Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor

A compound of the formula (11):

• or a pharmaceutically acceptable salt thereof, wherein
• Y is Q and Z is hydrogen;
• or Y is hydrogen and Z is Q, wherein Q is
• R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or (CH2)nOR23;
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R4, R5, R10, and R23 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or (CH2)nOR23;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX1R12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or —CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• (CH2)mCO2R11;
• or —(CH2)mCONR11R12;
• R11 and R12 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• X1 is —O-, —NR12-, or —SOm-;
• each m is independently 0, 1, or 2;
• and each n is independently 0, 1, 2, 3, or 4.

A method of synthesizing a compound comprising:

• a) reacting an aminopyridine of the formula (III):
• wherein R29 is Cl or Br,
• R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or —CON(R13)(R14);
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)—alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 hereroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(CH2)nOR23;
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R23 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• X1 is —O—, —NR12—, or SOm−;
• R12 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each m is independently 0, 1, or 2;
• each n is independently 0, 1, 2, 3, or 4;
• under conditions effective to bring about cyclization, thereby providing a compound having the formula (IV):
• wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R232, —CON(R23)2, or —(CH2)nOR23;
• and
• R28 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• b) reacting the compound of formula (IV) with a piperazine, thereby providing a compound having the formula (V):
• R4, R5, R21, R22, R24, R25, R26, and R27 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• c) reacting the free amine of the piperazine of formula (V) under conditions effective to provide a compound of the formula (IA):
• wherein R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(CH2)nOR23;
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX1R12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or —CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)mCO2R11;
• or —(CH2)mCONR11R12;
• and
• each R10 is independently hydrogen;
• or linear or branched C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• R11 is hydrogen;
• linear or branched C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• and
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

A method of synthesizing a compound comprising:

• a) reacting an aminopyridine of the formula (VI):
• wherein R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or —CONR(R13)(R14);
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(CH2)nOR23;
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R23 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• X1 is —O—, —NR12—, or SOm−;
• R12 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each m is independently 0, 1, or 2;
• each n is independently 0, 1, 2, 3, or 4;
• under conditions effective to bring about cyclization, thereby providing a compound having the formula (VII):
• wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(CH2)nOR23;
• R28 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• b) halogenating the compound of the formula (VII) and reacting with a piperazine, thereby providing a compound having the formula (VIII):
• wherein R4, R5, R21, R22, R24, R25, R26, and R27 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• and
• c) reacting the free amine of the piperazine of formula (VIII) under conditions effective to provide a compound of the formula (IB):
• wherein R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(CH2)nOR23;
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX1R12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or —CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)mCO2R11;
• or —(CH2)mCONR11R12;
• each R10 is independently hydrogen;
• or linear or branched C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• R11 is hydrogen;
• linear or branched C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• and
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

A method of synthesizing a compound comprising:

• a) reacting an aminopyridine of the formula (VI):
• wherein R18, R19, and R20 are each independently hydrogen;
• linear or branched (C 1-C6)- alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or —CON(R, 3)(R14);
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R23 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• X1 is —O-, —NR12-, or —SOm;
• R12 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each m is independently 0, 1, or 2;
• each n is independently 0, 1, 2, 3, or 4;
• under conditions effective to provide a diaminopyridinium iodide having the formula (IX):
• b) reacting the compound of the formula (IX) under conditions effective to bring about cyclization, thereby providing a compound having the formula (X):
• wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R 14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• c) halogenating the compound of the formula (X) and reacting with a piperazine, thereby providing a compound having the formula (XI):
• wherein R4, R5, R21, R22, R24, R25, R26, and R27 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• and
• d) reacting the free amine of the piperazine of formula (XI) under conditions effective to provide a compound of the formula (IC):
• wherein R, and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX1R12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or—CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)mCO2R11;
• or (CH2)mCONR11R12;
• each R10 is independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• R11 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• and
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

A method of synthesizing a compound comprising:

• a) reacting a hydrazinonitropyridine of the formula (XII):
• wherein R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or CON(R13)(R14);
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(C H,)nOR23;
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R23 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• X1 is —O-, —NR12-, or —SOm;
• R12 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each m is independently 0,1, or 2;
• each n is independently 0, 1, 2, 3, or 4;
• under conditions effective to provide a compound of the formula (XIII):
• wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• b) treating the compound of formula (XIII) under conditions effective to bring about isomerization to provide a compound of the formula (XIV):
• c) reducing the nitro group to provide a compound of the formula (XV):
• d) diazotizing and halogenating the compound of formula (XV) and reacting with piperazine, thereby providing a compound of the formula (XVI):
• wherein 1(4, 1(5, R21, R22, R24, R25, R26, and R27 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• and
• e) reacting the free amine of the piperazine of formula (XVI) under conditions effective to provide a compound of the formula (ID):
• wherein R11 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl,
• (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R11 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX1R12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or—CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• (CH2)mCO2R11;
• or (CH2)mCONR11R12;
• each R10 is independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2—C6)-alkenyl, or (C2-C6)-alkynyl;
• R11 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

A compound of the formula (IA):

• prepared by a method comprising:
• a) reacting a compound of the formula (III):
• under conditions effective to bring about cyclization, thereby providing a compound having the formula (IV):
• b) reacting the compound of formula (IV) with a piperazine, thereby providing a compound having the formula (V):
• c) reacting the free amine of the piperazine of formula (V) under conditions effective to provide a compound of the formula (IA);
• wherein
• R29 is Cl or Br;
• Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R4, R5, R10, R21, R22, R23, R24, R25, R26, R27, and R28 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nXiR12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or—CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)mCO2R11;
• or —(CH2)mCONR11R12;
• R11 and R12 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or
• X1 is —O-, —NR12-, or —SOm;
• each m is independently 0,1, or 2;
• and
• each n is independently 0, 1, 2, 3, or 4.

