Flouro-naphthyl derivatives

Abstract

The present invention relates to compounds of formula ##STR00001## wherein R.sup.1 is C.sub.4-6-cycloalkyl or C.sub.4-6-heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl; A is phenyl, pyridinyl or piperidinyl; R.sup.2 is hydrogen, halogen, lower alkyl, cyano, C.sub.4-6-cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five- or six-membered heteroaryl, optionally substituted by lower alkyl; n is 1 or 2; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment or prophylaxis of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

Claims

1. A compound of formula I ##STR00037## wherein R.sup.1 is C.sub.4-6-cycloalkyl or C.sub.4-6-heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl; A is phenyl, pyridinyl or piperidinyl; R.sup.2 is hydrogen, halogen, lower alkyl, cyano, C.sub.4-6-cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five- or six-membered heteroaryl, optionally substituted by lower alkyl; n is 1 or 2; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

2. A compound of formula I according to claim 1, wherein A is phenyl and the other substituents are as described in claim 1.

3. A compound of formula I according to claim 2, which compounds are 1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-methylbenzyl)-2-naphthamide 4-benzyl-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide 4-(4-chlorobenzyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide 4-(4-cyanobenzyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide 1-fluoro-4-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide 1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-(trifluoromethoxy)benzyl)-2-naphthamide or 1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-2-naphthamide.

4. A compound of formula I according to claim 1, wherein A is pyridinyl and the other substituents are as described in claim 1.

5. A compound of formula I according to claim 4, wherein the compounds are 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclopentyl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2R)-2-hydroxycyclopentyl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxy-2-methylcyclohexyl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2RS)-2-hydroxy-2-methylcyclohexyl)-2-naphthamide 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2RS)-2-hydroxycyclohexyl)-2-naphthamide 1-fluoro-N-((1S,2 S)-2-hydroxycyclhexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)-2-naphthamide 1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide 1-fluoro-N-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-4-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]naphthalene-2-carboxamide 1-fluoro-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-4-[[6-(1-methylpyrazol-4-yl)-3-pyridyl]methyl]naphthalene-2-carboxamide 1-fluoro-N-((3S,4 S)-4-hydroxytetrahydro-2H-pyran-3-yl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide 1-fluoro-N-((1SR,2RS)-2-hydroxy-2-methylcyclohexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-naphthamide 1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-4-((6-methylpyridin-3-yl)methyl)-2-naphthamide 4-((6-cyclopropylpyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide or 4-[(6-chloropyridin-3-yl)methyl]-1-fluoro-N-[(3S,4R)-3-hydroxyoxan-4-yl]naphthalene-2-carboxamide.

6. A compound of formula I according to claim 1, wherein A is piperidinyl and the other substituents are as described above.

7. A compound of formula I according to claim 6, wherein the compound is 4-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-1-fluoro-N-((1S,2 S)-2-hydroxycyclohexyl)-2-naphthamide.

8. A process for the manufacture of a compound of formula I as defined in claim 1, which process comprises reacting a compound of formula 1: ##STR00038## with a compound of formula 2:
R.sup.1NH.sub.2(2) in the presence of an activating agent, selected from BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or thionyl chloride, to a compound of formula I: ##STR00039## wherein the substituents are as defined in claim 1, and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

9. A compound manufactured by the process of claim 8.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant.

11. Pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant for use in the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

12. A method for the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders, which method comprises administering an effective amount of a compound as defined in claim 1.

Description

EXPERIMENTAL PART

Preparation of Intermediates

Example A.1

4-[(6-Chloro-3-pyridyl)methyl]-1-fluoro-naphthalene-2-carboxylic acid

(1) ##STR00007##

Step 1: 4-Bromo-1-fluoro-2-naphthoic acid

(2) A solution of 2,2,6,6-tetramethylpiperidine (6.85 g, 8.25 ml, 48.0 mmol) in THF (70.0 ml) was cooled to 78 C. under nitrogen atmosphere and n-butyl lithium (29.9 ml, 47.9 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 78 C. for 30 min and a solution of 1-bromo-4-fluoronaphthalene (10 g, 43.5 mmol) in THF (20 ml) was added dropwise at 78 C. The mixture was stirred for 1 h and solid CO.sub.2 was added at the same temperature. The reaction was stirred for 2 h and treated with 20% aqueous ammonium chloride solution. The mixture was allowed to warm to room temperature, was acidified by a solution of HCl 1N and was diluted with EtOAc. The aqueous layer was extracted two times with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed into vacuo. The precipitate was taken up in CH.sub.2Cl.sub.2 and filtered to provide the title compound (8.6 g, 74%) as white solid. MS (m/e): 267.2, 269.2 (M+H).sup.+

