Patent Grant
8772300
This application claims the benefit of European Patent Application No. 11162945.7, filed Apr. 19, 2011 and European Patent Application No. 11185137.4, filed Oct. 14, 2011, which is hereby incorporated by reference in its entirety.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency (Expert Opin. Ther. Patents (2002), 12, (12)).
A new avenue for developing selective modulators is to identify compounds which act through allosteric mechanism, modulating the receptor by binding to site different from the highly conserved orthosteric binding site. Positive allosteric modulators of mGluR5 have emerged recently as novel pharmaceutical entities offering this attractive alternative. Positive allosteric modulators have been described, for example in WO2008/151184, WO2006/048771, WO2006/129199 and WO2005/044797 and in Molecular Pharmacology, 40, 333-336, 1991; The Journal of Pharmacology and Experimental Therapeutics, Vol 313, No. 1, 199-206, 2005;
Positive allosteric modulators are compounds that do not directly activate receptors by themselves, but markedly potentiate agonist-stimulated responses, increase potency and maximum of efficacy. The binding of these compounds increase the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Positive allosteric modulation is thus an attractive mechanism for enhancing appropriate physiological receptor activation. There is a scarcity of selective positive allosteric modulators for the mGluR5 receptor. Conventional mGluR5 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral bioavailability. Therefore, there remains a need for compounds that overcome these deficiencies and that effectively provide selective positive allosteric modulators for the mGluR5 receptor.
The present invention provides ethynyl derivatives of formula I
wherein
Compounds of formula I are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5).
Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of disorders, relating to positive allosteric modulators for the mGluR5 receptor.
The most preferred indications for compounds which are positive allosteric modulators are schizophrenia and cognition.
The present invention provides compounds of formula I and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, processes for their production, and their use in the treatment or prevention of disorders relating to positive allosteric modulators for the mGluR5 receptor, such as schizophrenia, tuberous sclerosis, and cognition.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1-4 carbon atoms. Examples for “alkyl” are methyl, ethyl, n-propyl, and isopropyl.
The term “lower alkyl substituted by halogen” denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen. Preferred is the group CF3.
The term “alkoxy” denotes a group —O—R′ wherein R′ is lower alkyl as defined above.
The term “halogen” denotes fluoro, chloro, bromo or iodo.
The term “C3-5cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 5 ring carbon atoms. Examples are cyclopropyl, cyclobutanyl, and cyclopentyl.
The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
The term “therapeutically effective amount” denotes an amount of a compound of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
One embodiment of the invention provides compounds of formula,
wherein
The following compounds of formula IA have been prepared:
A further embodiment of the invention provides compounds of formula I, wherein R1 is phenyl, optionally substituted by halogen, for example the following compounds
A further embodiment of the invention provides compounds of formula I, wherein R1 is pyridinyl, optionally substituted by halogen, for example the following compounds
One further embodiment of the invention provides compounds of formula I-1
wherein
Another embodiment of the invention provides compounds of formula I-2
wherein
The preparation of compounds of formula I of the present invention can be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following scheme 1. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before.
The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods, known in the art, for example by the process variants described below, which process comprises
a) reacting a compound of formula
with a suitable compound of formula
R1-hal 7
to form a compound of formula
wherein the substituents are described above or
b) reacting a compound of formula
with a suitable compound of formula
to form a compound of formula
c) reacting a compound of formula
with a suitable compound of formula
to form a compound of formula
wherein the substituents are described above or if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
The preparation of compounds of formula I is further described in more detail in schemes 1, 2 and 3 and in examples 1-68.
An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can be obtained for example by reacting a 5-bromo-pyridine-2-carboxylic acid or 5-bromo-pyrimidine-2-carboxylic acid 1 with an appropriate amine 2 in presence of a base such as Hunig's Base and a peptide coupling reagent such as TBTU in a solvent such as dioxane or by preparing in-situ the corresponding acid chloride with oxalyl chloride and DMF (cat.) in a solvent such as dichloromethane followed by reaction with the amine 2 in the presence of a base such as pyridine. Sonogashira coupling of the 5-bromo-pyridine-2-carboxylic acid amide or 5-bromo-pyrimidine-2-carboxylic acid amide 3 with an appropriately substituted arylacetylene 4 yield the desired ethynyl compounds of general formula I (scheme 1). Introduction of the R2′ substituent can also be realized at various points in the synthetic sequence via alkylation of the corresponding intermediate where R2′═H.
