# US 2019/0169160 A1 · Ire1 small molecule inhibitors

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- Number: US 2019/0169160 A1
- Document ID: US20190169160A1
- Status: Published application
- Kind: A1
- Application number: 16/184,916
- Filed: 2018-11-08
- Published: 2019-06-06
- Earliest claimed: 2017-11-10
- Assignees: Quentis Therapeutics, Inc.
- Applicants: Quentis Therapeutics, Inc.
- Inventors: Joseph P. VACCA; Dansu LI; Sarah BETTIGOLE
- Web page: https://patentgrep.com/patent/US20190169160A1

## CPC

- C07D 401/10: linked by a carbon chain containing aromatic rings
- A61P 35/00: Antineoplastic agents
- C07D 217/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D 239/84: Nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.

## Claims

### Claim 1

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is —CN, —OR8, —SR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted —O—C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted —O—C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted —O—C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
each R5 is independently H, halogen, —CN, —OR8, —SR8, —N(R8)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R2 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R6 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 is optionally substituted C3-C6cycloalkylalkyl or R7 is methyl, ethyl, —CH2CF3, —CH2-cyclopropyl, or —CH2CH2OCH3;
each R8 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RA1 and RA2 are each independently H, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
provided that both RA1 and RA2 are not H;
n is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein R7 is methyl, ethyl, —CH2CF3, —CH2-cyclopropyl, or —CH2CH2OCH3.

### Claim at position 3

3-4. (canceled)

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein R6 is optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, or optionally substituted C3-C6cycloalkylalkyl.

### Claim 6 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof, wherein R6 is methyl.

### Claim 7

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is —CN, —OR8, —SR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted —O—C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted —O—C3-C6cycloalkyl, optionally substituted C3-C6heterocycloalkyl, optionally substituted —O—C3-C6heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl;
each R5 is independently H, halogen, —CN, —OR8, —SR8, —N(R8)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R2 is independently H, halogen, —CN, —OR8, —SR8, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8)2, —NR8S(═O)2R9, —C(═O)R9, —OC(═O)R9, —C(═O)OR8, —OC(═O)OR9, —N(R8)2, —OC(═O)N(R8)2, —NR8C(═O)R9, —NR8C(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R6 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 is optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C6cycloalkylalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or R6 and R7 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R8 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R8 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
RA1 and RA2 are each independently H, halogen, —OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
provided that both RA1 and RA2 are not H;
n is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4.

### Claim at position 7

8-21. (canceled)

### Claim 22 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein R6 is H.

### Claim at position 9

23-26. (canceled)

### Claim 27 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R1 is independently H, halogen, —CN, —OR8, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C1-C4heteroalkyl.

### Claim at position 11

28-30. (canceled)

### Claim 31 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is optionally substituted C1-C4alkyl.

### Claim 32

(canceled)

### Claim 33 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein R3 is —OR8, optionally wherein R8 is optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted C3-C6cycloalkyl.

### Claim 34

(canceled)

### Claim 35 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein R4 is halogen, —CN, —OR8, optionally substituted C1-C4alkyl, or optionally substituted C1-C4fluoroalkyl.

### Claim at position 17

36-55. (canceled)

### Claim 56 (depends on 1)

The compound of claim 1, wherein the compound has the structure of formula (Ib), or a pharmaceutically acceptable salt, or solvate thereof,

### Claim at position 19

57-58. (canceled)

### Claim 59 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA1 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, or optionally substituted C1-C4fluoroalkyl.

### Claim at position 21

60-61. (canceled)

### Claim 62 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA2 is H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, or optionally substituted C1-C4fluoroalkyl.

### Claim at position 23

63-64. (canceled)

### Claim 65 (depends on 62)

The compound of claim 62, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA2 is ethyl.

### Claim at position 25

66-69. (canceled)

### Claim 70 (depends on 1)

The compound of claim 1, wherein the compound has the structure of formula (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt, or solvate thereof:

### Claim at position 27

71-73. (canceled)

### Claim 74 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein optional substituents are independently selected from D, halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2(C1-C4alkyl), —CH2NH2, —C(═O)NH2, —C(═O)NH(C1-C4alkyl), —C(═O)N(C1-C4alkyl)2, —S(═O)2NH2, —S(═O)2NH(C1-C4alkyl), —S(═O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, —SC1-C4alkyl, —S(═O)C1-C4alkyl, and —S(═O)2C1-C4alkyl.

### Claim 75 (depends on 74)

The compound of claim 74, or a pharmaceutically acceptable salt, or solvate thereof, wherein optional substituents are independently selected from D, halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CH2NH2, —CF3, —OCH3, and —OCF3.

### Claim 76

(canceled)

### Claim 77 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, selected from:
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide; and
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide.

