Substituted pyrrolidine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to a substituted pyrrolidine compound as well as a preparation method, a pharmaceutical composition and application thereof, in particular to a type II orexin receptor agonist compound, and the structure of the compound is shown as a formula (I). The compound provided by the invention can be used for treating, preventing and relieving diseases related to OX2R agonist activity.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry and chemotherapy, and in particular, the present application relates to a class of substituted pyrrolidine compounds, processes for their preparation, pharmaceutical compositions and uses thereof. BACKGROUND

[0002] Orexins are neuropeptides that are specifically produced in certain neurons sparsely located in the lateral hypothalamus and its surrounding regions, and include two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands for orexin receptors, which are G protein-coupled receptors mainly present in the brain, and two subtypes of the orexin receptors, type 1 and type 2, are known.

[0003] Since orexin-producing neurons (orexin neurons) are located near the center of feeding, and intracerebroventricular administration of orexin results in an increase in food intake, orexin was initially focused on as a neuropeptide having a modulation of feeding behavior. However, it was later reported that a genetic mutation of the type 2 orexin receptor is the cause of narcolepsy in dogs, and the role of orexin in controlling sleep and wakefulness has also been focused on.

[0004] From studies using transgenic mice having degenerated orexin neurons and double transgenic mice obtained by crossing the transgenic mice with transgenic mice overexpressing orexin, it was clearly found that the narcolepsy-like symptoms caused by degeneration of orexin neurons disappeared due to the sustained expression of orexin. Similarly, when orexin was intracerebroventricularly administered to transgenic mice having degenerated orexin neurons, an improvement in narcolepsy-like symptoms was also observed. Studies on type 2 orexin receptor gene knockout mice suggested that the type 2 orexin receptor is important in maintaining wakefulness. Such a background suggests that a type 2 orexin receptor agonist becomes a therapeutic drug for narcolepsy or a therapeutic drug for other sleep disorders exhibiting excessive sleepiness. In addition, a peptide agonist selectively acting on the type 2 orexin receptor can also be used for other indications, such as improving obesity in mice caused by a high-fat diet load, shortening the general anesthesia time in rats, improving sleep apnea syndrome, improving cognitive dysfunction, improving heart failure, improving daytime sleepiness in Parkinson's disease patients, regulating bone formation and bone loss, and thus treating related diseases such as osteoporosis, rheumatoid arthritis.

[0005] Therefore, compounds with type 2 orexin receptor agonist activity are expected to be used as novel therapeutics and anesthetic antagonists for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbances of consciousness such as coma, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, etc., as well as drugs for the prevention or treatment of side effects.

[0006] In summary, there is an urgent need in this field to develop novel type 2 orexin receptor agonists. Summary of the Invention

[0007] This invention provides a novel class of substituted pyrrolidine compounds, their preparation methods, pharmaceutical compositions, and uses. The compounds of this invention possess type 2 orexin receptor agonist activity and can be used as agents for the prevention or treatment of narcolepsy, sleep apnea, hypersomnia, cognitive impairment, etc., helping to improve sleep problems and enhance sleep quality.

[0008] In a first aspect, the present invention provides a compound of formula (I), or an enantiomer, a non-enantiomer, a racemic mixture thereof, or a mixture thereof, a pharmaceutically acceptable salt, crystalline hydrate, or a solvate thereof.

[0009]

[0010] in,

[0011] X is CH;

[0012] Ring A is a 5-12 member saturated heterocycle containing nitrogen, wherein the saturated heterocycle is selected from the group consisting of: bicyclic fused rings, bridged rings, and spirocycles; and ring A is optionally surrounded by one or more R... a Substituent substitution; R a Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl groups, -SO2R9, -OSO2R9, -OCOR9;

[0013] Ring B is selected from the following group: C 6-10 Aromatic rings, 5-10 quintone aromatic rings, C 3-8 The B ring is a saturated carbon ring or a 9-15 fused tricyclic ring, wherein the tricyclic ring is a carbon ring or a heterocyclic ring; and the B ring is optionally surrounded by one or more R rings. b Substituent substitution; R b Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6Alkyl groups, -SO2R9, -OSO2R9, -OCOR9;

[0014] L represents CHR5 or (CH2). m NHC(O)(CHR5) n m and n are each independently 0, 1, 2, 3 or 4;

[0015] R1 is selected from the following group: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-7 heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 5-7 membered heterocycles; and R1 is optionally further divided by one or more R c Substituent substitution; R c Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl groups, -SO2R9, -OSO2R9, -OCOR9;

[0016] The prerequisite is that, when L is the aforementioned CHR5, R1 is not hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy;

[0017] R2 is -C(O)R4, -SO2R 4、 -PO(R4)2、

[0018] The R4 mentioned is selected from the group consisting of: hydroxyl, C 0-6 Alkylamine, C 1-6 Alkyl, C 6-10 Aryl, 5-7 quinone heteroaryl, C 3-12 Cycloalkyl, 5-7 membered heterocycles, C 1-6 Alkylphenyl, -COOC 1-6 Alkyl, C 1-6 alkyl 5-7-membered heteroaryl; and the R4 is optionally surrounded by one or more R d Substituent substitution; R d Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted amino, -SO2R9, -OSO2R9, -NHCOR 9、 -OCOR9;

[0019] R5 is selected from the following group: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C. 1-6 alkyl;

[0020] Or the R mentioned above a R5 and the atoms that separate them together form a substituted or unsubstituted 5-7 member carbon ring or heterocycle, wherein the carbon ring or heterocycle is a fully saturated ring, a partially unsaturated ring, or an aromatic ring.

[0021] Or the R mentioned above b R5 and the atoms that separate them together form a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle, or an aromatic heterocycle.

[0022] Or, R2 and R5 and the atoms between them together constitute a substituted or unsubstituted 5-7 member carbon ring or heterocycle, wherein the carbon ring or heterocycle is a fully saturated ring, a partially unsaturated ring, or an aromatic ring.

[0023] Q is selected from O and NH;

[0024] R3 is selected from the following group: hydrogen, deuterium, tritium, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 0-6 Alkylamine, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-7 heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 5-7 membered heterocycles, substituted or unsubstituted C 1-6 Alkylphenyl, substituted or unsubstituted C 1-6 Alkyl 5-7-membered heteroaryl, substituted or unsubstituted C 1-6 Alkylene-CN;

[0025] R9 is selected from the following group: hydrogen, deuterium, tritium, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-7 heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 5-7 membered heterocycles, substituted or unsubstituted C 1-6 Alkylphenyl, substituted or unsubstituted C 1-6 Alkyl 5-7-membered heteroaryl groups;

[0026] Wherein, the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, unsubstituted, or halogen or C. 3-6 Cycloalkyl-substituted C 1-6 (preferably C) 1-4 )alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4Straight-chain or branched alkyl-substituted amino, hydroxyl, cyano, nitro, oxygen atom (=O), hydroxyl-C 1-6 Alkyl, carboxyl, mercapto, unsubstituted or substituted with 1-3 halogens or hydroxyl groups 6-10 Aryl, unsubstituted or halogenated 5-7 membered heterocycles, unsubstituted or halogenated C 2-6 Acyl group, C 1-6 Hydroxyalkyl, -NR9R 10 -NCOR9R 10 , -SO2R9, -OSO2R9, -SO2NR9R 10 -COOR9 or -OCOR9;

[0027] The R mentioned 10 Selected from the following group: hydrogen, deuterium, tritium, C 1-6 alkyl;

[0028] Unless otherwise specified, the heterocycle or heteroaromatic ring comprises 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of N, S or O.

[0029] In another preferred embodiment, R9 is selected from the group consisting of: hydrogen, deuterium, tritium, and C. 1-6 Alkyl, C 6-10 Aryl.

[0030] In another preferred embodiment, Q is 0.

[0031] In another preferred embodiment, R2 is -C(O)R4.

[0032] In another preferred embodiment, the compound has the structure shown in the following formula:

[0033]

[0034] In another preferred embodiment, the compound has the structure shown by the following general formulas I-1, I-2, I-3 or I-4:

[0035]

[0037] In another preferred embodiment, R1 is selected from the group consisting of substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted 5-7 membered heteroaryl; and said R1 is optionally further divided by one or more R c Substituent substitution; R c Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl.

[0038] In another preferred embodiment, the B ring is selected from the group consisting of substituted or unsubstituted C rings.6-10 Aryl, substituted or unsubstituted 5-7 membered heteroaryl; and the B ring is optionally further separated by one or more R b Substituent substitution; R b Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl.

[0039] In another preferred embodiment, L is CHR5, and R5 is hydrogen;

[0040] Or the R mentioned above a R5 and the atoms that separate them together form substituted or unsubstituted 5-7 membered carbon rings or heterocycles;

[0041] Or the R mentioned above b R5 and the atoms that separate them together form substituted or unsubstituted 5-7 membered heterocycles;

[0042] Or, R2 and R5, together with the atoms that separate them, together constitute a substituted or unsubstituted 5-7 member carbon ring or heterocycle.

[0043] In another preferred embodiment, R9 is selected from the group consisting of: hydrogen, deuterium, tritium, and C. 1-6 Alkyl, C 6-10 Aryl.

[0044] In another preferred embodiment, the A ring is selected from the group consisting of:

[0045]

[0046] In another preferred embodiment, the compound is selected from the group consisting of:

[0047] Table 1 Examples of Preferred Compounds

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] A second aspect of the invention provides a pharmaceutical composition comprising: (A) a therapeutically effective amount of the compound as described in the first aspect of the invention, its enantiomers, diastereomers, racemates and mixtures thereof, and one or more of its pharmaceutically acceptable salts, hydrates and solvates; and (B) a pharmaceutically acceptable carrier.

[0078] A third aspect of the present invention provides a method for preparing a compound of formula (I) as described in the first aspect of the present invention, comprising the steps of:

[0079]

[0080] (1) Compound 1 and compound 2 were reacted via a nucleophilic substitution reaction to obtain compound 3;

[0081] (2) Compound 3 was converted to compound 4 by a reductive amination reaction;

[0082] (3) Compound 4 and compound 5 are reacted via sulfonation to obtain compound I;

[0083] LG is selected from halogens, and the definitions of the other groups are as described in the first aspect of the present invention.

[0084] The fourth aspect of the invention provides the use of the compounds, their enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, as described in the first aspect of the invention, for the preparation of pharmaceutical compositions for the prevention or treatment of indications related to type 2 orexin receptor (OX2R) agonism.

[0085] In another preferred embodiment, the indication is narcolepsy.

[0086] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0087] Figure 1 The results of sleep stages in mice after administration of compound A065.

[0088] Figure 2 This describes the wakefulness-inducing effect of compound A065 in mice. Detailed Implementation

[0089] Through long-term and in-depth research, the inventors unexpectedly discovered that compounds represented by general formula I can be used as highly effective OX2R agonists, exhibiting significant wakefulness-promoting effects in animal experiments, and therefore can be used for the prevention and treatment of narcolepsy. Based on the above discovery, the inventors completed this invention.

[0090] the term

[0091] In this document, unless otherwise specified, the term "substitution" refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, C1-C 12 Alkyl or cycloalkyl, C1-C 12 Alkoxy group, oxygen atom (i.e., =O), unsubstituted or C-substituted 1-4 Alkylamine-substituted C1-C12 Alkylamine, C2-C6 ester, C2-C6 acyl, C2-C6 amide, thioC1-C 12 Alkyl, carboxyl, C5-C 12 Aryl or heteroaryl, C5-C 12 Heterocyclic group (containing 1-5, preferably 1-3, heteroatoms selected from N, O or S).

[0092] The term "C1-C" 12 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0093] The term "C1-C" 12 "Cycloalkyl" refers to a compound having 1-12 alkyl groups, preferably 3-12 (i.e., C12-12 alkyl groups). 3-12 ) A cycloalkyl group with a carbon atom, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups.

[0094] The term "C1-C" 12 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 12 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups.

[0095] The term "halogen" refers to F, Cl, Br, and I.

[0096] The term "C1-C" 12 "Alkylamine group (or alkylamine group)" refers to a C1-C group that has been substituted with an amino group. 12 Alkyl groups, for example, those having "C1-C 12 Alkyl-NH- or (alkyl)2-N- (total number of carbon atoms is 1-12) or -C1-C 12 Groups with the structures "alkylene-NH2", "alkyl-N-alkylene-(total number of carbon atoms 1-12)", or "(alkyl)2-N-alkylene-(total number of carbon atoms 1-12)", such as CH3NH-, C2H5NH-, C3H7NH-, (CH3)2N-, -CH2NH2, -C2H5NH2, -C3H7NH2, -C2H4N(CH3)2, or similar groups. Where C... 1-12 The definition of alkyl groups is as described above.

[0097] The term "C2-C6 ester group" refers to a substituent with a structure of "straight-chain or branched alkyl / cycloalkyl / aryl / heteroaryl-carbonyl-oxy-" having 1-5 carbon atoms, such as ethyl ester, propyl ester, butyl ester, or similar groups.

[0098] The term "C1-C6 amide group" refers to a substituent with a structure of "a straight-chain or branched alkyl / cycloalkyl / aryl / heteroaryl-carbonyl-amine-" having 0-5 carbon atoms, such as acetamido, propionamido, butyramido, or similar groups.

[0099] The term "C6-C" 10 "Aryl" refers to a group having 1-12 (preferably 6-10, i.e., C) groups. 6-10 The aryl group of the carbon atom, such as phenyl, naphthyl, etc., may be substituted or unsubstituted.

[0100] The term "C1-C" 12 "Heteroaryl" refers to a heteroaryl group having 1-12 carbon atoms and one or more (preferably 1-3) heteroatoms selected from O, S and / or N, preferably C5-C8 heteroaryl. The heteroaryl group may be substituted or unsubstituted.

[0101] The term "5-7 membered heterocycle" refers to a cyclic saturated, partially unsaturated or aromatic group having 5-7 members, wherein the heterocycle has at least one ring atom selected from the group consisting of O, S and / or N.

[0102] The term "5-7 membered heteroaryl" refers to a cyclic aromatic group having 5-7 members, wherein the heterocycle has at least one ring atom selected from the group consisting of O, S and / or N.

[0103] Specifically, expressions in the form "C1-Cn" indicate that the group has 1 to n carbon atoms. For example, expressions in the form "C1-C12" indicate that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; "C6~C10" indicates that the group has 6, 7, 8, 9 or 10 carbon atoms.

[0104] In this invention, the term "pharmaceuticalally acceptable" refers to a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a substance with a reasonable benefit / risk ratio.

[0105] In this invention, the term "effective amount" refers to the amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or the amount that exhibits a detectable therapeutic or preventative effect. The precise effective amount for a given subject depends on that subject's body size and health status, the nature and severity of the condition, and the choice of the therapeutic agent and / or combination of therapeutic agents administered. Therefore, it is useless to pre-specify an accurate effective amount. However, for a given condition, the effective amount can be determined using routine experiments, and a clinician can judge it accordingly.

[0106] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0107] As used herein, the term "compound of the invention" refers to a compound of Formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of Formula I.

[0108] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0109] Compound of formula (I)

[0110] This invention provides a compound represented by formula (I):

[0111]

[0112] In another preferred embodiment, ring A, ring B, X, L, R1, R2, R3, R4, R5, R a R b R c R d R9 and n are each independently the groups shown in the specific embodiments.

[0113] And the chiral carbon atom in the compound of general formula (I) has an R-type or S-type configuration.

[0114] More preferably, the compounds of the present invention are selected from the compounds in Table 1.

[0115] Preparation of compound (I)

[0116] This invention provides a method for preparing compounds of the following formulas Aa, Bb and Cc. The preparation method is carried out according to the following scheme. Unless otherwise specified, the following raw materials and reagents can be purchased commercially.

[0117] plan:

[0118]

[0119] Compounds of general formula (I) can be conveniently prepared by the method shown in the scheme, through nucleophilic substitution, reductive amination and sulfonamide reactions to obtain compounds of formula (I).

[0120] Pharmaceutical Compositions and Administration

[0121] Because the compounds of this invention possess excellent OX2R agonist activity, the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat, prevent, and alleviate diseases related to OX2R agonist activity. According to the prior art, the compounds of this invention can be used to prepare novel therapeutic agents and anesthetic antagonists for the prevention and treatment of narcolepsy, idiopathic hypersomnia, excessive sleep, sleep apnea syndrome, disturbances of consciousness such as coma, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Klein-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, etc., or for the prevention or treatment of side effects.

[0122] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0123] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0124] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0125] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0126] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0127] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0128] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0129] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0130] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0131] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0132] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0133] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0134] Compared with the prior art, the main advantages of the present invention include:

[0135] (1) A novel class of OX2R agonist compounds is provided, the preparation method of which has the advantages of mild reaction conditions, abundant and readily available raw materials, simple operation and post-processing, and good selectivity. The compounds described have excellent OX2R agonist activity.

[0136] (2) The OX2R agonist compounds and derivatives of the present invention have good pharmacokinetic properties in animals.

[0137] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0138] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0139] Example 1A001 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide

[0140]

[0141] Synthesis route:

[0142]

[0143] Step 1: 1-(2-(benzyloxy)-2-methylpropionyl)indol-3-one (1c)

[0144] At room temperature, triethylamine (22.8 g, 225.3 mmol) was added to a tetrahydrofuran (100 mL) solution of compound 1a (10 g, 75.1 mmol), and the mixture was stirred at room temperature for 1 hour. Then, a tetrahydrofuran (30 mL) solution of 1b (19.17 g, 90.1 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction was quenched with water (200 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed successively with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 1c (12.3 g, yield: 53%). 1 H NMR (500MHz, CDCl3) δ7.99 (dd, J=8.2, 1.5Hz, 1H), 7.62 (td, J=7.8, 1.6Hz, 1H), 7.41 (dd, J=7.5, 1.4 Hz,1H),7.37–7.27(m,6H),4.91(s,2H),4.64–4.60(m,2H),1.45(s,6H).LC-MS(ESI,m / z):310[M+H] + .

[0145] Step 2: 1-(2-(benzyloxy)-2-methylpropionyl)-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)indol-3-one (1e)

[0146] Under argon protection, N,N,N',N'-tetramethylethylenediamine (20.7 g, 177.8 mmol) and freshly prepared lithium diisopropylamino (15.7 mL, 39.1 mmol, 2.5 M) were added dropwise to a tetrahydrofuran (200 mL) solution of compound 1c (11 g, 35.6 mmol). The resulting mixture was stirred at -78 °C for 30 min, followed by the addition of compound 1d (10.95 g, 42.7 mmol), and then slowly heated to room temperature with stirring for 2 h. After the reaction was complete, the reaction was quenched dropwise with saturated ammonium chloride solution (200 mL) at -78 °C, and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed sequentially with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 1e (6.4 g, yield: 34%). 1 H NMR (500MHz, CDCl3) δ7.94 (dd, J=8.6, 1.5Hz, 1H), 7.68–7.63 (m, 1H), 7.57 –7.49(m,2H),7.38–7.25(m,7H),7.18–7.13(m,1H),7.11–7.04(m,2H),6.9 5–6.89(m,1H),5.46(t,J=7.7Hz,1H),4.67–4.56(m,2H),3.23–3.27(m,1H ),3.13–3.07(m,1H),1.46(s,2H),1.41(s,3H).LC-MS(ESI,m / z):530[M+H] + .

[0147] Step 3: 1-(3-amino-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)indol-1-yl)-2-(benzyloxy)-2-methylprop-1-one (1f)

[0148] Ammonium formate (4.8 g, 75.5 mmol) and (N-(4-(dimethylamino)phenyl)methylpyridinamide)(1,2,3,4,5-pentamethylcyclopenta-2,4-dien-1-yl)iridium(III) chloride (115.6 mg, 0.19 mmol) were added to a methanol (175 mL) solution of compound 1e (5 g, 9.4 mmol). The mixture was stirred at 70 °C for 12 hours. After the reaction was complete, the reaction was quenched with water (200 mL) and then extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed successively with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate) to give compound 1f (2.6 g, yield: 52%).1 H NMR (500MHz, CDCl3) δ7.72–7.62(m,2H),7.46–7.41(m,1H),7.37–7.26(m,7H),7.25–7.20(m ,2H),7.13(td,J=8.1,1.4Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),4.66–4.59(m,2H),4 .58–4.53(m,1H),4.32–4.25(m,1H),3.21–3.16(m,1H),3.11–3.06(m,1H),3.03(dd,J=7.1,4 .9Hz,1H),2.97(dd,J=7.1,4.9Hz,1H),1.46(s,2H),1.41(s,3H).LC-MS(ESI,m / z):531[M+H] + .

[0149] Step 4: N-(1-(2-(benzyloxy)-2-methylpropionyl)-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)indol-3-yl)ethanesulfonamide (1g)

[0150] At room temperature, triethylamine (1.7 mL, 11.9 mmol) and ethylsulfonyl chloride (610.6 mg, 4.8 mmol) were added to a tetrahydrofuran (50 mL) solution of compound 1f (2.1 g, 4.0 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with water (100 mL), and then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed successively with saturated brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the compound, which was further purified by Prep-HPLC (C18 Gemini-NX5 μm, 100 RRX 100 x 30 mm; acetonitrile / water (5 mM NH4HCO3), 55-95%, 40 mL / min, 12 min) to give 1 g of the cis isomer (1.2 g, yield: 46%). 1H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.38–7.28(m,5H),7.27–7.19(m,2 H),7.16(td,J=8.4,1.4Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.63(d,J=9.2Hz,1H),5 .02(td,J=7.1,5.5Hz,1H),4.67–4.56(m,2H),4.41(dd,J=9.2,5.5Hz,1H),3.16–3.10(m,1H), 3.08–2.96(m,3H),1.46(s,2H),1.41(s,3H),1.26(t,J=8.7Hz,3H).LC-MS(ESI,m / z):623[M+H] + .

[0151] Step 5: N-(1-(2-hydroxy-2-methylpropionyl)-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl)indol-3-yl)ethanesulfonamide (A001)

[0152] At room temperature, 10% palladium / carbon (120 mg) was added to a methanol (50 mL) solution of 1 g (0.8 g, 1.3 mmol) of the compound, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the target compound A001. 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7. 26–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6 .63(d,J=9.2Hz,1H),4.86–4.81(m,1H),4.53(s,1H),4.41(dd,J=9.2,5.5Hz,1H),3. 16–3.10(m,1H),3.08–2.97(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0153] LRMS(ESI,m / z):533[M+H] +

[0154] Example A002 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(hydroxycyclopropyl)carbonyl]-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A002)

[0155] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.25–7 .20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63(d,J=9 .2Hz,1H),4.82(td,J=7.0,5.4Hz,1H),4.53(s,1H),4.41(dd,J=9.2,5.5Hz,1H),3.17–3. 11(m,1H),3.10–2.96(m,3H),1.60–1.50(m,2H),1.26(t,J=8.7Hz,3H),1.13–1.04(m,2H).

[0156] LRMS(ESI,m / z):531[M+H] +

[0157] Example A003 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-{[(hydroxymethyl)cyclopropyl]carbonyl}-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A003)

[0158] 1 H NMR(500MHz, CDCl3)δ7.67–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.25–7.2 0(m,2H),7.16(td,J=8.3,1.6Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63(d,J=9.1Hz ,1H),4.80(td,J=7.0,5.4Hz,1H),4.41(dd,J=9.1,5.5Hz,1H),3.99(t,J=4.8Hz,1H),3.75( d,J=4.8Hz,2H),3.19–3.13(m,1H),3.11–2.96(m,3H),1.80–1.71(m,2H),1.30–1.19(m,5H).

[0159] LRMS(ESI,m / z):545[M+H]+

[0160] Example A004 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A004)

[0161] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.57(dd,J=8.0,1.6Hz,1H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H ),7.26–7.20(m,2H),7.16(td,J=8.3,1.6Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63(d,J=9.1Hz,1H) ,4.75(td,J=7.3,6.5Hz,1H),4.40(dd,J=9.1,6.6Hz,1H),3.95–3.88(m,1H),3.77(d,J=4.4Hz,1H),3.63–3. 57(m,1H),3.17–3.11(m,1H),3.10–2.96(m,3H),2.25–2.20(m,2H),1.96–1.90(m,2H),1.26(t,J=8.7Hz,3H).

