IP Library › Granted Patent US 6,969,721

Granted Patent B2

US 6,969,721 · App. 10/457,902 · Granted Nov 29, 2005

Tricyclic-2-pyridone compounds useful as HIV reverse transcriptase inhibitors

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Quick Facts

Patent No.: US 6,969,721
App. No.: 10/457,902
Granted: Nov 29, 2005
Kind: B2

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Abstract

The present invention relates to tricyclic 2-pyridone compounds of formula (I): or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

Claims (169)

1. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof, wherein:

A is a ring selected from:

P is O or S;

R b , at each occurrence, is independently selected from H, F, Cl, Br, I, CN, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl-O—, or C 1-4 alkyl-NH—, NH 2 ;

R c , at each occurrence, is independently selected from H, C 1-4 alkyl, C 1-4 alkenyl, and C 1-4 alkynyl;

W is CR 3 ;

X is CR 3a ;

Y is CR 3b ;

Z is CR 3c ;

R 1 is selected from the group C 1-4 alkyl substituted with 0-9 halogen, cyclopropyl, hydroxymethyl, and CN;

R 2 is selected from the group C 1-6 alkyl substituted with 1-2 R 4 , C 2-5 alkenyl substituted with 1-2 R 4 , C 2-5 alkynyl substituted with 1 R 4 , and a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3d ;

R 3 is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , CF 3 , F, Cl, Br, I, —(CH 2 ) t NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —(CH 2 ) t NHC(O)R 7 , —(CH 2 ) t NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —S—C 1-4 alkyl, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —SO 2 NR 5 R 5a , and a 5-6 membered heteroaromatic ring having 1-4 heteroatoms selected from the group O, N, and S;

R 3a is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , CF 3 , F, Cl, Br, I, —(CH 2 ) t NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —(CH 2 ) t NHC(O)R 7 , —(CH 2 ) t NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —S—C 1-4 alkyl, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —SO 2 NR 5 R 5a , and a 5-6 membered heteroaromatic ring having 1-4 heteroatoms selected from the group O, N, and S;

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3b is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

alternatively, R 3a and R 3b together form —OCH 2 O—;

R 3c is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

alternatively, R 3b and R 3c together form —OCH 2 O—;

R 3d , at each occurrence, is independently selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

R 3e , at each occurrence, is independently selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

R 3f , at each occurrence, is independently selected from the group H, F, Cl, Br, I, C 1-4 alkyl, CN, —OH, —O—R 11 , OCF 3 , —O(CO)—R 13 , —OS(O) 2 C 1-4 alkyl, —NR 12 R 12a , —C(O)R 13 , —NHC(O)R 13 , —SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —NHSO 2 R 10 , and —SO 2 NR 12 R 12a ;

R 4 is a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3e ;

R 5 and R 5a are independently selected from the group H and C 1-4 alkyl;

alternatively, R 5 and R 5a , together with the nitrogen to which they are attached, combine to form a 5-6 membered ring having 0-1 O or N atoms;

R 6 is selected from the group H, OH, C 1-4 alkyl, C 1-4 alkoxy, and NR 5 R 5a ;

R 7 is selected from the group H, C 1-3 alkyl and C 1-3 alkoxy;

R 8 is selected from the group H, (C 1-6 alkyl)carbonyl, C 1-6 alkoxy, (C 1-4 alkoxy)carbonyl, C 6-10 aryloxy, (C 6-10 aryl)oxycarbonyl, (C 6-10 aryl)methylcarbonyl, (C 1-4 alkyl)carbonyloxy(C 1-4 alkoxy)carbonyl, C 6-10 arylcarbonyloxy(C 1-4 alkoxy)carbonyl, C 1-6 alkylaminocarbonyl, phenylaminocarbonyl, phenyl(C 1-4 alkoxy)carbonyl, and NR 5 R 5a (C 1-6 alkyl)carbonyl;

R 9 is selected from H, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, (C 1-6 alkyl)carbonyl, C 1-6 alkoxy, (C 1-4 alkoxy)carbonyl, C 6-10 aryloxy, (C 6-10 aryl)oxycarbonyl, (C 6-10 aryl)methylcarbonyl, (C 1-4 alkyl)carbonyloxy(C 1-4 alkoxy)carbonyl, C 6-10 arylcarbonyloxy(C 1-4 alkoxy)carbonyl, C 1-6 alkylaminocarbonyl, phenylaminocarbonyl, phenyl(C 1-4 alkoxy)carbonyl, and NR 5 R 5a (C 1-6 alkyl) carbonyl;

