HK1140765A - 5-furopyridinone substituted indazoles - Google Patents

Description

5-furopyridinone substituted indazoles

RELATED APPLICATIONS

This application claims priority from U.S. provisional application No. 60/884,351 filed on 10/1/2007 and U.S. provisional application No. 60/951,202 filed on 21/7/2007. The contents of both applications are hereby incorporated by reference.

Technical Field

The present invention relates to human Melanin Concentrating Hormone (MCH) for the treatment of obesity₁) Receptor selective antagonists 5-furopyridinone substituted indazoles, pharmaceutical compositions containing these compounds and methods for treating obesity, anxiety, depression and psychiatric disorders in a mammal.

Background

Obesity and most co-morbidities associated with obesity, such as diabetes, dyslipidemia, coronary heart disease, and certain cancers, are major public health concerns. The current drug therapies available for the treatment of obesity have limited efficacy and side effects that limit their use. Therefore, there is a significant medical need for better drug therapy for obesity.

Melanin Concentrating Hormone (MCH) has been identified as an appetite stimulating peptide that acts on food intake and weight regulation. MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incerta and lateral hypothalamus in response to energy restriction and leptin deficiency. MCH is known to stimulate food when injected into the lateral ventricles of rats, and MCH mRNA is up-regulated in the hypothalamus of genetically obese (ob/ob) mice and in fasting controls and ob/ob animals. Furthermore, animals treated with MCH show an increase in glucose levels, insulin levels and leptin levels, mimicking human metabolic syndrome (Gomori, a. chronic infusion of MCH causes obesity in mice) am.j.physiol.endocrinol.meta.284, E583, 2002). Mice deficient in MCH are reduced in appetite (hypophagic) and are lean with increased metabolic rates, whereas animals overexpressing MCH gain excessive body weight on standard and high fat diets. MCH is thought to have a role in other nervous system functions as well (Rocksz, L.L.biological Examination of Melanin Concentrating Hormene 1: Multi-tasking from the hypothalamus (bioassay of Melanin Concentrating Hormone 1: multitask assignment of the hypothalamus) Drug News Perscope 19(5), 273, 2006). Recently, orphan G protein-coupled receptors (GPCRs) have been identified as receptors for MCH. Thus, disruption of binding between MCH and MCH receptors (i.e., MCH antagonism mechanisms) can be used to attenuate the action of MCH (McBriar, m.d. recentintroduction in the discovery of melanin-concentrating hormone receptor antagonists) curr. opin. drug dc. & dev.9(4), 496, 2006).

Summary of The Invention

According to an embodiment of the invention, there is provided a compound of formula I:

wherein

n is 1 or 2;

r is NR¹R²Wherein R is¹And R²Each independently selected from H and optionally substituted alkyl, or R¹And R²Together with the N atom to which they are attached form a 4-7 membered optionally substituted non-aromatic heterocyclic ring optionally containing 1 or 2 heteroatoms in addition to the N atom shown;

R³and R⁴Each independently selected from H and alkyl, or R, R³And R⁴Can combine to form an optionally substituted imidazolin-2-yl group;

b is aryl or heteroaryl; and

R⁵、R⁶、R⁷each independently selected from H, -OH, -O-alkyl, halogen, -CF₃and-CN;

with the proviso that the compound is not one of the following compounds:

according to certain embodiments of the invention, R is selected from the group consisting of pyrrolidin-1-yl, morpholin-4-yl, piperazin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, and 3-hydroxy-pyrrolidin-1-yl. In certain embodiments, R is selected from the group consisting of S-2-hydroxymethylpyrrolidin-1-yl, R-2-hydroxymethylpyrrolidin-1-yl, S-3-hydroxypyrrolidin-1-yl, and R-3-hydroxypyrrolidin-1-yl. In certain embodiments, R, R³And R⁴Combine to form imidazolin-2-yl optionally independently substituted with alkyl at each of the 1-position, 4-position and 5-position. According to certain embodiments of the invention, R³And R⁴Are all H. In certain embodiments, n is 1. In other embodiments, n is 2.

In certain embodiments of the invention, B is phenyl. In certain embodiments, B is taken together with R⁵、R⁶And R⁷Together selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-trifluoromethylphenyl, 2-cyano-4-fluorophenyl, 2, 4-dichlorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-methoxyphenyl, 2-fluorophenyl, 2, 4-difluorophenyl, 2-fluoro-4-methylphenyl, and 4-methylphenyl. In certain embodiments of the invention, B is pyridine. In certain embodiments, B is taken together with R⁵、R⁶And R⁷Together selected from the group consisting of 5-chloropyridin-2-yl, pyridin-3-yl, 5-fluoropyridin-2-yl, and pyridin-2-yl. In certain embodiments of the invention, B is pyridazine. In certain embodiments, B is taken together with R⁵、R⁶And R⁷Together are a 6-methylpyridazin-3-yl group. In certain embodiments of the invention, B is a pyrimidine. In certain embodiments, B is taken together with R⁵、R⁶And R⁷Together is pyrimidin-2-yl.

In certain embodiments of the invention, R⁵、R⁶And R⁷Each independently selected from H, -O-alkyl, haloElemental, -CF₃and-CN;

in certain embodiments of the invention, the compound is selected from one of the following compounds:

in certain embodiments of the invention, the compound is in the form of a pharmaceutically acceptable salt. In certain embodiments, the compound is in the form of a hydrochloride salt.

Also provided according to an embodiment of the invention are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier, excipient, or diluent.

Also provided according to an embodiment of the present invention is a method of treating obesity comprising administering to a patient in need of weight loss a weight-loss effective amount of a compound as described herein.

There is also provided, in accordance with an embodiment of the present invention, a method of treating anxiety, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein.

There is also provided, in accordance with an embodiment of the present invention, a method of treating depression, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein.

There is also provided, in accordance with an embodiment of the present invention, a method of treating non-alcoholic fatty liver disease, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein.

Also provided according to embodiments of the invention are MCH-susceptible therapies₁A method of treating an affected disease or condition with a receptor modulator, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described herein.

Definition of

Throughout this specification, the terms and substituents retain their definitions.

Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Without further limitation, the term refers to alkyl groups of 20 or less carbons. Lower alkyl refers to alkyl groups of 1,2, 3, 4,5, and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl and t-butyl and the like. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4,5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, bornyl, adamantyl, and the like.

C₁To C₂₀Hydrocarbons (e.g. C)₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、C₁₂、C₁₃、C₁₄、C₁₅、C₁₆、C₁₇、C₁₈、C₁₉、C₂₀) Including alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. The term "phenylene" refers to an ortho, meta, or para residue of the formula:

alkoxy (alkoxy) or alkoxy (alkxyl) refers to a group of 1,2, 3, 4,5, 6, 7, or 8 carbon atoms in a linear, branched, cyclic configuration, and combinations thereof, attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy (cyclopropoxy), cyclohexyloxy (cyclohexoxyloxy), and the like. Lower alkoxy means a group containing 1 to 4 carbons. For purposes of this application, alkoxy also includes methylenedioxy and ethylenedioxy, where each oxygen atom is bonded to the atom, chain or ring from which the methylenedioxy or ethylenedioxy is pendant to form a ring. Thus, for example, a phenyl group substituted by an alkoxy group may be, for example,

oxaalkyl (Oxaalkyl) refers to an alkyl residue in which one or more carbons (and the hydrogen to which they are bound) is substituted with oxygen. Examples include methoxypropoxy, 3, 6, 9-trioxadecyl, and the like. The term oxaalkyl is intended to be understood in the art [ see nomenclature and Indexing of the Chemical Abstracts published by the American Chemical society (Naming and indicating of Chemical substructures for Chemical Abstracts),196, but not limited toLimitation of 127(a)]That is, oxaalkyl refers to a compound in which oxygen is bound to its adjacent atoms by a single bond (forming an ether bond). Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons are substituted with sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

Acyl refers to a group of 1,2, 3, 4,5, 6, 7, or 8 carbon atoms that is straight, branched, cyclic, saturated, unsaturated, and aromatic, and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be substituted with nitrogen, oxygen, or sulfur, so long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl, benzyloxycarbonyl, and the like. Lower acyl refers to a group containing 1 to 4 carbons.

Aryl and heteroaryl refer to an aromatic ring or a heteroaromatic ring, respectively, as substituents, and heteroaryl contains 1,2 or 3 heteroatoms selected from O, N or S. Both groups refer to a 5-or 6-membered monocyclic aromatic ring or heterocyclic aromatic ring, a 9-or 10-membered bicyclic aromatic ring or heterocyclic aromatic ring, and a 13-or 14-membered tricyclic aromatic ring or heterocyclic aromatic ring. Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered carbocycles include, for example, benzene, naphthalene, indane, tetralin and fluorene, and 5, 6, 7, 8, 9 and 10 membered aromatic heterocycles include, for example, imidazole, pyridine, indole, thiophene, benzopyrone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

Aralkyl refers to an alkyl residue attached to an aromatic ring. Examples are benzyl, phenethyl and the like.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl and the like refer to alkyl, aryl, cycloalkyl or heterocyclyl groups in each residue in which up to 3H atoms are substituted by: halogen, haloalkyl, hydroxy, lower alkoxy, carboxy, carbonylalkoxy (also known as alkoxycarbonyl), amido (also known as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, amido, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "prodrug" refers to a compound that is more active in vivo. Conversion of the prodrug to the drug typically occurs through an enzymatic process in the liver or blood of the mammal. Many of the compounds of the invention can be chemically modified so as not to be absorbed into the systemic circulation, and in those cases activation in the body can be produced by chemical action (such as acid-catalyzed cleavage in the stomach) or by mediation (intermediacy) of enzymes and microbiota in the gastrointestinal tract.

In the characterization of some substituents, it should be noted that certain substituents may combine to form a ring. Unless otherwise specified, it is contemplated that such rings may exhibit a variety of degrees of unsaturation (from fully saturated to fully unsaturated), may contain heteroatoms, and may be substituted with lower alkyl or alkoxy groups.

It will be understood that the compounds of the invention can exist in radiolabeled form, i.e., the compounds can contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine, iodine and chlorine, respectively, include³H、¹⁴C、³⁵S、¹⁸F、³²P、³³P、¹²⁵I and³⁶and (4) Cl. Compounds containing those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. The radiolabeled compounds described herein and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds may be prepared by replacing the non-radiolabeled reagent with a readily available radiolabeled reagent as disclosed in the examples and schemes.

The term "method of treatment or prevention" refers to the amelioration, prevention, or reduction of symptoms and/or effects associated with dyslipidemia. The term "prevention" as used herein refers to the pre-administration of an agent to prevent or alleviate an acute attack, or to reduce the likelihood or severity of a chronic condition. The term "prevention" is not an absolute term (absolute term) as understood by a person of ordinary skill in the medical field (to which the present method claims relate). In the medical field, the term is understood to mean that the prophylactic administration is carried out in order to substantially reduce the likelihood or severity of a pathology, which is intended to be implied by the applicant's claims. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.

Throughout this application, various references are referenced. Each of the patents, patent applications, patent publications, and references mentioned herein is incorporated by reference in its entirety.

The term "mammal" is used in its dictionary meaning. The term "mammal" includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats and horses, monkeys, dogs (e.g., canis domestica), cats, rabbits, guinea pigs, and primates, including humans.

The compounds described herein may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms. In terms of absolute stereochemistry, each chiral center may be defined as (R) -or (S) -. The present invention is intended to include all such possible isomers and mixtures thereof, including racemic and optically pure forms. Optically active (R) -and (S) -, (-) -and (+) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, it is contemplated that the compounds include both E and Z geometric isomers, unless otherwise specified. Similarly, all tautomeric forms are also contemplated.

As used herein and as will be understood by those of skill in the art, reference to "a compound" is intended to include salts, solvates, and inclusion complexes of the compound, as well as any stereoisomeric form, or mixtures of any such form of the compound in any ratio. Thus, according to certain embodiments of the present invention, including in the context of pharmaceutical compositions, methods of treatment, and compounds per se, the compounds described herein are provided in the form of salts. According to certain embodiments of the invention, the salt is a hydrochloride salt.

The term "enantiomeric excess" is well known in the art and is defined as the resolution of ab into a + b

The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The ee value is a number from 0 to 100, 0 is racemic and 100 is a pure, single enantiomer. The compound, which in the past could be termed 98% optically pure, is now more accurately described as 96% ee; in other words, 90% ee reflects the presence of 95% of one enantiomer and 5% of the other enantiomer in the material in question.

The configuration of any carbon-carbon double bond present herein is chosen for convenience only and is not intended to designate a particular configuration; thus, any carbon-carbon double bond described herein as E may be Z, E or a mixture of the two in any ratio.

Terms relating to "protecting", "deprotecting" and "protected" functionalities appear at the beginning and end of the present application. Such terms are well known to those skilled in the art and are used in the context of processes that include sequential treatment with a series of reagents. In that context, a protecting group refers to a group that is used in a process step to mask a functionality that would otherwise react in the process step, which is undesirable. Protecting groups prevent reactions from occurring in that step, but can be subsequently removed to expose the original functionality. Removal or "deprotection" occurs after the reaction is complete where functionality can interfere. Thus, when the order of reagents is specified, as in the methods of the invention, the skilled person can readily envision those groups that would be suitable as "protecting groups". Suitable groups for this purpose are discussed in standard textbooks in the chemical field, for example of t.w. greeneProtective Groups in Organic Synthesis(protecting group in organic Synthesis) [ John Wiley& Sons，New York，1991]This book is hereby incorporated by reference. Of particular interest is the section entitled "Protection for the Hydroxyl Group, incorporation 1, 2-and 1, 3-Diols (Including Protection of the Hydroxyl groups of 1, 2-Diols and 1, 3-Diols)" (pages 10-86).

