Kinase inhibitors

A compound of the formula I,

• 41
• the racemic-diastereomeric mixtures, optical isomers, pharmaceutically-acceptable salts, prodrugs or biologically active metabolites thereof, wherein
• the dotted line in the structure of formula (I) represents an optional double bond;
• X is CR1 or NR1;Y is O, CRq or N;
• Q is N, NR2or O;
• R3 for each occurrence is independently hydrogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
• when X is CR1, Y is CRq, Q is O and there is a double bond between X and Y;
• or when X is CR1, Y is N, Q is O and there is a double bond between X and Y;
• or when X is CR1, Y is O, Q is N and there is a double bond between Q and the pyrimidinyl ring, then
• 42
• where Z100 is nitro, optionally substituted amino,
• 43
• or a group optionally substituted with Rb selected from the group consisting of cycloalkyl, naphthyl, tetrahydronaphthyl, benzothienyl, furanyl, thienyl, benzoxazolyl, benzothiazolyl,
• 44
• thiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyrrolyl, oxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolinyl, indazolyl, benzoisothiazolyl, pyrido-oxazolyl, pyrido-thiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl and benzimidazolyl;
• when a is 1 and D1, G1, J1, L1 and M1 are each independently selected from the group consisting of CRa and N, provided that at least two of D1, G1, J1, L1 and M1 are CRa;
• or
• when a is 0, and one of D1, G1, L1 and M1 is NRa, one of D1, G1, L1 and M1 is CRa and the remainder are independently selected from the group consisting of CRa and N;
• when b is 1 and D2, G2, J2, L2 and M2 are each independently selected from the group consisting of CRa and N, provided that at least two of D2, G2, J2, L2 and M2 are CRa;
• or
• when b is 0, and one of D2, G2, L2 and M2 is NRa, one of D2, G2, L2 and M2 is CRa and the remainder are independently selected from the group consisting of CRa and N;
• Ra and Rb each represent one or more substituents and are for each occurrence independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —C(O)OH, —C(O)H, —OH, —C(O)O-alkyl, -Z105-C(O)N(R)2, -Z105-N(R)—C(O)-Z200, -Z105-N(R)—S(O)2-Z200, -Z105-N(R)—C(O)—N(R)-Z200, Rc, CH2ORc, tetrazolyl, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, and an optionally substituted group selected from the group consisting of carboxamido, alkyl, alkoxy, aryl, alkenyl, aryloxy, heteroaryloxy, arylalkyl, alkynyl, amino, aminoalkyl, amido groups, heteroarylthio and arylthio;
• Z105 for each occurrence is independently a covalent bond or (C1-C6);
• Z200 for each occurrence is independently an optionally substituted (C1-C6), optionally substituted phenyl, or optionally substituted —(C1-C6)-phenyl;
• Rc for each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, —CH2—NRdRe, —W—(CH2)t—NRdRe, —W—(CH2)t-Oalkyl, —W—(CH2)t—S-alkyl or —W—(CH2)t—OH;
• Rd and Re for each occurrence are independently H, alkyl, alkanoyl or SO2—alkyl;
• or Rd, Re and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring;
• t for each occurrence is independently an integer from 2 to 6;
• W for each occurrence is independently a direct bond or O, S, S(O), S(O)2, or NRf;
• Rf for each occurrence is independently H or alkyl;
• Z110 is a covalent bond, or an optionally substituted (C1-C6) which is optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO2, COOH, optionally substituted amino and optionally substituted phenyl;
• Z111 is a covalent bond, an optionally substituted (C1-C6) or an optionally substituted —(CH2)n-cycloalkyl-(CH2)n—;
• where the optionally substituted groups are optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO2, COOH, optionally substituted amino and optionally substituted phenyl;
• or R1 is a substituted or unsubstituted carbocyclic or heterocyclic ring fused with ring 2;
• A is a covalent bond, —O—;
• —S—;
• —S(O)p—;
• —N(R)—;
• —N(C(O)OR)—;
• —N(C(O)R)—;
• —N(SO2R)—;
• —CH2O—;
• —CH2S—;
• —CH2N(R)—;
• —CH(NR)—;
• —CH2N(C(O)R))—;
• —CH2N(C(O)OR)—;
• —CH2N(SO2R)—;
• —CH(NHR)—;
• —CH(NHC(O)R)—;
• —CH(NHSO2R)—;
• —CH(NHC(O)OR)—;
• —CH(OC(O)R)—;
• —CH(OC(O)NHR);
• —CH═CH—;
