WO2013092791A1 - Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders - Google Patents

Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders Download PDF

Info

Publication number
WO2013092791A1
WO2013092791A1 PCT/EP2012/076275 EP2012076275W WO2013092791A1 WO 2013092791 A1 WO2013092791 A1 WO 2013092791A1 EP 2012076275 W EP2012076275 W EP 2012076275W WO 2013092791 A1 WO2013092791 A1 WO 2013092791A1
Authority
WO
WIPO (PCT)
Prior art keywords
ylmethoxy
dioxan
dihydro
pyrimido
isoquinolin
Prior art date
Application number
PCT/EP2012/076275
Other languages
French (fr)
Inventor
Frédéric Gilbert LABÉGUÈRE
Gregory John Robert NEWSOME
Luke Jonathan ALVEY
Laurent Raymond Maurice SANIÈRE
Stephen Robert Fletcher
Original Assignee
Galapagos Nv
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
Priority to NZ626473A priority Critical patent/NZ626473B2/en
Priority to EP17184834.4A priority patent/EP3378862B1/en
Priority to DK12812237.1T priority patent/DK2794604T3/en
Priority to EP22155038.7A priority patent/EP4019519A1/en
Priority to LTEP12812237.1T priority patent/LT2794604T/en
Priority to KR1020147020306A priority patent/KR102012268B1/en
Priority to PL12812237T priority patent/PL2794604T3/en
Priority to AU2012357067A priority patent/AU2012357067B2/en
Priority to UAA201408294A priority patent/UA111767C2/en
Priority to IN1033MUN2014 priority patent/IN2014MN01033A/en
Priority to BR112014015142-3A priority patent/BR112014015142B1/en
Priority to PL17184834T priority patent/PL3378862T3/en
Priority to EA201491245A priority patent/EA023826B1/en
Priority to SI201231087T priority patent/SI2794604T1/en
Application filed by Galapagos Nv filed Critical Galapagos Nv
Priority to ES12812237.1T priority patent/ES2643379T3/en
Priority to EP12812237.1A priority patent/EP2794604B1/en
Priority to SG11201403169PA priority patent/SG11201403169PA/en
Priority to CA2859578A priority patent/CA2859578C/en
Priority to CN201280061536.3A priority patent/CN103998448B/en
Priority to MX2014007363A priority patent/MX351681B/en
Priority to JP2014547997A priority patent/JP6062453B2/en
Publication of WO2013092791A1 publication Critical patent/WO2013092791A1/en
Priority to PH12014501178A priority patent/PH12014501178B1/en
Priority to IL233212A priority patent/IL233212B/en
Priority to ZA2014/04607A priority patent/ZA201404607B/en
Priority to HK15102096.2A priority patent/HK1201528A1/en
Priority to HRP20171404TT priority patent/HRP20171404T1/en
Priority to CY20171101053T priority patent/CY1119434T1/en
Priority to IL257581A priority patent/IL257581A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to novel compounds that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions.
  • the present invention also provides methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • GPR84 was recently isolated and characterized from human B cells (Wittenberger et al., 2001, J
  • GPR84 also known as EX33
  • EX33 remained an orphan GPCR until the identification of medium-chain
  • GPR84 was described to be activated by capric acid (C10:0), undecanoic acid (CI 1 :0) and lauric acid (C12:0) with potencies of 5 ⁇ , 9 ⁇ and 11 ⁇ , respectively.
  • Two small molecules were also described to have some GPR84 agonist activity: 3,3' di-indolylmethane (DIM) (Wang et al. (2006) J. Biol.
  • GPR84 expression has been shown to be expressed in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells, B cells.
  • PMN polymorphonuclear leukocytes
  • neutrophils neutrophils
  • monocytes monocytes
  • T cells T cells
  • B cells B cells.
  • GPR84 expression was demonstrated in tissues that may play a role in the propagation of the inflammatory response such as lung, spleen, bone marrow.
  • Du Bois reported the current status of therapies for lung interstitial diseases, such as idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • GPR84 was highly up-regulated in monocytes/macrophages upon LPS stimulation (Wang et al., 2006, The Journal of Biological Chemistry, 281, 45, 3457-3464).
  • GPR84 knock-out mice are viable and indistinguishable from wild-type littermate controls (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153).
  • the proliferation of T and B cells in response to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153).
  • T helper 2 (Th2) differentiated T cells from GPR84 KO secreted higher levels of IL4, IL5, IL13, the 3 major Th2 cytokines, compared to wild-type littermate controls.
  • Thl cytokine, INFy was similar in Thl differentiated T cells from GPR84 KO and wild-type littermate (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153).
  • capric acid, undecanoic acid and lauric acid dose dependently increased the secretion of interleukin-12 p40 subunit (IL-12 p40) from RAW264.7 murine macrophage-like cells stimulated with LPS.
  • the pro-inflammatory cytokine IL-12 plays a pivotal role in promoting cell-mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 (Thl) responses and inhibiting T helper 2 (Th2) responses.
  • Thl T helper 1
  • Th2 T helper 2
  • Medium-chain FFAs through their direct actions on GPR84, may affect T l/T 2 balance.
  • Berry et al. identified a whole-blood 393-gene transcriptional signature for active tuberculosis (TB) (Berry et al., 2010, Nature, 466, 973-979). GPR84 was part of this whole-blood 393-gene transcriptional signature for active TB indicating a potential role for GPR84 in infectious diseases.
  • GPR84 expression was also described in microglia, the primary immune effector cells of the central nervous system (CNS) from myeloid-monocytic origin (Bouchard et al., 2007, Glia, 55 :790-800). As observed in peripheral immune cells, GPR84 expression in microglia was highly inducible under inflammatory conditions such as TNFa and IL1 treatment but also notably endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuro-inflammatory processes.
  • CNS central nervous system
  • GPR84 would be up-regulated in CNS not only during endotoxemia and multiple sclerosis, but also in all neurological conditions in which TNFa or IL lb pro-inflammatory cytokines are produced, including brain injury, infection, Alzheimer's disease (AD), Parkinson's disease (PD).
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • the present invention provides novel compounds, processes for their preparation and their use in the preparation of a medicament for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g.
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention relates to novel dihydropyrimidinoisoquinolinone compounds that antagonize GPR84, and that are potentially useful for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • a compound of the invention having a Formula la:
  • R is H, Me, or halo
  • Li is absent or is -0-, -S-, or -NR 4a -; G is
  • W is Ci_4 alkylene, C 2 _ 4 alkenylene having one double bond, or C 2 _ 4 alkynylene having one triple bond;
  • L 2 is absent or is -0-;
  • Ci_8 alkyl optionally substituted with one to three groups independently selected from
  • o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
  • o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
  • 4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R 5 groups,
  • 5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one to three independently selected R 6 groups, or
  • L 3 is -NR 4b -;
  • o C 6 -io aryl optionally substituted with one or more independently selected R 7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R 7 groups,
  • heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R 7 groups, or
  • R 4a and R 4b is independently selected from H, C1 alk l, and C 3 . 7 cycloalk l;
  • R 5 is oxo or R 6 ;
  • Ci_6 alkyl optionally substituted with one to three groups independently selected from halo, and OH,
  • Ci-6 alkoxy optionally substituted with one to three groups independently selected from halo, and
  • 4- 7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or
  • R 7 is Ci_4 alkyl, or halo
  • each of R 8 , R 9 , R 10 and R 11 is independently selected from H and Ci_ 4 alkyl.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • a compound of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein is pharmaceutically acceptable as prepared and used.
  • the pharmaceutical composition may additionally comprise further active ingredients suitable for use in combination with a compound of the invention.
  • this invention provides novel compounds of the invention for use in therapy.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution, for example inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • idiopathic pulmonary fibrosis IPF
  • neuroinflammatory conditions infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions
  • method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the present invention provides a compound of the invention for use in the treatment or prevention of a condition selected from those listed herein, particularly such conditions as may be associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution expression such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • this invention provides methods for synthesizing a compound of the invention, with representative synthetic protocols and pathways disclosed herein.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • a still further object of this invention is to provide pharmaceutical compositions that may be used in the treatment or prevention of a variety of disease states, including the diseases associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the articles 'a' and 'an' may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • 'an analogue' means one analogue or more than one analogue.
  • alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms.
  • Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and 1 ,2-dimethylbutyl.
  • Particular alkyl groups have between 1 and 4 carbon atoms.
  • 'Alkylene' refers to divalent alkane radical groups having the number of carbon atoms specified, in particular 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), the propylene isomers (e.g., -CH 2 -CH 2 -CH 2 - and -CH(CH 3 )-CH 2 -) and the like.
  • Alkynylene' refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C ⁇ C-, -CH 2 -C ⁇ C-, and -C(CH 3 )H-C ⁇ CH-.
  • alkoxy' refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -0-Ci-C 6 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2- dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • 'Amino' refers to the radical -NH 2 .
  • 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes the number of ring members specified.
  • Particular aryl groups have from 6 to 10 ring members. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
  • Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • Carboxy' refers to the radical -C(0)OH.
  • 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having the number of carbon atoms specified. Particular cycloalkyl groups have from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and the number of ring members specified. Particular heteraryl groups have 5 to 10 ring members, or 5 to 6 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • heterocycloalkyl refers to a stable heterocyclic non-aromatic ring and/or rings containing one or more heteroatoms independently selected from N, O and S, fused thereto wherein the group contains the number of ring members specified.
  • Particular heterocycloalkyl groups have 4-10 ring members or 5 to 7 ring members, or 5 to 6 ring members.
  • the heterocycloalkyl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heterocycloalkyl ring contains at least one ring nitrogen atom.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • pyrrolidinyl 1 - pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl
  • pyrrolidone pyran (2H-pyran or 4H-pyran)
  • dihydrothiophene dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine.
  • thiomorpholine and its S-oxide and S,S-dioxide particularly thiomorpholine
  • Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
  • heterocycloalk l groups are shown in the following illustrative examples:
  • each W is selected from CH 2 , NH, O and S; and each Y is selected from NH, O, CO, S0 2 , and S.
  • 'Nitro' refers to the radical -N0 2 .
  • Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • 'Thiol' refers to the group -SH.
  • 'Thioalkoxy' refers to the group -SR 10 where R 10 is an alkyl group with the number of carbon atoms specified.
  • R 10 is a Ci-C 6 alkyl.
  • Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, thioisopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1 ,2-dimethylthiobutoxy.
  • Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular thioalkoxy groups have between 1 and 4 carbon atoms.
  • the term 'substituted with one or more' refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • 'Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulf
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the term 'pharmaceutically acceptable cation' refers to an acceptable cationic counter- ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs' refers to compounds, including derivatives of the compounds of the invention,which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. 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 isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the "effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • the term 'inflammatory condition(s)' refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, vasculitis, psoriasis, gout, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), and endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure).
  • allergic airway disease e.g. asthma, rhinitis
  • inflammatory bowel diseases e.g. Crohn's disease, ulcerative colitis
  • endotoxin-driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure.
  • the term refers to rheumatoid arthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
  • the term 'infectious diseases' refers to bacterial infectious diseases and includes but is not limited to conditions such as sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, or enterobacteria species.
  • SIRS systemic inflammatory response syndrome
  • enteritis enterocolitis
  • tuberculosis and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, or enterobacteria species.
  • autoimmune disease(s)' refers to the group of diseases including obstructive airways disease (including conditions such as COPD (Chronic obstructive pulmonary disease)), psoriasis, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g.
  • COPD Choronic obstructive pulmonary disease
  • psoriasis e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma
  • chronic or inveterate asthma for example late asthma and air
  • Atherosclerosis Crohn's disease and ulcerative colitis
  • amyotrophic lateral sclerosis Particularly the term refers to COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
  • the term 'endocrine and/or metabolic disease(s)' refers to the group of conditions involving the body's over- or under-production of certain hormones, while metabolic disorders affect the body's ability to process certain nutrients and vitamins.
  • Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome), among others.
  • Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
  • the term 'diseases involving impairment of immune cell functions' includes conditions with symptoms such as recurrent and drawn out viral and bacterial infections, and slow recovery. Other invisible symptoms may be the inability to kill off parasites, yeasts and bacterial pathogens in the intestines or throughout the body.
  • 'neuroinflammatory conditions refers to diseases or disorders characterized by abrupt neurologic deficits associated with inflammation, demyelination, and axonal damage, and includes but is not limited to conditions such as Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
  • GBS Guillain-Barre syndrome
  • multiple sclerosis multiple sclerosis
  • axonal degeneration autoimmune encephalomyelitis
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the Ci to C 8 alkyl, , and substituted or unsubstitutedC 6 -io aryl, esters of the compounds of the invention.
  • the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as U C, 18 F, 15 0 and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention relates to novel compounds that antagonize GPR84 and that may be useful for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention also provides methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention and methods for treating diseases involving inflammatory conditions (for example inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, by administering a compound of the invention.
  • a compound of the invention is an inhibitor of GPR84.
  • a compound of the invention having a Formula la:
  • Pv 1 is H, Me, or halo
  • Li is absent or is -0-, -S-, or -NR 4a -;
  • W is Ci_4 alkylene, C 2 _ 4 alkenylene having one double bond, or C 2 _ 4 alkynylene having one triple bond;
  • L 2 is absent or is -0-;
  • Ci_8 alkyl optionally substituted with one to three groups independently selected from o OH,
  • o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
  • o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
  • 4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R 5 groups,
  • 5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one to three independently selected R 6 groups, or
  • L 3 is -NR 4b -;
  • o C 6 -io aryl optionally substituted with one or more independently selected R 7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R 7 groups,
  • heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R 7 groups, or
  • Each R 4a and R 4b is independently selected from H, C 1 alkyl, and C 3 . 7 cycloalkyl;
  • R 5 is oxo or R 6 ;
  • Ci_6 alkyl optionally substituted with one to three groups independently selected from halo, and OH
  • Ci-6 alkoxy optionally substituted with one to three groups independently selected from halo, and OH
  • 4- 7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or
  • R 7 is Ci_4 alkyl, or halo
  • each of R 8 , R 9 , R 10 and R 11 is independently selected from H and Ci_ 4 alkyl.
  • a compound of the invention having a Formula lb:
  • the compound of the invention is according to Formula la, lb or Ic, wherein R 1 is Me, F, or CI.
  • the compound of the invention is according to Formula la, lb or Ic, wherein R 1 is H.
  • the compound of the invention is according to any one of Formulae Ia-IVc, wherein Li is absent, or is -0-. In a preferred embodiment, Li is absent.
  • the compound of the invention is according to any one of Formulae Ia- IVc, wherein Li is -NR 4a -, wherein R 4a is as described previously.
  • R 4a is H, Me, Et, or cyclopropyl.
  • R 4a is H.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IVc, wherein W is C 1 alkylene.
  • W is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 - CH(CH 3 )-, -CH 2 -CH(-CH 2 -CH 3 )-, -CH 2 -C(CH 3 ) 2 -, or -CH 2 -CH 2 -CH 2 -.
  • W is -CH 2 -.
  • W is-CH 2 -CH 2 -.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IVc, wherein W is C 2 _4 alkenylene having one double bond.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IVc, wherein W is C 2 . 4 alkynylene having one triple bond.
  • W is -C ⁇ C-, - CH 2 -C ⁇ C-, or -C ⁇ C-CH 2 -.
  • W is -C ⁇ C-.
  • W is -CH 2 -C ⁇ C-.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein L 2 is absent. In another embodiment, L 2 is -0-.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li is absent or is -0-, W is Ci_ 4 alkylene; and L 2 and R 2 are as described previously.
  • W is -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -.
  • W is - CH 2 -.
  • W is-CH 2 -CH 2 -.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li is absent or is -0-, W is C 2 . 4 alkenylene having one double bond; and L 2 and R 2 are as described previously.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li is absent, W is C 2 . 4 alkynylene having one triple bond; and L 2 and R 2 are as described previously.
  • W is -C ⁇ C-, -CH 2 -C ⁇ C-, or -C ⁇ C-CH 2 -.
  • W is -C ⁇ C-.
  • W is -CH 2 -C ⁇ C-.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li and L 2 are absent, W is C w alkylene; and R 2 is as described previously.
  • W is -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -.
  • W is -CH 2 -.
  • W is -CH 2 -CH 2 -.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li and L 2 are absent, W is C 2 . 4 alkenylene having one double bond; and R 2 is as described previously.
  • the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li and L 2 are absent, W is C 2 . 4 alkynylene having one triple bond; and R 2 is as described previously.
  • W is -C ⁇ C-, -CH 2 -C ⁇ C-, or -C ⁇ C-CH 2 -.
  • W is -C ⁇ C-.
  • W is -CH 2 -C ⁇ C-.
  • the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R 2 is H.
  • the compound of the invention is according to any one of Formulae any one of Formulae Ia-IIIc, wherein R 2 is Ci_ 8 alk l.
  • R 2 is Me, Et, n-Pr, z ' -Pr, z ' -Bu, or t-Bu.
  • R 2 is Me, Et, z ' -Pr or t-Bu.
  • R 2 is t- Bu.
  • the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R 2 is Ci.g alkyl substituted with one to three groups selected from OH, halo, CN, Ci_6 alkoxy, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • R 2 is Ci.g alkyl substituted with one to three groups selected from OH, halo, CN, Ci_6 alkoxy, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • R 2 is Me, Et, n-Pr, z ' -Pr, z ' -Bu, or t-Bu substituted with one to three groups selected from OH, halo, CN, Ci_ 6 alkoxy, C 3 . 7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • Ci_ 8 alkyl substituted with one to three groups selected from OH, F, CI, CN, -OMe, -OEt, Oz ' -Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl.
  • R 2 is Me, Et, n-Pr, z ' -Pr, z ' -Bu, or t-Bu substituted with one to three groups selected from OH, F, CI, CN, - OMe, -OEt, -Oz ' -Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl.
  • the compound of the invention is according to any one of Formulae Ia- IIIc, wherein R 2 is Ci_ 8 alkyl substituted with one group selected from OH, halo, CN, Ci_ 6 alkoxy, C 3 . 7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • R 2 is Ci_ 8 alkyl substituted with one group selected from OH, halo, CN, Ci_ 6 alkoxy, C 3 . 7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • R 2 is Me, Et, n-Pr, z ' -Pr, z ' -Bu, or t-Bu substituted with one group selected from OH, halo, CN, Ci_6 alkoxy, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • Ci_ 8 alkyl substituted with one group selected from OH, F, CI, CN, -OMe, -OEt, - Oz ' -Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl.
  • R 2 is Me, Et, n-Pr, z ' -Pr, z ' -Bu, or t-Bu substituted with one group selected from OH, F, CI, CN, -OMe, -OEt, - Oz ' -Pr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl.
  • R 2 is -CH 2 -OH, -C(CH 3 ) 2 -OH, -CH(OH)CH 3 , -CH(OH)-C 2 H 5 , -CH(OH)-C 3 H 7 , - C(OH)(C 2 H 5 ) 2 , -C(OH)H-CH(CH 3 ) 2 , -C(OH)H-CH 2 -CH(CH 3 ) 2 , -C(OH)H-C(CH 3 ) 3 , -CH 2 -CN, -CH 2 -OCH 3 , - CH 2 -CH 2 -OCH 3 , -CH(OCH 3 )-CH 3 , -C(OCH 3 )H-CH(CH 3 ) 2 , -CH 2 -F, -CH 2 -CH 2 -F, -CH 2 -cyclopropyl, -CH 2 - cyclopentyl, -CH 2 -CH 2 -
  • the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R 2 is C 4 . 7 cycloalkenyl comprising one double bond. In a preferred embodiment, R 2 is cyclohexenyl.
  • the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R 2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S.
  • R 2 is dihydropyranyl.
  • the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R 2 is C 3 _7 cycloalkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is cyclopropyl.
  • the compound of the invention is according to any one of Formulae Ia- IIIc, wherein R 2 is C 3 . 7 cycloalkyl substituted with one to three independently selected R 5 groups.
  • R 2 is C 3 . 7 cycloalkyl substituted with one R 5 group.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group.
  • R 2 is C 3 .
  • R 7 cycloalkyl substituted with one R 5 group, wherein R 5 is oxo, or R 6 wherein R 6 is selected from OH, or Ci_ 6 alkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is oxo, or R 6 wherein R 6 is selected from OH, or Ci_6 alkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is R 6 , and R 6 is selected from OH.
  • the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R 2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O.
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
  • the compound of the invention is according to any one of Formulae Ia- IIIc, R 2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O substituted with one to three independently selected R 5 groups.
  • R 2 is 4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and Osubstituted with one R 5 group.
  • R 2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O substituted with one R 5 group, wherein R 5 is selected from oxo, or R 6 wherein R 6 is selected from OH, and Ci_ 6 alkyl.
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is substituted with one R 5 group .
  • R 2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is substituted with one R 5 group, wherein R 5 is selected from oxo, or R 6 wherein R 6 is selected from OH, and Ci_6 alkyl,
  • the compound of the invention is according to any one of Formulae Ia-IIIc, R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
  • the compound of the invention is according to any one of Formulae Ia- IIIc, R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted substituted with one to three independently selected R 6 groups. In a prefered embodiment, R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted substituted with one or two independently selected R 6 groups.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R 6 groups.
  • R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, halo, Ci_ 6 alkyl, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 . 7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, halo, Ci_ 6 alkyl, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 .
  • R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ⁇ -Bu, -CF 3 , -OMe, -OEt, Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, or phenyl.
  • R is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ⁇ -Bu, -CF 3 , -OMe, -OEt, -Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, mo ⁇ holinyl, piperidinyl, and phenyl.
  • the compound of the invention is according to any one of Formulae Ia- IIIc, R 2 is C 6 -io aryl. In a preferred embodiment, R 2 is phenyl.
  • the compound of the invention is according to any one of Formulae Ia- IIIc, R 2 is Ce- ⁇ aryl substituted with one or more independently selected R 6 groups.
  • R 2 is C 6 _io aryl substituted with one or two independently selected R 6 groups.
  • R 2 is C 6 _io aryl substituted with one or two independently selected R 6 groups, wherein each R 6 group is selected from halo, CN, Ci_ 6 alkyl, Ci_ 6 alkoxy, or alkyl.
  • R 2 is phenyl substituted with one or two independently selected R 6 groups.
  • R 2 is phenyl substituted with one or two independently selected R 6 groups, wherein each R 6 group is selected from halo, CN, Ci_ 6 alkyl, Ci_ 6 alkoxy, and alkyl.
  • the compound of the invention is according to any one of Formulae Ia-Ic, rVa, IVb or IVc, wherein L 3 is -NR 4b -, and R 4b is as decribed previously.
  • R 4b is H, Me, Et, or cyclopropyl.
  • R 4a is H.
  • the compound of the invention is according to any one of Formulae Ia-Ic, rVa, IVb or IVc, wherein R 3 is Ci_ 4 alkyl substituted with C 6 _io aryl optionally substituted with one or more independently selected R 7 groups, or 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R 7 groups.
  • R 3 is Me or Et, each of which is substituted with C 6 _io aryl optionally substituted with one or more independently selected R 7 groups), or 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R 7 groups.
  • R 3 is Ci_ 4 alkyl substituted with phenyl, or pyridyl, each of which is optionally substituted with one or more independently selected R 7 groups.
  • R 3 is C1 alkyl substituted with phenyl, or pyridyl.
  • R 3 is C M alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or CI. In a most preferred embodiment, R 3 is Me or Et, each of which is substituted with phenyl, or pyridyl. In a more preferred embodiment, R 3 is Me or Et, each of which is substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or CI.
  • the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb or IVc, wherein R 3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R 3 is pyridyl.
  • the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R 3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R 7 groups, wherein each R 7 group is as described previously.
  • R 3 is pyridyl, substituted with one or more independently selected R 7 groups, wherein each R 7 group is as described previously.
  • R 3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R 7 groups, wherein each R 7 group is selected from Me, Et, F, and CI.
  • R 3 is pyridyl substituted with one or more independently selected R 7 groups, wherein each R 7 group is selected from Me, Et, F, and CI.
  • R 3 is pyridyl substituted with one R 7 group selected from Me, Et, F, and CI.
  • the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R 3 is C 6 _io aryl. In a preferred embodiment, R 3 is phenyl.
  • the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R 3 is C 6 _io aryl substituted with one or more independently selected R 7 groups, wherein each R 7 group is as described previously.
  • R 3 is phenyl, substituted with one or more independently selected R 7 groups, wherein each R 7 group is as described previously.
  • R 3 is C 6 _io aryl substituted with one or more independently selected R 7 groups, wherein each R 7 group is selected from Me, Et, F, and CI.
  • R 3 is phenyl substituted with one or more independently selected R 7 groups, wherein each R 7 group is selected from Me, Et, F, and CI. In a most preferred embodiment, R 3 is phenyl substituted with one R 7 group selected from Me, Et, F, and CI.
  • the compound of the invention is according to Formula Va, Vb, Vc or Vd:
  • the compound of the invention is not according to Formula Va, Vb, Vc or Vd.
  • the compound of the invention is according to Formula Via, VIb, Vic or
  • the compound of the invention is not according to Formula Via, VIb, Vic or VId.
  • the compound of the invention is according to Formula Vila, Vllb, VIIc
  • the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or VIIb,wherein R 2 is C3-7 cycloalkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is cyclopropyl.
  • the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or Vllb, wherein R 2 is not C3-7 cycloalkyl.
  • R 2 is not cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is not cyclopropyl.
  • the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or Vllb, wherein R 2 is C 3 _ 7 cycloalkyl substituted with one to three independently selected R 5 groups.
  • R 2 is C 3 _ 7 cycloalkyl substituted with one R 5 group.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group.
  • R 2 is C 3 _ 7 cycloalkyl substituted with one R 5 group, wherein R 5 is oxo, or R 6 wherein R 6 is selected from OH, or Ci_ 6 alkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is oxo, or R 6 wherein R 6 is selected from OH, and Ci_6 alkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is OH.
  • the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or Vllb, wherein R 2 is not C 3 . 7 cycloalkyl substituted with one to three independently selected R 5 groups.
  • R 2 is not C 3 . 7 cycloalkyl substituted with one R 5 group.
  • R 2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group.
  • R 2 is not C 3 .
  • R 2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is oxo, or R 6 wherein R 6 is selected from OH, and Ci_ 6 alkyl.
  • R 2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is oxo, or R 6 wherein R 6 is selected from OH, and Ci_ 6 alkyl.
  • R 2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R 5 group, wherein R 5 is OH.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId,
  • R 2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
  • R 2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one to three independently selected R 6 groups.
  • R is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R 6 groups.
  • R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, halo, Ci_ 6 alk l, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 _ 7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, halo, Ci_ 6 alkyl, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 .
