PROCESSES FOR THE PREPARATION OF N-(1-METHYLCYCLOPROPYL)-2-(3-PYRIDINYL)-2H-INDAZOLE-4-CARBOXAMIDE AND INTERMEDIATES THEREOF

1 . A process for preparing compound 092, the process comprising:

(1) step 1 comprising forming a reaction mixture comprising compound 061, a chlorinating reagent, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 930 according to the following reaction scheme

 and

(2) step 2 comprising forming a reaction mixture comprising compound 930, compound 070, a base, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 092 according to the following reaction scheme

2 . The process of claim 1 , wherein for step 1:

(1) (a) the solvent system comprises a non-polar solvent, a polar aprotic solvent, or a combination thereof, (b) the solvent system comprises toluene and dimethylformamide, (c) the solvent system comprises toluene and pyridine or (d) the solvent system comprises toluene;

(2) the chlorinating reagent is selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride, cyanuric chloride, diphosgene triphosgene, and phosgene; and/or

3 . The process of claim 1 or claim 2 , wherein the step 1 reaction mixture further comprises a catalyst.

4 . The process of any one of claims 1 to 3 , wherein the catalyst is selected from dimethylformamide or pyridine.

5 . The process of any one of claims 1 to 4 , wherein for step 2:

(1) (a) the solvent system comprises a nonpolar solvent, a polar aprotic solvent, or a combination thereof, (b) the solvent system comprises toluene, xylene, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, dimethylacetamide, isopropyl acetate, tetrahydrofuran, dichloromethane, pyridine, sulfolane, or a combination thereof, (c) the solvent system comprises a polar solvent, or (d) the solvent system comprises acetonitrile, (e) the solvent system comprises acetonitrile and N-methyl-2-pyrrolidone, (f) the solvent system comprises a non-polar solvent, (g) the solvent system comprises toluene, or (h) the solvent system comprises toluene and N-methyl-2-pyrrolidone;

(2) (a) the base is an inorganic base or an organic base, (b) the base is an organic base selected from triethylamine, N,N-diisopropylethylamine, pyridine, 3-methylpyridine, dimethylaniline, N-methylimidazole, N-methylmorpholine, DABCO, and DBU, (c) the organic base is triethylamine, (d) the organic base is N,N-diisopropylethylamine, or (e) the base is an inorganic base selected from sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

6 . A process for preparing compound 092, the processing comprising forming a reaction mixture solution comprising compound 061, an activator, a base, compound 070, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 092 according to the following reaction scheme

7 . The process of claim 6 , wherein (a) the activator is selected from an acyl chloride, an anhydride, an alkyl chloroformate, a sulfonyl chloride, an acyl imidazole, and a triazine chloride or (b) the activator is p-toluene sulfonyl chloride.

8 . The process of claim 6 and claim 7 , wherein (a) the base is an organic base, (b) the base is a tertiary amine base, (c) the base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, (d) the base is selected from pyridine, 2,6-lutidine, 3-picoline, imidazole, or N-methylimidazole, or (e) the base is N-methylimidazole.

9 . A process for the preparation of compound 092 according to the following scheme, the process comprising forming a reaction mixture comprising compound 038, compound 070, a base, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 092

10 . The process of claim 9 , wherein (a) the base is an organometallic base, (b) the base is selected from organolithium, organomagnesium, or organoaluminium bases, (c) the base is selected from methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, or (d) the base is isopropyl magnesium chloride.

11 . A process for preparing compound 092, the process comprising forming a reaction mixture comprising compound 093a or 93b, compound 070, a catalyst, a ligand, CO, a base, and a solvent system, and reacting the reaction mixture to form a reaction product mixture comprising compound 092 according to the following reaction scheme

12 . The process of claim 11 , wherein:

(1) (a) the catalyst is a transition metal catalyst, (b) the catalyst is selected from a palladium catalyst, a nickel catalyst, or a platinum catalyst, (c) the catalyst is a palladium catalyst, (d) the catalyst is a palladium on carbon catalyst, or (e) the catalyst is palladium (II) acetate;

(2) (a) the ligand a diphosphine ligand, (b) the ligand is selected from 1,3-bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate), 1,3-bis(dicyclohexylphosphino)propane, 1,3-bis(diphenylphosphinium) bis(tetrafluoroborate), and 1,3-bis(diphenylphosphino)propane, (c) the ligand is 1,3-bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate), or (d) the ligand is 1,3-bis(dicyclohexylphosphino)propane;

(3) (a) the base comprises at least one inorganic base, (b) the base is a carbonate or a phosphate, (c) the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate dibasic, and potassium phosphate tribasic or combinations thereof, or (d) the base is potassium phosphate tribasic;

(4) (a) the reaction atmosphere comprises or predominately comprises a mixture of CO and N 2 , (b) the reaction atmosphere comprises or predominately comprises CO, (c) the reaction temperature is at least 100° C.;

(5) the solvent system comprises (a) a polar aprotic solvent, (b) is selected from diglyme, dioxane, acetonitrile, DMF, DMAc, sulfolane, or dimethylsulfoxide, or (c) dimethylsulfoxide.

13 . A polymorph of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide designated Form A characterized by a X-ray powder diffraction pattern in accordance with FIG. 1 .

14 . A polymorph of N-(1-methylcyclopropyl)-2-(3-pyridinyl)-2H-indazole 4-carboxamide designated Form B characterized by a X-ray powder diffraction pattern in accordance with FIG. 2 .

15 . A process for preparing compound 092 salt, the process comprising forming a reaction mixture comprising compound 092, a solvent system, an acid, and reacting the reaction mixture to form a reaction product mixture comprising compound 092 salt according to the following reaction scheme