Substituted arylpyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
View Patent ↗The invention relates to substituted arylpyrazolopyridines according to the general formula (I): in which A, B, D, E, R a , R 1 , R 2 , R 3 , R 4 , R 5 and q are as defined in the claims, and salts thereof, to pharmaceutical compositions comprising said substituted arylpyrazolopyridines, to methods of preparing said substituted arylpyrazolopyridines as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth, wherein the compounds effectively interfere with Tie2 signalling.
1. A compound of formula (I):
in which:
R 1 represents —C(O)R b or is selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R 6 ;
R 2 stands for hydrogen, —NR d1 R d2 , —C(O)R b , or is selected from branched or unbranched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted, independently from each other, by R 7 ;
R 3 is selected from hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, and cyano;
R 4 , R 5 , R 6 , R 7 ,
R 8 independently from each other, are selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)R b , —S(O) 2 R b , —OR c , —NR d1 R d2 , and —OP(O)(OR c ) 2 , wherein C 1 -C 6 -alkyl, C 3 -C 10 -heterocycloalkyl and C 3 -C 10 -cycloalkyl of R 4 , R 5 , R 6 , and R 7 are each optionally substituted one or more times, in the same way or differently, by R 8 , and wherein C 1 -C 6 -alkyl, C 3 -C 10 -heterocycloalkyl and C 3 -C 10 -cycloalkyl of R 8 , are optionally substituted once with R 8 ;
R a is hydrogen or C 1 -C 6 -alkyl;
R b is selected from hydroxyl, —OR c , —SR c , —NR d1 R d2 , and C 1 -C 6 -alkyl;
R c is selected from hydrogen, —C(O)R b , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are optionally substituted one or more times, in the same way or differently, by hydroxyl, halogen, aryl, or —NR d1 R d2 and wherein C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted once with —OR c or —OP(O)(OR c ) 2 ;
R d1 , R d2 independently from each other are selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl, heteroaryl, —C(O)R c , —S(O) 2 R b , —C(O)NR d1 R d2 , —C(O)R c , —S(O) 2 R b , and —C(O)NR d1 R d2 , wherein C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —OR c , —C(O)R b , —S(O) 2 R b , or —OP(O)(OR c ) 2 and wherein C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted once by an —NR d1 R d2 group; or
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, in the same way or differently, by NH, NR d1 , oxygen or sulphur, and is optionally interrupted one or more times, in the same way or differently, by a —C(O)—, —S(O)—, and/or —S(O) 2 —, and optionally contains one or more double bonds;
A is selected from —C(O)—, —C(S)—, —C(═NR a )—, —C(═NR a )NR a —, —S(O) 2 —, —S(O)(═NR a )—, —S(═NR a ) 2 —, —C(S)NR a —, —C(O)C(O)—, —C(O)C(O)NR a —, —C(O)NR a C(O)—, —C(S)NR a C(O)—, and —C(O)NR a C(S)—;
B is a bond, C 1 -C 6 -alkylene, or C 3 -C 10 -cycloalkylene;
D, E are, independently from each other, arylene or heteroarylene; and
q represents an integer of 0, 1, or 2;
or a salt or an N-oxide thereof, or an in vivo hydrolysable ester thereof,
wherein, when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
2. The compound according to claim 1 , wherein:
R 1 represents —C(O)R b or is selected from C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R 6 ;
R 2 stands for hydrogen, —NR d1 R d2 , or —C(O)R b , or is selected from branched or unbranched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R 7 ;
R 3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, or cyano;
R 4 , R 5 , R 6 , R 7 ,
R 8 independently from each other, are each selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)R b , —S(O) 2 R b , —OR c , —NR d1 R d2 , and —OP(O)(OR c ) 2 , wherein C 1 -C 6 -alkyl, C 3 -C 10 -heterocycloalkyl and C 3 -C 10 -cycloalkyl of R 4 , R 5 , R 6 , and R 7 , are each optionally substituted one or more times by R 8 , and wherein C 1 -C 6 -alkyl, C 3 -C 10 -heterocycloalkyl and C 3 -C 10 -cycloalkyl of R 8 , are optionally substituted once with R 8 ;
R a is hydrogen or C 1 -C 6 -alkyl;
R b is selected from hydroxyl, —OR c , —SR c , —NR d1 R d2 , and C 1 -C 6 -alkyl;
R c is selected from hydrogen, —C(O)R b , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted one or more times by hydroxyl, halogen, aryl, or —NR d1 R d2 , and wherein C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted once by —OR c or —OP(O)(OR c ) 2 ;
