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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

• the invention relates to spirotricyclic derivatives, the process for their preparation, and their use as phosphodiesterase 7 (PDE7) inhibitors.
• Phosphodiesterases play an important role in various biological processes by hydrolysing the key second messengers adenosine and guanosine 3′,5′-cyclic monophosphates (cAMP and cGMP respectively) into their corresponding 5′-monophosphate nucleotides. Therefore, inhibition of PDE activity produces an increase of cAMP and cGMP intracellular levels that activate specific protein phosphorylation pathways involved in a variety of functional responses.
• At least eleven isoenzymes of mammalian cyclic nucleotide phosphodiesterases numbered PDE 1 through PDE 11, have been identified on the basis of primary structure, substrate specificity or sensitivity to cofactors or inhibitory drugs.
• PDE7 is a cAMP-specific PDE.
• PDE7 activity or protein has been detected in T-cell lines, B-cell lines, airway epithelial (AE) cell lines and several foetal tissues.
• AE airway epithelial
• AE cells actively participate in inflammatory airway diseases by liberating mediators such as arachidonate metabolites and cytokines.
• mediators such as arachidonate metabolites and cytokines.
• Selective inhibition of PDE7 may be a useful anti-inflammatory approach for treating AE cells related diseases.
• WO 88/01508 discloses compounds of formula
• R is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, halo, cyano, carbamoyl, alkyl carbamoyl, formyl, alkylamino or amino;
• X is —(CR4R5)a-NR6-(CR4R5)b-;
• R1, R2, R3, and R5 are hydrogen or alkyl
• R4 and R5 groups on vicinal carbon atoms may together form a carbon-carbon double bond; and geminal R4 and R5 groups may together form a spiro substitutent, —(CH2)d-, where d is 2 to 5; or a pharmaceutically acceptable salt thereof. These compounds are described as cardiotonics.
• WO 00/66560 discloses compounds of formula
• the invention provides the use of spirotricyclic derivatives, which are PDE inhibitors and more particularly PDE7 inhibitors, having the following formula (I), (II) or (III):
• X 1 , X 2 , X 3 and X 4 are the same or different and are selected from:
• N provided that not more than two of the groups X 1 , X 2 , X 3 and X 4 simultaneously represent a nitrogen atom, or,
• R 1 is selected from:
• X 5 is selected from:
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted
• heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or a bicyclic group, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• OR 2 OC( ⁇ O)R 2 , C( ⁇ O)OR 2 , SR 2 , S( ⁇ O)R 2 , C( ⁇ O)—NH—SO 2 —CH 3 , NR 3 R 4 , Q-R 2 , Q-NR 3 R 4 , NR 2 -Q-NR 3 R 4 or NR 3 -Q-R 2 in which Q is selected from C( ⁇ NR), C( ⁇ O), C( ⁇ S) or SO 2 , R is selected from hydrogen, CN, SO 2 NH 2 or lower alkyl and R 2 , R 3 and R 4 are the same or different and are selected from:
• lower alkyl optionally interrupted with C( ⁇ O), Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or Q4-cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, in which
• Q4 is selected from (CH 2 ) n , lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl, these groups being optionally substituted with lower alkyl, OR′ or NR′R′′ in which R′ and R′′ are the same or different and are selected from hydrogen or lower alkyl;
• n is an integer selected from 0, 1, 2, 3 or 4;
• these groups being unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, CH 3 , SO 3 H, SO 2 CH 3 , C( ⁇ O)—NH—SO 2 —CH 3 , CF 3 , OR 6 , COOR 6 , C( ⁇ O)R 6 , NR 6 R 7 , NR 6 C( ⁇ O)R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 or N, and which may be substituted with,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N; or,
• X 1 and X 2 both represent C—R 1
• the 2 substituents R 1 may form together with the carbon atoms to which they are attached, a 5-membered heterocyclic ring comprising a nitrogen atom and optionally a second heteroatom selected from O, S or N;
• X is O, S or NR 9 , in which R 9 is selected from,
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 , COOR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Y is selected from O, S or N—R 12 , in which R 12 is selected from:
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, R 10 , COOR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Z is chosen from CH—NO 2 , O, S or NR 13 in which R 13 is selected from:
• R 14 and R 15 being independently selected from hydrogen or lower alkyl, or, R 14 and R 15 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl, or,
• R 12 and R 13 may form together a —CH ⁇ N— group or a —C ⁇ C— group,
• R 9 and R 13 may form together a —CH ⁇ N— group or a —C ⁇ C— group;
• Z 1 is chosen from H, CH 3 or NR 16 R 17 in which R 16 and R 17 are the same or different and are selected from:
• lower alkyl unsubstituted or substituted with one or several groups selected from OR 14 , COOR 14 or NR 14 R 15 ,
• R 14 and R 15 being chosen from hydrogen or lower alkyl, and,
• R 14 and R 15 , and/or, R 16 and R 17 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl;
• A is a cycle chosen from:
• a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are the same or different and are selected from O, S, C, C( ⁇ O), SO, SO 2 or N—R 18 in which R 18 is selected from:
• aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• [0070] * represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y;
• each carbon atom of the cycle A is unsubstituted or substituted with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 , lower haloalkyl, CN, F, ⁇ O, SO 2 NR 19 R 20 , OR 19 , SR 19 , C( ⁇ O)OR 19 , C( ⁇ O)NR 19 R 20 or NR 19 R 20 in which R 19 and R 20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 in which R 21 and R 22 are identical or different and are selected from hydrogen or lower alkyl, and,
• R 19 and R 20 , and/or, R 21 and R 22 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N;
• the invention also relates to compounds, which are PDE7 inhibitors, having the following formula (I), (II) or (III)
• X 1 , X 2 , X 3 and X 4 are the same or different and are selected from:
• N provided that not more than two of the groups X 1 , X 2 , X 3 and X 4 simultaneously represent a nitrogen atom, or,
• R 1 is selected from:
• X 5 is selected from:
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or a bicyclic group, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• lower alkyl optionally interrupted with C( ⁇ O), Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or Q4-cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, in which
• Q4 is selected from (CH 2 ) n , lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl, these groups being optionally substituted with lower alkyl, OR′ or NR′R′′ in which R′ and R′′ are the same or different and are selected from hydrogen or lower lower alkyl;
• n is an integer selected from 0, 1, 2, 3 or 4;
• these groups being unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, CH 3 , SO 3 H, SO 2 CH 3 , C( ⁇ O)—NH—SO 2 —CH 3 , CF 3 , OR 6 , COOR 6 , C( ⁇ O)R 6 , NR 6 R 7 , NR 6 C( ⁇ O)R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 , or N, and which may be substituted with,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N; or,
• R 1 when X 1 and X 2 both represent C—R 1 , the 2 substituents R 1 may form together with the carbon atoms to which they are attached, a 5-membered heterocyclic ring comprising a nitrogen atom and optionally a second heteroatom selected from O, S or N;
• X is O or NR 9 , in which R 9 is selected from,
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 , COOR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Y is selected from O, S or N—R 12 , in which R 12 is selected from:
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with, cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 , COOR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Z is chosen from CH—NO 2 , O, S or NR 13 in which R 13 is selected from:
• lower alkyl unsubstituted or substituted with one or several groups which are the same or different and which are selected OR 14 , COOR 10 or NR 14 R 15 ;
• R 14 and R 15 being independently selected from hydrogen or lower alkyl, or, R 14 and R 15 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl, or,
• Y is N—R 12 and Z is N—R 13 , may form together a —CH ⁇ N— group or a —C ⁇ C— group,
• R 9 and R 13 may form together a —CH ⁇ N— group or a —C ⁇ C— group;
• Z 1 is chosen from H, CH 3 or NR 16 R 17 in which R 16 and R 17 are the same or different and are selected from:
• R 14 and R 15 being chosen from hydrogen or lower alkyl, and,
• R 14 and R 15 , and/or, R 16 and R 17 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl;
• A is a cycle chosen from:
• a 1 , A 2 , A 4 , A 5 and A 6 are the same or different and are selected from O, S, C, C( ⁇ O), SO, SO 2 or N—R 18 in which R 18 is selected from:
• aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• lower alkyl unsubstituted or substituted with aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, CN, NR 19 R 20 , C( ⁇ O)NR 19 R 20 , OR 19 , C( ⁇ O)R 19 or C( ⁇ O)OR 19 in which R 19 and R 20 are identical or different and are selected from hydrogen or lower alkyl;
• a 3 is selected from O, S, C, C( ⁇ O), SO or SO 2 , or N—R 18 when A 1 and/or A 2 are C( ⁇ O) or when Y is O or S, wherein R 18 is as defined above;
• each carbon atom of the cycle A is unsubstituted or substituted. with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 , lower haloalkyl, CN, F, ⁇ O, SO 2 NR 19 R 20 , OR 19 , SR 19 , C( ⁇ O)OR 19 , C( ⁇ O)NR 19 R 20 or NR 19 R 20 in which R 19 and R 20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 in which R 21 and R 22 are identical or different and are selected from hydrogen or lower alkyl, and,
• R 19 and R 20 , and/or, R 21 and R 22 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N;
• the cycle A does not contain more than 2 carbon atoms in an sp 2 hybridization state
• These compounds are selective PDE7 inhibitors. They can be used in the treatment of various diseases, such as T-cell-related diseases, autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), asthma, cancer, acquired immune deficiency syndrome (AIDS), allergy or inflammatory bowel disease (IBD).
