MX2011008349A - Histamine h3 inverse agonists and antagonists and methods of use thereof. - Google Patents

Abstract

Provided herein are fused imidazolyl compounds, methods of synthesis, and methods of use thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders and metabolic disorders. Compounds provided herein inhibit the activity of histamine H3 receptors and modulate the release of various neurotransmitters, such as histamine, acetylcholine, norepinephrine, and dopamine (e.g. at the synapse). Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.

Description

AGENTS AND ANTAGONISTS INVERSE OF HISTAMINE H3 AND METHODS TO USE THEM This application claims priority before the Request Provisional Patent U.S. No. 61 / 151,817, filed on February 11, 2009, the content of which is hereby incorporated by reference in its entirety.

I. COUNTRYSIDE Provided herein are compounds useful as inverse agonists or antagonists of histamine H3 receptors, compositions containing the compounds, and methods for their use.

II. ANTECEDENT The histamine-producing cells are located in the tuberomamymal nucleus (TMN) and are projected along the brain and spinal cord to form a histamine neurotransmitter system. To date, four recipients have been identified. of histamine, the histamine Hl, H2, H3 and H4 receptors. The human H3 receptor was cloned in 1999. See, p. ex. , Lovenberg et al., Mol. Pharmacol. 55 (6): 1101-07 (1999).

Histamine H3 receptors (also referred to herein as H3 or H3 receptors) are expressed in neurons through the CNS (central nervous system), particularly the frontal part of the brain. The H3 receptors are located mainly in the presynaptic site of the neurons and act as autoreceptors to regulate the release of neurotransmitters. The H3 receptor is a receptor coupled to the G protein (GPCR) that sends signals mainly through the Gi / o pathway. Activation of pre-synaptic H3 receptors located in histaminergic neurons leads to a decrease in histamine release; whereas the inhibition of the H3 receptors with an antagonist or inverse agonist gives rise to an increase of the histamine in the synapse. Thus, the ligands of the H3 receptors are capable of modifying the histaminergic neurotransmission in the brain: the agonists decrease it, and the antagonists or inverse agonists increase it. The H3 receptors of the brain have a significant constitutive activity in the absence of agonists. Consequently, inverse agonists will reduce receptor activity, increase histamine release, and activate histaminergic neurons. See, p. eg, Goodman & Gilman's Pharmacological Basis of Therapeutics, 629 (lia Ed. 2006).

H3 receptors are also found at the terminals of other neurotransmitter-producing neurons, where they serve as pre-synaptic hetero-receptors to regulate the release of other neurotransmitters. Antagonists of the H3 receptors have been shown to increase acetylcholine, norepinephrine and dopamine in the extra-cellular fluid. The ability of H3 receptors to modulate the release of a variety of neurotransmitters suggests a wide range of therapeutic indications for antagonists and inverse H3 agonists.

Antagonists or inverse agonists of the H3 receptors that cross the blood-brain barrier have a range of central effects through the activation of histaminergic neurons. For example, in animal experiments, antagonists or inverse H3 agonists induced remarkable alertness and wakefulness, improved attention and learning and demonstrated beneficial effects in animal models of seizures. Thus, these compounds can be used to treat conditions such as cognitive impairment, pathological daytime somnolence and epilepsy without presenting sedative side effects. The ability of these compounds to improve the waking state could also give rise to an improved sleep pattern, and thus antagonists or inverse H3 agonists may also be useful in treating sleep disorders, such as insomnia.

Preclinical research with antagonists and inverse H3 agonists suggests that this class of ligands may offer novel treatments for a variety of disorders, including but not limited to, cognitive impairments (such as those associated with Alzheimer's and Parkinson's diseases), schizophrenia, attention deficit hyperactivity disorder (ADHD), pain and obesity. In addition, these ligands have been shown to have properties that favor wakefulness in pre-clinical and clinical studies and can be used in disorders associated with excessive daytime sleepiness. Other uses of the H3 ligands may be, but are not limited to, mood disorders such as anxiety and depression, seizures, vertigo, movement disorders and gastrointestinal (GI) motility disorders.

In addition, it is reported that H3 receptors may be associated with some other neurological disorders. Therefore, there is a great need for inverse agonists and H3 antagonists as therapeutics for the treatment of various disorders, such as neurological disorders.

III. COMPENDIUM The compounds having the formula (I), or the salts, solvates or stereoisomers accepted for pharmaceutical use thereof are provided herein: I wherein RN, R5, R6, R7, R8 and n are defined herein in another section. The compounds are useful as inverse agonists or antagonists of histamine H3 receptors.

Also provided herein are pharmaceutical compositions and forms containing the compounds provided herein. The compositions and dosage forms provided herein may contain one or more additional active ingredients.

Methods for the treatment, prevention and / or management of various disorders using the compounds and compositions provided herein are also provided herein. Also provided herein are uses of the compounds and compositions provided herein for the manufacture of a medicament for the treatment, prevention and / or management of various disorders as mentioned herein. Also provided herein are compounds and compositions for use in the treatment, prevention, and / or management of various disorders provided herein. The disorders that can be treated, prevented and / or managed can be, but are not limited to, neurological disorders; neurodegenerative diseases; schizophrenia; Alzheimer disease; Parkinson's disease; affective disorders; attention deficit hyperactivity disorder (ADHD); psychosis; convulsion; epileptic seizures; Vertigo; epilepsy; narcolepsy; pain (eg, neuropathic pain); sensitization that accompanies many neuropathic pain disorders; mood disorders such as depression and anxiety; Excessive daytime sleepiness such as that seen in narcolepsy, Parkinson's disease, multiple sclerosis, shift workers and time differences, or as a relief from the side effects of other medications; insomnia; substance abuse; cognitive impairments such as those associated with Alzheimer's disease, Parkinson's disease, schizophrenia, and ADHD; metabolic disorders such as diabetes and obesity; disorders related to satiety and gastric activity or as a relief of side effects of other medications; diseases that affect the enteric system, such as acid secretion, digestion, and intestinal motility; and movement disorders such as Parkinson's disease, restless legs syndrome (RLS), Huntington's disease; and any other neurological disorder described herein in some other part.

In another embodiment, a method for inhibiting or decreasing the activity of histamine H3 receptors is provided herein. The method consists in contacting the H3 receptor with a compound that is provided herein.

Also provided herein is a method for regulating the release of neurotransmitters, which includes, but is not limited to, histamine, acetylcholine, norepinephrine and dopamine at the synapses. The method is to contact the cell with a compound provided herein. In an exemplary embodiment, the cell is a brain cell, such as, for example, a neuronal cell or a glial cell.

IV. DETAILED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art. All publications and patents referred to herein are incorporated by reference herein in their entirety.

A. Definitions When used herein and unless otherwise indicated, the term "alkyl" refers to a saturated monovalent, linear or branched hydrocarbon radical, wherein alkyl may, as an option, be substituted with one or more substituents . The term "alkyl" also comprises linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a monovalent, saturated, linear hydrocarbon radical having 1 to 20 (Ci_2o), 1 to 15 (Ci-is), 1 to 12 (d_12), 1 to 10 (C ^ io) or 1 to 6 (Ci_6) carbon atoms, or a monovalent, saturated, branched hydrocarbon radical of 3 to 20 (C3_2O) A from 3 to 15 (C3-15), from 3 to 12 (C3-12), from 3 to 10 (C3-10) or from 3 to 6 (C3-6) carbon atoms. When used herein, branched Ci_6 linear and C3_6 alkyl groups are also referred to as "lower alkyl." Examples of alkyl groups may be, but are not limited to, methyl, ethyl, propyl (as well as all isomeric forms), n-propyl, isopropyl, butyl (as well as all isomeric forms), n-butyl, isobutyl , t-butyl, pentyl (as well as all isomeric forms), and hexyl (as well as all isomeric forms). For example, Ci_6 alkyl refers to a monovalent, saturated, linear hydrocarbon radical of 1 to 6 carbon atoms or a saturated, branched, monovalent hydrocarbon radical of 3 to 6 carbon atoms.

When used herein, and unless otherwise specified, the term "alkenyl" refers to a monovalent, straight or branched hydrocarbon radical, containing one or more, in one embodiment, one to five, carbon double bonds -carbon. The alkenyl radical may be optionally substituted by one or more substituents. The term "alkenyl" also comprises radicals having "cis" and "trans", or otherwise, "E" and "Z" configurations, as will be understood by those skilled in the art. When used herein, the term "alkenniium" comprises straight or branched alkenium, unless otherwise specified. For example, C2_6 alkenium refers to a linear, unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or an unsaturated, branched, monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkeneium radical is a linear, monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 12 (C2_12), 2 to 10 (C2-io) or 2 to 6 (C2_6) carbon atoms, or a monovalent, branched hydrocarbon radical of 3 to 20 (C3_2o), 3 to 15 (C3-.15), 3 to 12 (C3-i2), 3 to 10 (C3- .10) or 3 to 6 (C3_6) carbon atoms. Examples of the alkenii groups can be, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl and 4-methylbutenyl.

When used herein, and unless otherwise specified, the term "alkynyl" refers to a monovalent, straight or branched hydrocarbon radical, containing one or more, in one embodiment, one to five carbon triple bonds. carbon. The alkynyl radical may be optionally substituted by one or more substituents. The term "alkynyl" also comprises linear and branched alkynyl, unless otherwise specified. In certain embodiments, alkynyl is a linear, monovalent hydrocarbon radical of 2 to 20 (C2_20), 2 to 15 (C2-i5), 2 to 12 (C2_12), 2 to 10 (C2_io), or 2 to 6 (C2) .6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3_20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6 (C3-e) carbon atoms. Examples of the alkynyl groups can be, but are not limited to, ethynyl (-C = CH) and propargyl (-CH2C = CH). For example, C2_6 alkynyl refers to an unsaturated monovalent hydrocarbon radical, linear of 2 to 6 carbon atoms or an unsaturated, branched, monovalent hydrocarbon radical of 3 to 6 carbon atoms.

When used herein, and unless otherwise specified, the term "cycloalkyl" refers to a saturated, cyclic, bridged and / or unbridged hydrocarbon radical that may be optionally substituted by one or more substituents, as described herein. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15) / from 3 to 12 (C3_i2), from 3 to 10 (C3-10), or from 3 to 7 (C3_7) carbon atoms. Examples of the cycloalkyl groups may be, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl and adamantyl.

When used herein, and unless otherwise specified, the term "heteroalkyl" refers to a straight or branched, stable chain or a cyclic hydrocarbon radical, or combinations of these, consisting of an established number of carbon atoms. carbon and from one to three heteroatoms selected from the group consisting of, 0, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (s) 0, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, as well as at the position at which the alkyl group is attached to the rest of the molecule. The heteroatom 0, N, or S can not be placed in the position in which the alkyl group is attached to the rest of the molecule. The heteroatom 0, N, or S may be placed in the external position distal to where the alkyl group is attached to the rest of the molecule. Examples can be -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2-S ( O) -CH3, -CH2-CH2-S (0) 2-CH3, -CH = CH-0-CH3, -Si (CH3) 3, -CH2-CH = N- OCH3, and -CH = CH-N (CH3) -CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si (CH3) 3. Also included in the term "heteroalkyl" are those radicals described as "heteroalkylene" and "heterocycloalkyl." The term "heteroalkylene" by itself or as part of another substituent means a divalent radical obtained from heteroalkyl, as exemplified by -CH 2 - CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. Still further, for heteroalkylene linker groups, as well as all other linker groups provided herein, no targeting of the linker group is implied.

When used herein, and unless otherwise specified, the term "aryl" refers to an aromatic, monocyclic, and monovalent, multicyclic, aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-2o) f from 6 to 15 (C6-15), or from 6 to 10 (C6-io) atoms in the ring. Examples of the aryl groups may be, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the other of the rings is which can be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may also be optionally substituted with one or more substituents.

When used herein, and unless otherwise specified, the term "arylalkyl" or "aralkyl" refers to a monovalent alkyl group substituted with aryl. In certain embodiments, alkyl and aryl may be optionally substituted with one or more substituents.

When used herein, and unless otherwise specified, the term "heteroaryl" refers to a monocyclic aromatic group and / or multicyclic aromatic group containing at least one aromatic ring, wherein at least one ring contains one or more heteroatoms independently selected from 0, S and N. Each ring of the heteroaryl group may contain one or two atoms of 0, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms of each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 atoms in the ring. Examples of the monocyclic heteroaryl groups can be, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples of the bicyclic heteroaryl groups may be, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl. isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl and thienopyridyl. Examples of the tricyclic heteroaryl groups may be, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, fenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and xanthenyl. In certain embodiments, the heteroaryl may be optionally substituted with one or more substituents.

When used herein, and unless otherwise specified, the term "heterocycloalkyl," "heterocyclyl," or "heterocyclic" refers to a non-aromatic, monocyclic ring system and / or a multicyclic ring system containing at least one non-aromatic ring, wherein at least one ring contains one or more heteroatoms independently selected from O, S or N; and those of the remaining ring are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 atoms in the ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a system of fused or bridged rings and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms it may optionally be quaternized and some rings may be partially or completely saturated, or aromatic. The heterocyclyl can be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals may be, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahidrotienilo, benzothiopyranyl, benzoxazinyl, ß-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihidrobenzisotiazinilo, dihidrobenzisoxazinilo, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamo rholinyl, thiazolidinyl, tetrahydroquinolinyl and 1,3,5-trityanil. In certain embodiments, the heterocyclic radical may be optionally substituted with one or more substituents.

When used herein, and unless otherwise specified, the term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine and / or iodine.

When used herein, and unless otherwise specified, the term "hydrogen" comprises the proton (^), deuterium (2H), tritium (3H) and / or mixtures thereof.

When used herein, and unless otherwise specified, the term "optionally substituted" is intended to indicate that a group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl, or heterocyclyl, may be substituted with one or more substituents independently selected from, p. ex. , (a) Cis alkyl, C2_6 alkenyl, C2_6 alkynyl / C3_7 cycloalkyl, C6_4 aryl, C7_.i5 aralkyl, heteroaryl and heterocyclyl, each optionally substituted with one or more , in one embodiment, one, two, three or four, substituents Q1; and (b) halo, cyano (-CN), nitro (-NO2), -C (0) Ra, -C (0) ORa, -C (0) NRbRc, -C (Ra) NRbRc, -ORa, - OC (0) Ra, -OC (0) ORa, -OC (0) NRbRc, -OC (= NRa) NRbR °, -0S (0) Ra, -0S (0) 2Ra, -OS (0) NRbRc, -OS (0) 2NRbR °, -NRbRc, -NRaC (O) Rd, -NRaC (0) 0Rd, -NRaC (0) NRbRc, -NRaC (= NRd) NRR °, -NRaS (O) Rd, -NRaS (0) 2Rd, -NRaS (O) RbRc, -NRaS (0) 2NRbRc, -SRa, -S (0) Ra, -S (0) 2Ra, -S (0) NRbRc, and -S (0) 2NRbR °, wherein each radical Ra, Rb, Rc and Rd is independently: (i) hydrogen; (ü) Ci_6 alkyl, C2_6 alkenyl C2_6 alkynyl, C3_7 cycloalkyl, C6_4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three or four substituents Q1; or (iii) Rb and Rc together with the N atom to which they are attached form heteroaryl or heterocyclyl, optionally substituted with one or more, in one, two, three or four, substituents Q1. When used herein, all groups that may be substituted are "optionally substituted," unless otherwise specified.

In one embodiment, each Q1 is independently selected from the group consisting of: (a) cyano, halo, and nitro; and (b) Ci-β alkyl, C2_6 alkenyl, C2_6 alkynyl / C3_7 cycloalkyl, C6_4 aryl, C7_i5 aralkyl / heteroaryl, and heterocyclyl; and (c) -C (0) Re, -C (0) ORe, -C (O) RfRg, -C (NRe) RfRg, -ORe, -OC (0) Re, -OC (0) ORe, - 0C (0) NRfRg, -OC (= NRe) NRfRg, -OS (0) Re, -0S (0) 2Re, -0S (0) NRfRg, -0S (0) 2NRfRg, -NR £ Rg, -NReC ( 0) Rh, -NReC (0) 0Rh, -NReC (0) RfRg, -NReC (= NRh) NRfRg, -NReS (0) Rh, -NReS (0) 2Rh, -NReS (O) RfRg, -NReS (0) 2NRfRg, -SRe, -S (0) Re, -S (0) 2Re, -S (0) NRfRg, and -S (0) 2NRfRg; wherein each Re, Rf, Rg and Rh is independently: (i) hydrogen; (ii) Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_7 cycloalkyl, C6-i4 aryl, C7_5 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heteroaryl or heterocyclyl.

When used herein, and unless otherwise specified, the term "accepted salts for pharmaceutical use" refers to salts that are prepared from non-toxic acids accepted for pharmaceutical use, such as inorganic acids and organic acids. Suitable non-toxic acids may be inorganic and organic acids such as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucuronic, galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pam, pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric, p-toluenesulfonic and Similar. In some embodiments, salt is formed from acid hydrochloric, hydrobromic, phosphoric or sulfuric, In one embodiment, the salt is formed from the hydrochloride salt.

When used herein, and unless otherwise specified, the term "solvate" refers to a compound that is provided herein or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent united by intermolecular, non-covalent forces. Where the solvent is water, the solvate is a hydrate.

When used herein, and unless otherwise specified, the term "stereoisomer" includes all enantiomeric / stereomeric pure and enantiomeric / enriched stereomeric compounds provided herein.

When used herein, and unless otherwise specified, the term "pure stereomeric" means a composition that contains a stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a pure stereomeric compound of a compound having a The chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be practically free of other diastereomers of the compound. A typical stereomerically pure compound contains more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound, or more than about 99% by weight of a stereoisomer of the compound and less than about 1% by weight of the other stereoisomer of the compound.

When used herein, and unless otherwise indicated, the term "stereomerically enriched" means a composition that contains more than about 55% by weight of a stereoisomer of a compound, more than about 60% by weight of a stereoisomer of a compound, more than about 70% by weight, or more than about 80% by weight of a stereoisomer of a compound.

When used herein, and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having a chiral center. Likewise, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having a chiral center.

In certain embodiments, when used herein, and unless otherwise specified, "optically active" and "enantiomerically active" refers to a collection of molecules, which have an enantiomeric excess of not less than about 50% , not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, the compound contains about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer, based on the total weight of the racemate in question.

To describe an optically active compound, the prefixes R and S are used to indicate the absolute configuration of the molecule around its chiral center (s). The sign (+) and (-) is used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optimally active compound. The prefix (-) indicates that the compound is rotating levo, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextro rotary, that is, the compound rotates the plane of polarized light to the right or with the hands of the clock. However, the sign of the optical rotation, (+) or (-), is not related to the absolute configuration of the molecule, R or S.

When used herein, and unless otherwise indicated, the term "approximate" or "approximately" means an acceptable error for a specific value as determined by a person skilled in the art, which depends in part on the manner in which a value is measured or determined. In certain modalities, the term "approximate" or "approximately" means within 1, 2, 3 or 4 standard deviations. In certain modalities, the term "approximate" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.05% of a certain value or interval.

When used herein, and unless otherwise specified, the term "accepted carrier for pharmaceutical use", "excipient accepted for pharmaceutical use", "accepted carrier in the physiological medium" or "excipient accepted in the physiological environment" "refers to a material, composition or vehicle accepted for pharmaceutical use, such as a diluent, diluent, solvent or liquid or solid encapsulating material. In one embodiment, each component is "accepted for pharmaceutical use accepted for pharmaceutical use" in the sense that it is compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without causing toxicity, irritation, allergic response, excessive immunogenicity or other problems or complications, consistent with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 2nd Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2,005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds. , The Pharmaceutical Press and the American Pharmaceutical Association: 2 005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical P reformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009. When used herein, and unless otherwise specified, the terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more excipients accepted for use. pharmaceutical, to an individual for the treatment, prevention or improvement of one or more symptoms of a state, disorder or disease. When used herein, "active ingredient" and "active substance" can be an optimally active isomer of a compound described herein.

When used herein, and unless otherwise specified, the terms "drug" and "therapeutic compound" refer to a compound, or a pharmaceutical composition thereof, which is administered to an individual for treatment, prevention, management or improvement of one or more symptoms of a state, disorder or disease.

When used herein, and unless otherwise indicated, the terms "treat", "treatment" refer to the eradication or improvement of a disease or disorder, or of one or more symptoms associated with the disease or disorder . In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder as a result of the administration of one or more prophylactic or therapeutic compounds to an individual exhibiting such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active compounds, after the onset of the symptoms of the particular disease.

When used herein, and unless otherwise indicated, the terms "prevent", "Prevention" refers to the prevention of the onset, recurrence or spread of a disease or disorder or one or more of these symptoms. In some embodiments, the terms refer to the treatment with or administration of a compound provided herein, with or without another additional active compound, prior to the onset of symptoms, particularly to patients at risk of presenting the disease or disorders that are present. they provide in the present. The terms include the inhibition or diminution of a symptom of the particular disease. Patients with a family history of a particular disease are candidates for preventive schemes in some modalities. In addition, patients who have a history of recurrent symptoms are also potential candidates for prevention. In this sense, the term "prevention" can be used interchangeably with the term "prophylactic treatment".

When used herein, and unless otherwise specified, the term "management" refers to the prevention or slowing down of the progress, spread or worsening of a disease or disorder, or of one or more symptoms of these. . Frequently the beneficial effects that an individual gets of a prophylactic and / or therapeutic compound do not lead to a cure of the disease or disorder. In this sense, the term "management" comprises the treatment of a patient who has suffered from a particular disease with an attempt to prevent or minimize the recurrence of the disease.

When used herein, and unless otherwise specified, an "effective therapeutic amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or carry at least one or more symptoms associated with the disease or disorder. An effective therapeutic amount of a compound means an amount of therapeutic compound, alone or in combination with other treatments, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder. The term "effective therapeutic amount" may comprise an amount that improves general therapy, reduces or avoids the symptoms or causes of the disease or disorder, or improves the therapeutic efficacy of another therapeutic compound.

When used herein, and unless otherwise specified, an "effective prophylactic amount" of a compound is an amount sufficient to prevent a disease or disorder, or to prevent its recurrence. An effective prophylactic amount of a compound means an amount of therapeutic compound, alone or in combination with other compounds, which provides a prophylactic benefit for the prevention of the disease. The term "effective prophylactic amount" may comprise an amount that improves general prophylaxis or improves the prophylactic efficacy of another prophylactic compound.

When used herein, and unless otherwise specified, the term "individual" is defined herein as animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific modalities, the individual is a human.

As used herein, and unless otherwise specified, the term "histamine receptor ligand" refers to any compound that binds to a histamine receptor. Unless you Specify otherwise, the histamine receptor may be, but is not limited to, the histamine H3 receptor. Ligands can be endogenous ligands for a particular histamine receptor as well as drug molecules and other compounds, such as synthetic molecules known to bind to a specific histamine receptor. In one example, the ligands may be those labeled with one or more radioisotopes, such as tritium, or otherwise labeled (eg, with fluorescence). Within the abilities of the skilled person is to select an appropriate ligand for a given histamine receptor. For example, known ligands for the histamine receptor can be histamine, R-Y-Me-histamine imetit, thioperamide, clobenpropit and the like.

When used herein, and unless otherwise specified, the term "neurological disorder" refers to any state of the central or peripheral nervous system of a mammal. The term "neurological disorder" may be, but is not limited to, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), neuropsychiatric diseases (eg, schizophrenia and anxieties such as anxiety general), and affective disorders (eg, depression and attention deficit disorder). Exemplary neurological disorders may be, but are not limited to, MLS (cerebellar ataxia), Huntington's disease, Down syndrome, dementia from multiple infarcts, epilecticus status, contusive lesions (eg, spinal cord injury and injury). of the head), neurodegeneration induced by viral infection (eg, AIDS, encephalopathies), epilepsy, benign forgetfulness, closed head injury, sleep disturbances, depression (eg, bipolar disorder), dementias, disorders of movement, psychosis, alcoholism, post-traumatic stress disorder and the like. "Neurological disorder" also includes any condition associated with the disorder. In one embodiment, a method for treating a neurodegenerative disorder consists of methods for treating memory loss and / or loss of cognition associated with a neurodegenerative disorder. In one embodiment, a method for treating a neurodegenerative disorder includes methods for treating cognitive function, memory performance, learning performance, reaction rate and / or response time associated with neurodegenerative disorder. An exemplary method would also include the treatment or prevention of loss of neuronal function characteristic of neurodegenerative disorder. "Neurological disorder" also includes any disease or condition that is involved, at least in part, in the monoamine signaling pathways (eg, norepinephrine) (eg, cardiovascular disease).

When used herein, and unless otherwise specified, the term "affective disorder" includes depression, attention deficit disorder, attention deficit hyperactivity disorder, bipolar and manic states, and the like. The terms "attention deficit disorder" (ADD) and "attention deficit hyperactivity disorder" (ADDH), or attention deficit / hyperactivity disorder (AD / HD), are used in the present in accordance with the meaning accepted as found in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., American Psychiatric Association (1997) (DSM-IV ™).

When used herein, and unless otherwise specified, the term "depression" includes all forms of depression such as, but not limited to, major depressive disorder (MDD), bipolar disorder, seasonal affective disorder (SAD) and dysthymia. "Major depressive disorder" is used in the present indistinctly with "unipolar depression" and "major depression" "Depression" can also include any condition commonly associated with depression, such as all forms of fatigue (eg, chronic fatigue syndrome) and cognitive deficits.

When used in the present, and unless otherwise specified, the term "obsessive-compulsive disorder", "substance abuse", "pre-menstrual syndrome", "anxiety", "eating disorders" and " migraine "are used in the present in a manner congruent with their meanings accepted in the art. See, p. eg, DSM-IV ™. For example, the term "eating disorders", when used herein, refers to abnormal compulsions to avoid eating or uncontrollable urges to consume abnormally large amounts of food. These disorders can affect not only the social welfare, but also the physical well-being of those who suffer it. Examples of eating disorders include, but are not limited to, anorexia nervosa, bulimia and compulsive eating disorder.

When used herein, and unless otherwise specified, the term "pain" refers to an unpleasant sensory and emotional experience. The term "pain", when used herein, refers to all categories of pain, including pain that is described in terms of stimulus or nervous response, p. ex. , somatic pain (normal nervous response to a noxious stimulus) and neuropathic pain (abnormal response of a damaged or altered sensory pathway, often with a clear harmful entry); pain that is categorized temporarily, p. eg, chronic pain and acute pain; pain that is categorized in terms of its severity, p. eg, mild, moderate or severe; and pain that is a symptom or a result of a disease or syndrome state, p. e j. , inflammatory pain, cancer pain, pain from AIDS (AIDS), arthropathy, migraine, trigeminal neuralgia, cardiac ischemia and diabetic peripheral neuropathic pain (See, eg, Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al, eds., 12th ed., 1991), Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), each incorporated herein by reference in its entirety). "Pain" is also understood to include pain of mixed origin, pain due to double mechanism, allodynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia and hyperalgesia. In addition, the term "pain" includes pain that results from nervous system dysfunction: organic pain states that share clinical characteristics of neuropathic pain and possible common pathophysiological mechanisms, but that are not initiated by an identifiable lesion in any part of the nervous system.

The term "somatic pain", when used in the present, refers to a normal nervous response to a noxious stimulus, such as injury or discomfort, p. ex. , trauma, burn, infection, inflammation or disease process such as cancer, and includes skin pain (eg, skin, muscle or joint derived) and visceral pain (eg, organ derivative).

The term "neuropathic pain", when used in the present, refers to a heterogeneous group of neurological states resulting from damage to the nervous system. The term also refers to pain that results from injury to or dysfunctions of peripheral and / or central sensory pathways, and from dysfunctions of the nervous system, where pain often occurs or persists without an obvious harmful entry. This includes pain related to peripheral neuropathies as well as central neuropathic pain. Common types of peripheral neuropathic pain include diabetic neutropathy (also known as diabetic peripheral neuropathic pain, or DN, DPN or DPNP), post-herpetic neuralgia (PHN) and trigeminal neuralgia (TGN). Central neuropathic pain, which involves damage to the brain or spinal cord, can occur after stroke, spinal cord injury and as a result of multiple sclerosis, and is also understood by the term. Other types of pain that are understood to be included in the definition of neuropathic pain may be, but are not limited to, pain of neuropathic cancer, pain induced by HIV / AIDS / AIDS, phantom limb pain and complex regional pain syndrome.

The term also includes the character 'common clinical sites of neuropathic pain such as, but not limited to, sensory loss, allodynia (pain produced by non-harmful stimuli), hyperalgesia and hyperpathy (delayed perception, summation and subsequent painful sensation). Pain is often a combination of nociceptive and neuropathic types, for example, mechanical spinal pain and radiculopathy or myelopathy.

When used herein, and unless otherwise specified, the term "acute pain" is refers to the normal physiological response, predicted to a harmful chemical, thermal or mechanical stimulus normally associated with invasive procedures, trauma and disease. It is usually limited in time and can be seen as an appropriate response to a stimulus that threatens and / or causes tissue injury. The term also refers to pain that is marked by short duration or sudden onset.

When used herein, and unless otherwise specified, the term "chronic pain" includes pain that occurs in a wide range of disorders, for example, trauma, malignancies and chronic inflammatory diseases such as rheumatoid arthritis. Chronic pain may last more than about six months. In addition, the intensity of the chronic pain may be disproportionate to the intensity of the noxious stimulus or to the underlying process. The term also refers to pain associated with a chronic disorder, or pain that persists beyond the resolution of an underlying disorder or the healing of an injury, and which is often more intense than would be predicted from the underlying process. This can be the object of frequent recurrence.

When used herein, and unless otherwise specified, the term "inflammatory pain" is pain in response to tissue injury and the resulting inflammatory process. Inflammatory pain is adaptive in that it triggers physiological responses that favor healing. However, inflammation can also affect neuronal function. Inflammatory mediators, such as PGE2 induced by the C0X2 enzyme, bradykinins and other substances, bind to receptors in pain transmitting neurons and alter their function, increasing their excitability and thus increasing the sensation of pain. A large part of chronic pain has an inflammatory component. The term also refers to pain that occurs as a symptom or a result of inflammation or a disorder of the immune system.

As used herein, and unless otherwise specified, the term "visceral pain" refers to pain that is localized to an internal organ.

When used herein, and unless otherwise specified, the term "pain of mixed etiology" refers to pain that contains inflammatory and neuropathic components.

When used herein, and unless otherwise specified, the term "double mechanism pain" refers to pain that is amplified and maintained by peripheral and central sensitization.

When used herein, and unless otherwise specified, the term "causalgia" refers to a syndrome of sustained burning, allodynia, and hyperpathy after a nerve nerve injury often combined with vasomotor and sudomotor dysfunction and changes. Later trophic When used herein, and unless otherwise specified, the term "central pain" refers to pain initiated by a primary lesion or dysfunction in the central nervous system.

When used herein, and unless otherwise specified, the term "hyperesthesia" refers to the increased sensitivity to stimulation, special meanings are excluded.

When used herein, and unless otherwise specified, the term "hyperpathia" refers to the painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repeated stimulus, as well as an increased threshold. It can occur with allodynia, hyperesthesia, hyperalgesia or dysesthesia.

When used herein, and unless otherwise specified, the term "dysesthesia" refers to an unpleasant abnormal sensation, whether spontaneous or evoked. In certain modalities, dysesthesia includes hyperalgesia and allodynia.

When used herein, and unless otherwise specified, the term "hyperalgesia" refers to an increased response to a stimulus that is usually painful. Reflects increased pain with stimulation above the threshold When used herein, and unless otherwise specified, the term "allodynia" refers to pain due to a stimulus that normally causes no pain.

When used herein, and unless otherwise specified, the term "diabetic peripheral neuropathic pain" (DPNP), also referred to as diabetic neuropathy, DN or peripheral neuropathy diabetic), refers to chronic pain caused by neuropathy associated with diabetes mellitus. The traditional presentation of DPNP is pain or tingling in the feet that can be described not only as "burning" but also as "severe pain". Less often, patients may describe the pain as itching, tearing or as a tooth pain. The pain may be accompanied by allodynia and hyperalgesia and an absence of symptoms such as numbness.

When used herein, and unless otherwise specified, the term "post-herpetic neuralgia," also referred to as "post-herpetic neuralgia (PH)," refers to a painful condition that affects nerve fibers and the skin. Without being limited by a particular theory, this is a complication of shingles, a second onset of varicella zoster virus (VZV), which initially causes smallpox.

When used herein, and unless otherwise specified, the term "neuropathic cancer pain" refers to peripheral neuropathic pain as a result of cancer, and may be caused directly by infiltration or compression of a nerve by a tumor , or indirectly for cancer treatment as radiation treatment and chemotherapy (neuropathy induced by chemotherapy).

When used herein, and unless otherwise specified, the term "peripheral neuropathy due to HIV / AIDS / SID" or "neuropathy related to HIV / AIDS / AIDS" refers to peripheral neuropathy caused by HIV / AIDS / AIDS, such as acute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as well as peripheral neuropathy that results as a side effect of drugs used to treat HIV / AIDS / AIDS.

When used herein, and unless otherwise specified, the term "phantom limb pain" refers to the pain from which a limb was amputated. Phantom limb pain can also occur in limbs after paralysis (eg, after spinal cord injury). "Phantom limb pain" is usually chronic.

When used herein, and unless otherwise specified, the term "Trigeminal neuralgia (TN)" refers to a disorder of the fifth cranial (trigeminal) nerve that results in episodes of intense pain type electrical shock in the areas of the face where branches of the nerves are distributed (lips, eyes, nose, scalp, forehead, upper jaw and lower jaw). It is also known as the "suicidal disease".

When used herein, and unless otherwise specified, the term "complex regional pain syndrome (CRPS)", formerly known as reflex sympathetic dystrophy (RSD), refers to a state of chronic pain whose The main symptom is an intense and continuous pain out of proportion to the severity of the injury, which worsens instead of improving over time. The term includes CRPS type 1, which includes conditions caused by tissue injury different from the peripheral nerve, and CRPS type 2, in which the syndrome is caused by a major nerve injury, and is sometimes called causalgia.

When used herein, and unless otherwise specified, the term "fibromyalgia" refers to a chronic condition characterized by diffuse or specific pain of the muscle, joint or bone together with fatigue and a range of other symptoms. Previously, fibromyalgia was known by others names such as fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and tension myalgia.

When used herein, and unless otherwise specified, the term "seizure" refers to a neurological disorder and is used interchangeably with "convulsions", although there are many types of seizures, some of which have subtle and mild symptoms instead of seizures. Seizures of all types can be caused by disorganized and sudden electrical activity in the brain. In some modalities, seizures are a rapid and uncontrollable shudder during which the muscles contract and relax rapidly.

B. Compounds In one embodiment, a compound of the formula (I) is provided herein: (i) or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is a bond, hydrogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (from 6 to 10 members) aryl, (Ci-Cio) heteroalkyl, heterocycloalkyl of (C3-C10), or heteroaryl (from 5 to 10 members), each of which is optionally substituted with one or more R '; each time R 'is independently hydrogen, halogen, cyano, (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-Ci0) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of (Ci-Cio), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R2; or two substituents R 'together can form a 3- to 10-membered ring optionally substituted with one or more R2; RA and B are independently hydrogen, halogen, cyano, alkyl of (d-C10), alkenyl of (C1-C10), cycloalkyl of (C3-C10), aryl (from 6 to 10 members), heteroalkyl of (C1) -C10), (C3-C10) heterocycloalkyl, heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more R "; or RA and RB together can form a ring (for example, phenyl and pyridyl) optionally substituted with one or more R "; each time R "is independently hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of ( C1-C10), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or two substituents R "together can form a 3- to 10-membered ring optionally substituted with one or more Ri each time Ri appears independently, hydrogen, halogen, cyano, = 0, -0R3, -NR3R4, -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C (0) OR3, -0C (0) R3, -S (0) raR3, -S (0 ) 2NR3R4, (C1-C10) alkyl, optionally substituted with one or more R2, (C3-Cio) cycloalkyl optionally substituted with one or more R2, (C3-Ci2) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, het eroalkyl (C1-C10) optionally substituted with one or more R2, (C3-C10) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (5-10 membered) optionally substituted with one or more R2; every time R2 appears it is independently hydrogen, (Ci-C6) alkyl optionally substituted with one or more R3 cycloalkyl of (C3-C6) optionally substituted with one or more R3, halogen, cyano, = 0, -OR3, -NR3R, -N (R3) C (0) ) R4, -C (0) NR3R4, -C (0) R3, -C (0) 0R3, -0C (0) R3 > -S (0) mR3 or -S (0) 2NR3R4; R3 and R4 are each independently, hydrogen, (d-G6) alkyl, (C3-C6) cycloalkyl, (C7-C10) aralkyl; heteroalkyl of (Ci-C6), heterocycloalkyl of (C3-C6) aryl (from 6 to 10 members), or heteroaryl (from 5 to 10 members); or R3 and R4 together can form a ring of 3 to 10 members; Y m is 0, 1 or 2.

In another embodiment, a compound of formula (la) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is a bond, hydrogen, alkyl of (Ci-C10), alkenyl of (Ci-Ci0), cycloalkyl of (C3-Ci0), aryl (of 6 to 10 members), heteroalkyl of (C1-C10), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), each of which is optionally substituted with one or more R '; each time R 'is independently hydrogen, halogen, cyano, (Ci-Ci0) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of ( C1-C10), (C3-C10) heterocycloalkyl, heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R2; or two substituents R 'together can form a 3- to 10-membered ring optionally substituted with one or more R2; R5, R6, R and Rs are each independently: (i) hydrogen, halogen or cyano; (ii) (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (6 to 10 membered) aryl, (C 1 -C 10) heteroalkyl, (C 3 -C 10) heterocycloalkyl ) / heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Rx; (iii) hydroxyl substituted with one or more R: '; or (iv) two adjacent radicals R5, R6, R7 and R8, together form a 3- to 10-membered ring optionally substituted with one or more Rlf Each time Ri appears it is independently hydrogen, halogen, cyano, = 0, -0R3, -NR3R4, -N (R3) C (O) R4, -C (0) NR3R4, -C (0) R3, -C ( 0) 0R3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, (Ci-Cio) alkyl optionally substituted with one or more R2, (C3-C10) cycloalkyl optionally substituted with one or more R2, aralkyl of (C6-Ci2) optionally substituted by one or more R2, aryl (from 6 to 10 members) optionally substituted by one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2 , (C3-Ci0) heterocycloalkyl optionally substituted by one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2; each time Ri 'is independently -C (0) NR3R4, -C (0) R3 (C3-Ci0) cycloalkyl optionally substituted with one or more R2, (C6-C12) aralkyl optionally substituted with one or more R2 , aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, heterocycloalkyl of (C3-C10) optionally substituted with one or more R2, or heteroaryl ( from 5 to 10 members) optionally substituted with one or more R2; each time R2 appears it is independently hydrogen, (Ci-C6) alkyl optionally substituted with one or more R3, (C3-C6) cycloalkyl optionally substituted with one or more R3, halogen, cyano, = 0, -OR3, -NR3R4, -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C (0) OR3 / -OC (0) R3, -S (0) mR3 or - S (0) 2NR3R4; R3 and R4 are each independently, hydrogen, (Ci-C6) alkyl, (C3-C6) cycloalkyl, (C7-C10) aralkyl; heteroalkyl of (Ci-C6), heterocycloalkyl of (C3-C6), aryl (from 6 to 10 members), or heteroaryl (from 5 to 10 members); or R3 and R4 together can form a ring of 3 to 10 members; m is 0, 1 or 2; n is 1, 2 or 3; Y when n is 1, (i) R5, R6, R7 and Re can not all be hydrogen; (ii) when one of R5, R6, R7 and Re is halogen, the other three of R5, R6, R7 and R8 can not all be hydrogen; and (iii) when R6 is (C1-C4) alkyl or (C1-C4) alkoxy optionally substituted with one or more halogen, R5, R7 and Re can not all be hydrogen.

In one modality, RN is a link. In another embodiment, RN is hydrogen. In another embodiment, RN is optionally substituted (C1-C10) alkyl. In another embodiment, RN is optionally substituted (C1-C10) alkenyl. In another embodiment, RN is optionally substituted (C3-Cio) cycloalkyl. In another embodiment, RN is optionally substituted aryl (from 6 to 10 members). In another embodiment, RN is heteroalkyl of (Ci-Cio) optionally substituted. In another embodiment, RN is optionally substituted (C3-C10) heterocycloalkyl. In another embodiment, RN is optionally substituted heteroaryl (from 5 to 10 members). Each RN can be substituted with one or more R '.

In one embodiment, RN is cyclopropyl optionally substituted with one or more R '. In another embodiment, RN is cyclobutyl optionally substituted with one or more R '. In another embodiment, RN is cyclopentyl optionally substituted with one or more R '. In another embodiment, RN is cyclohexyl optionally substituted with one or more R '.

In one embodiment, R 'is hydrogen. In another embodiment, R 'is halogen. In another modality, R 'is cyano. In another embodiment, R 'is optionally substituted (C1-C10) alkyl. In another embodiment, R 'is optionally substituted (C1-C10) alkenyl. In another embodiment, R 'is optionally substituted (C3-C10) cycloalkyl. In another embodiment, R 'is optionally substituted aryl (from 6 to 10 members). In another embodiment, R 'is optionally substituted (C 1 -C 10) heteroalkyl. In another embodiment, R 'is optionally substituted heterocycloalkyl (C3-C10). In another embodiment, R1 is heteroaryl (from 5 to 10 members) optionally replaced. In another embodiment, R 'is optionally substituted hydroxyl. In another embodiment, R 'is optionally substituted alkoxy. In another embodiment, R 'is optionally substituted aminoalkyl. In another embodiment, R 'is optionally substituted amino. In another embodiment, R1 is optionally substituted imino. In another embodiment, R 'is optionally substituted amido. In another embodiment, R 'is optionally substituted carbonyl. In another embodiment, R 'is optionally substituted thiol. In another embodiment, R 'is optionally substituted sulfinyl. In another embodiment, R 'is optionally substituted sulfonyl. In another embodiment, two substituents R 'together can form a 3- to 10-membered ring optionally substituted with one or more R2. In another embodiment, two gemological substituents R together form a 3- to 10-membered ring optionally substituted with one or more R2. In another embodiment, two R 'vicinal substituents together form a 3- to 10-membered ring optionally substituted with one or more R 2. Each time R1 appears it is optionally substituted with one or more R2.

In one embodiment, RA is hydrogen. In another embodiment, RA is halogen. In another modality, RA is cyano. In another embodiment, RA is optionally substituted (Ci-Cio) alkyl. In another embodiment, RA is alkenyl of (Ci-Ci0) optionally substituted. In another embodiment, RA is optionally substituted (C3-C10) cycloalkyl. In another embodiment, R is optionally substituted aryl (from 6 to 10 members). In another embodiment, R¾ is optionally substituted (C 1 -C 10) heteroalkyl. In another embodiment, RA is optionally substituted (C3-C10) heterocycloalkyl. In another embodiment, RA is optionally substituted heteroaryl (from 5 to 10 members). In another embodiment, RA is optionally substituted hydroxyl. In another embodiment, RA is optionally substituted alkoxy. In another embodiment, RA is optionally substituted aminoalkyl. In another embodiment, RA is optionally substituted amino. In another embodiment, RA is optionally substituted imino. In another embodiment, RA is optionally substituted amido. In another embodiment, RA is optionally substituted carbonyl. In another embodiment, RA is optionally substituted thiol. In another embodiment, RA is optionally substituted sulfxyl. In another embodiment, RA is optionally substituted sulfonyl. Each time RA appears it is optionally substituted with one or more R ".

In one embodiment, RB is hydrogen. In another embodiment, RB is halogen. In another modality, RB is cyano. In another embodiment, RB is optionally substituted (C 1 -C 10) alkyl. In another embodiment, RB is alkenyl of (C 1 -C 10) optionally substituted. In another embodiment, RB is optionally substituted (C3-C10) cycloalkyl. In another embodiment, RB is optionally substituted aryl (from 6 to 10 members). In another embodiment, RB is optionally substituted (C 1 -C 10) heteroalkyl. In another embodiment, RB is optionally substituted with (C3-C10) heterocycloalkyl. In another embodiment, RB is optionally substituted heteroaryl (from 5 to 10 members). In another embodiment, RB is optionally substituted hydroxyl. In another embodiment, RB is optionally substituted alkoxy. In another embodiment, RB is optionally substituted aminoalkyl. In another embodiment, RB is optionally substituted amino. In another embodiment, RB is optionally substituted imino. In another embodiment, RB is optionally substituted amido. In another embodiment, RB is optionally substituted carbonyl. In another embodiment, RB is optionally substituted thiol. In another embodiment, RB is optionally substituted sulfinyl. In another embodiment, RB is optionally substituted sulfonyl. Each time RB appears, it is optionally substituted with one or more R ".

In one embodiment, RA and RB together form a ring, which is optionally substituted with one or more R ". In another embodiment, RA and RB together form a phenyl ring, which is optionally substituted with one or plus R. "In another embodiment, RA and RB together form a thiophene ring, which is optionally substituted with one or more R". In another embodiment, RA and RB together form a furan ring, which is optionally substituted with one or more R ". In another embodiment, RA and RB together form a pyrrole ring, which is optionally substituted with one or more R". In another embodiment, RA and RB together form a pyridine ring, which is optionally substituted with one or more R ". In another embodiment, RA and RB together form a pyrimidine ring, which is optionally substituted with one or more R". In another embodiment, RA and RB together form a pyrazine ring, which is optionally substituted with one or more R ". In another embodiment, RA and RB together form a tetrahydro-pyridine ring, which is optionally substituted with one or more R " In another embodiment, RA and RB together form a pyridone ring, which is optionally substituted with one or more R ". In another embodiment, RA and RB together form a pyrimidone ring, which is optionally substituted with one or more R". In another embodiment, RA and RB together form a pyridazinone ring, which is optionally substituted with one or more R ". In another embodiment, RA and RB together form a pyrazinone ring, which is optionally substituted with one or more R".

In one embodiment, R "is hydrogen In another embodiment, R" is halogen. In another embodiment, R "is cyano In another embodiment, R" is optionally substituted (C1-C10) alkyl. In another embodiment, R "is optionally substituted alkenyl (Ci-C10) In another embodiment, R" is optionally substituted (C3-C10) cycloalkyl. In another embodiment, R "is optionally substituted aryl (from 6 to 10 members) In another embodiment, R" is optionally substituted (Ci-C10) heteroalkyl. In another embodiment, R "is optionally substituted (C3-C10) heterocycloalkyl In another embodiment, R" is optionally substituted heteroaryl (from 5 to 10 members). In another embodiment, R "is optionally substituted hydroxyl In another embodiment, R" is optionally substituted alkoxy. In another embodiment, R "is optionally substituted aminoalkyl In another embodiment, R" is optionally substituted amino. In another embodiment, R "is optionally substituted imino In another embodiment, R" is optionally substituted amido. In another embodiment, R "is optionally substituted carbonyl In another embodiment, R" is optionally substituted thiol. In another embodiment, R "is optionally substituted sulfinyl In another embodiment, R" is optionally substituted sulfonyl. In another embodiment, two substituents R "together form a ring from 3 to 10 members optionally substituted with one or more Ri. In another embodiment, two gem-substituents R, together form a 3- to 10-membered ring optionally substituted with one or more Ri. In another embodiment, two R "vicinal substituents, together form a 3- to 10-membered ring optionally substituted with one or more Ri. Each time R "appears it is optionally substituted with one or more Ri.

In one embodiment, Rx is hydrogen. In another embodiment, Ri is halogen. In another modality, Ri is cyano. In another mode, Ri is = 0. In another mode, Ri is -0R3. In another embodiment, Ri is -NR3R4. In another embodiment, Ri is -N (R3) C (O) R. In another embodiment, Ri is -C (0) NR3R4. In another embodiment, Ri is -C (0) R3. In another embodiment, Ri is -C (0) OR3. In another mode, Ri is -0C (0) R3. In another embodiment, Ri is -S (0) mR3. In another embodiment, i is -S (0) 2NR3R4. In another embodiment, Ri is (Ci-Cio) alkyl optionally substituted with one or more R2. In another embodiment, Rx is (C3-Ci0) cycloalkyl optionally substituted with one or more R2. In another embodiment, Ri is aralkyl of (C6-Ci2) optionally substituted with one or more R2. In another embodiment, Ri is aryl (from 6 to 10 members) optionally substituted with one or more R2. In another embodiment, Ri is heteroalkyl of (Ci-Cio) optionally substituted with one or more R2. In another embodiment, Ri is (C3-C10) heterocycloalkyl optionally substituted with one or more R2. In another embodiment, Ri is heteroaryl (from 5 to 10 members) optionally substituted with one or more R2.

In one embodiment, R2 is hydrogen. In another embodiment, R2 is (Ci-C6) alkyl optionally substituted with one or more R3. In another embodiment, R2 is (C3-C6) cycloalkyl optionally substituted with one or more R3. In another embodiment, R2 is halogen. In another modality, R2 is cyano. In another embodiment, R2 is = 0. In another embodiment, R2 is -0R3. In another embodiment, R2 is -NR3R4. In another embodiment, R2 is -N (R3) C (0) R4. In another embodiment, R2 is -C (0) NR3R4. In another embodiment, R2 is -C (0) R3. In another embodiment, R2 is -C (0) 0R3. In another embodiment, R2 is -0C (0) R3. In another embodiment, R2 is -S (0) mR3. In another embodiment, R2 is -S (0) 2NR3R.

In one embodiment, R3 is hydrogen. In another embodiment, R3 is (C1-C6) alkyl. In another embodiment, R3 is (C3-C6) cycloalkyl. In another embodiment, R3 is aralkyl of (C7-C10). In another embodiment, R3 is heteroalkyl of (Ci-C6). In another embodiment, R3 is (C3-C6) heterocycloalkyl. In another modality, R3 is arilo (from 6 to 10 members). In another embodiment, R3 is heteroaryl (from 5 to 10 members).

In one embodiment, R4 is hydrogen. In another embodiment, R 4 is (Ci-Ce) alkyl. In another embodiment, R 4 is (C 3 -C 6) cycloalkyl. In another embodiment, R4 is aralkyl (C7-Ci0). In another embodiment, R 4 is heteroalkyl of (Ci-6). In another embodiment, R 4 is (C 3 -C 6) heterocycloalkyl. In another embodiment, R is aryl (from 6 to 10 members). In another embodiment, R 4 is heteroaryl (from 5 to 10 members).

In one embodiment, R3 and R4 together form a ring of 3 to 10 members. In another embodiment, two gem-like instances of R3 and R4 together form a ring of 3 to 10 members. In another embodiment, two neighborhood instances of R3 and R4 together form a ring of 3 to 10 members. In one embodiment, R3 and R together form a ring which is optionally substituted.

In one embodiment, R5 is hydrogen. In another embodiment, R5 is halogen. In another embodiment, R5 is cyano. In another embodiment, R5 is (C1-C10) alkyl optionally substituted with one or more Ri. In another embodiment, R5 is (C1-C10) alkyl substituted with one or more Ri '. In other embodiment, R5 is (C1-C10) alkenyl optionally substituted with one or more Ri. In another embodiment, R5 is (C3-C10) cycloalkyl optionally substituted with one or more i. In another embodiment, R5 is aryl (from 6 to 10 members) optionally substituted with one or more i. In another embodiment, R5 is (C1-C10) heteroalkyl optionally substituted with one or more Ri. In another embodiment, R5 is (C3-C10) heterocycloalkyl optionally substituted with one or more Ri. In another embodiment, R5 is heteroaryl (from 5 to 10 members) optionally substituted with one or more Rj. In another embodiment, R5 is hydroxyl optionally substituted with Ri. In another embodiment, R5 is hydroxyl substituted with Ri '. In another embodiment, R5 is alkoxy optionally substituted with one or more Ri. In another embodiment, R5 is alkoxy substituted with one or more Ri '. In another embodiment, R5 is aminoalkyl optionally substituted with one or more Ri. In another embodiment, R5 is amino optionally substituted with one or more Ri. In another embodiment, R5 is imino optionally substituted with one or more Ri. In another embodiment, R5 is amido optionally substituted with one or more Ri. In another embodiment, R5 is carbonyl optionally substituted with one or more Ri. In another embodiment, R5 is thiol optionally substituted with one or more Ri. In another embodiment, R5 is sulfinyl optionally substituted with one or more Rl In another embodiment, R5 is sulfonyl optionally substituted with one or more Ri. i and i 'are defined elsewhere herein.

In one embodiment, R6 is hydrogen. In another embodiment, R6 is halogen. In another modality, R6 is cyano. In another embodiment, R6 is (C1-C10) alkyl optionally substituted with one or more Ri. In another embodiment, R6 is (C1-C10) alkyl substituted with one or more Ri '. In another embodiment, R6 is (Ci-Cio) alkenyl optionally substituted with one or more Ri. In another embodiment, R6 is (C3-C10) cycloalkyl optionally substituted with one or more Ri. In another embodiment, R6 is aryl (from 6 to 10 members) optionally substituted with one or more Ri. In another embodiment, R6 is heteroalkyl of (Ci-Cio) optionally substituted with one or more Rx. In another embodiment, R6 is (C3-C10) heterocycloalkyl optionally substituted with one or more Rx. In another embodiment, R6 is heteroaryl (from 5 to 10 members) optionally substituted with one or more Ri. In another embodiment, R6 is hydroxyl optionally substituted with Ri. In another embodiment, R6 is hydroxyl substituted with Ri '. In another embodiment, R6 is alkoxy optionally substituted with one or more Ri. In another embodiment, R6 is alkoxy substituted with one or more Ri '. In another modality, R6 is aminoalkyl optionally substituted with one or more Ri. In another embodiment, R6 is amino optionally substituted with one or more Ri. In another embodiment, R6 is imino optionally substituted with one or more Ri. In another embodiment, R6 is amido optionally substituted with one or more Ri. In another embodiment, R6 is carbonyl optionally substituted with one or more Ri. In another embodiment, R6 is thiol optionally substituted with one or more Ri. In another embodiment, R6 is sulfinyl optionally substituted with one or more Ri. In another embodiment, R6 is sulfonyl optionally substituted with one or more Ri. Ri and Ri 'are defined elsewhere in the present.

