IP Library › Granted Patent US 11,725,008
Granted Patent B2
US 11,725,008 · App. 17/307,568 · Granted Aug 15, 2023

Ethanediamine-heterocycle derivatives as inhibitors of protein arginine methyltransferases

Inventors: Maria Emilia Di Francesco (Houston, TX); Philip Jones (Houston, TX); Timothy Joseph McAfoos (Pearland, TX)
Assignee: Board of Regents, The University of Texas System
C07D471/04A61P3/00A61P35/02C07D487/04C07D498/04A61K45/06
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Quick Facts
Patent No.
US 11,725,008
App. No.
17/307,568
Granted
Aug 15, 2023
Kind
B2
Abstract

The present invention relates to ethanediamine-heterocycle compounds that are able to act as inhibitors of PRMTs (protein arginine methyltransferases) for treating cancer and other diseases mediated by PRMTs.

Claims (74)

1. A method of treatment of a cancer chosen from acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor, comprising the administration of a therapeutically effective amount of a compound of structural Formula I

or a salt thereof, wherein:

A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:

X 1 and X 2 ,

Z, which is chosen from —CH 2 —, —CHR 3 —, —C(R 3 ) 2 —, —N(R 5a )—, N(COR 5a )—, N(CONR 5a R 5b )—, N(SO 2 R 5a )—, —O—, and —SO 2 —, and

all other ring members Y, which are chosen from —CH 2 —, —CHR 2 —, and —C(R 2 ) 2 —;

R 1a , R 1b , and R 1c are independently chosen from H and CH 3 ;

either X 1 is C and X 2 is N, or X 1 is N and X 2 is C;

each R 2 and R 3 is independently chosen from cyano, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, (C 1-6 alkoxy)C 1-6 alkyl; OR 5a , C(O)R 5a , C(O)OR 5a , C(O)NR 5a R 5b , SO 2 R 5a ; SO 2 NR 5a R 5b , NR 5a R 5b , NR 5a C(O)R 5b , NR 5a C(O)OR 5b , NR 5c C(O)NR 5a R 5b , and NR 5a SO 2 R 5b , or

any two R 2 or R 3 , when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R 4 is chosen from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted with 1, 2, 3, or 4 R 6 groups;

each R 5a and R 5b is independently chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl; C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, and (C 3-6 alkoxy)C 3-6 cycloalkyl, or

R 5a and R 5b , when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R 5c is chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl; C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, and (C 3-6 alkoxy)C 3-6 cycloalkyl;

each R 6 is independently chosen from C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (haloC 1-6 alkoxy)C 1-6 alkyl, C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, (C 3-6 alkoxy)C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-6 alkyl, (heterocycloalkyl)C 1-6 alkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, ((C 1-6 alkyl)aryl)C 1-6 alkyl, ((C 1-6 (alkyl)heteroaryl)C 1-6 alkyl, OR 7 , CH 2 OR 7 , CH 2 CH 2 OR 7 , COR 7 , COOH, COOR 7 , CONH 2 , CONHR 7 , CON(R 7 ) 2 , NHCOR 7 , NR 7 COR 7 , NHCONH 2 , NHCONHR 7 , NHCON(R 7 ) 2 , NR 7 CONH 2 , NR 7 CONHR 7 , NR 7 CON(R 7 ) 2 , SO 2 R 7 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , NHSO 2 R 7 , NR 7 SO 2 R 7 , carboxy, cyano, halo, hydroxy, and oxo;

each R 7 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl, heterocycloalkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, (cycloalkyl)C 1-6 alkyl, and (heterocycloalkyl)C 1-6 alkyl, any of which is optionally substituted with 1 or 2 R 8 groups; and

each R 8 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, and haloC 3-6 cycloalkyl;

to a patient in need thereof.

2. The method as recited in claim 1 , further comprising the administration of a non-chemical method of cancer treatment.

3. The method as recited in claim 2 , wherein said non-chemical method of cancer treatment is chosen from surgery, radiation therapy, thermoablation, focused ultrasound therapy, and cryotherapy.

