IP Library › Granted Patent US 7,989,463

Granted Patent B2

US 7,989,463 · App. 12/553,694 · Granted Aug 2, 2011

Biccyclic compounds as GATA modulators

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Quick Facts

Patent No.: US 7,989,463
App. No.: 12/553,694
Granted: Aug 2, 2011
Kind: B2

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Abstract

Novel bicyclic compounds of the formula (I), stereoisomers, and/or pharmaceutically acceptable salts of the novel bicyclic compounds, and/or pharmaceutically acceptable salts of the stereoisomers of the novel bicyclic compounds are provided. Additionally, methods of forming novel bicyclic compounds, stereoisomers, and/or pharmaceutically acceptable salts of the novel bicyclic compounds, and/or pharmaceutically acceptable salts of the stereoisomers of the novel bicyclic compounds are provided: wherein R 1 , R 2 , m, and n are defined herein.

Claims (133)

1. A compound of formula (I),

a stereoisomer of a compound formula (I), a pharmaceutically acceptable salt of a compound of formula (I), or a pharmaceutically acceptable salt of a stereoisomer of a compound of formula (I); wherein

R 1 is —R, —OR, or —NR a R b ;

R 2 is

R is selected from an optionally substituted group selected from alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein one or more optional substituents on R are selected from halogen, hydroxy, cyano, alkyl, haloalkyl, cycloalkyl, —CO-alkyl, —(CH 2 ) r —OH, —(CH 2 ) r -alkoxy, aryl, heteroaryl, —(CH 2 ) r SO 2 NR f R g or —(CH 2 ) r SO 2 R h ;

A is a 3- to 7-member cycloalkyl ring;

R a and R b are each independently selected from hydrogen, —(CH 2 ) r -hydroxy, —(CH 2 ) r -halogen, and an optionally substituted group selected from alkyl, —(CH 2 ) r -cycloalkyl, —(CH 2 ) r -heterocyclyl, —(CH 2 ) r -aryl or —(CH 2 ) r -heteroaryl, wherein one or more optional substituents on R a and R b are each independently selected from halogen, hydroxy, cyano, alkyl, haloalkyl, cycloalkyl, —CO-alkyl, —(CH 2 ) r —OH, —(CH 2 ) r -alkoxy, aryl, heteroaryl, —(CH 2 ) r SO 2 NR f R g or —(CH 2 ) r SO 2 R h ; or

R a and R b optionally combine with the nitrogen atom, to which they are attached, to form an optionally substituted 5- to 6-membered heterocyclic ring optionally having 1 to 3 additional hetero atoms or groups selected from nitrogen, oxygen, sulfur, SO 2 or CO, wherein one or more optional substituents on the 5- to 6-membered heterocyclic ring are selected from halogen, hydroxy, alkyl, haloalkyl, —CO-alkyl, —(CH 2 ) r —OH or —(CH 2 ) r -alkoxy; R c is selected from hydrogen or alkyl;

R d is selected from cyano, —(CH 2 ) r —OH, —(CH 2 ) r -alkoxy, alkyl, aryl, —NH-aryl, heteroaryl, —(CH 2 ) r CO-alkyl, —(CH 2 ) r COOR e , —(CH 2 ) r CONR f R g , —(CH 2 ) r SO 2 NR f R g or —(CH 2 ) r SO 2 R h ;

R e is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R f and R g are each independently selected from hydrogen or an optionally substituted group selected from alkyl, cycloalkyl, alkoxy, aryl, heteroaryl or heterocyclyl, wherein one or more optional substituents on R f and R g are each independently selected from halogen, hydroxyl or alkyl;

R h is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

m is an integer from 0 to 2;

n is an integer from 1 to 3; and

r is an integer from 0 to 3.

2. The compound as claimed in claim 1 , having the formula (III),

a stereoisomer of a compound of formula (III), a pharmaceutically acceptable salt of a compound of formula (III), or a pharmaceutically acceptable salt of a stereoisomer of a compound of formula (III).

