Anti-infective compounds
The present invention relates to small molecule compounds having the general formula (I): wherein A is a moiety selected from the group consisting of formulae (A) to (K) and their use in the treatment of bacterial infections, in particular Tuberculosis.
1. A compound having the general formula I:
wherein
n 1 and n 2 are independently 0, 1, 2, or 3;
m is 1;
A is a moiety selected from the group consisting of
R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 3 , —CN, —NO 2 , —NH 2 , —NR b R c , aryl, heteroaryl and heterocyclyl wherein each of said alkyl, cycloalkyl, aryl heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 2 is selected from the group consisting of hydrogen, halogen, C 2 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 3 , —CN, —NO 2 , —NH 2 , —NR 6 C(O)R c , —(NR d )(V) p R e , aryl, heteroaryl, heterocyclyl and groups of formula Ia shown below,
wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
wherein,
o is independently, at each occurrence, 0, 1, 2 or 3;
p is 0 or 1,
q is 0 or 1;
X 1 is C═O, O, S, —S(O) 2 —, —S(O) 2 NR 6 —, —C(O)O—, —C(O)NR 6 —, —NHC(O)— or —(NR 6 )—;
X 2 is CR b R c , O, S, or NR 6 ;
Y is C 2 -C 6 alkylene, S or NR 6 ;
V and W are independently, at each occurrence, C 1 -C 6 alkylene;
R 3 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 haloalkyl C 1 -C 6 alkyl-O-alkyl, C 2 -C 10 alkenyl, C 3 -C 10 cycloalkenyl, C 2 -C 10 alkynyl, aryl, heteroaryl and heterocyclyl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 6 , —CN, —NO 2 , —NH 2 , —NR b R c , —N(R 6 )C(O)R 6 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR b R c , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 NR b R c , aryl, heteroaryl and heterocyclyl wherein each of said alkyl, cycloalkyl, —OR 6 aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 6 , —CN, —NO 2 , —NH 2 , —NR b R c , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 6 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR b R c , —CHOHR 6 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 NR b R c , aryl, heteroaryl and heterocyclyl wherein each of said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one to four R a groups;
R 6 is independently, at each occurrence, selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, aryl, heteroaryl and heterocyclyl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
Z is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, OR 7 , aryloxy, aryl, heteroaryl, heterocyclyl, and groups of formula Ib shown below, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and groups of formula Ib is optionally substituted with one, three or four R a groups;
wherein,
p is 0 or 1;
l is 1, 2 or 3;
X 3 is, independently at each occurrence, CH or N;
X 4 is C═O, CR b R c , O, S, or NR 7 ;
R e , if denoted in formula Ib, may also occur twice as substituent at the same carbon atom wherein R e is independently selected at each occurrence;
R a is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted with aryl, C 1 -C 3 haloalkyl, hydroxyl, C 1 -C 3 alkylhydroxyl, —CN, NO 2 , —NR b R c , —C(O)NR b R c , —OR c , —C(O)R c , —C(O)OR c , sulfonyl, sulfoxide, C 3 -C 10 cycloalkyl, heterocyclyl, heteroaryl and aryl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four C 1 -C 3 alkyl, C 1 -C 4 alkoxy, aryl, halogen, C 1 -C 3 haloalkyl, hydroxyl, —NH 2 , wherein such substitution, if present, may occur in such a manner that there is more than one substituent, per carbon atom, and wherein these substituents may be the same or different;
R b and R c are independently, at each occurrence selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyl-O-alkyl, C 2 -C 10 alkenyl, C 1 -C 4 alkoxy, C 1 -C 3 alkylhydroxyl, C 3 -C 10 cycloalkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, aryl, alkylaryl, heteroaryl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four C 1 -C 3 alkyl, C 1 -C 4 alkoxy, halogen, aryloxy, C 1 -C 3 haloalkyl, hydroxyl, C 1 -C 3 alkylhydroxyl, —CN, —NO 2 , —NH 2 , sulfonyl, sulfoxide, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein such substitution, if present, may occur in such a manner that there is more than one substituent per carbon atom, wherein such substituents may be the same or different; or
R b and R c are connected to each other to make a four, five or six membered saturated or unsaturated cyclic or heterocyclic ring, or they are connected to make a fused cyclic or heterocyclic ring structure;
R d is independently, at each occurrence, selected from the group consisting of hydrogen, C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, heteroaryl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R e is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 7 , —CN, —(CH 2 ) l R 7 , with l being 0, 1, 2 or 3, —NO 2 , —NH 2 , —NR b R c , —N(R 7 )C(O)R 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR b R c , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR b R c , heteroaryl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 7 is independently, at each occurrence, selected from the group consisting of C 2 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups, and pharmaceutically acceptable salts thereof.
