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EP-4213843-B1 - MODIFIED IMIDAZOPYRIDINES AS GLUCOSYLCERAMIDE SYNTHASE INHIBITORS

EP4213843B1EP 4213843 B1EP4213843 B1EP 4213843B1EP-4213843-B1

Inventors

  • FORD, Melissa, C.
  • FRALEY, MARK, E.
  • JONES, KRISTEN, L. G.
  • LOUGHRAN, H. MARIE
  • MULHEARN, James, J.
  • ROECKER, ANTHONY, J.
  • SCHIRRIPA, KATHY, M.
  • TONG, LING

Dates

Publication Date
20260506
Application Date
20210915

Claims (18)

  1. A compound of the formula I: or a pharmaceutically acceptable salt thereof, wherein X is C or N; Z is -C R 4 -, each R 1 is independently C1-C4 alkyl, C1-C4 fluoroalkyl, -C0-C4alkylOH, cyano, C1-C4alkoxy, or halo; each R 4 is independently hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -C0-C4alkylOH, cyano, C1-C4alkoxy, or halo; Ⓑ is selected from (C1-C6 haloalkyl)aminocarbonyl, (C1-C6 haloalkyl)oxy, (C1-C6 alkyl)aminocarbonyl, (C0-C6 alkyl)amino(C1-C4 alkyl), (C0-C4 alkyl)amino(C1-C4 alkyl)aminocarbonyl, (C1-C4 haloalkyl)amino(C1-C4 alkyl)aminocarbonyl, -C1-C8alkylOH, cycloalkylC0-C4 alkyl, cycloalkylC0-C4 alkylaminocarbonyl, cycloalkyl(C0-C4 alkyl)carbonyl, heterocycloalkylC0-C4 alkyl, heterocycloalkyl(C0-C4 alkyl)aminocarbonyl, heterocycloalkyl(C0-C4 alkyl)carbonyl, heteroarylC0-C4 alkyl, heteroaryl(C0-C4 alkyl)aminocarbonyl, heteroaryl(C0-C4 alkyl)carbonyl, arylC0-C4 alkyl, aryl(C0-C4 alkyl)aminocarbonyl, and aryl(C0-C4 alkyl)carbonyl; wherein each cycloalkyl is independently selected decalinyl, spiro[4.5]decanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentyl, bicyclo [2.2.1]heptyl, [1.1.1]-bicyclo pentanyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, 2,3-dihydro-1H-indenyl, and norbornyl; each heterocycloalkyl is independently selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, oxiranyl, aziridinyl, oxetanyl, oxetenyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, I-oxothiomorpholinyl, decahydroisoquinoline, 1,4-dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, dioxa-9-azospiro[4.5]decanyl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, 4,5-dihydrooxazolyl, oxa-2,8-diazaspiro[3.5]nonanyl, dioxaazaspiro[3.5]nonanyl, 5,6-dihydroimidazo[1,2-a]pyrazinyl, azabicyclo[3.1.0]hexanyl, 2,7diazaspiro[3.4]octenyl, and 1,1-dioxothiomorpholinyl; each heteroaryl is independently selected from azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo[d]isothiazole, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, 5H-pyrrolo[3,4-b]pyridine, thiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, and isoquinolinyl, and oxazolyl; and each aryl is naphthyl; each R 2 is independently selected from halo, (C1-C4 fluoroalkyl)oxy, hydroxy, C1-C4 alkyl, and -(C0-C4 alkyl)O(C1-C4 alkyl); and each R 3 is independently selected from C1-C4 alkyl, halo, oxo, cyano, amino, C1-C4 fluoroalkyl, hydroxy, -(C0-C4alkyl)O(C1-C4 alkyl), and □(C1-C4 alkyl)OH.
  2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently methyl, ethyl, propyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxy, hydroxymethyl, cyano, methoxy, ethoxy, chloro, or fluoro.
  3. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently chloro, trifluoromethyl, methoxy, fluoro, or cyano.
  4. The compound of any of Claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein each R 2 independently is chloro, fluoro, trifluoromethoxy, trifluoroethoxy, 2,2,2-trifluoroethoxy, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy, ethoxymethyl, or methoxymethyl.
  5. The compound of any of Claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein each R 3 independently is selected from methyl, ethyl, propyl, isopropyl, butyl, fluoro, chloro, oxo, cyano, amino, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxy, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, and 2-hydroxy(prop-2yl).
  6. The compound of any of Claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein each R 3 independently is selected from fluoro, methyl, hydroxymethyl, fluoromethyl, aminomethyl, 2-hydroxy(prop-2yl), hydroxy, cyano, methoxyethyl, methoxymethyl, trifluoromethyl and methoxy.
  7. The compound of any of Claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein each R 4 independently is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, fluoromethyl, difluoromethyl, difluoroethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, hydroxypropyl, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, chloro, fluoro, and bromo.
  8. The compound of any of Claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein each R 4 independently is hydrogen or fluoro.
