Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor

A compound of the formula (Ia):

• or a pharmaceutically acceptable salt thereof, 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 a 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;
• —XR13;
• or —COR13;
• and when 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;
• R11XR12;
• —(CH2)nR17;
• —COXR11;
• —XR11;
• —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 —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;
• X 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) treating a compound of the formula (II):
• wherein R19, and R20 are each independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• under conditions effective to bring about chlorination and esterification, thereby providing a compound having the formula (III):
• b) reacting the compound of formula (III) with an amine under conditions effective to produce an amide of the formula (IV):
• wherein R18 is hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• c) subjecting the amide of formula (IV) to conditions effective to provide an amine of the formula (V):
• d) reacting the compound of formula (V) under conditions effective to provide a nitrated and protected piperazine of the formula (VI):
• 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
• PG is hydrogen or an amine protecting group;
• e) subjecting the protected piperazine of the formula (VI) to conditions effective to provide a deprotected piperazine of the formula (VII):
• f) reacting the compound of formula (VII) with an aryl aldehyde under conditions effective to bring about cyclization, thereby providing a piperazine-imidazo[4,5-b]pyridine having the formula (VIII):
• 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;
• —XR13;
• or —COR13;
• and when 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;
• X is —O—, —NR12—, or —SOm—;
• each m is independently 0, 1, or 2;
• and
• 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 —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;
• each R23 is independently hydrogen;
• or linear or branched (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• g) reacting the free amine of the piperazine of the piperazine-imidazo[4,5-b]pyridine of the formula (VIII) under conditions effective to provide the compound of the formula (I)
• 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;
• and
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to a 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;
• —R11XR12;
• —(CH2)nR17;
• —COXR11;
• —XR11;
• —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 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 cyclic group containing up to 3 heteroatoms selected from N, O, or S;
• R17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• and
• each n is independently 0, 1, 2, 3, or 4.

A compound of the formula (I):

• prepared by the method comprising:
• a) treating a compound of the formula (II):
• under conditions effective to bring about chlorination and esterification, thereby providing a compound having the formula (III):
• b) reacting the compound of formula (III) with an amine under conditions effective to produce an amide of the formula (IV):
• c) subjecting the amide of formula (IV) to conditions effective to provide an amine of the formula (V):
• d) reacting the amine of formula (V) under conditions effective to provide a nitrated and protected piperazine of the formula (VI):
• e) subjecting the protected piperazine of the formula (VI) to conditions effective to provide a deprotected piperazine of the formula (VII):
• f) reacting the compound of formula (VII) with an aryl aldehyde under conditions effective to bring about cyclization, thereby providing a piperazine-imidazo[4,5-b]pyridine having the formula (VIII):
• g) reacting the free amine of the piperazine of the piperazine-imidazo[4,5-b]pyridine of the formula (VIII) under conditions effective to provide the compound of formula (I);
• wherein PG is hydrogen or an amine protecting group;
• 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 —CH2)nOR23;
• R3 is one of the following:
• each R3 also having up to three R10 substituents attached to a ring of R3 containing at least one N;
• R4, R5, R10, R18, R19, R20, 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;
• —XR13;
• or —COR13;
• and when 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;
• —R11XR12;
• —(CH2)nR17;
• —COXR11;
• —XR11;
• —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 —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;
• X is —O—, —NR12—, or —SOm—;
• each m is independently 0, 1, or 2;
• and
• each n is independently 0, 1, 2, 3, or 4.