Cyclobutyl amine derivatives

1. A compound of formula:

or a pharmaceutically acceptable salt, ester, or amide thereof, wherein:

one of R 1 and R 2 is a group of the formula -L 2 -R 6a -L 3 -R 6b ;

the other of R 1 and R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;

R 3 , R 3a , and R 3b are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;

R 4 and R 5 are each independently selected from the group consisting of alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl, 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, cycloalkyl, and alkyl;

R 11 , R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;

R 6a is a 5- to 6-membered heteroaryl ring, or an 8- to 10-membered bicyclic heteroaryl ring;

R 6b is hydrogen,

Q is O or S;

L is —[C(R 16 )(R 17 )] k ;

L 2 is a bond;

L 3 is a bond;

R 16 and R 17 at each occurrence are independently selected from the group consisting of hydrogen and alkyl;

R x and R y at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;

k is 0, 1, or 2;

m is an integer from 1 to 5; and

n is 0 or 1.

2. The compound of claim 1 , wherein R 1 is -L 2 -R 6a -L 3 -R 6b , wherein L 2 is a bond, R 6b is hydrogen, L 3 is a bond, and R 6a is selected from a 5- or 6-membered heteroaryl ring.

3. The compound of claim 2 , wherein R 6a is an unsubstituted or substituted ring selected from the group consisting of furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazin-onyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, pyridazinonyl, pyridonyl, and pyrimidinonyl.

4. The compound of claim 2 , wherein R 6a is an unsubstituted or substituted heteroaryl ring selected from the group consisting of pyrimidinyl, pyridazinonyl, pyridinyl, and pyrazolyl.

5. The compound of claim 1 , wherein R 1 is -L 2 -R 6a -L 3 -R 6b , wherein L 2 is a bond, R 6b is hydrogen, L 3 is a bond, and R 6a is selected from a 8- to 10-membered bicyclic heteroaryl ring.

6. The compound of claim 5 , wherein R 6a is an unsubstituted or substituted ring selected from the group consisting of indolyl, benzothienyl, benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, and pyrrolopyrimidinyl.

7. The compound of claim 6 , wherein R 6a is unsubstituted or substituted benzothiazolyl.

8. The compound of claim 1 , wherein one of R 3 , R 3a , and R 3b is halogen and the others are hydrogen.

9. 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).

10. The compound of claim 9 , 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 alkyl, fluoro, or hydroxy.

11. 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 or (2S)-methylpyrrolidine ring.

12. The compound of claim 1 , wherein the compound has the formula

wherein L, n, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , and R 5 are each as defined in claim 1 .

13. The compound of claim 12 , wherein R 1 is -L 2 -R 6a -L 3 -R 6b , wherein L 2 is a bond, R 6b is hydrogen, L 3 is a bond, R 6a is selected from a 5- or 6-membered heteroaryl ring, and 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).

14. The compound of claim 1 , wherein the compound has the formula

wherein L, n, R 1 , R 2 , R 3 , R 3a , R 3b , R 4 , and R 5 are each as defined in claim 1 .

15. The compound of claim 14 , wherein R 1 is -L 2 -R 6a -L 3 -R 6b , wherein L 2 is a bond, R 6b is hydrogen, L 3 is a bond, R 6a is selected from a 5- or 6-membered heteroaryl ring, and 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).

16. The compound of claim 1 , selected from the group consisting of

5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyrimidine;

2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-cis-cyclobutyl]-phenyl}-pyridine;

2,6-difluoro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

2,6-dimethyl-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

2,6-dichloro-3-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-2H-pyridazin-3-one;

5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2,4-dimethoxy-5-{4-[3-({2S}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-nicotinonitrile;

2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-benzothiazole;

2-methyl-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyridine;

1,3,5-trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-1H-pyrazole;

5-{2-fluoro-4-[3-({2R}-2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-pyrimidine;

2,6-difluoro-3-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyridine;

5-{4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine;

1,3,5-trimethyl-4-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-1H-pyrazole;

2-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H-pyridazin-3-one;

2-methoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine; and

2,4-dimethoxy-5-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-pyrimidine.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.