IP Library › Granted Patent US 7,994,317
Granted Patent B2
US 7,994,317 · App. 12/513,186 · Granted Aug 9, 2011

sEH inhibitors and their use

Assignee: GlaxoSmithKline, LLC
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Quick Facts
Patent No.
US 7,994,317
App. No.
12/513,186
Granted
Aug 9, 2011
Kind
B2
Abstract

The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme.

Claims (121)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

is a 6-membered aryl or heteroaryl ring;

R 1 is hydrogen, CO 2 H, CO 2 (C 1 -C 6 )alkyl, CONR′R″ wherein R′ and R″ are each independently hydrogen or (C 1 -C 6 )alkyl, araalkyl, heteroaralkyl, —(C 2 -C 10 )alkylene-NR′R″, —(C 2 -C 10 )alkylene-OR′, and —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo;

each R 2 is if present independently halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo;

n is 0 or 1;

x is 0, 1, or 2;

R 3 is hydrogen or (C 1 -C 6 )alkyl;

p is 0, 1, 2, or 3;

each R 4 if present is independently halo, (C 1 -C 6 )alkyl, or —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

y is 0, 1, or 2;

R 5 is hydrogen or (C 1 -C 6 )alkyl;

R 6 is hydrogen or (C 1 -C 6 )alkyl;

R 7 is hydrogen, halo, or (C 1 -C 6 )alkyl; or

R 6 and R 7 together with the atoms to which they are attached, form a 3-10 membered ring, optionally substituted on carbon with 1, 2, or 3 groups selected from halo, (C 1 -C 6 )alkyl, and —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

R 8 is hydrogen, halo, or (C 1 -C 6 )alkyl, or is

 wherein  indicates the point of attachment and wherein

R 9 is hydrogen, halo, or (C 1 -C 6 )alkyl;

X is absent or is O, S(O) m wherein m is 0, 1, or 2, —CH 2 —S—, —CH 2 —O—, —CH 2 —NH—, or —CH 2 —N(C 1 -C 6 )alkyl-;

 is (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, aryl, or heteroaryl;

each R 10 if present is independently halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

z is 0, 1, or 2;

Z 1 , Z 2 , and Z 3 are N;

Y is H, halo, OR 11 , or NR 11 R 12 ;

R 11 is hydrogen or (C 1 -C 6 )alkyl; and

R 12 is hydrogen, (C 1 -C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, -alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, -alkylene-(C 3 -C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, any of which may be optionally substituted on carbon with 1 or 2 groups selected from halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl.

2. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

is a 6-membered aryl or heteroaryl ring;

R 1 is hydrogen, CO 2 H, CO 2 (C 1 -C 6 )alkyl, CONR′R″ wherein R′ and R″ are each independently hydrogen or (C 1 -C 6 )alkyl, araalkyl, heteroaralkyl, —(C 2 -C 10 )alkylene-NR′R″, —(C 2 -C 10 )alkylene-OR′, and —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo;

each R 2 is if present independently halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo;

n is 0 or 1;

x is 0, 1, or 2;

R 3 is hydrogen or (C 1 -C 6 )alkyl;

p is 0, 1, 2, or 3;

each R 4 if present is independently halo, (C 1 -C 6 )alkyl, or —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

y is 0, 1, or 2;

R 5 is hydrogen or (C 1 -C 6 )alkyl;

R 6 is hydrogen or (C 1 -C 6 )alkyl;

R 7 is hydrogen, halo, or (C 1 -C 6 )alkyl;

R 9 is hydrogen, halo, or (C 1 -C 6 )alkyl;

X is absent or is O, S(O) m wherein m is 0, 1, or 2, —CH 2 —S—, —CH 2 —O—, —CH 2 —NH—, or —CH 2 —N(C 1 -C 6 )alkyl-;

 is (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, aryl, or heteroaryl;

each R 10 if present is independently halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

z is 0, 1, or 2;

Z 1 , Z 2 , and Z 3 are N;

Y is H, halo, OR 11 , or NR 11 R 12 ;

R 11 is hydrogen or (C 1 -C 6 )alkyl; and

R 12 is hydrogen, (C 1 -C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, -alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, -alkylene-(C 3 -C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, any of which may be optionally substituted on carbon with 1 or 2 groups selected from halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl.

3. A compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

is a 6-membered aryl or heteroaryl ring;

R 1 is hydrogen, CO 2 H, CO 2 (C 1 -C 6 )alkyl, CONR′R″ wherein R′ and R″ are each independently hydrogen or (C 1 -C 6 )alkyl, araalkyl, heteroaralkyl, —(C 2 -C 10 )alkylene-NR′R″, —(C 2 -C 10 )alkylene-OR′, and —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo;

each R 2 is if present independently halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo;

n is 0 or 1;

x is 0, 1, or 2;

R 3 is hydrogen or (C 1 -C 6 )alkyl;

p is 0, 1, 2, or 3;

each R 4 if present is independently halo, (C 1 -C 6 )alkyl, or —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

y is 0, 1, or 2;

Z 1 , Z 2 and Z 3 are N;

R 5 is hydrogen or (C 1 -C 6 )alkyl;

 is a 3-10 membered ring, optionally containing 1 additional heteroatom selected from O, S(O) m wherein m is 0, 1, or 2, or NR′″, wherein R′″ is hydrogen or (C 1 -C 6 )alkyl, and wherein indicate points of attachment;

each R 13 if present is independently halo, (C 1 -C 6 )alkyl, or —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl, any of which may be optionally substituted on carbon with 1, 2, or 3 halo, or taken together with the attached carbon forms C═O;

w is 0, 1, or 2;

Y is H, halo, OR 11 , or NR 11 R 12 ;

R 11 is hydrogen or (C 1 -C 6 )alkyl; and

R 12 is hydrogen, (C 1 -C 6 )alkyl, aryl, aralkyl, (C 3 -C 6 )cycloalkyl, -alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycloalkyl, -alkylene-(C 3 -C 6 )heterocycloalkyl, heteroaryl, heteroaralkyl, any of which may be optionally substituted on carbon with 1 or 2 groups selected from halo, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —S—(C 1 -C 6 )alkyl.

