Inhibitors of protein tyrosine kinase activity

A compound of Formula (I):

• and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein,
• D is selected from the group consisting of an aromatic, heteroaromatic, cycloalkyl or heterocyclic ring system, each of which is optionally substituted with 1 to 5 independently selected R38;
• M is an optionally substituted fused heterocyclic moiety;
• Z is selected from the group consisting of covalent bond, —O—, —O—CH2—, —CH2—O—, —S(O)0-2—, —CH2—, —N(R5)—, —N(R5)—CH2— and —CH2—N(R5)—;
• Ar is a 5 to 7 membered cycloalkyl, aromatic, heterocyclic or heteroaromatic ring system, any of which is optionally substituted with 0 to 4 R2 groups;
• and
• G is a group B-L-T, wherein
• B is selected from the group consisting of absent, —N(R13)—, —N(SO2R13)—, —O—, —S(O)0-2 and —C(═O)—;
• L is selected from the group consisting of absent, —C(═S)N(R13)—, —C(═NR14)N(R13)—, —SO2N(R13)—, —SO2—, —C(═O)N(R13)—, —N(R13)—, —C(═O)C1-2alkyl-N(R13)—, —N(R13)C1-2alkyl-C(═O)—, —C(═O)C0-1alkyl-C(═O)N(R13)—, —C0-4alkylene, —C(═O)C0-1alkyl-C(═O)OR3—, —C(═NR14)—C0-1alkyl-C(═O)—, —C(═O)—, —C(═O)C0-1alkyl-C(═O)— and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen, wherein an alkyl group of the aforementioned L group is optionally substituted;
• and
• T is selected from the group consisting of —H, —R13, —C0-5alkyl, —C0-5alkyl-Q, —O—C0-5alkyl-Q, —C0-5alkyl-O-Q, —N(R13)—C0-5alkyl-Q, —C0-5alkyl-SO2—C0-5alkyl-Q, —C(═O)—C0-5alkyl-Q, —C(═S)—C0-5-alkyl-Q, —C(═NR14)—C0-5-alkyl-Q, —C0-5alkyl-N(R13)-Q, —C(═O)—N(R13)—C0-5alkyl-Q, —C(═S)—N(R13)—C0-5alkyl-Q, —C(═NR14)—N(R13)—C0-5alkyl-Q, —(C0-5alkyl-C(O))0-1—C0-5alkyl-Q wherein each C0-5alkyl is optionally substituted;
• or G is a group
• or G is selected from the group consisting of:
• wherein
• each R38 is independently selected from the group consisting of halo, optionally substituted C1-C6 alkyl, —C(O)NR36R39, —C(O)O—(CH2)nNR36R39, —(CH2)jNR39(CH2)iS(O)j(C1-C6 alkyl), —(CH2)jNR39(CH2)nR36, —C(O)(CH2)jNR39(CH2)nR36, —(CH2)nP(═O)(C1-C6alkyl)2, —(CH2)jNR39CH2(CH2)nP(═O)(C1-C6alkyl)2, —NR13C(X1)NR13-arylP(═O)(C1-C6alkyl)2 and —NR13C(X1)NR13-heteroarylP(═O)(C1-C6alkyl)2, —(CH2)jNR39(CH2)i[O(CH2)i]x(CH2)jR99, —(CH2)jNR39(CH2)iSO(0-2)(CH2)i[O(CH2)i]j(CH2)jR99, —(CH2)jNR39(CH2)jR100
• wherein each j is an integer independently ranging from 0 to 4, n is an integer ranging from 0 to 6, x is an integer ranging from 1-6, each i is an integer independently ranging from 1 to 3, and the —(CH2)i— and —(CH2)n— moieties of the foregoing R38 groups are optionally substituted, and optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6;
• R36 is selected from the group consisting of H, —OH, C1-C6 alkyl, C3-C10 cycloalkyl, —(CH2)n(C6-C10 aryl), —(CH2)n(5-10 membered heterocyclyl) and —(CH2)nA4R37, wherein each n is an integer independently ranging from 0 to 6, A4 is selected from the group consisting of O, S, SO, SO2, and the alkyl, cycloalkyl, aryl and heterocyclyl moieties of the foregoing R36 groups are optionally substituted, 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 R37 and R41 is independently selected from H, —O—C1-C6 alkyl, —O—C3-C10 cycloalkyl, —O—(CH2)n(C6-C10 aryl), —O—(CH2)n(5-10 membered heterocyclyl), optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted —O—(CH2)nA4-C1-C6 alkyl, optionally substituted —O—(CH2)nA4-C2-C6 alkenyl, optionally substituted —O—(CH2)nA4-C2-C6 alkynyl and optionally substituted —O—(CH2)nA4-C3-C10cyclaoalkyl;
