Phenylalkynes

A method of making a compound of formula (I)

• 102
• wherein n is an integer from 0 to 1;
• R1 and R2 are independently selected from C1-3 alkyl, allyl, and C3-8 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;
• one of R3 and R5 is G, one of the remaining and R4 is H, and the other is selected from hydrogen, fluoro, and chloro;
• G is L2Q;
• L2 is methylene;
• Q is NR8R9 wherein R8 is independently selected from hydrogen, C1-6 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1-6 alkylene, and (phenyl) C1-6 alkylene;
• and R9 is independently selected from C1-6 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1-6 alkylene, and (phenyl) C1-6 alkylene;
• or
• Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;
• wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C1-3 alkyl;
• and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C1-6 alkyl, 5-9-membered heterocyclyl, N(C1-6 alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C1-3 alkylene, phenyl, C1-2-hydroxyalkylene, C2-6 alkoxy, (C3-6 cycloalkyl)-O—, phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy;
• a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting at least one of the compounds of formulae (XXIIIw) and (XXIIIow) with a compound of formula (V)
• 103
• wherein W is C(O)H or G, and X2 is a suitable leaving group in a coupling reaction with an alkyne.

A method of making a compound of formula (I)

• 104
• wherein n is an integer from 0 to 1;
• R1 and R2 are independently selected from C1-3 alkyl, allyl, and C3-8 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;
• one of R3, R4, and R5 is G, one of the remaining two is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;
• G is L2Q;
• L2 is methylene;
• Q is NR8R9 wherein R8 is independently selected from hydrogen, C1-6 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1-6 alkylene, and (phenyl) C1-6 alkylene;
• and R9 is independently selected from C1-6 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1-6 alkylene, and (phenyl) C1-6 alkylene;
• or
• Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;
• wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C1-3 alkyl;
• and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C1-6 alkyl, 5-9-membered heterocyclyl, N(C1-6 alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C1-3 alkylene, phenyl, C1-2-hydroxyalkylene, C2-6 alkoxy, (C3-6 cycloalkyl)-O—, phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy;
• a pharmaceutically acceptable salt, ester, or amide thereof, comprising reacting a compound of formula (VII)
• 105
• with an organic base R1R2NH in the presence of a trialkylphosphonium halide and a base.

A method of making a compound of formula (I)

• 106
• wherein n is an integer from 0 to 1;
• R1 and R2 are independently selected from C1-3 alkyl, allyl, and C3-8 cycloalkyl, or taken together with the nitrogen to which they are attached, they form a non-aromatic 4-7 membered heterocyclyl optionally including up to two additional heteroatoms independently selected from O, S, and N;
• R4 is G, one of the remaining R3 and R5 is hydrogen, and the other is selected from hydrogen, fluoro, and chloro;
• G is L2Q;
• L2 is methylene;
• Q is NR8R9 wherein R8 is independently selected from hydrogen, C1-6 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1-6 alkylene, and (phenyl) C1-6 alkylene;
• and R9 is independently selected from C1-6 alkyl, C3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered heterocyclyl)C1-6 alkylene, and (phenyl) C1-6 alkylene;
• or
• Q is a saturated 3-13 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-13 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and N;
• wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be independently and optionally substituted with between 1 and 3 substituents independently selected from methoxy, halo, amino, nitro, hydroxyl, and C1-3 alkyl;
• and wherein 1-3 substituents of Q can be further independently selected (in addition to the preceding paragraph) from tert-butyloxycarbonyl, carboxamide, C1-6 alkyl, 5-9-membered heterocyclyl, N(C1-6 alkyl)(5-9 membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered heterocyclyl), (5-9 membered heterocyclyl)C1-3 alkylene, phenyl, C1-2-hydroxyalkylene, C2-6 alkoxy, (C3-6 cycloalkyl)-O—, phenyl, (phenyl)C1-3 alkylene, and (phenyl)C1-3 alkylene-O— and where said substituent groups of Q may optionally have between 1 and 3 substituents independently selected from trifluoromethyl, halo, nitro, cyano, and hydroxy;
• a pharmaceutically acceptable salt, ester, or amide thereof, comprising:
• reacting a compound of formula (XXIIImw) with a compound of formula (V).
• 107
• wherein W is C(O)H or G, and X2 is a suitable leaving group in a coupling reaction with an alkyne.