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HK1164867B - Biologically active amides - Google Patents

Biologically active amides Download PDF

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Publication number
HK1164867B
HK1164867B HK12105590.9A HK12105590A HK1164867B HK 1164867 B HK1164867 B HK 1164867B HK 12105590 A HK12105590 A HK 12105590A HK 1164867 B HK1164867 B HK 1164867B
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HK
Hong Kong
Prior art keywords
phenyl
pyridin
piperidin
compound
acetamide
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HK12105590.9A
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Chinese (zh)
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HK1164867A1 (en
Inventor
John Matthew Peterson
Chien-An Chen
Bin Chen
Lingyun Wu
Michael Lloyd Sabio
Original Assignee
H. Lundbeck A/S
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Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority claimed from PCT/US2009/062956 external-priority patent/WO2010053861A2/en
Publication of HK1164867A1 publication Critical patent/HK1164867A1/en
Publication of HK1164867B publication Critical patent/HK1164867B/en

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Description

Biologically active amides
Technical Field
The present invention relates to compounds which are ligands of the neuropeptide Y Y5 receptor and are therefore useful in the treatment of disorders related to mood (mood), stress (stress), cognition, stress (stress) and dementia.
Background
Neuropeptide y (npy) is a 36 amino acid neuropeptide expressed in the peripheral and central nervous systems. This peptide is a member of the pancreatic polypeptide family, which also includes Pancreatic Polypeptide (PP) and peptide yy (pyy). Furthermore, the biological effects of NPY are mediated through its interaction with receptors belonging to the superfamily of G protein-coupled receptors.
Currently, five NPY receptor subtypes have been cloned: y1(D.Larhammar et al J.biol.chem., 1992, 267, 10935-; y2(C.Gerald et al J.biol.chem., 1995, 270, 26758-; y4(J.Bard et al J.biol.chem., 1995, 270, 26762) -26765); y5(C.Gerald et al J.biol.chem., 1995, 270, 26758-; and y6(P.Gregor et al J.biol.chem., 1996, 271, 27776-. All of these receptor subtypes are expressed in some species, except the y6 subtype (which has been shown to be expressed in mice and rabbits, but not in rats and primates). The Y3 subtype has been proposed based on pharmacological data. However, the Y3 subtype has not yet been cloned, and its presence is yet to be fully established.
NPY exerts a number of physiological effects. Based on animal studies, it is clear that there is a contributing relationship between NPY and its receptors and disorders such as depression, anxiety and obesity. For example, NPY expression was shown to be sensitive to energy status, while administration of NPY decreased energy expenditure. Another significant ability of NPY is to stimulate food intake acutely (s.kalra et al endocr.rev., 1999, 20, 68-100). The NPY Y5 receptor has also been shown to be a receptor subtype responsible for NPY-induced food intake (C. Gerald et al Nature, 1996, 382, 168-171).
The association between NPY and mood disorders (e.g. depression and anxiety) is established in the literature. For example, rats undergoing chronic mild stress exhibit a deficit in interest that is characteristic of clinical depression (p.willner et al, eur.j.pharmacol, 1997, 340, 121-; they also contain elevated levels of NPY mRNA in the hypothalamus, with concomitant reduction in NPY mRNA levels in the hippocampus (v. sergeyev et al, psychopharmacography, 2005, 178, 115-one 124). Behavioral changes associated with chronic mild stress are reversed by various antidepressants (p.willner et al eur.j.pharmacol, 1997, 340, 121-. In one study of antidepressant drug treatment, rats treated with citalopram showed increased levels of hippocampal NPY receptor binding, but no change in NPY-like immunoreactivity (h. husum et al, Neuropsychopharmacology, 2001, 2, 183-191); in contrast, electrical tic shock causes an increase in the level of hippocampal NPY-like immunoreactivity with no change in NPY receptor binding. These findings indicate that abnormal levels of NPY play a role in depressive disorders, and that agents capable of modulating NPY and/or NPY receptor function (especially in the limbic region) are useful in the treatment of depression. Y5 is the NPY receptor expressed in the border region (M.Wolak et al J Comp. Neurol., 2003, 22, 285-103311; and K.Nichol et al J. Neurosci., 1999, 19, 10295-10304). Accordingly, agents capable of modulating Y5 receptor function are therefore predicted to be useful in the treatment of depression.
Animal models of anxiety also show abnormal levels of NPY. In one example, mother-infant isolated (matricial separated) rats show anxiety and depressive phenotypes throughout the adult period (r.huot, Psychopharmacology, 2001, 158, 366-73); they also contain elevated levels of NPY-like immunoreactivity in the hypothalamus with concomitant reduction in the levels of NPY-like immunoreactivity in the hippocampus and cortex (P.Jimenez-Vasquez, Brain Res.Dev., 2001, 26, 149-. In a second example, rats subjected to fear conditioning (fearconditioning) showed an increase in anxiety-like behavior; they also contain elevated levels of NPY in the hypothalamus, tonsils and nucleus accumbens, with concomitant reduction in NPY levels in the frontal cortex. Behavioral changes through fear conditioning can be reversed by treatment with anxiolytic drugs. In one study of fear conditioning, changes in anxiety-like behavior and NPY expression were reversed by treatment with diazepam (r. krysiak et al, Neuropeptides, 2000, 34, 148-57). These findings further illustrate that NPY plays a role in anxiety, and that agents capable of modulating NPY and/or receptor function, particularly in the limbic region, are useful in the treatment of anxiety disorders. Y5 is the NPY receptor expressed in the border region (M.Wolak et al, J.Comp.Neurol., 2003, 22, 285-. Accordingly, agents capable of modulating the function of the Y5 receptor are therefore predicted to be useful in the treatment of anxiety.
Some groups have disclosed a link between the NPY Y5 receptor and sleep disorders associated with disruption of circadian rhythms (nexus). This relationship is based on the following findings: in response to NPY application, NPY Y5 receptors mediate important physiological responses in the suprachiasmatic nucleus (SCN) of the hypothalamus. For example, WO 99/05911 and WO 05/30208 disclose such a connection and suggest the use of NPY Y5 receptor ligands for the treatment of sleep disorders. Accordingly, it is expected that the compounds of formula I may be useful in the treatment of sleep disorders (including primary insomnia).
The pharmaceutical industry is also aimed at NPY Y5 receptor antagonists as potential therapies for the treatment of cognitive impairment/dysfunction (dysfunction) disorders. For example, NPYY5 receptor antagonists (MK-0557) are currently used in clinical trials to treat cognitive impairment in patients with schizophrenia. In support of this indication (indication), WO 03/51356 suggests that NPY Y5 receptor antagonism may be useful in the treatment of dementia. Accordingly, it is contemplated that the compounds of formula I may be used to treat cognitive impairment/dysfunction disorders, such as cognitive impairment associated with schizophrenia (CIAS); schizophrenia; dementia; autism disorder; ADHD; and alzheimer's disease. The compounds of the invention are also expected to treat both the positive and negative aspects of schizophrenia (positive and negative aspects); dementia; autism disorder; ADHD; and alzheimer's disease.
WO 02/28393 discloses a method of reducing self-administration of alcohol in a patient suffering from alcoholism comprising administering an NPY Y5 receptor antagonist. Accordingly, it is contemplated that the compounds of formula I may be useful in the treatment of substance dependence/abuse disorders, such as alcoholism and nicotine and cocaine addiction.
Furthermore, it is contemplated that the compounds of formula I may be used to treat metabolic disorders, such as dyslipidemia; hyperlipidemia; insulin hyposensitivity; hyperglycemia; metabolic syndrome; and diabetes.
NPY expression has been shown to be sensitive to energy status while, given NPY, it reduces energy expenditure, another significant ability of NPY is to stimulate food intake acutely (s.kalra et al, endocr.rev., 1999, 20, 68-100). The NPY Y5 receptor has also been shown to be a receptor subtype responsible for NPY-induced food intake (C. Gerald et al, Nature, 1996, 382, 168-171). Accordingly, it is expected that the compounds of formula I may be useful in the treatment of eating disorders, such as bulimia; bulimia nervosa; binge eating disorder (binge eating disorder); and night eating disorders (night eating disorders).
Following intrathecal and ICV administration, and following direct infusion into specific brain regions, analgesic-like effects of NPY have been shown in both rats and mice. These studies have used a "spinal cord" pain model or an "supraspinal" model. The involvement of the Y5 receptor subtype has been linked to chronic pain disorders (Woldbye et al Brain Research, 2007, 49-55). Accordingly, it is contemplated that the compounds of formula I may be used to treat chronic pain conditions, such as neuropathic pain; neuralgia; migraine headache; fibromyalgia; IBS; chronic fatigue syndrome; chronic tension type headache; chronic low back pain (chronic low back pain); myofascial pain and chronic osteoarthritis.
Additionally, it is contemplated that treatment of cognitive and mood impairment in parkinson's disease may be an indicative target for the compound of formula I. The compounds of formula I may also be useful in the treatment of disorders related to impulsivity and aggression.
Summary of The Invention
It is an object of the present invention to provide compounds which are ligands of the NPY Y5 receptor. Accordingly, the present invention relates to compounds of formula I:
wherein R is1Is phenyl, pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, wherein said phenyl, pyrazoylOxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are optionally substituted with one or more R4Substitution;
wherein R is2Is C1-C7Alkyl radical, C1-C7Alkoxy, NH (C)1-C7Alkyl group), (CH)2)vOC(O)C1-C7Alkyl radical, C3-C7Cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, furyl, or pyrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, furyl, and pyrazolyl are optionally substituted with one or more R5Substitution;
wherein R is3Is H or C1-C7Alkyl, or wherein R3Can be reacted with R2Combined to form optionally coated C1-C4Alkyl substituted C1-C4An alkylene group;
wherein R is4Is C1-C7An alkyl group; c1-C7A perfluoroalkyl group; c (O) C1-C7An alkyl group; or optionally with one or more C1-C7Alkyl radical, C1-C7Perfluoroalkyl group, C1-C7Alkoxy or halogen substituted phenyl;
wherein R is5Is C1-C7Alkyl radical, C1-C7Perfluoroalkyl group, C1-C7Alkoxy or halogen;
wherein A is CH, COH or N;
wherein X is C (O), CO2Or S (O)2；
Wherein each RaAnd RbIndependently is H or C1-C7Alkyl, or wherein RaAnd RbCan be combined to form C3-C7A cycloalkyl group;
wherein each RcIndependently is H or C1-C7An alkyl group;
wherein each m and v is independently an integer from 1 to 4 (an integer from 1 to 4 inclusive); and
where n is an integer from 0 to 2 (an integer from 0 to 2 inclusive).
In a separate embodiment of the invention, the compound is selected from one of the specific compounds disclosed in the experimental section.
In addition, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also provides a process for preparing a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating a subject (subject) suffering from a mood disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In addition, the present invention further provides a method of treating a subject suffering from anxiety comprising administering to the subject a therapeutically effective amount of a compound of formula I. The invention further provides a method of treating a subject suffering from a cognitive disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I.
In addition, the invention relates to the use of a compound as defined in formula I for the preparation of a medicament useful for the treatment of mood disorders. The present invention relates to the use of a compound as defined in formula I for the preparation of a medicament useful for the treatment of anxiety disorders. The invention further provides the use of a compound as defined in formula I for the manufacture of a medicament useful for the treatment of cognitive disorders.
In a separate embodiment of the invention, the method or use is selected from one of the specific conditions mentioned in the detailed description of the invention.
Detailed Description
In the present invention, the term "C1-C7Alkyl "refers to a straight or branched chain saturated hydrocarbon having 1 to 7 carbon atoms (carbon atom municipal). Examples of such substituents include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, n-pentyl, and n-hexyl. Similarly, the term "straight or branched C1-C4Alkyl "refers to saturated hydrocarbons having 1 to 4 carbon atoms. Examples of such substituents include, but are not limited to, methyl, ethyl, and n-butyl.
Also, the term "C1-C7Alkoxy "refers to a straight or branched chain saturated alkoxy group having 1 to 7 carbon atoms, wherein the oxygen has an open valency (open valency). Examples of such substituents include, but are not limited to, methoxy, ethoxy, n-butoxy, t-butoxy, and n-heptyloxy.
The term "C3-C6Cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "C" as used herein1-C7Perfluoroalkyl "refers to a straight or branched chain saturated hydrocarbon having 1 to 7 carbon atoms, substituted with one or more fluorine atoms. Examples of such substituents include, but are not limited to, trifluoromethyl, pentafluoroethyl, 1-fluoroethyl, 1, 2-difluoroethyl and 3, 4-difluoroheptyl. Similarly, the term "straight or branched C1-C4Fluoroalkyl "refers to a saturated hydrocarbon having 1 to 4 carbon atoms, each carbon atom being substituted with one or more fluorine atoms.
The term "mood disorder" as used herein includes major depressive disorder; mild depression; dysthymia (dyshymia); a ring character gas quality; bipolar depression; depressed NUD; and depressive obesity. In addition, "major depressive disorder" is further classified as melancholia or atypical depression.
The term "anxiety disorder" as used herein includes panic disorder; agoraphobia; social phobia (also known as social anxiety disorder); obsessive compulsive disorder; and generalized anxiety disorder.
The term "stress-related disorders" as used herein includes acute stress disorders; adaptation disorders; post-traumatic stress disorder; exhaustion depression (exhaustion depression); and stress after, for example, surgery and febrile conditions.
The term "sleep disorder" as used herein includes primary insomnia and disorders associated with circadian rhythm disturbances.
The term "cognitive impairment/dysfunction" as used herein includes cognitive impairment associated with schizophrenia, dementia, autism, ADHD and alzheimer's disease. In addition, "dementia" is further classified into age-progressive dementia (age preceding dementia) or AIDS dementia.
The term "substance dependence/abuse" as used herein includes alcohol, nicotine and cocaine addiction.
The term "metabolic disorder" as used herein includes dyslipidemia; hyperlipidemia; insulin hyposensitivity; overweight/obesity; hyperglycemia; metabolic syndrome; and diabetes.
The term "chronic pain condition" as used herein includes neuropathic pain; neuralgia; migraine headache; fibromyalgia; IBS; chronic fatigue syndrome; chronic tension type headache; chronic lower back pain; myofascial pain and chronic osteoarthritis.
As used herein, a "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount sufficient to achieve this goal is defined as a "therapeutically effective amount". The effective amount for each purpose depends on the severity of the disease or injury as well as the weight and general state of the subject. It will be appreciated that determination of the appropriate dosage may be achieved using routine experimentation by constructing a matrix of values and testing different points in the matrix, all within the ordinary skill of a trained physician.
The term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a condition (e.g., a disease or disorder). The term is intended to include the full spectrum of treatments for a given condition suffered by a patient, e.g., administration of an active compound to alleviate symptoms or complications; delay of progression of the disease, disorder, or condition; alleviating or alleviating symptoms and complications; and/or cure or eliminate a disease, disorder, or condition; and preventing a condition, wherein prevention is understood to be the management and care of a patient for the purpose of combating a disease, condition or disorder, including the administration of an active compound to prevent the onset of symptoms or complications. Nevertheless, prophylactic (prevention) treatment and therapeutic (cure) treatment are two separate aspects of the present invention. The patient to be treated is a mammal, especially a human.
In addition, while various aspects of the invention are explained in greater detail below, this description is not intended to be an exhaustive list of all the various ways in which the invention can be practiced or all the features that can be added to the invention. Accordingly, the following description is intended to illustrate some embodiments of the invention and not to exhaustively specify all permutations, combinations and variations thereof.
The present invention further provides the following embodiments:
in one embodiment, X is c (o). In one embodiment, X is CO2. In another embodiment, X is S (O)2. In yet another embodiment, X is CO2Or S (O)2。
In another embodiment, R1Is optionally substituted by one or more R4A substituted phenyl group.
In one embodiment, R1Is optionally substituted by one or more R4A substituted pyrazolyl group.
In one embodiment, R1Is optionally substituted by one or more R4Substituted [1,3 ]]A pyrazolyl group.
In a separate embodiment, R1Is optionally substituted by one or more R4A substituted imidazolyl group.
In one embodiment, R1Is optionally substituted by one or more R4Substituted isoxazolyl.
In one embodiment, R1Is optionally substituted by one or more R4Substituted [1,3, 4]]An oxadiazolyl group.
In yet another embodiment, R1Is optionally substituted by one or more R4Substituted [1,3, 4]]A thiadiazolyl group.
In one embodiment, R1Is optionally substituted by one or more R4A substituted pyridyl group.
In one embodiment, R1Is pyrimidinyl or pyrazinyl, wherein said pyrimidinyl and pyrazinyl are optionally substituted with one or more R4And (4) substitution.
In yet another embodiment, a is CH; n is 1.
In one embodiment, a is N; n is 1 or 2.
In another embodiment, a is COH; n is 1.
In one embodiment, R2Is C3-C6A cycloalkyl group; r3Is H or C1-C4An alkyl group.
In one embodiment, R2Is C1-C7Alkoxy, NH (C)1-C4Alkyl) or (CH)2)vC(O)C1-C4An alkyl group; r3Is H or C1-C4An alkyl group; v is 1 or 2.
In one embodiment, R2Is C1-C4An alkyl group; r3Is H or C1-C4An alkyl group.
In a separate embodiment, R2And R3Form C by bonding2-C4An alkylene group.
In a separate embodiment, R2And R3Combine to form methylene.
In one embodiment, R2Is optionally substituted by one or more R5A substituted phenyl group.
In another embodiment, R2Is a pyridyl, pyrimidinyl, pyrazinyl or triazinyl group, wherein said pyridyl, pyrimidinyl, pyrazinyl and triazinyl group is optionally substituted with one or more R5And (4) substitution.
In one embodiment, R2Is optionally substituted by one or more R5A substituted pyridyl group.
In one embodiment, R2Is optionally substituted by one or more R5A substituted pyrimidinyl group.
In another embodiment, R2Is optionally substituted by one or more R5A substituted pyrazinyl group.
In one embodiment, R2Is optionally substituted by one or more R5A substituted triazinyl group.
In one embodiment, R2Is tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl and pyrazolyl, wherein the tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl and pyrazolyl are optionally substituted with one or more R5And (4) substitution.
In one embodiment, R2Is optionally substituted by one or more R5A substituted tetrazolyl group.
In one embodiment, R2Is optionally substituted by one or more R5A substituted thiazolyl group.
In a further embodiment of the process of the present invention,R2is optionally substituted by one or more R5A substituted oxazolyl group.
In one embodiment, R2Is optionally substituted by one or more R5A substituted imidazolyl group.
In a separate embodiment, R2Is optionally substituted by one or more R5Substituted isoxazolyl.
In one embodiment, R2Is optionally substituted by one or more R5A substituted pyrazolyl group.