An ethynyl-pyridine or ethynyl-pyrimidine compound of formula I can be obtained by Sonogashira coupling of a 5-bromo-pyridine-2-carboxylic acid amide or 5-bromo-pyrimidine-2-carboxylic acid amide 3 with ethynyltrimethylsilane 5 to yield the corresponding 5-trimethylsilanylethynyl-derivatives 6. Sonogashira coupling with in-situ desilylation of 6 and an appropriately substituted aryl-halogenide 7 yields the desired ethynyl-pyridine or ethynyl-pyrimidine compounds of formula I (scheme 2). Introduction of the R2′ substituent can also be realized at various points in the synthetic sequence via alkylation of the corresponding intermediate where R2′═H.
Generally speaking, the sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases, for example by first running the Sonogashira coupling with 5-bromo-pyridine-2-carboxylic acid methyl ester or 5-bromo-pyrimidine-2-carboxylic acid methyl ester 8 and an appropriately substituted arylacetylene 4 followed by saponification with a base such as LiOH to yield the corresponding acid 9. Reacting the corresponding acid 9 with an appropriate amine 2 in presence of a base such as Hunig's Base and a peptide coupling reagent such as TBTU in a solvent such as dioxane or by preparing in-situ the corresponding acid chloride with oxalyl chloride and DMF (cat.) in a solvent such as dichloromethane followed by reaction with the amine 2 in the presence of a base such as pyridine yield the desired ethynyl compounds of general formula I (scheme 3). Introduction of the R2′ substituent can also be realized at various points in the synthetic sequence via alkylation of the corresponding intermediate where R2═H.
Preferably, the compound of formula I as described herein as well as its pharmaceutically acceptable salt is used in the treatment or prevention of psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, chronic and acute pain, restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments, muscle spasms, convulsions, migraine, urinary incontinence, gastrointestinal reflux disorder, liver damage or failure whether drug or disease induced, Fragile-X syndrome, Down syndrome, autism, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, eating disorders, in particular bulimia or anorexia nervosa, and depressions, particularly for the treatment and prevention of acute and/or chronic neurological disorders, anxiety, the treatment of chronic and acute pain, urinary incontinence and obesity.
The preferred indications are schizophrenia and cognitive disorders.
Present invention further relates to the use of a compound of formula I as described herein, as well as its pharmaceutically acceptable salt, for the manufacture of a medicament, preferably for the treatment and prevention of the above-mentioned disorders.
A monoclonal HEK-293 cell line stably transfected with a cDNA encoding for the human mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow the differentiation of agonistic versus PAM activity. Cells were cultured according to standard protocols (Freshney, 2000) in Dulbecco's Modified Eagle Medium with high glucose supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50 μg/ml hygromycin and 15 μg/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland).
About 24 hrs before an experiment, 5×104 cells/well were seeded in poly-D-lysine coated, black/clear-bottomed 96-well plates. The cells were loaded with 2.5 μM Fluo-4AM in loading buffer (1×HBSS, 20 mM HEPES) for 1 hr at 37° C. and washed five times with loading buffer. The cells were transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions of test compound at 37° C. were added and the cells were incubated for 10-30 min with on-line recording of fluorescence. Following this pre-incubation step, the agonist L-glutamate was added to the cells at a concentration corresponding to EC20 (typically around 80 μM) with on-line recording of fluorescence; in order to account for day-to-day variations in the responsiveness of cells, the EC20 of glutamate was determined immediately ahead of each experiment by recording of a full dose-response curve of glutamate.
Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence without addition of L-glutamate), normalized to the maximal stimulatory effect obtained with saturating concentrations of L-glutamate. Graphs were plotted with the % maximal stimulatory using XLfit, a curve fitting program that iteratively plots the data using Levenburg Marquardt algorithm. The single site competition analysis equation used was y=A+((B−A)/(1+((x/C)D))), where y is the % maximal stimulatory effect, A is the minimum y, B is the maximum y, C is the EC50, x is the log 10 of the concentration of the competing compound and D is the slope of the curve (the Hill Coefficient). From these curves the EC50 (concentration at which half maximal stimulation was achieved), the Hill coefficient as well as the maximal response in % of the maximal stimulatory effect obtained with saturating concentrations of L-glutamate were calculated.
Positive signals obtained during the pre-incubation with the PAM test compounds (i.e. before application of an EC20 concentration of L-glutamate) were indicative of an agonistic activity, the absence of such signals were demonstrating the lack of agonistic activities. A depression of the signal observed after addition of the EC20 concentration of L-glutamate was indicative of an inhibitory activity of the test compound.
In the table below are shown the prepared compounds 1-68 with corresponding results (EC50 in nM).
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as therapeutics, e.g. in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, the invention provides pharmaceutical compositions containing a compound of formula (I) or pharmaceutically acceptable salts thereof and a therapeutically inert excipient, a process for the production of such pharmaceutical compositions which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
As further mentioned earlier, the present invention provides the use of the compounds of formula (I) for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases.