Step 2: Methyl 4-bromo-1-fluoro-2-naphthoate

(3) To a suspension of 4-bromo-1-fluoro-2-naphthoic acid (8.68 g, 32.3 mmol) in dichloromethane (97 ml) were added a few drops of N,N-dimethylformamide. Under nitrogen atmosphere at room temperature, oxalyl chloride (25.1 g, 16.9 ml, 194 mmol) was added dropwise. The mixture reaction was heated at 40 C. for 3 h. The solvent was removed in vacuo. The crude material was quenched with MeOH and stirred for 1 h. The precipitate obtained was filtered and dried to give the title compound (8.35 g, 91%) as white powder. MS (m/e): 330.4 (M+H).sup.+

Step 3: Methyl 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoate

(4) A solution of methyl 4-bromo-1-fluoro-2-naphthoate (3.7 g, 13.1 mmol) and bis(tri-tert-butylphosphine)palladium (667 mg, 1.28 mmol) in THF (48 ml) under nitrogen atmosphere was cooled to 60 C. A ((6-chloropyridin-3-yl)methyl)zinc(II) chloride solution (0.5M in THF; 39.2 ml, 19.6 mmol) was added dropwise at 60 C. The mixture was stirred at 60 C. for 1 h. Another portion of ((6-chloropyridin-3-yl)methyl)zinc(II) chloride solution (0.5M in THF; 39.2 ml, 19.6 mmol) was added dropwise. The mixture was stirred at 60 C. for 30 min, then allowed to warm to room temperature and stirred for 1 h. The mixture was quenched by dropwise addition of a 20% NH.sub.4Cl solution. The suspension was diluted with EtOAc. The aqueous layer was extracted two times with EtOAc. The combined organic layers were dried over Na.sub.2SO4, filtered and concentrated in vacuo. The yellow-brown precipitate formed when CH.sub.2Cl.sub.2 was added was filtered and the mother liquor was concentrated leaving the crude product as orange oil which was purified by silica gel chromatography using an EtOAc/heptane gradient as eluent. The product-containing fractions were combined and concentrated. The oily solid thus obtained was triturated with diethyl ether, filtered and dried to provide the title compound (1.6 g, 37%) as light yellow solid. MS (m/e): 330.4 (M+H).sup.+

Step 4: 4-[(6-Chloro-3-pyridyl)methyl]-1-fluoro-naphthalene-2-carboxylic acid

(5) To a solution of methyl 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoate (1.6 g, 4.85 mmol) in THF (13 ml), methanol (6.5 ml) and water (6.5 ml) was added lithium hydroxide monohydrate (750 mg, 17.9 mmol). The mixture was stirred at room temperature for 2 hours and cooled in an ice-bath, then brought to pH 1 by the dropwise addition of HCl 5N (3 ml). The solvent was removed in vacuo. The residue was stirred in water. The solid was filtered and dried to obtain the title compound (1.47 g, 96%) as white crystals.

(6) MS (m/e): 316.4 (M+H).sup.+

Example A.2

4-((6-Chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoyl chloride

(7) ##STR00008##

(8) To a suspension of 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoic acid (example A.1; 1.27 g, 4.02 mmol) in dichloromethane (12 ml) was added one drop of DMF. Then, oxalyl chloride (3.13 g, 2.11 ml, 24.1 mmol) was added dropwise. The mixture was heated to 40 C. for 1 h. Another portion of oxalyl chloride (620 mg, 419 l, 4.79 mmol) was added dropwise. The mixture was stirred at 40 C. for 1.5 h. The mixture was concentrated and dried to provide the title compound (1.46 g, quant.; 92% purity) as light yellow solid.

