# US 2014/0155419 A1 · Compounds and methods

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2014/0155419 A1
- Document ID: US20140155419A1
- Status: Published application
- Kind: A1
- Application number: 14/235,481
- Filed: 2012-07-27
- Published: 2014-06-05
- Earliest claimed: 2011-07-29
- Inventors: Erkan Baloglu; Shomir Ghosh; Mercedes Lobera; Darby R. Schmidt
- Web page: https://patentgrep.com/patent/US20140155419A1

## CPC

- C07D 239/52: Two oxygen atoms
- C07C 235/34: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 213/30: Oxygen atoms
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/40: Acylated substituent nitrogen atom
- C07D 213/65: attached in position 3 or 5
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/36: as doubly bound oxygen atom or as unsubstituted hydroxy radical
- C07D 239/54: as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.

## Claims

### Claim 1

A compound according to Formula (I):
wherein:
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
X1, X2, X3, X4, and X5 are each independently selected from N, N+—O−, CH, and CR5, wherein 0-3 of X1, X2, X3, X4, and X5 are N or N+—O− and 1-3 of X1, X2, X3, X4, and X5 are CR5;
one of Y1 and Y2 is O or NR8 and the other is a bond;
or X1 is CR5, Y1 is NR8, Y2 is a bond, and R5 and R8 taken together with the atoms to which they are attached form a five to seven membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (C1-C4)alkyl;
Cy is (C3-C8)cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one, two, or three times, independently, by (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, oxo, cyano, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, —((C0-C3)alkyl)NHCO2R7, —((C0-C3)alkyl)N((C1-C4)alkyl)C2R7, —((C0-C3)alkyl)NHC(O)R7, —((C0-C3)alkyl)N((C1-C4)alkyl)C(O)R7, —((C0-C3)alkyl)CO2R7, —((C0-C3)alkyl)CONR7R8, —((C0-C3)alkyl)C(O)R7, (C1-C4)alkoxy(C1-C6)alkyl, amino(C1-C6)alkyl, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C6)alkyl, (C1-C4)alkylamino(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl(C1-C4)alkyl)amino, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
Z is O, S, SO2, C═O, NR6, or a bond;
A1, A2, A3, A4, and A5 are each independently selected from N, N+—O−, CH, and CR10, wherein 0-3 of A1, A2, A3, A4, and A5 are N or N+—O− and 0-3 of A1, A2, A3, A4, and A5 are CR10;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy, (C1-C6)alkoxy(C1-C2)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one, two, or three times, independently, by R5;
R2 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl;
or R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one, two, or three times, independently, by R5;
R3 and R3a are each independently hydrogen, hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, (C1-C6)alkoxy, amino, (C1-C4)alkylamino, or ((C1-C4)alkyl)((C1-C4)alkyl)amino;
each R4 is independently selected from hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, —CO2R7, —CONR7R8, —OR9, and —NR8R9, wherein said (C1-C6)alkyl or (C1-C6)haloalkyl is optionally substituted by hydroxyl, —OR9, —CO2R7, —CONR7R8, or —NR8R9;
each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and (C1-C6)alkyl;
or R4 and R4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, —CO2R7, —CONR7R8, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, —NHCO2R7, —N((C1-C4)alkyl)CO2R7, —NHC(O)R7, or —N((C1-C4)alkyl)C(O)R7;
each R5 is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, and heterocycloalkyl;
R6 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy(C1-C6)alkyl, —((C0-C3)alkyl)CO2R7, —((C0-C3)alkyl)CONR7R8, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
R7 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C4)alkoxy(C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl;
or R7 and R8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, —CO2H, —CO2(C1-C4)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, or ((C1-C4)alkyl)((C1-C4)alkyl)amino;
R9 is —C(O)R7, —CO2R7, —C(O)NR7R8, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl is optionally substituted by —CO2R7, —CONH2, —CONH(C1-C4)alkyl, —CON((C1-C4)alkyl)((C1-C4)alkyl), hydroxyl, (C1-C4)alkoxy, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, —NHCO2R7, —N((C1-C4)alkyl)CO2R7, —NHC(O)R7, or —N((C1-C4)alkyl)C(O)R7;
or R8 and R9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, —CO2H, —CO2(C1-C4)alkyl, —CONR7R8, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, —NHCO2R7, —N((C1-C4)alkyl)CO2R7, —NHC(O)R7, or —N((C1-C4)alkyl)C(O)R7; and
R10 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, —((C0-C3)alkyl)CO2R7, —((C0-C3)alkyl)CONR7R8, amino(C1-C6)alkyl, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C6)alkyl, (C1-C4)alkylamino(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
or a salt thereof.

