AHR agonist

Abstract

To provide AHR agonist compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat immune-mediated diseases.SOLUTION: A pharmaceutical composition comprising a compound of the formula: wherein R1 is selected from phenyl, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl optionally substituted with 1-2 R I, and the like; R2 is selected from H and OH; X is selected from a bond, -C (R3) 2 -, and -C (R3) 2C (R3) 2 -; Y is selected from -C (R3) 2 -, -O, and -N (R j) -; R3 is independently selected from H and C1-C3 alkyl; R I is selected from halogen, CH3, OCH3, and CF3; R j is C1-C3 alkyl; or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents or excipients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel AHR agonist compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat certain physiological disorders.

[0002] The present invention is in the field of treatment of certain immune-mediated diseases (IMDs), particularly psoriasis, via activation of the aryl hydrocarbon receptor (AHR).

[0003] IMD encompasses a wide range of chronic and debilitating inflammatory conditions that affect approximately 4% of the population worldwide. In view of the limited efficacy of currently available treatments, there is a significant unmet need for potent, selective, and safer drugs for the treatment of IMD.

[0004] The AHR is a transcription factor that regulates many aspects of immunological function, most notably the suppression of adaptive immune responses (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Prototypic AHR agonists include halogenated dibenzodioxins such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), L-kynurenine, bilirubin, and tryptophan metabolites such as PGE2. Results from studies of AHR agonists, particularly TCDD, suggest that immunosuppression results from AHR-induced expression of regulatory T cells (Tregs), Th17 cells, and dendritic cells (DCs) (Rothhammer et al., Nat. Rev. Immunol., 19, 184-197 (2019)). TCDD is associated with type 1 diabetes (Kerkvliet et al., Immunotherapy, 1,539-547 (2009)), autoimmune encephalomyelitis (Quintana et al., Nature, 453, 65-71, (2008)), and autoimmune uveoretinitis (Zhang et al. al., Invest.Opthalmol.Vis.Sci.,51,2109-2117(2010)), inflammatory bowel disease (Takamura et al.,Immunol.Cell.Biol.,88,685-689(2010), Benson et al.,Toxicol.Sci.,120,68-78(2011), Singh et al.,PLoS One,6(8),e23522(2011)) and transplant tolerance (Pauly at al., Toxicol. Environ. Chem., 94, 1175-1187 (2012)) and several models of allergic disease (Schulz et al., Toxicol. Sci., 123, 491-500 (2011); Li et al., PLoS One, 11, e0150551 (2016); Luebke et al., Toxicol. Sci., 62, 71-79 (2001)).

[0005] The AHR also regulates the expression of CYP1A1, CYP1A2, and CYP1B1, which catalyze the metabolism of polycyclic aromatic hydrocarbons (PAHs) and other aromatic compounds (e.g., estrogens). In some cases (e.g., beno[a]pyrene), this metabolism results in the formation of reactive species; however, CYP induction is also thought to be important for the detoxification and metabolic clearance of PAHs, reducing the probability of bioactivation and DNA adduct formation. Several marketed drugs have been found to activate the AHR (and thus upregulate CYP1A1, CYP1A2, and CYP1B1) after FDA approval, and their long-term use has not been associated with dioxin-like toxicity (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)). Thus, CYP induction is no longer considered a barrier to the adoption of AHR agonists in therapy (Ehrlich et al., Curr. Opin. Toxicol., 2, 72-78 (2017)).

[0006] The bacterial stilbenoid DMVT-505 (tapinarof), formulated as a 1% topical cream, is currently undergoing phase 3 clinical trials for the treatment of plaque psoriasis in adults (NCT04053387). Despite this, there remains a need for novel, oral, selective, and potent AHR agonists for the treatment of IMD.

[0007] Ukrainets, IV, et al., Chemistry of Heterocyclic Compounds, 42(6), 2006, 765-775, discloses certain 4-hydroxy-2-oxo-5,6,7,8-tetrahydro-1H-quinoline-3-carboxamide compounds having antibacterial properties. US Patent Publication No. 2009 / 0325948(A1) discloses certain cycloalkyl-fused 4-hydroxy-2-oxo-1H-pyridine-3-carboxamide compounds that are inhibitors of bacterial undecaprenyl pyrophosphate synthase (UPPS).

[0008] The present invention provides certain compounds that are agonists of the AHR.

[0009] Thus, the present invention provides compounds of formula I, [ka] During the ceremony, R 1 is phenyl, C1-C6 alkyl, C3-C6 cycloalkyl, optionally 1 to 2 R i and optionally, 1 to 2 R i 8-10 membered bicyclic heteroaryl substituted with R 2 is selected from H and OH; X is a bond, -C(R 3 )2-, and -C(R 3 )2C(R 3 )2- is selected from Y is -C(R 3 )2-, -O, and -N(R j )-selected from R 3 is independently selected from H and C1-C3 alkyl; R i is selected from halogen, CH3, OCH3, and CF3; R jis C1-C3 alkyl, or a pharmaceutically acceptable salt thereof.

[0010] The present invention also provides R 1 is phenyl, and optionally, 1 to 2 R i or a pharmaceutically acceptable salt thereof.

[0011] The present invention relates to a compound in which Y is -C(R 3 )2-, or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides a method for producing a compound of formula (I) 3 is independently selected from H, CH3, CH2CH3, and CH(CH3)2, or a pharmaceutically acceptable salt thereof.

[0013] The present invention provides compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is a bond.

[0014] The present invention provides [ka] A compound of formula I selected from or a pharmaceutically acceptable salt thereof.

[0015] The present invention provides [ka] A compound of formula I selected from: or a pharmaceutically acceptable salt thereof.

[0016] The present invention also provides [ka] A compound of formula I selected from: or a pharmaceutically acceptable salt thereof.

[0017] The present invention provides [ka] A compound of formula I selected from: or a pharmaceutically acceptable salt thereof.

[0018] The invention also provides compounds of formula I according to any of the above embodiments as the free base.

[0019] The present invention further provides a pharmaceutical composition comprising a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0020] The present invention provides a method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a composition according to any of the above embodiments.

[0021] The invention also provides a method of treating a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a composition according to any of the above embodiments.

[0022] The present invention provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0023] The present invention also provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis.

[0024] Further, the present invention provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an immune-mediated disease. Additionally, the present invention provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis.

[0025] As used herein, the term "alkyl," used alone or as part of a larger moiety, refers to a saturated, straight-chain, or branched-chain hydrocarbon group containing one or more carbon atoms.

[0026] As used herein, the term "cycloalkyl" refers to a saturated ring system containing at least three carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0027] As used herein, the term "heteroaryl" refers to a group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, with 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes oxidized forms of nitrogen or sulfur and quaternized forms of basic nitrogen. Heteroaryl groups include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The term "bicyclic heteroaryl" includes groups in which a heteroaryl ring is fused to one more aryl or heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.

[0028] As used herein, the term "OR isomer" in combination with the terms "isomer 1" or "isomer 2" refers to a compound with a specific but undetermined (either R or S) stereochemistry. The terms "isomer 1" and "isomer 2" refer to either the R and S enantiomers, or the S and R enantiomers, of the same molecule.

[0029] As used herein, when X is a bond, the saturated ring is a five-membered ring. 3 When X is CR 3 -CR 3 When the ring is a seven-membered ring,

[0030] As used herein, the term "immune-mediated disease" encompasses a group of autoimmune inflammatory disorders characterized by alterations in cellular homeostasis. Immune-mediated diseases can be caused by environmental factors, dietary habits, infectious agents, and genetic predisposition.

[0031] As used herein, the term "treating" or "to treat" includes inhibiting, slowing, arresting, or reversing the progression or severity of an existing condition or disorder.

[0032] As used herein, the term "patient" refers to a human.

[0033] As used herein, the term "effective amount" refers to an amount or dosage of a compound of the present invention or a pharmaceutically acceptable salt thereof that, when administered in single or multiple doses to a patient, provides the desired effect in the patient being diagnosed or treated.

[0034] The effective amount can be easily determined by those skilled in the art using known techniques. In determining the effective amount for a patient, several factors are taken into consideration, including but not limited to, the species of the patient; its size, age and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0035] The compounds of the present invention are generally effective over a wide range of dosages. For example, the daily dosage is usually within the range of about 0.1 to about 15 mg / kg body weight. In some cases, dosage levels lower than the lower limit of the aforementioned range may be more than sufficient, while in other cases, higher doses may be used with acceptable side effects. Therefore, the above dosage ranges are not intended to limit the scope of the present invention in any way.

[0036] The compounds of the present invention are preferably formulated as pharmaceutical compositions to be administered by any route that makes the compounds bioavailable, including oral and transdermal routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for their preparation are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23 rd Edition, Elsevier Academic Press, 2020).

[0037] The compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitution of solvents and co-reagents is within the skill of the art. Similarly, those skilled in the art will understand that synthetic intermediates can be isolated and / or purified by various well-known techniques as necessary or desired, and that in many cases, various intermediates can be used directly in subsequent synthetic steps with little or no purification. By way of example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, or directly by filtration or crystallization. Furthermore, those skilled in the art will understand that in some circumstances, the order in which moieties are introduced is not critical. The specific order of steps required to produce the compounds of the present invention will depend on the particular compound being synthesized, the starting compound, and the relative disadvantages of the substituting moieties, and is well understood by skilled chemists. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and understood in the art.

[0038] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "BSA" refers to bovine serum albumin, "DCM" refers to dichloromethane, "DCE" refers to 1,2-dichloroethane, "DEA" refers to diethylamine, "DIPEA" refers to N,N-diisopropylethylamine, "DMEM" refers to Dulbecco's modified Eagle's medium, "DMF-DMA" refers to N,N-dimethylformamide dimethyl acetal, "DMF" refers to N,N-dimethylformamide, "DPBS" refers to Dulbecco's phosphate buffered saline, "DMSO" refers to dimethyl sulfoxide, "EGFP" refers to enhanced green fluorescent protein, "ES / MS" refers to electrospray ionization / mass spectrometry, "EtOAc" refers to ethyl acetate, and "EtOH" refers to ethanol or ethyl alcohol. "FBS" refers to fetal bovine serum, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "h" refers to hours, "IPA" refers to isopropyl alcohol or isopropanol, "MeOH" refers to methanol or methyl alcohol, "min" refers to minutes, "MTBE" refers to methyl tert-butyl ether, "m / z" refers to mass-to-charge ratio, "NMI" refers to N-methylimidazole, "RT" refers to room temperature or ambient temperature, "SFC" refers to supercritical fluid chromatography, "T3P" refers to propanephosphonic anhydride, "TCFH" refers to N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate, and "THF" refers to tetrahydrofuran.