• —C(═NOR)—;
• —C(O)—;
• —CH(OR)—;
• —C(O)N(R)—;
• —N(R)C(O)—;
• —N(R)S(O)p—;
• —OC(O)N(R)—;
• ;
• —N(R)—C(O)—(CH2)n—N(R)—, —N(R)C(O)O—;
• —N(R)—(CH2)n+1—C(O)—, —S(O)pN(R)—;
• —O—(CR2)n+1—C(O)—, —O—(CR2)n+1—O—, —N(C(O)R)S(O)p—;
• —N(R)S(O)pN(R)—;
• —N(R)—C(O)—(CH2)n—O—, —C(O)N(R)C(O)—;
• —S(O)pN(R)C(O)—;
• —OS(O)pN(R)—;
• —N(R)S(O)pO—;
• —N(R)S(O)pC(O)—;
• —SOpN(C(O)R)—;
• —N(R)SOpN(R)—;
• —C(O)O—;
• —N(R)P(ORg)O—;
• —N(R)P(ORg)—;
• —N(R)P(O)(ORg)O—;
• —N(R)P(O)(ORg)—;
• —N(C(O)R)P(ORg)O—;
• —N(C(O)R)P(ORg)—;
• —N(C(O)R)P(O)(ORg)—, or —N(C(O)R)P(ORg)—;
• p is 1 or 2;
• R for each occurrence is independently H, optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted aryl;
• Rg for each occurrence is independently H, or an optionally substituted group selected from the group consisting of alkyl, arylalkyl, cycloalkyl and aryl;
• or R, Rg, the nitrogen atom and the phosphorus atom, together form a five- or six-membered heterocyclic ring when R and Rg are in a phosphorus containing group;
• or
• A is NRSO2 and R, Ra and the nitrogen atom together form an optionally substituted five or-six-membered heterocyclic ring fused to ring 1;
• n for each occurrence is independently an integer from 0 to 6;
• Rq is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaralkyl, optionally substituted (heterocycloalkyl)alkyl, and halo;
• wherein the arylalkyl, the cycloalkyl, the cycloalkylalkyl, the heteroaralkyl, and the (heterocycloalkyl)alkyl are each optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkyl, hydroxy, hydroxyalkyl and nitro;
• or
• when X is NR1 and R3 are each H, then Y is N, Q is CR2, there is a double bond between Y and Q, and
• R1 is
• 45
• wherein Ra is H or —OMe;
• A is —NH—CO—, —NH—SO2—, —NH—C(O)O—or —NH—C(O)—NH—;
• B is N-methyl-indol-2-yl, (fluoro)(trifluoromethyl)phenyl, phenyl or benzyl;
• R2 is H, 4-piperidinyl,
• 46
• N-ethylpiperidin-4-yl or
• 47
• when X is CR1 and one of R3 is not H, then Y is N, Q is NR2, there is a double bond between X and Y, and
• 48
• where Z100 is nitro, optionally substituted amino,
• 49
• or a group optionally substituted with Rb selected from the group consisting of cycloalkyl, naphthyl, tetrahydronaphthyl, benzothienyl, furanyl, thienyl, benzoxazolyl, benzothiazolyl,
• 50
• thiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyrrolyl, oxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolinyl, indazolyl, benzoisothiazolyl, pyrido-oxazolyl, pyrido-thiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl and benzimidazolyl;
• when a is 1 and D1, G1, J1, L1 and M1 are each independently selected from the group consisting of CRa and N, provided that at least two of D1, G1, J1, L1and M1 are CRa;
• or
• when a is 0, and one of D1, G1, L1 and M1 is NRa, one of D1, G1, L1 and M1 is CRa and the remainder are independently selected from the group consisting of CRa and N;
• when b is 1 and D2, G2, J2, L2 and M2 are each independently selected from the group consisting of CRa and N, provided that at least two of D2, G2, J2, L2 and M2 are CRa;
• or
• when b is 0, and one of D2, G2, L2 and M2 is NRa, one of D2, G2, L2 and M2 is CRa and the remainder are independently selected from the group consisting of CRa and N;
• Ra and Rb each represent one or more substituents and are for each occurrence independently selected from the group consisting of hydrogen, halogen, —CN, —NO2, —C(O)OH, —C(O)H, —OH, —C(O)O-alkyl, -Z105-C(O)N(R)2, -Z105-N(R)—C(O)—Z200, -Z105-N(R)—S(O)2Z200, -Z105 -N(R)—C(O)—N(R)-Z200, Rc, CH2ORc, tetrazolyl, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, and an optionally substituted group selected from the group consisting of carboxamido, alkyl, alkoxy, aryl, alkenyl, aryloxy, heteroaryloxy, arylalkyl, alkynyl, amino, aminoalkyl, amido groups, heteroarylthio and arylthio;
• Z105 for each occurrence is independently a covalent bond or (C1-C6);
• Z200 for each occurrence is independently an optionally substituted (C1-C6), optionally substituted phenyl, or optionally substituted —(C1-C6)-phenyl;
• Rc for each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, —CH2—NRdRe, —W—(CH2)t—NRdRe, —W—(CH2)t-Oalkyl, —W—(CH2)t—S-alkyl or —W—(CH2)t—OH;
