IP Library › Granted Patent US 7,919,488
Granted Patent B2
US 7,919,488 · App. 11/770,698 · Granted Apr 5, 2011

Therapeutic compounds

Assignee: Pfizer Inc.
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Quick Facts
Patent No.
US 7,919,488
App. No.
11/770,698
Granted
Apr 5, 2011
Kind
B2
Abstract

The present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, methods for their preparation, methods for their use, and pharmaceutical formulations comprising them.

Claims (92)

1. A compound of formula (IIb),

wherein:

R 2 is 5-9 membered heteroaryl, optionally substituted with one or more R 11 groups;

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t OR 11 , —(CR 9 R 10 ) t N(R 11 R 12 ), —CN, —NO 2 , —CF 3 , —C(O)R 9 , and —C(O) 2 R 9 ;

each R 9 and R 10 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl;

each R 11 and R 12 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, 5-9 membered heteroaryl, —CN, halo, —(CR 16 R 17 ) t OR 18 , and —(CR 16 R 17 ) t C(O)R 18 , wherein each of said C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl groups is optionally substituted with one more R 15 groups;

each R 15 is independently selected from —(CR 9 R 10 ) t R 16 , —(CR 9 R 10 ) t (3-10 membered heterocyclyl), —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t (5-9 membered heteroaryl), —(CR 9 R 10 ) t (C 6 -C 10 aryl), —(CR 9 R 10 ) t N(R 16 R 17 ), —(CR 9 R 10 )NR 16 C(O)R 17 , —(CR 9 R 10 ) t OR 16 , —(CR 9 R 10 ) t C(O)R 16 , —(CR 9 R 10 ) t C(O) 2 R 16 , —(CR 9 R 10 ) t C(O)N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)OR 17 —(CR 9 R 10 ) t NR 16 S(O)N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O) 2 N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O)R 17 , —(CR 9 R 10 ) t NR 16 S(O) 2 R 17 , —(CR 9 R 10 ) t NR 16 C(O)N(R 17 R 18 ), —(CR 9 R 10 ) t (halo), —(CR 9 R 10 ) t —OR 16 , and —(CR 9 R 10 ) t S(O) 2 R 16 , wherein each said 3-10 membered heterocyclyl, C 3 -C 8 cycloalkyl, 5-9 membered heteroaryl, and C 6 -C 10 aryl is optionally substituted with one or more R 16 groups;

each R 16 , R 17 , and R 18 is independently selected from hydrogen, C 1 -C 8 alkyl, —(CH 2 ) t (C 3 -C 8 cycloalkyl), —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5-9 membered heteroaryl), —(CH 2 ) t (3-10 membered heterocyclyl), halo, —OCH 3 , and —OH;

R 19 and R 20 are independently selected from hydrogen and C 1 -C 8 alkyl; and

each t is independently selected from 0, 1, 2, 3, and 4; or

a pharmaceutically acceptable salt thereof.

2. A compound of formula (IIc),

wherein:

R 2 is 5-9 membered heteroaryl, optionally substituted with one or more R 11 groups;

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t OR 11 , —(CR 9 R 10 ) t N(R 11 R 12 ), —CN, —NO 2 , —CF 3 , —C(O)R 9 , and —C(O) 2 R 9 ;

each R 9 and R 10 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl;

each R 11 and R 12 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, 5-9 membered heteroaryl, —CN, halo, —(CR 16 R 17 ) t OR 18 , and —(CR 16 R 17 ) t C(O)R 18 , wherein each of said C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl groups is optionally substituted with one more R 15 groups;

each R 15 is independently selected from —(CR 9 R 10 ) t R 16 , —(CR 9 R 10 ) t (3-10 membered heterocyclyl), —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t (5-9 membered heteroaryl), —(CR 9 R 10 ) t (C 6 -C 10 aryl), —(CR 9 R 10 ) t N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)R 17 , —(CR 9 R 10 ) t OR 16 , —(CR 9 R 10 ) t C(O)R 16 , —(CR 9 R 10 ) t C(O) 2 R 16 , —(CR 9 R 10 ) t C(O)N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)OR 17 —(CR 9 R 10 ) t NR 16 S(O)N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O) 2 N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O)R 17 , —(CR 9 R 10 ) t NR 16 S(O) 2 R 17 , —(CR 9 R 10 ) t NR 16 C(O)N(R 17 R 18 ), —(CR 9 R 10 ) t (halo), —(CR 9 R 10 ) t —OR 16 , and —(CR 9 R 10 ) t S(O) 2 R 16 , wherein each said 3-10 membered heterocyclyl, C 3 -C 8 cycloalkyl, 5-9 membered heteroaryl, and C 6 -C 10 aryl is optionally substituted with one or more R 16 groups;

each R 16 , R 17 , and R 18 is independently selected from hydrogen, C 1 -C 8 alkyl, —(CH 2 ) t (C 3 -C 8 cycloalkyl), —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5-9 membered heteroaryl), —(CH 2 ) t (3-10 membered heterocyclyl), halo, —OCH 3 , and —OH;

R 19 and R 20 are independently selected from hydrogen and C 1 -C 8 alkyl; and

each t is independently selected from 0, 1, 2, 3, and 4; or

a pharmaceutically acceptable salt thereof.

