WO2019104011A1 - Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies - Google Patents

Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies Download PDF

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WO2019104011A1
WO2019104011A1 PCT/US2018/061965 US2018061965W WO2019104011A1 WO 2019104011 A1 WO2019104011 A1 WO 2019104011A1 US 2018061965 W US2018061965 W US 2018061965W WO 2019104011 A1 WO2019104011 A1 WO 2019104011A1
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compound
certain embodiments
pharmaceutically acceptable
ring
acceptable salt
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PCT/US2018/061965
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Bing Wang
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Biomarin Pharmaceutical Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • ceramide Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods to treat or prevent diseases or disorders associated with the enzyme ceramide
  • CCT galactosyltransferase
  • diseases or disorders include, for example, lysosomal storage diseases (LSDs).
  • LSDs lysosomal storage diseases
  • examples of lysosomal storage diseases include Krabbe disease and Metachromatic Leukodystrophy.
  • CCT Ceramide galactosyltransferase
  • GSL Glycosphingolipids
  • Ceramides play a central role in sphingolipid metabolism, and CGT facilitates conversion of ceramides to galactosylceramides.
  • Galactosylceramides can be further modified by the enzyme cerebroside sulfotransferase (CST) to form sulfatides.
  • CST cerebroside sulfotransferase
  • Galactosylceramides and sulfatides are primarily produced by the myelin generating cells of the central and peripheral nervous systems, oligodendrocytes and Schwann cells respectively, where these glycolipids make up a large proportion of the lipids in the myelin sheath.
  • Galactosylceramide and sulfatide are also found on the extracellular leaflet of the plasma membrane of other cells in eukaryotic organisms where they have been reported to be involved in a diverse range of functions.
  • ASA arylsulfatase A
  • MLD metachromatic leukodystrophy
  • molecules that inhibit the activity of CGT may be used to treat Parkinson's disease, epilepsy and audiogenic seizures that are associate with overexpression or accumulation of galactosylceramides/sulfatides.
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups;
  • L is a bond, -O-, C(O), or -[C(R 4 R 5 )] P -;
  • p 1 or 2;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or alkoxycarbonylamino;
  • each R 4 is independently H or alkyl
  • each R 5 is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl are independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • dialkylaminocarbonyloxy aminocarbonyloxy, alkylcarbonylamino, or
  • R 2 is not amino-substituted
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups;
  • L is a bond, C(O), or -[C(R 4 R 5 )] P -;
  • p 1 or 2;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • dialkylaminocarbonyloxy aminocarbonyloxy, alkylcarbonylamino, or
  • the compound of Formula (I) is that when ring B is piperidinyl or pyrrolidinyl, then R 2 is not amino-substituted imidazolyl;
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic
  • heterocycloalkyl ring wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • dialkylaminocarbonyloxy aminocarbonyloxy, alkylcarbonylamino, or
  • composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
  • a method of treating a lysosomal storage disease with a compound or composition disclosed herein is for use in a method of treating a lysosomal storage disease.
  • the lysosomal storage disease is Krabbe disease or
  • “Acceptable” with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.
  • alkenyl means a straight or branched hydrocarbon group having from 2 to 8 carbon atoms and at least one double bond.
  • alkenyl includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, or l-hex-5-enyl.
  • alkoxy means a group of the formula -OR, where R is alkyl.
  • alkoxy includes methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.
  • Alkoxycarbonyl means a group of the formula -C(0)R, where R is alkoxy, as defined herein.
  • Alkoxycarbonylamino means a group of the formula -NHC(0)R, where R is alkoxy, as defined herein.
  • Alkoxycarbonyloxy means a group of the formula -OC(0)R, where R is alkoxy, as defined herein.
  • Alkyl means a straight or branched saturated hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms. In certain embodiments, alkyl includes 1-4 carbon atoms (“Ci-4 alkyl”). In certain embodiments alkyl includes 1-3 carbon atoms (“C1-3 alkyl”).
  • alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.
  • Alkylaminocarbonyl means a group of the formula -C(0)R, where R is alkylamino, as defined herein.
  • Alkylaminocarbonyloxy means a group of the formula -OC(0)R, where R is alkylamino, as defined herein.
  • Alkylcarbonylamino means a group of the formula -NHC(0)R, where R is alkyl, as defined herein.
  • Alkylene refers to a divalent group formed by removal of a hydrogen atom from alkyl.
  • alkynyl means a straight or branched hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond.
  • alkynyl includes ethynyl, propynyl, l-but-3-ynyl, l-pent-3-ynyl, or l-hex-5-ynyl.
  • Amino means an -NIL ⁇ group.
  • Aminocarbonyl means an -C(0)ML ⁇ group.
  • Aminocarbonyloxy means a group of formula -0C(0)ML ⁇
  • alkylamino means a group of the formula -NHR, where R is alkyl as defined herein.
  • alkylamino includes methylamino, ethylamino, //-propylamino, Ao-propylamino, //-butyl ami no, Ao-butylamino, or A 7-butylamino.
  • Alkylcarbonyl means a group of the formula -C(0)R, where R is alkyl, as defined herein.
  • Alkylcarbonyloxy means a group of the formula -OC(0)R, where R is alkyl, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono-, bi-, or tri- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic or tricyclic ring is aromatic.
  • aryl includes phenyl, naphthyl, indanyl, or anthracenyl.
  • (Aryl)alkylene means an alkylene group, as defined herein, substituted with aryl group as defined herein.
  • the (aryl)alkylene is benzyl.
  • Aryloxy means a group of the formula -OR, where R is aryl, as defined herein. In certain embodiments, aryloxy is phenoxy.
  • Carboxy means an -C(0)OH group.
  • Cyano means an -CN group.
  • Cycloalkyl means a monocyclic or bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon ring of three to ten carbon ring atoms.
  • Cycloalkyl groups include fused and bridged bicyclic rings.
  • the cycloalkyl group may comprise two rings that share adjacent atoms ( e.g ., one covalent bond).
  • the cycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • a cycloalkyl group contains from 3-10 carbon atoms, it may be referred to herein as C3-1 0 cycloalkyl.
  • a cycloalkyl group contains from 5-6 carbon atoms, it may be referred to herein as C5- 6 cycloalkyl.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • (Cycloalkyl)alkyl means an alkyl group, as defined herein, substituted with at least one cycloalkyl groups as defined herein. In certain embodiments, alkyl is substituted with 1 cycloalkyl group. In certain embodiments, alkyl is substituted with 1 or 2 cycloalkyl groups. In certain embodiments, (cycloalkyl)alkyl includes cyclobutylmethyl,
  • (Cycloalkyl)alkoxy means a group of the formula -OR, where R is a
  • (cycloalkyl)alkyl group as defined herein.
  • (cycloalkyl)alkoxy includes cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy.
  • Cycloalkyloxy means a group of the formula -OR, where R is cycloalkyl, as defined herein. In certain embodiments, cycloalkyloxy includes cyclobutyloxy,
  • Dialkylamino means a group of the formula -NRR', where R and R' are independently alkyl as defined herein.
  • dialkylamino includes dimethylamino, diethylamino, A', A f -m ethyl propyl am i n o or N, A - m et h y 1 et h y 1 am i n o .
  • Dialkylaminocarbonyl means a group of the formula -C(0)R, where R is dialkylamino, as defined herein.
  • Dialkylaminocarbonyloxy means a group of the formula -OC(0)R, where R is dialkylamino, as defined herein.
  • Halo means a fluoro, chloro, bromo, or iodo group.
  • Haloalkoxy means an alkoxy group, substituted with one or more halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, or 3 halo atoms. Certain embodiments of haloalkoxy include difluoromethoxy, trifluorom ethoxy, or 1,1,1 - trifluoroethoxy.
  • Haloalkyl means an alkyl group substituted with one or more halo atoms.
  • haloalkyl is an alkyl group substituted by 1, 2, 3, 4, 5, or 6 halo atoms.
  • haloalkyl is an alkyl group substituted by 1, 2, or 3 halo atoms.
  • haloalkyl is an alkyl group substituted with 2 halo atoms.
  • haloalkyl is an alkyl group substituted with 1 halo atom.
  • haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl.
  • Certain other embodiments of haloalkyl include chloromethyl, fluoromethyl, difluorom ethyl, trifluoromethyl, or l,l,l-trifluoroethanyl.
  • (Haloalkyl)cycloalkyl means a cycloalkyl group substituted with one or more haloalkyl groups, as defined herein.
  • (haloalkyl)cycloalkyl includes l-(haloalkyl)cyclopropyl, 2-(haloalkyl)cyclopropyl, l-(haloalkyl)cyclobutyl, 2- (haloalkyl)cyclobutyl, 3-(haloalkyl)cyclobutyl, l-(haloalkyl)cyclopentyl, 2- (haloalkyl)cyclopentyl, 3-(haloalkyl)cyclopentyl, l-(haloalkyl)cyclohexyl, 2- (haloalkyl)cyclohexyl, 3-(haloalkyl)cyclohexyl, 4-(haloalkyl)cyclohexyl, 2,3- bis(haloalkyl
  • heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, oxazolyl, isooxazolyl,
  • oxadiazolyl thiadiazolyl (including, for example, l,3,4-thiadiazolyl), indolyl, 2,3-dihydro- l//-indolyl (including, for example, 2, 3 -di hydro- 1 //-i ndol -2-y 1 or 2,3-dihydro- l//-indol-5- yl), indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or
  • pyrrolo[3,2-c]pyridinyl including, for example, pyrrolo[3,2- c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl
  • heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 4 to 7 rings atoms, or a saturated or partially unsaturated bicyclic group of 7 to 9 ring atoms.
  • heterocycloalkyl group contains only one or two nitrogen atoms, and the remaining ring atoms are carbon.
  • a heterocycloalkyl group contains from 4 to 7 ring atoms, it may be referred to herein as 4-7 membered heterocycloalkyl.
