IP Library › Granted Patent US 11,866,450

Granted Patent B2

US 11,866,450 · App. 17/323,267 · Granted Jan 9, 2024

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

Inventors: Jeremy J. Clemens (San Diego, CA); Alexander Russell Abela (Escondido, CA); Corey Don Anderson (San Diego, CA); Brett B. Busch (San Diego, CA); Weichao George Chen (San Diego, CA); Thomas Cleveland (San Marcos, CA); Timothy Richard Coon (Carlsbad, CA); Bryan Frieman (La Jolla, CA); Senait G. Ghirmai (San Diego, CA); Peter Grootenhuis (Del Mar, CA); Anton V. Gulevich (San Diego, CA); Sara Sabina Hadida Ruah (La Jolla, CA); Clara Kuang-Ju Hsia (San Diego, CA); Ping Kang (San Diego, CA); Haripada Khatuya (San Diego, CA); Jason McCartney (Cardiff by the Sea, CA); Mark Thomas Miller (San Diego, CA); Prasuna Paraselli (San Diego, CA); Fabrice Pierre (La Jolla, CA); Sara E. Swift (San Diego, CA); Andreas Termin (Encinitas, CA); Johnny Uy (San Diego, CA); Carl V. Vogel (Carlsbad, CA); Jinglan Zhou (San Diego, CA)

Assignee: Vertex Pharmaceuticals Incorporated

C07D513/22 A61K31/404 A61K31/439 A61K31/47 A61P11/00 C07D515/22

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Quick Facts

Patent No.: US 11,866,450
App. No.: 17/323,267
Granted: Jan 9, 2024
Kind: B2

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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 (294)

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

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 heteroatom in -(Y) k -R 7 is not bonded to another heteroatom in -(Y) k -R 7 , wherein:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

Z is a divalent linker of formula (L) r, wherein:

r is 3, 4, or 5;

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, 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.

4. The method of claim 1 , wherein the compound of Formula I is a compound of Formula IV-A:

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 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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

Z is a divalent linker of formula (L) r , wherein:

r is 3, 4, or 5;

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, 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.

5. The method of claim 1 , wherein the compound of Formula I is a compound of Formula IV-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 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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

r is 3 or 4;

each R 8 and R 9 is independently chosen from hydrogen, halogens, 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.

6. The method of claim 1 , wherein the compound of Formula I is a compound of Formula IV-C:

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;

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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

r is 3 or 4;

each R 8 and R 9 is independently chosen from hydrogen, halogens, 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.

7. The method of claim 1 , wherein the compound of Formula I is a compound of Formula V-A:

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 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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

Z is a divalent linker of formula (L) r , wherein:

r is 3, 4, or 5;

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, 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.

8. The method of claim 1 , wherein the compound of Formula I is a compound of Formula V-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 D is a phenyl ring, a 5-membered heterocyclyl ring, a6-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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

r is 3, 4, or 5; and

each R 8 and R 9 is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups.

9. The method of claim 1 , wherein the compound of Formula I is a compound of Formula VI-A or VI-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 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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

Z is a divalent linker of formula (L) r, wherein:

r is 3, 4, or 5;

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, 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.

10. The method of claim 1 , wherein the compound of Formula I is a compound of Formula VI-C or VI-D:

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 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;

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 a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

q is 1 or 2;

r is 3 or 4; and

each R 8 and R 9 is independently chosen from hydrogen, halogens, C 1 -C 2 alkyl groups, a hydroxyl group, C 1 -C 2 alkoxyl groups, and C 1 -C 2 haloalkoxyl groups.

11. The method of claim 1 , wherein Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (R 1 ) m .

12. The method of claim 1 , wherein each R 1 is independently chosen from deuterium, C 1 -C 2 alkyl groups, and a hydroxyl group, and m is 0 or 1.

13. The method of claim 1 , wherein n is 0.

14. The method of claim 1 , wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4 ) q .

15. The method of claim 1 , wherein Ring D is a phenyl ring, pyridinyl ring, pyrazolyl ring, imidazolidinone ring, a pyrrolidinone ring, or a pyridinone ring, wherein Ring D is substituted with (R 4 ) q .

16. The method of claim 1 , wherein Ring D is a pyrazolyl ring, or a pyridinone ring, wherein Ring D is substituted with (R 4 ) q .

17. The method of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring, wherein Ring D is substituted with (R 4 ) q .

18. The method of claim 1 , wherein Ring D is

wherein

indicates the point of attachment of Ring D to Ring B.

