US2010125139A1PendingUtilityA1
Process for preparing quinazoline rho-kinase inhibitors and intermediates thereof
Est. expiryMar 22, 2022(expired)· nominal 20-yr term from priority
Inventors:Donald BankstonDhanaphalan NagarathnamDavoud AsgariJianxing ShaoXiao-Gao LiuUday KhireChunguang WangBarry HartStephen BoyerOlaf WeberMark Lynch
A61P 7/02A61P 35/00A61P 9/10A61P 35/04A61P 9/12A61P 43/00A61P 27/06C07D 239/93C07D 403/14A61P 19/10A61P 11/06C07D 239/91C07D 403/12C07D 405/14A61P 15/10C07D 307/79C07D 405/04C07D 239/86
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Claims
Abstract
A process for the preparation of various quinazoline compounds which are useful as Rho-Kinase inhibitors, and thus having utility in the treatment of hypertension and other indications.
Claims
exact text as granted — not AI-modified1 . A process for the preparation of a compound of Formula (I)
comprising reacting a compound of Formula 1
with a compound of Formula
to produce a compound of Formula 2
cyclizing 2 to form a compound of Formula 3
replacing the hydroxy group of 3 with a leaving group
to form a compound of Formula 4′
optionally isolating said compound of Formula 4′;
reacting a mixture of said compound of Formula 4′ and a compound of Formula 5
and optionally isolating said compound of Formula (I);
wherein in Formulas 3, 4′, 5 and (I)
a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —;
b is —CR 5 ═ or —N═;
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl,
which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 1 , and R 6 and R 8 -R 11 are each independently H or C 1-6 alkyl;
R 2 -R 5 are each independently (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-40 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl; and
p=0, 1, 2 or 3;
LG is Br or S-alkyl; and
Q is CONH 2 ;
with the proviso that compound I is not
2 . A process for the preparation of a compound of Formula (I)
comprising reacting a compound of Formula 4
and a compound of Formula 5
wherein in Formulas 3, 4, 5 and (I)
a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —;
b is —CR 5 ═ or —N═;
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO —NHR 9 ;
R 1 , R 6 and R 8 -R 11 are each independently H or C 1-6 alkyl;
R 2 -R 5 are each independently (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-40 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl; and
p=0, 1, 2 or 3;
LG is Br or S-alkyl;
with the proviso that compound I is not
3 . A process for the preparation of a compound of Formula 3
from a compound of Formula 2
comprising
mixing said compound of Formula 2, where Q is —CO—NH 2 , with about 0.1 N to about 10 N aqueous hydroxide, and
heating from a temperature of about 30° C. to about 120° C.;
wherein
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO —NHR 9 ;
R 5 is (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-10 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
p=0, 1, 2, or 3
R 8 -R 11 are each independently H or C 1-6 alkyl R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl,
and wherein Formulas 2 and 3 encompass tautomers, optical isomers, or salts thereof.
4 . A process for the preparation of a compound of Formula 3,
from a carboxylic acid of Formula A-CO 2 H and a compound of Formula 1,
comprising in a single vessel,
treating said carboxylic acid with a chlorinating agent, with optional addition of a catalytic amount of DMF, to form an acid chloride of Formula A-CO—Cl;
adding a non-nucleophilic amine base and a non-protic solvent with stirring at room temperature to form a compound of Formula 2;
and
adding of a base and heating the mixture up to about 50° C.; for a sufficient time to effect reaction;
wherein Q is CO—NH 2 ,
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 5 is (i) C 1 -C 10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-10 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
p=0, 1, 2, or 3
R 8 -R 11 are each independently H or C 1-6 alkyl
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl,
and wherein Formulas 2 and 3 encompass tautomers, optical isomers, or salts thereof.
