US 11,992,494 B2
Cyclopentathiophene carboxamide derivatives as platelet activating factor receptor antagonists
Matthias Eckhardt, Biberach an der Riss (DE); Ferenc Kontes, Biberach an der Riss (DE); Christofer Siegfried Tautermann, Biberach an der Riss (DE); Dieter Wiedenmayer, Biberach an der Riss (DE); and Marina Kristina Willwacher, Biberach an der Riss (DE)
Assigned to Boehringer Ingelheim International GmbH, Ingelheim am Rhein (DE)
Filed by Boehringer Ingelheim International GmbH, Ingelheim am Rhein (DE)
Filed on Dec. 19, 2022, as Appl. No. 18/083,602.
Claims priority of application No. 21216739 (EP), filed on Dec. 22, 2021.
Prior Publication US 2023/0190763 A1, Jun. 22, 2023
Int. Cl. C07D 495/14 (2006.01); A61K 31/551 (2006.01); C07D 519/00 (2006.01)
CPC A61K 31/551 (2013.01) [C07D 495/14 (2013.01); C07D 519/00 (2013.01)] 13 Claims
 
1. A compound of formula (I)

OG Complex Work Unit Chemistry
wherein
R1 is selected from the group consisting of C1-4-alkyl and C3-4-cycloalkyl,
wherein the C1-4-alkyl group of R1 is optionally substituted with 1 to 3 F;
n is selected from the group consisting of 0, 1, 2, and 3;
R2 is independently selected from the group consisting of F, Cl, Br, I, C1-4-alkyl, C3-4-cycloalkyl, —CN, —CONH2, —CONH(C1-4-alkyl), —CON(C1-4-alkyl)2, —COOH, —COO—C1-4-alkyl, NH2, OH, —O—C1-4-alkyl, and —S(O)r-C1-4-alkyl with r=0, 1, or 2;
wherein the C1-4-alkyl group of R2 is optionally substituted with 1 to 3 F or with 1 —CN, with 1 OH, or with 1 O—C1-4-alkyl, and
wherein the —O—C1-4-alkyl group of R2 is optionally substituted with 1 to 3 F;
R3 is selected from the group consisting of H and C1-4-alkyl optionally substituted with 1 to 5 F; and
R4 is selected from the group consisting of C1-6-alkyl
optionally substituted with 1 to 3 F or optionally substituted with 1 to 2 substituents independently selected from
—CN, —CONH2, —CONH(C1-4-alkyl), —CON(C1-4-alkyl)2, —COOH, —COO—C1-4-alkyl, C1-3-alkyl-CO—NH—, C1-3-alkyl-S(═O)2—NH—, OH, and —O—C1-3-alkyl optionally substituted with 1 to 3 F;
or
R4 is selected from the group consisting of —C0-3-alkylene-C3-10-cycloalkyl and —C0-3-alkylene-C3-10-heterocyclyl,
wherein said alkylene moiety of the —C0-3-alkylene-C3-10-cycloalkyl and —C0-3-alkylene-C3-10-heterocyclyl groups of R4 is optionally substituted with 1 to 2 substituents selected from F and CH3,
wherein 1 CH2 group of said alkylene moiety of the —C0-3-alkylene-C3-10-cycloalkyl and —C0-3-alkylene-C3-10-heterocyclyl groups of R4 is optionally replaced by a

OG Complex Work Unit Chemistry
 moiety,
wherein said cycloalkyl moiety of the —C0-3-alkylene-C3-10-cycloalkyl group of R4 and said heterocyclyl moiety of the —C0-3-alkylene-C3-10-heterocyclyl group of R4 are saturated mono- or bicyclic ring systems,
wherein said heterocyclyl moiety of the —C0-3-alkylene-C3-10-heterocyclyl group of R4 contains 1 to 2 ring members independently selected from N, NH, N(C1-4-alkyl), NCO(C1-4-alkyl), NCOO(C1-4-alkyl), NS(═O)2(C1-4-alkyl), N-phenyl, N-pyridinyl, N-pyrimidinyl, and O, and optionally 1 ring member selected from C═O, and S(═O)r, with r=0, 1, or 2,
provided that said heterocyclyl moiety of the —C0-3-alkylene-C3-10-heterocyclyl group of R4 does not contain any heteroatom-heteroatom bonds other than N—N, N—O, and N—S(═O)r=1,2 between ring members, and
wherein said cycloalkyl moiety of the —C0-3-alkylene-C3-10-cycloalkyl group of R4 and said heterocyclyl moiety of the —C0-3-alkylene-C3-10-heterocyclyl group of R4 are optionally substituted with 1 to 2 F and optionally substituted with 1 to 2 substituents independently selected from
a) Cl,
b) —CN,
c) —CONH2,
d) —CONH(C1-4-alkyl),
e) —CON(C1-4-alkyl)2,
f) —COOH,
g) —COO—C1-4-alkyl,
h) OH,
i) —O—C1-3-alkyl optionally substituted with 1 to 3 F,
j) S(═O)2—C1-4-alkyl and
k) C1-4-alkyl optionally substituted with 1 to 3 F or with 1 substituent selected from —CN, OH, —O—C1-4-alkyl;
or
R4 is selected from the group consisting of —C0-3-alkylene-phenyl and —C0-3-alkylene-heteroaryl,
wherein said alkylene moiety of the —C0-3-alkylene-phenyl and —C0-3-alkylene-heteroaryl groups of R4 is optionally substituted with 1 to 2 substituents selected from F and CH3,
wherein 1 CH2 group of said alkylene moiety of the —C0-3-alkylene-phenyl and —C0-3-alkylene-heteroaryl groups of R4 is optionally replaced by a

