IP Library › Granted Patent US 9,278,940

Granted Patent B2

US 9,278,940 · App. 14/729,959 · Granted Mar 8, 2016

Cyclic amines as bromodomain inhibitors

Inventors: David John Fairfax (Slingerlands, NY); Bryan Cordell Duffy (Glenmont, NY); Gregory Scott Martin (Colonie, NY); John Frederick Quinn (Albany, NY); Shuang Liu (Schenectady, NY); Gregory Steven Wagner (Foster City, CA); Peter Ronald Young (San Francisco, CA)

Assignee: Zenith Epigenetics Corp.

C07D239/91 A61K31/517 A61K31/5377 A61K45/06 C07D265/32 C07D401/04 C07D401/14

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Quick Facts

Patent No.: US 9,278,940
App. No.: 14/729,959
Granted: Mar 8, 2016
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.

Claims (157)

1. A method of inhibiting BET proteins in a mammal by administering a therapeutically effective amount of a compound of Formula I:

or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,

wherein:

W 1 is selected from N and CR 1 ;

W 2 is selected from N and CR 2 ;

W 3 is selected from N and CR 3 ;

W 4 is selected from N and CR 4 ;

each W may be the same or different from each other;

A is selected from N and CH;

R 1 and R 4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, amino, hydroxyl, and halogen;

R 2 and R 3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;

two adjacent substituents selected from R 1 , R 2 , R 3 , and R 4 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;

AR1 is a group selected from the following:

and

B is a group selected from the following:

each ring system may be substituted with one or more substituents independently selected from R 10 and R 11 :

R 5 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;

R 6 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, and halogen;

R 7 is selected from hydrogen, alkyl, —SO 2 R 12 , —C(O)NR 12 R 13 , and —C(O)R 12 ;

R 8 and R 9 are independently selected from hydrogen, aryl, alkenyl, alkyl, —SO 2 R 12 , —C(O)NR 12 R 13 , and —C(O)R 12 ;

R 10 and R 11 are independently selected from hydrogen, halogen, alkyl, alkoxy, aryl, and hydroxyl;

R 12 and R 13 are independently selected from hydrogen, aryl, and alkyl;

Y is selected from NH, O, and S; and

two adjacent substituents selected from R 5 , R 6 , R 8 , R 9 , R 10 , and R 11 may be connected in a 5- or 6-membered ring to form a carbocycle or heterocycle.

2. The method according to claim 1 ,

wherein R 1 and R 4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino;

wherein R 2 and R 3 are independently selected from hydrogen, alkyl, alkoxy, and halogen;

wherein at least one of R 1 , R 2 , R 3 , and R 4 is not hydrogen;

wherein R 5 is selected from hydrogen, alkyl, alkoxy, and halogen;

wherein R 6 is selected from hydrogen and alkoxy optionally substituted with a hydroxyl or amino; and

wherein Y is N.

3. The compound according to claim 2 ,

wherein AR1 is selected from

wherein B is selected from

wherein R 7 is selected from hydrogen and alkyl;

wherein R 8 and R 9 are independently selected from hydrogen and alkyl;

wherein R 10 and R 11 are independently selected from hydrogen and halogen; and

wherein R 12 and R 13 are independently selected from hydrogen and alkyl.

4. The method according to claim 1 , wherein the compound is selected from:

2-(3-(4-Isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3-(4-Isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;

2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(6-(4-Isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;

Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate;

2-(6-(4-(1-Hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide;

2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid;

3-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoic acid;

2-(5-(2-(Isopropylamino)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one bis(trifluoroacetate);

2-(5-(2-Hydroxyethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one acetate;

2-(6-(4-Isopropylpiperazin-1-yl)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;

5,7-Dimethoxy-2-(6-morpholinopyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;

2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;

5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;

5,7-Dimethoxy-2-(6-(4-propionylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one dihydrochloride;

2-(3-(4-Isopropylpiperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

7-Fluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Hydrochloride;

7-(Benzyloxy)-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Hydrochloride;

2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxy-7-phenylquinazolin-4(3H)-one;

8-(Benzyloxy)-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-5-methoxyquinazolin-4(3H)-one;

4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N-isopropylpiperazine-1-carboxamide Hydrochloride;

2-(6-(4-Isopropyl-2-oxopiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;

2-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;

2-(3-Chloro-5-(piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; and

stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof.

5. The method according to claim 1 , wherein R 6 is selected from the group represented by Formula II:

wherein:

D is selected from O and S;

E is selected from O, N, and S;

R 14 and R 15 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein if E is O or S, only one of R 14 and R 15 is present; and

n is selected from 1, 2, and 3.

6. The method according to claim 5

wherein D is O;

wherein n=1;

wherein R 14 and R 15 are independently selected from hydrogen, and alkyl; and

wherein R 6 is selected from hydrogen, methoxy,

7. The method of claim 1 , further comprising treating a disease, disorder, or condition characterized by dysregulation of cell cycle control, inflammatory cytokine expression, viral transcription, hematopoietic differentiation, insulin transcription, or adipogenesis.

8. The method of claim 7 , wherein the disease, disorder, or condition is an autoimmune disease.

9. The method of claim 8 , wherein the autoimmune disease is selected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura, Behcet's Disease, Bullous pemphigoid, Castleman's Disease, Celiac Disease, Churg-Strauss syndrome, Crohn's Disease, Cogan's syndrome, Dry eye syndrome, Essential mixed cryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis, Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giant cell arteritis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (Wegener's), Graves' Disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, Type I diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclastic vasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Sjogren's syndrome, Takayasu's arteritis, Transverse myelitis, Ulcerative colitis, Uveitis, and Vitiligo.

10. The method of claim 7 , wherein the disease, disorder, or condition is an inflammatory disease.

11. The method of claim 10 , wherein the inflammatory disease or disorder is selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections.

12. The method of claim 7 , wherein the disease, disorder, or condition is a cardiovascular disease.

13. The method of claim 7 , wherein the disease, disorder, or condition is insulin resistance diabetes.

14. The method of claim 7 , wherein the disease, disorder, or condition is a neurological disorder.

15. The method of claim 7 , wherein the disease, disorder, or condition is HIV.

16. The method of claim 7 , wherein the disease, disorder, or condition is cancer.

17. The method according to claim 16 ,