The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Tablets of the following composition are produced in a conventional manner:
5-Bromopicolinic acid (200 mg, 0.99 mmol) was dissolved in dioxane (2 ml) and Hunig's Base (520 μl, 2.97 mmol, 3 equiv.), TBTU (350 mg, 1.09 mmol, 1.1 equiv.) and tert-butyl amine (124 μl, 1.19 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 50:50. The desired 5-bromo-pyridine-2-carboxylic acid tert-butylamide (235 mg, 92% yield) was obtained as a colorless oil, MS: m/e=257.0/259.0 (M+H+).
Bis-(triphenylphosphine)-palladium(II)dichloride (31 mg, 44.7 μmol, 0.05 equiv.) was dissolved in 2 ml DMF. (230 mg, 894 μmol) 5-Bromo-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) and phenylacetylene (183 mg, 196 μl, 1.79 mmol, 2 equiv.) were added at room temperature. Triethylamine (272 mg, 374 μl, 2.68 mmol, 3 equiv.), triphenylphosphine (7 mg, 26.8 μmol, 0.03 equiv.) and copper(I)iodide (5 mg, 26.8 μmol, 0.03 equiv.) were added and the mixture was stirred for 2 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (174 mg, 70% yield) was obtained as a light yellow solid, MS: m/e=279.1 (M+H+).
(74 mg, 266 μmol) 5-Phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 2) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (14 mg, 319 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (22 μl, 346 μmol, 1.3 equiv.) was added, and the mixture was then stirred for 1 hour at room temperature. The reaction mixture was evaporated and treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 g, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (48 mg, 62% yield) was obtained as a light yellow solid, MS: m/e=293.0 (M+H+).
The title compound was obtained as a white solid, MS: m/e=271.2/273.2 (M+H+), using chemistry similar to that described in Example 2 from 5-bromo-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) and iodomethane.
The title compound was obtained as a yellow solid, MS: m/e=289.2 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 1) and ethynyltrimethylsilane.
5-Trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) (60 mg, 0.2 mmol) was dissolved in DMF (1 ml). 1-Fluoro-3-iodobenzene (74 mg, 0.33 mmol, 1.6 equiv.), Et3N (87 μl, 0.62 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (7 mg, 10.4 μmol, 0.05 equiv.) and copper(I)iodide (0.4 mg, 2 μmol, 0.01 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (230 μl, 0.23 mmol, 1.1 equiv.) was added dropwise over a period of 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated in presence of Isolute® sorbent to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0→70:30. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-methyl-amide (64 mg, 99% yield) was obtained as a colorless oil, MS: m/e=311.5 (M+H+).
The title compound was obtained as a light yellow solid, MS: m/e=311.5 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) and 1-fluoro-4-iodobenzene.
The title compound was obtained as a light yellow solid, MS: m/e=329.1 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) and 1,4-difluoro-2-iodobenzene.
The title compound was obtained as a light yellow solid, MS: m/e=294.1 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) and 3-iodopyridine.
The title compound was obtained as a white solid, MS: m/e=328.1/330.0 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) and 3-chloro-5-iodopyridine.
The title compound was obtained as a white solid, MS: m/e=312.2 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 3, step 2) and 3-fluoro-5-iodopyridine.
5-Bromopyrimidine-2-carboxylic acid (1 g, 4.93 mmol) was suspended in dichloromethane (10 ml) and DMF (20 μl). Oxalyl chloride (520 μl, 5.91 mmol, 1.2 equiv.) was added drop wise at room temperature and the mixture was stirred for 16 hours. The reaction mixture was then cooled to 0-5° C. and pyridine (480 μl, 5.91 mmol, 1.2 equiv.) and tert-butyl amine (621 μl, 5.91 mmol, 1.2 equiv.) were added drop wise at 0-5° C. The mixture was stirred for 4 hours at room temperature. The reaction mixture was extracted with saturated NaHCO3 solution and dichloromethane. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The desired 5-bromo-pyrimidine-2-carboxylic acid tert-butylamide (960 mg, 76% yield) was obtained as a light yellow solid, MS: m/e=258.0/259.9 (M+H+).
5-Bromo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 1) (950 mg, 3.68 mmol) was dissolved in dioxane (10 ml). Sodium iodide (2.2 g, 14.7 mmol, 4 equiv.), copper(I)iodide (66 mg, 0.74 mmol, 0.2 equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (CAS 67579-81-1) (105 mg, 0.74 mmol, 0.2 equiv.) were added and the mixture was stirred for 16 hours at 100° C. The reaction mixture was extracted with saturated NaHCO3 solution and two times with ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (870 mg, 78% yield) was obtained as a yellow solid, MS: m/e=306.0 (M+H+).
