US2022213112A1PendingUtilityA1
Pyrrole tricyclic compounds as a2a / a2b inhibitors
Est. expiryApr 9, 2038(~11.7 yrs left)· nominal 20-yr term from priority
C07D 487/14
65
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Claims
Abstract
This application relates to compounds of Formula (I):or pharmaceutically acceptable salts or stereoisomers thereof, which modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors, and are useful in the treatment of diseases related to the activity of adenosine receptors including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
R 3 is selected from H and C 1-6 alkyl;
R 4 is selected from H and C 1-6 alkyl;
R 5 is selected from H, halo, CN, C 1-6 alkyl, phenyl, and pyrazol-4-yl, wherein pyrazol-4-yl is optionally substituted by 1, 2, 3, or 4 R A ;
R 6 is selected from H, phenyl, and pyrazol-4-yl, wherein said phenyl and pyrazol-4-yl of R 6 are each independently substituted by 1, 2, 3, or 4 independently selected R A substituents;
each R A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, OR a16 , SR a16 , NHOR a16 , C(O)R b16 , C(O)NR C16 R d16 , C(O)NR c16 (OR a16 ), C(O)OR a16 , OC(O)R b16 , OC(O)NR c16 R d16 , NR c16 R d16 , NR c16 C(O)R b16 , NR c16 C(O)OR a16 , NR c16 C(O)NR c16 R d16 , NR c16 S(O) 2 R b16 , NR c16 S(O) 2 NR c16 R d16 , S(O) 2 R b16 , and S(O) 2 NR c16 R d16 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R A are each optionally substituted with 1, 2, 3, or 4 independently selected R B substituents;
each R a16 , R b16 , R c16 and R d16 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a16 R b16 , R c16 and R d16 , are each optionally substituted with 1, 2, 3, or 4 independently selected R B substituents;
each R B is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, OR a26 , SR a26 , NHOR a26 , C(O)R b26 , C(O)NR c26 R d26 , C(O)OR a26 , OC(O)R b26 , OC(O)NR c26 R d26 , NR c26 R d26 , NR c26 C(O)R b26 , NR c26 C(O)OR a26 , NR c26 C(O)NR c26 R d26 , NR c26 S(O) 2 R b26 , NR c26 S(O) 2 NR c26 R d26 , S(O) 2 R b26 , and S(O) 2 NR c26 R d26 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 ) aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 ) cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R B are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents;
each R a26 , R b26 , R c26 , and R d26 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein the C 1-6 alkyl of R a26 , R b26 , R c26 , and R d26 is optionally substituted with 1, 2, 3, or 4 independently selected R C substituents;
each R C is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a36 , SR a36 , NHOR a36 , C(O)R b36 , C(O)NR c36 R d36 , C(O)OR a36 , OC(O)R b36 , OC(O)NR c36 R d36 , NR c36 R d36 , NR c36 C(O)R b36 , NR c36 C(O)OR a36 , NR c36 C(O)NR c36 R d36 , NR c36 S(O) 2 R b36 , NR c36 S(O) 2 NR c36 R d36 , S(O) 2 R b36 , and S(O) 2 NR c36 R d36 , wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R C are each optionally substituted with 1, 2, 3, or 4 independently selected R D substituents;
each R a36 R b36 , R c36 and R d36 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, of R d36 , R b36 , R c36 , and R d36 , are each optionally substituted with 1, 2, 3, or 4 independently selected R D substituents; and
each R D is independently selected from OH, CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
2 . The compound of claim 1 , wherein 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attached to carbon atoms of “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”, “cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C 1-6 alkyl-” linking groups, are optionally replaced by deuterium atoms.
3 .- 6 . (canceled)
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H, CH 3 , CD 3 , or CF 3 .
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 or CF 3 .
9 . (canceled)
10 . (canceled)
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is butyl or pentyl.
13 . (canceled)
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
15 .- 19 . (canceled)
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, Br, CN, CH 3 , phenyl, and pyrazol-4-yl, wherein pyrazol-4-yl is optionally substituted with benzyl.
21 .- 27 . (canceled)
28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, and S(O) 2 NR c16 R d16 , wherein the (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R A are each optionally substituted with 1, 2, 3, or 4 independently selected R B substituents; and
each R c16 and R d16 is independently selected from H and C 6-10 aryl, wherein the C 6-10 aryl of R c16 and R d16 is optionally substituted with 1, 2, 3, or 4 independently selected R B substituents.
29 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R A is independently selected from S(O) 2 NR c16 R d16 , benzyl, azetidin-3-yl, pyridin-3-yl, thieno[3,2-b]pyridin-6-ylmethyl, imidazo[1,2-a]pyridin-7-ylmethyl, 1,5-naphthyridin-3-ylmethyl, 1H-pyrazolo[4,3-b]pyridin-6-ylmethyl, and 1,2,3,4-tetrahydroisoquinolin-6-ylmethyl, each which are optionally substituted by 1, 2, 3, or 4 independently selected R B substituents.
30 . (canceled)
31 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently selected from halo, C 1-6 alkyl, 5-10 membered heteroaryl, C(O)R b26 , and C(O)NR c26 R d26 , wherein the 5-10 membered heteroaryl of R B are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents; and
each R b26 , R c26 , and R d26 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R b26 , R c26 , and R d26 are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents.