R 10 is selected from the group C 1-4 alkyl and phenyl;

R 11 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl substituted with C 3-6 cycloalkyl substituted with 0-2 R 3e , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle substituted with 0-2 R 3e ;

R 12 and R 12a are independently selected from H, C 1-6 alkyl, C 1-6 alkyl substituted with C 3-6 cycloalkyl substituted with 0-2 R 3e , and C 3-6 carbocycle substituted with 0-2 R 3e ;

alternatively, R 12 and R 12a can join to form 4-7 membered heterocyclic ring;

R 13 is selected from the group H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, —O—C 2-6 alkenyl, —O—C 2-6 alkynyl, NR 12 R 12a , C 3-6 carbocycle, and —O—C 3-6 carbocycle; and

t is selected from 0 and 1.

2. A compound of claim 1 or pharmaceutically acceptable salt forms thereof, wherein:

R 2 is selected from the group C 1-5 alkyl substituted with 1-2 R 4 , C 2-5 alkenyl substituted with 1-2 R 4 , C 2-5 alkynyl substituted with 1 R 4 , and a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3d , wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl;

R 3 and R 3a , at each occurrence, are independently selected from the group H, C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , —CN, C(O)R 6 , NHC(O)R 7 , NHC(O)NR 5 R 5a , and a 5-6 membered heteroaromatic ring having 1-4 heteroatoms selected from the group O, N, and S;

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3b and R 3c , at each occurrence, are independently selected from the group H, C 1-4 alkyl, OH, C 1-4 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , —CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, R 3a and R 3b together form —OCH 2 O—;

R 4 is a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3e ;

R 5 and R 5a are independently selected from the group H, CH 3 and C 2 H 5 ;

R 6 is selected from the group H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ; and

R 7 is selected from the group CH 3 , C 2 H 5 , CH(CH 3 ) 2 , OCH 3 , OC 2 H 5 , and OCH(CH 3 ) 2 .

3. A compound of claim 2 , wherein:

P is O;

Ring A is:

R b , at each occurrence, is selected from H, F, Cl, and Br, C 1-4 alkyl, CN, C 1-4 alkyl-NH—, NH 2 ;

R c is selected from H and methyl;

W is CR 3 ;

X is CR 3a ;

Y is CR 3b ;

Z is CR 3c ;

R 2 is selected from the group C 1-3 alkyl substituted with 1-2 R 4 , C 2-3 alkenyl substituted with 1-2 R 4 ; and C 2-3 alkynyl substitued with 1 R 4

R 3 , R 3a , R 3b , and R 3c , at each occurrence, are independently selected from the group H, C 1-3 alkyl, OH, C 1-3 alkoxy, F, Cl, Br, I, NR 5 R 5a , NO 2 , —CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3e , at each occurrence, is independently selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, —NR 5 R 5a , —C(O)R 6 , and —SO 2 NR 5 R 5a ;

R 3f , at each occurrence, is independently selected from the group H, F, Cl, Br, I, C 1-4 alkyl, CN, —OH, —O—R 11 , —O(CO)—R 13 , —SR 11 , —S(O)R 11 , —S(O) 2 R 11 , and —NR 12 R 12a ;

R 4 is and a 6-membered heterocyclic system having 1 N atom substituted with 0-1 R 3e , wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl;

R 5 and R 5a are independently selected from the group H, CH 3 and C 2 H 5 ;

R 6 is selected from the group H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;

R 7 is selected from the group CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;

R 8 is H;

R 9 is H, methyl, ethyl, propyl, and i-propyl;

R 11 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, and C 3-6 carbocycle substituted with 0-2 R 3e wherein the C 3-6 carbocycle is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl; and

R 12 and R 12a are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, and C 3-6 carbocycle substituted with 0-2 R 3e wherein the C 3-6 carbocycle is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl.