  • R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ⁇ -Bu, -CF 3 , -OMe, -OEt, Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ⁇ -Bu, -CF 3 , -OMe, -OEt, -Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R 2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one to three independently selected R 6 groups.
  • R 2 is n o t 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups.
  • R 2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R 6 groups.
  • R 2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, halo, Ci_ 6 alkyl, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 . 7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
  • R 2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, halo, Ci_6 alkyl, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 .
  • R 2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, F, CI, Me, Et, Pr, z ' -Pr, ⁇ -Bu, -CF 3 , -OMe, -OEt, Oz ' -Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
  • R 2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R 6 groups, wherein each R 6 is independently selected from OH, F, CI, Me, Et, Pr, z ' -Pr, t-Bu, -CF 3 , -OMe, -OEt, -Oz ' -Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R 2 is C 6 _io aryl. In a preferred embodiment, R 2 is phenyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic or VId, wherein R 2 is not C 6 .io aryl. In a preferred embodiment, R 2 is not phenyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R 2 is Ce- ⁇ aryl substituted with one or more independently selected R 6 groups.
  • R 2 is C 6 .io aryl substituted with one or two independently selected R 6 groups.
  • R 2 is C 6 _io aryl substituted with one or two independently selected R 6 groups, wherein each R 6 group is selected from halo, CN, Ci_ 6 alkyl, Ci_ 6 alkoxy, and alkyl.
  • R 2 is phenyl substituted with one or two independently selected R 6 groups.
  • R 2 is phenyl substituted with one or two independently selected R 6 groups, wherein each R 6 group is selected from halo, CN, Ci_ 6 alkyl, Ci_ 6 alkoxy, and alkyl.
  • the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R 2 is not C 6 _io aryl substituted with one or more independently selected R 6 groups.
  • R 2 is not Ce- ⁇ aryl substituted with one or two independently selected R 6 groups.
  • R 2 is not Ce- ⁇ aryl substituted with one or two independently selected R 6 groups, wherein each R 6 group is selected from halo, CN, C i_ 6 alkyl, Ci_ 6 alkoxy, and alkyl.
  • R 2 is not phenyl substituted with one or two independently selected R 6 groups.
  • R 2 is not phenyl substituted with one or two independently selected R 6 groups, wherein each R 6 group is selected from halo, CN, Ci_ 6 alkyl, Ci_ 6 alkoxy, and alkyl.
  • the compound of the invention is selected from:
  • the compound of the invention is selected from:
  • the compound of the invention is 9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-
  • the compound of the invention is not 9-cyclopropylethynyl-2-((S)-l -
  • a compound of the invention is not an isotopic variant.
  • a compound of the invention is present as the free base.
  • a compound of the invention is a pharmaceutically acceptable salt.
  • a compound of the invention is present as the free base or a pharmaceutically acceptable salt.
  • a compound of the invention is a solvate.
  • a compound of the invention is a solvate of a pharmaceutically acceptable salt of the compound.
  • the present invention provides prodrugs and derivatives of a compound of the invention according to the formula above.
  • Prodrugs are derivatives of a compound of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H. Design of Prodrugs, pp.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • R 1 is H, Me, or halo
  • Li is absent or is -0-, -S-, or -NR 4a -;
  • W is Ci_4 alkylene, C 2 _ 4 alkenylene having one double bond, or C 2 _ 4 alk nylene having one triple bond;
  • L 2 is absent or is -0-;
  • Ci-8 alkyl optionally substituted with one to three groups independently selected from
  • o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
  • o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
  • 5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O optionally substituted with one to three independently selected R 6 groups, or
  • L 3 is -NR 4b -;
  • o C 6 -io aryl optionally substituted with one or more independently selected R 7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R 7 groups,
  • heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R 7 group, or Ce- ⁇ aryl optionally substituted with one or more independently selected R 7 groups;
  • Each R 4a and R 4b is independently selected from H, C alkyl, and C3- 7 cycloalkyl;
  • R 5 is oxo or R 6 ;
  • Ci-6 alkyl optionally substituted with one to three groups independently selected from halo, and OH,
  • Ci_6 alkoxy optionally substituted with one to three groups independently selected from halo, and OH,
  • R 7 is Ci_ 4 alkyl, or halo
  • each of R 8 , R 9 , R 10 and R 11 is independently selected from H and Ci_ 4 alkyl
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-3, wherein R 1 is H.
  • R 2 is Ci_ 8 alkyl substituted with one group selected from OH, halo, CN, Ci_ 6 alkoxy, C 3 _ 7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 -7, or 9-25, wherein R 2 is Me, Et, n-Pr, z ' -Pr, z ' -Bu, or ⁇ -Bu, each of which is substituted with one group selected from OH, halo, CN, Ci_ 6 alkoxy, C 3 . 7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
  • R 2 is Ci_8 alkyl substituted with one group selected from OH, F, CI, CN, -OMe, -OEt, -Oz ' -Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 -7, or 9-25, wherein R 2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S.
  • R 5 is oxo
  • R 6 is selected from OH, and Ci_ 6 alkyl.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, substituted with one R 5 group.
  • R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups.
  • each R 6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C 3 . 7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
  • R 2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
  • R 6 is selected from halo, CN, d_ 6 alkyl, d_ 6 alkoxy, wherein each R 9 and R 10 is independently selected from from H and Ci_ 4 alkyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 -5, or 8-21 , wherein R 3 is Ci_ 4 alkyl substituted with phenyl, or pyridyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1 -5, or 8-21 , wherein R 3 is Ci_ 4 alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or CI
  • R 3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
  • R 2 is as described previously.
  • R 2 is as described previously.
  • R 2 is as described previously.
  • a compound or pharmaceutically acceptable salt thereof according to clause 64, 65, 68, 69, 72, or 73, wherein R 2 is C 3 . 7 cycloalkyl substituted with one R 5 group.
  • a compound or pharmaceutically acceptable salt thereof according to clause 66, 67, 70, 71 , 74, or 75, wherein R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
  • a compound or pharmaceutically acceptable salt thereof according to clause 66, 67, 70, 71 , 74, or 75, wherein R 2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R 6 groups.
  • R 6 is selected from OH, halo, Ci_ 6 alkyl, Ci_ 6 alkyl substituted with one or more halo, Ci_ 6 alkoxy, -CN, C 3 . 7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
  • a compound or pharmaceutically acceptable salt thereof according to clause 66, 67, 70, 71 , 74, or 75, wherein R 2 is C 6 _io aryl.
  • a compound or pharmaceutically acceptable salt thereof according to clause 66, 67, 70, 71 , 74, or 75, wherein R 2 is C 6 _io aryl substituted with one or two independently selected R 6 groups.
  • R 6 is selected from halo, CN, Ci_ 6 alkyl, Ci_ 6 alkoxy, and each R 9 and R 10 is independently selected from from H and Ci_ 4 alkyl.
  • a compound of the invention When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of a compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, intranasal and inhalation.
  • a compound of this invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • a compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10%> by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • a compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • a compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
  • a compound of the invention (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
  • a compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/niL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • a compound of the invention may be used as a therapeutic agent for the treatment of conditions in mammals that are causally related or attributable to aberrant activity of GPR84 and/ or aberrant GPR84 expression and/or aberrant GPR84 distribution.
  • a compound and pharmaceutical compositions of the invention find use as therapeutics for the prophylaxis and/or treatment of inflammatory conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, in mammals including humans.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicament.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament.
  • the present invention provides a method of treating a mammal having, or at risk of having a disease disclosed herein.
  • the present invention provides a method of treating a mammal having, or at risk of having inflammatory conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, in mammals including humans.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of inflammatory conditions.
  • the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of inflammatory conditions.
  • the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with inflammatory conditions, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
  • the present invention provides a method of treating a mammal having, or at risk of having a disease selected from inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
  • GBS Guillain-Barre syndrome
  • multiple sclerosis axonal degeneration
  • autoimmune encephalomyelitis encephalomyelitis
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
  • GRS Guillain-Barre syndrome
  • multiple sclerosis axonal degeneration
  • autoimmune encephalomyelitis encephalomyelitis
  • this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • GRS Guillain-Barre syndrome
  • multiple sclerosis axonal degeneration
  • autoimmune encephalomyelitis which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of infectious disease.
  • infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of infectious disease.
  • infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
  • this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with infectious disease, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of autoimmune diseases, and/or diseases involving impairment of immune cell functions.
  • the autoimmune diseases and/or diseases involving impairment of immune cell functions is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of autoimmune diseases and/or diseases involving impairment of immune cell functions.
  • the autoimmune diseases, and/or diseases involving impairment of immune cell functions is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
  • this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with autoimmune diseases and/or diseases involving impairment of immune cell functions, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the autoimmune diseases and/or diseases involving impairment of immune cell functions is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of endocrine and/or metabolic diseases.
  • the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of endocrine and/or metabolic diseases.
  • the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
  • this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with endocrine and/or metabolic diseases, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
  • a compound of the invention for use as a medicament especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
  • a particular regimen of the present method comprises the administration to a subject in suffering from an inflammatory condition, of an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the subject, and preferably terminate, the processes responsible for said inflammation.
  • a special embodiment of the method comprises administering of an effective amount of a compound of the invention to a subject suffering from or susceptible to the development of inflammatory condition , for a period of time sufficient to reduce or prevent, respectively, inflammation of said patient, and preferably terminate, the processes responsible for said inflammation.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of an inflammatory condition;
  • agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
  • immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g. rheumatoid arthritis); particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin), and biological DMARDS (for example but without limitation Infliximab, Etanercept, Adalimumab, Rituximab, Golimumab, Certolizumab pegol, Tocilizumab, Interleukin 1 blockers and Abatacept).
  • NSAIDS non-steroidal anti-inflammatory drugs
  • DMARDS for example but without limitation methotrexate, leflunomide, s
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/ or prevention of autoimmune diseases; particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g.
  • dactinomycin anthracyclines mitomycin C, bleomycin, and mithramycin
  • antibodies e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®
  • cyclosporin tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN- ⁇ ), TNF binding proteins (e.g. infliximab (RemicadeTM), etanercept (EnbrelTM), or adalimumab (HumiraTM)), mycophenolate, Fingolimod, and Myriocin.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of infectious diseases; particular agents include but are not limited to antibiotics.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of infections of any organ of the human body; particular agents include but are not limited to: aminoglycosides, ansamycins, carbacephem, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclins, anti-mycobacterial agents, as well as chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol and imidazole.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of vasculitis
  • therapeutic agents include but are not limited to steroids (for example prednisone, prednisolone), cyclophosphamide and eventually antibiotics in case of cutaneous infections (for example cephalexin)
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of IPF, particular agents include but are not limited to pirfenidone and bosentan.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD;
  • agents include but are not limited to: beta 2 -adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled) Long-acting p 2 -agonists (e.g.
  • salmeterol, formoterol, bambuterol, and sustained-release oral albuterol combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), phosphodiesterase-4 inhibitors (e.g. Roflumilast), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
  • bronchodilators e.g. flutica
  • a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
  • oxygen or heliox administration ebulized salbutamol or terbutaline
  • an anticholinergic e.g. ipratropium
  • systemic steroids oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone
  • intravenous salbutamol e.g. pred
  • epinephrine isoetharine, isoproterenol, metaproterenol
  • anticholinergics IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium
  • methylxanthines theophylline, aminophylline, bamiphylline
  • inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD);
  • agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and ciclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
  • glucocorticoids e.g. prednisone, budesonide
  • immunomodulatory agents e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and ciclospor
  • any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation this is not essential. The agents may be administered in different formulations and at different times.
  • a compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • Analytic LCMS Columns used, Waters Acquity UPLC BEH C18 1.7 ⁇ , 2.1mm ID x 50mm L or Waters Acquity UPLC BEH C18 1.7 ⁇ , 2.1mm ID x 30mm L or Waters XBridge C18 3.5 ⁇ , 2.1mm ID x 50mm L. All the methods are using MeCN/H 2 0 gradients. MeCN and H 2 0 contain either 0.1% Formic Acid or NH 3 (lOmM).
  • Preparative LCMS Column used, Waters XBridge Prep C18 5 ⁇ ODB 30mm ID x 100mm L. All the methods are using either MeOH/H 2 0 or MeCN/H 2 0 gradients.
  • MeOH, MeCN and H 2 0 contain either 0.1% Formic Acid or 0.1 %> Diethylamine.
  • Analytic chiral LC Column used, Chiralpak IA 5 ⁇ 250 x 4.6 mm. Microwave heating was performed with a Biotage Initiator.
  • Compound 1 was prepared using general method A starting from 2-hydroxymethyl-[l ,4]dioxane. (3 ⁇ 4 CDC1 3 ) ⁇ (ppm): 7.66 (IH, d), 6.94 (IH, dd), 6.83 (IH, d), 6.32 (IH, s), 6.11 -6.04 (IH, m), 5.47 (IH, dd), 5.35 (IH, dd), 4.65-4.63 (2H, m), 4.491 -4.40 (2H, m), 4.22 (2H, t), 4.02-3.99 (IH, m), 3.90-3.46 (6H, m), 3.00 (2H, t)
  • Compound 117 was prepared using general method A starting from (S) 2-hydroxymethyl- [l,4]dioxane.
  • Step 1 9-(Benzhydrylidene-amino)-2-((S)-l -fl ,4J dioxan-2-ylmethoxy)-6, 7-dihydro-pyrimido[6,l - aJisoquinolin-4-one (Intermediate 12)
  • Step 2 9-amino-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4-one hydrochloride (Intermediate 13) [00232] To a solution of intermediate 12 in a minimum of DCM/ Et 2 0 was added HC1 2N in Et 2 0 (4 mL). The precipitate was filtered off and dried to afford intermediate 13.
  • Tetrahydro-pyran-4-ol (152 mg, 1.49 mmol, 2 eq.) was added to a solution of NaH (60 mg, 1.49 mmol, 2 eq., 60% in mineral oil) in THF (4 mL) at 0 °C. The reaction was warmed to RT for 30 min then cooled again at 0 °C. Bromo methyltrifluoroborate (150 mg, 0.75 mmol, 1 eq.) was added to the reaction in one portion and the mixture was stirred at RT for 1 day (monitoring by 19 F-NMR).
  • a vial is charged with intermediate 9, 10 or 11 (1 eq.), the appropriate boronic acid, boronic ester or potassium trifluoroborate (4.4 eq.), Cs 2 C0 3 (2.6 eq.), (DPPF)PdCl 2 .DCM (0.05 eq.), in 1 ,4-dioxane/H 2 0 (10/1 , v/v), and the mixture is degassed with N 2 .
  • the vial is sealed and heated at 80 °C. When the reaction is complete, the vial is cooled to RT and the reaction is either worked up or volatiles are evaporated under vacuum. The product is then obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative HPLC-MS.
  • a vial was charged with intermediate 11 (84 mg, 0.074 mmol, 1 eq.), pyridine-3 -boronic acid (40 mg, 0.327 mmol, 4.4 eq.), Cs 2 C0 3 (62 mg, 0.190 mmol, 2.6 eq.), (DPPF)PdCl 2 .DCM (3.3 mg, 0.004 mmol, 0.05 eq.), in 1,4-dioxane (1 mL) and H 2 0 (0.1 mL), and the mixture was degassed with N 2 .
  • the vial was sealed and heated at 80 °C. After lh, the vial was cooled to RT and volatiles were evaporated under vacuum. The residue was then purified by flash chromatography on silica gel, eluting with 7.5% MeOH/DCM to afford compound 2.
  • tBuOK (5.19 mg, 0.046 mmol, 0.95 eq.) was added to a solution of compound 90 (20 mg, 0.049 mmol, 1 eq.) in THF (2 mL), Mel (0.030 mL, 0.487 mmol, 10 eq.) was then added and the reaction was stirred at RT for 16 h. Some more tBuOK (11 mg, 0.097 mmol, 2 eq.) was added and the reaction was stirred for an extra day. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by preparative TLC eluting with 2% MeOH/DCM to yield compound 110.
  • a vial is charged with Pd/C (10% w/w) and a solution of the appropriate alk ne (1 eq.) in MeOH is added.
  • the system is purged with N 2 before being filled with H 2 then the reaction is stirred at RT until completion.
  • the reaction is filtered through Celite and the filtrate is evaporated to dryness. Clean product is obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative HPLC-MS.
  • Step 1 2-((S)-l-ll,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-l-ynyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 15)
  • Compound 2 2-([l,4]dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
  • This compound is prepared via general method E using intermediate 11 and pyridine-4-boronic acid.
  • Compound 4 2-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- benzonitrile.
  • This compound is prepared via general method E using intermediate 11 and 2- cyanophenylboronic acid.
  • This compound is prepared via general method E using intermediate 11 and 3- cyanophenylboronic acid.
  • This compound is prepared via general method E using intermediate 11 and 4- cyanophenylboronic acid.
  • This compound is prepared via general method F using intermediate 8 and bromo-acetonitrile, KI was not used in the experiment.
  • This compound is prepared via general method F using intermediate 8 and pyridin-2-yl-methanol hydrochloride.
  • Compound 10 9-(3,5-dichloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
  • This compound is prepared via general method E using intermediate 11 and l -benzofuran-2- ylboronic acid.
  • This compound is prepared via general method E using intermediate 11 and l-(tert- butoxycarbonyl)- 1 H-indol-2-ylboronic acid.
  • This compound is prepared via general method E using intermediate 11 and 2-methoxy-5- pyridineboronic acid.
  • Compound 15 2-([l,4]dioxan-2-ylmethoxy)-9-(6-trifluo
  • This compound is prepared via general method E using intermediate 11 and 2-(trifluoromethyl) pyridine-5-boronic acid.
  • This compound is prepared via general method F using intermediate 8 and 5-(tert-butyl)-3- (chloromethyl)- 1 ,2,4-oxadiazole.
  • This compound is prepared via general method E using intermediate 11 and 2-(N- methylaminocarbonyl) pyridine-5-boronic acid pinacol ester.
  • This compound is prepared via general method G using intermediate 11 and pent-l-yne.
  • Step 1 2-([l ,4] dioxan-2-ylmethoxy)-9-((E)-2-pyridin-2-yl-vinyl)-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4- one (intermediate 22).
  • Step 1 2-([l ,4] dioxan-2-ylmethoxy)-9-((E)-2-pyrazin-2-yl-vinyl)-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4- one (intermediate 23).
  • Step 2 2-([lA]dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6 -dihydro-pyrimido
  • This compound is prepared via general method E intermediate 11 and using 5-indolylboronic acid.
  • Compound 23 2-([l ,4]dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l -ajisoquinolin- 4 -one.
  • This compound is prepared via general method E using intermediate 11 and 2- methoxyphenylboronic acid.
  • Compound 24 2-([l,4]dioxan-2-ylmethoxy)-9-(5-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
  • This compound is prepared via general method E using intermediate 11 and 3-methoxy-5- pyridineboronic acid pinacol ester.
  • Compound 25 2-([l,4]dioxan-2-ylmethoxy)-9-(lH-indazol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoqum one.
  • This compound is prepared via general method E using intermediate 11 and lH-indazole-5- boronic acid.
  • This compound is prepared via general method E using intermediate 11 and 4- methoxyphenylboronic acid.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound according to Formula (Ia) wherein L1, and G, and R1 are as described herein. The present invention relates to novel compounds according to Formula (I) that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.

Description

NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY
DISORDERS.
FIELD OF THE INVENTION
[0001] The present invention relates to novel compounds that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions.
[0002] The present invention also provides methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.
BACKGROUND OF THE INVENTION
[0003] GPR84 was recently isolated and characterized from human B cells (Wittenberger et al., 2001, J
Mol Biol, 307, 799-813) as the result of an expressed sequence tag data mining strategy, and also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach aimed to identify novel chemokine receptors expressed in neutrophils (Yousefi S et al. 2001 J Leukoc Biol;69, 1045-52).
[0004] GPR84 (also known as EX33) remained an orphan GPCR until the identification of medium-chain
FFAs with carbon chain lengths of 9-14 as ligands for this receptor (Wang et al. (2006) J. Biol. Chem.
281 :3457-64). GPR84 was described to be activated by capric acid (C10:0), undecanoic acid (CI 1 :0) and lauric acid (C12:0) with potencies of 5 μΜ, 9 μΜ and 11 μΜ, respectively. Two small molecules were also described to have some GPR84 agonist activity: 3,3' di-indolylmethane (DIM) (Wang et al. (2006) J. Biol.
Chem. 281 :3457-64) and embelin (WO 2007/027661).
[0005] GPR84 expression has been shown to be expressed in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells, B cells. (Wang et al., 2006, The Journal of Biological Chemistry, 281, 45, 3457-3464, Yousefi et al., 2001, Journal of Leukocyte Biology, 69, 1045-1052, Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153, WO2007/027661 A2). Higher levels of GPR84 were measured in neutrophils and eosinophils than in T-cells and B-cells. GPR84 expression was demonstrated in tissues that may play a role in the propagation of the inflammatory response such as lung, spleen, bone marrow. [0006] For example, in a recent review, Du Bois reported the current status of therapies for lung interstitial diseases, such as idiopathic pulmonary fibrosis (IPF). There are almost 300 distinct injurious or inflammatory causes of interstitial lung disease that can result in diffuse lung scarring, and the initial stages of the IPF pathology are very likely to involve inflammation (Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129), and combination therapies involving anti- inflammatory treatment could be advantageously used.
[0007] The expression of GPR84 was highly up-regulated in monocytes/macrophages upon LPS stimulation (Wang et al., 2006, The Journal of Biological Chemistry, 281, 45, 3457-3464).
[0008] GPR84 knock-out (KO) mice are viable and indistinguishable from wild-type littermate controls (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153). The proliferation of T and B cells in response to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153). T helper 2 (Th2) differentiated T cells from GPR84 KO secreted higher levels of IL4, IL5, IL13, the 3 major Th2 cytokines, compared to wild-type littermate controls. In contrast, the production of the Thl cytokine, INFy, was similar in Thl differentiated T cells from GPR84 KO and wild-type littermate (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153).
[0009] In addition, capric acid, undecanoic acid and lauric acid dose dependently increased the secretion of interleukin-12 p40 subunit (IL-12 p40) from RAW264.7 murine macrophage-like cells stimulated with LPS. The pro-inflammatory cytokine IL-12 plays a pivotal role in promoting cell-mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 (Thl) responses and inhibiting T helper 2 (Th2) responses. Medium-chain FFAs, through their direct actions on GPR84, may affect T l/T 2 balance.
[0010] Berry et al. identified a whole-blood 393-gene transcriptional signature for active tuberculosis (TB) (Berry et al., 2010, Nature, 466, 973-979). GPR84 was part of this whole-blood 393-gene transcriptional signature for active TB indicating a potential role for GPR84 in infectious diseases.
[0011] GPR84 expression was also described in microglia, the primary immune effector cells of the central nervous system (CNS) from myeloid-monocytic origin (Bouchard et al., 2007, Glia, 55 :790-800). As observed in peripheral immune cells, GPR84 expression in microglia was highly inducible under inflammatory conditions such as TNFa and IL1 treatment but also notably endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuro-inflammatory processes. Those results suggest that GPR84 would be up-regulated in CNS not only during endotoxemia and multiple sclerosis, but also in all neurological conditions in which TNFa or IL lb pro-inflammatory cytokines are produced, including brain injury, infection, Alzheimer's disease (AD), Parkinson's disease (PD).
[0012] GPR84 expression was also observed in adipocytes and shown to be enhanced by inflammatory stimuli (Nagasaki et al, 2012). The results suggest that GPR84 emerges in adipocytes in response to TNFa from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity, and therefore the inhibition of GPR84 activity might be beneficial for the treatment of endocrine and/or metabolic diseases. [0013] Therefore, the present invention provides novel compounds, processes for their preparation and their use in the preparation of a medicament for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
SUMMARY OF THE INVENTION [0014] The present invention relates to novel dihydropyrimidinoisoquinolinone compounds that antagonize GPR84, and that are potentially useful for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
[0015] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
[0016] Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a Formula la:
Figure imgf000005_0001
la wherein
R is H, Me, or halo;
Li is absent or is -0-, -S-, or -NR4a-; G is
R2,
-W-L2-R2, or
W is Ci_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple bond;
L2 is absent or is -0-;
R2 is
- H,
Ci_8 alkyl, optionally substituted with one to three groups independently selected from
o OH,
o halo,
o CN,
o Ci_6 alkoxy,
o C3.7 cycloalkyl,
o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
o phenyl,
C4.7 cycloalkenyl comprising one double bond,
5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S,
C3.7 cycloalkyl optionally substituted with one or more independently selected R5 groups,
4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 groups,
5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one to three independently selected R6 groups, or
C6-io aryl optionally substituted with one or more independently selected R6 groups;
L3 is -NR4b-;
R3 is
Ci-4 alkyl substituted with
o C6-io aryl optionally substituted with one or more independently selected R7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R7 groups,
5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R7 groups, or
C6-io aryl optionally substituted with one or more independently selected R7 groups; Each R4a and R4b is independently selected from H, C1 alk l, and C3.7 cycloalk l;
R5 is oxo or R6;
R6 is
- OH,
halo,
Ci_6 alkyl optionally substituted with one to three groups independently selected from halo, and OH,
Ci-6 alkoxy optionally substituted with one to three groups independently selected from halo, and
OH,
C3.7 cycloalkyl,
- -C(=0)OR8,
- -C(=0)NR9R10,
-
Figure imgf000007_0001
alkyl,
- -CN,
phenyl,
-O-phenyl,
4- 7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or
5- 6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S; optionally substituted with one or more indepentently selected C1 alkyl, Ci_4 alkoxy, CN, halo, and -C(=0)ORu;
R7 is Ci_4 alkyl, or halo, and
each of R8, R9, R10 and R11 is independently selected from H and Ci_4 alkyl.
[0017] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. Moreover, a compound of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein, is pharmaceutically acceptable as prepared and used. In this aspect of the invention, the pharmaceutical composition may additionally comprise further active ingredients suitable for use in combination with a compound of the invention.
[0018] In another aspect of the invention, this invention provides novel compounds of the invention for use in therapy.
[0019] In a further aspect of the invention, this invention provides a method of treating a mammal susceptible to or afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution, for example inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[0020] In a further aspect, the present invention provides a compound of the invention for use in the treatment or prevention of a condition selected from those listed herein, particularly such conditions as may be associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution expression such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
[0021] In additional aspects, this invention provides methods for synthesizing a compound of the invention, with representative synthetic protocols and pathways disclosed herein.
[0022] Accordingly, it is a principal object of this invention to provide a compound of the invention, which can modify the activity of GPR84 and thus prevent or treat any conditions that may be causally related thereto.
[0023] It is further an object of this invention to provide a compound of the invention that can treat or alleviate conditions or diseases or symptoms of same, such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, that may be causally related to the activity and / or expression and/or distribution of GPR84.
