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1. WO2018102751 - IRE1 SMALL MOLECULE INHIBITORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

WHAT IS CLAIMED IS:

1.A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:


wherein,



is an optionally substituted C3-C10 heterocyclyl containing at least one N, O,

S, S(=O), or S(=O)2; wherein if is substituted, then
is substituted with 0-3 R5;

is a substituted C3-C10 cycloalkyl that is substituted with 1-3R4 and 0-3R5;

each R4 is independently -OR6, -SR6, -S(=O)R7, -S(=O)2R7, or -N(R6)2;

each R5 is independently halogen, -CN, -OR8, -SR8, -S(=O)R9, -S(=O)2R9, - S(=O)2N(R8)2, -NR8S(=O)2R9, -C(=O)R9, -OC(=O)R9, -CO2R8, -OCO2R9, -N(R8)2, OC(=O)N(R8)2, -NR8C(=O)R9, -NR8C(=O)OR9, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

A1 is N or CRA; A2 is N or CRA; A3 is N or CRA; A4 is N or CRA; A5 is N or CRA; each RA is independently H or optionally substituted C1-C6alkyl;

R1 and R2 are each independently H or optionally substituted C1-C6alkyl;

L1 and L2 are each independently -CHY-, -CH2- or -NH-;

Y is optionally substituted C1-C6alkyl;


is optionally substituted aryl or optionally substituted heteroaryl,

wherein if is substituted, then is substituted with 0-4


Rc;

each Rc is independently H, halogen, -CN, -OR10, -SR10, -S(=O)R11, -S(=O)2R11, - S(=O)2N(R10)2, -NR10S(=O)2R11, -C(=O)R11, -OC(=O)R11, -CO2R10, -OCO2R11, - N(R10)2, -OC(=O)N(R10)2, -NR10C(=O)R11, -NR10C(=O)OR11, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R3 is independently H or optionally substituted C1-C6alkyl;


or LD;

is optionally substituted heterocyclyl containing at least one N atom; wherein

if
is substituted, th
en is substituted with 0-4 RD;

LD is -N(R12)-(optionally substituted C1-C6 alkyl), -N(R13)-(optionally substituted C1-C6 alkylene)-N(R14)2 or -(optionally substituted C1-C6 alkylene)-N(R14)2; wherein if LD is substituted, then LD is substituted with 0-4 RD;

each RD is independently halogen, -CN, -OR15, -SR15, -S(=O)R16, -S(=O)2R16, - S(=O)2N(R15)2, -NR15S(=O)2R16, -C(=O)R16, -OC(=O)R16, -CO2R15, -OCO2R16, - N(R15)2, -OC(=O)N(R15)2, -NR15C(=O)R16, -NR15C(=O)OR16, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R6 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R6 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R7 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R8 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, 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-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R10 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R10 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R11 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R12 and R13 is independently H or optionally substituted C1-C6alkyl;

each R14 is independently H or optionally substituted C1-C6alkyl; or

two R14 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R15 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R15 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle; and

each R16 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof,

wherein

3. The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted C4-C7 heterocyclyl containing at least one N, O, S,

S(=O), or S(=O)2; wherein if is substituted, then
is substituted with 0-3

R5.

4. The compound of claim 2, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is


o is 0, 1, or 2; and p is 0, 1, 2, or 3.

5. The compound of claim 4, or a pharmaceutically acceptable salt, or solvate thereof,

wherein and o is 0, 1, or 2.


6. The compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof,

wherein


7. The compound of claim 6, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is substituted C4-C7 cycloalkyl that is substituted with 1-3R4 and 0-3R5.

8. The compound of claim 6, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is


q is 0, 1, 2, or 3.

9. The compound of claim 8, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is


q is 0, 1, 2, or 3.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, or solvate thereof, wherein A1 is CH; A2 is N or CRA; A3 is N or CRA; A4 is CH; and A5 is CH.

11. The compound of claim 10, or a pharmaceutically acceptable salt, or solvate thereof, wherein A2 is N.

12. The compound of claim 10, or a pharmaceutically acceptable salt, or solvate thereof, wherein A2 is CRA.

13. The compound of any one of claims 10-12, or a pharmaceutically acceptable salt, or solvate thereof, wherein A3 is CRA.

