US2008008720A1PendingUtilityA1
Substituted Tricyclic Heterocycles and their Uses
Est. expiryOct 10, 2023(expired)· nominal 20-yr term from priority
Inventors:Charles CywinRoman FleckEugene Richard HickeyWeimin LiuTina MorwickJohn ProudfootDenice Spero
A61P 35/00A61P 37/00A61P 43/00A61P 37/08A61P 3/10A61P 37/06A61P 25/00A61P 29/00A61P 27/02A61P 1/04A61P 19/02C07D 495/14A61P 17/06A61P 11/06A61P 17/00A61P 11/08
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Claims
Abstract
Disclosed are substituted tricyclic heterocycle compounds of the formulas (I), (II) and (III) shown below, wherein R 1 , R 2 , R 3 and R 4 are described herein, which are active as anti-inflammatory agents. Also disclosed are methods of using and making such compounds.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I)
wherein:
R 1 is
(a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R a ,
(b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,
(c) R b (CH 2 ) m O—,
(d) C 3-6 -cycloalkyl,
(e) C 3-6 -cycloalkylC 1-3 alkyl
(f) R b OCH 2 —,
(g) R b (CH 2 ) m NH—,
(h) R b (CH 2 ) p (CH═CH) m .,—
(i) C 1-6 alkyl,
(j) C 1-8 alkoxy,
(k) C 1-8 alkylthio,
(l) C 1-6 alkoxyC 1-6 alkoxy,
(m) —CF 3 ,
(n) —CHO,
(o) —OCH 2 CO 2 H,
(p) —OSO 2 CF 3 ,
(q) —N(R c )(R d ), or
(r) —C(O)NR c R d ;
R 2 is
(a) C 1-6 alkyl-OC(O)C 1-6 alkoxy,
(b) hydroxyC 1-6 alkyl-,
(c) hydroxyC 1-6 alkoxy-, optionally substituted with —C(O)C 1-6 alkyl,
(d) (R c )(R d )NC 1-6 alkoxy-,
(e) (R c )(R d )NC 1-6 alkyl-,
(f) hydroxyC 1-6 alkylamino-,
(g) (R c )(R d )NC 1-6 alkylamino-,
(h) C 1-6 alkoxyC 1-6 alkylamino-,
(i) heterocyclyl(CH 2 ) m — wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ,
(j) heterocyclyl(CH 2 ) m O— wherein the heterocyclyl is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl, optionally substituted with C 1-6 alkyl,
(k) R b (CH 2 ) m O—,
(l) heteroaryl(CH 2 ) m O—, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(m) heteroarylC 1-6 alkylamino, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(n) —SC 1-6 alkyl, or
(o) —SC 1-6 alkylC(O)N(R c )(R d );
R 3 is —N(R c )(R d );
R 4 is hydrogen or —NH 2 ;
R a is chosen from C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O) n C 1-6 alkyl, —NO 2 , —OH, —CF 3 , —N(R c )(R d ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R c )(R d ) and phenyl optionally substituted with halogen, C 1-6 alkyl, —CN or C 1-6 alkoxy;
R b is a phenyl group optionally substituted with one or two groups selected from halogen, pyridyl, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)N(R c )(R d ), NO 2 and C 1-6 alkoxy, or R b is C 3-6 cycloalkyl, naphthyl, pyridyl, quinolinyl and isoquinolinyl;
R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—,
and wherein if R c and R d are both C 1-6 alkyl, they may optionally form a 4-7 member ring, together with the nitrogen they are attached to;
R e is selected from —OH,NHCHO, —O(CH 2 )phenyl, amino,-CN, oxo-CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), N(R c )(R d ), —CH 2 N(R c )(R d ), —NHCH 2 CO 2 H, —NHCH 2 CO N(R c )(R d ), —NHCOObenzyl, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R g )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl;
R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , benzyl or R b ;
R g is C 1-6 alkyl, an aryl or a heteroaryl group selected from phenyl, naphthyl, imidazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzothiophenyl, benzothiazolyl, indolyl, benzimidazoyl, quinolinyl, isoquinolinyl, benzo[1,3]dioxoly, 2,3-dihydro-benzo[1,4]dioxinyl, 1-oxo-1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl and 2-oxo-2,3-dihydro-benzooxazoly,