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 moiety or by a

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 moiety, or
wherein 1 —CH2—CH2— group of said alkylene moiety of the —C0-3-alkylene-phenyl and —C0-3-alkylene-heteroaryl groups of R4 is optionally replaced by a

OG Complex Work Unit Chemistry
 moiety or by a

OG Complex Work Unit Chemistry
 moiety,
wherein said heteroaryl moiety of the —C0-3-alkylene-heteroaryl group of R4 is a 5-membered monocycle containing 1 ring member selected from N, NH, O, and S and optionally further containing 1 to 2 ring members N, or a 6-membered monocycle containing 1 to 2 ring members N, and
wherein said phenyl moiety of the —C0-3-alkylene-phenyl group of R4 and said heteroaryl moiety of the —C0-3-alkylene-heteroaryl group of R4 are optionally substituted with 1 to 3 substituents independently selected from
a) F, Cl, Br,
b) C3-4-cycloalkyl,
c) —CN,
d) —CONH2,
e) —CONH(C1-4-alkyl),
f) —CON(C1-4-alkyl)2,
g) —COOH,
h) —COO—C1-4-alkyl,
i) —NHCO—C1-4-alkyl,
j) —NHS(═O)2—C1-4-alkyl,
k) —S(═O)r-C1-4-alkyl with r=0, 1, or 2,
l) —O—C1-4-alkyl optionally substituted with 1 to 3 F, and
m) C1-4-alkyl optionally substituted with 1 to 3 F or with 1 substituent selected from —CN, OH, and —O—C1-4-alkyl,
or
R4 is selected from the group consisting of 7- to 12-membered fused bicyclic aryl, heteroaryl, or heterocyclyl
wherein said bicyclic aryl, heteroaryl, or heterocyclyl of R4 consists of one non-aromatic ring that is attached to the amide N atom in formula (I) and optionally contains 1 to 2 ring members independently selected from N—, NH, N(C1-4-alkyl), N(CO—C1-3-alkyl), N(S(═O)2-C1-3-alkyl), and O, and
optionally contains 1 ring member selected from C═O and S(═O)r, with r=0, 1, or 2, and of
one aromatic ring selected from phenyl, pyrrole, furan, and thiophene in each of which 1 to 2 CH ring members are optionally replaced with N,
wherein said bicyclic aryl, heteroaryl, or heterocyclyl of R4 is optionally substituted with 1 to 4 F,
is optionally substituted with 1 to 4 C1-3-alkyl optionally substituted with 1 to 4 F, and
is optionally substituted with 1 to 2 substituents selected from the group consisting of Cl, —CN, —CONH2, —CONH(C1-4-alkyl), —CON(C1-4-alkyl)2, —COOH, —COO—C1-4-alkyl, HO—C1-3-alkylene-, C1-3-alkyl-O—C1-3-alkylene-, NH2, C1-3-alkyl-CO—NH—, C1-3-alkyl-S(═O)2-NH—, OH, and C1-3-alkyl-O— optionally substituted with 1 to 3 F;
or
R3 and R4 are selected from the group in which R3 and R4, together with the amide N atom they are attached to, form a saturated 3- to 8-membered monocyclic heterocyclyl optionally further containing 1 to 2 ring members independently selected from NH, N(C1-4-alkyl), N(CO—C1-3-alkyl), N(S(═O)2-C1-3-alkyl), and O, and
optionally containing 1 ring member selected from C═O and S(═O)r, with r=0, 1, or 2, provided that said saturated 3- to 8-membered monocyclic heterocyclyl formed by R3 and R4 together with the amide N atom they are attached to does not contain any heteroatom-heteroatom bonds other than N—N, N—O, and N—S(═O)r=1,2 between ring members,
wherein said heterocyclyl formed by R3 and R4 together with the amide N atom they are attached to is optionally substituted with 1 to 4 F,
is optionally substituted with 1 to 4 C1-3-alkyl optionally substituted with 1 to 3 F, and
is optionally substituted with 1 to 2 substituents selected from Cl, —CN, —CONH2, —CONH(C1-4-alkyl), —CON(C1-4-alkyl)2, —COOH, —COO—C1-4-alkyl, HO—C1-3-alkylene-, C1-3-alkyl-O—C1-3-alkylene-, C1-3-alkyl-CO—NH—, C1-3-alkyl-S(═O)2—NH—, OH, and C1-3-alkyl-O— optionally substituted with 1 to 3 F;
or
R3 and R4 are selected from the group in which R3 and R4, together with the amide N atom they are attached to, form a saturated 5- to 12-membered bicyclic heterocyclyl optionally further containing 1 to 3 ring members independently selected from N—, NH, N(C1-4-alkyl), N(CO—C1-3-alkyl), N(S(═O)2—C1-3-alkyl), and O, and
optionally containing 1 ring member selected from C═O and S(═O)r, with r=0, 1, or 2, provided that said saturated 5- to 12-membered bicyclic heterocyclyl formed by R3 and R4 together with the amide N atom they are attached to does not contain any heteroatom-heteroatom bonds other than N—N, N—O, and N—S(═O)r=1,2 between ring members
wherein said saturated 5- to 12-membered bicyclic heterocyclyl formed by R3 and R4 together with the amide N atom they are attached to is optionally substituted with 1 to 6 F,
is optionally substituted with 1 to 4 C1-3-alkyl optionally substituted with 1 to 3 F, or is optionally substituted with 1 to 2 substituents selected from Cl, —CN, —CONH2, —CONH(C1-4-alkyl), —CON(C1-4-alkyl)2, —COOH, —COO—C1-4-alkyl, HO—C1-3-alkylene-, C1-3-alkyl-O—C1-3-alkylene-, C1-3-alkyl-CO—NH—, C1-3-alkyl-S(═O)2-NH—, OH, and C1-3-alkyl-O—;
or a salt thereof.