Patent Grant
10577332
This application is a 371 national phase application of International Patent Application No. PCT/EP2016/058594, filed Apr. 19, 2016, and claims priority to European Patent Application No. 15164885.4, filed on Apr. 23, 2015, the entire contents of each of which are incorporated herein by reference.
The present invention relates to compounds of formula I
wherein
It has been surprisingly been found that the compounds of general formula I are EAAT3 inhibitors.
The excitatory amino acid transporter 3 (EAAT3), also referred to in human studies as solute carrier family 1, member 1 (systematic gene name: SLC1A1) and in rodents as excitatory amino acid carrier 1 (EAAC1), is a high-affinity anionic amino acid transporter found in neurons throughout the cortex and in the hippocampus, basal ganglia (striatum, thalamus), and the olfactory bulb. EAAT3 functions to buffer local glutamate concentrations at excitatory synapses, for example in the hippocampus, and modulates the differential recruitment of glutamate receptor subtypes at extrasynaptic sites. Furthermore, EAAT3 is thought to be involved in facilitating GABA and glutathione biosynthesis. EAAT3 is a member of the EAAT family that mediates the uptake of glutamate into neuronal and glial cells of the mammalian CNS. Two transporters expressed primarily in glia, EAAT1 and EAAT2, are crucial for glutamate homeostasis in the adult mammalian brain and for rapid clearance of glutamate from the synaptic cleft. Three neuronal transporters (EAAT3, EAAT4, and EAAT5) appear to have additional functions in regulating and processing cellular excitability with EAAT3 being abundantly expressed throughout the CNS (EAAT4 is unique to Purkinje cells of the cerebellum and EAAT5 is expressed in rod photoreceptor and bipolar cells of the retina).
EAATs are assembled as trimers, and the existence of multiple isoforms raises the question of whether certain isoforms can form hetero-oligomers. In the mammalian brain, the specificity of excitatory synaptic transmission depends on rapid diffusion of glutamate away from active synapses and the powerful uptake capacity of glutamate transporters in astrocytes. The extent to which neuronal glutamate transporters influence the lifetime of glutamate in the extracellular space remains unclear, but it is thought to be minor. EAAT3, the predominant neuronal glutamate transporter at excitatory synapses in hippocampal area CA1, buffers glutamate released during synaptic events and prolongs the time course of its clearance by astrocytes. EAAT3 does not significantly alter activation of receptors in the synaptic cleft. Instead, it reduces recruitment of perisynaptic/extrasynaptic NR2B-containing NMDARs, thereby facilitating induction of long-term potentiation by short bursts of high-frequency stimulation. Specific EAAT3 inhibitors may have the potential to locally and specifically strengthen particular synapses.
Obsessive-compulsive disorder (OCD) is among the most common mental disorders (prevalence 1-3%), and is at least as prevalent as schizophrenia and bipolar disorder. In the United States, one in 50 adults suffers from OCD. OCD affects children and adolescents as well as adults. Roughly one third to one half of adults with OCD reports a childhood onset of the disorder, and the disorder is typically chronic in nature. Treatment consists of predominantly serotonergic TCAs (clomipramine) or SSRIs in combination with cognitive-behavioral therapy (CBT). Overall, response to these interventions is of some but still limited benefit (approximately comparable to antidepressant response in MDD), and given the chronicity of OCD, the unmet medical need remains very high. OCD has been linked to serotonin and glutamate abnormalities. The hypothesis of glutamate signaling dysfunction in OCD is based on findings from neuroimaging, animal models, positional cloning and treatment studies.
The obsessive-compulsive symptomatology in OCD has considerable phenomenological, epidemiological and possibly (aetio)-pathophysiological overlap with a core autism spectrum disorder criterion: “restricted, repetitive patterns of behavior, interests, or activities” (taken from proposed DSM-5 revision). In support of this notion, human genetics studies have linked both the serotonin transporter and EAAT3 (SLC1A1) genes to autism spectrum disorder (ASD) or rigid-compulsive behavior in ASD and to OCD.
In addition, obsessive-compulsive symptoms induced by antipsychotics in schizophrenic bipolar disorder patients have been linked to EAAT3 (SLC1A1) gene variants. Post-mortem brain studies have shown that both classic and atypical antipsychotics reduce EAAT3, suggesting an involvement of this transporter in neuroleptic mechanisms beyond dopamine and serotonin modulation. Moreover, genetic variation in the human gene EAAT3 (SLC1A1) has been associated with antipsychotic drug response.
There is converging evidence from neurobiological data, human genetics, imaging studies and experimental treatments that EAAT3 is a key pathophysiological element in OCD and rigid-compulsive behavior in autism and in schizophrenia.
Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of disorders, relating to EAAT3 inhibitors. The most preferred indications for compounds which are EAAT3 inhibitors are psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.
The present invention relates to compounds of formula I and to their pharmaceutically acceptable salts for use in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder, to compounds of formula IA as pharmaceutically active substances, to the processes for their production as well as to their use in the treatment or prevention of disorders, relating to EAAT3 inhibitors, such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder and to pharmaceutical compositions containing the compounds of formula IA
A further object of the present invention is a method for the treatment or prophylaxis of psychiatric disorder such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder, which method comprises administering an effective amount of a compound of formula I or IA to a mammal in need.
Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers, or analogues containing isotopes of hydrogen, fluorine, carbon, oxygen or nitrogen.
One object of the present invention are novel compounds of formula IA,
wherein
R1 is methyl, ethyl, CF3, CH2OH, cyclopropyl or cyano;
R2 is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl or CF3;
R3 is Cl, F, CF3, methyl, methoxy, isopropyl or cyclopropyl;
R4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
One further object of the invention are compounds of formula IA-1,
wherein
R2 is hydrogen, methyl, ethyl, isopropyl, tertbutyl, cyclopropyl or CF3;
R3 is Cl, F, CF3, methyl, methoxy, isopropyl or cyclopropyl;
R4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof, for example the following compounds
One further object of the present invention are compounds of formula IA-2
wherein
One further object of the invention are compounds of formula IA-3
wherein
One further object of the invention are compounds of formula IA-4
wherein
One further object of the invention are compounds of formula IA-5
wherein
One further object of the invention are compounds of formula IA-6
wherein
One further object of the invention are compounds of formula IA-7 for use in the treatment of schizophrenia, obsessive-compulsive disorder or autism
wherein
The preparation of compounds of formula IA of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes 1 and 2. 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 may be prepared by methods, known in the art, for example by the process variant described below, which process comprises
with a compound of formula
to a compound of formula I
wherein the substituents are as described above, or
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
with a compound of formula
to a compound of formula I
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 scheme 1 to 4 and in examples 1-123.
The tetrazole derivatives I can be prepared from the intermediate acids IX by amide formation with the commercially available amines X using standard reagents like N,N-diisopropylethyl amine and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).
The acids IX can be prepared starting from commercially available 3-iodo-5-nitrobenzoic acid II. Coupling reaction with commercially available boronic acid derivatives III led to the acids IV which were subsequently esterified using standard procedure like thionyl chloride in methanol. The methyl esters V can be reduced with tin(II)chloride to yield the aniline derivatives VI. Tetrazole formation can be achieved using sodium azide and triethyl orthoformate in case of the unsubstituted derivatives VIIa, whereas for the substituted tetrazole derivatives VIIb the anilines VI can be transformed into the amides VIII using standard methods like acyl chlorides and triethylamine, and subsequent tetrazole formation can be achieved using sodium azide and silicium tetrachloride. Transformation of the esters VIIa/VIIb into the acids IX can be achieved by standard methods like lithium hydroxide in water/THF.
