Sglt-2 inhibitors, methods of making them, and uses thereof

A compound of formula (II):

• wherein X is selected from the group consisting of
• wherein each X is optionally substituted 1-3 times by Rf and a CH2 unit in a ring of X can be optionally substituted by oxo or thio;
• R5 is Cl, methyl or F;
• R6 to R8 are H;
• R9 is CH2OH or SMe;
• Rf is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NCORgRh, SO2Rg, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted 1-3 times by CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, SO2Rg, or CO2Rg;
• and
• Rg and Rh are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
• or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.

A compound of formula (III):

• wherein
• Y is
• R5 is Cl, F, or methyl;
• R6, R7, and R8 are H;
• R9 is CH2OH or SMe;
• R10 is H, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, or lower alkynyl is optionally substituted 1-3 times by Re;
• R11 is H, methyl, ethyl, or gem-dimethyl;
• Re is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, SO2Rg, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein the each of the 3 to 10-membered carbocycle or 3-10-membered heterocycle is optionally substituted 1-3 times with halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, or SO2Rg;
• and
• Rg and Rh are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
• or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.

A compound of formula (III):

• wherein
• Y is
• R5 is Cl or methyl;
• R6, R7, and R8 are H;
• R9 is CH2OH;
• R10 is H, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, or lower alkynyl is optionally substituted 1-3 times by Re;
• R11 is H methyl, ethyl or gem-dimethyl;
• Re is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, SO2Rg, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein the each of the 3 to 10-membered carbocycle or 3-10-membered heterocycle is optionally substituted 1-3 times with halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, or SO2Rg;
• and
• Rg and Rh are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
• or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.

A process for preparation of a product compound of formula (I):

• wherein
• A is O or S;
• R1 is H;
• R2 is H, halogen, CN, ORa, NRbRc, CORd, CONRbRc, SO2Rd, lower alkyl, lower alkenyl, lower alkynyl, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein each of lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted from 1-3 times by Re and each 3 to 10-membered carbocycle or 3 to 10-membered heterocycle is optionally substituted 1-3 times by Rf;
• R3 is H, halogen, methyl, ethyl, isopropyl, CH2OH, CH2CH2OH, CF3 or CF2H;
• R4 is H;
• R5 is Cl, F, or methyl;
• R6, R7, and R8 are H;
• R9 is CH2OH;
• Ra is H, lower alkyl, lower alkenyl, lower alkynyl, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein each of lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted from 1-3 times by Re and each 3 to 10-membered carbocycle or 3 to 10-membered heterocycle is optionally substituted 1-3 times by Rf;
• Rb and Rc are, independently, H, CORd, SO2Rd, lower alkyl, lower alkenyl, lower alkynyl, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein each of lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted from 1-3 times by Re and each 3 to 10-membered carbocycle or 3 to 10-membered heterocycle is optionally substituted 1-3 times by Rf;
• Rb and Rc can be taken together with the nitrogen to which they are attached to form a ring which is selected from the group consisting of:
• wherein each of these rings is optionally substituted 1-3 times by Rf and one or two of the ring CH2 units or the sulphur can be optionally substituted by an oxo or thio group;
• Rd is NRbRc, lower alkyl, lower alkenyl, lower alkynyl, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein each of lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted from 1-3 times by Re and each 3 to 10-membered carbocycle or 3 to 10-membered heterocycle is optionally substituted 1-3 times by Rf;
• Re is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCOR11, SO2Rg, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein the each of the 3 to 10-membered carbocycle or 3-10-membered heterocycle is optionally substituted 1-3 times with halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCOR11, or SO2Rg;
• Rf is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NCORgRh, SO2Rg, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted 1-3 times by CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, SO2Rg, or CO2Rg;
• and
• Rg and Rh are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
• said process comprising:
• treating an intermediate compound of formula IA:
• wherein M is acetyl, para-methoxybenzyl, or methoxylmethyl and Q is halogen or OH, under conditions effective to produce the product compound.

A process for preparation of a product compound of formula (II):

• wherein X is selected from the group consisting of
• wherein each X is optionally substituted 1-3 times by Rf and a CH2 unit in a ring of X can be optionally substituted by oxo or thio;
• R5 is Cl, methyl, or F;
• R6 to R8 are H;
• R9 is CH2OH;
• Rf is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NCORgRh, SO2Rg, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, and lower alkynyl is optionally substituted 1-3 times by CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, SO2Rg, or CO2Rg;
• and
• Rg and Rh are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
• said process comprising:
• treating an intermediate compound of formula IA:
• wherein M is acetyl, para-methoxybenzyl, or methoxylmethyl and Q is halogen or OH, under conditions effective to produce the product compound.

A process for preparation of a product compound of formula (III):

• wherein
• Y is
• R5 is Cl, F, or methyl;
• R6, R7, and R8 are H;
• R9 is CH2OH;
• R10 is H, lower alkyl, lower alkenyl, or lower alkynyl, wherein each lower alkyl, lower alkenyl, or lower alkynyl is optionally substituted 1-3 times by Re;
• R11 is H, methyl, ethyl, or gem-dimethyl;
• Re is halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, SO2Rg, 3 to 10-membered carbocycle, or 3 to 10-membered heterocycle, wherein the each of the 3 to 10-membered carbocycle or 3-10-membered heterocycle is optionally substituted 1-3 times with halogen, CF3, CF2H, OCF3, OCF2H, CN, ORg, NRgRh, CORg, CONRgRh, NRgCORh, or SO2Rg;
• and
• Rg and Rh are each, independently, H, lower alkyl, lower alkenyl, or lower alkynyl;
• said process comprising:
• treating an intermediate compound of formula IA:
• wherein M is acetyl, para-methoxybenzyl, or methoxylmethyl and Q is Cl, Br, or I, under conditions effective to produce the product compound.