US 10,118,916 B2Granted

Modulators of cystic fibrosis transmembrane conductance regulator protein

AssigneesAbbVie S.á.r.l., Galapagos NV

InventorsRobert J. Altenbach, Andrew Bogdan, Vincent Chan, Timothy A. Grieme, John R. Koenig, Philip R. Kym, Bo Liu, Karine Fabienne Malagu, Sachin V. Patel, Marc Scanio, Xenia B. Searle, Shashank Shekhar, Xueqing Wang, Ming C. Yeung

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Abstract

The present invention provides for compounds of formula (I) wherein R1, m, Z, G1, R2, and R3 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

Claims50

Dependent claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
Z is O;
R1 groups are optional substituents on the benzo ring, and are each independently halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, —ORj, or —SRj;
m is 0, 1, 2, 3, or 4;
R2 is hydrogen or C1-C3 alkyl;
R3 is formula (a)
wherein
R3a and R3b are each independently C1-C3 alkyl;
or R3a and R3b together with the carbon atom to which they are attached, form a cyclopropyl, a cyclobutyl, or a cyclopentyl;
wherein the cyclopropyl, the cyclobutyl, and the cyclopentyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halogen;
and
G2 is formula (b), phenyl, or —O-phenyl, wherein the phenyl and the phenyl moiety of —O-phenyl are each optionally substituted with 1, 2, 3, or 4 Rx groups;
wherein
each Rx is independently halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —ORj, or —SRj;
X1 is a bond or O;
Y1 is O, CH2, or —O—CH2— wherein the —O—CH2— is connected to the benzo ring via the oxygen atom;
Y2 is O;
R4 and R5 are each independently hydrogen or halogen;
R6 groups are optional substituents on the benzo ring, and are each independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, —CN, —ORj, or —SRj;
and
n is 0, 1, 2, or 3;
G1 is phenyl, monocyclic heteroaryl, or C3-C6 cycloalkyl;
wherein each G1 is optionally substituted with 1, 2, 3, or 4 R9 groups;
each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, oxo,
NO2, —ORj, —OC(O)Rk, —OC(O)N(Rj)2, —SRj, —S(O)2Rj, —S(O)2N(Rj)2, —C(O)Rj, —C(O)ORj, —C(O)N(Rj)2, —C(O)N(Rj)S(O)2Rk, —N(Rj)2, —N(Rj)C(O)Rk, —N(Rj)S(O)2Rk, —N(Rj)C(O)O(Rk), —N(Rj)C(O)N(Rj)2, —(C1-C6 alkylenyl)-ORj, —(C1-C6 alkylenyl)-OC(O)Rk, —(C1-C6 alkylenyl)-OC(O)N(Rj)2, —(C1-C6 alkylenyl)-SRj, —(C1-C6 alkylenyl)-S(O)2Rj, —(C1-C6 alkylenyl)-S(O)2N(Rj)2, —(C1-C6 alkylenyl)-C(O)Rj, —(C1-C6 alkylenyl)-C(O)ORj, —(C1-C6 alkylenyl)-C(O)N(Rj)2, —(C1-C6 alkylenyl)-C(O)N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)-N(Rj)2, —(C1-C6 alkylenyl)-N(Rj)C(O)Rk, —(C1-C6 alkylenyl)-N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)-N(Rj)C(O)O(Rk), —(C1-C6 alkylenyl)-N(Rj)C(O)N(Rj)2, or —(C1-C6 alkylenyl)-CN;
Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
and
Rk, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl;
with the proviso that when R2 is hydrogen, Z is O, R3 is formula (a), R3a and R3b together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, and G2 is formula (b) wherein Y1 is O, R4 and R5 are halogen, X1 is a bond, n is 0 or 1, and R6 is halogen;
then G1 is optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, or
wherein * is the point of connection, R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
and s is 0, 1, 2, or 3.

29 more elements

A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
Z is O;
R1 groups are optional substituents on the benzo ring, and are each independently halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, —ORj, or —SRj;
m is 0, 1, 2, 3, or 4;
R2 is hydrogen or C1-C3 alkyl;
R3 is formula (c)
wherein
X2 is O or CH2;
RA is Ci-C3 alkyl;
R7 groups are optional substituents on the benzo ring, and are each independently halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —ORj, or —SRj;
and
p is 0, 1, 2, 3, or 4;
G1 is phenyl, monocyclic heteroaryl, or C3-C6 cycloalkyl;
wherein each Gl is optionally substituted with 1, 2, 3, or 4 R9 groups;
each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, oxo,
NO2, —ORj, —OC(O)Rk, —OC(O)N(Rj)2, —SRj, —S(O)2Rj, —S(O)2N(Rj)2, —C(O)Rj, —C(O)ORj,—C(O)N(Rj)2, —C(O)N(Rj)S(O)2Rk, —N(Rj)2, —N(Rj)C(O)Rk, —N(Rj)S(O)2Rk, —N(Rj)C(O)O(Rk), —N(Rj)C(O)N(Rj)2, —(C1-C6 alkylenyl)—ORj, —(C1-C6 alkylenyl)—OC(O)Rk, —(C1-C6 alkylenyl)—OC(O)N(Rj)2, —(C1-C6 alkylenyl)—SRj, —(C1-C6 alkylenyl)—S(O)2Rj, —(C1-C6 alkylenyl)—S(O)2N(Rj)2, —(C1-C6 alkylenyl)—C(O)Rj, —(C1-C6 alkylenyl)-C(O)ORj, —(C1-C6 alkylenyl)—C(O)N(Rj)2, —(C1-C6 alkylenyl)—C(O)N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)—N(Rj)2, —(C1-C6 alkylenyl)—N(Rj)C(O)Rk, —(C1-C6 alkylenyl)—N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)—N(Rj)C(O)O(Rk), —(C1-C6 alkylenyl)—N(Rj)C(O)N(Rj)2, or —(C1-C6 alkylenyl)—CN;
Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
and
Rk, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl;
with the proviso that when R2 is hydrogen, Z is O, R3 is formula (a), R3a and R3b together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, and G2 is formula (b) wherein Y1 is O, R4 and R5 are halogen, X1 is a bond, n is 0 or 1, and R6 is halogen;
then G1 is optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, or
wherein * is the point of connection, R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
and s is 0, 1, 2, or 3.

20 more elements

A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
Z is O;
R1 groups are optional substituents on the benzo ring, and are each independently halogen, —CN, C1-C3 alkyl, C1-C3 haloalkyl, —ORj, or —SRj;
m is 0, 1, 2, 3, or 4;
R2 is hydrogen or C1-C3 alkyl;
R3 is formula (d)
wherein
r is 1 or 2;
q is 0, 1, 2, 3, or 4;
RB is C1-C3 alkyl;
R8 groups are optional substituents on the benzo ring, and are each independently halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —ORj, or —SRj;
G1 is phenyl, monocyclic heteroaryl, or C3-C6 cycloalkyl;
wherein each G1 is optionally substituted with 1, 2, 3, or 4 R9 groups;
each R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, oxo,
NO2, —ORj, —OC(O)Rk, —OC(O)N(Rj)2, —SRj, —S(O)2Rj, —S(O)2N(Rj)2, —C(O)Rj, —C(O)ORj, —C(O)N(Rj)2, —C(O)N(Rj)S(O)2Rk, —N(Rj)2, —N(Rj)C(O)Rk, —N(Rj)S(O)2Rk, —N(Rj)C(O)O(Rk), —N(Rj)C(O)N(Rj)2, —(C1-C6 alkylenyl)—ORj, —(C1-C6 alkylenyl)—OC(O)Rk, —(C1-C6 alkylenyl)—OC(O)N(Rj)2, —(C1-C6 alkylenyl)—SRj, —(C1C6 alkylenyl)—S(O)2Rj, —(C1-C6 alkylenyl)—S(O)2N(Rj)2, —(C1-C6 alkylenyl)—C(O)Rj, —(C1-C6 alkylenyl)—C(O)ORj, —(C1-C6 alkylenyl)—C(O)N(Rj)2, —(C1-C6 alkylenyl)—C(O)N(R)S(O)2Rk, —(C1-C6 alkylenyl)—N(Rj)2, —(C1-C6 alkylenyl)—N(Rj)C(O)Rk, —(C1-C6 alkylenyl)—N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)—N(Rj)C(O)O(Rk), —(C1-C6 alkylenyl)—N(Rj)C(O)N(Rj)2, or —(C1-C6 alkylenyl)—CN;
Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
and
Rk, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl;
with the proviso that when R2 is hydrogen, Z is O, R3 is formula (a), R3a and R3b together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, and G2 is formula (b) wherein Yl is O, R4 and R5 are halogen, X1 is a bond, n is 0 or 1, and R6 is halogen;
then G1 is optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, or
wherein * is the point of connection, R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
and s is 0, 1, 2, or 3.

19 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/496,094Filed 25 Apr 2017 · us provisional application
Priority: 26 Apr 2016
Published: US 2017/0305891 A126 Oct 2017
Granted: 6 Nov 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 407/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/353
Condensed with carbocyclic rings, e.g. methantheline: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
A61K 31/36
Having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel: compounds containing methylenedioxyphenyl groups, e.g. sesamin
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…

Family

Application62/327,669Us provisional application · filed 26 Apr 2016
US 2017/0305891 A1Pre-grant publication · published 26 Oct 2017
US 10,118,916 B2This patent

From the US filing history. Foreign family members aren’t listed.

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