Process for preparing substituted pyridines

A process for preparing a compound of the formula

• 76
• wherein n is 0, 1, 2 or 3;
• R1 is hydrogen or halo;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R3 is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetcting group;
• X is halo, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy or p-nitrobenzenexulfonyloxy;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy,(C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C1)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above;
• comprising (a) reacting a compound of the formula
• 77
• wherein n, R1 and R2 as defined above, with a reducing agent followed by hydrolsis with an acid or base;
• (b) reacting the intermediate of formula XIII so formed
• 78
• wherein n, R1 and R2 are as defined above, with a methylating agent to form a vinylpyridine compound of the formula
• 79
• (c) reacting the vinylpyridine compound so formed in step (b) with a dihydroxylating agent, with or without a co-oxidant and/or a coordinating ligand to form the compound of the formula
• 80
• wherein n, R1 and R2 are as defined above;
• (d) reacting the compound of formula XI so formed with a sulfonyl chloride in the presence of a base to form the compound of the formula X
• 81
• wherein n, R1, R2 and X are as defined above;
• and
• (e) reacting the compound of formula X so formed with silyating agent in the presence of a base.

A process for preparing a compound of the formula

• 82
• wherein n is 0, 1, 2 or 3;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above;
• R6 is COR7 or CO2R7 wherein R7 is (C1-C8)alkyl;
• and
• Y is
• 83
• wherein:
• Q1 is oxygen, nitrogen or sulfur;
• Q2 is carbon or nitrogen;
• Q3 is hydrogen, —(CH2)q-phenyl, —(C1-C10)alkyl, —(CH2)q—NG1G2, —(CH2)q—CO2G3, (CH2)qCONG1G2, (CH2)qOG3, (CH2)qSO3G3, —(CH2)q—SO2—(C1-C6)alkyl, —(CH2)q—SO2NG1G2, or a heterocycle selected from the group consisting of —(CH2)q-pyridyl, —(CH2)q-pyrimidyl, —(CH2)q-pyraziqyl, —(CH2)q-isoxazolyl, —(CH2)q-oxazolyl, —(CH2)q-thiazolyl, —(CH2)q-(1,2,4-oxadiazolyl), —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C8)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C1-C8)alkyl optionally independently substituted with one or more halo atoms, nitro, cyano, —(CH2)q—NG1G2, —(CH2)q—CO2G3, —(CH2)q—CO-NG1G2, (CH2)q—OG3, (CH2)q—SO3G3, —(CH2)q—SO2-(C1-C6)alkyl and —(CH2)q—SO2NG1G2;
• wherein the phenyl moiety of said —(CH2)q-phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C1-C6)alkoxy optionally independently substituted with one or more halo atoms, (C1-C6)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH2)q—NG1G2, (CH2)qCO2G3, (CH2)qCO—NG1G2, (CH2)q—OG3, (CH2)qSO3G3, (CH2)qSO2—(C1-C6)alkyl, —(CH2)q—SO2NG1G2;