Example A.3

1-Fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthamide

(9) ##STR00009##

Step 1: 4-Bromo-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide

(10) To a suspension of 4-bromo-1-fluoro-2-naphthoic acid (example A.1, step 1; 400 mg, 1.49 mmol) in dichloromethane (8.00 ml) were added (3SR,4RS)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (example B.1; 228 mg, 1.49 mmol), BOP (874 mg, 1.98 mmol) and triethylamine (451 mg, 621 l, 4.46 mmol). The solution was stirred at room temperature for 17 hours. The solvent was removed in vacuo. The solid was stirred in water, filtered and dried, then taken up in EtOAc (5 ml), filtered and dried to give the title compound (600 mg, 99%, 90% purity) as white solid. MS (m/e): 366.3 (MH); MS (m/e): 366.3; 368.3 (MH).sup.

Step 2: 1-Fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthamide

(11) A mixture of 4-bromo-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide (300 mg, 733 mol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (285 mg, 1.1 mmol), Pd.sub.2(dba).sub.3 (34.6 mg, 36.7 mol), tribasic potassium phosphate (353 mg, 1.61 mmol) and tricyclohexylphosphine (30.8 mg, 110 mol) in dioxane (6 ml) was heated in an 80 C. oil bath for 12 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The aqueous layer was back-extracted once with ethyl acetate. The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (240 mg, 79%) as white solid.

(12) MS (m/e): 416.5 (M+H).sup.+

Example B.1

(3R,4S)-4-Aminotetrahydropyran-3-ol hydrochloride

(13) ##STR00010##

Step 1: Methanesulfonic acid tetrahydro-pyran-4-yl ester

(14) To a solution of tetrahydro-2H-pyran-4-ol (25 g, 245 mmol) and triethyl amine (40.1 ml, 294 mmol) in CH.sub.2Cl.sub.2 (500 ml) at 0 C. was added dropwise methanesulfonylchloride (20.7 ml, 269 mmol) over a period of 40 min, keeping the temperature between 0-4 C. The reaction mixture was then allowed to stir at 0 C. for 1 hr. The cooling bath was removed and the mixture was stirred for another 90 mins at 25 C. The mixture was washed with water (2125 ml), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum to get methanesulfonic acid tetrahydro-pyran-4-yl ester (38 g, 86%; crude) as liquid that was used in the next step without any further purification.

Step 2: 3,6-Dihydro-2H-pyran

(15) A mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (20 g, 111 mmol) and DBU (18.8 ml, 125.6 mmol) was distilled under normal atmospheric pressure. The fraction at 90-96 C. was 6-dihydro-2H-pyran (6 g, 64%) as colourless liquid.

Step 3: (1SR, 6RS)-3,7-Dioxa-bicyclo[4.1.0]heptane

(16) To a solution of 3,6-dihydro-2H-pyran (6 g, 71.4 mmol,) in CH.sub.2Cl.sub.2 (300 ml) was added 3-chloroperbenzoic acid (25 g, 107.1 mmol) portionwise at 25 C., and stirred at that temperature for 21 hrs. The resultant white suspension was diluted with water (250 ml) and then with aqueous solution of Na.sub.2SO.sub.3. The mixture was stirred at 25 C. for 10 min, then basified by addition of saturated aqueous solution of NaHCO.sub.3. The organic layer was separated, and the aqueous layer was re-extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with saturated aqueous solution of NaHCO.sub.3 (100 ml), and brine (80 ml), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (5 g, 70%; crude) as yellow liquid.

Step 4: (3SR,4RS)-4-Azidotetrahydropyran-3-ol

(17) To a solution of (1SR,6RS)-3,7-dioxabicyclo[4.1.0]heptane (5 g, 49.9 mmol) in MeOH (50 ml) were added sodium azide (24.3 g, 374.6 mmol), ammonium chloride (20 g, 374.6 mmol) and water (5 ml), and the resultant mixture was stirred at 25 C. for 19 hrs, and then at 70 C. for 2 hrs. The mixture was cooled 0 C., and the precipitated solid was filtered and washed with methanol. The filtrate was concentrated in vacuo. Resultant residue was taken in ethyl acetate, and filtered. Removal of the filtrate in vacuo yielded the title compound (5 g, 70%; crude) as yellow liquid.