The title compound was obtained as a yellow solid, MS: m/e=298.4 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 2) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a yellow solid, MS: m/e=298.5 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a white solid, MS: m/e=272.2/274.1 (M+H+), using chemistry similar to that described in Example 9, step 1 from 5-bromopyrimidine-2-carboxylic acid and tert-butyl-methyl-amine.
The title compound was obtained as a white solid, MS: m/e=319.9 (M+H+), using chemistry similar to that described in Example 9, step 2 from 5-bromo-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide (Example 11, step 1).
The title compound was obtained as a yellow solid, MS: m/e=312.3 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide (Example 11, step 2) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a light brown solid, MS: m/e=312.2 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide (Example 11, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as an orange oil, MS: m/e=294.0 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 2) and 1-ethynyl-3-methyl-benzene.
The title compound was obtained as a light yellow solid, MS: m/e=314.0/316.0 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butylamide (Example 9, step 2) and 1-chloro-3-ethynylbenzene.
The title compound was obtained as an orange solid, MS: m/e=290.1 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-iodo-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide (Example 11, step 2) and ethynyltrimethylsilane.
The title compound was obtained as a light yellow solid, MS: m/e=312.3 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide (Example 15, step 1) and 1,4-difluoro-2-iodobenzene.
The title compound was obtained as a light yellow solid, MS: m/e=329.0/331.2 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyrimidine-2-carboxylic acid tert-butyl-methyl-amide (Example 15, step 1) and 3-chloro-5-iodopyridine.
The title compound was obtained as a yellow oil, MS: m/e=285.0/286.9 (M+H+), using chemistry similar to that described in Example 9, step 1 from 5-bromo-3-methylpicolinic acid and tert-butyl-methyl-amine.
The title compound was obtained as a yellow solid, MS: m/e=325.3 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 17, step 1) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a yellow solid, MS: m/e=325.3 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 17, step 1) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a brown solid, MS: m/e=303.0 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 17, step 1) and ethynyltrimethylsilane.
The title compound was obtained as a white solid, MS: m/e=343.1 (M+H+), using chemistry similar to that described in Example 3, step 3 from 3-methyl-5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 19, step 1) and 1,4-difluoro-2-iodobenzene.
The title compound was obtained as a yellow solid, MS: m/e=342.1/344.0 (M+H+), using chemistry similar to that described in Example 3, step 3 from 3-methyl-5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 19, step 1) and 3-chloro-5-iodopyridine.
The title compound was obtained as a light yellow oil, MS: m/e=288.9/290.9 (M+H+), using chemistry similar to that described in Example 9, step 1 from 5-bromo-3-fluoropicolinic acid and tert-butyl-methyl-amine.
The title compound was obtained as a yellow oil, MS: m/e=329.0 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 21, step 1) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a light yellow solid, MS: m/e=329.1 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 21, step 1) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a light yellow solid, MS: m/e=307.3 (M+H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 21, step 1) and ethynyltrimethylsilane.
The title compound was obtained as a light yellow solid, MS: m/e=347.0 (M+H+), using chemistry similar to that described in Example 3, step 3 from 3-fluoro-5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 23, step 1) and 1,4-difluoro-2-iodobenzene.
The title compound was obtained as a white solid, MS: m/e=346.0/348.0 (M+H+), using chemistry similar to that described in Example 3, step 3 from 3-fluoro-5-trimethylsilanylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 23, step 1) and 3-chloro-5-iodopyridine.
The title compound was obtained as a light yellow solid, MS: m/e=239.8 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl ester and 1-ethynyl-3-fluoro-benzene followed by saponification with LiOH.
The title compound was obtained as a white solid, MS: m/e=295.1 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 25, step 1) and cyclobutanamine.
The title compound was obtained as a light yellow oil, MS: m/e=309.1 (M+H+), using chemistry similar to that described in Example 2 from 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid cyclobutylamide (Example 25, step 2) and iodomethane.
The title compound was obtained as a yellow solid, MS: m/e=297.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 25, step 1) and oxetan-3-amine hydrochloride.
The title compound was obtained as a light yellow solid, MS: m/e=271.1/273.1 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and 3-methyloxetan-3-amine.
The title compound was obtained as a white solid, MS: m/e=285.0/286.9 (M+H+), using chemistry similar to that described in Example 2 from 5-bromo-pyridine-2-carboxylic acid (3-methyl-oxetan-3-yl)-amide (Example 27, step 1) and iodomethane.
The title compound was obtained as a brown oil, MS: m/e=325.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide (Example 27, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a yellow oil, MS: m/e=325.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide (Example 27, step 2) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a yellow solid, MS: m/e=303.2 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide (Example 27, step 2) and ethynyltrimethylsilane.
The title compound was obtained as a yellow oil, MS: m/e=343.1 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide (Example 29, step 1) and 1,4-difluoro-2-iodobenzene.