• —(CH2)q—NG3—SO2-G3 and —(CH2)q—NG3—SO2—NG1G2;
• Q4 is —(CH2)q—CN, —(CH2)qCO2G3, —(CH2)q—SO3G3, —(CH2)q—SO2—(C1-C6)alkyl, (CH2)qSO2NG1G2, —(CH2)qCH2OH, (CH2)qCHO, (CH2)qCOG3, (CH2)q—CONG1G2, or a heterocycle selected from —(CH2)q-thiazolyl, —(CH2)q-oxazolyl, —(CH2)q-imidazolyl, —(CH2)q-triazolyl, ——(CH2)q-1,2,4-oxadiazolyl, —(CH2)q-isoxazolyl, —(CH2)q-tetrazolyl and —(CH2)q-pyrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo atoms, —(CH2)q—CO-NG1G2, —(CH2)q—CO2G3, halo, nitro, cyano, —(CH2)q—CO-NG1G2, —(CH2)q—OG3, —(CH2)q—SO3G3, —(CH2)qSO2—(C1-C6)alkyl, or —(CH2)q—SO2NG1G2;
• Q5 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q6 is a covalent bond, oxygen or sulfur;
• Q7 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q8 and Q9 are independently a covalent bond, oxygen, sulfur, NH or N-(C1-C6)alkyl;
• Q10 is nitro, amino, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, (CH2)pOR11, (CH2)qCO2H, (CH2)qCOR13, (CH2)qSO2NR11R12, (CH2)q—NR11SO2R10, (CH2)qP(O)(OR8)(OR9), (CH2)qO(CH2)pCO2H, (CH2)qO(CH2)pCOR13, (CH2)q—O—(CH2)pP(O)(OR8)(OR9), (CH2)q—O—(CH2)pSO2NR11R2, or (CH2)qO(CH2)p—NR11SO2R10;
• R8 and R9 are each independently hydrogen or (C1-C6)alkyl;
• and
• wherein G1 and G2 for each occurrence are each independently hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo, (C1-C8)alkoxy(C1-C6)alkyl or (C3-C8)cycloalkyl, or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
• G3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
• R10 for each occurrence is independently (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
• R11 and R12 are taken separately and, for each occurrence, are independently hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl, or
• R11 and R12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C1-C4)alkyl or (C1-C4)alkoxy;
• R13 for each occurrence is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, NR11R12, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl wherein R11 and R12 are as defined above;
• R14 and R15 are each independently hydrogen, halo, (C1-C6)alkyl, nitro, cyano, trifluoromethyl, SO2R10, SO2NR11R12, NR11R12, COR13, CO2R11, (C1-C6)alkoxy, NR11SO2R10, NR11COR13, NR11CO2R11 or OR11;
• p for each occurrence is independently an integer of 1 to 6;
• and
• q for each occurrence is independently 0 or an integer of 1 to 6;
• with the proviso that when Q9 is O or S then n is not 0;
• with the proviso that when Q1 is oxygen or sulfur then Q3 is absent;
• and
• with the proviso that when Q2 is nitrogen then Q5 is absent;
• comprising reacting a compound of the formula
• 84
• wherein n, R2, R6 and Y are as defined above;
• and R3 is tetrahydrofuranyl, tetrahydropyranyl or a silyl protecting group;
• with tetra-n-butylammonium fluoride.

