IP Library › Granted Patent US 7,544,697

Granted Patent B2

US 7,544,697 · App. 11/097,715 · Granted Jun 9, 2009

Pyrazolopyridines and analogs thereof

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Quick Facts

Patent No.: US 7,544,697
App. No.: 11/097,715
Granted: Jun 9, 2009
Kind: B2

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Abstract

Pyrazolopyridin-4-amines, pyrazoloquinolin-4-amines, pyrazolonaphthyridin-4-amines, and 6,7,8,9-tetrahydropyrazoloquinolin-4-amines, pharmaceutical compositions containing the compounds, intermediates, methods of making, and methods of use of these compounds as immunomodulators, for inducing or inhibiting cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases, are disclosed.

Claims (263)

1. A compound of the formula (I):

wherein:

R A and R B make a phenyl ring;

R′ is selected from the group consisting of hydrogen and non-interfering substitutents;

R″ is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene orheterocyclylene and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

—O—,

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—C(═N—O—R 8 )—NH—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyiheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyiheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;

R 7 is C 2-7 alkylene;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;

Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )—;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—;and —S(O) 2 —; and

a and b are independently integers from 1 to 6 with the proviso that a+b is≦7; with the proviso that at least one of R A1 , R B1 , R 1 , or R 2 is other than hydrogen; and with the further proviso that when R A1 and R B1 form a fused benzene ring unsubstituted or substituted with chloro, and RI is hydrogen, then R 2 is other than phenyl or phenyl substituted with methyl, methoxy, chloro, or fluoro;

or a pharmaceutically acceptable salt thereof;

R′″ is a non-interfering substitutent; and

with the proviso that at least one of R A , R B , R′, or R″ is other than hydrogen; and with the further proviso that when R A and R B form a benzene ring unsubstituted or substituted with chloro, and R′ is hydrogen, then R″ is other than phenyl or phenyl substituted with methyl, methoxy, chloro, or fluoro;

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula (II):

wherein:

R A1 and R B1 make a phenyl ring;

R 1 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 ,

—X—Y—X—Y—R 4 , and

—X—R 5 ;

R 2 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

Y is selected from the group consisting of:

—O—,

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—C(═N—O—R 8 )—NH—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

Z is a bond or —O—;

R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;

R 7 is C 2-7 alkylene;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —, and

a and b are independently integers from 1 to 6 with the proviso that a+b is≦7;

with the proviso that at least one of R A1, R B1 , R 1 , or R 2 is other than hydrogen; and with the further proviso that when R A1 and R B1 form a fused benzene ring unsubstituted or substituted with chloro, and RI is hydrogen, then R 2 is other than phenyl or phenyl substituted with methyl, methoxy, chloro, or fIuoro;

or a pharmaceutically acceptable salt thereof.

3. A compound of the formula (III):

wherein:

R is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

R 1 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 ,

—X—Y—X—Y—R 4 , and

—X—R 5 ;

R 2 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

R 3 is selected from the group consisting of:

-Z-R 4 ,

-Z-X—R 4 ,

-Z-X—Y—R 4 ,

-Z-X—Y—X—Y—R 4 , and

-Z-X—R 5 ,

n is 0;

m is 0;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

—O—,

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—C(═N—O—R 8 )—NH—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

Z is a bond or —O—;

R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;

R 7 is C 2-7 alkylene;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—; and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, and —S(O) 0-2 —; and

a and b are independently integers from 1 to 6 with the proviso that a+b is≦7;

with the proviso that when R 1 is hydrogen, m is 0, and R is chloro, then R 2 is other than phenyl or phenyl substituted with methyl, methoxy, chloro, or fluoro;

or a pharmaceutically acceptable salt thereof.

4. A compound of the formula (IX):

wherein:

R A2 and R B2 make a phenyl ring;

R 1 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 ,

—X—Y—X—Y—R 4 , and

—X—R 5 ;

R 2 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

—O—,

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R,6)—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(N—O—R 8 )—,

—C(═N—O—R 8 )—NH—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, al kylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyiheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyiheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;

R 7 is C 2-7 alkylene;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl and heteroarylalkylenyl;

R 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;

Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, —C(R 6 )—S—, and —C(R 6 )—N(OR 9 )

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and

a and b are independently integers from 1 to 6 with the proviso that a+b is≦7;

with the proviso that at least one of R A2 , R B2 , R 1 , or R 2 is other than hydrogen; or a pharmaceutically acceptable salt thereof.

5. The compound or salt of claim 4 wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-cyclohexylethyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 2-[(cyclohexylcarbonyl)amino]-2-methylpropyl, 2-{[(isopropylamino)carbonyl]amino)ethyl, 4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, 3-amino-2,2-dimethyl-3-oxopropyl, 2,2-dimethyl-4-oxopentyl, and 4-methanesulfonylaminobutyl; R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, and benzyl.