  • a heterocycloalkyl group contains from 7 to 9 ring atoms, it may be referred to herein as 7-9 membered
  • Heterocycloalkyl groups include fused or bridged heterocycloalkyl bicyclic rings.
  • a fused heterocycloalkyl group may comprise two rings that share adjacent atoms ( e.g ., one covalent bond).
  • the heterocycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro- 1 //-pyrrol inyl, 2,5-dihydro- 1 //-pyrrolyf piperidinyl, morpholinyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, l,3-dioxinyl, l,3-dioxanyl, l,4-dioxinyl, l,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thiamorpholinyl, thi
  • (Heterocycloalkyl)alkyl means an alkyl group, as defined herein, substituted with at least one, in another example 1 or 2, heterocycloalkyl groups as defined herein.
  • Heterocycloalkyloxy means a group of the formula -OR, where R is heterocycloalkyl group, as defined herein.
  • (Hetercycloalkyl)alkoxy means a group of the formula -OR, where R is a
  • heterocycloalkyl alkyl group as defined herein.
  • Haldroxy alkyl means an alkyl group, as defined herein, substituted with at least one, or in other embodiments 1, 2, or 3 hydroxy groups.
  • Haldroxyalkoxy means an alkoxy group, as defined herein, substituted with at least one, or in other embodiments 1, 2, or 3 hydroxy groups.
  • “Hydroxy” means an -OH group.
  • the terms“hydroxy” and“hydroxyl” are used interchangeably and mean an -OH group.
  • Niro means an -NO2 group.
  • compounds of the described herein exist as stereoisomers, wherein asymmetric or chiral centers are present.
  • the term (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem ., (1976), 45: 13-30, hereby incorporated by reference.
  • the embodiments described herein specifically includes the various stereoisomers and mixtures thereof.
  • Stereoisomers include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or
  • individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.
  • “Amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • an“effective amount” or“therapeutically effective amount,” refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • Excipient or“pharmaceutically acceptable excipient” means a
  • compositions such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and
  • each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of
  • “Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined.
  • Examples of a salt that the compound forms with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric
  • composition refers to a mixture of a compound described herein with other chemical components, such as an excipient.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • Subject refers to an animal, including, but not limited to, a primate (e.g ., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g ., human
  • monkey e.g ., monkey
  • cow pig
  • sheep goat
  • horse dog
  • cat rabbit
  • rat or mouse
  • the terms “subject” and“patient” are used interchangeably.
  • the subject is a mammal.
  • the subject is a human.
  • the subject is an adult human.
  • the subject is a human child.
  • the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a human child.
  • Treat,”“treating,” and“treatment,” in the context of treating a disease or disorder are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.
  • the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
  • the compound of Formula (I) is that wherein:
  • L is a bond, C(O), or -[C(R 4 R 5 )] P -;
  • p 1 or 2;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy,
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently halo or amino
  • R 4 is H
  • R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl;
  • each R 6 is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl;
  • ring A is a 4-7 membered monocyclic
  • heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; provided that when ring A is piperazinyl then ring A is optionally substituted with 1, 2, or 3 R 3 groups.
  • ring A is a 4-7 membered monocyclic
  • heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups; provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R 3 groups.
  • ring A is a 4-7 membered monocyclic
  • heterocycloalkyl ring other than piperazinyl, which ring contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; or ring A a 7-9 membered bicyclic heterocycloalkyl ring, which contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; or ring A is piperazinyl which is optionally substituted with 1, 2, or 3 R 3 groups.
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms.
  • ring B is piperazinyl, piperidinyl, or pyrrolidinyl. In certain embodiments, ring B is piperazinyl.
  • the compound of Formula (I) is according to
  • the compound of Formula (I) is according to
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy,
  • each R 3 is independently halo or amino;
  • R 4 is H;
  • R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl;
  • each R 6 is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is according to
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R 3 is independently halo or amino; R 4 is H; R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R 6 is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is according to
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy,
  • each R 3 is independently halo or amino;
  • R 4 is H;
  • R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl;
  • each R 6 is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • Formula (I) is that wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; L is C(O); R 1 is aryl optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy; R 2 is aryl, optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; and each R 6 is independently haloalkyl, haloalkoxy, or aryl, wherein the aryl is optionally substituted with halo.
  • Formula (I) is according to Formula (Id) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; R 1 is aryl optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy; R 2 is aryl, optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; and each R 6 is independently haloalkyl, haloalkoxy, or aryl, wherein the aryl is optionally substituted with halo.
  • Formula (I) is that wherein: L is -[C(R 4 R 5 )] P -; R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R 3 is independently halo or amino; p is 1 or 2; each R 4 is H; each R 5 is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R 6 is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl.
  • Formula (I) is according to Formula (Ie) wherein: R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R 3 is independently halo or amino; p is 1 or 2; each R 4 is H; each R 5 is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R 6 is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl.
  • Formula (I) is according to Formula (Ie) wherein: R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R 3 is independently halo or amino; p is 1 or 2; each R 4 is H; each R 5 is H; and each R 6 is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl.
  • Formula (I) is according to Formula (Ie) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; R 1 is aryl optionally substituted with (cycloalkyl)alkoxy; R 2 is aryl, optionally substituted with an R 6 group; each R 3 is independently halo or amino; p is 1; R 4 is H; R 5 is alkyl; and R 6 is aryl optionally substituted with halo.
  • Formula (I) is according to Formula (Ie) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups R 1 is aryl optionally substituted with (cycloalkyl)alkoxy; R 2 is aryl, optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; p is 1; R 4 is H; R 5 is cycloalkyl; and R 6 is haloalkyl.
  • Formula (I) is according to Formula (Ie) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups
  • R 1 is aryl optionally substituted with (cycloalkyl)alkoxy
  • R 2 is aryl optionally substituted with 1 or 2 R 6 groups
  • each R 3 is independently halo or amino
  • p is 1
  • R 4 is H
  • R 5 is aryl optionally substituted with haloalkyl
  • R 6 is haloalkyl.
  • R 5 is unsubstituted aryl.
  • R 5 is substituted aryl.
  • ring A is a 4-7 membered monocyclic
  • heterocycloalkyl ring wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; L is a bond; R 1 is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or
  • R 2 is aryl, wherein the aryl is optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; and each R 6 is independently haloalkyl.
  • Formula (I) is according to Formula (If) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; L is a bond; R 1 is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or
  • R 2 is aryl, wherein the aryl is optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; and each R 6 is independently haloalkyl.
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • the compound of Formula (II) is that wherein: R 1 is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy; R 2 is aryl, wherein the aryl is optionally substituted with 1 or 2 R 6 groups; each R 3 is
  • each R 6 is independently halo, haloalkyl, alkoxy, aryl, or aryloxy, wherein aryl is optionally substituted with halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is that wherein ring B is piperazinyl, piperidinyl, or pyrrolidinyl. In certain embodiments, ring B is piperidinyl or pyrrolidinyl. In certain embodiments, ring B is piperidinyl. In certain embodiments, ring B is pyrrolidinyl.
  • the compound of Formula (II) is according to
  • the compound of Formula (II) is according to
  • R 1 is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or cycloalkyl)alkoxy;
  • R 2 is aryl, wherein the aryl is optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; and each R 6 is independently halo, haloalkyl, alkoxy, aryl, or aryloxy, wherein aryl is optionally substituted with halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is according to Formula (Ha):
  • R 1 is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or
  • R 2 is aryl, wherein the aryl is optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino; and each R 6 is independently halo, haloalkyl, or aryl, wherein aryl is optionally substituted with halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is according to Formula (lib):
  • R 1 is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or
  • R 2 is aryl, wherein the aryl is optionally substituted with 1 or 2 R 6 groups; each R 3 is independently amino; and each R 6 is independently halo, alkoxy, aryl, or aryloxy; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that where L is C(O).
  • L is a bond.
  • L is -[C(R 4 R 5 )] P -, wherein p is 1 or 2.
  • L is C(O) or a bond.
  • L is -[C(R 4 R 5 )] P - or C(O), wherein p is 1 or 2.
  • L is -[C(R 4 R 5 )] P - or a bond, wherein p is 1 or 2.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that where L is -[C(R 4 R 5 )] P -, wherein, p is 1 or 2, wherein each R 4 is H and each R 5 is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl.
  • L is -CH2-.
  • L is -CH2CH2-.
  • L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is alkyl.
  • L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is methyl.
  • L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is cycloalkyl. In certain embodiments, L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is cyclopropyl, cyclopentyl, or cyclohexyl. In certain embodiments, L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is phenyl, wherein the phenyl is optionally substituted with haloalkyl.
  • L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is phenyl, wherein the phenyl is optionally substituted with trifluorom ethyl. In certain embodiments, L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is phenyl, wherein the phenyl is substituted with trifluoromethyl. In certain embodiments, L is - C(R 4 R 5 )-, wherein R 4 is H and R 5 is unsubstituted aryl. In certain embodiments, L is - C(R 4 R 5 )-, wherein R 4 is H and R 5 is unsubstituted phenyl.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that where each R 4 is independently H. In certain embodiments, R 4 is alkyl. In certain embodiments, each R 4 is independently H or alkyl.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2. In certain embodiments, p is 1. In certain embodiments, p is 2.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2, wherein each R 5 is independently H, alkyl, alkenyl, alkynyl, or haloalkyl. In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2, wherein each R 5 is H.
  • p is 1, wherein R 5 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl is each independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy,
  • alkoxycarbonyl aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1, wherein R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl.
  • R 5 is H.
  • R 5 is alkyl.
  • R 5 is methyl, ethyl propyl, butyl, pentyl, or hexyl.