[0162] LRMS(ESI,m / z):545[M+H] +

[0163] Example A005 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxybicyclo[1.1.1]pent-1-yl)carbonyl]-5-methyl-4-vinyl-2,3-dihydro-1H-pyrrole-3-yl)ethanesulfonamide (A005)

[0164] 1H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.25–7.2 0(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63(d,J=9.2Hz ,1H),4.78(td,J=7.1,5.5Hz,1H),4.41(dd,J=9.2,5.5Hz,1H),3.94(s,1H),3.19–3.13(m,1 H),3.09–2.96(m,3H),2.75(d,J=12.5Hz,3H),2.29(d,J=12.3Hz,3H),1.26(t,J=8.7Hz,3H).

[0165] LRMS(ESI,m / z):557[M+H] +

[0166] Example A006 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[2-(dimethylamino)-3-hydroxypropionyl]-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A006)

[0167] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.60(dd,J=7.9,1.6Hz,1H),7.52–7.47(m,1H),7.28( t,J=8.9Hz,1H),7.26–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.85( m,1H),6.63(d,J=9.2Hz,1H),5.00(td,J=7.3,6.6Hz,1H),4.43–4.38(m,1H),4.26–4.19(m,1H ),3.77–3.68(m,3H),3.17–3.11(m,1H),3.10–2.96(m,3H),2.39(s,6H),1.26(t,J=8.7Hz,3H).

[0168] LRMS(ESI,m / z):562[M+H] +

[0169] Example A007 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-5-methyl-4-vinyl-2,3-dihydro-1H-pyrrole-3-yl]ethanesulfonamide (A007)

[0170] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.2 5–7.20(m,2H),7.16(td,J=8.3,1.6Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63 (d,J=9.1Hz,1H),4.77(td,J=7.0,5.4Hz,1H),4.41(dd,J=9.1,5.5Hz,1H),3.19–3.13( m,1H),3.09–2.96(m,3H),2.17–2.07(m,4H),2.00–1.91(m,3H),1.26(t,J=8.7Hz,3H).

[0171] LRMS(ESI,m / z):541[M+H] +

[0172] Example A008 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxetanebut-2-ylcarbonyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A008)

[0173] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.60(dd,J=8.0,1.6Hz,1H),7.52–7.47(m,1H),7.28(t,J=8.9Hz, 1H),7.26–7.20(m,2H),7.16(td,J=8.3,1.6Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63(d,J=9.1Hz ,1H),4.82(td,J=7.3,6.5Hz,1H),4.45(t,J=4.2Hz,1H),4.44–4.37(m,1H),4.02–3.96(m,1H),3.93–2.87 (m,1H),3.16–3.10(m,1H),3.08–2.96(m,3H),2.42–2.38(m,1H),2.12–2.96(m,1H),1.26(t,J=8.7Hz,3H).

[0174] LRMS(ESI,m / z):531[M+H] +

[0175] Example A009 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxoylidene-λ6-thio)amino]-2,3-dihydro-1H-indol-1-yl)-2-oxoylidene ethyl acetate (A009)

[0176] 1 H NMR (500MHz, CDCl3) δ8.65 (dd, J=8.0, 1.5Hz, 1H), 7.67–7.62 (m, 1H), 7.53–7.4 7(m,1H),7.30–7.22(m,2H),7.20–7.13(m,1H),7.13–7.04(m,3H),6.95–6.85( m,1H),6.67(d,J=9.2Hz,1H),5.15–5.10(m,1H),4.41(dd,J=9.1,6.4Hz,1H),4 .28(q,J=7.1Hz,2H),3.22–3.08(m,2H),3.06–3.00(m,2H),1.30–1.20(m,6H).

[0177] LRMS(ESI,m / z):547[M+H] +

[0178] Example A010 N-[1-(2-amino-2-methylpropionyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3-dihydro-1H-indol-3-yl]ethanesulfonamide (A010)

[0179] 1H NMR (500MHz, CDCl3) δ7.68–7.63(m,1H),7.59(dd,J=7.9,1.6Hz,1H),7.52–7.47(m,1H),7.28( t,J=8.9Hz,1H),7.26–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.85 (m,1H),6.63(d,J=9.2Hz,1H),4.80(td,J=7.1,5.5Hz,1H),4.41(dd,J=9.2,5.5Hz,1H),3.19– 3.13(m,1H),3.11–2.96(m,3H),2.73(s,2H),1.45(s,2H),1.40(s,3H),1.26(t,J=8.7Hz,3H).

[0180] LRMS(ESI,m / z):532[M+H] +

[0181] Example A011 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxane-λ6-thio)amino]-N,N-dimethyl-2,3-dihydro-1H-indole-1-carboxamide (A011)

[0182] 1 H NMR(500MHz, CDCl3)δ8.24(dd,J=8.0,1.5Hz,1H),7.68–7.63(m,1H),7.48–7.42(m,1H),7.2 8(t,J=8.9Hz,1H),7.24(dd,J=7.9,1.4Hz,1H),7.17–7.11(m,1H),7.10–7.06(m,2H),7.05–6 .98(m,1H),6.95–6.85(m,1H),6.61(d,J=9.2Hz,1H),5.06(td,J=7.5,6.6Hz,1H),4.41(dd, J=9.1,6.6Hz,1H),3.19–3.08(m,2H),3.06–3.00(m,1H),2.98(s,6H),1.26(t,J=8.7Hz,3H).

[0183] LRMS(ESI,m / z):518[M+H] +

[0184] Example A012 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-fluoroacetyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A012)

[0185] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.2 6–7.20(m,2H),7.16(td,J=8.3,1.6Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.6 3(d,J=9.1Hz,1H),5.18(d,J=5.3Hz,1H),5.09(d,J=5.3Hz,1H),4.80(td,J=7.5,6.3H z,1H),4.43–4.36(m,1H),3.16–3.10(m,1H),3.08–2.96(m,3H),1.26(t,J=8.7Hz,3H).

[0186] LRMS(ESI,m / z):507[M+H] +

[0187] Example A013 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-fluorocyclobutyl)carbonyl]-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A013)

[0188] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.57(dd,J=8.0,1.6Hz,1H),7.52–7.47(m,1H),7.28(t,J=8.9 Hz,1H),7.26–7.20(m,2H),7.16(td,J=8.3,1.6Hz,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.63(d,J =9.1Hz,1H),4.75(td,J=7.3,6.6Hz,1H),4.70–4.65(m,1H),4.61–4.55(m,1H),4.40(dd,J=9.1,6.6Hz, 1H),3.17–3.11(m,1H),3.08–2.96(m,4H),2.39–2.25(m,2H),2.18–2.04(m,2H),1.26(t,J=8.7Hz,3H).

[0189] LRMS(ESI,m / z):547[M+H] +

[0190] Example A014 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxane-λ6-thio)amino]-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole-1-carboxamide (A014)

[0191] 1 H NMR(500MHz, CDCl3)δ8.24(dd,J=8.0,1.5Hz,1H),7.67–7.62(m,1H),7.48–7.42(m,1H), 7.32–7.21(m,2H),7.16–7.12(m,1H),7.10–7.06(m,2H),7.06–7.00(m,2H),6.95–6.85( m,1H),6.61(d,J=9.2Hz,1H),4.81(td,J=7.3,6.5Hz,1H),4.44–4.37(m,1H),3.98–3.94 (m,2H),3.19–3.13(m,1H),3.11–3.06(m,1H),3.06–3.00(m,2H),1.26(t,J=8.7Hz,3H).

[0192] LRMS(ESI,m / z):572[M+H] +

[0193] Example A015 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(1,1,1-trifluoro-2-oxoylidene-2-yl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A015)

[0194] 1 H NMR (500MHz, CDCl3) δ7.99 (dd, J=7.9, 1.6Hz, 1H), 7.67–7.62 (m, 1H), 7.51–7.46 ( m,1H),7.28(t,J=9.1Hz,1H),7.23(td,J=8.0,1.5Hz,1H),7.18–7.13(m,2H),7.11 –7.04(m,2H),6.95–6.85(m,1H),6.66(d,J=9.1Hz,1H),4.87–4.82(m,1H),4.41(d d,J=9.1,5.5Hz,1H),3.16–3.10(m,1H),3.09–2.96(m,3H),1.26(t,J=8.7Hz,3H).

[0195] LRMS(ESI,m / z):543[M+H] +

[0196] Example A016 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxoylidene-λ6-thio)amino]-2,3-dihydro-1H-indol-1-yl)-3,3-dimethyl-1-oxoylidene-2-yl]-2,2,2-trifluoroacetamide (A016)

[0197] 1 H NMR(500MHz, CDCl3)δ7.87(d,J=12.4Hz,1H),7.67–7.62(m,1H),7.60(dd,J=7.9,1.6Hz,1H),7.5 2–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.26–7.20(m,2H),7.16(td,J=8.3,1.5Hz,1H),7.11–7.04( m,2H),6.95–6.85(m,1H),6.63(d,J=9.2Hz,1H),5.00(td,J=7.3,6.6Hz,1H),4.61(d,J=12.4Hz, 1H), 4.43–4.38 (m, 1H), 3.19–3.13 (m, 1H), 3.11–2.96 (m, 3H), 1.26 (t, J = 8.7Hz, 3H), 1.00 (s, 9H).

[0198] LRMS(ESI,m / z):656[M+H] +

[0199] Example A017 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(1,1,1-trichloro-2-oxoylidene-2-yl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A017)

[0200] 1H NMR (500MHz, CDCl3) δ7.70–7.62(m,2H),7.52–7.46(m,1H),7.28(t,J=8.9 Hz,1H),7.25–7.19(m,2H),7.19–7.12(m,1H),7.11–7.04(m,2H),6.95–6.8 5(m,1H),6.63(d,J=9.1Hz,1H),5.09(td,J=7.0,5.5Hz,1H),4.41(dd,J=9. 1,5.5Hz,1H),3.19–3.13(m,1H),3.11–2.96(m,3H),1.26(t,J=8.7Hz,3H).

[0201] LRMS(ESI,m / z):592[M+H] +

[0202] Example A018 N-[1-(cyclopropyldioxane-λ6-thio)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3-dihydro-1H-indol-3-yl]ethanesulfonamide (A018)

[0203] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.48–7.42(m,1H),7.37(dd,J=7.9,1.5Hz,1H),7.28(t,J=9 .0Hz,1H),7.24(td,J=8.1,1.5Hz,1H),7.20–7.16(m,1H),7.11–7.04(m,2H),6.96–6.87(m,2H),6.51 (d,J=8.8Hz,1H),4.69(td,J=8.2,7.1Hz,1H),4.05–3.98(m,1H),3.33–3.28(m,1H),3.27–3.22(m,1H ),3.13–3.08(m,1H),3.06–3.00(m,2H),1.79–1.71(m,2H),1.70–1.62(m,2H),1.26(t,J=8.7Hz,3H).

[0204] LRMS(ESI,m / z):551[M+H] +

[0205] Example A019 N-(2-{[3-(3,5-difluorophenyl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A019)

[0206] 1 H NMR (500MHz, CDCl3) δ7.64 (dd, J=7.9, 1.5Hz, 1H), 7.53–7.48 (m, 2H), 7.45 (t, J=7.9Hz, 1H), 7. 42–7.40(m,1H),7.23(td,J=8.0,1.5Hz,1H),7.23–7.18(m,1H),7.17(dd,J=8.4,1.6Hz,1H),7. 15–7.10(m,2H),6.95–6.89(m,1H),6.63(d,J=9.2Hz,1H),4.81(q,J=5.7Hz,1H),4.53(s,1H),4 .39(dd,J=9.2,5.5Hz,1H),3.11–2.94(m,4H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0207] LRMS(ESI,m / z):515[M+H] +

[0208] Example A020 ​​N-(2-{[6-(3,5-difluorophenyl)pyridin-2-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A020)

[0209] 1 H NMR (500MHz, CDCl3) δ7.66–7.59(m,3H),7.58–7.54(m,2H),7.49–7.43(m,1H), 7.23(td,J=8.0,1.4Hz,1H),7.19–7.12(m,1H),7.00–6.92(m,2H),6.61(d,J=9 .2Hz,1H),4.86–4.79(m,1H),4.53(s,1H),4.45(dd,J=9.1,6.4Hz,1H),3.20–3 .09(m,2H),3.06–3.00(m,2H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0210] LRMS(ESI,m / z):516[M+H] +

[0211] Example A021 N-(2-{[2-(3,5-difluorophenyl)-1,3-thiazacyclopentanyl-4-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A021)

[0212] 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=7.9,1.5Hz,1H),7.49–7.43(m,1H),7.30–7.26(m,2H),7 .23(td,J=8.0,1.4Hz,1H),7.16(td,J=8.4,1.5Hz,1H),7.04(s,1H),6.95–6.89(m,1H),6 .61(d,J=9.2Hz,1H),5.12–5.07(m,1H),4.70(dd,J=9.1,6.4Hz,1H),4.53(s,1H),3.13(d d,J=14.1,5.5Hz,1H),3.10–2.96(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0213] LRMS(ESI,m / z):522[M+H] +

[0214] Example A022 N-(2-{[1-(3,5-difluorophenyl)-2-oxoylidenepyridin-3-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A022)

[0215] 1 H NMR (500MHz, CDCl3) δ7.76 (dd, J=7.7, 1.3Hz, 1H), 7.64 (dd, J=7.9, 1.5Hz, 1H), 7.52–7.46 (m, 1H ),7.37–7.33(m,2H),7.31–7.28(m,1H),7.23(td,J=8.0,1.4Hz,1H),7.20–7.13(m,1H),6.79–6 .70(m,2H),6.36–6.30(m,1H),5.12(q,J=5.9Hz,1H),4.53(s,1H),4.43–4.36(m,1H),3.16–3.1 0(m,1H),3.06–3.00(m,2H),2.97–2.95(m,1H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0216] LRMS(ESI,m / z):532[M+H] +

[0217] Example A023 N-(2-{[3-(3,5-difluorophenyl)bicyclo[1.1.1]pent-1-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A023)

[0218] 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=7.9,1.5Hz,1H),7.48–7.43(m,1H),7.23(td,J=8.0,1.4Hz ,1H),7.16(td,J=8.2,1.5Hz,1H),6.91–6.86(m,1H),6.83–6.79(m,2H),6.64(d,J=8.8Hz,1 H),4.77–4.71(m,1H),4.65–4.59(m,1H),4.53(s,1H),3.06–3.00(m,2H),2.08–2.05(m,1H) ,2.05(s,5H),1.75(dd,J=13.2,3.8Hz,1H),1.41(s,3H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0219] LRMS(ESI,m / z):505[M+H] +

[0220] Example A024 N-(2-{[4-(3,5-difluorophenyl)bicyclo[2.1.1]hex-1-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A024)

[0221] 1 H NMR (500MHz, CDCl3) δ7.64 (dd, J=7.9, 1.5Hz, 1H), 7.48–7.43 (m, 1H), 7.23 (td, J=8.0, 1.4Hz, 1H ),7.16(td,J=8.2,1.5Hz,1H),6.90–6.84(m,1H),6.83–6.77(m,2H),6.64(d,J=8.8Hz,1H),4.7 7–4.71(m,1H),4.65–4.59(m,1H),4.53(s,1H),3.06–3.00(m,2H),2.13–2.06(m,2H),2.06–1.9 6(m,4H),1.76–1.66(m,3H),1.65–1.57(m,1H),1.41(s,3H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0222] LRMS(ESI,m / z):519[M+H] +

[0223] Example A025 N-(2-{[2-(3,5-difluorophenyl)pentacyclo[4.2.0.03,8.02,5.04,7]oct-7-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A025)

[0224] 1 H NMR (500MHz, CDCl3) δ7.64 (dd, J=7.9, 1.5Hz, 1H), 7.48–7.43 (m, 1H), 7.23 (td, J=8.0, 1.4Hz, 1H), 7. 16(td,J=8.2,1.5Hz,1H),7.08–7.04(m,2H),6.89–6.84(m,1H),6.64(d,J=8.8Hz,1H),4.79(q,J=5. 8Hz,1H),4.69(dd,J=8.8,6.2Hz,1H),4.53(s,1H),3.08–2.97(m,5H),2.17(dd,J=12.9,5.7Hz,1H), 1.52(dd,J=12.9,5.7Hz,1H),1.41(s,2H),1.35(s,2H),1.31(t,J=3.8Hz,3H),1.26(t,J=8.7Hz,3H).

[0225] LRMS(ESI,m / z):541[M+H] +

[0226] Example A026 3-(3,5-difluorophenyl)-N-{3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-2-yl}-2-(methylamino)propionamide (A026)

[0227] 1H NMR(500MHz, CDCl3)δ7.99(dd,J=7.9,1.6Hz,1H),7.67(d,J=7.0Hz,1H),7.53–7.48(m,1H),7.28(td,J =7.9,1.3Hz,1H),7.19–7.14(m,1H),6.90–6.85(m,1H),6.81–6.74(m,2H),6.14(dd,J=7.1,4.0Hz,1H), 5.68(d,J=9.2Hz,1H),5.53–5.49(m,1H),5.17–5.11(m,1H),4.49(s,1H),3.68(q,J=6.4Hz,1H),3.07– 3.01(m,2H),2.95–2.90(m,2H),2.43(d,J=4.8Hz,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0228] LRMS(ESI,m / z):525[M+H] +

[0229] Example A027 3-(3,5-difluorophenyl)-N-{[1-(2-hydroxy-2-methylpropionyl)-3-[(methyldioxane-λ6-thio)amino]-2,3-dihydro-1H-indol-2-yl]methyl}-2-(methylamino)propionamide (A027)

[0230] 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=7.9,1.5Hz,1H),7.52–7.46(m,1H),7.41(t,J=5.7Hz,1H),7.23(td,J=8 .0,1.4Hz,1H),7.20–7.12(m,1H),6.90–6.85(m,1H),6.81–6.77(m,2H),6.68(d,J=9.0Hz,1H),5.43–5.38 (m,1H),4.80–4.75(m,1H),4.53(s,1H),4.41–4.35(m,1H),3.72(q,J=6.6Hz,1H),3.54–3.49(m,2H),3.0 6–3.00(m,2H),2.96–2.84(m,2H),2.43(d,J=4.6Hz,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0231] LRMS(ESI,m / z):539[M+H] +

[0232] Example A028 3-(3,5-difluorophenyl)-N-({3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-2-yl}methyl)-3-(methylamino)propionamide (A028)

[0233] 1 H NMR(500MHz, CDCl3)δ7.68(t,J=5.5Hz,1H),7.64(dd,J=7.9,1.5Hz,1H),7.52–7.46(m,1H),7.23(td,J= 8.0,1.4Hz,1H),7.20–7.12(m,1H),7.00–6.96(m,2H),6.96–6.92(m,1H),6.68(d,J=9.0Hz,1H),5.28–5. 23(m,1H),4.81–4.76(m,1H),4.53(s,1H),4.41–4.35(m,1H),4.28–4.24(m,1H),3.58–3.46(m,2H),3.06 –3.00(m,2H),2.68–2.55(m,2H),2.47(d,J=4.9Hz,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0234] LRMS(ESI,m / z):539[M+H] +

[0235] Example A029 N-{2-[(2-fluoro-3-phenylphenyl)methyl]-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl}ethanesulfonamide (A029)

[0236] 1H NMR(500MHz, CDCl3)δ7.69–7.65(m,1H),7.64(dd,J=7.9,1.5Hz,1H),7.51–7.43(m,3 H),7.43–7.35(m,3H),7.27(d,J=8.9Hz,1H),7.25–7.20(m,2H),7.19–7.14(m,1H),6 .63(d,J=9.2Hz,1H),4.87–4.82(m,1H),4.53(s,1H),4.41(dd,J=9.2,5.5Hz,1H),3. 16–3.10(m,1H),3.08–2.96(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0237] LRMS(ESI,m / z):497[M+H] +

[0238] Example A030 N-(2-{[2-fluoro-3-(pyridin-3-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A030)

[0239] 1 H NMR(500MHz, CDCl3)δ8.76(t,J=2.0Hz,1H),8.65(dd,J=4.7,1.7Hz,1H),7.86–7.80(m,1H),7.68 –7.61(m,2H),7.52–7.47(m,1H),7.38(dd,J=8.3,4.8Hz,1H),7.31(t,J=9.0Hz,1H),7.27–7.19(m ,2H),7.19–7.13(m,1H),6.63(d,J=9.2Hz,1H),4.86–4.80(m,1H),4.53(s,1H),4.41(dd,J=9.2,5 .5Hz,1H),3.17–3.13(m,1H),3.09–2.96(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0240] LRMS(ESI,m / z):498[M+H] +

[0241] Example A031 N-(2-{[2-fluoro-3-(pyrimidin-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A031)

[0242] 1 H NMR (500MHz, CDCl3) δ8.74 (d, J=3.9Hz, 2H), 7.78–7.73 (m, 1H), 7.64 (dd, J=7.9, 1.5Hz, 1H), 7.52–7. 47(m,1H),7.33(dd,J=10.6,9.1Hz,1H),7.28–7.24(m,1H),7.22(dd,J=8.0,1.4Hz,1H),7.20–7.13( m,1H),7.08(t,J=4.0Hz,1H),6.63(d,J=9.2Hz,1H),4.86–4.80(m,1H),4.53(s,1H),4.41(dd,J=9.2 ,5.5Hz,1H),3.15–3.10(m,1H),3.08–2.97(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0243] LRMS(ESI,m / z):499[M+H] +

[0244] Example A032 N-(2-{[2-fluoro-3-(2H,1H-1,2-azaboronecyclohexyl-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)ethanesulfonamide (A032)

[0245] 1 H NMR(500MHz, CDCl3)δ7.68–7.61(m,2H),7.56–7.52(m,1H),7.51–7.47(m,1H),7.27–7.20(m,1H) ,7.19–7.15(m,1H),7.12–7.06(m,2H),7.03–6.98(m,1H),6.96(t,J=8.4Hz,1H),6.63(d,J=9.2H z,1H),6.31–6.26(m,1H),6.08–6.03(m,1H),4.85–4.80(m,1H),4.53(s,1H),4.41(dd,J=9.2,5. 5Hz,1H),3.10–3.00(m,3H),2.99–2.94(m,1H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0246] LRMS(ESI,m / z):498[M+H] +

[0247] Example A033 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,7,9-trifluoro-6H-benzo[c]chromen-2-yl)methyl]-2,3-dihydro-1H-indol-3-yl]ethanesulfonamide (A033)

[0248] 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=7.9,1.5Hz,1H),7.52–7.47(m,1H),7.31–7.27(m,1H),7.23 (td,J=8.0,1.4Hz,1H),7.16(td,J=8.4,1.5Hz,1H),7.12–7.07(m,1H),6.93–6.85(m,2H),6. 63(d,J=9.2Hz,1H),5.04–4.92(m,2H),4.86–4.80(m,1H),4.53(s,1H),4.41(dd,J=9.2,5.5H z,1H),3.13–3.08(m,1H),3.07–2.97(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0249] LRMS(ESI,m / z):561[M+H] +

[0250] Example A034 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,7,9-trifluoro-5,6-dihydrophenanthridine-2-yl)methyl]-2,3-dihydro-1H-indol-3-yl]ethanesulfonamide (A034)

[0251] 1H NMR (500MHz, CDCl3) δ7.64 (dd, J=7.9, 1.5Hz, 1H), 7.52–7.47 (m, 1H), 7.23 (td, J=8.0, 1.5Hz, 1H), 7.20 –7.14(m,2H),7.05–6.97(m,1H),6.89(td,J=8.0,2.2Hz,1H),6.65(dd,J=17.8,9.3Hz,2H),5.60(t,J=5 .8Hz,1H),4.86–4.83(m,1H),4.68(dd,J=12.2,5.8Hz,2H),4.53(s,1H),4.41(dd,J=9.2,5.5Hz,1H),3. 33–3.28(m,1H),3.11–3.01(m,2H),3.01–2.94(m,1H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0252] LRMS(ESI,m / z):560[M+H] +

[0253] Example A035 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,8,10-trifluoro-5,7-dihydrodibenzo[1,2-c:1',2'-e]oxetane-2-yl)methyl]-2,3-dihydro-1H-indol-3-yl]ethanesulfonamide (A035)

[0254] 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=7.9,1.5Hz,1H),7.52–7.47(m,1H),7.23(td,J=8.0,1.4Hz,1H),7.20–7 .12(m,1H),7.04–6.98(m,1H),6.97(dd,J=7.9,2.2Hz,1H),6.95–6.91(m,2H),6.63(d,J=9.2Hz,1H),5.0 7(s,1H),5.03(s,1H),4.97(dd,J=13.9,0.9Hz,2H),4.83(td,J=7.1,5.5Hz,1H),4.53(s,1H),4.41(dd,J =9.2,5.5Hz,1H),3.13–3.08(m,1H),3.07–2.97(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0255] LRMS(ESI,m / z):575[M+H] +

[0256] Example A036 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,8,10-trifluoro-6-methyl-6,7-dihydro-5H-dibenzo[1,2-c:1',2'-e]azacycloheptan-2-yl)methyl]-2,3-dihydro-1H-indol-3-yl]ethanesulfonamide (A036)

[0257] 1 H NMR(500MHz, CDCl3)δ7.64(dd,J=7.9,1.5Hz,1H),7.52–7.47(m,1H),7.23(td,J=8.0,1.4Hz,1H),7.19– 7.12(m,1H),7.07–7.01(m,1H),6.95(td,J=8.0,2.2Hz,1H),6.93–6.87(m,2H),6.63(d,J=9.2Hz,1H),4 .83(td,J=7.1,5.5Hz,1H),4.53(s,1H),4.41(dd,J=9.2,5.5Hz,1H),3.58–3.52(m,2H),3.52–3.47(m,2 H),3.14–3.06(m,1H),3.06–2.96(m,3H),2.24(s,2H),1.41(s,3H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0258] LRMS(ESI,m / z):588[M+H] +

[0259] Example A037 N-{2-[(8,10-difluoro-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline-2-yl)methyl]-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl}ethanesulfonamide (A037)

[0260] 1H NMR (500MHz, CDCl3) δ7.64 (dd, J=7.9, 1.5Hz, 1H), 7.48–7.43 (m, 1H), 7.23 (td, J=8.0, 1.4Hz, 1H), 7.16 (td,J=8.2,1.6Hz,1H),6.84–6.75(m,2H),6.68(d,J=9.0Hz,1H),4.70(td,J=6.6,5.7Hz,1H),4.61–4. 56(m,1H),4.53(s,1H),3.64–3.58(m,1H),3.11–2.96(m,3H),2.96–2.84(m,4H),2.73–2.68(m,1H),2. 05–1.91(m,2H),1.90–1.80(m,1H),1.80–1.66(m,4H),1.41(s,3H),1.35(s,3H),1.26(t,J=8.7Hz,3H).