4. The method as recited in claim 1 , wherein the compound of structural Formula I is of structural Formula II:

or a salt thereof, wherein:

A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:

X 1 and X 2 ,

Z, which is chosen from —CH 2 —, —CHR 3 —, —C(R 3 ) 2 —, —N(R 5a )—, N(COR 5a )—, N(CONR 5a R 5b )—, N(SO 2 R 5a )—, —O—, and —SO 2 —, and all other ring members Y, which are chosen from —CH 2 —, —CHR 2 —, and —C(R 2 ) 2 —;

R 1a , R 1b , and R 1c are independently chosen from H and CH 3 ;

either X 1 is C and X 2 is N, or X 1 is N and X 2 is C;

each R 2 and R 3 is independently chosen from cyano, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, (C 1-6 alkoxy)C 1-6 alkyl; OR 5a , C(O)R 5a , C(O)OR 5a , C(O)NR 5a R 5b , SO 2 R 5a ; SO 2 NR 5a R 5b , NR 5a R 5b , NR 5a C(O)R 5b , NR 5a C(O)OR 5b , NR 5c C(O)NR 5a R 5b , and NR 5a SO 2 R 5b , or any two R 2 or R 3 , when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R 4a and R 4b , together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 R 6 groups;

each R 5a and R 5b is independently chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl; C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, and (C 3-6 alkoxy)C 3-6 cycloalkyl, or

R 5a and R 5b , when attached directly to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R 5c is chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl; C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, and (C 3-6 alkoxy)C 3-6 cycloalkyl;

each R 6 is independently chosen from C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (haloC 1-6 alkoxy)C 1-6 alkyl, C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, (C 3-6 alkoxy)C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-6 alkyl, (C 3-6 heterocycloalkyl)C 1-6 alkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, ((C 1-6 alkyl)aryl)C 1-6 alkyl, ((C 1-6 alkyl)heteroaryl)C 1-6 alkyl, OR 7 , CH 2 OR 7 , CH 2 CH 2 OR 7 , COR 7 , COOH, COOR 7 , CONH 2 , CONHR 7 , CON(R 7 ) 2 , NHCOR 7 , NR 7 COR 7 , NHCONH 2 , NHCONHR 7 , NHCON(R 7 ) 2 , NR 7 CONH 2 , NR 7 CONHR 7 , NR 7 CON(R 7 ) 2 , SO 2 R 7 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , NHSO 2 R 7 , NR 7 SO 2 R 7 , carboxy, cyano, halo, hydroxy, and oxo;

each R 7 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, (cycloalkyl)C 1-6 alkyl, and (heterocycloalkyl)C 1-6 alkyl, any of which is optionally substituted with 1 or 2 R 8 groups; and

each R 8 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, and haloC 3-6 cycloalkyl.

5. The method as recited in claim 4 , wherein:

A comprises 5 or 6 ring members; and

each R 6 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (haloC 1-6 alkoxy)C 1-6 alkyl, (C 3-6 cycloalkyl)C 1-6 alkyl, (C 3-6 heterocycloalkyl)C 1-6 alkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, ((C 1-6 alkyl)aryl)C 1-6 alkyl, and ((C 1-6 alkyl)heteroaryl)C 1-6 alkyl.

6. The method as recited in claim 5 , wherein:

R 4a and R 4b , together with the atom to which they are attached, form a ring chosen from oxetane, tetrahydrofuran, oxane, azetidine, pyrrolidine, and piperidine, any of which is optionally substituted with 1 or 2 R 6 groups.

7. The method as recited in claim 6 , wherein the compound of structural Formula II is chosen from:

or a salt thereof.

8. The method as recited in claim 1 , wherein the compound of structural Formula I is of structural Formula III

or a salt thereof, wherein:

A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:

X 1 and X 2 ,

Z, which is chosen from —CH 2 —, —CHR 3 —, —C(R 3 ) 2 —, —N(R 5a )—, N(COR 5a )—, N(CONR 5a R 5b )—, N(SO 2 R 5a )—, —O—, and —SO 2 —, and all other ring members Y, which are chosen from —CH 2 —, —CHR 2 —, and —C(R 2 ) 2 —;

R 1a , R 1b , and R 1c are independently chosen from H and CH 3 ;

either X 1 is C and X 2 is N, or X 1 is N and X 2 is C;

W is chosen from C(R 6b ) and N;

each R 2 and R 3 is independently chosen from cyano, halo, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, (C 1-6 alkoxy)C 1-6 alkyl; OR 5a , C(O)R 5a , C(O)OR 5a , C(O)NR 5a R 5b , SO 2 R 5a ; SO 2 NR 5a R 5b , NR 5a R 5b , NR 5a C(O)R 5b , NR 5a C(O)OR 5b , NR 5c C(O)NR 5a R 5b , and NR 5a SO 2 R 5b , or

any two R 2 or R 3 , when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;

each R 5a and R 5b is independently chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl; C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, and (C 3-6 alkoxy)C 3-6 cycloalkyl, or R 5a and R 5b , when attached directly to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;

