Functionalised Amine Derivatives as IL-17 Modulators
20220073485 · 2022-03-10
Inventors
- Anne Marie Foley (Slough, Berkshire, GB)
- Jag Paul Heer (Slough, Berkshire, GB)
- Fabien Claude Lecomte (Slough, Berkshire, GB)
- Nathaniel Julius Thomas Monck (Abingdon, Oxforshire, GB)
- Matthew Duncan Selby (Slough, Berkshire, GB)
- Mengyang Xuan (Slough, Berkshire, GB)
- Lihu Yang (Cambridge, MA, US)
Cpc classification
C07D405/04
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
C07D309/04
CHEMISTRY; METALLURGY
C07D261/18
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
International classification
Abstract
A series of functionalised amine derivatives of formula (I) as defined herein, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
##STR00001##
Claims
1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: ##STR00059## wherein X represents an optionally substituted benzene ring; or an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and imidazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl; A represents C.sub.3-9 cycloalkyl, C.sub.3-7 heterocycloalkyl or C.sub.4-9 heterobicycloalkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.1 represents —COR.sup.a or —SO.sub.2R.sup.b; or R.sup.1 represents C.sub.1-6 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, C.sub.5-9 spirocycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.a represents hydrogen; or R.sup.a represents C.sub.1-6 alkyl, C.sub.2-7 alkenyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, C.sub.3-9 cycloalkylidenyl(C.sub.1-6)alkyl, C.sub.4-9 bicycloalkyl(C.sub.1-6)alkyl, C.sub.4-9 bicycloalkylidenyl(C.sub.1-6)alkyl, C.sub.5-9 spirocycloalkyl(C.sub.1-6)alkyl, C.sub.9-11 tricycloalkyl-(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkylidenyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and R.sup.b represents C.sub.1-6 alkyl, C.sub.2-7 alkenyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, C.sub.3-9 cycloalkylidenyl(C.sub.1-6)alkyl, C.sub.4-9 bicycloalkyl(C.sub.1-6)alkyl, C.sub.4-9 bicycloalkylidenyl-(C.sub.1-6)alkyl, C.sub.5-9 spirocycloalkyl(C.sub.1-6)alkyl, C.sub.9-11 tricycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)-alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkylidenyl-(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.
2. A compound as claimed in claim 1 wherein X represents an optionally substituted benzene ring; or an optionally substituted five-membered heteroaromatic ring selected from pyrazolyl, isoxazolyl and thiazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl; wherein the optional substituents on X include one, two or three substituents independently selected from halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
3. A compound as claimed in claim 1 wherein A represents tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl or morpholinyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from cyano, hydroxy, hydroxy(C.sub.1-6)alkyl, oxo, C.sub.1-6 alkoxy, di(C.sub.1-6)alkylaminocarbonyl and difluoroazetidinylcarbonyl.
4. A compound as claimed in claim 1 wherein R.sup.1 represents —COR.sup.a, in which R.sup.a is as defined in claim 1.
5. A compound as claimed in claim 4 wherein R.sup.a represents —CH(R.sup.5)N(H)C(O)R.sup.6, —CH(R.sup.5)N(H)S(O).sub.2R.sup.6, —C(═CR.sup.5aR.sup.5b)N(H)C(O)R.sup.6, —CH(R.sup.5)R.sup.7, —CH(R.sup.5)N(H)R.sup.7 or —CH(R.sup.5)C(O)N(H)R.sup.7, in which R.sup.5 represents hydrogen; or R.sup.5 represents C.sub.1-5 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cyclo-alkyl(C.sub.1-5)alkyl, C.sub.4-9 bicycloalkyl, C.sub.4-9 bicycloalkyl(C.sub.1-5)alkyl, C.sub.5-9 spirocycloalkyl, C.sub.5-9 spirocycloalkyl(C.sub.1-5)alkyl, C.sub.9-11 tricycloalkyl, C.sub.9-11 tricycloalkyl(C.sub.1-5)alkyl, aryl, aryl-(C.sub.1-5)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-5)alkyl, heteroaryl or heteroaryl(C.sub.1-5)alkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.5a represents C.sub.3-7 cycloalkyl, C.sub.4-9 bicycloalkyl, aryl, C.sub.3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and R.sup.5b represents hydrogen or C.sub.1-6 alkyl; or R.sup.5a and R.sup.5b, when taken together with the carbon atom to which they are both attached, represent C.sub.3-7 cycloalkyl, C.sub.4-9 bicycloalkyl or C.sub.3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents; R.sup.6 represents —NR.sup.6aR.sup.6b or —OR.sup.6c; or R.sup.6 represents C.sub.1-9 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl-(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl or spiro[(C.sub.3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents; R.sup.6a represents hydrogen; or R.sup.6a represents C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cyclo-alkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)-alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl or spiro[(C.sub.3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents; R.sup.6b represents hydrogen or C.sub.1-6 alkyl; R.sup.6c represents C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl or heteroaryl(C.sub.1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and R.sup.7 represents aryl, heteroaryl or spiro[(C.sub.3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents.
6. A compound as claimed in claim 5 represented by formula (IIA), or a pharmaceutically acceptable salt thereof: ##STR00060## wherein V represents N or C—R.sup.2; W represents N or C—R.sup.11; R.sup.2 represents hydrogen, halogen, cyano, C.sub.1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, formyl, C.sub.2-6 alkylcarbonyl, carboxy, C.sub.2-6 alkoxycarbonyl, aminocarbonyl, C.sub.1-6 alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl or di(C.sub.1-6)alkylaminosulfonyl; R.sup.3 represents hydrogen, halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; R.sup.11 represents hydrogen, C.sub.1-6 alkyl, halogen, cyano, trifluoromethyl, hydroxy, hydroxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, C.sub.2-6 alkylcarbonyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, aminocarbonyl, C.sub.1-6 alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl or difluoroazetidinylcarbonyl; and R.sup.5 and R.sup.6 are as defined in claim 5.
7. A compound as claimed in claim 5 wherein R.sup.5 represents C.sub.1-5 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-5)alkyl, C.sub.4-9 bicycloalkyl, C.sub.4-9 bicycloalkyl(C.sub.1-5)alkyl, C.sub.5-9 spirocycloalkyl, C.sub.9-11 tricycloalkyl, C.sub.9-11 tricycloalkyl(C.sub.1-5)alkyl, aryl, aryl(C.sub.1-5)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-5)alkyl or heteroaryl(C.sub.1-5)alkyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, phenyl, hydroxy, C.sub.1-6 alkoxy and aminocarbonyl.
8. A compound as claimed in claim 5 wherein R.sup.6 represents —NR.sup.6aR.sup.6b or —OR.sup.6c; or R.sup.6 represents C.sub.1-9 alkyl, aryl, C.sub.3-7 heterocycloalkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl or spiro[(C.sub.3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, nitro, C.sub.1-6 alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, fluorophenyl, hydroxy, hydroxy(C.sub.1-6)alkyl, oxo, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, difluoromethoxy, trifluoromethoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, 6)alkylsulfonyl(C.sub.1-6)alkyl, C.sub.1-6 alkylsulfonyloxy, amino, amino(C.sub.1-6)alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl, pyrrolidinyl, dioxoisothiazolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C.sub.2-6 alkylcarbonylamino, C.sub.2-6 alkylcarbonylamino(C.sub.1-6)alkyl, C.sub.2-6 alkoxycarbonylamino, C.sub.1-6 alkylsulfonylamino, formyl, C.sub.2-6 alkylcarbonyl, carboxy, C.sub.2-6 alkoxycarbonyl, aminocarbonyl, C.sub.1-6 alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl, 6)alkylaminosulfonyl and di(C.sub.1-6)alkylsulfoximinyl.
9. A compound as claimed in claim 1 which is N-{2-[3-Chloro-4-(morpholin-4-yl)anilino]-1-cyclooctyl-2-oxoethyl}-3-methylisoxazole-4-carboxamide; N-[4-(4-Cyanotetrahydropyran-4-yl)-3-methylphenyl]-2-cyclooctyl-2-[(3-methylisoxazol-4-yl)formamido]acetamide; 4-(4-{2-Cyclooctyl-2-[(3-methylisoxazol-4-yl)formamido]acetamido}-2-methylphenyl)-N,N-dimethyltetrahydropyran-4-carboxamide; N-{1-Cyclooctyl-2[3-methyl-4-(morpholin-4-yl)anilino]-2-oxo-ethyl}-3-methyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-[3-fluoro-4-(morpholin-4-yl)anilino]-2-oxo-ethyl}-3-methyl-isoxazole-4-carboxamide; N-(1-Cyclooctyl-2-{[6-(morpholin-4-yl)-pyridin-3-yl]amino}-2-oxoethyl)-3-methyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-oxo-2-[4-(tetrahydro-pyran-4-yl)anilino]-ethyl}-3-methyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-oxo-2[4-(tetrahydro-furan-3-yl)anilino]ethyl}-3-methyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-oxo-2[4-(5-oxo-pyrrolidin-2-yl)-anilino]ethyl}-3-methylisoxazole-4-carboxamide; N-(1-Cyclooctyl-2-oxo-2-{[5-(tetrahydropyran-4-yl)isoxazol-3-yl]-amino}ethyl)-3-methylisoxazole-4-carboxamide; N-(1-Cyclooctyl-2-{[4-methyl-3-(tetrahydro-pyran-4-yl)isoxazol-5-yl]amino}-2-oxoethyl)-3-methylisoxazole-4-carboxamide; N-{1-Cyclooctyl-2[3-methoxy-4-(morpholin-4-yl)anilino]-2-oxo-ethyl}-3-methyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2[3,5-difluoro-4-(morpholin-4-yl)-anilino]-2-oxoethyl}-3-methylisoxazole-4-carboxamide; N-(2-{[5-Chloro-6-(morpholin-4-yl)-pyridin-3-yl]amino}-1-cyclooctyl-2-oxoethyl)-3-methylisoxazole-4-carboxamide; N-(1-Cyclooctyl-2{[5-fluoro-6-(morpholin-4-yl)pyridin-3-yl]-amino}-2-oxoethyl)-3-methylisoxazole-4-carboxamide; N-{1-Cyclooctyl-2[4-(4-hydroxytetrahydro-pyran-4-yl)anilino]-2-oxoethyl}-3-methyl-isoxazole-4-carboxamide; N-{2-[4-(4-Cyano-tetrahydropyran-4-yl)-anilino]-1-cyclooctyl-2-oxoethyl}-3-methyl-isoxazole-4-carboxamide; N-(1-Cyclooctyl-2-oxo-2-{[5-(tetrahydropyran-4-yl)pyridin-2-yl]-amino}ethyl)-3-methylisoxazole-4-carboxamide; 4-(4-{2-Cyclooctyl-2-[(3-methylisoxazol-4-yl)formamido]-acetamido}phenyl)-N,N-dimethyl-tetrahydropyran-4-carboxamide; 2-[(7Z)-5-Chlorobicyclo[4.2.0]octa-1,3,5-trien-7-ylidene]-2-[(3-methylisoxazol-4-yl)-formamido]-N-[4-(tetrahydropyran-4-yl)phenyl]acetamide; 3-Ethyl-N-{(1 S)-1-(trans-4-methylcyclohexyl)-2-oxo-2[4-(tetrahydropyran-4-yl)anilino]-ethyl}isoxazole-4-carboxamide; 3-Ethyl-N-{(1S)-2-[3-fluoro-4-(tetrahydro-pyran-4-yl)anilino]-1-(trans-4-methylcyclo-hexyl)-2-oxoethyl}-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-oxo-2-[4-(tetrahydro-pyran-4-yl)anilino]-ethyl}-3-ethyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-oxo-2-[3-(tetrahydro-pyran-4-yl)anilino]-ethyl}-3-methyl-isoxazole-4-carboxamide; N-(1-Cyclooctyl-2-{4-[4-(hydroxymethyl)-tetrahydropyran-4-yl]-anilino}-2-oxoethyl)-3-methylisoxazole-4-carboxamide; N-{2-[3-Bromo-4-(morpholin-4-yl)-anilino]-1-cyclooctyl-2-oxoethyl}-3-methyl-isoxazole-4-carboxamide; N-{(1S)-1-(4-Methyl-cyclohexyl)-2-oxo-2[4-(tetrahydropyran-4-yl)anilino]ethyl}-3-(methylsulfonyl-methyl)benzamide; 3-(Methane-sulfonamido)-N-{(1S)-1-(trans-4-methyl-cyclohexyl)-2-oxo-2[4-(tetrahydropyran-4-yl)anilino]ethyl}benzamide; 3-{[Dimethyl(oxo)-λ.sup.6-sulfanylidene]amino}-N-[(1S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-{[1-(tetrahydro-pyran-4-yl)pyrazol-4-yl]amino}ethyl]benzamide; N-{(1S)-2[3,5-Difluoro-4-(tetrahydro-pyran-4-yl)anilino]-1-(trans-4-methyl-cyclohexyl)-2-oxo-ethyl}-3-ethyl-isoxazole-4-carboxamide; (2S)—N-[3-Fluoro-4-(tetrahydropyran-4-yl)phenyl]-2-(trans-4-methylcyclohexyl)-2-{[methyl(tetrahydropyran-4-yl)carbamoyl]amino}acetamide; 3-Methyl-N-[(1 S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-{[5-(tetrahydropyran-4-yl)-isoxazol-3-yl]amino}ethyl]isoxazole-4-carboxamide; 3-Methyl-N-[(1 S)-1-(trans-4-methyl-cyclohexyl)-2-oxo-2{[6-(tetrahydropyran-4-yl)pyridin-3-yl]-amino}ethyl]isoxazole-4-carboxamide; 3-Methyl-N-[(1S)-1-(trans-4-methyl-cyclohexyl)-2-oxo-2{[5-(tetrahydropyran-4-yl)thiazol-2-yl]amino}ethyl]isoxazole-4-carboxamide; N-[(1S)-2{[6-(4-Methoxytetrahydro-pyran-4-yl)pyridin-3-yl]amino}-1-(trans-4-methylcyclohexyl)-2-oxoethyl]-3-methyl-isoxazole-4-carboxamide; 3-Methyl-N-[(1S)-1-(trans-4-methyl-cyclohexyl)-2-oxo-2{[3-(tetrahydropyran-4-yl)isoxazol-5-yl]amino}ethyl]isoxazole-4-carboxamide; N-[(1S)-2-{[6-(4-Hydroxytetrahydro-pyran-4-yl)pyridin-3-yl]amino}-1-(trans-4-methylcyclohexyl)-2-oxoethyl]-3-methyl-isoxazole-4-carboxamide; N-{1-Cyclooctyl-2-oxo-2-[4-(tetrahydropyran-4-yl)anilino]ethyl}-2-ethylpyrazole-3-carboxamide; or N-[(1S)-1-Cyclohexyl-2-{4-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]-anilino}-2-oxoethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide.
