US 11,878,020 B2
Modulators of Rho-associated protein kinase
Clifford D. Jones, Macclesfield (GB); Peter Bunyard, Macclesfield (GB); Gary Pitt, Macclesfield (GB); Liam Byrne, Macclesfield (GB); Thomas Pesnot, Macclesfield (GB); and Nicolas E. S. Guisot, Macclesfield (GB)
Assigned to Redx Pharma PLC, Macclesfield (GB)
Filed by Redx Pharma PLC, Alderley Edge (GB)
Filed on Aug. 26, 2022, as Appl. No. 17/896,626.
Application 17/896,626 is a continuation of application No. 16/964,904, granted, now 11,497,751, previously published as PCT/GB2019/050215, filed on Jan. 25, 2019.
Claims priority of application No. 1801226 (GB), filed on Jan. 25, 2018.
Prior Publication US 2023/0021916 A1, Jan. 26, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/538 (2006.01); A61K 31/4196 (2006.01); A61K 31/5377 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01)
CPC A61K 31/538 (2013.01) [A61K 31/4196 (2013.01); A61K 31/5377 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 413/14 (2013.01)] 20 Claims
 
1. A compound of formula (I) and pharmaceutically acceptable salts thereof:

OG Complex Work Unit Chemistry
 wherein

OG Complex Work Unit Chemistry
A1, A2 or A3 are each independently selected from the group consisting of C—H, C—F, C—Cl, C-Me, C-Et, C-i-Pr, C-cyclopropyl, C-ethenyl, C-propenyl, C—CN, C—CF3, and N;
B represents a 5 or 6 membered carbocyclic ring which is aromatic or unsaturated, a 5 or 6 membered heterocyclic ring which is aromatic or unsaturated, a 9 or 10 membered carbocyclic bicyclic ring system, or a 9 or 10 membered heterocyclic bicyclic ring system; wherein the bicyclic ring system is either aromatic or one of the rings within the bicyclic ring system is aromatic or unsaturated and the other ring is saturated;
R1 is L-R2, wherein
 L is a bond or -L1-L2-,
 wherein L1 is selected from the group consisting of a bond, —(CRARB)1-3—, —O(CRARB)1-3—, —(CRARB)0-3O—, and —NRC(CRARB)1-3—; and
 L2 is selected from the group consisting of a bond, —(CRARB)1-3—, —O—, —NRD—, —C(O)NRD—, —NRDC(O)—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)2NRD—, —NRDS(O)2—, —S(O)2—, —S(O)(NRD)—, —NRDC(O)NRE—, —OC(O)NRD—, and —C(O)NRDS(O)2—; and
R2 is selected from the group consisting of H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with —ORF, C1-6 alkyl substituted with —NRFRG, C1-4 haloalkyl substituted with —ORF, C3-8 cycloalkyl substituted with OH, C1-4 alkyl substituted with 3 to 8 membered heterocycloalkyl, C1-4 alkyl substituted with 6 membered heteroaryl, —(CRHRI)1-3ORF, —(CRHRI)1-3NRFRG, —(CRNRO)1-3C(O)ORF, —(CRNRO)1-3C(O)NRFRG, C3-10 carbocyclic ring system, and 3 to 10 membered heterocyclic ring system; wherein the carbocyclic ring or heterocyclic ring system is unsubstituted or substituted with: ═O, —NRFRG, —C(O)RF, halo, —CN, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkyl substituted with —ORF;
R4 is independently selected at each occurrence from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl, —CN, C1-4 alkyl substituted with —ORJ, C1-4 alkyl substituted with —NRJRK, and 3 to 8 membered heterocycloalkyl;
R5 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkyl substituted with —ORF, C1-4 alkyl substituted with —NRLRL, C3-8 cycloalkyl, substituted or unsubstituted phenyl, C1-4 alkyl substituted with a 3 to 8 membered heterocycloalkyl, and substituted or unsubstituted 5 or 6 membered heteroaryl; wherein the phenyl or heteroaryl group may be substituted by 1 or 2 R9;
R6 is selected from the group consisting of H and methyl;
R8 is selected from the group consisting of H, Cl, F, CN, and Me;
R9 is selected from the group consisting of halo and C1-4 alkyl;
 n is 0, 1, or 2;
RA and RB are selected from the group consisting of H, C1-4 alkyl, and C1-4 haloalkyl; or RA and RB together with the atom to which they are attached form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring;
RC, RD, RE, RF and RG are each independently selected from the group consisting of H, C1-4 alkyl, and C1-4 haloalkyl;
RH and RI are each H except one pair of RH and RI on the same carbon atom, together with that carbon atom, form a 3 to 6 membered cycloalkyl ring or a 3 to 6 membered heterocycloalkyl ring; and
RJ, RK, RL, RM, RN and RO are each independently at each occurrence selected from the group consisting of H and C1-4 alkyl.