# US 2019/0375704 A1 · Modulators of the eif2alpha pathway

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- Number: US 2019/0375704 A1
- Document ID: US20190375704A1
- Status: Published application
- Kind: A1
- Application number: 16/418,858
- Filed: 2019-05-21
- Published: 2019-12-12
- Earliest claimed: 2013-03-15
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Peter Walter; Carmela Sidrauski; Diego Acosta Alvear; Michelle R. Arkin; Christopher G. Wilson; Kean Hooi Ang; Brian R. Hearn; Punitha Vedantham; Adam R. Renslo; Mervyn Maze; Susana Vacas
- Web page: https://patentgrep.com/patent/US20190375704A1

## CPC

- C07C 235/14: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/4192: 1,2,3-Triazoles
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07C 211/29: the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
- C07C 235/20: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 235/22: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C 235/24: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 255/54: containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
- C07C 257/14: having carbon atoms of amidino groups bound to acyclic carbon atoms
- C07C 271/24: with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C 271/52: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 317/22: with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C 317/44: having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C 323/60: with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 495/04: Ortho-condensed systems
- C07F 7/081: {comprising at least one atom selected from the elements N, O, halogen, S, Se or Te}
- C07C 2601/04: with a four-membered ring
- C07C 2601/14: The ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Provided herein, inter alia, are compounds and methods useful for modulating the translational effects of eIF2α phosphorylation, the Integrated Stress Response (ISR), and the unfolded protein response (UPR); for treating diseases; for increasing protein production, and for improving long-term memory.

## Claims

### Claim 1

A method of treating an integrated stress response-associated disease, a disease associated with phosphorylation of eIF2α, or an inflammatory disease, in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to said patient, wherein said compound has the formula:
wherein,
ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene;
L1, L2, L3, and L4 are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;
R1, R3, R5, R6 and R7 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —C(NN)CF3, —C(NH—NH)CF3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH3, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 and R4 are independently ═NR7, ═O, or ═S;
z2 and z4 are independently 0 or 1; and
z5 and z6 are independently an integer from 0 to 5.

### Claim at position 2

-12.

### Claim 13

A method of inhibiting growth of plasmacytoma or increasing protein expression by a cell or in vitro expression system in a patient, said method comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to said patient, wherein said compound has the formula:
wherein,
ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene;
L1, L2, L3, and L4 are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;
R1, R3, R5, R6 and R7 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —C(NN)CF3, —C(NH—NH)CF3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH3, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 and R4 are independently ═NR7, ═O, or ═S;
z2 and z4 are independently 0 or 1; and
z5 and z6 are independently an integer from 0 to 5.

### Claim 14

(canceled)

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound has the formula:

### Claim at position 6

-21. (canceled)

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound has the formula:
wherein,
R8 and R9 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH3, —OCF3, —OCHF2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
b and d are independently 0 or 1.

### Claim 23 (depends on 22)

The method of claim 22, wherein the compound has the formula:

### Claim at position 9

-25. (canceled)

### Claim 26 (depends on 1)

The method of claim 1, wherein the compound has the formula:

### Claim at position 11

-34. (canceled)

### Claim 35 (depends on 1)

The method of claim 1, wherein the compound has the formula:
R5.1 and R6.1 are independently hydrogen, halogen, —CF3, —CN, —N3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted 5 to 6 membered heteroaryl,
R5.2 and R6.2 are independently hydrogen, halogen, —CCSi(CH3)3, —CF3, —NO2, —CN, —N3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted 5 to 6 membered heteroaryl,

### Claim at position 13

-37. (canceled)

### Claim 38 (depends on 1)

The method of claim 1, wherein the compound is

### Claim 39 (depends on 1)

The method of claim 1, wherein the compound is

### Claim 40

A compound, or a pharmaceutically acceptable salt thereof, having the formula:
wherein,
ring A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted arylene;
L1, L2, L3, and L4 are independently a bond, —NH—, —O—, —S—, —S(O)—, —S(O)2—, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;
R1, R3, R5, R6 and R7 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —C(NN)CF3, —C(NH—NH)CF3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH3, —OCF3, —OCHF2, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 and R4 are independently ═NR7, ═O, or ═S;
z2 and z4 are independently 0 or 1; and
z5 and z6 are independently an integer from 0 to 5;
with the proviso that the compound is not

### Claim 41 (depends on 40)

The compound of claim 40, wherein said compound has the formula:

### Claim at position 18

-47. (canceled)

### Claim 48 (depends on 40)

The compound of claim 40, wherein the compound has the formula:
wherein,
R8 and R9 are independently hydrogen, halogen, —OCH3, —OCH2Ph, —C(O)Ph, —CH3, —CF3, —CCl3, —CN, —S(O)CH3, —OH, —NH2, —COOH, —CONH2, —NO2, —C(O)CH3, —CH(CH3)2, —CCSi(CH3)3, —CCH, —CH2CCH, —SH, —SO2Cl, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC═(O)NHNH2, —NHC═(O)NH2, —NHSO2H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH3, —OCF3, —OCHF2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
b and d are independently 0 or 1.

### Claim 49 (depends on 48)

The compound of claim 48, wherein the compound has the formula:

### Claim at position 21

-51. (canceled)

### Claim 52 (depends on 40)

The compound of claim 40, wherein the compound has the formula:

### Claim at position 23

-60. (canceled)

### Claim 61 (depends on 60)

The compound of claim 60, wherein the compound has the formula:
R5.1 and R6.1 are independently hydrogen, halogen, —CF3, —CN, —N3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted 5 to 6 membered heteroaryl,
R5.2 and R6.2 are independently hydrogen, halogen, —CCSi(CH3)3, —CF3, —NO2, —CN, —N3, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted 5 to 6 membered heteroaryl,

### Claim at position 25

-63. (canceled)

### Claim 64 (depends on 40)

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, of claim 40.

### Claim 65 (depends on 13)

The method of claim 13, wherein the plasmacytoma is a subcutaneous plasmacytoma.