Pyridine or pyrimidine derivatives
10155741 ยท 2018-12-18
Assignee
Inventors
Cpc classification
C07D239/24
CHEMISTRY; METALLURGY
A61K31/444
HUMAN NECESSITIES
A61P25/18
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
C07D401/04
CHEMISTRY; METALLURGY
International classification
C07D401/04
CHEMISTRY; METALLURGY
A61P25/18
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
C07D211/80
CHEMISTRY; METALLURGY
C07D239/24
CHEMISTRY; METALLURGY
Abstract
The present invention relates to compounds of formula I ##STR00001##
wherein R.sup.1 is methyl; R.sup.1 is methyl, ethyl, CF.sub.3, CH.sub.2OH, cyclopropyl or cyano, or R.sup.1 and R.sup.1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl; R.sup.3 is Cl, F, CF.sub.3, methyl, methoxy, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; X is N or CH; Y is N or CH; with the proviso that X and Y are not simultaneously CH;
or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer. The compounds of formula I may be used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.
Claims
1. A compound of formula I: ##STR00087## wherein R.sup.1 is methyl; R.sup.1 is methyl, ethyl, CF.sub.3, CH.sub.2OH, cyclopropyl or cyano, or R.sup.1 and R.sup.1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl; R.sup.3 is Cl, F, CF.sub.3, methyl, methoxy, or cyclopropyl; R.sup.4 is hydrogen, methyl, F or Cl; X is N or CH; Y is N or CH; with the proviso that X and Y are not simultaneously CH; or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer.
2. A compound of formula IA according to claim 1: ##STR00088## wherein R.sup.1 is methyl; R.sup.1 is methyl, ethyl, CF.sub.3, CH.sub.2OH, cyclopropyl or cyano, or R.sup.1 and R.sup.1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl; R.sup.3 is Cl, F, CF.sub.3, methyl, methoxy, or cyclopropyl; R.sup.4 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.
3. A compound of formula IA according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-propan-2-yl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide; N-tert-Butyl-2-(4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(3,4-difluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-fluoro-3-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-chloro-3-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-cyclopropyl-phenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; 2-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; 2-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; 2-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; 2-(4-Chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-methoxyphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(3-fluoro-4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; (RS)-2-(4-Fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carb oxamide; 2-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-ethyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyrimidin-5-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-cyclopropylpyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-tert-butylpyrimidin-5-yl)-6-(4-chlorophenyl)-pyridine-4-carboxamide; and N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide.
4. A compound of formula IB according to claim 1: ##STR00089## wherein R.sup.1 is methyl; R.sup.1 is methyl, ethyl, CF.sub.3, CH.sub.2OH, cyclopropyl or cyano, or R.sup.1 and R.sup.1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R.sup.2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl; R.sup.3 is Cl, F, CF.sub.3, methyl, methoxy, or cyclopropyl; R.sup.4 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.
5. A compound of formula IB according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-chlorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide; N-tert-Butyl-2-(4-propan-2-yl-pyridin-3-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide; N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide; and N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide.
6. A process for the manufacture of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1, which process comprises: a) reacting a compound of formula ##STR00090## with a compound of formula ##STR00091## to form a compound of formula I ##STR00092## or b) reacting a compound of formula ##STR00093## with a compound of formula ##STR00094## to form a compound of formula I ##STR00095##
7. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
8. A method for the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder in a mammal, which method comprises administering an effective amount of a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, to the mammal.
Description
LIST OF EXAMPLES AND DATA
(1) TABLE-US-00001 EAAT3 Kb Structure Compound name [M] 1
(2) 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, drages, 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.
(3) 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, drages 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.
(4) 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.
(5) 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.
(6) 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.
(7) 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.