[0261] LRMS(ESI,m / z):548[M+H] +

[0262] Example A038 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)methanesulfonamide (A038)

[0263] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(d,J=17.9Hz,1H) ,7.26–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m, 1H),6.77(d,J=9.0Hz,1H),4.82(td,J=7.1,5.1Hz,1H),4.53(s,1H),4.44–4.38(m ,1H),3.16–3.10(m,1H),3.07–3.01(m,1H),2.97(s,3H),1.41(s,2H),1.35(s,3H).

[0264] LRMS(ESI,m / z):519[M+H] +

[0265] Example A039 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)propane-2-sulfonamide (A039)

[0266] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.26–7.19( m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.99(d,J=9.3Hz,1H),6.95–6.89(m,1H) ,4.82(td,J=7.0,5.2Hz,1H),4.76–4.70(m,1H),4.53(s,1H),3.25–3.20(m,1H),3.15–3.10(m, 1H),3.07–3.01(m,1H),1.41(s,2H),1.35(s,3H),1.26(d,J=7.9Hz,3H),1.21(d,J=8.1Hz,3H).

[0267] LRMS(ESI,m / z):547[M+H] +

[0268] Example A040 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)-1-fluoromethanesulfonamide (A040)

[0269] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.25–7. 20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.58(d,J=10 .1Hz,1H),5.28(d,J=1.1Hz,1H),5.19(d,J=1.1Hz,1H),4.81(td,J=7.0,5.4Hz,1H),4.53( s,1H),4.46–4.39(m,1H),3.15–3.08(m,1H),3.06–3.00(m,1H),1.41(s,2H),1.35(s,3H).

[0270] LRMS(ESI,m / z):537[M+H] +

[0271] Example A041 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)-1,1-difluoromethanesulfonamide (A041)

[0272] 1 H NMR(500MHz, CDCl3)δ7.67–7.61(m,2H),7.55(d,J=11.2Hz,1H),7.52–7.46(m,1H),7 .28(t,J=8.9Hz,1H),7.25–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H ),6.94–6.89(m,1H),6.50(t,J=57.3Hz,1H),4.81(td,J=7.0,5.2Hz,1H),4.53(s,1H ),4.49–4.42(m,1H),3.15–3.10(m,1H),3.06–3.00(m,1H),1.41(s,2H),1.35(s,3H).

[0273] LRMS(ESI,m / z):555[M+H] +

[0274] Example A042 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)-1,1,1-trifluoromethanesulfonamide (A042)

[0275] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.35–7.26(m,2 H),7.26–7.18(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.94 –6.89(m,1H),4.82(td,J=7.1,4.9Hz,1H),4.75(dd,J=12.0,5.1Hz,1H),4. 53(s,1H),3.16–3.10(m,1H),3.07–3.02(m,1H),1.41(s,2H),1.35(s,3H).

[0276] LRMS(ESI,m / z):573[M+H]+

[0277] Example A043 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indole-3-yl)cyclopropanesulfonamide (A043)

[0278] 1 H NMR (500MHz, CDCl3) δ7.67–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.26– 7.20(m,3H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),4.82(td ,J=7.1,5.2Hz,1H),4.72–4.66(m,1H),4.53(s,1H),3.47(p,J=7.1Hz,1H),3.15–3.09(m ,1H),3.07–3.01(m,1H),1.78–1.65(m,2H),1.65–1.54(m,2H),1.41(s,3H),1.35(s,3H).

[0279] LRMS(ESI,m / z):545[M+H] +

[0280] Example A044 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)-1-fluoroethanesulfonamide (A044)

[0281] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.32–7.25(m,2H ),7.25–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6. 89(m,1H),4.83(td,J=7.1,4.9Hz,1H),4.53(s,1H),4.47–4.40(m,1H),3.16– 3.11(m,1H),3.07–3.01(m,1H),2.26–2.04(m,4H),1.41(s,2H),1.35(s,3H).

[0282] LRMS(ESI,m / z):563[M+H] +

[0283] Example A045 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)prop-2-ene-1-sulfonamide (A045)

[0284] 1 H NMR (500MHz, CDCl3) δ7.67–7.61(m,2H),7.52–7.47(m,1H),7.28(d,J=17.9Hz,1H),7.25–7.2 0(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),5.87(d,J=9.2Hz, 1H),5.71–5.67(m,1H),5.30–5.23(m,2H),4.83(td,J=7.1,5.5Hz,1H),4.53(s,1H),4.44–4. 37(m,1H),3.83–3.70(m,2H),3.19–3.13(m,1H),3.04–2.98(m,1H),1.41(s,2H),1.35(s,3H).

[0285] LRMS(ESI,m / z):545[M+H] +

[0286] Example A046 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indole-3-yl)benzenesulfonamide (A046)

[0287] 1 H NMR(500MHz, CDCl3)δ7.81–7.76(m,2H),7.75(dt,J=7.4,1.4Hz,1H),7.68–7.61(m,2 H),7.52–7.42(m,4H),7.28(t,J=8.9Hz,1H),7.25–7.19(m,2H),7.16(td,J=8.4,1.5H z,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),4.82(td,J=7.0,5.2Hz,1H),4.53(s,1H ),4.47–4.40(m,1H),3.16–3.10(m,1H),3.07–3.01(m,1H),1.41(s,2H),1.35(s,3H).

[0288] LRMS(ESI,m / z):581[M+H] +

[0289] Example A047 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)-1,1-dimethylazinesulfonamide (A047)

[0290] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H), 7.25–7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1 H),6.51(d,J=8.6Hz,1H),4.82(td,J=7.0,5.4Hz,1H),4.53(s,1H),4.45–4.38(m, 1H),3.15–3.10(m,1H),3.07–3.01(m,1H),2.69(s,6H),1.41(s,2H),1.35(s,3H).

[0291] LRMS(ESI,m / z):548[M+H] +

[0292] Example A048 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indole-3-yl)tetrahydropyrrole-1-sulfonamide (A048)

[0293] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.25– 7.20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.77(d, J=8.8Hz,1H),4.82(td,J=7.0,5.4Hz,1H),4.53(s,1H),4.45–4.39(m,1H),3.26–3.15(m ,4H),3.14–3.09(m,1H),3.07–3.01(m,1H),1.83–1.72(m,4H),1.41(s,2H),1.35(s,3H).

[0294] LRMS(ESI,m / z):574[M+H] +

[0295] Example A049 N-cyclopropyl-1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indol-3-yl)azaalkylsulfonamide (A049)

[0296] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.26–7.20( m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.48(dd,J=9.5,4.0H z,2H),5.04(td,J=7.1,5.1Hz,1H),4.53(s,1H),4.44–4.38(m,1H),3.16–3.11(m,1H),3.06–3 .00(m,1H),2.64–2.60(m,1H),1.41(s,2H),1.35(s,3H),0.75–0.66(m,2H),0.66–0.59(m,2H).

[0297] LRMS(ESI,m / z):560[M+H] +

[0298] Example A050 1-Cyano-N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3-dihydro-1H-indole-3-yl)methanesulfonamide (A050)

[0299] 1H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.52–7.47(m,1H),7.28(t,J=8.9Hz,1H),7.26–7. 20(m,2H),7.16(td,J=8.4,1.5Hz,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.44(d,J=9. 0Hz,1H),4.84(td,J=7.1,5.5Hz,1H),4.65(d,J=12.6Hz,1H),4.60(d,J=12.6Hz,1H),4.53 (s,1H),4.46–4.39(m,1H),3.16–3.10(m,1H),3.07–3.01(m,1H),1.41(s,2H),1.35(s,3H).

[0300] LRMS(ESI,m / z):544[M+H] +

[0301] Example A051 1-(3-{[aza-ylidene(ethyl)(oxonyl)-λ6-thio]amino}-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3-dihydro-1H-indol-1-yl)-2-hydroxy-2-methylprop-1-one (A051)

[0302] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.53–7.47(m,1H),7.36(s,1H),7.28(t,J=8 .9Hz,1H),7.25–7.19(m,2H),7.19–7.12(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H) ,4.74(td,J=7.0,5.2Hz,1H),4.53(s,1H),4.42–4.36(m,1H),3.60(d,J=7.7Hz,1H),3 .22–3.12(m,1H),3.12–3.01(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=7.5Hz,3H).

[0303] LRMS(ESI,m / z):532[M+H] +

[0304] Example A052 1-(3-{[aza-ylidene (cyclopropyl))(oxonyl)-λ6-thio]amino}-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3-dihydro-1H-indol-1-yl)-2-hydroxy-2-methylprop-1-one (A052)

[0305] 1 H NMR (500MHz, CDCl3) δ7.68–7.61(m,2H),7.53–7.47(m,1H),7.36(s,1H),7.28(t,J=8 .9Hz,1H),7.25–7.19(m,2H),7.19–7.12(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H) ,4.74(td,J=7.0,5.2Hz,1H),4.53(s,1H),4.42–4.36(m,1H),3.60(d,J=7.7Hz,1H),3 .22–3.12(m,1H),3.12–3.01(m,3H),1.41(s,2H),1.35(s,3H),1.26(t,J=7.5Hz,3H).

[0306] LRMS(ESI,m / z):542[M+H] +

[0307] Example A053 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(hydroxycyclopropyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A053)

[0308] 1 H NMR (400MHz, CD3CN) δ7.56–7.13(m,5H),7.05–6.91(m,1H),5.91–5.59(m,1H),5.08–4.66(m,1H),4.53–3. 59(m,3H),3.28–2.84(m,4H),1.82–1.71(m,1H),1.38–1.24(m,3H),1.23–1.15(m,1H),1.11–0.54(m,5H).

[0309] LRMS(ESI,m / z):495[M+H] +

[0310] Example A054 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-{[(hydroxymethyl)cyclopropyl]carbonyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A054)

[0311] 1 H NMR(400MHz, DMSO-d6)δ7.86–7.54(m,1H),7.40-7.21(m,5H),7.14(t,J=7.6Hz,1H),4.87–4.32(m,2H),4.04–3.53(m, 2H),3.48–3.36(m,2H),3.14–2.96(m,3H),2.88-2.55(m,1H),1.99–1.69(m,1H),1.32–1.08(m,4H),1.02–0.19(m,5H).

[0312] LRMS(ESI,m / z):509[M+H] +

[0313] Example A055 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A055)

[0314] 1 H NMR(400MHz,CD3CN)δ7.33(q,J=7.2Hz,2H),7.25-7.14(m,3H),7.04-6.97(m,1H),5.91-5.39(m,1H),4.85-4.50(m,1H),4.14-3.92(m,1H),3 .79-3.68(m,1H),3.22-3.14(m,2H),3.12–3.06(m,3H),3.03–2.94(m, 1H),2.94–2.78(m,2H),2.52–2.22(m,2H),1.85–1.78(m,1H),1.56(br d,J=8.4Hz,1H),1.33(t,J=7.3Hz,3H),1.26–1.15(m,2H),1.04–0.70(m,1H).

[0315] LRMS(ESI,m / z):509[M+H] +

[0316] Example A056 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxybicyclo[1.1.1]pent-1-yl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A056)

[0317] 1 H NMR (400MHz, CD3CN) δ7.54–7.10(m,5H),7.06–6.93(m,1H),5.97–5.62(m,1H),4.86–4.60(m,1H),4.48–4.16(m,1H),3.81–3.56( m,1H),3.35–2.72(m,5H),2.15(s,1H),2.01(s,4H),1.88-1.79(m,1H),1.38–1.17(m,4H),1.05–0.86(m,1H),0.84–0.74(m,1H).

[0318] LRMS(ESI,m / z):521[M+H] +

[0319] Example A057 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-{[3-(trifluoromethyl)cyclobutyl]carbonyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A057)

[0320] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.25–7.18(m,1H),7.11–7. 04(m,2H),6.95–6.89(m,1H),5.85(d,J=7.7Hz,1H),4.44(td,J=6.6,4.5Hz,1H),3.81–3.70 (m,2H),3.21–3.08(m,2H),3.08–2.96(m,3H),2.65–2.60(m,1H),2.41–2.36(m,2H),2.28–2 .22(m,2H),2.10–2.03(m,1H),1.84–1.79(m,1H),1.69–1.63(m,1H),1.25(t,J=8.6Hz,3H).

[0321] LRMS(ESI,m / z):560[M+H] +

[0322] Example A058 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[2-(dimethylamino)-3-hydroxypropionyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A058)

[0323] 1 H NMR (400MHz, CD3CN) δ7.40–7.29(m,2H),7.21(m,3H),7.00(br t,J=9.3Hz,1H),5.82(br d,J=8.3Hz,1H),4.88(m,1H),3.78(m,1H),3.68–3.60(m,1H),3.47–3.39(m,1H),3.35–3.28(m,2H) ,3.22–3.08(m,3H),2.95–2.84(m,1H),2.31(s,6H),1.90–1.80(m,1H),1.38–1.26(m,5H),0.87(br s,1H).

[0324] LRMS(ESI,m / z):526[M+H] +

[0325] Example A059 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(4-hydroxytetrahydro-1H-pyrrolo-3-yl)carbonyl]-2,3,3a,4a-tetrahydro-1H-pyrrolo-3-yl)ethanesulfonamide (A059)

[0326] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.11–7.04(m,2H),6.95 –6.89(m,1H),5.85(d,J=7.7Hz,1H),4.45(td,J=6.4,4.4Hz,1H),4.20–4.12(m,2H),3.87(q,J=5.0Hz,1H), 3.80–3.75(m,1H),3.22–3.13(m,2H),3.13–3.07(m,1H),3.07–2.97(m,3H),2.95–2.90(m,2H),2.70–2.65 (m,1H),2.60–2.55(m,1H),2.09–2.05(m,1H),1.85–1.80(m,1H),1.69–1.63(m,1H),1.25(t,J=8.6Hz,3H).

[0327] LRMS(ESI,m / z):524[M+H] +

[0328] Example A060 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxacyclobut-3-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A060)

[0329] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7.11 –7.04(m,2H),6.95–6.89(m,1H),5.85(d,J=7.7Hz,1H),4.47–4.41(m,1H),3.86(dd,J= 12.3,4.2Hz,2H),3.80–3.71(m,4H),3.31–3.27(m,1H),3.14–3.09(m,1H),3.08–2.96( m,3H),2.11–2.04(m,1H),1.84–1.79(m,1H),1.69–1.63(m,1H),1.25(t,J=8.6Hz,3H).

[0330] LRMS(ESI,m / z):495[M+H] +

[0331] Example A061 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A061)

[0332] 1H NMR(400MHz,DMSO-d6)δ7.45–7.39(m,1H),7.35–7.26(m,4H),7.22–7.14(m,1H),5.2 7(dd,J=7.2,8.5Hz,1H),4.75–4.64(m,1H),4.48–4.35(m,1H),4.19(td,J=5.9,9.0Hz ,1H),3.65(dd,J=2.4,5.9Hz,1H),3.16–2.99(m,5H),2.88–2.72(m,2H),2.25–2.13(m ,1H),1.90–1.77(m,1H),1.25(t,J=7.3Hz,3H),1.17–1.09(m,1H),0.90-0.83(m,1H).

[0333] LRMS(ESI,m / z):495[M+H] +

[0334] Example A062 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]ethanesulfonamide (A062)

[0335] 1 H NMR (400MHz, CD3CN) δ7.54–7.12(m,5H),7.07–6.92(m,1H),5.99–5.56(m,1H),4.84–4.63(m,1H),4.42(br d,J=6.4Hz,1H),3.82–3.60(m,1H),3.39–3.25(m,1H),3.21–2.74(m,4H),2.47–2.31(m,1H ),2.13(s,1H),2.00–1.98(m,4H),1.88–1.52(m,1H),1.39–1.16(m,4H),1.06–0.75(m,1H).

[0336] LRMS(ESI,m / z):505[M+H] +

[0337] Example A063 N-[1-(2-amino-2-methylpropionyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]ethanesulfonamide (A063)

[0338] 1H NMR(400MHz,CD3CN)δ7.40–7.14(m,5H),7.03–6.96(m,1H),5.87–5.46(m,1H),5.04–4 .67(m,1H),4.61–4.33(m,1H),3.79–3.61(m,1H),3.18(dd,J=5.1,13.1Hz,1H),3.11– 3.04(m,1H),3.04–2.96(m,1H),2.92(dd,J=9.4,12.6Hz,1H),2.12–2.06(m,2H),1.33 (dd,J=6.9,13.4Hz,5H),1.28–1.22(m,2H),1.18(d,J=2.4Hz,3H),1.07–0.83(m,2H).

[0339] LRMS(ESI,m / z):496[M+H] +

[0340] Example A064 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxane-λ6-thio)amino]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-2-oxanediethyl ethyl acetate (A064)

[0341] 1 H NMR(400MHz,CD3CN)7.48–7.30(m,2H),7.27–7.17(m,3H),7.06–6.95(m,1H),5.90(br d,J=8.9Hz,1H),4.78–4.49(m,1H),4.34–4.23(m,2H),3.95–3.82(m,1H),3 .64–3.44(m,1H),3.20–3.02(m,4H),1.38–1.24(m,6H),1.22–0.87(m,3H).

[0342] LRMS(ESI,m / z):511[M+H] +

[0343] Example A065 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A065)

[0344] 1H NMR(500MHz, CDCl3)δ7.93(t,J=4.5Hz,1H),7.67–7.61(m,1H),7.28(t,J=9.0Hz,1H),7.23–7 .19(m,1H),7.11–7.04(m,2H),6.96–6.90(m,1H),5.86(d,J=7.7Hz,1H),4.61(td,J=6.8,4.2 Hz,1H),3.91–3.86(m,1H),3.85(td,J=5.2,4.4Hz,1H),3.33–3.28(m,2H),3.11–2.95(m,4H) ,2.10–2.05(m,1H),1.88–1.83(m,1H),1.70(ddd,J=12.3,5.2,3.9Hz,1H),1.28–1.19(m,6H).

[0345] LRMS(ESI,m / z):510[M+H] +

[0346] Example A066 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxane-λ6-thio)amino]-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A066)

[0347] 1 H NMR(400MHz,CD3CN)δ7.41–7.31(m,2H),7.26–7.16(m,3H),7.05–6.95(m,1H),5.67(br d,J=9.8Hz,1H),4.31–4.18(m,1H),3.85–3.73(m,1H),3.35–3.24(m,1H),3.06–2.95(m,3H),2.91(br d,J=7.6Hz,1H),2.88(s,6H),1.69–1.57(m,1H),1.30(t,J=7.3Hz,3H),0.80–0.68(m,2H).

[0348] LRMS(ESI,m / z):482[M+H] +

[0349] Example A067 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(trimethylacetazono)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A067)

[0350] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19( m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),5.90(d,J=7.5Hz,1H),4.62(td ,J=6.7,4.5Hz,1H),3.85–3.75(m,2H),3.11–2.98(m,7H),2.60(s,5H),2.0 7–2.00(m,1H),1.83–1.78(m,1H),1.63–1.57(m,1H),1.25(t,J=8.6Hz,3H).

[0351] LRMS(ESI,m / z):511[M+H] +

[0352] Example A068: Methyl methane {[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxoylidene-λ6-thio)amino]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3-methyl-1-oxoylidenebut-2-yl]amino} (A068)

[0353] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.04(m,2H),6.95 –6.89(m,1H),6.49(d,J=9.3Hz,1H),5.85(d,J=7.7Hz,1H),4.45(td,J=6.6,4.5Hz,1H),4.40(dd,J=9.3,6 .6Hz,1H),3.88(q,J=4.9Hz,1H),3.80–3.76(m,1H),3.60(s,3H),3.16–3.10(m,1H),3.09–2.95(m,3H),2. 11–1.99(m,2H),1.86–1.80(m,1H),1.72–1.67(m,1H),1.25(t,J=8.6Hz,3H),0.88(dd,J=6.9,1.1Hz,6H).

[0354] LRMS(ESI,m / z):568[M+H] +

[0355] Example A069 P-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxane-λ6-thio)amino]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-P-ethylphosphonic acid (A069)

[0356] 1 H NMR(400MHz,CD3CN)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.17(m,1H),7.11–7.0 4(m,2H),6.95–6.89(m,1H),6.77(s,1H),5.92(d,J=7.1Hz,1H),3.85–3.80(m,1H),3.64(td, J=7.0,3.7Hz,1H),3.15(td,J=5.6,4.0Hz,1H),3.11–2.95(m,4H),2.15–2.10(m,1H),2.02– 1.97(m,2H),1.83–1.78(m,1H),1.69–1.65(m,1H),1.25(t,J=8.6Hz,3H),1.14–1.08(m,3H).

