# Patent

## Title
Cyclic vinylogous amides as bromodomain inhibitors

## Abstract

Cyclic vinylogous amides of Formula I are disclosed




The compounds are useful for treating diseases that arise from inappropriate activity of proteins containing an acetyl-lysine. The compositions comprise a genus of cyclic vinylogous amides that are inhibitors of bromodomain.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national phase filing under 35 U.S.C. § 371 of PCT International Application PCT/US2014/053527, filed Aug. 29, 2014, and published under PCT Article 21(2) in English as WO 2015/031824 A1 on Mar. 5, 2015. This application claims priority from U.S. provisional application 61/872,303, filed Aug. 30, 2013. The entire disclosures of these applications are hereby incorporated herein by reference.


GOVERNMENT RIGHTS STATEMENT
This invention was made with U.S. Government support under R01HG004508, R01CA87658 and R33DA029963 awarded by National Institutes of Health. The U.S. Government has certain rights in the invention.


BACKGROUND OF THE INVENTION
Technical Field
The present application relates generally to compositions for treating diseases that arise from inappropriate activity of proteins containing an acetyl-lysine. The compositions comprise a genus of cyclic vinylogous amides that are inhibitors of bromodomain.
Background Information
BRD4 is a member of the bromodomains and extra terminal domain (BET) family of proteins that recognize acetylated chromatin structures through their bromodomains and act as transcriptional activators. Brd4 functions as an associated factor and positive regulator of P-TEFb, a Cdk9-cyclin T heterodimer that stimulates transcriptional elongation by RNA polymerase II. Bromodomain-containing protein 4 (BRD4) contains two tandem bromodomains (BrD1 and BrD2) that bind preferentially to acetylated lysine residues found in histones and nonhistone proteins. This molecular recognition allows Brd4 to associate with acetylated chromatin throughout the cell cycle and regulates transcription at targeted loci.
Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. In a recent current study, Herrmann et al. [Oncotarget. 2012 December; 3 (12):1588-99] showed that inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all donors. BRD4-inhibition is therefore recognized as promising new therapeutic approach in AML.
NF-κB-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-κB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In a study published in the Journal of Biological Chemistry, Zhang et al. [J Biol Chem. 2012 Nov. 9; 287(46):38956] showed that a Bromodomain and Extra-Terminal domain-specific bromodomain inhibitor MS417 effectively ameliorated inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIV-associated nephropathy.
Thus, there is a need for inhibitors of BRD4 as therapeutic agents for leukemia and HIV-associated nephropathy.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to compounds of formula I




wherein:

    U is (CH2)n, where n=1, 2 or 3;
    R1 is selected from the group consisting of: (C1-C10)alkyl, substituted (C1-C10)alkyl, and nitrile;
    Cy is a carbocycle or heterocycle;
    R11 and R12 are independently selected from the group consisting of: H, (C1-C10)alkyl, (C1-C10)perfluoroalkyl, halogen, nitrile, hydroxy, (C1-C10)alkoxy, perfluoro(C1-C10)alkoxy, (C1-C10)alkylthio, amino, (C1-C10)alkylamino, (C1-C10)acylamino, aryl, heteroaryl, aminocarbonyl, carboxyl, and (C1-C10)alkoxycarbonyl; or


taken together, R11 and R12 may form a 5, 6, or 7-membered carbocycle or heterocycle wherein said carbocycle or heterocycle may be optionally substituted with R2;

    R2 is selected from the group consisting of: halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo(C1-C4)alkoxy, carboxy, amino, (C1-C4)alkylamino and di(C1-C4)alkylamino;
    Y is selected from H,






    L and L′ are independently a bond or (CR3R4)m where R3 and R4 are independently selected from the group consisting of H and (C1-C4)alkyl, and m is 1 or 2;
    R10 is chosen from alkyl, carbocycle and heterocycle, wherein said alkyl, carbocycle or heterocycle is optionally substituted with R7 and/or R8;
    R20 is —C(═O)OR21;
    R21 is chosen from H and (C1-C4)alkyl;
    R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, (C1-C10)hydrocarbyl, halo(C1-C10)hydrocarbyl, and (C1-C10)alkoxy;
    R7 and R8 are independently selected from the group consisting of: hydroxy, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylcarbonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, oxo, (C1-C4)alkylsulfonyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C4)acylamino, aminocarbonyl, carboxyl, and (C1-C4)alkoxycarbonyl, where each said alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, may be further optionally substituted with hydroxy, oxo, carboxy, carboxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycarbonyl(C1-C4)alkyl, amino, (C1-C4)alkylamino, di (C1-C4)alkylamino, amido, (C1-C4)alkylamido, di (C1-C4)alkylamido, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
    or, taken together, R5 and R6, or R7 and R8 may form a 5, 6, or 7-membered carbocycle or heterocycle, wherein said carbocycle or heterocycle is optionally substituted with R9;
    R9 is selected from the group consisting of: halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo(C1-C4)alkoxy, amino, (C1-C4)alkylamino and di(C1-C4)alkylamino.


In a second aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound described herein.
In a third aspect, the invention relates to method for treating a disease or disorder arising from inappropriate activity of proteins containing an acetyl-lysine residue. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein.
In a fourth aspect, the invention relates to a method for inhibiting bromodomain in a cell. The method comprises contacting the cell with an inhibitory amount of a compound described herein.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of body weight as percent change from baseline vs time (in weeks) for treated and untreated mice in which inflammatory colitis has been induced.
FIG. 2 is a gray-scale rendering of a photograph showing the gross morphology of the intestines for treated and untreated mice in which inflammatory colitis has been induced compared to a normal (control) intestine.



DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the invention relates to compounds having general formula I:




In some embodiments, Cy is aliphatic, for example cyclohexyl, or heteroaliphatic; in others it is aryl, for example phenyl or naphthyl, or heteroaryl, for example pyridinyl. When Cy is naphthyl, Y is often hydrogen. When Cy is phenyl, the compounds have the general formula:




In some embodiments, U is —CH2CH2—, and the vinylogous amide is an N-substituted 3-aminocyclohex-2-enone. In other embodiments, U is —CH2—, and the vinylogous amide is an N-substituted 3-aminocyclopent-2-enone. In both series, the cycloalkenone is substituted at the 2-position with a substituent R1. In some embodiments, R1 is nitrile. In other embodiments, R1 is substituted or unsubstituted (C1-C10)alkyl. In some embodiments, R1 is preferably (C1-C6)alkyl, most commonly methyl.
In some embodiments, R11 and R12 are independently selected from the group consisting of H, (C1-C10)alkyl, (C1-C10)perfluoroalkyl, halogen, nitrile, hydroxy, (C1-C10)alkoxy, perfluoro(C1-C10)alkoxy, (C1-C10)alkylthio, amino, (C1-C10)alkylamino, (C1-C10)acylamino, aryl, heteroaryl, aminocarbonyl, carboxyl, and (C1-C10)alkoxycarbonyl. In some embodiments, at least one of R11 and R12 is hydrogen. In some embodiments, taken together, R11 and R12 may form a 5, 6, or 7-membered carbocycle or heterocycle. In these embodiments, the carbocycle or heterocycle may be optionally substituted with R2. In some embodiments, R2 is selected from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo(C1-C4)alkoxy, carboxy, amino, (C1-C4)alkylamino or di(C1-C4)alkylamino.
In some embodiments, Y is a sulfonamide, such as




In some embodiments Y is a urea, such as





In some embodiments Y is a carboxamide, such as





In such compounds, L may be a direct bond, L′ may be a direct bond or both L and L′ may be direct bonds. In one embodiment, Y is





and both L and L′ are direct bonds, i.e. Y is





In some embodiments, Y is





In these compounds, the wavy line indicates that a particular stereochemical configuration is not designated; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. In some embodiments, R20 is —C(═O)OR21. In some of these embodiments, R21 is hydrogen. In some of these embodiments, R21 is (C1-C4)alkyl, particularly methyl. In some embodiments, Y is





In some of these embodiments, R21 is (C1-C4)alkyl. In other embodiments, R21 is hydrogen. In some embodiments, L is a direct bond and R21 is hydrogen. In some embodiments, Y is





In these compounds the dotted line represents an optional double bond, which encompasses compounds in which Y is -L-CH2CH2—R10 and -L-CH═CH—R10. In other embodiments, Y may be a 5-membered heterocycle, particularly an aromatic 5-membered heterocycle, substituted with L-R10. The 5-membered heterocycle will usually contain more than one heteroatom in the ring, and 1,2,3-triazoles are preferred. When Y is a substituted 5-membered heterocycle, L may be -(CR3R4)m, particularly —CH2—.

In many embodiments in which Y is a sulfonamide, a urea, a carboxamide or a 5-membered heterocycle, R10 may be cyclohexyl, cyclopentyl, phenyl, naphthyl, thiophenyl, pyrrolyl, pyridinyl, or pyrimidinyl, each optionally substituted with R7 and/or R8. Cyclohexyl, phenyl and naphthyl are preferred. When R10 is phenyl, in some embodiments it may be only singly substituted with R7, and, in those embodiments, the structure may be represented:




In these compounds, R7 may be halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy or aminocarbonyl. Fluoro, chloro, methyl and methoxy are preferred. In some embodiments, R10 is phenyl substituted with both R7 and R8. In these embodiments, R7 and R8 may each independently be halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy or aminocarbonyl. In some embodiments, R8 is fluoro.

In a second aspect, the invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound described herein.
In a third aspect, the invention relates to method for treating a disease or disorder arising from inappropriate activity of proteins containing an acetyl-lysine residue. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein. In some embodiments, the disease or disorder is chronic inflammation. In some embodiments, the disease or disorder is autoimmune disease. In some embodiments, the disease or disorder is cancer. In some embodiments, an additional therapeutic agent may be administered.
In a fourth aspect, the invention relates to a method for inhibiting bromodomain in a cell. The method comprises contacting the cell with an inhibitory amount of a compound described herein.
For convenience and clarity certain terms employed in the specification, examples and claims are described herein.
C1 to C20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, adamantyl, camphoryl and naphthylethyl. Hydrocarbyl refers to any substituent comprised of hydrogen and carbon as the only elemental constituents. Aliphatic hydrocarbons are hydrocarbons that are not aromatic; they may be saturated or unsaturated, cyclic, linear or branched. Examples of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl, cyclopentyl, norbornyl, etc. Aromatic hydrocarbons include benzene (phenyl), naphthalene (naphthyl), anthracene, etc.
Unless otherwise specified, alkyl (or alkylene) is intended to include linear or branched saturated hydrocarbon structures and combinations thereof. Alkyl refers to alkyl groups from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
Cycloalkyl is a subset of hydrocarbon and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the like.
Unless otherwise specified, the term “carbocycle” is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. Thus (C3-C10) carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene and cyclohexene; (C8-C12) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, if not otherwise limited, refers to monocycles, bicycles and polycycles.
Heterocycle means an aliphatic or aromatic carbocycle residue in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O, and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Unless otherwise specified, a heterocycle may be non-aromatic (heteroaliphatic) or aromatic (heteroaryl). Examples of heterocycles include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like. Examples of heterocyclyl residues include piperazinyl, piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl (also historically called thiophenyl), benzothienyl, thiamorpholinyl, oxadiazolyl, triazolyl and tetrahydroquinolinyl.
Alkoxy or alkoxyl refers to groups of from 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms of a straight or branched configuration attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy.
The term “halogen” means fluorine, chlorine, bromine or iodine atoms. In one embodiment, halogen may be a fluorine or chlorine atom.
Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 2002 edition, ¶196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples of azaalkyl include ethylaminoethyl and aminohexyl.
As used herein, the term “optionally substituted” may be used interchangeably with “unsubstituted or substituted”. The term “substituted” refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein one or more H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, lower alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl [—C(═O)O-alkyl], alkoxycarbonylamino [HNC(═O)O-alkyl], aminocarbonyl (also known as carboxamido) [—C(═O)NH2], alkylaminocarbonyl [—C(═O)NH-alkyl], cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, alkylthio, sulfoxide, sulfone, sulfonylamino, alkylsulfinyl, alkyl sulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, benzyloxyphenyl, and benzyloxy. “Oxo” is also included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). In one embodiment, 1, 2, or 3 hydrogen atoms are replaced with a specified radical. In the case of alkyl and cycloalkyl, more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine. In preferred embodiments, substituents are halogen, haloalkyl, alkyl, acyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyl oxaalkyl, carboxy, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkyl sulfonyl, alkylsulfonylamino aryl sulfonyl, arylsulfonylamino, and benzyloxy. Most preferred are halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and aminocarbonyl.
Substituents Rn are generally defined when introduced in a claim and retain that definition throughout the all the claims. Certain Rn in the detailed description have definitions that are associated only with a particular set of exemplary syntheses; the Rn in the exemplary syntheses do not necessarily correlate with the Rn in the claims or summary of the invention.
As used herein, and as would be understood by the person of skill in the art, the recitation of “a compound”—unless expressly further limited—is intended to include salts of that compound. Thus, for example, the recitation “a compound of formula I” as depicted above, which incorporates a substituent COOH, would include salts in which the substituent is COO−M+, wherein M is any counterion. Examples 02-01 to 02-07 below are examples of such carboxylic acids that can undergo salt formation. Similarly, a compound of formula I as depicted above may include a substituent NH2, such as in Example 05-25 below, and therefore would also include salts in which the substituent is NH3+X−, wherein X is any counterion. In a particular embodiment, the term “compound of formula I” refers to the compound or a pharmaceutically acceptable salt thereof.
The term “pharmaceutically acceptable salt” refers to salts whose counter ion derives from pharmaceutically acceptable non-toxic acids and bases. Suitable pharmaceutically acceptable acids for salts of the amino-substituted compounds of the present invention include, for example, acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p-toluenesulfonic, and the like. Suitable pharmaceutically acceptable base addition salts for the carboxylate-substituted compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Alternatively, a plurality of molecules of a single structure may include at least one atom that occurs in an isotopic ratio that is different from the isotopic ratio found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, chlorine and iodine include 2H, 3H, 11C, 13C, 14C, 15N, 35S, 18F, 36Cl, 125I, 124I, and 131I respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3H, and carbon-14, i.e., 14C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes 11C, 13N, 15O, 124I and 18F are well suited for positron emission tomography. Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
Although this invention is susceptible to embodiment in many different forms, preferred embodiments of the invention are shown. It should be understood, however, that the present disclosure is to be considered as an exemplification of the principles of this invention and is not intended to limit the invention to the embodiments illustrated. It may be found upon examination that certain members of the claimed genus are not patentable to the inventors in this application. In this event, subsequent exclusions of species from the compass of applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention; the invention encompasses all of the members of the genus I that are not already in the possession of the public.
While it may be possible for the compounds of formula I to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compositions may be formulated for oral, topical, or parenteral administration. For example, they may be given intravenously, intraarterially, subcutaneously, and directly into the CNS either intrathecally or intracerebroventricularly.
Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), rectal and topical (including dermal, buccal, sublingual, and intraocular) administration. The compounds are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining a therapeutic benefit in the form of eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological systems associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. The compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological systems of a disease, even though a diagnosis of this disease may not have been made.
Terminology related to “protecting”, “deprotecting” and “protected” functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group, which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes described herein, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups”. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.
A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations”, is incorporated herein by reference.
In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here. The starting materials are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used. Those skilled in the art will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described.
The reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
The description of this invention utilizes conventional American Chemical Society abbreviations well known to those skilled in the art, in addition to the following:

    AcCl: acetyl chloride
    Ac2O: acetic anhydride
    AcOH: acetic acid
    Alk: alkyl
    BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
    cat: catalytic
    CH2Cl2: dichloromethane; methylenechloride
    CHCl3: chloroform
    Δ: heat
    DI H2O: deionized water
    DMA: dimethylacetamide
    DMF-DMA: 1,1-dimethyoxy-N,N-dimethylmethanamine
    DMF: N,N-dimethylformamide
    EDCCl: 3-(ethyliminomethylene-amino)-N,N-dimethyl-propan-1-amine hydrochloride
    eq: equivalence
    ESS: eluting solvent system
    EtOAc: ethyl acetate
    EtOH: ethanol
    H+: acid
    HCl: hydrochloric acid
    HCO2H: formic acid
    IBCF: isobutylchloroformate
    LCMS: liquid chromatography mass spectra
    MeOH: methanol
    NaOH: sodium hydroxide
    NMM: N-methylmorpholine
    PG: protecting group
    PS-CDI: polystyrene carbodiimidazole
    pTSA: para-toluensulfonic acid
    rt: room temperature
    sat: saturated
    TEA: triethylamine
    TFA: trifluoroacetic acid
    THF: tetrahydrofuran
    TMS: tetramethylsilane


1H Nuclear Magnetic Resonance (NMR) spectra were in all cases consistent with the proposed structures. 13CNMR spectra were in relevant cases consistent with the proposed structures. NMR were acquired on a Bruker® DRX-600 spectrometer at 600 MHz for 1H and 125 MHz for 13C. Characteristic chemical shifts (δ) are expressed in parts per million downfield from tetramethylsilane (TMS) using conventional abbreviations for designation of major peaks: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl3, deuterochloroform; D6-DMSO, deuterodimethyl-sulfoxide; MeOD, deuteromethanol.
Mass Spectra were in all cases consistent with the proposed structures. Liquid chromatography mass spectra, LCMS, with retention time, t, in minutes, min, and with mass to charge ratio, m/z, were recorded using peak elution time and electrospray ionization, ESI. LCMS analysis was performed on an Agilent® 1200 HPLC equipped with a Zorbax® 300SB-C18 column held at 45° C., and a G1969A API-TOF in positive mode. Purity of all Examples was estimated at >95% by the DAD trace using the following LC method: solvent system (A)/(B) with 0.1% buffer=H2O/acetonitrile with formic acid, flow rate=0.4 mL/min, and timed percentage of solvent B=0-1 min (1%), gradient 1-4 min (1-99%), 4-8 min (99%). Theoretical mass to charge ratios were calculated, Calcd, using ChemDraw® software. In relevant cases identifiable, radical cation of mass plus hydrogen, [M+H]+; mass plus sodium, [M+Na]+; two masses plus hydrogen, [2M+H]+; and two masses plus sodium, [2M+Na]+ data were recorded. In relevant Examples containing bromine atoms, the two stable isotopes 79Br and 81Br, for [M+H]+ and [M+Na]+ were recorded.
Melting points (mp) were determined on an automated Standford Research System OptiMelt MPA100 heating at a rate of 10° C./min.
Synthetic Procedures
In the tabulated experimental details that follow, the Examples and Intermediates were prepared according to the corresponding reference method (i.e. Example 01-01, Intermediate 03, and so on). The skilled person will appreciate that, in the synthesis of any specific Example or Intermediate, it may be necessary to make minor variations to the reaction conditions and purification procedures of the reference method (e.g. with regard to ratios, time, and so on).
Reagents used in the preparation of the compounds of this invention can be either obtained commercially or prepared by standard literature procedures. Unless otherwise stated, all reagents and solvents were obtained from commercial suppliers and used without further purification.
Certain compounds of the Examples and Preparations were continuously irradiated at 2.45 gigahertz, GHz in a sealed microwave vial contained in a single mode Biotage®-Initiator cavity.
Certain compounds of the Examples and Preparations were purified using automated chromatography. Isocratic, or stepwise gradient mobile phases were used on normal-phase KP-SilTM silica-gel columns attached to a Biotage®-Isolera Four instrument, monitoring UV Trace at 254 nm and 365 nm. Solvent systems utilized one, two, or three solvents (acetone, hexanes, EtOAc, or MeOH) running from non-polar to polar steps. Eluting Solvent System (ESS) is the solvent step which eluted the product and is indicated below in the following format ESS=H:E (X:X), or the percentage of MeOH (%) in EtOAc. Additional monitoring by analytical thin layer chromatography (TLC) was performed employing EMD Chemicals Inc. TLC Silica gel 60 F254 on aluminium, visualized either by exposure to UV light or, staining agents such as: iodine impregnated silica gel; 10% phosphomolybdic acid in EtOH and so on.
Schemes 1-4 present general synthetic approaches. The details of each example are described in the Examples. Compounds may be prepared according to the reactions in Scheme 1. R1 can be present from commercial reagents, added through C-alkylation, or formed through ring opening chemistry. R2 can be hydrogen, present from commercial reagents, or prepared as in Scheme 2, have appended acid, ester, nitro, or protected amine functionalities. R8 can be from reagents bearing a halogen.




Appended acid, or ester, compounds can undergo reactions in Scheme 2. Compounds can be protected commercial reagents, or from Scheme 1. R3 can be added with an appended ester functionality and undergo a second iteration of base hydrolysis and amide bond formation.




Amine compounds, deprotected or reduced from nitro, can undergo reactions in Scheme 3. R5 can be from carboxylic acids, acid halides, anhydrides, cyclic anhydrides, or activated acids. R6 can be from sulfonic acids, or sulfonyl chlorides. R7 can be from aldehydes. R8 can be from reagents bearing a halogen.




Alkynes can undergo reactions in Scheme 4. R9 can be from azides or amines.




Specific Examples follow:





INTERMEDIATE 01
Preparation of 2-Benzylcyclopentane-1,3-dione (INTERMEDIATE 01)
1,3-Cyclopentandione (0.98 g, 10.0 mmol, 1.0 eq, Synth. Comm. 1993, 23(22), p. 3095-3108) was treated with 40% aq Triton B (3.95 mL<1.0 eq) in DI H2O (5.0 mL) followed by benzyl bromide (1.4 mL, 1.2 eq). The reaction mixture was stirred at rt for 24 h. The crude was extracted with EtOAc and dried over anhyd sodium sulfate. The reaction on a 10.0 mmol scale yielded 0.9 g of the title intermediate after recrystallization from EtOAc (48% yield). 1H NMR (D6-DMSO) δ 2.39 (br s, 4H), 3.36 (br s, 2H), 7.10-7.17 (m, 3H), 7.20-7.25 (m, 2H), 11.71 (br s, 1H). LCMS t=4.3 min, m/z Calcd for C12H13O2; C12H12NaO2; C24H25O4; C24H24NaO4 189.09; 211.07; 377.16; 399.16 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 189.18; 211.14; 377.16; 399.13.




INTERMEDIATE 02
Preparation of 2-(4-Hydroxybenzyl)cyclopentane-1,3-dione (INTERMEDIATE 02)
1,3-Cyclopentandione (491 mg, 5.0 mmol, 1.0 eq, J. Org. Chem. 1988, 53, p. 891-893) was treated with AcOH (315 mL, 1.1 eq) followed by p-hydroxybenzyl alcohol (683 mg, 1.1 eq). Microwave irradiation was applied to a sealed microwave vial for 10 min in a single mode Biotage®-Initiator cavity, producing continuous irradiation to hold 120° C. at 2.45 GHz. The crude material was added directly to a KP-SilTM column (10 g) in a small amount of CH2Cl2 with products separating from impurities using stepwise gradients on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The reaction on a 5.0 mmol scale yielded 0.55 g of the title intermediate after chromatography (ESS=H:E (1:3), 54% yield). 1H NMR (D6-DMSO) δ 2.37 (br s, 4H), 3.36 (br s, 2H), 6.60 (d, J=8.1 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 9.06 (br s, 1H), 11.62 (br s, 1H). LCMS t=3.9 min, m/z Calcd for C12H13O3; C12H12NaO3; C24H25O6; C24H24NaO6 205.09; 227.07; 409.17; 431.15 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 205.16; 227.13; 409.14; 431.12.


















INTERME-
TITLED





DIATE #
INTERMEDIATE NAME
R1
R2
R3







03
2-Chloro-4-(o-tolylcarba-
Cl
CH3
H



moyl)benzenaminium Chloride


04
2-Fluoro-4-((4-methoxy-
F
H
OCH3



phenyl)carbamoyl)benzenaminium



Chloride


05
2-Bromo-4-((4-methoxy-
Br
H
OCH3



phenyl)carbamoyl)benzenaminium



Chloride









INTERMEDIATE 03
Preparation of 2-Chloro-4-(o-tolylcarbamoyl)benzenaminium Chloride (INTERMEDIATE 03)
Step 1, N-Formylation: A mixture of formic acid (18.1 mL, 40 eq, Chem. Pharm. Bull. 2002, 50(7), p. 941-959) and acetic anhydride (11.3 mL, 10 eq) were heated to 50° C. for 1 h. After addition of 4-amino-3-chlorobenzoic acid (2.1 g, 12.0 mmol, 1.0 eq), the whole was heated to 65° C. for 2 h and cooled to rt. The reaction mixture was poured into cold H2O and the precipitates were collected by filtration, washed with H2O, and dried on the frit. The reaction on a 12.0 mmol scale yielded 2.2 g of 3-chloro-4-formamidobenzoic acid, white microcrystals (mp=227-229° C., 92% yield). LCMS t=4.0 min, m/z Calcd for C8H7ClNO3; C8H6ClNNaO3 200.01; 221.99 [M+H]+; [M+Na]+, Found 200.09; 222.06.
Step 2, IBCF Method C: 3-Chloro-4-formamidobenzoic acid and o-toluidine were coupled according to the procedure of Example 04-13; 5.0 mmol scale yielded 1.0 g of 3-chloro-4-formamido-N-(o-tolyl)benzamide from precipitate (69% yield). LCMS t=5.1 min, m/z Calcd for C15H14ClN2O2; C15H13ClN2NaO2; C30H27Cl2N4O4; C30H26Cl2N4NaO4 289.07; 311.06; 577.14; 599.12 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 289.07; 311.05; 577.14; 599.12.
Step 3, N-Deformylation: Acetyl chloride (14 eq, Org. Lett. 2011, 13(12), p. 3028-3031) was added to a CH2Cl2:MeOH (20 mL, 1:1) mixture at 0° C., followed by the 3-chloro-4-formamido-N-(o-tolyl)benzamide (0.87 g, 3.0 mmol, 1.0 eq). After warming to rt, HCl salts were collected by filtration and dried on the frit. The reaction on a 3.0 mmol scale yielded 0.8 g of 2-chloro-4-(o-tolylcarbamoyl)benzenaminium chloride, the title intermediate (90% yield). 1H NMR (D6-DMSO) δ 2.20 (s, 3H), 4.60 (br s, 3H), 6.84 (d, J=8.4 Hz, 1H), 7.14 (t, J=7.3 Hz, 1H), 7.19 (t, J=7.3 Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 9.56 (s, 1H). 13C NMR (D6-DMSO) δ 18.0, 114.2, 122.2, 125.7, 125.9, 126.6, 127.8, 128.9, 130.2, 133.7, 136.7, 147.7, 164.0. LCMS t=5.0 min, m/z Calcd for C14H14ClN2O; C14H13ClN2NaO; C28H26Cl2N4NaO2 261.08; 283.06; 543.13 [M+H]+; [M+Na]+; [2M+Na]+, Found 261.12; 283.09; 543.09.
INTERMEDIATE 04
Preparation of 2-Fluoro-4-((4-methoxyphenyl)carbamoyl)benzenaminium Chloride (INTERMEDIATE 04)
Step 1, N-Formylation: 4-Amino-3-fluorobenzoic acid (5.0 g, 32.3 mmol) was N-formylated according to the procedure of Intermediate 03; the reaction on a 32.3 mmol scale yielded 4.0 g of 3-fluoro-4-formamidobenzoic acid, white microcrystals (mp=238-240° C., 68% yield). LCMS t=3.0 min, m/z Calcd for C8H7FNO3; C8H6FNNaO3; C16H13F2N2O6 184.04; 206.02; 367.07 [M+H]+; [M+Na]+; [2M+H]+, Found 184.04; 202.05; 367.07.
Step 2, IBCF Method C: 3-Fluoro-4-formamidobenzoic acid and p-anisidine were coupled according to the procedure of Example 04-13; 5.0 mmol scale yielded 1.0 g of 3-fluoro-4-formamido-N-(4-methoxyphenyl)benzamide from precipitate (69% yield). LCMS t=4.8 min, m/z Calcd for C15H14FN2O3; C30H27F2N4O6; C30H26F2N4NaO6 289.10; 577.19; 599.17 [M+H]+; [2M+H]+; [2M+Na]+, Found 289.10; 577.19; 599.17.
Step 3, N-Deformylation: The title intermediate was prepared from 3-fluoro-4-formamido-N-(4-methoxyphenyl)benzamide according to the procedure of Intermediate 03; 3.3 mmol scale, with solvent (20 mL), yielded 0.9 g of 2-fluoro-4-((4-methoxyphenyl)carbamoyl)-benzenaminium chloride (92% yield). LCMS t=4.6 min, m/z Calcd for C14H14FN2O2; C14H13FN2NaO2; C28H27F2N4O4; C28H26F2N4NaO4 261.10; 283.09; 521.20; 543.18 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 261.10; 283.07; 521.19; 543.17.
INTERMEDIATE 05
Preparation of 2-Bromo-4-((4-methoxyphenyl)carbamoyl)benzenaminium Chloride (INTERMEDIATE 05)
Step 1, N-Formylation: 4-Amino-3-bromobenzoic acid (5.0 g, 23.1 mmol) was N-formylated according to the procedure of Intermediate 03; the reaction on a 23.1 mmol scale yielded 3.0 g of 3-bromo-4-formamidobenzoic acid, white microcrystals (mp=232-234° C., 79% yield). LCMS t=4.1 min, m/z Calcd for C8H7BrNO3; C16H13Br2N2O6; C16H12Br2N2NaO6 243.96, 245.96; 488.91; 510.89 [M+H]+; [2M+H]+; [2M+Na]+, Found 243.96, 245.96; 488.91; 510.90.
Step 2, IBCF Method C: 3-Bromo-4-formamidobenzoic acid and p-anisidine were coupled according to the procedure of Example 04-13; 5.0 mmol scale (exothermic) yielded 0.27 g of 3-bromo-4-formamido-N-(4-methoxyphenyl)benzamide from precipitate (15% yield). LCMS t=5.0 min, m/z Calcd for C15H14BrN2O3; C15H13BrN2NaO3; C30H27Br2N4O6; C30H26Br2N4NaO6 349.02, 351.02; 371.00, 372.10; 699.03; 721.01 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 349.01, 351.01; 370.99, 372.99; 699.01; 720.99.
Step 3, N-Deformylation: The title intermediate was prepared from 3-bromo-4-formamido-N-(4-methoxyphenyl)benzamide according to the procedure of Intermediate 03; 0.75 mmol scale, with solvent (10 mL), yielded 0.16 g of 2-bromo-4-((4-methoxyphenyl)carbamoyl)-benzenaminium chloride (66% yield). LCMS t=4.9 min, m/z Calcd for C14H14BrN2O2; C14H13BrN2NaO2; C28H27Br2N4O4; C28H26Br2N4NaO4 321.02, 323.02; 343.01, 345.00; 643.04; 665.02 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.04, 323.04; 343.02, 345.02; 643.07; 665.05.




INTERMEDIATE 06
Preparation of 2,6-Dioxocyclohexanecarbonitrile (INTERMEDIATE 06)
Step 1: 1,3-Cyclohexandione (2.24 g, 20.0 mmol, J. Med. Chem. 2011, 54, p. 5070-5081) and 1,1-dimethyoxy-N,N-dimethylmethanamine (DMF-DMA, 26.5 mL, 200 mmol, 10 eq) were mixed and heated under reflux for 3 h. The solvent was removed on the rotovap to provide the product in suitable purity for the next step. The reaction on a 20.0 mmol scale yielded 3.25 g of 2-((dimethylamino)methylene)-cyclohexane-1,3-dione (97% yield). 1H NMR (CDCl3) δ 1.85-1.90 (m, 2H), 2.38-2.41 (m, 4H), 3.11 (s, 3H), 3.33 (s, 3H), 7.98 (s, 1H). 13C NMR (CDCl3) δ 19.4, 38.1, 44.5, 48.4, 109.2, 162.1, 196.1. LCMS t=1.4 min, m/z Calcd for C9H14NO2; C9H13NNaO2; C18H27N2O4; C18H26N2NaO4 168.10; 190.08; 335.20; 357.18 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 168.11; 190.09; 335.21; 357.19.
Step 2: 2-((Dimethylamino)-methylene)cyclohexane-1,3-dione (2.675 g, 16.0 mmol, Synthesis 2002, 12, p. 1669-1674) and hydroxylamine hydrochloride (1.15 g, 1.04 eq) were mixed in DI H2O (1.5 mL) and agitated on a vortex shaker for 30 sec. After 5 min, the product was isolated by filtration. The reaction on a 16 mmol scale yielded 1.75 g of 6,7-dihydrobenzoisoxazol-4-one hydrochloride (mp=88-90° C., 63% yield). 1H NMR (CDCl3) δ 1.70-1.90 (m, 2H), 2.20-2.60 (m, 4H), 8.10 (s, 1H), 11.25 (br s, 1H). LCMS t=1.2 min, m/z Calcd for C7H8NO2; C7H7NNaO2; C14H15N2O4; C14H14N2NaO4 138.06; 160.04; 275.10; 297.09 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 138.06; 160.04; 275.12; 297.10.
Step 3: 6,7-Dihydrobenzoisoxazol-4-one hydrochloride (2.88 mmol, J. Het. Chem. 1983, 20, p. 645-648) was added to toluene and heated under reflux, for 48 h. The product was filtered from toluene. The reaction on a 2.88 mmol scale yielded 0.3 g of the title intermediate, 2,6-dioxocyclohexanecarbonitrile (mp=208-210° C., 76% yield). 1H NMR (D6-DMSO) δ 1.85-1.91 (m, 2H), 2.44-2.50 (m, 4H). 13C NMR (D6-DMSO) δ 19.8, 33.0, 91.9, 115.1, 191.7. LCMS t=1.0 min, m/z Calcd for C7H8NO2; C7H7NNaO2; C14H15N2O4; C14H14N2NaO4 138.06; 160.04; 275.10; 297.09 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 138.06; 160.04; 275.11; 297.10.
SYNTHESIS OF EXEMPLARY SPECIES
EXAMPLES 01-01 to 01-39



















Example







01-#
TITLE COMPOUND NAME
R1
R2
R3
R4







01
Methyl 4-((3-oxocyclopent-1-en-1-
H
H
CO2CH3
H



yl)amino)benzoate


02
4-((3-Oxocyclopent-1-en-1-
H
H
CONH2
H



yl)amino)benzoamide


03
3-((2-Methyl-3-oxocyclopent-1-en-
H
CO2H
H
H



1-yl)amino)benzoic acid


04
Methyl 3-((2-methyl-3-
H
CO2CH3
H
H



oxocyclopent-1-en-1-



yl)amino)benzoate


05
3-((2-Methyl-3-oxocyclohex-1-en-
H
CONH2
H
H



1-yl)amino)benzamide


06
4-((2-Methyl-3-oxocyclopent-1-en-
H
H
SO2NH2
H



1-yl)amino)benzenesulfonamide


07
4-((2-Methyl-3-oxocyclopent-1-en-
H
H
CN
H



1-yl)amino)benzonitrile


08
3-((3-Bromophenyl)amino)-2-
H
Br
H
H



methylcyclopent-2-enone


09
3-((4-Acetylphenyl)amino)-2-
H
H
COCH3
H



methylcyclopent-2-enone


10
2-Chloro-4-((2-methyl-3-
H
Cl
CO2H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


11
Methyl 3-chloro-4-((2-methyl-3-
Cl
H
CO2CH3
H



oxocyclopent-1-en-1-



yl)amino)benzoate


12
3-Methoxy-4-((2-methyl-3-
OCH3
H
CO2H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


13
Methyl 2-methoxy-4-((2-methyl-3-
H
OCH3
CO2CH3
H



oxocyclopent-1-en-1-



yl)amino)benzoate


14
3-Methyl-4-((2-methyl-3-
CH3
H
CO2H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


15
2-Methoxy-3-((2-methyl-3-
OCH3
CO2H
H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


16
2-Methyl-4-((2-methyl-3-
H
CH3
CO2H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


17
2,5-Dichloro-4-((2-methyl-3-
Cl
H
CO2H
Cl



oxocyclopent-1-en-1-



yl)amino)benzoic acid


18
2-((2-Methyl-3-oxocyclopent-1-en-
CONH2
H
H
H



1-yl)amino)benzamide


19
Methyl 2-((2-methyl-3-
CO2CH3
H
H
H



oxocyclopent-1-en-1-



yl)amino)benzoate


20
Methyl 5-chloro-2-((2-methyl-3-
CO2CH3
H
Cl
H



oxocyclopent-1-en-1-



yl)amino)benzoate


21
Methyl 3-fluoro-4-((2-methyl-3-
F
H
CO2CH3
H



oxocyclopent-1-en-1-



yl)amino)benzoate


22
Methyl 3-bromo-4-((2-methyl-3-
Br
H
CO2CH3
H



oxocyclopent-1-en-1-



yl)amino)benzoate


23
2-Chloro-6-((2-methyl-3-
CO2H
Cl
H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


24
Methyl 4-chloro-2-((2-methyl-3-
CO2CH3
H
H
Cl



oxocyclopent-1-en-1-



yl)amino)benzoate


25
4-Chloro-3-((2-methyl-3-
Cl
H
H
CO2H



oxocyclopent-1-en-1-



yl)amino)benzoic acid









EXAMPLE 01-01
Preparation of methyl 4-((3-oxocyclopent-1-en-1-yl)amino)benzoate (01-01): 2-methyl-1,3-cyclopentandione (5.0 g, 45.0 mmol) and methyl-4-aminobenzoate (7.5 g, 1.1 eq) were heated to reflux in toluene. Upon reflux the solution was removed from heating, and p-TSA (cat.) was added. The apparatus was equipped with a Dean-Stark condenser and returned to reflux for 18 h, unless more time was required. The solvent was removed on the rotovap and the subsequent crude material was recrystallized to give the title compound as product from the indicated solvent(s). The reaction on a 45.0 mmol scale yielded 10.0 g of gray microcrystals from MeOH/H2O (mp=210-212° C., 91% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.24-2.26 (m, 2H), 2.78-2.80 (m, 2H), 3.81 (s, 3H), 7.32 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 9.18 (s, 1H). 13C NMR (D6-DMSO) δ 8.0, 26.7, 33.4, 52.3, 112.9, 120.8, 123.9, 130.8, 145.2, 166.2, 168.2, 203.0. LCMS t=4.8 min, m/z Calcd for C14H16NO3; C14H15NNaO3; C28H31N2O6; C28H30N2NaO6 246.11; 268.10; 491.22; 513.20 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 246.12; 268.11; 491.24; 513.22.
EXAMPLE 01-02
Preparation of 4-((3-oxocyclopent-1-en-1-yl)amino)benzamide (01-02): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-aminobenzamide according to the procedure of Example 01-01; 25.0 mmol scale yielded 5.0 g of yellow microcrystals from H2O (mp=192-195° C., 87% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.76 (s, 2H), 7.28 (d, J=7.8 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.90 (s, 1H), 9.11 (s, 1H). LCMS t=2.8 min, m/z Calcd for C13H15N2O2; C13H14N2NaO2; C26H28N4NaO4 231.11; 253.10; 483.20 [M+H]+; [M+Na]+; [2M+Na]+, Found 231.12; 253.11; 483.22.
EXAMPLE 01-03
Preparation of 3((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-03): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-aminobenzoic acid according to the procedure of Example 01-01; 30.0 mmol scale refluxed for 48 h yielded 5.0 g of white microcrystals from toluene (mp=236-238° C., 72% yield). 1H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.23 (s, 2H), 2.70 (s, 2H), 7.46-7.50 (m, 2H), 7.66-7.67 (m, 1H), 7.78 (s, 1H), 9.11 (s, 1H), 13.11 (s, 1H). LCMS t=4.4 min, m/z Calcd for C13H14NO3; C13H13NNaO3; C26H27N2O6; C26H26N2NaO6 232.10; 254.08; 463.19; 485.17 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 232.11; 254.09; 463.21; 485.19.
EXAMPLE 01-04
Preparation of methyl 3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-04): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 3-benzoate according to the procedure of Example 01-01; 30.0 mmol scale yielded 7.0 g of white microcrystals from EtOAc (mp=133-135° C., 95% yield). 1H NMR (D6-DMSO) δ 1.57 (s, 3H), 2.22-2.24 (m, 2H), 2.70 (s, 2H), 3.86 (s, 3H), 7.49-7.54 (m, 3H), 7.67 (d, J=7.5 Hz, 1H), 7.80 (s, 1H), 9.13 (s, 1H). LCMS t=5.0, m/z Calcd for C14H16NO3; C28H31N2O6; C28H30N2NaO6 246.11; 491.22; 513.20 [M+H]+; [2M+H]+; [2M+Na]+, Found 246.13; 491.24; 513.22.
EXAMPLE 01-05
Preparation of 3((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (01-05): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-aminobenzamide according to the procedure of Example 01-01; 30.0 mmol scale yielded 5.0 g of grey microcrystals from MeOH (mp=269-271° C., 72% yield). 1H NMR (D6-DMSO) δ 1.57 (s, 3H), 2.21-2.23 (m, 2H), 2.67 (s, 2H), 7.37-7.42 (m, 3H), 7.63 (d, J=7.5 Hz, 2H), 7.71 (s, 1H), 8.00 (s, 1H), 9.08 (s, 1H). LCMS t=3.1 min, m/z Calcd for C13H15N2O2; C13H14N2NaO2; C26H29N4O4; C26H28N4NaO4 231.11; 253.10; 461.22; 483.20 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 231.12; 253.11; 461.24; 483.22.
EXAMPLE 01-06
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzenesulfonamide (01-06): The title compound was prepared from 2-methyl-1,3-cyclopentandione and sulfanilamide according to the procedure of Example 01-01; 30.0 mmol scale yielded 7.0 g of yellow microcrystals from THF/H2O (mp=245-247° C., 88% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.25-2.26 (m, 2H), 2.78 (s, 2H), 7.29 (s, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 9.22 (s, 1H). LCMS t=2.9 min, m/z Calcd for C12H15N2O3S; C24H28N4NaO6S2 267.08; 555.13 [M+H]+; [2M+Na]+, Found 267.09; 555.16.
EXAMPLE 01-07
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzonitrile (01-07): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-aminobenzonitrile according to the procedure of Example 01-01; 30.0 mmol scale yielded 4.0 g of yellow microcrystals from H2O (mp=204-206° C., 63% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.27 (m, 2H), 2.82 (s, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 9.27 (s, 1H). LCMS t=5.3 min, m/z Calcd for C13H13N2O; C13H12N2NaO; C26H24N4NaO2 213.10; 235.08; 447.18 [M+H]+; [M+Na]+; [2M+Na]+, Found 213.17; 235.14; 447.15.
EXAMPLE 01-08
Preparation of 3-((3-bromophenyl)amino)-2-methylcyclopent-2-enone (01-08): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-bromoaniline according to the procedure of Example 01-01; 50.0 mmol scale yielded 6.1 g of brown microcyrstals from EtOAc (mp=291-294° C., 46% yield). 1H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.22 (s, 2H), 2.69 (s, 2H), 7.25-7.31 (m, 3H), 7.45 (s, 1H), 9.04 (s, 1H). LCMS t=5.8 min, m/z Calcd for C12H13BrNO; C12H12BrNNaO; C24H24Br2N2NaO2 266.02, 268.02; 288.00, 290.00; 555.01 [M+H]+; [M+Na]+; [2M+Na]+, Found 266.07, 268.06; 288.04, 290.03; 554.98.
EXAMPLE 01-09
Preparation of 3-((4-acetylphenyl)amino)-2-methylcyclopent-2-enone (01-09): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-aminoacetophenone according to the procedure of Example 01-01; 25.0 mmol scale yielded 0.5 g of orange microcrystals from toluene (mp=270-273° C., 9% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26 (s, 2H), 2.82 (s, 2H), 3.36 (s, 3H), 7.33 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 9.23 (s, 1H). LCMS t=5.2 min, m/z Calcd for C14H16NO2; C14H15NNaO2; C28H30N2NaO4 230.12; 252.10; 481.21 [M+H]+; [M+Na]+; [2M+Na]+, Found 230.19; 252.16; 481.21.
EXAMPLE 01-10
Preparation of 2-chloro-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-10): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-amino-2-chlorobenzoic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 4.3 g of yellow needles from acetone (mp=239-241° C., 65% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.27 (s, 2H), 2.83 (s, 2H), 7.27 (d, J=6.8 Hz, 1H), 7.38 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 9.21 (s, 1H), 13.1 (s, 1H). LCMS t=5.1 min, m/z Calcd for C13H13ClNO3; C13H12ClNNaO3; C26H24Cl2N2NaO6  266.06; 288.04; 553.09 [M+H]+; [M+Na]+; [2M+Na]+, Found 266.12; 288.09; 553.09.
EXAMPLE 01-11
Preparation of methyl 3-chloro-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-11): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 4-amino-3-chlorobenzoate according to the procedure of Example 01-01; 25.0 mmol scale yielded 3.4 g from EtOAc (49% yield). 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.24-2.26 (m, 2H), 2.54-2.55 (m, 2H), 3.86 (s, 3H), 7.42 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 8.98 (s, 1H). LCMS t=5.7 min, m/z Calcd for C14H15ClNO3; C14H14ClNNaO3; C28H28Cl2N2NaO6 280.07; 302.06; 581.12 [M+H]+; [M+Na]+; [2M+Na]+, Found 280.13; 302.10; 581.12.
EXAMPLE 01-12
Preparation of 3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-12): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-amino-3-methoxybenzoic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 4.8 g of tan needles from EtOH (mp=231-234° C., 74% yield). 1H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.19-2.21 (m, 2H), 2.55-2.56 (m, 2H), 3.89 (s, 3H), 7.28 (d, J=8.5 Hz, 1H), 7.55-7.57 (m, 2H), 8.56 (s, 1H), 12.96 (s, 1H). LCMS t=5.1 min, m/z Calcd for C14H16NO4; C14H15NNaO4; C28H30N2NaO8 262.11; 284.09; 545.19 [M+H]+; [M+Na]+; [2M+Na]+, Found 262.17; 284.14; 545.19.
EXAMPLE 01-13
Preparation of methyl 2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-13): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 4-amino-2-methoxybenzoate according to the procedure of Example 01-01; 25.0 mmol scale yielded 6.8 g of tan microcrystals from toluene (mp=193-196° C., 99% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.26 (m, 2H), 2.84 (s, 2H), 3.75 (s, 3H), 3.82 (s, 3H), 6.88 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 9.15 (s, 1H). LCMS t=5.3 min, m/z Calcd for C15H18NO4; C15H17NNaO4; C30H34N2NaO8 276.12; 298.11; 573.22 [M+H]+; [M+Na]+; [2M+Na]+, Found 276.18; 298.15; 573.24.
EXAMPLE 01-14
Preparation of 3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-14): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-amino-3-methylbenzoic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 3.0 g of tan sheets from EtOH (mp=233-236° C., 49% yield). 1H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.19-2.21 (m, 2H), 2.30 (s, 3H), 2.47 (s, 2H), 7.24 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 8.74 (s, 1H), 12.88 (s, 1H). LCMS t=5.1 min, m/z Calcd for C14H16NO3; C14H15NNaO3; C26H30N2NaO6 246.11; 268.10; 513.20 [M+H]+; [M+Na]+; [2M+Na]+, Found 246.19; 268.15; 513.20.
EXAMPLE 01-15
Preparation of 2-methoxy-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-15): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-amino-2-methoxybenzoic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 4.0 g of grey microcrystals from EtOH (mp=220-223° C., 61% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.16-2.19 (m, 2H), 2.44 (s, 2H), 3.72 (s, 3H), 7.19 (t, J=7.8 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 8.72 (s, 1H), 13.03 (s, 1H). 13C NMR (D6-DMSO) δ 7.2, 25.3, 32.7, 61.3, 109.1, 123.7, 127.1, 127.7, 130.6, 133.7, 153.6, 167.0, 170.3, 202.0. LCMS t=1.2 min, m/z Calcd for C14H16NO4; C14H15NNaO4; C28H30N2NaO8 262.11; 284.09; 545.19 [M+H]+; [M+Na]+; [2M+Na]+, Found 262.21; 284.18; 545.27.
EXAMPLE 01-16
Preparation of 2-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-16): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-amino-2-methylbenzoic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 3.0 g of black needles from EtOH (mp=213-216° C., 49% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.23-2.25 (m, 2H), 2.52 (s, 3H), 2.78 (s, 2H), 7.11-7.13 (m, 2H), 7.83 (d, J=8.2 Hz, 1H), 9.07 (s, 1H), 12.58 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 21.7, 26.2, 33.0, 111.8, 118.1, 123.7, 124.4, 131.9, 141.0, 143.2, 168.0, 168.3, 202.4. LCMS t=5.1 min, m/z Calcd for C14H16NO3; C14H15NNaO3; C26H30N2NaO6 246.11; 268.10; 513.20 [M+H]+; [M+Na]+; [2M+Na]+, Found 246.22; 268.19; 513.27.
EXAMPLE 01-17
Preparation of 2,5-dichloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-17): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-amino-2,5-dichlorobenzoic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 5.0 g of yellow needles from EtOH (mp=229-232° C., 82% yield). 1H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.21 (s, 2H), 2.45 (s, 2H), 7.64-7.66 (m, 2H), 8.97 (s, 1H), 13.85 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 25.5, 32.7, 110.4, 126.6, 129.4, 131.5, 134.9, 139.1, 165.7, 168.9, 202.8. LCMS t=5.1 min, m/z Calcd for C13H12O2NO3; C26H22C14N2NaO6 300.02; 623.01 [M+H]+; [2M+Na]+, Found 300.10; 623.09.
EXAMPLE 01-18
Preparation of 2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (01-18): The title compound was prepared from 2-methyl-1,3-cyclopentandione and anthranilamide according to the procedure of Example 01-01; 20.0 mmol scale yielded 3.0 g of yellow microcrystal from EtOH (mp=235-238° C., 65% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.26-2.29 (m, 2H), 2.91 (s, 2H), 7.07-7.11 (m, 1H), 7.47-7.49 (m, 2H), 7.75 (s, 1H), 7.78 (d, J=7.9 Hz, 1H) 8.25 (s, 1H), 11.14 (s, 1H). 13C NMR (D6-DMSO) δ 6.6, 26.3, 33.3, 112.2, 119.8, 121.3, 121.8, 129.2, 132.3, 140.9, 168.4, 170.9, 201.6. LCMS t=4.3 min, m/z Calcd for C13H15N2O2; C13H14N2NaO2; C26H29N4O4; C26H28N4NaO4 231.11; 253.10; 461.22; 483.20 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 231.11; 253.10; 461.22; 483.20.
EXAMPLE 01-19
Preparation of methyl 2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-19): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl anthranilate according to the procedure of Example 01-01; 20.0 mmol scale yielded 4.0 g from EtOAc (82% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.29-2.31 (m, 2H), 2.88 (s, 2H), 3.87 (s, 3H), 7.17 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H) 10.11 (s, 1H). 13C NMR (D6-DMSO) δ 6.7, 26.3, 33.2, 52.5, 112.7, 117.9, 120.9, 122.6, 131.3, 134.3, 141.6, 167.7, 168.3, 201.8. LCMS t=5.3 min, m/z Calcd for C14H16NO3; C14H15NNaO3; C28H31N2O6; C28H30N2NaO6 246.11; 268.10; 491.22; 513.20 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 246.11; 268.09; 491.22; 513.20.
EXAMPLE 01-20
Preparation of methyl 5-chloro-2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-20): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 5-chloroanthranilate according to the procedure of Example 01-01; 5.0 mmol scale yielded 1.0 g of yellow microcrystals from EtOAc (mp=162-165° C., 82% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.29-2.31 (m, 2H), 2.86 (s, 2H), 3.88 (s, 3H), 7.54 (d, J=8.9 Hz, 1H), 7.65 (dd, J=8.9, 2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 9.96 (s, 1H). 13C NMR (D6-DMSO) δ 6.8, 26.2, 33.2, 52.8, 113.2, 119.6, 122.9, 126.2, 130.4, 133.8, 140.5, 166.6, 167.7, 202.1. LCMS t=5.7 min, m/z Calcd for C14H15ClNO3; C14H14ClNNaO3; C28H28Cl2N2NaO6 280.07; 302.06; 581.12 [M+H]+; [M+Na]+; [2M+Na]+, Found 280.07; 302.05; 581.12.
EXAMPLE 01-21
Preparation of methyl 3-fluoro-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-21): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 4-amino-3-fluorobenzoate according to the procedure of Example 01-01; 20.0 mmol scale yielded 4.5 g of beige microcrystals from EtOAc (mp=198-201° C., 85% yield). 1H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.24-2.26 (m, 2H), 2.57 (s, 2H), 3.86 (s, 3H), 7.40-7.44 (m, 1H), 7.77-7.79 (m, 2H), 9.09 (s, 1H). LCMS t=5.0 min, m/z Calcd for C14H15FNO3; C14H14FNNaO3; C28H29F2N2O6; C28H28F2N2NaO6 264.10; 286.09; 527.20; 549.18 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 264.10; 286.08; 527.20; 549.18.
EXAMPLE 01-22
Preparation of methyl 3-bromo-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-22): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 4-amino-3-bromobenzoate according to the procedure of Example 01-01; 20.0 mmol scale yielded 4.0 g of white microcrystals from EtOAc (mp=155-158° C., 62% yield). 1H NMR (D6-DMSO) δ 1.43 (s, 3H), 2.23-2.25 (m, 2H), 2.50-2.53 (m, 2H), 3.86 (s, 3H), 7.44 (d, J=8.3 Hz, 1H), 7.94-7.95 (m, 1H), 8.17 (d, J=1.4 Hz, 1H), 8.91 (s, 1H). 13C NMR (D6-DMSO) δ 7.8, 25.9, 32.7, 52.4, 111.4, 119.1, 126.9, 127.6, 129.1, 133.5, 142.5, 164.6, 168.2, 203.0. LCMS t=5.2 min, m/z Calcd for C14H15BrNO3; C14H14BrNNaO3; C28H29Br2N2O6; C28H28Br2N2NaO6 324.02, 326.02; 346.01, 348.00; 649.04; 671.02 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 324.02, 326.02; 346.00, 348.00; 649.04; 671.02.
EXAMPLE 01-23
Preparation of 2-chloro-6((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-23): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 6-chloroanthranilic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 3.0 g of white microcrystals from EtOH (mp=277-280° C., 56% yield). 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.14-2.16 (m, 2H), 2.36-2.38 (m, 2H), 7.31 (dd, J=6.5, 2.1 Hz, 1H), 7.45-7.48 (m, 2H), 8.95 (s, 1H). 13C NMR (D6-DMSO) δ 7.1, 25.3, 32.6, 109.1, 127.0, 127.4, 129.6, 130.7, 132.9, 137.6, 166.3, 170.3, 202.2. LCMS t=4.5 min, m/z Calcd for C13H13ClNO3; C26H25Cl2N2O6 266.06; 531.11 [M+H]+; [2M+H]+, Found 266.06; 531.11.
EXAMPLE 01-24
Preparation of methyl 4-chloro-2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-24): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 4-chloroanthranilate according to the procedure of Example 01-01; 20.0 mmol scale yielded 4.6 g of yellow sheets from EtOAc (mp=167-170° C., 82% yield). 1H NMR (CDCl3) δ 1.82 (s, 3H), 2.53-2.55 (m, 2H), 3.02-3.03 (m, 2H), 3.95 (s, 3H), 6.98 (dd, J=8.6, 1.7 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 10.67 (s, 1H). 13C NMR (CDCl3) δ 7.2, 27.8, 33.9, 52.8, 113.9, 117.2, 117.9, 121.4, 133.4, 140.7, 144.3, 166.8, 168.3, 204.0. LCMS t=5.7 min, m/z Calcd for C14H15ClNO3; C14H14ClNNaO3; C28H29Cl2N2O6; C28H28Cl2N2NaO6 280.07; 302.06; 559.14; 581.12 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 280.07; 302.05; 559.14; 581.12.
EXAMPLE 01-25
Preparation of 4-chloro-3((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-25): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-amino-4-chlorobenzoic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 5.0 g of white microcrystals from EtOH (mp=272-275° C., 94% yield). 1H NMR (D6-DMSO) δ 1.42 (s, 3H), 2.20-2.22 (m, 2H), 2.41-2.43 (m, 2H), 7.69 (d, J=7.9 Hz, 1H), 7.79-7.81 (m, 2H), 8.97 (s, 1H), 13.31 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 25.7, 32.6, 109.7, 127.8, 128.7, 130.2, 134.5, 136.9, 166.1, 169.2, 202.6. LCMS t=4.3 min, m/z Calcd for C13H13ClNO3; C26H25Cl2N2O6 266.06; 531.11 [M+H]+; [2M+H]+, Found 266.06; 531.07.




