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EP-4294800-B1 - APOL1 INHIBITORS AND METHODS OF USE

EP4294800B1EP 4294800 B1EP4294800 B1EP 4294800B1EP-4294800-B1

Inventors

  • LEE, Patrick Sang Tae
  • EWING, Todd Jonathan August
  • REID, Adam Neil
  • SINZ, CHRISTOPHER JOSEPH
  • ZHANG, BIRONG
  • BRONNER, Sarah M.
  • MORGANS JR., DAVID JOHN
  • HOEK, Maarten
  • ASSIMON, Victoria Anne

Dates

Publication Date
20260506
Application Date
20220218

Claims (15)

  1. A compound of formula (A'): or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is absent or is -N-(C 1-6 alkyl); Y is O or -N-(C 1-6 alkyl), provided that, when Q is -N(C 1-6 alkyl), then Y is O; R a , R b , and R c are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a , R b , or R c is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl, or any two of R a , R b , and R c are taken, together with the atoms to which they are attached, to form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl, and the other of R a , R b , and R c is H or C 1-6 alkyl, wherein the C 1-6 alkyl of R a , R b , or R c is independently optionally substituted with one or more -OH, C 1-6 alkoxy, or -S(O) 2 -C 1-6 alkyl; L is selected from the group consisting of: (i) wherein A is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R x is H, or R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; R 1 and R 2 are independently H, halo, or -OH, or one of R 1 and R 2 is taken together with R x , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1 and R 2 is H, halo, or -OH; R 3 is H, -OH, halo, or C 1-6 alkoxy; and R 4 and R 5 are independently H, or R 4 and R 5 are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that either: (1) R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, or (2) R 4 and R 5 are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl, (ii) wherein E is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); p is 0 or 1, provided that, when p is 1, then E is O; R 6 is H or -OH; R y is H, or R y is taken together with R 7 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or R y is taken together with one of R 8 and R 9 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 7 is H, or R 7 is taken together with R y , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; R 8 and R 9 are independently H or C 1-6 alkyl, or one of R 8 and R 9 is taken together with R y , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, and the other of R 8 and R 9 is H or C 1-6 alkyl, or one of R 8 and R 9 is taken together with R 10 , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and the other of R 8 and R 9 is H or C 1-6 alkyl; and R 10 is H, or R 10 is taken together with one of R 8 and R 9 , and the atoms to which they are attached, to form a C 3-8 cycloalkyl, provided that: (1) R y is taken together with R 7 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (2) R y is taken together with one of R 8 and R 9 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, or (3) one of R 8 and R 9 is taken together with R 10 and the atoms to which they are attached, to form a C 3-8 cycloalkyl, and (iii) wherein G is O, NH, N(C 1-6 alkyl), CH 2 , or CH(C 1-6 alkyl); R z is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more C 3-8 cycloalkyl; R 11 and R 12 are independently H, -OH, halo, or C 1-6 alkyl; and R 13 and R 14 are independently H, C 1-6 alkyl, or C 3-8 cycloalkyl, or R 13 and R 14 are taken, together with the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein, for each of (i)-(iii), # denotes the point of attachment to the phenyl ring bearing moiety Q, and ## denotes the point of attachment to the phenyl ring bearing moieties X 1 -X 4 ; and X 1 , X 2 , X 3 , and X 4 are, independently of each other, H, halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1 , X 2 , X 3 , and X 4 is halo, -CN, C 1-6 alkyl, C 1-6 alkoxy, or SF 5 , wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.
  2. The compound of claim 1, wherein the compound is a compound of formula (A): or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: X 1 , X 2 , X 3 , and X 4 are, independently of each other, H, halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo, provided that at least one of X 1 , X 2 , X 3 , and X 4 is halo, -CN, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more halo.
  3. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound is of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; optionally wherein one of (a) or (b) applies: (a) A is O, such that the compound is of formula (I-A): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; (b) A is CH 2 , such that the compound is of formula (I-A3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  4. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A1) and either: R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy; or R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy.