[0357] LRMS(ESI,m / z):502[M+H] +

[0358] Example A070 N-[1-(cyclopropyldioxane-λ6-thio)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropyl[1,2-b]pyrrolo-3-yl]ethanesulfonamide (A070)

[0359] 1H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.04(m ,2H),6.95–6.89(m,1H),5.86(d,J=7.5Hz,1H),4.22(td,J=7.5,5.1Hz,1H),3.89–3.84(m,1H),3 .43–3.37(m,1H),3.37–3.31(m,1H),3.21–3.17(m,1H),3.11–2.93(m,3H),1.99–1.93(m,1H),1. 89–1.84(m,1H),1.79–1.73(m,1H),1.73–1.66(m,2H),1.65–1.56(m,2H),1.25(t,J=8.6Hz,3H).

[0360] LRMS(ESI,m / z):515[M+H] +

[0361] Example A071 N-[1-(1-aza-2,2-dimethylpropyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]ethanesulfonamide (A071)

[0362] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H) ,7.11–7.04(m,2H),6.95–6.89(m,1H),5.89(s,1H),5.74(d,J=7.7Hz,1H),4.36– 4.30(m,1H),3.75–3.70(m,1H),3.61–3.55(m,1H),3.14–2.95(m,4H),2.02–1.95 (m,1H),1.88–1.83(m,1H),1.71–1.65(m,1H),1.25(t,J=8.6Hz,3H),1.20(s,9H).

[0363] LRMS(ESI,m / z):494[M+H] +

[0364] Example A072 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(5-hydroxy-2-methyl-3,4-dihydro-2H-pyrazol-3-yl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A072)

[0365] 1 H NMR (500MHz, CDCl3) δ8.26 (s, 1H), 7.68–7.63 (m, 1H), 7.28 (t, J = 9.0Hz, 1H), 7.23–7.19 (m, 1H), 7. 11–7.04(m,2H),6.95–6.89(m,1H),5.85(d,J=7.7Hz,1H),4.49–4.43(m,1H),4.31–4.26(m,1H),3 .84(q,J=4.9Hz,1H),3.81–3.76(m,1H),3.14–3.08(m,1H),3.08–2.95(m,7H),2.63–2.55(m,1H), 2.28–2.21(m,1H),2.10–2.03(m,1H),1.86–1.80(m,1H),1.71–1.67(m,1H),1.25(t,J=8.6Hz,3H).

[0366] LRMS(ESI,m / z):537[M+H] +

[0367] Example A073 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(1,3-thiazacyclopentanyl-4-yl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A073)

[0368] 1H NMR(500MHz, CDCl3)δ8.53(d,J=1.6Hz,1H),7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.21– 7.14(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.45(d,J=1.6Hz,1H),5.78(d,J=7.5Hz, 1H),4.48–4.42(m,1H),3.86–3.80(m,1H),3.69(q,J=5.3Hz,1H),3.15–3.10(m,1H),3.09–2 .95(m,3H),2.05–1.98(m,1H),1.95–1.90(m,1H),1.81–1.77(m,1H),1.25(t,J=8.6Hz,3H).

[0369] LRMS(ESI,m / z):494[M+H] +

[0370] Example A074 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-fluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A074)

[0371] 1 H NMR (400MHz, CD3CN) δ7.53–7.31(m,2H),7.27–7.17(m,3H),7.06–6.97(m,1H),5.92–5.64(m,1H),5.15–4.56( m,3H),3.82–3.34(m,1H),3.23–2.87(m,5H),1.91–1.81(m,1H),1.40–1.24(m,3H),1.23–1.17(m,1H),0.90(br d,J=6.1Hz,1H).

[0372] LRMS(ESI,m / z):471[M+H] +

[0373] Example A075 N-(1-carbonyl-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A075)

[0374] 1H NMR (500MHz, CDCl3) δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.11–7.04(m,2H),6.95–6.89(m,1H),6.13(t,J=57.2Hz,1H),5.85(d,J=7.7Hz ,1H),4.51–4.87(m,1H),3.85–3.76(m,2H),3.14–3.08(m,1H),3.08–2.97(m,3H) ,2.13–2.06(m,1H),1.86–1.80(m,1H),1.71–1.67(m,1H),1.25(t,J=8.6Hz,3H).

[0375] LRMS(ESI,m / z):489[M+H] +

[0376] Example A076 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(1,1,1-trifluoro-2-oxoylidene-2-yl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A076)

[0377] 1 H NMR(400MHz,CD3CN)δ7.62–6.94(m,6H),6.07–5.62(m,1H),5.13–4.58(m,2H),3.75(br s,1H),3.52–3.27(m,1H),3.22–2.71(m,6H),2.64–2.33(m,2H),2.19– 2.01(m,1H),1.91–1.69(m,1H),1.42–1.16(m,4H),1.09–0.61(m,1H).

[0378] LRMS(ESI,m / z):507[M+H] +

[0379] Example A077 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(1,1,1-trichloro-2-oxoylidene-2-yl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A077)

[0380] 1H NMR (400MHz, CD3CN) δ7.54–7.32(m,2H),7.27–7.15(m,3H),7.04–6.95(m,1H),6.11–5.71(m,1H),5.05–4. 46(m,1H),4.14–3.66(m,2H),3.34–2.74(m,4H),2.16–2.01(m,1H),1.42–1.21(m,4H),1.18–1.01(m,1H).

[0381] LRMS(ESI,m / z):556[M+H] +

[0382] Example A078 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-fluorocyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A078)

[0383] 1 H NMR(400MHz,CD3CN)δ7.49–7.30(m,2H),7.20(br t,J=7.4Hz,3H),7.06–6.95(m,1H),6.01–5.74(m,1H),4.91–4.49(m,1H),3.91–3.50 (m,2H),3.33–2.77(m,4H),2.14–2.05(m,1H),1.40–1.18(m,4H),1.11–0.94(m,1H).

[0384] LRMS(ESI,m / z):511[M+H] +

[0385] Example A079 N-{1-[(3,3-difluorocyclobutyl)carbonyl]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl}ethanesulfonamide (A079)

[0386] 1H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7 .04(m,2H),6.95–6.89(m,1H),5.85(d,J=7.7Hz,1H),4.47–4.40(m,1H),3.81–3.76(m,1H) ,3.74(q,J=4.9Hz,1H),3.16–3.09(m,2H),3.08–2.95(m,3H),2.61–2.57(m,2H),2.48–2. 42(m,2H),2.11–2.06(m,1H),1.84–1.78(m,1H),1.69–1.63(m,1H),1.25(t,J=8.6Hz,3H).

[0387] LRMS(ESI,m / z):529[M+H] +

[0388] Example A080 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxane-λ6-thio)amino]-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A080)

[0389] 1 H NMR(400MHz,CD3CN)δ7.39–7.28(m,2H),7.24–7.13(m,3H),7.03–6.98m,1H ),5.85–5.73(m,2H),4.58(td,J=5.4,10.5Hz,1H),3.83–3.74(m,1H),3.73 –3.61(m,2H),3.15–3.03(m,4H),3.02–2.91(m,1H),1.87–1.76(m,1H),1.3 2(t,J=7.4Hz,3H),1.17(td,J=5.1,8.7Hz,1H),0.76(dt,J=2.3,4.9Hz,1H).

[0390] LRMS(ESI,m / z):536[M+H] +

[0391] Example A081 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-[(ethyldioxoylidene-λ6-thio)amino]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxoylidene-2-yl]-2,2,2-trifluoroacetamide (A081)

[0392] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.4Hz,1H),7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7. 23–7.19(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),5.85(d,J=7.7Hz,1H),4.62(d,J=12 .3Hz,1H),4.49–4.43(m,1H),3.85–3.75(m,2H),3.17–3.08(m,1H),3.08–2.95(m,3H),2. 11–2.04(m,1H),1.86–1.80(m,1H),1.71–1.67(m,1H),1.25(t,J=8.6Hz,3H),0.95(s,9H).

[0393] LRMS(ESI,m / z):620[M+H] +

[0394] Example A082 N-{1-[(difluoromethyl)dioxane-λ6-thio]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl}ethanesulfonamide (A082)

[0395] 1H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7 .04(m,2H),6.95–6.89(m,1H),6.24(t,J=57.3Hz,1H),5.86(d,J=7.3Hz,1H),4.35(td,J=7 .4,4.9Hz,1H),3.89–3.85(m,1H),3.58(td,J=6.0,5.2Hz,1H),3.23–3.18(m,1H),3.11–2. 94(m,3H),2.09–2.05(m,1H),1.89–1.83(m,1H),1.76–1.70(m,1H),1.25(t,J=8.6Hz,3H).

[0396] LRMS(ESI,m / z):525[M+H] +

[0397] Example A083 N-(2-{[3-(3,5-difluorophenyl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A083)

[0398] 1 H NMR(400MHz,CD3CN)δ7.58(s,1H),7.52–7.46(m,1H),7.42–7.36(m,2H),7.33(dd ,J=2.0,9.0Hz,2H),7.02–6.90(m,1H),6.02–5.55(m,1H),5.01–4.74(m,1H),4.0 1–3.87(m,1H),3.84–3.76(m,1H),3.58–3.49(m,1H),3.17(dd,J=5.9,13.7Hz,1H ),3.09–2.94(m,3H),1.91–1.78(m,2H),1.36(s,3H),1.31–1.24(m,6H),0.86(br s,1H).

[0399] LRMS(ESI,m / z):479[M+H] +

[0400] Example A084 N-(2-{[6-(3,5-difluorophenyl)pyridin-2-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A084)

[0401] 1 H NMR(500MHz, CDCl3)δ7.62–7.59(m,2H),7.59–7.53(m,2H),6.98–6.94(m,1H),6.92–6.85 (m,1H),5.89(d,J=7.7Hz,1H),4.60(td,J=4.9,4.1Hz,1H),3.99(s,1H),3.81(td,J=4.8, 3.6Hz,1H),3.73(m,1H),3.13(dd,J=14.5,4.9Hz,1H),3.10–2.95(m,3H),2.14–2.09(m,1 H),1.88–1.83(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0402] LRMS(ESI,m / z):480[M+H] +

[0403] Example A085 N-(2-{[5-(3,5-difluorophenyl)pyridin-3-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A085)

[0404] 1 H NMR (500MHz, CDCl3) δ8.59(t,J=1.8Hz,1H),8.39(t,J=1.8Hz,1H),7.81(t,J=2.0Hz,1H), 7.15–7.10(m,2H),6.92(m,1H),5.85(d,J=7.7Hz,1H),4.50(td,J=6.0,3.3Hz,1H),3.99( s,1H),3.81(td,J=4.8,3.7Hz,1H),3.71–3.67(m,1H),3.16–2.95(m,4H),2.14–2.08(m,1 H),1.88–1.83(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0405] LRMS(ESI,m / z):480[M+H] +

[0406] Example A086 N-(2-{[6-(3,5-difluorophenyl)pyrazin-2-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A086)

[0407] 1 H NMR(500MHz, CDCl3)δ8.93(d,J=1.8Hz,1H),8.24(d,J=1.6Hz,1H),7.54–7.48(m,2H) ,7.03–6.98(m,1H),5.90(d,J=7.5Hz,1H),4.64(td,J=5.8,4.2Hz,1H),3.99(s,1H),3 .82(td,J=4.7,3.6Hz,1H),3.76–3.70(m,1H),3.17–2.95(m,4H),2.14–2.09(m,1H),1 .88–1.83(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0408] LRMS(ESI,m / z):481[M+H] +

[0409] Example A087 N-(2-{[2-(3,5-difluorophenyl)-1,3-thiazacyclopentanyl-4-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A087)

[0410] 1 H NMR (500MHz, CDCl3) δ7.30–7.25(m,2H),7.03(s,1H),6.98–6.95(m,1H),5. 89(d,J=7.7Hz,1H),4.62(q,J=4.5Hz,1H),3.99(s,1H),3.82(td,J=4.7,3.6 Hz,1H),3.75–3.70(m,1H),3.11–2.90(m,4H),2.14–2.09(m,1H),1.88–1.82 (m,1H),1.72–1.68(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0411] LRMS(ESI,m / z):486[M+H] +

[0412] Example A088 N-(2-{[3-(3,5-difluorophenyl)isoxazol-5-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A088)

[0413] 1 H NMR (500MHz, CDCl3) δ7.41–7.37(m,2H),6.97–6.92(m,1H),6.13(s,1H),5.90( d,J=7.7Hz,1H),4.58(q,J=5.1Hz,1H),3.99(s,1H),3.79–3.72(m,1H),3.60–3. 55(m,1H),3.34(d,J=5.1Hz,2H),3.11–2.95(m,2H),2.15–2.10(m,1H),1.88–1 .82(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0414] LRMS(ESI,m / z):470[M+H] +

[0415] Example A089 N-(2-{[1-(3,5-difluorophenyl)-2-oxoylidenepyridin-3-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A089)

[0416] 1 H NMR(400MHz,CD3CN)δ7.54–7.43(m,1H),7.43–7.33(m,1H),7.21–7.04(m,4H),6.44–6.22(m,1H),4.68 –4.31(m,2H),4.01(s,2H),3.11–2.54(m,4H),1.53–1.42(m,6H),1.31–1.21(m,3H),1.20–0.76(m,3H).

[0417] LRMS(ESI,m / z):496[M+H] +

[0418] Example A090 N-(2-{[3-(3,5-difluorophenyl)bicyclo[1.1.1]pent-1-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A090)

[0419] 1 H NMR (500MHz, CDCl3) δ6.90–6.84(m,1H),6.83–6.79(m,2H),5.71(d,J=7.3Hz,1H),4. 23(q,J=3.3Hz,1H),3.99(s,1H),3.85–3.80(m,1H),3.63–3.57(m,1H),3.11–2.95(m, 2H),2.11–2.06(m,1H),1.95(dd,J=13.1,3.2Hz,1H),1.88–1.83(m,1H),1.75(dd,J= 13.2,3.1Hz,1H),1.71–1.65(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0420] LRMS(ESI,m / z):469[M+H] +

[0421] Example A091 N-(2-{[4-(3,5-difluorophenyl)bicyclo[2.1.1]hex-1-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A091)

[0422] 1 H NMR (500MHz, CDCl3) δ6.89–6.85(m,1H),6.83–6.77(m,2H),5.71(d,J=7.3Hz,1H),4.20(q,J =3.4Hz,1H),3.99(s,1H),3.85–3.80(m,1H),3.63–3.57(m,1H),3.11–2.95(m,2H),2.20–2. 14(m,2H),2.13–2.05(m,3H),2.03–1.93(m,2H),1.88–1.83(m,1H),1.79(dd,J=13.3,3.6Hz ,1H),1.75–1.65(m,3H),1.65–1.60(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0423] LRMS(ESI,m / z):483[M+H] +

[0424] Example A092 N-(2-{[2-(3,5-difluorophenyl)pentacyclo[4.2.0.03,8.02,5.04,7]oct-7-yl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A092)

[0425] 1 H NMR (500MHz, CDCl3) δ7.09–7.03(m,2H),6.89–6.83(m,1H),5.71(d,J=7.3Hz,1H),4.35–4.30(m,1H),3.99(s,1H),3.86–3.76(m,2H),3.11–2 .95(m,5H),2.13–2.03(m,2H),1.88–1.83(m,1H),1.77–1.65(m,2H),1 .38(s,2H),1.33(s,3H),1.31(t,J=3.8Hz,3H),1.25(t,J=8.7Hz,3H).

[0426] LRMS(ESI,m / z):505[M+H] +

[0427] Example A093 3-(3,5-difluorophenyl)-N-{3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-2-yl}-2-(methylamino)propionamide (A093)

[0428] 1H NMR(500MHz, CDCl3)δ7.29(d,J=6.4Hz,1H),6.91–6.85(m,1H),6.81–6.77(m,2H),5.83(d,J =7.7Hz,1H),5.53–5.48(m,1H),5.44(dd,J=6.4,1.8Hz,1H),4.04(s,1H),3.74–3.67(m,2H), 3.67–3.64(m,1H),3.10–2.98(m,2H),2.96–2.90(m,2H),2.43(d,J=4.8Hz,3H),2.06–2.00(m ,1H),1.89–1.82(m,1H),1.74–1.68(m,1H),1.38(s,2H),1.33(s,3H),1.26(t,J=8.7Hz,3H).

[0429] LRMS(ESI,m / z):489[M+H] +

[0430] Example A094 3-(3,5-difluorophenyl)-N-{3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-2-yl}-4-methyl-2-(methylamino)pentanamide (A094)

[0431] 1 H NMR(500MHz, CDCl3)δ7.28(d,J=6.6Hz,1H),6.95–6.88(m,2H),6.88–6.85(m,1H),5.83(d,J=7.7Hz ,1H),5.50(dd,J=6.6,1.8Hz,1H),5.25–5.20(mz,1H),4.04(s,1H),3.77–3.64(m,3H),3.20–3.13(m ,1H),3.11–2.95(m,2H),2.42(d,J=4.6Hz,3H),211–2.07(m,1H),2.06–2.00(m,1H),1.89–1.83(m,1 H),1.74–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.26(t,J=8.7Hz,3H),0.87(dd,J=6.7,1.0Hz,6H).

[0432] LRMS(ESI,m / z):531[M+H] +

[0433] Example A095 3-(3,5-difluorophenyl)-N-({3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-2-yl}methyl)-2-(methylamino)propionamide (A095)

[0434] 1 H NMR(500MHz, CDCl3)δ7.22(t,J=6.5Hz,1H),6.90–6.85(m,1H),6.81–6.75(m,2H),5.93(d,J=7 .5Hz,1H),5.44–5.39(m,1H),4.18–4.13(m,1H),3.99(s,1H),3.82–3.78(m,1H),3.75–3.68(m, 2H),3.44–3.38(m,2H),3.11–2.95(m,2H),2.95–2.84(m,2H),2.43(d,J=4.6Hz,3H),2.13–2.08 (m,1H),1.87–1.81(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0435] LRMS(ESI,m / z):503[M+H] +

[0436] Example A096 3-(3,5-difluorophenyl)-N-{3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-2-yl}-3-(methylamino)propionamide (A096)

[0437] 1H NMR(500MHz, CDCl3)δ7.62(d,J=6.2Hz,1H),7.00–6.96(m,2H),6.97–6.92(m,1H),5.83(d,J=7.7Hz,1H ),5.49(dd,J=6.3,1.5Hz,1H),5.28–5.23(m,1H),4.29–4.21(m,1H),4.04(s,1H),3.72–3.66(m,2H),3 .11–2.95(m,2H),2.67(dd,J=16.8,7.3Hz,1H),2.60(dd,J=16.8,7.1Hz,1H),2.47(d,J=4.9Hz,3H),2. 06–2.00(m,1H),1.89–1.82(m,1H),1.74–1.68(m,1H),1.38(s,2H),1.33(s,3H),1.26(t,J=8.7Hz,3H).

[0438] LRMS(ESI,m / z):489[M+H] +

[0439] Example A097 3-(3,5-difluorophenyl)-N-({3-[(ethyldioxane-λ6-thio)amino]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-2-yl}methyl)-3-(methylamino)propionamide (A097)

[0440] 1 H NMR(500MHz, CDCl3)δ7.00(t,J=6.2Hz,1H),6.99–6.96(m,2H),6.96–6.91(m,1H),5.93(d,J=7.5Hz ,1H),5.28–5.23(m,1H),4.28–4.23(m,1H),4.14–4.08(m,1H),3.99(s,1H),3.81–3.76(m,1H),3.75 –3.70(m,1H),3.44–3.33(m,2H),3.11–2.95(m,2H),2.68–2.55(m,2H),2.47(d,J=4.9Hz,3H),2.13– 2.08(m,1H),1.87–1.80(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0441] LRMS(ESI,m / z):503[M+H] +

[0442] Example A098 2-Hydroxy-1-{2-[(R)-[3-(3,5-difluorophenyl)-2-fluorophenyl](hydroxy)methyl]-3-(mercaptoamino)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl}-2-methylprop-1-one (A098)

[0443] 1 H NMR(500MHz, CDCl3)δ7.73(dd,J=8.8,1.1Hz,1H),7.45–7.40(m,1H),7.20(d,J=2.2Hz,2H),7.17( dd,J=9.4,8.7Hz,1H),6.99(t,J=2.1Hz,1H),5.21–5.17(m,1H),4.74(dd,J=6.5,4.5Hz,1H),4.26( d,J=4.9Hz,1H),4.04(s,1H),3.82–3.74(m,2H),3.70(d,J=5.9Hz,1H),2.57–2.50(m,2H),2.20–2 .15(m,1H),1.88–1.83(m,1H),1.66–1.60(m,1H),1.47(d,J=7.4Hz,3H),1.38(s,3H),1.33(s,3H).

[0444] LRMS(ESI,m / z):499[M+H] +

[0445] Example A099 N-{2-[(2-fluoro-3-phenylphenyl)methyl]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl}ethanesulfonamide (A099)

[0446] 1 H NMR (400MHz, CD3CN) δ7.61–7.52(m,2H),7.51–7.45(m,2H),7.44–7.37(m,1H),7.34–7.22(m,2H),7.21–7.11(m,1H),5.80(br d,J=8.8Hz,1H),5.06–4.37(m,1H),4.17–3.73(m,2H),3.55–2.68(m,5H),1 .46–1.26(m,7H),1.25–1.15(m,3H),1.10–1.03(m,1H),0.94–0.85(m,1H).

[0447] LRMS(ESI,m / z):461[M+H] +

[0448] Example A100 N-(2-{[2-fluoro-3-(pyridin-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A100)

[0449] 1 H NMR (400MHz, CD3CN) δ8.72–8.64(m,1H),7.91–7.85(m,1H),7.80–7.75(m,1H),7.65(dt,J=1.8,7.6Hz,1H),7.37(dt,J=1.0, 6.2Hz,2H),7.18(t,J=7.6Hz,1H),5.84(brd,J=7.5Hz,1H),5.00–4.87(m,1H),4.61–4.48(m,1H),3.82–3.71(m,1H),3.62(br d,J=3.3Hz,1H),3.19–3.08(m,3H),3.04–2.95(m,1H),1.34(t,J=7.4Hz,3H),1.30–1.22(m,8H),0.91–0.83(m,1H).

[0450] LRMS(ESI,m / z):462[M+H] +

[0451] Example A101 N-(2-{[2-fluoro-3-(pyrimidin-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A101)

[0452] 1 H NMR(400MHz,CD3CN)δ8.88(d,J=4.8Hz,2H),7.78(dt,J=1.8,7.5Hz,1H),7.49–7.33(m,2H),7.20(t,J=7.6Hz,1H),5.81(br d,J=8.4Hz,1H),4.89(td,J=5.3,10.0Hz,1H),4.61(br s,1H),3.82–3.63(m,2H),3.16–3.10(m,3H),3.08–3.00(m,1H),1.35(t,J=7.4Hz,3H),1.32–1.18(m,8H),0.89–0.81(m,1H).