### Claim 2 (depends on 1)

The compound or salt according to claim 1, wherein m is 1 and n is 1 or 2.

### Claim 3 (depends on 1)

The compound or salt according to claim 1, wherein X1 and X5 are each independently selected from N, N+—O−, CH, and CR5, and X2, X3, and X4 are each independently selected from CH and CR5.

### Claim 4 (depends on 1)

The compound or salt according to claim 1, wherein X1 is a carbon atom substituted by halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, cyano, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino, and X2, X3, X4, and X5 are each independently a carbon atom substituted by hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, cyano, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino, wherein 2-4 of X2, X3, X4, and X5 are a carbon atom substituted by hydrogen.

### Claim 5 (depends on 1)

The compound or salt according to claim 1, wherein Y1 is NH or NCH3 and Y2 is a bond.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The compound or salt according to claim 1, wherein Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted one or two times, independently, by (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, cyano, (C1-C4)alkoxy, (C1-C4)alkyl)((C1-C4)alkyl)amino, —((C0-C3)alkyl)CO2H, —((C0-C3)alkyl)CO2(C1-C6)alkyl, or —((C0-C3)alkyl)CONH(C1-C6)alkyl.

### Claim 8 (depends on 1)

The compound or salt according to claim 1, wherein Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, cyano, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino.

### Claim 9 (depends on 1)

The compound or salt according to claim 1, wherein Z is a bond, O, or NH.

### Claim 10 (depends on 1)

The compound or salt according to claim 1, wherein R7 is (C3-C6)alkyl, (C3-C6)cycloalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl is optionally substituted one or two times, independently, by halogen, (C1-C4)alkyl, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino.

### Claim 11 (depends on 1)

The compound or salt according to claim 1, wherein R1 is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (C1-C4)alkyl, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino.

### Claim 12 (depends on 1)

The compound or salt according to claim 1, wherein R2 is hydrogen or methyl.

### Claim 13 (depends on 1)

The compound or salt according to claim 1, wherein R3 and R3a are each independently hydrogen or methyl.

### Claim 14 (depends on 1)

The compound or salt according to claim 1, wherein each R4 is independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, —OR9, and —NR8R9, wherein said (C1-C4)alkyl or (C1-C4)haloalkyl is optionally substituted by hydroxyl, —OR9, —CO2R7, —CONR7R8, or —NR8R9.

### Claim 15 (depends on 1)

The compound or salt according to claim 1, wherein each R4 is independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C2-C4)alkoxy, (C1-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, —O((C1-C3)alkyl)CO2H, —O((C1-C3)alkyl)CO2(C1-C4)alkyl, —O((C1-C3)alkyl)CONH2, —O((C1-C3)alkyl)CONH(C1-C4)alkyl, and —O((C1-C3)alkyl)CON((C1-C4)alkyl)((C1-C4)alkyl).

### Claim 16 (depends on 1)

The compound or salt according to claim 1, wherein each R4a is independently selected from hydrogen and methyl.

### Claim 17

(canceled)

### Claim 18 (depends on 1)

The compound or salt according to claim 1, wherein A2 and A4 are each independently selected from N, N+—O−, CH, and C((C1-C4)alkyl), and A1, A3, and A5 are each independently selected from CH and C((C1-C4)alkyl), wherein at least one of A2 and A4 is N+—O.

