US2024025919A1PendingUtilityA1

Aza-tetracyclic oxazepine compounds and uses thereof

Assignee: GENENTECH INCPriority: May 19, 2022Filed: May 19, 2023Published: Jan 25, 2024
Est. expiryMay 19, 2042(~15.8 yrs left)· nominal 20-yr term from priority
A61P 35/04A61P 35/00A61K 31/553C07D 498/22A61K 45/06C07D 519/00
72
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Claims

Abstract

Provided herein are aza-tetracyclic oxazepinyl compounds useful in the treatment of cancers.

Claims

exact text as granted — not AI-modified
1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6—or 7-membered ring Ring A; 
         p is 0, 1, or 2, 
         R 1  is formula 
       
       
         
           
           
               
               
           
         
       
       wherein X 1  is N or CR 7C  and R 7C  is hydrogen or halogen;
 each R 7A  is independently halogen, CN, NH 2 , N(Me) 2 , R 7B -substituted or unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or unsubstituted cyclopropyl; 
 R 7B  is CN, oxo, or C 1-3  alkyl; 
 L 1  is R L1 -substituted or unsubstituted C 1-4  alkylene; 
 R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3.4 cycloalkyl; 
 R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
 R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3 0.4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
 each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
 R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
 each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
 R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
 or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
 two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ; 
 R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
 R 6  is hydrogen, R 6A -substituted or unsubstituted C 1 -6 alkyl, R 6A -substituted or unsubstituted C 1 -s haloalkyl, R 6A -substituted or unsubstituted C 1 -6 alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
 R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
 R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
 
     
     
         2 - 3 . (canceled) 
     
     
         4 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6— or 7-membered ring Ring A; 
         p is 0, 1, or 2; 
         R 1  is (E2) or (E3) 
       
       
         
           
           
               
               
           
         
         each R 7A  is independently hydrogen, halogen, unsubstituted C 1-3  alkyl or unsubstituted C 1-3  haloalkyl; 
         L 1  is R L1 -substituted or unsubstituted C 1-4  alkylene; 
         R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3.4 cycloalkyl; 
         R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
         R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3-4  cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
         each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
         R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
         each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
         R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
         two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ; 
         R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
         R 6  is hydrogen, R 6A -substituted or unsubstituted C 1 -6 alkyl, R 6A -substituted or unsubstituted C 1 -s haloalkyl, R 6A -substituted or unsubstituted C 1 -6 alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
         R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
         R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
       
     
     
         5 - 8 . (canceled) 
     
     
         9 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6— or 7-membered ring Ring A; 
         p is 0, 1, or 2; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         L 1  is R L i-substituted or unsubstituted C 1-4  alkylene; 
         R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3-4 cycloalkyl; 
         R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
         R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3 0.4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
         each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
         R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
         each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
         R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
         two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ; 
         R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
         R 6  is hydrogen, R 6A -substituted or unsubstituted C 1 -6 alkyl, R 6A -substituted or unsubstituted C 1 -s haloalkyl, R 6A -substituted or unsubstituted C 1 -6 alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
         R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
         R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
       
     
     
         10 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6— or 7-membered ring Ring A; 
         p is 0, 1, or 2; 
         R 1  is R 7A -substituted phenyl or R 7A  substituted pyridinyl; 
         each R 7A  is independently halogen, NH 2 , unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         L 1  is R L1 -substituted or unsubstituted C 1-4  alkylene; 
         R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3.4 cycloalkyl; 
         R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
         R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3 0.4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
         each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
         R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
         each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
         R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
         two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of 0 or NR 11 ; 
         R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
         R 6  is hydrogen, R 6A -substituted or unsubstituted C 1 -6 alkyl, R 6A -substituted or unsubstituted C 1 -s haloalkyl, R 6A -substituted or unsubstituted C 1-6  alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
         R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
         R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
       
     
     
         11 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6— or 7-membered ring Ring A; 
         p is 0, 1, or 2; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         L 1  is R L1 -substituted or unsubstituted C 1-4  alkylene; 
         R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3.4 cycloalkyl; 
         R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
         R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3 0.4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
         each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
         R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
         each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
         R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
         two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ; 
         R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
         R 6  is hydrogen, R 6A -substituted or unsubstituted C 1-6  alkyl, R 6A -substituted or unsubstituted C 1 -s haloalkyl, R 6A -substituted or unsubstituted C 1 -6 alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
         R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
         R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
       
     
     
         12 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6— or 7-membered ring Ring A; 
         p is 0, 1, or 2; 
         R 1  is of formula 
       
       
         
           
           
               
               
           
         
         each R 7A  is independently halogen, CN, NH 2 , N(Me) 2 , R 7B -substituted or unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or unsubstituted cyclopropyl; 
         R 7B  is CN, oxo, or C 1-3  alkyl; 
         L 1  is R L i-substituted or unsubstituted C 1-4  alkylene; 
         R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3.4 cycloalkyl; 
         R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
         R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3 0.4 cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
         each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
         R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
         each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
         R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
         two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ; 
         R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
         R 6  is hydrogen, R 6A -substituted or unsubstituted C 1-6  alkyl, R 6A -substituted or unsubstituted C 1-6  haloalkyl, R 6A -substituted or unsubstituted C 1-6  alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
         R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
         R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
       
