.15 (d, J = 6.4 Hz, 6H); MS (El) for C 32 H 39 N 3? 5: 546.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b) indole-5-carboxylate: 1 H NMR (400 MHz, DMSO-d 6): d 10.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (s) , 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.15 (m, 1H), 7.07 (m , 2H), 6.98 (t, J = 7.2 Hz, 1H), 5.03 (sept, J = 6.0 Hz, 1H), 4.02 (t, J = 6.0 Hz, 2H ), 3.97 (bs, 2H), 2.34 (bt, J = 7.2 Hz, 2H), 2.33 (bs, 4H), 1.84 (quint, J = 7.2 Hz, 2H) ), 1.52 (s, 6H), 1.45 (m, 4H), 1.34 (m, 2H), 1.15 (d, J = 6.4 Hz, 6H); MS (El) for C 33 H 41 N 3 O 4: 544.3 (MH +). 1-methylethyl 3- [(3- {[3- (diethyl) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepine [4,5 -b] indole-5 -carboxy lat: 2H NMR (400 MHz, DMSO-d6): d 10.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7, 70 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.16 (m, 1H), 7, 06 (m, 2H), 6.97 (t, J = 7.2 Hz, 1H), 5.03 (sept, J = 6.0 Hz, 1H), 4.03 (t, J = 6.4) Hz, 2H), 3.96 (bs, 2H), 1.80 (bquint, J = 6.0 Hz, 2H), 1.52 (s, 6H), 1.22 (m, 4H), 1, 15 (d, J = 6.4 Hz, 6H), 0.91 (bt, J = 6.8 Hz); MS (El) for C 32 H 41 N 3 4 4: 532, 3 (MH +).

EXAMPLE 9 PREPARATION OF N- ( { 3- [(3,4-Difluorophenyl) Carbonyl] -1, 1-D? Met? L-1,2,3,4,5,6-Hexahydroazepine [4, 5 -b] Indol-5-yl.}. Carbon? l) -β-Alanine: o o I f NaBH3CN F 2M NaOH 'N || [AcOH N THF | l f - 'r «o o H 0 o 0 eocí ° • N CMPEA N 1 í butyl-p-alanineHCi F H Q "OH S 0 NH O O 4M HCI dioxane N H 0 'NH O ñ Q NH O OH Sodium cyanoborohydride (0.137 g, 2.17 mmol) was added to a solution of ethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-d? methyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate (0.461 g, 1.09 mmol) in glacial acetic acid (10 mL) at room temperature for five hours. After clarifying the solution, the reaction was cooled with 2M HCl until gas evolution ceased, then it was poured on ice, the precipitate was neutralized to pH 7 with 5M of ammonium hydroxide and the aqueous phase was washed with CH2C12 ( 4 x 50 mL). The organic layers were combined and washed with brine, then separated and dried over Na2SO4, filtered and concentrated in isolation to give ethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,4,5,6-hexahydroazepine. [, 5-b] indole-5-carboxylate (0.460 g, 99% yield) as a white foam. The crude residue (0.460 g, 1.09 mmol) was dissolved in THF (5.0 mL) and 2M NaOH solution (0.109 L, 2.18 mmol) was added. The reaction was stirred at room temperature for 24 hours or until no initial material was found concentrated to a minimum volume. The reaction was acidified by dropwise addition of 1M HCl until the precipitate formed, which was collected by vacuum filtration, and dried to provide 3- [(3,4-difluorophenyl) carbonyl] -1: 1 acid. dimethyl-1, 2, 3, 4, 5, 6-hexahydroazepino [4, 5-b] indole-5-carboxylic acid (0.399 g, 92% yield) as a bone-colored solution.

EDCI (0.130 g, 0.678 mmol) was added to a solution of carboxylic acid (0.090 g, 0.226 mmol) and t-butyl β-alanine ester hydrochloride (0.082 g, 0.452 mmol) and diisopropylethylamine (0.112 mL, 0.678 mmol) in Anhydrous THF (1.0 mL) at room temperature. After 12 hours, the reaction was concentrated in isolation and the residue was purified in reverse phase HPLC (25 mM ammonium acetate: acetonitr 20-90% gradient). The product was collected and lyophilized to provide 1,1-dimethylethyl N- ({3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,4,5,5,6- hexahydroazepino [4, 5-b] indol-5-yl.} carbonyl) -β-alaninate (60 mg, 51% yield) as a white solid. The title compound was obtained by treating a solution of t-butyl ester (0.042 g, 0.080 mmol) in dioxane (1.0 mL) with 4M HCl in dioxane (0.5 mL) at room temperature for 30 minutes. The corresponding acid was concentrated in isolation and precipitated from dioxane and ethyl ether to give the title compound (0.010 g, 26% yield) as a tan solid: 1 H NMR (400 MHz, DMSO-d 6): d 10.80 ( s, 1H), 10.74 (s, 1H), 7.66 (bd, J = 8.0 Hz, 1H), 7.52 (m, 2H), 7.26 (m, 2H), 6, 98 (t, J = 7.2 Hz, 1H), 6.92 (m, 1H), 3.92 (bs, 2H), 3.78 (m, 2H), 3.52 (t, J = 6 , 0 Hz, 2H), 3.18 (m, 1H), 3.06 (bt, J = 6.0 Hz, 2H), 1.46 (bs, 6H); MS (El) for C 25 H 25 F 2 N 3? 4: 468.3 (MH ").

EXAMPLE 10 PREPARATION OF 3- [(3,4-Difluorophenyl) Carbonyl] -1, 1-Dimethyl-N- (1-methylethyl) -1, 2, 3,, 5, 6-Hexahydroazepino [4, 5-b] Indole-5- Carboxamide: HATU 0 Isopropylamine 0, N '. F DMF / CH2Cl2 N F 1 F F W 0 OH H 0 H HATU (0.338 g, 0.888 mmol) was added to a solution of 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,4,5,6-hexahydroazepine [4, 5-b] indole-5-carboxylic acid (0.118 g, 0.291 mmol) and isopropylamine (200 DL, 2.37 mmol) in anhydrous 1: 1 DMF: CH2C1.

The reaction was tightly capped and mixed at room temperature overnight. The reaction was concentrated in isolation and passed through Si02 and the residue was purified to give the title compound (21 mg, 16% yield) as a white solid: XH NMR (400 MHz, DMSO-d6): d 10.79 ( s, 1H), 10.73 (s, 1H), 7.66 (bd, J = 8.0 Hz, 1H), 7.52 (m, 2H), 7.26 (m, 2H), 6.98 (t, J = 7.2 Hz, 1H), 6.92 (m, 1H), 3.96 (m, 1H), 3.92 (s, 1H), 3.78 (m, 1H), 3.52 (m, 1H), 3.18 (m, 1H), 3.06 (bt, J = 6.0 Hz, 1H), 1.46 (bs, 3H), 1.19 (bd, J = 6.0 Hz, 3H), 1.17 (bs, 3H), 1.11 (bd, J = 6.0 Hz, 3H); MS (El) for C25H27F2N302: 440.2 (MH +).

EXAMPLE 11 PREPARATION OF N- ( { 3- [(3, 4-D? F luorofenyl) Carbonyl] -1, 1-D? Met? L-1,2,3,6-Tetrah? Droazepino [4 , 5-b] Indol-5-? L.}. Carbon? L) -β-The baby: DBU (57 μL, 0.381 mmol) was added to a solution of 1,1-dimethylethyl N- ((3- [(3,4-d? Fluorophenyl) carbonyl] -1, 1-d? Met? L-1, 2,3,4,5,6-hexahydroazep? No [4,5-b]? Ndol-5-? L.} Carbonyl) -β-alaninate (40 mg, 0.0761 mmol) and trichlorobromomethane (38 μL) 0.381 mmol) in anhydrous THF (1.0 mL) at room temperature After 12 hours, the reaction was concentrated in isolation and purified in reversed phase HPLC (25 mM ammonium acetate: acetonitr 20-90% gradient) provide 1,1-dimethylethyl N- ( { 3- [(3,4-difluorophenyl) carbonyl] -1,1-d? met? l-1,2,3,6-tetrahydroazep? no [4 , 5-b]? Ndol-5-? L.} Carbon? L) -β-alaninate (22 mg, 55% yield) as a yellow solid.

Trifluoroacetic acid (100 μL) was added to a solution of t-butyl ester (0.022 g, 0.0420 mmol) in anhydrous CH2C12 (2.0 mL) at room temperature. After 12 hours, the reaction was diluted with CH2C12 (50 mL) and poured into water (50 mL). The organic layer was separated, washed with brine (50 mL) and dried over Na 2 SO 4, filtered and concentrated in isolation. The residue was redissolved in a minum amount of CH2C12 and the precipitate with hexanes to give the title compound (2 mg, 10% yield) as a solid product: 2H NMR (400 MHz, CDC13): d 10.31 (s) , 1H), 7.80 (bd, J = 7.6 Hz, 1H), 7.47 (m, 1H), 7.38 (bd, J = 8.4 Hz, 1H), 7.30 (m , 1H), 7.17 (m, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.96 (bs, 1H), 6.51 (bs, 1H), 4.03 (bs, 2H), 3.60 (m, 2H), 2.67 (t, J = 6.0 Hz, 2H), 1.60 (bs, 6H); MS (El) for C 25 H 23 F 2 N 3 O 4: 468.1 (MH +).

EXAMPLE 12 PREPARATION OF 1-Methylethyl 3- [(3,4-Difluorophenyl) Carbonyl] -8- [( { [2- (Dimethylamine) Ethyl] amine.}. Carbonyl) Oxi] -1, 1-Dimethyl- 1, 2,3,6-tetrahydroazepino [4, 5-b] Indol-5-carboxylate: LTrifosgen ^ • Düsopropylamine or NH, HO 3. HN Trifosgen was added to the mixed solution of 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepine 4,5-b] indole -5-carboxylate (100 mg, 0.23 mmol) and diisopropylamine (0.8 mL, 4.6 mmol) in dichloromethane dried (10 mL) at 0 ° C under N2. The resulting mixture was stirred at room temperature for 1.5 h and N, N-dimethylene diamine (125 μL, 1.15 mmol) was added and then allowed to warm to room temperature overnight. The solvent was evaporated and applied directly to the LC preparation to provide the title compound in (56 mg, 43% yield) as a solid product: XH NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.76 (s, 1H), 7.74 (d, 1H), 7.50 (t, 1H), 7.39 (m, 1H), 7.30 (d, 1H), 7, 20 (s, 1H), 6.82 (dd, J = 8.6, 2.4 Hz, 1H), 5.18 (m, 1H), 4.10 (br, 2H), 3.64 (m , 2H), 3.30 (m, 2H), 2.93 (s, 6H), 1.60 (s, 6H), 1.24 (d, J = 6.4 Hz, 6H); MS (El) for C 30 H 3 F 2 N 4 O 5: 569.48 (MH +).

Using the same or analogous synthetic techniques and / or substituting with alternative reagents, the following compounds of the invention were prepared: l-Methylethyl3- [(3,4-difluorophenyl) carbonyl] -1, l-dimethyl-8- ([(methylamine) carbonyl] oxy}. -1, 2, 3, 6-tetrahydroazepino [4, 5-b] ] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.20 (d, 1H), 7.18 (s, 1H), 6.80 (dd, 1H), 5.18 (m, 1H), 4, 10 (br, 2H), 2.90 (s, 3H), 1.60 (s, 6H), 1.23 (d, 6H), MS (El) for C27H27F2N3O5: 512.35 (MH +). 1-Methylethyl 8- [( { [3- (diethylamine) propyl] amine} carbonyl) oxy] -3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDCl 3): d 10.62 (s, 1H), 7.74 (s, 1H), 7, 72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 7.18 (s, 1H), 6.82 (dd, 1H) ), 5.18 (m, 1H), 4.10 (br, 2H), 3.38 (m, 2H), 2.60 (br, 6H), 1.78 (br, 2H), 1.60 (s, 6H), 1.20 (m, 9H), 1.02 (t, 3H); MS (El) for C33H40F2N4O5: 611.56 (MH +). 1-met? Let? L 3- [(3, 4-d? Fluorophenyl) carbonyl] -1, ld? Met? L-8- (([(2-p? Rrol? Dm-1-? Let? L ) amine] carbonyl.}. ox?) - 1, 2,3,6-tetrahydroazepmo [4, 5-b] mdol-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.62 (s) , 1H), 7.74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 7 , 18 (s, 1H), 6.82 (dd, 1H), 5.18 (m, 1H), 4.10 (br, 2H), 3.58 (m, 2H), 3.00 (br, 4H), 2.00 (br, 6H), 1.60 (s, 6H), 1.23 (d, 6H), MS (El) for 032 ^^ 2 ^ 05: 595, 3 (MH +). 1-met? Let? L 3- [(3, 4-d? Fluorophenyl) carbonyl] -1, ld? Met? L-8- ( { [(2-p? Per? Dm-1-? Let ?) amine] carbonyl.} 0x1) -1,2, 3,6-tetrahydroazepino [4,5-b]? ndol-5-carboxylate: 1TI NMR (400 MHz, CDCl 3): d 10.62 (s, 1H), 7.74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H) , 7.18 (s, 1H), 6.82 (dd, 1H), 5.18 (m, 1H), 4.10 (br, 2H), 3.78 (m, 2H), 3.20 ( m, 2H), 2.10 (br, 4H), 1.70 (br, 6H), 1.60 (s, 6H), 1.23 (d, 6H); MS (El) for C 33 H 38 F 2 N 4 O 5: 609.3 (MH +). 1-met? Let? L 8- [( { [2- (diethylamine) ethyl] amine.} Carbonyl) 0x1] -3- [(3,4-d? Fluorophenyl) carbonyl] -1, 1- d? meth? ll, 2,3,6-tetrahydroazepino [4, 5-b] mdol-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.70 (s, 1H), 7.76 (s, 1H), 7.74 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.30 (m, 1H), 7.20 (s, 1H) 6.82 (dd, 1H), .18 (m, 1H), 4.10 (br, 2H), 3.58 (br, 2H), 2.90 (br, 6H), 1.60 (s, 6H), 1.25 (br, 6H), 1.23 (d, 6H); MS (El) for C 32 H 38 F 2 N 4 O 5: 567.52 (MH +).

EXAMPLE 13 PREPARATION of 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl; (([[(1, 1-Dimethylethyl) oxy] Carbonyl.} Oxy] -1, 1-Dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] Indole-5-carboxylate: Boc anhydride (76 mg, 0.36 mmol) was added to a mixed solution of l-methylethyl 3 - [(3,4-difluorophenyl) carbonyl] -8-hydroxy-1,1-dimethyl-l, 2,3,6 -tetrahydroazepino [4,5-b] indole-5-carboxylate (102 mg, 0.23 mmol) in dry dichloromethane (10 mL) at room temperature. The resulting mixture was stirred for 1.5 h and the solvent was evaporated and then applied directly to prep-LC to give the title compound in (52 mg, 40% yield) as a solid product: 1 H NMR (400 MHz, CDC13 ): d 10.70 (s, 1H), 7.76 (s, 1H), 7.74 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7, 30 (d, 1H), 7.20 (s, 1H), 6.90 (dd, 1H), 5.18 (m, 1H), 4.10 (br, 2H), 2.93 (s, 6H) ), 1.60 (m, 9H), 1.24 (d, 6H); MS (El) for C3oH32F2N206: 555.20 (MH +).

EXAMPLE 14 PREPARATION OF 1-Methylethyl 3- [(3,4-Difluorophenyl) Carbonyl] -8- ([2- (Dimethylamine) Ethyl] oxy] -1, 1-Dimethyl-1, 2,3,6- Tetrahydroazepino [4, 5-b] Indol-5-carboxylate: Triphenylphosphine (89.3 mg, 0.34 mmol), dimethylamine ethanol (34.3 μL, 0.34 mmol) and diisoproylazodicarboxylate (66 μL, 0.34 mmol) were added successively to a mixed solution of 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate (100 mg, 0.23 mmol ) in dry toluene (10 mL) at 0 ° C under N2. It was allowed to cool to room temperature overnight. The solvent was evaporated and then applied directly to prep-LC to provide the title compound in (43.0 mg, 36% yield) as a solid product: 1 H NMR (400 MHz, CDC13): d 10.50 (s) , 1H), 7.74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 6.83 (s, 1H), 6.78 (dd, 1H), 5.18 (m, 1H), 4.20 (m, 2H), 4.10 (br, 2H), 2.85 (br, 2H), 2.42 (s, 6H), 1.60 (s, 6H), 1.23 (d, 6H); MS (El) for C 29 H 33 F 2 N 304: 526.42 (MH +).

Using the same or analogous synthetic techniques and / or substituting with alternative reagents, the following compounds of the invention were prepared: 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8-. { [3- (dimethylamine) propyl] oxy} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.50 (s, 1H), 7, 74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 6.83 (s, 1H) ), 6.78 (dd, 1H), 5.18 (m, 1H), 4.10 (m, 2H), 2.60 (m, 2H), 2.38 (s, 6H), 2.10 (m, 2H), 1.92 (br, 2H), 1.60 (s, 6H), 1.23 (d, 6H); MS (El) for C 30 H 35 F 2 N 3? 4: 540.44 (MH +). 1-Methylethyl 8 - ([2- (diethylamine) ethyl] oxy}. 3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.50 (s, 1H), 7.74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 6.83 (s, 1H), 6.78 (dd, 1H), 5.18 (m, 1H) , 4.20 (m, 3H), 2.70 (m, 2H), 2.60 (m, 3H), 2.00 (m, 2H), 1.60 (s, 6H), 1.23 ( d, 6H), 1.02 (t, 6H); MS (El) for C3? H37F2N304: 554.45 (MH +). 1-methylethyl 8-. { [3- (diet i lamina) propyl] oxy} -3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13) : d 10.50 (s, 1H), 7.74 (s, 1H), 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 6.83 (s, 1H), 6.78 (dd, 1H), 5.18 (m, 1H), 4.18 (m, 2H), 4.10 (br, 2H) , 2.98 (m, 2H), 2.70 (m, 4H), 1.60 (s, 6H), 1.23 (m, 8H), 1.02 (t, 6H); MS (El) for C 32 H 39 F 2 N 304: 568.48 (MH +). 1-methylethyl 3 - [(3,4-difluorofenyl) carbonyl] -1, 1-dimethyl-8-. { [2- (I use oxy) ethyl] oxy} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.50 (s, 1H), 7.74 (s, 1H) , 7.72 (d, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.20 (d, 1H), 6.83 (s, 1H), 6.78 ( dd, 1H), 5.18 (m, 1H), 4.18 (m, 2H), 4.10 (br, 2H), 3.80 (m, 2H), 3.42 (s, 3H), 1.60 (s, 6H), 1.23 (d, 6H); MS (El) for C28H3oF2N2? 5: 513.45 (MH +).