[0024] A still further object of this invention is to provide pharmaceutical compositions that may be used in the treatment or prevention of a variety of disease states, including the diseases associated with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
[0025] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0026] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0027] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term 'substituted' is to be defined as set out below. It should be further understood that the terms 'groups' and 'radicals' can be considered interchangeable when used herein.
[0028] The articles 'a' and 'an' may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example 'an analogue' means one analogue or more than one analogue.
[0029] 'Alkyl' means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and 1 ,2-dimethylbutyl. Particular alkyl groups have between 1 and 4 carbon atoms.
[0030] 'Alkylene' refers to divalent alkane radical groups having the number of carbon atoms specified, in particular 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), the propylene isomers (e.g., -CH2-CH2-CH2- and -CH(CH3)-CH2-) and the like.
[0031] 'Alkenylene' refers to divalent alkene radical groups having the number of carbon atoms and the number of double bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CH=CH-, - CH2-CH=CH-, -C(CH3)=CH-, -C(CH3)=CH-CH2-, -C(CH3)=C(CH3)-, and -CH2-C(CH3)=CH-.
[0032] 'Alkynylene' refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C≡C-, -CH2-C≡C-, and -C(CH3)H-C≡CH-.
[0033] 'Alkoxy' refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -0-Ci-C6 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2- dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[0034] 'Amino' refers to the radical -NH2.
[0035] 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes the number of ring members specified. Particular aryl groups have from 6 to 10 ring members. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
[0036] 'Carboxy' refers to the radical -C(0)OH.
[0037] 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having the number of carbon atoms specified. Particular cycloalkyl groups have from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[0038] 'Cyano' refers to the radical -CN.
[0039] 'Halo' or 'halogen' refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0040] 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
[0041] 'Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and the number of ring members specified. Particular heteraryl groups have 5 to 10 ring members, or 5 to 6 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
[0042] Examples of representative heteroaryls include the following:
Figure imgf000011_0001
wherein each Y is selected from >C=0, NH, O and S.
[0043] As used herein, the term 'heterocycloalkyl' refers to a stable heterocyclic non-aromatic ring and/or rings containing one or more heteroatoms independently selected from N, O and S, fused thereto wherein the group contains the number of ring members specified. Particular heterocycloalkyl groups have 4-10 ring members or 5 to 7 ring members, or 5 to 6 ring members. The heterocycloalkyl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heterocycloalkyl ring contains at least one ring nitrogen atom. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1 - pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine. Particular examples of heterocycloalk l groups are shown in the following illustrative examples:
Figure imgf000012_0001
wherein each W is selected from CH2, NH, O and S; and each Y is selected from NH, O, CO, S02, and S.
[0044] 'Hydroxy' refers to the radical -OH.
[0045] 'Nitro' refers to the radical -N02.
[0046] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
[0047] 'Thiol' refers to the group -SH.
[0048] 'Thioalkoxy' refers to the group -SR10 where R10 is an alkyl group with the number of carbon atoms specified. In particular thioalkoxy groups where R10 is a Ci-C6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, thioisopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1 ,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular thioalkoxy groups have between 1 and 4 carbon atoms.
[0049] As used herein, the term 'substituted with one or more' refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
[0050] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[0051] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
[0052] 'Pharmaceutically acceptable salt' refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2- ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term 'pharmaceutically acceptable cation' refers to an acceptable cationic counter- ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. [0053] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[0054] 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention,which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
[0055] 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. 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 isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[0056] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.
[0057] 'Effective amount' means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[0058] 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[0059] The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[0060] 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.
[0061] As used herein the term 'inflammatory condition(s)' refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, vasculitis, psoriasis, gout, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), and endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure). Particularly the term refers to rheumatoid arthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
[0062] As used herein, the term 'infectious diseases' refers to bacterial infectious diseases and includes but is not limited to conditions such as sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, or enterobacteria species.
[0063] As used herein the term 'autoimmune disease(s)' refers to the group of diseases including obstructive airways disease (including conditions such as COPD (Chronic obstructive pulmonary disease)), psoriasis, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
[0064] As used herein the term 'endocrine and/or metabolic disease(s)' refers to the group of conditions involving the body's over- or under-production of certain hormones, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome), among others. Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[0065] As used herein, the term 'diseases involving impairment of immune cell functions' includes conditions with symptoms such as recurrent and drawn out viral and bacterial infections, and slow recovery. Other invisible symptoms may be the inability to kill off parasites, yeasts and bacterial pathogens in the intestines or throughout the body.
[0066] As used herein the term 'neuroinflammatory conditions' refers to diseases or disorders characterized by abrupt neurologic deficits associated with inflammation, demyelination, and axonal damage, and includes but is not limited to conditions such as Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
[0067] 'Compound(s) of the invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[0068] When ranges are referred to herein, for example but without limitation, Ci_6 alkyl, the citation of a range should be considered a representation of each member of said range.
[0069] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci to C8 alkyl, , and substituted or unsubstitutedC6-io aryl, esters of the compounds of the invention.
[0070] As used herein, the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound For example, an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as UC, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[0071] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention. [0072] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.
[0073] Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
[0074] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
[0075] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0076] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
[0077] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
[0078] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.
THE COMPOUNDS
[0079] The present invention relates to novel compounds that antagonize GPR84 and that may be useful for the treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
[0080] The present invention also provides methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention and methods for treating diseases involving inflammatory conditions (for example inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, by administering a compound of the invention. A compound of the invention is an inhibitor of GPR84.
[0081] Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a Formula la:
Figure imgf000018_0001
wherein
Pv1 is H, Me, or halo;
Li is absent or is -0-, -S-, or -NR4a-;
G is
R2,
-W-L2-R2, or
W is Ci_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple bond;
L2 is absent or is -0-;
R2 is
- H,
Ci_8 alkyl, optionally substituted with one to three groups independently selected from o OH,
o halo, o CN,
o Ci-6 alkoxy,
o C3.7 cycloalkyl,
o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
o phenyl,
C4-7 cycloalkenyl comprising one double bond,
5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S,
C3.7 cycloalkyl optionally substituted with one or more independently selected R5 groups,
4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 groups,
5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one to three independently selected R6 groups, or
C6-io aryl optionally substituted with one or more independently selected R6 groups;
L3 is -NR4b-;
R3 is
Ci_4 alkyl substituted with
o C6-io aryl optionally substituted with one or more independently selected R7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups,
5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R7 groups, or
C6-io aryl optionally substituted with one or more independently selected R7 groups;
Each R4a and R4b is independently selected from H, C 1 alkyl, and C3.7 cycloalkyl;
R5 is oxo or R6;
R6 is
- OH,
halo,
Ci_6 alkyl optionally substituted with one to three groups independently selected from halo, and OH, Ci-6 alkoxy optionally substituted with one to three groups independently selected from halo, and OH,
C3.7 cycloalkyl,
- -C(=0)OR8,
- -C(=0)NR9R10,
-
Figure imgf000020_0001
alkyl,
- -CN,
phenyl,
-O-phenyl,
4- 7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or
5- 6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S; optionally substituted with one or more indepentently selected C1 alkyl, Ci_4 alkoxy, CN, halo, and -C(=0)ORu;
R7 is Ci_4 alkyl, or halo; and
each of R8, R9, R10 and R11 is independently selected from H and Ci_4 alkyl.
[0082] In a further embodiment, a compound of the invention is disclosed having a Formula lb:
Figure imgf000020_0002
wherein R1, Li and G are as previously described.
[0083] In yet a further embodiment, a compound of the invention is disclosed having a Formula Ic:
Figure imgf000020_0003
wherein R1, Li and G are as previously described.
[0084] In one embodiment, the compound of the invention is according to Formula la, lb or Ic, wherein R1 is Me, F, or CI.
[0085] In one embodiment, the compound of the invention is according to Formula la, lb or Ic, wherein R1 is H.
[0086] :
Figure imgf000021_0001
lla Mb l ie
wherein Li, and R2 are as decribed previously.
Figure imgf000021_0002
IVa IVb
wherein Li, W, L3, and R3 are as decribed previously. [0089] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IVc, wherein Li is absent, or is -0-. In a preferred embodiment, Li is absent.
[0090] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IVc, wherein Li is -NR4a-, wherein R4a is as described previously. In a preferred embodiment, R4a is H, Me, Et, or cyclopropyl. In a more preferred embodiment, R4a is H.
[0091] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IVc, wherein W is C 1 alkylene. In a preferred embodiment, W is -CH2-, -CH2-CH2-, -CH2-CH2- CH(CH3)-, -CH2-CH(-CH2-CH3)-, -CH2-C(CH3)2-, or -CH2-CH2-CH2-. In a more preferred embodiment, W is -CH2-. In another more preferred embodiment, W is-CH2-CH2-.
[0092] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IVc, wherein W is C2_4 alkenylene having one double bond. In a preferred embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-. In a more preferred embodiment, W is -CH=CH-. In another more preferred embodiment, W is -CH2-CH=CH-.
[0093] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IVc, wherein W is C2.4 alkynylene having one triple bond. In a preferred embodiment, W is -C≡C-, - CH2-C≡C-, or -C≡C-CH2-. In a more preferred embodiment, W is -C≡C-. In another more preferred embodiment, W is -CH2-C≡C-.
[0094] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein L2 is absent. In another embodiment, L2 is -0-.
[0095] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li is absent or is -0-, W is Ci_4 alkylene; and L2 and R2 are as described previously. In a preferred embodiment, W is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In a more preferred embodiment, W is - CH2-. In another preferred embodiment, W is-CH2-CH2-.
[0096] In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li is absent or is -0-, W is C2.4 alkenylene having one double bond; and L2 and R2 are as described previously. In a preferred embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-. In a more preferred embodiment, W is -CH=CH-. In another more preferred embodiment, W is -CH2-CH=CH-.
[0097] In yet another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li is absent, W is C2.4 alkynylene having one triple bond; and L2 and R2 are as described previously. In a preferred embodiment, W is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-. In a more preferred embodiment, W is -C≡C-. In another more preferred embodiment, W is -CH2-C≡C-.
[0098] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li and L2 are absent, W is Cw alkylene; and R2 is as described previously. In a preferred embodiment, W is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In a more preferred embodiment, W is -CH2-. In another more preferred embodiment, W is -CH2-CH2-.
[0099] In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li and L2 are absent, W is C2.4 alkenylene having one double bond; and R2 is as described previously. In a preferred embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-. In a more preferred embodiment, W is -CH=CH-. In another more preferred embodiment, W is -CH2-CH=CH-.
[00100] In yet another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or Illa-IIIc, wherein Li and L2 are absent, W is C2.4 alkynylene having one triple bond; and R2 is as described previously. In a preferred embodiment, W is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-. In a more preferred embodiment, W is -C≡C-. In another more preferred embodiment, W is -CH2-C≡C-.
[00101] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is H.
[00102] In another embodiment, the compound of the invention is according to any one of Formulae any one of Formulae Ia-IIIc, wherein R2 is Ci_8 alk l. In a preferred embodiment, R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or t-Bu. In a more preferred embodiment, R2 is Me, Et, z'-Pr or t-Bu. In a more preferred embodiment, R2 is t- Bu.
[00103] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is Ci.g alkyl substituted with one to three groups selected from OH, halo, CN, Ci_6 alkoxy, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In a preferred embodiment, R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or t-Bu substituted with one to three groups selected from OH, halo, CN, Ci_6 alkoxy, C3.7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In another preferred embodiment, is Ci_8 alkyl substituted with one to three groups selected from OH, F, CI, CN, -OMe, -OEt, Oz'-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a more preferred embodiment, R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or t-Bu substituted with one to three groups selected from OH, F, CI, CN, - OMe, -OEt, -Oz'-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl.
[00104] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, wherein R2 is Ci_8 alkyl substituted with one group selected from OH, halo, CN, Ci_6 alkoxy, C3.7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In a preferred embodiment, R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or t-Bu substituted with one group selected from OH, halo, CN, Ci_6 alkoxy, C3-7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In another preferred embodiment, is Ci_8 alkyl substituted with one group selected from OH, F, CI, CN, -OMe, -OEt, - Oz'-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a more preferred embodiment, R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or t-Bu substituted with one group selected from OH, F, CI, CN, -OMe, -OEt, - Oz'-Pr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a most preferred embodiment, R2 is -CH2-OH, -C(CH3)2-OH, -CH(OH)CH3, -CH(OH)-C2H5, -CH(OH)-C3H7, - C(OH)(C2H5)2, -C(OH)H-CH(CH3)2, -C(OH)H-CH2-CH(CH3)2, -C(OH)H-C(CH3)3, -CH2-CN, -CH2-OCH3, - CH2-CH2-OCH3, -CH(OCH3)-CH3, -C(OCH3)H-CH(CH3)2, -CH2-F, -CH2-CH2-F, -CH2-cyclopropyl, -CH2- cyclopentyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, or -CH2-tetrahydropyranyl.
[00105] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is C4.7 cycloalkenyl comprising one double bond. In a preferred embodiment, R2 is cyclohexenyl.
[00106] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S. In a preferred embodiment, R2 is dihydropyranyl.
[00107] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is C3_7 cycloalkyl. In a preferred embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more preferred embodiment, R2 is cyclopropyl.
[00108] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, wherein R2 is C3.7 cycloalkyl substituted with one to three independently selected R5 groups. In a preferred embodiment, R2 is C3.7 cycloalkyl substituted with one R5 group. In a more preferred embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group. In another more prefered embodiment, R2 is C3.7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, or Ci_6 alkyl. In a most prefered embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, or Ci_6 alkyl. In a further most prefered embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is R6, and R6 is selected from OH.
[00109] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O. In a preferred embodiment, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl. [00110] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O substituted with one to three independently selected R5 groups. In a preferred embodiment, R2 is 4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and Osubstituted with one R5 group. In a more preferred embodiment, R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O substituted with one R5 group, wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl. In another more preferred embodiment, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is substituted with one R5 group . In a most preferred embodiment, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is substituted with one R5 group, wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl,
[00111] In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
[00112] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted substituted with one to three independently selected R6 groups. In a prefered embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R6 groups. In another more preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In most preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In another most preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ί-Bu, -CF3, -OMe, -OEt, Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, or phenyl. In further most preferred embodiment, R is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ί-Bu, -CF3, -OMe, -OEt, -Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, moφholinyl, piperidinyl, and phenyl.
[00113] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, R2 is C6-io aryl. In a preferred embodiment, R2 is phenyl.
[00114] In another embodiment, the compound of the invention is according to any one of Formulae Ia- IIIc, R2 is Ce-ιο aryl substituted with one or more independently selected R6 groups. In a prefered embodiment, R2 is C6_io aryl substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is C6_io aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, Ci_6 alkyl, Ci_6 alkoxy, or
Figure imgf000026_0001
alkyl. In another more preferred embodiment, R2 is C6_io aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=0)NR9R10, and each R9 and R10 is independently selected from from H and Cw alkyl. In yet another more preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups. In a most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, Ci_6 alkyl, Ci_6 alkoxy, and
Figure imgf000026_0002
alkyl. In another most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=0)NR9R10, and each R9 and R10 is independently selected from from H and Ci_4 alkyl. In a further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from F, CI, CN, Me, -OMe, -OEt, and -NHC(=0)Me. In another further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from - C(=0)NH2, and -C(=0)NHMe.
[00115] In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, rVa, IVb or IVc, wherein L3 is -NR4b-, and R4b is as decribed previously. In a preferred embodiment, R4b is H, Me, Et, or cyclopropyl. In a more preferred embodiment, R4a is H.
[00116] In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, rVa, IVb or IVc, wherein R3 is Ci_4 alkyl substituted with C6_io aryl optionally substituted with one or more independently selected R7 groups, or 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups. In a preferred embodiment, R3 is Me or Et, each of which is substituted with C6_io aryl optionally substituted with one or more independently selected R7 groups), or 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups. In another preferred embodiment, R3 is Ci_4 alkyl substituted with phenyl, or pyridyl, each of which is optionally substituted with one or more independently selected R7 groups. In a more preferred embodiment, R3 is C1 alkyl substituted with phenyl, or pyridyl. In a more preferred embodiment, R3 is CM alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or CI. In a most preferred embodiment, R3 is Me or Et, each of which is substituted with phenyl, or pyridyl. In a more preferred embodiment, R3 is Me or Et, each of which is substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or CI.
[00117] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb or IVc, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R3 is pyridyl.
[00118] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R7 groups, wherein each R7 group is as described previously. In a preferred embodiment, R3 is pyridyl, substituted with one or more independently selected R7 groups, wherein each R7 group is as described previously. In another preferred embodiment, R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R7 groups, wherein each R7 group is selected from Me, Et, F, and CI. In a more preferred embodiment, R3 is pyridyl substituted with one or more independently selected R7 groups, wherein each R7 group is selected from Me, Et, F, and CI. In a most preferred embodiment, R3 is pyridyl substituted with one R7 group selected from Me, Et, F, and CI.
[00119] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R3 is C6_io aryl. In a preferred embodiment, R3 is phenyl.
[00120] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, IVa, IVb, or IVc, wherein R3 is C6_io aryl substituted with one or more independently selected R7 groups, wherein each R7 group is as described previously. In a preferred embodiment, R3 is phenyl, substituted with one or more independently selected R7 groups, wherein each R7 group is as described previously. In another preferred embodiment, R3 is C6_io aryl substituted with one or more independently selected R7 groups, wherein each R7 group is selected from Me, Et, F, and CI. In a more preferred embodiment, R3 is phenyl substituted with one or more independently selected R7 groups, wherein each R7 group is selected from Me, Et, F, and CI. In a most preferred embodiment, R3 is phenyl substituted with one R7 group selected from Me, Et, F, and CI.
[00121] In one embodiment, the compound of the invention is according to Formula Va, Vb, Vc or Vd:
Figure imgf000028_0001
[00122] In a further embodiment, the compound of the invention is not according to Formula Va, Vb, Vc or Vd.
[00123] In another embodiment, the compound of the invention is according to Formula Via, VIb, Vic or
Figure imgf000028_0002
[00124] In a further embodiment, the compound of the invention is not according to Formula Via, VIb, Vic or VId.
[00125] In another embodiment, the compound of the invention is according to Formula Vila, Vllb, VIIc
Figure imgf000028_0003
wherein R is as described previously.
[00126] In one embodiment, the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or VIIb,wherein R2 is C3-7 cycloalkyl. In a preferred embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more preferred embodiment, R2 is cyclopropyl. [00127] In one embodiment, the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or Vllb, wherein R2 is not C3-7 cycloalkyl. In a preferred embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more preferred embodiment, R2 is not cyclopropyl.
[00128] In another embodiment, the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or Vllb, wherein R2 is C3_7 cycloalkyl substituted with one to three independently selected R5 groups. In a preferred embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group. In a more preferred embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group. In another more prefered embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, or Ci_6 alkyl. In a most prefered embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl. In a further most prefered embodiment, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is OH.
[00129] In another embodiment, the compound of the invention is according to Formula Va, Vb, Via, VIb, Vila, or Vllb, wherein R2 is not C3.7 cycloalkyl substituted with one to three independently selected R5 groups. In a preferred embodiment, R2 is not C3.7 cycloalkyl substituted with one R5 group. In a more preferred embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group. In another more prefered embodiment, R2 is not C3.7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl. In a most prefered embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl. In a further most prefered embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein R5 is OH.
[00130] In one embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
[00131] In one embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId,
VIIc or Vlld, wherein R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O. In a preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
[00132] In another embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one to three independently selected R6 groups. In a prefered embodiment, R is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R6 groups. In another more preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, Ci_6 alk l, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3_7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In a most preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In another most preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ί-Bu, -CF3, -OMe, -OEt, Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In a further most preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, CI, Me, Et, Pr, z-Pr, ί-Bu, -CF3, -OMe, -OEt, -Oz-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
[00133] In another embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one to three independently selected R6 groups. In a prefered embodiment, R2 is n o t 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R6 groups. In another more preferred embodiment, R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In a most preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl. In another most preferred embodiment, R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, CI, Me, Et, Pr, z'-Pr, ί-Bu, -CF3, -OMe, -OEt, Oz'-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In a further most preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently selected from OH, F, CI, Me, Et, Pr, z'-Pr, t-Bu, -CF3, -OMe, -OEt, -Oz'-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
[00134] In another embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R2 is C6_io aryl. In a preferred embodiment, R2 is phenyl.
[00135] In another embodiment, the compound of the invention is according to Formula Vc, Vd, Vic or VId, wherein R2 is not C6.io aryl. In a preferred embodiment, R2 is not phenyl.
[00136] In another embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R2 is Ce-ιο aryl substituted with one or more independently selected R6 groups. In a prefered embodiment, R2 is C6.io aryl substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is C6_io aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, Ci_6 alkyl, Ci_6 alkoxy, and
Figure imgf000031_0001
alkyl. In another more preferred embodiment, R2 is C6_io aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=0)NR9R10, and each R9 and R10 is independently selected from from H and Ci_4 alkyl. In another more preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups. In a most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, Ci_6 alkyl, Ci_6 alkoxy, and
Figure imgf000031_0002
alkyl. In another most preferred embodiment, R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=0)NR9R10, and each R9 and R10 is independently selected from from H and Ci_4 alkyl. In a further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from F, CI, CN, Me, -OMe, -OEt, - and -NHC(=0)Me. In a further most preferred embodiment R2 is phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from C(=0)NH2, and -C(=0)NHMe.
[00137] In another embodiment, the compound of the invention is according to Formula Vc, Vd, Vic, VId, VIIc or Vlld, wherein R2 is not C6_io aryl substituted with one or more independently selected R6 groups. In a prefered embodiment, R2 is not Ce-ιο aryl substituted with one or two independently selected R6 groups. In a more preferred embodiment, R2 is not Ce-ιο aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, C i_6 alkyl, Ci_6 alkoxy, and
Figure imgf000032_0001
alkyl. In another more preferred embodiment, R2 is not C6_io aryl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=0)NR9R10, and each R9 and R10 is independently selected from from H and Ci_4 alkyl. In another more preferred embodiment, R2 is not phenyl substituted with one or two independently selected R6 groups. In a most preferred embodiment, R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from halo, CN, Ci_6 alkyl, Ci_6 alkoxy, and
Figure imgf000032_0002
alkyl. In another most preferred embodiment, R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -C(=0)NR9R10, and each R9 and R10 is independently selected from from H and C alkyl. In a further most preferred embodiment R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from F, CI, CN, Me, -OMe, -OEt, - and -NHC(=0)Me. In a further most preferred embodiment R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is selected from C(=0)NH2, and -C(=0)NHMe.
[00138] In one embodiment, the compound of the invention is selected from:
9-Allyloxy-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzonitrile, 3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzonitrile, 4-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzonitrile,
[2-([l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yloxy]-acetonitrile, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 9-(3,5-Dichloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 9-Benzofuran-2-yl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -indole- 1 -carboxylic acid tert-butyl ester,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-indol-2-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-trifluoromethyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one, 9 -(5 -tert-Butyl- [ 1 ,2 ,4 ] oxadiazol-3 -ylmethoxy)
a]isoquinolin-4-one,
5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -pyridine-2- carboxylic acid methylamide,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pent-l -ynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -(2-pyridin-2-yl- rt^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-indol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -(5 -methoxy-p^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-indazol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzamide, 5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -2-fluoro- benzamide,
N-{3-[2-([l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-phenyl}- acetamide,
9-Cyclopropylethynyl-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(l-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyrimidin-5-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
9-Cyclohex- 1 -enyl-2-([ 1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6, 1 -a]isoquinolin-4-one,
2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -( 1 -methyl- 1 H
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-methyl-pyr^^
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop
5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -pent-4-ynenitrile,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
2-([l ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-o^
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolm^
4-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -N-methyl- benzamide,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-(2-Chloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin- 9 -(1 ,5 -Dimethyl- 1 H-pyrazol-3 -ylmethoxy^
a]isoquinolin-4-one,
2-([ 1 ,4]Dioxan-2-ylmethoxy)-9 -( 1 -methyl- 1 H-pyrazol-3 -ylmethoxy)-6,7 -dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-[l,2,4]oxadiazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2- ([l ,4]Dioxan-2-ylmethoxy)-9-(4-moφholin-4-yl-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
3 - [2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -4-fluoro- benzamide,
3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -5 -fluoro- benzamide,
9-(3,3-Dimethyl-but-l-ynyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-4-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4- one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4- one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
9-(3,6-Dihydro-2H-pyran-4-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -pyridine-2- carbonitrile,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-moφholin-4-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin- one,
9-(2,3-Dimethoxy-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-
4 - one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -isonicotinonitrile, 9-(2,5-Dimethoxy-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3,4,5,6-tetrahydro-2H-[l ,2']bipyridinyl-5'-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 9-(2,6-Dimethoxy-pyridin-3-yl)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido
4-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -nicotinonitrile,
9-tert-Butoxymethyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-pyn-olidin-l-yl-pyridin-3-yl)-6,7-dihydro-pyrim
one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-pyn-olidin-l-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[
one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4- one,
9-(5-tert-Butyl-oxazol-2-ylmethoxy)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoq one,
9-(5-Cyclopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-ethyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-methyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-isopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
9-Cyclopentylethynyl-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-Cyclohexylethynyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([ 1 ,4]Dioxan-2-ylmethoxy)-9 -(3 -methyl-but- 1 -ynyl)-6,7 -dihydro-pyrimido [6, 1 -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-hex-l-ynyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-[3-(Benzyl-methyl-amino)-prop-l-ynyl]-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoqu^ one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4^ 9-Cyclopropyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm 4 -one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-but-l-ynyl)-6,7-dihydro-pyrimido[6,l-a] one,
9-(3-Benzylamino-prop-l -ynyl)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoqum^ 2-([l ,4]Dioxan-2-ylmethoxy)-9-[(foran-2-ylmethyl)-amm^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(l-ethyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm^
2-([l ,4]Dioxan-2-ylmethoxy)-9-[l-(3-methyl-butyl)-lH-pyrazol-4-yl]-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -(5 -methyl-fc
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
9-(3,5-Dimethyl-lH-pyrazol-4-yl)-2-([l ,4]dio^
one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(l-propyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin 2-[2-((R)-l -[l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-benzonM 2-[2-((S)-l -[l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-
9-(5-Cyclopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin- 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoqum^ 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoqum^ 4 -one,
9-Cyclopropylethynyl-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinoli^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoqum
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-l -yl-prop-1 -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one,
9-(2-Cyclopropyl-ethyl)-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolm 9-Cyclopentyloxymethyl-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro-pyrimido[6,l-a]isoqum 4 -one,
9-Allyloxy-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-Allyloxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran^
a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-{3-[(pyridin-3-ylme&^
a]isoquinolin-4-one,
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
9-(2-Cyclopropyl-ethyl)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-pyrimido[6,l -a]isoquin
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6,7-dihydro-pyrim a]isoquinolin-4-one,
9-(2,2-Dimethyl-butylamino)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a^ one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy
4 -one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyrimido[6,l-a]isoqum^ 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-o^
9-Cyclopropylmethoxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-fluoro-ethoxy^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-l-ynyl]-6,7-dihydro-pyrimido[6,l ^ a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-l-ynyl]-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-l -ynyl]-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
9-(2,2-Dimethyl-propoxymethyl)-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
9 -Cyclohexyloxymethyl-2-((S)- 1 - [ 1 ,4]dioxan-2-ylm
9-Cyclopropylmethoxymethyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-bu^
9-(4,4-Dimethyl-pentyloxy)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoqum^ one, 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-meth^
4 -one,
9-(3-Cyclopropyl-propoxy)-2-((S)-l-[l,4]dioxan-2-ylmeth^
one,
9-Cyclohexylamino-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-o
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
9-Cyclopentylmethoxymethyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-pyrimido[6,l -a]isoquinoto one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pen
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin
9-(Cyclohexyl-methyl-amino)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoqum^ one,
9-(Cyclohexylmethyl-amino)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoqum^ one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[(tetrahyd
a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydro^
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro-pyrimido[6,l -a]is one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^ 9-(2,2-Dimethyl-propoxy)-2-((S)-l-[l,4]dioxan-2-ylme^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,l-a]isoq 4 -one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-o 9-(3-Cyclopropyl-propoxy)-2-((R)-l-[l ,4]dioxan-2-ylmeth^
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[2-(l -hydro
a]isoquinolin-4-one,
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
[00139] In one embodiment, the compound of the invention is selected from:
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[2-(l -hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, and
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00140] In one embodiment, the compound of the invention is 9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-
2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one.