  • R 5 is methyl. In certain embodiments, R 5 is cycloalkyl. In certain embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R 5 is cyclopropyl. In certain embodiments, R 5 is cyclopentyl. In certain embodiments, R 5 is cyclohexyl. In certain embodiments, R 5 is aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R 5 is phenyl, wherein the phenyl is optionally substituted with haloalkyl. In certain embodiments, R 5 is phenyl, wherein the phenyl is optionally substituted with trifluoromethyl,
  • R 5 is phenyl, wherein the phenyl is optionally substituted with trifluoromethyl. In certain embodiments, R 5 is aryl, wherein the aryl is optionally substituted with trifluoromethyl, difluorom ethyl, l,l,l-trifluoroethyl, or trichloromethyl. In certain embodiments, R 5 is aryl, wherein the aryl is optionally substituted with trifluoromethyl. In certain embodiments, R 5 is aryl, wherein the aryl is substituted with haloalkyl.
  • R 5 is phenyl, wherein the phenyl is substituted with haloalkyl. In certain embodiments, R 5 is phenyl, wherein the phenyl is substituted with trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, or trichloromethyl. In certain embodiments, R 5 is phenyl, wherein the phenyl is substituted with trifluoromethyl. In certain embodiments, R 5 is aryl, wherein the aryl is substituted with trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, or trichloromethyl.
  • R 5 is aryl, wherein the aryl is substituted with trifluoromethyl. In certain embodiments, R 5 is unsubstituted aryl. In certain embodiments, R 5 is unsubstituted phenyl.
  • R 5 is H, alkyl, or cycloalkyl. In certain embodiments, R 5 is H, alkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R 5 is H, alkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R 5 is alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R 5 is alkyl or cycloalkyl. In certain embodiments, R 5 is H or alkyl. In certain embodiments, R 5 is H or cycloalkyl.
  • R 5 is H or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R 5 is alkyl or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R 5 is cycloalkyl or aryl, wherein the aryl is optionally substituted with haloalkyl. [00108] In certain embodiments, R 1 is aryl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is aryl optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy.
  • R 1 is aryl optionally substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is aryl optionally substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R 1 is aryl optionally substituted with haloalkoxy. In certain embodiments, R 1 is aryl optionally substituted with cycloalkyloxy. In certain embodiments, R 1 is aryl optionally substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is aryl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.
  • R 1 is aryl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is aryl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is aryl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R 1 is aryl substituted with haloalkoxy. In certain embodiments, R 1 is aryl substituted with cycloalkyloxy. In certain embodiments,
  • R 1 is aryl substituted with (cycloalkyl)alkoxy.
  • R 1 is unsubstituted aryl.
  • R 1 is optionally substituted phenyl, napthyl, or indanyl. In certain embodiments, R 1 is optionally substituted phenyl. In certain embodiments,
  • R 1 is optionally substituted napthyl. In certain embodiments, R 1 is optionally substituted indanyl.
  • R 1 is phenyl or napththyl, each of which is optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,
  • alkylcarbonyloxy alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, alkoxy carbonylamino, cycloalkyloxy,
  • heterocycloalkyloxy (heterocycloalkyl)alkoxy or (cycloalkyl)alkoxy.
  • R 1 is phenyl, optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is phenyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.
  • R 1 is phenyl substituted with trifluorom ethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy.
  • R 1 is phenyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy.
  • R 1 is phenyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is phenyl substituted with trifluoromethoxy or cyclohexylmethoxy. In certain embodiments, R 1 is phenyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R 1 is phenyl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is phenyl substituted with cyclopentyloxy or cyclohexylmethoxy.
  • R 1 is phenyl substituted with cycloalkyloxy or haloalkoxy. In certain embodiments, R 1 is phenyl substituted with cyclopentyloxy or trifluoromethoxy. In certain embodiments, R 1 is phenyl substituted with haloalkoxy. In certain embodiments, R 1 is phenyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R 1 is phenyl substituted with trifluoromethoxy.
  • R 1 is phenyl substituted with cycloalkyloxy.
  • R 1 is phenyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cylcohexyloxy. In certain embodiments, R 1 is phenyl substituted with cyclopentyloxy. In certain embodiments, R 1 is phenyl substituted with (cycloalkyl)alkoxy. In certain
  • R 1 is phenyl substituted with cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R 1 is phenyl substituted with cyclohexylmethoxy.
  • R 1 is unsubstituted phenyl.
  • R 1 is ortho substituted phenyl.
  • R 1 is meta substituted phenyl. In certain embodiments, R 1 is para substituted phenyl.
  • R 1 is naphthyl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.
  • R 1 is naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy.
  • R 1 is naphthyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy.
  • R 1 is naphthyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R 1 is naphthyl substituted with trifluoromethoxy or cyclopentyloxy. In certain embodiments, R 1 is naphthyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is naphthyl substituted with trifluoromethoxy or cyclohexylmethoxy. In certain embodiments, R 1 is naphthyl substituted with
  • R 1 is naphthyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R 1 is naphthyl substituted with haloalkoxy. In certain embodiments, R 1 is naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R 1 is naphthyl substituted with trifluoromethoxy. In certain embodiments, R 1 is naphthyl substituted with trifluoromethoxy. In certain embodiments, R 1 is naphthyl substituted with trifluoromethoxy.
  • R 1 is naphthyl substituted cycloalkyloxy. In certain embodiments, R 1 is naphthyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyl cohexyl oxy. In certain embodiments, R 1 is naphthyl substituted with cyclopentyloxy. In certain embodiments, R 1 is naphthyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is naphthyl substituted with
  • R 1 is naphthyl substituted with cyclohexylmethoxy.
  • R 1 is 1 -naphthyl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 1 -naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.
  • R 1 is 1 -naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy.
  • R 1 is 1 -naphthyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy.
  • R 1 is 1 -naphthyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R 1 is 1 -naphthyl substituted with trifluoromethoxy or cyclopentyloxy. In certain embodiments, R 1 is 1 -naphthyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 1 -naphthyl substituted with
  • R 1 is 1 -naphthyl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 1- naphthyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R 1 is 1 -naphthyl substituted with haloalkoxy. In certain embodiments, R 1 is 1 -naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or
  • R 1 is 1 -naphthyl substituted with
  • R 1 is 1 -naphthyl substituted with
  • R 1 is 1 -naphthyl substituted cycloalkyloxy. In certain embodiments, R 1 is 1 -naphthyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cylcohexyloxy. In certain embodiments, R 1 is 1 -naphthyl substituted with cyclopentyloxy. In certain embodiments, R 1 is 1 -naphthyl substituted with
  • R 1 is 1 -naphthyl substituted with cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R 1 is 1 -naphthyl substituted with cyclohexylmethoxy.
  • R 1 is 2-naphthyl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.
  • R 1 is 2-naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy.
  • R 1 is 1 -naphthyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy.
  • R 1 is 2-naphthyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R 1 is 2-naphthyl substituted with trifluoromethoxy or cyclopentyloxy. In certain embodiments, R 1 is 2-naphthyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-naphthyl substituted with
  • R 1 is 2-naphthyl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2- naphthyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R 1 is 2-naphthyl substituted with haloalkoxy. In certain embodiments, R 1 is 2-naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or
  • R 1 is 2-naphthyl substituted with
  • R 1 is 2-naphthyl substituted with
  • R 1 is 2-naphthyl substituted cycloalkyloxy. In certain embodiments, R 1 is 2-naphthyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cylcohexyloxy. In certain embodiments, R 1 is 2-naphthyl substituted with cyclopentyloxy. In certain embodiments, R 1 is 2-naphthyl substituted with
  • R 1 is 2-naphthyl substituted with
  • R 1 is 2-naphthyl substituted with cyclohexylmethoxy.
  • R 1 is unsubstituted naphthyl.
  • R 1 is l-naphthyl or 2-naphthyl. In certain embodiments, R 1 is l-naphthyl. In certain embodiments, R 1 is 2-naphthyl.
  • R 1 is heteroaryl, optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is heteroaryl, optionally substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is heteroaryl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is heteroaryl substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-pyridyl, 3-pyridyl, or quinolinyl, each of which is substituted with (cycloalkyl)alkoxy.
  • R 1 is 2-pyridyl or 3-pyridyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-pyridyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-pyridyl, 3-pyridyl, or quinolinyl, each of which is substituted with
  • R 1 is 2-pyridyl, or 3-pyridyl, each of which is substituted with cyclohexylmethoxy. In certain embodiments, R 1 is 2-pyridyl substituted with cyclohexylmethoxy.
  • R 1 is unsubstituted heteroaryl.
  • R 1 is 2-pyridyl, optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-pyridyl, substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-pyridyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R 1 is 2-pyridyl substituted with cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or
  • R 1 is 2-pyridyl substituted with
  • R 1 is unsubstituted 2-pyridyl.
  • ring A is a 4-7 membered monocyclic
  • heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R 3 groups.
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R 3 groups.
  • ring A is a 5 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is a 6 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups wherein each R 3 group is independently halo or amino.
  • ring A is substituted. In certain embodiments, ring A is substituted piperidinyl. In certain embodiments, ring A is substituted pyrrolidinyl.
  • ring A is optionally substituted piperazinyl.
  • ring A is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, or diazepanyl, each of which is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino; or ring A is unsubstituted piperazinyl.
  • ring A is piperidinyl or pyrrolidinyl, each of which is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino; or ring A is unsubstituted piperazinyl.
  • ring A is unsubstituted piperazinyl or piperidinyl substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is unsubstituted piperazinyl or pyrrolidinyl substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is piperazinyl optionally substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is unsubstituted piperazinyl.
  • ring A is piperidinyl substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino. In certain embodiments, ring A is piperidinyl substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently selected from fluoro, chloro, bromo, and amino. In certain embodiments, ring A is piperidinyl substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently fluoro or amino. In certain embodiments, ring A is piperidinyl substituted with an amino group. In certain embodiments, ring A is piperidinyl substituted with a halo group.
  • ring A is pyrrolidinyl substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino. In certain embodiments, ring A is pyrrolidinyl substituted with amino.
  • ring A is: , wherein n is 1 to 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.