EXAMPLE 01-26
Preparation of 2-methyl-3-(naphthalen-1-ylamino)cyclopent-2-enone (01-26): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 1-naphthylamine according to the procedure of Example 01-01; 12.5 mmol scale yielded 1.0 g of tan needles from EtOAc (mp=166-168° C., 34% yield). 1H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.15-2.16 (m, 2H), 2.38 (s, 2H), 7.42 (d, J=7.1 Hz, 1H), 7.52-7.61 (m, 3H), 7.87 (d, J=8.1 Hz, 1H), 8.00 (t, J=8.6 Hz, 2H), 9.26 (s, 1H). LCMS t=5.4 min, m/z Calcd for C16H16NO; C16H15NNaO; C32H31N2O2; C32H30N2NaO2 238.12; 260.11; 475.24; 497.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 238.14; 260.12; 475.26; 497.24.




EXAMPLE 01-27
Preparation of 2-methyl-3-(naphthalen-2-ylamino)cyclopent-2-enone (01-27): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 2-naphthylamine according to the procedure of Example 01-01; 6.0 mmol scale yielded 0.2 g of yellow needles from EtOAc (mp=248-250° C., 14% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.23-2.25 (m, 2H), 2.77-2.78 (m, 2H), 7.42-7.51 (m, 3H), 7.71 (s, 1H), 7.85-7.90 (m, 3H), 9.16 (s, 1H). LCMS t=5.5 min, m/z Calcd for C16H16NO; C16H15NNaO; C32H31N2O2; C32H30N2NaO2 238.12; 260.11; 475.24; 497.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 238.13; 260.12; 475.26; 497.24.


















Example






01-#
TITLE COMPOUND NAME
X
Y
Z







28
2-Methyl-3-(pyridin-2-
N
CH
CH



ylamino)cyclopent-2-enone


29
2-Methyl-3-(pyridin-3-
CH
N
CH



ylamino)cyclopent-2-enone


30
2-Methyl-3-(pyridin-4-
CH
CH
N



ylamino)cyclopent-2-enone









EXAMPLE 01-28
Preparation of 2-methyl-3-(pyridin-2-ylamino)cyclopent-2-enone (01-28): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 2-aminopyridine according to the procedure of Example 01-01; 30.0 mmol scale yielded 0.6 g of yellow sheets from EtOAc (mp=163-165° C., 11% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 2.23 (s, 2H), 3.18 (s, 2H), 6.96 (d, J=5.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.69-7.71 (m, 1H), 8.23 (s, 1H), 9.32 (s, 1H). LCMS t=4.4 min, m/z Calcd for C11H13N2O; C11H12N2NaO; C22H25N4O2; C22H24N4NaO2 189.10; 211.08; 377.20; 399.18 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 189.11; 211.09; 377.21; 399.20.
EXAMPLE 01-29
Preparation of 2-methyl-3-(pyridin-3-ylamino)cyclopent-2-enone (01-29): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-aminopyridine according to the procedure of Example 01-01; 30.0 mmol scale yielded 1.6 g of grey microneedles from EtOAc (mp=133-135° C., 28% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.22 (s, 2H), 2.66 (s, 2H), 7.38 (dd, J=7.7, 4.7 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 8.32 (d, J=3.6 Hz, 1H), 8.51 (s, 1H), 9.07 (s, 1H). LCMS t=1.4 min, m/z Calcd for C11H13N2O; C11H12N2NaO; C22H25N4O2; C22H24N4NaO2 189.10; 211.08; 377.20; 399.18 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 189.11; 211.09; 377.22; 399.20.
EXAMPLE 01-30
Preparation of 2-methyl-3-(pyridin-4-ylamino)cyclopent-2-enone (01-30): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-aminopyridine according to the procedure of Example 01-01; 20.0 mmol scale for 72 h yielded 0.02 g of yellow microcrystals from EtOAc (mp=203-205° C., 1% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.28-2.29 (m, 2H), 2.90 (s, 2H), 7.20 (d, J=4.9 Hz, 2H), 8.38 (s, 2H), 9.15 (s, 1H). LCMS t=1.4 min, m/z Calcd for C11H13N2O 189.10 [M+H]+, Found 189.12.




EXAMPLE 01-31
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(pyridin-2-yl)benzenesulfonamide (01-31): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 4-amino-N-(2-pyridinyl)benzenesulfonamide according to the procedure of Example 01-01; 10.0 mmol scale yielded 2.0 g of yellow microcrystals from H2O (mp=230-233° C., 58% yield). 1H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.23-2.25 (m, 2H), 2.77 (s, 2H), 6.88 (t, J=5.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 9.18 (s, 1H). LCMS t=4.9 min, m/z Calcd for C17H18N3O3S; C17H17N3NaO3S; C34H34N6NaO6S2 344.11; 366.09; 709.19 [M+H]+; [M+Na]+; [2M+Na]+, Found 344.11; 366.08; 709.16.




EXAMPLE 01-32
Preparation of tert-Butyl 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)piperidine-1-carboxylate (01-32): The title compound was prepared from 2-methyl-1,3-cyclopentandione and tert-butyl 4-aminopiperidine-1-carboxylate according to the procedure of Example 01-01; 5.0 mmol scale yielded 0.6 g of grey microcrystals from H2O (mp=189-191° C., 41% yield). 1H NMR (D6-DMSO) δ 1.40-1.46 (m, 14H), 1.76 (d, J=11.6 Hz, 2H), 2.10-2.11 (m, 2H), 2.51 (d, J=5.8 Hz, 2H), 2.73 (s, 2H), 2.65-2.90 (m, 2H), 3.52 (s, 1H), 3.94 (s, 2H), 6.88 (d, J=8.3 Hz, 1H). LCMS t=5.6 min, m/z Calcd for C16H27N2O3; C16H26N2NaO3; C32H52N4NaO6 295.20; 317.18; 611.38 [M+H]+; [M+Na]+; [2M+Na]+, Found 295.26; 317.20; 611.35.




EXAMPLE 01-33
Preparation of trans-(1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclo6hexane-carboxylic acid (01-33): The title compound was prepared from 2-methyl-1,3-cyclopentandione and trans-(1R,4R)-4-aminocyclohexanecarboxylic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 4.0 g of white microneedles from H2O (mp=236-238° C., 67% yield). 1H NMR (D6-DMSO) δ 1.35-1.45 (m, 7H), 1.84 (d, J=9.3 Hz, 2H), 1.87-1.93 (m, 1H), 2.10 (s, 2H), 2.50 (s, 2H), 3.34 (br s, 2H), 6.88 (d, J=7.6 Hz, 1H), 12.1 (s, 1H). LCMS t=4.7 min, m/z Calcd for C13H20NO3; C13H19NNaO3; C26H39N2O6; C26H38N2NaO6 238.14; 260.13; 475.28; 497.26 [M+H]+; [M+Na]+; [2M+H]2+; [2M+Na]+, Found 238.21; 260.18; 475.26; 497.24.




EXAMPLE 01-34
Preparation of cis-(1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxylic acid (01-34): The title compound was prepared from 2-methyl-1,3-cyclopentandione and cis-(1S,4S)-4-aminocyclohexanecarboxylic acid according to the procedure of Example 01-01; 25.0 mmol scale yielded 2.6 g of tan microneedles from H2O (mp=233-235° C., 44% yield). 1H NMR (D6-DMSO) δ 1.46-1.52 (m, 7H), 1.66 (d, J=8.8 Hz, 2H), 2.03-2.11 (m, 3H), 2.51 (s, 2H), 3.38 (br s, 2H), 6.94 (d, J=7.6 Hz, 1H), 12.25 (s, 1H). LCMS t=4.9 min, m/z Calcd for C13H20NO3; C13H19NNaO3; C26H39N2O6; C26H38N2NaO6 238.14; 260.13; 475.28; 497.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 238.21; 260.18; 475.26; 497.24.




EXAMPLE 01-35
Preparation of 4((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (01-35): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 4-aminobenzamide according to the procedure of Example 01-01; 12.5 mmol scale yielded 1.0 g of tan microsheets from CH2Cl2/hexanes (mp=221-223° C., 33% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.81 (t, J=5.7 Hz, 2H), 2.24 (t, J=5.8 Hz, 2H), 2.53 (s, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.28 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.89 (s, 1H), 8.36 (s, 1H). LCMS t=3.9 min, m/z Calcd for C14H17N2O2; C14H16N2NaO2; C28H32N4NaO4 245.13; 267.11; 511.23 [M+H]+; [M+Na]+; [2M+Na]+, Found 245.15; 267.12; 511.26.



















Example







01-#
TITLE COMPOUND NAME
R1
R2
R3
R4







36
4-Chloro-3-((2-methyl-3-oxocyclohex-1-
Cl
H
H
CO2H



en-1-yl)amino)benzoic acid


37
2-(3-((2-Methyl-3-oxocyclohex-1-en-1-
H
CH2CO2H
H
H



yl)amino)phenyl)acetic acid


38
2-(4-((2-Methyl-3-oxocyclohex-1-en-1-
H
H
CH2CO2H
H



yl)amino)phenyl)acetic acid


39
3-((2-Methyl-3-oxocyclohex-1-en-1-
CF3
H
H
CO2H



yl)amino)-4-(trifluoromethyl)benzoic acid


40
4-((2-Methyl-3-oxocyclohex-1-en-1-
CF3
H
CO2H
H



yl)amino)-4-(trifluoromethyl)benzoic acid









EXAMPLE 01-36
Preparation of 4-chloro-3((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid (01-36): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-amino-4-chlorobenzoic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 5.0 g of tan microcrystals from EtOH (mp=232-235° C., 89% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.76-1.80 (m, 2H), 2.21 (t, J=6.2 Hz, 2H), 2.26 (t, J=5.6 Hz, 2H), 7.66 (dd, J=8.3, 1.0 Hz, 1H), 7.12 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.09 (s, 1H), 13.29 (br s, 1H). 13C NMR (D6-DMSO) δ 9.2, 21.0, 27.2, 36.3, 107.9, 127.4, 128.8, 130.1, 130.3, 134.8, 137.5, 158.2, 166.2, 194.9. LCMS t=4.7 min, m/z Calcd for C14H15ClNO3; C28H28Cl2N2NaO6 280.07; 581.12 [M+H]+; [2M+Na]+, Found 280.06; 581.11.
EXAMPLE 01-37
Preparation of 2-(3((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)acetic acid (01-37): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-aminophenylacetic acid according to the procedure of Example 01-01; 2.5 mmol scale yielded 0.25 g of orange microcrystals from EtOH (mp=203-207° C., 39% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 2.20 (t, J=6.4 Hz, 2H), 2.43 (t, J=5.6 Hz, 2H), 3.56 (s, 2H), 6.99-7.02 (m, 3H), 7.27 (t, J=7.9 Hz, 1H), 8.18 (s, 1H), 12.38 (br s, 1H). 13C NMR (D6-DMSO) δ 9.6, 22.2, 27.8, 36.9, 41.01, 107.5, 123.00, 125.6, 125.7, 129.0, 136.2, 140.2, 158.6, 173.0, 194.8. LCMS t=4.4 min, m/z Calcd for C15H18NO3; C15H17NNaO3; C30H34N2NaO6 260.13; 282.11; 541.23 [M+H]+; [M+Na]+; [2M+Na]+, Found 260.11; 282.09; 541.19.
EXAMPLE 01-38
Preparation of 2-(4((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)acetic acid (01-38): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 4-aminophenylacetic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 3.6 g of brown sheets from EtOH (mp=215-219° C., 69% yield). 1H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.75-1.78 (m, 2H), 2.19 (t, J=6.4 Hz, 2H), 2.42 (t, J=5.7 Hz, 2H), 3.55 (s, 2H), 7.06 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 8.16 (s, 1H), 12.31 (br s, 1H). 13C NMR (D6-DMSO) δ 9.5, 22.1, 27.7, 36.8, 40.5, 107.0, 124.9, 130.2, 131.4, 138.8, 158.9, 173.2, 194.6. LCMS t=4.3 min, m/z Calcd for C15H18NO3; C15H17NNaO3; C30H34N2NaO6 260.13; 282.11; 541.23 [M+H]+; [M+Na]+; [2M+Na]+, Found 260.11; 282.09; 541.19.
EXAMPLE 01-39
Preparation of 3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-4-(trifluoromethyl)benzoic acid (01-39): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-amino-4-(trifluoromethyl)benzoic acid according to the procedure of Example 01-01; 2.5 mmol scale yielded 0.5 g of tan microcrystals from EtOH/EtOAc (mp=209-212° C., 64% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 1.73-1.76 (m, 2H), 2.20-2.25 (m, 4H), 7.11 (d, J=7.7 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 8.26 (s, 1H). LCMS t=4.6 min, m/z Calcd for C15H15F3NO3; C30H28F6N2NaO6 314.10; 649.17 [M+H]+; [2M+Na]+, Found 314.09; 649.12.
EXAMPLE 01-40
Preparation of 4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-4-(trifluoromethyl)benzoic acid (01-40): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 4-amino-3-(trifluoromethyl)benzoic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 2.5 g of tan microneedles from EtOH (mp=229-231° C., 40% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 1.78-1.81 (m, 2H), 2.24 (t, J=6.2 Hz, 2H), 2.36-2.40 (m, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.88 (s, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.18 (s, 1H), 13.36 (br s, 1H). 13C NMR (D6-DMSO) δ 10.1, 21.3, 28.4, 36.9, 111.5, 123.7 (JCF=28.6 Hz), 123.8 (JCF=274.0 Hz), 127.5, 128.0, 128.6, 134.3, 143.3, 157.6, 166.2, 196.1. LCMS t=4.7 min, m/z Calcd for C15H15F3NO3; C15H14F3NNaO3; C30H28F6N2NaO6 314.10; 336.08; 649.17 [M+H]+; [M+Na]+; [2M+Na]+, Found 314.08; 336.06; 649.13.




EXAMPLE 01-41
Preparation of 6((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-2-naphthoic acid (01-41): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 6-amino-2-naphthoic acid according to the procedure of Example 01-01; 20.0 mmol scale yielded 2.7 g of brown microcrystals from EtOH (mp=259-263° C., 46% yield). 1H NMR (D6-DMSO) δ 1.73 (s, 3H), 1.83-1.86 (m, 2H), 2.27-2.30 (m, 2H), 2.61-2.63 (m, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.56 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 12.97 (br s, 1H). 13C NMR (D6-DMSO) δ 10.1, 22.2, 28.2, 37.0, 109.9, 118.7, 124.6, 126.2, 127.0, 127.7, 129.1, 130.4, 130.7, 136.0, 140.5, 157.7, 167.9, 195.5. LCMS t=4.7 min, m/z Calcd for C18H18NO3; C36H35N2O6; C36H34N2NaO6 296.13; 591.25; 613.23 [M+H]+; [2M+H]+; [2M+Na]+, Found 296.15; 591.27; 613.25.



















Example







01-#
TITLE COMPOUND NAME
R1
R2
R3
R4







42
N-(4-Chloro-3-((2-methyl-3-
Cl
H
H
NAc



oxocyclopent-1-en-1-yl)amino)phenyl)-



acetamide


43
Methyl 3-iodo-4-((2-methyl-3-
I
H
CO2CH3
H



oxocyclopent-1-en-1-yl)amino)benzoate


44
2-Chloro-3-((2-methyl-3-oxocyclopent-1-
Cl
CO2H
H
H



en-1-yl)amino)benzoic acid


45
3-((2-Methyl-3-oxocyclopent-1-en-1-
H
SO2NH2
H
H



yl)amino)benzenesulfonamide


46
4-Chloro-3-((2-methyl-3-oxocyclopent-1-
Cl
H
SO2NH2
H



en-1-yl)amino)benzene-sulfonamide









EXAMPLE 01-42
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-acetamide (01-42): The title compound was prepared from 2-methyl-1,3-cyclopentandione and N-(3-amino-4-chloropheny)lacetamide according to the procedure of Example 01-01; 20.0 mmol scale yielded 5.5 g (99% yield) of tan microcrystals. A portion was recrystallized from EtOH:EtOAc (1:1.1) (mp=265-268° C., 50% recovery). 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.05 (s, 3H), 2.18-2.21 (m, 2H), 2.40-2.41 (m, 2H), 7.41 (dd, J=8.7, 2.3 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 8.86 (s, 1H), 10.13 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 24.1, 25.6, 32.6, 109.3, 117.8, 118.4, 123.3, 129.7, 136.6, 138.7, 168.7, 169.5, 202.4. LCMS t=4.3 min, m/z Calcd for C14H16ClN2O2; C14H15ClN2NaO2; C28H31Cl2N4O4; C28H30Cl2N4NaO4 279.09; 301.07; 557.17; 579.15 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 279.11; 301.09; 557.13; 579.11.
EXAMPLE 01-43
Preparation of methyl 3-iodo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoate (01-43): The title compound was prepared from 2-methyl-1,3-cyclopentandione and methyl 3-iodo-4-aminobenzoate according to the procedure of Example 01-01; 10 mmol scale yielded 1.7 g of white prisms from EtOAc (mp=178-180° C., 46% yield). 1H NMR (D6-DMSO) δ 1.43 (s, 3H), 2.21-2.23 (m, 2H), 2.44-2.47 (m, 2H), 3.86 (s, 3H), 7.41 (d, J=8.3 Hz, 1H), 7.96 (dd, J=8.3, 1.8 Hz, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.86 (s, 1H). 13C NMR (D6-DMSO) δ 7.7, 25.9, 32.7, 52.4, 97.7, 110.5, 126.7, 128.1, 129.8, 139.6, 145.7, 164.5, 168.5, 202.6. LCMS t=4.6 min, m/z Calcd for C14H15INO3; C14H14INNaO3; C28H28I2N2NaO6 372.01; 393.99; 764.99 [M+H]+; [M+Na]+; [2M+Na]+, Found 372.04; 393.96; 764.95.
EXAMPLE 01-44
Preparation of 2-chloro-3((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (01-44): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-amino-2-chlorobenzoic acid according to the procedure of Example 01-01; 2.5 mmol scale yielded 415 mg of white microneedles from EtOH (mp=230-232° C., 62% yield). 1H NMR (D6-DMSO) δ 1.46 (s, 3H), 2.18-2.02 (m, 2H), 2.37-2.40 (m, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.54 (dd, J=7.9, 1.6 Hz, 1H), 7.62 (dd, J=7.7, 1.6 Hz, 1H), 8.93 (s, 1H), 13.53 (br s, 1H). 13C NMR (D6-DMSO) δ 7.3, 25.4, 32.6, 109.4, 127.4, 127.7, 128.3, 130.8, 133.5, 137.7, 166.9, 169.7, 202.3. LCMS t=1.8 min, m/z Calcd for C13H13ClNO3; C13H12ClNNaO3; C26H24Cl2N2NaO6 266.06; 288.04; 553.09 [M+H]+; [M+Na]+; [2M+Na]+, Found 266.09; 288.06; 553.03.
EXAMPLE 01-45
Preparation of 3((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzenesulfonamide (01-45): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-aminobenzenesulfonamide according to the procedure of Example 01-01; 5.0 mmol scale yielded 600 mg of light brown microcrystals from H2O (mp=223-225° C., 45% yield). 1H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.22-2.27 (m, 2H), 2.68-2.75 (m, 2H), 7.40-7.47 (m, 3H), 7.53 (d, J=5.2 Hz, 2H), 7.65 (s, 1H), 9.22 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 25.8, 32.9, 111.1, 119.0, 120.4, 125.0, 129.8, 140.5, 144.9, 168.6, 202.3. LCMS t=2.6 min, m/z Calcd for C12H15N2O3S; C12H14N2NaO3S; C24H29N4O6S2; C24H28N4NaO6S2 267.083; 289.062; 533.152; 555.135 [M+H]+; [2M+H]+; [2M+H]+; [2M+Na]+, Found 267.083; 289.061; 533.151; 555.133.
EXAMPLE 01-46
Preparation of 4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzene-sulfonamide (01-46): The title compound was prepared from 2-methyl-1,3-cyclopentandione and 3-amino-4-chlorobenzenesulfonamide according to the procedure of Example 01-01; 5.0 mmol scale yielded 800 mg of light brown microcrystals from H2O (mp=223-225° C., 53% yield). 1H NMR (D6-DMSO) δ 1.42 (s, 3H), 2.20-2.28 (m, 2H), 2.45-2.49 (m, 2H), 7.55 (s, 2H), 7.66 (dd, J=8.2, 2.1 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 9.07 (s, 1H). 13C NMR (D6-DMSO) δ 7.8, 25.8, 32.7, 110.4, 123.9, 124.8, 130.5, 132.8, 137.2, 143.4, 168.8, 202.9. LCMS t=3.4 min, m/z Calcd for C12H15ClN2O3S; C12H14ClN2NaO3S; C24H29Cl2N4O6S2; C24H28Cl2N4NaO6S2 301.041; 323.023; 601.075; 623.057 [M+H]+; [2M+H]+; [2M+H]+; [2M+Na]+, Found 301.040; 323.021; 601.071; 623.056.



















Example







01-#
TITLE COMPOUND NAME
R1
R2
R3
R4







47
N-(4-Chloro-3-((2-methyl-3-
Cl
H
H
NAc



oxocyclopent-1-en-1-



yl)amino)phenyl)-acetamide


48
Methyl 3-iodo-4-((2-methyl-
Br
H
H
CO2H



3-oxocyclopent-1-en-1-



yl)amino)benzoate









EXAMPLE 01-47
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-acetamide (01-47): The title compound was prepared from 2-methyl-1,3-cyclohexandione and N-(4-amino-3-chloropheny)lacetamide according to the procedure of Example 01-01; 10.0 mmol scale yielded 2.9 g of pale orange microcrystals from EtOAc (mp=234-236° C., 99% yield). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.75-1.79 (m, 2H), 2.05 (s, 3H), 2.18-2.24 (m, 4H), 7.42-7.46 (m, 2H), 7.58 (d, J=1.9 Hz, 1H), 8.04 (s, 1H), 10.12 (s, 1H). 13C NMR (D6-DMSO) δ 9.0, 21.1, 24.0, 27.0, 36.3, 107.1, 117.7, 118.8, 123.9, 129.7, 137.1, 138.8, 158.8, 168.6, 194.4. LCMS t=4.5 min, m/z Calcd for C15H18ClN2O2; C15H17ClN2NaO2; C30H35Cl2N4O4; C30H34Cl2N2NaO4 293.11; 315.09; 585.20; 607.19 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 293.13; 315.10, 585.16; 607.15.
EXAMPLE 01-48
Preparation of 4-bromo-3((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid (01-48): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-amino-4-bromobenzoic acid according to the procedure of Example 01-01; 10.0 mmol scale yielded 2.9 g of white microneedles from EtOH (mp=265-267° C., 89% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 1.75-1.80 (m, 2H), 2.18-2.23 (m, 4H), 7.69-7.72 (m, 2H), 7.84 (d, J=8.1 Hz, 1H), 8.07 (s, 1H), 13.31 (s, 1H). 13C NMR (D6-DMSO) δ 9.2, 21.1, 27.2, 36.4, 107.5, 126.9, 127.9, 129.2, 131.0, 133.3, 139.1, 158.1, 166.3, 194.8. LCMS t=4.2 min, m/z Calcd for C14H15BrNO3; C14H14BrNNaO3; C28H28Br2N2NaO6 324.02, 326.02; 346.01, 348.00; 671.02 [M+H]+; [M+Na]+; [2M+Na]+, Found 324.03, 326.02; 345.99, 347.99; 670.96.

















Example





01-#
TITLE COMPOUND NAME
X
Y







49
3-[(3-Chloropyridin-2-yl)amino]-2-
N
CH



methylcyclohex-2-en-1-one


50
3-[(3-Chloropyrazin-2-yl)amino]-2-
N
N



methylcyclohex-2-en-1-one









EXAMPLE 01-49
Preparation of 3-[(3-chloropyridin-2-yl)amino]-2-methylcyclohex-2-en-1-one (01-49): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-chloropyridin-2-amine according to the procedure of Example 01-01 (mp=113-115° C.). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.84 (quin, J=6.4 Hz, 2H), 2.28 (t, J=6.1 Hz, 2H), 2.67-2.80 (m, 2H), 7.07 (dd, J=8.5, 4.9 Hz, 1H), 7.91 (s, 1H), 7.93 (d, J=6.1 Hz, 1H), 8.25 (d, J=4.9 Hz, 1H). 13C NMR (D6-DMSO) δ ppm 9.4, 21.3, 28.1, 36.7, 113.6, 119.2, 120.8, 138.2, 146.3, 149.7, 155.6, 196.2. LCMS t=4.3 min, m/z Calcd for C12H14ClN2O; C12H13ClN2NaO; C24H26Cl2N4NaO2 237.080; 259.061; 495.133 [M+H]+; [M+Na]+; [2M+Na]+, Found 237.080; 259.060; 495.131.
EXAMPLE 01-50
Preparation of 3-[(3-chloropyrazin-2-yl)amino]-2-methylcyclohex-2-en-1-one (01-50): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-chloropyrazin-2-amine according to the procedure of Example 01-01 (mp=116-118° C.). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 1.87 (quin, J=6.1 Hz, 2H), 2.32 (t, J=6.1 Hz, 2H), 2.71-2.76 (m, 2H), 8.00 (d, J=2.4 Hz, 1H), 8.18 (s, 1H), 8.28 (d, J=2.4 Hz, 1H). 13C NMR (D6-DMSO) δ 10.6, 21.6, 28.8, 37.2, 118.6, 135.9, 137.9, 141.3, 147.8, 154.3, 197.5. LCMS t=4.1 min, m/z Calcd for C11H13ClN3O; C11H12ClN3NaO; C22H24Cl2N6NaO2 238.075; 260.060; 497.120 [M+H]+; [M+Na]+; [2M+Na]+, Found 238.075; 260.056; 497.122.




EXAMPLE 01-51
Preparation of 3-[(3-chloropyridin-4-yl)amino]-2-methylcyclohex-2-en-1-one (01-51): 3-amino-2-methylcyclohex-2-enone (500 mg, 4 mmol), 4-bromo-3-chloropyridine (950 mg, 5 mmol), palladium acetate (90 mg, 0.4 mmol), BINAP (197 mg, 0.8 mmol), cesium carbonate (2.6 g, 8 mmol) and toluene (10 mL) were combined in a sealed flask and heated at 100° C., for 18 h. At rt, the mixture was filtered and the filtrate was diluted with EtOAc (30 mL), washed with brine (3×10 mL), dried with Na2SO4. The crude was purified by HPLC to afford the title compound (140 mg, 15% yield, white microcrystal, mp=135-138° C.). 1H NMR (D6-DMSO) δ 1.46 (s, 3H), 1.83-1.88 (m, 2H), 2.31 (t, J=6.7 Hz, 2H), 2.53-2.57 (m, 2H), 6.84 (d, J=6.1 Hz, 1H), 8.06 (s, 1H), 8.29 (d, J=6.1 Hz, 1H), 8.48 (s, 1H). 13C NMR (D6-DMSO) δ 10.9, 20.6, 28.7, 36.7, 115.7, 117.1, 121.2, 144.7, 148.3, 148.3, 149.2, 154.4, 197.0. LCMS t=1.9 min, m/z Calcd for C12H14ClN2O; C12H13ClN2NaO 237.080; 259.061 [M+H]+; [2M+H]+, Found 237.080; 259.180.


















Example
TITLE





01-#
COMPOUND NAME
R1
R2
R3







52
3-[(2-Methyl-3-oxocyclohex-
H
H
CO2H



1-en-1-yl)amino]naphthalene-



1-carboxylic acid


53
5-Chloro-6-[(2-methyl-3-
Cl
CO2H
H



oxocyclohex-1-en-1-yl)ami-



no]naphthalene-2-carboxylic acid









EXAMPLE 01-52
Preparation of 3-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]naphthalene-1-carboxylic acid (01-52): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-amino-1-naphthoic acid according to the procedure of Example 01-01; 4.0 mmol scale refluxed for 48 h yielded 1.2 g of crude filtered from toluene (97% yield), brown microcrystals were obtained after acetone titration (mp=270-272° C.). 1H NMR (D6-DMSO) δ 1.71 (s, 3H), 1.81-1.85 (m, 2H), 2.25-2.28 (m, 2H), 2.57-2.50 (m, 2H), 7.52-7.57 (m, 2H), 7.76 (d, J=1.9 Hz, 1H), 7.92-7.95 (m, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.77-8.79 (m, 1H), 13.23 (br s, 1H). 13C NMR (D6-DMSO) δ 9.5, 21.8, 27.6, 36.6, 108.6, 110.6, 124.1, 125.4, 126.3, 126.7, 127.5, 128.0, 128.4, 134.1, 136.7, 157.4, 169.2, 194.9. LCMS t=4.3 min, Calcd for C18H18NO3; C18H17NNaO3; C36H34N2NaO6 296.13; 318.11; 613.23 [M+H]+; [M+Na]+; [2M+Na]+, Found 296.15; 318.11; 613.17.
3-Amino-1-naphthoic acid: mp=179-181° C. 1H NMR (D6-DMSO) δ 5.57 (br s, 2H), 7.02 (d, J=2.1 Hz, 1H), 7.18-7.22 (m, 1H), 7.31-7.35 (m, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 8.57 (d, J=8.5 Hz, 1H), 12.91 (br s, 1H). 13C NMR (D6-DMSO) δ 110.6, 122.0, 122.4, 124.0, 125.4, 125.9, 126.0, 128.4, 135.6, 145.5, 168.8. LCMS t=3.1 min, Calcd for C11H10NO2; C11H9NNaO2 188.07; 210.05 [M+H]+; [M+Na]+, Found 188.16; 210.13.
EXAMPLE 01-53
Preparation of 5-chloro-6-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]naphthalene-2-carboxylic acid (01-53): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 6-amino-5-chloro-2-naphthoic acid according to the procedure of Example 01-01; 0.54 mmol scale refluxed for 48 h yielded 17 mg of grey microneedles after recrystallization from EtOH (mp=272-275° C. decomp, 10% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.78-1.83 (m, 2H), 2.23-2.26 (m, 2H), 2.37-2.40 (m, 2H), 7.49 (d, J=8.8 Hz, 1H), 8.12-8.15 (m, 2H), 8.24-8.27 (m, 2H), 8.66 (d, J=1.5 Hz, 1H), 13.21 (s, 1H). 13C NMR (D6-DMSO) δ 9.6, 21.1, 27.8, 36.6, 109.4, 124.0, 124.1, 126.4, 127.3, 128.1, 128.9, 130.7, 130.9, 132.7, 137.7, 157.6, 167.0, 195.3. LCMS t=4.8 min, m/z Calcd for C18H17ClNO3; C18H16ClNNaO3; C36H32Cl2N2NaO6 330.09; 352.07; 681.15 [M+H]+; [M+Na]+; [2M+Na]+, Found 330.08; 352.06, 681.14.
6-Amino-5-chloro-2-naphthoic acid: 6-Amino-2-naphthoic acid (0.17 g, 0.9 mmol), N-chlorosuccinimide (0.12 g, 1 eq), and carbon tetrachloride (25 mL) were combined in a round bottom flask, and heated under reflux for 1 h. After cooling to rt, the solid was filtered. The subsequent crude materials were added directly to KP-SilTM columns (10 g) with products separating from impurities using an isocratic solvent system CH2Cl2:MeOH (1:19), on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The 0.9 mmol scale yielded 120 mg of white microcrystals after chromatography (mp=274-276° C. decomp, 60% yield). 1H NMR (D6-DMSO) δ 6.14 (s, 2H), 7.19 (d, J=8.8 Hz, 1H), 7.85 (dd, J=42.2, 8.8 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.96 (d, J=1.7 Hz, 1H), 8.39 (d, J=1.7 Hz, 1H), 12.78 (s, 1H). 13C NMR (D6-DMSO) 107.5, 118.9, 121.1, 123.5, 125.8, 126.9, 129.3, 130.9, 133.8, 145.0, 167.5. LCMS t=4.2 min, Calcd for C11H9ClNO2; C11H8ClNNaO2 222.03; 244.01 [M+H]+; [M+Na]+, Found 222.09; 244.06.





















Example









01-#
TITLE COMPOUND NAME
Q
R
T
X
Y
Z






















54
2-Methyl-3-[(quinolin-6-
CH
CH
N
CH
CH
CH



yl)amino]cyclohex-2-en-1-one


55
3-[(Isoquinolin-6-yl)amino]-2-
CH
CH
CH
N
CH
CH



methylcyclohex-2-en-1-one


56
3-[(Isoquinolin-7-yl)amino]-2-
CH
CH
CH
CH
N
CH



methylcyclohex-2-en-1-one


57
2-Methyl-3-[(quinolin-7-
CH
CH
CH
CH
CH
N



yl)amino]cyclohex-2-en-1-one


58
3-[(Isoquinolin-3-yl)amino]-2-
N
CH
CH
CH
CH
CH



methylcyclohex-2-en-1-one


59
2-Methyl-3-[(quinolin-3-
CH
N
CH
CH
CH
CH



yl)amino]cyclohex-2-en-1-one


60
2-Methyl-3-[(quinoxalin-6-
CH
CH
N
CH
CH
N



yl)amino]cyclohex-2-en-1-one


61
2-Methyl-3-[(quinazolin-6-
CH
CH
N
CH
N
CH



yl)amino]cyclohex-2-en-1-one









EXAMPLE 01-54
Preparation of 2-methyl-3-[(quinolin-6-yl)amino]cyclohex-2-en-1-one (01-54): The title compound was prepared from 2-methyl-1,3-cyclohexandione and quinolin-6-amine according to the procedure of Example 01-01 (brown microcrystals, mp=208-210° C.). 1H NMR (D6-DMSO) δ 1.71 (s, 3H), 1.77-1.88 (m, 2H), 2.26 (t, J=6.7 Hz, 2H), 2.58 (t, J=5.5 Hz, 2H), 7.46-7.52 (m, 1H), 7.54-7.62 (m, 2H), 7.96 (d, J=9.8 Hz, 1H), 8.28 (d, J=7.3 Hz, 1H), 8.48 (s, 1H), 8.80 (d, J=6.1 Hz, 1H). 13C NMR (D6-DMSO) δ 9.6, 21.8, 27.7, 36.6, 108.7, 119.2, 121.8, 127.2, 128.2, 129.4, 135.2, 138.1, 144.8, 149.2, 157.5, 194.9. LCMS t=3.6 min, m/z Calcd for C16H17N2O; C16H16N2NaO; C32H32N4NaO2 253.134; 275.116; 527.242 [M+H]+; [M+Na]+; [2M+Na]+, Found 253.131; 275.112; 527.231.
EXAMPLE 01-55
Preparation of 3-[(isoquinolin-6-yl)amino]-2-methylcyclohex-2-en-1-one (01-55): The title compound was prepared from 2-methyl-1,3-cyclohexandione and isoquinolin-6-amine according to the procedure of Example 01-01 (brown microcrystals, mp=163-165° C.). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.81-1.89 (m, 2H), 2.29 (t, J=6.1 Hz, 2H), 2.63 (t, J=6.1 Hz, 2H), 7.40 (s, 1H), 7.45 (dd, J=8.5, 2.4 Hz, 1H), 7.70 (d, J=4.9 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 8.40 (d, J=4.9 Hz, 1H), 8.58 (s, 1H), 9.17 (s, 1H). 13C NMR (D6-DMSO) δ 10.1, 21.7, 28.1, 36.7, 111.0, 115.2, 119.6, 124.1, 124.6, 128.4, 136.1, 142.1, 143.3, 156.5, 195.6. LCMS t=2.9 min, m/z Calcd for C16H17N2O; C16H16N2NaO 253.134; 275.116; [M+H]+; [M+Na]+, Found 253.129; 275.112.
EXAMPLE 01-56
Preparation of 3-[(isoquinolin-7-yl)amino]-2-methylcyclohex-2-en-1-one (01-56): The title compound was prepared from 2-methyl-1,3-cyclohexandione and isoquinolin-7-amine according to the procedure of Example 01-01 (yellow microcrystals, mp=145-147° C.). 1H NMR (D6-DMSO) δ 1.70 (s, 3H), 1.84 (quin, J=6.1 Hz, 2H), 2.27 (t, J=6.1 Hz, 2H), 2.59 (t, J=6.1 Hz, 2H), 7.61 (dd, J=8.5, 2.4 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.80 (d, J=6.1 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 8.42 (d, J=6.1 Hz, 1H), 8.54 (s, 1H), 9.25 (s, 1H). 13C NMR (D6-DMSO) δ 9.7, 21.7, 27.7, 36.6, 109.2, 118.3, 120.3, 127.2, 128.4, 128.7, 131.9, 139.2, 141.3, 151.2, 157.2, 195.1. LCMS t=2.8 min, m/z Calcd for C16H17N2O; C16H16N2NaO; C32H32N4NaO2 253.134; 275.116; 527.242 [M+H]+; [M+Na]+; [2M+Na]+, Found 253.128; 275.108; 527.227.
EXAMPLE 01-57
Preparation of 2-methyl-3-[(quinolin-7-yl)amino]cyclohex-2-en-1-one (01-57): The title compound was prepared from 2-methyl-1,3-cyclohexandione and quinolin-7-amine according to the procedure of Example 01-01 (yellow microcrystals, mp=133-135° C.). 1H NMR (D6-DMSO) δ 1.70 (s, 3H), 1.84 (quin, J=6.1 Hz, 2H), 2.28 (t, J=6.7 Hz, 2H), 2.62 (t, J=5.5 Hz, 2H), 7.39-7.45 (m, 2H), 7.54 (d, J=2.4 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.29 (d, J=6.1 Hz, 1H), 8.53 (s, 1H), 8.82-8.85 (m, 1H). 13C NMR (D6-DMSO) δ 9.8, 21.8, 27.9, 36.6, 109.7, 119.2, 120.1, 123.8, 124.3, 128.4, 135.6, 141.3, 148.3, 151.0, 157.1, 195.3. LCMS t=3.4 min, m/z Calcd for C16H17N2O; C16H16N2NaO; C32H32N4NaO2 253.134; 275.116; 527.242 [M+H]+; [M+Na]+; [2M+Na]+, Found 253.127; 275.109; 527.228.
EXAMPLE 01-58
Preparation of 3-[(isoquinolin-3-yl)amino]-2-methylcyclohex-2-en-1-one (01-58): The title compound was prepared from 2-methyl-1,3-cyclohexandione and isoquinolin-3-amine according to the procedure of Example 01-01 (grey microneedles, mp=205-208° C.). 1H NMR (D6-DMSO) δ 1.72 (s, 3H), 1.84 (quin, J=6.1 Hz, 2H), 2.27 (t, J=6.7 Hz, 2H), 2.80 (t, J=5.5 Hz, 2H), 7.41 (s, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.84 (d, J=8.5 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 8.20-8.20 (m, 1H), 8.70 (s, 1H), 9.12 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 21.8, 28.1, 36.7, 108.7, 110.2, 125.0, 125.4, 125.7, 127.7, 130.9, 137.3, 148.9, 151.1, 157.0, 195.4. LCMS t=4.8 min, m/z Calcd for C16H17N2O; C16H16N2NaO; C32H32N4NaO2 253.134; 275.116; 527.242 [M+H]+; [M+Na]+; [2M+Na]+, Found 253.131; 275.108; 527.227.
EXAMPLE 01-59
Preparation of 2-methyl-3-[(quinolin-3-yl)amino]cyclohex-2-en-1-one (01-59): The title compound was prepared from 2-methyl-1,3-cyclohexandione and quinolin-3-amine according to the procedure of Example 01-01 (tan microcrystals, mp=172-175° C.). 1H NMR (D6-DMSO) δ 1.73 (s, 3H), 1.83 (quin, J=6.1 Hz, 2H), 2.26 (t, J=6.1 Hz, 2H), 2.58 (t, J=6.1 Hz, 2H), 7.57-7.61 (m, 1H), 7.64-7.69 (m, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.95-8.01 (m, 2H), 8.51 (s, 1H), 8.78 (d, J=2.4 Hz, 1H). 13C NMR (D6-DMSO) δ 9.4, 21.7, 27.2, 36.5, 108.8, 126.4, 127.1, 127.5, 127.7, 128.1, 128.6, 133.8, 144.2, 148.3, 157.4, 194.9. LCMS t=4.5 min, m/z Calcd for C16H17N2O; C16H16N2NaO; C32H32N4NaO2 253.134; 275.116; 527.242 [M+H]+; [M+Na]+; [2M+Na]+, Found 253.130; 275.106; 527.227.
EXAMPLE 01-60
Preparation of 2-methyl-3-[(quinoxalin-6-yl)amino]cyclohex-2-en-1-one (01-60): The title compound was prepared from 2-methyl-1,3-cyclohexandione and quinolin-6-amine according to the procedure of Example 01-01 (yellow microcrystals, mp=110-112° C.). 1H NMR (D6-DMSO) δ 1.69 (s, 3H), 1.83-1.90 (m, 2H), 2.30 (t, J=6.7 Hz, 2H), 2.63-2.70 (m, 2H), 7.52 (d, J=2.4 Hz, 1H), 7.66 (dd, J=8.5, 2.4 Hz, 1H), 8.01 (d, J=9.8 Hz, 1H), 8.66 (s, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.86 (s, 1H). 13C NMR (D6-DMSO) δ 10.1, 21.7, 28.0, 36.7, 111.3, 117.4, 126.8, 129.4, 138.9, 142.0, 143.0, 143.6, 145.9, 156.4, 195.7. LCMS t=4.2 min, m/z Calcd for C15H16N3O; C15H15N3NaO; C30H31N6NaO2 254.129; 276.111; 529.233 [M+H]+; [M+Na]+; [2M+Na]+, Found 254.121; 276.102; 529.219.
EXAMPLE 01-61
Preparation of 2-methyl-3-[(quinazolin-6-yl)amino]cyclohex-2-en-1-one (01-61): The title compound was prepared from 2-methyl-1,3-cyclohexandione and quinazolin-6-amine according to the procedure of Example 01-01 (tan microcrystals, mp=215-216° C.). 1H NMR (D6-DMSO) δ 1.69 (s, 3H), 1.83-1.88 (m, 2H), 2.29 (t, J=6.1 Hz, 2H), 2.61-2.64 (m, 2H), 7.63 (d, J=2.4 Hz, 1H), 7.79-7.85 (m, 1H), 7.96 (d, J=8.5 Hz, 1H), 8.61 (s, 1H), 9.18 (s, 1H), 9.51 (s, 1H). 13C NMR (D6-DMSO) δ ppm 10.0, 21.7, 27.8, 36.7, 110.4, 116.7, 125.2, 128.3, 131.5, 139.7, 146.0, 153.7, 156.6, 159.5, 195.4. LCMS t=3.8 min, m/z Calcd for C15H16N3O; C15H15N3NaO; C30H31N6NaO2 254.129; 276.111; 529.233 [M+H]+; [M+Na]+; [2M+Na]+, Found 254.120; 276.102; 529.218.