14. The compound of claim 13, or a pharmaceutically acceptable salt, or solvate thereof, wherein RAis optionally substituted C1-C6alkyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt, or solvate thereof, wherein RAis methyl, ethyl, propyl or butyl.

16. The compound of claim 14, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA is ethyl, propyl or butyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is optionally substituted C1-C6alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is methyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, or solvate thereof, wherein R2 is H.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 and L2 are each -NH-.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 is -CH2- and L2 is -NH-.

22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 is -NH- and L2 is -CH2-.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or

solvate thereof, wherein
is optionally substituted aryl, wherein if

is substituted, then is substituted with 0-4 Rc.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or

solvate thereof, wherein
is optionally substituted heteroaryl wherein if


is substituted, then
is substituted with 0-4 Rc.

25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, or

solvate thereof, wherein


C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

26. The compound of claim 25, or a pharmaceutically acceptable salt, or solvate thereof, wherein C1 is CRC; C2 is CRC; C3 is CRC; and C4 is CRC.

27. The compound of claim 26, or a pharmaceutically acceptable salt, or solvate thereof, wherein C1 is CRC; C2 is CH; C3 is CH; and C4 is CH.

28. The compound of claim 27, or a pharmaceutically acceptable salt, or solvate thereof, wherein R is optionally substituted C1-C6fluoroalkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt, or solvate thereof, wherein R is -CF3.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R3 is independently H.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, or

solvate thereof wherein


32. The compound of claim 31, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted heterocyclyl containing at least one N atom; and if


is substituted, then
is substituted with 0-4 RD.

33. The compound of claim 31, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted heterocyclyl containing one N atom; and if


is substituted, then
is substituted with 0-4 RD.

34. The compound of claim 31, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted heterocyclyl containing two N atoms; and if


is substituted, then
is substituted with 0-4 RD.

35. The compound of claim 31, or a pharmaceutically acceptable salt, or solvate thereof,

wherein is



r is 0, 1, or 2.

36. The compound of claim 35, or a pharmaceutically acceptable salt, or solvate thereof,

wherein and r is 0, 1, or 2.


37. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, or

solvate thereof wherein is LD.


38. The compound of claim 37, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-(optionally substituted C1-C6 alkyl), -N(R13)-(optionally substituted C1-C6 alkyl ene)-N(R14)2 or -(optionally substituted C1-C6 alkyl ene)-N(R14)2; and if LD is substituted, then LD is substituted with 0-4 RD.

39. The compound of claim 38, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-(optionally substituted C1-C6 alkyl), and if LD is substituted, then LD is substituted with 0-4 RD.

40. The compound of claim 39, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-CH2-CH2-CH2-CH3, -N(R12)-CH2-CH2-CH3, -N(R12)-CH2-CH3, or -N(R12)-CH3.

41. The compound of claims 39 or 40, or a pharmaceutically acceptable salt, or solvate thereof, wherein R12 is H or С14alkyl.

42. The compound of claims 39 or 40, or a pharmaceutically acceptable salt, or solvate thereof, wherein R12 is H or C3-C4alkyl.

43. The compound of claim 38, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R13)-(optionally substituted C1-C6 alkylene)-N(R14)2, and if LD is substituted, then LD is substituted with 0-4 RD.

44. The compound of claim 43, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R13)-CH2-CH2-CH2-CH2-N(R14)2, -N(R13)-CH2-CH2-CH2-N(R14)2, -N(R13)-CH2-CH2-N(R14)2, or -N(R13)-CH2-N(R14)2.

45. The compound of claims 43 or 44, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R13 and R14 is independently H or С14alkyl.

46. The compound of claim 38, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is or -(optionally substituted C1-C6 alkyl ene)-N(R14)2; and if LD is substituted, then LD is substituted with 0-4 RD.

47. The compound of claim 46, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -CH2-CH2-CH2-CH2-N(R14)2, -CH2-CH2-CH2-N(R14)2, -CH2-CH2-N(R14)2, or -CH2-N(R14)2.

48. The compound of claims 46 or 47, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R14 is independently H or С14alkyl.