10-12. (canceled)
13. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
14. A pharmaceutical composition as claimed in claim 13 further comprising an additional pharmaceutically active ingredient.
15-16. (canceled)
17. A method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
18. A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
19. A compound as claimed in claim 6 wherein R.sup.5 represents C.sub.1-5 alkyl, C.sub.3-9 cycloalkyl, C.sub.3-9 cycloalkyl(C.sub.1-5)alkyl, C.sub.4-9 bicycloalkyl, C.sub.4-9 bicycloalkyl(C.sub.1-5)alkyl, C.sub.5-9 spirocycloalkyl, C.sub.9-11 tricycloalkyl, C.sub.9-11 tricycloalkyl(C.sub.1-5)alkyl, aryl, aryl(C.sub.1-5)alkyl, C.sub.3-7 heterocycloalkyl, C.sub.3-7 heterocycloalkyl(C.sub.1-5)alkyl or heteroaryl(C.sub.1-5)alkyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, phenyl, hydroxy, C.sub.1-6 alkoxy and aminocarbonyl.
20. A compound as claimed in claim 6 wherein R.sup.6 represents —NR.sup.6aR.sup.6b or —OR.sup.6c; or R.sup.6 represents C.sub.1-9 alkyl, aryl, C.sub.3-7 heterocycloalkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl or spiro[(C.sub.3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, nitro, C.sub.1-6 alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, fluorophenyl, hydroxy, hydroxy(C.sub.1-6)alkyl, oxo, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, difluoromethoxy, trifluoromethoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, 6)alkylsulfonyl(C.sub.1-6)alkyl, C.sub.1-6 alkylsulfonyloxy, amino, amino(C.sub.1-6)alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl, pyrrolidinyl, dioxoisothiazolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C.sub.2-6 alkylcarbonylamino, C.sub.2-6 alkylcarbonylamino(C.sub.1-6)alkyl, C.sub.2-6 alkoxycarbonylamino, C.sub.1-6 alkylsulfonylamino, formyl, C.sub.2-6 alkylcarbonyl, carboxy, C.sub.2-6 alkoxycarbonyl, aminocarbonyl, C.sub.1-6 alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl, 6)alkylaminosulfonyl and di(C.sub.1-6)alkylsulfoximinyl.
21. A compound as claimed in claim 7 wherein R.sup.6 represents —NR.sup.6aR.sup.6b or —OR.sup.6c; or R.sup.6 represents C.sub.1-9 alkyl, aryl, C.sub.3-7 heterocycloalkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl or spiro[(C.sub.3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, cyano, nitro, C.sub.1-6 alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, fluorophenyl, hydroxy, hydroxy(C.sub.1-6)alkyl, oxo, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy(C.sub.1-6)alkyl, difluoromethoxy, trifluoromethoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, 6)alkylsulfonyl(C.sub.1-6)alkyl, C.sub.1-6 alkylsulfonyloxy, amino, amino(C.sub.1-6)alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino(C.sub.1-6)alkyl, pyrrolidinyl, dioxoisothiazolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C.sub.2-6 alkylcarbonylamino, C.sub.2-6 alkylcarbonylamino(C.sub.1-6)alkyl, C.sub.2-6 alkoxycarbonylamino, C.sub.1-6 alkylsulfonylamino, formyl, C.sub.2-6 alkylcarbonyl, carboxy, C.sub.2-6 alkoxycarbonyl, aminocarbonyl, C.sub.1-6 alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, aminosulfonyl, C.sub.1-6 alkylaminosulfonyl, di(C.sub.1-6) alkylaminosulfonyl and di(C.sub.1-6)alkylsulfoximinyl.
Description
EXAMPLES
[0310]
TABLE-US-00001 Abbreviations DCM: dichloromethane DMF: N,N-dimethylformamide MeOH: methanol THF: tetrahydrofuran DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine EtOH: ethanol EtOAc: ethyl acetate TFA: trifluoroacetic acid EDC.HCl: N-(3-dimethylaminopropyl)-N′- ethylcarbodiimide hydrochloride HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate XPhos: 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl {Ir[dF(CF.sub.3)ppy].sub.2(dtbpy)}PF.sub.6: [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine-N.sup.1,N.sup.1′]bis- {3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C}iridium(III) hexafluoro-phosphate h: hour r.t.: room temperature M: mass RT: retention time HPEC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry ES+: Electrospray Positive Ionisation LED: light-emitting diode PTFE: poly(tetrafluoroethylene)
Analytical Conditions
[0311] Compounds were named with the aid of ACD/Name Batch (Network) version 11.01, and/or Accelrys Draw 4.2, and/or Elemental, Dotmatics, and/or Chemaxon.
[0312] All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.
[0313] NMR spectra were recorded on a Bruker Avance III HD 500 MHz, 400 MHz, 300 MHz or 250 MHz spectrometer.
[0314] uPLC-MS
[0315] Performed on a Waters Acquity UPLC system coupled to a Waters Acquity PDA detector, an ELS detector and an MSD (Scan Positive: 150-850).
[0316] Method 1
[0317] Phenomenex Kinetex-XB, C18 (2.1×100 mm, 1.7 μm) column
[0318] Mobile Phase A: 0.1% formic acid in water
[0319] Mobile Phase B: 0.1% formic acid in acetonitrile
[0320] Gradient: Flow rate 0.6 mL/minute; column temperature 40° C.
TABLE-US-00002 Time A % B % 0.00 95.00 5.00 5.30 0.00 100.0 5.80 0.00 100.0 5.82 95.00 5.00 7.00 95.00 5.00
[0321] HPLC-MS
[0322] Performed on a Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and PL 2100 detectors.
[0323] Method 2
[0324] Phenomenex Kinetex Core-Shell C8 (2.1×50 mm, 5 μm) column, protected by a
[0325] Phenomenex ‘Security Guard’ column
[0326] Mobile Phase A: 0.1% formic acid in water
[0327] Mobile Phase B: 0.1% formic acid in acetonitrile
[0328] Gradient: Flow rate 1.2 mL/minute; column temperature 40° C.
TABLE-US-00003 Time A % B % 0.00 95.00 5.00 1.20 0.00 100.0 1.30 0.00 100.0 1.31 95.00 5.00
[0329] Performed on an Agilent 1200-6120 LC-MS system coupled to Detection (230 to 400 nm and 215 nm) and Mass Spec Detection Agilent 6120 Mass Spectrometer (ES) m/z 120 to 800.
[0330] Method 3
[0331] Waters X-Bridge C18 (2.1×20 mm, 2.5 μm) column
[0332] Mobile Phase A: 10 mM ammonium formate in water+0.1% formic acid
[0333] Mobile Phase B: acetonitrile+5% water+0.1% formic acid
[0334] Gradient: Flow rate 1 mL/minute
TABLE-US-00004 Time A % B % 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00
[0335] Performed on a Waters ZQ system coupled to Waters 2996 PDA and Waters 2420 detectors.
[0336] Method 4
[0337] Phenomenex Gemini-NX C18 (2.0×50 mm, 3 μm) column
[0338] Mobile Phase A: 2 mM ammonium bicarbonate modified to pH 10 with NH.sub.4OH
[0339] Mobile Phase B: acetonitrile
[0340] Gradient: Flow rate 1 mL/minute; column temperature 40° C.
TABLE-US-00005 Time A % B % 0.00 99.00 1.00 1.80 0.00 100.0 2.10 0.00 100.0 2.30 99.00 1.00 3.50 99.00 1.00
[0341] Automated Preparative Reverse Phase HPLC Purification
[0342] Performed using a Gilson system with a Gilson 331&332 pump, a Gilson GX281 autoinjector, a Gilson GX281 fraction collector and a Gilson 155&157 UV detector.
[0343] Method 5
[0344] X-Bridge C18 Waters (30×100 mm, 10 μm) column
[0345] Mobile Phase A: water+0.2% ammonia solution
[0346] Mobile Phase B: acetonitrile+0.2% ammonia solution
[0347] Gradient: Flow rate 40 mL/minute
TABLE-US-00006 Time A % B % 0.00 90 10 0.55 90 10 14.44 5 95 16.55 5 95 16.75 90 10
[0348] Performed using a Gilson system with a Gilson 331&332 pump, a Gilson GX281 autoinjector, a Gilson GX281 fraction collector and a Gilson 159 UV detector.
[0349] Method 6
[0350] Sunfire C18 Waters (30×100 mm, 10 μm) column
[0351] Mobile Phase A: water+0.1% formic acid
[0352] Mobile Phase B: acetonitrile+0.1% formic acid
[0353] Gradient: Flow rate 40 mL/minute
TABLE-US-00007 Time A % B % 0.00 90.00 10.00 0.55 90.00 10.00 11.00 5.00 95.00 13.10 5.00 95.00 13.31 90.00 10.00
[0354] Performed using an Agilent 1260-6120 LC-MS system, with an Agilent binary pump and Agilent DAD (240-400 nm) module. 6120 mass detection (ES) m/z 120-1000
[0355] Method 7
[0356] X-Bridge C18 (2.1×20 mm, 2.5 μm) column
[0357] Mobile Phase A: 10 nM ammonium formate in water+0.1% ammonium hydroxide
[0358] Mobile Phase B: acetonitrile+5% water+0.1% ammonium hydroxide
[0359] Gradient: Flow rate 1 mL/minute
TABLE-US-00008 Time A % B % 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00
[0360] Performed using an Agilent 1200RR-6140 LC-MS system, with an Agilent binary pump and Agilent DAD (230-400 nm) module. 6140 mass detection (ES) m/z 100-1000
[0361] Method 8
[0362] X-Bridge C18 (2.1×20 mm, 2.5 μm) column
[0363] Mobile Phase A: 10 nM ammonium formate in water+0.1% ammonia solution
[0364] Mobile Phase B: acetonitrile+5% water+0.1% ammonia solution
[0365] Gradient: Flow rate 1 mL/minute
TABLE-US-00009 Time A % B % 0.00 95.10 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.10 5.00
[0366] Method 9
[0367] X-Bridge C18 (2.1×20 mm, 2.5 μm) column
[0368] Mobile Phase A: 10 nM ammonium formate in water+0.1% formic acid
[0369] Mobile Phase B: acetonitrile+5% water+0.1% formic acid
[0370] Gradient: Flow rate 1 mL/minute
TABLE-US-00010 Time A % B % 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00
[0371] Performed using an Agilent 1290-MSD-XT LC-MS system, with an Agilent binary pump and Agilent DAD (230-400 nm) module. MSD-XT mass detection (ES) m/z 100-1000.