• Rd and Re for each occurrence are independently H, alkyl, alkanoyl or SO2-alkyl;
• or Rd, Re and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring;
• t for each occurrence is independently an integer from 2 to 6;
• W for each occurrence is independently a direct bond or O, S, S(O), S(O)2, or NRf;
• Rf for each occurrence is independently H or alkyl;
• Z110 is a covalent bond, or an optionally substituted (C1-C6) which is optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO2, COOH, optionally substituted amino and optionally substituted phenyl;
• Z111 is a covalent bond, an optionally substituted (C1-C6) or an optionally substituted —(CH2)n-cycloalkyl-(CH2)n—;
• where the optionally substituted groups are optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO2, COOH, optionally substituted amino and optionally substituted phenyl;
• or R1 is a substituted or unsubstituted carbocyclic or heterocyclic ring fused with ring 2;
• A is a covalent bond, —O—;
• —S—;
• —S(O)p—;
• —N(R)—;
• —N(C(O)OR)—;
• —N(C(O)R)—;
• —N(SO2R)—, —CH2O—;
• —CH2S—;
• —CH2N(R)—;
• —CH2N(C(O)R))—;
• —CH2N(CO)OR)—;
• —CH2N(SO2R)—;
• —CH(NHR)—;
• —CH(NHC(O)R)—;
• —CH(NHSO2R)—;
• —CH(NHC(O)OR)—;
• —CH(OC(O)R)—;
• —CH(OC(O)NHR);
• —CH═CH—;
• —C(═NOR)—;
• —C(O)—;
• —CH(OR)—;
• —C(O)N(R)—;
• —N(R)C(O)—;
• —N(R)S(O)p—;
• —OC(O)N(R)—;
• ;—N(R)—C(O)—(CH2)n—N(R)—, —N(R)C(O)O—;
• —N(R)—(CH2)n+1—C(O)—, —S(O)pN(R)—;
• —O—(CR2)n+1—C(O)—, —O—(CR2)n+1—O—, —N(C(O)R)S(O)p—;
• —N(R)S(O)pN(R)—;
• —N(R)—C(O)—(CH2)n—O—, —C(O)N(R)C(O)—;
• —S(O)pN(R)C(O)—;
• —OS(O)pN(R)—;
• —N(R)S(O)pO—;
• —N(R)S(O)pC(O)—;
• —SOpN(C(O)R)—;
• —N(R)SOpN(R)—;
• —C(O)O—;
• —N(R)P(ORg)O—;
• —N(R)P(ORg)—;
• —N(R)P(O)(ORg)O—;
• —N(R)P(O)(ORg)—;
• —N(C(O)R)P(ORg)O—;
• —N(C(O)R)P(ORg)—;
• —N(C(O)R)P(O)(ORg)O—, or —N(C(O)R)P(ORg)—;
• p is 1 or 2;
• R for each occurrence is independently H, optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted aryl;
• Rg for each occurrence is independently H, or an optionally substituted group selected from the group consisting of alkyl, arylalkyl, cycloalkyl and aryl;
• or R, Rg, the nitrogen atom and the phosphorus atom, together form a five- or six-membered heterocyclic ring when R and Rg are in a phosphorus containing group;
• or
• A is NRSO2 and R, Ra and the nitrogen atom together form an optionally substituted five or-six-membered heterocyclic ring fused to ring 1;
• R2 is -Z101-Z102;
• Z101 is a covalent bond, —(C1-C6)—, —(C1-C6)—O—, —(C1-C6)—C(O)—, —(C1-C6)—C(O)O—, —(C1-C6)—C(O)—NH—, —(C1-C6)—C(O)—N((C1-C6))—or an optionally substituted phenyl group;
• Z102 is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted saturated or unsaturated heterocyclic group, or an optionally substituted saturated or unsaturated heterobicyclic group;
• said substituted heterocyclic or substituted heterobicyclic group having one or more substituents each independently selected from the group consisting of hydroxyl, cyano, optionally substituted alkoxy, optionally substituted sulfonamido, optionally substituted ureido, optionally substituted carboxamido;
• optionally substituted amino, oxo, a saturated or unsaturated or aromatic optionally substituted heterocyclic group;
• wherein the heterocyclic group comprises one or more nitrogen atoms, one or more oxygen atoms or a combination thereof and where said nitrogen atoms are independently optionally substituted by a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl;
• or
• R2 is of the formula B-E;
• B is hydroxy or an optionally substituted group selected from the group consisting of cycloalkyl, azacycloalkyl, amino, aminoalkylsulfonyl, alkoxyalkyl, alkoxy, aminoalklylcarbonyl, alkylenyl, aminoalkyl, alkylenylcarbonyl and aminoalkylcarbonyl;
• E is an optionally substituted group selected from the group consisting of azacycloalkyl, azacycloalkylcarbonyl, azacycloalkylsulfonyl, azacycloalkylalkyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkyl, azacycloalkylcarbonylamino, heteroarylcarbonylamino and aryl;
• and
• n for each occurrence is independently an integer from 0 to 6.