In one embodiment, each R isaAnd RbIndependently is H or C1-C4An alkyl group; wherein m is 0 or 1.
In another embodiment, RaAnd RbForm C by bonding3-C7A cycloalkyl group; wherein m is 0 or 1.
In one embodiment, each R iscIndependently is H or C1-C4An alkyl group; wherein m is 0 or 1.
In one embodiment, R4Is optionally substituted by one or more C1-C4Alkyl radical, C1-C4Alkoxy, fluorine or chlorine substituted phenyl.
In a separate embodiment, R4Is C1-C4Alkyl or C1-C4A perfluoroalkyl group.
In one embodiment, R5Is C1-C4Alkyl, fluoro or chloro.
Pharmaceutically acceptable salts
The invention also includes salts (typically pharmaceutically acceptable salts) of the compounds of the invention. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.
Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, ethylenediaminetetraacetic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, and 8-halotheophyllines (e.g., 8-bromotheophylline, and the like). Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in s.m. berge et al, j.pharm.sci., 1977, 66, 2.
In addition, the compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
The racemic form can be resolved into the optical antipodes by known methods, for example by separation of the diastereomeric salts thereof with an optically active acid, liberating the optically active amine compound by treatment with a base. The separation of such diastereomeric salts can be achieved, for example, by fractional crystallization. Optically active acids suitable for this purpose may include, but are not limited to, d-or l-tartaric acid, mandelic acid (madelic acid), or camphorsulfonic acid. Another method for resolving racemates into the optical antipodes is based on chromatography (on an optically active substrate). The compounds of the invention can also be resolved by: diastereomeric derivatives are formed and chromatographically separated from chiral derivatizing reagents (e.g., chiral alkylating or acylating reagents) followed by cleavage of the chiral auxiliary. Any of the above methods may be applied to resolve the optical antipode of the compound of the invention itself, or to resolve the optical antipode of a synthetic intermediate, which may then be converted to the final product of the optical resolution (which is the compound of the invention) by the methods described herein.
Additional methods for resolving optical isomers known to those skilled in the art may be used. Such methods include those discussed by j.jaques, a.collet and s.wilen in enertiomers, racemes, and resolution (John Wiley and Sons, New York, 1981). The optically active compound can also be prepared from optically active starting materials.
Pharmaceutical composition
The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the experimental section and a pharmaceutically acceptable carrier.
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient, in single or multiple doses. The pharmaceutical compositions of The present invention may be formulated with pharmaceutically acceptable carriers or diluents, and any other known adjuvants and excipients, in accordance with conventional techniques (e.g., those disclosed in Remington: The Science and practice of Pharmacy, 19 th edition, Gennaro eds, Mack Publishing Co., Easton, PA, 1995).
The pharmaceutical compositions may be specifically formulated for administration by any suitable route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees (dragees), pills, dragees (lozenes), powders and granules. Where appropriate, the compositions may be prepared with coatings (e.g., enteric coatings) or they may be formulated according to methods well known in the art to provide controlled release (e.g., sustained or extended release) of the active ingredient. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous or non-aqueous injectable solutions, dispersions, suspensions or emulsions; and sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use.
Other suitable forms of administration include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
Typical oral dosages range from about 0.001 to about 100mg/kg body weight/day. Typical oral dosages also range from about 0.01 to about 50mg/kg body weight/day. Typical oral dosages are further from about 0.05 to about 10mg/kg body weight/day. Oral doses are usually administered in one or more doses, typically 1 to 3 doses per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject being treated, the nature and severity of the condition being treated, any concomitant diseases to be treated, and other factors which will be apparent to those skilled in the art.
The formulations may also be presented in unit dosage form by methods known to those skilled in the art. By way of illustration, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000mg, from about 0.05 to about 500mg, or from about 0.5 to about 200 mg.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar routes of administration, typical doses are on the order of about half the dose used for oral administration.
The invention also provides a process for preparing a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. In one embodiment of the invention, the compound used in the above method is one of the specific compounds disclosed in the experimental section.
The compounds of the invention are generally employed as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having utility as a free base. When the compound of formula I contains a free base, such salts are prepared in a conventional manner by treating a solution or suspension of the free base of formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.
For parenteral administration, solutions of the compounds of formula I in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be used. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I can be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. The pharmaceutical compositions formed by combining the compounds of formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms appropriate to the disclosed route of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the invention suitable for oral administration may be presented as discrete units (e.g., capsules or tablets), each containing a predetermined amount of the active ingredient, and optionally suitable excipients. Furthermore, orally available formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.
If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule as a powder or granules, or it may be in the form of a troche (troche) or lozenge. The amount of solid carrier can vary widely, but each dosage unit is from about 25mg to about 1 g. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.
Treatment of disorders
As mentioned above, the compounds of formula I are ligands of the NPY Y5 receptor. The present invention provides a method of treating a subject suffering from a mood disorder comprising administering to the subject a therapeutically effective amount of a compound of the present invention. The present invention provides a method of treating a subject suffering from a cognitive disorder comprising administering to the subject a therapeutically effective amount of a compound of the present invention. The present invention further provides a method of treating a subject suffering from obesity comprising administering to the subject a therapeutically effective amount of a compound of the present invention. In one embodiment of the invention, the subject is a human.
Furthermore, the invention relates to the use of the compounds according to the invention for the preparation of medicaments which are useful for the treatment of depression. In addition, the present invention relates to the use of the compounds of the invention for the preparation of a medicament useful for the treatment of anxiety disorders. The invention further provides the use of a compound of the invention in the manufacture of a medicament useful in the treatment of obesity.
The invention will be better understood from the experimental details that follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed therein are merely illustrative of the invention as described more fully in the claims that follow thereafter. In addition, the variables described in schemes 1-6 are consistent with the variables recited in the summary of the invention.
One embodiment relates to a method of treating a subject suffering from a mood disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the mood disorder is major depressive disorder; mild depression; dysthymia; a ring character gas quality; bipolar depression; and depression NUD; or depressive obesity.
Another embodiment relates to a method of treating a subject suffering from anxiety comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the mood anxiety is panic disorder; agoraphobia; social phobia (also known as social anxiety disorder); obsessive compulsive disorder; and generalized anxiety disorder.
Yet another embodiment relates to a method of treating a subject suffering from a stress-related disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the stress-related disorder is an acute stress disorder; adaptation disorders; post-traumatic stress disorder; debilitating depression (exaustinodepression); or stress after e.g. surgery and febrile conditions.
Another embodiment relates to a method of treating a subject suffering from a sleep disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the sleep disorder comprises primary insomnia or a disorder associated with circadian rhythm disorders.
Yet another embodiment relates to a method of treating a subject suffering from a cognitive impairment/dysfunction condition comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the cognitive impairment/dysfunction is cognitive impairment associated with schizophrenia, dementia, autism, ADHD or alzheimer's disease. In addition, "dementia" is further classified as progressive age dementia or AIDS dementia.
Another embodiment relates to a method of treating a subject suffering from a substance dependence/abuse disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the substance dependence/abuse disorder is alcohol, nicotine, or cocaine addiction.
One embodiment relates to a method of treating a subject suffering from a metabolic disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the metabolic disorder is dyslipidemia; hyperlipidemia; insulin hyposensitivity; overweight/obesity; hyperglycemia; metabolic syndrome; or diabetes.
Another embodiment relates to a method of treating a subject suffering from a chronic pain condition comprising administering to the subject a therapeutically effective amount of a compound of formula I. In a separate embodiment, the chronic pain condition is neuropathic pain; neuralgia; migraine headache; fibromyalgia; IBS; chronic fatigue syndrome; chronic tension type headache; chronic lower back pain; myofascial pain or chronic osteoarthritis.
Experimental part
The general method comprises the following steps: anhydrous solvents were purchased from Aldrich Chemical Company and used as received. NMR spectra were measured on a Bruker Avance 400 spectrometer and/or 300MHz (Varian), using CDCl3、DMSO-d6Or CD3OD as solvent. Chemical shifts (. delta.) are expressed in ppm, coupling constants (J) are expressed in Hz, and cleavage patterns (splitting patterns) are described as follows: s is singlet; d is bimodal; t is a triplet; q is quartet; sept ═ heptad; br is broad peak; m is multiplet; dd ═ doublet; dt is double triplet; td is triple doublet; dq is double quartet.
Unless otherwise stated, mass spectra were obtained using electrospray ionization (ESMS, Micromass Platform II or Quattro Micro) or Waters ZQ mass spectrometry (with an Agilent 1100 HPLC system with an autosampler using DAD/UV and a Waters ELSD detection system and Inertsil ODS-3 column). For the LC-MS assay, two methods were used: the method A comprises the following steps: c18 column, neutral pH, 20% to 90% acetonitrile/water (containing 0.2% ammonium formate); or method B: c8 column, neutral pH, 10% to 90% acetonitrile/water (containing 0.2% ammonium formate).
In some cases, methods of preparing the compounds of the present invention are generally described by reference to representative reagents (e.g., bases or solvents). The particular agents identified are representative, but not exhaustive, and do not limit the invention in any way.
It should be noted that scheme 6 describes the use of selective protecting groups during the synthesis of the compounds of the present invention. One skilled in the art will be able to select the appropriate protecting group for a particular reaction. Furthermore, in the synthetic methods for the synthesis of compounds of formula I as described below, it may be necessary to introduce protection and deprotection strategies for substituents (e.g., amino, amide, carboxylic acid, and hydroxyl groups). Methods for protection and deprotection of such Groups are well known in the art and can be found in T.Green et al, Protective Groups in Organic Synthesis (1991, 2 nd edition, John Wiley & Sons, New York).
Preparation of Compounds of formula I
Scheme 1
a. Diisopropylethylamine, toluene, room temperature to about 60 ℃.
b. Aryl boronic acid, Pd (PPh)3)4，K2CO3Dioxane, water, about 80 deg.C
Compounds of formula I wherein a is N can be synthesized following the procedure described in scheme 1. The starting materials of formulae II and III are commercially available or can be synthesized by procedures known in the art. In general, aryl bromides of formula II are coupled with acid chlorides of formula III to give amide intermediates of formula IV, which are generated in situ, or isolated and reacted with amines of formula V to give higher intermediates of formula VI. Coupling of an arylboronic acid with formula VI affords a compound of formula I.
Representative intermediates were synthesized according to scheme 1.
Intermediates of formula VI
2- (4-acetyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide: 2-amino-5-bromopyridine (1.438g, 8.312mmol) and N, N-diisopropylethylamine (4.34ml, 24.9mmol) were dissolved in toluene (50ml) at room temperature. Chloroacetyl chloride (0.73ml, 9.14mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-acetylpiperazine (2.13g, 16.6 mmol). The reaction mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature and transferred to a separatory funnel. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2X 50ml) followed by water (1X 50 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography, eluting with 1/1 ethyl acetate/hexane followed by 10/2/1 ethyl acetate/methanol/triethylamine to afford 1.56g of the title compound.1H NMR(400MHz，CDCl3)δ9.48(br s，1H)，8.34(d，J＝2.7Hz，1H)，8.18(d，J＝8.8Hz，1H)，7.82(dd，J＝8.8Hz，J＝2.7Hz，1H)，3.72(t，J＝5.0Hz，2H)，3.57(t，J＝5.2Hz，2H)，3.20(s，2H)，2.64-2.58(m，4H)，2.11(s，3H)。ESI-MS m/z：342.9(M+H)+。
Intermediates of formula VI
N- (5-bromo-pyridin-2-yl) -2- (6-oxo-hexahydro-pyrrolo [1, 2-a)]Pyrazin-2-yl) -acetamide: n- (5-bromo-2-pyridinyl) -2-chloroacetamide (253mg, 1.01mmol) is dissolved in DMF (5ml) at room temperature. Successively adding hexahydro-pyrrolo [1, 2-a ] compounds]Pyrazin-6-one (142mg, 1.01mmol) (Christensen et al WO2008046882) and potassium carbonate (350mg, 2.53 mmol). The reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25ml), and transferred to a separatory funnel. The reaction mixture was washed with water (3 × 25 ml). The organic phase was dried over magnesium sulfate, filtered through a pad of silica (a pad of silica) and then concentrated. The product was isolated by preparative thin layer chromatography (eluting with 98/2 dichloromethane/methanol) to give 95mg of the title compound.1H NMR(400MHz，CDCl3)δ9.47(br s，1H)，8.34(d，J＝2.3Hz，1H)，8.18(d，J＝9.0Hz，1H)，7.82(dd，J＝9.0Hz，J＝2.3Hz，1H)，4.13-4.05(m，2H)，3.83-3.74(m，1H)，3.22(dd，J＝15.4Hz，J＝4.8Hz，2H)，3.07-2.96(m，2H)，2.91-2.86(m，2H)，2.48-2.39(m，2H)，2.33-2.17(m，2H)，1.68-1.57(m，1H)。ESI-MS m/z：354.9(M+H)+。
Compounds of the invention
The following compounds were prepared following the procedure in scheme 1.
Example 1a 2- (4-acetyl-piperazin-1-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
2- (4-acetyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide (171mg, 0.50mmol) was dissolved in 1, 4-dioxane (4ml) at room temperature. Aqueous potassium carbonate (1M, 1ml) and 3, 5-difluorophenylboronic acid (119mg, 0.75mmol) were added successively. Nitrogen was bubbled through the (bubbed through) reaction mixture for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (116mg, 0.1mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with 10ml of ethyl acetate and transferred to a separatory funnel. The organic phase was washed with aqueous sodium hydroxide (1N, 1X 10ml) followed by brine (1X 10 ml). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The product was purified by flash chromatography, eluting with ethyl acetate followed by 9/1 ethyl acetate/methanol, to give a brown oil. Trituration with ether afforded 97mg of the desired compound.1H NMR(400MHz，CDCl3)δ9.70(br s，1H)，8.51(d，J＝2.1Hz，1H)，8.37(d，J＝8.8Hz，1H)，7.92(dd，J＝8.8Hz，J＝2.3Hz，1H)，7.09(dt，J＝6.6Hz，J＝2.1Hz，2H)，6.86(dt，J＝8.9Hz，J＝2.2Hz，1H)，3.78(br s，2H)，3.65(br s，2H)，2.70(br s，4H)，2.14(s，3H)。ESI-MS m/z：375.6(M+H)+。
Likewise, the following compounds were prepared in a similar manner to example 1 a:
example 1b 2- (4-acetyl-piperazin-1-yl) -N- (5-phenyl-pyridin-2-yl) -acetamide
From 2- (4-acetyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and phenylboronic acid. LC-MS (m/z)339.3 (MH)+)；tR1.05min (method a).
Example 1c N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (6-oxo-hexahydro-pyrrolo [1, 2-a ] pyrazin-2-yl) -acetamide
From N- (5-bromo-pyridin-2-yl) -2- (6-oxo-hexahydro-pyrrolo [1, 2-a)]Pyrazin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid.1H NMR(400MHz，CDCl3)δ9.55(br s，1H)，8.50(dd，J＝2.5Hz，J＝0.7Hz，1H)，8.34(dd，J＝8.6Hz，J＝0.7Hz，1H)，7.89(dd，J＝8.8Hz，J＝2.4Hz，1H)，7.10-7.06(m，2H)，6.84(tt，J＝8.8Hz，J＝1.6Hz，1H)，4.12-4.07(m，1H)，3.86-3.77(m，1H)，3.26(dd，J＝16.6Hz，J＝4.6Hz，2H)，3.10-3.00(m，2H)，2.92(br d，J＝11.2Hz，1H)，2.47-2.40(m，2H)，2.33(dd，J＝12.0Hz，J＝3.6Hz，1H)，2.28-2.16(m，1H)，1.69-1.56(m，1H)。LC-MS(m/z)387.0(MH+)；tR1.16min (method a).
Example 1d 2- ((R) -4-acetyl-3-methyl-piperazin-1-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- ((R) -4-acetyl-3-methyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)389.0 (MH)+)；tR1.12min (method a).
Example 1e 2- ((S) -4-acetyl-3-methyl-piperazin-1-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- ((S) -4-acetyl-3-methyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)389.0 (MH)+)；tR1.12min (method a).
Example 1f 2- ((R) -4-acetyl-2-methyl-piperazin-1-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- ((R) -4-acetyl-2-methyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)389.1 (MH)+)；tR1.11min (method a).
Example 1g 2- ((S) -4-acetyl-2-methyl-piperazin-1-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- ((S) -4-acetyl-2-methyl-piperazin-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)389.1 (MH)+)；tR1.13min (method a).
Example 1h 2- ((R) -1-acetyl-2-methyl-piperidin-4-yl) -N- [4- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- ((R) -4-acetyl-3-methyl-piperazin-1-yl) -N- (4-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)389.0 (MH)+)；tR1.13min (method a).
Example 1i N- [4- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (6-oxo-hexahydro-pyrrolo [1, 2-a ] pyrazin-2-yl) -acetamide
From N- (4-bromo-pyridin-2-yl) -2- (6-oxo-hexahydro-pyrrolo [1, 2-a)]Pyrazin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)387.0 (MH)+)；tR1.02min (method a).
Example 1j 2- (4-acetyl-piperazin-1-yl) -N- [4- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
From 2- (4-acetyl-piperazin-1-yl) -N- (4-bromo-pyridin-2-yl) -acetamideAnd 3, 5-difluorophenylboronic acid. LC-MS (m/z)375.0 (MH)+)；tR1.01min (method A).
Example 1k N- [6- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (6-oxo-hexahydro-pyrrolo [1, 2-a ] pyrazin-2-yl) -acetamide
From N- (6-bromo-pyridin-2-yl) -2- (6-oxo-hexahydro-pyrrolo [1, 2-a)]Pyrazin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)387.0 (MH)+)；tR1.10min (method a).
Example 1l 2- (4-acetyl- [1, 4] diazepan-1-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
From 2- (4-acetyl- [1, 4)]Diazepan-1-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)389.0 (MH)+)；tR1.09min (method a).
Example 1m N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- ((S) -1, 1-dioxo-hexahydro-1. lambda.6. thia-5, 7 a-diaza-inden-5-yl) -acetamide
Prepared from N- (5-bromo-pyridin-2-yl) -2- ((S) -1, 1-dioxo-hexahydro-1 λ 6-thia-5, 7 a-diaza-inden-5-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)423.0 (MH)+)；tR1.13min (method a).
Preparation of Compounds of formula I
Scheme 2
a. Diisopropylethylamine, toluene, room temperature to about 60 ℃.
b. Aryl boronic acid, Pd (PPh)3)4，K2CO3Dioxane, water, about 80 deg.C
Following the procedure described in scheme 2, compounds of formula I can also be synthesized. The starting materials of formulae II and VII are commercially available or can be synthesized by procedures known in the art (procedures). Coupling the aryl bromide of formula II with the acid chloride of formula VII to provide the amide intermediate of formula VIII. Coupling with an arylboronic acid to give the compound of formula I.