[0372] Method 10
[0373] Acquity UPLC BEH C18 (2.1×50 mm, 1.7 μm) column
[0374] Mobile Phase A: 10 mM ammonium formate in water+0.1% ammonia solution
[0375] Mobile Phase B: acetonitrile+5% water+0.1% ammonia solution
[0376] Gradient: Flow rate 1.5 mL/minute
TABLE-US-00011 Time A % B % 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00
[0377] Method 11
[0378] Acquity UPLC BEH C18 (2.1×50 mm, 1.7 μm) column
[0379] Mobile Phase A: 10 mM ammonium formate in water+0.1% formic acid
[0380] Mobile Phase B: acetonitrile+5% water+0.1% formic acid
[0381] Gradient: Flow rate 1.5 mL/minute
TABLE-US-00012 Time A % B % 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00
[0382] Performed using a QDA Waters simple quadrupole mass spectrometer with an ESI source and a UPLC Acquity Classic with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m/z 70 to 800 in positive/negative mode.
[0383] Method 12
[0384] Waters Acquity UPLC BEH C18 (2.1×50 mm, 1.7 μm) column
[0385] Mobile Phase A: water/acetonitrile/ammonium formate (95/5/63 mg/L)+100 μg/L NH.sub.4OH
[0386] Mobile Phase B: acetonitrile/water/ammonium formate (95/5/63 mg/L)+100 μg/L NH.sub.4OH
[0387] Gradient: Flow rate 0.4 mL/minute to 0.5 mL/minute
TABLE-US-00013 Time A % B % 0 99 1 0.3 99 1 3.2 0 100 3.25 0 100 4 0 100 4.1 99 1 4.8 90 1
[0388] Performed using a QDA Waters simple quadrupole mass spectrometer with an ESI source and a UPLC Acquity with diode array detector (200 to 400 nm). Data are acquired in a full MS scan from m/z 70 to 800 in positive/negative mode.
[0389] Method 13
[0390] Waters Acquity UPLC XSelect HSS T3 (2.1×50 mm, 1.8 μm) column
[0391] Mobile Phase A: water/acetonitrile/formic acid (95:5:0.05)
[0392] Mobile Phase B: acetonitrile/formic acid (99.95:0.05)
[0393] Gradient: Flow rate 0.4 mL/minute to 0.5 mL/minute
TABLE-US-00014 Time A % B % 0 99 1 0.3 99 1 3.2 5 95 3.25 5 95 4 5 95 4.1 99 1 5.5 99 1
[0394] Performed using a SYNAPT G2-SI Waters Q-TOF mass spectrometer for QC analysis, with an ESI source and a Waters Acquity H-class UPLC with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m/z 50 to 1200 in positive mode.
[0395] Method 14
[0396] Acquity UPLC HSS T3 C18 (1.8 μm, 2.1×50 mm) column
[0397] Solvent A: water/acetonitrile/formic acid (95/5/750 μg/L)
[0398] Solvent B: water/acetonitrile/formic acid (5/95/500 μg/L)
[0399] Gradient: Flow rate 0.5 mL/minute to 0.8 mL/minute
TABLE-US-00015 Time A % B % 0 98 2 0.3 98 2 3 5 95 4 5 95 4.1 98 2 5.1 98 2
[0400] Performed using a Waters I-Class UPLC system coupled to PDA and QDa MS detectors.
[0401] Method 15
[0402] Waters XBridge BEH C18 XP (2.5 μm, 2.1×50 mm) column
[0403] Mobile Phase A: 10 mM ammonium formate+0.1% NH.sub.3 (pH 10)
[0404] Mobile Phase B: acetonitrile+5% water+0.1% NH.sub.3 (pH 10)
[0405] Gradient: Flow rate 1 mL/minute
TABLE-US-00016 Time A % B % 0 95 5 0.1 95 5 2.6 5 95 2.75 5 95 2.8 95 5 3 95 5
[0406] Method 16
[0407] Waters XBridge BEH C18 XP (2.5 μm, 2.1×50 mm) column
[0408] Mobile Phase A: 10 mM ammonium formate+0.1% formic acid (pH 3)
[0409] Mobile Phase B: acetonitrile+5% water+0.1% formic acid (pH 3)
[0410] Gradient: Flow rate 1 mL/minute
TABLE-US-00017 Time A % B % 0 95 5 0.1 95 5 2.6 5 95 2.75 5 95 2.8 95 5 3 95 5
[0411] Performed using LCMS purification (Basic mode, LCMS prep) using SQD Waters single quadrupole mass spectrometer with an ESI source, Waters 2535 quaternary pump coupled with 2767 Sample Manager and with diode array detector (210 to 400 nm). Data are acquired in a full MS scan from m/z 100 to 850 in positive and negative modes with a basic elution.
[0412] Method 17
[0413] Waters XBridge OBD MS C18 (5 μm, 30×50 mm) column
[0414] Mobile Phase A: water+10 mM NH.sub.4HCO.sub.3+50 μg/L NH.sub.4OH
[0415] Mobile Phase B: acetonitrile
[0416] Mobile Phase D: water+100 mM NH.sub.4HCO.sub.3+500 μg/L NH.sub.4OH (pH˜8.5)
[0417] Gradient: Flow rate 35 mL/minute to 45 mL/minute
TABLE-US-00018 Time A % B % D % 0 85 5 10 1 85 5 10 7 10 85 5 9 10 85 5 12 10 85 5
[0418] Performed on a Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and Softa Model 400 ELS detectors.
[0419] Method 18
[0420] Waters XBridge C18 (50 mm×3.0 mm, 2.5 μm) column
[0421] Mobile Phase A: 5 mM ammonium bicarbonate in water
[0422] Mobile Phase B: acetonitrile
[0423] Gradient program: Flow rate 1.2 mL/minute; column oven: 50° C.
TABLE-US-00019 Time A % B % 0.0 100 0 2.0 5 95 3.0 5 95 3.2 100 0 4.0 100 0
[0424] Performed on a Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and PL 2100 detectors.
[0425] Method 19
[0426] Waters Atlantis dC18 (2.1×100 mm, 3 μm) column
[0427] Mobile Phase A: 0.1% formic acid in water
[0428] Mobile Phase B: 0.1% formic acid in acetonitrile
[0429] Gradient program: Flow rate 0.6 mL/minute; column temperature 40° C.
TABLE-US-00020 Time A % B % 0.00 95.00 5.00 5.00 0.00 100.0 5.40 0.00 100.0 5.42 95.00 5.00
[0430] Method 20
[0431] Waters Acquity UPLC BEH C18 (2.1×50 mm, 1.7 μm) column
[0432] Solvent A: 10 mM ammonium formate in water+0.1% formic acid
[0433] Solvent B: acetonitrile+5% water+0.1% formic acid
[0434] Gradient: Flow rate 0.7 mL/minute
TABLE-US-00021 Time A % B % 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00
[0435] Performed using a Waters I-Class UPLC system coupled to PDA and QDa MS detectors.
[0436] Method 21
[0437] X-Bridge C18 (2.1×20 mm, 2.5 μm) column
[0438] Mobile Phase A: 10 mM ammonium formate in water+0.1% ammonia solution
[0439] Mobile Phase B: acetonitrile+5% water+0.1% ammonia solution
[0440] Gradient program: Flow rate 1 mL/minute
TABLE-US-00022 Time A % B % 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00
[0441] Method 22
[0442] Waters Thar 3100 SFC system connected to a Waters 2998 PDA detector
[0443] Column: Amylose-2 25 cm
[0444] Isocratic eluent: 80% heptane-20% 2-propanol at 1 mL/minute
[0445] Method 23
[0446] Waters Thar 3100 SFC system connected to a Waters 2998 PDA detector
[0447] Column: Chiralpak AS-H 25 cm
[0448] Isocratic eluent: 10% methanol-90% CO.sub.2 at 4 mL/minute
[0449] LC-MS (Basic Method)
[0450] Performed on a Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and Softa Model 400 ELS detectors.
[0451] Method 24
[0452] Waters XBridge C18 (30 mm×2.1 mm, 2.5 μm) column
[0453] Mobile Phase A: 0.1% ammonia in 5 mM ammonium formate buffer
[0454] Mobile Phase B: 0.1% NH.sub.3 in acetonitrile/5 mM ammonium formate buffer (95:5)
[0455] Gradient program: Flow rate 1.0 mL/minute
TABLE-US-00023 Time A % B % 0.0 95 5 4.0 5 95 5.0 5 95 5.1 95 5 6.5 95 5
Intermediate 1
Methyl 2-cyclooctylidene-2-formamidoacetate
[0456] A solution of potassium tert-butoxide in THF (1M, 48 mL, 48 mmol) was added dropwise to a solution of methyl isocyanoacetate (4.0 mL, 41.8 mmol) in anhydrous THF (40 mL) at approximately −65° C. under nitrogen. After stirring for 5 minutes, a solution of cyclooctanone (5 g, 39.62 mmol) in anhydrous THF (20 mL) was added slowly at −70° C. The reaction mixture was stirred at −70° C. for 30 minutes, then the cooling bath was removed and the mixture was allowed to warm to 20° C. with stirring under nitrogen for 60 h. The resultant deep red solution was quenched with water (100 mL) and stirred at 20° C. for 1 h. The residue was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude viscous orange oil was separated by flash column chromatography, using a gradient of ethyl acetate in heptane (0-90%), to afford the title compound (5.37 g, 58%) as a viscous orange oil, which solidified upon standing. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.31 (s, 1H), 8.01 (d, J 1.5 Hz, 1H), 3.60 (s, 3H), 2.52-2.47 (m, 2H), 2.31-2.23 (m, 2H), 1.74-1.60 (m, 4H), 1.50-1.31 (m, 6H). HPLC-MS (method 7): MNa+ m/z 248, RT 1.63 minutes.
Intermediate 2
Methyl 2-cyclooctyl-2-formamidoacetate
[0457] Magnesium turnings (3.15 g, 129.6 mmol) were added carefully to a stirred solution of Intermediate 1 (2.91 g, 12.95 mmol) in anhydrous methanol (65 mL) at 0° C. under nitrogen. The suspension was stirred at 0° C. for 1 h, then allowed to warm to 20° C. over 2 h. Stirring of the turbid suspension was continued at 20° C. for 16 h. An additional portion of magnesium turnings (1 g, 41.14 mmol) was added, and the suspension was stirred at 20° C. for 3.5 h under nitrogen. The mixture was carefully concentrated in vacuo. The residue was suspended in ethyl acetate (100 mL) and water (200 mL), then cooled to 0° C. The mixture was treated with aqueous hydrochloric acid to aid dissolution of the solids (approx. pH 1). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude orange viscous oil was separated by flash column chromatography, using a gradient of ethyl acetate in heptane (0-80%), to afford the title compound (1.53 g, 48%) as a viscous orange oil. Major rotamer: δ.sub.H (500 MHz, DMSO-d.sub.6) 8.46 (d, J 8.5 Hz, 1H), 8.06 (s, 1H), 4.29 (dd, J 8.6, 6.1 Hz, 1H), 3.64 (s, 3H), 2.04-1.93 (m, 1H), 1.73-1.19 (m, 14H). HPLC-MS (method 19): MH+ m/z 228, RT 3.94 minutes.