EXAMPLE 15 PREPARATION OF 1-Methylethyl 1, l-Dimethyl-3-. { [3- (Morpholin-4-ylmethi; Phenyl] carbonyl.} -1,2,3,6-tetrahydroazepino [4,5-b] Indo 1 -5-carboxylate N | H O O Morpholine (290 μL, 3.32 mmol) was added to the mixed solution of 2 (1H-indol-3-yl) -2-methylpropan-1-amine hydrochloride (100 mg, 0.23 mmol) in acetonitrile: dichloromethane. (5 mL, 5: 1 ratio) at room temperature. The reaction was mixed overnight. The solvent was evaporated and the residue applied directly to prep-LC to provide the title compound in (41.5 mg, 36% yield) as a solid product: 1 H NMR (400 MHz, CDC13): d 10.62 ( s, 1H), 7.82 (d, 1H), 7.80 (s, 1H), 7.40 (m, 5H), 7.20 (m, 1H), 7.15 (m, 1H), 5.18 (m, 1H), 4.10 (br, 2H), 3.62 (s, 4H), 3.50 (s, 2H), 2.40 (s, 4H), 1.60 (s) , 6H), 1.23 (d, 6H); MS (El) for C 30 H 35 N 3 O 4: 502.3 (MH +).

Using the same or analogous techniques and / or substituting alternative reagents, the following compounds of the invention were separated: 1-Methylethyl 3- ((3- [(diethylamine) methyl] phenyl} carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.62 (s, 1H), 7.82 (d, 1H), 7.80 (s, 1H), 7.40 (m, 5H), 7.20 ( m, 1H), 7.15 (m, 1H), 5.18 (m, 1H), 4.10 (br, 4H), 2.80 (br, 4H), 1.80 (br, 6H), 1.60 (s, 6H), 1.23 (d, 6H); MS (El) for C30H37N3O3: 488.84 (MH +). 1-methylethyl 3-. { [2-fluoro-5- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.62 (s, 1H), 7, 82 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.20 (t, 1H) ), 7.10 (m, 2H), 5.18 (m, 1H), 4.10 (br, 2H), 3.70 (m, 4H), 3.60 (s, 2H), 2.40 (m, 4H), 1.60 (s, 6H), 1.23 (d, 6H); MS (El) for C30H34FN3O4: 520.30 (MH +). 1-Methylethyl 3- ([4-fluoro-3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole -5-carboxylate: XH NMR (400 MHz, CDC13): d 10.62 (s, 1H), 7.82 (d, 1H), 7.70 (br, 1H), 7.42 (m, 2H) , 7.38 (d, 1H), 7.18 (m, 1H), 7.10 (m, 2H), 5.18 (m, 1H), 4.10 (br, 2H), 3.70 ( m, 4H), 3.60 (s, 2H), 2.40 (m, 4H), 1.60 (s, 6H), 1.23 (d, 6H), MS (El) for C30H34FN3O4: 520, 30 (MH +). 1-methylethyl 3-. { [2-f luoro-5- (piperidin-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.62 (s, 1H), 7.82 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.20 (t , 1H), 7.10 (m, 2H), 5.18 (m, 1H), 4.10 (br, 2H), 3.50 (s, 2H), 2.40 (s, 4H), 1 , 60 (s, 6H), 1.45 (m, 4H), 1.40 (m, 2H), 1.20 (d, 6H); MS (El) for C 31 H 36 F 3 O 3: 518.30 (MH +). 1-methylethyl 3-. { [4-fluoro-3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDC13): d 10.62 (s, 1H), 7, 82 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.20 (t, 1H) ), 7.10 (m, 2H), 5.18 (m, 1H), 4.10 (br, 2H), 3.50 (s, 2H), 2.40 (s, 4H), 1.60 (s, 6H), 1.45 (m, 4H), 1.40 (m, 2H), 1.20 (d, 6H); MS (El) for C 31 H 36 FN 3 O 3: 518.30 (MH +).

EXAMPLE 16 PREPARATION OF 1-Methylethyl 1, 1-Dimethyl-3-. { [3- (Pyrrolidin-1-ylmethyl) phenyl] carbonyl} -l, 2, 3, 6-Tetrahydroazepino [4, 5-b] Indol-5-carboxylate: or N H N ACN N H '' rt d uurraannttie night [p1 O O O 9 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1, 1-d? Methyl-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate (60.0 mg, 0.133 mmol) was dissolved in 2 mL CAN. Pyrrolidine (142 mg, 2.00 mmol) was added to the solution and allowed to mix overnight at room temperature. The sample was purified by liquid chromatography using 20% -55% gradient of ACN / H20 with 0.05% TFA for 8 minutes. The desired fractions were combined and made basic by saturated NaHCO 3 and diluted with ethyl acetate. The organic layer was extracted with water and brine and dried over Na2SO3 and filtered. The yellow solution was reduced until dry and lyophilized overnight in ACN / H20 to form the bright powder (25.9 mg, 40% yield) of the title compound: XH NMR (400 MHz, CDC13): d 10, 71 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.46 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 5, 11 (sept, J = 6.4, 1H), 4.05 (br s, 2H), 3.75 (br s, 2H), 2.57 (br s, 4H), 1.84 (br s , 4H), 1.64 (s, 6H), 1.18 (s, 3H), 1.17 (s, 3H); MS (El) for C 30 H 36 N 3 O 3, 486.2 (MH +).

Using the same or analogous techniques and / or substituting alternative reagents, the following compounds of the invention were separated: 1-Methylethyl 1, l-dimethyl-3- ([3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate : 1 H NMR (400 MHz, CDC13): d 10.72 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.57 (br s, 1H), 7.51 (s, 1H), 7.41 (m, 3H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2) Hz, 1H), 5.09 (sept, J = 6.0, 1H), 4.07 (br s, 2H), 3.56 (br s, 2H), 2.41 (br s, 4H) 1.64 (s, 6H), 1.43 (br s, 4H), 1.26 (s, 2H), 1.17 (s, 3H), 1.16 (s, 3H), MS (El) for C31H38N3? 3, 500.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(4-methyl-piperazin-1-yl) methyl] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b) indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H ), 7.54 (s, 1H), 7.46 (m, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 6.8 Hz, 1H ), 7.08 (t, J = 7.2 Hz, 1H), 5.10 (sept, J = 6.0, 1H), 4.06 (br s, 2H), 3.54 (br s) , 2H), 2. 53 (br s, 8H), 2.36 (s, 3H), 1.64 (s, 6H), 1.17 (s, 3H) 1.16 (s, 3H); MS (El) for C3? H39N4? 3, 515.3 (MH +). 1-Methylethyl 3- ( { 3- [(4-ethylpiperazin-1-yl) methyl] f-ethyl) carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxy lato:? ti NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.80 ( s, 1H), 7.55 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H), 7.38 ( m, 3H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 5.10 (sept, J = 6.4, 1H), 4.06 (br s, 2H), 3. 54 (s, 2H), 2.51 (br s, 8H), 2.43 (q, J = 7.2, 2H), 1.64 (s, 6H), 1.17 (s, 3H), 1.16 (s, 3H), 1.09 (t, J = 7.2, 3H); MS (El) for C 32 H 41 N 4 O 3, 529.3 (MH +). 1-Methylethyl 3- ( { 3- [(4-acetylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4, 5] b) indo1-5-carboxylate: 1R NMR (400 MHz, CDC13): d 10.67 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H ), 7.55 (s, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.0 Hz, 1H), 7.39 (m, 3H) ), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 5.13 (sept, J = 6.4, 1H), 4.09 (br s, 2H), 3.59 (t, J = 3.6 Hz, 2H), 3.54 (s, 2H), 3.42 (t, J = 3.6 Hz, 2H) , 2.41 (m, 4H), 2.07 (m, 4H), 2.07 (s, 3H), 1.64 (s, 6H), 1.18 (s, 3H), 1.16 ( s, 3H); MS (El) for C 32 H 39 N 4 O 4, 543.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (methylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -l, 2,3,6-tetrahydroazepine [ 4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.69 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 6.8 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 5.11 (Sept.J = 6.0 Hz, 1H), 4.10 ( br s, 2H), 3.58 (s, 2H), 3.17 (m, 4H), 2.67 (s, 3H), 2.53 (t, J = 4.4 Hz, 4H), 1 , 65 (s, 6H), 1.18 (s, 3H), 1.16 (s, 3H); MS (El) for C 31 H 39 N 4 O 5 S: 579.4 (MH +). 1-methylethyl 3-. { [3- (azepan-1-ylmethyl) phenyl] carbonyl} -1, 1 -dimet i 1-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.66 (s, 1H), 8.02 (br s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.73 (brs, 1H), 7.55 (s) , 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 6.8 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H ), 5.30 (s, 2H), 5.13 (m, 1H), 4.21 (br m, 4H), 3.52 (br s, 2H), 2.82 (br s, 2H), 2.02 (br s, 2H), 1.80 (br s, 2H), 1.64 (s, 8H), 1.23 (s, 3H), 1.19 (s, 3H); MS (El) for C 32 H 40 N 3 O 3: 514.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- (. {3- [3- (4-methyl-1,4-diazepan-1-yl) methyl] phenyl] carbonyl) -1,2,3,6- tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDC13): d 10.69 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7 , 77 (s, 1H), 7.56 (s, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7 , 19 (t, J = 6.8 Hz, 1H), 7.09 (t, J = 6.8 Hz, 1H), 5.31 (s, 2H), 5.11 (sept, J = 6 , 0 Hz, 1H), 4.10 (br s, 2H), 3.70 (s, 2H), 2.94 (br s, 2H), 2.84 (br s, 2H), 2.72 ( t, J = 6.0 Hz, 2H), 2.42 (s, 3H), 2.03 (m, 2H), 1.65 (s, 6H), 1.18 (s, 3H), 1, 17 (s, 3H); MS (El) for C 32 H 41 N 4 O 3: 529.4 (MH +). 1-Methylethyl 3- ( { 3- [(4. {[[(1,1-dimethylethyl) oxy] carbonyl} piperazin-1-yl) methyl] phenyl} carbonyl) -1, 1 dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.71 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.51 (m, 2H), 7.51 (m, 2H), 7.41 (m, 3H), 7.18 (m, 2H). t, J = 6.8 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.10 (sept, J = 6.0 Hz, 1H), 4.09 (br s , 2H), 3.53 (s, 2H), 3.40 (m, 4H), 2.36 (m, 4H), 2.36 (m, 4H), 1.64 (s, 6H), 1 , 45 (s, 9H), 1.17 (s, 3H), 1.16 (s, 3H); MS (El) for 035 ^ 5 ^ 05: 601.4 (MH +). 1-methylethyl 3-. { [3- (Azocan-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1TI NMR (400 MHz, CDC13): d 10.71 (s, 1H), 7, 83 (d, J = 8.4 Hz, 1H), 7.58 (s, 2H), 7.38 (d, J = 8.4 Hz, 3H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 5.10 (sept, J = 6.0 Hz, 1H), 4.10 (br s, 2H), 3.62 (s, 2H), 2.52 (s, 2H), 1.64 (s, 6H), 1.59 (s, 2H), 1.51 (s, 8H), 1.18 (s, 3H) , 1.16 (s, 3H); MS (El) for C 34 H 43 N 4 O 4: 528.3 (MH +). 1-Methylethyl 3- ( { 3- [(4-acetyl-1,4-diazepan-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1,3,6,6- tetrahydroazepine [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.68 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7 , 79 (s, 1H), 7.55 (s, 2H), 7.44 (br s, 1H), 7.39 (br s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.11 (m, 1H), 4.08 (br s) , 2H), 3.60 (m, 4H), 2.64 (br m, 2H), 2.08 (s, 3H), 1.64 (s, 6H), 1.17 (m, 6H); MS (El) for C 33 H 42 N 3 O 3: 557.3 (MH +).

EXAMPLE 17 PREPARATION OF 1-Methylethyl 1, l-Dimethyl-3- [(3- ([(1-Methylpiperidin-4-yl) Oxi] Methyl.} Phenyl) Carbonyl] -1,2,3,6-tetrahydroazepine [4,5-b] Indole-5-carboxylate: 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate (30.0 mg, 0.0666 mmol) was dissolved in 2 mL THF, N, N ' -diisopropylethylamine (194 mg, 0.150 mmol) and 4-hydroxy-N-methylpiperidine (115 mg, 0.998 mmol) was added to the mixed solution. The reaction mixture was brought to 65 ° C and allowed to mix for 4 hours. The sample purified by liquid chromatography using 20% -55% gradient of ACN / H20 with 0.05% TFA for 8 minutes. The desired fractions were combined and made basic by saturated NaHCO3 and ethyl acetate. The organic layer was extracted with water and brine, then dried over Na2SO3 and filtered. The yellow solution was reduced to dryness and lyophilized overnight in ACN / H20 to form the yellow powder (10.5 mg, 30% yield) of the title compound: 1 H NMR (400 MHz, CDC13): d 10.64 (s, 1H), 7.97 (m, 1H), 7.80 (m, 1H), 7.67 (m, 3H), 7.55 (t, J = 8.0 Hz, 1H), 7 , 19 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H), 5.13 (m, 1H), 4.06 (br s, 2H), 3.70 (br s, 4H), 2.05 (m, 4H), 1.66 (s, 3H), 1.62 (s, 6H) 1.21 (m, 6H); MS (El) for C 32 H 40 N 3 O 4, 530.3 (MH +).

EXAMPLE 18 PREPARATION OF 1-Methylethyl 1, 1-Dimethyl-3- [(3 { [4- (Phenylsulfonyl) Piperazin-1-yl] Methyl.} Phenyl) Carbonyl] -1,2,3,6 -Tetrahydroazepino [4, 5-b] Indol-5-carboxylate: N OCE N N DLEA _ "Cl N ', rt during the night N' H o o N s O H o o O ',' Piperazin-1-carboxylic acid tert-butyl ester (1.00 g, 5.37 mmol) was dissolved in 10 mL CAN. To the solution was added N, N'-diisopropylethylamine (2.08 g, 16.1 mmol) and benzenesulfonyl chloride (948 mg, 5.37 mmol) and allowed to stir for 1 hour. When TLC indicated complete disappearance of sulfonyl chloride, the solution was evaporated to dryness. The white powder was dissolved in 20 mL of acetone and diluted with 20 mL of 4N HCl in dioxane. 20 minutes later the white precipitate of N-phenylsulfonylpiperazine hydrochloride that formed was filtered and washed with cold acetone. 1-Methylethyl 3- was dissolved. { [3- (chloromethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate (80.0 mg, 0.177 mmol) in 4 mL DCE, N, N'-diisopropylethylamine (344) mg, 2.66 mmol) and N-phenylsulfonylpiperazine hydrochloride (699 mg, 2.66 mmol) were added to the mixed solution. The mixture was allowed to react at room temperature overnight. The sample was filtered with Millipore Millex-GN filter, then purified by liquid chromatography using 50% -100% gradient of ACN / H20 with 0.05% TFA for 8 minutes. The desired fractions were combined and made basic by saturated NaHCO 3 and diluted with ethyl acetate. The organic layer was extracted with water and brine, and dried over Na2SO3 and filtered. The yellow solution was reduced until dry and lyophilized overnight in ACN / H0 to form a yellow powder (114 mg.38% yield) of the title compound: XH NMR (400 MHz, CDC13): d 10.67 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.73 (s) , 3H), 7.60 (m, 3H), 7.52 (m, 3H), 7.37 (m, 4H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 5.11 (sept, J = 6.4 Hz, 1H), 4.05 (br s, 2H), 3.52 (s, 2H), 3, 01 (br s, 4H), 2.51 (t, J = 4.4 Hz, 4H), 1.62 (s, 6H), 1.17 (s, 3H), 1.16 (s, 3H); MS (El) for 03 ^ 4x ^ 055: 641.3 (MH +). Using the same or analogous techniques and / or substituting alternative reagents, the following compounds of the invention were separated: 1-methylethyl 3-. { [3- ( { 4- [(4-f1uorophenyl) sulfonyl] piperazin-1-yl}. Methyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.67 (s, 1H), 7, 83 (d, J = 8.0 Hz, 1H), 7.73 (m, 3H), 7.47 (m, 2H), 7.38 (m, 3H), 7.19 (m, 2H), 7.09 (t, J = 6.8 Hz, 1H), 5.10 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 3.52 (s, 2H) , 2.99 (br s, 4H), 2.51 (t, J = 4.0 Hz, 4H), 1.62 (s, 6H), 1.17 (s, 3H), 1.15 (s) , 3H); MS (El) for C36H4oFN4? 5S: 659.3 (MH +). 1-Methylethyl 3- [(3- {[[4- (ethylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [, 5-b] indo1-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.68 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.76 (s) , 1H), 7.55 (s, 1H), 7.48 (m, 1H), 7.40 (m, 2H), 7.31 (s, 1H), 7.19 (t, J = 8, 0 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.12 (sept, J = 6.4 Hz, 1H), 4.17 (brs, 2H), 3, 60 (s, 2H), 3.27 (br s, 4H), 2.88 (q, J = 6.8 Hz, 2H), 2.53 (m, 4H), 1.64 (s, 6H) , 1.57 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H); MS (El) for C32H4iN405S: 593.3 (MH +). 1-Methylethyl 3- [(3- {[[4- (cyclopropylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 ( s, 1H), 7.55 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.40 ( m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 5.11 (sept, J = 6.4 Hz, 1H), 4.08 (br s, 2H), 3.63 (d, J = 14.4 Hz, 4H), 3.55 (s, 2H), 2.43 (d, J = 23.6 Hz , 4H), 1.70 (m, 4H), 1.64 (s, 6H), 1.17 (s, 3H), 1.16 (s, 3H), 0.98 (s, 2H), 0 75 (s, 2H); MS (El) for C 34 H 41 N 4 O 4: 564, 4 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (2-methylpropanoyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.70 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7, 79 (s, 1H), 7.55 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7, 39 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.11 (sept, J = 6.4) Hz, 1H), 4.06 (br s, 2H), 3.60 (br s, 4H), 3.54 (s, 2H), 3.48 (t, J = 4.8 Hz, 2H), 2.76 (q, J = 6.4 Hz, 1H), 2.41 (t, J = 4.4 Hz, 4H), 1.64 (s, 6H), 1.18 (s, 3H), 1.16 (s, 3H), 1.12 (s, 3H), 1.11 (s, 3H); MS (El) for C3H43N404: 571.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (phenylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDC13): d 10.69 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.78 ( s, 1H), 7.52 (m, 3H), 7.40 (m, 7H), 7.19 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.2) Hz, 1H), 5.09 (m, 1H), 4.06 (br s, 2H), 3.55 (s, 2H), 3.40 (br s, 4H), 2.37 (br s, 4H), 1.64 (s, 6H), 1.17 (s, 3H), 1.16 (s, 3H); MS (El) for C 37 H 41 N 4 O 4: 605.4 (MH +).

