# US 10,118,916 B2 · Modulators of cystic fibrosis transmembrane conductance regulator protein

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- Number: US 10,118,916 B2
- Document ID: US10118916B2
- Status: Granted
- Kind: B2
- Application number: 15/496,094
- Filed: 2017-04-25
- Published: 2017-10-26
- Granted: 2018-11-06
- Earliest claimed: 2016-04-26
- Assignees: AbbVie S.á.r.l.; Galapagos NV
- Applicants: AbbVie S.à.r.l.; Galapagos NV
- Inventors: Robert J. Altenbach; Andrew Bogdan; Vincent Chan; Timothy A. Grieme; John R. Koenig; Philip R. Kym; Bo Liu; Karine Fabienne Malagu; Sachin V. Patel; Marc Scanio; Xenia B. Searle; Shashank Shekhar; Xueqing Wang; Ming C. Yeung
- Web page: https://patentgrep.com/patent/US10118916B2

## CPC

- C07D 407/12: linked by a chain containing hetero atoms as chain links
- A61K 31/353: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K 31/36: Compounds containing methylenedioxyphenyl groups, e.g. sesamin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 311/58: other than with oxygen or sulphur atoms in position 2 or 4
- C07D 311/60: with aryl radicals attached in position 2
- C07D 311/68: with nitrogen atoms directly attached in position 4
- C07D 311/70: with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D 407/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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

## Claims

### Claim 1

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

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Z is O and R2 is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, cyclopropyl, or cyclohexyl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R9 groups.

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —ORj or —C(O)ORj, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Z is O,
R2 is hydrogen;
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —C(O)ORj wherein Rj is hydrogen or C1-C6 alkyl, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl;
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 6 (depends on 1)

The compound of claim 1 of formula (I-a) or a pharmaceutically acceptable salt thereof
wherein
R1, m, Z, G1, R2, R3a, and R3b are as set forth in claim 1;
G2 is formula (b), phenyl, or —O-phenyl, wherein the phenyl and the phenyl moiety of —O-phenyl are each optionally substituted with 1, 2, 3, or 4 Rx groups;
wherein
each Rx is independently halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —ORj, or —SRj;
X1 is O;
Y1 is O, CH2, or —O—CH2— wherein the —O—CH2— is connected to the benzo ring via the oxygen atom;
Y2 is O;
R4 and R5 are hydrogen or R4 and R5 are halogen;
R6 groups are optional substituents on the benzo ring, and are each independently C1-C3 alkyl, C1-C3 haloalkyl, halogen, —CN, —ORj, or —SRj; and
n is 0, 1, 2, or 3; and
Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

### Claim 7 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G2 is phenyl or —O-phenyl, wherein the phenyl and the phenyl moiety of —O-phenyl are each optionally substituted with 1, 2, 3, or 4 Rx groups.

### Claim 8 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G2 is phenyl optionally substituted with 1, 2, 3, or 4 Rx groups.

### Claim 9 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G2 is formula (b) wherein Y1 is O;
R4 and R5 are hydrogen; and
R3a and R3b are methyl.

### Claim 10 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R2 is hydrogen; and
R3a and R3b are each independently C1-C3 alkyl; or R3a and R3b together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl; wherein the cyclopropyl and the cyclobutyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halogen.

### Claim 11 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —ORj or —C(O)ORj, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl;
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 12 (depends on 6)

The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R2 is hydrogen;
Y1 is O;
R3a and R3b are methyl; or R3a and R3b together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl; wherein the cyclopropyl and the cyclobutyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halogen;
G2 is phenyl which is optionally substituted with 1, 2, 3, or 4 Rx groups;
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —C(O)ORj wherein Rj is hydrogen or C1-C6 alkyl, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl;
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 13 (depends on 1)

The compound of claim 1 of formula (I-a-i) or a pharmaceutically acceptable salt thereof
wherein
R1, m, G1, R3a, and R3b are as set forth in claim 1;
G2 is phenyl which is optionally substituted with 1, 2, 3, or 4 Rx groups;
each Rx is independently halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —ORj, or —SRj;
Z is O;
R2 is hydrogen; and
Rj, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

### Claim 14 (depends on 13)

The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein
R3a and R3b are methyl; or R3a and R3b together with the carbon atom to which they are attached, form a cyclopropyl which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halogen.