Representative intermediates were synthesized according to scheme 2.
Intermediates of formula VIII
2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyridin-2-yl) -acetamide: 2-amino-5-bromopyridine (346mg, 2.00mmol) and triethylamine (400. mu.l, 2.87mmol) were dissolved in tetrahydrofuran (15ml) with stirring. A solution of (1-acetyl-piperidin-4-yl) -acetyl chloride (407mg, 2.00mmol) in dichloromethane (5ml) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with 100ml of ethyl acetate and washed with 50ml of water. The organic phase is dried over sodium sulfate, filtered and dried onto 2g of silica gel. The product was isolated by flash chromatography (using 10% methanol in dichloromethane). The pure fractions were combined and dried to give 276mg of the title compound as a brown powder in 41% yield. NMR CDCl3δ8.32(d，1H，J＝2.4)，8.25(bs，1H)，8.17(d，1H，J＝9.0)，7.81(d，1H，J＝7.8)，4.65(d，1H，J＝13.6)，3.82(d，1H，J＝13.6)，3.1(t，1H，J＝13.6)，2.59(t，1H，J＝12.9)，2.37-2.32(q，2H)，2.17(m，1H)，2.10(s，3H)，1.84(t，2H，J＝16.8)，1.31-1.12(m，2H)。ESI-MS m/z：342.9(M+H)+。
Compounds of the invention
The compounds of example 2a-2an were prepared according to the procedure in scheme 2.
Example 2a 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyridin-2-yl) -acetamide (300mg, 0.818mmol) was dissolved in 1, 2-dimethoxyethane (15ml) with stirring, followed by the addition of 3, 5-difluorophenylboronic acid (158mg, 1.00 mmol). 1M aqueous potassium carbonate (5ml, 5mmol) was then added and the reaction degassed with nitrogen for 5 minutes. Tetrakis (triphenylphosphine) -palladium (0) (80mg, 0.07mmol) was added and the reaction mixture heated at reflux under nitrogen for 2 h. The reaction was diluted with ethyl acetate (100ml) and washed with water (50 ml). The organic phase is dried over sodium sulfate, filtered, dried onto 2g of silica gel and purified by flash chromatography (using 5% methanol in dichloromethane). The pure fractions were combined and triturated with ethyl acetate to give 225mg of white crystalline product in 68.3% yield. NMR (CDCl)3)δ8.46(d，1H，J＝2.4)，8.33(d，1H，J＝8.5)，7.94(d，1H，J＝2.6)，7.91(d，1H，J＝2.6)，7.1(d，2H，J＝7.0)，6.64(t，1H，J＝8.8)，4.6(d，1H，J＝13.2)，3.84(d，1H，J＝13.1)，3.11(t，1H，J＝12.9)，2.61(t，1H，J＝13.1)，2.4(d，2H，J＝6.3)，2.2(m，1H)，2.1(s，3H)，1.86(q，2H，J＝13.2)，1.25(m，2H)。LC-MS(m/z)374.1(MH+)；tR1.08min (method a).
Likewise, the following compounds were prepared in a similar manner to example 2 a:
example 2b 2- (1-acetyl-piperidin-4-yl) -N- (2' -fluoro-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 2-fluorophenylboronic acid. LC-MS (m/z)355.1 (MH)+)；tR1.10min (method a).
Example 2c 2- (1-acetyl-piperidin-4-yl) -N- (3' -fluoro-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 3-fluorophenylboronic acid. LC-MS (m/z)355.1 (MH)+)；tR1.12min (method a).
Example 2d 2- (1-acetyl-piperidin-4-yl) -N- (4' -fluoro-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 4-fluorophenylboronic acid. LC-MS (m/z)355.1 (MH)+)；tR1.10min (method a).
Example 2e 2- (1-acetyl-piperidin-4-yl) -N- (3' -methyl-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 3-methylphenylboronic acid. LC-MS (m/z)351.3 (MH)+)；tR1.20min (method a).
Example 2f 2- (1-acetyl-piperidin-4-yl) -N- (4' -methyl-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 4-methylphenylboronic acid. LC-MS (m/z)351.1 (MH)+)；tR1.19min (method a).
Example 2g 2- (1-acetyl-piperidin-4-yl) -N- (2' -methoxy-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 2-methoxyphenylboronic acid. LC-MS (m/z)367.1 (MH)+)；tR1.07min (method a).
Example 2h 2- (1-acetyl-piperidin-4-yl) -N- (3' -methoxy-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 3-methoxyphenylboronic acid. LC-MS (m/z)367.1 (MH)+)；tR1.07min (method a).
Example 2i 2- (1-acetyl-piperidin-4-yl) -N- (4' -methoxy-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 4-methoxyphenylboronic acid. LC-MS (m/z)367.1 (MH)+)；tR1.04min (method a).
Example 2j 2- (1-acetyl-piperidin-4-yl) -N- (2 ', 3' -difluoro-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 2, 3-difluorophenylboronic acid. LC-MS (m/z)373.1 (MH)+)；tR1.15min (method a).
Example 2k 2- (1-acetyl-piperidin-4-yl) -N- (3 ', 4' -difluoro-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 3, 4-difluorophenylboronic acid. LC-MS (m/z)373.1 (MH)+)；tR1.17min (method a).
Example 2l 2- (1-acetyl-piperidin-4-yl) -N- (2 ', 5' -difluoro-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 2, 5-difluorophenylboronic acid. LC-MS (m/z)373.1 (MH)+)；tR1.14min (method a).
Example 2m 2- (1-acetyl-piperidin-4-yl) -N- (3 ', 5' -difluoro-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)373.1 (MH)+)；tR1.19min (method a).
Example 2N 2- (1-acetyl-piperidin-4-yl) -N- (2' -methyl-biphenyl-4-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 2-methylphenylboronic acid. LC-MS (m/z)351.1 (MH)+)；tR1.17min (method a).
Example 2o 2- (1-acetyl-4-methyl-piperidin-4-yl) -N- (3 ', 5' -difluoro-biphenyl-4-yl) -acetamide
Prepared from 2- (1-acetyl-4-methyl-piperidin-4-yl) -N- (4-bromo-phenyl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)387.0 (MH)+)；tR1.29min (method a).
Example 2p 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyrimidin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrimidin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)375.0 (MH)+)；tR0.79min (method a).
Example 2q 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-dimethyl-phenyl) -pyrimidin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrimidin-2-yl) -acetamide and 3, 5-dimethylphenylboronic acid. LC-MS (m/z)367.0 (MH)+)；tR0.96min (method A).
Example 2r 2- (1-acetyl-piperidin-4-yl) -N- [6- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (6-bromo-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)374.0 (MH)+)；tR1.18min (method a).
Example 2s 2- (1-acetyl-piperidin-4-yl) -N- [5- (2-fluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 2-fluorophenylboronic acid. LC-MS (m/z)356.1 (MH)+)；tR1.01min (method A).
Example 2t 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrazin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)375.1 (MH)+)；tR1.08min (method a).
Example 2u 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-dichloro-phenyl) -pyrazin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrazin-2-yl) -acetamide and 3, 5-dichlorophenyl boronic acid. LC-MS (m/z)409.0 (MH)+)；tR1.08min (method a).
Example 2v 2- (1-acetyl-piperidin-4-yl) -N- [5- (3-chloro-phenyl) -pyrazin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrazin-2-yl) -acetamide and 3-chlorophenylboronic acid. LC-MS (m/z)374.1 (MH)+)；tR1.12min (method a).
Example 2x 2- (1-acetyl-piperidin-4-yl) -N- [5- (3-trifluoromethyl-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 3-trifluoromethylphenylboronic acid. LC-MS (m/z)406.1 (MH)+)；tR1.21min (method a).
Example 2y 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -3-methyl-pyridin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-3-methyl-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)388.0 (MH)+)；tR0.96min (method A).
Example 2z 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -3, 4-dimethyl-pyridin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-3, 4-dimethyl-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)402.1 (MH)+)；tR0.98min (method a).
Example 2aa 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -6-methyl-pyridin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-6-methyl-pyridin-2-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)388.0 (MH)+)；tR1.17min (method a).
Example 2ab 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-dichloro-phenyl) -6-methyl-pyridin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-6-methyl-pyridin-2-yl) -acetamide and 3, 5-dichlorophenyl boronic acid. LC-MS (m/z)421.1 (MH)+)；tR1.43min (method a).
Example 2ac 2- (1-acetyl-piperidin-4-yl) -N- [5- (2-fluoro-phenyl) -pyrazin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrazin-2-yl) -acetamide and 2-fluorophenylboronic acid. LC-MS (m/z)357.0 (MH)+)；tR0.93min (method a).
Example 2ad 2- (1-acetyl-piperidin-4-yl) -N- [5- (2, 4-difluoro-phenyl) -pyrazin-2-yl ] -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrazin-2-yl) -acetamide and 2, 4-difluorophenylboronic acid. LC-MS (m/z)375.0 (MH)+)；tR1.00min (method a).
Example 2ae 2- (1-acetyl-piperidin-4-yl) -N- (5-o-tolyl-pyridin-2-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 2-methylphenylboronic acid. LC-MS (m/z)352.0 (MH)+)；tR1.08min (method a).
Example 2af 2- (1-acetyl-piperidin-4-yl) -N- [5- (2, 3, 5-trifluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyridin-2-yl) -acetamide and 2, 3, 5-trifluorophenylboronic acid. LC-MS (m/z)392.0 (MH)+)；tR1.10min (method a).
Example 2ag 2- (1-acetyl-piperidin-4-yl) -N- [5- (2, 3, 5-trifluoro-phenyl) -pyrazin-2-yl ] -acetamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -N- (5-bromo-pyrazin-2-yl) -acetamide and 2, 3, 5-trifluorophenylboronic acid. LC-MS (m/z)393.0 (MH)+)；tR1.09min (method a).
Example 2ah 2- (1-acetyl-piperidin-4-yl) -N- (4-phenyl-pyridin-2-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-pyridin-2-yl) -acetamide and phenylboronic acid. LC-MS (m/z)338.1 (MH)+)；tR0.95min (method a).
Example 2ai 2- (1-acetyl-piperidin-4-yl) -N- (4-p-tolyl-pyridin-2-yl) -acetamide
From 2- (1-acetyl-piperidin-4-yl) -N- (4-bromo-pyridin-2-yl) -acetamide and 4-methylphenylboronic acid. LC-MS (m/z)352.0 (MH)+)；tR1.09min (method a).
Example 2aj N- [6- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide
Prepared from N- (6-bromo-pyridin-3-yl) -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)410.1 (MH)+)；tR1.16min (method a).
Example 2ak N- [6- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -2- [1- (propane-1-sulfonyl) -piperidin-4-yl ] -acetamide
From N- (6-bromo-pyridin-3-yl) -2- [1- (propane-1-sulfonyl) -piperidin-4-yl]-acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)438.0 (MH)+)；tR1.35min (method a).
Example 2al N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide
Prepared from N- (5-bromo-pyridin-2-yl) -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)410.0 (MH)+)；tR1.20min (method a).
Example 2am N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (propane-1-sulfonyl) -piperidin-4-yl ] -acetamide
From N- (5-bromo-pyridin-2-yl) -2- [1- (propane-1-sulfonyl) -piperidin-4-yl]-acetamide and 3, 5-difluorophenylboronic acid. LC-MS (m/z)438.0 (MH)+)；tR1.40min (method a).
Example 2an N- [5- (2-fluoro-phenyl) -pyridin-2-yl ] -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide
From N- (5-bromo-pyridin-2-yl) -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide and 2-fluorophenylAnd (3) preparing boric acid. LC-MS (m/z)392.1 (MH)+)；tR1.13min (method a).
Preparation of Compounds of formula I
Scheme 3
Alternatively, compounds of formula I may also be synthesized following the procedure described in scheme 3. Intermediates of formula VII can be synthesized by reacting an acid of formula IX with oxalyl chloride to form an acid chloride. Then reacting the acid chloride with R1-NH2Coupling to give the compound of formula I.
Preparation of higher intermediates of formula IXa: (3-oxo-octahydro-indolizin-7-yl) -acetic acid
Step 11, 4-dioxa-8-aza-spiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester: to a mixture of dioxane (200ml) and aqueous NaOH (9.36g, 234mmol, in 100ml water) was added 1, 4-dioxa-8-aza-spiro [4.5 ]]Decane. The mixture was cooled to 0 ℃. Di-tert-butyl dicarbonate (37.4g, 172mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The residue is suspended in 200ml of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the desired product as a white solid (35.4g, 93%). 1H NMR CDCl3，δ4.00(s，4H)，3.53-3.47(m，4H)，1.70-1.65(m，4H)，1.44(s，9H)；MS(ES，m/z)244M+H+。
Step 27-formyl-1, 4-dioxa-8-aza-spiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester: adding 1, 4-dioxa-8-aza-spiro to round bottom flask[4.5]Tert-butyl decane-8-carboxylate (3.54g, 14.5mmol), ether (40.0ml) and TMEDA (2.03g, 17.4 mmol). The reaction was cooled to-78 ℃. Sec-butyllithium (12.5ml, 1.4M in cyclohexane) was added dropwise. The reaction was stirred at-78 deg.C for 2 hours, then DMF (2.13g, 29.1mmol) was added. The mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature and held for 1 hour. The reaction was quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated. The crude product was purified by column chromatography (hexane to ethyl acetate gradient) to afford the desired product as a white solid (2.16, 55%). 1H NMR CDCl3，δ9.58(1H，S)，4.80-4.52(m，1H)，4.20-3.85(m，5H)，3.32-3.10(m，1H)，2.32-2.25(m，1H)，2.00-1.90(m，1H)，1.80-1.55(m，2H)，1.55-1.40(b，9H)；MS(ES，m/z)272M+H+。
Step 37- ((E) -2-ethoxycarbonyl-vinyl) -1, 4-dioxa-8-aza-spiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester: to a suspension of NaH (446mg, 11.1mmol, 60% in mineral oil) in THF (30.0ml) was added triethyl phosphonoacetate (2.50g, 11.1mmol) at room temperature. The reaction was stirred at room temperature for 15 minutes. To the reaction was added 7-formyl-1, 4-dioxa-8-aza-spiro [4.5 ] at room temperature]A solution of tert-butyl decane-8-carboxylate (2.16g, 7.96mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 2 hours and then quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated. The crude product was purified by column chromatography (hexane to ethyl acetate gradient) to afford the desired product as a colorless oil (1.27, 47%). 1H NMR CDCl3，δ7.10-7.00(m，1H)，5.82-5.77(m，1H)，5.10-5.00(m，1H)，4.25-4.18(m，2H)，4.12-4.05(m，1H)，4.00-3.93(m，4H)，3.15-3.08(m，1H)，2.05-1.95(m，1H)，1.92-1.85(m，1H)，1.70-1.60(m，2H)，1.50(s，9H)，1.35-1.25(m，3H)；MS(ES，m/z)242M+H+。
Step 47- (2-ethoxycarbonyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester: to 7- ((E) -2-ethoxycarbonyl-ethaneAlkenyl) -1, 4-dioxa-8-aza-spiro [4.5]To a solution of tert-butyl decane-8-carboxylate (1.27g, 3.72mmol) in methanol (20.0ml) was added Pd (OH)2(20% on activated charcoal (charpore), 0.261 g). The reaction mixture was purged with nitrogen and then under H2Stir overnight under atmosphere (1 atm). The reaction mixture was filtered through celite and concentrated to give the desired product as a pale yellow oil (1.28g, 100%). 1H NMR CDCl3，δ4.44-4.35(m，1H)，4.20-3.90(m，7H)，3.05-2.95(m，1H)，2.35-2.20(m，3H)，1.90-1.60(m，5H)，1.49(s，9H)，1.30-1.25(m，3H)；MS(ES，m/z)344M+H+。
Step 53- (1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-7-yl) -propionic acid ethyl ester: to 7- (2-ethoxycarbonyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5 ]]To a solution of tert-butyl decane-8-carboxylate (1.28g, 3.72mmol) in methanol (20.0ml) was added a 4M HCl solution in dioxane (4.65ml, 18.6 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated. The resulting oil was dissolved in water, then basified with aqueous ammonium hydroxide, the aqueous solution extracted with ethyl acetate, and the combined organic layers were dried and concentrated. The crude material was used without further purification. MS (ES, M/z)244M + H+。
Step 6 tetrahydro-1' H-spiro [ [1,3 ]]Dioxolane-2, 7' -indolizines]-3 '(2' H) -one: the 3- (1, 4-dioxa-8-aza-spiro [4.5 ] produced in the preceding step]Dec-7-yl) -propionic acid ethyl ester in methanol (20.0ml) was refluxed overnight. The solution was concentrated and the residue was dissolved in ethyl acetate and filtered through a short plug of silica gel (ashort plug of silica gel). The filtrate was concentrated to give the crude product as a pale yellow oil (733mg, 100%). 1H NMR CD3OD，δ4.76-4.65(m，5H)，4.45-4.35(m，1H)，3.55-3.45(m，1H)，3.33-3.28(m，1H)，3.05-2.88(m，3H)，2.69-2.62(m，1H)，2.48-2.44(m，1H)，2.38-2.15(m，3H)；MS(ES，m/z)198M+H+。
Step 7 hexahydro-indolizine-3, 7-dione: to a solution of ketal-protected bicyclic ketone (0.733g, 3.72mmol) in acetone (10.0ml) was added water (10.0ml) followed by sulfuric acid (0.500ml,9.40 mmol). The mixture was heated to 65 ℃ overnight. The reaction was cooled to room temperature and then concentrated. The residue was dissolved in water and neutralized with ammonium hydroxide. The aqueous solution was extracted with ethyl acetate. The combined organic layers were dried and concentrated to give the desired product (569mg, 100%). 1H NMR CDCl3，δ4.29-4.22(m，1H)，3.78-3.70(m，1H)，2.92-2.84(m，1H)，2.52-2.45(m，1H)，2.38-2.15(m，6H)，1.68-1.58(m，1H)；MS(ES，m/z)154M+H+。
Step 8 [ 3-oxo-hexahydro-indolizin- (7E) -ylidene]-ethyl acetate: to a suspension of sodium hydride (60% in mineral oil, 202mg, 5.05mmol) in THF (15ml) was added triethyl phosphonoacetate (1.00ml, 5.05 mmol). The mixture was stirred at room temperature for 30 minutes, then a solution of hexahydro-indolizine-3, 7-dione (645mg, 4.21mmol) in THF (5.00ml) was added. The reaction mixture was stirred at room temperature for 3 hours and then quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic layers were dried and concentrated. The crude product was purified by column chromatography (hexanes to ethyl acetate gradient) to afford the desired product (mixture of E/Z isomers) as a pale yellow oil (663mg, 71%). 1H NMR CDCl3δ 5.82-5.78(s, 1H, two singlet), 4.25-3.85(m, 4H), 3.58-3.48(m, 1H), 2.80-2.65(m, 1H), 2.50-2.20(m, 4H), 2.14-2.90(m, 1H), 1.80-1.60(m, 1H), 1.35-1.25(m, 3H); MS (ES, M/z)224M + H+。
Step 9 (3-oxo-octahydro-indolizin-7-yl) -acetic acid ethyl ester: to [ 3-oxo-hexahydro-indolizin- (7E) -ylidene]Ethyl acetate (663mg, 2.97mmol) in methanol (20.0ml) Pd (OH) was added2(20% on activated charcoal, 208 mg). The reaction mixture was purged with nitrogen and then under H2Stir overnight under atmosphere (1 atm). The reaction mixture was then filtered through celite and concentrated to give the desired product as a pale yellow oil. The crude material was used without further purification. MS (ES, M/z)226M + H+。
Step 10 (3-oxo-octahydro-indolizin-7-yl) -acetic acid: to (3-oxo-octahydro-indolizin-7-yl) -acetic acid ethyl ester (2)97mmol, crude from the previous step) in THF (20ml) was added 10% aqueous NaOH solution (20 ml). The reaction mixture was stirred at room temperature overnight. The volatiles were removed and the aqueous solution was then acidified by dropwise addition of concentrated HCl. The aqueous solution was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the desired product (452mg, 77%). 1H NMR CDCl3，δ10.8-11.4(br，1H)，4.22-4.34(m，1H)，3.58-3.48(m，1H)，2.77-2.65(m，1H)，2.48-2.18(m，5H)，2.08-1.96(m，2H)，1.85-1.78(m，1H)，1.68-1.56(m，1H)，1.22-1.06(m，1H)，1.04-0.90(m，1H)；MS(ES，m/z)198M+H+。
Preparation of the higher intermediate of formula IXb:((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid
Step 1 ((S) -1-phenyl-ethylimino) -acetic acid ethyl ester: to a round bottom flask was added ethyl glyoxylate (50% by weight in toluene, 11.5ml, 55.7 mmol). The solution was heated to reflux for 30 minutes and then cooled to room temperature. The above solution was added to a solution of (S) - α -methyl-benzylamine (7.18ml, 55.7mmol) in dichloromethane (100ml) at 0 ℃ in the presence of molecular sieve (3A, 6.50 g). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for one hour. The mixture was filtered and the filtrate was concentrated and used directly in the next step without characterization.