EXAMPLE 19 PREPARATION OF 1-Methylethyl 1, 1-Dimethyl-3-. { [3- (Piperazin-1-ylmethyl) phenyl] carbonyl} -l, 2, 3, 6-Tetrahydroazepino [4, 5-b] Indol-5-carboxylate: or N '"O 1 DCE, i-PrNEt N NH p., during the nodule Cl' • - O 2 acetone O or 4N HCl in dioxa mo O, N N N H NH O O HCl 1-met? Let? 3-. { [3- (chloromethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazep [no, 5-b]? Ndol-5-carboxylate (80.0 mg, 0.1774 mmol) was dissolved in 3 mL DCE, N, N'-diisopropylethylamine (344 mg, 2.6610 mmol) and P-peraz? n-1-carboxylic acid tert-butyl ester (496 mg, 2.66 mmol) were added and allowed to mix the night at room temperature. When TLC indicated that the initial material was no longer found, the sample was evaporated to dryness and dissolved in 20 mL acetone, 20 mL 4N HCl in dioxane was added to the mixed solution and allowed to react at room temperature for 2 hrs. The light yellow precipitate was filtered and washed with cold acetone yielding 100.1 mg (98%) of the title compound: XH NMR (400 MHz, CDC13): d 9.30 (s, 1H), 7.79 (d , J = 7.6 Hz, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.62 (m, 3H), 7.42 (d, J = 8.0 Hz , 1H), 7.12 (t, J = 6.8 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 5.13 (m, 1H), 3.54 (s) , 4H), 3.30 (s, 4H), 1.62 (s, 6H), 1.20 (s, 3H), 1.18 (s, 3H); MS (El) for C 30 H 37 N 4 O 3: 501.2 (MH +).

EXAMPLE 20 PREPARATION OF 1-Methylethyl 1, 1-Dimethyl-3-. { [3- ( { 4- [(Phenylamine) Carbonyl] Piperazin-1-y1.] Methyl) Phenyl] Carbonyl} -1,2,3, 6-Tetrahydroazepino [4, 5-b] Indole-5-carboxylate 0 HCl 0 C 1 DCM. rt 1 5 hr ° - N NH > - HN N or N 2 acetone,? HCl in Dioxane HN OR N DCE N N ^ DIEA N H, i Mrt. overnight N H. O 9 O or O NH Piperazin-1-carboxylic acid tert-butyl ester (2.00 g, 10.7 mmol) was dissolved in 10 mL DCM, Phenyl isocyanate (1.66 g, 14.0 mmol) was added and the reaction allowed to mix for 1.5 h. When LCMS indicated the desired mass, the solution was diluted with 50 mL of ethyl acetate with 2 x 50 mL of water and 1 x 50 mL of brine. The organic layer was dried over Na2SO3 and filtered. The sample was evaporated to a colorless oil, which was diluted in 20 mL of acetone and 20 mL 4N HCl in dioxane, 30 minutes after the white precipitate of phenylamine hydrochloride of the piperazine-1-carboxylic acid that formed was filtered and washed with cold acetone. 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate (100 mg, 0.221 mmol) was dissolved in 3 mL DCE, N, N'-diisopropylethylamine (860) mg, 6.65 mmol) and phenylamine hydrochloride of piperazine-1-carboxylic acid (804 mg, 3.32 mmol) were added to the solution. The reaction mixture was mixed at room temperature overnight. The sample was filtered with Millipore Millex-GN filter, then purified by liquid chromatography using 20% -80% gradient of ACN / H20 with 0.05% TFA for 15 minutes. The desired fractions were combined and made basic by saturated NaHCO 3 and diluted with ethyl acetate. The organic layer was washed with water and brine and dried over a2S03 and filtered. The yellow solution was reduced to dryness and lyophilized overnight in ACN / H20 to form the yellow powder (137.3 mg, 28% yield) of the title compound: XH NMR (400 MHz, CDC13): d 10.67 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.40 (m, 8H), 7.18 (m, 2H), 7 , 07 (m, 2H), 5.11 (sept, J = 6.0 Hz, 1H), 3.51 (br s, 4H), 2.53 (br s, 4H), 1.65 (s) , 6H), 1.18 (s, 3H), 1.17 (s, 3H); MS (El) for C 37 H 41 N 5 O 4: 620.4 (MH +).

Using the same or analogous techniques and / or substituting alternative reagents, the following compounds of the invention were separated: 1-methylethyl 3-. { [3- ( { 4- [(ethylamine) carbonyl] piperazin-1-yl}. Methyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDC13): d 10.69 (s, 1H), 7, 83 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7, 45 (d, J = 7.6 Hz, 1H), 7.39 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 6.8) Hz, 1H), 5.11 (sept, J = 6.4 Hz, 1H), 4.04 (br s, 2H), 3.55 (s, 2H), 3.33 (m, 4H), 2.70 (m, 2H), 2.41 (m, 4H), 1.64 (s, 6H), 1.18 (s, 3H), 1.16 (s, 3H), 1.14 (s) , 3H); MS (El) for C33H41N5O4: 572.4 (MH +).

EXAMPLE 24 PREPARATION OF 2-. { [(3, 4-Difluorophenyl) carbonyl] oxy} -1-Methylethyl 3- [(3, -Difluorophenyl) Carbonyl] -1, 1-Dimethyl-l, 2, 3, 6-tetrahydroazepino [4, 5-b] Indol-5-carboxylate EXAMPLE 25 PREPARATION OF 2-Hydroxyethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-Dimethyl-1, 2,3,6-tetrahydroazepin [4,5-b] Indole-5-carboxylate: EXAMPLE 26 PREPARATION OF (E) -Isopropyl 1, l-dimethyl-3- (4- (3-morpholino-propoxy) benzoyl) -1,2,3,6-tetrahydroazepino [4,5-b] indo-1-5-carboxylate To a solution of methyl 4-hydroxybenzoate (5 g, 32.86 mmol) in acetone (50 mL) was added benzoyl bromide (5.63 g, 32.86 mmol) and potassium carbonate (9.08 g, 65.72 mmol). The reaction mixture was heated to reflux overnight under stirring. After 12 hours the reaction was concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate and washed with water. The organic compounds were dried over sodium sulfate, filtered and concentrated and gave 7.29 g of the product. XH NMR (400 MHz, CDC13): d 8.01-6.98 (m, 9H), 5.12 (s, 1H), 3.89 (s, 3H).

To a solution of methyl 4- (benzyloxy) benzoate (7.29 g, 30.09 mmol) in THF was added an aqueous solution of sodium hydroxide (12.0 g, 30.0 mmol, 50 mL). The reaction mixture was heated at 64 ° C for 4 hours. After finishing the reaction (monitored by LC / MS), the reaction mixture was neutralized with 3N aqueous HCl. The product (6.79 g) was collected by filtration.

To a round-bottomed flask containing thionyl chloride (15 mL) was added 4- (benzyloxy) benzoic acid (1.44 g, 6.3 mmol) at room temperature. Then the reaction mixture was heated to reflux for 2 hours. After removing the excess thionyl chloride on a rotary evaporator, the residue was added to a solution of (E) -isopropyl 1,1-d? Meth? Ll, 2, 3,6-tetrahydroazepine [4, 5-b ]? ndol-5-carboxylate (large scale preparation in DC paper) in DICE (30 mL) and 2 equivalents of dusopropylethyl amine was added to the mixture of the preceding reaction. The reaction mixture was then stirred overnight at room temperature. After aqueous workup, the product (1.4 g) was isolated by purification using silica gel column chromatography with 10% acetate / hexane as eluent. XH NMR (400 MHz, CDC13): d 10.73 (bs, 1H), 7.89-6.90 (m, 13H), 5.13 (m, 3H), 4.09 (bs, 2H), 1.62 (s, 6H), 1.22 (d, J = 6.00 Hz, 6H).

To a solution of 1-methylethyl 1, l-dimethyl-3- (. {4- [(phenylmethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate (0.24 g, 0.47 mmol) in methanol was added 1,4-cyclohexadiene (0.378 g, 4.72 mmol) and Pd (OH) 2 / C (120 mg) in a sealed tube . The reaction mixture was heated at 64 ° C for 12 hours. The reaction mixture was filtered and the solvent was evaporated and gave the crude title product (0.180 g, 91% yield). The material was used as it was in the subsequent reaction. XH NMR (400 MHz, CDC13): d 10.71 (bs, 1H), 7.83-6.99 (m, 9H), 5.92 (s, 1H), 5.13 (m, 1H), 4.05 (bs, 2H), 1.63 (s, 6H), 1.20 (d, J = 6, 4 Hz, 6H).

To a solution of 1-methylethyl 3- [(4-hydroxyphenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate (90 mg, 0.215 mmol ) in THF (5 mL) was added 3-morpholinopropanol (62 mg, 0.43 mmol), diisopropyl azodicarboxylate (87 mg, 0.43 mmol) and triphenylphosphine polystyrene (90 mg, 0.43 mmol). The reaction mixture was stirred at room temperature overnight. After filtering, the solvent was stirred on a rotary evaporator. The crude material was purified by preparative liquid chromatography using 10% -90% gradient of ACN / H20 with 0.05% TFA for 11 minutes. The desired fractions were combined and neutralized by partitioning between aqueous NaHCO3 and ethyl acetate. The organic layer was dried over Na2SO4 and filtered. Concentration on the rotary evaporator gave the desired product (52 mg, 44% yield). 1 NMR (400 MHz, CDCl 3): d 10.72 (bs, 1H), 7.89-6.90 (m, 9H), 5.15 (m, 1H), 4.09 (bs, 2H), 4.07 (t, J = 6.2 Hz, 2H), 3.72 (m, 4H), 2.52 (t, J = 7.4 Hz, 2H), 2.47 (m, 4H), 1.99 (dt, J = 6.2, 7.4 Hz, 2H), 1.62 (s, 6H), 1.22 (d, J = 6.00 Hz, 6H); MS (El) for C 32 H 39 N 3? 5: 546.2 (MH +).

EXAMPLE 27 PREPARATION OF 1-. { 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indol-5-i1} Etanone Q Benzene and Reflux Cl O Cl NH NH3 * CI N 1 EtO H / 'Vegetable Charcoal N H Reflux H 0 2 Pindina DMAP 80 ° C O Cl O NH N N DIEA / DCE p H O O EXAMPLE 28 PREPARATION OF 1-methylethyl 3- ( { [3- (dimethylamino) propyl] amino.} Carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4,5-b Indole-5-carboxylate Chloroformate of p-nitrophenyl (0.658 g, 3.26 mmol) was added in portions to a solution of 1-methylethyl 1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5 carboxylate (0.927 g, 3.11 mmol) and diisopropylethylamine (1.03 mL, 6.22 mmol) in CH2C12 (40 mL) at room temperature. After 12 hours, the reaction was concentrated in vacuo and the residue was purified on SiO2 (10% ethyl acetate: hexanes) and gave 5- (1-methylethyl) 3- (4-nitrophenyl) -1, 1-dimethyl-1 , 6-dihiroazepino [4,5-b] indol-3,5 (2H) -dicarboxylate (1.24 g, 86% yield) as a light yellow solid. A solution of 5- (1-methylethyl) 3- (4-nitrophenyl) -1, 1-dimethyl-l, 6-dihydroazepino [4, 5-b] indole-3,5 (2H) -dicarboxylate (0.101 g), 0.218 mmol) and N, N '-dimethylpropanediamine (110 μL, 0.872 mmol) in anhydrous acetonitrile (1.0 mL) was stirred at room temperature under a nitrogen atmosphere. After one hour or the disappearance of the initial material, the reaction was concentrated in vacuo and purified by inverted phase HPLC (25 mM ammonium acetate: acetonitrile, 20-90% gradient). The product was collected and lyophilized and gave the title compound (82 mg, 89% yield) as a yellow solid. X H NMR (400 MHz, DMSO-d 6): d 8.12 (s, 1 H), 7.78 (t, J = 5.2 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.01 (dt, J = 7.2, 1.2 Hz, 1H), 6.96 (dt, J = 7.2 , 1.2 Hz, 1H) 5.12 (sept., J = 6.0 Hz, 1H), 3.17 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.12 (s, 6H), 1.61 (quint., J = 6.8 Hz, 2H), 1.44 (bs, 6H), 1.33 (d, J = 6.0 Hz, 6H); MS (El) for C 24 H 34 N 4 O 3: 427.3 (MH +).

