NZ720129B2 - Selectively substituted quinoline compounds - Google Patents

Selectively substituted quinoline compounds Download PDF

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Publication number
NZ720129B2
NZ720129B2 NZ720129A NZ72012914A NZ720129B2 NZ 720129 B2 NZ720129 B2 NZ 720129B2 NZ 720129 A NZ720129 A NZ 720129A NZ 72012914 A NZ72012914 A NZ 72012914A NZ 720129 B2 NZ720129 B2 NZ 720129B2
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New Zealand
Prior art keywords
methyl
cyanoquinolinyl
quinolinecarbonitrile
methylmorpholino
morpholino
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NZ720129A
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NZ720129A (en
Inventor
Eric Carlson
Heather Davis
Atsushi Endo
Hans Hansen
Lynn Hawkins
Sally Ishizaka
Matthew Mackey
Chikako Ogawa
Shawn Schiller
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Eisai R&D Management Co Ltd
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Priority claimed from PCT/US2014/060418 external-priority patent/WO2015057659A1/en
Publication of NZ720129A publication Critical patent/NZ720129A/en
Publication of NZ720129B2 publication Critical patent/NZ720129B2/en

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • 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
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Abstract

Embodiments of the disclosure relate to selectively substituted quinoline compounds of formula (I) that act as antagonists or inhibitors for Toll-like receptors 7 and/or 8, and their use in pharmaceutical compositions effective for treatment of systemic lupus erythematosus (SLE) and lupus nephritis.

Description

Selectively Substituted Quinoline Compounds CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to United States provisional patent application no. 61/890,718, filed on October 14, 2013. That application is incorporated by reference herein.
BACKGROUND Field of the Disclosure Embodiments of the disclosure relate to selectively substituted quinoline compounds and pharmaceutical agents comprising one or more of those compounds as active ingredient(s). More particularly, embodiments of the disclosure relate to those compounds that act as an antagonist or inhibitor for Toll-like receptors (TLR) 7 and 8, and their use in a pharmaceutical composition effective for treatment of systemic lupus erythematosus (SLE) and lupus nephritis.
Description of Related Art Systemic lupus erythematosus (SLE) and lupus nephritis are autoimmune diseases characterized by inflammation and tissue damage. For example, SLE may cause damage to the skin, liver, kidneys, joints, lungs, and central nervous system. SLE sufferers may experience general symptoms such as extreme fatigue, painful and swollen joints, unexplained fever, skin rash, and kidney dysfunction. Because organ involvement differs amongst patients, symptoms may vary. SLE is predominantly a disease of younger women, with peak onset between 15-40 years of age and an approximate 10-fold higher prevalence in women vs. men.
Current treatments for SLE typically involve immunomodulatory drugs such as belimumab, hydroxychloroquine, prednisone, and cyclophosphamide. All of these drugs may have dose-limiting side effects, and many patients still have poorly controlled disease.
BRIEF SUMMARY OF THE DISCLOSURE [0006a] In a first aspect of the invention, there is provided a compound of formula (I) or pharmaceutically acceptable salt thereof: (21642937_1):MXC wherein at least one of R and R is –H, methyl, or ethyl, and the other is -H; or the other is C -C alkyl that is optionally substituted with: –OH, methoxy, ethoxy, -OCH(CH ) , -O(CH ) CH, phenyl, 3 2 2 2 3 furanyl, -O(CH )OH, phenoxy, methylthio, -F, -N(CH ), cyano, 2 2 3 2 pyridinyloxy, fluorophenoxy, isochromanyl, phenol, benzylamino, -NHCH , oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected from O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fluoro, methylamino, or trifluoromethyl; or the other is C -C cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from O, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifluoromethyl; or R and R , together with the nitrogen atom to which they are attached, form an 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a four to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, (ethylamino)methyl, (dimethylamino)methyl, dimethylamino, (methylamino)methyl, and amino; and wherein R is –H or methyl. (23600103_1):AXG [0006b] In a second aspect of the invention, there is provided a compound of Formula (II) or pharmaceutically acceptable salt thereof: (II) wherein R is methyl; R is C -C alkyl that is saturated, or unsaturated, and that is optionally 1 5 substituted with: -H, -Cl, -F, -OH, -NH , oxo-, -N(CH CH ) , phenyl, cyclohexyl, phenyltriazolyl, 2 2 3 2 cyclohexyltriazolyl, pyridinyl, pyrrolidinyl, morpholinyl optionally substituted with methyl or hydroxymethyl, -O-, substituted with: C -C alkyl, methylphenyl, methylcyclohexyl, pyridinyl, diazinyl, or phenyl optionally substituted with –F or methyl, -NH-, substituted with: C -C alkyl that is linear, branched, or cyclic, saturated or unsaturated, and optionally substituted with oxo-, phenyl, methyl, or –OH, pyridinyl optionally substituted with methyl, methoxy, phenyl, or amino, diazinyl optionally substituted with ethyl, benzoimidazolyl, methylphenyl, phenylpyrazolyl, naphthyridyl, phenyl optionally substituted with –F, methyl, ethyl, or ethoxy, imidazolidinyl optionally substituted with methyl or R is , wherein n is 1-3, and wherein the cyclic amine is optionally substituted with C -C alkyl optionally substituted with -OH, -F, phenyl, -NH , cyclohexyl, -N(CH ) , -C(O)NH , 2 3 2 2 methylsulfonamidyl, benzenesulfonamidyl, methylbenzenesulfonamidyl, or (26914509_1):AXG pyrrolidinyl optionally substituted with methyl or hydroxyl, or -NHC(O)R , wherein R is C -C alkyl, phenyl, pyridinyl, fluorophenyl, methylsulfonyl, fluorobenzenesulfonyl, dimethyl pyrazole sulfonyl, or pyrazolyl optionally substituted with methyl; piperidinyl optionally substituted with –C(O)CH , -C(O)CH CH , methyl, oxo-, 3 2 3 C(O)Ph, -NH , -NH-C(O)CH , or , piperazinyl optionally substituted with –C(O)OC(CH ) , methyl, -C(O)CH , -C(O)Ph, C(O)CH(CH ) , -C(O)CH , or methylsulfonyl; or 3 3 2 3 R is , where n is 1 or 2, and wherein the cyclic diamine is optionally substituted on at least one carbon atom with methyl, oxo-, -N(CH ) , amino, -CH CH , or 3 2 2 3 piperidinyl optionally substituted with methyl, -C(O)CH , -C(O)CH(CH ) , -C(O)Ph, or –C(O)OC(CH ) , and 3 3 2 3 3 wherein R is –H, phenyl, -C(O)CH , C -C alkyl, -C(O)NH , or –C(O)Ph; and 7 3 1 3 2 R is methoxy or cyano. [0006c] In a third aspect of the invention, there is provided a compound or pharmaceutically acceptable salt thereof, wherein said compound or salt is selected from the group consisting of 5-(3-methyl((4-methylpiperazinyl)methyl)phenyl)quinoline- 8-carbonitrile, 5-(3-(chloromethyl)methylphenyl)quinolinecarbonitrile, 5-((2S,6R)- 2-([1,4'-bipiperidin]-1'-ylmethyl)methylmorpholino)quinolinecarbonitrile 5- ((2R,7R)(hydroxymethyl)methyl-1,4-oxazepanyl)quinolinecarbonitrile, 5- ((2S,7R)-2([1,4’-bipiperidin]-1’-ylmethyl)methyl-1,4-oxazepanyl)quinoline carbonitrile, 5-((2R,6S)-2,6-diethylmorpholino)quinolinecarbonitrile, 5-((2S,6R) (((1,8-naphthyridinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; (2R,6S)(8-chloro-1,7-naphthyridinyl)-2,6-dimethylmorpholine, and 5-((2R,6R) (26914509_1):AXG ((benzyloxy)methylethylmorpholino)quinolinecarbonitrile; or a pharmaceutically acceptable salt thereof. [0006d] In a fourth aspect of the invention, there is provided a compound of Formula (III) or pharmaceutically acceptable salt thereof: (III) wherein R is H or methyl; R is H or, when both R and R are H, is methyl-1,4’-bipiperidinyl; 11 9 R is –H or is –CH - substituted by 1,4’-bipiperidinyl, oxo-, hydroxyl, methylpyridinyl, or piperidinyl optionally substituted with hydroxyl, -N(CH ) , or piperidinyl. [0006e] In a fifth aspect of the invention, there is provided a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt of the first to fourth aspects of the invention and at least one pharmaceutically acceptable carrier. [0006f] In a sixth aspect of the invention, there is provided use of a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt of the first to fourth aspects of the invention for the manufacture of a medicament for treating lupus in a subject in need thereof. [0006g] In an seventh aspect of the invention, there is provided use of a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt of the first to fourth aspects of the invention for the manufacture of a medicament for antagonizing TLR7. [0006h] In a eighth aspect of the invention, there is provided use of a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt of the first to fourth aspects of the invention for the manufacture of a medicament for antagonizing TLR8. (26914509_1):AXG Embodiments of the disclosure provide compounds and methods of use for preventing or treating diseases or conditions characterized by Toll-like receptor 7 or 8 activation in patients. One embodiment features a compound of formula (I): (26914509_1):AXG is -H, methyl, or ethyl, and the other is wherein at least one ofR1 and R -H; or the other is C1-C6 alkyl that is optionally substituted with: -OH, methoxy, ethoxy, -OCH(CH3)2, -O(CH ) CH , phenyl, franyl, - 2 2 3 O(CH ) 0H, phenoxy, methylthio, -F, -N(CH3) , cyano, pyridinyloxy, 2 2 2 fluorophenoxy, isochromanyl, phenol, benzylamino, -NHCH , oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected fom O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fuoro, methylamino, or trifuoromethyl; or the other is C3-C cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from 0, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifuoromethyl; or R and R , together with the nitrogen atom to which they are attached, form an 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a fur to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, ( ethylamino )methyl, ( dimethylamino )methyl, dimethylamino, (methylamino )methyl, and amino; and wherein R3 is -H or methyl.