Another method to prepare the tetrazoles I can be the coupling reaction of the iodo- or bromo-derivatives XIII or XVI with the commercially available boronic acid derivatives III. The iodo derivatives XIII can be prepared starting from the commercially available 3-iodo-5-nitrobenzoic acid II. Amide formation with the commercially available amines X using standard conditions leads to the amides XI which can be reduced with tin(II)chloride to yield the aniline derivatives XII. Tetrazole formation can be achieved as described above for the derivatives VII to yield the iodo intermediates XIII.
The corresponding bromo derivatives XVI can be prepared starting from commercially available 3-amino-5-bromobenzoic acid XIV which can be transformed into the bromo derivatives XVI via the amides XV as described above for the derivatives VII.
Generally speaking, the sequence of steps used to synthesize the compounds of formula I can also be modified in certain cases.
The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmaceutical properties. Specifically, it has been found that the compounds of the present invention are EAAT3 inhibitors for use in the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorders.
The compounds were investigated in accordance with the test given hereinafter.
The FLIPR Membrane Potential (FMP) Assay
HEK-293 cells stably expressing human EAAT3 were seeded at 55 000 cells/well in growth medium (DMEM glutamate free (Invitrogen 11960-044), 1% Pen Strep (10 ml/l GIBCO BRL No 15140-023), 10% FCS non dialysed heat inactivated, 5 mg/l puromycin) in poly-D-lysine treated 96-well black microtiter plates with clear-bottom. After 24 h, the growth medium was removed and 100 μl/well of Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, 11 mM HEPES, 10 mM D-glucose, pH=7.4) added. The cells were then loaded by adding 100 μl/well FMP assay dye (FLIPR Membrane Potential assay reagent, Molecular Devices). The 96-well plates were then incubated at 37° C. for 1 h. The depolarization of the cells will cause more dye to enter in the cells, where it will bind to intracellular proteins and lipids and cause an increase in the fluorescence signal. Antagonist potency at human EAAT3 was determined by using L-glutamate as agonist at a concentration which gives 80% of the maximum response. The antagonists were applied 15 min before the application of the agonist L-glutamate. The assays were performed at room temperature and measurements done by using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices) and filter #2. Responses were measured as peak increase in fluorescence minus basal (i.e. fluorescence without addition of L-glutamate). Kb was determined using the Cheng-Prusoff equation Kb=IC50/[1+(A/EC50)], where IC50 is the concentration of the antagonist producing 50% inhibition, A is the concentration of the agonist against which the IC50 is being determined (at EC80) and EC50 is the concentration of the agonist producing 50% inhibition.
The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine 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 preparations. 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 gelatin capsules. Suitable carriers for soft gelatin 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 gelatin 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 preparations 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, medicaments containing a compound of formula (I) or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments 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 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 is also an object of the present invention.
The dosage 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 manufactured in the usual manner:
Manufacturing Procedure
Capsules of the following composition are manufactured:
Manufacturing Procedure
A compound of formula I lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.
Injection solutions of the following composition are manufactured:
Manufacturing Procedure
A compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.
Step A
To a stirred solution of commercially available 3-iodo-5-nitrobenzoic acid (3.67 g, 12.5 mmol) and Pd(Ph3P)4 (463 mg, 401 μmol) in toluene (71.3 ml) and ethanol (11.9 ml) was added at room temperature commercially available 4-fluoro-phenylboronic acid (1.93 g, 13.8 mmol) and a solution of Cs2CO3 (4.49 g, 13.8 mmol) in water (4.78 ml). The reaction mixture was stirred under reflux conditions for 18 h and then cooled to room temperature. To the mixture was added 2N NaOH (52 ml), and the reaction mixture was stirred for 30 min at room temperature. Some precipitated material was collected by filtration. The organic layer was separated, and to the water layer together with the precipitated material was added conc. hydrochloric acid (19 ml) to reach pH<4. The mixture was extracted with ethyl acetate (2×75 ml), the combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield crude 3-(4-fluorophenyl)-5-nitrobenzoic acid (3.73 g) as brown solid, MS (ISN) m/z=260.1 [(M−H)+], which was subsequently dissolved in methanol (35.1 ml). To the stirred solution was added dropwise thionyl chloride (1.87 g, 1.14 ml, 15.7 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature, and was afterwards stirred under reflux conditions for 2 h. The solvent was removed in vacuo to yield crude methyl 3-(4-fluorophenyl)-5-nitrobenzoate (3.65 g) as a light brown solid, MS (ISP) m/z=279.1 [(M+H)+], which was subsequently dissolved in methanol (35.1 ml). To the stirred solution was added at room temperature tin(II)chloride (10.0 g, 52.9 mmol), the reaction mixture was stirred under reflux conditions for 3 h, evaporated, the residue was dissolved in water (200 ml) and basified to pH=9 by addition of Na2CO3. The mixture was extracted with dichloro-methane (3×75 ml), the combined organic layers were washed with water (150 ml), brine (150 ml), dried (MgSO4) and evaporated to yield methyl 3-amino-5-(4-fluorophenyl)-benzoate (3.0 g, 98%) as a light yellow solid, MS (ISP) m/z=246.1 [(M+H)+], mp 124° C.
Step B
To a stirred solution of methyl 3-amino-5-(4-fluorophenyl)-benzoate (2.99 g, 12.2 mmol) and sodium azide (1.47 g, 22.6 mmol) in AcOH (23.6 ml) was added at room temperature triethyl orthoformate (8.67 g, 9.74 ml, 58.5 mmol). The reaction mixture was stirred under reflux conditions for 2.5 h, poured into ice/water (100 ml) and extracted with dichloromethane (2×75 ml). The combined organic layers were washed with brine (75 ml), dried (MgSO4) and evaporated. The crude product (3.93 g) was purified by flash chromatography on silica gel [heptane/ethyl acetate (20-100%)] and trituration in diethyl ether (10 ml) to yield methyl 3-(4-fluorophenyl)-5-(tetrazol-1-yl)-benzoate (3.17 g, 87%) as an off-white solid, MS (ISP) m/z=299.1 [(M+H)+], mp 175° C.
Step C
A solution of lithium hydroxide monohydrate (578 mg, 13.8 mmol) in water (12.5 ml) was added dropwise to a stirred and cooled (0° C.) suspension of methyl 3-(4-fluorophenyl)-5-(tetrazol-1-yl)-benzoate (3.16 g, 10.6 mmol) in THF (7.8 ml). The reaction mixture was stirred at room temperature for 15 h resulting in a clear solution, THF was evaporated, and the aqueous solution was acidified by addition of 25% hydrochloric acid (pH=3). The resulting precipitate was collected by filtration and dried to yield the title compound (2.84 g, 94%) as white solid, MS (ISP) m/z=285.1 [(M+H)+], mp 240° C.
Step A
Methyl 3-amino-5-[4-(trifluoromethyl)phenyl]-benzoate, orange solid (2.28 g, 63%), MS (ISP) m/z=296.1 [(M+H)+], mp 117° C., was prepared in accordance with the general method of intermediate 1, step A, from commercially available 3-iodo-5-nitrobenzoic acid (3.6 g, 12.3 mmol) and commercially available 4-(trifluoromethyl)-phenylboronic acid (2.57 g, 13.5 mmol).