[0453] LRMS(ESI,m / z):463[M+H]+

[0454] Example A102 N-(2-{[2-fluoro-3-(2H,1H-1,2-azaboronecyclohexyl-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A102)

[0455] 1 H NMR(500MHz, CDCl3)δ7.65(d,J=5.7Hz,1H),7.58–7.51(m,1H),7.12–7.06(m,2H),7.00–6.92(m,2H ),6.30–6.25(m,1H),6.08–6.02(m,1H),5.85(d,J=7.7Hz,1H),4.51(td,J=6.3,3.5Hz,1H),3.99(s ,1H),3.81(td,J=4.8,3.6Hz,1H),3.77–3.68(m,1H),3.10–2.99(m,2H),2.99–2.90(m,2H),2.14–2 .08(m,1H),1.88–1.83(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0456] LRMS(ESI,m / z):462[M+H] +

[0457] Example A103 N-(2-{[2-fluoro-3-(furan-3-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A103)

[0458] 1H NMR(500MHz, CDCl3)δ7.81(q,J=1.8Hz,1H),7.64–7.58(m,2H),7.30(t,J=9.0Hz,1H),7.21–7 .16(m,1H),6.82(q,J=1.7Hz,1H),5.85(d,J=7.7Hz,1H),4.51–4.45(m,1H),3.99(s,1H),3.81 (td,J=4.8,3.6Hz,1H),3.77–3.71(m,1H),3.15–3.10(m,1H),3.10–2.96(m,4H),2.14–2.09( m,1H),1.88–1.83(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0459] LRMS(ESI,m / z):451[M+H] +

[0460] Example A104 N-(2-{[2-fluoro-3-(2-methyl-1,3-thiazacyclopentanyl-4-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A104)

[0461] 1 H NMR(400MHz,CD3CN)δ8.00–7.89(m,1H),7.67(d,J=2.4Hz,1H),7.50–7.20(m,1H),7.20–7.10(m,1H),5.95–5.43(m ,1H),4.95(td,J=5.3,10.7Hz,1H),4.80–4.70(m,1H),4.51–4.41(m,1H),4.12(dt,J=2.9,6.4Hz,1H),3.77(dd,J=2 .9,6.2Hz,1H),3.59–3.46(m,1H),3.20(dd,J=4.3,13.5Hz,1H),3.15–3.01(m,2H),3.00–2.89(m,1H),2.75(s,3H) ,1.42–1.33(m,3H),1.33–1.30(m,3H),1.30–1.25(m,1H),1.25–1.20(m,3H),1.11–1.02(m,1H),0.93–0.86(m,1H).

[0462] LRMS(ESI,m / z):482[M+H] +

[0463] Example A105 N-(2-{[2-fluoro-3-(1,3-oxazacyclopentanyl-5-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A105)

[0464] 1 H NMR (500MHz, CDCl3) δ8.32(d,J=1.8Hz,1H),7.86(t,J=1.8Hz,1H),7.73–7.68(m,1H),7.26(d d,J=10.2,9.1Hz,1H),7.23–7.19(m,1H),5.85(d,J=7.7Hz,1H),4.51–4.46(m,1H),3.99(s,1 H),3.84–3.78(m,1H),3.77–3.71(m,1H),3.18–3.12(m,1H),3.11–2.95(m,3H),2.14–2.08(m ,1H),1.88–1.83(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0465] LRMS(ESI,m / z):452[M+H] +

[0466] Example A106 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,7,9-trifluoro-6H-benzo[c]chromen-2-yl)methyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]ethanesulfonamide (A106)

[0467] 1H NMR(500MHz, CDCl3)δ7.25–7.20(m,1H),7.09(dt,J=8.0,2.1Hz,1H),6.93–6.85(m,2H),5. 85(d,J=7.7Hz,1H),5.04–4.92(m,2H),4.49(td,J=6.2,3.3Hz,1H),3.99(s,1H),3.81(td, J=4.8,3.6Hz,1H),3.77–3.71(m,1H),3.14–3.08(m,1H),3.08–2.95(m,3H),2.14–2.08(m, 1H),1.88–1.83(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0468] LRMS(ESI,m / z):525[M+H] +

[0469] Example A107 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,7,9-trifluoro-5,6-dihydrophenanthridine-2-yl)methyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]ethanesulfonamide (A107)

[0470] 1 H NMR (500MHz, CDCl3) δ7.16–7.11(m,1H),6.99(dt,J=7.9,2.1Hz,1H),6.89(td,J=8.0,2.2Hz,1H),6.67(d,J =9.4Hz,1H),5.85(d,J=7.7Hz,1H),5.60(t,J=5.8Hz,1H),4.68(dd,J=12.2,5.8Hz,2H),4.49(td,J=6.3,3. 5Hz,1H),3.99(s,1H),3.81(td,J=4.8,3.6Hz,1H),3.76–3.70(m,1H),3.11–3.07(m,1H),3.07–2.96(m,3H) ,2.13–2.08(m,1H),1.88–1.83(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0471] LRMS(ESI,m / z):524[M+H] +

[0472] Example A108 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,8,10-trifluoro-6,7-dihydrodibenzo[1,2-b:1',2'-d]oxacycloheptan-2-yl)methyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]ethanesulfonamide (A108)

[0473] 1 H NMR (500MHz, CDCl3) δ7.26–7.20(m,1H),6.94–6.88(m,1H),6.70(d,J=10.0Hz,1H),5.85( d,J=7.7Hz,1H),4.49(td,J=6.2,3.3Hz,1H),4.39–4.31(m,2H),3.99(s,1H),3.81(td,J= 4.8,3.6Hz,1H),3.76–3.70(m,1H),3.17–3.14(m,1H),3.13–2.97(m,6H),2.14–2.09(m,1 H),1.87–1.81(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0474] LRMS(ESI,m / z):539[M+H] +

[0475] Example A109 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,8,10-trifluoro-5,7-dihydrodibenzo[1,2-c:1',2'-e]oxacycloheptan-2-yl)methyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]ethanesulfonamide (A109)

[0476] 1H NMR(500MHz, CDCl3)δ7.02(dt,J=9.3,1.0Hz,1H),7.00–6.90(m,3H),5.85(d,J=7.7Hz,1H),5.0 7(s,1H),5.03(s,1H),4.97(dd,J=13.9,0.9Hz,2H),4.49(td,J=6.3,3.5Hz,1H),3.99(s,1H),3 .81(td,J=4.8,3.6Hz,1H),3.76–3.70(m,1H),3.16–3.10(m,1H),3.11–2.95(m,3H),2.14–2.08 (m,1H),1.87–1.81(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0477] LRMS(ESI,m / z):539[M+H] +

[0478] Example A110 N-[1-(2-hydroxy-2-methylpropionyl)-2-[(1,8,10-trifluoro-6-methyl-6,7-dihydro-5H-dibenzo[1,2-c:1',2'-e]azacycloheptan-2-yl)methyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]ethanesulfonamide (A110)

[0479] 1 H NMR(500MHz, CDCl3)δ7.04(dt,J=9.4,1.0Hz,1H),6.99–6.87(m,3H),5.85(d,J=7.7Hz,1H),4. 49(td,J=6.3,3.5Hz,1H),3.99(s,1H),3.81(td,J=4.8,3.6Hz,1H),3.76–3.70(m,1H),3.58–3 .52(m,2H),3.52–3.47(m,2H),3.16–3.10(m,1H),3.11–2.95(m,3H),2.24(s,2H),2.13–2.07( m,1H),1.88–1.83(m,1H),1.71–1.66(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0480] LRMS(ESI,m / z):552[M+H] +

[0481] Example A111 N-{2-[(8,10-difluoro-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline-2-yl)methyl]-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl}ethanesulfonamide (A111)

[0482] 1 H NMR (500MHz, CDCl3) δ6.81–6.75(m,2H),5.86(d,J=7.5Hz,1H),4.13(td,J=5.9,3.5Hz,1H),3.9 9(s,1H),3.81(td,J=4.8,3.7Hz,1H),3.59–3.54(m,1H),3.54–3.48(m,1H),3.10–2.98(m,4H),2 .98–2.88(m,3H),2.88–2.82(m,1H),2.69(dt,J=12.4,7.1Hz,1H),2.10–2.05(m,1H),2.01–1.9 1(m,1H),1.88–1.67(m,8H),1.61–1.56(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0483] LRMS(ESI,m / z):512[M+H] +

[0484] Example A112 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A112)

[0485] 1H NMR (400MHz, CD3CN) δ7.61–7.29(m,2H),7.27–7.14(m,3H),7.08–6.92(m,1H),6.59–6.10(m,1H),5.42–5.07(m,2H),5.03–4.70(m,1H),4.53(br dd,J=5.9,9.3Hz,1H),4.15(td,J=3.1,6.3Hz,1H),3.97–3.80(m,2H),3.65–3.48(m,1H),3.19(br dd,J=4.9,13.6Hz,1H),2.96(br dd,J=10.3,13.3Hz,1H),2.77(br dd,J=4.0,14.4Hz,1H),1.95–1.88(m,1H),1.44(d,J=1.5Hz,1H),1.33(s,2H),1.27–1.19(m,3H),1.07(br s,1H),0.90(br s,1H).

[0486] LRMS(ESI,m / z):501[M+H] +

[0487] Example A113 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-difluoromethanesulfonamide (A113)

[0488] 1 H NMR(400MHz,CD3CN)δ7.44–7.31(m,2H),7.26–7.12(m,3H),7.04–6.98(m,1H), 6.51(t,J=53.3Hz,1H),5.07–4.83(m,1H),3.97(dd,J=2.2,6.3Hz,1H),3.85(br d,J=9.4Hz,1H),3.57(br t,J=4.7Hz,1H),3.18(br dd,J=5.1,13.6Hz,1H),2.98(br dd,J=10.3,13.3Hz,2H),1.33(s,3H),1.28–1.16(m,4H),0.90(br s,1H).

[0489] LRMS(ESI,m / z):519[M+H] +

[0490] Example A114 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1,1-trifluoromethanesulfonamide (A114)

[0491] 1 H NMR (500MHz, CDCl3) δ7.67–7.61(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.11– 7.04(m,2H),7.00(d,J=10.4Hz,1H),6.95–6.90(m,1H),4.52(td,J=6.2,2.7Hz,1H),3.99 (s,1H),3.93–3.87(m,1H),3.81(td,J=4.8,3.6Hz,1H),3.15–3.10(m,1H),3.05–3.00(m ,1H),2.10–2.05(m,1H),1.88–1.83(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H).

[0492] LRMS(ESI,m / z):537[M+H] +

[0493] Example A115 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-2,2,2-trifluoroethanesulfonamide (A115)

[0494] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.1 1–7.04(m,2H),6.95–6.89(m,1H),6.04(d,J=6.8Hz,1H),4.49(td,J=6.2,3.3Hz,1H), 4.18–4.13(m,2H),3.99(s,1H),3.84–3.74(m,2H),3.15–3.10(m,1H),3.05–3.00(m,1 H),2.14–2.09(m,1H),1.88–1.83(m,1H),1.71–1.65(m,1H),1.38(s,2H),1.33(s,3H).

[0495] LRMS(ESI,m / z):551[M+H] +

[0496] Example A116 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)cyclopropanesulfonamide (A116)

[0497] 1 H NMR (400MHz, CD3CN) δ7.64–7.12(m,5H),7.07–6.92(m,1H),5.99–5.63(m,1H),5.10–4.67(m,1H),4.52(br s,1H),3.93(br d,J=9.0Hz,1H),3.84(br dd,J=1.9,5.9Hz,1H),3.60–3.44(m,1H),3.21(dd,J=4.9,13.6Hz,1H),2.94(dd ,J=10.3,13.2Hz,1H),2.82–2.45(m,1H),1.45–1.19(m,6H),1.16–0.83(m,6H).

[0498] LRMS(ESI,m / z):509[M+H] +

[0499] Example A117 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluorocyclopropanesulfonamide (A117)

[0500] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.1 1–7.04(m,2H),6.95–6.89(m,1H),6.62(d,J=8.4Hz,1H),4.52(td,J=6.2,2.7Hz,1H), 3.99(s,1H),3.84–3.77(m,2H),3.15–3.10(m,1H),3.05–3.00(m,1H),2.24–2.11(m,3 H),2.11–2.04(m,2H),1.88–1.83(m,1H),1.72–1.66(m,1H),1.38(s,3H),1.33(s,3H).

[0501] LRMS(ESI,m / z):527[M+H] +

[0502] Example A118 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)oxetane-3-sulfonamide (A118)

[0503] 1 H NMR (500MHz, CDCl3) δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7. 11–7.04(m,2H),6.95–6.89(m,1H),6.64(d,J=7.7Hz,1H),4.53–4.44(m,2H),4.01–3. 94(m,3H),3.88–3.78(m,3H),3.78–3.74(m,1H),3.15–3.10(m,1H),3.05–3.00(m,1H ),2.11–2.06(m,1H),1.88–1.83(m,1H),1.71–1.67(m,1H),1.38(s,2H),1.33(s,3H).

[0504] LRMS(ESI,m / z):525[M+H] +

[0505] Example A119 1-Cyano-N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)methanesulfonamide (A119)

[0506] 1H NMR(400MHz,CD3CN)δ7.66–7.30(m,2H),7.28–7.13(m,3H),7.07–6.92(m,1H ),5.14-4.73(m,1H),4.58(dd,J=5.8,9.6Hz,1H),4.37–4.23(m,2H),4.19(br d,J=2.6Hz,1H),4.07-3.76(m,2H),3.62–3.48(m,1H),3.18(br dd,J=5.1,13.6Hz,1H),3.07–2.92(m,2H),2.80-2.74(m,1H),1.44–1.18(m,6H),1.11–0.85(m,1H).

[0507] LRMS(ESI,m / z):508[M+H] +

[0508] Example A120 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A120)

[0509] 1 H NMR (400MHz, CD3CN) δ7.61–7.29(m,2H),7.20(br dd,J=7.8,16.6Hz,3H),7.04–6.96(m,1H),5.79(br d,J=1.1Hz,1H),5.06–4.94(m,1H),4.73(td,J=4.4,8.8Hz,1H),4.41(br d,J=5.5Hz,1H),4.10(br d,J=2.6Hz,1H),3.91(br s,1H),3.75(br s,1H),3.53–3.44(m,1H),3.21(dd,J=4.6,13.7Hz,1H),3.13–2.86(m,1H),2.81–2.68(m,6H),1 .43(d,J=3.4Hz,1H),1.33(s,2H),1.27(td,J=5.6,8.8Hz,1H),1.22(s,2H),1.09–0.82(m,1H).

[0510] LRMS(ESI,m / z):512[M+H] +

[0511] Example A121 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)tetrahydropyrrole-1-sulfonamide (A121)

[0512] 1 H NMR(400MHz,CD3CN)δ7.35(q,J=7.8Hz,2H),7.27–7.12(m,3H),7.07–6.92(m,1H),5.90–5.45(m ,1H),5.10–4.61(m,1H),4.51–4.33(m,1H),4.18–3.85(m,1H),3.76(brd,J=3.4Hz,1H),3.48(br t,J=4.9Hz,1H),3.28(br t,J=6.7Hz,3H),3.24–2.99(m,2H),2.97–2.64(m,1H),1.93–1.90(m,3H),1.86–1.78(m,1H),1.45–1.20(m,6H),1.07–0.86(m,1H).

[0513] LRMS(ESI,m / z):538[M+H] +

[0514] Example A122 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)benzenesulfonamide (A122)

[0515] 1 H NMR (400MHz, CD3CN) δ7.99–7.84(m,2H),7.75–7.52(m,3H),7.40–7.18(m,4H),7.17–7. 09(m,1H),7.04–6.95(m,1H),6.49–5.94(m,1H),4.95–4.63(m,1H),4.35(dd,J=5.9,9.6 Hz,1H),4.07–3.80(m,1H),3.68(dd,J=2.6,6.2Hz,1H),3.46–3.31(m,1H),3.07–2.67(m ,2H),1.65–1.50(m,1H),1.39–1.15(m,6H),1.04(td,J=5.7,8.7Hz,1H),0.72(brs,1H).

[0516] LRMS(ESI,m / z):545[M+H] +

[0517] Example A123 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-3-methylimidazolium-5-sulfonamide (A123)

[0518] 1 H NMR(400MHz,CD3CN)δ7.66–7.45(m,2H),7.36–7.10(m,5H),7.00(br t,J=9.3Hz,1H),6.39–5.83(m,1H),4.89(td,J=5.3,10.2Hz,1H),4.74–3.98(m,1H),3.95–3.81(m,1H),3.75–3.66(m,4 H),3.48–3.36(m,1H),3.17–2.82(m,2H),1.83–1.57(m,1H),1.43–1.37(m,1H),1.29(s,3H),1.22–1.10(m,3H),1.02(br d,J=7.0Hz,1H),0.85–0.70(m,1H).

[0519] LRMS(ESI,m / z):549[M+H] +

[0520] Example A124 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)prop-2-ene-1-sulfonamide (A124)

[0521] 1H NMR(400MHz,CD3CN)δ7.65–7.12(m,5H),7.06–6.94(m,1H),6.84–6.62(m,1H),6.34–6.2 3(m,1H),6.17–5.65(m,1H),5.58–5.34(m,1H),5.08–4.65(m,1H),4.51–4.41(m,1H),4. 36–4.24(m,1H),4.19–4.05(m,1H),3.96–3.69(m,3H),3.65–3.41(m,1H),3.38–3.13(m, 1H),3.08–2.83(m,1H),2.77–2.65(m,1H),1.95–1.80(m,2H),1.43–1.15(m,4H),1.04(br d,J=4.1Hz,1H),0.89(br s,1H).

[0522] LRMS(ESI,m / z):509[M+H] +

[0523] Example A125 1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1'-(ethyldioxane-λ6-thio)-1,1',2,3',3a,4',4a,5'-octahydrospiro[cyclopropano[1,2-b]pyrrole-3,2'-pyrrole]-1-yl)-2-hydroxy-2-methylprop-1-one (A125)

[0524] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.16(m,1H),7.11–7.04( m,2H),6.95–6.85(m,1H),4.26(t,J=7.1Hz,1H),3.99(s,1H),3.70–3.65(m,1H),3.42–3.30(m, 2H),3.22–3.13(m,2H),3.12–3.06(m,1H),2.96–2.90(m,1H),2.11(q,J=4.6Hz,1H),1.94–1.85 (m,1H),1.85–1.72(m,4H),1.69–1.63(m,1H),1.38(s,3H),1.33(s,3H),1.30(t,J=9.0Hz,3H).

[0525] LRMS(ESI,m / z):537[M+H] +

[0526] Example A126 2'-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1'-(2-hydroxy-2-methylpropionyl)-1',2',3a',4a'-tetrahydro-1λ6-spiro[1,2-thiazazacyclopentane-3,3'-cyclopropano[1,2-b]pyrrole]-1,1-dione (A126)

[0527] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.22–7.16(m,1H),7.11–7.0 4(m,2H),6.95–6.85(m,1H),6.22(s,1H),4.23(t,J=6.4Hz,1H),3.99(s,1H),3.67–3.62(m, 1H),3.26–3.14(m,2H),3.14–3.08(m,1H),2.96–2.90(m,1H),2.34–2.29(m,1H),2.20–2.14 (m,1H),2.14–2.08(m,1H),1.81–1.76(m,1H),1.69–1.62(m,1H),1.38(s,2H),1.33(s,3H).

[0528] LRMS(ESI,m / z):495[M+H] +

[0529] Example A127 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-2-oxanediacetic acid methyl ester (A127)

[0530] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7 .11–7.04(m,2H),6.95–6.85(m,1H),6.16(d,J=8.6Hz,1H),5.24(s,1H),5.15(s,1H ),4.58–4.53(m,1H),3.90–3.85(m,1H),3.81(s,3H),3.75–3.70(m,1H),3.11–3.05 (m,1H),3.03–2.98(m,1H),2.09–2.03(m,1H),1.87–1.82(m,1H),1.74–1.69(m,1H).

[0531] LRMS(ESI,m / z):501[M+H] +

[0532] Example A128 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A128)

[0533] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.04(m,2H) ,6.95–6.85(m,1H),6.19(d,J=8.6Hz,1H),5.24(s,1H),5.15(s,1H),4.48(t,J=4.2Hz,1H),4.31–4. 26(m,1H),3.99–3.94(m,1H),3.89–3.80(m,2H),3.74–3.68(m,1H),3.15–3.10(m,1H),3.05–3.00(m ,1H),2.40–2.35(m,1H),2.23–2.17(m,1H),2.12–2.05(m,1H),1.85–1.80(m,1H),1.73–1.68(m,1H).

[0534] LRMS(ESI,m / z):499[M+H] +

[0535] Example A129 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A129)

[0536] 1H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7. 11–7.04(m,2H),6.95–6.85(m,1H),6.16(d,J=8.6Hz,1H),5.24(s,1H),5.15(s,1H), 4.63–4.58(m,1H),3.82(q,J=5.1Hz,1H),3.72–3.67(m,1H),3.10–3.05(m,1H),3.03 –2.97(m,1H),2.94(s,6H),2.07–2.00(m,1H),1.81–1.76(m,1H),1.64–1.58(m,1H).

[0537] LRMS(ESI,m / z):486[M+H] +

[0538] Example A130 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1-fluoromethanesulfonamide (A130)

[0539] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.11–7.04(m,2H),6.95–6.85(m,1H),6.19(d,J=8.6Hz,1H),5.24(s,1H),5.15 (s,1H),4.35–4.30(m,1H),3.78–3.70(m,2H),3.16–3.10(m,1H),3.05–3.00(m, 1H),2.15–2.05(m,5H),1.93–1.84(m,3H),1.85–1.80(m,1H),1.69–1.63(m,1H).

[0540] LRMS(ESI,m / z):509[M+H] +

[0541] Example A131 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A131)

[0542] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H),7.10–7.04(m,2H),6.95 –6.85(m,1H),6.19(d,J=8.6Hz,1H),5.24(s,1H),5.15(s,1H),4.47–4.41(m,1H),3.92–3.86(m,1H),3.85 –3.79(m,1H),3.77(d,J=4.4Hz,1H),3.74(q,J=4.9Hz,1H),3.14–3.09(m,1H),3.02–2.97(m,1H),2.90–2. 84(m,1H),2.22–2.16(m,2H),2.10–2.03(m,1H),1.94–1.90(m,2H),1.84–1.79(m,1H),1.69–1.65(m,1H)..

[0543] LRMS(ESI,m / z):513[M+H] +

[0544] Example A132 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A132)

[0545] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H),7.11–7.0 4(m,2H),6.95–6.85(m,1H),6.47(t,J=5.3Hz,1H),6.16(d,J=8.6Hz,1H),5.24(s,1H),5.15 (s,1H),4.25–4.19(m,1H),3.92–3.84(m,2H),3.81(q,J=4.8Hz,1H),3.77–3.73(m,1H),3.1 2–3.07(m,1H),3.04–2.98(m,1H),2.07–2.00(m,1H),1.86–1.80(m,1H),1.66–1.61(m,1H).

[0546] LRMS(ESI,m / z):540[M+H] +

[0547] Example A133 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxomylidenebut-2-yl]-2,2,2-trifluoroacetamide (A133)

[0548] 1 H NMR (500MHz, CDCl3) δ7.80 (d, J=12.4Hz, 1H), δ7.67–7.63 (m, 1H), 7.28 (t, J=9.0Hz, 1H), 7.23–7. 19(m,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.19(d,J=8.6Hz,1H),5.24(s,1H),5.15(s,1H) ,4.62(d,J=12.3Hz,1H),4.49–4.44(m,1H),3.82(q,J=5.0Hz,1H),3.76–3.70(m,1H),3.18–3.12 (m,1H),3.03–2.98(m,1H),2.11–2.04(m,1H),1.86–1.80(m,1H),1.72–1.67(m,1H),0.95(s,9H).

[0549] LRMS(ESI,m / z):624[M+H] +

[0550] Example A134: 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-2-oxanediacetic acid methyl ester (A134)

[0551] 1H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H ),7.11–7.04(m,2H),6.95–6.85(m,1H),6.14(d,J=7.1Hz,1H),4.55–4.50(m,1H) ,3.94–3.89(m,1H),3.89–3.85(m,1H),3.81(s,3H),3.11–3.06(m,1H),3.04–2. 89(m,1H),2.69(s,6H),2.02–1.97(m,1H),1.87–1.82(m,1H),1.73–1.68(m,1H).

[0552] LRMS(ESI,m / z):512[M+H] +

[0553] Example A135 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A135)

[0554] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H),7.1 1–7.04(m,2H),6.95–6.85(m,1H),6.14(d,J=7.1Hz,1H),4.52–4.45(m,2H),3.99–3.93 (m,1H),3.89–3.76(m,3H),3.15–3.09(m,1H),3.04–2.98(m,1H),2.69(s,6H),2.39–2. 35(m,1H),2.23–1.98(m,1H),2.07–1.99(m,1H),1.85–1.79(m,1H),1.74–1.68(m,1H).