The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethylsulfonyl, tosyl and mesyl, respectively. A general list of abbreviations used by organic chemistry workers (i.e., those of ordinary skill in the art) appears inJournal of Organic ChemistryThe first phase of each volume. This List, which is typically presented in a table entitled "Standard List of Abbreviations," is incorporated herein by reference.

While it is possible for the compounds of formula I to be administered as raw chemicals, it is generally preferred that they be provided as part of a pharmaceutical composition. According to an embodiment of the present invention there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutical carriers thereof and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Furthermore, although the description of the term "compound" in paragraph 33 above also includes salts thereof, so that the independent claims referring to "compound" will be understood to also refer to salts thereof, if a compound or a pharmaceutically acceptable salt thereof is referred to in an independent claim, it is understood that claims dependent on the independent claim referring to such a compound also include pharmaceutically acceptable salts of the compound, even if the salt is not explicitly referred to in the dependent claims.

Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be provided as follows: as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. The pharmaceutical composition may comprise a "pharmaceutically acceptable inert carrier" and the expression is intended to include one or more inert excipients including starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents and the like. If desired, tablet dosages of the disclosed compositions can be coated by standard aqueous or non-aqueous techniques. The "pharmaceutically acceptable carrier" also includes controlled release means.

Optionally, the pharmaceutical composition may also contain other therapeutic ingredients, anti-caking agents, preservatives, sweeteners, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredients must be compatible with the compound of formula I to ensure stability of the formulation. If desired, the composition may contain other additives including, for example, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, inositol, and the like, and hydrates thereof, and amino acids such as alanine, glycine, and betaine, as well as peptides and proteins such as albumin.

Examples of excipients and the aforementioned additional ingredients that serve as pharmaceutically acceptable carriers and pharmaceutically acceptable inert carriers include, but are not limited to, binders, fillers, disintegrants, lubricants, antimicrobial agents, and coating agents.

The dosage for adults will generally range from 0.005 mg/day to 10 g/day orally. Tablets or other presentation forms provided in discrete units may conveniently contain an amount of a compound of formula I which is effective at such a dose or as a plurality of such doses, for example a unit containing from 5mg to 500mg, typically from about 10mg to 200 mg. The precise amount of the compound administered to the patient will be the responsibility of the attending physician. However, the dosage employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and the severity of the condition.

A dosage unit (e.g., oral dosage unit) can comprise, for example, 1 to 30mg, 1 to 40mg, 1 to 100mg, 1 to 300mg, 1 to 500mg, 2 to 500mg, 3 to 100mg, 5 to 20mg, 5 to 100mg (e.g., 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg) of a compound described herein.

For additional information on pharmaceutical compositions and their formulations, see, e.g., Remington: the science and Practice of Pharmacy, 20 th edition, 2000.

The agent may, for example, be administered by the following route: intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intra-articular (in the joint), intradermal, buccal, ocular (including intraocular), intranasal (including the use of cannulae), or by other routes. The medicament may be administered orally, for example, as a tablet or cachet, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granule containing a predetermined amount of the active ingredient, as a solution or suspension in an aqueous liquid or non-aqueous liquid, as an oil-in-water or water-in-oil liquid emulsion, by micellar formulation (see, e.g., WO 97/11682), by liposomal formulation (see, e.g., EP 736299, WO 99/59550 and WO 97/13500), by the formulation described in WO 03/094886, or in some other form. The agent may also be administered transdermally (i.e., via a reservoir-type or matrix-type patch, microneedle, thermal perforation, hypodermic needle, iontophoresis, electroporation, ultrasound or other form of sonophoresis, jet injection, or a combination of any of the foregoing methods (praussnitz et al 2004, Nature Reviews Drug Discovery 3: 115)). The agent may be administered locally (e.g., at the site of injury) to the injured blood vessel. The agent may be coated on the stent. The medicament may be administered using the high speed transdermal particle injection technique employing the hydrogel particle formulation described in US 20020061336. Other granular formulations are described in WO00/45792, WO 00/53160 and WO 02/19989. An example of a transdermal formulation containing a plaster and an absorption enhancer dimethylisosorbide can be found in WO 89/04179. WO96/11705 provides formulations suitable for transdermal administration. The agents may be administered in the form of suppositories or by other vaginal or rectal routes. The agent may be administered as a transmembrane formulation as described in WO 90/07923. The medicament may be administered non-invasively via the dehydrated granules described in US6,485,706. The medicament may be administered as an enterically coated pharmaceutical formulation as described in WO 02/49621. The medicament may be administered intranasally using the formulation described in US 5,179,079. Formulations suitable for parenteral injection are described in WO 00/62759. The medicament may be administered using casein formulations as described in US 20030206939 and WO 00/06108. The medicament may be administered using the granular formulation described in US 20020034536.

The agents alone or in combination with other suitable components may be administered by the pulmonary route by using several techniques including, but not limited to, tracheal perfusion (solution delivered to the lungs by syringe), tracheal delivery of liposomes, insufflation (powder formulation administered to the lungs by syringe or any other similar device), and nebulization inhalation. Aerosols (e.g., jet or ultrasonic nebulizers, Metered Dose Inhalers (MDIs), and Dry Powder Inhalers (DPIs)) may also be used in intranasal applications. Aerosols are stable dispersions or suspensions of solid materials and liquid droplets in gaseous media and can be placed in pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e., HFA-134a and HFA-227, or mixtures thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants, such as mixtures of propellants 11, 12, and/or 114), propane, nitrogen, and the like. Pulmonary formulations may include penetration enhancers such as fatty acids as well as sugars, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, spandex 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (typically to 5% but possibly to 20% by weight). Ethanol is typically included in aerosol compositions because ethanol can improve the function of the metering valve and in some cases also improve the stability of the dispersion). Pulmonary formulations may also include surfactants including, but not limited to, bile salts and surfactants described in US6,524,557 and references therein. Surfactants described in US6,524,557, e.g. C₈-C₁₆Fatty acid salts, bile salts, phospholipids or alkylsaccharides are advantageous because some of them are reported to also enhance the absorption of compounds in the formulation. In addition, dry powder formulations comprising a therapeutically effective amount of the active compound in admixture with a suitable carrier and suitable for inhalation with a dry powder are also suitable for use in the present inventionThe applicator is used in combination. Absorption enhancers which may be added to the dry powder formulation of the present invention include the absorption enhancers described in US6,632,456. WO 02/080884 describes a new method for powder surface modification. Aerosol formulations may include US 5,230,884, US 5,292,499, WO 017/8694, WO 01/78696, US 2003019437, US 20030165436 and WO 96/40089 (which include vegetable oils). Sustained release formulations suitable for inhalation are described in US 20010036481a1, 20030232019a1 and US 20040018243a1 and WO 01/13891, WO 02/067902, WO 03/072080 and WO 03/079885. Pulmonary formulations containing microparticles are described in WO03/015750, US 20030008013 and WO 00/00176. Pulmonary formulations containing stable glassy powders are described in US 20020141945 and US6,309,671. Other aerosol formulations are described in EP 1338272a1, WO 90/09781, US 5,348,730, US6,436,367, WO 91/04011 and US6,294,153, and US6,290,987 describes liposome-based formulations which can be administered by aerosol or other means. Powder formulations for inhalation are described in US 20030053960 and WO 01/60341. The medicament may be administered intranasally as described in US 20010038824.

Aerosols are typically generated in nebulizers using solutions of the drug in buffered salts and similar vehicles. Simple atomizers operate according to the bernoulli principle and use a stream of air or oxygen to produce spray particles. More complex atomizers use ultrasound to produce spray particles. Both types are well known in The art and are described in standard pharmaceutical texts such as American Pharmacy (USA Pharmacy) by Sprowls and The Science and Practice of Pharmacy (Science and Practice of Pharmacy) by Remington. Other devices for generating aerosols use compressed gases, typically hydrofluorocarbons and chlorofluorocarbons, mixed with a medicament and any necessary excipients in a pressurised container, again as described in standard texts such as Sprowls and Remington.

The agent may be incorporated into liposomes to increase half-life. The agents may also be conjugated with polyethylene glycol (PEG) chains. The methods can be described in Harris and Chess, Nature Reviews Drug Discovery 2: 214-22 and references therein find methods of pegylation and other PEG-conjugate containing formulations (i.e., PEG-based hydrogels, PEG-modified liposomes). The agent may be administered via a nano snail shell (nanocolleate) or a snail shell (cochleate) delivery vehicle (BioDelivery Sciences International). The drug may be delivered transmucosally (i.e. via a mucosal surface such as the vagina, eye or nose) using a formulation such as that described in US 5,204,108. The medicament may be formulated in microcapsules as described in WO 88/01165. The medicament may be administered orally using the formulations described in US 20020055496, WO 00/47203 and US6,495,120. The agents may be delivered using nanoemulsion formulations described in WO 01/91728a 2.

Table 1 lists representative compounds of embodiments of the invention.

In general, the compounds of formula I can be prepared by the methods illustrated in the general reaction schemes (e.g., as described below) or variations thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, variants which are known per se but are not mentioned here can also be used.

The process for obtaining the compounds of formula I is given below. Other compounds of formula I may be prepared in a manner analogous to the synthesis of the compounds exemplified herein. The following steps illustrate such a method. Furthermore, although the syntheses described herein may result in the preparation of enantiomers of particular stereochemistry, compounds of formula I in any stereoisomeric form are included within the scope of the invention, and the preparation of compounds of formula I in stereoisomeric forms other than those described herein will be apparent to those of ordinary skill in the chemical arts based on the methods described herein.

Synthesis method

Scheme 1

A compound of formula 2 (wherein Z¹Is chlorine,Bromine or iodine) can be prepared by reacting NaNO in acetic acid at room temperature₂By treating a compound of formula 1.

Scheme 2

Alternatively, the compound of formula 2 can be prepared by using NaNO₂And copper halide treatment of aminoindazole 3.

Scheme 3

Alternatively, the compound of formula 2 can be prepared by treating aldehyde 4 with hydrazine under heating.

Scheme 4

A compound of formula 2 may be treated with a base and a compound of formula 5 (wherein Z2 ═ halogen, mesylate, tosylate, or the like; n ═ 1 or 2) at ambient temperature or with heating to give a compound of formula 6. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), acetonitrile, and Tetrahydrofuran (THF).

Scheme 5

Alternatively, the base and the compound of formula 7 (wherein Z is²Halogen, mesylate, tosylate or the like; o, OR where Y is⁹Or H; r⁸Alkyl, H or a protecting group such as tert-butyldimethylsilyl; r⁹Alkyl; n ═ 1 or 2) treating the compound of formula 2 to obtain the compound of formula 8. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran. For when Y is OR⁹In this case, the compound of formula 8 may be treated under acidic reaction conditions to provide the compound of formula 9. For when Y ═ H and R⁸In the case of protecting groups, the compound of formula 8 may be treated under appropriate deprotection conditions to provide a compound of formula 8, wherein R is⁸H. For when Y ═ H and R⁸In the case of H, the compound of formula 8 may be treated with an oxidizing agent such as Dess-Martin oxidizer (Dess-Martin periodane) or oxalyl chloride and DMSO to provide the compound of formula 9. Treatment of compound 9 with an amine 10 and a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or picoline borane complex can provide a compound of formula 11, wherein n ═ 1 or 2.

Scheme 6

Furthermore, for when Y ═ O and R⁸In the case of alkyl, diamine 12 (wherein R may be used)¹⁰、R¹¹、R¹²Each independently H or alkyl) and trimethylaluminum to provide a compound of formula 13.

Scheme 7

A compound of formula 15 (wherein Z⁴Are, for example, chlorine, bromine, iodine, B (OH)₂、B(OR¹³)₂、SnR¹³ ₃Or an activating group of the like and R¹³Alkyl) may be substituted by furo [3, 2-c]Pyridin-4 (5H) -one (Compound 14). For when Z⁴In the case of bromine, compound 14 can be treated with a brominating agent such as pyridinium perbromide hydrobromide in acetic acid under ambient to heated conditions to yield the compound of formula 15. Next, with a compound of formula 16 (wherein Z³Chlorine, bromine, iodine, B (OH)₂、B(OR¹³)₂、SnR¹³ ₃Or the like and R¹³Alkyl), a catalyst such as palladium (O), and a base such as potassium carbonate treating a compound of formula 15 under heating can provide a compound of formula 17.

Scheme 8

The compound of formula 6 can be treated with a catalyst such as copper iodide, a ligand such as trans-1, 2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate, and the compound of formula 17 under heating to produce the compound of formula 18.

Scheme 9

Alternatively, a catalyst such as copper iodide, may be usedLigands such as trans-1, 2-diaminocyclohexane or 8-hydroxyquinoline, bases such as potassium carbonate, caesium carbonate or potassium phosphate and furo [3, 2, c ]]Treating the compound of formula 6 with pyridin-4 (5H) -one under heating to yield the compound of formula 19. Next, a suitable activating group can be attached to the furopyridine ring to yield a compound of formula 20 (wherein Z is⁴Chlorine, bromine, iodine, B (OH)₂、B(OR¹³)₂、SnR¹³ ₃Or the like and R¹³Alkyl). For when Z⁴In the case of bromine, the compound of formula 19 can be treated with a brominating agent such as perbrominated pyridine hydrobromide in acetic acid under ambient to heated conditions to yield the compound of formula 20. With compounds of formula 16 (wherein Z³Chlorine, bromine, iodine, B (OH)₂、B(OR¹³)₂、SnR¹³ ₃Or the like and R¹³Alkyl), a catalyst such as palladium (O), and a base such as potassium carbonate treating a compound of formula 20 under heating can provide a compound of formula 18.

