US 2016/0107997 A1Published application

Cxcr7 receptor modulators

AssigneeActelion Pharmaceuticals Ltd.

InventorsHeinz FRETZ, Philippe GUERRY, Thierry KIMMERLIN, Francois LEHEMBRE, Julien POTHIER, Hervé SIENDT, Anja VALDENAIRE

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Abstract

The present invention relates to derivatives of formula (I) wherein (R1)n, R2a, R2b, R3a, R3b, R4, L1, L2, X, Y and Ar1 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as CXCR7 receptor modulators.

Claims20

Dependent claims

A compound of formula (I)

wherein
X represents NR5, and Y represents CHRY wherein RY represents hydrogen, or (C1-3)alkyl;
and
R3a and R3b together with the carbon atom to which they are attached to form a carbonyl group, or
two of R2a, R2b, R3a and R3b independently represent hydrogen, or (C1-3)alkyl;
and the remaining of R2a, R2b, R3a and R3b represent hydrogen;
or
X represents CHRX wherein RX represents hydrogen, or (C1-3)alkyl, and Y represents NR5;
and
R2a and R2b together with the carbon atom to which they are attached to form a carbonyl group, or
two of R2a, R2b, R3a and R3b independently represent hydrogen, or (C1-3)alkyl;
and the remaining of R2a, R2b, R3a and R3b represent hydrogen;
or
X represents NR5 and Y represents a direct bond;
R2a and R2b both represent hydrogen;
and R3a and R3b both represent hydrogen;
or
X represents NR5, Y represents —C(O)—;
and R2a, R2b, R3a and R3b all represent hydrogen;
or
X represents —C(O)—;
Y represents NR5, and R2a, R2b, R3a and R3b all represent hydrogen;
R5 represents
(C1-6)alkyl;
(C1-4)alkyl mono-substituted with (C1-3)alkoxy, cyano, vinyl;
ethynyl, or (C1-3)alkoxy-carbonyl;
—CO—R10 wherein R10 represents (C1-5)alkyl;
(C1-5)alkoxy;
phenyl;
phenyl-oxy-;
phenyl-(C1-3)alkyl-;
phenyl-(C1-3)-alkyl-oxy-;
(C3-6)cycloalkyl-(C1-3)alkyl;
(C3-4)alkenoxy;
(C3-4)alkynoxy;
(C1-3)fluoroalkyl;
(C1-3)fluoroalkoxy;
(C1-3)alkoxy-(C2-3)alkoxy;
(C1-3)alkoxy-(C1-3)alkyl;
(C3-6)cycloalkyl optionally having one ring oxygen atom, wherein said cycloalkyl is optionally mono- or di-substituted wherein the substituents independently are fluoro or (C1)fluoroalkyl;
unsubstituted 5-membered heteroaryl;
or —NR10aR10b wherein R10a and R10b independently represent hydrogen, (C1-4)alkyl or (C3-6)cycloalkyl, or R10a and R10b together with the nitrogen to which they are attached to form a 5- to 7-membered saturated ring;
—SO2—R11 wherein R11 represents (C1-5)alkyl or phenyl;
(C2-4)fluroroalkyl;
(C3-6)cycloalkyl optionally having one ring oxygen atom;
(C3-6)cycloalkyl-(C1-3)alkyl, wherein the (C3-6)cycloalkyl group optionally has one ring oxygen atom;
wherein said cycloalkyl is optionally substituted with one or two methyl substituents;
phenyl-(C0-3)alkyl-, or 5- or 6-membered heteroaryl-(C0-3)alkyl-, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, or cyano;
(R1)n represents one or two optional substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, or cyano;
L1 represents a one- or two-membered linker group selected from —NH—CH2—*;
—NR16a—CH2—* wherein R16a represents (C1-3)alkyl;
—NH—CHR16b—* wherein R16b represents (C1-3)alkyl;