The title compound was obtained as a yellow oil, MS: m/e=343.3 (M+H+), using chemistry similar to that described in Example 3, step 3 from 5-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl-(3-methyl-oxetan-3-yl)-amide (Example 29, step 1) and 1,2-difluoro-4-iodobenzene.
The title compound was obtained as a colorless oil, MS: m/e=255.0/257.0 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and 1-methylcyclopropanamine hydrochloride.
The title compound was obtained as a colorless oil, MS: m/e=269.1/271.1 (M+H+), using chemistry similar to that described in Example 2 from 5-bromo-pyridine-2-carboxylic acid (1-methyl-cyclopropyl)-amide (Example 31, step 1) and iodomethane.
The title compound was obtained as a yellow oil, MS: m/e=309.0 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(1-methyl-cyclopropyl)-amide (Example 31, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a yellow oil, MS: m/e=309.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(1-methyl-cyclopropyl)-amide (Example 31, step 2) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a white solid, MS: m/e=308.9/311.0 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and 1-(trifluoromethyl)cyclopropanamine.
The title compound was obtained as a colorless oil, MS: m/e=323.0/325.1 (M+H+), using chemistry similar to that described in Example 2 from 5-bromo-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide (Example 33, step 1) and iodomethane.
The title compound was obtained as a brown oil, MS: m/e=379.2/381.2 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide (Example 33, step 2) and 1-ethynyl-3-chloro-benzene.
The title compound was obtained as a brown oil, MS: m/e=359.0 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide (Example 33, step 2) and 1-ethynyl-3-methyl-benzene.
The title compound was obtained as a yellow solid, MS: m/e=339.3 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 25, step 1) and 2,2-dimethylmorpholine.
The title compound was obtained as a colorless oil, MS: m/e=299.2/301.1 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and 2,2-dimethylmorpholine.
The title compound was obtained as a yellow oil, MS: m/e=317.1 (M−H+), using chemistry similar to that described in Example 1, step 2 from (5-bromo-pyridin-2-yl)-(2,2-dimethyl-morpholin-4-yl)-methanone (Example 36, step 1) and ethynyltrimethylsilane.
The title compound was obtained as a yellow oil, MS: m/e=357.1 (M+H+), using chemistry similar to that described in Example 3, step 3 from (2,2-dimethyl-morpholin-4-yl)-(5-trimethylsilanylethynyl-pyridin-2-yl)-methanone (Example 36, step 2) and 1,4-difluoro-2-iodobenzene.
The title compound was obtained as a white solid, MS: m/e=283.0/285.0 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and piperidin-4-one hydrochloride.
1-(5-Bromo-pyridine-2-carbonyl)-piperidin-4-one (Example 37, step 1) (135 mg, 0.48 mmol) was dissolved in THF (3 ml) and the mixture was cooled to 0-5° C. 3M Methylmagnesium bromide (190 μl, 0.57 mmol, 1.2 equiv.) was added drop wise at 0-5° C. and the mixture was stirred for 2 hours at 0-5° C. The reaction mixture was extracted with saturated NH4Cl solution and two times with ethyl acetate. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired (5-bromo-pyridin-2-yl)-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone (35 mg, 25% yield) was obtained as a colorless oil, MS: m/e=299.2/301.1 (M+H+).
The title compound was obtained as a brown oil, MS: m/e=339.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from (5-bromo-pyridin-2-yl)-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone (Example 37, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a white solid, MS: m/e=314.4 (M+H+), using chemistry similar to that described in Example 9, step 1 from 5-bromo-pyridine-2-carbonyl chloride and (RS)-2,2-dimethyl-piperidin-4-ol (CAS 937681-12-4).
The title compound was obtained as a white solid, MS: m/e=335.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyridin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 38, step 1) and phenylacetylene.
The title compound was obtained as a white solid, MS: m/e=314.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and (RS)-3,3-dimethyl-piperidin-4-ol (CAS 373603-88-4).
The title compound was obtained as a colorless oil, MS: m/e=335.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyridin-2-yl)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone (Example 39, step 1) and phenylacetylene.
The title compound was obtained as a light yellow solid, MS: m/e=353.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyridin-2-yl)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone (Example 39, step 1) and 1-ethynyl-4-fluoro-benzene.
The title compound was obtained as a yellow oil, MS: m/e=353.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyridin-2-yl)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone (Example 39, step 1) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a white solid, MS: m/e=273.1/275.1 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid and 1-methylcyclopropanamine hydrochloride.
The title compound was obtained as a white solid, MS: m/e=286.9/288.9 (M+H+), using chemistry similar to that described in Example 2 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid (1-methyl-cyclopropyl)-amide (Example 42, step 1) and iodomethane.