R g is optionally substituted with one to three R h groups selected from halogen, hydroxyl, C 1-6 alkyl, benzyl, C 1-6 alkoxy, phenoxy, phenylamino, hydroxyC 1-6 alkyl, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —N(R c )(R d ), C 1-6 alkylN(R c )(R d ), —C(O)N(R c )(R d ), —NO 2 , —S(O) n C 1-6 alkyl and —S(O) n N(R c )(R d ), or R h is an aryl or a heteroaryl group selected from phenyl, imidazolyl, pyrazolyl, thienyl, oxazoly, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzo[1,3]dioxoly, and quinolinyl, or R h is morpholinyl,
R h is optionally substituted with one to three R i groups selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —N(R c )(R d ) and C(O)N(R c )(R d );
m is 0 or 1;
n is 0, 1 or 2; and
p is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
2 . A compound of claim 1 wherein:
R 1 is
(a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R a ,
(b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,
(c) R b (CH 2 ) m O—,
(d) C 3-6 -cycloalkyl,
(e) C 3-6 -cycloalkylC 1-3 alkyl
(f) R b OCH 2 —,
(g) R b (CH 2 ) m NH—,
(h) R b (CH 2 ) p (CH═CH) m ,—
(i) C 1-6 alkyl,
(j) C 1-8 alkoxy,
(k) C 1-8 alkylthio,
(l) C 1-6 alkoxyC 1-6 alkoxy,
(m) —CF 3 ,
(n) —CHO,
(o) —OCH 2 CO 2 H,
(p) —OSO 2 CF 3 ,
(q) —N(R c )(R d ), or
(r) —C(O)NR c R d ;
R 2 is
(a) C 1-6 alkyl-OC(O)C 1-6 alkoxy,
(b) hydroxyC 1-6 alkyl-,
(c) hydroxyC 1-6 alkoxy-, optionally substituted with —C(O)C 1-6 alkyl,
(d) (R c )(R d )NC 1-6 alkoxy-,
(e) (R c )(R d )NC 1-6 alkyl-,
(f) hydroxyC 1-6 alkylamino-,
(g) (R c )(R d )NC 1-6 alkylamino-,
(h) C 1-6 alkoxyC 1-6 alkylamino-,
(i) heterocyclyl(CH 2 ) m — wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ,
(j) heterocyclylCH 2 O— wherein the heterocyclyl is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl, optionally substituted with C 1-6 alkyl,
(k) R b (CH 2 ) m O—,
(l) heteroaryl(CH 2 ) m O—, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(m) heteroarylC 1-6 alkylamino, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(n) —SC 1-6 alkyl, or
(o) —SC 1-6 alkylC(O)N(R c )(R d );
R 3 is —N(R c )(R d ); R 4 is hydrogen or —NH 2 ; R a is chosen from C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O) n C 1-6 alkyl, —NO 2 , —OH, —CF 3 , —N(R c )(R d ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R c )(R d ) and phenyl optionally substituted with halogen, C 1-6 alkyl, —CN or C 1-6 alkoxy; R b is a phenyl group optionally substituted with one or two groups selected from halogen, pyridyl, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)N(R c )R d ), NO 2 and C 1-6 alkoxy, or R b is C 3-6 cycloalkyl, naphthyl, pyridyl, quinolinyl and isoquinolinyl; R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—; R e is selected from —OH, —NHCHO, O(CH 2 )phenyl, amino,-CN, oxo, —CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), —N(R c )(R d ), —CH 2 N(R c )(R d ), C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R g )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O),C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl; R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , phenyl or benzyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
3 . A compound of formula I from claim 1 wherein
R 1 is
(a) C 1-6 alkyl,
(b) C 3-6 -cycloalkyl,
(c) C 3-6 -cycloalkylC 1-3 alkyl
(d) C 1-4 alkoxy,
(e) C 1-4 alkylthio,
(f) —CF 3 , or
(g) —C(O)NR c R d ;
R 2 is heterocyclyl wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e , R 3 is —NH 2 ; R 4 is hydrogen; and R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—; R e is selected from —OH,NHCHO, —O(CH 2 )phenyl, —CN, oxo-CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), N(R c )(R d ), —CH 2 N(R c )(R d ), —NHCOObenzyl, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R b )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O),C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl; R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , phenyl or benzyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
4 . A compound of formula (II)
wherein:
R 1 is
