US2020255423A1PendingUtilityA1
Inhibitors of tyrosine kinase 2 mediated signaling
Est. expiryMar 12, 2038(~11.7 yrs left)· nominal 20-yr term from priority
Inventors:Maria A. ArgiriadiEric C. BreinlingerEllen ChienMarlon D. CowartKristine E. FrankMichael FriedmanDavid J. HardeeJ. Martin HeroldHuaqing LiuWei QiuMarc J. ScanioMichael R. SchrimpfThomas R. VargoStacy A. Van EppsMatthew P. WebsterAndrew LittleMatthew H. KatcherTheresa A. DunstanDavid A. Schiedler
C07D 487/04C07D 471/04
57
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Claims
Abstract
Disclosed herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4a , R 4b , X 1 , X 2 , X 3 , X 4 , X 5 , and n are as defined herein, pharmaceutical compositions comprising same, and methods of preparation and use.
Claims
exact text as granted — not AI-modified1 - 30 . (canceled)
31 . A compound of claim 64 , wherein the compound is of Formula (II-a) or Formula (II-b):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is unsubstituted or substituted C 1-3 alkyl, unsubstituted or substituted C 3-4 carbocyclyl, or unsubstituted or substituted 4- to 5-membered heterocyclyl;
R 2 is —NH 2 , —NHR 2a , or unsubstituted or substituted C 1-3 alkyl, and R 2a is unsubstituted or substituted C 1-3 alkyl;
R 3 is —(C 1-3 alkylene) m -OR 3a , —(C 1-3 alkylene) m -N(R 3a ) 2 , C 1-3 alkyl, or C 1-3 haloalkyl, wherein m is 0 or 1, and each instance of R 3a is independently hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl;
each instance of R 4a and R 4b is hydrogen;
R 5 is hydrogen, —CN, —OR 5a , —NHR 5a , or unsubstituted or substituted C 1-6 alkyl, wherein R 5a is unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 carbocyclyl, unsubstituted or substituted C 3-6 carbocyclylC 1-3 alkyl, unsubstituted or substituted 4- to 6-membered heterocyclyl, or unsubstituted or substituted 4- to 6-membered heterocyclylC 1-3 alkyl;
n is 0 or 1; and
each instance of substituted is independent substitution with 1, 2, or 3 substituents selected from the group consisting of halogen, —CN, —OH, C 1-3 alkyl, C 1-3 haloalkyl, —OC 1-3 alkyl, and —OC 1-3 haloalkyl.
32 . (canceled)
33 . The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , F,
34 . The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —NH 2 , —NHCH 3 , —OCH 3 , —CH 3 , or —CH 2 OH.
35 . The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —OH, —OCH 3 , —CH 2 OH, —CH 2 NH 2 , —CH(OH)CH 3 , —CH 3 , or CH 2 CH 3 .
36 . The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —OCHF 2 , —OCH 2 CN,
37 . (canceled)
38 . The compound of claim 31 , wherein the compound is of Formula (III-a) or Formula (IV-a):
or a pharmaceutically acceptable salt thereof.
39 . The compound of claim 38 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is —CH 3 , —CH 2 F, —CHF 2 , —CF 3
R 2 is —NH 2 , —NHCH 3 , —OCH 3 , —CH 3 , or —CH 2 OH;
R 5 is hydrogen, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 —OCH(CH 3 ) 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —OCHF 2 , —OCH 2 CN,
and
n is 1.
40 . (canceled)
41 . The compound of claim 38 , or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or —CH 3 .
42 - 51 . (canceled)
52 . The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-ii-II-a) or (I-iii-II-a):
or a pharmaceutically acceptable salt thereof, wherein each of R 1a and R 1b is independently hydrogen or —CH 3 , and R 1c is C 1-3 alkyl, C 1-3 haloalkyl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl.
53 . The compound of claim 52 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is —NH 2 , —NHCH 3 , —OCH 3 , —CH 3 , or —CH 2 OH; R 3 is —OH, —OCH 3 , —CH 2 OH, —CH 2 NH 2 , —CH(OH)CH 3 , —CH, or CH 2 CH 3 ; R 5 is hydrogen, —CN, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —OCHF 2 , —OCH 2 CN,
and
n is 1.
54 - 56 . (canceled)
57 . A compound of claim 64 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
58 - 63 . (canceled)
64 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen, or R 1 is unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 carbocyclyl, or unsubstituted or substituted 4- to 6-membered heterocyclyl;
R 2 is —NH 2 , —NHR 2a , —OR 2a , unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted C 3 carbocyclyl, and R 2a is unsubstituted or substituted C 1-6 alkyl or unsubstituted or substituted C 3 carbocyclyl;
R 3 is hydrogen, —(C 1-3 alkylene) m -OR 3a , —(C 1-3 alkylene) m -N(R 3a ) 2 , C 1-3 alkyl, or C 1-3 haloalkyl, wherein m is 0 or 1, and each instance of R 3a is independently hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl;
n is 0 or 1, and each instance of R 4a and R 4b is independently hydrogen, halogen, C 1-3 alkyl, or C 1-3 haloalkyl, or R 4a and R 4b are joined to form an oxo (═O) group; or
n is 1, R 4a is hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl, and R 4b is —OH, —OR 4c , or —OC(═O)R 4d , wherein each instance of R 4c and R 4d is independently unsubstituted or substituted C 1-3 alkyl;
X 3 is N or CR 5 , wherein R 5 is hydrogen, —CN, —OR 5a , —NHR 5a , or unsubstituted or substituted C 1-6 alkyl, and R 5a is unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 carbocyclyl, unsubstituted or substituted C 3-6 carbocyclylC 1-3 alkyl, unsubstituted or substituted 4- to 6-membered heterocyclyl, or unsubstituted or substituted 4- to 6-membered heterocyclylC 1-3 alkyl;
each instance of X 1 , X 2 , X 4 , and X 5 is independently N or CH, provided no more than two of X 2 , X 3 , and X 4 is N; and
each instance of substituted is independent substitution with 1, 2, or 3 substituents selected from the group consisting of halogen, —CN, —OH, C 1-3 alkyl, C 1-3 haloalkyl, —OC 1-3 alkyl, and —OC 1-3 haloalkyl.
