Thiazine and oxazine derivatives as MMP-13 inhibitors

1- A compound of formula (I):

• 31
• wherein:
• X1, X2, and X3, independently of each other, represent a nitrogen atom or a group —CR3 in which R3 represents a group selected from hydrogen, (C1-C6)alkyl, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxy, (C1-C6)alkoxy, and halogen, it being understood that not more than two of the groups X1, X2 and X3 simultaneously represent a nitrogen atom,
• G1 represents an oxygen atom or a group S(O)p in which p represents an integer from 0 to 2 inclusive,
• G2 represents a group selected from carbon-carbon triple bond, C═O, C═S, S(O)q in which q represents an integer from 0 to 2 inclusive, or a group of formula (i/a):
• 32
• in which the carbon atom with the number 1 is attached to the bicycle of the compound of formula (I), Y1 represents a group selected from oxygen, sulphur, —NH and —N(C1-C6)alkyl, and Y2 represents a group selected from oxygen, sulphur, —NH and —N(C1-C6)alkyl,
• n represents an integer from 0 to 6 inclusive,
• Z1 represents —CR4R5, wherein R4 and R5, identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, trihalogeno(C1-C6)alkyl, halogen, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino in which each alkyl moiety is identical or different, —OR6, —SR6, and —C(═O)OR6, in which R6 is hydrogen atom or (C1-C6)alkyl, and
• wherein when n is greater than or equal to 2, the hydrocarbon chain Z1 optionally contains one to two isolated or conjugated multiple bonds,
• and/or wherein when n is greater than or equal to 2 one of said —CR4R5 may be replaced with a group selected from oxygen, S(O)r in which r represents an integer from 0 to 2 inclusive, —NH and —N(C1-C6)alkyl,
• A represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being a 5- or 6-membered monocycle, or bicycle itself composed of two 5- or 6-membered monocycles,
• R1 represents a group selected from:
• hydrogen,
• (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, these groups may be optionally substituted with one or more groups, which may be identical or different independently of each other, selected from amino, cyano, trihalogeno(C1-C6)alkyl, cycloalkyl, —C(═O)NR7R8, —C(═O)OR7, OR7, and SR7, in which R7 and R8, which may be identical or different independently of each other, represent hydrogen or (C1-C6)alkyl,
• and the group of formula (i/b):
• 33
• in which s is an integer from 0 to 8 inclusive,
• Z2 represents —CR9R10 wherein R9 and R10, identical or different independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, phenyl, trihalogeno(C1-C6)alkyl, halogen, amino, OR6, SR6 and —C(═O)OR6 in which R6 is as defined hereinbefore, and
• wherein when s is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or two isolated or conjugated multiple bonds,
• and/or wherein when p is greater or equal to 2, one of said —CR9R10 may be replaced with a group selected from oxygen, S(O)u in which u is an integer from 0 to 2 inclusive, —NH, —N(C1-C6)alkyl, and carbonyl,
• B represents a group selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, these groups being a 5- or 6-membered monocycle, or bicycle itself composed of two 5- or 6-membered monocycles,
• t is an integer from 0 to 7 inclusive,
• the group(s) G3, which may be identical or different independently of each other, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, CF3, OCF3, —(CH2)kNR11R12, —N(R11)C(═O)R12, —N(R11)C(═O)OR12, —N(R11)SO2R12, —N(SO2R11)2, —OR11, —S(O)k1R11, —SO2—N(R11)—(CH2)k2—NR12R13, —(CH2)kSO2NR11R12, —X4(CH2)kC(═O)OR11, —(CH2)kC(═O)OR11, —C(═O)O—(CH2)k2—NR11R12, —C(═O)O—(CH2)k2—C(═O)OR14, —X4(CH2)kC(═O)NR11R12, —(CH2)kC(═O)NR11R12, —R15—C(═O)OR11, —X5—R16, and —C(═O)—R17—NR11R12 in which:
• X4 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by a hydrogen or a (C1-C6)alkyl group,
• k is an integer from 0 to 3 inclusive,
• k1 is an integer from 0 to 2 inclusive,
• k2 is an integer from 1 to 4 inclusive,
• R11, R12 and R13, which may be identical or different independently of each other, are selected from hydrogen and (C1-C6)alkyl,
• R14 represents a group selected from (C1-C6)alkyl, —R17—NR11R12, —R17—NR11—C(═O)—R17—NR12R13, and —C(═O)O—R17—NR11R12 in which R17 represents a linear or branched (C1-C6)alkylene group, and R11, R12 and R13 are as defined hereinbefore,
• R15 represents a (C3-C6)cycloalkyl group,
• X5 represents a group selected from a single bond, —CH2—, oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C1-C6)alkyl,
• R16 represents a group selected from:
• a 5- or 6-membered monocyclic aryl or heteroaryl, which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C1-C6)alkyl, halogen, hydroxy, cyano, tetrazolyl, amino, and —C(═O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl,
• and a 5- or 6-membered monocyclic cycloalkyl or heterocycloalkyl, which is optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C1-C6)alkyl, halogen, hydroxy, oxo, cyano, tetrazolyl, amino, and -C(═O)OR7 wherein R7 represents hydrogen or (C1-C6)alkyl,
• m is an integer from 0 to 7 inclusive,
• the group(s) R2, which may be identical or different independently of each other, is (are) selected from (C1-C6)alkyl, halogen, —CN, —NO2, —SCF3, —CF3, —OCF3, —NR7R8, —OR7, —SR7, —SOR7, —SO2R7, —(CH2)kSO2NR7R8, —X7(CH2)kC(═O)OR7, —(CH2)kC(═O)OR7, —X7(CH2)kC(═O)NR7R8, —(CH2)kC(═O)NR7R8, and —X8—R18 in which:
• X7 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C1-C6)alkyl,
• k is an integer from 0to 3 inclusive,
• R7 and R8, which may be identical or different independently of each other, are selected from hydrogen and (C1-C6)alkyl,
• X8 represents a group selected from single bond, —CH2—, oxygen, sulphur optionally substituted by one or two oxygen, and nitrogen substituted by hydrogen or (C1-C6)alkyl,
• R18 represents a group selected from phenyl, a 5- or 6-membered monocyclic, heteroaryl, and a 5- or, 6-membered monocyclic cycloalkyl, each of these groups being optionally substituted by one or more groups, which may be identical or different independently of each other, selected from (C1-C6)alkyl, halogen, hydroxy and amino,
• or a racemic form, isomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is not 6-(2,4-dioxo-3,4-dihydro-2H-1,3-benzothiazine)-benzoate, 6-phenylthio-2,4-dioxo-3,4-dihydro-2H-1,3-benzothiazine, 6-benzylsulphonyl-2,4-dioxo-3,4-dihydro-2H-1.3-benzothiazine, 6-benzophenone-2,4-dioxo-3,4-dihydro-2H-1,3-benzothiazine or 6-(2,4-dihydroxy)-benzophenone-2,4-dioxo-3,4-dihydro-2H-1,3-benzothiazine.