Methods of producing pyrazole compounds

A method for producing a compound of Formula (XIX),

• wherein:
• R2 and R3 are each independently selected from H, C1-6 alkyl, C1-6 alkoxy, or halogen;
• R4 is selected from H, C1-10 saturated or unsaturated alkyl, C1-10 substituted or unsubstituted arylalkyl, C3-10 cycloalkyl, aryl, heteroaryl, C1-10 alkyl silyl, C1-10 alkyl silyl ethers, substituted or unsubstituted haloalkyl, or C1-20 alkyl tricyclic;
• n is 1 to 5;
• comprising
• condensing a compound of Formula (XXI),
• wherein R2 and R3 are as defined above;
• with a compound of Formula (VII),
• wherein R4 and n are as defined above, and X is a leaving group;
• to obtain the compound of Formula (XIX).

A method for producing substituted pyrazole compound of Formula (I):

• wherein:
• R1, R2 and R3 are each independently selected from H, C1-6 alkyl, C1-6 alkoxy, or halogen;
• R4 is selected from H, C1-10 saturated or unsaturated alkyl, C1-10 substituted or unsubstituted arylalkyl, C3-10 cycloalkyl, aryl, heteroaryl, C1-10 alkyl silyl, C1-10 alkyl silyl ethers, substituted or unsubstituted haloalkyl, or C1-20 alkyl tricyclic;
• n is 1 to 5;
• or its pharmaceutically acceptable salts, solvates, co-crystals, and hydrates thereof;
• comprising
• condensing a compound of Formula (XX),
• wherein R is H or Pg1,
• wherein Pg1 is hydroxy protecting group, and R1 is as defined above;
• with a compound of Formula (XXII),
• wherein R2 and R3 are as defined above;
• in the presence of a condensing agent to obtain a compound of Formula (VIb),
• wherein R, R1, R2, and R3 are as defined above;
• cyclizing the compound of Formula (VIb) with hydrazine to yield a compound of Formula (VIc),
• wherein R, R1, R2, and R3 are as defined above;
• and converting the compound of Formula (VIc) to substituted pyrazole compound of Formula (I).

A method for producing substituted pyrazole compound of Formula (I):

• wherein:
• R1, R2 and R3 are each independently selected from H, C1-6 alkyl, C1-6 alkoxy, or halogen;
• R4 is selected from H, C1-10 saturated or unsaturated alkyl, C1-10 substituted or unsubstituted arylalkyl, C3-10cycloalkyl, aryl, heteroaryl, C1-10 alkyl silyl, C1-10 alkyl silyl ethers, substituted or unsubstituted haloalkyl, or C1-20 alkyl tricyclic;
• n is 1 to 5;
• or its pharmaceutically acceptable salts, solvates, co-crystals, and hydrates thereof;
• comprising
• condensing a compound of Formula (XX),
• wherein R is H or Pg1;
• wherein Pg1 is hydroxy protecting group, and R1 is as defined above;
• with a compound of Formula (XXIII),
• wherein IV, and R3 are as defined above and R5 is H or Pg3;
• wherein Pg3 is amino protecting group;
• in the presence of a condensing agent to obtain a compound of Formula (XXIV),
• wherein R, R1, R2, R3, and R5 are as defined above;
• optionally deprotecting the compound of Formula (XXIV) to yield a compound of Formula (VIc),
• wherein R, R1, R2, and R3 are as defined above;
• and converting the compound of Formula (VIc) to substituted pyrazole compound of Formula (I).

A method for producing substituted pyrazole compound of Formula (I):

• wherein:
• R1, R2 and R3 are each independently selected from H, C1-6 alkyl, C1-6 alkoxy, or halogen;
• R4 is selected from H, C1-10 saturated or unsaturated alkyl, C1-10 substituted or unsubstituted arylalkyl, C1-10 alkyl silyl, C1-10 alkyl silyl ethers, substituted or unsubstituted haloalkyl, or C1-20 alkyl tricyclic;
• n is 1 to 5;
• or its pharmaceutically acceptable salts, solvates, co-crystals, and hydrates thereof;
• comprising
• condensing a compound of Formula (XXV),
• wherein R2, R3 and n are as defined above, and R6 is selected from mono or di-carboxylic acid, acid chloride, ester, nitrile, aldehyde, alcohol, amide, alkyl, alkenyl, alkynyl, alkyl halide, or keto group;
• with a compound of Formula (XX),
• wherein R is H or Pg′,
• wherein Pg1 is hydroxy protecting group, and R1 is as defined above;
• in the presence of a condensing agent to obtain a compound of Formula (XVIIIa),
• wherein R, R1, R2, R3, R4, R6 and n are as defined above;
• optionally converting the compound of Formula (XVIIIa) to a compound of Formula (VIIIa),
• wherein R, R1, R2, R3, R4, and n are as defined above;
• and optionally deprotecting and/or hydrolysing the compound of Formula (VIIIa) to yield substituted pyrazole compound of Formula (I).

A method for producing a compound of Formula (IX),

• wherein R1 is selected from H, C1-6 alkyl, C1-6 alkoxy, and halogen;
• comprising
• protecting a compound of Formula (XIII),
• wherein IV is as defined above;
• with a suitable protecting group to obtain a compound of Formula (XIV),
• wherein R1 as defined above and Pg2 is hydroxy protecting group selected from tosyl or benzoyl;
• reacting a compound of Formula (XIV) with 2,2-dimethyl-1,3-dioxane-4,6-dione to obtain a compound of Formula (XV),
• wherein R1 and Pg2 are as defined above;
• cyclizing the compound of Formula (XV) to obtain a compound of Formula (XVI),
• wherein R1 and Pg2 are as defined above;
• deprotecting the compound of Formula (XVI) to obtain a compound of Formula (XVII),
• wherein R1 are as defined above;
• and reducing the compound of Formula (XVII) to yield a compound of Formula (IX),
• [OR]
• reducing the compound of Formula (XVI),
• wherein R1 are as defined above;
• to obtain a compound of Formula (XVIa),
• wherein IV and Pg2 are as defined above;
• and deprotecting the compound of Formula (XVIa) to obtain a compound of Formula (IX).