Step B
Methyl 3-(tetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoate, off-white solid (1.11 g, 94%), MS (ISP) m/z=349.1 [(M+H)+], mp 193° C., was prepared in accordance with the general method of intermediate 1, step B, from methyl 3-amino-5-[4-(trifluoromethyl)-phenyl]-benzoate (1.0 g, 3.39 mmol).
Step C
The title compound, off-white solid (1.02 g, 96%), MS (ISN) m/z=333.2 [(M−H)−], mp 208° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(tetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoate (1.11 g, 3.19 mmol).
Step A
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI) (2.94 g, 15.4 mmol) was added in one portion to a stirred and cooled (0° C.) solution of commercially available 3-iodo-5-nitrobenzoic acid (3 g, 10.2 mmol), hydroxybenzotriazole (HOBT) (2.08 g, 15.4 mmol), 2-methylbutan-2-amine (911 mg, 1.22 ml, 10.2 mmol) and N-methyl-2-pyrrolidone (NMP) (1.53 g, 1.49 ml, 15.4 mmol) in dichloromethane (50 ml) and DMF (4.2 ml). The reaction mixture was allowed to stir for 15 h at room temperature, washed with 2N NaOH (30 ml), water (30 ml) and brine (30 ml), dried (MgSO4) and evaporated. The crude product (4 g brown oil) was purified by flash chromatography on silica gel [heptane/ethyl acetate (10-60%)] to yield 3-iodo-N-(2-methylbutan-2-yl)-5-nitrobenzamide (2.38 g, 64%) as an off white solid, MS (ISP) m/z=363.1 [(M+H)+], mp 117° C.
Step B
To a stirred solution of 3-iodo-N-(2-methylbutan-2-yl)-5-nitrobenzamide (2.38 g, 6.57 mmol) in methanol (50 ml) was added at room temperature tin(II)chloride (5.93 g, 26.3 mmol). The reaction mixture was stirred under reflux conditions for 3 hours, evaporated and the residue was dissolved in water (150 ml), basified (pH=9) by addition of Na2CO3, and extracted with dichloromethane (2×75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried (MgSO4) and evaporated to yield 3-amino-5-iodo-N-(2-methylbutan-2-yl)-benzamide (2.18 g, 100%) as a colorless oil, MS (ISP) m/z=333.2 [(M+H)+].
Step C
The title compound, off-white foam (2.25 g, 89%), MS (ISP) m/z=386.2 [(M+H)+], was prepared in accordance with the general method of intermediate 1, step B, from 3-amino-5-iodo-N-(2-methylbutan-2-yl)-benzamide (2.18 g, 6.56 mmol).
Step A
To a stirred solution of methyl 3-amino-5-(4-methylphenyl)-benzoate [CAS No. 1000587-31-4] (2.13 g, 8.83 mmol) and triethylamine (2.68 g, 3.69 ml, 26.5 mmol) in dichloromethane (46.4 ml) was added at room temperature isobutyryl chloride (1.15 g, 1.14 ml, 10.6 mmol), the reaction mixture was stirred for additional 2 h, water (50 ml) was added, and the solution was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product (3.21 g) was purified by flash chromatography on silica gel [heptane/ethyl acetate (20-100%)] to yield methyl 3-(4-methylphenyl)-5-(2-methylpropanoylamino)-benzoate (2.66 g, 97%) as an off-white solid, MS (ISP) m/z=312.1 [(M+H)+], mp 152° C.
Step B
To a stirred solution of methyl 3-(4-methylphenyl)-5-(2-methylpropanoylamino)-benzoate (2.65 g, 8.51 mmol) in acetonitrile (21 ml) sodium azide (553 mg, 8.51 mmol) and SiCl4 (3.73 g, 2.52 ml, 21.3 mmol) were added at room temperature. The reaction mixture was stirred at 60° C. for 36 h. Since TLC showed that the reaction was not finished, sodium azide (277 mg, 4.26 mmol) and SiCl4 (1.87 mg, 1.26 ml, 10.6 mmol) were added, and the reaction was stirred for additional 18 h at 60° C. The reaction mixture was poured into cold saturated NaHCO3 solution (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with brine (75 ml), dried (MgSO4) and evaporated. The crude product (2.64 g) was purified by flash chromatography on silica gel [dichloromethane/dichloromethane-MeOH 9:1 (0-25%)] and trituration from diethyl ether (3 ml) to yield methyl 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoate (2.11 g, 74%) as a white solid, MS (ISP) m/z=337.2 [(M+H)+], mp 157° C.
Step C
The title compound, white solid (1.95 g, 97%), MS (ISP) m/z=323.1 [(M+H)+], mp 225° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoate (2.1 g, 6.24 mmol).
Step A
Methyl 5-(2-cyclopropanecarbonylamino)-3-(4-methylphenyl)-benzoate, off-white solid (2.31 g, 90%), MS (ISP) m/z=310.2 [(M+H)+], was prepared in accordance with the general method of intermediate 4, step A, from 3-amino-5-(4-methylphenyl)-benzoate [CAS No. 1000587-31-4] (2.0 g, 8.29 mmol) and cyclopropanecarbonyl chloride (1.04 g, 9.95 mmol).
Step B
Methyl 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)benzoate, light brown solid (2.43 g, 97%), MS (ISP) m/z=335.2 [(M+H)+], was prepared in accordance with the general method of intermediate 4, step B, from methyl 5-(2-cyclopropane-carbonylamino)-3-(4-methyl-phenyl)-benzoate (2.31 g, 7.47 mmol).
Step C
The title compound, white solid (2.15 g, 93%), MS (ISP) m/z=321.2 [(M+H)+], mp 183° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)benzoate (2.42 g, 7.24 mmol).
Step A
Methyl 3-(4-methylphenyl)-5-(propanoylamino)-benzoate, off-white solid (1.81 g, 82%), MS (ISP) m/z=298.2 [(M+H)+], was prepared in accordance with the general method of intermediate 4, step A, from 3-amino-5-(4-methylphenyl)-benzoate [CAS No. 1000587-31-4] (1.79 g, 7.42 mmol) and propionyl chloride (824 mg, 721 μl, 8.9 mmol).
Step B
Methyl 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)benzoate, light yellow solid (1.86 g, 96%), MS (ISP) m/z=323.2 [(M+H)+], mp 147.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(4-methylphenyl)-5-(propanoylamino)-benzoate (1.79 g, 6.02 mmol).
Step C
The title compound, white solid (1.65 g, 93%), MS (ISP) m/z=309.2 [(M+H)+], mp 195° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)-benzoate (1.86 g, 5.77 mmol).
Step A
Methyl 3-amino-5-(4-chlorophenyl)-benzoate, yellow solid (2.29 g, 71%), MS (ISP) m/z=262.1 [(M+H)+], mp 120° C., was prepared in accordance with the general method of intermediate 1, step A, from commercially available 3-iodo-5-nitrobenzoic acid (3.6 g, 12.3 mmol) and commercially available 4-chloro-phenylboronic acid (2.11 g, 13.5 mmol).
Step B
Methyl 3-(4-chlorophenyl)-5-(2-methylpropanoylamino)-benzoate, light yellow oil (0.83 g, 91%), MS (ISP) m/z=332.1 [(M+H)+], was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-chlorophenyl)-benzoate (0.60 g, 2.29 mmol) and isobutyryl chloride (299 mg, 296 μl, 2.75 mmol).
Step C
Methyl 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoate, light yellow solid (0.76 g, 94%), MS (ISP) m/z=357.1 [(M+H)+], mp 167.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(4-chlorophenyl)-5-(2-methylpropanoylamino)-benzoate (0.83 g, 2.28 mmol).
