Inhibitors of vegf receptor and hgf receptor signaling

A method of treating a cell proliferative disease in a patient, the method comprising administering to the patient in need of such treatment an effective therapeutical amount of a compound of formula A or a composition thereof

• or a pharmaceutically acceptable salt, or hydrate thereof, wherein,
• D is selected from the group consisting of R7 and R21, wherein
• R7 is selected from the group consisting of —NR42R43, heteroaryl and 5-10 membered heterocyclyl, and the aforementioned R7 groups are optionally substituted by 1 to 5 R38, or R7 is -heterocycle, optionally substituted with 1 to 3 independently selected Y2 groups, wherein
• each Z3 is selected from the group consisting of H, F and (C1-C6)alkyl, or
• two Z3 groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
• each Y2 is selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, azido, —C(O)Z7, —OC(O)NH2, —OC(O)NHZ7, —OC(O)NZ7Z8, —NHC(O)Z7, —NHC(O)NH2, —NHC(O)NHZ7, —NHC(O)NZ7Z8, —C(O)OH, —C(O)OZ7, —C(O)NH2, —C(O)NHZ7, —C(O)NZ7Z8, —P(O)3H2, —P(O)3(Z7)2, —S(O)3H, —S(O)Z7, —S(O)2Z7, —S(O)3Z7, —Z7, —OZ7, —OH, —NHZ7, —NZ7Z8, —C(═NH)NH2, —C(═NOH)NH2, —N-morpholino, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C6)haloalkynyl, (C1-C6)haloalkoxy, —(CZ9Z10)rNH2, —(CZ9Z10)rNHZ3, —(CZ9Z10)rNZ7Z8, —X6(CZ9Z10)r—(C3-C8)cycloalkyl, —X6(CZ9Z10)r—(C5-C8)cycloalkenyl, —X6(CZ9Z10)r-aryl and —X6(CZ9Z10)r-heterocycle, wherein
• r is 1, 2, 3 or 4;
• X6 is selected from the group consisting of O, S, NH, —C(O)—, —C(O)NH—, —C(O)O—, —S(O)—, —S(O)2— and —S(O)3—;
• Z7 and Z8 are independently selected from the group consisting of an alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an alkynyl of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or
• Z7 and Z8 together may optionally form a heterocycle;
• Z9 and Z10 are independently selected from the group consisting of H, F, a (C1-C12)alkyl, a (C6-C14)aryl, a (C5-C14)heteroaryl, a (C7-C15)aralkyl and a (C5-C14)heteroaralkyl, or
• Z9 and Z10 are taken together form a carbocycle, or
• two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle;
• or
• any two Y2 groups attached to adjacent carbon atoms may be taken together to be —O[C(Z9)(Z10)]rO or —O[C(Z9)(Z10)]r+1, or
• any two Y2 groups attached to the same or adjacent carbon atoms may be selected together to form a carbocycle or heterocycle;
• and wherein
• any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halogen, (C1-C4)alkyl, (C1-C4)alkoxy and an —N [(C1-C4)alkyl][(C1-C4)alkyl];
• R21 is the group defined by —(Z11)—(Z12)m—(Z13)m1, wherein
• Z11 is heterocyclyl, when m and m1 are 0, or heterocyclylene, when either in or ml are 1;
• Z12 is selected from the group consisting of OC(O), OC(S) and C(O);
• Z13 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (C1-C3)alkyl, —OR52, halo, S(O)2R56, (C1-C3)hydroxyalkyl and (C1-C3)haloalkyl;
• m is 0 or 1;
• m1 is 0 or 1;
• R52 is selected from the group consisting of H, —(CH2)qS(O)2R54, —(C1-C6) alkyl-NR53R53 (C1-C3)alkyl, —(CH2)qOR53, —C(O)R54 and —C(O)OR53;
• each R53 is independently (C1-C3)alkyl;
• R54 is (C1-C3)alkyl or N(H)R53;
• R56 is selected from the group consisting of NH2, (C1-C3)alkyl and OR52;
• A1 is —S—;
• A2 is CR, wherein R is —H;
• A3 is CH;
• Ar is a group of the formula C,
• wherein,
• A4, A5, A6 and A7 are —CH—;
• R2 at each occurrence is independently selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —S(O)2NR3R3, —C(O)OR3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, alkoxy, C1-C4 alkylthio, —O(CH2)naryl, —O(CH2)nheteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, wherein T2 is selected from the group consisting of —OH, —OMe, —OEt, —NH2, —NHMe, —NMe2, —NHEt and —NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• and
• q is an integer from 0 to 4;
• G is selected from the group consisting of
• wherein any methylene group is independently optionally substituted with R25, wherein
• R25 is selected from the group consisting of halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —SO2NR3R3, —CO2R3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, and an optionally substituted (C1-C6)alkyl,
• two R25, together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic, and