### Claim 15 (depends on 14)

The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —C(O)ORj wherein Rj is hydrogen or C1-C6 alkyl, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

### Claim 16 (depends on 14)

The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein
G1 is
wherein * is the point of connection, and Rj is hydrogen or C1-C6 alkyl.

### Claim 17 (depends on 16)

The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 18 (depends on 1)

The compound of claim 1 of formula (I-a-ii) or a pharmaceutically acceptable salt thereof,
wherein R1, m, Z, G1, R2, R3a, R3b, R6, n, Y1, and Y2 are as set forth in claim 1; and
R4 and R5 are hydrogen, or R4 and R5 are halogen;
with the proviso that when R2 is hydrogen, Z is O, R3a and R3b together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, Y1 is O, R4 and R5 are halogen, n is 0 or 1, and R6 is halogen, then G1 is optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, or
wherein * is the point of connection, R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen; and s is 0, 1, 2, or 3.

### Claim 19 (depends on 18)

The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R2 is hydrogen; and
R3a and R3b together with the carbon atom to which they are attached, form an unsubstituted cyclopropyl.

### Claim 20 (depends on 19)

The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein
Y1 is O; and
G1 is
wherein * is the point of connection, Rj is hydrogen or C1-C6 alkyl; R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen; and s is 0, 1, 2, or 3.

### Claim 21 (depends on 18)

The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R2 is hydrogen; and
R3a and R3b are methyl; or R3a and R3b together with the carbon atom to which they are attached, form a cyclopropyl which is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halogen.

### Claim 22 (depends on 21)

The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —ORj or —C(O)ORj, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

### Claim 23 (depends on 1)

The compound of claim 1 of formula (I-a-iii) or a pharmaceutically acceptable salt thereof
wherein R1, m, G1, R3a, R3b, R6, and n, are as set forth in claim 1;
Y1 and Y2 are O;
R4 and R5 are hydrogen, or R4 and R5 are halogen;
Z is O; and
R2 is hydrogen;
with the proviso that when R3a and R3b together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, R4 and R5 are halogen, n is 0 or 1, and R6 is halogen, then G1 is optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, or
wherein * is the point of connection; R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen; and s is 0, 1, 2, or 3.

### Claim 24 (depends on 23)

The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein
R3a and R3b together with the carbon atom to which they are attached, form an unsubstituted cyclopropyl.

### Claim 25 (depends on 24)

The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein
G1 is
wherein * is the point of connection, Rj is hydrogen or C1-C6 alkyl; R9 is C1-C3 alkyl, C1-C3 haloalkyl, or halogen; and s is 0, 1, 2, or 3.

### Claim 26 (depends on 23)

The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein
R3a and R3b are methyl; or R3a and R3b together with the carbon atom to which they are attached, form a cyclopropyl which is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, and halogen.

### Claim 27 (depends on 26)

The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —C(O)ORj wherein Rj is hydrogen or C1-C6 alkyl, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