Step 5: (3SR,4RS)-4-Aminotetrahydropyran-3-ol

(18) To a solution of (3SR,4RS)-4-azidotetrahydropyran-3-ol (5 g, 35 mmol) in ethyl acetate (50 ml), was added Pd(OH).sub.2 on charcoal (1.25 g, 1.4 mmol). The mixture was purged with argon, and then allowed to stir under a balloon pressure of hydrogen for 21 hrs at 25 C. Removal of the catalyst by filtration followed by evaporation of the filtrate in vacuo afforded the title compound (4 g, crude).

Step 6: (3S,4R)-3-Hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester and ((3R,4S)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester

(19) To a solution of (3SR,4RS)-4-aminotetrahydropyran-3-ol (10 g, 85.4 mmol) and Et.sub.3N (23.6 ml, 170.9 mmol) in CH.sub.2Cl.sub.2 (100 ml) was added benzyl chloroformate (9.8 ml, 59.9 mmol) dropwise at 0 C. After completion of addition, the mixture was stirred at 25 C. for 2 hrs. The mixture was washed with water (60 ml). The aqueous layer was re-extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to get the mixture the two regioisomeric pairs of enantiomers (16 g). This crude product was purified by silica gel chromatography using 45% EtOAc in hexane as eluent to get the pair of enantiomers with the desired regioisomery as white solid (4.5 g, 21%). This enantiomeric mixture was subject to chiral separation by SFC to afford (3S,4R)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester (1.7 g, 8%) and ((3R,4S)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester (1.7 g, 8%) both as white solid.

Step 7: (3R,4S)-4-Amino-tetrahydro-pyran-3-ol hydrochloride

(20) To a solution of ((3R,4S)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester (1.1 g, 4.4 mmol) in MeOH (50 ml) was added 10% palladium on charcoal (140 mg, 0.13 mmol), and stirred the reaction mixture under hydrogen atmosphere for 1 hr. The catalyst was filtered off. The filtrate was acidified with 1.25 M HCl in MeOH and concentrated in vacuo to get (3R,4S)-4-amino-tetrahydro-pyran-3-ol hydrochloride as off white solid (500 mg, 97%).

DESCRIPTION OF EXAMPLES

Example 1

4-((6-Chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-2-naphthamide

(21) ##STR00011##

(22) To a suspension of 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoic acid (example A.1; 147.2 mg, 466 mol) in dichloromethane (3 ml) were added trans-2-aminocyclohexanol hydrochloride (89.0 mg, 581 mol), BOP (282.1 mg, 625 mol) and triethylamine (189 mg, 260 l, 1.86 mmol). The solution was stirred at room temperature for 22 h, then diluted with dichloromethane and washed twice with water. The aqueous layer was back-extracted once with dichloromethane. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel column chromatography using a heptane/EtOAc gradient as eluent to provide the title compound (165 mg, 86%) as white solid.

(23) MS (m/e): 413.5 (M+H)

(24) In analogy to example 1, examples 2 and 3 of the following table were prepared by coupling 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoic acid (example A.1) with an amine.

(25) TABLE-US-00004 MW Exp. Systematic Starting found No. Structure Name materials (MH.sup.+) 2 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro-2H-pyran- 4-yl)-2-naphthamide (3RS,4SR)-4- aminotetrahydro- 2H-pyran-3-ol (CAS 215940- 92-4) 415.5 3 4-((6-chloropydridin-3- yl)methyl)-1-fluoro-N-((1S,2S)- 2-hydroxycyclohexyl)-2- naphthamide (1S,2S)-2- aminocyclohexanol hydrochloride (CAS 74111-21-0) 413.4

Example 4

4-((6-Chloropyridin-3-yl)methyl)-1-fluoro-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-2-naphthamide

(26) ##STR00014##

(27) To a solution of (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (CAS 1240390-32-2; 19.3 mg, 165 mol) and triethylamine (60.6 mg, 83.3 l, 598 mol) in dichloromethane (2.0 ml) was added 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoyl chloride (example A.2; 50 mg, 150 mol). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was stirred in water. The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na.sub.2SO.sub.4, filtered and concentrated to give a light yellow solid which was triturated in ether, filtered, washed with ether and hexane and dried providing the title compound (45 mg, 73%) as white solid. MS (m/e): 415.4 (M+H).sup.+