In a further embodiment the compound is a compound of Formula (I), having the stereochemistry set fmih in one of Formula (Ia), (lb), (le), or (Id), having the same substituent options as set fo1ih above fr Formula (Ia): A frther embodiment provides a compound of Formula (le) (relative stereochemistry indicated): (Ie) In a frther embodiment the compound is a compound of Formula (II): (II) wherein � is -H or methyl; R is C1-C alkyl that is saturated, paiiially saturated, or unsaturated, and that is optionally substituted with: -H, -Cl, -F, -OH, -NH , oxo-, -N(CH CH ) , phenyl, cyclohexyl, phenyltriazolyl, 2 2 3 2 cyclohexyltriazolyl, pyridinyl, pyITolidinyl, morpholinyl optionally substituted with methyl or hydroxymethyl, , substituted with: C -C alkyl, methylphenyl, methylcyclohexyl, pyridinyl, diazinyl, or phenyl optionally substituted with -F or methyl, -NH-, substituted with: C -C alkyl that is linear, branched, or cyclic, saturated or unsaturated, and optionally substituted with oxo-, phenyl, methyl, or -OH, pyridinyl optionally substituted with methyl, methoxy, phenyl, or amino, diazinyl optionally substituted with ethyl, Scheme 19 ERHCI ERHCI ER-895194 or 38: To a stirred solution of 13 (231.0 g, 815.3 mmol) in DCM (3.93 L) at 0 – 5 C was added iodobenzene diacetate (525 g, 1630.6 mmol) while maintaining the temperature at < 5 C. TEMPO (25.4 g, 162.8 mmol) was added followed by water (151 mL) after which time the resulting reaction mixture was warmed to 10 C, stirred for 30 minutes and then allowed to warm to rt and stirred for 15 h. The completed reaction was cooled to < 15 C and quenched by the slow addition of 1.34 L of a 10 % (w/v) solution of sodium thiosulfate in water while maintaining the reaction temperature ≤ 15 C followed by additional stirring at rt for 45 min. The pH of the quenched reaction was adjusted to pH 9 by the slow addition of 1M sodium hydroxide in water while maintaining the temperature at ≤ 25 C. The stirring layers were separated and the organic layer was washed with water (560 mL). 1-Butanol (2.31 L) was added to the combined aqueous layers after which time the mixture was cooled to 10 – 15 C followed by the slow addition of 5 M sulfuric acid (231 mL) maintaining the temperature at ≤ 25 C to obtain an approximate pH 5. The resultant layers were separated and the aqueous layer was extracted 3 times with 1-butanol (2.31 L) while maintaining the pH of the aqueous layer approximately pH 5 between extractions. The combined aqueous layers were concentrated while warming to 50 – 55 C after which time the resultant yellow solid-slurry was concentrated via azeotroping three times with n-heptane (11269998_1):KZA (693 mL each) to a volume of 1.5 L followed by the addition of DCM (2.31 L). The yellow solid suspension was stirred at rt for 1 h followed by filtration, washing the filter pad two times with DCM (462 mL). The collected yellow cake was dried under vacuum) overnight at 40 C followed by suspending in toluene (1.16 L) and concentrated to complete dryness at 45 C in vacuo to provide 38 or ER-895194 (187 g, 629 mmol, 77% yield) as a yellow solid.
To a stirred solution of 38 (300 mg, 1.01 mmol) in DCM (2 mL) was added the mixture of (3S,4R)-tert-butyl 3-aminofluoropyrrolidinecarboxylate and (3R,4S)- tert-butyl 3-aminofluoropyrrolidinecarboxylate, 77 (205.3 mg, 1.005 mmol mmol), HBTU (247 mg, 1.211 mmol) and DIEA (0.70 mL, 4.04 mmol) followed by stirring at rt for 16 h. The was found complete and concentrated to dryness followed by dissolving in EtOAc (20 mL), washed 1 time with water (10 mL), 2 N citric acid in water (10 mL), saturated NaHCO (10 mL), and brine (10 mL). The combined aqueous layers were extracted 3 times with EtOAc (10 mL ea.) after which time the combined organic fractions were dried over MgSO4, filtered and concentrated to dry. The crude product was purified over a 25 g Biotage silica gel column eluting with 0-10% MeOH in DCM (200 mL total) to provide the diastereomeric mixture of 78 and 79. 78 and 79 were separated using Chiral Technologies’ 5 uM Chiralpak IA column of appropriate size eluting with a Heptane:EtOH:MeOH:DEA (70:15:15:0.1) solvent system. Obtained after concentration and bringing to a dry solid via house vacuum: 78 (95 mg, 0.196 mmol, 19.5 % yield) as the first eluted fraction; and 79 (75 mg, 0.155 mmol, 15.4% yield) as the second eluted fraction. 78 (95 mg, 0.196 mmol) was dissolved with stirring in dioxane (17 uL) followed by a dropwise addition of 4 N HCl in dioxane (0.49 mL 1.97 mmol, 10 equivalents) over a 3-minute period at rt. The reaction was stirred for an additional 4 h after which time the completed reaction was concentrated and azeotroped 3 times using toluene (10 mL each) to dryness and then high vacuumed dried to obtain ERHCl (69 mg, 0.164 mmol, 84% yield) as the HCl salt that did not require further purification.