2. A compound having the general formula III:
wherein
n is 0, 1, 2 or 3;
m is 1;
o is 0, 1, 2 or 3;
q is 0 or 1;
X 2 is CR b R c , O, S, or NR 6 ;
Y is C 2 -C 6 alkylene, S or NR 6 ;
W is C 1 -C 6 alkylene;
R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 6 , —CN, —NO 2 , —NH 2 , —NR b R c , —N(R 6 )C(O)R 6 , —N(R 6 )C(O)OR 6 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR b R c , —CHOHR 6 , —S(O)R 6 , —S(O) 2 R 6 , —S(O) 2 NR b R c , aryl, heteroaryl and heterocyclyl group wherein each of said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one to four R a groups;
R 6 is independently, at each occurrence, selected from the group consisting of C 2 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, aryl, heteroaryl and heterocyclyl group, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 8 is selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 9 , —CN, —NO 2 , —NH 2 , aryl, heteroaryl and heterocyclyl group wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 9 is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, aryl, heteroaryl and heterocyclyl group wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
Z is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, OR 6 , aryloxy, aryl, heteroaryl, heterocyclyl, and groups of formula Ib shown below, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and groups of formula Ib is optionally substituted with one, three or four R a groups;
wherein,
p is 0 or 1;
l is 1, 2 or 3;
X 3 is, independently at each occurrence, CH or N;
X 4 is C═O, CR b R c , O, S, or NR 7 ;
R e , if denoted in formula Ib, may also occur twice as substituent at the same carbon atom wherein R e is independently selected at each occurrence;
R a is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted with aryl, aryloxy, C 1 -C 3 haloalkyl, hydroxyl, C 1 -C 3 alkylhydroxyl, —CN, NO 2 , —NR b R c , —C(O)NR b R c , —OR c , —C(O)R c , —C(O)OR c , sulfonyl, sulfoxide, C 3 -C 10 cycloalkyl, heterocyclyl, heteroaryl and aryl, benzyl, alkylaryl wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four C 1 -C 3 alkyl, C 1 -C 4 alkoxy, halogen, C 1 -C 3 haloalkyl, hydroxyl, —NH 2 wherein such substitution, if present, may occur in such a manner that there is more than one substituent, per carbon atom, wherein such substituents may be the same or different;
R b and R c are independently, at each occurrence, selected from the group consisting of hydrogen, C 1 -alkyl, C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkyl-O-alkyl, C 2 -C 10 alkenyl, C 1 -C 4 alkoxy, C 1 -C 3 alkylhydroxyl, C 3 -C 10 cycloalkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, aryl, alkylaryl, heteroaryl, and heterocyclyl; wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four C 1 -C 3 alkyl, C 1 -C 4 alkoxy, halogen, aryloxy, C 1 -C 3 haloalkyl, hydroxyl, C 1 -C 3 alkylhydroxyl, —CN, —NO 2 , —NH 2 , sulfonyl, sulfoxide, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein such substitution, if present, may occur in such a manner that there is more than one substituent, per carbon atom, wherein such substituents may be the same or different; or
R b and R c are connected to each other to make a four, five or six membered saturated or unsaturated cyclic or heterocyclic ring, or they are connected to make a fused cyclic or heterocyclic ring structure;
R e is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, hydroxyl, —OR 7 , —CN, —(CH 2 ) l R 7 with l being 0, 1, 2 or 3, —NO 2 , —NH 2 , —NR b R c , —N(R 7 )C(O)R 7 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR b R c , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR b R c , aryl, heteroaryl and heterocyclyl group, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups;
R 7 is independently, at each occurrence, selected from the group consisting of C 2 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 3 haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one to four R a groups, and pharmaceutically acceptable salts thereof.
3. A compound having one of the formulae:
No.
Structure
35
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4. The compound according to claim 1 , having an inhibitory activity on the growth of M. tuberculosis , inside a macrophage, at a concentration of less than 1 μM.
5. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.
6. The compound, according to claim 3 , having a formula selected from formulae:
No.
Structure
35
38
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41
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7. The compound, according to claim 6 , having a formula selected from formulae:
No.
Structure
35
38
39
40
41
42
43
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45
46
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49
50
53
54
55
58
61
63
66
68
72
74
76
77
78
79
80
83
84
85
86
90
91
95
96
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100
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103
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105
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112
114
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118
119
120
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288
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307
308
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314
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334
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359
360
8. A compound having one of the following formulae:
No.
Structure
13
14
32
9. A pharmaceutical composition comprising a compound according to claim 2 , and a pharmaceutically acceptable carrier.