[00141] In another embodiment, the compound of the invention is not 9-cyclopropylethynyl-2-((S)-l -
[ 1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6, 1 -a]isoquinolin-4-one.
[00142] In one embodiment a compound of the invention is not an isotopic variant.
[00143] In one aspect a compound of the invention is present as the free base.
[00144] In one aspect a compound of the invention is a pharmaceutically acceptable salt.
[00145] In one aspect a compound of the invention is present as the free base or a pharmaceutically acceptable salt.
[00146] In one aspect a compound of the invention is a solvate.
[00147] In one aspect a compound of the invention is a solvate of a pharmaceutically acceptable salt of the compound.
[00148] In certain aspects, the present invention provides prodrugs and derivatives of a compound of the invention according to the formula above. Prodrugs are derivatives of a compound of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. [00149] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H. Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
[00150] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.
[00151] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
[00152] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.
CLAUSES
1. A compound according to Formula la:
Figure imgf000041_0001
wherein
R1 is H, Me, or halo;
Li is absent or is -0-, -S-, or -NR4a-;
G is
R2,
-W-L2-R2, or
W is Ci_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alk nylene having one triple bond;
L2 is absent or is -0-;
R2 is
- H,
Ci-8 alkyl, optionally substituted with one to three groups independently selected from
o OH,
o halo,
o CN,
o Ci_6 alkoxy,
o C3.7 cycloalkyl,
o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
o phenyl,
C4.7 cycloalkenyl comprising one double bond,
5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S,
C3.7 cycloalkyl optionally substituted with one or more independently selected R5 groups, 4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 groups,
5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O optionally substituted with one to three independently selected R6 groups, or
C6-io aryl optionally substituted with one or more independently selected R6 groups;
L3 is -NR4b-;
R3 is
Ci-4 alkyl substituted with
o C6-io aryl optionally substituted with one or more independently selected R7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups,
5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R7 group, or Ce-ιο aryl optionally substituted with one or more independently selected R7 groups;
Each R4a and R4b is independently selected from H, C alkyl, and C3-7 cycloalkyl;
R5 is oxo or R6;
R6 is
- OH,
halo,
Ci-6 alkyl optionally substituted with one to three groups independently selected from halo, and OH,
Ci_6 alkoxy optionally substituted with one to three groups independently selected from halo, and OH,
C3.7 cycloalkyl,
- -C(=0)OR8,
- -C(=0)NR9R10,
-
Figure imgf000042_0001
alkyl,
- -CN,
phenyl,
-O-phenyl,
4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S, optionally substituted with one or more indepentently selected Cw alkyl, CM alkoxy, CN, halo), and -C(=0)ORu;
R7 is Ci_4 alkyl, or halo; and
each of R8, R9, R10 and R11 is independently selected from H and Ci_4 alkyl,
or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable salt.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula lb:
Figure imgf000043_0001
wherein R1, Li and G are as previously described.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Ic:
Figure imgf000043_0002
wherein R1, Li and G are as previously described.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-3, wherein R1 is Me, F, or CI.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-3, wherein R1 is H. A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, wherein the compound is according to Formula Ila, lib or lie:
Figure imgf000044_0001
lla Mb l ie wherein Li, and R are as described in claim 1.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, wherein the
Figure imgf000044_0002
wherein Li, W, L2, and R are as decribed previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, wherein the compound is according to Formula IVa, IVb, or IVc:
Figure imgf000044_0003
IVa IVb IVc wherein Li, W, L3, and R3 are as described in claim 1. 9. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein Li is absent.
10. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein 11. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein Li is -NR4a-, and R4a is H, Me, Et, or cyclopropyl.
12. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein Li is -NR4a-, and R4a is H.
13. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11 , wherein W is C1.4 alkylene.
14. A compound or pharmaceutically acceptable salt thereof, according to clause 13, wherein W is -CH2-, -CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH2-CH(-CH2-CH3)-, -CH2-C(CH3)2-, or -CH2-CH2-CH2-.
15. A compound or pharmaceutically acceptable salt thereof, according to clause 14, wherein W is -CH2- CH2-.
16. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11 , wherein W is C2.4 alkenylene having one double bond.
17. A compound or pharmaceutically acceptable salt thereof, according to clause 16, wherein W is - CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2.
18. A compound or pharmaceutically acceptable salt thereof, according to clause 17, wherein W is - CH=CH-.
19. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11 , wherein W is C2.4 alkynylene having one triple bond.
20. A compound or pharmaceutically acceptable salt thereof, according to clause 19, wherein W is -C≡C-,
Figure imgf000045_0001
21. A compound or pharmaceutically acceptable salt thereof, according to clause 20, wherein W is -C≡C-.
22. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, 7, or 9- 21 , wherein L2 is -0-.
23. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, 7, or 9- 21 , wherein L2 is absent.
24. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, 7, or 9- 21 , wherein Li and L2 are absent, and W is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-.
25. A compound or pharmaceutically acceptable salt thereof, according to clause 1 -5, 7, or 9-21, wherein Li and L2 are absent, and W is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-.
26. A compound or pharmaceutically acceptable salt thereof, according to clause 1 -5, 7, or 9-21, wherein Li and L2 are absent, and W is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-. 27. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is H.
28. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is Ci_8 alkyl.
29. A compound or pharmaceutically acceptable salt thereof, according to clause 28, wherein R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or t-Bu.
30. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is Ci_8 alkyl substituted with one group selected from OH, halo, CN, Ci_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
31. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is Me, Et, n-Pr, z'-Pr, z'-Bu, or ί-Bu, each of which is substituted with one group selected from OH, halo, CN, Ci_6 alkoxy, C3.7 cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), and phenyl.
32. A compound or pharmaceutically acceptable salt thereof, according to any one of clause 30, wherein R2 is Ci_8 alkyl substituted with one group selected from OH, F, CI, CN, -OMe, -OEt, -Oz'-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl.
33. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is C4.7 cycloalkenyl comprising one double bond.
34. A compound or pharmaceutically acceptable salt thereof, according to clause 33, wherein R2 is cyclohexenyl.
35. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S.
36. A compound or pharmaceutically acceptable salt thereof, according to clause 35, wherein R2 is dihydropyranyl.
37. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is C3.7 cycloalkyl.
38. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is C3.7 cycloalkyl substituted with one R5 group.
39. A compound or pharmaceutically acceptable salt thereof, according to clause 38, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl. 40. A compound or pharmaceutically acceptable salt thereof, according to clauses 37, 38 or 39, wherein R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
41. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O.
42. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, substituted with one R5 group.
43. A compound or pharmaceutically acceptable salt thereof, according to clause 42, wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and Ci_6 alkyl.
44. A compound or pharmaceutically acceptable salt thereof, according to clause 41 , 42 or 43, wherein R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
45. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
46. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups.
47. A compound or pharmaceutically acceptable salt thereof, according to clause 46, wherein each R6 is independently selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
48. A compound or pharmaceutically acceptable salt thereof, according to clause 45, 46 or 47, wherein R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
49. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is C6_io aryl.
50. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -7, or 9-25, wherein R2 is Ce-ιο aryl, substituted with one or two independently selected R6 groups.
51. A compound or pharmaceutically acceptable salt thereof, according to clause 50, wherein R6 is selected from halo, CN, d_6 alkyl, d_6 alkoxy,
Figure imgf000047_0001
wherein each R9 and R10 is independently selected from from H and Ci_4 alkyl.
52. A compound or pharmaceutically acceptable salt thereof, according to clause 49, 50 or 51 , wherein R2 is phenyl. 53. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein L3 is -NR4b-, and R4b is H, Me, Et, or cyclopropyl.
54. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein R3 is Ci_4 alkyl substituted with phenyl, or pyridyl.
55. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein R3 is Ci_4 alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F, or CI
56. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
57. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R7 groups.
58. A compound or pharmaceutically acceptable salt thereof, according to clause 57 wherein R7 is selected from Me, Et, F, and CI.
59. A compound or pharmaceutically acceptable salt thereof, according to clause 56, 57, or 58 wherein R3 is pyridyl.
60. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein R3 is C6_io aryl.
61. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -5, or 8-21 , wherein R3 is C6_io aryl, substituted with one or more independently selected R7 groups.
62. A compound or pharmaceutically acceptable salt thereof, according to clause 61 , wherein R7 is selected from Me, Et, F, and CI.
63. A compound or pharmaceutically acceptable salt thereof, according to clause 60, 61 , or 62, wherein R3 is phenyl.
64. A compound or pharmaceutically acceptable salt thereof, according to clause 1 , wherein the compound is according to Formula Va:
Figure imgf000048_0001
wherein R is as described previously. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vb:
Figure imgf000049_0001
Vb
wherein R2 is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vc:
Figure imgf000049_0002
Vc
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vd:
Figure imgf000049_0003
Vd
wherein R2 is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Via:
Figure imgf000050_0001
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vlb:
Figure imgf000050_0002
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vic:
Figure imgf000050_0003
Vic
wherein R2 is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VId:
Figure imgf000051_0001
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vila:
Figure imgf000051_0002
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vllb:
Figure imgf000051_0003
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIIc:
Figure imgf000052_0001
Vile
wherein R is as described previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 , wherein the compound is according to Formula Vlld:
Figure imgf000052_0002
wherein R is as described previously.
76. A compound or pharmaceutically acceptable salt thereof, according to clause 64, 65, 68, 69, 72, or 73, wherein R2 is C3.7 cycloalkyl.
77. A compound or pharmaceutically acceptable salt thereof, according to clause 64, 65, 68, 69, 72, or 73, wherein R2 is C3.7 cycloalkyl substituted with one R5 group.
78. A compound or pharmaceutically acceptable salt thereof, according to clause 77, wherein R5 is oxo, or R6 wherein R6 is OH, or d_6 alkyl.
79. A compound or pharmaceutically acceptable salt thereof, according to clause 76, 77 or 78, wherein R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
80. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71 , 74, or 75, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O.
81. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71 , 74, or 75, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6 groups.
82. A compound or pharmaceutically acceptable salt thereof, according to clause 81 , wherein R6 is selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalkyl , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
83. A compound or pharmaceutically acceptable salt thereof, according to clause 80, 81 or 82, wherein R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
84. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71 , 74, or 75, wherein R2 is C6_io aryl.
85. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71 , 74, or 75, wherein R2 is C6_io aryl substituted with one or two independently selected R6 groups.
86. A compound or pharmaceutically acceptable salt thereof, according to clause 85, wherein R6 is selected from halo, CN, Ci_6 alkyl, Ci_6 alkoxy,
Figure imgf000053_0001
and each R9 and R10 is independently selected from from H and Ci_4 alkyl.
87. A compound or pharmaceutically acceptable salt thereof, according to clause 84, 85 or 86, wherein R2 is phenyl.
88. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is 9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
89. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is not 9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
PHARMACEUTICAL COMPOSITIONS
[00153] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of a compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
[00154] The pharmaceutical compositions of the invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, intranasal and inhalation. Depending on the intended route of delivery, a compound of this invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
[00155] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, a compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
[00156] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[00157] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10%> by weight with the remainder being the injectable carrier and the like.
[00158] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
[00159] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety. [00160] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
[00161] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
[00162] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets
[00163] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
Formulation 2 - Capsules
[00164] A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
Formulation 3 - Liquid
[00165] A compound of the invention (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Sufficient water may be then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[00166] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
Formulation 5 - Injection
[00167] A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/niL. Formulation 6 - Topical
[00168] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
METHODS OF TREATMENT
[00169] A compound of the invention may be used as a therapeutic agent for the treatment of conditions in mammals that are causally related or attributable to aberrant activity of GPR84 and/ or aberrant GPR84 expression and/or aberrant GPR84 distribution.
[00170] Accordingly, a compound and pharmaceutical compositions of the invention find use as therapeutics for the prophylaxis and/or treatment of inflammatory conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, in mammals including humans.
[00171] Accordingly, in one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicament.
[00172] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament.
[00173] In yet another aspect, the present invention provides a method of treating a mammal having, or at risk of having a disease disclosed herein. In a particular aspect, the present invention provides a method of treating a mammal having, or at risk of having inflammatory conditions (e.g. inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, in mammals including humans.
[00174] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of inflammatory conditions. In a specific embodiment, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). [00175] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of inflammatory conditions. In a specific embodiment, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
[00176] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with inflammatory conditions, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
[00177] In another aspect, the present invention provides a method of treating a mammal having, or at risk of having a disease selected from inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions.
[00178] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
[00179] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
[00180] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00181] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of infectious disease. In a specific embodiment, the infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
[00182] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of infectious disease. In a specific embodiment, the infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
[00183] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with infectious disease, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the infectious diseases is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
[00184] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of autoimmune diseases, and/or diseases involving impairment of immune cell functions. In a specific embodiment, the autoimmune diseases and/or diseases involving impairment of immune cell functions is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
[00185] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of autoimmune diseases and/or diseases involving impairment of immune cell functions. In a specific embodiment, the autoimmune diseases, and/or diseases involving impairment of immune cell functions is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
[00186] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with autoimmune diseases and/or diseases involving impairment of immune cell functions, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the autoimmune diseases and/or diseases involving impairment of immune cell functions is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease. [00187] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or treatment of endocrine and/or metabolic diseases. In a specific embodiment, the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[00188] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and/or treatment of endocrine and/or metabolic diseases. In a specific embodiment, the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[00189] In additional method of treatment aspects, this invention provides methods of treatment and/or prophylaxis of a mammal susceptible to or afflicted with endocrine and/or metabolic diseases, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described. In a specific embodiment, the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[00190] As a further aspect of the invention there is provided a compound of the invention for use as a medicament especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
[00191] A particular regimen of the present method comprises the administration to a subject in suffering from an inflammatory condition, of an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the subject, and preferably terminate, the processes responsible for said inflammation. A special embodiment of the method comprises administering of an effective amount of a compound of the invention to a subject suffering from or susceptible to the development of inflammatory condition , for a period of time sufficient to reduce or prevent, respectively, inflammation of said patient, and preferably terminate, the processes responsible for said inflammation.
[00192] Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
[00193] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[00194] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[00195] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
[00196] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of an inflammatory condition; particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
[00197] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g. rheumatoid arthritis); particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin), and biological DMARDS (for example but without limitation Infliximab, Etanercept, Adalimumab, Rituximab, Golimumab, Certolizumab pegol, Tocilizumab, Interleukin 1 blockers and Abatacept).
[00198] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/ or prevention of autoimmune diseases; particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies(e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-β), TNF binding proteins (e.g. infliximab (Remicade™), etanercept (Enbrel™), or adalimumab (Humira™)), mycophenolate, Fingolimod, and Myriocin. [00199] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of infectious diseases; particular agents include but are not limited to antibiotics. In a particular embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of infections of any organ of the human body; particular agents include but are not limited to: aminoglycosides, ansamycins, carbacephem, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclins, anti-mycobacterial agents, as well as chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol and imidazole.
[00200] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of vasculitis, particular agents include but are not limited to steroids (for example prednisone, prednisolone), cyclophosphamide and eventually antibiotics in case of cutaneous infections (for example cephalexin)
[00201] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of IPF, particular agents include but are not limited to pirfenidone and bosentan.
[00202] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD; particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled) Long-acting p2-agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), phosphodiesterase-4 inhibitors (e.g. Roflumilast), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
[00203] Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate. [00204] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD); particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and ciclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
[00205] By co-administration is included any means of delivering two or more therapeutic- agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation this is not essential. The agents may be administered in different formulations and at different times.
GENERAL SYNTHETIC PROCEDURES
General
[00206] A compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[00207] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley- Blackwell; 4th Revised edition edition (2006), and references cited therein.
[00208] The following methods are presented with details as to the preparation of representative 6,7- dihydro-pyrimido[6,l -a]isoquinolin-4-one that have been listed hereinabove. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
[00209] All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica standard (30-70 μιη). Thin layer chromatography was carried out using pre-coated silica gel 60 F-254 plates (thickness 0.25 mm). ¾ NMR spectra were recorded on a Bruker Advance 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for LH NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak as internal reference. Multiplicities are given as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet (m) and broad (br). Electrospray MS spectra were obtained either on a Waters platform LC/MS spectrometer or on an Agilent 1100 Series LC/MSD. Analytic LCMS: Columns used, Waters Acquity UPLC BEH C18 1.7μηι, 2.1mm ID x 50mm L or Waters Acquity UPLC BEH C18 1.7μηι, 2.1mm ID x 30mm L or Waters XBridge C18 3.5μηι, 2.1mm ID x 50mm L. All the methods are using MeCN/H20 gradients. MeCN and H20 contain either 0.1% Formic Acid or NH3 (lOmM). Preparative LCMS: Column used, Waters XBridge Prep C18 5μηι ODB 30mm ID x 100mm L. All the methods are using either MeOH/H20 or MeCN/H20 gradients. MeOH, MeCN and H20 contain either 0.1% Formic Acid or 0.1 %> Diethylamine. Analytic chiral LC: Column used, Chiralpak IA 5 μιη 250 x 4.6 mm. Microwave heating was performed with a Biotage Initiator.
[00210] Table I: List of abbreviations used in the :perimental section:
microliter DMAP 4-Dimethylaminopyridine
DME Dimethoxyethane
AcOH Acetic acid
DMF N,N-dimethylformamide
Aq. aqueous
DMSO Dimethylsulfoxide
ATP Adenosine 5 '-Triphosphate
Dulbecco's Phosphate-Buffered
2,2'-bis(diphenylphosphino)-l ,Γ- DPBS
ΒΓΝΑΡ Saline
binaphthyl
Boc tert-Butyloxy-carbonyl DPPF U'-
Bis(diphenylphosphino)ferrocene
Boc20 Di-/er/-butyl dicarbonate
EtOAc Ethyl acetate br s broad singlet
Et20 Diethyl ether
Calcd calculated
eq. equivalent
Cat. Catalytic amount
g gram
D doublet
guanosine 5'-0-[gamma-
GTPD S
Dd Doublet of doublet thio]triphosphate
DCC N,N'-Dicyclohexylcarbodiimide h hour
DCE 1 ,2-Dichloroethane H Heptane
DCM Dichloromethane High-performance liquid
HPLC
chromatography
DIAD Diisopropyl azodicarboxylate
zPrOH isopropanol
DIPEA N,N-diisopropylethylamine
zPr20 Diisopropyl ether KHMDS Potassium hexamethyldisilazane obsd observed
Liquid Chromatography- Mass Pd(OAc)2 Palladium(II) acetate
LCMS
Spectrometry
Tetrakis(triphenylphosphine)palladi
L Liter Pd(PPh3)4
um(0)
M multiplet Pd/C Palladium on Carbon 10%
MeOH Methanol ppm part-per-million
MeCN Acetonitrile q quadruplet
Mel Methyl iodide rpm revolutions per minute
MEK Methyl ethyl ketone RT Room temperature
Mg milligram Rt retention time
Min minute 2-Dicyclohexylphosphino-2',6'-di-i-
RuPhos
propoxy-1 ,1 '-biphenyl mL milliliter
s singlet
Mmol millimole
SM Starting material
MS mass spectrometry
spA Scintillation proximity assay
MW Molecular weight
SPE Solid phase extraction
MW
Molecular weight calculated
(calc) STAB sodiumtriacetoxyborohydride
MW (obs) Molecular weight observed t triplet
Nicotinamide adenine dinucleotide TBAF Tetra-n-butylammonium fluoride
NADP
phosphate
TEA Triethylamine
NEAA Non-Essential Amino Acid
TFA Trifluoroacetic acid
NMP N-Methyl-2-pyrrolidone
THF T etrahydrofuran
NMR Nuclear Magnetic Resonnance
TLC Thin layer chromatography
General Synthetic Method
Intermediates
[00211] The intermediates to prepare the compounds according to the invention can be produced according to the followin schemes.
Figure imgf000065_0001
Intermediate 6
Intermediate 8
Figure imgf000065_0002
Intermediate 1: [2-(3-methoxy-phenyl)-ethyl]-urea
100212] A solution of 3-methoxyphenethylamine (100 g, 661.3 mmol, 1 eq.), urea (157.3 g, 2619.0 mmol, 4 eq.), AcOH (36 mL) and aq. HCl (12 mL) in H20 (800 mL) was heated under reflux for 5 days. The reaction mixture was cooled to RT, the solid was filtered off, washed with water and dried to afford intermediate 1.
(¾ CDCI3) δ (ppm): 7.24 (1H, t), 6.82-6.77 (3H, m), 5.10 (1H, br s), 4.52 (2H, br), 3.81 (1H, s), 3.42 (2H, br t), 2.80 (2H, t)
Intermediate 2: [2-(3-hydroxy-phenyl)-ethyl]-urea
[00213] A solution of intermediate 1 (72 g, 370.7 mmol) in concentrated HBr (500 mL) was heated under reflux overnight. The reaction mixture was brought to basic pH by addition of NaHC03 and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated under vacuum to afford intermediate 2. (¾ MeOD-d4) δ (ppm): 7.15 (1H, t), 6.76-6.68 (3H, m), 3.40-3.36 (2H, t), 2.77-2.74 (2H, t)
Intermediate 3: [2-(3-allyloxy-phenyl)-ethyl]-urea
[00214] To a solution of intermediate 2 (45 g, 249.7 mmol, 1 eq.) and K2C03 (103.5 g, 749.1 mmol, 3 eq.) in anhydrous DMF (300 mL) under a nitrogen atmosphere, was added allylbromide (50.5 mL, 499.4 mmol, 2 eq.). The reaction mixture was stirred for 2.5 days, then DMF was evaporated to dryness. The residue was dissolved in EtOAc, washed with saturated Na2C03, brine, dried over MgS04 and concentrated under vacuum to afford intermediate 3.
(¾ MeOD-d4) δ (ppm): 7.24 (1H, t), 6.87-6.81 (3H, m), 6.16-6.06 (1H, m), 5.45 (1H, dd), 5.29 (1H, dd), 4.59-4.57 (2H, m), 3.38 (2H, t), 2.80 (2H, t)
Intermediate 4 : 1 - [2 -(3-allyloxy-p henyl)-ethy 1] -py r imidine-2 ,4,6-tr io ne
[00215] Sodium (20.06 g, 872 mmol, 1 eq.) was dissolved in EtOH (1.4 L). Diethyl malonate (132.4 mL, 872 mmol, 1 eq.) was added and the reaction mixture was heated under reflux for lh. Intermediate 3 (96 g, 436 mmol, 0.5 eq.) in EtOH (300 mL) was added and the reaction mixture was heated under reflux for 12 h. The reaction was cooled to RT, IN aq. HCl was added and the precipitate was filtered, washed with water and dried to afford intermediate 4.
(¾ CDCI3) δ (ppm): 8.40 (1H, br s), 7.25 (1H, t), 6.88-6.82 (3H, m), 6.14-6.04 (1H, m), 5.45 (1H, dd), 5.32 (1H, dd), 4.58-4.56 (2H, m), 4.13 (2H, t), 3.64 (2H, s), 2.92 (2H, t)
MW (calcd): 288.3; MW (obsd): 289.3 (M + 1)
Intermediate 5: 9-allyloxy-2-chloro-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
[00216] A solution of intermediate 4 (20 g, 69.4 mmol, 1 eq.) in POCl3 (150 mL) was stirred at 50°C for 3 days. POCI3 was evaporated under vacuum and the residue was dissolved in DCM and quenched with saturated NaHC03. The organic layer was washed with water, dried over MgS04 and concentrated to afford intermediate 5. (¾ CDCI3) δ (ppm): 7.71 (2H, d), 6.97 (IH, dd), 6.86 (IH, d), 6.71 (IH, s), 6.13-6.04 (IH, m), 5.47 (IH, dd), 5.36 (IH, dd), 4.67-4.65 (2H, m), 4.27 (2H, t), 3.05 (2H, t)
MW (calcd): 288.7; MW (obsd): 289.3 (M+l)
General methods
Figure imgf000067_0001
[00217] To a solution of NaH (2 eq., 60% in mineral oil) in anhydrous DCM at 0°C, is added 2- hydroxymethyl-[l,4]dioxane (2 eq.) with the appropriate chirality, after 15 min, intermediate 5 (1 eq.) is added at 0°C, and the reaction is stirred at RT until completion. Saturated NH4C1 is added to the reaction mixture, the organic layer is washed with water, dried over MgS04 and concentrated. The desired product is purified by flash chromatography on silica gel.
[00218] 2-Hydroxymethyl-[l,4]dioxane, (R) 2-hydroxymethyl-[l,4]dioxane and (S) 2-hydroxymethyl- [l,4]dioxane are commercially available or can easily be prepared [Young Kim et al ; Bioorganic & Medicinal Chemistry 15 (2007) 2667-2679].