Indirect determination of the absolute stereochemistry of ER-899742 Scheme 20 (13886486_1):MXC ER-899836: A stirred solution of ER-899477 (76 mg, .191 mmol) in solution of 37 % formaldehyde in water (0.5 g, 16.652 mmol) and formic acid (0.5 ml, 13.036 mmol) was warmed to 80 °C for 3 h after which time the completed reaction is cooled to rt. The mixture was azeotroped to dryness four times with toluene (2 mL each) and the resultant (11269998_1):KZA

Claims (20)

Claims:
1. A compound of formula (I) or pharmaceutically acceptable salt thereof: wherein at least one of R and R is –H, methyl, or ethyl, and the other is 5 -H; or the other is C -C alkyl that is optionally substituted with: –OH, methoxy, ethoxy, -OCH(CH ) , -O(CH ) CH , phenyl, 3 2 2 2 3 furanyl, -O(CH2)2OH, phenoxy, methylthio, -F, -N(CH3)2, cyano, pyridinyloxy, fluorophenoxy, isochromanyl, phenol, 10 benzylamino, -NHCH , oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected from O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fluoro, methylamino, or trifluoromethyl; or the other is 15 C -C cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from O, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifluoromethyl; or R1 and R2, together with the nitrogen atom to which they are attached, form an 20 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a four to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, (ethylamino)methyl, (dimethylamino)methyl, dimethylamino, (methylamino)methyl, and amino; and wherein R is –H or methyl. (26914509_1):AXG
2. The compound or pharmaceutically acceptable salt of claim 1, wherein said compound or salt has a stereochemical configuration selected from one of those shown in the group consisting of Formula (Ia), Formula (Ib), Formula (Ic), and Formula (Id): (Ia) 5 (Ib) (Ic) (Id). (26914509_1):AXG
3. The compound or pharmaceutically acceptable salt of claim 1, wherein said compound or salt is selected from the group consisting of: (2R,6R)(8-cyanoquinolinyl)-N-ethylmethylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-isopropylmethylmorpholine 5 carboxamide; (6R)(8-cyanoquinolinyl)methylmorpholinecarboxamide; 5-((2R,6R)((S)ethylpiperazinecarbonyl)methylmorpholino)quinoline- 8-carbonitrile; (2R,6R)(8-cyanoquinolinyl)-N-(3,4-difluorobenzyl)methylmorpholine- 10 2-carboxamide; 5-((2R,6R)((S)aminopyrrolidinecarbonyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)(azetidinecarbonyl)methylmorpholino)quinoline carbonitrile; 15 5-((2R,6R)([1,4'-bipiperidine]-1'-carbonyl)methylmorpholino)quinoline carbonitrile; (2R,6R)(8-cyanoquinolinyl)-N-cyclopropylmethylmorpholine carboxamide; 5-((2R,6R)(3-aminoazetidinecarbonyl)methylmorpholino)quinoline 20 carbonitrile; (2R,6R)(8-cyanoquinolinyl)-N-(2-hydroxyethyl)methylmorpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-methoxyethyl)methylmorpholine carboxamide; 25 (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxypropyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxypropanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxypropanyl) 30 methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxybutanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxymethylbutanyl) methylmorpholinecarboxamide; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxyphenylethyl)- 6- methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxyphenylethyl) methylmorpholinecarboxamide; 5 (2R,6R)(8-cyanoquinolinyl)-N-(2-hydroxybutyl)methylmorpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-ethoxyethyl)methylmorpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxybutanyl) 10 methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(1,3-dihydroxypropanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2,3-dihydroxypropyl) methylmorpholinecarboxamide; 15 (2R,6R)(8-cyanoquinolinyl)methyl-N-(((R)-tetrahydrofuran yl)methyl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((tetrahydrofuran yl)methyl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(2-propoxyethyl)morpholine 20 carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxypentanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-isopropoxyethyl)methylmorpholine carboxamide; 25 (2R,6R)(8-cyanoquinolinyl)-N-(1-methoxybutanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-(2-fluorophenyl)hydroxyethyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxymethylbutanyl) 30 methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2,2-dimethoxyethyl)methylmorpholine- 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-(2-hydroxyethoxy)ethyl) methylmorpholinecarboxamide; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)-N-((1S,2S)hydroxycyclohexyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-hydroxycyclohexyl) methylmorpholinecarboxamide; 5 (2R,6R)(8-cyanoquinolinyl)-N-(1-hydroxyhexanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxy-3,3-dimethylbutanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxyhexanyl) 10 methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((2S,3S)hydroxymethylpentanyl)- 6-methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxymethylpentanyl) methylmorpholinecarboxamide; 15 (2R,6R)(8-cyanoquinolinyl)-N-((R)hydroxymethylpentanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((4-methylmorpholin yl)methyl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxy(methylthio)butanyl)- 20 6-methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(2-phenoxyethyl)morpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((S)hydroxyphenylpropanyl) methylmorpholinecarboxamide; 25 (2R,6R)(8-cyanoquinolinyl)methyl-N-(2-phenoxypropyl)morpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-hydroxyphenylpropyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(2-(pyridin 30 yloxy)propyl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-(4-fluorophenoxy)ethyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-(3-fluorophenyl)hydroxyethyl) methylmorpholinecarboxamide; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)-N-((S)cyclohexylhydroxypropanyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(isochromanylmethyl) methylmorpholinecarboxamide; 5 (2R,6R)(8-cyanoquinolinyl)-N-(2-hydroxyphenoxypropyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((1S,2R)hydroxy(4- hydroxyphenyl)propanyl)methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((1S)-1,3-dihydroxyphenylpropanyl)- 10 6-methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(2-hydroxy(piperazinyl)propyl) methylmorpholinecarboxamide; (2R,6R)-N-(azetidinyl)(8-cyanoquinolinyl)methylmorpholine carboxamide; 15 (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-pyrrolidinyl)morpholine- 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-pyrrolidinyl)morpholine- 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-piperidinyl)morpholine 20 carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-piperidinyl)morpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-pyrrolidin ylmethyl)morpholinecarboxamide; 25 (2R,6R)-N-(2-(benzylamino)ethyl)(8-cyanoquinolinyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(pyridinyl)morpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(6-methylpyridin 30 yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(5-methylisoxazol yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(2,2,2-trifluoroethyl)morpholine- 2-carboxamide; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)-N-(2,2-difluoroethyl)methylmorpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(3,3,3- trifluoropropyl)morpholinecarboxamide; 5 (2R,6R)(8-cyanoquinolinyl)-N-(2-(dimethylamino)methylpropyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-morpholin ylmethyl)morpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)methyl-N-(((S)methylmorpholin 10 yl)methyl)morpholinecarboxamide acetic acetate; (2R,6R)(8-cyanoquinolinyl)-N-(2-fluoroethyl)methylmorpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(3-fluoropropyl)methylmorpholine carboxamide; 15 (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-1,1,1-trifluoropropan yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-1,1,1-trifluoropropan yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(1,3-dimethyl-1H-pyrazolyl) 20 methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-methyl-1H-pyrazol yl)morpholinecarboxamide; (2R,6R)-N-(cyanomethyl)(8-cyanoquinolinyl)methylmorpholine carboxamide; 25 (2R,6R)-N-(1-cyanocyclopropyl)(8-cyanoquinolinyl)methylmorpholine- 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1,2,4-thiadiazolyl)morpholine- 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(3-methyl-1,2,4-thiadiazol 30 yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(piperidinyl)morpholine carboxamide; 5-((2R,6R)methyl(2,6-diazaspiro[3.4]octane carbonyl)morpholino)quinolinecarbonitrile hydrochloride; (26914509_1):AXG 5-((2R,6R)methyl(3-((methylamino)methyl)azetidine carbonyl)morpholino)quinolinecarbonitrile hydrochloride; (2R,6R)(8-cyanoquinolinyl)-N-((4-fluoropiperidinyl)methyl) methylmorpholinecarboxamide hydrochloride; 5 (2R,6R)-N-(azetidinylmethyl)(8-cyanoquinolinyl)methylmorpholine- 2-carboxamide hydrochloride; 5-((2R,6R)methyl(2,6-diazaspiro[3.5]nonanecarbonyl)morpholino) quinolinecarbonitrile hydrochloride; 5-((2R,6R)methyl(1,6-diazaspiro[3.4]octanecarbonyl)morpholino) 10 quinolinecarbonitrile hydrochloride; 5-((2R,6R)methyl(1,7-diazaspiro[4.4]nonanecarbonyl)morpholino) quinolinecarbonitrile hydrochloride; (2R,6R)-N-(3-carbamoylmethyl-1H-pyrazolyl)(8-cyanoquinolinyl) methylmorpholinecarboxamide; 15 (2R,6R)(8-cyanoquinolinyl)methyl-N-(oxetanylmethyl)morpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(tetrahydro-2H-pyran yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(tetrahydrofuranyl)morpholine- 20 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((3-methyloxetan yl)methyl)morpholinecarboxamide; 5-((2R,6R)methyl(2-oxaazaspiro[3.3]heptanecarbonyl)morpholino) quinolinecarbonitrile; 25 (2R,6R)(8-cyanoquinolinyl)methyl-N-(oxetanyl)morpholine carboxamide; (2R,6R)-N-((3-(aminomethyl)oxetanyl)methyl)(8-cyanoquinolinyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(oxetanylmethyl)morpholine 30 carboxamide; 5-((2R,6R)methyl(piperazinecarbonyl)morpholino)quinoline carbonitrile hydrochloride; (2R,6R)(8-cyanoquinolinyl)methyl-N-(2- (methylamino)ethyl)morpholinecarboxamide; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-3,3,3-trifluoro hydroxypropyl) morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-3,3,3-trifluoro hydroxypropyl) morpholinecarboxamide; 5 Methyl 2-((2R,6R)(8-cyanoquinolinyl)methylmorpholine carboxamido) acetate; (2R,6R)(8-cyanoquinolinyl)-N-(2-(dimethylamino)ethyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-4,4,4-trifluoro 10 hydroxybutyl) morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-4,4,4-trifluoro hydroxybutyl) morpholinecarboxamide; (2R,6R)-N-(3-amino-4,4,4-trifluorobutyl)(8-cyanoquinolinyl)methyl morpholinecarboxamide; 15 2-((2R,6R)(8-cyanoquinolinyl)methylmorpholinecarboxamido)acetic acid; 1-((2R,6R)(8-cyanoquinolinyl)methylmorpholinecarbonyl)azetidine- 3-carboxamide; 5-((2R,6R)methyl(2,7-diazaspiro[4.4]nonanecarbonyl)morpholino) 20 quinolinecarbonitrile hydrochloride; 5-((2R,6R)methyl(3,9-diazaspiro[5.5]undecanecarbonyl)morpholino) quinolinecarbonitrile hydrochloride; (2R,6R)-N-(3-carbamoylpyridinyl)(8-cyanoquinolinyl)methyl morpholinecarboxamide; 25 (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-morpholinylmethyl) morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(pyridinyl)morpholine carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(pyridinyl)morpholine 30 carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-(piperidinyl)-1H-pyrazol yl)morpholinecarboxamide hydrochloride; (2R,6R)-N-(1-(azetidinyl)-1H-pyrazolyl)(8-cyanoquinolinyl) methylmorpholinecarboxamide hydrochloride; (26914509_1):AXG (2R,6R)-N-((1H-pyrazolyl)methyl)(8-cyanoquinolinyl)methyl morpholinecarboxamide; (2R,6R)-N-((1H-pyrazolyl)methyl)(8-cyanoquinolinyl)methyl morpholinecarboxamide; 5 (2R,6R)(8-cyanoquinolinyl)methyl-N-((3-(trifluoromethyl)pyridin yl)methyl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-(pyridin yl)ethyl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(pyridinylmethyl)morpholine- 10 2-carboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((6-methylpyridinyl)methyl) morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-((1-methylpiperidinyl)methyl) morpholinecarboxamide; 15 (2R,6R)(8-cyanoquinolinyl)methyl-N-((3-methylpyridinyl)methyl) morpholinecarboxamide; (2R,6R)-N-(4-cyano-1H-pyrazolyl)(8-cyanoquinolinyl)methyl morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoromethylpyrrolidinyl)- 20 6-methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoropiperidinyl)-N,6- dimethylmorpholinecarboxamide hydrochloride; 5-((2R,6R)(3-(aminomethyl)azetidinecarbonyl)methylmorpholino) quinolinecarbonitrile; 25 5-((2R,6R)(3-((ethylamino)methyl)azetidinecarbonyl) methylmorpholino) quinolinecarbonitrile; 5-((2R,6R)(3-((dimethylamino)methyl)azetidinecarbonyl)methyl morpholino)quinolinecarbonitrile; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-methylazepan 30 yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)methyl-N-(((2R,6R)methylmorpholin yl)methyl)morpholinecarboxamide; 5-((2R,6R)methyl(octahydropyrrolo[3,4-c]pyrrolecarbonyl)morpholino) quinolinecarbonitrile; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)-pyrrolidinylmethyl) morpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)methyl-N-((S)-piperidinylmethyl) morpholinecarboxamide hydrochloride; 5 (2R,6R)-N-((1R,3R,5S)azabicyclo[3.2.1]octanyl)(8-cyanoquinolinyl)- 6-methylmorpholinecarboxamide hydrochloride; (2R,6R)-N-(azepanyl)(8-cyanoquinolinyl)methylmorpholine carboxamide hydrochloride; (2R,6R)-N-((1R,5S,6S)azabicyclo[3.1.0]hexanyl)(8-cyanoquinolinyl)- 10 6-methylmorpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)-Ndimethylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(((2S,6R)-4,6-dimethylmorpholin yl)methyl)methylmorpholinecarboxamide; 5-((2R,6R)(4-(dimethylamino)piperidinecarbonyl)methylmorpholino) 15 quinolinecarbonitrile; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-methylpiperidin yl)morpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoropyrrolidinyl)methyl morpholinecarboxamide hydrochloride; 20 (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoropiperidinyl)methyl morpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)methyl-N-(2-azaspiro[3.3]heptan yl)morpholinecarboxamide hydrochloride; (2R,6R)-N-(1-(2-aminooxoethyl)piperidinyl)(8-cyanoquinolinyl) 25 methylmorpholinecarboxamide; 5-((2R,6R)(4-aminopiperidinecarbonyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)(4-aminomethylpiperidinecarbonyl)methylmorpholino) quinolinecarbonitrile; 30 (2R,6R)(8-cyanoquinolinyl)-N,6-dimethyl-N-((R)-piperidin yl)morpholinecarboxamide hydrochloride; (2R,6R)-N-(2-carbamoylpyridinyl)(8-cyanoquinolinyl) methylmorpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)-Ndimethyl-N-((S)-piperidin 35 yl)morpholinecarboxamide hydrochloride; (26914509_1):AXG (2R,6R)(8-cyanoquinolinyl)-N-(1-ethylpiperidinyl) methylmorpholinecarboxamide; (2R,6R)(8-cyanoquinolinyl)-N-(1-ethylpiperidinyl) methylmorpholinecarboxamide; 5 (2R,6R)(8-cyanoquinolinyl)methyl-N-((R)methylpiperidin yl)morpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)methyl-N-(4-methylpiperidin yl)morpholinecarboxamide; (2R,6R)-N-(2-aminomethylpropyl)(8-cyanoquinolinyl)methyl 10 morpholinecarboxamide; rel-(2R,6R)(8-cyanoquinolinyl)-N-((3R,4S)fluoropyrrolidinyl) methylmorpholinecarboxamide hydrochloride; rel-(2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoropyrrolidinyl) methylmorpholinecarboxamide hydrochloride; 15 (2R,6R)-N-(azepanyl)(8-cyanoquinolinyl)methylmorpholine carboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-methylazepan yl)morpholinecarboxamide hydrochloride; (2R,6R)(8-cyanoquinolinyl)-N-(1,4-dimethylpiperidinyl) 20 methylmorpholinecarboxamide; and (2R,6R)(8-cyanoquinolinyl)-N-(4-fluoromethylpiperidinyl) methylmorpholinecarboxamide hydrochloride.
