US2024043423A1PendingUtilityA1
Compounds and methods for treatment of hedgehog pathway associated conditions
Assignee: SUZHOU MEDNES PHARMA TECH CO LTDPriority: Jun 25, 2018Filed: Aug 7, 2023Published: Feb 8, 2024
Est. expiryJun 25, 2038(~11.9 yrs left)· nominal 20-yr term from priority
C07D 471/04C07D 209/24C07D 209/30C07D 235/10C07D 235/12C07D 235/16C07D 403/06C07D 413/06A61P 35/00C07D 209/08C07D 209/12C07D 209/22C07D 235/08
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Claims
Abstract
This invention presents the novel compounds of formula (I), (II), (III), (IV), and (V) as described in the specification, and pharmaceutically acceptable salts, solvates, and prodrugs, and compositions thereof, and methods of measuring hedgehog pathway activation in tumor cells, examining tumor cell proliferation, differentiation and apoptosis and using the compounds and pharmaceutical compositions disclosed for treatment of diseases and disorders associated with the hedgehog signaling pathway.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a disease or disorder associated with the hedgehog pathway, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (II):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 1 is C 1-8 alkyl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, C 6-10 aryl, —(C 1-6 alkylene)-C 3-6 cycloalkyl, —(C 1-6 alkylene)-C 6-10 aryl, or —(C 1-6 alkylene)-(5- to 10-membered heteroaryl or heterocyclyl);
R 2 is hydrogen, C 1-8 alkyl, C 6-10 aryl, —C(O)OR 8 , —C(O)NR a R b , —(C 1-6 alkylene)-C 6-10 aryl, —(C 1-6 alkylene)-(5- to 10-membered heteroaryl or heterocyclyl), —(C 1-6 alkylene)-C(O)OR 8 , or —(C 1-6 alkylene)-C(O)NR a R b ;
R 3 is hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or —C(O)OR 11 ;
R 4 is hydrogen, halogen, hydroxyl, or C 1-6 alkyl;
R 5 is hydrogen, C 1-8 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, —C(O)OR 8 , —C(O)R 9 , or —S(O) n R 10 (n is 0, 1, or 2);
R 8 is hydrogen, C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or —(C 1-6 alkylene)-C 6-10 aryl;
R 9 is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or —(C 1-6 alkylene)-C 6-10 aryl;
R 10 is C 1-10 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or —(C 1-6 alkylene)-C 6-10 aryl;
wherein any said alkyl or cycloalkyl is optionally substituted by one or two substituents independently selected from the group consisting of C 6-10 aryl, 5- to 10-membered heteroaryl, C(O)OR 11 , OR 12 , and C(O)NR a R b ; and any said aryl or heteroaryl is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, —C(O)OR 11 , —(C 1-6 alkylene)-OR 12 , —(C 1-6 alkylene)-CN, —(C 1-6 alkylene)-C(O)OR 11 , and —(C 1-6 alkylene)-C(O)NR a R b ;
R 11 is hydrogen or C 1-6 alkyl;
R 12 is hydrogen or C 1-6 alkyl; and
R a and R b are each independently hydrogen, C 1-6 alkyl, C 6-10 aryl, or benzyl;
provided, however, that the following compound is excluded:
2 . The method of claim 1 , wherein:
R 1 is selected from the group consisting of benzyl, C 3-6 cycloalkyl-methyl, 5- or 6-membered heterocyclyl-methyl, and 5 or 6-membered heteroaryl-methyl, each optionally substituted; and R 2 is C 1-6 alkyl, phenyl, or 5-membered heteroaryl, wherein the C 1-8 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, C(O)OR 11 , OR 12 , and C(O)NR a R b ; and any said heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, —C(O)OR 11 , —(C 1-4 alkylene)-OR 12 , —(C 1-4 alkylene)-CN, and —(C 1-4 alkylene)-C(O)OR 11 ; R 3 is hydrogen, C 1-6 alkyl, halogen, hydroxyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or —C(O)OR 11 ; R 4 is hydrogen, halogen, hydroxyl, or C 1-6 alkyl; R 5 is C 1-8 alkyl, phenyl optionally substituted by a C 1-6 alkyl, 5- to 6-membered heteroaryl, —C(O)OR 8 , —C(O)R 9 , or —S(O)R 10 (n is 0, 1, or 2), wherein the C 1-8 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of C 6-10 aryl, 5- to 10-membered heteroaryl, C(O)OR 11 , OR 12 , C(O)NR a R b , and —(C 1-8 alkyl)-(C 6-10 aryl); and any aryl or heteroaryl is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and cyano; R 8 is hydrogen, C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or benzyl; R 9 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, or —(C 1-4 alkylene)-phenyl; R 10 is C 1-8 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or benzyl; R 11 is hydrogen or C 1-6 alkyl; R 12 is hydrogen or C 1-6 alkyl; and R a and R b are independently hydrogen or C 1-6 alkyl.