• R39 is selected from the group consisting of H, —OH, C1-C6 alkyl, —C(O)—C1-C6alkyl, —SO2—C1-C6alkyl, —C(O)—O—C1-C6alkyl-aryl and a protecting group used to protect secondary amino groups, 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;
• R99 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, P(═O)(OH)2, —P(═O)(C1-C6alkyl)2, —SO3H—C(O)R3, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)0-6aryl, —O(CH2)0-6heteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), -, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• R100 is a 12 to 24-membered optionally substituted heteroalicyclic macrocycle containing 4 to 8 oxygen atoms;
• R5 is selected from the group consisting of H, an optionally substituted (C1-C5)acyl and C1-C6 alkyl-O—C(O), wherein C1-C6 alkyl is optionally substituted;
• 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, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)0-6aryl, —O(CH2)0-6heteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —CH2(CH2)0-4-T2, wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• T2 is selected from the group consisting of —OH, —OMe, —OEt, —NH2, —NHMe, —NMe2, —NHEt and —NEt2;
• 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;
• each R13 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, —C(O)SR3, C1-C4 alkoxy, C1-C4 alkylthio, —O(CH2)0-6aryl, —O(CH2)0-6heteroaryl, —(CH2)0-5(aryl), —(CH2)0-5(heteroaryl), —(CH2)0-5(cycloalkyl), 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 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;
• R14 is selected from the group —H, —NO2, —NH2, —N(R3)R4, —CN, —OR3, an optionally substituted (C1-C6)alkyl, an optionally substituted heteroalicyclylalkyl, an optionally substituted aryl, an optionally substituted arylalkyl and an optionally substituted heteroalicyclic,
• 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;
• or
• two R60, when attached to a non-aromatic carbon, can be oxo;
• Q is C1-C6alkyl or a three- to ten-membered ring system, optionally substituted with between zero and four of R20;
• each R20 is independently selected from the group consisting of —H, halogen, trihalomethyl, —O-trihalomethyl, oxo, —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, C1-C4 alkylthio, —O(CH2)0-6aryl, —O(CH2)0-6heteroaryl, —(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 and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• L1 is selected from the group consisting of O, S and N(R14);
• L2 is selected from the group consisting of —C(O)—, —C(S)—, —C(NH)—, >C═N(C1-C6 alkyl) and —CH2—;
• L3 is selected from the group consisting of —CH—, —C(C1-C6 alkyl)- and N;
• L4 is selected from the group consisting of —CH— and N;
• n1 is an integer from 0 to 5;
• each X is independently selected from the group consisting of O, S, NH, N-alkyl, N—OH, N—O— alkyl and NCN;
• R11 and R12 are independently selected from the group consisting of H, C1-C6alkyl, halo, cyano and nitro, wherein the alkyl is optionally substituted;
• or
• R11 and R12, taken together with the atom to which they are attached, form a C3-C7cycloalkyl;
• E is selected from the group consisting of O, S, —CH2—, —CH(C1-C6alkyl), —N(H)—, —N(C1-C6alkyl)-, —CH2N(H)— and —N(H)CH2—;
• R11a and R12a are independently selected from the group consisting of H, halogen, —OH, unsubstituted —O—(C1-C6alkyl), substituted —O—(C1-C6alkyl), unsubstituted —O-(cycloalkyl), substituted —O-(cycloalkyl), unsubstituted —NH(C1-C6alkyl), substituted —NH(C1-C6alkyl), —NH2, —SH, unsubstituted —S—(C1-C6alkyl), substituted —S—(C1-C6alkyl), unsubstituted C1-C6alkyl and substituted C1-C6alkyl;