  5. The compound of claim 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-B 1), (I-C1), (I-D1), (I-E1), (I-F1) or (I-G1): wherein in formula (I-B1), n is optionally 0, or n is optionally 1 or 2; wherein in formula (I-C1) n is optionally 0, or n is optionally 1 or 2; wherein in formula (I-D1) n is optionally 0, or n is optionally 1 or 2; wherein in formula (I-E1) n is optionally 0; wherein in formula (I-F1) n is optionally 0; wherein in formula (I-G1) n is optionally 0; or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  6. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is of formula (I-A) and wherein R 4 and R 5 are taken, together with the atoms to which they are attached, to form a C 3-8 cycloalkyl; optionally wherein the compound is of formula (I-H1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; wherein R 1 , R 2 , and R 3 are optionally each H.
  7. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-A1) and either: (a) R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1 and R 2 is H, halo, or -OH; or (b) R x is taken together with one of R 1 and R 2 , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is substituted with n independently selected R g substituents, wherein n is an integer from 0-6, and R g is -OH, halo, C 1-6 alkyl, or C 1-6 alkoxy, and the other of R 1 and R 2 is H, halo, or -OH; optionally wherein the compound is of formula (I-C3): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  8. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound is of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; optionally wherein E is O, such that the compound is of formula (II-A1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; optionally wherein either: (a) R y in formula (II-A1) is taken together with R 7 , and the atoms to which they are attached, to form a 3-8 membered heterocyclyl; or (b) R y is taken together with R 7 , and the atoms to which they are attached, to form a 5-6 membered heterocyclyl; further optionally wherein one of R 8 and R 9 is taken together with R 10 , and the atoms to which they are attached, to form a C 3-8 cycloalkyl.
  9. The compound of claim 8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (II-B1), (II-C1), (II-D1) or (II-E1): wherein in formula (II-C1) optionally R 6 is -OH, R 8 is C 1-6 alkyl, and R 9 is C 1-6 alkyl; wherein in formula (II-D1) optionally R 6 is -OH, R 8 is H, and R 9 is H; wherein in formula (II-E1) optionally R 6 is -OH and R 7 is H; or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  10. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is such that the compound is of formula (III): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  11. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein either: (a) Q is absent, Y is O, and R a , R b , and R c are each independently H, such that the compound is of formula (B-2): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (b) Q is absent, Y is -N(CH 3 ), and R a , R b , and R c are each independently H, such that the compound is of formula (B-5): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or (c) Q is -N(CH 3 ), Y is O, and R a , R b , and R c are each independently H, such that the compound is of formula (C-1): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  12. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the following: Compound No. Structure Chemical name 1 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) azepane 2 ( R ) or ( S )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) azepane 3 ( S ) or ( R )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) azepane 4 1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-3-ol 5 ( R ) or ( S )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-3-ol 6 ( S ) or ( R ) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-3-ol 7 N -(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 8 ( S ) or ( R )- N -(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 9 ( R ) or ( S )- N -(4-((1-(3-chlorophenethyl)piperidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 10 N -(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)- N -methylmethanesulfonamide 11 ( R ) or ( S )- N -(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)- N- methylmethanesulfonamide 12 ( S ) or ( R )- N -(4-((4-(3-chlorophenethyl)-1,4-oxazepan-2-yl)methoxy)phenyl)- N- methylmethanesulfonamide 13 ( S )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperazine 14 ( R )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperazine 15 ( R )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 16 ( S )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 17 1-(3-chlorophenyl)-2-(( S )-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethan-1-ol 18 ( R ) or ( S )-1-(3-chlorophenyl)-2-(( S )-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethan-1-ol 19 ( S ) or ( R )-1-(3-chlorophenyl)-2-(( S )-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethan-1-ol 20 1-(3-chlorophenyl)-2-(( R )-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethanol 21 ( R ) or ( S )-1-(3-chlorophenyl)-2-(( R )-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethanol 22 ( S ) or ( R )-1-(3-chlorophenyl)-2-(( R )-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-1-yl)ethanol 23 ( S )-1-(( R ) or ( S )-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 24 ( S )-1-(( S ) or ( R )-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 25 ( R )-1-(( R ) or ( S )-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 26 ( R )-1-(( S ) or ( R )-2-(3-chlorophenyl)-2-methoxyethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 27 rac-trans or cis -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol 28 rac-cis or trans -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol 29 (3 S ,4 R ) or (3 R, 4 R ) or (3 S ,4 S ) or (3 R ,4 S )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol 30 (3 R ,4 R ) or (3 S ,4 S ) or (3 R ,4 S ) or (3 S ,4 R ) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol 31 (3 R ,4 R ) or (3 S ,4 S ) or (3 R ,4 S ) or (3 S ,4 R ) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol 32 (3 S ,4 S ) or (3 R ,4 S ) or (3 S ,4 R ) or (3 R ,4 R ) -1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) piperidin-4-ol 33 rac-trans or cis-1-(3- chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine 34 rac-cis or trans -1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy) methyl)piperidine 35 (3 S ,4 R ) or (3 R, 4 R ) or (3 S ,4 S ) or (3 R ,4 S )-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 36 (3 R ,4 R ) or (3 S ,4 S ) or (3 R ,4 S ) or (3 S ,4 R )-1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 37 (3 R ,4 R ) or (3 S ,4 S ) or (3 R ,4 S ) or (3 S ,4 R ) -1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 38 (3 S ,4 S ) or (3 R ,4 S ) or (3 S ,4 R ) or (3 R ,4 R ) -1-(3-chlorophenethyl)-4-methoxy-3-((4-(methylsulfonyl)phenoxy)methyl) piperidine 39 1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperi dine 40 ( S ) or ( R )-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperi dine 41 ( R ) or ( S )-1-(3-chlorophenethyl)-3-(4-(methylsulfonyl)phenethyl)piperi dine 42 1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine 43 ( S ) or ( R )-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy) methyl) pyrrolidine 44 ( R ) or ( S )-1-(3-chlorophenethyl)-2,2-dimethyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 45 rac-trans-N -(4-((1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 46 N -(4-(((3 S ,4 S ) or (3 R, 4 R )-1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 47 N -(4-(((3 R ,4 R ) or (3 S ,4 S ) -1-(3-chlorophenethyl)-4-methylpyrrolidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 48 trans-N -(4-(3-((3-chlorophenethyl)amino)cyclobuto xy)phenyl)- N- methylmethanesulfonamide 49 ( S )- N -(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 50 ( R )- N -(4-((1-(3-chlorophenethyl)pyrrolidin-3-yl)methoxy)phenyl)- N- methylmethanesulfonamide 51 ( S )-1-(3-chlorophenethyl)-3-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 52 rac-trans- 1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 53 rac-trans or cis -1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 54 rac-cis or trans -1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 55 (2 R ,4 S ) or (2 R ,4 R ) or (2 S, 4 R ) or (2 S ,4 S )-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 56 (2 R ,4 R ) or ( 2S, 4 R ) or (2 S ,4 S ) or (2 R ,4 S )-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 57 (2 S ,4 R ) or (2 S ,4 S ) or (2 R ,4 S ) or (2 R ,4 R )-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 58 (2 S ,4 S ) or (2 R ,4 S ) or (2 R ,4 R ) or (2S,4R)-1-(3-chlorophenethyl)-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidine 59 ( S )- N -(4-(3-((3-chlorophenethyl)(cyclopropylmet hyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 60 ( S )- N -(4-(3-((3-chlorophenethyl)(ethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 61 ( R )- N -(4-(3-((3-chlorophenethyl)amino)-2-methylpropoxy)phenyl)- N- methylmethanesulfonamide 62 (2 S )-1-(2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 63 ( S )-1-(( S ) or ( R )-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 64 ( S )-1-(( R ) or ( S )-2-(3-chlorobenzyl)piperidin-1-yl)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 65 N -(4-(( S )-3-(( trans -3-(3-chlorophenyl)cyclobutyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 66 ( S )-1-(( trans -3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 67 ( R )-1-(( trans -3-(3-chlorophenyl)cyclobutyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 68 N -(4-((2 S )-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 69 N -(4-(( S )-3-(( S ) or ( R )-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 70 N -(4-(( S )-3-(( R ) or ( S )-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 71 N -(4-((2 R )-3-(3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 72 N -(4-(( R )-3-(( S ) or ( R )-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 73 N -(4-(( R )-3-(( R ) or ( S )-3-(3-chlorophenyl)-2,2-dimethylpyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 74 N -(4-((2 S )-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 75 N -(4-(( S )-3-(( S ) or ( R )-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 76 N -(4-(( S )-3-(( R ) or ( S )-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 77 N -(4-((2 R )-3-(3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 78 N -(4-(( R )-3-(( S ) or ( R )-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 79 N -(4-(( R )-3-(( R ) or ( S )-3-(3-chlorophenyl)pyrrolidin-1-yl)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 80 N -(4-((2 S )-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 81 N -(4-(( S )-3-(( S ) or ( R )-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 82 N -(4-(( S )-3-(( R ) or ( S )-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 83 N -(4-((2 R )-3-(2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 84 N -(4-(( R )-3-(( R ) or ( S )-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 85 N -(4-(( R )-3-(( S ) or ( R )-2-(3-chlorophenyl)morpholino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 86 ( S )- N -(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 87 ( R )- N -(4-(3-((3-chlorophenethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 88 N -(4-(( R )-3-((( S ) or ( R )-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 89 N -(4-(( R )-3-((( R ) or ( S )-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 90 ( S )- N -(4-(3-((2,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 91 ( S )- N -(4-(3-((3,5-dichlorophenethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 92 N -(4-((2 R )-3-((3-(3-chlorobenzyl)tetrahydrofuran-3-yl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 93 ( S )-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 94 ( R )-1-((3-chlorophenethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 95 N -(4-(( S )-3-((( S ) or ( R )-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 96 N -(4-(( S )-3-((( R ) or ( S )-1-(3-chlorophenyl)propan-2-yl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 97 ( R )-1-((1-(3-chlorophenyl)-2-methylpropan-2-yl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 98 ( S )- N -(4-(2-hydroxy-3-((2-methoxyphenethyl)amino)propox y)phenyl)- N- methylmethanesulfonamide 99 ( S )- N -(4-(3-((3-cyanophenethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 100 ( S )- N -(4-(3-((2-ethylphenethyl)amino)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 101 ( S )- N -(4-(3-((2-(difluoromethoxy)phenethyl)amin o)-2-hydroxypropoxy)phenyl)- N- methylmethanesulfonamide 102 (2 R )-1-((2-(3-chlorophenyl)-1-cyclopropylethyl)amino)-3-(4-(methylsulfonyl)phenoxy)propan-2-ol 103 ( R ) or ( S )- N -(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)- N- methylmethanesulfonamide 104 ( S ) or ( R )- N -(4-(3-((3-chlorophenethyl)amino)-2-hydroxy-2-methylpropoxy)phenyl)- N- methylmethanesulfonamide 105 N -(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)- N- methylmethanesulfonamide 106 ( R ) or ( S )- N -(4-((3-((3-chlorophenethyl)amino)-2-hydroxypropyl)amino)phenyl)- N- methylmethanesulfonamide 107 (3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methanesulfonylethanesulfonyl)p henoxy]methyl}-4-methylpyrrolidine 108 3-chloro-5-{2-[(3 S ,4 S )-3-{[4-(2-methanesulfonylethanesulfonyl)p henoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile 109 rac-trans -1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy] methyl}-4-methylpyrrolidine 110 (3 R ,4 R or 3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy] methyl}-4-methylpyrrolidine 111 (3 S ,4 S or 3 R ,4 R )-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(2-methoxyethanesulfonyl)phenoxy] methyl}-4-methylpyrrolidine 112 2-(4-{[(3 R ,4 R or 3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl)etha n-1-ol 113 2-(4-{[(3 S ,4 S or 3 R ,4 R )-1-[2-(3-chlorophenyl)ethyl]-4-methylpyrrolidin-3-yl]methoxy}benzenesulfonyl)etha n-1-ol 114 3-chloro-5-[(1 S or 1 R )-1-hydroxy-2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzonitrile 115 3-chloro-5-[(1 R or 1 S )-1-hydroxy-2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl]-2-methylpyrrolidin-1-yl]ethyl]benzonitrile 116 3-[(1 R or 1 S )-1-hydroxy-2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzonitrile 117 3-[(1 S or 1 R )-1-hydroxy-2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzonitrile 118 5-[(1 R or 1 S )-1-hydroxy-2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile 119 5-[(1 S or 1 R )-1-hydroxy-2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile 120 3-chloro-5-{1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile 121 3-chloro-5-[(1 S or 1 R )-1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile 122 3-chloro-5-[(1 R or 1 S )-1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl]-4-methylpyrrolidin-1-yl]ethyl]benzonitrile 123 1-(3-chlorophenyl)-2-((3 S ,4 S )-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-1-yl)ethan-1-ol 124 (1 R or 1 S )-1-(3-chlorophenl)-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethan-1-ol 125 (1 S or 1 R )-1-(3-chlorophenyl)-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethan-1-ol 126 3-[1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile 127 3-[(1 S or 1 R )-1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile 128 3-[(1 R or 1 S )-1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzonitrile 129 5-{1-hydroxy-2-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile 130 5-[(1 R or 1 S )-1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile 131 5-[(1 S or 1 R )-1-hydroxy-2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl]benzene-1,3-dicarbonitrile 132 5-{2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile 133 (3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 134 (2 S ,5 S )-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperidine 135 rac-cis or t rans -3-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 136 rac-trans or cis -3-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 137 3-{2-[(2 S ,4 R or 2 R ,4 S or 2 R ,4 R or 2 S ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 138 3-{2-[(2 R ,4 S or 2 S ,4 R or 2 R ,4 R or 2 S ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 139 3-{2-[(2 S ,4 S or 2 S ,4 R or 2 R ,4 S or 2 R ,4 R )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 140 3-{2-[(2 R ,4 R or 2 S ,4 S or 2 S ,4 R or 2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 141 5-chloro-3-{2-[(2 R ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile 142 3-chloro-5-[(2 R or 2 S )-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile 143 3-chloro-5-[(2 S or 2 R )-1-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile 144 5-chloro-3-{2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}-2-methylbenzonitrile 145 