Pyridine derivatives

Patent metadata

Field	Value
Publication number	US-9533981-B2
Application number	US-201314078612-A
Country	US
Kind code	B2
Filing date	Nov 13, 2013
Priority date	Sep 30, 2011
Publication date	Jan 3, 2017
Grant date	Jan 3, 2017

Abstract

The present application provides novel pyridine compounds and pharmaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. These compounds are useful in inhibiting CYP17 activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with CYP17 activity. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer, such as prostate cancer.

First claim

What is claimed is:

1. A compound of formula (I) of the structure:

wherein:
A is phenyl optionally substituted with one or more of optionally substituted alkyl, halogen, OH, NH 2 , alkylamino-, di(alkyl)amino-, cyano, COOH, (alkoxy)carbonyl-, alkylcarboxy-, (alkyl)carboxamido-, alkylsulfonyl, —C(O)NH 2 , (alkyl)amido-, di(alkyl)amido-, NO 2 , or alkoxy, or A is optionally substituted 5-membered or 6-membered heteroaryl group which contains at least one ring hetero atom selected from the hetero atoms oxygen and nitrogen, wherein the optional substituent is one or more of optionally substituted alkyl, F, Cl, OH, NH 2 , alkylamino-, di(alkyl)amino-, cyano, COOH, (alkoxy)carbonyl-, alkylcarboxy-, alkylsulfonyl, —C(O)NH 2 , (alkyl)amido-, di(alkyl)amido-, NO 2 , or alkoxy;
B is optionally substituted monocyclic 5-membered or 6-membered heteroaryl group which contains at least one ring atom selected from the heteroatoms oxygen, sulphur, and nitrogen, wherein the heteroaryl B is optionally substituted with one or more of optionally substituted alkyl, F, Cl, OH, NH 2 , alkylamino-, di(alkyl)amino-, cyano, COOH, (alkoxy)carbonyl-, alkylcarboxy-, (alkyl)carboxamido-, alkylsulfonyl, —C(O)NH 2 , (alkyl)amido-, di(alkyl)amido-, NO 2 , or alkoxy;
Q is O or NH;
R 1 is:
(a) C 1 to C 4 alkyl; or
(b) two or three methylene fragments that are joined to a carbon atom at the 3-position of the pyridine ring;

or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound according to claim 1 , wherein A is optionally substituted pyridine.

3. The compound according to claim 1 , wherein B is an optionally substituted pyridine.

4. The compound according to claim 1 , wherein B is of the structure:

wherein:
X and Y are independently selected from the group consisting of CR 23 and N;
Z is NR 24 , O or S;
each R 23 is, independently, H, F, Cl, CH 3 , CF 3 or CN; and
R 24 is H or C 1 to C 4 alkyl.

5. The compound according to claim 4 , wherein B is of the structure:

6. The compound according to claim 4 , wherein B is:

7. The compound according to claim 6 , wherein B is:

8. The compound according to claim 7 , wherein B is:

9. The compound according to claim 4 , wherein B is:

10. The compound according to claim 9 , wherein B is:

11. The compound according to claim 4 , wherein B is:

12. The compound according to claim 1 , wherein O represents oxygen.

13. The compound according to claim 1 , in the form of an acid salt.

14. The compound according to claim 13 , wherein said acid is selected from the group consisting of acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, trifluoroacetic, and camphorsulfonic acid.

15. The compound according to claim 1 , which is:
6′-(1-hydroxy-1-pyridin-4-ylethyl)-3,3′-bipyridine-6-carbonitrile;
5-[5-(1-hydroxy-1-pyridin-4-yl-ethyl)thien-2-yl]-1-methyl-pyridin-2(1H)-one;
(R)-5-[5-(1-Hydroxy-1-pyridin-4-yl-ethyl)-thiophen-2-yl]-1-methyl-1H-pyridin-2-one;
(S)-5-[5-(1-Hydroxy-1-pyridin-4-yl-ethyl)-thiophen-2-yl]-1-methyl-1H-pyridin-2-one;
1-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-propan-1-ol;
(R)-1-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-propan-1-ol;
(S)-1-[2-(1H-pyrazol-4-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-propan-1-ol;
1-[2-(6-fluoropyridin-3-yl)-1,3-thiazol-5-yl]-1-(pyridin-4-yl)-ethanol;
4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-hydroxy-1-(pyridin-4-yl)propyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrole-2-carbonitrile;
1-(5-(1H-pyrazol-4-yl)oxazol-2-yl)-1-(pyridin-4-yl)propan-1-ol;
5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)furan-2-yl)-1-methylpyridin-2(1H)-one;
5-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)oxazol-2-yl)-1-methylpyridin-2(1H)-one;
1-(6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridin]-6-yl)pentan-1-one; or
1-(pyridin-4-yl)-1-(2-(pyrimidin-5-yl)thiazol-5-yl)ethanol.

16. The compound according to claim 1 , which is:
4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-hydroxy-1-(pyridin-4-yl)propyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-hydroxy-1-(pyridin-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrole-2-carbonitrile;
4-(5-(1-amino-1-(pyridin-4-yl)ethyl)thiazol-2-yl)-1H-pyrrole-2-carbonitrile;
5-(5-(1-amino-1-(pyridin-4-yl)ethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one; or
1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-amine.

17. The compound according to claim 1 , wherein the pharmaceutically acceptable salt is the hydrochloride, 4-methylbenzene sulfonic acid, benzene sulfonic acid, methanesulfonic acid, sulfuric acid or nitric acid salt.

18. The compound according to claim 1 , which is 1-(2-(4-fluorophenyl)-thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol.

19. The compound 1-(2-(5-cyano-1H-pyrrol-3-yl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl acetate, or a pharmaceutically acceptable salt or prodrug thereof.

20. A method for inhibiting CYP17, said method comprising administering a therapeutically effective amount of a compound of claim 1 or claim 19 to a patient in need thereof.

21. A method of treating cancer in a patient, said method comprising administering a compound of claim 1 or claim 19 to said patient, wherein said cancer is prostate cancer.

Assignees

• Asana Biosciences Llc

Inventors

• Smith Roger A
• Laping Nicholas James
• Venkatesan Aranapakam M
• Kethiri Raghava Reddy
• Venkateshappa Chandregowda
• Kulkarni Bheemashankar
• Dewang Purushottam
• Kristam Rajendra
• Devraj Rajesh

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D213/30

  Oxygen atoms · CPC title

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title