5 . A process for the preparation of a compound of Formula (I)
comprising replacing the hydroxy group of a compound of Formula 3
with a leaving group LG
to form a compound of Formula 4
optionally isolating said compound of Formula 4;
reacting a mixture of said compound of Formula 4 and a compound of Formula 5
and optionally
isolating said compound of Formula (I);
wherein in Formulae 3, 4, 5 and (I)
a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —;
b is —CR 5 ═ or —N═;
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 1 , R 6 and R 8 -R 11 are each independently H or C 1-6 alkyl;
R 2 -R 5 are each independently (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-40 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl;
p=0, 1, 2 or 3; and
LG is Br or S-alkyl
with the proviso that compound I is not
6 . A process for the preparation of a compound of Formula I′
wherein Y is ═N— or ═CR 17 ,
X is —(CH 2 ) x —, —O—(CH 2 ) n —, —S—(CH 2 ) n —, —NR 7 —CO—(CH 2 ) n —,
—NR 7 —SO 2 —(CH 2 ) n —, —NR 7 —(CH 2 ) n —, or —(O)C—NR 7 —,
each n is an integer which is independently 0, 1, 2 or 3,
x is 0-3
p is 0-3
a and c are each independently —CR5═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —, and b is —CR5═ or —N═;
A is H, halogen, —CO—OR 8 , —CO—R 8 , cyano, —OR 8 , —NR 8 R 9 , —CO—NR 8 R 9 , —NR 8 —CO—R 9 , —NR 8 —CO—OR 9 , —NR 8 —SO 2 —R 9 , —SR 8 , —SO 2 —R 8 , —SO 2 —NR 8 R 9 , NR 8 —CO—NHR 9 ,
or
A is a 3-20 atom, cyclic or polycyclic moiety, containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 - alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 ; (x)(x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
Ring B is optionally independently substituted up to 3 times in any position by R 5 ,
R 1 and R 6-11 are each independently hydrogen or C 1-6 alkyl,
R 2 -R 5 are each independently (i) hydrogen, (ii) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (iii) C 3-10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iv) C 3-10 -cycloalkenyl; (v) partially unsaturated C 5-10 -heterocyclyl; (vi) aryl; (vii) heteroaryl; (viii) halogen; (ix) —CO—OR 10 ; (x) —OCOR 10 ; (xi) —OCO 2 R 10 ; (xii) —CHO; (xiii) cyano; (xiv) —OR 16 ; (xv) —NR 10 R 15 ; (xvi) nitro; (xvii) —CO—NR 10 R 11 ; (xviii) —NR 10 —CO—R 12 ; (xix) —NR 10 —CO—OR 11 ; (xx) —NR 10 —SO 2 R 12 ; (xxi) —SR 16 ; (xxii) —SOR 16 ; (xxiii) —SO 2 —R 16 ; (xxiv) —SO 2 —NR 10 R 11 ; (xxv) NR 10 —CO—NHR 11 ; (xxvi) amidino; (xxvii) guanidine; (xxviii) sulfo; (xxix) —B(OH) 2 ; (xxx) —OCON(R 10 ) 2 ; or (xxxi) —NR 10 CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy, R 14 is C 1-6 alkyl or phenyl;
R 15 is C 1-6 alkyl, halogen, amino, N-lower alkyl amino, N,N dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl; and
R 17 is H, C 1-6 alkyl or CN,
or a pharmaceutically acceptable salt thereof,
with the provisos that A is not hydrogen when x is 0, and that Formula I is not
said process comprising
(a) reacting a compound of Formula II
with a compound of Formula III
in the presence of a base, to produce a compound of Formula IV
and optionally further reacting IV with arylboronic acid or A-NH 2 , or
(b) reacting a substituted benzoyl chloride with dimethylamine to produce a compound of Formula V
wherein R′″ is (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ,
reacting V with chloro-2-amino-benzonitrile to produce a compound of Formula VI
and reacting VI with aminoindazole.
7 . A process for preparing
comprising reacting 3-fluoro-4-phenylbenzoic acid
with 4-bromo-2-fluorobiphenyl to produce 2[(3-fluoro-4-phenylphenyl)carbonylamino]-benzamide
cyclizing to produce 2-(3-fluoro-1,1′-biphenyl-4-yl)-4(3H)-quinazolinone
reacting to produce 4-chloro-2-(3-fluoro-4-phenylphenyl)quinazoline
and then reacting with aminoindazole to produce
8 . A process for the preparation of a compound of Formula (I)
comprising reacting a compound of Formula 3
with a compound of Formula
to produce a compound of Formula 2
cyclizing 2 to form a compound of Formula 3
replacing the hydroxy group of 3 with a leaving group LG to form a compound of Formula 4′
optionally isolating said compound of Formula 4′;
reacting a mixture of said compound of Formula 4′ and a compound of Formula 5
and optionally isolating said compound of Formula (I);
wherein in Formulas 3, 4′, 5 and (I)
a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —;
b is —CR 5 ═ or —N═;
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 1 , and R 6 and R 8 -R 11 are each independently H or C 1-6 alkyl;
R 2 -R 5 are each independently (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-40 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 —CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl; and
p=0, 1, 2 or 3;
LG is Cl; and
Q is CN;
with the proviso that compound I is not
9 . A process for the preparation of a compound of Formula (I)
comprising reacting a compound of Formula 4′
and a compound of Formula 5
wherein in Formulas 3, 4′, 5 and (I)
a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —;
b is —CR 5 ═ or —N═;
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 1 , R 6 and R 8 -R 11 are each independently H or C 1-6 alkyl;
R 2 -R 5 are each independently (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-40 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 —CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl; and
p=0, 1, 2 or 3;
with the proviso that compound I is not
10 . A process for the preparation of a compound of Formula 3
from a compound of Formula 2
comprising
mixing said compound of Formula 2, where Q is —CN,—with about 0.1 N to about 10 N (or 20%) aqueous hydroxide and about 3 to about 30% H 2 O 2 , or with about 0.5 to 2.5 M mineral acid,
heating the mixture from a temperature of about 30° C. to about 120° C.;
wherein A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 5 is (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-10 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
p=0, 1, 2, or 3
R 8 -R 11 are each independently H or C 1-6 alkyl R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl,
and wherein Formulas 2 and 3 encompass tautomers, optical isomers, or salts thereof.