4. A compound of claim 3 , or a pharmaceutically acceptable salt form thereof, wherein:

R 2 is selected from the group C 1-3 alkyl substituted with 1 R 4 , C 2-3 alkenyl substituted with 1 R 4 , and C 2-3 alkynyl substituted with 1 R 4 ;

R 3 , R 3a , R 3b , and R 3c , at each occurrence, are independently selected from the group H, C 1-3 alkyl, OH, C 1-3 alkoxy, F, Cl, NR 5 R 5a , NO 2 , —CN, C(O)R 6 , NHC(O)R 7 , and NHC(O)NR 5 R 5a ;

alternatively, R 3 and R 3a together form —OCH 2 O—;

R 3e , at each occurrence, is independently selected from the group CH 3 , —OH, OCH 3 , OCF 3 , F, Cl, and —NR 5 R 5a ;

R 3f , at each occurrence, is independently selected from the group H, F, Cl, Br, I, C 1-4 alkyl, —OH, CN, —O—R 11 , —O(CO)—R 13 , and —NR 12 R 12a , —SR 11 , —S(O)R 11 , —S(O) 2 R 11 , and —OS(O) 2 methyl;

R 4 is a 6-membered heterocyclic system having 1 N atom substituted with 0-1 R 3e , wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, and 4-pyridyl;

R 5 and R 5a are independently selected from the group H, CH 3 and C 2 H 5 ;

R 6 is selected from the group H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;

R 7 is selected from the group CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ; and

R 9 is selected from H and methyl.

5. A compound of claim 4 , or a pharmaceutically acceptable salt form thereof, wherein:

R 2 is selected from the group methyl substituted with 1 R 4 , ethyl substituted with 1 R 4 , propyl substituted with 1 R 4 , ethenyl substituted with 1 R 4 , 1-propenyl substituted with 1 R 4 , 2-propenyl substituted with 1 R 4 , ethynyl substituted with 1 R 4 , 1-propynyl substituted with 1 R 4 , and 2-propynyl substituted with 1 R 4 ;

R 3e , at each occurrence, is independently selected from the group CH 3 , —OH, OCH 3 , OCF 3 , F, Cl, and —NR 5 R 5a ;

R 4 is a 6-membered heterocyclic system having 1 N atom substituted with 0-1 R 3e , wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, and 4-pyridyl;

R 5 and R 5a are independently selected from the group H, CH 3 and C 2 H 5 ;

R 6 is selected from the group H, OH, CH 3 , C 2 H 5 , OCH 3 , OC 2 H 5 , and NR 5 R 5a ;

R 7 is selected from the group CH 3 , C 2 H 5 , OCH 3 , and OC 2 H 5 ;

R 8 is H.

6. A compound of claim 5 , or a pharmaceutically acceptable salt form thereof, wherein:

R 1 is selected from methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, CF 3 , CF 2 CH 3 , CN, and hydroxymethyl;

R 3 , R 3b , and R 3c are H;

R 3e is CH 3 ;

R 3f , at each occurrence, is independently selected from the group H, F, Cl, Br, I, C 1-4 alkyl, CN, —OH, —O—R 11 , —SR 11 , —S(O)R 11 , —S(O) 2 R 11 , and —NR 12 R 12a ;

R 4 is a 6-membered heterocyclic system having 1 N atom wherein the heterocyclic system is selected from the group 2-pyridyl, 3-pyridyl, and 4-pyridyl;

R 12 and R 12a are independently selected from H, methyl, ethyl, propyl, and i-propyl, and C 3-6 carbocycle substituted with 0-2 R 3e wherein the C 3-6 carbocycle is selected from cyclopropyl.

7. A compound of claim 6 , or a pharmaceutically acceptable salt form thereof, wherein the compound is of formula (Ic):

8. A compound of claim 1 , or a pharmaceutically acceptable salt form thereof, wherein the compound of formula (I) is selected from:

7-fluoro-2-methyl-5-[(6-methyl-2-pyridinyl)methyl]-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

7-fluoro-5-(2-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

7-fluoro-5-(3-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

7-fluoro-5-(4-pyridylmethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

7-fluoro-5-(2-pyridylethynyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

7-fluoro-5-(2-(2-pyridyl)ethyl)-5-(trifluoromethyl)-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one;

7-Chloro-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one; and

7-Chloro-3-methyl-5-(2-pyridylmethyl)-5-trifluoromethyl-5,10-dihydrobenzo[b]-1,7-naphthyridin-1(2H)-one.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt form thereof.