EXAMPLE 01-62
Preparation of 3-[(1H-indol-6-yl)amino]-2-methylcyclohex-2-en-1-one (01-62): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 1H-indol-6-amine according to the procedure of Example 01-01 (white microneedles, mp=227-230° C.). 1H NMR (D6-DMSO) δ 1.71 (s, 3H), 1.72-1.77 (m, 2H), 2.17 (t, J=6.7 Hz, 2H), 2.36-2.40 (m, 2H), 6.41 (br s, 1H), 6.79-6.83 (m, 1H), 7.15 (s, 1H), 7.33 (t, J=2.4 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 8.20 (s, 1H), 11.09 (br s, 1H). 13C NMR (D6-DMSO) δ 8.9, 21.7, 27.2, 36.4, 101.0, 104.9, 108.5, 118.1, 119.8, 125.3, 125.8, 133.3, 135.8, 159.7, 193.6. LCMS t=4.6 min, m/z Calcd for C15H17N2O; C15H16N2NaO; C30H32N4NaO2 241.134; 263.116; 503.242 [M+H]+; [M+Na]+; [2M+Na]+, Found 241.141; 263.106; 503.224.




EXAMPLE 01-63
Preparation of 5-[(2-methyl-3-oxocyclohex-1-en-1-yl)amino]-2,3-dihydro-1H-1,3-benzodiazol-2-one (01-63): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 5-amino-1H-benzo[d]imidazol-2(3H)-one according to the procedure of Example 01-01 (brown microcrystals, mp=233-235° C.). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.70-1.77 (m, 2H), 2.16 (t, J=6.1 Hz, 2H), 2.29-2.36 (m, 2H), 6.71 (s, 1H), 6.73 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 10.63 (d, J=13.4 Hz, 2H). 13C NMR (D6-DMSO) δ 8.8, 21.6, 27.0, 36.4, 105.1, 106.6, 108.2, 118.5, 127.2, 129.9, 132.7, 155.5, 159.4, 193.7. LCMS t=3.2 min, m/z Calcd for C14H16N3O2; C14H15N3NaO2; C28H30N6NaO4 258.124; 280.106; 537.222 [M+H]+; [M+Na]+; [2M+Na]+, Found 258.123; 280.096; 537.206.




EXAMPLE 01-64
Preparation of 54(2-methyl-3-oxocyclohex-1-en-1-yl)amino)-1H-indole-2-carboxylic acid (01-64): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 5-amino-1H-indole-2-carboxylic acid according to the procedure of Example 01-01 (brown microcrystals, mp=310-315° C.). 1H NMR (D6-DMSO) δ 1.69-1.77 (m, 5H), 2.17 (t, J=6.3 Hz, 2H), 2.32-2.37 (m, 2H), 6.98-7.17 (m, 2H), 7.33-7.50 (m, 2H), 8.21 (s, 1H), 11.84 (s, 1H), 13.05 (br s, 1H). 13C NMR (D6-DMSO) δ 8.8, 21.6, 27.1, 36.4, 104.8, 107.3, 112.6, 118.6, 124.0, 126.9, 129.4, 132.2, 135.2, 159.8, 162.7, 193.7. LCMS t=3.8 min, m/z Calcd for C16H17N2O3; C32H33N4O6; C32H32N4NaO6 285.124; 569.240; 591.221 [M+H]+; [2M+H]+; [2M+Na]+, Found 285.123; 569.239; 591.220.
EXAMPLES 02-01 to 02-07


















EXAMPLE
TITLE





02-#
COMPOUND NAME
R1
R2
R3







01
4-((2-Methyl-3-
H
H
CO2H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


02
3-Chloro-4-((2-methyl-3-
Cl
H
CO2H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


03
2-Methoxy-4-((2-methyl-3-
H
OCH3
CO2H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


04
2-((2-Methyl-3-
CO2H
H
H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


05
5-Chloro-2-((2-methyl-3-
CO2H
H
Cl



oxocyclopent-1-en-1-



yl)amino)benzoic acid


06
3-Fluoro-4-((2-methyl-3-
F
H
CO2H



oxocyclopent-1-en-1-



yl)amino)benzoic acid


07
3-Bromo-4-((2-methyl-3-
Br
H
CO2H



oxocyclopent-1-en-1-



yl)amino)benzoic acid









EXAMPLE 02-01
Preparation of 4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-01): Example 01-01 (1.0 g, 4.1 mmol) was stirred in a THF:H2O (70 mL, 2:1) solution with sodium hydroxide (0.8 g, 5 eq), for 18 h. Aqueous hydrochloric acid was added until pH paper read at, or below, 3. Additional THF was added forming one layer and precipitating the hydrolyzed product, which was collected by filtration. The reaction on a 4.1 mmol scale yielded 0.36 g of the title compound, yellow microneedles (mp=228-230° C., 43% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26 (s, 2H), 2.80 (s, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 9.19 (s, 1H). LCMS t=4.7 min, m/z Calcd for C13H14NO3; C13H13NNaO3; C26H27N2O6; C26H26N2NaO6 232.10; 254.08; 463.19; 485.17 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 232.11; 254.09; 463.21; 485.19.
EXAMPLE 02-02
Preparation of 3-chloro-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-02): The title compound was prepared from Example 01-11 according to the procedure of Example 02-01; 6.0 mmol scale yielded 1.2 g of yellow microcrystals (mp=226-230° C., 86% yield). 1H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.23-2.25 (m, 2H), 2.52-2.54 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 8.97 (s, 1H), 13.21 (br s, 1H). LCMS t=5.2 min, m/z Calcd for C13H13ClNO3; C13H12ClNNaO3; C26H24Cl2N2NaO6 266.06; 288.04; 553.09 [M+H]+; [M+Na]+; [2M+Na]+, Found 266.11; 288.09; 553.08.
EXAMPLE 02-03
Preparation of 2-methoxy-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-03): The title compound was prepared from Example 01-13 according to the procedure of Example 02-01; 18.0 mmol scale yielded 3.6 g of yellow microcrystals (mp=240-243° C., 87% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.27 (m, 2H), 2.82-2.84 (m, 2H), 3.85 (s, 3H), 6.86 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 9.16 (s, 1H). LCMS t=4.9 min, m/z Calcd for C14H16NO4; C14H15NNaO4; C28H30N2NaO8 262.11; 284.09; 545.19 [M+H]+; [M+Na]+; [2M+Na]+, Found 262.17; 284.14; 545.20.
EXAMPLE 02-04
Preparation of 2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-04): The title compound was prepared from Example 01-19 according to the procedure of Example 02-01; 13.7 mmol scale yielded 3.0 g of yellow microcrystals (mp=245-248° C., 95% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.30-2.32 (m, 2H), 2.96-2.98 (m, 2H), 7.11 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.56-7.60 (m, 1H), 7.99 (d, J=7.9 Hz, 1H), 10.68 (s, 1H). 13C NMR (D6-DMSO) δ 6.6, 26.6, 33.3, 113.1, 117.2, 119.3, 121.8, 131.8, 134.2, 142.4, 167.9, 169.8, 201.8. LCMS t=4.7 min, m/z Calcd for C13H14NO3; C13H13NNaO3; C26H27N2O6; C26H26N2NaO6 232.10; 254.08; 463.19; 485.17 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 232.10; 254.08; 463.19; 485.17.
EXAMPLE 02-05
Preparation of 5-chloro-2-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-05): The title compound was prepared from Example 01-20 according to the procedure of Example 02-01; 2.5 mmol scale yielded 0.54 g of yellow microcrystals (mp=242-245° C., 81% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.32-2.34 (m, 2H), 2.93-2.95 (m, 2H), 7.55 (d, J=8.9 Hz, 1H), 7.62 (dd, J=8.9, 2.6 Hz, 1H), 7.93 (d, J=2.6 Hz, 1H), 10.60 (s, 1H). LCMS t=5.1 min, m/z Calcd for C13H13ClNO3; C13H12ClNNaO3; C26H25Cl2N2O6; C26H24Cl2N2NaO6 266.06; 288.04; 531.11; 553.09 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 266.06; 288.04; 531.10; 553.09.
EXAMPLE 02-06
Preparation of 3-fluoro-4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-06): The title compound was prepared from Example 01-21 according to the procedure of Example 02-01; 15.0 mmol scale yielded 2.9 g of yellow microcrystals (mp=210-213° C., 77% yield). 1H NMR (D6-DMSO) δ 1.52 (s, 3H), 2.23-2.25 (m, 2H), 2.54-2.56 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.73-7.78 (m, 2H), 9.07 (s, 1H). LCMS t=4.4 min, m/z Calcd for C13HBFNO3; C13H12FNNaO3; C26H25F2N2O6; C26H24F2N2NaO6 250.09; 272.07; 499.17; 521.15 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 250.09; 272.07; 499.17; 521.15.
EXAMPLE 02-07
Preparation of 3-bromo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-07): The title compound was prepared from Example 01-22 according to the procedure of Example 02-01; 9.5 mmol scale yielded 1.7 g of yellow microcrystals (mp=246-248° C., 58% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.26-2.28 (m, 2H), 2.50-2.52 (m, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.94 (dd, J=8.2, 1.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 9.13 (s, 1H). 13C NMR (D6-DMSO) δ 7.63, 25.9, 32.5, 110.9, 119.4, 127.3, 129.3, 133.6, 141.9, 165.6, 169.7, 202.5. LCMS t=4.6 min, m/z Calcd for C13H13BrNO3; C13H12BrNNaO3; C26H25Br2N2O6; C26H24Br2N2NaO6 310.01, 312.01; 331.99, 333.99; 621.01; 642.99 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 310.01, 312.01; 331.99, 333.99; 621.00; 642.99.
EXAMPLE 02-08
Preparation of 3-iodo-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzoic acid (02-08): The title compound was prepared from Example 01-43 according to the procedure of Example 02-01; 5.5 mmol scale yielded 1.7 g of yellow precipitate (87% yield), pale yellow microcrystals from EtOH (mp=263-264° C.). 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.20-2.23 (m, 2H), 2.42-2.44 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.94 (dd, J=8.2, 1.7 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.86 (s, 1H), 13.22 (s, 1H). 13C NMR (D6-DMSO) δ 7.6, 25.8, 32.7, 97.9, 110.2, 126.9, 129.5, 129.9, 139.8, 145.3, 165.5, 168.7, 202.5. LCMS t=4.4 min, m/z Calcd for C13H13INO3; C13H12INNaO3; C26H24I2N2NaO6 357.994; 379.976; 736.962 [M+H]+; [M+Na]+; [2M+Na]+, Found 357.995; 379.965; 736.944.




EXAMPLE 02-09
Preparation of methyl 4-bromo-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoate (02-09): Acetyl chloride (14 eq) was added to a CH2Cl2:MeOH (60 mL, 1:2) mixture at 0° C., followed by Example 01-48 (1.6 g, 5.0 mmol). After warming to rt, the mixture was stirred overnight. The solvent was removed on the rotovap to provide the crude material. 5.0 mmol scale yielded 1.23 g of brown microcrystals slowly from EtOAc (mp=211-213° C., 76% yield). 1H NMR (D6-DMSO) δ 1.74 (s, 3H), 1.78-1.81 (m, 2H), 2.25-2.29 (m, 2H), 2.38-2.41 (m, 2H), 3.88 (s, 3H), 7.81 (dd, J=8.4, 2.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 9.30 (s, 1H). 13C NMR (D6-DMSO) δ 8.9, 20.7, 27.2, 34.0, 52.6, 106.8, 127.2, 128.9, 129.3, 130.0, 133.7, 138.2, 165.1, 192.3. LCMS t=5.0 min, m/z Calcd for C15H17BrNO3; C15H16BrNNaO3; C30H33Br2N2NaO6 338.04, 340.04; 360.02, 362.02; 699.05 [M+H]+; [M+Na]+; [2M+Na]+, Found 324.03, 326.02; 345.99, 347.99; 670.96.


















EXAMPLE
TITLE





02-#
COMPOUND NAME
R1
R2
R3







10
3-((5-Amino-2-
H
H
NH2



chlorophenyl)amino)-2-



methylcyclohex-2-enone


11
3-((3-Amino-2-
NH2
H
H



chlorophenyl)amino)-2-



methylcyclohex-2-enone


12
3-((4-Amino-2-
H
NH2
H



chlorophenyl)amino)-2-



methylcyclohex-2-enone









EXAMPLE 02-10
Preparation of 3-((5-amino-2-chlorophenyl)amino)-2-methylcyclohex-2-enone (02-10): 3-((2-Chloro-5-nitrophenyl)amino)-2-methylcyclohex-2-enone (2 g, 7 mmol), Fe (1.6 g, 28 mmol), and NH4Cl (0.76 g, 14 mmol) were stirred in THF:EtOH:H2O (48 mL, 1:1:0.4) at 90° C., for 2 h. The mixture was filtered. The filtrate was diluted with EtOAc (50 mL), washed with brine (2×30 mL), dried with Na2SO4, and filtered. The second filtrate was concentrated to provide the title compound (1.5 g, 84% yield, mp=182-184° C.). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.71-1.82 (m, 2H), 2.15 (t, J=6.1 Hz, 2H), 2.18-2.22 (m, 2H), 5.37 (s, 2H), 6.45 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.84 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 21.2, 26.7, 36.4, 105.8, 113.2, 114.1, 116.6, 129.6, 137.0, 148.5, 159.2, 194.1. LCMS t=3.8 min, m/z Calcd for C13H16ClN2O; C13H15ClN2NaO; C26H30Cl2N4NaO2 251.095; 273.077; 523.164 [M+H]+; [M+Na]+; [2M+Na]+, Found 251.095; 273.076; 523.163.
3-((2-Chloro-5-nitrophenyl)amino)-2-methylcyclohex-2-enone (5.6 g of yellow solid, 50% yield) was prepared from 2-methyl-1,3-cyclohexandione (40 mmol) and 2-chloro-5-nitroaniline according to the procedure of Example 01-01.
EXAMPLE 02-11
Preparation of 3-((3-amino-2-chlorophenyl)amino)-2-methylcyclohex-2-enone (02-11): The title compound was prepared from 3-((2-chloro-3-nitrophenyl)amino)-2-methylcyclohex-2-enone according to the procedure of Example 02-10. 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.73 (quin, J=6.1 Hz, 2H), 2.15 (t, J=6.1 Hz, 2H), 2.19 (t, J=6.1 Hz, 2H), 5.49 (br s, 2H), 6.47 (d, J=7.3 Hz, 1H), 6.70 (d, J=9.8 Hz, 1H), 7.01 (t, J=7.9 Hz, 1H), 7.87 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 21.3, 26.6, 36.3, 105.7, 105.7, 113.0, 115.3, 116.1, 126.9, 137.3, 145.8, 159.4, 194.0. LCMS t=4.0 min, m/z Calcd for C13H16ClN2O; C13H15ClN2NaO; C26H30Cl2N4NaO2 251.095; 273.077; 523.164 [M+H]+; [M+Na]+; [2M+Na]+, Found 251.095; 273.076; 523.163.
3-((2-Chloro-3-nitrophenyl)amino)-2-methylcyclohex-2-enone was prepared from 2-methyl-1,3-cyclohexandione and 2-chloro-3-nitroaniline according to the procedure of Example 01-01.
EXAMPLE 02-12
Preparation of 3-((4-amino-2-chlorophenyl)amino)-2-methylcyclohex-2-enone (02-12): The title compound was prepared from 3-((2-chloro-4-nitrophenyl)amino)-2-methylcyclohex-2-enone according to the procedure of Example 02-10 (mp=156-158° C.). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.71 (quin, J=6.1 Hz, 2H), 2.07 (t, J=5.5 Hz, 2H), 2.12 (t, J=6.1 Hz, 2H), 5.47 (s, 2H), 6.51 (dd, J=8.5, 2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 7.77 (s, 1H). 13C NMR (D6-DMSO) δ 8.4, 21.2, 26.2, 36.2, 104.2, 112.8, 113.4, 124.2, 130.9, 132.6, 149.0, 160.8, 193.5. LCMS t=3.7 min, m/z Calcd for C13H16ClN2O; C13H15ClN2NaO; C26H30Cl2N4NaO2 251.095; 273.077; 523.164 [M+H]+; [M+Na]+; [2M+Na]+, Found 251.095; 273.077; 523.164.
3-((2-Chloro-4-nitrophenyl)amino)-2-methylcyclohex-2-enone was prepared from 2-methyl-1,3-cyclohexandione and 2-chloro-4-nitroaniline according to the procedure of Example 01-01.


















EXAMPLE
TITLE





02-#
COMPOUND NAME
R1
R2
R3







13
3-((3-Amino-2-
NH2
H
H



chlorophenyl)amino)-2-



methylcyclopent-2-enone


14
3-((4-Amino-2-
H
NH2
H



chlorophenyl)amino)-2-



methylcyclopent-2-enone


15
3-((5-Amino-2-
H
H
NH2



chlorophenyl)amino)-2-



methylcyclopent-2-en-1-one









EXAMPLE 02-13
Preparation of 3-((3-amino-2-chlorophenyl)amino)-2-methylcyclopent-2-enone (02-13): The title compound was prepared from 3-((2-chloro-3-nitrophenyl)amino)-2-methylcyclopent-2-enone according to the procedure of Example 02-10 (mp=223-225° C.). 1H NMR (D6-DMSO) δ 1.46 (s, 3H), 2.12-2.17 (m, 2H), 2.32-2.39 (m, 2H), 5.49 (br s, 2H), 6.53 (d, J=7.3 Hz, 1H), 6.71 (d, J=6.1 Hz, 1H), 6.99-7.03 (m, 1H), 8.72 (s, 1H). 13C NMR (D6-DMSO) δ 7.1, 25.3, 32.6, 108.2, 113.1, 114.6, 115.5, 127.0, 136.9, 145.8, 170.3, 201.8. LCMS t=3.7 min, m/z Calcd for C12H14ClN2O; C12H13ClN2NaO; C24H27Cl2N4O2; C24H26Cl2N4NaO2 237.080; 259.061; 473.151; 495.133 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 237.080; 259.060; 473.150 495.132.
3-((2-Chloro-3-nitrophenyl)amino)-2-methylcyclopent-2-enone was prepared from 2-methyl-1,3-cyclopentandione and 2-chloro-3-nitroaniline according to the procedure of Example 01-01.
EXAMPLE 02-14
Preparation of 3-((4-amino-2-chlorophenyl)amino)-2-methylcyclopent-2-enone (02-14): The title compound was prepared from 3-((2-chloro-4-nitrophenyl)amino)-2-methylcyclopent-2-enone according to the procedure of Example 02-10. 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.09-2.13 (m, 2H), 2.18-2.27 (m, 2H), 5.47 (br s, 2H), 6.50 (dd, J=8.5, 2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 8.58 (s, 1H). 13C NMR (D6-DMSO) δ 6.9, 25.1, 32.5, 107.0, 112.7, 113.4, 123.9, 130.4, 131.9, 149.0, 171.9, 201.4. LCMS t=3.5 min, m/z Calcd for C12H14ClN2O; C12H13ClN2NaO; C24H27Cl2N4O2; C24H26Cl2N4NaO2 237.080; 259.061; 473.151; 495.133 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 237.080; 259.061; 473.151 495.132.
3-((2-Chloro-4-nitrophenyl)amino)-2-methylcyclopent-2-enone was prepared from 2-methyl-1,3-cyclopentandione and 2-chloro-4-nitroaniline according to the procedure of Example 01-01.
EXAMPLE 02-15
Preparation of 3-((5-amino-2-chlorophenyl)amino)-2-methylcyclopent-2-en-1-one (02-15): The title compound was prepared from 3-((2-chloro-5-nitrophenyl)amino)-2-methylcyclopent-2-enone according to the procedure of Example 02-10 (mp=166-168° C.). 1H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.13-2.21 (m, 2H), 2.34-2.40 (m, 2H), 5.38 (s, 2H), 6.47 (dd, J=8.5, 2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 8.69 (s, 1H). 13C NMR (D6-DMSO) δ 7.2, 25.4, 32.6, 108.4, 113.2, 113.4, 115.8, 129.6, 136.5, 148.4, 170.1, 202.0. LCMS t=3.6 min, m/z Calcd for C12H14ClN2O; C12H13ClN2NaO; C24H26Cl2N4NaO2 237.080; 259.061; 495.133 [M+H]+; [M+Na]+; [2M+Na]+, Found 237.080; 259.061; 495.133.
3-((2-Chloro-5-nitrophenyl)amino)-2-methylcyclopent-2-enone was prepared from 2-methyl-1,3-cyclopentandione and 2-chloro-5-nitroaniline according to the procedure of Example 01-01.
EXAMPLES 03-01 to 03-23



















EXAMPLE







03-#
TITLE COMPOUND NAME
R1
R2
R3
R4







01
4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
H
H



yl)amino)-N-phenylbenzamide


02
N-Methyl-4-((2-methyl-3-oxocyclopent-1-
CH3
H
H
H



en-1-yl)amino)-N-phenylbenzamide


03
N-(2-Fluorophenyl)-4-((2-methyl-3-
H
F
H
H



oxocyclopent-1-en-1-yl)amino)benzamide


04
N-(3-Fluorophenyl)-4-((2-methyl-3-
H
H
F
H



oxocyclopent-1-en-1-yl)amino)benzamide


05
N-(4-Chlorophenyl)-4-((2-methyl-3-
H
H
H
Cl



oxocyclopent-1-en-1-yl)amino)benzamide


06
N-(4-Methoxyphenyl)-4-((2-methyl-3-
H
H
H
OCH3



oxocyclopent-1-en-1-yl)amino)benzamide


07
4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
H
CH3



yl)amino)-N-(p-tolyl)benzamide


08
4-((2-Methyl-3-oxocyclopent-1-en-1-
H
CH3
H
H



yl)amino)-N-(o-tolyl)benzamide


09
4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
CH3
H



yl)amino)-N-(m-tolyl)benzamide


10
N-(2-Methoxyphenyl)-4-((2-methyl-3-
H
OCH3
H
H



oxocyclopent-1-en-1-yl)amino)benzamide


11
N-(3-Methoxyphenyl)-4-((2-methyl-3-
H
H
OCH3
H



oxocyclopent-1-en-1-yl)amino)benzamide


12
4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
CF3
H



yl)amino)-N-(3-



(trifluoromethyl)phenyl)benzamide


13
N-(4-(tert-Butyl)phenyl)-4-((2-methyl-3-
H
H
H
C(CH3)3



oxocyclopent-1-en-1-yl)amino)benzamide


14
N-(3-Bromophenyl)-4-((2-methyl-3-
H
H
Br
H



oxocyclopent-1-en-1-yl)amino)benzamide


15
N-(4-Bromophenyl)-4-((2-methyl-3-
H
H
H
Br



oxocyclopent-1-en-1-yl)amino)benzamide









EXAMPLE 03-01
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (03-01): Example 02-01 (150 mg, 0.65 mmol, 1.3 eq) was dissolved in THF:DMF (1.5:1.0, 7.5 mL) and added to aniline (0.046 mL, 0.5 mmol) and PS-CDI (1.0 g, loading=1.33 mmol/g) in a dry reaction vessel. The reaction vessel was sealed and shaken for 18 h at rt. Resin was filtered from the solvent, washed with 1 vol of the reaction solvent, and THF (3×8 mL). IsoluteTM HM-N was added to the crude solution and dried on the rotovap. The crude material absorbed to IsoluteTM was packed into an empty samplet (1 g) and placed into the receiving KP-SilTM column (10 g). Products were separated from impurities using an isocratic solvent system, EtOAc:acetone (17:3), on Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The reaction on a 0.5 mmol scale yielded 15 mg of the title compound (10% yield). 41 NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.27 (m, 2H), 2.80-2.81 (m, 2H), 7.09 (t, J=7.3 Hz, 1H), 7.33-7.37 (m, 4H), 7.77 (d, J=7.7 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 9.18 (s, 1H), 10.16 (s, 1H). LCMS t=5.4 min, m/z Calcd for C19H19N2O2; C19H18N2NaO2; C38H37N4O4; C38H36N4NaO4 307.14; 329.13; 613.28; 635.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 307.16; 329.14; 613.31; 635.29.
EXAMPLE 03-02
Preparation of N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (03-02): The title compound was prepared from Example 02-01 and N-methylaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 30 mg (19% yield). 1H NMR (MeOD) δ 1.59 (s, 3H), 2.35-2.37 (m, 2H), 2.68-2.69 (m, 2H), 3.47 (s, 3H), 7.08 (d, J=8.2 Hz, 2H), 7.15 (d, J=7.6 Hz, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.26-7.31 (m, 4H). LCMS t=5.4 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.17; 343.16; 641.34; 663.32.
EXAMPLE 03-03
Preparation of N-(2-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-03): The title compound was prepared from Example 02-01 and 2-fluoroaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 10 mg (6% yield). 1H NMR (CDCl3) δ 1.60 (s, 3H), 2.76-2.78 (m, 2H), 3.34-3.36 (m, 2H), 6.68 (s, 1H), 7.10-7.28 (m, 5H), 7.92 (d, J=8.2 Hz, 2H), 8.04 (s, 1H), 8.45 (t, J=8.0 Hz, 1H). LCMS t=5.4 min, m/z Calcd for C19H18FN2O2; C19H17FN2NaO2; C38H35F2N4O4; C38H34F2N4NaO4 325.14; 347.12; 649.26; 671.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 325.15; 347.13; 649.29; 671.27.
EXAMPLE 03-04
Preparation of N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-04): The title compound was prepared from Example 02-01 and 3-fluoroaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 18 mg (11% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.28 (m, 2H), 2.80-2.82 (m, 2H), 6.91-6.93 (m, 1H), 7.36-7.39 (m, 3H), 7.56 (d, J=8.1 Hz, 1H), 7.76 (d, J=11.8 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 9.19 (s, 1H), 10.34 (s, 1H). LCMS t=5.5 min, m/z Calcd for C19H18FN2O2; C19H17FN2NaO2; C38H35F2N4O4; C38H34F2N4NaO4 325.14; 347.12; 649.26; 671.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 325.15; 347.13; 649.29; 671.28.
EXAMPLE 03-05
Preparation of N-(4-chlorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-05): The title compound was prepared from Example 02-01 and 4-chloroaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 10 mg (6% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.27 (m, 2H), 2.80-2.81 (m, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 9.19 (s, 1H), 10.29 (s, 1H). LCMS t=5.7 min, m/z Calcd for C19H18ClN2O2; C19H17ClN2NaO2; C38H35Cl2N4O4; C38H34Cl2N4NaO4 341.11; 363.09; 681.20; 703.19 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+. Found 341.12; 363.09; 681.23; 703.21,
EXAMPLE 03-06
Preparation of N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-06): The title compound was prepared from Example 02-01 and 4-aminoanisole according to the procedure of Example 03-01; 0.5 mmol scale yielded 12 mg (7% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.27 (m, 2H), 2.79-2.80 (m, 2H), 3.74 (s, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 9.17 (s, 1H), 10.05 (s, 1H). LCMS t=5.2 min, m/z Calcd for C20H21N2O3; C40H41N4O6; C40H41N4NaO6 337.16; 673.30; 695.28 [M+H]+; [2M+H]+; [2M+Na]+, Found 337.17; 673.33; 695.31.
EXAMPLE 03-07
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (03-07): The title compound was prepared from Example 02-01 and 4-aminotoluene according to the procedure of Example 03-01; 0.5 mmol scale yielded 25 mg (16% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.25-2.28 (m, 5H), 2.79-2.81 (m, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 9.17 (s, 1H), 10.08 (s, 1H). LCMS t=5.5 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.17; 343.16; 641.34; 663.32.
EXAMPLE 03-08
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (03-08): The title compound was prepared from Example 02-01 and o-toluidine according to the procedure of Example 03-01; 0.5 mmol scale yielded 1 mg (1% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.31 (s, 3H), 2.80-2.82 (m, 2H), 6.91 (d, J=6.4 Hz, 1H), 7.22 (s, 1H), 7.36 (d, J=6.9 Hz, 2H), 7.56 (d, J=6.4 Hz, 1H), 7.62 (s, 1H), 7.94 (d, J=6.9 Hz, 2H), 9.18 (s, 1H), 10.08 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.18; 343.16; 641.29; 663.28.
EXAMPLE 03-09
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (03-09): The title compound was prepared from Example 02-01 and m-toluidine according to the procedure of Example 03-01; 0.5 mmol scale yielded 13 mg (8% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.23 (s, 3H), 2.24-2.26 (m, 2H), 2.79-2.80 (m, 2H), 7.16 (t, J=7.3 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.27 (d, J=7.3 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.18 (s, 1H), 9.81 (s, 1H). LCMS t=5.5 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.18; 343.16; 641.29; 663.28.
EXAMPLE 03-10
Preparation of N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-10): The title compound was prepared from Example 02-01 and o-anisidine according to the procedure of Example 03-01; 0.5 mmol scale yielded 8 mg (5% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.27 (m, 2H), 2.79-2.81 (m, 2H), 3.84 (s, 3H), 6.97 (t, J=7.2 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 7.17 (t, J=7.3 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.77 (d, J=7.4 Hz, 1H), 7.94 (d, J=7.9 Hz, 2H), 9.18 (s, 1H), 9.34 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H21N2O3; C20H20N2NaO3; C40H40N4NaO6 337.16; 359.14; 695.28 [M+H]+; [M+Na]+; [2M+Na]+, Found 337.17; 359.14; 695.27.
EXAMPLE 03-11
Preparation of N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-11): The title compound was prepared from Example 02-01 and m-anisidine according to the procedure of Example 03-01; 0.5 mmol scale yielded 4 mg (2% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.80-2.82 (m, 2H), 3.75 (s, 3H), 6.67 (d, J=7.3 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.47 (s, 1H), 7.94 (d, J=8.3 Hz, 2H), 9.18 (s, 1H), 10.12 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H21N2O3; C20H20N2NaO3; C40H40N4NaO6 337.16; 359.14; 695.28 [M+H]+; [M+Na]+; [2M+Na]+, Found 337.17; 359.14; 695.28.
EXAMPLE 03-12
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(3-(trifluoromethyl)phenyl)benzamide (03-12): The title compound was prepared from Example 02-01 and 3-(trifluoromethyl)aniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 3 mg (2% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.81-2.83 (m, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.97 (d, J=7.9 Hz, 2H), 8.05 (d, J=7.6 Hz, 1H), 8.26 (s, 1H), 9.21 (s, 1H), 10.47 (s, 1H). LCMS t=5.9 min, m/z Calcd for C20H18F3N2O2; C20H17F3N2NaO2; C40H34F6N4NaO6 375.13; 397.11; 771.24 [M+H]+; [M+Na]+; [2M+Na]+, Found 375.13; 397.11; 771.24.
EXAMPLE 03-13
Preparation of N-(4-(tert-butyl)phenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (03-13): The title compound was prepared from Example 02-01 and 4-tert-butylaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 4 mg (2% yield). 1H NMR (D6-DMSO) δ 1.28 (s, 9H), 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.79-2.81 (m, 2H), 7.36 (d, J=8.0 Hz, 4H), 7.68 (d, J=8.2 Hz, 2H), 7.94 (d, J=8.1 Hz, 2H), 9.18 (s, 1H), 10.10 (s, 1H). LCMS t=6.1 min, m/z Calcd for C23H27N2O2; C23H26N2NaO2; C46H53N4O4; C46H52N4NaO4 363.21; 385.19; 725.41; 747.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 363.21; 385.19; 725.41; 747.39.
EXAMPLE 03-14
Preparation of N-(3-bromophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-14): The title compound was prepared from Example 02-01 and 3-bromoaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 4 mg (2% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.81-2.83 (m, 2H), 7.29-7.34 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 8.11 (s, 1H), 9.20 (s, 1H), 10.31 (s, 1H). LCMS t=5.9 min, m/z Calcd for C19H18BrN2O2; C19H17BrN2NaO2; C38H34BrN4NaO6 385.06, 387.05; 407.04, 409.04; 793.08 [M+H]+; [M+Na]+; [2M+Na]+, Found 385.05, 387.05; 407.03, 409.03; 793.09.
EXAMPLE 03-15
Preparation of N-(4-bromophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-15): The title compound was prepared from Example 02-01 and 4-bromoaniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 3 mg (2% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.80-2.82 (m, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 9.19 (s, 1H), 10.28 (s, 1H). LCMS t=5.9 min, m/z Calcd for C19H15BrN2O2; C19H17BrN2NaO2; C38H34BrN4NaO6 385.06, 387.05; 407.04, 409.04; 793.08 [M+H]+; [M+Na]+; [2M+Na]+, Found 385.05, 387.05; 407.03, 409.03; 793.09.




EXAMPLE 03-16
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide (03-16): The title compound was prepared from Example 02-01 and 1-aminonaphthalene according to the procedure of Example 03-01; 0.5 mmol scale yielded 11 mg (6% yield). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 2.27-2.29 (m, 2H), 2.82-2.84 (m, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.54-7.60 (m, 4H), 7.81-7.87 (m, 2H), 7.98-8.00 (m, 2H), 8.08 (d, J=8.3 Hz, 2H), 9.21 (s, 1H), 10.36 (s, 1H). LCMS t=5.6 min, m/z Calcd for C23H21N2O2; C23H20N2NaO2; C46H41N4O4; C46H40N4NaO4 357.16; 379.14; 713.31; 735.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 357.18; 379.18; 713.34; 735.33.




EXAMPLE 03-17
Preparation of 4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(pyridin-2-yl)benzamide (03-17): The title compound was prepared from Example 02-01 and 2-aminopyridine according to the procedure of Example 03-01; 0.5 mmol scale yielded 2 mg (1% yield). 1H NMR (D6-DMSO) δ 1.62 (s, 3H), 2.26-2.28 (m, 2H), 2.81-2.82 (m, 2H), 7.16 (s, 1H), 7.34 (d, J=7.8 Hz, 2H), 7.83-7.84 (m, 1H), 8.03 (d, J=7.7 Hz, 2H), 8.18 (d, J=8.0 Hz, 2H), 8.39 (s, 1H), 9.18 (s, 1H), 10.68 (s, 1H). LCMS t=5.1 min, m/z Calcd for C18H18N3O2; C18H17N3NaO2; C36H34N6NaO4 308.14; 330.12; 637.25 [M+H]+; [M+Na]+; [2M+Na]+, Found 308.16; 330.13; 637.22.




EXAMPLE 03-18
Preparation of N-benzyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-18): The title compound was prepared from Example 02-01 and benzylamine according to the procedure of Example 03-01; 0.5 mmol scale yielded 20 mg (13% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.76-2.78 (m, 2H), 4.47 (d, J=5.7 Hz, 2H), 7.23-7.30 (m, 7H), 7.87 (d, J=8.2 Hz, 2H), 8.98 (s, 1H), 9.12 (s, 1H). LCMS t=5.3 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.17; 343.16; 641.24; 663.32.




EXAMPLE 03-19
Preparation of N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-19): The title compound was prepared from Example 02-01 and cyclohexylamine according to the procedure of Example 03-01; 0.5 mmol scale yielded 11 mg (7% yield). 1H NMR (MeOD) δ 1.21-1.25 (m, 2H), 1.34-1.42 (m, 4H), 1.69 (s, 3H), 1.80-1.83 (m, 2H), 1.94-1.96 (m, 2H), 2.40-2.43 (m, 2H), 2.82-2.83 (m, 2H), 3.85-3.86 (m, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). LCMS t=5.4 min, m/z Calcd for C19H25N2O2; C19H24N2NaO2; C38H49N4O4; C38H48N4NaO4 313.19; 335.17; 625.38; 647.38 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 313.21; 335.19; 625.40; 647.39.




EXAMPLE 03-20
Preparation of N,N-dimethyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (03-20): The title compound was prepared from Example 02-01 and dimethylamine according to the procedure of Example 03-01; 0.5 mmol scale yielded 55 mg (43% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.21-2.23 (m, 2H), 2.73-2.74 (m, 2H), 2.96 (s, 6H), 7.27 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 9.07 (s, 1H). LCMS t=5.0 min, m/z Calcd for C15H19N2O2; C15H18N2NaO2; C30H37N4O4; C30H36N4NaO4 259.14; 281.13; 517.28; 539.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 259.19; 281.16; 517.25; 539.23.




EXAMPLE 03-21
Preparation of 2-methyl-3-((4-(piperidine-1-carbonyl)phenyl)amino)cyclopent-2-enone (03-21): The title compound was prepared from Example 02-01 and piperidine according to the procedure of Example 03-01; 0.5 mmol scale yielded 33 mg (22% yield). 1H NMR (D6-DMSO) δ 1.50 (br s, 8H), 1.59 (s, 3H), 2.22-2.24 (m, 2H), 2.72-2.24 (m, 2H), 3.53 (br s, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 9.06 (s, 1H). LCMS t=5.4 min, m/z Calcd for C18H23N2O2; C18H22N2NaO2; C36H45N4O4; 299.18; 321.16; 619.33 [M+H]+; [M+Na]+; [2M+Na]+, Found 299.20; 321.17; 619.29.




EXAMPLE 03-22
Preparation of 2-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)cyclopent-2-enone (03-22): The title compound was prepared from Example 02-01 and morpholine according to the procedure of Example 03-01; 0.5 mmol scale yielded 59 mg (39% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.22-2.24 (m, 2H), 2.73-2.75 (m, 2H), 3.40-3.70 (m, 8H), 7.28 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 9.08 (s, 1H). LCMS t=4.9 min, m/z Calcd for C17H21N2O3; C17H20N2NaO3; C34H40N4NaO6 301.16; 323.14; 623.28 [M+H]+; [M+Na]+; [2M+Na]+, Found 301.18; 323.15; 623.25.




EXAMPLE 03-23
Preparation of 3((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (03-23): The title compound was prepared from Example 01-03 and aniline according to the procedure of Example 03-01; 0.5 mmol scale yielded 8 mg (5% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.74 (m, 2H), 7.11 (t, J=7.1 Hz, 1H), 7.36 (t, J=7.5 Hz, 2H), 7.46 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.8 Hz, 2H), 7.79 (s, 1H), 9.15 (s, 1H), 10.26 (s, 1H). LCMS t=5.6 min, m/z Calcd for C19H19N2O2; C19H18N2NaO2; C38H37N4O4; C38H36N4NaO4 307.14; 329.13; 613.28; 635.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 307.17; 329.15; 613.26; 635.24.
EXAMPLES 04-01 to 04-103




EXAMPLE 04-01
Preparation of N-cyclohexyl-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-01): Method A; Isobutylchloroformate (IBCF, 0.285 mL, 2.0 eq) was added to Example 01-03 (250 mg, 1.1 mmol, 1.0 eq) stirring in CH2Cl2 (1.0 mL), in a screw-capped vial. N-Methylmorpholine (NMM, 0.36 mL, 3.0 eq) was added at 0° C. in 3 portions. After stirring for 1 h, cyclohexylamine (0.15 mL, 1.2 eq) was added, sealed, and stirred for 18 h at rt. Crude materials were purified by recrystallization. The reaction on a 1.1 mmol scale yielded 140 mg of the title compound after recrystallization from CHCl3 (41% yield). 1H NMR (D6-DMSO) δ 1.10-1.16 (m, 1H), 1.30-1.36 (m, 4H), 1.57 (s, 3H), 1.61 (d, J=9.7 Hz, 1H), 1.73-1.74 (m, 2H), 1.80-1.82 (m, 2H), 2.20-2.23 (m, 2H), 2.64-2.66 (m, 2H), 3.75-3.77 (m, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.69 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 9.08 (s, 1H). LCMS t=5.8 min, m/z Calcd for C19H25N2O2; C19H24N2NaO2; C38H49N4O4; C38H49N4NaO4 313.19; 335.17; 625.38; 647.36 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 313.23; 335.20; 625.37; 647.37.




EXAMPLE 04-02
Preparation of 3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide (04-02): The title compound was prepared from Example 01-03 and 1-aminonaphthalene according to the procedure of Example 04-01; 1.1 mmol scale yielded 100 mg after recrystallization from CHCl3 (26% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.23-2.25 (m, 2H), 2.74-2.76 (m, 2H), 7.50 (d, J=7.9 Hz, 2H), 7.53-7.58 (m, 4H), 7.60 (d, J=7.2 Hz, 2H), 7.87 (t, J=8.9 Hz, 2H), 7.91 (s, 1H), 7.96-8.00 (m, 2H), 9.17 (s, 1H), 10.46 (s, 1H). LCMS t=5.9 min, m/z Calcd for C23H21N2O2; C23H20N2NaO2; C46H41N4O4; C46H40N4NaO4 357.16; 379.14; 713.31; 735.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 357.18; 379.15; 713.32; 735.31.




EXAMPLE 04-03
Preparation of 3-(2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(pyridin-4-yl)benzamide (04-03): The title compound was prepared from Example 01-03 and 4-aminopyridine according to the procedure of Example 04-01; 1.1 mmol scale yielded 60 mg after recrystallization from MeOH (18% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.49-7.54 (m, 2H), 7.72 (d, J=7.1 Hz, 1H), 7.80 (s, 3H), 8.49 (d, J=4.7 Hz, 2H), 9.17 (s, 1H), 10.62 (s, 1H). LCMS t=3.0 min, m/z Calcd for C18H18N3O2; C18H17N3NaO2; C36H34N6NaO4 308.14; 330.12; 637.25 [M+H]+; [M+Na]+; [2M+Na]+, Found 308.17; 330.14; 637.24.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







04
N-(4-Methoxyphenyl)-3-((2-methyl-3-
H
H
OCH3



oxocyclopent-1-en-1-yl)amino)benzamide


05
3-((2-Methyl-3-oxocyclopent-1-en-1-
CH3
H
H



yl)amino)-N-(o-tolyl)benzamide


06
3-((2-Methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)benzamide


07
3-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)benzamide


08
N-(2-Fluorophenyl)-3-((2-methyl-3-
F
H
H



oxocyclopent-1-en-1-yl)amino)benzamide


09
N-(3-Bromophenyl)-3-((2-methyl-3-oxocyclopent-
H
Br
H



1-en-1-yl)amino)benzamide


10
N-(4-Bromophenyl)-3-((2-methyl-3-oxocyclopent-
H
H
Br



1-en-1-yl)amino)benzamide


11
3-((2-Methyl-3-oxocyclopent-1-en-1-yl)amino)-N-
H
CF3
H



(3-(trifluoromethyl)phenyl)benzamide


12
3-((2-Methyl-3-oxocyclopent-1-en-1-yl)amino)-N-
H
H
CF3



(4-(trifluoromethyl)phenyl)benzamide









EXAMPLE 04-04
Preparation of N-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-04): Method B; IBCF (0.98 eq) was added to Example 01-03 (250 mg, 1.1 mmol, 1.0 eq) stirring in CH2Cl2 (3.0 mL), in a screw-capped vial. NMM (0.95 eq) was added at 0° C. After stirring for 1 h, 4-aminoanisole (163 mg, 1.0 eq) was added, sealed, and stirred for 18 h at rt. Crude materials were added directly to KP-SilTM columns (10 g) with products separating from impurities using stepwise gradients on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The stepwise gradient utilized two, or three, solvents (acetone, hexanes, EtOAc, or MeOH) running from non-polar to polar steps. Typical increments used were hexanes:EtOAc (H:E) steps 1:1-1:3-1:19-100% EtOAc, then when necessary 2-5% increments of MeOH were applied. Eluting Solvent System (ESS) is the solvent step which eluted the product and is indicated below in the following format ESS=H:E (X:X), or the percentage of MeOH (%) in EtOAc. Subsequent triturations or recrystallizations were performed from suitable solvents. The reaction on a 1.1 mmol scale yielded 30 mg of the title compound after chromatography (ESS=EtOAc:acetone (1:3)) and recrystallization from EtOAc (8% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.23-2.25 (m, 2H), 2.70-2.72 (m, 2H), 3.75 (s, 3H), 6.93 (d, J=8.7 Hz, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.70 (d, J=7.5 Hz, 1H), 7.78 (s, 1H), 9.14 (s, 1H), 10.14 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H21N2O3; C20H20N2NaO3; C40H41N4O6; C40H40N4NaO6 337.16; 359.14; 673.30; 695.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 337.19; 359.17; 673.33; 695.32.
EXAMPLE 04-05
Preparation of 3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-05): The title compound was prepared from Example 01-03 and o-toluidine according to the procedure of Example 04-04; 1.1 mmol scale yielded 10 mg after chromatography (ESS=H:E (1:1)) and recrystallization from MeOH (3% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.23-2.25 (m, 5H), 2.71-2.73 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.81 (s, 1H), 9.13 (s, 1H), 9.90 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.19; 343.16; 641.31; 663.32.
EXAMPLE 04-06
Preparation of 3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (04-06): The title compound was prepared from Example 01-03 and m-toluidine according to the procedure of Example 04-04; 1.1 mmol scale yielded 30 mg after chromatography (ESS=EtOAc) and recrystallization from MeOH (9% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.22-2.25 (m, 2H), 2.31 (s, 3H), 2.70-2.72 (m, 2H), 6.93 (d, J=7.5 Hz, 1H), 7.23 (t, J=7.7 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 9.15 (s, 1H), 10.18 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.19; 343.16; 641.31; 663.29.
EXAMPLE 04-07
Preparation of 3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (04-07): The title compound was prepared from Example 01-03 and p-toluidine according to the procedure of Example 04-04; 1.1 mmol scale yielded 10 mg after chromatography (ESS=EtOAc) and recrystallization from CHCl3 (3% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.22-2.25 (m, 2H), 2.28 (s, 3H), 2.70-2.72 (m, 2H), 7.16 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 9.14 (s, 1H), 10.18 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.19; 343.16; 641.31; 663.30.
EXAMPLE 04-08
Preparation of N-(2-fluorophenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-08): The title compound was prepared from Example 01-03 and 2-fluoroaniline according to the procedure of Example 04-04; 1.1 mmol scale yielded 40 mg after chromatography (ESS=EtOAc) and recrystallization from MeOH (11% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 2.22-2.25 (m, 2H), 2.70-2.72 (m, 2H), 7.21-7.25 (m, 1H), 7.29-7.33 (m, 2H), 7.48-7.52 (m, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 9.15 (s, 1H), 10.14 (s, 1H). LCMS t=5.6 min, m/z Calcd for C19H18FN2O2; C19H17FN2NaO2; C38H35F2N4O4; C38H34F2N4NaO4 325.14; 347.12; 649.26; 671.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+. Found 325.16; 347.14; 649.26; 671.26.
EXAMPLE 04-09
Preparation of N-(3-bromophenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-09): The title compound was prepared from Example 01-03 and 3-bromoaniline according to the procedure of Example 04-04; 1.1 mmol scale yielded 40 mg after chromatography (ESS=EtOAc) and recrystallization from MeOH (9% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.31-7.34 (m, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.79 (s, 1H), 8.11 (s, 1H), 9.16 (s, 1H), 10.40 (s, 1H). LCMS t=5.9 min, m/z Calcd for C19H18BrN2O2; C19H17BrN2NaO2; C38H35BrN4O4; C38H34BrN4NaO6 385.06, 387.05; 407.04, 409.04; 771.10; 793.08 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.06, 387.06; 407.04, 409.04; 771.12; 793.11.
EXAMPLE 04-10
Preparation of N-(4-bromophenyl)-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-10): The title compound was prepared from Example 01-03 and 4-bromoaniline according to the procedure of Example 04-04; 1.1 mmol scale yielded 10 mg after chromatography (ESS=EtOAc) and recrystallization from CHCl3 (2% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.26 (m, 2H), 2.71-2.73 (m, 2H), 7.47-7.48 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.70 (d, J=7.7 Hz, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.79 (s, 1H), 9.14 (s, 1H), 10.38 (s, 1H). LCMS t=5.9 min, m/z Calcd for C19H18BrN2O2; C19H17BrN2NaO2; C38H35BrN4O4; C38H34BrN4NaO6 385.06, 387.05; 407.04, 409.04; 771.10; 793.08 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.06, 387.06; 407.04, 409.03; 771.12; 793.11.
EXAMPLE 04-11
Preparation of 3-(2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(3-(trifluoromethyl)phenyl)-benzamide (04-11): The title compound was prepared from Example 01-03 and 3-(trifluoromethyl)aniline according to the procedure of Example 04-04; 1.1 mmol scale yielded 30 mg after chromatography (ESS=EtOAc) and recrystallization from CHCl3 (7% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.46-7.50 (m, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.82 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 9.16 (s, 1H), 10.56 (s, 1H). LCMS t=6.1 min, m/z Calcd for C20H18F3N2O2; C20H17F3N2NaO2; C40H35F6N4O4; C40H34F6N4NaO6 375.13; 397.11; 749.26; 771.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 375.14; 397.12; 749.27; 771.26.
EXAMPLE 04-12
Preparation of 3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(4-(trifluoromethyl)phenyl)-benzamide (04-12): The title compound was prepared from Example 01-03 and 3-(trifluoromethyl)aniline according to the procedure of Example 04-04; 1.1 mmol scale yielded 10 mg after chromatography (ESS=EtOAc) and recrystallization from CHCl3 (2% yield). 1H NMR (D6-DMSO) δ 1.60 (s, 3H), 2.23-2.25 (m, 2H), 2.71-2.73 (m, 2H), 7.49-7.50 (m, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.72-7.75 (m, 3H), 7.81 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 9.16 (s, 1H), 10.59 (s, 1H). LCMS t=6.1 min, m/z Calcd for C20H18F3N2O2; C20H17F3N2NaO2; C40H34F6N4NaO6 375.13; 397.11; 771.24 [M+H]+; [M+Na]+; [2M+Na]+, Found 375.16; 397.12; 771.26.