Using the same synthetic or other analogous techniques and / or substituting with alternative reagents, the following compounds of the invention were prepared: 1-methylethyl 1, l-dimethyl-3- (piperidin-1-ylcarbonyl) -1,2,3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, DMSO-d 6): d 10.85 (bs, 1H), 7.74-6.93 (m, 5H), 5.13 (m, 1H), 3.98 (bs, 2H), 3.71 (bs, 2H), 3.25 (m, 4H), 1.60-1.50 (m, 6H), 1 , 43 (s, 6H), l, 32 (d, J = 6.4Hz, 6H); MS (El) for C 24 H 31 N 3 O 3: 410.1 (MH +). 1-Methylethyl 1, l-dimethyl-3- ( { [4- (4-methyl-piperazin-1-yl) -phenyl] -amino} -carbonyl-1, 2,3,6-tetrahydroazepine [4, 5-b] ] indole-5-carboxylate: XH NMR (400 MHz, DMSO-6): d 10.95 (s, 1H), 9.49 (s, 1H), 8.10 (s, 1H), 7.71 ( d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.33 (m, 2H), 7.04 (dt, J = 7.2, 1 , 2 Hz, 1H), 6.94 (dt, J = 7.2, 1.2 Hz, 1H), 6.90 (m, 2H), 5.14 (sept, J = 6.4 Hz, 1H ), 3.07 (m, 4H), 2.44 (m, 4H), 2.21 (s, 3H), 1.90 (s, 2H), 1.47 (bs, 6H), 1.33 (d, J = 6.4 Hz, 6H); MS (El) for C30H37N5O3: 516.3 (MH +). 1-Methylethyl 3- ( { [2- (dimethylamino) ethyl] amino (carbonyl) -1 , 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, DMSO-d6): d 10.91 (s, 1H), 8, 13 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 8.8 Hz, 1H), 6.90 (m, 2H), 5.12 (sept, J = 6.4 Hz, 1H), 3.30 ( m, 4H), 2.57 (m, 2H), 2.33 (bs, 2H), 1.45 (bs, 6H), 1.33 (d, J = 6, 4 Hz, 6H); MS ( He) for C23H32N4O3: 413.3 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [(3-morpholin-4-ylpropyl) amino] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.90 (s, 1H), 8.11 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H) , 6.96 (t, J = 8.8 Hz, 1H), 5.12 (sept, J = 6.4 Hz, 1H), 3.74 (bs, 2H), 3.55 (bs, 4H) , 3.19 (m, 3H), 2.31 (m, 5H), 1.63 (m, 2H), 1.44 (bs, 6H), 1.33 (d, J = 6.4 Hz, 6H); MS (El) for C 26 H 36 N 4 O 4: 469.3 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [(2-morpholin-ethyl) amino] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1TI NMR (400 MHz, DMSO-d6): d 10.92 (s, 1H), 8.11 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 (bt, J = 5.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H) , 7.02 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 5.13 (sept, J = 6.4 Hz, 1H), 3 , 73 (bs, 2H), 3.55 (m, 4H), 3.26 (m, 2H), 2.43 (m, 6H), 1.45 (bs, 6H), 1.33 (d, J = 6.0 Hz, 6H); MS (El) for C 25 H 34 N 4 O 4: 455.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(propylamino) carbonyl] -l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate:? H NMR (400 MHz, DMSO -d6): d 10.91 (s, 1H), 8.14 (s, 1H), 7.70 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7, 01 (dt, J = 7.2, 1.2 Hz, 1H), 6.93 (dt, J = 7.2, 1.2 Hz, 1H), 5.11 (sept, J = 6.0 Hz) , 1H), 3.73 (bs, 2H), 3.11 (m, 2H), 1.48 (m, 2H), 1.44 (bs, 6H), 1.33 (d, J = 6, 0 Hz, 6H), 0.86 (t, J = 7.2 Hz, 2H); MS (El) for C 22 H 29 3 O 3: 384.4 (MH +). 1-Methylethyl 3- (([2- (diethylamino) ethyl] (ethyl) amino.} Carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5 -carboxylate: 1H NMR (400 MHz, DMSO-d6): d 10.86 (s, 1H), 7.73 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 5, 14 (sept, J = 6.4 Hz, 1H), 3.70 (bs, 2H), 3.22 (m, 4H), 2.55 (bt, J = 6.8 Hz, 2H), 2, 43 (q, J = 6.8 Hz, 4H), 1.43 (bs, 6H), 1.31 (d, J = 6.4 Hz, 6H), 1.12 (t, J = 6.8) Hz, 3H), 0.91 (t, J = 6.8 Hz, 6H), MS (El) for C27H40N4O3: 469.2 (MH +), 1-methylethyl 1, l-dimethyl-3- [(4- pyrrolidin-1-ylpiperidin-1-yl) carbonyl] -l, 2,3,6-tetrahydroazepino [4, 5-b] i ndol-5 -car oxy oxy: XH NMR (400 MHz, DMSO-d6): d 10.84 (s, 1H), 7.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H) , 7.04 (t, J = 8.4 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 5.13 (sept, J = 6.4 Hz, 1H), 3 , 71 (bs, 2H), 3.64 (bd, J = 12.4 Hz, 2H), 2.95 (bt, J = 12.4 Hz, 4H), 2.55 (m, 2H), 2.41 (m, 3H), 1.68 (bs, 4H), 1.43 (bs, 6H), 1.39 (m, 2H), 1.32 (d, J = 6.4 Hz, 6H ); MS (El) for C2sH38N4? 3: 479.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- ((4- [(1-methylpiperidin-4-yl) methyl] pipe-razin-1-yl.} Carbonyl) -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 8 , 0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.03 (dt, J = 7.2, 0.8 Hz, 1H), 6.94 (dt, J = 6.8, 0.8 Hz, 1H), 5.13 (sept, J = 6.0 Hz, 1H), 3.70 (bs, 2H), 3.26 (bs, 4H), 2.70 (m, 2H), 2.34 (bs, 4H), 2.11 (s, 3H), 2.10 (m, 2H), 1.78 (bt, J = 11.6 Hz, 2H), 1 , 61 (bd, J = 11.2 Hz, 2H), 1.43 (bs, 6H), 1.33 (d, J = 6.4 Hz, 6H), 1.06 (m, 3H); (El) for C30H43N5O3: 522.5 (MH +). 1-methylethyl 3-. { [4- (diethylamino) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-carboxy lat: XH NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.77 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.52 (d , J = 8.0 Hz, 1H), 7.03 (dt, J = 7.2, 1.2 Hz, 1H), 6.95 (dt, J = 6.8, 0.8 Hz, 1H) , 5.14 (sept, J = 6.4 Hz, 1H), 3.71 (bd, J = 11.6 Hz, 4H), 3.26 (bs, 4H), 2.84 (bt, J = 11.6 Hz, 4H), 2.68 (m, 2H), 2.45 (q, J = 7.2 Hz, 4H), 1.69 (bd, J = 10.8 Hz, 2H), 1 , 43 (bs, 6H), 1.38 (m, 1H), 1.32 (d, J = 6.4 Hz, 6H), 0.94 (t, J = 7.2 Hz, 6H); MS (El) for C28H40 4? 3: 481.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- ([4- (2-oxo-2-pyrrolidin-1-ylethyl) piperazin-1-yl] carbonyl] -l, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate: H NMR (400 MHz, DMSO-d6): d 10.86 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 8 , 0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.95 (t, J = 8.2 Hz, 1H), 5.13 (sept, J = 6.0 Hz, 1H), 3.71 (bs, 2H), 3.52-3.19 (m, 14H), 3.14 (bs, 2H ), 1.83 (m, 2H), 1.74 (m, 2H), 1.43 (bs, 6H), 1.34 (d, J = 6.0 Hz, 6H); MS (El) for C 29 H 39 N 504: 522.3 (MH +). 1-Methylethyl 3- ( { - [2- (diethylamino) ethyl] piperazin-1-yl}. Carbonyl) -1,1-dimethyl-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5-carboxylate: X H NMR (400 MHz, DMSO-d 6): d 10.83 (s, 1 H), 7.73 (s, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.50 ( d, J = 8.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.92 (t, J = 8.4 Hz, 1H), 5.11 (Sept. J = 6.4 Hz, 1H), 3.68 (bs, 2H), 3.24 (bs, 4H), 2.46-2.32 (m, 12H), 1.40 (bs, 6H), 1.31 (d, J = 6.4 Hz, 6H), 0.89 (t, J = 6.8 Hz, 6H); MS (El) for C29H43N5O3: 510, 3 (MH +). 1-methylethyl 3-. { [3- (dimethylamino) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5 -carboxy lat: 1 NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.72 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.55 (d , J = 8.0 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.4 Hz, 1H), 5.11 (Sept. = 6.0 Hz, 1H), 3.91 (bs, 2H), 3.66 (m, 1H), 3.59 (m, 1H), 3.50 (m, 1H), 2.80 (m , 2H), 2.21 (m, 1H), 2.12 (s, 6H), 1.85 (m, 1H), 1.75 (m, 1H), 1.43 (m, 7H), 1 , 31 (t, J = 6.4 Hz, 6H); MS (El) for C 26 H 36 N 4 O 3: 453.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- ([4- (4-methylpiperazin-1-yl) pipe r idin-1-yl] carbonyl] -l, 2,3,6-tetrahydroazepine [4,5 -b] indole-5 -carboxy lat: XH NMR (400 MHz, DMSO-d6): d 10.84 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 8 , 0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.96 (t, J = 8.4) Hz, 1H), 5.14 (sept, J = 6.0 Hz, 1H), 3.72 (bs, 2H), 3.68 (bs, 2H), 3.40 (bs, 2H), 2, 85 (m, 3), 2.45 (m, 4H), 2.27 (m, 3H), 2.12 (s, 3H), 1.77 (m, 2H), 1.42 (bs, 6H) ), 1.31 (d, J = 6.0 Hz, 6H); MS (El) for C29H41N5? 3: 508.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- (morpholin-4) -carbonyl) -1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, DMSO-dg): d 10.83 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.01 (dt, J = 7.2, 1.2 Hz, 1H), 6.93 (dt, J = 6.8, 1.2 Hz, 1H), 5.11 (sept, J = 6.0 Hz, 1H), 3.71 (bs, 2H), 3.59 (m, 4H), 3.26 (m, 4H), 1.42 (bs, 6H), 1.32 (d, J = 6.4 Hz, 6H), MS (El) for C23H29N3O4: 412.2 (MH +). 1-Methylethyl 3- ( {3 - [(dimethylamino) methyl] piperidin-1-yl.} Carbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.86 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.04 (dt, J = 7.2, 1.2 Hz, 1H), 6.94 (dt, J = 6.8. , 1.2 Hz, 1H), 5.10 (sept, J = 6.4 Hz, 1H), 3.87 (bs, 2H), 3.72 (m, 1H), 3.59 (m, 1H ), 2.83 (m, 1H), 2.54 (m, 1H), 2.06 (m, 1H), 2.02 (s, 6H), 1.96 (m, 1H), 1.70 (m, 3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.32 (d, J = 6.0 Hz, 6H), 1.11 (m, 2H); MS (El) for C27H38N4? 3: 467.3 (MH +). 1-Methylethyl 3- ( { (3S) -3- [(dimethylamino) methyl] pipe ridin-1-yl.} Carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 8 , 0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.94 (t, J = 8.0) Hz, 1H), 5.09 (sept, J = 6.4 Hz, 1H), 3.85 (bs, 2H), 3.72 (m, 1H), 3.57 (m, 2H), 2, 83 (m, 2H), 2.55 (m, 1H), 2.07 (m, 6H), 1.71 (m, 3H), 1.43 (s, 3H), 1.41 (s, 3H) ), 1.31 (d, J = 6.0 Hz, 6H), 1.11 (m, 2H); MS (El) for C27H38N4? 3: 467.3 (MH +). 1-methylethyl 3- ( { (3R) -3- [(dimethylamino) methyl] piperidin-1-yl}. Carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 8, 4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.04 (dt, J = 7.2, 1.2 Hz, 1H), 6.95 (dt, J = 8.0, 1.2 Hz, 1H), 5.10 (sept, J = 6.0 Hz, 1H), 3.88 (bs, 2H), 3.72 (m, 1H), 3.59 (m, 1H), 2.83 (m, 2H), 2 , 53 (m, 1H), 1.99 (m, 7H), 1.73 (m, 3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.31 (d, J = 6.0 Hz, 6H), 1.09 (m, 2H); MS (El) for C27H38N4? 3: 467.3 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [3- (morpholin-4-ylmethyl) piperidin-1-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.84 (s, 1H), 7.72 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.01 (dt, J = 7.2, 1.2 Hz, 1H), 6 , 94 (dt, J = 8.0, 1.2 Hz, 1H), 5.09 (sept, J = 6.0 Hz, 1H), 3.80-3.57 (m, 4H), 3, 26 (m, 3H), 2.81 (m, 2H), 2.53 (m, 1H), 2.29-2.03 (m, 6H), 1.68 (m, 3H), 1.44. (s, 3H), 1.42 (s, 3H), 1.31 (d, J = 6.0 Hz, 6H), 1.09 (m, 2H); MS (El) for C29H40N4? 4: 509, 4 (MH +). 1-methylethyl 3-. { [3- ( { [3- (dimethylamino) propyl] oxy} methyl) piperidin-1-yl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.68 (s, 1H), 7, 76 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.2) Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 5.22 (sept, J = 6.4 Hz, 1H), 3.97 (m, 2H), 3.67 ( m, 4H), 3.52 (d, J = 13.2 Hz, 2H), 3.44 (dd, J = 13.6, 5.6 Hz, 1H), 3.26 (m, 2H), 3.20 (s, 3H), 3.19 (s, 3H), 3.03 (m, 2H), 2.92 (m, 1H), 2.15 (m, 1H), 1.98 (m , 2H), 1.54 (s, 3H), 1.51 (s, 3H), 1.46 (m, 2H), 1.37 (d, J = 6.4 Hz, 6H); MS (El) for C30H44N O4: 525.3 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [(3R) -3- (morpholin-4-ylmethyl) piperidin-1-yl] carbonyl} -l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.73 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H) , 6.95 (t, J = 8.0 Hz, 1H), 5.10 (sept, J = 6.4 Hz, 1H), 3.88 (bs, 2H), 3.76 (m, 2H) , 3.62 (m, 1H), 3.29 (m, 3H), 2.81 (m, 1H), 2.55 (m, 1H), 2.24 (m, 2H), 2.12- 2.07 (m, 3H), 1.73-1.62 (m, 4H), 1.44 (s, 3H), 1.42 (s, 3H), 1.32 (d, J = 6, 4 Hz, 6H), 1.10 (m, 2H); MS (El) for C29H4o 4? 4: 509.4 (MH +). 1-methyl ethyl, l-dimethyl-3-. { [(3R) -3- (piperidin-1-ylmethyl) piperidin-1-yl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.85 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H) , 6.94 (t, J = 8.0 Hz, 1H), 5.10 (sept, J = 6.4 Hz, 1H), 3.86-3.61 (m, 6H), 2.80 ( m, 1H), 2.54 (m, 1H), 2.21 (m, 2H), 2.02 (m, 4H), 1.65 (m, 4H), 1.45 (s, 3H), 1.42 (s, 3H), 1.41 (m, 1H), 1.32 (d, J = 6.4 Hz, 6H), 1.17 (m, 4H); MS (El) for C3? H42N4? 3: 507.5 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [4- (phenylmethyl) -1,4-diazepane-1-yl] carbonyl} -l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.83 (s, 1H), 7.72 (s) , 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.22 (m, 5H), 7.04 (t , J = 7.2 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 5.11 (sept, J = 6.4 Hz, 1H), 3.72 (bs, 2H) ), 3.57 (s, 2H), 3.38 (m, 4H), 2.67 (m, 2H), 2.54 (m, 2H), 1.79 (m, 2H), 1.46 (s, 6H), 1.32 (d, J = 6.4 Hz, 6H); MS (El) for C3iH38N403: 515.4 (MH +). 1-Methylethyl 3- [(3'R) -l, 3'-bipiperidin-l '-ilcarbonyl] -1, 1 -dimet i 1-1, 2, 3, 6-tetrahydroazepino [4,5-b] indole -5-carboxylate: XH NMR (400 MHz, DMS0-d6): d 10.86 (s, 1H), 7.71 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H) , 7.53 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 5 , 13 (sept, J = 6.4 Hz, 1H), 3.91 (bs, 2H), 3.68 (m, 2H), 3.60-3.45 (m, 3H), 2.80 ( m, 3H), 2.41 (m, 4H), 1.75 (m, 3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.41 (m, 3H), 1.32 (d, J = 6.4 Hz, 6H); MS (El) for C29H4oN 03: 493.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- (pyrrolidin-1-ylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: H NMR (400 MHz, DMSO-de ): d 10.81 (bs, 1H), 7.74-6.92 (m, 5H), 5.08 (m, 1H), 3.67 (bs, 2H), 3.71 (bs, 2H) ), 3.29 (s, 4H), 1.60-1.50 (m, 6H), 1.43 (s, 6H), 1.32 (d, J = 6.4Hz, 6H); MS (El) for C 24 H 31 N 3 O 3: 410.1 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1ti NMR (400 MHz, DMSO-d6): d 10.85 (bs, 1H), 7.75-6.93 (m, 5H), 5.13 (m, 1H), 3.71 (bs, 2H), 3, 71 (bs, 2H), 3.27 (bs, 4H), 2.32 (bs, 4H), 2.17 (s, 3H), 1.43 (s, 6H), 1.34 (d, J = 6.4Hz, 6H); MS (El) for C 24 H 32 N 4? 3: 425, 4 (MH +). 1-Methylethyl 3- [(4-ethylpiperazin-1-yl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate:? H NMR ( 400 MHz, DMSO-d6): d 10.83 (bs, 1H), 7.74-6.93 (m, 5H), 5.11 (m, 1H), 3.69 (bs, 2H), 3 , 25 (bs, 4H), 2.36 (bs, 4H), 2.32 (bs, 4H), 2.30 (q, J = 7.6 Hz, 2H), 1.41 (s, 6H) , l, 31 (d, J = 6.4Hz, 6H), 0.955 (t, J = 7.6Hz, 3H); MS (El) for ^ 5 ^ 4 ^ 03: 439.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- (piperazin-1-ylcarbonyl) -1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, DMS0-d6 ): d 10.83 (bs, 1H), 7.73-6.92 (m, 5H), 5.11 (m, 1H), 3.69 (bs, 2H), 3.16 (bs, 4H ), 2.67 (bs, 4H), 1.41 (s, 6H), 1.31 (d, J = 6.4Hz, 6H); MS (E) for C23H3oN4? 3: 425.4 (MH +). 1-methylethyl 1, l-dimethyl-3-. { [4- (1-methylethyl) piperazin-1-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.84 (bs, 1H), 7.75-6, 92 (m, 5H), 5.11 (m, 1H), 3.69 (bs, 2H), 3.23 (bs, 4H), 2.64 (m, 1H), 2.43 (bs, 4H) ), 1.41 (s, 6H), 1.31 (d, J = 6.4Hz, 6H), 0.92 (d, J = 6.8 Hz, 6H); MS (El) for C 26 H 36 N 4 3 3: 453.4 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(4-propylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, DMSO-d6): d 10.83 (bs, 1H), 7.73-6.92 (m, 5H), 5.11 (m, 1H), 3.68 (bs, 2H), 3, 25 (bs, 4H), 2.35 (bs, 4H), 2.20 (t, J = 7.6 Hz, 2H), 1.41 (s, 6H), 1.38 (m, 2H), 1.31 (d, J = 6.4Hz, 6H), 0.81 (t, J = 7.6 Hz, 3H); MS (El) for C 26 H 36 N 4 3 3: 453.2 (MH +). 1-Methylethyl 9-f luoro-1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxy lato: XH NMR (400 MHz, DMSO-d6): d 10.96 (bs, 1H), 7.76 (s, 1H), 7.52-6.87 (m, 3H), 5.11 (m , 1H), 3.68 (bs, 2H), 3.27 (bs, 4H), 2.37 (bs, 4H), 2.20 (s, 3H), 1.38 (s, 6H), 1 , 31 (d, J = 6.4Hz, 6H); MS (El) for C 24 H 31 FN 403: 443.4 (MH +). 1 -Met Ilethyl 3- (azepan-1-ylcarbonyl) -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13) : d 10.74 (s, 1H), 7.79 (d, 2H), 7.39 (d, 1H), 7.18 (t, 1H), 7.06 (t, 1H), 5.21 (m, 1H), 3.82 (bs, 2H), 3.43 (m, 4H), 1.79 (s, 4H), 1.62 (s, 4H), 1.58 (s, 6H) , 1.38 (d, 6H); MS (El) for C 25 H 33 N 303: 424.2 (MH +). 1 -Met ileethyl 1, 1-dimethyl-3- ([(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl.] -1, 2, 3 , 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.68 (s, 1H), 7.80 (m, 2H), 7.36 (d , 1H), 7.15 (t, 1H), 7.05 (t, 1H), 5.23 (m, 1H), 4.28 (bs, 2H), 3.41 (m, 4H), 2 , 95 (d, 1H), 2.72 (d, 1H), 2.38 (s, 1H), 1.89 (d, 1H), 1.68 (d, 1H), 1.53 (d, J = 15.64 Hz, 6H), 1.36 (t, 6H); MS (El) for C25H32N4? 3: 437.3 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(4- methyl-l, 4-diazepan-l-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1H NMR (400 MHz, CDC13): d 10.68 (s, 1H), 7.77 (d, J = 8.21 Hz, 1H), 7.69 (s, 1H), 7.37 (d, J = 8.21 Hz, 1H), 7.15 (t, 1H), 7.06 (t, 1H), 5.23 (m, 1H), 3.84 (bs, 2H), 3.67 (s, 2H), 3.43 (t, 2H) , 2.93 (s, 2H), 2.72 (s, 2H), 2.47 (s, 3H), 2.08 (s, 2H), 1.54 (s, 6H), 1.36 ( d, 6H); MS (El) for C25H34N4O3: 439.2 (MH +). 1-Methylethyl 3- [(cyclopentylamino) carbonyl] -1, 1-dimet il-l, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.69 (s, 1H), 8.00 (s, 1H ), 7.78 (d, 1H), 7.35 (d, 1H), 7.14 (t, 1H), 7.05 (t, 1H), 5.22 (m, 1H), 4.76 (d, 1H), 4.18 (m, 1H), 3.82 (bs, 2H), 2.04 (m, 2H), 1.67 (m, 2H), 1.54 (s, 6H) , 1.45 (m, 2 H), 1.38 (d, 6H); MS (El) for C 24 H 31 N 3 O 3: 410.3 (MH +). 1-Met ileethyl 3- [(cyclohexylamino) carbonyl] -1,1-dimethyl-1,2,6,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: 1ti NMR (400 MHz, CDC13) : d 10.69 (s, 1H), 8.02 (s, 1H), 7.78 (d, 1H), 7.36 (d, 1H), 7.15 (t, 1H), 7.05 (t, 1H), 5.22 (m, 1H), 4.71 (d, 1H), 3.79 (bs, 2H), 3.74 (m, 1H), 2.00 (m, 2H) , 1.72 (m, 2H), 1.63 (m, 1H), 1.55 (s, 6H), 1.43 (m, 1H), 1.38 (d, 6H), 1.21 ( m, 4H); MS (El) for C 25 H 33 N 3 O 3: 424.4 (MH +). 1-Methylethyl 3- [(cycloheptylamino) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDC13): d 10 , 70 (s, 1H), 8.02 (s, 1H), 7.78 (d, 1H), 7.36 (d, 1H), 7.15 (t, 1H), 7.05 (t, 1H), 5.22 (m, 1H), 4.77 (d, 1H), 3.93 (m, 1H), 3.80 (bs, 2H), 1.98 (m, 2H), 1, 64 (m, 4H), 1.55 (d, 6H), 1.53 (m, 6H), 1.38 (d, 6H); MS (El) for C 26 H 35 N 3 O 3: 438.4 (MH +). 1 -Met ileethyl 1, l-dimethyl-3-. { [(phenylmethyl) amino] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10.66 (s, 1H), 8.30 (s, 1H) , 7.78 (d, 1H), 7.32 (m, 6H), 7.15 (t, 1H), 7.05 (t, 1H), 5.19 (m, 2H), 4.54 ( d, J = 5.48 Hz, 2H), 3.86 (bs, 2H), 1.56 (s, 6H), 1.36 (d, J = 6.26 Hz, 6H); MS (El) for C 26 H 29 N 3 O 3: 432.4 (MH +). 1-Methylethyl 3- [(diethylamino) carbonyl] -1,1-dimethyl-1,2,6,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: 1 H NMR (400 MHz, CDCl 3): d 10.73 (s, 1H), 7.78 (m, 2H), 7.36 (d, 1H), 7.14 (t, 1H), 7.05 (t, 1H), 5.23 (m , 1H), 3.82 (bs, 2H), 3.26 (q, 4H), 1.52 (s, 6H), 1.35 (d, J = 6.41 Hz, 6H), 1.18 (t, 6H); MS (El) for C 23 H 31 N 3 O 3: 398.2 (MH +). 1 -Met ileethyl 1, l-dimethyl-3-. { [(3S) -piperidin-3-ylamino] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDCl 3): d 10.74 (s, 1H), 8.12 (s, 1H) , 7.77 (d, 1H), 7.35 (d, 1H), 7.13 (t, 1H), 7.04 (t, 1H), 6.31 (bs, 1H), 5.20 ( m, 1H), 4.07 (bs, 1H), 3.81 (bs, 2H), 2.97 (m, 3H), 2.88 (m, 2H), 2.77 (m, 1H), 1.74 (m, 2H), 1.55 (d, 6H), 1.37 (d, 6H); MS (El) for C 24 H 32 N 403: 425.2 (MH +). 1-Methylethyl 1, l-dimethyl-3- [(piperidin-3-ylamino) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.74 (s, 1H), 8.12 (s, 1H), 7.77 (d, 1H), 7.35 (d, 1H), 7.13 (t, 1H), 7.04 (t, 1H), 6.31 (bs, 1H), 5.20 (m, 1H), 4.07 (bs, 1H), 3.81 (bs, 2H), 2.97 (m, 3H), 2.88 (m, 2H), 2.77 (m, 1H), 1.74 (m, 2H), 1.55 (d, 6H), 1.37 (d, 6H); MS (El) for C 24 H 32 N 4? 3: 425, 3 (MH +).

