[go: up one dir, main page]

WO2013142396A1 - Iminopyrimidinones substituées en n3 en tant qu'inhibiteurs de la rénine, compositions et leur utilisation - Google Patents

Iminopyrimidinones substituées en n3 en tant qu'inhibiteurs de la rénine, compositions et leur utilisation Download PDF

Info

Publication number
WO2013142396A1
WO2013142396A1 PCT/US2013/032743 US2013032743W WO2013142396A1 WO 2013142396 A1 WO2013142396 A1 WO 2013142396A1 US 2013032743 W US2013032743 W US 2013032743W WO 2013142396 A1 WO2013142396 A1 WO 2013142396A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
compound
tautomer
stereoisomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2013/032743
Other languages
English (en)
Inventor
Tanweer Khan
Hubert Josien
Brian Mckittrick
Henry Vaccaro
Thomas Bara
John Caldwell
Charles R. Heap
William B. Geiss
Surnya MITRA
Andrew J. ZYCH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Publication of WO2013142396A1 publication Critical patent/WO2013142396A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to novel renin inhibitors of the general Formula (I).
  • the invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising one or more compounds of Formula (I), and to their use as renin inhibitors and in indications in which renin inhibition may be desirable, including but not limited to cardiovascular events, hypertension, and renal insufficiency.
  • Aspartic proteases including renin, ieta-secretase (BACE), Candida albican secreted aspartyl proteases, HIV protease, HTLV protease, and plasmepsins I and ⁇ , are implicated in a number of disease states.
  • BACE ieta-secretase
  • Candida albican secreted aspartyl proteases HIV protease
  • HTLV protease HTLV protease
  • plasmepsins I and ⁇ are implicated in a number of disease states.
  • angiotensin I the product of renin-catalyzed cleavage of angiotensinogen
  • Elevated levels of beta- amyloid the product of BACE activity on amyloid precursor protein, are widely believed to be responsible for the amyloid plaques present in the brains of Alzheimer's disease patients.
  • Plasmodium falciparum uses plasmepsins I and ⁇ to degrade hemoglobin.
  • renin-angiotensin II biologically active peptide angiotensin II (Ang ⁇ ) is generated by a two-step mechanism.
  • the highly specific renin enzyme cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE).
  • Ang II is known to act on four receptor subtypes, AT 1-4 . ATi seems to transmit most of the known functions of Ang II, i.e.,
  • AT 2-4 are less well- characterized; AT 2 may antagonize the effects of ATi (see, e.g., Porrello, E.R., et al, Frontiers in Bioscience, 2009, 14, 958).
  • ACE inhibitors and angiotensin receptor blockers have been used to treat hypertension.
  • ACE inhibitors are in clinical use for renal protection (Kshirsagar, K.V., et al, Americal Journal of Kidney Diseases, 2000, 35, 695), the prevention of congestive heart failure (Konstam M.A., et al, Circulation, 1992, 6, 431) and the treatment of myocardial infarction (Pfeffer, M.A., et al N. Engl Med, 1992, 327, 669).
  • Renin inhibitors present an attractive therapeutic approach due to the specificity of renin (Kleinert H.D., Cardiovasc. Drugs, 1995, 9, 645; Mclnnes, G.T., J. Human
  • Angiotensinogen is the only substrate known for renin.
  • ACE cleaves bradykinin in addition to Ang I, and Ang I can also be cleaved by chymase, a serine protease (Husain, A., J. Hypertens., 1993, 11, 1555).
  • ACE inhibitors leads to bradykinin accumulation, causing cough and potentially life-threatening angioneurotic edema ( Kirili, Z.H., et al, Annals of Internal Medicine, 1992, 117, 234).
  • renin inhibitors would be expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ARBs with regard to efficacy in blocking the RAS, they may represent an alternative to some of the more harmful aspects of these agents.
  • Renin inhibitors are known in the art. Among the early renin inhibitors discovered include peptidomimetics. Peptidomimetic renin inhibitors have seen limited clinical experience due to their peptidomimetic character, which imparts insufficient oral activity at a high cost of goods. Azizi M., et al, J. Hypertens., 1994, 12, 419; Neutel J. M., et al, Am. Heart, 1991, 122, 1094. Certain non-peptide renin inhibitors are described which exhibit good in vivo activity.
  • Renin inhibitors are disclosed or mentioned in the following patent and literature references:
  • WO 2009001915 Al Kuroita, Takanobu, et al, (Takeda Pharmaceutical Company Limited, Japan).
  • US2008-146073 20080625 Yokokawa, Fumiaki, et al, U.S. Pat. Appl. Publ. (2008).
  • WO2008153135 Al Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan). PCT Int. Appl. (2008).
  • WO2008153182 Al Akatsuka, Hidenori, et al, (Mitsubishi Tanabe Pharma Corporation, Japan; Shanghai Pharmaceutical (Group) Co., Ltd.).
  • WO2008141462 Al Wu, Tom Yao-Hsiang, et al, (Merck Frosst Canada Ltd., Can.),
  • WO2008139941 Al Kuroita, Takanobu, et al, (Takeda Pharmaceutical Company Limited, Japan).
  • WO2008136457 Al Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan).
  • WO2008093737 Al Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan).
  • WO2008089005 A2 Kwok, Lily, et al, (Takeda Pharmaceutical Company Limited, Japan).
  • WO2008077917 Al Herold, Peter, et al, (Speedel Experimenta AG, Switz.).
  • WO2008058387 Al Dube, Daniel, et al, (Merck Frosst Canada Ltd., Can.).
  • WO2007148775 Al Miyazaki, Shojiro, et al, (Daiichi Sankyo Company, Limited, Japan), PCT Int. Appl. (2007).
  • WO2007144769 A2 Bocskei, Jozsef Zsolt, et al, (Sanofi-Aventis, Fr.), PCT Int. Appl. (2007).