• diseases such as T-cell-related diseases, autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), asthma, cancer, acquired immune deficiency syndrome (AIDS), allergy or inflammatory bowel disease (IBD).
• the invention also relates to a process for preparing the above compounds.
• the invention further concerns the use of a compound of formula (I), (II) or (III) for the preparation of a medicament for the prevention or the treatment of disorders for which therapy by a PDE7 inhibitor is relevant.
• the invention also provides a method for the treatment of a disorder for which therapy by a PDE7 inhibitor is relevant, comprising administering to a mammal in need thereof an effective amount of compound of formula (I), (II) or (III).
• the invention also provides a method for the treatment of T-cell-related diseases, autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), asthma, cancer, acquired immune deficiency syndrome (AIDS), allergy or inflammatory bowel disease (IBD), comprising administering to a mammal in need thereof an effective amount of compound of formula (I), (II) or (III).
• the invention also concerns a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), (II) or (III) together with a pharmaceutically acceptable carrier, excipient, diluent or delivery system.
• the present invention provides the use of compounds, which are PDE7 inhibitors, having formula (I), (II) or (III),
• X 1 , X 2 , X 3 and X 4 are the same or different and are selected from:
• N provided that not more than two of the groups X 1 , X 2 , X 3 and X 4 simultaneously represent a nitrogen atom, or,
• R 1 is selected from:
• X 5 is selected from:
• lower alkyl, lower alkenylene or lower alkynylene optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, ,the carbon atoms of these groups being unsubstituted or substituted with one or several groups, identical or different, selected from SR 6 , OR 6 , NR 6 R 7 , ⁇ O, ⁇ S or ⁇ N—R 6 in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl, and,
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or a bicyclic group, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• OR 2 OC( ⁇ O)R 2 , C( ⁇ O)OR 2 , SR 2 , S( ⁇ O)R 2 , NR 3 R 4 , Q-R 2 , Q-NR 3 R 4 , NR 2 -Q-NR 3 R 4 or NR 3 -Q-R 2 in which Q is selected from C( ⁇ NR), C( ⁇ O), C( ⁇ S) or SO 2 , R is selected from hydrogen or lower alkyl and R 2 , R 3 and R 4 are the same or different and are selected from:
• lower alkyl optionally interrupted with C( ⁇ O), (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, (CH 2 ) n -cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N or (CH 2 ) n -cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, in which n is an integer selected from 0, 1, 2, 3 or 4;
• these groups being unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, SO 3 H, CH 3 , SO 2 CH 3 , CF 3 , C( ⁇ O)—NH—SO 2 —CH 3 , OR 6 , COOR 6 , NR 6 R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 or N, and which may be substituted with,
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• X is O, S or NR 9 , in which R 9 is selected from,
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Y is selected from O, S or N—R 12 , in which R 12 is selected from:
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with, cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl; d) Z is chosen from CH—NO 2 , O, S or NR 13 in which R 13 is selected from:
• R 14 and R 15 being independently selected from hydrogen or lower alkyl, or, R 14 and R 15 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl;
• Z 1 is chosen from H, CH 3 or NR 16 R 17 in which R 16 and R 17 are the same or different and are selected from:
• R 14 and R 15 being chosen from hydrogen or lower alkyl, and,
• R 14 and R 15 , and/or, R 16 and R 17 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl;
• A is a cycle chosen from:
• a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are the same or different and are selected from O, S, C, C( ⁇ O), SO, SO 2 or N—R 18 in which R 18 is selected from:
• aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• [0189] represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y;
• each carbon atom of the cycle A is unsubstituted or substituted with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or R 21 or CONR 21 R 22 , lower haloalkyl, CN, F, ⁇ O, SO 2 NR 19 R 20 , OR 19 , SR 19 , C( ⁇ O)OR 19 , C( ⁇ O)NR 19 R 20 or NR 19 R 20 in which R 19 and R 20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 in which R 21 and R 22 are identical or different and are selected from hydrogen or lower alkyl, and,
• R 19 and R 20 , and/or, R 21 and R 22 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N;
• X 1 , X 2 and X 3 are the same or different and are C—R 1 , in which R 1 is selected from:
• R 6 and R 7 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from halogen, CN, OR 2 , COOR 2 , NR 3 R 4 , SO 2 NR 3 R 4 or C( ⁇ O)NR 3 R 4 in which R 2 , R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl, and,
• R 3 and R 4 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• X 5 is selected from a lower alkylene or a single bond, and,
• R 5 is selected from phenyl, pyridyl or indolyl, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3 in which Q3 is selected from:
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N, and which may be substituted with
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• X 4 is C—R 1 in which R 1 is selected from hydrogen, halogen, CN, NO 2 , SO 2 CH 3 , SO 3 H, CH 3 , CF 3 , OR 2 , SR 2 , NR 2 R 3 , COOR 2 , CONR 2 R 3 , SO 2 NR 2 R 3 in which R 2 and R 3 are the same or different and are selected from hydrogen or lower alkyl;
• Z 1 is chosen from NR 16 R 17 in which R 16 and R 17 are the same or different and are selected from:
• R 14 and R 15 being chosen from hydrogen or lower alkyl, and,
• R 14 and R 15 , and/or, R 16 and R 17 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N, and which may be substituted with a lower alkyl;
• A is a cycle chosen from:
• a 1 , A 2 , A 3 , A 4 and A 5 are the same or different and are selected from:
• a carbon atom unsubstituted or substituted with 1 or 2 groups, identical or different selected from lower alkyl, OH or F, or,
• X 1 , X 2 and X 3 are the same or different and are C—R 1 , in which R 1 is selected from:
• R 6 and R 7 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from halogen, CN, SO 3 H, OR 2 , COOR 2 , NR 3 R 4 , SO 2 NR 3 R 4 or C( ⁇ O)NR 3 R 4 in which R 2 , R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl, and,
• R 3 and R 4 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• X 5 is selected from a lower alkylene or a single bond, and,
• R 5 is selected from phenyl, pyridyl or indolyl,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N, and which may be substituted with,
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• X 4 is C—R 1 in which R 1 is selected from hydrogen, halogen, CN, NO 2 , SO 2 CH 3 , SO 3 H, CH 3 , CF 3 , OR 2 , SR 2 , NR 2 R 3 , COOR 2 , CONR 2 R 3 , SO 2 NR 2 R 3 in which R 2 and R 3 are the same or different and are selected from hydrogen or lower alkyl;
• Z is chosen from O, S or NR 13 in which R 13 is hydrogen or CN;
• A is a cycle chosen from:
