US2019142813A1PendingUtilityA1
Multisubstituted aromatic compounds as serine protease inhibitors
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
A61K 31/5377C07D 409/14A61K 9/0048A61K 31/4545A61P 27/02A61K 31/415C07D 403/04C07D 231/38A61K 31/4439C07D 405/14A61K 31/444C07D 401/04A61K 31/506A61K 45/06A61P 43/00
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Claims
Abstract
There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of kallikrein, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which disease or disorder is amenable to treatment or prevention by the inhibition of kallikrein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for treating or preventing a kallikrein-related disease or disorder in a subject, comprising administering a compound of Formula (Ia):
or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, to a subject in need thereof in an amount effective to treat or prevent said disease or disorder;
wherein:
Ring A is substituted or unsubstituted pyrazolyl, or substituted or unsubstituted triazolyl;
L 1 , L 2 , and L 4 are independently absent, a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 7 —;
L 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 7 —;
R 1 , R 2 , and R 4 are independently 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 R 1 is absent when L 1 is absent, R 2 is absent when L 2 is absent, and R 4 is absent when L 4 is absent;
R 3 is 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 R 2 is absent when L 2 is absent, R 3 is absent when L 3 is absent, and R 4 is absent when L 4 is absent; and
R 7 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 cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.
2 . The method according to claim 1 , wherein L 4 and R 4 are absent.
3 . The method according to claim 2 , wherein said compound has the structure of Formula (IIa):
4 . The method according to claim 3 , wherein L 3 is a bond, and R 3 is substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.
5 . The method according to claim 4 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
6 . The method according to claim 4 , wherein R 3 is substituted or unsubstituted phenyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxanyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted naphthyl or substituted or unsubstituted benzodioxinyl.
7 . The method according to claim 3 , wherein L 3 is a bond or substituted or unsubstituted alkylene, and R 3 is substituted or unsubstituted aryl, or substituted or unsubstituted heterocycloalkyl.
8 . The method according to claim 3 , wherein L 3 is —C(O)O—, and R 3 is substituted or unsubstituted alkyl.
9 . The method according to claim 3 , wherein L 3 is —C(O)NR 5 —, R 5 is hydrogen or alkyl, and R 3 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
10 . The method according to any of claims 3 to 9 , wherein L 1 is —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.
11 . The method according to claim 10 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
12 . The method according to claim 11 , wherein R 1 is chloro-substituted thienyl.
13 . The method according to claim 10 , wherein R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxanyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted naphthyl or substituted or unsubstituted benzodioxinyl.
14 . The method according to claim 10 , wherein L 2 and R 2 are absent.
15 . The method according to claim 10 , wherein L 3 and R 3 are absent.
16 . The method according to claim 10 , wherein L 2 is substituted or unsubstituted alkylene or —C(O)—, and R 2 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.
17 . The method according to claim 16 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
18 . The method according to claim 16 , wherein R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxanyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted naphthyl or substituted or unsubstituted benzodioxinyl.
19 . The method according to claim 2 , wherein said compound has the structure of Formula (III):
20 . The method according to claim 19 , 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 heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkyl.
21 . The method according to claim 20 , wherein R 3 is phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, furyl, morpholinyl, oxanyl, oxetanyl, or benzodioxinyl.
22 . The method according to claim 19 , wherein L 3 is —C(O)O—, and R 3 is substituted or unsubstituted alkyl.
23 . The method according to claim 19 , wherein L 3 is —C(O)NR′—, R′ is hydrogen or alkyl, and R 3 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
24 . The method according to any of claims 19 to 23 , wherein L 1 is —S—, —NR 7 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, R 7 is a hydrogen or alkyl, 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.
25 . The method according to claim 24 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
26 . The method according to claim 25 , wherein R 1 is chloro-substituted thienyl.
27 . The method according to claim 24 , wherein R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxanyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted naphthyl or substituted or unsubstituted benzodioxinyl.
28 . The method according to claim 24 , wherein L 2 is a bond and R 2 is hydrogen.
29 . The method according to claim 24 , wherein L 2 is substituted or unsubstituted alkylene or —C(O)—, and R 2 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.
30 . The method according to claim 29 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
31 . The method according to claim 29 , wherein R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted oxanyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted naphthyl or substituted or unsubstituted benzodioxinyl.
32 . The method according to claim 1 , wherein said compound has the following structure of Formula (IV):
33 . The method according to claim 32 , wherein L 4 is a bond, and R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
34 . The method according to claim 33 , wherein R 4 is halogen.
35 . The method according to claim 33 , wherein R 4 is unsubstituted alkyl.
36 . The method according to claim 33 , wherein R 4 is phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
37 . The method according to claim 1 , wherein said compound is selected from any of Tables B or C.
38 . The method according to any of claims 1 to 37 , wherein said kallikrein-related disorder is a thrombotic disease, a fibrinolytic disease, a type of cancer, an inflammatory condition, or a dermatological condition.
39 . The method according to any of claims 1 to 38 , wherein said kallikrein-related disorder is an ophthalmic disease.
40 . The method according to claim 39 , wherein said ophthalmic disease is diabetic macular edema, age-related macular degeneration, or diabetic retinopathy.
41 . The method according to claim 38 , wherein said type of cancer is cervical-, testicular-, or non-small-cell lung adenocarcinoma.