  • WO2007144129 A2 Maibaum, Juergen Klaus, et al, (Novartis A.-G., Switz.; Novartis Pharma G.m.b.H.), PCT Int. Appl. (2007).
  • WO2007120523 A2 Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2007). WO2007117961 A2, Jones, Benjamin, et al, (Takeda Pharmaceutical Company
  • WO2005058311 discloses certain substituted imino heterocyclic compounds, including certain substituted iminohydantoins and substituted iminopyrmidinones, as inhibitors of aspartyl protease. Additional disclosures of mono- and multicyclic iminoheterocyclic compounds are known in the art, including:
  • Such compounds are not disclosed as being selective inhibitors of renin, however.
  • the present invention provides certain N3 -substituted iminopyrimidinone compounds, which are collectively or individually referred to herein as "compound(s) of the invention", as described in Formula (I) below and elsewhere herein.
  • the present invention further provides compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent.
  • the present invention further provides processes for the preparation of the compounds of the invention, as well as pharmaceutical compositions comprising one or more of said compounds in the free form or in pharmaceutically acceptable salt form, together with one or more customary pharmaceutical excipient(s). Combinations of the compounds of the invention together with one or more additional pharmaceutically active agents are also provided.
  • the present invention further provides methods for the inhibition of renin activity and of treatment, prevention, ameliroation and/or delaying onset of diseases or disorders in which the inhibition of renin has or may have a therapeutic effect.
  • Such conditions include
  • hypertension congestive heart failure, cardiac hypertrophy, cardiac fibrosis, postinfarction cardiomyopathy, nephropathy, vasculopathy, neuropathy, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperadosteronism, anxiety states.
  • hypertension elevated levels of antiogensin I, the product of renin catalyzed cleavage of angiotensinogen, are present.
  • the compounds of the invention are contemplated for use in the treatment of hypertension, heart failure, including acute and chronic congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy (e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy); supraventricular and ventricular arrhythmias; atrial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina (stable or unstable); renal failure conditions, including but not limited to diabetic nephropathy; glomerulonephritis; renal fibrosis;
  • cardiomyopathy e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy
  • supraventricular and ventricular arrhythmias e.g., atrial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina (stable or unstable)
  • renal failure conditions including but not limited to diabet
  • scleroderma glomerular sclerosis
  • microvascular complications including diabetic retinopathy; renal vascular hypertension; vasculopathy; neuropathy; complications resulting from diabetes, including nephropathy, vasculopathy, retinopathy and neuropathy, diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty, eye diseases and associated abnormalities including raised intra-ocular pressure, glaucoma, retinopathy, abnormal vascular growth and remodeling, angiogenesis-related disorders, including neovascular age related macular degeneration;
  • the present invention also provides methods of inhibiting renin activity, wherein said method comprises administering a compound of the invention in an amount sufficient to provide an effective amount for renin inhibition in an organism.
  • each variable (including those in each of Formula (I) and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated.
  • the compounds of the invention have the general structure shown in Formula (I):
  • n and m are each an integer independently selected from 0 to 2;
  • W is selected from the group consisting of-C(O)- and -S(0) 2 -;
  • ring A is selected from the group consisting of phenyl, heteroaryl, and heterocycloalkyl;
  • -Li- is a divalent moiety selected from the group consisting of
  • R L1 and R L3 are each independently selected from the group conisisting of H and methyl;
  • R L2 is selected from the group consisting of H, -(Ci-C 6 )alkyl, -(C Ce ⁇ eteroalkyl, and , -(C C 3 )alkyl-N(R L4 )C(0)R L5 ;
  • R M is selected from the group consisting of H and -(Ci-C 3 )alkyl
  • R L5 is selected from the group consisting of H, -(Ci-C 3 )alkyl, -0(C 1 -C 3 )alkyl, and
  • each R 1 (when present) is independently selected from the group consisting of halo, -CN, -(d-C 6 )alkyl, -(C r C 6 )alkoxy, -(C ! -C 6 )haloalkyl, -NHS(0) 2 alkyl, and
  • each R 2 (when present) is independently selected from the group consisting of halo, -CN, -(Ci-C 6 )alkyl, -(Ci-C 6 )haloalkyl, -NHS(0) 2 alkyl, and -N((CrC 6 )alkyl)S(0) 2 alkyl;
  • R 3 and R 4 are each independently selected from the group consisting of H, F and alkyl, wherein said alkyl of R 3 is unsubstituted or substituted with from 1-2 groups independently selected from the group consisting of halo, hydroxyl and alkoxy;
  • R 5 is selected from the group consisting of H, -(Cj-C 6 )alkyl, -(CrC 6 )haloalkyl, and phenyl;
  • R 6 is selected from the group consisting of H, -(Q-C ⁇ alkyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein each of said alkyl and said cyclopropyl, cyclobutyl, and cyclopentyl of R 6 is unsubstituted or substituted with from 1-2 groups independently selected from the group consisting of halo, hydroxyl, and alkoxy; and
