MX2008006988A

MX2008006988A - Bradykinin 1 receptor antagonists

Info

Publication number: MX2008006988A
Application number: MXMX/A/2008/006988A
Authority: MX
Inventors: Jeffrey Chen Jian; Zhu Jiawang; Qian Wenyuan; Brooks Human Jason
Original assignee: Amgen Inc; Jeffrey Chen Jian; Brooks Human Jason; Qian Wenyuan; Zhu Jiawang
Priority date: 2005-12-07
Filing date: 2008-05-30
Publication date: 2008-09-02

Abstract

The invention encompasses novel compounds and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for treatment of diseases mediated by B1 bradykinin receptor.

Description

BRADIQUININ RECEIVER ANTAGONISTS 1 FIELD OF THE INVENTION This invention is directed to compounds that are bradykinin 1 receptor antagonists, compositions comprising the same, and methods for treating diseases mediated by the bradykinin 1 receptor such as disorders related to inflammation, including pain.

BACKGROUND OF THE INVENTION More than two million people in the United States alone are incapacitated by chronic pain on any day (T. Jessell &D. Kelly, Pain and Analgesia in PRINCIPLES of NEURAL SCIENCE, third edition (E. Kandel, J Schwartz, T. Jessell, eds., (1991).) Unfortunately, current treatments for pain are only partially effective, and many cause lifestyle disruption, debilitation, and / or dangerous side effects. Non-steroidal anti-inflammatory drugs ("NSAID") such as aspirin, ibuprofen, and indomethacin are moderately effective against inflammatory pain but are also renally toxic, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding, increased cardiovascular risk, and confusion Patients treated with opioids frequently experience Ref. 193242 confusion and constipation; and long-term opioid use is associated with tolerance and dependence. Local anesthetics such as locaine and mixellitine simultaneously inhibit pain and cause loss of normal sensation. In addition, when used systematically, local anesthetics are associated with adverse cardiovascular effects. Accordingly, there is currently an unfulfilled need in the treatment of chronic pain. Pain is a perception based on signals received from the environment and transmitted and interpreted by the nervous system (for review, see M. Millan, Prog. Neurobiol., 57: 1-164 (1999)). Harmful stimuli such as heat and touch cause specialized sensory receptors in the skin to send signals to the central nervous system ("CNS"). This process is called nociception, and the peripheral sensory neurons that mediate it are nociceptors. Depending on the resistance of the nociceptor signal and the abstraction and elaboration of this signal by the CNS, a person may or may not experience a noxious stimulus as painful. When one's pain perception is appropriately calibrated to the intensity of the stimulus, the pain serves its proposed protective function. However, certain types of tissue damage cause a phenomenon, known as hyperalgesia or pronociception, in which relatively innocuous stimuli are perceived as intensely painful because the person's pain thresholds have decreased. Both inflammation and nerve damage can induce hyperalgesia. Accordingly, persons afflicted with inflammatory conditions, such as sunburn, osteoarthritis, colitis, carditis, dermatitis, myositis, neuritis, inflammatory bowel disease, vascular collagen diseases (which include rheumatoid arthritis and lupus) and the like, frequently they experience improved sensations of pain. Similarly, trauma, surgery, amputation, abscesses, causalgia, vascular collagen diseases, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, herpes infections, acquired immunodeficiency syndrome ("AIDS "), toxins and chemotherapy cause nerve injuries that result in pain. Just as the mechanisms by which nociceptors transduce external signals under normal and hyperalgesic conditions become better understood, the processes involved in hyperalgesia can be directed to inhibit the decrease in pain threshold and thereby reduce the amount of pain experienced . Bradykinin (BK) and the related peptide, calidin (Lys-BK), mediate the physiological actions of kinins in the cardiovascular and renal systems. Without However, the active peptides, BK and calidin, are rapidly degraded by peptidases in plasma and other biological fluids and by those released from a variety of cells, so that the half-life of BK in plasma is reported to be approximately 17 seconds ( 1) . Bk and kallidin are rapidly metabolized in the body by carboxypeptidase N, which removes the carboxyterminal arginine residue to generate des-Arg BK or des-Arg-kallidin. Des-Arg-calidin is among the quinine predominant in man and mediates the pathophysiological actions of quinines in man.

In addition to being a very potent pro-inflammatory peptide, des-Arg-BK or des-Arg-calidin is known to induce vasodilation, vascular permeability, and bronchoconstriction (for review, see Regoli and Barabe, Pharmacological Rev, 32 (1), 1-46 (1980)). In addition, des-Arg-BK and des-Arg-calidin appear to be particularly important mediators of inflammation and inflammatory pain as well as are involved in its maintenance. There is also a considerable body of evidence involving the over-production of des-Arg-calidin under conditions in which pain is a predominant feature such as septic shock, arthritis, angina, and migraine. The membrane receptors that mediate the peyotropic actions of quinines are of two different classes, designated Bl and B2. Both kinds of receptors have been cloned and sequenced from a variety of species, including man (Menke, et al, J. Biol. Chem. 269, 21583-21586 (1994); Hess et al., Biochem. Biophys., Res. Commun. 184, 260-268. ] 992)). They are typical G protein coupled receptors that have seven putative expanded membrane regions. In several tissues, the BK receptors are coupled to every second known messenger. B2 receptors, which have a higher affinity for BK, appear to be the most frequent form of bradykinin receptor. Essentially all normal physiological responses and many pathophysiological responses to bradykinin are mediated by B2 receptors. The Bl receptors, on the other hand, have a higher affinity for des-Arg-BK compared to BK, whereas des-Arg-BK is inactive at the B2 receptors. In addition, B receptors are not normally expressed in most tissues. Its expression is induced in tissue damage or injury as well as in certain types of chronic inflammation or systemic attack (F. Marceau, et al., Immunopharmacology, 30, 1-26 (1995)). In addition, the responses mediated by the Bl receptors are over-regulated at a null level after the administration of bacterial lipopolysaccharide (LPS) or inflammatory cytokines in rabbits, rats, and pigs. The properties that induce pain of the kinins coupled with the inducible expression of Bl receptors make to the receptor Bl an interesting target in the development of anti-inflammatory, antinociceptive, antihyperalgesic and analgesic agents that can specifically target injured tissues with minimal actions in normal tissues. Certain compounds have been described as bradykinin artagonists. WO 03/07958, published on January 30, 2003, describes tetrahydroquinoxalines. The dihydroquinoxalinones are described in a JACS release. Piperazin-2, 3, 5-triones are described in Tet. Lett., 40, 7557-7560 (1999). The European application 641779, published on March 8, 1995, describes 3,6-dioxopiperazines as inhibitors of platelet aggregation. Clearly, there is a need for new safe and effective treatments for inflammation and pain. Such agents are provided in the present invention.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, this invention is directed to a compound of formula (I): (I) wherein: R is hydrogen or alkyl; R1 is aryl or heteroaryl optionally substituted with Ra, Rb, and Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylamino, dialkylamino, or alkoxy; R 2 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R3 is bridged heterocyclyl, bridged cycloalkyl wherein bridged heterocyclyl or bridged cycloalkyl is optionally substituted with one, two or three substituents selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl, or alkoxyalkyl; or R3 is a group of formula (a) where: n is 0, 1, 2, or 3; Y is -CH2- or -NH-; Z is -C (O) -, -C (= NOH), -CONH-, -O-, -C (0) 0-, -S-, - SO-, -S02-, -NH-, or - CH2 ~; R, R, and R are independently selected from hadrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, ai coxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, ammoalkyl, ammoalkoxy, carboxyalkyl, ai coxycarbonylalkyl, cyanoalkyl, cycloalkyl, c: chloralkylalkyl, amino, monosubstituted orth, di-substituted ammo, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy where the ring, heteroaryl, or heterocyclyl ring in R4, R5 , and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; and R7 and R8 are independently hydrogen or alkyl; or R4 and R7, when attached to the same carbon atom, can be combined together with the carbon atom to which they are attached to form a saturated or unsaturated monocyclic (C3-C8) cycloalkyl optionally substituted with Rd, Re, and Rf as was previously defined; or a saturated or unsaturated monocyclic heterocyclyl ring containing three to six ring atoms wherein one or two ring atoms ring are selected from -C (0) -, -C (= N0H), -0-, -S-, -SO-, -S02-, or -NH- and wherein the heterocyclyl ring is substituted with Rm, Rn and R ° wherein Rm and Rn are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or alkoxycarbonyl and R ° is selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl , alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl , heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy and wherein the aryl, heteroaryl, or heterocyclyl ring in R ° is optionally substituted with Rd, Re, and Rf as defined above; provided that when Y and Z are -CH2- and R4 and R7 do not form a cycloalkyl or heterocyclyl ring, then at least one of R4, R5, R6, R7, and R8 is not hydrogen; or R and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl or heterocycloamino spiro each of which is substituted with Rg, Rh, and R1 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy , acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring on Rg, Rh, and R1 is optionally substituted with X, Rk, or R1 independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano provided that when R2 and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl, then at least one of Rg, Rh, and R1 is not hydrogen; or an N-oxide; and / or a pharmaceutically acceptable salt thereof provided that: (i) when R is hydrogen, R1 is 3,4-dichlorophenyl then R2 and R3 together with the nitrogen atom to which they are attached do not form 2- and 3-phenylpyrrolidin- 1-yl, 2- and 3-benzylpyrrolidin-1-yl, 2-phenylpiperidin-1-yl, 4-phenylpiperidin-1-yl, 4-phenylpiperazin-1-yl, 2-, 3- and 4-hydroxymethylpiperidin-1 -yl, 2-, 3-, and 4-benzylpiperidin-1-yl, 2-, 3- and 4-methylpiperidin-1-yl, 3-phenylpiperidin-1-yl, azabicyclo [3.2.2] non-3- ilo, azabicyclo [3.2.1] oct-6-yl, 1,3, 3-trimethylazabicyclo [3.2.1] oct-6-yl, 2-phenylazepin-1-yl, 4- (pyridin-2-yl) piperazin-1-yl, 3-, or 4- (cyanomethyl) piperazin-1-yl, 4-hydroxyazepan-1-yl, or 4-hydroxy-4-methylazepan-1-yl (ii) when R is hydrogen, R 1 is 4-methylphenyl then R 2 and R 3 together with the nitrogen atom at which they bind do not form 4- (2-hydroxyethyl) piperazin-1-yl, 2- (4-methoxycarbonylphenyl) pyrrolidin-1-yl, 2- (-methoxycarbonylphenyl) piperidin-1-yl, 2- (4-hydroxymethylphenyl) piperidin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (4-phenylpiperidin-1-yl) piperidin-1-yl, 2- (4-piperidin-1-ylmethylphenyl) ) piperidin-1-yl, or 5-oxa-2-aza-bicyclo [2.2.1] heptan-2-yl (iii) when R is hydrogen, R1 is 2,3-dichlorophenyl, then R2 and R3 together with the Nitrogen atom to which they bind does not form 4-benzylpiperazin-1-yl, 2-phenylpyrrolidin-1-yl, 2- (4-piperidin-1-ylmethylphenyl) piperidin-1-yl, 2- (3-piperidin-1) -ylmethylphenyl) piperidin-1-yl, 2- (4-piperidin-l-ylmethylphenyl) pyrrole idin-1-yl, 2- (3-piperidin-l-ylmethylphenyl) pyrrolidin-1-yl, or 2-phenylpiperidin-1-yl (iv) when R is hydrogen, R 1 is 4-methylphenyl, and R 2 is hydrogen then R3 is not l-benzylpiperidin-4-yl, 2-, 3-, and 4-me ~ il-cyclohexyl, 2-, 3-, and 4-hydroxycyclohexyl, 2-benzyloxycyclohexyl, 2-ethyloxycarbonyl-cyclohexyl, tricyclo [3.3.1.1-3 , 7] dec-1-ilo, 3- hi droxitricyclo [3.3.1.1-3, 7] dec-1-yl, admant-1-yl, or 2- or 3-hydroxymethylcyclohexyl, and (v) when R is hydrogen, R1 is 2,5-dimethylphenyl, and R2 is hydrogen then R3 is not 2-methylcyclohexyl. In a second aspect, this invention is directed to a compound of Formula (Ia): (la) wherein: R is hydrogen or alkyl; R1 is aryl or heteroaryl optionally substituted with Ra, Rb, and Rc independently selected from hydrogen, alkyl, or halo; R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R3 is bridged heterocyclyl, bridged cycloalkyl wherein bridged heterocyclyl, or bridged cycloalkyl is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl, or alkoxyalkyl; or R3 is a gppo of formula (a): (to) where: n is 0, 1, 2, or 3; Z is -C (O) -, -C (= NOH), -CONH-, -O-, -C (0) 0-, -S-, -SO-, -S02-, -NH-, or - CH2-; and R4, R5, and R6 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl amino, amino monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, tertiarycyclylalkyl or heterocyclylalkyloxy where the aryl, heteroaryl, or heterocyclyl ring in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; provided that when Z is -CH2- then at least one of R4, R5, and R6 is not hydrogen; or R2 and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl substituted with R9, Rh, and R1 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl , hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein aryl, heteroaryl, or heterocyclyl ring in R9, Rh, and R1 is optionally substituted with R], Rk, and R1 independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano provided that at least one of R9, Rh, and R1 is not hydrogen; or a pharmaceutically acceptable salt thereof provided that (i) when R is hydrogen, R1 is 3,4-dichlorophenyl then R2 and R3 together with the nitrogen atom to which they are attached do not form 2- and 3-phenylpyrrolidin-1-yl , 2- and 3-benzylpyrrolidin-1-yl, 2-phenylpiperidin-1-yl, 4-phenylpiperidin-1-yl, 4-phenylpiperazin-1-yl, 2-, 3- and 4-hydroxymethylpiperidin-1-yl, 2-, 3-, and 4-benzylpiperidin-l- ilo, 2-, 3- and 4-methylpiperidin-1-yl, 3-phenylpiperidin-1-yl, azabicyclo [3.2.2] non-3-yl, azabicyclo [3.2.1] oct-6-yl, 1, 3, 3-trimethylazabicyclo [3.2.1] oct-6-yl, 2-phenylazepin-1-yl, 4- (pyridin-2-yl) piperazin-1-yl, 3-, or 4- (cyanomethyl) piperazin- 1-yl, 4-hydroxyazepan-1-yl, or 4-hydroxy-4-methylazepan-1-yl (ii) when R is hydrogen, R 1 is 4-methylphenyl then R 2 and R 3 with the nitrogen atom to which bind do not form 4- (2-hydroxyethyl) piperazin-1-yl, 2- (4-methoxycarbonylphenyl) pyrrolidin-1-yl, 2- (4-methoxycarbonylphenyl) piperidin-1-yl, 2- (4-hydroxymethylphenyl) piperidin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (4-phenylpiperidin-1-yl) piperidin-1-yl, 2- (4-piperidin-1-ylmethylphenyl) ) piperidin-1-yl, or 5-oxa-2-aza-bicyclo [2.2.1] heptan-2-yl (iii) when R is hydrogen, R1 is 2,3-dichlorophenyl, then R2 and R3 together with the Nitrogen atom to which they are attached does not form 4-benzylpiperazin-1-yl, 2-phenylpyrrolidin-1-yl, 2- (4-pipe Ridin-1-ylmethylphenyl) piperidin-1-yl, 2- (3-piperidin-1-ylmethylphenyl) piperidin-1-yl, 2- (4-piperidin-1-yl-ethylphenyl) pyrrolidin-1-yl, 2- ( 3-piperidin-l-ylmethylphenyl) pyrrolidin-1-yl, or 2-phenylpiperidin-1-yl (iv) when R is hydrogen, R1 is 4-methylphenyl, and R2 is hydrogen then R3 is not l-benzylpiperidin-4- ilo, 2-, 3-, and 4-methylcyclohexyl, 2-, 3-, and 4-hydroxycyclohexyl, 2- benzyloxycyclohexyl, 2-ethyloxycarbonylcyclohexyl, tricyclo [3.3.1.1 ~ 3.7] dec-1-yl, 3-hydroxytricyclo [3.3.1.1-3, 7] dec-1-yl, admant-1-yl, or 2- o 3-hydroxymethylcyclohexyl, and (v) when R is hydrogen, R1 is 2,5-dimethylphenyl, and R2 is hydrogen then R3 is not 2-methylcyclohexyl. In a third aspect, this invention is directed to a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In a fourth aspect, this invention is directed to a method for treating a disease in a patient mediated by the receptor Bl which comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a salt thereof. same pharmaceutically acceptable and a pharmaceutically acceptable excipient. Specifically, the compounds of the present invention could be useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immunodeficiency syndrome ("AIDS"), toxins and Chemotherapy, general headache, migraine, histaminic headache, non-vascular and vascular mixed syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, bladder disorders unstable or inflammatory, psoriasis, skin diseases with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and hyperalgesia and associated allodynia, neuropathic pain and hyperalgesia and associated allodynia , pain due to diabetic neuropathy, sympathetically maintained pain, differentiation syndromes, asthma, allergic or vasomotor rhinitis, damage or dysfunction of epithelial tissue, herpes simplex, post-herpetic neuralgia, visceral motility disturbances in respiratory, genitourinary, gastrointestinal or vascular regions, I have rides, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders. In a fifth aspect, this invention is directed to the use of one or more compounds of the present invention in the 1! manufacture of a medicament for the treatment of a Bl-mediated disorder such as acute pain, dental pain, back pain, low back pain, pain from trauma, surgical pain, pain resulting from amputation or abscesses, causalgia, fibromyalgia, demyelinating diseases , trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immunodeficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, histaminic headache, mixed vascular and non-vascular syndromes, pain tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, unstable or inflammatory bladder disorders, psoriasis, skin diseases with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, infl conditions chronic amatoria, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and hyperalgesia and associated allodynia, pain due to diabetic neuropathy, sympathetically maintained pain, differentiation syndromes, asthma, allergic or vasomotor rhinitis, damage or dysfunction of epithelial tissue, herpes simplex, neuralgia post-herpetic, disturbances of visceral motility in respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders.

DETAILED DESCRIPTION OF THE INVENTION Definitions: Unless stated otherwise, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning: "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms) ), and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, for example, methylene, ethylene, propylene, 1- methylpropylene, 2-methylpropylene, butylene, pentylene, and the like. "Alkoxy" means a radical -OR where R is alkyl as defined above, for example, methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, for example, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like. "Alkoxyalkyloxy" means a radical -OR where R is alkoxyalkyl as defined above, for example, methoxyethoxy, 2-ethoxyethoxy, and the like. "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR 'wherein R is hydrogen, alkyl, or acyl and R 'is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl for example, aminomethyl, aminoethyl, 1,3-diaminopropyl, dimethylaminomethyl, diethylaminoethyl, acetylaminopropyl, and the like. "Aminoalkoxy" means a radical -OR where R is aminoalkyl as defined above, for example, 2-aminoethoxy, 2-dimethylaminopropoxy, and the like. "Acyl" means a radical -C (0) R where R is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl as defined above, for example, acetyl, trifluoroacetyl, benzoyl, and the like. "Alkoxycarbonyl" means a radical -C (0) 0R where R is alkyl as defined above, for example, methoxycarbonyl, ethoxycarbonyl, and the like. "Alkoxycarbonylalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxycarbonyl group, preferably one or two alkoxycarbonyl groups, as defined above, for example, 2-methoxycarbonylethyl, 1-, 2-, or 3-ethoxycarbonylpropyl, 2-ethoxycarbonylethyl, and the like. "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms eg phenyl or naphthyl. "Aralkyl" means a radical - (alkylene) -R where R is aryl as defined above.

"Aryloxy" means a radical -OR where R is aryl as defined above, for example, phenoxy, and the like. "Aralkyloxy" means a radical -O- (alkylene) -R where R is aryl as defined above for example, benzyloxy. "Bridged cycloalkyl" refers to cycloalkyl rings as defined below of seven to ten ring atoms where two non-adjacent ring members are joined by an alkylene chain of one or two carbon atoms for example, and ~ - ~, "&" The "bridged heterocyclyl" refers to heterocyclyl rings as defined later by seven to nine ring atoms wherein two non-adjacent ring members are joined by an alkylene chain of one or two carbon atoms for example, and similar. "Carboxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one carboxy group, preferably one or two alkoxy groups, as defined above, for example, 2-carboxyethyl, 1-, 2-, or 3-carboxypropyl, 2-carboxyethyl, and the like.

"Cycloalkyl" means a cyclic saturated or unsaturated monovalent hydrocarbon radical of three to ten carbon atoms and optionally fused to phenyl unless otherwise stated, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. "Cycloalkylalkyl" means a radical (alkylene) -R where R is cycloalkyl as defined above; for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like. "Cyanoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one cyano group, preferably one or two cyano groups, as defined above, for example, 2-cyanoethyl, 1-, 2-, or 3-cyanopropyl, and the like. "Disubstituted amino" means -NRR 'wherein R and R' sen independently selected from alkyl, acyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl as defined herein. When R and R 'are alkyl, the group is also referred to herein as dialkylamino. "Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

"Haloalkyl" means alkyl substituted with one or more halogen atoms, preferably one to five halogen atoms, preferably fluoro or chloro, including those substituted with different halogens, for example, -CH2C1, -CF3, -CHF2, -CF2CF3, - CF (CH3) 3, and the like. "Haloalkoxy" means a radical -OR where R is haloalkyl as defined above for example, -OCF3, -OCHF2, and the like. "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if both hydroxy groups are present both are not in the same atom of carbon. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3 -dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- ( hydroxymethyl) -2-hydroxyethyl. "Hydroxyalkoxy or" hydroxyalkyloxy "means a radical -OR where R is hydroxyalkyl as defined above.