EXAMPLE 29 PREPARATION OF 1-methylethyl 8-fluoro-1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4,5- b] indole 5-carboxylate ÍDCM.ÜWNQ. ?? "*» 2Ju trifoíg «ru> *. *? Ml ß -Ofe C n Tere-butyl ester of 8-fluoro-1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylic acid (100 mg, 0.316 mmol) was dissolved in 10 ml of dry DCM. N, N'-Diisopropylethylamine (77.9 mg, 0.603 mmol) was added and the solution was brought to 0 ° C under N2. Triphosgene (165 mg, 0.556 mmol) was added slowly and the mixture was allowed to stir for 1.5 hour at 0 ° C. N-methylpiperazine (158 mg, 1.58 mmol) was added; the reaction mixture was brought to room temperature, allowed to stir overnight. When the TLC indicated that the initial material was no longer present, the sample was purified by preparative liquid chromatography using 40% -100% gradient of ACN / H20 with 0.05% TFA for 10 minutes. The desired fractions were combined and made basic by saturated NaHCO 3 and diluted with ethyl acetate. The organic layer was extracted with water and brine, then dried over Na2SO3 and filtered. The yellow solution was reduced to dryness and lyophilized overnight in ACN / H20 to form a bright yellow powder (26.5 mg, 19% yield) of the title compound. XH NMR (400 MHz, CDC13): d 10.73 (s, 1H), 7.77 (s, 1H), 7.67 (m, 1H), 7.02 (dd, J = 9.2, 2 , 4 Hz, 1H), 6.82 (td, J = 9.2, 2.4 Hz, 1H), 5.23 (sept., J = 6.4, 1H), 3.81 (br s, 2H), 3.47 (m, 4H), 2.47 (m, 4H), 2.35 (s, 3H), 1.50 (s, 6H) 1.38 (s, 3H) 1.36 ( s, 3H); MS (El) for C 24 H 32 FN 4 3 3, 443.2 (MH +).

Using the same synthetic or other analogous techniques and / or substituting with alternative reatives, the following compounds of the invention were prepared: 1-methylethyl 3- [(4-ethylpiperazin-1-yl) carbonyl] -8-fluoro-1, 1 dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate: XH NMR (400 MHz, CDC13): d 10.74 (s, 1H), 7.78 (s, 1H), 7.66 (m, 1H), 7.02 (dd, J = 9.2, 2.4 Hz, 1H), 6.82 (td, J = 9.2, 2.4 Hz, 1H) ), 5.23 (sept., J = 6.4, 1H), 3.80 (br s, 2H), 3.47 (m, 4H), 3.11 (q, J = 6.8, 2H ), 2.45 (m, 4H), 1.50 (s, 6H), 1.37 (s, 3H) 1.35 (s, 3H), 1.09 (t, J = 7.2, 3H ); MS (El) for C25H34FN4? 3, 457.1 (MH +) EXAMPLE 30 TR-FRET Test of Resolved Time-Resolved Fluorescence Energy Transfer The TR-FRET assay was performed by incubating 8 nM GST-farnesoid receptor -LBD (comprising glutathione-S-transferase fused in frame with the receptor ligand farnesoid X receptor, (amino acids 244-471 of human farnesoid receptor X)), 8 nM Europium-labeled anti-GST antibody (Wallac / PE Life Sciences Cat # AD0064), 16 nM biotin-SRC-1 peptide [5'-biotin-CPSSHSSLTERHKILHRLLQEGSPS- C0NH2], 20 nM APC-SA [conjugated streptavidin alloficocianin] (Wallac / PE Life Sciences, Cat # AD0059A) in FRET assay buffer (20 mM KH2P04 / K2HP04 (f 7.3), 150 mM NaCl, 2 mM CAPS, 2 mM EDTA, 1 mM DTT) in the presence of the test compounds for 2-4 hours at room temperature in a test dish 384 with openings. The data was collected using LJL Analyst using general operating instructions with readings of emission wavelengths of 615 nm and 665 nm. After a delay of 65 Ds and an excitation wavelength of 330 nm.

EXAMPLE 31 Co-Transfection Test The basic co-transfection protocol for measuring farnesoid receptor activity is as follows. Mono African Liver Cells CV-1 were placed in a dish 24 hours before transfection to achieve approximately 70-80 confluence. The cells were transfected with the following expression vectors, the farnesoid receptor CMX (farnesoid human X-receptor of full extension) Lucl2 ((ECREx7-Tk-Luciferase) luciferase reporter gene construct, (See WO 00/76523, Venkateswaran et al. , (2000) J, Biol, Cem, 27_5 14700-14707) A CMX-β-Galactosidase expression vector was used as a transfection control.The transfection reagent used was DOTAP (Boehringer Mannheim) .The cells were incubated with the DOTAP / DNA mixture for 5 hours After which the cells were harvested and planted in the 96-well or 384-well plates containing the appropriate concentration of the test compound.The test continued for another 18-20 hours, after which cells dissolved with the dissolution buffer (1% triton X 100, 10% glycerol, 5 mM Dithiothreitol, 1 mM EGTA, 25 mM Tricine, pH 7.8) and the luciferase activity was measured in the presence of the buffer lucifera za (0.73 mM ATP, 22.3 mM Tricine, 0.11 mM EGTA, 0.55 mM Luciferin, 0.15 mM Coenzyme A, 0.5 mM HEPES, 10 mM magnesium sulfate) in a plate reader standard (PE Biosystems, NortStar Reader), using instructions and recommended operating conditions.

EXAMPLE 32 Experimental Design and Formulation A. Solution Formulation The test article was administered intravenously at 3 mg / kg formulated in a carrier carrier vehicle suitable for IV administration of the test article. Oral solution doses (or suspension) of 3, 10, 30, 100, 300 and 1000 mg / kg were administered using a suitable carrier dose vehicle. The compound was also administered in 10 mg / kg as a gelatin capsule. The experimental groups consisted of five animals for each dose group. Blood was collected (100 μL) in heparinized tubes by jugular catheter at 0.02, 0.08, 0.25, 0.5.1, 2, 4, 6, 8, 10, 12, 24, 32, 48 and 72 hours post dose for groups IV. Samples were collected in a manner similar to 0.08, 0.25, 0.5.1, 2, 4, 6, 8, 10, 12, 24, 32, 48 and 72 hours post-dose for the PO groups. The obtained plasma was stored at -80 ° C and a volume of 50 μL was used for the analysis.

B. SOLID DOSAGE Torpac mini size 9 porcine gelatin capsules were used for the oral dose test article in solid form at 3 or 10 mg / kg. The capsules were filtered into the powder compound based on body weight. The capsules were administered directly into the stomach of the rat with the use of a stainless steel dosing device similar to an oral priming needle. Pilot studies with empty capsules showed that the capsules dissolve in less than 7 minutes in the stomach.

BIOANALYTIC ANALYSIS The concentration of the test article in the plasma and tissue samples was determined by HPLC / MS / MS analyzes using sample preparation and analytical conditions suitable for the quantification of the test article by this method. A model without compartments was applied to calculate the pharmacokinetic parameters (PK) of all administration routes using WinNonlin 3.1 software (Farsight Co,, Mountain View, CA).

The compounds of the present invention showed highly enhanced and improved pharmacokinetic improvements.

EXAMPLE 33 KINETIC SOLUBILITY ASSAY The kinetic solubility of the test compounds in the buffer was evaluated using a filter plate format with 96 openings, a test solution of 500 μM in PBS, pH7.4 (or another test buffer, as necessary) was generated of a DM50 solution (up to 10 mM). Samples were transferred to 96-well 96 Millipore MultiScreen HTS filter plate (Cat # MSSLBPC10) mixed by shaking for 1.5 hours and processed by filtration before quantification by HPLC-UV. Amiodarone and testosterone were used as reference controls. Local historical data show that the solubility of amiodarone is between 3-5 μM and that of testosterone is approximately 330 μM. We used Agilent Cemstation using Waters 4 x 23mm cartridge YMC / AQ S-5 120A C18 column for analysis separation at an average mobile phase flow of 2.2 mL / min. The mobile phase was 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B). The column was maintained at 37 ° C and detection of analysis was achieved by quantification of UV signal at 220 nm and 254 nm following an injection volume of 10 μL.

The compounds demonstrated kinetic solubility in the average of the Example, approximately 500 μM or less, 400 μM or less, 300 μM or less, 200 μM or less, 100 μM or less. In an advantageous embodiment, the kinetic solubility is about 50 μM or less, 20 μM or less, 10 μM or less, 5 μM or less, 2.5 μM or less, or 1 μM or less, EXAMPLE 34 In Vivo Studies General Methods Young adult mice (8 weeks old) were purchased from conventional vendors and grouped (3-4 / cage) with unlimited access for food and water, in a vivarium with controlled temperature and light ( lights on at 06:00 hours, off at 18:00 hours). The compounds were administered daily orally in the morning (08:00 hrs.). In a final volume of 0.1 ml / mouse, with the first dose of the compound delivered on study day 0, the compounds were solubilized by gentle mixing in PEG400: Tween80 (4: 1) for at least several hours and usually during the night before starting the dose. When necessary, the solutions were briefly sonicated to ensure solubilization of the complete compound.

Blood samples (0.15 ml / mouse) were obtained from the retro orbital sinus of mice anesthetized with non-fatty insoglurane, 3 hours after the dose. The blood samples were obtained in tubes covered by heparin, and the plasma was recovered followed by centrifugation. Total plasma cholesterol and triglyceride levels were determined by commercially available colorimetric enzymatic assays that were adapted to 96-well plate formats. Plasma cholesterol (HDL-C) was determined by extracting non-HDL-C from the plasma with a precipitation reagent, and then determining plasma cholesterol levels in the remaining HDL-C fraction. Concentrations of triglycerides in the plasma, determined by a blood sample obtained during the 24 hours before the first dose, were used in the group of mice so that the triglyceride levels before the study between groups were equivalent before initiation of the dose regimen.

The representative data of these experiments are shown in Figures 1,2 and 3 for the effect of Compound A ((ethyl 3- (3, 4-difluorobenzoyl) -1-methy1-1, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate), Compound B (Ethyl 3- (3,4-difluorobenzoyl) -1, 1- dimethyl-1, 2,3,6-tetrahydro-azepino [4,5-b] indole-5-carboxylate) and Compound C (isopropyl 3- (3,4-difluorobenzoyl) -1,1-dimethyl-1,2 , 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate). Effects of the Compound on Normolipidemic Mice C57BL / 6 mice (Hablan Seraje Dawley, San Diego, CA) consumed standard laboratory food (4.5% fat w / w) without limit and were treated with Compound A (Figure 1) daily with an oral dose of 0.1, 1.0 or 10 mg / kg / day for seven days (n = 6 / group). Figure 1 shows triglyceride levels in the plasma of C57BL / 6 mice that are treated with either Compound A (Figure 1A) or Compound B (Figure IB) daily with 0.1 oral dose (filled triangles), 1, 0 (completely filled triangles) or 10 mg / kg / day (Diamonds) for seven days (n = 6 / group) compared to the vehicle alone (filled squares). Surprisingly in this dose range, both compounds significantly reduced triglycerides in the plasma 25-30% on day 7 of study (* p <0.05 against controls treated with vehicle on the day of treatment). Even at the lowest dose tested (0.1 mg / kg) the compounds unexpectedly show the ability to significantly reduce plasma triglyceride levels.

Effects of the Compound on LDLR- / ~ hyperlipidemic mice induced on diet LDLR_ / ~ mice (JAX Mice, Bar Harbor, ME) consumed a "Western" diet (21% fat, 0.02% cholesterol w / w) without limit, for two weeks before and during treatment with Compound C daily by oral dose of 10 mg / kg / day for 7 days (n = 9-10 / group). The results (Figure 2) show that at day 7 of the study, the compound has reduced plasma triglyceride concentrations to levels observed before the introduction of high-fat food. Surprisingly, Compound C also significantly reduced total cholesterol levels by 40% at day 7 of study, despite continued consumption of high-fat, supplemented food (Figure 2B, * p < 0.05 vs., treated controls with vehicle on the day of treatment). In a separate study using the same model (n = 12-16 / group) subject to dietary conduction for 8 weeks, LDLR ~ _ mice were treated with Compound B at a dose of 10 mg / kg / day for 6 weeks . Surprisingly, Compound B also decreases cholesterol and triglyceride concentrations in the plasma with a time similar to that observed with Compound C resulted in a sustained normalization of plasma lipid profiles through a 6-week "Western" diet. The data demonstrate in sum that the claimed compounds unexpectedly show high efficiency and potency by modulating cholesterol and triglycerides in the plasma in animals and animal models of hyperlipidemia. In such manner, said compounds show great potential for the development of therapeutic agents and specific utility for use in various methods disclosed herein. Results of Examples 30 and 31 Both the transgene assay of the farnesoid receptor X / ECREx7 c (EXAMPLE 31) and the TR-FRET assay (EXAMPLE 30) can be used to establish the EC50 / IC50 values for potency and percent activity or inhibition for the effectiveness Efficiency defines the activity of a compound relative to the high control (cenodeoxicolic acid, CDCA) or low control (DMSO / vehicle). The dose response curves are generated from a curve 8 with concentrations that differ by LOG units, the point Eac represents the average of 4 data openings from a plate of 384 openings. A curve for the data is generated using the equation: Y = lower + (upper-lower) / (1 + 10? ((LogEC50-X) * HillSlope)) EC50 / IC50 is also defined as the concentration at which the antagonist elicits a response that is half between the values from the top (maximum) and the bottom (base line). The EC50 / IC50 values represented are the averages of at least 3 independent experiments. The determination of relative efficacy or% control for an agonist is by comparison with the maximum response achieved by the cenodeoxicolic acid found individually in each dose response experiment. For the antagonist assay, CDCA is added to each plate aperture of 384 apertures to elicit a response. The% inhibition for each antagonist is also a measure of the inhibition of CDCA activity. In this example, 100% inhibition would indicate that the CDCA activity has been reduced to the baseline levels, defined as the assay activity in the presence of DMSO alone. The compounds of the invention demonstrated the ability to bind FXR when tested in this assay. Preferably, the compound binds FXR with a binding affinity, for example, 50 μM or less, 20 μM or less, 10 μM or less, 5 μM or less, 2.5 μM or less or 1 μM or less. In an advantageous embodiment, IC50 of the binding compounds is about 0.3μM or less, 0.1μM or less, about 0.08μM or less, about 0.06μM or less, about 0.05μM or less, about 0, 04μM or less, 0.03μM or less, preferably, approximately 0, 03μM or less, For the antagonist assay, CDCA is added to each plate aperture of 384 apertures to elicit a response. The% inhibition for each antagonist is also a measure of the inhibition of CDCA activity. In this example, 100% inhibition would indicate that the CDCA activity has been reduced to the baseline levels, defined as the assay activity in the presence of DMSO alone. Most of the compounds disclosed herein and tested exhibited activity in at least one of the aforementioned assays (EC50 or IC50 less than 10 uM). Most of the activity was below 1 μM. For example, the compounds showed agonist activity with less than 1 μM EC5o and more than 100% efficacy as shown by the transfection assay. Compounds showed agonist activity with less than 250 nM EC50 and more than 100% efficacy as measured by one or more of the in vitro assays described herein as shown in Table 1. IC50 and solubility data were represented by as follows: A = 0, 001-0, OlμM, B = 0.01-0, lμM, C = 0, ll, 0μM, and D = l, 0-10μM, E = >10μM. The efficiency% represents as follows: A = > 100% 80-100%; C = -80% 40-60%; E = < 40í Table I Solubil Cpto EC50 idad Name of IUPAC Structure Ef icací N ° μM Cinétic a μM 1-Methylethyl 1,1-dimethyl-3- (pyrrolidin-1-ylcarbonyl) - 15 B A 1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate 1-Methylethyl 1,1-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -16 C A 1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate Solubil Cpto EC50 idad Name of IUPAC Structure Ef icací N ° μM Cinétic a μM 1-Methylethyl 3- ( { [2- (dimethylamino) ethyl] amino.} Carbonyl) -1,1-dimethyl-17 1,2,3,6-tetrahydroazepino [4,5-b] indole-5 - carboxylate 1-methylethyl 1,1-dimethyl-3-. { [(3- morpholin-4-ylpropyl) amino] D carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate Solubil Cpto EC50 idad Name of IUPAC Structure Ef icací N ° μM Cinétic a μM 1-Methylethyl 1, 1- dimethyl-3- ( { 4- [(3-piperidin-1-ylpropyl) oxy] phenyl] 191 DA carbonyl) -1,2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate 1-Methylethyl 1,1-dimethyl-3- ( { 4- [(3-morpholin-4-ylpropyl) oxy] phenyl}. 192 AA carbonyl) -l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate All US patents, publications of US patent applications, US patent applications, foreign patents, foreign patent applications and non-patent publications cited in this specification and / or listed in the Patent Application Data Sheet , are incorporated herein by reference in their entirety.