3 . The method of claim 1 , wherein:
R 1 is selected from the group consisting from C 1 -C 6 alkyl,
wherein each X is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or CN; and each R 13 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl,
wherein R x is halogen, —(CH 2 ) n CN, or —(CH 2 ) n OR 14 , wherein each n is 0, 1, or 2; each R 14 is independently H or C 1 -C 6 alkyl; and R a and R b are independently hydrogen or C 1-6 alkyl;
R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and —C(O)OR 15 , wherein R 15 is H or C 1 -C 6 alkyl;
R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl, and C 1 -C 6 alkoxy; and/or
R 5 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, 5-membered heteroaryl,
and —C(O)—R 9 , where R 9 is C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl; and each R 16 is independently halogen or C 1 -C 6 alkyl.
4 . The method of claim 1 , wherein:
R 1 is
wherein X is Cl;
R 2 is selected from
wherein each R 14 is independently H or C 1 -C 6 alkyl;
R 3 is isopropyl, hydroxyl, or methoxy;
R 4 is hydrogen; and
R 5 is
5 . The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
6 . The method of claim 1 , wherein the disease or disorder is selected from medulloblastoma, basal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, advanced stomach cancer, oesophageal cancer, glioblastoma multiforme, acute leukemia, chronic myeloid leukemia, myelofibrosis, essential thrombocythaemia, metastatic colorectal cancer, small-cell lung cancer, and chondrosarcoma.
7 . The method of claim 5 , wherein the disease or disorder is selected from medulloblastoma, basal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, advanced stomach cancer, oesophageal cancer, glioblastoma multiforme, acute leukemia, chronic myeloid leukemia, myelofibrosis, essential thrombocythaemia, metastatic colorectal cancer, small-cell lung cancer, and chondrosarcoma.
8 . A method of treating a disease or disorder associated with the hedgehog pathway, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (II):
or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
R 1 is C 1-8 alkyl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, C 6-10 aryl, —(C 1-6 alkylene)-C 3-6 cycloalkyl, —(C 1-6 alkylene)-C 6-10 aryl, or —(C 1-6 alkylene)-(5- to 10-membered heteroaryl or heterocyclyl);
R 2 is hydrogen, C 1-8 alkyl, C 6-10 aryl, —C(O)OR 8 , —C(O)NR a R b , —(C 1-6 alkylene)-C 6-10 aryl, —(C 1-6 alkylene)-(5- to 10-membered heteroaryl or heterocyclyl), —(C 1-6 alkylene)-C(O)OR 8 , or —(C 1-6 alkylene)-C(O)NR a R b ;
R 3 is hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or —C(O)OR 11 ;
R 4 is hydrogen, halogen, hydroxyl, or C 1-6 alkyl;
R 5 is hydrogen, C 1-8 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, —C(O)OR 8 , —C(O)R 9 , or —S(O) n R 10 (n is 0, 1, or 2);
R 8 is hydrogen, C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or —(C 1-6 alkylene)-C 6-10 aryl;
R 9 is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or —(C 1-6 alkylene)-C 6-10 aryl;
R 10 is C 1-10 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or —(C 1-6 alkylene)-C 6-10 aryl;
wherein any said alkyl or cycloalkyl is optionally substituted by one or two substituents independently selected from the group consisting of C 6-10 aryl, 5- to 10-membered heteroaryl, C(O)OR 11 , OR 12 , and C(O)NR a R b ; and any said aryl or heteroaryl is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, —C(O)OR 11 , —(C 1-6 alkylene)-OR 12 , —(C 1-6 alkylene)-CN, —(C 1-6 alkylene)-C(O)OR 11 , and —(C 1-6 alkylene)-C(O)NR a R b ;
R 11 is hydrogen or C 1-6 alkyl;
R 12 is hydrogen or C 1-6 alkyl; and
R a and R b are each independently hydrogen, C 1-6 alkyl, C 6-10 aryl, or benzyl;
provided, however, that the following compound is excluded:
9 . The method of claim 8 , wherein:
R 1 is selected from the group consisting of benzyl, C 3-6 cycloalkyl-methyl, 5- or 6-membered heterocyclyl-methyl, and 5 or 6-membered heteroaryl-methyl, each optionally substituted; and R 2 is C 1-6 alkyl, phenyl, or 5-membered heteroaryl, wherein the C 1-8 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, C(O)OR 11 , OR 12 , and C(O)NR a R b ; and any said heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, —C(O)OR 11 , —(C 1-4 alkylene)-OR 12 , —(C 1-4 alkylene)-CN, and —(C 1-4 alkylene)-C(O)OR 11 ; R 3 is hydrogen, C 1-6 alkyl, halogen, hydroxyl, C 1-4 alkoxy, C 3-6 cycloalkyl, or —C(O)OR 11 ; R 4 is hydrogen, halogen, hydroxyl, or C 1-6 alkyl; R 5 is C 1-8 alkyl, phenyl optionally substituted by a C 1-6 alkyl, 5- to 6-membered heteroaryl, —C(O)OR 8 , —C(O)R 9 , or —S(O)R 10 (n is 0, 1, or 2), wherein the C 1-8 alkyl is optionally substituted by one or two substituents independently selected from the group consisting of C 6-10 aryl, 5- to 10-membered heteroaryl, C(O)OR 11 , OR 12 , C(O)NR a R b , and —(C 1-8 alkyl)-(C 6-10 aryl); and any aryl or heteroaryl is optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and cyano; R 8 is hydrogen, C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or benzyl; R 9 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl, or —(C 1-4 alkylene)-phenyl; R 10 is C 1-8 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or benzyl; R 11 is hydrogen or C 1-6 alkyl; R 12 is hydrogen or C 1-6 alkyl; and R a and R b are independently hydrogen or C 1-6 alkyl.
10 . The method of claim 8 , wherein:
R 1 is selected from the group consisting from C 1 -C 6 alkyl,
wherein each X is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or CN; and each R 13 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl,
wherein R x is halogen, —(CH 2 ) n CN, or —(CH 2 ) n OR 14 , wherein each n is 0, 1, or 2; each R 14 is independently H or C 1 -C 6 alkyl; and R a and R b are independently hydrogen or C 1-6 alkyl;
R 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and —C(O)OR 15 , wherein R 15 is H or C 1 -C 6 alkyl;
R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxyl, and C 1 -C 6 alkoxy; and/or
R 5 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, 5-membered heteroaryl,
and —C(O)—R 9 , where R 9 is C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl; and each R 16 is
independently halogen or C 1 -C 6 alkyl.
11 . The method of claim 8 , wherein:
R 1 is
wherein X is Cl;
R 2 is selected from
wherein each R 14 is independently H or C 1 -C 6 alkyl;
R 3 is isopropyl, hydroxyl, or methoxy;
R 4 is hydrogen; and
R 5 is
12 . The method of claim 8 , wherein the compound is selected from:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
13 . The method of claim 8 , wherein the disease or disorder is selected from medulloblastoma, basal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, advanced stomach cancer, oesophageal cancer, glioblastoma multiforme, acute leukemia, chronic myeloid leukemia, myelofibrosis, essential thrombocythaemia, metastatic colorectal cancer, small-cell lung cancer, and chondrosarcoma.
14 . The method of claim 12 , wherein the disease or disorder is selected from medulloblastoma, basal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, advanced stomach cancer, oesophageal cancer, glioblastoma multiforme, acute leukemia, chronic myeloid leukemia, myelofibrosis, essential thrombocythaemia, metastatic colorectal cancer, small-cell lung cancer, and chondrosarcoma.
15 . The method of claim 8 , wherein the pharmaceutical composition is a formulation selected from capsules, cachets, pills, tablets, lozenges, powders, granules, pastilles, solutions, suspensions, emulsions, elixirs, and syrups.
16 . The method of claim 8 , wherein said administering is selected from oral, nasal, topical, rectal, vaginal, and/or parenteral administrations.Join the waitlist — get patent alerts
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