(a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R a ,
(b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,
(c) R b (CH 2 ) m O—,
(d) C 3-6 -cycloalkyl,
(e) C 3-6 -cycloalkylC 1-3 alkyl
(f) R b OCH 2 —,
(g) R b (CH 2 ) m NH—,
(h) R b (CH 2 ) p (CH═CH) m ,—
(i) C 1-6 alkyl,
(j) C 1-8 alkoxy,
(k) C 1-8 alkylthio,
(l) C 1-6 alkoxyC 1-6 alkoxy,
(m) —CF 3 ,
(n) —CHO,
(o) —OCH 2 CO 2 H,
(p) —OSO 2 CF 3 ,
(q) —N(R c )(R d ), or
(r) —C(O)NR c R d ;
R 2 is
(a) C 1-6 alkyl-OC(O)C 1-6 alkoxy,
(b) hydroxyC 1-6 alkyl-,
(c) hydroxyC 1-6 alkoxy-, optionally substituted with —C(O)C 1-6 alkyl,
(d) (R c )(R d )NC 1-6 alkoxy-,
(e) (R c )(R d )NC 1-6 alkyl-,
(f) hydroxyC 1-6 alkylamino-,
(g) (R c )(R d )NC 1-6 alkylamino-,
(h) C 1-6 alkoxyC 1-6 alkylamino-,
(i) heterocyclyl(CH 2 ) m — wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ,
(j) heterocyclyl(CH 2 ) m O— wherein the heterocyclyl is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl, optionally substituted with C 1-6 alkyl,
(k) R b (CH 2 ) m O—,
(l) heteroaryl(CH 2 ) m O—, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(m) heteroarylC 1-6 alkylamino, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(n) —SC 1-6 alkyl, or
(o) —SC 1-6 alkylC(O)N(R 4 )(R 5 );
R 3 is —N(R c )(R d );
R a is chosen from C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O) n C 1-6 alkyl, —NO 2 , —OH, —CF 3 , —N(R c )(R d ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R c )(R d ) and phenyl optionally substituted with halogen, C 1-6 alkyl, —CN or C 1-6 alkoxy;
R b is a phenyl group optionally substituted with one or two groups selected from halogen, 1-naphthyl, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)N(R c )R d ), NO 2 and C 1-6 alkoxy, or R b is C 3-6 cycloalkyl;
R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—,
and wherein if R c and R d are both C 1-6 alkyl, they may optionally form a 4-7 member ring, together with the nitrogen they are attached to;
R e is selected from —OH,NHCHO, —O(CH 2 )phenyl, amino,-CN, oxo-CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), N(R c )(R d ), —CH 2 N(R c )(R d ), —NHCH 2 CO 2 H, —NHCH 2 CO N(R c )(R d ), —NHCOObenzyl, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R g )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl;
R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , benzyl or R b ;
R g is C 1-6 alkyl, an aryl or a heteroaryl group selected from phenyl, naphthyl, imidazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzothiophenyl, benzothiazolyl, indolyl, benzimidazoyl, quinolinyl, isoquinolinyl, benzo[1,3]dioxoly, 2,3-dihydro-benzo[1,4]dioxinyl, 1-oxo-1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl and 2-oxo-2,3-dihydro-benzooxazoly,
R g is optionally substituted with one to three R h groups selected from halogen, hydroxyl, C 1-6 alkyl, benzyl, C 1-6 alkoxy, phenoxy, phenylamino, hydroxyC 1-6 alkyl, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —N(R c )(R d ), C 1-6 alkylN(R c )(R d ), —C(O)N(R c )(R d ), —NO 2 , —S(O) n C 1-6 alkyl and —S(O) n N(R c )(R d ), or R h is an aryl or a heteroaryl group selected from phenyl, imidazolyl, pyrazolyl, thienyl, oxazoly, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzo[1,3]dioxoly, and quinolinyl, or R h is morpholinyl,
R h is optionally substituted with one to three R i groups selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —N(R c )(R d ) and C(O)N(R c )(R d );
m is 0 or 1;
n is 0, 1 or 2; and
p is 0, 1, 2 or 3
or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
5 . A compound of formula (II) of claim 4 wherein: R 1 is
(a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R a ,
(b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,
(c) R b (CH 2 ) m O—,
(d) C 3-6 -cycloalkyl,
(e) C 3-6 -cycloalkylC 1-3 alkyl
(f) R b OCH 2 —,
(g) R b (CH 2 ) m NH—,
(h) R b (CH 2 ) p (CH═CH) m ,—
(i) C 1-6 alkyl,
