US 10,118,902 B2Granted

Small molecule agonists of neurotensin receptor 1

AssigneeSanford Burnham Prebys Medical Discovery Institute

InventorsAnthony B. Pinkerton, Paul M. Hershberger, Satyamaheshwar Peddibhotla, Patrick R. Maloney, Michael P. Hedrick

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Abstract

Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

Claims21

Dependent claims

A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein,
ring A is phenyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, or monocyclic heteroaryl;
A is CH or N;
R1 is halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, —OH, or —N(Ra)2;
and R3 is hydrogen, C1-C4alkyl, or C1-C4haloalkyl;
or
R1 is hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, or —N(Ra)2;
and R3 and R9 are taken together with the intervening atoms to form an optionally substituted C2-C6heterocycloalkyl;
each Ra is independently selected from the group consisting of hydrogen, C1-C4 alkyl, —C(═O)R11, —C(═O)—O—R11, —S(═O)2R11, —C(═O)R11, or 2 Ra taken together with the nitrogen to which they are attached form an optionally substituted C2-C6heterocycloalkyl;
L1 is absent, C1-C4alkylene, C1-C4alkenylene, C1-C4alkynylene, or —N(Rb)—;
Rb is hydrogen, C1-C4alkyl, C1-C4haloalkyl, —C(═O)R11, —C(═O)—O—R11, —S(═O)2R11, or —C(═O)R11;
R2 is hydrogen, halogen, —CN, —OH, —NO2, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkoxy, optionally substituted C1-C4haloalkyl, optionally substituted C1-C4haloalkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R5 and R6 are each independently selected from hydrogen, halogen, —OH, and C1-C4alkyl, or when on the same carbon, R5 and R6 are taken together form an oxo;
R7 is hydrogen, halogen, —CN, —OH, —NO2, —N(R12)—R13, —C(═O)—N(R12)—R13, —NR12C(═O)R11, —C(═O)—O—R11, —O—C(═O)—R11, —SR12, —S(═O)R11, —S(═O)2R11, —N(R12)S(═O)2R11, —S(═O)2—N(R12)—R13, —C(═O)R11, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkoxy, optionally substituted C1-C4haloalkyl, optionally substituted C1-C4haloalkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R8 is hydrogen, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, or —N(Ra)2;
R9 is hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl;
X is —O— or —N(Rb)—;
R10 is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, —C(═O)R11, —C(═O)—O—R11, —C(═O)N(R12)R13, —S(═O)2R11, or —C(═O)R11;
each R11 is independently selected from the group consisting of optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
each of R12 and R13 is independently selected from the group consisting of hydrogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted C2-C6heterocycloalkyl;
n is 1, 2 or 3;
and
m is 1, 2, 3 or 4.

21 more elements

A compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:

wherein,
ring A is C3-C6cycloalkyl, C2-C6heterocycloalkyl, or monocyclic heteroaryl;
ring B is an optionally substituted hetereocycloalkyl, wherein if ring B is substituted then it is substituted with R5 and R6;
R1 is hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, or —N(Ra)2;
each Ra is independently selected from the group consisting of hydrogen, C1-C4 alkyl, —C(═O)R11, —C(═O)—O—R11, —S(═O)2R11, and —C(═O)R11, or 2 Ra taken together with the nitrogen to which they are attached form an optionally substituted C2-C6heterocycloalkyl;
L1 is absent, C1-C4alkylene, C1-C4alkenylene, C1-C4alkynylene, —O—, or —N(Rb)—;
Rb is hydrogen, C1-C4alkyl or C1-C4haloalkyl, —C(═O)R1, —C(═O)—O—R11, S(═O)2R11, or —C(═O)R11;
R2 is hydrogen, halogen, —CN, —OH, —NO2, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkoxy, optionally substituted C1-C4haloalkyl, optionally substituted C1-C4haloalkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
L2 is absent or an optionally substituted C1-C4alkylene;
R3 is hydrogen, C1-C4alkyl, or C1-C4haloalkyl;
R4 is hydrogen, optionally substituted C1-C4 alkyl, —C1-C4 alkylene-C(═O)OR11, —C1-C4 alkylene-OR10, or —C1-C4 alkylene-N(Rb)(R10);
R10 is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, —C(═O)R11, —C(═O)—O—R11, —C(═O)N(R12)R13, S(═O)2R11, or —C(═O)R11;
or R10 and Rb are taken together with the N atom to which they are attached to form a C2-C6heterocycle;
or R3 and R4 taken together with the nitrogen to which they are attached form an optionally substituted C2-C6heterocycloalkyl;
R5 and R6 are each independently selected from hydrogen, halogen, —OH, and C1-C4alkyl, or when on the same carbon, R5 and R6 are taken together form an oxo;
R7 is hydrogen, halogen, —CN, —OH, —NO2, —N(R12)—R13, —C(═O)—N(R12)—R13, —NR12C(═O)R11, —C(═O)—O—R11, —O—C(═O)—R11, —SR12, —S(═O)R11, —S(═O)2R11, —N(R12)S(═O)2R11, —S(═O)2—N(R12)—R13, —C(═O)R11, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkoxy, optionally substituted C1-C4haloalkyl, optionally substituted C1-C4haloalkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R8 is hydrogen, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, or —N(Ra)2;
each R11 is independently selected from the group consisting of optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
each of R12 and R13 is independently selected from the group consisting of hydrogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted C2-C6heterocycloalkyl;
n is 1, 2 or 3;
and
m is 1, 2, 3 or 4.