—NH—CR16cR16d-* wherein R16c and R16d together with the carbon to which they are attached to form a (C3-6)cycloalkyl ring;
—CH2—NH—**;
—O—CH2—*;
—O—CHR17a-* wherein R17a represents (C1-3)alkyl;
—O—CR17bR17c-* wherein R17b and R17c together with the carbon to which they are attached to form a (C3-6)cycloalkyl ring;
—CH2—;
—CH2CH2—;
—CH═CH—;
and —CH═C(CH3)—*;
wherein the asterisks indicate the bond with which the group L1 is attached to the carbonyl group;
L2 represents —(C1-4)alkylene- or —(C3-4)alkenylene-;
Ar1 represents phenyl, or 5- or 6-membered heteroaryl;
wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from (C1-4)alkyl;
(C1-4)alkoxy;
(C1-3)fluoroalkyl;
(C1-3)fluoroalkoxy;
halogen;
cyano;
or NR18aR18b wherein R18a and R18b independently represent hydrogen or (C1-3)alkyl;
and
R4 represents
(C2-6)alkyl;
(C2-5)alkyl which is mono-substituted with (C1-4)alkoxy, benzyloxy, cyano, or hydroxy;
or disubstituted wherein the substituents are independently selected from (C1-3)alkoxy, or hydroxy
(C2-3)fluoroalkyl which is optionally further substituted with one hydroxy;
—(C2-4)alkylene-NR6R7, wherein R6 and R7 independently represent hydrogen;
(C1-4)alkyl;
—CO—(C1-4)alkoxy;
(C3-5)alkenyl;
(C3-4)alkynyl;
benzyl;
—SO2—(C1-3)alkyl;
(C2-3)fluoroalkyl;
or (C3-6)cycloalkyl or (C3-6)cycloalkyl-(C1-3)alkyl, wherein in the above groups the (C3-6)cycloalkyl group optionally contains one ring oxygen atom, and wherein said (C3-6)cycloalkyl group is optionally substituted with methyl;
—(C1-3)alkylene-CO—R8, wherein R8 represents (C1-4)alkoxy;
or R8 represents NR81R82 wherein R81 and R82 independently represent hydrogen or (C1-4)alkyl, or R81 and R82 together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally substituted with two fluoro substituents;
—(C1-3)alkylene-SO2—R9 wherein R9 represents (C1-3)alkyl, or amino;
(C3-6)cycloalkyl or (C3-6)cycloalkyl-(C1-3)alkyl, wherein the cycloalkyl group is optionally mono-substituted with —CO—(C1-4)alkoxy or hydroxy;
(C4-7)heterocyclyl or (C4-7)heterocyclyl-(C1-3)alkyl, wherein in the above groups the (C4-7)heterocyclyl independently has one or two ring heteroatoms independently selected from nitrogen, sulfur or oxygen;
wherein in the above groups said (C4-7)heterocyclyl independently is unsubstituted, or mono-, di-, or tri-substituted wherein the substituents are independently selected from:
one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen;
and/or
two methyl substituents attached to a ring carbon atom in alpha position to a ring nitrogen atom;
and/or
two oxo substituents at a ring sulfur ring atom;
and/or
(C1-4)alkyl or —CO—(C1-4)alkoxy attached to a ring nitrogen atom having a free valency;
and/or
two fluoro substituents attached to a ring carbon atom;
and/or
in case of a (C4-7)heterocyclyl-(C1-3)alkyl group, methyl attached to a ring carbon atom which is attached to the linking (C1-3)alkyl group;
2-oxo-2,3-dihydropyridin-4-yl-(C1-2)alkyl;
phenyl-(C1-3)alkyl-, or 5- or 6-membered heteroaryl-(C1-3)alkyl-, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, or cyano;
or a pharmaceutically acceptable salt thereof.