(j) C 1-8 alkoxy,
(k) C 1-8 alkylthio,
(l) C 1-6 alkoxyC 1-6 alkoxy,
(m) —CF 3 ,
(n) —CHO,
(o) —OCH 2 CO 2 H,
(p) —OSO 2 CF 3 ,
(q) —N(R c )(R d ), or
(r) —C(O)NR c R d ;
R 2 is
(a) C 1-6 alkyl-OC(O)C 1-6 alkoxy,
(b) hydroxyC 1-6 alkyl-,
(c) hydroxyC 1-6 alkoxy-, optionally substituted with —C(O)C 1-6 alkyl,
(d) (R c )(R d )NC 1-6 alkoxy-,
(e) (R c )(R d )NC 1-6 alkyl-,
(f) hydroxyC 1-6 alkylamino-,
(g) (R c )(R d )NC 1-6 alkylamino-,
(h) C 1-6 alkoxyC 1-6 alkylamino-,
(i) heterocyclyl(CH 2 )m- wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ,
(j) heterocyclylCH 2 O— wherein the heterocyclyl is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl, optionally substituted with C 1-6 alkyl,
(k) R b (CH 2 ) m O—,
(l) heteroaryl(CH 2 ) m O—, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(m) heteroarylC 1-6 alkylamino, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(n) —SC 1-6 alkyl, or
(o) —SC 1-6 alkylC(O)N(R 4 )(R 5 );
R 3 is —N(R c )(R d ); R a is chosen from C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O) n C 1-6 alkyl, —NO 2 , —OH, —CF 3 , —N(R c )(R d ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R c )(R d ) and phenyl optionally substituted with halogen, C 1-6 alkyl, —CN or C 1-6 alkoxy; R b is a phenyl group optionally substituted with one or two groups selected from halogen, 1-naphthyl, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)N(R c )R d ), NO 2 and C 1-6 alkoxy, or R b is C 3-6 cycloalkyl; R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—; R e is selected from —OH, —NH 2 , —NHCHO, —O(CH 2 )phenyl, amino,-CN, oxo, —CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), —N(R c )(R d ), —CH 2 N(R c )(R d ), —CH 2 OH, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R b )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl; R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , phenyl or benzyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; and pharmaceutically acceptable derivatives thereof.
6 . A compound of formula (JJ) of claim 4 wherein:
R 1 is
(a) C 1-6 alkyl,
(b) C 1-4 alkoxy,
(c) C 3-6 -cycloalkyl,
(d) C 3-6 -cycloalkylC 1-3 alkyl
(e) C 1-4 alkylthio,
(f) —CF 3 , or
(g) —C(O)NR c R d ;
R 2 is heterocyclyl wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ; R 3 is —NH 2 ; and R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—; R e is selected from —OH, —NH 2 , —NHCHO, —O(CH 2 )phenyl, amino,-CN, oxo, —CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), —N(R c )(R d ), —CH 2 N(R c )(R d ), —CH 2 OH, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R b )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl; R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , phenyl or benzyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
7 . A compound of formula (III):
wherein:
R 1 is
(a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R a ,
(b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,
(c) R b (CH 2 ) m O—,
(d) C 3-6 -cycloalkyl,
(e) C 3-6 -cycloalkylC 1-3 alkyl
(f) R b OCH 2 —,
(g) R b (CH 2 ) m NH—,
(h) R b (CH 2 ) p (CH═CH) m ,—
(i) C 1-6 alkyl,
(j) C 1-8 alkoxy,
(k) C 1-8 alkylthio,
(l) C 1-6 alkoxyC 1-6 alkoxy,
(m) —CF 3 ,
(n) —CHO,
(o) —OCH 2 CO 2 H,
(p) —OSO 2 CF 3 ,
(q) —N(R c )(R d ), or
(r) —C(O)NR c R d ;
R 2 is
(a) C 1-6 alkyl-OC(O)C 1-6 alkoxy,
(b) hydroxyC 1-6 alkyl-,
(c) hydroxyC 1-6 alkoxy-, optionally substituted with —C(O)C 1-6 alkyl,
(d) (R c )(R d )NC 1-6 alkoxy-,
(e) (R c )(R d )NC 1-6 alkyl-,
(f) hydroxyC 1-6 alkylamino-,
(g) (R c )(R d )NC 1-6 alkylamino-,
(h) C 1-6 alkoxyC 1-6 alkylamino-,
(i) heterocyclyl(CH 2 ) m — wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ,
(j) heterocyclylCH 2 O— wherein the heterocyclyl is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl, optionally substituted with C 1-6 alkyl,
(k) R b (CH 2 ) m O—,