(8) Preparation of Pharmaceutical Compositions Comprising Compounds of the Invention:
(9) Tablets of the following composition are manufactured in the usual manner:
(10) TABLE-US-00002 mg/tablet ingredient 5 25 100 500 Compound of formula I 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total 167 167 167 831
(11) Manufacturing Procedure
(12) 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
(13) 2. Dry the granules at 50 C.
(14) 3. Pass the granules through suitable milling equipment.
(15) 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.
(16) Capsules of the following composition are manufactured:
(17) TABLE-US-00003 mg/capsule ingredient 5 25 100 500 Compound of formula I 5 25 100 500 Hydrous Lactose 159 123 148 Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5 Total 200 200 300 600
(18) Manufacturing Procedure
(19) 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.
(20) 2. Add ingredients 4 and 5 and mix for 3 minutes.
(21) 3. Fill into a suitable capsule.
(22) 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.
(23) Injection solutions of the following composition are manufactured:
(24) TABLE-US-00004 ingredient mg/injection solution. Compound of formula I 3 Polyethylene Glycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml
(25) Manufacturing Procedure
(26) 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.
Experimental Section
Intermediates
Intermediate 1: 2-Bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide
(27) ##STR00050##
Step A
(28) To a stirred solution of commercially available 2,6-dibromoisonicotinic acid (3 g, 10.7 mmol) in THF (77 ml) was added N,N-diisopropylethylamine (3.45 g, 4.66 ml, 26.7 mmol), commercially available 2-methylpropan-2-amine (956 mg, 1.37 ml, 12.8 mmol) and TBTU (4.46 g, 13.9 mmol). The reaction mixture was allowed to stir for 17 h at room temperature, filtered, evaporated and purified by flash chromatography on silica gel [heptane/ethyl acetate (0-50%)] to yield 2,6-dibromo-N-tert-butylpyridine-4-carboxamide (3.28 g, 91%) as an off-white solid, MS (ISP) m/z=337.0 [(M+H).sup.+], mp 148 C.
(29) Step B
(30) A mixture of 2,6-dibromo-N-tert-butylpyridine-4-carboxamide (3.28 g, 9.76 mmol), commercially available (4-fluorophenyl)-boronic acid (1.37 g, 9.76 mmol), potassium carbonate (1.35 g, 9.76 mmol) and PdCl.sub.2(dppf) (239 mg, 293 mol) in methanol (39 ml) was heated at 100 C. for 10 min in a microwave reactor. The reaction mixture was filtered and purified by flash chromatography on silica gel [heptane/ethyl acetate 4:1] to give 3.32 g of an off-white solid which was further purified by reverse phase HPLC (acetonitrile/formic acid 98:2) to yield the title compound (1.59 g, 46%) as an off-white solid, MS (ISP) m/z=351.1 [(M+H).sup.+], mp 209 C.
Intermediate 2: 2-Bromo-N-tert-butyl-6-(4-chlorophenyl)-pyridine-4-carboxamide
(31) ##STR00051##
(32) The title compound, white solid (0.74 g, 31%), MS (ISP) m/z=369.0 [(M+H).sup.+], mp 208 C., was prepared in accordance with the general method of intermediate 1, step B, from 2,6-dibromo-N-tert-butylpyridine-4-carboxamide (intermediate 1, step A) (2.18 g, 6.49 mmol) and commercially available (4-chlorophenyl)-boronic acid (1.01 g, 6.49 mmol).
Intermediate 3: 2-Bromo-N-tert-butyl-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide
(33) ##STR00052##
(34) The title compound, white solid (1.02 g, 40%), MS (ISP) m/z=403.0 [(M+H).sup.+], mp 239 C., was prepared in accordance with the general method of intermediate 1, step B, from 2,6-dibromo-N-tert-butylpyridine-4-carboxamide (intermediate 1, step A) (2.15 g, 6.40 mmol) and commercially available (4-trifluoromethylphenyl)-boronic acid (1.22 g, 6.40 mmol).