  9. The compound of any of Claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein Ⓑ is selected from (tetrahydropuranyl)aminocarbonyl, (tetrahydro-2H-puranyl)aminocarbonyl, (1,1,1-trifluoro-2-methylprop-2yl)aminocarbonyl, (tetrahydrofuranyl)aminocarbonyl, cyclopropylaminocarbonyl, piperazinylcarbonyl, isobutylaminocarbonyl, (3,3,3-trifluoroprop-2yl)aminocarbonyl, tert butylaminocarbonyl, (6,7-dihydropyrrolo[3,4-b]pyridyl)carbonyl ((6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl)carbonyl), 1-hydroxyethyl, 2-hydroxyprop-2yl, hydroxymethyl, dihydrooxazolyl, 4,5-dihydrooxazolyl, pyridinylaminocarbonyl, 2-pyridylaminocarbonyl, 3-pyridylaminocarbonyl, (4-pyridyl)aminocarbonyl, piperidinylaminocarbonyl, (bicyclo[2.2.2]octanyl)aminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, (trifluoromethylaminomethyl)aminocarbonyl, (trifluoromethylaminoethyl)aminocarbonyl, (bicyclo[2.2.1]heptyl)aminocarbonyl, tetrahydropyranylaminocarbonyl, N -(tetrahydro-2H-pyran-3-yl)aminocarbonyl, (pyridylmethyl)aminocarbonyl, cyclobutylaminocarbonyl, (bicyclo[1.1.1]pentyl)aminocarbonyl, (azabicyclo[2.1.1]hexyl)carbonyl, (2-azabicyclo[2.1.1]hexyl)carbonyl, (oxadiazaspiro[3.5]nonyl)carbonyl, (5-oxa-2,8-diazaspiro[3.5]nonyl)carbonyl, (dioxaazaspiro[4.5]decyl)carbonyl, (2,9-dioxa-6-azaspiro[4.5]decyl)carbonyl, (dioxaazaspiro[3.5]nonyl)carbonyl, (2,5-dioxa-8-azaspiro[3.5]nonyl)carbonyl, dihydrooxazolyl, 4,5-dihydrooxazolyl, (pyridylmethyl)aminocarbonyl, (2-pyridylmethyl)aminocarbonyl, (oxetanyl)aminocarbonyl, (3-oxetanyl)aminocarbonyl, oxadiazaspiro[3.4]octenyl, 5-oxa-2,7-diazaspiro[3.4]oct-6-enyl, (pyrrolidinylethyl)aminocarbonyl, (5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl)carbonyl, aminomethyl, (azabicyclo[3.1.0]hexyl)carbonyl, (3-azabicyclo[3.1.0]hexyl)carbonyl, cyclopropylmethyl, and (tert-butyl)aminomethyl, (tetrahydropyranyl)methyl, (tetrahydro-2 H -pyranyl)methyl, and cyclobutylcarbonylamino.
  10. The compound of any of Claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein X is C.
  11. The compound of any of Claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein X is N.
  12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from: N -(1-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-N-(tetrahydro-2H-pyran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(tetrahydro-2H-pyran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(1,1,1-trifluoro-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-8-(2-(2,2,2-trifluoroethoxy)phenyl)-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-6-chloro-N-(tetrahydrofuran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-(1-(methoxymethyl)cyclopropyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; (6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)(3,3,4-trimethylpiperazin-1-yl)methanone; 6-chloro-N-(2-cyano-2-methylpropyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-N-(1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-N-(1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(1,1,1-trifluoro-3-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(1-methoxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; (5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanone; N-( tert -butyl)-6-fluoro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-6-chloro-N-(3-methyltetrahydrofuran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-6-chloro-N-(3-methyltetrahydrofuran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(pyridin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(trans-4-fluoropiperidin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-N-(4,4-difluoropiperidin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(4,4-difluoropiperidin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(trans-3-hydroxycyclopentyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-(1-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(1-(hydroxymethyl)cyclopentyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-((1S,2R,4S)-2-fluoro-4-hydroxycyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-((1R, 2S,4R)-2-fluoro-4-hydroxycyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(2-amino-3,3,3-trifluoropropyl)-6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-(trans-4-hydroxycyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; cis-6-fluoro-N-(4-hydroxy-4-methylcyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; trans-6-fluoro-N-(4-hydroxy-4-methylcyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-fluoro-N-(cis-4-(hydroxymethyl)cyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-cyclopentyl-6-fluoro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(trans-4-(hydroxymethyl)cyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 8-(5-chloro-2-methoxyphenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(cis-3-(hydroxymethyl)cyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 3-fluoro-N-(trans-4-hydroxycyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 3-fluoro-N-(1, 1, 1-trifluoro-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(3-cyanotetrahydrofuran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-6-chloro-N-(3-methyltetrahydro-2H-pyran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-6-chloro-N-(3-methyltetrahydro-2H-pyran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(trans-4-hydroxycyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(1-hydroxy-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; ( R )-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-cyano-N-(trans-4-hydroxycyclohexyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-cis-3-(hydroxymethyl)cyclobutyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-fluoro-N-(1, 1, 1-trifluoro-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; ( S )-N-(tetrahydro-2H-pyran-3 -yl)-8 -(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-methoxy-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-cyano-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-((3R,4R)-4-fluorotetrahydrofuran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-chloro-N-((3S,4R)-4-fluorotetrahydrofuran-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; (1-(fluoromethyl)-2-azabicyclo[2.1.1]hexan-2-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanone; (2-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanone; ( R )-(2,6-dioxa-9-azaspiro[4.5]decan-9-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanone; ( S )-(2,6-dioxa-9-azaspiro[4.5]decan-9-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanone; (2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanone; N-(pyridin-2-ylmethyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(2,2-dimethyloxetan-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; (5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanone; N-(4-methylpyridin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4-fluoropyridin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; 3-(8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamido)pyridine 1-oxide; N-(3-cyanopyridin-4-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; (6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)((1R,5R)-6-(hydroxymethyl)-3-azabicyclo[3 .1.0]hexan-3-yl)methanone; 6-fluoro-N-(pyridin-3-yl)-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridine-2-carboxamide; (8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol; ( R ) 1-(8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol; ( S ) 1-(8-(2-(2,2,2-trifluoroethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol; 1-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]ethanol; [6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-cyclopropyl-methanol; 2-(6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol; 2-(6-chloro-8-(4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl) propan-2-ol; (6-fluoro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanol; 2-(6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-5,5-dimethyl-4,5-dihydrooxazole; 6-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-2-methyl-5-oxa-2,7-diazaspiro[3.4]oct-6-ene; (2-(6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-5-methyl-4,5-dihydrooxazol-5-yl)methanol; [2-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-4,5-dihydrooxazol-4-yl]methanol; [2-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-4-methyl-5H-oxazol-4-yl]methanol; (2-(6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-4,5-dihydrooxazol-5-yl)methanamine; 2-(2-(6-chloro-8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-4,5-dihydrooxazol-4-yl)propan-2-ol; 2-[2-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-4,5-dihydrooxazol-5-yl]propan-2-ol; 2-[2-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-5-methyl-4H-oxazol-5-yl]propan-2-ol; 2-[2-[6-chloro-8-[2-(2,2,2-trifluoroethoxy)phenyl]imidazo[1,2-a]pyridin-2-yl]-4-methyl-5H-oxazol-4-yl]propan-2-ol; 2-methyl-N-((8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methyl)propan-2-amine; (8-(2-(2,2,2-trifluoroethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)methanamine; cis-3-hydroxy-N-(8-(2-(2,2,2-trifluoroethoxy)phenyl)quinolin-2-yl)cyclobutane-1-carboxamide; trans-3-hydroxy-N-(8-(2-(2,2,2-trifluoroethoxy)phenyl)quinolin-2-yl)cyclobutane-1-carboxamide; trans-N-(5-fluoro-8-(2-(2,2,2-trifluoroethoxy)phenyl)quinolin-2-yl)-3-hydroxycyclobutane-1-carboxamide; and N-cis-3-hydroxycyclobutyl)-5-(2-(2,2,2-trifluoroethoxy)phenyl)isoquinoline-3-carboxamide.
  13. A pharmaceutical composition comprising an effective amount of a compound of any of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  14. The pharmaceutical composition of Claim 13, or a Pharmaceutically acceptable salt thereof, further comprising one or more additional therapeutic agents.
  15. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in a method for treatment of lysosomal storage diseases, kidney disease, neurodegenerative disease, diabetes related diseases, or cancers where GSL synthesis is abnormal or overexpression of GCS disrupts ceramide-induced apoptosis.
  16. A compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in therapy.
  17. A compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment of dementia with Lewy bodies, polycystic kidney disease, renal hypertrophy, diabetes mellitus, obesity, hyperglycemia, hyperinsulemia, leukemia, papillary renal cancer, and thyroid carcinomas.
  18. A combination comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmacologically active agents.