"Heterocyclyl" means a saturated or unsaturated monovalent cyclic group of 3 to 10 ring atoms in which one or two ring atoms are heteroatoms selected from -CO-, N, O, or S (0) n, where n is an integer from 0 to 2, preferably N, O, or S (0) n, the remaining ring atoms are C and where one or two ring carbon atoms can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, tetrahydroquinolinyl and thiomorpholino, and the like. When the heterocyclyl ring is monocyclic it is also referred to herein as a monocyclic heterocyclyl ring. "Heterocyclylalkyl" means a radical (alkylene) -R where R is heterocycloalkyl ring as defined above for example, piperazinylmethyl, morpholinylethyl, and the like. "Heterocyclyloxy" means a radical -OR where R is heterocyclyl as defined above, for example, piperazinyloxy, pyrrolidinyloxy, and the like. "Heterocyclylalkyloxy" means a radical -0- (alkylene) -R where R is heterocyclyl as defined above for example, piperidinylmethyloxy, piperazinylmethyloxy, and the like. "Heteroaryl" means an aromatic radical monocyclic or monovalent bicyclic of 5 to 10 aryl atoms wherein one or more, preferably one, two, or three, ring atoms are heteroatoms selected from N, O, or S, the remaining ring atoms are carbon. More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzopyranyl. , and thiazolyl, and the like. "Heteroaralkyl" means a radical (alkylene) -R where R is heteroaryl as defined above. "Heteroaryloxy" means a radical -OR where R is heteroaryl as defined above, for example, pyridinyloxy, furanyloxy, thienyloxy, and the like. "Heteroaralkyloxy" means a radical -0- (alkylene) -R where R is heteroaralkyl as defined above for example, pyridinmethyloxy, furanmethyloxy, and the like. "Monosubstituted amino" means -NHR 'wherein R' is selected from hydrogen, alkyl, acyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or haloalkyl as defined herein. When R 'is alkyl, the group is also referred to in the present as alkylamino. The present invention also includes prodrugs of the compounds of the formula (I). The term "prodrug" is intended to represent ccvalently linked carriers, which are capable of releasing the active ingredient of formula (I) when the prodrug is administered to a mammalian subject. The release of the active ingredient occurs in vivo. The prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify the appropriate functional groups in a given compound. These modified functional groups, however, regenerate the original functional groups by routine manipulation or in vivo. Prodrugs of compounds of formula (I) include compounds wherein a hydroxy, amino, carboxylic, or the like group is modified. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy or amino functional groups in compounds of Formula (I) ), amides (eg, trifluoroacetylamino, acetylamino, and the like), and the like. Prodrugs of compounds of Formula (I) are also within the scope of this invention. A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the pharmacological activity of the compound of origin. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, acid 4-To-sulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid , glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference. The compounds of the present invention may have asymmetric centers. The compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific isomeric or stereochemical form is specifically indicated. Additionally, as used herein the terms alkyl include all possible isomeric forms of the alkyl group although only a few examples are described. Further, when cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all positional isomers although only a few examples are disclosed. In addition, all the polymorphic and hydrate forms of a compound of the formula (I) are within the scope of this invention. "Optional" or "optionally" means that the event or circumstance subsequently described may but need not occur, and that the description includes cases where the event or circumstance occurs and cases in which it does not. For example, "heterocycloalkyl group optionally mono- or disubstituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is mcno- or disubstituted with an alkyl group and situations where the group Heterocycloalkyl is not substituted with the alkyl group. "Heterocycloamino spiro" means a saturated or unsaturated bicyclic group of 7 to 12 ring atoms where the rings are connected through only one atom and in which one, two, or three ring atoms are heteroatoms selected from -CO- , N, O, or S (0) n, where n is an integer from 0 to 2, the remaining ring atoms are C provided that the bicyclic group contains at least one nitrogen atom of the ring. A "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and non-biologically or otherwise. undesirably, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes both one and more than one excipient. The expression "wherein the aryl, heteroaryl, or heterocyclyl ring in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf "and like terms in the claims means that all the mentioned rings, if they are directly linked or are a part of another group, for example, aralkyl, heteroaralkyl, acyl, mono- or disubstituted amino, etc. are optionally Additionally, the rings may be mono-, di-, or tri-substituted as indicated in the claims. "Treating" or "treating" a disease includes: (1) preventing the disease, ie causing the symptoms of the disease are not developed in a mammal that may be exposed to or predisposed to the disease but still does not experience or exhibit symptoms of the disease; (2) inhibit the disease, that is, stop or reduce the development of the disease or its clinical symptoms; or (3) relieving the disease, that is, causing the regression of the disease or its clinical symptoms.

The representative compounds of the formula (I) wherein R2 is H and other groups are as listed in Table I below are: Table 1 Note: In Table 1, in the compounds with * following the compound number, the stereochemistry at position 4 (chiral center) was arbitrarily assigned based on chiral HPLC separation of the tetraspecific or diastereomeric syntheses. The stereochemistry was not unequivocally confirmed. The representative compounds of the formula (I) wherein R1, R2 and R3 are as listed in table II below are: Table II Representative compounds of the formula where R is as listed in Table III and R and R together with the nitrogen atom to which they are attached they form a group as listed in Table III below are: Table III The compounds in Tables I, II, and III are named as follows but may not necessarily follow the preceding compound numbering: (3R) -3- (2- (3-azabicyclo [3.2.2] non-3-yl) -2-oxoethyl) -4- ((3,4-dichlorophenyl) -sulfonyl) -3,4-dihydro-2 (1H) -pyrazinone; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-te rahydro-2-pyrazinyl) -N- ((1R, 2R, 4R) -1 , 7,7-trimethylbicyclo [2.2.1] hept-2-yl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((1R, 2S, 4R) -1 , 7, 7-trimethylbicyclo [2.2.1] hept-2-yl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,4-tetrahydro-2-pyrazinyl) -N- (1-phenyl-4-piperidinyl) acetamide; N- ((1S, 2S) -2- (1,1-dimethylethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4 -tetrahydro-2-pyrazinyl) acetamide; N - ((1R, 2R) -2- (1, 1-dimethylethyl) -cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 2R) -2- (1,1-di-methylethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-DXO-I, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; and N - ((1R, 2S) -2- (1,1-dimethylethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,4-tetrahydro-2-pyrazinyl) -N- ((3S) -1- (phenylmethyl) - 3-pyrrolidinyl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -1- (phenylmethyl) -3-pyrrolidinyl) acetamide; N- ((3R) -l-azabicyclo [2.2.2] oct-3-yl) -2- ((2R) -1- ((4-me-ethylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (1- (2-pyrimidinyl) -4- piperidinyl) acetamide; (3R) -3 - ((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; and (3S) -3- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1- 1.1- piperidinecarboxylate dimethylethyl; 2- ((2R) -1- ((4-Methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-Methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -1- (phenylmethyl) - 3-piperidinyl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3S) -1- (phenylmethyl) -3-piperidinyl) acetamide; N- ((3R) -1- (1-methylethyl) -3-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3, 4- tetrahydro-2-pyrazinyl) acetamide; and N- ((3S) -1- (1-methylethyl) -3-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4 -tetrahydro-2-pyrazinyl) acetamide; 4 - ((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1.1 -dimethylethyl; 2- ((2R) -1- ((4-Methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinylmethyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- ((3S) -1- (4-pyridinylmethyl) ) -3-piperidinyl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -1- (4- pyridinylmethyl) -3-piperidinyl) acetamide; (4R) -3,3-dimethyl-4- ((((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; and (4S) -3,3-dimethyl-4- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl ) 1,1-dimethylethyl amino) -1-piperidinecarboxylate; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,4-tetrahydro-2-pyrazinyl) -N- (1-methyl-4-piperidinyl) acetamide; N- ((4S) -3,3-dimethyl-4-piperidinyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro- 2-pyrazinyl) acetamide; and N- ((4R) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro -2-pyrazinyl) acetamide; N- (1-acetyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro- 2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (2-methylpropyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2-methylpropyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-dimethyl-1- (phenylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (phenylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1,3,3-trimethyl-4-) piperidinyl) acetamide; N- ((4R) -3,3-dimethyl-1- (1-methylethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4S) -3,3-dimethyl-1- (1-methylethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo -1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (4-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N - ((4S) -3,3-dimethyl-1- (4-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo -l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (2-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-1- (2-pyridinimethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4- tetrahydro-2-pyrazinyl) -N- (1- (phenylcarbonyl) -4-piperidinyl) acetamide; N- ((4S) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3 , 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4R) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1,2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- (trans -4- (methyloxy) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pi razinyl) acetamide; N- (cis-4-aminociclohexil) -2- ((2R) -1- ((4-met ilphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi.razinyl) acetamide; N- (trans -4-aminocyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi-razinyl) acetamide; N- (trans-4-aminocyclohexyl) -2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((3-endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo -l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((3-exo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3- oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- (cis-4- ((1-methylethyl) amino) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4,4-tetrahydro-2-pyrazinyl) acetamide; N- (trans -4- ((1-methylethyl) amino) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3,4-tetrahydro -2-pyrazinyl) acetamide; N- ((IR) -2,2-dimethyl-4-oxocyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pyrazinyl) acetamide; and N- ((1S) -2, 2-dimethyl-4-oxocyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro -2-pyrazinyl) acetamide; N- (2,3-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (4-methyl-l-piperazinyl) acetamide; Nl, l'-bi (cyclohexyl) -2-U-2- ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi azinyl) acetamide; N- (4- (3-fluoro-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1R, 4S) -4- (4-fluoro-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1R, 4R) -4- (4-fluoro-1-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4- methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4- (4-fluoro-1-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((1S, 4R) -4- (4-fluoro-l-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4R) -4- (cyclopropylamino) -2,2-diiaethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, S) -4- (cyclopropylamino) -2, 2-dimethylcyclohexyl) -2 - ((2R) -l - ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -4- (cyclopropylamino) -2,2-dithiethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((IR, 4S) -4- (cyclopropylamino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, S) -4- ((2,2-dimethylpropyl) amino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -1,2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1R, 4R) -4- ((2,2-dimethylpropyl) amino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -1, 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4- ((2,2-dimethylpropyl) amino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((1S, 4R) -4- ((2,2-dimethylpropyl) amino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-l, 2,3,4-tetrahydro-2-pi azinyl) acetamide; N- ((4S) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4R) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2,2,2-trifluoroethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) - 3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N - ((4S) -3,3-dimethyl-1- (2,2, 2-trifluoroethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) -3, 3- dimethyl-4-piperidinyl) acetamide; and 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((4R) -3,3 -dimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) - 3, 3-dimethyl-4-piperidinyl) acetamide; and 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((4R) -3,3-dimethyl-4-piperidinyl) acetamide; 2 - ((2R) -l - ((3,4-d? Chlorophen? L) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? -N- ((4R) -3,3-d? Met? L-4-piperidinyl) acetamide; and 2- ((2R) -1- ((3,4-di-lorophenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-p? i?) -N - ((4S) -3, 3-d? Met? L-4-p? Per? D? N? L) acetamide; N- ((IR, 4S) -2,2-d? Met? L-4- (1-pyrrolidinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3 -oxo-l, 2,3,4-tetrahydro-2-p? raz? n? l) acetam? da; N- ((IR, 4R) -2, 2-d? Met? L-4- (1-p? Rrol? D? N? L) cyclohexyl) -2- ((2R) -1- ((4- meacyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-picazinyl) acetamide; N - ((1S, 4S) -2, 2-d? Met? L-4- (1-pyrrolidinyl) cyclohexyl) -2- ((2R) -1- ((4-met? L-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-p? Raz? N) l) acetamide; and N- ((1S, 4R) -2,2-d? met? l-4- (1-p? rrol? d? n? l) cyclohexyl) -2 - ((2R) -l - ((4 methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pi-azinyl) acetamide; N- ((IR, 4S) -2,2-d? Met? L-4- (1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-met? L-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-p? Raz? N) l) acetamide; N- ((IR, 4R) -2,2-d? Met? L-4- (1-p? Per? D? N? L) cyclohexyl) -2- ((2R) -1- ((4- methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazimyl) acetamide; N- ((1S, 4S) -2, 2-d? Met? L-4- (1-pipepdinyl) cyclohexyl) -2- ((2R) -1- ((4-met? L-phenyl) sulfonyl) -3-oxo-l, 2, 3, -tetrah? Dro-2-p? Raz? N) l) acetamide; and N - ((1S, 4R) -2, 2-dimethy1-4- (1-p? per? d? n? l) cyclohexyl) -2- ((2R) -1- ((4-methyl- phenyl) sulfonyl) -3-oxo-l, 2,3,4,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4R) -2,2-Dimethyl-4- (4-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N - ((1S, 4S) -2,2-dimethyl-4- (4-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -l, 2, 3, 4-tetrahydro-2-pi razinyl) acetamide; N- ((IR, 4R) -2, 2-dimethyl-1-4- (4-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -1, 2, 3, -tetrahydro-2-pyrazinyl) acetamide; and N - ((1R, 4S) -2, 2-dimethy1-4- (-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -l, 2,3, -tetrahydro-2-pyrazinyl) acetamide; N - ((1R, 4S) -4- (3, 3-dimethyl-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N - ((1R, 4R) -4- (3,3-dimethyl-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4- (3, 3-dimethyl-l-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((1S, 4R) -4- (3, 3-dimethyl-l-piperidinyl) -2, 2-dimethylcyclohexyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3 -oxo-1, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, R) -2,2-dimethyl-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -l- ((4-methyl-phenyl) sulfonyl) -3-oxo-l , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -2, 2-dimethy1-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1 , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N - ((1R, 4R) -2,2-dimethyl-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1 , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((IR, 4S) -2, 2-dimethyl-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4R) -4-hydroxy-2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4 -tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4-hydroxy-2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1, 2, 3, 4 -tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -4-hydroxy-2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4 -tetrahydro-2-pyrazinyl) acetamide; and N- ((1R, 4S) -4-hydroxy-2,2-dimethylcyclohexyl) -2 - ((2R) -l - ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pi azinyl) acetamide; N- ((4S) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro- 2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-4-piperidinyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro- 2- pyrazinyl) acetamide; N- (1- (2-phenethyl) -4-piperidinyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2- pyrazinyl) acetamide; N- ((4S) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyltetrahydro-2 H -pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; N - ((3R) -3-piperidinyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((3S) -3-piperidinyl) -2- ((2R) -1- ((4-mephenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi-razinyl acetamide; 4 -methyl-4- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; N- (4-methyl-4-piperidinyl) -2- ((2R) -1- ((4-mephenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi razinyl) acetamide; N- (3- (hydroxymethyl) bicyclo [2.2.1] hept-2-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4 -tetrahydro-2-pyrazinyl) acetamide; N- ((1RS, 2RS) -2- (1-hydroxy-1-methylethyl) cyclohexyl) - 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; 4 - ((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1.1 -dimethylethyl; N- ((4RS) -2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4RS) -3,3-dimethyl-1,4'-bipiperidin-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1RS, 2RS) -2- (hydroxymethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2 -pyrazinyl) acetamide; (3RS) -3- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-pyoeridinecarboxylate of 1,1-dimethylethyl; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,4-tetrahydro-2-pyrazinyl) -N- (tetrahydro-2H-pyran-4-yl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2-methylpropyl) -4-pi eridinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1 , 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; trifluoroacetic acid salt of N- ((4R / S) -4-azspanyl) -2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -4-azepanyl) -2- ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide and N- ((4S) -4-azepanyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -3-pyrrolidinyl) acetamide; N- ((1R / S, 4R / S) -4-hydroxy-2,2,4-trimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1,2,2,6,6- pentamethyl-4-piperidinyl) acetamide; N- ((4R / S) -l-methyl-4-azepanyl) -2 - ((2R) -l - ((4-mephenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro -2-pi razinyl) acetamide; N- (trans -4- (dimethylamino) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pi razinyl) acetamide; N- (cis / trans-5-aminociclooctil) -2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pi azinyl acetamide; N- ((4R) -3,3-dimethyl-1- (4-pyridinylmethyl) -4- pyoeridinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (4-pyridinylmethyl) -4-pyoeridinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (3-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (3-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; 3, 3, 3-trifluoropropanoic acid salt of 2 - ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) - N- (-methyl-l-piperazinyl) acetamide; N- (4,4-difluorocyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi razinyl) acetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro-2-pyrazinyl) -N- (4-methyl- l-piperazinyl) acetamide; (4S) -3,3-Dimethyl-4- ((((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi razinyl) acetyl ) 1,1-dimethylethyl amino) -1-piperidinecarboxylate; (4R) -3,3-dimethyl-4- ((((2R) -1- ((4-methylphenyl) - sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester; N- (l-cyclopropyl-4-piperidinyl) -2- ((2R) -1- ((4-mephenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R / S) -l-cyclopropyl-4-azepanyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro -2-pi razinyl) acetamide; trifluoroacetic acid salt of 2- ((2R) -1- ((-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ( (4R / S) -1-cyclopropy1-4 -azepanyl) acetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) - 3, 3-dimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- ((4S) -1, 3, 3 trimethyl-4-piperidinyl) acetamide; N- ((4S) -l-ethyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-dimethyl-l-propyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -1- (2,2-dimethylpropyl) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -l-cyclobutyl-3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methyphenyl) -sulfonyl) -3-oxo-1,2, 3, 4-tetrahydro-2-pi razinyl) acetamide; N- ((4S) -l-cyclopentyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; (4S) -4 - ((((2R) -l - ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -3 , 1,1-dimethylethyl 3-dimethyl-1-piperidinecarboxylate; 2- ((2R) -1- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) - 1,3,3-trimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((2,3-dichloro phenyl) sulfonyl) -3-oxo-1,2,3,4-heptohydro-2-pyrazinyl) -N- ((4S) -3, 3-dimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-ethohydro-2-pyrazinyl) -N- ((4S) -1, 3 , 3-trimethyl-4-pipieridinyl) acetamide; N- ((4S) -l- (2,2-dimethylpropanoyl) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pi razinyl) acetamide; N-5-azocanyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; (4S) -4 - ((((2R) -l- ((4-chloro-2, 5- dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -3,3-dimethyl-1-piperidinecarboxylate 1,1-dimethylethyl; N- ((1RS, 2RS) -2-hydroxy-2-methylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinylmethyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N-l-piperidinylacetamide; N- ((8RS) -7,7-dimeti1-1,4-dioxaespiro [4.5] dec-8-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo -l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3S) -6-oxo-3-- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -6-oxo-3-- piperidinyl) acetamide; (4RS) -4- ((((2R) 1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2- pyrazinyl) acetyl) amino) -1-azepanecarboxylate 1,1-dithiethylethyl; N- ((4S) -3,3-dimethyl-l, '-bipiperidin-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-1,4'-bipiperidin-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((2,3-dichloro-phenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -2 - ((2R) -l - ((2,3-dichloro-phenyl) sulfonyl) -3-oxo-1, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (2-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2- (methyloxy) ethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -1,2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N-oxide ((4S) and 4 (R) -l-cyclopropyl-3, 3-di? ethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N-methyl-N- (l-methyl-4-) piperidinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-methyl-N- (1-methyl-1) 4-piperidinyl) acetamide; 2- ((2R) -1- ((3,4-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-methyl-N- (l-methyl- 4-piperidinyl) acetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-methyl-N- ( l-methyl-4-piperidinyl) acetamide; N- (cis-4-aminocyclohexyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N- (trans-4-aminocyclohexyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl acetamide; N- ((4R) -3,3-dimethyl-4-piperidinyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4S) -3,3-dimethyl-4-piperidinyl) -N-me-il-2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2 , 3,4-te rahydro-2-pyrazinyl) acetamide; N- ((4RS) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2, 3,4- tetrahydro-2-pyrazinyl) acetamide; 4- (ethyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate 1, 1-dimethylethyl; N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- 4 -piperidinylacetamide; N-ethyl-2- ((2R) -1- ((4-methyphenylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; N-propyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N-methyl-N- (l-methyl-4-piperidinyl) acetamide; 4- (Methyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate 1, 1-dimethylethyl; 4- ((((2R) -l- ((4-methyphenyl) sulfonyl) -3-oxo-l, 2,4- tetrahydro-2-pyrazinyl) acetyl) (propyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; N- (2- (methyloxy) ethyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (l-methyl-4-piperidinyl) acetamide; (4RS) -4- (Methyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3- or o-1,2,3,4-tetrahydro-2-pi razinyl) acetyl) amino) - 1, 1-dimethylethyl 1-azepancarboxylate; (4R / S) -4- (ethyl (((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) - 1, 1-dimethylethyl 1-azepancarboxylate; N- ((4R / S) -4-azepanyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro- 2-pyrazinyl) acetamide; N- ((4R / S) -4-azepanyl) -N-ethyl-2- ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro- 2-pyrazinyl) acetamide; 4- (cyclopropyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate 1, 1-dimethylethyl; N-cyclopropyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) -N- (1-methyl-4 - piperidinyl) acetamide; (3R) -3- (2- (2- (4- (methyloxy) phenyl) -4-thiomorpholinyl) -2-oxoethyl) -4- ((4-methyl-phenyl) sulfonyl) -3,4-dihydro- 2 (1 H) -pyrazinone; (3R) -3- (2- (2- (4-Chlorophenyl) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) -sulfonyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-Dichlorophenyl) sulfonyl) -3- (2 - ((3S) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3,4-dihydro-2 (1 HOUR) - pi razmona; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pi razinone; (3R) -3- (2- ((3S) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 (1H ) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -3- (2- (1,4'-bipiperidin-1-yl) -2-oxoethyl) -4- ((4-chloro-2,5-dimethylphenyl) -sulfonyl) -3,4- dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (4- (dimethylamino) -1-piperidinyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- ((3S) -3- (amino) -4 (R) -4-pheny1-1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) - 3, 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- ((3S) -3- (1-pyrrolidinyl) -1-piperidinyl) ethyl) - 3, 4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- ((3'S) -l, 3'-bipyrrolidin-1-yl) -2-oxoethyl) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3 , 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3S) -3- (dimethylamino) -1-piperidinyl) -2-oxoethyl) -3,4 -dihydro-2 (LH) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3S) -3- (dimethylamino) -1-azepanyl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (4- (hydroxymethyl) -1-piperidinyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R / S) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R) -3- (hydroxymethyl) -1-piperidinyl) -2-oxoethyl) - 3, 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((2R / S) -2- (hydroxymethyl) -1-piperidinyl) -2-oxoethyl) - 3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- (4- (1-pyrrolidinylmethyl) -1-piperidinyl) ethyl) -3, 4- dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- ((3R / S) -3- (1-pyrrolidinylmethyl) -1-piperidinyl) ethyl ) -3, -dihydro-2 (1H) -pyrazinone; (3R) -3- (2- ((3S) -3-amino-l-pyrrolidinyl) -2-oxoethyl) -4- ((4-chloro-2,5-dimethyl-phenyl) sulfonyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R / S) -4- (dimethylamino) -1-azepane? L) -2-oxoet? L) -3,4-d? H? Dro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-d? -methylphenyl) sulfonyl) -3- (2- ((3R / S) -3- ((dimethylamino) -methyl) -1-p ? pepd? n? l) -2-oxoet? l) -3,4-d? h? dro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-d? Meth? Phenyl) sulfonyl) -3- (2-oxo-2- ((3S) -3- (1-p? Rrol? D? n? l) -1-azepane? l) ethyl) -3,4-d? h? dro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-d? -methylphenyl) sulfonyl) -3- (2- ((3'R / S, 4 'R / S) -4' -methyl- 1,3 '-b? P? Rrol? Dm-1' -ll) -2-oxoet? L) -3,4-d? H? Dro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-d? -methylphenyl) sulfonyl) -3- (2-oxo-2- ((3R / S) -3- (1-p? Rrol? d? n? l-met? l) -1-pyrrolidone) ethyl) -3,4-d? -hydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-d? Meth? Lphenyl) sulfonyl) -3- (2- (2,7-d? Azasp? Ro [4.4] non-2-? L) -2-oxoet? L) -3,4-d? H? Dro-2 (1 H) -pyrazinone; (3R) -4- ((2, 3-d? Chlorophen? L) sulfonyl) -3- (2- ((4R / S) -4- (dimethylamino) -1-azepane? L) -2-oxoet? l) -3,4-d? h? dro-2 (1 H) -pyrazinone; trifluoroacetic acid salt of (3R) -4- ((4-chloro-2,5-d? met? lfen? l) sulfonyl) -3- (2 - ((4R / S) -4- (cyclopropyl (methyl) ) amino) -1-azepane? l) -2-oxoet? l) -3,4-d? h? dro-2 (1 H) -pyrazinone; (3R) -4- ((4-chloro-2,5-d? Met? Lphenyl) sulfoml) -3- (2- ((R / S) -4-hydroxy-3, 3-dimethyl-l-piperidinyl) -2-oxoethyl) -3,4-dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R / S) -3,3-dimethyl-4- (1-pyrrolidinyl) -1-piperidinyl ) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; trifluoroacetic acid salt of (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-piperidinyl) -2-oxoethyl ) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (7-methyl-2-, 7-diazaspiro- [.4] non-2-yl) -2- oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R) -4- (dimethylamino) -1-azocanyl) -2-oxoethyl) -3,4 -dihydro-2 (H) -pyrazinone; (3R) -4 - ((2,3-dichlorophenyl) sulfonyl) -3- (2 - ((4R / S) -4- (dimethylamino) -1-azocanyl) -2-oxoethyl) -3,4-dihydro -2 (1H) -pyrazinone; (3R) -3- (2- (2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -4- ((2,3-dichlorophenyl) sulfonyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-Dichlorophenyl) sulfonyl) -3- (2- (7- (l-methylethyl) -2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (7- (1-methylethyl) -2,7-diazaspiro [4.4] non-2-yl) - 2-oxoethyl) - 7í 3, -dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (7-cyclopropyl-2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- (7-methyl-2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pyrazinone; N- (l- (2 - ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) -4-piperidinyl) benzamide; (3R) -3- (2- (4- ((1-methylethyl) amino) -1-piperidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 ( 1H) -pyrazinone; (3R) -4- ((4-methylphenyl) sulfonyl) -3- (2-oxo-2- (2RS- (phenylmethyl) -1-pyrrolidinyl) ethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-methylphenyl) sulfonyl) -3- (2-oxo-2- (2RS-phenyl-1-pyrrolidinyl) ethyl) -3,4-dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-methylphenyl) sulfonyl) -3- (2-oxo-2- (4- (phenyloxy) -1-piperidinyl) ethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-methylphenyl) sulfonyl) -3- (2-oxo-2- (3-oxo-1-piperazinyl) ethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- (2-RS- ((methyloxy) methyl) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methyl-phenyl) sulfonyl) -3, -dihydro-2 (1H) -pyrazinone; (3R) -3- (2- (2-RS- ((4- (methyloxy) phenyl) methyl) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -3- (2- (4- (4-Methylphenyl) -1-piperidinyl) -2-oxoethyl) -4- ((4-methylphenyl) -sulfonyl) -3,4-dihydro-2 (1H) -pyrazinone; 8- (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) -2,8-diazaspiro [4.5] decan- canvas; (3R) -3- (2- (2-RS- (lH-indol-2-yl) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro -2 (1H) -pyrazinone; (3R) -3- (2- (4- ((2-chlorophenyl) oxy) -1-piperidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 ( 1H) -pyrazinone; (3R) -4- ((4-Methylphenyl) sulfonyl) -3- (2-oxo-2- (2-RS-phenyl-4-thiomorpholinyl) ethyl) -3,4-dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Methylphenyl) sulfonyl) -3- (2-oxo-2- (2-RS-phenyl-4-morpholinyl) ethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- (4- (lH-indol-3-yl) -l-piperidinyl-2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 ( 1H) -pi-raminone; (3R) -3- (2- (2- (2-RS-methylphenyl) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4 -dihydro-2 (1H) -pyrazinone; SW (3R) -4- ((2,3-Dichlorophenyl) sulfonyl) -3- (2- (4-methyl-1, -diazepan-1-yl) -2-oxoethyl) -3,4-dihydro-2 ( 1H) -pyrazinone; Y (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone.