In one embodiment, R7 is hydrogen. In another embodiment, R7 is halogen. In another modality, R7 is cyano. In another embodiment, R7 is (Ci-Cio) alkyl optionally substituted with one or more Ri. In another embodiment, R7 is (Ci-Cio) alkyl substituted with one or more Ri '. In another embodiment, R7 is (Ci-Cio) alkenyl optionally substituted with one or more Rx. In another embodiment, R7 is (C3-C10) cycloalkyl optionally substituted with one or more Ri. In another embodiment, R7 is aryl (from 6 to 10 members) optionally substituted with one or more Ri. In another embodiment, R7 is heteroalkyl of (C1-C10) optionally substituted with one or more Ri. In other embodiment, R7 is (C3-Ci0) heterocycloalkyl optionally substituted with one or more Ri. In another embodiment, R7 is heteroaryl (from 5 to 10 members) optionally substituted with one or more Ri. In another embodiment, R7 is hydroxyl optionally substituted with Ri. In another embodiment, R7 is hydroxyl substituted with Rx '. In another embodiment, R7 is alkoxy optionally substituted with one or more Ri. In another embodiment, R7 is alkoxy substituted with one or more Ri '. In another embodiment, R7 is aminoalkyl optionally substituted with one or more Ri. In another embodiment, R7 is amino optionally substituted with one or more i. In another embodiment, R7 is imino optionally substituted with one or more Ri. In another embodiment, R7 is amido optionally substituted with one or more Ri. In another embodiment, R7 is carbonyl optionally substituted with one or more R2. In another embodiment, R7 is thiol optionally substituted with one or more Ri. In another embodiment, R7 is sulfinyl optionally substituted with one or more ?? . In another embodiment, R7 is sulfonyl optionally substituted with one or more Rx. Ri and Rx 'are defined elsewhere in the present.

In one embodiment, R8 is hydrogen. In another embodiment, R8 is halogen. In another embodiment, R8 is cyano. In another embodiment, R8 is (Ci-Ci0) alkyl optionally substituted with one or more Ri. In another embodiment, Rg is (C1-C10) alkyl substituted with one or more Rx '. In another embodiment, R8 is (C1-C10) alkyl optionally substituted with one or more Ri. In another embodiment, R8 is (C1-C10) alkenyl optionally substituted with one or more Ri. In another embodiment, R8 is (C3-Ci0) cycloalkyl optionally substituted with one or more Ri. In another embodiment, R8 is aryl (from 6 to 10 members) optionally substituted by one or more Ri. In another embodiment, R8 is heteroalkyl of (Ci-Cio) optionally substituted with one or more Ri. In another embodiment, R8 is heterocycloalkyl of (C3-C10) optionally substituted with one or more Ri · In another embodiment, R8 is heteroaryl (from 5 to 10 members) optionally substituted with one or more Ri. In another embodiment, R8 is hydroxyl optionally substituted with Ri. embodiment, R8 is hydroxyl substituted with Ri '. In another embodiment, R8 is alkoxy optionally substituted with one or more Ri. In another embodiment, R8 is alkoxy substituted with one or more Ri '. In another embodiment, R8 is aminoalkyl optionally substituted with one or more Ri. In another embodiment, R8 is amino optionally substituted with one or more Ri. In another embodiment, R8 is optionally substituted with one or more RL. In another embodiment, R8 is amido optionally substituted with one or more Ri. In another embodiment, R8 is optionally carbonyl substituted with one or more Ri. In another embodiment, R8 is thiol optionally substituted with one or more Ri. In another embodiment, Re is sulfinyl optionally substituted with one or more R2. In another embodiment, R8 is sulfonyl optionally substituted with one or more R \. Ri and Ri 'are defined elsewhere in the present.

In one embodiment, R5 is (C1-C10) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -0R3, -NR3R4, -N (R3) C (0) R4, - C (0) NR3R4, -C (0) R3, -C (0) OR3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, optionally substituted (C3-C10) cycloalkyl with one or more R2, aralkyl of (C6-Ci2) optionally substituted with one or more R2, aryl (of 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, (C3-Ci0) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R6 is (C1-C10) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -OR3, -NR3R4, -N (R3) C (0) R, - C (0) NR3R4, -C (0) R3, -C (0) OR3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, optionally substituted (C3-C10) cycloalkyl with one or more R2, aralkyl of (C6-C12) optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (Ci-Cio) optionally substituted with one or more R2, heterocycloalkyl of (C3-C10) optionally substituted with one or more R2, or heteroaryl (of 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R7 is (C 1 -C 10) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -0R3, -NR3R4, -N (R3) C (0) R4 , -C (0) NR3R4, -C (0) R3, -C (0) 0R3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, cycloalkyl of (C3-Ci0) optionally substituted with one or more R2, (C6-C2) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R, optionally substituted (C1-C10) heteroalkyl with one or more R2, (C3-Ci0) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R 8 is (C 1 -C 10) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -OR 3, -NR 3 R 4, -N (R 3) C (0) R 4, -C (0) NR3R4, -C (0) R3, -C (0) 0R3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, cycloalkyl of (C3-C10) optionally substituted with one or more R2, (C6-C2) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally replaced with one or more R2, (C3-C10) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (5 to 10 members) optionally substituted with one or more R2.

In one embodiment, R5 is hydroxy substituted with one or more -C (0) NR3R4, -C (0) R3, (C3-C10) cycloalkyl optionally substituted with one or more R2, optionally substituted (C6-C12) aralkyl with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, heterocycloalkyl of (C3-C10) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R6 is hydroxy substituted with one or more -C (0) NR3R4, -C (0) R3, (C3-C10) cycloalkyl optionally substituted with one or more R2, optionally substituted (C6-Ci2) aralkyl with one or more R2, aryl (of 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, heterocycloalkyl of (C3-Ci0) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R7 is hydroxyl substituted with one or more -C (0) NR3R, -C (0) R3, (C3-C10) cycloalkyl optionally substituted with one or more R2, (C6-Ci2) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (Ci-Cio) optionally substituted with one or more R2, (C3-C10) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, Rg is hydroxyl substituted with one or more -C (0) NR3R4, -C (0) R3, (C3-C10) cycloalkyl optionally substituted with one or more R2, optionally substituted (C6-C12) aralkyl with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2 / (Ci-Cio) heteroalkyl optionally substituted with one or more R2, (C3-C10) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2.

In one embodiment, R5 is (Ci-Cio) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -0R3, -NR3R4 - (R3) C (0) R4, -C ( 0) NR3R4, -C (0) R3, -C (0) OR3, -OC (0) R3, -S (0) mR3, -S (0) 2NR3R4, aralkyl of (C6-C12) optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, (C3-C10) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R6 is (C1-C10) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -OR3, -NR3R4, -N (R3) C (0) R4, - C (0) NR3R4, -C (0) R3, -C (0) 0R3, -OC (0) R3, -S (0) mR3, -S (0) 2NR3R4, aralkyl of (C6-Ci2) optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, heterocycloalkyl of (C3-C10) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R7 is (C1-C10) alkyl or alkoxy, each of which is substituted with one or more cyano, = 0, -OR3, -NR3R4, -N (R3) C (0) R4 / - C (0) NR3R, -C (0) R3, -C (0) OR3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, aralkyl of (C6-Ci2) optionally substituted with one or more aryl R2 (of 6 to 10 members) optionally substituted with one or more R2, (C1-C10) heteroalkyl optionally substituted with one or more R2, (C3-C10) heterocycloalkyl optionally substituted with one or more R2 , or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R8 is (C1-C10) alkyl or alkoxy, each one of which is substituted with one or more cyano, = 0, -0R3, -NR3R4, -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C (0 ) 0R3, -0C (0) R3 -S (0) mR3, -S (0) 2NR3R4, aralkyl (C6-Ci2) optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2 / heteroalkyl of (C1-C10) optionally substituted by one or more R2, heterocycloalkyl of (C3-Ci0) optionally substituted by one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2 .

In one embodiment, R5 is hydroxyl substituted with one or more -C (0) NR3R, -C (0) R3, aralkyl (C6-Ci2) optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl (C1-C10) optionally substituted by one or more R2, heterocycloalkyl of (C3-Ci0) optionally substituted by one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R6 is hydroxyl substituted with one or more -C (0) NR3R4, -C (0) R3, aralkyl of (C6-Ci2) optionally substituted with one or more R2, aryl (of 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-) C10) optionally substituted with one or more R2, heterocycloalkyl of (C3-Ci0) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R7 is hydroxy substituted with one or more -C (0) NR3R4 / -C (0) R3, (C6-Ci2) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (Ci-Cio) optionally substituted with one or more R2, heterocycloalkyl of (C3-C10) optionally substituted with one or more R2, or heteroaryl (of 5 to 10 members) optionally substituted with one or more R2. In one embodiment, R8 is hydroxyl substituted with one or more -C (0) NR3R4, -C (0) R3, aralkyl of (C6-Ci2) optionally substituted with one or more R2, aryl (of 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-) C10) optionally substituted with one or more R2, (C3-Ci0) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2.

In one embodiment, R5 and R6 together form a 3 to 10 member ring, which is optionally substituted with one or more R. In another modality, R6 and R7 together form a 3 to 10 member ring, which is optionally substituted with one or more Ri. In another embodiment, R7 and R8 together form a 3 to 10 member ring, which is optionally substituted with one or more Ri. Ri is defined in another part of the present.

In one embodiment, Ri 'is -C (0) NR3R4. In another embodiment, Ri 'is -C (0) R3. In another embodiment, R 'is (C3-Ci0) cycloalkyl optionally substituted with one or more R2. In another embodiment, Ri 'is aralkyl of (C6-Ci2) optionally substituted with one or more R2. In another embodiment, Ri 'is aryl (from 6 to 10 members) optionally substituted with one or more R2. In another embodiment, Ri 'is heteroalkyl of (C1-C10) optionally substituted with one or more R2. In another embodiment, Ri is (C3-C10) heterocycloalkyl optionally substituted with one or more R2. In another embodiment, Ri 'is heteroaryl of (5 to 10 members) optionally substituted with one or more R2- In one mode, m is 0. In another mode, m is 1. In another mode, m is 2.

In one modality, n is 1. In another modality, n is 2. In another modality, n is 3. In a modality, n is 1 or 2.

In one embodiment, when n is 1, R5, R6, R7 and Rs are not all hydrogen. In one embodiment, when n is 1 and when one of R5, R6, R7 and R8 is halogen, the other three of R5, R6 / R7 and R8 are not all hydrogen. In one embodiment, when n is 1 and when R6 is (C1-C4) alkyl or (C1-C4) alkoxy optionally substituted with one or more halogen, R5, R7 and Rs are not all hydrogen.

Any of the combinations of RA, RB, RN, R 'I R ", Ri, R2, R3, R4, R5, R6 / R ?, Re, Ri' / m and n are included in this description and are specifically provided herein.

In one embodiment, a compound of formula (lia) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein: R5, R6, R7 and Re are independently hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-Cio) cycloalkyl, aryl (from 6 to 10) members), heteroalkyl of (C1-C10), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; or two adjacent radicals R5, R6, R7, and R8, together can form a ring of 3 to 10 members; Y RN and Ri are defined elsewhere in this.

In another embodiment, a compound of formula (lia), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, is provided herein.

R5, R6, R7 and Re are each independently: (i) hydrogen, halogen or cyano; (ii) (C1-C10) alkyl, (Ci-Ci0) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, (C3-C10) heterocycloalkyl ), heteroaryl (from 5 to 10 members), alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, (iii) hydroxyl substituted with one or more Ri '; or (iv) two adjacent radicals R5, R6, R7, and R8, together form a 3- to 10-membered ring optionally substituted with one or more Ri; R5, Re, R7 and Re can not all be hydrogen; when one of R5, R6, R7 and Rs is halogen, the other three of R5, R6, R7 and Rs can not all be hydrogen; when R6 is (C1-C4) alkyl or (C1-C4) alkoxy optionally substituted with one or more halogen, R5, R7 and R8 can not all be hydrogen; Y RN, Ri and Ri 'are defined elsewhere in this.

In one embodiment, two adjacent radicals R5, R6, R7 and Re, together form a 3- to 10-membered ring optionally substituted with one or more Ri. In one embodiment, two adjacent radicals R5, R6, R7, and Rs, together form a 5-6 membered ring optionally substituted with one or more Ri. In one embodiment, two adjacent radicals R5, Re, R7, and R8, together form a 5-6 membered partially saturated heterocycloalkyl ring optionally substituted with one or more Ri. In one embodiment, the 5-6 membered ring contains at least a nitrogen atom in the ring. Specific examples include, but are not limited to, compounds of the following structure: In another embodiment, a compound of formula (Ilb) is provided herein: (Ilb) or a salt, solvate, or stereoisomer accepted for pharmaceutical use thereof, wherein R6, R7 and R3 are independently hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of ( C1-C10), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or two adjacent radicals R6, R7 and Rs, together they can form a ring of 3 to 10 members; Y RN and Ri are defined elsewhere in this.

In one embodiment, the compounds of formula (Ilb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) cycloalkyl optionally substituted with one or more R 'are provided herein; R6 and R8 are hydrogen; and R7 is hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, (C3-C10) heterocycloalkyl, (5-10 membered) heteroaryl, hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri Ri 'and Ri are defined elsewhere in the I presented. In one embodiment, RN is optionally substituted cyclobutyl. In one embodiment, R7 is halogen. In another embodiment, R7 is optionally substituted phenyl. In another embodiment, R7 is optionally substituted pyridine. In another embodiment, R7 is optionally substituted pyrimidine. In another embodiment, R7 is optionally substituted pyrazine. In another embodiment, R7 is optionally substituted five-membered heteroaryl. In another embodiment, R7 is optionally substituted six-membered heteroaryl.

Specific examples include, but are not limited to, compounds of the following structures: In another embodiment, a compound of formula (lie) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R5, R7 and Ra are independently hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of Cio), (C3-C10) heterocycloalkyl, heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or R7 and R8 together can form a 3 to 10 member ring; Y RN and Ri are defined elsewhere in this.

In another embodiment, a compound of formula (lid) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R5, R6 and R8 are independently hydrogen, halogen, cyano, (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of (C1) -C10), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; or R5 and R6 together can form a ring of 3 to 10 members; Y RN and Ri are defined elsewhere in this.

In another embodiment, a compound of formula (lie) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R5, R6 and R7 are independently hydrogen, halogen, cyano, (Ci-Ci0) alkyl, alkenyl (Ci-Cio), cycloalkyl of (C3-Ci0), aryl (from 6 to 10 members), heteroalkyl of Ci0), (C3-C10) heterocycloalkyl, heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or two adjacent radicals R5, R6 and R7, together can form a ring of 3 to 10 members; Y RN and Ri are defined elsewhere in this.

In one embodiment, a compound of formula (Ilf) is provided herein: (Ilf) or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R5, R6, R7 and Re are each independently, hydrogen, halogen, cyano, (C1-C10) alkyl, alkenyl of (Ca-Cio), cycloalkyl of (C3-C10), aryl (of 6 to 10 members) , heteroalkyl of (C1-C10), heterocycloalkyl of (C3-C10), heteroaryl (of 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of the which is optionally substituted with one or more Ri; Y RN and Ri are defined elsewhere in this.

In another embodiment, a compound of formula (Ilf), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, is provided herein.

R5, R6, R7 and Re are each independently: (i) hydrogen, halogen or cyano; (ü) (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; (iii) hydroxyl substituted with one or more Ri '; or (iv) two adjacent radicals R5, R6 R7 and Rs, together form a 3- to 10-membered ring optionally substituted with one or more Rx; Y RN, Ri and Ri 'are defined elsewhere in this.

In one embodiment, a compound of formula (Illa) is provided herein: (Illa) or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RAr is (i) cyano; (ii) (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (6 to 10 membered) aryl, (C 1 -C 10) heteroalkyl, (C 3 -C 10) heterocycloalkyl ), heteroaryl (from 5 to 10 members), alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or (iii) hydroxyl substituted with one or more Ri '; RA r is not (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy optionally substituted with one or more halogen; Y RN, Ri and Ri 'are defined elsewhere in this.

In one embodiment, RAr is not alkyl of (C1-C4). In one embodiment, RAr is not (C 1 -C 4) alkyl optionally substituted with one or more halogen. In one embodiment, RAr is not (C 1 -C 4) alkyl optionally substituted with cycloalkyl. In one embodiment, RAr is not (C 1 -C 4) alkoxy optionally substituted with one or more halogen. In one embodiment, RAr is not (C 1 -C 4) alkoxy optionally substituted with cycloalkyl.

In one embodiment, RAr is (i) cyano; (ii) aryl (from 6 to 10 members), heteroalkyl of (C1-C10), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri; or (iii) (C1-C10) alkyl / alkoxy, or hydroxyl, each of which is substituted with one or more Ri '.

In one embodiment, a compound of formula (Illb) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RAr is (i) cyano; (ii) (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C0) cycloalkyl, (6 to 10 membered) aryl, (C i -C io) heteroalkyl, (C3-) heterocycloalkyl C10), heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Rj.; or (iii) hydroxyl substituted with one or more Ri '; Y RN, Ri and Ri 'are defined elsewhere in this.

In one embodiment, RAr is hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (6 to 10 members), heteroalkyl (C1) -C10), (C3-C10) heterocycloalkyl, heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri.

In one embodiment, RAr is (C1-C10) alkyl or alkoxy, each of which is substituted with one or more halogen, cyano, = 0, -0R3, -NR3R4, -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C (0) 0R3, -0C (O) R3, -S (0) mR3, -S (0) 2NR3R4 / cycloalkyl of (C3-Ci0) optionally substituted with one or more R2, (C6-C12) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, (C1-C10) heteroalkyl optionally substituted with one or more R2, heterocycloalkyl (C3-Cio) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2.

In one embodiment, RAr is (C1-C10) alkyl or alkoxy, each of which is substituted with one or more halogen, cyano, = 0, -0R3, -NR3R4 -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C (0) 0R3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, optionally substituted aralkyl (C6-Ci2) with one or more R2, aryl (of 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2, heterocycloalkyl of (C3-Cio) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2.

In one embodiment, R r is hydrogen. In another modality, RAr is halogen. In another modality, RAr is cyano. In another embodiment, RAr is (C1-C10) alkyl optionally substituted with one or more RL. In another embodiment, RAr is (C1-C10) alkyl substituted with one or more Ri '. In another embodiment, RAr is (C1-C10) alkenyl optionally substituted with one or more Ri. In another embodiment, RAr is (C3-C10) cycloalkyl optionally substituted with one or more Rx. In another embodiment, RAr is aryl (from 6 to 10 members) optionally substituted with one or more Ri. In another embodiment, RAr is heteroalkyl of (C1-C10) optionally substituted with one or more Ri. In another embodiment, RAr is (C3-C10) heterocycloalkyl optionally substituted with one or more Ri. In another embodiment, RAr is heteroaryl (from 5 to 10 members) optionally substituted with one or more Rx. In another embodiment, RAr is hydroxyl optionally substituted with one or more Ri. In another embodiment, RAr is hydroxyl substituted with one or more R: '. In another embodiment, RAr is alkoxy optionally substituted with one or more Ri. In another embodiment, RAr is alkoxy substituted with one or more Ri '. In another embodiment, RAr is aminoalkyl optionally substituted with one or more Ri. In another embodiment, RAr is amino optionally substituted with one or more Rx. In another embodiment, R r is optionally substituted with one or plus Ri. In another embodiment, RAr is amido optionally substituted with one or more Ri. In another embodiment, RAr is optionally substituted carbonyl with one or more Ri. In another embodiment, RAr is thiol optionally substituted with one or more Ri. In another embodiment, RAr is sulfinyl optionally substituted with one or more Ri. In another embodiment, RAr is sulfonyl optionally substituted with one or more Ri. In one modality, RAr is fluorine. In another modality, RAr is chlorine. In another modality, RAr is bromine. In another modality, RAr is iodine. In another modality, RAr is cyano. In another modality, RAr is -ORi. In another modality, RAr is -ORi '. In another modality, RAr is -OCH2R1. In another embodiment, R r is -OCH2Ri '. In another modality, RAr is -NHRi. In another modality, RAr is -NHCH2Ri. In another modality, RAT is -N (Ri) 2. In another embodiment, RAr is -C (O) R). In another modality, RAr is -C (0) N (Ri) 2. In another modality, RAr is -CH2Ri. In another embodiment, R r is -CH2Ri '. In another modality, RAr is -CH2N (Ri) 2. In another modality, RAr is -CH2OR1. In another modality, RAr is -CH20Ri '. Ri and Ri 'are defined elsewhere in the present.

Any of the combinations of RAr, RN, Ri and Ri 1 is included in this description and are specifically provided herein.

In one embodiment, a compound of formula (Illa), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) cycloalkyl optionally substituted with one or more R 'is provided herein.; and RA r is halogen, cyano, (C 1 -C 10) alkyl, aryl (6 to 10 members), heteroalkyl (C 1 -C 10), heterocycloalkyl (C 3 -C 10), heteroaryl (5 to 10 members), hydroxyl , alkoxy, aminoalkyl, amino, amido, or carbonyl, each of which is optionally substituted with one or more Ri. R 'and Ri are defined elsewhere in the present.

In one embodiment, a compound of formula (Illa), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) cycloalkyl or (C1-C10) alkyl) is provided. , each of which is optionally substituted with one or more R '; RAr is (i) cyano; (ii) (C1-C10) alkyl, aryl (from 6 to 10 members), heteroalkyl (Ci-C10), heterocycloalkyl (C3-C10), heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri; or (iii) hydroxyl substituted with one or more Ri '; RAr is not (C1-C4) alkyl or (C1-C4) alkoxy optionally substituted with one or more halogen; and R ', Rj and Ri' are defined elsewhere in the present.

In one embodiment, a compound of formula (Illa), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) cycloalkyl or (C1-) alkyl, is provided. C 10), each of which is optionally substituted with one or more R '; RAr is (i) cyano; (ii) aryl (from 6 to 10 members), heteroalkyl (C 1 -C 10), heterocycloalkyl (C 3 -C 10), heteroaryl (from 5 to 10 members), aminoalkyl, amino, amido, or carbonyl, each of which is optionally substituted with one or more Rlf or (iii) (C 1 -C 10) alkyl, alkoxy or hydroxyl, each of which is substituted with one or more Ri; and R ', Ri and Ri' are defined elsewhere in the present.

In one embodiment, RN is optionally substituted cyclobutyl. In one embodiment, RN is optionally substituted t-butyl. In one modality, RAr is fluorine. In another modality, RAr is chlorine. In another modality, RAr is bromine. In another modality, RAr is iodine. In another modality, RAr is cyano. In another embodiment, RAr is optionally substituted phenyl. In another embodiment, RAr is optionally substituted six-membered heteroaryl. In another embodiment, RAr is optionally substituted five-membered heteroaryl. In another embodiment, RAr is optionally substituted 8 to 10 membered heteroaryl. In another embodiment, RAr is optionally substituted six-membered heterocycloalkyl. In another modality, RAr is optionally substituted five-membered heterocycloalkyl. In another modality, RAr is -ORi. In another modality, RAr is -ORi '. In another embodiment, Rr is -OCH2Ri. In another modality, RAr is -0CH2Ri '. In another modality, RAr is -NHRi. In another modality, RAr is -NHCH2Ri. In another modality, RAr is -N (Ri) 2. In another modality, RAr is -C (0) Ri. In another embodiment, RAr is -C (0) N (R1) 2. In another embodiment, Rr is -CH2Ri. In another modality, RAr is -CH2Ri '. In another modality, RAr is -CH2N (R!) 2. In another modality, RAr is -CH2ORi. In another modality, RAr is -CH2ORi '.

In one embodiment, RAr is cyano, optionally substituted phenyl, optionally substituted six-membered heteroaryl, optionally substituted five-membered heteroaryl, optionally substituted heteroaryl (from 8 to 10), optionally substituted six-membered heterocycloalkyl, optionally substituted five-membered heterocycloalkyl. , -0R, ', -OCH2Ri', -NHRi, -NHCH2R1, -N (R!) 2, -C (0) Ri, -C (0) N (Ri) 2, -CH2Ri ', -CH2N (Ri ) 2, -CH20H or -CH20Ri '.

Specific examples include, but not limited to, the following structures: q ^, crf, ^ o¾. ^ ¾ In one embodiment, a compound of formula (IVa) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein whenever X is present it is independently N, CH or CRi; and Ri is defined elsewhere in the present. Examples include, but are not limited to, the following compounds: In one embodiment, there is provided herein a compound of formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (Ci-Ci0) alkyl optionally substituted with one or more R '; and RAR is hydrogen, halogen, cyano, (Ci-Ci0) alkyl, (Ci-Ci0) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl (from (C1-C10)) , (C3-C10) heterocycloalkyl, heteroaryl (from to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri. R 'and Ri are defined elsewhere in the I presented.

In one embodiment, a compound of formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (Ci-Cio) alkyl optionally substituted with one or more R 'is provided herein; and RAr is (i) cyano; (ii) (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, (C3-C10) heterocycloalkyl ), (from 5 to 10 members) heteroaryl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more RL or (iii) hydroxyl substituted with one or more Ri '. R ', ¾ and ¾' are defined elsewhere in the present.

In one embodiment, RAr is (i) cyano; (ii) (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl (Ci-Ci0), heterocycloalkyl from (C3-C10), heteroaryl (from 5 to 10 members) ), aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; or (iii) (C1-C10) alkyl, hydroxyl or alkoxy, each of which is substituted with one or more Ri '. R ', Ri and ¾' are defined elsewhere in the present.

Specific examples include, but are not limited to, compounds of the following structures: In another embodiment, compounds of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) heterocycloalkyl optionally substituted with one or more R are provided herein. '; and RA r is hydrogen, halogen, cyano, (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, C3-C10 cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of (Cx-Cio) heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino , amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri. R 'and Ri are defined elsewhere herein.

In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) heterocycloalkyl optionally substituted with one or more R is provided herein. '; and RAr is (i) cyano; (ii) (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (6 to 10 membered) aryl, (C 1 -C 10) heteroalkyl, (C 3 -C 10) heterocycloalkyl ), heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; or (iii) hydroxyl substituted with one or more Ri '. R ', Ri, and Ri' are defined elsewhere in the present.

In one embodiment, a compound of formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, is provided herein. where RN is (C3-C10) heterocycloalkyl optionally substituted with one or more R '; and RAr is (i) cyano; (ü) (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, aryl (6 to 10 members), heteroalkyl (C 1 -C 10), heterocycloalkyl (C 3 -C 10), heteroaryl (5 to 10) members), aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or (iii) (C1-C10) alkyl, hydroxyl or alkoxy, each one of which is substituted with one or more Ri '. R ', Ri, and Ri' are defined elsewhere in the present.

Specific examples include, but are not limited to, compounds of the following structures: In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C3-C10) cycloalkyl optionally substituted with one or more R is provided herein. ' In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for Pharmaceutical use thereof, wherein RN is (C3-C6) cycloalkyl optionally substituted with one or more R '. In one embodiment, there is provided herein a compound of formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is (C4-C6) cycloalkyl optionally substituted with one or more R ' .

In another embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclohexyl optionally substituted with one or more R '; and RAR is hydrogen, halogen, cyano, (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-Ci0) cycloalkyl, aryl (from 6 to 10 members), heterocycloalkyl (Ci-Cio), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more R ±. R 'and Ri are defined elsewhere herein.

In one embodiment, a compound of formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, is provided herein. where RN is cyclohexyl optionally substituted with one or more R '; and RAr is (i) cyano; (ii) (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (6 to 10 membered) aryl, (C 1 -C 10) heteroalkyl, (C 3 -C 10) heterocycloalkyl ) / heteroaryl (from 5 to 10 members), alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri or (iii) hydroxyl substituted with one or more Ri '. R ', Ri and Ri' are defined elsewhere in this.

In one embodiment, there is provided herein a compound of formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclohexyl optionally substituted with one or more R '; and RAr is (i) cyano; (ii) (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, aryl (6 to 10 members), heteroalkyl (C 1 -C 10), heterocycloalkyl (C 3 -C 10), heteroaryl (5 to 10) members), aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; or (iii) (C1-C10) alkyl, hydroxyl, or alkoxy, each of which is substituted with one or more Ri '. R ', Ri and Rx' are defined elsewhere in the present.

Specific examples include, but not limited to, compounds of the following structures: In another embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclopentyl optionally substituted with one or more R 'is provided.; and RAR is hydrogen, halogen, cyano, (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-Ci0) cycloalkyl, aryl (from 6 to 10 members), heterocycloalkyl (Ci-Cio), heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri . R 'and Ri are defined elsewhere in the present.

In one embodiment, there is provided herein a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclopentyl optionally substituted with one or more R '; and RAr is (i) cyano; (ii) (Ci-Cio) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of (Ci-Cio), heterocycloalkyl of (C3-C10), heteroaryl (of 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each one of which is optionally substituted with one or more Ri; or (iii) hydroxyl substituted with one or more Ri '. R ', Ri and Ri' are defined elsewhere in this.

In one embodiment, there is provided herein a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclopentyl optionally substituted with one or more R '; and RAr is (i) cyano; (ii) alkenyl of (CiCio), cycloalkyl of (C3-Ci0), aryl (of 6 to 10 members), heteroalkyl of (Cx-Cio), heterocycloalkyl of (C3-C10), heteroaryl (of 5 to 10 members) , aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or (iii) (C1-C10) alkyl, hydroxyl or alkoxy, each of which is substituted with one or more Ri '. R ', Ri and Rl' are defined elsewhere herein.

Specific examples include, but are not limited to, compounds of the following structures: In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R is a five-membered heteroaryl optionally substituted with one or more Ri is provided. In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R ', and RAr is a five-membered heteroaryl optionally substituted with one or more Ri. R 'and Ri are defined elsewhere herein. Specific examples include, but are not limited to, compounds of the following structures: In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R is 8 to 10 membered heteroaryl optionally substituted with one or more Ri is provided herein . In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R ', and RAr is heteroaryl is provided herein from 8 to 10 members optionally substituted with one or more Ri. R 'and Ri are defined elsewhere in the present. In one embodiment, RAr is a 9 to 10-membered heteroaryl optionally substituted with one or more Ri. In one embodiment, RAr is 9-membered heteroaryl optionally substituted with one or more Ri. Specific examples include, but are not limited to, compounds of the following structures 104 In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein R <r> is (C3-C10) heterocycloalkyl optionally substituted with one or more Ri . In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R ', and RAr is heterocycloalkyl is provided herein of (C3-C10) optionally substituted with one or more Ri. R 'and Ri are defined elsewhere herein. In one embodiment, RAr is 5- to 6-membered heterocycloalkyl optionally substituted with one or more Rx. In one embodiment, RAr is 9 to 10 membered heterocycloalkyl optionally substituted with one or more Ri. Specific examples include, but are not limited to, compounds of the following structures: o-G¾- -Q ?? ¾- - ?? ¾ ?? 106 In another embodiment, there is provided herein a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R '; and RA r is halogen, cyano, (C 1 -C 10) alkyl, (C 1 -C 10) heteroalkyl, hydroxyl, alkoxy, aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri. R 'and Ri are defined elsewhere in the present.

In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RAr is (i) cyano is provided; (ü) (Ci-Cio) alkyl, (Ci-Cio) heteroalkyl, alkoxy, aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri; or (iii) hydroxyl substituted with one or more Ri '. In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein Rñr is (i) cyano is provided; (ii) heteroalkyl of (Ci-Cio), aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri; or (iii) (Ci-Cio) alkyl, hydroxyl or alkoxy, each of which is substituted with one or more Ri '. In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R '; and RAr is (i) cyano; (ii) (C1-C10) alkyl, (C1-C10) heteroalkyl, alkoxy, aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri, or (iii) hydroxyl substituted with one or more Ri '. In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R '; and RAr is (i) cyano; (ii) heteroalkyl of (Ci-Cio), aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri, or (iii) alkyl of (Ci-Cio), hydroxyl or alkoxy, each one of which is substituted with one or more Ri '. R ', Ri and Ri' are defined elsewhere in the present.

In one modality, RAr is fluorine. In another modality, RAr is chlorine. In another modality, RAr is bromine. In another modality, RAr is iodine.

In one modality, RAr is cyano. In another embodiment, RAr is (C1-C10) alkyl substituted with one or more Ri. In another embodiment, RAr is (C1-C10) alkyl substituted with one or more R \ '. In another modality, RAr is -CH2Ri. In another modality, RAr is -CH2Ri '. In another modality, RAr is -CH (Ri) 2- In another modality, RAr is -CH (R1 ') 2. In another modality, RAr is -CH (OH) R !. In another embodiment, RAr is -CH (OH) Ri '. In another modality, RAr is -CH2ORi. In another modality, RAr is -CH2ORi '. In another embodiment, RAr is -CH2OH. In another embodiment, RAr is hydroxyl or alkoxy substituted with one or more Ri. In another embodiment, RAr is hydroxyl or alkoxy substituted with one or more Ri '. In another modality, RAr is -ORi. In another modality, RAr is -ORi '. In another modality, RAr is -0CH2Ri. In another modality, RAr is -OCH2Ri '. In another embodiment, RAr is amino, amido or carbonyl, each of which is optionally substituted with one or more Ri. In another embodiment, RAr is -NHRi. In another modality, RAr is -NHCH2Ri. In another modality, RAr is -N (R!) 2. In another embodiment, R r is -C (0) R !. In another modality, RAr is -C (0) N (Ri) 2. In another modality, RAr is -CH2NiR02.

Specific examples include, but are not limited to, compounds of the following structures: 110 In another embodiment, there is provided herein a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R '; and RAr is 10-membered aryl optionally substituted with one or more Rx. In one embodiment, RAr is naphthyl. The specific example includes, but is not limited to, the compound of the following structure: In one embodiment, a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, is provided herein. where RAr is phenyl or naphthyl, each of which is optionally substituted with one or more Ri. In one embodiment, there is provided herein a compound of the formula (Illb), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RAr is six-membered heteroaryl, optionally substituted with one or more Ri.

In one embodiment, a compound of the formula (IVb) is provided herein: (IVb) or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein whenever X is present it is independently N, CH or CRi; and Ri is defined elsewhere in the present. Examples include, but are not limited to, the following compounds: In one embodiment, a compound of the formula (V) is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RAr is hydrogen, halogen, cyano, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), (C1-C10) heteroalkyl, heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with RN and Ri are defined elsewhere in this.

In one embodiment, there is provided herein a compound of the formula (V), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RAr is (i) hydrogen, halogen or cyano; (ii) (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, (C3-C10) heterocycloalkyl , heteroaryl (from 5 to 10 members), alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which it is optionally substituted with one or more Ri, or (i) hydroxyl substituted with one or more Ri '; Y RN, Rx and Ri 'are defined elsewhere herein.

In one embodiment, a compound of the formula (V), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, is provided herein.

RAr is (i) hydrogen, halogen or cyano; (ü) alkenyl of (Ci-Cio), cycloalkyl of (C3-Ci0), aryl (of 6 to 10 members), heteroalkyl of (Ci-Cio), heterocycloalkyl of (C3-C10) / heteroaryl (from 5 to 10) members), aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; or (iii) (C1-C10) alkyl, hydroxyl or alkoxy, each of which is substituted with one or more Ri '; Y RN, Ri and Ri 'are defined elsewhere in this.

Specific examples include, but are not limited to, compounds of the following structure: Any of the combinations of RN and RAr are included in this description and are specifically provided herein.

In one embodiment, a compound of the formula (I), (la), (lia), (Ilb), (lie), (lid), (He), (Illf), (Illa), is provided, (Illb) or (V), or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is cyclobutyl optionally substituted with one or more R '. In one embodiment, a compound having the following structure is provided herein: or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof.

It should be noted that if there is a difference between a structure represented and a name given to that structure, the structure must be given greater importance. In addition, if the stoichiometry of a structure or a part of a structure is not indicated with, for example, bold or discontinuous lines, the structure or part of the structure must be interpreted comprising all the stereoisomers thereof. Where the compound provided herein contains an alkenyl or alkenylene group, the compound can exist as one or a mixture of cis / trans (or Z / E) geometric isomers. Where the structural isomers can be interconverted, the compound can exist as a single tautomer or a mixture of tautomers. This may take the form of a proton tautomerism in the compound containing, for example, an imino, keto or oxime group; or the so-called valence tautomerism in the compound that contains an aromatic portion. What follows is that a single compound can present more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or may be stereoisomeric mixtures, such as a mixture of enantiomers, e.g. ex. , a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. In some cases, for compounds that suffer In vivo epimerization, one skilled in the art will realize that the administration of a compound in its (R) form is equivalent to the administration of the compound in its (S) form. The traditional techniques for the preparation / isolation of the individual enantiomers can be the synthesis from the optically pure precursor, asymmetric synthesis from achiral starting materials, or the resolution of a mixture of enantiomers, for example, by chiral chromatography, recrystallization , resolution, formation of the diastereomeric salt or derivation in products of the diastereomer addition followed by separation.

When the compound provided herein contains an acidic or basic portion, it can also be provided as a salt accepted for pharmaceutical use (See, eg, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use, Stahl and Ermuth, ed.; Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of acceptable pharmaceutical salts may be, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, acid adipic, alginic acid, ascorbic acid, L-aspartic acid, benzensulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+) - camphoric acid, camphorsulfonic acid, (+) - (lS) -canfor-10 acid -sulfonic, capric acid, capric acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactharic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, acid (+) - l-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) - 1-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naph acid talen-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, protic acid, oxalic acid, palmitic acid, pamico acid, perchloric acid, phosphoric acid , L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, acid (+) -1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid.

Suitable bases for use in the preparation of acceptable pharmaceutical salts may be, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; and organic bases, such as primary, secondary, tertiary and quaternary, aliphatic and aromatic amines such as L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine , ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2- hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol and tromethamine.

In certain embodiments, the compounds provided herein are pharmacologically salts acceptable of the compounds with one or more of the hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and isethionic acids; or with one or more of potassium carbonate, sodium or potassium hydroxide, ammonia, triethylamine and triethanolamine.

The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of the formula I and which is readily convertible to the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. These can be, for example, bioavailable by oral administration while the precursor compound does not. The prodrug may also have better solubility in the pharmaceutical compositions relative to the precursor compound. A prodrug can be converted into the precursor drug by various mechanisms such as enzymatic processes and metabolic hydrolysis. See, p. Ex., Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in Design of Biopharmaceutical Properties through Prodrugs and Analogs, Roche ed. , APHA Acad. Pharm. Sci. 1977; Bioreversible Carriers in Drug in Drug Design, Theory and Application, Roche ed. , APHA Acad. Pharm. Sci. 1987; Design of Prodrugs, Bundgaard, Elsevier, 1985; Wang et al, Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al, Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al, Pharm. Biotech 1998, 11, 345-365; Gaignault et al, Pract. Med. Chem. 1996, 671-696; Asgharnejad in Transport Processes in Pharmaceutical Systems, Amidon et al, ed. , Marcell Dekker, 185-218, 2000; Balant et al, Eur. J. Drug Metab. Pharmacokinet. 1990, 75, 143-53; Balimane & Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al, Methods Enzymol. 1985, 112, 360-381; Farquhar et al, J. Pharm. Sci. 1983, 72, 324-325; Freeman et al, J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al, Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 2AX-TTÍ; Stella et al, Drugs 1985, 29, 455-73; Tan et al, Adv. Drug Delivery Rev. 1999, 39, 117-151; Tailoor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. CHn. Pharmac. 1989, 28, 497-507.

C. Synthetic schemes The following schemes provide exemplary synthetic methods for the preparation of the compounds that are provided in the presnete. One skilled in the art will understand that similar methods can be employed to prepare the compounds provided herein. In other words, one skilled in the art will recognize that appropriate settings for reagents, protecting groups, reaction conditions and reaction sequences can be used to prepare a desired embodiment. The reactions can be scaled up or down to adjust the amount of material to be prepared.

In one embodiment, a compound of the formula (I) may be prepared following Scheme 1. Compound I-A may be available from a commercial source, or may be readily prepared following the procedures known from the literature. Compound I-A becomes I-B in one or more steps following the standardized procedures. Compound I-B is treated with TosCl under basic conditions, such as TEA / DCM. Subsequently, the Boc protective group is eliminated using a normal condition, such as treatment with TFA, to generate I-C. Compound I-C is treated with base, such as K2C03 in aqueous 2-propanol, to produce I-D. Compound I-D can be converted to I-E in one or more steps, such as through reductive alkylation by ketones or aldehydes, or alkylation by alkyl halides. As an option, other organic transformations can convert RA 'and RB' to groups RA and RB- In one embodiment, a compound of formula (la) can be prepared by following the steps of Scheme la. Compound I-A 'may be available from a commercial source or can be prepared easily following the known procedures of the literature. Compound I-A 'is converted to I-B' in one or more steps following standard procedures. Compound I-B 'is treated with TosCl in basic condition, such as TEA / DCM. Subsequently, the Boc protective group is eliminated using a normal condition, such as treatment with TFA, to generate I-C. Compound I-C is treated with base, such as K2C03 in aqueous 2-propanol, to produce I-D '. Compound I-D 'can be converted to I-E' in one or more steps, such as through reductive alkylation by ketones or aldehydes, or alkylation by alkyl halides. As an option, subsequent organic transformations can convert R5, 6, R7, and g into other suitable embodiments of R5, R6, R7, and Re that are provided herein.

Scheme the: I-D "» · £? (The) The specific schemes for preparing the compounds provided herein are shown below. Details of reaction conditions are provided for various specific examples herein. A person with ordinary skill in the art will understand that the following schemes can be modified with reagents, protecting groups, conditions, starting materials or appropriate reaction sequences to suit the preparation of other embodiments provided herein.

In one embodiment, a compound of formula (Illb) can be prepared following Scheme 2. 1, 4-dichloro-2-nitrobenzene (1-1) is treated with 2-aminoethanol in n-butanol to produce 2- (4-) chloro-2-nitrophenylamino) ethanol (1-2). Compound 1-2 is reduced, as it can be with Na2S204 in 40% ethanol to obtain the corresponding aniline 1-3. 1-3 is coupled with 3-aminopropanoic acid and cyclized under acidic conditions, such as in 6N HC1, to produce benzimidazole 1-4. The amino group of 1-4 is protected, as it can be with the Boc protecting group and subsequently the alcohol is converted to the corresponding tosylate, such as the treatment with TosCl in Et3N and DCM, to produce 1-6. The Boc protective group of 1-6 is removed, as can be by TFA, to produce 1-7. 1-7 is treated with base, such as K2C03 in 20% aqueous 2-propanol, to obtain 1-8. 1-8 is converted to IIIb-A in one or more steps, such as by reductive alkylation by ketones or aldehydes, or alkylation by alkyl halides. IIIb-A can be converted through one or more reactions in another Illb with appropriate RAr. The chloride of 1-8 can also be converted through the known reactions to another appropriate RAr, and further converted to appropriate Illb, through alkylation. Specific examples of the reactions and conditions that convert IIIb-A to Illb are provided herein below.

A compound of formula (Illb) can also be prepared following Scheme 3. 4-bromo-l-fluoro-2-nitrobenzene (1-9) is treated with 2-aminoethanol in n-butanol to produce 2- (4-bromo) -2-nitrophenyloamino) ethanol (1-10). 1-10 is reduced, as can be with hydrazine / Raney Nickel to provide the corresponding aniline 1-11. 1-11 is coupled with 3- (tert-butoxycarbonylamino) propane acid to produce amide 1-12. 1-12 is treated with acid, such as HOAc, and cyclized to produce benzimidazole 1-13. The alcohol of 1-13 is converted to the corresponding tosylate, by treatment with TosCl in Et3N and DCM, to produce 1-14. The Boc protecting group of 1-14 is removed, as can be by TFA, to produce 1-15. 1-15 is treated with base, such as K2C03 in 20% aqueous 2-propanol to produce 1-16. 1-16 becomes IIIb-B in one or more steps, as it may be by reductive alkylation by ketones or aldehydes, or alkylation by alkyl halides. IIIb-B can be converted by one or more reactions of IIIb with appropriate RAR. The 1-16 bromide can also be converted through known reactions to another appropriate RAr, and further converted to the appropriate Illb, as it could be by alkylation. Specific examples of the reactions and conditions that convert III-B to Illb are provided herein below.

Scheme 3 In one embodiment, a compound of the formula (Illa) can be prepared following Scheme 4. The 4-bromo-2-fluoro-l-nitrobenzene (1-19) is treated with 2-aminoethanol in n-butanol to produce 1 -twenty. 1-20 is reduced, as can be with hydrazine / Raney Nickel to provide the corresponding aniline 1-21. 1-21 copulates with 3- (tert-butoxycarbonylamino) -propanoic acid to produce the amide 1-22. 1-22 is treated with acid, such as HOAc, and cyclized to produce benzimidazole 1-23. The alcohol of 1-23 is converted to the corresponding tosylate, such as by treatment with TosCl in Et3N and DCM, to produce 1-24. The Boc protective group of 1-24 is removed, as can be by TFA, to produce 1-25. 1-25 is treated with base, such as K2C03 in 2- 20% aqueous propanol, to produce 1-26. 1-26 is converted to IIIa-A in one or more steps, such as by reductive alkylation by ketones or aldehydes or alkylation by alkyl halides. IIIa-A can be converted by one or more reactions to another Illa with appropriate RAR. The bromide of 1-26 can also be converted by the known reactions into another appropriate RAr, and furthermore converted into the appropriate Illa via the alkylation. Specific examples of the reactions and conditions that convert Illa-A to Illa are provided herein below.

In one embodiment, a compound of formula (V) can be prepared by following Scheme 5. Hydrazine Monoprotected with Boc (1-86) is treated with CbzCl to produce 1-87. 1-87 is treated with 1, 3-dibromopropane to produce 1-88, the Boc protecting group of which is removed by treatment with TFA to produce 1-89. 1-89 is treated with 3-chloropropanoyl chloride to produce 1-90, the Cbz protecting group which is removed by catalytic hydrogenation giving rise to 1-91 bicyclic. 1-91 is reduced, as can be with Raney nickel to provide the corresponding 1-92 lactam. 1-92 is converted to compound V-A in one or more steps, such as by reductive alkylation by ketones or aldehydes, or alkylation by alkyl halides. VA is coupled with l-bromo-4-chloro-2-nitrobenzene using catalytic palladium to obtain compound VB which is recovered to the corresponding aniline by treatment with excess elemental iron in acetic acid and the aniline intermediate is cyclized in situ to provide the VC compound. V-C can be converted by one or more reactions into another V with the appropriate RAr. The V-C chloride can also be converted by known reactions into another appropriate RAr, and also converted into the appropriate V, such as by alkylation. Specific examples of the reactions and the conditions which convert V-C to V are provided hereinafter.

Scheme 5: Cbi CBz í Cbz o ? G N TFA N, c, - ^ ci J Hj hNHBoc CtiHN-NKBcc "» G I-BS 1-87 1-88 -88 1-90 A compound of formula VII can be prepared following Scheme 6. The nitration of 5-bromopyridin-2-ol (1-99), as can be with concentrated H2SO4 and HN03, yield 1-100. 1-100 is chlorinated, as can be with P0C13, to produce 1-101. 1-101 is treated with 2-amino-ethanol to produce 1-102. 1-102 is reduced, as can be with hydrazine / Raney nickel to provide the corresponding aniline 1-103. 1-103 is coupled with 3- (tert-butoxycarbonylamino) -propanoic acid by two steps to produce amide 1-105. 1-105 is treated with acid, such as HOAc, and cyclized to produce benzimidazole I-106. The 1-106 ester is hydrolyzed with base, such as aqueous LiOH to obtain the 1-107 alcohol. The alcohol of 1-107 is converted into the corresponding tosylate, such as by treatment with TosCl in Et3N and DCM, for produce 1-108. The Boc protecting group of 1-108 is removed, as can be by TFA, to produce 1-109. 1-109 is treated with base, such as K2C03 in aqueous 2-propanol to produce 1-110. 1-110 becomes VI I-A in one or more steps, as it may be through reductive alkylation by ketones or aldehydes, or alkylation by alkyl halides. VI I-A can be converted by one or more reactions into another VII with the appropriate RAr. The 1-110 bromide can be converted through known reactions into another appropriate RAr and further converted to the appropriate VII, such as through alkylation. Specific examples of the reactions and conditions that convert VII-A to VII are provided herein below.

Scheme 6: 0 » D. Methods of treatment, prevention and / or management 1. Union to the histamine receptor In various embodiments, a method for attaching a compound provided herein to a histamine receptor, such as a histamine H3 receptor, is provided herein. The method consists in contacting the histamine receptor with a compound provided herein.

In other embodiments, a method for inhibiting the binding of a ligand of the histamine receptor to a histamine receptor, such as a histamine H3 receptor, is provided herein. The method consists in contacting the histamine receptor with a compound provided herein. In one embodiment, the ligand of the histamine receptor is an endogenous ligand. In another embodiment, the ligand is a drug molecule or other small molecule known to have binding affinity for the histamine receptor. In another embodiment, the histamine receptor ligand is a compound with a radioactive label, known to bind to the histamine receptor. In another embodiment, the ligand is an agonist, partial agonist, antagonist or inverse agonist of the histamine receptor.

In one embodiment, the inhibition of ligand binding is evaluated using an in vitro binding assay, such as those described herein. In another embodiment, the compound provided herein inhibits the average binding by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, approximately 80%, approximately 90%, approximately 95%, approximately 99% or more, compared to the vehicle. In one embodiment, the inhibition of the middle junction is dose dependent. 2. Inhibition of histamine receptor activity In some embodiments, a method for modulating (eg, inhibiting or increasing) the activity of a histamine receptor, such as a histamine H3 receptor, is provided herein. The method consists in contacting the histamine receptor, such as the histamine H3 receptor, with a compound provided herein, in vitro or in vivo. In one embodiment, the histamine receptor, such as the histamine H3 receptor, is contacted with a compound provided herein administered to an individual an effective therapeutic amount of the compound provided herein, or an acceptable pharmaceutical salt or solvate thereof. The individual can be a human. In another embodiment, the histamine receptor is the histamine H3 receptor.

In other embodiments, the compound provided herein inhibits or decreases the activity of a histamine receptor, such as the histamine H3 receptor. The inhibition of histamine receptor activity can be measured using assays known in the art. In some embodiments, the activity of a histamine receptor is inhibited or decreased by about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70 %, about 80%, about 90%, about 95%, about 99% or more, compared to the activity that is obtained without contacting it with the compounds provided herein. In one embodiment, the inhibition or decrease in receptor activity depends on the dose. Exemplary assay methods may be, but are not limited to, in vitro functional assays. In one modality, the trial functional uses expression in an appropriate cleft line of a desired histamine receptor. In other embodiments, the functional assay uses synaptosomes isolated from brain tissue of an appropriate organism. In other embodiments, the inhibition of histamine receptor activity can be assessed using receptor binding experiments known in the art, e.g. eg, using appropriate membrane preparations. In one embodiment, the assay consists of treating an experimental subject (eg, a rat) with a compound provided herein as well as a reference compound, followed by isolation of brain tissue and ex vivo analysis of the occupation of the receiver.

In certain embodiments, methods for inhibiting or decreasing the activity of a histamine receptor, e.g. eg, the H3 receptor, in an individual (eg, a human) which consists in administering to the individual an effective amount of a compound provided herein. In some embodiments, the activity of the histamine receptor is inhibited or decreased by approximately 1%, approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 95%, approximately 99% or more, when measured using an assay described hereinabove.

In one embodiment, a method for inhibiting or decreasing the activity of a histamine receptor, such as the histamine H3 receptor, is provided by a ligand of the histamine receptor. In one embodiment, the method consists in contacting the histamine receptor with an antagonist or a reverse agonist of the histamine receptor. In another embodiment, an antagonist or a reverse agonist of the histamine receptor is a compound that is provided herein. 3. Modulation of histamine release In some embodiments, a method for inhibiting a histamine receptor to increase the release of histamine in a cell is provided herein. The method consists in contacting the cell with a compound provided herein. In one embodiment, the cell is a brain cell, such as a neuron or a glial cell. In one embodiment, the release of histamine occurs in vivo. So, in Certain embodiments are provided herein for methods for increasing the level of histamine release, which consist of administering to an individual (e.g., a human) an effective amount of a compound provided herein. In an organism, the release of histamine can occur, for example, at the synapse. Thus, in one embodiment, the neuronal cell is in contact with the synapse of a mammal. In another embodiment, histamine release occurs in vitro. In some embodiments, the cell can be a brain cell, such as a neuronal cell or a cell type that expresses a histamine receptor, such as a histamine H3 receptor.

The stimulation of histamine release can be demonstrated, for example, by making various functional assays in vitro using a cell type that expresses a certain type of histamine receptor, such as a histamine H3 receptor, together with a receptor ligand. of appropriately labeled histamine. In some embodiments, inhibition of the histamine receptor is demonstrated when an antagonist or inverse agonist (eg, a compound provided herein) has an IC50 of, for example, between about 0.1 nM and about 10 μ ?, between about 1 nM and about 1 μ ?, between about 1 nM and about 500 nM, and between about 1 nM and about 100 nM, in a functional assay of the histamine receptor, such as those described herein. 4. Treatment, prevention and / or management of disorders related to the H3 receptor In one embodiment, methods for the treatment, prevention and / or management of a disorder related to the histamine H3 receptor, such as a neurological disorder provided herein, are provided herein. In one embodiment, the uses of the compounds and compositions provided herein are provided for the manufacture of a medicament for the treatment, prevention and / or management of a disorder related to the histamine H3 receptor, such as a neurological disorder In one embodiment, compounds and compositions that are used in the treatment, prevention and / or management of a disorder related to the histamine H3 receptor, such as a neurological disorder provided herein, are provided herein.

In some embodiments, a method for the treatment, prevention and / or management of a disorder related to the histamine H3 receptor, such as a neurological disorder, is provided herein. Without being limited by a particular theory, the treatment, prevention and / or management is done by inhibiting or decreasing the activity of the histamine H3 receptor. The histamine H3 receptors modulate the release of neurotransmitters, such as, but not limited to, histamine, acetylcholine, norepinephrine and dopamine, involving a wide variety of therapeutic indications. See, p. ex. , Haas et al., Physio. Rev. 88: 1183-241 (2008); Brown et al, Prog. Neurobio. 63: 637-72 (2001); Esbenshade et al., Mol. Intervene 6 (2): 77-88 (2006); Esbenshade et al., British J. Pharmacol. 154 (6): 1166-81 (2008); Sander et al., Bio. Pharm. Bull. 21: 2163-81 (2008).

In one embodiment, the method consists in administering to an individual (e.g., a human) an effective therapeutic or prophylactic amount of a composition or compound provided herein. In one modality, the individual is a human. In another embodiment, the compound provided herein inhibits the activity of a histamine receptor. In In another embodiment, the compound provided herein inhibits the activity of the histamine H3 receptor. In certain embodiments, the compounds provided herein are inverse agonists of the histamine H3 receptor. In other embodiments, the compounds provided herein are antagonists of the histamine H3 receptors. In certain embodiments, the compounds provided herein are selective for the histamine H3 receptor on other targets related to the central nervous system (CNS). In one embodiment, the compounds provided herein are highly penetrable in the brain in animals such as rodents, and humans. In some embodiments, the inhibition of histamine receptor activity can be evaluated by functional assays as described herein elsewhere. In certain embodiments, the effective concentration of the compounds provided herein is less than 10 nM, less than 100 nM, less than 1 μ ?, less than 10 μ ?, less than 100 μ? or less than 1 mM. In other embodiments, the activity of the compound can be assessed in various animal models recognized in the art as described elsewhere herein.