R d1 , R d2 independently from each other are each hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl, heteroaryl, —C(O)R c , —S(O) 2 R b , or —C(O)NR d1 R d2 , wherein C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —OR c , —C(O)R b , —S(O) 2 R b , or —OP(O)(OR c ) 2 , and wherein C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted once by —NR d1 R d2 ; or
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NR d1 , oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, by a —C(O)—, —S(O)—, and/or —S(O) 2 — group, and optionally contains one or more double bonds;
A is selected from —C(O)—, —S(O) 2 —, —C(S)NR a —, —C(O)C(O)—, —C(O)C(O)NR a —, —C(O)NR a C(O)—, —C(S)NR a C(O)—, and —C(O)NR a C(S)—;
B is a bond, C 1 -C 6 -alkylene, or C 3 -C 10 -cycloalkylene;
D is phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
3. The compound according to claim 1 , wherein:
R 1 represents —C(O)R b or is selected from C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R 6 ;
R 2 stands for hydrogen, or is selected from branched or unbranched C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 10 -heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R 7 ;
R 3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, or cyano;
R 4 , R 5 , R 6 , R 7 ,
R 8 independently from each other, are selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)R b , —S(O) 2 R b , —OR c , —NR d1 R d2 , and —OP(O)(OR c ) 2 , wherein C 1 -C 6 -alkyl, C 3 -C 10 -heterocycloalkyl and C 3 -C 10 -cycloalkyl of R 4 , R 5 , R 6 , and R 7 , are each optionally substituted one or more times by R 8 , and wherein C 1 -C 6 -alkyl, C 3 -C 10 -heterocycloalkyl and C 3 -C 10 -cycloalkyl of R 8 , are optionally substituted once with R 8 ;
R a is hydrogen or C 1 -C 6 -alkyl;
R b is selected from hydroxyl, —OR c , —SR c , —NR d1 R d2 , and C 1 -C 6 -alkyl;
R c is selected from hydrogen, —C(O)R b , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted one or more times by hydroxyl, halogen, aryl, or —NR d1 R d2 , and wherein C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted once with —OR c or —OP(O)(OR c ) 2 ;
R d1 , R d2 independently from each other are each hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl, heteroaryl, —C(O)R c , —S(O) 2 R b , or —C(O)NR d1 R d2 , wherein C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —OR c , —C(O)R b , —S(O) 2 R b , or —OP(O)(OR c ) 2 , and wherein C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and C 3 -C 10 -heterocycloalkyl are each optionally substituted once by —NR d1 R d2 ; or
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NR d1 , oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, by —C(O)—, —S(O)—, and/or —S(O) 2 —, and optionally contains one or more double bonds;
A is —C(O)— or —S(O) 2 —;
B is a bond, C 1 -C 6 -alkylene, or C 3 -C 10 -cycloalkylene;
D is para-phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
4. The compound according to claim 1 , wherein:
R 1 represents —C(O)R b , or is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R 6 ;
R 2 is H, or is branched or unbranched C 1 -C 6 alkyl, C 3 -C 6 -heterocycloalkyl, aryl, or heteroaryl, which in each case is unsubstituted or singly or multiply substituted, independently from each other, by R 7 ;
R 3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, or cyano;
R 4 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, cyano, nitro, or —OR c , wherein C 1 -C 6 -alkyl is optionally substituted one or more times by R 8 ;
R 5 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by R 8 ;
R 6 is hydrogen, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 3 -C 6 -heterocycloalkyl is optionally substituted one or more times by R 8 ;
R 7 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by R 8 ;
R 8 is C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , —NR d1 R d2 ;
R a is hydrogen;
R b is —OR c —NR d1 R d2 , and C 1 -C 6 -alkyl;
R c is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by —NR d1 R d2 , and wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are each optionally substituted once by —OR c ;
R d1 , R d2 independently from each other are hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C(O)R c or —C(O)NR d1 R d2 , wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —OR c , or —C(O)R b , and wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted once by —NR d1 R d2 ; or
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NR d1 , or oxygen;
A is —C(O)— or —S(O) 2 —;
B is a bond C 1 -C 3 -alkylene, or C 3 -C 6 -cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being be identical or different.