(l) heteroaryl(CH 2 ) m O—, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(m) heteroarylC 1-6 alkylamino, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(n) —SC 1-6 alkyl, or
(o) —SC 1-6 alkylC(O)N(R c )(R d );
R 3 is —N(R c )(R d );
R a is chosen from C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O) n C 1-6 alkyl, —NO 2 , —OH, —CF 3 , —N(R c )(R d ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R c )(R d ) and phenyl optionally substituted with halogen, C 1-6 alkyl, —CN or C 1-6 alkoxy;
R b is a phenyl group optionally substituted with one or two groups selected from halogen, 1-naphtyl, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)N(R c )R d ), NO 2 and C 1-6 alkoxy, or R b is C 3-6 cycloalkyl;
R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—,
and wherein if R c and R d are both C 1-6 alkyl, they may optionally form a 4-7 member ring, together with the nitrogen they are attached to;
R e is selected from —OH,NHCHO, —O(CH 2 )phenyl, amino,-CN, oxo-CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), N(R c )(R d ), —CH 2 N(R c )(R d ), —NHCH 2 CO 2 H, —NHCH 2 CON(R c )(R d ), —NHCOObenzyl, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R g )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl;
R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , benzyl or R b ;
R g is C 1-6 alkyl, an aryl or a heteroaryl group selected from phenyl, naphthyl, imidazolyl, thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzothiophenyl, benzothiazolyl, indolyl, benzimidazoyl, quinolinyl, isoquinolinyl, benzo[1,3]dioxoly, 2,3-dihydro-benzo[1,4]dioxinyl, 1-oxo-1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl and 2-oxo-2,3-dihydro-benzooxazoly,
R g is optionally substituted with one to three R h groups selected from halogen, hydroxyl, C 1-6 alkyl, benzyl, C 1-6 alkoxy, phenoxy, phenylamino, hydroxyC 1-6 alkyl, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —N(R c )(R d ), C 1-6 alkylN(R c )(R d ), —C(O)N(R c )(R d ), —NO 2 , —S(O) n C 1-6 alkyl and —S(O) n N(R c )(R d ), or R h is an aryl or a heteroaryl group selected from phenyl, imidazolyl, pyrazolyl, thienyl, oxazoly, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzo[1,3]dioxoly, and quinolinyl, or R h is morpholinyl,
R h is optionally substituted with one to three R i groups selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —N(R c )(R d ) and C(O)N(R c )(R d );
m is 0 or 1;
n is 0, 1 or 2; and
p is 0, 1, 2 or 3;
or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
8 . A compound of formula (JJJ) as described in claim 7 wherein:
R 1 is
(a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R a ,
(b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,
(c) R b (CH 2 ) m O—,
(d) C 3-6 -cycloalkyl,
(e) C 3-6 -cycloalkylC 1-3 alkyl
(f) R b OCH 2 —,
(a) R b (CH 2 ) m NH—,
(b) R b (CH 2 ) p (CH═CH) m ,—
(c) C 1-6 alkyl,
(d) C 1-8 alkoxy,
(e) C 1-8 alkylthio,
(f) C 1-6 alkoxyC 1-6 alkoxy,
(g) —CF 3 ,
(h) —CHO,
(i) —OCH 2 CO 2 H,
(j) —OSO 2 CF 3 ,
(k) —N(R c )(R d ), or
(l) —C(O)NR c R d ;
R 2 is
(a) C 1-6 alkyl-OC(O)C 1-6 alkoxy,
(b) hydroxyC 1-6 alkyl-,
(c) hydroxyC 1-6 alkoxy-, optionally substituted with —C(O)C 1-6 alkyl,
(d) (R c )(R d )NC 1-6 alkoxy-,
(e) (R c )(R d )NC 1-6 alkyl-,
(f) hydroxyC 1-6 alkylamino-,
(g) (R c )(R d )NC 1-6 alkylamino-,
(h) C 1-6 alkoxyC 1-6 alkylamino-,
(i) heterocyclyl(CH 2 ) m — wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ,
(j) heterocyclylCH 2 O— wherein the heterocyclyl is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl and 1-pyrrolidinyl, optionally substituted with C 1-6 alkyl,
(k) R b (CH 2 ) m O—,
(l) heteroaryl(CH 2 ) m O—, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(m) heteroarylC 1-6 alkylamino, wherein the heteroaryl is selected from furanyl, thienyl, imidazolyl, pyridyl, indolyl and pyrrolyl,
(n) —SC 1-6 alkyl, or