### Claim 28 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-{(2R,4R)-4-[2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-({1-[4-(trifluoromethoxy)phenyl]cyclopropane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(4-bromophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-({1-[4-(trifluoromethyl)phenyl]cyclopropane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[1-(4-methylphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
ethyl trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;
trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
ethyl trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl[amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;
trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
methyl cis-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;
methyl trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;
cis-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]-3,3-difluoro-1-phenylcyclobutane-1-carboxamide;
1-(3,4-difluorophenyl)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]cyclobutane-1-carboxamide;
2-(4-chlorophenoxy)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methylpropanamide;
N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]-1-(3-fluorophenyl)cyclopropane-1-carboxamide;
N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]-1-(4-fluorophenyl)cyclopropane-1-carboxamide;
1-(4-chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]cyclopropane-1-carboxamide;
2-(4-chlorophenyl)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]-2-methylpropanamide;
N-[2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-1-benzopyran-4-yl]-2-(4-methoxyphenyl)-2-methylpropanamide;
3-{(2R,4S)-7-methoxy-4-[2-(4-methoxyphenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-{(2R,4R)-7-methoxy-4-[2-(4-methoxyphenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-[(2R,4R)-7-methoxy-4-{2-methyl-2-[4-(2-methylpropoxy)phenyl]propanamido}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-{(2R,4R)-4-[2-(2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-{(2R,4R)-4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-[(2R,4R)-7-methoxy-4-{2-methyl-2-[4-(trifluoromethoxy)phenyl]propanamido}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-7-methoxy-4-({1-[4-(trifluoromethoxy)phenyl]cyclopropane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[1-(4-chlorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[1-(4-bromophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-7-methoxy-4-{[1-(4-methoxyphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-{(2R,4R)-4-[2-(4-chlorophenoxy)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-{(2R,4R)-4-[2-methyl-2-(2-methylphenyl)propanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-[(2R,4R)-4-{2-methyl-2-[4-(trifluoromethyl)phenyl]propanamido}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-{(2R,4R)-4-[2-(2,4-dichlorophenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-7-methoxy-4-({1-[4-(trifluoromethoxy)phenyl]cyclobutane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[2-(2,3-dihydro-1-benzofuran-5-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[(3,3-difluoro-1-phenylcyclobutane-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(3-chlorophenoxy)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[1-(4-methoxyphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-7-methoxy-4-[(1-phenylcyclopropane-1-carbonyl)amino]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-4-{[1-(4-chlorophenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[2-(4-chloro-3-methylphenoxy)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-7-methoxy-4-{2-methyl-2-[3-(trifluoromethyl)phenoxy]propanamido}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-(2-ethyl-2-phenylbutanamido)-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[(3,3-difluoro-1-phenylcyclopentane-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-4-{[1-(3,4-difluorophenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-({1-[2-(trifluoromethyl)phenyl]cyclobutane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-({1-[3-(trifluoromethoxy)phenyl]cyclobutane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(4-fluorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3-fluorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[1-(3-methoxy-4-methylphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3-cyanophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3-bromophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(2-bromophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3-fluorophenyl)cyclopentane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(2-fluorophenyl)cyclopentane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(4-cyanophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(4-fluorophenyl)cyclopentane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(2-bromophenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3,4-dichlorophenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(2-chlorophenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-7-methoxy-4-[(1-phenylcyclopentane-1-carbonyl)amino]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-4-{[1-(4-chlorophenyl)cyclopentane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{2-[(2H-1,3-benzodioxol-5-yl)oxy]-2-methylpropanamido}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3-chlorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-7-methoxy-4-[(1-phenylcyclobutane-1-carbonyl)amino]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[1-(2-methoxyphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(4-bromophenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[(2,2-difluoro-1-phenylcyclopropane-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-4-{[1-(2-fluorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[2-(4-cyanophenoxy)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-4-{[1-(4-chlorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-{2-methyl-2-[4-(trifluoromethoxy)phenyl]propanamido}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[2-(4-chlorophenyl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(4-fluorophenyl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(3-fluoro-4-methoxyphenyl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[1-(4-methoxyphenyl)cyclopentane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[1-(4-methoxyphenyl)cyclobutane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[1-(3,4-dimethoxyphenyl)cyclobutane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-{(2R,4R)-4-[2-(2-fluoro-4-methoxyphenyl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(4-fluorophenoxy)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(4-chlorophenoxy)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-4-[2-(2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
4-{(2R,4R)-7-methoxy-4-[2-(4-methoxyphenyl)-2-methylpropanamido]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid.

### Claim 29 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 30 (depends on 1, 29)

A compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29, for use in medicine.

### Claim 31 (depends on 1, 29)

A compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29, for use in the treatment of cystic fibrosis.

### Claim 32 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.

### Claim 33 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

### Claim 34 (depends on 33)

The pharmaceutical composition of claim 33 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.

### Claim 35 (depends on 33)

The pharmaceutical composition of claim 33 wherein the additional therapeutic agents are CFTR modulators.

