4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
The present invention relates to Gonadotropin Releasing Hormone (GnRH, also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.
1. A compound of the formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
R 1 and R 2 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; or R 1 and R 2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R 1 and R 2 is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —(CH 2 ) n OR 23 ;
R 3 is one of the following:
each R 3 also having up to three R 10 substituents attached to a ring of R 3 containing at least one N;
R 4 , R 5 , R 10 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl;
each R 6 is independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; —NR 13 R 14 ; —C(OH)(CF 3 ) 2 ; —CH(CF 3 ) 2 ; C(CF 3 ) 3 ; —XR 13 ; or —COR 13 ; and when two R 6 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 R 6 groups is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —CH 2 ) n OR 23 ;
R 7 and R 9 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; —R 11 XR 12 ; —(CH 2 ) n R 17 ; —COXR 11 ; —XR 11 ; —CO 2 R 11 ; or —CONR 11 R 12 ;
R 8 is hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; —(CH 2 ) m CO 2 R 11 ; or —(CH 2 ) m CONR 11 R 12 ;
R 11 and R 12 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; or R 11 and R 12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
R 13 and R 14 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; aryl; or aryl optionally substituted with one to three substituents selected from halogen, R 15 , —OR 15 , or —NR 15 R 16 ; or R 13 and R 14 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 R 13 and R 14 is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —CH 2 ) n OR 23 ;
R 15 and R 16 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; or both R 15 and R 16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
R 17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
X is —O—, —NR 12 —, or —SO m —;
each m is independently 0, 1, or 2; and
each n is independently 0, 1, 2, 3, or 4.
2. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein Ar is phenyl.
3. The compound or pharmaceutically acceptable salt of the compound of claim 2 , wherein one R 6 substituent is attached at the 4 position of phenyl.
4. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 1 is methyl and R 2 is hydrogen.
5. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 4 is methyl or ethyl and R 5 is hydrogen.
6. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein when R 4 is other than hydrogen, the compound or pharmaceutically acceptable salt of the compound is the S-enantiomer with respect to the carbon to which 4 is bound.
7. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 6 is independently hydrogen, ethyl, t-butyl, —N(CH 2 CH 3 ) 2 , pyrrolidine, 2-hydroxymethylpyrrolidine, or isopropyl.
8. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 3 is
9. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 3 is
10. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein
R 2 , R 5 , R 18 , R 19 , R 20 , R 21 , R 22 , R 24 , R 25 , R 26 , and R 27 are each hydrogen;
R 1 and R 4 are each independently hydrogen, methyl, or ethyl;
Ar is phenyl;
one R 6 is attached at the 4-position of phenyl;
each R 6 is ethyl, t-butyl, —N(CH 2 CH 3 ) 2 , pyrrolidine, 2-hydroxymethylpyrrolidine, or isopropyl; and
R 3 is
11. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein the compound is
6-{4-[2-(4-tert-butyl-phenyl)-1H-imidazo[4,5-c]pyridin-4-yl]-piperazin-1-ylmethyl}quinoxaline;
6-{4-[2-(4-tert-butyl-phenyl)-1H-imidazo[4,5-c]pyridin-4-yl]-piperazin-1-ylmethyl}-1,4-dihydroquinoxaline-2,3-dione;
2-{4-[2-(4-tert-butyl-phenyl)-1H-imidazo[4,5-c]pyridin-4-yl]-piperazin-1-ylmethyl}-quinoxaline;
2-(4-tert-butyl-phenyl)-4-[4-(2-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-1H-imidazo[4,5-c]pyridine;
2-(4-tert-butyl-phenyl)-4-[4-(1,2-dimethyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-1H-imidazo[4,5-c]pyridine;
5-{4-[2-(4-tert-butyl-phenyl)-1H-imidazo[4,5-c]pyridin-4-yl]-piperazin-1-ylmethyl}-1H-pyrimidine-2,4-dione; or
5-{4-[2-(4-tert-butyl-phenyl)-1H-imidazo[4,5-c]pyridin-4-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione.
12. A compound of the formula (Ia):
or a pharmaceutically acceptable salt thereof,
wherein
R 1 and R 2 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; or R 1 and R 2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R 1 and R 2 is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —(CH 2 ) n OR 23 ;
R 3 is one of the following:
each R 3 also having up to three R 10 substituents attached to a ring of R 3 containing at least one N;
R 4 , R 5 , R 10 , and R 23 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl;
each R 6 is independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; —NR 13 R 14 ; —C(OH)(CF 3 ) 2 ; —CH(CF 3 ) 2 ; —C(CF 3 ) 3 ; —XR 13 ; or —COR 13 ; and when two R 6 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 R 6 groups is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —(CH 2 ) n OR 23 ;
R 7 and R 9 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; R 11 XR 12 ; —(CH 2 ) n R 17 ; —COXR 11 ; —XR 11 ; —CO 2 R 11 ; or —CONR 11 R 12 ;
R 8 is hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; —(CH 2 ) m CO 2 R 11 ; or —(CH 2 ) m CONR 11 R 12 ;
R 11 and R 12 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; or R 11 and R 12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
R 13 and R 14 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 —, —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; aryl; or aryl optionally substituted with one to three substituents selected from halogen, R 15 , —OR 15 , or —NR 15 R 16 ; or R 13 and R 14 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 R 13 and R 14 is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —CH 2 ) n OR 23 ;
R 15 and R 16 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; or both R 15 and R 16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
R 17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
X is —O—, —NR 12 —, or —SO m —;
each m is independently 0, 1, or 2; and
each n is independently 0, 1, 2, 3, or 4.