EXAMPLE 04-13
Preparation of 3-chloro-N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-13): Method C; NMM (1.2 eq) and IBCF (1.2 eq) were added to Example 02-02 (100 mg, 0.38 mmol, 1.0 eq), stirring in CH2Cl2 (10 mL), in a screw-capped vial. After stirring for 30 min amine, methylamine (2M, 225 mL, 0.45 mmol, 1.2 eq), and a second aliquot of NMM (1.2 eq) were added, sealed, and stirred at rt for 48 h. Crude materials were added directly to KP-SilTM columns (10 g) with products separating from impurities using stepwise gradients (see Example 04-04 Method B) on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. Some reactions performed at higher concentrations allowed the crude solid product to precipitate. In these cases the purification was filtration with CH2Cl2, H2O, and diethyl ether rinsing. The reaction on a 0.38 mmol scale yielded 35 mg of the title compound after chromatography (ESS=MeOH (6%)) and EtOAc trituration (33% yield). 1H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.21-2.23 (m, 2H), 2.47-2.49 (m, 2H), 2.78 (s, 3H), 7.44 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 8.56-8.58 (m, 1H), 8.93 (s, 1H). LCMS t=5.1 min, m/z Calcd for C14H16ClN2O2; C14H15ClN2NaO2; C28H31Cl2N4O4; C28H30Cl2N4NaO4 279.09; 301.07; 557.17; 579.15 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 279.14; 301.11; 557.16; 579.15.




EXAMPLE 04-14
Preparation of 3-chloro-N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-14): The title compound was prepared from Example 02-02 and cyclohexylamine according to the procedure of Example 04-13; 0.38 mmol scale yielded 56 mg after chromatography (ESS=EtOAc) and EtOAc trituration (43% yield). 1H NMR (D6-DMSO) δ 1.10-1.18 (m, 1H), 1.23-1.34 (m, 4H), 1.45 (s, 3H), 1.61 (d, J=12.1 Hz, 1H), 1.73 (s, 2H), 1.81 (s, 2H), 2.20-2.23 (m, 2H), 2.46-2.48 (m, 2H), 3.75 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.95 (s, 1H). LCMS t=6.0 min, m/z Calcd for C19H24ClN2O2; C19H23ClN2NaO2; C36H47Cl2N4O4; C36H47Cl2N4NaO4 347.15; 369.13; 693.30; 715.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 347.17; 369.15; 693.32; 715.30.




EXAMPLE 04-15
Preparation of 3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)-benzamide (04-15): The title compound was prepared from Example 02-02 and 1-aminonaphthalene according to the procedure of Example 04-13; 0.38 mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (17% yield). 1H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.24-2.26 (m, 2H), 2.54-2.56 (m, 2H), 7.52-7.61 (m, 4H), 7.89 (d, J=8.0 Hz, 1H), 7.98-8.01 (m, 3H), 8.06 (d, J=7.7 Hz, 1H), 8.27 (s, 1H), 9.03 (s, 1H), 10.55 (s, 1H). LCMS t=5.9 min, m/z Calcd for C23H20ClN2O2; C23H19ClN2NaO2; C46H39Cl2N4O4; C46H38Cl2N4NaO4 391.12; 413.10; 781.23; 803.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 391.22; 413.11; 781.26; 803.25.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







16
3-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
H



yl)amino)-N-phenylbenzamide


17
3-Chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-
OCH3
H
H



oxocyclopent-1-en-1-yl)amino)benzamide


18
3-Chloro-N-(3-methoxyphenyl)-4-((2-methyl-3-
H
OCH3
H



oxocyclopent-1-en-1-yl)amino)benzamide


19
3-Chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-
H
H
OCH3



oxocyclopent-1-en-1-yl)amino)benzamide


20
3-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
CH3
H
H



yl)amino)-N-(o-tolyl)benzamide


21
3-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)benzamide


22
3-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)benzamide









EXAMPLE 04-16
Preparation of 3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (04-16): The title compound was prepared from Example 02-02 and aniline according to the procedure of Example 04-13; 0.38 mmol scale yielded 20 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (16% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.25 (m, 2H), 2.50-2.51 (m, 2H), 7.12 (t, J=7.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 2H), 7.50 (d, J=8.3 Hz, 1H), 7.77 (d, J=7.9 Hz, 2H), 7.94 (dd, J=8.2, 1.4 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H), 9.00 (s, 1H), 10.34 (s, 1H). LCMS t=5.8 min, m/z Calcd for C19H18ClN2O2; C19H17ClN2NaO2; C38H34Cl2N4NaO4 341.11; 363.09; 703.19 [M+H]+; [M+Na]+; [2M+Na]+, Found 341.13; 363.10; 703.20.
EXAMPLE 04-17
Preparation of 3-chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-17): The title compound was prepared from Example 02-02 and o-anisidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 55 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (39% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.22-2.25 (m, 2H), 2.50-2.52 (m, 2H), 3.83 (s, 3H), 6.97 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 9.00 (s, 1H), 9.67 (s, 1H). LCMS t=5.9 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.11; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.13; 393.11; 741.26; 763.24.
EXAMPLE 04-18
Preparation of 3-chloro-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-18): The title compound was prepared from Example 02-02 and m-anisidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 3 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (2% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.25 (m, 2H), 2.50-2.52 (m, 2H), 3.76 (s, 3H), 6.70 (d, J=8.3 Hz, 1H), 7.26 (t, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.93 (dd, J=8.3, 1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 9.00 (s, 1H), 10.30 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.11; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.13; 393.11; 741.26; 763.23.
EXAMPLE 04-19
Preparation of 3-chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-19): The title compound was prepared from Example 02-02 and 4-aminoanisole according to the procedure of Example 04-13; 0.38 mmol scale yielded 5 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (4% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.22-2.25 (m, 2H), 2.50-2.51 (m, 2H), 3.75 (s, 3H), 6.94 (d, J=8.9 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.9 Hz, 2H), 7.93 (dd, J=8.3, 1.2 Hz, 1H), 8.12 (s, 1H), 8.98 (s, 1H), 10.22 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.11; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.13; 393.10; 741.24; 763.23.
EXAMPLE 04-20
Preparation of 3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-20): The title compound was prepared from Example 02-02 and o-toluidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 45 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (32% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.25 (m, 5H), 2.50-2.51 (m, 2H), 7.18-7.23 (m, 2H), 7.28 (d, J=7.3 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 8.14 (s, 1H), 8.99 (s, 1H), 10.02 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.14; 377.12; 709.25; 731.24.
EXAMPLE 04-21
Preparation of 3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (04-21): The title compound was prepared from Example 02-02 and m-toluidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 42 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (30% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.22-2.25 (m, 2H), 2.31 (s, 3H), 2.50-2.51 (m, 2H), 6.94 (d, J=7.4 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.98 (s, 1H), 10.26 (s, 1H). LCMS t=5.9 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.14; 377.12; 709.25; 731.24.
EXAMPLE 04-22
Preparation of 3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (04-22): The title compound was prepared from Example 02-02 and p-toluidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (18% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.23-2.24 (m, 2H), 2.29 (s, 3H), 2.50-2.51 (m, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.2 Hz, 1H), 8.13 (s, 1H), 8.96 (s, 1H), 10.25 (s, 1H). 13C NMR (D6-DMSO) δ 7.7, 20.5, 25.7, 32.7, 110.8, 120.5, 127.2, 128.8, 128.9, 129.0, 132.9, 136.4, 139.4, 163.3, 168.7, 202.7. LCMS t=5.9 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.12; 377.10; 709.21; 731.20.




EXAMPLE 04-23
Preparation of (1R,4R)—N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide (04-23): The title compound was prepared from Example 01-33 and methylamine according to the procedure of Example 04-13; 0.42 mmol scale yielded 40 mg after chromatography (ESS=MeOH (15%)) and EtOAc trituration (38% yield). 1H NMR (D6-DMSO) δ 1.33-1.50 (m, 9H), 1.73 (d, J=12.0 Hz, 2H), 1.84 (d, J=10.6 Hz, 2H), 2.04-2.09 (m, 1H), 2.09-2.11 (2H), 2.54 (d, J=4.5 Hz, 2H), 3.25-3.30 (m, 1H), 6.84-6.87 (m, 1H), 7.70 (d, J=4.3 Hz, 1H). LCMS t=1.2 min, m/z Calcd for C14H23N2O2; C14H22N2NaO2; C28H45N4O4; C28H44N4NaO4 251.18; 273.16; 501.34; 523.33 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 251.28; 273.25; 501.41; 523.40.




EXAMPLE 04-24
Preparation of (1R,4R)—N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-24): The title compound was prepared from Example 01-33 and cyclohexylamine according to the procedure of Example 04-13; 0.42 mmol scale yielded 75 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (56% yield). 1H NMR (D6-DMSO) δ 1.10-1.18 (m, 4H), 1.20-1.28 (m, 2H), 1.30-1.40 (m, 2H), 1.40-1.50 (5H), 1.54 (d, J=10.8 Hz, 1H), 1.62-1.75 (m, 7H), 1.83 (d, J=10.4 Hz, 1H), 2.00-2.08 (m, 1H), 2.10-2.13 (m, 2H), 3.46-3.53 (m, 1H), 6.85-6.67 (m, 1H), 7.57 (d, J=7.4 Hz, 1H). LCMS t=5.4 min, m/z Calcd for C19H31N2O2; C19H30N2NaO2; C38H61N4NaO4; C38H60N4NaO4 319.24; 341.22; 637.47; 659.45 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 319.32; 341.29; 637.57; 659.60.




EXAMPLE 04-25
Preparation of (1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)cyclohexanecarboxamide (04-25): The title compound was prepared from Example 01-33 and 1-aminonaphthalene according to the procedure of Example 04-13; 0.42 mmol scale yielded 23 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (15% yield). 1H NMR (D6-DMSO) δ 1.45-1.55 (m, 5H), 1.62 (q, J=12.1 Hz, 2H), 1.94 (d, J=10.8 Hz, 2H), 2.01 (d, J=12.7 Hz, 2H), 2.11-2.13 (m, 2H), 2.51-2.55 (m, 3H), 3.35-3.45 (m, 1H), 6.92 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.94 (d, J=7.1 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 9.85 (s, 1H). LCMS t=5.6 min, m/z Calcd for C23H27N2O2; C23H26N2NaO2; C46H53N4O4; C46H52N4NaO4 363.21; 385.18; 725.41; 747.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 363.34; 385.25; 725.53; 747.52.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







26
(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
H



yl)amino)-N-phenylcyclohexanecarboxamide


27
(1R,4R)-N-(2-Methoxyphenyl)-4-((2-methyl-3-
OCH3
H
H



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


28
(1R,4R)-N-(3-Methoxyphenyl)-4-((2-methyl-3-
H
OCH3
H



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


29
(1R,4R)-N-(4-Methoxyphenyl)-4-((2-methyl-3-
H
H
OCH3



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


30
(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1-
CH3
H
H



yl)amino)-N-(o-tolyl)cyclohexanecarboxamide


31
(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)cyclohexanecarboxamide


32
(1R,4R)-4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)cyclohexanecarboxamide


33
(1R,4R)-N-(3-Fluorophenyl)-4-((2-methyl-3-
H
F
H



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


34
(1R,4R)-N-(4-Chlorophenyl)-4-((2-methyl-3-
H
H
Cl



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide









EXAMPLE 04-26
Preparation of (1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylcyclohexane-carboxamide (04-26): The title compound was prepared from Example 01-33 and aniline according to the procedure of Example 04-13; 0.42 mmol scale yielded 65 mg after chromatography (ESS=MeOH (10%)) and EtOAc trituration (50% yield). 1H NMR (D6-DMSO) δ 1.38-1.60 (m, 8H), 1.83-1.98 (m, 5H), 2.08-2.18 (m, 2H), 2.28-2.39 (m, 1H), 3.28-3.30 (m, 1H), 6.89 (s, 1H), 7.01 (s, 1H), 7.28 (s, 2H), 7.60 (s, 2H), 9.85 (s, 1H). LCMS t=5.4 min, m/z Calcd for C19H25N2O2; C19H24N2NaO2; C38H49N4O4; C38H48N4NaO4 313.19; 335.17; 625.37; 647.36 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 313.27; 335.25; 625.47; 647.46.
EXAMPLE 04-27
Preparation of (1R,4R)—N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide (04-27): The title compound was prepared from Example 01-33 and o-anisidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 75 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (52% yield). 1H NMR (D6-DMSO) δ 1.40-1.56 (m, 8H) 1.84-1.89 (m, 5H), 2.10-2.12 (m, 2H), 2.47-2.52 (m, 2H), 3.83 (s, 3H), 6.86-6.91 (m, 2H), 7.01-7.07 (m, 2H), 7.94 (d, J=7.8 Hz, 1H), 9.02 (s, 1H). LCMS t=5.5 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H53N4O6; C40H52N4NaO6 343.20; 365.18; 685.40; 707.38 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 343.30; 365.25; 685.51; 707.57.
EXAMPLE 04-28
Preparation of (1R,4R)—N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide (04-28): The title compound was prepared from Example 01-33 and m-anisidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 70 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (49% yield). 1H NMR (D6-DMSO) δ 1.40-1.57 (m, 7H), 1.85-1.91 (m, 5H), 2.11-2.13 (m, 2H), 2.28 (t, J=11.6 Hz, 1H), 2.52-2.54 (m, 2H), 3.71 (s, 3H), 6.60 (d, J=7.6 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 9.84 (s, 1H). LCMS t=5.4 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H53N4O6; C40H52N4NaO6 343.20; 365.18; 685.40; 707.38 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 343.27; 365.25; 685.51; 707.50.
EXAMPLE 04-29
Preparation of (1R,4R)—N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide (04-29): The title compound was prepared from Example 01-33 and p-anisidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 35 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (24% yield). 1H NMR (D6-DMSO) δ 1.38-1.58 (m, 7H), 1.84-1.90 (m, 5H), 2.10-2.12 (m, 2H), 2.25 (t, J=11.7 Hz, 1H), 2.51-2.54 (m, 2H), 3.71 (s, 3H), 6.84-6.89 (m, 3H), 7.50 (d, J=8.7 Hz, 2H), 9.71 (s, 1H). LCMS t=5.3 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H53N4O6; C40H52N4NaO6 343.20; 365.18; 685.40; 707.38 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 343.27; 365.25; 685.50; 707.49.
EXAMPLE 04-30
Preparation of (1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)cyclohexanecarboxamide (04-30): The title compound was prepared from Example 01-33 and o-toluidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 22 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (16% yield). 1H NMR (D6-DMSO) δ 1.41-1.59 (m, 7H), 1.89-1.92 (m, 4H), 2.11-2.13 (m, 2H), 2.18 (s, 3H), 2.37 (t, J=10.9 Hz, 1H), 2.51-2.53 (m, 2H), 6.88-6.93 (m, 1H), 7.07 (t, J=6.9 Hz, 1H), 7.14 (t, J=7.1 Hz, 1H), 7.19 (d, J=7.1 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 9.22 (s, 1H). LCMS t=5.3 min, m/z Calcd for C20H27N2O2; C20H26N2NaO2; C40H53N4O4; C40H52N4NaO4 327.21; 349.19; 653.41; 675.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 327.28; 349.26; 653.50; 675.49.
EXAMPLE 04-31
Preparation of (1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)cyclohexanecarboxamide (04-31): The title compound was prepared from Example 01-33 and m-toluidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 70 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (51% yield). 1H NMR (D6-DMSO) δ 1.38-1.58 (m, 7H), 1.84-1.91 (m, 4H), 2.10-2.12 (m, 2H), 2.26-2.31 (m, 4H), 2.51-2.53 (m, 2H), 3.33-3.35 (m, 1H), 6.83 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 725 (d, J=7.8 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 9.77 (s, 1H). LCMS t=5.5 min, m/z Calcd for C20H27N2O2; C20H26N2NaO2; C40H53N4O4; C40H52N4NaO4 327.21; 349.19; 653.41; 675.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 327.28; 349.26; 653.50; 675.49.
EXAMPLE 04-32
Preparation of (1R,4R)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)-cyclohexanecarboxamide (04-32): The title compound was prepared from Example 01-33 and p-toluidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 60 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (44% yield). 1H NMR (D6-DMSO) δ 1.28-1.58 (m, 7H), 1.84-1.90 (m, 4H), 2.10-2.12 (m, 2H), 2.23-2.30 (m, 4H), 2.51-2.53 (m, 2H), 3.30-3.35 (m, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 9.76 (s, 1H). 13C NMR (D6-DMSO) δ 6.8, 20.4, 23.8, 28.1, 32.5, 32.7, 43.8, 51.6, 105.0, 119.0, 129.0, 131.8, 136.9, 172.1, 173.6, 200.0. LCMS t=5.6 min, m/z Calcd for C20H27N2O2; C20H26N2NaO2; C40H53N4O4; C40H52N4NaO4 327.21; 349.19; 653.41; 675.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 327.28; 349.26; 653.50; 675.49.
EXAMPLE 04-33
Preparation of (1R,4R)—N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-33): The title compound was prepared from Example 01-33 and m-fluoroaniline according to the procedure of Example 04-13; 0.42 mmol scale yielded 72 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (52% yield). 1H NMR (D6-DMSO) δ 1.38-1.57 (m, 7H), 1.86-1.91 (m, 4H), 2.10-2.12 (m, 2H), 2.29 (t, J=11.9 Hz, 1H), 2.51-2.53 (m, 2H), 3.33-2.35 (m, 1H), 6.83-6.90 (m, 2H), 7.29-7.33 (m, 2H), 7.61 (d, J=11.9 Hz, 1H), 10.08 (s, 1H). LCMS t=5.5 min, m/z Calcd for C19H24FN2O2; C19H23FN2NaO2; C38H47F2N4O4; C38H46F2N4NaO4 331.18; 353.16; 661.36; 683.34 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 331.27; 353.23; 661.45; 683.44.
EXAMPLE 04-34
Preparation of (1R,4R)—N-(4-chlorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-34): The title compound was prepared from Example 01-33 and p-chloroaniline according to the procedure of Example 04-13; 0.42 mmol scale yielded 30 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (21% yield). 1H NMR (D6-DMSO) δ 1.38-1.58 (m, 7H), 1.86-1.91 (m, 4H), 2.10-2.12 (m, 2H), 2.28 (t, J=11.9 Hz, 1H), 2.51-2.53 (m, 2H), 3.33-3.35 (m, 1H), 6.88 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 10.01 (s, 1H). LCMS t=5.7 min, m/z Calcd for C19H24ClN2O2; C19H23ClN2NaO2; C38H47Cl2N4O4; C38H46Cl2N4NaO4 347.15; 369.13; 693.30; 715.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 347.22; 369.20; 693.40; 715.39.




EXAMPLE 04-35
Preparation of (1S,4S)—N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)cyclohexanecarboxamide (04-35): The title compound was prepared from Example 01-34 and methylamine according to the procedure of Example 04-13; 0.42 mmol scale yielded 11 mg after chromatography (ESS=MeOH (12%)) and EtOAc trituration (10% yield). 1H NMR (D6-DMSO) δ 1.45-1.52 (m, 5H), 1.58-1.65 (m, 4H), 1.93-2.00 (m, 2H), 2.09-2.13 (m, 2H), 2.26-2.30 (m, 1H), 2.49-2.51 (m, 2H), 2.58 (d, J=3.9 Hz, 3H), 3.33-3.35 (m, 1H), 6.80-6.86 (m, 1H), 7.60-7.66 (m, 1H). LCMS t=1.4 min, m/z Calcd for C14H23N2O2; C14H22N2NaO2; C28H44N4NaO4 251.18; 273.16; 523.33 [M+H]+; [M+Na]+; [2M+Na]+, Found 251.28; 273.25; 523.40.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







36
(1S,4S)-4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
H



yl)amino)-N-phenylcyclohexanecarboxamide


37
(1S,4S)-N-(2-Methoxyphenyl)-4-((2-methyl-3-
OCH3
H
H



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


38
(1S,4S)-N-(3-Methoxyphenyl)-4-((2-methyl-3-
H
OCH3
H



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


39
(1S,4S)-4-((2-Methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)cyclohexanecarboxamide


40
(1S,4S)-4-((2-Methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)cyclohexanecarboxamide


41
(1S,4S)-N-(3-Fluorophenyl)-4-((2-methyl-3-
H
F
H



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide


42
(1S,4S)-N-(4-Chlorophenyl)-4-((2-methyl-3-
H
H
Cl



oxocyclopent-1-en-1-



yl)amino)cyclohexanecarboxamide









EXAMPLE 04-36
Preparation of (1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylcyclohexane-carboxamide (04-36): The title compound was prepared from Example 01-34 and aniline according to the procedure of Example 04-13; 0.42 mmol scale yielded 16 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (12% yield). 1H NMR (D6-DMSO) δ 1.45-1.55 (m, 3H), 1.61-1.68 (m, 5H), 1.74-1.81 (m, 2H), 2.00-2.18 (m, 2H), 2.09-2.12 (m, 2H), 2.53-2.55 (m, 2H), 3.40-3.60 (m, 1H), 6.88 (s, 1H), 7.02 (t, J=7.4 Hz, 1H), 7.28 (t, J=7.9 Hz, 2H), 7.62 (d, J=7.9 Hz, 2H), 9.74 (s, 1H). LCMS t=5.5 min, m/z Calcd for C19H25N2O2; C19H24N2NaO2; C38H48N4NaO4 313.19; 335.17; 647.36 [M+H]+; [M+Na]+; [2M+Na]+, Found 313.28; 335.25; 647.46.
EXAMPLE 04-37
Preparation of (1S,4S)—N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-37): The title compound was prepared from Example 01-34 and o-anisidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 60 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (42% yield). 1H NMR (D6-DMSO) δ 1.45-1.54 (m, 3H), 1.60-1.69 (m, 5H), 1.71-1.77 (m, 2H), 1.98-2.05 (m, 2H), 2.08-2.12 (m, 2H), 2.51-2.53 (m, 1H), 2.68-2.72 (m, 1H), 3.42-3.58 (m, 1H), 3.83 (s, 3H), 6.85-6.92 (m, 2H), 7.02-7.08 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.87 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H52N4NaO6 343.20; 365.18; 707.38 [M+H]+; [M+Na]+; [2M+Na]+, Found 343.28; 365.26; 707.52.
EXAMPLE 04-38
Preparation of (1S,4S)—N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-38): The title compound was prepared from Example 01-34 and m-anisidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 3 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (2% yield). 1H NMR (D6-DMSO) δ 1.45-1.53 (m, 3H), 1.59-1.69 (m, 5H), 1.73-1.78 (m, 2H), 1.99-2.08 (m, 2H), 2.09-2.12 (m, 2H), 2.49-2.51 (m, 2H), 3.45-3.55 (m, 1H), 3.72 (s, 3H), 6.60 (d, J=6.8 Hz, 1H), 6.88-6.92 (m, 1H), 7.14-7.20 (m, 2H), 7.37 (s, 1H), 9.74 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H52N4NaO6 343.20; 365.18; 707.38 [M+H]+; [M+Na]+; [2M+Na]+, Found 343.20; 365.18; 707.35.
EXAMPLE 04-39
Preparation of (1S,4S)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)-cyclohexanecarboxamide (04-39): The title compound was prepared from Example 01-34 and m-toluidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 1 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (1% yield). 1H NMR (D6-DMSO) δ 1.46-1.53 (m, 3H), 1.59-1.69 (m, 5H), 1.73-1.81 (m, 2H), 2.00-2.07 (m, 2H), 2.09-2.14 (m, 2H), 2.26 (s, 3H), 2.50-2.53 (m, 2H), 3.40-3.53 (m, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.85-6.90 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 9.66 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H27N2O2; C20H26N2NaO2; C40H52N4NaO4 327.21; 349.19; 675.39 [M+H]+; [M+Na]+; [2M+Na]+, Found 327.29; 349.25; 675.52.
EXAMPLE 04-40
Preparation of (1S,4S)-4-(2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)-cyclohexanecarboxamide (04-40): The title compound was prepared from Example 01-34 and p-toluidine according to the procedure of Example 04-13; 0.42 mmol scale yielded 1 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (1% yield). 1H NMR (D6-DMSO) δ 1.46-1.53 (m, 3H), 1.58-1.68 (m, 5H), 1.73-1.80 (m, 2H), 2.00-2.07 (m, 2H), 2.09-2.13 (m, 2H), 2.24 (s, 3H), 2.50-2.53 (m, 2H), 3.40-3.53 (m, 1H), 6.87-6.92 (m, 1H), 7.08 (d, J=7.9 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 9.65 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H27N2O2; C20H26N2NaO2; C40H53N4O4; C40H52N4NaO4 327.21; 349.19; 653.41; 675.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 327.29; 349.26; 653.50; 675.49.
EXAMPLE 04-41
Preparation of (1S,4S)—N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-41): The title compound was prepared from Example 01-34 and m-fluoroaniline according to the procedure of Example 04-13; 0.42 mmol scale yielded 16 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (12% yield). 1H NMR (D6-DMSO) δ 1.46-1.53 (m, 3H), 1.60-1.70 (m, 5H), 1.72-1.79 (m, 2H), 1.90-2.07 (m, 2H), 2.09-2.13 (m, 2H), 2.50-2.58 (m, 2H), 3.45-3.60 (m, 1H), 6.83-6.93 (m, 2H), 7.30-7.36 (m, 2H), 7.64 (d, J=12.0 Hz, 1H), 9.98 (s, 1H). LCMS t=5.7 min, m/z Calcd for C19H24FN2O2; C19H23FN2NaO2; C38H47F2N4O4; C38H46F2N4NaO4 331.18; 353.16; 661.36; 683.34 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 331.26; 353.23; 661.45; 683.44.
EXAMPLE 04-42
Preparation of (1S,4S)—N-(4-chlorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-cyclohexanecarboxamide (04-42): The title compound was prepared from Example 01-34 and p-chloroaniline according to the procedure of Example 04-13; 0.42 mmol scale yielded 13 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (9% yield). 1H NMR (D6-DMSO) δ 1.46-1.54 (m, 3H), 1.59-1.69 (m, 5H), 1.72-1.79 (m, 2H), 2.00-2.07 (m, 2H), 2.09-2.13 (m, 2H), 2.50-2.54 (m, 2H), 3.40-3.58 (m, 1H), 6.83-6.92 (m, 1H), 7.34 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 9.90 (s, 1H). LCMS t=5.7 min, m/z Calcd for C19H24ClN2O2; C19H23ClN2NaO2; C38H46Cl2N4NaO4 347.15; 369.13; 715.28 [M+H]+; [M+Na]+; [2M+Na]+, Found 347.22; 369.20; 715.39.




EXAMPLE 04-43
Preparation of 2-chloro-N-cyclohexyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-43): The title compound was prepared from Example 01-10 and cyclohexylamine according to the procedure of Example 04-13; 0.38 mmol scale yielded 1 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (1% yield). 1H NMR (D6-DMSO) δ 1.10-1.18 (m, 2H), 1.27-1.33 (m, 4H), 1.58 (s, 3H), 1.70-1.73 (m, 2H), 1.81-1.83 (m, 2H), 2.23-2.25 (m, 2H), 2.72-2.75 (m, 2H), 3.32-3.70 (m, 1H), 7.22 (dd, J=8.2, 1.7 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.95 (s, 1H). LCMS t=5.7 min, m/z Calcd for C19H24ClN2O2; C19H23ClN2NaO2; C36H4702N4O4; C36H47Cl2N4NaO4 347.15; 369.13; 693.30; 715.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 347.23; 369.20; 693.41; 715.41.




EXAMPLE 04-44
Preparation of 2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)-benzamide (04-44): The title compound was prepared from Example 01-10 and 1-aminonaphthalene according to the procedure of Example 04-13; 0.38 mmol scale yielded 40 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (27% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.27-2.29 (m, 2H), 2.80-2.82 (m, 2H), 7.35 (d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.54-7.59 (m, 3H), 7.70-7.74 (m, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 9.19 (s, 1H), 10.50 (s, 1H). LCMS t=5.8 min, m/z Calcd for C23H20ClN2O2; C23H19ClN2NaO2; C46H39Cl2N4O4; C46H38Cl2N4NaO4 391.12; 413.10; 781.23; 803.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 391.19; 413.17; 781.39; 803.38.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







45
2-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
H



yl)amino)-N-phenylbenzamide


46
2-Chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-
OCH3
H
H



oxocyclopent-1-en-1-yl)amino)benzamide


47
2-Chloro-N-(3-methoxyphenyl)-4-((2-methyl-3-
H
OCH3
H



oxocyclopent-1-en-1-yl)amino)benzamide


48
2-Chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-
H
H
OCH3



oxocyclopent-1-en-1-yl)amino)benzamide


49
2-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
CH3
H
H



yl)amino)-N-(o-tolyl)benzamide


50
2-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)benzamide


51
2-Chloro-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)benzamide


52
2-Chloro-N-(3-fluorophenyl)-4-((2-methyl-3-
H
F
H



oxocyclopent-1-en-1-yl)amino)benzamide









EXAMPLE 04-45
Preparation of 2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (04-45): The title compound was prepared from Example 01-10 and aniline according to the procedure of Example 04-13; 0.38 mmol scale yielded 17 mg after chromatography (ESS=EtOAc) and EtOAc trituration (13% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.25-2.28 (m, 2H), 2.78-2.80 (m, 2H), 7.10 (t, J=7.4 Hz, 1H), 7.30 (dd, J=8.3, 1.6 Hz, 1H), 7.35 (t, J=7.8 Hz, 2H), 7.41 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.9 Hz, 2H), 9.16 (s, 1H), 10.43 (s, 1H). LCMS t=5.6 min, m/z Calcd for C19H18ClN2O2; C19H17ClN2NaO2; C38H35Cl2N4O4; C38H34Cl2N4NaO4 341.11; 363.09; 681.20; 703.19 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 341.18; 363.16; 681.31; 703.31.
EXAMPLE 04-46
Preparation of 2-chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-46): The title compound was prepared from Example 01-10 and o-anisidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 45 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (30% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.79-2.80 (m, 2H), 3.83 (s, 3H), 6.97 (t, J=6.9 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 7.39 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.96 (d, J=6.6 Hz, 1H), 9.16 (s, 1H), 9.51 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.11; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.18; 393.16; 741.36; 763.35.
EXAMPLE 04-47
Preparation of 2-chloro-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-47): The title compound was prepared from Example 01-10 and m-anisidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 47 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (34% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.25-2.28 (m, 2H), 2.78-2.79 (m, 2H), 3.75 (s, 3H), 6.69 (d, J=7.0 Hz, 1H), 7.22-7.31 (m, 3H), 7.40-7.42 (m, 2H), 7.54 (d, J=8.3 Hz, 1H), 9.16 (s, 1H), 10.41 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.11; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.18; 393.16; 741.36; 763.35.
EXAMPLE 04-48
Preparation of 2-chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-48): The title compound was prepared from Example 01-10 and p-anisidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 17 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (12% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.77-2.79 (m, 2H), 3.74 (s, 3H), 6.92 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 9.15 (s, 1H), 10.29 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.11; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.18; 393.16; 741.35; 763.34.
EXAMPLE 04-49
Preparation of 2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-49): The title compound was prepared from Example 01-10 and o-toluidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (19% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.29 (m, 5H), 2.78-2.80 (m, 2H), 7.15 (t, J=7.1 Hz, 1H), 7.21-7.23 (m, 1H), 7.26 (d, J=7.1 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.40-7.43 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 9.16 (s, 1H), 9.91 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.19; 377.17; 709.34; 731.34.
EXAMPLE 04-50
Preparation of 2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (04-50): The title compound was prepared from Example 01-10 and m-toluidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 36 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (27% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.30 (s, 3H), 2.78-2.79 (m, 2H), 6.92 (d, J=7.3 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 9.16 (s, 1H), 10.36 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.19; 377.17; 709.35; 731.34.
EXAMPLE 04-51
Preparation of 2-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (04-51): The title compound was prepared from Example 01-10 and p-toluidine according to the procedure of Example 04-13; 0.38 mmol scale yielded 21 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (16% yield). 1H NMR (D6-DMSO) δ 1.61 (2, 3H), 2.27-2.29 (m, 5H), 2.77-2.78 (m, 2H), 7.15 (d, J=7.8 Hz, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.60 (d, J=7.9 Hz, 2H), 9.16 (s, 1H), 10.34 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.19; 377.17; 709.34; 731.33.
EXAMPLE 04-52
Preparation of 2-chloro-N-(3-fluorophenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-52): The title compound was prepared from Example 01-10 and m-fluoroaniline according to the procedure of Example 04-13; 0.38 mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (18% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.26-2.28 (m, 2H), 2.78-2.80 (m, 2H), 6.94 (d, J=8.2 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.46 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.68 (d, J=11.3 Hz, 1H), 9.17 (s, 1H), 10.65 (s, 1H). LCMS t=5.8 min, m/z Calcd for C19H17ClFN2O2; C19H16ClFN2NaO2; C38H33Cl2F2N4O4; C38H32Cl2F2N4NaO4 359.10; 381.08; 717.18; 739.17 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 359.16; 381.14; 717.30; 739.29.




EXAMPLE 04-53
Preparation of 3-methoxy-N-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-53): The title compound was prepared from Example 01-12 and methylamine according to the procedure of Example 04-13; 0.40 mmol scale yielded 25 mg after chromatography (ESS=MeOH (7%)) and EtOAc trituration (23% yield). 1H NMR (D6-DMSO) δ 1.51 (s, 3H), 2.16-2.19 (m, 2H), 2.48-2.51 (m, 2H), 2.79 (d, J=4.5 Hz, 1H), 3.87 (s, 3H), 7.25 (d, J=8.1 Hz, 1H), 7.43 (dd, J=8.1, 1.4 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 8.42-8.44 (m, 1H), 8.51 (s, 1H). LCMS t=4.9 min, m/z Calcd for C15H19N2O3; C15H18N2NaO3; C30H36N4NaO6 275.14; 297.12; 571.25 [M+H]+; [M+Na]+; [2M+Na]+, Found 275.23; 297.21; 571.42.




EXAMPLE 04-54
Preparation of N-cyclohexyl-3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-54): The title compound was prepared from Example 01-12 and cyclohexylamine according to the procedure of Example 04-13; 0.40 mmol scale yielded 52 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (38% yield). 1H NMR (D6-DMSO) δ 1.20-1.28 (m, 1H), 1.32-1.35 (m, 4H), 1.51 (s, 3H), 1.62 (d, J=11.9 Hz, 1H), 1.75 (s, 2H), 1.82 (s, 2H), 2.16-2.19 (m, 2H), 2.47-2.50 (m, 2H), 3.75-3.78 (m, 1H), 3.88 (s, 3H), 7.24 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.53 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H52N4NaO6 343.20; 365.18; 707.38 [M+H]+; [M+Na]+; [2M+Na]+, Found 343.27; 365.25; 707.55.




EXAMPLE 04-55
Preparation of 3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)-benzamide (04-55): The title compound was prepared from Example 01-12 and 1-aminonaphthalene according to the procedure of Example 04-13; 0.40 mmol scale yielded 41 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (27% yield). 1H NMR (D6-DMSO) δ 1.55 (s, 3H), 2.21-2.23 (m, 2H), 2.56-2.58 (m, 2H), 3.95 (s, 3H), 7.36 (d, J=8.1 Hz, 1H), 7.55-7.60 (m, 4H), 7.73 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.98-8.00 (m, 2H), 8.60 (s, 1H), 10.43 (s, 1H). LCMS t=5.8 min, m/z Calcd for C24H23N2O3; C24H22N2NaO3; C48H45N4O6; C48H44N4NaO6 387.17; 409.15; 773.33; 795.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 387.24; 409.22; 773.48; 795.47.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







56
3-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
H



yl)amino)-N-phenylbenzamide


57
3-Methoxy-N-(2-methoxyphenyl)-4-((2-methyl-3-
OCH3
H
H



oxocyclopent-1-en-1-yl)amino)benzamide


58
3-Methoxy-N-(3-methoxyphenyl)-4-((2-methyl-3-
H
OCH3
H



oxocyclopent-1-en-1-yl)amino)benzamide


59
3-Methoxy-N-(4-methoxyphenyl)-4-((2-methyl-3-
H
H
OCH3



oxocyclopent-1-en-1-yl)amino)benzamide


60
3-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-
CH3
H
H



yl)amino)-N-(o-tolyl)benzamide


61
3-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)benzamide


62
3-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)benzamide


63
N-(3-Fluorophenyl)-3-methoxy-4-((2-methyl-3-
H
F
H



oxocyclopent-1-en-1-yl)amino)benzamide


64
N-(4-Chlorophenyl)-3-methoxy-4-((2-methyl-3-
H
H
Cl



oxocyclopent-1-en-1-yl)amino)benzamide









EXAMPLE 04-56
Preparation of 3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (04-56): The title compound was prepared from Example 01-12 and aniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (26% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.19-2.22 (m, 2H), 2.53-2.55 (m, 2H), 3.93 (s, 3H), 7.11 (t, J=8.1 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.36 (t, J=7.8 Hz, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.76 (d, J=7.8 Hz, 2H), 8.57 (s, 1H), 10.21 (s, 1H). LCMS t=5.6 min, m/z Calcd for C20H21N2O3; C20H20N2NaO3; C40H41N4O6; C40H40N4NaO6 337.16; 359.14; 673.30; 695.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 337.23; 359.21; 673.41; 695.41.
EXAMPLE 04-57
Preparation of 3-methoxy-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-57): The title compound was prepared from Example 01-12 and o-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 30 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (20% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.53-2.55 (m, 2H), 3.84 (s, 3H), 3.92 (s, 3H), 6.98 (t, J=7.5 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.55 (s, 1H), 9.46 (s, 1H). LCMS t=5.9 min, m/z Calcd for C21H23N2O4; C21H22N2NaO4; C42H45N4O8; C42H44N4NaO8 367.17; 389.15; 733.32; 755.31 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 367.24; 389.22; 733.46; 755.46.
EXAMPLE 04-58
Preparation of 3-methoxy-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-58): The title compound was prepared from Example 01-12 and m-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 53 mg after chromatography (ESS=EtOAc) and EtOAc trituration (36% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.19-2.22 (m, 2H), 2.53-2.55 (m, 2H), 3.76 (s, 3H), 3.93 (s, 3H), 6.69 (dd, J=8.1, 2.0 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.47 (s, 1H), 7.58-7.61 (m, 2H), 8.57 (s, 1H), 10.18 (s, 1H). LCMS t=5.7 min, m/z Calcd for C21H23N2O4; C21H22N2NaO4; C42H45N4O8; C42H44N4NaO8 367.17; 389.15; 733.32; 755.31 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 367.24; 389.22; 733.46; 755.45.
EXAMPLE 04-59
Preparation of 3-methoxy-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-59): The title compound was prepared from Example 01-12 and p-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 55 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (38% yield). 1H NMR (D6-DMSO) δ1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.52-2.53 (m, 2H), 3.75 (s, 3H), 3.92 (s, 2H), 6.94 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.66 (d, J=8.7 Hz, 2H), 8.56 (s, 1H), 10.10 (s, 1H). 13C NMR (D6-DMSO) δ 7.3, 25.5, 32.8, 55.2, 55.9, 109.8, 110.9, 113.7, 119.9, 122.2, 124.7, 131.1, 132.1, 132.3, 152.4, 155.6, 164.4, 169.6, 202.1. LCMS t=5.6 min, m/z Calcd for C21H23N2O4; C21H22N2NaO4; C42H45N4O8; C42H44N4NaO8 367.17; 389.15; 733.32; 755.31 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 367.23; 389.21; 733.44; 755.43.
EXAMPLE 04-60
Preparation of 3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-60): The title compound was prepared from Example 01-12 and o-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 60 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (43% yield). 1H NMR (D6-DMSO) δ 1.54 (s, 3H), 2.20-2.22 (m, 2H), 2.24 (s, 3H), 2.53-2.55 (m, 2H), 3.92 (s, 3H), 7.18 (t, J=7.1 Hz, 1H), 7.23 (t, J=7.2 Hz, 1H), 7.29 (d, J=7.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.66 (s, 1H), 8.58 (s, 1H), 9.89 (s, 1H). LCMS t=5.7 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.45; 723.44.
EXAMPLE 04-61
Preparation of 3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (04-61): The title compound was prepared from Example 01-12 and m-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 47 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (34% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.32, (s, 3H), 2.53-2.55 (m, 2H), 3.93 (m, 3H), 6.93 (d, J=7.3 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.56-7.62 (m, 4H), 8.57 (s, 1H), 10.13 (s, 1H). 13C NMR (D6-DMSO) δ 7.3, 21.2, 25.5, 32.8, 55.9, 109.9, 110.93, 117.7, 120.1, 121.1, 124.4, 124.6, 128.4, 131.2, 132.2, 137.7, 139.0, 152.4, 164.7, 169.6, 202.1. LCMS t=5.8 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.44; 723.43.
EXAMPLE 04-62
Preparation of 3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (04-62): The title compound was prepared from Example 01-12 and p-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 45 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (32% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.29 (s, 3H), 2.53-2.55 (m, 2H), 3.92 (s, 3H), 7.16 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 8.57 (s, 1H), 10.14 (s, 1H). 13C NMR (D6-DMSO) δ 7.3, 20.5, 25.5, 32.8, 55.9, 109.9, 110.9, 120.0, 120.6, 124.7, 129.0, 131.2, 132.3, 132.7, 136.6, 152.4, 164.6, 169.6, 202.1. LCMS t=5.8 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.44; 723.43.
EXAMPLE 04-63
Preparation of N-(3-fluorophenyl)-3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-63): The title compound was prepared from Example 01-12 and m-fluoroaniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 51 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (36% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.40-2.56 (m, 2H), 3.93 (s, 3H), 6.94 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.40 (dd, J=15.2, 7.9 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.59 (d, J=11.7 Hz, 1H), 8.58 (s, 1H), 10.39 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 25.6, 32.8, 55.9, 107.0 (JCF=26.2 Hz), 110.1 (JCF=15.7 Hz), 111.0, 116.1, 120.1, 124.5, 130.2 (JCF=9.1 Hz), 131.6 (JCF=19.6 Hz), 141.0, 152.2, 162.1 (JCF=241.2 Hz), 165.1, 169.4, 202.2. LCMS t=5.8 min, m/z Calcd for C20H20FN2O3; C20H19FN2NaO3; C40H39F2N4O6; C40H38F2N4NaO6 355.15; 377.13; 709.28; 731.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.21; 377.19; 709.39; 731.38.
EXAMPLE 04-64
Preparation of N-(4-chlorophenyl)-3-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-64): The title compound was prepared from Example 01-12 and p-chloroaniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 52 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (35% yield). 1H NMR (D6-DMSO) δ 1.53 (s, 3H), 2.20-2.22 (m, 2H), 2.53-2.55 (m, 2H), 3.93 (s, 3H), 7.33 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.58-7.61 (m, 3H), 7.81 (d, J=8.6 Hz, 2H), 8.57 (s, 1H), 10.33 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 25.6, 32.8, 55.9, 110.0, 111.1, 120.1, 122.0, 124.5, 127.3, 128.5, 131.5, 131.8, 138.1, 152.3, 164.9, 169.5, 202.1. LCMS t=5.9 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.12; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.18; 393.16; 741.35; 763.34.




EXAMPLE 04-65
Preparation of 2-methoxy-N-methyl-4-(2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-65): The title compound was prepared from Example 02-03 and methylamine according to the procedure of Example 04-13; 0.40 mmol scale yielded 25 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (22% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 2.23-2.26 (m, 2H), 2.78-2.80 (m, 5H), 3.89 (s, 3H), 6.89 (dd, J=8.4, 1.7 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.03-8.05 (m, 2H), 9.08 (s, 1H). LCMS t=4.6 min, m/z Calcd for C15H19N2O3; C15H18N2NaO3; C30H36N4NaO6 275.14; 297.12; 571.25 [M+H]+; [M+Na]+; [2M+Na]+, Found 275.23; 297.21; 571.34.




EXAMPLE 04-66
Preparation of N-cyclohexyl-2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-66): The title compound was prepared from Example 02-03 and cyclohexylamine according to the procedure of Example 04-13; 0.40 mmol scale yielded 90 mg after chromatography (ESS=EtOAc) and EtOAc trituration (66% yield). 1H NMR (D6-DMSO) δ 1.18-1.28 (m, 1H), 1.30-1.35 (m, 4H), 1.56 (d, J=12.9 Hz, 1H), 1.61 (s, 3H), 1.66-1.69 (m, 2H), 1.81-1.84 (m, 2H), 2.24-2.26 (m, 2H), 2.78-2.80 (m, 2H), 3.77-3.79 (m, 1H), 3.90 (s, 3H), 6.90 (dd, J=8.4, 1.6 Hz, 1H), 6.97 (d, J=1.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.53 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H27N2O3; C20H26N2NaO3; C40H53N4O6; C40H52N4NaO6 343.20; 365.18; 685.40; 707.38 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 343.28; 365.26; 685.50; 707.52.