(o) —SC 1-6 alkylC(O)N(R 4 )(R 5 );
R 3 is —N(R c )(R d ); R a is chosen from C 1-6 alkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O) n C 1-6 alkyl, —NO 2 , —OH, —CF 3 , —N(R c )(R d ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R c )(R d ) and phenyl optionally substituted with halogen, C 1-6 alkyl, —CN or C 1-6 alkoxy; R b is a phenyl group optionally substituted with one or two groups selected from halogen, 1-naphtyl, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)N(R c )R d ), NO 2 and C 1-6 alkoxy, or R b is C 3-6 cycloalkyl; R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—; R e is selected from —OH, —NH 2 , —NHCHO, —O(CH 2 )phenyl, amino-CN, oxo, —CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), —N(R c )(R d ), —CH 2 N(R c )(R d ), —CH 2 OH, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R b )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl; R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , phenyl or benzyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
9 . The compound of formula III of claim 8 wherein:
R 1 is
(a) C 1-6 alkyl,
(b) C 1-4 alkoxy,
(c) C 3-6 -cycloalkyl,
(d) C 3-6 -cycloalkylC 1-3 alkyl
(e) C 1-4 alkylthio,
(f) —CF 3 , or
(g) —C(O)NR c R d ;
R 2 is heterocyclyl wherein said heterocycle is selected from 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 1-azepanyl, 1-pyrrolidinyl, diazepan-1-yl, 1,4-diazacycloheptan-1-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, and is optionally substituted with one or two R e ; R 3 is —NH 2 ; and R c and R d are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—; R e is selected from —OH, —NH 2 , —NHCHO, —O(CH 2 )phenyl, amino,-CN, oxo, —CO 2 C 1-6 alkyl, —CO 2 H, —C(O)N(R c )(R d ), —N(R c )(R d ), —CH 2 N(R c )(R d ), —CH 2 OH, C 1-6 alkyl, —CO 2 benzyl, hydroxyC 1-6 alkyl, —C(O)C 1-6 alkylN(R c )(R d ), —NHCO 2 C 1-6 alkyl, HOCH(R b )CH 2 NH—, —NHC(O)N(R c )(R d ), —S(O) n C 1-6 alkyl, (CH 3 ) 3 COC(O)—, phenyl, pyridyl, H 2 NCH(R f )C(O)— and —C(O)heterocyclyl, wherein said heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl; R f is selected from C 1-6 alkyl, —(CH 2 ) 1-4 NH 2 , phenyl or benzyl; m is 0 or 1; n is 0, 1 or 2; and p is 0, 1, 2 or 3; or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
10 . A compound chosen from:
Compound
No.
Name
Structure
1.
7-(4-Methyl-[1,4]diazepan-1-yl)-9- propyl-pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-4-ylamine
2.
7-(4-Benzyloxy-piperidin-1-yl)-9- propyl-pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-4-ylamine
3.
N-[1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-yl]- formamide
4.
[1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-yl]- carbamic acid benzyl ester
5.
1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-ol
6.
N-[1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-yl)- methanesulfonamide
7.
7-(4-Amino-piperidin-1-yl)-9- propyl-pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-4-ylamine
8.
1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-one
9.
2-[1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4- ylamino]-1-naphthalen-1-yl-ethanol
10.
(S)-2-[1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4- ylamino]-1-phenyl-ethanol
11.
4-{2-[1-(4-Amino-9-propyl- pyrido[3′,2:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4- ylamino]-1-hydroxy-ethyl}- benzamide
12.
7-(4-Amino-piperidin-1-yl)-9- trifluoromethyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-4-ylamine
13.
N-[1-(4-Amino-9-trifluoromethyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-yl]- formamide
14.
1-(2,4-Diamino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d]pyrimidin-7-yl)-piperidin-4-ol
15.
1-(4-Amino-9-propyl- pyrido[3′,2′:4,5]thieno[3,2- d][1,2,3]triazin-7-yl)-piperidin-4-ol
16.
1-(8-Amino-4-propyl-9-thia-1,7- diaza-fluoren-2-yl)-piperidin-4-one
17.
