Bicyclic compounds and their uses as dual c-SRC / JAK inhibitors

• US 8,440,679 B2
• Filed: 02/17/2011
• Issued: 05/14/2013
• Est. Priority Date: 02/17/2010
• Status: Expired due to Fees

• Current Assignee: Debiopharm SA (Debiopharm), Aurigene Discovery Technologies Limited (Dr. Reddy's Laboratories Ltd.)
• Original Assignee: Debiopharm SA (Debiopharm), Aurigene Discovery Technologies Limited (Dr. Reddy's Laboratories Ltd.)
• Inventors: Murone, Maximilien, Sengupta, Saumitra, Shetty, Shankar Jayaram, Mc Allister, Andrs
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US13/578,656
• Publication Number:
  US 20130012518A1
• Time in Patent Office: 817 Days
• Field of Search: 544/279, 514/264.1
• US Class Current: 514/264.1
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to substituted aromatic bicyclic compounds containing pyrimidine and pyridine rings of formula (I) having the structure as well as pharmaceutically acceptable salts thereof. The compounds of the present invention are useful as tyrosine kinase inhibitors, preferably SRC family kinases (SFKs) inhibitors, in particular as multi SFK/JAK. kinases inhibitors and even preferably as dual c-SRC/JAK kinases inhibitors, thereby inhibiting the STAT3 activation and therefore abnormal growth of particular cell types. Notably, the compounds of the present invention are useful for the treatment or inhibition of certain diseases that are the result of deregulation of STAT3.

Claims

1. A compound of formula (I) having the structure

2. The compound according to claim 1, of formula (II) having the structure

3. The compound according to claim 1, wherein R3 is selected from the group consisting of:

4. The compound according to claim 1, wherein

R1 is substituted phenyl or substituted pyridine;

X is CH₂ or C═

O;

R2 is H, CH₃, Cl or F;

R3 is selected from the group consisting of;

5. The compound according to claim 1, wherein

R1 is selected from the group consisting of:

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

N-(4-Methyl-3-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-c]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

N-(4-Methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

5-{6-[2-Methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamino}-pyridine-2-carboxylic acid cyclopropylamide;

N-{3-[2-(4-Cyclopropylsulfamoyl-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;

N-(4-Chloro-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

4-Trifluoromethyl-pyridine-2-carboxylic acid {4-chloro-3-[2-(4-methylcarbamoyl-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-amide;

4,4,4-Trifluoro-3-methyl-N-[4-methyl-3-(2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamino}-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-phenyl]-butyramide;

1-Cyclopentyl-3-(4-methyl-3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-urea;

N-(4-Methyl-3-{5-oxo-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

N-{4-Chloro-3-[2-(4-cyclopropylcarbamoylmethoxy-phenylamino)-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;

N-(4-Chloro-3-{2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

3-Bromo-N-(4-methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-benzamide; and

N-(4-Chloro-3-{2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, selected from the group consisting of:

N-(4-Methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;

5-{6-[2-Methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-ylamino}-pyridine-2-carboxylic acid cyclopropylamide; and

4-Trifluoromethyl-pyridine-2-carboxylic acid {4-chloro-3-[2-(4-methylcarbamoyl-phenylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-amide;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, selected from the group consisting of:

N-(4-Chloro-3-{2-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide; and

N-{4-Chloro-3-[2-(4-cyclopropylcarbamoylmethoxy-phenylamino)-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 1 and at least one pharmaceutically acceptable excipient, carrier or diluent.