Scheme 10

In addition, the compound of formula 8 (wherein Y is O, OR) may be treated with a catalyst such as copper iodide, a ligand such as trans-1, 2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate, and a compound of formula 17 under heating (wherein Y is O, OR)⁹Or H; r⁸Alkyl, H or a protecting group such as tert-butyldimethylsilyl; r⁹Alkyl; n-1 or 2) to yield a compound of formula 21. For when Y is OR⁹In this case, the compound of formula 21 can be treated under acidic reaction conditions to provide the compound of formula 22. For when Y ═ H and R⁸In the case of protecting groups, the compound of formula 21 may be treated under appropriate deprotection conditions to provide a compound of formula 21, wherein R is⁸H. For when Y ═ H and R⁸As is the case with H,compounds of formula 21 can be treated with an oxidizing agent such as dess-martin oxidizing agent or oxalyl chloride and DMSO to provide compounds of formula 22. Treatment of compound 22 with amine 10 and a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or picoline-borane complex can provide a compound of formula 18, wherein n ═ 1 or 2.

Scheme 11

Furthermore, for when Y ═ O and R⁸In the case of alkyl, the compound of formula 21 may be treated with diamine 12 and trimethylaluminum to provide the compound of formula 23.

Scheme 12

Alternatively, the compound of formula 24 (wherein Z is treated with a base such as potassium carbonate or cesium carbonate and the compound of formula 17 in a solvent such as DMF under heating conditions⁵An activating group such as fluorine, chlorine, bromine, or iodine) to yield a compound of formula 25. Next, the reaction may be carried out in a reaction chamber such as SnCl₂Iron powder and NH₄Cl, or treating the compound of formula 25 under reducing conditions of palladium on carbon under hydrogen atmosphere to provide the compound of formula 26. At room temperature, with NaNO in acetic acid₂Treatment of a compound of formula 26 can provide a compound of formula 27. The base and the compound of formula 5 (wherein Z is²Halogen, mesylate, tosylate or the like; n-2 or 3) to yield a compound of formula 18. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran.

Scheme 13

Further, the compound of formula 7 (wherein Z is²Halogen, mesylate, tosylate or the like; o, OR where Y is⁹Or H; r⁸Alkyl, H or a protecting group such as tert-butyldimethylsilyl; r⁹Alkyl; n-1 or 2) treating a compound of formula 27 to yield a compound of formula 21. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran.

Scheme 14

Furthermore, a base and a compound of formula 28 (wherein n ═ 1 or 2 and Z is Z) may be used under ambient temperature or heating conditions⁶And Z⁷Halogen, mesylate, tosylate, or the like) to yield a compound of formula 29. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran. Treatment of a compound of formula 29 with amine 10 at ambient temperature or with heating can provide a compound of formula 18 (where n ═ 1 or 2).

Scheme 15

Alternatively, the compound of formula 20 may be prepared starting from the compound of formula 24. Can be heated with a base such as sodium carbonate or cesium carbonate and furo [3, 2-c]Treatment of a compound of formula 24 (wherein Z is H) with pyridin-4 (5H) -one (Compound 14) in a solvent such as DMF⁵An activating group such as fluorine, chlorine, bromine, or iodine) to yield a compound of formula 30. Next, a suitable activating group can be attached to the furopyridine ring to yield the compound of formula 31 (wherein Z is⁴Chlorine, bromine, iodine, B (OH)₂、B(OR¹³)₂、SnR¹³ ₃Or the like and R¹³Alkyl). For when Z⁴In the case of bromine, the compound of formula 30 can be treated with a brominating agent such as perbrominated pyridine hydrobromide in acetic acid under ambient to heated conditions to yield the compound of formula 31. May be in a solvent such as SnCl₂Or iron powder and NH₄Treating the compound of formula 31 under reducing conditions of Cl to provide the compound of formula 32. At room temperature, with NaNO in acetic acid₂Treating compound 32 can provide a compound of formula 33. The compound of formula 5 (wherein Z is²Halogen, mesylate, tosylate, or the like) to yield a compound of formula 20. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran.

Scheme 16

Alternatively, the compound of formula 21 may be prepared starting from the compound of formula 33. The compound of formula 7 (wherein Z is²Halogen, mesylate, tosylate or the like; o, OR where Y is⁹Or H; r⁸Alkyl, H or e.g. tert-butylA protecting group for the dimethylsilyl group; r⁹Alkyl; n-1 or 2) treating the compound of formula 33 to obtain the compound of formula 34. Typical bases include, but are not limited to, cesium carbonate, potassium carbonate, and sodium hydride. Typical solvents include, but are not limited to, N-dimethylformamide, dimethylsulfoxide, acetonitrile, and tetrahydrofuran. With compounds of formula 16 (wherein Z³Chlorine, bromine, iodine, B (OH)₂、B(OR¹³)₂、SnR¹³ ₃Or the like and R¹³Alkyl), a catalyst such as palladium (O) and a base such as potassium carbonate treatment of a compound of formula 34 under heating can provide a compound of formula 21, which compound of formula 21 can be converted to a compound of formula 18 as shown above.

Examples

Unless otherwise indicated, reagents and solvents were used as received from commercial suppliers. Proton Nuclear Magnetic Resonance (NMR) spectra were obtained on a Bruker spectrometer at 300, 400 or 500 MHz. The spectra are given in ppm (δ) and the coupling constant, J, is reported in hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were acquired using either Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) or massVarian 1200L single quadrupole mass spectrometer (ESI). High Performance Liquid Chromatography (HPLC) analysis (method a) was obtained using a Luna C18(2) column (250 x 4.6mm, Phenomenex) with a standard solvent gradient program, detected at 254nm uv.

The method A comprises the following steps:

time (min)

Flow rate (mL/min)

％A

％B

0.0	1.0	90.0	10.0
				20.0	1.0	10.0	90.0
30.0	1.0	10.0	90.0
				31.0	1.0	90.0	10.0

A ═ water containing 0.05% trifluoroacetic acid

Acetonitrile containing 0.05% trifluoroacetic acid

Example 1

2-phenyl-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridine compound Preparation of (E) -4(5H) -keto hydrochloride

a) 2-phenyl-5H-furo [3, 2-c ] pyridin-4-one

Belstein accession number 7705392

The molecules were prepared according to the synthetic methods described in Krutosikova and Sleziak, Collection, Czech, chem, Commun, 1996, 61, 1627-.

b) 5-iodo-1H-indazoles

Belstein accession No. 3262

With NaNO₂A solution of 4-iodo-2-methylaniline (10.0g, 42.9mmol) in glacial acetic acid (400mL) was treated with a solution of (2.96g, 42.9mmol) in water (10 mL). After stirring for 6 hours, the mixture was concentrated to dryness and dissolved in ethyl acetate (EtOAc). Filtration through a silica gel pad (EtOAc) afforded the title compound as a dark purple solid (10.4g, 99%). ESI MS M/z 245[ M + H ]]⁺。

c) 5-iodo-1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazole

1- (2-chloroethyl)Yl) pyrrolidine hydrochloride (9.88g, 58.1mmol) 5-iodo-1H-indazole (8.86g, 36.3mmol) and Cs were added₂CO₃(50.8g, 456mmol) in anhydrous DMSO (100mL) and the resulting suspension was stirred at 25 ℃ for 14 h. Water (100mL) was added and the aqueous solution was extracted with EtOAc (3X 200 mL). The combined organic extracts were washed with brine (2X 200mL) and MgSO₄Dried and concentrated under reduced pressure. Flash chromatography on silica gel (9: 1 Et)₂O/Et₃N) gave 6.473g (52%) of the title compound as a yellow solid:¹H NMR(300MHz，CDCl₃)δ8.08(br d，J＝1.3Hz，1H)，7.91(d，J＝0.9Hz，1H)，7.60(dd，J＝8.7，1.3Hz，1H)，7.25(d，J＝8.7Hz，1H)，4.50(t，J＝7.4Hz，2H)，2.98(t，J＝7.4Hz，2H)，2.59-2.50(m，4H)，1.82-1.70(m，4H)。

d) 2-phenyl-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

Add 5-iodo-1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazole (0.316g, 0.923mmol) in N-methylpyrrolidone (NMP) (2.7mL) to 2-phenyl-5H-furo [3, 2-c)]Pyridin-4-one (0.232g, 110mmol), Cs₂CO₃(0.601g, 1.84mmol), trans-1, 2-diaminocyclohexane (21.2mL, 0.184mmol) and CuI (0.210g, 1.10mmol) and deoxygenated with argon for 30 minutes. After stirring at 110 ℃ for 48 hours, the reaction mixture was cooled and washed with MeOH (3mL) and 7: 1 MeOH/NH₄A solution of OH (3mL) was diluted and then filtered through Celite (Celite). Concentrating the filtrate, then using CH₂Cl₂(20mL) and Water (20mL) the filtrate was suspended and CH was used₂Cl₂Extraction (4X 50 mL). The combined organics were dried (Na)₂SO₄) And concentrated. By flash chromatography (silica gel, CH)₂Cl₂/(80∶18∶2CH₂Cl₂/MeOH/NH₄OH) from 100: 0 to 0: 100) to give brownTitle compound as a solid (29.6mg, 7%):¹H NMR(500MHz，CDCl₃)δ8.05(s，1H)，7.80(d，J＝7.5Hz，2H)，7.73(d，J＝2.0Hz，1H)，7.57(d，J＝9.0Hz，1H)，7.47-7.42(m，3H)，7.37-7.33(m，3H)，6.68(d，J＝7.5Hz，1H)，4.60(t，J＝7.0Hz，2H)，3.06(br m，2H)，2.62(br m，4H)，1.81(br m，4H)；ESIMS m/z 425[M+H]⁺(ii) a HPLC (method A) 96.4% (AUC), t_R＝15.0min。

e) 2-phenyl-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one hydrochloride

Treatment of 2-phenyl-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous HCl in diethyl ether (65.0. mu.L, 0.065mmol, 1.0M)]Pyridin-4 (5H) -one (27.6mg, 0.065mmol) in CH₂Cl₂(0.5mL) solution. After stirring at ambient temperature for 1 hour, Et₂The reaction mixture was diluted with O (50 mL). The resulting solid was collected by filtration and dried in a vacuum oven to give the title compound as a brown solid (14.6mg, 48%):¹H NMR(500MHz，DMSO-d₆)δ10.07(br s，0.5H)，8.28(s，1H)，7.92-7.89(m，4H)，7.66(d，J＝7.5Hz，1H)，7.56-7.48(m，4H)，7.40(t，J＝7.5Hz，1H)，6.91(d，J＝7.5Hz，1H)，4.87(t，J＝6.0Hz，2H)，3.77-3.73(m，2H)，3.56-3.55(m，2H)，3.09-3.06(m，2H)，2.01(br m，2H)，1.89-1.84(br m，2H)；ESI MS m/z 425[M+H]⁺(ii) a HPLC (method A) 95.4% (AUC), t_R＝15.3min。

Example 2

2- (4-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one hydrochloride

a)2- (4-chlorophenyl) -5H-furo [3, 2-c ] pyridin-4-one

Belstein accession number 7708433

The molecules were prepared according to the synthetic methods described in Krutosikova and Sleziak, Collection, Czech, chem, Commun, 1996, 61, 1627-.

b) 5-bromo-1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazole

Following the procedure of example 1 (steps b-c) but replacing 4-iodo-2-methylaniline with 4-bromo-2-methylaniline, the title compound was prepared as an orange oil:¹H NMR(500MHz，CDCl₃)δ7.93(s，1H)，7.86(d，J＝1.8Hz，1H)，7.45(dd，J＝8.8，1.7Hz，1H)，7.34(d，J＝8.9Hz，1H)，4.51(t，J＝7.2Hz，2H)，3.00(t，J＝7.3Hz，2H)，2.56(m，4H)，1.79-1.76(m，4H)；ESI MS m/z 294[M+H]⁺。

c)2- (4-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

A solution of 5-bromo-1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazole (0.349g, 1.18mmol) in NMP (3.3mL) was added to 2- (4-chlorophenyl) -5H-furo [3, 2-c ]]Pyridin-4-one (0.347g, 1.41mmol), Cs₂CO₃(0.768g，2.36mmol), trans-1, 2-bis (methylamino) cyclohexane (0.035mL, 0.236mmol) and CuI (0.269g, 1.41mmol) and deoxygenated with argon for 30 minutes. After stirring for 48 hours at 110 ℃ the reaction mixture was cooled and quenched with CH₂Cl₂Diluted (10mL) and water (10mL) and diluted with CH₂Cl₂Extraction (4X 50 mL). The organics were filtered through Celite and concentrated. By flash chromatography (silica gel, CH)₂Cl₂/(80∶18∶2 CH₂Cl₂/MeOH/NH₄OH), 100: 0 to 0: 100), followed by preparative HPLC (Phenomenex Luna C18(2), 250.0X 50.0mm, 10 μm, H containing 0.05% trifluoroacetic acid (TFA)₂O and CH with 0.05% TFA₃CN) to give the title compound as a light yellow solid (7.5mg, 13%): ESI MS M/z 459[ M + H ]]⁺。

d)2- (4-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one hydrochloride

Treatment of 2- (4-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous HCl in diethyl ether (14.5. mu.L, 0.014mmol, 1.0M)]Pyridin-4 (5H) -one (6.7mg, 0.014mmol) in CDCl₃(0.7mL) solution. After stirring for 1 hour at ambient temperature, the reaction mixture was concentrated and dissolved in CH₃CN and H₂O, partial concentration, then lyophilization afforded the title compound as a pale yellow solid (6.5mg, 91%):¹H NMR(500MHz，DMSO-d₆)δ9.81(br s，0.5H)，8.28(s，1H)，7.92-7.89(m，4H)，7.68(d，J＝7.5Hz，1H)，7.63(s，1H)，7.56(d，J＝8.5Hz，2H)，7.53(dd，J＝9.0，1.5Hz，1H)，6.91(d，J＝7.5Hz，1H)，4.86(t，J＝6.0Hz，2H)，3.76(t，J＝6.0Hz，2H)，3.57-3.56(m，2H)，3.11-3.07(m，2H)，2.01(br m，2H)，1.87-1.84(br m，2H)；ESI MS m/z 459[M+H]⁺(ii) a HPLC (method A) 97.0% (AUC), t_R＝17.0min。

