Class of isoindolone-imide ring-1,3-dione-2-ene compounds, composition and use thereof
The present invention provides an isoindolone-imide ring-1,3-dione-2-ene compound, and a preparation method, a pharmaceutical composition and use thereof. Specifically, the present invention provides a compound of Formula (I) below or a pharmaceutically acceptable salt thereof, wherein Ar is an isoindolinone-imide group represented by Formula (II), L is absent or is a divalent, trivalent or tetravalent linking group, and X is a group represented by Formula (III). Definitions of the other groups are as described in the specification. The compound of Formula (I) is an autophagy modulators, particularly a mammalian ATG8 homolog modulator.
1. A compound of General Formula (I) or a pharmaceutically acceptable salt thereof:
Ar-L(-X) p (I)
wherein p is 1, 2 or 3;
Ar is an isoindolone-imide group represented by Formula (II):
wherein one of A and B is C═O, and the other is C═O or CH 2 ;
R 1 is selected from hydrogen, deuterium, halo, and C1-C4 alkyl;
one of R 6 , R 7 , R 8 and R 9 is a divalent group selected from O, S, SO 2 , and NH, which is attached to L or directly to X, and the remaining three of R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halo, C1-C4 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5-10 membered heteroaryl; and R 10 is hydrogen; or
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halo, C1-C4 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5-10 membered heteroaryl, and NR b1 R b′ , in which R b1 and R b′ are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5-10 membered heteroaryl; and R 10 is absent, and the nitrogen attached to R 10 is directly attached to L or X;
L is absent, or is a divalent, trivalent or tetravalent linking group, where when L is absent or is a divalent linking group, p is 1; when L is a trivalent linking group, p is 2; when L is a tetravalent linking group, p is 3; and when p is 2 or 3, the 2 or 3 Xs linked to L are the same or different; and
X is a group represented by General Formula (III):
wherein
R 2 is selected from hydrogen, deuterium, halo, C1-C6 alkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5-10 membered heteroaryl;
W and T are each independently absent, —C(R a1 )(R a1′ )—, —C(R a1 )(R a1′ ) C(R a2 )(R a2′ ))—, —O—, —S— or —NR a3 —, where R a1 , R a1′ , R a2 , R a2′ and R a3 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, halo, CN, CO 2 R a4′ , CONR a5 R a5′ , C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, unsubstituted or substituted —CONH—(C6-C10) aryl, unsubstituted or substituted —CH═CH—(C6-C10) aryl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10 aryl-C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl-C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl-C1-C6 alkyl or unsubstituted or substituted C1-C6 alkyl-5-10 membered heteroaryl;
Z is selected from N, O or CR d , in which R d is hydrogen, deuterium, halo, C1-C4 alkyl or C6-C12 aryl; and when Z is O, R 3 is absent;
R 3 is selected from the group consisting of hydrogen, deuterium, hydroxyl, amino, halo, CN, CO 2 R e1′ , CONR e2 R e2′ , C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, —O(C6-C10) aryl, unsubstituted or substituted —S(C6-C10) aryl, unsubstituted or substituted —NH(C6-C10) aryl, unsubstituted or substituted —NHC(═O)(C6-C10) aryl, unsubstituted or substituted —CONH—(C6-C10) aryl, unsubstituted or substituted —CH═CH—(C6-C10) aryl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10 aryl-C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl-C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl-C1-C6 alkyl or unsubstituted or substituted C1-C6 alkyl-5-10 membered heteroaryl; and R 3 forms, together with the adjacent W and T, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, 5-10 membered cycloalkyl or 5-10 membered heterocycloalkyl, where R e1 , R e1′ and R e2′ are each independently hydrogen, hydroxyl, and C1-C6 alkyl; and
Q is absent, O, N(R f ), S or SO 2 , where R f is selected from hydrogen or C1-C4 alkyl, where “unsubstituted or substituted” indicates that the group is unsubstituted or substituted with one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; and
represents the point of attachment.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a group represented by General Formula (IIa):
wherein
B is C═O or CH 2 ;
R 1 is selected from hydrogen, deuterium, halo, and C1-C4 alkyl;
R 10 is H, and Y 1 is NH or O, and is attached to L or directly to X; or
R 10 is absent, and the N attached to R 10 is directly attached to L or X; and Y 1 is H, NH 2 or halo; or
Ar is selected from the groups of:
wherein
represents the point of attachment.
3. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein X is selected from the groups represented by General Formulas
where
R 2 is selected from hydrogen, deuterium, halo, C1-C4 alkyl, and unsubstituted or substituted phenyl;
Q is absent, or selected from NH and O;
W is selected from CR g1 R g1′ , O, and NR g2 , in which R g1 , R g1′ and R g2 are each independently hydrogen, C1-C6 alkyl, CO 2 R g3 or CONR g4 R g4′ ; where R g3 , R g4 and R g4′ are each independently hydrogen or C1-C6 alkyl;
R 3 is selected from the group consisting of unsubstituted or substituted —CONH—(C6-C10) aryl, —CO 2 —(C6-C10) aryl, unsubstituted or substituted —CH═CH—(C6-C10) aryl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C1-C6 alkyl-C6-C10 aryl, unsubstituted or substituted —O(C6-C10) aryl, unsubstituted or substituted —S(C6-C10) aryl, unsubstituted or substituted —NH(C6-C10) aryl, unsubstituted or substituted —NHC(═O)(C6-C10) aryl, or unsubstituted or substituted C1-C6 alkyl-5-10 membered heteroaryl;
Z is selected from CR e3 and N, in which R e3 is selected from hydrogen, C1-C6 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and unsubstituted or substituted C6-10 aryl; and
the ring C is unsubstituted or substituted C6-C10 aryl, or unsubstituted or substituted 5-10 membered heteroaryl;
where “unsubstituted or substituted” indicates that the group is unsubstituted or substituted with one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halo, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6hydroxyl alkyl; and
represents the point of attachment.
4. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein R 3 is selected from the groups of:
wherein
X 1 is hydrogen, halo or CF 3 ;
X 2 is hydrogen, halo or CF 3 ;
R c1 , R c2 , R c3 , R c4 , R c5 and R c6 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halo, cyano, nitro, formyl, CO 2 R h , CONR h1 R h1 , NR h2 R h2′ , C1-C4 alkyl, C1-C10 heteroalkyl, C2-C4 alkenyl, C2-C4 alkynyl, unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted 3-7 membered heterocycloalkenyl, unsubstituted or substituted C6-C10 aryl-C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl-C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl-C1-C6 alkyl, and unsubstituted or substituted C1-C6 alkyl-5-10 membered heteroaryl, in which R h , R h1 , R h1′ , R h2 and R h2′ are each independently selected from hydrogen and C1-C4 alkyl; or
R c1 and R c2 , or R c2 and R c3 , or R c3 and R c4 , or R c5 and R c6 form, together with the ring atoms in the ring to which they are attached, unsubstituted or substituted C6-C10 aryl, or unsubstituted or substituted 5-10 membered heteroaryl,
where “unsubstituted or substituted” indicates that the group is unsubstituted or substituted with one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyl alkyl; or
R 3 is selected from the groups of:
wherein
represents the point of attachment.
5. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein X is selected from the groups of:
wherein
represents the point of attachment.
6. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein
L is absent, or is a divalent group represented by General Formula (IV) or a trivalent group represented by General Formula (V):
wherein
J and M are each independently absent, NR i , O, S, SO 2 , C(═O) or C(═S), in which R i is 11 hydrogen, C1-C4 alkyl or C6-C10 aryl;
K is absent, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, unsubstituted or substituted C6-C10 arylene, unsubstituted or substituted 5-10 membered heteroarylene, unsubstituted or substituted C3-C8 cycloalkylene, unsubstituted or substituted 3-10 membered non-aromatic heterocyclylene, peptidylene consisting of 2 to 8 identical or different amino acids, or any combination of two, three, or four identical or different groups thereof; and
K 1 is a bivalent group, selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-10 membered non-aromatic heterocyclyl, peptidyl consisting of 2 to 8 identical or different amino acids, and any combination of two, three, or four identical or different groups thereof,
where “unsubstituted or substituted” indicates that the group is unsubstituted or substituted with one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyl alkyl;
preferably, the divalent and trivalent groups represented by General Formulas (IV) and (V) are selected from the following groups or any combinations of identical or different groups thereof:
wherein m and n are each independently 0, 1, 2, 3, 4 or 5;
X b , X c , X h and X i are each independently absent, O, S or NH;
R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 32 , R 33 and R 34 are each independently absent, C1-C10 alkylene, C3-C10 cycloalkylene, C1-C6 heteroalkylene, C2-C6 alkenylene, C2-C6 alkynylene, unsubstituted or substituted C6-C10 arylene, unsubstituted or substituted 5-10 membered heteroaryl ene, unsubstituted or substituted C3-C8 cycloalkylene, unsubstituted or substituted 3-10 membered non-aromatic heterocyclylene, or any combination of two, three, or four identical or different groups thereof;
R 30 and R 31 are each independently H, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted 3-10 membered non-aromatic heterocyclyl, or any combination of two, three, or four identical or different groups thereof;
An and Ar 2 are each independently unsubstituted or substituted C6-C10 arylene, or unsubstituted or substituted 5-10 membered heteroarylene; and
the rings D and E are each independently unsubstituted or substituted 3-10 membered nitrogen-containing heterocyclic ring,
where “unsubstituted or substituted” indicates that the group is unsubstituted or substituted with one or more substituents selected from hydroxyl, amino, cyano, nitro, carboxyl, halo, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 hydroxyalkyl; and
preferably, the divalent and trivalent groups represented by General Formulas IV and V are selected from the groups of:
wherein the group is attached to Ar at the end
and to the fragment X at the end
7. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the compound is selected from the compounds of General Formulas (VI), (VII), (VIII), (IX), (X) and (XI):
wherein A, B, Ra, R 2 , R 3 , Q, L, W, T, and Z are as defined in corresponding claims;
Y 2 is H, NH 2 or halo; and
Y 3 is NH or O.
8. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the compound is selected from:
Compound
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9. A pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 , and optionally a pharmaceutically acceptable excipient.