Modulators of Cystic Fibrosis Transmembrane Conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators

Patent metadata

Field	Value
Publication number	US-11866450-B2
Application number	US-202117323267-A
Country	US
Kind code	B2
Filing date	May 18, 2021
Priority date	Feb 15, 2018
Publication date	Jan 9, 2024
Grant date	Jan 9, 2024

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.

First claim

The invention claimed is:

1. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of Formula I:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:
Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
Ring B is a pyridinyl ring;
Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
X is O, NH, or an N(C1-C4 alkyl);
each R 1 is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
m is 0, 1, 2, 3, or 4;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
n is 0, 1, or 2;
each R 3 is methyl;
each R 4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7 groups, or optionally two R 4 , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; wherein:
k is 0, 1, 2, 3, 4, 5, or 6;
each Y is independently chosen from C(R 5 )(R 6 ) groups, —O—, and —NR a — groups, wherein a heteroatom in -(Y) k -R 7 is not bonded to another heteroatom in -(Y) k -R 7 , wherein:
each R 5 and R 6 is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5 and R 6 on the same carbon together form a C 3-5 cycloalkyl group or oxo;
 each of R 5 and R 6 is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and
each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

R 7 is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens;

q is 1, 2, 3 or 4; and
Z is a divalent linker of formula (L) r , wherein:
r is 1, 2, 3, 4, 5, or 6;
each L is independently chosen from C(R 8 )(R 9 ) groups, —O—, and —NR b — groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein:
each R 8 and R 9 is independently chosen from hydrogen, halogens, C 1 -C 2 haloalkyl groups, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and
each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

2. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula II-A or II-B:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:
the carbon denoted by * has S-stereochemistry or R-stereochemistry;
Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
Ring B is a pyridinyl ring;
Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
each R 1 is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
m is 0, 1, 2, 3, or 4;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
n is 0, 1, or 2;
each R 3 is methyl;
each R 4 is independently chosen from halogens, a hydroxyl group, an oxo group, a cyano group, and -(Y) k -R 7 groups, or optionally two R 4 , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein:
k is 0, 1, 2, 3, 4, 5, or 6;
each Y is independently chosen from C(R 5 )(R 6 ) groups, —O—, and —NR a — groups, wherein a heteroatom in -(Y) k -R 7 is not bonded to another heteroatom in -(Y) k -R 7 , wherein:
each R 5 and R 6 is independently chosen from hydrogen, halogens, a hydroxyl group, C 1 -C 4 alkyl groups, and C 3-5 cycloalkyl groups, or R 5 and R 6 on the same carbon together form a C 3-5 cycloalkyl group or oxo;
 each of R 5 and R 6 is optionally independently substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, halogens, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and
each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

R 7 is chosen from hydrogen, halogens, a cyano group, and C 3 -C 10 cycloalkyl groups optionally substituted with one or more groups chosen from C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, and halogens;

q is 1, 2, 3, or 4;
Z is a divalent linker of formula (L) r , wherein:
r is 1,2, 3, 4, 5, or 6;
each L is independently chosen from C(R 8 )(R 9 ) groups, —O—, and —NR b — groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein:
each R 8 and R 9 is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, C 1 -C 2 haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups; and
each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

3. The method of claim 1 , wherein the compound of Formula I is a compound of Formula III-A or III-B:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:
the carbon denoted by * has S-stereochemistry or R-stereochemistry;
Ring A is a phenyl, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
Ring D is a phenyl ring, a 5-membered heterocyclyl ring, a 6-membered heterocyclyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;
each R 1 is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
m is 0, 1, 2, 3, or 4;
each R 2 is independently chosen from C 1 -C 2 alkyl groups, C 1 -C 2 alkoxyl groups, C 1 -C 2 haloalkyl groups, C 1 -C 2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group;
n is 0, 1, or 2;
each R 3 is methyl;
each R 4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y) k -R 7 groups or optionally two R 4 , together with the atom(s) they are attached to, form a 5-6 membered cycloalkyl or heterocyclyl ring that is optionally and independently substituted with one or more groups chosen from halogens, C 1 -C 2 alkyl groups, haloalkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups, wherein:
k is 0, 1, 2, 3, 4, 5, or 6;
each Y is independently chosen from C(R 5 )(R 6 ) groups, —O—, and —NR a — groups, wherein a heteroat

Assignees

• Vertex Pharma

Inventors

• Clemens Jeremy J
• Abela Alexander Russell
• Anderson Corey Don
• Busch Brett B
• Chen Weichao George
• Cleveland Thomas
• Coon Timothy Richard
• Frieman Bryan
• Ghirmai Senait G
• Grootenhuis Peter
• Gulevich Anton V
• Hadida Ruah Sara Sabina
• Hsia Clara Kuang-Ju
• Kang Ping
• Khatuya Haripada
• Mccartney Jason
• Miller Mark Thomas
• Paraselli Prasuna
• Pierre Fabrice
• Swift Sara E
• Termin Andreas
• Uy Johnny
• Vogel Carl V
• Zhou Jinglan

Classifications

• C07D513/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title