Illustrative synthesis of general method A:
Compound 118: 9-allyloxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin- 4-one
[00219] A solution of (R) 2-hydroxymethyl-[l,4]dioxane (56.6 g, 479 mmol, 2 eq.) and NaH (19.9 g, 479 mmol, 2 eq., 60% in mineral oil) in anhydrous DCM (300 niL) was stirred for 30 min at 0°C. Intermediate 5 (69.2 g, 240 mmol, 1 eq.) in solution in anhydrous DCM (700 niL) was added at 0°C. The reaction mixture was stirred for 2 h. Saturated NH4C1 was added, the organic layer was washed with water, dried over MgS04 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (MeOH/DCM) to afford compound 118.
(¾ CDCI3) δ (ppm): 7.66 (IH, d), 6.94 (IH, dd), 6.83 (IH, d), 6.32 (IH, s), 6.15-6.03 (IH, m), 5.47 (IH, dd), 5.37 (IH, dd), 4.65-4.63 (2H, m), 4.51 -4.39 (2H, m), 4.23 (2H,t), 4.06-3.98 (IH, m), 3.92-3.47 (6H, m), 3.01 (2H, t) Compound 1: 9-allyloxy-2-(-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
[00220] Compound 1 was prepared using general method A starting from 2-hydroxymethyl-[l ,4]dioxane. (¾ CDC13) δ (ppm): 7.66 (IH, d), 6.94 (IH, dd), 6.83 (IH, d), 6.32 (IH, s), 6.11 -6.04 (IH, m), 5.47 (IH, dd), 5.35 (IH, dd), 4.65-4.63 (2H, m), 4.491 -4.40 (2H, m), 4.22 (2H, t), 4.02-3.99 (IH, m), 3.90-3.46 (6H, m), 3.00 (2H, t)
MW (calcd): 370.4; MW (obsd): 371.4 (M+l)
Compound 117: 9-allyloxy-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin- 4-one
[00221] Compound 117 was prepared using general method A starting from (S) 2-hydroxymethyl- [l,4]dioxane.
(¾ CDCI3) δ (ppm): 7.66 (IH, d), 6.94 (IH, dd), 6.83 (IH, d), 6.31 (IH, s), 6.12-6.04 (IH, m), 5.49 (IH, dd), 5.36 (IH, dd), 4.65-4.63 (2H, m), 4.50-4.42 (2H, m), 4.23 (2H, t), 4.04-4.00 (IH, m), 3.91-3.50 (6H, m), 3.01 (2H, t)
MW (calcd): 370.4; MW (obsd): 371.2 (M+l)
Figure imgf000068_0001
[00222] To a suspension of compound 1, 117 or 118 (1 eq.) in a mixture of DCM/MeOH (1/1) is added K2C03 (2 eq.) and Pd(PPh3)4 (0.05 eq.). The reaction mixture is degassed before stirring at RT. After completion, water is added to the reaction mixture and the aqueous layer is separated. The pH of the aqueous solution is adjusted to pH 1 with 2M aq. HC1. The precipitate is filtered off, washed with water and dried to afford intermediate 6, 7 or 8. Illustrative synthesis of general method B:
Intermediate 6: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimido[6,l-a]isoquinolin- 4-one
[00223] To a suspension of compound 118 (31.15 g, 84.2 mmol, 1 eq.) in a mixture of DCM/MeOH (1/1,
800 niL) was added K2C03 (23.2 g, 138.2 mmol, 2 eq.) and Pd(PPh3)4 (4.86 g, 4.21 mmol, 0.05 eq.). The reaction mixture was stirred at RT for 2 h. Water (800 mL) was added, and the aqueous layer was separated. The pH of the aqueous solution is adjusted to pH 1 with 2 M aq. HCl. The precipitate was filtered off, washed with water and dried to afford intermediate 6.
(¾ DMSO-i½) δ (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45 (1H, s), 4.25-4.23 (2H, m), 3.99 (2H, t), 3.87-3.75 (3H, m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.30 (1H, m), 2.91 (2H, t)
MW (calcd): 330.4; MW (obsd): 331.3 (M+l)
Intermediate 7: 2-((R)-l-[l,4]dioxan-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimido[6,l-a]isoquinolin- 4-one
[00224] Intermediate 7 was prepared using general method B starting from compound 117.
(¾ DMSO-i½) δ (ppm): 7.83 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.44 (1H, s), 4.27-4.20 (2H, m), 3.98 (2H, t), 3.87-3.74 (3H, m), 3.68-3.57 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t)
Intermediate 8: 2-([l,4]dioxan-2-ylmethoxy)-9-hydroxy-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
[00225] Intermediate 8 was prepared using general method B starting from compound 1.
(¾ DMSO-i½) δ (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45 (1H, s), 4.27-4.20 (2H, m); 3.99 (2H, t), 3.88-3.73 (3H, m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t)
MW (calcd): 330.4; MW (obsd): 331.0 (M+l)
General method C:
[00226] A solution of intermediate 6, 7 or 8 (1 eq.), N-phenyl-bis(trifluoromethanesulfonimide) (1.2 eq.) and Et3N (1.3 eq.) in DCM under nitrogen is stirred at RT until completion. The reaction mixture is concentrated and the crude is purified by crystallization from z'PrOH to afford intermediate 9, 10 or 11.
Illustrative synthesis of general method C:
Intermediate 9: trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,l-a]isoquinolin-9-yl ester
[00227] A solution of intermediate 6, (24 g, 72.7 mmol, 1 eq.), N-phenyl-bis(trifluoromethanesulfonimide) (31.15 g, 87.2 mmol, 1.2 eq.) and Et3N (13.2 mL, 94.4 mmol, 1.3 eq.) in DCM (700 mL) under a nitrogen atmosphere is stirred at RT overnight. The reaction mixture is concentrated. The crude is taken in z'PrOH (75 mL) heated under reflux and cool to RT. After two days at RT, the solid is filtered off and dried to afford intermediate 9.
(¾ CDC13) δ (ppm): 7.83 (1H, d), 7.35 (1H, dd), 7.29 (1H, d), 6.41 (1H, s), 4.51 -4.42 (2H, m), 4.28 (2H, t), 4.06-4.01 (lH, m), 3.89-3.69 (5H, m), 3.52 (lH, m), 3.11 (2H, t) Intermediate 10: trifluoro-methanesulfonic acid 2-((R)-l-[l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro- 4H-pyrimido[6,l-a]isoquinolin-9-yl ester
[00228] Intermediate 10 was prepared using general method C starting from intermediate 7.
[00229] (¾ CDC13) δ (ppm): 7.83 (1H, d), 7.34 (1H, dd), 7.29 (1H, d), 6.41 (1H, s), 4.51 -4.41 (2H, m), 4.28 (2H, t), 4.05-4.00 (1H, m), 3.91-3.66 (5H, m), 3.52 (1H, t), 3.11 (2H, t)
Intermediate 11: trifluoro-methanesulfonic acid 2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H- pyrimido[6,l-a]isoquinolin-9-yl ester
[00230] Intermediate 11 was prepared using general method C starting from intermediate 8.
(¾ DMSO-i½) δ (ppm): 8.21 (1H, d), 7.65 (1H, d), 7.54 (1H, dd), 6.75 (1H, s), 4.28-4.26 (2H, m), 4.04 (2H, t), 3.90-3.84 (1H, m), 3.81 -3.75 (2H, m), 3.68-3.58 (2H, m), 3.53-3.47 (1H, m), 3.41 -3.36 (1H, m), 3.10 (t, 2H)
MW (calcd): 462.4; MW (obsd): 463.3 (M+l)
Figure imgf000070_0001
Intermediate 13: 9-amino-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4- one hydrochloride
Step 1: 9-(Benzhydrylidene-amino)-2-((S)-l -fl ,4J dioxan-2-ylmethoxy)-6, 7-dihydro-pyrimido[6,l - aJisoquinolin-4-one (Intermediate 12)
[00231] A solution of intermediate 9 (1 g, 2.16 mmol, 1 eq.), Pd(OAc)2 (24 mg, 0.11 mmol 0.05 eq.), Cs2C03 (2.11 g, 6.48 mmol, 3 eq.) ΒΓΝΑΡ (134 mg, 0.21 mmol, 0.1 eq.) and benzophenonimine (587 mg, 3.24 mmol, 1.5 eq.) in toluene (20 mL) was heated at 150°C in a microwave for 45 min. The solvent was evaporated to dryness and the crude mixture was taken in water and extracted with EtOAc. The organic layer was dried over MgS04 and concentrated under vacuum. 9-(Benzhydrylidene-amino)-2-((S)-l -[l,4]dioxan-2- ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one intermediate 12 was obtained after purification by flash chromatography on silica gel and immediately used in next step.
Step 2: 9-amino-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4-one hydrochloride (Intermediate 13) [00232] To a solution of intermediate 12 in a minimum of DCM/ Et20 was added HC1 2N in Et20 (4 mL). The precipitate was filtered off and dried to afford intermediate 13.
(¾ DMSO-i½) δ (ppm): 7.82 (1H, d), 7.45 (3H, br), 6.68 (1H, d), 6.67 (1H, s), 6.51 (1H, s), 4.32 (2H, d), 3.99 (2H, t), 3.90-3.84 (1H, m), 3.82-3.35 (6H, m), 2.88 (2H, t)
MW (calcd): 329.4; MW (obsd): 330.2 (M+l)
General method D:
/OH + Br^ , BF,K ^ , ,CL , BF3K
[00233] The corresponding alcohol (2 eq.) is added to a solution of NaH (2 eq., 60% in mineral oil) in THF at 0 °C. The reaction is warmed to RT for 30 min then cooled again at 0 °C. Bromo methyltrifluoroborate (1 eq.) is added to the reaction in one portion and the mixture is stirred at RT from few hours to 3 days (monitoring by 19F-NMR). The reaction is quenched with a solution of KHF2 (1.5 M, 3 eq.) and the mixture is evaporated to dryness. The residue is suspended in acetone, the inorganics are filtered off and the filtrate is evaporated to dryness. The residue is suspended in a minimum amount of acetone, Et20 is added and the product is obtained by filtration.
Illustrative synthesis of general method D:
Intermediate 14: tet -2H-pyran-4-ol-methyl trifluoroborate
Figure imgf000071_0001
Intermediate 14
[00234] Tetrahydro-pyran-4-ol (152 mg, 1.49 mmol, 2 eq.) was added to a solution of NaH (60 mg, 1.49 mmol, 2 eq., 60% in mineral oil) in THF (4 mL) at 0 °C. The reaction was warmed to RT for 30 min then cooled again at 0 °C. Bromo methyltrifluoroborate (150 mg, 0.75 mmol, 1 eq.) was added to the reaction in one portion and the mixture was stirred at RT for 1 day (monitoring by 19F-NMR). The reaction was quenched with a solution of KHF2 (1.5 mL, 1.5 M, 3 eq.) and the mixture was evaporated to dryness. The residue was suspended in acetone, the inorganics were filtered off and the filtrate was evaporated to dryness. The residue was suspended in a minimum amount of acetone (1.5 mL), and Et20 (6 mL) was added. Intermediate 14 was obtained by filtration.
(¾ DMSO- ) δ ppm 3.78 (2 H, d), 3.31 - 3.21 (2 H, m), 3.18 - 3.08 (1 H, m), 2.50 - 2.45 (2 H, m), 1.86 - 1.74 (2 H, m), 1.34 - 1.19 (2 H, m) Intermediate 15: potassium 3-oxy-oxetanemethyltrifluoroborate
Figure imgf000072_0001
Intermediate 15
[00235] Intermediate 15 was prepared via general method D with oxetan-3-ol (the trifluoroborate reagent was recovered with the inorganics rather than the filtrate).
(¾ DMSO- ) δ ppm 4.56 (2 H, s), 4.32 (3 H, d), 2.40 (2 H, d)
Intermediate 16: pota ium (3-methyl-3-methyloxy-oxetane-methyltrifluoroborate
Figure imgf000072_0002
Intermediate 16
[00236] Intermediate 16 was prepared via general method D with (3-methyloxetan-3-yl) methanol (the trifluoroborate reagent was recovered with the inorganics rather than the filtrate).
(¾ DMSO- ) δ ppm 4.34 (2 H, d), 4.14 (2 H, d), 3.26 (2 H, s), 2.59 - 2.52 (2 H, m), 1.19 (3 H, s)
Intermediate 17 : pota ium 2,2-dimethyl-propyloxy-methyltrifluoroborate
Figure imgf000072_0003
Intermediate 17
[00237] Intermediate 17 was prepared via general method D with 2,2-dimethyl-propan-l-ol.
(¾ DMSO- ) δ ppm 2.88 (2 H, s), 2.51 - 2.45 (2 H, m), 0.83 (9 H, s)
Intermediate 18: potassium cyclopro lmethox -meth ltrifluoroborate
Figure imgf000072_0004
Intermediate 18
[00238] Intermediate 18 was prepared via general method D wOith cyclopropyl-methanol.
(¾ DMSO- ) δ ppm 3.00 (2 H, d), 2.46 (2 H, d), 1.00 - 0.82 (1 H, m), 0.46 - 0.31 (2 H, m), 0.13 - 0.00 (2
H, m) Intermediate 19: cyclo entylmethoxy-meth ltrifluoroborate
Figure imgf000073_0001
Intermediate 19
[00239] Intermediate 19 was prepared via general method D with cyclopentyl-methanol.
(¾ DMSO-d6) 6 ppm 3.04 (2 H, d), 2.46 (2 H, d), 2.08 - 1.94 (1 H, m), 1.47 (6 H, br. s.), 1.07 - 1.22 (2 H, m)
Intermediate 20: potassium 2-cyclopropyl-ethyl-trifluoroborat
Figure imgf000073_0002
Intermediate 20
[00240] A 2-neck round bottom flask equipped with a reflux condenser and an addition funnel was charged with Mg (193 mg, 8.05 mmol, 3 eq.) and Et20 (1 mL) under N2. One drop of neat (2-bromo-ethyl)- cyclopropane was added followed by two drops of dibromoethane. Once the 1 st bubbles appeared, (2-bromo- ethyl)-cyclopropane (400 mg, 2.68 mmol, 1 eq.) in Et20 (5 mL) was added dropwise. Upon completion of the addition, the resulting suspension was stirred at RT for 1 h. In a separate flask, purged with N2, a solution made of B(OMe)3 (0.45 mL, 4.02 mmol, 1.5 eq.) in THF (6 mL) was cooled to -78 °C. To this solution, the 2- cyclopropyl-ethyl magnesium bromide suspension was added dropwise via a double ended needle. The mixture was allowed to stir for 1 h at -78 °C and then was warmed to RT for 1 h. After cooling the mixture to 0 °C, a saturated aqueous solution of KHF2 (2.5 mL, 4.5 M, 4.1 eq.) was added dropwise and the reaction mixture was allowed to warm to RT. After 30 min, the solution was concentrated in-vacuo. The dried solids were triturated with hot acetone and filtered to remove inorganic salts. The resulting filtrate was concentrated and the solid residue was triturated with Et20. Potassium 2-cyclopropyl-ethyl-trifluoroborate was filtered and dried in-vacuo.
(¾ DMSO- ) δ ppm 1.07 - 0.92 (2 H, m), 0.66 - 0.53 (1 H, m), 0.27 - 0.21 (2 H, m), 0.067 - -0.07 (2 H, m), -0.117 - -0.17 (2 H, m)
General method E:
Figure imgf000074_0001
Intermediate 9, 10, 11
[00241] A vial is charged with intermediate 9, 10 or 11 (1 eq.), the appropriate boronic acid, boronic ester or potassium trifluoroborate (4.4 eq.), Cs2C03 (2.6 eq.), (DPPF)PdCl2.DCM (0.05 eq.), in 1 ,4-dioxane/H20 (10/1 , v/v), and the mixture is degassed with N2. The vial is sealed and heated at 80 °C. When the reaction is complete, the vial is cooled to RT and the reaction is either worked up or volatiles are evaporated under vacuum. The product is then obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative HPLC-MS. Illustrative synthesis of general method E:
Compound 2: 2-([l 4]dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
Figure imgf000074_0002
Intermediate 11 Compound 2
[00242] A vial was charged with intermediate 11 (84 mg, 0.074 mmol, 1 eq.), pyridine-3 -boronic acid (40 mg, 0.327 mmol, 4.4 eq.), Cs2C03 (62 mg, 0.190 mmol, 2.6 eq.), (DPPF)PdCl2.DCM (3.3 mg, 0.004 mmol, 0.05 eq.), in 1,4-dioxane (1 mL) and H20 (0.1 mL), and the mixture was degassed with N2. The vial was sealed and heated at 80 °C. After lh, the vial was cooled to RT and volatiles were evaporated under vacuum. The residue was then purified by flash chromatography on silica gel, eluting with 7.5% MeOH/DCM to afford compound 2.
(¾ CDC13) δ ppm 8.89 (1 H, s), 8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1 H, d), 7.61 (1 H, d), 7.53 (1 H, s), 7.43 (1 H, dd), 6.43 (1 H, s), 4.51 - 4.37 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, m), 3.92 - 3.60 (5 H, m), 3.49 (1 H, m), 3.10 (2 H, t) General method F:
Figure imgf000075_0001
Intermediate 6, 7, 8
[00243] A solution of intermediate 6, 7, or 8 (1 eq.), the appropriate alkylating agent (1.5 eq.), K2C03 (2 eq.), KI (1 eq.) in MEK is heated at 80 °C. When the reaction is complete, the volatiles are evaporated to dryness and the residue is purified by flash chromatography on silica gel to give the desired product.
Illustrative synthesis of general method F:
Compound 8: 2-([l,4]dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one
Figure imgf000075_0002
Intermediate 8 Compound 8
[00244] A solution of intermediate 8 (40 mg, 0.12 mmol, 1 eq.), 2-chloromethyloxazole (21 mg, 0.18 mmol, 1.5 eq.), K2C03 (33 mg, 0.24 mmol, 2 eq.), KI (20 mg, 0.12 mmol, 1 eq.) in MEK (2 mL) was heated at 80 °C for 16 h. The reaction was evaporated to dryness and the residue was purified by flash chromatography on silica gel, eluting with 4% MeOH/DCM to give compound 8.
(¾ CDC13) δ ppm 7.72 (1 H, d), 7.68 - 7.60 (1 H, m), 7.18 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.23 (2 H, s), 4.49 - 4.33 (2 H, m), 4.19 (2 H, t), 4.02 - 3.94 (1 H, m), 3.89 - 3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t)
MW (calcd): 411.4; MW (obsd): 412.4 (M+l) General method G:
Figure imgf000076_0001
Intermediate 9, 10, 11
[00245] Intermediate 9, 10, 11 (1 eq.) is dissolved in DMF, the appropriate alkyne (3 eq.) is added followed by TEA (3.5 eq.), and the mixture is degassed. Pd(PPh3)3Cl2 (0.05 eq.) is added with Cul (0.2 eq.) and the reaction mixture is heated at 80 °C. When the reaction is gone to completion, it is cooled to RT and either worked up or volatiles are evaporated to dryness. The product is then obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative HPLC-MS.
Illustrative synthesis of general method G:
Compound 16: 2-([l,4]dioxan-2-ylmethoxy)-9-(l-methyl-lH-imidazol-2-ylethynyl)-6,7-dihydro- pyrimido[6,l-a]iso uinoiin-4-one
Figure imgf000076_0002
[00246] Intermediate 11 (1.4 g, 3.03 mmol, 1 eq.) was dissolved in DMF (20 niL), 5 -ethynyl-1 -methyl- 1H- imidazole (0.92 mL, 9.09 mmol, 3 eq.) was added followed by TEA (1.48 mL, 10.61 mmol, 3.5 eq.). The mixture was degassed and Pd(PPh3)3Cl2 (106 mg, 0.15 mmol, 0.05 eq.) was added with Cul (115 mg, 0.61 mmol, 0.2 eq.). The reaction mixture was heated at 80 °C for 16 h. The reaction was cooled to RT and quenched with brine, the mixture was then extracted with EtOAc. The organic layer was dried over MgS04 and the solvent was evaporated under vacuum. The crude product was then purified by flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM to give compound 16. (¾ CDCI3) δ ppm 7.73 (1 H, d), 7.57 - 7.50 (2 H, m), 7.48 - 7.45 (1 H, m), 7.42 (1 H, d), 6.42 (1 H, s), 4.53 - 4.39 (2 H, m), 4.28 - 4.23 (2 H, m), 4.07 - 3.97 (1 H, m), 3.94 - 3.64 (8 H, m), 3.52 (1 H, dd), 3.06 (2 H, t)
MW (calcd): 418.4; MW (obsd): 419.4 (M+l)
General method H:
Figure imgf000077_0001
[00247] tBuOK (3 eq.) is added to a solution of the corresponding acetylenic alcohol (1 eq.) in THF, Mel (10 eq.) is then added and the reaction is stirred at RT. When the reaction has gone to completion, the reaction mixture is filtered and the filtrate is evaporated to dryness. Product is obtained after purification by preparative TLC.
Illustrative synthesis of general method H:
Compound 110: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-l-ynyl)-6,7-dihydro- pyrimido[6,l-a]iso uinolin-4-one
Figure imgf000077_0002
Compound 91 Compound 110
[00248] tBuOK (5.19 mg, 0.046 mmol, 0.95 eq.) was added to a solution of compound 90 (20 mg, 0.049 mmol, 1 eq.) in THF (2 mL), Mel (0.030 mL, 0.487 mmol, 10 eq.) was then added and the reaction was stirred at RT for 16 h. Some more tBuOK (11 mg, 0.097 mmol, 2 eq.) was added and the reaction was stirred for an extra day. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by preparative TLC eluting with 2% MeOH/DCM to yield compound 110. (¾ CDCI3) δ ppm 7.70 - 7.60 (1 H, d), 7.50 - 7.42 (1 H, d), 7.39 (1 H, s), 6.37 (1 H, s), 4.50 - 4.35 (2 H, m), 4.25 - 4.15 (2 H, m), 4.05 - 3.95 (2 H, m), 3.92 - 3.60 (5 H, m), 3.56 - 3.45 (4 H, m), 3.05 - 3.95 (2 H, m), 2.15 - 1.95 (1 H, m), 1.15 - 1 (6 H, t)
MW (calcd): 424.5; MW (obsd): 425.2 (M+l)
General method I:
Figure imgf000078_0001
[00249] A vial is charged with Pd/C (10% w/w) and a solution of the appropriate alk ne (1 eq.) in MeOH is added. The system is purged with N2 before being filled with H2 then the reaction is stirred at RT until completion. The reaction is filtered through Celite and the filtrate is evaporated to dryness. Clean product is obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative HPLC-MS.
Illustrative synthesis of general method I:
Compound 116: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro- pyrimido[6,l-a]iso uinolin-4-one
Figure imgf000078_0002
Compound 108 Compound 116
[00250] A vial was charged with Pd/C (9 mg, 10% w/w) and a solution of compound 108 (87 mg 0.20 mmol, 1 eq.) in MeOH (10 mL) was added. The system was purged with N2 before being filled with H2 then the reaction was stirred for 16 h at RT. The reaction was filtered through Celite and the filtrate was evaporated to dryness. The crude product was purified by preparative HPLC-MS to give compound 116. (¾ CDCI3) δ ppm 8.60 - 8.48 (2 H, m), 7.73 (1 H, d), 7.61 (1 H, d), 7.30 (1 H, dd), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.77 (1 H, dd), 4.47 - 4.33 (2 H, m), 4.18 (2 H, t), 3.97 (1 H, m), 3.90 - 3.60 (5 H, m), 3.48 (1 H, t), 2.96 (2 H, t), 2.90 - 2.70 (2 H, m), 2.15 (1 H, m), 2.10 - 1.98 (1 H, m), 1.38 (1 H, t)
MW (calcd): 449.5; MW (obsd): 450.1 (M+l)
General method J:
Figure imgf000079_0001
Intermediate 13
[00251] Intermediate 13 (1 eq.) is dissolved in DMF, the appropriate aldehyde (4 eq.) is added followed by KOH (1 eq.). The reaction is stirred for 15 min at RT before STAB (10 eq.) is added, the mixture is then stirred at RT until completion of the reaction. The mixture is then quenched with brine, extracted with EtOAc, the organic layer is dried over MgS04 and evaporated to dryness. Purification by preparative HPLC- MS affords the corresponding product.
Illustrative synthesis of general method J:
Compound 126: 9-(2,2-dimethyl-butylamino)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l-a]iso uinolin-4-one
Figure imgf000079_0002
Intermediate 13 Compound 126
[00252] Intermediate 13 (50 mg, 0.14 mmol, 1 eq.) was dissolved in DMF (2 niL), 2,2-dimethylbutanal (56 mg, 0.56 mmol, 4 eq.) was added followed by KOH (8 mg, 0.14 mmol, 1 eq.). The reaction was stirred for 15 min at RT before STAB (297 mg, 1.40 mmol, 10 eq.) was added, the mixture was then stirred for 2 days at RT. The reaction was quenched with brine and the mixture was extracted with EtOAc. The organic layer was dried over MgS04 and evaporated to dryness. The crude product was purified by preparative HPLC-MS to give compound 126.
(¾ CDCI3) δ ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48 (1 H, s), 6.21 (1 H, s), 4.47 - 4.34 (2 H, m), 4.21 - 4.14 (2 H, m), 4.01 - 3.91 (1 H, m), 3.89 - 3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, s), 2.90 (2 H, t), 1.36 (2 H, dd), 0.96 (6 H, s), 0.87 (3 H, t)
MW (calcd): 413.5; MW (obsd): 414.4 (M+l)
Figure imgf000080_0001
I ntermed iate 9 I ntermed iate 15
Step 1: 2-((S)-l-ll,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-l-ynyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 15)
[00253] Intermediate 15 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-l-ynyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one was synthesised via general method E with intermediate 9 and prop-2-yn- l -ol.
Step 2:
[00254] Intermediate 15 (1 eq.) is dissolved in a mixture of THF/DMF (1/1), NaH (1.1 eq., 60% in mineral oil) is added followed by the appropriate alkylating agent (1 eq.) and the reaction is stirred at 70 °C. When the reaction has gone to completion, the mixture is worked up with brine and EtOAc, the organic layer is dried over MgS04 and evaporated to dryness. Purification by preparative HPLC-MS provides the corresponding product.
Illustrative synthesis of general method K:
Compound 133: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-l-ynyl]-6,7-dihydro- pyrimido[6,l-a]iso
Figure imgf000081_0001
Intermediate 15 Compound 133
[00255] Intermediate 15 (92 mg, 0.25 mmol, 1 eq.) was dissolved in a mixture of THF/DMF (6 mL, 1/1), NaH (11 mg, 0.275 mmol, 1.1 eq., 60% in mineral oil) was added followed by l-bromo-2-methoxy-ethane (35 mg, 0.25 mmol, 1 eq.) and the reaction was stirred at RT for 16 h, then at 70 °C for 1 day. The mixture was worked up with brine and EtOAc, the organic layer was dried over MgS04 and evaporated to dryness. The crude product was purified by preparative HPLC-MS to provide compound 133.