• a 1 , A 2 , A 3 , A 4 and A 5 are the same or different and are selected from:
• a preferred group of compounds of formula (II) or (III) are those in which,
• X 1 , X 2 and X 3 are the same or different and are C—R 1 , in which R 1 is selected from:
• R 6 and R 7 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from halogen, CN, OR 2 , COOR 2 , NR 3 R 4 , SO 2 NR 3 R 4 or C( ⁇ O)NR 3 R 4 in which R 2 , R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl, and,
• R 3 and R 4 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• X 5 is selected from a lower alkylene or a single bond, and,
• R 5 is selected from phenyl, pyridyl or indolyl,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N, and which may be substituted with
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• X 4 is C—R 1 in which R 1 is selected from hydrogen, halogen, CN, NO 2 , SO 2 CH 3 , SO 3 H, CH 3 , CF 3 , OR 2 , SR 2 , NR 2 R 3 , COOR 2 , CONR 2 R 3 or SO 2 NR 2 R 3 in which R 2 and R 3 are the same or different and are selected from hydrogen or lower alkyl;
• Z 1 is chosen from NR 16 R 17 in which R 16 and R 17 are the same or different and are selected from:
• R 14 and R 15 being chosen from hydrogen or lower alkyl, and,
• R 14 and R 15 , and/or, R 16 and R 17 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N, and which may be substituted with a lower alkyl;
• A is a cycle chosen from:
• a 1 , A 2 , A 3 , A 4 and A 5 are the same or different and are selected from:
• a preferred group of compounds of formula (II) or (III) are the one in which X 1 , X 2 , X 3 , X 4 , X, Y, Z 1 and A are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• X 1 , X 2 , X 3 and X 4 are the same or different and are selected from:
• N provided that not more than two of the groups X 1 , X 2 , X 3 and X 4 simultaneously represent a nitrogen atom, or,
• R 1 is selected from:
• X 5 is selected from:
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or a bicyclic group, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• OR 2 OC( ⁇ O)R 2 , C( ⁇ O)OR 2 , SR 2 , S( ⁇ O)R 2 , NR 3 R 4 , Q-R 2 , Q-NR 3 R 4 , NR 2 -Q-NR 3 R 4 or NR 3 -Q-R 2 in which Q is selected from C( ⁇ NR), C( ⁇ O), C( ⁇ S) or SO 2 , R is selected from hydrogen or lower alkyl and R 2 , R 3 and R 4 are the same or different and are selected from:
• lower alkyl optionally interrupted with C( ⁇ O), (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, (CH 2 ) n -cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N or (CH 2 ) n -cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, in which n is an integer selected from 0, 1, 2 or 3;
• these groups being unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, SO 3 H, CH 3 , SO 2 CH 3 , CF 3 , C( ⁇ O)—NH—SO 2 —CH 3 , OR 6 , COOR 6 , NR 6 R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 or N, and which may be substituted with
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• X is NR 9 , in which R 9 is selected from,
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Y is selected from O, S or N—R 12 , in which R 12 is selected from:
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with, cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, aryl, heteroaryl, OR 10 or NR 10 R 11 in which R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl;
• Z is chosen from CH—NO 2 , O, S or NR 13 in which R 13 is selected from:
• R 14 and R 15 being independently selected from hydrogen or lower alkyl, or, R 14 and R 15 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl;
• A is a cycle chosen from:
• a 1 , A 2 , A 4 , A 5 and A 6 are the same or different and are selected from O, S, C, C( ⁇ O), SO, SO 2 or N—R 18 in which R 18 is selected from:
• aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• a 3 is selected from O, S, C, C( ⁇ O), SO or SO 2, or N—R 18 when A 1 and/or A 2 are C( ⁇ O) or when Y is O or S, wherein R 18 is as defined above;
• each carbon atom of the cycle A is unsubstituted or substituted with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 , lower haloalkyl, CN, F, ⁇ O, SO 2 NR 19 R 20 , OR 19 , SR 19 , C( ⁇ O)OR 19 , C( ⁇ O)NR 19 R 20 or NR 19 R 20 in which R 19 and R 20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 in which R 21 and R 22 are identical or different and are selected from hydrogen or lower alkyl, and,
• R 19 and R 20 , and/or, R 21 and R 22, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N;
• the cycle A does not contain more than 2 carbon atoms in an Sp2 hybridization state.
• a preferred group of compounds of formula (I) is a group in which X 1 , X 2 , X 3 , X 4 , X, Y, Z and A are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• Preferred compounds of formula (I) are those in which,
• X 1 , X 2 , X 3 and X 4 are the same or different and are selected from:
• N provided that not more than two of the groups X 1 , X 2 , X 3 and X 4 simultaneously represent a nitrogen atom, or,
• R 1 is selected from:
• X 5 is selected from:
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S or N, cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S or N, or a bicyclic group,
• these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• Q1, Q2, Q3 are the same or different and are selected from:
• OR 2 OC( ⁇ O)R 2 , C( ⁇ O)OR 2 , SR 2 , S( ⁇ O)R 2 , NR 3 R 4 , Q-R 2 , Q-NR 3 R 4 , NR 2 -Q-NR 3 R 4 or NR 3 -Q-R 2 in which Q is selected from C( ⁇ NR), C( ⁇ O), C( ⁇ S) or SO 2 , R is selected from hydrogen or lower alkyl and R 2 , R 3 and R 4 are the same or different and are selected from:
• lower alkyl optionally interrupted with C( ⁇ O), (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, (CH 2 ) n -cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S or N or (CH 2 ) n -cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S or N, in which n is an integer selected from 0, 1, 2 or 3;
• these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from halogen, CN, SO 3 H, CH 3 , SO 2 CH 3 , CF 3 , OR 6 , COOR 6 , NR 6 R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 or N, and which may be substituted with
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• Z is chosen from O, S or NR 13 in which R 13 is hydrogen or CN;
• A is a cycle chosen from:
• a 1 , A 2 , A 4 and A 5 are the same or different and are selected from O, S, C, C( ⁇ O), SO, SO 2 or N—R 18 in which R 18 is selected from:
• aryl, heteroaryl, cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N
• a 3 is selected from O, S, C, C( ⁇ O), SO or SO 2 , or N—R 18 when A 1 and/or A 2 are C( ⁇ O) or when Y is 0 or S, wherein R 18 is as defined above;
• [0381] represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y;
• each carbon atom of the cycle A is unsubstituted or substituted with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 , lower haloalkyl, CN, F, ⁇ O, SO 2 NR 19 R 20 , OR 19 , SR 19 , C( ⁇ O)OR 19 or C( ⁇ O)NR 19 R 20 or NR 19 R 20 in which R 19 and R 20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR 21 , NR 21 R 22 , COOR 21 or CONR 21 R 22 in which R 21 and R 22 are identical or different and are selected from hydrogen or lower alkyl, and,
• R 19 and R 20 , and/or, R 21 and R 22 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N;
• the cycle A does not contain more than 2 carbon atoms in an Sp 2 hybridization state.