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


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

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


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

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


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

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


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

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


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

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


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


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


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


58. A compound of Formula (II), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,

Z is H,

is optionally substituted C3-C10 heterocyclyl conteining at least one N,O,

S, A(=O), or S(=O)2; wherein if is substituted, then is


substituted with 0-3 R5;

is a substituted C3-C10 cycloalkyl that is substituted with 1-3R4 and 0-3R5;

each R4 is independently -OR6, -SR6, -S(=O)R7, -S(=O)2R7, or -N(R6)2;

each R5 is independently halogen, -CN, -OR8, -SR8, -S(=O)R9, -S(=O)2R9, - S(=O)2N(R8)2, -NR8S(=O)2R9, -C(=O)R9, -OC(=O)R9, -CO2R8, -OCO2R9, -N(R8)2, - OC(=O)N(R8)2, -NR8C(=O)R9, -NR8C(=O)OR9, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

A1 is N or CRA; A2 is N or CRA; A4 is N or CRA; A5 is N or CRA;

each RA is independently H or optionally substituted C1-C6alkyl;

RA is optionally substituted C1-C6alkyl;

R1 and R2 are each independently H or optionally substituted C1-C6alkyl;

L1 and L2 are each independently -CHY-, -CH2- or -NH-;

Y is optionally substituted C1-C6alkyl;

is optionally substituted aryl or optionally substituted heteroaryl,

wherein if
is substituted, then is substituted with 0-4

Rc;

each Rc is independently H, halogen, -CN, -OR10, -SR10, -S(=O)R11, -S(=O)2R11, - S(=O)2N(R10)2, -NR10S(=O)2R11, -C(=O)R11, -OC(=O)R11, -CO2R10, -OCO2R11, - N(R10)2, -OC(=O)N(R10)2, -NR10C(=O)R11, -NR10C(=O)OR11, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aiyl, or optionally substituted heteroaryl;

each R3 is independently H or optionally substituted C1-C6alkyl;

or LD;



is optionally substituted heterocyclyl containing at least one N atom; wherein

if
is substituted, then is
substituted with 0-4 RD;

LD is -N(R12)-(optionally substituted C1-C6 alkyl), -N(R13)-(optionally substituted C1-C6 alkylene)-N(R14)2 or -(optionally substituted C1-C6 alkylene)-N(R14)2; wherein if LD is substituted, then LD is substituted with 0-4 RD;

each RD is independently halogen, -CN, -OR15, -SR15, -S(=O)R16, -S(=O)2R16, - S(=O)2N(R15)2, -NR15S(=O)2R16, -C(=O)R16, -OC(=O)R16, -CO2R15, -OCO2R16, - N(R15)2, -OC(=O)N(R15)2, -NR15C(=O)R16, -NR15C(=O)OR16, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aiyl, or optionally substituted heteroaryl;

each R6 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R6 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R7 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R8 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, 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-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R10 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R10 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R11 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R12 and R13 is independently H or optionally substituted C1-C6alkyl;

each R14 is independently H or optionally substituted C1-C6alkyl; or

two R14 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R15 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R15 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle; and

each R16 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

59. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein Z is H.

60. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein Z is


61. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein is optionally substituted C4-C7 heterocyclyl containing at least one

N, O, S, S(=O), or S(=O)2; wherein if is substituted, then is substituted

with 0-3 R5.

62. The compound of claim 60, or a pharmaceutically acceptable salt, or solvate thereof wherein
is

o is 0, 1, or 2; and p is 0, 1, 2, or 3.

63. The compound of claim 62, or a pharmaceutically acceptable salt, or solvate

thereof, wherein and o is 0, 1, or 2.


64. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein Z is


65. The compound of claim 64, or a pharmaceutically acceptable salt, or solvate thereof, wherein
is substituted C4-C7 cycloalkyl that is substituted with 1-3R4 and 0-3R5.

66. The compound of claim 64, or a pharmaceutically acceptable salt, or solvate thereof,


wherein is


q is 0, 1, 2, or 3.

67. The compound of claim 66, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is


q is 0, 1, 2, or 3.

68. The compound of any one of claims 58-67, or a pharmaceutically acceptable salt, or solvate thereof, wherein A1 is CH; A2 is N or CRA; A4 is CH; and A5 is CH.

69. The compound of claim 68, or a pharmaceutically acceptable salt, or solvate thereof, wherein A2 is N.

70. The compound of claim 68, or a pharmaceutically acceptable salt, or solvate thereof, wherein A2 is CRA.

71. The compound of any one of claims 58-70, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA is optionally substituted С14alkyl.

