Small molecule agonists of neurotensin receptor 1
Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
1. A method for treating substance abuse in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate, thereof:
wherein,
ring A is phenyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, or monocyclic heteroaryl;
A is CH or N;
R 1 is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or —N(R a ) 2 ; and R 3 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;
or
R 1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or —N(R a ) 2 ; and R 3 and R 9 are taken together with the intervening atoms to form an optionally substituted C 2 -C 6 heterocycloalkyl;
each R a is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, —C(═O)R 11 , —C(═O)—O—R 11 , and —S(═O) 2 R 11 , or 2 R a taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl;
L 1 is absent, C 1 -C 4 alkylene, C 1 -C 4 alkenylene, C 1 -C 4 alkynylene, or —N(R b )—;
R b is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —C(═O)—O—R 11 , —S(═O) 2 R 11 , or —C(═O)R 11 ;
R 2 is hydrogen, halogen, —CN, —OH, —NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 haloalkoxy, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
R 5 and R 6 are each independently selected from hydrogen, halogen, —OH, and C 1 -C 4 alkyl, or when on the same carbon, R 5 and R 6 taken together form an oxo;
R 7 is hydrogen, halogen, —CN, —OH, —NO 2 , —N(R 12 )—R 13 , —C(═O)—N(R 12 )—R 13 , —NR 12 C(═O)R 11 , —C(═O)—O—R 1 , —O—C(═O)—R 11 , —SR 12 , —S(═O)R 11 , —S(═O) 2 R 11 , —N(R 12 )S(═O) 2 R 11 , —S(═O) 2 —N(R 12 )—R 13 , —C(═O)R 11 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 haloalkoxy, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R 8 is hydrogen, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, or —N(R a ) 2 ;
R 9 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl;
X is —O— or —N(R b )—;
R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —C(═O)—O—R 11 , —C(═O)N(R 12 )R 13 , —S(═O) 2 R 11 , or —C(═O)R 11 ;
each R 11 is independently selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
each of R 12 and R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; or R 12 and R 13 , when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted C 2 -C 6 heterocycloalkyl;
n is 1, 2, or 3; and
m is 1, 2, 3, or 4.
2. The method of claim 1 , wherein:
the substance abused is an amphetamine, an opioid, a cannabinoid, a barbiturate, a benzodiazepine, nicotine, alcohol, a hallucinogen, cocaine, or combinations thereof.
3. The method of claim 1 , wherein:
the substance abused is a psychostimulant.
4. The method of claim 1 , wherein:
the compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, has the following structure of Formula (Ia), or a pharmaceutically acceptable salt, or solvate thereof:
5. The method of claim 4 , wherein:
R 1 is halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or —N(R a ) 2 ; and
R 3 is hydrogen or C 1 -C 4 alkyl.
6. The method of claim 4 , wherein:
R 1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or —N(R a ) 2 ; and
R 3 and R 9 are taken together with the intervening atoms to form an optionally substituted C 2 -C 6 heterocycloalkyl.
7. The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, has the following structure of Formula (Ib), or a pharmaceutically acceptable salt, or solvate thereof:
8. The method of claim 7 , wherein the compound of Formula (Ib), or a pharmaceutically acceptable salt, or solvate thereof, has one of the following structures, or a pharmaceutically acceptable salt, or solvate thereof:
9. The method of claim 7 , wherein:
A is CH;
R 7 is hydrogen, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy;
R 8 is C 1 -C 4 alkoxy or —N(R a ) 2 ;
R 10 is hydrogen or C 1 -C 4 alkyl;
m is 1 or 2; and
n is 1 or 2.