Example 3

(R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) Furo [3, 2-c ]]Preparation of pyridin-4 (5H) -one hydrochloride

a)1- (2, 2-Dimethoxyethyl) -5-iodo-1H-indazole

2-Bromoacetaldehydedimethyl acetate (7.9mL, 68mmol) and Cs₂CO₃(44.1g, 136mmol) A solution of 5-iodo-1H-indazole (8.28g, 33.9mmol) in DMSO (104mL) was added. The reaction mixture was stirred at 40 ℃ for 18 h; then using H₂The reaction mixture was diluted with O (100mL) and EtOAc (175 mL). The partitioned material was extracted with EtOAc (4X 175 mL). The organics were washed with brine (2X 100mL) and dried (Na)₂SO₄) Filtered, and concentrated. By flash chromatography (silica gel, (containing 0.1% Et)₃Hexane of N)/(Et 0.1%₃EtOAc of N), 100: 0 to 90: 10) to afford the title compound as a light orange powder (4.49g, 46%):¹H NMR(500MHz，CDCl₃)δ8.07(d，J＝1.0Hz，1H)，7.92(d，J＝0.5Hz，1H)，7.60(dd，J＝9.0，1.5Hz，1H)，7.28(d，J＝9.0Hz，1H)，4.71(t，J＝5.5Hz，1H)，4.44(d，J＝5.5Hz，2H)，3.33(s，6H)。

b)2- (4-chlorophenyl) -5- (1- (2, 2-dimethoxyethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

Reacting 2- (4-chlorophenyl) -5H-furo [3, 2-c]Pyridin-4-one (2.32g, 9.46mmol), Cs₂CO₃(3.39g, 10.4mmol), 8-hydroxyquinoline (0.274g, 1.89mmol) and CuI (2.16g, 11.4mmol) A solution of 1- (2, 2-dimethoxyethyl) -5-iodo-1H-indazole (3.14g, 9.46mmol) in DMSO (11.2mL) was added. The solution was evacuated under high vacuum for 15 minutes and then re-aerated with argon. This process was repeated 3 times. The reaction mixture was stirred at 128 ℃ for 5 h; the reaction mixture was then cooled to 100 ℃ and held at this temperature for 18 h. With 10% NH₄H of OH₂The reaction mixture was diluted with O (100mL) solution and the resulting solid was diluted with additional 10% NH₄H of OH₂O (300mL) solution. Solid dissolved in CH₂Cl₂(100mL) with H₂O (2X 50 mL). The organics were filtered to remove any remaining solids and then concentrated. By flash chromatography (silica gel, containing 0.1% Et)₃Hexane of N to contain 0.1% Et₃Hexane/MTBE/EtOAc 35: 1.25: 0.25 to containing 0.1% Et₃hexane/MTBE/EtOH 35: 1.25: 0.25, to CH of N₂Cl₂/(80∶18∶2 CH₂Cl₂/MeOH/NH₄OH), 1: 1) to afford the title compound as a brown solid (1.78g, 41%):¹H NMR(500MHz，CDCl₃)δ8.06(s，1H)，7.73-7.71(m，3H)，7.60(d，J＝9.0Hz，1H)，7.43-7.41(m，3H)，7.35(d，J＝7.5Hz，1H)，7.25(s，1H)，6.67(d，J＝7.5Hz，1H)，4.78(t，J＝5.5Hz，1H)，4.51(d，J＝5.0Hz，2H)，3.38(s，6H)；ESI MS m/z 450[M+H]⁺。

c)2- (4-chlorophenyl) -5- (1- (2, 2-dihydroxyethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

HCl in H at 40 deg.C₂O solution (36mL, 2.0M) was added 2- (4-chlorophenyl) -5- (1- (2, 2-dimethoxyethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridine compound-4-ketone (1.66g, 3.69mmol) in THF (36 mL). The solution was heated to 70 ℃ for 3h and then to 80 ℃ for 2 h. By H₂O (70mL) and CH₂Cl₂The reaction mixture was diluted (75 mL). The resulting solid was collected by filtration and dried to give the title compound as a light brown solid (1.00g, 64%). ESI MS M/z422[ M + H ]]⁺。

d) (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

(R) -2-Hydroxymethylpyrrolidine (60. mu.L, 0.61mmol) and picoline borane complex (21.8mg, 0.204mmol) was added to 2- (4-chlorophenyl) -5- (1- (2, 2-dihydroxyethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridin-4-one (86mg, 0.20mmol) in CH₂Cl₂(2.0mL), MeOH (1.0mL), and AcOH (0.30 mL). The solution was stirred at ambient temperature for 18 h. The reaction mixture was concentrated, then diluted with 1N HCl (2.0mL) and stirred at ambient temperature for 45 minutes. With NaHCO₃The mixture is made basic and CH is used₂Cl₂(3X 15 mL). The organic was dried (Na)₂SO₄) Filtered and concentrated. By flash chromatography (silica gel, containing 10% NH)₄CH of OH₂Cl₂EtOH, 97.5: 2.5) gave the title compound as a near white powder (65mg, 65%):¹H NMR(500MHz，CDCl₃)δ8.07(s，1H)，7.73-7.71(m，3H)，7.51(d，J＝9.0Hz，1H)，7.45(d，J＝2.0Hz，1H)，7.42(d，J＝8.5Hz，2H)，7.36(d，J＝7.5Hz，1H)，7.25(s，1H)，6.67(d，J＝7.5Hz，1H)，4.57-4.47(m，2H)，3.46(dd，J＝11.0，3.5Hz，1H)，3.43-3.37(m，1H)，3.27(d，J＝10.5Hz，1H)，3.20(dt，J＝10.0，3.0Hz，1H)，2.90-2.86(m，1H)，2.71-2.68(m，1H)，2.53(br s，1H)，2.424-2.37(m，1H)，1.87-1.64(m，4H)；ESI MS m/z 489[M+H]⁺(ii) a HPLC (method)A)＞99％(AUC)，t_R＝15.7min。

e) (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one hydrochloride

(R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] is treated with anhydrous HCl in diethyl ether (0.13mL, 0.13mmol, 1.0M)]Pyridin-4-one (65mg, 0.13mmol) in CH₂Cl₂(2.0mL) solution. After stirring at ambient temperature for 3h, the solid was concentrated and dried to give the title compound as a near white solid (63.5mg, 90%):¹H NMR(500MHz，DMSO-d₆)δ9.77(br s，1H)，8.25(s，1H)，7.92-7.89(m，4H)，7.69(d，J＝7.5Hz，1H)，7.63(s，1H)，7.57-7.51(m，3H)，6.91(d，J＝7.5Hz，1H)，5.52-5.51(m，1H)，4.94-4.85(m，2H)，3.96-3.94(m，1H)，3.81-3.78(m，1H)，3.71-3.65(m，3H)，3.57-3.35(m，1H)，3.18-3.13(m，1H)，2.11-1.98(m，2H)，1.88-1.72(m，2H)；ESI MS m/z 489[M+H]⁺(ii) a HPLC (method A) > 99% (AUC), t_R＝16.3min。

Example 4

(S) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) Furo [3, 2-c ]]Preparation of pyridin-4 (5H) -one hydrochloride

a) (S) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

Following the procedure of example 3, but replacing (R) -2-hydroxymethylpyrrolidine with (S) -2-hydroxymethylpyrrolidine, the title compound was prepared as a near white solid (64.9mg, 65%):¹H NMR(500MHz，CDCl₃)δ8.07(s，1H)，7.73-7.71(m，3H)，7.51(d，J＝8.5Hz，1H)，7.46-7.41(m，3H)，7.36(d，J＝7.0Hz，1H)，7.25(s，1H)，6.67(d，J＝7.5Hz，1H)，4.57-4.48(m，2H)，3.46(dd，J＝11.0，3.5Hz，1H)，3.43-3.37(m，1H)，3.28-3.26(m，1H)，3.20(dt，J＝9.5，2.5Hz，1H)，2.90-2.86(m，1H)，2.72-2.68(m，1H)，2.53(br s，1H)，2.42-2.37(m，1H)，1.87-1.65(m，4H)；ESI MS m/z489[M+H]⁺(ii) a HPLC (method A) > 99% (AUC), t_R＝15.7min。

b) (S) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one hydrochloride

The procedure of example 3 was followed except using (S) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Substitution of pyridin-4-one for (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridin-4-one, the title compound was prepared as a near white solid (58mg, 84%):¹H NMR(500MHz，DMSO-d₆)δ9.62(br s，1H)，8.27(s，1H)，7.92-7.88(m，4H)，7.68(d，J＝7.5Hz，1H)，7.63(s，1H)，7.57-7.52(m，3H)，6.91(d，J＝7.5Hz，1H)，5.54-5.53(m，1H)，4.93-4.84(m，2H)，3.96-3.94(m，1H)，3.81-3.78(m，1H)，3.70-3.65(m，3H)，3.57-3.56(m，1H)，3.17-3.14(m，1H)，2.12-1.99(m，2H)，1.88-1.72(m，2H)；ESI MS m/z 489[M+H]⁺(ii) a HPLC (method A) > 99% (AUC), t_R＝16.4min。

Example 5

(S) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxy) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furan Pyrano [3, 2-c ] s]Preparation of pyridin-4 (5H) -one hydrochloride

a) (S) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

Following the procedure of example 3, but replacing (R) -2-hydroxymethylpyrrolidine with (S) -3-hydroxypyrrolidine, the title compound was prepared as an off-white solid (11.5mg, 45%):¹H NMR(500MHz，CDCl₃)δ8.05(s，1H)，7.73-7.15(m，3H)，7.55(d，J＝9.0Hz，1H)，7.44-7.41(m，3H)，7.35(d，J＝7.5Hz，1H)，7.25(s，1H)，6.67(d，J＝7.5Hz，1H)，4.56(t，J＝7.0Hz，2H)，4.32(s，1H)，3.04(t，J＝7.0Hz，2H)，2.98-2.93(m，1H)，2.73(d，J＝9.5Hz，1H)，2.57-2.54(m，1H)，2.39-2.34(m，1H)，2.16-2.14(m，1H)，1.79-1.72(m，2H)；ESI MS m/z 475[M+H]⁺HPLC (method A) 96.2% (AUC), t_R＝16.2min。

b) (S) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one hydrochloride

The procedure of example 3 was followed except using (S) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Substitution of pyridin-4-one for (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) Furo [3, 2-c ]]Pyridin-4-one, the title compound was prepared as a near white solid (11.2mg, 91%):¹H NMR(500MHz，DMSO-d₆)δ10.24(br s，1H)，8.28-8.27(m，1H)，7.92-7.87(m，4H)，7.68(d，J＝7.5Hz，1H)，7.55(dd，J＝7.0，2.0Hz，2H)，7.52(d，J＝9.0Hz，1H)，6.90(d，J＝7.5Hz，1H)，5.48(s，1H)，4.88-4.87(m，2H)，4.44-4.37(m，1H)，3.80-3.61(m，3H)，3.41(br s，1H)，3.15-3.00(m，2H)，2.23(br s，1H)，1.96-1.82(m，2H)；ESI MS m/z 475[M+H]⁺(ii) a HPLC (method A) 95.3% (AUC), t_R＝15.5mm。

Example 6

(R) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxy) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furan Pyrano [3, 2-c ] s]Preparation of pyridin-4 (5H) -one hydrochloride

a) (R) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

Following the procedure of example 3, but replacing (R) -2-hydroxymethylpyrrolidine with (R) -3-hydroxypyrrolidine, the title compound was prepared as an off-white solid (21.8mg, 29%):¹H NMR(300MHz，CDCl₃)δ8.05(s，1H)，7.74-7.54(m，5H)，7.44-7.41(m，3H)，7.36(d，J＝7.8Hz，1H)，6.67(d，J＝7.2Hz，1H)，4.57(t，J＝6.9Hz，2H)，4.32(s，1H)，3.04(t，J＝6.9Hz，2H)，3.00-2.93(m，1H)，2.74(d，J＝9.9Hz，1H)，2.58-2.53(m，1H)，2.40-2.32(m，1H)，2.20-2.12(m，1H)，1.86-1.71(m，2H)；ESI MS m/z 475[M+H]⁺(ii) a HPLC (method A) 97.4% (AUC), t_R＝15.7min。

b) (R) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one hydrochloride

The procedure of example 3 was followed except using (R) -2- (4-chlorophenyl) -5- (1- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Substitution of pyridin-4-one for (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridin-4-one, the title compound was prepared as an off-white solid (22.2mg, quantitative): mp 242 + 246 deg.C (decomposition); ESI MS M/z 475[ M + H ]]⁺(ii) a HPLC (method A) 97.6% (AUC), t_R＝15.4min。

Example 7

2- (4-chlorophenyl) -5- (1- ((4, 5 dihydro-1H-imidazol-2-yl) methyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

a) Furo [3, 2-c ] pyridin-4 (5H) -ones

Belstein accession number 742679

The compound is as followsEtc., collect.czech.chem.Commun.1997, 52, 192-198.

b) 2-bromo-5- (3-methyl-4-nitrophenyl) furo [3, 2-c ] pyridin-4 (5H) -one

4-fluoro-2-methyl-1-nitrobenzene (2.3mL, 19mmol) was added to furo [3, 2-c]Pyridin-4 (5H) -one (2.115g, 15.67mmol) and Cs₂CO₃(5.097g, 15.67mmol) in anhydrous DMF (100mL) and the resulting suspension was heated to 125 ℃ and stirred for 15 h. Addition of H₂O and filtering the aqueous suspension. The solid was dried under reduced pressure to give 4.6g of crude 5- (3-methyl-4-nitrophenyl) furo [3, 2-c)]Pyridin-4 (5H) -one, which was used without further purification.