  • ring A is
  • ring A is
  • ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with an amino group.
  • ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one ring nitrogen atom, with remaining ring atoms being carbon atoms, and is substituted with an amino group. In certain embodiments, ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with an amino group.
  • ring A is 8-azabicyclo[3.2. l]octanyl or (lR,5S)-3- azabicyclo[3.2.l] octanyl, each of which is substituted with an amino group. In certain embodiments, ring A is 8-azabicyclo[3.2. l]octanyl substituted with an amino group. In certain embodiments, ring A is (lR,5S)-3-azabicyclo[3.2.l] octanyl substituted with an amino group. [00136] In certain embodiments, ring A is
  • ring A is
  • ring A is
  • ring A is
  • ring A is:
  • R 3 is independently halo or amino. In certain embodiments, R 3 is independently fluoro, chloro, bromo, or amino. In certain embodiments, R 3 is independently fluoro or amino. In certain embodiments, R 3 is independently halo. In certain embodiments, R 3 is independently fluoro, chloro, or bromo. In certain embodiments, R 3 is independently fluoro. In certain embodiments, R 3 is independently amino.
  • R 2 is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is optionally substituted aryl. In certain embodiments, R 2 is optionally substituted heteroaryl. In certain embodiments, R 2 is unsubstituted aryl. In certain embodiments, R 2 is unsubstituted heteroaryl.
  • R 2 is aryl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is aryl optionally substituted with 1 R 6 group. In certain embodiments, R 2 is aryl optionally substituted with 2 R 6 groups. In certain embodiments, R 2 is aryl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is aryl substituted with 1 R 6 group. In certain embodiments, R 2 is aryl substituted with 2 R 6 groups.
  • R 2 is phenyl, napthyl, or indanyl, each of which is optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is phenyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is naphthyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is indanyl optionally substituted with 1 or 2 R 6 groups.
  • R 2 is phenyl optionally substituted with 1 R 6 group.
  • R 2 is phenyl optionally substituted with 2 R 6 groups. In certain embodiments, R 2 is phenyl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is phenyl substituted with 1 R 6 group. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups. In certain embodiments, R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from halo, alkoxy, haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, aryloxy, and heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 2 is phenyl substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from butoxy, chloro, trifluoromethyl, trifluoromethoxy,
  • R 2 is phenyl substituted with 1 or 2 R 6 groups at the ortho position of the phenyl. In certain embodiments, R 2 is phenyl substituted with 1 or 2 R 6 groups at the meta position of the phenyl. In certain embodiments, R 2 is phenyl substituted with 1 R 6 group at the para position of the phenyl. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups at the ortho and the meta positions of the phenyl. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups at the ortho and the para positions of the phenyl.
  • R 2 is phenyl substituted with 2 R 6 groups at the meta and the para positions of the phenyl. In certain embodiments, R 2 is phenyl substituted with a aryl group at the meta position of the phenyl and a halo group at the para position of the phenyl. In certain embodiments, R 2 is phenyl substituted with an alkoxy group at the meta position of the phenyl and a halo group at the para position of the phenyl. In certain embodiments, R 2 is phenyl substituted with an aryloxy group at the meta position of the phenyl and a halo group at the para position of the phenyl.
  • R 2 is phenyl substituted with a phenyl group at the meta position of the phenyl and a chloro group at the the para position of the phenyl. In certain embodiments, R 2 is phenyl substituted with an n-butoxy group at the meta position of the phenyl and a chloro group at the para position of the phenyl. In certain embodiments, R 2 is phenyl substituted with a phenoxy group at the meta position of the phenyl and a chloro group at the para position of the phenyl.
  • R 2 is phenyl is optionally substituted with an R 6 group, wherein R 6 group is selected from consisting of haloalkyl, haloalkoxy,
  • R 2 is phenyl substituted with an R 6 group, wherein R 6 group is selected from trifluoromethyl, trifluoromethoxy, (trifluoromethyl)cyclopropyl, phenyl, and 2-pyridyl, wherein each phenyl and 2-pyridyl, is independently substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy .
  • R 2 is phenyl substituted with optionally substituted phenyl. In certain embodiments, R 2 is phenyl optionally substituted with phenyl , which is optionally substituted with halolakyl. In certain embodiments, R 2 is phenyl substituted with phenyl , which is optionally substituted with halolakyl. In certain embodiments, R 2 is phenyl substituted with phenyl, which is substituted with trifluoromethyl. In certain embodiments,
  • R 2 is phenyl substituted with chlorophenyl. In certain embodiments, R 2 is phenyl substituted with fluorophenyl.
  • R 2 is phenyl optionally substituted with an R 6 group, wherein R 6 group is haloalkyl, haloalkoxy, or aryl, wherein the aryl is optionally substituted with halo.
  • R 2 is phenyl optionally substituted with an R 6 group, wherein R 6 group is trifluoromethyl, trifluoromethoxy, or phenyl, wherein the phenyl is optionally substituted with fluoro, chloro or bromo.
  • R 2 is phenyl substituted with haloalkoxy.
  • R 2 is phenyl substituted with trifluoromethoxy.
  • R 2 is phenyl substituted with haloalkyl. In certain embodiments, R 2 is phenyl substituted with trifluoromethyl. [00151] In certain embodiments, R 2 is phenyl optionally substituted with an R 6 group, wherein R 6 group is selected from haloalkyl, (haloalkyl)cycloalkyl, aryl, and heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 2 is phenyl substituted with an R 6 group, wherein R 6 group is selected from trifluoromethyl, (trifluoromethyl)cyclopropyl, phenyl, and 2-pyridyl, wherein each phenyl or 2-pyridyl, is independently substituted with fluoro, chloro, trifluoromethyl, or trifluorom ethoxy.
  • R 2 is phenyl substituted with haloalkyl.
  • R 2 is phenyl substituted with trifluoromethyl.
  • R 2 is phenyl substituted with (haloalkyl)cycloalkyl.
  • R 2 is phenyl substituted with (trifluorom ethyl)cy cl opropyl. In certain embodiments, R 2 is phenyl substituted with aryl, wherein the aryl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 2 is phenyl substituted with unsubstituted phenyl.
  • R 2 is phenyl substituted with an R 6 group, wherein R 6 group is phenyl optionally substituted with fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, 1,1,1- trifluoroethyl, trichlorom ethyl, trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy.
  • R 2 is phenyl substituted with heteroaryl, wherein heteroaryl is optionally substituted with halo or haloalkoxy.
  • R 2 is phenyl substituted with 2-pyridyl or 3-pyridyl, wherein 2-pyridyl or 3-pyridyl is optionally substituted with fluoro, chloro, bromo, trifluoromethoxy, difluoromethoxy, 1,1,1- trifluoroethoxy, or trichloromethoxy.
  • R 2 is phenyl substituted with 2-pyridyl or 3-pyridyl, wherein 2-pyridyl or 3-pyridyl is substituted with fluoro, chloro, or trifluoromethoxy.
  • R 2 is phenyl substituted with 2-pyridyl, which is substituted with fluoro, chloro, or trifluoromethoxy.
  • R 2 is phenyl optionally substituted with an R 6 group, wherein R 6 group is haloalkoxy. In certain embodiments, R 2 is phenyl optionally substituted with an R 6 group, wherein R 6 group is trifluoromethoxy.
  • R 2 is indanyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is indanyl optionally substituted with 1 R 6 group. In certain embodiments, R 2 is indanyl optionally substituted with 2 R 6 groups. In certain embodiments, R 2 is indanyl optionally substituted with haloalkyl. In certain embodiments, R 2 is indanyl optionally substituted with trifluoromethyl. In certain embodiments, R 2 is unsubstituted indanyl. In certain embodiments, R 2 is indanyl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is indanyl substituted with 1 R 6 group. In certain embodiments, R 2 is indanyl substituted with 2 R 6 groups. In certain embodiments, R 2 is indanyl substituted with haloalkyl. In certain embodiments, R 2 is indanyl substituted with trifluoromethyl.
  • R 2 is phenyl optionally with 1 or 2 R 6 groups, wherein R 6 group is independently selected from halo, haloalkyl, aryloxy, alkoxy, and aryl optionally substituted with halo.
  • R 2 is phenyl optionally substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from fluoro, chloro, bromo, trifluorm ethyl, difluorom ethyl, l,l,l-trifluoroethyl, trichloromethyl, phenoxy, methoxy, ethoxy, propoxy, n-butoxy, and phenyl optionally substituted with fluoro, chloro, or bromo.
  • R 2 is phenyl optionally substituted with an R 6 group selected from chloro, trifluorm ethyl, phenyl, and chlorophenyl.
  • R 2 is phenyl optionally substituted with 2 R 6 groups, wherein each R 6 groups are independently selected from chloro, phenoxy, n-butoxy, and phenyl.
  • R 2 is phenyl substituted with halo.
  • R 2 is phenyl substituted with fluoro, chloro, or bromo.
  • R 2 is phenyl substituted with halo substituted phenyl.
  • R 2 is phenyl substituted with chlorophenyl.
  • R 2 is phenyl substituted with haloalkyl.
  • R 2 is phenyl substituted with phenyl substituted with trifluoromethyl. In certain embodiments, R 2 is phenyl substituted with unsubstituted phenyl. In certain embodiments, R 2 is unsubstituted phenyl.
  • R 2 is phenyl optionally with an R 6 group, wherein the R 6 group is selected from halo, haloalkyl, and aryl optionally substituted with halo.
  • R 2 is phenyl optionally with an R 6 group, wherein the R 6 group is selected from fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl,
  • R 2 is phenyl optionally substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from alkoxy, halo, aryl, and aryloxy.
  • R 2 is phenyl optionally substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, phenyl and phenoxy.
  • R 2 is phenyl substituted with 2 R 6 groups, wherein each R 6 group is independently alkoxy or halo.