Intermediate 3
Methyl 2-amino-2-cyclooctylacetate hydrochloride
[0458] Acetyl chloride (1.9 mL, 26.7 mmol) was added cautiously at 0° C. to a stirred solution of Intermediate 2 (1.54 g, 6.77 mmol) in methanol (68 mL) under nitrogen. After stirring for 5 minutes, the solution was heated at 50° C. for 2 h, then the mixture was concentrated in vacuo. The resulting crude orange powder was triturated from diethyl ether (40 mL) and the solids were collected by filtration, washing with diethyl ether (2×20 mL). The solids were dried in vacuo at 50° C. for 6 h to afford the title compound (1.43 g, 81%) as a tan powder. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.61 (br s, 3H), 3.86 (d, J 4.4 Hz, 1H), 3.73 (s, 3H), 2.19-2.09 (m, 1H), 1.68-1.37 (m, 13H), 1.32-1.20 (m, 1H).
Intermediate 4
Methyl 2-cyclooctyl-2-[(3-methylisoxazole-4-carbonyl)amino]acetate
[0459] To a solution of 3-methyl-4-isoxazolecarboxylic acid (1.65 g, 12.7 mmol) and Intermediate 3 (3 g, 12.73 mmol) in DMF (20 mL) at 0° C. was added HATU (5.99 g, 15.3 mmol), followed by DIPEA (8.9 mL, 51 mmol, 8.9 mL). The mixture was stirred overnight, with warming to r.t., then diluted with water (100 mL) and extracted with EtOAc (2×80 mL). The organic extracts were dried over sodium sulfate, then filtered and evaporated to dryness. The residue was purified by flash chromatography, using a gradient of EtOAc/hexanes (10-80%), to yield the title compound (3.85 g, 98%) as a tan oil. δ.sub.H (400 MHz, CDCl.sub.3) 8.77 (d, J 0.7 Hz, 1H), 6.32 (d, J 8.6 Hz, 1H), 4.72 (dd, J 8.6, 4.8 Hz, 1H), 3.80 (s, 3H), 2.54 (d, J 0.6 Hz, 3H), 2.28-2.12 (m, 1H), 1.83-1.32 (m, 14H). HPLC-MS (method 7): [M+H].sup.+ m/z 309, RT 1.37 minutes.
Intermediate 5
2-Cyclooctyl-2-[(3-methylisoxazole-4-carbonyl)amino]acetic acid
[0460] To a solution of Intermediate 4 (3.85 g, 12.5 mmol) in THF (40 mL) was added a solution of lithium hydroxide monohydrate (786 mg, 18.7 mmol) in water (10 mL). The reaction mixture was stirred for 72 h at r.t., then diluted with water (30 mL) and acidified to pH 3 with 2N aqueous HCl (approx. 10 mL). The material was extracted with EtOAc (50 mL). The aqueous extracts were dried over sodium sulfate, then filtered and evaporated. To the resulting beige oil was added acetonitrile (50 mL) with stirring. The precipitated solid was filtered and dried on a sintered funnel for 2 h to give the title compound (560 mg). The mother liquor was concentrated. To the resulting white slurry was added diethyl ether (60 mL) with stirring, then the mixture was concentrated. The resultant gum was lyophilised from acetonitrile (10 mL) and water (30 mL) to give another crop of the title compound (1.7 g). δ.sub.H (400 MHz, CDCl.sub.3) 8.79 (s, 1H), 6.25 (d, J 8.5 Hz, 1H), 4.78 (dd, J 8.5, 4.5 Hz, 1H), 2.55 (s, 3H), 2.28 (s, 1H), 1.86-1.36 (m, 14H). HPLC-MS (method 21): [M+H].sup.+ m/z 295, RT 0.91 minutes.
Intermediate 6
Methyl 2-[(tert-butoxycarbonyl)amino]-2-cyclooctylacetate
[0461] To Intermediate 3 (40 g, 0.17 mol) dissolved in DCM (500 mL), at 0° C., were added triethylamine (68.4 g, 0.68 mol) and di-tert-butyl dicarbonate (38.8 g, 0.18 mol). The reaction mixture was stirred at r.t. for 20 h, then diluted with water (400 mL) and extracted with DCM (2×500 mL). The organic layer was washed with brine (400 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The crude residue was triturated with petroleum ether to afford the title compound (45.2 g, 89%) as a white solid. δ.sub.H (250 MHz, DMSO-d.sub.6) 7.14 (d, J 8.6 Hz, 1H), 4.03-3.78 (m, 1H), 3.61 (s, 3H), 2.02-1.84 (m, 1H), 1.75-1.19 (m, 23H).
Intermediate 7
2-[(tert-Butoxycarbonyl)amino]-2-cyclooctylacetic acid
[0462] Lithium hydroxide monohydrate (75 mg, 1.78 mmol) was added to a stirred solution of Intermediate 6 (485 mg, 1.62 mmol) in 2:1 THF-water (12 mL). The reaction mixture was stirred at 20° C. for 15 h, then concentrated and dried in vacuo for 2 h. The resulting crude material (471 mg) was suspended in EtOAc (20 mL) and treated with saturated aqueous ammonium chloride solution (20 mL), followed by aqueous hydrochloric acid (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (50 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo, to give the title compound as a white powder. δ.sub.H (400 MHz, CDCl.sub.3) 4.97 (d, J 9.1 Hz), 4.24 (dd, J 9.2, 4.5 Hz), 2.14 (s, 2H), 1.45 (s, 21H).
Intermediate 8
4-(4-Bromo-2-methylphenyl)oxane-4-carbonitrile
[0463] Sodium bis(trimethylsilyl)amide solution in THF (1M, 19.5 mL, 19.5 mmol) was added dropwise to a solution of 2-(4-bromo-2-methylphenyl)acetonitrile (3.75 g, 17.85 mmol) in THF (90 mL) at 0° C. After stirring for 0.5 h, the cooling bath was removed and the reaction mixture was stirred at 20° C. for 0.5 h. 1-Iodo-2-(2-iodoethoxy)ethane (2.8 mL, 19.67 mmol) was added dropwise. The reaction mixture was stirred for 0.5 h at 20° C. Sodium bis(trimethylsilyl)amide solution in THF (1M, 19.5 mL, 19.5 mmol) was added dropwise. The reaction mixture was stirred for 18 h at 20° C., then quenched with saturated aqueous ammonium chloride solution (25 mL) and diluted with water (25 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting brown oil was purified by flash column chromatography, using a gradient of tert-butyl methyl ether in heptane (0-25%), to afford the title compound (2.3 g, 45%) as a yellow solid. δ.sub.H (250 MHz, CDCl.sub.3) 7.47-7.36 (m, 2H), 7.16 (d, J 8.4 Hz, 1H), 4.16-4.06 (m, 2H), 4.06-3.91 (m, 2H), 2.65 (s, 3H), 2.33-2.21 (m, 2H), 2.17-1.99 (m, 2H). HPLC-MS (method 9): [M+water]+ m/z 297 and 299, RT 1.80 minutes.
Intermediate 9
tert-Butyl N-[4-(4-cyanooxan-4-yl)-3-methylphenyl]carbamate
[0464] A sealable tube was charged with Intermediate 8 (200 mg, 0.71 mmol), tert-butyl carbamate (167 mg, 1.43 mmol) and cesium carbonate (395 mg, 1.21 mmol). The reagents were suspended in toluene (2 mL). The reaction mixture was charged with palladium(II) acetate (4.8 mg, 21.4 μmol) and XPhos (20.4 mg, 42.8 μmol), then purged with nitrogen and sonicated for 5 minutes. The reaction vessel was sealed and heated at 90° C. for 3 h. The reaction mixture was quenched with water (10 mL), then extracted with EtOAc (20 mL) and filtered. The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (10 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was separated by column chromatography, using a gradient of tert-butyl methyl ether/heptane (0-50%), to afford the title compound (237 mg, 95%) as a beige solid. δ.sub.H (250 MHz, CDCl.sub.3) 7.31-7.27 (m, 1H), 7.26-7.16 (m, 2H), 6.45 (s, 1H), 4.14-4.05 (m, 2H), 4.05-3.92 (m, 2H), 2.61 (s, 3H), 2.34-2.20 (m, 2H), 2.16-1.98 (m, 2H), 1.52 (s, 9H).
[0465] HPLC-MS (method 4): [M+H].sup.+ m/z 317, RT 1.79 minutes.
Intermediate 10
4-(4-Amino-2-methylphenyl)oxane-4-carbonitrile
[0466] TFA (0.8 mL, 10.5 mmol) was added to a solution of Intermediate 9 (90% purity, 0.24 g, 0.68 mmol) in DCM (5 mL). The reaction mixture was stirred for 5 h at 20° C., then quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL) and stirred for 15 minutes at 20° C. The layers were separated. The aqueous layer was extracted with DCM (2×15 mL). The combined organic extracts were filtered using a hydrophobic frit, and the solvent was concentrated in vacuo, to afford the title compound (0.15 g, 99%) as a brown solid. δ.sub.H (250 MHz, CDCl.sub.3) 6.96 (d, J 8.3 Hz, 1H), 6.52-6.41 (m, 2H), 4.04-3.94 (m, 2H), 3.94-3.82 (m, 2H), 3.60 (br s, 2H), 2.47 (s, 3H), 2.23-2.09 (m, 2H), 2.05-1.88 (m, 2H). HPLC-MS (method 2): [M+H].sup.+ m/z 217, RT 0.73 minutes.
Intermediate 11
4-(4-Bromo-2-methylphenyl)oxane-4-carboxamide
[0467] Potassium hydroxide (78.5 mg, 1.40 mmol) was added to a solution of Intermediate 8 (100 mg, 0.35 mmol) in ethylene glycol (2 mL) and water (0.4 mL). The reaction mixture was heated at 120° C. for 20 h. An additional portion of potassium hydroxide (109 mg, 1.94 mmol) was added, and heating was recommenced at 140° C. for 3 h. The reaction mixture was cooled to 20° C., then water (5 mL) was added and the aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), then dried over magnesium sulfate and filtered. The solvent was concentrated in vacuo, and azeotroped with heptane, to afford the title compound (107 mg, 98%) as a sticky cream-coloured solid. δ.sub.H (250 MHz, CDCl.sub.3) 7.36-7.26 (m, 2H), 7.25-7.20 (m, 1H), 5.23 (br s, 1H), 4.94 (br s, 1H), 4.00-3.85 (m, 2H), 3.74-3.61 (m, 2H), 2.38-2.22 (m, 2H), 2.28 (s, 3H), 2.06-1.91 (m, 2H). HPLC-MS (method 2): [M+H].sup.+ m/z 298 and 300, RT 1.01 minutes.
Intermediate 12
4-(4-Bromo-2-methylphenyl)-N,N-dimethyloxane-4-carboxamide
[0468] Intermediate 11 (95% purity, 107 mg, 0.34 mmol) in THF (2 mL) was added dropwise to a suspension of sodium hydride (60% purity, 40.9 mg, 1.02 mmol) in THF (1 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then iodomethane (63.7 μL, 1.02 mmol) was added. The reaction mixture was warmed to 20° C. and stirred for 18 h, then cooled to 0° C. and quenched with water (2 mL). The mixture was warmed to 20° C., and was extracted with diethyl ether (2×10 mL). The organic extracts were washed with brine (5 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The oily residue was separated by flash column chromatography, using a gradient of tert-butyl methyl ether/heptane (0-100%), to afford the title compound (88 mg, 73%) as a white solid. δ.sub.H (250 MHz, CDCl.sub.3) 7.32-7.26 (m, 1H), 7.24-7.20 (m, 2H), 4.00-3.85 (m, 2H), 3.83-3.71 (m, 2H), 2.86 (s, 3H), 2.42 (s, 3H), 2.27-2.13 (m, 2H), 2.17 (s, 3H), 2.05-1.85 (m, 2H). HPLC-MS (method 2): [M+H].sup.+ m/z 326 and 328, RT 1.15 minutes.