Intermediate 4: 2-Bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(35) ##STR00053##
(36) The title compound, yellow foam (0.57 g, 45%), MS (ISP) m/z=377.1 [(M+H).sup.+], was prepared in accordance with the general method of intermediate 1, step B, from 2,6-dibromo-N-tert-butylpyridine-4-carboxamide (intermediate 1, step A) (1.13 g, 3.37 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (0.56 g, 3.37 mmol).
Intermediate 5: 2-Bromo-6-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-pyridine-4-carboxamide
(37) ##STR00054##
Step A
(38) 2,6-Dibromo-N-(2-cyclopropylpropan-2-yl)-pyridine-4-carboxamide, white solid (2.48 g, 96%), MS (ISP) m/z=363.0 [(M+H).sup.+], mp 119 C., was prepared in accordance with the general method of intermediate 1, step A, from commercially available 2,6-dibromo-isonicotinic acid (2.0 g, 7.12 mmol) and commercially available 2-cyclopropylpropan-2-amine hydrochloride (1.16 g, 8.54 mmol).
(39) Step B
(40) The title compound, white solid (0.70 g, 26%), MS (ISP) m/z=395.0 [(M+H).sup.+], mp 185 C., was prepared in accordance with the general method of intermediate 1, step B, from 2,6-dibromo-N-(2-cyclopropylpropan-2-yl)-pyridine-4-carboxamide (intermediate 5, step A) (2.48 g, 6.85 mmol) and commercially available (4-chlorophenyl)-boronic acid (1.07 g, 6.85 mmol).
Intermediate 6: 2-Bromo-6-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide
(41) ##STR00055##
Step A
(42) A mixture of commercially available methyl 2-bromoisonicotinate (3.0 g, 13.9 mmol), commercially available (4-chlorophenyl)-boronic acid (2.61 g, 16.7 mmol), potassium carbonate (2.30 g, 16.7 mmol) and PdCl.sub.2(dppf) (340 mg, 417 mol) in methanol (27 ml) was heated at 100 C. for 10 min in a microwave reactor. The reaction mixture was filtered and purified by flash chromatography on silica gel [heptane/ethyl acetate 4:1] to yield methyl 2-(4-chlorophenyl)-pyridine-4-carboxylate (3.16 g, 92%) as a white solid, MS (ISP) m/z=248.1 [(M+H).sup.+], mp 74 C.
(43) Step B
(44) A stirred solution of methyl 2-(4-chlorophenyl)-pyridine-4-carboxylate (3.15 g, 12.7 mmol) in dichloromethane (36 ml) was cooled to 0 C. in an ice-bath, m-chloro-perbenzoic acid (5.7 g, 25.4 mmol) was added and the reaction mixture was allowed to stir for 17 h at room temperature. 1N NaOH (60 ml) was added and the mixture was extracted with dichloromethane (250 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (50 ml) and brine (50 ml), dried (MgSO.sub.4) and evaporated to yield methyl 2-(4-chlorophenyl)-1-oxido-1-pyridinium-4-carboxylate (3.15 g, 94%) as an off-white solid, MS (ISP) m/z=264.0 [(M+H).sup.+], mp 135 C.
(45) Step C
(46) A stirred solution of methyl 2-(4-chlorophenyl)-1-oxido-1-pyridinium-4-carboxylate (3.15 g, 11.9 mmol) in toluene (60 ml) was heated to 80 C., phosphorus oxybromide (13.7 g, 47.8 mmol) was added and the reaction mixture was allowed to stir for 2 h at 80 C. The reaction mixture was cooled to room temperature, poured into ice/water (100 ml) and extracted with ethyl acetate (270 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO.sub.4) and evaporated. The crude product (4.25 g) was further purified by flash chromatography on silica gel (DCM/MeOH 95:5) to yield methyl 2-bromo-6-(4-chlorophenyl)-pyridine-4-carboxylate (1.40 g, 36%) as an off-white solid, MS (ISP) m/z=327.9 [(M+H).sup.+], mp 101 C.