MODALITIES While the broader definition of this invention is described in the Brief Description of the Invention, certain compounds of the formula (I) and (la) are preferred. For example, A. A preferred group of compounds is that wherein R2 is hydrogen. B. Another preferred group of compounds is that wherein R2 is alkyl, alkoxyalkyl, or cycloalkyl, preferably alkyl. More preferably, R 2 is 2-methoxyethyl, cyclopropyl, methyl, ethyl, propyl, or butyl, preferably methyl, ethyl, propyl or butyl. (i) Within the above groups A and B, and groups contained therein, a preferred group of compounds is that wherein R3 is bridged heterocyclyl optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl , or alkoxyalkyl.

II (i :.) Within the above groups A and B, and groups contained therein, another preferred group of compound is that wherein R3 is bridged cycloalkyl optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hyroxy , hydroxylalkyl, or alkoxyalkyl. (iii) Within the above groups A and B, and groups contained therein, yet another preferred group of compound is that wherein R 3 is cyclopentyl or cyclohexyl substituted with R 4, R 5 and R 6 independently selected from alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, substituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heerocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring on R4, R5, and Rd is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, Hyperoxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano, and R1 and R ° are hydrogen. Preferably, R3 is a group of formula wherein R 4 and R 5 are independently hydrogen or alkyl, preferably hydrogen or methyl, even more preferably methyl and R 6 is as defined immediately above. Preferably R6 is alkyl, halo, hydroxyl, alkoxy, hydroxyalkyl, aminoalkyl, monosubstituted or disubstituted amino, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, optionally substituted with Rd, Re, and Rf as defined in the Brief Description of the Invention. Preferably, R3 is 2- (2-hydroxymethyl) cyclohexyl, 2,2-dimethyl-4- (hydroxy) 4-methylcyclohexyl, 4-direthylaminocyclohexyl, 4,4-difluorocyclohexyl, 2-hydroxy-2-methylcyclohexyl, 2-methylcyclohexyl, 4-hydroxycyclohexyl, benzyloxycyclohexyl, 2- (ethoxycarbonyl) - cyclohexyl, 2- (hydroxymethyl) ciciohexyl, 2-tert-butylcyclohexyl, 2- (2-hydroxypropan-2-yl) cyclohexyl, 4-methoxycyclohexyl, 4-ammocyclohexyl, 4- (isopropylamino) cyclohexyl, 2,3-dimethylcyclohexyl, 2,2-dimethyl-4- (3-fluoropiperidin-1-yl) cyclohexyl, 2,2-dimethyl-4- (4-fluoropiperidin-1-yl) cyclohexyl, 2 , 2-dimethyl-4-cyclopropylaminocyclohexyl, 2,2-dimethyl-1-4- (2,2-dimethylpropylamino) cyclohexyl, 2,2-dinethyl-4-pyrrolidin-1-yl-cyclohexyl, 2,2-dimethyl-4-piperidin- 1-ylcyclohexyl, 2, 2-dimethyl-4- (4-methylpiperidin-l- 13 il) cyclohexyl, 2,2-dimethyl-4- (3, 3-dimethylpiperidin-1-yl) cyclohexyl, 2,2-dimethyl-4- (morpholin-4-yl) cyclohexyl, 2, 2-dimethyl-4- (hydroxy) cyclohexyl, or 2,2-dimethyl-4-piperidin-4-ylcyclohexyl. Preferably, R3 is 2-methylcyclohexyl, 4-hydroxycyclohexyl, benzyloxycyclohexyl, 2- (ethoxycarbonyl) -cyclohexyl, 2- (hydroxymethyl) cyclohexyl, 2-tert-butylcyclohexyl, 2- (2-hydroxypropan-2-yl) cyclohexyl, 4- methoxycyclohexyl, 4-aminocyclohexyl, 4- (isopropylamino) cyclohexyl, 2,3-dimethylcyclohexyl, 2,2-dimethyl-4- (3-fluoropiperidin-1-yl) cyclohexyl, 2,2-dimethyl-4- (4-fluoropiperidine) -1-yl) cyclohexyl, 2,2-dimethyl-4-cyclopropylamino-cyclohexyl, 2,2-dimethyl-4,2-, 2-dimethylpropylamino-cyclohexyl, 2,2-dimethyl-4-pyrrolidin-1-yl-cyclohexyl, 2,2-dimethyl 4-piperidin-1-cyclohexyl, 2,2-dimethyl-4- (4-methylpiperidin-1-yl) cyclohexyl, 2, 2-dimethyl-4- (3, 3-dimethylpiperidin-1-yl) cyclohexyl, 2 , 2-dimethyl-4- (morpholin-4-yl) ciciohexyl, 2,2-dimethyl-4- (hydroxy) ciciohexyl, or 2,2-dimethyl-4-piperidin-4-ylcciohexyl. (iv) Within the above groups A and B, and groups contained therein, yet another preferred group of compound is that wherein R is Where n is 0, 1, 2 or 3 and Z is -NH- and R4, R5, and R6 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy , heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring on R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl , haloalkoxy, or cyano; and R7 and R8 are hydrogen. Preferably, R3 is piperidinyl, pyrrolidinyl, azocanyl, or azepanyl attached to the amide nitrogen via a ring carbon atom and substituted with R4 and R5 which are independently hydrogen or alkyl, and R6 is as defined immediately above. Preferably R6 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, acyl, aminoalkyl, or alkoxyalkyl. Preferably, R3 is where R4 and R5 are independently hydrogen or alkyl, preferably hydrogen or methyl and R6 are as defined immediately above. Preferably R6 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, acyl, aminoalkyl, or alkoxyalkyl optionally substituted with Rd, Re, and Rf as defined in the Brief Description of the Invention. Preferably, R3 is 3,3-dimethylpiperidin-4-yl, 1-benzyl-3, 3-dimethylpiperidin-4-yl, 1-methyl-3, 3-dimethylpiperidin-4-yl, 1- (isobutyl) -3, 3-dimethylpiperidin-4-yl, 1- (pyridin-2-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (2-propyl) -3,3-dimethylpiperidin-4-yl, 1- (pyridine -4-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (benzyl) -3,3-dimethylpiperidin-4-yl, 1- (acetyl) -3,3-dimethylpiperidin-4-yl, 1- (2-phenethyl) -piperidin-4-yl, 1- (phenyl) -piperidin-4-yl, 1- (pyridin-4-ylmethyl) piperidin-4-yl, 1- (pyridin-4-yl) piperidin- 4-yl, 1- (benzyl) piperidin-3-yl, 1- (benzyl) pyrrolidin-3-yl, 1- (tere-bu i-oxy-carbonyl) piperidin-4-yl, 1- (pyridin-4-ylmethyl) ) piperidin-3-yl, 1- (methyl) piperidin-4-yl, piperidin-3-yl, 1- (tert-butyloxycarbonyl) -3,3-dimethyl-piperidin-4-yl, 1- (2-propyl) ) piperidin-3-yl, 1- (pyrimidin-2-yl) piperidin-4-yl, 1- (benzoyl) piperidin-4-yl, 3,4-dimethylpiperidin-4-yl, l-cyclopropyl-3, 3 -dimethylpiperidin-4-yl, 1- (pyridin-3-ylmethyl) -3,3-dimethyl piperidin-4-yl, 1- (2-methoxyethyl) -3,3-di-ethyl-piperidin-4-yl, 3,3-dimethyl-1- (2, 2, 2- tr_fluoroet? l) p? per? d? n-4-? lo, l- (tert-but? lox? -carbonyl) p? per? d? n? 3-? lo, p? per? d? n- 3-? Lo, p? Rrol? D? N-3-? Lo, l-pet? Lazepan-4-? Lo, lc? Cloprop? Lp? Per? D? N? 4-? Lo, 1-c? cloprop? lazepan-4-? lo, l-et? l-3, 3-d? met? lp? per? d? n-4-? lo, ln-prop? l-3, 3-d? met? lp? per? d? n-4-? lo, 1-2, 2-d? met? lprop? l-3, 3-d? met? lp? per? d? n-4-? lo, lc? clobut? l-3, 3-d? met? lp? per? d? n? 4-? lo, lc? clopent? l-3, 3-d? met? lp? pend? n-4-ílo, azocan -5-? Lo, or 1- (tert-butyloxy-carbonyl) azepane-4-? Lo. Preferably, R3 is 3, 3-d? Met? Lp? Per? D? N? 4-? Lo, 1-benc? L-3, 3-d? Met? Lp? Per? D? N-4-? what, l-met? l-3, 3-d? met? lp? per? d? n-4-idlo, 1- (isobutyl) -3, 3-d? met? lp? per? d? n- 4-? Lo, 1- (p? R? D? N-2-ylmetil) -3, 3-d? Met? Lp? Per? D? N-4-? Lo, 1- (2-prop? L ) -3, 3-d? Rnet? Lp? Per? D? N-4-? Lo, 1- (p? R? D? N-4-? Lmet? L) -3, 3-d? Met? lp? per? d? n-4-? lo, 1- (benzyl) -3, 3-d? met? lp? per? d? n-4-lio, 1- (acetyl) -3, 3-d ? met? lp? per? d? n? 4-? lo, 1- (2-phenethyl) -p? per? d? n-4-? lo, 1- (phenyl) -p? per? d? n -4-? Lo, 1- (p? R? D? N-4-ílmetil) p? Pepd? N-4-? Lo, 1- (p? Pd? N-4-? L) p? Per? d? n-4-? lo, 1- (benzyl) p? per? d? n? 3-? lo, 1- (benzyl) p? rrol? d? n? 3-? lo, 1- (tert- butyloxy-carbonyl) p? per? d? n? 4-? lo, l- (p? pd? n-4-ylmethyl) p? per? d? n? 3-? lo, 1- (methyl) p? per? dm-4-? lo, piperidin-3- rlo, 1- (tert-butyloxycarbonyl) -3, 3-d? met? lp? per? d? n-4 -? lo, l- (2-prop l) p? per? d? n-3-? lo, 1- (p? r? m? d? n-2-? l) p? per? d? n-4-l, 1- (benzoyl ) p? pepd? n-4-? lo, 3, 4 -d? met? lp? per? dm-4 -? lo, lc? cloprop? l-3, 3-d? met? lp? per? d ? n-4 -? lo, 1- (p? r? d? n-3-ílme useful) -3, 3-d? met? lp? per? d? n-4 -? lo, or 1- (2-methox? et? l) -3, 3- 17 dimethylpiperidin-4-yl. Preferably, R3 is 3,3-dimethylpiperidin-4-yl, l-benzyl-3, 3-dimethylpiperidin-4-yl, l-methyl-3, 3-dimethylpiperidin-4-yl, 1- (isobutyl) -3, 3-dimethylpiperidin-4-yl, 1- (pyridin-2-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (2-propyl) -3,3-dimethylpiperidin-4-yl, 1- (pyridine -4-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (benzyl) -3,3-dimethylpiperidin-4-yl, 1- (acetyl) -3,3-dimethylpiperidin-4-yl, 1- (tert-butyloxycarbonyl) -3,3-dimethyl-piperidin-4-yl, l-cyclopropyl-3, 3-dimethylpiperidin-4-yl, 1- (pyridin-3-ylmethyl) -3,3-dimethylpiperidin-4- ilo, or 1- (2-methoxyethyl) -3,3-dimethylpiperidin-4-yl. (v) Within the above preferred groups A and B, and more preferred groups contained therein, yet another preferred group of compounds is that wherein R3 is a group of formula (a) wherein n is 1, Y is -CH2- and Z is O and R4, R5, and R6 are as defined in the Brief Description of the Invention and R7 and R8 are hydrogen. Preferably, R3 is: " wherein n is 0, 1, or 2, preferably 0 or 1, R4 and R5 are independently hydrogen or alkyl, preferably hydrogen or methyl and R6 is as defined in the Brief Description of the Invention, (vi) Within the groups previous preferred A and B, and other more preferred groups contained therein, still another preferred group of compounds is that wherein R3 is a group of formula (a) wherein n is 0, 1, or 2, Y is -CH2-, and Z is S or SW? and R4, R5, and R6 are as defined in the Brief Description of the Invention; and R7 and R8 are hydrogen. Preferably, R3 is where R 4 and R 5 are independently hydrogen or alkyl, preferably hydrogen or methyl and R 6 are as defined immediately above. (vii) Within the above preferred groups A and B, and more preferred groups contained therein, yet another preferred group of compounds is that wherein R3 is a group of formula (a) wherein n is 1, Y is -CH2- , and Z is -CONH- and R4, R5, and R6 are as defined in the Brief Description of the Invention; and R7 and R8 are hydrogen. Preferably, R3 is wherein R 4 and R 5 are independently hydrogen or alkyl, preferably hydrogen or methyl and R 6 is as defined immediately above. (viii) Within the above groups A and B, and groups contained therein, still another preferred group of compounds is that wherein R 3 is a group of formula (a) wherein R 4 and R 7 combine together with the carbon atom at which join to form a cycloalkyl of (C3- Ca) monocyclic saturated or unsaturated optionally substituted with Rd, Re, and Rf as defined in the Brief Description of the Invention, preferably R4 and R7 are combined together with the carbon atom to which they are attached to form a C3-C8 cycloalkyl monocyclic saturated optionally substituted with Rc Rg and R. Preferably, X is where n and Z are as defined in the Brief Description of the Invention, preferably n is 0, 1, or 2 and Z is -NR6- where R6 is as defined in the Brief Description of the Invention. (ix) Within the above groups A and B, and groups contained therein, still another preferred group of compounds is that wherein R3 is a group of formula (a) wherein R4 and R7 can be combined together with the carbon atom at which join to form a saturated or unsaturated monocyclic heterocyclyl ring containing three to six ring atoms wherein one or two ring atoms are selected from -C (O) -, -O-, -S-, -SO- , -S02-, or -NH- and wherein the heterocyclic ring is substituted with Rm, Rn and R ° are as defined in the Brief Description of the Invention. Preferably, R3 is: O-, or -NH-, n is 0, 1, or 2, preferably 0 or 1, and Z 'is -NH-, -O-, or -S02-, and the rings are substituted with R6, R8, Rm and R ° as defined in the Brief Description of the Invention with R5 and Rn being hydrogen. C. Yet another preferred group of compounds is that wherein R2 and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl substituted with R9, Rh, and R1 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, boxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy of the aryl, heteroaryl, or heterocyclyl ring in Rg, R, and R1 is optionally substituted with R3, Rk, or R1 independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano so long as at least one of Rg, Rh, and R1 is not hydrogen; preferably, R2 and R3 together with the nitrogen atom to which they bind form morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, azepan-1-yl or azopan-1-yl, more preferably piperidin-1-yl, piperazin-1-yl , azepan-1-yl or azopan-1-yl, optionally substituted with the groups listed above, preferably Rg, Rh, and R 1 independently selected from hydrogen, alkyl, phenyl (optionally substituted with alkyl, haloalkyl, alkoxy, or halo), hydroxyl, phenoxy (optionally substituted by alkyl, haloalkyl, alkoxy, or halo), amino, monosubstituted amino, or disubstituted amino, heterocyclyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or heterocyclylalkyl, more preferably amino, monosubstituted amino, or disubstituted amino; and R7 and R8 are hydrogen. D. Yet another preferred group of compounds is that wherein R2 and R3 together with the nitrogen atom to which they are attached form heterocycloamino spiro each of which is substituted with Rg, Rh, and R1 as defined in the Brief Description of the invention. Preferably, R2 and R3 together form: wherein n "is 0-2 and Z 'is -NH-, -O-, or -S02- and the rings are optionally substituted with Rg, Rh and R1 as defined in the Brief Description of the Invention, Preferably, Rg and Rh are hydrogen and R 1 is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, Within the above groups A, B, C, D, A (i-viii), (i-viii), and B (i-viii) and groups contained herein, a particularly preferred group is that wherein R1 is phenyl substituted with Ra, R, or Rc independently selected from hydrogen, alkyl, or halo, preferably methyl, chloro or fluoro, more preferably R1 is 4-methylphenyl, 2, 3-dichlorophenyl, 3,4-dichlorophenyl, and 2,5-dimethyl-4-chlorophenyl, Within the above groups A, B, C, D, A (i-viii), (i-viii), and B (i-viii) and groups contained herein, a particularly preferred group is that wherein R 1 is heteroaryl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo. Within the above groups A, B, C, D, A (i-viii), (i-viii), and B (i-viii) and groups contained herein, a particularly preferred group is that in which R is hydrogen and R1 is phenyl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo, preferably methyl, chloro or fluoro, more preferably R1 is 4-methylphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, and 2,5-dimethyl-4-chlorophenyl. Within the above groups A, B, C, D, A (i-viii), (i-viii), and B (i-viii) and groups contained herein, a particularly preferred group is that in which R is hydrogen and R1 is heteroaryl substituted with Ra, Rbr or Rc independently selected from hydrogen, alkyl, or halo. E. In another embodiment, the invention is directed to compounds of Formula I wherein: R and R2 are hydrogen, R3 is a group of formula (a) wherein R4 and R7 are attached to the same carbon atom and are combined together with the carbon atom to which they join to form a saturated or unsaturated monocyclic (C3-Cβ) cycloalkyl optionally substituted with Rd, Re and Rf as defined in the Brief Description of the Invention; or a saturated or unsaturated monocyclic heterocyclyl ring containing three to six ring atoms in where one or two ring atoms are selected from -C (0) -, -C (== NOH), -0-, -S-, -SO-, -S02-, or -NH- and wherein the ring heterocyclic is substituted with Rm, Rn and R ° where Rm and Rn are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or alkoxycarbonyl and R ° is selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, boxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl , heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy and where the aryl, heteroaryl, or heterocyclyl ring in R ° is optionally substituted with Rd, Re, and Rf as defined in the Brief Description of a Invention; or R2 and R3 together with the nitrogen atom to which they are attached form spiro heterocycloamino substituted with Rg, Rh, and R1 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy where the aryl, heteroaryl, or heterocyclyl ring in Rg, Rh, and R1 is optionally substituted with R:, Rk, or R1 independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano. Within this embodiment, E, a group of compounds is that wherein R1 is phenyl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo, preferably methyl, chloro or fluoro, more preferably R1 is 4-methylphenyl , 2, 3-dichlorophenyl, 3,4-dichlorophenyl, and 2,5-dimethyl-4-chlorophenyl. Within this embodiment, E another group of compounds is that wherein R1 is heteroaryl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo, preferably methyl, chloro or fluoro. F. In another embodiment, the invention is directed to compounds of Formula I wherein R and R 2 are hydrogen, R 1 is 4-methylphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, and 2,5-dimethyl-4-chlorophenyl. , and R3 is 3, 3-dimethylpiperidin-4-yl, 1-benzyl-3, 3-dimethylpiperidin-4-yl, l-methyl-3,3- dimethylpiperidin-4-yl, 1- (isobutyl) -3,3-dimethylpiperidin-4-yl, 1- (pyridin-2-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (2-propyl) - 3, 3-dimethylpiperidin-4-yl, 1- (pyridin-4-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (benzyl) -3,3-dimethylpiperidin-4-yl, 1- (acetyl) ) -3, 3-dimethylpiperidin-4-yl, l- (tert-butyloxycarbonyl) -3,3-dimethyl-piperidin-4-yl, 1-cyclopropyl-3, 3-dimethylpiperidin-4-yl, 1- (pyridine) -3-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (2-methoxyethyl) -3,3-dimethylpiperidin-4-yl, 3,3-dimethyl-1- (2,2,2-trifluoroethyl) ) piperidin-4-yl, l-ethyl-3, 3-dimethylpiperidin-4-yl, l-propyl-3, 3-dimethylpiperidin-4-yl, 1-2,2-dimethylpropyl-3, 3-dimethylpiperidin-4 -yl, l-cyclobutyl-3, 3-dimethylpiperidin-4-yl, or l-cyclopentyl-3, 3-dimethylpiperidin-4-yl wherein the stereochemistry at the carbon atom in the 4-position of the piperidin-4- ring ilo is (R), (S), or (RS), preferably (R) or (S).