• a preferred group of compounds of formula (I) is a group in which X 1 , X 2 , X 3 , X 4 , X, Y, Z and A are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• X 1 , X 2 and X 3 are the same or different and are C—R 1 , in which R 1 is selected from:
• R 6 and R 7 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from halogen, CN, SO 3 H, OR 2 , COOR 2 , NR 3 R 4 , SO 2 NR 3 R 4 or C( ⁇ O)NR 3 R 4 in which R 2 , R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl, and,
• R 3 and R 4 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• X 5 is selected from a lower alkylene or a single bond, and,
• R 5 is selected from phenyl, pyridyl or indolyl, these groups being unsubstituted or substituted with 1, 2 or 3 groups 30 selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3 in which Q3 is selected from:
• halogen CN, SO 3 H, NO 2 , CF 3 , OR 2 , OC( ⁇ O)R 2 , C( ⁇ O)R 2 , C( ⁇ O)OR 2 , NH—C( ⁇ O)R 2 , NR 3 R 4 , SO 2 NR 3 R 4 or C( ⁇ O)NR 3 R 4 in which R 2 , R 3 and R 4 are the same or different and are selected from: hydrogen, lower alkyl unsubstituted or substituted with one or several groups selected from halogen, OR 6 , COOR 6 or NR 6 R 7 in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N, and which may be substituted with,
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N;
• X 4 is C—R 1 in which R 1 is selected from hydrogen, halogen, CN, NO 2 , SO 2 CH 3 , SO 3 H, CH 3 , CF 3 , OR 2 , SR 2 , NR 2 R 3 , COOR 2 , CONR 2 R 3 or SO 2 NR 2 R 3 in which R 2 and R 3 are the same or different and are selected from hydrogen or lower alkyl;
• Z is chosen from O, S or NR 13 in which R 13 is hydrogen or CN;
• A is a cycle chosen from:
• a 1 , A 2 , A 3 , A 4 and A 5 are the same or different and are selected from:
• a carbon atom unsubstituted or substituted with 1 or 2 groups, identical or different selected from lower alkyl, OH or F, or,
• [0414] represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain;
• a preferred group of compounds of formula (I) is a group in which X 1 , X 2 , X 3 , X 4 , X, Y, Z and A are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• X 1 , X 2 and X 3 are the same or different and are C—R 1 , in which R 1 is selected from:
• lower alkyl, lower alkenyl or lower alkynyl these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from halogen, CN, SO 3 H, OR 2 , COOR 2 , NR 3 R 4 , SO 2 NR 3 R 4 or C( ⁇ O)NR 3 R 4 in which R 2 ,
• R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl, and,
• R 3 and R 4 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring;
• X 4 is C—R 1 in which R 1 is selected hydrogen, halogen, CH 3 , CN, OR 2 , in which
• R 2 is selected from hydrogen or lower alkyl
• e) Z is chosen from O, S or NR 13 in which R 13 is hydrogen or CN; f) A is a cycle chosen from:
• a 1 , A 2 A 3 , A 4 and A 5 are the same or different and are selected from carbon atoms, unsubstituted or substituted with CH 3 ;
• [0432] represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y;
• 2 atoms of the cycle A which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain.
• X 1 , X 2 , X 3 and X 4 are the same or different and are C—R 1 , in which R 1 is selected from:
• X 5 is selected from
• a lower alkylene optionally interrupted with 1 heteroatoms chosen from O, S and N
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or a bicyclic group,
• these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• OR 2 OC( ⁇ O)R 2 , C( ⁇ O)OR 2 , SR 2 , S( ⁇ O)R 2 , C( ⁇ O)—NH—SO 2 —CH 3 , NR 3 R 4 , Q-R 2 , Q-NR 3 R 4 , NR 2 -Q-NR 3 R 4 or NR 3 -Q-R 2 in which Q is selected from C( ⁇ NR), C( ⁇ O), C( ⁇ S) or SO 2 , R is selected from hydrogen or lower alkyl and R 2 , R 3 and R 4 are the same or different and are selected from:
• lower alkyl optionally interrupted with C( ⁇ O), Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or Q4-cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, in which
• Q4 is selected from (CH 2 ) n , lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl, these groups being optionally substituted with lower alkyl, OR′ or NR′R′′ in which R′ and R′′ are the same or different and are selected from hydrogen or lower alkyl;
• n is an integer selected from 0, 1, 2, 3 or 4;
• these groups being unsubstituted or substituted with 1 or 2 groups selected from lower alkyl, halogen, CN, CH 3 , SO 3 H, SO 2 CH 3 , CF 3 , C( ⁇ O)NH—SO 2 CH 3 , OR 6 , COOR 6 , C( ⁇ O)R 6 , NR 6 R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 or N, and which may be substituted with,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N.
• a preferred group of compounds of formula (I) is a group in which X 1 , X 2 , X 3 and X 4 , are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• X 1 , X 2 , X 3 and X 4 are the same or different and are C—R 1 , in which R 1 is selected from:
• lower alkyl or lower alkynyl these groups being unsubstituted or substituted with 1, 2 or 3 fluor atoms, OR 3 , COOR 3 or NR 3 R 4 in which R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl;
• R 3 and R 4 together with the nitrogen atom to which they are linked, may also form a 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N;
• OR 2 C( ⁇ O)OR 2 , NR 3 R 4 , C( ⁇ O)NR 3 R 4 or SO 2 NR 3 R 4 in which R 2 , R 3 l and R 4 are the same or different and are selected from:
• these groups being unsubstituted or substituted with 1 or 2 groups selected from lower alkyl, CN, SO 3 H, C( ⁇ O)—NH—SO 2 —CH 3 , OR 6 , COOR 6 or NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N, and which may be substituted with,
• a 6-membered heterocyclic ring which may contain one or two heteroatoms selected from O or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N.
