HALOGENOPYRAZOLES AS INHIBITORS OF THROMBIN
There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
1 . A compound with structure of Formula (Ia):
or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof;
wherein
Ring A is substituted or unsubstituted pyrazolyl;
L 1 and L 3 are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 4 —;
L 2 is absent, a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 4 —;
R 1 and R 3 are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl;
R 2 is absent, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl, provided that when L 2 is absent, R 2 is absent;
R 4 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, and substituted or unsubstituted fused ring aryl or substituted or unsubstituted heteroaryl; and
Y is a halogen.
2 . The compound according to claim 1 , wherein L 2 and R 2 are absent.
3 . The compound according to claim 1 , with structure of Formula (IIa) or Formula (IIb):
4 . The compound according to claim 3 , with structure of Formula (IIa), wherein L 3 is a bond, or substituted or unsubstituted alkylene, and R 3 is substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl, and Y is fluorine.
5 . The compound according to claim 3 , with structure of Formula (IIa), wherein L 3 is —C(O)O—, R 3 is substituted or unsubstituted alkyl, and Y is fluorine.
6 . The compound according to claim 3 , with structure of Formula (IIa), wherein L 3 is —C(O)NR 5 —, R 5 is hydrogen or alkyl, R 3 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and Y is fluorine.
7 . The compound according to claim 4 , wherein R 3 is substituted or unsubstituted phenyl.
8 . The compound according to claim 4 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
9 . The compound according to claim 8 , wherein R 3 is chloro-substituted thienyl.
10 . The compound according to claim 4 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
11 . The compound according to claim 4 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
12 . The compound according to any of claims 4 to 11 , wherein L 1 is a bond, —S—, —NR 4 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.
13 . The compound according to claim 12 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
14 . The compound according to claim 13 , wherein R 1 is chloro-substituted thienyl.
15 . The compound according to claim 12 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
16 . The compound according to claim 12 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
17 . The compound according to claim 12 , wherein R 1 is substituted or unsubstituted phenyl.
18 . The compound according to claim 4 , wherein L 2 is a bond, and R 2 is hydrogen.
19 . The compound according to claim 4 , wherein L 2 is substituted or unsubstituted alkylene or —C(O)—, and R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.
20 . The compound according to claim 19 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
21 . The compound according to claim 19 , wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
22 . The compound according to claim 21 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
23 . The compound according to claim 19 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
24 . The compound according to claim 19 , wherein R 2 is substituted or unsubstituted phenyl.
25 . The compound according to claim 3 , with structure of Formula (IIb), wherein L 3 is a bond, or substituted or unsubstituted alkylene, R 3 is substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl, and Y is fluorine.
26 . The compound according to claim 3 , with structure of Formula (IIb), wherein L 3 is —C(O)O—, R 3 is substituted or unsubstituted alkyl, and Y is fluorine.
27 . The compound according to claim 3 , with structure of Formula (IIb), wherein L 3 is —C(O)NR 5 —, R 5 is hydrogen or alkyl, R 3 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and Y is fluorine.
28 . The compound according to claim 25 , wherein R 3 is substituted or unsubstituted phenyl.
29 . The compound according to claim 25 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
30 . The compound according to claim 29 , wherein R 3 is chloro-substituted thienyl.
31 . The compound according to claim 25 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
32 . The compound according to claim 25 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
33 . The compound according to any of claims 25 to 32 , wherein L 1 is a bond, —S—, —NR 4 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.
34 . The compound according to claim 33 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
35 . The compound according to claim 34 , wherein R 1 is chloro-substituted thienyl.
36 . The compound according to claim 33 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
37 . The compound according to claim 33 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
38 . The compound according to claim 33 , wherein R 1 is substituted or unsubstituted phenyl.
39 . The compound according to claim 25 , wherein L 2 is a bond, and R 2 is hydrogen.
40 . The compound according to claim 25 , wherein L 2 is substituted or unsubstituted alkylene or —C(O)—, and R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.
41 . The compound according to claim 40 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
42 . The compound according to claim 40 , wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
43 . The compound according to claim 42 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
44 . The compound according to claim 40 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
45 . The compound according to claim 40 , wherein R 2 is substituted or unsubstituted phenyl.
46 . The compound according to any of claims 1 to 45 as set forth in Table A.
47 . A pharmaceutical composition comprising a compound according to any of claims 1 to 45 , or a compound as set forth in Table A, and a pharmaceutically acceptable excipient.
48 . A method for treating a disease or disorder in a subject, comprising administering a compound according to any of claims 1 to 46 or a pharmaceutical composition according to claim 47 , to a subject in need thereof in an amount effective to treat said disease or disorder.
49 . The method according to claim 48 , wherein said disease or disorder is a thrombotic disorder.
50 . The method according to claim 49 , wherein said thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.
51 . The method according to claim 48 , wherein said disease or disorder is fibrosis.
52 . The method according to claim 48 , wherein said disease or disorder is Alzheimer's Disease.
53 . The method according to claim 48 , wherein said disease or disorder is multiple sclerosis.
54 . The method according to claim 48 , wherein said disease or disorder is pain.
55 . The method according to claim 48 , wherein said disease or disorder is cancer.
56 . A method for preventing a disease or disorder in a subject, comprising administering a compound according to any of claims 1 to 46 or a pharmaceutical composition according to claim 47 , to a subject in need thereof in an amount effective to prevent said disease or disorder.
57 . The method according to claim 56 , wherein said disease or disorder is a thrombotic disorder.
58 . The method according to claim 56 , wherein said thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.
59 . The method according to claim 56 , wherein said thrombotic disorder is disseminated intravascular coagulation.
60 . The method according to claim 56 , wherein said thrombotic disorder involves the presence or the potential formation of a blood clot thrombus.