US2021115058A1PendingUtilityA1
Spirocyclic compounds
Est. expiryOct 5, 2036(~10.2 yrs left)· nominal 20-yr term from priority
A61K 31/444A61P 35/00C07D 487/10C07D 519/00
62
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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):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of C 3-4 cycloalkyl, halophenyl, C 1-4 alkoxyphenyl, C 1-4 alkoxyhalophenyl, C 1-4 dialkoxyphenyl, halopyridinyl, C 1-4 alkoxypyridinyl, C 1-4 alkylpyridinyl, C 3-5 cycloalkoxypyridinyl, methylbenzoxazolyl and tetrahydropyranyl;
R 2 and R 3 are each independently methyl, hydrogen or deuterium;
Y 1 and Y 2 are each independently CH or N;
Y 3 is C, CH or N; and
Y 9 and Y 10 are each independently CH or N;
Z 1 is C 1-3 alkyl optionally substituted with hydroxy;
wherein is a single bond when Y 3 is N or CH and is a double bond when Y 3 is C; and
wherein the compound of Formula (I) is not
2 - 22 . (canceled)
23 . A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R 4 is a methyloxazolopyridinyl, or a pyridinyl substituted with one or two substituents independently selected from the group consisting of methyl, C 1-4 alkoxy, C 3-5 cycloalkoxy, isopropylthio, fluoro, chloro, cyano, trifluoromethyl, pyrrolidinyl and —C(═O)NHCH 3 ; or
R 4 is a dimethylbenzodioxolyl, a methylbenzoxazolyl, an isopropylbenzoxazolyl, a methylindazolyl, a methylbenzoisoxazolyl, or a phenyl substituted with one or two substituents independently selected from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and —C(═O)NHCH 3 ;
R 5 is
R 6 and R 7 are each independently hydrogen or deuterium;
R 8 is H or methyl;
R 13 is hydrogen or fluoro;
Y 4 is N, CH or CF;
Y 5 is N, C, CH or CF; and
Y 6 is N or CH;
wherein is a single bond when Y 5 is N, CH or CF and is a double bond when Y 5 is C;
wherein the compound of Formula (II) is not selected from the group consisting of
24 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, of the Formula (IIA):
wherein
R 4 is a methyloxazolopyridinyl, or a pyridinyl substituted with one or two substituents independently selected from the group consisting of methyl, C 1-4 alkoxy, isopropylthio, fluoro, chloro, cyano, trifluoromethyl, and —C(═O)NHCH 3 ; or
R 4 is a dimethylbenzodioxolyl, a methylbenzoxazolyl, or a phenyl substituted with one or two substituents independently selected from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and —C(═O)NHCH 3 ; and
R 5 is
25 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein when Y 4 is CH and R 5 is
then R 4 cannot be pyridinyl substituted with a single substituent selected from the group consisting of methyl, methoxy, fluoro, trifluoromethyl and isopropoxy.
26 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein when Y 4 is CH, Y 5 is C and R 5 is
then R 4 cannot be phenyl substituted with a single substituent selected from the group consisting of fluoro, methoxy and cyano.
27 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein when Y 4 is CH, Y 5 is C and R 5 is
then R 4 cannot be phenyl substituted with both a methoxy and a cyano and R 4 cannot be phenyl substituted with both a trifluoromethyl and a cyano.
28 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein when Y 4 is CH, Y 5 is C and R 5 is
then R 4 cannot be pyridinyl substituted with a single isopropoxy and R 4 cannot be phenyl substituted with a single cyano.
29 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein when Y 4 is CH, Y 5 is C and R 5 is
then R 4 cannot be phenyl substituted with both a methoxy and a cyano.
30 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein when Y 4 is CH, Y 5 is C and R 5 is
then R 4 cannot be a dimethylbenzodioxolyl and R 4 cannot be a methylbenzoxazolyl.