In some embodiments, a method for the treatment, prevention and / or management of a disorder associated with excessive daytime sleepiness, such as narcolepsy, Parkinson's disease, multiple sclerosis, shift workers, schedule changes per flight, relief is provided herein. of side effects of other drugs and the like, which consists of administering to an individual an effective amount of a compound provided herein. For example, without being limited to a particular theory, antagonists or inverse H3 agonists may have weak promoter effects. See, p. e. , Lin et al., Br. Res. 523: 325-30 (1990); Barbier et al, Br. J. Pharm. 143: 649-61 (2004); Lin et al., Neurobiol. Dis. 30 (1): 74-83 (2008).

In another embodiment, a method for the treatment, prevention and / or management of a sleep disorder such as insomnia, which consists of administering to an individual an effective amount of a compound provided herein, is provided herein. For example, without being limited by a particular theory, Antagonists or inverse H3 agonists can improve alertness and lead to an improved sleep pattern, and therefore antagonists or inverse H3 agonists may be useful for treating insomnia.

In another embodiment, there is provided herein a method for the treatment, prevention and / or management of substance abuse, which comprises administering to an individual an effective amount of a compound provided herein. For example, without being limited by a particular theory, H3 antagonists can alter the self-administration of methamphetamine in rats, and therefore H3 antagonists can lessen the desire for addictive drugs. See, p. ex. , Munzar et al, Neuropsychopharmacology 29: 705-17 (2004).

In another embodiment, a method for treatment, prevention and / or management of a disorder related to cognitive impairments, impairment of learning, deterioration of memory and / or deterioration of attention, vigilance and / or speed of response is provided herein. , such as those associated with Alzheimer's disease, Parkinson's disease, schizophrenic and attention deficit hyperactivity disorder (ADHD), and the like, which consist in administering to an individual an effective amount of a compound provided herein . For example, without being limited by a particular theory, antagonists or inverse agonists of H3 can have pro-cognitive effects such as passive avoidance, recognition of novel objects, social recognition and changes in the fixation of attention. See, p. eg, Medhurst et al., JPET 321: 1032-45 (2007); Medhurst et al, Biochem. Pharmcol. 73: 1 182-94 (2007); Fox et al., JPET 313: 176-190 (2005); Fox et al., JPET 305: 897-908 (2003). Furthermore, without being limited by a particular theory, antagonists or inverse agonists of the H3 receptor can improve social memory, increase the acquisition of an environment and reverse the deficiencies induced by scopolamine. Antagonists or inverse H3 agonists can also reverse the deficiencies induced by scopolamine in a passive avoidance memory test.

In another embodiment, a method is provided herein for the treatment, prevention and / or management of a disorder related to psychosis, schizophrenia, ADHD, and / or mood disorders such as depression and / or anxiety, which consists of administering to an individual an effective amount of a compound provided herein. For example, without being limited by a particular theory, the agntagonists or inverse agonists of H3 they can improve gait deficiencies of DBA / 2 mice observed in the inhibition test by previous stimulation (PPI) and reverse hyperlocomotor activity induced by methamphetamine. See, p. eg, Fox et al, JPET 313: 176-190 (2005). Without being limited to a particular theory, antagonists or inverse H3 agonists can: 1) reverse the hyperlocomotor activity induced by amphetamine (see, eg, Clapham et al, Eur. J. Pharmacol. 259: 107-14 ( 1994)); 2) be useful as anti-psychotic agents and sparingly dosed (see, eg, Zhang et al., Br. Res. 1045: 142-49 (2005)); 3) improve attention and modulate impulsivity (See, eg, Day et al., Biochem Pharmacol 73: 1123-34 (2007)); 4) improve learning parameters in ADHD (See, eg, Fox et al., JPET 313: 176-90 (2005), Fox et al, JPET 305: 897-908 (2003), Fox et al, Behav, Br. Res. 131: 151-61 (2002), omater et al, Psychopharm 167: 363-72 (2003); Esbenshade et al, Biochem. Pharmacol. 68: 933-45 (2004)); 5) improve learning ability and reduce anxiety in behavior tests (See, e.g., Rizk et al, Eur. J. Neurosci. 19: 1992-96 (2004)); and 6) have an anti-depressant effect (See, eg, Perez-Garcia et al, Psychopharm, 142 (2): 215-20 (1999)).

In another embodiment, a method for using the compounds provided herein as psycho-stimulants, which may lack abuse responsibilities generally associated with other classes of psycho-stimulants, is provided. Without being limited by a particular theory, antagonists or inverse agonists of H3 increase the levels of histamine, dopamine, norepinephrine and acetylcholine in the prefrontal cortical area, which is consistent with their pro-cognitive effects and their effects promoting the state of alertness observed in animal models. For example, antagonists or inverse H3 agonists may increase dopamine in the frontal cortex but not in the striatum. Antagonists or inverse H3 agonists may not induce increased locomotor activity or sensitization that is associated with other psycho-stimuli. See, p. ex. , Komater et al, Psychopharm. 167: 363-72 (2003).

In another embodiment, a method for the treatment, prevention and / or management of a disorder such as convulsion (eg, epilepsy), convulsions, vertigo and pain, which consists of administering an effective amount to an individual is provided herein. of a compound provided herein. For example, without be limited by a particular theory, antagonists or inverse agonists of H3 can protect against convulsions induced by pentylenetetrazole (PTZ) and electrical. See, p. eg, Vohora et al., Life Sci. 22: 297-301 (2000); Vohora et al, Pharmacol. Biochem. Behav. 68 (4): 735-41 (2001); Zhang et al, Eur. J. Pharmacol. 15 (581): 169-75 (2003). Antagonists or inverse H3 agonists may increase the seizure threshold in humans. See, p. ex. , WO 2006/084833. Antagonists or inverse H3 agonists can decrease the electrical discharge of afferent neurons in a preparation of the inner ear. See, p. e j. , Chavez et al, Brain Res. 1064 (1-2): 1-9 (2005). In addition, the H3 receptors are located in neurons in the dorsal horn of the spinal cord, an important area for the transmission of nociceptive information in humans, and have shown efficacy in preclinical pain models. Thus, without being limited by a particular theory, antagonists or inverse agonists of the H3 receptor can increase the threshold of neuropathic pain which was demonstrated in models such as the chronic constriction injury (CCI) model, model induced by herpes virus and model of allodynia induced by capsaicin. See, p. eg, Medhurst et al, Pain 138: 61-69 (2008); Medhurst et al, Biochem. Pharmacol 73: 1182-94 (2007).

Thus, in some embodiments, the compounds provided herein are used for their analgesic effects to treat, prevent and / or manage disorders involving pain and the sensation that accompanies many of the neuropathic pain disorders.

In yet another embodiment, a method of treating, preventing and / or managing a disorder related to satiety, gastric activity, irritable bowel syndrome (IBS), chronic constipation (CC) and / or metabolic disorders such as diabetes and obesity, which consists in administering to an individual an effective amount of a compound provided herein. In other embodiments, a method for mitigating weight gain associated with other therapeutic compounds, which is to administer to an individual an effective amount of a compound provided herein, is provided herein. For example, without being limited to a particular theory, the H3 receptor plays a role in satiety. See, p. ex. , Masaki et al, Curr. Diabetes Rev. 3: 212-16 (2007); Ishizuka et al, Behav. Br. Res. 188: 250-54 (2008). Antagonists or inverse H3 agonists can decrease food intake, decrease weight gain, decrease concentrations of plasma triglycerides, modulate energy expenditure, decrease body weight and body fat and normalize insulin tolerance. See, p. e.g., Malmlof et al, Obesity 14: 2154-62 (2006); Hancock et al, Eur J. Pharm. 487: 183-97 (2004). Antagonists or inverse H3 agonists can also block the decrease in satiety induced by olanzepine. See, p. ex. , WO 2006/084833.

In another embodiment, a method for the treatment, prevention and / or management of a disorder of the enteric system and / or the exocrine pancreatic system, such as acid secretion, intestinal digestion and motility, which consists in administering to an individual an effective amount of a compound provided herein. See, p. eg, Breunig et al, J. Physiol. 583 (2): 731-42 (2007); Singh et al, Inflamm. Res. 46: 159-65 (1997); Bertaccini et al, Dig. Dis. ScL 40: 2052-63 (1995).

In another embodiment, a method for the treatment, prevention and / or management of movement disorders is provided herein, such as Parkinson's disease, Restless Legs Syndrome (RLS) and Huntington's Disease, which consists in administering to an individual an effective amount of a compound provided herein. For example, without being limited to a particular theory, an increased expression of H3 receptors has been found in the portem brain of individuals with Parkinson's disease. See, p. ex. , Anichtchik et al., Neurobiol. Dis. 8: 707-16 (2001); Anichtchik et al, Eur. J. Pharm. 12: 3823-32 (2000). In addition, it was reported that a polymorphism in the primary enzyme that metabolizes histamine in the brain, the Thrl05lle polymorphism, results in a functional alteration of the activity of the enzyme. This polymorphism has been associated with movement disorders such as Parkinson's disease and essential tremor. See, p. ex. , Preuss et al, JPET 53: 708-17 (1998); Agundez et al, Neuromol. Med. 10 (1): 10-16 (2008); Ledesma et al, Neuromol. Med. 10 (4): 356-61 (2008). Thus, antagonists or inverse H3 agonists may be useful for the treatment of Parkinson's disease. See, p. ex. , Gomez-Ramirez et al, Mov. Disord. 21: 839-46 (2006).

In some embodiments, the compounds provided herein are active in at least one model, which can be used to measure the activity of the compounds and estimate their effectiveness for the treatment of a neurological disorder. For example, when the model is for depression (eg, medium immobility), the compounds are active when they inhibit the average immobility of an individual to be tested at about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, when compared to the vehicle. In some embodiments, the compounds provided herein produce a similar disparity at the end point measured between treated animals and animals administered with the vehicle.

In other embodiments, a method for effecting a therapeutic effect as described elsewhere herein is provided. The method consists in administering to an individual (e.g., a mammal) an effective therapeutic amount of a compound or composition provided herein. The particular therapeutic effects can be measured using any model system known in the art and described herein, such as those in which an animal model of a disease is involved.

In some modalities, the neurological disorder is: depression (eg, major depressive disorder, bipolar disorder, unipolar disorder, dysthymia, and seasonal affective disorder); cognitive deficiencies; fibromyalgia; pain (eg, neuropathic pain); sleep-related disorders (eg, sleep apnea, insomnia, narcolepsy, cataplexy) including those sleep disorders that occur due to psychiatric conditions; Chronic Fatigue Syndrome; Attention deficit disorder (ADD); attention deficit hyperactivity disorder (ADHD); leg syndrome without rest; schizophrenia; anxieties (eg, general anxiety disorder, social anxiety disorder, panic disorders); obsessive-compulsive disorder; post-traumatic stress disorder; seasonal affective disorder (SAD); premenstrual dysphoria; post-menopausal vasomotor symptoms (eg, hot flushes, night sweats); neurodegenerative disease (eg, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis); manic states; dysthymic disorder; cyclothymic disorder; obesity; or substance abuse or dependence (eg, cocaine addiction, nicotine addiction). In another embodiment, the compounds provided herein are useful for treating, preventing and / or managing two or more states / disorders that are co-morbid, such as cognitive impairment and depression.

Neurological disorders include disorders of brain function, including without limitation, senile dementia, Alzheimer's type dementia, cognition, memory loss, amnesia / amnestic syndrome, epilepsy, consciousness disorders, coma, decreased attention, speech disorders , Lennox syndrome, autism and hyperkinetic syndrome.

Neuropathic pain includes, without limitation, post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy / causalgia or nerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheral neuropathy (such as diabetic neuropathy or neuropathy). arises from the chronic use of alcohol).

Other exemplary diseases and conditions that can be treated, prevented and / or managed using the methods, compounds and / or compositions provided herein may be, but are not limited to: obesity; migraine or migraine headache; urinary incontinence, which includes, without limitation, the involuntary emptying of urine, leakage or leakage of urine, urinary incontinence stress (SUI), urge incontinence, stress urinary incontinence, reflex incontinence, passive incontinence and overflow incontinence; and sexual dysfunction, in males or females, including, without limitation, sexual dysfunction caused by psychological and / or physiological factors, erectile dysfunction, premature ejaculation, vaginal dryness, absence of sexual arousal, inability to obtain orgasm and psycho-sexual dysfunction, which includes, without limitation, inhibited sexual desire, inhibited sexual arousal, inhibited female orgasm, inhibited male orgasm, functional dyspareunia, functional vaginismus and atypical psycho-sexual dysfunction.

In one modality, the neurological disorder is excessive daytime sleepiness. In another modality, the neurological disorder is cognitive deterioration. In another modality, the neurological disorder is mood disorders. In another modality, the neurological disorder is movement disorders. In another modality, the neurological disorder is schizophrenia. In another modality, the neurological disorder is attention disorder. In another modality, the neurological disorder is anxiety disorder. In another modality, the neurological disorder is convulsion. In another modality, the neurological disorder is epilepsy. In another modality, the neurological disorder is vertigo. In another modality, the neurological disorder is pain. In another modality, the neurological disorder is neuropathic pain. In another modality, neuropathic pain is diabetic neuropathy. In another modality, the neurological disorder is sleep disorders. In another modality, the neurological disorder is insomnia. In another modality, the neurological disorder is substance abuse.

In one embodiment, the neurological disorder is a neurodegenerative disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In another embodiment, the neurodegenerative disorder is Alzheimer's disease.

In one embodiment, the disorder is obesity and the effective therapeutic amount of the compound to be delivered to a patient is sufficient so that the patient feels satiated. In another modality, the disorder is diabetes. In another modality, the disorder is metabolic diseases. In another modality, the disorder is a disease that affects the enteric system.

In one embodiment, the compound described in the present invention prevents and / or manages a central nervous disorder, without causing addiction to the compounds.

Any suitable route of administration can be employed to provide the patient with an effective therapeutic or prophylactic dose of an active ingredient. For example, the oral, mucosal (eg, nasal, sublingual, buccal, rectal, vaginal), parenteral (eg, intravenous, intramuscular), transdermal and subcutaneous routes can be used. Exemplary routes of administration may be oral, transdermal and mucosal. The pharmaceutical forms suitable for such routes can be, but are not limited to, transdermal patches, ophthalmic solutions, sprays and aerosols. The transdermal compositions can also take the form of creams, lotions and / or emulsions, which can be included in a suitable adhesive for application to the skin or can be included in a transdermal patch of the matrix or deposit type as are traditional in the art. for this purpose. An exemplary transdermal dosage form is a "reservoir type" or "matrix type" patch, which is applied to the skin and used for a specific time to allow the penetration of a desired amount of the active ingredient. The patchNST it can be replaced by a new patch when necessary to provide cont administration of the active ingredient to the patient.

The amount that is to be administered to a patient to treat, prevent and / or manage the disorders described herein will depend on a variety of factors including the activity of the specific compound that is employed, or the ester, salt or amide thereof. , the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound used, age, sex , weight, condition, general health and previous medical history of the patient being treated and similar factors well known in the medical art.

A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the effective amount necessary. For example, the doctor or veterinarian could start with doses of the compounds used in concentrations lower than necessary to obtain the desired therapeutic effect and Gradually increase the dose until the desired effect is obtained.

In general, an appropriate daily dose of a compound provided herein will be that amount of the compound that is the lowest effective dose to produce a therapeutic or prophylactic effect. Such an effective dose will generally depend on the factors described above. In general, the oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds provided herein for a patient will range from about 0.005 mg per kilogram to about 5 mg per kilogram of body weight per day. In one embodiment, the oral dose of a compound that is provided herein will range from about 10 mg to about 300 mg per day. In another embodiment, the oral dose of a compound that is provided herein will comprise from about 20 mg to about 250 mg per day. In another embodiment, the oral dose of a compound that is provided herein will comprise from about 100 mg to about 300 mg per day. In another embodiment, the oral dose of a compound that is provided herein will range from about 10 mg to about 100 mg per day. In other embodiment, the oral dose of a compound that is provided herein will range from about 25 mg to about 50 mg per day. In another embodiment, the oral dose of a compound that is provided herein will range from about 50 mg to about 200 mg per day. Each of the aforementioned dose ranges can be formulated as single or multiple unit dose formulations.

In some embodiments, the compounds described herein may be used in combination with one or more second active compounds to treat, prevent and / or manage the disorders described herein. 5. Pharmaceutical compositions and pharmaceutical forms The pharmaceutical compositions may be used for the preparation of individual unit dosage forms, the pharmaceutical compositions and the dosage forms provided herein contain a compound provided herein, or an acceptable pharmaceutical salt, solvate, stereoisomer, clathrate or prodrug thereof. East. The compositions Pharmaceuticals and pharmaceutical forms may also contain one or more excipients.

The pharmaceutical compositions and dosage forms provided herein may also contain one or more additional active ingredients. Examples of the optional second or additional active ingredients are also described herein.

The simple unit dosage forms provided herein are suitable for oral, mucosal (eg, nasal, sublingual, vaginal, buccal or rectal), parenteral (eg, subcutaneous, intravenous, bolus injection) administration. , intramuscular or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient. Examples of pharmaceutical forms can be, but are not limited to: tabletsrness. ; caplets; capsules, such as soft elastic gelatin capsules; cachets; trociscos; dragees; dispersions; suppositories; powder; aerosols (eg, nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including the > suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, liquid water-in-oil emulsions), solutions and elixirs; liquid pharmaceutical forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, form and types of dosage forms will normally vary depending on their use. For example, a pharmaceutical form that is used for the acute treatment of a disease may contain larger amounts of one or more active ingredients than a pharmaceutical form that is used for the chronic treatment of the same disease. Likewise, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients that contains an oral dosage form used to treat the same disease. These and other forms in which the specific dosage forms are used will vary from one another and will be readily apparent to those skilled in the art. See, p. ex. , Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

In one embodiment, the pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of the appropriate excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art such as, but not limited to, the manner in which the dosage form will be administered to a patient. For example, oral pharmaceutical forms as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a specific excipient may also depend on the specific active ingredients in the pharmaceutical form. For example, the decomposition of some active ingredients can be accelerated with some excipients such as lactose, or when exposed to water. Active ingredients containing primary or secondary amines are particularly susceptible to such accelerated decomposition. As a result, the pharmaceutical compositions and dosage forms that contain little, if any, amount of lactose other mono- or disaccharides [sic]. As used herein, the term "lactose free" means that the amount of lactose present, if any, is insufficient to significantly increase the rate of degradation of an active ingredient.

The lactose-free compositions may contain excipients that are well known in the art and are listed, for example, in the United States Pharmacopeia (USP) 25-NF20 (2002). In general, the lactose-free compositions contain active ingredient, a binder / diluent and a lubricant in compatible and acceptable pharmaceutical amounts. In one embodiment, the lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate.

Anhydrous pharmaceutical compositions and pharmaceutical forms containing the active ingredients are also provided, since water can facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in the pharmaceutical art as a means of simulate the storage for a long time to determine the characteristics such as shelf life or stability of the formulations over time. See, p. eg, Jens T. Carstensen, Drug Stability: Principies & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water in a formulation can be of great importance since moisture and / or hydration are commonly encountered during the manufacture, handling, packaging, storage, shipping and use of the formulations.

The pharmaceutical compositions and anhydrous dosage forms can be prepared using anhydrous or low moisture ingredients and conditions of low hydration or low humidity. Pharmaceutical compositions and pharmaceutical forms containing lactose and at least one active ingredient containing a primary or secondary amine are preferably anhydrous if considerable contact with moisture and / or hydration is expected during manufacture, packaging and / or storage.

An anhydrous pharmaceutical composition must be prepared and stored in a manner that maintains its nature anhydrous Accordingly, in one embodiment, the anhydrous compositions are packaged using known materials to prevent exposure to water so that they can be included in appropriate formulation kits. Examples of suitable containers may be, but are not limited to, hermetically sealed foils, plastics, unit dose containers (eg, vials), blister or blister packs and strip containers.

Also provided herein are pharmaceutical compositions and dosage forms that contain one or more compounds that slow down the rate at which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers", may be, but are not limited to, antioxidants such as ascorbic acid, buffer solutions or saline buffer solutions.

Like the amounts and types of excipients, the specific amounts and types of active ingredient in a pharmaceutical form may differ depending on factors such as, but not limited to, the route by which it will be administered to patients. In one embodiment, the pharmaceutical forms contain a compound provided herein in an amount from about 0.10 to about 500 mg. In other embodiments, the dosage forms contain a compound provided herein in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250 , 300, 350, 400, 450 or 500 mg.

In other embodiments, the dosage forms contain the second active ingredient in an amount from 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. Of course, the specific amount of the second active agent will depend on the specific agent being used, the diseases or disorders being treated or handled and the amount (s) of a compound provided herein, and any optional active compound , additional that is administered at the same time to the patient. 5. 1 Oral pharmaceutical forms Pharmaceutical compositions that are suitable for oral administration may be provided as small dosage forms, as they may be, but not limited to, tablets (eg, chewable tablets), caplets, capsules and liquids (eg, flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and can be prepared by pharmacy methods well known to those skilled in the art. See, generally, Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

The oral dosage forms provided herein are prepared by combining the active ingredients in an intimate mixture with at least one excipient according to the techniques of the conventional pharmaceutical composition. The excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms may contain, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules and caplets) can be, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents.

In one embodiment, the oral dosage forms are tablets or capsules, in which case solid excipients are used. In another embodiment, the tablets may be coated by standard aqueous or non-aqueous techniques. Such pharmaceutical forms can be prepared by any of the methods of the pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredients with liquid carriers, finely divided solid carriers or both, and then shaping the product into the desired presentation, if necessary.

For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. The molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of the excipients that may be used for the oral dosage forms provided herein may be, but are not limited to, binders, diluents, disintegrators and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose , (eg, Nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof.

Suitable forms of microcrystalline cellulose can be, but are not limited to, materials marketed as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viseose Division, Avicel Sales, Marcus Hook, PA), and mixtures of these. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose marketed as AVICEL RC-581. The Suitable anhydrous or low moisture additives or additives can be AVICEL-PH-103 ™ and Starch 1500 LM.

Examples of suitable diluents for use in the pharmaceutical compositions and dosage forms provided herein may be, but are not limited to, talc, calcium carbonate (eg, in granules or powder), microcrystalline cellulose, cellulose powder, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch and mixtures thereof. The binder or diluent of the compositions of the invention, in one embodiment, is present in an amount of from about 50 to about 99 by weight of the pharmaceutical composition or dosage form.

The disintegrants can be used in the compositions to provide tablets that disintegrate when exposed to an aqueous medium. Tablets that contain too much disintegrant may disintegrate during storage, while those that contain too little may not disintegrate at the desired rate or under the desired conditions. So, a sufficient amount of disintegrant that is not too much or too little to alter in a harmful way the release of the active ingredients can be used to form the solid oral dosage forms. The amount of disintegrant that is used varies based on the type of formulation, and can be easily ascertained for those skilled in the art. In one embodiment, the pharmaceutical compositions contain from about 0.5 to about 15 weight percent of the disintegrant, or from about 1 to about 5 weight percent of the disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosage forms can be, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algin, other celluloses, gums and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosage forms can be, but are not limited to, calcium stearate, magnesium stearate, mineral oil, mineral oil light, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium laurel sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil , olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar and mixtures thereof. Additional lubricants may be, for example, a siloid silica gel (AEROSIL200, manufactured by the R. Grace Co. of Baltimore, MD), a synthetic silica coagulated aerosol (marketed by Degussa Co. of Plano, TX), CAB -O-SIL (a pyrogenic silicon dioxide product marketed by Cabot Co. of Boston, MA), and mixtures thereof. If used, the lubricants can be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms in which they are incorporated.

In one embodiment, a solid oral dosage form contains a compound provided herein, and optional excipients such as anhydrous lactose, microcrystalline cellulose, polyvinyl pyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin. 5. 2 Controlled release pharmaceutical forms The active ingredients that are provided herein may be administered by controlled release means or by delivery devices that are well known to those skilled in the art. Examples may be, but are not limited to, those described in U.S. Pat. Nos .: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such pharmaceutical forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose [sic], other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres. or a combination of these to provide the desired release profile in different proportions. Appropriate controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active compounds provided herein. In one embodiment, unit dosage forms are provided simple ones suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps and caplets that are adapted for controlled release.

In one embodiment, controlled release pharmaceuticals improve medicinal therapy over that obtained by their uncontrolled counterparts. In another embodiment, the use of a controlled release preparation in medical treatment is characterized by a minimum of active substance used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations can be extended drug activity, reduced frequency of the dose and increase in patient compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug and can thus affect the presence of side effects (eg, adverse).

In another embodiment, the controlled release formulations are designed to initially release an amount of drug (active ingredient) that readily produces the desired therapeutic or prophylactic effect, and little by little and continuously release the other amounts of drug to maintain this level of therapeutic or prophylactic effect for a prolonged period of time. In one embodiment, to maintain the constant level of drug in the body, the drug can be released from the dosage form at a rate that will replace the amount of drug metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various states including, but not limited to, pH, temperature, enzymes, water or other physiological or compound states. 5. 3 Parenteral pharmaceutical forms Parenteral dosage forms can be administered to patients by various routes that may be, but are not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intra-arterial. In some embodiments, the administration of a parenteral dosage form derives the patient's natural defenses against contaminants, and thus, in these embodiments, the parenteral dosage forms are sterile or can be sterilized before being administered to a patient. Examples of parenteral dosage forms may be, but not they are limited to ready-to-inject solutions, dry products ready to be dissolved or suspended in an acceptable pharmaceutical vehicle for injection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples may be, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, sodium chloride injection, ringer's injection, dextrose injection, dextrose and sodium chloride injection and lactated Ringer's Injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients described herein may also be incorporated into parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility of a compound that is provided herein. See, p. e.g., U.S. Pat. No. 5,134,127, which is incorporated herein by reference. 5. 4 Topical and mucosal pharmaceutical forms The topical and mucosal dosage forms provided herein may be, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations or other forms known to one skilled in the art. See, p. Remington's Pharmaceutical Sciences, 16th and 18th eds. , Mack Publishing, Easton PA (1980 &1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed. , Read & Febiger, Philadelphia (1985). Appropriate pharmaceutical forms for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide the topical and mucosal dosage forms comprised herein are well known to those skilled in the pharmaceutical art, and depend on the specific tissue to which a certain composition or pharmaceutical form will be applied. In one modality, the excipients can be, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butan-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures of these to form solutions, emulsions or gels, which are non-toxic and accepted for pharmaceutical use. Humidifiers or humectants can also be added to the compositions and dosage forms. Examples of the additional ingredients are well known in the art. See, p. ex. , Remingtoh's Pharmaceutical Sciences, 16th and 18th eds. , Mack Publishing, Easton PA (1980 &; 1990).

The pH of a composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Likewise, the polarity of a solvent carrier, its ionic concentration or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to the compositions or dosage forms to alter the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In other embodiments, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, or as a delivery enhancing compound. or speaker of penetration. In other embodiments, the salts, solvates, prodrugs, clathrates or stereoisomers of the active ingredients can be used to further adjust the properties of the resulting composition. 6. Kits In one embodiment, the active ingredients that are provided herein are not administered to a patient at the same time or by the same route of administration. In another embodiment, kits are provided that can simplify the administration of the appropriate amounts of the active ingredients.

In one embodiment, a kit contains a pharmaceutical form of a compound provided herein. The kits may also contain one or more second active ingredients as described herein or a pharmacologically active mutant or derivative thereof, or a combination thereof.

In other embodiments, the kits may also contain devices that are used to administer the active ingredients. Examples of such devices may be, but are not limited to, syringes, drip bags, patches and inhalers.

The kits may also contain cells or blood for transplantation as well as vehicles accepted for pharmaceutical use which may be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may contain a sealed container of an appropriate vehicle in which the active ingredient can be dissolved to form a sterile, particle-free solution. that is appropriate for parenteral administration. Examples of vehicles accepted for pharmaceutical use may be, but are not limited to: Water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection and Ringer-lactate injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

V. EXAMPLES Certain modalities are illustrated by the following non-limiting examples.

A. Synthesis of the Compounds In the following examples, unless otherwise indicated, all temperatures are set in degrees Celsius and all parts and percentages are by weight. Reagents can be purchased from commercial suppliers, such as Sigma-Aldrich Chemical Company, and can be used without purification unless otherwise indicated. The reagents can also be prepared following the standard procedures of the literature, known to those skilled in the art. Solvents can be purchased from Aldrich in Sure-Seal bottles and used as received. All solvents can be purified using standard methods known to the person skilled in the art, unless otherwise indicated.

The reactions set forth below were generally made at room temperature, unless otherwise indicated. The reaction flasks were adapted with rubber plugs for the introduction of sustsancias and reagents through a syringe Analytical thin layer chromatography (TLC) was done using plates previously coated with silica gel, with glass support (Merck Art. 5719) and eluted with adequate proportions of solvents (v / v). The reactions were assayed by TLC or LCMS, and were terminated as judged by the consumption of the starting material. The observation of the TLC plates was done with UV light (wavelength 254) or with a solvent to visualize the appropriate TLC, such as a basic aqueous solution, activated with KMn04. Flash column chromatography (See, e.g., Still et al., J. Org. Chem., 43: 2923 (1978)) was made using silica gel 60 (Merck Art. 9385) or various MPLC systems.

The structures of the compound of the following examples were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy, mass spectroscopy, elemental macroanalysis and melting point. The proton magnetic resonance spectra (1H-NMR) were determined using an NMR spectrometer operating at a certain field strength. Chemical shifts are reported in parts per million (ppm, d) to the lowest field of an internal standard, such as TMS.

Otherwise, the ^ -NMR spectra were referenced to residual proton signals in deuterated solvents as follows: CDC13 = 7.25 ppm; DMSO-d6 = 2.49 ppm; C6D6 = 7.16 ppm; CD3OD = 3.30 ppm. The multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, triplet double; q, quartet; br, expanded; and m, multiplet. Coupling constants are given in Hertz (Hz). The mass spectral (MS) data were obtained using a mass spectrometer with APCI or ESI ionization. 1. Compound 1: (3-cyclobutyl-9- (4- (aminomethyl) phenyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a-J-benzimidazole] A solution of CoCl2.6H20 (48 mg, 0.2 mmol), compound 2 (68 mg, 0.2 mmol) in a mixture of THF and H20 (10 mL and 5 mL) was stirred at 0 ° C and two drops of acetic acid were added. . The reaction mixture was stirred for 10 minutes and solid NaBH4 (24 mg, 0.6 mmol) was added. The reaction mixture was stirred for 2 hours and an aqueous solution of ammonia (2 mL) was added. The The reaction mixture was filtered and the filtrate was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative HPLC to give compound 1 as a white solid (15 mg, 22%). 1H-NMR (500MHz, CD3OD), d 7.77 (m, 1H), 7.62-7.63 (m, 2H), 7.48-7.54 (m, 2H), 7.42-7.43 (m, 2H), 4.35 (t, 2H, J = 5.0Hz), 3.87 (s, 2H), 3.20 ~ 3.23 (m, 2H), 2.95-3.01 (m, 1H), 2.62-2.69 (m, 4H), 2.14 ~ 2.16 (m, 2H), 1.92 -1.96 (m, 2H), 1.70-7.74 (m, 2H). MS (ESI: m / z 347 (M + H +). 2. Compound 2: (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) A flask was charged with a hexane solution of tri-t-butylphosphine (610 mg, 0.3 mmol) and evacuated to remove the hexane. The flask was refilled with argon and 8 (275 mg, 1.0 mmol), 4-cyanophenylboronic acid (221 mg, 1.5 mmol), Pd2 (dba) 3 (970 mg, 0.1 mmol) and anhydrous KF (203 mg) were added. 3.5 mmol). 1,4-dioxane (5 mL, freshly distilled sodium) was added and the reaction flask was filled with argon (2x repeated). The The reaction mixture was refluxed for 16 hours and diluted with ethyl acetate. The organic layer was collected, the solids were removed by filtration and the filtrate was purified by preparative TLC or preparative HPLC to give 2 as a white solid (55 mg, 16%). : H-NMR (400MHz, Acetone-d6): d 8.04 (s, lH), 7.71-7.85 (m, 6H), 4.96 (t, 2H, J = 4.4Hz), 3.50-3.82 (m, 7H), 2.48-2.54 (m, 2H), 2.24-2.30 (m, 2H), 1.59-1.74 (m, 2H). MS (ESI): m / z 343 (M + H +). 3. Compound 3: (N- (4- (3- (1-cyclopropylethyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) phenyl acetamide) This compound was prepared in 7% yield as described for compound 2 but using 4-acetamidophenylboronic acid as the starting material. 1H-NMR (500MHz, CDC13), d 7.87 (s, lH), 7.56-7.60 (m, 4H), 7.46-7.48 (m, 1H), 7.26-7.34 (m, 2H), 4.27 (m, 2H) , 3.28 (m, 2H), 2.93-2.96 (m, 1H), 2.63-2.64 (m, 4H), 2.21 (s, 3H), 2.11-2.16 (m, 2H), 1.91-1.94 (m, 2H) 1.64-1.70 (m, 2H.MS (ESI): m / z (375 M + H +). 4. Compound 4: (3-cyclobutyl-9- (1H-indol-5-yl) -2, 3, 4, 5-tetrahydro-β- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 16% yield as described for compound 2 but using 1H-indol-5-ylboronic as the starting material. 1H-NMR (400MHz, DMSOd6): d 11.11 (s, 1H), 7.76 (d, 2H, J = 21.2Hz), 7.45 ~ 7.54 (m, 3H), 7.36 ~ 7.41 (m, 2H), 6.48 (d , 1H, J = 2.0Hz), 4.31 (t, 2H, J = 4.4Hz), 3.13 (m, 2H), 2.94 (m, 1H), 2.50 ~ 2.58 (m, 4H), 2.06-2.07 (m, 2H), 1.80 ~ 1.85 (m, 2H), 1.61 ~ 1.64 (m, 2H). MS (ESI): m / z 357 (M + H +). 5. Compound 5: (3- (l-cyclopropylethyl) -9- (4- (aminomethyl) phenyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 10% yield as described for compound 1 but using compound 6 as the starting material. 1H-NMR (500MHZ, CD3OD), d 7.78 (d, 1H, J = 1.5Hz), 7.63 ~ 7.65 (d, 2H, J = 8.0Hz), 7.53-7.55 (dd, 1H, Ji = 1.0Hz, J2 = 8.0Hz), 7.49 ~ 7.50 (d, 1H, J = 8.0Hz), 7.43 ~ 7.45 (d, 2H, J = 8.0Hz), 4.25 ~ 4.34 (m, 2H), 3.89 (s, 2H), 3.16 -3.21 (m, 2H), 2. 75 ~ 2.86 (m, 5H), 2.43 ~ 2.48 (m, 1H), 1.72-2.05 (m, 6H), 0.89 (d, 3H). MS (ESI): m / z375 (M + H +). 6. Compound 6: (4- (3- (1-cyclopropylethyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) This compound was prepared in 65% yield as described for compound 2 but using compound 11 and 4-cyanophenylboronic acid as the starting materials. 1H-NMR (400MHz, Acetone-d6), d 8.09 (s, 1H), 7.75-7.85 (m, 6H), 5.00 (t, 2H, J = 4.4Hz), 3.58-3.88 (m, 7H), 2.75 ~ 2.77 (m, 1H), 1.62-2.03 (m, 6H), 1.30 (d, 3H). MS (ESI): m / z 371 (M + H +). 7. Compound 7: (N- (4- (3- (1-cyclopropylethyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) phenyl acetamide) This compound was prepared in 12% yield as described for compound 2 but using compound 11 and 4-acetamidophenylboronic acid as the initial materials. 1H-NMR (500MHz, CDCI3), d 7.85 (d, 1H, J = 1.2Hz), 7.54-7.58 (m, 5H), 7.26-7.29 (m, 1H), 7.45 ~ 7.54 (m, 1H), 4.18 -4.22 (m, 2H), 3.20 ~ 3.23 (m, 2H), 2.70-2.87 (m, 5H), 2.37-2.39 (m, 1H), 2.21 (s, 3H), 1.63 ~ 2.01 (m, 6H) , 0.88 (d, 3H). MS (ESI): m / z 403 (M + H +). 8. Compound 8: (3-cyclobutyl-9-chloro-2,3,4,5-tetrahydro-1? - [1,4] diazepino [1,7-a] benzimidazole) To a solution of intermediate yield 1-8 (1.1 g, 5.0 mmol) in dichloromethane (30 mL) was added acetic acid (0.45 g, 7.5 mmol, 1.5 eq.) And the reaction mixture was stirred at room temperature for 5 hours. minutes Cyclobutanone (0.53 g, 7.5 mmol, 1.5 eq.) Was added and the reaction mixture was stirred for 20 minutes. Solid NaBH (OAc) 3 (1.6 g, 7.5 mmol, 1.5 eq.) Was added and the reaction mixture was stirred for 2 hours. The saturated aqueous solution of NaHCO 3 was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na 2 SC, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give compound 8 as a Pale yellow solid (1.3g, 95%). 1H-NMR (400MHz, CDCI3): d 7.66 (d, 1H, J = 1.6Hz), 7.21 (dd, 1H, Ji = 1.6Hz, J2 = 8.8Hz), 7.15 (d, 1H, J = 8.4Hz) , 4.21 (t, 2H, J = 4.8Hz), 3.24 (t, 2H, J = 4.8Hz), 2.93 (m, 1H), 2.59-2.65 (m, 4H), 2.09-2.13 (m, 2H), 1.89-1.91 (m, 2H), 1.65-1.76 (m, 2H). MS (ESI): m / z 276 (M + H +). 9. Compound 9: (N- (4- (3- (l-methylpiperidin-4-yl) -2,4,5,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9 -yl) phenyl) acetamide) This compound was prepared in 9% yield as described for compound 2 but using compound 14 and 4-acetamidophenylboronic acid as the starting materials. 1H-NMR (500MHz, CDC13), d 7.85 (d, 1H, J = 0.8Hz), 7.58 ~ 7.60 (m, 4H), 7.42-7.47 (m, 2H), 7.27-7.30 (m, 1H), 4.23 (t, 2H, J = 3.6Hz), 3.24 ~ 3.26 (m, 2H), 2.98-3.01 (m, 2H), 2.89-2.93 (m, 4H), 2.61 ~ 2.63 (m, 1H), 2.33 (s) , 3H), 2.21 (s, 3H), 2.01-2.07 (m, 3H), 1.73 ~ 7.76 (m, 3H). MS (ESI): m / z 418 (M + H +). 10. Compound 10: (3- (1-cyclopropylethyl) -9- (lH-indol-5-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole ) This compound was prepared in 18% yield as described for compound 2 but using compound 11 and lH-indol-5-ylboronic acid as the starting materials and tricyclohexylphosphine as the ligand. 1H-NMR (400MHz, CDC13), d 8.26 (s, 1H), 7.9 (d, 2H, J = 20.8Hz), 7.46-7.57 (m, 2H), 7.24-7.31 (m, 2H), 6.62 (t , IH, J = 2.0Hz), 4.22 (t, 2H, J = 4.4Hz), 3.23 (t, 2H, J = 7.2Hz), 2.70-2.89 (m, 5H), 2.37-2.40 (m, 1H), 1.55 ~ 1.91 (m, 6H), 0. 9 (d, 3H). MS (ESI): m / z 385 (M + H +).

II. Compound 11: (3- (1-cyclopropylethyl) -9-chloro-2,3,4,5-tetrahydro-lH- [1,4] diazepinof 1,7-a] benzimidazole) This compound was prepared in 64% yield as described for compound 8 but using 1-cyclopropyletanone as the starting material. 1H NMR (400MHz, CDC13): d 7.65 (d, 1H, J = 2.0Hz), 7.20 (dd, 1H, Ji, = 2.0, Hz J2 = 9.2Hz), 7.14 (d, 1H, J = 8.8Hz) , 4.14 (t, 2H, J = 7.2Hz), 3.17 (t, 2H, J = 7.2Hz), 2.68-2.85 (m, 5H), 2.35 (m, 1H), 1.67-2.00 (m, 6H), 0.9 (s, 3H). MS (ESI): m / z304 (M + H +). 12. Compound 12: (4- (3- (l-methyl-piperidin-4-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazol-9-yl) benzonitrile) This compound was prepared in 26% yield as described for compound 2 but using compound 14 and 4-cyanophenylboronic acid as the starting materials. 1H-NMR (400MHz, CDC13), d 7.90 (d, 1H, J = 1.6Hz), 7.73 (s, 4H), 7.49 (dd, 1H, J = 8.4Hz,. J2 = 1.6Hz), 7.35 (d, 1H, J = 8.4Hz), 4.25 (t, 2H, J = 4.4Hz), 3.26 (m, 2H), 2.90-2.97 (m, 6H), 2.30 (s, 3H), 1.99 (t, 2H, J = 9.6Hz), 1.67-1.77 (m, 4H). MS (ESI): m / z 386 (M + H +). 13. Compound 13: (3- (l-methylpiperidin-4-yl) -9- (lH-indol-5-yl) -2, 3, 4, 5-tetrahydro-1 H- [1,4] diazepine [1.7 -a] encimidazole) This compound was prepared in 13% yield as described for compound 2 but using compound 14 and lH-indol-5-ylboronic acid as the starting materials. 1 H-NMR (400MHz, CDC13), d 8.32 (s, 1H), 7.90 (d, 2H, J = 20.8Hz), 7.45-7.57 (m, 3H), 7. 24-7.32 (m, 2H), 6.62 (s, 1H), 4.24 (t, 2H, J = 4.4), 3.26 (t, 2H, J = 4.8Hz), 2.90-2.94 (m, 6H), 2.57 ~ 2.60 (m, 1H), 2.29 (s, 3H), 1.99 (t, 2H, J = 8.8Hz), 1.67-1.77 (m, 4H). S (ESI): m / z400 (M + H +).

Compound 14: (3- (l-methyl-piperidin-4-yl) -9-chloro, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 79% yield as described for compound 8 but using 1-methylpiperidin-4-one as the starting material. 1H-NMR (400MHz, CDC13): d 7.65 (s, 1H), 7.14-7.21 (m, 2H), 4.18 (t, 2H, J = 4.0Hz), 3.22 (t, 2H, J = 4.8Hz), 2.96 ~ 2.99 (m, 2H), 2.88 ~ 2.92 (m, 4H), 2.57 ~ 2.62 (m, 1H), 2.30 (s, 3H), 1.99-2.04 (m, 2H), 1.69-1.74 (inf 4H) . MS ESI): m / z 319 (M + H +). 15. Compound 15: (3- (1H-imidazol-5-yl) methyl) -9-chloro-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole).