5-{2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzene-1,3-dicarbonitrile 146 3-chloro-5-[1-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile 147 3-chloro-5-[(2 R or 2 S )-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile 148 3-chloro-5-[(2 S or 2 R )-1-[(3S,4S)-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]propan-2-yl]benzonitrile 149 3-{2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile 150 rac-cis -1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 151 (3 R ,4 S or 3 S ,4 R )-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 152 (3 S ,4 R or 3 R ,4 S )-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 153 (2 R ,4 S )-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidine 154 (3 R ,4 R or 3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 155 (3 S ,4 S or 3 R ,4 R )-1-[2-(3-chlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 156 3-{2-[(2 R ,4 S )-4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile 157 3-{2-[(2 R ,4 S )-2-methyl-4-({4-[methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl}benzonitrile 158 3-{2-[(2 R ,4 S )-2-methyl-4-({4-[( R or S )methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy}methyl)pyrroli din-1-yl]ethyl}benzonitrile 159 3-{2-[(2 R ,4 S )-2-methyl-4-({4-[( S or R )methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy}methyl)pyrroli din-1-yl]ethyl}benzonitrile 160 (2 R ,5 S )-1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperidine 161 3-{2-[(2 R ,4 S )-4-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile 162 3-{2-[(2 R ,4 S )-4-{ [4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile 163 (3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methyl-1-{2-[3-(pentafluoro-λ 6 -sulfanyl)phenyl]ethyl}pyrrolidine 164 3-chloro-5-{2-[(2 R ,4 S )-4-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile 165 3-chloro-5-{2-[(2 R ,4 S )-4-{[4-(2-hydroxyethanesulfonyl)phenoxy] methyl}-2-methylpyrrolidin-1-yl]ethyl}benzonitrile 166 3-chloro-5-{2-[(3 S ,4 S )-3-{[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile 167 3-chloro-5-{2-[(3 S ,4 S )-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile 168 3-{ 2-[(3 S ,4 S )-3-{ [4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile 169 3-{2-[(3 S ,4 S )-3-methyl-4-({4-[methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl }benzonitrile 170 3-{2-[(3 S ,4 S )-3-methyl-4-({4-[( R or S )-methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl }benzonitrile 171 3-{2-[(3 S ,4 S )-3-methyl-4-({4-[( S or R )-methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy }methyl)pyrroli din-1-yl]ethyl}benzonitrile 172 3-{2-[(3 S ,4 S )-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile 173 3-{2-[(3 S ,4 S )-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-4-methylpyrrolidin-1-yl]ethyl}-5-chlorobenzonitrile 174 3-chloro-5-{2-[(3 S ,4 S )-3-{[4-(2-hydroxyethanesulfonyl)phenoxyl methyl}-4-methylpyrrolidin-1-yl]ethyl}benzonitrile 175 rac-trans -1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine 176 (3 R ,4 R or 3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine 177 (3 S ,4 S or 3 R ,4 R )-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}-4-methylpyrrolidine 181 (3 S ,4 S )-1-[2-(3-chloro-5-fluorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidine 182 3-chloro-5-{2-[(3 S )-3-{[4-(2-hydroxyethanesulfonyl)phenoxy] methyl}piperazin-1-yl]ethyl}benzonitrile 183 3-chloro-5-{2-[(3 S )-3-1[4-(1-hydroxy-2-methylpropane-2-sulfonyl)phenoxy]methyl}piperaz in-1-yl]ethyl}benzonitrile 184 (3 S )-1-[2-(3-chlorophenyl)ethyl]-3-{[4-(3-methanesulfonylpropanesulfonyl) phenoxy]methyl}piperazine 185 (3 S )-3-{[4-(azetidine-3-sulfonyl)phenoxy]methyl}-1-[2-(3-chlorophenyl)ethyl]piperazine 186 3-chloro-5-{2-[(3 S )-3-({4-[methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy}methyl)piperaz in-1-yl]ethyl}benzonitrile 187 3-chloro-5-{2-[(3S)-3-({4-[( S or R )-methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy }methyl)piperaz in-1-yl]ethyl }benzonitrile 188 3-chloro-5-{2-[(3 S )-3-({4-[( R or S )-methyl(methylimino)oxo-λ 6 -sulfanyl]phenoxy }methyl)piperaz in-1-yl]ethyl}benzonitrile 189 3-chloro-5-{2-[(3 S )-3-[(4-methanesulfonylphenoxy)methyl] piperazin-1-yl]ethyl}benzonitrile 190 (3 S )-1-[2-(3,5-dichlorophenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] piperazine 191 (3 S )-1-[2-(5-chloro-2-methoxyphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] piperazine 192 (3 S )-1-{2-[5-chloro-2-(difluoromethoxy)phenyl]ethyl}-3-[(4-methanesulfonylphenoxy)methyl] piperazine 193 3-{2-[(3 S )-3-[(4-methanesulfonylphenoxy)methyl] piperazin-1-yl]ethyl}-5-(trifluoromethyl)benzonitrile 194 3-chloro-5-{2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile 195 3-fluoro-5-{2-[(3 S ,4 S )-3 -[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile 196 3-bromo-5-{2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}benzonitrile 197 (3 S )-1-[2-(5-chloro-2-methylphenyl)ethyl]-3-[(4-methanesulfonylphenoxy)methyl] piperazine 198 3-{2-[(3 S ,4 S )-3-[(4-methanesulfonylphenoxy)methyl] -4-methylpyrrolidin-1-yl]ethyl}-5-methylbenzonitrile 199 rac-cis or trans- 3- chloro -5-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 200 3-chloro-5-12-[(2R,4S or 2S,4R or 2R,4R or 2 S ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 201 3-chloro-5-{2-[(2 S ,4 R or 2 R ,4 S or 2 R ,4 R or 2 S ,4 S )-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 202 rac-trans or cis -3-chloro-5-{2-[4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethyl}benzonitrile 203 3-chloro-5-(2-((2 R ,4 S or 2 S ,4 R or 2 R ,4 R or 2 S ,4 S )-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-1-yl)ethyl)benzonitrile 204 3-chloro-5-(2-((2 R ,4 S or 2 S ,4 R or 2 S ,4 S or 2 R. 4 R )-2-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-1-yl)ethyl)benzonitrile 205 rac-cis- 1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol 206 (3 R ,4 R or 3 S ,4 S )-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol 207 (3 S ,4 S or 3 R ,4 R )-1-(3-chlorophenethyl)-3-methyl-4-((4-(methylsulfonyl)phenoxy)methyl) pyrrolidin-3-ol 208 rac-trans -1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol 209 (3 R ,4 S or 3 S ,4 R )-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol 210 (3 S ,4 R or 3 R ,4 S )-1-[2-(3-chlorophenyl)ethyl]-4-[(4-methanesulfonylphenoxy)methyl] -3-methylpyrrolidin-3-ol 211 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperazine 212 rac-cis or trans- 1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperazine 213 rac-trans or cis -1-[2-(3-chlorophenyl)ethyl]-5-[(4-methanesulfonylphenoxy)methyl] -2-methylpiperazine 214 (1 R ) or (1 S )-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethan-1-ol 215 (1 S ) or (1 R )-1-(3-chlorophenyl)-2-[(2R,4S)-4-[(4-methanesulfonylphenoxy)methyl] -2-methylpyrrolidin-1-yl]ethan-1-ol or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  13. A pharmaceutical composition, comprising (i) a compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.
  14. The compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition according to claim 13, for use in treating or delaying the development of a disease, disorder, or condition selected from: a kidney disease; a disease, disorder, or condition selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis.
  15. A kit, comprising (i) a compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 13, and (ii) instructions for use in treating an APOL1-mediated disease, disorder, or condition in an individual in need thereof; wherein the disease, disorder, or condition is optionally: a kidney disease; or a disease, disorder, or condition selected from the group consisting of chronic kidney disease, focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1-associated nephropathy, viral nephropathy, COVID-19 associated nephropathy, preeclampsia, and sepsis; optionally wherein the individual has an APOL1 mutation, such as a gain-of-function mutation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/151,605 filed on February 19, 2021. BACKGROUND OF THE INVENTION Apolipoprotein L1 (APOL1) is a pore forming innate immunity factor, protecting individuals from trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83-87). The secreted form of APOL1 circulates in blood as part of distinct high-density lipoprotein (HDL) complexes, known as trypanosome lytic factors (TLFs) (Rifkin, M. R. Proc. Natl. Acad. Sci. USA. (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910-1916). TLFs