US2015246029A1PendingUtilityA1
Positive Allosteric Modulators and Uses Thereof
Est. expiryFeb 2, 2031(~4.5 yrs left)· nominal 20-yr term from priority
A61P 29/00A61P 25/28A61P 25/22A61P 25/18A61P 25/16A61P 25/14A61P 25/24C07C 2601/02A61K 31/4409A61K 31/415C07C 233/60C07C 233/59C07C 311/46A61P 25/00C07D 213/75C07D 317/46C07D 209/46A61K 31/357A61K 31/4412C07D 275/06A61K 31/167C07C 2602/50C07D 277/46C07C 311/16C07D 231/40A61K 31/426
37
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Claims
Abstract
The present invention relates to compounds useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR). The invention also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of α7nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and also inflammatory diseases.
Claims
exact text as granted — not AI-modified1 .- 21 . (canceled)
22 . A method for the treatment of cognitive deficits associated with neurodegeneration or neuropsychiatric diseases, said method including the step of administering a compound of formula (I) or a salt thereof:
wherein
R 1 is selected from optionally substituted aryl, optionally substituted heteroaryl (excluding optionally substituted porphyrins), or optionally substituted heterocyclyl;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is selected from hydrogen or optionally substituted alkyl;
wherein when both R 2 and R 3 are Cl, R 4 is an optionally substituted heteroaryl or optionally substituted heterocyclyl, and
provided that the following compounds are excluded:
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
23 . A method for the treatment of inflammatory diseases, said method including the step of administering a compound of formula (I) or a salt thereof:
wherein
R 1 is selected from optionally substituted aryl, optionally substituted heteroaryl (excluding optionally substituted porphyrins), or optionally substituted heterocyclyl;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is selected from hydrogen or optionally substituted alkyl;
wherein when both R 2 and R 3 are Cl, R 4 is an optionally substituted heteroaryl or optionally substituted heterocyclyl, and
provided that the following compounds are excluded:
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
24 . A method of positively modulating α7nAChRs in a cell by contacting the cell with a compound of formula (I) or a salt thereof:
wherein
R 1 is selected from optionally substituted aryl, optionally substituted heteroaryl (excluding optionally substituted porphyrins), or optionally substituted heterocyclyl;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is selected from hydrogen or optionally substituted alkyl;
wherein when both R 2 and R 3 are Cl, R 4 is an optionally substituted heteroaryl or optionally substituted heterocyclyl, and
provided that the following compounds are excluded:
or a salt thereof, to said cell.
25 . A method for the treatment of cognitive deficits associated with neurodegeneration or neuropsychiatric diseases, said method including the step of administering a compound of formula (II) or a salt thereof:
wherein
R 1 is selected from optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
R 2 and R 3 together form C 4-9 cycloalkyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; and
R 5 is selected from hydrogen or optionally substituted alkyl,
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
26 . A method for the treatment of inflammatory diseases, said method including the step of administering a compound of formula (II) or a salt thereof:
wherein
R 1 is selected from optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
R 2 and R 3 together form C 4-9 cycloalkyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; and
R 5 is selected from hydrogen or optionally substituted alkyl,
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
27 . A method of positively modulating α7nAChRs in a cell by contacting the cell with a compound of formula (II) or a salt thereof:
wherein
R 1 is selected from optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;
R 2 and R 3 together form C 4-9 cycloalkyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; and
R 5 is selected from hydrogen or optionally substituted alkyl,
or a salt thereof, to said cell.
