Piperidine or piperazine linked imidazole and triazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug

Patent metadata

Field	Value
Publication number	US-2016297792-A1
Application number	US-201415036268-A
Country	US
Kind code	A1
Filing date	Nov 7, 2014
Priority date	Nov 12, 2013
Publication date	Oct 13, 2016
Grant date	—

Abstract

The present invention relates to piperidine or piperazine linked imidazole and triazole derivatives, compositions comprising said compounds, alone or in combination with other drugs, and methods of using the compounds for improving the pharmacokinetics of a drug. The compounds of the invention are useful in human and veterinary medicine for inhibiting CYP3A4 and for improving the pharmacokinetics of a therapeutic compound that is metabolized by CYP3A4.

First claim

1 . A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
n is 0 or 1;
W is —N═ or —CH═;
X is —C(R 3 )(R 4 )—, —N(R 3 )— or —S(O) 2 —;
R 1 is selected from —(C 1 -C 6 alkylene)-aryl, —(C 1 -C 6 alkylene)-(5 or 6-membered heteroaryl), —(C 1 -C 6 alkylene)-O-aryl, —(C 1 -C 6 alkylene)-O-(5 or 6-membered heteroaryl) and C 3 -C 6 cycloalkyl, wherein any aryl, heteroaryl or C 3 -C 6 cycloalkyl group can be optionally substituted with up to four R 9 groups, which can be the same or different, and wherein said C 3 -C 6 cycloalkyl group can be fused to a benzene ring and said fused benzene ring can be optionally substituted with up to four R 9 groups, which can be the same or different;
each occurrence of R 2 is independently selected from H, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl) and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl); or the two R 2 groups can be joined together with the atom to which they are attached to form a C 3 -C 6 cycloalkyl ring;
R 3 and R 4 are independently selected from H, halo, —OH, —CN, Y, —O—Y, —C(O)—Y,

—C(O)—O—Y, —(C 1 -C 6 alkylene)-Y, —(C 1 -C 6 alkylene)-C(O)—Y, —(C 1 -C 6 alkylene)-C(O)—O—Y and —(C 1 -C 6 alkylene)-O—Y, wherein each Y is independently selected from:
(1) C 1 -C 6 alkyl,
(2) C 1 -C 6 haloalkyl,
(3) C 1 -C 6 hydroxyalkyl,
(4) C 3 -C 6 cyclohaloalkyl,
(5) C 3 -C 6 cycloalkyl,
(6) phenyl, wherein said phenyl group can be optionally substituted with up to four R 7 groups,
(7) 5 or 6-membered heteroaryl, wherein said 5 or 6-membered heteroaryl group can be optionally substituted with up to four R 7 groups, and
(8) 5 or 6-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can optionally form a spirocycle with a C 3 -C 6 cycloalkyl group or another 5 or 6-membered monocyclic heterocycloalkyl group, and wherein said 5 or 6-membered monocyclic heterocycloalkyl group and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to four R 7 groups, which can be the same or different, and wherein a ring carbon atom of a 5 or 6-membered monocyclic heterocycloalkyl group may be functionalized as a carbonyl group;
or R 3 and R 4 together with the carbon atom to which they are attached are joined together to form a 5 or 6-membered monocyclic heterocycloalkyl group, wherein said heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to four R 7 groups, which can be the same or different, and wherein a ring carbon atom of a 5 or 6-membered monocyclic heterocycloalkyl group may be functionalized as a carbonyl group;
R 5 is selected from H, C 1 -C 6 alkyl, phenyl, —C(O)N(R 8 ) 2 and —C(O)—Z, wherein Z is selected from piperidinyl, piperazinyl and morhoplinyl and wherein said Z is optionally substituted with 1 to 3 halo groups, and phenyl is optionally substituted with —N(R 8 ) 2 ,
R 6 is H or may be joined together with R 5 to form carbonyl,
each occurrence of R 7 and each occurrence of R 9 are independently selected from C 1 -C 6 alkyl, phenyl, benzyl, 5 or 6-membered heteroaryl, —CH 2 -(5 or 6-membered heteroaryl), 5 or 6-membered heterocycloalkyl, —CH 2 — (5 or 6-membered heterocycloalkyl), C 1 -C 6 hydroxyalkyl,

