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US 2003/0158195 A1Published application
1,6 naphthyridines useful as inhibitors of SYK kinase
OwnerCharles L. Cywin, Scott E. Jakes +7inventors
InventorsCharles L. Cywin, Scott E. Jakes, Joachim Heider, Mark A. Bobko, Renee L. Des Jarlais, Mark Player, James Rinker, Michael Winters, Bao-Ping Zhao
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds of formula (I): 1 wherein R3, R5, R7 and R8 are defined herein, which are useful as inhibitors SYK kinase and are thus useful for treating diseases resulting from inappropriate mast cell activation, which include allergic and inflammatory diseases. Also disclosed are pharmaceutical compositions comprising these compounds and processes for preparing these compounds.
Claims14
A compound of formula (I)
- 59
- wherein:
- R3 is H, C1-3alkyl, halogen or phenyl;
- R5 is N(R9 )(R10) or OR11 , wherein
- R9 is H or C1-3alkyl,
- R10 is aminoC2-6 alkyl, C1-4alkylaminoC2-6alkyl, diC1-4alkylaminoC2-6alkyl, C1-4alkoxyC2-6alkyl or hydroxyC2-6alkyl, wherein one methylene group in said C2-6alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH3, and wherein each methylene group in said C2-6alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R10 is C3-7cycloalkyl, heterocycloalkyl, heteroaryl, C3-7cycloalkylC1-4alkyl, heterocycloalkylC1-4alkyl, arylC1-4alkyl or heteroarylC1-4alkyl each optionally substituted with one or more C1-4alkyl, amino, C1-4alkylamino, diC1-4alkylamino, aminoC1-3alkyl, C1-4alkylaminoC1-3alkyl, diC1-4alkylaminoC1-3alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, or R9 and R10 together with the nitrogen they are bonded to may form a heterocycloalkyl group containing one or more heteroatoms which is optionally substituted with one or more C1-4alkyl, amino, C1-4alkylamino, diCi1-4alkylamino, aminoCl1-3alkyl, C1-4alkylaminoC1-3alkyl, diC1-4alkylaminoC1-3alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, and
- R11 is aminoC2-6alkyl, C1-4alkylaminoC2-6alkyl, diC1-4alkylaminoC2-6alkyl, C1-4alkoxyC2-6alkyl or hydroxyC2-6alkyl, wherein one methylene group in said C2-6alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH3, and wherein each methylene group in said C2-6alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R11 is C3-7cycloalkyl, heterocycloalkyl, heteroaryl, C3-7cycloalkylC1-4alkyl, heterocycloalkylC1-4alkyl, arylC1-4alkyl or heteroarylC1-4alkyl each optionally substituted with one or more C1-4alkyl, amino, C1-4alkylamino, diC1-4alkylamino, aminoC1-3alkyl, C1-4alkylaminoC1-3alkyl, diC1-4alkylaminoC1-3alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;
- R7 is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C1-3alkoxy, halogen, CF3, CF3O, hydroxy, C1-3alkyl, amino, C1-3alkylamino, diC1-3alkylamino, C1-3alkylaminoC1-3alkyl, diC1-3alkylaminoC1-3alkyl, (C1-3alkylaminoC1-3alkyl)(C0-3alkyl)amino, (diC1-3alkylaminoC1-3alkyl)(C0-3alkyl)amino, C1-3alkylthio, aminocarboxy, C1-3alkylcarbonyl, ureido optionally substituted with C1-3alkyl, C(O)OC1-4alkyl, C(O)OH, acetamido or heterocycloalkyl groups, or with a phenyl group which is optionally substituted with one or more C1-3alkoxy, halogen, CF3, CF3O, hydroxy, C1-3alkyl, amino, C1-3alkylamino, diC1-3alkylamino, C1-3alkylaminoC1-3alkyl, diCi1-3alkylaminoC1-3alkyl, C1-3alkylthio, aminocarboxy, C1-3alkylcarbonyl, ureido optionally substituted with C1-3alkyl, C(O)OC1-4alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups;
- and
- R8 is H, halogen or cyano.
- or a pharmaceutically acceptable salt thereof.
8 more elements
A compound selected from the group
- 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76
- or a pharmaceutically acceptable salt thereof.
A compound selected from the group
- 77 78 79 80
- or a pharmaceutically acceptable salt thereof.