[0039] In any step, a pharmaceutically acceptable salt of a compound according to any of the above embodiments can be formed by reacting a suitable free base with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions.In addition, the formation of such salts can occur simultaneously during the deprotection of nitrogen protecting groups.The formation of such salts is well known and understood in the art. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977). "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986). Those skilled in the art will understand that compounds according to any of the above embodiments can be readily converted to and isolated as pharmaceutically acceptable salts.

[0040] The compound of Formula I, or a pharmaceutically acceptable salt thereof, can be prepared by a variety of procedures known in the art, some of which are illustrated in the following schemes, preparations, and examples. Specific synthetic steps for each of the described routes may be combined in different ways or with steps from different schemes to prepare the compound of Formula I, or a pharmaceutically acceptable salt thereof. The product of each step in the following schemes may be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the following schemes, all substituents are as previously defined unless otherwise indicated. The reagents and starting materials are readily available to those skilled in the art.

[0041] Scheme 1. General synthetic route for preparing compounds of formula I [ka]

[0042] Scheme 1 shows the general preparation of compounds of formula I.

[0043] In the first alternative, an organocuprate undergoes 1,4-addition with an unsaturated cyclic ketone (1). The intermediate enol is then trapped in situ with N,N-dimethylformamide dimethyl acetal to give intermediate (2). Subsequent cyclization of (2) with methyl cyanoacetate, followed by methylation with iodomethane and ester hydrolysis, gives the carboxylic acid intermediate (5).

[0044] In a second alternative, ketoester (3) is first reacted with methylamine to give an enamine intermediate, which is then alkylated with 3-chloro-3-oxo-propanoate to give intermediate (4). Intramolecular cyclization of (4) using base at elevated temperature, followed by ester hydrolysis, gives carboxylic acid intermediate (5).

[0045] Finally, the carboxylic acid intermediate (5) undergoes an amide coupling reaction to give the compound of formula I.

[0046] Preparations and Examples The following preparations and examples further illustrate the present invention.

[0047] Preparation 1 1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid [ka]

[0048] Step A: Cuprous iodide (56 g, 294 mmol) and tributylphosphine (150 mL, 570 mmol) are stirred in THF (300 mL) under N for 10 minutes. The mixture is cooled to -78°C, and methyllithium (1.6 mol / L in diethyl ether) (180 mL, 290 mmol) is added dropwise. After the addition is complete, the mixture is stirred at -78°C under N for 30 minutes. After this time, boron trifluoride diethyl etherate (34 mL, 268.8 mmol) is added, stirred for 5 minutes, and cyclopent-2-en-1-one (20 g, 243.6 mmol) is added. The mixture is stirred at -68°C for 10 minutes, then warmed to -55°C, stirred for 20 minutes, warmed again to -40°C, and stirred under N for 10 minutes. DMF-DMA (81 mL, 607 mmol) was then added and the mixture was warmed to 20° C. and N 2 The mixture is stirred under reduced pressure for 16 h. The yellow mixture is poured into brine (500 mL) and extracted with EtOAc (4 x 200 mL). The organic layers are recombined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The residue is purified via flash silica gel chromatography (330 g, 0-100% EtOAc in petroleum ether) to give (2Z)-2-(dimethylaminomethylene)-3-methyl-cyclopentanone as a yellow oil (34 g, 199.7 mmol, 82%). ES / MS (m / z): 154.2 (M+H).

[0049] Step B: (2Z)-2-(dimethylaminomethylene)-3-methyl-cyclopentanone (13.46 g, 87.85 mmol) is dissolved in MeOH (100 mL). To this mixture is added piperidine (7.5 g, 88 mmol), followed by methyl cyanoacetate (17.6 g, 176 mmol). The mixture is heated to 80 °C under N for 18 h. After this time, the volatile organics are evaporated under reduced pressure, and the residue is purified via silica gel chromatography (120 g, 0-60% EtOAc in petroleum ether) to afford methyl 5-methyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate as a brown solid (14 g, 60.8 mmol, 69%). 1 H NMR(400.15MHz,CDCl3):7.96(s,1H),7.21(s,1H),3.86(s,3H),3.12-3.03(m,1H ),2.92-2.82(m,2H),2.35-2.28(m,1H),1.64-1.55(m,1H),1.19(d,J=6.9Hz,3H).

[0050] Step C: Methyl 5-methyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate (3.2 g, 15 mmol) is dissolved in acetone (200 mL). To this solution is added potassium carbonate (4.2 g, 30 mmol), followed by iodomethane (8.6 g, 61 mmol). The mixture is stirred at 20 °C for 12 h. After this time, the reaction is quenched by adding a saturated aqueous solution of ammonium chloride (100 mL). The mixture is then extracted with EtOAc (2 × 200 mL). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The residue is purified via flash silica gel chromatography (120 g, 0-80% EtOAc in petroleum ether) to give methyl 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a yellow oil (2.82 g, 12.7 mmol, 84%). ES / MS (m / z): 222.3 (M+H).

[0051] Step D; Preparation 1: Methyl 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (4.48 g, 20.2 mmol) is dissolved in THF (50 mL) and water (50 mL). To this solution, lithium hydroxide (5.78 g, 229 mmol) is added and stirred at 40° C. for 2 hours. After this time, the mixture is cooled to room temperature, diluted with water (30 mL), and then adjusted to pH 4 with 1 M aqueous HCl. The mixture is extracted with EtOAc (3×300 mL), and the organic layers are combined and dried over anhydrous sodium sulfate, then filtered, and the solvent is evaporated to give the title product as a yellow solid (4.1 g, 20 mmol, 98%). 1 H NMR (400.14MHz, d6-DMSO): 14.93(s,1H),8.26(s,1H),3.59(s,3H),3.22-3.10(m,3H),2.41-2.32(m,1H),1.69-1.63(m,1H),1.23(d,J=6.9Hz,3H).

[0052] Preparation 2 (5R)-4-Hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid. [ka]

[0053] Step A: (5R)-2-Isopropylidene-5-methyl-cyclohexanone (95 g, 511.7 mmol) is stirred in DCM (400 mL). Formylperoxysodium (26.2 g, 312 mmol) is added and cooled to −10° C. Bromine (38.37 mL, 747 mmol) is added dropwise over 40 minutes, and stirring is continued at −10° C. for 1 hour after addition is complete. The mixture is filtered, and the filtrate is cooled to −40° C. Sodium ethoxide (20% wt. solution in EtOH, 450 mL) is added to the solution, and the reaction is stirred at −40° C. for 1 hour, then allowed to warm to room temperature and stirred for an additional 16 hours. The mixture is quenched with 1 N aqueous HCl (300 mL) and extracted with EtOAc (2×500 mL). The organic layers are combined and washed with brine (300 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture is purified via silica gel chromatography (200 g, 5% EtOAc in heptane) to give ethyl (5R)-2-isopropylidene-5-methyl-cyclopentanecarboxylate as a yellow oil (60 g, 306.7 mmol, 60%). ES / MS (m / z): 197.0 (M+H).

[0054] Step B: (5R)-2-isopropylidene-5-methyl-cyclopentanecarboxylate (25 g, 127.4 mmol) is dissolved in 5% aqueous acetone (500 mL) and cooled to 0 °C. Ozone is sparged through the solution for 12 hours while maintaining the temperature below 5 °C. The mixture is purged with argon for 30 minutes, then diluted with water (400 mL) and extracted with DCM (300 mL x 2). The organics are combined, washed with brine (300 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (2R)-2-methyl-5-oxo-cyclopentanecarboxylate as a colorless syrup (20.1 g, 70.8 mmol, 56%). ES / MS (m / z): 171.9 (M+H).

[0055] Step C: (2R)-2-methyl-5-oxo-cyclopentanecarboxylate (10 g, 58.8 mmol) is dissolved in THF (50 mL). Methanamine (2 M in THF, 176 mL, 352 mmol) is added and stirred at room temperature for 24 hours, then concentrated in vacuo. The residue is diluted with water (100 mL) and extracted with EtOAc (150 mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. ES / MS (m / z): 184.05 (M+H). The residue is dissolved in toluene (100 mL) and the mixture is cooled to 0 °C. 3-Chloro-3-oxo-propanoate (6.2 g, 41.2 mmol) and sodium acetate (6.8 g, 81 mmol) are added, and the mixture is stirred at room temperature for 16 hours, then diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The organic layers are combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give ethyl (5R)-2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-5-methyl-cyclopentene-1-carboxylate (8.6 g, 17.4 mmol, 25%). ES / MS (m / z): 298.0 (M+H).

[0056] Step D: (5R)-2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-5-methyl-cyclopentene-1-carboxylate (17.2 g, 57.8 mmol) is dissolved in EtOH (180 mL), sodium ethoxide (29.5 g, 86.7 mmol) is added, and the mixture is stirred at room temperature for 2 hours. The mixture is concentrated in vacuo, 100 mL of 1N aqueous HCl is added, and then extracted with DCM (200 mL × 2). The organic layers are combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give ethyl (5R)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a brown solid (11 g, 36.8 mmol, 64%). ES / MS (m / z): 251.9 (M+). Chiral method: Column: Chiral Pak IG (250 x 4.6 mm x 5 um). Mobile phase A: 0.1% DEA n n-hexane. Phase B: DCM / MeOH (50 / 50). A / B = 80 / 20 at 1.0 mL / min. Retention time: 9.137 min.

[0057] Step E; Preparation 2: Ethyl (5R)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (300 mg, 1.19 mmol) is diluted with 3N aqueous HCl (10 mL) and stirred at 65° C. for 24 hours. The mixture is diluted with water (50 mL) and extracted with EtOAc (30 mL×2). The organic layers are combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title product as a white solid (110 mg, 492 mmol, 62%). ES / MS (m / z): 223.8 (M+).