Step D
The title compound, white solid (0.68 g, 93%), MS (ISP) m/z=343.1 [(M+H)+], mp 253° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoate (0.76 g, 2.13 mmol).
Step A
Methyl 3-(2-methylpropanoylamino)-5-[4-(trifluoromethyl)-phenyl]-benzoate, off-white solid (0.73 g, 98%), MS (ISP) m/z=366.1 [(M+H)+], mp 165.5° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-[4-(trifluoromethyl)-phenyl]-benzoate (intermediate 2, step A) (0.60 g, 2.03 mmol) and isobutyryl chloride (265 mg, 263 □l, 2.44 mmol).
Step B
Methyl 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoate, light yellow solid (0.73 g, 95%), MS (ISP) m/z=391.2 [(M+H)+], mp 146° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(2-methylpropanoylamino)-5-[4-(trifluoromethyl)-phenyl]-benzoate (0.72 g, 1.97 mmol).
Step C
The title compound, white solid (0.65 g, 92%), MS (ISP) m/z=377.1 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoate (0.73 g, 1.87 mmol).
Step A
Methyl 3-(4-chlorophenyl)-5-(cyclopropanecarbonylamino)-benzoate, white solid (0.83 g, 100%), MS (ISP) m/z=355.1 [(M+H)+], mp 194.5° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-chlorophenyl)-benzoate (intermediate 8, step A) (0.66 g, 2.52 mmol) and cyclopropane-carbonyl chloride (323 mg, 283 μl, 3.03 mmol).
Step B
Methyl 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoate, white solid (0.79 g, 89%), MS (ISP) m/z=357.1 [(M+H)+], mp 190.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(4-chlorophenyl)-5-(cyclopropanecarbonylamino)-benzoate (0.83 g, 2.52 mmol).
Step C
The title compound, white solid (0.68 g, 90%), MS (ISP) m/z=341.1 [(M+H)+], mp 230° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoate (0.79 g, 2.23 mmol).
Step A
Methyl 3-(4-fluorophenyl)-5-(2-methylpropanoylamino)-benzoate, white solid (0.66 g, 100%), MS (ISP) m/z=316.2 [(M+H)+], mp 150° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-fluorophenyl)-benzoate (intermediate 1, step A) (0.515 g, 2.10 mmol) and isobutyryl chloride (274 mg, 272 μl, 2.52 mmol).
Step B
Methyl 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoate, off-white solid (0.70 g, 100%), MS (ISP) m/z=341.2 [(M+H)+], mp 161.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(4-fluorophenyl)-5-(2-methylpropanoylamino)-benzoate (0.65 g, 2.06 mmol).
Step C
The title compound, white solid (0.67 g, 100%), MS (ISP) m/z=327.1 [(M+H)+], mp 240.5° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoate (0.70 g, 2.06 mmol).
Step A
Methyl 3-(cyclopropanecarbonylamino)-5-(4-fluorophenyl)-benzoate, off-white solid (0.76 g, 98%), MS (ISP) m/z=314.2 [(M+H)+], mp 160° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-fluorophenyl)-benzoate (intermediate 1, step A) (0.61 g, 2.49 mmol) and cyclopropane-carbonyl chloride (318 mg, 279 μl, 2.98 mmol).
Step B
Methyl 3-(5-cyclopropyltetrazol-1-yl)-5-(4-fluorophenyl)-benzoate, light yellow solid (0.79 g, 96%), MS (ISP) m/z=339.2 [(M+H)+], mp 122° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(cyclopropanecarbonylamino)-5-(4-fluorophenyl)-benzoate (0.76 g, 2.43 mmol).
Step C
The title compound, white solid (0.76 g, 100%), MS (ISP) m/z=325.1 [(M+H)+], mp 187° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(5-cyclopropyltetrazol-1-yl)-5-(4-fluorophenyl)-benzoate (0.79 g, 2.33 mmol).
Step A
Methyl 3-acetamido-5-(4-fluorophenyl)-benzoate, light yellow solid (0.61 g, 99%), MS (ISP) m/z=288.1 [(M+H)+], mp 122° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-fluorophenyl)-benzoate (intermediate 1, step A) (0.515 g, 2.10 mmol) and acetyl chloride (200 mg, 181 □l, 2.52 mmol).
Step B
Methyl 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoate, light yellow solid (0.70 g, 93%), MS (ISP) m/z=313.1 [(M+H)+], mp 132° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-acetamido-5-(4-fluorophenyl)-benzoate (0.61 g, 2.06 mmol).
Step C
The title compound, off-white solid (0.56 g, 90%), MS (ISP) m/z=299.1 [(M+H)+], mp 213.5° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoate (0.65 g, 2.08 mmol).
Step A
Methyl 3-acetamido-5-(4-chlorophenyl)-benzoate, light yellow solid (0.59 g, 93%), MS (ISP) m/z=304.1 [(M+H)+], mp 151° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-chlorophenyl)-benzoate (intermediate 8, step A) (0.547 g, 2.09 mmol) and acetyl chloride (197 mg, 178 μl, 2.51 mmol).
Step B
Methyl 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoate, light brown solid (0.57 g, 89%), MS (ISP) m/z=329.1 [(M+H)+], mp 147.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-acetamido-5-(4-chlorophenyl)-benzoate (0.59 g, 1.94 mmol).
Step C
The title compound, off-white solid (0.53 g, 99%), MS (ISP) m/z=315.1 [(M+H)+], mp 216° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoate (0.56 g, 1.70 mmol).
Step A
A mixture of 2,2,2-trifluoroacetic acid (257 mg, 174 μl, 2.25 mmol), triphenylphosphine (1.48 g, 5.64 mmol) and triethylamine (228 mg, 314 μl, 2.25 mmol) in carbon tetrachloride (3.6 ml) was stirred at 0° C. for 10 min, methyl 3-amino-5-(4-chlorophenyl)-benzoate (intermediate 7, step A) (590 mg, 2.25 mmol) was added, the reaction mixture was stirred under reflux conditions for 2 h, and purified by flash chromatography on silica gel [heptane/ethyl acetate (0-50%)] to yield (Z)-methyl 4′-chloro-5-((1-chloro-2,2,2-trifluoroethylidene)-amino)-[1,1′-biphenyl]-3-carboxylate (0.52 g, 1.38 mmol) as a yellow oil, which was subsequently dissolved in acetonitrile (3.7 ml). To the stirred solution was added at room temperature sodium azide (180 mg, 2.76 mmol), the reaction mixture was allowed to stir at room temperature for 15 h, poured into cold 2N Na2CO3 solution (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product (0.55 g) was purified by flash chromatography on silica gel [dichloromethane/dichloromethane-MeOH 9:1 (0-25%)] to yield methyl 3-(4-chlorophenyl)-5-[5-(trifluoromethyl)-tetrazol-1-yl]-benzoate (0.46 g, 53%) as an off-white solid, MS (ISP) m/z=383.0 [(M+H)+], mp 195° C.
Step B
The title compound, white solid (0.42 g, 95%), MS (ISN) m/z=367.2 [(M−H)−], mp 228° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(4-chlorophenyl)-5-[5-(trifluoromethyl)-tetrazol-1-yl]-benzoate (0.46 g, 1.20 mmol).