[0555] LRMS(ESI,m / z):510[M+H] +

[0556] Example A136 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A136)

[0557] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H) ,7.11–7.04(m,2H),6.95–6.85(m,1H),6.15(d,J=7.3Hz,1H),4.65–4.60(m,1H), 3.93–3.88(m,1H),3.82(q,J=5.1Hz,1H),3.10–3.04(m,1H),3.03–2.98(m,1H),2 .94(s,6H),2.69(s,6H),2.09–2.03(m,1H),1.84–1.78(m,1H),1.64–1.59(m,1H).

[0558] LRMS(ESI,m / z):497[M+H] +

[0559] Example A137 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1,1-dimethylazinesulfonamide (A137)

[0560] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,2H),7.28(t,J=9.0Hz,2H),7.24–7.18(m,2H) ,7.11–7.04(m,4H),6.95–6.85(m,2H),6.14(d,J=7.1Hz,2H),4.45–4.40m,2H),3. 79–3.70(m,4H),3.17–3.11(m,2H),3.05–2.98(m,2H),2.69(s,12H),2.15–2.04(m ,9H),2.04–2.01(m,1H),1.93–1.85(m,6H),1.85–1.79(m,2H),1.69–1.63(m,2H).

[0561] LRMS(ESI,m / z):520[M+H] +

[0562] Example A138 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A138)

[0563] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7.11–7.04(m, 2H),6.95–6.85(m,1H),6.14(d,J=7.1Hz,1H),4.50–4.45(m,1H),3.91–3.86(m,1H),3.82–3.79(m ,1H),3.78–3.72(m,2H),3.15–3.09(m,1H),3.03–2.97(m,1H),2.86(p,J=7.0Hz,1H),2.69(s,6H ),2.22–2.17(m,2H),2.05–1.98(m,1H),1.95–1.90(m,2H),1.84–1.79(m,1H),1.69–1.65(m,1H).

[0564] LRMS(ESI,m / z):524[M+H] +

[0565] Example A139 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A139)

[0566] 1H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7.11– 7.04(m,2H),6.95–6.85(m,1H),6.47(t,J=5.3Hz,1H),6.15(d,J=7.3Hz,1H),4.49–4.45 (m,1H),3.96–3.90(m,1H),3.91–3.85(m,2H),3.81(q,J=4.8Hz,1H),3.11–3.05(m,1H), 3.03–2.98(m,1H),2.69(s,6H),2.06–1.99(m,1H),1.86–1.80(m,1H),1.65–1.59(m,1H).

[0567] LRMS(ESI,m / z):551[M+H] +

[0568] Example A140 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A140)

[0569] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m ,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.14(d,J=7.1Hz,1H),4.61–4.56 (m,1H),3.91–3.86(m,1H),3.81–3.76(m,1H),3.16–3.10(m,1H),3.05–2.98( m,1H),2.69(s,6H),2.03–1.96(m,1H),1.86–1.80(m,1H),1.70–1.66(m,1H).

[0570] LRMS(ESI,m / z):522[M+H] +

[0571] Example A141 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxomylidenebut-2-yl]-2,2,2-trifluoroacetamide (A141)

[0572] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.4Hz,1H),7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H), 7.23–7.19(m,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.14(d,J=7.1Hz,1H),4.62(d, J=12.3Hz,1H),4.31–4.26(m,1H),3.86–3.76(m,2H),3.16–3.10(m,1H),3.03–2.97(m, 1H),2.69(s,6H),2.07–2.00(m,1H),1.86–1.80(m,1H),1.72–1.67(m,1H),0.95(s,9H).

[0573] LRMS(ESI,m / z):635[M+H] +

[0574] Example A142 2-{3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropyl[1,2-b]pyrrolo-1-yl}-2-oxonylacetate (A142)

[0575] 1H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7.11 –7.04(m,2H),6.95–6.85(m,1H),6.70(d,J=7.7Hz,1H),4.54–4.49(m,1H),3.90–3.85(m ,1H),3.85–3.81(m,1H),3.81(s,3H),3.44(p,J=7.1Hz,1H),3.12–3.06(m,1H),3.04–2 .98(m,1H),2.06–2.00(m,1H),1.87–1.81(m,1H),1.76–1.64(m,3H),1.64–1.55(m,2H).

[0576] LRMS(ESI,m / z):509[M+H] +

[0577] Example A143 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)cyclopropanesulfonamide (A143)

[0578] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),77.24–7.18(m,1H),7.11–7.04(m, 2H),6.95–6.85(m,1H),6.69(d,J=7.8Hz,1H),4.51–4.44(m,2H),3.99–3.93(m,1H),3.89–3.84(m ,1H),3.84–3.78(m,2H),3.47–3.41(m,1H),3.15–3.09(m,1H),3.04–2.98(m,1H),2.40–2.34(m,1 H),2.22–2.17(m,1H),2.06–1.98(m,1H),1.86–1.80(m,1H),1.75–1.65(m,3H),1.65–1.55(m,2H).

[0579] LRMS(ESI,m / z):507[M+H] +

[0580] Example A144 3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A144)

[0581] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H) ,7.11–7.04(m,2H),6.95–6.85(m,1H),6.70(d,J=7.7Hz,1H),4.62–4.57(m,1H),3 .86–3.79(m,2H),3.47–3.41(m,1H),3.10–3.04(m,1H),3.03–2.98(m,1H),2.94(s ,6H),2.01–1.96(m,1H),1.82–1.76(m,1H),1.75–1.66(m,2H),1.64–1.55(m,3H).

[0582] LRMS(ESI,m / z):494[M+H] +

[0583] Example A145 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]cyclopropanesulfonamide (A145)

[0584] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.25–7.18(m,1H),7 .11–7.04(m,2H),6.95–6.85(m,1H),6.69(d,J=7.9Hz,1H),4.32–4.26(tm,1H),3.7 8–3.70(m,2H),3.47–3.43(m,1H),3.16–3.10(m,1H),3.05–2.99(m,1H),2.15–2.03 (m,5H),1.92–1.85(m,3H),1.85–1.79(m,1H),1.75–1.64(m,3H),1.63–1.55(m,2H).

[0585] LRMS(ESI,m / z):517[M+H] +

[0586] Example A146 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)cyclopropanesulfonamide (A146)

[0587] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.10–7.04(m,2H),6.95–6 .85(m,1H),6.69(d,J=7.8Hz,1H),4.48–4.43(m,1H),3.92–3.84(m,1H),3.84–3.79(m,1H),3.77(d,J=4.4Hz, 1H),3.74(q,J=4.9Hz,1H),3.47–3.41(m,1H),3.14–3.08(m,1H),3.02–2.97(m,1H),2.89–2.85(m,1H),2.22 –2.17(m,2H),2.03–1.98(m,1H),1.95–1.89(m,2H),1.84–1.78(m,1H),1.76–1.64(m,3H),1.63–1.55(m,2H).

[0588] LRMS(ESI,m / z):521[M+H] +

[0589] Example A147 3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A147)

[0590] 1H NMR(500MHz, CDCl3)δ7.67–7.62(m,2H),7.28(t,J=9.0Hz,2H),7.23–7.18(m,2H),7.11–7 .04(m,4H),6.95–6.85(m,2H),6.70(d,J=7.7Hz,2H),6.47(t,J=5.3Hz,2H),4.49–4.44(m, 2H),3.92–3.83(m,6H),3.81(q,J=4.8Hz,2H),3.47–3.41(m,2H),3.12–3.06(m,2H),3.03 –2.97(m,2H),2.06–1.98(m,2H),1.86–1.81(m,2H),1.75–1.66(m,4H),1.66–1.55(m,7H).

[0591] LRMS(ESI,m / z):548[M+H] +

[0592] Example A148 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)cyclopropanesulfonamide (A148)

[0593] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,2H),7.28(t,J=9.0Hz,2H),7.23–7.18(m,2H),7 .11–7.04(m,4H),6.95–6.85(m,2H),6.70(d,J=7.8Hz,2H),4.66–4.60(m,2H),3.91 –3.87(m,2H),3.81–3.76(m,2H),3.47–3.42(m,2H),3.16–3.11(m,2H),3.05–2.99( m,2H),2.06–2.00(m,2H),1.86–1.80(m,2H),1.75–1.64(m,7H),1.63–1.55(m,4H).

[0594] LRMS(ESI,m / z):519[M+H] +

[0595] Example A149 N-(1-{3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2,3,3a,4a-tetrahydro-1H-cyclopropyl[1,2-b]pyrrolo-1-yl}-3,3-dimethyl-1-oxomylidene-2-yl)-2,2,2-trifluoroacetamide (A149)

[0596] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.4Hz,1H),7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23– 7.18(m,1H),7.11–7.04(m,2H),6.95–6.85(m,1H),6.69(d,J=7.9Hz,1H),4.62(d,J=12.3Hz,1 H),4.31–4.26(m,1H),3.85–3.78(m,2H),3.47–3.42(m,1H),3.16–3.10(m,1H),3.03–2.97(m, 1H),2.06–2.00(m,1H),1.85–1.80(m,1H),1.76–1.66(m,3H),1.66–1.55(m,2H),0.95(s,9H).

[0597] LRMS(ESI,m / z):632[M+H] +

[0598] Example A150 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)ethanesulfonamide (A150)

[0599] 1H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.11 –7.04(m,2H),6.95–6.85(m,1H),5.96(d,J=7.3Hz,1H),4.58–4.52(m,1H),4.01–3.95(m ,2H),3.79–3.74(m,1H),3.17–3.12(m,1H),3.10–2.95(m,3H),2.07–2.00(m,1H),1.38( s,2H),1.33(s,3H),1.25(t,J=8.6Hz,3H),1.03(t,J=1.6Hz,3H),0.98(t,J=1.5Hz,3H).

[0600] LRMS(ESI,m / z):525[M+H] +

[0601] Example A151: 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-2-oxanediacetic acid methyl ester (A151)

[0602] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.10–7.06(m,2H),6.95–6.85(m,1H),6.47(d,J=8.2Hz,1H),5.24(s,1H),5.15 (s,1H),4.60–4.55(m,1H),3.94–3.90(m,1H),3.89–3.84(m,1H),3.81(s,2H),3. 10–2.98(m,2H),2.10–2.05(m,1H),1.03(t,J=1.6Hz,3H),0.98(t,J=1.5Hz,3H).

[0603] LRMS(ESI,m / z):529[M+H] +

[0604] Example A152 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A152)

[0605] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.0 5(m,2H),6.95–6.89(m,1H),6.47(d,J=8.2Hz,1H),5.24(s,1H),5.15(s,1H),4.51(t,J=4.1H z,1H),4.31–4.26(m,1H),4.01–3.93(m,2H),3.89–3.78(m,2H),3.14–2.98(m,2H),2.40–2.3 3(m,1H),2.23–2.16(m,1H),2.05–2.00(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0606] LRMS(ESI,m / z):527[M+H] +

[0607] Example A153 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-4,4,N,N-tetramethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A153)

[0608] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.11–7.05(m,1H),6.95–6.90(m,1H),6.45(d,J=8.1Hz,1H),5.24(s,1H),5.15 (s,1H),4.64–4.60(m,1H),3.94–3.90(m,1H),3.89–3.84(m,1H),3.12–2.97(m,2 H),2.94(s,6H),2.06–2.02(m,1H),1.04(t,J=1.6Hz,3H),0.99(t,J=1.5Hz,3H).

[0609] LRMS(ESI,m / z):514[M+H] +

[0610] Example A154 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1-fluoromethanesulfonamide (A154)

[0611] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H), 7.10–7.05(m,2H),6.94–6.90(m,1H),6.47(d,J=8.2Hz,1H),5.24(s,1H),5.15(s, 1H),4.46–4.42(m,1H),3.88–3.80(m,2H),3.12–3.06(m,2H),2.16–2.05(m,4H),2 .05–2.01(m,1H),1.93–1.83(m,3H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0612] LRMS(ESI,m / z):537[M+H] +

[0613] Example A155 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-4-methyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A155)

[0614] 1H NMR(500MHz, CDCl3)δ7.68–7.64(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.06(m, 2H),6.94–6.90(m,1H),6.47(d,J=8.2Hz,1H),5.24(s,1H),5.15(s,1H),4.48–4.44(m,1H),3.91– 3.87(m,1H),3.85–3.78(m,2H),3.77(d,J=4.4Hz,1H),3.09–3.03(m,2H),2.89–2.85(m,1H),2.21 –2.17(m,2H),2.03–1.98(m,1H),1.95–1.89(m,2H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0615] LRMS(ESI,m / z):543[M+H] +

[0616] Example A156 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-4,4-dimethyl-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A156)

[0617] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H), 7.11–7.04(m,2H),6.95–6.89(m,1H),6.45(d,J=8.0Hz,1H),6.37(t,J=5.4Hz,1H), 5.24(s,1H),5.15(s,1H),4.51–4.45(m,1H),3.93–3.84(m,3H),3.83–3.78(m,1H), 3.16–2.94(m,2H),2.07–2.01(m,1H),1.04(t,J=1.5Hz,3H),0.99(t,J=1.5Hz,3H).

[0618] LRMS(ESI,m / z):568[M+H] +

[0619] Example A157 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (157)

[0620] 1 H NMR (500MHz, CDCl3) δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m, 1H),7.10–7.06(m,2H),6.95–6.89(m,1H),6.47(d,J=8.2Hz,1H),5.24(s,1H) ,5.15(s,1H),4.68–4.63(m,1H),3.98–3.93(m,1H),3.89–3.83(m,1H),3.10– 3.05(m,2H),2.08–2.01(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.4Hz,3H).

[0621] LRMS(ESI,m / z):539[M+H] +

[0622] Example A158: 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-2-oxanediacetic acid methyl ester (A158)

[0623] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.5Hz,1H),7.69–7.64(m,1H),7.28(t,J=9.0Hz,1H),7.24 –7.19(m,1H),7.11–7.04(m,3H),6.95–6.90(m,1H),6.47(d,J=8.2Hz,1H),5.24(s,1H),5.15 (s,1H),4.62(d,J=12.3Hz,1H),4.48–4.44(m,1H),3.94–3.89(m,1H),3.86–3.82(m,1H),3.0 9–3.05(m,3H),2.06–2.00(m,1H),1.03(t,J=1.6Hz,4H),0.98(t,J=1.5Hz,4H),0.95(s,9H).

[0624] LRMS(ESI,m / z):652[M+H] +

[0625] Example A159 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxanedibutyl-2-yl]-2,2,2-trifluoroacetamide (A159)

[0626] 1 H NMR (500MHz, CDCl3) δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m, 1H),7.11–7.05(m,2H),6.95–6.90(m,1H),6.55(d,J=7.0Hz,1H),4.57–4.52( m,1H),3.94–3.89(m,1H),3.84–3.81(m,1H),3.81(s,3H),3.23–2.91(m,2H), 2.69(s,5H),2.10–2.06(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0627] LRMS(ESI,m / z):540[M+H] +

[0628] Example A160 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (160)

[0629] 1H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.12–7 .03(m,2H),6.95–6.90(m,1H),6.55(d,J=7.0Hz,1H),4.51(t,J=4.1Hz,1H),4.30–4.26(m ,1H),4.00–3.91(m,2H),3.90–3.75(m,2H),3.20–2.97(m,2H),2.69(s,6H),2.40–2.35(m ,1H),2.22–2.17(m,1H),2.06–2.00(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0630] LRMS(ESI,m / z):538[M+H] +

[0631] Example A161 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4,N,N-tetramethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A161)

[0632] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m, 1H),7.11–7.05(m,2H),6.95–6.90(m,1H),6.52(d,J=6.8Hz,1H),4.63–4.58( m,1H),3.93–3.89(m,1H),3.85–3.80(m,1H),3.16–2.97(m,2H),2.94(s,6H), 2.69(s,6H),2.03–1.98(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0633] LRMS(ESI,m / z):525[M+H] +

[0634] Example A162 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1,1-dimethylazinesulfonamide (A162)

[0635] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19 (m,1H),7.12–7.05(m,2H),6.94–6.90(m,1H),6.55(d,J=7.0Hz,1H),4.45 –4.40(m,1H),3.87–3.80(m,2H),3.12–3.09(m,2H),2.69(s,5H),2.19–2. 03(m,5H),1.94–1.84(m,3H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0636] LRMS(ESI,m / z):549[M+H] +

[0637] Example A163 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A163)

[0638] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.29(d,J=9.1Hz,1H),7.24–7.19(m,1H),7.11–7.04 (m,2H),6.94–6.90(m,1H),6.55(d,J=7.0Hz,1H),4.51–4.44(m,1H),3.93–3.87(m,1H),3.85– 3.79(m,2H),3.77(d,J=4.4Hz,1H),3.19–3.13(m,2H),2.90–2.83m,1H),2.69(s,5H),2.22–2. 16(m,2H),2.07–2.01(m,1H),1.95–1.88(m,2H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0639] LRMS(ESI,m / z):552[M+H] +

[0640] Example A164 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4-dimethyl-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A164)

[0641] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.13–7.06(m,2H),6.93–6.89(m,1H),6.52(d,J=6.8Hz,1H),6.37(t,J=5.4Hz ,1H),4.54–4.49(m,1H),3.95–3.82(m,3H),3.82–3.78(m,1H),3.16–2.94(m,2H ),2.69(s,5H),2.03–1.98(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0642] LRMS(ESI,m / z):579[M+H] +

[0643] Example A165 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A165)

[0644] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19 (m,1H),7.13–7.05(m,2H),6.93–6.89(m,1H),6.55(d,J=7.0Hz,1H),4.65 –4.60(m,1H),3.97–3.94(m,1H),3.83–3.79(m,1H),3.13–3.07(m,2H),2. 69(s,5H),2.08–2.03(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0645] LRMS(ESI,m / z):550[M+H] +

[0646] Example A166 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxomylidenebut-2-yl]-2,2,2-trifluoroacetamide (A166)

[0647] 1 H NMR(500MHz, CDCl3)δ7.67–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19 (m,1H),7.13–7.05(m,2H),6.93–6.89(m,1H),6.55(d,J=7.0Hz,1H),4.65 –4.60(m,1H),3.97–3.94(m,1H),3.83–3.79(m,1H),3.13–3.07(m,2H),2. 69(s,5H),2.08–2.03(m,1H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0648] LRMS(ESI,m / z):663[M+H] +

[0649] Example A167 2-{3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl}-2-oxanediacetic acid methyl ester (A167)

[0650] 1H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11– 7.05(m,2H),6.94–6.89(m,1H),6.84(d,J=7.3Hz,1H),4.50–4.44(m,1H),3.95–3.90(m, 1H),3.81(s,2H),3.78–3.72(m,1H),3.47–3.42(m,1H),3.07–3.01(m,2H),2.08–2.02(m ,1H),1.77–1.65(m,2H),1.65–1.53(m,2H),1.03(t,J=1.6Hz,3H),0.98(t,J=1.5Hz,3H).

[0651] LRMS(ESI,m / z):537[M+H] +

[0652] Example A168 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)cyclopropanesulfonamide (A168)

[0653] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.24–7.19(m,1H),7.10–7.05(m,2H),6.95 –6.89(m,1H),6.85(d,J=7.3Hz,1H),4.51(t,J=4.1Hz,1H),4.29–4.24(m,1H),4.01–3.92(m,2H),3.88–3. 82(m,1H),3.79–3.73(m,1H),3.44(p,J=7.0Hz,1H),3.17–2.97(m,2H),2.40–2.35(m,1H),2.21–2.16(m,1 H),2.08–2.02(m,1H),1.76–1.65(m,2H),1.65–1.55(m,2H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0654] LRMS(ESI,m / z):535[M+H] +

[0655] Example A169 3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4,N,N-tetramethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A169)

[0656] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.10– 7.05(m,2H),6.95–6.89(m,1H),6.81(d,J=7.3Hz,1H),4.58–4.52(m,1H),3.96–3.90(m, 1H),3.81–3.75(m,1H),3.47–3.41(m,1H),3.11–2.98(m,2H),2.94(s,5H),2.06–2.00(m ,1H),1.78–1.65(m,2H),1.66–1.53(m,2H),1.04(t,J=1.6Hz,3H),0.99(t,J=1.5Hz,3H).

[0657] LRMS(ESI,m / z):522[M+H] +

[0658] Example A170 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]cyclopropanesulfonamide (A170)

[0659] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7.13–7 .04(m,2H),6.94–6.89(m,1H),6.85(d,J=7.3Hz,1H),4.48–4.42(m,1H),3.87–3.81(m,1H) ,3.77–3.71(m,1H),3.47–3.41(m,1H),3.11–3.05(m,2H),2.16–2.06(m,4H),2.07–2.01( m,1H),1.93–1.83(m,3H),1.77–1.65(m,2H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.4Hz,3H).

[0660] LRMS(ESI,m / z):545[M+H] +

[0661] Example A171 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)cyclopropanesulfonamide (A171)

[0662] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.11–7.05(m,2H),6.93 –6.89(m,1H),6.85(d,J=7.3Hz,1H),4.49–4.42(m,1H),3.92–3.86(m,1H),3.83(dp,J=4.6,1.5Hz,1H),3.8 0–3.71(m,2H),3.47–3.41(m,1H),3.09–3.03(m,2H),2.89–2.83(m,1H),2.21–2.17(m,2H),2.06–2.01(m, 1H),1.94–1.89(m,2H),1.76–1.65(m,2H),1.64–1.55(m,2H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0663] LRMS(ESI,m / z):549[M+H] +

[0664] Example A172 3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A172)

[0665] 1H NMR (500MHz, CDCl3) δ7.68–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.23–7.19(m,1H),7.11–7.04(m ,2H),6.94–6.89(m,1H),6.81(d,J=7.3Hz,1H),6.37(t,J=5.4Hz,1H),4.50–4.46(m,1H),3.92– 3.85(m,2H),3.84–3.74(m,2H),3.47–3.41(m,1H),3.12–3.06(m,1H),3.03–2.98(m,1H),2.06– 2.01(m,1H),1.76–1.66(m,2H),1.65–1.55(m,2H),1.04(t,J=1.5Hz,3H),0.99(t,J=1.4Hz,3H).

[0666] LRMS(ESI,m / z):576[M+H] +

[0667] Example A173 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)cyclopropanesulfonamide (A173)

[0668] 1 H NMR(500MHz, CDCl3)δ7.68–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.23–7.19(m,1H),7.11–7 .04(m,2H),6.95–6.89(m,1H),6.85(d,J=7.3Hz,1H),4.67–4.62(m,1H),3.98–3.93(m,1H) ,3.80–3.74(m,1H),3.47–3.41(m,1H),3.17–3.12(m,1H),3.04–2.99(m,1H),2.07–2.01( m,1H),1.76–1.65(m,2H),1.65–1.55(m,2H),1.03(t,J=1.5Hz,3H),0.98(t,J=1.5Hz,3H).

[0669] LRMS(ESI,m / z):547[M+H] +

[0670] Example A174 N-(1-{3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl}-3,3-dimethyl-1-oxomylidenebut-2-yl)-2,2,2-trifluoroacetamide (A174)

[0671] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.5Hz,1H),7.68–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H) ,7.11–7.04(m,2H),6.95–6.89(m,1H),6.85(d,J=7.3Hz,1H),4.62(d,J=12.3Hz,1H),4.48–4.42(m,1H), 3.93–3.87(m,1H),3.79–3.74(m,1H),3.47–3.41(m,1H),3.15–3.10(m,1H),3.03–2.99(m,1H),2.07–2.0 1(m,1H),1.76–1.65(m,2H),1.65–1.55(m,2H),1.03(t,J=1.6Hz,3H),0.98(t,J=1.5Hz,3H),0.95(s,9H).

