NZ808123A - Macrocycles as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cystic fibrosis, and process for making them - Google Patents

Macrocycles as modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions thereof, their use in the treatment of cystic fibrosis, and process for making them

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Publication number
NZ808123A
NZ808123A NZ808123A NZ80812319A NZ808123A NZ 808123 A NZ808123 A NZ 808123A NZ 808123 A NZ808123 A NZ 808123A NZ 80812319 A NZ80812319 A NZ 80812319A NZ 808123 A NZ808123 A NZ 808123A
Authority
NZ
New Zealand
Prior art keywords
groups
halogens
independently chosen
chosen
hydrogen
Prior art date
Application number
NZ808123A
Inventor
Alexander Russell Abela
Corey Don Anderson
Brett B Busch
Weichao George Chen
Jeremy J Clemens
Thomas Cleveland
Timothy Richard Coon
Bryan Frieman
Senait G Ghirmai
Peter Grootenhuis
Original Assignee
Vertex Pharmaceuticals Incorporated
Filing date
Publication of NZ808123A publication Critical patent/NZ808123A/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated

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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 (39)

1. A compound of Formula I: (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; 1104 - 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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and 1105 - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 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(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 haloalkyl groups, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
2. The compound of paragraph 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): 1106 (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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; 1107 - each R3 is methyl; - each R4 is independently chosen from halogens, a hydroxyl group, an oxo group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 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(R8 )(R9 ) groups, –O–, and –NRb – groups , wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, C1-C2 haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and 1108 - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
3. The compound of paragraph 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): (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 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; 1109 - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; 1110 - Z is a divalent linker of formula (L) r, wherein: - r is 3, 4, or 5; - each L is independently chosen from C(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
4. The compound of paragraph 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: (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; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; 1111 - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - Z is a divalent linker of formula (L) r, wherein: - r is 3, 4, or 5; 1112 - each L is independently chosen from C(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
5. The compound of paragraph 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: (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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; 1113 - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups. 1114
6. The compound of paragraph 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: (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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; 1115 - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
7. The compound of paragraph 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: 1116 (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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: 1117 - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - 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(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1-C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
8. The compound of paragraph 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: 1118 (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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; 1119 - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3, 4, or 5; and - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups.
9. The compound of paragraph 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: (VI-A) or 1120 (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 R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; 1121 - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - 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(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
10. The compound of paragraph 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: 1122 (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; - X is O, NH, or an N(C1-C4 alkyl); - each R1 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - m is 0, 1, 2, 3, or 4; - each R2 is independently chosen from C1-C2 alkyl groups, C1-C2 alkoxyl groups, C1-C2 haloalkyl groups, C1-C2 haloalkoxyl groups, halogens, a cyano group, and a hydroxyl group; - n is 0, 1, or 2; - each R3 is methyl; 1123 - each R4 is independently chosen from halogens, an oxo group, a hydroxyl group, a cyano group, and -(Y)k-R 7 groups, or optionally two R4 , 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, C1-C2 alkyl groups, haloalkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups, wherein: - k is 0, 1, 2, 3, 4, 5, or 6; - each Y is independently chosen from C(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , wherein: - each R5 and R6 is independently chosen from hydrogen, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R 5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens; - q is 1 or 2; - r is 3 or 4; and - each R8 and R9 is independently chosen from hydrogen, halogens, C1- C2 alkyl groups, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups.
11. The compound of any one of paragraphs 1-3, 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 (R1 )m. 1124
