US2022306606A1PendingUtilityA1
Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
Est. expirySep 30, 2036(~10.2 yrs left)· nominal 20-yr term from priority
Inventors:Timothy AlcacioMinson BaekPeter Diederik Jan GrootenhuisSara S. Hadida RuahRobert Michael HughesAli Keshavarz-ShokriRachel Mcauley-AokiJason MccartneyMark MillerFredrick Van GoorBeili ZhangCorey AndersonThomas ClevelandBryan A. FriemanHaripada KhatuyaPramod JoshiPaul KrenitskyVito MelilloFabrice PierreAndreas P. TerminJohnny UyJinglan ZhouAlexander Russell AbelaBrett B. BuschPrasuna Paraselli
C07D 401/14A61K 31/4439C07B 59/002C07B 2200/05A61P 11/00C07D 471/14A61K 31/5365A61P 1/16C07D 498/14A61K 31/519A61P 11/12A61P 43/00A61P 1/18
71
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Claims
Abstract
Compounds of Formula I:pharmaceutically acceptable salts thereof, deuterated derivatives of any of the foregoing, and metabolites of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
Claims
exact text as granted — not AI-modified1 - 62 . (canceled)
63 . A compound of Formula I:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
one of Y 1 and Y 2 is N and the other is CH;
X is chosen from O, NH, and N(C 1 -C 4 alkyl) groups;
R 1 is chosen from —(CR 2 ) k —O—(CR 2 ) m (CR) n (Ring A) n+1 groups,
wherein each Ring A is independently chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and
wherein each R is independently chosen from H, OH, and C 1 -C 2 alkyl groups optionally substituted with one or more halogens;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, C 1 -C 2 alkoxy groups, halogens, and cyano;
each R 3 is independently chosen from C 1 -C 2 alkyl groups optionally substituted with one or more OH groups;
each R 4 is independently chosen from halogens;
k is 0 or 1;
r is 0 or 1;
m is 0, 1, 2, or 3;
n is 0 or 1;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
64 . A compound of claim 63 , wherein the compound is of Formula II:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
X is chosen from O, NH, and N(C 1 -C 4 alkyl) groups;
R 1 is chosen from —(CR 2 ) k —O—(CR 2 ) m (CR) n (Ring A) n+1 groups,
wherein each Ring A is independently chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and wherein each R is independently chosen from H, OH, and C 1 -C 2 alkyl groups optionally substituted with one or more halogens;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, C 1 -C 2 alkoxy groups, halogens, and cyano;
each R 3 is independently chosen from C 1 -C 2 alkyl groups optionally substituted with one or more OH groups;
each R 4 is independently chosen from halogens;
k is 0 or 1;
r is 0 or 1;
m is 0, 1, 2, or 3;
n is 0 or 1;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
65 . A compound of claim 63 , wherein the compound is of Formula III:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R 1 is chosen from —(CR 2 ) k —O—(CR 2 ) m (CR) n (Ring A) n+1 groups,
wherein each Ring A is independently chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and
wherein each R is independently chosen from H, OH, and C 1 -C 2 alkyl groups optionally substituted with one or more halogens;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, C 1 -C 2 alkoxy groups, halogens, and cyano;
each R 3 is independently chosen from C 1 -C 2 alkyl groups optionally substituted with one or more OH groups;
each R 4 is independently chosen from halogens;
k is 0 or 1;
r is 0 or 1;
m is 0, 1, 2, or 3;
n is 0 or 1;
p is 0, 1, 2, 3, 4, or 5; and
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
66 . A compound according to claim 63 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein if R 2 is cyano, then R 2 is meta or para relative to the sulfur atom.
67 . A compound according to claim 63 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each Ring A is independently chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and each R is independently chosen from H and OH; each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, C 1 -C 2 alkoxy groups, and halogens; R 4 is F; k is 0; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; r is 0; and wherein m and n are not 0 at the same time.
68 . A compound according to claim 67 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R 1 is chosen from —O—(CR 2 ) m -Ring A groups,
wherein Ring A is chosen from C 3 -C 10 cycloalkyl groups groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and
m is 1 or 2.
69 . A compound according to claim 68 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 3 is a methyl group and q is 3 or 4.
70 . A compound according to claim 69 having Formula IV:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Ring A is chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C2alkyl groups, and halogens; and
each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, F, Cl, and C 1 -C 2 alkoxy groups;
m is 1 or 2; and
p is 0, 1, or 2.
71 . A compound according to claim 70 , wherein p is 0 or 1.
72 . A compound according to claim 70 having Formula V:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Ring A is chosen from 0 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens; and
each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, F, Cl, and C 1 -C 2 alkoxy groups;
m is 1 or 2; and
p is 0, 1, or 2.
73 . A compound according to claim 63 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 2 is independently chosen from CH 3 , OH, F, and OCH 3 .
74 . A compound according to claim 73 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 0 or 1.
75 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is a cyclopropyl group substituted with a halogenated C 1 alkyl group or a halogenated C 2 alkyl group.
76 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is a cyclopropyl group substituted with a CF 3 group.
77 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1, Ring A is a cyclopropyl group substituted with a CF 3 group, p is 0 or 1, and R 2 , if present, is a methyl group, a hydroxy group, or a methoxy group.
78 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 2, Ring A is a C 3 cycloalkyl group substituted with a CF 3 group, p is 0 or 1, and R 2 , if present, is a methyl group, a hydroxy group, or a methoxy group.
79 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 2, Ring A is a cyclopropyl group substituted with a CF 3 group, and p is 0.
80 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is chosen from C5 bicycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens.
81 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is a C 5 bicycloalkyl group optionally substituted with a halogen.