(47) Step D
(48) To a stirred solution of methyl 2-bromo-6-(4-chlorophenyl)-pyridine-4-carboxylate (1.40 g, 4.29 mmol) in THF (7 ml), methanol (7 ml) and water (7 ml), lithium hydroxide monohydrate (234 mg, 5.57 mmol) was added and the reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was concentrated to one third, 2N HCl solution (5 ml) was added, the precipitate was collected by filtration, washed with water and dried to yield 2-bromo-6-(4-chlorophenyl)-pyridine-4-carboxylic acid (1.18 g, 88%) as a white solid, MS (ISP) m/z=313.9 [(M+H).sup.+], mp 191 C.
(49) Step E
(50) A stirred solution of 2-bromo-6-(4-chlorophenyl)-pyridine-4-carboxylic acid (500 mg, 1.6 mmol) in THF (12.8 ml) was cooled in an ice bath to 0 C., oxalyl chloride (4.63 g, 3.19 ml, 36.5 mmol) and DMF (64.2 l) were added, the reaction mixture was allowed to stir for 1 h at room temperature, and evaporated. THF (13 ml), 1,1,1-trifluoro-2-methylpropan-2-amine (244 mg, 220 l, 1.92 mmol) and N,N-diisopropylethylamine (724 mg, 958 l, 5.6 mmol) were added, the reaction mixture was allowed to stir for 17 h at room temperature and evaporated. Purification by flash chromatography on silica gel [heptane/ethyl acetate (0-50%)] yielded the title compound (0.58 g, 86%) as an off-white solid, MS (ISN) m/z=421.2 [(MH).sup.], mp 192 C.
Intermediate 7: 2-Bromo-6-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-pyridine-4-carboxamide
(51) ##STR00056##
(52) The title compound, light brown foam (352 mg, 93%), MS (ISP) m/z=380.0 [(M+H).sup.+], was prepared in accordance with the general method of intermediate 6, step E, from 2-bromo-6-(4-chlorophenyl)-pyridine-4-carboxylic acid (intermediate 6, step D) (313 mg, 1.0 mmol) and commercially available 2-amino-2-methylpropanenitrile (126 mg, 1.5 mmol).
Intermediate 8: 2-Bromo-6-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-pyridine-4-carboxamide
(53) ##STR00057##
(54) To a stirred solution of 2-bromo-6-(4-chlorophenyl)-pyridine-4-carboxylic acid (intermediate 6, step D) (313 mg, 1.0 mmol) in THF (7.2 ml) was added at room temperature N,N-diisopropylethylamine (323 mg, 437 l, 2.5 mmol), commercially available 2-amino-2-methylpropan-1-ol (134 mg, 144 l, 1.5 mmol) and TBTU (514 mg, 1.6 mmol). The reaction mixture was allowed to stir for 17 h at room temperature, filtered and purified by flash chromatography [heptane/ethyl acetate (20-80%)] to yield title compound (284 mg, 74%) as a white solid, MS (ISN) m/z=385.0 [(M+H).sup.+], mp 174 C.
Intermediate 9: (RS)-2-Bromo-6-(4-fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-pyridine-4-carboxamide
(55) ##STR00058##
Step A
(56) (RS)-2,6-Dibromo-N-(3-methyl-1,1-dioxothiolan-3-yl)-pyridine-4-carboxamide, white foam (0.97 g, 94%), MS (ISP) m/z=413.0 [(M+H).sup.+], was prepared in accordance with the general method of intermediate 1, step A, from commercially available 2,6-dibromo-isonicotinic acid (0.70 g, 2.50 mmol) and commercially available (RS)-3-amino-3-methyltetrahydro-thiophene 1,1-dioxide hydrochloride (0.56 g, 3.0 mmol).
