US 12,735,397 B2 · IL-17A modulators

Abstract

The present invention relates to compounds that are IL-17A modulators. The compounds have the structural Formula I as shown below, wherein X1, X2, X3, X4, Y, R1, R2, R3, and R4 are as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with modulation of IL-17A activity.

A compound of Formula I

wherein:
two of X1, X2, X3, and X4 are CR5, and two are N;
or three of X1, X2, X3, and X4 are CR5, and the other is N;
Y is heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of halo, C1-4alkyl, C1-4alkoxy, and C1-4haloalkyl;
R1 and R2:
(A) are both phenyl optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-4alkyl, C1-4alkoxy, and C1-4haloalkyl, and wherein the phenyl groups are optionally linked by a bond or a C1-2alkylene moiety;
OR
(B) together with the carbon atom to which they are attached form a 4- to 10-membered cycloalkyl or a 4- to 10-membered heterocyclyl ring, wherein the cycloalkyl or heterocyclyl ring:
a. is optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, and C1-4haloalkoxy;
b. optionally comprises one or two C═C double bonds;
c. is optionally bridged by a C1-3alkylene group connecting two carbon atoms of the ring;
and
d. is optionally spiro-attached to a C3-5cycloalkyl group;
R3 is hydrogen, fluoro, or C1-4alkyl;
R4 is:
(A) a 5- to 10-membered heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C (O) NR8R9, CO2R10, and C1-3alkylene-R11;
(B) 5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, oxo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano NR6R7, C(O)NR8R9, CO2R10, and C1-3alkylene-R11;
(C) a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl ring, each of which rings is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, oxo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9, CO2R10, and C1-3alkylene-R11;
or
(D) a partially unsaturated heterocyclic ring, optionally fused to a 5- to 6-membered heteroaryl ring and optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halo, oxo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9, and CO2R10;
R5 is hydrogen, fluoro, chloro, methyl, methoxy, or trifluoromethyl;
R11 is hydroxy, halo, C1-4alkoxy, cyano, NR12R13, C(O)R14, aryl or heteroaryl;
R14 is hydroxy, C1-4alkyl, C1-4alkoxy or NR15R16;
R6, R7, R8, R9, R10, R12, and R13 are independently hydrogen or C1-4alkyl;
R15 and R16 are independently hydrogen or C1-4alkyl;
or
R15 and R16, taken together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclyl ring, the ring optionally containing a further heteroatom selected from the group consisting of O, S, and N and the ring being optionally substituted with C1-4alkyl;
or a pharmaceutically acceptable salt thereof.

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IL-17A modulators

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IL-17A modulators

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Abstract

Claims15