12. The compound of any one of paragraphs 1-11, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R1 is independently chosen from deuterium, C1-C2 alkyl groups, and a hydroxyl group, and m is 0 or 1.
13. The compound of any one of paragraphs 1-11, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein n is 0.
14. The compound of any one of paragraphs 1-5, and 7-10, 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.
15. The compound of paragraph 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.
16. The compound of paragraph 2, 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 .
17. The compound of any one of paragraphs 3-5 and 7-10, 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 compound of any one of paragraphs 1-5 and 7-10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein Ring D is 1125 , , , , , or , wherein indicates the point of attachment of Ring D to Ring B .
19. The compound of paragraph 18, 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 .
20. The compound of any one of paragraphs 1-19, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R4 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(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , and wherein: - each R5 and R6 is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl 1126 groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens.
21. The compound of any one of paragraphs 1-20, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R4 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(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , and wherein: - each R5 and R6 is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens. 1127
22. The compound of any one of paragraphs 1-19, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R4 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(R5 )(R6 ) groups, –O–, and –NRa – groups, wherein a heteroatom in -(Y)k-R 7 is not bonded to another heteroatom in -(Y)k-R 7 , and wherein: - each R5 and R6 is independently chosen from hydrogen, deuterium, halogens, a hydroxyl group, C1-C4 alkyl groups, and C3-5 cycloalkyl groups, or R5 and R6 on the same carbon together form a C3-5 cycloalkyl group or oxo; - each of R5 and R6 is optionally independently substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, halogens, a hydroxyl group, C1-C2 alkoxyl groups, and C1-C2 haloalkoxyl groups; and - each R a is independently chosen from hydrogen and C1-C2 alkyl groups; and - R 7 is chosen from hydrogen, halogens, a cyano group, and C3-C10 cycloalkyl groups optionally substituted with one or more groups chosen from C1-C2 alkyl groups, C1-C2 haloalkyl groups, and halogens.
23. The compound of any one of paragraphs 1-22, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R4 is independently chosen from , , , , , 1128 , , , , , , , , , , , , , , , , , , , , , , f3c X f3c r f3c f3c f3c F3C 0 r °v / O f3c f3c °V f3cX o f3c 7 °v f3c 0 f3c °V f3c 0 OH f3c °v f3c °v 1129 , , , , , , , , , , , , , , , V •O^ °v °Y oA V OH V 1130 , , , , , , , , , , , , , F F3C o X o °V \ °V o o o \ o 1131 , , , and , wherein indicates the point of attachment of R4 to Ring D.
24. The compound of any one of paragraphs 1-23, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein k is 3, 4, 5, or 6.
25. The compound of any one of paragraphs 1 to 24, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein q is 1.
26. The compound of any one of paragraphs 1 to 25, 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(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and wherein: - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
27. The compound of any one of paragraphs 1 to 25, 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; 1132 - each L is independently chosen from C(R8 )(R9 ) groups and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and: - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is independently chosen from hydrogen and methyl.
28. The compound of any one of paragraphs 1 to 25, 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(R8 )(R9 ) groups and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, and wherein: - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is hydrogen.
29. The compound of any one of paragraphs 1 to 25, 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(R8 )(R9 ) groups, –O–, and –NRb – groups, wherein a heteroatom in Z is not bonded to another heteroatom in Z, wherein: - each R8 and R9 is hydrogen; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
30. The compound of any one of paragraphs 1 to 29, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein each R3 is independently CD3. 1133
31. The compound of paragraph 5 or paragraph 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
32. The compound of paragraph 5 or paragraph 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is independently chosen from hydrogen and methyl.
33. The compound of paragraph 5 or paragraph 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; - each R8 and R9 is independently chosen from hydrogen and deuterium; and - each Rb is hydrogen.
34. The compound of paragraph 5 or paragraph 6, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; - each R8 and R9 is hydrogen; and - each Rb is independently chosen from hydrogen and C1-C2 alkyl groups.
35. The compound of paragraph 8 or paragraph 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; and - each R8 and R9 is independently chosen from hydrogen and deuterium. 1134
36. The compound of paragraph 8 or paragraph 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; and - each R8 and R9 is hydrogen.
37. The compound of paragraph 8 or paragraph 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3, 4, or 5; and - each R8 and R9 is deuterium.
38. The compound of paragraph 8 or paragraph 10, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of the foregoing, wherein: - r is 3 or 4; and - each R8 and R9 is hydrogen.
39. A compound selected from the compounds depicted in
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