US 12,336,991 B2
Factor XIIA inhibitors
Helen Philippou, Leeds (GB); Richard Foster, Leeds (GB); Colin Fishwick, Leeds (GB); Charlotte Revill, Leeds (GB); Ian Yule, Leeds (GB); Roger Taylor, Leeds (GB); Alan Naylor, Harston (GB); Philip Spencer Fallon, Saffron Walden (GB); Stuart Crosby, Saffron Walden (GB); Anna Hopkins, Saffron Walden (GB); Lucie Juliette Guetzoyan, Saffron Walden (GB); Alistair James Macnair, Saffron Walden (GB); Mark Richard Stewart, Saffron Walden (GB); and Natalie Louise Winfield, Saffron Walden (GB)
Assigned to University of Leeds, (GB)
Appl. No. 17/040,604
Filed by UNIVERSITY OF LEEDS, Leeds (GB)
PCT Filed Mar. 28, 2019, PCT No. PCT/GB2019/050883
§ 371(c)(1), (2) Date Sep. 23, 2020,
PCT Pub. No. WO2019/186164, PCT Pub. Date Oct. 3, 2019.
Claims priority of application No. 1805174 (GB), filed on Mar. 29, 2018.
Prior Publication US 2022/0305011 A1, Sep. 29, 2022
Int. Cl. A61K 31/506 (2006.01); A61K 31/40 (2006.01); A61K 31/4192 (2006.01); A61K 31/437 (2006.01); A61K 31/4439 (2006.01); A61K 31/454 (2006.01); A61P 7/02 (2006.01); C07D 207/16 (2006.01); C07D 401/06 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 471/04 (2006.01)
CPC A61K 31/506 (2013.01) [A61K 31/40 (2013.01); A61K 31/4192 (2013.01); A61K 31/437 (2013.01); A61K 31/4439 (2013.01); A61K 31/454 (2013.01); A61P 7/02 (2018.01); C07D 207/16 (2013.01); C07D 401/06 (2013.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 471/04 (2013.01)] 20 Claims
 
1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein
Y is selected from the group consisting of:

OG Complex Work Unit Chemistry
X is a bond, —C(O)NH—, —C(O)O— or —C(O)—;
L-(CRcRd)n— is selected from the group consisting of: a bond, CH2, —NH—, —NHCH2—, —NH(CH2)2—, —NH(CH2)3—, —N(Me)—, —N(C(O)Me)CH2—, —NHC(O)—, —NHC(O)CH2—, —NHC(O)(CH2)2—, or NHC(O)(CH2)3;
Ar is a substituted or unsubstituted 9 to 10 membered bicyclic heteroaromatic ring, wherein the bicyclic heteroaromatic ring is an aromatic hydrocarbon ring with at least one heteroatom within the ring selected from the group consisting of O, N and S or a bicyclic ring which is not completely aromatic but contains an aromatic ring, wherein the at least one heteroatom is present within the aromatic ring or the non-aromatic ring, and wherein, when substituted, the Ar is substituted with 1, 2, or 3 substituents selected from the group consisting of: halo, C1-6 alkyl, —ORg, —NRgRh or C1-4 alkyl substituted by —NRgRh; m is selected from the group consisting of 1, 2, or 3;
n is 0, 1, 2, 3, or 4;
o is 1 or 2;
R1 is selected from the group consisting of substituted or unsubstituted: —NR8R9, 5 to 10 membered carbocyclic ring or a 5 to 10 membered heterocyclic ring;
wherein when substituted R1 is substituted with 1, 2, or 3 groups selected from the group consisting of: ═O, CN, —OH, or —O—C1-6 alkyl, halo, C1-6 alkyl or C1-6 haloalkyl;
R1a and R1b taken together form a substituted or unsubstituted: 5 or 6 membered heteroaromatic ring or a phenyl ring;
wherein, when the ring formed from R1a and R1b is substituted, it is substituted with 1, 2, or 3 Rz groups, wherein Rz is independently selected at each occurrence from: ═O, CN, —OH, —O—C1-6 alkyl, halo and C1-6 alkyl;
R2 is H, C1-6 alkyl, C1-6 haloalkyl, phenyl, benzyl, —C(O)R2a, and S(O)2R2a; and
wherein R2a is selected from the group consisting of: C1-6 alkyl, phenyl, or benzyl;
R3a is H or C1-6 alkyl; and
R4 is ═CH2, —CN, halo, C1-4 alkyl, C1-4 haloalkyl, —OR10, —NR10R11, 6 to 10 membered aryl, C3-8 cycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, wherein the C3.8 cycloalkyl, 3 to 6 membered heterocycloalkyl, 6 to 10 membered aryl, or 5 to 10 membered heteroaryl group is unsubstituted or substituted with 1, 2 or 3 R12;
R4a is H, —OH, halo or C1-4 alkyl;
R5 is H or C1-6 alkyl;
R8 and R9 are independently selected from the group consisting of: H, C1-6 alkyl, C3-6 cycloalkyl, phenyl, C1-4 alkyl substituted with —ORi, or C1-4 alkyl substituted with phenyl, or R8 and R9 taken together with the atom to which they are attached form 3 to 8 membered heterocycloalkyl ring, which is unsubstituted or substituted with: CN, halo, C1-6 alkyl or —ORi;
R12 is independently at each occurrence selected from the group consisting of: halo, C1-4 alkyl, C1-4 haloalkyl, —OR13, —CN, —C(O)R10, ═O, SO2R10, benzyl, phenyl, unsubstituted 5 or 6 membered heteroaryl, or methyl substituted 5 or 6 membered heteroaryl;
R10 and R11 are independently at each occurrence selected from the group consisting of: H or C1-4 alkyl;
R13 is H, C1-4 alkyl, C1-4 haloalkyl, phenyl or benzyl;
Ra and Rb are independently at each occurrence selected from the group consisting of: H, C1-4 alkyl, and —ORj; and
Re, Rf, R9, Rh, Ri and Rj are independently at each occurrence selected from the group consisting of: H or C1-4 alkyl.