72. The compound of any one of claims 58-70, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA is methyl, ethyl, propyl, and butyl.

73. The compound of any one of claims 58-70, or a pharmaceutically acceptable salt, or solvate thereof, wherein RA ethyl, propyl, and butyl.

74. The compound of any one of claims 58-73, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is optionally substituted C1-C6alkyl.

75. The compound of claim 74, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is methyl.

76. The compound of any one of claims 58-75, or a pharmaceutically acceptable salt, or solvate thereof, wherein R2 is H.

77. The compound of any one of claims 58-76, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 and L2 are each -NH-.

78. The compound of any one of claims 58-76, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 is -CH2- and L2 is -NH-.

79. The compound of any one of claims 58-76, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 is -NH- and L2 is -CH2-.

80. The compound of any one of claims 58-79, or a pharmaceutically acceptable salt, or

solvate thereof, wherein
is optionally substituted aryl, wherein if


is substituted, then
is substituted with 0-4 Rc.

81. The compound of any one of claims 58-79, or a pharmaceutically acceptable salt, or

solvate thereof, wherein
is optionally substituted heteroaryl wherein if


is substituted, then
is substituted with 0-4 Rc.

82. The compound of any one of claims 58-79, or a pharmaceutically acceptable salt, or

solvate thereof, wherein

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

83. The compound of claim 82, or a pharmaceutically acceptable salt, or solvate thereof, wherein C1 is CRC; C2 is CRC; C3 is CRC; and C4 is CRC.

84. The compound of claim 83, or a pharmaceutically acceptable salt, or solvate thereof, wherein C1 is CRC; C2 is CH; C3 is CH; and C4 is CH.

85. The compound of claim 84, or a pharmaceutically acceptable salt, or solvate thereof, wherein RC is optionally substituted C1-C6fluoroalkyl.

86. The compound of claim 85, or a pharmaceutically acceptable salt, or solvate thereof, wherein RC is -CF3.

87. The compound of any one of claims 58-86, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R3 is independently H.

88. The compound of any one of claims 58-87, or a pharmaceutically acceptable salt, or

solvate thereof wherein

89. The compound of claim 88, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted heterocyclyl containing at least one N atom; and if


is substituted, then
is substituted with 0-4 RD.

90. The compound of claim 88, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted heterocyclyl containing one N atom; and if

is substituted, then is substituted with 0-4 RD.

91. The compound of claim 88, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is optionally substituted heterocyclyl containing two N atoms; and if


is substituted, then
is substituted with 0-4 RD.

92. The compound of claim 88, or a pharmaceutically acceptable salt, or solvate thereof,

wherein
is

r is 0, 1, or 2.

93. The compound of claim 92, or a pharmaceutically acceptable salt, or solvate thereof,

wherein and r is 0, 1, or 2.


94. The compound of any one of claims 58-93, or a pharmaceutically acceptable salt, or

solvate thereof wherein is LD.


95. The compound of claim 94, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-(optionally substituted C1-C6 alkyl), -N(R13)-(optionally substituted C1-C6 alkyl ene)-N(R14)2 or -(optionally substituted C1-C6 alkyl ene)-N(R14)2; and if LD is substituted, then LD is substituted with 0-4 RD.

96. The compound of claim 95, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-(optionally substituted C1-C6 alkyl), and if LD is substituted, then LD is substituted with 0-4 RD.

97. The compound of claim 96, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-CH2-CH2-CH2-CH3, -N(R12)-CH2-CH2-CH3, -N(R12)-CH2-CH3, or -N(R12)-CH3.

98. The compound of claims 96 or 97, or a pharmaceutically acceptable salt, or solvate thereof, wherein R12 is H or С14alkyl.

99. The compound of claims 96 or 97, or a pharmaceutically acceptable salt, or solvate thereof, wherein R12 is H or C3-C4alkyl.

100. The compound of claim 95, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R13)-(optionally substituted C1-C6 alkyl ene)-N(R14)2, and if LD is substituted, then LD is substituted with 0-4 RD.

101. The compound of claim 100, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R13)-CH2-CH2-CH2-CH2-N(R14)2, -N(R13)-CH2-CH2-CH2-N(R14)2, -N(R13)-CH2-CH2-N(R14)2, or -N(R13)-CH2-N(R14)2.

102. The compound of claims 100 or 101, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R13 and R14 is independently H or С14alkyl.

103. The compound of claim 95, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is or -(optionally substituted C1-C6 alkylene)-N(R14)2; and if LD is substituted, then LD is substituted with 0-4 RD.

104. The compound of claiml03, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -CH2-CH2-CH2-CH2-N(R14)2, -CH2-CH2-CH2-N(R14)2, -CH2-CH2-N(R14)2, or -CH2-N(R14)2.

105. The compound of claims 103 or 104, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R14 is independently H or С14alkyl.

106. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIa)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

107. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIb)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

108. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIe)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

109. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IId)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

110. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIe)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

111. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIf)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

112. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIg)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

113. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIh)


114. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIi)


115. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIj)

116. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIk)


117. The compound of claim 58, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (III)


118. The compound of claim 58, or a pharmaceutically acceptable salt, or thereof, wherein the compound has the structure of formula (IIm)


119. A compound of Formula (III), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,

Z is H,

is an optionally substituted C3-C10 heterocyclyl containing at least one N, O,

S, S(=O), or S(=O)2; wherein if is substituted, then is


substituted with 0-3 R5;

is a substituted C3-C10 cycloalkyl that is substituted with 1-3R4 and 0-3R5;

each R4 is independently -OR6, -SR6, -S(=O)R7, -S(=O)2R7, or -N(R6)2;

each R5 is independently halogen, -CN, -OR8, -SR8, -S(=O)R9, -S(=O)2R9, - S(=O)2N(R8)2, -NR8S(=O)2R9, -C(=O)R9, -OC(=O)R9, -CO2R8, -OCO2R9, -N(R8)2, - OC(=O)N(R8)2, -NR8C(=O)R9, -NR8C(=O)OR9, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

A1 is N or CRA; A2 is N or CRA; A3 is N or CRA; A4 is N or CRA; A5 is N or CRA; each RA is independently H or optionally substituted C1-C6alkyl;

R1 and R2 are each independently H or optionally substituted C1-C6alkyl;

L1 and L2 are each independently -CHY-, -CH2- or -NH-;

Y is optionally substituted C1-C6alkyl;


is optionally substituted aryl or optionally substituted heteroaryl,

wherein if is substituted, then is substituted with 0-4

Rc;

each Rc is independently H, halogen, -CN, -OR10, -SR10, -S(=O)R11, -S(=O)2R11, - S(=O)2N(R10)2, -NR10S(=O)2R11, -C(=O)R11, -OC(=O)R11, -CO2R10, -OCO2R11, - N(R10)2, -OC(=O)N(R10)2, -NR10C(=O)R11, -NR10C(=O)OR11, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R3 is independently H or optionally substituted C1-C6alkyl;

LD is -N(R12)-(optionally substituted C1-C6 alkyl), -N(R13)-(optionally substituted C1-C6 alkylene)-N(R14)2 or -(optionally substituted C1-C6 alkylene)-N(R14)2; wherein if LD is substituted, then LD is substituted with 0-4 RD;

each RD is independently halogen, -CN, -OR15, -SR15, -S(=O)R16, -S(=O)2R16, - S(=O)2N(R15)2, -NR15S(=O)2R16, -C(=O)R16, -OC(=O)R16, -CO2R15, -OCO2R16, - N(R15)2, -OC(=O)N(R15)2, -NR15C(=O)R16, -NR15C(=O)OR16, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1- C6heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R6 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R6 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R7 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R8 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, 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-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R10 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R10 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R11 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R12 is independently H or optionally substituted C3-C6alkyl;

R13 is H or optionally substituted C1-C6alkyl;

each R14 is independently H or optionally substituted C1-C6alkyl; or

two R14 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;

each R15 is independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3-C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R15 are taken together with the N atom to which they are attached to form an optionally substituted heterocycle; and

each R16 is independently optionally substituted C1-C6alkyl, optionally substituted C1- C6fluoroalkyl, optionally substituted C1-C6heteroalkyl, optionally substituted C3- C10cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

120. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein Z is H.

121. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate

thereof, wherein Z is


122. The compound of claim 121, or a pharmaceutically acceptable salt, or solvate

thereof, wherein optionally substituted C4-C7 heterocyclyl containing at least one

N, O, S, S(=O), or S(=O)2; wherein if
is substituted, then is sub
stituted

with 0-3 R5.

123. The compound of claim 121, or a pharmaceutically acceptable salt, or solvate

thereof, wherein
is

o is 0, 1, or 2; and p is 0, 1, 2, or 3.

124. The compound of claim 123, or a pharmaceutically acceptable salt, or solvate

thereof, wherein
and o is 0, 1, or 2.

125. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate

thereof, wherein Z is


126. The compound of claim 125, or a pharmaceutically acceptable salt, or solvate

thereof, wherein is substituted C4-C7 cycloalkyl that is substituted with 1-3R and 0-

3R5.

127. The compound of claim 125, or a pharmaceutically acceptable salt, or solvate

thereof, wherein
is


q is 0, 1, 2, or 3.

128. The compound of claim 127, or a pharmaceutically acceptable salt, or solvate

thereof, wherein is


q is 0, 1, 2, or 3.

129. The compound of any one of claims 119-128, or a pharmaceutically acceptable salt, or solvate thereof, wherein A1 is CH; A2 is N or CRA; A3 is N or CRA; A4 is CH; and A5 is CH.

130. The compound of claim 129, or a pharmaceutically acceptable salt, or solvate thereof, wherein A2 is N.

131. The compound of claim 129, or a pharmaceutically acceptable salt, or solvate thereof, wherein A2 is CRA.

132. The compound of any one of claims 129-131, or a pharmaceutically acceptable salt, or solvate thereof, wherein A3 is CRA.

133. The compound of claim 132, or a pharmaceutically acceptable salt, or solvate thereof, wherein RAis optionally substituted C1-C6alkyl.

134. The compound of claim 133, or a pharmaceutically acceptable salt, or solvate thereof, wherein RAis methyl, ethyl, propyl or butyl.

135. The compound of claim 133, or a pharmaceutically acceptable salt, or solvate thereof, wherein RAis methyl, propyl or butyl.

136. The compound of any one of claims 119-135, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is optionally substituted C1-C6alkyl.

137. The compound of claim 136, or a pharmaceutically acceptable salt, or solvate thereof, wherein R1 is methyl.

138. The compound of any one of claims 119-137, or a pharmaceutically acceptable salt, or solvate thereof, wherein R2 is H.

139. The compound of any one of claims 119-138, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 and L2 are each -NH-.

140. The compound of any one of claims 119-138, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 is -CH2- and L2 is -NH-.

141. The compound of any one of claims 119-138, or a pharmaceutically acceptable salt, or solvate thereof, wherein L1 is -NH- and L2 is -CH2-.

142. The compound of any one of claims 119-141, or a pharmaceutically acceptable

salt, or solvate thereof, wherein
is optionally substituted aryl, wherein if

is substituted, then is substituted with 0-4 Rc.

143. The compound of any one of claims 119-141, or a pharmaceutically acceptable

salt, or solvate thereof, wherein
is optionally substituted heteroaryl wherein if


is substituted, then
is substituted with 0-4 Rc.

144. The compound of any one of claims 119-141, or a pharmaceutically acceptable

salt, or solvate thereof, wherein

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

145. The compound of claim 144, or a pharmaceutically acceptable salt, or solvate thereof, wherein C1 is CRC; C2 is CRC; C3 is CRC; and C4 is CRC.

146. The compound of claim 145, or a pharmaceutically acceptable salt, or solvate thereof, wherein C1 is CRC; C2 is CH; C3 is CH; and C4 is CH.

147. The compound of claim 146, or a pharmaceutically acceptable salt, or solvate thereof, wherein RC is optionally substituted C1-C6fluoroalkyl.

148. The compound of claim 147, or a pharmaceutically acceptable salt, or solvate thereof, wherein R is -CF3.

149. The compound of any one of claims 119-148, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R3 is independently H.

150. The compound of any one of claims 119-149, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-(optionally substituted C1-C6 alkyl), -N(R13)- (optionally substituted C1-C6 alkylene)-N(R14)2 or -(optionally substituted C1-C6 alkylene)- N(R14)2; and if LD is substituted, then LD is substituted with 0-4 RD.

151. The compound of claim 150, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-(optionally substituted C1-C6 alkyl), and if LD is substituted, then LD is substituted with 0-4 RD.

152. The compound of claim 151, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R12)-CH2-CH2-CH2-CH3, -N(R12)-CH2-CH2-CH3, -N(R12)-CH2-CH3, or -N(R12)-CH3.

153. The compound of claims 151 or 152, or a pharmaceutically acceptable salt, or solvate thereof, wherein R12 is H or C3-C4alkyl.

154. The compound of claim 150, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R13)-(optionally substituted C1-C6 alkylene)-N(R14)2, and if LD is substituted, then LD is substituted with 0-4 RD.

155. The compound of claim 154, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -N(R13)-CH2-CH2-CH2-CH2-N(R14)2, -N(R13)-CH2-CH2-CH2-N(R14)2, -N(R13)-CH2-CH2-N(R14)2, or -N(R13)-CH2-N(R14)2.

156. The compound of claims 154 or 155, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R13 and R14 is independently H or С14alkyl.

157. The compound of claim 150, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is or -(optionally substituted C1-C6 alkylene)-N(R14)2; and if LD is substituted, then LD is substituted with 0-4 RD.

158. The compound of claim 157, or a pharmaceutically acceptable salt, or solvate thereof, wherein LD is -CH2-CH2-CH2-CH2-N(R14)2, -CH2-CH2-CH2-N(R14)2, -CH2-CH2-N(R14)2, or -CH2-N(R14)2.

159. The compound of claims 157-158, or a pharmaceutically acceptable salt, or solvate thereof, wherein each R14 is independently H or С14alkyl.

160. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIa)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

161. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIb)

wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

162. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIc)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

163. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIId)


wherein,

C1 is N or CRC; C2 is N or CRC; C3 is N or CRC; and C4 is N or CRC.

164. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIe)


165. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIf)

166. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIg)


167. The compound of claim 119, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of formula (IIIh)


168. The compound of any one of claims 1-167, or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound or pharmaceutically acceptable salt, or solvate thereof, selectively binds to IRE1α at one or more binding sites.

169. The compound of claim 168, wherein the IRE1α comprises an RNase domain, a kinase domain, or any combination thereof.

170. The compound of claim 169, wherein the kinase domain is an auto-transphosphorylation kinase domain.

171. The compound of claim 169 or 170, wherein the kinase domain comprises an ATP-binding pocket.

172. The compound of any one of claims 168-171, wherein the kinase domain comprises an activation loop.

173. The compound of any one of claims 168-172, wherein at least one binding site is within the RNase domain.

174. The compound of any one of claims 168-173, where at least one binding site is within the kinase domain.

175. The compound of claim 174, wherein the at least one binding site is within the ATP-binding pocket of the kinase domain.

176. The compound of claim 174, wherein the at least one binding site is within the activation loop of the kinase domain.

177. The compound of any one of claims 168-176, wherein binding occurs at a first binding site.

178. The compound of claim 177, wherein the first binding site is located within the RNase domain, kinase domain, ATP-binding pocket, or activation loop.

179. The compound of any one of claims 177-178, wherein the first binding site comprises at least one amino acid residue of within amino acid residues 465-977 of SEQ ID NO: 1.

180. The compound of claim 179, wherein the first binding site comprises at least one amino acid residue within amino acid residues 568-833 of SEQ ID NO: 1.

181. The compound of claim 179, wherein the first binding site comprises at least one amino acid residue within amino acid residues 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1.

182. The compound of claim 179, wherein the first binding site comprises at least one amino acid residue within amino acid residues 710-725 or 729-736 of SEQ ID NO: 1.

183. The compound of claim 179, wherein the first binding site comprises at least one amino acid residue within amino acid residues 835-963 of SEQ ID NO: 1.

184. The compound of any one of claims 177-183, wherein binding further occurs at a second binding site.

185. The compound of claim 184, wherein the second binding site is located within the RNase domain, the kinase domain, the ATP-binding pocket, or the activation loop.

186. The compound of claim 184, wherein the second binding site comprises at least one amino acid residue of within amino acid residues 465-977 of SEQ ID NO: 1.

187. The compound of claim 184, wherein the second binding site comprises at least one amino acid residue within amino acid residues 568-833 of SEQ ID NO: 1.

188. The compound of claim 184, wherein the second binding site comprises at least one amino acid residue within amino acid residues 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1.

189. The compound of claim 184, wherein the second binding site comprises at least one amino acid residue within amino acid residues 710-725 or 729-736 of SEQ ID NO: 1.

190. The compound of claim 184, wherein the second binding site comprises at least one amino acid residue within amino acid residues 835-963 of SEQ ID NO: 1.

191. The compound of any one of claims 168-190, wherein binding occurs when the IRE1α is in a homo-dimerized conformation.

192. The compound of any one of claims 168-190, wherein binding occurs when the IRE1α is in an oligomerized conformation.

193. The compound of any one of claims 168-190, wherein binding occurs when the IRE1α is in a non-oligomerized or non-dimerized conformation.

194. The compound of any one of claims 168-193, wherein binding occurs when the IRE1α is in an ATP-bound state.

195. The compound of any one of claims 168-193, wherein binding occurs when the IRE1α is in a non-ATP-bound state.

196. The compound of any one of claims 168-195, wherein the compound selectively binds to a first IRE1α.

197. The compound of claim 196, wherein selectively binding to the first IRE1α blocks dimerization of the first IRE1α to a second IRE1α.

198. The compound of claim 196, wherein selectively binding to the first IRE1α blocks auto-transphosphorylation of the first IRE1α.

199. The compound of claim 196, wherein selectively binding to the first IRE1α blocks auto-transphosphorylation of a second IRE1α to which the first IRE1α is dimerized.

200. The compound of claim 196, wherein selectively binding to the first IRE1α blocks activation of the first IRE1α.

201. The compound of claim 196, wherein selectively binding to the first IRE1α blocks activation a second IRE1α to which the first IRE1α is dimerized.

202. The compound of claim 196, wherein selectively binding to the first IRE1α blocks kinase activity of the first IRE1α.

203. The compound of claim 196, wherein selectively binding to the first IRE1α blocks kinase activity of a second IRE1α to which the first IRE1α is dimerized.

204. The compound of claim 196, wherein selectively binding to the first IRE1α blocks RNase activity of the first IRE1α.

205. The compound of claim 196, wherein selectively binding to the first IRE1α blocks RNase activity of a second IRE1α to which the first IRE1α is dimerized.

206. A compound that selectively binds a first IRE1α at two or more sites, wherein when the compound is bound to the first IRE1α protein, the compound binds to an ATP-binding pocket of the first IRE1α and blocks the binding of ATP to the first IRE1α.

207. The compound of claim 206, wherein the ATP binding pocket is comprised within a kinase domain.

208. The compound of claim 206 or 207, wherein the ATP binding pocket is comprised within amino acid residues 465-977 of SEQ ID NO: 1

209. The compound of any one of claims 206-208, wherein the ATP binding pocket is comprised within amino acid residues 568-833 of SEQ ID NO: 1.

210. The compound of any one of claims 206-209, wherein the ATP binding pocket comprises one or more of amino acid resides 577-586, 597, 599, 626, 642-643, 645, 648, 688, 692-693, 695, or 711 of SEQ ID NO: 1.

211. A pharmaceutical composition comprising a compound according to any one of claims 1-196, or a pharmaceutically acceptable salt or solvate thereof.

212. The pharmaceutical composition of claim 211, comprising one or more pharmaceutically acceptable excipients.

213. 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 pharmaceutical composition, wherein the pharmaceutical composition comprises the compound of any one of claims 1-210.

214. The method of claim 213, wherein the disease is cancer.

215. The method of claim 214, wherein the cancer is a solid cancer or a hematologic cancer.

216. The method of claim 214, wherein the cancer is ovarian cancer, breast cancer, or triple negative breast cancer (TNBC).

217. A method for treating or ameliorating a cell proliferative disorder, the method comprising administering a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, or solvate thereof, that selectively binds to at least one amino acid residue of a IRE1 family protein comprising an RNase domain and kinase domain.

218. The method of claim 217, wherein the IRE1 family protein is IRE1α.

219. The method of claim 218, wherein the compound binds to an ATP-binding site of

IRE1α.

220. The method of any one of claims 217-219, wherein the cell proliferative disorder is cancer.

221. The method of claim 220, wherein the cancer is a solid cancer or a hematologic cancer.

222. The method of any one of claims 217-221, wherein the pharmaceutical composition comprises the compound of any one of claims 1-210.