  • R 7 is selected from the group consisting of H, -(C)-C 6 )alkyl, and cyclopropyl, wherein each of said alkyl and said cyclopropyl of R 7 is unsubstituted or substituted with from 1- 2 groups independently selected from the group consisting of halo, hydroxyl, and alkoxy.
  • each R 1 (when present) is independently selected from the group consisting of halo, -CN, -(CrC 6 )alkyl, -(C r C 6 )alkoxy, -(CrC ⁇ haloalkyl, -NHS(0) 2 alkyl, and
  • each R 2 (when present) is independently selected from the group consisting of halo, -CN, -(Ci-Ce)alkyl, -(CrC 6 )haloalkyl; and the remaining variables are as defined in Formula (I) above.
  • W is -C(O)-.
  • W is -S(0) 2 -.
  • R 3 is H and R 4 is H.
  • R 6 and R 7 are each independently selected from the group consisting of methyl, ethyl, propyl, /-propyl, rc-propyl, cyclopropyl, -butyl, w-butyl, and /-butyl.
  • R 6 is selected from the group consisting of methyl, ethyl, propyl, /-propyl, «-propyl, rc-butyl, /-butyl, /-butyl, cyclopropyl, and cyclobutyl; and R 7 is selected from the group consisting of methyl and ethyl.
  • R 3 is H
  • R 4 is selected from the group consisting of H and methyl
  • R 6 is selected from the group consisting of methyl, ethyl, /- propyl, ⁇ -propyl, cyclopropyl, /-butyl, H-butyl, /-butyl
  • R 7 is selected from the group consisting of methyl and ethyl.
  • R 5 is selected from the group consisting of H, methyl, and phenyl.
  • R 5 is selected from the group consisting of H and methyl.
  • R 5 is selected from the group consisting of phenyl.
  • R L2 is selected from the group consisting of H, -(Ci-C 6 )alkyl, -(Q- C 6 )ether, and-(C 1 -C 3 )alkyl-N(R L4 )C(0)R L5 , wherein R M is selected from the group consisting of H and -(Ci-C3)alkyl, and R L5 is selected from the group consisting of H, -(Ci-C3)alkyl, -0(Ci- C 3 )alkyl, and -OH.
  • -L ⁇ - is -C(0)-NH-CH(R L2 )-, and R L2 is selected from the group consisting of H, -(Ci-C6)alkyl, and -(CrC 6 )ether.
  • R L2 include H, methyl, ethyl, propyl, /-propyl, ⁇ -propyl, cyclopropyl, /-butyl, ra-butyl, /-butyl, -CH 2 (CH 2 ) p -0-(CH 2 ) q (CH 3 ), wherein each of p and q are, independently, 0, 1, and 2.
  • -Li- is a divalent moiety selected from the group consisting of
  • R L1 and R L3 are each independently selected from the group conisisting of H and methyl;
  • R L2 is selected from the group consisting of H, -(C 1 -C 6 )alk;yl, -( -Ce ⁇ eteroalkyl,
  • R M is selected from the group consisting of H and -(Ci-C 3 )alkyl
  • R L5 is selected from the group consisting of H, -(Ci-C 3 )alkyl, -0(C 1 -C 3 )alkyl, and
  • ring A is phenyl
  • ring A is heteroaryl.
  • Non- limiting examples of ring A as heteroaryl include: thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, purazolyl, furazanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl, (e.g., 1,2,4-thiadiazolyl), pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridone, pyrazinyl, pyridone, pyrazinyl, pyridazinyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
  • ring A is heterocycloalkyl.
  • ring A as heterocycloalkyl include: piperidyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, and oxides thereof.
  • ring A is selected from the group consisting of phenyl, thienyl, thiazolyl, isoxazylyl, pyridyl, pyrimidinyl, and pyrrolidinyl.
  • n, m, R 1 and R 2 is as defined in Formula (I).
  • R is selected from the group conisisting of H and methyl.
  • -L ⁇ - is a divalent moiety selected from the group consisting of
  • R is selected from the group conisisting of H and methyl, and the moiety
  • each of ring A, R 1 , R 2 , m, and n are as defined in Formulas (I) or ( ⁇ ) above.
  • ring A is phenyl and R 1 , R 2 , m, and n are as defined in Formulas (I) or ( ⁇ ) above.
  • ring A is heteroaryl, wherein said heteroaryl is selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, purazolyl, fiirazanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridone, pyrazinyl, pyridone, pyrazinyl, pyridazinyl, and triazinyl, and oxides thereof and R 1 , R 2 , m, and n are as defined in Formulas (I) or ( ⁇ ) above.
  • ring A is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of piperidyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, and oxides thereof and R 1 , R 2 , m, and n are as defined in Formulas (I) or ( ⁇ ) above.
  • ring A is selected from the group consisting of phenyl, thienyl, thiazolyl, isoxazylyl, pyridyl, pyrimidinyl, and pyrrolidinyl and R 1 , R 2 , m, and n are as defined in Formulas (I) or ( ⁇ ) above.
  • R 1 is selected from the group consisting of F, CI, CN, methyl, CF 3 , -NHS(0) 2 CH 3 , and -N(CH 3 )S(0) 2 CH 3 .
  • R 2 is selected from the group consisting of F, CI, CN, methyl, and CF 3.
  • 1 to 3 carbon atoms of the compounds of the invention may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
  • a composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent.
  • each variable is selected independently of the others unless otherwise indicated.
  • Non-human animals include those research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, canine (e.g., dogs), and feline (e.g., house cats).
  • “Pharmaceutical composition” means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, or they may contain one or more pharmaceutically acceptable carriers or diluents.
  • pharmaceutically acceptable carriers or diluents may contain one or more pharmaceutically acceptable carriers or diluents.
  • pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • Halogen and halo mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being as described herein or independently selected from the group consisting of halo, alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , -0-C(0)-alkyl, -0-C(0)-aryl, -O- C(0)-cycloalkyl, carboxy and -C(0)0-alkyl.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Haloalkyl means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
  • Heteroalkyl means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical. Suitable such heteroatoms include O, S, S(O), S(0) 2 , and -NH-, -N(alkyl)-. Non-limiting examples include ethers, thioethers, amines, and the like.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • substituents include ethenyl, propenyl, n-butenyl, 3-methylbut-2- enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene. More generally, the suffix "ene” on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e.g., -CH 2 CH 2 - is ethylene, and is para-phenylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Alkenylene means a difunctional group obtained by removal of a hydrogen atom from an alkenyl group that is defined above.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • “Monocyclic aryl” means phenyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more substituents, which may be the same or different, as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • monocyclic heteroaryl refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
  • Non-limiting examples of monocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.
  • thiadiazolyl e.g., 1,2,4-thiadiazolyl
  • imidazolyl e.g., 1,2,4-triazinyl
  • oxides thereof e.g., 1,2,4-triazinyl
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein.
  • Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • Further non-limiting examples of c cloalkyl include the following:
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more
  • the term "monocyclic cycloalkenyl” refers to monocyclic versions of cycloalkenyl groups described herein and includes non-aromatic 3- to 7-membered monocyclic cycloalkyl groups which contains one or more carbon-carbon double bonds.
  • Non-limiting examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl, cyclohepta-l,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Heterocycloalkyl (or “heterocyclyl”) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein.
  • heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • oxide when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide.
  • An example of such a moiety is pyrrolidinone (or
  • pyrrolidone As used herein, the term "monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moities decribed herein and include a 4- to 7- membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S- oxide, S(O), and S(0) 2 . The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof.
  • lower alkyl-substituted oxetanyl examples include the moiety: .
  • Heterocycloalkenyl (or “heterocyclenyl”) means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2- dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,
  • the term "monocyclic heterocycloalkenyl” refers to monocyclic versions of the heterocycloalkenyl moities described herein and include 4- to 7-membered monocyclic heterocycloalkenyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(0) 2 .
  • the point of attachment to the parent moiety is to any available ring carbon or ring heteroatom.
  • Non-limiting examples of monocyclic heterocyloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, and oxides thereof. It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent O or S, as well as
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and «-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • variables can be the same or different.
  • the solid line as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry.
  • the possible isomers e.g., containing (R)- and (S)-stereochemistry.
  • ring systems such as, for example n cates t at the indicated line (bond) may be attached to any of the substitutable ring atoms.
  • Oxo is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or other ring described herein, In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system.
  • the compounds of the invention, and/or compositions comprising them are present in isolated and/or purified form.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified in purified form or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • prodrugs and/or solvates of the compounds of the invention.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and
  • prodrug means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Cj- C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, l-(alkanoyloxy
  • alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C 2 -C3)alkyl (such as ⁇ - dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di (Ci-C 2 )alkylcarbamoyl-(Cl-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2 -C3)alkyl, and the like.
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C6)alkanoyloxymethyl, l-((C 1 -C6)alkanoyloxy)ethyl, 1-methyl- l-((C 1 -C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(Ci-
  • each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(Ci-C6)alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural a- aminoacyl, -C(OH)C(0)OY' wherein Y 1 is H, (C C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (Q-C4) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy (Ci-Ce)alkyl, amino(C 1 -C4)aIkyl or mono-N- or di- N,N-(Ci-C 6 )alkyla