10. A method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salt form thereof.

11. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof, wherein:

A is a ring selected from:

P is O or S;

R b is H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl-O—, or C 1-4 alkyl-NH—;

W is CR 3 ;

X is CR 3a ;

Y is CR 3b ;

Z is CR 3c ;

R 1 is selected from the group C 1-3 alkyl substituted with 0-7 halogen and cyclopropyl;

R 2 is —R 2c ;

R 2c is selected from the group C 1-6 alkyl substituted with 1-2 R 4 , C 2-5 alkenyl substituted with 1-2 R 4 , C 2-5 alkynyl substituted with 1 R 4 , and a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3d ;

R 3 is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —SO 2 NR 5 R 5a , and a 5-6 membered heteroaromatic ring having 1-4 heteroatoms selected from the group O, N, and S;

R 3a is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —SO 2 NR 5 R 5a , and a 5-6 membered heteroaromatic ring having 1-4 heteroatoms selected from the group O, N, and S;

alternatively, R 3 and R 3a together form —OCH 2 O—;

alternatively, R 3a and R 3b together form —OCH 2 O—;

alternatively, R 3b and R 3c together form —OCH 2 O—;

R 3f , at each occurrence, is independently selected from the group H, F, Cl, Br, I, C 1-4 alkyl, —OH, —O—R 11 , —O—C 3-10 carbocycle substituted with 0-2 R 3e , OCF 3 , —O(CO)—R 13 , —OS(O) 2 C 1-4 alkyl, —NR 12 R 12a , —C(O)R 13 , —NHC(O)R 13 , —NHSO 2 R 10 , and —SO 2 NR 12 R 12a ;

R 4 is a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3e ;

R 5 and R 5a are independently selected from the group H and C 1-4 alkyl;

alternatively, R 5 and R 5a , together with the nitrogen to which they are attached, combine to form a 5-6 membered ring having 0-1 O or N atoms;

R 6 is selected from the group H, OH, C 1-4 alkyl, C 1-4 alkoxy, and NR 5 R 5a ;

R 7 is selected from the group H, C 1-3 alkyl and C 1-3 alkoxy;

R 9 is selected from H, C 1-4 alkyl, C 1-4 alkenyl, and C 1-4 alkynyl;

R 10 is selected from the group C 1-4 alkyl and phenyl;

R 11 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl substituted with C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycle substituted with 0-2 R 3e ;

R 12 and R 12a are independently selected from H, C 1-6 alkyl, and C 3-6 carbocycle substituted with 0-2 R 3e ;

alternatively, R 12 and R 12a can join to form 4-7 membered ring; and

12. A compound of formula (I):

or a stereoisomeric form or mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof, wherein:

A is a ring selected from:

P is O or S;

R b is H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 1-4 alkyl-O—, or C 1-4 alkyl-NH—;

W is CR 3 ;

X is CR 3a ;

Y is CR 3b ;

Z is CR 3c ;

R 1 is selected from the group C 1-3 alkyl substituted with 0-7 halogen and cyclopropyl;

R 2 is —R 2c ;

R 3 is selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, —NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , —SO 2 NR 5 R 5a , and a 5-6 membered heteroaromatic ring having 1-4 heteroatoms selected from the group O, N, and S;

alternatively, R 3 and R 3a together form —OCH 2 O—;

alternatively, R 3a and R 3b together form —OCH 2 O—;

alternatively, R 3b and R 3c together form —OCH 2 O—;

R 3e , at each occurrence, is independently selected from the group H, C 1-4 alkyl, —OH, C 1-4 alkoxy, OCF 3 , F, Cl, Br, I, NR 5 R 5a , —NO 2 , —CN, —C(O)R 6 , —NHC(O)R 7 , —NHC(O)NR 5 R 5a , —NHSO 2 R 10 , and —SO 2 NR 5 R 5a ;

R 4 is a 6-membered heterocyclic system having 1 N atom substituted with 0-2 R 3e ;

R 5 and R 5a are independently selected from the group H and C 1-4 alkyl;

alternatively, R 5 and R 5a , together with the nitrogen to which they are attached, combine to form a 5-6 membered ring having 0-1 O or N atoms;

R 6 is selected from the group H, OH, C 1-4 alkyl, C 1-4 alkoxy, and NR 5 R 5a ;

R 7 is selected from the group H, C 1-3 alkyl and C 1-3 alkoxy;

R 9 is selected from H, C 1-4 alkyl, C 1-4 alkenyl, and C 1-4 alkynyl; and

R 10 is selected from the group C 1-4 alkyl and phenyl.