Intermediate 13
tert-Butyl N-{4-[4-(dimethylcarbamoyl)oxan-4-yl]-3-methylphenyl}carbamate
[0469] A sealable tube was charged with Intermediate 12 (83% purity, 95.9 mg, 0.24 mmol), tert-butyl carbamate (57 mg, 0.49 mmol) and cesium carbonate (135 mg, 0.41 mmol). The reagents were suspended in toluene (1 mL). The reaction mixture was charged with palladium(II) acetate (1.6 mg, 7.3 μmol) and XPhos (7.0 mg, 14.6 μmol), then purged with nitrogen and sonicated for 5 minutes. The reaction vessel was sealed and heated at 90° C. for 3 h. The reaction mixture was cooled to 20° C. and quenched with water (10 mL), then extracted with EtOAc (10 mL) and filtered. The layers were separated. The aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were washed with brine (5 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting orange oil was purified by column chromatography, using a gradient of tert-butyl methyl ether/heptane (0-100%), to afford the title compound (68 mg, 61%) as a pale yellow solid. δ.sub.H (250 MHz, CDCl.sub.3) 7.38-7.32 (m, 1H), 7.27-7.13 (m, 2H), 6.40 (s, 1H), 4.12-3.94 (m, 2H), 3.91-3.79 (m, 2H), 2.92 (br s, 3H), 2.49 (br s, 3H), 2.36-2.20 (m, 2H), 2.22 (s, 3H), 2.17-1.94 (m, 2H), 1.52 (s, 9H). HPLC-MS (method 4): [M+H].sup.+ m/z 363, RT 1.69 minutes.
Intermediate 14
4-(4-Amino-2-methylphenyl)-N,N-dimethyloxane-4-carboxamide
[0470] TFA (0.17 mL, 2.25 mmol) was added to a solution of Intermediate 13 (86%, 68 mg, 0.16 mmol) in DCM (2 mL). The reaction mixture was stirred for 3 h at 20° C., then quenched with saturated aqueous sodium hydrogen carbonate solution (5 mL) and stirred for 15 minutes at 20° C. The layers were separated, and the aqueous layer was extracted with DCM (2×10 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution (5 mL) and filtered using a hydrophobic frit, then the solvent was concentrated in vacuo, to afford the title compound (46.9 mg, 97%) as a brown solid. δ.sub.H(250 MHz, CDCl.sub.3) 7.19 (d, J 8.4 Hz, 1H), 6.58 (dd, J 8.5, 2.6 Hz, 1H), 6.50 (d, J 2.5 Hz, 1H), 4.12-3.92 (m, 2H), 3.91-3.77 (m, 2H), 2.94 (br s, 3H), 2.55 (br s, 3H), 2.36-2.23 (m, 2H), 2.18 (s, 3H), 2.12-1.94 (m, 2H), 1.81-1.43 (m, 2H). HPLC-MS (method 2): [M+H].sup.+ m/z 263, RT 0.55 minutes.
Intermediate 15
4-{5-Chlorobicyclo[4.2.0]octa-1(6),2,4-trien-7-ylidene}-2-(3-methylisoxazol-4-yl)-4,5-dihydro-1,3-oxazol-5-one
[0471] To a stirred solution of 2[(3-methylisoxazole-4-carbonyl)amino]acetic acid (44.2 g, 240 mmol) in anhydrous DCM (440 mL) was added EDC.HCl (59.8 g, 312 mmol) portion wise. The reaction mixture was stirred at ambient temperature for 1.5 h, then diluted with DCM (200 mL) and quenched with water (500 mL). The organic layer was separated and washed with brine (2×500 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo to afford 2-(3-methylisoxazol-4-yl)-4H-oxazol-5-one (34 g) as a yellow solid, which was utilised without further purification. δ.sub.H (400 MHz, CDCl.sub.3) 8.83 (s, 1H), 4.37 (s, 2H), 2.56 (s, 3H).
[0472] Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at 0° C. A solution of 2-(3-methylisoxazol-4-yl)-4H-oxazol-5-one (0.2 g, 1.20 mmol) in anhydrous THF (1.5 mL) and a solution of 5-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-one (0.2 g, 1.32 mmol) in anhydrous THF (1.5 mL) were added dropwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes. Anhydrous pyridine (0.78 mL, 14.47 mmol) was added dropwise at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for a further 2 h, then at 20° C. for 16 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (12 mL), and was stirred for a further 10 minutes. The solution was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was separated by column chromatography, using a gradient of EtOAc/heptane (0-100%), to afford the title compound (311 mg, 83%) as a yellow solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 7.54 (dd, J 8.1, 7.2 Hz, 1H), 7.48 (d, J 8.0 Hz, 1H), 7.39 (d, J 7.0 Hz, 1H), 4.06 (s, 2H), 2.60 (s, 3H). HPLC-MS (method 3): [M+H].sup.+ m/z 301 and 303, RT 1.99 minutes.
Intermediate 16
tert-Butyl N-(4-bromo-3-fluorophenyl)carbamate
[0473] 4-Bromo-3-fluoroaniline (2.48 g, 12.7 mmol) was suspended in water (20 mL) and treated with di-tert-butyl dicarbonate (3.42 g, 15.2 mmol) portionwise. The resulting suspension was stirred rapidly at r.t. for 40 h. The thick off-white suspension was diluted with water (20 mL) and stirred for 20 minutes, then filtered through a sintered funnel. The isolated solid was washed with water (2×10 mL), then dried under suction for 45 minutes, to yield the title compound (3.46 g, 94%) as an off-white solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.44-7.37 (m, 2H), 6.90 (ddd, J 8.7, 2.5, 1.0 Hz, 1H), 6.51 (s, 1H), 1.52 (s, 9H). HPLC-MS (method 7): [M−.sup.tBu+H].sup.+ m/z 234 and 236, RT 1.22 minutes.
Intermediate 17
3-Fluoro-4-(tetrahydropyran-4-yl)aniline
[0474] In a capped vial, nickel chloride dimethoxyethane adduct (5.4 mg, 0.024 mmol) and 4,4′-di-tert-butyl-2,2′-dipyridyl (8 mg, 0.029 mmol) were suspended in anhydrous 1,2-dimethoxyethane (2 mL). Nitrogen gas was bubbled through the suspension, which was stirred for 10 minutes. In a second vial, Intermediate 16 (75 mg, 0.26 mmol) and {Ir[dF(CF.sub.3)ppy].sub.2(dtbpy)}PF.sub.6 (3 mg, 2.6 μmol) were dissolved in anhydrous 1,2-dimethoxyethane (2.4 mL) under a gentle stream of nitrogen, then 4-bromotetrahydropyran (44 μL, 0.26 mmol), 2,6-lutidine (62 μL, 0.527 mmol) and tris(trimethylsilyl)silane (80 μL, 0.26 mmol) were added. A portion of the nickel chloride/dipyridyl solution (0.1 mL) was added, and the second vial was sparged with nitrogen for 15 minutes. The resulting mixture was sealed and stirred at ambient temperature, whilst undergoing irradiation with a blue LED (450 nm) for 1 h. The residue was purified by column chromatography, using a gradient of 0-100% EtOAc/isohexane. The resulting crude tert-butyl N-[3-fluoro-4-(tetrahydropyran-4-yl)phenyl]carbamate (54 mg) was dissolved in DCM (2 mL), treated with TFA (0.5 mL) and stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM (5 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous layer was re-extracted twice with DCM. The organic layers were combined, then filtered through a PTFE phase separator cartridge and concentrated in vacuo. The crude residue was purified by column chromatography, using a gradient of 0-100% EtOAc/isohexane, to yield the title compound (25 mg, 48%). HPLC-MS (method 7): [M+H].sup.+ m/z 196, RT 1.15 minutes.
Intermediate 18
trans-(4-Methylcyclohexyl)methanol
[0475] To a cold (−20° C. to −5° C.) solution of trans-4-methylcyclohexanecarboxylic acid (68.5 g, 0.481 mol) in THF (550 mL) was added a solution of lithium aluminum hydride (2.4M in THF, 200 mL, 0.48 mol) slowly over circa 1 h. The mixture was stirred at −20° C. for 1.5 h, then allowed to warm to ambient temperature. The mixture was re-cooled in an ice-salt bath before water (16 mL), aqueous sodium hydroxide solution (15 wt %, 16 mL), and water (40 mL) were slowly and cautiously added. The resulting viscous mixture was stirred for 10 minutes, then diethyl ether (500 mL) was added. The resulting suspension was filtered through a pad of kieselguhr. The solvents were evaporated under reduced pressure to afford the title compound (63.5 g, 100%) as a clear, colourless mobile oil. δ.sub.H (500 MHz, CDCl.sub.3) 3.44 (d, J 6.3 Hz, 2H), 1.79-1.69 (m, 4H), 1.47-1.23 (m, 3H), 1.04-0.89 (m, 4H), 0.88 (d, J 6.6 Hz, 3H).
Intermediate 19
trans-4-Methylcyclohexanecarbaldehyde
[0476] To a cold (−10° C. to −5° C.) solution of Intermediate 18 (30.31 g, 0.229 mol) in DCM (250 mL), DIPEA (122 mL, 1.15 mol) and DMSO (81.4 mL, 0.688 mol) was added solid pyridine-sulfur trioxide complex (73 g, 0.458 mol) portionwise, maintaining the internal temperature below 20° C. The reaction mixture was stirred at ambient temperature for 16 h, then washed in turn with aqueous citric acid (1M, 200 mL) and brine (200 mL). The organic layer was filtered through phase separating filter paper. The solvent was removed under reduced pressure to afford the title compound (34.9 g, 100%) as a pale yellow oil. δ.sub.H (250 MHz, CDCl.sub.3) 9.61 (d, J 1.6 Hz, 1H), 2.28-2.03 (m, 1H), 1.95 (m, 2H), 1.80 (m, 2H), 1.56-1.14 (m, 3H), 1.07-0.80 (m, 5H, including the Me signal at δ 0.90 (d, J 6.5 Hz)).
Intermediate 20
(S)-4-Methyl-N-[(1E)-(trans-4-methylcyclohexyl)methylidene]benzenesulfinamide
[0477] To a solution of Intermediate 19 (34.9 g, 229 mmol) and (S)-4-methylbenzenesulfinamide (35.6 g, 229 mmol) in DCM (1.2 L) was added titanium(IV) ethoxide (85-90% purity, 174.5 g, 160 mL). The resulting solution was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, then water (300 mL) was added slowly. The resulting thick paste was filtered through a pad of kieselguhr, then rinsed with DCM (300 mL) and water (300 mL). The two phases were separated. The DCM phase was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated, to give the title compound (55.7 g, 78%) as a yellow oil, which partially solidified upon standing. δ.sub.H (250 MHz, CDCl.sub.3) 8.11 (d, J 4.9 Hz, 1H), 7.70-7.49 (m, 2H), 7.29 (m, 2H), 2.40 (s, 2H), 2.38-2.24 (m, 1H), 2.06-1.66 (m, 4H), 1.53-1.16 (m, 4H), 1.07-0.91 (m, 2H), 0.89 (d, J 6.5 Hz, 3H).
Intermediate 21
N—[(S)-Cyano(trans-4-methylcyclohexyl)methyl]-(S)-4-methylbenzenesulfinamide
[0478] To a solution of diethylaluminium cyanide (1M in toluene, 103 mL, 103 mmol) in THF (400 mL) at −78° C. was added anhydrous isopropyl alcohol (5.3 mL, 69 mmol). The mixture was stirred at −78° C. for 30-60 minutes, then cannulated into a solution of Intermediate 20 (90% purity, 20.2 g, 69 mmol) in THF (800 mL) at −78° C. over circa 45 minutes. The mixture was allowed to warm to room temperature, then stirred overnight. The mixture was cooled in an ice-water bath, then saturated aqueous ammonium chloride solution (300 mL) was added; some gas was evolved and the internal temperature increased to circa 30° C. After 1 h, the mixture was filtered through a pad of kieselguhr, then the pad was washed with water (300 mL) and ethyl acetate (300 mL). The organic layers were divided, and the aqueous layers were washed with more ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated. The resulting pale yellow oil, which solidified upon standing, was taken up in hot heptane-ethyl acetate, then allowed to crystallise, to afford the title compound (7.78 g, 38%) as a white solid. The residues were evaporated and purified by automated column chromatography to give a clean mixture of the two diastereoisomers. Recrystallisation of this mixture from ethyl acetate-heptane, seeded using some of the first crop, gave a further batch of the title compound (4.05 g, 20%). δ.sub.H (250 MHz, CDCl.sub.3) 7.61 (d, J 8.3 Hz, 2H), 7.36 (d, J 8.2 Hz, 3H), 4.50 (d, J 7.8 Hz, 1H), 3.95 (dd, J 7.9, 5.8 Hz, 1H), 2.43 (s, 3H), 2.25-1.78 (m, 3H), 1.44-0.91 (m, 5H), 0.89 (d, J 6.5 Hz, 3H).