Step 2 (R) -4-oxo-1- ((S) -1-phenyl-ethyl) -piperidine-2-carboxylic acid ethyl ester: to a solution of ((S) -1-phenyl-ethylimino) -acetic acid ethyl ester (15.3g, 55.7mmol) in dichloromethane (100ml) was added trifluoroacetic acid (6.34g, 55.7mmol) at-78 ℃. After stirring at-78 ℃ for 5 minutes, 2-trimethylsilyloxy-1, 3-butadiene (7.91g, 55.7mmol) was added. The reaction mixture was stirred at about-30 ℃ for 2 hours and then quenched by the addition of water (20 ml). Will be mixed withThe mixture was stirred at room temperature for 30 minutes and additional water (20ml) was added. By adding solid NaHCO3The pH was adjusted to about 9. The mixture was extracted with ethyl acetate. The organic phase was dried, filtered and concentrated. The crude material was purified by column chromatography (gradient of hexanes to hexanes with 20% ethyl acetate) to afford the desired product as a white solid (6.80g, 44%). 1H NMR CDCl3，δ7.45-7.20(m，5H)，4.25-4.15(m，3H)，3.92-3.80(m，1H)，2.90-2.82(m，2H)，2.78-2.60(m，2H)，2.50-2.20(m，2H)，1.50-1.40(m，3H)，1.35-1.20(m，3H)；MS(ES，m/z)276M+H+。
Step 3 (R) -8- ((S) -1-phenyl-ethyl) -1, 4-dioxa-8-aza-spiro [ 4.5)]Decane-7-carboxylic acid ethyl ester: to a round bottom flask equipped with a dean-Stark trap (trap) were added (R) -4-oxo-1- ((S) -1-phenyl-ethyl) -piperidine-2-carboxylic acid ethyl ester (6.80g, 24.7mmol), ethylene glycol (5.00ml, 89.7mmol), p-toluenesulfonic acid (425mg, 2.47mmol), and toluene (60.0 ml). The reaction was heated at reflux for 3 hours. Saturated NaHCO was added by pouring3The reaction was quenched in aqueous solution and the aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude oil was purified by column chromatography (gradient of hexanes to hexanes with 20% ethyl acetate) to afford the desired product as a pale yellow solid (5.64g, 71%). 1H NMR CDCl3，δ7.50-7.15(m，5H)，4.30-4.10(m，3H)，4.05-3.80(m，5H)，2.98-2.90(m，1H)，2.60-2.50(m，1H)，2.30-2.22(m，1H)，2.00-1.95(m，1H)，1.70-1.50(m，2H)，1.40-1.20(m，6H)；MS(ES，m/z)320M+H+。
Step 4 [ (R) -8- ((S) -1-phenyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-7-yl]-methanol: (R) -8- ((S) -1-phenyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5 ] under a nitrogen atmosphere]A solution of ethyl decane-7-carboxylate (5.64g, 17.6mmol) in ether (10.0ml) was added dropwise to a suspension of LAH (1.34g, 35.3mmol) in ether (100 ml). The reaction was allowed to stir overnight and quenched by the sequential addition of water (1.5ml), 20% NaOH solution (3.0ml) and water (4.5 ml). The mixture was stirred for 30 minutes, then filtered through celite and washed with ethyl acetate.The filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The oil obtained was used directly in the next step without further purification. 1H NMR CDCl3，δ7.50-7.25(m，5H)，4.30-4.15(m，1H)，4.05-3.90(m，4H)，3.75-3.60(m，2H)，3.00-2.90(m，1H)，2.80-2.70(m，2H)，2.55-2.45(br，1H)，1.90-1.80(m，1H)，1.75-1.60(m，2H)，1.55-1.45(m，1H)，1.40-1.30(m，3H)；MS(ES，m/z)278M+H+。
Step 5 (R) -1- (1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-7-yl) -methanol: [ (R) -8- ((S) -1-phenyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5 ] at 50psi on a Parr (Paar) apparatus]Decan-7-yl]Methanol (4.90g, 17.7mmol) and Pd (OH)2A mixture of activated charcoal in methanol (100ml) was hydrogenated overnight. The mixture was filtered through celite. The filtrate was concentrated and used in the next step without further purification. 1H NMR CD3OD，δ4.05-3.95(m，4H)，3.80-3.75(m，1H)，3.60-3.55(m，1H)，3.45-3.35(m，2H)，3.20-3.10(m，1H)，1.95-1.78(m，4H)；MS(ES，m/z)174M+H+。
Step 6 (R) -7, 7' - (1, 3-dioxolane) -hexahydro-oxazolo [3, 4-a)]Pyridine-3-one: n, N-carbonyldiimidazole (3.44g, 3.70mmol) was added to (R) -1- (1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-7-yl) -methanol (3.06g, 17.7mmol) in THF (30.0 ml). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography (gradient of hexanes to ethyl acetate) to afford the desired product as a pale yellow oil (2.67g, 76%). 1H NMR CDCl3，δ4.50-4.40(m，1H)，4.05-3.90(m，7H)，3.15-3.05(m，1H)，1.95-1.85(m，1H)，1.75-1.60(m，3H)；MS(ES，m/z)200M+H+。
Step 7 (R) -tetrahydro-oxazolo [3, 4-a]Pyridine-3, 7-dione: sulfuric acid (3.52ml, 66.0mmol) was added dropwise to (R) -7, 7' - (1, 3-dioxolane) -hexahydro-oxazolo [3, 4-a ]]Pyridin-3-one (2.67g, 13.5mmol) in acetone (30)0ml) and water (30.0 ml). The mixture was stirred at 70 ℃ overnight. Volatiles were removed in vacuo. The resulting aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography (gradient of hexanes to ethyl acetate) to afford the desired product as a white solid (1.15g, 56%). 1H NMR CDCl3，δ4.55-4.47(m，1H)，4.30-4.22(m，1H)，4.10-4.05(m，2H)，3.30-3.18(m，1H)，2.63-2.40(m，4H)。
Step 8 ((R) -3-oxo-tetrahydro-oxazolo [3, 4-a)]Pyridin-7-ylidene) -acetic acid ethyl ester: to a suspension of NaH (60% in mineral oil, 415mg, 10.4mmol) in THF (20ml) was added triethyl phosphonoacetate (2.06ml, 10.4 mmol). The mixture was stirred at room temperature for 30 minutes. Adding (R) -tetrahydro-oxazolo [3, 4-a]Pyridine-3, 7-dione in THF (10 ml). The reaction mixture was stirred at room temperature for 3 hours and then quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography (gradient of hexane to ethyl acetate) to afford the desired product as a mixture of E/Z isomers (1.42g, 85%). 1H NMRCDCl3(one of the pure isomers), δ 5.82(s, 1H), 4.45-4.40(m, 1H), 4.20-4.00(m, 5H), 3.80-3.70(m, 1H), 3.00-2.90(m, 1H), 2.40-2.25(m, 2H), 1.95-1.90(m, 1H), 1.35-1.25(m, 3H); MS (ES, M/z)226M + H+。
Step 9 ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid ethyl ester: (R) -3-oxo-tetrahydro-oxazolo [3, 4-a ] is reacted under balloon pressure (balloon pressure)]Pyridin-7-ylidene) -acetic acid ethyl ester (1.42g, 6.30mmol) and Pd (OH)2A mixture of/active carbon (443mg, 0.630mmol) in methanol (100ml) was hydrogenated overnight. The mixture was filtered through celite. The filtrate was concentrated and used directly in the next step without further purification. 1H NMR CDCl3δ4.50-4.40(m，1H)，4.00-3.90(m，1H)，3.90-3.80(m，2H)，3.05-2.95(m，1H)，2.35-2.25(m，2H)，2.10-1.95(m，2H)，1.85-1.80(m，1H)，1.30-1.10(m，2H)；MS(ES，m/z)228M+H+。
Step 10 ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid: to ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid ethyl ester (1.43g, 6.29mmol) in methanol (30.0ml) was added LiOH (753mg, 31.5mmol) and three drops of water. The mixture was stirred at room temperature overnight. Volatiles were removed in vacuo. The residual aqueous solution was acidified by addition of concentrated HCl solution and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude solid was used in the next step without further purification (850mg, 68%). 1H NMR CDCl3δ4.40-4.30(m，1H)，4.15-4.00(m，2H)，3.85-3.75(m，2H)，3.75-3.65(m，1H)，2.90-2.80(m，1H)，2.25-2.15(m，2H)，2.00-1.85(m，2H)，1.70-1.60(m，1H)，1.25-1.00(m，5H)；MS(ES，m/z)200M+H+。
Preparation of the higher intermediate of formula IXc:((7S, 8aR) -3-oxo-1, 1' -dimethyl-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid
Step 11, 4-dioxa-8-aza-spiro [4.5 ]]Decane-8-carboxylic acid tert-butyl ester: to a mixture of dioxane (200ml) and aqueous NaOH (9.36g, 234mmol, in 100ml water) was added 1, 4-dioxa-8-aza-spiro [4.5 ]]Decane. The mixture was cooled to 0 ℃. Di-tert-butyl dicarbonate (37.4g, 172mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The residue is suspended in 200ml of water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired product as a white solid (35.4g, 93%). 1H NMR CDCl3，δ4.00(s，4H)，3.53-3.47(m，4H)，1.70-1.65(m，4H)，1.44(s，9H)；MS(ES，m/z)244M+H+。
Step 27- (1-hydroxy-1-methyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5]Decane-8-carboxylic acid tert-butyl ester: adding 1, 4-dioxa-8-aza-spiro [4.5 ] to a round bottom flask]Tert-butyl decane-8-carboxylate (5.038g, 20.7mmol) and ether (50.0ml) and TMEDA (3.75g, 24.8 mmol). The reaction was cooled to-78 ℃. Sec-butyllithium (17.7ml, 1.4M in cyclohexane, 24.8mmol) was added dropwise to the reaction. The reaction was stirred at-78 ℃ for 2h and then treated with acetone (3.04ml, 41.4 mmol). The mixture was stirred at-78 ℃ for 2 hours. The reaction was quenched by pouring into water and the aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (hexanes to ethyl acetate gradient) to afford the desired product as a white solid (2.65g, 42%). MS (ES, M/z)302M + H+。
Step 32- (1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-7-yl) -propan-2-ol: to 7- (2-ethoxycarbonyl-ethyl) -1, 4-dioxa-8-aza-spiro [4.5 ]]To a solution of tert-butyl decane-8-carboxylate (2.65g, 8.79mmol) in methanol (60.0ml) was added a 4M HCl solution in dioxane (11.0ml, 44.0 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated. The crude oil was dissolved in water and then basified with aqueous ammonium hydroxide. The aqueous solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was used in the next step without further purification. MS (ES, M/z)202M + H+。
Step 4 (R) -7, 7 '- (1, 3-dioxolane) -1, 1' -dimethyl-hexahydro-oxazolo [3, 4-a)]Pyridine-3-one: n, N-carbonyldiimidazole (2.14g, 13.2mmol) and DMAP (1.29g, 10.6mmol) were added to (R) -1- (1, 4-dioxa-8-aza-spiro [4.5 ]]Decan-7-yl) -methanol (1.77g, 8.79mmol) in THF (60.0 ml). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography (ethyl acetate to 10% methanol in ethyl acetate gradient) to give the desired product as a pale yellow oil (750mg, 37%). 1H NMR CDCl3，δ4.10-3.90(m，4H)，3.57-3.50(m，1H)，3.25-3.20(m，1H)，3.12-3.05(m，1H)，1.73-1.55(m，4H)，1.47(s，3H)，1.33(s，3H)；MS(ES，m/z)228M+H+。
Step 5 (R) -1, 1' -dimethyl-tetrahydro-oxazolo [3, 4-a]Pyridine-3, 7-dione: sulfuric acid (0.500ml, 9.38mmol) was added dropwise to (R) -7, 7 '- (1, 3-dioxolane) -1, 1' -dimethyl-hexahydro-oxazolo [3, 4-a ]]Pyridin-3-one (750mg, 3.30mmol) in acetone (34.3ml) and water (34.3 ml). The mixture was stirred at 65 ℃ overnight. Volatiles were removed in vacuo. The resulting aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was filtered through a short plug of silica gel and washed with ethyl acetate and methanol. The filtrate was concentrated and used directly in the next step (560mg, 93%). 1H NMR CDCl3，δ4.25-4.15(m，1H)，3.55-3.50(m，1H)，3.15-3.05(m，1H)，2.55-2.30(m，4H)，1.42(s，3H)，1.31(s，3H)；MS(ES，m/z)184M+H+。
Step 6 ((R) -3-oxo-1, 1' -dimethyltetrahydro-oxazolo [3, 4-a)]Pyridin-7-ylidene) -acetic acid ethyl ester: to a suspension of NaH (60% in mineral oil, 171mg, 4.28mmol) in THF (20ml) was added triethyl phosphonoacetate (0.849ml, 4.28 mmol). The mixture was stirred at room temperature for 30 minutes, then (R) -1, 1' -dimethyl-tetrahydro-oxazolo [3, 4-a ] was added]Pyridine-3, 7-dione (560mg, 3.00mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography (gradient of hexane to ethyl acetate) to give the desired product as a mixture of E/Z isomers (613mg, 79%). 1H NMR CDCl3δ 5.82-5.70(m, 1H, E/Z mixture), 4.20-3.80(m, 4H), 3.35-3.20(m, 1H), 2.93-2.75(m, 1H), 2.30-1.75(m, 3H), 1.50-1.15(m, 9H); MS (ES, M/z)254M + H+。
Step 7 ((7S, 8aR) -3-oxo-1, 1' -Dimethyl-hexahydro-oxazolo [3, 4-a ]]Pyridin-7-yl) -acetic acid ethyl ester: (R) -3-oxo-1, 1' -dimethyl-tetrahydro-oxazolo [3, 4-a ] under balloon pressure]Pyridin-7-ylidene) -acetic acid ethyl ester (613mg, 2.42mmol) and 20% Pd (OH)2A mixture of/active carbon (510mg, 0.726mmol) in methanol (40ml) was hydrogenated overnight. The mixture was filtered through celite. The filtrate was concentrated. The crude product was used in the next step without further purification. 1H NMR CDCl3δ4.22-4.10(m，2H)，3.95-3.85(m，1H)，3.30-3.25(m，1H)，2.90-2.80(m，1H)，2.35-2.25(m，2H)，2.10-1.85(m，1H)，1.80-1.65(m，2H)，1.45(s，3H)，1.36-1.00(m，8H)；MS(ES，m/z)256M+H+。
Step 8 ((7S, 8aR) -3-oxo-1, 1' -dimethyl-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid: to ((7S, 8aR) -3-oxo-1, 1' -dimethyl-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid ethyl ester (614mg, 2.40mmol) in methanol (20.0ml) LiOH (288mg, 12.0mmol) and five drops of water were added. The mixture was stirred at room temperature overnight. Volatiles were removed in vacuo. The resulting aqueous solution was acidified by addition of concentrated HCl solution and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude solid was used in the next step without further purification (546mg, 99%). 1H NMR CDCl3δ3.95-3.85(m，1H)，3.25-3.20(m，1H)，2.85-2.75(m，1H)，2.35-2.25(m，2H)，2.00-1.85(m，1H)，1.75-1.65(m，2H)，1.42(s，3H)，1.25(s，3H)，1.25-1.00(m，2H)；MS(ES，m/z)228M+H+。
Preparation of higher intermediates
Step 1 (4-chloro-2-fluorophenyl) -hydrazine: the flask was charged with 4-chloro-2-fluoroaniline (5.09g, 35.0mmol) at 0 deg.C, and then concentrated HCl solution (30.0ml) was added dropwise. The solution was stirred at 0 deg.CAfter 5 minutes, an aqueous solution (10.0ml) of sodium nitrite (2.42g, 35.1mmol) was added. The reaction was stirred at room temperature for 30 minutes, then cooled to 0 ℃ and tin (II) chloride dihydrate (15.9g, 70.0mmol) was added (in a minimum amount of concentrated HCl solution). The reaction was stirred at 0 ℃ for 30 minutes and then at room temperature for 4 hours. The reaction mixture was filtered and the solid was washed with cold ethanol. The solvent was removed in vacuo. The crude product was used directly in the next step without further purification (5.10g, 62%). 1H NMR CD3OD δ 7.33-7.28(m, 1H), 7.26-7.23(m, 1H), 7.15-7.09(m, 1H); MS (ES, M/z)161M + H+。
Step 21- (4-chloro-2-fluoro-phenyl) -1H-pyrazol-3-ylamine: a round bottom flask was charged with (4-chloro-2-fluorophenyl) -hydrazine HCl salt (1.97g, 10.0mmol), ethanol (8.00ml), 2.80M sodium ethoxide in ethanol (10.0ml, 28.0mmol), and 3-ethoxyacrylonitrile (1.85ml, 18.0 mmol). The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and then quenched by pouring into water. The aqueous solution was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (gradient of hexanes to hexanes with 50% ethyl acetate) to afford the desired product as a brown solid (334mg, 16%). 1H NMR CD3OD δ 7.79(br, 1H), 7.72-7.64(m, 1H), 7.32-7.20(m, 2H), 5.94(br, 1H); MS (ES, M/z)212M + H+。
Compounds of the invention
The following compounds were prepared according to the procedure in scheme 3.