• a preferred group of compounds of formula (I) is a group in which X 1 , X 2 X 3 and X 4 , are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• a preferred group of compounds is the group in which one of X 1 , X 2 , X 3 and X 4 is C—R 1 in which R 1 is hydrogen while the others are identical or different and are C—R 1 in which R 1 is selected from:
• X 5 is selected from:
• a lower alkylene optionally interrupted with 1 heteroatoms chosen from O, S and N
• R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or a bicyclic group, these groups being unsubstituted or substituted with 1, 2 or 3 groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3;
• OR 2 OC( ⁇ O)R 2 , C( ⁇ O)OR 2 , SR 2 , S( ⁇ O)R 2 , C( ⁇ O)—NH—SO 2 —CH 3 , NR 3 R 4 , Q-R 2 , Q-NR 3 R 4 , NR 2 -Q-NR 3 R 4 or NR 3 -Q-R 2 in which Q is selected from C( ⁇ NR), C( ⁇ O), C( ⁇ S) or SO 2 , R is selected from hydrogen or lower alkyl and R 2 , R 3 and R 4 are the same or different and are selected from:
• lower alkyl optionally interrupted with C( ⁇ O), Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, or Q4-cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, S( ⁇ O), SO 2 or N, in which
• Q4 is selected from (CH 2 ) n , lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl, these groups being optionally substituted with lower alkyl, OR′ or NR′R′′ in which R′ and R′′ are the same or
• n is an integer selected from 0, 1, 2, 3 or 4;
• these groups being unsubstituted or substituted with 1 or 2 groups selected from lower alkyl, halogen, CN, CH 3 , SO 3 H, SO 2 CH 3 , CF 3 , C( ⁇ O)—NH—SO 2 —CH 3 , OR 6 , COOR 6 , C( ⁇ O)R 6 , NR 6 R 7 , C( ⁇ O)NR 6 R 7 or SO 2 NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S( ⁇ O), SO 2 or N, and which may be substituted with,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N.
• a preferred group of compounds of formula (I) is a group in which X 1 , X 2 , X 3 and X 4 , are as disclosed hereabove wherein when X 2 is C—R 1 and R 1 is X 5 —R 5 , then X 5 is not a single bond;
• a preferred group of compounds is the group in which one of X 1 , X 2 , X 3 and X 4 is C—R 1 in which R 1 is hydrogen while the others are identical or different and are C—R 1 in which R 1 is selected from:
• lower alkyl or lower alkynyl these groups being unsubstituted or substituted with 1, 2 or 3 groups halogen or with OR 3 , COOR 3 or NR 3 R 4 in which R 3 and R 4 are the same or different and are selected from hydrogen or lower alkyl;
• R 3 and R 4 together with the nitrogen atom to which they are linked, may also form a 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N;
• OR 2 C( ⁇ O)OR 2 , NR 3 R 4 , C( ⁇ O)NR 3 R 4 or SO 2 NR 3 R 4 in which R 2 , R 3 and R 4 are the same or different and are selected from:
• these groups being unsubstituted or substituted with 1 or 2 groups selected from lower alkyl, CN, SO 3 H, C( ⁇ O)—NH—SO 2 —CH 3 , OR 6 , COOR 6 or NR 6 R 7 , in which R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR 8 in which R and R 8 are hydrogen or lower alkyl, and,
• R 6 and R 7 , and/or, R 3 and R 4 , together with the nitrogen atom to which they are linked, can form a 4- to 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N, and which may be substituted with,
• a 6-membered heterocyclic ring which may contain one or two heteroatoms selected from O or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N.
• a preferred group of compound is the group disclosed hereabove in which X 3 is C—R 1 in which R 1 is hydrogen.
• X 3 is C—R 1 , in which R 1 is selected from:
• R 5 is a single bond and R 5 is aryl, preferably phenyl or heteroaryl, preferably pyridyl, optionally substituted with one, two or three groups which are the same or different and which are selected from halogen, CN, CF 3 , SO 2 Me, OR 2 , COOR 2 , NR 2 R 3 , SO 2 NR 2 R 3 and CONR 2 R 3 in which R 2 and R 3 are the same or different and are selected from hydrogen and lower alkyl.
• X 3 is C—R 1 , in which R 1 is selected from hydrogen or halogen, preferably Cl.
• X 3 is C—R 1 in which R 1 is hydrogen.
• X 4 is C—R 1 , in which R 1 is selected from
• lower alkyl optionally substituted with OR 2 , COOR 2 or SO 2 NR 2 R 3 in which R 2 and R 3 are the same or different and are selected from hydrogen and lower alkyl.
• X 4 is C—R 1 , in which R 1 is selected from hydrogen, halogen, CF 3 , methyl and methoxy.
• X 1 is C—R 1 , in which R 1 is selected from
• lower alkyl, Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, or N
• Q4-cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 or 2 heteroatoms chosen from O, S, or N, in which
• Q4 is selected from (CH 2 ) n , lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl;
• n is an integer selected from 0,1, 2 or 3;
• R 6 and R 7 are the same or different and are selected from hydrogen or lower alkyl, optionally substituted with NH 2 , COOH, OH;
• R 6 and R 7 together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N and which may be substituted with,
• COR′ or lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from hydrogen or lower alkyl;
• lower alkyl optionally substituted with CN, SO 3 H, OR 3 , NR 3 R 4 , COOR 3 or CONR 3 R 4 in which R 3 and R 4 are the same or different and are selected from
• lower alkyl optionally substituted with OH, COOH or NH 2
• X 5 is a lower alkylene optionally interrupted with a heteroatom selected O and N and R 5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S or N and cycloalkenyl optionally interrupted with C( ⁇ O) or with 1, 2, or 3 heteroatoms chosen from O, S or N,
• R 3 and R 4 together with the nitrogen atom to which they are linked, can form a 4- to 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N, and which may be substituted with,
• X 1 is C—R 1 , in which R 1 is selected from hydrogen, halogen, preferably Cl or Br, or OR 2 in which R 2 is selected from
• Q4-oxadiazole, Q4-tetrazole, Q4-morpholine, Q4-furan, Q4-isoxazole in which Q4 is selected from lower alkyl interrupted with one heteroatom selected from O, S or N and (CH 2 ) n in which n is an integer selected from 1 and 2;
• X 2 is C—R 1 , in which R 1 is X 5 —R 5 , in which
• X 5 is a single bond
• R 5 is phenyl or pyridyl
• a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N.
• X 2 is C—R 1 , in which R 1 is X 5 —R 5 , in which
• X 5 is a single bond
• R 5 is phenyl
• a 6-membered heterocyclic ring which may contain one or two nitrogen atoms and which may be substituted with a lower alkyl, or,
• a lower alkyl optionally substituted with OR′, NR′R′′, C( ⁇ O)NR′R′′ or COOR′ in which R′ and R′′ are the same or different and are selected from,
• lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and,
• R′ and R′′ together with the nitrogen atom to which they are linked, can form a 6-membered heterocyclic ring, which may contain one or two heteroatoms selected from O or N;
• compounds of the invention are compounds of formula (I).
• X is NH
• Y is NH
• Z is O.
• X is NH
• Y is NH
• Z is O
• A is selected from cyclohexyl or cycloheptyl, optionally interrupted with C( ⁇ O) or 0, and unsubstituted or substituted with CH 3 , OH or OCH 3 .
• A is selected from unsubstituted cyclohexyl or cycloheptyl.
• A is unsubstituted cyclohexyl.
• X is NH
• Y is NH
• Z is O
• A is unsubstituted cyclohexyl.
• X is NH
• Y is NH
• Z is O
• A is unsubstituted cyclohexyl
• X 3 is C—R 1 in which R 1 is hydrogen and X 4 is C—R 1 , in which R 1 is selected from hydrogen, halogen, CF 3 , methyl or methoxy.