4. The compound or pharmaceutically acceptable salt of claim 3, wherein said compound or salt is selected from the group consisting of rel-(2R,6R)(8-cyanoquinolin- 25 5-yl)-N-((3R,4S)fluoropyrrolidinyl)methylmorpholinecarboxamide hydrochloride and (2R,6R)(8-cyanoquinolinyl)methyl-N-(1-methylpiperidin yl)morpholinecarboxamide. (26914509_1):AXG
5. A compound of claim 1 as shown below or a pharmaceutically acceptable salt thereof:
6. A compound of Formula (II) or pharmaceutically acceptable salt thereof: 5 (II) wherein R is methyl; R is C -C alkyl that is saturated, or unsaturated, and that is optionally 5 1 5 substituted with: 10 -H, -Cl, -F, -OH, -NH , oxo-, -N(CH CH ) , phenyl, cyclohexyl, phenyltriazolyl, 2 2 3 2 cyclohexyltriazolyl, pyridinyl, pyrrolidinyl, morpholinyl optionally substituted with methyl or hydroxymethyl, -O-, substituted with: C -C alkyl, methylphenyl, methylcyclohexyl, pyridinyl, diazinyl, or phenyl 15 optionally substituted with –F or methyl, -NH-, substituted with: C -C alkyl that is linear, branched, or cyclic, saturated or unsaturated, and optionally substituted with oxo-, phenyl, methyl, or –OH, pyridinyl optionally substituted with methyl, methoxy, phenyl, or amino, 20 diazinyl optionally substituted with ethyl, benzoimidazolyl, methylphenyl, phenylpyrazolyl, naphthyridyl, phenyl optionally substituted with –F, methyl, ethyl, or ethoxy, (26914509_1):AXG imidazolidinyl optionally substituted with methyl or R is , wherein n is 1-3, and wherein the cyclic amine is optionally substituted with C1-C3 alkyl optionally substituted with 5 -OH, -F, phenyl, -NH , cyclohexyl, -N(CH ) , -C(O)NH , 2 3 2 2 methylsulfonamidyl, benzenesulfonamidyl, methylbenzenesulfonamidyl, or pyrrolidinyl optionally substituted with methyl or hydroxyl, or -NHC(O)R , wherein R is C1-C5 alkyl, phenyl, pyridinyl, fluorophenyl, methylsulfonyl, 10 fluorobenzenesulfonyl, dimethyl pyrazole sulfonyl, or pyrazolyl optionally substituted with methyl; piperidinyl optionally substituted with –C(O)CH3, -C(O)CH2CH3, methyl, oxo-, C(O)Ph, -NH , -NH-C(O)CH , or , piperazinyl optionally substituted with –C(O)OC(CH ) , 15 methyl, -C(O)CH , -C(O)Ph, C(O)CH(CH ) , -C(O)CH , or methylsulfonyl; or 3 3 2 3 R is , where n is 1 or 2, and wherein the cyclic diamine is optionally substituted on at least one carbon atom with methyl, oxo-, -N(CH ) , amino, -CH CH , or 3 2 2 3 piperidinyl optionally substituted with 20 methyl, -C(O)CH , -C(O)CH(CH ) , -C(O)Ph, or –C(O)OC(CH ) , and 3 3 2 3 3 wherein R is –H, phenyl, -C(O)CH , C -C alkyl, -C(O)NH , or –C(O)Ph; and 7 3 1 3 2 R is methoxy or cyano. (26914509_1):AXG
7. The compound or pharmaceutically acceptable salt of claim 6, wherein said compound or salt is selected from the group consisting of: 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile; 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile dihydrochloride; 5 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile methanesulfonate; 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile bis(2,2,2-trifluoro- acetate); 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile bis(sulfonate); 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile sulfonate; 10 5-((2S,6R)-2,6-dimethylmorpholino)quinolinecarbonitrile 2,3-dihydroxy- succinate; 5-((2S,6R)-2,6-dimethylmorpholino)quinolinecarbonitrile dimethanesulfonate; N-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)acetamide; 15 (2R,6R)-methyl 4-(8-cyanoquinolinyl)methylmorpholinecarboxylate; N-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)pivalamide; 5-((2S,6S)-2,6-dimethylmorpholino)quinolinecarbonitrile; 5-((2S,6R)(aminomethyl)methylmorpholino)quinolinecarbonitrile; 20 5-(2-(hydroxymethyl)methylmorpholino)quinolinecarbonitrile; (2R,6S)(8-methoxyquinolinyl)-2,6-dimethylmorpholine; 5-((2R,6S)-2,6-dimethylmorpholino)quinolinecarboxamide; 5-((2R,6R)(hydroxymethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)(methoxymethyl)methylmorpholino)quinolinecarbonitrile; 25 5-((2R,6R)((benzyloxy)methyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)(fluoromethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)(ethoxymethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)(isopropoxymethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)(isobutoxymethyl)methylmorpholino)quinolinecarbonitrile; 30 5-((2R,6R)(chloromethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)((hexyloxy)methyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)((cyclohexylmethoxy)methyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6S)methylpropylmorpholino)quinolinecarbonitrile; 35 5-((2S,6S)(fluoromethyl)methylmorpholino)quinolinecarbonitrile; (26914509_1):AXG 5-((2S,6S)(chloromethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)((2,6-dimethylphenoxy)methyl)methylmorpholino)quinoline carbonitrile; 5 5-((2R,6S)methylpentylmorpholino)quinolinecarbonitrile; 5-((2R,6R)formylmethylmorpholino)quinolinecarbonitrile; N-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl) phenylpropanamide; 5-((2R,6R)(1-hydroxyallyl)methylmorpholino)quinolinecarbonitrile; 10 5-((2R,6R)((S)hydroxyallyl)methylmorpholino)quinolinecarbonitrile; N-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl) phenylcyclobutanecarboxamide; 5-((2R,6R)((R)hydroxyallyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(pyrrolidinylmethyl)morpholino)quinoline 15 carbonitrile; 5-((2S,6R)((diethylamino)methyl)methylmorpholino)quinoline carbonitrile; 5-((2S,6R)((benzylamino)methyl)methylmorpholino)quinoline carbonitrile; 20 5-((2R,6R)methyl(phenoxymethyl)morpholino)quinolinecarbonitrile; 5-((2R,6R)methyl((m-tolyloxy)methyl)morpholino)quinoline carbonitrile; 5-((2R,6R)methyl((p-tolyloxy)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6R)(1-hydroxypropyl)methylmorpholino)quinolinecarbonitrile; 25 5-((2R,6R)((R)hydroxypentyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)((S)hydroxypentyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)((R)-cyclohexyl(hydroxy)methyl)methylmorpholino)quinoline- 30 8-carbonitrile; 5-((2R,6R)((S)-cyclohexyl(hydroxy)methyl)methylmorpholino)quinoline- 8-carbonitrile; N-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl) phenylacetamide; (26914509_1):AXG 5-((2R,6R)((R)hydroxyphenylethyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)((S)hydroxyphenylethyl)methylmorpholino)quinoline carbonitrile; 5 5-((2R,6R)((R)hydroxyphenylpropyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)((S)hydroxyphenylpropyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6S)methyl((phenylamino)methyl)morpholino)quinoline 10 carbonitrile; 5-((2R,6S)methyl((m-tolylamino)methyl)morpholino)quinoline carbonitrile; 5-((2R,6S)methyl((o-tolylamino)methyl)morpholino)quinoline carbonitrile; 15 5-((2R,6S)methyl((p-tolylamino)methyl)morpholino)quinoline carbonitrile; 5-((2R,6R)((3,4-difluorophenoxy)methyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)((3-fluorophenoxy)methyl)methylmorpholino)quinoline 20 carbonitrile; 