3. A compound of formula (IId),

wherein:

R 2 is 5-9 membered heteroaryl, optionally substituted with one or more R 11 groups;

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t OR 11 , —(CR 9 R 10 ) t N(R 11 R 12 ), —CN, —NO 2 , —CF 3 , —C(O)R 9 , and —C(O) 2 R 9 ;

each R 9 and R 10 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl;

each R 11 and R 12 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, 5-9 membered heteroaryl, —CN, halo, —(CR 16 R 17 ) t OR 18 , and —(CR 16 R 17 ) t C(O)R 18 , wherein each of said C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl groups is optionally substituted with one more R 15 groups;

each R 15 is independently selected from —(CR 9 R 10 ) t R 16 , —(CR 9 R 10 ) t (3-10 membered heterocyclyl), —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t (5-9 membered heteroaryl), —(CR 9 R 10 ) t (C 6 -C 10 aryl), —(CR 9 R 10 ) t N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)R 17 , —(CR 9 R 10 ) t OR 16 , —(CR 9 R 10 ) t C(O)R 16 , —(CR 9 R 10 ) t C(O) 2 R 16 , —(CR 9 R 10 ) t C(O)N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)OR 17 —(CR 9 R 10 ) t NR 16 S(O)N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O) 2 N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O)R 17 , —(CR 9 R 10 ) t NR 16 S(O) 2 R 17 , —(CR 9 R 10 ) t NR 16 C(O)N(R 17 R 18 ), —(CR 9 R 10 ) t (halo), —(CR 9 R 10 ) t —OR 16 , and —(CR 9 R 10 ) t S(O) 2 R 16 , wherein each said 3-10 membered heterocyclyl, C 3 -C 8 cycloalkyl, 5-9 membered heteroaryl, and C 6 -C 10 aryl is optionally substituted with one or more R 16 groups;

each R 16 , R 17 , and R 18 is independently selected from hydrogen, C 1 -C 8 alkyl, —(CH 2 ) t (C 3 -C 8 cycloalkyl), —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5-9 membered heteroaryl), —(CH 2 ) t (3-10 membered heterocyclyl), halo, —OCH 3 , and —OH;

R 19 and R 20 are independently selected from hydrogen and C 1 -C 8 alkyl; and

each t is independently selected from 0, 1, 2, 3, and 4; or

a pharmaceutically acceptable salt thereof.

4. A compound of formula

wherein:

R 1 is —(CR 9 R 10 )C(O) N(R 13 R 14 );

R 2 is 5-9 membered heteroaryl, optionally substituted with one or more R 11 groups;

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t OR 11 , —(CR 9 R 10 ) t N(R 11 R 12 ), —CN, —NO 2 , —CF 3 ,—C(O)R 9 , and —C(O) 2 R 9 ,

each R 9 and R 10 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl;

each R 11 and R 12 is independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, 5-9 membered heteroaryl, —CN, halo, —CR 16 R 17 ) t OR 18 , and —(CR 16 R 17 ) t C(O)R 18 , wherein each of said C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3-10 membered heterocyclyl, and 5-9 membered heteroaryl groups is optionally substituted with one more R 15 groups;

R 13 and R 14 , together with the nitrogen atom to which they are attached, form a 3-10 membered heterocyclyl group, optionally substituted with one or more R 15 groups;

