Bicyclic-substituted amines having cyclic-substituted monocyclic substituents
View Patent ↗Compounds of formula (I) wherein R 1 or R 2 is an aromatic or non-aromatic ring directly joined or joined by a linker, as represented by L 2 and L 3 , to a heteroaromatic core, and X, X′, Y, Y′, Z, Z′, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , R 5 , L, L 2 , and L 3 are as defined herein, are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).
1. A compound of the formula:
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
Y is N;
Y′ is CH; or CF;
X, X′, Z, and Z′ are each;
R 1 is a group of the formula -L 2 -R 6a -L 3 -R 6b ;
R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy;
R 3 is absent when X′ is N or R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;
R 3a is selected from the group consisting of hydrogen, methyl, alkoxy, halogen, and cyano;
R 3b is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, and thioalkoxy;
R 4 and R 5 are each independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NR A R B )alkyl, or R 4 and R 5 taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:
R 7 , R 8 , R 9 , and R 10 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl; or one of the pair R 7 and R 8 or the pair R 9 and R 10 is taken together to form a C 3 –C 6 ring, wherein 0, 1, or 2 heteroatoms selected from O, N, or S replace a carbon atom in the ring;
R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro;
R 6a and R 6b are each independently selected from the group consisting of a 5- to 6-membered heteroaryl, a 6-membered aryl, and a 5- to 6-membered heterocycle;
Q is selected from the group consisting of a bond, O, S, and NR 15 ;
L is —[C(R 16 )(R 17 )] k —;
L 2 is selected from the group consisting of a bond, —O—, —C(═O)—, —S—, —[C(R 18 )(R 19 )] q —, —O—[C(R 18 )(R 19 )] q —, —NH— and —N(alkyl)-;
L 3 is selected from the group consisting of a bond, —[C(R 16 )(R 17 )] r O—, —O—, —C(═O)—, —S—, —[C(R 18 )(R 19 )] q —, —O—[C(R 18 )(R 19 )] q —, —NH— and —N(alkyl)-;
R 15 is selected from the group consisting of hydrogen, alkyl, acyl, alkoxycarbonyl, amido, and formyl;
R 16 and R 17 at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and fluoro;
R 18 and R 19 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro;
R x and R y at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, dialkylamino, and fluoro, or one of R x or R y represents a covalent bond when taken together with R x or R y on an adjacent carbon atom such that a double bond is represented between the adjacent carbon atoms;
k is an integer from 1 to 6;
m is an integer from 1 to 5;
p is an integer from 2 to 6;
q is an integer from 1 to 4; and
r is an integer from 1 to 2.
2. The compound of claim 1 , wherein R 1 is -L 2 -R 6a -L 3 -R 6b , wherein L 2 is a bond, L 3 is a bond or —CH 2 O—, and R 6a and R 6b are each independently selected from a 5- or 6-membered heteroaryl ring, phenyl, and a non-aromatic 4- to 8-membered ring.
3. The compound of claim 2 , wherein R 6a and R 6b are each independently selected from the group consisting of isoxazolyl, morpholinyl, phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and cyclobutanyl.
4. The compound of claim 2 , wherein R 6a is selected from the group consisting of isoxazolyl, phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thienyl, triazolyl, and cyclobutanyl; and R 6b is selected from the group consisting of isoxazolyl, morpholinyl, phenyl, pyridazinyl, pyridinyl, pyrazinyl, pyrazolyl, thiadiazolyl, thiazolyl, and thienyl.
5. The compound of claim 1 , wherein at least one of R 6a and R 6b is 5- to 6-membered heteroaryl.
6. The compound of claim 1 , wherein R 6a is 5- to 6-membered heteroaryl and R 6b is 5- to 6-membered heterocycle.
7. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a).
8. The compound of claim 7 , wherein at least one substituent represented by R 7 , R 8 , R 9 , and R 10 is selected from the group consisting of alkyl, fluoroalkyl, and hydroxyalkyl or at least one substituent represented by R x or R y is selected from the group consisting of hydrogen, hydroxy, and fluoro.
9. The compound of claim 1 , wherein R 4 and R 5 are taken together with the nitrogen atom to which each is attached to form a (2R)-methylpyrrolidine ring.
10. The compound of claim 1 , selected from the group consisting of
6-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}-2-(4-methyl-2-thien-2-yl 1,3-thiazol-5-yl)quinoline;
6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-[2-(4-methyl-[1,2,3]thiadiazol-5-yl)-thiazol-4-yl]-quinoline;
2-(4-methyl-2-pyrazin-2-yl-thiazol-5-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazol-4-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-[2-(4-chloro-phenoxymethyl)-thiazol-4-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-[5-methyl-1-(6-methyl-4-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-[3-(4-chloro-phenyl)-isoxazol-5-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
6-[2-(2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-[5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophen-2-yl]-quinoline;
2-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(2-phenyl-thiazol-5-yl)-quinoline;
2-(4-methyl-2-pyridin-2-yl-thiazol-5-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-[3-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-isoxazol-5-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-(4-methyl-2-pyridin-4-yl-thiazol-5-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(2-phenyl-thiazol-4-yl)-quinoline;
2-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
1-(4-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-phenyl)-1H-pyridin-4-one;
6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(4-piperidin-1-yl-phenyl)-quinoline;
2-(5′-methyl-[2,2′]bithiophenyl-5-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-(6-methyl-2-phenyl-pyrimidin-4-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl ]-quinoline;
2-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(1-pyridin-3-yl-cyclobutyl)-quinoline;
2-methyl-3-[1-(5-methyl-isoxazol-3-yl)-1H-[1,2,4]triazol-3-yl]-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline;
2-[1-(2,4-difluoro-phenyl)-5-methyl-1H-[1,2,3]triazol-4-yl]-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
2-[1-(6-ethoxy-pyridazin-3-yl)-5-methyl-1H-pyrazol-4-yl]-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
2-(2′-methyl-[2,4′]bithiazolyl-4-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
2-[2-(5-methyl-isoxazol-3-yl)-thiazol-4-yl]-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
2-[2-(2,6-dichloro-pyridin-4-yl)-thiazol-4-yl]-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-{2-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-thiazol-4-yl}-quinoline;
2-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
2-(5-methyl-3-phenyl-isoxazol-4-yl)-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline;
6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-(3-phenyl-isoxazol-5-yl)-quinoline;
2-[4-(4,5-dichloro-imidazol-1-yl)-phenyl]-6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-quinoline; and
6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-(4-methyl-2-pyrrolidin-1-yl-pyrimidin-5-yl)-quinoline.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
12. A method of treating Alzheimer's disease, attention-deficit hyperactivity disorder, or schizophrenia comprising administering a compound of claim 1 .
13. A method of treating cognitive deficits of schizophrenia comprising administering a compound of claim 1 .