This compound was prepared in 40% yield as described for compound 8 but using 1H- imidazole-5-carbaldehyde as the starting material. 1H-NMR (400MHz, DMSOd6), d 11.97 (s, 1H), 7.53-7.57 (m, 3H), 7.21 (dd, 1H, Chi, = 2.0Hz, J2 = 8.8Hz), 6.93 (s, 1H) , 4.31 (t, 2H, J = 4.4Hz), 3.67 (s, 2H), 3.13 (t, 2H, J = 4.8Hz), 2.68 ~ 2.76 (m, 4H). S (ESI): m / z 302 (M + H +). 16. Compound 16: (3- (1-methylpiperidin-4-yl) -9- (4- (aminomethyl) phenyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] diazepino [1, 7 a] benzimidazole) This compound was prepared in 19% yield as described for compound 1 but using compound 12 as the starting material. XH-NMR (400MHz, CD30D) d 7.87 (s, 1H), 7.74-7.81 (m, 2H), 7.64 (d, 2H, J = 8.0), 7.45 (d, 2H, J = 8.4Hz), 4.67 ( t, 2H, J = 4.0Hz), 4.05 (s, 2H), 3.49 ~ 3.55 (m, 4H), 3.27 ~ 3.36 (m, 5H), 3.15 ~ 3.17 (m, 2H), 2.74 (s, 3H) , 1.94-2.10 (m, 4H). MS (ESI): m / z 390 (M + H +). 17. Compound 17: (3- (lH-imidazol-5-yl) -9- (4- (minomethyl) phenyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepinof 1,7-a ] benzimidazole) This compound was prepared in 18% yield as described for compound 1 but using compound 18 as the starting material. 1H-NMR (400MHz, CD30D) d 7.79 (s, 1H), 7.68 ~ 7.72 (m, 3H), 7.50 ~ 7.57 (m, 4H), 7.05 (d, 1H, J = 3.2Hz), 4.40 (t, 2H, J = 4.0Hz), 4.08 (s, 2H), 3.80 (s, 2H), 3.25 ~ 3.28 (m, 1H), 2.84-2.91 (m, 4H). MS (ESI): m / z 373 (M + H +). 18. Compound 18: (4- (3- (lH-imidazol-5-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepinof 1, 7-] benzimid zol-9-yl) benzonitrile ) Intermediate 1-8 was converted to intermediate 1-9 as described for compound 2 but using intermediate compound 1-8 as the starting material. Intermediate 1-9 was converted to 18 as described for compound 8 but using intermediate 1-9 and lH-imidazole-5-carbaldehyde as the starting materials. The total product was 78%. ^ - MR (400MHz, DMS0-d6): d 11.9 (s, 1H), 7.87 ~ 7.95 (m, 5H), 7.56-7.64 (m, 3H), 4.34 (m, 2H), 3.64 ~ 3.70 (m, 2H), 3. 12-3.19 (m, 2H), 2.69 ~ 2.76 (m, 4H). MS (ESI): m / z 369 (M + H +). 19. Compound 19: (N- (4- (3- (lH-imidazol-5-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9 - l) phenyl) acetamide) This compound was prepared in 15% yield as described for compound 18 but using 4-acetamidophenylboronic acid as the starting material. 1H-NR (500MHz, CD3OD), d 7.74 (s, 1H), 7.61 ~ 7.66 (m, 1H), 7.57-7.58 (m, 2H), 7.49-7.51 (m, 2H), 7.44-7.49 (m, 2H), 7.03 (s, 1H), 4.34 (t, 2H, J = 4.0Hz), 3.77 (s, 2H), 3.23 (t, 2H, J = 4.5Hz), 2.81 ~ 2.86 (m, 4H), 2.14 (s, 3H). MS (ESI): m / z 401 (M + H +). 20. Compound 20: (3- (lH-imidazol-5-yl) -9- (lH-indol-5-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1.7a ] benzimidazole) This compound was prepared in 22% yield as described for compound 18 but using lH-indol-5-ylboronic acid as the starting material. 1H-NMR (500MHz, CD3OD) d 7.67 (dd, H, J] = 1.5Hz, J2 = 4.5Hz), 7.56 (s, 1H), 7.45 (dd, 1H, Ji = 2.0Hz, J2 = 3.5Hz), 7.34 ( d, 2H, J = 8.5Hz), 7.29 (dd, 1H, J2 = 8.5Hz), 7.159 (d, 1H, J = 3.0Hz), 6.93 (s, 1H), 6.39 (s, 1H, J = 2.5Hz), 4.25 (t, 2H, J = 4.5Hz), 3.67 (s, 2H), 3.13-3.15 (m, 2H), 2.72-2.7 (m, 4H). MS (ESI): m / z 383 (M + H +). 21. Compound 21: (3-cyclobutyl-9-bromo-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 93% yield (3.8g) as described for compound 8 but using intermediate 1-16 as the starting material. MS (ESI): m / z 321 (M + H +). 22. Compound 22: (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) -2-fluorobenzonitrile) Intermediate 1-17 (100 mg), 4-bromo-2-fluorobenzonitrile (32 mg), Pd (dppf) Cl2 (15 mg) and sodium hydroxide were dissolved in DMF (3 mL) in a microwave tube that was filled with argon. The reaction mixture was stirred at 100 ° C for 30 minutes with microwave irradiation, diluted with ethyl acetate and filtered through a short plug of silica gel. The filtrate was washed with water, the combined organic layers were dried over Na 2 SO 4, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give 22 as a white powder (17 mg, 17%). ^ - R (400MHz, CDC13): d 7.89 (d, 1H, J = 1.2Hz), 7.66-7.65 (m, 1H), 7.51 (dd, 1H, J2 = 8.0Hz), 7.48-7.45 (m, 2H), 7.34 (d, 1H, J = 8.4Hz), 4.28 (t, 2H, J = 4.4Hz), 3.28 (t, 2H, J = 5.2Hz) , 2.96-2.92 (m, 1H), 2.65 (td, 4H, Ji = 4.4Hz, J2 = 16.0Hz), 2.15-2.12 (m, 2H), 1.95-1.90 (m, 2H), 1.77-1.65 (m , 2H). MS (ESI): m / z 361 (M + H +). 23. Compound 23: (3-cyclobutyl-9- (2-methoxypyrimidin-5-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 30% yield as described for compound 22 but using 5-bromo-2-methoxypyrimidine as the starting material. 1 H-NMR (400MHz, CDCl 3): d 8.68 (s, 2H), 7.74 (d, 1H, J = 1.2Hz), 7. 32-7.26 (m, 2H), 4.20 (m, 2H), 3.99 (s, 3H), 3.20 (m, 2H), 2. 87 (m, 1H), 2.61-2.54 (m, 4H), 2.07-2.03 (m, 2H), 1. 87 ~ 1.82 (m, 2H), 1.68-1.57 (m, 2H). MS (ESI): m / z 350 (M + H +). 24. Compound 24: (3-cyclobutyl-9- (pyrazin-2-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 28% yield as described for compound 22 but using 2-iodopyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 9.08 (d, 1H, J = 1.2Hz), 8.62 (s, 1H), 8.47 (d, 1H, J = 2.4Hz), 8.31 d, 1H, J = 1.2Hz ), 7.98 (dd, 1H, J! = 1.6Hz, J2 = 8.8Hz), 7.37 (d, 1H, J = 8.8Hz), 4.28 (m, 2H), 3.28 (m, 2H), 2.96 ~ 2.92 ( m, lH), 2.65 (m, 4H), 2.14-2.3 (m, 2H), 1.95 ~ 1.90 (m, 2H), 1.76 ~ 1.65 (m, 2H). MS (ESI): m / z 320 (M + H +). 25. Compound 25: (5- (3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) -nicotinonitrile) This compound was prepared in 18% yield as described for compound 22 but using 5-bromonicotinonitrile as the starting material. H-NMR (400MHz, CDC13): d 9.08 (d, 1H, J = 2.4Hz), 8.83 (d, 1H, J = 2.0Hz), 8.17 (t, 1H, J = 1.6Hz), 7.89 (d, 1H, J = 2.0Hz), 7.46-7.38 (m, 2H), 4.30 (m, 2H), 3.29 (m, 2H), 2.99 ~ 2.92 (m, 1H), 2.67 (m, 4H), 2.16 ~ 2.14 (m, 2H), 1.96 ~ 1.91 (m, 2H), 1.77 ~ 1.67 (m, 2H). MS (ESI): m / z 344 (M + H +). 26. Compound 26: (3-Cyclobutyl-9- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1.7 -a] benzimidazole) This compound was prepared in 28% yield as described for compound 22 but using 4-bromo-1,3,5-trimethyl-1H-pyrazole as the starting material. XH-NMR (400MHz, CDCI3): d 7.76 (s, 1H), 7.30 (s, 1H), 7.14 (dd, 1H, J! = 1.2Hz, J2 = 8.4Hz), 4.28 (m, 2H), 3.80 (s, 3H), 3.29 (m, 2H), 2.99-2.90 (m, 1H), 2.68 (m, 4H), 2.25 (s, 3H), 2.24 (s, 3H), 2.15 ~ 2.11 (m, 2H) ), 2.00-1.93 (m, 2H), 1.77-1.66 (m, 2H). MS (ESI): m / z 350 (M + H +). 27. Compound 27: (5- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) -picolinonitrile) This compound was prepared in 20% yield as described for compound 22 but using 5-bromopicolinonitrile as the starting material. ^ - MR (400MHz, CDC13): d 8.99 (d, 1H, J = 1.2Hz), 8.04 (dd, 1H, 7. 76 (d, lH, J = 8.0Hz), 7.49 (dd, 1H, Ji = 1.2Hz, J2 = 8.0Hz), 7.38 (d, lH, J = 8.8Hz), 4.29 (m, 2H), 3.29 ( m, 2H), 2.98 ~ 2.90 (m, lH), 2.66 (m, 4H), 2.15 ~ 2.13 (m, 2H), 1.95-1.90 (m, 2H), 1.79 ~ 1.75 (m, 2H). MS (ESI): m / z 344 (M + H +). 28. Compound 28: (3-cyclobutyl-9- (imidazo [1,2-a] pyridin-6-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] ] benzimidazole) This compound was prepared in 40% yield as described for compound 22 but using 6-bromoimidazo [1,2-a] pyridine as the starting material. 1 H-NMR (400MHz, CDCl 3): d 8.31 (m, 1H), 7.85 (d, 1H, J = I.6Hz), 7.69 ~ 7.64 (m, 3H), 7.49 ~ 7.42 (m, 2H), 7.33 ( dd, 1H, Ji = 0.4Hz, J2 = 8.0Hz), 4.27 (m, 2H), 3.27 (m, 2H), 2.99 ~ 2.90 (m, 1H), 2.65 (m, 4H), 2.14-2.12 (m, 2H), 1.94 ~ 1.90 (m, 2H), 1.76 ~ 1.66 (m, 2H). MS (ESI): m / z 359 (M + H +). 29. Compound 29: (3-cyclobutyl-9-imidazo [1,2- a] pyridin-8-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 20% yield as described for compound 22 but using 8-bromoimidazo [1,2-a] pyridine as the starting material. 1H-NMR (400MHz, CDC13): d 8.13-8.07 (m, 3H), 7.66 (dd, 2H, Ji = I.2Hz, J2 = 7.2Hz), 7.36 (d, 1H, J = 8.4Hz), 7.30 (dd, 1H, Ji = 1.2Hz, J2 = 6.8Hz), 6.88 (m, 1H), 4.27 (m, 2H), 3.27 (m, 2H), 2.96 ~ 2.91 (m, 1H), 2.66 ~ 2.60 ( m, 4H), 2.14 ~ 2.10 (m, 2H), 1.95 ~ 1.90 (m, 2H), 1.76-1.65 (m, 2H). MS (ESI): m / z 359 (M + H +). 30. Compound 30: (3-cyclobutyl-9- (1H-pyrazol-4-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 20% yield as described for compound 22 but using 4-bromo-l-tosyl-1H-pyrazole as the starting material. 1 H-NMR (400MHz, CDC13): d 7.89 ~ 7.82 (m, 2H), 7.43 (d, 1H, J = 7.6Hz), 7.26 ~ 7.24 (m, 3H), 4.26 (m, 2H), 3.28 (m , 2H), 2.97 ~ 2.94 (m, 1H), 2.70-2.65 (m, 4H), 2.17-2.11 (m, 2H), 1.97 ~ 1.91 (m, 2H), 1.78-1.66 (m, 2H). MS (ESI): m / z 308 (M + H +). 31. Compound 31: (3-cyclobutyl-9- (lH-pyrrolo [2, 3-b] pyridin-3-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepinof 1,7- a] benzimidazole) This compound was prepared in 20% yield as described for compound 22 but using 3-bromo-lH-pyrrolo [2, 3-b] pyridine as the starting material. ^ -NMR (400MHz, D20): d 8.75 (d, 1H, J = 4.0Hz), 8.29 (d, 1H, J = 2.8Hz), 7.94 (s, 1H), 7.85 ~ 7.80 (m, 3H), 7.51 ~ 7.48 (m, 1H), 3.86 ~ 3.81 (m, 1H), 3.72-3.55 (m, 6H), 2.35 ~ 2.22 (m, 4H), 1.82 ~ 1.69 (m, 2H). MS (ESI): m / z 358 (M + H +). XH-NMR was collected in the 3xHCl salt and signals for two overlapping protons with the H20 peak. 32. Compound 32: (4- (3-isopropyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-] benzimidazol-9-yl) benzonitrile) This compound was prepared in 91% yield (60 mg) as described for compound 18 but using acetone as the starting material. 1H-NMR (400MHz, D20): d 8.02 (s, 1H), 7.95 (m, 2H), 7.79 ~ 7.85 (m, 4H), 5.11 (m, 2H), 3.93 ~ 3.97 (m, 7H), 1.47 (d, 6H, J = 6.8Hz). MS (ESI): m / z 331 (M + H +). : H-NMR was collected in the 2xHCl salt of compound 32. 33. Compound 33: (4- (3-cyclopentyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) This compound was prepared in 96% yield as described for compound 18 but using cyclopentanone as the starting material. 1 H-NMR (400MHz, CDC13): d 7.91 (s, 1H), 7.72 (m, 4H), 7.50 (dd, 1H, J2 = 8.4Hz), 7.34 (d, 1H, J = 8.4Hz), 4.29 (m, 2H), 3.30 (m, 2H), 3.04 (m, 1H), 3.02 (m, 2H), 2.94 (m, 2H), 1.90-1.92 (m, 2H), 1.73 (m, 2H), 1.58-1.61 (m, 4H). MS (ESI): m / z 357 (M + H +). 34. Compound 34: (rac-cis / trans-4- (3- (3-methylcyclopentyl) -2, 3, 4, 5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole-9- il) benzonitrile) This compound was prepared in 92% yield as described for compound 18 but using (rac) -3-methylcyclopentanone as the starting material. 1H-NMR (400MHz, CDC13): d 7.91 (s, 1H), 7.72 (d, 4H, J = 8.4Hz), 7.48 (d, 1H, J = 8.0Hz), 7.34 (d, 1H, J = 8.4 Hz), 4.28 (m, 2H), 3.29 (m, 2H), 3.03-3.18 (m, 1H), 2.85 ~ 2.93 (m, 4H), 1.50 ~ 2.04 (m, 6H), 1.13 (m, 1H) , 1.00 ~ 1.04 (m, 3H). MS (ESI): m / z 371 (M + H +). 35. Compound 35: (rac-cis / trans-4- (3- (2-methylcyclopentyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9- i1) benzonitrile) This compound was prepared in 78% yield as described for compound 18 but using (rac) -2-methylcyclopentanones as the starting material. 1 H-NMR (400MHz, CDCl 3): d 7.90 (d, 1H, J = 1.6Hz), 7.72 (m, 4H), 7. 48 (dd, 1H, Ji = 1.6Hz, J2 = 8.4Hz), 7.34 (d, 1H, J = 8.4Hz), 4.29 (m, 2H), 3.30 (m, 2H), 2.78-2.94 (m, 5H) ), 2.25 (m, 1H), 1.47 ~ 1.92 (m, 6H), 0.92 (d, 3H, J = 7.2Hz). MS (ESI): m / z 371 (M + H +). 36. Compound 36: (4- (3-cyclohexyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) This compound was prepared in 93% yield as described for compound 18 but using cyclohexanone (as the starting material) 1 H-NMR (400MHz, CDC13): d 7.90 (s, 1H), 7.70 (s, 4H), 7.48 (dd, 1H, J2 = 8.8Hz), 7.34 (d, 1H, J = 8.4Hz), 4.25 (m, 2H), 3.26 (m, 2H), 2.94 (m, 2H), 2.90 (m, 2H), 2.59 (m, 1H), 1.81-1.85 (m, 4H), 1.64-1.67 (m, 1H), 1.22-1.32 (m, 4H), 1.07-1.13 (m, 1H). MS (ESI: m / z 371 (M + H +). 37. Compound 37: (cis / trans-4- (3- (4-methylcyclohexyl) -2,3,4, 5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazol-9-yl) benzonitrile) This compound was prepared in 78% yield as described for compound 18 but using 4-methylcyclohexanone as the starting material. 1H-NMR (400MHz, CDC13): d 7.91 (t, 1H, J = 0.8Hz), 7.72 (s, 4H), 7.47 (dd, 1H, J! = 0.8Hz, J2 = 8.4Hz), 7.34 (d , 1H, J = 8.4Hz), 4.24 (m, 2H), 3.26-3.28 (m, 2H), 2.92 ~ 3.00 (m, 4H), 2.58 (m, 1H), 1.78-1.88 (m, 3H), 1.53-1.58 (m, 5H), 1.30 ~ 1.34 (m, 1H), 0.88-0.99 (d, 3H, J = 6.4Hz). MS (ESI): m / z 385 (M + H +). 38. Compound 38: (4- (3- (tetrahydro-2H-pyran-4-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9- il) benzonitrile) This compound was prepared in 95% yield as described for compound 18 but using dihydro-2H-pyran-4 (3H) -one as the starting material. 1H-NMR (400MHz, CDC13): d 7.91 (s, 1H), 7.72 (s, 4H), 7.48 (d, 1H, J = 8.0Hz), 7.35 (d, 1H, J = 8.4Hz), 4.27 ( m, 2H), 4.06 (m, 2H), 3.37-3.43 (m, 2H), 3.28 (m, 2H), 2.92 ~ 2.98 (m, 4H), 2.82 ~ 2.85 (m, 1H), 1.62-1.72 ( m, 4H). MS (ESI): m / z 373 (M + H +). 39. Compound 39: (4- (3- (cyclopropylmethyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) Intermediate 1-18 (78 mg, 0.27 mmol) and (bromomethyl) cyclopropane (73 mg, 0.54 mmol, 2.0 eq.) Were dissolved in DIPEA (3 mL) and stirred at 100 ° C for 90 minutes. The reaction mixture was diluted with dichloromethane and washed with water. The combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 39 as a pale yellow solid (25 mg, 27%). 1H-NMR (400MHz, CDC13): d 7.92 (d, 1H, J = 0.8Hz), 7.72 (s, 4H), 7.49 (dd, 1H, J! = 1.2Hz, J2 = 8.4Hz), 7.34 (d , 1H, J = 8.8Hz), 4.32 (m, 2H), 3.32 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.56 (m, 2H), 0.93-0.95 (m, 1H), 0.56-0.61 (m, 2H), 0.14-0.17 (m, 2H). MS (ESI): m / z 343 (M + H +). 40. Compound 40: (3-cyclobutyl-8-bromo-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 93% yield (5.2 g) as described for compound 8 but with intermediate 1-26 as the starting material. 1H-NMR (400MHz, CDC13): d 7.54 (d, 1H, J = 8.4Hz), 7.40 (d, 1H, J = 1.6Hz), 7.31 (dd, 1H, 4. 18 (m, 2H), 3.22 (m, 2H), 2.90 ~ 2.94 (m, 1H), 2.59 ~ 2.64 (m, 4H), 2.09-2.13 (m, 2H), 1.88-1.93 (m, 2H) ), l.65-1.75 (m, 2H). MS (ESI): m / z 321 (M + H +). 41. Compound 41: (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-8-yl) benzonitrile) Compound 40 (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (93 mg, 0.6 5 mmol, 1.3 eq), Pd (dppf) C12 (37 mg, 0.05 mmol, 10 mol%) and K2C03 were dissolved in DMF (3 mL ) in a microwave tube that was filled with argon. The mixture was stirred at 100 ° C for 30 minutes with microwave irradiation. The reaction mixture was diluted with ethyl acetate, filtered through a short plug of silica gel and filtered It was washed with water. The combined organic layers were dried over magnesium sulfate. The solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 41 as a white powder (68 mg, 40%). 1 H-NMR (400MHz, CDCl 3): d 7.73-7.78 (m, 5H), 7.45-7.47 (m, 2H), 4.30 (m, 2H), 3.28 (m, 2H), 2.95 (m, 1H), 2.64 -2.69 (m, 4H), 2.13 ~ 2.15 (m, 2H), 1.88-1.95 (m, 2H), 1.66-1.83 (m, 2H). MS (ESI): m / z 343 (M + H +). 42. Compound 42: (N- (4- (3- (1-cyclopropylethyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-8-yl) phenyl acetamide) This compound was prepared in 32% yield as described for compound 41 but using 4-acetamidophenylboronic acid as the starting material. 1H-NMR (400MHz, CDC13): d 7.70 (d, 1H, J = 8.4Hz), 7.56 ~ 7.60 (m, 5H), 7.43 (dd, 1H, J! = 1.2Hz, J2 = 8.4Hz), 7.38 (s, 1H), 4.27 (m, 2H), 3.26 (m, 2H,), 2.92-2.95 (m, 1H), 2.66 (m, 2H), 2.62 (m, 2H), 2.20 (s, 3H) 2.10 ~ 2.16 (m, 2H), 1.90-1.97 (m, 2H), 1.65-1.76 (m, 2H). MS (ESI): m / z 375 (M + H +). 43. Compound 43: (3-cyclobutyl-8- (1H-indol-5-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 11% yield as described for compound 41 but using lH-indol-5-ylboronic acid as the starting material. 1H-NMR (400MHz, CDC13): d 8.48 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H, J = 8.8Hz), 7.54 (dd, 1H, Ji = 2.0Hz, J2 = 8.4 Hz), 7.44-7.50 (m, 3H), 7.24 ~ 7.26 (m, 1H), 6.60 ~ 6.61 (m, 1H), 4.29 (m, 2H), 3.26 (m, 2H), 2.93 (m, 1H) , 2.67 (m, 2H), 2.62 (m, 2H), 2.10-2.14 (m, 2H), 1.90-1.95 (m, 2H), 1.65-1.76 (m, 2H). MS (ESI): m / z 357 (M + H +). 44. Compound 44: (3-cyclobutyl-8- (4- (aminomethyl) phenyl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) To a solution of C0Cl2.6H2O (48 mg, 0.2 mmol) and compound 41 (54 mg, 0.16 mmol) in a 2: 1 mixture of THF and water (15 mL) was added solid NaBH4 (3.0 eq.) And the The reaction mixture was stirred for 1 hour. The The crude reaction mixture was filtered through a short plug of Celite, the filtrate was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 44 as a white solid (30 mg, 55%). ^ - MR (400MHz, CDCl3): d 7.73 (dr 1H, J = 8.0Hz), 7.60 (d, 2H, J = 8.4Hz), 7.46 (dd, 1H, Ji = 2.0Hz, J2 = 8.0Hz), 7.38-7.42 (m, 3H), 4.27 (m, 2H), 3.92 (s, 2H), 3.26 (m, 2H), 2.91-2.95 (m, 1H), 2.66 (m, 2H), 2.62 (m, 2H), 2.10-2.14 (m, 2H), 1.89-1.94 (m, 2H), 1.63-1.76 (m, 2H). MS (ESI): m / z 347 (M + H +). 45. Compound 45: (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-8-yl) -2-fluorobenzonitrile) This compound was prepared in 44% yield (35 mg) as described for compound 22 but using intermediate 1-27 as the starting material. ^ - MR (400MHz, CDC13): d 7.76-7.28 (m, 1H), 7.68 (m, 1H), 7.52 (dd, 1H, Jx = 1.6Hz, J2 = 8.0Hz), 7.48 (d, 1H, J = I.6Hz), 7.46 (m, 1H), 7.43 (s, 1H), 4.30 (m, 2H), 3.28 (m, 2H), 2.96 ~ 2.92 (m, 1H), 2.68 (m, 2H) , 2.64 (m, 2H), 2.15 ~ 2.11 (m, 2H), 1.95-1.89 (m, 2H), 1.76-1.66 (mf 2H). MS (ESI): m / z 361 (M + H +). 46. Compound 46: (5- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-8-yl) -nicotinonitrile) This compound was prepared in 31% yield as described for compound 45 but using 5-bromopicolinonitrile as the starting material. 1H-NMR (400MHz, CDC13): d 8.99 (d, 1H, J = 3.2Hz), 8.05 (dd, 1H, 7. 77 (d, 1H, J = 8.0Hz), 7.74 (m, 2H), 4.31 (m, 2H), 3.29 (m, 2H), 2.97 ~ 2.93 (m, 1H), 2.69 (m, 2H), 2.64 (m, 2H), 2.15 ~ 2.11 (m, 2H), 1.77 ~ 1.66 (m, 2H). MS (ESI): m / z 344 (M + H +). 47. Compound 47: (3-cyclobutyl-8- (imidazo [1,2-a] pyridin-6-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7a] benzimidazole ) This compound was prepared in 31% yield as described for compound 45 but using 6-bromoimidazo [1,2-a] pyridine as the starting material. 1 H-NMR (400MHz, CDC13): d 8.32 (s, 1H), 7.75 (m, 1H), 7.69 ~ 7.63 (m, 3H), 7.46 (d, 1H, J = 9.2Hz), 7.41-7.39 (m , 2H), 4.28 (m, 2H), 3.27 (m, 2H), 2.96 ~ 2.92 (m, 1H), 2.67 (m, 2H), 2.62 (m, 2H), 2.14 ~ 2.12 (m, 2H), 1.94 ~ 1.90 (m, 2H), 1.76 ~ 1.65 (m, 2H). MS (ESI): m / z 358 (M + H +). 48. Compound 48: (3-cyclobutyl-8- (pyrazin-2-yl) -2, 3, 4, 5-tetrahydro-β- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 20% yield as described for compound 45 but using 2-iodopyrazine as the starting material. ^ -NMR (400MHz, CDC13): d 9.03 (s, 1H), 8.56 ~ 8.55 (m, 1H), 8.42 (d, 1H, J = 2.4Hz) 7.96 (d, 1H, J = 1.2Hz), 7.77 ~ 7.71 (m, 2H), 4.27 (m, 2H), 3.22 (m, 2H), 2.80 ~ 2.77 (m, 1H), 2.62 ~ 2.56 (m, 4H), 2.08 ~ 2.04 (m, 2H), 1.89 -1.85 (m, 2H), 1.70-1.59 (m, 2H). MS (ESI): m / z 319 (M + H +). 49. Compound 49: (3-cyclobutyl-9- (1H-pyrazol-4-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepinof 1,7-a] benzimidazole) This compound was prepared in 30% yield as described for compound 45 but using 4-bromo-l-tosyl-1H-pyrazole as the starting material. 1H-NR (400MHz, d6-DMSO): d 12.87 (s, 1H), 7.97 ~ 8.14 (m, 2H), 7.74 (d, 1H, J = 0.8Hz), 7.47 (d, 1H, J = 8.4Hz ), 7.39 (dd, 1H, Ji = 1.2Hz, J2 = 8.0Hz), 4.30-4.32 (m, 2H), 3.09-3. ll (m, 2H), 2.93-2.97 (m, 1H), 2.50 ~ 2.59 (m, 4H), 2.05 ~ 2.07 (m, 2H), 1.80-1.85 (m, 2H), 1.61-1.66 (m, 2H) ). MS (ESI): m / z 308 (M + H +). 50. Compound 50: (6- (3-cyclobutyl-2, 3, 4, 5-tetrahydro-1H- [1,4] diazepinof 1,7-a] benzimidazol-9-yloxy) -N-methylnicotinamide) Intermediate 1-28 (60 mg), 6-chloro-N-methylnicotinamide (1.5 eq.) And uOK (1.5 eq.) Were dissolved in dry DMSO (1.0 mL) and stirred at 120 ° C for the entire night. The mixture was purified by preparative reverse phase HPLC to give compound 50 (30 mg, 33%). 1 H-NMR (400MHz, CDC13): d 8.53 (d, 1H, J = 2.0Hz), 8.10 (dd, 1H, J1 = 8.8Hz, J2 = 2.0Hz), 7.42 (s, 1H), 7.26 (d, 1H, J = 8.8Hz), 7.03 (d, 1H, J = 8.4Hz), 6.89 (d, 1H, J = 8.4Hz), 6.6 (brs, 1H), 4.23 (m, 2H), 3.22 (m, 2H), 2.98 (s, 3H), 2. 3-2.97 ( m, 1H), 2.65 (m, 2H), 2.60 (m, 2H), 2.12-2.14 (m, 2H), 1.89-1.94 (m, 2H), 1.68 ~ 1.76 (m, 2H). MS (ESI): m / z 392 (M + H +). 51. Compound 51: (3-cyclobutyl-9- (pyrazin-2-yloxy) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a-J-benzimidazole] This compound was prepared in 26% yield as described for compound 50 but using 2-iodopyrazine as the starting material. XH-NMR (400MHz, CDC13): d 8.43 (d, 1H, J = 1.2Hz), 8.23 (d, 1H, J = 2.8Hz), 8.07 (dd, 1H, J! = 1.6Hz, J2 = 2.8Hz) ), 7.48 (d, 1H, J = 2.0Hz), 7.27 (d, 1H, J = 8.8Hz), 7.06 (dd, 1H, Ji = 2.0Hz, J2 = 8.8Hz), 4.25 (m, 2H), 3.26 (m, 2H), 2.92-2.96 (m, 1H), 2.67 (m, 2H), 2.62 (m, 2H), 2.12-2.14 (m, 2H), 1.91-1.95 (m, 2H), 1.66- 1.77 (m, 2H). MS (ESI): m / z 336 (M + H +). 52. Compound 52: (6- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yloxy) -nicotinonitrile) Intermediate 1-28 (23 mg, 0.089 mmol), 6-chloronicotinonitrile (25 mg, 0.178 mmol) and cesium carbonate (58 mg, 0.0178 mmol) were dissolved in DMSO (5 mL) and stirred at room temperature for 60 minutes. The crude reaction mixture was purified by reverse phase preparative HPLC to give compound 52 as a pale yellow solid (20 mg, 62%). 1H-NMR (400MHz, CDC13): d 8.45 (d, 1H, J = 3.2Hz), 7.90 (dd, 1H, Ji = 2.4Hz, J2 = 9.2Hz), 7.45 (d, lH, J = 2.4Hz) , 7.29 (d, 1H, J = 8.4Hz), 7.01 ~ 7.05 (m, 2H), 4.25 (m, 2H), 3.26 (m, 2H), 2.92-2.96 (m, 1H), 2.66 (m, 2H) ), 2.62 (m, 2H), 2.11-2.15 (m, 2H), 1.89 ~ 1.94 (m, 2H), 1.64-1.76 (m, 2H). MS (ESI): m / z 360 (M + H +). 53. Compound 53: (4- ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yloxy) methyl) benzonitrile) ? ß 53 Intermediate 1-28 (70 mg), 4- (bromomethyl) benzonitrile (100 mg) and potassium carbonate (14 mg) were dissolved in butanol (5.0 mL) and stirred at room temperature for 60 minutes. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 53 as a pale yellow solid (12 mg, 11%). 1H-NMR (400MHz, CDC13): d 7.55 ~ 7.57 (m, 2H), 7.46 ~ 7.48 (m, 2H), 7.08 (d, 1H, J = 2.4Hz), 7.04 (d, 1H, J = 8.8Hz ), 6.85 (dd, 1H, J! = 2.4Hz, J2 = 8.8Hz), 5.07 (s, 2H), 4.10 (m, 2H), 3.12 (m, 2H), 2. 9-2.87 (m, 1H ), 2.54 (m, 2H), 2.50 (m, 2H), 2.01 ~ 2.04 (m, 2H), 1.80-1.84 (m, 2H), 1.55-1.66 (m, 2H). MS (ESI): m / z 373 (M + H +). 54. Compound 54: (3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole-9-carbonitrile) Compound 21 (1.0 g), Zn (CN) 2 (l.l eq.) And Pd (PPh3) 4 (catalytic, 10 mol%) were dissolved in DMF (8 mL) in a microwave tube which was filled with argon. The mixture was stirred at 120 ° C for 90 minutes with microwave irradiation. The reaction mixture was diluted with ethyl acetate and filtered through a short plug of silica gel. The filtrate was washed with water, the combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by chromatography to give compound 54 (670 mg, 85%). 1 -NMR (400MHz, CDC13): d 8.02 (d, 1H, J = 1.2Hz), 7.52 (dd, 1H, 4. 28 (m, 2H), 3.28-3.30 (m, 2H), 2.95 (m, 1H), 2.64-2.69 (m, 4H), 2.13-2.15 (m, 2H), 1.92-1.93 (m, 2H), 1.66-1.75 (m, 2H). MS (ESI): m / z 267 (M + H +). 55. Compound 55: (3-cyclobutyl-9- (4-phenylpiperidin-1-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 12% yield as described for intermediate 1-38 but using 4-phenylpiperidine as the starting material. ^ -NMR 400MHz, CDC13): d 7.30 (m, 5H), 7.22 (t, 1H, J = 7.1Hz), 7.15 (d, 1H, J = 8.8Hz), 7.06 (dd, 1H, Ji = 2.0Hz , J2 = 8.8Hz), 4.19 (d, 2H, J = 8.9Hz), 3.71 (d, 2H, J = 12.0Hz), 3.21 (d, 2H, J = 10.4Hz), 2.92 (m, 1H), 2.82 (m, 2H), 2. 58 ~ 2.64 (m, 5H), 2.12 (dd, 2H, Ji = 9.3Hz, J2 = 16.6Hz), 1.97-2.01 (m, 3H), 1.91 (t, 2H, J = 9.5Hz), 1.62-1.75 (m, 3H). MS (ESI): m / z 401 (M + H ÷). 56. Compound 56: ((3-Cyclobutyl-2,3,4,5-tetrahydro- [1,4] diazepino [1,7- a] benzimidazol-9-yl) (morpholino) -methanone) To a mixture of intermediate 1-40 (100 mg), HOBt (1.5 eq.), EDC (1.5 eq.) In dichloromethane was added triethylamine. The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane and washed with water. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 56 (10 mg, 8%). 1H-NMR (400MHz, CDC13): d 7.72 (s, 1H), 7.37 (dd, 1H, Ji = 2.0Hz, J2 = 8.4Hz), 7.30 (s, lH), 4.26 (m, 2H), 3.69- 3.71 (m, 8H), 3.25-3.28 (m, 2H), 2.94 (m, 1H), 2.66 (m, 2H), 2.63 (m, 2H), 2.12-2.14 (m, 2H), 1.89-1.95 ( m, 2H), 1.68 (m, 2H). MS (ESI): m / z 355 (M + H +). 57. Compound 57: (3-cyclobutyl-N, N-dimethyl-2,3,4,5-tetrahydro-β- [1,4] diazepino [1,7-a] benzimidazole-9-carboxamide) This compound was prepared in 21% yield as described for compound 56 but using dimethylamine as the starting material. 1H-NMR (400MHz, CDC13): d 7.74 (d, 1H, J = 1.2Hz), 7.38 (dd, 1H, Ji = 1.6Hz, J2 = 8.4Hz), 7.28 (s, 1H), 4.26 (m, 2H), 3.26 (m, 2H), 3.13 (m, 3H), 3.03 (m, 3H), 2.87-2.95 (m, 1H), 2.66 (m, 2H), 2.62 (m, 2H),, 2.10- 2.14 (m, 2H), 1.89 ~ 1.95 (m, 2H), 1.65-1.76 (m, 2H). MS (ESI): m / z 313 (M + H +). 58. Compound 58: ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) (4-methylpiperazin-1-yl) methanone ) This compound was prepared in 8% yield as described for compound 56 but using N-methylpiperazine as the starting material. 1 H-NMR (400MHz, CDCl 3): d 7.73 (d, 1H, J = 0.8Hz), 7.37 (dd, 1H, Ji = 1.6Hz, J2 = 8.8Hz), 7.29 (s, 1H), 4.25 (m, 2H), 3.5 ~ 3.8 (m, 4H), 3. 26 (m, 2H), 2.92-2.95 (m, 1H), 2.66 (111, 2H), 2.62 (m, 2H), 2.44 (m, 4H), 2.32 (s, 3H), 2.12-2.14 (m, 2H), 1.89-1.92 (m, 2H), 1.76-1.80 (m, 2H). MS (ESI): m / z 368 (M + H +). 59. Compound 59: ((3-cyclobutyl-2,3,4,5-tetrahydro- [1,4] diazepino [1,7- a] benzimidazol-9-yl) (piperidin-1-yl jmetanone) This compound was prepared in 23% yield as described for compound 56 but using piperidine as the starting material. 1 H-NMR (400MHz, CDC13): d 7.71 (s, 1H), 7.35 (d, 1H, J = 8.4Hz), 7.28 (d, 1H), 4.25 (m, 2H), 3.4-3.7 (m, 4H ), 3.26 (m, 2H), 2.93 (m, 1H), 2.65 (m, 2H), 2.62 (m, 2H), 2.12 ~ 2.14 (m, 2H), 1.89 ~ 1.94 (m, 2H), 1.58- 1.76 (m, 8H). MS (ESI): m / z 353 (M + H +). 60. Compound 60: ((3-cyclobutyl-2,3,4,5-tetrahydro- [1,4] diazepino [1,7- a] benzimidazol-9-yl) (pyrrolidin-1-yl) methanone) This compound was prepared in 16% yield as described for compound 56 but using pyrrolidine as the starting material. 1H-NMR (400MHz, CDC13): d 7.84 (d, 1H, J = 0.8Hz), 7.51 (dd, 1H, Ji = 1.2Hz, J2 = 8.4Hz), 7.26 (d, 1H, J = 8.4Hz), 4.25 (m, 2H ), 3.68 (m, 2H), 3.49 (m, 2H), 3.26 (m, 2H), 2.92-2.96 (m, 1H), 2.66 (m, 2H), 2.62 (m, 2H), 2.12-2.14 ( m, 2H), 1.68-1.97 (m, H). MS (ESI): m / z 339 (M + H +). 61. Compound 61: (3-cyclobutyl-N- (4-cyanophenyl) -2,3,4,5,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9-carboxamide) To a solution of 1-40 (80 mg) in methanol was added sulfuric acid (2 mL) and the reaction mixture was refluxed for 5 hours. The reaction mixture was basified and concentrated. The residue was diluted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated to yield intermediate 1-41 (77 mg, 92%).

A solution of 4-aminobenzonitrile (33 mg, 1.0 eq) in dichloromethane was cooled to 0 ° C, a toluene solution of Al (CH 3) 3 was added and the reaction was stirred for 15 minutes. A solution of 1-41 (77 mg) in dichloromethane is added and the reaction was stirred for 10 minutes. The reaction mixture was refluxed overnight. The aqueous solution of sodium hydroxide (0.3 mL) was added and the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 61 (15 mg, 15%). aH-NMR (400MHz, CDC13): d 8.66 (s, 1H), 8.25 (s, 1H), 7.86 ~ 7.89 (m, 3H), 7.66 (d, 1H, J = 8.4Hz), 7.35 (d, lH , J = 8.4Hz), 4.27 (m, 2H), 3.23 (m, 2H), 2.91-2.93 (m, 1H), 2.67 (m, 2H), 2.59 (m, 2H), 2.10-2.14 (m, 2H), 1.64-1.93 (m, 4H). MS (ESI): m / z 386 (M + H +). 62. Compound 62: (3-Cyclobutyl-N- (4-fluorobenzyl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazole-9-amine) A mixture of K2CO3 (86 mg), 1-30 (60 mg), and 1- (bromomethyl) -4-fluorobenzene (42 mg) in butan-2-one (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and diluted with acetate of ethyl and washed with water. The combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by chromatography to give compound 62 (35 mg, 41%). 1H-NMR (400MHz, CDC13): d 7.60 (d, 2H, J = 8.0Hz), 7.50 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 8.4Hz), 6.80 (d, 1H, J = 2.4Hz), 6.62 (dd, 1H, 4. 46 (s, 2H), 4.14 (m, 2H), 3.17 (m, 2H), 2.88-2.92 (m, lH), 2.61 (m, 2H), 2.57 (m, 2H), 2.08-2.12 (m, 2H), 1.87 ~ 1.92 (m, 2H), 1.64 ~ 1.74 (m, 2H). MS ESI): m / z 365 (M + H +). 63. Compound 63: (4- ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-ylamino) methyl) -benzonitrile) This compound was prepared in 34% yield as described for compound 62 but using 4- (bromomethyl) benzonitrile as the starting material. 1H-NMR (400MHz, CDC13): d 7.34-7.38 (m, 2H), 6.98 ~ 7.04 (m, 3H), 6.90 (d, 1H, J = 2.0Hz), 6.64 (dd, 1H, J1 = 2.0Hz , J2 = 8.8Hz), 4.33 (s, 2H), 4.15 (m, 2H), 3.19 (m, 2H), 2.89 ~ 2.93 (m, 1H), 2. 62 (m, 2H), 2.58 (m, 2H), 2.08-2.13 (m, 2H), 1.88-1.93 (m, 2H), 1.64 ~ 1.75 (m, 2H). MS (ESI): m / z 372 (M + H +). 64. Compound 64: (3-cyclobutyl-N- (4-methoxypyrimidin-2-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7a] benzimidazole-9-amine) Intermediate 1-30 (50 mg, 0.20 mmol), 2-chloro-4-methoxypyrimidine (56 mg, 0.39 mmol) and 4-methylbenzenesulfonic acid monohydrate (37 mg, 0.20 mmol) were dissolved in a 2: 1 mixture of dioxane and water (2.0 mL) and the reaction mixture was stirred at 120 ° C for 50 minutes with microwave irradiation. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 64 as a pale yellow solid (60mg, 85%). 1H-NMR (400MHz, CDCI3): d 8.10 (d, 1H, J = 5.6Hz), 8.05 (d, 1H, J = 2.0Hz), 7.35 (dd, 1H, Ji = 2.0Hz, J2 = 8.8Hz) , 7.30 (s, 1H), 7.18 (d, 1H, J = 8.8Hz), 6.16 (d, 1H, J = 5.6Hz), 4.22 (m, 2H), 3.97 (s, 3H), 3.24 (m, 2H), 2.93 (m, 1H), 2.64 (m, 2H), 2.60 (m, 2H), 2.11 ~ 2.14 (m, 2H), 1.88-1.91 (m, 2H), 1.65 -1.76 (m, 2H). MS (ESI): m / z 365 (M + H +). 65. Compound 65: (3-cyclobutyl-N- (pyrazin-2-yl) -2, 3, 4, 5-tetrahydro-β- [1,4] diazepino [1,7-a] benzimidazole-9-amine) Intermediate 1-30 (50 mg) and 2-chloro pyrazine were dissolved in DMF (3 mL) and the reaction mixture was stirred at 150 ° C for 1 hour with microwave irradiation. The crude reaction mixture was purified by chromatography to give compound 65 as a pale yellow solid (5 mg, 8%). 1H-NMR (400MHz, CDC13): d 8.15 (d, 1 ?, J = 2.0Hz), 8.06-8.07 (m, 1H), 7.94 (d, 1H, J = 2.8Hz), 7.70 (d, lH, J = 1.6Hz), 7.28 (dd, 1H, Ji = 2.0Hz, J2 = 8.4Hz), 7.24 (d, 1H, J = 8.4Hz), 6.62 (s, 1H), 4.26 (m, 2H), 3.27 (m, 2H), 2.92-3.01 (m, 1H), 2.69 (m, 2H), 2.64 (m, 2H), 2.11 ~ 2.20 (m, 2H), 1.90-1.98 (m, 2H), 1.69 ~ 1.77 (m, 2H). MS (ESI): m / z 335 (M + H +). 66. Compound 66: (3-cyclobutyl-9- (1H-imidazol-1-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) Compound 21 (100 mg), Cul (10% mol) and CsC03 (1.5 eq.) Were dissolved in NMP (0.5 mL) and the reaction flask was flushed with argon. The reaction mixture was stirred at 150 ° C overnight, diluted with dichloromethane and washed with water. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative reverse phase HPLC to give compound 66 (40 mg, 42%). ^ - MR (400MHz, CDC13): d 7.84 (s, 1H), 7.68 (d, 1H, J = 1.6Hz), 7.26 ~ 7.33 (m, 3H), 7.21 (s, 1H), 4.27 (m, 2H ), 3.27 (m, 2H), 2.94 (m, 1H), 2.68 (m, 2H), 2.63 (m, 2H), 2.13-2.15 (m, 2H), 1.92-1.93 (m, 2H), 1.66 ~ 1.74 (m, 2H). MS (ESI): m / z 308 (M + H +). 67. Compound 67: (3-cyclobutyl-9- (1H-pyrazol-1-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 42% yield as described for compound 66 but using 1H- pyrazole as the initial material. 1H-NMR (400MHz, CDC13): d 7.93 (d, 1H, J = 2.4Hz), 7.88 (d, 1H, J = 2.0Hz), 7.73 (d, 1H, J = 1.2Hz), 7.68 (dd, 1H, J! = 1.6, Hz J2 = 8.4Hz), 7.30 (d, 1H, J = 8.4Hz), 6.47 ~ 6.48 (m, 1H), 4.26 (m, 2H), 3.27 (m, 2H), 2.94 (m, 1H), 2.67 (m, 2H), 2.63 (m, 2H), 2.12-2.14 (m, 2H), 1.89-1.95 (m, 2H), 1.66-1.76 (m, 2H). MS (ESI): m / z 308 (M + H +). 68. Compound 68: (3-cyclobutyl-9- (1H-benzimidazol-1-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 23% yield as described for compound 66 but using 1H-benzo [d] imidazole as the starting material. ^ - MR (400MHz, CDC13): d 8.14 (s, 1H), 7.88 ~ 7.90 (m, 1H), 7.81 (d, 1H, J = 1.6Hz), 7.50-7.56 (m, 1H), 7.31 ~ 7.42 (m, 4H), 4.31 (m, 2H), 3.30 (m, 2H), 2.92 ~ 2.96 (m, 1H), 2.71 (m, 2H), 2.65 (m, 2H), 2.14 ~ 2.16 (m, 2H) ), 1.93-1. 6 (m, 2H), 1.70 ~ 7.75 (m, 2H). MS (ESI): m / z 358 (M + H +). 69. Compound 69: (3-cyclobutyl-9- (lH-indazol-1-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 14% yield as described for compound 66 but using 1H-indazole as the starting material. 1H-NMR (400MHz, CDC13): d 8.21 (d, 1H, J = 0.8Hz), 7.98 (d, 1H, J = 1.6Hz), 7.81 (dd, 1H, J = 1.2Hz, J = 7.6Hz) 7.73 (dd, 1H, 7. 61 (dd, 1H, J2 = 8.4Hz), 7.37-7.41 (m, 2H), 7.22 ~ 7.24 (m, 1H), 4.30 (m, 2H), 3.29 (m, 2H), 2.92-2.96 (m, 1H), 2.70 (m , 2H), 2.65 (m, 2H), 2.13-2.15 (m, 2H), 1.92-1.93 (m, 2H), 1.6-1.8 (m, 2H). MS (ESI): m / z 358 (M + H +). 70. Compound 70: (3-cyclobutyl-9- (lH-pyrrolo [2, 3-b] pyridin-1-yl) -2,4,4,5-tetrahydro-1H- [1,4] diazepino [1, 7] -a] benzimidazole) This compound is prepared in 17% yield as described for compound 66 but using 1H-pyrrolo [2, 3-b] pyridine as the starting material. 1 H-NMR (400MHz, CDC13): d 8.34 (dd, 1H, J2 = 8.4Hz), 7.98 (dd, 1H, J ^ .OHz, J2 = 8.0Hz), 7.87 (d, 1H, J = 1.6Hz), 7.68 (dd, 1H, J2 = 8.4Hz), 7.52 (d, 1H, J = 3.2Hz), 7. 37 (d, 1H, J = 8.4Hz), 7.10-7.13 (m, 1H), 6.63 (d, 1H, J = 3.2Hz), 4.28 (m, 2H), 3.27 (m, 2H), 2.93 (m , 1H), 2.66 (m, 2H), 2.62 (m, 2H), 2.13-2.15 (m, 2H), 1.92-1.93 (m, 2H), 1.6-1.8 (m, 2H). MS (ESI): m / z 358 (M + H +). 71. Compound 71: (2- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) pyridazin-3 (2H) -one ) Compound 21 (100 g,), Cul (20% mol) 3,4,7,8-tetramethylphenanthroline (0.4 eq.) And K2C03 (1.2 eq.) Were dissolved in DMF (2.5 mL) in a microwave tube that Washed by flushing with argon. The reaction mixture was stirred at 140 ° C for 60 minutes, diluted with dichloromethane and filtered through a short plug of Celite. the filtrate was concentrated and the crude reaction mixture was purified by reverse phase chromatography to give compound 71 (20mg, 19%). 1H-NMR (400MHz, CDCI3): d 7.90 (dd, 1H, Ji = 2.0Hz, J2 = 3.6Hz), 7.84 (d, 1H, J = 2.0Hz), 7.44 (dd, 1H, Ji = 2.4Hz, J2 = 8.8Hz), 7.24 ~ 7.32 (m, 2H), 7.07 (dd, 1H, Ji = 1.6Hz, J2 = 9.6Hz), 4.26 (m, 2H), 3.26 (m, 2H), 2.93 (m, 1H), 2.64 (m, 2H), 2. 61 (m, 2H), 2.10-2.14 (m, 2H), 1.89-1.94 (m, 1. 55-1.73 (m, 2H). MS (ESI): m / z 336 (M + H +). 72. Compound 72: (1- (3-cyclobutyl-2, 3, 4, 5-tetrahydro [1,4] diazepino [1,7-a] benzimidazol-9-yl) -lH-benzo [d] imidazole-2 (3H) -one) This compound was prepared in 19% yield as described for compound 71 but using 1H-benzo [d] imidazole-2 (3H) -one as the starting material. 1H-NMR (400MHz, CDC13): d 9.83 (s, 1H), 7.83 (d, 1H, J = 0.8Hz), 7.41 ~ 7.42 (m, 2H), 7.13 (d, 1H, J = 6.0Hz), 7.08 (dt, 1H, J! = 0.8Hz, J2 = 6.0Hz), 7.03 (dt, 1H, Jx = 0.8Hz, J2 = 6.4Hz), 6.99 (d, 1H, J = 6.0Hz), 4.30 (m , 2H), 3.30 (m, 2H), 2.95 (m, 1H), 2.68 (m, 2H), 2.64 (m, 2H), 2.14-2.15 (m, 2H), 1.91 ~ 1.95 (m, 2H), 1.67-1.79 (m, 2H). MS (ESI): m / z 374 (M + H +). 73. Compound 73: (3-cyclobutyl-9- (4-methyl-piperazin-1-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 56% yield as described for compound 1-38 but using N-methylpiperazine as the starting material. 1H-NMR (400MHz, CDC13): d 7.24 (d, 1H, J = 2.1Hz), 7.13 (d, 1H, J = 8.8Hz), 7.00 (dd, 1H, Ji = 2.0Hz, J2 = 8.8Hz) , 4.17 (m, 2H), 3.20 (m, 6H), 2.90 (m, 1H), 2.62 (m, 4H), 2.58 (m, 2H), 2.36 (s, 3H), 2.10 (m, 2H), 1.90 (m, 2H), 1.71 (m, 4H). MS (ESI): m / z 340 (M + H +). 74. Compound 74: (3-cyclobutyl-9- (morpholin-1-ylmethyl) -2,3,4,5-tetrahydro-1 H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 42% yield (20 mg) as described for compound 8 but using intermediate 1-31 and morpholine as starting materials. ^ -NMR (400MHz, CDC13): d 7.61 (d, 1H, J = 0.4Hz), 7.25 (dd, 1H, 7. 19 (d, 1H, J = 8.4Hz), 4.22 (m, 2H), 3.70 (m, 4H), 3.61 (s, 2H), 3.24 (m, 2H), 2.85-2.97 (m, 1H), 2.64 (m, 2H), 2.60 (m, 2H), 2.46 (m, 4H), 2.07 ~ 2.15 (m, 2H), 1.89 ~ 1.97 (m, 2H), 1.75-1.81 (m, 2H). MS (ESI): m / z 341 (M + H +). 75. Compound 75: (3-cyclobutyl-9- (pyrrolidin-1-ylmethyl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 54% yield as described for compound 8 but using intermediate 1-31 and pyrrolidine as starting materials. XH-NMR (400MHz, CDC13): d 7.60 (s, 1H), 7.28 (dd, 1H, J! = I.2Hz, J2 = 8.4Hz), 7.19 (d, 1H, J = 8.0Hz), 4.22 ( m, 2H), 3.73 (s, 2H), 3.23 (m, 2H), 2.90 ~ 2.94 (m, 1H), 2.64 (m, 2H), 2.60 (m, 2H), 2.52 (m, 4H), 2.09 ~ 2.15 (m, 2H), 1.88-1.93 (m, 2H), 1.62-1.79 (m, 6H). MS (ESI): m / z 325 (M + H +). 76. Compound 76: (6- (3-cyclobutyl-2,3,4,5-tetrahydro- [1,4] diazepinof 1,7-a] benzimidazol-8-yloxy) -N-methyl-nicotinamide) Intermediate 1-32 (30 mg), 6-chloro-N-methylnicotinamide (1.5 eq.) And uOK (1.5 eq.) Were dissolved in dry DMSO (1.0 mL) in a microwave tube and the mixture of the The reaction was stirred at 120 ° C for 30 minutes with microwave irradiation. The mixture was purified by reverse phase chromatography to give compound 76 (29 mg, 64%). 1H-NMR (400MHz, CDC13): d 8.52 (d, 1H, J = 2.0Hz), 8.13 (dd, 1H, J2 = 2.0Hz), 7.68 (d, 1H, J = 8.8Hz), 7.06 (d, 1H, J = 2.0Hz), 6.99 (dd, 1H, J: = 8.4Hz, J2 = 2.0Hz), 6.94 ( d, 1H, J = 8.4Hz), 6.25 (brs, 1H), 4.20 (m, 2H), 3.26 (m, 2H), 3.01 (d, 3H, J = 4.8Hz), 2.65 (m, 4H), 2.10-2.18 (m, 2H), 1.88 ~ 1.98 (m, 2H), 1.65-1.79 (m, 2H). MS (ESI): m / z 392 (M + H +). 77. Compound 77: (3-cyclobutyl-8- (pyrazin-2-yloxy) -2,3,4,5-tetrahydro-lH- [1,4] diazepinof 1,7-a] benzimidazole) This compound was prepared in 92% yield as described for compound 76 but using 2-chloropyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.43 (d, 1H, J = 1.2Hz), 8.23 (d, 1H, J = 2.8Hz), 8.07 (dd, 1H, J! = 1.6Hzf J2 = 2.8Hz) , 7.48 (d, 1H, J = 2.0Hz), 7.27 (d, 1H, J = 8.8Hz), 7.06 (dd, 1H, Ji = 2.0Hz, J2 = 8.8Hz), 4.25 (m, 2H), 3.26 (m, 2H), 2.92-2.96 (m, 1H), 2.67 (m, 2H), 2.62 (m, 2H), 2.12-2.14 (m, 2H), 1.91 ~ 1.95 (m, 2H), 1.66 ~ 1.77 (m, 2H). MS (ESI): m / z 336 (M + H +). 78. Compound 78: (3-cyclobutyl-8- (4-methoxypyrimidin-yloxy) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 47% yield as described for compound 76 but using 2-chloro-4-methoxypyrimidine as the starting material. 1H-NMR (400MHz, CDC13): d 8.17 (d, 1H, J = 5.6Hz), 7.68 (d, 1H, J = 8.8Hz), 7.10 (m, 2H), 6.45 (d, 1H, J = 5.6 Hz), 4.20 (m, 2H), 3.97 (s, 3H), 3.26 (m, 2H), 2.94 (m, 1H), 2.62-2.68 (m, 4H), 2.12-2.14 (m, 2H), 1.91 -1.96 (m, 2H), 1.63-1.78 (m, 2H). MS (ESI): m / z 366 (M + H +). 79. Compound 79: (4- ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-8-yloxy) methyl) -benzonitrile) This compound was prepared in 42% yield (18 mg) as described for compound 52 but using intermediate 1-32 and 4- (bromomethyl) benzonitrile as starting materials. 1H-NMR (400MHz, CDC13): d 7.55-7.57 (m, 2H), 7.46-7.48 (m, 2H), 7.08 (d, 1H, J = 2.4Hz), 7.04 (d, 1H, J = 8.8Hz ), 6.85 (dd, 1H, J2 = 8.8Hz), 5.07 (s, 2H), 4.10 (m, 2H), 3.12 (m, 2H), 2.79-2.87 (m, 1H), 2.54 (m, 2H), 2.50 (m, 2H), 2.01 ~ 2.04 (m, 2H), 1.80 ~ 1.84 (m, 2H), 1.55-1.66 (m, 2H). MS (ESI): m / z 373 (M + H +). 80. Compound 80: (-cyclobutyl-N- (4-methoxypyrimidin-2-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazol-8-amine) This compound was prepared in 79% yield (45 mg) as described for compound 64 but using intermediate 1-34 as the starting material. 1H-NMR (400MHz, CDC13): d 8.14 (d, 1H, J = 5.6Hz), 7.97 (d, 1H, J = 1.6Hz), 7.59 (d, 1H, J = 8.4Hz), 7.36 (s, 1H), 7.11 (dd, 1H, Ji = 3.0Hz, J2 = 8.4Hz), 6.19 (d, 1H, J = 5.6Hz), 4.21 (m, 2H), 3.96 (s, 3H), 3.22 (m, '2H), 2.90 ~ 2.94 (m, 1H), 2.64 (m, 2H), 2.60 (m, 2H), 2.09-2.15 (m, 2H), 1.88 ~ 1.93 (m, 2H), 1.65-1.75 (m , 2H). MS (ESI): m / z 365 (M + H +). 81. Compound 81: (4- ((3-cyclobutyl-2,3,4,5-tetrahydro-1α- [1,4] diazepino [1,7- a] benzimidazol-8-ylamino) methyl) - Intermediate 1-34 (50 mg, 0.20 mmol), 4- (bromomethyl) benzonitrile (38 mg, 0.20 mmol) and CsC03 (127 mg, 0.39 mmol) were dissolved in acetone (5 mL) and the reaction mixture it was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 81 (35 mg, 49%). 1 H-NMR (400MHz, CDC13): d 7.63 (m, 2H), 7.46-7.52 (m, 3H), 6.58 (m, 1H), 6.29 (s, 1H), 4.46 (s, 2H), 4.26 (m , 1H), 4.05 (m, 2H), 3.16 (m, 2H), 2.88-2.92 (m, 1 H), 2.58 (m, 4H), 2.05-2.11 (m, 2H), 1.84-1.91 (m, 2H), 1.61-1.74 (m, 2H). S (ESI): m / z 372 (M + H +). 82. Compound 82: (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-8-carbonitrile) This compound was prepared in 86% yield (710 mg) as described for compound 54 but using compound 40 as the starting material. MS (ESI): m / z 267 (+ H +). 83. Compound 83: (6- ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) piperazin-1-yl) benzonitrile ) This compound was prepared in 12% yield as described for 1-38 but using 4- (piperazin-1-yl) benzonitrile as the starting material. 1H-NMR (400MHz, CDC13): d 7.52 (d, J = 9.0Hz, 2H), 7.27 (d, J = 2.1Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.02 (dd, J = 2.2, 8.8Hz, 1H), 6.92 (d, J = 9.0Hz, 2H), 4.19 (d, J = 9.lHz, 2H), 3.50 (m, 4H), 3.27-3.30 (m, 3H) , 3.21 (d, J = 10.5Hz, 2H), 2.92 (t, J = 7.5Hz, 1H), 2.58-2.64 (m, 3H), 2.11 (m, 2H), 1.90 (m, 2H), 1.68 ( m, 4H). MS (ESI): m / z 427 (M + H +). 84. Compound 84: ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-8-yl) (morpholino) -methanone) This compound was prepared in 57% yield (50 mg) as described for compound 56 but using intermediate 1-37 as the starting material. 1 H-NMR (400MHz, CDCl 3): d 7.67 (d, 1H, J = 8.4Hz), 7. 45 (d, 1H, J = 0.8Hz), 7.23 (dd, 1H, Ji = 1.2Hz, J2 = 8.4Hz), 4.25 (m, 2H), 3.69 (m, 8H), 3.26 (m, 2H), 2.91-2. 5 (m, 1H), 2.60 ~ 2.66 (m, 4H), 2.10-2.14 (m, 2H), 1.65 ~ 1.94 (m, 4H). MS (ESI): m / z 355 (M + H +). 85. Compound 85: (3-cyclobutyl-N, N-dimethyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-8-carboxamide) This compound was prepared in 30% yield as described for compound 84 but using dimethylamine as the starting material. 1H-NMR (400MHz, CDC13): d 7.66 (d, 1H, J = 8.4Hz), 7.44 (s, 1H), 7.26 (d, 1H, J = 8.4 Hz), 4.24 (m, 2H), 3.26 ( m, 2H), 3.03-3.12 (m, 6H), 2.93 (m, 1H), 2.60 ~ 2.65 (m, 4H), 2.12-2.14 (m, 2H), 1.88-1.94 (m, 2H), 1.68- 1.73 (m, 2H). MS (ESI): m / z 313 (M + H +). 86. Compound 86: ((3-cyclobutyl-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-8-yl) (pyrrolidin-1-yl) methanone) This compound was prepared in 60% yield as described for compound 84 but using pyrrolidine as the starting material. 1H-NMR (400MHz, CDC13): d 7.66 (d, 1H, J = 8.0Hz), 7.56 (d, 1H, J = 0.8Hz), 7.38 (dd, 1H, Chi, 1.6Hz, J2 = 8.4Hz) , 4.26 (m, 2H), 3.68 (m, 2H), 3.50 (m, 2H), 3.27 (m, 2H), 2.91-2.95 (m, 1H), 2.63 (m, 4H), 2.10-2.17 (m , 2H), 1.70-2.01 (m, 8H). MS (ESI): m / z 339 (M + H +). 87. Compound 87: (3-Cyclobutyl-8- ((dimethylamino) methyl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) The aqueous dimethylamine solution was cooled to -60 ° C to freeze the water. The resulting dimethylamine oil was transferred to a solution of intermediate 1-36 (21 mg) in dry THF at -60 ° C. The reaction mixture was stirred at -60 ° C for 10 minutes and for 2 hours at room temperature, concentrated and the residue was purified by preparative HPLC to give compound 87 (15 mg, 70%). 1H-NMR (400MHz, CDCI3): d 7.59 (d, 1H, d, J = 8.0Hz), 7.25 (s, 1H), 7.12 (dd, 1H, J ^ SO, J2 = 1.6Hz,), 4.21- 4.23 (m, 2H), 3.53 (s, 2H), 3.21-3.23 (m, 2H), 2.90 (m, 1H), 2.57-2.62 (m, 4H), 2.11 (s, 6H), 2. 10-2.12 (m, 2H), 1.87 ~ 1.92 (m, 2H), 1.63 ~ 1.71 (m, 2H). MS (ESI): m / z 299 (M + H +). 88. Compound 88: (3-cyclobutyl-8- (morpholin-1-ylmethyl) -2,3,4,5-tetrahydro-1 H- [1,4] diazepino [1,7-a] benzimidazole) 1-36 (21 mg) was dissolved in morpholine (5 mL) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the crude product was purified by preparative HPLC to give compound 88 (13 mg, 91%). 1H-NMR (400MHz, CDC13): d 7.54 (d, 1H, d, J = 8.0Hz), 7.19 (s, 1H), 7.10 (dd, 1H, J! = 8.0Hz, J2 = 1.2Hz), 4.16 (m, 2H, m), 3.64 (m, 4H), 3.55 (s, 2H), 3.15 (m, 2H), 2.90 (m, 1H), 2.52-2.58 (m, 4H), 2.41 (m, 4H) ), 2.10 (m, 2H), 2.05 (m, 2H), d 1.8 (m, 2H). MS (ESI): m / z 341 (M + H +). 89. Compound 89: (3-cyclobutyl-8- (pyrrolidin-1-ylmethyl) -2,3,4,5-tetrahydro-1 H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 85% yield as described for compound 88 but using pyrrolidine as the initial material. 1 H-NMR (400 MHz, CDC13): d 7.59-7.61 (d, 1H, J = 8.0Hz), 7.32 (s, 1H), 7.15-7.17 (dd, 1H, Jx = 8.0Hz, J2 = 1.6Hz) , 4.23-4.25 (m, 2H), 3.77 (s, 2H), 3.22-3.25 (m, 2H), 2.92 (m, 1H), 2.58-2.64 (m, 8H), 2.11-2.14 (m, 2H) , 1.93 ~ 1.94 (m, 2H), 1.89 (m, 4H), 1.80 ~ 1.88 (m, 2H). MS (ESI): m / z 325 (M + H +). 90. Compound 90: (3-cyclobutyl-8- (furan-2-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 26% yield as described for compound 41 but using furan-2-ylboronic acid as the starting material. The reaction was run at 85 ° C. 1H-NMR (400MHz, d6-Acetone), d 7.67 (d, 1H, J = 8.8Hz), 7.53 ~ 7.58 (m, 2H), 7.47 (s, 1H), 6.63 ~ 6.64 (m, 1H), 6.48 ~ 6.49 (m, 1H), 4.27 (m, 2H), 3.25 (m, 2H), 2.90-2. 7 (m, 1H), 2.66 (m, 2H), 2.62 (m, 2H), 2.12 ~ 2.17 (m, 2H), 1.88-1.97 (m, 2H), 1.68-1.76 (m, 2H). MS (ESI): m / z 308 (M + H +). 91. Compound 91: (3-cyclobutyl-9- (5- (pyrrolidin-1-yl) pyrazin-2-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1, 7- a] benzimidazole) The compound was prepared in 25% yield as described for compound 22 but using 2-bromo-5- (pyrrolidin-1-yl) pyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.55 (d, 1H, J = 1.6Hz), 8.12 (d, 1H, J = 1.6Hz), 7.96 (d, 1H, J = 1.2Hz), 7.84 (dd, 1H, J 1.6Hz, J2 = 8.4Hz), 7.28 (d, 1H, J = 8.4Hz), 4.26-4.24 (m, 2H), 3.56-3.53 (m, 4H), 3.27 ~ 3.24 (m, 2H) , 2.98-2.80 (m, 1H), 2.67-2.61 (m, 4H), 2.13-2.01 (m, 2H), 2.07-2.05 (m, 4H), 1.95 ~ 1.90 (m, 2H), 1.73-1.67 ( m, 2H). MS (ESI): m / z 389 (M + H +). 92. Compound 92: (3-cyclobutyl-9- (5- (4-methyl-piperazin-1-yl) -pyrazin-2-yl) -2,4,4,5-tetrahydro-1H- [1,4] diazepino [1, 7-a] benzimidazole) This compound was prepared in 30% yield as described for compound 22 but using 2-bromo-5- (4-methylpiperazin-1-yl) pyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.58 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.85 (d, 1H, J = 8.8Hz), 7.31 (d, 1H, J = 8.4Hz), 4.27-4.25 (m, 2H), 3.68 ~ 3.66 (m, 4H), 3. 28 ~ 3.25 (m, 2H), 2.98-2.90 (m, 1H), 2.68 ~ 2.57 (m, 8H), 2. 38 (s, 3H), 2.17-2.1 l (m, 2H), 1.98-1.87 (m, 2H), 1.80-1.65 (m, 2H). MS (ESI): m / z 418 (M + H +). 93. Compound 93: (3-cyclobutyl-9- (5-methoxypyrazin-2-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 30% yield as described for compound 22 but using 2-bromo-5-methoxypyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.56 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.88 (d, 1H, J = 8.4Hz), 7.33 (d, 1H, J = 8.4Hz), 4.29-4.27 (m, 2H), 4.01 (s, 3H), 3.29 ~ 3.27 (m, 2H), 2.96 ~ 2.92 (m, 1H), 2.69 ~ 2.63 (m, 4H), 2.17- 2.10 (m, 2H), 1.96-1.91 (m, 2H), 1.76 ~ 1.65 (m, 2H) MS (ESI): m / z 350 (M + H +). 94. Compound 94: (3-cyclobutyl-9- (6- (pyrrolidin-yl) pyrazin-2-yl) -2, 3, 4, 5-tetrahydro-lH [1,4] diazepino [1, "a] benzimidazole) This compound was prepared in 28% yield as described for compound 22 but using 2-bromo-6- (pyrrolidin-1-yl) pyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.39 (s, 1H), 8.31 (s, 1H), 7.95 (d, 1H, J = 8.4Hz), 7.77 (S, 1H), 7.30 (d, 1H, J = 8.8Hz), 4.25 (d, 2H, J = 6.0Hz), 3.58 (s, 4H), 3.27-3.25 (m, 2H), 2.95-2.91 (m, 1H), 2.67-2.62 (m, 4H) , 2.13 ~ 2.09 (m, 2H), 2.04 (sf 4H), 1.94 ~ 1.87 (m, 2H), 1.75-1.65 (m, 2H). MS (ESI): m / z 389 (M + H +). 95. Compound 95: (3-Cyclobutyl-9- (6- (4-methylpiperazin-1-yl) pyrazin-2-yl) -2,3,4,5-tetrahydro-lH-1,4] diazepine [1.7 -a] benzimidazole) This compound was prepared in 50% yield as described for compound 22 but using 2-bromo-6- (4-methylpiperazin-1-yl) pyrazine as the starting material. 1 H-NMR (400MHz, CDCl 3): d 8.78 (d, 2H, J = 7.2Hz), 8.04 (s, 1H), 7.92 (d, 1H, J = 8.8Hz), 7.30 (d, 1H, J = 8.4 Hz), 4.27-4.25 (m, 2H), 3.75-3.73 (m, L 4H), 3.27-3.25 (m, 2H), 2.95-2.91 (m, 1H), 2.67 ~ 2.61 (m, 4H), 2.58 -2.56 (m, 4H), 2.37 (s, 3H), 2.14-2.12 (m, 2H), 1.94-1.89 (m, 2H), 1.76-1.65 (m, 2H). MS (ESI): m / z 418 (M + H +). 96. Compound 96: (3-cyclobutyl-9- (6-methoxypyrazin-2-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 49% yield as described for compound 22 but using 2-bromo-6-methoxypyrazine as the starting material. 1 H-NMR (400MHz, CDC13): d 8.63 (3, 1H), 8.40 (s, 1H), 8.1 l (s, 1H), 7.95 (d, 1H, J = 8.0Hz), 7.32 (d, 1H, J = 8.8Hz), 4.26 (d, 2H, J = 6.4Hz), 4.07 (s, 3H), 3.29-3.26 (m, 2H), 2.95 ~ 2.91 (m, 1H), 2.67-2.61 (m, 4H) ), 2.13-2.11 (m, 2H), 1.94-1.89 (m, 2H), 1.75 ~ 1.65 (m, 2H). MS (ESI): m / z 350 (M + H +). 97. Compound 97: (3-cyclobutyl-9- (piperazin-1-yl) -2,3,4,5-tetrahydro-1 H- [1,4] diazepino [1,7-a] benzimidazole) 1-38 (0.50 g, 1.2 mmol) was dissolved in TFA (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and saturated aqueous NaHCO3 was added. The combined organic layers are washed with brine, dried over Na2SO4, the solids were filtered. and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC. The purified compound 97 was made acidic with methanolic HCl solution and the HCl salt of 97 was obtained after crystallization of MeOH (0.50 g, 97%). 1H-NMR (400 MHz, CD3OD and D20) d: 7.80 (d, 1H, J = 9.2Hz), 7.4.5 (dd, 1H, Chi, 2.4Hz, J2 = 9.2Hz), 7.32 (d, 1H, J = 2.4Hz), 3.93 (m, 1H), 3.83-3.80 (m, 2H), 3.69-3.61 (m, 4H), 3.54-3.51 (m, 4H), 3.41-3.39 (m, 4H), 3.27 (m, 2H), 2.44-2.40 (m, 4H), 1.91-1.77 (m, 2H). MS (ESI): m / z 326 (M + H +). 98. Compound 98: (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) piperazine-1-benzyl carboxylate) Compound 97 (50 mg, 0.15 mmol) and Et3N (38 mg, 0.38 mmol) were dissolved in dichloromethane (2 mL), pure CbzCl (52 mg, 0.31 mmol) was added and the mixture was stirred at room temperature. After the TLC analysis indicated the complete disappearance of compound 97 the reaction mixture was washed with brine, the combined organic layers were dried at 2S04, the solids they were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 98 (16 mg, 23%). H-NMR (400MHz, CDCI3): d 7.39-7.37 (m, 4H), 7.36-7.32 (m, 1H), 7.24 (d, 1H, J = 2.0Hz), 7.17 (d, 1H, J = 8.8Hz), 7.00 (dd, 1H, Chi, 2.0Hz, J2 = 8.8Hz), 5.17 (s, 2H), 4.20 (m, 2H), 3.72 (m, 4H), 3.23 (m, 2H), 3.11 br, 4H), 2.96-2.88 (m, 1H), 2. 64-2.58 (m, 4H), 2.13-2.11 (m, 2H), 1.79-1.73 (m, 2H), 1.68-1.63 (m, 2H). MS (ESI): m / z 460 (+ H +). 99. Compound 99: (3-cyclobutyl-9- (4-cyclobutylpipe-1-yl) -2,3,4,5,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 25% yield (24 mg) as described for compound 21 but using compound 97 as the starting material. ^ - MR (400MHz, CDCI3): d 7.26 (s, 1H), 7.15 (d, 1H, J = 8.8Hz), 7.01 (d, 1H, J = 8.8Hz), 4.19-4.17 (m, 2H), 3.22-3.19 (m, 6H), 2.93-2.80 (m, 2H), 2.63-2.56 (m, 8H), 2.13-2.07 (m, 4H), 1.97-1.88 (m, 4H), 1.76-1.62 (m , 4H). MS (ESI): m / z 380 (M + H +). 100. Compound 100: (3-cyclobutyl-9- (4-cyclopentyl-piperazin-1-yl) -2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 32% yield as described for compound 99 but using cyclopentanone as the starting material. 1H-NMR (400MHz, CDC13): d 7.26 (d, 1H, J = 2.0Hz), 7.15 (d, 1H, J = 8.8Hz), 7.02 (dd, 1H, Chi, 2.0Hz, J2 = 8.8Hz) , 4.18 (m, 2H), 3.19 (m, 6H), 2.94-2.86 (m, 1H), 2.71 (m, 4H), 2.55 (m, 5H), 2.11-2.09 (m, 2H), 1.91-1.89 (m, 4H), 1.71 (m, 4H), 1.56 (m, 2H), 1.44 (m, 2H). S (ESI): m / z 394 (M + H +). 101. Compound 101: (rac-3-cyclobutyl-9- (- (tetrahydrofuran-3-yl) piperazin-1-yl) -2, 3, 4, 5-tetrahydro-1H- [1,4] diazepino [1.7 -a] benzimidazole) This compound was prepared in 18% yield as described for compound 999 but using dihydrofuran-3 (2H) -one as the starting material. "" "H-NMR (400MHz, CDCI3): d 7.23 (d, 1H, J = 2.0Hz), 7.14 (d, 1H, J = 8.8Hz), 6.99 (dd, 1H, Ji = 2.0Hz, J2 = 8.8Hz), 4.18 (m, 2H), 3.97-3.93 (m, 2H), 3.84 (q, 1H, J = 8.0Hz) , 3.68 (t, 1H, J = 8.0Hz), 3.21-3.17 (m, 6H), 3.03-3.01 (m, 1H), 2.92-2.88 (m, 1H) 2.77-2.73 (m, 2H), 2.62- 2.56 (m, 6H), 2.11-2.08 (m, 3H), 1.92-1.71 (m, 3H), 1.68-1.63 (m, 2H). MS (ESI): m / z 396 (M + H +). 102. Compound 102: (3-cyclobutyl-9- (-cyclopentyl-piperazin-1-yl) -2, 3,, 5-tetrahydro-1H- [1,4] diazepino [1,7-a-J-benzimidazole] compound was prepared in 13% yield as described for compound 99 but using cyclohexanone as the starting material. XH-NMR (400MHz, CD30D): d 7.37 (d, 1H, J = 8.8Hz), 7.13 (s, 1H, J = 8.8Hz), 7.08 (d, 1H, J = 8.8Hz), 4.30 (m, 2H), 3.20 (m, 6H), 2.95 (m, 5H), 2.65 (m, 2H), 2.58 (m, 3H), 2.14 (m, 2H), 2.04 (m, 2H), 1.91-1.86 (m , 5H), 1.70 (m, 3H), 1.35-1.28 (m, 4H). MS (ESI): m / z 408 (M + H +). 103. Compound 103: (3-cyclobutyl-9- (4- (etrahydro-2H-pyran-4-yl) piperazin-1-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [ l, 7-a] benzimidazole) This compound was prepared in 25% yield as described for compound 99 but using dihydro-2H-pyran-4 (3H) -one as the starting material. XH-NMR (400MHz, CDC13): 67.26 (s, 1H), 7.17 (d, 1H, J = 8.8Hz), 7.01 (d, 1H, J = 8.8Hz), 4.22 (m, 2H), 4.08-4.06 (m, 2H), 3.44 (t, 2H, J = 7.2Hz), 3.27 (br, 6H), 2.92 (br, 5H), 2.65 (br, 5H), 2.13-2.11 (m, 2H), 1.95- 1.87 (m, 4H), 1.75-1.67 (m, 4H). MS (ESI): m / z 410 (M + H +). 104. Compound 104: (3-Cyclobutyl-9- (4- (cyclopropylmethyl) piperazin-1-yl) -2, 3, 4, 5-tetrahydro-1H- [1,4] diazepino [1,7-a-J-benzimidazole] This compound was prepared in 29% yield as described for compound 99 but using 1-cyclopropyletanone as the starting material. XH-NMR (400MHz, CDCI3): d 7.24 (s, 1H), 7.12 (d, 1H, J = 8.8Hz), 6.99 (d, 1H, J = 8.8Hz), 4.16 (m, 2H), 3.20- 3.17 (m, 6H), 2.90-2.86 (m, 1H), 2.75 (br, 4H), 2.60-2.54 (m, 4H), 2.35 (d, 2H, J = 6.4Hz), 2.10-2.06 (m, 2H), 1.90-1.85 (m, 2H), 1. 72-1.61 (m, 2H), 0.92-0.90 (m, 1H), 0.54 (d, 2H, J = 7.6Hz), 0.14 (d, 2H, J = 4.8Hz). MS (ESI); m / z 380 (M + H +). 105. Compound 105: (3-Cyclobutyl-9- ((dimethylamino) methyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazole) This compound was prepared in 16% yield as described for compound 74 but using dimethylamine as the starting material. 1H-NM (400MHz, CDC13): d 7.59 (s, 1H), 7.29 ~ 7.31 (m, 1H), 7.22-7.25 (m, 1H), 4.24 ~ 4.26 (m, 2H), 3.61 (s, 2H) , 3.25 ~ 3.28 (m, 2H), 2.95 (m, 1H), 2.62 ~ 2.68 (m, 4H), 2.30 (s, 6H), 2.14-2.16 (m, 2H), 1.91-1.96 (m, 2H) , 1.63-1.78 (m, 2H). MS (ESI): m / z 299 (M + H +). 106. Compound 106: (2- (3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) methanol) To a solution of intermediate 1-31 (186 mg) in methanol (7 mL) was added solid NaBH4 (105 mg, 4. 0 eq.) In a portion at 0 ° C and the reaction mixture was stirred at 0 ° C for 30 minutes. Water (2 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed with water. The combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated to give compound 106 as a white solid (178 mg, 95%). 1H-NMR (400MHz, CDC13): d 7.66 (s, 1H), 7.22-7.30 (m, 2H), 4.78 (s, 2H), 4.22-4.24 (m, 2H), 3.23 ~ 3.25 (m, 2H) , 2.90 ~ 2.94 (m, 1H), 2.59 ~ 2.65 (m, 4H), 2.09-2.16 (m, 2H), 1.89 ~ 1.94 (m, 2H), 1.65 ~ 1.76 (m, 2H). MS (ESI): m / z 272 (M + H +). 107. Compound 107: (3-cyclobutyl-9- ((4-methoxypyrimidin-2-yloxy) methyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepine [1,7- To a solution of 106 (33 mg) in DMF was added sodium hydride (2.0 eq.) And the reaction mixture was stirred at room temperature for 30 minutes. Solid 2-chloro-4-methoxypyrimidine (1.5 eq.) Was added and the reaction mixture was stirred at 50 ° C for the entire night. Saturated aqueous sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 107 (26 mg, 57%). 1H-NMR (400MHz, CDC13): d 8.18 (d, 1H, J = 4.8Hz), 7.80 (s, 1H), 7.41 (d, 1H, J = 6.8Hz), 7.23 (d, 1H, J = 6.8 Hz), 6.35 (d, 1H, J = 4.4Hz), 5.53 (s, 2H), 4.22 ~ 4.23 (m, 2H), 3.96 (s, 3H), 3.23 ~ 3.25 (m, 2H), 2.90 ~ 2.93 (m, 1H), 2.59-2.64 (m, 4H), 2.10-2.14 (m, 2H), 1.89 ~ 1.93 (m, 2H), 1.65 ~ 1.75 (m, 2H). MS (ESI): m / z 380 (M + H +). 108. Compound 108: (6- ((3-cyclobutyl-2, 3, 4, 5-tetrahydro-1? - [1,4] diazepino [1,7- a] benzimidazol-9-yl) me oxy) nicotino-nitrile ) This compound was prepared in 88% yield as described for compound 107 but using 6-chloronicotinonitrile as the starting material. The reaction was run at room temperature. ^ - MR (400MHz, CDCI3): d 8.51 (d, 1H, J = I.2Hz), 7.75-7.78 (m, 2H), 7.34 (d, 1H, J = 6.8Hz), 7.26 (d, 1H, J = 6.8 Hz), 6.84 (d, 1H, J = 7.2Hz), 5.54 (s, 2H), 4.23 ~ 4.25 (m, 2H), 3.23 ~ 3.26 (m, 2H), 2.90-2.93 (m, 1H), 2.59 -2.64 (m, 4H), 2.10-2.15 (m, 2H), 1.89-1.93 (m, 2H), 1.65-1.75 (m, 2H). MS (ESI): m / z 374 (M + H +). 109. Compound 109: (3-cyclobutyl-9- ((pyrazin-iloxy) methyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 91% yield as described for compound 107 but using 2-chloropyrazine as the starting material. ! H-NMR (400MHz, CDCI3): d 8.25 (s, 1H), 8.10 ~ 8.12 (m, 2H), 7.80 (s, 1H), 7.36 (d, 1H, J = 6.8Hz), 7.26 (d, 1H, J = 7.2Hz), 5.50 (s, 2H), 4.23-4.25 (m, 2H), 3.24 ~ 3.26 (m, 2H), 2.89 ~ 2.93 (m, 1H), 2.59-2.64 (m, 4H) , 2.10 ~ 2.15 (m, 2H), 1.87 ~ 1.95 (m, 2H), 1.63 ~ 1.77 (m, 2H). MS (ESI): m / z 350 (M + H +). 110. Compound 110: (2- (3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-8-yl) methanol) This compound was prepared in 96% yield (130 mg) as described for compound 106 but using intermediate 1-39 as the starting material. 1H-NMR (400MHz, CD30D): d 7.42 (d, 1H, J = 8.0Hz), 7.35 (d, 1H, J = 0.8Hz), 7.13 (dd, 1H, Ji = 1.2 Hz, J2 = 8.0Hz) , 4.62 (s, 2H), 4.24 ~ 4.26 (m, 2H), 3.09-3.12 (m, 2H), 2.87 ~ 2.91 (m, 1H), 2.51 ~ 2.59 (m, 4H), 2.02-2.09 (m, 2H), 1.83 ~ 1.87 (m, 2H), 1.58-1.67 (m, 2H). MS (ESI): m / z 272 (M + H +). 111. Compound 111: (3-cyclobutyl-8- ((4-methoxypyrimidin-2-yloxy) methyl) -2,4,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 74% yield as described for compound 107 but using compound 110 as the starting material. 1H-NMR (400MHz, CDC13): d 8.20 (d.1H, J = 5.6Hz), 7.66 (d, 1H, J = 8.0Hz), 7.44 (d, 1H, J = 0.8Hz), 7.32 (dd, 1H, Jif1.2 Hz, J2 = 8.0Hz), 6.38 (d, 1H, J = 5.6Hz), 5.54 (s, 2H), 4.23-4.25 (m, 2H), 3. 97 (s, 3H), 3.23-3.25 (m, 2H), 2.92 (m, 1H), 2.59 ~ 2.64 (m, 4H), 2.10 ~ 2.18 (m, 2H), 1.88-1.93 (m, 2H), 1.65-1.73 (m, 2H). MS (ESI): m / z 380 (M + H +). 112. Compound 112: (6- ((3-cyclobutyl-2, 3, 4, 5-tetrahydro-1? - [1,4] diazepino [1,7- a] benzimidazol-8-yl) methoxy) nicotino-nitrile) This compound was prepared in 94% yield as described for compound 110 but using compound 110 and 2-chloro-5-cyanopyridine as starting materials. The reaction was run at room temperature. XH-NMR (400MHz, CDC13): d 8.52 (s, 1H), 7.78 (dd, 1H, J2 = 8.4Hz), 7.69 (d, 1H, J = 8.0Hz), 7.36 (s, 1H), 7.31 (d, 1H, J = 8.8Hz), 6.86 (d, 1H, J = 8.4Hz), 5.55 (s, 2H), 4.23 ~ 4.26 (m, 2H), 3.24 ~ 3.26 (m, 2H), 2.88 ~ 2.95 (m, 1H), 2.60-2.66 (m, 4H), 2.10-2.16. { m, 2H), 1.86-1.94 (m, 2H), 1.63 ~ 1.76 (m, 2H). MS (ESI): m / z 374 (M + H +). 113. Compound 113: (3-Cyclobutyl-9- ((pyrazin-2-yloxy) methyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) The composite was prepared in 89% yield as described for compound 107 but using compound 110 and 2-chloropyrazine as the starting materials. JH-NMR (400MHz, CDC13): d 8.28 (d, 1H, J = 1.2Hz), 8.1 l-8.15 (m, 2H), 7.69 (d, 1H, J = 8.4Hz), 7.38 (s, 1H) , 7.32 (dd, 1H, J2 = 8.4Hz), 5.50 (s, 2H), 4.24 ~ 4.26 (m, 2H), 3.24 ~ 3.27 (m, 2H), 2.9. ~ 2.94 (m, 1H), 2.59 ~ 2.66 (m, 4H), 2.09-2.14 (m, 2H), 1.88-1.93 (m, 2H), 1.65 ~ 1.76 (m, 2H). MS (ESI): m / z 350 (M + H +). 114. Compound 114: (3-cyclobutyl-9- (pyridin-2-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 38% yield as described for compound 22 but using 2-bromopyridine as the starting material. 1H-NMR (400MHz, CDC13): d 1.65-1.75 (m, 2H), 1.85-1.95 (m, 2H), 2.10-2.15 (m, 2H), 2.62-2.68 (m, 4H), 2.91-2.95 ( m, 1H), 3.28 (m, 2H), 4.27 (m, 2H), 7.18-7.22 (m, 1H), 7.34 (d, 1H), 7.74-7.79 (m, 2H), 8.02 ((dd, 1H) ), 8.23 (s, H), 8.68 (d, 1H), MS (ESI): m / z 319.0 (M + H +). 115. Compound 115: (3-cyclobutyl-9- (iridin-3-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepinof 1,7-a] benzimidazole) This compound was prepared in 17% yield as described for compound 22 but using 2-bromopyridine as the starting material. 1 H-NMR (400 MHz, CDC13) d: 1.65-1.80 (m, 2H), 1.85-1.95 (m, 2H), 2.11-2.16 (m, 2H), 2.62-2.68 (m, 4H), 2.92-2.96 (m, 1H), 3.28 (m, 2H), 4.28 (m, 2H), 7.33-7.38 (m, 2H), 7.47 (dd, 1H), 7.89-7.92 (m, 2H), 8.56 (d, 1H) ), 8.89 (s, 1H). MS (ESI): m / z 319.0 (M + H +). 116. Compound 116: (3-cyclobutyl-9- (pyridin-4-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepinof 1,7-a] benzimidazole) This compound was prepared in 14% yield as described for compound 22 but using 2-bromopyridine as the starting material. 1 H-NMR (400MHz, CDCl 3) d: 1.65-1.75 (m, 2H), 1.85-1.95 (m, 2H), 2.11-2.16 (m, 2H), 2.61-2.67 (m, 4H), 2.91-2.95 ( m, 1H), 3.27 (m, 2H), 4.27 (m, 2H), 7.34 (d, 1H), 7.52-7.56 (m, 3H), 7.97 (s, 1H), 8.64 (d, 2H). MS (ESI): m / z 319.0 (M + H +). 117. Compound 117: (- ((3-cyclobutyl-2,3,4,5-tetrahydro-1H- [1,4] diazepino [1,7- a] benzimidazol-9-yl) methyl) iridin-3-amine) This compound was prepared in 14% yield as described for compound 74 but using pyridin-3-amine as the starting material. 1H-NMR (400MHz, CDC13): d 8.08 (d, 1H, J = 2.8Hz), 7.95 (d, 1H, J = 4.4Hz), 7.67 (s, 1H), 7.21-7.25 (m, 2H), 7.03 ~ 7.07 (m, 1H), 6.90-6.9 l (m, 1H), 4.44 (s, 2H), 4.22 ~ 4.24 (m, 2H), 4.16 (brs, 1H), 3.23 ~ 3.25 (m, 2H) , 2.92 (m, 1H), 2.59 ~ 2.65 (m, 4H), 2.11 ~ 2.14 (m, 2H), 1.89-1.94 (m, 2H), 1.68 ~ 1.76 (m, 2H). MS (ESI): m / z 348 (M + H +). 118. Compound 118: (3-cyclobutyl-9- (4-isopropylopiperazin-1-yl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepinof 1,7-a] benzimidazole) This compound was prepared in 23% yield as described for compound 99 but using acetone as the starting material. 1H-NMR (400MHz, CD3OD): 57.50 (d, 1H, J = 8.8Hz), 7.23 (s, 1H), 7.18 (d, 1H, J = 8.8Hz), 4.55 (br, 2H), 3.61-3.57 (m, 2H), 3.46 (br, 10H), 3.14- 3. 08 (m, 4H), 2.27-2.22 (m, 4H), 1.85-1.74 (m, 2H), 1.44 (d, 6H, J = 6.8 Hz). MS (ESI): m / z 368 (M + H +). 119. Compound 119: (mixture of 4- (3- (tert-butyl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin- 8-yl) benzonitrile and 4- (3- (tert-butyl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diacepin 9-yl) benzonitrile) This compound was prepared in 30% yield (19 mg) as described for compound 41 but using intermediate 1-44 as the starting material. 1 H-NMR (400 MHz, CDC13) d: 7.91-7.33 (m, 7H), 4.26 (t, 2H, J = 8.4Hz), 3.26 (t, 2H, J = 4.8Hz), 2.96 (t, 2H, J = 8.4Hz), 2.90 (t, 2H, J = 4.8Hz), 1.16 (s, 9H). MS (ESI): m / z 345.1 (M + H +). 120. Compound 120: (3-cyclobutyl-2,3,4,5-tetrahydro-benzo [4,5] imidazo [1,2-d] [1,4] diacepin-8-yl) (pyrazin-2-yl) methanol) To a solution of "BuMgCl (0.17 mmol, 0.33 eq) in dry THF (4 mL) was added nBuLi (0.55 mmol, 1.1 eq) at -20 ° C and the reaction mixture was stirred at -20 ° C for 30 minutes. 2-iodopyrazine (103 mg, 0.50 mmol, 1.0 eq) was added at -20 ° C and the reaction mixture was stirred at -10 ° C for 2 hours. The reaction mixture was cooled to -20 ° C and a solution of intermediate 1-31 (135 mg, 0.50 mmol, 1.0 eq) in THF (1 mL) was added. The reaction mixture was stirred at -20 ° C for 1 hour and then at room temperature until TLC analysis indicated complete disappearance of the starting material. The reaction mixture was quenched by adding saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by preparative TLC to give compound 120 (130 mg, 74%). iH-NMR (400MHZ, CDC13): d 8.63 (d, 1H, J = 0.8Hz), 8.49 (dd, 1H, Ji, 0.8Hz, J2 = 2.8Hz), 8.44 (d, 1H, J = 2.8Hz) , 7.68 (s, 1H), 7.25 (dd, 1H, Ji = lHz, J2 = 8.8Hz), 7.20 (d, 1H, J = 8.8Hz), 5.98 (S, 1H), 5.30 (s, 1H), 4.18-4.20 (m, 2H), 3.18 ~ 3.21 (m, 2H), 2.88 ~ 2.91 (m, 1H), 2.54-2.61 (m, 4H), 2.08-2.14 (m, 2H), 1.86-1.91 (m , 2H), 1.61-1.74 (m, 2H). MS (ESI): m / z 350 (M + H +). 121. Compound 121: ((3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepin-8-yl) (pyrazin-2) -yl) methanone) To a solution of compound 120 (3.6 mg, 0.010 mmol, 1.0 eq) in dichloromethane (5 mL) was added MnC > 2 (2.0 mg, 0.021 mmol, 2.0 eq) and the reaction mixture was stirred at room temperature for 60 minutes. The solids were removed by filtration through a short plug of silica gel and the filtrate was concentrated by evaporation to give compound 121 (3.5 mg, 98%). 1H-NMR (400MHz, CD30D): d 9.04 (d, 1H, J = 1.6Hz), 8.73 (d, 1H, J = 2.4Hz), 8.65 (dd, 1H, Ji = 1.6Hz, J2 = 2.4Hz), 8.27 (d, 1H , J = 1.2Hz), 7.96 (dd, 1H, Chi, 2.0Hz, J2 = 8.4Hz), 7.50 (d, 1H, J = 8.4Hz), 4.31-4.34 (m, 2H), 3.15 ~ 3.17 (m , 2H), 2.90-2.93 (m, 1H), 2.55 ~ 2.63 (m, 4H), 2.03-2. l (m, 2H), 1.80 ~ 1.90 (m, 2H), 1.57-1.67 (m, 2H). MS (ESI): m / z 348 (M + H +). 122. Compound 122: (3-Cyclobutyl-8- (pyrazin-2-ylmethyl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) To a solution of compound 121 (54 mg, 0.15 mmol, 1.0 eq) in acetic acid (8 ml) was added solid I2 (38 mg) and H3P02 (50% solution in water, 100 mg, 0.75 mmol, 5.0 eq. ) and the reaction mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated by evaporation; the residue was dissolved in an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product from the crude reaction was purified by preparative TLC to give compound 122 (25 mg, 51%) as a pale yellow solid. LH-NMR (400MHz, CDC13): d 8.50 (dd, 1H, Ji, 2.4Hz, J2 = 1.6Hz), 8.46 (d, 1H, J = 1.2Hz), 8.38 (d, 1H, J = 2.8Hz) , 7.58 (s, 1H), 7.15-7.21 (m, 2H), 4.29 (s, 2H), 4.20 ~ 4.22 (m, 2H), 3.21-3.24 (m, 2H), 2.90-2.93 (m, 1H) , 2.58 ~ 2.64 (m, 4H), 2.08-2.15 (mf 2H), 1.87-1.93 (m, 2H), 1.65-1.75 (m, 2H). MS (ESI): m / z 334 (M + H +). 123. Compound 123: (3-cyclobutyl-8- (pyrimidin-2-yl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) This compound was prepared in 38% yield (20 mg) as described for compound 22 but using 2-chloropyrimidine as the starting material. 1 H-NMR (400MHz, CDC13) d: 8.78-8.81 (m, 3H), 8.40 (dd, 1H, J1 (8.4Hz, J2 = 1.2 Hz), 7.28-7.33 (m, 1H), 7.13 (m, 1H ), 4.24-4.27 (m, 2H), 3.25-3.28 (m, 2H), 2.89-2.92 (m, 1H), 2.60-2.67 (m, 4H), 2.09-2.13 (m, 2H), 1.88-1.93 (m, 2H), 1.64-1.74 (m, 2H) MS (ESI): m / z 320.0 (M + H +). 124. Compound 124: (3-cyclobutyl-8- (pyrimidin-4-yl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) compound was prepared in 36% yield mg) as described for compound 22 but using 4-chloropyrimidine as the starting material. 1 H-NMR (400MHz, CDCl 3) d: 9.25 (d, J = 0.8Hz, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.12 (dd, J = 8.4, 1.6 Hz, 1H), 7.77 (dd, Jx = 5.2Hz, Ji = Ll Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 4.27-4.30 (m, 2H), 3.27- 3.30 (m, 2H), 2.92-2.96 (m, 1H), 2.62-2.69 (m, 4H), 2.11-2.17 (m, 2H), 1.89-1.94 (m, 2H), 1.65-1.76 (m, 2H) ). MS (ESI): m / z 320.0 (M + H +). 125. Compound 125: (3-cyclobutyl-8- (pyridazin-3-yl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) This compound was prepared in 25% yield (25 mg) as described for compound 22 but using 3-chloropyridazine as the starting material. ^ -NMR (400MHz, CDC13) d: 9.12 (dd, Ji = 4.8Hz, Jx = 1.6Hz, 1H), 8.26 (d, J = 1.2Hz, 1H), 8.19 (dd, J2 = 1.6Hz, 1H), 7.90 (dd, J1 (8.4Hz, J2 = 1.2Hz, 1H), 7.51-7.55 (m, 1H), 7.40 (d, J = 8.4Hz, 1H), 4.28-4.30 ( m, 2H), 3.27-3.29 (m, 2H), 2.92-2.96 (m, 1H), 2.62-2.69 (m, 4H), 2.10-2.16 (m, 2H), 1.89-1.94 (m, 2H) ), 1.65-1.76 (m, 2H) MS (ESI): m / z 320.0 (M + H +). 126. Compound 126: (3-cyclobutyl-8- (pyrimidin-5-yl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazof 1,2-d] [1,4] diazepine) This compound was prepared in 15% yield (8 mg) as described for compound 22 but using 5-bromopyrimidine as the starting material. 1H-NMR (400MHz, CDC13) d: 9.19 (s, 1H), 8.99 (s, 2H), 7.90 (s, 1H), 7.46 (dd, Ji = 8.4Hz, J2 = 1.2 Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 4.28-4.30 (m, 2H), 3.27-3.30 (m, 2H), 2.90-2.98 (m, 1 H), 2.63-2.69 (m, 4H), 2.1 1 -2.17 (m, 2H), 1.88-1.98 (m, 2H), 1.61-1.79 (m, 2H). MS (ESI): m / z 320.0 (M + H +). 127. Compound 127: (3-cyclobutyl-8- (pyridazin-4-yl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) This compound was prepared in 23% yield (12 mg) as described for compound 22 but using 4-bromopyridazine as the starting material. 1H-NMR (400MHz, CDC13) d: 9.52 (s, 1H), 9.19 (d, J = 5.2Hz, 1H), 8.01 (s, 1H), 7.68 (dd, Ji = 5.6Hz, J2 = 2.4Hz, 1H), 7.56 (dd, Ji, 8.0Hz, J2 = 2.4 Hz, 1H), 7.40 (d, J = 8.0Hz, 1H), 4.28-4.30 (m, 2H), 3.27-3.30 (m, 2H), 2.91-2.98 (m, 1H), 2.63-2.69 (m, 4H), 2.11-2.17 (m, 2H), 1.87-1.97 (m, 2H), 1.61-1.79 (m, 2H). MS (ESI): m / z 320.0 (M + H +). 128. Compound 128: (3-cyclobutyl-cyclobutylpiperidin-3-yl) -2,3,4,5-tetrahydro-lH-benzo [, 5] imidazo [1,2-d] [1,] diazepine) This compound was prepared in 30% yield (15 mg) as described for compound 8 but using intermediate 1-45 as the starting material. 1H-NMR (400MHz, CD3OD) d: 7.31 (s, 1H), 7.26 (d, J = 6.8Hz, 1H), 7.06-7.08 (m, 1H), 4.19-4.21 (m, 2H), 3.20-3.21 (m, 2H), 2.86-2.96 (m, 3H), 2.84-2.86 (m, 1H), 2.73-2.78 (m, 1H), 2.48-2.54 (m, 4H), 2.01-2.06 (m, 2H) , 1.98-2.01 (m, 1H), 1.96-1.98 (m, 1H), 1.88-1.92 (m, 5H), 1.67-1.84 (m, 3H), 1.59-1.64 (m, 5H), 1.41-1.50 ( m, 1H). MS (ESI): m / z 379 (M + H +). 129. Compound 129: (3-Cyclobutyl-8- (1- (pyrazin-iloi) piperidin-3-yl) -2,4,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d ] [1, 4] diazepine) This compound was prepared in 16% yield (6 mg) as described for compound 65 but using intermediate 1-45 as the starting material. 1H-NMR (400 MHz, CD3OD) d: 8.13 (d, J = 1.2 Hz, 1H), 8.00-8.02 (m, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 8.4Hz, 1H), 7.18 (dd, Ji, 8.4Hz, J2 = 1.2Hz ( 1H), 4.41-4.84 (m, 2H), 4.25-4.27 (m, 2H), 3.12-3.15 (rn, 2H), 2.90-2.95 (m, 3H), 2.78-2.84 (m, 1H), 2.54-2.61 (m, 4H), 2.00-2.12 (m, 3H), 1.82-1.90 (m, 4H), 1.62-1.70 (m, 3H). MS (ESI): m / z 403 (M + H +). 130. Compound 130: (3-cyclobutyl-8- (1- (pyrimidin-2-yl) piperidin-3-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4,5] imidazo [1, 2 -d] [1, 4] diazepine) This compound was prepared in 10% yield (6 mg) as described for compound 65 but using intermediate 1-45 as the starting material. 1 H-NMR (400 MHz, CD 3 OD) d: 8.21 (d, J = 4.0 Hz, 2 H), 7.41 (s, 1 H), 7.73 (d, J = 6.4 Hz, 1 H), 7.16 (d, J = 8.0 Hz , 1H), 6.44-6.47 (m, 1H), 4.68-4.75 (m, 2H), 4.23-4.25 (m, 2H), 3.11-3.13 (m, 2H), 2.87-2.91 (m, 3H), 2.76 -2.75 (m, 1H), 2.53-2.59 (m, 4H), 1.98-2.09 (m, 3H), 1.77-1.90 (m, 4H), 1.51-1.70 (m, 3H). MS (ESI): m / z 403 (M + H +). 131. Compound 131: (3-cyclobutyl-8- (2- (pyrrolidin-1-yl) irimidin-4-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4,5] imidazo [1,2 -d] [1,4] diazepine) Intermediate 1-17 (50 mg, 0.14 mmol, 1.0 eq), 4-bromo-2- (pyrrolidin-yl) pyrimidine (46 mg, 0.20 mmol 1.5 eq), Pd (PPh3) 4 (16 mg, 0.014 mmol , 0.1 eq) and potassium carbonate (113 mg, 0.82 mmol, 6.0 eq) were dissolved in a mixture of dioxane (1.5 mL) and water (0.5 mL) and degassed by bubbling argon. The reaction mixture was stirred at 120 ° C with microwave irradiation for 60 minutes, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by preparative TLC to give compound 131 (30mg, 58%) as a pale yellow solid. 1H-NMR (400MHz, CDC13) d: 8.83 (d, 1H, J = 1.2Hz), 8.38 (dd, 1H, J1 = 1.2Hz, J2 = 8.8Hz), 8.26 (d, 1H, J = 6.0Hz) , 7.26 (m, 1H), 6.16 (d, 1H, J = 6.0Hz), 4.24-4.26 (m, 2H), 3.35-3.76 (brm, 4H), 3.25 ~ 3.27 (m, 2H), 2.92 (m , 1H), 2.61-2.66 (m, 4H), 2.10-2.13 (m, 2H), 2.03 (m, 4H), 1.89-1.93 (m, 2H), 1.64 ~ 1.75 (m, 2H). MS (ESI): m / z 389 (M + H +). 132. Compound 132: (3-cyclobutyl-8- (2-methoxypyrimidin-4-yl) -2, 3,, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1, 4] diazepine) This compound was prepared in 27% yield (13 mg) as described for compound 22 but using 4-bromo-2-methoxypyrimidine as the starting material. 1H-NMR (400MHz, CDC13) d 8.77 (d, J = I .2Hz, 1H). 8.42 (d, J = 6.0Hz, 1H), 8.33 (dd, Jlf1.6Hz, J2 = 8.8Hz, 1H), 7.23 (d, J = 8.8Hz, 1H), 6.52 (d, J = 6.0Hz, 1H) ), 4.20 (m, 2H), 4.03 (s, 3H), 3.20 (m, 2H), 2.87 (m, 1H), 2.58 (m, 4H), 2.06 (m, 2H), 1.85 (m, 2? ), 1 · 64 (m, 2H). MS (ESI): m / z 350 (M + H +). 133. Compound 133: (3-Cyclobutyl-8- (6- (pyrrolidin-1-yl) pyridazin-3-yl) -2,4,4,5-tetrahydro-1-libenzo [4, 5] imidazo [1,2-d] ] [1,4] diazepine) Intermediate 1-17 (50 mg, 0.14 mol, 1.0 eq), 3-chloro-6- (pyrrolidin-1-yl) pyridazine (37 mg, 0.20 mmol, 1.5 eq), Pd (PPh3) 4 (16 mg , 0.014 mmol, 0.1 eq) and potassium carbonate (56 mg, 0.41 mmol, 3.0 eq) were dissolved in a mixture of DME (1.0 mL) and water (0.5 mL) and degassed by bubbling argon. The reaction mixture was stirred at 85 ° C with microwave irradiation for 70 minutes, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product from the crude reaction was purified by preparative TLC to give compound 133 (12 mg, 23%) as a pale yellow solid. 1H-NMR (400MHz, CDC13) d: 8.12-8.14 (m, 2H), 7.68 (d, 1H, J = 9.2Hz), 7.33 (d, 1H, J = 9.2Hz), 6.73 (d, 1H, J = 9.6Hz), 4.25-4.27 (m, 2H), 3.59 ~ 3.62 (m, 4H), 3.25 ~ 3.28 (m, 2H), 2.91 ~ 2.95 (m, 1H), 2.61 ~ 2.67 (m, 4H), 2.11-2.14 (m, 2H), 2.04 ~ 2.09 (m, 4H), 1.89-1.94 (m, 2H), 1.50-1.76 (m, 2H). MS (ESI): m / z 389 (+ H +). 134. Compound 134: (3-cyclobutyl-8- (6-methoxypyridazin-3-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1, 4 Jdiazepine) This compound was prepared in 13% yield (6 mg) as described for compound 133 but using 3- bromo-6-methoxypyridazine as the starting material, ^ -NMR (400MHz, CDCI3) d: 8.19 (d, J = 1.6Hz, 1H). 8.11 (dd, Jx = 1.6Hz, J2 = 8.4Hz, 1H), 7.85 (d, J = 9.2Hz, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.06 (d, J = 9.2Hz, 1H), 4.28 (m, 2H), 4.19 (s, 3H), 3.28 (m, 2H), 2.94 (m, 1H), 2.65 (m, 4H), 2.15 (m, 2H), 1.91 (m, 2H) ), 1.71 (m, 2H). MS (ESI): m / z 350 (M + H +). 135. Compound 135: (3-cyclobutyl-8- (6- (pyrrolidin-yl) pyridin-2-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1, This compound was prepared in 15% yield (8 mg) as described for compound 22 but using 2-bromo-6- (pyrrolidin-1-yl) pyridine as the starting material. 1H-NMR (400MHz, CDC13) d: 8.33 (m, 1H), 7.96 (d, 1H, J = 8.8Hz), 7.41-7.45 (m, 1H), 7.21 (m, 1H), 6.99 (d, 1H) , J = 7.6Hz), 6.22 (d, 1H, J = 8.0Hz), 4.21 ~ 4.22 (m, 2H), 3.49 (m, 4H), 3.23 (m, 2H), 2.89 (m, 1H), 2.60 (m, 4H), 2.04 ~ 2.08 (m, 2H), 1.88-1.95 (m, 6H), 1.56 ~ 1.62 (m, 2H). MS (ESI): m / z 388 (M + H +). 136. Compound 136: (3-Cyclobutyl-8- (6- (4-methylpiperazin-1-yl) pyridin-2-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1 , 2-d] [1,4] diazepine) This compound was prepared in 26% yield (15 mg) as described for compound 22 but using 1- (6-bromopyridin-2-yl) -4-methylpiperazine as the starting material. 1H-NMR (400MHz CDC13) d: 8.37 (d, 1H, J = 1.2Hz), 7.97 (dd, 1H, 7. 53-7.57 (m, 1H), 7.27 (d, 1H, J = 8.8Hz), 7.16 (d, 1H, J = 7.2Hz), 6.57 (d, 1H, J = 8.0Hz), 4.24-4.26 (m , 2H), 3.68 ~ 3.70 (m, 4H), 3.24-3.27 (m, 2H), 2.91 ~ 2.93 (m, 1H), 2.61-2.67 (m, 4H), 2.55 ~ 2.58 (m, 4H), 2.37 (s, 3H), 2.10-2.14 (m, 2H), 1.89 ~ 1.94 (m, 2H), 1.65-1.76 (m, 2H). MS (ESI): m / z 417 (M + H +). 137. Compound 137: (3-cyclobutyl-8- (6-methoxypyridin-2-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1, 4 Jdiazepine) compound was prepared in 10% yield mg) as described for compound 22 but using 2-bromo-6-methoxypyridine as the starting material. 1H-NMR (400MHz, CDC13) d: 8.19 (d, J = 1.2 Hz, 1H), 8.01 (dd, Ji = 1.6Hz, J2 = 8.4Hz, 1H), 7.63 (m, 1H), 7.38 (d, J = 7.6Hz, 1H), 7.30 (d, J = 8.8Hz, 1H), 6.65 (d, J = 7.6Hz, 1H), 4.29 (m, 2H), 4.05 (s, 3H), 3.29 (m, 2H), 2.95 (m, 1H), 2.66 (m, 4H), 2.13 (m, 2H), 1.97 (m, 2H) ), 1.73 (m, 2H). MS (ESI): m / z 349 (M + H +). 138. Compound 138: (2- (3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl) ethanamine) To a solution of intermediate 1-46 (312 mg, 1. 0 mmol, 1.0 eq) in MeOH (10 mL) was added NaBH 4 (120 mg, 3.0 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 2 hours. The solids were removed by filtration through a short plug of Celite to give a solution of intermediate 1-47 (MS (ESI): m / z 315.0 (M + H +)) to which an aqueous suspension of Raney was added. Ni (300 mg) and the reaction mixture was stirred at room temperature under H2 atmosphere (1 atm) for 2 hours. The solids were removed by filtration through a short plug of Celite, the filtrate was concentrated by evaporation and the crude reaction product was purified by reverse phase column chromatography to give compound 138 (140 mg, 50%) as solid white. 1H-NMR (400MHz, CD3OD) d: 7.45 (t, J = 8.8Hz, 2H), 7.20 (dd, J = 8.8Hz, 1H), 4.36 (t, J = 4.4Hz, 2H), 3.23 (t, J = 4.8Hz, 2H), 2.97-3.11 (m, 5H), 2.63-2.70 (dt, J = 4.8Hz, 4H), 2.18 (m, 2H), 1.97 (m, 2H), 1.71-1.76 (m, 2H). MS (ESI): m / z 285.0 (M + H +). 139. Compound 139: (2- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl) -, -dimethylethanamine) To a solution of compound 138 (20 mg, 0.07 mmol) in formic acid (3 mL) was added solid paraformaldehyde (50 mg, 1.6 mmol, 22 eq) and the reaction mixture was stirred at 50 ° C for 16 hours. The excess solvent was removed by evaporation and the crude reaction product was purified by preparative TLC to give compound 139 (6 mg, 30%). XH-NMR (400MHz, CD3OD) d: 7.45 (t, J = 8.8Hz 2H), 7.20 (dd, J = 8.8Hz, 1H), 4.36 (t, J = 4.4Hz, 2H), 3.23 (t, J) = 4.8Hz, 2H), 2.97-3.02 (m, 3H), 2.83 (m, 2H), 2.64-2.71 (dt, J = 4.8Hz, 4H), 2.50 (s, 6H), 2.18 (m, 2H) , 1.97 (m, 2H), 1.71-1.76 (m, 2H). MS (ESI): m / z 313.0 (M + H +). 140. Compound 140: ((3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo [4,5] imidazo [1,2-d] [1,4] diazepin-8-yl) methanamine) This compound was prepared in 90% yield (1.1 g) as described for compound 1 but using compound 54 as the starting material. 1H-NMR (400MHz, CD30D) d: 7.59 (s, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.30 (dd, J = 8.0 Hz, 1H), 4.35 (t, J = 4.8Hz, 2H), 3.99 (s, 2H), 3.21 (t, J = 4.8Hz, 2H), 3.00 (q, J = 7.6Hz, 1H), 2.62-2.69 (m, 4H), 2.12-2.18 (m, 2H) ), 1.92-1.97 (m, 2H), 1.69-1.77 (m, 2H). MS (ESI): m / z 271 (M + H +). 141. Compound 141: (benzyl ((3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl) methyl) This compound was prepared in 40% yield (89 mg) as described for compound 98 but using compound 140 as the starting material. H NMR (400MHz, CDC13) d: 7.59 (s, 1H), 7.30-7.37 (m, 5H), 7.21 (s, 1H), 5.12 (s, 2H), 4.49 (d, J = 6.0Hz, 2H), 4.27 (s, 2H), 3.28 (t, J = 4.4 Hz, 2H), 2.97 (q, J = 7.6 Hz, 1H), 2.65 (m, 4H), 2.11-2.18 (m, 2H), 1.95-2.00 (m, 2H), 1.66-1.78 (m, 2H). MS (ESI): m / z 405 (M + H +). 142. Compound 142: (((3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1,2- d] [1,4] diazepin-8-yl) methyl) ( methyl) benzyl carbamate) To a solution of compound 141 (122 mg, 0.30 mmol, 1.0 eq) in THF (5 mL) was added NaH (13 mg, 60% dispersion in mineral oil, 0.33 mmol, 1.1 eq) and the reaction was stirred at room temperature for 30 minutes. Pure TMSCH2I (96 mg, 0.14 mmol, 4.6 eq) was added and the reaction mixture was refluxed for an additional 18 hours and concentrated by evaporation. The product of the crude reaction was purified by reverse phase column chromatography of Ci8 to give compound 142 (90 mg, 71%). 1H-NMR (400MHz, CDC13) d: 7.43 (br, 1H), 7.17-7.24 (m, 5H), 7.09 (s, 1H), 5.06 (s, 2H), 4.46 (s, 2H), 4.10 (t , J = 4.4Hz, 2H), 3.11 (t, J = 4.4Hz, 2H), 2.72-2.81 (m, 4H), 2.49 (m, 4H), 1.97-2.00 (m, 2H), 1.76-1.81 ( m, 2H), 1.52-1.62 (m, 2H). MS (ESI): m / z 419 (M + H +). 143. Compound 143: (2-benzyl-8-cyclobutyl-7, 8, 9, 10-tetrahydro- [1,4] diazepino [1 ', 7': 1, 2] imidazo [4,5-f] isoindol-l , 3 (2H, 6H) -dione) To a solution of intermediate product 1-58 (0.50 g, 1. 1 mmol, 1.0 eq) in acetic acid (10 mL) was added elemental iron (0.25 g, 4.4 mmol, 4.0 eq) and the reaction mixture was stirred at 80 ° C for 3 hours. The solids were removed by filtration through a short plug of Celite and the filtrate was concentrated by evaporation. The residue was dissolved with dichloromethane and the neutral pH was adjusted by adding an aqueous solution of Na2CC > 3 and the crude reaction mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO 4. The solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give compound 143 (200 mg, 48%). 1 H-NMR (400MHz, CDC13) 6: 8.10 (s, 1H), 7.73 (s, 1H), 7.45 (d, J = 7.6Hz, 2H), 7.32 (t, J = 7.2Hz, 3H), 4.87 ( s, 2H), 4.32 (s, 2H), 3.30 (s, 2H), 2.94 (t, J = 4.4Hz, 1H), 2.65 (m, 4H), 2.13-2.18 (m, 2H), 1.89-1.93 (m, 2H), 1.66-1.77 (m, 2H). MS (ESI): m / z 401.0 (M + H +). 144. Compound 144: 2-benzyl-8-cyclobutyl-1,2,3,6,7,8,9, 10-octahydro- [1,4] diazepinof 1 ', 7': 1, 2] imidazo [4, 5 -f] isoindol) To a solution of compound 143 (1.3 g, 3.2 mmol, 1.0 eq) in THF (10 mL) was added dropwise a suspension of LiAlH4 (350 mg, 9.6 mmol, 3.0 eq) in dry THF (20 mL) and the mixture of the reaction was refluxed for 3 hours. The reaction was quenched by adding a saturated aqueous Na 2 SO solution. The crude reaction mixture was extracted with dichloromethane, the combined organic layers were dried over anhydrous MgSO 4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give compound 144 (850 mg, 70%). ^ -NMR (400MHz, CDC13) d: 7.44 (d, J = 9.2Hz, 3H), 7.36 (t, J = 7.6Hz, 2H), 7.30 (d, J = 7.6Hz, 1H), 7.02 (s, 1H), 4.18 (t, J = 4.8Hz, 2H), 4.02 (s, 4H), 3.95 (s, 2H), 3.21 (t, J = 4.8Hz, 2H), 2.94 (q, J = 4.0Hz, 1H), 2.58-2.63 (m, 4H), 2.09-2.17 (m, 2H), 1.88-1.93 (m, 2H), 1.64-1.75 (m, 2H). MS (ESI): m / z 373 (M + H +). 145. Compound 145: (8-cyclobutyl-1, 2, 3, 6, 7, 10-octahydro- [1,4] diazepino [1 ', 7': 1, 2] imidazo [4, 5-f] isoindole) To a solution of compound 144 (400 mg, 1.1 mmol, 1.0 eq) in acetic acid (10 mL) was added palladium on carbon (0.30 g, 0.08 eq) and the reaction mixture was stirred at room temperature under H2 ( 1 atm) for 16 hours. The solids were removed by filtration through a short plug of Celite and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by reverse phase column chromatography to give compound 145 (150 mg, fifty%). ^ - MR (400MHz, CD3OD) d: 7.59 (s, 1H), 7.54 (s, 1H), 4.66 (s, 4H), 4.38 (t, J = 4.4Hz, 2H), 3.24 (s, 2H), 3.01 (q, J = 4.4Hz, 1H), 2.66-2.71 (m, 4H), 2.14-2.20 (m, 2H), 1.94-2.05 (m, 2H), 1.70-1.78 (m, 2H). MS (ESI): m / z 284 (M + H +). 146. Compound 146: (8-cyclobutyl-2-methyl-1, 2, 3, 6, 7, 8, 9, 10-octahydro- [1,4] diazepino [1 ', 7': 1, 2] imidazo [4 , 5-f] isoindol) This compound was prepared in 33% yield (7 mg) as described for compound 139 but using compound 145 as the starting material. 1 H-NMR (400MHz, CDCl 3) d: 7.49 (s, 1H), 7.08 (s, 1H), 4.20 (t, J = 4.4Hz, 2H), 4.15 (S, 4H), 3.22 (t, J = 4.4 Hz, 2H), 2.92 (q, J = 4.4Hz, 1H), 2.72 (s, 3H), 2.58-2.63 (m, 4H), 2.10-2.13 (m, 2H), 1.88-1.94 (m, 2H) , 1.65-1.73 (m, 2H). MS (ESI): m / z 297.0 (M + H +). 147. Compound 147: (8-cyclobutyl-2- (cyclopropylmethyl) 1,2,3,6,7,8,9, 10-octahydro- [1,4] diazepino [1 ', 7': 1, 2] imidazo [ 4, 5-f] isoindol) This compound was prepared in 30% yield (6 mg) as described for compound 8 but using compound 145 and cyclopropancarbaldehyde as the starting materials. 1H-NMR (400MHz, CDC13) d: 7.50 (s, 1H), 7.08 (s, 1H), 4.19 (s, 6H), 3.23 (t, J = 4.4Hz, 2H), 2.92 (q, J = 4.4 Hz, 1H), 2.73 (d, J = 6.4Hz, 2H), 2.59-2.64 (m, 4H), 2.09-2.15 (m, 2H), 1.86-1.98 (m, 2H), 1.62-1.78 (m, 2H), 1.08-1.11 (m, 1H), 0.60 (m, 2H), 0.28 (m, 2H). MS (ESI): m / z 337.1 (M + H +). 148. Compound 148: (8-cyclobutyl-2- (pyrimidin-2-yl) -1,2,3,6,7,8,9, 10-octahydro- [1,4] diazepino [1 ', 7':] imidazo [4, 5-f] isoindol) This compound was prepared in 27% yield (10 mg) as described for compound 65 but using compound 145 and 2-bromopyrimidine as the starting materials. 1H-NMR (400MHz, CDC13) d: 8.41 (s, 1H), 8.40 (s, 1H), 7.60 (s, 1H), 7.18 (s, 1H), 6.57 (t, J = 4.8Hz, 1H), 5.01 (S, 4H), 4.25 (t, J = 4.4Hz, 2H), 3.26 (t, J = 4.4Hz, 2H), 2.94 (q, J = 4.4Hz, 1H), 2.61-2.67 (m, 4H) ), 2.10-2.17 (m, 2H), 1.88-1.96 (m, 2H), 1.72-1.79 (m, 2H). MS (ESI): m / z 361.1 (M + H +). 149. Compound 149: (8-cyclobutyl-2- (pyrazin-2 1,2,3,6,7,8,9,10-octahydro [1,4] diazepino [11, 7 ': 1, 2] imidazo [4 , 5-f] isoi This compound was prepared in 25% yield (10 mg) as described for compound 65 but using compound 145 and 2-iodopyrazine as starting materials. 1H-NMR (400MHz, CDC13) d: 8.13 (s, 1H), 8.05 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.20 (s, 1H), 4.95 (s, 4H), 4.25 (t, J = 4.4Hz, 2H), 3.26 (t, J = 4.4 Hz, 2H), 2.94 (q, J = 4.4Hz, 1H), 2.62-2.68 (m, 4H), 2.1 1-2.17 (m, 2H), 1.89-1.96 (m, 2H) , 1.66-1.77 (m, 2H). MS (ESI): m / z 361.1 (M + H +). 150. Compound 150: (3-cyclobutyl-8- (1 H-1,2,3-triazol-1-yl) -2,3,4,5,5-tetrahydro-lH-benzo [4,5] imidazo [1,2- d] [1,4] diazepine) 151. Compound 151: (3-cyclobutyl-8- (2H-1,2,3-triazol-2-yl) -2,3,4,5,5-tetrahydro-1H-benzo [4, 5] imidazo [1, 2 d] [1, 4] diazepine) The compound was prepared in 40% yield (150 mg) and compound 151 was prepared in 10% yield (38 mg) by preparative reverse phase HPLC separation of a mixture of regioisomers prepared as described for compound 66 but using 1,2,3-triazole as the starting material.