Step A
Methyl 3-(4-chlorophenyl)-5-(2,2-dimethylpropanoylamino)-benzoate, light yellow solid (0.64 g, 90%), MS (ISP) m/z=346.2 [(M+H)+], mp 183° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-chlorophenyl)-benzoate (intermediate 8, step A) (0.54 g, 2.06 mmol) and pivaloyl chloride (298 mg, 304 μl, 2.47 mmol).
Step B
Methyl 3-(5-tert-butyltetrazol-1-yl)-5-(4-chlorophenyl)-benzoate, off-white solid (0.64 g, 93%), MS (ISP) m/z=371.2 [(M+H)+], mp 195.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(4-chlorophenyl)-5-(2,2-dimethylpropanoylamino)-benzoate (0.64 g, 1.85 mmol).
Step C
The title compound, off-white solid (0.61 g, 99%), MS (ISP) m/z=357.1 [(M+H)+], mp 276.5° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(5-tert-butyltetrazol-1-yl)-5-(4-chlorophenyl)-benzoate (0.64 g, 1.73 mmol).
Step A
Methyl 3-(2,2-dimethylpropanoylamino)-5-(4-fluorophenyl)-benzoate, light yellow solid (0.78 g, 100%), MS (ISP) m/z=330.2 [(M+H)+], mp 125.5° C., was prepared in accordance with the general method of intermediate 4, step A, from methyl 3-amino-5-(4-fluorophenyl)-benzoate (intermediate 1, step A) (0.58 g, 2.36 mmol) and pivaloyl chloride (342 mg, 349 μl, 2.84 mmol).
Step B
Methyl 3-(5-tert-butyltetrazol-1-yl)-5-(4-fluorophenyl)-benzoate, white solid (0.78 g, 93%), MS (ISP) m/z=355.1 [(M+H)+], mp 177.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-(2,2-dimethylpropanoylamino)-5-(4-fluorophenyl)-benzoate (0.78 g, 2.37 mmol).
Step C
The title compound, white solid (0.75 g, 100%), MS (ISP) m/z=341.1 [(M+H)+], mp 241° C., was prepared in accordance with the general method of intermediate 1, step C, from methyl 3-(5-tert-butyltetrazol-1-yl)-5-(4-fluorophenyl)-benzoate (0.78 g, 2.20 mmol).
Step A
To a stirred solution of commercially available 3-amino-5-bromobenzoic acid (4 g, 18.5 mmol) in MeOH (45 ml) was added dropwise at 0° C. thionyl chloride (2.42 g, 1.49 ml, 20.4 mmol), the reaction mixture was allowed to warm to room temperature, afterwards stirred under reflux conditions for 2 h and evaporated. The crude product was acylated without further purification using pivaloyl chloride (2.66 g, 2.72 ml, 22.1 mmol) according to the general method of intermediate 4, step A, to yield methyl 3-bromo-5-pivalamidobenzoate as light yellow oil (5.81 g, 100%), MS (ISP) m/z=316.0 [(M+H)+].
Step B
3-Bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoate, white solid (6.06 g, 97%), MS (ISP) m/z=339.0 [(M+H)+], mp 135.5° C., was prepared in accordance with the general method of intermediate 4, step B, from methyl 3-bromo-5-pivalamidobenzoate (5.81 g, 18.5 mmol).
Step C
To a stirred solution of methyl 3-bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoate (6.05 g, 17.8 mmol) in THF (29.7 ml), MeOH (29.7 ml) and water (29.7 ml), lithium hydroxide monohydrate (973 mg, 23.2 mmol) was added at room temperature, the reaction mixture was stirred at room temperature for 2.5 h, concentrated to one third and 2N hydrochloride solution (35.6 ml) was added. The precipitate was collected by filtration, washed with water (10 ml) and dried to yield 3-bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoic acid as white solid (5.77 g, 99%), MS (ISP) m/z=325.0 [(M+H)+], mp 218° C.
Step D
The title compound, white foam (1.17 g, 99%), MS (ISP) m/z=380.1 [(M+H)+], mp 99.5° C., was prepared in accordance with the general method of example 1 from 3-bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoic acid (1.01 g, 3.10 mmol) and commercially available 2-methylpropan-2-amine (278 mg, 399 μl, 3.72 mmol).
The title compound, white solid (1.19 g, 95%), MS (ISP) m/z=406.1 [(M+H)+], mp 164° C., was prepared in accordance with the general method of example 1 from 3-bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoic acid (intermediate 16, step C) (1.01 g, 3.10 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (505 mg, 3.72 mmol).
The title compound, white solid (0.58 g, 86%), MS (ISP) m/z=434.1 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 3-bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoic acid (intermediate 16, step C) (504 mg, 1.55 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (241 mg, 1.86 mmol).
The title compound, yellow solid (0.38 g, 63%), MS (ISP) m/z=393.1 [(M+H)+], mp 175.5° C., was prepared in accordance with the general method of example 1 from 3-bromo-5-(5-(tert-butyl)-1H-tetrazol-1-yl)-benzoic acid (intermediate 16, step C) (504 mg, 1.55 mmol) and commercially available 2-amino-2-methyl-propanenitrile (156 mg, 1.86 mmol).
To a stirred solution of commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol) in THF (1.8 ml) was added N,N-diisopropylethylamine (80.8 mg, 107 μl, 625 μmol), 3-(4-fluorophenyl)-5-(tetrazol-1-yl)-benzoic acid (intermediate 1) (85.3 mg, 0.30 mmol) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (128 mg, 400 μmol). The reaction mixture was stirred at room temperature for 17 h and purified by flash chromatography on silica gel [heptane/ethyl acetate (0-100%)] and trituration from dichloromethane (1 ml) and heptane (15 ml) to yield the title compound (85 mg, 96%) as a white solid, MS (ISP) m/z=354.1 [(M+H)+], mp 200° C.
The title compound, off-white solid (57 mg, 71%), MS (ISP) m/z=404.2 [(M+H)+], mp 168° C., was prepared in accordance with the general method of example 1 from 3-(tetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 2) (80.2 mg, 0.24 mmol) and commercially available 2-methylbutan-2-amine (17.4 mg, 23.4 μl, 0.2 mmol).
The title compound, off-white solid (48 mg, 62%), MS (ISP) m/z=390.2 [(M+H)+], mp 108° C., was prepared in accordance with the general method of example 1 from 3-(tetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 2) (80.2 mg, 0.24 mmol) and commercially available 2-methylpropan-2-amine (14.9 mg, 21.4 μl, 0.2 mmol).
The title compound, white solid (100 mg, 96%), MS (ISP) m/z=416.2 [(M+H)+], mp 146.5° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(tetrazol-1-yl)-benzoic acid (intermediate 1) (85.3 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
A mixture of 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 3-fluoro-4-methylphenylboronic acid (50.0 mg, 325 μmol) in 1,2-dimethoxyethane (1.67 ml) and 2 M Na2CO3 solution (416 μl, 832 μmol) was purged with argon in an ultrasonic bath for 5 min, triphenylphosphine (13.1 mg, 50.0 μmol) and palladium(II)acetate (5.61 mg, 25.0 μmol) were added at room temperature, and afterwards the reaction mixture was stirred for 3 h under reflux conditions. The reaction mixture was cooled to room temperature and purified by flash chromatography on silica gel [heptane/ethyl acetate (10-50%)] and crystallization from dichloromethane/heptane to yield the title compound (63 mg, 69%) as a white solid, MS (ISP) m/z=368.2 [(M+H)+], mp 161° C.
The title compound, off-white solid (61 mg, 66%), MS (ISP) m/z=368.2 [(M+H)+], mp 120° C., was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 4-fluoro-3-methylphenylboronic acid (50.0 mg, 325 μmol).