19. The method of claim 1 , wherein Ring D is

wherein

indicates the point of attachment of Ring D to Ring B.

20. The method of claim 19 , wherein each R 4 is independently chosen from an oxo group or -(Y) k -R 7 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 , and wherein:

each R 5 and R 6 is independently chosen from hydrogen, deuterium, 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;

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

21. The method of claim 19 , wherein each R 4 is independently chosen from an oxo group or —O-(Y) k -R 7 groups, wherein:

k is 0, 1, 2, 3, 4, or 5;

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 , and wherein:

each R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

22. The method of claim 19 , wherein each R 4 is independently chosen from

wherein

indicates the point of attachment of R 4 to Ring D.

23. The method of claim 1 , wherein k is 3, 4, 5, or 6.

24. The method of claim 1 , wherein q is 1.

25. The method of claim 1 , wherein Z is a divalent linker of formula (L) r , wherein:

r is 3, 4, or 5;

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, and wherein:

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and

each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

26. The method of claim 1 , wherein Z is a divalent linker of formula (L) r , wherein:

r is 3, 4, or 5;

each L is independently chosen from C(R 8 )(R 9 ) groups and —NR b — groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and:

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and

each R b is independently chosen from hydrogen and methyl.

27. The method of claim 1 , wherein Z is a divalent linker of formula (L) r , wherein:

r is 3, 4, or 5;

each L is independently chosen from C(R 8 )(R 9 ) groups and —NR b — groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and wherein:

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and

each R b is hydrogen.

28. The method of claim 1 , wherein Z is a divalent linker of formula (L) r , wherein:

r is 3, 4, or 5;

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 hydrogen; and

each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

29. The method of claim 1 , wherein each R 3 is independently CD 3 .

30. The method of claim 5 , wherein:

r is 3 or 4;

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and

each R b is independently chosen from hydrogen and C 1 -C 2 alkyl groups.

31. The method of claim 5 , wherein:

each R 8 and R 9 is independently chosen from hydrogen and deuterium; and

each R b is hydrogen.

32. The method of claim 6 , wherein each R 8 and R 9 is independently chosen from hydrogen and deuterium.

33. The method of claim 6 , each R 8 and R 9 is hydrogen.

34. The method of claim 1 , wherein the compound is selected from:

a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the compounds, or a pharmaceutically acceptable salt of any deuterated derivatives of those compounds.

35. The method of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

36. The method of claim 1 , wherein the compound is administered in combination with one or more of:

(a) Compound II:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and

(b) Compound III or Compound III-d:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

37. A method of treating cystic fibrosis comprising administering to a patient in need thereof a compound of the formula:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

38. The method of claim 37 , wherein the compound is in the form of a pharmaceutically acceptable salt.

39. The method of claim 38 , wherein the pharmaceutically acceptable salt is a calcium salt.

40. The method of claim 37 , wherein the compound is administered in combination with one or more of:

(a) Compound II:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing; and

(b) Compound III or Compound III-d:

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

41. The method of claim 40 , wherein the compound is administered in combination with Compound II and Compound III-d.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 14, 2023

From: BUSCH, BRETT B.; CLEMENS, JEREMY J.; CLEVELAND, THOMAS; COON, TIMOTHY RICHARD; FRIEMAN, BRYAN; GROOTENHUIS, PETER; HSIA, CLARA KUANG-JU; KANG, PING; MILLER, MARK THOMAS; HADIDA RUAH, SARA SABINA; TERMIN, ANDREAS; UY, JOHNNY; ZHOU, JINGLAN

To: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

Reel/Frame 064260/0982 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 14, 2023

From: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

To: VERTEX PHARMACEUTICALS INCORPORATED

Reel/Frame 064261/0008 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 14, 2023

From: ABELA, ALEXANDER RUSSELL; ANDEERSON, COREY DON; CHEN, WEICHAO GEORGE; GHIRMAI, SENAIT G.; GULEVICH, ANTON V.; KHATUYA, HARIPADA; MCCARTNEY, JASON; PARASELLI, PRASUNA; PIERRE, FABRICE; SWIFT, SARA E.; VOGEL, CARL V.

To: VERTEX PHARMACEUTICALS INCORPORATED

Reel/Frame 064261/0013 →

Continuity (3)

Division 16276350 · Feb 14, 2019

Provisional Application 62631453 · Feb 15, 2018

Related Publication 20220106331A1 · Apr 7, 2022

Cited By (2)

US 12,421,251 US 12,612,416