[0058] Alternative preparation 2 (5R)-4-Hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid. [ka]

[0059] Step A: (5R)-2-Isopropylidene-5-methyl-cyclohexanone (95 g, 511.7 mmol) is stirred in DCM (400 mL). Sodium bicarbonate (26.2 g, 312 mmol) is added and cooled to −10° C. Bromine (38.37 mL, 747 mmol) is added dropwise over 40 minutes, and stirring is continued at −10° C. for 1 hour after addition is complete. The mixture is filtered, and the filtrate is cooled to −40° C. Sodium ethoxide (20% wt. solution in EtOH, 450 mL) is added to the solution, and the reaction is stirred at −40° C. for 1 hour, then allowed to warm to room temperature and stirred for an additional 16 hours. The mixture is quenched with 1 N aqueous HCl (300 mL) and extracted with EtOAc (500 mL×2). The organic layers are combined and washed with brine (300 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture is purified via silica gel chromatography (200 g, 5% EtOAc in heptane) to give ethyl (5R)-2-isopropylidene-5-methyl-cyclopentanecarboxylate as a yellow oil (60 g, 306.7 mmol, 60%). ES / MS (m / z): 197.0 (M+H).

[0060] Step B: Ethyl (5R)-2-isopropylidene-5-methyl-cyclopentanecarboxylate (25 g, 127.4 mmol) is dissolved in 5% aqueous acetone (500 mL) and cooled to 0° C. Ozone is sparged through the solution for 12 hours while maintaining the temperature below 5° C. The mixture is purged with argon for 30 minutes, then diluted with water (400 mL) and extracted with DCM (300 mL×2). The organics are combined, washed with brine (300 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford ethyl (2R)-2-methyl-5-oxo-cyclopentanecarboxylate as a colorless syrup (20.1 g, 70.8 mmol, 56%), which is carried forward without purification.

[0061] Step C: (2R)-2-methyl-5-oxo-cyclopentanecarboxylate (10 g, 58.8 mmol) is dissolved in THF (50 mL). Methanamine (2 M in THF, 176 mL, 352 mmol) is added and stirred at room temperature for 24 hours, then concentrated in vacuo. The residue is diluted with water (100 mL) and extracted with EtOAc (150 mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. ES / MS (m / z): 184.05 (M+H). The residue is dissolved in toluene (100 mL) and the mixture is cooled to 0 °C. Ethyl 3-chloro-3-oxopropanoate (6.2 g, 41.2 mmol) and sodium acetate (6.8 g, 81 mmol) are added, and the mixture is stirred at room temperature for 16 hours, then diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The organic layers are combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give ethyl (5R)-2-[(3-ethoxy-3-oxopropanoyl)-methyl-amino]-5-methyl-cyclopentene-1-carboxylate (8.6 g, 17.4 mmol, 25%). ES / MS (m / z): 298.0 (M+H).

[0062] Step D: (5R)-2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-5-methyl-cyclopentene-1-carboxylate (17.2 g, 57.8 mmol) is dissolved in EtOH (180 mL), sodium ethoxide (29.5 g, 86.7 mmol) is added, and the mixture is stirred at room temperature for 2 hours. The mixture is concentrated in vacuo, 100 mL of 1N aqueous HCl is added, and then extracted with DCM (200 mL × 2). The organic layers are combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give ethyl (5R)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a brown solid (11 g, 36.8 mmol, 64%). ES / MS (m / z): 251.9 (M+H). Chiral method: Column: Chiral Pak IG (250 x 4.6 mm x 5 um). Mobile phase A: 0.1% DEA in n-hexane. Phase B: DCM / MeOH (50 / 50). A / B = 80 / 20 at 1.0 mL / min. Retention time: 9.137 min.

[0063] Step E; Preparation 2: Ethyl (5R)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (300 mg, 1.19 mmol) is diluted with 3N aqueous HCl (10 mL) and stirred at 65° C. for 24 hours. The mixture is diluted with water (50 mL) and extracted with EtOAc (30 mL×2). The organic layers are combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title product as a white solid (110 mg, 492 mmol, 62%). ES / MS (m / z): 223.8 (M+H).

[0064] Preparation 3 Ethyl (5S)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate [ka]

[0065] Step A: Diatomaceous earth (100 g) is stirred in DCM (1.25 L) and pyridinium chlorochromate (202 g, 918 mmol) is added at room temperature. To this orange suspension, (3S)-3,7-dimethyloct-6-en-1-ol (50 g, 304 mmol) is added dropwise over 15 minutes and stirring is continued for 36 hours. The reaction is filtered through Celite and the bed is washed with MTBE (1 L). The filtrate is washed with 1 N aqueous HCl (500 mL x 2) and saturated aqueous sodium bicarbonate (300 mL). The organics are then dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give (5S)-2-isopropenyl-5-methyl-cyclohexanone as a brown oil (43 g, 282 mmol, 84%). ES / MS (m / z): 152.9 (M+).

[0066] Step B: (5S)-2-Isopropenyl-5-methyl-cyclohexanone (43 g, 282 mmol) is dissolved in EtOH (300 mL). Sodium hydroxide (5.64 g, 141 mmol) is added and heated to 80° C. for 24 hours. The solvent is evaporated to give (5S)-2-isopropylidene-5-methyl-cyclohexanone as a brown oil (20 g, 131 mmol, 47%). ES / MS (m / z): 152.9 (M+).

[0067] Step C; Preparation 3: Starting from (5S)-2-isopropylidene-5-methyl-cyclohexanone, prepare ethyl (5S)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate in a manner essentially similar to that of Preparation 2, using appropriate reagents and adjusting the reaction time to determine completion. ES / MS (m / z): 252.1 (M+H). Chiral Method: Column: Chiral Pak IG (250 x 4.6 mm x 5 um). Mobile Phase A: 0.1% DEA in n-hexane, Mobile Phase B: DCM / MeOH (50 / 50). A / B = 80 / 20 at 1.0 mL / min. Retention Time: 9.942 min.

[0068] Preparation 4 (5R)-1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid. [ka]

[0069] Step A: Ethyl (5R)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (2.4 g, 9.6 mmol) (from Preparation 2, Step D) is dissolved in DCM (50 mL) and cooled to 0 °C under N. Triethylamine (4 mL, 28.7 mmol) is added, followed by trifluoromethylsulfonyl trifluoromethanesulfonate (2.4 mL, 14 mmol) and stirred for 2 h. After this time, the mixture is poured into ice water (20 mL) and extracted with DCM (200 mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give ethyl (5R)-1,5-dimethyl-2-oxo-4-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a dark brown syrup (3.6 g, 9.4 mmol, 98%). ES / MS (m / z): 384.0 (M+H).

[0070] Step B: Ethyl (5R)-1,5-dimethyl-2-oxo-4-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (3.5 g, 9.1 mmol) is dissolved in DMF (50 mL) under N2. Triethylsilane (1.2 g, 10 mmol), N,N-diethyleneamine (4 mL, 28 mmol), and dichloropalladium triphenylphosphine (640 mg, 0.91 mmol) are added, and the mixture is heated to 80 °C for 4 hours. The mixture is diluted with water (400 mL) and then extracted with EtOAc (200 mL x 2). The organic layers are combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles are evaporated under vacuum. The residue is purified via silica gel chromatography (120 g, 5% MeOH in DCM) to give ethyl (5R)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (800 mg, 3.4 mmol, 37%). ES / MS (m / z): 236.0 (M+H). Chiral method: Column: Chiral Pak IC (150 x 4.6 mm x 3 um), Mobile phase A: 0.1% DEA n n-hexane, Mobile phase B: DCM / MeOH (50 / 50). A / B = 70 / 30 at 0.7 mL / min. Retention time: 11.937 min.

[0071] Step C; Preparation 4: Ethyl (5R)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (100 mg, 0.425 mmol) is dissolved in THF (1 mL) and water (1 mL), lithium hydroxide (36 mg, 0.841 mmol) is added, and the mixture is stirred for 16 hours. The mixture is diluted with water (40 mL) and washed with DCM (20 mL x 2). The aqueous layer is acidified with 1N aqueous HCl (3 mL) and extracted with DCM (30 mL x 2). The organic layers are combined, dried over sodium sulfate, filtered, and evaporated under vacuum to give the title product as a brown solid (60 mg, 0.289 mmol, 68%). ES / MS (m / z): 207.9 (M+).

[0072] Alternatively, this product may be prepared by separating methyl 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (from Preparation 1) via chiral SFC chromatography (0.1% NHOH-IPA; column: DAICEL CHIRALPAK® AS (250 mm × 30 mm, 10 μm); starting B: 20%; final B: 20%; flow rate: 60 mL / min) and treating isomer 2 in a manner similar to Preparation 1, Step D, using appropriate reagents and adjusting the reaction time to determine reaction completion.

[0073] Alternative preparation 4 (5R)-1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid. [ka]

[0074] Step A: Ethyl (5R)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (2.4 g, 9.6 mmol) (from Preparation 2, Step D) is dissolved in DCM (50 mL) and cooled to 0 °C under N. Triethylamine (4 mL, 28.7 mmol) is added, followed by trifluoromethylsulfonyl trifluoromethanesulfonate (2.4 mL, 14 mmol) and stirred for 2 h. After this time, the mixture is poured into ice water (20 mL) and extracted with DCM (200 mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give ethyl (5R)-1,5-dimethyl-2-oxo-4-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a dark brown syrup (3.6 g, 9.4 mmol, 98%). ES / MS (m / z): 384.0 (M+H).

[0075] Step B: Ethyl (5R)-1,5-dimethyl-2-oxo-4-(trifluoromethylsulfonyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (3.5 g, 9.1 mmol) is dissolved in DMF (50 mL) under N2. Triethylsilane (1.2 g, 10 mmol), trimethylamine (4 mL, 28 mmol), and bis(triphenylphosphine)palladium(II) dichloride (640 mg, 0.91 mmol) are added, and the mixture is heated to 80 °C for 4 h. The mixture is diluted with water (400 mL) and then extracted with EtOAc (200 mL × 2). The organic layers are combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles are evaporated under vacuum. The residue is purified via silica gel chromatography (120 g, 5% MeOH in DCM) to give ethyl (5R)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (800 mg, 3.4 mmol, 37%). ES / MS (m / z): 236.0 (M+H). Chiral method: Column: Chiral Pak IC (150 x 4.6 mm x 3 um), Mobile phase A: 0.1% DEA n n-hexane, Mobile phase B: DCM / MeOH (50 / 50). A / B = 70 / 30 at 0.7 mL / min. Retention time: 11.937 min.