EXAMPLE 04-67
Preparation of 2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide (04-67): The title compound was prepared from Example 02-03 and 1-aminonaphthalene according to the procedure of Example 04-13; 0.40 mmol scale yielded 13 mg after chromatography (ESS=EtOAc) and EtOAc trituration (8% yield). 1H NMR (D6-DMSO) δ 1.65 (s, 3H), 2.28-2.30 (m, 2H), 2.87-2.89 (m, 2H), 4.10 (s, 3H), 7.02 (d, J=8.1 Hz, 1H), 7.12 (s, 1H), 7.55-7.60 (m, 2H), 7.64 (t, J=7.5 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 2H), 9.19 (s, 1H), 10.31 (s, 1H). LCMS t=6.0 min, m/z Calcd for C24H23N2O3; C24H22N2NaO3; C48H45N4O6; C48H44N4NaO6 387.17; 409.15; 773.33; 795.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 387.24; 409.22; 773.49; 795.47.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







68
2-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-
H
H
H



1-yl)amino)-N-phenylbenzamide


69
2-Methoxy-N-(2-methoxyphenyl)-4-((2-methyl-
OCH3
H
H



3-oxocyclopent-1-en-1-yl)amino)benzamide


70
2-Methoxy-N-(3-methoxyphenyl)-4-((2-methyl-
H
OCH3
H



3-oxocyclopent-1-en-1-yl)amino)benzamide


71
2-Methoxy-N-(4-methoxyphenyl)-4-((2-methyl-
H
H
OCH3



3-oxocyclopent-1-en-1-yl)amino)benzamide


72
2-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-
CH3
H
H



1-yl)amino)-N-(o-tolyl)benzamide


73
2-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-
H
CH3
H



1-yl)amino)-N-(m-tolyl)benzamide


74
2-Methoxy-4-((2-methyl-3-oxocyclopent-1-en-
H
H
CH3



1-yl)amino)-N-(p-tolyl)benzamide


75
N-(3-Fluorophenyl)-2-methoxy-4-((2-methyl-3-
H
F
H



oxocyclopent-1-en-1-yl)amino)benzamide


76
N-(4-Chlorophenyl)-2-methoxy-4-((2-methyl-3-
H
H
Cl



oxocyclopent-1-en-1-yl)amino)benzamide









EXAMPLE 04-68
Preparation of 2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (04-68): The title compound was prepared from Example 02-03 and aniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 52 mg after chromatography (ESS=EtOAc) and EtOAc trituration (39% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.25-2.28 (m, 2H), 2.82-2.83 (m, 2H), 3.95 (s, 3H), 6.95 (dd, J=8.4, 1.6 Hz, 1H), 7.03 (s, 1H), 7.08 (t, J=8.4 Hz, 1H), 7.34 (t, J=7.8 Hz, 2H), 7.70-7.74 (m, 3H), 9.14 (s, 1H), 9.99 (s, 1H). LCMS t=5.8 min, m/z Calcd for C20H21N2O3; C20H20N2NaO3; C40H41N4O6; C40H40N4NaO6 337.16; 359.14; 673.30; 695.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 337.23; 359.21; 673.42; 695.40.
EXAMPLE 04-69
Preparation of 2-methoxy-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-69): The title compound was prepared from Example 02-03 and o-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 60 mg after chromatography (ESS=MeOH (2%)) and EtOAc trituration (41% yield). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 2.27-2.29 (m, 2H), 2.88-2.90 (m, 2H), 3.96 (s, 3H), 4.08 (s, 3H), 6.96 (d, J=8.0 Hz, 1H), 7.02 (dd, J=8.6, 1.6 Hz, 1H), 7.06-7.10 (m, 3H), 8.04 (d, J=8.6 Hz, 1H), 8.47 (d, J=7.8 Hz, 1H), 9.19 (s, 1H), 10.57 (s, 1H). LCMS t=5.9 min, m/z Calcd for C21H23N2O4; C21H22N2NaO4; C42H45N4O8; C42H44N4NaO8 367.17; 389.15; 733.32; 755.31 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 367.24; 389.21; 733.45; 755.45.
EXAMPLE 04-70
Preparation of 2-methoxy-N-(3-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-70): The title compound was prepared from Example 02-03 and m-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 55 mg after chromatography (ESS=EtOAc) and EtOAc trituration (38% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H), 3.75 (s, 3H), 3.94 (s, 3H), 6.67 (d, J=8.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 7.02 (s, 1H), 7.21-7.28 (m, 2H), 7.45 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 9.14 (s, 1H), 9.97 (s, 1H). LCMS t=5.8 min, m/z Calcd for C21H23N2O4; C21H22N2NaO4; C42H45N4O8; C42H44N4NaO8 367.17; 389.15; 733.32; 755.31 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 367.24; 389.22; 733.45; 755.45.
EXAMPLE 04-71
Preparation of 2-methoxy-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-71): The title compound was prepared from Example 02-03 and p-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 29 mg after chromatography (ESS=EtOAc) and EtOAc trituration (20% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H), 3.74 (s, 3H), 3.94 (s, 3H), 6.91 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.3 Hz, 1H), 7.02 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.3 Hz, 1H), 9.13 (s, 1H), 9.85 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 26.1, 33.1, 55.2, 56.1, 105.0, 111.7, 113.1, 113.8, 118.5, 121.4, 131.1, 132.2, 143.9, 155.4, 157.4, 163.1, 168.3, 202.2. LCMS t=5.8 min, m/z Calcd for C21H23N2O4; C21H22N2NaO4; C42H45N4O8; C42H44N4NaO8 367.17; 389.15; 733.32; 755.31 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 367.23; 389.21; 733.53; 755.44.
EXAMPLE 04-72
Preparation of 2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-72): The title compound was prepared from Example 02-03 and o-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 70 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (50% yield). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 2.27-2.29 (m, 2H), 2.32 (s, 3H), 2.86-2.88 (m, 2H), 4.03 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.04-7.09 (m, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 9.18 (s, 1H), 9.78 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 17.7, 26.2, 33.1, 56.5, 104.7, 112.2, 113.2, 116.4, 122.2, 124.1, 126.3, 128.6, 130.3, 132.2, 136.9, 144.7, 157.7, 162.4, 168.1, 202.4. LCMS t=5.9 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.44; 723.43.
EXAMPLE 04-73
Preparation of 2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (04-73): The title compound was prepared from Example 02-03 and m-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 55 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (39% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.30 (s, 3H), 2.82-2.84 (m, 2H), 3.95 (s, 3H), 6.90 (d, J=6.9 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.53 (d, J=7.4 Hz, 1H), 7.57 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 9.14 (s, 1H), 9.91 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 21.2, 26.1, 33.1, 56.1, 105.0, 112.0, 113.1, 117.0, 118.4, 120.3, 124.2, 128.5, 131.2, 137.9, 138.9, 144.1, 157.4, 163.8, 168.3, 202.3. LCMS t=5.9 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.45; 723.44.
EXAMPLE 04-74
Preparation of 2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (04-74): The title compound was prepared from Example 02-03 and p-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 30 mg after chromatography (ESS=EtOAc) and EtOAc trituration (21% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.27-2.29 (m, 5H), 2.82-2.85 (m, 2H), 3.94 (s, 3H), 6.95 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.3 Hz, 1H), 9.13 (s, 1H), 9.90 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 20.5, 26.1, 33.1, 56.1, 105.0, 111.7, 113.1, 118.5, 119.8, 129.1, 131.2, 132.4, 136.5, 144.0, 157.4, 163.23, 168.2, 202.3. LCMS t=5.9 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.45; 723.44.
EXAMPLE 04-75
Preparation of N-(3-fluorophenyl)-2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-75): The title compound was prepared from Example 02-03 and m-fluoroaniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 75 mg after chromatography (ESS=EtOAc) and EtOAc trituration (53% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H), 2.94 (s, 3H), 6.91 (d, J=7.7 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 7.03 (s, 1H), 7.37 (dd, J=15.3, 7.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.74 (d, J=11.5 Hz, 1H), 9.15 (s, 1H), 10.16 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 26.1, 33.1, 56.1, 104.9, 106.5 (JCF=26.2 Hz), 109.8 (JCF=20.8 Hz), 111.9, 113.0, 115.6, 118.3, 130.3 (JCF=9.2 Hz), 131.1, 140.7 (JCF=11.4 Hz), 144.3, 157.5, 163.5 (JCF=241.3 Hz), 164.0, 168.2, 202.3. LCMS t=5.9 min, m/z Calcd for C20H20FN2O3; C20H19FN2NaO3; C40H39F2N4O6; C40H38F2N4NaO6 355.15; 377.13; 709.28; 731.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.22; 358.22; 709.40; 731.39.
EXAMPLE 04-76
Preparation of N-(4-chlorophenyl)-2-methoxy-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-76): The title compound was prepared from Example 02-03 and p-chloroaniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 70 mg after chromatography (ESS=EtOAc) and EtOAc trituration (47% yield). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 2.26-2.28 (m, 2H), 2.82-2.84 (m, 2H), 3.93 (s, 3H), 6.95 (d, J=8.3 Hz, 1H), 7.02 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 9.14 (s, 1H), 10.10 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 26.1, 33.1, 56.1, 104.9, 111.9, 113.1, 118.4, 121.4, 127.0, 128.6, 131.1, 138.0, 144.2, 157.4, 163.8, 168.3, 202.3. LCMS t=6.0 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N4NaO6 371.12; 393.10; 741.22; 763.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.18; 393.16; 741.35; 763.34.




EXAMPLE 04-77
Preparation of N,3-dimethyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-77): The title compound was prepared from Example 01-14 and methylamine according to the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg after chromatography (ESS=MeOH (8%)) and EtOAc trituration (34% yield). 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.16-2.19 (m, 2H), 2.28 (s, 3H), 2.41-2.43 (m, 2H), 2.77 (d, J=4.4 Hz, 3H), 7.23 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.74 (s, 1H), 8.38-8.39 (m, 1H), 8.69 (s, 1H). LCMS t=4.9 min, m/z Calcd for C15H19N2O2; C15H18N2NaO2; C30H37N4O4; C30H36N4NaO4 259.14; 281.13; 517.28; 539.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 259.24; 281.22; 517.35; 539.42.




EXAMPLE 04-78
Preparation of N-cyclohexyl-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-78): The title compound was prepared from Example 01-14 and cyclohexylamine according to the procedure of Example 04-13; 0.40 mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (19% yield). 1H NMR (D6-DMSO) δ 1.10-1.18 (m, 1H), 1.23-1.34 (m, 4H), 1.44 (s, 3H), 1.61 (d, J=12.4 Hz, 1H), 1.73 (s, 2H), 1.80 (s, 2H), 2.16-2.19 (m, 2H), 2.28 (s, 3H), 2.40-2.42 (m, 2H), 3.75 (s, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.70 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H27N2O2; C20H26N2NaO2; C40H53N4O4; C40H52N4NaO4 327.21; 349.19; 653.41; 675.39 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 327.28; 349.26; 653.50; 675.54.




EXAMPLE 04-79
Preparation of 3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(naphthalen-1-yl)benzamide (04-79): The title compound was prepared from Example 01-14 and 1-aminonaphthalene according to the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (24% yield). 1H NMR (D6-DMSO) δ 1.50 (s, 3H), 2.21-2.23 (m, 3H), 2.36 (s, 3H), 2.48-2.50 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.54-7.60 (m, 4H), 7.87 (d, J=7.9 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.97-8.02 (m, 3H), 8.78 (s, 1H), 10.40 (s, 1H). LCMS t=5.8 min, m/z Calcd for C24H23N2O2; C24H22N2NaO2; C48H45N4O4; C48H44N4NaO4 371.18; 393.16; 741.34; 763.33 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.24; 393.22; 741.47; 763.46.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







80
3-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
H



yl)amino)-N-phenylbenzamide


81
N-(2-Methoxyphenyl)-3-methyl-4-((2-methyl-
OCH3
H
H



3-oxocyclopent-1-en-1-yl)amino)benzamide


82
N-(3-Methoxyphenyl)-3-methyl-4-((2-methyl-
H
OCH3
H



3-oxocyclopent-1-en-1-yl)amino)benzamide


83
N-(4-Methoxyphenyl)-3-methyl-4-((2-methyl-
H
H
OCH3



3-oxocyclopent-1-en-1-yl)amino)benzamide


84
3-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1-
CH3
H
H



yl)amino)-N-(o-tolyl)benzamide


85
3-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1-
H
CH3
H



yl)amino)-N-(m-tolyl)benzamide


86
3-Methyl-4-((2-methyl-3-oxocyclopent-1-en-1-
H
H
CH3



yl)amino)-N-(p-tolyl)benzamide


87
N-(3-Fluorophenyl)-3-methyl-4-((2-methyl-3-
H
F
H



oxocyclopent-1-en-1-yl)amino)benzamide


88
N-(4-Chlorophenyl)-3-methyl-4-((2-methyl-3-
H
H
Cl



oxocyclopent-1-en-1-yl)amino)benzamide









EXAMPLE 04-80
Preparation of 3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-phenylbenzamide (04-80): The title compound was prepared from Example 01-14 and aniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (27% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.21 (m, 2H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 7.10 (t, J=7.3 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.35 (t, J=7.7 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 8.74 (s, 1H), 10.20 (s, 1H). LCMS t=5.7 min, m/z Calcd for C20H21N2O2; C20H20N2NaO2; C40H41N4O4; C40H40N4NaO4 321.16; 343.14; 641.31; 663.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 321.24; 343.21; 641.41; 663.41.
EXAMPLE 04-81
Preparation of N-(2-methoxyphenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-81): The title compound was prepared from Example 01-14 and o-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 30 mg after chromatography (ESS=EtOAc) and EtOAc trituration (21% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.22 (m, 2H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 3.84 (s, 3H), 6.97 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.89 (s, 1H), 8.74 (s, 1H), 9.40 (s, 1H). LCMS t=5.8 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.45; 723.48.
EXAMPLE 04-82
Preparation of N-(3-methoxyphenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-82): The title compound was prepared from Example 01-14 and m-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 31 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (22% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.22 (m, 2H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 3.76 (s, 3H), 6.68 (d, J=8.2 Hz, 1H), 7.25 (t, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.86 (s, 1H), 8.74 (s, 1H), 10.17 (s, 1H). LCMS t=5.7 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.45; 723.44.
EXAMPLE 04-83
Preparation of N-(4-methoxyphenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-83): The title compound was prepared from Example 01-14 and p-anisidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 20 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (14% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.22 (m, 2H), 2.33 (s, 3H), 2.44-2.46 (m, 2H), 2.75 (s, 3H), 6.93 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.86 (s, 1H), 8.74 (s, 1H), 10.09 (s, 1H). 13C NMR (D6-DMSO) δ 7.6, 17.7, 25.6, 32.7, 55.2, 108.9, 113.7, 121.9, 125.7, 126.1, 129.8, 132.1, 132.3, 133.5, 140.9, 155.5, 164.6, 169.7, 202.2. LCMS t=5.6 min, m/z Calcd for C21H23N2O3; C21H22N2NaO3; C42H45N4O6; C42H44N4NaO6 351.17; 373.15; 701.33; 723.32 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 351.24; 373.22; 701.45; 723.43.
EXAMPLE 04-84
Preparation of 3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-84): The title compound was prepared from Example 01-14 and o-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 28 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (21% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.19-2.21 (m, 2H), 2.24 (s, 3H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 7.17 (d, J=7.3 Hz, 1H), 7.22 (d, J=7.4 Hz, 1H), 7.26-7.34 (m, 3H), 7.83 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 8.75 (s, 1H), 9.85 (s, 1H). 13C NMR (D6-DMSO) δ 7.6, 17.8, 18.0, 25.6, 32.7, 109.0, 125.8, 126.0, 126.2, 126.6, 130.0, 130.3, 131.6, 133.6, 133.8, 136.5, 141.0, 164.8, 169.7, 202.2. LCMS t=5.6 min, m/z Calcd for C21H23N2O2; C21H22N2NaO2; C42H45N4O4; C42H44N4NaO4 335.18; 357.16; 669.34; 691.33 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 335.28; 357.23; 669.45; 691.43.
EXAMPLE 04-85
Preparation of 3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(m-tolyl)benzamide (04-85): The title compound was prepared from Example 01-14 and m-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 22 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (16% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.21 (m, 2H), 2.31 (s, 3H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 6.92 (d, J=7.4 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.61 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 8.74 (s, 1H), 10.12 (s, 1H). LCMS t=5.8 min, m/z Calcd for C21H23N2O2; C21H22N2NaO2; C42H45N4O4; C42H44N4NaO4 335.18; 357.16; 669.34; 691.33 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 335.26; 357.23; 669.44; 691.43.
EXAMPLE 04-86
Preparation of 3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(p-tolyl)benzamide (04-86): The title compound was prepared from Example 01-14 and p-toluidine according to the procedure of Example 04-13; 0.40 mmol scale yielded 35 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (26% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.21 (m, 2H), 2.28 (s, 3H), 2.33 (s, 3H), 2.44-2.46 (m, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.86 (s, 1H), 8.74 (s, 1H), 10.12 (s, 1H). LCMS t=5.8 min, m/z Calcd for C21H23N2O2; C21H22N2NaO2; C42H45N4O4; C42H44N4NaO4 335.18; 357.16; 669.34; 691.33 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 335.25; 357.23; 669.44; 691.43.
EXAMPLE 04-87
Preparation of N-(3-fluorophenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-87): The title compound was prepared from Example 01-14 and m-fluoroaniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 30 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (22% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.22 (m, 2H), 2.34 (s, 3H), 2.46-2.48 (m, 2H), 6.93 (t, J=8.3 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.39 (dd, J=15.4, 7.8 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.75 (d, J=11.7 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 8.75 (s, 1H), 10.39 (s, 1H). 13C NMR (D6-DMSO) δ 7.6, 17.7, 25.6, 32.7, 106.9 (JCF=26.2 Hz), 109.2, 110.0 (JCF=20.8 Hz), 115.9, 125.9 (JCF=25.8 Hz), 130.1 (JCF=38.9 Hz), 131.6, 133.5, 141.0, 141.3, 162.1 (JCF=240.7.3 Hz), 165.3, 169.6, 202.2. LCMS t=5.7 min, m/z Calcd for C20H20FN2O2; CzoH19FN2NaO2; C40H39F2N4O4; C40H38F2N4NaO4 339.15; 361.13; 677.29; 699.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 339.25; 361.20; 677.40; 600.39.
EXAMPLE 04-88
Preparation of N-(4-chlorophenyl)-3-methyl-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-benzamide (04-88): The title compound was prepared from Example 01-14 and p-chloroaniline according to the procedure of Example 04-13; 0.40 mmol scale yielded 25 mg after chromatography (ESS=H:E (1:19)) and EtOAc trituration (18% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.19-2.22 (m, 3H), 2.33 (s, 3H), 2.45-2.47 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.79-7.82 (m, 3H), 7.86 (s, 1H), 8.75 (s, 1H), 10.33 (s, 1H). 13C NMR (D6-DMSO) δ 7.6, 17.7 25.6, 32.7, 109.1, 121.8, 125.9, 126.1, 127.2, 128.5, 130.0, 131.7, 133.5, 138.2, 141.3, 165.1, 169.6, 202.2. LCMS t=5.9 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.19; 377.17; 709.35; 731.34.




EXAMPLE 04-89
Preparation of 4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-89): The title compound was prepared from Example 01-25 and o-toluidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 50 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (28% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.23 (m, 5H), 2.45-2.47 (m, 2H), 7.17-7.24 (m, 2H), 7.28 (d, J=7.3 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 9.03 (s, 1H), 10.01 (s, 1H). 13C NMR (D6-DMSO) δ 7.9, 18.3, 26.0, 33.1, 110.0, 126.5, 126.7, 127.2, 128.0, 130.4, 130.8, 133.9, 134.2, 134.3, 136.5, 137.2, 140.1, 160.5, 170.0, 202.9. LCMS t=4.8 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H3902N4O4; C40H38Cl2N4NaO4 355.12; 377.10; 709.23; 731.22 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.12; 377.11; 709.24; 731.22.

















EXAMPLE





04-#
TITLE COMPOUND NAME
R1
R2







90
4-Chloro-N-(4-methoxyphenyl)-3-((2-
H
OCH3



methyl-3-oxocyclohex-1-en-1-yl)ami-



no)benzamide


91
4-Chloro-3-((2-methyl-3-oxocyclohex-1-
CH3
H



en-1-yl)amino)-N-(o-tolyl)benzamide









EXAMPLE 04-90
Preparation of 4-chloro-N-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (04-90): The title compound was prepared from Example 01-36 and p-anisidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 90 mg from solid precipitate (47% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.77-1.80 (m, 2H), 2.19-2.22 (m, 2H), 2.24-2.27 (m, 2H), 3.75 (s, 3H), 6.93 (d, J=9.0 Hz, 2H), 7.66 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.1 Hz, 1H), 7.86-7.89 (m, 2H), 8.11 (s, 1H), 10.19 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 21.6, 27.4, 36.8, 55.6, 107.7, 114.2, 122.6, 126.8, 128.4, 130.2, 132.3, 134.4, 134.7, 137.7, 156.2, 158.8, 163.7, 195.1. LCMS t=5.0 min, m/z Calcd for C21H22ClN2O3; C21H21ClN2NaO3; C42H43Cl2N4O6; C42H42Cl2N4NaO6 385.13; 407.11; 769.26; 791.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.12; 407.10; 769.23; 791.21.
EXAMPLE 04-91
Preparation of 4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide (04-91): The title compound was prepared from Example 01-36 and o-toluidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 55 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (30% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.77-1.80 (m, 2H), 2.19-2.23 (m, 5H), 2.26-2.28 (m, 2H), 7.17-7.24 (m, 2H), 7.28 (d, J=7.3 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.87-7.89 (m, 2H), 8.13 (s, 1H), 10.00 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 18.3, 21.6, 27.5, 36.8, 107.9, 126.5, 126.7, 127.2, 128.3, 130.3, 130.8, 134.2, 134.3, 136.5, 137.8, 158.8, 164.1, 195.2. LCMS t=5.0 min, m/z Calcd for C21H22ClN2O2; C21H21ClN2NaO2; C42H43Cl2N4O4; C42H43Cl2N4NaO4 369.14; 391.12; 737.27; 759.25 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 369.14; 391.12; 737.27; 759.25.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







92
Methyl 3-(4-chloro-
CO2CH3
H
H



3-((2-methyl-3-



oxocyclohex-1-en-1-



yl)amino)benzamido)-



2-methylbenzoate


93
Methyl 3-(4-chloro-
H
H
CO2CH3



3-((2-methyl-3-



oxocyclohex-1-en-1-



yl)amino)benzamido)-



4-methylbenzoate


94
Methyl 4-(4-chloro-
H
CO2CH3
H



3-((2-methyl-3-



oxocyclohex-1-en-1-



yl)amino)benzamido)-



3-methylbenzoate









EXAMPLE 04-92
Preparation of methyl 3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-2-methylbenzoate (04-92): The title compound was prepared from Example 01-36 and methyl 3-amino-2-methylbenzoate according to the procedure of Example 04-13; 2.0 mmol scale yielded 340 mg from precipitate (40% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.19-2.22 (m, 2H), 2.27-2.29 (m, 2H), 2.34 (s, 3H), 3.85 (s, 3H), 7.35 (t, J=7.8 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.88-7.90 (m, 2H), 8.14 (s, 1H), 10.20 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 15.7, 21.6, 27.4, 36.8, 52.6, 107.9, 126.3, 126.8, 128.2, 128.4, 130.4, 131.2, 132.0, 133.9, 134.5, 135.3, 137.7, 137.8, 158.7, 164.4, 168.1, 195.2. LCMS t=5.1 min, m/z Calcd for C23H24ClN2O4; C23H23ClN2NaO4; C46H4702N4O8; C46H46Cl2N4NaO8 427.14; 449.12; 853.28; 875.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 427.16; 449.14; 853.31; 875.29.
EXAMPLE 04-93
Preparation of methyl 3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-4-methylbenzoate (04-93): The title compound was prepared from Example 01-36 and methyl 3-amino-4-methylbenzoate according to the procedure of Example 04-13; 2.0 mmol scale yielded 310 mg from precipitate (36% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.19-2.22 (m, 2H), 2.27-2.29 (m, 2H), 2.31 (s, 3H), 3.85 (s, 3H), 7.45 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.87-7.90 (m, 2H), 7.97 (s, 1H), 8.14 (s, 1H), 10.14 (s, 1H). LCMS t=5.1 min, m/z Calcd for C23H24ClN2O4; C23H23ClN2NaO4; C46H47Cl2N4O8; C46H46Cl2N4NaO8 427.14; 449.12; 853.28; 875.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 427.16; 449.14; 853.32; 875.29.
EXAMPLE 04-94
Preparation of methyl 4-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-3-methylbenzoate (04-94): The title compound was prepared from Example 01-36 and methyl 4-amino-3-methylbenzoate according to the procedure of Example 04-13; 2.0 mmol scale yielded 175 mg from precipitate (21% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.19-2.22 (m, 2H), 2.29-2.32 (m, 5H), 3.86 (s, 3H), 7.58 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.85-7.90 (m, 3H), 8.11 (s, 1H), 10.10 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 18.3, 21.6, 27.5, 36.8, 52.5, 108.0, 126.5, 126.8, 127.2, 127.6, 128.3, 130.4, 131.8, 133.9, 134.0, 134.5, 137.9, 141.2, 158.7, 164.3, 166.4, 195.2. LCMS t=5.1 min, m/z Calcd for C23H24ClN2O4; C23H23ClN2NaO4; C46H4702N4O8; C46H46Cl2N4NaO8 427.14; 449.12; 853.28; 875.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 427.16; 449.14; 853.31; 875.29.


















EXAMPLE
TITLE





04-#
COMPOUND NAME
R1
R2
R3







95
3-(4-Chloro-3-((2-methyl-
CO2H
H
H



3-oxocyclohex-1-en-1-



yl)amino)benzamido)-



2-methylbenzoic acid


96
3-(4-Chloro-3-((2-methyl-
H
H
CO2H



3-oxocyclohex-1-en-1-



yl)amino)benzamido)-



4-methylbenzoic acid


97
4-(4-Chloro-3-((2-methyl-
H
CO2H
H



3-oxocyclohex-1-en-1-



yl)amino)benzamido)-



3-methylbenzoic acid









EXAMPLE 04-95
Preparation of 3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-2-methylbenzoic acid (04-95): The title compound was prepared from Example 04-92 according to the procedure of Example 02-01; 0.75 mmol scale yielded 0.29 g (93% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.78-1.81 (m, 2H), 2.21 (t, J=6.3 Hz, 2H), 2.27-2.29 (m, 2H), 2.37 (s, 3H), 7.32 (t, J=7.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.88-7.90 (m, 2H), 8.12 (s, 1H), 10.16 (s, 1H), 12.98 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 15.7, 21.6, 27.4, 36.8, 107.9, 126.1, 126.8, 128.3, 130.4, 130.8, 133.2, 133.9, 134.5, 135.2, 137.6, 137.8, 158.7, 164.4, 169.5, 195.1. LCMS t=4.7 min, m/z Calcd for C22H22ClN2O4; C22H21ClN2NaO4; C44H43Cl2N4O8; C44H42Cl2N4NaO8 413.13; 435.11; 825.25; 847.23 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 413.14; 435.12; 825.28; 847.25.
EXAMPLE 04-96
Preparation of 3-(4-Chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-4-methylbenzoic acid (04-96): The title compound was prepared from Example 04-93 according to the procedure of Example 02-01; 0.7 mmol scale yielded 0.26 g (88% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.78-1.81 (m, 2H), 2.21 (t, J=6.4 Hz, 1H), 2.26-2.30 (m, 5H), 7.41 (d, J=8.0 Hz, 1H), 7.72-7.76 (m, 2H), 7.87-7.89 (m, 2H), 7.92 (s, 1H), 8.11 (s, 1H), 10.11 (s, 1H), 12.91 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 18.6, 21.6, 27.4, 36.8, 107.9, 126.8, 127.4, 127.9, 128.4, 129.3, 130.3, 131.1, 134.0, 134.5, 136.7, 137.8, 139.6, 158.7, 164.3, 167.4, 195.1. LCMS t=4.7 min, m/z Calcd for C22H22ClN2O4; C44H43Cl2N4O8 413.13; 825.25 [M+H]+; [2M+H]+, Found 413.14; 825.29.
EXAMPLE 04-97
Preparation of 4-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-3-methylbenzoic acid (04-97): The title compound was prepared from Example 04-94 according to the procedure of Example 02-01; 0.4 mmol scale yielded 0.1 g (61% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.78-1.81 (m, 2H), 2.21 (t, J=6.4 Hz, 1H), 2.26-2.32 (m, 5H), 7.53 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.86-7.78 (m, 3H), 8.11 (s, 1H), 10.09 (s, 1H), 12.87 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 18.3, 21.6, 27.5, 36.8, 108.0, 126.4, 126.8, 127.7, 128.3, 128.5, 130.4, 131.9, 133.7, 134.0, 134.5, 137.8, 140.8, 158.7, 164.2, 167.5, 195.2. LCMS t=4.8 min, m/z Calcd for C22H22ClN2O4; C22H21ClN2NaO4; C44H43Cl2N4O8; C44H42Cl2N4NaO8 413.13; 825.25 [M+H]+; [2M+H]+, Found 413.14; 825.28.




EXAMPLE 04-98
Preparation of N-(4-methoxyphenyl)-2-(3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-acetamide (04-98): The title compound was prepared from Example 01-37 and p-anisidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 10 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (6% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.75-1.78 (m, 2H), 2.18-2.21 (m, 2H), 2.42-2.45 (m, 2H), 3.59 (s, 2H), 3.71 (s, 3H), 6.87 (d, J=8.7 Hz, 2H), 6.99 (d, J=7.5 Hz, 1H), 7.08 (s, 2H), 7.28 (t, J=7.8 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 8.20 (s, 1H), 10.01 (s, 1H). 13C NMR (D6-DMSO) δ 9.7, 22.1, 27.8, 36.9, 43.5, 55.6, 107.6, 114.3, 121.1, 122.9, 125.4, 129.1, 129.1, 132.8, 137.3, 140.3, 155.6, 158.5, 168.8, 194.8. LCMS t=4.9 min, m/z Calcd for C22H25N2O3; C22H24N2NaO3; C44H49N4O6; C44H48N4NaO6 365.19; 387.17; 729.37; 751.35 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 365.17; 387.14; 729.31; 751.29.

















EXAMPLE





04-#
TITLE COMPOUND NAME
R1
R2


















99
N-(4-Methoxyphenyl)-2-(4-((2-methyl-3-
H
OCH3



oxocyclohex-1-en-1-



yl)amino)phenyl)acetamide


100
2-(4-((2-Methyl-3-oxocyclohex-1-en-1-
CH3
H



yl)amino)phenyl)-N-(o-tolyl)acetamide









EXAMPLE 04-99
Preparation of N-(4-methoxyphenyl)-2-(4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-acetamide (04-99): The title compound was prepared from Example 01-38 and p-anisidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 31 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (17% yield). 1H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.75-1.77 (m, 2H), 2.17-2.20 (m, 2H), 2.41-2.43 (m, 2H), 3.57 (s, 2H), 3.71 (s, 3H), 6.87 (d, J=8.6 Hz, 2H), 7.08 (d, J=7.8 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 8.14 (s, 1H), 10.00 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 22.1, 27.7, 36.9, 43.0, 55.6, 107.0, 115.3, 121.1, 125.0, 129.8, 132.5, 132.8, 138.7, 156.0, 158.8, 169.0, 194.6. LCMS t=4.8 min, m/z Calcd for C22H25N2O3; C22H24N2NaO3; C44H49N4O6; C44H48N4NaO6 365.19; 387.17; 729.37; 751.35 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 365.16; 387.14; 729.30; 751.28.
EXAMPLE 04-100
Preparation of 2-(4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-N-(o-tolyl)acetamide (04-100): The title compound was prepared from Example 01-37 and o-toluidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 40 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (23% yield). 1H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.75-1.78 (m, 2H), 2.16 (s, 3H), 2.18-2.21 (m, 2H), 2.41-2.44 (m, 2H), 3.65 (s, 3H), 7.05-7.21 (m, 5H), 7.27-7.39 (m, 3H), 8.18 (s, 1H), 9.49 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 18.2, 22.2, 27.7, 36.9, 42.6, 106.9, 112.6, 119.5, 125.0, 125.5, 125.7, 126.4, 129.8, 130.7, 132.2, 132.7, 136.7, 138.7, 158.9, 169.5, 194.6. LCMS t=4.7 min, m/z Calcd for C22H25N2O2; C22H24N2NaO2; C44H49N4O4; C44H48N4NaO4 349.19; 371.17; 697.37; 719.36 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 349.18; 371.14; 697.31; 719.29.

















EXAMPLE





04-#
TITLE COMPOUND NAME
R1
R2







101
N-(4-Methoxyphenyl)-3-((2-methyl-3-
H
OCH3



oxocyclohex-1-en-1-yl)amino)-4-



(trifluoromethyl)benzamide


102
3-((2-Methyl-3-oxocyclohex-1-en-1-
CH3
H



yl)amino)-N-(o-tolyl)-4-



(trifluoromethyl)benzamide









EXAMPLE 04-101
Preparation of N-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-4-(trifluoromethyl)benzamide (04-101): The title compound was prepared from Example 01-39 and p-anisidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 10 mg after chromatography (ESS=H:E (1:1)) and EtOAc trituration (5% yield). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.75-1.77 (m, 2H), 2.19-2.21 (m, 4H), 3.76 (s, 3H), 6.95 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.95 (s, 2H), 8.00 (s, 1H), 8.05-8.07 (m, 1H), 10.32 (s, 1H). 13C NMR (D6-DMSO) δ 9.2, 21.6, 27.6, 36.7, 55.5, 107.2, 114.3, 122.7, 126.6, 127.5, 129.2 (JCF=28.8 Hz), 130.1, 132.0, 138.8, 139.7, 156.4, 159.2, 163.4, 195.0. LCMS t=5.1 min, m/z Calcd for C22H22F3N2O3; C22H21F3N2NaO3; C44H43F6N4O6; C44H42F6N4NaO6 419.16; 441.14; 837.31; 859.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 419.14; 441.09; 837.22; 859.20.
EXAMPLE 04-102
Preparation of 3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)-4-(trifluoromethyl)benzamide (04-102): The title compound was prepared from Example 01-39 and o-toluidine according to the procedure of Example 04-13; 0.50 mmol scale 10 mg after chromatography (ESS=H:E (1:1)) and EtOAc trituration (5% yield). 1H NMR (D6-DMSO) δ 1.65 (s, 3H), 1.75-1.78 (m, 2H), 2.18-2.24 (m, 7H), 7.19-7.26 (m, 2H), 7.30 (d, J=7.3 Hz, 1H), 7.34 (d, J=7.4 Hz, 1H), 7.93-7.99 (3H), 8.07 (d, J=7.9 Hz, 1H), 10.15 (s, 1H). 13C NMR (D6-DMSO) δ 9.3, 18.3, 21.6, 27.6, 36.7, 107.4, 126.6, 127.0, 127.2, 127.6, 129.2 (JCF=29.9 Hz), 130.0, 130.9, 134.4, 136.3, 139.0, 139.3, 159.1, 163.8, 195.0. LCMS t=5.1 min, m/z Calcd for C22H22F3N2O2; C22H21F3N2NaO2; C44H43F6N4O4; C44H42F6N4NaO4 403.16; 425.15; 805.32; 827.30 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 403.15; 425.10; 805.24; 827.22.




EXAMPLE 04-103
Preparation of N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-3-(trifluoromethyl)benzamide (04-103): The title compound was prepared from Example 01-40 and p-anisidine according to the procedure of Example 04-13; 0.50 mmol scale yielded 60 mg after chromatography (ESS=H:E (1:1)) and EtOAc trituration (31% yield). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 1.77-1.80 (m, 2H), 2.21-2.24 (m, 2H), 2.29-1.31 (m, 2H), 3.75 (s, 3H), 6.95 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.91 (s, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.30 (s, 1H), 10.33 (s, 1H). 13C NMR (D6-DMSO) δ 9.8, 21.5, 28.1, 36.9, 55.6, 109.6, 114.2, 122.6, 123.9 (JCF=273.6 Hz), 124.8 (JCF=87.6, 29.2 Hz), 126.5, 129.7, 132.3, 132.4, 132.8, 141.6, 156.2, 158.2, 163.6, 195.7. LCMS t=5.1 min, m/z Calcd for C22H22F3N2O3; C22H21F3N2NaO3; C44H43F6N4O6; C44H42F6N4NaO6 419.16; 441.14; 837.31; 859.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 419.14; 441.09; 837.22; 859.20




EXAMPLE 04-104
Preparation of 3-iodo-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (04-104): The title compound was prepared from Example 02-08 and p-anisidine according to the procedure of Example 04-13; 0.15 mmol scale yielded 110 mg of pale yellow microcrystals after chromatography (ESS H:E=1:19, mp=222-224° C., 52% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.20-2.22 (m, 2H), 2.41-2.46 (m, 1H), 3.75 (s, 3H), 6.94 (d, J=8.9 Hz, 2H), 7.46 (d, J=8.2 Hz, 1H), 7.66 (d, J=8.9 Hz, 2H), 7.98 (dd, J=8.1, 1.2 Hz, 1H), 8.47 (d, J=1.3 Hz, 1H), 8.90 (s, 1H), 10.21 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 25.7, 32.7, 55.2, 98.6, 109.6, 113.8, 122.1, 127.2, 128.4, 132.0, 133.9, 138.0, 144.0, 155.7, 162.9, 169.1, 202.3. LCMS t=4.9 min, Calcd for C20H20IN2O3; C20H19IN2NaO3; C40H39I2N4O6; C40H38I2N4NaO6 463.05; 485.03; 925.10; 947.09 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 463.08; 485.00; 925.11; 947.09.

















EXAMPLE





04-#
TITLE COMPOUND NAME
R1
R2







105
N-(4-Methoxyphenyl)-3-((2-methyl-3-
H
OCH3



oxocyclohex-1-en-1-yl)amino)-1-



naphthamide


106
3-((2-Methyl-3-oxocyclohex-1-en-1-
CH3
H



yl)amino)-N-(o-tolyl)-1-naphthamide









EXAMPLE 04-105
Preparation of N-(4-methoxyphenyl)-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-1-naphthamide (04-105): The title compound was prepared from Example 01-52 and p-anisidine according to the procedure of Example 04-13; 0.5 mmol scale yielded 1 mg of off-white microcrystals after chromatography (ESS E:H=1:1, 1% yield). 1H NMR (D6-DMSO) δ 1.74 (s, 3H), 1.83-1.86 (m, 2H), 2.25-2.28 (m, 2H), 2.63-2.65 (m, 2H), 3.76 (s, 3H), 6.95 (d, J=8.8 Hz, 2H), 7.47-7.50 (m, 1H), 7.53-7.58 (m, 2H), 7.67 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.92 (d, J=8.1 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 10.43 (s, 1H). 13C NMR (D6-DMSO) δ 9.4, 21.8, 27.5, 36.5, 55.2, 108.5, 113.9, 121.0, 121.4, 122.9, 125.1, 125.7, 126.5, 126.9, 127.7, 132.3, 133.8, 135.7, 136.8, 155.6, 157.8, 166.2, 194.7. LCMS t=4.7 min, Calcd for C25H25N2O3; C25H24N2NaO3; C50H49N4O6; C50H48N4NaO6 401.187; 423.169; 801.365; 823.347 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 401.184; 423.138; 801.345; 823.331.
EXAMPLE 04-106
Preparation of 3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)-1-naphthamide (04-106): The title compound was prepared from Example 01-52 and o-toluidine according to the procedure of Example 04-13; 0.5 mmol scale yielded 12 mg of pale yellow microcrystals after chromatography (ESS=1:1, mp=249-250° C. decomp, 7% yield). 1H NMR (D6-DMSO) δ 1.75 (s, 3H), 1.83-1.86 (m, 2H), 2.26-2.29 (m, 2H), 2.34 (s, 3H), 2.64-2.66 (m, 2H), 7.18-7.21 (m, 1H), 7.24-7.31 (m, 3H), 7.48-7.57 (m, 3H), 7.66 (d, J=15.7 Hz, 2H), 7.93 (d, J=8.0 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 8.48 (s, 1H), 10.07 (s, 1H). 13C NMR (D6-DMSO) δ 9.4, 18.1, 21.9, 36.6, 108.6, 121.2, 123.0, 125.1, 125.7, 126.1, 126.3, 126.7, 126.9, 127.7, 130.4, 133.3, 133.8, 135.5, 136.2, 136.8, 157.7, 166.9, 194.8. LCMS t=5.0 min, Calcd for C25H25N2O2; C25H24N2NaO2; C50H49N4O4; C50H48N4NaO4 385.19; 407.17; 769.37; 791.36 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.18; 407.16; 769.35; 791.34.
EXAMPLES 05-01 to 05-86




EXAMPLE 05-01
Preparation of 3-((3-chlorophenyl)amino)-2-methylcyclopent-2-enone (05-01): 2-Methyl-1,3-cyclopentandione (112 mg, 1.0 mmol, 1.0 eq) and 3-chloroaniline (106 □L, 1.0 eq) were mixed and treated with AcOH (200 □L, 3.5 eq). Microwave irradiation was applied to a sealed microwave vial for 10 min in a single mode Biotage®-Initiator cavity, producing continuous irradiation to hold temp at 2.45 GHz. The crude products were recrystallized, or were added directly to a KP-SilTM column (10 g) in a small amount of CH2Cl2 with products separating from impurities using stepwise gradients on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The reaction on a 1.0 mmol scale yielded 90 mg of the title compound after recrystallization from EtOAc (41% yield). 1H NMR (D6-DMSO) δ 1.58 (s, 3H), 2.21-2.23 (m, 2H), 2.70-2.72 (m, 2H), 7.15 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.35 (s, 1H), 7.36 (t, J=8.0 Hz, 1H), 9.02 (s, 1H). LCMS t=5.7 min, m/z Calcd for C12H13ClNO; C12H12ClNNaO; C24H25Cl2N2O2; C24H24Cl2N2NaO2 222.07; 244.05; 443.13; 465.11 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 222.07; 244.05; 443.13; 465.11.



















EXAMPLE







05-#
TITLE COMPOUND NAME
R1
R2
R3
R4







02
2-Benzyl-3-((4-
H
H
H
OCH3



methoxyphenyl)amino)cyclo-



pent-2-enone


03
2-(4-((2-Benzyl-3-oxocyclo-
H
H
H
CH2CN



pent-1-en-1-yl)amino)phe-



nyl)acetonitrile


04
Methyl 4-((2-benzyl-3-oxocyclo-
H
Cl
H
CO2CH3



pent-1-en-1-yl)amino)-3-



chlorobenzoate









EXAMPLE 05-02
Preparation of 2-benzyl-3-((4-methoxyphenyl)amino)cyclopent-2-enone (05-02): The title compound was prepared from Intermediate 01 and p-anisidine according to the procedure of Example 05-01; 0.53 mmol scale yielded 30 mg after chromatography (ESS=H:E (1:3)) and recrystallization from EtOAc (19% yield). 1H NMR (D6-DMSO) δ 2.18-2.20 (m, 2H), 2.54-2.56 (m, 2H), 3.48 (s, 2H), 3.75 (s, 3H), 6.91 (d, J=8.8 Hz, 2H), 7.10-7.13 (m, 1H), 7.15 (d, J=8.7 Hz, 2H), 7.21-7.23 (m, 4H), 9.03 (s, 1H). 13C NMR (D6-DMSO) δ 25.4, 26.8, 32.5, 55.3, 112.0, 114.1, 125.4, 125.9, 128.0, 128.1, 132.1, 140.9, 156.7, 170.9, 201.1. LCMS t=5.1 min, m/z Calcd for C19H20NO2; C19H19NNaO2; C38H39N2O4; C38H38N2NaO4 294.15; 316.13; 587.29; 609.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 294.18; 316.14; 587.24; 609.34.
EXAMPLE 05-03
Preparation of 2-(44(2-benzyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)acetonitrile (05-03): The title compound was prepared from Intermediate 01 and 4-aminobenzyl cyanide according to the procedure of Example 05-01; 0.53 mmol scale yielded 10 mg after chromatography (ESS=H:E (1:3)) and recrystallization from EtOAc (6% yield). 1H NMR (D6-DMSO) δ 2.23-2.25 (m, 2H), 2.70-2.72 (m, 2H), 3.53 (s, 2H), 4.01 (s, 2H), 7.10-7.3 (m, 1H), 7.19-7.24 (4H), 7.26 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 9.19 (s, 1H). 13C NMR (D6-DMSO) δ 21.8, 25.6, 26.8, 32.8, 113.5, 119.3, 123.6, 125.4, 127.1, 128.0, 128.1, 128.8, 139.0, 140.6, 169.8, 201.5. LCMS t=4.9 min, m/z Calcd for C20H19N2O; C20H18N2NaO; C40H37N4O2; C40H36N4NaO2 303.15; 325.13; 605.29; 627.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 303.17; 332.15; 605.24 627.25.
EXAMPLE 05-04
Preparation of methyl 4((2-benzyl-3-oxocyclopent-1-en-1-yl)amino)-3-chlorobenzoate (05-04): The title compound was prepared from Intermediate 01 and methyl 4-amino-3-chlorobenzoate according to the procedure of Example 05-01; 1.07 mmol scale and 30 min irradiation, yielded 20 mg after chromatography (ESS=H:E (1:3)) and recrystallization from EtOAc (5% yield). 1H NMR (D6-DMSO) δ 2.28-2.30 (m, 2H), 2.59-2.61 (m, 2H), 3.46 (s, 2H), 3.86 (s, 3H), 7.05-7.12 (m, 3H), 7.14-7.20 (m, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 9.01 (s, 1H). 13C NMR (D6-DMSO) δ 25.8, 27.3, 32.7, 52.5, 114.9, 125.6, 126.9, 127.9, 128.0, 128.5, 130.3, 139.9, 140.6, 164.7, 168.7, 202.5. LCMS t=5.3 min, m/z Calcd for C20H19ClNO3; C20H18ClNNaO3; C40H36Cl2N2NaO6 356.11; 378.09; 733.18 [M+H]+; [M+Na]+; [2M+Na]+, Found 356.11; 378.07; 733.15.




EXAMPLE 05-05
Preparation of 2-(4-hydroxybenzyl)-3-((4-methoxyphenyl)amino)cyclopent-2-enone (05-05): The title compound was prepared from Intermediate 02 and p-anisidine according to the procedure of Example 05-01; 0.5 mmol scale yielded 20 mg after chromatography (ESS=EtOAc) and recrystallization from EtOAc (13% yield). 1H NMR (D6-DMSO) δ 2.17-2.19 (m, 2H), 2.50-2.53 (m, 2H), 3.37 (s, 2H), 3.75 (3H), 6.61 (d, J=7.8 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 7.00 (d, J=7.8 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 8.96 (s, 1H), 9.05 (s, 1H). 13C NMR (D6-DMSO) δ 25.3, 25.9, 32.5, 55.3, 112.8, 114.1, 114.7, 125.8, 129.0, 130.9 132.2, 155.1, 156.7, 170.6, 201.1. LCMS t=4.7 min, m/z Calcd for C19H20NO3; C19H19NNaO3; C38H39N2O6; C38H38N2NaO6 310.14; 332.13; 619.28; 641.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 310.17; 332.13; 619.23; 641.25.

















EXAMPLE
TITLE COMPOUND




05-#
NAME
X
Y







06
2-Benzyl-3-(quinolin-3-
CH
N



ylamino)cyclopent-2-enone


07
2-Benzyl-3-(quinolin-2-
N
CH



ylamino)cyclopent-2-enone









EXAMPLE 05-06
Preparation of 2-benzyl-3-(quinolin-3-ylamino)cyclopent-2-enone (05-06): The title compound was prepared from Intermediate 01 and 3-aminoquinoline according to the procedure of Example 05-01; 0.53 mmol scale yielded 15 mg after chromatography (ESS=H:E (1:3)) and recrystallization from EtOAc (9% yield). 1H NMR (D6-DMSO) δ 2.30-2.32 (m, 2H), 2.86-2.88 (m, 2H), 3.59 (s, 2H), 7.12-7.15 (m, 1H), 7.22-7.24 (m, 4H), 7.60 (t, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 8.84 (d, J=2.1 Hz, 1H), 9.48 (s, 1H). 13C NMR (D6-DMSO) δ 25.6, 26.9, 32.9, 114.7, 125.6, 125.7, 127.2, 127.6, 127.8, 128.1, 128.3, 128.6, 133.4, 140.3, 144.5, 147.5, 169.6, 201.9. LCMS t=4.9 min, m/z Calcd for C21H19N2O; C21H18N2NaO; C42H37N4O2; C42H36N4NaO2 315.15; 337.13; 629.29; 651.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 315.17; 337.14; 629.24; 651.29.
EXAMPLE 05-07
Preparation of 2-benzyl-3-(quinolin-2-ylamino)cyclopent-2-enone (05-07): The title compound was prepared from Intermediate 01 and 2-aminoquinoline according to the procedure of Example 05-01; 0.53 mmol scale yielded 5 mg after chromatography (ESS=H:E (1:3)) and recrystallization from EtOAc (3% yield). 1H NMR (D6-DMSO) δ 2.35-2.37 (m, 2H), 3.52-3.54 (m, 2H), 3.68 (s, 2H), 7.11-7.14 (m, 1H), 7.22-7.25 (m, 4H), 7.39 (d, J=8.8 Hz, 1H), 7.42 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.4 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 9.74 (s, 1H). 13C NMR (D6-DMSO) δ 26.7, 28.5, 33.2, 114.7, 117.8, 124.4, 125.6, 127.1, 127.7, 128.0, 128.1, 129.9, 138.0, 140.2, 146.3, 152.5, 168.0, 203.4. LCMS t=5.4 min, m/z Calcd for C21H19N2O; C21H18N2NaO; C42H37N4O2; C42H36N4NaO2 315.15; 337.13; 629.29; 651.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 315.17; 337.13; 629.25; 651.32.


