GENERAL SYNTHETIC PROCEDURES The compounds of this invention can be made by the methods depicted in the reaction schemes shown below. The starting materials and reagents used in the preparation of these compounds are either available from commercial suppliers such as Aldrichh Chemical Co. , (Milwaukee, is.), Bachem (Torrance, Calif), or Sigma (St.

Louis, Mo. ) or are prepared by methods known to those skilled in the art following the procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1994); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 2003), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are only illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested by one skilled in the art who has referred to this description. The starting materials and intermediates of the reaction can be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including spectral data and physical constants. Unless otherwise specified, the reactions described herein take place at atmospheric pressure over a temperature range of about -78 ° C to about 150 ° C, more preferably from about 0 ° C to about 125 ° C and most preferably at about room temperature (ambient), for example, about 20 ° C. The compounds of the formula (I) can be prepared as shown in the subsequent reaction Schemes A and B.

Reaction scheme A The reaction of an acid of formula 1 with an amine of formula 2 wherein, n, Z, R, and R1-R8 are as defined in the Brief Description of the Invention under standard peptide coupling reaction conditions provides a compound of the formula (I). The reaction is carried out in the presence of a coupling agent such as are coupled with substituted amine 2 using coupling agent under conditions of standard peptide coupling (for example, benzotriazol-1-yloxy-tr Lspyrrolidinophosphonium hexafluorophosphate (PyBOP®), hydrochloride of l- (3-dimethylamino-propyl) -3-ethylcarbodiimide (EDCI), O- (7-) azabenzotriazol-1-yl) -1,1,3,3, tetra-methyluronium-hexafluorophosphate (HATU), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (HBTU) , 1,3-dicyclohexylcarbodiimide (DCC), or the like) and optionally an appropriate catalyst (for example, 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt) or the like) and non-nucleophilic base (e.g., triethylamine, N-methylmorpholine, and the like, or any suitable combination thereof) at room temperature. Suitable reaction solvents include, but are not limited to, dimethylformamide, methylene chloride, and the like. The amines of formula 2 are commercially available or can be prepared by methods well known in the art. For example, (R) -2, 2-dimethylcyclohexanamine can be prepared according to the literature procedure (Moss, Neil; Gautier, Jean; Ferland, Jean-Marie. Synlett (1995), 2, 142-4) of 2, 2-dimethylcyclohexanone and R - (+) - alpha-Phenylethylamine. Similarly, (S) 2,2-dimethylcyclohexanamine can be prepared from S - (+) - alpha-phenylethylamine. Detailed descriptions of amine synthesis are given in the following working examples. A few representative examples of commercially available amines are: 2-methylcyclohexanamine, 1-phenylpiperidin-4-amine, l-benzylpiperidin-4-amine, 4-aminoazepan-1-carboxylate of tert-butyl, 4- tert-butyl aminocyclohexylcarbamate, 2,7-diaza-spiro [4.4] nonan-2-carboxylic acid tert-butyl ester, 3-, 9-diazaspiro [5.5] undecan-3-carboxylic acid t-butyl ester, pyrrolidin- 3-ylcarbamate of (R) -tert-butyl, and pyrrolidin-3-ylcarbamate of (S) -tert-butyl. The compounds of formula 1 wherein B is hydrogen can be prepared as described in Reaction Scheme B below.

Reaction scheme B The sulfonylation of 2-amino-4-tert-butoxy-4-oxobutanoic acid with a sulfonyl chloride of the formula provides a compound of formula 6. The reaction is carried out in the presence of a base, preferably an inorganic base such as sodium carbonate and a suitable organic solvent optionally in the presence of a base such as dioxane and water. Compound 4 such as (R) -2-amino-4-tert-butoxy-4-oxobutanoic acid is commercially available from a number of vendors including Chem-Impex international, Inc.) or is prepared in accordance with the procedures of literature such as Schabbert, S .; Pierschbacher, M.D .; Mattern, R.; Goodman, M. Bioorg. Med Chem. 2002, 10, 3331-7; and Bold, G .; Duthaler, R.O .; Riediker, M. Angew. Chem. 1989, 101, 491-3. The compounds of formula 5 are commercially available or can be prepared by methods well known in the art. The compounds of formula 1 wherein R is alkyl can be prepared using the compounds of formula 4 substituted with the alkyl group. Compound 6 can be converted to a compound of formula 1 via Method (a) or (b) shown above. In method (a), compound 6 is reacted with amine 7 under coupling reaction conditions described above to provide a compound of formula 8. Compound 8 is cyclized to compound 9 in the presence of a catalytic amount of an acid such as TsOH under elevated temperature such as at 60 ° C. The hydrolysis of the ester group under 10 under reaction conditions of acid hydrolysis such as TFA in DCM yields acid 10. In method (b), compound 6 is coupled to amine alcohol 11 under coupling reaction conditions described above to provide a compound of formula 12. Alcohol 12 then is oxidized to the corresponding carbonyl compound 13 with an oxidizing agent such as Dess-Martin periodinane (see J. Org. Chem. 1983, 48, 4155), and the like. The carbon 13 compound is then cyclized to compound 1 under acid conditions described above. The compound of the formula (I) can be converted to other compounds of the formula (I). For example, the free amino group in the compound of the formula (I) can be alkylated with electrophiles (for example, alkyl halides) or aldehydes (through reductive aminations). The examples of these transformations are illustrated in the experimental section. The salts of a compound of the formula I with a salt-forming group can be prepared in a manner known per se. The acid addition salts of the compounds of the formula I can therefore be obtained by treatment with an acid or a suitable anion exchange reagent. A salt with two acid molecules (for example a dihalide of a compound of formula I) can also be converted into a salt with one molecule of acid per compound (for example a monohalogenide); this can be done by heating a melt, or for example by heating a solid under a high vacuum at elevated temperature, for example from 130-170 ° C, an acid molecule is expelled by the molecule of a compound of formula I. The salts can usually be converted to free compounds, for example by treatment with suitable basic agents, for example with alkali metal carbonate, alkali metal acid carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.

Utility The compounds of the formula (I) are receptor Bl antagonists and are therefore useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscesses, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes , acquired immunodeficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, histaminic headache, mixed non-vascular and vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, unstable or inflammatory bladder disorders, psoriasis, skin diseases with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, vascular collagen diseases , chronic inflammatory conditions, inflammatory pain and hyperalgesia and associated allodynia, neuropathic pain and hyperalgesia and associated allodynia, pain due to diabetic neuropathy, sympathetically maintained pain, differentiation syndromes, asthma, allergic or vasomotor rhinitis, damage or dysfunction of epithelial tissue, herpes simplex , post-herpetic neuralgia, visceral motility disturbances in respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders.

Biological Test The in vitro binding affinity of the compounds of the invention to human bradykinin Bl and B2 receptors can be tested using the radioligand binding assay described in Biological Example 1 below. Antagonistic activity of the compounds of the invention for the human bradykinin Bl and B2 receptors can be tested using the calcium flux assay, rabbit endothelial cell specific PGI2 secretion assay Bl, and umbilical vein assay described in Biological Examples 2 and 3 later. The nociceptive activity of the compounds of the invention was determined using the rat and monkey pain models described in Example 4 below. The anti-inflammatory activity of the compounds of the invention was determined using the Green Mono LPS inflammation model described in Example 5 below.

Pharmaceutical Compositions and Administration Also included within this invention is a class of pharmaceutical compositions comprising the active compounds of the invention in association with one or more pharmaceutically acceptable, non-toxic carriers and / or diluents and / or adjuvants (collectively referred to herein) as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in an effective dose for the proposed treatment. The compounds and compositions of the present invention, for example, can be administered orally, mucosally, topically, rectally, pulmonarily, subcutaneously, intramuscularly, intrasternally and infusion techniques, in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The pharmaceutically active compounds of this invention can be processed in accordance with conventional pharmacy methods to produce medicinal agents for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, they may contain an amount of active ingredient from about 1 to 200 mg, preferably from about 1 to 500 mg or 5 to 1000 mg. A suitable daily dose for a human or other mammal can vary widely depending on the patient's condition and other factors, but, once again, it can be determined using routine methods. The amount of compounds which are administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of this invention depends on a variety of factors, include the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound used. Accordingly, the dosage regimen can vary widely, but can be determined routinely using standard methods. A daily dose of about 0.01 to 500 mg / kg, preferably between about 0.1 and about 50 mg / kg, and more preferably about 0.1 and about 20 mg / kg of body weight may be appropriate. The daily dose can be administered in one to four doses per day. For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds can be mixed with lactose, sucrose, powdered starch, cellulose esters of alkanoic acids, esters of alkyl cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of Phosphoric and sulfuric acids, gelatin, acacia gum, alginate sodium, plivinylpyrrolidone, and / or polyvinyl alcohol, and then tabletting or encapsulating for convenient administration. Such capsules or tablets may contain a controlled laberation formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of cmpums of this invention to the affected area two or four times a day. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably once or twice a day. For topical administration, the active ingredient may comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w / w, but preferably not more than 5% w / w, and more preferably from 0.1% to 1% of the formulation. When formulated in an ointment, the active ingredients can be used with either ointment base paraffinic or miscible in water. Alternatively, the active ingredients can be formulated in a cream with a base of oil in water. If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. the same. The topical formulation may desirably include a compound which improves the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably the transdermal administration will be performed using a patch either of the porous membrane type or reservoir or of a variety of solid matrix. In any case, the active agent is continuously supplied from the reservoir or microcapsules through a membrane in the adhesive permeable to active agent, which is in contact with the skin or mucosa of the receptor. If the active agent is absorbed through the skin, the controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also function as the membrane. The oily phase of the emulsions of this invention can be constituted of known ingredients in a known manner. While the phase may comprise only one emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil with both a fat and an oil. Preferably, a hydrophilic emulsifier is included with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifiers with or without stabilizers complete the so-called emulsifying wax, and the wax together with the oil and fat complete the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art. The choice of oils and greases suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most of the oils likely to be used in pharmaceutical emulsion formulations is very low. Therefore, the cream should preferably be a product not greasy, that does not stain and washable with adequate consistency to avoid the leakage of tubes or other containers. Straight or branched chain mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, say oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of branched chain esters. They can be used alone or in combination depending on the required properties. Alternatively, high melting lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w / w. Formulations for parenteral administration may be in the form of sterile aqueous or non-aqueous isotonic suspensions or solutions for injection. These solutions and suspensions can be prepared from sterile granules or powders using one or more of the carriers or diluents mentioned for use in formulations for oral administration or using other suitable dispersing or wetting agents or suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient can also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (ie, Captisol), cosolvent (ie, propylene glycol) solubilization or micellar solubilization (i.e. Tween 80). The sterile injectable preparation can also be a sterile injectable suspension or solution in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose any soft fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. For pulmonary administration, the pharmaceutical composition can be administered in the form of an aerosol or with an inhaler including dry powder aerosol. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. The tablets and pills can be further prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring and fragrant agents. While the compounds of the invention can be administered as the active pharmaceutical agent alone, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents are they may be formulated as separate compositions that are administered concurrently or consecutively at different times, or the therapeutic agents may be given as a single composition. The phrase "co-therapy" (or "combination therapy"), in the definition of use of a compound of the present invention and another pharmaceutical agent, is proposed to encompass the administration of each agent in a consecutive manner in a regime that will provide beneficial effects of the drug combination, and it is also proposed that it encompasses the co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple separate capsules for each agent. The present compounds can also be used in combination therapies with opioids and other anti-pain analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (ie, non-addictive) analgesics, monoamine absorption inhibitors. , adenosine regulatory agents, cannabinoid derivatives, Substance P antagonists, neurokinin 1 receptor antagonists, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib, parecoxib, and darecoxib, NSAID's, and sodium channel blockers, among others. The most preferred combinations could be with cmpts selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocin, meptazinol, hydrocodone, oxycodone, methadone, tetrahydrocanibinol, pregabalin, Tramadol [(+) enantiomer], DuP 747, Dinorphin A, Enadoline, RP-60180, HN -11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene, nalbuphine, E-4018, filnadol, mirtentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dinorphin A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99.994, and CP- 99, 994. Alternatively, the present compounds can also be used in co-therapies with other inflammation treatments, for example steroids, NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, receptor antagonists. LTB4 and inhibitors of hydrolase LTA4.

Examples For the invention described herein to be more easily understood, the following preparations of compounds of the formula (I) and intermediates (References) are described. It should be understood that these examples are for illustrative purposes only and will not be construed as limiting this invention in any way. Unless you point out otherwise, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures. The melting points were determined on a Buchi apparatus and were not corrected. The mass spectral data were determined by electro-ionization ionization technique. All examples were purified to > 90% purity as determined by high performance liquid chromatography.

Synthetic Examples Reference 1 Synthesis of (R) -2- (3-oxo-l-tosyl-1, 2, 3, 4-tetrahydropyrazin-2-yl) acetic acid Step 1 To (D) -aspartic acid β-tert-butyl ester (Chem-impex, 29.5 q, 0.142 mol) in dioxane (500 mL) and water (500 mL) at room temperature was added sodium carbonate (38.7 g) ) followed by p-toluenesulfonyl chloride (28 g, 0.146 mol) in portions. The reaction mixture was stirred overnight and then acidified carefully with 10% HCl and brine. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried, and evaporated to yield (R) -4-tert-butoxy-2- (4-methylphenylsulfonamido) -4-oxobutanoic acid.

Step 2 (R) -4-tert-Butoxy-2- (4-methylphenylsulfonamido) -4-oxobutanoic acid (60 g) was dissolved, 0.124 mol) in anhydrous DMF (400 mL) and HOBt (Aldrich, 19.2 g) and arrinoacetaldehyde dimethyl acetal (Aldrich, 16 mL) were added followed by EDCI (Aldrich, 30 g). The reaction mixture was stirred at room temperature overnight. EtOAc (1000 mL) and water (1000 mL) were added. The EtOAc layer was washed with brine, diluted with HCl / brine, and 10% sodium carbonate / brine, dried, and evaporated to yield 4- (2, 2-dimethoxyethylamino) -3- (4-methylphenylsulfonamido). ) (R) tert-butyl-4-oxobutanoate.

Step 3 4- (2, 2-Dimethoxyethylamino) -3- (4-methylphenylsulfonamido) -4-oxobutanoate (R) -tert-butyl (54 g) was dissolved in anhydrous dioxane (1 L) and p-acid was added. toluenesulfonic (6.6 g). The reaction mixture was heated at 60 ° C for 17 h until the LC / MS indicated that the game was consumed. The reaction mixture was cooled to RT and concentrated to approximately 100 mL. EtOAc (1 L) was added and the solution was washed with sodium bicarbonate solution / brine, dried and evaporated. Cyclumn chromatography (20-50% EtOAc / hexanes, silica gel) yielded 2- (3-oxo-l-tosyl-1,2,3,4-tetrahydropyrazin-2-yl) acetate of (R) -terc -butyl Step 4 2- (3-Oxo-l-tosyl-1,2,4,4-tetrahydropyrazin-2-yl) acetate of (R) -tert-butyl (33.5 g) was dissolved in DCM (400 mL) and added TFA (160 mL). The reaction mixture was stirred at RT until the CCD (50% EtOAc / hexanes) indicated that the reaction was complete. The reaction mixture was evaporated. DCM (200 mL) was added and the solution was evaporated again. The resulting residue was stirred with ether (500 mL) for 1 h. The solids were filtered and washed with ether to yield (R) -2- (3-oxo-l-tosyl-1,2,3,4-tetrahydropyrazin-2-yl) acetic acid. After the procedure described above, the following compounds were prepared: (R) -2- (3-oxo-l- (phenylsulfonyl) -1,2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (2-methylphenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (3-Methylphenylsulfonyl) -3-oxo-l, 2, 3, - acid tetrahydropyrazin-2-yl) acetic; (R) -2- (L- (3-chlorophenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (4-Chlorophenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (4-methoxyphenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (L- (3-trifluorophenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (3,4-Dichlorophenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (2,3-Dichlorophenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid; (R) -2- (1- (4-Chloro-2,5-dimethylphenylsulfonyl) -3-oxo-1,2,3,4-tetrahydropyrazin-2-yl) acetic acid; and (R) -2- (l- (cyclopropylsulfonyl) -3-oxo-l, 2,3,4-te: trahydropyrazin-2-yl) acetic acid.

Reference 2 Synthesis of (R) -2- (5-methyl-3-oxo-l-tosyl-1, 2, 3, 4-tetrahydropyrazin-2-yl) acetic acid Step 1 4- (L-hydroxypropan-2-ylamino) -3- (4-methylphenylsulfonamido) -4-oxobutanoate of (3R) -tert-butyl was prepared from (R) -4-tert-butoxy-2-acid - (4-methylphenylsulfonamido) -4-oxobutanoic acid and 2-aminopropan-1-ol according to Example 1, Step 1.

Stage 2 A (3R) -tert-butyl 4- (l-hydroxypropan-2-ylamino) -3- (4-methylphenylsulfonamido) -4-oxobutanoate (3R) -tert-butyl ester (1.5 g, 3.7 mmol) in humid dichloromethane (in a separatory funnel dichloromethane was shaken with water and separated) Dess-Martin periodinane (Aldrich, 3.2 g, 7.5 mmol) was added and the reaction mixture was stirred by a h. An additional 9 ml of wet DCM was added and the stirring was continued for an additional 1 h. The reaction mixture was then concentrated. EtOAc was added and the mixture was washed with 10% Na2S203 and sat. NaHC03 (20 mL), brine, dried, and evaporated to yield 3- (4-methylphenylsulfonamido) -4-oxo-4- (1-oxopropanol). Crude (3R) -tert-butyl 2-ylamino) butanoate.

Step 3: 3- (4-Methylphenylsulfonamido) -4-oxo-4- (1-oxopropan-2-ylamino) butanoate (3R) -tert-butyl (1.1 g, 3 mmol) in dioxane was added p-toluenesulfonic acid monohydrate (0.3 g, 2 mmol) and the reaction mixture was heated at 60 ° C for 23 h and then concentrated. EtOAc was added and the mixture was washed with NaHCO3 / brine, brine, dried and evaporated. Purification by column chromatography (silica gel, 20-33% EtOAc / hexanes) of the residue yielded 2- (5-methyl-3-oxo-l-tosyl-1,2,3,4-tetrahydropyrazin-2-yl) ) (R) -tert-butyl acetate.

Step 4: 2- (5-Methyl-3-oxo-l-tosyl-l, 2,3,4-tetrahydropyrazin-2-yl) acetate of (R) -tert-butyl (0.27 g, 0.71 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred for 3 h and concentrated and the residue was then co-evaporated with DCM. The residue was titrated with ether to yield the title compound. MS: 323 (M-1).

Reference 3 Synthesis of trans-4-methoxycyclohexylamine Step 1: To a 100 mL round bottom flask containing (IR, 4R) -4-aminocyclohexanol (4.00 g, 26.4) hydrochloride. mmol, Aldrich), di-tert-butyldicarbonate (5.76 g, 26.4 mmol, Aldrich) and sodium carbonate (3.91 g, 36.9 mmol, J.T. Baker) in THF / H20 (20 mL / 20 mL) was added. The reaction mixture was stirred at RT for 10 h. The product was extracted with EtOAc (20 mL), and the organic phase was washed with 5% brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to yield (IR, 4R) -4 -tert-butyl hydroxycyclohexylcarbamate.