From the foregoing it will be appreciated that, while specific embodiments of the invention have been described herein for purposes of exemplification, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims.

Claims (98)

1. A compound of the formula (I) or a pharmaceutically acceptable derivative thereof, wherein: R1 is -C (J) RU, -C (J) ORn, or -C (J) N (R10) (R11); J is a direct link, 0 or NR 10; n is from 0 to 4; R3 is hydrogen, -C (0) R9, or CON (R11) (R12); R6 or R7 is independently optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkylalkyl; R8 is selected from the group consisting of hydroxy, alkyl optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted, halo, haloalkyl, haloalkoxy, cycloalkyl optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted aralkyl optionally substituted , optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OC (0) N (R15) (R16), R9 is selected from the group consisting of alkyl optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted, aralkyl optionally substituted cycloalkyl optionally substituted, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclyl, OR10 and N (R12) (R13); R10 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl; each R11 is independently selected from the group consisting of hydrogen, alkyl optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted , optionally substituted heteroaralkyl, -OR14 and -N (R15) (R16); R12 and R13 are independently from the group consisting of hydrogen, alkyl optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, and optionally substituted heteroaralkyl; or R12 and R13, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl; R10, R11 R12 and R13 are selected as in (a) or (b) in the following manner: (a) R10, R11 R12 and R13 each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl optionally substituted, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or (b) R10, R11, R12 and R13 together with the atoms to which they are attached form an optionally substituted heterocyclic ring or an optionally substituted heteroaryl ring; and the others of R10, R11, R12, and R13, are selected as in (a), above each R14 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, cycloalkylalkyl optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted aralkyl optionally substituted heteroaryl, optionally substituted, optionally substituted heteroaralkyl, -OR18, -SR18, and -N (R20) (R21); R15 and R16 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, -OR18, -SR18 and -N (R20) (R21); or R15 and R16, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; R17 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; each R 18 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl , or optionally substituted heteroaralkyl; R19 is alkylene or direct bond; R20 and R21 are independently from the group consisting of hydrogen, alkyl optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted, or optionally substituted heteroaralkyl; or R20 and R21, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; each R22 is independently selected from the group consisting of hydrogen, alkyl optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted, aralkyl optionally substituted, heteroaryl optionally substituted , optionally substituted heteroaralkyl, -R19-OR23, -R19-N (R23) (R24), -R19-C (J) R23, -R19-C (J) OR23, and -R19-C (J) N (R23) ) (R24); each R23 and R24 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted aralkyl optionally substituted heteroaryl optionally substituted, optionally substituted heteroaralkyl, -R19-OR25, -R19-N (R25) (R26), -R19-C (J) R25, -R19-C (J) OR25, and -R19-C (J) N (R25) (R26); or R23 and R24, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; each R25 and R26 is independently selected from the group consisting of hydrogen, alkyl optionally substituted alkyl, alkenyl optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl optionally substituted heterocyclylalkyl optionally substituted aryl, optionally substituted aralkyl optionally substituted heteroaryl optionally substituted and optionally substituted heteroaralkyl; each R1-R26, when substituted, is substituted with one or more substituents that are independently selected from Q1. where Q1 is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, amino, hydroxyalkyl, hidroxialquilariloxi, hydroxyaryl, hydroxyalkyl-, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, diaryl, hydroxyaryl, alkylaryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, alquilaralquilo, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, I triarylsilyl , alkylidene, arylalkylidene, alkylcarbonyl, alkylarylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, heteroarylalkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylaryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, heterocyclylcarbonylalkaryl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, Minocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, haloalkoxy, alkoxyaryloxy, alkylaryloxy, diaryloxy, alkylaryloxyalkyl, alkyldiaryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aryloxyalkoxy, aralkoxyaryloxy, alkylarylcycloalkyloxy, heterocycloxyAlkoxyalkyl, alkoxyalkoxyalkyl, alquilheteroariloxi, alkylcycloalkoxy, cycloalkyloxy, heterocyclyloxy, aralkoxy, haloaryloxy, heteroaryloxy, alquilheteroariloxi, alcoxicarbonilheterocicloxi, alquilcarbonilariloxi, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, alkoxyaryloxy, aralcoxicarboniloxi, ureido, alkylureido, arylureido, amino, aminoalkyl, alkylaminoalkyl , dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, haloalquilarilamino, arylamino, diarylamino, alkylarylamino, aralkylamino, alkylcarbonylamino, ara1quilcarbónilamino, haloalkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, ariloxicarbonilaminoalquilo, ariloxiarilcarbonilamino, aryloxycarbonylamino, alquilendioxialquilo, dialquilalquilendioxialquilo, alkylsulfonylamino , arylsulfonylamino, azido, dialkylphosphonyl, alkylaryl phosphonyl, diarylphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyan, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two groups of Q1, which substitute atoms in an 1,2 or 1,3 arrangement together form alkylenedioxy (ie, -O- (CH 2) z-0-), thioalkyleneoxy (ie, -S- (CH 2) z -0-) or alkylenedithioxy (i.e., -S- (CH2) ZS-) where z is 1 or 2; and each Q1 is independently unsubstituted or substituted with one or more substituents, in one embodiment, from one to three or four substituents, each independently selected from Q2, wherein Q2 is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro , formyl, mercapto, amino, hydroxyalkyl, hydroxyaryl, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, heterocyclyl, aryl, heteroaryl , aralkyl, aralkenyl, aralkynyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, arylcarbonylalkyl, aminocarbonyl, alkoxy, aryloxy, aralkoxy, alkylenedioxy, amino, aminoalkyl, dialkylamino, arylamino, diarylamino, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, aralkylamino, alkoxycarbonylamino , arylcarbonylamino, alkylthio or arylthio; provided that the compound is not a compound of Table 2.
2. 2. The compound according to claim 1 wherein R1 is -C (J) 0R1X; J is 0; R3 is COR9; R9 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; R6 or R7 is optionally substituted alkyl; and n is 0-3.
3. 3. The compound according to claim 1, wherein R9 is optionally substituted alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
4. 4. The compound according to claim 1, wherein R9 is selected from the group consisting of optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.
5. 5. The compound according to claim 1, wherein R9 is selected from the group consisting of optionally substituted heteroaryl and optionally substituted heteroaralkyl.
6. 6. The compound according to claim 1, wherein R9 is selected from the group consisting of optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl.
7. 7. The compound according to claim 2, wherein R 11 is optionally substituted alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
8. 8. The compound according to claim 1, wherein R1 is -C (J) ORn; J is 0; R3 is CON (R11) (R12); R11 is hydrogen or optionally substituted alkyl; R 12 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl; R6 or R7 is optionally substituted alkyl; and n is 0.
9. 9. The compound according to claim 1, wherein R11 and R12 together with the atom to which they are attached form optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.
10. 10. The compound according to claim 1, wherein R11 and R12 together with the atom to which they are attached form optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, optionally substituted with one or more Q1.
11. 11. The compound according to claim 8, wherein when R3 is CON (Rn) (R12); R11 is hydrogen and R12 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylamino, dimethylamino, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 2-morpholin-4-ylethyl, -morpholin-4-ylpropyl, 3-morpholin-4-ylpropyl) amino, and piperidinyl.
12. 12. The compound according to claim 9, wherein R11 and R12 together with the atom to which they are attached form optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl selected from the group consisting of pyrrolidin-1-yl, 4-pyrrolidin-1-yl, piperidin -1-yl, 4-methylpiperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-piperazin-1-yl, 4-propyl-piperazin-1-yl, piperidin-3-yl, piperidinyl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl and azepanyl.
13. 13. The compound according to claim 2, wherein R9 is optionally substituted aryl or aralkyl, optionally substituted with one or more Q1.
14. 14. The compound according to claim 10, wherein Q 1 is selected from the group consisting of methyl, ethyl, propyl, diethylamino, dimethylamino, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyloxymethyl, phenyl, phenylmethyl, pyrrolidinyl, piperazinyl, piperidinyl, methylpiperidinyl, methylpiperazinyl, 2- oxo-2-pyrrolidin-1-ylethyl, and morpholino-4-methyl.
15. 15. The compound according to claim 13, wherein Q1 is selected from the group consisting of hydroxy, cyano, 2-methyl; 3-methyl; methylpiperazinyl, 3-chloromethyl, 3,4-difluoro; 3-methyl, 4-methyl; 2-methyloxy; 3-methyloxy; 4-methyloxy; 3-fluoro-4-methyl; 4-fluoro-3-methyl; 2-trifluoromethyloxy; 2-chloro; 3-chloro; 4-chloro; 2,4-dichloro; 2-chloro-3,6-difluoro, 3-chloro-2,6-difluoro, 2-fluoro; 3-fluoro; 2-bromine; 3-trifluoromethyl; 2, 3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6-difluoro; 3, 4-difluoro; 3,6-difluoro; 3, 4-difluoro; 2,3-difluoro-4-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 2-fluoro-3-trifluoromethyl; 3-fluoro-5-trifluoromethyl; 2,5-bistrifluoromethyl; 3, 5-bistrifluoromethyl; 3-chloro-2-fluoro-4-trifluoromethyl 3-fluoro-4-trifluoromethyl; 4-fluoro-3-trifluoromethyl; 4-fluoro-2-trifluoromethyl; 2-chloro-4-fluoro; 3-chloro-4-fluoro; 2-trifluoromethyl; 4-trifluoromethyl; 2, 3, 4-trifluoro; 2, 4, 6-trifluoro; 2, 4, 5-trifluoro; 3,4-bis (methyloxy); 3-phenylmethyloxy; metiloxifenilmetiloxi, 4-piperidin-4-yl, 3-piperidin-4-yl, 3-piperidin-4-ylmethyl, piperidin-4-ylmethyl, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, 4-methylsulfonylpiperazin-1-yl, 3-azepan-1-ylmethyl, 4-methyl-1, 4-diazepane-1-yl, 3-pyrrolidin-1-ylethyl, 4-methyl-piperazin-1-ylmethyl; 4-ethylpiperazin-1-ylmethyl; 3-piperazin-1-ylmethyl; morpholin-4-ylmethyl; 3-morpholin-4-ylmethyl; 2-morpholin-4-ylethyloxy; 2-piperidin-1-ylethyloxy; 3-morpholin-4-ylpropyloxy-1H-pyrazol-1-yl, 4-trifluoromethyl-1H-pyrazol-1-yl, 4-acetylpiperazin-1-ylmethyl; methylbenzotriazolyl, dimethylethyloxycarbonylpiperazin-1-ylmethyl, 4-phenylsulfonylpiperazin-1-ylmethyl, 4-fluorophenylsulfonylpiperazin-1-yl, 4-ethylsulphonylpiperazin-1-ylmethyl, 4-cyclopropylcarbonylpiperazin-1-ylmethyl, 2-methylpropanoylpiperazin-1-ylmethyl, 4-acetyl-l, 4-diazepan-l-yl -fenilcarbonil piperazin-1-ylmethyl, 3-azocan-l-ylmethyl, 4-phenylamino-1-ylmethyl carbonilpiperazin; 4-ethylaminocarbonylpiperazin-1-ylmethyl; 3-piperidin-1-ylpropyloxy, 2-pyrrolidin-1-ylethyloxy; 3-piperidin-1-ylpropyloxy; and 3-morpholin-4-ylpropyloxy.
16. 16. The compound according to claim 1, wherein R9 is optionally substituted heteroaryl or optionally substituted heteroaralkyl, optionally substituted with one or more QX
17. 17. The compound according to claim 16, wherein Q 1 is selected from the group consisting of optionally substituted alkyl, halo and haloalkyl.
18. 18. The compound according to claim 2, wherein R9 is optionally substituted heterocyclyl or heterocyclylalkyl optionally substituted with one or more Q1.
19. 19. The compound according to claim 18, wherein Q1 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl.
20. 20. The compound according to claim 1, wherein R9 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, cycloheptyl; dimethylaminopropyl, 4-methylpentyl; (3s, 5s, 7s) -trip. { 3.3.1.1-3, 7 ~] dec-1-yl; 1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl]; phenyl, isoxazolyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, benzodioxolyl, and benzotriazolyl.
21. 21. The compound according to claim 1, wherein Q1 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl.
22. 22. The compound according to claim 1, wherein R8 is hydroxy, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, and heterocyclylalkyl. optionally substituted.
23. 23. The compound according to claim 1, wherein R8 is selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
24. 24. The compound according to claim 1, wherein n is 0.
25. 25. The compound according to claim 1, wherein R6 or R7 is optionally substituted alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
26. 26. The compound according to claim 1, wherein R1 is -C (J) OR?: L and R11 is selected from the group consisting of 2,2-dimethyl-1,3-dioxolan-4-yl; 2-piperidin-1-ylethylaminocarbonyl; 2,3-dihydroxypropyl or 2-fluoro-1- (fluoromethyl) ethyl, hydroxyethyl, phenylmethyloxyethyl, 3,4-difluorophenylcarbonyloxy-1-methylethyl, and 2-hydroxy-1-methylethyl.
27. 27. The compound according to claim 1, wherein R1 is C (J) N (R10) (R11) and R11 is optionally substituted alkyl, selected from the group consisting of isopropyl; beta-alanine, 2,3-dihydroxypropyl; and 2-hydroxy-1- (hydroxymethyl) ethyl.
28. 28. The compound according to any of claims 26-27, wherein Q1 is selected from the group consisting of optionally substituted alkyl, and halogen.
29. 29. The compound according to claim 28, wherein Q1 is selected from the group consisting of methyl, chloro, bromo, fluoro, and 3,4-difluoro.
30. 30. The compound that has the formula la: wherein each R6, R7 or R11 is optionally substituted alkyl; n is 0; R9 is optionally substituted alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.
31. 31. The compound according to claim 30, wherein R9 is optionally substituted with one or more Q1.
32. 32. The compound according to claim 30, selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- [(1-methylpiperidin-3-yl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(1-methylpiperidin-4-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; and 1-methylethyl 3- [4- (dimethylamino) butanoyl] -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate.
33. 33. The compound according to claim 30, wherein R9 is optionally substituted alkyl, opotatively substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl.
34. 34. The compound according to claim 33, wherein R9 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, cycloheptyl; dimethylaminopropyl, 4-methylpentyl, and (3s, 5s, 7s) -tricyclo [3.3.1.1-3, 7 ~] dec-1-yl.
35. 35. The compound according to claim 33, wherein R9 is optionally substituted with one or more Q1.
36. 36. The compound according to claim 35, selected from the group consisting of: 1-methylethyl 3- (cyclohexylcarbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5- carboxylate; 1-Methylethyl 3-acetyl-1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3-butanoyl-l, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5- b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3-pentanoyl-1, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-Methylethyl 3- (cyclopentylcarbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- (2,2-dimethyl propanoyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- (2-ethylbutanoyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (3-methylbutanoyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- (cycloheptylcarbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3-propanoyl-l, 2, 3, 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, 1-dimethyl-3- [(3s, 5s, 7s) -trichyclo [3.3.1.1-3, 7 ~] dec-1-ylcarbonyl] -1,2,3,6-tetrahydroazepine [5 -b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (4-methylpentanoyl) -1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate.
37. 37. The compound that has the formula Ib wherein each R6 and R7 is independently optionally substituted alkyl, n is 0-3; R8 is optionally substituted alkyl or halo; R11 is hydrogen or optionally substituted alkyl; R 12 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
38. 38. The compound according to claim 37, wherein R12 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylamino, dimethylamino, 2-morpholin-4-ylethyl, 3-morphholin-4-ylpropyl. , 3-morpholin-4-ylpropyl) amino, or piperidinyl.
39. 39. The compound according to claim 37, wherein R11 and R12 together with the atom to which they are attached form optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.
40. 40. The compound according to claim 37, wherein R11 and R12 are selected from the group consisting of pyrrolidin-1-yl, 4-pyrrolidin-1-yl, piperidin-1-yl, 4-methylpiperazin-1-yl, 4- ethylpiperazin-1-yl, 4-piperazin-1-yl, 4-propyl-piperazin-1-yl, piperidin-3-yl, piperidinyl, (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] Hept-2-yl and azepanyl.
41. The compound according to claim 37, wherein R11 and R12 together are optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heterocyclylalkyl.
42. 42. The compound according to claim 41, wherein Q 1 is methyl, ethyl, propyl, diethylamino, dimethylamino, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyloxymethyl, phenyl, phenylmethyl, pyrrolidinyl, piperazinyl, piperidinyl, methylpiperidinyl, methylpiperazinyl, 2-oxo-2-pyrrolidin. -lilethyl, and morpholino-4-methyl.