The title compound was obtained as a yellow oil, MS: m/e=327.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid methyl-(1-methyl-cyclopropyl)-amide (Example 42, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a yellow oil, MS: m/e=304.9/307.0 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-3-chloro-pyridine-2-carboxylic acid and tert-butyl-methyl-amine.
The title compound was obtained as an orange solid, MS: m/e=327.1/329.0 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-chloro-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 43, step 1) and phenylacetylene.
The title compound was obtained as a yellow solid, MS: m/e=310.0/312.0 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyrimidine-2-carboxylic acid and 1-(trifluoromethyl)cyclopropanamine
The title compound was obtained as a white solid, MS: m/e=324.0/326.1 (M+H+), using chemistry similar to that described in Example 2 from 5-bromo-pyrimidine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide (Example 44, step 1) and iodomethane.
The title compound was obtained as a brown solid, MS: m/e=364.1 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyrimidine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide (Example 44, step 2) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a white solid, MS: m/e=222.8 (M−H+), using chemistry similar to that described in Example 25, step 1 from 5-bromo-pyrimidine-2-carboxylic acid.
The title compound was obtained as a brown solid, MS: m/e=300.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-phenylethynyl-pyrimidine-2-carboxylic acid (Example 45, step 1) and 3,3-difluoro-azetidine hydrochloride.
The title compound was obtained as an orange oil, MS: m/e=320.4 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-phenylethynyl-pyrimidine-2-carboxylic acid (Example 45, step 1) and 3,3-dimethylpiperidine.
The title compound was obtained as a white solid, MS: m/e=315.2 (M+H+), using chemistry similar to that described in Example 9, step 1 from 5-bromo-pyrimidine-2-carboxylic acid and (RS)-2,2-dimethyl-piperidin-4-ol (CAS 937681-12-4).
The title compound was obtained as a white solid, MS: m/e=336.2 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyrimidin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 47, step 1) and phenylacetylene.
The title compound was obtained as a white solid, MS: m/e=315.4 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyrimidine-2-carboxylic acid and (RS)-3,3-dimethyl-piperidin-4-ol (CAS 373603-88-4).
The title compound was obtained as a brown solid, MS: m/e=336.2 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyrimidin-2-yl)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone (Example 48, step 1) and phenylacetylene.
The title compound was obtained as a light yellow solid, MS: m/e=354.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyrimidin-2-yl)-(4-hydroxy-3,3-dimethyl-piperidin-1-yl)-methanone (Example 48, step 1) and 1-ethynyl-3-fluoro-benzene.
The title compound was obtained as a yellow solid, MS: m/e=239.8 (M−H+), using chemistry similar to that described in Example 25, step 1 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid.
The title compound was obtained as a light yellow solid, MS: m/e=311.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 3-fluoro-5-phenylethynyl-pyridine-2-carboxylic acid (Example 50, step 1) and 3-methyloxetan-3-amine.
The title compound was obtained as a light yellow semi-solid, MS: m/e=325.4 (M+H+), using chemistry similar to that described in Example 2 from 3-fluoro-5-phenylethynyl-pyridine-2-carboxylic acid (3-methyl-oxetan-3-yl)-amide (Example 50, step 2) and iodomethane.
The title compound was obtained as a light yellow solid, MS: m/e=337.1 (M+H+), using chemistry similar to that described in Example 1, step 1 from 3-fluoro-5-phenylethynyl-pyridine-2-carboxylic acid (Example 50, step 1) and (RS)-1,1,1-trifluoropropan-2-amine hydrochloride.
The title compound was obtained as a light yellow oil, MS: m/e=351.3 (M+H+), using chemistry similar to that described in Example 2 from (RS)-3-fluoro-5-phenylethynyl-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (Example 51, step 1) and iodomethane.
A suspension of 5-bromo-pyridine-2,3-dicarboxylic acid (700 mg, 2.85 mmol) in acetic anhydride (0.88 ml, 9.39 mmol, 3.3 equiv.) was heated at 80° C. for 10 min and then refluxed for 1 h. Acetic anhydride was evaporated off in vacuo. The resulting solid was triturated with hexane to afford 3-bromo-furo[3,4-b]pyridine-5,7-dione (510 mg, 79%) as off white solid.
To a solution of 3-bromo-furo[3,4-b]pyridine-5,7-dione (200 mg, 0.877 mmol) in THF (3 ml) at −10° C. was added Mg(ClO4)2 (235 mg, 1.053 mmol, 1.2 equiv.) and the reaction mixture was stirred for 5 min at that temperature. Then isopropanol (6 ml) was added and the reaction mixture was stirred at 25° C. for 16 hours. The volatilities were removed in vacuo and the resultant residue was dissolved in EtOAc (30 ml). The organic layer was washed with water (15 ml) and brine (15 ml), dried over anhydrous Na2SO4, filtered and evaporated off in vacuo. The crude material thus obtained was purified by column chromatography over normal silica gel (30-50% EtOAc/hexane) to afford 5-bromo-pyridine-2,3-dicarboxylic acid 2-isopropyl ester (210 mg, 83.1%) as light brown solid, MS: m/e=286.0 (M−H+).