5-((2S,6R)(((1,2-dimethyl-1H-benzo[d]imidazolyl)amino)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)(((1-ethylmethyl-1H-benzo[d]imidazolyl)amino)methyl) methylmorpholino)quinolinecarbonitrile; 25 5-((2S,6R)((cyclohexylamino)methyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)((2-fluorophenoxy)methyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)methylpropionylmorpholino)quinolinecarbonitrile; 30 5-((2R,6R)(cyclohexanecarbonyl)methylmorpholino)quinoline carbonitrile; 5-((2R,6R)methyl(3-phenylpropanoyl)morpholino)quinolinecarbonitrile; 5-((2R,6R)methyl((o-tolyloxy)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((pyrimidinylamino)methyl)morpholino)quinoline 35 carbonitrile; (26914509_1):AXG 5-((2R,6S)methyl((pyridinylamino)methyl)morpholino)quinoline carbonitrile; 5-((2R,6S)methyl(((6-methylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5 5-((2R,6S)methyl(((5-methylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2S,6R)(((R)(hydroxymethyl)pyrrolidinyl)methyl) methylmorpholino) quinolinecarbonitrile; 5-((2R,6R)((2,2-dimethylpyrrolidinyl)methyl) 10 methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)((2-isopropylpyrrolidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(((S)methylpyrrolidin yl)methyl)morpholino)quinolinecarbonitrile; 15 5-((2R,6S)methyl(((S)phenylpyrrolidin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(((R)methylpyrrolidin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2S,6R)(((S)hydroxypyrrolidinyl)methyl)methylmorpholino) 20 quinolinecarbonitrile; 5-((2R,6S)methyl(((4-methylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((3-phenylpyrrolidinyl)methyl)morpholino)quinoline- 8-carbonitrile; 25 5-((2S,6R)(((6-methoxypyridinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((R)methylpyrrolidin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2S,6R)((2,5-dimethylpyrrolidinyl)methyl) 30 methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)(((4-methoxypyridinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((6-methoxypyridinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; (26914509_1):AXG 5-((2R,6S)methyl(((1-phenyl-1H-pyrazolyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2S,6R)(((S)(hydroxymethyl)pyrrolidinyl)methyl) methylmorpholino) quinolinecarbonitrile; 5 5-((2S,6R)(((R)hydroxypyrrolidinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((S)methylpyrrolidin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2S,6R)((3,3-dimethylpyrrolidinyl)methyl) 10 methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)methyl((R)phenyl(pyrrolidinyl)propyl)morpholino) quinolinecarbonitrile; 5-((2R,6R)methyl((S)phenyl(pyrrolidinyl)propyl)morpholino) quinolinecarbonitrile; 15 5-((2S,6R)(((3-methoxypyridinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((R)hydroxypiperidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)(((2R,6S)-2,6-dimethylpiperidinyl)methyl)methylmorpholino) 20 quinolinecarbonitrile; 5-((2S,6R)(((S)hydroxypiperidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)((4-hydroxypiperidinyl)methyl)methylmorpholino)quinoline- 8-carbonitrile; 25 5-((2S,6R)((2-(hydroxymethyl)piperidinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((2-methylpiperidinyl)methyl)morpholino)quinoline carbonitrile; 5-((2S,6R)((2-ethylpiperidinyl)methyl)methylmorpholino)quinoline 30 carbonitrile; 5-((2S,6R)((2,3-dimethylpiperazinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((pyridinylamino)methyl)morpholino)quinoline carbonitrile; (26914509_1):AXG 5-((2R,6S)methyl((pyridinylamino)methyl)morpholino)quinoline carbonitrile; 5-((2R,6S)methyl(((S)(trifluoromethyl)pyrrolidin yl)methyl)morpholino) quinolinecarbonitrile; 5 5-((2R,6S)methyl((4-methylpiperidinyl)methyl)morpholino)quinoline carbonitrile; 5-((2S,6R)((4,4-difluoropiperidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((4-phenylpiperidinyl)methyl)morpholino)quinoline 10 carbonitrile; 5-((2S,6R)((4-fluoropiperidinyl)methyl)methylmorpholino)quinoline carbonitrile; 5-((2S,6R)((cyclopentylamino)methyl)methylmorpholino)quinoline carbonitrile; 15 5-((2R,6S)methyl(((3- methylcyclohexyl)amino)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(((3-methylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6R)ethyl(hydroxymethyl)morpholino)quinolinecarbonitrile; 20 5-((2R,6S)methyl(((4-phenylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(piperazinylmethyl)morpholino)quinoline carbonitrile; 5-((2R,6S)methyl((4-phenylpiperazinyl)methyl)morpholino)quinoline 25 carbonitrile; 5-((2S,6R)(((6-aminopyridinyl)amino)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)((2,5-dimethylpiperazinyl)methyl) methylmorpholino)quinolinecarbonitrile; 30 5-((2S,6R)((4-acetylpiperazinyl)methyl)methylmorpholino)quinoline carbonitrile; 5-((2S,6R)(((2S,4R)hydroxy(hydroxymethyl)pyrrolidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(((R)methylpiperazin 35 yl)methyl)morpholino)quinolinecarbonitrile; (26914509_1):AXG 5-((2R,6S)methyl(((R)methylpiperazin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(((S)methylpiperazin yl)methyl)morpholino)quinolinecarbonitrile; 5 5-((2S,6R)(((2R,5R)-2,5-dimethylpiperazinyl)methyl) methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((2R,5S)-2,5-dimethylpiperazinyl)methyl) methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((4- 10 methylcyclohexyl)amino)methyl)morpholino)quinolinecarbonitrile; 5-((2S,6R)((cyclobutylamino)methyl)methylmorpholino)quinoline carbonitrile; 5-((2S,6R)((cycloheptylamino)methyl)methylmorpholino)quinoline carbonitrile; 15 5-((2S,6R)(((4-hydroxycyclohexyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((2-hydroxycyclopentyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((2- 20 methylcyclohexyl)amino)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl(((5-phenylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((3-phenylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 25 5-((2S,6R)((((1S,3R)hydroxycyclopentyl)amino)methyl)methyl- morpholino)quinolinecarbonitrile; 5-((2S,6R)(((3-ethoxypyridinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((2-phenylpyridinyl)amino)methyl)morpholino) 30 quinolinecarbonitrile; 5-((2R,6S)methyl(((6-phenylpyridinyl)amino)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((2-methyloxopiperazinyl)methyl)morpholino) quinolinecarbonitrile; (26914509_1):AXG 5-((2R,6S)methyl((4-methylpiperazinyl)methyl)morpholino)quinoline- 8-carbonitrile; 5-((2R,6S)methyl((4-propylpiperazinyl)methyl)morpholino)quinoline carbonitrile; 5 5-((2S,6R)((4-(dimethylamino)piperidinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)([1,4'-bipiperidin]-1'-ylmethyl)methylmorpholino)quinoline carbonitrile; 5-((2S,6R)([1,4'-bipiperidin]-1'-ylmethyl)methylmorpholino)quinoline 10 carbonitrile dihydrochloride; 5-((2S,6R)(((R)aminopiperidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)((4-aminopiperidinyl)methyl)methylmorpholino)quinoline carbonitrile; 15 5-((2S,6R)(((5-fluoropyrimidinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(piperidinylmethyl)morpholino)quinoline carbonitrile; 5-((2R,6S)methyl(morpholinomethyl)morpholino)quinolinecarbonitrile; 