43. 43. The compound according to claim 42, selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3-. { [(1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-pyrrolidin-1-ylpiperidin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (piperidin-1-ylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { [3- (dimethylamino) propyl] amino.} Carbonyl) -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { [4- (-methylpiperazin-1-yl) phenyl] amino} carbonyl) -1, 2, 3, 6-tetrahydroazepine [4,5- b ] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- (pyrrolidin-1-ylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { [2- (dimethylamino) ethyl] amino.} Carbonyl) -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [(3-morpholin-4-ylpropyl) amino] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4,5- b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [(2-morpholin-4-ethyl) amino] carbonyl} - 1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4-ethylpiperazin-1-yl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (piperazin-1-ylcarbonyl) -1, 2, 3, 6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { [2- (diethylamino) ethyl] (ethyl) amino.} Carbonyl) -1, 1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ((- [(1-methylpiperiin-4-yl) methyl] piperazin-1-yl.] Carbonyl) -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3. {[4- (1-methylethyl) piperazin-1-yl] carbonyl] -1, 2, 3, 6 -tetrahydroazepine [4, 5-b] indol-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- [(4-propylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-methylethyl 9-fluoro-1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indo1-5-carboxylate; -methylethyl 3-. { [4- (diethylamino) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 8-fluoro-1, l-dimethyl-3- [(4-methylpiperazin-1-yl) carbonyl] -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; -methylethyl 3- [(4-ethylpiperazin-1-yl) carbonyl] -8-fluoro-1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 1, l-dimethyl-3-. { [4- (2-oxo-2-pyrrolidin-1-ylethyl) piperazin-1-yl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 3- ( { - [2- (diethylamino) ethyl] piperazin-1-yl.} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4,5-b] indole-5-carboxylate; -methylethyl 3-. { [3- (dimethylamino) piperidin-1-yl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 3- (azepan-1-ylcarbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 1, l-dimethyl-3-. { [4- (4-methylpiperazin-1-yl) piperidin-1-yl] carbonyl} -l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -methylethyl 1, l-dimethyl-3- [(4-methyl-1, 4-diazepan-1-yl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; -met? let? l 1, ld? met? l-3- (morpholm-4-? lcarbon? l) -1, 2, 3, 6-tetrahydroazepmo [4,5-b]? ndol-5- carboxylate; -methemyl 3- ((3- [(dimethylamino) methyl] p? per? d? n-1-? l.} carbon? l) -1,1-d? met? ll, 2.3, 6- tetrahydroazepmo [4, 5-b]? ndol-5-carboxylate; -met? let? l 3- ( { (3S) -3- [(dimethylamine) met? l] p? per? d? nl -? l.} carbon? l) -1, 1-d? meth? ll, 2, 3, 6-tetrahydroazep? no [4, 5-b]? ndol-5-carbox? lato; -met ? let? l 3- ( { (3R) -3- [(dimethylammo) methyl] p? per? d? n-1? l.} carbon? l) -1, 1-dimethyl-l, 2 , 3, 6-tetrahydroazole? [4,5- b]? Ndol-5-carbox? Lato; -met? let? l 3- [(diethylamino) carbonyl] -1, 1-d? meth? ll, 2, 3, 6-tetrahydroazep? no [4,5-b]? ndol-5-carboxy? lato; -met? let? l 1, l-d? met? l-3-. { [3- (morpholine-4? Lmet? L) p? Pepd? N-1-l] carbonyl} -1, 2, 3, 6-tetrahydroazole [4, 5-b]? Nol-5-carboxylate; -met? let? l 1, 1-dimet? l-3-. { [(3S) -piper? D? N-3-? Lamino] carbonyl} 1,2,3,6-tetrahydroazep [no, 5-b]? Ndol-5-carboxylate; -met? let? l 3-. { [3- ( { [3- (dimethylamino) propyl] oxy} met? L) piperidin-l-yl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazep? No [4,5-b]? Ndol-5-carbox? Lato; -met? let? l 1, ld? met? l-3- [(p? pepd? n-3-? lam? no) carbonyl] - 1,2,3,6-tetrahydro azepino [4,5 -b]? ndol-5-carbox? lato; 1-Methylethyl 1, 1-dimethyl-3- ([(3R) -3- (morpholin-4-ylmethyl) piperidin-1-yl] carbonyl] -1, 2, 3, 6-tetrahydroazepine [4, 5 -b] indole-5-carboxylate, 1-methylethyl 1, 1-dimethyl-3. {[[(3R) -3- (piperidin-1-ylmethyl) piperidin-1-yl] carbonyl] -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3 { [4- (phenylmethyl) -1,4-diazepane-1-yl ] carbonyl.] - 1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate, and 1-methylethyl 3- [(3'R) -1,3 '-bipiperidin-1' -carbonyl] -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate.
44. 44. The compound according to claim 37, wherein each R6 and R7 is independently optionally substituted alkyl; n is 0; R11 is independently hydrogen or optionally substituted alkyl; R 12 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, or optionally substituted aralkyl.
45. 45. The compound according to claim 44, which is selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- [(propylamino) carbonyl] -1, 2,3,6-tetrahydroazepino [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 3- [(cyclopentylamino) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(cyclohexylamino) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(cycloheptylamino) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; and 1-methylethyl 1, l-dimethyl-3-. { [(phenylmethyl) amino] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate.
46. 46. The compound that has the formula wherein each R6 and R7 is independently optionally substituted alkyl, n is 0-3; R8 is optionally substituted alkyl or halo; R11 is independently optionally substituted alkyl, and Q1 is independently hydroxy, halogen, haloalkyl, haloalkoxy, optionally substituted alkyl, alkoxy, cyano, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and m is 0-3.
47. 47. The compound according to claim 46, wherein Q1 is selected from the group consisting of hydroxy, cyano, 2-methyl; 3-methyl; methylpiperazinyl, 3-chloromethyl, 3,4-difluoro; 3-methyl, 4-methyl; 2-methyloxy; 3-methyloxy; 4-methyloxy; 3-fluoro-4-methyl; 4-fluoro-3-methyl; 2-trifluoromethyloxy; 2-chloro; 3-chloro; 4-chloro; 2,4-dichloro; 2-chloro-3,6-difluoro, 3-chloro-2,6-difluoro, 2-fluoro; 3-fluoro; 2-bromine; 3-trifluoromethyl; 2, 3-difluoro; 2,4-difluoro; 2,5-difluoro; 2,6-difluoro; 3, 4-difluoro; 3,6-difluoro; 3, 4-difluoro; 2,3-difluoro-4-trifluoromethyl; 2-fluoro-4-trifluoromethyl; 2-fluoro-3-trifluoromethyl; 3-fluoro-5-trifluoromethyl; 2,5-bistrifluoromethyl; 3, 5-bistrifluoromethyl; 3-chloro-2-fluoro-trifluoromethyl 3-fluoro-4-trifluoromethyl; 4-fluoro-3-trifluoromethyl; 4-fluoro-2-trifluoromethyl; 2-chloro-4-fluoro; 3-chloro-4-fluoro; 2-trifluoromethyl; 4-trifluoromethyl; 2, 3, 4-trifluoro; 2, 4, 6-trifluoro; 2, 4, 5-trifluoro; 3,4-bis (methyloxy); 3-phenylmethyloxy; or methyloxyphenylmethyloxy.
48. 48. The compound according to claim 46, selected from the group consisting of: 1-methylethyl 3- [(2-chloro-3,6-difluorophenyl) carbonyl] -1,1-dimethyl- 1, 2, 3, 6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (phenylcarbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-fluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [2- (trifluoromethyl) phenyl] carbonyl} - 1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [4- (trifluoromethyl) phenyl] carbonyl} - 1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-chlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2-bromophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2-methylphenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [2- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {2- 2- [(trifluoromethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5- carboxylate; 1-methylethyl 3- [(2-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(2, -difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(2, 3-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(2,6-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2,5-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2,3,4-trifluorophenyl) carbonyl] -1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2,4,6-trifluorophenyl) carbonyl] -1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(2,4,5-trifluorophenyl) carbonyl] -1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-chlorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(4-chlorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3-fluoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3-methylphenyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(4-methylphenyl) carbonyl] -1,2,3-6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ([3- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; methylethyl 1, l-dimethyl-3 { [4- (methyloxy) phenyl] carbonyl} -1, 2, 3, 6-tetrahydro azepino [4, 5-b] indole-5-carboxylate; [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-N- (1-methylethyl) -1,2,3,4,5,6-hexahydro azepino [4, 5-b] indole-5- carboxamide; 1-methylethyl 3- {[3,4-bis (methyloxy) phenyl] carbonyl} -1, 1-dimethyl-1, 2, 3, 6-tetrahydro azepino [4,5-b] indole -5-carboxylate; l- { 3- [(3, -difluorophenyl) carbonyl] -1,1-dimethyl-l, 2, 3,6-tetrahydroazepino [4, 5-b] indol-5-yl} ethanone; 1-methylethyl 1, l-dimethyl-3- [(5-methylisoxazol-3-yl) carbonyl] -1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- {[4-fluoro-2- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate; 1-methylethyl 3- [(2-chloro-4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2, 3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 2-chloro-l-. { 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-yl} ethanone; methyl 3- [(3, -difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(phenylmethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5- carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (trifluoromethyl) phenyl] carbonyl} - 1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-fluoro-4-methylphenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro- - (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3-chloro-2-fluoro-4- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-3- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3-fluoro-5- (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3,5-bis (trifluoromethyl) phenyl] carbonyl} -l, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2,5-bis (trifluoromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2,3-difluoro-4- (trifluoromethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-carboxylate; 1-methylethyl 3- [(3-hydroxyphenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(3-cyanophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(2,4-dichlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(4-fluoro-3-methylphenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3-chloro-2,6-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(3-chloro-4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(3,4-dichlorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(4-chloro-2,5-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [4,5-b] indole-5-carboxylate; 1-methylethi 3- [(3-bromo-4-fluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydro azepino [5-b] indole-5-carboxylate; and 1-met? let? 3-. { [3, 4-d? Fluoro-5- ( { [4- (methyloxy) phen? L] met? L.}. Ox?) Phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepmo [4,5-b]? Ndol-5-carboxylate.
49. 49. The compound according to claim 30, wherein each R6 and R7 is independently optionally substituted alkyl; n is 0; R9 is optionally substituted, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroalkyl.
50. 50. The compound according to claim 49, wherein R9 is optionally substituted with one or more Q1 selected from the group consisting of optionally substituted alkyl, halogen, and haloalkyl.
51. 51. The compound according to claim 50, wherein R9 is 1,3-benzod? Oxol-5-? Lo or met? L? Soxazol-3-? Lo.
52. 52. The compound according to claim 49, selected from the group consisting of: 1-met? Let? 3- (1, 3-benzod? Oxol-5? Lcarbon? L) -1, 1-d? Met? Ll , 2, 3, 6-tetrahydro azepino [4, 5-b]? Ndol-5-carboxylate; 1-met? Let? L 3- [(2, 2-difluoro-1, 3-benzod? Oxol-4-? L) carbonyl] -1,1-d? Met? L-1, 2.3, 6 -tetrah? droazep? no [4, 5-b] mdol-5-carboxylate; 1-Methylethyl 3- [(2,2-difluoro-l, 3-benzodioxol-5-yl) carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxylate; Y 1-Methylethyl 1, l-dimethyl-3- [(5-methylisoxazol-3-yl) carbonyl] -1,2,3,6-tetrahydro azepino [4, 5-b] indole-5-carboxylate.
53. 53. The compound according to claim 46, wherein each R6 and R7 is independently optionally substituted alkyl; n is 0; R10 is independently optionally substituted alkyl, Q1 is independently optionally substituted alkyl, halogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; m is 0-3.
54. 54. The compound according to claim 53, wherein Q 1 is 3,4-difluoro; 4-piperidin-4-yl, 3-piperidin-4-yl, 3-piperidin-4-ylmethyl, piperidin-4-ylmethyl, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, 4-methylsulfonylpiperazin-1-yl, 3- azepan-1-ylmethyl, 4-methyl-1, 4-diazepane-1-yl, 3-pyrrolidin-1-ylethyl, 4-methyl-piperazin-1-ylmethyl; 4-ethylpiperazin-1-ylmethyl; 3-piperazin-1-ylmethyl; morpholin-4-ylmethyl; 3-morpholin-4-ylmethyl; 2-morpholin-4-ylethyloxy; 2-piperidin-1-ylethyloxy; 3-morpholin-4-ylpropyloxy-1H-pyrazol-1-yl, 4-trifluoromethyl-1H-pyrazol-1-yl, 4-acetylpiperazin-1-ylmethyl; methylbenzotriazolyl, dimethylethyloxycarbonylpiperazin-1-ylmethyl, 4-phenylisulfonylpiperazin-1-ylmethyl, 4-fluorophenylsulfonylpiperazin-1-yl, 4-ethylsulphonylpiperazin-1-ylmethyl, 4-cyclopropylcarbonylpiperazin-1-ylmethyl, 2-methylpropanoylpiperazin-1-ylmethyl, phenylcarbonyl piperazin-1-ylmethyl, 3-azocan-l-ylmethyl, 4-acetyl-l, 4-diazepan-l-yl, 4-phenylaminocarbonylpiperazin-1-ylmethyl; 4-ethylaminocarbonylpiperazin-1-ylmethyl; 3-piperidin-1-ylpropyloxy, 2-pyrrolidin-1-ylethyloxy; 3-piperidin-1-ylpropyloxy; or 3-morpholin-4-ylpropyloxy.
55. 55. The compound according to claim 53, selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- [(4-piperidin-4-ylphenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- [(3-piperidin-4-ynyl) carbonyl] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- ( { 4- [(dimethylamino) methyl] phenyl} carbonyl) -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 3- ( { 3- [(dimethylamino) methyl] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-Methylethyl 3- (. {3 - [(diethylamino) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (pyrrolidin-1-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [5-b] indol-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (piperidin-1-ylmethyl) phenyl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, 1-dimethyl-3- ((3- [(4-methyl-piperazin-1-yl) methyl] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- (. {3- [3- (4-ethylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-l, 2,3,6- tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, 1-dimethyl-3 { [3- (morpholin-4-ylmethyl) phenyl] carbonyl.} -1,2,3 , 6-tetrahydroazepino [4,5- b] indolyl-5-carboxylate, 1-methylethyl 3- [(3. {[[2- (dimethylamino) ethyl] oxy} phenyl) carbonyl] -1,1- dimethyl-1, 2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3 { [4- (lH-pyrazol-1-yl) phenyl ] carbonyl.} - 1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- (. {3- [4-acetylpiperazin-1-yl] methyl) ] phenyl.} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3. {[[4- (methylsulfonyl) piperazin-1-yl] methyl] phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5- b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (azepan-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {3, 3- [(4-methyl-1, 4-diazepan-1-yl) methyl] phenyl} carbonyl) -1, 2, 3, 6 tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-5- (morpholin-4-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indol-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(1-methyl-1 H-1, 2, 3-benzotriazol-5-yl) carbonyl] -1,2,3,6-tetrahydroazepino [5-b] indole -5- carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { - [4- (trifluoromethyl) -lH-pyrazol-1-yl] phenyl} carbonyl) -1,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -l, 2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-5- (piperidin-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indo1-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indo1-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4. {[[(1, 1-dimethylethyl) oxy] carbonyl} piperazin-1-yl) methyl] phenyl} carbonyl) -1, 1 -dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (phenylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5- b] indole-5-carboxylate; 1-methylethyl 3-. { [3- ((- [(4-fluorophenyl) sulfonyl] piperazin-1-yl} methyl) phenyl] carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepine [4,5 -b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[4- (ethylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[4- (cyclopropylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3. {[[4- (2-methylpropanoyl) piperazin-1-yl] methyl] phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3. {[[4- (phenylcarbonyl) piperazin-1-yl] methyl] phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5- b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (Azocan-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4-acetyl-l, -diazepan-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4, 5-b] indolyl-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (piperazin-1-ylmethyl) phenyl] carbonyl} -l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- ( {3,4-difluoro-5- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,1-dimethyl-l, 2,3,6- tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-met? Let? 3- ( {3, 4 -difluoro-5- [(2-p? Pepd? Nl-? Let? L) ox?] Phenyl.} Carbonyl) -1, 1- d? met? ll, 2,3,6-tetrahydroazepino [4,5-b]? ndol-5-carboxylate; 1-met? Let? 1, ld? Met? L-3- ((4- [(2-morph? N-4-? Let? L) ox?] Phenyl.} Carbon? L) -1, 2,3,6-tetrahydroazepine [4,5- b]? Ndol-5-carbox? Lato; 1-met? Let? L 1, 1-dimeti1-3- ( { 4- [( 2-p? Per? D? Nyl-ethyl) oxy] phenyl} carbon? L) -1,2,3,6-tetrahydroazep? No [4,5-b] mdol-5-carbox? Lato; 1-met? Let? L 1, ld? Met? L-3- ( { 3- [(3-morfol? N-4-lpropyl) oxy] phenyl.} Carbon? L) -1.2 , 3, 6-tetrahydroazole? [4,5-b]? Ndol-5-carbox? Lato; 1-met? Let? L 1, 1-dimet11-3- ([3- ((4- [4- (phenylamino) carbonyl] p? peraz? nl-? l.) met? l) phenyl] carbonyl.} - 1,2,3,6-tetrahydroazep? no [4, 5-b]? ndol- 5-carboxylate; 1-methylethyl 3- {[[3- (. {4 - [(ethylamino) carbonyl] p? Peraz? N-1-yl.} Methyl} phenyl] carbonyl} -1, 1-d? Meth? Ll, 2,3,6-tetrahydroazepino [4, 5-b]? Ndol-5-carbox? Lato; 1-met? Let? L 1, 1-dimet11-3- (. {3- 3- [(3-p? Pepd? Nl-? Lprop? L) ox?] Phen? L.} Carbonyl) -1, 2, 3, 6-tetrahydroazole [4, 5 - b] β-dd-5-carboxylate; 1-methylethyl 3- [(4. {[2- (dimethylamino) e t? l] ox ?} phenol) carbonyl] -1,1-d? met? l-1, 2,3,6-tetrahydroazep? no [5-b]? ndol-5-carboxylate; 1-methylethyl 3- [(3- {[[3- (diethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 3- [(4. {[[3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] ] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {4- [(2-pyrrolidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4,5 - b] indolyl-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 4- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; and 1-methylethyl 1, l-dimethyl-3- ( { 4- [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4,5 - b] indole-5-carboxylate.
56. 56. The compound that has the formula Id
57. 57. The compound according to claim 56, wherein each R6 and R7 is independently optionally substituted alkyl; R11 is independently optionally substituted alkyl, p is 1-3; m is 0-3; Q1 is optionally substituted alkyl or halo; and R28 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
58. 58. The compound according to claim 56, wherein R28 is phenyl, dimethylamino, diethylamino, N-ethyl, N-methyl amino, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, or 4-methyloxyphenyl.
