US2020268714A1PendingUtilityA1
Spirocyclic compounds
Est. expiryApr 3, 2035(~8.7 yrs left)· nominal 20-yr term from priority
Inventors:Peter Qinhua HuangMehmet KahramanDeborah Helen SleeKevin Duane BunkerChad Daniel HopkinsJoseph Robert PinchmanSunny AbrahamRakesh Kumar SitDaniel Lee Severance
C07D 487/10C07D 471/10A61K 31/5377A61K 31/506A61K 31/496A61K 31/4545A61K 31/444A61K 31/4439A61P 35/00A61K 31/416A61K 31/4162
63
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Claims
Abstract
Disclosed herein are spirocyclic compounds, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
wherein:
R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted or a substituted monocyclic C 3-8 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted 5- to 10-membered monocyclic or bicyclic heteroaryl, an unsubstituted or a substituted 5- to 10-membered monocyclic heterocyclyl, cyano, an unsubstituted C 1-6 haloalkyl, amino, a mono-C 1-6 alkyl substituted amino group and a di-C 1-6 alkyl substituted amino group;
Y 1 is C or N,
provided that when Y 1 is C, then R 2a is selected from the group consisting of hydrogen, halogen, an unsubstituted C 1-6 alkyl, hydroxy, an unsubstituted C 1-6 alkoxy, cyano, nitro and amino, and when Y 1 is N, then R 2a is absent;
Y 2 is C, and R 2b is selected from the group consisting of hydrogen, halogen, an unsubstituted C 1-6 alkyl, hydroxy, an unsubstituted C 1-6 alkoxy, cyano, nitro and amino;
Y 3 is C, and R 2c is selected from the group consisting of hydrogen, halogen, an unsubstituted C 1-6 alkyl, hydroxy, an unsubstituted C 1-6 alkoxy, cyano, nitro and amino;
each R 3a , each R 3b , R 3c , R 3d , each R 3e , each R 3f , R 3g , R 3h , R 3i and R 3j are independently selected from the group consisting of hydrogen, halogen, an unsubstituted alkyl, hydroxy, an unsubstituted alkoxy and amino;
each R 4a and each R 4b are independently hydrogen or deuterium;
R 5a , R 5b , R 5c , R 5e , R 5f , R 5g and R 5h are independently selected from the group consisting of hydrogen and an unsubstituted alkyl;
R 6 is an unsubstituted or a substituted phenyl, an unsubstituted or a substituted 5- to 6-membered monocyclic heteroaryl or an unsubstituted or a substituted 5- to 6-membered monocyclic heterocyclyl;
A 1 is selected from the group consisting of an unsubstituted bridged C 3-10 cycloalkyl, an unsubstituted or a substituted phenyl and an unsubstituted or a substituted monocyclic heteroaryl;
X 1 is hydrogen, O or S, provided that when X 1 is hydrogen, then ------- is a single bond, and when X 1 is O or S, then ------- is a double bond;
X 2 is O or S;
Y 4 is C(Y 1a ), C or N,
Y 1a is selected from the group consisting of hydrogen, halogen, an unsubstituted C 1-4 alkyl and —O—C 1-4 alkyl;
is a single or double bond;
wherein when Y 4 is C(Y 1a ) and is a single bond, then R 5d is selected from the group consisting of hydrogen and an unsubstituted alkyl;
wherein when Y 4 is C and is a double bond, then R 5d is absent; and
wherein when Y 4 is N, then is a single bond and R 5d is selected from the group consisting of hydrogen and an unsubstituted alkyl;
m is 1 or 2;
n is 1 or 2; and
p is 1.
2 . (canceled)
3 . The compound of claim 1 , wherein m is 1; n is 1; and each R 3a , each R 3b , R 3c , R 3d , each R 3e , each R 3f , R 3g , R 3h , R 3i and R 3j are each hydrogen.
4 . (canceled)
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . (canceled)
9 . The compound of claim 3 , wherein X 1 is hydrogen, and ------- is a single bond.
10 . The compound of claim 3 , wherein X 1 is O, and ------- is a double bond.