[0076] Step C; Preparation 4: Ethyl (5R)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (100 mg, 0.425 mmol) is dissolved in THF (1 mL) and water (1 mL), lithium hydroxide (36 mg, 0.841 mmol) is added, and the mixture is stirred for 16 hours. The mixture is diluted with water (40 mL) and washed with DCM (20 mL x 2). The aqueous layer is acidified with 1N aqueous HCl (3 mL) and extracted with DCM (30 mL x 2). The organic layers are combined, dried over sodium sulfate, filtered, and evaporated in vacuo to give the title product as a brown solid (60 mg, 0.289 mmol, 68%). ES / MS (m / z): 207.9 (M+H).

[0077] Alternatively, this product may be prepared by separating methyl 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (from Preparation 1) via chiral SFC chromatography (0.1% NHOH-IPA; column: DAICEL CHIRALPAK® AS (250 mm × 30 mm, 10 μm); starting B: 20%; final B: 20%; flow rate: 60 mL / min) and treating isomer 2 in a manner similar to Preparation 1, Step D, using appropriate reagents and adjusting the reaction time to determine reaction completion.

[0078] Preparation 5 (5S)-1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid [ka]

[0079] Starting from (5S)-4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid, this compound is prepared essentially similarly to the method of Preparation 4, using appropriate reagents and adjusting the reaction time to determine completion of the reaction. ES / MS (m / z): 207.8 (M+). 1 H NMR (400.13MHz, d6-DMSO): 1.23 (d, J = 6.9 Hz, 3H), 1.69-1.63 (m, 1H), 2.41-2.32 (m, 1H), 3.21-3.10 (m, 3H), 3.59 (s, 3H), 8.25 (s, 1H).

[0080] Alternatively, this product may be prepared by separating methyl 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (from Preparation 1) via chiral SFC chromatography (0.1% NHOH-IPA; Column: DAICEL CHIRALPAK® AS (250 mm x 30 mm, 10 um); Starting B: 20%; Final B: 20%; Flow rate: 60 mL / min), and treating Isomer 1 in a manner similar to Preparation 1, Step D, using appropriate reagents and adjusting the reaction time to determine reaction completion.

[0081] Preparation 6 4-Hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid and 4-hydroxy-1,6-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid [ka]

[0082] Step A: 3-Methylhexanedioic acid (5 g, 31.2 mmol) is dissolved in sulfuric acid (1.1 g, 11 mmol) and MeOH (62 mL). The mixture is stirred at 68 °C for 15 hours, concentrated in vacuo, diluted with EtOAc (200 mL), and washed with water (100 mL x 2). The organic layer is dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give dimethyl 3-methylhexanedioate as a pale yellow liquid (5.2 g, 28 mmol, 89%). 1 H NMR (400.14MHz, d6-DMSO): 3.34 (s, 6H), 3.24-3.12 (m, 3H), 2.40-2.33 (m, 2H), 1.69-1.65 (m, 2H), 1.23 (d, J = 6.8Hz, 3H).

[0083] Step B: Dimethyl 3-methylhexanedioate (36.94 g, 157 mmol) is dissolved in toluene (300 mL). Potassium t-butoxide (37.2 g, 315 mmol) is added and stirred at room temperature for 12 hours. The mixture is poured into EtOAc (500 mL) and 1N aqueous HCl (500 mL). The organic layer is separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue is purified via silica gel chromatography (0-80% EtOAc in petroleum ether) to give methyl 2-methyl-5-oxo-cyclopentanecarboxylate and methyl 4-methyl-2-oxo-cyclopentanecarboxylate as a mixture of regioisomers and stereoisomers as a red liquid (19.3 g, 47.6 mmol, 30%). ES / MS (m / z): 157.0 (M+H). 1 H NMR(400.13MHz,CDCl3):4.15-4.04(m,1H),3.68(t,J=5.4Hz,6H),3.29-3.24(m,1H),3.17(dd,J=8.1, 12.2Hz, 1H), 2.58-2.46 (m, 7H), 1.97 (s, 1H), 1.47-1.37 (m, 1H), 1.13-1.11 (m, 4H), 1.05-1.02 (m, 2H).

[0084] Step C: A mixture of methyl 2-methyl-5-oxo-cyclopentanecarboxylate and methyl 4-methyl-2-oxo-cyclopentanecarboxylate (13.9 g, 34.3 mmol) is dissolved in methylamine (2 M solution in THF, 147 mL, 294 mmol) containing 4A molecular sieves (5 g) and stirred at 40 °C for 48 h. The mixture is diluted with EtOAc (500 mL) and washed with water (300 mL × 2). The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography (120 g, 11% EtOAc in petroleum ether) to give methyl 4-methyl-2-(methylamino)cyclopentene-1-carboxylate and methyl 5-methyl-2-(methylamino)cyclopentene-1-carboxylate as a mixture of regioisomers and stereoisomers as a white solid (10.75 g, 24.8 mmol, 72%). ES / MS(m / z): 170.2(M+H). 1H NMR(400.14MHz,CDCl3):3.60(d,J=4.0Hz,6H),2.83(dd,J=2.8,5.3Hz,6H),2.79-2.73(m,1H),2.67-2.60(m,2H),2.58 -2.41(m,2H),2.11-2.03(m,3H),2.01-1.96(m,1H),1.43-1.41(m,1H),1.21-1.16(m,1H),1.00(dd,J=3.9,6.8Hz,6H).

[0085] Step D: A mixture of methyl 4-methyl-2-(methylamino)cyclopentene-1-carboxylate and methyl 5-methyl-2-(methylamino)cyclopentene-1-carboxylate (9 g, 20 mmol) is dissolved in toluene (150 mL). Sodium acetate (8.12 g, 98 mmol) and ethyl malonyl chloride (10.9 g, 70 mmol) are added. The mixture is heated to 80° C. under N for 2 hours, then cooled to room temperature, diluted with EtOAc (500 mL), and washed with water (400 mL×2). The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography (220 g, 30% EtOAc in petroleum ether) to give methyl 2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-3-methyl-cyclopentene-1-carboxylate and methyl 2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-4-methyl-cyclopentene-1-carboxylate as a mixture of regioisomers and stereoisomers as a white solid (14.2 g, 17.8 mmol, 86%). ES / MS (m / z): 283.9 (M+H). 1 H NMR(400.14MHz,CDCl3):4.16-4.04(m,4H),3.66(d,J=4.5Hz,6H),3.35-3.30(m,3H),2.83-2.67(m,4H) ,2.44-2.33(m,2H),2.27-2.16(m,4H),1.22-1.18(m,6H),1.10(d,J=6.8Hz,3H),1.04(d,J=6.8Hz,3H).

[0086] Step E: A mixture of methyl 2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-3-methyl-cyclopentene-1-carboxylate and methyl 2-[(3-ethoxy-3-oxo-propanoyl)-methyl-amino]-4-methyl-cyclopentene-1-carboxylate (13 g, 16.4 mmol) is dissolved in ethanol (100 mL). Sodium ethoxide (1.44 g, 21.2 mmol) is added and stirred at room temperature for 1 hour. The mixture is diluted with EtOAc (500 mL) and washed with water (300 mL x 2). The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography (220 g, 100% EtOAc in petroleum ether) to give ethyl 4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate and ethyl 4-hydroxy-1,6-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a mixture of regioisomers and stereoisomers as a yellow solid (8.7 g, 16 mmol, 100%). ES / MS (m / z): 251.9 (M+H). 1 H NMR(400.14MHz,CDCl3):13.36(d,J=16.3Hz,2H),4.35(q,J=7.1Hz,4H),4.15-4.02(m,1H), 3.33(d,J=3.1Hz,6H),3.03(dd,J=8.3,17.1Hz,1H),2.95-2.88(m,2H),2.76(ddd,J=17.5,9 .6,4.9Hz,1H),2.61-2.52(m,1H),2.46(dd,J=6.3,17.1Hz,1H),2.35-2.27(m,2H),1.63(dd d,J=17.8,8.9,4.4Hz,1H),1.37(t,J=7.1Hz,6H),1.21-1.17(m,2H),1.12(d,J=6.8Hz,4H).

[0087] Step F; Preparation 6: A mixture of ethyl 4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate and ethyl 4-hydroxy-1,6-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (1 g, 1.9 mmol) is dissolved in acetic acid (10 mL). Hydrobromic acid (33% by weight in acetic acid, 9 mL) is added, and the mixture is heated to 80 °C for 3 hours. The mixture is cooled to room temperature and concentrated to give the title product (850 mg, 1.85 mmol, 95%) as a mixture of regioisomers and stereoisomers. ES / MS (m / z): 224.0 (M+H). 1 H NMR(400.13MHz,CDCl3):15.48(d,J=12.9Hz,2H),13.55(d,J=29.3Hz,2H),3.53(d,J=3.1Hz,6H),3.47-3.43(m,1H),3.22-3.15(m,1H),3. 10-3.03(m,2H),2.97-2.89(m,1H),2.77-2.63(m,2H),2.51-2.42(m,2H),1.90-1.89(m,1H),1.31(d,J=6.9Hz,2H),1.24(d,J=6.8Hz,4H).

[0088] Preparation 7 4-Hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid [ka]

[0089] Step A: Methyl 2-methyl-5-oxo-cyclopentanecarboxylate (5 g, 32 mmol) is dissolved in THF (50 mL). Methylamine (2 M in THF, 96 mL, 192 mmol) is added and stirred at room temperature for 6 hours. Volatiles are removed under vacuum. The mixture is washed with water (100 mL), followed by brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give methyl 5-methyl-2-(methylamino)cyclopentene-1-carboxylate as a brown syrup (5.5 g, 28 mmol, 86%). ES / MS (m / z): 170.2 (M+H).

[0090] Step B: Methyl 5-methyl-2-(methylamino)cyclopentene-1-carboxylate (5.5 g, 33 mmol) is dissolved in toluene (55 mL) under N2. Sodium acetate (8 g, 97 mmol) is added and the mixture is cooled to 10 °C. Ethyl 3-chloro-3-oxo-propanoate (5.3 g, 39 mmol) is added dropwise and stirred for 2 h. The mixture is diluted with EtOAc (200 mL) and water (100 mL). The organic layer is separated and washed with brine (100 mL). The organics are dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give methyl 2-[(3-methoxy-3-oxo-propanoyl)-methyl-amino]-5-methyl-cyclopentene-1-carboxylate as a yellow oil (7.2 g, 27 mmol, 82%). ES / MS (m / z): 270.2 (M+H).