4. A compound chosen from:

cis-N-[(2,4-dichlorophenyl)methyl]-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino} cyclohexanecarboxamide;

cis-N-[(2-fluorophenyl)methyl]-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino} cyclohexanecarboxamide hydrochloride;

cis-N-[(3,4-difluorophenyl)methyl]-4-{[4-(methylamino)-6-(4-methyl-1 -piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

cis-N-cyclohexyl-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)- 1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

cis-N-(cyclohexylmethyl)-4-{[4-(methylamino)-6-(4-methyl-1 -piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

cis-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3 ,5-triazin-2-yl]amino}-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide hydrochloride;

cis-N-[(2-chlorophenyl)methyl]-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

cis-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3 ,5-triazin-2-yl]amino}-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide hydrochloride;

trans-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1 ,3,5-triazin-2-yl]amino}-N- {[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide trifluoroacetate;

trans-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1 ,3,5-triazin-2-yl]amino}-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide trifluoroacetate;

trans-N-[(2,4-dichlorophenyl)methyl]-4-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide trifluoroacetate;

N-[(3,4-difluorophenyl)methyl]-3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

N-(cyclohexylmethyl)-3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}-N- {[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide hydrochloride;

N-[(2-chlorophenyl)methyl]-3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

N-[(2-fluorophenyl)methyl]-3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide hydrochloride;

3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide hydrochloride;

N-[(2,4-dichlorophenyl)methyl]-3-{[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide trifluoroacetate;

cis-N-[(2,4-dichlorophenyl)methyl]-4-{methyl[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxamide;

cis-4-{methyl[4-(methylamino)-6-(4-methyl-1-piperazinyl)- 1,3,5-triazin-2-yl]amino}-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide trifluoroacetate;

cis-4-{methyl[4-(methylamino)-6-(4-methyl-1-piperazinyl)- 1,3,5-triazin-2-yl]amino}-N-({2-[(trifluoromethyl)oxy]phenyl}methyl)cyclohexanecarboxamide trifluoroacetate;

(1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

(1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethylthio)benzyl)cyclohexanecarboxamide;

(1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethoxy)benzyl)cyclohexanecarboxamide;

(1S,4S)-N-benzyl-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamide;

(1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-(4-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

(1S,4S)-N-(4-fluorobenzyl)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamide;

(1S,4S)-N-(2-fluorobenzyl)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamide;

(1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-o-tolylcyclohexanecarboxamide;

(1R,4R)-N-benzyl-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamide;

methyl-4-4(((1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamido)methyl)benzoate;

methyl-4-(((1R,4R)-4-(4-(methylamino)-6-((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamido)methyl)benzoate;

4-(((1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamido)methyl)benzoic acid;

4-(((1R,4R)-4-(4-(methylamino)-6-((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamido)methyl)benzoic acid;

2-(4-((1S,4S)-4-(4-(methylamino)-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamido)phenyl)acetic acid;

(1S,4S)-4-(4-(methylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

cis-4- {[4-(methylamino)-6-(4-methyl-l-piperazinyl)-1,3,5-triazin-2-yl]amino}-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide hydrochloride;

cis-4-(4-(methylamino)-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

cis-4-(4-(benzylamino)-6-(methylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

cis-4-(4-((2-(dimethylamino)ethyl)(methyl)amino)-6-(methylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

cis-4-(4-(azepan-1-yl)-6-(methylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethoxy) benzyl)cyclohexanecarboxamide;

cis-4-(4-amino-6-(azepan-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethoxy) benzyl)cyclohexanecarboxamide;

(1S,4S)-4-(4-amino-6((R)-2-phenylpropylamino)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethoxy)benzyl)cyclohexanecarboxamide;

trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide;

3-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)-N-(2-(trifluoromethyl)benzyl)cyclohexanecarboxamide.

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

6. A pharmaceutical composition comprising a compound or salt according to claim 2 and one or more pharmaceutically-acceptable excipients.

7. A pharmaceutical composition comprising a compound or salt according to claim 3 and one or more pharmaceutically-acceptable excipients.

8. A method for treating asthma or COPD comprising administering a safe and effective amount of a compound or salt according to claim 1 to a patient in need thereof.

9. A method for treating asthma or COPD comprising administering a safe and effective amount of a compound or salt according to claim 2 to a patient in need thereof.

10. A method for treating asthma or COPD comprising administering a safe and effective amount of a compound or salt according to claim 3 to a patient in need thereof.

11. A method for treating asthma or COPD comprising administering a safe and effective amount of a compound or salt according to claim 4 to a patient in need thereof.

Assignments (1)
CHANGE OF NAME Recorded Jun 28, 2011
From: SMITHKLINE BEECHAM CORPORATION
To: GLAXOSMITHKLINE LLC
Reel/Frame 026511/0115 →
Continuity (2)
Provisional Application 60864178 · Nov 3, 2006
Related Publication 20100069391A1 · Mar 18, 2010