The title compound, light brown solid (66 mg, 72%), MS (ISP) m/z=366.2 [(M+H)+], mp 150° C., was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 4-methoxyphenylboronic acid (49.4 mg, 325 μmol).
The title compound, white foam (81 mg, 86%), MS (ISP) m/z=378.3 [(M+H)+], was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 4-isopropylphenylboronic acid (53.3 mg, 325 μmol).
The title compound, white foam (75 mg, 80%), MS (ISP) m/z=376.2 [(M+H)+], was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 4-cyclopropylphenylboronic acid (52.6 mg, 325 μmol).
The title compound, white solid (81 mg, 83%), MS (ISP) m/z=392.3 [(M+H)+], mp 104° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 4) (96.7 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white solid (67 mg, 90%), MS (ISP) m/z=370.2 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1138323-00-8] (72.2 mg, 0.24 mmol) and commercially available 2-methylbutan-2-amine (17.4 mg, 23.4 μl, 0.2 mmol).
The title compound, white solid (50 mg, 70%), MS (ISP) m/z=356.2 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1138323-00-8] (80.2 mg, 0.24 mmol) and commercially available 2-methylpropan-2-amine (14.9 mg, 21.4 μl, 0.2 mmol).
The title compound, white solid (65 mg, 67%), MS (ISP) m/z=390.2 [(M+H)+], mp 190.5° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1000587-33-6] (70.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.3 mmol).
The title compound, white foam (77 mg, 78%), MS (ISP) m/z=394.3 [(M+H)+], mp 75° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 4) (96.7 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white solid (12 mg, 16%), MS (ISP) m/z=372.2 [(M+H)+], mp 137° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1138323-00-8] (80.2 mg, 0.24 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white solid (61 mg, 71%), MS (ISP) m/z=432.2 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1138323-00-8] (80.2 mg, 0.24 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (37.1 mg, 0.2 mmol).
The title compound, white solid (100 mg, 88%), MS (ISP) m/z=454.3 [(M+H)+], mp 112° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 4) (96.7 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, off-white solid (0.02 mg, 20%), MS (ISP) m/z=394.2 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(tetrazol-1-yl)-benzoic acid (intermediate 1) (71.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.3 mmol).
The title compound, white foam (100 mg, 93%), MS (ISP) m/z=432.3 [(M+H)+], mp 79° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 4) (80.6 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.3 mmol).
The title compound, white foam (95 mg, 94%), MS (ISP) m/z=404.3 [(M+H)+], mp 78° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 4) (96.7 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine (24.8 mg, 0.25 mmol).
The title compound, white solid (85 mg, 93%), MS (ISP) m/z=366.2 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(tetrazol-1-yl)-benzoic acid (intermediate 1) (85.3 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine (24.8 mg, 0.25 mmol).
The title compound, white foam (89 mg, 98%), MS (ISP) m/z=364.3 [(M+H)+], mp 80° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-methyltetrazol-1-yl)benzoic acid [CAS No. 1000587-69-8] (88.3 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (85 mg, 97%), MS (ISP) m/z=350.3 [(M+H)+], mp 85° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-methyltetrazol-1-yl)benzoic acid [CAS No. 1000587-69-8] (88.3 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, off-white foam (100 mg, 94%), MS (ISP) m/z=426.2 [(M+H)+], mp 69° C., was prepared in accordance with the general method of example 1 from 3-(4-methylphenyl)-5-(5-methyltetrazol-1-yl)benzoic acid [CAS No. 1000587-69-8] (88.3 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (90 mg, 84%), MS (ISP) m/z=430.3 [(M+H)+], mp 82° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)-benzoic acid (intermediate 5) (80.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.3 mmol).
The title compound, white foam (70 mg, 67%), MS (ISP) m/z=418.3 [(M+H)+], mp 78° C., was prepared in accordance with the general method of example 1 from 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)benzoic acid (intermediate 6) (77.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.3 mmol).
The title compound, white foam (95 mg, 98%), MS (ISP) m/z=390.3 [(M+H)+], mp 75° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)-benzoic acid (intermediate 5) (96.1 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (90 mg, 95%), MS (ISP) m/z=378.3 [(M+H)+], mp 71.5° C., was prepared in accordance with the general method of example 1 from 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)benzoic acid (intermediate 6) (92.5 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (60 mg, 64%), MS (ISP) m/z=376.3 [(M+H)+], mp 91° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)-benzoic acid (intermediate 5) (96.1 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (90 mg, 99%), MS (ISP) m/z=364.3 [(M+H)+], mp 73° C., was prepared in accordance with the general method of example 1 from 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)benzoic acid (intermediate 6) (92.5 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white solid (40 mg, 53%), MS (ISP) m/z=382.3 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1138323-00-8] (80.2 mg, 0.24 mmol) and commercially available 2-cyclopropylpropan-2-amine (19.8 mg, 0.20 mmol).
The title compound, colorless oil (50 mg, 51%), MS (ISP) m/z=392.3 [(M+H)+], was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)-benzoic acid (intermediate 5) (96.1 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (100 mg, 89%), MS (ISP) m/z=452.3 [(M+H)+], mp 130.5° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)-benzoic acid (intermediate 5) (96.1 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (100 mg, 91%), MS (ISP) m/z=440.3 [(M+H)+], mp 122° C., was prepared in accordance with the general method of example 1 from 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)benzoic acid (intermediate 6) (92.5 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (70 mg, 70%), MS (ISP) m/z=402.3 [(M+H)+], mp 74.5° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyltetrazol-1-yl)-5-(4-methylphenyl)-benzoic acid (intermediate 5) (96.1 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine (24.8 mg, 0.25 mmol).
The title compound, white foam (90 mg, 92%), MS (ISP) m/z=390.3 [(M+H)+], mp 59.5° C., was prepared in accordance with the general method of example 1 from 3-(5-ethyltetrazol-1-yl)-5-(4-methylphenyl)benzoic acid (intermediate 6) (92.5 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine (24.8 mg, 0.25 mmol).
The title compound, white foam (57 mg, 59%), MS (ISP) m/z=388.2 [(M+H)+], was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 μmol).
The title compound, white solid (59 mg, 58%), MS (ISP) m/z=404.2 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 325 μmol).
The title compound, white solid (25 mg, 27%), MS (ISP) m/z=372.2 [(M+H)+], mp 189° C., was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 325 μmol).
The title compound, white solid (56 mg, 58%), MS (ISP) m/z=388.2 [(M+H)+], mp 205° C., was prepared in accordance with the general method of example 7 from 3-iodo-N-tert-pentyl-5-(1H-tetrazol-1-yl)-benzamide (intermediate 3) (96.3 mg, 0.25 mmol) and commercially available 3-chloro-4-fluoro-phenylboronic acid (56.7 mg, 325 μmol).
3-(4-Chlorophenyl)-5-(tetrazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide
The title compound, white solid (62 mg, 61%), MS (ISP) m/z=410.2 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(tetrazol-1-yl)-benzoic acid [CAS No. 1138323-00-8] (75.2 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.3 mmol).
The title compound, white foam (80 mg, 78%), MS (ISP) m/z=412.2 [(M+H)+], mp 85° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoic acid (intermediate 7) (103 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (90 mg, 91%), MS (ISP) m/z=398.3 [(M+H)+], mp 90° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoic acid (intermediate 7) (103 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (100 mg, 94%), MS (ISP) m/z=424.2 [(M+H)+], mp 83° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoic acid (intermediate 7) (103 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine (24.8 mg, 0.25 mmol).