32 . (canceled)
33 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R C is independently selected from halo, C 1-6 alkyl, CN, OR a36 , and NR c36 R d36 , wherein the C 1-6 alkyl of R C are each optionally substituted with 1, 2, 3, or 4 independently selected R D substituents; and
each R a36 , R c36 , and R d36 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R a36 , R c36 , and R d36 is optionally substituted with 1, 2, 3, or 4 independently selected R D substituents.
34 .- 35 . (canceled)
36 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R D is OH.
37 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein: R 2 is selected from C 1-6 alkyl and C 1-6 haloalkyl; R 4 is H; wherein 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attached to carbon atoms of “alkyl” are optionally replaced by deuterium atoms.
38 . (canceled)
39 . (canceled)
40 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is H; each R A is independently selected from (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, and S(O) 2 NR c16 R d16 , wherein the (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R A are each optionally substituted with 1, 2, 3, or 4 independently selected R B substituents; and each R c16 and R d16 is independently selected from H and C 6-10 aryl, wherein the C 6-10 aryl of R c16 and R d16 is optionally substituted with 1, 2, 3, or 4 independently selected R B substituents; each R B is independently selected from halo, C 1-6 alkyl, 5-10 membered heteroaryl, C(O)R b26 , and C(O)NR c26 R d26 , wherein the 5-10 membered heteroaryl of R B are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents; each R b26 , R c26 , and R d26 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R b26 , R c26 , and R d26 are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, CN, OR a36 , and NR c36 R d36 , wherein the C 1-6 alkyl of R C are each optionally substituted with 1, 2, 3, or 4 independently selected R D substituents; and each R a36 , R c36 , and R d36 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R a36 , R c36 , and R d36 is optionally substituted with 1, 2, 3, or 4 independently selected R D substituents; and wherein 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attached to carbon atoms of “alkyl”, “aryl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C 1-6 alkyl-” linking groups, are optionally replaced by deuterium atoms.
41 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from C 1-6 alkyl and C 1-6 haloalkyl; R 3 is C 1-6 alkyl; R 4 is H; each R A is independently selected from (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, and S(O) 2 NR c16 R d16 , wherein the (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R A are each optionally substituted with 1, 2, 3, or 4 independently selected R B substituents; and each R c16 and R d16 is independently selected from H and C 6-10 aryl, wherein the C 6-10 aryl of R c16 and R d16 is optionally substituted with 1, 2, 3, or 4 independently selected R B substituents; each R B is independently selected from halo, C 1-6 alkyl, 5-10 membered heteroaryl, C(O)R b26 , and C(O)NR c26 R d26 , wherein the 5-10 membered heteroaryl of R B are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents; each R b26 , R c26 , and R d26 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R b26 , R c26 , and R d26 are each optionally substituted with 1, 2, 3, or 4 independently selected R C substituents; each R C is independently selected from halo, C 1-6 alkyl, CN, OR a36 , and NR c36 R d36 , wherein the C 1-6 alkyl of R C are each optionally substituted with 1, 2, 3, or 4 independently selected R D substituents; and each R a36 , R c36 , and R d36 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl of R a36 , R c36 , and R d36 is optionally substituted with 1, 2, 3, or 4 independently selected R D substituents; wherein 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attached to carbon atoms of “alkyl”, “aryl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C 1-6 alkyl-” linking groups, are optionally replaced by deuterium atoms.
42 . (canceled)
43 . (canceled)
44 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein only one of R 5 and R 6 contains cyclic groups.
45 . (canceled)
46 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
47 . A method of inhibiting an activity of an adenosine receptor, comprising contacting the receptor with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
48 . A method of treating a disease or disorder in a patient, wherein the disease or disorder is head and neck cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, colorectal cancer or pancreatic cancer, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
49 . (canceled)
50 . (canceled)
51 . The method of claim 48 , wherein the disease or disorder is non-small cell lung cancer (NSCLC), metastatic castrate-resistant prostate carcinoma (mCRPC), or colorectal carcinoma (CRC).
52 .- 61 . (canceled)
62 . A method of treating or preventing atherosclerotic plaque formation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
63 . The method of claim 48 , wherein the disease or disorder is head and neck cancer.
64 . The method of claim 63 , wherein the head and neck cancer is head and neck squamous cell carcinoma.
65 . The method of claim 48 , wherein the disease or disorder is lung cancer.
66 . The method of claim 65 , wherein the lung cancer is non-small cell lung cancer (NSCLC).
67 . The method of claim 48 , wherein the disease or disorder is ovarian cancer.
68 . The method of claim 48 , wherein the disease or disorder is prostate cancer.
69 . The method of claim 68 , wherein the prostate cancer is metastatic castration-resistant prostate cancer.
70 . The method of claim 48 , wherein the disease or disorder is breast cancer.
71 . The method of claim 48 , wherein the disease or disorder is bladder cancer.
72 . The method of claim 48 , wherein the disease or disorder is colorectal cancer.
73 . The method of claim 48 , wherein the disease or disorder is pancreatic cancer.Join the waitlist — get patent alerts
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