Example 3a
To a solution of (3-oxo-octahydro-indolizin-7-yl) -acetic acid (113mg, 0.574mmol) in dichloromethane (5.00ml) was added oxalyl chloride (73.0. mu.L, 0.861mmol) followed by DMF (7.00. mu.L, 0.0574 mmol). The reaction was allowed to stir at room temperature1 hour, then concentrated and dried under high vacuum for 30 minutes. The crude acid chloride was redissolved in DCM (2.00ml) and added dropwise to a solution of 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine (142mg, 0.688mmol) in DCM (3.00ml) in the presence of triethylamine (160 μ L, 1.14 mmol). The reaction was stirred at room temperature for 1 hour and then quenched by pouring into water. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried and concentrated. The crude material was purified by column chromatography (hexanes to ethyl acetate gradient) to afford the desired product as a white solid (20.8mg, 9.4%). 1H NMR CDCl3，δ8.60-8.40(m，2H)，8.28-8.36(m，1H)，7.92-7.86(m，1H)，7.12-7.02(m，2H)，6.88-6.78(m，1H)，4.20-4.10(m，1H)，3.58-3.45(m，1H)，2.78-2.44(m，1H)，2.50-2.00(m，7H)，1.90-1.50(m，2H)，1.25-1.10(m，1H)，1.10-0.90(m，1H)；MS(ES，m/z)386MH+。
Likewise, the following compounds were prepared in a similar manner to example 3 a:
example 3b 2- (1-acetyl-piperidin-4-yl) -N- [6- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -acetamide
Prepared from (1-acetyl-piperidin-4-yl) -acetyl chloride and 6- (3, 5-difluoro-phenyl) pyridin-3-ylamine. LC-MS (m/z)374.0 (MH)+)；tR1.14min (method B).
Example 3c 2- (1-acetyl-piperidin-4-yl) -N- [6- (3-fluoro-phenyl) -pyridin-3-yl ] -acetamide
From (1-acetyl-piperidin-4-yl) -acetyl chloride and 6- (3-fluoro-phenyl) pyridin-3-ylamine. LC-MS (m/z)356.0(MH+)；tR1.06min (method B).
Example 3d 2- (1-acetyl-piperidin-4-yl) -N- [6- (3-methoxy-phenyl) -pyridin-3-yl ] -acetamide
Prepared from (1-acetyl-piperidin-4-yl) -acetyl chloride and 6- (3-methoxy-phenyl) pyridin-3-ylamine. LC-MS (m/z)368.0 (MH)+)；tR1.01min (method B).
Example 3e 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-dichloro-phenyl) -pyridin-2-yl ] -acetamide
From (1-acetyl-piperidin-4-yl) -acetyl chloride and 5- (3, 5-dichloro-phenyl) pyridin-2-ylamine. LC-MS (m/z)407.1 (MH)+)；tR1.34min (method a).
Example 3f 2- (1-acetyl-piperidin-4-yl) -N- [4- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -acetamide
Prepared from (1-acetyl-piperidin-4-yl) -acetyl chloride and 4- (3, 5-difluoro-phenyl) pyridin-2-ylamine. LC-MS (m/z)374.0 (MH)+)；tR1.07min (method a).
Example 3g N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.50-8.46(m, 1H), 8.35-8.30(m, 1H), 8.14(br, 1H), 7.94-7.90(m, 1H), 7.12-7.08(m, 2H), 6.89-6.83(m, 1H), 4.00-3.92(m, 1H), 3.36-3.30(m, 1H), 2.97-2.90(m, 1H), 2.50-2.36(m, 2H), 2.24-2.10(m, 1H), 1.86-1.78(m, 2H), 1.46(s, 3H), 1.33(s, 3H), 1.33-1.10(m, 2H); MS (ES, M/z)416M + H+(method B).
Example 3h N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -2- (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyrazin-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.60(br, 1H), 8.65(m, 1H), 8.03(br, 1H), 7.58-7.50(m, 2H), 6.93-6.84(m, 1H), 4.00-3.92(m, 1H), 3.36-3.30(m, 1H), 2.98-2.88(m, 1H), 2.57-2.41(m, 2H), 2.26-2.14(m, 1H), 1.88-1.78(m, 2H), 1.46(s, 3H), 1.32(s, 3H), 1.32-1.10(m, 2H); MS (ES, M/z)417M + H+(method B).
Example 3i 2- (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -N- [1- (2-fluoro-phenyl) -1H-pyrazol-3-yl ] -acetamide
From 1- (2-fluoro-phenyl) -1H-pyrazol-3-yl-amine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.75(br, 1H), 7.93-7.91(m, 1H), 7.77-7.73(m, 1H), 7.31-7.21(m, 3H), 7.00-6.99(m, 1H), 3.91-3.85(m, 1H), 3.28-3.24(m, 1H), 2.90-2.81(m, 1H), 2.29-2.01(m, 3H), 1.75-1.63(m, 2H), 1.41(s, 3H), 1.29(s, 3H), 1.11-0.85(m, 2H); MS (ES, M/z)387M + H+(method B).
Example 3j N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.47(br, 1H), 8.36-8.28(m, 2H), 7.94-7.89(m, 1H), 7.10-7.04(m, 2H), 6.88-6.80(m, 1H), 4.45-4.40(m, 1H), 3.98-3.88(m, 2H), 3.82-3.72(m, 1H), 3.00-2.90(m, 1H), 2.50-2.34(m, 2H), 2.30-2.12(m, 1H), 2.04-1.96(m, 1H), 1.86-1.79(m, 1H), 1.34-1.14(m, 2H); MS (ES, M/z)388M + H+(method B).
Example 3k N- [5- (3-fluoro-phenyl) -pyrazin-2-yl ] -2- (3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3-fluoro-phenyl) -pyrazin-2-ylamine and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.58-9.46(br, 1H), 8.62-8.50(br, 1H), 7.66(br, 1H), 7.58-7.54(m, 2H), 7.48-7.44(m, 1H), 7.04-7.02(m, 1H), 4.40-4.34(m, 1H)，1H)，3.92-3.80(m，2H)，3.78-3.68(m，1H)，2.94-2.84(m，1H)，2.46-2.30(m，2H)，2.26-2.10(m，1H)，2.00-1.92(m，1H)，1.80-1.72(m，1H)，1.28-1.06(m，2H)；MS(ES，m/z)371M+H+(method B).
Example 3l N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -2- (3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyrazin-2-ylamine and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.64-9.52(br, 1H), 8.76-8.56(br, 1H), 8.08-8.02(br, 1H), 7.58-7.48(m, 2H), 6.92-6.86(m, 1H), 4.46-4.42(m, 1H), 4.00-3.90(m, 2H), 3.84-3.74(m, 1H), 3.02-2.92(m, 1H), 2.52-2.38(m, 2H), 2.32-2.18(m, 1H), 2.06-2.00(m, 1H), 1.88-1.80(m, 1H), 1.34-1.02(m, 2H); MS (ES, M/z)389M + H+(method B).
Example 3m N- [5- (3-chloro-phenyl) -pyridin-2-yl ] -2- (3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3-chloro-phenyl) -pyridin-2-ylamine and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.54-8.46(br, 1H), 8.34-8.28(m, 1H), 8.22-8.16(br, 1H), 7.96-7.92(m, 1H), 7.58-7.54(m, 1H), 7.50-7.36(m, 3H), 4.48-4.40(m, 1H), 4.00-3.70(m, 3H), 3.02-2.92(m, 1H), 2.50-2.34(m, 2H), 2.30-2.14(m, 1H), 2.06-2.00(m, 1H), 1.88-1.80(m, 1H), 1.36-1.10(m, 2H); MS (ES, M/z)386M + H+(method B).
Example 3n N- [5- (3, 5-difluoro-phenyl) -pyrimidin-2-yl ] -2- (3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyrimidin-2-ylamine and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.96-8.90(br, 1H), 8.86-8.76(br, 2H), 7.12-7.06(m, 2H), 6.96-6.86(m, 1H), 4.48-4.40(m, 1H), 4.00-3.72(m, 3H), 3.02-2.70(m, 3H), 2.34-2.16(m, 1H), 2.12-2.04(m, 1H), 1.92-1.84(m, 1H), 1.40-1.14(m, 2H); MS (ES, M/z)389M + H+(method B).
Example 3o N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.62(br, 1H), 8.44-8.36(m, 2H), 7.94-7.89(m, 1H), 7.10-7.04(m, 2H), 6.88-6.80(m, 1H), 4.45-4.40(m, 1H), 3.98-3.88(m, 2H), 3.82-3.72(m, 1H), 3.00-2.90(m, 1H), 2.50-2.34(m, 2H), 2.30-2.12(m, 1H), 2.04-1.96(m, 1H), 1.86-1.79(m, 1H), 1.34-1.14(m, 2H); MS (ES, M/z)388M + H+(method B).
Example 3p N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyrazin-2-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.60-9.56(m, 1H), 8.66-8.62(m, 1H), 8.60-8.56(br, 1H), 7.58-7.48(m, 2H), 6.92-6.84(m, 1H), 4.46-4.40(m, 1H), 4.00-3.90(m, 2H), 3.84-3.74(m, 1H), 3.02-2.92(m, 1H), 2.54-2.40(m, 2H), 2.30-2.18(m, 1H), 2.06-1.96(m, 1H), 1.86-1.80(m, 1H), 1.32-1.12(m, 2H); MS (ES, M/z)389M + H+(method B).
Example 3q N- [1- (2-fluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2-fluoro-phenyl) -1H-pyrazol-3-yl staurophylline and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.46-9.42(br, 1H), 7.90-7.87(m, 1H), 7.76-7.70(m, 1H), 7.30-7.18(m, 3H), 6.99-6.96(m, 1H), 4.38-4.32(m, 1H), 3.86-3.78(m, 2H), 3.70-3.60(m, 1H), 2.88-2.78(m, 1H), 2.16-1.96(m, 3H), 1.84-1.76(m, 1H), 1.64-1.56(m, 1H), 1.00-0.76(m, 2H); MS (ES, M/z)359M + H+(method B).
Example 3r N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- ((7S, 8aR) -1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo[3，4-a]Pyridin-7-yl) -acetic acid preparation followed by chiral separation. 1H NMR CDCl3 delta 8.56-8.24(m, 3H), 7.94-7.90(m, 1H), 7.12-7.04(m, 2H), 6.89-6.83(m, 1H), 4.00-3.92(m, 1H), 3.36-3.30(m, 1H), 2.97-2.90(m, 1H), 2.50-2.36(m, 2H), 2.24-2.10(m, 1H), 1.86-1.78(m, 2H), 1.46(s, 3H), 1.33(s, 3H), 1.33-1.10(m, 2H); MS (ES, M/z)416M + H+(method B).
Example 3s N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- ((7R, 8aS) -1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid preparation followed by chiral separation. 1H NMR CDCl3 delta 8.50-8.46(m, 1H), 8.35-8.30(m, 1H), 8.14(br, 1H), 7.94-7.90(m, 1H), 7.12-7.08(m, 2H), 6.89-6.83(m, 1H), 4.00-3.92(m, 1H), 3.36-3.30(m, 1H), 2.97-2.90(m, 1H), 2.50-2.36(m, 2H), 2.24-2.10(m, 1H), 1.86-1.78(m, 2H), 1.46(s, 3H), 1.33(s, 3H), 1.33-1.10(m, 2H); MS (ES, M/z)416M + H+(method B).
Example 3t N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -2- ((7S, 8aR) -1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyrazin-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid preparation followed by chiral separation. 1H NMR CDCl3 delta 9.60(br, 1H), 8.65(m, 1H), 8.33(br, 1H), 7.58-7.50(m，2H)，6.93-6.84(m，1H)，4.00-3.92(m，1H)，3.36-3.30(m，1H)，2.98-2.88(m，1H)，2.57-2.41(m，2H)，2.26-2.14(m，1H)，1.88-1.78(m，2H)，1.46(s，3H)，1.32(s，3H)，1.32-1.10(m，2H)；MS(ES，m/z)417M+H+(method B).
Example 3u N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -2- ((7R, 8aS) -1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (3, 5-difluoro-phenyl) -pyrazin-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid preparation followed by chiral separation. 1H NMR CDCl3 delta 9.60(br, 1H), 8.65(m, 1H), 8.40(br, 1H), 7.58-7.50(m, 2H), 6.93-6.84(m, 1H), 4.00-3.92(m, 1H), 3.36-3.30(m, 1H), 2.98-2.88(m, 1H), 2.57-2.41(m, 2H), 2.26-2.14(m, 1H), 1.88-1.78(m, 2H), 1.46(s, 3H), 1.32(s, 3H), 1.32-1.10(m, 2H); MS (ES, M/z)417M + H+(method B).
Example 3v N- [5- (2, 4-difluoro-phenyl) - [1,3, 4] thiadiazol-2-yl ] -2- (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (2, 4-difluoro-phenyl) - [1,3, 4]]Thiadiazol-2-ylamine and (1, 1-dimethyl-3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CD3OD δ 8.27-8.19(m, 1H), 7.10-7.02(m, 2H), 3.87-3.80(m, 1H), 3.39-3.34(m, 1H), 2.97-2.87(m, 1H), 2.60-2.46(m, 2H), 2.20-2.06(m, 1H), 1.84-1.76(m, 2H), 1.44(s, 3H), 1.32(s, 3H), 1.32-1.10(m, 2H); MS (ES, m)/z)423M+H+(method B).
Example 3w N- [5- (2, 4-difluoro-phenyl) - [1,3, 4] oxadiazol-2-yl ] -2- (3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 5- (2, 4-difluoro-phenyl) - [1,3, 4]]Oxadiazol-2-ylamines and (3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CD3OD delta 8.06-7.98(m, 1H), 7.13-7.04(m, 2H), 4.48-4.42(m, 1H), 3.96-3.76(m, 3H), 3.02-2.92(m, 1H), 2.54-2.40(m, 2H), 2.33-2.10(m, 1H), 2.04-1.96(m, 1H), 1.86-1.77(m, 1H), 1.32-1.10(m, 2H); MS (ES, M/z)379M + H+(method B).
Example 3x N- [1- (2, 4-difluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2, 4-difluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.06-8.02(br, 1H), 7.86-7.82(m, 1H), 7.76-7.68(m, 1H), 7.04-6.94(m, 3H), 4.44-4.38(m, 1H), 3.96-3.84(m, 2H), 3.80-3.70(m, 1H), 2.98-2.90(m, 1H), 2.40-2.12(m, 3H), 2.04-1.96(m, 1H), 1.84-1.77(m, 1H), 1.30-1.08(m, 2H); MS (ES, M/z)377M + H+(method B).
Example 3y N- [1- (3-fluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (3-fluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.60(br, 1H), 7.86-7.83(m, 1H), 7.44-7.34(m, 3H), 7.01-6.94(m, 2H), 4.42-4.36(m, 1H), 3.94-3.82(m, 2H), 3.78-3.68(m, 1H), 2.94-2.85(m, 1H), 2.34-2.08(m, 3H), 1.96-1.90(m, 1H), 1.80-1.68(m, 1H), 1.20-0.98(m, 2H); MS (ES, M/z)359M + H+(method B).
Example 3z N- [1- (4-fluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (4-fluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.17(br, 1H), 7.78-7.76(m, 1H), 7.59-7.32(m, 2H), 7.17-7.11(m, 2H), 6.94-6.92(m, 1H), 4.43-4.37(m, 1H), 3.95-3.82(m, 2H), 3.78-3.70(m, 1H), 2.97-2.88(m, 1H), 2.38-2.10(m, 3H), 2.01-1.94(m, 1H), 1.82-1.74(m, 1H), 1.30-1.05(m, 2H); MS (ES, M/z)359M + H+(method B).
Example 3aa N- [1- (3, 5-difluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (3, 5-difluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridine-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.31(br, 1H), 7.84-7.78(m, 1H), 7.22-7.10(m, 2H), 7.02-6.96(m, 1H), 6.74-6.66(m, 1H), 4.46-4.37(m, 1H), 3.98-3.68(m, 3H), 2.99-2.88(m, 1H), 2.44-2.08(m, 3H), 2.03-1.92(m, 1H), 1.84-1.70(m, 1H), 1.32-1.06(m, 2H); MS (ES, M/z)377M + H+(method B).
Example 3bb N- [1- (2, 5-difluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2, 5-difluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.34(br, 1H), 8.02-7.96(m, 1H), 7.60-7.52(m, 1H), 7.24-7.14(m, 1H), 7.02-6.88(m, 2H), 4.46-4.37(m, 1H), 3.98-3.68(m, 3H), 2.98-2.87(m, 1H), 2.40-2.10(m, 3H), 2.03-1.92(m, 1H), 1.84-1.70(m, 1H), 1.30-1.04(m, 2H); MS (ES, M/z)377M + H+(method B).
Example 3cc N- [1- (4-chloro-2-fluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (4-chloro-2-fluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.28(br, 1H), 7.90-7.88(m, 1H), 7.75-7.69(m, 1H), 7.29-7.20(m, 2H), 6.98-6.96(m, 1H), 4.43-4.37(m, 1H), 3.96-3.84(m, 2H), 3.78-3.68(m, 1H), 2.97-2.88(m, 1H), 2.38-2.10(m, 3H), 2.00-1.92(m, 1H), 1.82-1.74(m, 1H), 1.28-1.05(m，2H)；MS(ES，m/z)393M+H+(method B).
Example 3dd N- [1- (2-ethoxy-6-fluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2-fluoro-6-ethoxy-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.75(br, 1H), 7.53-7.49(m, 1H), 7.39-7.28(m, 1H), 6.95-6.90(m, 1H), 6.88-6.78(m, 2H), 4.43-4.36(m, 1H), 4.10-4.00(m, 2H), 3.94-3.82(m, 2H), 3.78-3.66(m, 1H), 2.96-2.84(m, 1H), 2.28-1.88(m, 4H), 1.76-1.66(m, 1H), 1.34-1.24(m, 3H), 1.20-0.93(m, 2H); MS (ES, M/z)403M + H+(method B).
