Preparation of 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-ones

A process for preparing a compound of formula VI:

• comprising:
• (c) contacting a compound of formula IV with a compound of formula V in the presence of a metal salt and a fourth solvent;
• wherein:
• metal salt is selected from a copper and a palladium salt;
• the fourth solvent is an alcoholic or an aprotic solvent;
• X2 is a leaving group selected from Cl, Br, I, OSO2Me, OSO2CF3, OSO2Ph, and OSO2Ph-p-Me;
• R1 is selected from C1-6 alkyl, C0-6 alkylene-phenyl, O—C1-6 alkyl, and O—C0-6 alkylene-phenyl;
• R2b is selected from C1-4 alkyl, phenyl, and benzyl;
• R4 is a 5-10 membered aromatic carbocyclic or heterocyclic ring consisting of carbon atoms and 0-4 heteroatoms selected from O, S(O)p, and N and R4 is substituted with 0-2 groups selected from F and C1-4 alkyl;
• Ar is
• ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of:
• carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p;
• ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
• E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
• alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1-2 R;
• alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5-6 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5-6 membered heterocycle is substituted with 0-1 carbonyl and 1-2 R and there are 0-3 ring double bonds;
• R is selected from H, C1-4 alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, (CR8R9)tC(O)R5, (CR8R9)tOR6, (CR8R9)tS(O)pR6, CN, C(═NR8)NR7R9, NHC(═NR8)NR7R9, ONHC(═NR8)NR7R9, NR8CH(═NR7), NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), CH2CH2N(C1-3 alkyl)2, (CR8R9)tC(O)H, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, (CR8R9)tNR7C(O)R7, (CR8R9)tS(O)pNR7R8, (CR8R9)tNR7S(O)pR7, and OCF3;
• alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
• R5, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-2 R5a, and —(CH2)r-5-10 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R5a;
• R5a, at each occurrence, is selected from H, ═O, (CH2)rOR6, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, (CH2)rCN, (CH2)rNO2, (CH2)rNR6R6a, (CH2)rC(O)R6, (CH2)rC(O)OR6, (CH2)rNR6C(O)R6, (CH2)r—C(O)NR6R6a, (CH2)rNR6C(O)NR6R6a, (CH2)r—C(═NR6)NR6R6a, (CH2)rNR6C(═NR6)NR6R6a, (CH2)rSO2NR6R6a, (CH2)rNR6SO2NR6R6a, (CH2)rNR6SO2—C1-4 alkyl, (CH2)rNR6SO2CF3, (CH2)rNR6SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (CH2)rS(O)p-phenyl, and (CH2)r(CF2)rCF3;
• R6, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• R6a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• alternatively, NR6R6a form a 5 or 6 membered ring consisting of:
• carbon atoms, the nitrogen atom to which R6 and R6a are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p, and there are 0-3 ring double bonds;
• R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkyl-C(O)—, C1-6 alkyl-O—, (CH2)n-phenyl, C1-6 alkyl-OC(O)—, C6-10 aryl-O—, C6-10 aryl-OC(O)—, C6-10 aryl-CH2—C(O)—, C1-4 alkyl-C(O)O—C1-4 alkyl-OC(O)—, C6-10 aryl-C(O)O—C1-4 alkyl-OC(O)—, C1-6 alkyl-NH2—C(O)—, phenyl-NH2—C(O)—, and phenyl-C0-4 alkyl-C(O)—;
• R8, at each occurrence, is selected from H, C1-6 alkyl, and (CH2)n-phenyl;
• alternatively, R7 and R8, when attached to the same nitrogen, combine to form a 5-10 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
• R9, at each occurrence, is selected from H, C1-6 alkyl, and (CH2)n-phenyl;
• R10 is selected from C1-20 alkyl, phenyl, and benzyl;
• R10a is selected from C1-18 alkyl, phenyl, and benzyl;
• R10c is selected from C1-18 alkyl, phenyl, and benzyl;
• R10c is selected from C1-18 alkyl, phenyl, and benzyl;
• R11 is selected from H, C1-4 alkyl, OC1-4, alkyl, F, Br, Cl, CN, NO2, phenyl, and benzyl;
• n, at each occurrence, is selected from 0, 1, 2, and 3;
• p, at each occurrence, is selected from 0, 1, and 2;
• r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;
• and
• t, at each occurrence, is selected from 0, 1, 2, and 3.