(S)-2-[1-(8-Amino-4-propyl-9-thia- 1,7-diaza-fluoren-2-yl)-piperidin-4- ylamino]-1-phenyl-ethanol
and pharmaceutically acceptable derivatives thereof.
11 . A compound of 10 chosen from:
N-[1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-yl]-methanesulfonamide, 7-(4-Amino-piperidin-1-yl)-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ylamine, 1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-one; 2-[1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-ylamino]-1-naphthalen-1-yl-ethanol, (S)-2-[1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-ylamino]-1-phenyl-ethanol, 4-{2-[1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-ylamino]-1-hydroxy-ethyl}-benzamide, 7-(4-Amino-piperidin-1-yl)-9-trifluoromethyl-pyrido [3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ylamine, N-[1-(4-Amino-9-trifluoromethyl-pyrido[3∝,2′:4,5]thieno [3,2-d]pyrimidin-7-yl)-piperidin-4-yl]-formamide; or the pharmaceutically acceptable salts, esters, isomers or tautomers thereof.
12 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.
13 . A method of treating an immunological disorder, said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 1 .
14 . A method of treating an inflammatory disorder, said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 1 .
15 . A method of treating an allergic disorder said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 1 .
16 . A method of treating a disease chosen from chronic inflammation, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, graft versus host disease, lupus erythematosus, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), bronchitis, conjunctivitis, dermatitis and allergic rhinitis said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 1 .
17 . A method of treating cancer said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 1 .
18 . A method administering a vaccine to an individual in need thereof comprising co-administration of a vaccine and a pharmaceutically effective amount of a compound according to claim 1 .
19 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 4 and one or more pharmaceutically acceptable carriers and/or adjuvants.
20 . A method of treating an immunological disorder, said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 4 .
21 . A method of treating an inflammatory disorder, said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 4 .
22 . A method of treating an allergic disorder said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 4 .
23 . A method of treating a disease chosen from chronic inflammation, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, graft versus host disease, lupus erythematosus, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), bronchitis, conjunctivitis, dermatitis and allergic rhinitis said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 4 .
24 . A method of treating cancer said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 4 .
25 . A method administering a vaccine to an individual in need thereof comprising co-administration of a vaccine and a pharmaceutically effective amount of a compound according to claim 4 .
26 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 7 and one or more pharmaceutically acceptable carriers and/or adjuvants.
27 . A method of treating an immunological disorder, said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 7 .
28 . A method of treating an inflammatory disorder, said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 7 .
29 . A method of treating an allergic disorder said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 7 .
30 . A method of treating a disease chosen from chronic inflammation, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, graft versus host disease, lupus erythematosus, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), bronchitis, conjunctivitis, dermatitis and allergic rhinitis said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 7 .
31 . A method of treating cancer said method comprising administering to a patient in need thereof a therapeutically effect amount of a compound according to claim 7 .
32 . A method administering a vaccine to an individual in need thereof comprising co-administration of a vaccine and a pharmaceutically effective amount of a compound according to claim 7 .
33 . A method of making a compound of formula (I) below, wherein R 1 , R 2 , R 3 , and R 4 are defined as in claim 1 , said method comprising:
reacting an alkynoate ester bearing R 1 , such as the methyl ester IV shown above 2-cyanothioacetamide in the presence of a suitable base such as morpholine to provide the mercaptopyridine V;
reacting an intermediate V with 2-bromoacetamide in the presence of a suitable base such as potassium carbonate to produce mercaptoacetamide Via;
reacting an intermediate VIa with a trifluoromethylsulfonylating reagent such as N-phenyltrifluoromethanesulfonimide in the presence of a suitable base such as triethylamine to form the trifluoromethanesulfonic acid ester VIIa;
reacting intermediate VIIa with a nucleophilic R 2 H in the presence of a suitable base provides intermediate VIIIa;
heating intermediate VIIIa with triethylorthoformate in a suitable solvent such as EtOH, in the presence of a catalytic amount of an acid such as glacial acetic acid to provide the pyridothienopyrimidinone IXa;
reaction intermediate IXa with a suitable chlorinating reagent such as phosphorous oxychloride to provides chloro intermediate Xa;
reacting intermediate Xa with the desired amine —NH(R c )(R d ), preferably while heating in a sealed vessel to provide compound of formula I (R 3 ′—NH(R c )(R d ), R 4 ═H).Join the waitlist — get patent alerts
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