LYSINE SPECIFIC DEMETHYLASE-1 INHIBITORS AND THEIR USE
First Claim
1. A compound of Formula 1
(A′
- )X-(A)-(B)—
(Z)-(L)-(D)
1wherein;
(A) is heteroaryl or aryl;
each (A′
), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl, haloalkoxy, and cyano, wherein each (A′
) is substituted with 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —
CH2C(═
O)NH2, heteroaryl, cyano, sulfonyl, and sulfinyl;
X is 0, 1, 2, or 3;
(B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B);
(Z) is —
NH—
;
(L) is chosen from a single bond, —
CH2—
, —
CH2CH2—
, —
CH2CH2CH2—
, and —
CH2CH2CH2CH2—
; and
(D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents independently chosen from —
NH2, —
NH(C1-C6 alkyl), —
N(C1-C6 alkyl)(C1-C6 alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy;
or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof;
with the proviso that the following compounds are excluded;
N-(2-phenylcyclopropyl)-cyclopentanamine;
10,11-dihydro-N-(2-phenylcyclopropyl)-5H-dibenzo[a,d]cyclohepten-5-amine; and
trans-N-(2-phenylcyclopropyl)-cyclohexanamine.
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Accused Products
Abstract
The present invention relates to a compound of Formula 1, wherein: (A) is heteroaryl or aryl; each (A′), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl, haloalkoxy, and cyano, wherein each (A′) is substituted with 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —CH2C(=0)NH2, heteroaryl, cyano, sulfonyl, and sulfinyl; X is 0, 1, 2, or 3; (B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B); (Z) is —NH—; (L) is chosen from a single bond, —CH2—, —CH2CH2—, —CH2CH2CH2—, and —CH2CH2CH2CH2—; and (D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents independently chosen from —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)(C1-C6 alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy. (A′)X-(A)-(B)—(Z)-(L)-(D) formula (I) The compounds of the invention show activity for inhibiting LSD1, which makes them useful in the treatment or prevention of diseases such as cancer.
-
Citations
35 Claims
-
1. A compound of Formula 1
(A′- )X-(A)-(B)—
(Z)-(L)-(D)
1wherein; (A) is heteroaryl or aryl; each (A′
), if present, is independently chosen from aryl, arylalkoxy, arylalkyl, heterocyclyl, aryloxy, halo, alkoxy, haloalkyl, cycloalkyl, haloalkoxy, and cyano, wherein each (A′
) is substituted with 0, 1, 2, or 3 substituents independently chosen from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, alkyl, alkoxy, amido, —
CH2C(═
O)NH2, heteroaryl, cyano, sulfonyl, and sulfinyl;X is 0, 1, 2, or 3; (B) is a cyclopropyl ring, wherein (A) and (Z) are covalently bonded to different carbon atoms of (B); (Z) is —
NH—
;(L) is chosen from a single bond, —
CH2—
, —
CH2CH2—
, —
CH2CH2CH2—
, and —
CH2CH2CH2CH2—
; and(D) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents independently chosen from —
NH2, —
NH(C1-C6 alkyl), —
N(C1-C6 alkyl)(C1-C6 alkyl), alkyl, halo, amido, cyano, alkoxy, haloalkyl, and haloalkoxy;or an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof; with the proviso that the following compounds are excluded; N-(2-phenylcyclopropyl)-cyclopentanamine; 10,11-dihydro-N-(2-phenylcyclopropyl)-5H-dibenzo[a,d]cyclohepten-5-amine; and trans-N-(2-phenylcyclopropyl)-cyclohexanamine. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 34, 35)
- )X-(A)-(B)—
-
31. A method for identifying a compound which is a selective inhibitor of LSD1, the method comprising selecting or providing a compound which is a substituted heteroarylcyclopropylamine or a substituted arylcyclopropylamine, and determining the ability of the compound to inhibit LSD1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSD1 to a greater extent than MAO-A and/or MAO-B is identified as a LSD1 selective inhibitor, and further wherein the substituted hetero arylcyclopropylamine or the substituted arylcyclopropylamine is defined as follows in Formula 2:
-
(R3)-(W)-(cyclopropyl)-(NH)-(L′
)-(R4)
2wherein; (R3) is present or not present, when present (R3) is chosen from arylalkyl, arylalkoxy, heterocyclylalkyl, and heterocycylalkoxy, wherein said (R3) group has 0, 1, 2, or 3 substituents independently chosen from halo, alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkoxy, haloalkyl, haloalkoxy, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heterocyclyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; (W) is an aryl or heteroaryl group, wherein said (W) has 0, 1, or 2 substituents chosen from halo, alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkoxy, haloalkyl, haloalkoxy, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heterocyclyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; (L′
) is a linker of formula —
(CH2)n—
where n is chosen from 0, 1, 2, 3, 4, 5, or 6; and(R4) is an aliphatic carbocyclic group or benzocycloalkyl, wherein said aliphatic carbocyclic group or said benzocycloalkyl has 0, 1, 2, or 3 substituents chosen from halo, alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkoxy, haloalkyl, haloalkoxy, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heterocyclyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. - View Dependent Claims (32, 33)
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Specification