The title compound, white foam (110 mg, 93%), MS (ISP) m/z=474.2 [(M+H)+], mp 73° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoic acid (intermediate 7) (103 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (100 mg, 90%), MS (ISP) m/z=446.3 [(M+H)+], mp 89° C., was prepared in accordance with the general method of example 1 from 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 8) (113 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (70 mg, 65%), MS (ISP) m/z=432.3 [(M+H)+], mp 92° C., was prepared in accordance with the general method of example 1 from 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 8) (113 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (110 mg, 96%), MS (ISP) m/z=458.3 [(M+H)+], mp 90° C., was prepared in accordance with the general method of example 1 from 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 8) (113 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine (24.8 mg, 0.25 mmol).
The title compound, white foam (120 mg, 95%), MS (ISP) m/z=508.3 [(M+H)+], mp 117° C., was prepared in accordance with the general method of example 1 from 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 8) (113 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, colorless oil (40 mg, 39%), MS (ISP) m/z=414.3 [(M+H)+], was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoic acid (intermediate 7) (103 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, colorless liquid (90 mg, 81%), MS (ISP) m/z=448.3 [(M+H)+], was prepared in accordance with the general method of example 1 from 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 8) (113 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (100 mg, 89%), MS (ISP) m/z=452.3 [(M+H)+], mp 90° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)benzoic acid (intermediate 7) (85.7 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (100 mg, 82%), MS (ISP) m/z=486.3 [(M+H)+], mp 91° C., was prepared in accordance with the general method of example 1 from 3-(5-propan-2-yltetrazol-1-yl)-5-[4-(trifluoromethyl)-phenyl]-benzoic acid (intermediate 8) (94.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (100 mg, 89%), MS (ISP) m/z=450.2 [(M+H)+], mp 91.5° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoic acid (intermediate 9) (85.2 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (80 mg, 78%), MS (ISP) m/z=410.3 [(M+H)+], mp 78° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoic acid (intermediate 9) (102 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (95 mg, 96%), MS (ISP) m/z=396.2 [(M+H)+], mp 90° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoic acid (intermediate 9) (102 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (110 mg, 93%), MS (ISP) m/z=472.2 [(M+H)+], mp 126° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoic acid (intermediate 9) (102 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (50 mg, 49%), MS (ISP) m/z=412.2 [(M+H)+], mp 110° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoic acid (intermediate 9) (102 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (100 mg, 92%), MS (ISP) m/z=436.2 [(M+H)+], mp 80° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 10) (81.6 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (90 mg, 91%), MS (ISP) m/z=396.3 [(M+H)+], mp 69° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 10) (97.9 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (70 mg, 73%), MS (ISP) m/z=382.2 [(M+H)+], mp 85° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 10) (97.9 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (70 mg, 70%), MS (ISP) m/z=398.3 [(M+H)+], mp 86.5° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 10) (97.9 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (110 mg, 96%), MS (ISP) m/z=458.2 [(M+H)+], mp 112.5° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 10) (97.9 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white solid (60 mg, 62%), MS (ISP) m/z=386.2 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 13) (86.5 mg, 0.275 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (90 mg, 81%), MS (ISP) m/z=446.2 [(M+H)+], mp 155.5° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 13) (86.5 mg, 0.275 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (90 mg, 94%), MS (ISP) m/z=384.2 [(M+H)+], mp 80.5° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 13) (86.5 mg, 0.275 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (40 mg, 43%), MS (ISP) m/z=370.2 [(M+H)+], mp 98° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 13) (86.5 mg, 0.275 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (103 mg, 96%), MS (ISP) m/z=394.3 [(M+H)+], mp 74° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 11) (97.3 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white foam (30 mg, 32%), MS (ISP) m/z=380.3 [(M+H)+], mp 82° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 11) (97.3 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (90 mg, 85%), MS (ISP) m/z=424.2 [(M+H)+], mp 96° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 13) (78.7 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (80 mg, 81%), MS (ISP) m/z=396.2 [(M+H)+], mp 80° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 11) (97.3 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (90 mg, 89%), MS (ISP) m/z=406.3 [(M+H)+], mp 73° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 11) (97.3 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, white foam (30 mg, 28%), MS (ISP) m/z=434.3 [(M+H)+], mp 81° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 11) (81.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white solid (80 mg, 73%), MS (ISP) m/z=438.2 [(M+H)+], mp 185° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[5-(trifluoromethyl)-tetrazol-1-yl]-benzoic acid (intermediate 14) (101 mg, 0.275 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white solid (90 mg, 85%), MS (ISP) m/z=424.3 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[5-(trifluoromethyl)-tetrazol-1-yl]-benzoic acid (intermediate 14) (101 mg, 0.275 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (80 mg, 73%), MS (ISP) m/z=440.2 [(M+H)+], mp 89° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[5-(trifluoromethyl)-tetrazol-1-yl]-benzoic acid (intermediate 14) (101 mg, 0.275 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (110 mg, 97%), MS (ISP) m/z=456.3 [(M+H)+], mp 120° C., was prepared in accordance with the general method of example 1 from 3-(5-cyclopropyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 11) (97.3 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (80 mg, 87%), MS (ISP) m/z=368.3 [(M+H)+], mp 83° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 12) (89.5 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white solid (100 mg, 84%), MS (ISP) m/z=478.2 [(M+H)+], mp 166.5° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-[5-(trifluoromethyl)-tetrazol-1-yl]-benzoic acid (intermediate 14) (92.2 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (84 mg, %), MS (ISP) m/z=354.2 [(M+H)+], mp 80° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 12) (89.5 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (90 mg, 85%), MS (ISP) m/z=422.2 [(M+H)+], mp 95° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-cyclopropyltetrazol-1-yl)-benzoic acid (intermediate 9) (102 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, white foam (100 mg, 98%), MS (ISP) m/z=408.3 [(M+H)+], mp 75° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 10) (97.9 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, white solid (90 mg, 91%), MS (ISP) m/z=396.2 [(M+H)+], mp 85° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 13) (94.4 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, white foam (50 mg, 54%), MS (ISP) m/z=370.2 [(M+H)+], mp 85° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 12) (89.5 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white foam (94.3 mg, 99%), MS (ISP) m/z=380.2 [(M+H)+], mp 78° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 12) (89.5 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, white foam (90 mg, 88%), MS (ISP) m/z=408.2 [(M+H)+], mp 86° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 12) (74.6 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white foam (100 mg, 93%), MS (ISP) m/z=430.2 [(M+H)+], mp 117° C., was prepared in accordance with the general method of example 1 from 3-(4-fluorophenyl)-5-(5-methyltetrazol-1-yl)-benzoic acid (intermediate 12) (89.5 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (100 mg, 94%), MS (ISP) m/z=428.2 [(M+H)+], mp 112° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-chlorophenyl)-benzoic acid (intermediate 15) (98.1 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=488.2 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-chlorophenyl)-benzoic acid (intermediate 15) (98.1 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white foam (100 mg, 94%), MS (ISP) m/z=426.3 [(M+H)+], mp 119° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-chlorophenyl)-benzoic acid (intermediate 15) (98.1 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white solid (70 mg, 68%), MS (ISP) m/z=412.3 [(M+H)+], mp 230.5° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-chlorophenyl)-benzoic acid (intermediate 15) (98.1 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white foam (100 mg, 91%), MS (ISP) m/z=438.2 [(M+H)+], mp 101° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-chlorophenyl)-benzoic acid (intermediate 15) (98.1 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, white solid (110 mg, 94%), MS (ISP) m/z=466.2 [(M+H)+], mp 218.5° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-chlorophenyl)-benzoic acid (intermediate 15) (89.2 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white solid (100 mg, 97%), MS (ISP) m/z=412.3 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (102 mg, 0.30 mmol) and commercially available 2-amino-2-methylpropan-1-ol (22.3 mg, 24.0 μl, 0.25 mmol).