are internalized by the parasites through endocytosis (Hager, K. M. et al. J. Cell Biol. (1994) 126, 155-167). Within trypanosomes, APOL1 forms cation pores, causing ion flux, swelling, and eventual lysis (Rifkin, M. R. Exp. Parasitol. (1984) 58, 81-93; Molina-Portela, M. P. et al. Mol. Biochem. Parasitol. (2005) 144, 218-226; Pérez-Morga, D. et al. Science. (2005) 309, 469-472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894-2899). Several Trypanosoma brucei subspecies (T b. rhodesiense and T. b. gambiense) developed resistance mechanisms to APOL1-dependent killing (Pays, E. et al. Nat. Rev. Microbiol. (2014) 12, 575-584). Positive selection resulted in APOL1 variants, G1 (S342G, I384M) and G2 (N388Δ, Y389Δ), capable of interfering with these resistance mechanisms (Genovese, G. et al. Science. (2010) 329, 841-845). However, individuals with any binary combination of these variants (G1/G1, G2/G2, or G1/G2), have a greater risk of developing a variety of chronic kidney diseases, including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIVAN) (Genovese, G. et al. Science. (2010) 329, 841-845; Tzur, S. et al. Hum. Genet. (2010) 128, 345-350; Kopp, J. B. et al. J. Am. Soc. Nephrol. (2011) 22, 2129-2137), sickle cell nephropathy (Ashley-Koch, A. E. et al. Br. J. Haematol. (2011) 155, 386-394), lupus nephritis (Freedman, B. I. et al. Arthritis Rheumatol. (2014) 66, 390-396), and an increased rate of Glomerular Filtration Rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med. (2013) 369, 2183-2196). The APOL1 high-risk genotype has also been associated with COVID-19 associated nephropathy and other viral nephropathies (Shetty, A. et al. J. Am. Soc. Nephrol. (2021) 32, 33-40; Chang, J. H. et al. Am. J. Kidney Dis. (2019) 73, 134-139). Moreover, decreased renal allograft survival has been observed after deceased-donor kidney transplantations from APOL1 high-risk genotype donors (Freedman, B. I. et al. Transplantation. (2016) 100, 194-202). In addition, having two APOL1 risk alleles increases risk for preeclampsia (Reidy, K. J. et al. Am. J. Hum. Genet. (2018) 103, 367-376) and sepsis (Chaudhary, N. S. et al. Clin. J. Am. Soc. Nephrol. (2019) 14, 1733-1740). There are no approved therapies for APOL1-associated nephropathy, and patients are treated based on the standard of care for their underlying form of chronic kidney disease. This presents a clear unmet need for therapies targeted to people with the APOL1 high-risk genotype. Numerous studies have shown that APOL1 risk variants are toxic when overexpressed in human cells (Wan, G. et al. J. Biol. Chem. (2008) 283, 21540-21549; Lan, X. et al. Am. J. Physiol. Renal Physiol. (2014) 307, F326-F336; Olabisi, O. A. et al. Proc. Natl. Acad. Sci. USA. (2016) 113, 830-837; Ma, L. et al. J. Am. Soc. Nephrol. (2017) 28, 1093-1105; Lannon, H. et al. Kidney Int. (2019) 96, 1303-1307). Recent findings suggest that this toxicity is associated with APOL1 pore function (Giovinazzo, J. A. et al. eLife. (2020) 9, e51185). Thus, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for inhibiting the activity of APOL1 using such compounds. US 2020/0377479 describes compounds comprising two cyclic units joined by a linking unit which act as APOL1 inhibitors, and their use in treating focal segmental glomerulosclerosis (FSGS) and/or non-diabetic kidney disease. US 2004/024024 describes compounds having a similar structure which act as MMP (matric metalloprotease) inhibitors. WO 91/13865 describes compounds also having this structure which act as antiarrhythmic agents. BRIEF SUMMARY OF THE INVENTION This disclosure describes compounds and compositions that may be useful for the treatment of APOL1-mediated diseases, including a variety of chronic kidney diseases such as FSGS, hypertension-attributed kidney disease, HIVAN, sickle cell nephropathy, lupus nephritis, diabetic kidney disease, viral nephropathy, COVID-19 associated nephropathy, and APOL1-associated nephropathy. The compounds and compositions may also find use in treating other APOL1-mediated disorders such as preeclampsia and sepsis. Additionally, for individuals with the APOL1 high-risk genotype, the disclosed compounds and compositions could have u