R 5c is chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl; C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, and (C 3-6 alkoxy)C 3-6 cycloalkyl;

R 6a and R 6b are independently chosen from H, C 1-6 alkyl, cyanoC 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (haloC 1-6 alkoxy)C 1-6 alkyl, C 3-6 cycloalkyl, cyanoC 3-6 cycloalkyl, haloC 3-6 cycloalkyl, hydroxyC 3-6 cycloalkyl, (C 3-6 alkoxy)C 3-6 cycloalkyl, (C 3-6 cycloalkyl)C 1-6 alkyl, (C 3-6 heterocycloalkyl)C 1-6 alkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, ((C 1-6 alkyl)aryl)C 1-6 alkyl, ((C 1-6 alkyl)heteroaryl)C 1-6 alkyl, OR 7 , CH 2 OR 7 , CH 2 CH 2 OR 7 , COR 7 , COOH, COOR 7 , CONH 2 , CONHR 7 , CON(R 7 ) 2 , NHCOR 7 , NR 7 COR 7 , NHCONH 2 , NHCONHR 7 , NHCON(R 7 ) 2 , NR 7 CONH 2 , NR 7 CONHR 7 , NR 7 CON(R 7 ) 2 , SO 2 R 7 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , NHSO 2 R 7 , NR 7 SO 2 R 7 , carboxy, cyano, halo, hydroxy, and oxo;

each R 7 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, aryl, heteroaryl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, (aryl)C 1-6 alkyl, (heteroaryl)C 1-6 alkyl, (cycloalkyl)C 1-6 alkyl, and (heterocycloalkyl)C 1-6 alkyl, any of which is optionally substituted with 1 or 2 R 8 groups;

each R 8 is independently chosen from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, and haloC 3-6 cycloalkyl; and

p is chosen from 1 and 2.

9. The method as recited in claim 8 , wherein:

A comprises 5 or 6 ring members; and

R 6a and R 6b are independently chosen from H, C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (haloC 1-6 alkoxy)C 1-6 alkyl, C 3-6 cycloalkyl, (C 3-6 alkoxy)C 3-6 cycloalkyl, OR 7 , COR 7 , COOH, COOR 7 , CONH 2 , CONHR 7 , CON(R 7 ) 2 , HCOR 7 , NHCONHR 7 , NHCON(R 7 ) 2 , SO 2 R 7 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , NHSO 2 R 7 , cyano, halo, hydroxy, and oxo.

10. The method as recited in claim 9 , wherein:

Z is chosen from —CH 2 —, —CF 2 —, —C(R 3 ) 2 —, —N(R 5a )—, N(COR 5a )—, and —O—; and

each Y is —CH 2 —.

11. The method of claim 10 , wherein:

R 6a and R 6b are independently chosen from H, C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (fluoroC 1-6 alkoxy)C 1-6 alkyl, C 3-6 cycloalkyl, (C 3-6 alkoxy)C 3-6 cycloalkyl, OR 7 , COR 7 , COOH, and COOR 7 ; and

each R 7 is independently chosen from C 1-6 alkyl and fluoroC 1-6 alkyl.

12. The method of claim 11 , wherein:

R 6a and R 6b are independently chosen from C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, (fluoroC 1-6 alkoxy)C 1-6 alkyl, C 3-6 cycloalkyl, (C 3-6 alkoxy)C 3-6 cycloalkyl, and OR 7 ;

W is C(R 6b );

p is 2; and

at least one of R 6a and R 6b is chosen from C 1-6 alkyl, (C 1-6 alkoxy)C 1-6 alkyl, and (fluoroC 1-6 alkoxy)C 1-6 alkyl.

13. The method as recited in claim 12 , wherein the compound of structural Formula II is chosen from:

or a salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 10, 2021
From: DI FRANCESCO, MARIA EMILIA; JONES, PHILIP; MCAFOOS, TIMOTHY JOSEPH
To: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM
Reel/Frame 056505/0226 →
Continuity (3)
Continuation 16290675 · Mar 1, 2019
Provisional Application 62637147 · Mar 1, 2018
Related Publication 20230027126A1 · Jan 26, 2023