EXAMPLE
TITLE





05-#
COMPOUND NAME
R1
R2
R3







08
3-((3-Chlorophenyl)amino)-2-
H
Cl
H



methylcyclohex-2-enone


09
2-Methyl-3-(o-tolylamino)cy-
CH3
H
H



clohex-2-enone


10
2-Methyl-3-(m-tolylamino)cy-
H
CH3
H



clohex-2-enone


11
2-Methyl-3-(p-tolylamino)cy-
H
H
CH3



clohex-2-enone


12
Methyl 3-chloro-4-((2-
Cl
H
CO2CH3



methyl-3-oxocyclohex-1-en-



1-yl)amino)benzoate









EXAMPLE 05-08
Preparation of 3-((3-chlorophenyl)amino)-2-methylcyclohex-2-enone (05-08): The title compound was prepared from 2-methyl-1,3-cyclohexandione and 3-chloroaniline according to the procedure of Example 05-01; 1.59 mmol scale yielded 300 mg after chromatography (ESS=CH2Cl2:EtOAc (9:1), 80% yield). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.78-1.81 (m, 2H), 2.21-2.24 (m, 2H), 2.47-2.50 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 7.12-7.15 (m, 2H), 7.33 (t, J=7.9 Hz, 1H), 8.26 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 21.7, 27.5, 36.5, 108.8, 121.9, 122.9, 123.2, 130.3, 133.0, 141.7, 157.2, 195.0. LCMS t=5.1 min, m/z Calcd for C13H15ClNO; C13H14ClNNaO; C26H29Cl2N2O2; C26H28Cl2N2NaO2 236.08; 258.07; 471.16; 493.14 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 236.10; 258.07; 471.14; 493.16.
EXAMPLE 05-09
Preparation of 2-methyl-3-(o-tolylamino)cyclohex-2-enone (05-09): The title compound was prepared from 2-methyl-1,3-cyclohexandione and o-toluidine according to the procedure of Example 05-01; 1.59 mmol scale yielded 130 mg after chromatography (ESS=CH2Cl2:EtOAc (9:1), 38% yield). 1H NMR (D6-DMSO) δ 1.67-1.73 (m, 5H), 2.13-2.21 (m, 7H), 7.11 (d, J=6.8 Hz, 1H), 7.18-7.22 (m, 2H), 7.28 (d, J=6.4 Hz, 1H), 7.84 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 17.7, 21.3, 26.8, 36.3, 105.0, 126.3, 126.4, 128.1, 130.5, 135.2, 138.4, 159.7, 193.8. LCMS t=4.9 min, m/z Calcd for C14H18NO; C14H17NNaO; C28H35N2O2; C28H34N2NaO2 216.14; 238.12; 431.27; 453.25 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 216.17; 238.12; 431.27; 453.46.
EXAMPLE 05-10
Preparation of 2-methyl-3-(m-tolylamino)cyclohex-2-enone (05-10): The title compound was prepared from 2-methyl-1,3-cyclohexandione and m-toluiline according to the procedure of Example 05-01; 1.59 mmol scale yielded 190 mg after chromatography (ESS=CH2Cl2:EtOAc (9:1), 56% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.74-1.79 (m, 2H), 2.17-2.20 (m, 2H), 2.29 (s, 3H), 2.41-2.44 (m, 2H), 6.91 (d, J=8.3 Hz, 1H), 6.94-6.96 (m, 2H), 7.21 (t, J=7.7 Hz, 1H), 8.12 (s, 1H). 13C NMR (D6-DMSO) δ 9.1, 20.9, 21.7, 27.3, 36.5, 106.7, 121.6, 124.9, 125.1, 128.6, 138.1, 139.7, 158.3, 194.3. LCMS t=5.0 min, m/z Calcd for C14H18NO; C14H17NNaO; C28H35N2O2; C28H34N2NaO2 216.14; 238.12; 431.27; 453.25 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 216.22; 238.12; 431.27; 453.25.
EXAMPLE 05-11
Preparation of 2-methyl-3-(p-tolylamino)cyclohex-2-enone (05-11): The title compound was prepared from 2-methyl-1,3-cyclohexandione and p-toluiline according to the procedure of Example 05-01; 1.59 mmol scale yielded 160 mg after chromatography (ESS=CH2Cl2:EtOAc (9:1), 47% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.74-1.77 (m, 2H), 2.16-2.19 (m, 2H), 2.28 (s, 3H), 2.36-2.29 (m, 2H), 7.02 (d, J=8.0 Hz, 2H), 7.15 (d, J=7.8 Hz, 2H), 8.09 (s, 1H). 13C NMR (D6-DMSO) δ 9.0, 20.5, 21.7, 27.1, 36.4, 106.0, 124.9, 129.2, 133.6, 137.2, 158.7, 194.0. LCMS t=5.0 min, m/z Calcd for C14H18NO; C14H17NNaO; C28H35N2O2; C28H34N2NaO2 216.14; 238.12; 431.27; 453.25 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 216.17; 238.12; 431.27; 453.26.
EXAMPLE 05-12
Preparation of methyl 3-chloro-4((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoate (05-10): The title compound was prepared from 2-methyl-1,3-cyclohexandione and methyl 4-amino-3-chlorobenzoate according to the procedure of Example 05-01; 1.59 mmol scale, irradiation for 30 min, yielded 260 mg after chromatography (ESS=CH2Cl2:EtOAc (9:1), 56% yield). 1H NMR (D6-DMSO) δ 1.52 (s, 3H), 1.81-1.83 (m, 2H), 2.24-2.27 (m 2H), 2.42-2.43 (m, 2H), 3.85 (s, 3H), 7.18 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 8.06 (s, 1H). LCMS t=5.1 min, m/z Calcd for C15H17ClNO3; C15H16ClNNaO3; C30H33Cl2N2O6; C30H32Cl2N2NaO6 294.09; 316.07; 587.17; 609.15 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 294.12; 316.09; 587.13; 609.15.

















EXAMPLE





05-#
TITLE COMPOUND NAME
R1
R2







13
3-Chloro-N-(4-methoxyphenyl)-4-((2-
H
OCH3



methyl-3-oxocyclohex-1-en-1-



yl)amino)benzamide


14
3-Chloro-N-(2-methoxyphenyl)-4-((2-
OCH3
H



methyl-3-oxocyclohex-1-en-1-



yl)amino)benzamide


15
3-Chloro-4-((2-methyl-3-oxocyclohex-
CH3
H



1-en-1-yl)amino)-N-(o-



tolyl)benzamide









EXAMPLE 05-13
Preparation of 3-chloro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (05-13): Example 05-12 (239 mg, 0.82 mmol) was hydrolyzed to 3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid to the procedure of Example 02-01. The title compound was prepared from 3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid and p-anisidine according to the procedure of Example 04-13; 0.21 mmol scale yielded 10 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (12% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.80-1.82 (m, 2H), 2.22-2.25 (m, 2H), 2.36-2.38 (m, 2H), 3.75 (s, 3H), 6.94 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.91 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 8.11 (s, 1H), 10.18 (s, 1H). 13C NMR (D6-DMSO) δ 9.6, 12.1, 27.6, 36.5, 55.2, 109.7, 113.8, 122.0, 126.6, 127.1, 128.4, 128.8, 132.0, 132.1, 140.1, 155.7, 157.3, 163.1, 195.3. LCMS t=5.0 min, m/z Calcd for C21H22ClN2O3; C21H21ClN2NaO3; C42H43Cl2N4O6; C42H42Cl2N4NaO6 385.13; 407.11; 769.26; 791.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.12; 407.09; 769.22; 791.22.
EXAMPLE 05-14
Preparation of 3-chloro-N-(2-methoxyphenyl)-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (05-14): The title compound was prepared from 3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid and o-anisidine according to the procedure of Example 05-13; 0.21 mmol scale yielded 5 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (6% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.80-1.87 (m, 2H), 2.23-2.25 (m, 2H), 2.37-2.39 (m, 2H), 3.83 (s, 3H), 6.96-7.01 (m, 1H), 7.10-7.15 (m, 1H), 7.21-7.26 (m, 1H), 7.30-7.35 (m, 1H), 7.67 (d, J=6.3 Hz, 1H), 7.92 (d, J=6.9 Hz, 1H), 8.07 (s, 1H), 8.11 (s, 1H), 9.60 (s, 1H). 13C NMR (D6-DMSO) δ 9.7, 21.1, 27.6, 36.5, 55.7, 109.9, 111.5, 120.2, 125.2, 126.2, 126.5, 126.6, 127.0, 128.4, 129.0, 131.6, 140.3, 152.0, 157.3, 163.3, 195.4.
LCMS t=5.3 min, m/z Calcd for C21H22ClN2O3; C21H21ClN2NaO3; C42H43O2N4O6; C42H42Cl2N4NaO6 385.13; 407.11; 769.26; 791.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 385.13; 407.09; 769.20; 791.39.
EXAMPLE 05-15
Preparation of 3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide (05-15): The title compound was prepared from 3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzoic acid and o-toluidine according to the procedure of Example 05-13; 0.21 mmol scale yielded 2 mg after chromatography (ESS=H:E (1:3)) and EtOAc trituration (3% yield). 1H NMR (D6-DMSO) δ 1.61 (s, 3H), 1.79-1.88 (m, 2H), 2.20-2.32 (m, 5H), 2.34-2.45 (m, 2H), 7.15-7.39 (m, 5H), 7.93 (s, 1H), 8.07 (s, 1H), 8.12 (s, 1H), 9.96 (s, 1H). 13C NMR (D6-DMSO) δ 9.7, 17.9, 21.1, 27.6, 36.5, 109.8, 126.0, 126.2, 126.7, 127.1, 128.5, 129.0, 130.4, 131.7, 133.8, 136.2, 140.3, 157.3, 163.5, 195.4. LCMS t=5.2 min, m/z Calcd for C21H22ClN2O2; C21H21ClN2NaO2; C42H42Cl2N4NaO4 369.14; 391.12; 759.25 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.14; 391.10; 759.24.




EXAMPLE 05-16
Preparation of 4-((2-benzyl-3-oxocyclopent-1-en-1-yl)amino)-3-chloro-N-(o-tolyl)benzamide (05-16): The title compound was prepared from Intermediate 01 and free base Intermediate 03 according to the procedure of Example 05-13; 0.25 mmol scale yielded 5 mg after chromatography (ESS=H:E (1:3)) and recrystallization from MeOH (5% yield). 1H NMR (D6-DMSO) δ 2.24 (s, 3H), 2.27-2.28 (m, 2H), 2.56-2.58 (m, 2H), 3.50 (s, 2H), 7.12-7.24 (m, 7H), 7.28 (d, J=7.0 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 8.10 (s, 1H), 9.06 (s, 1H), 10.00 (s, 1H). LCMS t=5.6 min, m/z Calcd for C26H24ClN2O2; C26H23ClN2NaO2; C52H47O2N4O4; C52H46Cl2N4NaO4 431.15; 453.13; 861.30; 883.28 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 431.15; 453.13; 861.30; 883.28.
















EXAMPLE




05-#
TITLE COMPOUND NAME
R1







17
3-Fluoro-N-(4-methoxyphenyl)-4-((2-methyl-3-
F



oxocyclopent-1-en-1-yl)amino)benzamide


18
3-Bromo-N-(4-methoxyphenyl)-4-((2-methyl-3-
Br



oxocyclopent-1-en-1-yl)amino)benzamide









EXAMPLE 05-17
Preparation of 3-fluoro-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (05-17): The title compound was prepared from 2-methyl-1,3-cyclopentandione and free base Intermediate 04 according to the procedure of Example 05-13; 0.25 mmol scale yielded 50 mg after recrystallization from MeOH (56% yield). 1H NMR (D6-DMSO) δ 1.54 (s, 3H), 2.22-2.25 (m, 2H), 2.50-2.52 (m, 2H), 3.75 (s, 3H), 6.92-6.95 (m, 2H), 7.44-7.48 (m, 1H), 7.65-7.67 (m, 2H), 7.80-7.82 (m, 1H), 7.88 (dd, J=11.3, 1.7 Hz, 1H), 9.03 (s, 1H), 10.15 (s, 1H). LCMS t=4.8 min, m/z Calcd for C20H20FN2O3; C20H19FN2NaO3; C40H39F2N4O6; C40H38F2N4NaO6 355.15; 377.13; 709.28; 731.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.17; 377.10; 709.24; 731.22.
EXAMPLE 05-18
Preparation of 3-bromo-N-(4-methoxyphenyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (05-18): The title compound was prepared from 2-methyl-1,3-cyclopentandione and free base Intermediate 05 according to the procedure of Example 05-13; 0.25 mmol scale yielded 10 mg after recrystallization from MeOH (10% yield). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.21-2.24 (m, 2H), 2.47-2.49 (m, 2H), 3.75 (s, 3H), 6.93-6.95 (m, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.9 Hz, 2H), 7.97 (dd, J=8.2, 1.6 Hz, 1H), 8.27 (d, J=1.7 Hz, 1H), 8.93 (s, 1H), 10.22 (s, 1H). LCMS t=4.9 min, m/z Calcd for C20H20BrN2O3; C20H19BrN2NaO3; C40H39Br2N4O6; C40H38Br2N4NaO6 415.07, 417.06; 437.05, 439.05; 831.12; 853.10 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 415.05, 417.05; 437.01, 439.01; 831.05; 853.03.




EXAMPLE 05-19
Preparation of tert-butyl (2-(44(2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)ethyl)-carbamate (05-19): tert-Butyl-N-(2-aminoethyl)carbamate (1.4 mL, 1.03 eq) was added to Example 02-01 (2.0 g, 8.65 mmol) stirring in CH2Cl2:DMF (90 mL, 1:1) at 0° C. 3-(Ethyliminomethylene-amino)-N,N-dimethyl-propan-1-amine hydrochloride (EDCCl, 2.0 g, 1.2 eq) was added and stirred for 2 h at 0° C. After warming to rt overnight, the solvent was removed on the rotovap. Work-up was performed with DI H2O (500 mL) and EtOAc (8×125 mL). The organic layer was dried over anhyd sodium sulfate and concentrated on the rotovap. Crude material was added directly to a KP-SilTM column (100 g) with products separating from impurities using stepwise gradients on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The reaction on a 8.65 mmol scale yielded 1.5 g of the title compound after chromatography (ESS=EtOAc, 46% yield). 1H NMR (D6-DMSO) δ 1.37 (s, 9H), 1.59 (s, 3H), 2.23-2.25 (m, 2H), 2.75-2.77 (m, 2H), 3.08-3.10 (m, 2H), 3.26-3.28 (m, 2H), 6.92 (s, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.81 (d, J=7.8 Hz, 2H), 8.38 (s, 1H), 9.11 (s, 1H). LCMS t=Direct Injection, m/z Calcd for C20H28N3O4; C20H27N3NaO4; C40H54N6NaO8 374.21; 396.19; 769.39 [M+H]+; [M+Na]+; [2M+Na]+, Found 374.21; 396.19; 769.39.




EXAMPLE 05-20
Preparation of 2-(44(2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)ethanaminium 2,2,2-trifluoroacetate (05-20): Example 05-19 (750 mg, 2.0 mmol) was stirred in a minimum amount of CH2Cl2:TFA (1:1) for 30 min at rt. Solvents were removed on the rotovap and the title compound was recrystallized from EtOAc. 1H NMR (MeOD) δ 1.68 (s, 3H), 2.41-2.43 (m, 2H), 2.84-2.86 (m, 2H), 3.15-3.18 (m, 2H), 3.65-3.67 (m, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H). LCMS t=3.0 min, m/z Calcd for C15H20N3O2; C15H19N3NaO2; C34H39N6O4; C30H38N6NaO4 274.16; 296.14; 547.30; 569.29 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 274.20; 296.17; 547.27; 569.26.




EXAMPLE 05-21
Preparation of N-(2-acetamidoethyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (05-21): Anhydride N-Acylation; Anhydride (5 eq), TEA (2 eq) and Example 05-20 (25 mg, 0.09 mmol, 1.0 eq) were mixed in CH2Cl2 and stirred at rt for 1 h. Solvents were removed on the rotovap. The crude was added to a KP-SilTM column (10 g). Alternatively a precipitate was filtered from the reaction mixture. The reaction on a 0.09 mmol scale yielded 15 mg of the title compound after chromatography (ESS=EtOAc, 53% yield). 1H NMR (D6-DMSO) δ 1.72 (s, 3H), 1.95 (s, 3H), 2.48-2.50 (m, 2H), 2.85-2.87 (m, 2H), 3.38-3.41 (m, 2H), 3.47-3.50 (m, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H). LCMS Direct Injection, m/z Calcd for C17H22N3O3; C17H21N3NaO3; C34H42N6NaO6 316.17; 338.15; 653.31 [M+H]+; [M+Na]+; [2M+Na]+, Found 316.17; 338.15; 653.31.




EXAMPLE 05-22
Preparation of N-(2-benzamidoethyl)-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (05-22): The title compound was prepared from Example 05-20 and phenylacetic anhydride according to the procedure of Example 05-21; 0.09 mmol scale yielded 10 mg after chromatography (ESS=EtOAc, 29% yield). 1H NMR (CD3OD) δ 1.68 (s, 3H), 2.40-2.43 (m, 2H), 2.82-2.84 (m, 2H), 3.61-3.63 (m, 4H), 7.33 (d, J=8.4 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.51 (t, J=7.3 Hz, 1H), 7.81 (d, J=7.6 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H). LCMS Direct Injection, m/z Calcd for C22H24N3O3; C22H23N3NaO3; C44H46N6NaO6 378.18; 400.16; 777.34 [M+H]+; [M+Na]+; [2M+Na]+, Found 378.18; 400.16; 777.34.




EXAMPLE 05-23
Preparation of 4((2-methyl-3-oxocyclopent-1-en-1-yl)amino)piperidin-1-ium 2,2,2-trifluoroacetate (05-23): The title compound was prepared from Example 01-32 according to the procedure of Example 05-20. 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.71 (dd, J=23.4, 10.5 Hz, 2H), 2.03 (d, J=12.9 Hz, 2H), 2.12-2.14 (m, 2H), 2.50-2.52 (m, 2H), 2.96 (t, J=12.1 Hz, 2H), 3.30-3.38 (m, 2H), 3.60-3.72 (m, 1H), 7.08 (d, J=8.9 Hz, 1H), 8.54 (br s, 1H), 8.77 (br s, 1H). LCMS t=1.1 min, m/z Calcd for C11H19N2O; C11H18N2NaO; C22H37N4O2, C22H36N4NaO2 195.15; 217.13; 389.29; 411.27 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 195.27; 217.25; 389.36; 411.34.




EXAMPLE 05-24
Preparation of tert-butyl 4-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)benzylcarbamate (05-24): The title compound was prepared from Example 02-02 and 4-(N-Boc)aminomethyl-aniline according to the procedure of Example 04-13; 1.0 mmol scale yielded 400 mg after chromatography (ESS=H:E (1:19), 85% yield). 1H NMR (D6-DMSO) δ 1.40 (s, 9H), 1.48 (s, 3H), 2.23-2.25 (m, 2H), 2.49-2.50 (m, 2H), 4.10 (d, J=4.6 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 7.36-7.38 (m, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.69 (d, J=7.8 Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 8.13 (s, 1H), 8.97 (s, 1H), 10.30 (s, 1H). LCMS t=5.9 min, m/z Calcd for C25H29ClN3O4; C25H28ClN3NaO4; C50H57Cl2N6O8; C50H56Cl2N6NaO8 470.18; 492.17; 939.36; 961.34 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 470.19; 492.13; 939.39; 961.37.




EXAMPLE 05-25
Preparation of (4-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamido)phenyl)methanaminium 2,2,2-trifluoroacetate (05-25): The title compound was prepared from Example 05-24 according to the procedure of Example 05-20. 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.24-2.26 (m, 2H), 2.49-2.51 (m, 2H), 4.01 (d, J=5.5 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 8.09 (br s, 3H), 8.14 (s, 1H), 8.98 (s, 1H), 10.42 (s, 1H). LCMS t=5.1 min, m/z Calcd for C20H21ClN3O2; C20H20ClN3NaO2; C40H41Cl2N6O4; C40H40Cl2N6NaO4 370.13; 392.11; 739.26; 761.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 370.13; 392.11; 739.26; 761.24.




EXAMPLE 05-26
Preparation of N-(4-(acetamidomethyl)phenyl)-3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)benzamide (05-26): The title compound was prepared from Example 05-25 and acetic anhydride according to the procedure of Example 05-21; 0.05 mmol scale yielded 10 mg from precipitate (49% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 1.87 (s, 3H), 2.23-2.25 (m, 2H), 2.49-2.51 (m, 2H), 4.22 (d, J=5.7 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.2 Hz, 1H), 8.14 (s, 1H), 8.13-8.15 (m, 1H), 8.97 (s, 1H), 10.31 (s, 1H). LCMS t=4.6 min, m/z Calcd for C22H23ClN3O3; C22H22ClN3NaO3; C44H44Cl2N6NaO6 412.14; 434.12; 845.26 [M+H]+; [M+Na]+; [2M+Na]+, Found 412.15; 434.09; 845.24.




EXAMPLE 05-27
Preparation of tert-butyl (2-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)ethyl)carbamate (05-27): The title compound was prepared from Example 01-36 and tert-butyl (2-aminoethyl)carbamate according to the procedure of Example 04-13; 0.5 mmol scale yielded 300 mg from precipitate (71% yield). 1H NMR (D6-DMSO) δ 1.36 (s, 9H), 1.65 (s, 3H), 1.76-1.78 (m, 2H), 2.18-2.21 (m, 4H), 3.09-3.11 (s, 2H), 3.26-3.29 (m, 2H), 6.93-6.95 (m, 1H), 7.64-7.66 (m, 1H), 7.72-7.75 (m, 2H), 8.08-8.10 (m, 1H), 8.58 (s, 1H). 13C NMR (D6-DMSO) δ 9.4, 21.6, 27.3, 28.6, 36.8, 78.1, 107.5, 126.6, 128.2, 130.1, 134.2, 134.3, 137.5, 156.2, 128.9, 165.2, 195.0. LCMS t=4.9 min, m/z Calcd for C21H29ClN3O4; C21H28ClN3NaO4; C42H57Cl2N6O8; C42H56Cl2N6NaO8 422.18; 444.17; 843.36; 865.34 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 422.20; 444.18; 843.39; 865.37.




EXAMPLE 05-28
Preparation of N-(2-aminoethyl)-4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (05-28): The title compound was prepared from Example 05-24 according to the procedure of Example 05-20. TFA salt was hygroscopic. Freebase was isolated. 1H NMR (D6-DMSO) δ 1.65 (s, 3H), 1.77-1.79 (m, 2H), 2.19-2.23 (m, 4H), 2.99-3.01 (m, 2H), 3.45-3.51 (m, 2H), 7.68 (d, J=8.2 Hz, 1H), 7.74-7.89 (m, 4H), 8.09-8.11 (m, 1H), 8.75 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 21.6, 27.4, 36.8, 37.6, 39.0, 107.7, 126.6, 128.2, 130.2, 133.9, 134.3, 137.6, 158.7, 165.8, 195.1. LCMS t=3.8 min, m/z Calcd for C16H21ClN3O2; C16H20ClN3NaO2; C32H41Cl2N6O4; C32H40Cl2N6NaO4 322.13; 344.11; 643.26; 665.24 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 322.14; 344.13; 643.28; 665.26.




EXAMPLE 05-29
Preparation of N-(2-acetamidoethyl)-4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamide (05-29): The title compound was prepared from Example 05-28 and acetic anhydride according to the procedure of Example 05-21; 0.10 mmol scale yielded 5 mg from precipitate (14% yield). 1H NMR (D6-DMSO) δ 1.65 (s, 3H), 1.77-1.81 (m, 5H), 2.19-2.23 (m, 4H), 3.19-3.21 (m, 2H), 3.28-3.30 (m, 2H), 7.65 (d, J=8.7 Hz, 1H), 7.73 (s, 2H), 7.97 (s, 1H), 8.06 (s, 1H), 8.62 (s, 1H). LCMS t=4.2 min, m/z Calcd for C18H23ClN3O3; C18H22ClN3NaO3; C36H45Cl2N6O6; C36H45Cl2N6NaO6 364.14; 386.12; 727.28; 749.26 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 364.15; 386.14; 727.30; 749.28.




EXAMPLE 05-30
Preparation of tert-butyl (2-(3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-2-methylbenzamido)ethyl)carbamate (05-30): The title compound was prepared from Example 04-95 and tert-butyl (2-aminoethyl)carbamate according to the procedure of Example 04-13; 0.5 mmol scale yielded 50 mg after chromatography (ESS=EtOAc, 18% yield). 1H NMR (D6-DMSO) δ 1.40 (s, 9H), 1.66 (s, 3H), 1.78-1.81 (m, 2H), 2.18-2.22 (m, 4H), 2.26-2.28 (m, 2H), 3.09-2.12 (m, 2H), 3.24-3.28 (m, 2H), 6.87 (t, J=5.4 Hz, 1H), 7.25-7.26 (m, 2H), 7.36 (t, J=4.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.86-7.89 (m, 2H), 8.12 (s, 1H), 8.31 (t, J=5.4 Hz, 1H), 10.07 (s, 1H). LCMS t=4.9 min, m/z Calcd for C29H36ClN4O5; C29H35ClN4NaO5; C58H71Cl2N8O10; C58H70Cl2N8NaO10 555.24; 577.22; 1109.47; 1131.45 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 555.26; 577.24; 1109.51; 1131.49.




EXAMPLE 05-31
Preparation of tert-butyl (2-(3-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)benzamido)-4-methylbenzamido)ethyl)carbamate (05-31): The title compound was prepared from Example 04-96 and tert-butyl (2-aminoethyl)carbamate according to the procedure of Example 04-13; 0.5 mmol scale yielded after chromatography (ESS=EtOAc, 36% yield). 1H NMR (D6-DMSO) δ 1.39 (s, 9H), 1.66 (s, 3H), 1.78-1.80 (m, 2H), 2.19-2.22 (m, 2H), 2.26-2.28 (m, 4H), 3.09-3.11 (m, 2H), 3.27-3.30 (m, 2H), 6.91 (t, J=5.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.87-7.90 (m, 2H), 8.11 (s, 1H), 8.43 (t, J=5.3 Hz, 1H), 10.12 (s, 1H). LCMS t=5.0 min, m/z Calcd for C29H36ClN4O5; C29H35ClN4NaO5; C58H71Cl2N8O10; C58H70Cl2N8NaO10 555.24; 577.22; 1109.47; 1131.45 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 555.26; 577.24; 1109.50; 1131.49.




EXAMPLE 05-32
Preparation of 2-((3-chlorophenyl)amino)-6-oxocyclohex-1-enecarbonitrile (05-32): The title compound was prepared from Intermediate 06 and 3-chloroaniline according to the procedure of Example 05-13; 1.3 mmol scale yielded 24 mg after chromatography (ESS=H:E (1:1), 8% yield). 1H NMR (D6-DMSO) δ 1.82-1.85 (m, 2H), 2.26-2.29 (m, 2H), 2.58-2.60 (m, 2H), 7.26 (d, J=7.7 Hz, 1H), 7.37-7.46 (m, 3H), 10.15 (s, 1H). 13C NMR (D6-DMSO) δ 20.6, 26.7, 36.4, 86.0, 116.2, 125.4, 126.6, 127.4, 130.9, 133.5, 139.1, 170.9, 193.2. LCMS t=4.6 min, m/z Calcd for C13H12ClN2O; C13H11ClN2NaO; C26H23Cl2N4O2; C26H22Cl2N4NaO2 247.06; 269.05; 493.12; 515.10 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 247.07; 269.06; 493.14; 515.12.




EXAMPLE 05-33
Preparation of 4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)benzoic acid (05-33): The title compound was prepared Intermediate 06 and 3-amino-4-chlorobenzoic acid according to the procedure of Example 01-01; 7.3 mmol scale yielded 0.7 g after chromatography (ESS=CH2Cl2:MeOH (19:1), 33% yield). 1H NMR (D6-DMSO) δ 1.85-1.88 (m, 2H), 2.28-2.30 (m, 2H), 2.50-2.58 (m, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.91-7.96 (m, 2H), 10.17 (s, 1H), 13.40 (br s, 1H). 13C NMR (D6-DMSO) δ 20.3, 29.1, 36.9, 85.5, 115.6, 130.6, 130.7, 130.9, 135.3, 136.7, 166.4, 193.4. LCMS t=4.1 min, m/z Calcd for C14H12ClN2O3; C14H11ClN2NaO3; C28H23Cl2N4O6; C28H23Cl2N4NaO6 291.05; 313.04; 581.10; 603.08 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 291.06; 313.05; 581.12; 603.10.

















EXAMPLE





05-#
TITLE COMPOUND NAME
R1
R2







34
4-Chloro-3-((2-cyano-3-oxocyclohex-1-en-
CH3
H



1-yl)amino)-N-(o-tolyl)benzamide


35
4-Chloro-3-((2-cyano-3-oxocyclohex-1-en-
H
OCH3



1-yl)amino)-N-(4-methoxyphenyl)ben-



zamide


36
4-Chloro-3-((2-cyano-3-oxocyclohex-1-en-
CH3
OCH3



1-yl)amino)-N-(4-methoxy-2-methylphe-



nyl)benzamide









EXAMPLE 05-34
Preparation of 4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)-N-(o-tolyl)benzamide (05-34): The title compound was prepared from Example 05-33 and o-toluidine according to the procedure of Example 04-13; 0.5 mmol scale yielded 130 mg from precipitate (67% yield). 1H NMR (D6-DMSO) δ 1.86-1.91 (m, 2H), 2.23 (s, 3H), 2.29-2.34 (m, 2H), 2.50-2.60 (m, 2H), 7.19-7.24 (m, 2H), 7.28-7.32 (m, 2H), 7.77 (d, J=6.8 Hz, 1H), 8.03 (s, 2H), 10.04 (s, 1H), 10.21 (s, 1H). LCMS t=4.7 min, m/z Calcd for C21H19ClN3O2; C21H18ClN3NaO2; C42H37Cl2N6O4; C42H36Cl2N6NaO4 380.12; 402.10; 759.23; 781.21 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 380.13; 402.11; 759.25; 781.24.
EXAMPLE 05-35
Preparation of 4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)-N-(4-methoxyphenyl)benzamide (05-35): The title compound was prepared from Example 05-33 and p-anisidine according to the procedure of Example 04-13; 0.5 mmol scale yielded 113 mg from precipitate (57% yield). 1H NMR (D6-DMSO) δ 1.85-1.91 (m, 2H), 2.28-2.35 (m, 2H), 2.50-2.62 (m, 2H), 3.75 (s, 3H), 6.94 (d, J=8.9 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 8.00-8.04 (m, 2H), 10.23 (s, 1H). LCMS t=4.7 min, m/z Calcd for C21H19ClN3O3; C21H18ClN3NaO3; C42H37Cl2N6O6; C42H36Cl2N6NaO6 396.11; 418.09; 791.22; 813.20 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 396.13; 418.11; 791.24; 813.23.
EXAMPLE 05-36
Preparation of 4-chloro-3-((2-cyano-3-oxocyclohex-1-en-1-yl)amino)-N-(4-methoxy-2-methylphenyl)benzamide (05-36): The title compound was prepared from Example 05-33 and 4-methoxy-2-methylaniline according to the procedure of Example 04-13; 0.5 mmol scale yielded 82 mg after chromatography (ESS=H:E (1:3), 41% yield). 1H NMR (D6-DMSO) δ 1.85-1.92 (m, 2H), 2.19 (s, 3H), 2.28-2.36 (m, 2H), 2.50-2.63 (m, 2H), 3.75 (s, 3H), 6.79 (d, J=7.1 Hz, 1H), 6.86 (s, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 8.03 (s, 2H), 9.92 (s, 1H), 10.21 (s, 1H). 13C NMR (D6-DMSO) δ 18.5, 20.4, 28.9, 36.4, 55.6, 85.6, 111.8, 115.8, 128.5, 129.1, 129.2, 129.5, 130.3, 134.3, 135.1, 135.2, 136.0, 157.9, 163.9, 193.3. LCMS t=4.7 min, m/z Calcd for C22H21ClN3O3; C22H20ClN3NaO3; C44H41Cl2N6O6; C44H40Cl2N6NaO6 410.13; 432.11; 819.25; 841.23 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 410.14; 432.12; 819.27; 841.26.

















EXAMPLE





05-#
TITLE COMPOUND NAME
R1
R2







37
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-
H
OCH3



1-en-1-yl)amino)phenyl)-4-methoxyben-



zamide


38
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-
CH3
H



1-en-1-yl)amino)phenyl)-2-methylben-



zamide









EXAMPLE 05-37
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-4-methoxybenzamide (05-37): Triethylamine (0.279 mL, 2.0 mmol) was added to Example 02-14 (0.27 g, 1.0 mmol) in dichloromethane (5 mL). p-Anisoyl chloride (0.142 mL, 1.05 mmol) was added to the solution stirring at 0° C. After 2 h, the solvent was removed on the rotovap and the subsequent crude material was added directly to a KP-SilTM column (10 g) with products separating from impurities using stepwise gradients, on the Biotage®-Isolera Four instrument, monitoring UV Trace at 254/365 nm. The stepwise gradient utilized two solvents (hexanes and EtOAc) running from non-polar to polar steps (3:1-1:1-1:3). The 1.0 mmol scale yielded 75 mg of pale yellow microcrystals after chromatography (ESS=H:E (1:3), mp=254-257° C., 20% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.20-2.23 (m, 2H), 2.44-2.48 (m, 2H), 3.84 (s, 3H), 7.07 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.3 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 8.89 (s, 1H), 10.25 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 25.6, 32.6, 55.5, 109.4, 113.7, 118.9, 119.6, 123.7, 126.5, 129.6, 129.7, 136.5, 138.8, 162.1, 165.1, 169.5, 202.3. LCMS t=5.0 min, m/z Calcd for C20H20ClN2O3; C20H19ClN2NaO3; C40H39Cl2N4O6; C40H38Cl2N2NaO6 371.116; 393.098; 741.225; 763.207 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 371.116; 393.090; 741.217; 763.203.
EXAMPLE 05-38
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzamide (05-38): The title compound was prepared from Example 02-14 and o-toluoyl chloride according to the procedure of Example 05-37; 1.0 mmol scale yielded 65 mg of pale yellow microcrystals after chromatography (ESS=H:E (1:3), mp=230-232° C., 18% yield). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.20-2.22 (m, 2H), 2.38 (s, 3H), 2.44-2.48 (m, 2H), 7.29-7.33 (m, 2H), 7.40 (t, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.7, 2.0 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 8.89 (s, 1H), 10.49 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 19.3, 25.6, 32.6, 109.4, 118.4, 118.9, 123.8, 125.7, 127.3, 129.8, 129.9, 130.6, 135.3, 136.6, 136.8, 138.7, 168.1, 169.5, 202.4. LCMS t=5.1 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N2NaO4 355.121; 377.103; 709.235; 731.217 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.126; 377.099, 709.220; 731.208.




EXAMPLE 05-39
Preparation of N-(4-chloro-3-[(2-methyl-3-oxocyclopent-1-en-1-yl)amino]phenyl)-cyclohexanecarboxamide (05-39): The title compound was prepared from Example 02-14 and cyclohexanecarbonyl chloride according to the procedure of Example 05-37 (mp=240-242° C.). 1H NMR (D6-DMSO) δ 1.12-1.30 (m, 3H), 1.34-1.43 (m, 2H), 1.44 (s, 3H), 1.62-1.67 (m, 1H), 1.71-1.84 (m, 5H), 2.17-2.22 (m, 2H), 2.26-2.34 (m, 1H), 2.41 (d, J=4.9 Hz, 2H), 7.39-7.50 (m, 2H), 7.69 (s, 1H), 8.86 (s, 1H), 10.02 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 25.2 (2C), 25.4, 25.6, 29.0 (2C), 32.6, 44.9, 109.3, 117.8, 118.4, 123.1, 129.7, 136.5, 138.9, 169.5, 174.6, 202.4. LCMS t=4.8 min, m/z Calcd for C19H24ClN2O2; C19H23ClN2NaO2; C38H47Cl2N4O4; C38H46Cl2N4NaO4 347.152; 369.135; 693.297; 715.279 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 347.152; 369.135; 693.297; 715.279.




EXAMPLE 05-40
Preparation of N-(4-chloro-3-[(2-methyl-3-oxocyclopent-1-en-1-yl)amino]phenyl)-naphthalene-1-carboxamide (05-40): The title compound was prepared from Example 02-14 and 1-naphthoyl chloride according to the procedure of Example 05-37 (mp=243-245° C.). 1H NMR (D6-DMSO) δ 1.49 (s, 3H), 2.19-2.25 (m, 2H), 2.47 (br s, 2H), 7.56 (d, J=8.5 Hz, 1H), 7.58-7.65 (m, 3H), 7.69 (dd, J=8.5, 2.4 Hz, 1H), 7.79 (d, J=7.3 Hz, 1H), 7.90 (d, J=2.4 Hz, 1H), 8.02-8.05 (m, 1H), 8.10 (d, J=7.3 Hz, 1H), 8.16-8.21 (m, 1H), 8.95 (s, 1H), 10.79 (s, 1H). 13C NMR (D6-DMSO) δ 7.5, 25.6, 32.6, 109.5, 118.6, 119.2, 124.0, 125.0, (2C), 125.7, 126.5, 127.2, 128.4, 129.6, 129.8, 130.5, 133.2, 134.2, 136.7, 138.7, 167.5, 169.5, 202.4. LCMS t=4.8 min, m/z Calcd for C23H20ClN2O2; C23H19ClN2NaO2; C46H39Cl2N4O4; C46H38Cl2N4NaO4 391.125; 413.103; 781.235; 803.217 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 391.122; 413.103; 781.235; 803.217.




EXAMPLE 05-41
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzamide (05-41): The title compound was prepared from Example 02-15 and o-toluoyl chloride according to the procedure of Example 05-37 (mp=280-283° C.). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.15-2.20 (m, 2H), 2.32-2.36 (m, 2H), 2.39 (s, 3H), 7.29-7.35 (m, 2H), 7.37-7.45 (m, 2H), 7.49 (d, J=7.3 Hz, 1H), 7.66 (dd, J=8.5, 2.4 Hz, 1H), 8.07 (s, 1H), 8.87 (s, 1H), 10.55 (s, 1H). 13C NMR (D6-DMSO) δ 7.1, 19.3, 25.2, 32.6, 108.4, 118.6, 119.9, 125.7, 127.3, 129.5, 129.9, 130.6, 130.8, 131.6, 135.4, 136.7, 138.6, 168.0, 170.4, 201.9. LCMS t=4.4 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39O2N4O4; C40H38Cl2N4NaO4 355.121; 377.103; 709.235; 731.217 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.121; 377.103; 709.235; 731.217.




EXAMPLE 05-42
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzamide (05-42): The title compound was prepared from Example 02-13 and o-toluoyl chloride according to the procedure of Example 05-37 (mp=118-120° C.). 1H NMR (D6-DMSO) δ 1.48 (s, 3H), 2.15-2.22 (m, 2H), 2.40 (br s, 2H), 2.45 (s, 3H), 7.25-7.35 (m, 3H), 7.40 (q, J=7.3 Hz, 2H), 7.48-7.60 (m, 2H), 8.96 (s, 1H), 10.07 (s, 1H). 13C NMR (D6-DMSO) δ 7.3, 19.5, 25.4, 32.6, 109.1, 125.6, 125.6, 125.9, 126.8, 126.9, 127.4, 129.9, 130.6, 135.6, 135.9, 136.3, 137.4, 167.9, 169.8, 202.2. LCMS t=4.4 min, m/z Calcd for C20H20ClN2O2; C20H19ClN2NaO2; C40H39Cl2N4O4; C40H38Cl2N4NaO4 355.121; 377.103; 709.235; 731.217 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 355.121; 377.103; 709.235; 731.217.

















EXAMPLE





05-#
TITLE COMPOUND NAME
R1
R2







43
N-(4-Chloro-3-((2-methyl-3-oxocyclohex-
H
OCH3



1-en-1-yl)amino)phenyl)-4-methoxyben-



zamide


44
N-(4-Chloro-3-((2-methyl-3-oxocyclohex-
CH3
H



1-en-1-yl)amino)phenyl)-2-methylben-



zamide









EXAMPLE 05-43
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-4-methoxybenzamide (05-43): The title compound was prepared from Example 02-10 and p-anisoyl chloride according to the procedure of Example 05-37; 1.0 mmol scale yielded 60 mg after chromatography (ESS=H:E (1:3), mp=190-195° C., 16% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.77-1.80 (m, 2H), 2.18-2.21 (m, 2H), 2.25-2.27 (m, 2H), 3.84 (s, 3H), 7.07 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.68 (dd, J=8.7, 2.1 Hz, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H), 8.00 (s, 1H), 10.25 (s, 1H). 13C NMR (D6-DMSO) δ 9.0, 21.2, 27.0, 36.4, 55.5, 107.1, 113.7, 118.9, 120.2, 124.5, 126.5, 129.5, 129.7, 137.0, 138.9, 158.4, 162.1, 165.1, 194.5. LCMS t=5.1 min, Calcd for C21H22ClN2O3; C21H21ClN2NaO3; C42H42Cl2N2NaO6 385.13; 407.11; 791.24 [M+H]+; [M+Na]+; [2M+Na]+, Found 385.20; 407.10; 791.22.
EXAMPLE 05-44
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzamide (05-44): The title compound was prepared from Example 02-10 and o-toluoyl chloride according to the procedure of Example 05-37 (mp=199-201° C.). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.76-1.80 (m, 2H), 2.19 (t, J=6.1 Hz, 2H), 2.25 (t, J=5.5 Hz, 2H), 2.38 (s, 3H), 7.28-7.36 (m, 2H), 7.38-7.43 (m, 1H), 7.44-7.56 (m, 2H), 7.62 (d, J=7.3 Hz, 1H), 7.74 (s, 1H), 8.03 (s, 1H), 10.50 (s, 1H). 13C NMR (D6-DMSO) δ 9.1, 19.3, 21.2, 27.0, 36.4, 107.2, 118.2, 119.4, 124.5, 125.7, 127.2, 129.7, 129.9, 130.6, 135.3, 136.8, 137.2, 138.7, 158.4, 168.0, 194.6. LCMS t=4.7 min, m/z Calcd for C21H22ClN2O2; C21H21ClN2NaO2; C42H42Cl2N4NaO4 369.137; 391.119; 759.248 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.137; 391.119; 759.248.




EXAMPLE 05-45
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanecarboxamide (05-45): The title compound was prepared from Example 02-10 and cyclohexanecarbonyl chloride according to the procedure of Example 05-37 (mp=192-195° C.). 1H NMR (D6-DMSO) δ 1.14-1.22 (m, 1H), 1.22-1.30 (m, 2H), 1.35-1.43 (m, 2H), 1.63 (s, 4H), 1.72-1.82 (m, 6H), 2.18 (t, J=6.1 Hz, 2H), 2.22 (t, J=5.5 Hz, 2H), 2.27-2.33 (m, 1H), 7.41-7.47 (m, 2H), 7.61 (s, 1H), 7.97 (s, 1H), 10.00 (s, 1H). 13C NMR (D6-DMSO) δ 9.1, 21.2, 25.2 (2C), 25.4, 27.0, 29.1 (2C), 36.4, 44.9, 107.1, 117.7, 118.9, 123.8, 129.6, 137.1, 138.9, 158.4, 174.6, 194.6. LCMS t=4.9 min, m/z Calcd for C20H26ClN2O2; C20H25ClN2NaO2; C40H50Cl2N4NaO4 361.168; 383.150; 743.311 [M+H]+; [M+Na]+; [2M+Na]+, Found 361.168; 383.150; 743.311.




EXAMPLE 05-46
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-1-naphthamide (05-46): The title compound was prepared from Example 02-10 and 1-naphthoyl chloride according to the procedure of Example 05-37 (mp=245-247° C.). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.77-1.83 (m, 2H), 2.20 (t, J=6.1 Hz, 2H), 2.26-2.31 (m, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.58-7.65 (m, 3H), 7.69 (d, J=7.3 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 8.02-8.07 (m, 2H), 8.10 (d, J=8.5 Hz, 1H), 8.16-8.20 (m, 1H), 10.77 (s, 1H). 13C NMR (D6-DMSO) δ 9.1, 21.2, 27.1, 36.4, 107.3, 118.4, 119.6, 124.7, 125.1 (2C), 125.7, 126.5, 127.2, 128.4, 129.6, 129.8, 130.4, 133.2, 134.3, 137.2, 138.7, 158.4, 167.5, 194.6. LCMS t=5.0 min, m/z Calcd for C24H22ClN2O2; C24H21ClN2NaO2; C48H43Cl2N4O4; C48H42Cl2N4NaO4 405.136; 427.118; 809.266; 831.248 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 405.136; 427.118; 809.266; 831.248.




EXAMPLE 05-47
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-1-naphthamide (05-47): The title compound was prepared from Example 02-12 and 1-naphthoyl chloride according to the procedure of Example 05-37 (mp=245-247° C.). 1H NMR (D6-DMSO) δ 1.69 (s, 3H), 1.77 (quin, J=6.4 Hz, 2H), 2.16-2.21 (m, 4H), 7.35 (d, J=8.5 Hz, 1H), 7.51-7.68 (m, 3H), 7.72 (dd, J=8.5, 2.4 Hz, 1H), 7.79 (d, J=7.3 Hz, 1H), 8.00-8.07 (m, 2H), 8.11 (d, J=8.5 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H), 8.17-8.23 (m, 1H), 10.82 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 21.2, 26.7, 36.3, 105.9, 118.8, 120.1, 125.1 (2C), 125.7, 126.5, 127.2, 128.4, 129.6, 130.0, 130.5, 131.4, 132.3, 133.2, 134.2, 138.5, 159.4, 167.5, 194.1. LCMS t=4.9 min, m/z Calcd for C24H22ClN2O2; C24H21ClN2NaO2; C48H43Cl2N4O4; C48H42Cl2N4NaO4 405.136; 427.118; 809.266; 831.248 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 405.136; 427.118; 809.266; 831.248.




EXAMPLE 05-48
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzamide (05-48): The title compound was prepared from Example 02-12 and o-toluoyl chloride according to the procedure of Example 05-37 (mp=234-236° C.). 1H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.76 (quin, J=6.1 Hz, 2H), 2.15-2.18 (m, 4H), 2.39 (s, 3H), 7.29-7.35 (m, 3H), 7.39-7.44 (m, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 8.00 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 10.55 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 19.3, 21.2, 26.7, 36.3, 105.9, 118.6, 119.9, 125.7, 127.3, 129.9, 130.0, 130.6, 131.4, 132.1, 135.4, 136.7, 138.5, 159.3, 168.0, 194.2. LCMS t=4.7 min, m/z Calcd for C21H22ClN2O2; C21H21ClN2NaO2; C42H42Cl2N4NaO4 369.137; 391.119; 759.248 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.137; 391.119; 759.248.




EXAMPLE 05-49
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanecarboxamide (05-49): The title compound was prepared from Example 02-12 and cyclohexanecarbonyl chloride according to the procedure of Example 05-37 (mp=248-250° C.). 1H NMR (D6-DMSO) δ 1.14-1.32 (m, 3H), 1.35-1.45 (m, 2H), 1.66 (s, 4H), 1.71-1.82 (m, 6H), 2.11-2.17 (m, 4H), 2.28-2.35 (m, 1H), 7.25 (d, J=9.8 Hz, 1H), 7.47 (dd, J=8.5, 2.4 Hz, 1H), 7.91-8.00 (m, 2H), 10.06 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 21.2, 25.2 (2C), 25.4, 26.6, 29.0 (2C), 36.3, 44.9, 105.7, 118.0, 119.3, 130.1, 131.5 (2C), 138.8, 159.4, 174.6, 194.1. LCMS t=4.8 min, m/z Calcd for C20H26ClN2O2; C20H25ClN2NaO2; C40H50Cl2N4NaO4 361.168; 383.150; 743.311 [M+H]+; [M+Na]+; [2M+Na]+, Found 361.168; 383.150; 743.311.




EXAMPLE 05-50
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzamide (05-50): The title compound was prepared from Example 02-11 and o-toluoyl chloride according to the procedure of Example 05-37. 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.74-1.81 (m, 2H), 2.18 (t, J=6.7 Hz, 2H), 2.23 (br s, 2H), 2.44 (s, 3H), 7.21 (d, J=7.3 Hz, 1H), 7.31 (d, J=7.3 Hz, 2H), 7.35-7.44 (m, 2H), 7.49-7.57 (m, 2H), 8.08 (s, 1H), 10.06 (s, 1H). 13C NMR (D6-DMSO) δ 9.0, 19.5, 21.2, 26.9, 36.4, 106.9, 107.9, 111.2, 115.9, 125.4, 125.7, 126.3, 126.9, 127.4, 129.9, 130.6, 135.6, 138.0, 158.7, 167.0, 194.5. LCMS t=4.5 min, m/z Calcd for C21H22ClN2O2; C21H21ClN2NaO2; C42H42Cl2N4NaO4 369.137; 391.119; 759.248 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.137; 391.119; 759.248.