To a solution of 5-bromo-pyridine-2,3-dicarboxylic acid 2-isopropyl ester (630 mg, 2.187 mmol) in pyridine (8 ml) at 0° C. was added methane sulfonyl chloride (0.34 ml, 4.37 mmol, 2 equiv.) and the reaction mixture was stirred for 1 hour at 25° C. Then NH3 gas was purged in to reaction mixture at 0° C. and stirred at 25° C. for 30 minutes. The excess NH3 was evaporated off in vacuo. The reaction mixture was cooled to 0° C., a fresh lot of methane sulfonyl chloride (1.35 ml, 17.49 mmol, 8 equiv.) was added drop wise to the mixture and stirring was continued at 25° C. for another 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (20 ml) and extracted with EtOAc (2×40 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness. The resulting crude material was purified by column chromatography over normal silica gel (10% EtOAc in hexane) to give 5-bromo-3-cyano-pyridine-2-carboxylic acid isopropyl ester (320 mg, 54%) as yellow oil.
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid isopropyl ester (70 mg, 0.26 mmol) in a mixture of THF (3 ml) and water (3 ml) was added lithium hydroxide monohydrate (32.75 mg, 0.78 mmol, 3 equiv.). The reaction mixture was stirred for 2 hours at 25° C. The mixture was acidified with 2N aqueous HCl solution (pH 5) and extracted with EtOAc (2×15 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give 5-bromo-3-cyano-pyridine-2-carboxylic acid (45 mg, 76%) as a yellow solid which was used in next step without further purification.
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid (100 mg, 0.44 mmol) in dichloromethane (5 ml) at 0° C. were added DIPEA (0.226 ml, 1.32 mmol, 3 equiv.), methyl tert-butyl amine (0.079 ml, 0.661 mmol, 1.5 equiv.) and HBTU (250 mg, 0.661 mmol, 1.5 equiv.). The reaction mixture was stirred at 25° C. for 14 hours. The solvent was removed in vacuum and the resulting crude material was purified by column chromatography over normal silica gel (10-20% EtOAc in hexane) to afford 5-bromo-3-cyano-pyridine-2-carboxylic acid tert-butyl-methyl-amide (85 mg, 65%) as colorless oil.
The title compound was obtained as a light brown solid, MS: m/e=318.0 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-3-cyano-pyridine-2-carboxylic acid tert-butyl-methyl-amide (Example 52, step 2) and phenylacetylene.
The title compound was obtained as a light yellow solid, MS: m/e=380.3/382.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid methyl-(1-trifluoromethyl-cyclopropyl)-amide (Example 33, step 2) and 3-chloro-5-ethynyl-pyridine.
The title compound was obtained as a colorless oil, MS: m/e=311.2/313.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and 1,1,1-trifluoro-2-methylpropan-2-amine.
The title compound was obtained as a yellow oil, MS: m/e=368.4/370.4 (M−H+), using chemistry similar to that described in Example 3, step 3 from 5-bromo-pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (Example 54, step 1) and 2-chloro-4-trimethylsilanylethynyl-pyridine.
The title compound was obtained as a white solid, MS: m/e=368.3/370.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (Example 54, step 1) and 3-chloro-5-ethynyl-pyridine.
The title compound was obtained as a white solid, MS: m/e=382.3/384.3 (M+H+), using chemistry similar to that described in Example 2 from 5-(5-chloro-pyridin-3-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (Example 55, step 1) and iodomethane.
The title compound was obtained as a light yellow solid, MS: m/e=367.3/369.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from 5-bromo-pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (Example 54, step 1) and 3-chlorophenylacetylene.
The title compound was obtained as a light yellow oil, MS: m/e=381.4/383.3 (M+H+), using chemistry similar to that described in Example 2 from 5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (Example 56, step 1) and iodomethane.
The title compound was obtained as a colorless oil, MS: m/e=297.2/299.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyridine-2-carboxylic acid and (RS)-1,1,1-trifluoropropan-2-amine.
The title compound was obtained as a light yellow solid, MS: m/e=354.3/356.3 (M−H+), using chemistry similar to that described in Example 3, step 3 from (RS)-5-bromo-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (Example 57, step 1) and 2-chloro-4-trimethylsilanylethynyl-pyridine.