20 5-((2S,6R)(((2S,6R)-2,6-dimethylmorpholino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((2R,6R)(hydroxymethyl)methylmorpholino)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((4-(pyridinyl)piperazinyl)methyl)morpholino) 25 quinolinecarbonitrile; 5-((2R,6S)methyl((4-(pyridinyl)piperazinyl)methyl)morpholino) quinolinecarbonitrile; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)acetamide; 30 N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)acetamide hydrochloride; 1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinecarboxamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin 35 yl)methyl)piperidinyl)benzamide; (26914509_1):AXG 5-((2S,6R)((4-isopropylpiperazinyl)methyl) methylmorpholino)quinolinecarbonitrile; 4-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperazinecarboxamide; 5 5-((2S,6R)((4-cyclohexylpiperidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((4-(pyrrolidinyl)piperidinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6R)((4-cyclohexyl-1H-1,2,3-triazolyl)methyl)methylmorpholino) 10 quinolinecarbonitrile; 5-((2R,6R)methyl((4-phenyl-1H-1,2,3-triazolyl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((2-oxo-[1,4'-bipiperidin]-1'- yl)methyl)morpholino)quinolinecarbonitrile; 15 5-((2S,6R)(((5-ethylpyrimidinyl)amino)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((6-amino-3,5-dimethylpyridinyl)amino)methyl)methyl- morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((pyrazinylamino)methyl)morpholino)quinoline 20 carbonitrile; 5-((2S,6R)(((1,3-dimethyl-1H-pyrazolyl)amino)methyl) methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)((4-ethylpiperazinyl)methyl)methylmorpholino)quinoline carbonitrile; 25 5-((2R,6S)methyl((3-(pyrrolidinyl)azetidinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((3-(piperidinyl)azetidinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2S,6R)(((R)-2,4-dimethylpiperazinyl)methyl)methylmorpholino) 30 quinolinecarbonitrile; 5-((2S,6R)((4-(hydroxymethyl)piperidinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)((R)-[1,3'-bipyrrolidin]-1'-ylmethyl) methylmorpholino)quinolinecarbonitrile; (26914509_1):AXG 5-((2R,6S)methyl(((R)(piperidinyl)pyrrolidin yl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((4-methyl-1,4-diazepan yl)methyl)morpholino)quinolinecarbonitrile; 5 5-((2S,6R)((4-benzoylpiperazinyl)methyl)methylmorpholino)quinoline- 8-carbonitrile; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)nicotinamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin 10 yl)methyl)piperidinyl)isonicotinamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)picolinamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)hexanamide; 15 N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)isobutyramide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)isobutyramide hydrochloride; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin 20 yl)methyl)piperidinyl)pivalamide; 5-((2R,6S)methyl((4-morpholinopiperidin yl)methyl)morpholino)quinolinecarbonitrile; tert-butyl 4-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl) piperidinyl)piperazinecarboxylate; 25 tert-butyl 4-(4-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl) piperazinyl)piperidinecarboxylate; 5-((2R,6S)methyl((4-(piperazinyl)piperidinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((4-(piperidinyl)piperazinyl)methyl)morpholino) 30 quinolinecarbonitrile; 5-((2R,6S)methyl((3-(4-methylpiperazinyl)azetidinyl)methyl) morpholino)quinolinecarbonitrile; 5-((2S,6R)([4,4'-bipiperidin]ylmethyl)methylmorpholino)quinoline carbonitrile; (26914509_1):AXG 5-((2S,6R)((1'-acetyl-[4,4'-bipiperidin]yl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((1'-methyl-[4,4'-bipiperidin]yl)methyl)morpholino) quinolinecarbonitrile; 5 5-((2R,6S)methyl((3-(piperazinyl)azetidinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2S,6R)((3-(4-acetylpiperazinyl)azetidinyl)methyl)methyl- morpholino)quinolinecarbonitrile; 5-((2S,6R)((1'-isobutyryl-[4,4'-bipiperidin]yl)methyl)methylmorpholino) 10 quinolinecarbonitrile; 5-((2S,6R)((3-(4-benzoylpiperazinyl)azetidinyl)methyl) methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)((1'-benzoyl-[4,4'-bipiperidin]yl)methyl)methylmorpholino) quinolinecarbonitrile; 15 5-((2R,6S)methyl((4-(1-methylpiperidinyl)piperazinyl)methyl)- morpholino)quinolinecarbonitrile; 5-((2S,6R)((4-(1-acetylpiperidinyl)piperazinyl)methyl)methyl- morpholino)quinolinecarbonitrile; 5-((2S,6R)((4-(1-isobutyrylpiperidinyl)piperazinyl)methyl)methyl- 20 morpholino)quinolinecarbonitrile; 5-((2S,6R)((4-(1-benzoylpiperidinyl)piperazinyl)methyl)methyl- morpholino)quinolinecarbonitrile; 5-((2S,6R)((3-(4-isobutyrylpiperazinyl)azetidinyl)methyl)methyl- morpholino)quinolinecarbonitrile; 25 5-((2S,6R)((4-(4-acetylpiperazinyl)piperidinyl)methyl)methyl- morpholino)quinolinecarbonitrile; 5-((2S,6R)((4-(4-isobutyrylpiperazinyl)piperidinyl)methyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)((4-(4-benzoylpiperazinyl)piperidinyl)methyl)methyl- 30 morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((4-(4-methylpiperazinyl)piperidinyl)methyl)- morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((4-(4-methylpiperazinyl)piperidinyl)methyl)- morpholino)quinolinecarbonitrile trihydrochloride; (26914509_1):AXG 5-((2S,6R)([1,4'-bipiperidin]-1'-ylmethyl)methylmorpholino)methyl- quinolinecarbonitrile; N-((R)(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- pyrrolidinyl)acetamide; 5 N-((R)(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- pyrrolidinyl)isobutyramide; 5-((2R,6S)methyl(((S)(piperidinyl)pyrrolidin yl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((S)(piperidinyl)pyrrolidin 10 yl)methyl)morpholino)-quinolinecarbonitrile dihydrochloride; 5-((2R,6S)methyl((3-morpholinoazetidin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2R,6S)methyl((3-((S)methylpyrrolidinyl)azetidinyl)methyl)- morpholino)quinolinecarbonitrile; 15 5-((2R,6S)methyl(((S)methylpiperazin yl)methyl)morpholino)quinolinecarbonitrile; 5-((2S,6R)(((S)-2,4-dimethylpiperazinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((R)-3,4-dimethylpiperazinyl)methyl)methylmorpholino) 20 quinolinecarbonitrile; 5-((2S,6R)(((S)-3,4-dimethylpiperazinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)(((S)ethylpiperazinyl)methyl)methylmorpholino)quinoline- 8-carbonitrile; 25 5-((2S,6R)(((S)ethylpiperazinyl)methyl)methylmorpholino)quinoline- 8-carbonitrile dihydrochloride; 5-((2S,6R)(((S)ethylmethylpiperazinyl)methyl)methylmorpholino) quinolinecarbonitrile; 5-((2S,6R)((4-(azepanyl)piperidinyl)methyl)methylmorpholino) 30 quinolinecarbonitrile; 5-((2S,6R)((S)-[1,3'-bipyrrolidin]-1'-ylmethyl) methylmorpholino)quinolinecarbonitrile; 5-((2S,6R)((3-(4-aminopiperidinyl)azetidinyl)methyl) methylmorpholino) quinolinecarbonitrile; (26914509_1):AXG N-(1-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- azetidinyl)piperidinyl)acetamide; 5-((2R,6S)methyl((3-(4-(methylsulfonyl)piperazinyl)azetidin yl)methyl)-morpholino)quinolinecarbonitrile; 5 