A process for preparing a compound of formula IIId, comprising:

• (a) contacting a compound of formula Id with a compound of formula IId to form a compound of formula IIId;
• wherein:
• X1 is a leaving group selected from Cl, Br, and I;
• X2 is a leaving group selected from Cl, Br, I, OSO2Me, OSO2CF3, OSO2Ph, and OSO2Ph-p-Me;
• R1 is selected from C1-6 alkyl, C0-6 alkylene-phenyl, O—C1-6 alkyl, and O—C0-6 alkylene-phenyl;
• R3 is selected from C1-6 alkyl, phenyl, and benzyl;
• R4 is a 5-10 membered aromatic carbocyclic or heterocyclic ring consisting of carbon atoms and 0-4 heteroatoms selected from O, S(O)p, and N and R4 is substituted with 0-2 groups selected from F and C1-4 alkyl;
• Ar is
• ring D, including the two atoms of Ring E to which it is attached, is a 5-6 membered ring consisting of:
• carbon atoms and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p;
• ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
• E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with 1-2 R;
• alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1-2 R;
• alternatively, ring D is absent and ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, and ring E is substituted with 1 R and with a 5-6 membered heterocycle consisting of:
• carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, wherein the 5-6 membered heterocycle is substituted with 0-1 carbonyl and 1-2 R and there are 0-3 ring double bonds;
• R is selected from H, C1-4 alkyl, F, Cl, Br, I, OH, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, (CR8R9)tC(O)R5, (CR8R9)tOR6, (CR8R9)tS(O)pR6, CN, C(═NR8)NR7R9, NHC(═NR8)NR7R9, ONHC(═NR8)NR7R9, NR8CH(═NR7), NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, C(═NH)NH2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), CH2CH2N(C1-3 alkyl)2, (CR8R9)tC(O)H, (CR8R9)tNR7R8, (CR8R9)tC(O)NR7R8, (CR8R9)tNR7C(O)R7, (CR8R9)tS(O)pNR7R8, (CR8R9)tNR7S(O)pR7, and OCF3;
• alternatively, when 2 R groups are attached to adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;
• R5, at each occurrence, is selected from CF3, OH, C1-4 alkoxy,
• C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-2 R5a, and —(CH2)r-5-10 membered heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 R5a;
• R5a, at each occurrence, is selected from H, ═O, (CH2)rOR6, (CH2)rF, (CH2)rCl, (CH2)rBr, (CH2)rI, C1-4 alkyl, (CH2)rCN, (CH2)rNO2, (CH2)rNR6R6a, (CH2)rC(O)R6, (CH2)rC(O)OR6, (CH2)rNR6C(O)R6, (CH2)r—C(O)NR6R6a, (CH2)rNR6C(O)NR6R6a, (CH2)r—C(═NR6)NR6R6a, (CH2)rNR6C(═NR6)NR6R6a, (CH2)rSO2NR6R6a, (CH2)rNR6SO2NR6R6a, (CH2)rNR6SO2—C1-4 alkyl, (CH2)rNR6SO2CF3, (CH2)rNR6SO2-phenyl, (CH2)rS(O)pCF3, (CH2)rS(O)p—C1-4 alkyl, (CH2)rS(O)p-phenyl, and (CH2)r(CF2)rCF3;
• R6, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• R6a, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
• alternatively, NR6R6a forms a 5 or 6 membered ring consisting of:
• carbon atoms, the nitrogen atom to which R6 and R6a are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O, and S(O)p, and there are 0-3 ring double bonds;
• R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkyl-C(O)—, C1-6 alkyl-O—, (CH2)n-phenyl, C1-6 alkyl-OC(O)—, C6-10 aryl-O—, C6-10 aryl-OC(O)—, C6-10 aryl-CH2—C(O)—, C1-4 alkyl-C(O)O—C1-4 alkyl-OC(O)—, C6-10 aryl-C(O)O—C1-4 alkyl-OC(O)—, C1-6 alkyl-NH2—C(O)—, phenyl-NH2—C(O)—, and phenyl-C0-4 alkyl-C(O)—;
• R8, at each occurrence, is selected from H, C1-6 alkyl, and (CH2)n-phenyl;
• alternatively, R7 and R8, when attached to the same nitrogen, combine to form a 5-10 membered heterocyclic ring consisting of carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, O, and S(O)p;
• R9, at each occurrence, is selected from H, C1-6 alkyl, and (CH2)n-phenyl;
• alternatively, R4—X2 is selected from:
• R4a is substituted with 0-2 R4d and selected from morpholine, 1,1-dioxo-thiomorpholine, dihydropyridine, piperidine, piperazine, pyrrolidine, imidazole, imidazoline, imidazolidine, oxazoline, and thiazoline;
• R4b, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2, CH2CCH, CH2CH2OH, CH2C(O)NH2, cyclopropyl, CH2-cyclopropyl, cyclobutyl, cyclopentyl, and thiazolyl;
• R4c, at each occurrence, is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2, CH2-cyclopropyl, cyclopropyl, and cyclopentyl;
• R4d is selected from —O, OH, OCH3, and CH3;
• n, at each occurrence, is selected from 0, 1, 2, and 3;
• p, at each occurrence, is selected from 0, 1, and 2;
• r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;
• and
• t, at each occurrence, is selected from 0, 1, 2, and 3.