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non- limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 0.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above- noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • salts denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen- containing groups may be quarteraized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci ⁇ alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleu),
  • tautomers of the compounds of the invention and salts, solvates, esters and prodrugs of said tautomers.
  • all tautomeric forms of such compounds are within the scope of the compounds of the invention.
  • all keto-enol and imine-enamine forms of the compounds, when present, are included in the invention.
  • the compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the
  • enantiomers may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • the compounds of the invention including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • isotopically-labelled compounds of the invention Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, ,4 C, 15 N, 18 0, 17 0, 31 P, 32 P, 3S S, 18 F, and 36 C1, respectively.
  • Certain isotopically-labelled compounds of the invention are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the invention.
  • different isotopic forms of hydrogen (H) include protium and deuterium ( 2 H).
  • the presence of deuterium in the compounds of the invention is indicated by "D”.
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically- enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Suitable dosages and dosage forms of the compounds of the invention may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of said compound.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • the compounds of this invention When used in combination with one or more additional therapeutic agents ("combination therapy"), the compounds of this invention may be administered together or sequentially. When administered sequentially, compounds of the invention may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference.
  • such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • Another embodiment provides combinations comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described above.
  • the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. Certain assays are exemplified elsewhere in this document.
  • compositions comprising a compound of the invention, either as the neat chemical or optionally further comprising additional ingredients.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington 's Pharmaceutical Sciences, 18 Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • Non-limiting examples of additional active agents useful in combination therapies for the treatment of hypertension and hypertension-related disorders include the following. Selection of such additional active ingredients will be according to the diseases or disorders present for which treatment is desired, as determined by the attending physician or other health care provider.
  • AlphaAAooksrs >eta-blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antihypertensive, angiontensin convertingn enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-recetor blockers (ARBs), aldosterone synthease inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists.
  • ACE angiontensin convertingn enzyme
  • NEP neutral endopeptidase
  • ARBs angiotensin-recetor blockers
  • aldosterone synthease inhibitors aldosterone-receptor antagonists
  • endothelin receptor antagonists endothelin receptor antagonists.
  • Non-limiting examples of ⁇ / ⁇ -blockers include doxazosin, prazosin, tamsulosin, and terazosin.
  • Non-limiting examples of >eta-blockers include atenolol, bisoprol, metoprolol, acetutolol, esmolol, celiprolol, taliprolol, acebutolol, oxprenolol, pindolol, propanolol, bupranolol, penbutolol, mepindolol, carteolol, nadolol, carvedilol, and their pharmaceutically acceptable salts.
  • Non-limiting examples of calcium channel blockers include dihydropyridines (DHPs) and non-DHPs.
  • DHPs include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, and nivaldipine, and their pharmaceutically acceptable salts.
  • Non-limiting examples of diuretics include thiazide derivatives, e.g., amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.
  • thiazide derivatives e.g., amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.
  • Non-limiting examples of ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril.
  • Preferred ACE inhibitors include benazepril, enalpril, lisinopril, and ramipril.
  • Non-limiting examples of dual ACE/NEP inhibitors include omapatrilat, fasidotril, and fasidotrilat.
  • Non-limiting examples of ARBs include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan.
  • Non-limiting examples of aldosterone synthease inhibitors include anastrozole, fadrozole, and exemestane.
  • Non-limiting examples of aldosterone receptor antagonists are spironolactone and eplerenone.
  • Non-limiting examples of and endothelin receptor antagonists include bosentan, enrasentan, atrasentan, darusentan, sitaxentan, and tezosentan and their pharmaceutically acceptable salts.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • compositions comprising a compound of the invention formulated for transdermal delivery.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • compositions comprising a compound of the invention formulated for subcutaneous delivery.
  • compositions suitable for oral delivery may be advantageous for the pharmaceutical preparation comprising one or more compounds of the invention be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the invention provides a method of inhibiting renin in a patient in need thereof comprising administering at least one compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, in a therapeutically effective amount to inhibit renin in said patient.
  • the invention provides a method of treating, preventing, and/or delaying the onset of one or more diseases or disorders for which the inhibition of renin is therapeutic.
  • Non-limiting examples of such disease or disorders include: hypertension, heart failure, including acute and chronic congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy (e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy); supraventricular and ventricular arrhythmias; atrial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina (stable or unstable); renal failure conditions, including but not limited to diabetic nephropathy; glomerulonephritis; renal fibrosis; scleroderma; glomerular sclerosis; microvascular complications, including diabetic retinopathy; renal vascular hypertension; vasculopathy; neuropathy; complications resulting from diabetes, including nephropathy, vasculopathy, retinopathy and neuropathy, diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty
  • the compounds in the invention may be produced by a variety of processes know to those skilled in the art and by know processes analogous thereto.
  • the invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. The practitioner is not limited to these methods.
  • the prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy and IR spectra.
  • reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents.
  • solvent or reagent it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme and in the preparations and examples described below.
  • ethylcarbodiimide hydrochloride EDCI Hours: hrs or h
  • 1,2-dichloroethane DCE 1 -Hydroxy-7-azabenzotriazole: HO
  • 3-Chloroperoxybenzoic acid mCPBA or 1-Hydroxybenzotriazole: HOBt or HOBT
  • Atmosphere atm Hydrogen chloride: HC1
  • Benzoyl isothiocyanate BzNCS
  • Isopropyl magnesium chloride iPrMgCl
  • n-Butyllithium nBuLi or n-BuLi
  • Iodomethane Mel
  • Carbon tetrachloride CC1 4 50
  • Lithium borohydride LiBH 4
  • Method A is a general alternate method for compounds of formula (I) that relies on the formation of intermediate A8.
  • a ketone represented by structure Al is condensed with a sulfoxamine such as A2 to provide an imine A3.
  • This imine A3 is subsequently reacted with an appropriate ester A4 under basic conditions to give intermediate A5 according to the procedures of Ellman et al.
  • Deprotection under acidic conditions to give amino ester A6 and coupling with a protected isothiocyanate (shown here for example using 2,4 dimethoxybenzyl isothiocyanate 1-3) affords an iminopyrimidinone A7.
  • Removal of the protecting group under hydrogenolysis conditions gives intermediate A8.
  • Condensation of A8 with alcohols such as A9 provides compounds of type A10 which can be further reacted under acidic conditions to provide the compound of formula (I).
  • Method B is a general alternate method for compounds of formula (I) that relies on using compounds such as B9 ( in place of A9) wherein the ring A contains a functional group (such as CI, Br, I, C0 2 Me, furan or CN) to provide compounds BIO.
  • the functional group (“FG") is then converted into the -Li-phenyl-(R 2 ) m substitutent and then subsequently deprotected to provide compounds of formula I.
  • the combined organic layer was dried over MgS0 4 , filtered, and concentrated to dryness.
  • the residue was further azeotroped with hexane 4L, and solidified upon cooling.
  • the solid was filtered, and washed with cold pentane.
  • the solid residue was triturated with 40/60 isopropanol:pentane, chilled and filtered. The solid was further washed with 40/60
  • Example 2 Step 5 Intermediate 2-6 from Step 4 (400 mg, 0.918 mmol) was reacted with (S)-alpha- methylbenzylamine using conditions similar to the ones described in Step 8 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes EtOAc 100:0 to 65:35), 372 mg (75%) of intermediate 2-7.
  • (R)-l-phenylethanamine could be used, as an altermative to (S)-alpha-methylbenzylamine, as in Table 1, example 1-H.
  • Example 2 including using procedures similar to those of Examples 1 and 3.
  • Methyl 3-acetylbenzoate was subjected to asymmetric reduction conditions similar to the ones described in Step 2 of Example 2 to provide intermediate 3-2 as a white solid.
  • DABCO-Me3Al Complex 3-4 was prepared according to a modification of Angew. Chem. Int. Ed. 2005, 44, 2232 -2234: 2N AlMe 3 in toluene (0.90 mL, 18 mmol) was added to a solution of freshly sublimed DABCO (1.12 g,10.0 mmol) in toluene (5 mL) at 0°C very slowly. The reaction was stirred for 1 h at 0°C, the resulting white precipitate was allowed to settle, and the supernatant toluene was removed by cannula.
  • the starting carboxylic acid 4-1 was prepared as described in Eur. J. Org Chem,
  • the compound in Table 4 was prepared from 3-benzoylbenzoic acid following procedures similar to those of Example 4 and including an extra step of reduction of the product of Step 1 with sodium borohydride.
  • Example 5 including using procedures similar to those of Examples 1, 2 and 3.
  • Step 1 Intermediate 7-3 from Step 1 (3.0 g, 13.4 mmol) was reacted with intermediate 1- 7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/Et 2 0 90:10 to 0:100 then with DCM/2N NH 3 in MeOH 100:0 to 90:10), 31.7 mg (21%) of intermediate 7-4.
  • Example 7 was concentrated in vacuo and the product triturated with DCM and hexanes to provide 28.2 mg (94%) of Example 7 as a solid.
  • the starting carboxylic acid 8-1 was prepared as described in Organometallics, 2008, 27, 1850. To a solution of this acid 8-1 (0.39 g, 2.0 mmol), EDCI (0.77 g, 4.0 mmol), HOAt (0.41 g, 3.0 mmol) and DMAP (0.25 g, 2.0 mmol) in anhydrous DCM (10 mL) was added 3-chlorobenzylamine (0.37 mL, 3.0 mmol), then DIPEA (1.05 mL, 6.03 mmol) and the reaction was stirred 16 h. The reaction mixture was washed with 10% aqueous citric acid and extracted twice with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over Na 2 S0 4 and concentrated in vacuo. The residue was purified by
  • intermediate 8-2 from Step 1 (0.45 g, 1.4 mmol) dropwise.
  • the reaction was allowed to warm to RT then quenched with saturated aqueous sodium sulfate solution, extracted with Et 2 0, dried over Na 2 S0 4 and concentrated in vacuo.
  • the residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 0:100) to give 0.16 g (40%) of intermediate 8-3.
  • Example 10 including using procedures similar to those of Examples 1, 2 and 3.
  • Step 2 (1.32 g, 7.00 mmol) in anhydrous THF (25 mL) at -78°C was slowly added 2.5N n-butyllithium in hexanes (3.65 mL, 9.07 mmol) over 5 min then the reaction was stirred 30 min at -78°C followed by the addition of intermediate 11-4 from Step 2 (3.65 g, 9.07 mmol) in anhydrous THF (10 mL). The reaction was stirred 45 min at -78°C then allowed to warm to and stirred 10 min.
  • the Europium/QSY-7-labeled BACEl FRET peptide substrate (QSY7- EISEVNLDAEFC-Eu-amide) was custom synthesized by PerkinElmer (Turku, Finland).
  • This peptide is derived from the amyloid precursor protein sequence and contains the familial AD Swedish mutation at the BACE cleavage site ( ⁇ , 8 ⁇ , underlined above), which significantly enhances BACEl -mediated proteolysis.
  • This peptide also contains the
  • Recombinant soluble human BACEl comprised of amino acids 1-454
  • AutoBACEl was used in all in vitro BACEl enzymatic assays.
  • Purified soluble mature mouse BACEl enzyme was purchased from R&D Systems.
  • Proteolytic activity of cathepin D, cathepsin E and pepsin was measured using the FRET peptide substrate Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2 (Bachem), while proteolytic activity of renin was measured using the FRET peptie substrate Arg-Glu(EDAN ⁇ S)-Ile- His-Pro-Phe-His-Leu- Val-Ile-His-Thr-Lys(dabcyl)-Arg (Molecular Probes/Invitrogen).
  • Inhibitor IC 50s at purified human autoBACEl determined in a time-resolved endpoint proteolysis assay that measures hydrolysis of the QSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay). BACE-mediated hydrolysis of this peptide results in an increase in relative fluorescence (RFU) at 620 nm after excitation with 320 nm light.
  • REU relative fluorescence
  • Inhibitor compounds prepared at 3x the desired final concentration in lx BACE assay buffer (20 mM sodium acetate pH 5.0, 10% glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO were pre-incubated with an equal volume of autoBACEl enzyme diluted in lx BACE assay buffer (final enzyme concentration 1 nM) in black 384- well NUNC plates for 30 minutes at 30°C.
  • DMSO was present at 5% final concentration in the assay. Following laser excitation of sample wells at 320 nm, the fluorescence signal at 620 nm was collected for 400 ms following a 50 ⁇ delay on a RUBYstar HTRF plate reader (BMG Labtechnologies). Raw RFU data was normalized to maximum (1.0 nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. IC 50s were determined by nonlinear regression analysis (sigmoidal dose response, variable slope) of percent inhibition data with minimum and maximum values set to 0 and 100 percent respectively.
  • novel compounds of the invention exhibit good potency for renin, and, surprisingly and advantageously, good selectivity for renin over other aspartyl proteases such as BACE and cathepsin D. Supporting biological data for these properties of the compounds of the invention are recited in the table below.
  • the antihypertensive effect of the compound from example 1 -I at 10 mpk PO was determined using the DTG rat model described by R.St-Jacgues, R, et al., "Characterization of a stable, hypertensive rat model suitable for the consecutive evaluation of human renin inhibitors," Journal of the Renin-Angiotensin-Aldosterone System, September 2011, 12(3):133-45.
  • the time course for the decrease in blood pressure in mm Hg is shown in the table below.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dans ses nombreux modes de réalisation, la présente invention concerne certaines iminopyrimidinones substituées en N3 de formule (I) et leurs tautomères et stéréoisomères, ainsi que des sels pharmaceutiquement acceptables desdits composés, desdits tautomères et desdits stéréoisomères, chaque variable présentée dans la formule étant telle que définie ici. Les nouveaux composés de l'invention sont utiles en tant qu'inhibiteurs de la rénine et/ou pour le traitement et la prévention de diverses pathologies apparentées, notamment les événements cardiovasculaires, l'hypertension et l'insuffisance rénale. L'invention concerne également les compositions pharmaceutiques qui contiennent un ou plusieurs de ces composés (seuls et en association avec un ou plusieurs autres principes actifs) et leurs procédés de préparation et d'utilisation.
PCT/US2013/032743 2012-03-23 2013-03-18 Iminopyrimidinones substituées en n3 en tant qu'inhibiteurs de la rénine, compositions et leur utilisation Ceased WO2013142396A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261614667P 2012-03-23 2012-03-23
US61/614,667 2012-03-23