5-((2S,6R)((3-((S)hydroxypyrrolidinyl)azetidinyl)methyl)methyl- morpholino)quinolinecarbonitrile; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)-1,3-dimethyl-1H-pyrazolecarboxamide; N-(1-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- 10 azetidinyl)piperidinyl)-1,3-dimethyl-1H-pyrazolecarboxamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)methanesulfonamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)benzenesulfonamide; 15 N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)piperidinyl)fluorobenzenesulfonamide; 5-((2S,6R)((3-aminoazetidinyl)methyl)methylmorpholino)quinoline carbonitrile; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin 20 yl)methyl)azetidinyl)acetamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)azetidinyl)fluorobenzamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)azetidinyl)methanesulfonamide; 25 N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)azetidinyl)fluorobenzenesulfonamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)azetidinyl)-1,3-dimethyl-1H-pyrazolesulfonamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin 30 yl)methyl)piperidinyl)-1,3-dimethyl-1H-pyrazolesulfonamide; N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)azetidinyl)isobutyramide; 5-((2R,6S)methyl(((S)methyloxopiperazinyl)methyl)morpholino) quinolinecarbonitrile; (26914509_1):AXG 5-((2R,6S)methyl(((R)methyloxopiperazinyl) methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl(((R)methyloxopiperazinyl)methyl)morpholino) quinolinecarbonitrile; 5 5-((2R,6S)methyl(((S)methyloxopiperazinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((2,4,5-trimethylpiperazinyl)methyl)morpholino) quinolinecarbonitrile; 5-((2R,6S)methyl((2,3,4-trimethylpiperazinyl)methyl)morpholino) 10 quinolinecarbonitrile; N-((R)(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)pyrrolidinyl)benzamide; 5-((2S,6R)(((R)(dimethylamino)pyrrolidinyl)methyl) methylmorpholino) quinolinecarbonitrile; 15 N-((S)(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- pyrrolidinyl)acetamide; N-((S)(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- pyrrolidinyl)isobutyramide; N-((S)(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)- 20 pyrrolidinyl)benzamide; 5-((2S,6R)(((S)(dimethylamino)pyrrolidinyl)methyl) methylmorpholino) quinolinecarbonitrile; 5-((2R,6R)methyl((pyrazinyloxy)methyl)morpholino)quinoline carbonitrile; 25 N-(1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholin yl)methyl)azetidinyl)benzamide; 5-((2S,6R)((3,3-dimethylpiperazinyl)methyl) methylmorpholino)quinolinecarbonitrile dihydrochloride; 5-((2R,6S)methyl((3,3,4-trimethylpiperazinyl)methyl)morpholino) 30 quinolinecarbonitrile dihydrochloride; 5-((2R,6R)((R)hydroxyethyl)methylmorpholino)quinoline carbonitrile; 1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)-N- ethylpiperidinecarboxamide; (26914509_1):AXG 1-(((2S,6R)(8-cyanoquinolinyl)methylmorpholinyl)methyl)-N- ethylpiperidinecarboxamide hydrochloride; 5-((2R,6R)((S)hydroxyethyl)methylmorpholino)quinolinecarbonitrile; 5-((2R,6R)methyl((pyridinyloxy)methyl)morpholino)quinoline 5 carbonitrile; 5-((2R,6R)methyl((pyrimidinyloxy)methyl)morpholino)quinoline carbonitrile; 5-((2R,6R)methyl((R)(pyrimidinyloxy)ethyl)morpholino)quinoline carbonitrile; 10 5-((2R,6R)methyl((S)(pyrimidinyloxy)ethyl)morpholino)quinoline carbonitrile; and 5-((2R,6R)((S)-hydroxy(pyridinyl)methyl)methylmorpholino)quinoline- 8-carbonitrile.
8. A compound or pharmaceutically acceptable salt thereof, wherein said 15 compound or salt is selected from the group consisting of 5-(3-methyl((4- methylpiperazinyl)methyl)phenyl)quinolinecarbonitrile, 5-(3-(chloromethyl) methylphenyl)quinolinecarbonitrile, 5-((2S,6R)([1,4'-bipiperidin]-1'-ylmethyl) methylmorpholino)quinolinecarbonitrile, 5-((2R,7R)(hydroxymethyl)methyl-1,4- oxazepanyl)quinolinecarbonitrile, 5-((2S,7R)-2([1,4’-bipiperidin]-1’-ylmethyl) 20 methyl-1,4-oxazepanyl)quinolinecarbonitrile, 5-((2R,6S)-2,6- diethylmorpholino)quinolinecarbonitrile, 5-((2S,6R)(((1,8-naphthyridin yl)amino)methyl)methylmorpholino) quinolinecarbonitrile, (2R,6S)(8-chloro-1,7- naphthyridinyl)-2,6-dimethylmorpholine, and 5-((2R,6R)((benzyloxy)methyl ethylmorpholino)quinolinecarbonitrile, or a pharmaceutically acceptable salt thereof. 25
9. A compound of Formula (III) or pharmaceutically acceptable salt thereof: (III) wherein R is H or methyl; (26914509_1):AXG R is H or, when both R and R are H, is methyl-1, 4’-bipiperidinyl; 10 11 9 R is –H or is –CH - substituted by 1,4’-bipiperidinyl, oxo-, hydroxyl, methylpyridinyl, or piperidinyl optionally substituted with hydroxyl, -N(CH ) , or piperidinyl. 5 10. The compound or pharmaceutically acceptable salt of claim 9, wherein said compound or salt is selected from the group consisting of: 5-(3-([1,4'-bipiperidin]-1'-ylmethyl)phenyl)quinolinecarbonitrile; 5-(4-([1,4'-bipiperidin]-1'-ylmethyl)phenyl)quinolinecarbonitrile; 5-(3-formylmethylphenyl)quinolinecarbonitrile;
10.5-(3-(hydroxymethyl)methylphenyl)quinolinecarbonitrile; 5-(3-((4-hydroxypiperidinyl)methyl)methylphenyl)quinoline carbonitrile; 5-(3-((4-(dimethylamino)piperidinyl)methyl)methylphenyl)quinoline carbonitrile; and 15 5-(3-([1,4'-bipiperidin]-1'-ylmethyl)methylphenyl)quinolinecarbonitrile.
11. A pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt of any one of claims 1-10 and at least one pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11, wherein the at least one compound 20 or pharmaceutically acceptable salt is the compound or pharmaceutically acceptable salt of claim 5.
13. The pharmaceutical composition of claim 11 or claim 12, wherein the at least one pharmaceutically acceptable salt is (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R) fluoropyrrolidinyl)methylmorpholinecarboxamide hydrochloride. 25
14. A pharmaceutically acceptable salt of claim 5, wherein the pharmaceutically acceptable salt is (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoropyrrolidinyl)- 6-methylmorpholinecarboxamide hydrochloride.
15. Use of a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1 to 10 for the manufacture of a medicament for 30 treating lupus in a subject in need thereof. (26914509_1):AXG
16. The use of claim 15, wherein the lupus is systemic lupus erythematosus, cutaneous lupus, or neuropsychiatric lupus.
17. Use of a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1 to 10 for the manufacture of a medicament for 5 antagonizing TLR7.
18. Use of a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1 to 10 for the manufacture of a medicament for antagonizing TLR8.
19. The use of any one of claims 15 to 18, wherein said compound or 10 pharmaceutically acceptable salt is the compound or pharmaceutically acceptable salt of claim 5.
20. The use of any one of claims 15 to 19, wherein said pharmaceutically acceptable salt is (2R,6R)(8-cyanoquinolinyl)-N-((3S,4R)fluoropyrrolidinyl) methylmorpholinecarboxamide hydrochloride. Eisai R&D Management Co., Ltd. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (26914509_1):AXG
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