• R9 is selected from the group consisting of a C1-6 alkyl on which one or more hydrogen atoms are optionally substituted by —R24, -T1-R15, or —NR16R17, a —N(R18)(R19) moiety and a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by a C1-6 alkyl, a C1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C1-6 alkoxy carbonyl, cyano, a cyano C1-6 alkyl, a C1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring wherein, when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group,
• wherein
• T1 is selected from the group consisting of —O—, —S— and —NH—;
• R21 represents a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;
• R15, R16, and R17, which may be the same or different, represent a C1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;
• wherein the three- to eight-membered carbocyclic or heterocyclic group represented by R21, R15, R16, and R17 is optionally substituted by a C1-6 alkyl, a C1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C1-6 alkoxy carbonyl, a cyano, a cyano C1-6 alkyl, a C1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring;
• and wherein when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain;
• and wherein the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;
• and
• R18 and R19, which may be the same or different, represent (1) a hydrogen atom, (2) a C1-6 alkyl which is optionally substituted by a C1-6 alkoxy, a C1-6 alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group in which the three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by a C1-6 alkyl, a C1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C1-6 alkoxy carbonyl, cyano, a cyano C1-6 alkyl, a C1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring and wherein when the three- to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, or (3) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group which is optionally substituted by a C1-6 alkyl, a C1-6 alkoxy, a halogen atom, nitro, a trifluoromethyl, a C1-6 alkoxy carbonyl, cyano, a cyano C1-6 alkyl, a C1-6 alkylthio, a phenoxy, an acetyl, or a saturated or unsaturated five- or six-membered heterocyclyl ring and in which, when the three to eight-membered carbocyclic or heterocyclic group is substituted by two C1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or the three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group;
• X and X1 are each independently selected from the group consisting of —H, halogen, cyano, nitro, C1-C6 alkyl, or
• X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
• M1 represents —C(R26)(R27)—, wherein
• R26 and R27 are independently selected from the group consisting of a hydrogen atom, a C1-4 alkyl, a C1-4 alkoxy and —N(R12), wherein
• R12 is a hydrogen atom or a C1-4 alkyl;
• R13 is selected from the group consisting of —H, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —S(O)2NR3R3, —C(O)OR3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, —C(O)SR3, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)naryl, —O(CH2)nheteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of —OH, —OMe, —OEt, —NH2, —NHMe, —NMe2, —NHEt and —NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• two R13, together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R60, wherein the heteroalicyclic can have up to four annular heteroatoms, and the heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case the aryl or heteroaryl is optionally substituted with an additional one to four of R60;
• each R3 is independently selected from the group consisting of —H and R4;
• R4 is selected from the group consisting of a (C1-C6)alkyl, an aryl, a lower arylalkyl, a heterocyclyl and a lower heterocyclylalkyl, each of which is optionally substituted, or
• R3 and R4, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;
• R60 is selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —NR3R4, —S(O)0-2R3, —SO2NR3R3, —CO2R3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)CO2R3, —C(O)R3, an optionally substituted (C1-C6)alkyl, an optionally substituted aryl, an optionally substituted heteroarylalkyl and an optionally substituted arylalkyl;
• two R60, when attached to a non-aromatic carbon, can be oxo;
• Q is selected from the group consisting of phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothienyl, and oxadiazolyl, each optionally substituted with between one and four of R20;