A process for preparing a compound of the formula

• 91
• wherein n is 0, 1, 2 or 3;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above;
• R6 is COR7 or CO2R7 wherein R7 is (C1-C8)alkyl;
• and
• Y is
• 92
• wherein:
• Q1 is oxygen, nitrogen or sulfur;
• Q2 is carbon or nitrogen;
• Q3 is hydrogen, —(CH2)q-phenyl, —(C1-C10)alkyl, —(CH2)q—NG1G2, —(CH2)q—CO2G3, (CH2)qCO—NG1G2, —(CH2)qOG3, (CH2)qSO3G3, —(CH2)q—SO2—(C1-C6)alkyl, —(CH2)q—SO2NG1G2, or a heterocycle selected from the group consisting of —(CH2)q-pyridyl, —(CH2)q-pyrimidyl, —(CH2)q-pyraziqyl, —(CH2)q-isoxazolyl, —(CH2)q-oxazolyl, —(CH2)q-thiazolyl, —(CH2)q-(1,2,4-oxadiazolyl), —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C8)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C1-C8)alkyl optionally independently substituted with one or more halo atoms, halo, nitro, cyano, —(CH2)q—NG1G2, —(CH2)q—CO2G3, —(CH2)qCO NG1G2, (CH2)q0G3, (CH2)qSO3G3—(CH2)q—SO2-(C1-C6)alkyl and —(CH2)q—SO2NG1G2;
• wherein the phenyl moiety of said —(CH2)q-phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C1-C6)alkoxy optionally independently substituted with one or more halo atoms, (C1-C6)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH2)q—NG1G2, —(CH2)q—CO2G3, —(CH2)q—CO—NG1G2, —(CH2)q—OG3, (CH2)qSO3G3, —(CH2)qSO2—(C1-C6)alkyl, —(CH2)q—SO2NG1G2;
• —(CH2)q—NG3_SO2-G3 and —(CH2)q—NG3—SO2—NG1G2;
• Q4 is (CH2)qCN, (CH2)qCO2G3, (CH2)qSO3G3, —(CH2)qSO2(C1-C6)alkyl, (CH2)qSO2NG1G2, (CH2)qCH2OH, (CH2)qCHO, (CH2)qCOG3, (CH2)qCONG1G2, or a heterocycle selected from —(CH2)q-thiazolyl, —(CH2)q-oxazolyl, —(CH2)q-imidazolyl, —(CH2)q-triazolyl, —(CH2)q-1,2,4-oxadiazolyl, —(CH2)q-isoxazolyl, —(CH2)q-tetrazolyl and —(CH2)q-pyrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo atoms, —(CH2)q—CO-NG1G2, —(CH2)q—CO2G3, halo, nitro, cyano, —(CH2)q—CO-NG1G2, —(CH2)q—OG3, (CH2)qSO3G3, (CH2)qSO2—(C1-C6)alkyl, or —(CH2)q—SO2NG1G2;
• Q5 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q6 is a covalent bond, oxygen or sulfur;
• Q7 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q8 and Q9 are independently a covalent bond, oxygen, sulfur, NH or N-(C1-C6)alkyl;
• Q10 is nitro, amino, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, (CH2)pOR11, (CH2)qCO2H, (CH2)qCOR13, (CH2)qSO2NR11R12, (CH2)qNR11SO2R10, (CH2)qP(O)(OR8)(OR9), (CH2)qO(CH2)pCO2H, (CH2)qO(CH2)pCOR13, (CH2)q—O—(CH2)pP(O)(OR8)(OR9), (CH2)q—O—(CH2)pSO2NR11R12, or (CH2)q—O—(CH2)p—NR11SO2R10;
• R8 and R9 are each independently hydrogen or (C1-C6)alkyl;
• and
• wherein G1 and G2 for each occurrence are each independently hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo, (C1-C8)alkoxy(C1-C6)alkyl or (C3-C8)cycloalkyl, or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
• G3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
• R10 for each occurrence is independently (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
• R11 and R12 are taken separately and, for each occurrence, are independently hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl, or R11 and R12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C1-C4)alkyl or (C1-C4)alkoxy;
• R13 for each occurrence is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, NR1R12, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl wherein R11 and R12 are as defined above;
• R14 and R15 are each independently hydrogen, halo, (C1-C6)alkyl, nitro, cyano, trifluoromethyl, SO2R10, SO2NR11R2, NR11R2, COR3, CO2R11, (C1-C6)alkoxy, NR11SO2R10, NR11COR13, NR11CO2R11 or OR11;
• p for each occurrence is independently an integer of 1 to 6;
• and
• q for each occurrence is independently 0 or an integer of 1 to 6;
• with the proviso that when Q9 is O or S then n is not 0;
• with the proviso that when Q1 is oxygen or sulfur then Q3 is absent;
• and
• with the proviso that when Q2 is nitrogen then Q5 is absent;
• comprising (a) reacting a compound of the formula
• 93
• wherein R1 is hydrogen or halo, and n, R1, R2, R3 and X are as defined above, with an amine of the formula H2NY, wherein Y is as defined above in the presence of N,N-diisopropylethylamine;
• (b) reacting the compound of formula IV so formed
• 94
• wherein R1 is hydrogen or halo and wherein n, R2, R3 and Y are as defined above with an organic acid anhydride, a dicarbonate or an organic acid chloride, to form a compound of the formula
• 95
• (c) treating the compound of formula II, wherein R1 is halo, so formed in step (b) with ammonium formate in the presence of palladium-on-carbon to form the compound of the formula
• 96
• wherein n, R2, R3, R6 and Y are as defined above, and
• (d) treating the compound of formula II so formed with tetra-n-butylammonium fluoride.