Compound 150: XH-NMR (400MHz, CD3OD) d: 8.57 (d, 1H, J = 0.8Hz), 8.03 (d, 1H, J = 2.4Hz), 7.94 (d, 1H, J = 1.2Hz), 7.80 (m, 1H), 7.70 (d, 1H, J = 8.8Hz), 4.45 (m, 2H), 3.30 (m, 2H), 3.05 (m, 1H), 2.71 (m, 4H), 2.21 (m, 2H), 1.99 (m, 2H), 1.78 (m, 2H). MS (ESI): m / z 309.2 (M + H +).

Compound 151: 1 H-NMR (400MHz, CD3OD) d: 8.22 (d, 1H, J = 2.0Hz), 8.03 (m, 1H), 7.91 (s, 2H), 7.60 (m, 1H), 4.40 (m, 2H), 3.25 (m, 2H), 3.02 (m, 1H), 2.71 (m, 4H), 2.16 (m, 2H), 1.98 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 309.2 (M + H +). 152. Compound 152: (3-cyclobutyl-8- (1 H-1,2,4-triazol-yl) -2,3,4,5,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepine) compound was prepared in 40% yield mg) as described for compound 66 but using 1,2,4-triazole as the starting material. 1H-NMR (400MHz, CD30D) d: 9.08 (s, 1H), 8.17 (s, 1H), 7.98 (d, 1H, J = 2.0Hz), 7.74 (m, 1H), 7.65 (d, 1H, J = 8.8Hz), 4.42 (m, 2H), 3.25 (m, 2H), 3.02 (m, 1H), 2.70 (m, 4H), 2.16 (m, 2H), 1.96 (m, 2H), 1.72 (m , 2H). MS (ESI): m / z 309.2 (M + H +). 153. Compound 153: (3-cyclobutyl-8- (2-methyl-lH-imidazol-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1, 4] diazepine) This compound was prepared in 30% yield (60 mg) as described for compound 66 but using 2-methyl-1H-imidazole as the starting material. 1H-NMR (400MHz, CDC13) d: 7.60 (d, 1H, J = 1.6Hz), 7.31 (m, 1H), 7.16 (m, 1H), 7.03 (s, 2H), 4.29 (m, 2H), 3.28 (m, 2H), 2.95 (m, 1H), 2.65 (m, 4H), 2.34 (s, 3H), 2.13 (m, 2H), 1.92 (m, 2H), 1.74 (m, 2H). MS (ESI): m / z 322.2 (M + H +). 154. Compound 154: (3-cyclobutyl-8- (1H-tetrazol-1-yl) -2,3,4,5-tetrahydro-1H-benzo [4,5] imidazo [1,2-d] [1, 4 ] diazepine) To a solution of intermediate 1-30 (100 mg, 0.39 mmol, 1.0 eq) and trimethoxymethane (62 mg, 0.59 mmol, 1.5 eq) in acetic acid (5 mL) was added NaN3 (40 mg, 0.59 mmol, 1.5 eq). ) and the reaction mixture was stirred at 100 ° C for 16 hours. A saturated aqueous solution of NaHCO 3 was added and the pH -8 adjusted. The crude reaction mixture was extracted with dichloromethane, the layers The combined organic extracts were dried over anhydrous MgSO.sub.4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel gel column chromatography to give compound 154 (72 mg, 60%). 1H-NMR (400MHz, DMSO-d6) d: 10.07 (s, 1H), 8.07 (d, 1H, J = 2.0Hz), 7.73 (m, 2H), 4.39 (m, 2H), 3.19 (m, 2H) ), 2.95 (m, 1H), 2.58 (m, 4H), 2.06 (m, 2H), 1.82 (m, 2H), 1.61 (m, 2H). MS (ESI): m / z 310.1 (M + H +). 155. Compound 155: (mixture of B-cyclobutyl-8- (5-methyl-1H-imidazol-1-yl) -2, 3,, 5-tetrahydro-1H-benzo [4,5] imidazo [1,2-d] [1,4] diazepine and 3-cyclobutyl-8 (4-methyl-lH-imidazol-1-yl) -2,4,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2- d] [1,4] diazepine) compound was prepared in 40% yield mg) as described for compound 66 but using 4-methyl-lH-imidazole as the starting material.

-NMR (400MHz, CD3OD) d: 8.11 (s, 1H), 7.69 (d, 1H, 2.4Hz), 7.59 (d, 1H, J = 9.2Hz), 7.45 (m, 1H), 7.33 (s,) , 4.43 (m, 2H), 3.26 (m, 2H), 3.05 (m, 1H), 2.75 (m, 4H), 2.28 (s, 3H), 2.17 (m, 2H), 1.99 (m, 2H), 1.78 (m, 2H). MS (ESI): m / z 322.2 (M + H +). 156. Compound 156: (3-Cyclobutyl-8- (5-methyl-1H-tetrazol-1-yl) -2,3,4,5-tetrahydro-1H-benzo [4,5] imidazo [1,2-d] [1,4 Jdiazepine) This compound was prepared in 50% yield (60 mg) as described for compound 154 but using 1,1,1-trimethoxyethane as the starting material. ^ - MR (400MHz, CD3OD) d: 7:71 (d, 1H, J = 2.0Hz), 7.42 (d, 1H, J = 8.4Hz), 7.33 (m, 1H), 4.36 (m, 2H), 3.33 (m, 2H), 2.98 (m, 1H), 2.73 (m, 4H), 2.59 (s, 3H), 2.15 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H). MS (ESI): m / z 324.2 (M + H +). 157. Compound 157: (3-Cyclobutyl-8- (3-methyl-4H-1, 2,4-triazol-4-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4,5] imidazo [ 1, 2-d] [1,4] diazepine) AcNHNHj »< MBO (JCKNM &J To a solution of (MeO) 2CHNMe2 (70 mg, 0.59 mmol, 1.5 eq) in acetonitrile (5 mL) was added AcNHNH2 (44 mg, 0. 59 mmol, 1.0 eq) and the reaction mixture was stirred at 50 ° C for 30 minutes. Acetic acid (100 mg, 1.6 mmol, 4.0 eq) and intermediate 1-30 (100 mg, 0.39 mmol, 1.0 eq) were added and the reaction mixture was stirred at 120 ° C for an additional 2 hours. The crude reaction mixture was concentrated by evaporation and the crude reaction product was purified by silica gel column chromatography to give compound 157 (69 mg, 55%). 1 H-NMR (400MHz, CD30D) d: 8.63 (s, 1H), 7.69 (m, 2H), 7.34 (m, 1H), 4.44 (m, 2H), 3.29 (m, 2H), 3.03 (m, 1H) ), 2.69 (m, 4H), 2.40 (s, 3H), 2.18 (m, 2H), 1.97 (m, 2H), 1.76 (m, 2H1). MS (ESI): m / z 323.2 (M + H +). 158. Compound 158: (mixture of 3-cyclobutyl-8- (2,4-dimethyl-1H-imidazol-1-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4, 5] imidazo [1, 2-d] [1,4] diazepine and 3-cyclobutyl-8- (2,5-dimethyl-lH-imidazol-l, -yl) -2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepine) This compound was prepared in 30% yield (63 mg) as described for compound 66 but using 2,4-dimethyl-1H-imidazole as the material initial. 1H-NMR (400MHz, CD3OD) d: 7.60 (m, 1H), 7.55 (ra, 1H), 7.27 (m, 1H), 6.94 (s, 1H), 4.43 (m, 2H), 3.25 (m, 2H), 3.02 (m, 1H), 2.70 (m, 4H), 2.27 (s, 3H), 2.22 (s, 3H), 2.16 (m, 2H), 1.96 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 336.2 (M + H +). 159. Compound 159: (3-Cyclobutyl-8- ((4-fluoropiperidin-1-yl) methyl) -2, 3, 4, 5-tetrahydro-1 H -benzo [4, 5] imidazo [1, 2-d] [ 1, 4] diazepine) This compound was prepared in 40% yield (27 mg) as described for compound 74 but using 4-fluoropiperidine as the starting material. H-NMR (400MHz, CD3OD): d 7.54 (s, 1H), 7.42 (d, 1H, J = 8.4Hz), 7.27 (dd, 1H, Ji = 8.4Hz, J2 = 1.6Hz), 4.65 (m, 1H), 4. 34 (m, 2H), 3.655 (s, 2H), 3.30 (m, 2H), 3.00 (m, 1H), 2. 65 (m, 6H), 2.45 (m, 2H), 2.15 (m, 2H), 1.60 (m, 8H). MS (ESI): m / z 357.2 (M + H +). 160. Compound 160: (3-cyclobutyl-8- ((4,4-difluoropiperidin-1-yl) methyl) -2, 3, 4, 5-tetrahydro-1H-benzo [4,5] imidazo [1, 2-d ] [1,4] diazepine) This compound was prepared in 43% yield (39 mg) as described for compound 74 but using 4, -difluoropiperidine as the starting material. 1H-NMR (400MHz, CDC13) d: 7.53 (s, 1H), 7.14 (m, 2H), 4.15 (m, 2H), 3.59 (s, 2H), 3.16 (m, 2H), 2.85 (m, 1H), 2.55 (m, 8H), 2.05 (m, 2H), 1.88 (m, 6H), 1.65 (m, 2H). MS (ESI): m / z 375.2 (M + H +). 161. Compound 161: (3-cyclobutyl-8- ((3-fluoropiperidin-1-yl) methyl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [ 1,4] diazepine) This compound was prepared in 34% yield (27 mg) as described for compound 74 but using 3-fluoropiperidine as the starting material. 1HNMR (400MHz, CDC13) d: 7.58 (s, 1H), 7.20 (m, 2H), 4.60 (m, 1H), 4.22 (m, 2H), 3.69 (s, 2H), 3.24 (m, 2H), 2.92 (m, 1H), 2.80 (m, 1H,), 2.63 (m, 4H), 2.50 (m, 1H), 2.30 (m, 2H), 2.13 (m, 2H), 1.50-1.95 (m, 8H ). MS (ESI): m / z 357.2 (M + H +). 162. Compound 162: (3-cyclobutyl-8- ((3,3-difluoropiperidin-1-yl) methyl) -2,3,4,5-tetrahydro-lH-benzof 4,5] imidazo [1,2-d] [1,4] diazepine) This compound was prepared in 59% yield (53 mg) as described for compound 74 but using 3, 3-difluoropiperidine as the starting material. 1H-NMR (400MHz, CDC13) d: 7.53 (s, 1H), 7.39 (d, 1H, .6Hz), 4.30 (m, 2H), 3.66 (s, 2H), 3.30 (m, 2H), 3.00 (m, 1H), 2.65 (m, 6H), 2.45 (m, 2H), 2.15 (m, 2H). MS (ESI): m / z 375.2 (M + H +). 163. Compound 163: (3-cyclobutyl-8- ((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) -2,3,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1, 2-d] [1,4] diazepine) This compound was prepared in 43% yield (40 mg) as described for compound 74 but using 1, 2, 3, 4-tetrahydroisoquinoline as the starting material. 1HNMR (400MHz, CD3OD) d: 7.61 (d, 1H, J = 1.2Hz), 7.44 (d, 1H, J = 8.4Hz), 7.33 (dd, 1H, Ji = 8.0Hz, J2 = 1.2Hz), 7.07 (m, 3H), 6.94 (d, 1H, J = 6.8Hz), 4.33 (m, 2H), 3.81 (s, 2H), 3.63 (s, 2H), 3.31 (m, 2H), 2.97 (m, 1H), 2.87 (m, 2H), 2.76 (m, 2H), 2.61 (m, 4H), 2.14 (m, 2H), 1.94 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 387.3 (M + H +). 164. Compound 164: (3-Cyclobutyl-8- ((6-fluoro-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) -2, 3, 4, 5-tetrahydro-lH-benzof 4, 5] imidazo [1, 2-d] [1, 4 jdiazepine) This compound was prepared in 54% yield (52 mg) as described for compound 74 but using 6-fluoro-1,2,3,4-tetrahydroisoquinoline as the starting material. 1H-NMR (400MHz, CD3OD): d 7.61 (s, 1H), 7.43 (d, 1H, J = 8.0Hz), 7.27 (dd, 1H, J2 = 1.6Hz), 6.95 (m, 1H), 6.81 (m, 2H), 4.33 (m, 2H), 3.79 (s, 2H), 3.57 (s, 2H), 3.20 (m, 2H), 2.95 ( m, 1H), 2.87 (m, 2H), 2.74 (m, 2H), 2.61 (m, 4H), 2.13 (m, 2H), 1.93 (m, 2H), 1.75 (m, 2H). MS (ESI): m / z 405.2 (M + H +). 165. Compound 165: (3-Cyclobutyl-8- ((3-fluoropyrrolidin-1-yl) methyl) -2,4,4,5-tetrahydro-lH-benzo [4, 5] imidazof 1,2-d] [1 , 4 Jdiazepine) This compound was prepared in 61% yield (51 mg) as described for compound 74 but using 3-difluoropyrrolidine as the starting material. XH-NMR (400MHz, CD30D) d: 7.55 (d, 1H, J = 1.2Hz), 7.41 (d, 1H, J = 8.4Hz), 7.29 (dd, 1H, Ji = 8.4Hz, J2 = 1.2Hz) , 5.18 (m, 1H), 4.34 (m, 2H), 3.77 (dd, 2H, J2 = 12.4Hz), 3.20 (m, 2H), 2.90 (m, 3H), 2.65 (m, 5H), 2.48 (m, 1H), 2.10 (m, 6H), 1.70 (m, 2H). MS (ESI): m / z 343.2 (M + H +). 166. Compound 166: (3-Cyclobutyl-8- ((3,3-difluoropyrrolidin-1-yl) methyl) -2, 3, 4, 5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d ] [1,4] diazepine) This compound was prepared in 26% yield (23 mg) as described for compound 74 but using 3,3-difluoropyrrolidine as the starting material. 1H-NMR (400MHz, D20): d 7.95 (s, 1H), 7.89 (d, 1H, J = 8.8Hz), 7.71 (d, 1H, J = 8.8Hz), 4.85 (br, 2H), 4.67 ( s, 2H), 3.88 (m, 4H), 3.70 (m, 7H), 2.66 (m, 2H), 2.30 (m, 4H), 1.80 (m, 2H). MS (ESI): mi z 361.3 (M + H +). 167. Compound 167: (1- (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [, 5] imidazo [1,2-d] [1,4] diazepin-8-yl) piperazin-1-yl) ethanone) To a solution of compound 97 (100 mg, 0.31 mmol, 1.0 eq) in dichloromethane was added pure triethylamine (79 mg, 0.77 mmol, 2.5 eq) followed by drip addition of acetyl chloride (49 mg, 0.62 mmol, 2.0 eq. ) at 0 ° C and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding methanol and the reaction mixture was concentrated by evaporation. The product of the crude reaction was purified by reverse phase silica gel column chromatography to give compound 167 (40 mg, 30%). 1H-NMR (400MHz, CDC13) d: 7.23 (d, 1H, J = 1.6Hz), 7.16 (d, 1H, J = 8.8Hz), 7.00 (m, 1H), 4.19 (m, 2H), 3.80 ( m, 2H), 3.65 (m, 2H), 3. 21 (m, 2H), 3.13 (m, 4H), 2.91 (m, 1H), 2.60 (m, 4H), 2. 13 (m, 5H), 1.90 (m, 2H), 1.68 (m, 2H). MS (ESI): m / z 368.2 (M + H +). 168. Compound 168: (4- (4- (3-cyclobutyl-2, 3,4,5-tetrahydro-lH-benzo [4, 5] imidazof 1,2-d] [1,4] diacepin-8-yl) piperazine-l-carbonyl) benzonitrile) This compound was prepared in 70% yield (95 mg) as described for compound 167 but using 4-cyanobenzoyl chloride as the starting material. 1 H-NMR (400MHz, CDCl 3) d: 7.74 (m, 2H), 7.56 (m, 2H), 7.23 (d, 1H, J = 2.4Hz), 7.17 (d, 1H, J = 8.8Hz), 6.99 ( m, 1H), 4.20 (m, 2H), 3.98 (m, 2H), 3.56 (m, 2H), 3.22 (m, 4H), 3.08 (m, 2H), 2.92 (m, 1H), 2.62 (m , 4H), 2.12 (m, 2H), 1.90 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 455.2 (M + H +). 169. Compound 169: ((4- (3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo [4,5] imidazof 1,2-d] [1,4] diazepin-8-yl) piperazine- 1-yl) (pyrazin-2-yl) methanone) This compound was prepared in 30% yield (40 mg) as described for compound 167 but using pyrazin-2-carbonyl chloride as the starting material. 1H-NMR (400MHz, CDC13) d: 9.00 (d, 1H, J = 1.6Hz), 8.66 (d, 1H, J = 2.0Hz), 8.58 (m, 1H), 7.26 (s, 1H), 7.17 ( d, 1H, J = 8.8Hz), 7.02 (m, 1H), 4.21 (m, 2H), 4.02 (m, 2H), 3.84 (m, 2H), 3.26 (m, 4H), 3.17 (m, 2H) ), 2.93 (m, 1H), 2.64 (m, 4H), 2.12 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H). MS (ESI): m / z 432.2 (M + H +). 170. Compound 170: ((4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl) piperazine -1-il) (cyclopropyl) methanone) This compound was prepared in 50% yield (60 mg) as described for compound 167 but using cyclopropanecarbonyl chloride as the starting material. 1H-NMR (400MHz, CDC13) d: 7.32 (m, 2H), 7.16 (d, 1H, J = 8.2Hz), 4.65 (m, 2H), 3.76 (m, 4H), 3.53 (m, 2H), 3.30 (m, 2H), 3.12 (m, 8H), 2.36 (m, 4H), 2.25 (m, 4H), 2.03 (m, 1H), 1.89 (m, 2H), 1.74 (m, 1H). MS (ESI): m / z 408.2 (M + H +). 171. Compound 171: (1- (3- (3-cyclobutyl-2, 3, 4, tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1,4] diazepin-8-yl) piperidine -l-il) ethanone) This compound was prepared in 80% yield (36 mg) as described for compound 167 but using compound 1-45 as the starting material. ^ -NMR (400MHz, CDCI3) d: 7.54 (s, 1H), 7.10-7.23 (m, 2H), 4.77 (m, 1H), 4.21 (m, 2H), 3.87 (m, 1H), 3.24 (m , 2H), 3.10 (m, 1H), 2.91 (m, 1H), 2.79 (m, 1H), 2.60 (m, 5H), 2. 11 (m, 6H), 1.57-1.93 (m, 7H). MS (ESI): m / z 367.2 (M + H +). 172. Compound 172: (4- (3- (3-Cyclobutyl-2,3,4,5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1,4] diacepin-8-yl ) piperidin-l-carbonyl) benzonitrile) This compound was prepared in 70% yield (38 mg) as described for compound 168 but using compound 1-45 as the starting material. 1H-NMR (400MHz, CDC13) d: 7.66-7.74 (m, 2H), 7.41-7.59 (m, 3H), 7.20 (m, 1H), 6.95-7.16 (m, 1H), 4.83 (m, 1H) , 4.22 (m, 2H), 3.68 (m, 1H), 3.27 (m, 2H), 2.79-3.12 (m, 4H), 2.63 (m, 4H), 2.13 (m, 3H), 1.62-2.02 (m , 7H). MS (ESI): m / z 454.2 (M + H +). 173. Compound 173: ((3- (3-cyclobutyl-2,3,4,5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1,4] diazepin-8-yl) piperidine -1-yl) (pyrazin-2-yl) methanone) This compound was prepared in 50% yield (26 mg) as described for compound 169 but using compound 1-45 as the starting material. 1 H-NMR (400MHz, CDC13) d: 8.91 (d, 1H, J = 11.6Hz), 8.59 (ra, 2H), 7.50-7.60 (m, 1H), 7.08-7.22 (m, 2H), 4.90 (m , 1H), 4.23 (m, 2H), 4.00 (m, 1H), 2.89-3.26 (m, 6H), 2.63 (m, 4H), 2.15 (m, 3H), 1.65-2.00 (m, 7H). MS (ESI): m / z 431.2 (M + H +). 174. Compound 174: ((3- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4.5] imidazof 1,2-d] [1,4] diazepin-8-yl) piperidin- 1-yl) (pyrazin-2-yl) methanone) This compound was prepared in 55% yield (28 mg) as described for compound 167 but using compound 1-45 and cyclobutanecarbonyl chloride as the starting materials. 1 H-NMR (400MHz, CDCl 3) d: 7.50 (d, · 1H, J = 3.6Hz), 7.07-7.21 (m, 2H), 4.75 (m, 1H), 4.22 (m, 2H), 3.76 (d, 1H, J = 12.4Hz), 3.25 (m, 3H), 2.95 (m, 2H), 2.65 (m, 6H), 2.38 (m, 2H), 2.19 (m, 5H), 1.55-2.00 (m, 9H ). MS (ESI): m / z 407.2 (M + H +). 175. Compound 175: (3-cyclobutyl-8- (piperidin-1-yl) -2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepine ) This compound was prepared in 45% yield (320 mg) as described for intermediate 1-38 but using piperidine as the starting material. 1H-NMR (400MHz, CDC13) d: 7.24 (d, J = 2.4Hz, 1H), 7.13 (d, J = 8.8Hz, 1H), 7.01 (m, 1H), 4.17-4.20 (m, 2H), 3.21-3.23 (m, 2H), 3.08-3.11 (m, 4H), 2.92 (m, 1H), 2.58-2.64 (m, 4H), 2.11-2.13 (m, 2H), 1.89-1.94 (m, 2H) ), 1.55-1.79 (m, 8H). MS (ESI): m / z 325 (M + H +). 176. Compound 176: (3-cyclobutyl-8-dihydroisoquinolin-2 (1H) -yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4 ] diazepine) This compound was prepared in 23% yield (16 mg) as described for intermediate 1-38 but using 1, 2, 3, 4-tetrahydroisoquinoline as the starting material. 1 H-NMR (400MHz, CDC13) d: 7.31 (d, J = 2.0Hz, 1H), 7.13-7.19 (m, 4H), 7.07 (m, 2H), 4.38 (s, 2H), 4.20-4.22 (m , 2H), 3.52-3.55 (m, 2H), 3.22-3.25 (m, 2H), 3.21-3.25 (m, 2H), 2.90-3.00 (m, 1H), 2.60-2.65 (m, 4H), 1.73 -1.94 (m, 2H), 1.73-1.94 (m, 2H), 1.62-1.73 (m, 2H). MS (ESI): m / z 373 (M + H +). 177. Compound 177: (3-cyclobutyl-8- (7-fluoro-3,4-dihydroisoquinolin-2 (1H) -yl) -2,3,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1 , 2-d] [1,4] diazepine) This compound was prepared in 13% yield (10 mg) as described for intermediate 1-38 but using 7-fluoro-1,2,3,4-tetrahydroisoquinoline as the starting material. 1H-NMR (400MHz, CDC13) d: 7.29 (d, J = 1.6Hz, 1H), 7.15 (d, J = 8.4Hz, 1H), 7.05-7.12 (m, 2H), 6.83 (m, 2H), 4.32 (s, 2H), 4.19-4.21 (m, 2H), 3.50-3.52 (m, 2H), 3.21-3.24 (m, 2H), 2.97-3.00 (m, 2H), 2.90-2.94 (m, 1H) ), 2.58-2.65 (m, 4H), 2.09-2.15 (m, 2H), 1.89-1.96 (m, 2H), 1.64-1.75 (m, 2?). MS (ESI): m / z 391 (M + H +).. 178. Compound 178: (3-cyclobutyl-8- (4,4-difluoropiperidin-1-yl) -2,3,4,5-tetrahydro-1H-benzo [4,5] imidazo [1,2-d] [1 , 4] diazepine) To a solution of compound 21 (150 mg, 0.47 mmol, 1.0 eq), 4,4-difluoropiperidine hydrochloride (88 mg, 0.56 mmol, 1.2 eq), Pd2 (dba) 3 (22 mg, 0.024 mmol, 0.05 eq), Xantphos (41 mg, 0.071 mmol, 0.15 eq.) and ^ uA (108 mg, 1.1 mmol, 2.4 eq) in toluene (4 mL) were degassed by bubbling argon and the mixture was stirred with microwave irradiation at 80 °. C for 60 minutes. The crude reaction mixture was diluted with ethyl acetate, the solids were removed by filtration through a short plug of silica gel and the filtrate was concentrated by evaporation. The product from the crude reaction was purified by silica gel column chromatography to give compound 178 (15 mg, 9%) as a pale yellow solid. 1 H-NMR (400MHz, CDC13) d: 7.26 (m, 1H), 7.13 (d, J = 8.8Hz, 1H), 6.98 (m, 1H), 4.11-4.22 (m, 2H), 3.22-3.30 (m , 6H), 2.91-2.95 (m, 1H), 2.60-2.65 (m, 4H), 2.09-2.20 (m, 6H), 1.91-1.95 (m, 2H), 1.54-1.76 (m, 2H). MS (ESI): m / z 361 (M + H +). 179. Compound 179: (3-cyclobutyl-8- (4-fluoropiperidin-1-yl) -2, 3, 4, 5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1, 4 ] diazepine) This compound was prepared in 6% yield (20 mg) as described for compound 178 but using 4-fluoropiperidine as the starting material. 1H-NMR (400MHz, CDC13) d: 7.25 (d, J = 1.6Hz, 1H), 7.12 (d, J = 8.8Hz, 1H), 6.98 (dd, Ji = 2.4Hz, J2 = 8.8Hz, 1H), 4.85 (m, 1H), 4.17 (m, 2H), 3.32 (m, 2H), 3.16 (m, 2H), 3.10 (m, 2H), 2.91 (m, 1H), 2.59 (m, 4H), 2.01 (m, 6H), 1.90 (m, 2H), 1.69 (m, 2H). MS (ESI): m / z 343 (M + H +). 180. Compound 180: (3-cyclobutyl-8- (3-fluoropiperidin-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1, 4 Jdiazepine) This compound was prepared in 13% yield (40 mg) as described for compound 178 but using 3-fluoropiperidine as the starting material. 1 H-NMR (400MHz, CDC13) d: 7.24 (d, J = 2.0 Hz, 1H), 7.14 (m, 1H), 7.00 (m, 1H), 4.85 (m, 1H), 4.17 (m, 2H), 3.43 (m, 1H), 3.16 (m, 4H), 3.03 (m, 1H), 2.93 (m, 1H), 2.59 (m, 4H), 2.11 (m, 2H), 1.97 (m, 4H), 1.79 (m, 4H). MS (ESI): m / z 343 (M + H +). 181. Compound 181: (3-Cyclobutyl-8- (3-fluoropyrrolidin-1-yl) -2,3,4,5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1,4 ] diazepine) This compound was prepared in 6% yield (17 mg) as described for compound 178 but using 3-fluoropyrrolidine as the starting material. 1H-NMR (400MHz, CDC13) d: 7.10 (d, J = 8.8Hz, 1H), 6.87 (d, J = 2.0Hz, 1H), 6.62 (dd, Ji = 2.0Hz, J2 = 8.8Hz, 1H) , 5.31 (m, 1H), 4.17 (m, 2H), 3.43 (m, 4H), 3.22 (m, 2H), 2.92 (m, lH), 2.60 (m, 4H), 2.10 (m, 4H), 1.91 (m, 2H), 1.67 (m, 2H). MS (ESI): m / z 329 (M + H +). 182. Compound 182: (3-cyclobutyl-difluoropyrrolidin-1-yl) -2,3,4,5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1,4] diazepine) This compound was prepared in 4% yield (4 mg) as described for compound 178 but using 3,3-difluoropyrrolidine as the starting material. 1H-NMR (400MHz, CDC13) d: 7.11 (d, J = 8.4Hz, 1H), 6.86 (d, J = 2.0Hz, 1H), 6.59-6.62 (m, 1H), 4.17-4.20 (m, 2H ), 3.71-3.75 (m, 2H), 3.51-3.54 (m, 2H), 3.21-3.23 (m, 2H), 2.90-2.94 (m, 1H), 2.45-2.64 (m, 4H), 2.13-2.15 (m, 2H), 1.85 (m, 6H). MS (ESI): m / z 347 (M + H +). 183. Compound 183: (9-cyclobutyl-2, 3, 4, 7, 8, 9, 10, 11-octahydro-lH- [1,4] diazepino [7 ', 1': 2, 3] imidazo [4, 5 -g] isoquinoline) To a solution of intermediate 1-64 (298 mg, 0.76 mmol, 1.0 eq) in methanol (10 mL) was added a solution of sodium hydroxide (61 mg, 1.5 mmol, 2.0 eq) in water (0.5 mL) and The reaction mixture was stirred at room temperature for 60 minutes. The crude reaction mixture was concentrated by evaporation and the residue was dissolved in dichloromethane and washed with water. The combined organic layers were dried over anhydrous Na 2 SO 4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give compound 183 (200 mg, 89%). 1 H-NMR (400MHz, CD30D) d: 7.23 (s, 1H), 7.18 (s, 1H), 4.27-4.29 (m, 2H), 4.07 (s, 2H), 3.20-3.22 (m, 2H), 3.15 ~ 3.18 (m, 2H), 2.93 ~ 3.01 (m, 3H), 2.59 ~ 2.67 (m, 4H), 2.12 ~ 2.18 (m, 2H), 1.89-1.99 (m, 2H), 1.66 ~ 1.80 (m, 2H). MS (ESI): m / z 297 (M + H +). 184. Compound 184: (10-cyclobutyl-2, 3, 4, 8,, 10, 11, 12-octahydro-lH- [1,4] diazepino [1 ',': 1, 2] imidazo [4,5-f ] isoquinoline) This compound was prepared in 89% yield (40 mg) as described for compound 183 but using intermediate 1-65 as the starting material. 1H-NMR (400MHz, CD30D) d: 7.0 (d, 1H, J = 8.4Hz), 6.90 (d, 1H, J = 8.4Hz), 4.20 ~ 4.22 (m, 2H), 4.10 (s, 2H), 3.22 ~ 3.27 (m, 4H), 3.13-3.16 (m, 2H), 2.91 (m, 1H), 2.58 ~ 2.64 (m, 4H), 2.1 l ~ 2.13 (m, 2H), 1.88-1.93 (m, 2H), 1.60-1.76 (m, 2H). MS (ESI): m / z 297 (M + H +). 185. Compound 185: (4- (9-cyclobutyl-2, 3, 4, 7, 8, 9, 10, 11-octahydro-lH- [1,4] diazepino [7 ', 1': 2, 3] imidazo [ 4, 5-g] isoquinoline-2-carbonyl) benzonitrile) This compound was prepared in 81% yield (35 mg) as described for compound 172 but using compound 183 as the starting material. 1H-NMR (400MHz, CDC13) d: 7.75 (d, 2H, J = 8.0Hz), 7.54 ~ 7.59 (m, 2H), 7.28 (s, 1H), 7.10 (s, 1H), 5.00 (s, 1H) ), 4.61 (s, 1H), 4.20-4.22 (m, 2H), 3.98-4.00 (m, 2H), 3.59 (m, 1H), 3.23 (m, 2H), 3.13 ~ 3.16 (m, 1H), 2.90-3.01 (m, 1H), 2.60 ~ 2.64 (m, 4H), 2.10-2.18 (m, 2H), 1.86-1. 6 (m, 2H), 1.63-1.78 (m, 2H). MS (ESI): m / z 426 (M + H +). 186. Compound 186: (cyclobutyl (9-cyclobutyl-3,4,8,9,10,11-hexahydro-1 H- [1,4] diazepino [7 ', 1': 2, 3] imidazo [4, 5-g ] isoquinolin-2 (7H) -yl) methanone) This compound was prepared in 79% yield (30 mg) as described for compound 174 but using compound 183 as the starting material. ^ MR (400MHZ, CDC13), 57.38 (s, 1H), 7.28 (s, 1H), 4.64 (m, 2H), 4.30 (m, 2H), 3.72 (m, 1H), 3.62-3.64 (m, 1H) ), 3.49-3.56 (m, 1H), 3.16 ~ 3.18 (m, 2H), 2.94 ~ 3.02 (m, 3H), 2.59 ~ 2.65 (m, 4H), 1.68 ~ 2.30 (m, 12H). MS (ESI): m / z 379 (M + H +). 187. Compound 187: (1- (9-cyclobutyl-3, 4, 8, 9, 10, 11-hexahydro-1H- [1,4] diazepino [7 ', 1': 2, 3] imidazo [4,5- g] isoquinolin-2 (7H) -yl) ethanone) This compound was prepared in 50% yield (20 mg) as described for compound 171 but using the compound 183 as the starting material. H-NMR (400MHz, CDC13) d: 7.49 (s, 1H), 7.05 (s, 1H), 4.72 (m, 2H), 4.20-4.21 (m, 2H), 3.81 (m, 1H), 3.68 (m , 1H), 3.21-3.24 (m, 2H), 3.04 (m, 1H), 2.99 (m, 1H), 2.90-2.92 (m, 1H), 2.58-2.63 (m, 4H), 2.22 (m, 3H) ), 2.10-2.13 (m, 2H), 1.88 ~ 1.93 (m, 2H), 1.65 ~ 1.75 (m, 2H). MS (ESI): m / z 339 (M + H +). 188. Compound 188: (1- (10-cyclobutyl-9, 10, 11, tetrahydro-lH- [1,4] diazepino [1 ', 7': 1, 2] imidazo [4,5-f] isoquinoline-3 ( 2H a) This compound was prepared in 100% yield (43 mg) as described for compound 184 but using compound 184 as the starting material. 1H-NMR (400MHz, CDC13) d: 7.13 (d, 1H, J = 8.4Hz), 7.00 (d, 1H, J = 8.4Hz), 4.72 (m, 2H), 4.40 (brs, 2H), 3.77- 3.91 (m, 2H), 3.44 (brs, 2H), 3.25 (m, 2H), 3.05 (m, 1H), 2.78 (brs, 4H), 2.21 (m, 3H), 2.08 ~ 2.20 (m, 4H) , 1.67 ~ 1.80 (m, 2H). MS (ESI): m / z 339 (M + H +). 189. Compound 189: (9-cyclobutyl-2, 3, 4, 7, 8, 9, 10, 11-octahydro-lH- [1,4] diazepinof 1 ', 7': 1, 2] imidazo [4,5- g] isoquinoline) This compound was prepared in 43% yield (30 mg) as described for compound 143 but using intermediate 1-73 as the starting material. 1H-NMR (400MHz, CDC13) d: 7.39 (s, 1H), 6.89 (S, 1H), 4.18 (m, 4H), 3.22 (m, 4H), 2.99 (m, 2H), 2.91 (m, 1H ), 2.59 (m, 4H), 2.20 (m, 2H), 1.92 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 291.4 (M + H +). 190. Compound 190: (9-cyclobutyl-2- (pyrazin-2-yl) -2,3,4,7,8,9,10,1-octahydro-lH- [1,4] diazepino [1 ', 7' : 1, 2] imidazo [4, 5-g] isoquinoline) This compound was prepared in 67% yield (11 mg) as described for compound 149 but using compound 189 as the starting material. 1E-NMR (400MHz, CDC13) d: 8.10 (m, 2H), 7.83 (d, J = 2.8 Hz, 1H), 7.51 (s, 1H), 7.12 (s, 1H), 4.88 (s, 2H), 4.22 (m, 2H), 3.81 (m, 2H), 3.24 (m, 2H), 3.14 (m, 2H), 2.92 (m, 1H), 2.61 (m, 4H), 2.1 1 (m, 2H), 1.90 (m, 2H), 1.67 (m, 2H). MS (ESI): m / z 375.5 (M + H +). 191. Compound 191: (cyclobutyl (9-cyclobutyl-3,4,8,9,10,11-hexahydro-1H- [1,] diazepino [1 ', 7': 1, 2] imidazo [4, 5-g] isoquinolin-2 (7H) -yl (methanone) This compound was prepared in 16% yield (3.9 mg) as described for compound 174 but using compound 189 as the starting material. 1 H-NMR (400MHz, CDC13) d: 7.45 (s, 1H), 7.00 (s, 1H), 4.82 (m, 2H), 4.20 (m, 2H), 3.70 (m, 2H), 3.38 (m, 1H) ), 3.24 (m, 2H), 3.00 (m, 2H), 2.92 (m, 1H), 2.62 (m, 4H), 2.40 (m, 2H), 2.20 (m, 4H), 2.00 (m, 2H) , 1.95 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 378.5 (M + H +). 192. Compound 192: (4- (9-cyclobutyl-2, 3, 4, 7, 8, 9, 10, 11-octahydro-lH- [1,4] diazepino [1 ', 7': 1, 2] imidazo [ 4, 5-g] isoquinoline-2-carbonyl) benzonitrile) This compound was prepared in 36% yield (10 mg) as described for compound 168 but using compound 189 as the starting material. 1 HOUR- NMR (400MHz, CDC13) d: 7.76 (d, J = 8.4Hz, 2H), 7.57 (m, 2H), 7.48 (m, 1H), 7.00 (m, 1H), 4.86 (m, 2H), 4.15 (m, 2H), 3.61 (m, 2H), 3.244 (m, 2H), 3.14 (m, 2H), 2.94 (m, 1H), 2.64 (m, 4H), 2.12 (m, 2H), 1.94 (m, 2H), 1.66 (m, 2H). MS (ESI): m / z 426.5 (M + H +). 193. Compound 193: (9-cyclobutyl-2- (pyrimidin-2-yl) -2,3,4,7,8,9,10,1-octahydro-1 H- [1,4] diazepino [1 ', 7' : 1, 2] imidazo [4, 5-g] isoquinoline) This compound was prepared in 55% yield (16 mg) as described for compound 48 but using compound 189 as the starting material. 1H- NMR (400MHz, CDCl 3) d: 8.36 (d, J = 4.8Hz, 2H), 7.50 (s, 1H), 7.10 (s, 1H), 6.50 (m, 1H), 5.02 (s, 2H), 4.21 (m, 2H), 4.01 (m, 2H), 3.23 (m, 2H), 3.10 (m, 2H), 2.92 (m, 1H), 2.62 (m, 4H), 2.11 (m, 2H), 1.93 (m, 2H), 1.67 (m, 2H). MS (ESI): m / z 375.5 (M + H +). 194. Compound 194: (1- (9-cyclobutyl-3, 4, 8, 9, 10, 11-hexahydro-1 H- [1,4 Jdiazepino [1 ', 7': 1, 2] imidazo [4, 5-g ] isoquinolin-2 (7H) -yl) ethanone) This compound was prepared in 17% yield (11 mg) as described for compound 167 but using compound 189 as the starting material. H-NMR (400 MHZ, CDC13) d: 7.40 (s, 1H), 6.97 (s, 1H), 4.70 (m, 2H), 4.15 (m, 2H), 3.61 (m, 2H), 3.18 (m, 2H), 2.88-2.98 (m, 3H), 2.57 (m, 4H), 2.09 (m, 5H), 1.87 (m, 2H), 1.62 (m, 2H). MS (ESI): m / z 339.4 (M + H +). 195. Compound 195: (3-Cyclobutyl-8- (2-methylimidazo [1,2- a] pyridin-6-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1, 2-d] [1,4] diazepine) This compound was prepared in 30% yield as described for the compound using intermediate 1-75 as the initial material. 1H-NMR (400MHz, CD3OD) d: 8.52 (br, 1H), 7.72 (s, 1H), 7.42- 7.56 (m, 5H), 4.29-4.31 (m, 2H), 3.15-3.18 (m, 2H) , 2.93 (m, 1H), 2.56-2.64 (m, 4H), 2.35 (s, 3H), 2.08-2.10 (m, 2H), 1.86-1.88 (m, 2H), 1.64-1.67 (m, 2H) . MS (ESI): m / z 372.2 (M + H +). 196. Compound 196: (3-cyclobutyl-8- (lH-pyrrolo [2,3-b] pyridin-6-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1, 2-d] [1, 4 Jdiazepine) Intermediates 1-17 (40 mg, 0.11 mmol, 1.0 eq) and 1-79 (17 mg, 0.11 mmol, 1.0 eq), Pd (PPh3) 2 Cl2 (5 mg, 0.007 mmol, 0.1 eq) and a solution of Na 2 CO 3 in water (0.5 mL, 2.0 M, 1.0 mmol, 10 eq) were mixed in acetonitrile (0.5 mL) and the solution was purged by bubbling argon. The reaction mixture was stirred at 150 ° C for 30 minutes in microwave irradiation, diluted with ethyl acetate, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give compound 196 (9 mg, 23%) as a white solid. 1H-NMR (400MHz, CD3OD) d: 11.66 (s, 1H), 8.51 (m, 1H), 8.19 (m, 1H), 7.80 (m, 1H), 7.49-7.60 (m, 3H), 6.49-6.50 (m, 1H) 4.31-4.34 (m, 2H), 3.13-3.18 (m, 2H), 2.95 (m, 1H), 2.57-2.59 (m, 4H), 2.09 (m, 2H), 1.82 (m, 2H), 1.60 (m, 2H). MS (ESI): m / z 358.2 (M + H +). 197. Compound 197: (3-cyclobutyl-8- (lH-pyrrolo [3,2- b] pyridin-5-yl) -2,4,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1, 2-d] [1,4] diazepine) This compound was prepared in 4% yield (2 mg) as described for compound 196 but using 5-chloro-lH-pyrrolo [3,2-b] pyridine as the starting material. 1H-NMR (400MHz, CD3OD) d: 8.29 (br, 1H), 8.22-8.23 (m, 1H), 8.10-8.12 (m, 1H), 7.75-7.77 (m, 1H), 7.64-7.66 (m, 1H), 7.45-7.47 (m, 1H), 7.33-7.35 (m, 1H), 6.84-6.85 (m, 1H), 4.27-4.29 (m, 2H), 3.26-3.29 (m, 2H), 2.95 ( m, 1H), 2.62-2.69 (m, 4H), 2.13-2.15 (m, 2H), 1.93 (m, 2H), 1.56-1.59 (m, 2H). MS (ESI): m / z 358.1 (M + H +). 198. Compound 198: (3-cyclobutyl-8- (imidazo [1, 5-a] pyridin-6-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4,5] imidazo [1, 2- d] [1, 4] diazepine) This compound was prepared in 17% yield (6 mg) as described for compound 22 but using intermediate 1-87 as the material initial. ^ - MR (400MHz, CD3OD) d: 8.51 (s, 1H), 8.38 (s, 1H), 7.83 (s, 1H), 1.51-1.64 (m, 3H), 7.40 (s, 1H), 7.18-7.21 (m, 1H), 4.38-4.40 (m, 2H), 3.24-3.27 (m, 2H), 3.02 (m, 1H), 2.66-2.73 (m, 4H), 2.17-2.19 (m, 2H), 1.95 -1.97 (m, 2H), 1.73-1.76 (m, 2H). MS (ESI): m / z 358.2 (M + H +). 199. Compound 199: (3-Cyclobutyl-8- (5H-pyrrolo [2, 3-b] pyrazin-2-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4,5] imidazo [1, 2-d] [1,4] diazepine) This compound was prepared in 8% yield (5 mg) as described for compound 196 but using intermediate 1-85 as the starting material. 1H-NMR (400MHz, CD3OD) d: 9.04 (br, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 8.03-8.05 (d, 1H, J = 8.0Hz), 7.62 (s, 1H ), 7.37-7.39 (d, 1H, J = 9.2Hz), 6.81 (s, 1H), 4.30 (m, 2H), 3.28-3.29 (m, 2H), 2.95 (m, 1H), 2.65-2.70 ( m, 4H), 2.11-2.15 (m, 2H), 1.91-1.96 (m, 2H), 1.64-1.67 (m, 2H). MS (ESI): m / z 359.1 (M + H +). 200. Compound 200: (3-cyclobutyl-8- (lH-pyrrolo [3,2- b] pyridin-6-yl) -2, 3,, 5-tetrahydro-1H-benzo [4,5] imidazo [1, 2 -d] [1,4] diazepine) This compound was prepared in 15% yield (7 mg) as described for compound 196 but using 6-iodo-lH-pyrrolo [3,2-b] pyridine as the starting material. XH-NMR (400MHz, CD3OD) d: 9.10 (br, 1H), 8.77 (d, J = 4.0Hz, 1H), 7.90-7.94 (m, 2H), 7.48-7.55 (m, 2H), 7.35-7.35 (m, 1H), 6.78-6.79 (m, 1H), 4.27-4.29 (m, 2H), 3.27-3.30 (m, 2H), 2.95 (m, 1H), 2.62-2.69 (m, 4H), 2.13 -2.15 (m, 2H), 1.90-1.95 (m, 2H), 1.26-1.79 (m, 2H). MS (ESI): m / z 358.1 (M + H +). 201. Compound 201: (6- (3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl) furo [ 3, 2-b] pyridine) This compound was prepared in 10% yield (5 mg) as described for compound 196 but using 6-iodofuro [3,2-b] pyridine as the starting material. 1 H-NMR (400 MHz, CD 3 OD) d: 8.85 (d, J = 2.0 Hz, 1 H), 7.93-7.99 (m, 2 H), 7.87 (d, J = 2.4 Hz, 1 H), 7.51-7.53 (m, 1H), 7.35-7.37 (m, 1H), 7.02-7.03 (m, 1 H), 4.28-4.30 (m, 2H), 3.27-3.30 (m, 2H), 2.95 (m, 1H), 2.63-2.70 (m, 4H), 2.13-2.15 (m, 2H), 1.90-1.93 (m, 2H), 1.64-1.77 ( m, 2H). MS (ESI): m / z 359.0 (M + H +). 202. Compound 202: (3-cyclobutyl-8- (3-methyl-3H-imidazo [4, 5-b] pyridin-6-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazof 1, 2-d] [1,4] diazepine) This compound was prepared in 11% yield (6 mg) as described for compound 196 but using 6-iodo-3-methyl-3H-imidazo [4, 5-b] pyridine as the starting material. 1H-NMR (400MHz, CD3OD) d: 8.70-8.71 (d, J = 2.0Hz, 1H), 8.28 (d, J = 2.0Hz, 1H), 8.07 (s, 1 H), 7.93 (d, J = 1.2Hz, 1H), 7.50-7.53 (m, 1H), 7.37-7.50 (m, 1 H), 4.27-4.30 (m, 2H), 3.98 (s, 3H), 3.27-3.30 (m, 2H), 2.95 (m, 1H), 2.63-2.70 (m, 4H), 2.13-2.15 (m, 2H), 1.91-1.93 (m, 2H), 1.76 (m, 2H). MS (ESI): m / z 373.0 (M + H +). 203. Compound 203: (8- ([1, 2, 4] triazolo [1, 5-a] pyridin-6-yl) -3-cyclobutyl-2, 3,4, 5-tetrahydro-lH-benzo [4, 5 ] imidazo [1,2-d] [1,4] diazepine) This compound was prepared in 4% yield (2 mg) as described for compound 22 but using 6-bromo- [1, 2, 4] triazolo [1, 5-a] pyridine as the starting material. HNR (400MHz, CD3OD) d: 8.81 (s, 1H), 8.37 (s, 1H), 7.90 (m, 1H), 7.84 (s, 2 H), 7.46-7.48 (m, 1H), 7.36-7.38 (m, 1H), 4.28-4.30 (m, 2H), 3.28-3.30 (m, 2H), 2.95 (m, 1H), 2.63-2.70 (m, 4H), 2.13-2.15 (m, 2H), 1.91 -1.95 (m, 2H), 1.69 (m, 2H). MS (ESI): m / z 359.1 (M + H +). 204. Compound 204: (8- ([1, 2, 4] triazolo [4, 3-a] pyridin-6-yl) -3-cyclobutyl-2, 3,4, 5-tetrahydro-lH-benzo [4, 5 ] imidazo [1,2-d] [1,4] diazepine) This compound was prepared in 26% yield (13 mg) as described for compound 22 but using 6-bromo- [1, 2, 4] triazolo [4, 3-a Jpyridine as the starting material. 1H-NMR (400MHz, CD3OD) d: 8.87 (s, 1H), 8.28 (s, 1H), 7.83-7.86 (m, 2H), 7.58-7.61 (m, 1H), 7.41-7.44 (m, 1H) , 7.34-7.37 (m, 1H), 4.27-4.30 (m, 2H), 3.27-3.30 (m, 2H), 2.95 (m, 1H), 2.63-2.70 (m, 4H), 2.13-2.15 (m, 2H), 1.93 (m, 2H), 1.68-1.72 (m, 2H). MS (ESI): m / z 359.1 (M + H +). 205. Compound 205: (3-cyclobutyl-8- (1-methyl-lH-indazol-6-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1, 4 Jdiazepine) This compound was prepared in 11% yield (5 mg) as described for compound 22 but using 6-bromo-l-methyl-lH-indazole as the starting material. ^ -NMR (400MHz, CD3OD) d: 7.98-8.00 (m, 2H), 7.77-7.80 (m, 1H), 7.56-7.59 (m, 2H), 7.45-7.47 (m, 1H), 7.33-7.35 ( m, 1H), 4.28-4.30 (m, 2H), 4.12 (s, 3H), 3.28-3.30 (m, 2H), 2.95 (m, 1H), 2.63-2.70 (m, 4H), 2.15 (m, 2H), 1.94 (m, 2H), 1.75 (m, 2H). MS (ESI): m / z 372.2 (M + H +). 206. Compound 206: (3-cyclobutyl-8- (2-methyl-2H-indazol-6-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1, 4] diazepine) This compound was prepared in 11% yield (6 mg) as described for compound 22 but using 6-bromo-2-methyl-2H-indazole as the starting material. 1H-NMR (400MHz, CD3OD) d: 7.90 (m, 1H), 7.98 (m, 2H), 7.70-7.72 (m, 1H), 7.57-7.59 (m, 1H), 7.42-7.44 (m, 1H) , 7.27-7.33 (m, 1H), 4.24-4.28 (m, 2H), 4.21 (s, 3H), 3.26-3.29 (m, 2H), 2.94 (m, 1H), 2.62-2.68 (m, 4H) , 2.12-2.17 (m, 2H), 1.87-1.95 (m, 2H), 1.68-1.74 (m, 2H). MS (ESI): m / z 372.2 (M + H +). 207. Compound 207: (3-cyclobutyl-8- (2-methyl-lH-benzo [d] imidazol-1-yl) -2,4,4,5-tetrahydro-1H-benzo [4, 5] imidazo [1, 2-d] [1,4] diazepine) A mixture of intermediate 1-30 (192 mg, 0.75 mmol, 1.5 eq), N- (2-bromophenyl) acetamide (106 mg, 0.50 mmol, 1.0 eq), Pd2 (dba) 3 (46 mg, 0.05 mmol, 0.1 eq), Xantphos (29 mg, 0.05 mmol, 0.1 eq), and K3P04 (265 mg, 1.3 mmol, 2.5 eq) in ^ uOH (5 mL) was stirred at 110 ° C for 60 minutes with microwave irradiation. The reaction mixture was concentrated by evaporation; The residue was diluted with dichloromethane and washed with water. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the reaction crude was purified by preparative TLC to give compound 207 (74 mg, 40%) as a pale yellow solid. H-NMR (400MHz, CDC13) d: 7.74 (d, J = 8.0Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 7.17-7.28 ( m, 3H), 7.07 (d, J = 2.0Hz, 1H), 4.31-4.34 (m, 2H), 3.29-3.32 (m, 2H), 2.93 (m, 1H), 2.65-2.71 (m, 4H) , 2.50 (s, 3H), 2.14 (m, 2H), 1.99 (m, 2H), 1.66 (m, 2H). MS (Cl): m / z 372 (M + H +). 208. Compound 208: (3-cyclobutyl-8- (6-fluoro-2-methyl-1H-benzof d] imidazol-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine) This compound was prepared in 30% yield (59 mg) as described for compound 207 but using N- (2-bromo-4-fluorophenyl) acetamide as the starting material. 1H-NMR (400MHz, CDC13) 6: 7.63-7.67 (m, 2H), 7.40 (d, J = 8.8Hz, 1H), 7.18-7.21 (m, 1H), 6.96-7.02 (m, 1H), 6.75 -6.78 (m, 1H), 4.32-4.34 (m, 2H), 3.30-3.33 (m, 2H), 2.97 (m, 1H), 2.65-2.74 (m, 4H), 2.48 (s, 3H), 2.10 -2.17 (m, 2H), 1.91-1.94 (m, 2H), 1.66-1.69 (m, 2H). MS (Cl): m / z 390 (M + H +). 209. Compound 209 (3-cyclobutyl-8- (2,6-dimethyl-1H-benzo [d] imidazol-1-yl) -2, 3, 4, 5-tetrahydro-1H-benzo [4, 5] imidazof 1, 2-d] [1,4] diazepine): This compound was prepared in 35% yield (68 mg) as described for compound 207 but using N- (2-bromo-4-methylphenyl) acetamide as the starting material. XH-NMR (400MHz, CDC13) 5: 7.67 (d, J = 8.0Hz, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.40 (d, J = 8.4Hz, 1H), 7.22 (m, 1H), 7.11-7.13 (m, 1H), 6.88-6.89 (m, 1H), 4.31-4.34 (m, 2H), 3.30-3.32 (m, 2H), 3.01 (m, 1H), 2.71 (m, 4H), 2.48 (s, 3H), 2.38 (s, 3H), 2.17 (m, 2H), 1.88 (m, 2H), 1.65 (m, 2H). MS (Cl): m / z 386 (M + H +). 210. Compound 210: (8- (benzo [d] [1,3] dioxol-5-yl) -3-cyclobutyl-2, 3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1, 2 -d] [1,4] diazepin) This compound was prepared in 59% yield (35 mg) as described for compound 41 but using compound 21 and benzo [d] [1, 3] dioxol-5 acid iloboronic as the initial material. H-NMR (400 MHz, CDC13) d: 7.81 (s, 1H), 7.40 (d, 1H, J = 8.4Hz), 7.26 (m, 2H), 7.10 (m, 1H), 6.90 (d, 1H, J = 8.4 Hz), 6.00 (s, 2H), 4.24 (m, 2H), 3.25 (m, 2H), 2.95 (m, 1H), 2.66-2.60 (m, 4H), 2.13 (m, 2H), 1.92 (m, 2H), 1.72 (m, 2H). MS (ESI): m / z 362 (M + H +). 211. Compound 211: (3-cyclobutyl-8- (3,4-dichlorophenyl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) This compound was prepared in 53% yield (32 mg) as described for compound 41 but using compound 21 and 2- (3,4-dichlorophenyl) -4,4,5,5-tetramethyl-1,3, 2-dioxaborolane as the initial material. XH-NMR (400MHz, CDC13) d: 7.84 (s, 1H), 7.70 (d, 1H, J = 2.0Hz), 7.51 (d, 1H, J = 8.4Hz), 7.46 (d, 1H, J = 2.0 Hz), 7.44 (d, 1H, J = 8.4Hz), 7.32 (d, 1H, J = 8.8Hz), 4.29 (m, 2H), 3.29 (m, 2H), 2.96 (m, 1H), 2.68- 2.63 (m, 4H), 2.13 (m, 2H), 1.93 (m, 2H), 1.76 (m, 2H). MS (ESI): m / z 387 (M + H +). 212. Compound 212: (8- (4- (tert-butyl) phenyl) -3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4,5] imidazof 1,2-d] [1, 4 ] diazepine) This compound was prepared in 38% yield (22 mg) as described for compound 41 but using compound 21 and 2- (4- (tert-butyl) phenyl) -4,4,5,5-tetramethyl-1 , 3, 2-dioxaborlane as the starting material. 1H-NMR (400MHz, CDC13) d: 7.90 (d, 1H, J = 1.6Hz), 7.58 (d, 2H, J = 8.4Hz), 7.51-7.47 (m, 3H), 7.29 (d, 1H, J = 8.4Hz), 4.27 (m, 2H), 3.27 (m, 2H), 2.94 (m, 1H), 2.68-2.63 (m, 4H), 2.14 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.37 (s, 9H). MS (ESI): m / z 374 (M + H +). 213. Compound 213: (3-cyclobutyl-8- (4- (trifluoromethyl) phenyl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazof 1,2-d] [1,4] diazepine ) This compound was prepared in 8% yield (5 mg) as described for compound 41 but using compound 21 and 4, 4, 5, 5-tetramethyl-2- (4- (trifluoromethyl) phenyl) -1, 3 , 2-dioxaborolane as the initial material. XH-NMR (400MHz, CDC13) d: 7.91 (s, 1H), 7.72 (m, 4H), 7.50 (d, 1H, J = 8.4Hz), 7.34 (d, 1H, J = 8.4Hz), 4.29 ( m, 2H), 3.29 (m, 2H), 2.94 (m, 1H), 2.68- 2. 63 (m, 4H), 2.13 (m, 2H), 1.93 (m, 2H), 1.76 (m, 2H). MS (ESI): m / z 386 (M + H +). 214. Compound 214: (3-cyclobutyl-8- (naphthalen-2-yl) -2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepine ) This compound was prepared in 33% yield (20 mg) as described for compound 22 but using 2-bromonapphthalene as the starting material. 1H-NMR (400MHz, CDC13) d: 8.07 (s, 1H), 8.03 (s, 1H), 7.91 (t, 2H, J = 8.0Hz), 7.87 (d, 1H, J = 8.0Hz), 7.81 (s, d, 1H, J = 8.0Hz), 7.63 (d, 1H, J = 8.4Hz), 7.48 (m, 2H), 7.35 (d, 1H, J = 8.4Hz), 4.27 (m, 2H), 3.29 ( m, 2H), 2.94 (m, 1H), 2.67 (m, 4H), 2.13 (m, 2H), 1.91 (m, 2H), 1.73 (m, 2H). MS (ESI): m / z 368 (M + H +). 215. Compound 215: (5- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1,4] diazepin-8-yl) benzo [ d] oxazole-2 (3H) -one) This compound was prepared in 11% yield (7 mg) as described for compound 22 but using 5-bromobenzo [d] oxazol-2 (3H) -one as the starting material. XH-NMR (400MHz, DMSO-d6) d: 7.70 (s, 1H), 7.53 (d, 1H, 7 = 8.4 Hz), 7.44 (d, 1H, J = 8.4Hz), 7.16-7.1 1 (m, 3H), 4.31 (m, 2H), 3.22 (m, 2H), 3.12 (m, 1H), 2.58-2.50 (m, 4H), 2.06 (m, 2H), 1.84 (m, 2H), 1.64 (m , 2H). MS (ESI): m / z 375 (M + H +). 216. Compound 216: 6- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diacepin-8-yl) -3, 4-dihydroquinolin-2 (1H) -one) This compound was prepared in 11% yield (7 mg) as described for compound 22 but using 6-bromo-3,4-dihydroquinolin-2 (1H) -one as the starting material. 1H-NMR (400MHz, CDC13) d: 7.85 (d, 2H, J = 10.4Hz), 7.45 (m, 3H), 7.28 (d, 1H, J = 8.4Hz), 6.83 (d, 1H, J = 8.8 Hz), 4.26 (m, 2H), 3.26 (m, 2H), 3.05 (m, 2H), 2.94 (m, 1H), 2.71-2.63 (m, 6H), 2.14 (m, 2H), 1.94 (m , 2H), 1.71 (m, 2H). MS (ESI): m / z 387 (M + H +). 217. Compound 217: (8- (?? - benzo [d] imidazol-5-yl) -3-cyclobutyl-2, 3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d ] [1, 4] diazepine) This compound was prepared in 16% yield (11 mg) as described for intermediate 1-18 but using intermediate 1-17 and 6-bromo-lH-benzo [d] imidazole as starting materials. 1H-NMR (400MHz, CDC13) d: 8.11 (s, 1H), 7.96 (s, 1H), 7.89 (br, 1H), 7.75 (br, 1H), 7.55 (d, 2H, J = 8.4Hz), 7.31 (d, 1H, J = 8.4Hz), 4.27 (m, 2H), 3.29 (m, 2H), 2.94 (m, 1H), 2.67 (m, 4H), 2.13 (m, 2H), 1.91 (m , 2H), 1.73 (m, 2H). MS (ESI): m / z 387 (M + H +). 218. Compound 218: (10-chloro-3-cyclobutyl-1, 2, 3, 4, 5, 6-hexahydrobenzo [4,5] imidazo [1,2-a] [1,5] diazocine) This compound was prepared in 70% yield (900 mg) as described for compound 143 but using intermediate 1-94 as the starting material. 1H-NMR (400MHz, CDC13) d: 7.67 (s, 1H), 7.19 (m, 2H), 4.39 (t, 2H, J = 5.6Hz), 3.13-3.09 (m, 3H), 2.78-2.76 (m, 2H), 2.07-2.00 (m, 4H), 1.77-1.57 (m, 6H). MS (ESI): m / z 290 (M + H +). 219. Compound 219: (4- (3-cyclobutyl- 1, 2, 3, 4, 5, 6-hexahydrobenzo [4,5] imidazo [1,2-a] [1,5] diazocin-10-yl) benzonitrile) This compound was prepared in 20% yield (15 mg) as described for compound 2 but using compound 218 as the starting material. ^ - MR (400MHz, CDC13): d 8.05-8.03 (m, 1H), 7.77-7.71 (m, 4H), 7.61 (d, 1H, J = 8.8Hz), 7.55-7.45 (m, 1H), 4.74 (s, 2H), 3.90-3.00 (m, 7H), 2.55-2.50 (m, 3H), 2.27-2.23 (m, 3H), 1.96-1.88 (m, 1H), 1.74-1.67 (m, 1H) . MS (ESI): m / z 357 (M + H +). 220. Compound 220: (3-cyclobutyl-10- (imidazo [1,2-a] pyridin-6-yl) -l, 2,3,4,5,6-hexahydrobenzo [4,5] imidazo [1,2- a] [1,5] diazocine) This compound was prepared in 61% yield (30 mg) as described for compound 41 but using intermediate 1-95 and 6-bromoimidazof 1,2-a] pyridine as the starting material. 1H-NMR (400MHz, CDC13): d 8.31 (s, 1H), 7.86 (d, 1H, J = 0.8Hz), 7.70-7.64 (m, 3H), 7.49 (dd, 1H, J2 = 8.8Hz), 7.44-7.37 (m, 2H), 4.45 (t, 2H, J = 6.0Hz), 3.16-3.13 (m, 3H), 2.78 (t, 2H, J = 5.6Hz), 2.13- 2.10 (m, 2H), 2.07-2.00 (m, 2H), 1.84-1.79 (m, 4H), 1.69-1.59 (m, 2H), MS (ESI): m / z 372 (M + H +). 221. Compound 221: (4- ((3-cyclobutyl-1,2,3,4,5,6-hexahydrobenzo [4,5] imidazo [1,2- a] [1,5] diazocin-10-yl) methyl ) morpholine) This compound was prepared in 63% yield (1.1 g) as described for compound 8 but using intermediate 1-98 and morpholine as the starting material. 1H-NMR (400MHz, CDC13): d 7.62 (s, 1H), 7.21-7.26 (m, 2H), 4.39-4.42 (t, J = 6.0Hz), 3.69-3.72 (t, J = 4.4Hz, 4H ), 3.62 (s, 2H), 3.09-3.12 (m, 3H), 2.75-2.78 (t, J = 5.2Hz, 2H), 2.47 (m, 4H), 1.98-2.08 (m, 4H), 1.58- 1.83 (m, 6H). MS (ESI): m / z 355 (M + H +). 222. Compound 222: (3-cyclobutyl-10- ((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) -l, 2,3,4,5,6-hexahydrobenzo [4, 5] imidazo [1, 2-a] [1,5] diazocine) This compound was prepared in 56% yield (1.1 g) as described for compound 8 but using intermediate 1-98 and 1,2,3,4-tetrahydroisoquinoline as the starting material. 1 H-NMR (400MHz, CDCl 3): d 7.66 (s, 1H), 7.32-7.35 (m, 1H), 7.24-7.27 (m, 1H), 7.07-7.10 (m, 3H), 6.95-6.97 (m, 1H), 4.39-4.42 (t, J = 6.0Hz, 2H), 3.80 (s, 2H), 3.65 (s, 2H), 3.09-3.16 (m, 3H), 2.87-2.91 (t, J = 6.0Hz , 2H), 2.76-2.79 (t, J = 6.0Hz, 4H), 1.98-2.08 (m, 4H), 1.58-1.83 (m, 6H). MS (ESI): m / z 401 (M + H +). 223. Compound 223: (3-Cyclobutyl-8- (1H-pyrazolo [3,4- b] pyridin-5-yl) -2, 3, 5-tetrahydro-1H-benzo [4,5] imidazo [1, 2 -d] [1,4] diazepine) a mixture of intermediate 1-17 (100 mg mmol, 1.0 eq), 6-bromo- [1, 2, 4] triazolo- [4, 3 a] pyridine (60 mg, 0.30 mmol, 1.1 eq) and Pd (dppf) Cl2 (20 mg, 0.03 mmol, 0.1 eq) was added an emulsion of Na2CO3 in water (0.6 mL, 1.2 mmol, 4.5 eq, 2.0 M) , toluene (1.5 mL) and ethanol (1.5 mL). The reaction flask was purged 3 times with argon and the reaction mixture was stirred at 100 ° C for 3 hours with microwave irradiation. The crude reaction mixture was diluted with ethyl acetate, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by flash chromatography on silica gel to give compound 223 (10 mg, 10%) as a white solid. 1 H-NMR (400 MHz, CD 3 OD): d 10.91 (br, 1 H), 8.87 (d, J = 2.4 Hz, 1 H), 8.28 (d, J = 1.6 Hz, 1 H), 8.16 (s, 1 H), 7.92. (d, J = 1.2Hz, 1H), 7.49-7.52 (m, 1H), 7.36-7.38 (m, 1H), 4.29-4.31 (m, 2H), 3.29-3.31 (m, 2H), '2.92- 2.99 (m, 1H), 2.64-2.71 (m, 4H), 2.14-2.16 (m, 2H), 1.91-1.96 (m, 2H), 1.67-1.77 (m, 2H). MS (ESI): m / z 359.1 (M + H +). 224. Compound 224: (8- (4-benzylpiperazin-1-yl) -3-cyclobutyl-2, 3,4,5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1, 4 ] diazepine) This compound was prepared in 23% yield (10 mg) as described for intermediate 1-38 but using 1-benzylpiperazine as the starting material. 1 H-NMR (400MHz, CDCl 3): d 7.35 (m, 5H), 7.23 (d, J = 2.0Hz, 1H), 7.12 (d, J2 = 8.8Hz, 1H), 4.17 (m, 2H), 3.59 (s, 1H), 3.18 (m, 6H), 2.90 (m, 1H), 2.61 (m, 7H), 2.11 (m, 2H), 1.89 (m, 2H), 1.66 (m, 3H). MS (ESI): m / z 416 (M + H +). 225. Compound 225: (4- (1- (3-cyclobutyl-2,3,4,5-tetrahydro-l-benzo [4,5] imidazo [1,2-d] [1,4] diacepin-8-yl ) piperidin-4-yl) morpholine) This compound was prepared in 6% yield as described for intermediate 1-38 but using 4- (piperidin-4-yl) morpholine as the starting material. 1H-NMR (400MHz, CDC13): d 7.24 (d, J = 2.0Hz, 1H), 7.12 (d, J = 8.8Hz, 1H), 7.00 (dd, Jlf2.2Hzf J2 = 8.8Hz, 1H), 4.17 (m, 2H), 3.74 (m, 2H), 3.64 (m, 2H), 3.20 (m, 2H), 2.91 (m, 1H), 2.70 (m, 2H), 2.59 (m, 6H), 2.32 (m, 2H). m, 1H), 2.11 (m, 2H), 1.91 (m, 4H), 1.70 (m, 8H). MS (ESI): m / z 410 (M + H +). 226. Compound 226: (3-Cyclobutyl-8- (pyrrolidin-1-yl) -2,3,4,5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d] [1,4 Jdiazepine] This compound was prepared in 9% yield (4.5 mg) as described for intermediate 1-38 but using pyrrolidine as the starting material. XH-NMR (400MHz, CDC13): 67.09 (m, 1H), 6.86 (m, 1H), 6.63 (dd, J! = 2.1Hz, J2 = 8.7Hz, 1H), 4.18 (m, 2H), 3.30 ( m, 3H), 3.19 (m, 2H), 2.91 (m, 1H), 2.60 (m, 4H), 2.11 (m, 2H), 2.01 (m, 3H), 1.90 (m, 3H), 1.69 (m , 3H). MS (ESI): m / z 311 (M + H +). 227. Compound 227: (3-cyclobutyl-8- (4-phenylpiperidin-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1, 4 ] diazepine) This compound was prepared in 12% yield as described for intermediate 1-38 but using 4-phenylpiperidine as the starting material. 1 H-NMR (400MHz, CDC13): 67.30 (m, 5H), 7.21 (m, 1H), 7.15 (d, J = 8.8Hz, 1H), 7.06 (dd, 1H), 4.19 (m, 2H), 3.71 (m, 2H), 3.21 (m, 2H), 2.92 (m, 1H), 2.82 (m, 2H), 2.61 (dt, Ji = 4.8Hz, J2 = 15.4Hz, 4H), 2.12 (m, 2H), 1.99 (m, 4H), 1.90 (m, 2H), 1.70 (m, 3H) . MS (ESI): m / z 401 (M + H +). 228. Compound 228: (4- (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl Piperazin-1-yl) benzonitrile) This compound was prepared in 17% yield as described for intermediate 1-38 but using 4- (piperazin-1-yl) benzonitrile as the starting material. 1H-NMR (400MHz, CDC13): d 7.52 (d, J = 9.0Hz, 2H), 7.27 (d, J = 2.1Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.02 (dd, Ji = 2.2Hz, J2 = 8.8Hz, 1H), 6.92 (d, J = 9.0Hz, 2H), 4.19 (m, 2H), 3.51 (m, 4H), 3.28 (m, 3H), 3.21 (m, 2H), 2.91 (m, 1H), 2.61 (dt, Ji = 4.8Hz, J2 = 15.4Hz, 4H), 2.12 (m, 2H), 1.90 (m, 2H), 1.70 (m, 3H). MS (ESI): m / z 427 (M + H +). 229. Compound 229: (3-cyclobutyl-8- (4-phenylpiperazin-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4, 5] imidazo [1,2-d] [1,4 Jdiazepine) This compound was prepared in 42% yield (31 mg) as described for intermediate 1-38 but using 1-phenylpiperazine as the starting material. 1 H-NMR (400MHz, CDCl 3): d 7.30 (m, 3H), 7.16 (d, J = 8.8Hz, 1H), 7.05 (dd, 1H), 7.00 (m, 2H), 6.89 (t, J = 7.3Hz, 1H), 4.19 (t, J = 4.5Hz, 2H), 3.35 (m, 7H), 3.21 (m, 2H), 2.92 ( m, 1H), 2.61 (dt, Ji = 4.9Hz, J2 = 14.8Hz, 4H), 2.12 (m, 2H), 1.91 (m, 2H), 1.70 (m, 3H). MS (ESI): m / z 402 (M + H +). 230. Compound 230: (3-cyclobutyl-8- (4- (pyridin-yl) piperazin-1-yl) -2,3,4,5-tetrahydro-1H-benzo [4, 5] imidazof 1,2-d] [1,4 Jdiazepine) This compound was prepared in 32% yield (25 mg) as described for intermediate 1-38 but using 1- (pyridin-2-yl) piperazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.22 (dd, Ji = 1.3Hz, J2 = 4.9Hz, 1H), 7.50 (m, 1H), 7.29 (d, J = 2.1Hz, 1H), 7.16 (d, J = 8.8Hz, 1H), 7.05 (dd, J2 = 8.8Hz, ??), 6.71 (d, J = 8.6Hz, 1H), 6.64 (m, 1H), 4.19 (t, J = 4.5Hz, 2H), 3.74 (m, 4H), 3.26 (m, 3H), 3.21 (m, 2H), 2.91 (m, 1H), 2.61 (dt, Ji = 4.8Hz, J2 = 15.3Hz, 4H), 2.10 (m, 2H), 1.90 (m, 2H), 1.69 (m, 3H) . MS (ESI): m / z 403 (M + H +). 231. Compound 231: (3-Cyclobutyl-8- (4- (4-fluorophenyl) piperazin-1-yl) -2, 3, 4, 5-tetrahydro-1 H -benzo [4,5] imidazo [1,2-d ] [1,4] diazepine) This compound was prepared in 27% yield (18 mg) as described for intermediate 1-38 but using 1- (4-fluorophenyl) -piperazine as the starting material. 1H-NMR (400MHz, CDC13): d 7.29 (d, J = 2.1Hz, 1H), 7.16 (d, J = 8.8Hz, 1H), 7.04 (dd, J2 = 8.8Hz, 1H), 6.93 (m, 4H), 4.19 (m, 2H), 3.49 (m, 2H), 3.30 (m, 5H), 3.21 (m, 2H), 2.91 (m, 1H), 2.61 (dt, Ji = 4.8, J2 = 15.0Hz, 4H), 2.12 (m, 2H), 1.90 (m, 2H), 1.68 (m, 3H). MS (ESI): m / z 420 (M + H +). 232. Compound 232: (2- (4- (3-cyclobutyl-2,3,4,5-tetrahydro-1 H -benzo [4, 5] imidazo [1,2-d] [1,4] diazepin-8-yl piperazin-1-yl) thiazole) This compound was prepared in 30% yield (12 mg) as described for intermediate 1-38 but using 2- (piperazin-1-yl) thiazole as the starting material. 1H-NMR (400MHz, CDC13): d 7.27 (d, J = 2.1Hz, 1H), 7.22 (d, J = 3.6Hz, 1H), 7.16 (d, J = 8.8Hz, 1H), 7.02 (dd, Ji = 2.2, J2 = 8.8Hz, 1H), 6.60 (d, J = 3.6Hz, 1H), 4.20 (m, 2H), 3.69 (m, 4H), 3.26 (m, 3H), 3.22 (m, 2H) ), 2.92 (m, 1H), 2.61 (m, 4H), 2.1 1 (m, 2H), 1.91 (m, 2H), 1.70 (m, 3H). MS (ESI): m / z 409 (M + H +). 233. Compound 233: (3-cyclobutyl-8- (4- (pyrazin-2-yl) piperazin-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazof 1, 2- d] [1,4] diazepine) compound was prepared in 10% yield as described for intermediate 1-38 but using 2- (piperazin-1-yl) pyrazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.20 (d, J = 1.4Hz, 1H), 8.09 (dd, Ji = 1.5Hz, J! = 2.6Hz, 1H), 7.87 (d, J = 2.6Hz, 1H ), 7.28 (d, J = 2.1Hz, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.03 (dd, Ji = 2.2, Ji = 8.8Hz, 1H), 4.19 (t, J = 4.5Hz, 2H), 3.79 (t, J = 5.1Hz, 4H), 3.26 (t, J = 5.1Hz, 3H), 3.21 ( m, 2H), 2.91 (m, 1H), 2.61 (dt, Ji = 4.8, J2 = 15.4Hz, 4H), 2.11 (m, 2H), 1.90 (m, 2H), 1.67 (m, 3H). MS (ESI): m / z 404 (M + H +). 2. 34. Compound 234: (3-cyclobutyl-9- (4- (pyridin-2-yl) piperazin-1-yl) -2, 3, 4, 5-tetrahydro-lH-benzof 4,5] imidazo [1, 2- d] [1,4] diazepine) This compound was prepared in 18% yield as described for intermediate 1-38 but using compound 40 and 1- (pyridin-2-yl) piperazine as the starting material. 1H-NMR (400MHz, CDC13): d 8.22 (dd, Ji = 1.2Hz, J2 = 4.9Hz, 1H), 7.58 (d, J = 8.7Hz, 1H), 7.51 (m, 1H), 6.99 (dd, Ji = 2.2, J2 = 8.8Hz, 1H), 6.78 (d, J = 2.0Hz, 1H), 6.72 (d, J = 8.6Hz, 1H), 6.66 (m, 1H), 4.19 (t, J = 4.5 Hz, 2H), 3.73 (t, J = 5.1Hz, 4H), 3.29 (t, J = 5.1Hz, 3H), 3.20 (m, 2H), 2.92 (m, 1H), 2.62 (dt, Ji = 4.8 , J2 = 18.6Hz, 4H), 2.12 (m, 2H), 1.90 (m, 2H), 1.69 (m, 3H). MS (ESI): m / z 403 (M + H +). 235. Compound 235: (7-Aza-3-cyclobutyl-9-bromo-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) Intermediate 1-110 (0.29 g, 1.1 mmol) and acetic acid (0.072 g, 1.2 mmol) were dissolved in dichloromethane (2 mL) and the reaction mixture was stirred in an ice bath for 30 minutes. Cyclobutanone (0.12 g, 1.6 mmol) was added and the mixture was stirred for 2 hours at room temperature. Solid NaBH (0Ac) 3 (0.92 g, 4.4 mmol) was added and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate and saturated aqueous solution of NaHCO 3 was added. The reaction mixture was stirred for 20 minutes at room temperature, the organic layer was collected and washed with brine, the combined organic layers were dried over Na 2 SO 4, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give compound 235 (0.20 g, 57%). : H NMR (400MHz, CDC13): d 8.34 (1H, d, J = 2.0 Hz), 8.06 (1H, d, J = 2.0 Hz), 4.43 (m, 2H), 3.25 (m, 2H), 2.92 ( m, 1H), 2.63 (m, 4H,), 2.10-2.14 (m, 2H), 1.92 (m, 2H), 1.65-1.73 (m, 2H). MS (ESI): m / z 322 (M + 1) +. 236. Compound 236: (7-Aza-3-cyclobutyl-9- (irazin-2-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) Intermediate 1-111 (0.10 g, 0.31 mmol), Pd (dppfhCl2 (23 mg, 0.03 mmol), NaOH (38 mg, 0.94 mmol) and 2-iodopyrazine (64 mg, 0.31 mmol) were dissolved in DMF (1 mL) in a microwave tube that was filled with argon The reaction mixture was stirred at 100 ° C for 1 h with microwave irradiation The reaction mixture was diluted with ethyl acetate and filtered through a plug The filtrate was washed with brine and the combined organic layers were dried over Na 2 SO 4, the solids were filtered and the filtrate was concentrated.The crude reaction mixture was purified by preparative TLC to give compound 236 (0.018 g, 21%). ?? NMR (400MHz, CDC13): d 9.08 (d, 2H), 8.98 (d, 1H, J = 2.0 Hz), 8.67 (m, 1H), 8.540 (m, 2H), 4.53 (m , 2H), 3.30 (m, 2H), 2.85-2.94 (m, 1H), 2.68 (m, 4H), 2.12-2.16 (m, 2H), 1.86-1.98 (m, 2H), 1.62-1.78 (m 2H) MS (ESI): m / z 321 (M + 1) +. 237. Compound 237: (4- (7-aza-3-cyclobutyl-2-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) This compound was prepared in 53% yield as described for compound 236 but using compound 235 and 4-cyanophenylboronic acid as the starting material. * H NMR (400MHz, CDC13): d 8.54 (d, 1H, J = 2.0 Hz). 8.14 (d, 1H, J = 2.0 Hz), 7.76 (d, 2H, J = 6.8 Hz), 7.69 (d, 2H, J = 8.8 Hz), 4.49 (m, 2H), 3.3 l (m, 2H) , 3.3 l (m, lH, m), 2.64-2.68 (m, 4H), 2.14 (m, 2H), 1.93 (m, 2H), 1.68-1.77 (m, 2H). MS (ESI): m / z 344 (M + 1) +. 238. Compound 238: (7-aza-3-cyclobutyl-8- (furan-2-yl) -2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) This compound was prepared in 56% yield as described for compound 236 but using compound 235 and furan-2-ylboronic acid as the starting material. aH NMR (400MHz, CDC13): d 8.66 (d, 1H, J = 2.0 Hz). 8.17 (d, 1H, J = 2.0 Hz), 7.52 (dd, 1H, J ^ O.8 Hz, J2 = 1.6 Hz), 6.68 (dd, 1H, Ji = 0.8 Hz, J2 = 3.2 Hz), 6.50 ( dd, 1H, Ji, 3.2 Hz, J2 = I .6 Hz), 4.46 (m, 2H), 3.26 (m, 2H), 2.85- 2. 97 (m, 1H), 2652 (m, 4H), 2.12 (m, 2H), 1.89-1.94 (m, 2H), 1.67-1.76 (m, 2H). MS (ESI): m / z 309 (M + 1) +. 239. Compound 239: (3-cyclobutyl- (aminomethyl) phenyl) -2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazole) Compound 237 (70 mg, 0.20 mmol) and CoCl2.6H20 (49 mg, 0.20 mmol) were dissolved in a 2: 1 mixture of THF and H20 and the reaction mixture was stirred for 30 minutes at room temperature. Solid NaBH (38 mg, 1.0 mmol) was added, the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed with brine. The combined organic layers were dried over Na 2 SO 4 / the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified with preparative TLC to give compound 239 (0.014 g, 20%). * H NMR (400MHz, CDC13): d 8.52 (d, 1H, J = 2.0 Hz). 8.09 (d, 1H, J = 2.0 Hz), 7.57 (d, 2H, J = 8.0 Hz), 7.42 (d, 2H, J = 8.0 Hz), 4.48 (m, 2H), 3.94 (s, 2H), 3.26 (m, 2H), 2.93 (m, 1H), 2.64 (m, 4H), 2.11 (m, 2H), 1.88-1.96 (m, 2H), 1.65-1.76 (m, 2H). MS (ESI): m / z 348 (M + 1) +. 240. Intermediate 1-2: ((2- (4-chloro-2-nitrophenylamino) ethanol) A mixture of 1,4-dichloro-2-nitrobenzene (1-1, Aldrich, I; 38.4 g, 0.2 mol) and 2-aminoethanol (24.4 g, 0.4 mol, 2 eq.) In n-butanol (100 mL) it was refluxed overnight. The solvent was evaporated and the residue was dispersed in petroleum ether (600 mL) and stirred overnight. The solids were filtered to give intermediate 1-2 as a yellow powder (37 g, 86%). 1H-NMR (400MHz, CDC13): d 8.24 (s, 1H), 8.19-8.20 (d, 1H, J = 2.4Hz), 7.39-7.42 (dd, 1H, Ji = 2.4Hz, J2 = 9.2Hz), 6.87-6.90 (d, 1H, J = 9.6Hz), 3.95-3.98 (t, 2H, J = 5.2Hz), 3.49-3.53 (dd, 2H, Jx = 4.8Hz, J2 = 10.4Hz). MS (ESI): m / z 217 (M + H +). 241. Intermediate 1-3: (2- (2-amino-4-chlorophenylamino) ethanol) «1-3 A slurry of Na2S204 (13.7 g, 78.8 mmol) in H20 (20 mL) was added over 5 minutes to a stirred solution of intermediate 1-2 (4.26 g, 19.7 mmol, 4.0 eq.) In 40% aqueous ethanol ( 90 mL). The reaction mixture was refluxed for 1 hour and concentrated. The solid was collected by filtration and dried in vacuo to give intermediate 1-3 as a pale yellow solid. The aqueous residue was basified with saturated aqueous NaHCO3, extracted with ethyl acetate, the combined organic layers were dried over Na2SO4, the solids were removed by filtration and the filtrate was concentrated to give the additional yellow solid. Both solids were combined to give intermediate 1-3 (3.1 g, 84%). XH-NMR (400MHz, DMSO-d6): d 6.54-6.55 (d, 1H, J = 2.4Hz), 6.44-6.47 (dd, 1H, J1 (2.4Hz, J2 = 6.4Hz), 6.35-3.37 (d , LH, J = 6.4Hz), 4.80 (s, 2H), 4.68 (t, 1H, J = 5.6Hz), 4.46 (t, 1H, J = 5.6Hz), 3.55-3.66 (dd, 2H, Ji = 6.0Hz, J2 = 12.0Hz), 3.03-3.08 (dd, 2H, Ji = 5.6Hz, J2 = 11.6Hz) MS (ESI): m / z 187 (M + H +). 242. Intermediate 1-5: (tert-butyl2- (5-chloro-1- (2-hydroxyethyl) -lH-benzo [d] imidazol-2-yl) ethylcarbamate) Intermediate 1-3 (6.1 g, 32.7 mmol) was added to a solution of 3-aminopropanoic acid (4.7 g, 52.3 mmol, 1.6 eq.) In 6N aqueous HC1 (70 mL) and refluxed for 24 h . The reaction mixture was basified with 20% aqueous NaOH and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, the solids were removed by filtration and the filtrate was concentrated to obtain crude intermediate 1-4 (6.7 g, 86%). This intermediate product was used in the next step without further purification. A sample for NMR analysis was purified by flash chromatography. 1H-NMR (400MHz, DMS0-d6): d 7.58-7.59 (d, 1H, J = 1.2), 7.51-7.53 (d, 1H, J = 8.4), 7.17-7.19 (dd, 1H, Ji = 8.4, J2 = 2.0), 4.25 (t, 2H, J = 9.6), 3.68 (t, 2H, J = 5.6), 2.92-3.01 (m, 4H). MS (ESD: m / z 240 (M + 1) +.