• Halogen includes fluoro, chloro, bromo, and iodo. Preferred halogens are F and Cl.
• Lower alkyl includes straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl and the like.
• Lower alkenyl includes straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and at least one double bond. Examples of such alkenyl groups are ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.
• Lower alkynyl includes straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and at least one triple bond. Examples of such alkynyl groups are ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
• Lower haloalkyl includes a lower alkyl as defined above, substituted with one or several halogens.
• a preferred haloalkyl is trifluoromethyl.
• Aryl is understood to refer to an aromatic carbocycle containing between 6 and 10, preferably 6, carbon atoms.
• a preferred aryl group is phenyl.
• Heteroaryl includes aromatic cycles which have from 5 to 10 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N.
• Preferred heteroaryl groups have 1, 2, 3 or 4 heteroatoms in a 5- or 6-membered aromatic ring. Examples of such groups are tetrazole, pyridyl, thienyl and the like.
• Preferred cycloalkyl contain from 3 to 8 carbon atoms. Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
• interrupted means that in a backbone chain, a carbon atom is replaced by an heteroatom or a group as defined herein.
• cycloalkyl or cycloalkenyl optionally interrupted with C( ⁇ O) or with 1 heteroatom chosen from O, S, S( ⁇ O), SO 2 or N the term “interrupted” means that C( ⁇ O) or a heteroatom can replace a carbon atom of the ring.
• Example of such groups are morpholine or piperazine.
• Cycloalkenyl includes 3- to 10- membered cycloalkyl containing at least one double bond.
• Heterocyclic ring include heteroaryl as defined above and cycloalkyl or cycloalkenyl, as defined above, interrupted with 1, 2 or 3 heteroatoms chosen from O, S, S( ⁇ O), SO 2 , or N.
• Bicyclic substituents refer to two cycles, which are the same or different and which are chosen from aryl, heterocyclic ring, cycloalkyl or cycloalkenyl, fused together to form said bicyclic substituents.
• a preferred bicyclic substituent is indolyl.
• Sp 2 hybridization state carbon atoms in an Sp 2 hybridization state are trigonal instead of tetraedric. It means that the carbon atoms in a SP 2 hybridization state are linked to three atoms and form a double bond with one of these three atoms.
• Preferred compounds are:
• One method for preparing a compound of the formula (I) defined above in which Y is N—R 12 , X is N—R 9 and Z is O comprises reacting a substituted urea of formula
• the compounds utilized in the invention include pharmaceutically acceptable derivatives of compounds of formula (I), (II) or (III) such as solvates, hydrates, pharmaceutically acceptable salts and polymorphs (different crystalline lattice descriptors).
• compositions having a basic part include salts having a basic part and salts having an acidic part.
• the expression pharmaceutically acceptable salt of a compound of formula (I), (II) or (III) having a basic part should be understood to refer to the addition salts of the compounds of formula (I), (II) or (III) which may be formed from non-toxic inorganic or organic acids such as, for example, hydrobromic, hydrochloric, sulfuric, phosphoric, nitric, acetic, succinic, tartaric, citric, maleic, hydroxymaleic, benzoic, fumaric and toluenesulfonic acid salts, and the like.
• the various quaternary ammonium salts of the derivatives (I), (II) or (III) are also included in this category of compounds of the invention.
• the expression pharmaceutically acceptable salt of a compound of formula (I), (II) or (III) having an acidic part is understood to refer to the usual salts of the compounds of formula (I), (II) or (III) which may be formed from non-toxic inorganic or organic bases such as, for example, the hydroxides of alkali metals and alkaline-earth metals (sodium, potassium, magnesium and calcium), amines (dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like) or alternatively quaternary ammonium hydroxides such as tetramethylammonium hydroxide. (See also “Pharmaceutical salts” by Berge S. M. et al. (1997) J. Pharm. Sci. 66: 1-19, which is incorporated herein by reference.).
• compositions which are appropriate for the nature, and severity of the complaint to be treated.
• the daily dose in humans is usually between 1 mg and 1 g of product, which may be taken in one or more individual doses.
• compositions are prepared in forms which are compatible with the intended route of administration, such as, for example, tablets, coated tablets, capsules, mouthwashes, aerosols, powders for inhalation, suppositories, enemas, foams (such as rectal foams) gels or suspensions.
• compositions are prepared by methods which are familiar to those skilled in the art and comprise from 0.5 to 60% by weight of active principle (compound of the invention) and 40 to 99.5% by weight of a pharmaceutical vehicle or carrier which is appropriate and compatible with the active principle and the physical form of the intended composition.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
• a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
• the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• the powders, tablets, cachets or encapsulated forms for capsules preferably contain 5% to about 70% of the active component.
• Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
• Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
• the drug may be delivered as a spray (either in a pressurized container fitted with an appropriate valve or in a non-pressurized container fitted with a metering valve).
• Liquid form preparations include solutions, suspensions, and emulsions.
• Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
• Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
• Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavouring agents, stabilizers, and thickening agents as desired.
• Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
• a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. Enemas are obtained according to known procedures to prepare solutions adapted for rectal administration. Foams are prepared according to known methods (these foams can notably be similar to those used to administer a drug such as 5-ASA for treating rectocolite).
• the pharmaceutical preparation is in unit dosage form.
• the preparation is divided into unit doses containing appropriate quantities of drug.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
• the compounds of the invention are PDE inhibitors, and particularly PDE7 inhibitors. These compounds have low IC 50 values, typically at most 5 ⁇ M, preferably below 1 ⁇ M, and even below 100 nM.
• selective PDE7 inhibitors refers to a compound which have an IC 50 for PDE7 at least 5 times lower than the IC 50 for a PDE distinct from PDE7, and preferably at least 10 times, 15 times, 20 times, 30 times, 40 times, 50 times or 100 times lower than the IC 50 value for a PDE distinct from PDE7.
• a PDE distinct from PDE7 refers preferably to a PDE chosen from PDE1, PDE3, PDE4 or PDE5.
• the compounds of the invention and more particularly the family of compounds given as examples in the present description, have an IC 50 value for the enzyme PDE7 which is often 100 times lower than the value of their IC 50 for a PDE distinct from PDE7, in particular PDE1, PDE3, PDE4 or PDE5.
• Compounds of the invention can be used in the treatment of various diseases, as they can modulate inflammatory and immunological processes due to the increase of intracellular cAMP levels.
• the diseases that can be treated are T-cell-related diseases, AE-cell-related diseases and immune disorders, such as autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, asthma, COPD, cancer, AIDS, inflammation, allergy and various inflammatory disorders such as, for example, inflammatory bowel disease (IBD).
• T-cell-related diseases such as autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, asthma, COPD, cancer, AIDS, inflammation, allergy and various inflammatory disorders such as, for example, inflammatory bowel disease (IBD).
• IBD inflammatory bowel disease
• the invention finally relates to a method for the treatment of the above-mentioned diseases comprising administering to a mammal, particularly a human, in need thereof an effective amount of compound of the invention.
• the compounds according to the present invention can be obtained by carrying out several synthetic processes. Some of these synthetic processes (protocols A-L) are described below.
• the starting materials are either commercially available or can be prepared according to routes known to the skilled person. If the starting urea in step 3 is not commercially available, it can be prepared by treating the corresponding isocyanate with a primary amine in a solvent such as tetrahydrofuran (step 1) or treating the corresponding aniline with a substituted isocyanate in an organic solvent such as dichloromethane or acetonitrile (step 2).