(57) Step B
(58) The title compound, white foam (498 mg, 50%), MS (ISP) m/z=429.0 [(M+H).sup.+], was prepared in accordance with the general method of intermediate 1, step B, from (RS)-2,6-dibromo-N-(3-methyl-1,1-dioxothiolan-3-yl)-pyridine-4-carboxamide (0.96 g, 2.33 mmol) and commercially available (4-fluorophenyl)-boronic acid (326 mg, 2.33 mmol).
Intermediate 10: 2-Bromo-6-(4-fluorophenyl)-N-(2-methylbutan-2-yl)-pyridine-4-carboxamide
(59) ##STR00059##
Step A
(60) 2,6-Dibromo-N-(2-methylbutan-2-yl)-pyridine-4-carboxamide, light brown solid (0.79 g, 90%), MS (ISP) m/z=351.0 [(M+H).sup.+], mp 92 C., was prepared in accordance with the general method of intermediate 1, step A, from commercially available 2,6-dibromo-isonicotinic acid (0.70 g, 2.50 mmol) and commercially available 2-methylbutan-2-amine (0.26 g, 3.0 mmol).
(61) Step B
(62) The title compound, white solid (303 mg, 37%), MS (ISP) m/z=367.1 [(M+H).sup.+], mp 193 C., was prepared in accordance with the general method of intermediate 1, step B, from 2,6-dibromo-N-(2-methylbutan-2-yl)-pyridine-4-carboxamide (0.78 g, 2.23 mmol) and commercially available (4-fluorophenyl)-boronic acid (312 mg, 2.23 mmol).
Example 1
N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(63) ##STR00060##
(64) In a tube a mixture of 2-bromo-N-tert-butyl-6-(4-chlorophenyl)-pyridine-4-carboxamide (intermediate 2) (91.9 mg, 0.25 mmol), (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol), 1,2-dimethoxyethane (1.7 ml) and 2M sodium carbonate solution (416 l, 833 mol) was purged with argon in an ultrasonic bath during 5 min, triphenylphosphine (13.1 mg, 50 mol) and palladium(II)acetate (5.61 mg, 25 mol) were added, the tube was sealed and the reaction mixture was allowed to stir for 5 h at 105 C. The crude reaction mixture was purified by flash chromatography on silica gel [heptane/ethyl acetate (20-80%)] to yield the title compound (69 mg, 68%) as a white foam, MS (ISP) m/z=409.2 [(M+H).sup.+].
Example 2
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(65) ##STR00061##
(66) The title compound, light brown foam (69 mg, 70%), MS (ISP) m/z=393.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol).
Example 3
N-tert-Butyl-2-(4-propan-2-yl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide
(67) ##STR00062##
(68) The title compound, off-white foam (79 mg, 71%), MS (ISP) m/z=443.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide (intermediate 3) (100 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol).
Example 4
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide
(69) ##STR00063##
(70) The title compound, light yellow foam (40 mg, 44%), MS (ISP) m/z=364.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and commercially available (4-methylpyridin-3-yl)-boronic acid (44.5 mg, 325 mol).
Example 5
N-tert-Butyl-2-(4-chlorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide
(71) ##STR00064##
(72) The title compound, off-white foam (31 mg, 33%), MS (ISP) m/z=380.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-chlorophenyl)-pyridine-4-carboxamide (intermediate 2) (91.9 mg, 0.25 mmol) and commercially available (4-methylpyridin-3-yl)-boronic acid (44.5 mg, 325 mol).
Example 6
N-tert-Butyl-2-(4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(73) ##STR00065##
(74) The title compound, off-white foam (70 mg, 72%), MS (ISP) m/z=389.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (94.3 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 325 mol).
Example 7
N-tert-Butyl-2-(3,4-difluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(75) ##STR00066##
(76) The title compound, light yellow solid (90 mg, 88%), MS (ISP) m/z=411.2 [(M+H).sup.+], mp 178 C., was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (94.3 mg, 0.25 mmol) and commercially available (3,4-difluoro-phenyl)-boronic acid (51.3 mg, 325 mol).
