sEH inhibitors and their use

• US 8,173,805 B2
• Filed: 10/10/2008
• Issued: 05/08/2012
• Est. Priority Date: 10/11/2007
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: GlaxoSmithKline LLC (GSK plc)
• Inventors: Ding, Yun, Thalji, Reema K., Marino, Joseph P. Jr.
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US12/682,073
• Publication Number:
  US 20100210656A1
• Time in Patent Office: 1,306 Days
• Field of Search: 544/197, 544/198, 544/208, 544/209, 514/245
• US Class Current: 544/197
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 241/46 Phenazines
• CPC Class Codes: C07D 251/18 with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 251/52 with an oxygen or sulfur atom attached to the third ring carbon atom
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula I:

wherein R1, R2, R4, R5, R6, A, B, Y, Z, n, and m are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Claims

1. A compound or salt of Formula I

2. A compound or salt of Formula I

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

5. A method for treating hypertension, heart failure, peripheral vascular disease, coronary artery disease, myocardial ischemia, and angina comprising administering a safe and effective amount of a compound or salt according to claim 2 to a human in need thereof.

6. A method for treating renal or liver failure comprising administering a safe and effective amount of a compound or salt according to claim 2 to a human in need thereof.

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

8. A method for treating glucose intolerance, insulin insensitivity, diabetes and obesity comprising administering a safe and effective amount of a compound or salt according to claim 2 to a human in need thereof.

9. A method according to claim 5 wherein the compound is administered orally.

10. A method according to claim 5 wherein the compound is administered intravenously.

11. A method according to claim 5 wherein the compound is administered by inhalation.

12. A method according to claim 7 wherein the compound is administered orally.

13. A method according to claim 7 wherein the compound is administered intravenously.

14. A method according to claim 7 wherein the compound is administered by inhalation.

3. A compound chosen from:

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

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

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

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

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

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

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

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

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

3-{4-(methylamino)-6-[(cis-4-{[({2-[(trifluoromethyl)oxy]phenyl}methyl)amino]carbonyl}cyclohexyl)amino]-1,3,5-triazin-2-yl}benzoic acid;

3-[4-(methylamino)-6-({cis-4-[({[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}amino)carbonyl]cyclohexyl}amino)-1,3,5-triazin-2-yl]benzoic acid;

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

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

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

3-[4-(methylamino)-6-({cis-4-[({[4-(trifluoromethyl)-3-pyridinyl]methyl}amino)carbonyl]cyclohexyl}amino)-1,3,5-triazin-2-yl]benzoic acid;

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

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

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

3-[4-{[cis-4-({[(2-chloro-4-cyanophenyl)methyl]amino}carbonyl)cyclohexyl]amino}-6-(methylamino)-1,3,5-triazin-2-yl]benzoic acid;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4-{[({cis-4-[(4-(methylthio)-6-{[(2R)-2-phenylpropyl]amino}-1,3,5-triazin-2-yl)amino]cyclohexyl}carbonyl)amino]methyl}benzoic acid;

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

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt thereof.

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

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