Dihydronaphthyridinyl(organo)methanone analogs as positive allosteric mGluR5 modulators
In one aspect, the invention relates to dihydronaphthyridinyl(organo)methanone analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A compound having a structure represented by a formula:
wherein one of Y 1 and Y 2 is N, and the other is C—R 3a ;
wherein Y 3 is O, N—R 7 , or a covalent bond;
wherein one of L 1 and L 2 is —O—, and the other is —C(R 1a , R 1b )—; provided that when Y 1 is N, L 1 is —O— and L 2 is —C(R 1a R 1b )—;
wherein Ar 1 is phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy, or Ar 1 is monocyclic heteroaryl having 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy;
wherein each of R 1a and R 1b is independently selected from hydrogen and C1-C4 alkyl;
wherein R 2 is selected from hydrogen; C1-C6 alkyl; (C1-C6 alkyloxy) C1-C6 alkyl; C3-C8 cycloalkyl; (C3-C8 cycloalkyl) C1-C6 alkyl; C2-C5 heterocyclyl; phenyl with 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy; and monocyclic heteroaryl having 0-3 substituents selected from halogen, cyano, C1-C4 alkyl, and C1-C4 alkyloxy;
wherein R 3a is selected from hydrogen, halogen, cyano, and C1-C4 alkyl;
wherein R 3b is selected from hydrogen, halogen, cyano, and C1-C4 alkyl, or R 3a and R 3b are substituted on adjacent carbons and are covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused ring selected from 4- to 7-membered cycloalkenyl, 5- to 7-membered heteroaryl, and 6-membered aryl;
wherein R 4a and R 4b are independently selected from hydrogen and C1-C4 alkyl, or R 4a and R 4b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl;
wherein R 5a and R 5b are independently selected from hydrogen and C1-C4 alkyl; or R 5a and R 5b are covalently bonded and, together with the intermediate carbon, comprise an optionally substituted 3- to 7-membered spirocycloalkyl; or R 4a and R 5a are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused cycloalkyl;
wherein R 6a and R 6b are independently selected from hydrogen and C1-C4 alkyl, or R 6a and R 6b together comprise an exocyclic double bond, or R 6a and R 6b arecovalently bonded and, together with the intermediate carbon, comprise cyclopropyl; and
wherein R 7 is selected from hydrogen and C1-C6 alkyl; and
or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
2. The compound of claim 1 , wherein halogen is fluoro, chloro, or bromo.
3. The compound of claim 1 , wherein Ar 1 is phenyl.
4. The compound of claim 1 , wherein Ar 1 is substituted with 1-3 halogens.
5. The compound of claim 1 , wherein Y 3 is a covalent bond.
6. The compound of claim 1 , wherein R 2 is phenyl.
7. The compound of claim 1 , wherein Y 1 is C—R 3a , and Y 2 is N.
8. The compound of claim 1 , wherein L 1 is —O—; and L 2 is —C(R 1a , R 1b )—.
9. The compound of claim 1 , wherein each of R 1a , R 1b , R 3a , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b is hydrogen.
10. The compound of claim 1 , having a structure represented by a formula:
11. The compound of claim 1 , having a structure represented by a formula:
wherein Ar 1 is phenyl substituted with 0-3 substituents selected from —F, —Cl, —Br, and —I; and wherein R 2 is phenyl substituted with 0-3 substituents selected from —F, —Cl, —Br, and —I.
12. The compound of claim 1 , wherein the compound exhibits potentiation of mGluR5 response to glutamate in human embryonic kidney cells transfected with rat mGluR5 with an EC 50 of less than about 10,000 nM.