• step 3 the urea is converted into the desired quinazolinone by reacting it with a cyclic ketone in polyphosphoric acid at 80-130° C.
• X 1 , X 2 , X 3 , X 4 , A and R 9 are as defined in the summary of the invention, Y may be O, S or NH and LG is a leaving group and R is lower alkyl.
• the starting compounds are either commercially available or can be prepared according to routes known to the skilled person.
• step 1 compound (2a) is reacted with dialkyl-carbamoyl chloride to form the desired N,N dialkyl-carbamate or thiocarbamate according to routes known to the skilled person. See Poirier, M.; Simard, M.; Wuest, J. D.; Organometallics, 1996, 15 (4), 1296-1300.
• oxygen-based directed metalation groups such as OMe, OMOM, OP(OR 2 ), OPO(NMe) 2 . See Snieckus, Chem. Rev., 1990, 90, 879-933.
• aniline derivative is protected as a t-butyl carbamate or as a pivaloyl amide according to routes known to the skilled person. See Tet Lett., 1994, 35(48), 9003-9006.
• step 2 compound ( 2b ) is converted to a lithium salt (when Y is O or S) or to a dilithium salt thereof by reaction with an excess of lithium compound-forming agent such as t-butyllithium in a mixed solvent of anhydrous ether (for example, diethyl ether and tetrahydrofuran) and alkane (for example pentane), and reacted with an appropriate ketone.
• the reaction is carried out at low temperature (between ⁇ 78° C. and 0° C. to give the expected tertiary entity.
• the organolithium intermediate can also be formed by halogen-metal exchange.
• the organolithium can also be transmetallated into another organometallic reagent such as a cerate (with anhydrous cerium trichloride for example) prior to treatment with the ketone.
• the protecting group is removed according to routes known to the skilled person either under reductive conditions (when Y ⁇ O—P or S—P), under acidic condition or under basic condition to give compound ( 2d ).
• step 4 compound ( 2d ) is reacted with an appropriate substituted isocyanate to obtain compound ( 2e ).
• step 5 treating compound ( 2e ) with an acid (mineral acid or lewis acid) triggers cyclisation to give compound ( 2f ).
• an acid mineral acid or lewis acid
• X 1 , X 2 , X 3 , X 4 and A are as defined in the summary of the invention
• Y may be O, S or NR 2
• X may be O
• S NR 9 and LG is a leaving group
• Z′ may be OR, SR, NR 16 R 17 or NR 13
• Hal is halogen
• Z 2 may be O or S and where R 12 , R 13 , R 16 , R 17 and R 9 are as defined in the summary of the invention and R is alkyl or benzyl.
• step 1 intermediate 2d obtained according to protocol B is reacted either with a carbonyl derivative such as a carbonate, a chloroformate, an isocyanate; a thiocarbonyl derivative such as an isothiocyanate, a thionochloroformate, or others such as cyanamide, 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate, S-methylisothiourea or equivalent.
• a carbonyl derivative such as a carbonate, a chloroformate, an isocyanate
• a thiocarbonyl derivative such as an isothiocyanate, a thionochloroformate, or others
• cyanamide 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate, S-methylisothiourea or equivalent.
• intermediate 2′e can be prepared in two steps by treating 2d with either cyanogens bromide or a carbonyl (or thiocarbonyl) derivative activated by two leaving groups such as phosgene (or thiophosgene), 1,1′-carbonyldiimidazole (or 1,1′-thiocarbonyldiimidazole), nitrophenylchloroformate or carbon disulfide, followed by addition of a nucleophile such as an amine, an alcohol or a thiol to introduce Z′.
• a nucleophile such as an amine, an alcohol or a thiol
• intermediates 2e obtained can be derivatized into other intermediates 2e according to routes known to the skilled person.
• an intermediate thiourea 2e wherein Y ⁇ NH, X ⁇ S and Z′ ⁇ NH 2 can be treated with an alkyl halide R—X according to reaction conditions known to the skilled person to give an intermediate 2e wherein Y ⁇ NH, X ⁇ NH and Z′ ⁇ SR.
• step 2 intermediate 2e is treated with a source of halonium such as iodine, N-iodosuccinimide, bromine or N-bromosuccinimide to yield intermediate 2′f .
• a source of halonium such as iodine, N-iodosuccinimide, bromine or N-bromosuccinimide
• intermediate 2f can be derivatized into different intermediates 2′f according to routes known to the skilled person.
• the halide 2f can be reduced to 2g as shown in step 3 under reaction conditions known to the skilled person, such as treatment with trialkyl tin hydride and a radical initiator like azobisisobutyronitrile (AIBN) in an inert organic solvent.
• AIBN azobisisobutyronitrile
• intermediate 2e could be directly transformed into 2g under acidic treatment according to conditions that can be determined by the skilled person. If necessary, intermediate 2′g can also be derivatized into different 2′g according to routes known to the skilled person.
• Z′ is OR or SR
• intermediate 2q ′ can be converted to 2′h as shown in step 4. This can be done according to conditions known to the skilled person by hydrolysis under aqueous acidic media or by hydrogenolysis when R is benzyl.
• X 1 , X 2 , X 3 , X 4 and A are as defined in the summary of the invention, R 9 is alkyl, aryl, alkylsulfonyl or arylsulfonyl, R is lower alkyl and Y may be O, S or NH.
• step 1 compound ( 3a ) is converted to a lithium salt (when Y is O or S) or to a dilithium salt (when Y is NH) thereof by reaction with an excess of lithium 15 compound-forming agent such as t-butyllithium in a mixed solvent of anhydrous ether (for example, diethyl ether and tetrahydrofuran) and alkane (for example pentane).
• anhydrous ether for example, diethyl ether and tetrahydrofuran
• alkane for example pentane
• the resulting organolithium is reacted with an appropriate imine at low temperature to give the expected tertiary amine ( 3b ).
• the organolithium can also be transmetallated into another organometallic reagent such as a cerate (with anhydrous cerium trichloride for example) prior to treatment with the ketone.
• step 2 the protecting group is removed according to routes known to the skilled person either under reductive conditions (when Y ⁇ O—P or S—P), under acidic condition or under basic condition to give compound ( 3c ).
• R 9 is alkyl or arylsulfonyl
• this group can be deprotected into the NH derivative by reductive methods or hydrolysis according to methods known to the skilled person.
• step 3 compound ( 3c ) is reacted with a compound selected from a carbonic acid halide such as phosgene a carbonic acid diester, 1,1′-carbonyldiimidazole and so on to obtain compound ( 3d ).
• step 4 compound (3c) is reacted with an orthoester, in the presence of an acid to obtain compound (3e) or its tautomeric forms.
• X 1 , X 2 , X 3 , X 4 , A, R 9 and R 12 are as defined in the summary of the invention, Z is O or S.
• the starting materials are either commercially available or can be prepared according to routes known to the skilled person.
• step 1 the starting anthranilic acid is treated with phosgene or an equivalent source of carbonyl such as triphosgene or carbonyl diimidazole.
• phosgene or an equivalent source of carbonyl such as triphosgene or carbonyl diimidazole.
• Various solvents and reaction conditions can be used and will be easily determined by the skilled person.