(28) In analogy to example 4, compounds 5 to 9 of the following table were prepared from 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-2-naphthoyl chloride (example A.2) and an amine:

(29) TABLE-US-00005 MW Exp. Systematic Starting found No. Structure Name materials (MH.sup.+) 5 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((1S,2S)-2- hydroxycyclopentyl)-2- naphthamide (1S,2S)-2- aminocyclopentanol hydrochloride 399.4 6 4-((6-chloropydridin-3- yl)methyl)-1-fluoro-N-((1S,2R)- 2-hydroxycyclopentyl)-2- naphthamide (1R,2S)-2- aminocyclopentanol hydrochloride 399.4 7 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((1SR,2SR)-2-hydroxy- 2-methylcyclohexyl)-2- naphthamide (1SR,2SR)-2-amino- 1-methylcyclohex- anol hydrochloride (CAS 837733-18-1) 427.4 8 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((1SR,2RS)-2-hydroxy- 2-methylcyclohexyl)-2- naphthamide (1RS,2SR)-2-amino- 1-methylcyclohex- anol hydrochloride (CAS 837377-17-0) 427.4 9 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((1SR,2RS)-2- hydroxycyclohexyl)-2- naphthamide (1RS,2SR)-2- aminocyclohexanol hydrochloride 413.4

Example 10

1-Fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4-methylbenzyl)-2-naphthamide

(30) ##STR00020##

(31) A mixture of 1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthamide (example A.3; 30 mg, 72.2 mol), Pd.sub.2(dba).sub.3 (3.31 mg, 3.61 mol), tricyclohexylphosphine (3.04 mg, 10.8 mol), tribasic potassium phosphate (35.3 mg, 166 mol) and 1-(chloromethyl)-4-methylbenzene (13.2 mg, 12.4 l, 93.9 mol) in dioxane (500 l) and water (200 l) was stirred at 140 C. under microwave irradiation for 30 minutes. The mixture was diluted with ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic fractions were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (19 mg, 67%) as off-white solid. MS (m/e): 394.5 (M+H)

(32) In analogy to Example 10, compounds 11 to 16 of the following table were prepared by reaction of 1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthamide (example A.3) with a benzyl chloride reagent.

(33) TABLE-US-00006 MW Expl. Systematic Starting found No. Structure Name materials (MH.sup.+) 11 4-benzyl-1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-2- naphthamide (chloromethyl)- benzene 380.4 12 4-(4-chlorobenzyl)- 1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-2- naphthamide 1-chloro-4- (chloromethyl)- benzene 414.5 13 4-(4-cyanobenzyl)- 1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-2- naphthamide 4-(chloromethyl) benzonitrile 405.5 14 1-fluoro-4-(2-fluoro- 4-(1-methyl-1H- pyrazol-4- yl)benzyl)-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-2- naphthamide 4-(4-(chloromethyl)-3- fluorophenyl)-1-methyl- 1H-pyrazole (CAS 1392081-37-6) 478.3 15 1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-4-(4- (trifluoromethoxy) benzyl)-2- naphthamide 1-(chloromethyl)-4- (trifluoromethoxy)- benzene 464.4 16 1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-4-(4- (1-methyl-1H- pyrazol-4-yl)benzyl)- 2-naphthamide 4-(4-(chloromethyl)- phenyl)-1-methyl- 1H-pyrazole 460.4

Example 17

1-Fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-4-((6-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)-2-naphthamide

(34) ##STR00027##

(35) To a solution of tribasic potassium phosphate (77.7 mg, 366 mol) in water (280 l) were added 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide (58.4 mg, 141 mol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.6 mg, 171 mol), Pd.sub.2(dba).sub.3 (3.2 mg, 3.39 mol) and tricyclohexylphosphine (3.8 mg, 13.1 mol) in dioxane (0.7 ml). The mixture was heated to 140 C. in a microwave reactor for 30 min, then diluted with EtOAc and water. The organic layer was separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude material was purified by silica gel chromatography using a heptane/EtOAc gradient to obtain the title compound (39 mg, 60%) as white powder. MS (m/e): 459.5 (M+H)

