Tetrahydronaphthyridine derivatives as mGluR2-negative allosteric modulators, compositions, and their use
View Patent ↗The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , L, X 1 , X 2 , and X 3 , are as defined herein. The compounds of the invention, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising them, are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a person in need thereof for diseases or disorders in which the mGluR2-NAM receptor plays a causative role, such as Alzheimer's disease, cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders.
1. A compound of Formula (I):
or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein:
X 1 is selected from the group consisting of —C(R X1 ) 2 —,
—CHcyclopropyl-, and —CHcyclobutyl-;
wherein each R X1 is independently selected from the group consisting of H, —(C 1-4 )alkyl, —(C 2-4 )alkenyl, and —(C 2-4 )alkynyl;
X 2 is selected from the group consisting of, —C(R X2 ) 2 —,
—CHcyclopropyl-, —CHcyclobutyl-;
wherein each R X2 is independently selected from the group consisting of H, —(C 1-4 )alkyl, —(C 2-4 )alkenyl, and —(C 2-4 )alkynyl;
X 3 is selected from the group consisting of —C(R X3 ) 2 —;
wherein each R X3 is independently selected from the group consisting of H, —(C 1-4 )alkyl, and fluoro;
R 1 is selected from the group consisting of phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of said phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 1 is unsubstituted or substituted with from 1 to 3 R 1A groups;
each R 1A (when present) is independently selected from the group consisting of halo, OH, CN, —(C 1-4 )alkyl, —(C 1-4 )haloalkyl, —(C 1-4 )alkoxy, —(C 1-4 )haloalkoxy, cyclopropyl, cyclobutyl, —NH 2 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —S(O) 2 (C 1-4 )alkyl, CH 2 OH, CH 2 CH 2 OH, NH(CO)CH 3 , oxadiazole, triazole, and pyrazole;
or, alternatively, two R 1A groups on the same or adjacent atoms are taken together with the ring atom of R 1 to which they are attached to form a a cyclopropyl, cyclobutyl, spirocyclopropyl, or spirocyclobutyl group;
-L- is a divalent moiety selected from the group consisting of —(C(R L1 ) 2 ) p —, —C(O)—, —C(O)CH 2 —, and —CH 2 C(O)—,
wherein p is 1 to 3, and each R L1 is independently selected from the group consisting of H, OH, —CH 3 , —CH 2 CH 3 , —CH 2 CF 3 , —CHF 2 , —CF 3 , and —CH 2 OH; and
R 2 is selected from the group consisting of phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein each of said phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl of R 2 is unsubstituted or substituted with from 1 to 3 R 2A groups;
each R 2A (when present) is independently selected from the group consisting of halo, OH, CN, —(C 1-4 )alkyl, —(C 1-4 )haloalkyl, —(C 1-4 )alkoxy, —(C 1-4 )haloalkoxy, cyclopropyl, cyclobutyl, —NH 2 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —S(O) 2 (C 1-4 )alkyl, CH 2 OH, CH 2 CH 2 OH, NH(CO)CH 3 , oxadiazole, triazole, and pyrazole;
or, alternatively, two R 2A groups on the same or adjacent atoms are taken together with the ring atom of R 2 to which they are attached to form a cyclopropyl, cyclobutyl, spirocyclopropyl, or spirocyclobutyl group.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula (II):
wherein each R X1 is independently selected from the group consisting of H, —(C 1-4 )alkyl, —(C 2-4 )alkenyl, and —(C 2-4 )alkynyl.
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of phenyl, cyclobutyl, cyclohexyl, cyclopentyl, benzimidazolyl, imidazolyl, imidazopyridinyl, imidazopyridinyl, imidazopyrimidinyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, oxetanyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, and triazolyl; and
R 1A is 1, 2, or 3 groups independently selected from the group consisting of F, OH, —(C 1-4 )alkyl, —(C 1-4 )haloalkyl, —(C 1-4 )alkoxy, —(C 1-4 )haloalkoxy, cyclopropyl, cyclobutyl, —NH 2 , —C(O)NH 2 , and —S(O) 2 —(C 1-4 )alkyl.
4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is selected from the group consisting of phenyl, azetidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, isothiazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, and thiazolyl; and
R 2A is 1, 2, or 3 groups independently selected from the group consisting of H, halo, CN, —(C 1-4 )alkyl, —(C 1-4 )haloalkyl, —(C 1-4 )alkoxy, cyclopropyl, and spirocyclopropyl.
5. A compound of claim 4 , wherein -L- is —(C(R L1 ) 2 ) p —, wherein p is 1 to 3, and each R L1 is independently selected from the group consisting of H, OH, —CH 3 , —CH 2 CH 3 , —CH 2 CF 3 , —CHF 2 , —CF 3 , and —CH 2 OH.
6. A compound of claim 5 , wherein -L- is —CH 2 —.
7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Structure
8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.