31 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 4 is a methyloxazolopyridinyl, or a pyridinyl substituted with one or two substituents independently selected from the group consisting of methyl, C 1-4 alkoxy, C 3-5 cycloalkoxy, isopropylthio, fluoro, chloro, cyano, trifluoromethyl, pyrrolidinyl and —C(═O)NHCH 3 .
32 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 4 is a dimethylbenzodioxolyl, a methylbenzoxazolyl, an isopropylbenzoxazolyl, a methylindazolyl, a methylbenzoisoxazolyl, or a phenyl substituted with one or two substituents independently selected from the group consisting of methoxy, fluoro, chloro, cyano, trifluoromethyl and —C(═O)NHCH 3 .
33 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 13 is fluoro.
34 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 13 is CH.
35 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is
36 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is
37 . The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is
38 . The compound of claim 23 , selected from the group consisting of
or a pharmaceutically acceptable salt of the foregoing.
39 . The compound of claim 24 , selected from the group consisting
or a pharmaceutically acceptable salt of the foregoing.
40 . The compound of claim 23 , selected from the group consisting of
(S)-2-(3-(5-fluoropyridin-2-yl)-1H-indazol-5-yl)-7-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl-1,1-d2)-2,7-diazaspiro[4.4]nonan-1-one; and (S)-7-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-2-(3-(2-methyloxazolo[4,5-b]pyridin-5-yl)-1H-indazol-5-yl)-2,7-diazaspiro[4.4] nonan-1-one; or a pharmaceutically acceptable salt of the foregoing.
41 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
R 9 is a heterocyclyl selected from the group consisting of piperidinyl, 1,1-dioxidotetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, 2-oxaazaspiro[3.5]nonanyl, and morpholino; wherein said heterocyclyl is optionally substituted with one or two substituents selected from the group consisting of methyl, fluoro and trifluoroethyl; or
R 9 is a five-membered heteroaryl selected from the group consisting of thiazolyl, pyrazolyl, and triazolyl; wherein said five-membered heteroaryl is substituted with methyl or isopropyl; or
R 9 is a
R 10 is
R 11 and R 12 are each independently hydrogen or deuterium;
Y 7 is N or CH; and
Y 8 is N, C, or CH;
wherein is a single bond when Y 8 is N or CH and is a double bond when Y 8 is C; and
wherein the compound of Formula (III) is not selected from the group consisting of
42 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein:
R 9 is a heterocyclyl selected from the group consisting of piperidinyl, 1,1-dioxidotetrahydrothiopyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, 2-oxaazaspiro[3.5]nonanyl, and morpholino; wherein said heterocyclyl is optionally substituted with one or two substituents selected from the group consisting of methyl, fluoro and trifluoroethyl; or R 9 is a five-membered heteroaryl selected from the group consisting of thiazolyl, pyrazolyl, and triazolyl; wherein said five-membered heteroaryl is substituted with methyl or isopropyl.
43 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein when Y 7 is CH, Y 8 is C and R 10 is
then R 9 cannot be tetrahydropyranyl, dihydropyranyl, methylpyrazolyl or morpholino.
44 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein when Y 7 is CH, Y 8 is C and R 10 is
then R 9 cannot be tetrahydropyranyl or morpholino.
45 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein R 9 is heterocyclyl.
46 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein R 9 is five-membered heteroaryl.
47 . The compound of claim 41 , wherein R 9 is a
48 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein R 10 is
49 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein R 10 is
50 . The compound of claim 41 , selected from the group consisting of
or a pharmaceutically acceptable salt of the foregoing.
51 . The compound of claim 42 , selected from the group consisting of
or a pharmaceutically acceptable salt of the foregoing.
52 . The compound of claim 41 , which is (S)-7-(2-(4-(4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-2-oxoethyl-1,1-d2)-2-(3-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)-2,7-diazaspiro[4.4]nonan-1-one, or a pharmaceutically acceptable salt thereof.
53 . 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.
54 . 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.
55 . 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 that 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.
56 . 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 that 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.
57 . 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.
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