Stage 2 To a 100 mL round bottom flask containing (IR, 4R) -4-hydroxy-cyclohexylcarbamate from tert-butyl (0.500 g, 2.32 mmol), silver dioxide (0.753 g, 3.25 mmol, Aldrich) and iodomethane (0.659 g, 4.64 mmol, Aldrich) in MeCN were added. (10 mL). The reaction mixture was stirred at 120 ° C under N2 for 2.5 h. The reaction mixture was quenched with 5% brine (10 mL), and the product was extracted with EtOAc (15 mL), and the organic phase was washed with 5% brine (15 mL), dried over Na 2 SO 4, filtered, and concentrated to yield (IR, 4R) -4-methoxycyclohexylcarbamate tert -butyl.

Step 3: To a 100 mL round bottom flask containing tert-butyl (IR, 4R) -4-methoxy-cyclohexylcarbamate (0.50 g, 2. 2 mmol) hydrochloric acid (11 ml, 44 mmol, 4 M, Aldrich) in 1,4-dioxane (Aldrich) was added. The reaction mixture was stirred at RT for 1 h. Evaporation of the solvent produced hydrochloride salt of (1R, 4R) -4-methylcyclohexylamine.

Reference 4 Synthesis of tert-butyl 4-amino-3, 3-dimethylpiperidine-l-carboxylate Step 1 To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (10.12 g, 50.8 mmol) in dry THF at 0 ° C was added NaH (2.56 g, 107 mmol, 60% in mineral oil, 4.27 g) and then iodomethane (7.91 ml, 127 mmol). The reaction mixture was stirred at RT for 48 h. The solvent was evaporated and the residue was extracted with ether, washed with water and brine. The organic phase was concentrated, treated with a small amount of hexanes to precipitate 3, 3-dimethyl-4-oxopiperidin-1-tert-butyl carboxylate.

Step 2 To a mixture of 3, 3-dimethyl-4-oxopiperidin-1-tert-butyl carboxylate (2.98 g, 13.1 mmol) and benzylamine (5.73 mL, 52.4 mmol) in 10 mL of 1,2-dichloroethane was added (4+) titanium isopropoxide (4.60 ml, 15.7 mmol) and the resulting mixture was stirred at RT for 12 h. The mixture was diluted with MeOH (15 mL) and sodium borohydride (1.39 mL, 39.3 mmol) was added. After stirring at RT for 20 min, the reaction mixture was quenched with 5 mL of sat. NHC1. and the solvent was evaporated to dryness. The residue was subjected to flash chromatography (Si02, EtOAc / Hexane = 1: 1 to 2: 1 to pure EtOAc) to produce tert-butyl 4- (benzylamino) -3,3-dimethylpiperidine-1-carboxylate as a sticky oil which was used directly in the next stage.

Step 3 A suspension of tert-butyl 4- (benzylamino) -3,3-dimethylpiperidine-1-carboxylate (2.5 g, 8 mmol) and palladium, 10% weight on activated carbon (250 mg) in EtOAc (80 mL) it was degassed and purged with hydrogen. After stirring under a hydrogen atmosphere for 48 h, the reaction mixture was filtered through a pad of silica gel with the aid of EtOAc / 2M NH3 in MeOH = 100: 30 to produce 4-amino-3, 3- dimethylpiperidine-l-carboxylate of tere- Butyl In a similar manner, 3, 3-dimethyltetrahydro-2H-pyran-4-amine (from tetrahydropyran-4-one) was prepared.

Reference 5 Synthesis of 3, 3-dimethyl-4- (methylamino) piperidine-1-carboxylate tert -butyl To a solution of methanamine (14.3 mL of 2M in THF) and 3,3-dimethyl-4-oxopiperidine-tert-butyl carboxylate (1.30 g, 5.719 mmol) in dichloroethane was added acetic acid, 99.5% (4,954 mL , 85,790 mmol) and sodium triacetoxyborohydride (2424 g, 11,439 mmol) and the resulting solution was stirred at RT overnight. After stirring at RT for 48 h, the solvent was evaporated to dryness and the reaction mixture was diluted with EtOAc, quenched with sat. NaHCO 3, extracted with EtOAc, dried over Na 2 SO 4 and evaporated to dryness. Column chromatography (Si02, EtOAc to EtOAc / 2M NH3 in MeOH = 100: 10 to 100: 20) afforded 3, 3-dimethyl-4- (methylamino) piperidine-1-carboxylic acid tert -butyl ester.

Reference 6 Synthesis of tert-butyl 4- (ethylamino) piperidine-1-carboxylate To a solution of ethanamine (30.0 ml, 60.0 mmol, 2M solution in THF) and tert-butyl 4-oxopiperidine-l-carboxylate (30.0 ml, 60.0 mmol) in THF (30.0 ml, 15.1 mmol) was added sodium triacetoxyborohydride (6.4612). g, 30.5 mmol), and stirred at rt. under N2. After 1 h, acetic acid (2.00 mL, 34.9 mmol) was added and the reaction mixture was stirred overnight before dilution with AcOEt (200 mL) and aq NaHCO3. saturated (100 ml). The aqueous layer was extracted with AcOEt and the combined organic layer was washed with aq. NaHCO3. saturated (100 ml) and saturated NaCl (100 ml), and dried over Na2SO4. The main portion of the product was found in the aqueous layer, so it was extracted with CH2C12 and dried over Na2SO4. The solvent was removed under reduced pressure and subjected to chromatography on silica (CH2C12 -> CH2Cl2 / MeOH + 2N NH3 = 10/1) to produce the desired product as a colorless liquid.

Reference 7 Synthesis of 4 (R / S) -aminoazepan-1-carboxylic acid 1-tert-butyl ester Step 1 To a solution of tert-butyl 4-oxoazepan-1-carboxylate (2 g, 9 mmol) and benzylamine (4.00 ml, 37 mmol) in tetrahydrofuran (15.0 ml, 9 mmol) and acetic acid (1.00 ml) was added. , 17 mmol) followed by sodium triacetoxyborohydride (4.018 g, 19 mmol). After 18 h, H20 (20 ml) was added. The solution was partitioned between CH2C12 (200 ml) and saturated NaHCO3 (100 ml), and the aqueous layer was extracted with CH2C12. The combined organic layer was washed with saturated NaHCO 3 (100 ml) and saturated NaCl (100 ml), and dried over Na 2 SO 4. The solvent was removed under reduced pressure and subjected to chromatography on silica (ISCO (40 g): CH2C12 to CH2Cl2 / MeOH + NH3 2N = 10/1) to produce tert-butyl 4- (benzylamino) azepan-1-carboxylate .

Step 2 4- (Benzylamino) azepan-1-carboxylic acid tert -butyl ester (2.3591 g) was dissolved in ethyl acetate (50.0 ml) and 10% Pd / C (0.94 g). The reaction mixture was stirred under a hydrogen atmosphere. After 36 h, the reaction mixture was filtered through Celite, the catalyst was washed with ethyl acetate, and concentrated under reduced pressure to yield the title compound.

Reference 8 Synthesis of 4 (R / S) - tert-butyl (ethylamino) azepane-1-carboxylate Step 1 To a solution of ethanamine (10.0 ml, 20 mmol) and tert-butyl 4-oxoazepan-1-carboxylate (1 g, 5 mmol) in THF (10.0 ml, 5 mmol) and acetic acid (0.650 ml, mmol) was added sodium triacetoxyborohydride (~ 2.4 g, 11 mmol). After 24 h, the reaction mixture was diluted in CH2C12 (100 mL) and aq NaHCO3. saturated (50 ml) [11:50], and the organic layer was extracted with CH2C12. The combined organic phase was washed with aq. NaHCO 3. saturated (50 ml) and NaCl aq. Saturated (50 ml), dried over Na2SO4. The solvent was removed under reduced pressure and subjected to chromatography on silica (ISCO (12g): CH2C12 -> CH2Cl2 / MeOH + NH3 2N = 10/1) to produce the title compound.

Reference 9 Synthesis of N, N-dimethylazene-4 (R / S) -amine HCl dihydrochloride yN HHCl Step 1 To a solution of tert-butyl 4-aminoazepane-l-carboxylate (0.3042 g, 1.42 mmol), formaldehyde (37% weight in water) (1.50 mL, 20.1 mmol) in THF (15.0 mL, 1.42 mmol ) sodium triacetoxyborohydride (0.6117 g, 2.89 mmol) was added. After 23 h, the reaction mixture was evaporated and the residue was partitioned between CH2C12 (50 mL) and aq NaHCO3. saturated (50 ml). The organic phase was collected and the aqueous layer was extracted with CH2C12 (50 ml x 2) and the combined organic layer was washed with aq NaCl. Saturated (50 ml), dried over Na2SO4. The solvent was removed under reduced pressure and dried in vacuo to yield 4- (R / S) - (dimethylamino) azepan-1-carboxylic acid tert-butyl ester.

Step 2 To a solution of tert-butyl 4- (dimethylamino) azepan-1-carboxylate (0.3032 g, 1.25 mmol) in 1,4-dioxane (2.00 mL, 23.4 mmol) was added hydrogen chloride (4M in 1, 4-dioxane) (10.0 ml, 40.0 mmol). After 24 h, methanol (2.00 ml, 1.25 mmol) was added and evaporated. The residue treated with Et20 and subjected to sonication and triturated to produce the title compound.

Reference 10 Synthesis of c? Clooctan-1, 5-diamine A mixture of NI, N5-dibenzylcyclooctan-l, 5-diamine (0.350 g, 1.09 mmol, prepared from cyclooctan-1,5-dione and benzylamine according to procedures similar to Reference 7) and 10% Pd / C (0.0231 g, 0.217 mmol), and acetic acid (0.0130 g, 0.217 mmol) in EtOAc / EtOH, was stirred under H2 atmosphere for 14 h. Filtration of the reaction mixture through celite, followed by removal of the solvent afforded the title compound.

Reference 11 Synthesis of tert-butyl 5-aminoazocan-1-carboxylate and tert-butyl 4-aminoazocan-1-carboxylate Step 1: To a solution of tert-butyl 4-oxoazepan-1-carboxylate (6.47 g, 30 mmol) in THF (20 ml), cooled to -35 ° C with a cooling bath (dry ice / isopropanol), simultaneously added a solution of ethyl diazoacetic acid (4.1 ml, 39 mmol) in 5 ml of THF and ether of BF3 (3.8 ml, 30 mmol) in 5 ml of THF over a period of 15 min. After the addition, the reaction mixture was stirred at the temperature for an additional 1 h, and then slowly warmed to RT and stirred at RT for 1.5 h. The reaction mixture was quenched with sat Na2CO3, and the product was extracted with EtOAc, washed with water, dried over Na2SO4, filtered, and concentrated to yield the crude product. Silica gel chromatography with 3: 1 hexane / EtOAc produced 4-oxoazocan-l, 5-dicarboxylic acid 1-tert-butyl 5-ethyl ester and 5-oxoazocan-1,4-dicarboxylic acid 1-tert-butyl 4- ethyl.

Step 2 A mixture of 1-tert-butyl 4-ethyl 5-oxoazocan-l, 4-dicarboxylate (2.50 g, 8.35 mmol) and lithium hydroxide hydrate (1.40 g, 33.4 mmol) in MeOH / H20 (5 ml / 5ml) was refluxed at 80 ° C for 2 h. The solvent was evaporated and the product was extracted with EtOAc, dried over Na 2 SO 4, concentrated to yield 5-oxoazocan-1-tert-butyl carboxylate.

Similarly, tert-butyl 4-oxoazocan-1-carboxylate was prepared from 5-oxoazocan-1,4-dicarboxylic acid 1-tert-butyl-4-ethyl ester. Both 5-oxoazocan-1-tert-butyl carboxylate and tert-butyl 4-oxoazocan-1-carboxylate were converted to the corresponding amines, tert-butyl 5-aminoazocan-1-carboxylate and 4-aminoazocan-1 -tert-butyl carboxylate, according to the procedures in Reference 7.

Reference 12 Synthesis of (5) -tert-butyl 4-amino-3, 3-dimethylpiperidine-l-carboxylate Step 1 To a solution of tert-butyl 4-oxopiperidine-l-carboxylate (150 g) in dry THF (750 ml) at 5 ° C was added sodium hydride (66 g) and the reaction mixture was heated to 20 ° C. ° C. Methyl iodide (113 ml) was added between 25-35 ° C in about 45 min. The reaction was stirred for 2 hrs. The solvent was evaporated and the residue was extracted with ether (3 x 600 ml), washed with water and brine. The phase Organic was concentrated and treated with hexane (350 ml) to precipitate 3, 3-dimethyl-4-oxopiperidin-1-tert-butyl carboxylate.

Step 2: Titanium tetrachloride (18 ml) was added dropwise to a vigorously stirred solution of S-phenylethylamine (48 g) and triethylamine (275 ml) in dry CH2C12 (450 ml) under nitrogen atmosphere. 3, 3-dimethyl-4-oxopiperidine-tert-butyl carboxylate (75 g) dissolved in CH2C12 (225 mL) was added to the above mixture for 10 min. The reaction mixture was stirred and refluxed for 4 h. After 4 h, the reaction mixture was cooled, diluted with diethyl ether (600 ml) and filtered through celite and concentrated in vacuo to provide 3,3-di methyl-4- (1-phenylethylimino). ) crude piperidine-1-carboxylate (S, E) -tert-butyl which was used directly in the next reaction.

Step 3 To the above solution of the imine (105 g) in absolute ethanol (600 ml) was added sodium borohydride (6 g) at -78 ° C. The reaction mixture was allowed to warm to -20 ° C and then quenched with 6N HCl. The ethanol was removed and the residue was mixed with water (500 ml) and then extracted with ether. The organic layer was washed with brine, dried and concentrated to provide the raw dough. This material was chromatographed (10% EtOAc in hexane) on silica gel to obtain 3,3-dimethyl-4- ((S) -l-phenylethylamino) -piperidine-1-carboxylate (S) -tert-butyl ester as pure liquid.

Step 4 3, 3-Dimethyl-4- ((S) -l-phenylethylamino) -piperidine-1-carboxylic acid (S) -tert-butyl ester (45 g) was dissolved in methanol (350 ml) and stirred under a hydrogen atmosphere (1 atm).

When the CCD revealed that no starting material was left, the reaction mixture was filtered and concentrated. The crude product was purified by column chromatography on silica gel (eluent, EtOAc, followed by 5% MeOH / EtOAc) to yield 4-amino-3, 3-dimethylpiperidin-1-carboxylate of (S) -tert-butyl as a liquid. The stereochemistry of the product was assigned based on the literature (Moss, Neil, Gauthier, Jean, Ferland, Jean-Marie, Synlett 1995, (2), 142-4). Similarly, (R) -tert-butyl 4-amino-3, 3-dimethylpiperidine-1-carboxylate was prepared using (R) -phenylethylamine. The (R) -3,3-dimethyl-tetrahydro-2H-pyran-4-amine and (S) -3,3-dimethyl-tetrahydro-2H-pyran-4-amine were prepared from 3,3-dimethyl -tetrahydropyran-4-one the which was prepared from tetrahydropyran-4-one EXAMPLE 1 Synthesis of 3, 3-dimethyl-4- (2- ((R) -3-oxo-l-tosyl-1,2,3-tetrahydropyrazin-2-yl) acetamido) piperidine-1-carboxylate tert-butyl A solution of (R) -2- (3-oxo-l-tosyl-1,2,3,4-tetrahydropyrazin-2-yl) acetic acid (4.0 g, 13 mmol), 4-amino-3,3- 3-tert-butyl dimethylpiperidine-1-carboxylate (3.50 g, 15 mmol), 1-hydroxybenzotriazole (1.7 g, 13 mmol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (2.5 g, 13 mmol) in DMF (1.5 mL) was stirred at RT for 12 h. The reaction mixture was quenched with sat. NaHCO 3, extracted with EtOAc / hexane = 2: 1, washed with brine, dried over Na 2 SO 4, filtered and evaporated to dryness. Column chromatography (Si02, EtOAc / hexane = 1: 1 to 2: 1 to neat EtOAc) yielded 3,3-dimethyl-4- (2- ((R) -3-oxo-l-tosyl-1, 2 , 3,4-tetrahydropyrazin-2-yl) acetamido) piperidine-1-carboxylic acid tert-butyl ester. MS 521 (M + 1).

Example 2 Synthesis of N- (3, 3-dimethylpiperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-1,2,3,4-tetrahydropyrazin-2-yl) acetamide To a solution of 3,3-dimethyl-4- (2- ((R) -3-oxo-l-tisyl-1,2,3,4-tetrahydropyrazin-2-yl) acetamido) piperidine-1-carboxylate from tert-butyl (2.50 g, 4.8 mmol) in DCM (20 mL) was added IN HCl (24 mL) in ether and the resulting solution was stirred overnight. The solvent was evaporated and the residue was solidified with 100 mL of ethyl ether to give the title product as a white solid. EM 421 (M + 1).

Example 3 Synthesis of N- (l-acetyl-3, 3-dimethylpiperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-1,2,3,4-tetrahydropyrazin-2-yl acetamide A solution of N- (3, 3-dimethylpiperidin-4-yl) -2- (Fl) -3-oxo-l-tosyl-1,2,4,4-tetrahydropyrazin-2-yl) acetamide (42 mg, 100 μmol), acetyl anhydride (12 μl, 130 μmol) and triethylamine (28 μl, 200 μmol) in DCM was stirred for 30 min. The solvent was diluted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered and evaporated to dryness. Flash chromatography (SiO2, hexane / EtOAc = 1: 1 to neat EtOAc to EtOAc / MeOH = 100: 10) yielded N- (l-acetyl-3, 3-dimethylpiperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-l, 2,3,4-tetrahydropyrazin-2-yl) acetamide as a white solid. EM 463 (M + 1).

Example 4 Synthesis of N- (3, 3-dimethyl-1- (pyridin-4-ylmethyl) piperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-1, 2, 3, 4-tetrahydropyrazin-2-yl) acetamide To a solution of 4-pyridinecarboxaldehyde (27 μl, 285 μmol) and N- (3, 3-dimethylpiperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-1, 2, 3, 4-tetrahydropyrazin-2-yl) acetamide (40 mg, 95 μmol) in dichloroethane was added sodium triacetoxyborohydride (40 mg, 190 μmol) and the resulting solution was stirred at RT overnight. The reaction was quenched with sat. NaHCO 3, extracted with EtOAc, dried over Na 2 SO and evaporated dryness. Flash chromatography (Si02, EtOAc to EtOAc / 2M NH3 in MeOH = 100: 10 to 100: 20) yielded N- (3,3-dimethyl-1- (pyridin-4-ylmethyl) piperidin-4-yl) -2 - ((R) -3-oxo-l-tosyl-1, 2, 3, 4-tetrahydropyrazin-2-yl) acetamide. MS 512 (M + 1).

Example 5 Synthesis of N- (3, 3-dimethyl-1- (2, 2, 2-trifluoroethyl) piperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-1, 2 , 3,4-tetrahydropyrazin-2-yl) acetamide N- (3, 3-dimethylpiperidin-4-yl) -2- (IR) -3-oxo-l-tosyl-l, 2,3,4-tetrahydropyrazin-2-yl) acetamide hydrochloride (65 mg, 142 μmol), carbonate monosodium acid (17 μl, 427 μmol), and 2,2,2-trifluoroethyl trichloromethanesulfonate (60 μl, 213 μmol) were combined in CHCN, and the reaction mixture was refluxed overnight. The mixture was then concentrated. Water and ethyl acetate were added, and the ethyl acetate layer was separated, dried with sodium sulfate, filtered and concentrated. The mixture was then purified by column chromatography (silica gel, with 0 to 10% MeOH in DCM) to yield title product. MS 503 (M + 1).

Example 6 Synthesis of 4- (N-et? L-2- (3-oxo-l-tos? Ll, 2, 3, 4- tetrah? Drop? Raz? N-2-? L) acetamido) p? Per ? rm-1-carboxylate of (R) -tere-butyl To a solution of (R) -2- (3-oxo-l-tosyl-1, 2, 3, -tetrah? Drop? Raz? N-2-?) Acetic acid (0.804 g, 2.59 mmol) and 4 Tere-butyl (ethylamino) p? per? d? n-1-carboxylate (0.6477 g, 2.84 mmol) in DIPEA (0.680 mL, 3.89 mmol) and DMF (5.00 mL, 2.59 mmol) was added (hexafluorophosphate) of l- (chloro-l-pa rrolidinylmethylene) pyrrolidinium) (0.9484 g, 2.85 mmol), and stirred overnight before adding another portion of 4- (ethylamino) p? per? d? n-1- tert-butyl carboxylate (0.2654 g, 1.16 mmol). The reaction mixture was stirred overnight and was partitioned between AcOEt (200 ml) and NaHC03 aq. saturated (100 ml), and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with aq. NaHCO 3. saturated (100 mL) and NaCl aq. saturated (100 ml), and dried over Na2SO4. The solvent was removed at reduced pressure and subjected to chromatography on silica (CH2C12 -> CH2Cl2 / MeOH = 10/1) then (CH2C12 -> AcOEt) to produce the title product as a whitish solid.

Example 7 Synthesis of (R) -N-et? L-2- (3-oxo-l-tos? Ll, 2, 3, 4- tetrah? Drop? Raz? N-2-? L) -N- ( p? per? d? n-4-? l) acetamide A solution of 4- (N-et? L-2- (3-oxo-l-cough? Ll, 2, 3, 4-tetrah? Drop? Raz? N-2-? L) acetamido) p? Per? d-n-1-carboxylate of (R) -tere-butyl (0.0203 g, 0.0390 mmol) in hydrogen chloride solution (4M in 1,4-d-oxane, 1.00 ml, 4.00 mmol) and 1, 4-D-oxano (0.500 ml) was stirred overnight. The reaction mixture was condensed under reduced pressure and the remaining solid was suspended with Et20 and the resulting solid was washed with Et20 and dried in vacuo to yield the product of t Ltulo as the HCl salt.