[0672] LRMS(ESI,m / z):660[M+H] +

[0673] Example A175 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A175)

[0674] 1H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.18(m,1 H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.06(d,J=7.1Hz,1H),4.62–4.57(m,1 H),4.43–4.32(m,1H),4.11–4.07(m,1H),3.99(s,1H),3.16–3.10(m,1H),3.08– 2.97(m,3H),2.97–2.85(m,1H),1.38(s,3H)1.33(s,3H),1.25(t,J=8.6Hz,3H).

[0675] LRMS(ESI,m / z):533[M+H] +

[0676] Example A176 2-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-2-oxonylacetate (A176)

[0677] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19 (m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.48(d,J=8.1Hz,1H),5.24 (s,1H),5.15(s,1H),4.61–4.57(m,1H),4.56–4.50(m,1H),4.14–4.09(m, 1H),3.81(s,3H),3.12–3.07(m,1H),3.05–3.00(m,1H),2.95–2.83(m,1H).

[0678] LRMS(ESI,m / z):537[M+H] +

[0679] Example A177 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A177)

[0680] 1H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.25–7.18(m,1H),7.11–7 .04(m,2H),6.95–6.89(m,1H),6.51(d,J=8.0Hz,1H),5.24(s,1H),5.15(s,1H),4.57–4.49 (m,2H),4.48–4.38(m,1H),4.05–3.99(m,1H),3.99–3.93(m,1H),3.88–3.82(m,1H),3.14 –3.08(m,1H),3.05–3.00(m,1H),2.97–2.86(m,1H),2.40–2.33(m,1H),2.23–2.16(m,1H).

[0681] LRMS(ESI,m / z):535[M+H] +

[0682] Example A178 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A178)

[0683] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19 (m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.51(d,J=8.1Hz,1H),5.24 (s,1H),5.15(s,1H),4.70–4.65(m,1H),4.47–4.36(m,1H),4.16–4.11(m, 1H),3.13–3.08(m,1H),3.05–3.00(m,1H),2.94(s,6H),2.93–2.81(m,1H).

[0684] LRMS(ESI,m / z):522[M+H] +

[0685] Example A179 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1-fluoromethanesulfonamide (A179)

[0686] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.25–7.18( m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.51(d,J=8.0Hz,1H),5.24(s, 1H),5.15(s,1H),4.51–4.38(m,2H),4.10–4.05(m,1H),3.15–3.10(m,1H), 3.05–3.00(m,1H),2.96–2.85(m,1H),2.15–2.04(m,4H),1.93–1.84(m,3H).

[0687] LRMS(ESI,m / z):545[M+H] +

[0688] Example A180 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A180)

[0689] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.23–7.18(m,1H),7.11–7.04(m ,2H),6.95–6.89(m,1H),6.51(d,J=8.0Hz,1H),5.24(s,1H),5.15(s,1H),4.56–4.49(m,1H),4. 46–4.40(m,1H),4.02–3.98(m,1H),3.93–3.89(m,1H),3.77(d,J=4.4Hz,1H),3.11–3.07(m,1H) ,3.03–2.89(m,1H),2.97–2.87(m,1H),2.87–2.83(m,1H),2.22–2.16(m,2H),1.95–1.89(m,2H).

[0690] LRMS(ESI,m / z):549[M+H] +

[0691] Example A181 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A181)

[0692] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.23–7.19(m,1H) ,7.10–7.06(m,2H),6.93–6.89(m,1H),6.51(d,J=8.0Hz,1H),6.35(t,J=5.3Hz,1 H),5.24(s,1H),5.15(s,1H),4.64–4.59(m,1H),4.44–4.24(m,1H),4.18–4.13(m ,1H),3.92–3.85(m,2H),3.11–3.05(m,1H),3.05–2.99(m,1H),2.89–2.78(m,1H).

[0693] LRMS(ESI,m / z):576[M+H] +

[0694] Example A182 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A182)

[0695] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=8.9Hz,1H),7.25–7.18(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.49(d,J=8.0Hz,1H ),5.24(s,1H),5.15(s,1H),4.69–4.65(m,1H),4.55–4.45(m,1H)4.12 –4.07(m,1H),3.18–3.12(m,1H),3.04–2.98(m,1H),2.91–2.80(m,1H).

[0696] LRMS(ESI,m / z):547[M+H] +

[0697] Example A183 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-3-{[(fluoromethyl)dioxane-λ6-thio]amino}-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxomylidenebut-2-yl]-2,2,2-trifluoroacetamide (A183)

[0698] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.4Hz,1H),7.67–7.63(m,1H),7.27(t,J=9.0Hz ,1H),7.23–7.19(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.51(d,J=8.1Hz, 1H),5.24(s,1H),5.15(s,1H),4.62(d,J=12.3Hz,1H),4.51–4.37(m,2H),4.03–3 .98(m,1H),3.16–3.10(m,1H),3.05–3.00(m,1H),2.95–2.84(m,1H),0.95(s,9H).

[0699] LRMS(ESI,m / z):660[M+H] +

[0700] Example A184 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A184)

[0701] 1H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.10–7.0 6(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8Hz,1H),4.60–4.56(m,1H),4.51(t,J=4.1Hz,1H), 4.48–4.38(m,1H),4.11–4.06(m,1H),3.99–3.93(m,1H),3.88–3.82(m,1H),3.10–3.07(m,1 H),3.05–3.00(m,1H),2.97–2.86(m,1H),2.69(s,6H),2.40–2.33(m,1H),2.23–1.26(m,1H).

[0702] LRMS(ESI,m / z):546[M+H] +

[0703] Example A185 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4-difluoro-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A185)

[0704] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.09–7.05(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8Hz,1H) ,4.70–4.65(m,1H),4.47–4.37(m,1H),4.10–4.06(m,1H),3.15–3.09( m,1H),3.05–2.99(m,1H),2.94(s,6H),2.92–2.84(m,1H),2.69(s,6H).

[0705] LRMS(ESI,m / z):533[M+H] +

[0706] Example A186 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1,1-dimethylazinesulfonamide (A186)

[0707] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.24–7.19(m ,1H),7.10–7.05(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8Hz,1H),4.53–4.48 (m,1H),4.46–4.35(m,1H),4.09–4.05(m,1H),3.15–3.09(m,1H),3.05–3.00( m,1H),2.95–2.83(m,1H),2.69(s,6H),2.13–2.06(m,4H),1.93–1.85(m,3H).

[0708] LRMS(ESI,m / z):556[M+H] +

[0709] Example A187 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A187)

[0710] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.0 4(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8Hz,1H),4.55–4.51(m,1H),4.51–4.40(m,1H),4.1 0–4.06(m,1H),3.93–3.86(m,1H),3.77(d,J=4.4Hz,1H),3.12–3.06(m,1H),3.04–2.98(m,1 H),2.97–2.89(m,1H),2.88–2.84(m,1H),2.69(s,6H),2.23–2.16(m,2H),1.95–1.89(m,2H).

[0711] LRMS(ESI,m / z):560[M+H] +

[0712] Example A188 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4-difluoro-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A188)

[0713] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.24–7.19(m, 1H),7.10–7.06(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8Hz,1H),6.35(t,J=5. 3Hz,1H),4.65–4.60(m,1H),4.46–4.36(m,1H),4.14–4.09(m,1H),3.92–3.85 (m,2H),3.14–3.08(m,1H),3.05–2.99(m,1H),2.92–2.81(m,1H),2.69(s,6H).

[0714] LRMS(ESI,m / z):587[M+H] +

[0715] Example A189 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1,1-dimethylazinesulfonamide (A189)

[0716] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.10–7.05(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8 Hz,1H),4.78–4.74(m,1H),4.57–4.47(m,1H),4.11–4.07(m,1H),3.18–3.12(m,1H),3.05–2.99(m,1H),2.95–2.84(m,1H),2.69(s,6H).

[0717] LRMS(ESI,m / z):558[M+H] +

[0718] Example A190 N-[1-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-4,4-difluoro-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl)-3,3-dimethyl-1-oxomylidenebut-2-yl]-2,2,2-trifluoroacetamide (A190)

[0719] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.4Hz,1H),7.67–7.63(m,1H),7.27(d,J=9.0Hz, 1H),7.23–7.19(m,1H),7.10–7.05(m,2H),6.95–6.89(m,1H),6.60(d,J=6.8Hz,1H) ,4.62(d,J=12.3Hz,1H),4.54–4.50(m,1H),4.48–4.38(m,1H),4.13–4.09(m,1H), 3.13–3.18(m,1H),3.04–2.98(m,1H),2.95–2.83(m,1H),2.69(s,6H),0.95(s,9H).

[0720] LRMS(ESI,m / z):671[M+H] +

[0721] Example A191 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(oxacyclobut-2-ylcarbonyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)cyclopropanesulfonamide (A191)

[0722] 1H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.34(d,J=7.3Hz,1H),7.27(t,J=8.9Hz,1H),7.23–7.19( m,1H),7.10–7.05(m,2H),6.95–6.89(m,1H),4.57–4.49(m,2H),4.48–4.38(m,1H),4.12–4.07(m, 1H),3.99–3.93(m,1H),3.88–3.82(m,1H),3.48–3.41(m,1H),3.13–3.07(m,1H),3.05–3.00(m,1H ),2.98–2.86(m,1H),2.40–2.33(m,1H),2.23–2.16(m,1H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0723] LRMS(ESI,m / z):543[M+H] +

[0724] Example A192 3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-N,N-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A192)

[0725] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.35(d,J=7.3Hz,1H),7.27(t,J=9.0Hz, 1H),7.23–7.19(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),4.66–4.62(m,1H),4 .47–4.36(m,1H),4.11–4.06(m,1H),3.48–3.41(m,1H),3.13–3.07(m,1H),3.05–2 .99(m,1H),2.94(s,6H),2.93–2.81(m,1H),1.76–1.65(m,2H),1.65–1.55(m,2H).

[0726] LRMS(ESI,m / z):530[M+H] +

[0727] Example A193 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]cyclopropanesulfonamide (A193)

[0728] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.34(d,J=7.3Hz,1H),7.28(t,J=8.9Hz,1H),7. 23–7.19(m,1H),7.09–7.05(m,2H),6.95–6.89(m,1H),4.53–4.49(m,1H),4.45–4.35(m, 1H),4.08–4.03(m,1H),3.48–3.41(m,1H),3.15–3.09(m,1H),3.05–2.99(m,1H),2.95–2 .84(m,1H),2.12–2.04(m,4H),1.93–1.86(m,3H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0729] LRMS(ESI,m / z):553[M+H] +

[0730] Example A194 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-[(3-hydroxycyclobutyl)carbonyl]-2,3,3a,4a-tetrahydro-1H-cyclopropanesulfonamide (A194)

[0731] 1H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.34(d,J=7.3Hz,1H),7.27(t,J=8.9Hz,1H),7.23–7.19(m,1H ),7.10–7.06(m,2H),6.95–6.89(m,1H),4.51–4.47(m,1H),4.47–4.40(m,1H),4.11–4.06(m,1H),3.93– 3.86(m,1H),3.77(d,J=4.4Hz,1H),3.48–3.40(m,1H),3.12–3.06(m,1H),3.03–2.98(m,1H),2.97–2.89 (m,1H),2.88–2.83(m,1H),2.23–2.16(m,2H),1.95–1.89(m,2H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0732] LRMS(ESI,m / z):557[M+H] +

[0733] Example A195 3-[(cyclopropyldioxane-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-N-(2,2,2-trifluoroethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A195)

[0734] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.35(d,J=7.3Hz,1H),7.28(t,J=8.9Hz,1H),7. 23–7.19(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),6.35(t,J=5.3Hz,1H),4.63–4.59( m,1H),4.44–4.34(m,1H),4.05–4.00(m,1H),3.92–3.85(m,2H),3.48–3.41(m,1H),3.11– 3.06(m,1H),3.05–2.99(m,1H),2.88–2.76(m,1H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0735] LRMS(ESI,m / z):584[M+H] +

[0736] Example A196 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-1-(trifluoroacetyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)cyclopropanesulfonamide (A196)

[0737] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.34(d,J=7.3Hz,1H),7.28(t,J=8.9H z,1H),7.23–7.19(m,1H),7.10–7.06(m,2H),6.95–6.89(m,1H),4.70–4.66(m, 1H),4.55–4.45(m,1H),4.04–4.00(m,1H),3.48–3.41(m,1H),3.18–3.13(m,1H ),3.05–3.00(m,1H),2.93–2.82(m,1H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0738] LRMS(ESI,m / z):555[M+H] +

[0739] Example A197 N-(1-{3-[(cyclopropyldioxylidene-λ6-thio)amino]-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4,4-difluoro-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-1-yl}-3,3-dimethyl-1-oxylidenebut-2-yl)-2,2,2-trifluoroacetamide (A197)

[0740] 1 H NMR(500MHz, CDCl3)δ7.80(d,J=12.4Hz,1H),7.67–7.63(m,1H),7.34(d,J=7.3Hz,1H),7.27( t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),4.62(d,J=12.3Hz,1 H),4.52–4.46(m,1H),4.44–4.38(m,1H),4.11–4.07(m,1H),3.48–3.41(m,1H),3.12–3.06(m, 1H),3.03–2.98(m,1H),2.95–2.84(m,1H),1.75–1.66(m,2H),1.65–1.55(m,2H),0.95(s,9H).

[0741] LRMS(ESI,m / z):668[M+H] +

[0742] Example A198 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-4-(trifluoromethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A198)

[0743] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.11–7.06(m,2H),6.95–6.89(m,1H),6.19(d,J=7.5Hz,1H),4.48–4.44(m,1H) ,4.17(t,J=7.5Hz,1H),3.99(s,1H),3.89–3.85(m,1H),3.15–3.08(m,1H),3.07– 2.95(m,3H),2.79–2.69(m,2H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.6Hz,3H).

[0744] LRMS(ESI,m / z):565[M+H] +

[0745] Example A199 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4-(trifluoromethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]-1-fluoromethanesulfonamide (A199)

[0746] 1H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=8.9Hz,1H),7.23–7.19(m,1H) ,7.10–7.06(m,2H),6.95–6.89(m,1H),6.41(d,J=8.2Hz,1H),5.24(s,1H),5.15( s,1H),4.31–4.27(m,1H),4.09(t,J=7.5Hz,1H),3.90–3.85(m,1H),3.15–3.08(m ,1H),3.04–2.98(m,1H),2.78–2.66(m,2H),2.15–2.04(m,4H),1.93–1.84(m,3H).

[0747] LRMS(ESI,m / z):577[M+H] +

[0748] Example A200 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-[(3-hydroxycyclobutyl)carbonyl]-4-(trifluoromethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl)-1-fluoromethanesulfonamide (A200)

[0749] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.27(t,J=8.9Hz,1H),7.23–7.19(m,1H),7.11–7 .04(m,2H),6.95–6.89(m,1H),6.41(d,J=8.2Hz,1H),5.24(s,1H),5.15(s,1H),4.26–4.2 1(m,1H),4.10(t,1H),3.93–3.84(m,2H),3.77(d,J=4.4Hz,1H),3.15–3.09(m,1H),3.04– 2.98(m,1H),2.93–2.86(m,1H),2.78–2.67(m,2H),2.22–2.16(m,2H),1.95–1.89(m,2H).

[0750] LRMS(ESI,m / z):581[M+H] +

[0751] Example A201 2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-{[(dimethylamino)dioxane-λ6-thio]amino}-N,N-dimethyl-4-(trifluoromethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-1-carboxamide (A201)

[0752] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m ,1H),7.10–7.05(m,2H),6.95–6.89(m,1H),6.36(d,J=7.0Hz,1H),4.58–4.5 2(m,1H),4.14(t,J=8.7Hz,1H),3.99–3.94(m,1H),3.10–3.03(m,1H),3.03– 2.97(m,1H),2.94(s,6H),2.75–2.69(m,1H),2.68(s,6H),2.65–2.60(m,1H).

[0753] LRMS(ESI,m / z):565[M+H] +

[0754] Example A202 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(oxacyclobut-2-ylcarbonyl)-4-(trifluoromethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)cyclopropanesulfonamide (A202)

[0755] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.28(t,J=8.9Hz,1H),7.23–7.19(m,1H),7.11–7.04(m,2H),6. 96–6.90(m,2H),6.89(d,J=7.5Hz,1H),4.50(t,J=4.2Hz,1H),4.29–4.24(m,1H),4.13(t,J=4.2Hz,1H),3 .99–3.93(m,1H),3.91–3.81(m,2H),3.47–3.41(m,1H),3.15–3.09(m,1H),3.04–2.98(m,1H),2.80–2.6 7(m,2H),2.70–2.66(m,1H),2.40–2.33(m,1H),2.22–2.16(m,1H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0756] LRMS(ESI,m / z):575[M+H] +

[0757] Example A203 N-[1-(bicyclo[1.1.1]pent-1-ylcarbonyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4-(trifluoromethyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl]cyclopropanesulfonamide (A203)

[0758] 1 H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.27(t,J=8.9Hz,1H),7.23–7.19(m,1H),7.11– 7.04(m,2H),6.96–6.90(m,1H),6.89(d,J=7.5Hz,1H),4.31–4.27(m,1H),4.09(t,J=7.5H z,1H),3.91–3.87(m,1H),3.48–3.41(m,1H),3.10–3.01(m,2H),3.01–2.92(m,2H),2.78– 2.66(m,2H),2.15–2.04(m,4H),1.93–1.84(m,3H),1.75–1.65(m,2H),1.65–1.55(m,2H).

[0759] LRMS(ESI,m / z):585[M+H] +

[0760] Example A204 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)hexahydro-1H-cyclobutano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A204)

[0761] 1H NMR (500MHz, CDCl3) δ7.67–7.62(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.04( m,2H),6.95–6.89(m,1H),5.79(d,J=8.2Hz,1H),4.46–4.43(m,1H),4.05(q,J=3.6Hz,1H),3.99 (s,1H),3.74–3.69(m,1H),3.11–3.00(m,3H),3.00–2.91(m,2H),2.46–2.41(m,1H),1.93–1.84 (m,1H),1.81–1.72(m,2H),1.67–1.58(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.6Hz,3H).

[0762] LRMS(ESI,m / z):511[M+H] +

[0763] Example A205 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)octahydrocyclopenta[1,2-b]pyrrole-3-yl)ethanesulfonamide (A205)

[0764] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.04(m,2H ),6.95–6.89(m,1H),5.71(d,J=9.2Hz,1H),4.46–4.40(m,1H),3.99(s,1H),3.82(q,J=3.0Hz,1H),3 .71–3.65(m,1H),3.10–3.01(m,2H),3.01–2.93(m,2H),2.25–2.21(m,1H),1.91–1.81(m,1H),1.81– 1.73(m,1H),1.68–1.60(m,2H),1.60–1.52(m,2H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0765] LRMS(ESI,m / z):525[M+H] +

[0766] Example A206 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)octahydro-1H-indol-3-yl)ethanesulfonamide (A206)

[0767] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11–7.06(m,2H ),6.95–6.89(m,1H),5.71(d,J=9.2Hz,1H),4.44–4.39(m,1H),3.99(s,1H),3.78–3.72(m,1H),3.7 1–3.65(m,1H),3.11–3.01(m,2H),3.01–2.91(m,2H),2.23–2.17(m,1H),1.92–1.83(m,1H),1.74–1 .67(m,1H),1.65–1.57(m,1H),1.56–1.38(m,6H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0768] LRMS(ESI,m / z):539[M+H] +

[0769] Example A207 N-(3-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2-(2-hydroxy-2-methylpropionyl)-2,3,4,4a-tetrahydro-1aH-oxacyclopropano[2,3-b]pyrrole-4-yl)ethanesulfonamide (A207)

[0770] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1 H),7.11–7.05(m,2H),6.95–6.89(m,1H),6.30(d,J=8.1Hz,1H),4.97(s,1H),4. 61–4.57(m,1H),4.00(s,1H),4.00–3.96(m,1H),3.95(d,J=3.8Hz,1H),3.17–3 .12(m,1H),3.11–2.95(m,3H),1.38(s,3H),1.33(s,3H),1.26(t,J=8.7Hz,3H).

[0771] LRMS(ESI,m / z):499[M+H]+

[0772] Example A208 N-(3-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2-(2-hydroxy-2-methylpropionyl)-2,3,4,4a-tetrahydro-1aH-azacyclopropano[2,3-b]pyrrole-4-yl)ethanesulfonamide (A208)

[0773] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.27(t,J=9.0Hz,1H),7.23–7.19(m,1H),7. 11–7.04(m,2H),6.95–6.89(m,1H),5.38(d,J=7.5Hz,1H),4.61(d,J=5.2Hz,1H),4.59 –4.55(m,1H),4.04(s,1H),3.79–3.75(m,1H),3.58–3.55(m,1H),3.17–3.11(m,1H),3 .10–2.95(m,3H),2.52–2.49(m,1H),1.38(s,3H),1.33(s,3H),1.26(t,J=8.7Hz,3H).

[0774] LRMS(ESI,m / z):498[M+H] +

[0775] Example A209 N-{6-[3-(3,5-difluorophenyl)-2-fluorophenyl]-4-hydroxy-4-methyl-3-oxoylide-1a,3,4,5,6,6a,7,7a-octahydrocyclopropano[1,2-b]indoleazine-7-yl}ethanesulfonamide (A209)

[0776] 1H NMR (500MHz, CDCl3) δ7.73–7.67(m,1H),7.37–7.28(m,2H),7.10–7.06(m,2H),6.95–6.89(m,1H), 5.85(d,J=7.9Hz,1H),4.77(dd,J=7.9,4.6Hz,1H),4.25(s,1H),3.97–3.93(m,1H),3.88–3.80(m, 1H),3.78–3.73(m,1H),3.11–2.95(m,2H),2.24(dd,J=12.4,6.3Hz,1H),2.16–2.11(m,1H),1.98( dd,J=12.5,6.4Hz,1H),1.93–1.87(m,1H),1.77–1.71(m,1H),1.38(s,3H),1.25(t,J=8.7Hz,3H).

[0777] LRMS(ESI,m / z):496[M+H] +

[0778] Example A210 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2-methyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A210)

[0779] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.31(t,J=9.0Hz,1H),7.17–7.13(m,1H ),7.11–7.04(m,2H),6.95–6.89(m,1H),5.62(d,J=8.2Hz,1H),4.09(s,1H),3.88 (q,J=4.4Hz,1H),3.82–3.75(m,1H),3.11–2.95(m,4H),1.86–1.81(m,1H),1.80– 1.75(m,1H),1.69–1.64(m,1H),1.38(s,6H),1.32(s,3H),1.25(t,J=8.7Hz,3H).

[0780] LRMS(ESI,m / z):511[M+H] +

[0781] Example A211 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3a,4a-difluoro-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A211)

[0782] 1 H NMR (500MHz, CDCl3) δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H ),7.10–7.04(m,2H),6.95–6.89(m,1H),6.41(d,J=8.1Hz,1H),4.48–4.38(m,1H) ,4.33(q,J=5.6Hz,1H),4.12(s,1H),3.16–3.10(m,1H),3.08–2.95(m,3H),2.47– 2.35(m,1H),2.35–2.25(m,1H),1.37(s,3H),1.32(s,3H),1.26(t,J=8.6Hz,3H).

[0783] LRMS(ESI,m / z):533[M+H] +

[0784] Example A212 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-3a,4a-dimethyl-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrole-3-yl)ethanesulfonamide (A212)

[0785] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.11 –7.05(m,2H),6.95–6.89(m,1H),6.16(d,J=7.9Hz,1H),4.26–4.22(m,1H),4.09(s,1H) ,3.95–3.91(m,1H),3.16–3.08(m,1H),3.08–2.94(m,3H),1.86(d,J=12.5Hz,1H),1.53 (d,J=12.5Hz,1H),1.37(s,3H),1.32(s,3H),1.29–1.21(m,6H),0.91(d,J=1.6Hz,3H).