5. The compound according to claim 1 , wherein:
R 1 represents —C(O)R b or is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R 6 ;
R 2 is H, or is branched or unbranched C 1 -C 6 -alkyl, or C 3 -C 6 -heterocycloalkyl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R 7 ;
R 3 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, or cyano;
R 4 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, nitro, halogen, or —OR c , wherein C 1 -C 6 -alkyl is optionally substituted one or more times by R 8 ;
R 5 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 ; wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are optionally substituted one or more times by R 8 ;
R 6 is hydrogen, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 3 -C 6 -heterocycloalkyl is optionally substituted one or more times by R 8 ;
R 7 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, —C(O)R b , S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by R 8 ;
R 8 is C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 ;
R a is hydrogen;
R b is selected from —OR c , —NR d1 R d2 , and C 1 -C 6 -alkyl;
R c is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by —NR d1 R d2 , and wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are optionally substituted once by —OR c ;
R d1 , R d2 independently from each other are selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, —C(O)R c and —C(O)NR d1 R d2 , wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —OR c , or —C(O)R b , and wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted once by —NR d1 R d2 ; or,
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NR d1 , or oxygen;
A is —C(O)— or —S(O) 2 —;
B is a bond, C 1 -C 3 -alkylene, or C 3 -cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
6. The compound according to claim 1 , wherein:
R 1 represents —C(O)R b or is selected from C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl, which in each case is unsubstituted or substituted one or more times,
independently from each other, by R 6 ;
R 2 stands for hydrogen, or branched or unbranched C 1 -C 6 -alkyl;
R 3 is hydrogen, methyl, or fluoro;
R 4 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, or —OR c , wherein C 1 -C 6 -alkyl is optionally substituted one or more times by R 8 ;
R 5 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by R 8 ;
R 6 is hydrogen, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 3 -C 6 -heterocycloalkyl is optionally substituted one or more times by R 8 ;
R 8 is C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 ;
R a is hydrogen;
R b is selected from —OR c , and —NR d1 R d2 ;
R c is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by —NR d1 R d2 , and wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are each optionally substituted once by —OR c ;
R d1 , R d2 independently from each other are selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C(O)R c and —C(O)NR d1 R d2 , wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —OR c , or —C(O)R b , and wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted once by —NR d1 R d2 ; or,
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NR d1 , or oxygen;
A is —C(O)— or —S(O) 2 —;
B is a bond, C 1 -C 3 -alkylene, or C 3 -cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of R a , R b , R c , R d1 , R d3 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
7. The compound according to claim 1 , wherein:
R 1 is C 1 -C 6 -alkyl;
R 2 stands for hydrogen, or branched or unbranched C 1 -C 6 -alkyl, wherein C 1 -C 6 -alkyl is unsubstituted or singly or multiply substituted, independently from each other, by R 7 ;
R 3 is hydrogen, methyl, or fluoro;
R 4 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, or —OR c , wherein C 1 -C 6 -alkyl is optionally substituted one or more times by R 8 ;
R 5 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by R 8 ;
R 7 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 , wherein C 1 -C 6 -alkyl and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by R 8 ;
R 8 is C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 ;
R a is hydrogen;
R b is —OR c or —NR d1 R d2 ;
R c is hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -heterocycloalkyl, wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are each optionally substituted one or more times by —NR d1 R d2 , and wherein C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -heterocycloalkyl are each optionally substituted once by —OR c ;
R d1 , R d2 independently from each other are selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, —C(O)R c and —C(O)NR d1 R d2 group, wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —OR c , or —C(O)R b , and wherein C 1 -C 6 -alkyl, and C 3 -C 6 -cycloalkyl are each optionally substituted once by —NR d1 R d2 ; or,
