Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia

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

• wherein:
• G is —(CR5R6)n—, where n=1, 2
• Z is —(CR10R11)m—, where m=1, 2
• R1 and R4 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R1 or R4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R2 and R3 are independently H, R14S(O)2—, R14S(O)—, R14S—, R14—(CR19R20)—;
• R5, R6, R10, and R11 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R5, R6, R10, or R11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• or
• R6 and R10 can combine to form a —(CH2)n—, wherein n represents an integer from 2 to 3;
• R7 is independently H, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —S(O)R15, —S(O)2R15, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R7 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R12 and R13 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R12 or R13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• or
• R14 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each R14 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of the R14 substituents further optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, H, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R15, R16, R17, and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R15, R16, R17, or R18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl;
• or R15 and R16 or R17 and R18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl;
• R19 and R20 are independently H or C1-C6 alkyl, wherein R19 and R20 can combine to form a —(CH2)n— where n represents an integer from 4-7;
• with the proviso that at least one of R2 and R3, but not both, is H;
• or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprising:
• providing a first intermediate compound having the structure:
• wherein X is Br, Cl, or I
• and
• converting the first intermediate compound to the compound of formula (I).

A process for the preparation of a compound of formula (VI) having the structure:

• wherein:
• G is —(CR5R6)n—, where n=1, 2
• Z is —(CR10R11)m—, where m=1, 2
• R1 and R4 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R1 or R4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R5, R6, R10, and R11 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R5, R6, R10, or R11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• or
• R6 and R10 can combine to form a —(CH2)n—, wherein n represents an integer from 2 to 3;
• R7 is independently H, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —S(O)R15, —S(O)2R15, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R7 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R12 and R13 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R12 or R13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• or
• R14 is independently a substituted or unsubstituted mono or polycyclic aryl or substituted or unsubstituted mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each R14 optionally substituted from 1 to 4 times for each cyclic ring with substituents selected from the group consisting of H, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each one of the R14 substituents further optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, H, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R15, R16, R17, and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R15, R16, R17, or R18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl;
• or R15 and R16 or R17 and R18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl;
• R19 is independently H or C1-C6 alkyl;
• with the proviso that at least one of R2 and R3, but not both, is H;
• or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprising:
• providing a first intermediate compound having the structure:
• wherein X is Br, Cl, or I
• reacting the first intermediate compound (II) with a lithiating agent;
• quenching the lithiated first intermediate compound with an aldehyde or ketone under conditions effective to produce the second intermediate compound (VII) of the following formula:
• and
• reacting the second intermediate compound (VII) under conditions effective to de-oxygenate a hydroxyl group attached to the carbon adjacent to R14 and produce the compound of formula (VI).

A process for the preparation of a compound of formula (VIII):

• wherein
• X is Br, Cl, or I;
• R1 and R4 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R1 or R4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R5, R6, R8, and R9 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R5, R6, R8, or R9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• or
• R6 and R8 can combine to form a —(CH2)n—, wherein n represents an integer from 2 to 3;
• R12 and R13 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R12 or R13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R15, R16, R17, and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R15, R16, R17, or R18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl;
• or R15 and R16 or R17 and R18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
• providing a phenoxylamine derivative compound having the formula:
• and
• reacting the phenoxylamine derivative compound with a piperidone derivative compound having the structure:
• wherein PG is H or a protective group under conditions effective to form the compound of formula (VIII).

A process for preparation of a compound of formula (XI):

• wherein
• X is Br, Cl, or I;
• R1 and R4 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R1 or R4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R5, R6, R8, and R9 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R5, R6, R8, or R9 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R12 and R13 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R12 or R13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R15, R16, R17, and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R15, R16, R17, or R18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl;
• or R15 and R16 or R17 and R18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
• providing a starting compound having the structure:
• and
• converting said starting compound under conditions effective to form the compound of formula (XI).

A process for preparation of a compound formula (XVII):

• wherein
• X is Br, Cl, or I;
• R1 and R4 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R1 or R4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R5, R6, R8, and R9 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R5, R6, R8, and R9 are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR47, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R10 and R11 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R10 or R11 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R12 and R13 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R12 or R13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R15, R16, R17, and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R15, R16, R17, or R18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl;
• or R15 and R16 or R17 and R18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
• providing a starting compound having the structure:
• and
• converting said starting compound under conditions effective to form the compound of formula (XVII).

A process for preparation of a compound formula (XXI):

• wherein
• PG is a protecting group that can be removed under acidic or basic conditions
• X is Br, Cl, or I;
• R1 and R4 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR45, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R1 or R4 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R5, R6, R8, and R9 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl C1-C6 alkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R5, R6, R8, and R9 are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, OR17, —C(O)R17, —C(O)OR17, —C(O)NR17R18, —NHR17, —NR17R18, —SR17, —S(O)R17, —S(O)2R17, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R12 and R13 are independently H, halogen, CF3, CHF2, CH2F, OH, OR15, —C(O)R15, —C(O)OR15, —C(O)NR15R16, —NHR15, —NR15R16, —SR15, —S(O)R15, —S(O)2R15, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, or mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each R12 or R13 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, NH2, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, mono or polycyclic aryl, and mono or polycyclic heteroaryl containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
• R15, R16, R17, and R18 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl or a monocyclic heteroaryl containing from 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, each R15, R16, R17, or R18 optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, and a monocyclic aryl;
• or R15 and R16 or R17 and R18 can combine to form a 3- to 7-membered heterocyclyl or a mono heteroaryl each containing from 1 to 5 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl or heteroaryl are optionally substituted from 1 to 3 times with substituents selected from the group consisting of halogen, OH, CN, NO2, NH2, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, a monocyclic aryl, and monocyclic heteroaryl, or an oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, said process comprises:
• providing a starting compound having the structure:
• and
• converting said starting compound under conditions effective to form the compound of formula (XXI).