### Claim 78 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, selected from:
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-7-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-ethylpyridin-2-yl)benzenesulfonamide;
N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-methylbenzenesulfonamide;
2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(ethyl(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-((cyclobutylmethyl)(methyl)amino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-(1,1-difluoroethyl)-2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(8-ethyl-2-(((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)quinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(trifluoromethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-(methoxymethyl)quinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1 s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1 s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1 s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1 s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1 s,4s)-4-(dimethylamino)-4-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide; and
2-chloro-N-(5-(2-(((1 s,4s)-4-(dimethylamino)cyclohexyl)amino)-8-methylquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide.

### Claim 79

A compound, or a pharmaceutically acceptable salt, or solvate thereof, selected from:
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylpyrimidin-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrazin-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)phenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-hydroxyquinazolin-6-yl)-3-methylphenyl)-2-chloro-N-methylbenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-methylphenyl)-2-chloro-N-methylbenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(2-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrimidin-5-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-ethylphenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-3-methylphenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methylthiazol-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)pyrimidin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-isopropylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)thiazol-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluoro-5-methoxyphenyl)-2-chlorobenzenesulfonamide;
N-(1-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-1H-pyrazol-4-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)isoxazol-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-methoxyquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-propylquinazolin-6-yl)-1-methyl-1H-pyrazol-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)pyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-5-fluoropyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-fluoropyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,5-difluorophenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-2,3-difluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(3-(((1r,4r)-4-aminocyclohexyl)amino)isoquinolin-7-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
(S)-2-amino-N-((1r,4S)-4-((6-(4-((2-chlorophenyl)sulfonamido)-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)-3-methylbutanamide;
N-((1r,4r)-4-((6-(4-((2-chlorophenyl)sulfonamido)-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)cyclohexyl)acetamide;
2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
2-chloro-N-(6-(8-ethyl-2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridazin-3-yl)benzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-3,5-difluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2,6-difluorophenyl)-2-chlorobenzenesulfonamide;
2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)pyridazin-3-yl)benzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methylpyridazin-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-4-methylpyrimidin-2-yl)-2-chlorobenzenesulfonamide;
2-chloro-N-(4-(2-(((1r,4r)-4-(dimethyl amino)cyclohexyl)amino)-8-ethyl quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
N-(4-(2-(((1R,3R,4 S)-4-amino-3-methylcyclohexyl)amino)-8-ethyl quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethyl quinazolin-6-yl)-2-fluoro-3-methylphenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
(S)-2-chloro-N-(4-(8-ethyl-2-(piperidin-3-ylamino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
N-(4-(2-(((1R,3R,4R)-4-amino-3-methylcyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
(S)-2-chloro-N-(2-fluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)benzenesulfonamide;
N-(4-(2-(((1R,3R)-3-aminocyclopentyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3R)-3-aminocyclopentyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclopentyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1R,3 S)-3-aminocyclopentyl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2r,5r)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2r,5r)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2s,5 s)-5-aminooctahydropentalen-2-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((2s, 5 s)-5-aminooctahydropentalen-2-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(4-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
2-chloro-N-(4-(8-ethyl-2-(((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)amino)quinazolin-6-yl)-2-fluorophenyl)benzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)-2-chlorobenzenesulfonamide;
N-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-7-methylquinazolin-6-yl)-2-fluorophenyl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyridin-2-yl)-2-chlorobenzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridin-3-yl)-2-chlorobenzenesulfonamide;
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyrazin-2-yl)-2-chlorobenzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-3-fluoropyridin-2-yl)benzenesulfonamide;
N-(6-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-ethylpyridazin-3-yl)-2-chlorobenzenesulfonamide; and
N-(5-(2-(((1r,4r)-4-aminocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)-2-chlorobenzenesulfonamide.

### Claim 80 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, selected from:
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(3-fluoro-6-methoxy-5-(2-(((1r,4r)-4-(methylamino)cyclohexyl)amino)quinazolin-6-yl)pyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1 S,2 S,4 S)-4-(dimethylamino)-2-fluorocyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2,3-dichloro-N-(5-(2-(((r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-4-methoxypyrimidin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methoxypyrazin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-fluorobenzenesulfonamide;
2-chloro-N-(6-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-5-methoxypyridazin-3-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-6-methylpyridin-2-yl)-3-methylbenzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-6-methylpyridin-2-yl)benzenesulfonamide;
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methylpyridin-2-yl)benzenesulfonamide; and
2-chloro-N-(5-(2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-8-ethyl-7-fluoroquinazolin-6-yl)-3-fluoro-6-methoxypyridin-2-yl)benzenesulfonamide.

### Claim 81 (depends on 7)

The compound of claim 7 having Formula (I*), or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently hydrogen, fluorine, chlorine or cyano;
R3 is —CN, optionally substituted C1-C3alkyl, optionally substituted C3-C4cycloalkyl, optionally substituted —O—C3-C4cycloalkyl, or optionally substituted —O—C1-C3alkyl;
R4 is chlorine, —CH3, cyano, —OCH3, or CF3;
each R5 is independently hydrogen, chlorine, —CH3, cyano, —OCH3, or CF3;
each R2 is independently hydrogen, fluorine, —CH3, or —OH;
R6 is H, or C1-C3alkyl;
R7 is optionally substituted C1-C3alkyl; C1-C3fluoroalkyl, C1-C3heteroalkyl, or C3-C4cycloalkyl-C1-C3alkyl;
or R6 and R7 are taken together with the N atom to which they are attached to form an optionally substituted 4 to 6 membered ring, the remainder of the ring atoms being carbon;
RA1 and RA2 are each independently H, optionally substituted C1-C3alkyl, C1-C3fluoroalkyl, optionally substituted C1-C3heteroalkyl, or optionally substituted C3-C4cycloalkyl-C1-C3alkyl, provided that both RA1 and RA2 are not hydrogen;
n is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4.

