Heterocyclic compounds useful as inhibitors of tyrosine kinases

A method of making a compound of the formula Ib below:

• 128
• wherein R is H, C1-3 alkyl or cyclopropyl, Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle;
• wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
• R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-0 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-0 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy;
• wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
• R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3 alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
• and R5 is selected from H, C1-10 alkyl branched or unbranched, C3-10 cycloalkyl, C5-7 cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 acyl, each being optionally substituted with one or more halogen, OH, oxo, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 alkoxy, NR8R9, ureido, guanidino, NR8COR10, SR10, CONR8R9, CO2R10, C3-10 cycloalkyl, C3-10 cycloalkylidene, C5-7 cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle;
• wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkylidene, C5-7 cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionally substituted with one or more C1-3 alkyl, C1-3 alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
• wherein one or more of the amino nitrogens in the ureido, amidino or guanidino groups in this paragraph may be optionally substituted with C1-3 alkyl, phenyl CO3 alkyl, C1-3 alkoxy or CO2R10;
• or R5 is selected from CO2R10, NR8R9, CONR8R9, aryl, heteroaryl, heterocycle, aryl-CO—, heteroaryl-CO— or heterocycle-CO—, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three:
• C1-3 alkoxy, halogen, NO2, CN, S(O)pNR8R9, C0-3 alkyl S(O)p, NR8R9, (CH2)nCO2R10, (CH2)nCONR8R9, CO(CH2)nNR8R9, O(CH2)2-4NR8R9, ureido, guanidino, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Z-, aryl-Z-, heteroaryl-Z-, heterocycle-Z-, or C1-3 alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-10 alkylene branched or unbranched, CO, S(O)p, O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3 alkyl, C1-3 alkoxy, halogen, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9, ureido or guanidino, wherein one or more of the amino nitrogens in the ureido or guanidino groups in this paragraph may be optionally substituted with C1-3 alkyl, phenyl CO3 alkyl or C1-3 alkoxy;
• and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
• or R5 is a C6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and S;
• and wherein said ring system may be optionally substituted with C1-3 alkyl, C1-3 alkoxy, halogen, CO2R10, ureido, guanidino, amidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
• wherein one or more of the amino nitrogens in the ureido, guanidino or amidino groups in this paragraph may be optionally substituted with C1-3 alkyl, phenyl CO3 alkyl or C1-3 alkoxy;
• R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3 alkoxy, C1-6 alkyl branched or unbranched, C3-6 alkenyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle;
• wherein said alkyl, cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3 alkoxy, C1-3 acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
• or R8 and R9 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached;
• wherein said alkylene chain is optionally interrupted by O, S(O)p, NCOR10, NCO2R10, NR11 or NC(═NR11)NR11R12;
• and wherein said ring is optionally substituted by C1-3 alkyl, C1-3 alkoxy, OH or —(CH2)nNR11R12;
• R10 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3 alkoxy, C1-3 alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3 alkyl, C1-3 alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
• R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3 alkoxy, OH or phenyl;
• or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
• m is 1-4;
• n is 0-3;
• and p is 0-2;
• said method comprising:
• (a) reacting the compound of formula XIX (wherein R4 is H) with an aldehyde of the formula R5CHO in the presence of an acid in a suitable solvent to form a compound of formula Id:
• 129
• (b) oxidizing the compound of formula Id with a suitable oxidizing agent to form the compound of formula Ib:
• 130

A method of making a compound of the formula Ib below:

• 131
• wherein R is H, C1-3 alkyl or cyclopropyl, Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle;
• wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
• R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy;
• wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
• R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3 alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
• and R5 is selected from H, C1-10 alkyl branched or unbranched, C3-10 cycloalkyl, C5-7 cycloalkenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 acyl, each being optionally substituted with one or more halogen, OH, oxo, CN, C16 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-3 alkoxy, NR8R9, ureido, guanidino, NR8COR10, SR10, CONR8R9, CO2R10, C3-10 cycloalkyl, C3-10 cycloalkylidene, C5-7 cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle;
• wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkylidene, C5-7 cycloalkenyl, aryloxy, arylthio, aryl, heteroaryl or heterocycle is optionally substituted with one or more C1-3 alkyl, C1-3 alkoxy, halogen, CN, NO2, amidino, guanidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
• wherein one or more of the amino nitrogens in the ureido, amidino or guanidino groups in this paragraph may be optionally substituted with C1-3 alkyl, phenyl C0-3 alkyl, C1-3 alkoxy or CO2R10;
• or R5 is selected from CO2R10, NR8R9, CONR8R9, aryl, heteroaryl, heterocycle, aryl-CO—, heteroaryl-CO— or heterocycle-CO—, wherein each aryl, heteroaryl or heterocycle is optionally substituted with one to three:
• C1-3 alkoxy, halogen, NO2, CN, S(O)pNR8R9, C0-3 alkyl S(O)p, NR8R9, (CH2)nCO2R10, (CH2)nCONR8R9, CO(CH2)nNR8R9, O(CH2)2-4NR8R9, ureido, guanidino, cycloalkyl, aryl, heteroaryl, heterocycle, cycloalkyl-Z-, aryl-Z-, heteroaryl-Z-, heterocycle-Z-, or C1-3 alkyl optionally substituted with phenyl or NR8R9, wherein Z is a bridging group selected from C1-10 alkylene branched or unbranched, CO, S(O)p, O, S, NH, CONH, NHCO, COO or OOC, and wherein each cycloalkyl, aryl, heteroaryl or heterocycle is optionally substituted with NO2, C1-3 alkyl, C1-3 alkoxy, halogen, CO2R10, (CH2)nNR8R9, O(CH2)2-4NR8R9, ureido or guanidino, wherein one or more of the amino nitrogens in the ureido or guanidino groups in this paragraph may be optionally substituted with C1-3 alkyl, phenyl C0-3 alkyl or C1-3 alkoxy;
• and wherein each alkyl, alkoxy and phenyl in this paragraph is optionally partially or fully halogenated;
• or R5 is a C6-12 bridged- or spiro-bicyclic ring system, optionally having one or two double bonds in the ring system, and wherein up to 3 carbon atoms in the ring system may be replaced by heteroatoms selected from N, O and S;
• and wherein said ring system may be optionally substituted with C1-3 alkyl, C1-3 alkoxy, halogen, CO2R10, ureido, guanidino, amidino, (CH2)nNR8R9, or O(CH2)2-4NR8R9;
• wherein one or more of the amino nitrogens in the ureido, guanidino or amidino groups in this paragraph may be optionally substituted with C1-3 alkyl, phenyl CO3 alkyl or C1-3 alkoxy;
• R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3 alkoxy, C1-6 alkyl branched or unbranched, C3-6 alkenyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle;
• wherein said alkyl, cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3 alkoxy, C1-3 acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
• or R8 and R9 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached;
• wherein said alkylene chain is optionally interrupted by O, S(O)p, NCOR1,O NCO2R10, NR11 or NC(═NR11)NR11R12;
• and wherein said ring is optionally substituted by C1-3 alkyl, C1-3 alkoxy, OH or —(CH2)nNR11R12;
• R10 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3 alkoxy, C1-3 alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3 alkyl, C1-3 alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
• R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3 alkoxy, OH or phenyl;
• or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
• m is 1-4;
• n is 0-3;
• and p is 0-2;
• said method comprising:
• (a) reacting the compound of formula XVIII (wherein R4 is H) with an acid halide of the formula R5COX, wherein X is a halogen, or with an acid anhydride of the formula (R5CO)2O, or with an acid of the formula R5CO2H and a coupling reagent, in a suitable solvent in the presence of a suitable base to form a compound of formula XX:
• 132
• (b) hydrolyzing and cyclizing the compound of formula XX by treatment with a suitable base and a suitable oxidant in a suitable solvent to form the compound of formula Ib:
• 133

A compound of the following formula XVIII:

• 134
• wherein:
• Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle;
• wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
• R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy;
• wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
• R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3 alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
• R is H, C1-3 alkyl or cyclopropyl;
• and
• R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3 alkoxy, C3-10-cycloalkyl, or C5-8 cycloalkenyl;
• or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R10, (CH2)nCONR8R9, phenyl, heteroaryl or heterocycle, each phenyl, heteroaryl or heterocycle being optionally substituted with C1-3 alkyl, C1-3 alkoxy, (CH2)mNR8R9, OH, SO3H or halogen;
• R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3 alkoxy, C1-6 alkyl branched or unbranched, C3-6 alkenyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle;
• wherein said alkyl, cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3 alkoxy, C1-3 acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
• or R8 and R9 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached;
• wherein said alkylene chain is optionally interrupted by O, S(O)p, NCOR10, NCO2R10, NR11 or NC(═NR11)NR11R12;
• and wherein said ring is optionally substituted by C1-3 alkyl, C1-3 alkoxy, OH or —(CH2)nNR11R12;
• R10 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3 alkoxy, C1-3 alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3 alkyl, C1-3 alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
• R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3 alkoxy, OH or phenyl;
• or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
• m is 1-4;
• and n is 0-3.

A compound of the following formula XIX:

• 135
• wherein:
• Ar1 is Ar1 is an aromatic or nonaromatic carbocycle, heteroaryl or heterocycle;
• wherein said carbocycle, heteroaryl or heterocycle is optionally substituted by one or more R1, R2 and R3;
• R1 and R2 are the same or different and are selected from H, halogen, CN, NO2, C1-10 branched or unbranched saturated or unsaturated alkyl, C1-10 branched or unbranched alkoxy, C1-10 branched or unbranched acyl, C1-10 branched or unbranched acyloxy, C1-10 branched or unbranched alkylthio, aminosulfonyl, di-(C1-3)alkylaminosulfonyl, NR8R9, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl and heteroaryloxy;
• wherein the abovementioned R1 and R2 are optionally partially or fully halogenated or optionally substituted with one to three groups independently selected from the group consisting of oxo, OH, NR8R9, C1-6 branched or unbranched alkyl, C3-7 cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono- or di(C1-3)alkylaminocarbonyl;
• R3 is selected from the group consisting of H, halogen, OH, (CH2)nNR8R9, (CH2)nCO2R10, C1-3 alkyl optionally substituted with OH, C1-3 alkoxy optionally halogenated and C1-3 alkylthio;
• R is H, C1-3 alkyl or cyclopropyl;
• and
• R4 is selected from H, C1-6 alkyl branched or unbranched, saturated or unsaturated, and optionally substituted with phenyl, OH or C1-3 alkoxy, C3-10-cycloalkyl, or C5-8 cycloalkenyl;
• or R4 is selected from (CH2)mNR8R9, (CH2)mNR8COR10, (CH2)nCO2R10) (CH2)nCONR8R9, phenyl, heteroaryl or heterocycle, each phenyl, heteroaryl or heterocycle being optionally substituted with C1-3 alkyl, C1-3 alkoxy, (CH2)mNR8R9, OH, SO3H or halogen;
• R8 and R9 are the same or different and are each independently selected from H, OH, CO2R10, C1-10 acyl branched or unbranched, C1-3 alkoxy, C1-6 alkyl branched or unbranched, C3-6 alkenyl, C3-8 cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle;
• wherein said alkyl, cycloalkyl, aryl, aryl C1-3 alkyl, aroyl, heteroaryl or heterocycle are optionally substituted with OH, C1-3 alkoxy, C1-3 acyloxy, CO2R10, NR11R12, O(CH2)2-4NR11R12, aryl or heteroaryl;
• or R8 and R9 together form a 3-7 member alkylene chain completing a ring about the N atom to which they are attached;
• wherein said alkylene chain is optionally interrupted by O, S(O)p, NCOR10, NCO2R10, NR11 or NC(═NR11)NR11R12;
• and wherein said ring is optionally substituted by C1-3 alkyl, C1-3 alkoxy, OH or —(CH2)nNR11R12;
• R10 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with phenyl, OH, C1-3 alkoxy, C1-3 alkanoyloxy or NR11R12, or R10 is phenyl optionally substituted with one to three C1-3 alkyl, C1-3 alkoxy, halogen, (CH2)mNR8R9, (CH2)nCONR8R9 or O(CH2)2-4NR8R9;
• R11 and R12 are each independently selected from H and C1-6 alkyl optionally substituted with C1-3 alkoxy, OH or phenyl;
• or R11 and R12 together form a chain completing a ring, said chain is (CH2)4-5 or (CH2)2O(CH2)2;
• m is 1-4;
• and n is 0-3.