82 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is chosen from C 7 bicycloalkyl groups and C 7 tricycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens.
83 . A compound according to claim 72 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is an unsubstituted C 7 tricycloalkyl group.
84 . A compound according to claim 63 having a formula chosen from any one of the formulae depicted below:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.
85 . A compound according to claim 63 having:
(a) the following formula:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; or
(b) the following formula:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; or
(c) the following formula:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; or
(d) the following formula:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; or
(e) the following formula:
or a pharmaceutically acceptable salt thereof; or
(f) the following formula:
or a pharmaceutically acceptable salt thereof; or
(g) the following formula:
or a pharmaceutically acceptable salt thereof.
86 . A pharmaceutical composition comprising a compound, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, as defined in claim 63 .
87 . A pharmaceutical composition comprising at least one compound chosen from the compound of claim 63 , a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, and optionally one or more of:
(a) Compound II:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing;
(b) Compound III:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing; and
(c) a pharmaceutically acceptable carrier.
88 . The pharmaceutical composition according to claim 87 for use in a method of treating cystic fibrosis.
89 . A method of preparing a compound of Formula (F):
or a deuterated derivative thereof, or a salt of any of the foregoing, comprising reacting a compound of Formula (D) or salt thereof with a compound of Formula (E) or a salt thereof to generate a compound of Formula (F) or a salt thereof:
wherein in each of the formulae:
one of Y 1 and Y 2 is independently N and the other is independently CH;
each R 1 is independently chosen from —(CR 2 ) k —O—(CR 2 ) m (CR) n (Ring A) n+1 groups,
wherein each Ring A is independently chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and
wherein each R is independently chosen from H, OH, and C 1 -C 2 alkyl groups optionally substituted with one or more halogens;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, OH, C 1 -C 2 alkoxy groups, halogens, and cyano;
each R 4 is independently chosen from halogens;
X a is chosen from F or Cl;
each k is independently 0 or 1;
each r is independently 0 or 1;
each m is independently 0, 1, 2, or 3;
each n is independently 0 or 1; and
each p is independently 0, 1, 2, 3, 4, or 5; optionally, wherein each Y 2 is independently N; and each Y 1 is independently CH.
90 . The method of claim 89 , wherein reacting a compound of Formula (D) or a salt thereof with a compound of Formula (E) or salt thereof is performed in the presence of a base;
or comprises reacting a compound of Formula (D-1) with a coupling reagent and subsequently with a compound of Formula (E-1) in the presence of a base.
91 . The method of claim 89 which is a method of preparing a compound of Formula (F-1):
or a deuterated derivative thereof, or a salt of any of the foregoing, comprising reacting a compound of Formula (D-1) and a compound of Formula (E-1) to generate a compound of Formula (F-1) or a salt thereof:
wherein each Xa is independently chosen from F or Cl.
92 . The method of claim 91 , wherein reacting a compound of Formula (D-1) or a salt thereof with a compound of Formula (E-1) or a salt thereof is performed in the presence of a base; or comprises reacting a compound of Formula (D-1) with a coupling reagent and subsequently with a compound of Formula (E-1) in the presence of a base.
93 . A method of preparing a compound of Formula (D):
or a deuterated derivative thereof, or a salt of any of the foregoing, comprising:
reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B) or a salt thereof to generate a compound of Formula (C) or a salt thereof:
and
(ii) hydrolyzing the —C(O)OR a group of a compound of Formula (C) to generate a compound of Formula (D) or a salt thereof, wherein in each of the formulae:
one of Y 1 and Y 2 is independently N and the other is independently CH;
each R 1 is independently chosen from —(CR 2 ) k —O—(CR 2 ) m (CR) n (Ring A) n+1 groups,
wherein each Ring A is independently chosen from C 3 -C 10 cycloalkyl groups optionally substituted with one or more substituents each independently chosen from C 1 -C 2 alkyl groups, halogenated C 1 -C 2 alkyl groups, and halogens, and
wherein each R is independently chosen from H, OH, and C 1 -C 2 alkyl groups optionally substituted with one or more halogens;
each R 4 is independently chosen from halogens;
each R a is independently chosen from C 1 -C 4 alkyl;
each X a is independently chosen from F or Cl;
each k is independently 0 or 1;
each r is independently 0 or 1;
each m is independently 0, 1, 2, or 3; and
each n is independently 0 or 1;
optionally, wherein each Y 2 is independently N; and each Y 1 is independently CH.
94 . The method of claim 93 , wherein the hydrolysis of the —C(O)OR a group is performed in the presence of a base; optionally, wherein reacting a compound of Formula (A) or a salt thereof with a compound of Formula (B) or salt thereof is performed in the presence of a base.
95 . The method of claim 93 , wherein R a is ethyl or t-butyl.
96 . The method of claim 93 which is a method of preparing a compound of Formula (D-1).
or a deuterated derivative thereof, or a salt of any of the foregoing, comprising:
reacting a compound of Formula (A-1) or a salt thereof and a compound of Formula (B-1) or a salt thereof to generate a compound of Formula (C-1) or a salt thereof:
and
(ii) hydrolyzing the —C(O)OR a group of a compound of Formula (C-1) or a salt thereof to generate a compound of Formula (D-1) or a salt thereof,
wherein each R a is independently chosen from C 1 -C 4 alkyl; and each —X a is independently chosen from F or Cl; optionally, wherein the hydrolysis of the —C(O)OR a group is performed in the presence of a base.
97 . The method of claim 96 , wherein reacting a compound of Formula (A-1) or a salt thereof and a compound of Formula (B-1) or a salt thereof is performed in the presence of a base; optionally, wherein R a is ethyl or t-butyl.Cited by (0)
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