Example 8
N-tert-Butyl-2-(4-fluoro-3-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(77) ##STR00067##
(78) The title compound, light yellow foam (93 mg, 92%), MS (ISP) m/z=407.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (94.3 mg, 0.25 mmol) and commercially available (4-fluoro-3-methyl-phenyl)boronic acid (50.0 mg, 325 mol).
Example 9
N-tert-Butyl-2-(4-chloro-3-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(79) ##STR00068##
(80) The title compound, white foam (52 mg, 49%), MS (ISP) m/z=427.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (94.3 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 325 mol).
Example 10
N-tert-Butyl-2-(4-cyclopropyl-phenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(81) ##STR00069##
(82) The title compound, light yellow foam (96 mg, 93%), MS (ISP) m/z=415.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (94.3 mg, 0.25 mmol) and commercially available (4-cyclopropyl-phenyl)-boronic acid (52.6 mg, 325 mol).
Example 11
2-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(83) ##STR00070##
(84) The title compound, off-white foam (92 mg, 85%), MS (ISP) m/z=435.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-6-(4-chlorophenyl)-N-(2-cyclopropylpropan-2-yl)-pyridine-4-carboxamide (intermediate 5) (98.4 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol).
Example 12
2-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(85) ##STR00071##
(86) The title compound, off-white foam (48 mg, 46%), MS (ISP) m/z=420.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-6-(4-chlorophenyl)-N-(2-cyanopropan-2-yl)-pyridine-4-carboxamide (intermediate 7) (94.7 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol).
Example 13
2-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(87) ##STR00072##
(88) The title compound, white foam (67 mg, 63%), MS (ISP) m/z=425.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-6-(4-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-pyridine-4-carboxamide (intermediate 8) (95.9 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol).
Example 14
2-(4-Chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-N-(1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide
(89) ##STR00073##
(90) The title compound, light yellow foam (73 mg, 63%), MS (ISP) m/z=463.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-6-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide (intermediate 6) (105 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (53.9 mg, 325 mol).
Example 15
N-tert-Butyl-2-(4-methoxyphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(91) ##STR00074##
(92) The title compound, off-white foam (98 mg, 97%), MS (ISP) m/z=405.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (94.3 mg, 0.25 mmol) and commercially available (4-methoxyphenyl)-boronic acid (49.4 mg, 325 mol).
Example 16
N-tert-Butyl-2-(3-fluoro-4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(93) ##STR00075##
(94) The title compound, light brown foam (67 mg, 84%), MS (ISP) m/z=407.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide (intermediate 4) (74.0 mg, 196 mol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (39.3 mg, 255 mol).
Example 17
(RS)-2-(4-Fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(95) ##STR00076##
(96) The title compound, light yellow foam (104 mg, 89%), MS (ISP) m/z=469.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from (RS)-2-bromo-6-(4-fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-pyridine-4-carboxamide (intermediate 9) (107 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (49.8 mg, 300 mol).
Example 18
2-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide
(97) ##STR00077##
(98) The title compound, light yellow foam (89 mg, 88%), MS (ISP) m/z=407.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-6-(4-fluorophenyl)-N-(2-methylbutan-2-yl)-pyridine-4-carboxamide (intermediate 10) (91.3 mg, 0.25 mmol) and commercially available (4-isopropyl-pyrimidin-5-yl)-boronic acid (49.8 mg, 300 mol).
Example 19
N-tert-Butyl-2-(4-ethyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide
(99) ##STR00078##
(100) The title compound, colorless semisolid (33 mg, 35%), MS (ISP) m/z=379.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and commercially available 4-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidine [CAS-No. 1375303-42-6] (76.1 mg, 325 mol).