  • R 2 is phenyl substituted with 2 R 6 groups, wherein each R 6 group is independently n-butoxy or chloro. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups, wherein each R 6 group is independently aryl or halo. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups, wherein each R 6 group is independently phenyl or chloro. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups, wherein each R 6 group is independently aryloxy or halo. In certain embodiments, R 2 is phenyl substituted with 2 R 6 groups, wherein each R 6 group is independently phenoxy or chloro.
  • R 2 is heteroaryl, optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is heteroaryl optionally substituted with 1 R 6 group. In certain embodiments, R 2 is heteroaryl optionally substituted with 2 R 6 groups. In certain embodiments, R 2 is heteroaryl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is heteroaryl substituted with 1 R 6 group. In certain embodiments, R 2 is heteroaryl substituted with 2 R 6 groups. In certain embodiments, R 2 is unsub stitutedheteroaryl.
  • R 2 is pyridyl, thiazolyl, or l,3,4-thiadiazolyl, wherein each R 2 is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl, 3-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl, 3-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl, 3-pyridyl, or thiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl, 3- pyridyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 3-pyridyl, thiazolyl, or 1,3,4- thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl or 3-pyridyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl or thiazolyl, wherein each of whchis independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 3- pyridyl or thiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 3-pyridyl or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is thiazolyl or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R 6 groups.
  • R 2 is pyridyl optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 3-pyridyl optionally substituted with 1 or 2 R 6 groups.
  • R 2 is thiazolyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is 2-thiazolyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is 4-thiazolyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is 5-thiazolyl optionally substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is l,3,4-thiadiazolyl optionally substituted with 1 or 2 R 6 groups.
  • R 2 is 2-pyridyl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is 3-pyridyl substituted with 1 or 2 R 6 groups. In certain
  • R 2 is 2-thiazolyl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is 3-thiazolyl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is 4-thiazolyl substituted with 1 or 2 R 6 groups. In certain embodiments, R 2 is l,3,4-thiadiazolyl substituted with 1 or 2 R 6 groups.
  • R 2 is selected from:
  • R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with R 6 , wherein R 6 is aryl or heteroaryl, each of which is optionally substituted with halo, haloalkyl, or haloalkoxy.
  • R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with a group selected from fluoro, chloro, trifluoromethyl, and trilfuorom ethoxy.
  • R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with 2-pyridyl, 3-pyridyl, or 4-pyridyl, wherein 2- pyridyl is optionally substituted with chloro.
  • R 2 is 2-pyridyl optionally substituted with aryl, wherein the aryl is optionally substituted with halo.
  • R 2 is 2-pyridyl optionally substituted with chlorophenyl.
  • R 2 is 3-pyridyl optionally substituted with aryl, wherein the aryl is optionally substituted with halo, haloalkyl or haloalkoxy.
  • R 2 is 3-pyridyl optionally substituted with phenyl, wherein the phenyl is optionally substituted with fluoro, chloro, trifluoromethyl, or trilfuorom ethoxy.
  • R 2 is 3-pyridyl optionally substituted with heteroaryl, wherein heteroaryl is optionally substituted with halo.
  • R 2 is 3-pyridyl optionally substituted with 2-pyridyl, wherein 2- pyridyl is optionally substituted with chloro.
  • R 2 is thiazolyl or 1,3,4- thiadiazolyl, each of which is optionally substituted with aryl, wherein the aryl is optionally substituted with halo.
  • R 2 is thiazolyl or l,3,4-thiadiazolyl, each of which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with chloro.
  • R 6 is independently halo, alkoxy, haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is each independently optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is independently methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, trichlorom ethyl, trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichlorom ethoxy,
  • R 6 is independently n-butoxy, chloro, trifluoromethyl, trifluoromethoxy
  • each R 6 is independently halo, alkoxy, haloalkyl, haloalkoxy, or (haloalkyl)cycloalkyl.
  • each R 6 is independently methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, trichloromethyl, trifluoromethoxy, difluoromethoxy, 1,1,1- trifluoroethoxy, trichloromethoxy, or (trifluoromethyl)cyclopropyl.
  • R 6 is independently butoxy, chloro, trifluoromethyl, trifluoromethoxy, or
  • R 6 is independently halo or alkoxy. In certain embodiments, R 6 is independently n-butoxy or chloro. In certain embodiments, R 6 is independently halo, alkoxy, or haloalkyl. In certain embodiments, R 6 is independently, n- butoxy, chloro, or trifluoromethyl. In certain embodiments, R 6 is independently halo, alkoxy, or (haloalkyl)cycloalkyl. In certain embodiments, R 6 is independently n-butoxy, chloro, trifluoromethoxy, or (trifluoromethyl)cyclopropyl. In certain embodiments, R 6 is
  • R 6 independently halo or (haloalkyl)cycloalkyl.
  • R 6 is independently chloro or (trifluoromethyl)cyclopropyl.
  • R 6 is independently halo.
  • R 6 is independently fluoro, chloro, or bromo.
  • R 6 is independently alkoxy.
  • R 6 is independently methoxy, ethoxy, propoxy, or n-butoxy.
  • R 6 is independently haloalkyl.
  • R 6 is independently trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, or trichlorom ethyl.
  • R 6 is independently haloalkoxy. In certain embodiments, R 6 is independently trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R 6 is independently (haloalkyl)cycloalkyl. In certain embodiments, R 6 is independently (trifluoromethyl)cyclopropyl.
  • R 6 is independently aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is each independently optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is independently aryl or heteroaryl, wherein each aryl or heteroaryl is independently optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is independently aryl, or aryloxy, wherein each aryl is independently optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is independently heteroaryl, or aryloxy, wherein each aryl or heteroaryl is independently optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is aryl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is aryl substituted with halo. In certain embodiments, R 6 is aryl substituted with haloalkoxy. In certain embodiments, R 6 is aryl substituted with haloalkyl.
  • R 6 is phenyl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is phenyl substituted with fluoro, chloro,
  • R 6 is phenyl substituted with halo. In certain embodiments, R 6 is phenyl substituted with fluoro or chloro. In certain embodiments, R 6 is phenyl substituted with haloalkoxy. In certain embodiments, R 6 is phenyl substituted with trifluoromethoxy. In certain embodiments, R 6 is phenyl substituted with haloalkyl. In certain embodiments, R 6 is phenyl substituted with trifluoromethyl.
  • R 6 is unsubstituted phenyl.
  • R 6 is heteroaryl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is heteroaryl substituted with halo or haloalkoxy. In certain embodiments, R 6 is heteroaryl substituted with halo. In certain embodiments, R 6 is heteroaryl substituted with haloalkoxy. In certain embodiments, R 6 is heteroaryl substituted with chloro. In certain embodiments, R 6 is heteroaryl substituted with fluoro. In certain embodiments, R 6 is heteroaryl substituted with trifluoromethoxy.
  • R 6 is 2-pyridyl substituted with halo or haloalkoxy.
  • R 6 is independently 2-pyridyl substituted with fluoro, chloro, or trifluoromethoxy. In certain embodiments, R 6 is 2-pyridyl substituted with halo. In certain embodiments, R 6 is independently 2-pyridyl substituted with fluoro or chloro. In certain embodiments, R 6 is independently 2-pyridyl substituted with fluoro. In certain embodiments, R 6 is independently 2-pyridyl substituted with chloro. In certain embodiments, R 6 is 2- pyridyl substituted with trifluorom ethoxy.
  • R 6 is independently unsubstituted2-pyridyl.
  • R 6 is aryloxy substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is unsubstituted aryl. In certain embodiments, R 6 is unsubstituted heteroaryl. In certain embodiments, R 6 is unsubstituted aryloxy.
  • R 6 is phenoxy
  • R 6 is independently halo or aryloxy, wherein aryloxy is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is independently halo or aryl, wherein the aryl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is independently halo or unsubstituted aryloxy. In certain embodiments, R 6 is independently halo or unsubstituted aryl.
  • R 6 is independently halo or phenyl, wherein the phenyl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is independently fluoro, chloro or phenyl.
  • R 6 is independently halo or phenoxy, wherein phenoxy is optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is independently fluoro, chloro or phenoxy.
  • ring B is piperazinyl, then R 2 is not furanyl or thiophenyl. In certain embodiments, R 2 is not furanyl or thiophenyl. In certain embodiments, R 2 is not furanyl. In certain embodiments, R 2 is not thiophenyl.
  • R 2 when ring B is piperidinyl or pyrrolidinyl, then R 2 is not imidazolyl. In certain embodiments, when ring B is piperidinyl, then R 2 is not imidazolyl. In certain embodiments, when ring B is pyrrolidinyl, then R 2 is not imidazolyl.
  • R 2 is not imidazolyl.
  • R 2 is not amino-substituted imidazolyl. In certain embodiments, when ring B is piperidinyl then R 2 is not amino-substituted imidazolyl. In certain embodiments, when ring B is pyrrolidinyl then R 2 is not amino-substituted imidazolyl. [00180] In certain embodiments, when R 1 is methoxy substituted phenyl, then R 2 is not unsubstituted phenyl. In certain embodiments, R 1 is not methoxy substituted phenyl. In certain embodiments, R 2 is not unsubstituted phenyl.
  • R 1 when R 1 is cyano substituted phenyl, then R 2 is not unsubstituted phenyl. In certain embodiments, R 1 is not cyano substituted phenyl.
  • R 1 is not substituted heteroaryl.
  • R 1 is not unsubstituted heteroaryl.
  • the compound of Formula (II) is wherein ring A is not pyrrolidinyl. In certain embodiments, the compound of Formula (II) is wherein ring A is not pyrrolidinyl.
  • the compound of Formula (II) is wherein R 1 is not substituted heteroaryl. In certain embodiments, the compound of Formula (II) is wherein R 1 is not un substituted heteroaryl.
  • the compound of Formula (II) is not A -[ l -[[(2L',4/ ⁇ )- l-[(3,4-dimethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)methoxy]-2-pyrrolidinyl]carbonyl]- 3-pyrrolidinyl]-acetamide or trifluoroacetate salt thereof.
