Substituted quinazoline compounds and preparation and uses thereof
The present invention relates quinazolinone compounds of Formula (I), as well as their preparation and uses, and further relates pharmaceutical compositions comprising these compounds and their uses; wherein the compounds or pharmaceutical compositions disclosed herein can be used for antagonizing the orexin receptor. The present invention also relates to uses of the compounds or pharmaceutical compositions in treating or preventing neurological and psychiatric disorders and diseases of the central nervous system in mammals, especially in humans.
1. A compound having Formula (I) or a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt,
wherein,
G is a 5-membered heterocycloalkyl or heteroaryl group containing at least one nitrogen, wherein G is optionally substituted with one or more R 8 ;
each R 1 is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylamino, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl or 5- to 12-membered heteroaryl, wherein each R 1 is optionally and independently substituted with one or more R 8 ;
each R 2 is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 hydroxyalkyl or C 1-4 haloalkyl;
each R 3 is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6-10 aryl or 5- to 12-membered heteroaryl, —(CR 4 R 4a ) q —OR 7 , —(CR 4 R 4a ) q —NR 5 R 6 , —(CR 4 R 4a ) q S(═O) r R 7 , —(CR 4 R 4a ) q S(═O) 2 NR 5 R 6 , —(CR 4 R 4a ) q C(═O)R 7 , —(CR 4 R 4a ) q OC(═O)R 7 , —(CR 4 R 4a ) q C(═O)OR 7 , —(CR 4 R 4a ) q —N(R 5 )C(═O)R 7 , —C(═NR 7 )NR 5 R 6 , —N(R 7 )C(═O)NR 5 R 6 , —(CR 4 R 4a ) q —N(R 5 )S(═O) r R 7 or —(CR 4 R 4a ) q C(═O)NR 5 R 6 , wherein each R 3 is optionally and independently substituted with one or more R 8 ;
wherein each R 4 and R 4a is independently H, D, F, Cl, Br, I, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 haloalkylamino, C 3-8 carbocyclyl, 3- to 8-membered heterocyclyl, C 6-10 aryl or 5- to 6-membered heteroaryl;
each R 5 , R 6 and R 7 is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkenyl, C 3-8 carbocyclyl, (C 3-6 cycloalkyl)-(C 1-4 alkylene)-, 3- to 8-membered heterocyclyl, (3- to 6-membered heterocyclyl)-(C 1-4 alkylene)-, phenyl, (C 6-10 aryl)-(C 1-4 alkylene)-, 5- to 6-membered heteroaryl or (5- to 6-membered heteroaryl)-(C 1-4 alkylene)-, or R 5 and R 6 together with the nitrogen atom to which they are attached, independently and optionally form 3- to 6-membered heterocyclyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 3-8 carbocyclyl is optionally and independently substituted with one or more substituents independently selected from D, F, Cl, Br, OH, NH 2 , CN, N 3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino;
each R 8 is independently H, D, F, Cl, Br, I, ═O, OH, NH 2 , NO 2 , CN, N 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl or C 1-4 haloalkylamino;
each m and n is independently 0, 1, 2, 3, or 4;
t is 0 or 1;
p is 0, 1, 2, 3, 4, or 5;
each r is independently 0, 1 or 2; and
each q is independently 0, 1, 2, 3, or 4.
2. The compound of claim 1 , wherein G is:
and G is optionally substituted with one or more R 8 .
3. The compound of claim 1 , wherein each R 1 is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 alkylamino, C 3-8 carbocyclyl, 3- to 8-membered heterocyclyl, C 6-10 aryl or 5- to 6-membered heteroaryl, wherein each R 1 is optionally and independently substituted with one or more R 8 .
4. The compound of claim 1 , wherein each R 1 is independently H, D, F, Cl, Br, OH, NH 2 , NO 2 , CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, methylamino, ethylamino, hydroxymethyl, hydroxyethyl, trifluoromethyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, thiazolyl or thienyl.
5. The compound of claim 1 , wherein each R 2 is independently H, F, Cl, OH, NH 2 , NO 2 , CN, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, propargyl, methoxy, ethoxy, methylamino, ethylamino, hydroxymethyl, hydroxyethyl or trifluoromethyl.
6. The compound of claim 1 , wherein each R 3 is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 carbocyclyl, 3- to 8-membered heterocyclyl, C 6-10 aryl, 5- to 6-membered heteroaryl, —(CR 4 R 4a ) q —OR 7 , —(CR 4 R 4a ) q —NR 5 R 6 , —(CR 4 R 4a ) q S(═O) r R 7 , (CR 4 R 4a ) q S(═O) 2 NR 5 R 6 , —(CR 4 R 4a ) q C(═O)R 7 , —(CR 4 R 4a ) q OC(═O)R 7 , —(CR 4 R 4a ) q C(═O)OR 7 , —(CR 4 R 4a ) q —N(R 5 )C(═O)R 7 , —C(═NR 7 )NR 5 R 6 , —N(R 7 )C(═O)NR 5 R 6 , —(CR 4 R 4a ) q —N(R 5 )S(═O) r R 7 or —(CR 4 R 4a ) q C(═O)NR 5 R 6 , wherein each R 3 is optionally and independently substituted with one or more R 8 .
7. The compound of claim 1 , wherein each R 3 is independently H, D, F, Cl, Br, OH, NH 2 , NO 2 , CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, methylamino, ethylamino, hydroxymethyl, hydroxyethyl, trifluoromethyl, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, thienyl, —C(═O)NH 2 or —COOH.
8. The compound of claim 1 , wherein each R 4 and R 4a is independently H, D, F, Cl, Br, I, CN, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, propargyl, methoxy, tert-butoxy, methylamino, —OCF 3 , —NHCF 3 , cyclopentyl, cyclohexyl, piperidin-1-yl, piperazin-1-yl, pyridin-2-yl, phenyl or naphthyl; and
each R 5 , R 6 and R 7 is independently H, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, propargyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, piperidin-1-yl, piperazin-1-yl, imidazol-1-yl, pyridin-4-yl-methyl, phenyl or benzyl, or R 5 and R 6 together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperazinyl, imidazolidinyl or morpholinyl.
9. The compound of claim 1 , wherein each R 8 is independently H, D, F, Cl, Br, I, ═O, OH, NH 2 , NO 2 , CN, N 3 , methyl, ethyl, ethynyl, propynyl, methoxy, tert-butoxy, methylamino, trifluoromethyl, trifluoromethoxy, hydroxymethyl or trifluoromethylamino.
10. The compound of claim 1 having one of the following structures:
11. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.