     
     
         13 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, 
         wherein 
         X is O or NR 6 ; 
         m is 1 or 2; 
         n is 1 or 2; 
         wherein n and m together make a 6— or 7-membered ring Ring A; 
         p is 0, 1, or 2; 
         R 1  is 
       
       
         
           
           
               
               
           
         
         L 1  is R L1 -substituted or unsubstituted C 1-4  alkylene; 
         R L1  is halogen or unsubstituted C 1-3  alkyl, or wherein two R L1  together form an unsubstituted C3.4 cycloalkyl; 
         R 2  is R 9 -substituted or unsubstituted 4-10 membered heterocycle comprising one or more heteroatoms selected from N, S, or O; 
         R 9  is independently halogen, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, R 10 -substituted or unsubstituted C 1-3  alkyl, R 10 -substituted or unsubstituted C 1-3  haloalkyl, unsubstituted C 1-3  alkoxy, R 10 -substituted or unsubstituted C 1-3  alkylidene, or R 10 -substituted or unsubstituted C 3-4  cycloalkyl, or R 10 -substituted or unsubstituted 3 or 4-membered heterocycle; or wherein two R 9  together form a R 10 -substituted or unsubstituted C 3-5  cycloalkyl or a R 10 -substituted or unsubstituted C 3-5  heterocycle comprising one or more oxygen atoms; or wherein two R 9  together form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1-3 carbons; 
         each R 10  is independently hydrogen, oxo, CN, halogen, or C 1-3  unsubstituted alkyl; 
         R 3  is hydrogen, —CN, halogen, unsubstituted C 1-3  alkyl, or unsubstituted cyclopropyl; 
         each R 4  is independently hydrogen, methyl, or C 1-3  haloalkyl; 
         R 5  is independently halogen, oxo, unsubstituted C 1-3  alkyl, or unsubstituted C 1-3  haloalkyl; 
         or wherein two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1-3 carbons and optionally one heteroatom selected from O and N; or 
         two R 5  together form a bridge between two carbon atoms of Ring A, wherein the bridge comprises one of O or NR 11 ; 
         R 11  is hydrogen, C(O)CH 3 , or unsubstituted C 1-3  alkyl; 
         R 6  is hydrogen, R 6A -substituted or unsubstituted C 1 -6 alkyl, R 6A -substituted or unsubstituted C 1 -s haloalkyl, R 6A -substituted or unsubstituted C 1 -6 alkenyl; R 6A -substituted or unsubstituted C 1-6  alkynyl, or R 6A -substituted or unsubstituted 3-4 membered heterocycle; 
         R 6A  is halogen, CN, OR 6B , SR 6C , S(O) 2 R 6C , C(O)R 6B , unsubstituted C 1-3  alkyl, unsubstituted C 1-3  haloalkyl, or R 6B -substituted or unsubstituted 3-4 membered heterocycle; and 
         R 6B  and R 6C  are each independently C 1-3  alkyl or C 1-3  haloalkyl. 
       
     
     
         14 - 23 . (canceled) 
     
     
         24 . The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 1 , wherein R 2  is: 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, wherein 
         R 9  is independently halogen or R 10 -substituted or unsubstituted C 1-3  alkylidene; 
         each R 10  is independently hydrogen or halogen; and 
         r is 1 or 2. 
       
     
     
         25 . The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 1 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof. 
     
     
         26 - 39 . (canceled) 
     
     
         40 . The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 1 , wherein the compound of formula (I) comprises formula: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. 
     
     
         41 . (canceled) 
     
     
         42 . A compound selected from compounds 1-291 in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. 
     
     
         43 - 51 . (canceled) 
     
     
         52 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 1 , and one or more pharmaceutically acceptable excipients. 
     
     
         53 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
         54 - 81 . (canceled) 
     
     
         82 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 4 , and one or more pharmaceutically acceptable excipients. 
     
     
         83 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 9 , and one or more pharmaceutically acceptable excipients. 
     
     
         84 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 10 , and one or more pharmaceutically acceptable excipients. 
     
     
         85 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 11 , and one or more pharmaceutically acceptable excipients. 
     
     
         86 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 12 , and one or more pharmaceutically acceptable excipients. 
     
     
         87 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 13 , and one or more pharmaceutically acceptable excipients. 
     
     
         88 . A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 42 , and one or more pharmaceutically acceptable excipients. 
     
     
         89 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 4 . 
     
     
         90 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 9 . 
     
     
         91 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 10 . 
     
     
         92 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 11 . 
     
     
         93 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 12 . 
     
     
         94 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 13 . 
     
     
         95 . A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of  claim 42 .

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