A process for preparing a compound of the formula

• 97
• wherein n is 0, 1, 2 or 3;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above;
• R6 is COR7 or CO2R7 wherein R7 is (C1-C8)alkyl;
• and
• Y is
• 98
• wherein:
• Q1 is oxygen, nitrogen or sulfur;
• Q2 is carbon or nitrogen;
• Q3 is hydrogen, —(CH2)q-phenyl, —(C1-C10)alkyl, —(CH2)q—NG1G2, —(CH2)q—CO2G3, (CH2)qCO—NG1G2, (CH2)qOG3, (CH2)qSO3G3, (CH2)qSO2(C1-C6)alkyl, —(CH2)q—SO2NG1G2, or a heterocycle selected from the group consisting of —(CH2)q-pyridyl, —(CH2)q-pyrimidyl, —(CH2)q-pyraziqyl, —(CH2)q-isoxazolyl, —(CH2)q-oxazolyl, —(CH2)q-thiazolyl, —(CH2)q-(1,2,4-oxadiazolyl), —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C8)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C1-C8)alkyl optionally independently substituted with one or more halo atoms, nitro, cyano, —(CH2)q—NG1G2, —(CH2)q—CO2G3, —(CH2)q—CO-NG1G2, (CH2)qOG3, —(CH2)q—SO3G3, —(CH2)q—SO2—(C1-C6)alkyl and —(CH2)q—SO2NG1G2;
• wherein the phenyl moiety of said —(CH2)q-phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C1-C6)alkoxy optionally independently substituted with one or more halo atoms, (C1-C6)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH2)q—NG1G2, (CH2)qCO2G3, (CH2)qCONG1G2, (CH2)qOG3, (CH2)qSO3G3, (CH2)qSO2—(C1-C6)alkyl, —(CH2)q—SO2NG1G2;
• —(CH2)q—NG3—SO2-G3 and —(CH2)q—NG3_SO2—NG1G2;
• Q4 is (CH2)qCN, —(CH2)qCO2G3, —(CH2)q—SO3G3, —(CH2)q—SO2-(C1-C6)alkyl, —(CH2)qSO2NG1G2, (CH2)qCH2OH, (CH2)qCHO, (CH2)qCO-G3, (CH2)qCONG1G2, or a heterocycle selected from —(CH2)q-thiazolyl, —(CH2)q-oxazolyl, —(CH2)q-imidazolyl, —(CH2)q-triazolyl, —(CH2)q-1,2,4-oxadiazolyl, —(CH2)q-isoxazolyl, —(CH2)q-tetrazolyl and —(CH2)q-pyrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo atoms, —(CH2)q—CO-NG1G2, —(CH2)q—CO2G3, halo, nitro, cyano, —(CH2)q—CO-NG1G2, —(CH2)q—OG3, _(CH2)q—SO3G3, —(CH2)q—SO2—(C1-C6)alkyl, or —(CH2)q—SO2NG1G2;
• Q5 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q6 is a covalent bond, oxygen or sulfur;
• Q7 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q8 and Q9 are independently a covalent bond, oxygen, sulfur, NH or N-(C1-C6)alkyl;
• Q10 is nitro, amino, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl. (CH2)pOR11, (CH2)qCO2H, (CH2)qCOR13, (CH2)qSO2NR11R2, (CH2)qNR11SO2R10, (CH2)qP(O)(OR8)(OR9), (CH2)q—O—(CH2)pCO2H, (CH2)q—O—(CH2)pCOR13, —(CH2)q—O—(CH2)pP(O)(OR8)(OR9), (CH2)q—O—(CH2)pSO2NR11R12, or (CH2)qO(CH2)p—NR11SO2R10;
• R8 and R9 are each independently hydrogen or (C1-C6)alkyl;
• and
• wherein G1 and G2 for each occurrence are each independently hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo, (C1-C8)alkoxy(C1-C6)alkyl or (C3-C8)cycloalkyl, or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
• G3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
• R10 for each occurrence is independently (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
• R11 and R12 are taken separately and, for each occurrence, are independently hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl, or
• R11 and R12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C1-C4)alkyl or (C1-C4)alkoxy;
• R13 for each occurrence is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, NR11R2, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl wherein R11 and R12 are as defined above;
• R14 and R15 are each independently hydrogen, halo, (C1-C6)alkyl, nitro, cyano, trifluoromethyl, SO2R10, SO2NR11R12, NR11R12, COR13, CO2R11, (C1-C6)alkoxy, NR11SO2R10, NR11COR13, NR11CO2R11 or OR11;
• p for each occurrence is independently an integer of 1 to 6;
• and
• q for each occurrence is independently 0 or an integer of 1 to 6;
• with the proviso that when Q9 is O or S then n is not 0;
• with the proviso that when Q9 is oxygen or sulfur then Q3 is absent;
• and
• with the proviso that when Q2 is nitrogen then Q5 is absent;
• comprising reacting a compound of the formula
• 99
• wherein R1 is halo and wherein n, R2, R3 and Y are as defined above, with ammonium formate in the presence of palladium-on-carbon.