In N₂Pyridine hydrobromide perbromide (1.14g, 3.57mmol) was added to crude 5- (3-methyl-4-nitrophenyl) furo [3, 2-c ] under gas flow]Pyridin-4 (5H) -one (963mg, 3.57mmol) in AcOH (10mL) and the resulting suspension heated to ≈ 45 ℃ for 2H. The suspension was concentrated under reduced pressure and concentrated in H₂The residue was diluted in O. The resulting aqueous suspension was filtered and the solid was dried under reduced pressure to give 1.7g of a yellow solid. Flash chromatography on silica gel (4: 1 hexanes/EtOAc) afforded the title compound as a yellow solid (417mg, 34%):¹H NMR(500MHz，CDCl₃)δ8.13(d，J＝8.4Hz，1H)，7.44-7.38(m，2H)，7.22(d，J＝7.5Hz，1H)，6.96(s，1H)，6.65(d，J＝7.5Hz，1H)，2.67(s，3H)；ESI MS m/z 349[M+H]⁺。

c) 2-bromo-5- (1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

Mixing Fe powder (1.30g, 23.2mmol) and NH₄Cl (69mg, 1.3mmol) was added 2-bromo-5- (3-methyl-4-nitrophenyl) furo [3, 2-c)]Pyridin-4 (5H) -one (896mg, 2.58mmol) in 4: 1 EtOH/H₂Suspension in O (60mL) and the resulting suspension was heated at reflux for 14 h. Filtering the suspension while hot through Celite, and concentrating the filtrate to obtainTo 800mg of crude 5- (4-amino-3-methylphenyl) -2-bromofuro [3, 2-c ] as a yellow solid]Pyridin-4 (5H) -one.

Adding NaNO₂(174mg, 2.52mmol) crude 5- (4-amino-3-methylphenyl) -2-bromofuro [3, 2-c ] was added]Pyridin-4 (5H) -one (800mg, 2.52mmol) at 5: 1 AcOH/H₂O (24mL), and the resulting solution was stirred at 25 ℃ for 14 h. The solution was concentrated under reduced pressure. Flash chromatography on silica gel (49: 1 CH)₂Cl₂MeOH) gave the title compound as a yellow solid (373mg, 44%):¹H NMR(300MHz，CDCl₃)δ13.30-13.25(br s，1H，NH)，8.16(s，1H)，7.81(d，J＝1.8Hz，1H)，7.69(d，J＝7.5Hz，1H)，7.64(d，J＝8.7Hz，1H)，7.35(dd，J＝8.7，1.8Hz，1H)，7.19(d，J＝0.6Hz，1H)，6.85(dd，J＝7.5，0.6Hz，1H)。

d)2- (5- (2-bromo-4-oxafuro [3, 2-c ] pyridin-5 (4H) -yl) 1H-indazol-1-yl) acetic acid methyl ester

Methyl bromoacetate (0.64mL, 6.8mmol) and Cs₂CO₃(4.44g, 13.6mmol) 2-bromo-5- (1H-indazol-5-yl) furo [3, 2-c) was added]Pyridin-4 (5H) -one (1.13g, 3.41mmol) in DMSO (10.5 mL). The reaction mixture was stirred at ambient temperature for 18 h; additional methyl bromoacetate (0.30mL) was then added. After 3h, additional methyl bromoacetate (0.30mL) was added. The reaction mixture was stirred for 3.5H, then the reaction mixture was washed with H₂O (50mL) diluted and CH₂Cl₂Extraction (4X 25 mL). The extract was washed with brine (3X 25mL) and dried (Na)₂SO₄) And concentrated. By flash chromatography (silica gel, CH)₂Cl₂MTBE, 4: 1) to give the title compound as a pale yellow solid (0.77g, 56%):¹H MR(500MHz，CDCl₃)δ8.10(s，1H)，7.73(s，1H)，7.43(s，2H)，7.30(d.J＝7.5Hz，1H)，6.97(s，1H)，6.60(d，J＝7.0Hz，1H)，5.21(s，2H)，3.77(s，3H)。

e)2- (5- (2- (4-chlorophenyl) -4-oxafuro [3, 2-c ] pyridin-5 (4H) -yl) -1H-indazol-1-yl) acetic acid methyl ester

4-Chlorophenylboronic acid (0.32g, 2.1mmol), K₂CO₃(0.52g, 3.8mmol) and bis (triphenylphosphine) palladium dichloride (bis (triphenylphosphine) palladium (II) chloride) (0.13g, 0.19mmol) 2(5- (2-bromo-4-oxafuro [3, 2-c)]Pyridin-5 (4H) -yl) 1H-indazol-1-yl) acetic acid methyl ester (0.77g, 1.9mmol) in DMSO (44 mL). The solution was evacuated at high vacuum and then re-aerated with argon. This process was repeated 3 times. The reaction mixture was stirred at 90 ℃ for 2 h; then using H₂The reaction mixture was diluted with O (20mL) and CH₂Cl₂Extraction (3X 40 mL). The extract was washed with brine (2X 50mL), dried (Na)₂SO₄) Filtered and concentrated. By flash chromatography (silica gel, CH)₂Cl₂/MTBE 100: 0 to 1: 1) to give the title compound as a pale yellow solid (0.38mg, 46%):¹H NMR(300MHz，CDCl₃)δ8.12(s，1H)，7.77-7.63(m，4H)，7.53-7.41(m，4H)，7.35(d，J＝7.5Hz，1H)，6.68(dd，J＝7.5，0.9Hz，1H)，5.22(s，2H)，3.78(s，3H)；ESI MS m/z 434[M+H]⁺。

f)2- (4-chlorophenyl) -5- (1- ((4, 5-dihydro-1H-imidazol-2-yl) methyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

Trimethylaluminum (0.50mL, 1.0M in toluene) was slowly added over 10 minutes to 0 deg.C 1, 2-ethylenediamine (68mL, 1.0mmol)In toluene (0.36 mL). The solution was allowed to stir at 0 ℃ for 5 minutes; then 2- (5- (2- (4-chlorophenyl) -4-oxafuro [3, 2-c) was added]A suspension of methyl pyridin-5 (4H) -yl) -1H-indazol-1-yl) acetate (0.22g, 0.50mmol) in toluene (7.27mL) and the reaction mixture was heated to reflux. The reaction mixture is refluxed and stirred for 18 h; then using H₂The reaction mixture was diluted with O (2mL) and the solids were removed by filtration. CH for filtrate₂Cl₂Extraction (3X 20mL) and drying of the extract (Na)₂SO₄) Filtered and concentrated. By flash chromatography (silica gel, CH)₂Cl₂9: 1 EtOH and NH₄OH, 100: 0 to 90: 10) to afford the title compound as an off-white solid (47.6mg, 21%)):¹H NMR(500MHz，DMSO-d₆)δ8.15(s，1H)，7.91(d，J＝9.0Hz，1H)，7.83(d，J＝1.5Hz，1H)，7.74(d，J＝9.0Hz，1H)，7.69(d，J＝7.5Hz，1H)，7.64(s，1H)，7.57-7.55(m，2H)，7.42(dd，J＝9.0，2.0Hz，2H)，6.89(d，J＝7.0Hz，1H)，5.21(s，2H)3.51(br s，1H)，3.30(s，4H)；ESI MS m/z 444[M+H]⁺(ii) a HPLC (method A) 95.7% (AUC), t_R＝15.8min。

g)2- (3-chlorophenyl) -5- (1- (2- (4, 5 dihydroimidazol-2-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one hydrochloride

The procedure of example 3 was followed except using 2- (3-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c)]Replacement of (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H) indazol-5-yl) furo [3, 2-c) with pyridin-4 (5H) -one]Pyridin-4-one, the title compound was prepared as an off-white solid (41.7mg, 86%):¹H NMR(500MHz，DMSO-d₆)δ10.14(br s，2H)，8.33(s，1H)，7.92-7.87(m，4H)，7.66(d，J＝7.5Hz，1H)，7.63(s，1H)，7.57-7.54(m，3H)，6.92(d，J＝7.5Hz，1H)，5.69(s，2H)，3.86(s，4H)；ESI MS m/z 444[M+H]⁺(ii) a HPLC (method A) 95.3% (AUC), t_R＝15.5min。

Example 8

2- (3-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one hydrochloride

a)2- (3-chlorophenyl) -5H-furo [3, 2-c ] pyridin-4-one

The molecule was prepared according to the synthetic methods described in Krutosikova and Sleziak, collection, czech, chem, commun, 1996, 61, 1627-:¹H NMR(500MHz，DMSO-d₆)δ11.53(s，1H)，7.91(t，J＝1.5Hz，1H)，7.81(d，J＝7.5Hz，1H)，7.60(s，1H)，7.50(t，J＝8.0Hz，1H)，7.42(dd，J＝7.0，1.0Hz，1H)，7.35(t，J＝7.0Hz，1H)，6.70(d，J＝7.0Hz，1H)。

b)2- (3-chlorophenyl) -5- (3-methyl-4-nitrophenyl) furo [3, 2-c ] pyridin-4 (5H) -one

5-fluoro-2-nitrotoluene (0.57mL, 4.7mmol) and Cs₂CO₃(1.32g, 4.08mmol) 2- (3-chlorophenyl) -5H-furo [3, 2-c) was added]Solution of pyridin-4-one (1.00g, 4.08mmol) in DMF (9.46 mL). After stirring at 120 ℃ for 48h, the reaction mixture was cooled and the solid was collected by filtration. The solid was washed with EtOAc (300ml) to give the title compound as a golden yellow solid (1.22g, 78%):¹H NMR(500MHz，DMSO-d₆)δ8.14(d，J＝8.6Hz，1H)，7.97(t，J＝1.7Hz，1H)，7.86(d，J＝6.9Hz，1H)，7.74(s，1H)，7.73(d，J＝7.0Hz，1H)，7.68(d，J＝2Hz，1H)，7.60(dd，J＝8.0，2.2Hz，1H)，7.53(t，J＝8.0Hz，1H)，7.46-7.44(m，1H)，6.97(d，J＝7.5Hz，1H)，2.58(s，3H)。

b)5- (4-amino-3-methylphenyl) -2- (3-chlorophenyl) furo [3, 2-c ] pyridin-4 (5H) -one

Using iron powder (1.52g, 28.3mmol) and NH₄Cl (72.2mg, 1.35mmol) treatment of 2- (3-chlorophenyl) -5- (3-methyl-4-nitrophenyl) furo [3, 2-c]Pyridin-4 (5H) -one (1.20g, 3.15mmol) in EtOH (21.2mL) and H₂Solution in O (5.16 mL). After stirring at reflux for 18h, the mixture is passed through CeliteThe reaction mixture was filtered and the filtrate was concentrated to give the title compound as a light orange solid (1.02g, 92%):¹H NMR(300MHz，DMSO-d₆)δ7.95(s，1H)，7.84(d，J＝7.5Hz，1H)，7.67(s，1H)，7.55-7.42(m，3H)，6.94-6.78(m，3H)，6.67(d，J＝8.4Hz，1H)，5.11(s，2H)，2.09(s，3H)。

c)2- (3-chlorophenyl) -5- (1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

With NaNO₂Treatment of 5- (4-amino-3-methylphenyl) -2- (3-chlorophenyl) furo [3, 2-c ] with a solution of (0.20g, 2.9mmol) in water (0.65mL)]Pyridin-4 (5H) -one (1.02g, 2.91mmol) in AcOH (23 mL). After stirring at ambient temperature for 12h, the reaction mixture was concentrated. The obtained solid is in CH₂Cl₂And in-water distribution. All solids were removed by filtration. By CH₂Cl₂The filtrate was extracted (4X 30 mL). Dry the organic (Na)₂SO₄) Filtered, combined with the removed solids and then concentrated. By flash chromatography (silica gel, CH)₂Cl₂MeOH, 100: 0 to 90: 10) yielded the title compound as a brown solid (0.409g, 40%):¹H NMR(300MHz，DMSO-d₆)δ13.29(s，1H)，8.17(m，1H)，7.96(t，J＝1.8Hz，1H)，7.87-7.83(m，2H)，7.73-7.71(m，2H)，7.65(d，J＝8.7Hz，1H)，7.52(t，J＝8.1Hz，1H)，7.46-7.43(m，1H)，7.38(dd，J＝9.0，2.1Hz，1H)，6.89(d，J＝7.8Hz，1H)。

d)2- (3-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

Mixing (2-chloroethyl) pyrrolidine hydrochloride (0.273g, 1.61mmol) and Cs₂CO₃(1.43g, 4.39mmol) 2- (3-chlorophenyl) -5- (1H-indazol-5-yl) furo [3, 2-c ] was added]Solution of pyridin-4 (5H) -one (0.365g, 0.732mmol) in DMSO (1.5mL) and NMP (0.94 mL). The reaction mixture was stirred at ambient temperature for 18 h; then using H₂The reaction mixture was diluted with O (10mL) and EtOAc (20 mL). The desired solid was collected by filtration. By flash chromatography (silica gel, CH)₂Cl₂/(80∶18∶2 CH₂Cl₂/MeOH/NH₄OH), 100: 0 to 0: 100) to afford the title compound as a pale yellow solid (83.8mg, 25%):¹H NMR(500MHz，CDCl₃)δ8.05(s，1H)，7.79(t，J＝2.0Hz，1H)，7.72(d，J＝1.5Hz，1H)，7.66(d，J＝7.5Hz，1H)，7.56(d，J＝9.0Hz，1H)，7.42(dd，J＝8.5，2.0Hz，1H)，7.39-7.35(m，2H)，7.33-7.31(m，1H)，7.29(s，1H)，6.68(d，J＝7.5Hz，1H)，4.58(t，J＝7.5Hz，2H)，3.03(t，J＝7.0Hz，2H)，2.60(m，4H)，1.80(m，4H)；ESI MS m/z 459[M+H]⁺(ii) a HPLC (method A) > 99% (AUC), t_R＝16.7min。

e)2- (3-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one hydrochloride

Treatment of 2- (3-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous HCl in diethyl ether (0.18. mu.L, 0.18mmol, 1.0M)]Pyridin-4 (5H) -one (83.mg, 0.18mmol) in CH₂Cl₂(1.5mL) solution. After stirring at ambient temperature for 3h, the solid was collected by filtration and dried to give the title compound as a pale yellow solid (76.3mg, 84%):¹H NMR(500MHz，DMSO-d₆)δ9.97(br s，1H)，8.24(s，1H)，7.96(t，J＝2.0Hz，1H)，7.92-7.85(m，3H)，7.71(s，1H)，7.69(d，J＝7.5Hz，1H)，7.54-7.51(m，2H)，7.45(dd，J＝8.0，1.5Hz，1H)，6.92(d，J＝8.0Hz，1H)，4.87(t，J＝6.0Hz，2H)，3.75-3.74(m，2H)，3.55(br m，2H)，3.08(br m，2H)，2.01(br m，2H)，1.85-1.84(br m，2H)；ESI MS m/z 459[M+H]⁺(ii) a HPLC (method A) > 99% (AUC), t_R＝16.0min。