20 more elements

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;
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.

92 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/319,329Filed 24 Jun 2015 · us provisional application
Priority: 25 Jun 2014
Published: US 2017/0240514 A124 Aug 2017
Granted: 6 Nov 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 239/94
With hetero atoms directly attached in position 4: nitrogen atoms
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Application62/017,046Us provisional application · filed 25 Jun 2014
US 2017/0240514 A1Pre-grant publication · published 24 Aug 2017
US 10,118,902 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein,
ring A is phenyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, or monocyclic heteroaryl;
A is CH or N;
R1 is halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, —OH, or —N(Ra)2;
and R3 is hydrogen, C1-C4alkyl, or C1-C4haloalkyl;
or
R1 is hydrogen, halogen, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, or —N(Ra)2;
and R3 and R9 are taken together with the intervening atoms to form an optionally substituted C2-C6heterocycloalkyl;
each Ra is independently selected from the group consisting of hydrogen, C1-C4 alkyl, —C(═O)R11, —C(═O)—O—R11, —S(═O)2R11, —C(═O)R11, or 2 Ra taken together with the nitrogen to which they are attached form an optionally substituted C2-C6heterocycloalkyl;
L1 is absent, C1-C4alkylene, C1-C4alkenylene, C1-C4alkynylene, or —N(Rb)—;
Rb is hydrogen, C1-C4alkyl, C1-C4haloalkyl, —C(═O)R11, —C(═O)—O—R11, —S(═O)2R11, or —C(═O)R11;
R2 is hydrogen, halogen, —CN, —OH, —NO2, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkoxy, optionally substituted C1-C4haloalkyl, optionally substituted C1-C4haloalkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R5 and R6 are each independently selected from hydrogen, halogen, —OH, and C1-C4alkyl, or when on the same carbon, R5 and R6 are taken together form an oxo;
R7 is hydrogen, halogen, —CN, —OH, —NO2, —N(R12)—R13, —C(═O)—N(R12)—R13, —NR12C(═O)R11, —C(═O)—O—R11, —O—C(═O)—R11, —SR12, —S(═O)R11, —S(═O)2R11, —N(R12)S(═O)2R11, —S(═O)2—N(R12)—R13, —C(═O)R11, optionally substituted C1-C4alkyl, optionally substituted C1-C4alkoxy, optionally substituted C1-C4haloalkyl, optionally substituted C1-C4haloalkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, or optionally substituted 5- or 6-membered heteroaryl;
R8 is hydrogen, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, or —N(Ra)2;
R9 is hydrogen, C1-C4alkyl, or C1-C4fluoroalkyl;
X is —O— or —N(Rb)—;
R10 is hydrogen, C1-C4alkyl, C1-C4fluoroalkyl, —C(═O)R11, —C(═O)—O—R11, —C(═O)N(R12)R13, —S(═O)2R11, or —C(═O)R11;
each R11 is independently selected from the group consisting of optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
each of R12 and R13 is independently selected from the group consisting of hydrogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C6heterocycloalkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;
or R12 and R13, when on the same nitrogen atom, are taken together with the nitrogen atom to which they are attached to form an optionally substituted C2-C6heterocycloalkyl;
n is 1, 2 or 3;
and
m is 1, 2, 3 or 4.

21 more elements

Facts

Application

15/319,329Filed 24 Jun 2015 · us provisional application

Priority

25 Jun 2014

Published

US 2017/0240514 A124 Aug 2017

Granted

6 Nov 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 239/94
With hetero atoms directly attached in position 4: nitrogen atoms
A61P 21/00
Drugs for disorders of the muscular or neuromuscular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids