# US 2023/0057166 A1 · Phenoxy-pyridyl-pyrimidine compounds and methods of use

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- Number: US 2023/0057166 A1
- Document ID: US20230057166A1
- Status: Published application
- Kind: A1
- Application number: 17/275,606
- Filed: 2019-09-12
- Published: 2023-02-23
- Earliest claimed: 2018-09-12
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Marie-Gabrielle Braun; Cuong Q. Ly; Georgette Castanedo; Paul Gibbons; Wendy Lee; Joachim Rudolph; Nicole Alice Blaquiere; Jacob Bradley Schwarz; Ramsay Beveridge; Jean-Philippe Leclerc; Alexandre Lemire; Leo Fu
- Web page: https://patentgrep.com/patent/US20230057166A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- 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

Described herein are phenoxy-pyridyl-pyrimidine compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I structure or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R0 is hydrogen or fluoro;
R1 is C3-12 cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —(C1-6 alkylene)-(C3-C12 cycloalkyl), or —(C1-6 alkylene)-(3- to 14-membered heterocyclyl), —(C1-6 alkylene)-OR1c, or —(C1-6 alkylene)-NR1aR1b; wherein the C3-12 cycloalkyl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, and C1-6 alkylene of R1 are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
each R1a, R1b and R1c is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R1a and R1b are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
R2A and R28 are independently hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —O(C1-6 alkyl), or —O(C1-6 haloalkyl);
R3 is hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —O(C1-6 alkyl), or —O(C1-6 haloalkyl);
R4 and R5 are independently hydrogen, halogen, cyano, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-20 aryl, 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, —OR7A, —NR8AR8B, —NR8C(O)R7, —NR8C(O)OR7A, —NR8C(O)NR8AR8B, —NR8SO2R9, —NR8SO2NR8AR8B, —NR8S(O)(═NR8C)R9, —C(O)N(R8)SO2R9, C(O)R7, —C(O)OR7A, —SO2R9, —NR8S(O)(═NR8C)R9, or —SO2NR8AR8B; wherein the C1-6 alkyl, C3-12 cycloalkyl, C6-20 aryl, 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl of R4 and R5 are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
n is 0, 1, 2, or 3;
each R6 is independently halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —O(C1-6 alkyl), —O(C1-6 haloalkyl), —SO2(C1-6 alkyl) or —SO2(C1-6 haloalkyl);
each R7 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R7 and R7A are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
each R7A is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl of R7 and R7A are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
each R8 is independently hydrogen or C1-C6 alkyl;
each R8A is independently hydrogen or C1-C6 alkyl;
each R8B is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, and 3- to 12-membered heterocyclyl of R8B are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
each R8C is independently hydrogen or C1-C6 alkyl;
each R9 is independently C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 14-membered heteroaryl and 3- to 12-membered heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10;
each R10 is independently oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, —C(O)Ra, —C(O)ORb, —C(O)NRcRd, —ORb, —OC(O)Ra, —OC(O)NRcRd, —SRb, —S(O)Re, —S(O)2Re, —S(O)(═NH)Re, —S(O)2NRcRd, —NRcRd, —N(Rf)C(O)Ra, —N(Rf)C(O)ORb, —N(Rf)C(O)NRcRd, —N(Rf)S(O)2Re, —N(Rf)S(O)2NRcRd, —P(O)RgRh or —SiRiRjRk; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R10 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Ra is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Ra are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Rb is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rb are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Rc and Rd is independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rc and Rd are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Re is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl; wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Re are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Rf is independently hydrogen or C1-6 alkyl;
each Rg and Rh is independently C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or —O—C1-6 alkyl; wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of Rg and Rh are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
or Rg and Rh are taken together with the phosphorus atom to which they are attached to form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R11;
each Ri, Rj and Rk is independently C1-6 alkyl;
each R11 is independently oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, —C(O)Ra1, —C(O)ORb1, —C(O)NRc1Rd1, —ORb1, —OC(O)Ra1, —OC(O)NRc1Rd1, —SRb1, —S(O)Re1, —S(O)2Re1, —S(O)2NRc1Rd1, —NRc1Rd1, —N(Rf1)C(O)Ra1, —N(Rf1)C(O)ORb1, —N(Rf1)C(O)NRc1Rd1, —N(Rf1)S(O)2Re1, —N(Rf1)S(O)2NRc1Rd1, —P(O)Rg1Rh1, or —SiRi1Rj1Rk1; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl of R11 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
each Ra1 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Ra1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
each Rb1 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rb1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
each Rc1 and Rd1 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rc1 and Rd1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
or Rc1 and Rd1 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
each Re1 is independently C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 8-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Re1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
each Rf1 is independently hydrogen or C1-6 alkyl;
each Rg1 and Rh1 is independently C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or —O—C1-6 alkyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclyl of Rg1 and Rh1 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
or Rg1 and Rh1 are taken together with the phosphorus atom to which they are attached to form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R12;
each Ri1, Rj1 and Rk1 is independently C1-6 alkyl;
each R12 is independently oxo, C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano,—C(O)Ra2, —C(O)ORb2, —C(O)NRc2Rd2, —ORb2, —OC(O)Ra2, —OC(O)NRc2Rd2, —S(O)2Re2, —S(O)2NRc2Rd2, —NRc2Rd2, —N(Rf2)C(O)Ra2, —N(Rf2)C(O)ORb2, —N(Rf2)C(O)NRc2Rd2, —N(Rf2)S(O)2Re2, —N(Rf2)S(O)2NRc2Rd2, or —P(O)Rg2Rh2; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R12 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
each Ra2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of Ra2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
each Rb2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 3- to 6-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl and 3- to 6-membered heterocyclyl of Rb2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
each Rc2 and Rd2 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 3- to 8-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl and 3- to 8-membered heterocyclyl of Rc2 and Rd2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
or Rc2 and Rd2 are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
each Re2 is independently C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of Re2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
each Rf2 is independently hydrogen or C1-6 alkyl;
each Rg2 and Rh2 is independently C1-6 alkyl, C3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or —O—C1-6 alkyl; wherein the C1-6 alkyl, C3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of Rg2 and Rh2 are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13;
or Rg2 and Rh2 are taken together with the phosphorus atom to which they are attached to form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R13; and
each R13 is independently oxo, halogen, hydroxyl, —CKC1-6 alkyl), cyano, C1-6 alkyl or C1-6 haloalkyl;
provided that the compound is other than
No.
Name
2x
2-Pyrrolidinone, 1-[3-[[4-[2-
(4-amino-2-methylphenoxy)-3-pyridinyl]-2-
pyrimidinyl]amino]propyl]-,
3x
4-Morpholinepropanamine, N-[4-[2-
(4-amino-2-methylphenoxy)-3-pyridinyl]-2-
pyrimidinyl]-,
4x
Urea, N-(3-fluoro-4-methylphenyl)-N′-[4-[[3-
[2-[[3-(4-morpholinyl)propyl]amino]-
4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
5x
Urea, N-(2,3-dihydro-1H-inden-5-yl)-N′-[4-
[[3-[2-[[3-(4-morpholinyl)propyl]amino]-
4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
6x
Urea, N-(4-chlorophenyl)-N′-[4-[[3-[2-
[[3-(4-morpholinyl)propyl]amino]-4-
pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
7x
Urea, N-[3-methyl-4-[[3-[2-[[3-(2-oxo-
1-pyrrolidinyl)propyl]amino]-4-pyrimidinyl]-2-
pyridinyl]oxy]phenyl]-N′-[3-(trifluoromethyl)phenyl]-,
8x
Urea, N-(5-chloro-2-methoxyphenyl)-N′-[3-
methyl-4-[[3-[2-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-
4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-, or
9x
Urea, N-(5-chloro-2-methoxyphenyl)-N′-[3-
methyl-4-[[3-[2-[[3-(4-morpholinyl)propyl]amino]-
4-pyrimidinyl]-2-pyridinyl]oxy]phenyl]-,
and salts thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2A and R2B are independently H, F, Cl or C1-C6 alkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R2A is H, F or methyl, and R2B is H, F, Cl or —CH3.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R3 is H, F, Cl, —CN, C1-6 alkyl, or C1-6 haloalkyl.

### Claim 5

(canceled)

### Claim 6

(canceled)

### Claim 7

(canceled)

### Claim 8

(canceled)

### Claim 9 (depends on 1)

The compound of claim 1, wherein R5 is H, F, Cl, —CN, C1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10, —NR8SO2R9, —NR8AR8B, or —C(O)N(R8)SO2R9.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R5 is C1-4 alkyl substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10, —NR8SO2R9, —NR8AR8B, or —C(O)N(R8)SO2R9.

### Claim 11

(canceled)

### Claim 12

(canceled)

### Claim 13 (depends on 10)

The compound of claim 10, wherein R5 is —CH2NHC(O)-(cyclopropyl), —NHCH2CH(OH)CF3, or —C(O)NHSO2-(2-chlorophenyl).

### Claim 14 (depends on 10)

The compound of claim 10, wherein R5 is —NHSO2R9, and R9 is C1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10, or C6-10 aryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10.

### Claim 15

(canceled)

### Claim 16 (depends on 1)

The compound of claim 1, wherein R4 is —NR8C(O)R7 or —NR8SO2R9.

### Claim 17

(canceled)

### Claim 18 (depends on 16)

The compound of claim 16, wherein R4 is —NH—SO2R9, and R9 is C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, or 5- to 14-membered heteroaryl, wherein the C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl and 5- to 14-membered heteroaryl of R9 are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10.