Example 20
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyrimidin-5-yl)-pyridine-4-carboxamide
(101) ##STR00079##
(102) The title compound, off-white foam (21 mg, 22%), MS (ISP) m/z=365.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and commercially available 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidine [CAS-No. 1370001-96-9] (82.5 mg, 375 mol).
Example 21
N-tert-Butyl-2-(4-cyclopropylpyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide
(103) ##STR00080##
(104) The title compound, off-white foam (9 mg, 9%), MS (ISP) m/z=391.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and commercially available 4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidine [CAS-No. 1375303-49-3] (92.3 mg, 375 mol).
Example 22
N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide
(105) ##STR00081##
Step A
(106) To a stirred solution of commercially available 5-bromo-4-(tert-butyl)-pyrimidine (215 mg, 1 mmol) in THF (1 ml) and toluene (4 ml) was added triisopropyl borate (229 mg, 282 l, 1.22 mmol) at 78 C. followed by a drop-wise addition of n-butyl lithium (1.6N in hexane) (731 l, 1.17 mmol) at 78 C. The solution was allowed to stir at 78 C. for 45 min and then allowed to warm to room temperature. The reaction mixture was quenched by addition of 1M hydrochloride solution (2.5 ml) to pH=1, diluted with water (5 ml) and extracted with diethyl acetate (240 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO.sub.4) and evaporated to yield (4-(tert-butyl)-pyrimidin-5-yl)-boronic acid (135 mg) as a light yellow oil, MS (ISP) m/z=181.1 [(M+H).sup.+], which was used without further purification.
(107) Step B
(108) The title compound, off-white foam (95 mg, 94%), MS (ISP) m/z=349.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and (4-(tert-butyl)-pyrimidin-5-yl)-boronic acid (65.0 mg, 0.36 mmol).
Example 23
N-tert-Butyl-2-(4-tert-butylpyrimidin-5-yl)-6-(4-chlorophenyl)-pyridine-4-carboxamide
(109) ##STR00082##
(110) The title compound, off-white foam (69 mg, 65%), MS (ISP) m/z=423.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-chlorophenyl)-pyridine-4-carboxamide (intermediate 2) (91.9 mg, 0.25 mmol) and (4-(tert-butyl)-pyrimidin-5-yl)-boronic acid (example 22, step A) (65.0 mg, 0.36 mmol).
Example 24
N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide
(111) ##STR00083##
(112) The title compound, light yellow foam (76 mg, 67%), MS (ISP) m/z=457.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide (intermediate 3) (100 mg, 0.25 mmol) and (4-(tert-butyl)-pyrimidin-5-yl)-boronic acid (example 22, step A) (65.0 mg, 0.36 mmol).
Example 25
N-tert-Butyl-2-(4-propan-2-yl-pyridin-3-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide
(113) ##STR00084##
(114) The title compound, white foam (110 mg, 100%), MS (ISP) m/z=442.3 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide (intermediate 3) (100 mg, 0.25 mmol) and commercially available (4-isopropyl-pyridin-3-yl)-boronic acid (53.6 mg, 325 mol).
Example 26
N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide
(115) ##STR00085##
(116) The title compound, white foam (102 mg, 100%), MS (ISP) m/z=408.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-chlorophenyl)-pyridine-4-carboxamide (intermediate 2) (91.9 mg, 0.25 mmol) and commercially available (4-isopropyl-pyridin-3-yl)-boronic acid (53.6 mg, 325 mol).
Example 27
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide
(117) ##STR00086##
(118) The title compound, white foam (97 mg, 99%), MS (ISP) m/z=392.2 [(M+H).sup.+], was prepared in accordance with the general method of example 1 from 2-bromo-N-tert-butyl-6-(4-fluorophenyl)-pyridine-4-carboxamide (intermediate 1) (87.8 mg, 0.25 mmol) and commercially available (4-isopropyl-pyridin-3-yl)-boronic acid (53.6 mg, 325 mol).