[0786] LRMS(ESI,m / z):525[M+H]+

[0787] Example A213 N-[4-(difluoromethyl)-2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-2,3,3a,4a-tetrahydro-1H-cyclopropano[1,2-b]pyrrolo-3-yl]ethanesulfonamide (A213)

[0788] 1 H NMR(500MHz, CDCl3)δ7.67–7.63(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.19(m,1H),7.10–7.0 4(m,2H),6.95–6.89(m,1H),6.24(d,J=7.5Hz,1H),6.05–5.80(m,1H),4.30–4.26(m,1H),4. 04(dd,J=6.8,5.7Hz,1H),3.99(s,1H),3.84–3.80(m,1H),3.13–3.08(m,1H),3.08–2.96(m, 3H),2.48–2.36(m,1H),2.35–2.31(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0789] LRMS(ESI,m / z):547[M+H] +

[0790] Example A214 (A214)

[0791] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H),7.11–7.04( m,2H),6.95–6.89(m,1H),6.26(d,J=7.9Hz,1H),4.27(td,J=5.9,3.5Hz,1H),4.13(dd,J=5.8,4 .5Hz,1H),3.99(s,1H),3.85–3.79(m,1H),3.68(s,3H),3.14–3.06(m,1H),3.06–2.95(m,3H),2 .90(dd,J=7.4,5.8Hz,1H),2.62–2.55(m,1H),1.38(s,3H),1.33(s,3H),1.25(t,J=8.7Hz,3H).

[0792] LRMS(ESI,m / z):555[M+H] +

[0793] Example A215 N-(3-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[2.1.1]hex-4-yl)ethanesulfonamide (A215)

[0794] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.17(m,1H),7.11– 7.04(m,2H),6.95–6.89(m,1H),6.42(s,1H),4.18(t,J=5.4Hz,1H),4.15–4.10(m,1H),3 .99(s,1H),3.08–3.03(m,2H),3.02–2.99(m,1H),2.97–2.91(m,1H),2.24(dd,J=12.5,3 .7Hz,2H),2.01(dd,J=12.4,3.6Hz,2H),1.38(s,3H),1.33(s,3H),1.27(t,J=8.4Hz,3H).

[0795] LRMS(ESI,m / z):497[M+H] +

[0796] Example A216 N-(3-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-5,5-difluoro-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[2.1.1]hex-4-yl)ethanesulfonamide (A216)

[0797] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.16(m,1H),7 .10(s,1H),7.09–7.06(m,2H),6.95–6.89(m,1H),4.49(t,J=4.9Hz,1H),4.38–4.31 (m,1H),3.99(s,1H),3.20–3.15(m,1H),3.13–2.98(m,3H),2.49(dd,J=12.4,5.0Hz ,1H),2.32(dd,J=12.4,5.0Hz,1H),1.38(s,3H),1.33(s,3H),1.27(t,J=8.4Hz,3H).

[0798] LRMS(ESI,m / z):533[M+H] +

[0799] Example A217 7-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4a-fluoro-6-(2-hydroxy-2-methylpropionyl)octahydro-2λ6-pyrrolo[3,4-c][1,2]thiazacyclohexane-2,2-dione (A217)

[0800] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.25–7.18( m,1H),7.11–7.04(m,2H),6.95–6.89(m,1H),5.16(d,J=8.5Hz,1H),4.19(dd ,J=8.6,4.9Hz,1H),4.14(d,J=1.8Hz,1H),4.13–4.08(m,1H),3.84–3.65(m ,2H),3.55–3.39(m,2H),3.16–3.10(m,1H),3.07–3.00(m,1H),2.55–2.49(m Hz,1H),2.30–2.22(m,1H),1.36(s,3H),1.31(s,3H).

[0801] LRMS(ESI,m / z):501[M+H] +

[0802] Example A218 6-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3a-fluoro-5-(2-hydroxy-2-methylpropionyl)-3,3a,4,5,6,6a-hexahydro-1H-2λ6-pyrrolo[3,4-c][1,2]thiazacyclopentanone-2,2-dione (A218)

[0803] 1H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.19(m,1H ),7.11–7.04(m,2H),6.95–6.89(m,1H),5.67(d,J=7.5Hz,1H),4.40–4.38(m,1H) ,4.14(s,1H),4.14–4.10(m,1H),3.87(d,J=2.2Hz,1H),3.82(d,J=2.2Hz,1H),3. 79–3.65(m,2H),3.12–3.06(m,1H),3.03–2.96(m,1H),1.36(s,3H),1.31(s,3H).

[0804] LRMS(ESI,m / z):487[M+H] +

[0805] Example A219 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-7,7-difluoro-3-(2-hydroxy-2-methylpropionyl)-3-azabicyclo[2.2.1]hept-1-yl)ethanesulfonamide (A219)

[0806] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.11–7 .04(m,2H),7.01(s,1H),6.95–6.89(m,1H),4.43(t,J=5.7Hz,1H),4.33–4.18(m,1H),3.99 (s,1H),3.15–3.07(m,1H),3.05(dd,J=8.4,4.2Hz,1H),3.05–2.98(m,1H),2.31–2.21(m,1 H),2.00–1.93(m,2H),1.93–1.84(m,1H),1.38(s,3H),1.33(s,3H),1.27(t,J=8.4Hz,3H).

[0807] LRMS(ESI,m / z):547[M+H] +

[0808] Example A220 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-3-(2-hydroxy-2-methylpropionyl)-3-azabicyclo[2.2.1]hept-1-yl)ethanesulfonamide (A220)

[0809] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7.11 –7.04(m,2H),6.95–6.89(m,1H),6.45(s,1H),3.99(s,1H),3.97–3.91(m,1H),3.88(t,J =6.1Hz,1H),3.13–2.96(m,3H),2.93–2.89(m,1H),2.18–2.11(m,1H),1.95–1.84(m,3H) ,1.84–1.77(m,1H),1.76–1.68(m,1H),1.38(s,3H),1.33(s,3H),1.27(t,J=8.4Hz,3H).

[0810] LRMS(ESI,m / z):511[M+H] +

[0811] Example A221 N-(7-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-6-(2-hydroxy-2-methylpropionyl)-6-azabicyclo[3.2.1]oct-1-yl)ethanesulfonamide (A221)

[0812] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.17(m,1H),7.11–7.04 (m,2H),6.95–6.89(m,1H),6.43(s,1H),4.01–3.94(m,2H),3.79–3.71(m,1H),3.13–2.96(m,3 H),2.93–2.87(m,1H),2.09(dd,J=12.4,4.3Hz,1H),1.89(dd,J=12.5,4.2Hz,1H),1.85–1.72( m,4H),1.58–1.49(m,1H),1.49–1.42(m,1H),1.38(s,3H),1.33(s,3H),1.27(t,J=8.4Hz,3H).

[0813] LRMS(ESI,m / z):525[M+H] +

[0814] Example A222 1-(7-{[4-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-6-(ethyldioxane-λ6-thio)-1,6-diazabicyclo[3.2.1]oct-2-yl)-2-hydroxy-2-methylprop-1-one (A222)

[0815] 1 H NMR (500MHz, CDCl3) δ7.40 (dd, J=9.5, 2.2Hz, 1H), 7.31–7.25 (m, 1H), 7.21 (dd, J=8.0, 2.2Hz, 1H), 7.17 –7.11(m,2H),6.95–6.89(m,1H),4.41(t,J=8.8Hz,1H),4.01(s,1H),3.66–3.60(m,1H),3.60–3.54(m,1 H),3.26(dd,J=12.5,4.2Hz,1H),3.17–3.10(m,2H),3.09–3.02(m,1H),2.95–2.87(m,1H),2.72(dd,J=1 2.4, 4.3Hz, 1H), 2.07–1.89 (m, 2H), 1.86–1.72 (m, 2H), 1.41 (s, 3H), 1.36 (s, 3H), 1.29 (t, J = 9.1Hz, 3H).

[0816] LRMS(ESI,m / z):511[M+H] +

[0817] Example A223 1-(7-{[4-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-6-(ethyldioxane-λ6-thio)-2,6-diazabicyclo[3.2.1]oct-2-yl)-2-hydroxy-2-methylprop-1-one (A223)

[0818] 1H NMR(500MHz, CDCl3)δ7.39(dd,J=9.6,2.2Hz,1H),7.26–7.18(m,2H),7.17–7.11(m,2H),6.95– 6.89(m,1H),4.34–4.28(m,1H),4.14(s,1H),4.02–3.97(m,1H),3.70–3.64(m,1H),3.58–3.50( m,1H),3.49–3.42(m,1H),3.26–3.07(m,2H),3.05–2.98(m,1H),2.98–2.92(m,1H),2.10–2.03 (m,1H),1.96–1.90(m,1H),1.89–1.79(m,2H),1.36(s,3H),1.31(s,3H),1.29(t,J=9.0Hz,3H).

[0819] LRMS(ESI,m / z):511[M+H] +

[0820] Example A224 N-(5-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-4-(2-hydroxy-2-methylpropionyl)-4-azaspiro[2,4]hept-6-yl)ethanesulfonamide (A224)

[0821] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,,1H),7.28(t,J=9.0Hz,1H),7.23–7.18(m,1H),7 .11–7.04(m,2H),6.95–6.89(m,1H),6.13(d,J=9.3Hz,1H),4.22(q,J=6.9Hz,1H),4.0 9(s,1H),3.75–3.69(m,1H),3.11–2.96(m,3H),2.96–2.89(m,1H),2.08(dd,J=12.4, 3.8Hz,1H),1.90–1.79(m,3H),1.75–1.65(m,2H),1.35(s,6H),1.25(t,J=8.7Hz,3H).

[0822] LRMS(ESI,m / z):511[M+H] +

[0823] Example A225 N-(6-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-5-(2-hydroxy-2-methylpropionyl)-5-azaspiro[3,4]oct-7-yl)ethanesulfonamide (A225)

[0824] 1 H NMR(500MHz, CDCl3)δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7 .11–7.04(m,2H),6.95–6.89(m,1H),6.13(d,J=9.3Hz,1H),4.26–4.20(m,1H),4.09( s,1H),3.72–3.65(m,1H),3.13–2.96(m,3H),2.95–2.88(m,1H),2.06(dd,J=12.4,4 .1Hz,1H),1.92–1.82(m,3H),1.74–1.51(m,4H),1.35(s,6H),1.25(t,J=8.7Hz,3H).

[0825] LRMS(ESI,m / z):525[M+H] +

[0826] Example A226 N-(2-{[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl}-1-(2-hydroxy-2-methylpropionyl)-1-azaspiro[4,4]non-3-yl)ethanesulfonamide (A226)

[0827] 1 H NMR (500MHz, CDCl3) δ7.68–7.62(m,1H),7.28(t,J=9.0Hz,1H),7.24–7.18(m,1H),7.11–7. 04(m,2H),6.95–6.89(m,1H),6.13(d,J=9.3Hz,1H),4.27–4.10(m,1H),4.09(s,1H),3.70–3 .62(m,1H),3.12–2.96(m,3H),2.95–2.89(m,1H),2.08(dd,J=12.4,4.5Hz,1H),1.88(dd,J= 12.5, 4.6Hz, 1H), 1.84–1.71 (m, 6H), 1.70–1.58 (m, 2H), 1.35 (s, 6H), 1.25 (t, J = 8.7Hz, 3H).

[0828] LRMS(ESI,m / z):539[M+H] +

[0829] Example 1: Determination of orexin type II receptor agonist activity

[0830] (1) Experimental methods

[0831] Downstream calcium signal detection:

[0832] In 96-well plates, CHO-K1 cells stably expressing OX2R were seeded at a density of 40 kJ per well and cultured for 24 hours. Calcium flow assays were then performed using Fluo-4 AM. The specific steps were as follows: cells were washed twice with 80 μL / well HBSS; 50 μL / well Fluo-4 AM loading buffer was added using a multichannel pipette, and the plates were incubated at 37°C for 45 minutes; cells were washed three times with Fluo-4 detection buffer, leaving 80 μL of Fluo-4 buffer in each well after the final wash. Fluorescence readings were then performed using a FlexStation 3, with 40 μL of the drug automatically added to each well to a final concentration of 1 μM to 1 pM, followed by a 10-fold dilution. After obtaining the fluorescence readings, data analysis was performed using a GraphPad Prism 10.

[0833] (2) Experimental Results

[0834] The OX2R test results of the compounds in the examples are as follows:

[0835] Table 2. OX2R test results of the compounds of this invention.

[0836]

[0837]

[0838] The above data show that the compounds in the embodiments of the present invention have good agonistic activity against OX2R, with the effective concentration of some compounds being only in the single digits. Among them, compound A054 has an EC50 of only 100%. 50 The value was as low as 0.59 nM, indicating that it can significantly stimulate OX2R even at low concentrations, demonstrating excellent biological activity.

[0839] Example 2: Determination of orexin type I receptor agonist activity

[0840] (1) Experimental methods

[0841] Downstream calcium signal detection:

[0842] In 96-well plates, CHO-K1 cells stably expressing OX1R were seeded at a density of 40K per well and cultured for 24 hours. Calcium flow assays were then prepared using Fluo-4 AM. The specific steps were as follows: cells were washed twice with 80 μL / well HBSS; 50 μL / well Fluo-4 AM loading buffer was added using a multichannel pipette, and the plates were incubated at 37°C for 45 minutes; cells were washed three times with Fluo-4 detection buffer, leaving 80 μL of Fluo-4 buffer in each well after the final wash. Fluorescence readings were then performed using a FlexStation 3, with 40 μL of the drug automatically added to each well to a final concentration of 1 mM to 1 μM, followed by a 10-fold dilution. After obtaining the fluorescence readings, data analysis was performed using a GraphPad Prism 10.

[0843] (2) Experimental Results

[0844] The OX1R test results of the compounds in the examples are as follows:

[0845] Table 3. OX1R test results of the compounds of this invention.

[0846]

[0847]

[0848] The above data show that the compounds in the embodiments of this invention have weak agonistic activity against OX1R, EC 0.5%. 50 A value above 1 μM indicates that the compound has good OX2R selectivity.

[0849] Example 3: Evaluation of its arousal effect in mice.

[0850] (1) Experimental methods

[0851] The arousal-promoting effect of the drug was measured using polysomnography. The measurement process included three stages: implantation of EEG and EMG electrodes, administration of the drug via gavage, and polysomnography recording and sleep staging analysis.

[0852] 1. Electrode implantation surgery

[0853] C57BL / 6 mice were used in the experiment. Throughout the surgery, the mice were anesthetized with 1.5% isoflurane and kept on a heating pad to maintain body temperature. During the surgery, two EEG electrodes were fixed to the skull above the prefrontal cortex using cranial screws, while a reference electrode and a ground electrode were fixed to the skull above the cerebellum. Simultaneously, two EMG electrodes were implanted into the muscles at the back of the neck. Finally, dental cement was used to fix the electrode bases to the top of the mouse's skull. Mice were allowed at least one week of postoperative recovery before subsequent experiments were conducted.

[0854] 2. Gavage administration and polysomnography

[0855] The same batch of mice was used as controls to test the arousal effects of multiple drug concentrations. Drug concentrations were tested in ascending order, with at least one day between each concentration. The drug was dissolved in 0.9% sodium carboxymethyl cellulose and administered by gavage at a dose of 0.1 mL / 10 g (volume / mouse body weight). Mice were acclimatized in a sleep recording chamber for at least one day prior to the experiment. Gavage was administered at the time of peak sleepiness, zeitgeber time (ZT) 5, immediately followed by polysomnography, with simultaneous recording of mouse movement trajectories for at least 3 hours. Polysomnography was recorded at a frequency of 2000 Hz.

[0856] 3. Sleep Stage Analysis

[0857] The AccuSleep sleep staging software was used to automatically analyze the three sleep stages—wakefulness, slow-wave sleep, and REM sleep—in 2.5-second windows, followed by manual verification and calibration. The staging criteria for the three sleep stages are as follows:

[0858] ①Awake: Low-amplitude fast brain waves accompanied by significant electromyographic activity;

[0859] ② Slow-wave sleep: high-amplitude slow-wave brain activity and low electromyographic activity;

[0860] ③Rapid eye movement sleep: low-amplitude fast brain waves, mainly theta waves, with no significant electromyographic activity;

[0861] (2) Experimental Results

[0862] The arousal effect of compound A065 in mice:

[0863] Table 4. Sleep stages in mice after oral administration of compound A065 of the present invention.

[0864]

[0865]

[0866] Experimental results are as follows Figure 1 and Figure 2As shown, compared with the blank control, a dose of 30 mg / kg of A065 significantly increased the wakefulness time of mice within 1.5 hours after administration, while significantly reducing slow-wave sleep and rapid eye movement sleep during the same period. Furthermore, the wakefulness-promoting effect of A065 was dose-dependent; the lower dose of 10 mg / kg of A065 had a weak but still significant wakefulness-promoting effect only within 1 hour after administration, while the higher dose of 100 mg / kg of A065 could maintain wakefulness in mice for at least 2-3 hours.

[0867] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), or its enantiomers, diastereomers, racemates, and mixtures thereof, and its pharmaceutically acceptable salts, hydrates, and solvates: in, X is CH; Ring A is a 5-12 member saturated heterocycle containing nitrogen, wherein the saturated heterocycle is selected from the group consisting of: bicyclic fused rings, bridged rings, and spirocycles; and ring A is optionally surrounded by one or more R... a Substituent substitution; R a Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl groups, -SO2R9, -OSO2R9, -OCOR9; Ring B is selected from the following group: C 6-10 Aromatic rings, 5-10 quintone aromatic rings, C 3-8 The B ring is a saturated carbon ring or a 9-15 fused tricyclic ring, wherein the tricyclic ring is a carbon ring or a heterocyclic ring; and the B ring is optionally surrounded by one or more R rings. b Substituent substitution; R b Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl groups, -SO2R9, -OSO2R9, -OCOR9; L represents CHR5 or (CH2). m NHC(O)(CHR5) n m and n are each independently 0, 1, 2, 3 or 4; R1 is selected from the following group: hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-7 heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 5-7 membered heterocycles; and R1 is optionally further divided by one or more R c Substituent substitution; R c Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl groups, -SO2R9, -OSO2R9, -OCOR9; The prerequisite is that, when L is the aforementioned CHR5, R1 is not hydrogen, deuterium, tritium, halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy; R2 is -C(O)R4、-SO2R 4、 -PO(R4)2、 The R4 mentioned is selected from the group consisting of: hydroxyl, C 0-6 Alkylamine (C0 is amino), C 1-6 Alkyl, C 6-10 Aryl, 5-7 quinone heteroaryl, C 3-12 Cycloalkyl, 5-7 membered heterocycles, C 1-6 Alkylphenyl, -COOC 1-6 Alkyl, C 1-6 alkyl 5-7-membered heteroaryl; and the R4 is optionally surrounded by one or more R d Substituent substitution; R d Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, C 1-4 Alkyl hydroxyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted amino, -SO2R9, -OSO2R9, -NHCOR 9、 -OCOR9; R5 is selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted amino groups; Or the R mentioned above a R5 and the atoms that separate them together form a substituted or unsubstituted 5-7 member carbon ring or heterocycle, wherein the carbon ring or heterocycle is a fully saturated ring, a partially unsaturated ring, or an aromatic ring. Or the R mentioned above b R5 and the atoms that separate them together form a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle, or an aromatic heterocycle. Or, R2 and R5 and the atoms between them together constitute a substituted or unsubstituted 5-7 member carbon ring or heterocycle, wherein the carbon ring or heterocycle is a fully saturated ring, a partially unsaturated ring, or an aromatic ring. Q is selected from O and NH; R3 is selected from the following group: hydrogen, deuterium, tritium, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 0-6 Alkylamine (C0 is amino), substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-7 heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 5-7 membered heterocycles, substituted or unsubstituted C 1-6 Alkylphenyl, substituted or unsubstituted C 1-6 Alkyl 5-7-membered heteroaryl, substituted or unsubstituted C 1-6 Alkylene-CN; or the atoms on the R3 and A rings and the atoms spaced therein together constitute a substituted or unsubstituted 5-7 membered carbon ring or heterocycle, wherein the carbon ring or heterocycle is a fully saturated ring, a partially unsaturated ring, or an aromatic ring; R9 is selected from the following group: hydrogen, deuterium, tritium, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-7 heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 5-7 membered heterocycles, substituted or unsubstituted C 1-6 Alkylphenyl, substituted or unsubstituted C 1-6 Alkyl 5-7-membered heteroaryl groups; Wherein, the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, unsubstituted, or halogen or C. 3-6 Cycloalkyl-substituted C 1-6 (preferably C) 1-4 )alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4 Straight-chain or branched alkyl-substituted amino, hydroxyl, cyano, nitro, oxygen atom (=O), hydroxyl-C 1-6 Alkyl, carboxyl, mercapto, unsubstituted or substituted with 1-3 halogens or hydroxyl groups 6-10 Aryl, unsubstituted or halogenated 5-7 membered heterocycles, unsubstituted or halogenated C 2-6 Acyl group, C 1-6 Hydroxyalkyl, -NR9R 10 -NCOR9R 10 , -SO2R9, -OSO2R9, -SO2NR9R 10 -COOR9 or -OCOR9; The R mentioned 10 Selected from the following group: hydrogen, deuterium, tritium, C 1-6 alkyl; Unless otherwise specified, the heterocycle or heteroaromatic ring comprises 1, 2, 3, 4 or 5 heteroatoms selected from the group consisting of N, S, O or B.

2. The compound of claim 1, including its enantiomers, diastereomers, racemates, and mixtures thereof, as well as its pharmaceutically acceptable salts, hydrates, and solvates, characterized in that... The compounds described have structures represented by the following general formulas I-1, I-2, I-3, or I-4:

3. The compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and its pharmaceutically acceptable salts, hydrates and solvates, characterized in that, The R1 is selected from the group consisting of substituted or unsubstituted C. 6-10 Aryl, substituted or unsubstituted 5-7 membered heteroaryl; and said R1 is optionally further divided by one or more R c Substituent substitution; R c Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl.

4. The compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and its pharmaceutically acceptable salts, hydrates and solvates, characterized in that, The B ring is selected from the group consisting of substituted or unsubstituted C rings. 6-10 Aryl, substituted or unsubstituted 5-7 membered heteroaryl; and the B ring is optionally further separated by one or more R b Substituent substitution; R b Selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl.

5. The compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and its pharmaceutically acceptable salts, hydrates and solvates, characterized in that, The L is CHR5, and R5 is hydrogen; Or the R mentioned above a R5 and the atoms that separate them together form substituted or unsubstituted 5-7 membered carbon rings or heterocycles; Or the R mentioned above b R5 and the atoms that separate them together form substituted or unsubstituted 5-7 membered heterocycles; Or, R2 and R5, together with the atoms that separate them, together constitute a substituted or unsubstituted 5-7 member carbon ring or heterocycle.

6. The compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and its pharmaceutically acceptable salts, hydrates and solvates, characterized in that, The A ring mentioned above is selected from the following group: When the linking site is not specified, it means that the linking site is located at any position (in which case a H atom is lost from the ring).

7. The compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and its pharmaceutically acceptable salts, hydrates and solvates, characterized in that, The compounds are selected from the following group: 。 8. A pharmaceutical composition, characterized in that, include: (A) a therapeutically effective amount of the compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and one or more of its pharmaceutically acceptable salts, hydrates and solvates; and (B) a pharmaceutically acceptable carrier.

9. The method for preparing the compound of formula (I) as described in claim 1, characterized in that, Including the following steps: (1) Compound 1 and compound 2 were reacted via a nucleophilic substitution reaction to obtain compound 3; (2) Compound 3 was converted to compound 4 by a reductive amination reaction; (3) Compound 4 and compound 5 are reacted via sulfonation to obtain compound I; LG is selected from halogens, and the definitions of the other groups are as described in claim 1.

10. Use of the compound of claim 1, its enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, characterized in that, Pharmaceutical compositions for the preparation of indications for the prevention or treatment of orexin receptor type 2 (OX2R) agonism.

11. The use as described in claim 10, characterized in that, The indicated indications are narcolepsy, sleep apnea, hypersomnia, and cognitive impairment.

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