each R 15 is independently selected from —(CR 9 R 10 ) t R 16 , —(CR 9 R 10 ) t (3-10 membered heterocyclyl), —(CR 9 R 10 ) t (C 3 -C 8 cycloalkyl), —(CR 9 R 10 ) t (5-9 membered heteroaryl), —(CR 9 R 10 ) t (C 6 -C 10 aryl), —(CR 9 R 10 ) t N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)R 17 , —(CR 9 R 10 ) t OR 16 , —(CR 9 R 10 ) t C(O)R 16 , —(CR 9 R 10 ) t C(O) 2 R 16 , —(CR 9 R 10 ) t C(O)N(R 16 R 17 ), —(CR 9 R 10 ) t NR 16 C(O)OR 17 —(CR 9 R 10 ) t NR 16 S(O)N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O) 2 N(R 17 R 18 ), —(CR 9 R 10 ) t NR 16 S(O)R 17 , —(CR 9 R 10 ) t NR 16 S(O) 2 R 17 , —(CR 9 R 10 ) t NR 16 C(O)N(R 17 R 18 ), —(CR 9 R 10 ) t (halo), —(CR 9 R 10 ) t —OR 16 , and —(CR 9 R 10 ) t S(O) 2 R 16 , wherein each said 3-10 membered heterocyclyl, C 3 -C 8 cycloalkyl, 5-9 membered heteroaryl and C 6 -C 10 aryl is optionally substituted with one or more R 16 groups;

each R 16 , R 17 , and R 18 is independently from hydrogen, C 1 -C 8 alkyl, —(CH 2 ) t (C 3 -C 8 cycloalkyl), —(C 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5-9 membered heteroaryl, —(CH 2 ) t (3-10 membered heterocyclyl), halo, —OCH 3 , and —OH;

R 19 and R 20 are independently selected from hydrogen and C 1 -C 8 alkyl; and

each t is independently selected from 0, 1, 2, 3, and 4; or

a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 , wherein R 2 is selected from pyridyl, pyrazolyl, pyrimidinyl, and imidazolyl, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 , wherein R 2 is selected from 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 4-pyrazolyl, 3-pyrimidinyl, and 4-imidazolyl, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6 , wherein R 2 is 4-pyridinyl, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 4 , wherein R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 4 , wherein R 19 and R 20 are hydrogen, or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 4 , selected from the group consisting of:

1-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyrrolidin-2-one;

4-(5-(4-fluorobenzyl)-1-{2-[4-methylsulfonyl)piperidin-1-yl]-2-oxoethyl}-1H-pyrazol-3-yl)pyridine;

1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine;

1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine;

1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyly}N-isopropylpiperidin-4-amine;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylpropanamide;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N,2-dimethylpropanamide;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylcyclobutanecarboxamide;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylcyclopropanecarboxamide;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylmethanesulfonamide;

methyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methylcarbamate;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N′-isopropyl-N-methylurea;

N-(1{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N′-isopropylurea;

N-(1-{2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)cyclobutanecarboxamide;

N-(1-{2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methanesulfonamide;

1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-3-ol;

1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-4-[methyl(propyl)amino]piperidine-4-carboxamide;

N-(1-{2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)propanamide;

N-(1-{2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)ethanesulfonamide;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-2-methylpropanamide;

methyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)carbamate;

1-ethyl-3-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)urea;

1-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-3-methylurea;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylacetamide;

N-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylethanesulfonamide;

isopropyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methylcarbamate;

ethyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methylcarbamate;

ethyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)carbamate;

3-ethyl-1-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1-methylurea;

isopropyl (1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)carbamate;

1-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-dimethylurea;

3-(1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-oxazolidin-2-one;

N-(1-{2-[5-(4-fluorobenzyl)-3-(1H-imidazol-4-yl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)methanesulfonamide;

4-[1-{2-[4-(1,1-dioxidoisothiazolidin-2-yl)piperidin-1-yl]-2-oxoethyl}-5-(4-fluorobenzyl)-1H -pyrazol-3-yl]pyridine; and

N-(1-{[5-(4-fluorobenzyl)-3-(1H-imidazol-4-yl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-N-methylacetamide;

or a pharmaceutically acceptable salt of each of the foregoing compounds.

11. A pharmaceutical composition, comprising an effective amount of at least one compound according claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A method of inhibiting the metabolism in a mammal of a first compound that is metabolized by cytochrome P450, comprising administering to said mammal said first compound and an effective amount of a second compound, wherein said second compound is a compound according to claim 4 , or a pharmaceutically acceptable salt thereof.

13. A method of improving the pharmacokinetics in a mammal of a first compound, comprising administering to said mammal said first compound and an effective amount of a second compound, wherein said second compound is a compound according to claim 4 , or a pharmaceutically acceptable salt thereof.

14. N-(1-(2-(5-(4-fluorobenzyl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methanesulfonamide, or a pharmaceutically acceptable salt thereof.

Continuity (4)
Provisional Application 60941808 · Jun 4, 2007
Provisional Application 60910988 · Apr 10, 2007
Provisional Application 60806596 · Jul 5, 2006
Related Publication 20080021011A1 · Jan 24, 2008