Small molecule agonists of neurotensin receptor 1

1. A compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

ring A is C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl or monocyclic heteroaryl;

ring B is an optionally substituted hetereocycloalkyl;

each Y 1 , Y 2 , Y 3 , and Y 4 is independently selected from N and CR 2 , provided that at least 1 of Y 1 , Y 2 , Y 3 , and Y 4 is N;

G is optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 haloalkyl, -L 1 -R d , or -L 3 -N(R b )—R d ;

L 1 is absent, C 1 -C 4 alkylene, C 1 -C 4 alkenylene, C 1 -C 4 alkynylene, —O— or —N(R b )—;

L 3 is absent or an optionally substituted C 1 -C 4 alkylene;

R b is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 haloalkyl, —C(═O)R 11 , —C(═O)—O—R 11 , —S(═O) 2 R 11 ;

R d is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 haloalkyl, or optionally substituted C 1 -C 6 heterocycloalkyl, wherein if R d is substituted then it is substituted with R 1 ;

or R b and R d taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl;

or G is -L 1 -R d ; L 1 is absent; and R d is an optionally substituted C 3 -C 6 cycloalkyl;

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 and C 1 -C 4 alkyl, —C(═O)R 11 , —C(═O)—O—R 11 , —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;

R 2 is hydrogen, halogen, —CN, —OH, —NO 2 , —N(R 3 )—R 4 , 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 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 );

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 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —C(═O)R 11 , —C(═O)—O—R 11 , —C(═O)N(R 12 )R 13 , or —S(═O) 2 R 11 ,

or R b and R 10 are taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl;

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, 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;

provided that the compound is not 2-cyclopropyl-6-methoxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)pyrido[3,4-d]pyrimidine or 2-cyclopropyl-4-(4-(2-methoxyphenyl)piperazin-1-yl)pyrido[2,3-d]pyrimidine.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is monocyclic heteroaryl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring A is pyridine, pyrimidine, pyrazine, pyridazine, or thiophene.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (VIII) has the following structure:

5. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula (VIII) has the structure of Formula (Villa):

6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

Y 2 is N;

R 2 is —N(R 3 )—R 4 ;

R 3 is hydrogen, C 1 -C 4 alkyl;

R 4 is hydrogen, optionally substituted C 1 -C 4 alkyl, —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)R 11 , —C(═O)—O—R 11 , —S(═O) 2 R 11 ,

or R b and R 10 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 6 heterocycloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

R b and R 10 are taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl, wherein the optionally substituted C 2 -C 6 hetercycloalkyl is optionally substituted pyrrolidinyl, piperidinyl, or morpholinyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

Y 2 is N;

R 2 is —N(R 3 )—R 4 , and

R 3 and R 4 taken together with the nitrogen to which they are attached form an optionally substituted C 2 -C 6 heterocycloalkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

the optionally substituted C 2 -C 6 heterocycloalkyl is optionally substituted azetidenyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

Y 2 is CR 2 ; and each R 2 is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 4 alkoxy.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring B is an N-containing optionally substituted monocyclic heterocycloalkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring B is

and 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 are taken together form an oxo.

13. The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 5 and R 6 are each hydrogen.

14. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring B is an N-containing optionally substituted bicyclic heterocycloalkyl or an N-containing optionally substituted tricyclic heterocycloalkyl, wherein the N-containing optionally substituted bicyclic heterocycloalkyl or an N-containing optionally substituted tricyclic heterocycloalkyl is octahydropyrrolo[3,4-c]pyrrolyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, or 2,6-diazaspiro[3.3]heptanyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

ring B is

16. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

G is -L 1 -R d ; L 1 is absent; and R d is an optionally substituted C 3 -C 6 cycloalkyl.

17. The compound of claim 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein:

R d is

R 1 is hydrogen; halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; and m is 1 or 2.

18. A compound that is:

or a pharmaceutically acceptable salt or solvate thereof.

19. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

20. A method of modulating neurotensin or neurotensin receptor 1 in a subject, comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.