10. The method of claim 7 , wherein:
A is N;
R 7 is hydrogen, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy;
R 8 is C 1 -C 4 alkoxy or —N(R a ) 2 ;
R 10 is hydrogen or C 1 -C 4 alkyl;
m is 1 or 2; and
n is 1 or 2,
11. A method for treating substance abuse in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, or solvate, thereof:
wherein,
ring A is C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, or monocyclic heteroaryl;
ring B is an optionally substituted hetereocycloalkyl, wherein if ring B is substituted then it is substituted with R 5 and R 6 ;
R 1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, or —N(R a ) 2 ;
each R a is independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, —C(═O)R 11 , —C(═O)—O—R 11 , and —S(═O) 2 R 11 , or 2 R a taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl;
L 1 is absent, C 1 -C 4 alkylene, C 1 -C 4 alkenylene, C 1 -C 4 alkynylene, —O—, or —N(R b )—;
R b is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —C(═O)—O—R 11 , —S(═O) 2 R 11 , or —C(═O)R 11 ;
R 2 is hydrogen, halogen, —CN, —OH, —NO 2 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 haloalkoxy, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
L 2 is absent or an optionally substituted C 1 -C 4 alkylene;
R 3 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;
R 4 is hydrogen, optionally substituted C 1 -C 4 alkyl, —C 1 -C 4 alkylene-C(═O)OR 11 , —C 1 -C 4 alkylene-OR 10 , or —C 1 -C 4 alkylene-N(R b )(R 10 );
R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —C(═O)—O—R 11 , —C(═O)N(R 12 )R 13 , —S(═O) 2 R 11 , or —C(═O)R 11 ; or R 10 and R b are taken together with the N atom to which they are attached to form a C 2 -C 6 heterocycle;
or R 3 and R 4 taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl;
R 5 and R 6 are each independently selected from hydrogen, halogen, —OH, and C 1 -C 4 alkyl, or when on the same carbon, R 5 and R 6 taken together form an oxo;
R 7 is hydrogen, halogen, —CN, —OH, —NO 2 , —N(R 12 )—R 13 , —C(═O)—N(R 12 )—R 13 , —NR 12 C(═O)R 11 , —C(═O)—O—R 11 , —O—C(═O)—R 11 , —SR 12 , —S(═O)R 11 , —S(═O) 2 R 11 , —N(R 12 )S(═O) 2 R 11 , —S(═O) 2 —N(R 12 )—R 13 , —C(═O)R 11 , optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 haloalkoxy, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R 8 is hydrogen, —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, or —N(R a ) 2 ;
each R 11 is independently selected from the group consisting of optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3- C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
each of R 12 and R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 fluoroalkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 2 -C 6 heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; or R 12 and R 13 , when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted C 2 -C 6 heterocycloalkyl; and
m is 1, 2, 3 or 4.
12. The method of claim 11 , wherein:
the substance abused is an amphetamine, an opioid, a cannabinoid, a barbiturate, a benzodiazepine, nicotine, alcohol, a hallucinogen, cocaine, or combinations thereof.
13. The method of claim 11 , wherein:
the substance abused is a psychostimulant.
14. The method of claim 11 , wherein:
ring A is monocyclic heteroaryl;
R 1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or —N(R a ) 2 ;
L 1 is absent;
L 2 is absent or —CH 2 —;
R 3 is hydrogen or C 1 -C 4 alkyl;
R 4 is C 1 -C 4 alkyl, —C 1 -C 4 alkylene-OR 10 , or —C 1 -C 4 alkylene-N(R b )(R 10 );
or R 3 and R 4 taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 5 heterocycloalkyl;
R 7 is hydrogen, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy; and
m is 1 or 2.
15. The method of claim 11 , wherein:
ring A is C 3 -C 6 cycloalkyl;
R 1 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or —N(R a ) 2 ;
L 1 is absent;
L 2 is absent or —CH 2 —;
R 3 is hydrogen or C 1 -C 4 alkyl;
R 4 is C 1 -C 4 alkyl, —C 1 -C 4 alkylene-OR 10 , or —C 1 -C 4 alkylene-N(R b )(R 10 );
or R 3 and R 4 taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 5 heterocycloalkyl;
R 7 is hydrogen, halogen, —CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, or C 1 -C 4 haloalkoxy; and
m is 1 or 2.
16. The method of claim 11 , wherein:
ring B is an N-containing optionally substituted monocyclic heterocycloalkyl.
17. The method of claim 11 , wherein:
ring B is an N-containing optionally substituted bicyclic heterocycloalkyl or an N-containing optionally substituted tricyclic heterocycloalkyl.