EXAMPLE 05-51
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanecarboxamide (05-51): The title compound was prepared from Example 02-11 and cyclohexanecarbonyl chloride according to the procedure of Example 05-37 (mp=205-208° C.). 1H NMR (D6-DMSO) δ 1.14-1.22 (m, 1H), 1.23-1.32 (m, 2H), 1.40 (qd, J=12.4, 3.1 Hz, 2H), 1.65 (br s, 4H), 1.71-1.78 (m, 4H), 1.80-1.87 (m, 2H), 2.13-2.24 (m, 4H), 2.44-2.49 (m, 1H), 7.10 (d, J=7.3 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 8.03 (s, 1H), 9.42 (s, 1H). 13C NMR (D6-DMSO) δ 9.4, 21.6, 25.7 (2C), 25.9, 27.3, 29.6 (2C), 36.8, 44.5, 107.1, 124.3, 125.7 (2C), 127.2, 136.5, 138.2, 159.2, 174.9, 194.9. LCMS t=5.3 min, m/z Calcd for C20H26ClN2O2; C20H25ClN2NaO2 361.168; 383.150 [M+H]+; [M+Na]+, Found 361.157; 383.138.




EXAMPLE 05-52
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-1-naphthamide (05-52): The title compound was prepared from Example 02-11 and 1-naphthoyl chloride according to the procedure of Example 05-37 (mp=178-180° C.). 1H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.73-1.84 (m, 2H), 2.19 (t, J=6.7 Hz, 2H), 2.26 (br s, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.38-7.47 (m, 1H), 7.56-7.67 (m, 4H), 7.79-7.91 (m, 1H), 8.03 (d, J=7.3 Hz, 1H), 8.08-8.15 (m, 2H), 8.34 (d, J=7.3 Hz, 1H), 10.36 (s, 1H). 13C NMR (D6-DMSO) δ 9.5, 21.6, 27.4, 36.8, 107.3, 125.5, 125.7, 126.0, 126.3, 126.9, 126.9, 127.4, 127.5, 128.0, 128.8, 130.2, 130.9, 133.6, 134.3, 136.4, 138.5, 159.2, 167.9, 195.0. LCMS t=4.7 min, m/z Calcd for C24H22ClN2O2; C24H21ClN2NaO2; C48H42Cl2N4NaO4 405.136; 427.118; 831.248 [M+H]+; [M+Na]+; [2M+Na]+, Found 405.136; 427.118; 831.248.
















EXAMPLE




05-#
TITLE COMPOUND NAME
R1







53
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
H



yl)amino)-phenyl)methanesulfonamide


54
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
Ph



yl)amino)phenyl)-1-phenylmethanesulfonamide









EXAMPLE 05-53
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-phenyl)-methanesulfonamide (05-53): The title compound was prepared from Example 02-14 and methanesulfonyl chloride according to the procedure of Example 05-37 (mp=213-215° C.). 1H NMR (D6-DMSO) δ 1.45 (s, 3H), 2.16-2.23 (m, 2H), 2.39-2.43 (m, 2H), 3.04 (s, 3H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.00 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 25.6, 32.6, 40.0, 109.6, 118.2, 118.8, 124.5, 130.4, 137.2, 137.8, 169.3, 202.4. LCMS t=3.8 min, m/z Calcd for C13H16ClN2O3S; C13H15ClN2NaO3S; C26H31Cl2N4O6S2; C26H30Cl2N4NaO6S2 315.057; 337.039; 629.106; 651.088 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 315.057; 337.039; 629.106; 651.088.
EXAMPLE 05-54
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1-phenylmethanesulfonamide (05-55): The title compound was prepared from Example 02-14 and phenylmethanesulfonyl chloride according to the procedure of Example 05-37 (mp=196-198° C.). 1H NMR (D6-DMSO) δ 1.47 (s, 3H), 2.17-2.25 (m, 2H), 2.37-2.42 (m, 2H), 4.54 (s, 2H), 7.05 (d, J=2.4 Hz, 1H), 7.07 (dd, J=8.5, 2.4 Hz, 1H), 7.21-7.28 (m, 2H), 7.31-7.38 (m, 3H), 7.48 (d, J=8.5 Hz, 1H), 8.87 (s, 1H), 10.09 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 25.5, 32.6, 57.1, 109.5, 117.3, 117.9, 123.9, 128.3, 128.4 (2C), 129.3, 130.3, 130.9 (2C), 137.1, 138.0, 169.4, 202.4. LCMS t=4.3 min, m/z Calcd for C19H20ClN2O3S; C19H19ClN2NaO3S; C38H39Cl2N4O6S2; C38H38Cl2N4NaO6S2 391.088; 413.070; 781.169; 803.151 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 391.088; 413.070; 781.169; 803.151.




EXAMPLE 05-55
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide (05-54): The title compound was prepared from Example 02-14 and cyclohexanesulfonyl chloride according to the procedure of Example 05-37 (mp=158-160° C.). 1H NMR (D6-DMSO) δ 1.08-1.23 (m, 3H), 1.35-1.46 (m, 5H), 1.54-1.61 (m, 1H), 1.72-1.78 (m, 2H), 2.00 (d, J=11.0 Hz, 2H), 2.18-2.23 (m, 2H), 2.39-2.43 (m, 2H), 2.99-3.07 (m, 1H), 7.09-7.19 (m, 2H), 7.48 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.02 (s, 1H). 13C NMR (D6-DMSO) δ 7.4, 24.3 (2C), 24.7, 25.6, 26.0 (2C), 32.6, 59.4, 109.5, 117.7, 118.3, 124.1, 130.4, 137.1, 138.2, 169.2, 202.5. LCMS t=4.1 min, m/z Calcd for C18H24ClN2O3S; C18H23ClN2NaO3S; C36H47Cl2N4O6S2; C36H46Cl2N4NaO6S2 383.120; 405.101; 765.231; 787.213 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 383.120; 405.103; 765.229; 787.213.
















EXAMPLE




05-#
TITLE COMPOUND NAME
R1







56
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
Cl



yl)amino)phenyl)-2-chlorobenzenesulfonamide


57
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
CH3



yl)amino)phenyl)-2-methylbenzenesulfonamide


58
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
F



yl)amino)phenyl)-2-fluorobenzenesulfonamide


59
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
CN



yl)amino)phenyl)-2-cyanobenzenesulfonamide


60
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
OCH3



yl)amino)phenyl)-2-methoxybenzenesulfonamide









EXAMPLE 05-56
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)-phenyl)-2-chlorobenzenesulfonamide (05-56): The title compound was prepared from Example 02-14 and 2-chlorobenzene-1-sulfonyl chloride according to the procedure of Example 05-37. 1H NMR (D6-DMSO) δ 1.32 (s, 3H), 2.15-2.20 (m, 4H), 6.98 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.5, 2.4 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.51-7.55 (m, 1H), 7.63-7.67 (m, 2H), 8.05 (d, J=7.3 Hz, 1H), 8.80 (s, H), 10.90 (s, 1H). 13C NMR (D6-DMSO) δ 7.2, 25.4, 32.5, 109.6, 117.9, 118.5, 124.9, 127.9, 130.4, 130.7, 131.8, 132.0, 135.0, 135.9, 136.4, 137.1, 169.0, 202.4. LCMS t=4.4 min, m/z Calcd for C18H17O2N2O3S; C18H16Cl2N2NaO3S; C36H33Cl4N4O6S2; C36H32Cl4N4NaO6S2 411.033; 433.016; 823.057; 843.041 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 411.033; 433.016; 823.057; 843.041.
EXAMPLE 05-57
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide (05-57): The title compound was prepared from Example 02-14 and 2-methylbenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=236-238° C.). 1H NMR (D6-DMSO) δ 1.33 (s, 3H), 2.17 (m, J=4.9 Hz, 4H), 2.59 (s, 3H), 6.94 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.5, 2.4 Hz, 1H), 7.33-7.45 (m, 3H), 7.52 (t, J=7.3 Hz, 1H), 7.87 (d, J=7.3 Hz, 1H), 8.80 (s, 1H), 10.68 (s, 1H). 13C NMR (D6-DMSO) δ 7.2, 19.7, 25.4, 32.5, 109.6, 117.6, 118.1, 124.4, 126.4, 129.4, 130.3, 132.8, 133.3, 136.8, 137.0, 137.0, 137.0, 169.0, 202.4. LCMS t=5.3 min, m/z Calcd for C19H20ClN2O3S; C19H19ClN2NaO3S; C38H38Cl2N4NaO6S2 391.088; 413.070; 803.151 [M+H]+; [M+Na]+; [2M+Na]+, Found 391.088; 413.071; 803.150.
EXAMPLE 05-58
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-fluorobenzenesulfonamide (05-58): The title compound was prepared from Example 02-14 and 2-fluorobenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=215-217° C.). 1H NMR (D6-DMSO) δ 1.32 (s, 3H), 2.16-2.22 (m, 4H), 7.00 (d, J=3.7 Hz, 1H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.41-7.46 (m, 2H), 7.69-7.73 (m, 1H), 7.82-7.87 (m, 1H), 8.82 (s, 1H), 10.88 (s, 1H). 13C NMR (D6-DMSO) δ 7.7, 25.9, 33.0, 110.0, 117.9 (JCF=21.8 Hz), 118.9, 119.5, 125.6, 126.9 (JCF=13.8 Hz), 130.8, 131.0, 136.8 (JCF=9.2 Hz), 137.0, 137.5, 158.5 (JCF=254.7 Hz), 169.5, 202.9. LCMS t=4.3 min, m/z Calcd for C18H17ClFN2O3S; C18H16ClFN2NaO3S; C36H33Cl2F2N4O6S2; C36H32Cl2F2N4NaO6S2 395.063; 417.045; 789.119; 811.101 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 395.063; 417.045; 789.119; 811.101.
EXAMPLE 05-59
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-cyanobenzenesulfonamide (05-59): The title compound was prepared from Example 02-14 and 2-cyanobenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=235-238° C.). 1H NMR (D6-DMSO) δ 1.31 (s, 3H), 2.14-2.19 (m, 2H), 2.21-2.26 (m, 2H), 6.96 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.85 (t, J=7.3 Hz, 1H), 7.91 (t, J=7.3 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 8.10 (d, J=7.3 Hz, 1H), 8.82 (s, 1H), 11.06 (s, 1H). 13C NMR (D6-DMSO) δ 7.3, 25.5, 32.5, 109.2, 109.7, 115.6, 119.0, 119.5, 125.5, 129.6, 130.5, 133.8, 134.1, 136.1, 136.2, 137.2, 140.5, 169.0, 202.5. LCMS t=4.3 min, m/z Calcd for C19H17ClN3O3S; C19H16ClN3NaO3S; C38H32Cl2N6NaO6S2 402.068; 424.050; 825.110 [M+H]+; [M+Na]+; [2M+Na]+, Found 402.068; 424.050; 825.110.
EXAMPLE 05-60
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methoxybenzenesulfonamide (05-60): The title compound was prepared from Example 02-14 and 2-methoxybenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=198-200° C.). 1H NMR (D6-DMSO) δ 1.33 (s, 3H), 2.12-2.17 (m, 4H), 3.86 (s, 3H), 6.97-7.01 (m, 2H), 7.05 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.34-7.41 (m, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 8.79 (s, 1H), 10.30 (s, 1H). 13C NMR (D6-DMSO) δ 7.1, 25.3, 32.5, 56.2, 109.4, 112.9, 118.2, 118.7, 120.2, 124.6, 125.7, 130.1, 130.4, 135.4, 136.8, 137.4, 156.3, 169.2, 202.3. LCMS t=4.2 min, m/z Calcd for C19H20ClN2O4S; C19H19ClN2NaO4S; C38H39Cl2N4O8S2; C38H38Cl2N4NaO8S2 407.083; 429.065; 813.159; 835.141 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 407.083; 429.065; 813.159; 835.141.
















EXAMPLE




05-#
TITLE COMPOUND NAME
X







61
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
CH2



yl)amino)phenyl)-piperidine-1-sulfonamide


62
N-(4-Chloro-3-((2-methyl-3-oxocyclopent-1-en-1-
O



yl)amino)phenyl)-morpholine-4-sulfonamide









EXAMPLE 05-61
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-piperidine-1-sulfonamide (05-61): The title compound was prepared from Example 02-14 and piperidine-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=78-80° C.). 1H NMR (D6-DMSO) δ ppm 1.36-1.48 (m, 9H), 2.18-2.22 (m, 2H), 2.38-2.41 (m, 2H), 3.05-3.14 (m, 4H), 7.04-7.14 (m, 2H), 7.47 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.14 (br s, 1H). 13C NMR (D6-DMSO) δ 7.3, 23.1, 24.7 (2C), 25.6, 32.6, 46.5 (2C), 109.4, 117.7, 118.3, 123.7, 130.1, 136.9, 138.3, 169.2, 202.4. LCMS t=4.5 min, m/z Calcd for C17H23ClN3O3S; C17H22ClN3NaO3S; C34H45Cl2N6O6S2; C34H44Cl2N6NaO6S2 384.114; 406.096; 767.221; 789.203 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 384.114; 406.096; 767.221; 789.203.
EXAMPLE 05-62
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-morpholine-4-sulfonamide (05-62): The title compound was prepared from Example 02-14 and morpholine-4-sulfonyl chloride according to the procedure of Example 05-37 (mp=60-67° C.). 1H NMR (D6-DMSO) δ 1.44 (s, 3H), 2.17-2.23 (m, 2H), 2.38-2.43 (m, 2H), 3.05-3.09 (m, 4H), 3.51-3.55 (m, 4H), 7.04-7.15 (m, 2H), 7.49 (d, J=8.5 Hz, 1H), 8.88 (s, 1H), 10.28 (br s, 1H). 13C NMR (D6-DMSO) δ ppm 7.4, 25.6, 32.6, 46.0 (2C), 65.4 (2C), 109.5, 118.1, 118.6, 124.1, 130.2, 137.0, 138.0, 169.3, 202.4. LCMS t=3.9 min, m/z Calcd for C16H21ClN3O4S; C16H20ClN3NaO4S; C32H41Cl2N6O8S2; C32H40Cl2N6NaO8S2 386.094; 408.076; 771.180; 793.162 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 386.094; 408.076; 771.180; 793.162.




EXAMPLE 05-63
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide (05-63): The title compound was prepared from Example 02-15 and 2-methylbenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=215-218° C.). 1H NMR (D6-DMSO) δ 1.35 (s, 3H), 2.09-2.15 (m, 2H), 2.22-2.27 (m, 2H), 2.59 (s, 3H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.26 (d, J=9.8 Hz, 1H), 7.36-7.42 (m, 2H), 7.53 (t, J=6.7 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 8.72 (s, 1H), 10.74 (s, 1H). 13C NMR (D6-DMSO) δ 7.0, 19.7, 25.2, 32.5, 108.5, 117.8, 119.1, 126.4, 129.4, 130.0, 131.2, 131.9, 132.8, 133.4, 136.8, 136.9, 137.0, 170.1, 202.0. LCMS t=4.3 min, m/z Calcd for C19H20ClN2O3S; C19H19ClN2NaO3S; C38H39Cl2N4O6S2; C38H38Cl2N4NaO6S2 391.088; 413.070; 781.169; 803.151 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 391.088; 413.070; 781.169; 803.151.




EXAMPLE 05-64
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide (05-64): The title compound was prepared from Example 02-15 and cyclohexanesulfonyl chloride according to the procedure of Example 05-37 (mp=210-213° C.). 1H NMR (D6-DMSO) δ 1.05-1.17 (m, 1H), 1.18-1.27 (m, 2H), 1.33-1.50 (m, 5H), 1.54-1.63 (m, 1H), 1.72-1.80 (m, 2H), 1.98-2.05 (m, 2H), 2.14-2.18 (m, 2H), 2.30-2.35 (m, 2H), 3.02-3.12 (m, 1H), 7.20 (dd, J=8.5, 2.4 Hz, 1H), 7.34-7.38 (m, 1H), 8.81 (s, 1H), 10.09 (s, 1H). 13C NMR (D6-DMSO) δ 7.0, 24.3 (2C), 24.7, 25.3, 26.0 (2C), 32.6, 59.6, 108.4, 117.9, 119.1, 130.1, 131.4, 131.7, 138.1, 170.4, 202.0. LCMS t=4.5 min, m/z Calcd for C18H24ClN2O3S; C18H23ClN2NaO3S; C36H47Cl2N4O6S2; C36H46Cl2N4NaO6S2 383.120; 405.101; 765.231; 787.213 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 383.120; 405.101; 765.231; 787.213.




EXAMPLE 05-65
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide (05-65): The title compound was prepared from Example 02-13 and 2-methylbenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=75-77° C.). 1H NMR (D6-DMSO) δ 1.32 (s, 3H), 2.10-2.13 (m, 2H), 2.15-2.19 (m, 2H), 2.61 (s, 3H), 7.21 (t, J=7.3 Hz, 1H), 7.19-7.24 (m, 1H), 7.26-7.31 (m, 2H), 7.39 (d, J=8.5 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 8.85 (s, 1H), 10.16 (s, 1H). 13C NMR (D6-DMSO) δ 7.1, 20.2, 25.3, 32.5, 109.0, 125.4, 126.2, 126.5, 127.1, 127.3, 128.9, 132.7, 133.0, 134.4, 137.1, 137.6, 138.2, 169.6, 202.2. LCMS t=4.3 min, m/z Calcd for C19H20ClN2O3S; C19H19ClN2NaO3S; C38H39Cl2N4O6S2; C38H38Cl2N4NaO6S2 391.088; 413.070; 781.169; 803.151 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 391.088; 413.070; 781.169; 803.151.




EXAMPLE 05-66
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide (05-66): The title compound was prepared from Example 02-10 and 2-methylbenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=246-248° C.). 1H NMR (D6-DMSO) δ 1.55 (s, 3H), 1.67-1.73 (m, 3H), 1.96 (t, J=5.5 Hz, 3H), 2.17 (t, J=6.7 Hz, 3H), 2.58 (s, 3H), 6.85 (d, J=2.4 Hz, 1H), 6.94 (dd, J=8.5, 2.4 Hz, 1H), 7.33-7.43 (m, 3H), 7.50-7.55 (m, 1H), 7.85-7.90 (m, 2H), 10.66 (s, 1H). 13C NMR (D6-DMSO) δ 9.0, 19.7, 21.1, 26.9, 36.4, 107.8, 117.3, 118.2, 124.7, 126.4, 129.5, 130.3, 132.7, 133.3, 136.8, 137.0 (2C), 137.6, 157.8, 194.7. LCMS t=4.7 min, m/z Calcd for C20H22ClN2O3S; C20H21ClN2NaO3S; C40H42Cl2N4NaO6S2 405.104; 427.086; 831.182 [M+H]+; [M+Na]+; [2M+Na]+, Found 405.104; 427.086; 831.182.




EXAMPLE 05-67
Preparation of N-(4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide (05-67): The title compound was prepared from Example 02-10 and cyclohexanesulfonyl chloride according to the procedure of Example 05-37 (mp=215-217° C.). 1H NMR (D6-DMSO) δ 1.08-1.15 (m, 1H), 1.16-1.24 (m, 2H), 1.39 (qd, J=12.4, 3.1 Hz, 2H), 1.58 (d, J=13.4 Hz, 1H), 1.62 (s, 3H), 1.72-1.79 (m, 4H), 1.96-2.03 (m, 2H), 2.17-2.24 (m, 4H), 2.97-3.06 (m, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 9.98-10.02 (m, 1H). 13C NMR (D6-DMSO) δ 9.1, 21.1, 24.4 (2C), 24.7, 26.0 (2C), 27.1, 36.4, 59.4, 107.7, 117.3, 118.5, 124.5, 130.3, 137.7, 138.2, 158.1, 194.7. LCMS t=4.7 min, m/z Calcd for C19H26ClN2O3S; C19H25ClN2NaO3S; C38H50Cl2N4NaO6S2 397.135; 419.117; 815.245 [M+H]+; [M+Na]+; [2M+Na]+, Found 397.135; 419.117; 815.244.




EXAMPLE 05-68
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide (05-68): The title compound was prepared from Example 02-12 and 2-methylbenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=248-250° C.). 1H NMR (D6-DMSO) δ 1.59 (s, 3H), 1.70 (quin, J=6.1 Hz, 2H), 2.05 (t, J=5.5 Hz, 2H), 2.12 (t, J=6.1 Hz, 2H), 2.59 (s, 3H), 7.03 (dd, J=8.5, 2.4 Hz, 1H), 7.15-7.21 (m, 2H), 7.36-7.44 (m, 2H), 7.53 (t, J=6.7 Hz, 1H), 7.84 (s, 1H), 7.90 (d, J=7.3 Hz, 1H), 10.74 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 19.7, 21.1, 26.6, 36.3, 106.0, 117.7, 119.1, 126.4, 129.4, 130.5, 131.8, 132.3, 132.3, 132.8, 133.4, 136.8, 137.1, 159.0, 194.2. LCMS t=4.6 min, m/z Calcd for C20H22ClN2O3S; C20H21ClN2NaO3S; C40H42Cl2N4NaO6S2 405.104; 427.086; 831.182 [M+H]+; [M+Na]+; [2M+Na]+, Found 405.104; 427.086; 831.182.




EXAMPLE 05-69
Preparation of N-(3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide (05-69): The title compound was prepared from Example 02-12 and cyclohexanesulfonyl chloride according to the procedure of Example 05-37 (mp=230-232° C.). 1H NMR (D6-DMSO) δ 1.07-1.17 (m, 1H), 1.18-1.27 (m, 2H), 1.36-1.46 (m, 2H), 1.56-1.62 (m, 1H), 1.65 (s, 3H), 1.73-1.79 (m, 4H), 2.02 (d, J=12.2 Hz, 2H), 2.13-2.17 (m, 4H), 3.03-3.11 (m, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.93 (s, 1H), 10.08 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 21.2, 24.3 (2C), 24.7, 26.0 (2C), 26.6, 36.3, 59.5, 105.9, 117.9, 119.2, 130.6, 132.0, 132.1, 138.0, 159.2, 194.1. LCMS t=4.3 min, m/z Calcd for C19H26ClN2O3S; C38H50Cl2N4NaO6S2 397.135; 815.245 [M+H]+; [2M+Na]+, Found 397.134; 815.245.




EXAMPLE 05-70
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-2-methylbenzenesulfonamide (05-70): The title compound was prepared from Example 02-11 and 2-methylbenzene-1-sulfonyl chloride according to the procedure of Example 05-37 (mp=185-187° C.). 1H NMR (D6-DMSO) δ 1.56 (s, 3H), 1.62-1.71 (m, 2H), 1.92 (t, J=5.5 Hz, 2H), 2.13 (t, J=6.1 Hz, 2H), 2.61 (s, 3H), 7.10 (d, J=7.3 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.24-7.31 (m, 2H), 7.38 (d, J=7.3 Hz, 1H), 7.50 (t, J=7.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.96 (s, 1H), 10.13 (br s, 1H). 13C NMR (D6-DMSO) δ 9.4, 20.7, 21.5, 27.1, 36.8, 107.3, 120.0, 125.6, 126.5, 127.2, 127.5, 128.2, 129.3, 133.1, 133.4, 135.0, 137.6, 138.6, 159.0, 194.9. LCMS t=4.5 min, m/z Calcd for C20H22ClN2O3S; C20H21ClN2NaO3S; 405.104; 427.086; 831.182 [M+H]+; [M+Na]+; Found 405.104; 427.086.




EXAMPLE 05-71
Preparation of N-(2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-cyclohexanesulfonamide (05-71): The title compound was prepared from Example 02-11 and cyclohexanesulfonyl chloride according to the procedure of Example 05-37. 1H NMR (D6-DMSO) δ 1.08-1.17 (m, 1H), 1.19-1.29 (m, 2H), 1.41 (qd, J=12.4, 3.1 Hz, 2H), 1.57-1.67 (m, 4H), 1.73-1.80 (m, 4H), 2.06-2.12 (m, 2H), 2.13-2.22 (m, 4H), 2.96-3.06 (m, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 7.39 (d, J=9.8 Hz, 1H), 8.04 (s, 1H), 9.48 (br s, 1H). 13C NMR (D6-DMSO) δ 9.0, 21.2, 24.5 (2C), 24.8, 26.2 (2C), 26.9, 36.4, 61.3, 104.7, 114.9, 115.4, 119.7, 127.1, 138.1, 143.9, 158.5, 194.5. LCMS t=4.5 min, m/z Calcd for C19H26ClN2O3S; C19H25ClN2NaO3S; C38H50Cl2N4NaO6S2 397.135; 419.117; 815.245 [M+H]+; [M+Na]+; [2M+Na]+, Found 397.135; 419.117; 815.245.




EXAMPLE 05-72
Preparation of 3-((2-chloro-5-((2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-72): Acetic acid (0.4 mL) was added to Example 02-10 (0.3 g, 1.20 mmol) and 2-methylbenzaldehyde (0.25 g, 2.04 mmol) stirring in MeOH (8 mL). After stirring for 1 h, borane-2-methylpyridine (0.17 g, 1.59 mmol) was added to the mixture. The mixture was stirred for 18 h. The crude was concentrated under vacuum and purified by HPLC to afford the title compound (0.13 g, 23% yield, mp=158-160° C.). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.70 (quin, J=6.4 Hz, 2H), 2.11-2.14 (m, 4H), 2.31 (s, 3H), 4.21 (d, J=4.9 Hz, 2H), 6.40 (t, J=5.5 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.53 (dd, J=9.2, 3.1 Hz, 1H), 7.08-7.22 (m, 4H), 7.23 (d, J=6.1 Hz, 1H), 7.84 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 18.6, 21.2, 26.6, 36.3, 44.6, 105.9, 111.6, 112.2, 116.7, 125.7, 126.8, 127.2, 129.5, 130.1, 135.9, 137.0, 137.0, 148.4, 159.2, 194.0. LCMS t=5.3 min, m/z Calcd for C21H24ClN2O; C21H23ClN2NaO; C42H46Cl2N4NaO2 355.158; 377.139; 731.290 [M+H]+; [M+Na]+; [2M+Na]+, Found 355.158; 377.139; 731.290.




EXAMPLE 05-73
Preparation of 3-((2-chloro-5-((2-methylphenethyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-73): The title compound was prepared from Example 02-10 and 2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72 (mp=85-87° C.). 1H NMR (D6-DMSO) δ 1.65 (s, 3H), 1.75 (quin, J=6.1 Hz, 2H), 2.15 (t, J=6.1 Hz, 2H), 2.21 (t, J=5.5 Hz, 2H), 2.28 (s, 3H), 2.81 (t, J=7.9 Hz, 2H), 3.15-3.26 (m, 2H), 6.05 (t, J=5.5 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.53 (dd, J=8.5, 2.4 Hz, 1H), 6.89-7.37 (m, 5H), 7.87 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 19.0, 21.3, 26.7, 32.1, 36.4, 43.3, 105.8, 111.5, 112.2, 116.7, 125.9, 126.2, 129.1, 129.6, 130.0, 135.8, 137.2, 137.8, 148.3, 159.3, 194.1. LCMS t=5.5 min, m/z Calcd for C22H26ClN2O; C22H25ClN2NaO; C44H50Cl2N4NaO2 369.173; 391.155; 759.321 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.173; 391.155; 759.321.

















EXAMPLE





05-#
TITLE COMPOUND NAME
R1
R2







74
3-((2-Chloro-5-((2-
F
H



fluorobenzyl)ami-



no)phenyl)amino)-2-



methylcyclohex-2-enone


75
3-((2-Chloro-5-((3-
CH3
F



fluoro-2-methylbenzyl)ami-



no)phenyl)amino)-2-methyl-



cyclo-hex-2-enone









EXAMPLE 05-74
Preparation of 3-((2-chloro-5-((2-fluorobenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-74): The title compound was prepared from Example 02-10 and 2-fluorobenzaldehyde according to the procedure of Example 05-72 (mp=103-105° C.). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.70 (quin, J=6.4 Hz, 2H), 2.09-2.15 (m, 4H), 4.31 (d, J=6.1 Hz, 2H), 6.45 (d, J=2.4 Hz, 1H), 6.50-6.56 (m, 2H), 7.09-7.25 (m, 3H), 7.26-7.33 (m, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.83 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 21.2, 26.6, 36.3, 40.0, 106.0, 111.7, 112.3, 115.2 (JCF=20.7 Hz), 117.1, 124.3, 126.1 (JCF=14.9 Hz), 128.9 (JCF=6.9 Hz), 129.4 (JCF=4.6 Hz), 129.6, 137.1, 147.9, 159.1, 160.4 (JCF=244.4 Hz), 194.1. LCMS t=5.1 min, m/z Calcd for C20H21ClFN2O; C20H20ClFN2NaO; 359.13; 381.12; [M+H]+; [M+Na]+, Found 359.13; 381.10.
EXAMPLE 05-75
Preparation of 3-((2-chloro-5-((3-fluoro-2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-75): The title compound was prepared from Example 02-10 and 2-fluoro-3-methylbenzaldehyde according to the procedure of Example 05-72 (mp=160-162° C.). 1H NMR (D6-DMSO) δ 1.63 (s, 3H), 1.71 (quin, J=6.4 Hz, 2H), 2.10-2.16 (m, 4H), 2.21 (s, 3H), 4.25 (d, J=6.1 Hz, 2H), 6.42-6.47 (m, 2H), 6.52 (dd, J=8.5, 2.4 Hz, 1H), 7.03-7.07 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.14-7.20 (m, 2H), 7.83 (s, 1H). 13C NMR (D6-DMSO) δ 9.2, 10.2 (JCF=5.7 Hz), 21.7, 27.1, 36.8, 44.8, 106.4, 112.1, 112.7, 113.9 (JCF=24.1 Hz), 117.4, 123.1 (JCF=16.1 Hz), 123.5, 127.2 (JCF=9.2 Hz), 130.1, 137.5, 140.5, 148.6, 159.6, 161.1 (JCF=242.1 Hz), 194.6. LCMS t=5.2 min, m/z Calcd for C21H23ClFN2O; C21H22ClFN2NaO; C42H44Cl2F2N4NaO2 373.148; 395.130; 767.271 [M+H]+; [M+Na]+; [2M+Na]+, Found 373.148; 395.130; 767.271.




EXAMPLE 05-76
Preparation of 3-((2-chloro-4-((2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-76): The title compound was prepared from Example 02-12 and 2-methylbenzaldehyde according to the procedure of Example 05-72 (mp=220-221° C.). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.71 (quin, J=6.4 Hz, 2H), 2.07 (t, J=6.1 Hz, 2H), 2.11 (t, J=6.7 Hz, 2H), 2.32 (s, 3H), 4.22 (d, J=4.9 Hz, 2H), 6.46 (t, J=5.5 Hz, 1H), 6.56 (dd, J=8.5, 2.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 7.11-7.22 (m, 3H), 7.25 (d, J=7.3 Hz, 1H), 7.78 (s, 1H). 13C NMR (D6-DMSO) δ 8.4, 18.6, 21.2, 26.3, 36.2, 44.7, 104.2, 111.1, 111.6, 124.3, 125.7, 126.9, 127.3, 130.1, 130.9, 132.8, 136.0, 136.8, 148.8, 160.7, 193.5. LCMS t=5.2 min, m/z Calcd for C21H24ClN2O; C21H23ClN2NaO; C42H46Cl2N4NaO2 355.158; 377.139; 731.290 [M+H]+; [M+Na]+; [2M+Na]+, Found 355.156; 377.139; 731.290.




EXAMPLE 05-77
Preparation of 3-((2-chloro-4-((2-methylphenethyl)amino)phenyl)amino)-2-methyl-cyclohex-2-enone (05-77): The title compound was prepared from Example 02-12 and 2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72 (mp=160-162° C.). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.72 (quin, J=6.1 Hz, 2H), 2.06-2.10 (m, 2H), 2.12 (t, J=6.1 Hz, 2H), 2.30 (s, 3H), 2.83 (t, J=7.3 Hz, 2H), 3.19-3.26 (m, 2H), 6.16 (t, J=5.5 Hz, 1H), 6.57 (dd, J=8.5, 2.4 Hz, 1H), 6.66-6.73 (m, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.08-7.18 (m, 3H), 7.21 (d, J=8.5 Hz, 1H), 7.80 (s, 1H). 13C NMR (D6-DMSO) δ 8.4, 19.0, 21.2, 26.3, 32.1, 36.2, 43.2, 104.3, 111.0, 111.4, 124.2, 125.9, 126.2, 129.1, 130.0, 130.9, 132.9, 135.8, 137.7, 148.7, 160.7, 193.5. LCMS t=5.4 min, m/z Calcd for C22H26ClN2O; C22H25ClN2NaO; C44H50Cl2N4NaO2 369.173; 391.155; 759.321 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.173; 391.155; 759.321.




EXAMPLE 05-78
Preparation of 3-((2-chloro-3-((2-methylbenzyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-78): The title compound was prepared from Example 02-11 and 2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72 (mp=132-135° C.). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.75 (quin, J=6.1 Hz, 2H), 2.16 (t, J=6.7 Hz, 2H), 2.21 (t, J=6.1 Hz, 2H), 2.34 (s, 3H), 4.38 (d, J=6.1 Hz, 2H), 6.07 (t, J=6.1 Hz, 1H), 6.39 (d, J=8.5 Hz, 1H), 6.51 (d, J=7.3 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 7.07-7.24 (m, 4H), 7.91 (s, 1H). 13C NMR (D6-DMSO) δ 8.7, 18.6, 21.3, 26.7, 36.4, 44.3, 105.8, 109.2, 115.9, 116.1, 125.7, 126.1, 126.5, 127.2, 130.1, 135.4, 136.8, 137.3, 144.9, 159.2, 194.1. LCMS t=5.1 min, m/z Calcd for C21H24ClN2O; C21H23ClN2NaO 355.158; 377.139; [M+H]+; [M+Na]+, Found 355.152; 377.133.




EXAMPLE 05-79
Preparation of 3-((2-chloro-3-((2-methylphenethyl)amino)phenyl)amino)-2-methylcyclohex-2-enone (05-79): The title compound was prepared from Example 02-11 and 2-(o-tolyl)acetaldehyde according to the procedure of Example 05-72 (mp=157-160° C.). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.74 (quin, J=6.4 Hz, 2H), 2.14-2.20 (m, 4H), 2.32 (s, 3H), 2.86-2.91 (m, 2H), 3.34-3.36 (m, 2H), 5.51 (t, J=5.5 Hz, 1H), 6.53 (d, J=8.5 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 7.09-7.17 (m, 4H), 7.20 (d, J=7.3 Hz, 1H), 7.92 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 19.0, 21.2, 26.6, 32.1, 36.3, 43.3, 105.8, 108.7, 116.0, 116.1, 125.9, 126.2, 127.4, 129.3, 130.0, 136.0, 137.4, 137.6, 144.9, 159.2, 194.1. LCMS t=5.5 min, m/z Calcd for C22H26ClN2O; C22H25ClN2NaO; C44H50Cl2N4NaO2 369.173; 391.155; 759.321 [M+H]+; [M+Na]+; [2M+Na]+, Found 369.175; 391.155; 759.321.




EXAMPLE 05-80
Preparation of 3-((2-chloro-3-(o-tolylamino)phenyl)amino)-2-methylcyclohex-2-enone (05-80): Example 02-11 (0.5 g, 2.00 mmol), 1-bromo-2-methylbenzene (0.408 g, 2.39 mmol), palladium acetate (0.045 g, 0.20 mmol), BINAP (0.249 g, 0.40 mmol), cesium carbonate (1.30 g, 3.99 mmol) and toluene (10 mL) were combined in a sealed flask and heated at 130° C., for 18 h. At rt, the mixture was filtered and the filtrate was diluted with EtOAc (30 mL), washed with brine (3×10 mL), dried with Na2SO4. The crude was purified by HPLC to afford the title compound (yellow microcrystal, 15 mg, 2.2%). 1H NMR (D6-DMSO) δ 1.68 (s, 3H), 1.73-1.82 (m, 2H), 2.14 (s, 3H), 2.18 (t, J=6.7 Hz, 2H), 2.25 (t, J=6.1 Hz, 2H), 6.42 (d, J=7.3 Hz, 1H), 6.70 (d, J=6.1 Hz, 1H), 7.09 (t, J=7.9 Hz, 3H), 7.20 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.97 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 17.7, 21.3, 26.8, 36.4, 106.2, 112.9, 118.4, 118.7, 124.4, 124.5, 126.8, 127.1, 130.9, 132.6, 137.9, 140.0, 143.3, 159.0, 194.2. LCMS t=5.1 min, m/z Calcd for C20H22ClN2O; C20H21ClN2NaO; C40H43Cl2N4O2; 341.142; 363.124; 703.258 [M+H]+; [M+Na]+; [2M+Na]+, Found 341.146; 363.124; 703.258.




EXAMPLE 05-81
Preparation of 3-((2-chloro-5-(o-tolylamino)phenyl)amino)-2-methylcyclohex-2-enone (05-81): The title compound was prepared from Example 02-10 according to the procedure of Example 05-80 (mp=165-168° C.). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.76 (quin, J=6.1 Hz, 2H), 2.14-2.17 (m, 2H), 2.19 (s, 3H), 2.22 (t, J=5.5 Hz, 2H), 6.66 (d, J=2.4 Hz, 1H), 6.71-6.76 (m, 1H), 6.98 (t, J=7.9 Hz, 1H), 7.13-7.20 (m, 2H), 7.23 (d, J=7.3 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.90 (s, 1H). 13C NMR (D6-DMSO) δ 8.8, 17.9, 21.2, 26.8, 36.4, 106.4, 114.2, 115.1, 119.3, 121.3, 123.1, 126.7, 129.9, 130.7, 131.1, 137.4, 140.2, 145.1, 158.9, 194.3. LCMS t=5.0 min, m/z Calcd for C20H22ClN2O; C20H21ClN2NaO; C40H42Cl2N4NaO2 341.142; 363.124; 703.258 [M+H]+; [M+Na]+; [2M+Na]+, Found 341.142; 363.124; 703.258.




EXAMPLE 05-82
Preparation of 3-((2-chloro-4-(o-tolylamino)phenyl)amino)-2-methylcyclohex-2-enone (05-82): The title compound was prepared from Example 02-12 according to the procedure of Example 05-80 (mp=68-70° C.). 1H NMR (D6-DMSO) δ 1.67 (s, 3H), 1.74 (quin, J=6.4 Hz, 2H), 2.10-2.16 (m, 4H), 2.19 (s, 3H), 6.77 (dd, J=8.5, 2.4 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.98-7.03 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.15-7.21 (m, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.80 (s, 1H), 7.85 (s, 1H). 13C NMR (D6-DMSO) δ 8.5, 17.9, 21.3, 26.4, 36.3, 104.7, 113.7, 114.7, 114.7, 121.7, 123.4, 126.7, 130.9, 131.0, 131.1, 132.6, 139.9, 145.5, 160.3, 193.7. LCMS t=5.1 min, m/z Calcd for C20H22ClN2O; C40H42Cl2N4NaO2 341.142; 703.258 [M+H]+; [2M+Na]+, Found 341.142; 703.261.




EXAMPLE 05-83
Preparation of (Z)-4-((4-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoic acid (05-83): Example 02-10 (0.5 g, 2.0 mmol) and furan-2,5-dione (0.196 g, 2.0 mmol) were stirred in THF (10 mL) at rt, for 18 h. The solvent was removed under vacuum and purified by HPLC to afford the title compound (0.19 g, 27.3% yield, mp=182-185° C.). 1H NMR (D6-DMSO) δ 1.64 (s, 3H), 1.73-1.81 (m, 2H), 2.19 (t, J=6.1 Hz, 2H), 2.23 (t, J=5.5 Hz, 2H), 6.31 (d, J=12.2 Hz, 1H), 6.40 (d, J=12.2 Hz, 1H), 7.41-7.52 (m, 2H), 7.61 (d, J=2.4 Hz, 1H), 8.02 (s, 1H), 10.89 (br s, 1H), 12.73 (br s, 1H). 13C NMR (D6-DMSO) δ 9.1, 21.2, 27.0, 36.4, 107.2, 118.0, 119.2, 124.6, 129.8, 131.0, 131.4, 137.3, 138.2, 158.3, 163.5, 167.0, 194.6. LCMS t=3.9 min, m/z Calcd for C17H18ClN2O4; C17H17ClN2NaO4; C34H35Cl2N4O8; C34H34Cl2N4NaO8 349.096; 371.078; 697.183; 719.165 [M+H]+; [M+Na]+; [2M+H]+; [2M+Na]+, Found 349.096; 371.075; 697.176; 719.166.




EXAMPLE 05-84
Preparation of (Z)-4-((3-chloro-4-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoic acid (05-84): The title compound was prepared from Example 02-12 according to the procedure of Example 05-83 (mp=200-202° C.). 1H NMR (D6-DMSO) δ 1.66 (s, 3H), 1.72-1.77 (m, 2H), 2.10-2.19 (m, 4H), 6.33 (d, J=12.2 Hz, 1H), 6.47 (d, J=12.2 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.5, 2.4 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.97 (s, 1H), 10.58 (br s, 1H), 12.92 (br s, 1H). 13C NMR (D6-DMSO) δ 8.8, 21.2, 26.7, 36.3, 106.0, 118.4, 119.7, 130.0, 130.2, 131.4, 131.6, 132.3, 137.9, 159.2, 163.5, 166.9, 194.2. LCMS t=3.9 min, m/z Calcd for C17H18ClN2O4; C17H17ClN2NaO4; C34H34Cl2N4NaO8 349.096; 371.078; 719.165 [M+H]+; [M+Na]+; [2M+Na]+, Found 349.096; 371.078; 719.164.