C 1 -C 6 haloalkyl, halo, —CN, —N(R 8 ) 2 , —(C 1 -C 6 alkylene)-N(R 8 ) 2 , —OR 8 , —C(O)OR 8 , —SR 8 , —S(O) 2 R 8 , —C(O)N(R 8 ) 2 , —(C 1 -C 6 alkylene)-C(O)OR 8 , —(C 1 -C 6 alkylene)-SR 8 , —(C 1 -C 6 alkylene)-S(O) 2 R 8 and —(C 1 -C 6 alkylene)-C(O)N(R 8 ) 2 , wherein said phenyl, 5 or 6-membered heteroaryl and 5 or 6-membered heterocycloalkyl groups can be optionally substituted with one to three groups selected from C 1 -C 6 alkyl, halo, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, halo, —CN, —N(R 8 ) 2 and —OR 8 ; and
each occurrence of R 8 is independently H, C 1 -C 6 alkyl or benzyl optionally substituted with one or two methoxy groups.

2 . The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 9 is —F or —CN.

4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is selected from (1) C 1 -C 6 alkyl, (2) C 3 -C 6 cycloalkyl, (3) phenyl, wherein said phenyl group can be optionally substituted with up to four halo groups, (4) 5 or 6-membered heteroaryl, wherein said 5 or 6-membered heteroaryl group can be optionally substituted with methyl, and (5) 5 or 6-membered monocyclic heterocycloalkyl; and R 4 is selected from —CN or —CH 3 .

5 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is selected from benzo[d]oxazol-2-yl and benzo[d]thiazol-2-yl, said benzo[d]oxazol-2-yl and benzo[d]thiazol-2-yl groups each optionally substituted with 1 to 3 groups independently selected from: halo, —CH 3 and —OCH 3 ; and R 4 is H.

6 . The compound of claim 1 , having the formula (Ib):

or a pharmaceutically acceptable salt thereof,

7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 9 is —F or —CN.

8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3 is thiazolyl substituted with —(C 1 -C 6 alkylene)-S(O) 2 R 8 , R 5 is H and R 6 is H.

9 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, R 5 is —C(O)—Z, wherein Z is selected from piperidinyl, piperazinyl and morhoplinyl and wherein said Z is optionally substituted with 1 to 3 halo groups, and R 6 is H.

10 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —C(O)—Y, Y is selected from (1) C 1 -C 6 alkyl, (2) 1-methylcyclopropyl, (3) cyclobutyl optionally substituted with one or two halo groups, (4) phenyl, (5) pyridinyl, and (6) tetrahydro-2H-pyran-4-yl, R 5 is selected from H, C 1 -C 4 alkyl and phenyl, and R 6 is H.

11 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is —CH 2 —Y, Y is selected from phenyl, imidazo[1,2-a]pyridinyl, oxadiazolyl and thiazolyl, wherein said Y is optionally substituted with a group selected from: (1) phenyl wherein said phenyl is optionally substituted with one or two methoxy groups, (2) —N(R 8 ) 2 , (3) morpholinyl, (4) piperazinyl wherein said piperazinyl is optionally substituted with a methyl group, and (5) triazolylmethyl; and R 5 and R 6 are joined together to form carbonyl.

12 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is selected from C 1 -C 6 hydroxyalkyl, —(C 1 -C 6 alkylene)-C(O)—Y, —(C 1 -C 6 alkylene)-C(O)—O—Y and —(C 1 -C 6 alkylene)-O—Y, where Y is C 1 -C 6 alkyl; and R 5 is H and R 6 is H.

13 . A compound selected from the following:
(R)-4-Ethyl-1-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)piperidine-4-carbonitrile; (R)-1-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-4-isopropylpiperidine-4-carbonitrile; (R)-1-((1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-5-yl)methyl)-4-methylpiperidine-4-carbonitrile; 1-((1-(benzo[d]thiazol-2-ylmethyl)-1H-imidazol-5-yl)methyl)-4-

Assignees

• Coburn Craig A
• Maletic Milana M
• Luo Yunfu
• Qi Zhiqi
• Yu Tingting
• Soll Richard
• Merck Sharp & Dohme

Inventors

• Coburn Craig A
• Maletic Milana M
• Luo Yunfu
• Qi Zhiqi
• Yu Tingting
• Soll Richard

Classifications

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title