Example 9

2- (2, 4-dichlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

a)5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

Reacting furo [3, 2-c ]]Pyridin-4 (5H) -one (402mg, 2.98mmol), 5-iodo-1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazole (1.22g, 3.58mmol), CuI (682mg, 3.58mmol), Cs₂CO₃(1.07g, 3.28mmol) and 8-hydroxyquinoline (87mg, 0.60mmol) were diluted with anhydrous DMSO (4mL) and the resulting suspension was degassed under reduced pressure for 45 min. The suspension was placed under an Ar atmosphere, heated to 130 ℃ and stirred for 20 h. The suspension is cooled and H is added₂O (10mL) and the aqueous suspension was filtered. NH for solids₄OH is washed and dissolved in CH₂Cl₂And passing through Na₂SO₄And (5) drying. The resulting solution was concentrated under reduced pressure to give 1.516g of a brown solid. Flash chromatography on silica gel (7: 3 Et)₂O/Et₃N) gave the title compound as a pale yellow powder (475mg, 46%):¹H NMR(500MHz，CDCl₃)δ8.04(d，J＝0.5Hz，1H)，7.70(dd，J＝2，0.5Hz，1H)，7.58-7.52(m，2H)，7.41(dd，J＝8.5，2.0Hz，1H)，7.33(d，J＝7.3Hz，1H)，7.04(dd，J＝3.5，1.8Hz，1H)，6.64(d，J＝7.3Hz，1H)，4.57(t，J＝7.5Hz，2H)，3.03(t，J＝7.5Hz，2H)，2.65-2.55(m，4H)，1.84-1.72(m，4H)。

b) 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

In N₂Pyridine hydrobromide perbromide (1.68g, 5.24mmol) was added to 5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] under gas flow]Pyridin-4 (5H) -one (1.22g, 3.49mmol) in AcOH (35mL) and the resulting suspension heated to 45 ℃ for 45 min. The suspension was cooled and AcOH was removed under reduced pressure. With 1: 1H₂O/saturated NaHCO₃The residue was diluted with solution (50mL) and the resulting aqueous solution was taken up with CH₂Cl₂(3X 50 mL). Through Na₂SO₄Drying boxThe organic extracts were concentrated under reduced pressure to give 2.5g of a purple solid. Flash chromatography on silica gel (9: 1 Et)₂O/(9∶1 MeOH/Et₃N)) yielded 550mg (-80% purity) of the title compound as a white powder:¹H NMR(500MHz，CDCl₃)δ8.01(d，J＝0.5Hz，1H)，7.69(dd，J＝1.8，0.5Hz，1H)，7.54(d，J＝8.8Hz，1H)，7.39(dd，J＝8.8，1.8Hz，1H)，7.31(d，J＝7.3Hz，1H)，6.96(d，J＝0.5Hz，1H)，6.60(dd，J＝7.3，0.5Hz，1H)，4.57(t，J＝7.3Hz，2H)，3.02(t，J＝7.3Hz，2H)，2.62-2.56(m，4H)，1.83-1.77(m，4H)；ESI MS m/z 427[M+H]⁺。

c)2- (2, 4-dichlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one hydrochloride

Reacting 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridin-4 (5H) -one (73mg, 0.17mmol), 2, 4-dichlorophenylboronic acid (36mg, 0.19mmol), K₂CO₃(47mg, 0.34mmol) and Pd (PPh)₃)₂Cl₂(12mg, 0.017mmol) was diluted with anhydrous DMSO (4mL) and the resulting suspension was degassed under reduced pressure for 45 min. The suspension was placed under an Ar atmosphere and heated to 95 ℃ for 1.75 h. The suspension is cooled and H is added₂And O. Filtering the aqueous suspension and dissolving the solid in CH₂Cl₂Diluting, and then adding Na₂SO₄The resulting solution was dried and concentrated under reduced pressure to give 50mg of a pink solid. Flash chromatography on silica gel (9: 1 Et)₂O/(4∶1 MeOH/Et₃N)) yielded 24mg (29%) of 2- (2, 4-dichlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c) as a white powder]Pyridin-4 (5H) -one. Treatment of 2- (2, 4-dichlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous HCl in diethyl ether (0.04mL, 0.04mmol, 1.0M)]Pyridin-4 (5H) -one (17mg, 0.035mmol) in CH₂Cl₂(5mL) and the resulting solution was stirred at 25 ℃ for 1 h. Et under reduced pressure₂O concentrate the solution to give the title compound as a white powder: mp 258-260 ℃;¹H NMR(500MHz，DMSO-d₆)δ9.74-9.82(br s，1H，NH)，8.29(s，1H)，7.99(d，J＝8.5Hz，1H)，7.92-7.87(m，2H)，7.84(d，J＝2.0Hz，1H)，7.74(d，J＝7.5Hz，1H)，7.63(dd，J＝8.5，2.0Hz，1H)，7.59(s，1H)，7.53(br d，J＝9.5Hz，1H)，6.94(d，J＝7.5Hz，1H)，4.87(t，J＝5.5Hz，2H)，3.80-3.70(m，2H)，3.61-3.52(m，2H)，3.15-3.02(m，2H)，2.08-1.92(m，2H)，1.90-1.79(m，2H)；ESI MS m/z 493[M+H]⁺。

example 10

2- (4-chloro-2-methoxyphenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furan And [3, 2-c ]]Preparation of pyridin-4 (5H) -one hydrochloride

Dilute 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous DMSO (4mL)]Pyridin-4 (5H) -one (78mg, 0.18mmol), 4-chloro-2-methoxyphenylboronic acid (38mg, 0.20mmol), K₂CO₃(51mg, 0.37mmol) and Pd (PPh)₃)₂Cl₂(13mg, 0.018mmol) and the resulting suspension degassed under reduced pressure for 45 min. The suspension was placed under an Ar atmosphere and heated to 95 ℃ for 2 h. The suspension was cooled and H was added₂And O. The aqueous suspension was extracted with EtOAc and the combined organic extracts were washed with brine, over Na₂SO₄Dried and concentrated under reduced pressure to give 47mg of a white powder. Flash chromatography on silica gel [ 9: 1Et₂O/(1∶1 MeOH/Et₃N)]20mg of white powder were produced. By preparative HPLC (Phenomenex Luna C18(2)) 250.0X 50.0mm, 10 μm, H containing 0.05% TFA₂O and CH with 0.05% TFA₃CN) to yield 9mg (10%) of 2- (4-chloro-2-methoxyphenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c) as a white solid]Pyridin-4 (5H) -one. The hydrochloride salt was prepared according to the procedure of example 9 to give the title compound as a white solid: mp 240-242 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.15-10.01(brs，1H，NH)，8.28(s，1H)，7.94-7.85(m，3H)，7.69(d，J＝7.2Hz，1H)，7.52(dd，J＝6.7，1.8Hz，1H)，7.36(s，1H)，7.31(d，J＝1.8Hz，1H)，7.19(dd，J＝8.4，1.8Hz，1H)，6.91(d，J＝7.2Hz，1H)，4.88(t，J＝6.0Hz，2H)，4.03(s，3H)，3.78-3.70(m，2H)，3.62-3.50(m，2H)，3.14-3.00(m，2H)，2.08-1.96(m，2H)，1.90-180(m，2H)；ESI MS m/z 489[M+H]⁺。

example 11

2- (2-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one hydrochloride

Dilute 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous DMSO (4mL)]Pyridin-4 (5H) -one (80mg, 0.19mmol), 2-chloro-phenylboronic acid (32mg, 0.21mmol), K₂CO₃(52mg, 0.38mmol) and Pd (PPh)₃)₂Cl₂(13mg, 0.019mmol) and the resulting suspension was degassed under reduced pressure for 45 min. The suspension was placed under an Ar atmosphere and heated to 95 ℃ for 2 h. The suspension was cooled and H was added₂And O. The aqueous suspension was extracted with EtOAc and the combined organic extracts were washed with brine, over Na₂SO₄Dried and concentrated under reduced pressure to yield 77mg of a white powder. Flash chromatography on silica gel [ 9: 1CH ]₂Cl₂/(9∶1 MeOH/Et₃N)]56mg of white powder were produced. By preparative HPLC (Phenomenex Luna C18(2), 250.0X 50.0mm, 10 μm, H containing 0.05% TFA₂O and CH with 0.05% TFA₃CN) Final purification to give 31mg (36%) of 2- (2-chlorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c as a white powder]Pyridin-4 (5H) -one. The hydrochloride salt was prepared according to the procedure of example 9 to give the title compound as a white solid: mp 102-;¹H NMR(500MHz，DMSO-d₆)δ9.90-9.80(br s，1H，NH)，8.29(s，1H)，7.98(dd，J＝8.0，1.5Hz，1H)，7.93-7.89(m，2H)，7.73(d，J＝7.3Hz，1H)，7.66(dd，J＝8.0，1.5Hz，1H)，7.57-7.51(m，3H)，7.46(ddd，J＝8.0，8.0，1.5Hz，1H)，6.94(d，J＝7.3Hz，1H)，4.87(t，J＝6.0Hz，2H)，3.79-3.72(m，2H)，3.60-3.52(m，2H)，3.13-3.02(m，2H)，2.08-1.97(m，2H)，1.90-1.81(m，2H)；ESI MS m/z 459[M+H]⁺。

example 12

5-fluoro-2- (4-oxa-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) -4, 5-dioxofuran Pyrano [3, 2-c ] s]Preparation of pyridin-2-yl) benzonitrile hydrochloride

Following the procedure of example 11, but replacing 2-chlorophenylboronic acid with 2-cyano-4-fluorophenylboronic acid, additional 2-cyano-4-fluorophenylboronic acid and K were added after 4h₂CO₃Total reaction time 5h, the title compound was prepared as a white powder (22mg, 23%): mp 120-122 ℃;¹H NMR(500MHz，DMSO-d₆)δ8.29(s，1H)，8.13(dd，J＝8.8，5.5Hz，1H)，8.07(dd，J＝8.8，2.5Hz，1H)，7.94-7.89(m，2H)，7.79(dd，J＝8.5，2.5Hz，1H)，7.76(d，J＝7.5Hz，1H)，7.69(s，1H)，7.54(dd，J＝9.0，1.5Hz，1H)，6.94(d，J＝7.5Hz，1H)，4.90-4.82(m，2H)，3.81-3.71(m，2H)，3.63-3.50(m，2H)，3.15-3.03(m，2H)，2.08-1.97(m，2H)，1.92-1.80(m，2H)；ESI MS m/z 468[M+H]⁺。

example 13

2- (2-chloro-4-fluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

Following the procedure of example 11, but substituting 2-chloro-4-fluorophenylboronic acid for 2-chlorophenylboronic acid, the title compound was prepared as a white powder (32mg, 34%): mp 140-142 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.20-10.10(br s，1H，NH)，8.29(s，1H)，8.01(dd，J＝8.3，6.0Hz，1H)，7.92(d，J＝9.0Hz，1H)，7.90(d，J＝1.8Hz，1H)，7.71(d，J＝6.5Hz，1H)，7.68(dd，J-9.0，2.8Hz，1H)，7.53(dd，J＝9.0，1.8Hz，1H)，7.51(s，1H)，7.44(ddd，J＝8.3，8.0，2.8Hz，1H)，6.93(d，J＝6.5Hz，1H)，4.89(t，J＝6.3Hz，2H)，3.76-3.70(m，2H)，3.58-3.52(m，2H)，3.10-3.02(m，2H)，2.05-1.98(m，2H)，1.90-1.81(m，2H)；ESI MS m/z 477[M+H]⁺。

example 14

2- (4-chloro-2-fluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

Following the procedure of example 11, but substituting 4-chloro-2-fluorophenylboronic acid for 2-chlorophenylboronic acid, the title compound was prepared as a white powder (31mg, 33%): mp 256-258 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.12-10.05(br s，1H，NH)，8.28(s，1H)，7.96(dd，J＝8.5，8.5Hz，1H)，7.94-7.88(m，2H)，7.74(d，J-7.5Hz，1H)，7.68(d，J＝11.0Hz，1H)，7.52(br d，J＝8.5Hz，1H)，7.48(d，J＝8.5Hz，1H)，7.36(s，1H)，6.94(d，J＝7.5Hz，1H)，4.92-4.80(m，2H)，3.80-3.71(m，2H)，3.60-3.49(m，2H)，3.13-3.01(m，2H)，2.07-1.92(m，2H)，1.90-1.80(m，2H)；ESI MS m/z 477[M+H]⁺。

example 15

2- (4-fluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one hydrochloride

a) 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one

1- (2-chloroethyl) pyrrolidine hydrochloride (213mg, 1.25mmol) was added to 2-bromo-5- (1H-indazol-5-yl) furo [3, 2-c]Pyridin-4 (5H) -one (187mg, 0.570mmol) and Cs₂CO₃(1.11g, 3.42mmol) in anhydrous DMSO (3mL) and the resulting suspension was stirred at 25 ℃ for 14 h. Addition of H₂O (10mL) and the aqueous suspension was filtered. The solid was dried under reduced pressure. Flash chromatography on silica gel [ 4.75: 0.5 MTBE/CH ]₂Cl₂/(9∶1EtOH/NH₄OH)]The title compound was obtained as a pale yellow powder (113mg, 47%) whose data matched those reported in example 9.