  • the compound of Formula (II) is that wherein R 1 is not unsubstituted heteroaryl.
  • the compound of Formula (II) is not/V-[l-[[-l-[(3,4- dimethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)methoxy]-2-pyrrolidinyl]carbonyl]-3- pyrrolidinyl]-acetamide or trifluoroacetate salt thereof.
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (I) is that according to one of the following formulas:
  • the compound of Formula (II) is that according to one of the following formulas:
  • the compound of Formula (II) is that according to one of the following formulas:
  • m is 1, 2, or 3, where all other groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is that according to one of the following formulas:
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms and is optionally substituted with 1, 2, or 3 R 3 groups;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • dialkylaminocarbonyloxy aminocarbonyloxy, alkylcarbonylamino, or
  • R 7 is hydrogen or alkyl
  • the compound of Formula (III) is that wherein ring B is piperidinyl or pyrrolidinyl. In certain embodiments, the compound of Formula (III) is that wherein ring B is piperidinyl. In certain embodiments, the compound of Formula (III) is that wherein ring B is pyrrolidinyl.
  • the compound of Formula (III) is according to Formula (Ilia):
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy,
  • the compound of Formula (III) is according to Formula (Ilia) that wherein:
  • ring A is a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with an amino; R 1 is aryl optionally substituted with cycloalkyloxy; and R 2 is aryl optionally substituted with 1 or 2 halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound or pharmaceutically acceptable salt of Formula (Ilia) is that wherein ring A is 8-azabicyclo[3.2.l]octanyl or (lR,5S)-3- azabicyclo[3.2.l] octanyl, each of which is substituted with an amino group; R 1 is phenyl or naphthyl, each R 1 independendtly substituted by cyclopentyloxy or cyclohexylmethoxy; and R 2 is phenyl substituted with a group selected from fluoro, chloro, and bromo.
  • the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), or (Iaf), or a single stereoisomer or mixture of stereoisomers thereof, as defined herein.
  • the compound or pharmaceutically acceptable salt thereof is a compound of Formula (II), (Ha), (lib), (He), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a single stereoisomer or mixture of stereoisomers thereof, as defined herein.
  • the compound or pharmaceutically acceptable salt thereof is a compound of Formula (III) or (Ilia), or a single stereoisomer or mixture of stereoisomers thereof, as defined herein.
  • the compound or pharmaceutically acceptable salt thereof is a compound from Table 1. In certain embodiments, the compound or or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-1,
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5, 6, 7, 5-2,
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5-2, 7-1, 12- 2, 14-2, 15-2, 16, 17, 11-4, 19-1, 19-2, 20, 22, 23, 25, 27, 26-2, 27, 28, 29, 32-1, 33, 36, 37,
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5, 6, 7, 5-2,
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5-2, 7-1, 12-
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 70, 69-1, 71, 72-1, 69-2, 69-3, 72-2, 72-
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 70, 69-1, 72-1, 69-2, 75, 76, 80, 79, 82, 83, 84, 96, 102, and 118-1, or a single stereoisomer or mixture of stereoisomers thereof.
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 59-1, 59-2, 60-1, 60-2, 61-1, 62-1, 61-2, 62-2, 63-2, 63-1, 64-1, 64-2, 65, 66-1, 66-2, 67-1, and 67-2, or a single stereoisomer or mixture of stereoisomers thereof.
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 64-2, 59-1, 60-1, 62-1, 63-1, 65, and 66- 2, or a single stereoisomer or mixture of stereoisomers thereof.
  • the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 68, 68-1, and 68-2, or a single stereoisomer or mixture of stereoisomers thereof.
  • a pharmaceutical composition comprising of a compound disclosed herein, for example, a compound of Formula (I), (la), (lb), (Ic), (Id),
  • the pharmaceutical composition comprises a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im),
  • the pharmaceutical composition comprises a compound of Table 1, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising of a compound disclosed herein, for example, a compound of Formula (III) or (Ilia), or a compound selected from of the compounds 68, 68-1, and 68-2, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • Suitable excipients are well known to those skilled in the art. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment of all diseases, disorders or conditions provided herein.
  • the compounds and pharmaceutical compositions provided herein are for use as a medicament.
  • compositions provided herein are for use in a method for the treatment of a disease or disorder that is mediated by the enzyme CGT.
  • compositions provided herein are for use in a method for the treatment of a disease or disorder in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder.
  • a compound provided herein is a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable
  • a method for treating any of the diseases or disorders described herein comprising administering to a subject in need of treatment thereof a compound according to any of the various embodiments described herein or a pharmaceutical composition according to any of the various embodiments described herein.
  • the compounds and pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder that is mediated by the enzyme CGT, or in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder.
  • the compounds and pharmaceutical compositions provided herein are used in the preparation or manufacture of medicaments for the treatment of a disease or disorder that is mediated by the enzyme CGT or in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III) or (Ilia), or a compound selected from of the compounds 68, 68-1, and 68-2, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition comprising a compound of Formula (III) or (Ilia), or a compound selected from of the compounds 68, 68-1, and 68-2, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the disease or disorder is a lysosomal storage disease.
  • the lysosomal storage disease or disorder is a defect in sphigolipid metabolism, Krabbe disease or Metachromatic Leukodystrophy (MLD).
  • MLD Metachromatic Leukodystrophy
  • the lysosomal storage disease or disorder is Krabbe disease or Metachromatic Leukodystrophy (MLD). In certain embodiments, the disease or disorder is Krabbe disease.
  • the disease or disorder is MLD. In certain embodiments, the disease or disorder is Parkinson’s disease.
  • compositions disclosed herein can be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • the compounds are typically administered as pharmaceutical compositions by any route which makes the compound bioavailable.
  • the composition is a solid formulation adapted for oral administration.
  • the composition is a tablet, powder, or capsule; or the composition is a tablet.
  • the composition is a liquid formulation adapted for oral administration.
  • the composition is a liquid formulation adapted for parenteral administration.
  • the composition is a solution, suspension, or emulsion; or the composition is a solution.
  • solid form compositions can be converted, shortly before use, to liquid form compositions for either oral or parenteral administration.
  • These particular solid form compositions are provided in unit dose form and as such are used to provide a single liquid dosage unit.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra;
  • the dosages may be varied depending on the requirement of the patient, the severity of the disease or disorder being treating and the particular compound and/or composition being employed. Determination of the proper dosage can be determined by one skilled in the medical arts.
  • the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery. In certain
  • the compounds are administered to a subject at a daily dosage of between 0.01 to about 50 mg/kg of body weight. In other embodiments, the dose is from 1 to 1000 mg/day. In certain embodiments, the daily dose is from 1 to 750 mg/day; or from 10 to 500 mg/day.
  • the pharmaceutical composition is in unit dosage form.
  • the composition can be subdivided into unit doses containing appropriate quantities of the active component(s).
  • the unit dosage form can be a tablet, capsule, or powder in a vial or ampule, or it may be the appropriate number of any of these in a packaged form.
  • the unit dosage form can be a packaged form, the package containing discrete quantities of composition such as packeted tablets, capsules, or powders in vials or ampules.
  • the quantity of active compound(s) in a unit dose of the composition may be varied or adjusted from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg.
  • the compounds or pharmaceutical compositions disclosed herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • a Compound of Formula (I) can be prepared according to General Scheme 1.
  • An intermediate of formula 1-3 can be prepared from an intermediate amine I-l and a sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the compounds of formulas I-l and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO3, in a solvent, such as dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-3.
  • a base either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO3
  • a solvent such as dichloromethane, DMF, or THF
  • An intermediate of formula 1-5 can be prepared from the intermediate 1-3 using standard amide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-3 can be treated with an amine intermediate 1-4, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in the presence of an amide coupling reagents, such as HATU or EDC, in a solvent, such as CH2CI2 or DMF, optionally with or without a base, such as DIPEA or Et 3 N, at ambient temperature or up to 50 °C, to yield the intermediate of formula 1-5.
  • an amide coupling reagents such as HATU or EDC
  • a solvent such as CH2CI2 or DMF
  • a base such as DIPEA or Et 3 N
  • the protecting group (Pg) on the nitrogen of the intermediate of formula 1-5 can be removed using the corresponding deprotection conditions, which are depended on the nature of the protecting groups. More specifically, the intermediate of formula 1-5 with an Fmoc (fluorenylmethyloxycarbonyl) protecting group, which can be deprotected using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, such as Et 2 NH or piperidine in as solvent such as dichloromethane or THF, at ambient temperature or up to 50 °C, to yield an intermediate of formula 1-6.
  • a base such as Et 2 NH or piperidine in as solvent such as dichloromethane or THF
  • a base such as NaFlCCb, Na2C0 3 , K2CO3, DIPEA, pyridine, or Et 3 N, optionally with or without Nal
  • EtOH, DMF, NMP, or THF at ambient temperature or up to 120 °C
  • a reducing reagent such as NaBH(AcO) 3 or NaBH 3 CN
  • a Lewis acid such as AcOH or KH2PO4 or Ti(/PrO)4
  • a compound of Formula (I) or according to any of the embodiments disclosed herein, can also be prepared according to General Scheme 2.
  • a base such as NaHCCb, Na2CCb, K2CO3, DIPEA, pyridine, or Et 3 N, optionally with or without Nal
  • EtOH, DMF, NMP, or THF at ambient temperature or up to 120 °C
  • a reducing reagent such as NaBH(AcO)3 or NaBEECN
  • a Lewis acid such as AcOH or KH2PO4 or Ti(/PrO)4, herein without an acid
  • a solvent such as EtOH, MeOH, l,2-dichloroethane, or THF
  • the protecting group (Pg) on the nitrogen of the intermediate of formula 1-9 can be removed using the corresponding deprotection conditions, which are depended on the nature of the protecting groups (Pg). More specifically, the intermediate of formula 1-9 that has a Boc (tert-butyloxycarbonyl) protecting group, which can be de-protected using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with an acid, such as HC1 or trifluoroacetic acid in as solvent such as dichloromethane or THF, at ambient temperature or up to 50 °C, to yield an intermediate of formula 1-10.