59. 59. The compound according to claim 56, selected from the group consisting of: 1-methylethyl 1, l-dimethyl-3- (. {3- [3 (phenylmethyl) oxy] phenyl] carbonyl) - 1,2,3 , 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate 1-methylethyl 3- [(3. {[[2- (dimethylamino) ethyl] oxy} phenyl) carbonyl] -1,1-dimethyl -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4,5-b] ] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ( { 3- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-methylethyl 3-. { [3,4-difluoro-5- (([4- (methyloxy) phenyl] methyl]} oxy) phenyl] carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- ( {3,4-difluoro-5- [(2-raorpholin-4-ylethyl) oxy] phenyl} carbonyl) -1, 1- dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- (. {3,4-difluoro-5- [(2-piperidin-1-ylethyl) ) oxy] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, 1-dimethyl-3- ( {. 4- [(2-morpholin-4-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4,5- b] indole-5-carboxylate; 1-methylethyl 1 , l-dimethyl-3- ( { 4- [(2-piperidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4,5- b] indole 5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ((3- [(3-morpholin-4-ylpropyl) oxy] phenyl} carbonyl) -1,3,6-tetrahydroazepine [4,5- b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3- ((3- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepine [ 4,5-b] indolyl-5-carboxylate; 1-methylethyl 3- [(4. {[[2- (dimethylamino) ethyl] oxy} phenyl) carbonyl] -1,1-dimethyl-1, 2 3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 3- [(3- {[[3- (diethylamino) propyl] oxy} phenyl) carbonyl] -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(4- ([3- (dimethylamino) propyl] oxy} phenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate, 1-methylethyl 1, l-dimethyl-3- (. {4- [( 2-pyrrolidin-1-ylethyl) oxy] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 1, 1-dimethyl-3- ( { 4- [(3-piperidin-1-ylpropyl) oxy] phenyl} carbonyl) -1,2, 3,6-tetra ahydroazepino [4,5-b] indole-5-carboxylate; and 1-methylethyl 1, l-dimethyl-3- ( { 4- [(3-morpholin-4-ylpropyl) oxy] phenyl} .carbonyl) -1, 2,3,6-tetrahydroazepine [4, 5 - b] indole-5-carboxylate.
60. 60. The compound that has the formula wherein each R6 and R7 is independently optionally substituted alkyl, n is 0; every R > ?? is independently optionally substituted alkyl, p is 1-3; R29 is halogen, optionally substituted alkyl, optionally substituted aplo, optionally substituted aralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
61. 61. The compound according to claim 60, wherein R29 is dimethylamino, diethylamino, N-ethyl, N-methyl amino, chloro, morpholomyl, piperidinyl, piperazmyl, piperazin-1-limemethola, p? Peraz? N-1 -? let? lo, pyrrolidil, morpholinyl, methyloxyphenyl; 4-acet? Lp? Peraz? N-l-? Lo; 4-methersulfon? Lp? Peraz? N-1-? Lo; azepanil; azocan-1-? lo; 4-met? L-1, 4-d? Azepan-l-? Lo; 4-acet? L-l, 4-d? Azepan-l-? Lo; dimethylethyloxycarbon? lp? peraz? n-1-? lo; 4-phenylsulfonyl p? Peraz? N-1-? Lo; 4-fluorophenylsulfon? Lp? Peraz? N-1-lio; ethylsulfonyl p? peraz? n-1-? lo; cyclopropylcarbonyl p? peraz? n-1-? lo; 2-met? Lpropane? Piperazm-1-yl; phenylcarbonyl piperazin-1-yl; 4-phenylaminocarbonylpiperazin-1-yl; or 4-ethylaminocarbonylpiperazin-1-yl; Q1 is halogen or optionally substituted alkyl, m is 0-3.
62. 62. The compound according to claim 60, selected from the group consisting of: 1-methylethyl 3- (. {3 - [(dimethylamino) methyl] phenyl} carbonyl) -1, 1-dimethyl-1, 2,3 , 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (chloromethyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(diethylamino) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole-5- carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (pyrrolidin-1-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- ((3- [(4-methylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,2,3,6-tetrahydroazepino [4,5- b] indole-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4-ethylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] ] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3-. { [3- (morpholin-4-ylmethyl) phenyl] carbonyl} -1, 2, 3, 6-tetrahydroazepino [4, 5-b] indol-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4-acetylpiperazin-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1,3,3,6-tetrahydroazepine [4, 5] b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (methy1sulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -l, 2,3,6-tetrahydroazepine [4 , 5- b] indolyl-5-carboxylate; 1-methylethyl 3-. { [3- (azepan-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- (. {3- [4-methyl-1, -diazepan-1-yl] methyl] phenyl] carbonyl) -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-5- (morpholin-4-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (morpholinyl-phenyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indol-5-carboxylate; 1-methylethyl 3-. { [2-fluoro-5- (piperidin-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [5-b] indol-5-carboxylate; 1-methylethyl 3-. { [4-fluoro-3- (piperidin-1-ylmethyl) phenyl] carbonyl} -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indol-5-carboxylate; 1-Methylethyl 3- ( { 3- [(4. {[[(1, 1-dimethylethyl) oxy] carbonyl} piperazin-1-yl) methyl] phenyl} carbonyl) -1, 1 -dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (phenylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5- b] indole-5-carboxylate; 1-methylethyl 3-. { [3- ( { - [(4-Fluorofhenyl) sulfonyl] piperazin-1-yl} methyl) phenyl] carbonyl} -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[4- (ethylsulfonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3- {[[4- (cyclopropylcarbonyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [4 , 5-b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3- {[4- (2-methylpropanoyl) piperazin-1-yl] methyl} phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4, 5 b] indole-5-carboxylate; 1-Methylethyl 1, l-dimethyl-3- [(3. {[[4- (phenylcarbonyl) piperazin-1-yl] methyl] phenyl) carbonyl] -1,2,3,6-tetrahydroazepine [4 , 5- b] indole-5-carboxylate; 1-methylethyl 3-. { [3- (Azocan-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- ((3- [(4-acetyl-1,4-diazepan-1-yl) methyl] phenyl} carbonyl) -1,1-dimethyl-1, 2,3,6-tetrahydroazepine [ 4, 5-b] indole-5-carboxylate; 1-methylethyl 1, l-dimethyl-3 { [3- (piperazin-1-ylmethyl) phenyl] carbonyl} -l, 2,3,6 -tetrahydroazepino [4,5-b] indol-5-carboxylate; 1-methylethyl 1, l-dimethyl-3 { [3- ( { 4- [(phenylamino) carbonyl] piperazin-1-yl} methyl) phenyl] carbonyl} - 1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate and 1-methylethyl 3- { [3- (. {4 - [(ethylamino) carbonyl] piperazin-1-ylmethyl) phenyl] carbonyl} -1, 1-dimethyl-l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate.
63. 63. The compound that has the formula Ha wherein each R6 and R7 is independently optionally substituted alkyl, n is 0. R11 is independently optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, heterocyclyl, or optionally substituted heterocyclylalkyl.
64. 64. The compound according to claim 63, wherein R8 is 2,2-dimethyl-l, 3-dioxolan-4-yl; 2-piperidin-1-ylethylaminocarbonyl; 2,3-dihydroxypropyl or 2-fluoro-l- (fluoromethyl) ethyl, hydroxyethyl, phenylmethyloxyethyl, 3,4-difluorophenyl-carbonyloxy-1-methylethyl, or 2-hydroxy-1-methylethyl.
65. 65. The compound according to claim 63, wherein Q1 is halogen or optionally substituted alkyl, and m is 0-3.
66. 66. The compound according to claim 63, selected from the group consisting of: (2,2-dimethyl-l, 3-dioxolan-4-yl) methyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1- dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 2,3-dihydroxypropyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; (2R) -2,3-dihydroxypropyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 2-fluoro-l- (fluoromethyl) ethyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1, l-dimethyl-8- ( { [(2-piperidin-1-ylethyl) amino] carbonyl}. Oxy) -l, 2 , 3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; (2S) -2,3-dihydroxypropyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 2-hydroxy-l-methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 2-. { [(3,4-difluorophenyl) carbonyl] oxy} -1-methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 2- [(phenylmethyl) oxy] ethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; and 2-hydroxyethyl 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate.
67. 67. The compound that has the formula Hb wherein each R6 and R7 is independently optionally substituted alkyl, n is 0-3; R11 is optionally substituted alkyl or halo; Q1 is halogen or optionally substituted alule; m is 0-3.
68. 68. The compound according to claim 67, wherein Q 1 is methyl, chloro, fluoro, bromo or 3,4-difluoro.
69. 69. The compound according to claim 67, wherein R10 is isopropyl; beta-alanine, 2,3-dihydroxypropyl; or 2-hydroxy-1- (hydroxymethyl) ethyl.
70. 70. The compound according to claim 67, selected from the group consisting of: N- ( { 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,4,5,5,6-hexahydroazepino [4,5-b] indol-5-yl .}. carbonyl) -beta-alanine; N- ( { 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4, 5-b] indol-5-yl.} Carbonyl ) -beta-alanine; 3- [(3,4-difluorophenyl) carbonyl] -N- [(2,3-dihydroxypropyl) oxy] -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4,5-b] indole 5-carboxamide; 3- [(3,4-difluorophenyl) carbonyl] -N- (2,3-dihydroxypropyl) -1, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxamide; 3- [(3,4-difluorophenyl) carbonyl] -N- [2-hydroxy-1- (hydroxymethyl) ethyl] -1,1-dimethyl-l, 2,3,6-tetrahydroazepine [4,5- b] indole-5-carboxamide; and 3- [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-N- (1-methylethyl) -1,2,4,4,5,6-hexahydroazepino [4,5-b] indole- 5-carboxamide.
71. 71. The compound that has formula III wherein each R6 and R7 is independently optionally substituted alkyl, R9 is optionally substituted aryl; R is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; R11 is independently optionally substituted alkyl.
72. 72. The compound according to claim 71, wherein R is 2- (dimethylamino) ethylaminocarbonyl; 1,1-dimethylethyloxycarbonyl; 2-diethyl aminoethylaminocarbonyl; dimethylaminopropyl; dimethylaminoethyl; methylamino carbonyl; diethylaminoethyl; methyloxyethyl; dimethylaminopropylaminocarbonyl; phenylmethyl; hydroxy; or 2-pyrrolidinyl-1-ylaminocarbonyl.
73. 73. The compound according to claim 71, selected from the group consisting of: 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8- [( { [2- (dimethylamino) ethyl] amino.}. carbonyl) oxy] -1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8- ( { [(1,1-dimethylethyl) oxy] carbonyl} oxy) -1, 1-dimethyl-l, 2,3 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 8 - [( { [2- (diethylamino) ethyl] amino.} Carbonyl) oxy] -3 - [(3, -difluorophenyl) carbonyl] -1,1-dimethyl-l, 2,3 6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -8- ([2- (dimethylamino) ethyl] oxy} - l, 1-dimethyl-l, 2,3,6-tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -8- { [3- (dimethylamino) propyl] oxy} -l, 1-dimethyl- 1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- { (methylamino) carbonyl] oxy] -1, 2, 3, 6-tetrahydroazepino [4,5-b] indole-5-carboxylate; 1-methylethyl 8- { [2- (diethylamino) ethyl] oxy} - 3 - [(3, 4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-methylethyl 8- ( [3- (diethylamino) propyl] oxy]. 3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole 5-carboxylate; 1-methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- ([2- (methyloxy) ethyl] oxy}. -l, 2,3,6- tetrahydroazepine [4, 5-b] indole-5-carboxylate; 1-methylethyl 8- [( { [3- (d ietylamino) propyl] amino} carbonyl) oxy] -3 - [(3,4-difluorophenyl) carbonyl] -1,1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; 1-Methylethyl 3- [(3,4-difluorophenyl) carbonyl] -1, 1-dimethyl-9 - [(phenylmethyl) oxy] -1,2,3,6-tetrahydroazepino [4, 5-b] indole-5 - carboxylate; 1-methylethyl 3- [(3, -difluorophenyl) carbonyl] -9-hydroxy-1-, 1-dimethyl-1, 2,3,6-tetrahydroazepino [4, 5-b] indole-5-carboxylate; and 1-methylethyl 3- [(3, 4-difluorophenyl) carbonyl] -1, 1-dimethyl-8- ( { [(2-pyrrolidin-1-ylethyl) amino] carbonyl.} oxy] -l, 2,3,6-tetrahydroazepino [, 5-b] indole-5-carboxylate.
74. 74. The compound having formula IV:
75. 75. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to any of claims 1-73 or a pharmaceutically acceptable derivative thereof.
76. 76. The pharmaceutical composition according to claim 75, wherein the pharmaceutical composition further comprises at least one additional active agent (s) selected from antihyperlipidemic agents, HDL-elevating agents in plasma, anti-hypercholesterolemic agents, inhibitors of cholesterol biosynthesis, inhibitors of HMG CoA reductase, inhibitors of acyl-coenzyme A cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate , benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B? 2, vitamin C, vitamin E, beta-blockers, anti-diabetes agents, sulfonylureas, biguanides, thiazolidinediones, activators of PPARa PPARβ and PPAR ?, dehydroepiandrosterone, antiglucocorticoids, inhibitors of TNF a, inhibitors of a-glucosidase, pramlintide, amylin, insulin, anta angiotensin II gonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, agonists, antagonists or partial agonists of LXR a, agonists, antagonists or partial agonists of LXR ß, phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, fentiramine, β3-adrenoreceptor agonist agents, sibutramine, gastrointestinal lipase inhibitors, neuropeptide Y, enterostatin, colecitocinin, bombesin, amylin, histamine H3 receptor agonists or antagonists, receptor agonists or antagonists dopamine D2, melanocyte stimulating hormone, corticotrophin release factor, leptins, galanin or gamma amino butyric acid (GABA), aspirin or fibric acid derivatives.
77. 77. A method of treating, preventing, inhibiting or ameliorating one or more of the symptoms of a disease or disorder in which the activity of the nuclear receptors is involved, which comprises administering to a subject in need, an effective amount of a compound of any one of claims 1-73 or a pharmaceutically acceptable derivative thereof.
78. 78. The method according to claim 77, wherein the nuclear receptor is the farnesoid X receptor.
79. 79. The method according to claim 78, wherein the method further comprises administering at least one additional active agent selected from antihyperlipidemic agents, HDL elevators in plasma, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors, HMG CoA inhibitors. reductase, inhibitors of acyl-coenzyme A cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate , gemfibrizol, vitamin B6, vitamin Bi2, vitamin C, vitamin E, beta-blockers, anti-diabetes agents, sulfonylureas, biguanides, thiazolidinediones, activators of PPARa PPARß and PPAR ?, dehydroepiandrosterone, antiglucocorticoids, TNF inhibitors, inhibitors of -glucosidase, pramlintide, amylin, insulin, angiotensin II antagonists, i angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, agonists, antagonists or partial agonists of LXR a, agonists, antagonists or partial agonists of LXR ß, phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine , dexfenfluramine, fentiramine, β3-adrenoreceptor agonist agents, sibutramine, gastrointestinal lipase inhibitors, neuropeptide Y, enterostatin, colecitocinin, bombesin, amylin, histamine H3 receptor agonists or antagonists, dopamine D2 receptor agonists or antagonists, stimulating hormone of melanocyte, corticotrophin releasing factor, leptins, galanin or gamma amino butyric acid (GABA), aspirin or fibric acid derivatives, simultaneously, before or after administration of the compound.
80. 80. The method according to claim 77, wherein the compound is an agonist, partial agonist, inverted agonist, partial antagonist or antagonist of the farnesoid X receptor.
81. 81. The method according to claim 77, wherein the disease or disorder is selected from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, atherosclerotic disease events, atherosclerotic cardiovascular disease, Syndrome X, diabetes mellitus, diabetes type II, Insensitivity to insulin, hyperglycemia, cholestasis and obesity.
82. 82. The method according to claim 81, wherein the disease or disorder is hyperlipidemia.
83. 83. The method according to claim 81, wherein the disease or disorder is hypertriglyceridemia.
84. 84. The method according to claim 81, wherein the disease or disorder is hypercholesterolemia.
85. 85. The method according to claim 81, wherein the disease or disorder is obesity.
86. 86. The method according to claim 81, wherein the disease or disorder is cholestasis.
87. 87. The method according to claim 81, wherein the method further comprises administering at least one additional active agent selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, fentiramine, ß3 adrenoceptor agonist agents, sibutramine, lipase inhibitors. gastrointestinal, agonists, partial agonists or antagonists of LXR a, agonists, partial agonists or antagonists of LXR ß, neuropeptide Y, enterostatin, colecitocinin, bombesin, amylin, histamine H3 receptor agonists or antagonists, dopamine D2 receptor agonists or antagonists Melanocyte stimulating hormone, corticotrophin releasing factor, leptin, galanin or gamma amino butyric acid (GABA) simultaneously, before or after administration of the compound.
88. 88. The method according to claim 77, wherein the disease or disorder is selected from the group consisting of hyperlipidemia, hypertriglyceridemia, hypercholesterolemia and dyslipidemia.
89. 89. The method according to claim 88, wherein the method further comprises administering at least one additional active agent selected from antihyperlipidemic agents, HDL elevators in plasma, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors, HMG CoA inhibitors. reductase, inhibitors of acyl-coenzyme A: cholesterol acitransferase (ACAT), probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B? 2, antioxidant vitamins, beta-blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin, agonists, partial agonists or antagonists of LXR a, agonist as, partial agonists or antagonists of LXR ß, or fibric acid derivatives, simultaneously, before or after the administration of the compound.
90. 90. The method according to claim 77, wherein the disease or disorder is selected from the group consisting of atherosclerosis, atherosclerotic disease, atherosclerotic disease events and atherosclerotic heart disease.
91. 91. The method according to claim 77, wherein the disease or disorder is selected from the group consisting of Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity and hyperglycemia.
92. 92. The method according to claim 91, wherein the method also comprises administering at least one additional active agent selected from sulfonylureas, biguanides, thiazolidinediones; activators of PPARa PPARß and PPAR ?; agonists, agonists, partial agonists or antagonists of LXR a, agonists, partial agonists or antagonists of LXR ß, dehydroepiandrosterone; antiglucocorticoids; TNF inhibitors a; inhibitors of β-glucosidase, pramlintide, amylin, insulin or insulin, simultaneously, before or after the administration of a compound according to claim 1 or a pharmaceutically acceptable derivative thereof.
93. 93. A method for reducing cholesterol levels in plasma in a subject in need thereof, comprising administering an effective amount of a compound of any of claims 1-73 or a pharmaceutically acceptable derivative thereof.
94. 94. A method for reducing triglyceride levels in plasma in a subject in need thereof, comprising administering an effective amount of a compound of any of claims 1-73 or a pharmaceutically acceptable derivative thereof.
95. 95. A method of treating, preventing, inhibiting or ameliorating one or more symptoms of a disease or disorder that is afflicted by abnormal levels of cholesterol, triglycerides or bile acids, which comprises administering to a subject in need thereof an effective amount of a compound of either of claims 1-73 or a pharmaceutically acceptable derivative thereof.
96. 96. A method for modulating the metabolism, catabolism, synthesis, absorption, reabsorption, secretion or excretion of cholesterol in a mammal, which comprises administering an effective amount of a compound of any of claims 1-73 or a pharmaceutically acceptable derivative thereof.
97. 97. A method for modulating the farnesoid X receptor activity comprising placing a cell in contact with a compound according to any of claims 1-77 or a pharmaceutically acceptable derivative thereof.
98. 98. The compound according to claim 1, selected from the compounds of Table 1.