18. A method for treating substance abuse in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound that is:
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine;
{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine;
{4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-[1-(methyl-propyl-amino)-cyclopropyl]-quinazolin-6-yl}-methyl-propyl-amine;
2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
N-[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine;
2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2-methoxy-ethyl)-methyl-amine;
N-[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine;
2-{[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2-methoxy-ethyl)-methyl-amine;
N-(2-methoxyethyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-2-(1-methylcyclopropyl)quinazolin-6-amine;
2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
{[4-[4-(2-Dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-Dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(2-Methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({2-(1-fluoro-cyclopentyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol;
{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(4-methoxy-piperidin-1-yl)-quinazoline;
(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-dimethyl-amine;
1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;
2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline;
(R)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;
(S)-1-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol;
(R)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline;
(S)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline;
[(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl)}-piperidin-4-yl)-methyl-amino]-acetic acid ethyl ester;
4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine;
4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2-dimethyl-N6,N6-dipropylquinazoline-2,6-diamine;
N2-Cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-N6-methyl-N6-propyl-quinazoline-2,6-diamine;
2-((2-(cyclobutylamino)-4-(4-(2-methoxyphenyl)piperidin-1-yl) quinazolin-6-yl)(methyl)amino)ethanol;
2-({2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-((2-cyclopropyl-4-(4-(3-methoxythiophen-2-yl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol;
2-((4-(4-cyclohexylpiperidin-1-yl)-2-(1-fluorocyclopropyl)quinazolin-6-yl)(methyl)amino)ethanol;
2-(4-{2-cyclopropyl-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-yl}-piperazin-1-yl)-cyclopentanol;
2-{4-[2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-yl]-piperazin-1-yl}-cyclopentanol;
2-(4-{2-cyclopropyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-quinazolin-4-yl}-piperazin-1-yl)-cyclopentanol;
(1-Fluoro-cyclopropyl)-{7-fluoro-6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-2-yl}-methanone;
{7-Chloro-6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-2-yl}-(1-fluoro-cyclopropyl)-methanone;
(S)-1-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol;
(S)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline;
(R)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl})-pyrrolidin-3-ol;
(R)-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline;
(S)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;
(R)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;
2-((2-(1-fluorocyclopropyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)acetic acid;
2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol;
3-{8-Chloro-2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl)}-cyclopentanol;
3-{8-Chloro-2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl)}-cyclopentanol;
2-({2-Cyclopropyl-4-[4-(2-methoxy-cyclopentyl)-piperazin-1-yl]-quinazolin-6-yl)}-methyl-amino)-ethanol;
2-cyclopropyl-4-(4-(2-methoxycyclopentyl)piperazin-1-yl)-N-methyl-N-propylquinazolin-6-amine
2-{[4-(4-Cyclohexyl-piperidin-1-yl)-2-(1-fluoro-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-cyclohexyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-({2-Cyclopropyl-4-[4-(3-methoxy-thiophen-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol;
1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;
1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;
2-({2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol;
1-{2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;
1-{2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;
2-({8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
1-{8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;
1-{8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;
2-{[8-Fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[4-[4-(3-Methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[2-(1-Fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-{[2-(1-Fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-{[2-(1-Fluoro-cyclopropyl)-4-(4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-{[2-(1-Fluoro-cyclopropyl)-4-(3′-methoxy-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-{[8-Fluoro-2-(1-fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-{[8-Fluoro-2-(1-fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;
2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-({2-(1-Fluoro-cyclopropyl)-4-[4-(4-iodo-2-methoxy-phenyl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-({2-(1-Fluoromethyl-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
2-({2-(1-Fluoro-cyclobutyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;
1-(6-((2-hydroxyethyl)(methyl)amino)-4-(4-(3-methoxypyrazin-2-yl)piperidin-1-yl)quinazolin-2-yl)cyclobutanol;
(2-(1-Fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine;
{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine;
2-{1-[6-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-(1-fluoro-cyclopropyl)-quinazolin-4-yl]-piperidin-4-yl}-phenol; or
2-[(2-(1-Fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-methyl-amino]-ethanol;
or a pharmaceutically acceptable salt, or solvate thereof.
19. The method of claim 18 , wherein:
the substance abused is an amphetamine, an opioid, a cannabinoid, a barbiturate, a benzodiazepine, nicotine, alcohol, a hallucinogen, cocaine, or combinations thereof.
20. The method of claim 18 , wherein:
the substance abused is a psychostimulant.