Intermediate 22
[(S)-Cyano(trans-4-methylcyclohexyl)methyl]ammonium chloride
[0479] To a stirred solution of Intermediate 21 (6.6 g, 22.73 mmol) in dry methanol (130 mL) was added 4M hydrogen chloride in 1,4-dioxane (60 mL) dropwise over 2 minutes, whereupon an exotherm to 26° C. had occurred. The reaction mixture was cooled externally and 4M hydrogen chloride (60 mL) in 1,4-dioxane was added over 3 minutes. After 5 minutes, the flask was stoppered and the reaction mixture was stirred at ambient temperature for 2 h. The volatiles were concentrated in vacuo. Diethyl ether (100 mL) was added, then the mixture was sonicated and stirred for 15 minutes. The solids were filtered off and washed with diethyl ether (3×100 mL), then dried under a stream of nitrogen gas, to afford the title compound (4.10 g, 96%) as a white solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.20 (s, 3H), 4.50 (d, J 5.5 Hz, 1H), 1.92-1.77 (m, 3H), 1.77-1.67 (m, 2H), 1.29 (ddp, J 11.4, 6.8, 3.4 Hz, 1H), 1.18-1.01 (m, 2H), 0.95-0.83 (m, 5H). HPLC-MS (method 1): [M+H].sup.+ m/z 153, RT 0.46 minutes (100%). Chiral LC (method 22): RT 8.84 minutes (S, 93%).
Intermediate 23
[(S)-Carboxy(trans-4-methylcyclohexyl)methyl]ammonium chloride
[0480] A stirred solution of Intermediate 22 (4.05 g, 21.46 mmol) in a mixture of acetic acid (17 mL) and concentrated hydrochloric acid (85 mL) was heated to an external temperature of 130° C. (105° C. internal temperature). After 3 h, another portion of concentrated hydrochloric acid (25 mL) was added, followed by another portion (25 mL) after a further 2 h. The reaction mixture was heated for 1 h, then cooled. The precipitated solid was filtered and rinsed with tert-butyl methyl ether, then dried in vacuo, to afford the title compound (3.04 g, 68%) as a white solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.35 (s, 3H), 3.69 (d, J 4.2 Hz, 1H), 1.82-1.65 (m, 4H), 1.64-1.54 (m, 1H), 1.32-1.18 (m, 2H), 1.15-1.02 (m, 1H), 0.93-0.80 (m, 5H). HPLC-MS (method 2): [M+H]+m/z 172, RT 0.63 minutes.
Intermediate 24
(2S)-2-(tert-Butoxycarbonylamino)-2-(trans-4-methylcyclohexyl)acetic acid
[0481] To a stirred suspension of Intermediate 23 (25.1 g, 120.8 mmol) in water (350 mL) was added sodium carbonate (55 g, 0.52 mol), then di-tert-butyl dicarbonate (39.6 g, 181 mmol) in 1,4-dioxane (500 mL). The reaction mixture was stirred for 4 h. The volatiles were removed in vacuo, then the suspension was cooled and 1N hydrochloric acid was carefully added to achieve a pH of 1. The mixture was extracted with ethyl acetate (3×250 mL). The organic layers were combined, washed in turn with water (200 mL) and brine (200 mL), then filtered through phase separating paper. The volatiles were evaporated. The resulting solid was triturated in heptane (500 mL), then filtered, washed with heptane (2×100 mL) and oven-dried, to give the title compound (28.8 g, 87%) as a white solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 12.40 (s, 1H), 6.89 (d, J 8.5 Hz, 1H), 3.81-3.74 (m, 1H), 1.69-1.53 (m, 5H), 1.37 (s, 9H), 1.28-1.19 (m, 1H), 1.09 (dp, J 22.9, 12.6, 11.6 Hz, 2H), 0.91-0.76 (m, 5H). HPLC-MS (method 1): [M+H]+m/z 271, RT 3.34 minutes. Chiral SFC (method 23): RT 2.61 minutes (100%). [α].sup.D.sub.20 28.3° (c 3.202, chloroform).
Intermediate 25 (Procedure A)
tert-Butyl N-{(1S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-anilino]ethyl}carbamate
[0482] Intermediate 24 (250 mg, 0.92 mmol) was dissolved in DCM (6 mL), then HATU (433 mg, 1.11 mmol) and DIPEA (0.321 mL, 1.85 mmol) were added at r.t. After 5-10 minutes, 4-(tetrahydropyran-4-yl)aniline (172 mg, 0.97 mmol) was added. The reaction mixture was stirred at r.t. overnight, then diluted with DCM (15 mL) and quenched with water (20 mL). The aqueous phase was extracted once with DCM. The combined organic extracts were passed through a hydrophobic phase separator and dried under vacuum. The resulting orange residue was purified by column chromatography, using a gradient of isohexane/EtOAc (0-100%), then MeOH/EtOAc (0-30%), to yield the title compound (411 mg, 98%) as a pale brown solid. δ.sub.H (300 MHz, CDCl.sub.3) 7.75 (s, 1H), 7.53-7.41 (m, 2H), 7.18 (d, J 8.4 Hz, 2H), 5.06 (s, 1H), 4.16-4.02 (m, 2H), 3.95 (dd, J 8.5, 6.7 Hz, 1H), 3.59-3.42 (m, 2H), 2.81-2.64 (m, 1H), 1.91-1.63 (m, 11H), 1.45 (s, 9H), 1.39-1.19 (m, 1H), 1.19-0.91 (m, 2H), 0.87 (d, J 6.5 Hz, 3H). HPLC-MS (method 7): [M-.sup.tBu+H].sup.+ m/z 375, RT 1.27 minutes.
Intermediate 26 (Procedure B)
{(1S)-1-(trans-4-Methylcyclohexyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)anilino]ethyl}-ammonium chloride
[0483] Intermediate 25 (411 mg, 0.91 mmol) was dissolved in MeOH (8 mL) and DCM (4 mL). The mixture was treated with HCl in 1,4-dioxane (4N, 1.82 mL, 7.28 mmol) and stirred at r.t. overnight. The reaction was concentrated in vacuo to afford the crude title compound, which was utilised without further purification.
Intermediate 27
tert-Butyl N-(4-bromo-3,5-difluorophenyl)carbamate
[0484] 4-Bromo-3,5-difluoroaniline (2.58 g, 11.32 mmol) was suspended in water (20 mL), and di-tert-butyl dicarbonate (3.08 g, 13.7 mmol) was added. The mixture was stirred vigorously for 72 h, then THF (10 mL) was added. After stirring at r.t. for 1.5 h, di-tert-butyl dicarbonate (1.65 g) was added portionwise. The mixture was stirred at r.t. for another 18 h, then concentrated in vacuo. The residue was purified by column chromatography, using a gradient of EtOAc/isohexane (0-20%), to yield the title compound (2.63 g, 75%) as a white crystalline solid. HPLC-MS (method 7): [M−.sup.tBu+H].sup.+ m/z 252 and 254, RT 1.28 minutes.
Intermediate 28
[3,5-Difluoro-4-(tetrahydropyran-4-yl)phenyl]ammonium trifluoroacetate
[0485] In a capped vial, nickel chloride dimethoxyethane adduct (5.4 mg, 0.024 mmol) and 4,4′-di-tert-butyl-2,2′-dipyridyl (8 mg, 0.029 mmol) were suspended in anhydrous 1,2-dimethoxyethane (2 mL). Nitrogen gas was bubbled through the suspension, which was stirred for 10 minutes. In a second vial, Intermediate 27 (100 mg, 0.325 mmol) and {Ir[dF(CF.sub.3)ppy].sub.2(dtbpy)}PF.sub.6 (3.8 mg, 3.2 μmol) were dissolved in anhydrous 1,2-dimethoxyethane (2.4 mL) under nitrogen, then 4-bromotetrahydropyran (58 μL, 0.33 mmol), 2,6-lutidine (76 μL, 0.646 mmol) and tris(trimethylsilyl)silane (100 μL, 0.33 mmol) were added. A portion of the nickel chloride/dipyridyl solution (0.1 mL) was added to the second vial, and the vessel was sparged with nitrogen for 10 minutes. The tube was sealed and the mixture was stirred at ambient temperature, whilst undergoing irradiation with a blue LED (450 nm) for 2 h. The residue was purified by column chromatography, using a gradient of EtOAc/isohexane (0-100%). The resulting crude tert-butyl N-[3,5-difluoro-4-(tetrahydropyran-4-yl)phenyl]carbamate, a brown solid (11 mg), was dissolved in DCM (1.5 mL), treated with TFA (0.2 mL) and stirred at r.t. for 18 h. The reaction mixture was concentrated in vacuo, and azeotroped with toluene, to yield the crude title compound (11 mg), which was utilised without further purification. HPLC-MS (method 7): [M+H].sup.+ m/z 214, RT 0.81 minutes.
Intermediate 29
Ethyl 2-(4-nitrophenyl)acetate
[0486] To a solution of 4-nitrophenylacetic acid (10.0 g, 55.2 mmol) in EtOH (80 mL) was added thionyl chloride (0.80 mL, 11.0 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was dissolved in DCM (600 mL), then washed with water (600 mL) and saturated aqueous sodium hydrogen carbonate solution (600 mL). The organic layer was separated, then dried over anhydrous sodium sulfate and concentrated in vacuo, to afford the title compound (11.0 g, 95%) as an off-white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 8.20 (d, J 8.31 Hz, 2H), 7.57 (d, J 8.31 Hz, 2H), 4.10 (q, J 6.85 Hz, 2H), 3.88 (s, 2H), 1.19 (t, J 7.09 Hz, 3H).
Intermediate 30
Ethyl 4-(4-nitrophenyl)tetrahydro-2H-pyran-4-carboxylate
[0487] To a solution of Intermediate 29 (11.0 g, 52.6 mmol) in DMF (100 mL) was added NaH (2.31 g, 57.8 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, then 1-bromo-2-(2-bromoethoxy)ethane (18.3 g, 78.9 mmol) was added dropwise. The reaction mixture was heated at 80° C. for 16 h, then cooled to room temperature, quenched with water (1000 mL) and extracted with EtOAc (3×600 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 10% EtOAc in hexanes) to afford the title compound (6.0 g, 41%) as an off-white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 8.23 (d, J 8.80 Hz, 2H), 7.67 (d, J 8.80 Hz, 2H), 4.11 (q, J 6.85 Hz, 2H), 3.78-3.87 (m, 2H), 3.42-3.49 (m, 2H), 2.40-2.43 (m, 2H), 1.89-1.99 (m, 2H), 1.11 (t, J 7.09 Hz, 3H).
Intermediate 31
4-(4-Nitrophenyl)tetrahydro-2H-pyran-4-carboxylic acid
[0488] To a solution of Intermediate 30 (0.70 g, 2.51 mmol) in THF (7 mL) and water (3 mL) was added LiOH.H.sub.2O (0.42 g, 10.0 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was diluted with water (15 mL), then acidified with 1M HCl to pH 4 and extracted with EtOAc (2×25 mL). The organic layer was separated, then dried over anhydrous sodium sulfate and concentrated in vacuo, to afford the title compound (0.60 g, 83%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 13.04 (br s, 1H), 8.23 (d, J 8.80 Hz, 2H), 7.69 (d, J 8.80 Hz, 2H), 3.80-3.86 (m, 2H), 3.46-3.51 (m, 2H), 2.40 (d, J 13.21 Hz, 2H), 1.84-1.93 (m, 2H).
Intermediate 32
N,N-Dimethyl-4-(4-nitrophenyl)tetrahydro-2H-pyran-4-carboxamide
[0489] To a solution of Intermediate 31 (0.60 g, 2.39 mmol) and dimethylamine (2M solution in THF, 3.58 mL, 7.16 mmol) in DCM (6 mL) were added DIPEA (0.83 mL, 4.78 mmol) and HATU (50%, 2.18 g, 2.87 mmol). The reaction mixture was stirred at r.t. for 4 h, then quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography (70% EtOAc in hexanes) to afford the title compound (0.42 g, 63%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 8.24 (d, J 8.80 Hz, 2H), 7.53 (d, J 8.80 Hz, 2H), 3.76-3.79 (m, 2H), 3.53-3.66 (m, 2H), 2.69 (s, 6H), 2.20 (d, J 13.69 Hz, 2H), 1.88-2.00 (m, 2H). HPLC-MS (method 18): [M+H].sup.+ m/z 279, RT 1.64 minutes.