13. The compound or pharmaceutically acceptable salt of the compound of claim 12 , wherein
R 1 and R 4 are each independently hydrogen, methyl, or ethyl;
R 2 and R 5 are hydrogen;
one R 6 is attached at the 4-position of phenyl;
each R 6 is ethyl, t-butyl, —N(CH 2 CH 3 ) 2 , pyrrolidine, 2-hydroxymethylpyrrolidine, or isopropyl; and
R 3 is
14. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier.
15. The composition of claim 14 , further comprising a therapeutic agent selected from the group consisting of androgen, estrogen, progesterone, antiestrogen, antiprogestogen, testosterone, angiotensin-converting enzyme inhibitor, angiotensin II-receptor antagonist, renin inhibitor, bisphosphonate, growth hormone secretagogue, 5a-reductase 2 inhibitor, a 5a-reductase 1 inhibitor, a dual inhibitor of 5a-reductase 1 and 5a-reductase 2, antiandrogen, alpha-1 blockers, growth hormone, and luteinizing hormone releasing compound; or a combination thereof.
16. The composition of claim 14 , wherein the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
17. A compound of the formula (I):
prepared by the method comprising:
a) reacting a compound of the formula (II):
with an aryl acid under conditions effective to bring about cyclization, thereby providing an imidazo[4,5-c]pyridine having the formula (III):
b) treating the imidazo[4,5-c]pyridine (III) under conditions effective to bring about chlorination, thereby providing a 4-chloro-imidazo[4,5-c]pyridine having the Formula (IV):
c) reacting the 4-chloro-imidazo[4,5-c]pyridine (IV) with a piperazine under conditions effective to produce a 4-piperazine-imidazo[4,5-c]pyridine having the formula (V):
and
d) reacting the free amine of the 4-piperazine-imidazo[4,5-c]pyridine of the formula (V) under conditions effective to provide the compound of formula (I);
wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl;
R 1 and R 2 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; or R 1 and R 2 may together form a three- to seven-membered cycloalkyl group, wherein the cycloalkyl group formed by R 1 and R 2 is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —CH 2 ) n OR 23 ;
R 3 is one of the following:
each R 3 also having up to three R 10 substituents attached to a ring of R 3 containing at least one N;
R 4 , R 5 , R 10 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl;
each R 6 is independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or —CON(R 23 ) 2 ; —NR 13 R 14 ; —C(OH)(CF 3 ) 2 ; —CH(CF 3 ) 2 ; —C(CF 3 ) 3 ; —XR 13 ; or —COR 13 ; and when two R 6 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 R 6 groups is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —(CH 2 ) n OR 23 ;
R 7 and R 9 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; —R 11 XR 12 ; —(CH 2 ) n R 17 ; —COXR 11 ; —XR 11 ; —CO 2 R 11 ; or —CONR 11 R 12 ;
R 8 is hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; —(CH 2 ) m CO 2 R 11 ; or —(CH 2 ) m CONR 11 R 12 ;
R 11 and R 12 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; or R 11 and R 12 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
R 13 and R 14 are each independently hydrogen; linear or branched (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , or CON(R 23 ) 2 ; aryl; or aryl optionally substituted with one to three substituents selected from halogen, —R 15 , —OR 15 , or —NR 15 R 16 ; or R 13 and R 14 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 R 13 and R 14 is optionally substituted with halogen, —N 3 , —NO 2 , —CN, —OR 23 , —SR 23 , —SO 2 R 23 , —SO 2 N(R 23 ) 2 , —N(R 23 ) 2 , —COR 23 , —CO 2 R 23 , —NR 23 CO 2 R 23 , —NR 23 COR 23 , —NR 23 CON(R 23 ) 2 , —CON(R 23 ) 2 , or —CH 2 ) n OR 23 ;
R 15 and R 16 are each independently hydrogen; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl, or (C 1 -C 6 )-alkynyl; or both R 15 and R 16 may together form a three- to seven-membered heterocyclic group containing up to 3 heteroatoms selected from N, O, or S;
R 17 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
X is —O—, —NR 12 —, or —SO m —;
each m is independently 0, 1, or 2; and
each n is independently 0, 1, 2, 3, or 4.