Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrillary

Patent metadata

Field	Value
Publication number	US-9808542-B2
Application number	US-201515317333-A
Country	US
Kind code	B2
Filing date	Jun 9, 2015
Priority date	Jun 13, 2014
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The present invention is directed to pyrrolopyridine compounds of formula (I) or their pharmaceutically acceptable salts, which may be suitable for imaging tau aggregates, b-sheet aggregates, beta-amyloid aggregates or alpha-synuclein aggregates, and hence are useful in binding and imaging tau aggregates in Alzheimer's patients. More specifically, this invention relates to a method of using the compounds of this invention as tracers in positron emission tomography (PET) imaging to study tau deposits in brain in vivo to allow diagnosis of Alzheimer's disease and other neurodegenerative diseases characterized by tau pathology. The invention further relates to a method of measuring clinical efficacy of therapeutic agents for Alzheimer's disease and other neurodegenerative diseases characterized by tau pathology.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof wherein;
X represents CH, or N;
R represents hydrogen, or —C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R a ;
R 1 represents hydrogen, —C 1-6 alkyl, —CN, —(CH 2 ) n NH(CH 2 ) n N(R) 2 , —C 2-6 alkenyl, —(CH 2 ) n OR, or —(CH 2 ) n halogen;
R 2 represents —OC 1-6 alkyl, —C 2-6 alkenylR 3 —(CH 2 ) n OR, —(CH 2 ) n halogen, —O(CH 2 ) n halogen, —C 6-10 aryl, —C 5-10 heterocyclyl, —O(CH 2 ) n R a , —N(CH 3 )(CH 2 ) n OR, —NRC(O)R, —NH(CH 2 ) n halo, —NC(O)C 6-10 aryl, —NC(O)C 5-10 heterocyclyl, —N(CH 3 )(CH 2 ) n halogen, —C(O)NC 6-10 aryl, said alkyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
or an adjacent R 1 can combine with R 2 to form a nine to ten membered bicyclic ring together with the ring to which R 1 and R 2 are attached, optionally interrupted with N, S, and/or O, said bicyclic ring optionally substituted with 1 to 3 groups of R a ;
R 3 represents hydrogen, —C 1-6 alkyl, —(CH 2 ) n halogen, —(CH 2 ) n N(R) 2 , —(CH 2 ) n NR(CH 2 ) n N(R) 2 , —C 6-10 aryl, —C 5-10 heteroaryl, said alkyl, aryl, and heteroaryl optionally substituted with 1 to 3 groups of R a ;
R a represents —CN, CF 3 , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, C 6-10 aryl, —C 5-10 heterocyclyl, —CN, NO 2 , (CH 2 ) halogen, —O(CH 2 ) n halogen, (CH 2 ) n OR, —O(CH 2 ) n C 6-10 aryl, —(CH 2 ) n N(R) 2 , —C(O)N(R) 2 , —N(CH 3 )(CH 2 ) n OR, —NRCOR, —COR, —NH(CH 2 ) n halo, —N(CH 3 )(CH 2 ) n halogen, C(O)C 6-10 aryl, or —CO 2 R, said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R b ;
R represents hydrogen, —C 1-6 alkyl, —OR, —(CH 2 ) n N(R) 2 , or halogen; and
n represents 0-4.

2. The compound according to claim 1 wherein X is CH.

3. The compound according to claim 1 wherein X is N.

4. The compound according to claim 1 wherein R 2 is selected from the group consisting of —C 2-6 alkenylR 3 , —C 2-6 alkynylR 3 , —NC(O)C 6-10 aryl, —NC(O)C 5-10 heterocyclyl, —C 6-10 aryl, and —C 5-10 heterocyclyl said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a .

5. The compound according to claim 1 wherein an adjacent R 1 is combined with an R 2 to form a 9 to 10 membered bicycle ring, said ring optionally interrupted with N, S, and/or O, and said ring optionally substituted with 1 to 3 groups of R a .

6. The compound according to claim 5 wherein the bicycle formed is selected from the group consisting of optionally substituted pyrrolopyridinyl, furopyridinyl, naphthryidinyl, tetrahydronaphthyridinyl, quinazolinyl, quinolinyl, and isoquinolinyl.