Intermediate 33
4-(4-Aminophenyl)-N,N-dimethyltetrahydro-2H-pyran-4-carboxamide
[0490] To a solution of Intermediate 32 (0.42 g, 1.51 mmol) in MeOH (6 mL) was added SnCl.sub.2.2H.sub.2O (1.02 g, 4.53 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was washed with 2% MeOH in DCM (3×25 mL), then decanted and dried in vacuo, to afford the title compound (0.50 g, 87%) as an off-white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 6.88 (d, J 8.80 Hz, 2H), 6.57 (d, J 8.80 Hz, 2H), 4.12 (br s, 2H), 3.68-3.75 (m, 2H), 3.54 (t, J 10.52 Hz, 2H), 3.17 (s, 6H), 2.11 (d, J 13.69 Hz, 2H), 1.76-1.85 (m, 2H). HPLC-MS (method 18): [M+H].sup.+ m/z 249, RT 1.38 minutes.
Intermediate 34
tert-Butyl N-{(1S)-2-[3-fluoro-4-(tetrahydropyran-4-yl)anilino]-1-(trans-4-methyl-cyclohexyl)-2-oxoethyl}carbamate
[0491] Intermediate 24 (100 mg, 0.37 mmol) was dissolved in DCM (3 mL), then HATU (173 mg, 0.44 mmol) and DIPEA (128 μL, 0.74 mmol) were added at r.t. After 5-10 minutes, Intermediate 17 (76 mg, 0.39 mmol) was added as a solution in DCM (2 mL). The reaction mixture was stirred at r.t. overnight, then diluted with DCM (5 mL) and quenched with water (5 mL). The aqueous phase was extracted three times with DCM. The combined organic layers were passed through a hydrophobic phase separator and concentrated in vacuo. The crude material was purified by column chromatography, using a gradient of EtOAc/DCM (0-50%), then MeOH/DCM (0-10%), to yield the title compound (191 mg, 97%) as an off-white solid. δ.sub.H (400 MHz, CDCl.sub.3) 7.96 (s, 1H), 7.46 (dd, J 12.2, 2.1 Hz, 1H), 7.14 (t, J 8.1 Hz, 1H), 7.09 (dd, J 8.4, 2.1 Hz, 1H), 5.05 (s, 1H), 4.09-4.03 (m, 2H), 3.94 (dd, J 8.5, 6.8 Hz, 1H), 3.54 (td, J 11.7, 2.3 Hz, 3H), 3.06 (tt, J 11.8, 3.9 Hz, 1H), 1.88-1.66 (m, 8H), 1.45 (s, 10H), 1.37-1.19 (m, 3H), 1.19-0.89 (m, 3H), 0.87 (d, J 6.5 Hz, 3H). HPLC-MS (method 7): [M−.sup.tBu+H].sup.+ m/z 393, RT 1.34 minutes.
Intermediate 35
(2S)-2-Amino-N-[3-fluoro-4-(tetrahydropyran-4-yl)phenyl]-2-(trans-4-methyl-cyclohexyl)acetamide trifluoroacetate Salt
[0492] Intermediate 34 (191 mg, 0.38 mmol) was dissolved in DCM (4 mL) under an atmosphere of nitrogen, then cooled to 0° C. (ice bath) and treated with TFA (0.5 mL, 7 mmol). The reaction mixture was stirred for 18 h, then concentrated in vacuo, to afford the crude title compound, which was utilised without further purification.
Intermediate 36
[4-(4-Aminophenyl)tetrahydropyran-4-yl](3,3-difluoroazetidin-1-yl)methanone
[0493] 4-(4-Aminophenyl)tetrahydropyran-4-carboxylic acid (500 mg, 2.26 mmol), 3,3-difluoroazetidine hydrochloride (324 mg, 2.37 mmol) and HATU (930 mg, 2.37 mmol) were added to a round-bottomed flask, followed by DCM (30 mL) and DIPEA (0.83 mL, 4.8 mmol). The reaction mixture was stirred at r.t. for 3 h, then quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with DCM (3×15 mL). The organic extracts were combined, filtered through a hydrophobic frit and concentrated in vacuo to afford the title compound (800 mg crude, 100%) as an off-white solid, which was utilised without further purification. δ.sub.H (300 MHz, DMSO-d.sub.6) 6.99-6.85 (m, 2H), 6.63-6.50 (m, 2H), 5.13 (s, 2H), 4.08 (s, 4H), 3.70 (dt, J 11.6, 4.0 Hz, 2H), 3.53 (td, J 11.6, 2.3 Hz, 2H), 2.14-2.09 (m, 2H), 1.80 (ddd, J 13.9, 10.0, 4.1 Hz, 2H). LCMS (method 8): MH+ m/z 297.0, RT 0.86 minutes.
Intermediate 37
Benzyl N-[(1S)-1-cyclohexyl-2-{4-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]anilino}-2-oxoethyl]carbamate
[0494] Intermediate 36 (500 mg, 1.68 mmol), (2S)-2-cyclohexyl-2-(phenoxycarbonyl-amino)acetic acid (516 mg, 1.77 mmol) and HATU (694 mg, 1.77 mmol) were added to a round-bottomed flask, followed by DCM (20 mL). The mixture was stirred at r.t., then DIPEA (0.62 mL, 3.6 mmol) was added. The mixture was stirred at r.t. for 18 h, then concentrated in vacuo and purified by column chromatography (silica, 10-50% gradient of EtOAc in DCM). The combined fractions were concentrated in vacuo to afford the title compound (430 mg, 45%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 10.13 (s, 1H), 7.65 (d, J 8.5 Hz, 2H), 7.49 (d, J 8.4 Hz, 1H), 7.41-7.28 (m, 4H), 7.27-7.19 (m, 2H), 5.03 (s, 2H), 4.47-4.00 (br s, 4H), 4.10-3.86 (m, 2H), 3.72 (d, J 11.5 Hz, 2H), 3.56 (t, J 10.6 Hz, 2H), 2.18 (d, J 13.4 Hz, 2H), 1.96-1.42 (m, 7H), 1.28-0.94 (m, 6H). LCMS (method 8): MH.sup.+ m/z 570.4, RT 2.21 minutes.
Intermediate 38
(2S)-2-Amino-2-cyclohexyl-N-{4-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]phenyl}acetamide
[0495] Intermediate 37 (405 mg, 0.71 mmol) was dissolved in ethanol (30 mL) and ethyl acetate (10 mL). Pd/C (10% w/w, 80 mg) was added. The mixture was degassed and placed under a hydrogen atmosphere (balloon), then stirred for 18 h. The mixture was degassed and filtered through a celite pad, then washed with ethanol (2×5 mL) and concentrated in vacuo, to afford the title compound (308 mg, 99%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 10.00 (br s, 1H), 7.77-7.59 (m, 2H), 7.28-7.17 (m, 2H), 4.35 (t, J 5.1 Hz, 1H), 4.12 (br s, 4H), 3.72 (dt, J 11.4, 4.0 Hz, 2H), 3.56 (t, J 10.5 Hz, 2H), 3.49-3.38 (m, 1H), 3.10 (d, J 5.7 Hz, 1H), 2.18 (d, J 13.4 Hz, 2H), 1.87 (ddd, J 13.6, 9.9, 3.9 Hz, 2H), 1.79-1.46 (m, 5H), 1.12 (m, 6H). LCMS (method 8): MH.sup.+ m/z 436.0, RT 1.57 minutes.
Example 1
[0496] ##STR00020##
N-{2-[3-Chloro-4-(morpholin-4-yl)anilino]-1-cyclooctyl-2-oxoethyl}-3-methylisoxazole-4-carboxamide
[0497] A solution of 3-chloro-4-(morpholin-4-yl)aniline (37 mg, 0.17 mmol) in DMF (700 μL) was added to Intermediate 5 (50 mg, 0.17 mmol), followed by DIPEA (40 μL, 0.187 mmol) and HATU (80 mg, 0.187 mmol). The resulting suspension was stirred at r.t. for 60 h in a sealed tube. The reaction mixture was purified by preparative HPLC (method 20) to yield the title compound (30 mg, 36%) as a white solid. δ.sub.H (400 MHz, DMSO-d.sub.6) 10.31 (s, 1H), 9.52-9.28 (m, 1H), 8.51 (d, J 8.6 Hz, 1H), 7.84 (d, J 2.4 Hz, 1H), 7.49 (dd, J 8.7, 2.5 Hz, 1H), 7.15 (d, J 8.8 Hz, 1H), 4.43 (t, J 8.7 Hz, 1H), 3.73 (t, J 4.5 Hz, 4H), 2.92 (t, J 4.7 Hz, 4H), 2.37 (s, 3H), 1.79-1.28 (m, 15H). uPLC-MS (method 15): [M+H].sup.+ m/z 489 and 491, RT 2.99 minutes.
Example 2
[0498] ##STR00021##
N-[4-(4-Cyanotetrahydropyran-4-yl)-3-methylphenyl]-2-cyclooctyl-2-[(3-methylisoxazol-4-yl)formamido]acetamide
[0499] A sealed tube was charged with EDC.HCl (81.4 mg, 0.42 mmol) and Intermediate 5 (125 mg, 0.42 mmol) in DCM (2 mL). The reaction mixture was stirred for 0.5 h at 20° C. The solvent was removed under a stream of nitrogen and Intermediate 10 (62.3 mg, 0.29 mmol) in THF (2 mL) was added, followed by acetic acid (0.25 mL, 4.33 mmol). The reaction mixture was sealed and heated at 60° C. for 1 h. After cooling, the reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting orange oil was purified by flash column chromatography, using a gradient of EtOAc/heptane (0-65%), to afford, after freeze-drying, the title compound (94 mg, 67%) as a cream-coloured solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 10.27 (s, 1H), 9.44 (s, 1H), 8.48 (d, J 8.6 Hz, 1H), 7.59-7.54 (m, 1H), 7.53 (d, J 2.1 Hz, 1H), 7.29 (d, J 8.8 Hz, 1H), 4.51-4.44 (m, 1H), 4.04-3.96 (m, 2H), 3.77-3.68 (m, 2H), 2.54 (s, 3H), 2.38 (s, 3H), 2.29-2.22 (m, 2H), 2.15-2.06 (m, 1H), 2.03-1.93 (m, 2H), 1.73-1.62 (m, 3H), 1.61-1.45 (m, 7H), 1.45-1.36 (m, 4H). uPLC-MS (method 1): [M+H].sup.+ m/z 493, RT 3.74 minutes.
Example 3 (Procedure C)
[0500] ##STR00022##
4-(4-{2-Cyclooctyl-2-[(3-methylisoxazol-4-yl)formamido]acetamido}-2-methylphenyl)-N,N-dimethyltetrahydropyran-4-carboxamide
[0501] A sealed tube was charged with EDC.HCl (52 mg, 0.27 mmol) and Intermediate 5 (80 mg, 0.27 mmol) in DCM (1 mL). The reaction mixture was stirred for 0.5 h at 20° C. The solvent was removed using a flow of nitrogen and Intermediate 14 (46.9 mg, 0.18 mmol) in THF (1 mL) was added, followed by acetic acid (0.15 mL, 2.68 mmol). The reaction mixture was sealed and heated at 60° C. for 1 h. After cooling, the reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting orange oil was separated by flash column chromatography, using a gradient of EtOAc/heptane (0-100%), followed by preparative HPLC (method 13), to afford, after freeze-drying, the title compound (44 mg, 44%) as a white solid. δ.sub.H (500 MHz, CD.sub.3OD) 9.14 (s, 1H), 7.55 (dd, J 8.7, 2.4 Hz, 1H), 7.48 (d, J 8.7 Hz, 1H), 7.41 (d, J 2.2 Hz, 1H), 4.51 (d, J 8.4 Hz, 1H), 4.04-3.88 (m, 2H), 3.87-3.79 (m, 2H), 2.94 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H), 2.38-2.30 (m, 2H), 2.27-2.20 (m, 4H), 2.21-1.96 (m, 2H), 1.85-1.74 (m, 3H), 1.74-1.63 (m, 4H), 1.62-1.49 (m, 7H). uPLC-MS (method 1): [M+H].sup.+ m/z 439, RT 3.45 minutes.
