IP Library › Granted Patent US 8,901,156

Granted Patent B2

US 8,901,156 · App. 13/522,044 · Granted Dec 2, 2014

Compounds and methods

Inventors: Erkan Baloglu (Cambridge, MA); Shomir Ghosh (Cambridge, MA); Mercedes Lobera (Cambridge, MA); Darby Schmidt (Cambridge, MA)

Assignee: Tempero Pharmaceuticals, Inc.

A61K31/497 C07D417/14 C07D413/14 C07D271/06 C07D413/12

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,901,156
App. No.: 13/522,044
Granted: Dec 2, 2014
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed are compounds having the formula: wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , Y, A, Z, L and n are as defined herein, and methods of making and using the same.

Claims (239)

1. A compound according to Formula I:

wherein:

R 1 is halo(C 1 -C 4 )alkyl, wherein said halo(C 1 -C 4 )alkyl contains at least 2 halo atoms;

Y is a bond and X 1 is O, N or NH, X 2 is N or CH and X 3 is N or NH,

A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,

wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A ;

Z is —C(═O)NR X —, —NR X C(═O)NR X , —NR X C(═O)—, —SO 2 —, —SO 2 NR X —, —NR X SO 2 —, —NHCH(CF 3 )—, —CH(CF 3 )NH—, —CH(CF 3 )—, —(C 1 -C 4 )alkyl-, —NR X —, or —(C 1 -C 3 )alkyl-NR X —;

n is 0-4;

when n is 0, R 2 and R 3 are independently selected from H and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, or

when n is 1-4, R 2 and R 3 are independently selected from H, fluoro, and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, wherein, when n is 1, R 2 is F and R 3 is H, then Z is —C(═O)NR X —, —NR X C(═O)NR X , —SO 2 NR X —, —NHCH(CF 3 )—, —CH(CF 3 )NH—, —CH(CF 3 )—, —(C 1 -C 4 )alkyl-, —NR X —, or —(C 1 -C 3 )alkyl-NR X —, or

when n is 1-4, R 2 is selected from —NR A R B , —(C 1 -C 4 )alkyl-NR A R B , —CONR A R B , —(C 1 -C 4 )alkyl-CONR A R B , —CO 2 H, —(C 1 -C 4 )alkyl-CO 2 H, hydroxyl, hydroxy(C 1 -C 4 )alkyl-, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )alkoxy(C 1 -C 4 )alkyl-, and R 3 is selected from H and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-,

wherein the aryl, cycloalkyl and each of the (C 1 -C 4 )alkyl moieties of said optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl- of any R 2 and R 3 are optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A , —((C 1 -C 4 )alkyl)NR A R A , and hydroxyl;

or R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, aryl(C 1 -C 4 )alkyl-, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, —OR Y , —NR Y R Y , —C(═O)OR Y , —C(═O)NR Y R Y , —NR Y C(═O)R Y , —SO 2 NR Y R Y , —NR Y SO 2 R Y , —OC(═O)NR Y R Y , —NR Y C(═O)OR Y , and —NR Y C(═O)NR Y R Y ; and

L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted,

wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C 1 -C 4 )alkyl;

R 4 is H, (C 1 -C 4 )alkyl, halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N(C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N(C 1 -C 4 )alkyl-, (C 1 -C 4 )haloalkoxy-, (C 1 -C 4 )alkylamino, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,

wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1, 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C 1 -C 4 )alkoxy, hydroxyl, —NR A R C and —((C 1 -C 4 )alkyl)NR A R C ;

or L-R 4 , taken together, form a 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1, 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C 1 -C 4 )alkoxy, hydroxyl, —NR A R C and —((C 1 -C 4 )alkyl)NR A R C ;

wherein each R A is independently selected from H and (C 1 -C 4 )alkyl;

R B is H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —C(═O)(C 1 -C 4 )alkyl, —C(═O)O(C 1 -C 4 )alkyl, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 )alkyl, —C(═O)N((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl), —SO 2 (C 1 -C 4 )alkyl, or R A and R B taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C 1 -C 4 )alkyl;