[0091] Step C: Methyl 2-[(3-methoxy-3-oxo-propanoyl)-methyl-amino]-5-methyl-cyclopentene-1-carboxylate (1 g, 2.97 mmol) is dissolved in MeOH (5 mL). Sodium methoxide (30% in MeOH, 3.6 mL) is added and stirred for 2 hours. The volatiles are removed in vacuo and the mixture is quenched with 1N aqueous HCl (20 mL). The mixture is extracted with DCM (100 mL x 2). The organics are combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give methyl 4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a brown solid (0.55 g, 2.3 mmol, 78%). ES / MS (m / z): 238.0 (M+H).

[0092] Step D; Preparation 7: Methyl 4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (3.6 g, 15 mmol) is dissolved in hydrobromic acid (5 mol / L in acetic acid, 20 mL) and stirred at 65° C. for 1 hour. The mixture is concentrated in vacuo to give the title product as a yellow solid (3 g, 11 mmol, 76%). ES / MS (m / z): 224.2 (M+H).

[0093] Preparation 8 4-Hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (isomer 1) and 4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (isomer 2) [ka]

[0094] The esters from Preparation 7 (Step C) can be separated into their enantiomers using chiral SFC chromatography (heptane-EtOH-0.1% NHOH, DAICEL CHIRALPAK® AY-H (250 m × 30 mm, 10 μm)). These esters are then treated in a manner similar to Preparation 7 (Step D) using appropriate reagents and adjusting the reaction time to determine completion to give the title acid products. ES / MS (m / z): 224.2 (M+H).

[0095] Preparation 9 4-Hydroxy-1,6,6-trimethyl-2-oxo-5,7-dihydrocyclopenta[b]pyridine-3-carboxylic acid [ka]

[0096] This acid is made using a method similar to Preparation 6, using appropriate reagents and adjusting the reaction time to determine completion of the reaction. ES / MS (m / z): 238.3 (M+H).

[0097] Preparation 10 2,2-dimethyl-5-oxo-cyclopentanecarboxylic acid methyl ester [ka]

[0098] Step A: Methyl 6-methyl-3-oxo-heptanoate (2 g, 10 mmol) and N-diazo-4-methyl-benzenesulfonamide (2.8 g, 11 mmol) are dissolved in ACN (20 mL) and cooled to 0 °C. Triethylamine (2.06 g, 20 mmol) is added and allowed to warm to room temperature overnight. The mixture is concentrated in vacuo and purified via silica gel chromatography (20 g, 100% petroleum ether) to give methyl 2-diazo-6-methyl-3-oxo-heptanoate as a yellow oil (1.2 g, 5.8 mmol, 57%) ES / MS (m / z): 199.2 (M+H). 1H NMR (400.14MHz, d6-DMSO): 3.77 (s, 3H), 2.80-2.76 (m, 2H), 1.64-1.57 (m, 1H), 1.45-1.40 (m, 2H), 0.87 (d, J = 6.6Hz, 6H).

[0099] Step B; Preparation 7: Dissolve rhodium acetate (85 mg, 0.19 mmol) in DCM (15 mL) and cool to 0 °C under N. Add methyl 2-diazo-6-methyl-3-oxo-heptanoate (1.2 g, 5.8 mmol) and allow to warm to room temperature over 4 h. Concentrate the mixture in vacuo and purify via silica gel chromatography (20 g, 0-5% EtOAc in petroleum ether) to afford methyl 2,2-dimethyl-5-oxo-cyclopentanecarboxylate as a brown oil (470 mg, 2.2 mmol, 38%). 1 H NMR (400.14MHz, d6-DMSO): 3.63 (s, 3H), 3.14 (s, 1H), 2.38-2.33 (m, 2H), 1.86-1.77 (m, 2H), 1.17 (s, 3H), 0.98 (s, 3H).

[0100] Preparation 11 4-Hydroxy-1,5,5-trimethyl-2-oxo-6,7-dihydrocyclopenta[b]pyridine-3-carboxylic acid [ka]

[0101] This acid is made using a method similar to Preparation 6, using appropriate reagents and adjusting the reaction time to determine completion of the reaction. ES / MS (m / z): 238.2 (M+H).

[0102] Preparation 12 1,6,6-trimethyl-2-oxo-7,8-dihydro-5H-quinoline-3-carboxylic acid [ka]

[0103] Step A: 4,4-Dimethylcyclohexanone (5 g, 39.6 mmol) is dissolved in methylamine (2 M in THF, 160 mL, 320 mmol). Sodium sulfate (11.5 g, 79 mmol) is added and stirred in a sealed tube for 18 h. The mixture is filtered and the solid is washed with DCM (10 mL). The filtrate is concentrated to give N,4,4-trimethylcyclohexaneimine (6.24 g, 44.8 mmol, 113%). ES / MS (m / z): 139.2 (M+H).

[0104] Step B: Dissolve N,4,4-trimethylcyclohexaneimine (220 mg, 1.58 mmol) in MeOH (5 mL). Add dimethyl methoxymethylenemalonate (370 mg, 2 mmol) and heat to 150 °C in a microwave for 3 h. Concentrate the mixture in vacuo and purify via silica gel chromatography (0 to 100% EtOAc in hexanes) to give methyl 1,6,6-trimethyl-2-oxo-7,8-dihydro-5H-quinoline-3-carboxylate (157 g, 0.63 mmol, 40%). ES / MS (m / z): 250.0 (M+H). 1 H NMR (399.80MHz, CDCl3): 0.99(s,6H),1.63(t,J=6.6Hz,2H),2.34(s,2H),2.68(t,J=6.6Hz,2H),3.55(s,3H),3.89(s,3H),7.88(s,1H).

[0105] Step C; Preparation 12: Methyl 1,6,6-trimethyl-2-oxo-7,8-dihydro-5H-quinoline-3-carboxylate (215.5 mg, 0.852 mmol) is dissolved in MeOH (10 mL). Sodium hydroxide (5 M in HO, 2 mL) is added and stirred at room temperature for 18 hours. The mixture is quenched with 5 M aqueous HCl (3 mL) and extracted with DCM (10 mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to give the title product (143.8 mg, 0.611 mmol, 72%). ES / MS (m / z): 235.0 (M+H).

[0106] Prepare the following compounds in Table 1 in a manner essentially similar to that used to prepare 1,6,6-trimethyl-2-oxo-7,8-dihydro-5H-quinoline-3-carboxylic acid (Preparation 12), using appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0107] [Table 1] a1 H NMR data: 1H NMR (400.16MHz, d6-DMSO): 2.08-2.01 (m, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 3.38 (s, 3H), 7.69 (s, 1H).

[0108] Preparation 17 Ethyl 4-hydroxy-1,6,6-trimethyl-2-oxo-7,8-dihydro-5H-quinoline-3-carboxylate [ka]

[0109] Step A: Dissolve 4,4-dimethylcyclohexanone (5 g, 39.6 mmol) in methylamine (2 M in THF, 160 mL, 320 mmol). Add sodium sulfate (11.5 g, 79 mmol) and stir in a sealed tube for 18 hours. Filter the mixture and wash the solid with DCM. Concentrate the filtrate to give N,4,4-trimethylcyclohexaneimine (6.24 g, 44.8 mmol, 113%). ES / MS (m / z): 139.2 (M+H).

[0110] Step B; Preparation 17: Dissolve N,4,4-trimethylcyclohexaneimine (801 mg, 5.75 mmol) in 1,2-dimethoxyethane (19 mL). Add triethyl methanetricarboxylate (2.5 mL, 11.6 mmol) and heat to 180 °C in a microwave for 3 hours. Quench the mixture with 1N aqueous HCl and extract the mixture with EtOAc. Combine the organics, wash with brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue via silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound (145 mg, 0.519 mmol, 9%). ES / MS (m / z): 280.1 (M+H).

[0111] Preparation 18 1,7,7-trimethyl-2-oxo-5,8-dihydropyrano[4,3-b]pyridine-3-carboxylic acid [ka]

[0112] Step A: Dissolve 2,2-dimethyltetrahydropyran-4-one (5 g, 39 mmol) in DMF-DMA (4.9 g, 39 mmol) and heat to 100 °C for 2 h. Dilute the mixture with EtOAc (50 mL) and wash with water (50 mL × 2). Dry the organics over anhydrous magnesium sulfate, filter, evaporate under vacuum, and purify via silica gel chromatography (40 g, 0 to 100% EtOAc in petroleum ether) to give (5Z)-5-(dimethylaminomethylene)-2,2-dimethyl-tetrahydropyran-4-one as a yellow solid (2.49 g, 13.6 mmol, 35%). 1 H NMR (400MHz, CDCl3) δ=7.58-7.44(m,1H),4.90-4.73(m,2H),3.08(s,6H),2.35(s,2H),1.30(s,6H).

[0113] Step B: (5Z)-5-(dimethylaminomethylene)-2,2-dimethyl-tetrahydropyran-4-one (2.49 g, 13.6 mmol) is dissolved in MeOH (50 mL). Piperidine (1.16 g, 13.6 mmol) and methyl cyanoacetate (2 g, 20.4 mmol) are added and heated to 100 °C via microwave for 1 h. The mixture is concentrated and purified via silica gel chromatography (20 g, 0-10% MeOH in EtOAc) to give methyl 7,7-dimethyl-2-oxo-5,8-dihydro-1H-pyrano[4,3-b]pyridine-3-carboxylate as a red solid (1.6 g, 6.54 mmol, 48%). 1 H NMR (400MHz, CDCl3) δ = 8.06-7.96 (m, 1H), 4.63 (s, 2H), 3.92 (s, 3H), 2.78 (s, 2H), 1.33 (s, 6H).

