Granted Patent B2

US 12,503,456 · App. 18/628,280 · Granted Dec 23, 2025

Inventors: Marco De Vivo (Genoa, IT); Anand Ganesan (Irvine, CA); Jose Antonio Ortega Martinez (Genoa, IT); Sohail Jahid (Irvine, CA)

Assignees: Fondazione Istituto Italiano Di Tecnologia; The Regents of the University of California

C07D401/14C07D405/04A61K45/06

Abstract

Claims (49)

1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 or 2 nitrogen atoms; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , OH, and OC 1-6 alkyl;

A′ is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 or 2 nitrogen atoms; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , OH, and OC 1-6 alkyl;

X 1 is —CH 2 —, —NR 2 —, or —O—;

X 2 is —CH 2 —, —NR 2 —, or —O—;

R 1 is H or C 1-6 alkyl;

R 2 is H, C 1-6 alkyl, C 1-6 alkyl-O(alkyl), C(O)C 1-6 alkyl, or C(O)C 1-6 alkyl-O(alkyl); and

Y is CH or N;

with the provisos that:

(1) X 1 and X 2 are not simultaneously —NR 2 —;

(2) X 1 and X 2 are not simultaneously —NR 2 — and —O—; and

(3) X 1 and X 2 are not simultaneously —O—.

2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is an unsubstituted 6-membered aromatic ring or a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring contains 1 nitrogen atom.

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is a 6-membered aromatic ring, wherein the 6-membered aromatic ring is substituted in the meta position or the para position with one substituent selected from the group consisting of N(CH 2 CH 3 ) 2 and OCH 3 .

4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 nitrogen atom; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , and OC 1-6 alkyl;

A′ is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 nitrogen atom; and

wherein the 6-membered aromatic ring or the 6-membered heteroaromatic ring is optionally substituted with one substituent selected from the group consisting of halogen, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , and OC 1-6 alkyl;

R 1 is H; and

R 2 is H.

5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring;

wherein the 6-membered heteroaromatic ring contains 1 nitrogen atom in position 2 or position 3; and

wherein the 6-membered aromatic ring is optionally substituted with one substituent selected from the group consisting of halogen and OC 1-3 alkyl;

A′ is a 6-membered aromatic ring, wherein the 6-membered aromatic ring is optionally substituted in the meta position or the para position with one substituent selected from the group consisting of halogen, N(C 1-6 alkyl) 2 , and OC 1-6 alkyl;

X 1 is —CH 2 —, —NH—, or —O—;

X 2 is —CH 2 — or —NH—;

R 1 is H; and

Y is CH;

with the proviso that X 1 and X 2 are not simultaneously —NH—.

6 . The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

7 . A medicament comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

8 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

9 . The pharmaceutical composition according to claim 8 , wherein the pharmaceutical composition further comprises a chemotherapeutic agent selected from the group consisting of carboplatin, cisplatin, dacarbazine, nedaplatin, oxaliplatin, satraplatin, temozolamide, and triplatin tetranitrate.

10 . The pharmaceutical composition according to claim 9 , wherein the ingredients of the pharmaceutical composition are administered separately, simultaneously, or sequentially.

11 . A method for inhibiting RhoJ activity or cell division control protein 42 (Cdc42) homolog-guanosine triphosphate hydrolyzing protein activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

12 . The method according to claim 11 , wherein the subject has a disease or disorder selected from the group consisting of a metastatic neoplastic disease, a primary neoplastic disease, and a pre-malignant condition.

13 . The method according to claim 12 , wherein the metastatic neoplastic disease, the primary neoplastic disease, or the pre-malignant condition is selected from the group consisting of a benign tumor, a cancer, a cancer metastasis, a cardiomyopathy, a dysplasia, a hyperplasia, a hyperproliferative disorder, a metaplasia, and a retinal disorder.

14 . The method according to claim 13 , wherein the cancer is melanoma.

Assignments (2)

Priority Claims (1)

Continuity (3)

References Cited (151)