# US 10,501,421 B1 · Substituted benzimidazoles as modulators of Ras signaling

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- Number: US 10,501,421 B1
- Document ID: US10501421B1
- Status: Granted
- Kind: B1
- Application number: 15/418,274
- Filed: 2017-01-27
- Granted: 2019-12-10
- Earliest claimed: 2017-01-27
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Steve Fesik; Alex Waterson; Michael Burns; Qi Sun; Jason Phan; James M. Salovich; Jason R. Abbott; Andrew Little
- Web page: https://patentgrep.com/patent/US10501421B1

## CPC

- C07D 235/30: Nitrogen atoms not forming part of a nitro radical
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Benzimidazole compounds that increase the rate of SOS-mediated nucleotide exchange on Ras by binding to a functionally relevant, chemically tractable pocket on the SOS protein, as part of the Ras:SOS:Ras complex.

## Claims

### Claim 1

A compound of the following formula:
X1A is C—R;
X2 is C—R6;
X3 is C—R6;
X4 and X5 together form
or substituted or unsubstituted cyclic amine (provided that the term cyclic amine excludes piperazine and azetidine);
R is unsubstituted or substituted with one or more independent R5, and is independently chosen from alkyl, cycloalkyl, phenyl, hydroxyl, heterocycloalkyl, cyclic amine, halogen, CF3, Cl, CONR3R4, aryl, heteroaryl, O—RA, O-alkyl-RA, O-aryl, O-heteroaryl, N—RA, N-aryl, N-heteroaryl, NHRA, NR2R3, heteroalkyl, benzyl, heteroaryl benzyl (CH2-heteroaryl), alkenyl, alkynyl, alkyl-cycloalkyl, CH2-cycloalkyl, CH2—CF3, hydroxyalkyl, alkyl-alkoxy, alkyl-cycloheteroalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF3, alkyl-CO—O-alkyl, alkyl-CO—NR3R4, CO-alkyl-sulfonyl-alkyl, CO-cycloheteroalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-cycloheteroalkyl, O-alkoxy, O-dioxothian, alkoxy, O-heteroalkyl, alkoxy-heteroalkyl, methylsulfonyl, O-cycloheteroalkyl, O-alkoxy-cycloheteroalkyl, O-alkoxy-aryl, O-heteroaryl, NR3COR2, amino-cycloalkyl, amino-cycloheteroalkyl, NR3-alkoxy, NR3-dioxothian, NR3-heteroalkyl, amino-heteroalkyl, NR3-cycloheteroalkyl, NR3-cycloheteroalkyl, NR3-aryl, NR3-heteroaryl, NR3—CO—CF3, alkyl-CO—NR3R4, NR3—CO-alkyl-sulfonyl-alkyl, NR3—CO— cycloheteroalkyl, CO—NR3-cycloalkyl, alkyl-carboxylic acid, alkoxy-heteroaryl, alkyl-phenyl, cycloheteroalkyl, amino, amino-heteroaryl, amino-phenyl, CO-alkyl, CONR3-alkyl, CH3, NH2, alkyl-amino, pyridine, pyrazole, furan, thiophene, pyrimidine, thiazole, isothiazole, oxazole, isoxazole, piperazine, pyrrole, pyrazine, dioxane, morpholine, thiomorpholine, triazole, imidazole, alkoxy;
RA is unsubstituted or substituted with one or more independent R5, and is independently chosen from H, alkyl, cycloalkyl, phenyl, hydroxyl, heterocycloalkyl, cyclic amine, halogen, CF3, Cl, CONR3R4, aryl, heteroaryl, O—R3, O-alkyl-R3, O-aryl, O-heteroaryl, N—R3, N-aryl, N-heteroaryl, NR2R3, heteroalkyl, benzyl, heteroaryl benzyl (CH2-heteroaryl), alkenyl, alkynyl, alkyl-cycloalkyl, CH2-cycloalkyl, CH2—CF3, hydroxyalkyl, alkyl-alkoxy, alkyl-cycloheteroalkyl, alkyl-heteroaryl, alkyl-carboxylic acid, CO—CF3, alkyl-CO—O-alkyl, alkyl-CO—NR3R4, CO-alkyl-sulfonyl-alkyl, CO-cycloheteroalkyl, CO—NH-cycloalkyl, CN, alkoxy-cycloalkyl, alkoxy-cycloheteroalkyl, O-alkoxy, O-dioxothian, alkoxy, O-heteroalkyl, alkoxy-heteroalkyl, methylsulfonyl, O-cycloheteroalkyl, O-alkoxy-cycloheteroalkyl, O-alkoxy-aryl, O-heteroaryl, NR3COR2, amino-cycloalkyl, amino-cycloheteroalkyl, NR3-alkoxy, NR3-dioxothian, NR3-heteroalkyl, amino-heteroalkyl, NR3-cycloheteroalkyl, NR3-cycloheteroalkyl, NR3-aryl, NR3-heteroaryl, NR3—CO—CF3, alkyl-CO—NR3R4, NR3—CO-alkyl-sulfonyl-alkyl, NR3—CO— cycloheteroalkyl, CO—NR3-cycloalkyl, alkyl-carboxylic acid, alkoxy-heteroaryl, alkyl-phenyl, cycloheteroalkyl, amino, amino-heteroaryl, amino-phenyl, CO-alkyl, CONR3-alkyl, CH3, NH2, alkyl-amino, pyridine, pyrazole, furan, thiophene, pyrimidine, thiazole, isothiazole, oxazole, isoxazole, piperazine, pyrrole, pyrazine, dioxane, morpholine, thiomorpholine, triazole, imidazole, alkoxy;
R2 is substituted by one or more R5, or unsubstituted and is selected from H, alkyl, alkene, alkyne, alkyl-heteroaryl, alkyl-heterocycloalkyl, alkyl-amino, or together with R3 forms a 3-6 membered ring;
R3 is substituted by one or more R5 or unsubstituted and is selected from H, alkyl, alkenyl, alkynyl, alkyl-heteroaryl, alkyl-heterocycloalkyl, alkyl-amino, or together with R2 forms a ring;
R4 is substituted by one or more R5, or unsubstituted and is selected from benzyl, methylcycloalkyl, cycloalkyl, alkyl-cycloalkyl;
R5 (i) appears once and is a halogen;
(ii) appears twice and is
two halogens,
alkyl and halogen,
CF3 and halogen;
(iii) appears three times and is:
a halogen, alkyl, and alkenyl,
a halogen, a alkyl, and alkynyl,
two alkyls and a halogen; or
three halogens;
R6 is independently selected from H, halogen, CH3, or CF3, provided that in connection with X2R6 is H or methyl, and in connection with X3, R6 is methyl, CF3, or halogen;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 2 (depends on 1)