Description

FIELD OF THE INVENTION The present invention is directed to a class of modified imidazopyridine compounds, their salts, pharmaceutical compositions comprising them and their use in the treatment of human disease. In particular, the invention is directed to a class of glucosylceramide synthase (GCS) inhibitors, and hence are useful in the treatment of lysosomal storage diseases, neurodegenerative disease, cystic disease, cancer, or a diseases or disorders associated with elevated levels of glucosylceramide (GlcCer), glucosylsphingosine (GlcSph) and/or other glucosylceramide-based glycosphingolipids (GSLs), either alone or in combination with enzyme replacement therapy. BACKGROUND OF THE INVENTION Glucosylceramide synthase (GCS) is a ubiquitously expressed, Golgi membrane-bound, 394 amino acid enzyme that glycosylates ceramide to form glucosylceramide (GlcCer), the first step in the biosynthesis of an extensive family of glycosphingolipids (GSLs) that are integral components of cellular structure and function (Ichikawa, S. et al. Proc. Natl. Acad. Sci. USA, 1996, 93, 4638). Inhibitors of GCS have been proposed and/or investigated for use in the treatment for a variety of diseases, including lysosomal storage diseases such as Niemann-Pick type C, Fabry, Tay-Sachs, and Sandhoff, among others (Platt, F. M., Nat. Rev. 2018, 17, 133). Gaucher's disease (GD) is lysosomal storage disorder resulting from the accumulation of GlcCer due to loss-of-function mutations in the GBA1 gene, which encodes glucocerbrosidase (GCase), a lysosomal hydrolase that metabolizes GlcCer and GlcSph. Eliglustat (Cerdelga®) is a GCS inhibitor (GCSi) approved for the treatment of type 1 GD (Balwani, M., et al., Mol. Genet. Metab. 2016, 117, 95). Mutations in GBA1 also represent a prevalent genetic risk factor for Parkinson's disease (PD) (Sidransky, E. et al., Lancet Neurol. 2012, 11, 986). In laboratory models, reduction of GCase activity through mutations or chemical inhibition has been shown to elevate levels of glycolipids and accelerate formation of α-synuclein aggregates, a pathological hallmark of PD (Mazzulli, J. R. et al., Cell 2011, 146, 37; Manning-Boǧ, A. B. et al., Neurotoxicology 2009, 30, 1127). Conversely, GCSi's have been shown to lower GSL levels and attenuate α-synuclein formation in similar models. As an example, eliglustat has been shown to reverse the formation of pathological α-synuclein aggregates in GD and PD patient-derived induced pluripotent stem cell (iPSC) neurons (Zunke, F. et al., Neuron 2018, 97, 92). Furthermore, a brain penetrant, GCSi has been shown to reduce central α-synuclein accumulation and attenuate cognitive impairment in a GBA-mutant mouse model (Sardi, S. P. et al., Proc. Natl. Acad. Sci. 2017, 114, 2699). These recent data support the proposal that GCSi's may be useful for the treatment of PD and related diseases, such as dementia with Lewy bodies. Additional proposed therapies for GCSi's include other diseases associated with elevated GSL levels, such as polycystic kidney disease, renal hypertrophy and diabetic nephropathy, diabetes mellitus and obesity, and hyperglycemia or hyperinsulemia, and cancers where GSL synthesis is abnormal, or overexpression of GCS disrupts ceramide-induced apoptosis. WO 2010/091104 discloses other GCSi compounds. SUMMARY OF THE INVENTION Any references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis). In one aspect, the present invention provides compounds of Formula I or pharmaceutically acceptable salts thereof, as defined in the appended claims: The invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which elevated levels of glucosylceramide (GlcCer), glucosylsphingosine (GlcSph), and/or other glucosylceramide-based glycosphingolipids (GSLs) are involved. The invention further involves use of the compounds as GCS inhibitors for the preparation of a medicament for the treatment and/or prevention of diseases associated with inhibiting GCS, which includes metabolic diseases, such as lysosomal storage diseases, neurodegenerative disease, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), cystic disease, and cancer. The invention is also directed to pharmaceutical compositions which include an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION The