Heterocyclic compounds and their uses

Patent metadata

Field	Value
Publication number	US-9873704-B2
Application number	US-201615219624-A
Country	US
Kind code	B2
Filing date	Jul 26, 2016
Priority date	Jun 25, 2009
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

First claim

We claim:

1. A compound having the structure:

or any pharmaceutically-acceptable salt thereof, wherein:
R 1 is phenyl or pyridyl, both of which are substituted by 0, 1, 2 or 3 substituents independently selected from halo, C 1-6 alk, C 1-4 haloalk, cyano, nitro, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═C)R a , —S(═O) 2 R a and —S(═O) 2 NR a R a
R 2 is H;
R 3 is selected from H and halo;
R 5 is, independently, in each instance, H or C 1-6 alk;
R 6 is NHR 9 ;
R 9 is H;
R 11 is selected from H, halo, C 1-6 alk, C 1-4 haloalk, cyano, nitro, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , —S(═O)R a , —S(═O) 2 R b , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R a , —S(═O) 2 N(R a )C(═O)OR a , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a , —NR a C 2-6 alkOR a , —NR a C 2-6 alkCO 2 R a , —NR a C 2-6 alkSO 2 R b , —CH 2 C(═O)R a , —CH 2 C(═O)OR a , —CH 2 C(═O)NR a R a , —CH 2 C(═NR a )NR a R a , —CH 2 OR a , —CH 2 OC(═O)R a , —CH 2 OC(═O)NR a R a , —CH 2 OC(═O)N(R a )S(═O) 2 R a , —CH 2 OC 2-6 alkNR a R a , —CH 2 OC 2-6 alkOR a , —CH 2 SR a , —CH 2 S(═O)R a , —CH 2 S(═O) 2 R b , —CH 2 S(═O) 2 NR a R a , —CH 2 S(═O) 2 N(R a )C(═O)R a , —CH 2 S(═O) 2 N(R a )C(═O)OR a , —CH 2 S(═O) 2 N(R a )C(═O)NR a R a , —CH 2 NR a R a , —CH 2 N(R a )C(═)R a , —CH 2 N(R a )C(═O)OR a , —CH 2 N(R a )C(═O)NR a R a , —CH 2 N(R a )C(═NR a )NR a R a , —CH 2 N(R a )S(═O) 2 R a , —CH 2 N(R a )S(═O) 2 NR a R a , —CH 2 NR a C 2-6 alkNR a R a , —CH 2 NR a C 2-6 alkOR a , —CH 2 NR a C 2-6 alkCO 2 R a , —CH 2 NR a C 2-6 alkSO 2 R b , —CH 2 R c , —C(═O)R c and —C(═O)N(R a )R c ;
R a is independently, at each instance, H or R b ;
R b is independently, at each instance, phenyl, benzyl or C 1-6 alk, the phenyl, benzyl and C 1-6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-4 alk, C 1-3 haloalk, —OH, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk and —N(C 1-4 alk)C 1-4 alk; and
R c is a saturated or partially-saturated 4-, 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S, the ring being substituted by 0, 1, 2 or 3 substituents selected from halo, C 1-4 alk, C 1-3 haloalk, —OC 1-4 alk, —NH 2 , —NHC 1-4 alk and —N(C 1-4 alk)C 1-4 alk.

2. A compound selected:
4-amino-6-(((1S)-1-(6-fluoro-3-(6-(methylsulfonyl)-2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-((1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-6-hydroxy-5-pyrimidinecarbonitrile;
4-amino-6-((1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1R)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5-quinolinecarbonitrile;
2-((1R)1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5-quinolinecarbonitrile;
4-amino-6-((1-(3-(2-pyridinyl)-1,8-naphthyridin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(3-(2-pyridinyl)-1,6-naphthyridin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-4-(methylsulfanyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((8-fluoro-3-(2-(methylsulfonyl)phenyl)-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((8-fluoro-3-(2-pyridinyl)-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((((8-fluoro-3-phenyl-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((5-fluoro-3-phenyl-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((5-fluoro-3-(3-fluorophenyl)-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((3-(3,5-difluorophenyl)-5-fluoro-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((5-fluoro-3-(2-(methylsulfonyl)phenyl)-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((5-fluoro-3-(2-pyridinyl)-2-quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(4-(dimethylamino)-6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(4-morpholinyl)-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(3-hydroxy-1-azetidinyl)-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3-phenyl-4-quinolinecarboxamide;
4-amino-6-(((1S)-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-4-(((3S)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(4-((1,1-dioxido-4-thiomorpholinyl)-carbonyl)-6-fluoro-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-quinolinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-quinolinecarbonitrile;
2-((1R)1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-quinolinecarbonitrile;
methyl 2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-quinolinecarboxylate;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-quinolinecarboxylic acid;
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-phenyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbonyl)-2-quinolinyl)eethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-((4-methyl-1-piperazinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3-phenyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-4-(((3R)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-3-phenyl-4-(1-pyrrolidinylcarbonyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(((3S)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(((3R)-3-hydroxy-1-pyrrolidinyl)-carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-carbonitrile;
4-amino-6-((1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-fluoro-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-carbonitrile;
4-amino-6-((1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-4-((3-methoxy-1-azetidinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-(1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-(2-(4-morpholinyl)ethyl)-3-phenyl-4-quinolinecarboxamide;
4-amino-6-(-1-(6-fluoro-4-(hydroxymethyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbon-yl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methy

Assignees

• Amgen Inc

Inventors

• Bui Minna
• Chen Yi
• Cushing Timothy David
• Duquette Jason A
• Fisher Benjamin
• Gonzalez Lopez De Turiso Felix
• Hao Xiaolin
• He Xiao
• Johnson Michael G
• Lucas Brian

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title