103 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I)

wherein
X represents NR5, and Y represents CHRY wherein RY represents hydrogen, or (C1-3)alkyl;
and
R3a and R3b together with the carbon atom to which they are attached to form a carbonyl group, or
two of R2a, R2b, R3a and R3b independently represent hydrogen, or (C1-3)alkyl;
and the remaining of R2a, R2b, R3a and R3b represent hydrogen;
or
X represents CHRX wherein RX represents hydrogen, or (C1-3)alkyl, and Y represents NR5;
and
R2a and R2b together with the carbon atom to which they are attached to form a carbonyl group, or
two of R2a, R2b, R3a and R3b independently represent hydrogen, or (C1-3)alkyl;
and the remaining of R2a, R2b, R3a and R3b represent hydrogen;
or
X represents NR5 and Y represents a direct bond;
R2a and R2b both represent hydrogen;
and R3a and R3b both represent hydrogen;
or
X represents NR5, Y represents —C(O)—;
and R2a, R2b, R3a and R3b all represent hydrogen;
or
X represents —C(O)—;
Y represents NR5, and R2a, R2b, R3a and R3b all represent hydrogen;
R5 represents
(C1-6)alkyl;
(C1-4)alkyl mono-substituted with (C1-3)alkoxy, cyano, vinyl;
ethynyl, or (C1-3)alkoxy-carbonyl;
—CO—R10 wherein R10 represents (C1-5)alkyl;
(C1-5)alkoxy;
phenyl;
phenyl-oxy-;
phenyl-(C1-3)alkyl-;
phenyl-(C1-3)-alkyl-oxy-;
(C3-6)cycloalkyl-(C1-3)alkyl;
(C3-4)alkenoxy;
(C3-4)alkynoxy;
(C1-3)fluoroalkyl;
(C1-3)fluoroalkoxy;
(C1-3)alkoxy-(C2-3)alkoxy;
(C1-3)alkoxy-(C1-3)alkyl;
(C3-6)cycloalkyl optionally having one ring oxygen atom, wherein said cycloalkyl is optionally mono- or di-substituted wherein the substituents independently are fluoro or (C1)fluoroalkyl;
unsubstituted 5-membered heteroaryl;
or —NR10aR10b wherein R10a and R10b independently represent hydrogen, (C1-4)alkyl or (C3-6)cycloalkyl, or R10a and R10b together with the nitrogen to which they are attached to form a 5- to 7-membered saturated ring;
—SO2—R11 wherein R11 represents (C1-5)alkyl or phenyl;
(C2-4)fluroroalkyl;
(C3-6)cycloalkyl optionally having one ring oxygen atom;
(C3-6)cycloalkyl-(C1-3)alkyl, wherein the (C3-6)cycloalkyl group optionally has one ring oxygen atom;
wherein said cycloalkyl is optionally substituted with one or two methyl substituents;
phenyl-(C0-3)alkyl-, or 5- or 6-membered heteroaryl-(C0-3)alkyl-, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, or cyano;
(R1)n represents one or two optional substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, or cyano;
L1 represents a one- or two-membered linker group selected from —NH—CH2—*;
—NR16a—CH2—* wherein R16a represents (C1-3)alkyl;
—NH—CHR16b—* wherein R16b represents (C1-3)alkyl;
—NH—CR16cR16d-* wherein R16c and R16d together with the carbon to which they are attached to form a (C3-6)cycloalkyl ring;
—CH2—NH—**;
—O—CH2—*;
—O—CHR17a-* wherein R17a represents (C1-3)alkyl;
—O—CR17bR17c-* wherein R17b and R17c together with the carbon to which they are attached to form a (C3-6)cycloalkyl ring;
—CH2—;
—CH2CH2—;
—CH═CH—;
and —CH═C(CH3)—*;
wherein the asterisks indicate the bond with which the group L1 is attached to the carbonyl group;
L2 represents —(C1-4)alkylene- or —(C3-4)alkenylene-;
Ar1 represents phenyl, or 5- or 6-membered heteroaryl;
wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from (C1-4)alkyl;
(C1-4)alkoxy;
(C1-3)fluoroalkyl;
(C1-3)fluoroalkoxy;
halogen;
cyano;
or NR18aR18b wherein R18a and R18b independently represent hydrogen or (C1-3)alkyl;
and
R4 represents
(C2-6)alkyl;
(C2-5)alkyl which is mono-substituted with (C1-4)alkoxy, benzyloxy, cyano, or hydroxy;
or disubstituted wherein the substituents are independently selected from (C1-3)alkoxy, or hydroxy
(C2-3)fluoroalkyl which is optionally further substituted with one hydroxy;
—(C2-4)alkylene-NR6R7, wherein R6 and R7 independently represent hydrogen;
(C1-4)alkyl;
—CO—(C1-4)alkoxy;
(C3-5)alkenyl;
(C3-4)alkynyl;
benzyl;
—SO2—(C1-3)alkyl;
(C2-3)fluoroalkyl;
or (C3-6)cycloalkyl or (C3-6)cycloalkyl-(C1-3)alkyl, wherein in the above groups the (C3-6)cycloalkyl group optionally contains one ring oxygen atom, and wherein said (C3-6)cycloalkyl group is optionally substituted with methyl;
—(C1-3)alkylene-CO—R8, wherein R8 represents (C1-4)alkoxy;
or R8 represents NR81R82 wherein R81 and R82 independently represent hydrogen or (C1-4)alkyl, or R81 and R82 together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally substituted with two fluoro substituents;
—(C1-3)alkylene-SO2—R9 wherein R9 represents (C1-3)alkyl, or amino;
(C3-6)cycloalkyl or (C3-6)cycloalkyl-(C1-3)alkyl, wherein the cycloalkyl group is optionally mono-substituted with —CO—(C1-4)alkoxy or hydroxy;
(C4-7)heterocyclyl or (C4-7)heterocyclyl-(C1-3)alkyl, wherein in the above groups the (C4-7)heterocyclyl independently has one or two ring heteroatoms independently selected from nitrogen, sulfur or oxygen;
wherein in the above groups said (C4-7)heterocyclyl independently is unsubstituted, or mono-, di-, or tri-substituted wherein the substituents are independently selected from:
one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen;
and/or
two methyl substituents attached to a ring carbon atom in alpha position to a ring nitrogen atom;
and/or
two oxo substituents at a ring sulfur ring atom;
and/or
(C1-4)alkyl or —CO—(C1-4)alkoxy attached to a ring nitrogen atom having a free valency;
and/or
two fluoro substituents attached to a ring carbon atom;
and/or
in case of a (C4-7)heterocyclyl-(C1-3)alkyl group, methyl attached to a ring carbon atom which is attached to the linking (C1-3)alkyl group;
2-oxo-2,3-dihydropyridin-4-yl-(C1-2)alkyl;
phenyl-(C1-3)alkyl-, or 5- or 6-membered heteroaryl-(C1-3)alkyl-, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, or cyano;
or a pharmaceutically acceptable salt thereof.

103 more elements