11 . A process for the preparation of a compound of Formula 3,
from a carboxylic acid of Formula A-CO 2 H and a compound of Formula 1,
comprising in a single vessel,
treating said carboxylic acid with a chlorinating agent, with optional addition of a catalytic amount of DMF, to form an acid chloride of Formula A-CO—Cl;
adding a non-nucleophilic amine base and a non-protic solvent with stirring at room temperature to form a compound of Formula 2;
and
adding of a base and heating the mixture at about 30 to 120° C.; for a sufficient time to effect reaction;
wherein Q is CN,
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO —NHR 9 ;
R 5 is (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-10 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 —OCON(R 10 ) 2 ;
p=0, 1, 2, or 3
R 8 -R 11 are each independently H or C 1-6 alkyl
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl,
and wherein Formulas 2 and 3 encompass tautomers, optical isomers, or salts thereof.
12 . A process for the preparation of a compound of Formula (I)
comprising replacing the hydroxy group of a compound of Formula 3
with a leaving group Cl to form a compound of Formula 4′
optionally isolating said compound of Formula 4;
reacting a mixture of said compound of Formula 4 and a compound of Formula 5
and optionally
isolating said compound of Formula (I);
wherein in Formulae 3, 4′, 5 and (I)
a and c are each independently —CR 5 ═, —N═, or —NR 6 —, wherein one of a or c is —NR 6 —;
b is —CR 5 ═ or —N═;
A is a 3-20 atom, cyclic or polycyclic moiety, e.g., containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C 1 -C 10 alkyl or C 2 -C 10 -alkenyl, each optionally substituted with halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl; (iii) aryl; (iv) heteroaryl; (v) halogen; (vi) —CO—OR 8 ; (vii) —CO—R 8 ; (viii) cyano; (ix) —OR 8 , (x) —NR 8 R 13 ; (xi) nitro; (xii) —CO—NR 8 R 9 ; (xiii) —C 1-10 -alkyl-NR 8 R 9 ; (xiv) —NR 8 —CO—R 12 ; (xv) —NR 8 —CO—OR 9 ; (xvi) —NR 8 —SO 2 —R 9 ; (xvii) —SR 8 ; (xviii) —SO 2 —R 8 ; (xix) —SO 2 —NR 8 R 9 ; or (xx) NR 8 —CO—NHR 9 ;
R 1 , R 6 and R 8 -R 11 are each independently H or C 1-6 alkyl;
R 2 -R 5 are each independently (i) C 1-10 alkyl or C 2-10 -alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR 10 , —COR 14 , —OCOR 14 , —OR 10 , C 5-10 -heteroaryl, C 5-10 -heteroaryloxy, or C 5-10 -heteroaryl-C 1-10 -alkoxy, halogen up to perhalo; (ii) C 3 -C 10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S; (iii) C 3-40 -cycloalkenyl; (iv) partially unsaturated C 5-10 -heterocyclyl; (v) aryl; (vi) heteroaryl; (vii) halogen; (viii) —CO—OR 10 ; (ix) —OCOR 10 ; (x) —OCO 2 R 10 ; (xi) —CHO; (xii) cyano; (xiii) —OR 16 ; (xiv) —NR 10 R 15 ; (xv) nitro; (xvi) —CO—NR 10 R 11 ; (xvii) —NR 10 —CO—R 12 ; (xviii) —NR 10 —CO—OR 11 ; (xix) —NR 10 —SO 2 —R 12 ; (xx) —SR 16 ; (xxi) —SOR 16 ; (xxii) —SO 2 —R 16 ; (xxiii) —SO 2 —NR 10 R 11 ; (xxiv) NR 10 —CO—NHR 11 ; (xxv) amidino; (xxvi) guanidino; (xxvii) sulfo; (xxviii) —B(OH) 2 ; (xxix) —OCON(R 10 ) 2 ; or (xxx) —NR 10 CON(R 10 ) 2 ;
R 12 is H, C 1-6 -alkyl or C 5-10 -aryl,
R 13 is H, C 1-6 -alkyl or C 1-6 -alkoxy,
R 14 is lower alkyl or phenyl;
R 15 is lower alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR 10 , —COR 14 or —OCOR 14 ;
R 16 is hydrogen, C 1-6 -alkyl optionally substituted by halogen, up to perhalo, or C 5-10 -heteroaryl;
p=0, 1, 2 or 3; and
LG is Br or S-alkyl
with the proviso that compound I is notCited by (0)
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