[0114] Step C: Dissolve methyl 7,7-dimethyl-2-oxo-5,8-dihydro-1H-pyrano[4,3-b]pyridine-3-carboxylate (1.61 g, 6.79 mmol) in acetone (20 mL). Add potassium carbonate (1.9 g, 14 mmol) and iodomethane (3 g, 21 mmol) and stir for 12 hours. Dilute the mixture with EtOAc (50 mL) and wash with water (30 mL x 2). Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify the residue via silica gel chromatography (20 g, 0-100% EtOAc in petroleum ether) to give methyl 1,7,7-trimethyl-2-oxo-5,8-dihydropyrano[4,3-b]pyridine-3-carboxylate as a red solid (985 mg, 3.9 mmol, 58%). ES / MS(m / z): 252(M+H). 1 H NMR (400MHz, CDCl3) δ = 7.88 (s, 1H), 4.58 (s, 2H), 3.91 (s, 3H), 3.52 (s, 3H), 2.59 (s, 2H), 1.34 (s, 6H).

[0115] Step D; Preparation 18: Methyl 1,7,7-trimethyl-2-oxo-5,8-dihydropyrano[4,3-b]pyridine-3-carboxylate (909 mg, 3.6 mmol) is dissolved in THF (3 mL) and water (3 mL). Lithium hydroxide (913 mg, 36 mmol) is added and stirred at 40 °C for 2 hours. The mixture is diluted with water (10 mL), acidified with 1 M aqueous HCl, and then extracted with EtOAc (10 mL x 3). The organics are combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title product as a yellow solid (680 mg, 2.86 mmol, 79%). ES / MS (m / z): 238 (M+H). 1 H NMR (400MHz, CDCl3) δ=14.57-14.25(m,1H),8.20-8.09(m,1H),4.63-4.52(m,2H),3.55(s,3H),2.64-2.50(m,2H),1.29(s,6H).

[0116] Prepare the following compounds in Table 2 in a manner essentially similar to that described for 1,7,7-trimethyl-2-oxo-5,8-dihydropyrano[4,3-b]pyridine-3-carboxylic acid (Preparation 18), using appropriate reagents and adjusting the reaction time to determine reaction completion.

[0117] [Table 2]

[0118] Preparation 22 5-Isopropyl-1-methyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid. [ka]

[0119] Step A: Cuprous iodide (13.9 g, 73 mmol) and tributylphosphine (38 mL, 140 mmol) are stirred in THF (150 mL) under N for 10 minutes. The mixture is cooled to -78 °C, and isopropyllithium (0.7 mol / L in pentane) (73 mL, 73 mmol) is added dropwise. After the addition is complete, the mixture is stirred at -78 °C under N for 30 minutes. After this time, boron trifluoride diethyl etherate (8.5 mL, 67 mmol) is added, stirred for 5 minutes, and cyclopent-2-en-1-one (5 g, 60.9 mmol) is added. The mixture is stirred at -55 °C under N for 40 minutes. DMF-DMA (20 mL, 150 mmol) is then added, and the mixture is warmed to 20 °C and cooled to 20 °C under N. 2 The mixture is stirred under reduced pressure for 16 hours. The yellow mixture is poured into brine (500 mL) and extracted with EtOAc (4 x 200 mL). The organic layers are recombined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The residue is purified via flash silica gel chromatography (330 g, 0-100% EtOAc in petroleum ether) to give (2Z)-2-(dimethylaminomethylene)-3-isopropyl-cyclopentanone as a yellow oil (1.8 g, 66 mmol, 11%). ES / MS (m / z): 182.1 (M+H).

[0120] Step B: (2Z)-2-(dimethylaminomethylene)-3-isopropyl-cyclopentanone (1.7 g, 6.2 mmol) is dissolved in MeOH (30 mL). To this mixture is added piperidine (0.53 g, 6.19 mmol), followed by methyl cyanoacetate (1.2 g, 12 mmol). The mixture is heated to 80 °C under N for 18 h. After this time, the volatile organics are evaporated under reduced pressure, and the residue is purified via silica gel chromatography (80 g, 0-100% EtOAc in petroleum ether) to give methyl 5-isopropyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate as a red solid (1.4 g, 5.1 mmol, 82%). ES / MS (m / z): 236.1 (M+H).

[0121] Step C: Methyl 5-isopropyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate (1 g, 3.66 mmol) is dissolved in acetone (15 mL). To this solution is added potassium carbonate (770 mg, 5.52 mmol), followed by iodomethane (0.92 mL, 15 mmol). The mixture is stirred at 25 °C for 15 h. After this time, the reaction is quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture is then extracted with EtOAc (2 × 20 mL). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The residue is purified via flash silica gel chromatography (12 g, 0-100% EtOAc in petroleum ether) to give methyl 5-isopropyl-1-methyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a red solid (0.9 g, 3.5 mmol, 97%). ES / MS (m / z): 250.1 (M+H).

[0122] Step D; Preparation 1: Methyl 5-isopropyl-1-methyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (0.7 g, 2.75 mmol) is dissolved in THF (6 mL), methanol (3.5 mL), and water (1.5 mL). To this solution, lithium hydroxide (0.48 g, 11.2 mmol) is added and stirred at 40 °C for 2 hours. After this time, the mixture is cooled to room temperature, diluted with water (10 mL), and then adjusted to pH 4 with 1 M aqueous HCl. The mixture is extracted with EtOAc (3 × 30 mL), and the organic layers are combined and dried over anhydrous sodium sulfate. The solvent is then filtered and evaporated to give the title product as a brown oil (4.1 g, 20 mmol, 98%). ES / MS (m / z): 236.1 (M+H).

[0123] Preparation 23 5-Ethyl-1-methyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid. [ka]

[0124] Step A: Cuprous iodide (14 g, 73.5 mmol) and tributylphosphine (38 mL, 140 mmol) are stirred in THF (150 mL) under N for 10 minutes. The mixture is cooled to -78 °C, and ethyllithium (1.6 mol / L in ether) (46 mL, 74 mmol) is added dropwise. After the addition is complete, the mixture is stirred at -78 °C under N for 30 minutes. After this time, boron trifluoride diethyl etherate (8.5 mL, 67 mmol) is added, stirred for 5 minutes, and cyclopent-2-en-1-one (5 g, 60.9 mmol) is added. The mixture is stirred at -55 °C under N for 40 minutes. DMF-DMA (20 mL, 150 mmol) is then added, and the mixture is warmed to 20 °C and stirred under N for 16 hours. The yellow mixture is poured into brine (500 mL) and extracted with EtOAc (4 x 200 mL). The organic layers are recombined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The residue is purified via flash silica gel chromatography (80 g, 0-100% EtOAc in petroleum ether) to give (2Z)-2-(dimethylaminomethylene)-3-ethyl-cyclopentanone as a yellow oil (1.5 g, 63 mmol, 10%). ES / MS (m / z): 168.2 (M+H).

[0125] Step B: (2Z)-2-(dimethylaminomethylene)-3-ethyl-cyclopentanone (1 g, 4.2 mmol) is dissolved in MeOH (15 mL). To this mixture is added piperidine (0.5 g, 6 mmol), followed by methyl cyanoacetate (0.84 g, 9.4 mmol). The mixture is heated to 80 °C under N for 18 h. After this time, the volatile organics are evaporated under reduced pressure, and the residue is purified via silica gel chromatography (12 g, 0-100% EtOAc in petroleum ether) to afford methyl 5-ethyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate as a yellow oil (1 g, 1.8 mmol, 43%). ES / MS (m / z): 222.2 (M+H).

[0126] Step C: 5-Ethyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylic acid (1 g, 1.8 mmol) is dissolved in acetone (10 mL). To this solution is added potassium carbonate (1 g, 7.2 mmol), followed by iodomethane (1.2 mL, 19 mmol). The mixture is stirred at 25 °C for 16 h. After this time, the reaction is quenched by adding a saturated aqueous solution of ammonium chloride (10 mL). The mixture is then extracted with EtOAc (2 × 20 mL). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The residue is purified via flash silica gel chromatography (12 g, 0-100% EtOAc in petroleum ether) to give methyl 5-ethyl-1-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate as a yellow oil (0.33 g, 1.1 mmol, 60%). ES / MS (m / z): 236.1 (M+H).

[0127] Step D; Preparation 1: 5-Ethyl-1-methyl-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (0.5 g, 1.4 mmol) is dissolved in THF (4 mL), methanol (2 mL), and water (1 mL). To this solution, lithium hydroxide (0.15 g, 6.2 mmol) is added and stirred at 25 °C for 18 hours. After this time, the mixture is diluted with water (50 mL) and then adjusted to pH 3 with 1 M aqueous HCl. The mixture is extracted with EtOAc (3 × 30 mL), and the organic layers are combined and dried over anhydrous sodium sulfate. The organic layers are then filtered, and the solvent is evaporated to give the title product as a yellow solid (0.36 g, 1.3 mmol, 94%). ES / MS (m / z): 222.0 (M+H).

[0128] Example 1 N-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide [ka]

[0129] 1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (300 mg, 1.45 mmol), 5-fluoropyrimidin-2-amine (245 mg, 2.17 mmol), and pyridine (345 mg, 4.34 mmol) were dissolved in DCM (6 mL). Phosphoryl chloride (271 mg, 1.73 mmol) was added and the mixture was stirred at 25 °C for 12 h. After this time, the volatiles were evaporated under reduced pressure, and the residue was purified via silica gel chromatography (20 g, 0-100% EtOAc in petroleum ether) to give the product as a white solid (368.3 mg, 1.21 mmol, 84%). ES / MS (m / z): 303.1 (M+H). 1 H NMR(400.14MHz,d6-DMSO):12.97(s,1H),8.79(s,2H),8.34(s,1H),3.57(s,3H) ,3.24-3.12(m,3H),2.40-2.33(m,1H),1.69-1.65(m,1H),1.23(d,J=6.8Hz,3H).

[0130] The following compounds in Table 3 are prepared in a manner essentially similar to that used to prepare N-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Example 1), using appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0131] [Table 3-1]

[0132] [Table 3-2]

[0133] Example 15 1,5-Dimethyl-2-oxo-N-thiazol-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide [ka]

[0134] 1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (500 mg, 2.4 mmol) and thiazol-2-amine (362 mg, 3.6 mmol) are dissolved in DCE (8 mL). 1-Propanephosphonic anhydride (1.7 mol / L in EtOAc) (3.07 g, 4.82 mmol) is added and the mixture is heated to 80 °C for 16 h. After this time, the volatiles are evaporated under reduced pressure and the residue is stirred in MeOH (5 mL) for 20 min. The solid formed is filtered to give the title product as an off-white solid (351.39 mg, 1.18 mmol, 49%). ES / MS (m / z): 290.3 (M+H). 1 H NMR(400.14MHz,d6-DMSO):13.49(s,1H),8.38(s,1H),7.52(d,J=4.8Hz,1H),7.28(d,J=4.8Hz,1 H),3.585(s,3H),3.30-2.93(m,3H),2.37-2.33(m,1H),1.69-1.61(m,1H),1.22(d,J=6.8Hz,3H).