EXAMPLE 8 Synthesis of N- (N- (S) -lc? Clopropyl-3, 3- d? Met? Lp? Pepd? N-4 -? L) -2- ((R) -3- N- oxide) oxo-l-cough? ll, 2, 3, 4 - tetrah? drop? raz? n-2-? l) a ce t amide To a solution of N- ((S) -l-cyclopropyl-3, 3-dimethylpiperidin-4-yl) -2- ((R) -3-oxo-l-tosyl-1, 2, 3, 4-tetrahydropyrazine -2-yl) acetamide (110 mg, 239 μmol) in MeCN (10 ml) was added 3-chloroperoxybenzoic acid (49 mg, 287 μmol). After stirring at RT for 1 h, the solvent was evaporated to dryness and the residue was subjected directly to column chromatography (SiO2, EtOAc / MeOH = 5: 1 to EtOAc / 2M NH3 in MeOH = 5: 1 to 3: 1 to 2: 1) to produce the title compound as a white solid. MS: 477 (M + 1).

Example 9 Synthesis of (R) -4- (4-chloro-2,5-dimethylphenylsulfonyl) -3- (2- (4- (hydroxymethyl) piperidin-1-yl) -2-oxoethyl) -3,4-dihydropyrazine - 2 (1H) -one A solution of (R) -2- (1- (4-chloro-2,5-dimethylphenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetic acid (100 mg, 279 μmol ), piperidin-4-ylmethanol (64 mg, 557 μmol), 1-hydroxybenzotriazole (38 mg, 279 μmol) and n- (3-dimethylaminopropyl) -n'-ethylcarbodiimide hydrochloride (53 mg, 279 μmol) in 1 mL of DMF for 12 h. The reaction mixture was quenched with sat. NaHCO 3, extracted with EtOAc / hexane = 2: 1, washed with brine, dried over Na 2 SO 4, filtered and evaporated to dryness. Flash chromatography (Si02, EtOAc to EtOAc / MeOH = 100: 5 to 100: 10) afforded the title compound as a sticky oil. MS: 456 (M +).

Example 10 Synthesis of (R) -4- (4-chloro-2,5-dimethylphenylsulfonyl) -3- (2-oxo-2- (4- (pyrrolidin-1-ylmethyl) piperidin-1-yl) ethyl) - 3, 4-dihydropyrazin-2 (1H) -one Step 1 To a solution of: RI '4-chloro-2,5-dimethylphenylsulfonyl) -3- (2- (4- (hydroxymethyl) -piperidin-1-yl) -2-oxoethyl) -3,4-dihydropyrazine 2 (1H) -one (46 mg, 101 μmol) in DCM (10 ml) was added triethylamine (31 mg, 303 μmol) and methanesulfonyl chloride (23 mg, 202 μmol). After stirring at RT for 10 min, the reaction mixture was loaded directly onto the column (Si02, EtOAc to EtOAc / MeOH = 100: 7) to produce methanesulfonate of (R) - (1- (2- (1- (4-chloro-2,5-dimethylphenylsulphonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) acetyl) piperidin-4-yl) -methyl as a film. MS: 534 (M +).

Step 2 A solution of (R) - (1- (2- (1- (4-chloro-2,5-dimethylphenylsulfonyl) -3-oxo-l, 2,3,4-tetrahydropyrazin-2-yl) methanesulfonate) acetyl) piperidin-4-yl) methyl (40 mg, 75 μmol) and pyrrolidine (53 mg, 749 μmol) in DCM was stirred to ?? for 36 h. The solvent was evaporated and the residue was loaded on preparative CCD (Si02, EtOAc / MeOH = 100: 30) to yield the title compound as a film. MS: 509 (M +).

Formulations The following are representative pharmaceutical formulations containing a compound of the formula (I).

Tablet formulation The following ingredients were intimately mixed and pressed into single-brand tablets.

Ingredient Amount per tablet, mg compound of this invention 400 corn starch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation The following ingredients were intimately mixed and loaded into a hard shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200 Lactose, spray dried 148 magnesium stearate 2 Suspension formulation The following ingredients were mixed to form a suspension for oral administration.

Ingredient Compound quantity of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml dyes 0.5 mg distilled water cs 100 ml Injectable formulation The following ingredients were mixed to form an injectable formulation.

Ingredient Compound amount of this invention 0.4 mg buffer solution of 2.0 ml sodium acetate, 0.4M HCl (IN) or NaOH (IN) q.s. at suitable pH water (distilled, sterile) q.s. to 20 ml Biological Test Example 1 Radioligand Binding Assay for human Bl and Human B2 bradykinin receptor Et apa 1 Preparation of membranes expressing human bradykinin B1 receptor: Membranes were prepared from CHO-d ~ AQN cells stably transfected with human bradykinin Bl receptor cDNA. For large scale production of membranes, the cells were grown in 100 L of suspension culture at 1.0E8 cells / ml then harvested using the V afuge at 1000 g continuous centrifugation. For pilot studies, the cells grew in 2 L of culture with centrifugal agitation and were collected by centrifugation (1900 g, 10 min, 4 ° C). The cell pellet was washed with PBS, centrifuged (1900 g, 10 min, 4 ° C), then the cells were resuspended in lysis buffer (25 mM HEPES, pH 7.4, 5 mM EDTA, 5 mM EGTA, 3 mM MgCl 2, 10% sucrose (w / v), Complete Protease Inhibitor tablets (EDTA free)) at a density of 14% w / v for passage through a microfluidizer (Microfluidics 110S, 3 steps, 6,000 psi). The resulting cell lysate was centrifuged (1900 g, 10 min, 4 ° C), and the crude particulate fraction was isolated by centrifugation (142, 000 g, 1 h, 4 ° C) of the low speed supernatant. The resulting pellet was resuspended in 1/3 volume of original lysis buffer, homogenized, and re-centrifuged as above. The membrane pellet was resuspended by homogenization in storage buffer (25 mM HEPES, pH 7.4, 3 mM MgCl 2, 1 C% sucrose (w / v) and Complete Protease Inhibitor tablets (EDTA free)). Single-use aliquots were made and instantly frozen in liquid N2 prior to storage at -80 ° C. Membranes containing the human bradykinin B2 receptor were purchased from Receptor Biology (now Perkin Elmer Life Sciences). They were derived from a line CHO-K1 stably expressing the human B2 receptor developed by Receptor Biology and subsequently purchased by Amgen. For some studies, the membranes were prepared Internally from this same cell line using the method described for the human Bl receptor membranes, except the cells grew in rotary bottles and were harvested using Cellmate.

Step 2 The binding assay of human Bl receptor was performed on 96-well polypropylene plates (Costar 3365) by adding 50 μl of [3 H] des-arg10 calidin (NET1064, Perkin Elmer Life Sciences) to 10 μl of diluted test compound in 90 μl of assay buffer (24 mM TES, pH 6.8, 1,10 o-phenanthroline 1 mM, 0.3% BSA, 0.5 mM Pefabloc SC, 2 μg / mL aprotinin, 5 μg / mL leupeptin, and 0.7 μg / ml of pepstatin A). The membranes (50 μl) were added to the latter. The [3H] des-arg10-calidin was diluted from the stock solution in assay buffer to produce a final concentration of -0.3 nM in the assay but was adjusted as necessary to ensure a concentration at or below the K determined for each batch. of receptor membranes. The non-specific binding was defined with des-Arg10Leu9 2 μM calidin. The membranes were diluted in assay buffer to produce a final hBl receptor concentration of 0.068 nM in the assay. The compounds were solubilized in either DMSO or ddH20, plated on polypropylene plates (Costar 3365), then serially diluted either in DMSO or dilution buffer (20 mM Hepes, pH 7.6, 0.1% BSft) to produce a final concentration of either 5% DMSO or no DMSO in the assay. The assay reaction mixture was incubated with shaking for 1 h at RT and then filtered through pre-soaked GF / C plates in 0.5% polyethyleneimine (Unifilter, Perkin Elmer Life Sciences) using a 96-well Filtermate harvester ( Perkin Elmer Life Sciences). The filter plates were washed rapidly 6 times with 200 μl of ice-cooled buffer (50 mM Tris, pH 7.4), dried in a vacuum oven at 55 ° C for 15-20 min, covered, and 40 μl per Microscint cavity 20. The plates were sealed and the activity was read in Topcount (Perkin Elmer Life Sciences) using a counting time of 3 min per channel. For the human bradykinin B2 receptor, the same procedure was followed with the following exceptions: [3 H] bradykinin (NET706, Perkin Elmer Life Sciences) was used at a final concentration of -0.2 nM and the non-specific binding was defined with bradykinin 2 μM. The concentration of; Human B2 receptor was 0.068 nM final in the assay.

Data Analysis The data was analyzed in X Fit with the logistics of four parameters y = A + ((B-A) / (1+ ((C / x)? D))) and fit with the Levenburg-Marquardt algorithm. Crude cpm were converted to a percentage of control values prior to analysis (POC = (cpm of compound - emp no specific) / (cpm no of compound - emp specific) * 100)). The Kx values were determined from the IC50 using the Cheng-Prusoff equation and the Kd values were determined by direct saturation binding of the radioligands.

EXAMPLE 2 Inhibition Activity of Bl In vi tro In Vitro Assay of the Human Receptor Bl Function Using Calcium Flow The activation of receptor Bl bound to Gq results in an increase in intracellular calcium. The calcium-sensitive aequorin photoprotein, therefore, can be used as an indicator of Bl receptor activation. Aequorin is a 21-kDa photoprotein that forms a bioluminescent complex when linked to the chromophor coelenterazine cofactor. After calcium binding to this complex, an oxidation reaction of coelenterazine results in the production of apoaequorin, coelenteramide, C02, and light that can be detected by conventional luminometry. A stable CHO D- / hBl / Aequorin cell line was established and the cells were kept in suspension in rotating bottles containing a 1: 1 ratio of DMEM and HAM F12 (Gibco 11765-047), high glucose (Gibco 11965-084), 1C% heat inactivated dialysis serum (Gibco 26300-061), IX Non-Essential Amino Acids (Gibco 11140-050), IX Glutamine-Pen-Strep (Gibco 10378-016), and Hygromycin, 300 μg / mL (Roche 843555). 15-24 h prior to the luminometer assay, 25,000 cells / well (2.5E6 cells / 10 mL / plate) were plated on 96-well black-sided light-bottomed assay plates (Costar # 3904). The media was removed from the cavities and replaced with 60 μl of serum free HAM 's F12 with 30 mM HEPES (pH 7.5) and 15 μM coelenterazine (Coelenterazine h Luciferin # 90608 from Assay Designs). The plates were incubated for 1.5-2 g. Ten-point IC5o compound plates containing 1: 3 or 1: 5 dilutions of antagonist compounds and an agonist activator plate (20 nM final des-Arg10-Calidin concentration, EC8o) were prepared using Ham's F12 with HEPES 30 mM, pH 7.5. After incubation of coelenterazine, an automated instantaneous luminometer platform was used to distribute the antagonist compounds BL (dissolved in DMSO and diluted with buffer to the desired concentration (final DMSO concentration <1% DMSO)) to the cell plate , a CCD camera located below the cell plate took 12 images of the cell plate at 5 second intervals to determine if there was any agonist activity with the compounds. Bl agonist, des-Argio-Calidin, was added to the cell plate and another 12 images were recorded for determine the IC5o of the antagonists.

In Vitro Assay of the hB2 Receptor Function using Calcium Flow The intracellular calcium flux induced by hB2 receptor activation was analyzed using a recombinant hB2 cell line (CHO-Kl) purchased from PerkinElmer (Catalog Number: RBHB2C000EA) in a Fluorometric imaging plate reader (FLIPR). The cavities were cultivated in T225 flask containing Ha 's F12 Nutrient Blend (Invitrogen Corp., Cat "11765-047), 10% Fetal Clone II Bovine Serum (HyClone, Cat # SH3006603), 1 mM sodium pyruvate ( 100 mM stock solution, Invitrogen Corp., Cat # 12454-013), and 0.4 mg / mL Geneticin (G418; 50 mg / mL active geneticin, Invitrogen, Cat # 10131-207) The culture medium was changed every day. 24 h prior to the FLIPR assay, the hB2 / CHO cells were washed once with PBS (Invitrogen) and 10 ml of Versene (1: 5000, Invitrogen, Cat # 15040-066) was added to each flask after 5 min. incubation at 37 ° C, the Versene was removed and the cells were removed from the flask and resuspended in culture medium.The cells were counted and 25,000 cells / well were plated in light-walled dark-walled test 96 cavities (Costar # 3904) The cells were incubated in a CG2 incubator at 37 ° C overnight.

The media was aspirated from the cells and replaced with 65 μL of ink-absorbing buffer. The loader buffer was prepared by diluting a 0.5 mM Fluo-4 AM stock solution (Molecular Probes, dissolved in DMSO containing 10% [w / v] pluronic acid) at a concentration of 1 μM in Eagle Medium Modified with Dulbecco Claro (DMEM) containing 0.1% BSA, 20 mM HEPES, and 2.5 mM probenecid. The cells were loaded with ink for 1 h at RT. The excess dye was removed by washing the 2x cells with assay buffer. The assay buffer consists of Hank's Balanced Salt Solution (HBSS) containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid. After the wash cycles, a volume of 100 μl was left in each cavity, and the plate was ready to be tested in the FLIPR system. Single-point POC antagonist compound plates (final concentration 10 μM) or 10-point IC50 compound plates containing 1: 3 or 1: 5 dilutions of antagonist compounds (dissolved in DMSO and diluted with buffer to the desired concentration ( final DMSO concentration <1% DMSO)) and an agonist activator plate (final bradaquinine concentration of 0.3 nM, ECso) were prepared using assay buffer. The cell plate and compound plates were loaded onto the FLIPR and during the assay, the fluorescence readings were taken simultaneously from all 96 wells of the plaque. cells Ten readings of 1 second were taken to establish a stable baseline for each cavity, then 25 μL of antagonist plate Bl were rapidly added (50 μL / sec). The fluorescence signal was measured in 1 second (1 min) followed by 6 second intervals (2 min) for a total of 3 min to determine if there is agonist activity with the compounds. The B2 agonist, bradykinin, was added to the cell plate and another 3 min was recorded to determine the inhibition percentage at 10 μM (POC plates) or the IC50 of the antagonist. The activity of some of the compounds of this invention in this assay is given in the following table. fifteen' For the purposes of this table, T-l-7 means Table 1, compound 7.

EXAMPLE 3 IN VITRO TRIALS AND HBI RECEIVER LINK TISSUE These studies established the antagonistic activity of several compounds on bradaquinine Bl receptors in isolated organ and cell-based assays in vi tro. 1. Secretion assay of rabbit specific endothelial cell Bl PGI2 2. Bl and B2 umbilical vein test Inhibition Activity of Bl In vi tro The effectiveness of the compounds as inhibitors of Bl activity (ie "neutralization" of Bl) is can evaluate by measuring the ability of each compound to block CGRP stimulated by Bl and release of substance P and calcium signaling in neural cultures of Dorsal Root Ganqlio (DRG).

Neuronal Dorsal Root Ganglion Cultures The dorsal root ganglia were sectioned one by one under aseptic conditions of all the spinal segments of 19-day-old embryonic rats (E19) that are surgically removed from the uterus of terminally anesthetized Sprague-Dawley rats at pregnancy period (Charles River, Wilmington, MA). The DRGs were collected on ice-cold L-15 media (GibcoBRL, Grand Island, NY) containing 5% heat inactivated horse serum (GibcoBRL), and any loose connective tissue and blood vessels were removed. The DRGs were rinsed twice in buffered saline with Ca2 + and Mg2 + free Dulbecco's phosphate (DPBS), pH 7.4 (GibcoBRL). The DRGs were dissociated in single cell suspension using a papain dissociation system (Worthington Biochemical Corp., Freehold, NJ). Briefly, the DRGs were incubated in a digestion solution containing 20 U / mL of papain in Earle's Balanced Saline Solution (EBSS) at 37 ° C for fifty minutes. The cells were dissociated by trituration through Pasteur pipettes burnished in a dissociation medium that consists of MEM / Ham's F12, 1: 1, 1 mg / mL ovomucoid inhibitor and 1 mg / mL ovalbumin, and 0.005% deoxyribonuclease I (DNase). The dissociated cells were plated at 200 x g for 5 min and re-suspended in EBSS containing 1 mg / mL ovomucoid inhibitor, 1 mg / mL ovalbumin and 0.005% DNase. The cell suspension was centrifuged through a gradient solution containing 1 mg / mL of ovomucoid inhibitor, 10 mg / mL of ovalbumin at 200 xg for 6 min to remove cell debris, then filtered through a nylon mesh. of 88 μM (Fisher Scientific, Pittsburgh, PA) to remove any lumps. The number of cells was determined with a hemocytometer, and the cells were seeded in 100 μg / ml poly-ornithine (Sigma, St. Louis, MO) and 1 μg / mL mouse laminin 96-well plates coated with (GibcoBRL) a 10 x 103 cells / well in complete medium. The complete medium consists of minimal essential medium (MEM) and Ham's F12, 1: 1, penicillin (100 U / mL), streptomycin (100 μg / mL), and 10% heat inactivated horse serum (GibcoBRL). The cultures were maintained at 37 ° C, C02 at 5% and 100% humidity. To control the growth of non-neuronal cells, 5-fluoro-2'-deoxyuridine (75μM) and uridine (180μM) were included in the medium. Two hours after plaque placement, cells were treated with recombinant rat β-bl or recombinant human β-bl at a concentration of 10 mg / ml (0.38). nm). Positive controls comprising anti-bl antibody diluted in series were added to ten concentrations using serial dilutions of 3.16 parts. All samples were diluted in complete medium before they were added to the cultures. The incubation time is usually around 40 h prior to the measurement of vrl expression.

Measurement of Expression of VR1 in DRG Neurons: Cultures were fixed with 4% paraformaldehyde in Hank's balanced salt solution for 15 min, blocked with Superblock (Pierce, Rockford, IL), and permeabilized with Nonidet P-40 at 0.25% (Sigma) in saline (TBS) buffered with Tris. HCl (Sigma) for 1 h at RT. The cultures were rinsed once with TBS containing 0.1% Tween 20 (Sigma) and incubated with rabbit anti-VR1 IgG (prepared in Amgen) for 1.5 h at RT, followed by incubation of second Eu-labeled anti-rabbit antibody. (Wallac Oy, Turku, Finland) for 1 ha TA. Washes with TBS (3 x five min with slow shaking) were applied after each antibody incubation. Improving solution (150 mL / well, Wallac, Oy) was added to the cultures. The fluorescence signal was measured in a fluorometer with temporal resolution (Wallac Oy). The expression of VR1 in samples treated with the compounds was determined by comparison with a dard titration curve of Bl from 0-1000 nq / mL. He Percent inhibition (compared to the maximum possible inhibition) of the effect of Bl on the expression of VR1 in DRG neurons was determined by comparison with controls that are not treated with Bl.

Example 4 Antinociceptive activity in vivo in rat model Rat Neuropathic Pain Model Male Sprague-Dawley rats (200 q) were anesthetized with isoflurane inhalant anesthesia and the left lumbar spinal nerves at the level of L5 and L6 are closely linked (4- 0 silk sutures) dit from the dorsal root ganglion and prior to entry into the sciatic nerve, as first described by Kim and Chung (Kim, SH; Chung, JM An experimental model for neuropathy produced by segmental spinal nerve ligation in the mouse, Pain 50: 355-363, (1992)). The incisions were closed and the rats were allowed to recover. This procedure results in mechanical (tactile) allodynia in the left hind paw as assessed by recording the pressure at which the affected paw (ipsilateral to the site of nerve injury) was removed from graded stimuli (Frey filaments ranging from 4.0 to 148.1 mN ) applied perpendicularly to the plantar surface of the paw (between the foot pads) through wire mesh observation cages. A Paw withdrawal threshold (PWT) was determined by consecutively increasing and decreasing the stimulus analysis and resice withdrawal data using a nonparametric Dixon test, as described by Chaplan et al. (Chaplan, S.R .; Bach, F.W .; Pogrel, J.W .; Chung, J.M., Yaksh, T.L. Quantitative assessment of tactile allodynia in the rat paw J. Neurosci.Meth., 53: 55-63 (1994)). Normal rats and sham surgery rats (isolated but not ligated nerves) withstood at least 148.1 mN (equivalent to 15 g) of unresponsive pressure. The rats with ligated spinal nerve responded as little as 4.0 mN (equivalent to 0.41 g) of pressure in the affected paw. The rats were included in the study only if they did not exhibit motor dysfunction (for example, fall or drag of foot and their PWT was below 39.2 mN (equivalent to 4.0 g) .At least seven days after surgery the rats were treated with compounds (usually a selected dose of 60 mg / kg) or control diluent (PBS) once per sc injection and the PWT was determined every day after 7 days.