### Claim 19 (depends on 18)

The compound of claim 18, wherein R9 is C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, or 5- to 14-membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10.

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22

(canceled)

### Claim 23 (depends on 18)

The compound of claim 18, wherein R9 is selected from the group consisting of cyclopentyl, cyclohexyl, phenyl, 2-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-(difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)phenyl, 3,5-difluorophenyl, 3-pyridyl, 1-methyl-1H-imidazol-4-yl, 1-methyl-1H-pyrazol-4-yl, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-cyanobenzyl, 4-cyanobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, (1-methyl-1H-pyrazol-3-yl)methyl, (5-methylisoxazol-3-yl)methyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, (6-(trifluoromethyl)pyridin-3-yl)methyl, (1-fluorocyclopropyl)methyl, cyclobutylmethyl, (2,2-difluorocyclobutyl)methyl, (3,3-difluorocyclobutyl)methyl, cyclopentylmethyl, cyclohexylmethyl, (spiro[3.3]heptan-2-yl)methyl, 2-(cyclohexyl)ethyl, 2-(2,2-difluorocyclopropyl)ethyl, w-propyl, 3-cyano-2,2-dimethylpropyl, 3,3,3-trifluoropropyl, n-butyl, 2,2-difluorobutyl, 3,3-difluorobutyl, 3,3-dimethylbutyl, 3-cyano-3-methylbutyl and 4,4-dimethylpentyl.

### Claim 24 (depends on 16)

The compound of claim 16, wherein R7 is selected from the group consisting of cyclopropyl, spiro[2.2]pentyl, cyclohexylmethyl and 4-chlorobenzyl.

### Claim 25 (depends on 1)

The compound of claim 1, wherein R1 is C3-12 cycloalkyl; 3- to 14-membered heterocyclyl; —(C1-6 alkylene)-(3- to 14-membered heterocyclyl), or —(C1-6 alkylene)-NR1aR1b; wherein the C3-12 cycloalkyl, 3- to 14-membered heterocyclyl, and C1-6 alkylene of R1 are independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R10.

### Claim 26

(canceled)

### Claim 27

(canceled)

### Claim 28

(canceled)

### Claim 29 (depends on 25)

The compound of claim 25, wherein R1 is selected from the group consisting of piperidin-3-yl, 5-fluoropiperidin-3-yl, 5-methylpiperidin-3-yl and 5-fluoro-5-methylpiperidin-3-yl.

### Claim 30

(canceled)

### Claim 31

(canceled)

### Claim 32

(canceled)

### Claim 33

(canceled)

### Claim 34 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula (Ia) or Formula (Ic):
wherein R6A is hydrogen or R6; and R1, R2A, R28, R3, R5, R6 and R9 are as defined in claim 1.

### Claim 35

(canceled)

### Claim 36

(canceled)

### Claim 37

(canceled)

### Claim 38

(canceled)

### Claim 39 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula (Ie):
wherein R6A is hydrogen or R6; R21 and R22 are independently H, F, —CH3 or —NH2, and R2A, R2B, R3, R5, R6 and R9 are as defined in claim 1.

### Claim 40 (depends on 39)

The compound of claim 39, wherein the compound is of the Formula (Ie-1), (Ie-2), (Ie-3), (Ie-4), (Ie-5), (Ie-6) or (Ie-7):

### Claim 41

(canceled)

### Claim 42 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof:
or
or a pharmaceutically acceptable salt thereof:
or
or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 1)

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

### Claim 44 (depends on 1)

A method of treating an IRE1-related disease or disorder, the method comprising administering to a subject having an IRE1-related disease or disorder an effective amount of the compound of claim 1, wherein the IRE1-related disease or disorder is cancer.

### Claim 45

(canceled)

### Claim 46 (depends on 44)

The method of claim 44, wherein the cancer is squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, squamous cell lung cancer, peritoneum cancer, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer.

### Claim 47 (depends on 44)

The method of claim 44, wherein the cancer is lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

### Claim 48 (depends on 44)

The method of claim 44, wherein the cancer is multiple myeloma or triple-negative breast cancer (TNBC).

### Claim 49

(canceled)

### Claim 50

(canceled)

### Claim 51 (depends on 44)

The method of claim 44, wherein the further comprising administering one or more additional therapeutic agents selected from the group consisting of a corticosteroid, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 antibody, an anti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-interleukin-6 antibody, or a combination thereof.

### Claim 52 (depends on 51)

The method of claim 51, wherein the corticosteroid comprises dexamethasone: wherein the proteasome inhibitor comprises carfilzomib, ixazomib or bortezomib; wherein the immunomodulatory agent comprises lenalidomide or pomalidomide; wherein the anti-PD-L1 antibody comprises avelumab, durvalumab, or atezolizumab; and wherein the anti-PD-1 antibody comprises pembrolizumab or nivolumab.

### Claim at position 53

-69. (canceled)