US 2014/0005165 A1Published application

Substituted 3-azabicyclo[3.1.0]hexane derivatives useful as ccr2 antagonists

OwnerAnilkumar G. Nair, Jose S. Duca +3inventors

InventorsAnilkumar G. Nair, Jose S. Duca, Michael P. Dwyer, Joseph A. Kozlowski, Stuart B. Rosenblum

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Abstract

Disclosed are CCR2 antagonists of Formula (I) or pharmaceutically acceptable thereof, wherein R1, L1 and A are defined herein. Also disclosed are pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and compositions to treat diseases or disorders associated with CCR2 activity.

Claims14

Dependent claims

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
L1 is selected from the group consisting of:
(a) —C(O)—,
(b) —C(O)-heterocyclyl-,
(c) —C(O)-heterocyclyl-O—,
(d) —C(O)-heterocyclyl-N(R4)—,
(e) —C(O)-heterocyclyl-N(R4)C(O)—,
(f) —C(O)N(R4)—,
(g) —C(O)N(R4)—C1-6alkylenyl-,
(h) —C(O)N(R4)—C1-6alkylenyl-O—,
(i) —C(O)N(R4)—C1-6alkylenyl-C3-8cycloalkyl-,
(j) —C(O)N(R4)—C1-6alkylenyl-C(O)—N(R4)—,
(k) —C(O)N(R4)-heterocyclyl-,
(l) —C(O)N(R4)-heterocyclyl-C(O)—, and
(m) 1,3,4-oxadiazolyl,
wherein said heterocyclyl or cycloalkyl groups are unsubstituted or substituted with 1-3 R6 groups, and wherein heterocyclyl is a 4-7-membered ring containing 1-2 N heteroatoms;
Ring A is selected from the group consisting of:
(a) aryl,
(b) C3-8cycloalkyl,
(c) C3-8 cycloalkenyl,
(d) 5 or 6-membered heterocyclyl,
(e) 5 or 6-membered heterocyclenyl,
(f) 5 or 6-membered monocyclic heteroaryl,
(g) 9- or 10-membered cycloalkylaryl,
(h) 9- or 10-membered heterocyclylheteraryl,
(i) 9- or 10-membered heterocyclylaryl, and
(j) 9- or 10-membered heteroarylaryl,
wherein said heterocyclyl, heterocyclenyl, or heteroaryl rings have 1-4 hetero-atoms selected from the group consisting of O, N, and S;
and wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, heteroaryl, 9- or 10-membered cycloalkylaryl, 9- or 10-membered heterocyclylheteroaryl, 9- or 10-membered heterocyclylaryl, or 9- or 10-membered heteroarylaryl are unsubstituted or substituted with 1-3 R5 groups;
R1 is selected from the group consisting of:
(a) C1-6alkyl,
(b) C3-8cycloalkyl,
(c) C3-8cycloalkenyl,
(d) 5 or 6-membered heterocyclyl, and
(e) 7- or 8-membered bicycloalkyl,
wherein said alkyl, cycloalkyl, cylcoalkenyl, heterocyclyl, and 7- or 8-membered bicycloalkyl groups are unsubstituted or substituted with 1-3 R2 groups, and wherein said heterocyclyl, or heteroaryl rings have 1-4 hetero-atoms selected from the group consisting of O, N, and S;
each R2 is independently selected from the group consisting of:
(a) hydrogen,
(b) HO—,
(c) halo,
(d) C1-6alkyl,
(e) —C1-6alkyl-OH,
(f) —O—C1-6alkyl,
(g) aryl-C1-6alkyl-O—C1-6alkyl-,
(h) C2-6alkenyl,
(i) oxo,
(j) —NH—C(O)—C1-6alkyl,
(k) —CO2—C1-6alkyl,
(l) —NH—CO2—C1-6alkyl,
(m) —NH—C(O)-aryl,
(n) —NH—SO2—C3-8cycloalkyl,
(o) —NH-aryl,
(p) aryl,
(q) aryl-C1-6alkyl-,
(r) C3-8cycloalkyl,
(s) 5-7-membered heterocyclyl,
(t) 5-7-membered heterocyclenyl,
(u) 5 or 6-membered monocyclic heteroaryl, and
(v) 9-membered heteroarylaryl,
wherein said alkyl, aryl, cycloalkyl, heterocyclyl, heterocyclenyl and heteroaryl groups are unsubstituted or substituted with 1-3 R3 groups, and wherein said heterocyclyl, heterocyclenyl, or heteroaryl rings have 1-4 hetero-atoms selected from the group consisting of O, N and S,
each R3 is independently selected from the group consisting of:
(a) oxo,
(b) HO—,
(c) halo,
(d) C1-6alkyl,
(e) aryl,
(f) aryl-C1-6alkyl-,
(g) C1-6alkoxyl,
(h) aryl-C1-6alkyl-O—, and
(i) cyano;
R4 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, and
(c) CF3-phenyl-C1-3alkyl-;
each R5 is independently selected from the group consisting of:
(a) oxo,
(b) HO—,
(c) halo,
(d) C1-6alkyl,
(e) C1-6haloalkyl,
(f) aryl,
(g) aryl-C1-6alkyl-,
(h) C1-6alkoxyl,
(i) aryl-C1-6alkyl-O—, and
(j) cyano;
(k) F5S—;
each R6 is independently selected from the group consisting of:
(a) hydrogen,
(b) bromo,
(c) chloro,
(d) fluoro,
(e) methyl,
(f) ethyl,
(g) hydroxyl,
(h) cyano,
(i) oxo,
(j) amino, and
(k) C1-3alkylamino;
and
m is 0, 1, 2, or 3.