A solution of intermediate 1-4 (6.7 g, 28 mmol) in DMF (80 mL) was added to a solution of BoC20 in DMF (20 mL) by dropping at room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over Na 2 SO 4, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-5 as a light yellow solid (8.0 g, 84% total yield from 1-3 to 1-5). 1H-NMR (400MHz, DMSO-d6): d 7.59-7.60 (d, 1H, J = 2.0Hz), 7.53-7.55 (d, 1H, J = 8.4Hz), 7.18-7.21 (dd, 1H, J ^ .OHz, J2 = 8.8Hz), 6.91 (t, 1H, J = 5.2Hz), 4.95 (t, 1H, J = 5.2Hz), 4.23 (t, 2H, J = 5.6Hz), 3.66 (dd, 2H , Ji = 5.2Hz, J2 = 10.4Hz), 3.39 (dd, 2H, 3. 01 (t, 2H, J = 7.2Hz), 1.3 (s, 9H). MS (ESI): m / z 340 (M + H +). 243. Intermediate 1-6: (2- (2- (2- (tert-butoxycarbonylamino) ethyl) -5-chloro-β-benzo [d] imidazol-1-yl) ethyl 4-methylbenzenesulfonate) To a solution of intermediate 1-5 (7.5 g, 22.2 mmol) in dichloromethane (100 mL) was added 4-methylbenzene-1-sulfonyl chloride (8.4 g, 44.4 mmol, 2.0 eq.) In dichloromethane (30 mL) drip at room temperature followed by pure triethylamine (6.7 g, 66.6 mmol, 3.0 eq.) and the reaction was stirred overnight. The precipitated solid was removed by filtration and dispersed in a mixture of dichloromethane and water. The product was extracted with dichloromethane and the organic layer was evaporated to give intermediate 1-6 as a white powder. The filtrate was evaporated to dryness, dichloromethane (20 mL) was added, the solid was dispersed by irradiation with ultrasound and the solid was collected by filtration. This procedure was repeated until all the triethylamine hydrochloride was removed. Intermediate 1-6 was obtained as a white powder (9.2 g, 84%). (Note: Any residual 4-methylbenzene-1-sulfonyl chloride can be removed by washing with petroleum ether). 1 H-NMR (400MHz, DMS0-C16): d 7.54 (d, 1H, J = I .6Hz), 7.31-7.36 (m, 3H), 7.09-7.11 (m, 3H), 6.90 (m, 1H), 4.43 ~ 4.46 (m, 2H), 4.27 ~ 4.30 (m, 2H), 3.33-3.39 (m, 2H), 2.89-2.92 (m, 2H), 2.29 (s, 3H), 1.36 (s, 9H). MS (ESI): m / z 494 (M + H +). 244. Intermediate 1-8: (9-Chloro-2,3,4,5,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) To a solution of intermediate 1-6 (7.2 g, 14.6 mmol) in dichloromethane (50 mL) was added 2, 2, 2-trifluoroacetic acid (49 g, 30 eq.) For several minutes and the reaction mixture was added. stirred at room temperature for 1 hour. The progress of the reaction is monitored by LC-MS. The reaction mixture was concentrated to give intermediate 1-7 as a light pink solid.

Intermediate 1-7 was dissolved in a 20% aqueous solution of 2-propanol (300 mL) containing solid K2CO3 (16.1 g, 8.0 eq.) And the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated and the aqueous residue was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was evaporated to give intermediate 1-8 as a yellow solid. pale (3.4 g, 91%). 1H-NMR (400MHz, CDCI3): d 1.66-7.61 (d, 1H, J = 2.0Hz), 7.20-7.23 (dd, 1H, Ji = 2.0Hz, J2 = 8.8Hz), 7.14-7.16 (d, 1H , J = 8.4Hz), 4.20 (t, 2H, J = 4.8Hz), 3.23-3.25 (m, 2H), 3.08-3.15 (m, 4H). MS (ESI): m / z 222 (M + H +). 245. Intermediate 1-10: (2- (4-bromo-2-nitrophenylamino) ethanol) A mixture of 4-bromo-l-fluoro-2-nitrobenzene (1-9, Aldrich, WI, 25 g, 0.11 mol) and 2-aminoethanol (13.9 g, 0. 23 mol, 2.0 eq. ) in n-butanol (300 mL) was heated under reflux for 1 hour. The reaction mixture was concentrated and the residue was dispersed in petroleum ether (600 mL) and stirred overnight. The solids were filtered to give intermediate 1-10 as a yellow powder (29 g, 98%). MS (ESI): m / z 262 (M + H +). 246. Intermediate 1-11: (2- (2-amino-4-bromophenylamino) ethanol) Raney-Ni was added dropwise to a solution of intermediate 1-10 (20 g, 76.9 mmol) and hydrazine (15 g) in methanol (300 mL) at 0 ° C and the resulting suspension was stirred for 1 hour. The solids were removed by filtration and the filtrate was concentrated to give crude product 1-11 (17 g, 96%). MS (ESI): m / z 232 (M + H +). 247. Intermediate 1-12: (3- (5-bromo-2- (2-hydroxyethylamino) phenylamino) -3-oxopropylcarbamate tert-butyl) To a solution of intermediate 1-11 (10 g, 43.4 mmol) in dichloromethane (250 mL) was added DCC (1.5 g, 55.8 mmol) and N-Boc-3-aminopropanoic acid (9.3 g, 49.2 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-12 (10 g, 57%). MS (ESI): m / z 403 (M + H +). 248. Intermediate 1-13: (2- (5-bromo-1- (2-hydroxyethyl) -lH-benzo [d] imidazol-2-yl) ethylcarbamate tert-butyl) Intermediate 1-12 (10 g, 24.9 mmol) was dissolved in acetic acid and stirred at 65 ° C for 2 hours. The progress of the reaction was followed by LC / MS to avoid esterification of the hydroxyl group after prolonged heating. The reaction mixture was concentrated to give intermediate 1-13 (8 g, 84%). MS (ESI): m / z 385 (M + H +). 249. Intermediate 1-14: (2- (5-bromo-2- (2- (tert-butoxycarbonylamino) ethyl) - ?? - benzo [d] imidazol-1-yl) sulfonate ethyl 4-methylbenzene) A solution of intermediate 1-13 (8 g, 20.9 mmol) in dichloromethane (200 mL) was added to a solution of 4-methylbenzene-1-sulfonyl chloride (7.9 g, 41.7 mmol, 2.0 eq.) And triethylamine ( 4.0 g, 42 mmol, 2.0 eq.) In dichloromethane (50 mL) was dripped at 0 ° C and the reaction mixture was stirred overnight. The crude reaction mixture was washed with water, the combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated to give crude intermediate 1-14. The crude product was washed with petroleum ether to give intermediate 1-14 (10 g, 90%). MS (ESI): m / z 539 (M + H +). 250. Intermediate 1-15: (2- (2- (2-aminoethyl) -5-bromo-lH-benzo [d] imidazol-1-yl) ethyl 4-methylbenzenesulfonate) To a solution of intermediate 1-14 (10 g, 18.6 mmol) in dichloromethane (50 mL) was added pure trifluoroacetic acid (50 mL) dropwise over the course of several minutes and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the crude product 1-15. The crude product was washed with petroleum ether to give intermediate 1-15 (7.9 g, 98%). S (ESI): m / z 439 (M + H +). 251. Intermediate 1-16: (9-Bromo-2, 3, 4, 5- tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) Intermediate 1-15 (6.5 g, 14.8 mmol) was dissolved in an aqueous solution containing 2-propanol 20% (200 mL) and solid K2C03 (6.1 g, 3 eq). The reaction mixture was refluxed for 2 hours and the reaction mixture was concentrated. The residue was dissolved in water, extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated to give intermediate 1-16 as a pale yellow solid (3.7 g. , 95%). MS (ESI): m / z 267 (M + H +). 252. Intermediate 1-17: (3-cyclobutyl-9- (4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) 2, 3, 4, 5-tetrahydro-1H- [1 , 4] diazepinof 1, 7-a jbencimidazol) Compound 21 (2.0 g, 6.25 mmol), 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-bi (1, 3, 2-dioxaborolane) (1.86 g), Pd (dppf) Cl2 (0.2 g) and potassium acetate (1.8 g) were dissolved in DMF (10 mL) in a microwave tube that was filled with argon. The reaction mixture was stirred at 100 ° C for 1 hour with microwave irradiation, diluted with ethyl acetate and filtered through a short plug of silica gel and the filtrate was evaporated to dryness. The crude product was purified by flash chromatography to give intermediate 1-17 (1.1 g, 50%). MS (ESI): m / z 368 (M + H +). 253. Intermediate 1-18: (4- (2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-9-yl) benzonitrile) Intermediate 1-8 (508 mg, 2.3 mmol), 4-cyanophenylboronic acid (406 mg, 2.76 mmol, 1.2 eq), Pd2 (dba) 3 (106 mg, 0.115 mmol, 5 mol%), P (Cy) 3 (97 mg, 0.345 mmol, 15 mol%) and KF were dissolved in dry dioxane (10 mL) in a microwave tube that was filled with argon. The mixture was stirred at 100 ° C with microwave irradiation and diluted with ethyl acetate. The crude reaction mixture was filtered through a short plug of silica gel and the organic filtrate was washed with water. The combined organic layers were concentrated and the crude reaction mixture was purified by preparative HPLC to give intermediate 1-18 as a white powder (395 mg, 60%). MS (ESI): m / z 289 (M + H +). 254. Intermediate 1-20: (2- (5-bromo-2-nitrophenylamino) ethanol) A mixture of 4-bromo-2-fluoro-l-nitrobenzene (1-19, Aldrich, WI; 25 g, 0.11 mol) and 2-aminoethanol (13.9 g, 0.23 mol, 2.0 eq.) In n-butanol (300 mL) was refluxed for 1 hour. The reaction mixture was concentrated and the residue was dispersed in petroleum ether (600 mL) and stirred overnight. The solids were removed by filtration to give intermediate 1-20 as a yellow powder (29 g, 98%). MS (ESI): m / z 262 (M + H +). 255. Intermediate 1-21: (2- (2-amino-5-bromophenylamino) ethanol) A suspension of Raney-Ni (1 g) was added to a solution of intermediate 1-20 (22.8 g, 87.4 mmol) and hydrazine (17 g) in methanol (300 mL) at 0 ° C and the reaction mixture it was stirred for 1 hour. The solids were removed by filtration to give intermediate 1-21 (9.5 g, 97%). MS (ESI): m / z 232 (M + H +). 256. Intermediate 1-22: (tert-butyl 3- (4-bromo-2- (2-hydroxyethylamino) phenylamino) -3-oxopropylcarbamate) To a solution of intermediate 1-21 (26 g, 112.6 mmol) in dichloromethane (500 mL) was added DCC (30.2 g, 146.4 mmol) and N-Boc-3-aminopropanoic acid (24.5 g, 129.5 mmol), and The reaction was stirred at 0 ° C for 1 hour and at room temperature overnight. The reaction mixture was concentrated and the residue was diluted with ethyl acetate and washed with water. The combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-22 (28 g, 62%). MS (ESI): m / z 403 (+ H +). 257. Intermediate 1-23: tert-butyl2- (6-bromo-l- (2-hydroxyethyl) -lH-benzo [d] imidazol-2-yl) ethylcarbamate) Intermediate 1-22 (20 g, 49.7 mmol) was dissolved in acetic acid and stirred at 65 ° C for 2 hours. The progress of the reaction was followed by LC / MS to avoid esterification of the hydroxyl group after prolonged heating. The reaction mixture was concentrated to give intermediate 1-23 (16 g, 83%). MS (ESD: m / z 385 (M + H +). 258. Intermediate 1-24: 2- (6-bromo-2- (2- (tert-butoxycarbonylamino) ethyl) -lH-benzo [d] imidazol-1-yl) ethyl-4-methylbenzenesulfonate) A solution of intermediate 1-23 (16 g, 29.7 mmol) in dichloromethane (200 mL) was added to a solution of 4-methylbenzene-1-sulfonyl chloride (9.6 g, 35.7 mmol, 1.2 eq.) And triethylamine ( 8.0 g, 84 mmol, 2 eq.) In dichloromethane (50 mL) at 0 ° C and the reaction mixture was stirred overnight. The reaction mixture was washed with water, the combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated. The crude reaction mixture was washed with petroleum ether to give intermediate 1-4 (20 g, 90%). MS (ESI): m / z 539 (M + H +). 259. Intermediate 1-25: 2- (2- (2-aminoethyl) -6-bromo-IH-benzo [d] imidazol-1-yl) ethyl-4-methylbenzenesulfonate) To a solution of intermediate 1-24 (15 g, 27.9 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (40 g) by dropping over the course of several minutes and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated to give a residue which was washed with ethyl ether to give intermediate 1-25 (12 g, 98%). MS (ESD: m / z 439 (M + H +). 260. Intermediate 1-26: (8-Bromo-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) Intermediate 1-25 (12 g, 27.3 mmol) was dissolved in an aqueous solution of 20% 2-propanol (300 mL) containing solid K2CO3 (30.2 g, 8.0 eq.). The reaction mixture was refluxed for 2 hours and concentrated. The residue was extracted with dichloromethane, the combined organic layers were dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated to give intermediate I-26 as a pale yellow solid (7 g, 95%). MS (ESI): m / z 267 (M + H +). 261. Intermediate 1-27: (3-cyclobutyl-8- (4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) 2, 3, 4, 5-tetrahydro-lH- [1 , 4] diazepino [1,7-a [benzimidazole] Compound 40 (2.0 g, 6.25 mmol), 4,4,4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 21 -bi (1, 3,2-dioxaborolane) (1.86 g) ), Pd (dppf) Cl2 (0.2 g) and potassium acetate (1.8 g) were dissolved in DMF (13 mL) in a microwave tube that was filled with argon. The mixture was stirred at 100 ° C for 1 hour with microwave irradiation. The reaction mixture was diluted with ethyl acetate, filtered through a short plug of silica gel and the filtrate was washed with water. The combined organic layers were evaporated to dryness and the crude reaction mixture was purified by flash chromatography to give intermediate 1-27 (1.1 g, 50%). MS (ESI): m / z 368 (M + H +). 262. Intermediate 1-28: (3-cyclobutyl-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9-ol) To an ice-cooled solution of intermediate 1-17 (100 mg) in a mixture of acetone and saturated aqueous NaHC03 solution (1 mL) was added 2KHS05-KHS04-K2S04 (230 mg). After 5 min, solid NaHS03 (1 g) was added and the reaction mixture was concentrated. The residue was dispersed in methanol and the solids filtered. The filtrate was purified by reverse phase chromatography to give intermediate 1-28 (23 mg, 33%). MS (ESI): m / z 258 (M + H +). 263. Intermediate 1-30: (3-cyclobutyl-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9-amine) Compound 21 (2.0 g, 6.25 mmol), diphenylmethanimine (2.83 g, 15.6 mmol, 2.5 eq.), Pd2 (dba) 3 (0.286 g, 0.313 mmol, 5 mol%), BINAP (390 mg, 0.626 mmol, 10 mol%) and tBuONa (0.84 g, 8.75 mmol) were dissolved in dry toluene (60 mL) and the flask was flushed with argon. The mixture was stirred at 110 ° C for 15 hours. After the LC / MS and TLC analyzes indicated complete consumption of 2L, the reaction mixture was filtered through a short plug of silica gel. The filtrate was washed with water, the combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was dissolved in a 1: 1 mixture of 1N HC1 and THF and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was dissolved in water and extracted with ethyl acetate. The combined aqueous layers were basified by adding aqueous sodium hydroxide solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by chromatography to give the intermediate product 1-30 (0.85 g, 53%). MS (ESD: m / z 257 (M + H +). 264. Intermediate 1-31: (3-cyclobutyl-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9-carbaldehyde) Compound 54 (108 mg) was dissolved in a mixture 4: 1 formic acid and water (15 mL) and 4 drops of a Raney-Ni suspension were added. The mixture was stirred for 1 hour at room temperature, the solids were filtered and the filtrate was concentrated by evaporation. The residue was basified to pH 8 and extracted with dichloromethane. The layers. The combined organic extracts were dried over sodium sulfate, the solids were filtered and the filtrate was evaporated. The resulting residue was dissolved in dichloromethane and solid Mn02 was added. The reaction mixture was stirred for 30 minutes at room temperature and the solid was filtered. The filtrate was concentrated and purified by preparative TLC to give intermediate 1-31 (40 mg, 36%). MS (ESI): m / z 270 (M + H +). 265. Intermediate 1-32: (3-cyclobutyl-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-8-ol) To an ice-cooled solution of intermediate 1-27 (432 mg) in acetone containing an aqueous saturated solution of NaHCO3 (4.3 mL) was added 2KHSO5.KHSO4.K2SO4 (900 mg) and the reaction mixture was stirred at room temperature. 0 ° C for 5 min. Solid NaHS03 (5 g) was added and the reaction mixture was concentrated. The residue was dispersed in methanol and the solids filtered. The filtrate was concentrated and purified by reverse phase chromatography to give intermediate 1-32 (150 mg, 50%). MS (ESI): m / z 258 (M + H +) 266. Intermediate 1-34: (3-cyclobutyl-2, 3, 4, 5-tetrahydro-1, 4- [1,4] diazepinof 1,7-a] benzimidazole-8-amine) 40 1-33 1-34 Compound 40 (0.64 g, 2 mmol), L-proline (0.3 eq.), Cul (0.2 eq.), NaN3 (3.0 eq.), And sodium hydroxide (1.0 eq.) Were dissolved in a mixture 21: 9 ethanol and water (30 mL) and the flask was flushed with argon. The reaction mixture was refluxed overnight and the solids filtered through a short plug of silica gel. The filtrate was washed with water, the combined organic layers were dried over sodium sulfate, the solid was filtered and the organic filtrate was concentrated. Crude intermediate I-33 was dissolved in methanol and palladium on carbon was added. The flask was filled with hydrogen gas and the progress of the reaction was monitored until all intermediate 1-34 was consumed. The solids were filtered through a short plug of silica gel and the filtrate was concentrated. The crude reaction mixture was purified by chromatography to give intermediate I-34 (0.15 g, 30%). MS (ESI): m / z 257 (M + H +). 267. Intermediate 1-35: (2- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7- a] benzimidazol-8-yl) methanol) Compound 82 (100 mg), a suspension of Ni-Al (20 drops) and HC02H (2 mL) were dissolved in H20 (120 mL) and stirred for 4 hours at room temperature. The The solids were filtered and the pH of the filtrate was adjusted to pH-12 by adding an aqueous solution of NaOH at 0 ° C. The aqueous solution was extracted with ethyl acetate, the combined organic layers were dried with Na 2 SO 4, the solid was filtered and the filtrate was filtered. He concentrated. The crude reaction mixture was purified by preparative HPLC to give intermediate 1-35 (37 mg, 36%). MS (ESI): m / z 272 (M + 1) +. 268. Intermediate 1-36: (3-cyclobutyl-8-chloromethyl-2, 3,4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) To a solution of intermediate 1-35 (20 mg) in CH2C12 (5 mL) was added pure S0C12 (0.5 mL) per drop at 0 ° C, the reaction mixture was warmed to room temperature and stirred for 90 minutes . The reaction mixture was concentrated to give intermediate I-36 as a yellow solid which was used directly in the next step. 269. Intermediate 1-37: (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-8-carboxylic acid) Compound 82 (610 mg) was dissolved in a 1: 1 mixture of acetic acid and aqueous HC1 was concentrated and the reaction mixture was stirred at 80 ° C for 3 hours. The reaction mixture was concentrated and the resulting residue was dissolved in water and basified to pH 5-6. The reaction mixture was concentrated and the residue was dispersed in methanol and the solids filtered. The filtrate was concentrated and the crude reaction mixture was purified by reverse phase chromatography to give intermediate 1-37 (300 mg, 46%). 1H-NMR (400MHz, CD3OD), d 8.18 (d, 1H, J = 0.8Hz), 7.94 (dd, 1H, Ji = 1.2Hz, J2 = 8.4Hz), 7.61 (d, 1H, J = 8.4Hz) , 4.44 (m, 2H), 3.18 (m, 2H), 3.09 (m, 1H), 2.79 (m, 2H), 2.73 (m, 2H), 2.17-2.19 (m, 2H), 1.97-2.02 (m , 2H), 1.73-1.76 (m, 2H). MS (ESD: m / z 286 (M + H +). 270. Intermediate 1-38: (4- (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepin [1,7- a] benzimidazol-9-yl) piperazine-l-carboxylate of tert-butyl) Compound 21 (0.52 g, 1.63 mmol), DCCP (0.12 g, 0.24 mmol), NaOtBu (0.22 g, 2.22 mmol), Pd2 (dba) 3 (75 mg, 0.08 mmol) and N-Boc-piperazine (0.36 g) , 1.96 mmol) were dissolved in toluene (8 mL) and the reaction mixture was heated at 100 ° C for 14 h. The reaction mixture was diluted with ethyl acetate and filtered through a short plug of Celite. The filtrate was concentrated and the residue was purified by flash chromatography to give intermediate 1-38 (0.75 g, 75%). MS (ESI) m / z 426 (M + 1) +. 271. Intermediate 1-39: (3-cyclobutyl-2, 3, 4, 5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-8-carbaldehyde) To a solution of compound 82 (60 mg) in dichloromethane at -78 ° C was added a solution of toluene from DIBAL (4.0 eq.) Per drop. The reaction was stirred at -78 ° C for 1 hour and a saturated aqueous solution of NH 4 Cl was added. The reaction mixture was stirred at room temperature for 3 hours and washed with water.