Example 3ee N- [1- (2, 3-difluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2, 3-difluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.12(br, 1H), 7.96-7.90(m, 1H), 7.60-7.50(m, 1H), 7.22-7.04(m, 2H), 7.02-6.96(m, 1H), 4.46-4.37(m, 1H), 3.98-3.68(m, 3H), 2.98-2.86(m, 1H), 2.40-2.10(m, 3H), 2.03-1.92(m, 1H), 1.84-1.74(m, 1H), 1.30-1.04(m, 2H); MS (ES, M/z)377M + H+(method B).
Example 3ff N- [1- (3, 5-difluoro-phenyl) -1H-imidazol-4-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (3, 5-difluoro-phenyl) -1H-imidazol-4-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.42(br, 1H), 8.08-7.70(m, 2H), 7.06-6.98(m, 2H), 6.92-6.86(m, 1H), 4.44-4.38(m, 1H), 3.98-3.70(m, 3H), 2.98-2.88(m, 1H), 2.48-2.10(m, 3H), 2.02-1.94(m, 1H), 1.84-1.76(m, 1H), 1.36-1.14(m, 2H); MS (ES, M/z)377M + H+(method B).
Example 3gg N- [1- (2-chloro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2-chloro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.01(br, 1H), 7.82-7.79(m, 1H), 7.57-7.50(m, 2H), 7.42-7.36(m, 2H), 7.00-6.97(m, 1H), 4.42-4.34(m, 1H), 3.92-3.82(m, 2H), 3.78-3.64(m, 1H), 2.94-2.82(m, 1H), 2.20-1.96(m, 3H), 1.92-1.84(m, 1H), 1.72-1.62(m, 1H), 1.10-0.84(m, 2H); MS (ES, M/z)375M + H+(method B).
Example 3hh 2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -N- [3- (3-trifluoromethyl-phenyl) -isoxazol-5-yl ] -acetamide
From 3- (3-trifluoromethyl-phenyl) -isoxazol-5-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.80-8.72(br, 1H), 8.09-8.06(m, 1H), 8.02-7.98(m, 1H), 7.74-7.70(m, 1H), 7.64-7.58(m, 1H), 6.79-6.75(m, 1H), 4.46-4.42(m, 1H), 4.00-3.88(m, 2H), 3.84-3.74(m, 1H), 3.02-2.92(m, 1H), 2.52-2.38(m, 2H), 2.30-2.16(m, 1H), 2.04-1.96(m, 1H), 1.86-1.78(m, 1H), 1.35-1.15(m, 2H); MS (ES, M/z)410M + H+(method B).
Example 3ii N- [1- (2-chloro-4-ethoxy-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 1- (2-chloro-4-ethoxy-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 9.06-9.02(br, 1H), 7.68-7.64(br, 1H), 7.42-7.36(m, 1H), 7.04-7.02(m, 1H), 6.94-6.86(m, 2H), 4.41-4.34(m, 1H), 4.10-4.05(m, 2H), 3.92-3.82(m, 2H), 3.78-3.66(m, 1H), 2.92-2.84(m, 1H), 2.16-1.64(m, 5H), 1.48-1.42(m, 3H), 1.16-0.88(m, 2H); MS (ES, M/z)419M + H+(method B).
Example 3jj N- [3- (2, 4-difluoro-phenyl) -isoxazol-5-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From 3- (2, 4-difluoro-phenyl) -isoxazol-5-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.84-8.78(br, 1H), 7.95-7.88(m, 1H),7.02-6.92(m，2H)，6.82-6.76(m，1H)，4.47-4.41(m，1H)，4.00-3.88(m，2H)，3.84-3.74(m，1H)，3.02-2.92(m，1H)，2.52-2.38(m，2H)，2.30-2.16(m，1H)，2.04-1.96(m，1H)，1.86-1.78(m，1H)，1.35-1.14(m，2H)；MS(ES，m/z)378M+H+(method B).
Example 3kk N- [1- (2-chloro-4-fluoro-phenyl) -1H-pyrazol-3-yl ] -2- ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a ] pyridin-7-yl) -acetamide
From (2-chloro-4-fluoro-phenyl) -1H-pyrazol-3-ylamine and ((7S, 8aR) -3-oxo-hexahydro-oxazolo [3, 4-a)]Pyridin-7-yl) -acetic acid. 1H NMR CDCl3 delta 8.54-8.50(br, 1H), 7.73-7.69(m, 1H), 7.50-7.44(m, 1H), 7.30-7.26(m, 1H), 7.14-7.07(m, 1H), 6.98-6.94(m, 1H), 4.44-4.36(m, 1H), 3.95-3.84(m, 2H), 3.81-3.70(m, 1H), 2.96-2.87(m, 1H), 2.35-2.10(m, 3H), 2.00-1.94(m, 1H), 1.82-1.74(m, 1H), 1.30-1.14(m, 2H); MS (ES, M/z)393M + H+(method B).
Preparation of Compounds of formula I
Scheme 4
In addition, compounds of formula I can also be synthesized from acids of formula IX as described in scheme 4. The acid may be activated using thionyl chloride or CDI.
An intermediate of formula IXd: 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid
Lda, THF, about-78 ℃ for 1 hour, then about 0 ℃ for about 0.5 hour.
Burgess reagent, toluene, about 90 ℃ for about 0.5 hours.
c.H2，Pd(OH)2C, EtOAC, MeOH, RT, overnight.
d. Acetyl chloride, triethylamine, DCM, room temperature, about 1.5 hours.
Tfa, DCM, room temperature, about 1 hour.
Step 14- (1-tert-butoxycarbonyl-cyclopropyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester: to a cooled (-78 ℃ C.) solution of 2.0M lithium diisopropylamide in heptane/THF/ethylbenzene (27.4ml, 54.8mmol) was added a solution of tert-butyl cyclopropanecarboxylate (7.08g, 49.8mmol) in THF (35 ml). After stirring for 1h at-78 deg.C, a solution of benzyl 4-oxo-piperidine-1-carboxylate (11.6g, 49.8mmol) in THF (50ml) was added. The reaction mixture was stirred at-78 ℃ for 3 hours and then warmed to room temperature. After stirring for 16 hours at ambient temperature, the mixture was saturated with NH4Aqueous Cl (150ml) was quenched and extracted with EtOAc (150ml x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes) to give benzyl 4- (1-tert-butoxycarbonyl-cyclopropyl) -4-hydroxy-piperidine-1-carboxylate (8.07g, 43%).1H NMR(400MHz，CDCl3) δ 7.36-7.28(m, 5H), 5.11(s, 2H), 4.50(s, 1H), 4.00(brs, 2H), 3.20(brs, 2H), 1.72-1.64(m, 2H), 1.42(s, 9H), 1.40-1.30(m, 2H), 1.10(dd, J ═ 7.0 and 2.4Hz, 2H), 0.88(dd, J ═ 7.0 and 2.4Hz, 2H).
Step 24- (1-tert-butoxycarbonyl-cyclopropyl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester: a mixture of benzyl 4- (1-tert-butoxycarbonyl-cyclopropyl) -4-hydroxy-piperidine-1-carboxylate (5.41g, 14.4mmol) and (methoxycarbonylsulfamoyl) -triethylammonium hydroxide (4.1g, 17mmol) in toluene (100ml) was added at 90 deg.CThe material was heated for 1 hour. The reaction mixture was quenched with water (50ml) and extracted with EtOAc (150ml × 3). The combined organic phases were washed with saturated NaHCO3The aqueous solution and brine were washed, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give benzyl 4- (1-tert-butoxycarbonyl-cyclopropyl) -3, 6-dihydro-2H-pyridine-1-carboxylate (4.32g, 84%).1H NMR(400MHz，CDCl3) δ 7.38-7.30(m, 5H), 5.51(m, 2H), 5.15(s, 2H), 3.96(m, 2H), 3.59(t, J ═ 5.3Hz, 2H), 2.25(brs, 2H), 1.41(s, 9H), 1.24(dd, J ═ 6.6 and 3.0Hz, 2H), 0.85(dd, J ═ 6.6 and 3.0Hz, 2H).
Step 31-piperidin-4-yl-cyclopropanecarboxylic acid tert-butyl ester: a solution of benzyl 4- (1-tert-butoxycarbonyl-cyclopropyl) -3, 6-dihydro-2H-pyridine-1-carboxylate (4.32g, 12.1mmol) and 20% palladium hydroxide/activated carbon (charcol) (2: 8, palladium: carbon black, 1.70g) in methanol (70ml) and EtOAc (70ml) was stirred overnight under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and concentrated in vacuo to afford the desired product (2.66g, 98%).1H NMR(400MHz，CDCl3) δ 6.93(S, 1H), 3.22(d, J ═ 12.2Hz, 2H), 2.63(dt, J ═ 12.5 and 2.2Hz, 1H), 1.80-1.70(m, 1H), 1.66-1.56(m, 2H), 1.56-1.40(m, 2H), 1.34(S, 9H), 0.98(dd, J ═ 6.8 and 2.6Hz, 2H), 0.62(dd, J ═ 6.8 and 2.6Hz, 2H). ESI-MS m/z: 226.1(M + H)+。
Step 41- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid tert-butyl ester: to a cooled (0 ℃ C.) solution of tert-butyl 1-piperidin-4-yl-cyclopropanecarboxylate (2.66g, 11.8mmol) and triethylamine (3.29ml, 23.6mmol) in dichloromethane (80ml) was added acetyl chloride (1.26ml, 17.7 mmol). The reaction mixture was warmed to room temperature and stirred for 4 hours. Saturated NH for reaction mixture4Aqueous Cl (80ml) was quenched and extracted with dichloromethane (50ml x 3). The combined organic phases were washed with saturated NaHCO3The aqueous solution and brine were washed, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylate (3.13g, 99%).1H NMR(400MHz，CDCl3)δ4.69-4.65(m，1H) 3.84-3.79(m, 1H), 2.98(dt, J ═ 12.0 and 2.5Hz, 1H), 2.43(dt, J ═ 12.0 and 2.5Hz, 1H), 2.07(s, 3H), 1.74-1.65(m, 2H), 1.63-1.56(m, 1H), 1.50-1.38(m, 2H), 1.41(s, 9H), 1.10-1.04(m, 2H), 0.70-0.60(m, 2H).
Step 51- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid: to a cooled (0 ℃) solution of tert-butyl 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylate (3.13g, 11.7mmol) and triethylsilane (4.67ml, 29.3mmol) in dichloromethane (25ml) was added trifluoroacetic acid (11.7ml, 152 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. Volatiles were removed in vacuo. The residue was dissolved in dichloromethane (150ml) and extracted with 2M NaOH (75 ml). The aqueous layer was acidified with 12N HCl and extracted with dichloromethane (150 ml. times.3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid (1.71g, 69%).1H NMR(400MHz，CDCl3)δ4.69(d，J＝12.0Hz，1H)，3.83(d，J＝12.0Hz，1H)，2.99(t，J＝12.0Hz，1H)，2.44(t，J＝12.0Hz，1H)，2.10(s，3H)，1.74-1.61(m，3H)，1.57-1.41(m，2H)，1.26-1.22(m，2H)，0.79-0.77(m，2H)。ESI-MS m/z：212.1(M+H)+。
An intermediate of formula IXe: 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid
Lda, THF, -78 ℃,1 hour, then 0 ℃,5 hours.
Burgess reagent, toluene, 90 ℃ for 0.5 hour.
(c)H2，Pd(OH)2C, EtOAC, MeOH, RT, overnight.
(d) Acetyl chloride, triethylamine, DCM, room temperature, 1.5 hours.
(e) NaOH, MeOH, reflux, overnight.
(f)KOC(CH3)3，H2O, ether, room temperature, 4 days.
Step 14- (1-ethoxycarbonyl-1-methyl-ethyl) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester: to a cooled (-78 ℃ C.) solution of 2.0M lithium diisopropylamide in heptane/THF/ethylbenzene (13.7ml, 27.4mmol) and THF (50ml) was added a solution of ethyl isobutyrate (3.32ml, 24.9mmol) in THF (20 ml). After stirring for 1h at-78 deg.C, a solution of benzyl 4-oxo-piperidine-1-carboxylate (5.80g, 24.9mmol) in THF (50ml) was added. After stirring for 2 hours at-78 ℃ the mixture was saturated with NH4Aqueous Cl (80ml) was quenched and extracted with EtOAc (100ml x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give benzyl 4- (1-ethoxycarbonyl-1-methyl-ethyl) -4-hydroxy-piperidine-1-carboxylate (6.91g, 79%).1HNMR(400MHz，CDCl3)δ7.37-7.28(m，5H)，5.13(s，2H)，4.17(q，J＝7.2Hz，2H)，4.05(brs，2H)，3.74(s，1H)，3.20(brs，2H)，1.62(brs，2H)，1.50-1.40(m，2H)，1.28(t，J＝7.2Hz，3H)，1.21(s，6H)。
Step 24- (1-ethoxycarbonyl-1-methyl-ethyl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester: a mixture of benzyl 4- (1-ethoxycarbonyl-1-methyl-ethyl) -4-hydroxy-piperidine-1-carboxylate (1.90g, 5.44mmol) and (methoxycarbonylsulfamoyl) -triethylammonium hydroxide (1.60g, 6.50mmol) in toluene (30ml) was heated at 90 ℃ for 1 h. The reaction mixture was quenched with water (50ml) and extracted with EtOAc (150ml x 3). The combined organic phases were washed with saturated NaHCO3The aqueous solution and brine were washed, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give benzyl 4- (1-ethoxycarbonyl-1-methyl-ethyl) -3, 6-dihydro-2H-pyridine-1-carboxylate (1.49g, 83%).1H NMR(400MHz，CDCl3)δ7.38-7.30(m，5H)，5.55(m，1H)，5.15(s，2H)，4.12(q，J＝7.1Hz，2H)，4.01(m，2H)，3.54(t，J＝5.4Hz，2H)，2.08(brs，2H)，1.30(s，6H)，1.22(t，J＝7.1Hz，3H)。
Step 32-methyl-2-piperidin-4-yl-propionic acid ethyl ester: a solution of benzyl 4- (1-ethoxycarbonyl-1-methyl-ethyl) -3, 6-dihydro-2H-pyridine-1-carboxylate (8.64g, 26.1mmol) and 20% palladium hydroxide on activated charcoal (2: 8, palladium: carbon black, 0.93g) in methanol (100ml) and EtOAc (100ml) was stirred under a hydrogen atmosphere (1atm) overnight. The reaction mixture was filtered and concentrated to give the desired product (4.93g, 95%).1HNMR(400MHz，CDCl3) δ 4.09(q, J ═ 7.1Hz, 2H), 3.15-3.05(m, 2H), 2.65-2.50(m, 3H), 1.68(tt, J ═ 12.2 and 3.3Hz, 1H), 1.54-1.46(m, 2H), 1.30-1.20(m, 2H), 1.22(t, J ═ 7.1Hz, 3H), 1.09(s, 6H).
Step 42- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid ethyl ester: to a cooled (0 ℃ C.) solution of ethyl 2-methyl-2-piperidin-4-yl-propionate (813mg, 4.08mmol) and triethylamine (1.14ml, 8.16mmol) in dichloromethane (20ml) was added acetyl chloride (0.44ml, 6.12 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched with 1N HCl (30ml) and extracted with dichloromethane (50ml x 3). The combined organic phases were washed with saturated NaHCO3The aqueous solution and brine were washed, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid ethyl ester (980mg, 99%).1H NMR(400MHz，CDCl3) δ 4.75-4.65(m, 1H), 4.13(q, J ═ 7.1Hz, 2H), 3.90-3.80(m, 1H), 3.00(dt, J ═ 13.1 and 2.4Hz, 1H), 2.50-2.40(m, 1H), 2.08(s, 3H), 1.85-1.75(m, 1H), 1.65-1.55(m, 2H), 1.30-1.15(m, 2H), 1.24(t, J ═ 7.1Hz, 3H), 1.10(d, J ═ 5.0Hz, 6H).
Step 52- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid. To a cooled (0 ℃) stirred suspension of potassium tert-butoxide (8.07g, 71.9mmol) in ether (100ml) was added water (0.32ml, 18.0 mmol). After stirring at 0 ℃ for 5min, a solution of 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid ethyl ester (2.17g, 8.99mmol) in ether (50ml) was added. The reaction mixture was warmed to room temperature and stirred for 4 days. The mixture is washed with ice water(50ml) quench. The aqueous layer was acidified with 12N HCl (6.5ml) and extracted with dichloromethane (100ml x 3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid (1.50g, 78%).1H NMR(400MHz，CDCl3) δ 4.75-4.65(m, 1H), 3.90-3.80(m, 1H), 3.02(dt, J ═ 12.9 and 2.3Hz, 1H), 2.48(dt, J ═ 13.0 and 2.4Hz, 1H), 2.10(s, 3H), 1.88-1.78(m, 1H), 1.72-1.62(m, 2H), 1.34-1.20(m, 2H), 1.16(d, J ═ 5.2Hz, 6H).
Compounds of the invention
The following compounds were prepared according to the procedure in scheme 4.
Example 4a 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -isobutyramide
To a cooled (0 ℃) solution of 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid (65mg, 0.30mmol) in dichloromethane (2ml) was added thionyl chloride (26.7 μ l, 0.37 mmol). After stirring for 30 min at 0 ℃, a solution of 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine in dichloromethane (2ml) was added. The reaction mixture was heated to reflux overnight. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl]Isobutyramide (14mg, 11%).1HNMR(400MHz，CDCl3) δ 8.47(d, J ═ 2.2Hz, 1H), 8.35(dd, J ═ 8.6 and 0.6Hz, 1H), 8.12(s, 1H), 7.88(dd, J ═ 8.7 and 2.5Hz, 1H), 7.09-7.05(m, 2H), 6.83(tt, J ═ 8.8 and 2.3Hz, 1H), 4.76-4.66(m, 1H), 3.89-3.84(m, 1H), 3.04(dt, J ═ 12.9 and 2.5Hz, 1H), 2.49(dt, J ═ 13.0 and 2.6Hz, 1H), 2.08(s, 3H), 2.00-1.90(m, 1H), 1.75-1.60(m, 2H), 1.35-1.20(m, 1H), 1.28.7H, 7H). ESI-MS m/z: 402.0(M + H)+。
Likewise, the following compounds were prepared in a similar manner to example 4 a:
example 4b 2- (1-acetyl-piperidin-4-yl) -N- (3 ', 5' -difluoro-biphenyl-4-yl) -propionamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -propionic acid and 3 ', 5' -difluoro-biphenyl-4-ylamine. LC-MS (m/z)387.0 (MH)+)；tR1.26min (method a).
