US2018354959A1PendingUtilityA1
Therapeutic compounds, compositions and methods of use thereof
Est. expiryFeb 18, 2036(~9.6 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 29/00A61P 11/06C07D 487/04
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Claims
Abstract
salts thereof and methods of use as Janus kinase inhibitors are described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 0 -C 3 alkyl)CN, —(C 0 -C 3 alkyl)OR a , —(C 0 -C 3 alkyl)R a , —(C 0 -C 3 alkyl)SR a , —(C 0 -C 3 alkyl)NR a R b , —(C 0 -C 3 alkyl)OCF 3 , —(C 0 -C 3 alkyl)CF 3 , —(C 0 -C 3 alkyl)NO 2 , —(C 0 -C 3 alkyl)C(O)R a , —(C 0 -C 3 alkyl)C(O)OR a , —(C 0 -C 3 alkyl)C(O)NR a R b , —(C 0 -C 3 alkyl)NR a C(O)R b , —(C 0 -C 3 alkyl)S(O) 1-2 R a , —(C 0 -C 3 alkyl)NR a S(O) 1-2 R b , —(C 0 -C 3 alkyl)S(O) 1-2 NR a R b , —(C 0 -C 6 alkyl)(5-6-membered heteroaryl) or —(C 0 -C 6 alkyl)phenyl, wherein R 1 is optionally substituted by one or more groups independently selected from the group consisting of halogen, C 1 -C 3 alkyl, oxo, —CF 3 , —(C 0 -C 3 alkyl)OR c and —(C 0 -C 3 alkyl)NR c R d ;
R a is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, —C(O)R c , —C(O)OR c , —C(O)NR c R d , —NR c C(O)R d , —S(O) 1-2 R, —NR c S(O) 1-2 R d or —S(O) 1-2 NR c R d , wherein any C 3 -C 6 cycloalkyl, and 3-10 membered heterocyclyl of R a is optionally substituted with one or more groups R e ;
R b is independently hydrogen or C 1 -C 3 alkyl, wherein said alkyl is optionally substituted by one or more groups independently selected from the group consisting of halogen and oxo;
R c and R d are independently selected from the group consisting of hydrogen, 3-6 membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 1 -C 3 alkyl, wherein any 3-6 membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 1 -C 3 alkyl of R c and R d is optionally substituted by one or more groups independently selected from the group consisting of halogen and oxo; or R c and R d are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by one or more groups independently selected from the group consisting of halogen, oxo, —CF 3 , and C 1 -C 3 alkyl;
each R e is independently selected from the group consisting of oxo, OR f , NR f R g , halogen, 3-10 membered heterocyclyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkyl, wherein any C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl of R e is optionally substituted by one or more groups independently selected from the group consisting of OR f , NR f R g , halogen, 3-10 membered heterocyclyl, oxo, and cyano, and wherein any 3-10 membered heterocyclyl of R e and any 3-10 membered heterocyclyl group substituted on a C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl of R e is optionally substituted by one or more groups independently selected from the group consisting of halogen, oxo, cyano, —CF 3 , NR h R k , 3-6 membered heterocyclyl, and C 1 -C 3 alkyl that is optionally substituted by one or more groups independently selected from the group consisting of halogen, oxo, OR f , and NR h R k ;
R f and R g are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, 3-6 membered heterocyclyl, and C 3 -C 6 cycloalkyl, wherein any C 1 -C 6 alkyl, 3-6 membered heterocyclyl, and C 3 -C 6 cycloalkyl of R f and R g is optionally substituted by one or more R m ;
R h and R k are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl that is optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, 3-6 membered heterocyclyl, and oxo; or R h and R k are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl that is optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, oxo, —CF 3 and C 1 -C 3 alkyl that is optionally substituted by one or more groups independently selected from the group consisting of halogen and oxo;
each R m is independently selected from the group consisting of halogen, cyano, oxo, C 3 -C 6 cycloalkyl, hydroxy, and NR h R k , wherein any C 3 -C 6 cycloalkyl of R m is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, cyano, and C 1 -C 3 alkyl;