11 . (canceled)
12 . (canceled)
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . (canceled)
17 . (canceled)
18 . (canceled)
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . (canceled)
26 . (canceled)
27 . (canceled)
28 . (canceled)
29 . The compound of claim 10 , wherein Y 1 is C; R 2a is hydrogen; Y 2 is C; R 2b is hydrogen; Y 3 is C; R 2c is hydrogen.
30 . (canceled)
31 . (canceled)
32 . (canceled)
33 . The compound of claim 10 , wherein Y 1 is N; R 2a is absent; Y 2 is C; R 2b is hydrogen; Y 3 is C; R 2c is hydrogen.
34 . (canceled)
35 . (canceled)
36 . (canceled)
37 . (canceled)
38 . (canceled)
39 . (canceled)
40 . (canceled)
41 . (canceled)
42 . (canceled)
43 . (canceled)
44 . (canceled)
45 . (canceled)
46 . (canceled)
47 . The compound of claim 29 , wherein each R 4a and each R 4b are each hydrogen; and X 2 is O.
48 . (canceled)
49 . (canceled)
50 . (canceled)
51 . The compound of claim 47 , wherein Y 4 is C(Y 1a ); is a single bond; and R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h are each hydrogen.
52 . (canceled)
53 . The compound of claim 47 , wherein Y 4 is C; is a double bond; R 5d is absent; and R 5a , R 5b , R 5c , R 5e , R 5f , R 5g and R 5h are each hydrogen.
54 . (canceled)
55 . The compound of claim 47 , wherein Y 4 is N; is a single bond; and R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g and R 5h are each hydrogen.
56 . (canceled)
57 . (canceled)
58 . (canceled)
59 . (canceled)
60 . (canceled)
61 . (canceled)
62 . (canceled)
63 . (canceled)
64 . The compound of claim 47 , wherein A 1 is an optionally substituted bicyclic C 3-10 cycloalkyl.
65 . (canceled)
66 . (canceled)
67 . (canceled)
68 . (canceled)
69 . The compound of claim 47 , wherein A 1 is an optionally substituted phenyl.
70 . (canceled)
71 . The compound of claim 47 , wherein A 1 is an optionally substituted monocyclic heteroaryl.
72 . (canceled)
73 . (canceled)
74 . (canceled)
75 . (canceled)
76 . (canceled)
77 . (canceled)
78 . (canceled)
79 . The compound of claim 69 , wherein R 6 is an optionally substituted monocyclic heteroaryl.
80 . (canceled)
81 . (canceled)
82 . The compound of claim 69 , wherein R 6 is an optionally substituted monocyclic heterocyclyl.
83 . (canceled)
84 . (canceled)
85 . (canceled)
86 . (canceled)
87 . (canceled)
88 . (canceled)
89 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
90 . A method for ameliorating or treating a cancer comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
91 . A method for inhibiting replication of a malignant growth or a tumor comprising contacting the growth or the tumor with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the malignant growth or tumor is due to a cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
92 . A method for ameliorating or treating a cancer comprising contacting a malignant growth or a tumor with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the malignant growth or tumor is due to a cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a tetracarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, a non-Hodgkin's lymphoma, a multiple myeloma, an anaplastic thyroid carcinoma and neurofibromatosis.
93 . A method for inhibiting the activity of ERK1 and/or ERK2 comprising providing an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a sample comprising a cancer cell, wherein the cancer cell is selected from the group consisting of a lung cancer cell, a pancreatic cancer cell, a colon cancer cell, a myeloid leukemia cell, a thyroid cancer cell, myelodysplastic syndrome (MDS) cell, a bladder carcinoma cell, an epidermal carcinoma cell, a melanoma cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, an ovarian cancer cell, a brain cancer cell, a cancer of mesenchymal origin cell, a sarcoma cell, a tetracarcinoma cell, a neuroblastoma cell, a kidney carcinoma cell, a hepatoma cell, a non-Hodgkin's lymphoma cell, a multiple myeloma cell and an anaplastic thyroid carcinoma cell and a neurofibromatosis cell.
94 . (canceled)
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