Example 4c (R) -2- (1-acetyl-piperidin-4-yl) -N- (3 ', 5' -difluoro-biphenyl-4-yl) -propionamide
Prepared from (R) -2- (1-acetyl-piperidin-4-yl) -propionic acid and 3 ', 5' -difluoro-biphenyl-4-ylamine. LC-MS (m/z)387.0 (MH)+)；tR1.24min (method a).
Example 4d (S) -2- (1-acetyl-piperidin-4-yl) -N- (3 ', 5' -difluoro-biphenyl-4-yl) -propionamide
Prepared from (S) -2- (1-acetyl-piperidin-4-yl) -propionic acid and 3 ', 5' -difluoro-biphenyl-4-ylamine. LC-MS (m/z)387.0 (MH)+)；tR1.24min (method a).
Example 4e 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -propionamide
Prepared from 2- (1-acetyl-piperidin-4-yl) -propionic acid and 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine. LC-MS (m/z)388.0 (MH)+)；tR1.18min (method a).
Example 4f 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -isobutyramide
Prepared from 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid and 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine. LC-MS (m/z)402.0 (MH)+)；tR1.27min (method a).
Example 4g 2- (1-acetyl-piperidin-4-yl) -N- [5- (3, 5-difluoro-phenyl) -pyrazin-2-yl ] -isobutyramide
Prepared from 2- (1-acetyl-piperidin-4-yl) -2-methyl-propionic acid and 5- (3, 5-difluoro-phenyl) -pyrazin-2-ylamine. LC-MS (m/z)403.0 (MH)+)；tR1.24min (method a).
Example 4h 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -amide.
A solution of 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid (352mg, 1.67mmol), 5- (3, 5-difluoro-phenyl) -pyridin-2-ylamine (378mg, 1.83mmol), N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (479mg, 2.50mmol) and 4-dimethylaminopyridine (20.4mg, 0.1mmol) in dichloromethane (25ml) was stirred at room temperature overnight. The mixture was concentrated in vacuo. Purification of the residue by HPLC gave 11- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid [5- (3, 5-difluoro-phenyl) -pyridin-2-yl]Amide (40mg, 6%).1H NMR(400MHz，CDCl3) δ 8.45-8.44(dd, J ═ 2.4 and 0.6Hz, 1H), 8.28(dd, J ═ 8.6 and 0.6Hz, 1H), 8.03(s, 1H), 7.87(dd, J ═ 8.6 and 2.4Hz, 1H), 7.10-7.04(m, 2H), 6.86-6.80(m, 1H), 4.80-4.71(m, 1H), 3.89-3.80(m, 1H), 3.04(dt, J ═ 12.0 and 2.2Hz, 1H), 2.49(dt, J ═ 12.0 and 2.2Hz, 1H), 2.08(s, 3H), 1.86-1.74(m, 3H), 1.44-1.31(m, 2H), 1.14-1.81 (m, 2H), 2.87(m, 0H). ESI-MS m/z: 400.0(M + H)+。
The following compounds are likewise prepared in analogy to example 4 h.
Example 4i 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide
Prepared from 1- (1-acetyl-piperidin-4-yl) -cyclopropanecarboxylic acid and 3 ', 5' -difluoro-biphenyl-4-ylamine. LC-MS (m/z)399.0 (MH)+)；tR1.26min (method a).
Preparation of Compounds of formula I
Scheme 5
2-chloro-1, 3-dimethylimidazolinium chloride (dimethylimidazolinium chloride), diisopropylethylamine, CH2Cl2
HCl, dioxane
c.R2XCl or R2XCl，NaHCO3Toluene, water
Representative intermediates were synthesized according to scheme 5.
An intermediate of formula XI: 4- (Biphenyl-4-ylcarbamoylmethyl) -piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 4-carboxymethylpiperidine-1-carboxylate (250mg, 1.03mmol) was dissolved in dichloromethane (5ml) at room temperature. Diisopropylethylamine (0.54ml, 3.09mmol) and 2-chloro-1, 3-dimethylimidazolinium chloride (174mg, 1.03mmol) were added successively. The reaction mixture was stirred at room temperature for 10 minutes. 4-Biphenylaniline (174mg, 1.03mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (25ml), transferred to a separatory funnel and washed with 1N HCl (1X 10ml) followed by saturated aqueous sodium bicarbonate (1X 10 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude reaction mixture was dissolved in ethyl acetate (1ml) and applied to a 5g SCX column (Supelco product No. 52691-U). Elution with ethyl acetate, followed by concentration gave 162mg of the title compound as a white solid.1H NMR(400MHz，CDCl3)δ7.53-7.49(m，5H)，7.36(t，J＝6.1Hz，2H)，7.26(t，J＝6.1Hz)，7.20-7.17(m，2H)，4.04(br d，J＝12.2Hz，2H)，2.68(br t，J＝12.3Hz，2H)，2.22(br d，J＝7.4Hz，2H)，2.07-1.98(m，2H)，1.71(br d，J＝11.5Hz，2H)，1.39(s，9H)，1.21-1.08(m，1H)。ESI-MS m/z：395.1(M+H)+。
An intermediate of formula XII: n-biphenyl-4-yl-2-piperidin-4-yl-acetamides
4- (Biphenyl-4-ylcarbamoylmethyl) -piperidine-1-carboxylic acid tert-butyl ester (152mg, 0.39mmol) was dissolved at room temperatureIn dioxane (1 ml). A solution of HCl in dioxane (4M, 5ml) was added and the reaction mixture was stirred at room temperature for 45 minutes. The resulting solid was collected by filtration and triturated with ether to give 114mg of the title compound as an off-white solid.1H NMR(400MHz，d-6DMSO)δ10.20(s，1H)，8.83(br d，J＝8.3Hz，1H)，8.65(br d，J＝8.3，1H)，7.71(d，J＝8.7，2H)，7.63(t，J＝8.1Hz，4H)，7.44(t，J＝5.6Hz，2H)，7.33(t，J＝9Hz，1H)，3.49(br s，2H)，3.24(br d，J＝13.1Hz，2H)，2.88(br q，J＝12.1Hz，2H)，2.33(d，J＝6.7Hz，2H)，2.12-2.02(m，1H)，1.83(br d，J＝13.4Hz，2H)，1.44(br q，J＝12.2Hz，2H)。ESI-MS m/z：295.1(M+H)+。
Example 5a 2- (1-acetyl-piperidin-4-yl) -N-biphenyl-4-yl-acetamide
To a solution of N-biphenyl-4-yl-2-piperidin-4-yl-acetamide HCl (15mg, 0.05mmol) in dichloromethane (0.5ml) was added triethylamine (0.1ml, 0.7mmol) followed by acetyl chloride (0.05ml, 0.73mmol) at room temperature. After stirring at room temperature for 10 minutes, the reaction mixture was placed on a 1g silica SPE cartridge. Elution with ethyl acetate followed by evaporation of the solvent gave 10mg of the title compound. NMR (400MHz, CDCl)3)δ8.02(br s，1H)，7.58(br d，J＝8.0Hz，2H)，7.50-7.47(m，4H)，7.35(t，J＝7.3Hz，2H)，7.25(t，J＝7.3Hz，1H)，4.56(br s，1H)，3.74(br s，1H)，3.03(br s，1H)，2.53(br s，1H)，2.24(br s，2H)，2.17(m，1H)，1.97(2，3H)，1.79(br s，2H)，1.13(br s，2H)。LC-MS(m/z)337.1(MH+)；tR1.18min (method B).
The following compounds were prepared in a similar manner to that described above:
EXAMPLE 5b acetic acid 2- [4- (Biphenyl-3-ylcarbamoylmethyl) -piperidin-1-yl ] -2-oxo-ethyl ester
From N-biphenyl-3-yl-2-piperidin-4-yl-acetamide and acetoxyacetyl chloride. LC-MS (m/z)395.1 (MH)+)；tR1.23min (method B)
Example 5c 2- (1-acetyl-piperidin-4-yl) -N-biphenyl-3-yl-acetamide
From N-biphenyl-3-yl-2-piperidin-4-yl-acetamide and acetyl chloride. LC-MS (m/z)337.1 (MH)+)；tR1.18min (method B).
Example 5d N-Biphenyl-4-yl-2- (1-propionyl-piperidin-4-yl) -acetamide
From N-biphenyl-4-yl-2-piperidin-4-yl-acetamide and propionyl chloride. LC-MS (m/z)351.1 (MH)+)；tR1.27min (method B).
Example 5e N-Biphenyl-4-yl-2- (1-isobutyryl-piperidin-4-yl) -acetamide
From N-biphenyl-4-yl-2-piperidin-4-yl-acetamide and isobutyryl chloride. LC-MS (m/z)365.1 (MH)+)；tR1.35min (method B).
Example 5f N-Biphenyl-4-yl-2- (1-cyclopropanecarbonyl-piperidin-4-yl) -acetamide.
From N-biphenyl-4-yl-2-piperidin-4-yl-acetamide and cyclopropanecarbonyl chloride. LC-MS (m/z)363.1 (MH)+)；tR1.31min (method B).
EXAMPLE 5g acetic acid 2- [4- (biphenyl-4-ylcarbamoylmethyl) -piperidin-1-yl ] -2-oxo-ethyl ester
From N-biphenyl-4-yl-2-piperidin-4-yl-acetamide and acetoxyacetyl chloride. LC-MS (m/z)395.1 (MH)+)；tR1.22min (method B).
Example 5h N-Biphenyl-4-yl-2- [1- (3, 3, 3-trifluoro-propionyl) -piperidin-4-yl ] -acetamide
From N-biphenyl-4-yl-2-piperidin-4-yl-acetamide and 3, 3, 3-trifluoro-propionyl chloride. LC-MS (m/z)405.0 (MH)+)；tR1.38min (method B).
Example 5i 1- [1- (pyridine-4-carbonyl) -piperidin-4-yl ] -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
From 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and isonicotinoyl chloride hydrochloride.1H NMR(300MHz，CDCl3) δ 8.69(brs, 2H), 7.62-7.49(m, 4H), 7.33-7.26(m, 3H), 7.12-7.02(m, 2H), 6.77(tt, J ═ 8.9 and 2.3Hz, 1H), 4.82(d, J ═ 12.0Hz, 1H), 3.67(d, J ═ 12.2Hz, 1H), 3.01(t, J ═ 12.8Hz, 1H), 2.72(t, J ═ 12.1Hz, 1H), 1.92-1.69(m, 3H), 1.61-1.45(m, 2H), 1.07(m, 2H), 0.83(m, 2H). LC-MS (m/z)462.0 (MH)+)；tR1.27min (method a).
Example 5j 1- (1-Cyclobutanecarbonyl-piperidin-4-yl) -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
From 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and cyclobutanecarbonyl chloride.1H NMR(300MHz，CDCl3) δ 7.60-7.55(m, 2H), 7.52-7.48(m, 2H), 7.33(brs, 1H), 7.10-7.02(m, 2H), 6.79-6.72(tt, J ═ 8.9 and 2.3Hz, 1H), 4.72-4.63(m, 1H), 3.78-3.73(m, 1H), 3.23(m, 1H), 2.95-2.85(m, 1H), 2.53-2.43(m, 1H), 2.39-2.24(m, 2H), 2.18-2.06(m, 2H), 1.98-1.71(m, 5H), 1.39-1.23(m, 2H), 1.03(m, 2H), 0.80(m, 2H). LC-MS (m/z)439.0 (MH)+)；tR1.53min (method A).
Example 5k 1- (1-Cyclopentanecarbonyl-piperidin-4-yl) -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
From 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro)-biphenyl-4-yl) -amide and cyclopentanecarbonyl chloride.1H NMR(300MHz，CDCl3)δ7.60-7.56(m，2H)，7.53-7.49(m，2H)，7.32(brs，1H)，7.11-7.03(m，2H)，6.80-6.72(tt，J＝8.9and 2.3Hz，1H)，4.76(d，J＝13.1Hz，1H)，4.05(d，J＝13.6Hz，1H)，3.02-2.82(m，2H)，2.49(t，J＝10.5Hz，1H)，1.87-1.53(m，11H)，1.53-1.28(m，2H)，1.04(m，2H)，0.80(m，2H)。LC-MS(m/z)453.0(MH+)；tR1.61min (method a).
Example 5l 1- (1-Cyclohexanecarbonyl-piperidin-4-yl) -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
From 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and cyclohexanecarbonyl chloride.1H NMR(300MHz，CDCl3) δ 7.60-7.56(m, 2H), 7.52-7.49(m, 2H), 7.29(brs, 1H), 7.10-7.03(m, 2H), 6.79-6.72(tt, J ═ 8.9 and 2.3Hz, 1H), 4.75(d, J ═ 11.7Hz, 1H), 3.99(d, J ═ 12.2Hz, 1H), 2.98(t, J ═ 12.1Hz, 1H), 2.50-2.41(m, 3H), 1.89-1.22(m, 14H), 1.04(m, 2H), 0.80(m, 2H). LC-MS (m/z)467.0 (MH)+)；tR1.66min (method A)
Example 5m 1- [1- (pyridine-2-carbonyl) -piperidin-4-yl ] -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
Prepared from 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and picolinoyl chloride hydrochloride.1H NMR(300MHz，CDCl3)δ8.58(d，J＝4..5Hz 1H)，7.79(dt, J ═ 7.7 and 1.7Hz, 1H), 7.61-7.57(m, 3H), 7.52-7.48(m, 2H), 7.37-7.31(m, 2H), 7.11-7.03(m, 2H), 6.76(tt, J ═ 8.9 and 2.3Hz, 1H), 4.85(d, J ═ 12.8Hz, 1H), 3.98(d, J ═ 13.5Hz, 1H), 3.06(t, J ═ 12.5Hz, 1H), 2.77(t, J ═ 10.7Hz, 1H), 1.93-1.84(m, 2H), 1.75-1.70(m, 1H), 1.59-1.44(m, 2H), 1.05(m, 2H), 0.84(m, 2H). LC-MS (m/z)462.0 (MH)+)；tR1.32min (method a).
Example 5n 1- [1- (3-cyano-benzoyl) -piperidin-4-yl ] -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
From 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and 3-cyanobenzoyl chloride.1H NMR(300MHz，CDCl3) δ 7.72-7.67(m, 2H), 7.65-7.61(dt, J ═ 7.9 and 1.4Hz, 1H), 7.60-7.48(m, 5H), 7.31(brs, 1H), 7.11-7.02(m, 2H), 6.76(tt, J ═ 8.9 and 2.3Hz, 1H), 4.91(brs, 1H), 3.70(brs, 1H), 3.04(brs, 1H), 2.73(brs, 1H), 1.87-1.73(m, 3H), 1.50(brs, 2H), 1.07(m, 2H), 0.84(m, 2H). LC-MS (m/z)486.0 (MH)+)；tR1.48min (method A).
Example 5o 1- [1- (2-trifluoromethyl-benzoyl) -piperidin-4-yl ] -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
Prepared from 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and 2-trifluoromethylbenzoyl chloride.1H NMR(300MHz，CDCl3)δ7.74-7.66(m，1H)，7.60-7.47(m，6H)，7.40-7.26(m，2H)，7.10-7.02(m，2H)，6.80-6.71(m，1H)，4.92-4.82(m，1H)，3.51-3.31(m，1H)，3.07-2.87(m，1H)，2.78-2.65(m，1H)，1.91-1.23(m，5H)，1.04(m，2H)，0.80(m，2H)。LC-MS(m/z)529.0(MH+)；tR1.62min (method a).
Example 5p 1- [1- (pyrazine-2-carbonyl) -piperidin-4-yl ] -cyclopropanecarboxylic acid (3, 5-difluoro-biphenyl-4-yl) -amide
From 1-piperidin-4-yl-cyclopropanecarboxylic acid (3 ', 5' -difluoro-biphenyl-4-yl) -amide and pyrazine-2-carbonyl chloride.1H NMR(300MHz，CDCl3) δ 8.90(d, J ═ 1.5Hz, 1H), 8.62(d, J ═ 2.5Hz, 1H), 8.53(dd, J ═ 2.5 and 1.5Hz, 1H), 7.61-7.56(dt, J ═ 8.7 and 2.4Hz, 2H), 7.52-7.48(dt, J ═ 8.7 and 2.3Hz, 2H), 7.34(brs, 1H), 7.09-7.03(m, 2H), 6.78-6.72(tt, J ═ 8.8 and 2.3Hz, 1H), 4.87-4.82(m, 1H), 4.05-4.00(m, 1H), 3.12-3.05(dt, J ═ 13.0 and 2.5Hz, 1H), 2.81-2.73 (m, 1H), 2.84-4.05 (m, 1H), 1H), 3.12-3.05(dt, J ═ 13.0 and 2.5Hz, 1H). LC-MS (m/z)462.9 (MH)+)；tR1.28min (method a).
Example 5q N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (2-methyl-2H-pyrazole-3-carbonyl) -piperidin-4-yl ] -isobutyramide
From N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and 2-methyl-2H-pyrazole-3-carbonyl chloride.1H NMR(400MHz，CDCl3) δ 8.46(dd, J ═ 2.4 and 0.6Hz, 1H), 8.35(dd, J ═ 8.8 and 0.6Hz, 1H), 8.16(brs, 1H), 7.89(dd, J ═ 8.7 and 2.5H)z, 1H), 7.43(d, J ═ 2.0Hz, 1H), 7.10-7.04(m, 2H), 6.83(tt, J ═ 8.8 and 2.3Hz, 1H), 6.29(d, J ═ 2.0Hz, 1H), 4.80(brs, 1H), 4.09(brs, 1H), 3.96(s, 3H), 3.06(brs, 1H), 2.73(brs, 1H), 2.04(tt, J ═ 12.2 and 2.8Hz, 1H), 1.70(m, 2H), 1.36-1.25(m, 2H), 1.30(s, 6H). LC-MS (m/z)467.9 (MH)+)；tR1.33min (method a).
Example 5r N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (isoxazole-5-carbonyl) -piperidin-4-yl ] -isobutyramide
From N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and isoxazole-5-carbonyl chloride.1H NMR(300MHz，CDCl3) δ 8.46(d, J ═ 2.5Hz, 1H), 8.35(d, J ═ 8.7Hz, 1H), 8.30(d, J ═ 1.9Hz, 1H), 8.14(brs, 1H), 7.88(dd, J ═ 8.8 and 2.6Hz, 1H), 7.09-7.05(m, 2H), 6.86-6.80(m, 1H), 6.74(d, J ═ 1.7Hz, 1H), 4.75(m, 1H), 4.26(m, 1H), 3.13(m, 1H), 2.79(m, 1H), 2.07(m, 1H), 1.82-1.37(m, 4H), 1.30(s, 6H). LC-MS (m/z)454.9 (MH)+)；tR1.39min (method a).