[0135] The following compounds in Table 4 are prepared in a manner essentially similar to that used to prepare 1,5-dimethyl-2-oxo-N-thiazol-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Example 15), using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0136] [Table 4-1]

[0137] [Table 4-2]

[0138] [Table 4-3]

[0139] [Table 4-4]

[0140] [Table 4-5]

[0141] Examples 54 and 55 N-(5-fluorothiazol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 1) and N-(5-fluorothiazol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 2). [ka]

[0142] N-(5-fluorothiazol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (496 mg) was purified via chiral SFC chromatography (0.1% NH4OH-EtOH; column: DAICEL CHIRALCEL® OJ (250 mm × 30 mm, 10 um); starting B: 35%; final B: 35%; flow rate: 80 mL / min) to give Isomer 1 (200 mg) as the first eluate from the column. ES / MS (m / z): 308.3 (M+H). 1H NMR (400.13 MHz, d6-DMSO): 13.44 (s, 1H), 8.34 (s, 1H), 7.36 (d, J = 2.5 Hz, 1H), 3.58 (s, 3H), 3.25-3.19 (m, 3H), 2.41-2.32 (m, 1H), 1.69-1.63 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), followed by isomer 2 (188 mg). ES / MS (m / z): 308.3 (M+H). 1 H NMR(400.13MHz,d6-DMSO):13.44(s,1H),8.34(s,1H),7.36(d,J=2.5Hz,1H),3.58(s ,3H),3.25-3.19(m,3H),2.41-2.32(m,1H),1.69-1.63(m,1H),1.24(d,J=6.8Hz,3H).

[0143] The following compounds in Table 5 are prepared in a manner essentially similar to that used to prepare N-(5-fluorothiazol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer-1) and N-(5-fluorothiazol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer-2) (Examples 54 and 55), using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0144] [Table 5-1]

[0145] [Table 5-2]

[0146] [Table 5-3]

[0147] Example 72 (5S)-N-(1H-indol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide [ka]

[0148] (5S)-1,5-Dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (90 mg, 0.434 mmol), 2,3-dihydro-1H-indol-2-imine hydrochloride (120 mg, 0.676 mmol), and NMI (165 mg, 2 mmol) were dissolved in ACN (4 mL). TCFH (150 mg, 0.524 mmol) was added and the mixture was stirred at 20 °C for 16 h. After this time, the volatiles were evaporated under reduced pressure, and the residue was purified via silica gel chromatography (20 g, 0-100% EtOAc in petroleum ether) to give the title product as a white solid (368.3 mg, 1.21 mmol, 84%). ES / MS (m / z): 322.0 (M+H). 1 H NMR(400.14MHz,d6-DMSO):12.70(s,1H),11.40(s,1H),8.36(s,1H),7.41-7.39(m,1H),7.32(d,J=7.8Hz,1H),7.01-6.93(m,2H),6. 48(d,J=1.3Hz,1H),3.59(s,3H),3.26-3.25(m,1H),3.13-3.08(m,2H),2.44-2.42(m,1H),1.70-1.64(m,1H),1.25(d,J=6.9Hz,3H).

[0149] The following compounds in Table 6 are prepared in a manner essentially similar to that used to prepare (5S)—N-(1H-indol-2-yl)-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Example 72), using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0150] [Table 6]

[0151] Examples 77 and 78 1,6-Dimethyl-2-oxo-N-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Isomer 1) and 1,6-Dimethyl-2-oxo-N-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (Isomer 2). [ka]

[0152] Step A: 3-Methylcyclopentanone (4.4 mL, 38.9 mmol) is dissolved in a 2 M solution of methylamine in THF (100 mL). Sodium sulfate (16.8 g, 116 mmol) is added and stirred for 18 hours. The mixture is concentrated to a total volume of 5 mL to give the (Z)-N,3-dimethylcyclopentanimine residue. ES / MS (m / z): 111.1 (M+).

[0153] Step B: Dissolve the residue from Step A (4.3 g, 38.7 mmol) in MeOH (100 mL), add dimethyl methoxymethylenemalonate (13.8 g, 77.7 mmol), and heat to 140 °C via microwave for 3 h. The mixture is concentrated and purified via silica gel chromatography (0-10% MeOH in DCM) to give methyl 1,6-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate and methyl 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate as a mixture of regioisomers and stereoisomers (7.17 g, 32.4 mmol, 83%). ES / MS (m / z): 222.0 (M+). 1H NMR(399.80MHz,CDCl3):1.17(d,J=6.8Hz,3H),1.24-1.21(m,3H),2.42-2.34(m,2H),2.55(dd,J=6.5,17.3Hz,1H),2.70 -2.61(m,2H),2.99-2.87(m,3H),3.15-3.07(m,2H),3.49(d,J=5.3Hz,6H),3.86(d,J=3.9Hz,6H),8.03(d,J=2.3Hz,2H).

[0154] Step C: Dissolve the product from Step B (7.17 g, 32.4 mmol) in MeOH (150 mL), add 5 M aqueous sodium hydroxide, and stir for 18 hours. The reaction is quenched with 5 N aqueous HCl and extracted with a 3:1 mixture of DCM / isopropanol. The organic layers are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give 1,6-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid and 1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid as a mixture of regioisomers and stereoisomers (5.0 g, 24 mmol, 74%). ES / MS (m / z): 208.0 (M+).

[0155] Step D: The product from Step C (300 mg, 1.45 mmol) is dissolved in DMF (10 mL). Aniline (0.3 mL, 3.3 mmol), DIEA (800 μL, 4.59 mmol), and T3P (50% by weight in dimethylformamide, 1.8 mL, 3.0 mmol) are added and heated to 100° C. in a microwave reactor for 1 h. The mixture is poured into a saturated solution of sodium bicarbonate (50 mL) and extracted with EtOAc (50 mL×3). The organic layers are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, evaporated in vacuo, and then purified via silica gel chromatography (0-100% EtOAc in hexanes) to give 1,6-dimethyl-2-oxo-N-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide and 1,5-dimethyl-2-oxo-N-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide as a mixture of regioisomers and stereoisomers (94 mg, 0.33 mmol, 23%). ES / MS (m / z): 283.0 (M+). 1 H NMR(399.80MHz,CDCl3):1.21(d,J=6.8Hz,4H),1.29(d,J=6.8Hz,2H),2.52-2.43(m ,2H),2.60(dd,J=6.5,17.1Hz,1H),2.75-2.66(m,1H),3.01-2.90(m,1H),3.18-3.03 (m,1H),3.22(q,J=7.2Hz,2H),3.60(d,J=6.0Hz,6H),7.10(td,J=7.4,1.1Hz,2H),7 .38-7.33(m,4H),7.79-7.76(m,4H),8.50(d,J=10.3Hz,2H),12.17(d,J=4.9Hz,2H).

[0156] Step E: Examples 77 and 78: The product from Step D (342 mg) is purified via chiral column chromatography (Chiralpak AD-H, 4.6 × 150 nm, 40% EtOH / CO2, 5 mL / min, 225 nm) to give Isomer-1 as the first eluent (86.6 mg), ES / MS (m / z): 283.0 (M+). 1H NMR(399.80MHz,d6-DMSO):1.14(d,J=6.7Hz,3H),2.47-2.42(m,1H),2.74-2.60(m,2H),3.03(dd,J=8.1,15.0Hz,1H),3.31-3.23(m, Subsequently, isomer-2 (82 mg) is obtained. ES / MS(m / z):283.0(M+). 1 H NMR (399.80 MHz, d6-DMSO): 1.14 (d, J = 6.7 Hz, 3H), 2.47-2.42 (m, 1H), 2.74-2.60 (m, 2H), 3.03 (dd, J = 8.1, 15.0 Hz, 1H), 3.31-3.23 (m, 1H), 3.56 (s, 3H), 7.12-7.07 (m, 1H), 7.38-7.32 (m, 2H), 7.70 (dd, J = 1.0, 8.6 Hz, 2H), 8.34 (s, 1H), 12.32 (s, 1H). (The third elution is Example 37, and the fourth elution is Example 38.)

[0157] The following compounds in Table 7 are prepared in a manner essentially similar to that used to prepare 1,6-dimethyl-2-oxo-N-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer-1) and 1,6-dimethyl-2-oxo-N-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer-2) (Examples 77 and 78), using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0158] [Table 7]

[0159] Examples 83, 84, 85, and 86 4-hydroxy-1,6-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 1), 4-hydroxy-1,6-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 2), 4-hydroxy-1,5-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 1), and 4-hydroxy-1,5-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 2) [ka]