6. A compound of the formula (Ia):

wherein:

R A3 and R B3 make a phenyl ring;

R 1 and R 2 are independently selected from the group consisting of hydrogen and non-interfering substitutents; and

with the proviso that at least one of R A3 , R B3 , R 1 , or R 2 is other than hydrogen; and with the further proviso that when R A3 and R B3 form a benzene ring unsubstituted or substituted with chloro, and R 1 is hydrogen, then R 2 is other than phenyl or phenyl substituted with methyl, methoxy, chloro, or fluoro;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of claim 1 in combination with a pharmaceutically acceptable carrier.

8. A compound of the formula (II-1):

wherein:

Y″ is selected from the group consisting of —C(O)—, —C(O)—O—, and —C(═NR 9 )—;

R 11 is alkyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C 1-4 alkoxy, aryl, heteroaryl, arylC 1-4 alkylenyl, heteroarylC 1-4 alkylenyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, —O—C(O)—CH 3 , —CO 2 CH 3 , —CONH 2 , —O—CH 2 —CONH 2 , —NH2, and —SO 2 —NH 2 ;

R A1 and R B1 make a phenyl ring;

R 1 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 ,

—X—Y—X—Y—R 4 , and

—X—R 5 ;

R 2 is selected from the group consisting of:

—R 4 ,

—X—R 4 ,

—X—Y—R 4 , and

—X—R 5 ;

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

—O—,

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

—O—N(R 8 )-Q-,

—O—N═C(R 4 )—,

—C(═N—O—R 8 )—,

—C(═N—O—R 8 )—NH—,

—CH(—N(—O—R 8 )-Q-R 4 )—,

Z is a bond or —O—;

R 5 is selected from the group consisting of

R 6 is selected from the group consisting of ═O and ═S;

R 7 is C 2-7 alkylene;

R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;

R 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and

a and b are independently integers from 1 to 6 with the proviso that a+b is≦7;

with the proviso that at least one of R A1 , R B1 , R 1 , or R 2 is other than hydrogen; and with the further proviso that when R A1 and R B1 form a fused benzene ring unsubstituted or substituted with chloro, and R 1 is hydrogen, then R 2 is other than phenyl or phenyl substituted with methyl, methoxy, chloro, or fluoro;

or a pharmaceutically acceptable salt thereof.

9. The compound or salt of claim 2 wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 2-[(cyclohexylcarbonyl)amino]-2-methylpropyl, 2-{[(isopropylamino)carbonyl]amino}ethyl, 4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, 3-amino-2,2-dimethyl-3oxopropyl, 2,2-dimethyl-4-oxopentyl, and 4-methanesulfonylaminobutyl; and R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, and benzyl.

10. The compound or salt of claim 8 wherein R 1 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methylpropyl, 2,2-dimethylpropyl, 2-hydroxy-2-methylpropyl, 2-(propylsulfonyl)ethyl, 2-methanesulfonylethyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, 2-[(cyclohexylcarbonyl)amino]-2-methylpropyl, 2-{[(isopropylamino)carbonyl]amino}ethyl, 4-[(morpholin-4-ylcarbonyl)amino]butyl, 2-(benzoylamino)ethyl, 3-amino-2,2-dimethyl-3oxopropyl, 2,2-dimethyl-4-oxopentyl, and 4-methanesulfonylaminobutyl; and R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, 2-methoxyethyl, 2-hydroxyethyl, and benzyl.

11. the compound or salt of claim 3 wherein the compounds is 1-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2-methylpropan-2-ol.

Assignments (4)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 22, 2011

From: COLEY PHARMACEUTICAL GROUP, INC.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 026167/0103 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 11, 2007

From: 3M COMPANY; 3M INNOVATIVE PROPERTIES COMPANY

To: COLEY PHARMACEUTICAL GROUP, INC.

Reel/Frame 019945/0698 →

CORRECT MIDDLE INITIAL OF SEVENTH INVENTOR 'PHILIP D. HEPPNER' ON A PREVIOUSLY RECORDED AT REEL 16285/FRAME 0932. DOCUMENT NUMBERS 700219842 AND 700183575 Recorded Dec 29, 2005

From: HAYS, DAVID S.; DANIELSON, MICHAEL E.; GERSTER, JOHN F.; NIWAS, SHRI; PRINCE, RYAN B.; KSHIRSAGAR, TUSHAR A.; HEPPNER, PHILIP D.; MOSER, WILLIAM H.; MOSEMAN, JOAN T.; RADMER, MATTHEW R.; KAVANAGH, MAUREEN A.; STRONG, SARAH A.; BONK, JASON D.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 017150/0816 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 31, 2005

From: HAYS, DAVID S.; DANIELSON, MICHAEL E.; GERSTER, JOHN F.; NIWAS, SHRI; PRINCE, RYAN B.; KSHIRSAGAR, TUSHAR A.; HEPPNER, PHILIP A.; MOSER, WILLIAM H.; MOSEMAN, JOAN T.; RADMER, MATTHEW R.; KAVANAGH, MAUREEN A.; STRONG, SARAH A.; BONK, JASON D.

To: 3M INNOVATIVE PROPERTIES COMPANY

Reel/Frame 016285/0932 →