Example 5s N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (thiazole-2-carbonyl) -piperidin-4-yl ] -isobutyramide
Prepared from N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and 1, 3-thiazole-2-carbonyl chloride.1H NMR(300MHz，CDCl3) δ 8.46(d, J ═ 2.3Hz, 1H), 8.36(d, J ═ 8.8Hz, 1H), 8.13(brs, 1H), 7.88(dd, J ═ 8.5 and 2.2Hz, 1H), 7.86(d, J ═ 3.2Hz, 1H), 7.5 (J ═ 3.2Hz, 1H), 7.51(d, J ═ 3.2Hz, 1H), 7.09-7.05(m, 2H), 6.83(tt, J ═ 8.6 and 2.3Hz, 1H), 5.59(d, J ═ 12.3Hz, 1H), 4.82(d, J ═ 11.4Hz, 1H), 3.10(t, J ═ 13.9Hz, 1H), 2.79(t, J ═ 12.2Hz, 1H), 2.07(m, 1H), 1.81-1.43(m, 4H), 1.30(s, 6H). LC-MS (m/z)470.8 (MH)+)；tR1.52min (method a).
Example 5t N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (1H-pyrrole-2-carbonyl) -piperidin-4-yl ] -isobutyramide
From N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and 1H-pyrrole-2-carboxylic acid.1H NMR(400MHz，CDCl3) δ 9.40(brs, 1H), 8.46(dd, J ═ 2.5 and 0.6Hz, 1H), 8.36(dd, J ═ 8.7 and 0.6Hz, 1H), 8.17(brs, 1H), 7.89(dd, J ═ 8.6 and 2.5Hz, 1H), 7.10-7.04(m, 2H), 6.90(dt, J ═ 2.6 and 1.2Hz, 1H), 6.83(tt, J ═ 8.8 and 2.3Hz, 1H), 6.50(m, 1H), 6.23(m, 1H), 4.72(d, J ═ 13.1Hz, 2H), 2.94(brs, 2H), 2.05(m, 1H), 1.74(d, J ═ 12.4, 2H), 1.45H, 1H), 1.35(m, 1H). LC-MS (m/z)452.9 (MH)+)；tR1.44min (method a).
Example 5u N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (1H-imidazole-4-carbonyl) -piperidin-4-yl ] -isobutyramide
From N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and 1H-imidazole-4-carboxylic acid.1H NMR(400MHz，CDCl3) δ 8.46(dd, J ═ 2.5 and 0.6Hz, 1H), 8.36(dd, J ═ 8.7 and 0.6Hz, 1H), 8.23(brs, 1H), 7.89(dd, J ═ 8.7 and 2.5Hz, 1H),7.46(dd, J ═ 1.7 and 0.8Hz, 1H), 7.11 to 7.04(m, 2H), 6.96(dd, J ═ 3.5 and 0.8Hz, 1H), 6.83(tt, J ═ 8.8 and 2.3Hz, 1H), 6.46(dd, J ═ 3.4 and 1.8Hz, 1H), 4.65(brs, 2H), 2.87(m, 2H), 2.04(tt, J ═ 12.3 and 3.3Hz, 1H), 1.74(d, J ═ 12.7Hz, 2H), 1.47 to 1.34(m, 2H), 1.29(s, 6H). LC-MS (m/z)454.0 (MH)+)；tR1.14min (method a).
Example 5v N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (furan-2-carbonyl) -piperidin-4-yl ] -isobutyramide
From N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and furan-2-carboxylic acid. LC-MS (m/z)453.8 (MH)+)；tR1.46min (method A).
Example 5w N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (pyridine-2-carbonyl) -piperidin-4-yl ] -isobutyramide
Prepared from N- (3 ', 5' -difluoro-biphenyl-4-yl) -2-piperidin-4-yl-isobutyramide and picolinoyl chloride hydrochloride.1H NMR(300MHz，CDCl3) δ 8.57(d, J ═ 4.7Hz, 1H), 8.46(d, J ═ 2.2Hz, 1H), 8.35(d, J ═ 8.7Hz, 1H), 8.11(brs, 1H), 7.87(dd, J ═ 8.7 and 2.4Hz, 1H), 7.78(dt, J ═ 7.7 and 1.7Hz, 1H), 7.60(d, J ═ 7.8Hz, 1H), 7.32(m, 1H), 7.10-7.03(m, 2H), 6.82(tt, J ═ 8.8 and 2.3Hz, 1H), 4.86(d, J ═ 13.1Hz, 1H), 4.02(d, J ═ 11.2Hz, 1H), 3.05(m, 1H), 2.81(m, 1H), 1H, 7.7.7.7 (d, 1H), 1H, 7.7.7.7.7 (m, 1H). LC-MS (m/z)464.9 (MH)+)；tR1.31min (method a).
The following higher order intermediates used in the schemes indicated above can be synthesized as follows:
● hexahydro-pyrrolo [1, 2-a ] pyrazin-6-one and its stereoisomers may be prepared according to Christensen et al WO 08/46882;
● 1- ((S) -2-methyl-piperazin-1-yl) -ethanone and 1- ((R) -2-methyl-piperazin-1-yl) -ethanone can be prepared according to Shima et al WO 98/35951;
● 1- ((R) -3-methyl-piperazin-1-yl) -ethanone and 1- ((S) -3-methyl-piperazin-1-yl) -ethanone can be prepared according to Manetti et al J.Med.chem., 2000, 43, 4499-;
● (S) -hexahydro-1-thia-5, 7 a-diaza-indene 1, 1-dioxide may be prepared according to Alvaro et al WO 07/028654;
● (1-acetyl-piperidin-4-yl) -acetic acid can be prepared according to Orjales et al J.Med.chem., 2003, 46, 5512-acid 5532;
● (1-methanesulfonyl-piperidin-4-yl) -acetic acid may be prepared according to Tsuchimori et al WO 03/090748; and
● Tert-butyl 4-carboxymethyl-4-methyl-piperidine-1-carboxylate can be prepared according to Faull et al WO 2006/0017152.
Example 6 in vitro pharmacological evaluation of cloned neuropeptide Y5 receptor
The pharmacological properties of the compounds of the invention against the cloned human NPY Y5 receptor were evaluated using the protocols disclosed in us patent 6,124,331, the contents of which are incorporated herein by reference. Procedures for cell culture, transient transfection and membrane harvest (membrane harvest) well known in the art are described therein.
Radioligands bound to membrane suspensions
Briefly, membrane suspensions from transfected cells (typically expressed in LM (tk-) cells) and125I-PYY radioligand (PerkinElmer, Waltham, Mass.) was diluted in binding buffer supplemented with 0.1% bovine serum albumin to give the optimal membrane protein concentration for membrane binding in the assay (assay)125I-PYY less than delivered to sample12510% of I-PYY (for competitive binding assays, 100,000 dpm/sample 0.08 nM). Test compounds were diluted to the desired concentration with supplemental binding buffer in the presence of 30% DMSO. In a 96-well polypropylene microtiter plate, the wells were prepared by mixing125I-PYY, test compound (25. mu.L) and finally membrane suspension (200. mu.L) were mixed and a binding assay was performed. Final DMSO 3%. The samples were incubated at room temperature for approximately 120 minutes. The incubation was terminated by filtration through Whatman GF/C filters (pre-coated with 1% polyethyleneimine and air-dried before use) followed by washing with ice-cold binding buffer. The filter-retained membranes were impregnated with Meltolex solid scintillator (Wallac, Turku, Finland) and paired in a Wallac MicroBeta Trilux125I-PYY was counted. Nonspecific binding was defined by 1000nM porcine NPY. Specific binding is typically 80%; most of the non-specific binding is associated with the filter. Binding data was analyzed using non-linear regression and statistical techniques available in the GraphPAD Prism package (San Diego, Calif).
Results of radioligand binding assays
In the present invention, the binding affinity of the above exemplified compounds to the human NPY Y5 receptor was determined to be 10. mu.M or less. The binding affinity of most compounds was determined to be 1.0. mu.M or less. The binding affinity of some compounds was determined to be 100nM or less.
Table I: binding affinity of selected compounds
Fruit of Chinese wolfberryExample number Ki(nM)
1a 220
1e 120
2a 46
2aj 28
3a 36
3i 50
3l 25
3o 17
3cc 8
3hh 39
4a 66
5a 120
5j 2.7
5m 14
5q 570
And (4) functional test: NPY Y5-dependent inhibition of forskolin-stimulated cAMP accumulation
Stably transfected cells were seeded into 96-well microtiter plates and cultured until confluent. To reduce the possibility of receptor desensitization, the serum component of the medium was reduced to 1.5% and held for 4 to 16 hours prior to testing. HBS (150mM NaCl, 20mM HEPES, 1mM CaCl) supplemented with 0.1% bovine serum albumin plus 100. mu.M MIBMX in Hank's buffered saline or HBS supplemented with 0.1% bovine serum albumin2，5mM KCl，1mMMgCl2And 10mM glucose). Test compounds were diluted to the desired concentration with assay buffer in the presence of 10% DMSO, then transferred to cell plates and allowed to incubate at 37 ℃ in 5% CO2Incubate for 20min (final DMSO ═ 1%). Cells were then stimulated with NPY (up to 10 μ M) for a period of 5 minutes, followed by stimulation with forskolin (10 μ M) for an additional 5 minutes. The assay was then terminated and intracellular cAMP was quantified using high throughput time-resolved fluorescence (HTRF kit from CisBio, Bedford, Mass.). The effect of test compounds on agonist (NPY) activity was analyzed using non-linear regression and statistical techniques available from GraphPAD Prism package (San Diego, CA).
Results of functional tests
The compounds of examples 2a and 4a were tested for their function as NPY Y5 receptor antagonists. Compounds of the invention were selected and tested for NPY5 binding and functional activity in the assays described above or similar assays described herein.
Example 7: in vivo assay
The in vivo effects of the compounds of the present invention can be evaluated by using the following in vivo behavioral animal models. The behavioral models described below are not intended to be the only models used to determine the efficacy of the compounds of the present invention for treating the corresponding conditions.
Agonist stimulated feeding test.Catheters were implanted into the lateral ventricles of Sprague-Dawley rats (250-275g) at Charles River Laboratories (Kingston, NY) and transported to the animal research laboratory 2-3 days later. Successful catheter placement was confirmed by a strong drinking water response to i.c.v. infusion of angiotensin II (100 μ g) after 1 week of acclimation period. Rats were acclimated to a cage with a wire grid floor (suspended above a waste tray with a stainless steel rack) at least 5 days prior to the start of the feeding study. The food was removed in the morning of the test. To study the Compound Pair Y5Inhibition of receptor-induced feeding animals were given either vehicle (20% cyclodextrin in distilled water) or compound alone orally, 1 hour later, i.c.v. infusion (5 μ l over 1 minute) of Y5Receptor selective peptide agonist cPP (0.6nmol in physiological saline). The cPP dose of 0.6nmol was chosen because it was well below ED50Dose (0.75nmol) (determined by preliminary experiments, data not shown), and provided a robust (robust) feeding signal. The animals were returned to the feeding cage and a pre-weighed amount of food was prepared, providing 1 hour. Net food intake-pre-weighed amount- (final amount + spilled amount). To test for non-specific inhibition of feeding response, we evaluated the effect of compound (30mg/kg) on 2nmol NPY (the dose that elicits the feeding response, equivalent to 0.6nmol cPP) induced feeding.
Forced (forced) swimming test in rats.The procedure which can be used here is the same as that described previously (Luki et al, Psychopharmacology 2001, 15)5,315-. Male Sprague-Dawley rats may be used. The rats were placed in a plexiglas cylinder (approximately 46cm high by 20cm diameter) filled with water to a depth of 30cm at approximately 23 ℃ for a swimming session of approximately 5 minutes. The compound of the invention or excipient (about 0.01% lactic acid, about pH6) was administered orally as a 1ml/kg solution. Trial sessions were videotaped and subsequent scores were recorded by a single rater (rater) blinded to the treatment status. Immobility was scored as the rat remained floating in the water, but moved to keep its head above the water surface. Swimming was scored as the rat underwent active swimming movements, more than necessary to keep its head above the water.
Rat Social interaction test. The procedure was carried out for approximately 15 minutes under low light conditions using pairs of strange male Sprague-Dawley rats (previously placed alone and exposed to the test site for approximately 15 minutes on the previous day) as previously described (File and Hyde br.j. pharmacol.1987, 62, 19-24). i.p. injection of a Compound of the invention, chlorine nitrogen, as a solution of about 1.0ml/kgOr an excipient. All experimental phases were recorded and recorded for subsequent scoring. Active social interactions (defined as sniffing, combing (groming), biting, paw-hitting (boosting) and crawling up and down) and motor activity (defined as criss-crossing (squares cross)) were scored by a single evaluator, who was blinded to the treatment of each pair of rats.
Chronic mild stress.As previously described (Papp et al, 2002), a Chronic Mild Stress (CMS) assay was performed using male Wistar rats. Rats were first trained to consume a 1% sucrose solution in a series of baseline trials during which the sucrose solution was provided in a home cage (home cage) for 1 hour after providing 14 hours of food and depriving water. Animals were scored based on their final sucrose intakeTwo matched groups were divided, one group was continuously subjected to chronic mild stress for 8-9 consecutive weeks, and the other group was placed alone as a non-stressed control group. During the training period, both groups were subjected to the sucrose consumption test once a week (approximately 10:00 am, and under similar conditions). After 2-3 weeks of stress, the stressed and control animals were further divided into matched groups (n-8 per group) using sucrose intake scoring. For the next 5 weeks, stressed and control animals received twice daily intraperitoneal injections of vehicle (0.25% hydroxypropyl beta methylcellulose, 1ml/kg), compound of the invention or citalopram (i.p. injections at approximately 10:00 and 17:00, except 17:00 were omitted on the days of the preceding sucrose test). After 5 weeks, i.p. injections were terminated in both groups. Twenty-four hours after the final i.p. injection, all animals were sacrificed and brains were removed.

Claims (21)

1. A compound of formula I:
formula I
Wherein R is1Is pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, wherein the pyrazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridylPyrimidinyl and pyrazinyl optionally substituted with one or more R4Substitution;
wherein R is2Is C1-C7Alkyl radical, C1-C7Alkoxy, NH (C)1-C7Alkyl group), (CH)2)vOC(O)C1-C7Alkyl radical, C3-C7Cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, furyl, or pyrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, furyl, and pyrazolyl are optionally substituted with one or more R5Substitution;
wherein R is3Is H or C1-C7Alkyl, or wherein R3Can be reacted with R2Combined to form optionally coated C1-C4Alkyl substituted C1-C4An alkylene group;
wherein R is4Is C1-C7An alkyl group; c1-C7A perfluoroalkyl group; c (O) C1-C7An alkyl group; or optionally with one or more C1-C7Alkyl radical, C1-C7Perfluoroalkyl group, C1-C7Alkoxy or halogen substituted phenyl;
wherein R is5Is C1-C7Alkyl radical, C1-C7Perfluoroalkyl group, C1-C7Alkoxy or halogen;
wherein A is CH, COH or N;
wherein X is S (O)2；
Wherein each RaAnd RbIndependently is H or C1-C7Alkyl, or wherein RaAnd RbCan be combined to form C3-C7A cycloalkyl group;
wherein each RcIndependently is H or C1-C7An alkyl group;
wherein each m and v is independently an integer from 1 to 4; and
wherein n is an integer of 0 to 2.
2. The compound of claim 1, wherein R1Is optionally substituted by one or more R4A substituted pyridyl group.
3. The compound of claim 1, wherein R1Is optionally substituted by one or more R4Substituted [1,3 ]]A pyrazolyl group.
4. The compound of claim 1, wherein R1Is pyrimidinyl or pyrazinyl, wherein said pyrimidinyl or pyrazinyl is optionally substituted with one or more R4And (4) substitution.
5. The compound of claim 1, wherein a is CH; wherein n is 1.
6. The compound of claim 1, wherein a is N; wherein n is 1 or 2.
7. The compound of claim 1, wherein R2Is C3-C6A cycloalkyl group; wherein R is3Is H or C1-C4An alkyl group.
8. The compound of claim 1, wherein R2Is C1-C7Alkoxy, NH (C)1-C4Alkyl) or (CH)2)vC(O)C1-C4An alkyl group; wherein R is3Is H or C1-C4An alkyl group; wherein v is 1 or 2.
9. The compound of claim 1, wherein R2And R3Combine to form methylene.
10. The compound of claim 1, wherein R2Is optionally substituted by one or more R5Substituted byA phenyl group.
11. The compound of claim 1, wherein R2Is a pyridyl, pyrimidinyl, pyrazinyl or triazinyl group, wherein said pyridyl, pyrimidinyl, pyrazinyl and triazinyl group is optionally substituted with one or more R5And (4) substitution.
12. The compound of claim 1, wherein R2Is tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl and pyrazolyl, wherein the tetrazolyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl and pyrazolyl are optionally substituted with one or more R5And (4) substitution.
13. The compound of claim 1, wherein each RaAnd RbIndependently is H or C1-C4An alkyl group; wherein m is 0 or 1.
14. The compound of claim 1, wherein RaAnd RbForm C by bonding3-C7A cycloalkyl group; wherein m is 0 or 1.
15. The compound of claim 1, wherein each RcIndependently is H or C1-C4An alkyl group; wherein m is 0 or 1.
16. The compound of claim 1, wherein R4Is optionally substituted by one or more C1-C4Alkyl radical, C1-C4Alkoxy, fluorine or chlorine substituted phenyl.
17. The compound of claim 1, wherein R4Is C1-C4Alkyl or C1-C4A perfluoroalkyl group.
18. The compound of claim 1, wherein R5Is C1-C4Alkyl, fluoro or chloro.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
20. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cognitive disorders.
21. The compound of claim 1 selected from the group consisting of N- [6- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide, N- [6- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -2- [1- (propane-1-sulfonyl) -piperidin-4-yl ] -acetamide, N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide, N- [5- (3, 5-difluoro-phenyl) -pyridin-2-yl ] -2- [1- (propane-1-sulfonyl) -piperidin-4-yl ] -acetamide and N- [5- (2-fluoro-phenyl) -pyridin-2-yl ] -2- (1-methanesulfonyl-piperidin-4-yl) -acetamide.
HK12105590.9A 2008-11-07 2009-11-02 Biologically active amides HK1164867B (en)

Applications Claiming Priority (5)

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US11233308P 2008-11-07 2008-11-07
US61/112333 2008-11-07
US16185409P 2009-03-20 2009-03-20
US61/161854 2009-03-20
PCT/US2009/062956 WO2010053861A2 (en) 2008-11-07 2009-11-02 Biologically active amides

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HK1164867B true HK1164867B (en) 2014-07-04

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