(36) In analogy to example 17, compounds 18 to 21 of the following table were prepared by Suzuki coupling between the indicated starting material and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

(37) TABLE-US-00007 MW Exp. Systematic Starting found No. Structure Name materials (MH.sup.+) 18 1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro- 2H-pyran-4-yl)-4- ((6-(1-methyl-1H- pyrazol-4-yl)pyridin- 3-yl)methyl)-2- naphthamide 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((3RS,4SR)-3- hydroxytetrahydro-2H- pyran-4-yl)-2- naphthamide (example 2) 461.6 19 1-fluoro-N-[(3S,4R)- 3-hydroxytetra- hydropyran-4-yl]-4- [[6-(1-methylpyrazol- 4-yl)-3-pyridyl]methyl]- naphthalene-2- carboxamide 4-((6-chloropyridin-3-yl)- methyl)-1-fluoro-N- ((3S,4R)-3-hydroxytetra- hydro-2H-pyran-4-yl)-2- naphthamide (example 25) 461.5 20 0 1-fluoro-N-[(3R,4S)-3- hydroxytetrahydro- pyran-4-yl]-4-[[6-(1- methylpyrazol-4-yl)-3- pyridyl]methyl]- naphthalene-2- carboxamide 4-((6-chloropyridin-3-yl)- methyl)-1-fluoro-N-((3R, 4S)-3-hydroxytetrahydro- 2H-pyran-4-yl)-2- naphthamide (example 25) 461.5 21 1-fluoro-N-((3S,4S)-4- hydroxytetrahydro-2H- pyran-3-yl)-4-((6-(1- methyl-1H-pyrazol-4- yl)pyridin-3-yl)- methyl)-2- naphthamide 4-((6-chloropyridin-3-yl)- methyl)-1-fluoro-N- ((3S,4S)-4-hydroxytetra- hydro-2H-pyran-3-yl)-2- naphthamide (example 4) 461.4 22 1-fluoro-N- ((1SR,2RS)-2- hydroxy-2- methylcyclohexyl)- 4-((6-(1-methyl-1H- pyrazol-4-yl)pyridin- 3-yl)methyl)-2- naphthamide 4-((6-chloropyridin-3- yl)methyl)-1-fluoro-N- ((1SR,2RS)-2-hydroxy-2- methylcyclohexyl)-2- naphthamide (example 8) 473.4

Example 23

1-Fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-4-((6-methylpyridin-3-yl)methyl)-2-naphthamide

(38) ##STR00033##

(39) To a solution of 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1SR,2SR)-2-hydroxycyclohexyl)-2-naphthamide (example 1; 45.2 mg, 109 mol) in THF (0.5 ml) was added 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (II) (8.01 mg, 10.9 mol). Dimethylzinc 1M in heptane (400 l, 400 mol) was added dropwise to the red suspension at 0 C. (exothermic reaction). The mixture was stirred at room temperature for 1 h 15 and then at 60 C. for 2 h. More catalyst 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (II) (8.01 mg, 10.9 mol) was added and the reaction was stirred at 60 C. for 4 h and then at room temperature for 2 days. During that time more dimethylzinc 1M in heptane (two times 400 l, 400 mol) was added. The mixture was quenched with saturated NaHCO.sub.3 solution and diluted with EtOAc. The precipitate was filtered and the filtrate was extracted 3 times with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (16 mg, 38%) as light brown solid.

(40) MS (m/e): 393.5 (M+H).sup.+

Example 24

4-((6-Cyclopropylpyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide

(41) ##STR00034##

(42) To a mixture of 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide (example 3; 40 mg, 96.9 mol), cyclopropylboronic acid (16.6 mg, 194 mol), tribasic potassium phosphate (72.0 mg, 339 mol), tricyclohexylphosphine (8.15 mg, 29.1 mol) in degassed toluene (1 ml) and water (40 l) was added palladium (II) acetate (3.26 mg, 14.5 mol). The mixture was stirred at 125 C. for 2 hours in a sealed tube and then cyclopropylboronic acid (8.32 mg, 96.9 mol) was added and the mixture was stirred at 125 C. for 2 hours. The mixture was diluted with ethyl acetate and washed with water, saturated solution of K.sub.2CO.sub.3 and saturated solution of NaCl. The aqueous layer was washed once with ethyl acetate. The combined extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (5 mg, 12%) as light brown solid. MS (m/e): 419.5 (M+H).sup.+.