The title compound was obtained as a light yellow solid, MS: m/e=312.2/314.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyrimidine-2-carboxylic acid and 1,1,1-trifluoro-2-methylpropan-2-amine.
The title compound was obtained as a brown solid, MS: m/e=369.3/371.2 (M−H+), using chemistry similar to that described in Example 3, step 3 from 5-bromo-pyrimidine-2-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide (Example 58, step 1) and 2-chloro-4-trimethylsilanylethynyl-pyridine.
The title compound, a white solid, MS: m/e=354.3/356.3 (M+H+), was prepared by separation of (RS)-5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (Example 57) using a chiral column (Reprosil chiral NR with heptane:isopropanol 80:20 as solvent).
The title compound, a white solid, MS: m/e=354.3/356.3 (M+H+), was prepared by separation of (RS)-5-(2-chloro-pyridin-4-ylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (Example 57) using a chiral column (Reprosil chiral NR with heptane:isopropanol 80:20 as solvent).
The title compound was obtained as a light yellow solid, MS: m/e=353.3/355.3 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-5-bromo-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (Example 57, step 1) and 3-chlorophenylacetylene.
The title compound was obtained as a colorless oil, MS: m/e=367.3/369.2 (M+H+), using chemistry similar to that described in Example 2 from (RS)-5-(3-chloro-phenylethynyl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (Example 61) and iodomethane.
The title compound was obtained as a light yellow solid, MS: m/e=353.4 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 25, step 1) and (RS)-2,2-dimethyl-piperidin-4-ol (CAS 937681-12-4).
The title compound was obtained as a light yellow solid, MS: m/e=371.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyridin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 38, step 1) and 2,5-difluorophenylacetylene.
The title compound was obtained as a white solid, MS: m/e=314.4/316.3 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-pyrimidine-2-carboxylic acid and (RS)-2,2-dimethyl-piperidin-4-ol (CAS 937681-12-4).
The title compound was obtained as a light yellow solid, MS: m/e=354.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyrimidin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 65, step 1) and 3-fluorophenylacetylene.
The title compound was obtained as a yellow solid, MS: m/e=372.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-pyrimidin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 65, step 1) and 2,5-difluorophenylacetylene.
The title compound was obtained as a yellow oil, MS: m/e=331.2/333.2 (M+H+), using chemistry similar to that described in Example 1, step 1 from 5-bromo-3-fluoro-pyridine-2-carboxylic acid and (RS)-2,2-dimethyl-piperidin-4-ol (CAS 937681-12-4).
The title compound was obtained as a yellow oil, MS: m/e=371.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-3-fluoro-pyridin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 67, step 1) and 3-fluorophenylacetylene.
The title compound was obtained as a yellow solid, MS: m/e=389.4 (M−H+), using chemistry similar to that described in Example 1, step 2 from (RS)-(5-bromo-3-fluoro-pyridin-2-yl)-(4-hydroxy-2,2-dimethyl-piperidin-1-yl)-methanone (Example 67, step 1) and 2,5-difluorophenylacetylene.
| Number | Date | Country | Kind |
|---|---|---|---|
| 11162945 | Apr 2011 | EP | regional |
| 11185137 | Oct 2011 | EP | regional |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20130123524 | Kellens et al. | May 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| WO 9902497 | Jan 1999 | WO |
| 2008151184 | Dec 2008 | WO |
| 2011015343 | Feb 2011 | WO |
| Entry |
|---|
| A. Ritzen et al., 19 Bioorganic & Medicinal Chemistry Letters, 3275-3278 (2009). |
| A.L. Rodriguez, et al., Molecular Pharmacology (2010), 78(6), 1105-1123. |
| A.G. Sams et al, Bioorganic & Medicinal Chemistry Letters (2011), 21(11), 3407-3410. |
| F. Gastambide et al., Neuropsychopharmacology (2012), 37(4), 1057-1066. |
| M. Noetzel, et al., Molecular Pharmacology (2012), 81(2), 120-133. |
| G. Gilmour et al., Neuropharmacology (2013), 64, 224-239. |
| F. Gastambide et al., Neuropharmacology (2013), 64, 240-247. |
| T. Kiritoshi, et al., Neuropharmacology (2013), 66, 170-178. |
| Cee, V. J. et al., Journal of Medicinal Chemistry (XP002675714), 50(4):627-640 (Jan. 25, 2007). |
| Patani G. A. et al., Chemical Reviews (XP000652176), 96(8):3147-3176 (Jan. 1, 1996). |
| Yasuyoshi, I. et al., Journal of Medicinal Chemistry (XP002568493), 49(3):1080-1100 (Jan. 1, 2006). |
| (International Search Report PCT/UP2012/056966 Apr. 17, 2012). |
| Number | Date | Country | |
|---|---|---|---|
| 20120270852 A1 | Oct 2012 | US |