A process for preparing a compound of the formula

• 104
• wherein n is 0, 1, 2 or 3;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above;
• R6 is COR7 or CO2R7 wherein R7 is (C1-C8)alkyl;
• and
• Y is
• 105
• wherein:
• Q1 is oxygen, nitrogen or sulfur;
• Q2 is carbon or nitrogen;
• Q3 is hydrogen, —(CH2)q-phenyl, —(C1-C10)alkyl, —(CH2)q—NG1G2, —(CH2)q—CO2G3, —(CH2)q—CO—NG1G2, —(CH2)q—OG3, —(CH2)q—SO3G3, —(CH2)q—SO2-(C1-C6)alkyl, —(CH2)q—SO2NG1G2, or a heterocycle selected from the group consisting of —(CH2)q-pyridyl, —(CH2)q-pyrimidyl, —(CH2)q-pyraziqyl, —(CH2)q-isoxazolyl, (CH2)q-oxazolyl, —(CH2)q-thiazolyl, —(CH2)q-(1,2,4-oxadiazolyl), —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C8)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C1-C8)alkyl optionally independently substituted with one or more halo atoms, nitro, cyano, —(CH2)q—NG1G2, —(CH2)q—CO2G3, —(CH2)q—CO-NG1G2, —(CH2)q—OG3, —(CH2)q—SO3G3, —(CH2)q—SO2-(C1-C6)alkyl and —(CH2)q—SO2NG1G2;
• wherein the phenyl moiety of said —(CH2)q-phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C1-C6)alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C1-C6)alkoxy optionally independently substituted with one or more halo atoms, (C1-C6)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH2)q—NG1G2, —(CH2)qCO2G3, (CH2)qCO—NG1G2, (CH2)qOG3, (CH2)qSO3G3, —(CH2)q—SO2—(C1-C6)alkyl, —(CH2)q—SO2NG1G2;
• —(CH2)q—NG3_SO2-G3 and —(CH2)q—NG3—SO2—NG1G2;
• Q4 is —(CH2)q—CN, —(CH2)qCO2G3, —(CH2)q—SO3G3, —(CH2)q—SO2-(C1-C6)alkyl, —(CH2)qSO2NG1G2, (CH2)qCH2OH, —(CH2)qCHO, (CH2)qCO-G3, (CH2)qCONG1G2, or a heterocycle selected from —(CH2)q-thiazolyl, —(CH2)q-oxazolyl, —(CH2)q-imidazolyl, —(CH2)q-triazolyl, —(CH2)q-1,2,4-oxadiazolyl, —(CH2)q-isoxazolyl, —(CH2)q-tetrazolyl and —(CH2)q-pyrazolyl;
• wherein one of the ring nitrogen atoms of said —(CH2)q-imidazolyl, —(CH2)q-triazolyl and —(CH2)q-tetrazolyl may optionally be substituted by (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo atoms, —(CH2)q—CO-NG1G2, —(CH2)q—CO2G3, halo, nitro, cyano, —(CH2)q—CO—NG1G2, —(CH2)q—OG3, —(CH2)q—SO3G3, (CH2)q—SO2(C1-C6)alkyl, or —(CH2)q—SO2NG1G2;
• Q5 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q6 is a covalent bond, oxygen or sulfur;
• Q7 is hydrogen or (C1-C6)alkyl optionally independently substituted with one or more halo atoms;
• Q8 and Q9 are independently a covalent bond, oxygen, sulfur, NH or N—(C1-C6)alkyl;
• Q10 is nitro, amino, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, (CH2)pOR11, (CH2)qCO2H, (CH2)qCOR3, (CH2)qSO2NR11R12, (CH2)qNR11SO2R10, (CH2)qP(O)(OR8)(OR9), (CH2)q—O—(CH2)pCO2H, (CH2)q—O—(CH2)pCOR13, (CH2)q—O—(CH2)pP(O)(OR8)(OR9), (CH2)q—O—(CH2)pSO2NR11R12, or (CH2)q—O—(CH2)p—NR11SO2R10;
• R8 and R9 are each independently hydrogen or (C1-C6)alkyl;
• and
• wherein G1 and G2 for each occurrence are each independently hydrogen, (C1-C6)alkyl optionally independently substituted with one or more halo, (C1-C8)alkoxy(C1-C6)alkyl or (C3-C8)cycloalkyl, or G1 and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
• G3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
• R10 for each occurrence is independently (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
• R11 and R12 are taken separately and, for each occurrence, are independently hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl, or R11 and R12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C1-C4)alkyl or (C1-C4)alkoxy;
• R13 for each occurrence is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, NR11R12, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl wherein R11 and R12 are as defined above;
• R14 and R15 are each independently hydrogen, halo, (C1-C6)alkyl, nitro, cyano, trifluoromethyl, SO2R10, SO2NR11R12, NR11R12, COR13, CO2R11, (C1-C6)alkoxy, NR11SO2R10, NR11COR13, NR11CO2R11 or OR11;
• p for each occurrence is independently an integer of 1 to 6;
• and
• q for each occurrence is independently 0 or an integer of 1 to 6;
• with the proviso that when Q9 is O or S then n is not 0;
• with the proviso that when Q1 is oxygen or sulfur then Q3 is absent;
• and
• with the proviso that when Q2 is nitrogen then Q5 is absent;
• comprising (a) reacting the compound of a formula
• 106
• wherein R1 is hydrogen or halo, and n, R1, R2, R3 and X are as defined above, with an amine of the formula H2NY, wherein Y is as defined above, in the presence of N,N-diisopropylethylamine;
• (b) reacting the compound of the formula VII so formed
• 107
• wherein R1 is hydrogen or halo, and wherein n, R2 and Y are as defined above with an organic acid anhydride, a dicarbonate or an organic acid chloride to form a compound of the formula
• 108
• wherein n, R1, R2, R6 and Y are as defined above and
• (c) reacting the compound of formula VI, wherein R1 is halo, so formed with ammonium formate in the presence of palladium-on-carbon.