(¾ CDC13) δ ppm 7.64 (1 H, s), 7.48 - 7.40 (1 H, m), 7.40 - 7.35 (1 H, m), 6.40 - 6.34 (1 H, m), 4.47 (4 H, s), 4.28 - 4.15 (1 H, m), 3.93 - 3.56 (10 H, m), 3.43 (5 H, s), 3.06 - 2.95 (2 H, m)
MW (calcd): 426.5; MW (obsd): 427.4 (M+l)
General method L:
Figure imgf000081_0002
Intermediate 6
[00256] To a solution of tBuOK (2.2 eq.) in DMF is added dropwise a solution of intermediate 6 (1 eq.) in DMF at 0 °C and the mixture is stirred for 1 h. A solution of the appropriate alkylating agent (10 eq.) in DMF is added dropwise to the previous solution at 0 °C, then the reaction is stirred at 80 °C. When the reaction has gone to completion, the mixture is cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers are dried over Na2S04 and evaporated to dryness. The product is isolated by purification by preparative TLC. Illustrative synthesis of general method L:
Compound 158: 9-(2,2-dimethyl-propoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one
Figure imgf000082_0001
[00257] To a solution of tBuOK (19 mg, 0.166 mmol, 1.1 eq.) in DMF (2 mL) was added dropwise a solution of intermediate 6 (50 mg, 0.151 mmol, 1 eq.) in DMF (2 mL) at 0 °C and the mixture was stirred for 1 h. A solution of 1 -iodo-2,2-dimethyl-propane (0.021 mL, 0.159 mmol, 1.05 eq.) in DMF (2 mL) was added dropwise to the previous solution at 0 °C, then the reaction was stirred at 80 °C for 1 day. Extra reagents were added, 1 -iodo-2,2-dimethyl-propane (0.4 mL, 10 eq.) and tBuOK (19 mg, 0.166 mmol, 1.1 eq.) and the reaction was stirred at 80 °C for one more day. The mixture was cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and evaporated to dryness. Compound 158 was obtained by purification by preparative TLC [DCM/MeOH, 98/2]. (¾ CDC13) δ ppm 7.70 - 7.56 (1 H, d), 6.95 - 6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1 H, s), 4.50 - 4.35 (2 H, m), 4.25 - 4.10 (2 H, m), 4.05 - 3.92 (1 H, m), 3.10 - 3.57 (8 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H, m), 1.05 (9H, s).
MW (calcd): 400.5; MW (obsd): 401.2 (M+l)
Compounds of the invention
[00258] The compounds according to the invention can be produced as described below.
Compound 1: 9-Allyloxy-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00259] Synthesis fully described above.
Compound 2: 2-([l,4]dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00260] Synthesis fully described above.
Compound 3: 2-([l,4]dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00261] This compound is prepared via general method E using intermediate 11 and pyridine-4-boronic acid. Compound 4: 2-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- benzonitrile.
[00262] This compound is prepared via general method E using intermediate 11 and 2- cyanophenylboronic acid.
Compound 5: 3-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- benzonitrile.
[00263] This compound is prepared via general method E using intermediate 11 and 3- cyanophenylboronic acid.
Compound 6: 4-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- benzonitrile.
[00264] This compound is prepared via general method E using intermediate 11 and 4- cyanophenylboronic acid.
Compound 7: [2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yloxy]- acetonitrile.
[00265] This compound is prepared via general method F using intermediate 8 and bromo-acetonitrile, KI was not used in the experiment.
Compound 8: 2-([l ,4]dioxan-2-ylmethoxy)-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00266] Synthesis fully described above. Compound 9: 2-([l ,4]dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00267] This compound is prepared via general method F using intermediate 8 and pyridin-2-yl-methanol hydrochloride. Compound 10: 9-(3,5-dichloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00268] This compound is prepared via general method E using intermediate 11 and 3,5- dichlorophenylboronic acid. Compound 11: 9-benzofuran-2-yl-2-([l,4]dioxan-2-ylme&
one.
[00269] This compound is prepared via general method E using intermediate 11 and l -benzofuran-2- ylboronic acid.
Compound 12: 2-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- indole-l-carboxylic acid tert-butyl ester.
[00270] This compound is prepared via general method E using intermediate 11 and l-(tert- butoxycarbonyl)- 1 H-indol-2-ylboronic acid.
Compound 13: 2-([l,4]dioxan-2-ylmethoxy)-9-(lH-indol-2-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
Figure imgf000084_0001
Compound 12 Compound 13
[00271] Compound 12 (57 mg, 0.11 mmol) was dissolved in a mixture of DCM/TFA (1/1, 2 mL) and the reaction was stirred at RT for 6h. The mixture was evaporated to dryness to recover compound 13 as a TFA salt.
(lH DMSO-Λ) δ ppm 8.11 (1 H, d), 7.95 - 7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H, d), 7.15 (1 H, t), 7.10 (1 H, d), 6.71 (1 H, s), 4.31 - 4.25 (2 H, m), 4.09 (2 H, t), 3.92 - 3.84 (1 H, m), 3.79 (2 H, td), 3.71 - 3.57 (2 H, m), 3.55 - 3.46 (1 H, m), 3.40 (1 H, dd), 3.08 (2 H, t)
MW (calcd): 429.5 MW (obsd): 430.5 (M+l)
Compound 14: 2-([l,4]dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00272] This compound is prepared via general method E using intermediate 11 and 2-methoxy-5- pyridineboronic acid. Compound 15: 2-([l,4]dioxan-2-ylmethoxy)-9-(6-trifluo
a]isoquinolin-4-one.
[00273] This compound is prepared via general method E using intermediate 11 and 2-(trifluoromethyl) pyridine-5-boronic acid.
Compound 16: 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00274] Synthesis fully described above.
Compound 17 : 9-(5-tert-butyl-[l ,2,4]oxadiazol-3-ylmethoxy)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00275] This compound is prepared via general method F using intermediate 8 and 5-(tert-butyl)-3- (chloromethyl)- 1 ,2,4-oxadiazole.
Compound 18: 5-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- pyridine-2-carboxylic acid methylamide.
[00276] This compound is prepared via general method E using intermediate 11 and 2-(N- methylaminocarbonyl) pyridine-5-boronic acid pinacol ester.
Compound 19: 2-([l ,4]dioxan-2-ylmethoxy)-9-pent-l-ynyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00277] This compound is prepared via general method G using intermediate 11 and pent-l-yne.
Compound 20: 2-([l,4]dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000085_0001
Step 1 : 2-([l ,4] dioxan-2-ylmethoxy)-9-((E)-2-pyridin-2-yl-vinyl)-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4- one (intermediate 22).
[00278] A round bottom flask was charged with intermediate 11 (50 mg, 0.11 mmol, 1 eq.), 2-vinyl- pyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdCl2.DCM (4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03 mL, 0.22 mmol, 2 eq.) under N2 then the flask was degassed. DMF (2 mL) was then added and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness, the residue was then purified by flash chromatography on silica gel, eluting from 0 to 3% MeOH/DCM affording intermediate 22 2-([l ,4]dioxan-2-ylmethoxy)-9-((E)-2-pyridin-2-yl-vinyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
(¾ CDC13) δ ppm 8.66 - 8.59 (1 H, m), 7.74 - 7.53 (4 H, m), 7.46 (1 H, s), 7.39 (1 H, d), 7.30 - 7.15 (2 H, m), 6.37 (1 H, s), 4.48 - 4.34 (2 H, m), 4.21 (2 H, t), 4.02 - 3.93 (1 H, m), 3.89 - 3.59 (5 H, m), 3.53 - 3.42 (1 H, m), 3.03 (2 H, m)
MW (calcd): 417.5; MW (obsd): 418.4 (M+l) Step 2: 2-([l ,4Jdioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6, 7-dihydro-pyrimido[6, 1 -a] ' isoquinolin-4-one (Compound 20).
[00279] A round bottom flask was charged with intermediate 22 (45 mg, 0.11 mmol, 1 eq.), Pt02 (6 mg, 0.025 mmol, 0.23 eq.) and THF (2 mL) was added. The system was purged with N2 before being filled with H2 then the reaction was stirred for 16 h at RT. The reaction mixture was filtered through a SPE guanidine cartridge and the solvent was evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 1 to 10% MeOH/DCM to give compound 20.
(¾ CDCI3) δ ppm 8.58 (1 H, dd), 7.66 - 7.56 (2 H, m), 7.22 (1 H, dd), 7.19 - 7.09 (3 H, m), 6.36 (1 H, s), 4.50 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.95 (1 H, m), 3.91 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4 H, s), 2.98 (2 H, t)
MW (calcd): 419.5; MW (obsd): 420.5 (M+l)
Compound 21 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000086_0001
Intermediate 11 Intermediate 23 Compound 21
Step 1 : 2-([l ,4] dioxan-2-ylmethoxy)-9-((E)-2-pyrazin-2-yl-vinyl)-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4- one (intermediate 23).
[00280] A round bottom flask was charged with intermediate 11 (50 mg, 0.11 mmol, 1 eq.), 2-vinyl- pyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdCl2.DCM (4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03 mL, 0.22 mmol, 2 eq.) under N2 then the flask was degassed. DMF (2 mL) was then added and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness, the residue was then purified by flash chromatography on silica gel, eluting from 0 to 4% MeOH/DCM affording intermediate 23 2-([l ,4]dioxan-2-ylmethoxy)-9-((E)-2-pyrazin-2-yl-vinyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm^
(¾ CDC13) δ ppm 8.69 (1 H, m), 8.63 - 8.58 (1 H, m), 8.49 (1 H, m), 7.84 - 7.71 (2 H, m), 7.63 (1 H, d), 7.53 (1 H, s), 7.31 (1 H, s), 6.42 (1 H, s), 4.52 - 4.39 (2 H, m), 4.30 - 4.22 (2 H, m), 4.02 (1 H, dd), 3.93 - 3.63 (5 H, m), 3.52 (1 H, dd), 3.08 (2 H, m)
MW (calcd): 418.5; MW (obsd): 419.4 (M+l)
Step 2: 2-([lA]dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6 -dihydro-pyrimido
(Compound 21) .
[00281] A round bottom flask was charged with intermediate 23 (38 mg, 0.09 mmol, 1 eq.), Pt02 (5 mg, 0.021 mmol, 0.23 eq.) and THF (2 niL) was added. The system was purged with N2 before being filled with H2 then the reaction was stirred for 16 h at RT. The reaction mixture was filtered through a SPE guanidine cartridge and the solvent was evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 1 to 10% MeOH/DCM to give compound 21.
(¾ CDCI3) δ ppm 8.55 (1 H, dd), 8.44 (2 H, dd), 7.63 (1 H, d), 7.22 (1 H, dd), 7.15 (1 H, s), 6.36 (1 H, s), 4.36 - 4.53 (2 H, m), 4.17 - 4.26 (2 H, m), 3.95 - 4.07 (1 H, m), 3.61 - 3.93 (5 H, m), 3.51 (1 H, dd), 3.17 (4 H, s), 2.99 (2 H, t)
MW (calcd): 420.5; MW (obsd): 421.5 (M+l)
Compound 22: 2-([l,4]dioxan-2-ylmethoxy)-9-(lH-indol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
[00282] This compound is prepared via general method E intermediate 11 and using 5-indolylboronic acid. Compound 23 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l -ajisoquinolin- 4 -one.
[00283] This compound is prepared via general method E using intermediate 11 and 2- methoxyphenylboronic acid. Compound 24: 2-([l,4]dioxan-2-ylmethoxy)-9-(5-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00284] This compound is prepared via general method E using intermediate 11 and 3-methoxy-5- pyridineboronic acid pinacol ester. Compound 25: 2-([l,4]dioxan-2-ylmethoxy)-9-(lH-indazol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoqum one.
[00285] This compound is prepared via general method E using intermediate 11 and lH-indazole-5- boronic acid.
Compound 26: 2-([l ,4]dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l -ajisoquinolin- 4 -one.
[00286] This compound is prepared via general method E using intermediate 11 and 4- methoxyphenylboronic acid.
Compound 27: 3-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- benzamide.
[00287] This compound is prepared via general method E using intermediate 11 and 3- aminocarbonyphenylboronic acid.
Compound 28: 5-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-2- fluoro-benzamide.
[00288] This compound is prepared via general method E using intermediate 11 and 3-(aminocarbonyl)-4- fluorobenzeneboronic acid.
Compound 29: N-{3-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- phenyl} -acetamide.
[00289] This compound is prepared via general method E intermediate 11 and using 3- acetamidophenylboronic acid.
Compound 30: 9-cyclopropylethynyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin- 4 -one.
[00290] This compound is prepared via general method G intermediate 11 and using ethynyl- cyclopropane.
Compound 31 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(l -hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00291] This compound is prepared via general method G intermediate 11 and using 1 -ethynyl- cyclopentanol. Compound 32: 2-([l,4]dioxan-2-ylmethoxy)-9-pyrimi
one.
[00292] This compound is prepared via general method E intermediate 11 and using 5-pyrimidinylboronic acid.
Compound 33: 9-cyclohex-l -enyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
[00293] This compound is prepared via general method E using intermediate 11 and cyclohexene-1 - boronic acid pinacol ester.
Compound 34: 2-([l,4]dioxan-2-ylmethoxy)-9-(l-methyl-lH-indol-5-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00294] This compound is prepared via general method E using intermediate 11 and 1 -methylindole-5 - boronic acid pinacol ester.
Compound 35: 2-([l ,4]dioxan-2-ylmethoxy)-9-(6-methyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00295] This compound is prepared via general method E using intermediate 11 and 6-methylpyridin-3- ylboronic acid.
Compound 36: 2-([l,4]dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin- 4 -one.
[00296] This compound is prepared via general method G using intermediate 11 and 2-ethynyl-pyridine. Compound 37: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-methoxy-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00297] This compound is prepared via general method G using intermediate 11 and 3-methoxy-propyne.
Compound 38: 5-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- pent-4-ynenitrile.
[00298] This compound is prepared via general method G using intermediate 11 and pent-4-ynenitrile.
Compound 39: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00299] This compound is prepared via general method G using intermediate 11 and prop-2-yn-l-ol. Compound 40: 2-([l,4]dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00300] This compound is prepared via general method G using intermediate 11 and l -ethynyl-4- methoxy-b enzene.
Compound 41 : 2-([l,4]dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin 4 -one.
[00301] This compound is prepared via general method G using intermediate 11 and 3-ethynyl-pyridine
Compound 42: 4-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l -a]isoquinolin-9-yl]-N- methyl-b enzamide.
[00302] This compound is prepared via general method E using intermediate 11 and 4-(N- methylaminocarbonyl)phenylboronic acid.
Compound 43 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l -ajisoquinolin- 4 -one.
[00303] This compound is prepared via general method E using intermediate 11 and 3- methoxyphenylboronic acid.
Compound 44: 9-(2-chloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
[00304] This compound is prepared via general method E using intermediate 11 and 2- chlorophenylboronic acid.
Compound 45: 2-([l,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00305] This compound is prepared via general method G using intermediate 11 and but-3-yn-l -ol.
Compound 46: 9-(l,5-dimethyl-lH-pyrazol-3-ylmethoxy)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00306] This compound is prepared via general method F using intermediate 8 and 3-chloromethyl-l ,5- dimethyl- 1 H-pyrazole. Compound 47 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(l -methyl-lH-pyrazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00307] This compound is prepared via general method F using intermediate 8 and 3-chloromethyl-l - methyl- 1 H-p yrazole.
Compound 48: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-methyl-[l,2,4]oxadiazol-5-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00308] This compound is prepared via general method F using intermediate 8 and 5-chloromethyl-3- methyl-[ 1 ,2,4]oxadiazole.
Compound 49: 2-([l,4]dioxan-2-ylmethoxy)-9-(4-moφholin-4-yl-phenyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00309] This compound is prepared via general method E using intermediate 11 and 4- moφholinophenylboronic acid, with CsF as base and DMF as solvent.
Compound 50: 3-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-4- fluoro-benzamide.
[00310] This compound is prepared via general method E using intermediate 11 and 5-carbamoyl-2- fluorobenzeneboronic acid, with CsF as base and DMF as solvent.
Compound 51: 3-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-5- fluoro-benzamide.
[00311] This compound is prepared via general method E using intermediate 11 and 3-(aminocarbonyl)-5- fluorobenzeneboronic acid, with CsF as base and DMF as solvent.
Compound 52: 9-(3,3-Dimethyl-but-l-ynyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00312] This compound is prepared via general method G using intermediate 11 and 3,3-dimethyl-but-l - yne.
Compound 53: 2-([l,4]dioxan-2-ylmethoxy)-9^yridin-4-ylethynyl-6,7-dihydro^yrimido[6,l -a]isoquinolin- 4 -one.
[00313] This compound is prepared via general method G using intermediate 11 and 4-ethynyl-pyridine. Compound 54: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00314] This compound is prepared via general method F using intermediate 8 and 5-chloromethyl-3- methyl-isoxazole.
Compound 55: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00315] This compound is prepared via general method G using intermediate 11 and 2-methyl-but-3-yn-2- ol.
Compound 56: 2-([l,4]dioxan-2-ylmethoxy)-9-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00316] This compound is prepared via general method E using intermediate 11 and 2-methoxy-3- pyridinyl boronic acid.
Compound 57: 2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00317] This compound is prepared via general method E using intermediate 11 and potassium
(cyanomethyl) trifluoroborate. Compound 58: 9-(3,6-dihydro-2H-pyran-4-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00318] This compound is prepared via general method E using intermediate 11 and 3,6-dihydro-2H- pyran-4-boronic acid pinacol ester. Compound 59: 5-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- pyridine-2-carbonitrile.
[00319] This compound is prepared via general method E using intermediate 11 and 2-cyanopyridine-5- boronic acid pinacol ester. Compound 60: 2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00320] This compound is prepared via general method E using intermediate 11 and 6- isopropoxypyridine-3-boronicacid pinacol ester. Compound 61: 2-([l,4]dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00321] This compound is prepared via general method E using intermediate 11 and 6-ethoxypyridine-3- boronic acid.
Compound 62: 2-([l,4]dioxan-2-ylmethoxy)-9-(6-moφholin-4-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00322] This compound is prepared via general method E using intermediate 11 and 4-[5-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-2-pyridinyl]moφholine.
Compound 63: 9-(2,3-dimethoxy-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00323] This compound is prepared via general method E using intermediate 11 and 2,3- dimethoxyphenylboronic acid.
Compound 64: 9-(3-chloro-2-methoxy-pyridin-4-yl)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00324] This compound is prepared via general method E using intermediate 11 and 3-chloro-2- methoxypyridine-4-boronic acid.
Compound 65: 2-([l ,4]dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00325] This compound is prepared via general method E using intermediate 11 and 2-methylpyridine-4- boronic acid pinacol ester.
Compound 66: 3-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- isonicotinonitrile .
[00326] This compound is prepared via general method E using intermediate 11 and 4-cyanopyridine-3- boronic acid pinacol ester.
Compound 67: 9-(2,5-dimethoxy-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00327] This compound is prepared via general method E using intermediate 11 and 2,5- dimethoxyphenylboronic acid. Compound 68: 2-([l ,4]dioxan-2-ylmethoxy)-9-(3,4,5,6-tetraliydro-2H-[l ,2']bipyridinyl-5'-yl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00328] This compound is prepared via general method E using intermediate 11 and l-[5-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperidine.
Compound 69: 2-([l,4]dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00329] This compound is prepared via general method E using intermediate 11 and 2-ethoxypyridine-3- boronic acid.
Compound 70: 9-(2,6-dimethoxy-pyridin-3-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00330] This compound is prepared via general method E using intermediate 11 and 2,6-dimethoxy-3- pyridineboronic acid.
Compound 71 : 4-[2-([l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]- nicotinonitrile.
[00331] This compound is prepared via general method E using intermediate 11 and 3-cyanopyridine-4- boronic acid, pinacol ester.
Compound 72: 9-tert-butoxymethyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
[00332] This compound is prepared via general method E using intermediate 11 and potassium tert- butoxymethyltrifluorob orate.
Compound 73: 2-([l,4]dioxan-2-ylmethoxy)-9-(2 -pyrrolidine
a]isoquinolin-4-one.
[00333] This compound is prepared via general method E using intermediate 11 and 2-(pyrrolidin-l -yl)-3- (4,4,5,5 -tetramethyl- 1,3,2 -dioxab orolan-2 -yl)pyridine .
Compound 74: 2-([l ,4]dioxan-2-ylmethoxy)-9-(6-pyrrolidin-l -yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00334] This compound is prepared via general method E using intermediate 11 and 2-(l-pyrrolidinyl)-5- (4,4,5,5 -tetramethyl- 1,3,2 -dioxab orolan-2 -yl)pyridine . Compound 75: 2-([l,4]dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00335] This compound is prepared via general method F using intermediate 8 and 2-chloromethyl-5- phenyl-oxazole.
Compound 76: 9-(5-tert-butyl-oxazol-2-ylmethoxy)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00336] This compound is prepared via general method F using intermediate 8 and 5-tert-butyl-2- chloromethyl-oxazole.
Compound 77 : 9-(5-cyclopropyl-[l ,2,4]oxadiazol-3-ylmethoxy)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00337] This compound is prepared via general method F using intermediate 8 and 3-chloromethyl-5- cyclopropyl- [ 1 ,2,4] oxadiazole.
Compound 78: 2-([l,4]dioxan-2-ylmethoxy)-9-(5-ethyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00338] This compound is prepared via general method F using intermediate 8 and 3-chloromethyl-5- ethyl-[l,2,4]oxadiazole.
Compound 79: 2-([l,4]dioxan-2-ylmethoxy)-9-(5-methyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00339] This compound is prepared via general method F using intermediate 8 and 3-chloromethyl-5- methyl-[ 1 ,2,4]oxadiazole.
Compound 80: 2-([l ,4]dioxan-2-ylmethoxy)-9-(5-isopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00340] This compound is prepared via general method F using intermediate 8 and 3-chloromethyl-5- isopropyl- [ 1 ,2,4] oxadiazole.
Compound 81: 9-cyclopentylethynyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin- 4 -one.
[00341] This compound is prepared via general method G using intermediate 11 and ethynyl- cyclopentane. Compound 82: 9-cyclohexylethynyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoqum 4 -one.
[00342] This compound is prepared via general method G using intermediate 11 and ethynyl-cyclohexane. Compound 83: 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00343] This compound is prepared via general method G using intermediate 11 and 3-methyl-but-l -yne.
Compound 84: 2-([l ,4]dioxan-2-ylmethoxy)-9-hex-l -ynyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00344] This compound is prepared via general method G using intermediate 11 and hex-l-yne.
Compound 85: 9-[3-(benzyl-methyl-amino)-prop-l-ynyl]-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00345] This compound is prepared via general method G using intermediate 11 and benzyl-methyl-prop - 2-ynyl-amine.
Compound 86: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00346] This compound is prepared via general method G using intermediate 11 and 5 -methyl-hex- l-yn-3- ol, with iPr2NH as base and THF as solvent.
Compound 87 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00347] This compound is prepared via general method G using intermediate 11 and but-3-yn-2-ol, with iPr2NH as base and THF as solvent.
Compound 88: 9-cyclopropyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one.
[00348] This compound is prepared via general method E using intermediate 11 and potassium cyclopropyltrifluorob orate.
Compound 89: 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00349] This compound is prepared via general method G using intermediate 11 and pent-l-yn-3-ol with iPr2NH as base and THF as solvent. Compound 90: 2-([l,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-metliyl-pent-l -ynyl)-6,7-diliydro- pyrimido[6,l -a]isoquinolin-4-one.
[00350] This compound is prepared via general method G using intermediate 11 and 4-methyl-pent-l-yn- 3-ol with iPr2NH as base and THF as solvent.
[00351] Compound 91: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-l-ynyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00352] This compound is prepared via general method G using intermediate 11 and 3 -ethyl-pent- l-yn-3- ol with iPr2NH as base and THF as solvent.
Compound 92: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00353] This compound is prepared via general method G using intermediate 11 and 2-phenyl-but-3-yn-2- ol with Cs2C03 as base and MeCN as solvent under reflux.
Compound 93: 9-(3-benzylamino-prop-l-ynyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00354] This compound is prepared via general method G using intermediate 11 and benzyl-prop-2-ynyl- amine with Cs2C03 as base and MeCN as solvent under reflux.
Compound 94: 2-([l,4]dioxan-2-ylmethoxy)-9-[(furan-2-ylmethyl)-amino]-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000097_0001
Intermediate 11 Compound 94
[00355] A suspension of intermediate 11 (200 mg, 0.433 mmol, 1 eq.), furan-2-ylmethanamine (0.038 mL, 0.433 mmol, 1 eq.) and Cs2CC<3 (0.17g, 0.519 mmol, 1.2 eq.) in toluene (4 mL) was degassed with Ar for 30 min before BINAP (+/-) (16 mg, 0.026 mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added. The reaction was heated to 65 °C for 16 h. The reaction was cooled to RT, BINAP (+/-) (16 mg, 0.026 mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added and the reaction was degassed. The reaction was heated to 80 °C for 1 extra day. The reaction was cooled to RT, BINAP (+/-) (16 mg, 0.026 mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added and the reaction was degassed. The reaction was heated to 80 °C for 1 extra day. The reaction was cooled to RT and diluted with DCM and washed with 0.5N aqueous KHS04. The aqueous layer was extracted with DCM, the combined organic layers were dried over Na2S04 and evaporated to dryness. The crude product was purified by preparative HPLC-MS [H20 (98^2): MeCN (2- 98) / 0.1%HCO2H] to give compound 94.
(¾ CDC13) δ ppm 7.57 - 7.48 (1 H, d), 7.38 (1 H, s), 6.68 - 6.55 (1 H, d), 6.49 (1 H, s), 6.35 (1 H, s), 6.28 (1 H, s), 6.20 (1 H, s), 4.60 - 4.50 (1 H, m), 4.38 - 4.30 (4 H, m), 4.22 - 4.15 (2 H, m), 4.03 - 3.93 (1 H, m), 3.95 - 3.60 (5 H, m), 3.55 -3.40 (1 H, t), 2.98 - 2.85 (2 H, m)
MW (calcd): 409.4; MW (obsd): 410.2 (M+l)
Compound 95: 2-([l,4]dioxan-2-ylmethoxy)-9-(l-ethyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00356] This compound is prepared via general method E using intermediate 11 and 1 -ethyl- lH-pyrazole- 4-boronic acid, pinacol ester.
Compound 96: 2-([l,4]dioxan-2-ylmethoxy)-9-[l-(3-methyl-butyl)-lH-pyrazol-4-yl]-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00357] This compound is prepared via general method E using intermediate 11 and l-(3-methylbutyl)- 1 H-pyrazole-4-boronic acid, pinacol ester.