• the resulting isatoic anhydride is treated with the Grignard reagent obtained from a dihalide and magnesium in a solvent such as tetrahydrofuran or ether (step 2).
• step 3 the aniline is converted to an urea by treatment with a substituted isocyanate.
• Various solvents and reaction conditions can be used and will be easily determined by the skilled person.
• the reaction can be performed at room temperature or reflux in an inert solvent such as dichloromethane, acetonitrile or tetrahydrofuran in the presence or not of a base such as triethylamine or pyridine.
• a base such as triethylamine or pyridine.
• the resulting hydroxy-urea is subjected to an acid with or without an organic solvent.
• the reaction can be carried out at 70-90° C. in sulfuric acid.
• a solvent such as toluene or acetic acid may be added.
• step 3′ compound 4c is converted to compound 4f by treatment with a carbonyl (or thiocarbonyl) derivative activated by two leaving groups such as phosgene (or thiophosgene), 1,1′-carbonyldiimidazole (or 1,1′-thiocarbonyldiimidazole).
• a carbonyl (or thiocarbonyl) derivative activated by two leaving groups such as phosgene (or thiophosgene), 1,1′-carbonyldiimidazole (or 1,1′-thiocarbonyldiimidazole).
• X 1 , X 3 , X 4 , X, Y and A are as defined in the summary of the invention.
• the starting tricyclic compound is reacted with an electrophile E + such as halonium or acylium in presence or not of an activating agent in an organic solvent.
• an electrophile E + such as halonium or acylium
• the starting material can be treated with a source of halonium such as N-iodo or N-bromosuccinimide in dimethylformamide at 60-70° C. to give the corresponding halide.
• the starting material can be reacted with an acyl halide and aluminium trichloride, as Lewis acid, in a solvent such as dichloroethane at 80° C.
• X 1 , X 2 , X 3 and X 4 , X, Y, Z and A are as defined in the summary of the invention, R is alkenyl, alkynyl, aryl or heteroaryl and R′ is H or alkyl.
• the starting aryl or heteroaryl iodide or bromide is subjected to a palladium-catalyzed cross-coupling reaction with an organometallic species, such as a boronate ester, a boronic acid, an organozinc (Hal ⁇ halogen) or a trialkylstannane in the presence of base when needed.
• organometallic species such as a boronate ester, a boronic acid, an organozinc (Hal ⁇ halogen) or a trialkylstannane in the presence of base when needed.
• the organometallic species can be replaced with a terminal alkene or alkyne in the coupling reaction.
• a source of copper(l) such as copper iodide
• Various palladium catalysts, solvents and reaction conditions can be used for these coupling reactions and will be easily determined by the skilled person.
• the starting aryl or heteroaryl iodide or bromide can be reacted with a boronic acid in dimethylformamide at 80° C. in the presence of tetrakis(triphenylphosphine)palladium as catalyst and an aqueous solution of potassium carbonate as a base.
• X 1 , X 2 , X 3 , X 4 , X, Y, Z, R 2 , R 3 , R 4 and A are as defined in the summary of the invention and R is selected from aryl, alkenyl, alkynyl or heteroaryl.
• step 1 the starting aryl or heteroaryl iodide or bromide is treated with bis(pinacolato)diboron under palladium catalysis to give the corresponding boronate ester.
• Various paladium catalysts, solvents and reaction conditions can be used and will be easily determined by the skilled person.
• the starting heteroaryl iodide or bromide can be reacted with bis(pinacolato)diboron in dimethylformamide at 80° C. in the presence of tetrakis(triphenylphosphine) palladium as catalyst.
• the resulting boronate ester is then coupled to an aryl, alkenyl, alkynyl or heteroaryl iodide, bromide or triflate catalyzed by a palladium species (step 2).
• a palladium species e.g., various paladium catalysts, solvents and reaction conditions can be used for this coupling reactions and will be easily determined by the skilled person.
• the boronate ester is reacted with an aryl, alkenyl, alkynyl or heteroaryl iodide in dimethylformamide at 80° C. in the presence of sodium acetate as base and tetrakis(triphenylphosphine)palladium as catalyst to give the coupled product.
• step 3 the boronate ester is hydrolyzed to the corresponding boronic acid. This can be done by treating it with acid, e.g. an aqueous solution of hydrochloric acid, in an organic solvent, e.g. methanol. The resulting boronic acid is coupled,
• step 4 under air with a phenol or heteroaryl alcohol, or,
• step 5 with a primary or secondary amine, heteroarylamine, aniline, amide, sulfonamide, urea, carbamate or imide,
• step 1 urea, carbamate or thio carbamate is initially converted into a halo-imine via a chlorinating agent such as POCl 3 which is then further reacted (step 2) with a suitable amine to form the final compound.
• the reaction can be carried out without solvent or in a solvent, for example an alcohol such as ethanol, at a temperature between 40 and 80° C. or under pressure for volatile amine, for example.
• step 3 the halo-imine is transformed into thio-derivative with thiourea.
• the process of scheme 9 above can also be applied to compounds of formula (I) in which Y is NH and X is N—R 9 .
• X 1 , X 2 , X 3 , X 4 , R 9 , R 12 and A are as defined in the summary of the invention and LG is a leaving group such as trifuoromethane sulfonate, mesylate or halogen.
• step 1 the quinazolinone is reacted with R 12 -LG to obtain the N-substituted quinazoline
• step 2 the N-substituted quinazolinone is reacted with R 9 -LG.
• Step 2 of the above process can also be applied to compounds of formula (I) in which Y is O or S.
• Step 1 of the above process can also be applied to compounds of formula (I) in which X is O or S.
• X 1 , X 2 , X 3 , X 4 , R 9 and A are as defined in the summary of the invention and LG is a leaving group such as trifuoromethane sulfonate, mesylate or halogen.
• step 1 the quinazolinone is reacted with paramethoxy-benzyl chloride (PMB).
• PMB paramethoxy-benzyl chloride
• Other protecting group can be used.
• Various solvents, operating conditions, bases, can be used and will be easily determined by the skilled person. For example, and without any limitation, one can use for the reaction cesium carbonate as base in dimethylformamide as solvent.
• step 2 the protected quinazolinone is reacted with R 9 -LG.
• Various solvents, operating conditions, bases can be used and will be easily determined by the skilled person. For example, and without any limitation, one can use for the reaction sodium hydride as base in dimethylformamide as solvent.
• step 3 treatment of the N1-PMB protected quinazolinone with TFA removed the protecting group.
• Other protecting groups and deprotecting conditions can be used.
• X 2 , X 3 , X 4 , and A and Y are as defined in the summary of the invention, R is alkyl or C( ⁇ O)-alkyl and LG is a leaving group.
• step 1 the starting methoxy derivative is demethylated with boron tribromide in a solvent such as dichloromethane.
• a solvent such as dichloromethane.
• the resulting phenol intermediate is treated in step 2 with an electrophile such as an alkyl halide, an acyl halide or the like in the presence of a base such as potassium carbonate, cesium carbonate or sodium hydride in a solvent like dimethylformamide.
• an electrophile such as an alkyl halide, an acyl halide or the like in the presence of a base such as potassium carbonate, cesium carbonate or sodium hydride in a solvent like dimethylformamide.
• Examples 1 to 100 illustrate, without limiting it, the synthesis of particularly active compounds of formula (I) according to the invention.

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