3. The compound as claimed in claim 1 , wherein

A is selected from cyclopropyl, cyclobutyl or cyclopentyl;

R 1 is selected from an optionally substituted group selected from alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein one or more optional substituents on R 1 are selected from halogen, hydroxy, cyano, alkyl, haloalkyl, cycloalkyl, —CO-alkyl, —(CH 2 ) r —OH, —(CH 2 ) r -alkoxy, aryl, heteroaryl, —(CH 2 ) r SO 2 NR f R g or —(CH 2 ) r SO 2 R h ;

R c is selected from hydrogen or alkyl;

R e is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R h is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

n is an integer selected from 1 or 2; and

r is an integer from 0 to 3.

4. The compound as claimed in claim 2 , wherein

A is selected from cyclopropyl, cyclobutyl or cyclopentyl;

R a is selected from hydrogen or (CH 2 ) r -cycloalkyl;

R b is selected from hydrogen and an optionally substituted group selected from alkyl, —(CH 2 ) r -cycloalkyl, —(CH 2 ) r -heterocyclyl, —(CH 2 ) r -aryl or —(CH 2 ) r -heteroaryl, wherein one or more optional substituents on R b are selected from halogen, hydroxy, alkyl, haloalkyl, —CO-alkyl, —(CH 2 ) r —OH, —(CH 2 ) r -alkoxy, —(CH 2 ) r SO 2 NR f R g or —(CH 2 ) r SO 2 R h ;

R c is selected from hydrogen or alkyl;

R e is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R h is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

n is an integer selected from 1 or 2; and

r is an integer from 0 to 3.

5. The compound as claimed in claim 4 , wherein

R d is COOH.

6. The compound as claimed in claim 2 , wherein

A is selected from cyclopropyl, cyclobutyl or cyclopentyl;

R a and R b combine with the nitrogen atom, to which they are attached, to form an optionally substituted 5- to 6-membered heterocyclic ring optionally having 1 to 3 additional hetero atoms or groups selected from nitrogen, oxygen, sulfur, SO 2 or CO, wherein one or more optional substituents on the 5- to 6-membered heterocyclic ring are selected from halogen, hydroxy, alkyl, haloalkyl or —CO-alkyl;

R c is selected from hydrogen or alkyl;

R e is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R h is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;

n is an integer selected from 1 or 2; and

r is an integer from 0 to 3.

7. The compound as claimed in claim 6 , wherein

R d is selected from —COOH;

R a and R b combine with the nitrogen atom, to which they are attached, to form an optionally substituted morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, dioxo-thiomorpholinyl, wherein one or more optional substituents on the heterocyclic ring formed may be selected from halogen, hydroxy, alkyl or —CO-alkyl.

8. A compound selected from:

1-[4-(2-Cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentanecarboxylic acid,

1-[4-(2-Cyclopentylmethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentanecarboxylic acid,

1-[4-(2-Cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-[4-(2-Morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-{4-[2-(4-Hydroxy-piperidin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-[4-(2-Pyrrolidin-1-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-{4-[2-(1-Methyl-1H-pyrazol-4-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-{4-[2-(4-Fluoro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclopentanecarboxylic acid,

1-{4-[2-(4-Acetyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-{4-[2-(3-Fluoro-phenylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-[4-(2-Cyclopentylamino-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-{4-[2-(Cyclopropylmethyl-amino)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-{4-[2-(Bis-cyclopropylmethyl-amino)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-{4-[2-(4-Methanesulfonyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

1-[4-(2-p-Tolyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-[4-(2-Phenyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-{4-[2-(2-Oxo-pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid methyl ester,

1-{4-[2-(6-Methyl-pyridin-3-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid,

{1-[4-(2-Morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutyl}-methanol,

1-[4-(2-Morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentanecarboxylic acid,

{1-[4-(2-Morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentyl}-methanol,

Sodium 1-[4-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylate,

1-{4-[2-(4,4-Difluoro-piperidin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-phenyl}-cyclobutanecarboxylic acid

1-[4-(2-Morpholin-4-yl-5,6,7,8-tetrahydro-quinazolin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-[4-(2-Phenoxy-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid,

1-[4-(2-Morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid cyclopentylamide,

1-(4-{2-[4-(Pyrrolidine-1-sulfonyl)-phenylamino]-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino}-phenyl)-cyclobutanecarboxylic acid,

1-[4-(2-Morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarbonitrile,

Sodium 1-{4-[ethyl-(2-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-amino]-phenyl}-cyclobutanecarboxylate,

a stereoisomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a stereoisomer thereof.

9. The compound as claimed in claim 8 , wherein the compound is