A method of making a compound of formula (I) below:
- 81
- wherein
- R3 is H, C1-3alkyl, halogen or phenyl;
- R5 is N(R9)(R10) wherein
- R9 is H or C1-3alkyl;
- R10 is aminoC2-6alkyl, C1-4alkylaminoC2-6alkyl, diC1-4alkylaminoC2-6alkyl, C1-4alkoxyC2-6alkyl or hydroxyC2-6alkyl, wherein one methylene group in said C2-6alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH3, and wherein each methylene group in said C2-6alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R10 is C3-7cycloalkyl, heterocycloalkyl, heteroaryl, C3-7cycloalkylC1-4alkyl, heterocycloalkylC1-4alkyl, arylC1-4alkyl or heteroarylC1-4alkyl each optionally substituted with one or more C1-4alkyl, amino, C1-4alkylamino, diC1-4alkylamino, aminoC1-3alkyl, C1-4alkylaminoC1-3alkyl, diC1-4alkylaminoC1-3alkyl, halogen, hydroxy, aminocarboxy or benzyl groups, or R9 and R10 together with the nitrogen they are bonded to may form a heterocycloalkyl group containing one or more heteroatoms which is optionally substituted with one or more C1-4alkyl, amino, C1-4alkylamino, diC1-4alkylamino, aminoC1-3alkyl, C1-4alkylaminoC1-3alkyl, diC1-4alkylaminoC1-3alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;
- R7 is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C1-3alkoxy, halogen, CF3, CF3O, hydroxy, C1-3alkyl, amino, C1-3alkylamino, diC1-3alkylamino, C1-3alkylaminoC1-3alkyl, diC1-3alkylaminoC1-3alkyl, (C1-3alkylaminoC1-3alkyl)(C0-3alkyl)amino, (diC1-3alkylaminoC1-3alkyl)(C0-3alkyl)amino, C1-3alkylthio, aminocarboxy, C1-3alkylcarbonyl, ureido optionally substituted with C1-3alkyl, C(O)OC1-4alkyl, C(O)OH, acetamido or heterocycloalkyl groups, or with a phenyl group which is optionally substituted with one or more C1-3alkoxy, halogen, CF3, CF3O, hydroxy, C1-3alkyl, amino, C1-3alkylamino, diC1-3alkylamino, C1-3alkylaminoC1-3alkyl, diC1-3alkylaminoC1-3alkyl, C1-3alkylthio, aminocarboxy, C1-3alkylcarbonyl, ureido optionally substituted with C1-3alkyl, C(O)OC1-4alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups;
- and
- R8is H;
- said method comprising:
- (a) reacting the compound of formula (II) with a nitrile of the formula R7CN in the presence of a strong base in a suitable solvent to form a compound of formula (III):
- 82
- (b) reacting the compound of formula (III) with a suitable chlorinating agent to form the compound of formula (IV):
- 83
- (c) reacting the compound of formula (IV) with an amine of the formula HN(R8)(R9) to provide the desired compound of formula (I) wherein R5 is N(R8)(R9) and R8 is H:
- 84
13 more elements
A method of making a compound of formula (I) below:
- 85
- wherein
- R3 is H, C1-3alkyl, halogen or phenyl;
- R5 is OR11 wherein
- R11 is aminoC2-6alkyl, C1-4alkylaminoC2-6alkyl, diC1-4alkylaminoC2-6alkyl, C1-4alkoxyC2-6alkyl or hydroxyC2-6alkyl, wherein one methylene group in said C2-6alkyl is optionally replaced with an oxygen, sulfur, NH, or NCH3, and wherein each methylene group in said C2-6alkyl is optionally substituted with a halogen, cyano or hydroxy group, or R11 is C3-7cycloalkyl, heterocycloalkyl, heteroaryl, C3-7cycloalkylC1-4alkyl, heterocycloalkylC1-4alkyl, arylC1-4alkyl or heteroarylC1-4alkyl each optionally substituted with one or more C1-4alkyl, amino, C1-4alkylamino, diC1-4alkylamino, aminoC1-3alkyl, C1-4alkylaminoC1-3alkyl, diC1-4alkylaminoC1-3alkyl, halogen, hydroxy, aminocarboxy or benzyl groups;
- R7 is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted with one or more C1-3alkoxy, halogen, CF3, CF3O, hydroxy, C1-3alkyl, amino, C1-3alkylamino, diC1-3alkylamino, C1-3alkylaminoC1-3alkyl, diC1-3alkylaminoC1-3alkyl, (C1-3alkylaminoC1-3alkyl)(C0-3alkyl)amino, (diC1-3alkylaminoC1-3alkyl)(C0-3alkyl)amino, C1-3alkylthio, aminocarboxy, C1-3alkylcarbonyl, ureido optionally substituted with C1-3alkyl, C(O)OC1-4alkyl, C(O)OH, acetamido or heterocycloaklyl groups, or with a phenyl group which is optionally substituted with one or more C1-3alkoxy, halogen, CF3, CF3O, hydroxy, C1-3alkyl, amino, C1-3alkylamino, diC1-3alkylamino, C1-3alkylaminoC1-3alkyl, diC1-3alkylaminoC1-3alkyl, C1-3alkylthio, aminocarboxy, C1-3alkylcarbonyl, ureido optionally substituted with C1-3alkyl, C(O)OC,1-4alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl groups;
- and
- R8 is H;
- said method comprising:
- (a) reacting the compound of formula (II) with a nitrile of the formula R7CN in the presence of a strong base in a suitable solvent to form a compound of formula (III):
- 86
- (b) reacting the compound of formula (III) with a suitable chlorinating agent to form the compound of formula (IV):
- 87
- (c) reacting the compound of formula (IV) with an alcohol of the formula HO(R10 ) in the presence of a suitable base in a suitable solvent to provide the desired compound of formula (I) wherein R5 is OR10 and R8 is H:
- 88
12 more elements
Dependencies are inferred from the claim text.