A compound of claim 1, wherein R6 is halogen, alkyl, alkenyl, alkynyl, or cycloalkyl.

### Claim 3 (depends on 1)

A compound of claim 1, wherein X1A is C—R; and wherein R is of the following formula:
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

### Claim 4 (depends on 1)

A compound of claim 1, wherein R6 is H, halogen, or C1-6 alkyl.

### Claim 5 (depends on 1)

A compound of claim 1, wherein R2 is selected from H, alkyl, alkyl-heterocycloalkyl, alkyl-azetidine, alkyl-amino.

### Claim 6 (depends on 1)

A compound of claim 1, wherein R3 is selected from H, alkyl, alkyl-heterocycloalkyl, alkyl-azetidine, alkyl-amino.

### Claim 7 (depends on 1)

A compound of claim 1, wherein R5 is independently selected from H, halogen, alkyl, CH3, alkene, heteroaryl, amino-alkyl, alkoxy.

### Claim 8 (depends on 1)

A compound of claim 1, wherein R1 and X5 further cyclize form a 6-membered ring containing one or two nitrogen ring members.

### Claim 9 (depends on 1)

A compound of claim 1, wherein X1A is C—R, and R is chosen from:
and stereoisomers thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein when R5 is alkyl, the alkyl is methyl.

### Claim 11 (depends on 1)

A compound of claim 1 the following formula:
pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A compound of claim 1 the following formula:
pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A compound of claim 1 of the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A compound of claim 1 the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 15

A compound of the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.