Examples 4 to 19
[0502] The title compounds were prepared according to Procedure C from Intermediate 5 and the appropriate aniline or heteroaryl amine.
[0503] The aniline or heteroaryl amine starting materials for Examples 4 to 18 are commercially available. The aniline starting material for Example 19 is Intermediate 33.
TABLE-US-00024 LCMS LCMS LCMS RT Ex. Structure Name Method Mass (min) 4
[0504] Selected .sup.1H NMR data
[0505] Example 4: δ.sub.H (400 MHz, CD.sub.3OD) 9.14 (s, 1H), 7.40 (s, 1H), 7.45-7.27 (m, 1H), 7.04 (d, J 8.3 Hz, 1H), 3.93-3.71 (m, 4H), 2.88 (m, 4H), 2.46 (d, J 0.6 Hz, 3H), 2.32 (s, 3H), 2.19 (m, 1H), 1.85-1.44 (m, 15H).
[0506] Example 5: δ.sub.H (400 MHz, DMSO-d.sub.6) 10.31 (s, 1H), 9.44 (s, 1H), 8.54 (d, J 8.6 Hz, 1H), 7.59 (dd, J 14.9, 2.3 Hz, 1H), 7.35-7.13 (m, 1H), 7.01 (dd, J 9.9, 8.8 Hz, 1H), 4.44 (t, J 8.7 Hz, 1H), 3.77-3.69 (m, 4H), 2.98-2.91 (m, 4H), 2.38 (s, 3H), 2.13-2.04 (m, 1H), 1.72-1.31 (m, 14H).
Example 20
[0507] ##STR00039##
2-[(7Z)-5-Chlorobicyclo[4.2.0]octa-1,3,5-trien-7-ylidene]-2-[(3-methylisoxazol-4-yl)-formamido]-N-[4-(tetrahydropyran-4-yl)phenyl]acetamide
[0508] Acetic acid (121 μL, 2.11 mmol) was added to a stirred solution of Intermediate 15 (65 mg, 0.21 mmol) and 4-(tetrahydro-2H-pyran-4-yl)aniline (38 mg, 0.21 mmol) in anhydrous THF (1.5 mL). The vessel was purged with nitrogen, sealed and stirred at 60° C. for 18 h. Upon cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (method 15) to afford, after freeze-drying, the title compound (14.1 mg, 13%) as an off-white solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 10.08 (s, 1H), 9.99 (s, 1H), 9.43 (s, 1H), 7.63 (d, J 8.5 Hz, 2H), 7.42-7.35 (m, 1H), 7.31 (d, J 8.0 Hz, 1H), 7.29 (d, J 7.1 Hz, 1H), 7.21 (d, J 8.6 Hz, 2H), 4.04-3.86 (m, 4H), 3.43 (td, J 11.3, 3.1 Hz, 2H), 2.80-2.67 (m, 1H), 2.40 (s, 3H), 1.82-1.57 (m, 4H). uPLC-MS (method 1): [M+H].sup.+ m/z 476 and 478, RT 3.31 minutes.
Example 21 (Procedure D)
[0509] ##STR00040##
3-Ethyl-N-{(1S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)anilino]-ethyl}isoxazole-4-carboxamide
[0510] 3-Ethylisoxazole-4-carboxylic acid (40.51 mg, 0.29 mmol), HATU (135.0 mg, 0.344 mmol) and DIPEA (200 μL, 1.15 mmol) were stirred in DCM (1 mL) for 15 minutes at r.t. Intermediate 26 (100 mg, 0.29 mmol) was added in one portion as a solution in DCM (3 mL). The reaction mixture was stirred at room temperature overnight, then concentrated under a stream of nitrogen. The residue was purified by column chromatography, using a gradient of EtOAc/isohexane (0-100%), then MeOH/EtOAc (0-20%), to yield the title compound as a white solid (98 mg, 67%). δ.sub.H (400 MHz, DMSO-d.sub.6) 10.34 (s, 1H), 9.41 (s, 1H), 8.50 (d, J 8.2 Hz, 1H), 7.57 (dd, J 13.2, 1.8 Hz, 1H), 7.32-7.24 (m, 2H), 4.36 (t, J 8.4 Hz, 1H), 3.98-3.86 (m, 2H), 3.44 (td, J 11.6, 2.3 Hz, 2H), 2.98 (tt, J 11.7, 3.9 Hz, 1H), 2.83 (q, J 7.6 Hz, 2H), 1.88-1.77 (m, 1H), 1.77-1.49 (m, 8H), 1.35-1.25 (m, 1H), 1.25-1.18 (m, 1H), 1.20-1.12 (m, 4H), 1.10-0.95 (m, 1H), 0.94-0.76 (m, 4H). HPLC-MS (method 8): [M+H].sup.+ m/z 454, RT 2.46 minutes.
Examples 22 to 30
[0511] The title compounds were prepared by a three-step procedure comprising:
[0512] (i) reacting Intermediate 7 or Intermediate 24 and the appropriate aniline or heteroaryl amine according to Procedure A;
[0513] (ii) deprotection of the material thereby obtained according to procedure B; and
[0514] (iii) reacting the material thereby obtained with a commercially available acid according to procedure D.
[0515] The aniline starting materials in step (i) for Examples 22 and 30 are Intermediates 17 and 28 respectively. The corresponding starting materials for Examples 23-29 are commercially available anilines or heteroaryl amines.
TABLE-US-00025 LCMS LCMS LCMS RT Ex. Structure Name Method Mass (min) 22
Example 31
[0516] ##STR00050##
(2S)—N-[3-Fluoro-4-(tetrahydropyran-4-yl)phenyl]-2-(trans-4-methylcyclohexyl)-2-{[methyl(tetrahydropyran-4-yl)carbamoyl]amino}acetamide
[0517] Intermediate 35 (33 mg, 0.095 mmol) was dissolved in DCM (1 mL) and treated with DIPEA (33 μL, 0.189 mmol), then N-methyl-N-(tetrahydropyran-4-yl)carbamoyl chloride (21 mg, 0.11 mmol) was added. The resulting mixture was stirred at r.t. for 18 h. DIPEA and N-methyl-N-(tetrahydropyran-4-yl)carbamoyl chloride (21 mg, 0.11 mmol) were each added repeatedly over the next 48 h, to bring the reaction to completion. The crude reaction mixture was purified by column chromatography, using a gradient of EtOAc/isohexane (0-100%), then MeOH/EtOAc (0-20%), to yield the title compound (25 mg, 21%), as a colourless glass. δ.sub.H (400 MHz, DMSO-d.sub.6) 10.15 (s, 1H), 7.61-7.51 (m, 1H), 7.31-7.18 (m, 2H), 6.10 (d, J 8.3 Hz, 1H), 4.15 (tt, J 11.8, 4.0 Hz, 1H), 4.05 (t, J 8.4 Hz, 1H), 3.90 (ddt, J 20.7, 10.6, 4.0 Hz, 4H), 3.48-3.34 (m, 4H), 2.98 (ddt, J 11.7, 7.8, 4.1 Hz, 1H), 2.71 (s, 3H), 1.83 (d, J 12.4 Hz, 1H), 1.77-1.55 (m, 8H), 1.50 (d, J 12.9 Hz, 1H), 1.40 (t, J 13.0 Hz, 3H), 1.23 (s, 1H), 1.18-1.04 (m, 1H), 1.02-0.88 (m, 1H), 0.85 (dd, J 8.5, 4.7 Hz, 5H). HPLC-MS (method 8): [M+H].sup.+ m/z 490, RT 2.42 minutes.
Example 32 (Procedure E)
[0518] ##STR00051##
3-Methyl-N-[(1S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-{[5-(tetrahydropyran-4-yl)-isoxazol-3-yl]amino}ethyl]isoxazole-4-carboxamide
[0519] Intermediate 24 (21 mg, 0.077 mmol) was dissolved in DMF (0.4 mL, 5 mmol), then 5-(tetrahydropyran-4-yl)isoxazol-3-amine (14 mg, 0.079 mmol), DIPEA (20 μL, 0.12 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution (51 mg, 0.08 mmol) were added. The vial was sealed and the reaction mixture was heated at 70° C. for 18 h, then diluted with DCM (0.5 mL) and water (0.5 mL). The mixture was shaken and filtered through a PTFE phase separator (3 mL), then concentrated in vacuo. The crude residue was dissolved in MeOH (0.4 mL) and treated with HCl in 1,4-dioxane (4N, 0.5 mL). The reaction mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The crude residue was suspended in DCM (1.0 mL) and treated with 3-methylisoxazole-4-carboxylic acid (10 mg, 0.08 mmol), HATU (75 mg, 0.2 mmol), and DIPEA (100 μL, 0.60 mmol). The reaction mixture was stirred at r.t. After 18 h, more HATU (50 mg, 0.13 mmol), and DIPEA (100 μL, 0.60 mmol) were added. The mixture was stirred at r.t. overnight, then purified by preparative HPLC (method 15), to yield the title compound (2.4 mg, 3%). HPLC-MS (method 13): [M+H].sup.+ m/z 431, RT 2.59 minutes.
Examples 33 to 37
[0520] The title compounds were prepared from Intermediate 24 and the appropriate commercially available heteroaryl amine according to Procedure E.
TABLE-US-00026 LCMS LCMS LCMS RT Ex. Structure Method Mass Name (min) 33
Example 38
[0521] ##STR00057##
N-{1-Cyclooctyl-2-oxo-2-[4-(tetrahydropyran-4-yl)anilino]ethyl}-2-ethylpyrazole-3-carboxamide
[0522] N-[4-(Tetrahydropyran-4-yl)phenyl]formamide (50 mg, 0.22 mmol) was dissolved in DCM (2 mL) and stirred at r.t., then treated with triethylamine (140 μL, 0.99 mmol). The reaction mixture was cooled to 0° C., and phosphorus oxychloride (35 μL, 0.37 mmol) was added. The reaction mixture was stirred at 0° C. for 15 minutes, then warmed to r.t. and stirred overnight, then quenched with water (2 mL) and DCM (1 mL). The layers were separated with a phase separating cartridge. The aqueous phase was extracted with DCM (1 mL). The organic layers were combined and concentrated in vacuo. The crude residue was dissolved in 2,2,2-trifluoroethanol (2 mL), and cyclooctanecarbaldehyde (31 mg, 0.21 mmol), 2-ethylpyrazole-3-carboxylic acid (30 mg, 0.21 mmol) and ammonia (7N in MeOH, 60 μL, 0.42 mmol) were added. The mixture was stirred at r.t. overnight, then concentrated in vacuo. The residue was purified by preparative HPLC (method 17) to yield the title compound (12 mg). HPLC-MS (method 12): [M+H].sup.+ m/z 467.4, RT 5.06 minutes.
Example 39
[0523] ##STR00058##
N-[(1S)-1-Cyclohexyl-2-{4-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]-anilino}-2-oxoethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide
[0524] Intermediate 38 (125 mg, 0.29 mmol), 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (43 mg, 0.30 mmol) and HATU (118 mg, 0.30 mmol) were added to a round-bottomed flask, followed by DCM (10 mL). The mixture was stirred, then DIPEA (0.10 mL, 0.60 mmol) was added. The mixture was stirred for 18 h at room temperature, then concentrated in vacuo and purified by preparative HPLC (method 15), to afford, after freeze-drying, the title compound (55 mg, 34%) as a white solid. δ.sub.H (300 MHz, DMSO-d.sub.6) 10.32 (s, 1H), 9.16 (d, J 8.0 Hz, 1H), 7.66 (d, J 8.3 Hz, 2H), 7.26 (d, J 8.3 Hz, 2H), 4.48 (t, J 8.1 Hz, 1H), 4.12 (br s, 4H), 3.84-3.45 (m, 4H), 2.90 (q, J 7.5 Hz, 2H), 2.18 (d, J 13.6 Hz, 2H), 2.00-1.54 (m, 7H), 1.35-0.89 (m, 9H). LCMS (method 8): MH.sup.+ m/z 560.4, RT 2.14 minutes.