IP Library › Granted Patent US 11,066,417

Granted Patent B2

US 11,066,417 · App. 16/276,350 · Granted Jul 20, 2021

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 11,066,417
App. No.: 16/276,350
Granted: Jul 20, 2021
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 (380)

1. 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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, 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, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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. A compound 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.

12. A pharmaceutical composition comprising a compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, and optionally one or more of:

(a) Compound II:

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

(b) Compound III or Compound III-d:

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

13. A method of preparing a compound of Formula (I):

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

coupling the NH group of Ring C and the Q b group of Ring B of a compound of Formula (Y-I):

a salt thereof, or a deuterated derivative of any of the foregoing, wherein:

Q b is a halogen;

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(C 1 -C 4 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;

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; 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;

to form a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing.

14. A method of preparing a compound of Formula (I)

a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is

comprising

reacting a compound of Formula (X), a salt thereof, or a deuterated derivative of any of the foregoing, with a compound of Formula (Z-1), a salt thereof, or a deuterated derivative of any of the foregoing:

wherein:

Q a is a halogen;

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(C 1 -C 4 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;

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; 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.

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

16. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring A is a phenyl ring, a pyridyl ring, or a pyrazolyl ring, wherein Ring A is optionally substituted with (R 1 ) m .

17. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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.

18. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0.

19. The compound of claim 1 or claim 5 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a 5-membered heteroaryl ring substituted with (R 4 ) q .

20. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 .

21. The compound of claim 1 or claim 5 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is a pyrazolyl ring, or a pyridinone ring, wherein Ring D is substituted with (R 4 ) q .

22. The compound of claim 3 , 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 .

23. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is

wherein

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

24. The compound of claim 1 or claim 5 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is

wherein

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

25. The compound of claim 24 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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

26. The compound of claim 24 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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 R a is independently chosen from hydrogen and C 1 -C 2 alkyl groups; and

27. The compound of claim 24 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 4 is independently chosen from

wherein

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

28. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6.

29. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1.

30. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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.

31. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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.

32. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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.

33. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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.

34. The compound of claim 1 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R 3 is independently CD 3 .

35. The compound of claim 5 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, 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.

36. The compound of claim 5 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:

r is 3 or 4;

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

each R b is hydrogen.

37. The compound of claim 6 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:

r is 3 or 4; and

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

38. The compound of claim 6 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:

r is 3 or 4; and

each R 8 and R 9 is hydrogen.

39. The compound of claim 6 , a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein:

r is 3 or 4; and

each R 8 and R 9 is hydrogen.

40. A compound of the formula:

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

41. A compound of the formula:

a pharmaceutically acceptable salt thereof.

42. The compound of claim 41 , wherein the compound is in the form of a pharmaceutically acceptable salt.

43. The compound of claim 42 , wherein the pharmaceutically acceptable salt is a calcium salt.

44. The compound of claim 42 , wherein the pharmaceutically acceptable salt is a sodium salt.

45. The compound of claim 42 , wherein the pharmaceutically acceptable salt is a potassium salt.

46. A pharmaceutical composition comprising the compound, salt, or deuterated derivative of any one of claims 40 to 45 , and optionally one or more of:

(a) Compound II:

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

(b) Compound III or Compound III-d:

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

47. A pharmaceutical composition comprising the pharmaceutically acceptable salt of any one of claims 42 to 45 , and optionally one or more of:

(a) Compound II:

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

(b) Compound III or Compound III-d:

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

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 15, 2019

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 048347/0658 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 15, 2019

From: ABELA, ALEXANDER RUSSELL; ANDERSON, 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 048347/0718 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 15, 2019

From: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

To: VERTEX PHARMACEUTICALS INCORPORATED

Reel/Frame 048347/0770 →

Continuity (2)

Provisional Application 62631453 · Feb 15, 2018

Related Publication 20190248809A1 · Aug 15, 2019

Cited By (5)

US 12,186,306 US 12,319,693 US 12,421,251 US 12,552,810 US 12,612,416