US 2023/0406885 A1 · CYCLIC PEPTIDES FOR TRAPPING INTERLEUKIN-1 BETA

Abstract

Provided are compounds of the Formula (I), or their pharmaceutically acceptable salts, wherein X1, X2, X3, A1, A2, R1-R7, R8a, R8b, R9a, R9b, R10 and R11 are as herein described. can trap IL-1β and are expected to have utility as therapeutic agents, for example, for treating cardiovascular disease and inflammatory disorders. The disclosure also provides pharmaceutical compositions which comprise the compounds disclosed herein or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cardiovascular disease and inflammatory disorders and for preparing pharmaceuticals for this purpose.

A compound of Formula (I)

wherein:
R1 is CH3C(O)NH—CH2CH2—O— or C1;
C1 is:
(i) a 5- to 6-membered monocyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
or
(ii) a 5- to 6-membered mono- or bicyclic, saturated cycloalkyl or heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
or
(iii) a 5- to 6-membered mono- or bicyclic cycloalkyl;
wherein C1 is unsubstituted or substituted by 1 to 3 RC1 substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, carboxy, C1-C3 alkoxy, and C2-C3 acyl;
R2 is H, C1-C3 alkyl, benzyl, or phenyl-CH2CH2—;
R3 is a 9- to 10-membered bicyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
wherein R3 is unsubstituted or substituted by 1 to 3 R3a substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy and C1-C3 alkoxy;
R4 is C1-C3 alkyl, HO2C—(CH2)m—, H2NC(O)—(CH2)m—, (CH3)2NC(O)—(CH2)m—, or tetrazolyl-(CH2)m—;
R5 is amino, H2N(CH2)n—, H2NC(O)—(CH2)n—, CH3C(O)NH—, CH3C(O)NH(CH2)n—, C5, or C5—CH2—,
C5 is:
(ii) a 5- to 6-membered monocyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
(ii) a 9- to 10-membered bicyclic aryl or heteroaryl, wherein said bicyclic heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S;
(iii) a 5- to 6-membered monocyclic or 9- to 10-membered heterocycloalkyl, wherein said heterocycloalkyl is saturated or partially unsaturated, and contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
(iv) a 5- to 6-membered monocyclic cycloalkyl;
(v) 2,3-dihydroindolyl;
wherein C5 is unsubstituted or substituted by 1 to 3 RC5 substituents independently selected from the group consisting of halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N—(CH2)k—, H2NC(O)—(CH2)k—, H2C═CH—CH2O—, and phenyl;
R6 is H, C1-C5 alkyl, H2N(CH2)p—, HOCH2—, (CH3)2NCH2—, H3CO—(CH2)q—, or C6—CH2—;
C6 is 5- or 6-membered monocyclic, saturated heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
and wherein C6 is unsubstituted or substituted by 1 to 3 RC6 substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy and C1-C3 alkoxy;
R7 is H or C1-C3 alkyl;
R8a is H, C1-C5 alkyl, HOCH2—, H2N(CH2)r—, (CH3)3N+(CH2)r—, or CH3C(O)NH(CH2)r—;
R8b is H or C1-C3 alkyl;
R9a is H or C1-C3 alkyl;
R9b is H, C1-C5 alkyl, C9—CH2—, or C9—CH2CH2—;
C9 is:
(i) a 5- to 6-membered monocyclic aryl or heteroaryl, wherein said heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
or
(ii) a 5- to 6-membered monocyclic, saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
wherein C9 is unsubstituted or substituted by 1 to 3 RC9 substituents independently selected from the group consisting of halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N—(CH2)k—, H2NC(O)—(CH2)k—, H2NCH2CH2O—, CH3C(O)NH—CH2CH2O—, and morpholinyl-CH2CH2O—;
R10 is H, halo, or C1-C3 alkyl;
R11 is H, halo, or C1-C3 alkyl;
each occurrence of subscript k is independently 1 or 2;
subscript m is 1 or 2;
subscript n is 1, 2, 3, or 4;
subscript p is 1, 2, 3, or 4;
subscript q is 1 or 2;
subscript r is 1, 2, 3, or 4;
X1, X2, and X3 are independently C(H) or N;
and
A1 and A2 are independently selected from the group consisting of HO2C—, H2NC(O)—, CH3C(O)N(H)—, H2NS(O)2—, CH3S(O)2N(H)—, tetrazolyl, and 5-oxo oxadiazolyl;
or
a pharmaceutically acceptable salt thereof.

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Cyclic peptides for trapping interleukin-1 beta

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Cyclic peptides for trapping interleukin-1 beta

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Abstract

Claims28