65 . (canceled)
66 . A method of treating a disease comprising administering an effective amount of a compound of claim 64 , or pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the disease is inflammatory bowel disease or psoriasis.
67 . A method of preparing a compound of claim 31 , or salt thereof, from a compound of Formula (D-II-a), or salt thereof, or from a compound of Formula (H-II-a), or salt thereof:
wherein LG 4 is a leaving group;
(i) the method comprising treating a compound of Formula (D-II-a), or salt thereof, with a compound of formula R 1 -LG 3 , wherein R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl, and LG 3 is a leaving group, to provide a compound of Formula (II-a), or salt thereof; or
(ii) the method comprising treating a compound of Formula (D-II-a), or salt thereof, with formaldehyde, under reductive amination conditions, to provide a compound of Formula (I), or salt thereof, wherein R 1 is —CH 3 ; or
(iii) the method comprising treating a compound of Formula (D-II-a), or salt thereof,
with an oxetan-3-one of Formula
wherein each of R 1a and R 1b is independently hydrogen or —CH 3 , followed by trapping of the in situ generated hemiaminal by fluorination to provide a fluorinated compound of Formula (I-i-II-a):
or salt thereof,
optionally wherein the compound of Formula (I-i-II-a), or salt thereof, is treated with a reducing agent to provide a compound of Formula (I-ii-II-a):
or salt thereof, or
optionally wherein the fluorine of the compound of Formula (I-i-II-a), or salt thereof, is replaced with a group R 1c , wherein R 1c is C 1-3 alkyl, C 1-3 haloalkyl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl, to provide a compound of Formula (I-iii-II-a):
or salt thereof; or
(iv) the method comprising coupling a compound of Formula (H-II-a), or salt thereof, with a compound of Formula R 2 C(═O)NH 2 , or salt thereof, in the presence of a palladium or copper catalyst, to provide a compound of Formula (I-II-a), or salt thereof.
68 . The method of claim 67 , wherein the compound of Formula (D-II-a), or salt thereof, is prepared from a compound of Formula (C-II-a):
or salt thereof, by deprotection of an amino protecting group, PG 1 .
69 . The method of claim 68 , wherein the compound of Formula (C-II-a), or salt thereof, is prepared from cross-coupling of a compound of Formula (A-II-a):
or salt thereof, with a compound of Formula (B-II-a):
or salt thereof, wherein LG 1 and LG 2 are each independently leaving groups.
70 . The method of claim 67 , wherein the compound of Formula (H-II-a), or salt thereof, is prepared from a compound of Formula (G-II-a):
or salt thereof;
(i) the method comprising treating a compound of Formula (G-II-a), or salt thereof, with a compound of formula R 1 -LG 3 , wherein R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 carbocyclyl, or optionally substituted 4- to 6-membered heterocyclyl, and LG 3 is a leaving group, to provide a compound of Formula (H-II-a), or salt thereof; or
(ii) the method comprising treating a compound of Formula (G-II-a), or salt thereof, with formaldehyde, under reductive amination conditions, to provide a compound of Formula (H-II-a), or salt thereof, wherein R 1 is —CH 3 ; or
(iii) the method comprising treating a compound of Formula (G-II-a), or salt thereof,
with an oxetan-3-one of Formula
wherein each of R 1a and R 1b is independently hydrogen or —CH 3 , followed by trapping of the in situ generated hemiaminal by fluorination, to provide a fluorinated compound of Formula (I-iv-II-a):
or salt thereof,
optionally wherein the compound of Formula (I-iv-II-a), or salt thereof, is treated with a reducing agent to provide a compound of Formula (I-v-II-a):
or salt thereof, or
optionally wherein the fluorine of the compound of Formula (I-iv-II-a), or salt thereof, is replaced with a group R 1c , wherein R 1c is C 1-3 alkyl, C 1-3 haloalkyl, —OC 1-3 alkyl, or —OC 1-3 haloalkyl, to provide a compound of Formula (I-vi-II-a):
or salt thereof.
71 . The method of claim 70 , wherein the compound of Formula (G-II-a), or salt thereof, is prepared from a compound of Formula (F-II-a):
or salt thereof, by deprotection of an amino protecting group, PG 1 .
72 . The method of claim 71 , wherein the compound of Formula (F-II-a), or salt thereof, is prepared from the cross-coupling of a compound of Formula (E-II-a):
or salt thereof, with a compound of Formula (B-II-a):
or salt thereof, wherein LG 1 and LG 2 are each independently leaving groups.
73 . A compound selected from the group consisting of:
and salts thereof, wherein n, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , LG 2 , LG 4 , R 1a , R 1b , R 1c , and PG 1 are as defined in claims 67 - 72 .Cited by (0)
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