Compound 97: 2-([l,4]dioxan-2-ylmethoxy)-9-(5-methyl-furan-2-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00358] This compound is prepared via general method E using intermediate 11 and 2-methylfurane-5- boronic acid pinacol ester.
Compound 98: 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00359] This compound is prepared via general method G using intermediate 11 and hex-l -yn-3-ol, Cs2C03 as base and MeCN as solvent under reflux.
Compound 99: 9-(3,5-dimethyl-lH-pyrazol-4-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00360] This compound is prepared via general method E using intermediate 11 and 3,5-dimethylpyrazole- 4-boronic acid pinacol ester. Compound 100: 2-([l,4]dioxan-2-ylmethoxy)-9-(lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm 4 -one.
[00361] This compound is prepared via general method E using intermediate 11 and pyrazole-4-boronic acid pinacol ester.
Compound 101 : 2-([l,4]dioxan-2-ylmethoxy)-9-(l-propyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00362] This compound is prepared via general method E using intermediate 11 and 1-propyl-lH- pyrazole-4-boronic acid, pinacol ester.
Compound 102: 2-[2-((R)-l-[l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l -a]isoquinolin-9- yl]-benzonitrile.
[00363] This compound is prepared via general method E using intermediate 10 and 2- cyanophenylboronic acid pinacol ester.
Compound 103: 2-[2-((S)-l-[l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l -a]isoquinolin-9- yl]-benzonitrile.
[00364] This compound is prepared via general method E using intermediate 9 and 2-cyanophenylboronic acid pinacol ester.
Compound 104: 9-(5-cyclopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7- dihydro-pyrimido[6, 1 -a]isoquinolin-4-one.
[00365] This compound is prepared via general method F using intermediate 7 and 3-chloromethyl-5- cyclopropyl- [ 1 ,2,4] oxadiazole.
Com ound 105: 2-([l,4]dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
Figure imgf000099_0001
Intermediate 11 Intermediate 24 Compound 105 Step 1: 2-(fl ,4Jdioxan-2-ylmethoxy)-9-prop-l-ynyl-6, 7-dihydro-pyrimido[6,l-aJisoquinolin-4-one (Intermediate 24).
[00366] Intermediate 24 2-([l ,4]dioxan-2-ylmethoxy)-9-prop-l-ynyl-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one is synthesised via general method E with intermediate 11 and ethynyl-trimethyl-silane. (¾ CDC13) δ ppm 7.66 - 7.61 (1 H, m), 7.47 - 7.43 (1 H, m), 7.42 - 7.38 (1 H, m), 6.37 (1 H, s), 4.50 - 4.36 (2 H, m), 4.23 - 4.16 (2 H, m), 4.04 - 3.93 (1 H, m), 3.90 - 3.60 (4 H, m), 3.53 - 3.44 (1 H, m), 3.02 - 2.97 (1 H, m), 0.27 (7 H, s)
MW (calcd): 410.5; MW (obsd): 411.4 (M+l) Step 2: 2-([l Jdioxan-2-ylmethoxy)-9-ethynyl-6, 7-dihydro-pyrimido[6,l-aJisoquinolin-4-one (Compound 105).
[00367] TBAF (4.06 mL, 4.06 mmol, 1.2 eq.) was added dropwise to a solution of intermediate 24 (1.39 g, 3.39 mmol, 1 eq.) in THF (40 mL) at 0 °C and the reaction was stirred for 1 h at 0 °C. The reaction was then evaporated to dryness, and the residue was re-dissolved in HCl IN. The aqueous phase was extracted with DCM, the combined organic layers were dried over MgS04 and the solvent evaporated under vacuum. The crude product was purified by flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM to furnish compound 105.
(¾ CDCI3) δ ppm 7.65 (1 H, s), 7.51 - 7.46 (1 H, m), 7.45 - 7.41 (1 H, m), 6.37 (1 H, s), 4.49 - 4.36 (2 H, m), 4.21 (2 H, s), 4.04 - 3.94 (1 H, m), 3.90 - 3.61 (5 H, m), 3.53 - 3.44 (1 H, m), 3.25 (1 H, s), 3.00 (2 H, s) MW (calcd): 330.3; MW (obsd): 331
Compound 106: 2-([l ,4]dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000100_0001
Compound 105 Compound 106
[00368] Compound 105 (50 mg, 0.15 mmol, 1 eq.) was dissolved in DMF (3 mL), 5-bromo-pyrimidine (47 mg, 0.30 mmol, 2 eq.) was added followed by TEA (0.062 mL, 0.44 mmol, 3 eq.), and the mixture was degassed. Pd(PPh3)3Cl2 (5 mg, 0.0074 mmol, 0.05 eq.) was added with Cul (6 mg, 0.029 mmol, 0.2 eq.) and the reaction mixture was heated at 80 °C for 16 h. The volatiles were evaporated to dryness and the crude product was purified by flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM to give compound 106. Compound 107 : 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00369] This compound is prepared via general method G using intermediate 11 and phenyl-prop-2-ynyl- amine with iPr2NH as base and THF as solvent. Compound 108: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-l -ynyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00370] This compound is prepared via general method G using intermediate 11 and l -pyridin-3-yl-prop- 2-yn-l-ol. Compound 109: 9-cyclopentyloxymethyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00371] This compound is prepared via general method E using intermediate 11 and potassium cyclopentoxymethyltrifluoroborate. Compound 110: 2-([l,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-l-ynyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00372] Synthesis fully described above.
Compound 111: 9-cyclopropylethynyl-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00373] This compound is prepared via general method G using intermediate 10 and ethynyl- cyclopropane.
Compound 112: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00374] This compound is prepared via general method G using intermediate 9 and 3-methyl-but-l -yne.
Compound 113 : 2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-l -yl-prop-1 -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one. [00375] This compound is prepared via general method G using intermediate 11 and l-prop-2-ynyl-lH- imidazole.
Compound 114: 9-(2-cyclopropyl-ethyl)-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000102_0001
Intermediate 10 Compound 114
[00376] A round bottom flask was charged with intermediate 10 (2 g, 4.33 mmol, 1 eq.), intermediate 20 (1.1 g, 6.5 mmol, 1.5 eq.), K2C03 (1.8 g, 13 mmol, 3 eq.), Pd(OAc)2 (19 mg, 0.087 mmol, 0.02 eq.), RuPhos (81 mg, 0.173 mmol, 0.04 eq.), toluene (30 niL) and H20 (3 niL). The mixture was degassed with N2 and was heated at 80 °C for 16 h. The reaction was cooled to RT, quenched with brine and extracted with EtOAc. The organic layer was dried over MgS04 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 70 to 90% EtOAc/H to give compound 114.
(¾ CDC13) δ ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.03 - 3.95 (1 H, m), 3.90 - 3.61 (5 H, m), 3.54 - 3.45 (1 H, m), 3.02 - 2.95 (2 H, m), 2.81 - 2.72 (2 H, m), 1.59 - 1.49 (2 H, m), 0.77 - 0.64 (1 H, m), 0.49 - 0.42 (2 H, m), 0.10 - 0.02 (2 H, m) MW (calcd): 382.5; MW (obsd): 383.4 (M+l)
Compound 115: 9-cyclopentyloxymethyl-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00377] This compound is prepared via general method E using intermediate 10 and potassium cyclopentoxymethyltrifluoroborate.
Compound 116: 2-([l ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00378] Synthesis fully described above.
Compound 117 : 9-allyloxy-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one.
[00379] Synthesis fully described above. Compound 118: 9-allyloxy-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolm one.
[00380] Synthesis fully described above.
Compound 119: 2-((R)-l-[l ,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-yloxymethyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00381] This compound is prepared via general method E using intermediate 10 and intermediate 14. Compound 120: 2-([l ,4]dioxan-2-ylmethoxy)-9-{3-[(pyridin-3-ylmethyl)-amino]-prop-l-ynyl}-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00382] This compound is prepared via general method G using intermediate 11 and prop-2-yn-l - yl(pyridin-3 -ylmethyl)amine. Compound 121: 2-((R)-l-[l,4]dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
[00383] This Compound is prepared via general method I using compound 111.
Compound 122: 9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00384] Intermediate 9 (13.5 g, 29.20 mmol, 1 eq.) was dissolved in degassed DMF (1000 mL) under an nitrogen atmosphere, ethynyl cyclopropane (3.5 g, 53.00 mmol, 1.8 eq.) was added followed by Pd(PPh3)3Cl2 (1.11 g, 1.58 mmol, 0.05 eq.), Cul (1.9 g, 9.98 mmol, 0.34 eq.) and TEA (12.5 mL, 89.7 mmol, 3.1 eq.). The reaction mixture was stirred 3h at 80 °C and 15 h at room temperature. The reaction was concentrated under vacuum. The crude product was then purified by trituration in hot z'PrOH to afford compound 122.
[00385] (1H, CDC13) δ ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H, s), 4.50 - 4.39 (2
H, m), 4.20 (2 H, t), 4.02 - 3.98 (1 H, m), 3.89 - 3.66 (5 H, m), 3.49 (1 H, t), 2.96 (2 H, t), 1.59 -
I .48 (1 H, m), 0.98 - 0.81 (4 H, m)
MW (calcd): 378.4; MW (obsd): 379.4
ee = 98.3% Compound 123 : 9-(2-cyclopropyl-ethyl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000104_0001
Intermediate 9 Compound 123
[00386] A round bottom flask was charged with intermediate 9 (2.08 g, 4.51 mmol, 1 eq.), intermediate 20 (1.35 g, 7.67 mmol, 1.7 eq.), K2C03 (1.87 g, 13.53 mmol, 3 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.02 eq.), RuPhos (84 mg, 0.18 mmol, 0.04 eq.), toluene (30 mL) and H20 (3 mL). The mixture was degassed with N2 and was heated at 80 °C for 1.5 days. The reaction was cooled to RT and some more reagents were added, potassium 2-cyclopropyl-ethyl-trifluoroborate (0.3 eq.), Pd(OAc)2 (0.02 eq.), RuPhos (0.04 eq.), the reaction was degassed and the reaction was heated at 80 °C for 16h. The reaction was cooled to RT, quenched with H20 and extracted with EtOAc. The organic layer was dried over MgS04 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel, eluting from 80 to 90% EtOAc/H to compound 123.
(¾ CDC13) δ ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.24 - 4.17 (2 H, m), 4.03 - 3.95 (1 H, m), 3.91 - 3.62 (5 H, m), 3.49 (1 H, dd), 3.03 - 2.95 (2 H, m), 2.81 - 2.73 (2 H, m), 1.59 - 1.50 (2 H, m), 0.71 (1 H, s), 0.49 - 0.42 (2 H, m), 0.09 - 0.03 (2 H, m)
MW (calcd): 382.5; MW (obsd): 383.4
Compound 124: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00387] This compound is prepared via general method E using intermediate 9 and intermediate 15.
Compound 125: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00388] This compound is prepared via general method E using intermediate 9 and intermediate 16.
Compound 126: 9-(2,2-dimethyl-butylamino)-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00389] Synthesis fully described above. Compound 127 : 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-4-metliyl-pentyl)-6,7-diliydro- pyrimido 6,l -a]isoquinolin-4-one.
Figure imgf000105_0001
Intermediate 9 Intermediate 25 Compound 127
Step 1: 2-((S)-l-fl JDioxan-2-ylmethoxy)-9-(3-hydroxy^-methyl^ent-l-ynyl)-6 -dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 25)
[00390] Intermediate 25 is prepared via general method G using intermediate 9, 4-Methyl-pent-l -yn-3-ol, z'Pr2NH as base and THF as solvent.
(¾ CDC13) δ ppm 7.65 - 7.60 (1 H, d), 7.48 - 7.40 (1 H, m), 7.37 (1 H, s), 6.36 (1 H, s), 4.50 - 4.30 (3 H, m), 4.25 - 4.15 (2 H, m), 4.05 - 3.95 (1 H, m), 3.92 - 3.60 (6 H, m), 3.68 - 3.40 (1 H, m), 3.05 - 2.92 (2 H, m), 2.10 - 1.95 (1 H, m), 1.93 - 1.80 (1 H, m), 1.15 - 1.00 (6 H, m)
MW (calcd): 410.5; MW (obsd): 411.2 (M+l)
Step 2: 2-((S)-l-fl,4Jdioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 127)
[00391] Compound 127 is prepared via general method I using intermediate 25.
Compound 128: 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00392] This compound is prepared via general method J using intermediate 13 and 2-ethyl-hexanal.
Compound 129: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00393] This compound is prepared via general method F using intermediate 6 and 1 -bromo-2-methoxy- ethane, KI was not used in this experiment.
Compound 130: 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one. [00394] This compound is prepared via general method F using intermediate 6 and 1 -bromo-2-ethoxy- ethane, KI was not used in this experiment.
Compound 131 : 9-cyclopropylmethoxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00395] This compound is prepared via general method F using intermediate 6 and bromomethyl- cyclopropane, KI was not used in this experiment.
Compound 132: 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-9-(2-fluoro-ethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00396] This compound is prepared via general method F using intermediate 6 and 1 -bromo-2-fluoro- ethane, KI was not used in this experiment.
Compound 133: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-l -ynyl]-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00397] Synthesis fully described above.
Compound 134: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-l -ynyl]-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00398] This compound is prepared via general method K using intermediate 21 and 1 -bromo-2-ethoxy- ethane.
Compound 135: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-l-ynyl]-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00399] This compound is prepared via general method K using intermediate 21 and 1 -bromo-2-fluoro- ethane.
Compound 136: 9-(2,2-dimethyl-propoxymethyl)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00400] This compound is prepared via general method E using intermediate 9, in a mixture of DME/H20 (2/1), in a microwave at 120 °C for 20 min and intermediate 17.
Compound 137: 9-cyclohexyloxymethyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one. [00401] This compound is prepared via general method E using intermediate 9 and potassium cyclohexyloxymethyltrifluoroborate in a mixture of DME/H20 (2/1), in a microwave at 120 °C for 20 min.
Compound 138: 9-cyclopropylmethoxymethyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00402] This compound is prepared via general method E using intermediate 9, in a mixture of DME/H20 (2/1), in a microwave at 120 °C for 20 min and intermediate 18.
Compound 139: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00403] This compound is prepared via general method F using intermediate 6 and 2-bromomethyl- tetrahydro-pyran, KI was not used in this experiment.
Compound 140: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6,7-dihydro-pyrimido[6,l - a]iso uinolin-4-one.
Figure imgf000107_0001
Intermediate 9 Intermediate 26 Compound 140
Step 1 : 2-((S)-l-[lA]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-l-ynyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 26).
[00404] Intermediate 26 was prepared via general method G using intermediate 9 and but-3-yn-2-ol, the crude product was used in the next step without characterization.
Step 2: 2-((S)-l-[lA]dioxan-2-ylmethoxy)-9-(3-hydroxy-butyl)-6 -dihydro^yrimido[6J-a]isoqm
(Compound 140).
[00405] Compound 140 was prepared via general method I using intermediate 26. Compound 141 : 9-(4,4-dimethyl-pentyloxy)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-diliydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000108_0001
Intermediate 6 Compound 141
[00406] Intermediate 6 (0.1 g, 0.303 mmol, 1 eq.), 4,4-dimethyl-pentan-l-ol (35 mg, 0.303 mmol, 1 eq.) and PPh3 (95 mg, 0.363 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was degassed with N2. DIAD (0.065 mL, 0.333 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by preparative TLC eluting with EtOAc to give compound 141.
(¾ CDC13) δ ppm 7.70 - 7.58 (1 H, d), 6.95 - 6.82 ( 1 H, d), 6.77 (1 H, s), 6.27 (1 H, s), 4.50 - 4.32 ( 2 H, m), 4.38- 4.15 (2 H, m), 4.05 - 3.92 (3 H, m), 3.92 - 3.60 (5 H, m), 3.55 - 3.42 (1 H, t), 3.05 - 2.92 (2 H, m), 1.85 - 1.70 (2 H, m), 1.40 - 1.30 (2 H, m), 0.92 (9 H, s)
MW (calcd): 428.5; MW (obsd): 429.2 (M+l)
Compound 142: 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro- pyrimido 6,l -a]isoquinolin-4-one.
Figure imgf000108_0002
Intermediate 25 Intermediate 27 Compound 142
Step 1: 2-((S)-l-[l ,4JDioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-l -ynyl)-6 ', "/ '-dihydro-pyrimido[6 - aJisoquinolin-4-one (Intermediate 27)
[00407] Intermediate 27 is prepared via general method H using intermediate 25.
MW (calcd): 424.5; MW (obsd): 425.2 (M+l) Step 2: 2-((S)-l-[l AJdioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 142).
[00408] Compound 142 is prepared via general method I using intermediate 27. Compound 143 : 9-(3-cyclopropyl-propoxy)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000109_0001
Intermediate 6 Compound 143
[00409] Intermediate 6 (2.12 g, 2.42 mmol, 1 eq.), 4,4-dimethyl-pentan-l-ol (0.77 g, 7.71 mmol, 1.2 eq.) and PPh3 (2.02 g, 7.71 mmol, 1.2 eq.) were suspended in 1,4-dioxane (50 mL) and the mixture was degassed with N2. DIAD (1.56 mL, 7.71 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc, the organic phase was dried over MgS04 and evaporated to dryness. Compound 143 was obtained by purification by flash chromatography on silica gel, eluting from 60 to 100% EtOAc/H.
(¾ CDC13) δ ppm 7.66 - 7.60 (1 H, m), 6.91 - 6.86 (1 H, m), 6.80 - 6.76 (1 H, m), 6.28 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.17 (2 H, m), 4.11 - 4.04 (2 H, m), 4.02 - 3.95 (1 H, m), 3.91 - 3.61 (5 H, m), 3.54 - 3.45 (1 H, m), 3.03 - 2.94 (2 H, m), 1.98 - 1.88 (2 H, m), 1.45 - 1.36 (2 H, m), 0.78 - 0.66 (1 H, m), 0.50 - 0.43 (2 H, m), 0.09 - 0.03 (2 H, m)
MW (calcd): 412.5; MW (obsd): 413.5
Compound 145: 9-cyclohexylamino-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00410] This compound is prepared via general method J using intermediate 13 and cyclohexanone. Compound 146: 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
Figure imgf000110_0001
Intermediate 9 Compound 146
Step 1 : 2-((S)-l-fl,4JDioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pent-l-ynyl)-6, 7-dihydro- pyrimido[6,l-a]isoquinolin-4-one (Intermediate 28).
[00411] Intermediate 28 is prepared via general method G using intermediate 9.
MW (calcd): 424.5; MW (obsd): 425.4 (M+l)
Step 2: 2-((S)-l-fl Jdioxan-2-ylmethoxy)-9-(3-hydroxy-4 -dimethyl-pentyl)-6, 7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 146).
[00412] Compound 146 is prepared via general method I using intermediate 28.
Compound 147: 9-cyclopentylmethoxymethyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00413] This compound is prepared via general method E using intermediate 9, in a mixture of DME/H20 (2/1), in a microwave at 120 °C for 20 min and intermediate 19.
Compound 148: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000110_0002
Intermediate 26 Intermediate 29 Compound 148
Step 1 : 2-((S)-l -[1 ,4] Dioxan-2-ylmethoxy)-9-(3-methoxy-but-l -ynyl)-6, 7-dihydro-pyrimido[6,l - aJisoquinolin-4-one (Intermediate 29)
[00414] Intermediate 29 is prepared via general method H using intermediate 26. MW (calcd): 396.4; MW (obsd): 397.2 (M+l)
Step 1: 2-((S)-l -[1,4] dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7 -dihydro-pyrimido [6,1 -a] isoquinolin-4- one (Compound 148)
[00415] Compound 148 is prepared via general method I using intermediate 29.
Compound 149: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one
Figure imgf000111_0001
Intermediate 9 Intermediate 30 Compound 149
Step 1: 2-((S)-l -[1 ,4] 'Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-l -ynyl)-6,7 '-dihydro-pyrimido [6,1 - aJisoquinolin-4-one (Intermediate 30)
[00416] Intermediate 30 is prepared via general method G using intermediate 9 and phenyl-prop-2-ynyl- amine.
MW (calcd): 443.5; MW (obsd): 444.2 (M+l)
Step 2: 2-((S)-l -[1,4] dioxan-2-ylmethoxy)-9-(3-phenylamino-propyl)-6,7 -dihydro-pyrimido [6,1- aJisoquinolin-4-one (Compound 149)
[00417] Compound 149 is prepared via general method I using intermediate 30.
Compound 150: 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,l - a]iso uinolin-4-one.
Figure imgf000111_0002
Intermediate 9 Intermediate 31 Compound 150 Step 1 : 2-((S)-l-[l , 4 ]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pent-l -ynyl)-6, 7-dihydro-pyrimido[6, 1 - aJisoquinolin-4-one (Intermediate 31)
[00418] Intermediate 31 was prepared via general method G using intermediate 9, pent-4-yn-2-ol, iPr2NH as base and THF as solvent.
MW (calcd): 396.4; MW (obsd): 397.2 (M+l)
Step 2: 2-((S) -[lA]dioxan-2-ylmethoxy)-9-(4-hydroxy-pentyl)-6 -dihydro-pyrimido[6 -a]isoq one (Compound 150)
[00419] Compound 150 was prepared via general method I using intermediate 31.
Compound 151 : 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimido[6,l - a]iso uinolin-4-one.
Figure imgf000112_0001
Intermediate 9 Intermediate 32 Compound 151
Step 1 : 2-((S)-l -[1 ,4] Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l - aJisoquinolin-4-one (Intermediate 32)
[00420] Intermediate 32 was prepared via general method G using intermediate 9, but-3-yn-l-ol, iPr2NH as base and THF as solvent.
(¾ CDC13) δ ppm 7.70 - 7.65 (1 H, m), 7.45 - 7.35 (1 H, m), 7.34 (1 H, s), 6.35 (1 H, s), 4.50 - 4.32 (2 H, m), 4.28 - 4.10 ( 2 H, m), 4.05 - 3.90 (1 H, m), 3.95 - 3.60 (7 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H, m), 2.80 - 2.65 ( 2 H, m), 2.00 - 1.80 (1 H, m)
MW (calcd):382.4; MW (obsd): 383.2 (M+l) Step 2: 2-((S) -[lA]dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6 -dihydro-pyrimido[^
(Compound 151).
[00421] Compound 151 was prepared via general method I using intermediate 32. Compound 152: 9-(cyclohexyl-methyl-amino)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-diliydro- pyrimido[6,l -a]iso uinolin-4-one.
Figure imgf000113_0001
Compound 147 Compound 152
[00422] Mel (0.007 mg, 0.11 mmol, 1.2 eq.) was added to compound 147 (38 mg, 0.092 mmol, 1 eq.) and NaH (6 mg, 0.15 mmol, 1.6 eq.) in DMF (5 mL) and the reaction was stirred at RT for 16 h. Some more NaH (6 mg, 0.15 mmol, 1.6 eq.) and Mel (0.07 mg, 0.11 mmol, 1.2 eq.) were added to the reaction mixture and it was stirred for a further 2 days. The mixture was quenched with brine and extracted with EtOAc. The organic layers were dried over MgS04 and evaporated to dryness. The residue was purified by preparative HPLC-MS to provide compound 152.
(¾ CDC13) δ ppm 7.57 - 7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H, s), 4.51 - 4.33 (2 H, m), 4.26 - 4.14 (2 H, m), 4.06 - 3.93 (1 H, m), 3.92 - 3.56 (6 H, m), 3.56 - 3.41 (1 H, m), 3.00 - 2.90 (2 H, m), 2.88 (3 H, s), 2.04 - 1.63 (2 H, m), 1.60 - 1.31 (5 H, m), 1.28 - 1.08 (1 H, m)
MW (calcd): 425.5; MW (obsd): 426.4 Compound 153: 9-(cyclohexylmethyl-amino)-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00423] This compound is prepared via general method J using intermediate 13 and cyclohexanecarbaldehyde . Compound 154: 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one.
[00424] This compound is prepared via general method J using intermediate 13 and tetrahydro-pyran-4- carbaldehyde. Compound 155: 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
I l l
Figure imgf000114_0001
Intermediate 9 Intermediate 33 Compound 155
Step 1 : 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-l-ynyl)-6, 7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 33)
[00425] Intermediate 33 is prepared via general method G using intermediate 9 and 3 -ethyl-pent- 1 -yn-3-ol. (¾ CDC13) δ ppm 7.51 - 7.46 (1 H, m), 7.28 - 7.24 (1 H, m), 7.22 - 7.19 (1 H, m), 6.20 (1 H, s), 4.30 - 4.19 (2 H, m), 4.08 - 4.00 (2 H, m), 3.87 - 3.79 (1 H, m), 3.75 - 3.47 (5 H, m), 3.39 - 3.30 (1 H, m), 3.03 (1 H, br. S), 2.88 - 2.80 (2 H, m), 1.746 - 1.56 (4 H, m), 0.97 (6 H, s)
MW (calcd): 424.5; MW (obsd): 425.5 (M+l)
Step 2: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pentyl)-6, 7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 155).
[00426] Compound 155 is prepared via general method I using intermediate 33. Compound 156: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro- pyrimido 6,l -a]isoquinolin-4-one
Figure imgf000114_0002
Intermediate 9 Intermediate 34 Compound 156
Step 1: 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9 -(3-hydroxy-3-methyl-but-l-ynyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 34) [00427] Intermediate 34 is prepared via general method G using intermediate 9 and 2-methyl-but-3-yn-2- ol.
(¾ CDC13) δ ppm 7.58 (1 H, d), 7.38 - 7.33 (1 H, m), 7.32 - 7.29 (1 H, m), 6.32 (1 H, s), 4.43 - 4.32 (2 H, m), 4.18 - 4.12 (2 H, m), 3.99 - 3.91 (1 H, m), 3.87 - 3.58 (5 H, m), 3.50 - 3.42 (1 H, m), 2.97 - 2.90 (2 H, m), 1.60 (6 H, s)
MW (calcd): 396.4; MW (obsd): 397.3 (M+l)
Step 2: 2-((S)-l-fl Jdioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 156)
[00428] Compound 156 is prepared via general method I using intermediate 34.
Compound 157 : 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,l - a]iso uinolin-4-one.
Figure imgf000115_0001
Step 1 : 2-((S)-l-[l , 4 ]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-l -ynyl)-6, 7-dihydro-pyrimido[6, 1 - aJisoquinolin-4-one (Intermediate 35)
[00429] Intermediate 35 is prepared via general method G using intermediate 9 and pent-1 -yn-3-ol.