### Claim 82

(canceled)

### Claim 83 (depends on 81)

The compound of claim 81, wherein the compound has the structure of formula (Ib*) or formula (Ic*), or a pharmaceutically acceptable salt, or solvate thereof:

### Claim 84

(canceled)

### Claim 85 (depends on 81)

The compound of claim 81, or a pharmaceutically acceptable salt, or solvate thereof, wherein R6 is H or methyl and R7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl, or CH2CH2OCH3.

### Claim 86 (depends on 81)

The compound of claim 81, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is methyl and R7 is methyl, ethyl, CH2CF3, CH2-cyclopropyl, or CH2CH2OCH3.

### Claim 87 (depends on 81)

The compound of claim 81, or a pharmaceutically acceptable salt, or solvate thereof, wherein one or more of R3, R7, RA1, and RA2 are optionally substituted, wherein optional substituents are each independently selected from fluorine, —OH, —OCH3, —OCH2CH3, —OCH2CH2CH3, —NH2, —NH(CH3), and —N(CH3)2.

### Claim at position 42

88-89. (canceled)

### Claim 90 (depends on 81)

The compound of claim 81, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA1 is H or C1-C3alkyl.

### Claim 91 (depends on 81)

The compound of claim 81, or a pharmaceutically acceptable salt, or solvate thereof, wherein q is zero.

### Claim 92 (depends on 81)

The compound of claim 81, or a pharmaceutically acceptable salt, or solvate thereof, wherein:
each Z is independently N or CR1, provided that at least one Z is N;
each R1 is independently hydrogen, fluorine, chlorine or cyano;
R3 is C1-C3alkyl or —OC1-C3alkyl;
RA1 is hydrogen, or C1-C3alkyl;
RA2 is C1-C3alkyl, C1-C3fluoroalkyl, or C1-C3heteroalkyl; provided that both RA1 and RA2 are not hydrogen;
R4 is chlorine;
each R5 is independently hydrogen, chlorine, —CH3, cyano, —OCH3, or CF3;
n is 0, 1, 2, 3, or 4; and
q is zero.

### Claim 93 (depends on 1)

The compound of claim 1 having Formula (Id*), or a pharmaceutically acceptable salt or solvate thereof:

### Claim 94 (depends on 93)

The compound of claim 93, or a pharmaceutically acceptable salt or solvate thereof:
wherein:
R3 is C1-C3alkyl or —OC1-C3alkyl;
RA1 is fluorine, chlorine, hydrogen, or C1-C3alkyl;
RA2 is C1-C3alkyl, —OC1-C3alkyl, hydrogen, C1-C3fluoroalkyl, fluorine, chlorine, or
each Z is independently N or CR1, provided that at least one Z is N;
each R5 is independently hydrogen, chlorine, fluorine, or C1-C3alkyl;
R4 is chlorine or C1-C3alkyl; C1-C3heteroalkyl; provided that both RA1 and RA2 are not hydrogen;
each R2 is independently hydrogen or fluorine;
R1 is hydrogen or fluorine.

### Claim at position 48

95-97. (canceled)

### Claim 98 (depends on 93)

The compound of claim 93, or a pharmaceutically acceptable salt or solvate thereof, wherein:

### Claim 99 (depends on 93)

The compound of claim 93, or a pharmaceutically acceptable salt or solvate thereof, wherein
each R5 is independently hydrogen, chlorine, fluorine, or —CH3;
R4 is chlorine or —CH3;
R3 is —CH3, —CH2CH3, or —OCH3;
RA1 is fluorine, chlorine, hydrogen, or —CH3;
RA2 is hydrogen, —CH3, —CH2CH3, —OCH3, CF3, CF2CH3, CH2OCH3, or fluorine;
provided that both RA1 and RA2 are not hydrogen;
each R2 is independently hydrogen or fluorine; and
R1 is hydrogen or fluorine.

### Claim 100 (depends on 93)

The compound of claim 93, or a pharmaceutically acceptable salt or solvate thereof, wherein
each R5 is hydrogen;
R4 is chlorine;
each R2 is hydrogen; and
R1 is hydrogen.

### Claim 101 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

### Claim 102 (depends on 1)

A method for treating or ameliorating the effects of a disease associated with altered IRE1 signaling, the method comprising administering to a subject in need thereof a compound of claim 1.

### Claim 103 (depends on 102)

The method of claim 102, wherein the disease is cancer.

### Claim at position 55

104-109. (canceled)