b)2- (4-fluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4 (5H) -one hydrochloride

Dilute 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous DMSO (2mL)]Pyridin-4 (5H) -one (82mg, 0.19mmol), 4-fluorophenylboronic acid (30mg, 0.21mmol), K₂CO₃(53mg, 0.38mmol) and Pd (PPh)₃)₂Cl₂(13mg, 0.019mmol) and the resulting suspension was degassed under reduced pressure for 45 min. The suspension was placed under an Ar atmosphere and heated to 95 ℃ for 2.5 h. The suspension was cooled and H was added₂And O. The resulting aqueous suspension was filtered and the solid was dried under reduced pressure to give 67mg of a brown powder. Flash chromatography on silica gel [ 85: 15 MTPE/(9: 1 EtOH/Et)₃N)]26mg of an off-white powder was produced. Dissolving the powder in CH₂Cl₂(10mL) and activated charcoal was added. The resulting suspension was stirred at 25 ℃ for 10 min. The suspension was filtered through Celite and the filtrate was concentrated under reduced pressure to yield 22mg of an off-white powder. By preparative HPLC (Phenomenex Luna C18(2), 250.0X 50.0mm, 10 μm, H containing 0.05% TFA₂O and CH with 0.05% TFA₃CN) Final purification yielded 17mg (20%) of 2- (4-fluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c) as a white powder]Pyridin-4 (5H) -one. The hydrochloride salt was prepared according to the procedure of example 9 to give the title compound as a white powder: mp 218-220 ℃;¹H NMR(500MHz，DMSO-d₆)δ9.90-9.82(br s，1H，NH)，8.28(s，1H)，7.95(dd，J＝9.0，5.0Hz，2H)，7.92-7.89(m，2H)，7.67(d，J＝7.5Hz，1H)，7.56(s，1H)，7.53(br d，J＝9.0Hz，1H)，7.36(dd，J＝9.0，9.0Hz，2H)，6.91(d，J＝7.5Hz，1H)，4.91-4.83(m，2H)，3.80-3.72(m，2H)，3.63-3.51(m，2H)，3.14-3.05(m，2H)，2.09-1.98(m，2H)，1.90-1.80(m，2H)；ESI MS m/z443[M+H]⁺。

example 16

5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) -2- (4- (trifluoromethyl) phenyl) furan And [3, 2-c ]]Preparation of pyridin-4 (5H) -one hydrochloride

Dilute 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous DMSO (2mL)]Pyridin-4 (5H) -one (83mg, 0.20mmol), 4- (trifluoromethyl) phenylboronic acid (41mg, 0.21mmol), K₂CO₃(54mg, 0.39mmol) and Pd (PPh)₃)₂Cl₂(14mg, 0.020mmol) and the resulting suspension was degassed under reduced pressure for 45 min. The suspension was placed under an Ar atmosphere and heated to 95 ℃ for 2 h. The suspension was cooled and H was added₂And O. The resulting aqueous suspension was filtered and the solid was dried under reduced pressure to yield 78mg of a brown powder. Flash chromatography on silica gel [ 9: 1CH ]₂Cl₂/(9∶1 MeOH/Et₃N)]Yielding 38mg of an off-white powder. Using a Strong cation exchange (SCX) column (MeOH to 7: 1 MeOH/NH)₄OH) to yield 16mg (17%) of 5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) -2- (4- (trifluoromethyl) phenyl) furo [3, 2-c) as a white powder]Pyridin-4 (5H) -one. The hydrochloride salt was prepared according to the procedure of example 9 to give the title compound as a white powder: mp 252-254 ℃;¹H NMR(500MHz，DMSO-d₆)δ9.79-9.68(brs，1H，NH)，8.29(s，1H)，8.12(d，J＝8.0Hz，2H)，7.94-7.88(m，2H)，7.86(d，J＝8.0Hz，2H)，7.81(s，1H)，7.73(d，J＝7.0Hz，1H)，7.56-7.51(m，1H)，6.95(d，J＝7.0Hz，1H)，4.90-4.82(m，2H)，3.79-3.71(m，2H)，3.62-3.53(m，2H)，3.15-3.04(m，2H)，2.09-1.99(m，2H)，1.93-1.81(m，2H)；ESI MS m/z 493[M+H]⁺。

example 17

2- (5-Chloropyridin-2-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one dihydrochloride

Dilute 2-bromo-5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] with anhydrous DMSO (4mL)]Pyridin-4 (5H) -one (145mg, 0.340mmol), Pd (PPh)₃)₂Cl₂(39mg, 0.034mmol) and hexamethylditin (0.14mL, 0.68mmol), and heating the resulting solution to 80 ℃ with N₂The resulting solution was bubbled. Once the oil bath temperature reached 80 ℃, bubbling was stopped and the reaction mixture was under N₂Stirring for 45min at 80 ℃ in the atmosphere. The solution was cooled and diluted with EtOAc (50 mL). The resulting organic solution was washed with brine (2X 50mL), Na₂SO₄Dried and concentrated under reduced pressure. The residue was diluted with anhydrous DMSO (4mL) 2-bromo-5-chloropyridine (174mg, 0.340mmol) and Pd (PPh)₃)₂Cl₂(39mg, 0.034 mmol). N for the resulting solution₂Degassed, heated to 110 ℃ and held at this temperature for 18 h. The solution was cooled, EtOAc (40mL) was added and H₂The resulting solution was washed with O (10 mL). The organic solution was washed with brine (2X 20mL), Na₂SO₄Dried and concentrated under reduced pressure to yield 55mg of a brown powder. Flash chromatography on silica gel [ 9: 1CH ]₂Cl₂/(9∶1 MeOH/Et₃N)]Yielding 46mg of a white powder. By preparative HPLC (Phenomenex Luna C18(2), 250.0X 50.0mm, 10 μm, H containing 0.05% TFA₂O and CH with 0.05% TFA₃CN) Final purification to give 2- (5-chloropyridin-2-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c) as a white powder]Pyridin-4 (5H) -one (9mg, 6%). The hydrochloride salt was prepared according to the procedure of example 9 to give the title compound as a white solid：mp 268-270℃；¹H NMR(500MHz，DMSO-d₆)δ9.72-9.60(br s，1H，NH)，8.72(d，J＝2.5Hz，1H)，8.28(s，1H)，8.08(dd，J＝8.5，2.5Hz，1H)，7.98(d，J＝8.5Hz，1H)，7.94-789(m，2H)，7.74(d，J＝7.5Hz，1H)，7.65(s，1H)，7.54(br d，J＝8.0Hz，1H)，6.95(d，J＝7.5Hz，1H)，4.90-4.82(m，2H)，3.80-3.73(m，2H)，3.63-3.51(m，2H)，3.14-3.03(m，2H)，2.07-1.95(m，2H)，1.91-1.82(m，2H)；ESI MS m/z 460[M+H]⁺。

Example 18

2- (2-fluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one hydrochloride

Following the procedure of example 11, but substituting 2-fluorophenylboronic acid for 2-chlorophenylboronic acid, the title compound was prepared as a white powder (32mg, 35%): mp 264-266 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.10-9.92(br s，1H，NH)，8.29(s，1H)，7.96(ddd，J＝8.0，8.0，2.0Hz，1H)，7.94-7.89(m，2H)，7.72(d，J＝7.5Hz，1H)，7.54(dd，J＝8.0，1.5Hz，1H)，7.51-7.46(m，1H)，7.45-7.37(m，2H)，7.30(d，J＝3.0Hz，1H)，6.95(d，J＝7.5Hz，1H)，4.88(t，J＝6.0Hz，2H)，3.78-3.72(m，2H)，3.60-3.51(m，2H)，3.12-3.03(m，2H)，2.06-1.97(m，2H)，1.91-1.80(m，2H)；ESI MS m/z 443[M+H]⁺。

example 19

2- (2, 4-difluorophenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

Following the procedure of example 11, but substituting 2, 4-difluoro-phenylboronic acid for 2-chlorophenylboronic acid, the title compound was prepared as a white powder (24mg, 28%): mp 256-258 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.15-9.90(br s，1H，NH)，8.29(s，1H)，8.03-7.96(m，1H)，7.94-7.88(m，2H)，7.72(d，J＝7.5Hz，1H)，7.53(dd，J＝9.0，1.5Hz，1H)，7.52(ddd，J＝9.5，9.5，2.5Hz，1H)，7.30(ddd，J＝8.5，8.5，2.5Hz，1H)，7.28(d，J＝3.0Hz，1H)，6.94(d，J＝7.5Hz，1H)，4.88(t，J＝6.0Hz，2H)，3.78-3.70(m，2H)，3.59-3.51(m，2H)，3.12-3.01(m，2H)，2.06-1.97(m，2H)，1.90-1.80(m，2H)；ESI MS m/z 461[M+H]⁺。

example 20

2- (2-fluoro-4-methylphenyl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

Following the procedure of example 11, but substituting 2-fluoro-4-methyl-phenylboronic acid for 2-chlorophenylboronic acid, the title compound was prepared as a white powder (21mg, 19%): mp 268-270 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.15-10.06(br s，1H，NH)，8.28(s，1H)，7.92(d，J＝9.0Hz，1H)，7.90(d，J＝2.0Hz，1H)，7.83(dd，J＝8.0，8.0Hz，1H)，7.70(d，J＝7.5Hz，1H)，7.53(dd，J＝9.0，2.0Hz，1H)，7.26(d，J＝12.5Hz，1H)，7.23-7.18(m，2H)，6.93(d，J＝7.5Hz，1H)，4.88(t，J＝6.0Hz，2H)，3.78-3.72(m，2H)，3.60-3.52(m，2H)，3.12-3.03(m，2H)，2.39(s，3H)，2.07-1.98(m，2H)，1.90-1.81(m，2H)；ESI MS m/z 457[M+H]⁺。

example 21

5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) -2-p-tolylfuro [3, 2-c)]Pyridine (II) Preparation of pyridine-4 (5H) -one hydrochloride

Following the procedure of example 11, but replacing 2-chlorophenylboronic acid with p-tolylboronic acid and triturating the free base with EtOAc and toluene, the title compound was prepared as a near white powder (19mg, 19%): mp 262-264 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.12-9.99(br s，1H，NH)，8.26(br s，1H)，7.92-7.75(m，2H)，7.79(d，J＝8.0Hz，2H)，7.65(d，J＝7.0Hz，1H)，7.51(br d，J＝7.5Hz，1H)，7.47(s，1H)，7.31(d，J＝8.0Hz，2H)，6.90(d，J＝7.5Hz，1H)，4.91-4.79(m，2H)，3.81-3.68(m，2H)，3.67-3.45(m，2H)，3.15-2.97(m，2H)，2.50(s，3H)，2.11-1.98(m，2H)，1.95-1.79(m，2H)；ESI MSm/z 439[M+H]⁺。

example 22

2- (pyridin-3-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one hydrochloride

The procedure of example 11 was followed, but using pyridine-3-boronic acid 1, 3-propanediol cyclic esterThe title compound was prepared as a white powder (7mg, 7%) replacing 2-chlorophenylboronic acid: mp 188-190 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.33-10.22(br s，1H，NH)，9.15(s，1H)，8.60(d，J＝4.5Hz，1H)，8.32-8.27(m，2H)，7.93(d，J＝9.0Hz，1H)，7.91(s，1H)，7.77(s，1H)，7.72(d，J＝7.3Hz，1H)，7.57(dd，J＝8.0，4.8Hz，1H)，7.53(br d，J＝9.0Hz，1H)，6.94(d，J＝7.3Hz，1H)，4.90(t，J＝6.0Hz，2H)，3.75-3.70(m，2H)，3.60-3.48(m，2H)，3.10-3.01(m，2H)，2.05-1.95(m，2H)，1.90-1.79(m，2H)；ESI MS m/z 426[M+H]⁺。

example 23

2- (5-Fluoropyridin-2-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one dihydrochloride

Following the procedure of example 17, but replacing 2-bromo-5-chloropyridine with 2-bromo-5-fluoropyridine, the title compound was prepared as a yellow powder (26mg, 13%): mp 266-268 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.27-10.19(br s，1H，NH)，8.68(d，J＝2.5Hz，1H)，8.28(s，1H)，8.04(dd，J＝9.0，4.5Hz，1H)，7.94-7.87(m，3H)，7.73(d，J＝7.5Hz，1H)，7.58(s，1H)，7.54(dd，J＝9.0，1.5Hz，1H)，6.94(d，J＝7.5Hz，1H)，4.89(t，J＝6.0Hz，2H)，3.78-3.71(m，2H)，3.65-3.49(m，2H)，3.11-3.02(m，2H)，2.06-1.95(m，2H)，1.89-1.81(m，2H)；ESI MS m/z 444[M+H]⁺。

example 24

2- (pyridin-2-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one dihydrochloride

Following the procedure of example 17, but substituting 2-bromopyridine for 2-bromo-5-chloropyridine, the title compound was prepared as a yellow powder (11mg, 1.3%): mp 50-52 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.15-10.04(br s，1H，NH)，8.69-8.65(m，1H)，8.28(d，J＝2.0Hz，1H)，7.98-7.88(m，4H)，7.75-7.71(m，1H)，7.59(d，J＝2.5Hz，1H)，7.56-7.52(m，1H)，7.43-7.38(m，1H)，6.95(dd，J＝7.5，2.0Hz，1H)，4.92-4.85(m，2H)，378-3.71(m，2H)，3.59-3.52(m，2H)，3.12-3.03(m，2H)，2.07-1.98(m，2H)，1.90-1.81(m，2H)；ESI MS m/z 426[M+H]⁺。

example 25

2- (6-methylpyridazin-3-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3，2-c]Preparation of pyridin-4 (5H) -one hydrochloride