The combined organic layers were dried over Na 2 SO 4, the solids were removed by filtration and the filtrate was evaporated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-39 as a white solid (300 mg, 50%). MS (ESI): m / z 270 (M + 1) +. 272. Intermediate 1-40: (3-cyclobutyl-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole-9-carboxylic acid) A solution of compound 54 (500 mg) in a 1: 1 mixture of acetic acid / concentrated HCl was stirred at 80 ° C for 3 hours. The reaction mixture was concentrated and the residue dissolved in water and basified to pH 5-6. The reaction mixture was concentrated and the crude reaction mixture was purified by reverse phase chromatography to give intermediate 1-40 (160 mg, 30%). MS (ESD: m / z 286 (M + 1) +. 273. Intermediate 1-42: (methyl 3- (tert-butylamino) propanoate) To a mixture of intermediate I-42a (3.7 g, 50 mmol, 1.0 eq) and methyl acrylate (5.2 g, 60 mmol, 1.2 eq) in DMSO (5 mL) were added 3 drops of H20 and the mixture of The reaction was stirred at room temperature for 60 minutes. The reaction mixture was diluted with EtOAc (50 mL) and washed with H20 and brine. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate 1-42 (3.9 g, 49%) as a pale yellow oil. 1 H-NMR (400 MHz, CDC13) d: 3.68 (s, 3 H), 2.83 (t, 2 H, J = 6.4 Hz), 2.51 (t, 2 H, J = 6.4 Hz), 1.11 (s, 9 H). MS (ESI): m / z 160.1 (M + H +). 274. Intermediate 1-43: (N- (2- (5-bromo-1 H -benzo [d] imidazol-2-yl) ethyl) -2-methylpropan-2-amine) Intermediate 1-42 (2.1 g, 13 mmol, 1.0 eq) and 4-bromobenzene-1,2-diamine (2.5 g, 13 mmol, 1.0 eq) were dissolved in aqueous HCl (4.0 M in water, 20 mL) and the The reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (50 mL) and the pH adjusted to 7-8 using an aqueous solution of ammonia. The crude reaction mixture was extracted with CH2C12, the combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product from the crude reaction was purified by silica gel column chromatography to give intermediate 1-43 (580 mg, 15%) as a yellow-brown solid. 1H-NMR (400 MHz, DMSO-d6) d: 7.67 (d, 1H, J = 1.6Hz), 7.43 (d, 1H, J = 8.4Hz), 7.25 (dd, 1H, J, = 1.6Hz, J2 = 8.4Hz), 2.92 (m, 4H), 1.05 (s, 9H). MS (ESD: m / z 296.1, 298.1 (M + H +). 275. Intermediate 1-44: (1: 1 mixture of 8-bromo and 9-bromo-3- (tert-butyl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1, 2-d] [1,4] diazepine) Intermediate 1-43 (550 mg, 1.9 mmol, 1.0 eq) was dissolved in pure 1,2-dibromoethane (2 mL) and solid NaH (220 mg, 5.6 mmol, 60% dispersion in mineral oil, 3.0 eq). It was added in portions. The reaction mixture was stirred at 80 ° C for 16 hours and quenched by adding water (5 mL). The crude reaction mixture was extracted with CH2Cl2 and washed with brine. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by preparative thin layer chromatography to give intermediate I-44 (60 mg, 10%) as a pale yellow solid. 1 H-NMR (400 MHz, DMSO- (I6) d: 7.81-7.73 (d, 1H, J = I .6Hz), 7.50-7.49 (d, 1H, J2 = 8.4Hz), 4.27 (t, 2H, J = 4.0Hz), 3.12 (t, 2H, J = 4.0Hz), 2.82 (m, 4H), 1.08 (s, 9H). MS (ESI): m / z 322.1, 324.1 (M + H +). 276. Intermediate 1-45: (3-cyclobutyl-8- (piperidin-3-yl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1,2-d] [1, 4] diazepine) Compound 115 (400 mg, 1.3 mmol, 1.0 eq) and Pd / C (10% w / w, 20 mg) were dissolved in acetic acid (10 mL) and the reaction mixture was stirred under a hydrogen atmosphere ( 1 atm) at 70 ° C for 12 hours. The solids were removed by filtration, the residue was dissolved in water (15 mL) and the pH adjusted to ~8 by adding an aqueous solution of NaHCO3. The crude reaction mixture was extracted with ethyl acetate, the combined organic layers were dried over a2SC > 4 anhydrous, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-45 (200 mg, 49%). MS (ESD: m / z 325 (M + H +). 277. Intermediate 1-46: ((E) -3-cyclobutyl-8-nitrovinyl) -2, 3, 4, 5-tetrahydro-lH-benzo [4,5] imidazo [1 d] [1,4] diazepine) Intermediate 1-31 (300 mg, 1.1 mmol, 1.0 eq) and NH4OAc (120 mg, 1.5 mmol, 1.4 eq) were suspended in CH3NO2 (10 mL) and the reaction mixture was stirred at 100 ° C for 4 hours. hours. The excess solvent was removed by evaporation and the crude reaction product was purified by silica gel column chromatography to give intermediate 1-46 (300 mg, 86%) as a yellow solid. 1H-NMR (400MHz, CDC13) d: 8.09 (d, 1H, J = 13.6Hz), 7.82 (d, 1H, J = I.2Hz), 7.56 (d, 1H, J = 13.6Hz), 7.40 (dd, 1H, J = 8.8Hz), 7.23 (d, 1H, J = 8.8Hz), 4.23 (s, 2H), 3.23 (s, 2H), 2.91 (s, 1H) , 2.61 (s, 4H), 2.09 (s, 2H), 1.93 (s, 1H), 1.70 (s, 1H), 1.58 (m, 2H). MS (ESI): m / z 313.0 (M + H +). 278. Intermediate 1-49: (4- (hydroxyimino) piperidin-l-carboxylate of tert-butyl) S ° m¾x am, -? * ???? ? ß 149 To a solution of intermediate 1-48 (50 g, 0.25 mol, 1.0 eq) in ethanol (300 mL) was added hydroxylamine hydrochloride (35 g, 0.50 mol, 2.0 eq) followed by sodium acetate (41 g, 0.50 g). mol, 2.0 eq) and the reaction mixture was stirred at 100 ° C for 7 hours. The solids were removed by filtration and the filtrate was concentrated by evaporation. Water was added to the waste; The reaction mixture was extracted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO 4, the solids were removed by filtration and the filtrate was concentrated to give intermediate 1-49 (54 g, 100%) as white solid which was used in the next step without further purification. MS (ESI): m / z 159.1 (M + H +). 279. Intermediate 1-50: (5-oxo-l, 4-diazepane-l-carboxylate of tert-butyl) To a solution of intermediate 1-49 (11 g, 50 mmol, 1.0 eq) in acetone (60 mL) was added a solution of Na 2 CO 3 (16 g, 150 mmol, 3.0 eq) in water (80 mL) and the mixture of the reaction was stirred for 5 minutes. A solution of p-toluenesulfonyl chloride (14 g, 75 mmol, 1.5 eq) in acetone (20 mL) was added slowly and the reaction mixture was stirred at room temperature for 3 hours. The excess solvent was removed by evaporation, water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO 4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-50 (5.0 g, 48%). MS (ESI) m / z 159.1 (M + H +). 280. Intermediate 1-52: (1-cyclobutyl-1,4-diazepane-5-one) Intermediate 1-50 (2.1 g, 10 mmol, 1.0 eq) was dissolved with dichloromethane (20 mL) and pure TFA (4 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and the excess solvent and TFA were removed by evaporation. The resulting intermediate 1-51 crude (MS (ESI): m / z 115.1 (M + H +)), cyclobutanone (1.1 g, 15 mmol, 1.5 eq) and acetic acid (0.5 mL, 0.8 eq) were dissolved in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature for 60 minutes. Solid NaBH (OAc) 3 (4.2 g, 20 mmol, 2.0 eq) was added and the reaction mixture was stirred at room temperature for additional 3 hours. The reaction mixture was neutralized by adding an aqueous solution of K2CO3 and extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO 4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give crude intermediate 1-52 (1.6 g, 98%) as white solid which was used in the next reaction without subsequent purification. 1 H-NMR (400 MHz, CDC13) d: 6.15 (s, 1H), 3.30 (q, J = 4.8Hz, 2H), 2.81 (q, J = 4.4Hz, 1H), 2.61-2.63 (m, 2H), 2.45-2.50 (m, 4H), 2.03- 2. 10 (m, 2H), 1.79-1.88 (m, 2H), 1.62-1.74 (m, 2H). MS (ESI): m / z 169.1 (M + H +). 281. Intermediate 1-54: (5-bromoisobenzofuran-1,3-dione) To a solution of intermediate 1-53 (22 g, 0.15 mol, 1.0 eq) in water (150 mL) was added solid NaOH (12 g, 0.30 mol, 2.0 eq) and pure Br2 (8.5 mL, 0.17 mol, 1.1 eq) and the reaction mixture was stirred at 90 ° C for 6 hours. The crude reaction mixture was cooled slowly to 0 ° C in a refrigerator and the light yellow solids were collected by filtration, washed with cold water and dissolved in pure S0C12 (60 mL). The reaction mixture was refluxed for 2.5 hours and concentrated by evaporation. The product of the crude reaction was crystallized from ethyl acetate to give intermediate 1-54 (22 g, 79%). MS (ESI): m / z 228 (M + H +). 282. Intermediate 1-55: (5-bromoisoindolin-l, 3-dione) A mixture of intermediate 1-54 (6.6 g, 0.30 mol, 1.0 eq) and formamide (10 mL, 2.4 mol, 8.0 eq) was stirred at 200 ° C for 2 hours and poured into a mixture of ice and water. The resulting crystals were collected by filtration and dried in vacuo to yield intermediate 1-55 (7.0 g, 99%). MS (ESI): m / z 227 (M + H +). 283. Intermediate 1-56: (5-bromo-6-nitroisoindolin-1,3-dione) Fuming nitric acid (9.2 mL, 0.22 mol, 1.0 eq) previously cooled to 0 ° C was added dropwise concentrated sulfuric acid (21 mL, 0.40 mol, 1.8 eq) followed by the portionwise addition of intermediate 1-55 (10 g, 44 mmol, 2.0 eq) and the resulting suspension was warmed at room temperature for 1 hour and stirred for an additional 24 hours at room temperature. The crude reaction mixture was poured into a mixture of ice and water and the solids were collected by filtration and dried in vacuo to give intermediate I-56 (11.8 g, 98%). MS (ESI): m / z 272 (M + H +). 284. Intermediate 1-57: (2-benzyl-5-bromo-6-nitroisoindolin-1,3-dione) To a mixture of intermediate 1-56 (10 g, 37 mmol, 1.0 eq) in DMF (30 mL) was added 2C03 solid (13 g, 93 mmol, 2.5 eq) and pure BnBr (6.6 mL, 55 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and brine. The combined organic layers were dried over anhydrous MgSO 4, the solids were removed by filtration and the filtrate was concentrated. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-57 (12 g, 90%). MS (ESI): m / z 362 (M + H +). 285. Intermediate 1-58: (2-benzyl-5- (4-cyclobutyl-7-oxo-l, 4-diazepan-1-yl) -6-nitroisoindolin-1,3-dione) A three neck, dry flask was charged with Pd2 (dba) 3 (0.28 g, 0.30 mmol, 0.1 eq), Xantphos (0.28 g, 0. 50 mmol, 0.16 eq), intermediate 1-52 (0.50 g, 3.0 mmol, 1.0 eq), Cs2C03 (1.2 g, 6.0 mmol, 2.0 eq), intermediate 1-57 (1.1 g, 3.0 mmol, 1.0 eq) and 1,4-dioxane (15 mL) and the reaction mixture was degassed by bubbling N2. The reaction mixture was stirred at 80 ° C for 5 hours, diluted with dichloromethane (50 mL), the solids were removed by filtration and the filtrate was concentrated in vacuo. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-58 (0.6 g, 36%) as a pale yellow solid. MS (ESI): m / z 449.0 (M + H +). 286. Intermediate 1-60: (2- (3-bromophenyl) ethanamine) A suspension of LiAH (2.5 g, 66 mmol, 1.6 eq) in dry THF (100 mL) was cooled to -5 ° C and concentrated H2SO4 (3.2 g, 33 mmol, 0.8 eq) was added dropwise while the temperature was maintained. below 3 ° C. The reaction mixture was stirred at 5 ° C for 40 minutes and a solution of intermediate 1-59 (8.0 g, 41 mmol, 1.0 eq) in THF was added dropwise. The reaction mixture is warm at room temperature and stir for an additional 60 minutes. The reaction mixture was cooled to 0 ° C and quenched by adding a mixture of THF (5 mL) and water (5 mL). Ether was added followed by a solution of sodium hydroxide (20 mL, 3.6 M in water) and the crude reaction mixture was filtered through a short plug of Celite. The combined organic layers were dried over anhydrous MgSC, the solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate 1-60 (8.0 g, 93%). MS (ESI): m / z 200 (M + H +). 287. Intermediate 1-61: (N- (3-bromophenethyl) -2, 2, 2-trifluoroacetamide) A mixture of intermediate 1-60 (8.0 g, 40 mmol, 1.0 eq) and 2,6-lutidine (4.8 mL, 41 mmol, 1.03 eq) in dry dichloromethane (160 mL) was cooled to 0 ° C and added by dripping pure TFAA (5.6 mL, 39.6 mmol, 0.99 eq). The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (150 mL) was added, the aqueous layer was extracted with dichloromethane and the combined organic layers were washed with aqueous HC1 (1.0 M in water) and a saturated aqueous solution of NaHCO3.

The combined organic layers were dried over anhydrous Na 2 SO 4, the solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate 1-61 (11 g, 92%). 1H-NMR (400MHz, CDC13) d: d 7.40 (d, 1H, J = 8.0Hz), 7.35 (t, 1H, J = I .6Hz), 7.20 (t, 1H, J = 7.6Hz), 7.12 ( d, 1H, J = 8.0Hz), 6.55 (brs, 1H), 3.59 (q, 2H, Jx = 6.4Hz, J2 = 13.2Hz), 2.86 (t, 2H, J = 6.8Hz). MS (ESD: m / z 296 (M + H +). 288. Intermediate 1-62: (1- (6-bromo-3,4-dihydroisoquinolin-2 (1H) -yl) -2,2,2-trifluoroethanone) A mixture of acetic acid (61 mL) and concentrated H2SO4 (40 mL) was added to a mixture of intermediate 1-61 (11 g, 37 mmol, 1.0 eq) and paraformaldehyde (1.8 g, 59 mmol, 1.6 eq) and The reaction mixture was stirred at room temperature for 72 hours. The crude reaction mixture was poured into a mixture of ice and water and extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous solution of NaHCO 3 and water and the combined organic layers were dried over anhydrous Na 2 SO 4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give pure intermediate 1-62 (3.8 g, 33%) and a mixture of intermediates 1-62 and 1-62 '(4.0 g, 36%) that were discarded. 1H-NMR (400MHz, CDC13) d: 7.33-7.37 (m, 2H), 7.00 (d, 1H, J = 8.4Hz), 7.02 (d, 1H, J = 8.4Hz), 4.72 (m, 2H), 3.84 (m, 2H), 2.91 ~ 2.96 (m, 2H). MS (ESD: m / z 308 (+ H +). 289. Intermediate 1-63: (1- (6-bromo-7-nitro-3,4-dihydroisoquinolin-2 (lH) -yl) -2,2, 2-trifluoroethanone) A solution of intermediate 1-62 (1.5 g, 5 mmol, 1.0 eq) in dichloromethane (25 mL) was cooled to -15 ° C, a solution of KN03 (505 mg, 5 mmol, 1.0 eq) in concentrated H2SO4 ( 2 mL) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was carefully diluted with ice and extracted with dichloromethane. The combined organic layers were dried over Na2SC > 4 anhydrous, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give pure intermediate 1-63 (800 mg, 45%), intermediate 1-63 '(110 mg, 6%), and a mixture of intermediates 1-63 and 1-63' (600 mg, 35%). 1 H-NMR (400MHz, CDC13) d: 7.72 (s, 1H), 7.60 (s, 1H), 4.77 (m, 2H), 3.94 (m, 2H), 2.99 ~ 3.04 (m, 2H). MS (ESI): m / z 353 (M + H +). 290. Intermediate 1-64: (1- (9-cyclobutyl-3, 4, 8, 9, 10, 11-hexahydro-lH- [1,4] diazepino [7 ', 1': 2, 3] imidazo [4 , 5-g] isoquinolin-2 (7H) -yl) -2, 2, 2-trifluoroethanone) This intermediate product was prepared in 63% yield (110 mg) using a reaction sequence described for intermediate 1-58 and compound 143 but using intermediate 1-63 as the starting material. MS (ESI): m / z 393 (M + H +). 291. Intermediate 1-65: (1- (10-cyclobutyl 9, 10, 11, 12-tetrahydro-lH- [1,4] diazepino [1 ', 1: 1,2] imidazo [4, 5-f] isoquinoline - 3 (2H, 4H, 8H) -yl) -2, 2, 2-trifluoroethanone) This intermediate product was prepared in 51% yield using a reaction sequence described for intermediate 1-58 and compound 143 but using intermediate 1-63 'as the starting material. MS (ESI): m / z 393 (M + H +). 292. Intermediate 1-67: ((E) - 1-bromo-4- (2-nitrovinyl J-benzene) A mixture of intermediate 1-66 (23 g, 100 mmol, 1.0 eq.), NH4OAc (18 g, 220 mmol, 2.2 eq), CH3N02 (70 mL) and acetic acid (17 mL) was stirred at 50 ° C for 5 hours. The precipitate was collected by filtration and washed with a mixture of ethanol (50 mL) and H20 (50 mL) and dry air to give intermediate 1-67 (14 g, 50%) as a yellow solid. 1 H-NMR (400MHz, DMSO-d 6) d: 7.95 (d, J = 13.6Hz, 1H), 7.60 (m, 3H), 7.42 (m, 2H). 293. Intermediate 1-68: (2- (4-bromophenyl) ethanamine) chloride To a stirred suspension of LiAlH4 (7.7 g, 203 mmol, 3.5 eq.) In THF (40 mL) was added dropwise a solution of intermediate 1-67 (13 g, 59 mmol, 1.0 eq.) In THF (40 g). mL) and the reaction mixture was stirred at room temperature for 2 hours and quenched by adding a solution of NaOH (30% in water). Ethyl acetate (100 mL) was added and the crude reaction mixture was stirred for another 30 minutes. The organic layer was separated and dried over anhydrous Na2SO4. HC1 gas was bubbled through the ethyl acetate solution at 0 ° C and the white precipitate was collected by filtration to give intermediate 1-68 (3.2 g, 23%). 1 H-NMR (400 MHz, DMSO-d 6) d: 7.52 (m, 2 H), 7.24 (m, 2 H), 3.18 (m, 2 H), 2.95 (m, 2 H). MS (ESI): m / z 198.1, 200.1 (M + H +). 294. Intermediate 1-69: (N- (4-bromophenethyl) -2, 2, 2-trifluoroacetamide) This intermediate product was prepared in 77% yield (3.2 g) as described for intermediate 1-61 but using intermediate I-68 as the starting material. 1H-NMR (400MHz, CDC13) d: 9. 48 (m, 1H), 7.49 (m, 2H), 7.17 (m, 2H), 3.41 (m, 2H), 2.78 (m, 2H). MS (ESI): m / z 296.0, 298.0 (M + H +). 295. Intermediate 1-70: (Ni- (7-bromo-3,4-dihydroisoquinolin-2 (lH) -yl) -2,2, 2-trifluoroethanone) This intermediate product was prepared in 78% yield (1.9 g) as described for intermediate 1-62 but using intermediate 1-69 as the starting material. 1 H-NMR (400MHz, CDC13) d: 7.34 (m, 2H), 7.05 (m, 1H), 4.75 (m, 2H), 3.86 (m, 2H), 2.91 (m, 2H). MS (ESI): m / z 308.0, 310.1 (M + H +). 296. Intermediate 1-71: (mixture of 1- (7-bromo-6-nitro-3,4-dihydroisoquinolin-2 (lH) -yl) -2,2,2-trifluoroethanone and 11- (7-bromo-8 -nitro-3, 4-dihydroisoquinolin-2 (lH) -yl) -2,2, 2-trifluoroethanone) This intermediate product was prepared in 87% yield (1.9 g) as described for intermediate 1-63 and 1-63 'but using product intermediate 1-70 as the initial material. MS (ESI): m / z 353.0, 355.1 (M + H +). 297. Intermediate 1-72: (7-bromo-6-nitro- 1, 2, 3, 4-tetrahydroisoquinoline) This intermediate product was prepared in 44% yield (0.8 g) as described for compound 183 but using intermediate 1-71 as the starting material. ^ "H-NMR (400MHz, CDC13) d: 7.65 (s, 1H), 7.38 (s, 1H), 4.03 (s, 2H), 3.14 (m, 2H), 2.81 (m, 2H), MS (ESI) ): m / z 257.0, 259.1 (M + H +). 298. Intermediate 1-73: (1-cyclobutyl-4- (6-nitro-1,2,3,4-tetrahydroisoquinolin-7-yl) -1,4-diazepane-5-one) This intermediate product was prepared in 71% yield (380 mg) as described for intermediate 1-58 but using intermediate 1-72 as the starting material. MS (ESI): m / z 345.4 (M + H +). 299. Intermediate 1-75: (6-bromo-2-methylimidazof 1,2-a] pyridine) Intermediate 1-74 (800 mg, 4.2 mmol, 1.0 eq) and chloroacetone (3.0 g, 13 mmol, 3.0 eq) were mixed in ethanol (10 mL) and the reaction mixture was refluxed for 24 hours. The crude reaction mixture was concentrated by evaporation; the residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-75 (188 mg, 19%). MS (ESI): m / z 212 (M + H +). 300. Intermediate 1-77: (3, 3, 5-tribromo-1H-pyrrolo [2, 3-b] pyridin-2 (3H) -one) Intermediate 1-76 (5.0 g, 42 mmol, 1.0 eq) was dissolved in a mixture of water (330 mL) and t-butanol (330 mL), pure bromine (27 mL, 530 mmol, 13 eq) was added dropwise at room temperature and the reaction mixture was stirred for 24 hours. t-Butanol was removed by evaporation and the pH was adjusted to -9 by adding a saturated aqueous solution of NaHCO 3. The precipitate was collected by filtration and dried in vacuo to give intermediate 1-77 (13 g, 83%) as a brown solid which was used in the next step without further purification. MS (ESI): m / z 372 (M + H +). 301. Intermediate 1-78: (5-bromo-lH-pyrrolo [2, 3-b] pyridin-2 (3H) -one) Elemental zinc (4.0 g, 61 mmol, 10 eq) was added to a solution of intermediate 1-77 (2.3 g, 6.1 mmol, 1.0 eq) in acetic acid (50 mL) and the solution was purged by bubbling nitrogen. The reaction mixture was stirred at room temperature for 5 hours and concentrated by evaporation. The residue was dissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation and azeotropic distillation with toluene. He The crude reaction product was purified by silica gel column chromatography to give intermediate 1-78 (0.3 g, 23%) as an orange solid. MS (ESI): m / z 214 (M + H +). 302. Intermediate 1-79: (5-bromo-lH-pyrrolo [2, 3-b] pyridine) 1 * 79 To a solution of intermediate 1-78 purged with N2 (0.30 g, 1.4 nunol, 1.0 eq) in anhydrous THF (10 mL) at 0 ° C was added to BH3 solution (5.7 mL, 1.0 M in THF, 5.7 mmol , 4.0 eq) and the reaction mixture was stirred at room temperature for 50 minutes. The crude reaction mixture was concentrated by evaporation and the residue was dissolved in a solution of HCl (6.0 M in water) and the reaction mixture was stirred heated until complete dissolution of all solids. After cooling to room temperature, the pH was adjusted to -9 by adding a solution of NaOH (6.0 M in water) and the crude reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The residue is dissolved in acetic acid (4 mL), added to a suspension of manganese (III) acetate (0.61 g, 2.3 mmol, 1.6 eq) in acetic acid (5 mL) and the reaction mixture was stirred at 75 ° C for 50 minutes The crude reaction mixture was concentrated by azeotropic distillation with toluene; the residue was dissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-79 (17 mg, 6%, in 2 steps) as a yellowish solid. MS (ESI): m / z 198 (M + H +). 303. Intermediate 1-81: (6-bromoimidazo [1,5-ajpyridine] Pure POC13 (3 mL) was added dropwise to a solution of intermediate 1-80 (360 mg, 1.7 mmol, 1.0 eq) in benzene (20 mL), the reaction mixture was refluxed for 14 hours and the reaction mixture was refluxed for 14 hours. He turned off with ice. The crude reaction mixture was basified with a saturated aqueous solution of NaHCO 3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product from the crude reaction was purified by silica gel column chromatography to give intermediate 1-81 (140 mg, 14%) as a yellow solid. MS (ESI): m / z 198 (M + H +). 304. Intermediate 1-83: (5-bromo-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine) To a solution of intermediate 1-82 (10 g, 40 mmol, 1.0 eq) in DMF (115 mL) was added pure triethylamine (53 mL), Pd (PPh3) 4 (2.3 g, 2.0 mmol, 0.05 eq) and Cul (0.90 g, 4.7 mmol, 0.12 eq) followed by dropwise addition of ethynyltrimethylsilane (6.7 mL, 48 mmol, 1.2 eq) and the reaction mixture was stirred for 30 minutes at 120 ° C. The crude reaction mixture was concentrated by evaporation and the crude reaction product was purified by silica gel column chromatography to give intermediate 1-83 (3.0 g, 17%) as a yellow oil. MS (ESD: m / z 271 (M + H +). 305. Intermediate 1-84: (N- (5-bromo-3- ((trimethylsilyl) ethynyl) pyrazin-2-yl) acetamide) I * » To a solution of intermediate 1-83 (3.0 g, 11 mmol, 1.0 eq) in anhydrous THF (45 mL) was added pure pyridine (2.2 g, 28 mmol, 2.5 eq) followed by AcCl (22 mmol, 2.0 eq). and the reaction mixture was stirred at room temperature for 16 hours and at 60 ° C for an additional 5 hours. The crude reaction mixture was concentrated by evaporation and the crude reaction product was purified by silica gel column chromatography to give intermediate 1-84 (1.0 g, 29%) as a yellow solid. MS (ESI): m / z 314 (M + H +). 306. Intermediate 1-85: (2-bromo-5H-pyrrolo [2, 3-b] pyrazine) To a solution of intermediate 1-84 (1.0 g, 3.2 mmol, 1.0 eq) in THF (8.5 mL) was added dropwise a TBAF solution (7.1 mL, 1.0 M in THF, 7.1 mmol, 2.2 eq) and the reaction mixture was subjected to reflux for 15 hours. The crude reaction was concentrated by evaporation; the residue was dissolved in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The product of the crude reaction was purified by silica gel column chromatography to give intermediate 1-85 (100 mg, 16%) as a yellow solid. MS (ESI): m / z 199 (M + H +). 307. Intermediate 1-87: (2-tert-butyl hydrazine-1,2-dicarboxylate 1-benzyl) t¾W-WHB0C - "| 0S¡¾HM-NHÉ $ e I-B6 W7 To a solution of intermediate 1-86 (20 g, 150 mmol, 1 eq) in dichloromethane (400 mL) was added dropwise pure CbzCl (28 g, 166 mmol, 1.1 eq) in a period of 20 minutes and the mixture of the reaction was stirred at room temperature overnight. The excess solvent was removed by evaporation and the residue was diluted with water and extracted with ether. The pH of the aqueous layer was adjusted to ~8 and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration. The filtrate was concentrated to give intermediate 1-87 (38 g, 94%) which was used in the next step without further purification. MS (ESI): m / z 167 (M + H +). 308. Intermediate 1-88: (2-tert-butyl pyrazolidin-1,2-dicarboxylic acid 1-benzyl) A suspension of sodium hydride (60% dispersion in mineral oil, 3.0 g, 75 mmol, 2.0 eq) in anhydrous DMF (120 mL) was cooled in an atmosphere of nitrogen at 0 ° C in an ice / water bath. Intermediate I-87 (10 g, 38 mmol, 1.0 eq) was added in portions and the reaction mixture was stirred for 20 minutes. 1,3-dibromopropane (7.5 g, 38 mmol, 1.0 eq) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. Glacial acetic acid (0.5 mL) was added and the excess solvent was removed by evaporation. The residue was diluted with 50% saturated aqueous brine and extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous MgSO 4; The solids were removed by filtration. The filtrate was concentrated by evaporation to give intermediate 1-88 crude (11 g, 95%), which was used in the next step without further purification. MS (ESI): m / z 307 (M + H +). 309. Intermediate 1-89: (benzyl pyrazolidin-1 carboxylate) Intermediate 1-88 (11 g, 35 mmol, 1.0 eq) was dissolved in pure trifluoroacetic acid (10 mL) under nitrogen at room temperature and the reaction mixture was stirred vigorously for 10 minutes. The excess solvent was removed by evaporation and the residue was dissolved in water and extracted with a 1: 1 mixture of ethyl acetate and hexane. To the organic phase inverted extraction was applied with aqueous hydrochloric acid (1.0 M) and the combined aqueous phases were basified with aqueous NaOH (50%). The basified aqueous layer was extracted with dichloromethane, the combined organic layers were dried over anhydrous Na2SO4 and the solids were removed by filtration. The filtrate was concentrated by evaporation to give intermediate 1-89 (5.5 g, 74%) which was used in the next step without further purification. MS (ESI): m / z 207 (M + H +). 310. Intermediate 1-90: (2- (3-chloropropanoyl) pyrazolidin-1-carboxylic acid benzyl) A solution of intermediate 1-89 (8.6 g, 41 mmol, 1.0 eq) and diisopropylethylamine (5.3 g, 41 mmol, 1.0 eq) in dichloromethane (100 mL) was cooled under a 0 ° C nitrogen bath in an ice bath. /Water. A solution of 3-chloropropionyl chloride (5.2 g, 41 mmol, 1.0 eq) in dichloromethane (30 mL) was added dropwise over 45 minutes and the reaction mixture was stirred for an additional 60 minutes. The reaction was quenched by adding aqueous hydrochloric acid (1.0 M) and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with aqueous HC1 (1.0 M), dried over anhydrous MgSO4 and the solids were removed by filtration. The filtrate was concentrated by evaporation and the crude reaction product was purified by silica gel column chromatography to give intermediate 1-90 (10 g, 81%). MS (ESI): m / z 297 (M + H +). 311. Intermediate 1-91: (tetrahydropyrazolo [1,2-a] pyrazole- (5H) -one) To a solution of intermediate 1-90 (10 g, 34 mmol, 1.0 eq) in absolute ethanol (200 mL) was added palladium on carbon (10% by weight, 1.0 g) and the reaction mixture was stirred under an atmosphere. of hydrogen (1 atm) overnight. The solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate 1-91 as the HC1 salt (5.3 g, 97%). MS (ESD: m / z 127 (M + H +). 312. Intermediate 1-92: (1, 5-diazocan-2-one) To a solution of intermediate 1-91 (5.0 g, 31.6 mmol, 1.0 eq) in absolute ethanol (25 mL) was added to Raney's nickel slurry (4 g, wet weight) and the reaction mixture was stirred at Hydrogen atmosphere (1 atm) for 4 days. The solids were removed by filtration and the filtrate was concentrated by evaporation to give intermediate 1-92 as the HC1 salt (5.1 g, 99%). MS (ESI): m / z 129 (M + H +). 313. Intermediate 1-93: (5-cyclobutyl-l, 5-diazocan-2-one) This intermediate product was prepared in 60% yield (4.4 g) as described for compound 8 but using intermediate 1-92 as the starting material. MS (ESI): m / z 183 (M + H +). 314. Intermediate 1-94: (1- (4-chloro-2-nitrophenyl) -5-cyclobutyl-l, 5-diazocan-2-one) This intermediate was prepared in 65% yield (1.2 g) as described for intermediate 1-58 but using intermediate I-93 and l-bromo-4-chloro-2-nitrobenzene as the starting material. MS (ESI): m / z 338 (M + H +). 315. Intermediate 1-95: (3-cyclobutyl-10- (4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -1, 2, 3, 4, 5, 6-hexahydrobenzo [4,5] imidazo [1,2-a] [1,5] diazozin) This intermediate product was prepared in 37% yield (50 mg) as described for intermediate 1-17 but using compound 218 as the starting material. MS (ESI): m / z 381 (M + H +). 316. Intermediate 1-96: (4 (S-cyclobutyl-1-oxo-1,5-diazocan-1-yl) -3-nitrobenzonitrile) This intermediate product was prepared in 36% yield (6.8 g) as described for intermediate 1-58 but using intermediate 1-93 and 4-bromo-3-nitrobenzonitrile as the starting materials. MS (ESD: m / z 329 (M + H +). 317. Intermediate 1-97: (3-cyclobutyl-1, 2, 3, 4, 5, 6-hexahydrobenzo [4,5] imidazof 1,2-a] [1,5] diazocin-10-carbonitrile) This intermediate product is prepared in 75% yield (6.8 g) as described for compound 143 but using intermediate 1-96 as the starting material. MS (ESI): m / z 281 (M + H +). 318. Intermediate 1-98: (3-cyclobutyl-l, 2, 3, 4, 5, 6-hexahydrobenzo [4,5] imidazo [1,2-a] [1/5] diazocin-10-carbaldehyde) This intermediate product is prepared in 65% yield (2.9 g) as described for intermediate 1-39 but using intermediate I-97 as the starting material. MS (ESI): m / z 284 (M + H +). 319. Intermediate 1-100: (5-bromo-3-nitropyridin-2-ol) A mixture of 5-bromopyridin-2-ol (1-99, Aldrich, I; 53 g, 0.30 mol) in concentrated H2SO4 (250 mL) was stirred by cooling with an ice bath and concentrated HN03 (105 mL) was added slowly to mix. The reaction mixture was stirred for 4 hours at room temperature and then poured onto ice and stirred for an additional 30 minutes. A yellow precipitate was filtered and used in the next step without further purification (45 g, 68%). MS (ESI): m / z 220 (M + l) +. 320. Intermediate 1-101: (5-bromo-2-chloro-3-nitropyridine) 1100 MOt A mixture of intermediate 1-100 (8.0 g, 36.7 mmol) and N, N-diethylaniline (7 mL) in POCI3 (30 mL) was refluxed for 4 hours. The reaction mixture was cooled to room temperature, poured onto ice and stirred for an additional 30 minutes. A yellow precipitate was filtered and used in the next step without further purification (7.2 g, 83%). MS (ESI): m / z 238 (M + 1) +. 321. Intermediate 1-102: (2- (5-bromo-3-nitropyridin-2-ylamino) ethanol) Intermediate 1-101 (3.2 g, 13.6 mmol), 2-aminoethanol (1 mL, 16.3 mmol) and Et 3 N (3.8 mL, 27.1 mmol) were dissolved in CH 3 CN (10 mL) and the reaction mixture was subjected to reflux for 3 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The layers The combined organic extracts were dried over Na2SO4, the solids were filtered and the filtrate was concentrated to give intermediate 1-102 (3.2 g, 90%). MS (ESI): m / z 263 (M + 1) +. 322. Intermediate 1-103: (2- (5-bromo-3-nitropyridin-2-ylamino) ethanol) Intermediate 1-102 (3.2 g, 12.3 mmol) and NH2NH2-H20 (2.5 g, 49 mmol) were dissolved in MeOH (40 mL) and the reaction mixture was stirred at room temperature while a slurry suspension was slowly added. Raney Ni. The reaction mixture was stirred for 1 hour at room temperature and filtered through a short plug of Celite, the filtrate was dried over Na 2 SO, the solids were filtered and the filtrate was concentrated to give intermediate 1-103 ( 2.8 g, 100%). MS (ESI): m / z 233 (M + 1) +. 323. Intermediate 1-104: (2- (5-bromo-3-nitropyridin-2-ylamino) ethanol) Intermediate 1-103 (36 g, 0.156 mol), EDCI (60 g, 0.31 mol), HOBt (44 g, 0.33 mol), DIPEA (60 g, 0.47 mol) and N-Boc-3-aminopropanoic acid (44 g, 0.23 mol) were dissolved in dioxane (50 mL) and the reaction mixture was stirred at 80 ° C for 16 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over Na2SO4, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-104 (23 g, 37%). MS (ESD: m / z 404 (M + l) \ 324. Intermediate 1-105: (2- (5-bromo-3- (3- (tert-butoxycarbonyl-amino) propanamido) pyridin-2-ylamino) ethyl-3- (tert-butoxy-carbonylamino propanoate)) NHBOC N H AND EDCHHQtt M O DIPEAWiow e H0 (.ios Intermediate 1-104 (16.6 g, 41.3 mmol), EDCI (11.9 g, 61.9 mmol), HOBt (11.1 g, 82.6 mmol), DIPEA (16 g, 124 mmol) and N-Boc-3-aminopropanoic acid (11.7 g, 61.9 mmol) were dissolved in dioxane (50 mL) and the reaction mixture was stirred at 80 ° C for 16 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over Na2SO4, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-105 (11.8 g, 50%). MS (ESI): m / z 575 (M + 1) +. 325. Intermediate 1-106: (2- (6-bromo-2- (2- (tert-butoxycarbonyl-amino) ethyl) -3H-imidazo [4, 5-b] pyridin-3-yl) ethyl 3 - (propanoate of tert-butoxycarbonylamino)) Intermediate 1-105 (4.20 g, 7.3 mmol) was dissolved in acetic acid (20 mL) and stirred at 80 ° C for 16 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over Na2SO4, the solids were filtered and the filtrate was concentrated to give the crude intermediate 1-106 which was used in the next step without further purification (3.2 g, 79%). MS (ESI): m / z 557 (M + 1) +. 326. Intermediate 1-107: (2- (6-bromo-3- (2-hydroxyethyl) -3H-imidazo [4, 5-b] pyridin-2-yl) ethylcarbamate tert -butyl) Intermediate 1-106 (3.2 g, 5.77 mmol) and LiO.H20 (0.73 g, 17.3 mmol) were dissolved in a 1: 1 mixture of THF and H20 (10 mL) and the reaction mixture was stirred for 2 hours. hours at room temperature. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried over Na2SC > 4, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography to give intermediate 1-107 (0.65 g, 30%). MS (ESI): m / z 386 (M + 1) +. 327. Intermediate 1-108: (2- (6-bromo-2- (2- (tert-butoxycarbonylamino) ethyl) -3H-imidazo [4, 5-b] pyridin-3-yl) sulfonate ethyl 4-methylbenzene) M07 08 Intermediate 1-107 (0.65 g, 1.69 mmo TosCl (0.65 g, 3.39 mmol) and Et 3 N (0.6 mL, 4.23 mmol) were dissolved in dichloromethane and the reaction mixture was stirred for 16 hours at room temperature. The reaction was concentrated and the residue was dissolved in ethyl acetate and washed with brine, the combined organic layers were dried over Na 2 SO 4, the solids were filtered and the filtrate was concentrated.The excess of TosCl was removed by washing the residue with ether. oil to give intermediate 1-108 (0.79 g, 87%) MS (ESI): m / z 540 (M + 1) +. 328. Intermediate 1-109: Ethyl 4-methylbenzene 2- (2- (2-aminoethyl) -6-bromo-3H-imidazo [4, 5-b] pyridin-3-yl) sulfonate) 1-108 1-109 Intermediate 1-108 (0.79 g, 1.47 mmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction mixture was stirred for 60 minutes at room temperature. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The combined organic layers were dried over Na2SO4, the solids were filtered and the filtrate was concentrated to give intermediate 1-109 (0.60 g, 94%). MS (ESI): m / z 440 (M + 1) +. 329. Intermediate 1-110: (7-Aza-9-bromo-2,3,4,5-tetrahydro-lH- [1,4] diazepino [1,7-a] benzimidazole) Intermediate 1-109 (0.60 g, 1.37 mmol) and K2C03 (0.47 g, 3.42 mmol) was dissolved in a 1: 1 mixture of isopropanol and H20 (4 mL) and the reaction mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The combined organic layers are dried over Na 2 SO 4, the solids were filtered and the filtrate was concentrated by evaporation to give intermediate 1-110 (0.30 g, 83%). MS (ESI): m / 268 (M + 1) +. 330. Intermediate 1-111: (7-Aza-3-cyclobutyl-9 (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) 2, 3, 4, 5-tetrahydro-? ? - [1, 4] diazepino- [1, 7-a] benzimidazole) Compound 235 (0.20 g, 0.63 mmol), Pd (dppf) 2C12 (0.10 g, 0.125 mmol), KOAc (0.21 g, 2.19 mmol) and 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -1, 3, 2-dioxaborlane (0.24 g, 0.94 mmol) was dissolved in DMF (1 mL) in a microwave tube which was filled with argon. The reaction mixture was stirred at 100 ° C for 1 hour with microwave irradiation. The reaction mixture was diluted with ethyl acetate and filtered through a short plug of Celite. The filtrate was washed with brine and the combined organic layers were dried over Na 2 SO 4, the solids were filtered and the filtrate was concentrated. The crude reaction mixture was purified by preparative TLC to give intermediate 1-111 (0.08 g, 48%). MS (ESI): m / z 369 (M + 1) +.

B. In Vitro Histamine H3 Assay The H3 GTPyS assay (SPA method) was done in EuroScreen (Belgium, ES-392-C) using traditional methods. Briefly, cells expressing the human histamine H3 receptor were homogenized in 15 mM Tris-HCl pH 7.5, 2 mM MgCl2, 0.3 mM EDTA and 1 mM EGTA. The membranes were washed twice in the aforementioned tris buffer, harvested by centrifugation (40,000 xg, 25 min), and re-suspended in 75 mM Tris-HCl pH 7.5, 12.5 mM MgCl 2, 0.3 mM EDTA, EGTA 1 mM and 250 mM sucrose. The membranes were frozen in liquid nitrogen until their use. During the test day the membranes were thawed and diluted in the buffer solution for the assay (20 mM HEPES pH 7.4, 100 mM NaCl, 10 g / ml saponin, 1 mM MgCl 2) to obtain 500 g / mL and mixed ( v / v) with GDP in buffer for the assay for dyeing a final GDP concentration of 10 μ? and incubated on ice for at least 15 min. PVT-WGA beads (Amersham, RPNQ001) were diluted in buffer solution for the assay at a concentration of 50 mg / mL and mixed with GTPy [35S] (Amersham, SJ1308) diluted in buffer for the assay to obtain -25,000 dpm / 10 pL and mixed vol / vol just before starting the reaction. The reaction was started by adding 50 μ? - of the compound to be tested, 20 μ ?, of the membrane mixture: GDP, 10 μ? * Of buffer and 20 μl of the mixture GTPy [35S]: beads in a 96 well plate Optiplate ™ (PerkinElmer, 6005299) covered with topseal (TopCount ™, PerkinElmer), mixed on an orbital shaker for 2 min, incubated for 1 hour at room temperature, centrifuged for 10 min at 2000 rpm, incubated for 1 h at room temperature environment, and the count was counted for 1 min in a TopCount ™ reader (PerkinElmer). The dose-response curves and the IC50 values (concentration to inhibit the reaction by 50%) were calculated by non-linear regression using the XLfit software (IDBS).

To test the antagonists, 10 μ? of a reference agonist (R-y-Me-Histamine) instead of 10 of buffer were added at a corresponding concentration for EC8o (30 nM). The control ligands were R-Y-Me-Histamine (Tocris, 0569), Imetit (Sigma, I-135), Thioperamide (Tocris, 0644) and Clobenpropit (Tocris, 0754) diluted in buffer solution for the assay.

The compounds provided herein were analyzed in the in vitro histamine H3 receptor assay. In one embodiment, the respective HC1 salts of the compounds provided herein were prepared using standard chemical procedures and tested in the in vitro histamine H3 assay. The functional potency of the compounds (as indicated by their IC50) is presented in Table 1.

Table 1. (++++) < = 10 (+++) < = ioo (++) < = 1 μ? (+) > = 1 μ The modalities described above are proposed to be exemplary only, and those skilled in the art will be aware, or will be able to ascertain using no more than routine experimentation, numerous equivalents of the specific compounds, materials and procedures. All of these equivalents are considered within the scope of the description and are encompassed by the appended claims.

All patents, patent applications and publications referred to herein are incorporated in their totals. Appointments or Identification of any reference in this application is not an admission that such a reference is available as a prior art for this application. The full scope of the description is better understood with reference to the appended claims.

Claims (1)

1. CLAIMS 1. A compound of the formula (la): or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein RN is a bond, hydrogen, (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (Ci-Cio) heteroalkyl, heterocycloalkyl (C3-C10) / heteroaryl (from 5 to 10 members), each of which is optionally substituted with one or more RCA times R 'is independently hydrogen, halogen, cyano, (Ci-Cio) alkyl, alkenyl of (Ci-Cio), cycloalkyl of (C3-Ci0), aryl (of 6 to 10 members), heteroalkyl of (Ci-Cio), heterocycloalkyl of (C3-C10), heteroaryl (of 5 to 10 members), hydroxyl , alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which is optionally substituted with one or more R2; or two substituents R 'together can form a 3- to 10-membered ring optionally substituted with one or more R2; R5, R6, R7 and Re are each independently: (i) hydrogen, halogen or cyano; (ü) (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, (C3-C10) heterocycloalkyl ), heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri; (iii) hydroxyl substituted with one or more Ri '; or (iv) two adjacent radicals R5, R6, R7 and Rs, together form a 3- to 10-membered ring optionally substituted with one or more Ri, each time Ri appears it is independently hydrogen, halogen, cyano, = 0, -OR3, -NR3R4, -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C ( 0) OR3, -0C (0) R3, -S (0) mR3, -S (0) 2NR3R4, (Ci-Cio) alkyl optionally substituted with one or more R2, (C3-Ci0) cycloalkyl optionally substituted with one or more R2, (C6-C12) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (C1-C10) optionally substituted with one or more R2 , (C3-C10) heterocycloalkyl optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2; each time Ri 'is independently -C (0) NR3R4, -C (0) R3, (C3-Ci0) cycloalkyl optionally substituted with one or more R2, (C6-Ci2) aralkyl optionally substituted with one or more R2, aryl (from 6 to 10 members) optionally substituted with one or more R2, heteroalkyl of (Ci-Cio) optionally substituted with one or more R2, heterocycloalkyl of (C3-C10) optionally substituted with one or more R2, or heteroaryl (from 5 to 10 members) optionally substituted with one or more R2; each time R2 appears is independently hydrogen, (C1-C6) alkyl optionally substituted with one or more R3, (C3-C6) cycloalkyl optionally substituted with one or more R3, halogen, cyano, = 0, -OR3, - NR3R4, -N (R3) C (0) R4, -C (0) NR3R4, -C (0) R3, -C (0) OR3, -0C (0) R3, -S (0) mR3 or -S (0) 2NR3R4; R3 and R4 are each independently, hydrogen, (Ci-C6) alkyl, (C3-C6) cycloalkyl, (C7-C10) aralkyl; heteroalkyl of (Ci-C6), heterocycloalkyl of (C3-C6), aryl (from 6 to 10 members), or heteroaryl (from 5 to 10 members); or R3 and R4 together can form a ring of 3 to 10 members; m is 0, 1 or 2; n is 1, 2 or 3; Y when n is 1, (i) R5, R6, R7 and Re can not all be hydrogen; (ii) when one of R5, R6, R7 and Re is halogen, the other three of R5, R6, R7 and Rs can not all be hydrogen; and (iii) when R6 is (C1-C4) alkyl or (C1-C4) alkoxy optionally substituted with one or more halogen, R5, R7 and Rs can not all be hydrogen. 2. The compound of claim 1, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, having the formula (lia): (He has) 3. The compound of claim 2, characterized in that two adjacent radicals R5, R6, R7, and s, together form a 3- to 10-membered ring optionally substituted with one or more Ri. 4. The compound of claim 3, characterized in that the compound is: 5. The compound of claim 2, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, having the formula (Illa): (Illa) where RAr is (i) cyano; (ü) alkyl of (Ci-Ci0), alkenyl of (Ci-Ci0), cycloalkyl of (C3-C10), aryl (of 6 to 10 members), heteroalkyl of (Ci-Cio), heterocycloalkyl of (C3-C10) ), heteroaryl (from 5 to 10 members), alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more R or (iii) hydroxy substituted with one or more R \ '; and RA r is not (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy optionally substituted with one or more halogen. 6. The compound of claim 5, characterized in that RN is (C3-C10) cycloalkyl or (C1-C10) alkyl, each of which is optionally substituted with one or more R1; and RAr is (i) cyano; (ii) aryl (from 6 to 10 members), heteroalkyl of (Ci-Cio) f heterocycloalkyl of (C3-C10), heteroaryl (from 5 to 10 members), aminoalkyl, amino, amido or carbonyl, each of which is optionally substituted with one or more Ri, or (iii) (C1-C10) alkyl, hydroxyl or alkoxy, each of which is substituted with one or more Ri '. 7. The compound of claim 5, characterized in that RN is optionally substituted cyclobutyl. 8. The compound of claim 5, characterized in that RAr is cyano, optionally substituted phenyl, optionally substituted six-membered heteroaryl, optionally five-membered heteroaryl substituted, optionally substituted (8 to 10) heteroaryl, optionally substituted six-membered heterocycloalkyl, optionally substituted five-membered heterocycloalkyl, -OR, 1, -OCH2Ri ', -NHRlf -NHCH2Ri, -N (Ri) 2, -C (0) Ri, -C (0) N (R02, -CH2Ri ', -CH2N (Ri) 2, -CH2OH or -CH2OR1'. 9. The compound of claim 5, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, having the formula (IVa): characterized in that X is independently N, CH or composed of the claim characterized in that the compound is: 11. The compound of claim 2, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, having the formula (HIb): where RAr is (i) cyano; (ii) (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (6 to 10 membered) aryl, (C 1 -C 10) heteroalkyl, (C 3 -C 10) heterocycloalkyl ), heteroaryl (from 5 to 10 members), alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri or (iii) hydroxyl substituted with one or more Ri '. 12. The compound of claim 11, characterized in that RN is (C1-C10) alkyl optionally substituted with one or more R '. 13. The compound of claim 11, characterized in that RN is (C3-C10) heterocycloalkyl optionally substituted with one or more R '. 14. The compound of claim 11, characterized in that RN is (C3-Ci0) cycloalkyl optionally substituted with one or more R '. 15. The compound of claim 14, characterized in that RN is cyclobutyl optionally substituted with one or more R '. 16 The compound of claim 11, characterized in that RAr is phenyl or naphthyl optionally substituted with one or more Ri. 17 The compound of claim 11, characterized in that RAr is six-membered heteroaryl optionally substituted with one or more Ri. 18 The compound of claim 1, characterized in that RAr is five-membered heteroaryl optionally substituted with one or more Ri. 19. The compound of claim 11, characterized in that RAr is 8 to 10 membered heteroaryl membered optionally substituted with one or more Ri. 20. The compound of claim 11, characterized in that RAr is (C3-Ci0) heterocycloalkyl optionally substituted with one or more Ri. 21. The compound of claim 11, characterized in that RAr is (Ci-Cio) alkyl or alkoxy, each of which is optionally substituted with one or more Ri. 22. The compound of claim 11, characterized in that RAr is hydroxy substituted with one or more Ri '. 23. The compound of claim 11, characterized in that RAr is amino, amido or carbonyl, each of which is optionally substituted with one or more Ri. 24. The compound of claim 11, having the formula (IVb): (IVb) or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, wherein X is independently N, CH or CRi. 25. The compound of claim 11, characterized in that the compound is: 427 428 430 26. The compound of claim 1, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof, having the formula (V): (V) wherein RAr is (i) hydrogen, halogen or cyano; (ii) (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (6 to 10 membered) aryl, (C1-C10) heteroalkyl, (C3-C10) heterocycloalkyl ), heteroaryl (from 5 to 10 members), alkoxyl, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, (iii) hydroxyl substituted with one or more Ri '; or (iv) two adjacent radicals R5, R6, R7, and Rs, together form a 3- to 10-membered ring optionally substituted with one or more Ri. 27. The compound of claim 26, characterized in that the compound is: 28. A compound of (Ilb): wherein R6, R7, and Rs are independently hydrogen, halogen, cyano, (Ci-Cio) alkyl, (Ci-Cio) alkenyl, (C3-C10) cycloalkyl, aryl (from 6 to 10 members), heteroalkyl of (Ci-Cio), (C3-C10) heterocycloalkyl, heteroaryl (from 5 to 10 members), hydroxyl, alkoxy, aminoalkyl, amino, imino, amido, carbonyl, thiol, sulfinyl or sulfonyl, each of which is optionally substituted with one or more Ri, or two adjacent radicals R6, R7 and R8, together can form a ring of 3 to 10 members. 29. The compound of claim 28, characterized in that R6 and Re are hydrogen, and RN is (C3-C10) cycloalkyl optionally substituted with one or more R '. 30. The compound of claim 28, characterized in that R7 is halogen, aryl (from 6 to 10 members) optionally substituted with one or more Ri, or heteroaryl (from 5 to 10 members) optionally substituted with one or more Ri. 31. The compound of claim characterized in that the compound is: 32. A pharmaceutical composition containing a compound of claim 1. 33. The pharmaceutical composition of claim 32, which further contains one or more additional active agents. 34. A method for decreasing the activity of the histamine receptor, the method is to contact the histamine receptor and a compound of claim 1, or a salt, solvate or stereoisomer accepted for pharmaceutical use thereof. 35. The method of claim 34, wherein the histamine receptor is an H3 receptor. 36. A method of treating, preventing or managing a disorder related to the histamine H3 receptor comprising administering to an individual an effective therapeutic or prophylactic amount of a compound of claim 1, or a salt, solvate or stereoisomer accepted for use pharmacist of this one. 37. The method of claim 36, wherein the individual is a human. 38. The method of claim 36, characterized in that the disorder is a neurological disorder, neurodegenerative disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, affective disorder, attention deficit hyperactivity disorder (ADHD), psychosis, convulsion, epileptic seizures, vertigo, epilepsy, narcolepsy, pain, neuropathic pain, sensitization that accompanies many neuropathic pain disorders, mood disorders such as depression and anxiety, excessive daytime sleepiness, narcolepsy, multiple sclerosis, shift workers, relief of side effects of other medications; insomnia; substance abuse; Cognitive impairments, metabolic disorders, diabetes, obesity, related disorders with satiety, disorder of gastric activity, diseases affecting the enteric system, pancreatic system disorder, acid secretion, digestion disorder, intestinal motility disorder; Movement disorder, Restless Legs Syndrome (RLS) or Huntington's disease.