  • an acid such as HC1 or trifluoroacetic acid in as solvent such as dichloromethane or THF
  • An intermediate of formula 1-11 can be prepared from the intermediate 1-10 and sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-10 and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO 3 , in a suitable solvent, such as dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-11.
  • a base either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO 3
  • a suitable solvent such as dichloromethane, DMF, or THF
  • the compounds of Formula (I) can be prepared from the intermediates 1-11 using standard amide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-11 can be treated with the amine intermediate of formula 1-4, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in the presence of an amide coupling reagents, such as ITATEG or EDC, in a solvent, such as CH2CI2 or DMF, optionally with or without a base, such as DIPEA or EtxN, at ambient temperature or up to 50 °C, to afford the Compound of Formula (I).
  • an amide coupling reagents such as ITATEG or EDC
  • a solvent such as CH2CI2 or DMF
  • a base such as DIPEA or EtxN
  • a reducing reagent such as NaBH(AcO)3 or NaBHiCN
  • a Lewis acid such as AcOH or KH2PO4 or Ti(/PrO)4
  • the protecting group (Pg) on the nitrogen of the intermediate of formula 1-13 can be removed using the corresponding deprotection conditions, which are depended on the nature of the protecting groups (Pg). More specifically, the intermediate of formula 1-13 that has a Boc (tert-butyloxycarbonyl) protecting group, which can be deprotected using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with an acid, such as HC1 or trifluoroacetic acid in as solvent such as dichloromethane or THF, at ambient temperature or up to 50 °C, to yield an intermediate of formula 1-14.
  • Boc tert-butyloxycarbonyl
  • An intermediate of formula 1-15 (where R is a Ci-Cs alkyl group) can be prepared from the intermediate of formula 1-14 and sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-14 and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO3, in a suitable solvent, such as
  • the intermediate of formula 1-11 can be prepared from the intermediate 1-15 (where R is an alkyl group, Ci-Cs) using standard ester hydrolysis conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-15 can be treated with a base, such as LiOH, or with a lithium salt, such as LiCl or LiBr, in a solvent with water, such as THF/water, MeOH/water, or dioxane/water, at ambient temperature or up to 100 °C, to yield the intermediate of formula 1-11.
  • a base such as LiOH
  • a lithium salt such as LiCl or LiBr
  • An intermediate of formula 1-17 (R is a Ci-Cx-alkyl group) can be formed from an intermediate amine of formula 1-12 and an intermediate aldehyde or ketone of formula 1-16 using benzotriazole mediated aminoalkylation conditions, which are disclosed herein or are known to one of ordinary skill in the art.
  • the intermediate of formula 1-12 can be treated with the intermediate of formula 1-16, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, and lH-benzo[d][l,2,3]triazole, optionally in the presence of an acid in catalytic amount, such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or methanesulfonic acid, or without an acid, herein without an acid, in a solvent such as benzene or toluene, with azeotropic removal of water, at boiling point temperature, to afford the intermediate of formula 1-17.
  • an acid in catalytic amount such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or methanesulfonic acid, or without an acid, herein without an acid, in a solvent such as benzene or toluene,
  • the intermediate of formula 1-13 (where R is a Ci-Cs alkyl group,) can be prepared from the intermediate of formula 1-17 using standard Grignard addition conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-17 can be treated with a Grignard reagent (R 5 -MgX), which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in a solvent, such as THF, dichloromethane, or l,4-dioxane, at temperature of -50 °C or up to ambient temperature, to yield the intermediate of formula 1-13.
  • a Grignard reagent R 5 -MgX
  • An intermediate of formula 1-19 can be prepared from an intermediate amine 1-18 (where R is a C i-Cx alkyl group) and sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-18 and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO3, in a solvent, such as dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-19.
  • a base either organic or inorganic base, such as DIPEA, Et 3 N, or K2CO3
  • a solvent such as dichloromethane, DMF, or THF
  • the intermediate of formula 1-20 and the compound of Formula (II) can also be prepared using standard Mitsunobu reaction conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-19 can be reacted with an compound R 2 -OH in the presence of a phosphine reagent, such as triphenylphosphine, and an azodicarboxylate, such as as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), in a suitable solvent such as THF, toluene, acetonitrile or diethyl ether, at -20 °C or up to 80 °C, to yield the intermediate of formula 1-20.
  • a phosphine reagent such as triphenylphosphine
  • an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azo
  • the intermediate of formula 1-21 can be prepared from the intermediate of formula 1-20 (where R is a C i-Cx alkyl group) using standard ester hydrolysis conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-20 can be treated with a base, such as LiOH, or with a lithium salt, such as LiCl or LiBr, in a solvent with water, such as
  • the Compound of Formula (II) can be prepared from the intermediates 1-21 using standard amide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-21 can be treated with the amine intermediate of formula 1-4, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in the presence of an amide coupling reagents, such as HATU or EDC, in a solvent, such as CH2CI2 or DMF, optionally with or without a base, such as DIPEA or Et 3 N, at ambient temperature or up to 50 °C, to afford the Compound of Formula (II).
  • an amide coupling reagents such as HATU or EDC
  • a solvent such as CH2CI2 or DMF
  • a base such as DIPEA or Et 3 N
  • dichloromethane (70 mL) was added B0C2O (5.55 g, 25.2 mmol) and triethylamine (3.8 mL, 27.5 mmol). The solution was heated at reflux overnight, diluted with dichloromethane (150 mL), and washed with 5% sodium bicarbonate (70 mL) and brine (70 mL). The organic layer was, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Compounds B4-1 and B4 were synthesized by employing the procedures described for compounds B3-5 and B3 using /er/-butyl (3,3-difluoropiperidin-4-yl)carbamate (B2) and Compound B4-1 in lieu of /er/-butyl piperidin-4-ylcarbamate and Compound B3-5.
  • Compound B4-1 LC-MS (ESI) m/z: 767[M+H-56] + .
  • Compound B4 LC-MS (ESI) m/z:
  • Compounds IE-1, 1F-1, 1G-1, and 1-1 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 1 using ( R)- ⁇ - ⁇ tert - butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE-1, 1F-1, and 1G-1 in lieu of 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE, IF, and 1G.
  • Compound IE-1 LC-MS (ESI) m/z: 43 l[M+H] + .
  • Compound 1F-1 LC-MS (ESI) m/z: 331 [M+H] + .
  • Compounds IE-2, 1F-2, 1G-2, and 1-2 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 1 using ⁇ S)- ⁇ - ⁇ tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE-2, 1F-2, and 1G-2 in lieu of 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE, IF, and 1G.
  • Compound IE-2 LC-MS (ESI) m/z: 431 [M+H] + .
  • Compound 1F-2 LC-MS (ESI) m/z: 331 [M+H] + .
  • Compounds 2A-1 and 2-1 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds Al, Bl, 1F-1, and 2A-1 in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 1G.
  • Compound 2A- 1 LC-MS (ESI) m/z: 813 [M+H] + .
  • Compounds 2A-2 and 2-2 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds Al, Bl, 1F-2, and 2A-2 in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 1G.
  • Compounds 2A- 2 LC-MS (ESI) m/z: 813 [M+H] + .
  • Compounds 3A-2 and 3-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Bl, 1F-2, and 3A-2 in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds IF, and 3A.
  • Compound 3A-2 LC-MS (ESI) m/z: 791 [M+H] + .
  • Compounds 5A and 5 were synthesized by employing the procedures described for Compounds 1G and 3 using (R)-tert- butyl pyrrolidin-3-ylcarbamate and Compound 5A in lieu of tert-butyl piperidin-4-ylcarbamate and Compound 3A.
  • Compound 5A LC-MS (ESI) m/z: 751 [M+H] + .
  • Compounds 6A-1 and 6-1 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl piperazine- l-carboxylate, Compounds 1F-1, and 6A-1 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A.
  • Compound 6A-1 LC-MS (ESI) m/z: 751 [M+H] + .
  • Compounds 7C-1, 7D-1, 7E-1, and 7-1 were synthesized by employing the procedures described for Compounds 7C, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 7C-1, 7D-1, and 7E-1 in lieu of (R)-l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE, IF, and 3A.
  • Compounds 8A and 8 were synthesized by employing the procedures described for Compounds 1G and 3 using 4-(trifluoromethoxy)benzene-l-sulfonyl chloride and Compound 8A in lieu of Compounds A2 and 3A.
  • Compound 8A LC-MS (ESI) m/z: 737 [M+H] + .
  • Compounds 8A-1 and 8-1 were synthesized by employing the procedures described for Compounds 1G and 3 using 4-(trifluoromethoxy)benzene-l-sulfonyl chloride, Compounds 1F-1, and 8A-1 in lieu of A2, Compounds IF, and 3A.
  • Compound 8A-1 LC- MS (ESI) m/z: 737 [M+H] + .
  • Compounds 8A-2 and 8-2 were synthesized by employing the procedures described for Compounds 1G and 3 using 4-(trifluoromethoxy)benzene-l-sulfonyl chloride, Compounds 1F-2, and 8A-2 in lieu of Compounds A2, IF, and 3A.
  • Compound 8A-2 LC-MS (ESI) m/z: 737 [M+H] + .
  • Compounds 9B, 9C, 9D, and 9 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 3 using Compounds 9A, 9B, 9C, Al, and 9 in lieu of Compounds ID, IE, IF, A2, and 3A.
  • Compound 9B LC-MS (ESI) m/z: 387 [M-H] .
  • Compound 9C LC-MS (ESI) m/z: 287 [M-H] .
  • Compound 9D LC-MS (ESI) m/z: 745
  • Compounds 9B-2, 9C-2, 9D-2, and 9-2 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 9A, 9B-2, 9C-2, and 9D-2 in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds ID, IE, IF, and 3A.