• or
• R11a and R12a taken together with the atom to which they are attached form a C3-C7 ring system, wherein said ring system is optionally substituted;
• each R13a is independently selected from the group consisting of H, C1-C6alkyl, substituted C1-C6alkyl, cycloalkyl, substituted cycloalkyl, OH, unsubstituted —O—(C1-C6alkyl), substituted —O—(C1-C6alkyl);
• or
• R12a and R13a taken together with the atoms to which they are attached optionally form a 4 to 8 membered cycloalkyl or heterocyclic ring system, which ring system is optionally substituted;
• R14a, R15a, R16a and R17a are independently selected from the group consisting of —H, halogen, trihalomethyl, —O-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, 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-T 2, 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 n is an integer ranging from 0 to 6, and the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
• or
• R13a and R14a taken together with the atoms to which they are attached optionally form a 4 to 8 membered cycloalkyl or heterocyclic ring system, which ring system is optionally substituted;
• R18a and R19a are independently selected from the group consisting of H, OH, halogen, NO2, unsubstituted —O—(C1-C6alkyl), substituted —O—(C1-C6alkyl), CH3, CH2F, CHF2, CF3, CN, C1-C6alkyl, substituted C1-C6alkyl, partially fluorinated C1-C6alkyl, per-fluorinated C1-C6alkyl, heteroalkyl, substituted heteroalkyl and —SO2(C1-C6alkyl);
• or
• R18a and R19a together with the atom to which they are attached form a 3 to 6 membered cycloalkyl or heterocycle, each of which is optionally substituted with 1 to 4 halo;
• W is selected from the group consisting of H, alkyl, alkenyl, alkynyl, —(CH2)0-5(five- to ten-membered cycloalkyl), —(CH2)0-5(aryl), —(CH2)0-5(heterocylic) and —(CH2)0-5(heteroaryl), each of which is optionally substituted;
• and
• is a single or double bond;
• X1 is selected from the group consisting of O, S, CH2, N—CN, N—O-alkyl, NH and N(C1-C6alkyl) when is a double bond, or
• X1 is selected from the group consisting of H, halogen, trihaloalkyl, alkyl, alkenyl, alkynyl, CN, alkoxy, NH(alkyl) and alkyl-thio, when is a single bond;
• La and L1a are independently selected from the group consisting of —CH—, N, —C(halogen)- and —C(C1-C6alkyl)-;
• L2a and L3a are independently selected from the group consisting of CH, CH2, N, O and S;
• L4a is selected from the group consisting of absent, CH, CH2, N, O and S;
• and
• the group
• is aromatic or non-aromatic, provided that two 0 are not adjacent to each other;
• K and K1 are independently selected from the group consisting of —C(O)—, —C(S)—, —C(NH)—, —C(NCN)— and —C(R18aR19a)—;
• U is selected from the group consisting of O, S, SO2, NH, and N(C1-C6alkyl), wherein the C1-C6alkyl is optionally substituted with a substituent selected from the group consisting of —OH, -alkoxy, amino, NH(C1-C6alkyl), N(C1-C6alkyl)2,
• U1 is a ring system selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• E1 is selected from the group consisting of —N(H)—, —N(C1-C6alkyl)-, —CH2N(H)— and —N(H)CH2—;
• E2 is selected from the group consisting of —N(H)—, —N(C1-C6alkyl)-, —CH2N(H)— and —N(H)CH2—;
• X2 is selected from the group consisting of O, S, NH, NOH, NOMe, NOEt and NCN;
• and
• n2 is 0, 1, 2, 3 or 4.