### Claim 36

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

### Claim 37

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

### Claim 38 (depends on 36)

The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-{(2R,4R)-4-[(1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-[(2R, 4R)-4-{[(1S)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-4-{[(1S)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R, 4R)-4-{ [(2R)-5-chloro-2-methyl-2,3-dihydro-1-benzofuran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R, 4R)-4-{[(2S)-5-chloro-2-methyl-2,3-dihydro-1-benzofuran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
methyl 3-[(2R,4R)-4-{[(1R)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
methyl 3-[(2R,4R)-7-methoxy-4-{[(1R)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-ylThenzoate;
methyl 3-[(2R,4R)-4-{[(1S)-5-methoxy-l-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
methyl 3-[(2R,4R)-7-methoxy-4-{[(1S)-5-methoxy-l-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
3-[(2R,4R)-4-{[(1R)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-7-methoxy-4-{[(1R)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(1S)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-7-methoxy-4-{[(1S)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-{(2R,4R)-4-[(5-chloro-1-methyl-2,3-dihydro-1H-indene-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
3-[(2R,4R)-4-{[(1S)-7-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(1S)-6-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(1R)-6-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(1R)-7-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(1R)-6-chloro-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(1S)-6-chloro-l-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[1-methyl-5-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-{(2R,4R)-4-[(6-methoxy-3-methyl-2,3-dihydro-1-benzofuran-3-carbonyl)amino]-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
methyl 3-[(2R,4R)-7-methoxy-4-{[1-methyl-6-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
3-[(2R,4R)-7-methoxy-4-{[1-methyl-6-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[(1S)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
4-[(2R,4R)-7-methoxy-4-{[(1R)-5-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-{(2R,4R)-4-[(1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic acid;
methyl 3-{(2R,4R)-4-[(1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl)amino]-7-methoxy-3 ,4-dihydro-2H-1-benzopyran-2-yl}benzoate;
methyl 4-{(2R,4R)-4-[(1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl)amino]-7-methoxy-3 ,4-dihydro-2H-1-benzopyran-2-yl}benzoate;
3-[(2R, 4R)-4-{[(1R)-1, 5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid; and
4-[(2R, 4R)-4-{[(1R)-1, 5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid.

### Claim 39 (depends on 37)

The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
methyl 4-[(2R,4R)-4-{[(2R)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
4-[(2R, 4R)-4-{[(2R)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
methyl 4-[(2R,4R)-4-{[(2S)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
4-[(2R, 4R)-4-{[(2S)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
methyl 3-[(2R,4R)-4-{[(2S)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate;
3-[(2R, 4R)-4-{[(2S)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R,4R)-4-{[(2R)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid;
3-[(2R, 4R)-4-{[(2R)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid; and
4-[(2R,4R)-4-{[(2R)-6-chloro-2-methyl-3,4-dihydro-2H-1-benzopyran-2-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic acid.

### Claim 40 (depends on 36)

The compound of claim 36 of formula (I-c) or a pharmaceutically acceptable salt thereof,
wherein R1, m, Z, G1, R2, X2, RA, R7, and p are as set forth in claim 36.

### Claim 41 (depends on 40)

The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R2 is hydrogen; and
RA is methyl.

### Claim 42 (depends on 41)

The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, cyclopropyl, or cyclohexyl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R9 groups.

### Claim 43 (depends on 41)

The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —ORj or —C(O)ORj, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl;
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 44 (depends on 36)

The compound of claim 36 of formula (I-c-i) or a pharmaceutically acceptable salt thereof,
wherein R1, m, G1, X2, R7, and p are as set forth in claim 36;
Z is O;
R2 is hydrogen; and
RA is methyl.

### Claim 45 (depends on 44)

The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —C(O)ORj wherein Rj is hydrogen or C1-C6 alkyl, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl.

### Claim 46 (depends on 44)

The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein
G1 is
wherein * is the point of connection; and Rj is hydrogen or C1-C6 alkyl;
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.

### Claim 47 (depends on 37)

The compound of claim 37 of formula (I-d) or a pharmaceutically acceptable salt thereof,
wherein R1, m, Z, G1, R2, RB, R8, q, and r are as set forth in claim 37.

### Claim 48 (depends on 47)

The compound of claim 47 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R2 is hydrogen; and
RB is methyl.

### Claim 49 (depends on 48)

The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, cyclopropyl, or cyclohexyl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R9 groups.

### Claim 50 (depends on 48)

The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein
G1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R9 groups; wherein one of the R9 groups is —ORj or —C(O)ORj, and the other 1, 2, or 3 optional R9 groups are independently C1-C3 alkyl, halogen, or C1-C3 haloalkyl;
m is 0 or 1; and
R1 is —ORj wherein Rj is C1-C6 alkyl or C1-C6 haloalkyl.