Publications (1)

Publication Number Publication Date
WO2013142396A1 true WO2013142396A1 (fr) 2013-09-26

Family

ID=49223287

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/032743 Ceased WO2013142396A1 (fr) 2012-03-23 2013-03-18 Iminopyrimidinones substituées en n3 en tant qu'inhibiteurs de la rénine, compositions et leur utilisation

Country Status (1)

Country Link
WO (1) WO2013142396A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017142825A3 (fr) * 2016-02-18 2017-09-21 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
US10844044B2 (en) * 2018-06-14 2020-11-24 Vanderbilt University WDR5 inhibitors and modulators
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100292203A1 (en) * 2003-12-15 2010-11-18 Schering Corporation Heterocyclic aspartyl protease inhibitors
US20100324010A1 (en) * 2007-10-15 2010-12-23 Takeda Pharmaceutical Company Limited Amide compounds and use of the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100292203A1 (en) * 2003-12-15 2010-11-18 Schering Corporation Heterocyclic aspartyl protease inhibitors
US20100324010A1 (en) * 2007-10-15 2010-12-23 Takeda Pharmaceutical Company Limited Amide compounds and use of the same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017142825A3 (fr) * 2016-02-18 2017-09-21 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
EP3416647A4 (fr) * 2016-02-18 2019-10-23 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
US11766435B2 (en) 2016-02-18 2023-09-26 Merck Sharp & Dohme Llc N3-substituted iminopyrimidinones as antimalarial agents
US10844044B2 (en) * 2018-06-14 2020-11-24 Vanderbilt University WDR5 inhibitors and modulators
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Similar Documents

Publication Publication Date Title
US8772505B2 (en) Antiviral compounds composed of three aligned aryl moieties to treat diseases such as hepatitis C
US9139569B2 (en) Fused tricyclic aryl compounds useful for the treatment of viral diseases
US8980920B2 (en) Antiviral compounds of three linked aryl moieties to treat diseases such as hepatitis C
EP2870140B1 (fr) Derives de tetrahydroquinazolinone comme inhibiteurs de parp
MX2010011563A (es) Compuestos 2-imino-3-metil pirrolo pirimidinona fenil-sustituidos como inhibidores de enzima de escision de proteina precursora amiloide sitio beta-1, composiciones y su uso.
EP2485590A1 (fr) Composés hétérocycliques de type imino-pentafluorosulfure utilisés en tant qu'inhibiteurs de bace1, compositions en contenant et leur utilisation
AU2007207711A1 (en) Hydantoin compounds for the treatment of inflammatory disorders
AU2018285131B2 (en) Heteroaromatic compounds as Vanin inhibitors
AU2022217353B2 (en) Pyridopyrimidinone derivative, preparation method therefor, and use thereof
WO2008005268A1 (fr) Pipéridines substituées qui augmentent l'activité p53 et leurs utilisations
WO2016147659A1 (fr) Dérivé imidazolo bicyclique
JP2013512246A (ja) ウイルス疾患治療に有用な縮合型三環式化合物およびその誘導体
CA2805440A1 (fr) Composes de biphenylene substitue et procedes d'utilisation desdits composes pour le traitement de maladies virales
WO2017142825A2 (fr) Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
TW202122382A (zh) 乙內醯脲衍生物
EP2914592A1 (fr) Inhibiteurs de cytomégalovirus
CA3030181A1 (fr) Utilisation de derives de thiohydantoine et d'hydantoine substituee en tant qu'antagonistes des recepteurs d'androgenes
AU2016345244A1 (en) Pyrrolidine derivatives
WO2013142396A1 (fr) Iminopyrimidinones substituées en n3 en tant qu'inhibiteurs de la rénine, compositions et leur utilisation
EP2346857B1 (fr) Composés pour le traitement de troubles inflammatoires
EP3500579A1 (fr) Composés tétracycliques à substitution chromane et leurs utilisations pour le traitement de maladies virales
WO2007021803A1 (fr) Composes pour traiter des maladies inflammatoires

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13763465

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13763465

Country of ref document: EP

Kind code of ref document: A1