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NR d1 , or oxygen;
A is —C(O)— or —S(O) 2 —;
B is a bond, C 1 -C 3 -alkylene, or C 3 -cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of R a , R b , R c , R d1 , R d2 r R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
8. The compound according to claim 1 wherein:
R 1 is C 1 -C 3 -alkyl;
R 2 stands for hydrogen or branched or unbranched C 1 -C 6 -alkyl;
R 3 is hydrogen, methyl, or fluoro;
R 4 is hydrogen, halogen, C 1 -C 3 -alkyl, or C 1 -C 3 -haloalkyl;
R 5 is hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, halogen, —OR c , or —NR d1 R d2 , wherein C 1 -C 3 -alkyl is optionally substituted by R 8 ;
R 8 is —OR c or —NR d1 R d2 ;
R a is hydrogen;
R c is hydrogen or C 1 -C 3 -alkyl, wherein C 1 -C 3 -alkyl is optionally substituted one or more times by —NR d1 R d2 , and wherein C 1 -C 3 -alkyl is optionally substituted once by —OR c ;
R d1 , R d2 independently from each other are selected from hydrogen and C 1 -C 3 -alkyl, wherein C 1 -C 3 -alkyl is optionally substituted one or more times, in the same way or differently, by —OR c , and wherein C 1 -C 3 -alkyl is optionally substituted once by —NR d1 R d2 ; or,
R d1 and R d2 together with the nitrogen atom to which they are attached, form a 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one time, by NH, NR d1 , or oxygen;
A is —C(O)—;
B is C 1 -C 3 alkylene or C 3 -cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of R a , R b , R c , R d1 or R d2 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 or R d2 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 or R d2 within a single molecule to be identical or different.
9. The compound according to claim 1 , wherein said compound is selected from:
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-acetamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-4-methoxy-benzamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-4-chloro-benzamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-C-phenyl-methanesulfonamide;
1-Phenyl-cyclopropanecarboxylic acid [4-(3-amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-(3-methoxy-phenyl)-acetamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-butyramide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-isobutyramide;
1-(3-Methoxy-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(3-Trifluoromethyl-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(4-Trifluoromethyl-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(4-Methoxy-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-Phenyl-cyclopropanecarboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide; and
pharmaceutically acceptable salts thereof.
10. A method of preparing a compound according to claim 1 , said method comprising:
reacting a compound of formula 6
in which X represents a leaving group,
with a substituted hydrazine of formula 6′:
H 2 N—NHR 1 , 6′
to provide a compound of formula (I):
11. A method of preparing a compound of general formula (I) according to claim 1 , said method comprising:
deprotecting an intermediate compound of formula 10
wherein
represents a phthalimide-protected amine of formula 10′:
by reaction with hydrazine,
to provide a compound of formula (I):
12. A method of preparing a compound according to claim 1 , said method comprising:
reacting the step of allowing an intermediate compound of formula 11:
with a compound of formula 11′:
X′—R 1 11′
wherein X′ is a leaving group,
to provide a compound of formula (I):
13. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier.
14. The compound according to claim 1 , wherein R 8 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)R b , —S(O) 2 R b , —OR c , —NR d1 R d2 , and —OP(O)(OR c ) 2 .
15. The compound according to claim 1 , wherein R 8 is C 1 -C 6 -haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)R b , —S(O) 2 R b , —OR c , or —NR d1 R d2 .
16. The compound according to claim 1 , wherein
R a is H;
R 2 is H or C 1 -C 6 -alkyl;
R 3 is H;
A is —C(O)— or —S(O) 2 —;
B is a bond, C 1 -C 3 -alkylene, or C 3 -cycloalkylene;
D is para-phenylene;
E is phenylene; and
q is 0.
17. The compound according to claim 1 , wherein said compound is selected from:
18. The compound according to claim 1 , wherein R 2 is hydrogen.
19. The compound according to claim 1 , wherein R 2 is methyl.
20. The compound according to claim 1 , wherein R 2 is tert-butyl.
21. The compound according to claim 1 , wherein R 2 is branched or unbranched C 1 -C 6 -alkyl which is singly or multiply substituted by R 7 .
22. A process according to claim 10 , where in X is trifluoromethylsulphonyl, Cl, F, acetate, or methoxy.
23. A process according to claim 12 , where in X′ is trifluoromethylsulphonyl, Cl, Br, I, methanesulfonyl, or acetate.