A compound of the formula (IB):

• prepared by a method comprising:
• a) reacting an aminopyridine of the formula (VI):
• under conditions effective to bring about cyclization, thereby providing a compound having the formula (VII):
• b) halogenating the compound of the formula (VII) and reacting with a piperazine, thereby providing a compound having the formula (VIII):
• c) reacting the free amine of the piperazine of formula (VIII) under conditions effective to provide a compound of the formula (IB);
• wherein
• Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R4, R5, R10, R21, R22, R23, R24, R25, R26, and R27, and R28 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23COR23, —NR23 COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23COR23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or (CH2)nOR23;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX R12;
• —(CH2)nR17, —COX1R11;
• —X1R11;
• —CO2R11;
• or —CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)mCO2R11;
• or 4CH2)mCONR11R12;
• R11 and R12 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(Rn)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or —(CH2)nOR23;
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl ;
• R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or
• X1 is —O-, —NR12-, or —SOm;
• each m is independently 0, 1, or 2;
• and
• each n is independently 0, 1, 2, 3, or 4.

A compound of the formula (IC):

• prepared by a method comprising:
• a) reacting an aminopyridine of the formula (VI):
• under conditions effective to provide a diaminopyridinium iodide having the formula (IX):
• b) reacting the compound of the formula (IX) under conditions effective to bring about cyclization, thereby providing a compound having the formula (X):
• c) halogenating the compound of the formula (X) and reacting with a piperazine, thereby providing a compound having the formula (XI):
• d) reacting the free amine of the piperazine of formula (XI) under conditions effective to provide a compound of the formula (IC);
• wherein
• Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R4, R5, R10, R21, R22, R23, R24, R25, R26, and R27 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R14—C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or (CH2)nOR23;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(GH2)nX1R12;
• —(CH2)nR17;
• —COX1R11;
• —X1R11;
• —CO2R11;
• or —CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)mCO2R12;
• or —(CH2)mCONR11R12;
• R11 and R12 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or CON(R13)(R 14);
• X1 is —O-, —NR12-, or —SOm;
• each m is independently 0, 1, or 2;
• and
• each n is independently 0,1, 2, 3, or 4.

A compound of the formula (ID):

• prepared by a method comprising:
• a) reacting a hydrazinonitropyridine of the formula (XII):
• under conditions effective to provide a compound of the formula (XIII):
• b) treating the compound of formula (XIII) under conditions effective to bring about isomerization to provide a compound of the formula (XIV):
• c) reducing the nitro group to provide a compound of the formula (XV):
• d) diazotizing and halogenating the compound of formula (XV) and reacting with piperazine, thereby providing a compound of the formula (XVI):
• e) reacting the free amine of the piperazine of formula (XVI) under conditions effective to provide a compound of the formula (ID);
• wherein
• Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
• R1 and R2 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• or R1 and R2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R1 and R2 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to the ring of R3 containing at least one N;
• R4, R5, R10, R21, R22, R23, R24, R25, R26, and R27 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• each R6 is independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• —NR13R 14;
• —C(OH)(CF3)2;
• —CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• or —COR13;
• and when the two R6 are ortho to each other, they may together form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the cyclic group formed by the ortho R6 groups is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or (CH2)nOR23;
• R7 and R9 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• —(CH2)nX1R12;
• —(CH2)nR17;
• —COX1Rn;
• —X1R11;
• —CO2R11;
• or—CONR11R12;
• R8 is hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• (CH2)mCO2R ;
• or (CH2)mCONR11R12;
• R11 and R12 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or R11 and R12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R13 and R14 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —R23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• aryl;
• or aryl optionally substituted with one to three substituents selected from halogen, R15, —OR15, or —NR15R16;
• or R13 and R14 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S, and wherein the heterocyclic group formed by R13 and R14 is optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, —CON(R23)2, or
• R15 and R16 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• or both R15 and R16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• R18, R19, and R20 are each independently hydrogen;
• linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each optionally substituted with halogen, —N3, —NO2, —CN, —OR23, —SR23, —SO2R23, —SO2N(R23)2, —N(R23)2, —COR23, —CO2R23, —NR23CO2R23, —NR23COR23, —NR23CON(R23)2, or —CON(R23)2;
• halogen;
• —NR13R14;
• —C(OH)(CF3)2;
• CH(CF3)2;
• —C(CF3)3;
• —X1R13;
• —COR13;
• —CO2R13;
• or —CON(R13)(R14);
• X1 is —O-, —NR12-, or —SOm-;
• each m is independently 0, 1, or 2;
• and
• each n is independently 0, 1, 2, 3, or 4.