42 . The method according to claim 38 , wherein said inflammatory condition is sepsis, inflammatory bowel disease, systemic inflammatory response syndrome, or rheumatoid arthritis.
43 . The method according to claim 38 , wherein said dermatological condition is atopic dermatitis, psoriasis, or Netherton Syndrome.
44 . The method according to claim 1 , wherein said compound acts by inhibiting kallikrein.
45 . The method according to claim 44 , wherein said compound acts by inhibiting tissue kallikrein.
46 . The method according to claim 44 , wherein said compound acts by inhibiting plasma kallikrein.
47 . The method according to claim 39 , wherein the compound or pharmaceutical composition is administered in the form of an ophthalmic composition applied topically to the eye.
48 . The method according to claim 47 , wherein the ophthalmic composition is in the form of eye drops.
49 . The method according to claim 39 , wherein said compound or pharmaceutical composition is administered in the form of an ophthalmic composition via intravitreal injection.
50 . A method for treating or preventing a kallikrein-related disease or disorder in a subject, comprising administering a compound from Table D or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient, to a subject in need thereof in an amount effective to treat or prevent said disease or disorder.
51 . A compound with structure of Formula (V):
or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof;
wherein
L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 7 —;
L 2 and L 5 are independently absent, a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 7 —;
R 1 is 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 and R 5 are independently 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; and
R 7 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, or substituted or unsubstituted heteroaryl.
52 . The compound according to claim 51 , wherein L 5 and R 5 are absent.
53 . The compound according to claim 51 , wherein L 2 and R 2 are absent.
54 . The compound according to claim 51 , wherein L 2 is —C(O)—, and R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.
55 . The compound according to claim 54 , wherein R 2 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
56 . The compound according to claim 55 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
57 . The compound according to claim 54 , wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
58 . The compound according to claim 57 , wherein said heterocycloalkyl is oxanyl, oxetanyl, or morpholinyl.
59 . The compound according to claim 54 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
60 . The compound according to claim 51 , wherein L 1 is bond, —S—, 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.
61 . The compound according to claim 60 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
62 . The compound according to claim 61 , wherein R 1 is chloro-substituted thienyl.
63 . The compound according to claim 60 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
64 . The compound according to claim 60 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
65 . The compound according to any of claims 54 to 64 , wherein L 5 is a bond or substituted or unsubstituted alkylene, and R 5 is substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.
66 . The compound according to claim 65 , wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.
67 . The compound according to claim 65 , wherein said fused ring aryl is benzodioxinyl or naphthyl.
68 . The compound according to any of claims 54 to 64 , wherein L 5 is substituted or unsubstituted alkylene, and R 5 is substituted or unsubstituted heterocycloalkyl.
69 . The compound according to claim 68 , wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
70 . A pharmaceutical composition comprising a compound according to any of claims 51 to 69 , or a compound as set forth in Table A, and a pharmaceutically acceptable excipient.
71 . A method for treating a disease or disorder in a subject, comprising administering a compound according to any of claims 51 to 69 or a pharmaceutical composition according to claim 70 , to a subject in need thereof in an amount effective to treat or prevent said disease or disorder.
72 . The method according to claim 71 , wherein said disease or disorder is a thrombotic disorder.
73 . The method according to claim 72 , wherein said thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism, cardiogenic thromboembolism, disseminated intravascular coagulation, or a blood clot thrombus.
74 . The method according to claim 71 , wherein said disease or disorder is fibrosis.
75 . The method according to claim 71 , wherein said disease or disorder is Alzheimer's Disease.
76 . The method according to claim 71 , wherein said disease or disorder is multiple sclerosis.
77 . The method according to claim 71 , wherein said disease or disorder is pain.
78 . The method according to claim 71 , wherein said disease or disorder is cancer.
79 . The method according to claim 71 , wherein said compound acts by inhibiting thrombin.
80 . The method according to claim 71 , wherein said disease or disorder is a kallikrein-related disorder.
81 . The method according to claim 80 , wherein said kallikrein-related disorder is a thrombotic disease, a fibrinolytic disease, a type of cancer, an inflammatory condition, or a dermatological condition.
82 . The method according to claim 80 , wherein said kallikrein-related disorder is an ophthalmic disease.
83 . The method according to claim 82 , wherein said ophthalmic disease is diabetic macular edema, age-related macular degeneration, or diabetic retinopathy.
84 . The method according to claim 80 , wherein said type of cancer is cervical-, testicular-, or non-small-cell lung adenocarcinoma.
85 . The method according to claim 80 , wherein said inflammatory condition is sepsis, inflammatory bowel disease, systemic inflammatory response syndrome, or rheumatoid arthritis.
86 . The method according to claim 80 , wherein said dermatological condition is atopic dermatitis, psoriasis, or Netherton Syndrome.
87 . The method according to claim 71 , wherein said compound acts by inhibiting kallikrein.
88 . The method according to claim 87 , wherein said compound acts by inhibiting tissue kallikrein.
89 . The method according to claim 87 , wherein said compound acts by inhibiting plasma kallikrein.
90 . The method according to claim 82 , wherein said compound or pharmaceutical composition is administered in the form of an ophthalmic composition applied topically to the eye.
91 . The method according to claim 90 , wherein the ophthalmic composition is in the form of eye drops.
92 . The method according to claim 82 , wherein said compound or pharmaceutical composition is administered in the form of an ophthalmic composition via intravitreal injection.Cited by (0)
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