The title compound, white solid (100 mg, 85%), MS (ISP) m/z=472.2 [(M+H)+], mp 258.5° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (102 mg, 0.30 mmol) and commercially available (RS)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (46.4 mg, 0.25 mmol).
The title compound, white solid (110 mg, 98%), MS (ISP) m/z=450.2 [(M+H)+], mp 224.5° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (85.1 mg, 0.25 mmol) and commercially available 1,1,1-trifluoro-2-methylpropan-2-amine (38.9 mg, 0.30 mmol).
The title compound, white solid (90 mg, 88%), MS (ISP) m/z=410.3 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (102 mg, 0.30 mmol) and commercially available 2-methylbutan-2-amine (21.8 mg, 29.2 μl, 0.25 mmol).
The title compound, white solid (98 mg, 99%), MS (ISP) m/z=396.2 [(M+H)+], mp 223.5° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (102 mg, 0.30 mmol) and commercially available 2-methylpropan-2-amine (18.6 mg, 26.7 μl, 0.25 mmol).
The title compound, white solid (100 mg, 95%), MS (ISP) m/z=422.3 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (102 mg, 0.30 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (33.9 mg, 0.25 mmol).
The title compound, off-white foam (30 mg, 30%), MS (ISP) m/z=407.2 [(M+H)+], mp 115° C., was prepared in accordance with the general method of example 1 from 3-(5-tert-butyl-tetrazol-1-yl)-5-(4-fluorophenyl)-benzoic acid (intermediate 16) (102 mg, 0.30 mmol) and commercially available 2-amino-2-methyl-propanenitrile (21.0 mg, 0.25 mmol).
The title compound, off-white foam (30 mg, 29%), MS (ISP) m/z=409.2 [(M+H)+], mp 107° C., was prepared in accordance with the general method of example 1 from 3-(4-chlorophenyl)-5-(5-propan-2-yltetrazol-1-yl)-benzoic acid (intermediate 7) (103 mg, 0.30 mmol) and commercially available 2-amino-2-methyl-propanenitrile (21.0 mg, 0.25 mmol).
The title compound, white solid (98 mg, 100%), MS (ISP) m/z=392.3 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 4-methylphenylboronic acid (44.2 mg, 325 μmol).
The title compound, white foam (90 mg, 88%), MS (ISP) m/z=410.3 [(M+H)+], mp 190.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 325 μmol).
The title compound, white solid (100 mg, 90%), MS (ISP) m/z=446.3 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 325 μmol).
The title compound, white solid (70 mg, 65%), MS (ISP) m/z=430.2 [(M+H)+], mp 240.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 μmol).
The title compound, white solid (100 mg, 97%), MS (ISP) m/z=414.3 [(M+H)+], mp 225.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 325 μmol).
The title compound, white foam (100 mg, 96%), MS (ISP) m/z=418.3 [(M+H)+], mp 115° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 4-cyclopropyl-phenylboronic acid (52.6 mg, 325 μmol).
The title compound, white solid (100 mg, 98%), MS (ISP) m/z=410.3 [(M+H)+], mp 227.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-N-tert-butyl-5-(5-tert-butyltetrazol-1-yl)-benzamide (intermediate 17) (95.1 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 325 μmol).
The title compound, white foam (100 mg, 96%), MS (ISP) m/z=418.3 [(M+H)+], mp 91.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 4-methylphenylboronic acid (44.2 mg, 325 μmol).
The title compound, white foam (100 mg, 92%), MS (ISP) m/z=436.3 [(M+H)+], mp 88° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 325 μmol).
The title compound, white foam (110 mg, 93%), MS (ISP) m/z=472.3 [(M+H)+], mp 95.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 325 μmol).
The title compound, white foam (90 mg, 79%), MS (ISP) m/z=456.2 [(M+H)+], mp 106.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 μmol).
The title compound, white foam (110 mg, 100%), MS (ISP) m/z=440.3 [(M+H)+], mp 90° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 325 μmol).
The title compound, white foam (110 mg, 99%), MS (ISP) m/z=444.3 [(M+H)+], mp 95° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 4-cyclopropyl-phenylboronic acid (52.6 mg, 325 μmol).
The title compound, white foam (100 mg, 92%), MS (ISP) m/z=436.3 [(M+H)+], mp 92° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyclopropylpropan-2-yl)-benzamide (intermediate 18) (102 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 325 μmol).
The title compound, white foam (120 mg, 96%), MS (ISP) m/z=500.2 [(M+H)+], mp 108° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide (intermediate 19) (109 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 325 μmol).
The title compound, white solid (100 mg, 90%), MS (ISP) m/z=446.2 [(M+H)+], mp 223.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide (intermediate 19) (109 mg, 0.25 mmol) and commercially available 4-methylphenylboronic acid (44.2 mg, 325 μmol).
The title compound, white solid (110 mg, 95%), MS (ISP) m/z=464.2 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide (intermediate 19) (109 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 325 μmol).
The title compound, white solid (90 mg, 74%), MS (ISP) m/z=484.2 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide (intermediate 19) (109 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 μmol).
The title compound, white solid (68 mg, 60%), MS (ISP) m/z=457.2 [(M+H)+], mp 276.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyanopropan-2-yl)-benzamide (intermediate 20) (97.8 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 325 μmol).
The title compound, white solid (60 mg, 54%), MS (ISP) m/z=441.2 [(M+H)+], mp 261.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyanopropan-2-yl)-benzamide (intermediate 20) (97.8 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 μmol).
The title compound, white solid (110 mg, 94%), MS (ISP) m/z=468.2 [(M+H)+], mp 221.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-benzamide (intermediate 19) (109 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 325 μmol).
The title compound, white solid (77 mg, 73%), MS (ISP) m/z=425.2 [(M+H)+], mp 263.5° C., was prepared in accordance with the general method of example 7 from 3-bromo-5-(5-tert-butyltetrazol-1-yl)-N-(2-cyanopropan-2-yl)-benzamide (intermediate 20) (97.8 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 325 μmol).
| Number | Date | Country | Kind |
|---|---|---|---|
| 15164885 | Apr 2015 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2016/058594 | 4/19/2016 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2016/169902 | 10/27/2016 | WO | A |
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| 2006-151954 | Jun 2006 | JP |
| 2010-540585 | Dec 2010 | JP |
| 2011-528658 | Nov 2011 | JP |
| 2007042545 | Apr 2007 | WO |
| 2008000645 | Jan 2008 | WO |
| 2009043780 | Apr 2009 | WO |
| 2009077365 | Jun 2009 | WO |
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| 2010009062 | Jan 2010 | WO |
| 2010033168 | Mar 2010 | WO |
| 2010051188 | May 2010 | WO |
| 2016169902 | Oct 2016 | WO |
| 2016193235 | Dec 2016 | WO |
| 2017009274 | Jan 2017 | WO |
| 2017072083 | May 2017 | WO |
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| 20180297961 A1 | Oct 2018 | US |