R 2 is phenyl, C 3 -C 6 cycloalkyl or 3-10 membered heterocyclyl, wherein R 2 is optionally substituted by 1-5 R n ;
each R n is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, oxo, halogen, —(C 0 -C 3 alkyl)CN, —(C 0 -C 3 alkyl)OR o , —(C 0 -C 3 alkyl)SR o , —(C 0 -C 3 alkyl)NR o R p , —(C 0 -C 3 alkyl)OCF 3 , —(C 0 -C 3 alkyl)CF 3 , —(C 0 -C 3 alkyl)NO 2 , —(C 0 -C 3 alkyl)C(O)R o , —(C 0 -C 3 alkyl)C(O)OR, —(C 0 -C 3 alkyl)C(O)NR o R p , —(C 0 -C 3 alkyl)NR o C(O)R p , —(C 0 -C 3 alkyl)S(O) 1-2 R o , —(C 0 -C 3 alkyl)NR o S(O) 1-2 R, —(C 0 -C 3 alkyl)S(O) 1-2 NR o R p , —(C 0 -C 3 alkyl)(C 3 -C 6 cycloalkyl), —(C 0 -C 3 alkyl)(3-6-membered heterocyclyl), —(C 0 -C 3 alkyl)C(O)(3-6-membered heterocyclyl), or —(C 0 -C 3 alkyl)phenyl, wherein R 5 is independently optionally substituted by halogen, C 1 -C 3 alkyl, oxo, —CF 3 , —(C 0 -C 3 alkyl)OR r or —(C 0 -C 3 alkyl)NR r R s ; or two R n are taken together to form —O(CH 2 ) 1-3 O—;
R 3 is H, halogen, cyano, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, —NH 2 , or —OR t
R 4 is H, halogen, cyano, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, —NH 2 , or —OR t ;
R 5 is H, halogen, cyano, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, —NH 2 , or —OR t ;
R 6 is H, halogen, cyano, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, —NH 2 , or —OR t ;
R o is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, (C 3 -C 6 cycloalkyl)C 1 -C 6 alkyl, (3-6-membered heterocyclyl)C 1 -C 6 alkyl, —C(O)(C 3 -C 6 cycloalkyl), or —C(O)(3-6-membered heterocyclyl), —C(O)R r , —C(O)OR r , —C(O)NR r R s , —NR r C(O)R s , —S(O) 12 R r , —NR r S(O) 1-2 R s or —S(O) 1-2 NR r R s , wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by oxo, C 1 -C 3 alkyl, OR r , NR r R s or halogen;
R p is independently hydrogen or C 1 -C 3 alkyl, wherein said alkyl is independently optionally substituted by halogen or oxo;
or R o and R p are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by halogen, oxo, or C 1 -C 3 alkyl optionally substituted by halogen;
R r and R s are independently hydrogen or C 1 -C 3 alkyl optionally substituted by halogen or oxo; or R r and R s are taken together with the atom to which they are attached to form a 3-6-membered heterocyclyl, optionally substituted by halogen, oxo, or C 1 -C 3 alkyl optionally substituted by halogen; and
each R t is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or —(C 0 -C 3 alkyl)phenyl.
2 . The compound of claim 1 wherein R 1 is —(C 0 -C 3 alkyl)NR a R b , or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 wherein R 1 is H or —(C 0 -C 3 alkyl)R a , or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 wherein R 1 is —(C 0 -C 3 alkyl)C(O)R a , or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, methyl,
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, methyl,
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R e is selected from the group consisting of methyl, ethyl,
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R e is selected from the group consisting of,
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl that is optionally substituted by 1-5 R n .
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl that is optionally substituted by 1-2 R n .
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
12 . The compound of claim 1 wherein R 3 is H, —NH 2 , or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 wherein R 4 is H, or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 wherein R 5 is H, chloro, or ethynyl, or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, R 4 is H, and R 5 is H.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, R 4 is H, and R 5 is chloro.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, R 4 is H, and R 5 is ethynyl.
18 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
20 . A method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
21 . The method of claim 20 , wherein the disease or condition is asthma.
22 . The method of claim 20 , wherein the Janus kinase is JAK1.Join the waitlist — get patent alerts
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