Inflammatory Pain Model GFA Rat Male Sprague-Dawley rats (200 g) were lightly anesthetized with isoflurane inhalant anesthesia and the left hind paw was injected with complete Freund's adjuvant (CFA), 0.15 ml. This procedure results in allodynia mechanical (tactile) in the left hind paw as assessed by recording the pressure at which the paw affects is removed from graded stimuli (von Frey filaments ranging from 4.0 to 148.1 mN) applied perpendicular to the flat surface of the paw (between plantar pads) through wire mesh observation cages. The PWT was determined by consecutively increasing and decreasing the stimulus analysis and resistance withdrawal data using a nonparametric Dixon test, as described by Chaplan et al. (1994). Rats were included in the study only if they did not exhibit motor dysfunction (eg, foot drop or drag) or cracked skin and their PWT was below 39.2 mN (equivalent to 4.0 g). At least seven days after injection of CFA the rats were treated with compounds (usually a selected dose of 60 mg / kg) or control solution (PBS) once per s.c. and the PWT was determined every day after 7 days. The average leg withdrawal threshold (PWT) was converted to the maximum possible effect percentage (% MPE) using the following formula_% MPE = 100 * (PWT of treated rats - PWT of control rats) / (15-PWT of rats) of control) . Therefore, the cutoff value of 15 g (148.1 mN) is equivalent to 100% of the MPE and the control response is equivalent to 0% MPE. At the 60 mg / kg selection dose, it was expected that the compounds in the vehicle would produce an antinociceptive effect with a PD ratio. The foregoing is only illustrative of the invention and is not intended to limit the invention to the disclosed compounds. All references, patents, applications and publications mentioned, are hereby incorporated by reference in their entirety, as so described. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. Compound of the formula (I): (I) characterized in that: R is hydrogen or alkyl; R1 is aryl or optionally substituted heteroaryl cCan Ra, Rb, and Rc independently selected from alkyl, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylamino, dialkylamino, or alkoxy; R 2 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R3 is bridged heterocyclyl, bridged cycloalkyl wherein bridged heterocyclyl or bridged cycloalkyl is optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl, or alkoxyalkyl; or R3 is a group of formula (a] (a) where: n is 0, 1, 2, or 3; Y is -CH2- or -NH-; Z is -C (O) -, -C (= NOH), -CONH-, -O-, -C (0) 0-, -S-, -SO-, -S02-, -NH-, or - CH2-; R4, R5, and R6 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, adcoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, amino monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, 16 < haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; and R7 and R8 are independently hydrogen or alkyl; or R4 and R7, when attached to the same carbon atom, can be combined together with the carbon atom to which they are attached to form a saturated or unsaturated monocyclic (C3-C8) cycloalkyl optionally substituted with Rd, Re, and Rf as was previously defined; or a saturated or unsaturated monocyclic heterocyclyl ring containing three to six ring atoms wherein one or two ring atoms are selected from -C (O) -, -C (= NOH), -O-, -S-, -SO-, -S02-, or -NH- and wherein the heterocyclyl ring is substituted with Rm, Rn and R ° where Rm and Rn are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy , or alkoxycarbonyl and R ° is selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino , monosubstituted amino, cycloalkylated amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy and wherein the aryl, heteroaryl, or heterocyclyl ring in R ° is optionally substituted with Rd, Re, and Rf as defined above; provided that when Y and Z are -CH2- and R4 and R7 do not form a cycloalkyl or heterocyclyl ring, then at least one of R4, R5, R6, R7, and R8 is not hydrogen; or R2 and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl or heterocycloamino spiro each of which is substituted with R9, Rh, and R1 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy , acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy , heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring on R9, Rh, and R1 is optionally substituted with Rj, Rk, or R1 independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl , haloalkoxy, or cyano provided that when R2 and R3 conjunct with the atom of nitrogen to which they are attached form monocyclic heterocyclyl, then at least one of Rg, Rh, and R1 is not hydrogen; or an N-oxide; and / or a pharmaceutically acceptable salt thereof provided that: (i) when R is hydrogen, R1 is 3,4-dichlorophenyl then R2 and R3 together with the nitrogen atom to which they are attached do not form 2- and 3-phenylpyrrolidin- 1-yl, 2- and 2-phenyl-piperidin-yl-3-yl-1-1-benzylpyrrolidine, 4-phenylpiperidine yl-1, 4-phenylpiperazin-1-yl, 2-, 3- and 4-hydroxymethylpiperidin-l -yl, 2-, 3-, and 4-benzylpiperidin-1-yl, 2-, 3- and 4-methylpiperidin-1-yl, 3-phenylpiperidin-1-yl, azabicyclo [3.2.2] non-3- ilo, azabicyclo [3.2.1] oct-6-yl, 1,3,3-trimethylazabicyclo [3.2.1] oct-6-yl, 2-phenylazepin-1-yl, 4- (pyridin-2-yl) piperazine -1-yl, 3-, or 4- (cyanomethyl) piperazin-1-yl, 4-hydroxyazepan-l-yl, or 4-hydroxy-4-methylazepan-1-yl (ii) when R is hydrogen, R1 is 4-methylphenyl then R2 and R3 together with the nitrogen atom to which they are attached do not form 4- (2-hydroxyethyl) piperazin-1-yl, 2- (4-me oxicarbonilfenil) pyrrolidin-l-yl, 2- (4-methoxycarbonylphenyl) piperidin-1 -yl, 2- (4-hydroxymethylphenyl) piperidin-1-yl, 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (4-phenylpiperidin-1-yl) piperidin-1-yl, 2- (4-piperidin-1-ylmethylphenyl) piperidin-1-yl, or 5-oxa-2-aza-bicyclo [2.

2.1] heptan-2-yl (iii) when R is hydrogen, R 1 is 2, 3 -dichlorophenyl, then R2 and R3 together with the atom nitrogen which they are attached do not form 2-yl phenylpyrrolidine-benzylpiperazine-1-4-yl-l, 2- piperidin-l-yl (4-piperidin-l-ylmethyl), 2- (3-piperidin-l- iÍmetilfenil) piperidin-1-yl, 2- (piperidin-l-4-ylmethyl) pyrrolidin-1-yl, 2- (pyrrolidin-1-yl yl 2-phenyl-piperidin-1-piperidin-l-3-ylmethyl), or (iv) when R is hydrogen, R1 is 4-methylphenyl, and R2 is hydrogen then R3 is not l-benzylpiperidin-4-yl, 2-, 3-, and 4-methylcyclohexyl, 2-, 3-, and 4- hydroxycyclohexyl, 2-benciloxiciclohexilo, 2-etiloxicarbonilciclohexilo, tricyclo [3.3.1.1 ~ 3,7] dec-l-yl, 3-hydroxytricyclo [3.3.1.1-3, 7] dec-1-yl-1-yl Admant, or 2- or 3-hydroxymethylcyclohexyl, and (v) when R is hydrogen, R1 is 2,5-dimethylphenyl, and R2 is hydrogen then R3 is not 2-methylcyclohexyl. Compound according to claim 1, characterized in that: R1 is aryl or heteroaryl optionally substituted with Ra, Rb, and Rc independently selected from hydrogen, alkyl, or halo; R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R3 is bridged heterocyclyl, bridged cycloalkyl wherein the bridged heterocyclic ring, or Bridged cycloalkyl is optionally substituted with one, three or three substituents independently selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl, or alkoxyalkyl; or a group of formula (a): (to) where: n is O, 1, 2, 0 3; Z is -C (O) -, -C (= NOH), -CONH-, -O-, -C (0) 0-, -S-, -SO-, -S02-, -NH-, or - CH2-; and R4, R5 and R6 are independently selected from hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl amino, amino monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; provided that when Z is -CH2- then at least one of R4, R5, and R6 is not hydrogen; or R2 and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl substituted with Rg, Rh, and R1 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl , aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring in R9, Rh, and R1 is optionally substituted with R3, Rk, and R1 independently selected from alkyl halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano so long as at least one of Rg, Rh, and R1 is not hydrogen.

3. Compound according to claim 1, characterized in that R2 is hydrogen.

4. Compound in accordance with the claim 1, characterized in that R2 is alkyl.

5. Compound in accordance with the claim 2, characterized in that R2 is hydrogen.

6. Compound according to claim 3, characterized in that R3 is bridged heterocyclyl optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hadroxyl, hydroxyalkyl, or alkoxyalkyl.

7. Compound according to claim 5, characterized in that R3 is cyclopentyl or cyclohexyl substituted with R4, R5, and R independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, to Icoxyalkyloxy , hydroxyalkyl, hydroxyalkyloxy, ammoalkyl, ammoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ammo, monosubstituted ammo, disubstituted ammo, aplo, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the ring aplo, heteroaryl, or heterocyclyl in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano and R7 and R8 are hydrogen.

8. Compound according to claim 3, characterized in that R3 is a group of the formula: where n is 0, 1, 2 or 3 and Z is -NH- and R4, R5, and R6 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hi hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cacloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, apho, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaploxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; and R7 and R8 are hydrogen.

9. Compound in accordance with the claim 3, characterized in that R3 is a group of formula: wherein R4 and R5 are independently hydroquinone or alkyl, provided that at least one is alkyl.

10. Compound in accordance with the claim 9, characterized in that R6 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, acyl, aminoalkyl, or alkoxyalkyl.

11. Compound in accordance with the claim 5, characterized in that R3 is a group of the formula: where n is 0, 1, 2 or 3 and Z is -NH- and R4, R5, and R6 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl , hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; and R7 and R8 are hydrogen.

12. Compound according to claim 5, characterized in that R3 is a group of the formula: wherein R 4 and R 5 are independently alkyl.

13. Compound according to claim 12, characterized in that R6 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, acyl, aminoalkyl, or alkoxyalkyl.

14. Compound according to claim 5, characterized in that R3 is a group of formula (a) wherein Z is -O- and R7 and R8 are hydrogen.

15. Compound according to claim 3, characterized in that R3 is a group of formula (a) wherein R4 and R7 are combined together with the carbon atom to which they are bound to form a saturated cycloalkyl (C3-Cß) cycloalkyl or unsaturated optionally substituted with R, Re, and Rf as defined above.

16. Compound in accordance with the claim 3, characterized in that R3 is a group of formula (a) wherein R4 and R7 are combined together with the carbon atom to which they are attached to form a saturated or unsaturated monocyclic heterocyclyl ring containing three to six atoms in the ring where one or two ring atoms are selected from -C (0) -, -0-, -S-, -SO-, -S02-, or -NH- and wherein the tert-cyclic ring is substituted with Rm, Rn and R ° as defined above.

17. Compound according to claim 5, characterized in that R2 and R3 together with the napogen atom to which they are attached form monocyclic heterocyclyl substituted with Rg, Rh and R1 as defined above.

18. Compound according to claim 3, characterized in that R2 and R3 together with the n? -trogen atom to which they bind form heterocycloamino spiro each of which is substituted with Rg, Rh and R1 as defined above.

19. Compound in accordance with the claim 11, characterized in that R is hydrogen and R1 is phenyl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo.

20. Compound in accordance with the claim 12, characterized in that R is hydrogen and R1 is phenyl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo.

21. Compound according to claim 13, characterized in that R is hydrogen and R1 is phenyl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo.

22. Compound in accordance with the claim 2, characterized in that R and R2 are hydrogen, R1 is 4-methylphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, and 2,5-dimethyl-4-chlorophenyl, and R3 is 3,3-dimethylpiperidin-4- ilo, 1-benzyl-3, 3-dimethylpiperidin-4-yl, 1- (isobutyl) -3,3-dimethylpiperidin-4-yl, 1- (pyridin-2-ylmethyl) -3,3-dimethylpiperidin-4- ilo, 1- (2-propyl) -3,3-dimethylpiperidin-4-yl, 1- (pyridin-4-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (acetyl) -3, 3- dimethylpiperidin-4-yl, 1- (tert-butyloxycarbonyl) -3,3-dimethyl-piperidin-4-yl, 1-cyclopropyl-3, 3-dimethylpiperidin-4-yl, 1- (pyridin-3-ylmethyl) - 3, 3-dimethylpiperidin-4-yl, 1- (2-methoxyethyl) -3,3-dimethylpiperidin-4-yl, 3,3-dimethyl-1- (2,2,2-trifluoroethyl) piperidin-4-yl , l- (tert-butyloxycarbonyl) piperidin-3-yl, l-ethyl-3, 3-dimethylpiperidin-4-yl, ln-propyl-3, 3-dimethylpiperidin-4-yl, 1-2, 2- dimethylpropyl-3, 3-dimethylpiperidin-4-yl, l-cyclobutyl-3, 3-dimethylpiperidin-4-yl, or l-cyclopentyl-3, 3-dimethylpiperidin-4-yl wherein the stereochemistry at the atom d The carbon in the 4-position of the piperidin-4-yl ring is (R), (S), or (RS).