EXAMPLE 05-85
Preparation of (Z)-4-((2-chloro-3-((2-methyl-3-oxocyclohex-1-en-1-yl)amino)phenyl)-amino)-4-oxobut-2-enoic acid (05-85): Example 02-11 (0.2 g, 0.8 mmol), furan-2,5-dione (0.392 g, 4.0 mmol) and AcOH (1 mL) were stirred in THF (10 mL) was stirred at rt, for 18 h. The solvent was removed under vacuum and purified by HPLC to afford the title compound (0.14 g, 50.3% yield). 1H NMR (D6-DMSO) δ 1.67 (s, 3 H), 1.73-1.79 (m, 2 H), 2.15-2.22 (m, 4 H), 4.06 (br s, 0.5H), 5.77 (d, J=13.4 Hz, 1 H), 6.19 (d, J=13.4 Hz, 1 H), 7.04 (d, J=7.3 Hz, 1 H), 7.12-7.33 (m, 3 H), 7.80 (d, J=7.3 Hz, 1 H), 8.01 (s, 0.5H). LCMS t=3.6 min, m/z Calcd for C17H18ClN2O4; C17H17ClN2NaO4 349.096; 371.078 [M+H]+; [M+Na]+, Found 349.096; 371.078.
EXAMPLES 06-01 to 06-011
















Example




06-#
TITLE COMPOUND NAME
R







01
3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone



02
2-methyl-3-((3-(1-phenyl-1H-1,2,3-triazol-4-
Ph



yl)phenyl)amino)cyclopent-2-enone


03
3-((3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-
4-OCH3Ph



2-methylcyclopent-2-enone


04
3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2Ph



methylcyclopent-2-enone


05
2-methyl-3-((3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-
CH2 4-



yl)phenyl)amino)cyclopent-2-enone
CH3Ph


06
3-((3-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 4-FPh



methylcyclopent-2-enone


07
3-((3-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 3-FPh



methylcyclopent-2-enone


08
3-((3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 2-FPh



methylcyclopent-2-enone


09
4-((4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-
CH2 4-



1,2,3-triazol-1-yl)methyl)benzamide
CONH2Ph


10
2-methyl-3-((3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-
CH2 2-



yl)phenyl)amino)cyclopent-2-enone
CH3Ph


11
2-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-
CH2 3-



yl)phenyl)amino)cyclopent-2-enone
Pyridyl









EXAMPLE 06-01
Preparation of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (06-01): 2-methylcyclopentane-1,3-dione (0.112 g, 0.996 mmol), 3-ethynylaniline (0.112 mL, 0.996 mmol), and acetic acid (0.029 mL, 0.499 mmol), were added to a 0.5-2 mL Biotage® microwave vial. The Biotage Intiator® microwave reactor was programmed to heat at 160° C. for 30 min. The reaction mixture was dissolved in dichloromethane, concentrated in vacuo, purified by combiflash (SiO2, 7% methanol in dichloromethane), triturated with ethylacetate, and filtered to give 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.046 g, 22%) as a yellow solid. 1H NMR (600 MHz, MeOD) δ 7.37-7.35 (2H, m), 7.31-7.27 (2H, m), 3.55-3.54 (1H, m), 2.72 (2H, bs), 2.40-2.38 (2H, m), 1.66 (3H, s); 13C NMR (150 MHz, MeOD) δ 205.3, 173.7, 139.6, 129.2, 128.7, 126.9, 124.2, 123.5, 110.2, 82.4, 78.2, 32.7, 25.8, 5.6; LCMS m/z 212.1827 ([M+H+], C14H14NO requires 212.1070).
General synthesis procedure for 3-((3-(1-substituted-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enones 06-02 to 06-011. To a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (1 Eq) and substituted azide (2 Eq) in a mixture of water and tert-butyl alcohol (1:1, 0.071 mmol/mL) was added sodium ascorbate (0.01 Eq, 1 M solution in water), followed by copper (II) sulfate pentahydrate (0.01 Eq). The heterogeneous mixture was stirred at RT for the specified time. The reaction mixture was diluted with water and cooled in an ice bath. The precipitate formed was filtered and washed with water. The precipitate was then dissolved in dichloromethane, dried (Na2SO4), concentrated, and purified as specified.
EXAMPLE 06-02
Preparation of 2-methyl-3-((3-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-02): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.015 g, 0.071 mmol) and azidobenzene (0.017 g, 0.142 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 14 h. Purification was done by washing the solid precipitate with dichloromethane to afford 2-methyl-3-((3-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.022 g, 96%) as a yellow solid. 1H NMR (600 MHz, MeOD) δ 8.97 (1H, s), 7.92 (2H, d, J=7.8 Hz), 7.84 (1H, bs), 7.78 (1H, d, J=7.2 Hz), 7.61 (2H, t, J=7.8 Hz), 7.53-7.49 (2H, m), 7.28 (1H, d, J=7.8 Hz), 2.80 (2H, bs), 2.41 (2H, bs), 1.70 (3H, s); 13C NMR (150 MHz, MeOD) δ 205.2, 174.0, 140.1, 137.2, 131.4, 129.8, 128.9, 123.8, 122.6, 120.9, 120.2, 119.5, 33.0, 29.5, 25.8, 5.7; LCMS m/z 331.2967 ([M+H+], C20H19N4O requires 331.1554).
EXAMPLE 06-03
Preparation of 3-((3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-03): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.050 g, 0.236 mmol) and 1-azido-4-methoxybenzene (0.070 g, 0.473 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 15 h. Purification was done by combiflash (SiO2, 90% ethylacetate in hexanes) to yield 34(3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.015 g, 18%) as a white solid. 1H NMR (600 MHz, MeOD) δ 8.87 (1H, s), 7.83-7.76 (4H, m), 7.52-7.49 (1H, m), 7.29 (1H, dd, J=1.8, 7.8 Hz), 7.15-7.13 (1H, m), 3.89 (3H, s), 2.82-2.80 (2H, m), 2.43-2.41 (2H, m), 1.71 (3H, s); LCMS m/z 361.3447 ([M+H+], C21H21N4O2 requires 361.1660).
EXAMPLE 06-04
Preparation of 3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-04): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.050 g, 0.236 mmol) and (azidomethyl)benzene (0.063 g, 0.472 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 14 h. Purification was done by combiflash (SiO2, 2%-5% methanol in dichloromethane) to yield 3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.040 g, 49%) as a white solid. 1H NMR (600 MHz, MeOD) δ 8.36 (1H, s), 7.70 (1H, s), 7.62 (1H, d, J=7.8 Hz), 7.43-7.40 (1H, m), 7.35-7.32 (4H, m), 7.21 (1H, d, J=7.8 Hz), 5.61 (2H, d, J=1.8 Hz), 2.72 (2H, bs), 2.36-2.35 (2H, m), 1.67 (3H, s); 13C NMR (150 MHz, MeOD) δ 205.1, 173.9, 147.2, 140.0, 135.5, 131.6, 129.7, 128.8, 128.4, 127.9, 123.4, 122.4, 121.4, 120.6, 53.8, 32.7, 25.8, 5.7; LCMS m/z 345.3331 ([M+H+], C21H21N4O requires 345.1710).
EXAMPLE 06-05
Preparation of 2-methyl-3-((3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-05): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 1-(azidomethyl)-4-methylbenzene (0.104 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 11 h. Purification was done by combiflash (SiO2, 3%-5% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.103 g, 81%) as a white solid. 1H NMR (600 MHz, MeOD) δ 8.33 (1H, bs), 7.70 (1H, s), 7.63 (1H, d, J=7.8 Hz), 7.43 (1H, t, J=7.8 Hz), 7.26-7.18 (5H, m), 5.57 (2H, s), 2.74 (2H, bs), 2.38-2.37 (2H, m), 2.31 (3H, s), 1.68 (3H, s); 13C NMR (150 MHz, MeOD) δ 205.1, 174.0, 147.2, 140.0, 138.5, 132.4, 131.6, 129.7, 129.4, 127.9, 123.5, 122.4, 121.3, 120.7, 110.0, 53.7, 32.7, 25.8, 19.9, 5.7; LCMS m/z 359.4512 ([M+H+], C22H23N4O requires 359.1867).
EXAMPLE 06-06
Preparation of 3-((3-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-06): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 1-(azidomethyl)-4-fluorobenzene (0.107 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 11 h. Purification was done by combiflash (SiO2, 3%-5% methanol in dichloromethane) to yield 343-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.063 g, 49%). 1H NMR (600 MHz, MeOD) δ 8.39 (1H, bs), 7.72 (1H, s), 7.65 (1H, d, J=7.2 Hz), 7.46-7.42 (3H, m), 7.24 (1H, d, J=7.8 Hz), 7.14-7.11 (2H, m), 5.63 (2H, s), 2.76 (2H, bs), 2.40-2.39 (2H, m), 1.68 (3H, s); 13C NMR (150 MHz, MeOD) δ 205.2, 174.1, 147.3, 140.0, 131.6, 131.5, 130.1, 129.7, 123.6, 122.5, 121.3, 120.7, 115.6, 115.5, 109.9, 53.0, 32.7, 25.8, 5.7; LCMS m/z 363.4738 ([M+H+], C21H20FN4O requires 363.1616).
EXAMPLE 06-07
Preparation of 3-((3-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-07): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 1-(azidomethyl)-3-fluorobenzene (0.107 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 11 h. Purification was done by combiflash (SiO2, 3%-5% methanol in dichloromethane) to yield 3-((3-(1-(3-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.115 g, 90%). 1H NMR (600 MHz, MeOD) δ 8.42 (1H, bs), 7.74-7.73 (1H, m), 7.66 (1H, dd, J=1.2, 6.6 Hz), 7.47-7.40 (2H, m), 7.25 (1H, dd, J=2.4, 8.4 Hz), 7.19 (1H, d, J=7.8 Hz), 7.14-7.10 (2H, m), 5.67 (2H, s), 2.78-2.77 (2H, m), 2.41-2.39 (2H, m), 1.69 (3H, s); 13C NMR (150 MHz, MeOD) δ 205.2, 174.1, 147.3, 140.0, 138.1, 131.5, 130.8, 130.7, 129.7, 123.6, 122.5, 121.6, 120.7, 115.2, 115.1, 114.7, 114.6, 53.1, 32.7, 25.8, 5.7; LCMS m/z 363.4598 ([M+H+], C21H20FN4O requires 363.1616).
EXAMPLE 06-08
Preparation of 3-((3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-08): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 1-(azidomethyl)-2-fluorobenzene (0.107 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 11 h. Purification was done by combiflash (SiO2, 3%-5% methanol in dichloromethane) to yield 3-((3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.115 g, 90%). 1H NMR (600 MHz, DMSO-d6) δ 9.05 (1H, bs), 7.71 (1H, s), 7.59 (1H, d, J=7.8 Hz), 7.44-7.38 (1H, m), 7.28-7.18 (3H, m), 5.70 (2H, s), 2.63 (2H, bs), 2.21-2.20 (2H, m), 1.56 (3H, s); 13C NMR (150 MHz, DMSO-d6) δ 202.5, 169.9, 146.8, 141.0, 131.9, 131.4, 130.2, 125.5, 123.4, 123.3, 122.7, 122.5, 121.4, 119.9, 116.4, 116.2, 110.5, 47.7, 33.5, 26.3, 8.0; LCMS m/z 363.3012 ([M+H+], C21H20FN4O requires 363.1616).
EXAMPLE 06-09
Preparation of 4-((4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide (06-09): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 4-(azidomethyl)benzamide (0.125 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 20 h. Purification was done by washing the solid precipitate with dichloromethane to afford 4-((4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide (0.120 g, 88%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 9.05 (1H, bs), 8.68 (1H, s), 7.97 (1H, s), 7.86 (1H, d, J=7.8 Hz), 7.71 (1H, s), 7.58 (1H, d, J=7.2 Hz), 7.41-7.38 (2H, m), 7.18 (1H, d, J=7.2 Hz), 5.70 (2H, s), 2.68 (2H, bs), 2.21-2.20 (2H, m), 1.56 (3H, s); 13C NMR (150 MHz, DMSO-d6) δ 202.5, 169.8, 168.0, 147.0, 141.0, 139.6, 134.7, 132.0, 128.6, 128.3, 122.6, 121.3, 119.9, 110.5, 53.3, 33.5, 26.3, 8.0; LCMS m/z 388.3432 ([M+H+], C22H22N5O2 requires 388.1768).
EXAMPLE 06-10
Preparation of 2-methyl-3-((3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-10): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 1-(azidomethyl)-2-methylbenzene (0.104 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 60 h. Purification was done by combiflash (SiO2, 3%-7% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.074 g, 58%). 1H NMR (600 MHz, MeOD) δ 8.23 (1H, bs), 7.70 (1H, s), 7.62 (1H, d, J=6.6 Hz), 7.41-7.40 (1H, m), 7.22-7.20 (4H, m), 5.64 (2H, s), 2.72 (2H, bs), 2.35-2.34 (5H, m), 1.66 (3H, s); LCMS m/z 359.4657 ([M+H+], C22H23N4O requires 359.1867).
EXAMPLE 06-11
Preparation of 2-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-11): Using the general procedure, a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (0.075 g, 0.355 mmol) and 3-(azidomethyl)pyridine (0.095 g, 0.710 mmol), sodium ascorbate, and copper (II) sulfate pentahydrate in a mixture of water and tert-butyl alcohol were stirred at RT for 60 h. Purification was done by washing the solid precipitate with dichloromethane to afford 2-methyl-3-((3-(1-(pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.067 g, 55%). 1H NMR (600 MHz, MeOD) δ 8.63 (1H, s), 8.54-8.53 (1H, m), 8.45 (1H, s), 7.85 (1H, dd, J=1.2, 7.8 Hz), 7.72 (1H, s), 7.64 (1H, dd, J=0.6, 7.8 Hz), 7.47-7.42 (2H, m), 7.24-7.23 (1H, m), 5.73 (2H, s), 2.74 (2H, bs), 2.38-2.37 (2H, m), 1.67 (3H, s); LCMS m/z 346.2856 ([M+H+], C20H20N5O requires 346.1663).
EXAMPLES 06-12 and 06-13















Example



06-#
TITLE COMPOUND NAME







12
3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone


13
3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-



methylcyclohex-2-enone









EXAMPLE 06-12
Preparation of 3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone (06-12): 2-methylcyclohexane-1,3-dione (0.200 g, 1.58 mmol), 3-ethynylaniline (0.178 mL, 1.58 mmol), acetic acid (0.181 mL, 3.17 mmol), were added to a 0.5-2 mL Biotage® microwave vial. The Biotage Intiator® microwave reactor was programmed to heat at 160° C. for 10 min. The reaction mixture was dissolved in methanol, concentrated in vacuo, purified by combiflash (SiO2, 2%-4% methanol in dichloromethane), to give 3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone (0.176 g, 49%) as a white solid. 1H NMR (600 MHz, MeOD) δ 7.34 (1H, t, J=7.8 Hz), 7.30 (1H, d, J=7.8 Hz), 7.25 (1H, bs), 7.17 (1H, d, J=8.4 Hz), 3.54 (1H, s), 2.47 (2H, t, J=6 Hz), 2.34 (2H, t, J=6.6 Hz), 1.88-1.84 (2H, m), 1.77 (3H, s); 13C NMR (150 MHz, MeOD) δ 197.6, 162.0, 139.6, 129.0, 128.8, 128.4, 125.8, 123.4, 107.1, 82.5, 78.2, 36.0, 27.3, 21.7, 7.6; LCMS m/z 226.4831 ([M+H+], C15H16NO requires 226.1227).
EXAMPLE 06-13
Preparation of 3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclohex-2-enone (06-13): To a suspension of 3-((3-ethynylphenyl)amino)-2-methylcyclohex-2-enone (0.075 g, 0.332 mmol) and (azidomethyl)benzene (0.089 g, 0.666 mmol) in a mixture of water and tert-butyl alcohol (1:1, 1.5 mL) was added sodium ascorbate (0.035 mL, 0.036 mmol, 1 M solution in water), followed by copper (II) sulfate pentahydrate (0.001 g, 0.004 mmol). The heterogeneous mixture was stirred at RT for 10 h. The reaction mixture was diluted with water (5 mL) and cooled in an ice bath. The ppt formed was filtered and washed with water and dichloromethane. The filtrate was extracted with dichloromethane, and the ppt was dissolved in dichloromethane. The combined dichloromethane layers were dried (Na2SO4) and purified by combiflash (SiO2, 2%-5% methanol in dichloromethane) to give 3-((3-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclohex-2-enone (0.048 g, 40%) as a white solid. 1H NMR (600 MHz, MeOD) δ 8.35 (1H, bs), 7.63 (1H, d, J=7.8 Hz), 7.61 (1H, s), 7.40 (1H, t, J=7.8 Hz), 7.37-7.32 (5H, m), 7.12 (1H, d, J=7.8 Hz), 5.62 (1H, d, J=10.8 Hz), 2.49 (2H, t, J=5.4 Hz), 2.31 (2H, t, J=6 Hz), 1.83-1.81 (2H, m), 1.79 (s, 3H); 13C NMR (150 MHz, MeOD) δ 197.4, 162.5, 147.2, 140.0, 135.5, 131.4, 129.5, 128.8, 128.4, 127.9, 125.1, 122.6, 122.3, 121.4, 106.7, 53.8, 36.0, 27.3, 21.8, 7.6; LCMS m/z 359.5227 ([M+H+], C22H23N4O requires 359.1867).
EXAMPLES 06-14 to 06-27
















Example




06-#
TITLE COMPOUND NAME
R







14
3-((3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 4-ClPh



methylcyclopent-2-enone


15
3-((3-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-
CH2 4-



2-methylcyclopent-2-enone
OCH3Ph


16
2-methyl-3-((3-(1-(naphthalen-1-ylmethyl)-1H-1,2,3-triazol-4-
CH2 1-



yl)phenyl)amino)cyclopent-2-enone
Naphthyl


17
2-methyl-3-((3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-
CH2 4-CF3Ph



yl)phenyl)amino)cyclopent-2-enone


18
2-methyl-3-((3-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-
CH2



yl)phenyl)amino)cyclopent-2-enone
CH(CH3)Ph


19
2-methyl-3-((3-(1-phenethyl-1H-1,2,3-triazol-4-
CH2 CH2Ph



yl)phenyl)amino)cyclopent-2-enone


20
3-((3-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 2-ClPh



methylcyclopent-2-enone


21
3-((3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 3-ClPh



methylcyclopent-2-enone


22
3-((3-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-
CH2 2-



2-methylcyclopent-2-enone
OCH3Ph


23
3-((3-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-
CH2 3-



2-methylcyclopent-2-enone
OCH3Ph


24
2-methyl-3-((3-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4-
CH2 3-



yl)phenyl)amino)cyclopent-2-enone
CH3Ph


25
3-((3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-
CH2 4-BrPh



methylcyclopent-2-enone


26
(R)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-
CH(COOH)Bn



1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid


27
(S)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-
CH(COOH)Bn



1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid









General synthesis procedure for 3-((3-(1-substituted-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enones 06-14 to 06-27. To a solution of substituted amine (1 Eq) in water (0.75 mmol/mL) was added in sequence methanol (0.27 mmol/mL), NaHCO3 (4 Eq), a solution of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl azide (1.5 Eq) in Et2O (0.50 mmol/mL) and copper sulfate pentahydrate (0.1 Eq). The reaction mixture was stirred at RT for 5 h. To the reaction mixture was added 3-((3-ethynylphenyl)amino)-2-methylcyclopent-2-enone (1.1 Eq) and sodium ascorbate (1.5 Eq). The reaction mixture was stirred at RT for the specified time. The reaction mixture was filtered, washed with dichloromethane (10 mL×3), filtrate was concentrated in vacuo and purified as specified.
EXAMPLE 06-14
Preparation of 3-((3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-14): Using the general procedure (4-chlorophenyl)methanamine (0.085 g, 0.6 mmol) was stirred for 60 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 3-((3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.092 g, 41%). 1H NMR (600 MHz, MeOD) δ 8.39 (1H, bs), 7.72 (1H, s), 7.65 (1H, d, J=7.2 Hz), 7.46-7.38 (4H, m), 7.24 (1H, d, J=8.4 Hz), 5.64 (2H, s), 2.77 (2H, bs), 2.40-2.39 (2H, m), 1.68 (3H, s); LCMS m/z 379.2597 ([M+H+], C21H20ClN4O requires 379.1321).
EXAMPLE 06-15
Preparation of 3-((3-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-15): Using the general procedure (4-methoxyphenyl)methanamine (0.082 g, 0.6 mmol) was stirred for 60 h. Purification was done by combiflash (SiO2, 3%-7% methanol in dichloromethane) to yield 3-((3-(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.117 g, 53%). 1H NMR (600 MHz, MeOD) δ 8.32 (1H, bs), 7.71 (1H, s), 7.64 (1H, d, J=7.2 Hz), 7.44 (1H, t, J=7.8 Hz), 7.34 (2H, d, J=8.4 Hz), 7.24 (1H, d, J=7.2 Hz), 6.94 (2H, d, J=8.4 Hz), 5.56 (2H, s), 3.78 (3H, s), 2.76 (2H, bs), 2.39 (2H, bs), 1.68 (3H, s); LCMS m/z 375.3921 ([M+H+], C22H23N4O2 requires 375.1816).
EXAMPLE 06-16
Preparation of 2-methyl-3-((3-(1-(naphthalen-1-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-16): Using the general procedure Naphthalen-1-ylmethanamine (0.094 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-(naphthalen-1-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.220 g, 94%). 1H NMR (600 MHz, MeOD) δ 8.24 (1H, bs), 8.12 (1H, d, J=7.8 Hz), 7.89 (2H, d, J=6.6 Hz), 7.65 (1H, bs), 7.57-7.48 (5H, m), 7.37 (1H, t, J=3.6 Hz), 7.17 (2H, d, J=7.2 Hz), 6.08 (2H, s), 2.67 (2H, bs), 2.31 (2H, bs), 1.65 (3H, s); LCMS m/z 395.2784 ([M+H+], C25H23N4O requires 395.1867).
EXAMPLE 06-17
Preparation of 2-methyl-3-((3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-17): Using the general procedure (4-(trifluoromethyl)phenyl)methanamine (0.105 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 3%-5% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.201 g, 81%). 1H NMR (600 MHz, MeOD) δ 8.43 (1H, bs), 7.72-7.63 (4H, m), 7.52 (2H, d, J=7.2 Hz), 7.42 (1H, t, J=7.2 Hz), 7.22 (1H, d, J=7.2 Hz), 5.74 (2H, s), 2.72 (2H, bs), 2.36 (2H, bs), 1.66 (3H, s); LCMS m/z 413.4756 ([M+H+], C22H20F3N4O requires 413.1584).
EXAMPLE 06-18
Preparation of 2-methyl-3-((3-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-18): Using the general procedure 1-phenylethanamine (0.073 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.162 g, 75%). 1H NMR (600 MHz, MeOD) δ 8.44 (1H, bs), 7.72 (1H, s), 7.65 (1H, d, J=7.2 Hz), 7.43 (1H, t, J=7.8 Hz), 7.38-7.31 (5H, m), 7.22 (1H, d, J=7.8 Hz), 5.94-5.93 (1H, m), 2.73 (2H, bs), 2.36 (2H, bs), 2.00 (3H, d, J=6.6 Hz), 1.67 (3H, s); LCMS m/z 359.4603 ([M+H+], C22H23N4O requires 359.1867).
EXAMPLE 06-19
Preparation of 2-methyl-3-((3-(1-phenethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-19): Using the general procedure 2-phenylethanamine (0.073 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-phenethyl-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.132 g, 61%). 1H NMR (600 MHz, MeOD) δ 8.14 (1H, bs), 7.65 (1H, s), 7.59 (1H, d, J=6 Hz), 7.45-7.44 (1H, m), 7.26-7.17 (6H, m), 4.70-4.69 (2H, m), 3.28-3.27 (2H, m), 2.77 (2H, bs), 2.41 (2H, bs), 1.69 (3H, s); LCMS m/z 359.4236 ([M+H+], C22H23N4O requires 359.1867).
EXAMPLE 06-20
Preparation of 3-((3-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-20): Using the general procedure (2-chlorophenyl)methanamine (0.085 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 3-((3-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.116 g, 65%). 1H NMR (600 MHz, MeOD) δ 8.35 (1H, bs), 7.73 (1H, s), 7.66 (1H, d, J=7.2 Hz), 7.50-7.31 (5H, m), 7.25 (1H, d, J=7.8 Hz), 5.79 (2H, s), 2.77 (2H, bs), 2.40 (2H, bs), 1.69 (3H, s); LCMS m/z 379.2943 ([M+H+], C21H20ClN4O requires 379.1321).
EXAMPLE 06-21
Preparation of 3-((3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-21): Using the general procedure (3-chlorophenyl)methanamine (0.085 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 3-((3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.130 g, 73%). 1H NMR (600 MHz, MeOD) δ 8.41 (1H, bs), 7.73 (1H, s), 7.66 (1H, bs), 7.45-7.26 (6H, m), 5.65 (2H, s), 2.77 (2H, bs), 2.40 (2H, bs), 1.68 (3H, s); LCMS m/z 379.2314 ([M+H+], C21H20ClN4O requires 379.1321).
EXAMPLE 06-22
Preparation of 3-((3-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-22): Using the general procedure (2-methoxyphenyl)methanamine (0.085 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 3-((3-(1-(2-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.059 g, 33%). 1H NMR (600 MHz, MeOD) δ 8.26 (1H, bs), 7.70 (1H, s), 7.64 (1H, d, J=7.8 Hz), 7.43 (1H, dt, J=3, 7.8 Hz), 7.38-7.35 (1H, m), 7.27-7.22 (2H, m), 7.04 (1H, dd, J=2.4, 8.1 Hz), 6.98-6.97 (1H, m), 5.62 (2H, d, J=3 Hz), 3.88 (3H, t, J=1.8 Hz), 2.76 (2H, bs), 2.40-2.38 (2H, m), 1.68 (3H, s); LCMS m/z 375.4430 ([M+H+], C22H23N4O2 requires 375.1816).
EXAMPLE 06-23
Preparation of 3-((3-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-23): Using the general procedure (3-methoxyphenyl)methanamine (0.082 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 3%-5% methanol in dichloromethane) to yield 3-((3-(1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.152 g, 86%). 1H NMR (600 MHz, MeOD) δ 8.36 (1H, bs), 7.72 (1H, s), 7.65 (1H, d, J=7.2 Hz), 7.45-7.24 (3H, m), 6.93-6.91 (3H, m), 5.61 (2H, s), 3.78 (3H, s), 2.76 (2H, bs), 2.39 (2H, bs), 1.68 (3H, s); LCMS m/z 375.4525 ([M+H+], C22H23N4O2 requires 375.1816).
EXAMPLE 06-24
Preparation of 2-methyl-3-((3-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (06-24): Using the general procedure m-tolylmethanamine (0.073 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 2-methyl-3-((3-(1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)cyclopent-2-enone (0.144 g, 85%). 1H NMR (600 MHz, MeOD) δ 8.35 (1H, bs), 7.71 (1H, s), 7.65 (1H, d, J=7.8 Hz), 7.44 (1H, t, J=8.4 Hz), 7.27-7.15 (5H, m), 5.61 (2H, s), 2.76 (2H, bs), 2.39 (2H, bs), 2.34 (3H, s), 1.68 (3H, s); LCMS m/z 359.3305 ([M+H+], C22H23N4O requires 359.1867).
EXAMPLE 06-25
Preparation of 3-((3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-25): Using the general procedure (4-bromophenyl)methanamine (0.112 g, 0.6 mmol) was stirred for 40 h. Purification was done by combiflash (SiO2, 2%-7% methanol in dichloromethane) to yield 3-((3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.147 g, 74%). 1H NMR (600 MHz, MeOD) δ 8.39 (1H, s), 7.72 (1H, t, J=1.8 Hz), 7.65 (1H, d, J=7.2 Hz), 7.56-7.55 (2H, m), 7.45 (1H, t, J=7.8 Hz), 7.31 (2H, d, J=8.4 Hz), 7.25 (1H, dd, J=1.8, 7.8 Hz), 5.63 (2H, s), 2.77-2.76 (2H, m), 2.41-2.39 (2H, m), 1.68 (3H, s); LCMS m/z 423.1297 ([M+H+], C21H20BrN4O requires 423.0815).
EXAMPLE 06-26
Preparation of (R)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid (06-26): Using the general procedure (R)-2-amino-3-phenylpropanoic acid (0.099 g, 0.6 mmol) was stirred for 40 h. The reaction mixture acidified to pH 1 with 1 M HCl, filtered and washed with dichloromethane to give (R)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid (0.091 g, 48%). 1H NMR (600 MHz, MeOD) δ 8.38 (1H, s), 7.67 (1H, s), 7.61 (1H, d, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.24-7.13 (6H, m), 5.71 (1H, dd, J=4.2, 10.5 Hz), 3.69 (1H, dd, J=4.8, 14.4 Hz), 3.56 (1H, dd, J=10.8, 15.9 Hz), 2.77 (2H, bs), 2.41-2.40 (2H, m), 1.69 (3H, s); LCMS m/z 403.3882 ([M+H+], C23H23N4O3 requires 403.1765).
EXAMPLE 06-27
Preparation of (S)-2-(4-(3-((2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid (06-27): Using the general procedure (S)-2-amino-3-phenylpropanoic acid (0.099 g, 0.6 mmol) was stirred for 40 h. The reaction mixture acidified to pH 1 with 1 M HCl, filtered and washed with dichloromethane to give (S)-2-(4-(3-(2-methyl-3-oxocyclopent-1-en-1-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-3-phenylpropanoic acid (0.040 g, 21%). 1H NMR (600 MHz, MeOD) δ 8.38 (1H, d, J=3 Hz), 7.67 (1H, d, J=1.8 Hz), 7.62-7.60 (1H, m), 7.46-7.42 (1H, m), 7.24-7.13 (6H, m), 5.72-5.70 (1H, m), 3.69 (1H, dd, J=4.2, 14.4 Hz), 3.56 (1H, dd, J=10.8, 14.4 Hz), 2.78-2.77 (2H, m), 2.41-2.40 (2H, m), 1.69 (3H, s); LCMS m/z 403.4457 ([M+H+], C23H23N4O3 requires 403.1765).
EXAMPLE 06-28















Example



06-#
TITLE COMPOUND NAME







28
3-((4-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl)amino)-2-



methylcyclopent-2-enone









EXAMPLE 06-28
Preparation of 3-((4-(4-benzyl-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-methylcyclopent-2-enone (06-28): To a suspension of 4-ethynylaniline (0.117 g, 0.998 mmol) and (azidomethyl)benzene (0.266 g, 1.996 mmol) in a mixture of water and tert-butyl alcohol (1:1, 4 mL) was added sodium ascorbate (0.095 mL, 0.099 mmol, 1 M solution in water), followed by copper (II) sulfate pentahydrate (0.002 g, 0.009 mmol). The heterogeneous mixture was stirred at RT for 4 h. The reaction mixture was diluted with 5 mL water and cooled in an ice bath. The precipitate formed was filtered and washed with water and dichloromethane, extracted with dichloromethane, dried (Na2SO4) and purified by combiflash (SiO2, 2%-4% methanol in dichloromethane) to give 4-(1-benzyl-1H-1,2,3-triazol-4-yl)aniline (0.042 g, 17%) which was used for the next step without further purification. LCMS m/z 251.3345 ([M+H+], C20H20N5O requires 251.1292).
2-methylcyclopentane-1,3-dione (0.019 g, 0.167 mmol), 4-(4-benzyl-1H-1,2,3-triazol-1-yl)aniline (0.042 g, 0.167 mmol), acetic acid (0.019 mL, 0.334 mmol), were added to a 0.5-2 mL Biotage® microwave vial. The Biotage Intiator® microwave reactor was programmed to heat at 160° C. for 30 min. The reaction mixture was purified by combiflash (SiO2, 2%-5% methanol in dichloromethane), to give 3-((4-(4-benzyl-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-methylcyclopent-2-enone (0.032 g, 55%). 1H NMR (600 MHz, MeOD) δ 8.31 (1H, s), 7.83-7.82 (2H, m), 7.38-7.32 (6H, m), 5.64 (2H, s), 2.76 (2H, bs), 2.39 (2H, bs), 1.68 (3H, s); LCMS m/z 345.3646 ([M+H+], C21H21N4O requires 345.1710).
Biological Assays
Fluorescence Anisotropy Binding Assay
Expression and purification of the first bromodomain (BrD1) of human BRD4 in poly-His tag form was performed using a procedure described in the literature [See Zeng et al. Structure 16, 643-652 (2008) and Zhang et al., J Biol Chem 287, 28840-28851 (2012).] The protein was purified by using affinity chromatography on a nickel-IDA column (Invitrogen), followed by the removal of poly-His tag by thrombin cleavage.
Binding affinity of the newly synthesized compounds to the BRD4 BrD1 was assessed in a fluorescence anisotropy assay using a fluorescein isothiocyanate (FITC)-labeled MS417 as an assay probe (Zhang et al. 2008 op.cit.). Competition binding was performed with a BrD protein (0.25 to 1 μM) and the fluorescent probe (80 nM), and increasing concentration of unlabeled competing ligand in a PBS buffer (pH 7.4) in total volume of 80 μL. Measurements were obtained after 1 hour incubation of the fluorescent ligand and the protein at 25° C. with Safire 2 microplate reader (Tecan). In the assay, fluorescent ligand concentration was ≦2Kd, and protein concentration was set at which 50-80% of fluorescent ligand is bound. Dissociation constant of a competing ligand was calculated with the correction to Cheng-Prussoff equation introduced by Nicolovska-Coleska and colleagues [Nikolovska-Coleska, Z. et al., Anal Biochem 332, 261-273 (2004). Assuming one-site competitive binding model, the equation used to calculate Ki's from IC50 values recovered from fitting data using Prism:




  
    
      K
      i
    
    =
    
      
        [
        
          I
          50
        
        ]
      
      
        
          
            [
            
              L
              50
            
            ]
          
          
            K
            d
          
        
        +
        
          
            [
            
              P
              0
            
            ]
          
          
            K
            d
          
        
        +
        1
      
    
  
  ,




where [I50] is the concentration of free inhibitor at 50% inhibition, [L50], the concentration of free labeled ligand at 50% inhibition, and [P0], concentration of free protein at 0% inhibition. Note that Kd for each protein-probe pair is the limit of resolvable Ki in a competition assay. The binding results for examples above are listed in Table 1.



















TABLE 1







Exam-


Examples





Exam-




ples
BRD4_1
BRD4_2
01-#
BRD4_1
BRD4_2
Examples
BRD4_1
BRD4_2
ples
BRD4_1
BRD4_2


01-#
IC50
IC50
cont.
IC50
IC50
02-#
IC50
IC50
03-#
IC50
IC50





01-1
++
++
01-51
++
+
02-1
++
+
03-1
++
++


01-2
++
++
01-52
++
++
02-2
++
++
03-2
+
+


01-3
+
++
01-53
+++
++
02-3
+
+
03-3
n.t.
n.t.


01-4
++
+
01-54
++
++
02-4
+
+
03-4
n.t.
n.t.


01-5
++
++
01-55
++
++
02-5
+
+
03-5
n.t.
n.t.


01-6
+
+
01-56
++
+
02-6
++
+
03-6
++
++


01-7
+
+
01-57
++
++
02-7
++
+
03-7
++
++


01-8
n.t.
n.t.
01-58
++
++
02-8
++
++
03-8
n.t.
n.t.


01-9
++
+
01-59
++
+
02-9
+
+
03-9
++
++


01-10
+
+
01-60
++
++
02-10
++
++
03-10
++
++


01-11
++
++
01-61
+
+
02-11
++
+
03-11
++
+


01-12
++
++
01-62
+++
++
02-12
++
++
03-12
n.t.
n.t.


01-13
++
++
01-63
++
++
02-13
++
++
03-13
n.t.
n.t.


01-14
++
++
01-64
+++
++
02-14
++
++
03-14
n.t.
n.t.


01-15
n.t.
n.t.



02-15
++
++
03-15
n.t.
n.t.


01-16
+
+






03-16
++
++


01-17
n.t.
n.t.






03-17
n.t.
n.t.


01-18
+
+






03-18
++
++


01-19
+
+






03-19
++
++


01-20
+
+






03-20
+
+


01-21
++
+






03-21
n.t.
n.t.


01-22
++
++






03-22
n.t.
n.t.


01-23
+
+






03-23
++
++


01-24
++
+


01-25
++
+


01-26
++
++


01-27
++
++


01-28
+
+


01-29
+
+


01-30
++
++


01-31
++
++


01-32
+
+


01-33
+
+


01-34
+
+


01-35
++
++


01-36
+
+


01-37
+
+


01-38
n.t.
n.t.


01-39
n.t.
n.t.


01-40
n.t.
n.t.


01-41
++
++


01-42
+++
++


01-43
++
++


01-44
++
+


01-45
++
++


01-46
++
++


01-47
+
+


01-48
++
+


01-49
++
+


01-50
+
+





















Exam-


Examples


Exam-


Examples




ples
BRD4_1
BRD4_2
04-#
BRD4_1
BRD4_2
ples
BRD4_1
BRD4_2
05-#
BRD4_1
BRD4_2


04-#
IC50
IC50
cont.
IC50
IC50
05-#
IC50
IC50
cont.
IC50
IC50





04-1
++
++
04-54
++
++
05-1
n.t.
n.t.
05-48
+++
++


04-2
++
++
04-55
++
++
05-2
n.t.
n.t.
05-49
+++
++


04-3
++
+
04-56
++
++
05-3
n.t.
n.t.
05-50
++
+


04-4
++
++
04-57
++
++
05-4
n.t.
n.t.
05-51
++
+


04-5
++
++
04-58
++
++
05-5
n.t.
n.t.
05-52
+++
++


04-6
++
+
04-59
++
++
05-6
n.t.
n.t.
05-53
++
++


04-7
++
+
04-60
++
++
05-7
n.t.
n.t.
05-54
+++
+++


04-8
++
++
04-61
++
++
05-8
n.t.
n.t.
05-55
+++
++


04-9
n.t.
n.t.
04-62
++
++
05-9
n.t.
n.t.
05-56
+++
+++


04-10
n.t.
n.t.
04-63
n.t.
n.t.
05-10
n.t.
n.t.
05-57
+++
+++


04-11
n.t.
n.t.
04-64
n.t.
n.t.
05-11
n.t.
n.t.
05-58
+++
+++


04-12
n.t.
n.t.
04-65
++
++
05-12
++
++
05-59
+++
+++


04-13
++
++
04-66
++
++
05-13
n.t.
n.t.
05-60
+++
+++


04-14
+++
++
04-67
+++
+
05-14
+++
++
05-61
+++
+++


04-15
+++
++
04-68
++
++
05-15
+++
++
05-62
+++
++


04-16
++
++
04-69
+++
+
05-16
n.t.
n.t.
05-63
+++
++


04-17
+++
++
04-70
++
++
05-17
++
++
05-64
+++
++


04-18
+++
++
04-71
++
++
05-18
+++
++
05-65
+++
++


04-19
+++
++
04-72
+++
++
05-19
n.t.
n.t.
05-66
+++
+++


04-20
+++
++
04-73
++
++
05-20
n.t.
n.t.
05-67
+++
+++


04-21
+++
++
04-74
++
++
05-21
n.t.
n.t.
05-68
+++
++


04-22
++
++
04-75
n.t.
n.t.
05-22
n.t.
n.t.
05-69
+++
++


04-23
n.t.
n.t.
04-76
n.t.
n.t.
05-23
n.t.
n.t.
05-70
+++
+


04-24
n.t.
n.t.
04-77
++
+
05-24
n.t.
n.t.
05-71
+++
++


04-25
n.t.
n.t.
04-78
++
++
05-25
n.t.
n.t.
05-72
+++
+++


04-26
+
+
04-79
++
++
05-26
n.t.
n.t.
05-73
++
++


04-27
n.t.
n.t.
04-80
++
++
05-27
n.t.
n.t.
05-74
+++
+++


04-28
n.t.
n.t.
04-81
++
++
05-28
n.t.
n.t.
05-75
+++
++


04-29
n.t.
n.t.
04-82
++
++
05-29
n.t.
n.t.
05-76
++
+


04-30
+
+
04-83
++
++
05-30
n.t.
n.t.
05-77
++
++


04-31
n.t.
n.t.
04-84
++
++
05-31
n.t.
n.t.
05-78
+++
++


04-32
+
+
04-85
++
++
05-32
+
+
05-79
++
+


04-33
n.t.
n.t.
04-86
++
++
05-33
+
+
05-80
+++
++


04-34
n.t.
n.t.
04-87
n.t.
n.t.
05-34
+
+
05-81
+++
++


04-35
n.t.
n.t.
04-88
n.t.
n.t.
05-35
+
+
05-82
+++
+


04-36
+
+
04-89
+++
++
05-36
+
+
05-83
++
+


04-37
n.t.
n.t.
04-90
n.t.
n.t.
05-37
+++
+
05-84
++
+


04-38
n.t.
n.t.
04-91
++
++
05-38
+++
+++
05-85
+++
+


04-39
n.t.
n.t.
04-92
++
+
05-39
+++
++


04-40
+
+
04-93
++
++
05-40
+++
+++


04-41
n.t.
n.t.
04-94
n.t.
n.t.
05-41
+++
++


04-42
n.t.
n.t.
04-95
+
+
05-42
+++
++


04-43
+
+
04-96
++
+
05-43
+
+


04-44
++
+
04-97
++
+
05-44
+++
++


04-45
+
+
04-98
+
+
05-45
+++
++


04-46
++
+
04-99
++
++
05-46
+++
++


04-47
+
+
04-100
n.t.
n.t.
05-47
+++
++


04-48
++
++
04-101
n.t.
n.t.


04-49
++
+
04-102
n.t.
n.t.


04-50
+
+
04-103
n.t.
n.t.


04-51
+
+
04-104
+++
++


04-52
+
+
04-105
+++
++


04-53
++
++
04-106
+++
++














Examples
BRD4_1
BRD4_2



06-#
IC50
IC50







06-1
++
+



06-2
++
++



06-3
n.t.
n.t.



06-4
+++
++



06-5
n.t.
n.t.



06-6
n.t.
n.t.



06-7
n.t.
n.t.



06-8
+++
++



06-9
n.t.
n.t.



06-10
+++
++



06-11
n.t.
n.t.



06-12
n.t.
n.t.



06-13
n.t.
n.t.



06-14
n.t.
n.t.



06-15
+++
++



06-16
n.t.
n.t.



06-17
n.t.
n.t.



06-18
n.t.
n.t.



06-19
n.t.
n.t.



06-20
n.t.
n.t.



06-21
n.t.
n.t.



06-22
n.t.
n.t.



06-23
n.t.
n.t.



06-24
n.t.
n.t.



06-25
n.t.
n.t.



06-26
n.t.
n.t.



06-27
n.t.
n.t.



06-28
+++
++







Note:



n.t. = not tested;



(+) = >10 uM;



(++) = 1-10 uM;



(+++) = <1 uM






LPS-Induced IL-6Secretion In Murine Macrophage Raw264.7 Cells RAW264.7 cells were cultivated in Dulbecco's modified Eagle medium (DMEM) (Hyclone, Logan, Utah) supplemented with 10% FBS (fetal bovine serum) (Hyclone, Logan, Utah) at 37° C. in a humidified atmosphere of 5% CO2. Cells in 96-well plates (0.1 ml, 3×105 cells/ml) were treated with the test compounds. After 30 min, all supernatants were removed and cells were treated with LPS (lipopolysaccharide) (1 μg/ml) (Sigma-Aldrich Chemical Co., St. Louis, Mo.) and compounds. After 24 hours, the supernatant was collected and mouse IL-6 protein level was measured using ELISA (enzyme-linked immunosorbent assay) (Thermo Scientific, Pittsburgh, Pa.). The compounds dissolved in DMSO were diluted with culture medium to concentrations from 0.28 to 50,000 nM. The final concentration of DMSO was adjusted to 0.05% (v/v). The assay was measured by an absorption reading at 570 nm using EnVison 2104 Multilabel Reader (PerkinElmer, Inc., Waltham, Mass.). Each experiment was performed at least in triplicate, and plotted using Prim, and an IC50 value was calculated. Examples 04-19 and 04-20 were tested in this assay and found to have IC50 values in the range of 0.2-1 μM.
LPS-Induced Transcriptional Activation of Cytokines in Murine Macrophage Cells RAW264.7 cells were cultivated with or without a treatment of the compounds as described above. Total RNA was isolated the cells using TRIzol reagent (Gibco, Grand Island, N.Y.) for homogenization. The concentration and integrity of RNA were determined by measuring absorbance at a 260 nm/280 nm ratio. Quantitative PCR was performed to determine the mRNA transcript levels of cytokines IL-6, IL-1β and TNFα with specific primers for these target genes. Each experiment was performed at least in triplicate, and plotted using Prim, and an IC50 value was calculated. Examples 01-36, 04-15, 04-17, 04-19, 04-20, 04-89, 04-91, 04-98, 05-15, and 06-4 were tested in this assay and found to have IC50 values in the range of 0.1-5 μM in inhibition of transcriptional activation of the cytokines IL-6, IL-1β and TNFα.
LPS-Stimulated Nitric Oxide (NO) Release in Murine Macrophage RAW264.7 Cells
RAW264.7 cells was cultivated in DMEM supplemented with 10% FBS at 37° C. in a humidified atmosphere of 5% CO2. Cells in 96-well plates (0.1 ml, 3×105 cells/ml) were treated with the test compounds. After 30 min, all supernatants were removed and cells were treated with LPS (1 μg/ml) and the test compounds. After 24 hours, the level of nitrite was measured using Griess reaction G2930 (Promega Corp., Madison, Wis.) [see Bredt and Snyder, Ann Rev Biochem 63, 175-195 (1994)]. The test compounds dissolved in DMSO were diluted with culture medium to concentrations from 0.28 to 50,000 nM. The final concentration of DMSO was adjusted to 0.05% (v/v). The nitrite production was measured by spectrophotometry at 520 nm using EnVison 2104 Multilabel Reader (PerkinElmer, Inc., Waltham, Mass.). Each experiment was performed at least in triplicate and plotted using Prism. Examples 01-36, 04-15, 04-17, 04-19, 04-20, 04-89, 04-91, 04-98, 05-15, and 06-4 were tested in this assay and found to have IC50 values in the range of 0.1-5 μM in inhibition of LPS-induced NO release in RAW264.7 cells.
ELISA Assay Assessing IL-8 Expression in BLBCs
Compounds of the Examples listed in Table 1 (“test compounds”) were evaluated for their activity to inhibit expression of IL-8 in human basal-like breast cancer cells (BLBCs). The human BLBCs were cultivated in DMEM (Hyclone, Logan, Utah) supplemented with 10% FBS (Hyclone, Logan, Utah) at 37° C. in a humidified atmosphere of 5% CO2. Upon 60-80% confluency of the culturing dish, the cells were trypsinized, centrifuged at 1000 rpm for 5 min, and resuspended with fresh culturing medium for seeding of cells in a 96-well plate (0.1 ml, 3×105 cells/ml) and incubated at the above-mentioned culturing conditions overnight. The following day upon cells adhesion to the plate bottom, all supernatants were carefully discarded followed by adding test compounds diluted in culturing medium. The test compounds dissolved in DMSO (Sigma-Aldrich Chemical Co., St. Louis, Mo.) were diluted with culturing medium in a 2-fold serial dilution from 1000 nM to 125 nM. The final concentration of DMSO was adjusted to 0.05% (v/v). At the end of 24-hour incubation, all supernatants were carefully removed and stored at −80° C. if the subsequent steps would not be performed immediately. The Human IL-8 ELISA Ready-Set-Go! (2nd generation) is used (Catalog No. 88-8086) against the prepared samples. The samples along with the Standard Human IL-8 Recombinant Protein (prepared in duplicates in a 2-fold serial dilution from 250 pg/ml to 2 pg/ml) were incubated overnight for maximal sensitivity. The assay was measured by an absorption reading at 450 nm using EnVision 2104 Multilabel Reader (PerkinElmer, Inc., Waltham, Mass.). Each experiment was performed at least in duplicate and plotted using Prism. The curve fitting equation used was “log(inhibitor) vs. response variable slope (four parameters)”. Examples 05-57, 05-68, and 05-70 were tested in this assay in a panel of human BLBC cells consisting of MDA-MB-435S, MDA-MB-231, BT-549, MDA-MB-157, HS578T, and SUM1315, and found to have IC50 values in the range of 0.1-1 μM.
Human, Rat, and Mouse Microsome Stability Assay
Microsome stability assays were performed on Compounds of the Examples listed in Table 1 (“test compounds”). Human, rat, and mouse liver microsomal incubations were carried out at 37° C. with a final incubation volume of 135 μL. Human liver microsomes (mixed gender, Catalog No. H2610) were obtained from XenoTech. Rat liver microsomes (male Sprague-Dawley, Catalog No. 452501) were obtained from BD Gentest. Mouse liver microsomes (male CD1, Catalog No. 452701) were obtained from BD Gentest. Incubations were conducted using a test compound (initially dissolved in DMSO at 5 μM concentration) concentration of 0.5 μM and 0.25 mg/mL microsomal protein in 50 mM phosphate buffer at pH 7.4. Time zero samples were prepared by transferring 13.5 μL of compound-microsomal mix to the quench plates containing 45 μL of quench solution made of 10 nM Buspirone (Sigma) or 50 nM Carbutamide (Princeton Bio) as internal standard in 1:1 methanol:acetonitrile. An aliquot of 1.5 μL Nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt (NADPH) was also added to the time zero plates. The reaction was then initiated by the addition of 13.5 μL NADPH to the compound-microsomal mix. At each of the remaining time points (5, 10, 15, 20, 30, 45 and 60 min) 15 μL of incubation mixture was added to 45 μL of quench solution. Samples were centrifuged for 15-30 minutes at 3800 rpm. Samples were then pooled for 6 per group. An aliquot of 60 μL of supernatant was transferred to 96-well plate, and a 5 μL aliquot was injected and analyzed by LC-MS (Applied Biosystems API 5500 QTrap). The intrinsic clearance of a compound was calculated by converting the peak area ratios (analyte peak area/IS peak area to % parent remaining using the area ratio at time 0 as 100%. The slope (k) was determined from the plot of the % parent remaining versus incubation time, from which the half life (t1⁄2; minutes), intrinsic clearance (CLint; μL/min/mg protein for liver microsomes and μL/min/million cells for hepatocytes) and scaled intrinsic clearance (scaled Clint; L/h/kg) were then derived. Examples 01-41, 01-47, 05-57, 05-66, 05-68, and 05-70 were tested in this assay and found to have the intrinsic clearance Clint values in the range of 25-250 μL/min/mg protein.
T-Cell-Transfer Colitis Study and Histopathology
Compound of Example 04-19 inhibits the development of colitis in mice as examined in the established T-cell-transfer colitis model [See (Totsuka, T. et al. J Immunol 178, 4737-4748 (2007) and Powrie, F. et al. International immunology 5, 1461-1471 (1993).] Briefly, purified CD4+CD45RBhi T cells from C57BL/6 mice were injected intra-peritoneally into Rag1−/− recipients (5×105 cells per mouse in 200 μl sterile PBS per injection). Mice were weighed every week throughout the course of experiments. FIG. 1 presents the results in graph form. It can be seen that compound 04-19 significantly (P<0.05) inhibits the loss of body weight. After 5-7 weeks, mice were killed and colon tissues were excised. Tissues were fixed in 10% buffered formalin and paraffin embedded. The sections (5 μm) of tissue samples stained with hematoxylin and eosin. All the slides were read and scored by an experienced pathologist without previous knowledge of the type of treatment. The degree of inflammation in the epithelium, submucosa and muscularis propria was scored separately. It can be seen from FIG. 2 that the gross morphology of the intestines is preserved in the treated mice and lost in the disease group.

## Claims

1. A compound of formula 1




wherein:
U is (CH2)n, where n=1, 2 or 3;
R1 is selected from the group consisting of: (C1-C10)alkyl, substituted (C1-C10)alkyl, and nitrile;
Cy is a carbocycle or heterocycle;
R11and R12 are independently selected from the group consisting of: H, (C1-C10)alkyl, (C1-C10)perfluoroalkyl, halogen, nitrile, hydroxy, (C1-C10)alkoxy, perfluoro(C1-C10)alkoxy, (C1-C10)alkylthio, amino, (C1-C10)alkylamino, (C1-C10)acylamino, aryl, heteroaryl, aminocarbonyl, carboxyl, and (C1-C10)alkoxycarbonyl; or
taken together, R11 and R12 may form a 5, 6,or 7-membered carbocycle or heterocycle wherein said carbocycle or heterocycle may be optionally substituted with R2;
R2 is selected from the group consisting of: halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo(C1-C4)alkoxy, carboxy, amino, (C1-C4)alkylamino and di(C1-C4)alkylamino;
Y is selected from




L and L′ are independently a bond or (CR3R4)m where R3 and R4 are independently selected from the group consisting of H and (C1-C4)alkyl, and m is 1or 2;
R10 is chosen from carbocycle and heterocycle, wherein said carbocycle or heterocycle is optionally substituted with R7 and/or R8;
R20 is —C(═O)OR R21;
R21 is chosen from H and (C1-C4)alkyl;
R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, (C1-C10)hydrcarbyl, halo(C1-C10)hydrocarbyl, and (C1-C10)alkoxy;
R7 and R8 are independently selected from the group consisting of: hydroxy, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylcarbonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, oxo, (C1-C4)alkylsulfonyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C4)acylamino, aminocarbonyl, carboxyl, and (C1-C4)alkoxycarbonyl, where each said alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, may be further optionally substituted with hydroxy, oxo, carboxy, carboxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycarbonyl(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amido, (C1-C4)alkylamido, di (C1-C4)alkylamido, halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
or, taken together, R5 and R6, or R7 and R8 may form a 5, 6, or 7-membered carbocycle or heterocycle, wherein said carbocycle or heterocycle is optionally substituted with R9;
R9 is selected from the group consisting of: halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo(C1-C4)alkoxy, amino, (C1-C4)alkylamino and di(C1-C4)alkylamino.

2. A compound according to claim 1 wherein Cy is aryl or heteroaryl.

3. A compound according to claim 2 wherein Cy is phenyl, having the formula:

4. A compound according to claim 3 wherein Y is chosen from

5. A compound according to claim 3 wherein R11 is hydrogen and R12 is halogen.

6. A compound according to claim 1 wherein U is —CH2CH2—.

7. A compound according to claim 1 wherein U is —CH2—.

8. A compound according to claim 1 wherein Y is

9. A compound according to claim 8 wherein L is —CH2—.

10. A compound according to claim 9 wherein R10 is chosen from cyclohexyl, cyclopentyl, phenyl, naphthyl, thiophenyl, pyrrolyl, pyridinyl, and pyrimidinyl, each optionally substituted with R7 and/or R8.

11. A compound according to claim 10 wherein R7 is chosen from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and aminocarbonyl.

12. A compound according to claim 1 wherein Y is

13. A compound according to claim 1 wherein Y is

14. A compound according to claim 1 wherein R21 is hydrogen or methyl.

15. A compound according to claim 1 wherein R10 is a phenyl, optionally substituted with R7 and/or R8.

16. A compound according to claim 1 wherein L is a direct bond, L′ is a direct bond or CH2 and R21 is H.

17. A compound according to claim 16 wherein R10 is chosen from cyclohexyl, cyclopentyl, phenyl, naphthyl, thiophenyl, pyrrolyl, pyridinyl, and pyrimidinyl, each optionally substituted with R7 and/or R8.

18. A compound according to claim 17 wherein R10 is

19. A compound according to claim 18 wherein R7 is chosen from halogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and aminocarbonyl.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.