28 . A method for the treatment of cognitive deficits associated with neurodegeneration or neuropsychiatric diseases, said method including the step of administering a compound represented by formula (Ia), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 or an integer from 1 to 5;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is selected from hydrogen or optionally substituted alkyl;
wherein when both R 2 and R 3 are Cl, R 4 is an optionally substituted heteroaryl or optionally substituted heterocyclyl, and
provided that the following compounds are excluded:
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
29 . A method for the treatment of inflammatory diseases, said method including the step of administering a compound represented by formula (Ia), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 or an integer from 1 to 5;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, F, Br, Cl, CN, or C 1 -C 4 haloalkyl; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is selected from hydrogen or optionally substituted alkyl;
wherein when both R 2 and R 3 are Cl, R 4 is an optionally substituted heteroaryl or optionally substituted heterocyclyl, and
provided that the following compounds are excluded:
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
30 . A method for the treatment of cognitive deficits associated with neurodegeneration or neuropsychiatric diseases, said method including the step of administering a compound represented by formula (Ib), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 or an integer from 1 to 5;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, F, Cl or Br;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, or Br; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is independently selected from hydrogen, or optionally substituted alkyl;
provided that the following compound is excluded:
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
31 . A method for the treatment of inflammatory diseases, said method including the step of administering a compound represented by formula (Ib), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 or an integer from 1 to 5;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, F, Cl or Br;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, or Br; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl;
R 5 is independently selected from hydrogen, or optionally substituted alkyl;
provided that the following compound is excluded:
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
32 . A method for the treatment of cognitive deficits associated with neurodegeneration or neuropsychiatric diseases, said method including the step of administering a compound represented by formula (Ic), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 or an integer from 1 to 5;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, F, Cl or Br;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, or Br; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from heteroaryl which may be independently substituted by one to three substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH); or aryl which may be independently substituted by one to three substituents selected from halogen, C 2-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH); and
R 5 is independently selected from hydrogen, or lower alkyl,
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
33 . A method for the treatment of inflammatory diseases, said method including the step of administering a compound represented by formula (Ic), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 or an integer from 1 to 5;
R 2 is selected from C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, F, Cl or Br;
R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 1 -C 4 haloalkyl, or Br; or
R 2 and R 3 together form C 4-9 cycloalkyl or C 4-9 cycloalkenyl;
R 4 is selected from heteroaryl which may be independently substituted by one to three substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH); or aryl which may be independently substituted by one to three substituents selected from halogen, C 2-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH); and
R 5 is independently selected from hydrogen, or lower alkyl,
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
34 . A method for the treatment of cognitive deficits associated with neurodegeneration or neuropsychiatric diseases, said method including the step of administering a compound represented by formula (IIa), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 an integer from 1 to 5;
R 2 and R 3 together form C 4-9 cycloalkyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; and
R 5 is independently selected from hydrogen or optionally substituted alkyl,
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
35 . A method for the treatment of inflammatory diseases, said method including the step of administering a compound represented by formula (IIa), or a salt thereof:
wherein
each R 1 ′ is independently selected from the group consisting of cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7 cycloalkyl, —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1 ′ together form heterocyclyl or heteroaryl;
n is 0 an integer from 1 to 5;
R 2 and R 3 together form C 4-9 cycloalkyl;
R 4 is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; and
R 5 is independently selected from hydrogen or optionally substituted alkyl,
or a pharmaceutically acceptable salt thereof, or a composition comprising a compound as defined above, or a pharmaceutically acceptable salt thereof.
36 . A method according to claim 22 , wherein R 1 is an optionally substituted aryl or optionally substituted heteroaryl group.
37 . A method according to claim 23 , wherein R 1 is an optionally substituted aryl or optionally substituted heteroaryl group.
38 . A method according to claim 22 , wherein R 4 is selected from heteroaryl or aryl each of which may be independently substituted by one to three substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH).
39 . A method according to claim 23 , wherein R 4 is selected from heteroaryl or aryl each of which may be independently substituted by one to three substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH).
40 . A method according to claim 22 , where R 4 is selected from:
(a)
wherein Hal is a halogen;
m is 0, 1 or 2; and
each R 6 is independently selected from halogen, hydroxy, CN, NO 2 , haloalkyl, aryl, heteroaryl, C 1-3 alkoxy, C 1-3 alkyl, or CO 2 R′ (where R′ is a lower alkyl or H);
or
(b) a heteroaryl substituted from 1 to 3 times from a group selected from C 1 -C 3 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkenyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH).
41 . A method according to claim 23 , where R 4 is selected from:
(a)
wherein Hal is a halogen;
m is 0, 1 or 2; and
each R 6 is independently selected from halogen, hydroxy, CN, NO 2 , haloalkyl, aryl, heteroaryl, C 1-3 alkoxy, C 1-3 alkyl, or CO 2 R′ (where R′ is a lower alkyl or H);
or
(b) a heteroaryl substituted from 1 to 3 times from a group selected from C 1 -C 3 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH).
42 . A method according to claim 40 , wherein the heteroaryl is pyridinyl, pyrazolyl or thiazolyl.
43 . A method according to claim 41 , wherein the heteroaryl is pyridinyl, pyrazolyl or thiazolyl.
44 . A method according to claim 22 , wherein R 2 and R 3 are C 1 -C 4 alkyl, or a pharmaceutically acceptable salt thereof.
45 . A method according to claim 23 , wherein R 2 and R 3 are C 1 -C 4 alkyl, or a pharmaceutically acceptable salt thereof.
46 . A method according to claim 22 , wherein R 2 and R 3 are methyl or ethyl.
47 . A method according to claim 23 , wherein R 2 and R 3 are methyl or ethyl.
48 . A method according to claim 22 , wherein R 5 is hydrogen or C 1-3 alkyl.
49 . A method according to claim 23 , wherein R 5 is hydrogen or C 1-3 alkyl.
50 . A method according to claim 22 , wherein n is 0, 1, 2, or 3, and R 1 ′, when present, is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-5 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH).
51 . A method according to claim 23 , wherein n is 0, 1, 2, or 3, and R 1 ′, when present, is halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 habalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —CN, —NO 2 , mercapto, —S(O) 2 NH 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH).Join the waitlist — get patent alerts
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