[0160] A mixture of 4-hydroxy-1,5-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid and 4-hydroxy-1,6-dimethyl-2-oxo-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (549 mg, 5.7 mmol) was dissolved in DCE (10 mL). T3P (1.7 mol / L in EtOAc) (4.89 g, 7.7 mmol) was added, and the mixture was heated to 80 °C for 2 h. After this time, the volatiles were evaporated under reduced pressure, and the residue was purified via silica gel chromatography (20 g, EtOAc in petroleum ether). The residue was further purified via a chiral column (DAICEL CHIRALCEL OD, 250 mm x 30 mm, 10 μm; mobile phase: 0.1% NH4OH-EtOH; B%: 40%-40%). The first product to elute from the column is 4-hydroxy-1,6-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 1) (150.66 mg, 0.5 mmol, 27%) as a white solid. ES / MS (m / z): 301.1 (M+H). 1H NMR(400.15MHz,d6-DMSO):15.15(s,1H),13.20(s,1H),8.73(d,J=4.9Hz,2H),7.28(t,J=4.9Hz,1H),3.43 (s,3H),3.31-3.29(m,1H),2.99-2.93(m,1H),2.71-2.63(m,2H),2.37-2.30(m,1H),1.14(d,J=6.8Hz,3H). Next eluted was 4-hydroxy-1,6-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 2) (217 mg, 0.72 mmol, 39%) as a white solid. ES / MS (m / z): 301.3 (M+H). 1 H NMR(400.15MHz,d6-DMSO):15.15(s,1H),13.20(s,1H),8.73(d,J=4.9Hz,2H),7.28(t,J=4.9Hz,1H),3.43 (s,3H),3.31-3.29(m,1H),2.99-2.93(m,1H),2.71-2.63(m,2H),2.37-2.30(m,1H),1.14(d,J=6.8Hz,3H). The third product eluting from the column is 4-hydroxy-1,5-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 1) (78.5 mg, 0.26 mmol, 14%) as a white solid. ES / MS (m / z): 301.3 (M+H). 1H NMR(400.15MHz,d6-DMSO):15.33-15.30(m,1H),13.22(s,1H),8.73(d,J=4.8Hz,2H),7.28(t,J=4.9Hz,1H),3.44(s,3H) ),3.31-3.26(m,1H),3.19-3.16(m,1H),3.03-2.99(m,1H),2.35-2.30(m,1H),1.69-1.61(m,1H),1.22(d,J=6.9Hz,3H). The final product is 4-hydroxy-1,5-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (isomer 2) (77 mg, 0.25 mmol, 14%) as a white solid. ES / MS (m / z): 301.1 (M+H). 1 H NMR(400.15MHz,d6-DMSO):15.33-15.30(m,1H),13.22(s,1H),8.73(d,J=4.8Hz,2H),7.28(t,J=4.9Hz,1H),3.44(s,3H) ),3.31-3.26(m,1H),3.19-3.16(m,1H),3.03-2.99(m,1H),2.35-2.30(m,1H),1.69-1.61(m,1H),1.22(d,J=6.9Hz,3H).

[0161] The following compounds in Table 8 are prepared in a manner essentially similar to that used to prepare 4-hydroxy-1,6-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide and isomers, and 4-hydroxy-1,5-dimethyl-2-oxo-N-pyrimidin-2-yl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide isomers (Examples 86, 87, 88, and 89), using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0162] [Table 8-1]

[0163] [Table 8-2]

[0164] [Table 8-3]

[0165] Example 103 1-Methyl-2-oxo-N-pyrimidin-2-yl-5,6,7,8-tetrahydroquinoline-3-carboxamide [ka]

[0166] 1-Methyl-2-oxo-1,2,5,6,7,8-hexahydro-3-quinolinecarboxylic acid (250 mg, 1.14 mmol) was dissolved in DMF (2.2 mL). 2-Aminopyrimidine (100 mg, 1.02 mmol), DIPEA (463 μL, 2.6 mmol), and HATU (499 mg, 1.31 mmol) were added and stirred at room temperature for 15 hours. The mixture was purified via reverse-phase HPLC to give the product (33 mg, 0.16 mmol, 11%). ES / MS (m / z): 285.0 (M+H). 1 H NMR(400.13MHz,d6-DMSO):1.71-1.65(m,2H),1.84-1.78(m,2H),2.68-2.63(m,2H),2.82(t,J=6 .3Hz,2H),3.58(s,3H),7.22(t,J=4.8Hz,1H),8.20(s,1H),8.70(d,J=4.8Hz,2H),12.88(s,1H).

[0167] The following compounds in Table 9 are prepared in a manner essentially similar to that used to prepare 1-methyl-2-oxo-N-pyrimidin-2-yl-5,6,7,8-tetrahydroquinoline-3-carboxamide (Example 103), using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

[0168] [Table 9]

[0169] Example 110 4-Hydroxy-1,6,6-trimethyl-2-oxo-N-phenyl-7,8-dihydro-5H-quinoline-3-carboxamide [ka]

[0170] Ethyl 4-hydroxy-1,3,6,6-tetramethyl-2-oxo-7,8-dihydro-5H-quinoline-3-carboxylate (181 mg, 0.62 mmol) is dissolved in toluene (3.5 mL). Aniline (0.1 mL, 1 mmol) is heated to 200 °C via microwave for 1 h, concentrated in vacuo, and purified via silica gel chromatography (0-50% EtOAc in hexanes) to give the title product (58.2 mg, 0.178 mmol, 29%). ES / MS (m / z): 327.2 (M+H). 1 H NMR(399.80MHz,CDCl3):1.03(s,6H),1.65(t,J=6.6Hz,2H),2.37(s,2H),2.68(t,J=6.6Hz ,2H),3.54(s,3H),7.17-7.13(m,1H),7.39-7.35(m,3H),7.70-7.68(m,2H),12.60(s,1H).

[0171] Example 111 4-Hydroxy-N-isopentyl-1-methyl-2-oxo-5,6,7,8-tetrahydroquinoline-3-carboxamide [ka]

[0172] 4-Hydroxy-N-isopentyl-2-oxo-5,6,7,8-tetrahydro-1H-quinoline-3-carboxamide (45.8 mg, 0.165 mmol) is dissolved in DMF (1 mL) and MeOH (1 mL). Potassium carbonate (50 mg, 0.36 mmol) and iodomethane (23 μL, 0.34 mmol) are added and stirred for 24 hours. The resulting mixture is purified via reverse-phase HPLC to give the title product (37.3 mg, 0.128 mmol, 78%). ES / MS (m / z): 293.2 (M+H). 1 H NMR(400.13MHz,d6-DMSO):0.91(d,J=6.6Hz,6H),1.42(q,J=7.1Hz,2H),1.6 6-1.58(m,3H),1.79-1.73(m,2H),2.39(t,J=6.1Hz,2H),2.72-2.67(m,2H). 1 H NMR(400.13MHz,d6-DMSO):0.91(d,J=6.6Hz,6H),1.42(q,J=7.1Hz,2H),1.66-1.58(m,3H),1.79-1.73(m,2H),2.39( t,J=6.1Hz,2H),2.72-2.67(m,2H),3.17(d,J=5.3Hz,1H),3.30(d,J=5.3Hz,1H),3.40(s,3H),10.39(t,J=5.5Hz,1H).

[0173] hAHR nuclear translocation assay Stable cell lines were established using the Jump-In™ T-REx™ HEK293 Retargeting Kit (Life Technologies). The hAhR cDNA was cloned into the pJTI R4 CMV-TO EGFP vector. EGFP was cloned at the C-terminus of the AhR to form an AhR-EGFP chimera. The pJTI R4 CMV-TO AhR-EGFP vector was transfected into Jump-In™ T-REx™ HEK293 cells using FuGENE® HD. Transfected cells were selected using 2.5 mg / ml G418 for 10-14 days, then expanded, harvested, and transfected to 2 x 10 7Cells were suspended in freezing medium (8% DMSO with FBS) at 1000 cells / mL and aliquots were stored in liquid nitrogen. One day before the assay, cells were thawed and resuspended in DMEM with 5% FBS in the presence of 1 μg / mL doxycycline. Cells were seeded at 12,000–15,000 cells / well onto ploy-L-lysine-coated CELLCARRIER-384 ULTRA Microplates (Perkin Elmer) at 12,000–15,000 cells / well and incubated overnight at 37°C and 5% CO2. On the day of the assay, compounds were serially diluted (1:2) with DMSO into 384-well nunc plates using acoustic dispensing (ECHO). The dose response was a 20-point curve. Compounds were resuspended in 40 μL of DMEM + 0.1% BSA. The culture medium was moistened, 25 μL of DMEM + 0.1% BSA was added, and then 25 μL of compound in DMEM + 0.1% BSA was added to the cell plate. Cells were incubated with compounds for 45 minutes at 37°C and 5% CO2. The final DMSO concentration was 0.2%. After 45 minutes of incubation, the medium was quenched. Cells were fixed with 40 μL of cold MeOH (-20°C) for 20 minutes. After wetting the MeOH, 50 μL of DPBS containing 1 μg / mL Hochst was added to the cell plate. EGFP intensity was quantified using an OPERA PHENIX® or Operetta® high-content imaging system (Perkin Elmer) with a 20× water objective and five fields per well. To determine AhR agonist potency, the ratio of nuclear to cytoplasmic EGFP fluorescence intensity was analyzed using a four-parameter nonlinear logistic equation.

[0174] Table 10 shows the hAHR nuclear translocation assay EC values ​​of exemplary compounds. 50 Indicates the value.

[0175] [Table 10]

[0176] The results of this assay indicate that the exemplary compounds are AhR agonists.

Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, R １ But phenyl, C １ -C ６ Alkyl, C ３ -C ６ cycloalkyl, optionally 1 to 2 R ｉ and optionally, one to two R ｉ 8-10 membered bicyclic heteroaryl substituted with R ２ is selected from H and OH; X is a bond, -C(R ３ ) ２ -, and -C(R ３ ) ２ C (R ３ ) ２ - is selected from, Y is -C(R ３ ) ２ -, -O, and -N(R ｊ ) - is selected from R ３ independently H and C １ -C ３ alkyl, R ｉ But halogen, CH ３ , OCH ３ , and CF ３ is selected from R ｊ But C １ -C ３ a compound, or a pharmaceutically acceptable salt thereof.

2. R １ is phenyl, and optionally, one to two R ｉ 2. The compound of claim 1, wherein the aryl is selected from the group consisting of 5- to 6-membered heteroaryl substituted with:

3. Y is -C(R ３ ) ２ 3. The compound according to claim 1 or 2, wherein R is -, or a pharmaceutically acceptable salt thereof.

4. R ３ However, independently, H, CH ３ , C.H. ２ CH ３ , and CH(CH ３ ) ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from:

5. 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is a bond. 【Request Item 6】 【Chemistry 2】 The compound according to any one of claims 1 to 4, selected from or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Chemistry 3】 The compound according to any one of claims 1 to 6, selected from or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 4】 The compound according to any one of claims 1 to 7, selected from or a pharmaceutically acceptable salt thereof. 【Request Item 9】 【Chemistry 5】 The compound according to any one of claims 1 to 7, selected from or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1 to 9, which is a free base.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

12. 12. A method of treating an immune-mediated disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 10, or a pharmaceutical composition of claim 11.

13. 12. A method of treating a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 10, or a pharmaceutical composition of claim 11.

14. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.

15. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis.

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