97 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/004,449Filed 14 Mar 2012
Priority: 17 Mar 2011
Published: 2 Jan 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 209/52
Condensed with one carbocyclic ring: condensed with a ring other than six-membered
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 401/08
Containing two hetero rings: linked by a carbon chain containing alicyclic rings
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…

Family

Application61/453,634Us provisional application · filed 17 Mar 2011
US 2014/0005165 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
L1 is selected from the group consisting of:
(a) —C(O)—,
(b) —C(O)-heterocyclyl-,
(c) —C(O)-heterocyclyl-O—,
(d) —C(O)-heterocyclyl-N(R4)—,
(e) —C(O)-heterocyclyl-N(R4)C(O)—,
(f) —C(O)N(R4)—,
(g) —C(O)N(R4)—C1-6alkylenyl-,
(h) —C(O)N(R4)—C1-6alkylenyl-O—,
(i) —C(O)N(R4)—C1-6alkylenyl-C3-8cycloalkyl-,
(j) —C(O)N(R4)—C1-6alkylenyl-C(O)—N(R4)—,
(k) —C(O)N(R4)-heterocyclyl-,
(l) —C(O)N(R4)-heterocyclyl-C(O)—, and
(m) 1,3,4-oxadiazolyl,
wherein said heterocyclyl or cycloalkyl groups are unsubstituted or substituted with 1-3 R6 groups, and wherein heterocyclyl is a 4-7-membered ring containing 1-2 N heteroatoms;
Ring A is selected from the group consisting of:
(a) aryl,
(b) C3-8cycloalkyl,
(c) C3-8 cycloalkenyl,
(d) 5 or 6-membered heterocyclyl,
(e) 5 or 6-membered heterocyclenyl,
(f) 5 or 6-membered monocyclic heteroaryl,
(g) 9- or 10-membered cycloalkylaryl,
(h) 9- or 10-membered heterocyclylheteraryl,
(i) 9- or 10-membered heterocyclylaryl, and
(j) 9- or 10-membered heteroarylaryl,
wherein said heterocyclyl, heterocyclenyl, or heteroaryl rings have 1-4 hetero-atoms selected from the group consisting of O, N, and S;
and wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, heteroaryl, 9- or 10-membered cycloalkylaryl, 9- or 10-membered heterocyclylheteroaryl, 9- or 10-membered heterocyclylaryl, or 9- or 10-membered heteroarylaryl are unsubstituted or substituted with 1-3 R5 groups;
R1 is selected from the group consisting of:
(a) C1-6alkyl,
(b) C3-8cycloalkyl,
(c) C3-8cycloalkenyl,
(d) 5 or 6-membered heterocyclyl, and
(e) 7- or 8-membered bicycloalkyl,
wherein said alkyl, cycloalkyl, cylcoalkenyl, heterocyclyl, and 7- or 8-membered bicycloalkyl groups are unsubstituted or substituted with 1-3 R2 groups, and wherein said heterocyclyl, or heteroaryl rings have 1-4 hetero-atoms selected from the group consisting of O, N, and S;
each R2 is independently selected from the group consisting of:
(a) hydrogen,
(b) HO—,
(c) halo,
(d) C1-6alkyl,
(e) —C1-6alkyl-OH,
(f) —O—C1-6alkyl,
(g) aryl-C1-6alkyl-O—C1-6alkyl-,
(h) C2-6alkenyl,
(i) oxo,
(j) —NH—C(O)—C1-6alkyl,
(k) —CO2—C1-6alkyl,
(l) —NH—CO2—C1-6alkyl,
(m) —NH—C(O)-aryl,
(n) —NH—SO2—C3-8cycloalkyl,
(o) —NH-aryl,
(p) aryl,
(q) aryl-C1-6alkyl-,
(r) C3-8cycloalkyl,
(s) 5-7-membered heterocyclyl,
(t) 5-7-membered heterocyclenyl,
(u) 5 or 6-membered monocyclic heteroaryl, and
(v) 9-membered heteroarylaryl,
wherein said alkyl, aryl, cycloalkyl, heterocyclyl, heterocyclenyl and heteroaryl groups are unsubstituted or substituted with 1-3 R3 groups, and wherein said heterocyclyl, heterocyclenyl, or heteroaryl rings have 1-4 hetero-atoms selected from the group consisting of O, N and S,
each R3 is independently selected from the group consisting of:
(a) oxo,
(b) HO—,
(c) halo,
(d) C1-6alkyl,
(e) aryl,
(f) aryl-C1-6alkyl-,
(g) C1-6alkoxyl,
(h) aryl-C1-6alkyl-O—, and
(i) cyano;
R4 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, and
(c) CF3-phenyl-C1-3alkyl-;
each R5 is independently selected from the group consisting of:
(a) oxo,
(b) HO—,
(c) halo,
(d) C1-6alkyl,
(e) C1-6haloalkyl,
(f) aryl,
(g) aryl-C1-6alkyl-,
(h) C1-6alkoxyl,
(i) aryl-C1-6alkyl-O—, and
(j) cyano;
(k) F5S—;
each R6 is independently selected from the group consisting of:
(a) hydrogen,
(b) bromo,
(c) chloro,
(d) fluoro,
(e) methyl,
(f) ethyl,
(g) hydroxyl,
(h) cyano,
(i) oxo,
(j) amino, and
(k) C1-3alkylamino;
and
m is 0, 1, 2, or 3.

97 more elements

Facts

Application

14/004,449Filed 14 Mar 2012

Priority

17 Mar 2011

Published

2 Jan 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 209/52
Condensed with one carbocyclic ring: condensed with a ring other than six-membered
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 401/08
Containing two hetero rings: linked by a carbon chain containing alicyclic rings
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…