• R20 is selected from the group consisting of —H, halogen, trihalomethyl, —CN, —NO2, —NH2, —OR3, —OCF3, —NR3R4, —S(O)0-2R3, —S(O)2NR3R3, —C(O)OR3, —C(O)NR3R3, —N(R3)SO2R3, —N(R3)C(O)R3, —N(R3)C(O)OR3, —C(O)R3, —C(O)SR3, C1-C4 alkoxy, alkylthio, —O(CH2)naryl, —O(CH2)nheteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl, C1-4 alkoxy, an amino optionally substituted by C1-4 alkyl optionally substituted by C1-4 alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of —OH, —OMe, —OEt, —NH2, —NHMe, —NMe2, —NHEt and —NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• each R38 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, —C(O)R40, —C(O)OR40, —OC(O)R40, —OC(O)OR40, —NR36C(O)R39, —C(O)NR36R39, —NR36R39, —OR37, —SO2NR36R39, C1-C6 alkyl, —(CH2)jO(CH2)iNR36R39, —(CH2)nO(CH2)iOR37, —(CH2)nOR37, —S(O)j(C1-C6 alkyl), —(CH2)nC6-C10 aryl), —(CH2)n(5-10 membered heterocyclyl);
• —C(O)(CH2)n(C6-C10 aryl), —(CH2)nO(CH2)j(C6-C10 aryl), —(CH2)nO(CH2)i(5-10 membered heterocyclyl), —C(O)(CH2)n(5-10 membered heterocyclyl), —(CH2)jNR39(CH2)iNR36R39, —(CH2)jNR39CH2C(O)NR36R39, —(CH2)jNR39(CH2)iNR37C(O)R40, —(CH2)jNR39(CH2)nO(CH2)iOR37, —(CH2)jNR39(CH2)iS(O)j(C1-C6 alkyl), —(CH2)jNR39(CH2)nR36, —SO2(CH2)nC6-C1, aryl), —SO2(CH2)n(5-10 membered heterocyclyl), —(CH2)nNR36R39, —NR37SO2NR36R39, SO2R36, C2-C6 alkenyl, C3-C10 cycloalkyl and C1-C6 alkylamino, wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclyl moieties of the foregoing R38 groups are optionally substituted by one or more substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R40, —C(O)OR40, —OC(O)R40, —OC(O)OR40, —NR36C(O)R39, —C(O)NR36R39, —(CH2)nNR36R39, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n(C6-C10 aryl), —(CH2)n(5-10 membered heterocyclyl), —(CH2)nO(CH2)iOR37, and —(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
• each R36 and R39 is independently selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)nC6-C10 aryl), —(CH2)n(5-10 membered heterocyclyl), —(CH2)nO(CH2)iOR37, —(CH2)nCN(CH2)nOR37, —(CH2)nCN(CH2)nR37, and —(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclyl moieties of the foregoing R36 and R39 groups are optionally substituted by one or more substituents independently selected from —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R40, —C(O)OR40, —CO(O)R40, —OC(O)OR40, —NR37C(O)R41, —C(O)NR37R41, —NR37R41, —C1-C6 alkyl, —(CH2)n(C6-C10 aryl), —(CH2)n(5 to 10 membered heterocyclyl), —(CH2)nO(CH2)iOR37, and —(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen;
• each R40 is independently selected from H, C1-C10 alkyl, —(CH2)n(C6-C10 aryl), C3-C10 cycloalkyl, and —(CH2)n(5-10 membered heterocyclyl), wherein n is an integer ranging from 0 to 6;
• each R37 and R41 is independently selected from H, OR36, C1-C6 alkyl and C3-C10 cycloalkyl;
• R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C5-C9 azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring are optionally substituted by 1 to 5 R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen;
• each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, —C(O)R40, —C(O)OR40, —OC(O)R40, —OC(O)OR40, —NR36C(O)R39, —C(O)NR36R39, —NR36R39, —OR37, —SO2NR36R39, —SO2R36, —NR36SO2R39, —NR36SO2NR37R41, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, —C1-C6 alkylamino, —(CH2)jO(CH2)iNR36R39, —(CH2)nO(CH2)iOR37, —(CH2)nOR37, —S(O)j(C1-C6 alkyl), —(CH2)n(C6-C10 aryl), —(CH2)n(5-10 membered heterocyclyl), —C(O)(CH2)nC6-C10 aryl), —(CH2)nO(CH2)j(C6-C10 aryl), —(CH2)nO(CH2)i(5 to 10 membered heterocyclyl), —C(O)(CH2)n(5 to 10 membered heterocyclyl), —(CH2)jNR39(CH2)iNR36R39, —(CH2)jNR39CH2C(O)NR36R39, —(CH2)jNR39(CH2)iNR37C(O)R40, —(CH2)jNR39(CH2)nO(CH2)iOR37, —(CH2)jNR39(CH2)iS(O)j(C1-C6 alkyl), —(CH2)jNR39(CH2)nR36, —SO2(CH2)n(C6-C10 aryl), and —SO2(CH2)n(5 to 10 membered heterocyclyl) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclyl moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R40, —C(O)OR40, —OC(O)R40, —OC(O)OR40, —NR36C(O)R39, —C(O)NR36R39, —(CH2)nNR36R39, —SO2R36, —SO2NR36R39, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n(C6-C10 aryl), —(CH2)n(5 to 10 membered heterocyclyl), —(CH2)nO(CH2)nOR37 and —(CH2)nOR37, wherein n is an integer from 0 to 6 and i is an integer from 2 to 6;
• and
• Z is selected from the group consisting of —O— and —S(O)0-2.