R C is H, (C 1 -C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R A and R C taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C 1 -C 4 )alkyl;

each R X is independently selected from H, (C 1 -C 6 )alkyl, and optionally substituted (C 2 -C 6 )alkyl, where said optionally substituted (C 2 -C 6 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl)NH—, or ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N—; and

each R Y is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and —(C 1 -C 4 )alkylphenyl;

provided that the compound is not:

4-methoxy-N-[2-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]-3-thienyl]-benzeneacetamide,

N-[(4-methoxyphenyl)methyl]-4-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine,

4-(trifluoromethyl)-N-[3-(trifluoromethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]-benzenepropanamide,

3-{7-methyl-2-[4-(3-methyl-5-isoxazolyl)butyl]-1-benzofuran-5-yl}-5-(trifluoromethyl)-1,2,4-oxadiazole,

1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,

7-methyl-1-[4-(3-methyl-5-isoxazolyl)butyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,

7-methyl-1-[5-(3-methyl-5-isoxazolyl)pentyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1H-indole,

7-methyl-1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-indole, or

N-(phenylmethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine;

or a salt thereof.

2. The compound or salt according to claim 1 , wherein R 1 is CHF 2 or CF 3 .

3. The compound or salt according to claim 1 , wherein when Y is a bond, X 1 is O, X 2 and X 3 are N.

4. The compound or salt according to claim 1 , having the formula:

wherein:

R 1 is —CF 3 ;

A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,

n is 0-4;

when n is 0, R 2 and R 3 are independently selected from H and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-, or

when n is 1-4, R 2 is selected from amino, hydroxyl, and (C 1 -C 4 )alkoxy, and R 3 is selected from H and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-,

wherein the aryl, cycloalkyl and each of the (C 1 -C 4 )alkyl moieties of said optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl- of any R 2 and R 3 are optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, halogen, —NR A R A , —((C 1 -C 4 )alkyl)NR A R A , (C 1 -C 4 )alkoxy, hydroxyl, cyano, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy;

L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted,

wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C 1 -C 4 )alkyl;

wherein each R A is independently selected from H and (C 1 -C 4 )alkyl;

R B is H, (C 1 -C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R A and R B taken together with the atom to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;

each R Y is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and —(C 1 -C 4 )alkylphenyl.

5. The compound or salt according to claim 1 , wherein:

A is a phenyl group optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A ;

or A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A , where each R A is independently H or methyl;

or A is naphthyl, optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A ;

or A is a 9-10 membered heteroaryl optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, oxo, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A ;

or A is a 5-6 membered heteroaryl optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A .

6. The compound or salt according to claim 1 , wherein:

A is isoquinolyl, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, or indolinyl;

or A is oxazolyl, pyrazolyl, or thienyl, optionally substituted by a methyl group;

or A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A , where each R A is independently H or methyl.

7. The compound or salt according to claim 1 , wherein Z is —C(═O)NH— or —CH 2 NH—.

8. The compound or salt according to claim 1 , wherein n is 0 or 1.

9. The compound or salt according to claim 1 , wherein R 2 and R 3 are independently selected from H and optionally substituted (C 1 -C 4 )alkyl, phenyl(C 1 -C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-.

10. The compound or salt according to claim 1 , wherein:

both R 2 and R 3 are H or both R 2 and R 3 are methyl;

or when n is 1, R 2 is hydroxyl and R 3 is H or methyl.

11. The compound or salt according to claim 1 , wherein R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C 1 -C 4 )alkyl, aryl(C 1 -C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-.

12. The compound or salt according to claim 1 , wherein R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1-2 substituents independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.

13. The compound or salt according to claim 1 , wherein L-R 4 , taken together, form a 1,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl group, optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl, and morpholinylpropyl-.