  • Compounds 9B-2 LC-MS (ESI) m/z: 389 [M+H] + .
  • Compounds 9C-2 LC-MS (ESI) m/z:
  • Compounds 10A-2 and 10-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds 9C-2 and 10A-2 in lieu of Compounds IF and 3A.
  • Compounds 10A-2 LC-MS (ESI) m/z: 723 [M+H] + .
  • Compounds 10-2 LC-MS (ESI) m/z: 623 [M+H] + ; 1H-NMR (CD 3 OD, 400 MHz): d (ppm) 1.09-1.58 (m, 7H), 1.73-2.08
  • n-Hexane/EtOH contained 0.1% DEA (50:50); S,S-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 13.64 minute.
  • Compounds 11A-2 and 11B were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds B2, 1F-2, and 11A-2 in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds IF, and 3A.
  • Compound 11A-2 LC-MS ESI (m/z): 801 [M+H] + .
  • Compound 11B was separated with preparative chiral -HPLC to give Compound 11-3 and Compound 11-4.
  • Compounds 12A and 12 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, Bl, 9C, and 12A in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A.
  • Compound 12A LC-MS (ESI) m/z: 771 [M+H] + .
  • Compound 13C-1 was synthesized by employing the procedure described for Compound IF using Compound 13B-1 in lieu of Compound IE: LC-MS (ESI) m/z: 311 [M+H] + .
  • Compounds 13B-2, 13C-2, 13D-2, 13E-2, 13F-2, and 13-2 were synthesized by employing the procedures described for Compounds 13B-1, IF, 13D-1, 13E-1, 13F-1, and 3 using l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate, Compounds 13B-2, 13C-2, 13D-2, 13E-2, and 13F-2 in lieu of l-(tert-butyl) 2-methyl (R)-piperazine-l,2-dicarboxylate, Compounds IE, 13C-1, 13D-1, 13E-1, and 3A.
  • Compound 13B-2 LC-MS (ESI) m/z: 411 [M+H] + .
  • Compound 13C-2 LC-MS (ESI) m/z: 311 [M+H] + .
  • Compound 13D-2 LC-MS (ESI) m/z: 563[M+H] + .
  • Compound 13E-2 LC-MS (ESI) m/z: 547[M-H] .
  • Compound 13F-2 LC-MS (ESI) m/z: 73 l[M+H] + .
  • Compounds 14G-2, 14H-2, 141-2, and 14-2 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 3 using (S)-l-(tert-butoxycarbonyl) piperazine-2-carboxylic acid, Compounds 14F, 14G-2, 14H-2, and 141-2 in lieu of l-(tert- butoxycarbonyl) piperazine-2-carboxylic acid, Compounds ID, IE, IF, and 3A.
  • Compound 14G-2 LC-MS (ESI) m/z: 429 [M+H] + .
  • Compound 14H-2 LC-MS (ESI) m/z: 329 [M+H] + .
  • Compounds 15A-1 and 15-1 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 14H-1, and 15A-1 in lieu of Compounds A2, IF, and 3A.
  • Compound 15A-1 LC-MS (ESI) m/z: 785 [M+H] + .
  • Compound 15-1 LC-MS (ESI) m/z: 343 [M/2+H] + ; 1 H-NMR (CD3OD, 400 MHz): d (ppm) 1.00-1.32
  • Compounds 15A-2 and 15-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 14B-2, and 15A-2 in lieu of Compounds A2, IF, and 3A.
  • Compound 15A-2 LC-MS (ESI) m/z: 785 [M+H] + .
  • Compounds 17A and 17 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl (8-azabicyclo[3.2. l]octan-3- yl)carbamate, Compounds 14B-2, and 17A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A.
  • Compound 17A LC-MS (ESI) m/z: 789 [M+H] + .
  • Compounds 18A and 18 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds B2, Al, and 18A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds A2, and 1G.
  • Compound 18 was separated with chiral HPLC to furnish Compound 18-1 and Compound 18-2.
  • Compound 18-1 LC-MS (ESI) m/z: 723 [M+H] + ; 1 H-NMR (CD 3 OD, 400 MHz): d (ppm) 1.28-3.29 (m, 17H), 3.49-4.64 (m, 5H), 4.99-5.03 (m, 2H), 5.61 (s, 1H), 6.92- 7.91 (m, 13H), 8.39 (s, 1H).
  • Compound 19 was separated by chiral HPLC to give Compound 19-1 and Compound 19-2.
  • Compounds 20B, 20C, 20D, and 20 were synthesized by employing the procedures described for Compounds 7C, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 20A, 20B, 20C, Al, and 20D in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 7B, IE, IF, Compounds A2, and Compound 3A.
  • Compound 20B LC-MS (ESI) m/z: 441 [M+Na] + .
  • Compound 20C was used directly in the next step without purification.
  • Compounds 21A and 21 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds 20C and 21A in lieu of Compounds IF and 3A.
  • Compound 21 A LC-MS (ESI) m/z: 775 [M+Na] + .
  • Compound 21 LC-MS: (ESI) m/z: 653[M+H] + .
  • Compounds 22A and 22 were synthesized by employing the procedures described for Compounds 1G and 3 using Bl, Compound Al, 14B-2, and 22A in lieu of 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compound A2, IF, and 3A.
  • Compound 22 A LC-MS (ESI) m/z: 811 [M+H] + .
  • Compounds 7B using DIPEA as base, IE, IF, A2, and 3A Compound 24B: LC-MS (ESI) m/z: 401 [M-H] .
  • Compound 24C LC-MS (ESI) m/z: 303 [M+H] + .
  • Compound 24D LC-MS (ESI) m/z: 759 [M+H] + .
  • Compounds 26B, 26C-1, and 26C-2 were synthesized by employing the procedures described for Compounds ID and IE using Compounds 26A, 26B, and l-(tert- butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate in lieu of Compounds 1C, ID, and l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid.
  • Compound 26B LC-MS (ESI) m/z: non- ionizable compound under routine conditions used.
  • the mixture of 26C-1 and 26C2 were separated with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40% v/v).
  • Compound 26C-1 LC-MS (ESI) m/z: 459 [M+H] + ; HPLC retention time: 1.66 minute (214 nm).
  • Compound 26C-2 LC-MS (ESI) m/z: 459 [M+H] + ; HPLC retention time: 1.65 minute (214 nm).
  • Compounds 26D-1, 26E-1, 26F-1, 26G-1, and 26-1 were synthesized by employing the procedures described for Compounds IF, 13D-1, 13E-1, 13F-1, and 3 using Compounds 26C-1, 26D-1, 26E-1, 26F-1, and 26G-1 in lieu of Compounds IE, 13C-1, 13D- 1, 13E-1, and 3A.
  • Compound 26D-1 LC-MS (ESI) m/z: 359 [M+H] + .
  • Compound 26E-1 LC-MS (ESI) m/z: 611 [M+H] + .
  • Compound 26F-1 LC-MS (ESI) m/z: 597 [M+H] + .
  • Compounds 26D-2, 26E-2, 26F-2, 26G-2, and 26-2 were synthesized by employing the procedures described for Compounds IF, 13D-1, 13E-1, 13F-1, and 3 using Compounds 26C-2, 26D-2, 26E-2, 26F-2, and 26G-2 in lieu of Compounds IE, 13C-1, 13D- 1, 13E-1, and 3A.
  • Compound 26D-2 LC-MS (ESI) m/z: 359 [M+H] + .
  • Compound 26E-2 LC-MS (ESI) m/z: 611 [M+H] + .
  • Compound 26F-2 LC-MS (ESI) m/z: 597 [M+H] + .
  • Compounds A2, IF, and 3A Compound 27A: LC-MS (ESI) m/z: 801 [M+H] + .
  • Compound 27 LC-MS (ESI) m/z: 701 [M+H] + ; 1 H-NMR (CD3OD, 400 MHz): d (ppm) 1.07-2.20 (m, 11H), 2.44-2.53 (m, 1H), 2.68-3.24 (m, 1H), 3.31-3.59 (m, 3H), 3.65-4.53 (m, 6H), 4.65-4.83 (m, 1H), 5.01-5.29 (m, 2H), 7.22-7.24 (m, 1H), 7.31-7.37 (m, 2H), 7.42-7.44 (m, 3H), 7.62- 7/76 (m, 5H), 7.90-7.92 (m, 2H), 8.23-8.33 (m, 1H).
  • Compounds 28C, 28D, 28E, 28F, 28G, 28H, and 28 were synthesized by employing the procedures described for Compounds ID, 13B-1, IF, 13D-1, 13E-1, 13F-1, and 3 using Compounds 28B, 28C, l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate, 28D, 28E, 28F, 28G, and 28H in lieu of Compounds 1C, 13A, l-(tert-butyl) 2-methyl (R)- piperazine-l,2-dicarboxylate, IE, 13C-1, 13D-1, 13E-1, and 3A.

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Abstract

L'invention concerne des composés, des procédés de fabrication de ces composés, des compositions pharmaceutiques et des médicaments contenant ces composés, et des procédés d'utilisation de ces composés pour traiter ou prévenir des maladies ou des troubles associés à l'enzyme céramide galactosyltransférase (CGT), par exemple les maladies lysosomales. Des exemples de maladies lysosomales, comprennent par exemple, la maladie de Krabbe et la leucodystrophie métachromatique.
PCT/US2018/061965 2017-11-21 2018-11-20 Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies WO2019104011A1 (fr)

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CN111437283A (zh) * 2020-03-09 2020-07-24 吉林大学 β1,4-半乳糖基转移酶抑制剂在制备治疗癌症的药物中的应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020028221A1 (fr) * 2018-07-30 2020-02-06 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement d'une maladie
CN111437283A (zh) * 2020-03-09 2020-07-24 吉林大学 β1,4-半乳糖基转移酶抑制剂在制备治疗癌症的药物中的应用

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