Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa

Patent metadata

Field	Value
Publication number	US-9688645-B2
Application number	US-201615057920-A
Country	US
Kind code	B2
Filing date	Mar 1, 2016
Priority date	Jun 6, 2008
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The invention relates to compounds of the formula (I) which are inhibitors of activated thrombin-activable fibrinolysis inhibitor. The compounds of the formula I are suitable for producing medicaments for prophylaxis, secondary prevention and treatment of one or more disorders associated with thromboses, embolisms, hypercoagulability or fibrotic changes.

First claim

The invention claimed is:

1. A compound of the formula (I)

or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, where
X is —C(O)— or —SO 2 —;
U is an oxygen atom, sulfur atom, or NH;
A is —(C 0 )-alkylene-;
V is —(C 2 -C 4 )-alkylene-, wherein said alkylene is unsubstituted or substituted independently of one another once, twice or three times by —OH, NH 2 or halogen;
D is —(C 1 -C 2 )-alkylene-;
Y is
1) —(C 3 -C 12 )-cycloalkyl, wherein said cycloalkyl is substituted independently of one another once, twice or three times by R15,
2) —(C 6 -C 14 )-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, or
3) Het, wherein Het is a 4- to 15-membered heterocyclic ring system having 4 to 15 ring atoms which are present in one, two or three ring systems which are connected together, and which comprise, depending on the ring size, one, two, three or four identical or different heteroatoms selected from the-group consisting of oxygen, nitrogen or sulfur, and
in which Het is unsubstituted or substituted independently of one another once, twice or three times by a —(C 1 -C 3 )-alkyl, halogen, —NH 2 , —CF 3 or —O—CF 3 ;
R1 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl,
3) —(C 1 -C 6 )-alkyl-OH,
4) —(C 0 -C 4 )-alkyl-(C 3 -C 6 )-cycloalkyl,
5) —(C 1 -C 10 )-alkyl-O—C(O)—O—R2,
6) —(CH 2 ) r —(C 6 -C 14 )-aryl, in which aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, and r is the integer zero, 1, 2 or 3, or
7) —(CH 2 ) s —Het, wherein Het is a 4- to 15-membered heterocyclic ring system having 4 to 15 ring atoms which are present in one, two or three ring systems which are connected together, and which comprise, depending on the ring size, one, two, three or four identical or different heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and in which Het is unsubstituted or substituted independently of one another once, twice or three times by R15, and s is the integer zero, 1, 2 or 3;
R2 is
1) —(C 1 -C 6 )-alkyl,
2) —(CH 2 ) r —(C 6 -C 14 )-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, and r is the integer zero, 1, 2 or 3, or
3) —(C 0 -C 4 )-alkyl-(C 3 -C 6 )-cycloalkyl;
R3 is
1) —(C 2 -C 6 )-alkylene-NH 2 , wherein said alkylene is unsubstituted or substituted once, twice, three or four times by halogen,
2) —(C 1 -C 4 )-alkylene-O—(C 1 -C 4 )-alkylene-NH 2 ,
3) —(C 1 -C 4 )-alkylene-SO 2 —(C 1 -C 4 )-alkylene-NH 2 ,
4) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above and is substituted by —NH 2 and once, twice or three times by R15,
5) —(C 0 -C 4 )-alkylene-(C 3 -C 8 )-cycloalkyl-NH 2 or
6) —(C 0 -C 6 )-alkylene-cyclic amine, wherein said cyclic amine is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, and thiomorpholinyl;
R6 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16,
3) —O—(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16,
4) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above, wherein said alkylene and Het are unsubstituted or substituted independently of one another once, twice or three times by R16,
5) —(C 0 -C 4 )-alkylene-aryl, wherein said alkylene and aryl are unsubstituted or substituted independently of one another once, twice or three times by R16, or
6) —(C 0 -C 4 )-alkylene-(C 3 -C 8 )-cycloalkyl, wherein said alkylene and cycloalkyl are unsubstituted or substituted independently of one another once, twice or three times by R16;
R7 is a hydrogen atom, halogen or —(C 1 -C 6 )-alkyl;
R8 is a hydrogen atom, halogen or —(C 1 -C 6 )-alkyl;
R9 is a hydrogen atom, halogen or —(C 1 -C 6 )-alkyl;
R15 is a hydrogen atom, —(C 1 -C 4 )-alkyl, —O—CF 3 , —NH 2 , —OH, —CF 3 or halogen; and
R16 is —O—CF 3 , —NH 2 , —OH, —CF 3 or halogen.

2. A compound of the formula (I) as claimed in claim 1 , or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, where
X is —C(O)— or —SO 2 —;
U is oxygen atom, sulfur atom, or NH;
A is —(C 0 )-alkylene-;
V is —(C 2 -C 4 )-alkylene-;
D is —(C 1 -C 2 )-alkylene-;
Y is
1) —(C 3 -C 6 )-cycloalkyl, wherein said cycloalkyl is substituted independently of one another once, twice or three times by R15,
2) —(C 6 -C 14 )-aryl, wherein said aryl is selected from the group of phenyl, naphthyl, anthryl or fluorenyl, and in which aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, or
3) Het, wherein Het is selected from the group consisting of acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, and
in which Het is unsubstituted or substituted independently of one another once, twice or three times by a —(C 1 -C 3 )-alkyl, halogen, —NH 2 , —CF 3 or —O—CF 3 ;
R1 is
1) a hydrogen atom or
2) —(C 1 -C 4 )-alkyl;
R3 is
1) —(C 2 -C 6 )-alkylene-NH 2 , wherein said alkylene is unsubstituted or substituted once, twice, three or four times by halogen,
2) —(C 1 -C 4 )-alkylene-SO 2 —(C 1 -C 4 )-alkylene-NH 2 or
3) —(C 0 -C 4 )-alkylene-Het, wherein said Het is as defined above and is substituted by —NH 2 and once, twice or three times by R15;
R6 is
1) a hydrogen atom,
2) —(C 1 -C 6 )-alkyl, wherein said alkyl is unsubstituted or substituted

Assignees

• Sanofi Sa

Inventors

• Kallus Christopher
• Broenstrup Mark
• Evers Andreas
• Globisch Anja
• Schreuder Herman
• Wagner Michael

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title