Following the procedure of example 17, but substituting 3-bromo-6-methylpyridazine for 2-bromo-5-chloropyridine, the title compound was prepared as a yellow powder (33mg, 4%): mp 282-284 ℃;¹H NMR(500MHz，DMSO-d₆)δ10.32-10.11(br s，1H，NH)，8.29(s，1H)，8.14(d，J＝9.0Hz，1H)，7.96-7.91(m，2H)，7.83(s，1H)，7.77(d，J＝7.3Hz，1H)，7.72(d，J＝9.0Hz，1H)，7.55(dd，J＝8.5，1.5Hz，1H)，6.98(d，J＝7.3Hz，1H)，4.89(t，J＝5.5Hz，2H)，3.78-3.71(m，2H)，3.70-3.45(m，2H)，3.12-3.01(m，2H)，2.68(s，3H)，2.06-1.98(m，2H)，1.90-1.81(m，2H)；ESI MS m/z 441[M+H]⁺。

example 26

2- (pyrimidin-2-yl) -5- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c] Preparation of pyridin-4 (5H) -one dihydrochloride

Following the procedure of example 11, but replacing 2-chlorophenylboronic acid with 2- (tributylstannyl) pyrimidine, the title compound was prepared as a white powder (14mg, 11%): mp 272 and 274 ℃;¹H NMR(500MHz，DMSO-d₆)δ9.91-9.82(br s，1H，NH)，8.92(d，J＝5.0Hz，2H)，8.29(s，1H)，7.95-7.90(m，2H)，7.79(d，J＝7.5Hz，1H)，7.69(s，1H)，7.55(brd，J＝9.0Hz，1H)，7.49(d，J＝5.0Hz，1H)，6.99(d，J＝7.5Hz，1H)，4.87(t，J＝6.0Hz，2H)，3.80-3.71(m，2H)，3.62-3.53(m，2H)，3.15-3.04(m，2H)，2.07-1.96(m，2H)，1.92-1.81(m，2H)；ESI MS m/z 427[M+H]⁺。

example 27

2- (4-chlorophenyl) -5- (1- (2- (morpholinoethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridine-4- Preparation of ketone hydrochloride

a)2- (4-chlorophenyl) -5- (1- (2- (morpholinoethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

The procedure of example 3 (step d) was followed, howeverSubstituting morpholine for (R) -2-hydroxymethylpyrrolidine to prepare the title compound as a light yellow powder (38mg, 26%):¹H NMR(500MHz，CDCl₃)δ8.05(s，1H)，7.73-7.72(m，3H)，7.54(d，J＝9.0Hz，1H)，7.47-7.42(m，3H)，7.36(d，J＝7.5Hz，1H)，7.25(s，1H)，6.68(d，J＝7.0Hz，1H)，4.56(t，J＝7.0Hz，2H)，3.69(t，J＝4.5Hz，4H)，2.91(t，J＝7.0Hz，2H)，2.53(t，J＝4.5Hz，4H)；ESI MS m/z 475[M+H]⁺。

b)2- (4-chlorophenyl) -5- (1- (2- (morpholinoethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one hydrochloride

The procedure of example 3 (step e) was followed except using 2- (4-chlorophenyl) -5- (1- (2- (morpholinoethyl) -1H-indazol-5-yl) furo [3, 2-c)]Substitution of pyridin-4-one for (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridin-4-one to prepare the title compound as a tan powder (34.2mg, 86%): mp 260 and 268 ℃ decomposition;¹H NMR(500MHz，DMSO-d₆)δ10.22(br s，1H)，8.28(s，1H)，7.93-7.90(m，4H)，7.69(d，J＝7.5Hz，1H)，7.63(s，1H)，7.58-7.53(m，3H)，6.91(d，J＝7.5Hz，1H)，4.93(br m，2H)，4.02-4.00(br m，2H)，3.71(br m，4H)，3.57-3.55(m，2H)，3.27-3.22(m，2H)；ESI MS m/z 475[M+H]⁺HPLC (method A) 98.0% (AUC), t_R＝15.6min。

Example 28

2- (4-chlorophenyl) -5- (1- (2- (piperazin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c]Pyridine (II) Preparation of pyridin-4-one hydrochloride

a)4- (2- (5- (2- (4-chlorophenyl) -4-oxafuro [3, 2-c ] pyridin-5- (4H) -yl) -1H-indazol-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester

Following the procedure of example 3 (step d), but replacing (R) -2-hydroxymethylpyrrolidine with tert-butyl 1-piperazinecarboxylate, the title compound was prepared as a light yellow powder (83.7mg, 56%):¹H NMR(500MHz，CDCl₃)δ8.04(d，J＝1.0Hz，1H)，7.73-7.72(m，3H)，7.54(d，J＝9.0Hz，1H)，7.47-7.42(m，3H)，7.36(d，J＝7.5Hz，1H)，7.25(s，1H)，6 68(d，J＝7.5Hz，1H)，4.55(t，J＝7.0Hz，2H)，3.41-3.40(m，4H)，2.91(t，J＝7.0Hz，2H)，2.47(br m，4H)，1.45(s，9H)。

b)2- (4-chlorophenyl) -5- (1- (2- (piperazin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one

Treatment of 4- (2- (5- (2- (4-chlorophenyl) -4-oxafuro [3, 2-c) with trichloroacetic acid (1.0mL)]Pyridin-5- (4H) -yl) -1H-indazol-1-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester (76mg, 0.13mmol) in CH₂Cl₂(1.0mL) of the solution. The solution was stirred at ambient temperature for 1h, then the solution was concentrated. Obtained CH for film₂Cl₂Diluted (5mL) and NaHCO₃And (4) neutralizing the saturated solution. CH for aquifer₂Cl₂Extraction (3X 20 mL). The organic extracts were washed with brine (2X 10mL), dried (Na)₂SO₄) Filtered and concentrated to give the title compound as an orange-yellow solid (32.0mg, 51%):¹H NMR(500MHz，CDCl₃)δ8.05(s，1H)，7.80-7.72(m，3H)，7.56(d，J＝9.0Hz，1H)，7.48-7.39(m，3H)，7.36(d，J＝7.5Hz，1H)，7.26(s，1H)，6.68(d，J＝7.5Hz，1H)，4.56(t，J＝7.0Hz，2H)，2.91-2.88(m，6H)，2.51(br m，4H)，ESIMS m/z 474[M+H]⁺(ii) a HPLC (method A) 96.5% (AUC), t_R＝14.3min。

c)2- (4-chlorophenyl) -5- (1- (2- (piperazin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c ] pyridin-4-one hydrochloride

The procedure of example 3 (step e) was followed except using 2- (4-chlorophenyl) -5- (1- (2- (piperazin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c)]Replacement of (R) -2- (4-chlorophenyl) -5- (1- (2- (2-hydroxymethyl) pyrrolidin-1-yl) ethyl) -1H-indazol-5-yl) furo [3, 2-c) with pyridin-4-one hydrochloride]Pyridin-4-one to prepare the title compound as an orange yellow powder (27.0mg, 78%): mp 298-¹H NMR(500MHz，DMSO-d₆)δ8.59(br s，2H)，8.18(s，1H)，7.92(d，J＝8.5Hz，2H)，7.86-7.84(m，2H)，7.70(d，J＝7.5Hz，1H)，7.64(s，1H)，7.57(d，J＝8.5Hz，2H)，7.45d，J＝10.0Hz，1H)，6.91(d，J＝7.5Hz，1H)，4.63(br s，2H)，3.05-2.81(m，6H)，2.70-2.58(m，4H)；ESI MS m/z 474[M+H]⁺HPLC (method A) 96.7% (AUC), t_R＝14.6min。

For human Melanin Concentrating Hormone (MCH)₁) Binding assays for receptors

For compounds to human MCH₁Evaluation of receptor affinity was done in transfected Chinese Hamster Ovary (CHO) cells, and was determined in radioligand binding assays, such as MacDonald et al, "Molecular characterization of the tumor-differentiating hormone/receptor complex: identification of the molecular characterization of the melanin concentrating hormone/receptor complex: identification of key residues involved in binding and activation "", Mol Pharmacol,58: 217 (2000). In the presence of 25mM Hepes/Tris(pH 7.4)、5mM MgCl₂、1mM CaCl₂And 0.5% Bovine Serum Albumin (BSA), in a buffer solution of 0.1nM [ mu ] m¹²⁵I][Phe¹³，Tyr¹⁹]MCH cell membrane homogenate (5. mu.g protein) was incubated at 22 ℃ for 60min with or without test compound. Non-specific binding was detected in the presence of 0.1. mu.M MCH. After incubation, the samples were rapidly filtered through a glass fiber filter (GF/B, Packard) under vacuum and filtered with 25mM Hepes/Tris (pH 7.4), 500mM NaCl, 5mM MgCl₂，1mM CaCl₂And 0.1% BSA in ice-cold buffer, washed several times using a 96-sample cell collector (Unifilter, Packard). The filters were dried and the radioactivity was then counted in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).

Results are expressed as percent inhibition of control radioligand specific binding. Determination of IC by competitive curve nonlinear regression analysis using Hill equation curve fitting₅₀Value (concentration producing half-maximal inhibition of control specific binding) and Hill coefficient (n)_H). The inhibition constant (K) was calculated according to the Cheng Prusoff equation_i)：

(K_i＝IC₅₀/(1+(L/K_D))，

Wherein L is the concentration of radioligand in the assay, and K_DAffinity of radioligand for receptor).

By the above method, the compounds listed in table 1 were synthesized and tested for biological activity. At the MCH₁In the binding assay, all compounds in Table 1 showed a K of less than or equal to 2.0. mu.M_i。

The present invention is not limited to the compounds found in the above examples, and many other compounds falling within the scope of the present invention can also be prepared using the procedures set forth in the above synthetic schemes. The use of these methods to prepare other compounds will be apparent to one of ordinary skill in the chemical arts.

The invention has been described in detail with particular reference to certain embodiments thereof, but it will be understood by those skilled in the art that variations and modifications can be effected within the spirit and scope of the invention.

Claims (25)

1. A compound of formula I:

wherein

n is 1 or 2_[MDS29]；

R is NR¹R²Wherein R is¹And R²Each independently selected from H and optionally substituted alkyl, or R¹And R²In conjunction withThe N atoms to which they are attached together form a 4-7 membered optionally substituted heterocyclic ring optionally containing 1 or 2 heteroatoms in addition to the N atoms shown;

R³and R⁴Each independently selected from H and alkyl, or R, R³And R⁴Can combine to form an optionally substituted imidazolin-2-yl group;

b is aryl or heteroaryl; and is

R⁵、R⁶、R⁷Each independently selected from H, -OH_[MDS30]-O-alkyl, halogen, -CF₃and-CN;

with the proviso that the compound is not one of the following compounds:

2. the compound of claim 1, wherein R is selected from the group consisting of pyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, 3-hydroxy-pyrrolidin-1-yl, and morpholin-4-yl and piperazin-1-yl.

3. The compound of claim 1 or 2, wherein R is selected from S-2-hydroxymethylpyrrolidin-1-yl, R-2-hydroxymethylpyrrolidin-1-yl, S-3-hydroxypyrrolidin-1-yl, and R-3-hydroxypyrrolidin-1-yl.

4. A compound according to any one of claims 1 to 3, wherein R³And R⁴Are all H.

5. The compound of claim 1, wherein R, R³And R⁴Combine to form imidazolin-2-yl optionally independently substituted with alkyl at each of the 1-position, 4-position and 5-position.

6. The compound according to any one of claims 1 to 5, wherein n is 1.

7. The compound according to any one of claims 1 to 5, wherein n is 2_[MDS31]。

8. The compound according to any one of claims 1 to 7, wherein B is phenyl.

9. The compound of claim 8, wherein B is taken together with R⁵、R⁶And R⁷Together selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-trifluoromethylphenyl, 2-cyano-4-fluorophenyl, 2, 4-dichlorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-methoxyphenyl, 2-fluorophenyl, 2, 4-difluorophenyl, 2-fluoro-4-methylphenyl, and 4-methylphenyl.

10. The compound according to any one of claims 1 to 7, wherein B is pyridine.

11. The compound of claim 10, wherein B is taken together with R⁵、R⁶And R⁷Together selected from the group consisting of 5-chloropyridin-2-yl, pyridin-3-yl, 5-fluoropyridin-2-yl, and pyridin-2-yl.

12. The compound of claim 1, wherein B is pyridazine.

13. The compound of claim 12, wherein B is taken together with R⁵、R⁶And R⁷Together are a 6-methylpyridazin-3-yl group.

14. The compound of claim 1, wherein B is pyrimidine.

15. The compound of claim 14, wherein B is taken together with R⁵、R⁶And R⁷Together is pyrimidin-2-yl.

16. The compound of any one of claims 1,2, 3, 4,5, 6, 7, 8, 10, 12, or 14, wherein R⁵、R⁶、R⁷Each independently selected from H, -O-alkyl, halogen, -CF₃and-CN;

17. the compound according to claim 1, selected from the following compounds:

18. a compound according to any one of claims 1 to 17 in the form of a pharmaceutically acceptable salt.

19. The compound of claim 18 in the form of a hydrochloride salt.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier, excipient or diluent.

21. A method of treating obesity comprising administering to a patient in need of weight loss a weight-loss effective amount of a compound of any one of claims 1 to 18.

22. A method of treating anxiety which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound as claimed in any one of claims 1 to 18.

23. A method of treating depression comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 18.

24. A method of treating non-alcoholic fatty liver disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 18.

25. A treatment susceptible to MCH₁A method of treating an affected disease or condition with a receptor modulator, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 18.