A process for preparing a compound of the formula

• 109
• wherein n is 0, 1, 2 or 3;
• R1 is hydrogen or halo;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above;
• comprising reacting the compound of the formula
• 110
• wherein n, R1, R2 and X are as defined above, with a non-nucleophilic base.

A compound of the formula

• 111
• wherein n is 0, 1, 2 or 3;
• R1 is hydrogen or halo;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above.

A compound of the formula

• 114
• wherein n is 0, 1, 2 or 3;
• R1 is hydrogen or halo;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above.

A compound of the formula

• 117
• wherein n is 0, 1, 2 or 3;
• R1 is hydrogen or halo;
• each R2 is independently hydrogen, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R3 is tetrahydrofuranyl, tetrahydropyranyl or a silyl protetcting group;
• X is halo, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy or p-nitrobenzenexulfonyloxy;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy,(C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above.

A compound of the formula

• 120
• wherein n is 0, 1, 2 or 3;
• m is 1 or 2;
• R1 is hydrogen or halo;
• each R2 is independently hydrogen, nitro, halo, trifluoromethyl, cyano, SR4, OR4, SO2R4, OCOR5, or (C1-C10)alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R4)2, SR4, trifluoromethyl, OR4, (C3-C8)cycloalkyl, (C6-C10)aryl, NR4COR5, COR5, SO2R5, OCOR5, NR4SO2R5 and NR4CO2 R4;
• R4 and R5, for each occurrence, are each independently selected from hydrogen, (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C8)cycloalkyl,(C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C1-C10)alkyl-CO2, (C1-C10)alkylsulfonyl, (C3-C8)cycloalkyl, (C1-C10)alkoxy, or (C1-C6)alkyl;
• and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C1-C6)alkyl)2amino, pyrrolidine, piperidine, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkylthio and (C1-C10)alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C1-C6)alkyl-CO2, (C1-C6)alkylsulfonyl, (C3-C8)cycloalkyl and (C1-C6)alkoxy;
• or R5 is N(R4)2 wherein R4 is as defined above.