Example 25

4-[(6-chloropyridin-3-yl)methyl]-1-fluoro-N-[(3S,4R)-3-hydroxyoxan-4-yl]naphthalene-2-carboxamide

(43) ##STR00035##

(44) The racemic 4-((6-chloropyridin-3-yl)methyl)-1-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-2-naphthamide (example 4; 175 mg, 422 mol) was separated on a Chiralpak AD column (D-7531) to provide the ()-enantiomer (74 mg, 42%) as a white solid with MS (m/e): 415.4 (M+H).sup.+ and the desired (+)-enantiomer (77 mg, 44%) as a light yellow solid with MS (m/e): 415.5 (M+H).sup.+.

Example 26

4-((4-Cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide

(45) ##STR00036##

Step 1: 4-Bromo-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide

(46) To a suspension of 4-bromo-1-fluoro-2-naphthoic acid (example A.1, step 1; 500 mg, 1.86 mmol) in dichloromethane (10 ml) were added (1S,2S)-2-aminocyclohexanol hydrochloride (282 mg, 1.86 mmol), BOP (1.09 g, 2.47 mmol) and triethylamine (564 mg, 776 l, 5.57 mmol). The solution was stirred at room temperature for 21 hours. The solvent was removed in vacuo. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to provide the title compound (328 mg, 48%) as white solid. MS (m/e): 366.4 (M).sup.+, 368.4 (M+2).sup.+

Step 2: 1-Fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-4-vinyl-2-naphthamide

(47) To a solution of tribasic potassium phosphate (291 mg, 1.37 mmol) in water (0.90 ml) was added 4-bromo-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide (228 mg, 623 dioxane (2.25 ml), potassium trifluoro(vinyl)borate (128 mg, 953 mol), Pd.sub.2(dba).sub.3 (28.5 mg, 31.1 mol) and tricyclohexylphosphine (17.5 mg, 62.3 mol). The mixture was stirred at 140 C. for 30 minutes under microwave irradiation twice. More potassium trifluoro(vinyl)borate (41.7 mg, 311 mol) was added and the mixture was stirred at 160 C. for 30 minutes under microwave irradiation, then diluted with water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by chromatography on Isolute Flash-NH.sub.2 silica gel (from Separtis) using a heptane/EtOAc gradient to obtain the title compound (96 mg, 49%) as off white solid.

(48) MS (m/e): 314.4 (M+H).sup.+.

Step 3: 1-Fluoro-4-formyl-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide

(49) To a solution of 1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-4-vinyl-2-naphthamide (20 mg, 63.8 mol) and ruthenium(III) chloride 0.035M in H.sub.2O (63.8 l, 2.23 mol) in MeCN (500 l) and water (83.3 l) was added sodium metaperiodate (27.3 mg, 128 mol) in portions.

(50) The mixture was stirred at room temperature for 1 hour 40 minutes. The mixture was quenched with a saturated solution of Na.sub.2S.sub.2O.sub.3 and the two layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic extract was washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (11 mg, 56%) as white solid.

(51) MS (m/e): 316.4 (M+H).sup.+.

Step 4: 4-((4-Cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-1-fluoro-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide

(52) To a solution of 1-fluoro-4-formyl-N-((1S,2S)-2-hydroxycyclohexyl)-2-naphthamide (40.5 mg, 128 mol) and 4-(pyridin-2-yl)piperidine-4-carbonitrile (CAS 767263-33-2; 24.0 mg, 128 mol) in 1,2-dichloroethane (1 ml) were added sodium triacetoxyhydroborate (38.1 mg, 180 mol) and acetic acid (7.71 mg, 7.35 l, 128 mol). The mixture was stirred at room temperature under nitrogen atmosphere for 19 hours, then was quenched with a 1N NaOH solution and dichloro-methane was added. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by silica gel chromatography using a heptan/EtOAc gradient as eluent to provide the title compound (32 mg, 52%) as white solid. MS (m/e): 487.4 (M+H).sup.+.