23. Compound, characterized in that it is selected of: (3R) -3- (2- (3-azabicyclo [3.2.2] non-3-yl) -2-oxoethyl) -4- ((3,4-dichlorophenyl) -sulfonyl) -3, 4- dihydro-2 (1 H) -pyrazinone; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,4-tetrahydro-2-pyrazinyl) -N- ((1R, 2R, 4R) -1, 7,7-trimethylbicyclo [2.2.1] hept-2-yl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((1R, 2S, 4R) -1 , 7, 7-trimethylbicyclo [2.2.1] hept-2-yl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1-phenyl-4-piperidinyl) acetamide; N - ((1S, 2S) -2- (1, 1-dimethylethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4 -tetrahydro-2-pi razinyl) acetamide; N - ((1R, 2R) -2- (1, 1-dimethylethyl) -cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1,2,3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 2R) -2- (1, 1-dimethylethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N - ((1R, 2S) -2- (1,1-dimethylethyl) cyclohexyl) -2- ((2R) -l- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3S) -1- (phenylmethyl) - 3-pyrrolidinyl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -1- (phenylmethyl) -3-pyrrolidinyl) acetamide; N- ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -2 - ((2R) -l - ((4- methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pi razinyl) acetamide; 2- ((2R) -1- ((4-Methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (2-pyrimidinyl) -4- pi peridinyl) acetamide; (3R) -3- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; and (3S) -3- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-p razinyl) acetyl) amino) -1 1,1-dimethylethylpiperidinecarboxylate; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -1- (phenylmethyl) - 3-piperidinyl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((3S) -1- (phenylmethyl) -3-piperidinyl) acetamide; N- ((3R) -1- (1-methylethyl) -3-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4- tetrahydro-2-pi razinyl) acetamide; and N- ((3S) -1- (1-methylethyl) -3-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4 -tetrahydro-2-pyrazyl) acetamide; 4 - (((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4- 17 í 1,1-dimethylethyl tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate; 2- ((2R) -1- ((-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinylmethyl) -4-piperidinyl acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- ((3S) -1- (4-pyridinylmethyl) ) -3-piperidinyl) acetamide; and 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -1- (4- pyridinylmethyl) -3-piperidinyl) acetamide; (4R) -3,3-Dimethyl-4- ((((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; and (4S) -3,3-dimethyl-4- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl ) 1,1-dimethylethyl amino) -1-piperidinecarboxylate; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- (1-methyl-4-piperidinyl) acetamide; N- ((4S) -3,3-dimethyl-1-4 -piperidinyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro -2-pyrazinyl) acetamide; and N- ((4R) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro -2-pyrazinyl) acetamide; N- (l-acetyl-3, 3-dimet i 1-4 -piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (2-methylpropyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2-methylpropyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-dimethyl-1- (phenylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-1- (phenylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (1,3,3-trimethyl-4-) piperidinyl) acetamide; N- ((4R) -3,3-dimethyl-1- (1-methylethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4S) -3,3-dimethyl-1- (1-methylethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo -1,2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (4-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N - ((4S) -3,3- dimethyl-1- (4-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2 -pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (2-pyridinylmethyl) -4-piperidinyl) -2 - ((2R) -l - ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (2-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; 2 - ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (phenylcarbonyl) -4-piperidinyl) acetamide; N- ((4S) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3 , 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4R) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1,2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- (trans -4- (methyloxy) cyclohexyl) -2- ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- (cis-4-aminocyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- (trans-4-aminocyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2- pyrazinyl) acetamide; N- (trans-4-aminocyclohexyl) -2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((3-endo) -8-methy1-8-azabicyclo [3.2.1] oct-3-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo -l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((3-exo) -8-methyl-E-azabicyclo [3.2.1] oct-3-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo -l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- (cis-4- ((1-methylethyl) amino) cyclohexyl) -2- ((2R) -1- ((-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2 -pyrazinyl) acetamide; N- (trans -4- ((1-methylethyl) amino) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro -2-pyrazinyl) acetamide; N- ((IR) -2,2-dimethyl-4-oxocyclohexyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pyrazinyl) acetamide; and N- ((1S) -2,2-dimethyl-4-oxocyclohexyl) 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro- 2-pyrazinyl) acetamide; N- (2,3-dimethylcyclohexyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,4-tetrahydro-2-pyrazinyl) - N - (- methyl-l-piperazinyl) acetamide; Nl, l'-bi (cyclohexyl) -2-yl-2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi. razinyl) acetamide; N- (4- (3-fluoro-l-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1,2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N - ((LR, 4S) -4- (4-Fluoro-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1R, 4R) -4- (4-fluoro-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4- (4-fluoro-1-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((1S, 4R) -4- (4-fluoro-l-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N - ((1S, 4R) -4- (cyclopropylamino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-lr 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4- (cyclopropylamino) -2,2-dimethylcyclohexyl) -2 - ((2R) -l - ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -4- (cyclopropylamino) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((IR, 4S) -4- (c Lclopropylamino) -2, 2-d? met? lc? clohex? l) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((LR, 4S) -4- ((2,2-d? Met? Lprop? L) am? No) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4- methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? ra? l) acetamide; N- ((IR, R) -4- ((2,2-d methylpropyl) amino) -2, 2-d? Met? Lc? Clohex? L) -2- ((2R) -l- ((4 -methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pj razinyl) acetamide; N- ((1S, 4S) -4- ((2,2-d? Met? Lprop? L) amino) -2, 2-d? Met? Lc? Clohex? L) -2- ((2R) - 1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? Rea? L) acetamide; and N- ((1S, R) -4- ((2, 2-d? met? lprop? l) amino) -2, 2-d? met? lc? clohex? l) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-p-lazinyl) acetamide; N - ((4S) -lc? Cloprop? L -3, 3-d? Met? L-4-p? Per? D? N? L) -2- ((2R) -l- ((4-met ? lphene) -sulphonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4R) -lc? clopropyl-3, 3-d? met? l-4-piperidinyl) -2- ((2R) -1- ((4-met? lphenyl) -sulfonyl) - 3-oxo-1, 2,3, 4-tetrahydro-2-p? Raz? N) l) acetamide; N- ((4R) -3,3-d? Met? Ll- (2, 2, 2-tr? Fluoroethyl) -4-piperidinyl) -2- ((2R) -1- ((4-met? L phenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-p? ra? l) acetamide; and N- ((4S) -3,3-d met? l-1- (2, 2, 2-tr? fluoroethyl) -4-p? pepd? n? l) -2- ((2R) -1 - ((4-ethyl-phenyl) sulfonyl) -3-oxo-l, 2,3,4,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) -3, 3- dimethyl-4-piperidinyl) acetamide; and 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4R) -3,3 -dimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) - 3, 3-dimethyl-4-piperidinyl) acetamide; and 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((4R) -3,3-dimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((3,4-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4R) -3, 3- dimethyl-4-piperidinyl) acetamide; and 2- ((2R) -1- ((3,4-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) -3,3 -dimethyl-4-piperidinyl) acetamide; N- ((1R, 4S) -2,2-dimethyl-4- (l-pyrrolidinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -2, 2-dimethyl-4- (1-pyrrolidinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1 , 2,3, 4-tetrahydro-2-pi razinyl) acetamide; N- ((1S, 4S) -2,2-dimethyl-4- (1-pi rolidinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N - ((1S, 4R) -2,2-dimethyl-4- (1-pyrrolidinyl) cyclohexyl) -2 - ((2R) -l - ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2- pyrazinyl) acetamide; N- ((1R, 4S) -2, 2-dimethyl-4- (1-piperidinyl) cyclohexyl) -2 - ((2R) -l- ((4-methyl-phenyl) sulfonyl) -3-oxo-l , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, R) -2, 2-dimethyl-4- (1-piperidinyl) cyclohexyl) -2 - ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2 , 3, 4-tetrahydro-2-pi razinyl) acetamide; N- ((1S, 4S) -2, 2-dimethyl-4- (1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-l , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N - ((1S, 4R) -2, 2-dimethyl-4- (1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrrazinyl) acetamide; N- ((1S, 4R) -2,2-Dimethyl-4- (4-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -2,2-dLmethyl-4- (4-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo -l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -2, 2-dimethy1-4- (4-methyl-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; and N - ((1R, 4S) -2, 2-dimethyl-4- (4-methy1-1-piperidinyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-1, 2,3, -tetrahydro-2-pi razinyl) acetamide; N- ((IR, 4S) -4- (3, 3-dimethyl-1-piperidinyl) -2,2-dimethylcyclohexyl) -2 - ((2R) -l- ((4-methylphenyl) sulfonyl) -3- oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N - ((1R, 4R) -4- (3,3-dimethyl-1-piperidinyl) -2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3- oxo-l, 2, 3, -tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4- (3, 3-dimethy1-1-piperidinyl) -2,2-dimethylcyclohexyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3- oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((1S, 4R) -4- (3, 3-dimethyl-l-piperidinyl) -2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3 -oxo-l, 2,3, -tetrahydro-2-pyrazinyl) acetamide; N - ((1S, 4R) -2,2-dimethyl-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1 , 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -2, 2-dimethy1-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo-1 , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -2,2-di methyl-4- (4-morpholinyl) cyclohexyl) -2 - ((2R) -l- ((-methylphenyl) sulfonyl) -3-oxo-l, 2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((IR, 4S) -2, 2-dimethyl-4- (4-morpholinyl) cyclohexyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4R) -4-hydroxy-2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4 -tetrahydro-2-pyrazinyl) acetamide; N- ((1S, 4S) -4-hydroxy-2,2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-1, 2, 3, 4 -tetrahydro-2-pyrazinyl) acetamide; N- ((IR, 4R) -4- hydroxy-2, 2-dimethylcyclohexy 1) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((IR, 4S) -4-hydroxy-2, 2-dimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-dimethyl-4-piperidinyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro- 2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pyrazinyl) acetamide; N- (1- (2-phenethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2- pyrazinyl) acetamide; N- ((4S) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyltetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((3R) -3-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; and N- ((3S) -3-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; l 4 - . 4 -methyl-4- ((((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; N- (4-methyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- (3- (hydroxymethyl) bicyclo [2.2.1] hept-2-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4 -tetrahydro-2-pi .razinyl) acetamide; N- ((1RS, 2RS) -2- (1-hydroxy-1-methylethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; 4 - ((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1.1 -dimethylethyl; N- ((4RS) -2,2-dimethyl-6-oxotetrahydro-2H-pyran-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4RS) -3,3-dimethyl-1,4'-bipiperidin-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((1RS, 2RS) -2- (hydroxymethyl) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro-2 -pyrazinyl) acetamide; (3RS) -3 - ((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo- 1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (t-tetrahydro-2H-pyran-4-) il) acetamide; N- ((4R) -3,3-dimethyl-1- (2-methylpropyl) -4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R / S) -4-azepanyl) -2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1, 2-trifluoroacetic acid salt , 3, 4-tetrahydro-2-pi razinyl) acetamide; N- ((4R) -4 -azepanyl) -2- ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide and N- ((4S) -4-azepanyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -3-pyrrolidinyl) acetamide; N- ((1R / S, 4 R / S) -4-hydroxy-2,2,4-trimethylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1 , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1, 2, 2, 6, 6 pentamethyl-4-piperidinyl) acetamide; N- ((4R / S) -l-methyl-4-azepanyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pyrazinyl) acetamide; N- (trans- (dimethylamino) cyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pi razinyl) acetamide; N- (cis / trans-5-aminociclooctil) -2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3, -tetrahydro-2-pi azinyl) acetamide; N- ((4R) -3,3-Dimethyl-1- (4-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (4-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -l- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-1- (3-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-Dimethyl-1- (3-pyridinylmethyl) -4-piperidinyl) -2- ((2R) -1- ((4-methyl-phenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; 3, 3, 3-trifluoropropanoic acid salt of 2 - ((2R) 1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N - (4-methyl-l-piperazinyl) acetamide; N- (4,4-difluorocyclohexyl) -2 - ((2R) -l - ((4- methylphenyl) sulfonyl) -3-oxo-l, 2,3,4,4-tetrahydro-2-pyrazinyl) acetamide; 2- ((2R) -1- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro-2-pyrazinyl) -N- (4-methyl-1) 1-piperazinyl) acetamide; (4S) -3,3-Dimeti1-4- ((((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1,1-dimethylethyl; (4R) -3,3-dimethy1-4- ((((2R) -1- ((4-methylphenyl) -su-L-phonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl ) amino) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester; N- (l-cyclopropyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R / S) -l-cyclopropyl-4-azepanyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro- 2-pyrazinyl) acetamide; trifluoroacetic acid salt of 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- ((4R / S) -l-cyclopropyl-4-azepanyl) acetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) - 3, 3-dimethyl-4-piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4- tetrahydro-2-pyrazinyl) -N- ((4S) -1,3,3-trimethyl-4-piperidinyl) acetamide; N- ((4S) -l-ethyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-dimethyl-l-propyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -1- (2,2-dimethylpropyl) -3,3-dimethyl-1-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1, 2,3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -l-cyclobutyl-3, 3-dimethyl-1-4 -piperidinyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3 , 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -l-cyclopentyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; (4S) -4 - ((((2R) -l - ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -3 , 1,1-dimethylethyl 3-dimethyl-1,1-piperidinecarboxylate; 2- ((2R) -1- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) - 1, 3, 3-trimethy1-4-piperidinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N- ((4S) -3, 3- dimethyl-4- piperidinyl) acetamide; 2- ((2R) -1- ((2,3-dichlorophenyl) sulfonyl) -3-oxo-1,2,3, -tetrahydro-2-pyrazinyl) -N- ((4S) -1, 3, 3 -trimethyl-4-piperidinyl) acetamide; N- ((4S) -1- (2,2-dimethylpropanoyl) -3,3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) acetamide; N-5-azocanyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetamide; (4S) -4 - ((((2R) -l- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -3, 3-dimethyl-1-piperidinecarboxylate 1,1-dimethylethyl; N- ((1RS, 2RS) -2-hydroxy-2-methylcyclohexyl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro- 2-pi azinyl) acetamide; 2- ((2R) -1- ((4-Methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- (1- (4-pyridinylmethyl) -4- piperidinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N-1-piperidinylacetamide; N- ((8RS) -7,7-dimethyl-1,4-dioxaespiro [4.5] dec-8-yl) - 2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-irazinyl) acetamide; 2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3,4-tet rahydro-2-pyrazinyl) -N- ((3S) -6-oxo-3) -piperidinyl) acetamide; 2- ((2R) -1- ((4-methyl phenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) -N- ((3R) -6-oxo-3 -piperidinyl) acetamide; (4RS) -4 - ((((2R) l- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino 1,1-dimethy1ethi1-azepane carboxylate; N- ((4S) -3,3-dimethyl-1,4'-bipiperidin-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -3,3-dimethyl-1,4'-bipiperidin-4-yl) -2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2 , 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4R) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -2- ((2R) -1- ((2,3-dichloro-phenyl) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -l-cyclopropyl-3, 3-dimethyl-1-4 -piperidinyl) -2- ((2R) -l - ((2,3-dichloro-phenyl) sulfonyl) -3-oxo-1 , 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; N- ((4S) -3,3-dimethyl-1- (2-pyridinylmethyl) -4- pipepdinil) -2- ((2R) -1- ((4-met? l-phenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-p? raz? n? acetamide; N- ((4R) -3,3-d? Met? Ll- (2-p? R? D? N? Lmet? L) -4-piperidyl) -2- ((2R) -1- ((4 -met? l-phenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? ra? l) acetamide; N- ((4R) -3,3-d? Met? Ll- (2- (methyloxy) ethyl) -4-piperidyl) -2- ((2R) -1- ((4-met? Lphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? Raz? N) l) acetamide; n-oxide of N - ((4S) and 4 (R) -lc? cloprop? l-3, 3-d? met? l-4-p? per? d? n? l) -2- ((2R ) -1- ((4-meth? Lphenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-p? Ra? L) acetamide; 2- ((2R) -1- ((4-met? Lfen? L) sulfonyl) -3-oxo-l, 2, 3,4-tecrah? Dro-2-p? Raz? N) -N -methyl-N- (l-met? l-4-paperidinyl) acetamide; 2- ((2R) -1- ((2,3-d? Chlorophen? L) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? -N-methyl-N- (l-met? L-4-pa pepdinil) acetamide; 2- ((2R) -1- ((3,4-d? Chlorophen? L) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-p? -N-methyl-N- (l-met? L-4-p Lperidyl) acetamide; 2- ((2R) -1- ((4-chloro-2,5-d? -methylphenyl) sulfonyl) -3- or < ol, 2, 3, 4-tetrahydro-2-p? ? n? l) -N-methyl-N- (l-met? l-4-prperidyl) acetamide; N- (c? S-4-ammoc? Clohex? L) -N-met? L-2- ((2R) -1- ((4-methyl phenyl) sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2- pyrazinyl) acetamide; and N- (trans-4-aminocyclohexyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl acetamide; N- ((4R) -3,3-dimethyl-4-piperidinyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3 , 4-tetrahydro-2-pyrazinyl) acetamide; and N- ((4S) -3,3-dimethyl-4-piperidinyl) -N-methyl-2- ((2R) -l- ((4-methylphenyl) -sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-pyrazinyl) acetamide; N- ((4RS) -l-cyclopropyl-3, 3-dimethyl-4-piperidinyl) -N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2, 3, 4-tetrahydro-2-pyrazinyl) acetamide; 4- (ethyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate 1, 1-dimethylethyl; N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; N-ethyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; N-propyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; 2- ((2R) -1- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N-methyl-N- ( l-methyl-4-piperidinyl) acetamide; 4- (Methyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1- 1, 1-dimethylethyl piperidinecarboxylate; 4 - (((((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) (propyl) amino) -1-piperidinecarboxylate 1,1-dimethylethyl; N- (2- (methyloxy) ethyl) -2 - ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N- (l-methyl-4-piperidinyl) acetamide; (4RS) -4- (methyl (((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-1, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1- 1, 1-dimethylethyl azepane carboxylate; (4R / S) -4- (ethyl (((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-1,2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) - 1, 1-dimethylethyl 1-azepancarboxylate; N- ((4R / S) -4 -azepanyl) -N-methyl-2- ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2, 3, 4-tetrahydro- 2-pi azinyl) acetamide; N- ((4R / S) -4-azepanyl) -N-ethyl-2- ((2R) -l - ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro- 2-pyrazinyl) acetamide; 4- (cyclopropyl (((2R) -1- ((-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) amino) -1-piperidinecarboxylate of 1.1 -dimethylethyl; N-cyclopropyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) -N-4-piperidinylacetamide; N-methyl-2- ((2R) -1- ((4-methylphenyl) sulfonyl) -3-oxo- 1,2,3,4-tetrahydro-2-pyrazinyl) -N- (1-methyl-4-piperidinyl) acetamide; (3R) -3- (2- (2- (4- (methyloxy) phenyl) -4-thiomorpholinyl) -2-oxoethyl) -4- ((4-methyl-phenyl) sulfonyl) -3,4-dihydro- 2 (1H) -pyrazinone; (3R) -3- (2- (2- (4-Chlorophenyl) -1-pyrrolidinyl) -2-oxoethyl) -4- ((-methylphenyl) -sulfonyl) -3,4-dihydro-2 (1H) - pyrazinone; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- ((3S) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-Dichlorophenyl) sulfonyl) -3- (2 - ((3R) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2 - ((3S) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 (1H ) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-pyrrolidinyl) -2-oxoethyl) -3, - dihydro-2 (1 H) -pyrazinone; (3R) -3- (2- (1,4'-bipiperidin-1-yl) -2-oxoethyl) -4- ((4-chloro-2,5-dimethylphenyl) -sulfonyl) -3,4- dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (4- (dimethylamino) -1-piperidinyl) -2-oxoethyl) -3,4-dihydro- 2 (1 H) -pyrazinone; (3R) -3- (2- ((3S) -3- (amino) -4 (R) -4-phenyl-1-pyrrolidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2, 5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- ((3S) -3- (1-pyrrolidinyl) -1-piperidinyl) ethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- ((3'S) -l, 3'-bipyrrolidin-1-yl) -2-oxoethyl) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3 , 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3S) -3- (dimethylamino) -1-piperidinyl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3S) -3- (dimethylamino) -1-azepanyl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (4- (hydroxymethyl) -1-piperidinyl) -2-oxoethyl) -3,4-dihydro-2 (1 H) -pyrazinone; (3R / S) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R) -3- (hydroxymethyl) -1-piperidinyl) -2-oxoethyl) - 3, 4-dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((2R / S) -2- (hydroxymethyl) -1-piperidinyl) -2-oxoethyl) -3 , 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- (4- (1-pyrrolidinylmethyl) -1-piperidinyl) ethyl) -3, 4- dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- ((3R / S) -3- (1-pyrrolidinylmethyl) -1-piperidinyl) ethyl ) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- ((3S) -3-amino-l-pyrrolidinyl) -2-oxoethyl) 4- ((4-chloro-2,5-dimethyl-phenyl) sulfonyl) -3, 4- dihydro-2 (1 H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R / S) -4- (dimethylamino) -1-azepanyl) -2-oxoethyl) -3 , 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R / S) -3- ((dimethylamino) -methyl) -1-piperidinyl) -2- oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- ((3S) -3- (1-pyrrolidinyl) -1-azepanyl) ethyl) - 3, 4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (i 3'R / S, 4 'R / S) -4' -methyl-1,3 ' -bipyrrolidin-1 '-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2-oxo-2- ((3R / S) -3- (1-pyrrolidinyl-methyl) -1-pyrrolidinyl ethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2 - ((4R / S) -4- (dimethylamino) -1-azepanyl) -2-oxoethyl) -3,4-dihydro -2 (1H) -pyrazinone; trifluoroacetic acid salt of (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R / S) -4- (cyclopropyl (methyl) amino) -1- azepanyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R / S) -4-hydroxy-3,3-dimethyl-1-piperidini1) -2 -oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R / S) -3,3-dimethyl-4- (1-pyrrolidinyl) -1-piperidinyl ) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; trifluoroacetic acid salt of (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-piperidinyl) -2-oxoethyl ) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (-methi-2-, 7-diazaspiro- [4.4] non-2-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- ((4R) -4- (dimethylamino) -1-azocanyl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- ((4R / S) -4- (dimethylamino) -1-azocanyl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -3- (2- (2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -4- ((2,3-dichlorophenyl) sulfonyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- (7- (1-methylethyl) -2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (7- (1-methylethyl) -2,7-diazaspiro [4.4] non-2-yl) - 2-oxoethyl) -3, -dihydro-2 (1H) -pyrazinone; (3R) -4- ((4-Chloro-2,5-dimethylphenyl) sulfonyl) -3- (2- (7-cyclopropyl-2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4-dihydro-2 (1H) -pyrazinone; (3R) -4- ((2,3-dichlorophenyl) sulfonyl) -3- (2- (7-methyl-2,7-diazaspiro [4.4] non-2-yl) -2-oxoethyl) -3,4 -dihydro-2 (1H) -pi razinone; N- (l- (2 - ((2R) -l- ((4-methylphenyl) sulfonyl) -3-oxo-l, 2,3,4-tetrahydro-2-pyrazinyl) acetyl) -4-piperidinyl) benzamide; (3R) -3- (2- (4- ((1-methylethyl) amino) -1-piperidinyl) -2-oxoethyl) -4- ((4-methylphenyl) sulfonyl) -3,4-dihydro-2 ( 1H) -pyrazinone; (3R) -4- ((4-Methylphenyl) sulfonyl) -3- (2-oxo-2- (2RS- (phenylmethyl) -1- pyrrolidinyl) ethyl) -3,4-dihydro-2 (1H) - pir azinone; (3R) -4- ((4-met? Lfen? L) sulfonyl) -3- (2-oxo-2- (2RS-phen? L-1-p? Rrol? D? N? L) ethyl) - 3, 4-d? H? Dro-2 (1 H) -pyrazinone; (3R) -4- ((4-met? Lfen? L) sulfonyl) -3- (2-oxo-2- (4- (phenyloxy) -1-p? Pepd? N? L) ethyl) -3, 4-d? H? Dro-2 (1 H) -pyrazmone; (3R) -4- ((4-met? Lfen? L) sulfonyl) -3- (2-oxo-2- (3-oxo-1-p? Peraz? N? L) ethyl) -3, 4- d? h? dro-2 (1 H) -pyrazinone; (3R) -3- (2- (2-RS- ((met? Lox?) Met? L) -1-p? Rrol? D? N? L) -2-oxoet? L) -4- (( 4-methyl-phenyl) sulfonyl) -3,4-d? -hydro-2 (1H) -pyrazinone; (3R) -3- (2- (2-RS- ((4- (methyloxy) phen?) Met? L) -1-pyrrolidinyl) -2-oxoet? L) -4- ((4-met? lphenyl) sulfonyl) -3,4-d? -hydro-2 (1H) -pyrazinone; (3R) -3- (2- (4- (4-met? Lfen? L) -1-p? Pepd? N? L) -2-oxoethyl) -4- ((4-met? Lphenyl) -sulfonyl) ) -3,4-d? H? Dro-2 (1 H) -pn azinone; 8- (((2R) -1- ((4-met? Lfen? L) sulfonyl) -3-oxo-l, 2, 3,4-tetrahydro-2-p? Raz? N) l) acet ? l) -2,8-d? azaesp? ro [4.5] decan-lona; (3R) -3- (2- (2-RS- (lH-mdol-2-? L) -1-p? Rrol? D? N? L) -2-oxoethyl) -4- ((4-met ? lphene) sulfonyl) -3,4-d? -hydro-2 (1 H) -pn azinone; (3R) -3- (2- (4- ((2-chlorophen? L) ox?) - lp? Pepd? N? L) -2-oxoethyl) -4- ((4-met? Lfen? L) sulfonyl) -3,4-d? h? dro-2 (1H) -puazinone; (3R) -4- ((4-met? Lfen? L) sulfonyl) -3- (2-oxo-2- (2-RS-phen? L-4-t? Omorpholinyl) ethyl) -3, 4- d? h? dro-2 (1 H) -pyrazinone; (3R) -4- ((4-met? Lfen? L) sulfonyl) -3- (2-oxo-2- (2-RS-phen? L-4-morpholinyl) ethyl) -3,4-d? H-dro-2 (1 H) -pyrazinone; (3R) -3- (2- (4- (lH-? Ndol-3? L) -lp? Pepd? N? L-2-oxoethyl) -4- ((4-met? Lfen? L) sulfonyl ) -3,4-d-H? Dro-2 (1H) -pyr azinone; (3R) -3- (2- (2- (2-RS-met? Lfen? L) -1-p? Rrol? d? n? l) -2-oxoethyl) -4- ((4-meth? lfeml) sulfonyl) -3,4-d? h? dro-2 (1H) -pyrazinone; (3R) -4- (( 2, 3-d? Chlorophen? L) sulfonyl) -3- (2- (4-meth? -1,4-d-azepane-1-yl) -2-oxoet? L) -3, 4- d? h? dro-2 (1 H) -pyrazinone; (3R) -4- ((2,3-d? Chlorophen? L) sulfonyl) -3- (2- ((3R) -3- (dimethylamino) -1-p? Rrol? D? N? L) - 2-oxoet? L) -3,4-d? H? Dro-2 (1H) -pyrazmone; or a pharmaceutically acceptable salt thereof.

24. Compound according to claim 1 or 2, characterized in that R2 is hydrogen.

25. Compound according to claim 1 or 2, characterized in that R2 is alkyl.

26. Compound according to claim 1 or 2, characterized in that R2 is haloalkyl, cycloalkyl, cyloalkylalkyl, hydroxyalkyl, alkoxyalkyl, or ama noalkyl.

27. Compound in accordance with any of the claims 1, 2, 24-26, characterized in that R3 is bridged heterocyclyl optionally substituted with one, two or three substituents independently selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl, or alkoxyalkyl.

28. Compound according to any of claims 1, 2, 24-26, characterized in that R3 is cyclopentyl or cyclohexyl substituted with R4, R5, and R6 independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, amino-substituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl, heteroaryl, or heterocyclyl ring on R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano and R7 and R8 are hydrogen.

29. Compound according to claim 1, 2, 24-26, characterized in that R1 is hydrogen and R3 is a group of the formula: where n is 0, 1, 2 or 3 and Z is -NH- and R4, R5, and R6 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, halo, haloalkyl, haloalkoxy, acyl, alkoxycarbonyl, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyl , hydroxyalkyloxy, aminoalkylaminoalkoxy, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl or heterocyclylalkyloxy wherein the aryl ring, heteroaryl , or heterocyclyl in R4, R5, and R6 is optionally substituted with Rd, Re, and Rf independently selected from alkyl, halo, alkoxy, haloalkyl, hydroxyl, carboxy, alkoxycarbonyl, haloalkoxy, or cyano; and R7 and R8 are hydrogen.

30. Compound in accordance with the claim 29, characterized in that R3 is a group of formula: wherein R 4 and R 5 are independently alkyl.

31. Compound in accordance with the claim 30, characterized in that R6 is hydrogen, alkyl, haloalkyl, alkoxycarbonyl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, acyl, aminoalkyl, or alkoxyalkyl.

32. Compound in accordance with the claim 1, 2, 24-26, characterized in that R3 is a group of formula (a) wherein Z is -O- and R4, R5, and R6 are as defined above and R7 and R8 are hydrogen.

33. Compound according to any of claims 1, 2, 24-26, characterized in that R3 is a group of formula (a) wherein R4 and R7 are combined together with the carbon atom to which they are attached to form a cycloalkyl of (C -Cs) saturated or unsaturated monocyclic optionally substituted with Rd, Re, and Rf as defined above.

34. Compound according to any of claims 1, 2, 24-26, characterized in that R is a group of formula (a) wherein R4 and R7 are combined together with the carbon atom to which they are bound to form a heterocyclyl ring monocyclic saturated or unsaturated containing three to six ring atoms wherein one or two ring atoms are selected from -C (O) -, -O-, -S-, -SO-, -S02-, or -NH and wherein the heterocyclic ring is substituted with Rm, Rn and R ° as defined above.

35. Compound in accordance with any of the 2OÍ claims 1, 2, 24-26, characterized in that R2 and R3 together with the nitrogen atom to which they are attached form monocyclic heterocyclyl substituted with R9, Rh and R1 as defined above.

36. Compound according to any of claims 1, 2, 24-26, characterized in that R2 and R3 together with the nitrogen atom to which they are attached form heterocycloamino spiro each of which is substituted with R9, Rh and R1 as It was defined earlier.

37. Compound according to any of claims 24-36, characterized in that R is hydrogen and R1 is phenyl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or halo.

38. Compound according to any of claims 24-36, characterized in that R is hydroquinone and R1 is heteroaryl substituted with Ra, Rb, or Rc independently selected from hydrogen, alkyl, or ha Lo.

39. Compound according to claim 30, characterized in that R and R2 are hydrogen, R1 is 4-merylphenyl, 2,3-dichlorophenyl, 3-dichlorophenyl, and 2,5-dimethyl-4-chlorophenyl, and R3 is 3, 3-dimethylpiperidin-4-yl, 1-metail-3, 3-dimethylpiperidin-4-yl, 1- (isobutyl) -3,3-dimethylpiperidin-4-yl, 1- (pyridin-2-ylmethyl) -3, 3-di eti lpiperidin-4-yl, 1- (2-propyl) -3,3-dimethylpiperidin-4- ilo, 1- (pyridin-4-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (acetyl) -3,3-dimethylpiperidin-4-yl, 1- (tert-bu-cycloxycarbonyl) -3, 3-dimethyl-piperidin-4-yl, 1-cyclopropyl-3, 3-dimethylpiperidin-4-yl, 1- (pyridin-3-ylmethyl) -3,3-dimethylpiperidin-4-yl, 1- (2-methoxyethyl) ) -3,3-dirnethylpiperidin-4-yl, 3, 3-dimethyl-1- (2,2,2-trifluoroethyl) piperidin-4-yl, 1- (tert-butyloxycarbonyl) piperidin-3-yl, l-ethyl-3, 3-dimethylpiperidin-4-yl, l-propyl-3, 3-dimethylpiperidin-4-yl, 1-2, 2-dimethylpropyl-3, 3-dimethylpiperidin-4-yl, l-cyclobutyl- 3, 3-dimethylpiperidin-4-yl, or l-cyclopentyl-3, 3-dimethylpiperidin-4-yl wherein the stereochemistry at the carbon atom at the 4-position of the piperidin-4-yl ring is (R), ( S), or (RS).

40. Pharmaceutical composition, characterized in that it comprises a compound according to any of claims 24-29 and a pharmaceutically acceptable excipient.

41. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of a disease in a patient which is mediated by the receptor Bl.

42. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of pain in a patient.

43. Pharmaceutical composition, characterized because comprises a compound according to any of claims 1-23 and a pharmaceutically acceptable excipient.

44. Method for treating a disease in a patient mediated by receptor Bl, characterized in that it comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1-23 and a pharmaceutically acceptable excipient.