14. The compound or salt according to claim 1 , wherein:

R 1 is CHF 2 or CF 3 ;

Y is a bond, X 1 is O, and X 2 and X 3 are N, or

A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group, or a thienyl, pyridyl, cyclopropyl, cyclopentyl or cyclohexyl group;

Z is —C(═O)NH— or —CH 2 NH—;

n is 0 or 1 and both R 2 and R 3 are H or both R 2 and R 3 are methyl, or

n is 1 and R 2 is hydroxyl and R 3 is H or methyl, or

n is 0 or 1 and R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl group;

L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group;

R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl, 2-bromophenyl-, 4-fluorophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4-methoxyphenyl, cyclohexyl, imidazolyl, thienyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; or

L-R 4 , taken together, form a 1,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.

15. The compound or salt according to claim 1 , wherein:

R 1 is CHF 2 or CF 3 ;

Y is a bond, X 1 is O, and X 2 and X 3 are N;

A is an unsubstituted phenyl or pyridyl group;

Z is —C(═O)NH— or —CH 2 NH—;

n is 1;

R 2 and R 3 are both methyl, or

R 2 is hydroxyl and R 3 is methyl, or

R 2 and R 3 are both hydrogen, or

R 2 is methyl and R 3 is hydrogen, or

R 2 is hydroxyl and R 3 is hydrogen, or

R 2 is dimethylamino and R 3 is H, or

R 2 is N,N-dimethylaminoethyl and R 3 is H, or

R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, or a 1-methyl-piperidinyl group;

L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group;

R 4 is phenyl, optionally substituted by halo, cyano, halo(C 1 -C 2 )alkyl, or (C 1 -C 2 )alkoxy.

16. A compound which is:

N-(4-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(4-(1H-imidazol-1-yl)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)methyl)benzamide,

1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)methanamine,

N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-((4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((1-(4-phenylthiazol-2-yl)cyclopentyl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(3-phenyl-1H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-methyl-2-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((1-methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-cyclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxamide,

N-((4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

3-fluoro-N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

3-methoxy-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(4-cyanophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzenesulfonamide,

3-ethyl-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide,

N-(2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)cyclopropanecarboxamide,

N-((1-methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinamide,

N-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinamide,

N-(2-(dimethylamino)-2-(4-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((1-(4-phenylthiazol-2-yl)cyclopropyl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

3-(4-(4-fluorophenyl)thiazol-2-yl)-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide,

N-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-phenylthiazol-2-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-((4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-methyl-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

2,2,2-trifluoro-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-1-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)ethanamine,

N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(3-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(5-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(3-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-methyl-2-(5-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-((2-(4-fluorophenyl)oxazol-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine,

3-(3-(4-(4-phenylthiazol-2-yl)butyl)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole,

N-(2-methyl-2-(5-phenyloxazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-phenylthiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-methyl-2-(2-phenylthiazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

2-fluoro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)oxazole-4-carboxamide,

N-(2-(1-methyl-2-phenyl-1H-imidazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)nicotinamide,

N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-methoxy-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-((4-(2-(4-chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine,

N-(2-(2-(4-fluorophenyl)oxazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-methoxyphenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)nicotinamide,

2-chloro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(2-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(1-methyl-2-phenyl-1H-imidazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(4-fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-([1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4′-fluoro-[1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-((4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-phenyloxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-phenyloxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-methyl-2-(3-phenyl-1H-pyrazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-((4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide,

N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide,

or a pharmaceutically-acceptable salt thereof.

17. A pharmaceutical composition comprising the compound or salt according to claim 1 and one or more pharmaceutically-acceptable excipients.

18. The compound or salt according to claim 1 , wherein A is a phenyl group optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR A R A and —((C 1 -C 4 )alkyl)NR A R A , where each R A is independently H or methyl.

19. The compound or salt according to claim 1 , wherein A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.

20. The compound or salt according to claim 1 , wherein R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl, cyclopropyl, cyclohexyl, 1-ethyl-piperidinyyl, tetrahydrofuranyl, piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl, 1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl, 1-methyl-azetidinyl, 1-benzyl-azetidinyl, or 1-cyclopropylmethyl-azetidinyl group.

21. The compound or salt according to claim 1 , wherein, L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl.

22. The compound or salt according to claim 1 , wherein L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl which is substituted by a methyl group.

Continuity (2)

Provisional Application 61294575 · Jan 13, 2010

Related Publication 20130059883A1 · Mar 7, 2013