### Claim 19

A compound according to Formula (Ia):
wherein:
m is 1;
n is 1 or 2;
X1, X2, X3, and X4 are each independently selected from N, N+—O−, CH, and CR5, wherein 0-2 of X1, X2, X3, and X4 are N or N+—O− and 0-2 X1, X2, X3, and X4 are CR5;
Y1 is NH or NCH3 and Y2 is a bond;
K1, K2, K3, and K4 are each independently selected from N, N+—O−, CH, and CR10, wherein 0-2 of K1, K2, K3, and K4 are N or N+—O− and 0-2 of K1, K2, K3, and K4 are CR10;
Z is O, NR6, or a bond;
A1, A2, A3, A4, and A5 are each independently selected from N, N+—O−, CH, and CR10, wherein 0-3 of A1, A2, A3, A4, and A5 are N or N+—O− and 0-3 of A1, A2, A3, A4, and A5 are CR10;
R1 is (C3-C6)alkyl, (C3-C6)haloalkyl, (C3-C8)cycloalkyl, (C3-C6)alkoxy, (C1-C6)alkoxy(C1-C2)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one, two, or three times, independently, by R5;
R2 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl;
or R1 and R2 taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one, two, or three times, independently, by R5;
R3 and R3a are each independently hydrogen, hydroxyl, (C1-C4)alkyl, (C1-C4)haloalkyl, halogen, (C1-C4)alkoxy, amino, (C1-C4)alkylamino, or ((C1-C4)alkyl(C1-C4)alkyl)amino;
each R4 is independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, —OR9, and —NR8R9, wherein said (C1-C4)alkyl or (C1-C4)haloalkyl is optionally substituted by hydroxyl, —OR9, —CO2R7, —CONR7R8, or —NR8R9;
each R4a is independently selected from hydrogen, halogen, hydroxyl, amino, and (C1-C4)alkyl;
each R5 is independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, and heterocycloalkyl;
R6 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy(C1-C6)alkyl, —((C0-C3)alkyl)CO2R7, —((C0-C3)alkyl)CONR7R8, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
R7 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C4)alkoxy(C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
R8 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl;
or R7 and R8 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, —CO2H, —CO2(C1-C4)alkyl, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, or ((C1-C4)alkyl)((C1-C4)alkyl)amino;
R9 is —C(O)R7, —CO2R7, —C(O)NR7R8, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl is optionally substituted by —CO2R7, —CONH2, —CONH(C1-C4)alkyl, —CON((C1-C4)alkyl)((C1-C4)alkyl), hydroxyl, (C1-C4)alkoxy, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, —NHCO2R7, —N((C1-C4)alkyl)CO2R7, —NHC(O)R7, or —N((C1-C4)alkyl)C(O)R7;
or R8 and R9 taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, —CO2H, —CO2(C1-C4)alkyl, —CONR7R8, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, —NHCO2R7, —N((C1-C4)alkyl)CO2R7, —NHC(O)R7, or —N((C1-C4)alkyl)C(O)R7; and
R10 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, halogen, cyano, hydroxyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C6)alkyl, —((C0-C3)alkyl)CO2R7, —((C0-C3)alkyl)CONR7R8, amino(C1-C6)alkyl, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C6)alkyl, (C1-C4)alkylamino(C1-C6)alkyl, amino, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The compound or salt according to claim 19, wherein:
X1, X2, X3, and X4 are each independently a carbon atom substituted by hydrogen, halogen, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino, wherein 2-4 of X1, X2, X3, and X4 are a carbon atom substituted by hydrogen;
K1, K2, K3, and K4 are each independently a carbon atom substituted by hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino, wherein 2-4 of K1, K2, K3, and K4 are a carbon atom substituted by hydrogen;
Z is O, NH, —N(C1-C4)alkyl, —N((C0-C3)alkyl)CO2R7, —N((C0-C3)alkyl)CONR7R8, or a bond;
A2 and A4 are each independently selected from N, N+—O−, CH, and C((C1-C4)alkyl), and A1, A3, and A5 are each independently selected from CH and C((C1-C4)alkyl), wherein at least one of A2 and A4 is N or N+—O−;
R2 is hydrogen;
R3 and R3a are each independently hydrogen or methyl;
each R4 is independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C2-C4)alkoxy, (C1-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino, (C1-C4)alkoxy(C1-C4)alkylamino, (C1-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, —O((C1-C3)alkyl)CO2H, —O((C1-C3)alkyl)CO2(C1-C4)alkyl, —O((C1-C3)alkyl)CONH2, —O((C1-C3)alkyl)CONH(C1-C4)alkyl, and —O((C1-C3)alkyl)CON((C1-C4)alkyl)((C1-C4)alkyl);
each R4a is independently selected from hydrogen, hydroxyl, amino, and (C1-C4)alkyl;
R7 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C4)alkoxy(C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or heterocycloalkyl; and
R8 is hydrogen, (C1-C6)alkyl, or (C1-C6)haloalkyl.

### Claim 21 (depends on 20)

The compound or salt according to claim 20, wherein:
Z is O, NH, —N(C1-C4)alkyl, or a bond;
R1 is phenyl optionally substituted one or two times, independently, by halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, cyano, (C1-C4)alkoxy, or ((C1-C4)alkyl)((C1-C4)alkyl)amino; and
each R4 is independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkylamino, ((C1-C4)alkyl(C1-C4)alkyl)amino, and (C1-C4)alkoxy.

### Claim 22

(canceled)

### Claim 23

(canceled)

### Claim 24 (depends on 19)

A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to claim 19 and a pharmaceutically acceptable excipient.

### Claim at position 25

25-35. (canceled)