7. The compound according to claim 1 wherein X is CH and R 2 is selected from the group consisting of —C 2-6 alkenylR 3 , —C 2-6 alkynylR 3 , —NC(O)C 6-10 aryl, —NC(O)C 5-10 heterocyclyl, —C 6-10 aryl, and —C 5-10 heterocyclyl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a and R 3 is selected from the group consisting of methyl, ethyl, propyl, (CH 2 ) n F, —(CH 2 ) n N(R) 2 , —(CH 2 ) n NR(CH 2 ) n N(R) 2 , optionally substituted phenyl, pyridyl and thiazolyl.

8. The compound according to claim 1 wherein X is CH and R 2 is combined with an adjacent R 1 to form a 9 to 10 membered bicycle ring together with the ring to which R 1 and R 2 are attached, said bicyclic ring optionally interrupted with N, S and/or O, said bicycle optionally substituted with 1 to 3 groups of R a .

9. The compound according to claim 8 wherein the bicycle ring formed is selected from the group consisting of optionally substituted pyrrolopyridinyl, furopyridinyl, naphthryidinyl, tetrahydronaphthyridinyl, quinolinyl, or isoquinolinyl.

10. The compound according to claim 7 wherein X is N, R 2 is selected from the group consisting of —C 2-6 alkenylR 3 , —C 2-6 alkynylR 3 , —NC(O)C 6-10 aryl, —NC(O)C 5-10 heterocyclyl, —C 6-10 aryl, and —C 5-10 heterocyclyl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a and R 3 is selected from the group consisting of methyl, ethyl, propyl, (CH 2 ) n F, —(CH 2 ) n N(R) 2 , —(CH 2 ) n NR(CH 2 ) n N(R) 2 , optionally substituted phenyl, pyridyl and thiazolyl.

11. The compound according to claim 1 wherein X is N and R 2 is combined with an adjacent R 1 to form a 9 to 10 membered bicycle ring together with the ring to which R 1 and R 2 are attached, said bicyclic ring optionally interrupted with N, S and/or O, said bicycle optionally substituted with 1 to 3 groups of R a .

12. The compound according to claim 1 which are isotopically labeled with 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 76 Br, 77 Br, 123 I, 124 I or 131 I.

13. The compound according to claim 1 presented by structural formula Ia:

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13 wherein R 2 is selected from the group consisting of —C 2-6 alkenylR 3 , —C 2-6 alkynylR 3 , C 6-10 aryl, —C 5-10 heterocyclyl, —NC(O) C 6-10 aryl, —NC(O) C 5-10 heterocyclyl, —N(CH 3 )(CH 2 ) n halogen, and C(O)NC 6-10 aryl, said aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a , and R 3 is selected from the group consisting of hydrogen, —(CH 2 ) n halogen, —(CH 2 ) n N(R) 2 , (CH 2 ) n NR(CH 2 ) n N(R) 2 , C 6-10 aryl, and —C 5-10 heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 groups of R a .

15. The compound according to claim 13 wherein R 2 combines with an adjacent R 1 to form a 9 to 10 membered bicycle ring together with the ring to which R 1 and R 2 are attached, said bicyclic ring optionally interrupted by N, S, O, said bicycle optionally substituted by 1 to 3 groups of R a .

16. The compound according to claim 13 which are isotopically labeled with 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 76 Br, 77 Br, 123 I, 124 I or 131 I.

17. The compound of claim 1 represented by structural formula II:

or a pharmaceutically acceptable salt there of wherein Ib=Ib1, Ib2, Ib3, or Ib4, and W, W 1 , W 2 , W 3 independently are selected from —CH— and —N— and R, R a and R b are as originally described.

18. The compound according to claim 1 represented by structural formula II:

wherein Ib is N

W, W 1 , W 2 , and W 3 are all —CH and R a is selected from the group consisting of —C 1-6 alkyl, —(CH 2 ) n halogen, —O(CH 2 ) n halogen, (CH 2 ) n OR, —(CH 2 ) n N(R) 2 , NO 2 , CN, —N(CH 3 )(CH 2 ) n OR, —NH(CH 2 ) n halo, and —N(CH 3 )(CH 2 ) n halogen-.

19. The compound according to claim 18 wherein R b is selected from the group consisting of hydrogen, C 1-6 alkyl, —OR, —(CH 2 ) n N(R) 2 , or halogen.

20. The compound according to claim 18 wherein R a is independently selected from the group consisting of hyd

Assignees

• Merck Sharp & Dohme

Inventors

• Walji Abbas W
• Hostetler Eric
• Greshock Thomas J
• Li Jing
• Moore Keith P
• Bennacef Idriss
• Mulhearn James
• Selnick Harold
• Wang Yaode
• Yang Kun
• Fu Jianmin

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K51/0455 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K51/0459

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title