Trk-INHIBITING COMPOUND

Patent metadata

Field	Value
Publication number	US-2016000783-A1
Application number	US-201414768727-A
Country	US
Kind code	A1
Filing date	Feb 18, 2014
Priority date	Feb 19, 2013
Publication date	Jan 7, 2016
Grant date	—

Abstract

The present invention provides a drug containing a compound having Trk-inhibiting activity as an active ingredient in prophylaxis and/or therapy for Trk-related diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease. A compound represented by the general formula (I), wherein all symbols represent the same meanings as described in the specification, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof is useful as a drug component having Trk-inhibiting activity in prophylaxis and/or therapy of diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease.

First claim

1 . A compound represented by the general formula I):

wherein:
a ring Cy 1 represents a C3-10 monocyclic carbocycle or bicyclic carbocycle or a 4- to 10-membered monocyclic heterocycle or bicyclic heterocycle;
a ring Cy 2 represents a 4- to 10-membered monocyclic heterocycle or bicyclic heterocycle excluding a heterocycle 1,3-thiazol-5-yl group;
R 1 represents:
(1) a halogen;
(2) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group optionally substituted with a substituent selected from the group consisting of (i) a halogen and (ii) a hydroxy group;
(3) a C5-6 monocyclic carbocycle optionally substituted with one or two R 5 groups;
(4) a 5- to 6-membered monocyclic heterocycle optionally substituted with one or two R 5 groups;
(5) —S(O) m1 —R 6 ;
(6) —SO 2 NR 7 R 8 ;
(7) —C(O)OR 9 ;
(8) —NR 10 C(O)R 11 ;
(9) —C(O)NR 12 R 13 ;
(10) —OR 14 ;
(11) —NR 15 R 16 ;
(12) a cyano group; or
(13) a nitro group;
R 5 represents:
(1) a halogen;
(2) —S(O) m2 —R 17 ;
(3) —SO 2 NR 18 R 19 ;
(4) —C(O)OR 20 ;
(5) —NR 21 C(O)R 22 ;
(6) —C(O)NR 23 R 24 ;
(7) —OR 25 ;
(8) —NR 26 R 27 ;
(9) a cyano group;
(10) a nitro group; or
(11) a C1-3 alkyl group optionally substituted with a substituent selected from the group consisting of (i) a halogen, (ii) a hydroxy group and (iii) an oxo group;
when two R 5 groups are present, the R 5 groups may be independently the same or different;
when, further, two R 5 groups are respectively and independently a C1-3 alkyl group or a hydroxy group and the R 5 groups are attached to carbon atoms adjacent to each other on the C5-6 monocyclic carbocycle or the 5- to 6-membered monocyclic heterocycle, the R 5 groups may together form a ring;
R 6 to R 27 respectively and independently represent (1) a hydrogen atom or (2) a C1-6 alkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
when R 18 and R 19 are respectively and independently a C1-6 alkyl group, R 18 and R 19 groups may together form a ring;
R 2 represents:
(1) a halogen;
(2) a C1-6 alkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
(3) a C3-6 cycloalkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
(4) a C1-6 alkoxy group optionally substituted with a halogen;
(5) —NR 28 R 29 ;
(6) a 3- to 7-membered monocyclic heterocycle; or
(7) —O-(3- to 7-membered monocyclic heterocycle);
R 28 and R 29 respectively and independently represent (1) a hydrogen atom or (2) a C1-6 alkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
A 1 and A 2 respectively and independently represent ═CR 3 — or ═N—;
A 3 , A 4 , A 5 and A 6 respectively and independently represent ═CR 4 — or ═N—;
R 3 and R 4 respectively and independently represent a hydrogen atom or a halogen;
m1 represents an integer of 0 to 2;
m2 represents an integer of 0 to 2;
p represents an integer of 0 to 7;
q represents an integer of 0 to 7;
r represents an integer of 0 to 2;
provided that when p, q and r respectively represent an integer of 2 or more, R 1 , R 2 and R 3 groups may be respectively and independently the same or different, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof.

2 . The compound according to claim 1 , wherein the ring Cy 2 is a 5- to 10-membered monocyclic aromatic heterocycle or bicyclic aromatic heterocycle excluding a heterocycle 1,3-thiazol-5-yl group.

3 . The compound according to claim 1 , wherein the ring Cy 2 is a pyridine ring, a pyrimidine ring, a pyrazolopyrimidine ring, an imidazopyridazine ring, an imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine ring or a pyrazolopyridine ring.

4 . The compound according to claim 1 ,
wherein one of A 1 and A 2 is ═N— and the other is ═CH— or both are ═N— and A 3 , A 4 , A 5 and A 6 are ═CH—.

5 . The compound according to claim 1 , wherein the general formula (I) is represented by the general formula (I-i) or the general formula (I-ii):

wherein R 2-a represents the same meaning as R 2 ; q-a represents an integer of 0 to 3; t represents an integer of 0 to 4; and other symbols represent the same meanings as those described in claim 1 , provided that when q-a and t represent an integer of 2 or more, R 2-a and R 4 groups may be respectively and independently the same or different.

6 . The compound according to claim 1 , wherein the general formula (I) is represented by the general formula (I-iii) or the general formula (I-iv):

wherein R 2-b represents the same meaning as R 2 ; q-b represents an integer of 0 to 4; and other symbols represent the same meanings as those described in claims 1 and 5 , provided that when q-b represents an integer of 2 or more, R 2-b groups may be respectively and independently the same or different.

7 . The compound according to claim 1 , wherein the ring Cy 1 is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle.

8 . The compound according to claim 7 , wherein the ring Cy 1 is a benzene ring, a pyridine ring or a pyrazole ring.

9 . The compound according to claim 1 , which is:
(1) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea; (2) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea; (3) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea; (4) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea; (5) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea; (6) 1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea; (7) 1-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea; (8) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea; (9) 1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea; (10) 1-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea; (11) 1-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea; (12) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea; (13) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea; (14) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea; (15) 1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyl]urea; (16) 1

Assignees

• Ono Pharmaceutical Co

Inventors

• Takeuchi Jun
• Itadani Satoshi
• Hashimura Kazuya
• Ikura Masahiro
• Higashino Masato
• Yasuhiro Tetsuya
• Nagaura Takeshi

Classifications

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/136 Primary

  having the amino group directly attached to the aromatic ring, e.g. benzeneamine · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• A61K31/663

  Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid · CPC title