(¾ CDCI3) δ ppm 7.62 - 7.57 (1 H, m), 7.41 - 7.35 (1 H, m), 7.33 (1 H, s), 6.34 (1 H, s), 4.60 - 4.53 (1 H, m), 4.45 - 4.33 (2 H, m), 4.20 - 4.14 (2 H, m), 4.00 - 3.92 (1 H, m), 3.88 - 3.59 (5 H, m), 3.51 - 3.42 (1 H, m), 2.99 - 2.90 (2 H, m), 1.90 - 1.74 (2 H, m), 1.07 (3 H, t)
Step 2: 2-((S) -[lA]dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6 -dihydro-pyrimido[6 -a^
one (Compound 157)
[00430] Compound 157 is prepared via general method I using intermediate 35.
Compound 158: 9-(2,2-dimethyl-propoxy)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00431] Synthesis fully described above. Compound 159: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmetlioxy)-6,7-diliydro- pyrimido[6,l -a]isoquinolin-4-one.
[00432] This compound is prepared via general method L with intermediate 6 and methanesulfonic acid tetrahydro-pyran-4-ylmethyl ester.
Compound 160: 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro- pyrimido 6,l -a]isoquinolin-4-one.
Figure imgf000116_0001
Intermediate 9 Intermediate 36 Compound 160
Step 1: 2-((S)-l-fl JDioxan-2-ylmethoxy)-9-(4-hydroxy^-methyl^ent-l-ynyl)-6 -dihydro-pyrimido[6,l- aJisoquinolin-4-one (intermediate 36)
[00433] A vial was charged with intermediate 9 (0.15 g, 0.324 mmol, 1 eq.), 2-methyl-5-trimethylsilanyl- pent-4-yn-2-ol (66 mg, 0.389 mmol, 1.2 eq), Cul (2.5 mg, 0.013 mmol, 0.04 eq.), iPr2NH (0.41 mL, 2.92 mmol, 9 eq.) and THF (2 mL). The solution was purged with Ar for 15 min., and Pd(PPh3)Ci2 (11 mg, 0.016 mmol, 0.05 eq.) was added with TBAF (0.39 mL, 0.39 mmol, 1.2 eq., 1M in THF). The vial was sealed and the reaction was heated to 80 °C for 16 h. The reaction mixture was evaporated to dryness and the crude product was purified by preparative TLC [DCM/MeOH, 98/2] to afford intermediate 36 2-((S)-l -[l,4]dioxan- 2-ylmethoxy)-9-(4-hydroxy-4-methyl-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one.
(¾ CDC13) δ ppm 7.70 - 7.58 (1 H, m), 7.45 - 7.38 (1 H, m), 7.35 (1 H, s), 6.37 (1H, s), 4.50 - 4.30 (2 H, m), 4.28 - 4.15 (2 H, m), 4.05 - 3.95 ( 1 H, m), 3.95 - 3.55 (5 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.95 (2 H, m), 2.62 (2 H, s), 1.39 (6 H, s)
MW (calcd): 410.5; MW (obsd): 411.4
Step 2: 2-((S)-l-fl,4Jdioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 160)
[00434] Compound 160 is prepared via general method I using intermediate 36.
Compound 161 : 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)-6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one. [00435] This compound is prepared via general method E using intermediate 9 and potassium 4- (tetrahydropyranylmethoxy)methyltrifluoroborate.
Compound 162: 2- l,4]dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one.
Figure imgf000117_0001
Compound 162 Intermediate 38
Step 1: l-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione (intermediate 37)
[00436] Sodium (236 mg, 10.2 mmol, 2 eq.) was added to degassed EtOH (18 mL), when sodium dissolved completely, ethyl malonate (1.56 mL, 10.2 mmol, 2 eq.) was added and the reaction was refluxed for 1 h. Intermediate 1 (995 mg, 5.12 mmol, 1 eq.) in EtOH (4 mL) was then added and the reaction was refluxed for 1 day. The desired intermediate 37 l-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione precipitated upon addition of 2N aqueous HC1, it was filtered and washed with H20 and finally dried.
(¾ DMSO- ) δ ppm 7.27 - 7.18 (1 H, m), 6.84 - 6.72 (3 H, m), 3.92 - 3.83 (2 H, m), 3.75 (3 H, s), 3.62 (2 H, s), 2.80 - 2.70 (2 H, m)
MW (calcd): 262.3; MW (obsd): 263.3 (M+l)
Step 2: 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,l-aJisoquinolin-4-one (intermediate 38)
[00437] Intermediate 37 (920 mg, 3.51 mmol, 1 eq.) was heated in POCl3 (5 mL) at 50°C for 2 days. The volatiles were evaporated under vacuum, the residue was dissolved in DCM and washed with a saturated aqueous solution of NaHC03, before drying over MgS04. Evaporation of the organic phase gave intermediate 38 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, which was used in the next step without further purification.
(¾ CDC13) δ ppm 7.73 - 7.66 (1 H, m), 6.98 - 6.90 (1 H, m), 6.85 - 6.80 (1 H, m), 6.69 (1 H, s), 4.00 - 4.20 (2 H, m), 3.91 (3 H, s), 3.04 (2 H, m) Step 3: 2-([l ,4] dioxan-2-ylmethoxy)-9-methoxy-6, 7-dihydro-pyrimido[6,l-a]isoquinolin-4-one (compound 162)
[00438] [l ,4]Dioxan-2-yl-methanol (42 mg, 0.36 mmol, 2 eq.) was dissolved in DCM (3 mL) with NaH (14 mg, 0.36 mmol, 2 eq., 60% in mineral oil). After 30 min, intermediate 38 (50 mg, 0.18 mmol, 1 eq.) was added to the mixture and the reaction was stirred at RT for 16h. The reaction mixture was evaporated to dryness and the crude product was purified by preparative HPLC-MS to provide compound 162.
(¾ CDC13) δ ppm 7.68 - 7.62 (1 H, m), 6.95 - 6.87 (1 H, m), 6.82 - 6.77 (1 H, m), 6.29 (1 H, s), 4.51 - 4.35 (2 H, m), 4.26 - 4.17 (2 H, m), 4.05 - 3.92 (1 H, m), 3.91 - 3.60 (8 H, m), 3.55 - 3.44 (1 H, m), 3.04 - 2.94 (2
H, m)
MW (calcd): 344.4; MW (obsd): 345.0
Compound 163: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(oxetan-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one.
[00439] This compound is prepared via general method L using intermediate 6 and methanesulfonic acid oxetan-3-ylmethyl ester.
Compound 164: 9-(3-cyclopropyl-propoxy)-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,l - a]isoquinolin-4-one.
[00440] A solution of intermediate 6 (1.15 g, 3.48 mmol, 1 eq.) and 3-cyclopropan-l-ol (0.349 g, 3.48 mmol, leq.) in 1 ,4-dioxane was degassed with Argon for 10 min. PPh3 (1.096 g, 4.18 mmol, 1.2 eq.) was added and the reaction mixture was degassed with Argon an additional 5 min. DIAD (0.745 mL, 3.83 mmol,
I .1 eq.) was added dropwise at 0°C. The reaction mixture was stirred at RT for 16 h. 3-Cyclopropylpropan-l - ol (0.150 mg, 1.49 mmol, 0.43 eq.) and PPh3 (0.30 g, 1.14 mmol, 0.33 eq.) were added. The reaction mixture was cooled to 0°C and DIAD (0.350 mL, 1.80 mmol, 5.2 eq.) was added. After 1 h at RT, the reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography on silica-gel to afford compound 164.
( DMSO-i/e) δ ppm 7.93 (1H, d), 6.97-6.92 (2 H, m), 6.53 (1H, s), 4.24-4.23 (2H, m), 4.08 (2H, t), 4.00 (2H, t), 3.98-3.74 (3H, m), 3.68-3.57 (2H, m), 3.51 -3.48 (1H, m), 3.37 (1H, t), 2.96 (2H, t), 1.84-1 .80 (2H, m), 1.36-1.30 (2H, m), 0.81 -0.63 (1H, m), 0.42-0.39 (2H, m), 0.04-0.02 (2H, m) MW (calcd): 412.5; MW (obsd): 413.0 (M+l) Compound 165: 2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-diliydro-pyrimido[6,l - a]isoquinolin-4-one.
Figure imgf000119_0001
Intermediate 9 Intermediate 39 Compound 165
Step 1: 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-l-ynyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 39)
[00441] Intermediate 39 was prepared via general method G using intermediate 9 and 3-methoxy-propyne. (¾ CDC13) δ ppm 7.68 (1 H, d), 7.48 (1 H, d), 7.42 (1 H, s), 6.40 (1 H, s), 4.50 - 4.41 (2 H, m), 4.38 (2 H, s), 4.23 (2 H, t), 4.05 - 3.98 (1 H, m), 3.89 - 3.70 (5 H, m), 3.55 - 3.50 (4 H, m), 3.03 (2 H, t)
MW (calcd): 382.4; MW (obsd): 383.4 (M+l)
Step 2: 2-((S)-l-[lA]dioxan-2-ylmethoxy)-9-(3-methoxy^ropyl)-6 -dihydro^yrimido[6 -a]isoquinolin-4- one (Compound 165)
[00442] Compound 165 was prepared via general method I using intermediate 39. Compound 166: 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-[2-(l -hydroxy-cyclopentyl)-ethyl]-6,7-dihydro- pyrimido 6,l -a]isoquinolin-4-one.
Figure imgf000119_0002
Intermediate 9 Intermediate 40 Compound 166
Step 1 : 2-((S)-l -fl ,4J Dioxan-2-ylmethoxy)-9-(l -hydroxy-cyclopentylethynyl)-6, 7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 40)
[00443] Intermediate 40 is prepared via general method G using intermediate 9 and 3-methoxy-propyne. (¾ CDCI3) δ ppm 7.54 (1 H, d), 7.31 (1 H, d), 7.26 (1 H, s), 6.28 (1 H, s), 4.39 - 4.30 (2 H, m), 4.12 (2 H, t), 3.95 - 3.91 (1 H, m), 3.82 - 3.58 (5 H, m), 3.50 (1 H, m), 3.16 (1 H, s), 2.89 (2 H, t), 2.05 - 1.98 (4 H, m), 1.90 - 1.70 (4H, m)
Step 2: 2-( (S)-l -[l,4]dioxan-2-ylmethoxy)-9-[2-(l-hydroxy-cyclopentyl)-ethyl]-6, 7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Compound 166)
[00444] Compound 166 was prepared via general method I using intermediate 40.
Compound 167: 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-6,7- dihydro-pyrimido[6, 1 -a]isoquinolin-4-one.
[00445] This compound is prepared via general method G using intermediate 10 and 4-Ethynyl-tetrahydro- pyran-4-ol.
Compound 168: 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one
Figure imgf000120_0001
Intermediate 10 Intermediate 41 Compound 168
Step 1: 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop-l-ynyl)-6,7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 40)
[00446] Intermediate 41 is prepared via general method G using intermediate 10 and 3-methoxy-propyne. (¾ CDCI3)□ ppm 7.56 (1 H, d), 7.48 (1 H, d), 7.33 (1 H, s), 6.27 (1 H, s), 4.32 - 4.27 (2 H, m), 4.23 (2 H, s), 4.08 (2 H, t), 3.88 - 3.85 (1 H, m), 3.76 - 3.49 (5 H, m), 3.40 - 3.34 (4 H, m), 2.90 (2 H, t)
Step 2: 2-((R)-l-[l ]dioxan-2-ylmethoxy)-9-(3-methoxy^ropyl)-6 -dihydro^yrimido[6 -a]isoquinolin-4- one (Compound 165)
[00447] Compound 168 is prepared via general method I using intermediate 41.
Compound 169 : 2-((R)- 1 -[ 1 ,4]Dioxan-2-ylmethoxy)-9-[2-(l -hydroxy-cyclopentyl)-ethyl] -6,7-dihydro- pyrimido[6,l -a]isoquinolin-4-one
Figure imgf000121_0001
Intermediate 10 Intermediate 42 Compound 169
Step 1 : 2-((S)-l -fl ,4J Dioxan-2-ylmethoxy)-9-(l -hydroxy-cyclopentylethynyl)-6, 7-dihydro-pyrimido[6,l- aJisoquinolin-4-one (Intermediate 42)
[00448] Intermediate 42 is prepared via general method G using intermediate 10 and 1-Ethynyl- cyclopentanol.
(¾ CDC13) δ ppm 7.47 (1 H, d), 7.25 (1 H, d), 7.20 (1 H, s), 6.22 (1 H, s), 4.32 - 4.24 (2 H, m), 4.05 (2 H, t), 3.88 - 3.85 (1H, m), 3.77 - 3.52 (5 H, m), 3.38 (1H, t), 2.83 (2 H, t), 2.02 - 1.90 (4H, m), 1.85 - 1.67 (4H, m)
Step 2: 2-((R)-l-[l ]Dioxan-2-ylmethoxy)-9-(l-hydroxy-cyclopentylethynyl)-6 -dihydro^yrimido[6,l- aJisoquinolin-4-one (Compound 169)
[00449] Compound 169 is prepared via general method I using intermediate 42.
Compound 170: 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one
Figure imgf000121_0002
Intermediate 6 Compound 170
[00450] Intermediate 6 (0.15 g, 0.45 mmol, 1 eq.), 2-Propoxy-ethanol (63 μί, 0.55 mmol, 1.2 eq.) and PPI13 (144 mg, 0.55 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was degassed with N2. DIAD (0.108 mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT overnight. 0.5 eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature for an extra 2h. Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgSC^ and concentrated. Crude product was purified on silicagel column to give compound 170.
Compound 171 : 2-((S)-l -[1 ,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one
Figure imgf000122_0001
Intermediate 6 Compound 171
[00451] Intermediate 6 (0.15 g, 0.45 mmol, 1 eq.), 2-isopropoxy-ethanol (63 \iL, 0.55 mmol, 1.2 eq.) and PPh3 (144 mg, 0.55 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was degassed with N2. DIAD (0.108 mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT for 5 h. 0.5 eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature overnight. Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgS04 and concentrated. The crude product was purified on silicagel column to give compound 171.
Compound 172 : 2-((R)-l -[1 ,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one
Figure imgf000122_0002
Intermediate 7 Compound 172
[00452] Intermediate 7 (0.25 g, 0.76 mmol, 1 eq.), 2-Propoxy-ethanol (105 μΐ,, 0.91 mmol, 1.2 eq.) and
PPh3 (238 mg, 0.91 mmol, 1.2 eq.) were suspended in 1 ,4-dioxane (10 mL) and the mixture was degassed with N2. DIAD (0.180 mL, 0.91 mmol, 1.2 eq.) was added and the reaction was stirred at RT overnight. 0.3 eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature for an extra 24h.
Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgS04 and concentrated. Crude product was purified on silicagel column to give compound 172. Compound 173: 2-((R)-l -[l,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-diliydro-pyrimido[6,l - a]isoquinolin-4-one
Figure imgf000123_0001
Intermediate 7 Compound 173
[00453] Intermediate 7 (0.25 g, 0.76 mmol, 1 eq.), 2-isopropoxy-ethanol (105 μί, 0.91 mmol, 1.2 eq.) and PPh3 (238 mg, 0.91 mmol, 1.2 eq.) were suspended in 1,4-dioxane (10 mL) and the mixture was degassed with N2. DIAD (0.180 mL, 0.91 mmol, 1.2 eq.) was added and the reaction was stirred at RT for 5 h. 0.3 eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature overnight. Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgS04 and concentrated. Crude product was purified on silicagel column to give compound 173.
Compound 174: 2-((S)-l -[1 ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one
Step 1 : potassium 3-met -propyl-trifluoroborate
Figure imgf000123_0002
Intermediate 43
[00454] In a 2-neck round bottom flask equipped with a reflux condenser and an addition funnel was charged with Mg (471 mg, 19.20 mmol, 3 eq.) and Et20 (2 mL) under N2. One drop of neat (2-bromo-ethyl)- cyclopropane was added followed by two drops of dibromoethane. Once the 1st bubbles appeared, 1 -Bromo- 3-methoxy-propane (1 g, 6.54 mmol, 1 eq.) in Et20 (10 mL) was added dropwise. Upon completion of the addition, the resulting suspension was stirred at RT for 1 h. In a separate flask, purged with N2, a solution made of B(OMe)3 (1.1 mL, 9.81 mmol, 1.5 eq.) in THF (12 mL) was cooled to -78 °C. To this solution, the 3- methoxy-propyl magnesium bromide suspension was added dropwise via a double ended needle. The mixture was allowed to stir for 1 h at -78 °C and then was warmed to RT for 1 h. After cooling the mixture to 0 °C, a saturated aqueous solution of KHF2 (5.8 mL, 4.5 M, 4.1 eq.) was added dropwise and the reaction mixture was allowed to warm to RT. After 30 min, the solution was concentrated in-vacuo. The dried solids were triturated with hot acetone and filtered to remove inorganic salts. The resulting filtrate was concentrated and the solid residue was triturated with Et20. Potassium 3-methoxy-propyl-trifluoroborate, intermediate 43, was filtered and dried in-vacuo.
(¾ DMSO- ) δ ppm 3.19 - 3.13 (5 H, m), 1.38 - 1.29 (2 H, m), -0.1 - 0.19 (2 H, m)
Step 2: 2-((S)-l-[l JDioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6 -dihydro^yrimido[6 -aJisoquinolin-4- one
[00455] Compound 174 is prepared via general method E using intermediates 9 and 43.
[00456] Table II: Mass spectral data of the Compounds of the Invention
MW: Molecular weight calc: calculated obs: observed
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Cpd
Structures Name MW MW
#
(calc) (obsd)
o 2-([l ,4]Dioxan-2-ylmethoxy)-9- pyridin-2 -ylethynyl-6 ,7 -
36 415 416 dihydro-pyrimido[6, 1 - a] isoquinolin-4 -one
2-([l ,4]Dioxan-2-ylmethoxy)-9- o
(3-methoxy-prop-l -ynyl)-6,7-
37 382 383 dihydro-pyrimido[6, 1 - a] isoquinolin-4 -one
5-[2-([l,4]Dioxan-2-
0
ylmethoxy)-4-oxo-6,7-dihydro-
38 391 392
N ll 4H-pyrimido[6,l -a]isoquinolin-
9 -yl] -pent-4 -ynenitrile
2-([l ,4]Dioxan-2-ylmethoxy)-9-
0
(3-hydroxy-prop-l-ynyl)-6,7-
39 368 369 dihydro-pyrimido[6, 1 - a] isoquinolin-4 -one
0 2-([l ,4]Dioxan-2-ylmethoxy)-9- (4-methoxy-phenylethynyl)-6,7-
40 444 445 dihydro-pyrimido[6, 1 - a] isoquinolin-4 -one
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Cpd
Structures Name MW MW
#
(calc) (obsd)
o 2-([l ,4]Dioxan-2-ylmethoxy)-9- pyridin-4 -ylethynyl-6 ,7 -
53 415 416 dihydro-pyrimido[6, 1 - a] isoquinolin-4 -one
2-([l ,4]Dioxan-2-ylmethoxy)-9- o
(3 -methyl-isoxazol-5 -
54 ylmethoxy)-6,7-dihydro- 425 426 pyrimido[6,l-a]isoquinolin-4- one
2-([l ,4]Dioxan-2-ylmethoxy)-9- (3 -hydroxy-3 -methyl-but- 1 -
55 ynyl)-6,7-dihydro- 396 397 pyrimido[6,l-a]isoquinolin-4- one
2-([l ,4]Dioxan-2-ylmethoxy)-9- (2-methoxy-pyridin-3-yl)-6,7-
56 421 422 dihydro-pyrimido[6, 1 - a] isoquinolin-4 -one
2-([ 1 ,4]Dioxan-2-ylmethoxy)-
57 6,7-dihydro-pyrimido[6, 1 - 314 NA
a] isoquinolin-4 -one
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
^i¾T one
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Cpd
Structures Name MW MW
#
(calc) (obsd)
9 - (4 ,4 -Dimethyl-p enty loxy) -2 - ((S)-l-[l,4]dioxan-2-
141 ylmethoxy)-6,7-dihydro- 428 429 pyrimido[6, 1 -a]isoquinolin-4- one
2-((S)-l-[l ,4]Dioxan-2- ylmethoxy)-9 -(3 -methoxy-4-
142 methyl-p entyl) -6,7 -dihydro- 428 429 pyrimido[6, 1 -a]isoquinolin-4- one
9-(3 -Cyclopropyl-propoxy)-2- ((S)-l-[l,4]dioxan-2-
143 ylmethoxy)-6,7-dihydro- 412 413 pyrimido[6, 1 -a]isoquinolin-4- one
9-Cyclohexylamino-2-((S)-l- [1 ,4]dioxan-2-ylmethoxy)-6,7-
145 411 413 dihydro-pyrimido[6, 1 -
N II a] isoquinolin-4 -one
2-((S)-l-[l ,4]Dioxan-2-
S ylmethoxy)-9-(3 -hydroxy-4,4-
146 dimethyl-pentyl)-6,7-dihydro- 428 429 pyrimido[6, 1 -a]isoquinolin-4- one
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Table III: NMR Data of the Compounds of the Invention
Figure imgf000162_0001
Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.87 (1 H, d), 7.83 - 7.76 (2 H, m), 7.64 (1 H, d), 7.56 (1 H, d), 7.41 - 7.32 (1 H, m), 7.31 - 7.23 (3 H, m), 7.18 (1 H, s), 6.43 (1 H, s), 4.46 (2 H,
11
br. s.), 4.27 (2 H, t), 4.06 - 3.96 (1 H, m), 3.97 - 3.61 (5 H, m), 3.51 (1 H, t), 3.11 (2 H, t)
(¾ CDC13) δ ppm 8.20 (1 H, d), 7.76 (1 H, d), 7.60 (1 H, d), 7.47 (1 H, dd), 7.42 - 7.35 (2 H, m), 7.336 - 7.26 (1 H, m), 6.68 (1 H, s), 6.44 (1 H, s), 4.54 - 4.40 (2
12
H, m), 4.27 (2 H, t), 4.08 - 3.96 (1 H, m), 3.91 - 3.65 (5 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.42 (9 H, s)
(¾ DMSO-i¾ δ ppm 8.11 (1 H, d), 7.95 - 7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H, d), 7.15 (1 H, t), 7.10 (1 H, d), 6.71 (1 H, s), 4.31 - 4.25 (2 H, m), 4.09 (2 H, t),
13
3.92 - 3.84 (1 H, m), 3.79 (2 H, td), 3.71 - 3.57 (2 H, m), 3.55 - 3.46 (1 H, m), 3.40 (1 H, dd), 3.08 (2 H, t)
(¾ CDCI3) δ ppm 8.45 (1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.56 (1 H, dd), 7.50
14 - 7.46 (1 H, m), 6.87 (1 H, d), 6.43 (1 H, s), 4.49 - 4.36 (2 H, m), 4.30 - 4.19 (2 H, m), 4.04 - 3.98 (4 H, m), 3.93 - 3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t)
(¾ CDCI3) δ ppm 8.97 (1 H, d), 8.09 (1 H, dd), 7.83 (2 H, dd), 7.63 (1 H, dd),
15 7.55 (1 H, s), 6.44 (1 H, s), 4.52 - 4.36 (2 H, m), 4.27 (2 H, t), 3.99 (1 H, tt), 3.91 - 3.59 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t)
(¾ CDCI3) δ ppm 7.73 (1 H, d), 7.57 - 7.50 (2 H, m), 7.48 - 7.45 (1 H, m), 7.42
16 (1 H, d), 6.42 (1 H, s), 4.53 - 4.39 (2 H, m), 4.28 - 4.23 (2 H, m), 4.07 - 3.97 (1 H, m), 3.94 - 3.64 (8 H, m), 3.52 (1 H, dd), 3.06 (2 H, t)
(¾ CDCI3) δ ppm 7.66 (1 H, d), 7.03 (1 H, dd), 6.94 (1 H, d), 6.29 (1 H, s), 5.22
17 (2 H, s), 4.50 - 4.33 (2 H, m), 4.27 - 4.14 (2 H, m), 4.03 - 3.93 (1 H, m), 3.90 - 3.61 (5 H, m), 3.49 (1 H, dd), 2.99 (2 H, t), 1.47 (9 H, s)
(¾ CDCI3) δ ppm 8.80 (1 H, d), 8.32 (1 H, d), 8.16 - 7.96 (2 H, m), 7.85 (1 H, d),
18 7.65 (1 H, dd), 7.57 (1 H, s), 6.45 (1 H, s), 4.56 - 4.37 (2 H, m), 4.28 (2 H, t), 4.01 (1 H, qd), 3.93 - 3.60 (5 H, m), 3.58 - 3.44 (1 H, m), 3.20 - 3.02 (5 H, m)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.41 (1 H, dd), 7.36 (1 H, s), 6.38 (1 H, s), 4.50 -
19 4.40 (2 H, m), 4.28 - 4.18 (2 H, m), 4.01 (1 H, m), 3.92 - 3.66 (5 H, m), 3.52 (1 H, dd), 3.01 (2 H, t), 2.45 (2 H, t), 1.68 (2 H, sxt), 1.09 (3 H, t)
(¾ CDCI3) δ ppm 8.58 (1 H, dd), 7.66 - 7.56 (2 H, m), 7.22 (1 H, dd), 7.19 - 7.09
20 (3 H, m), 6.36 (1 H, s), 4.50 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.95 (1 H, m), 3.91 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4 H, s), 2.98 (2 H, t) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 8.55 (1 H, dd), 8.44 (2 H, dd), 7.63 (1 H, d), 7.22 (1 H, dd),
21 7.15 (1 H, s), 6.36 (1 H, s), 4.53 - 4.36 (2 H, m), 4.26 - 4.17 (2 H, m), 4.07 - 3.95 (1 H, m), 3.93 - 3.61 (5 H, m), 3.51 (1 H, dd), 3.17 (4 H, s), 2.99 (2 H, t)
(¾ CDC13) δ ppm 8.51 (1 H, br. s.), 7.94 (1 H, s), 7.79 - 7.67 (2 H, m), 7.61 (1 H, s), 7.58 - 7.47 (2 H, m), 7.33 (1 H, t), 6.67 (1 H, br. s.), 6.43 (1 H, s), 4.56 - 4.40
22
(2 H, m), 4.29 (2 H, t), 4.04 (1 H, td), 3.97 - 3.65 (5 H, m), 3.61 - 3.48 (1 H, m), 3.11 (2 H, t)
(¾ CDCI3) δ ppm 7.76 (1 H, d), 7.58 (1 H, d), 7.50 (1 H, s), 7.45 - 7.32 (2 H, m),
23 7.13 - 7.01 (2 H, m), 6.43 (1 H, s), 4.45 (2 H, m), 4.27 (2 H, t), 4.01 (1 H, m), 3.94 - 3.63 (8 H, m), 3.52 (1 H, t), 3.08 (2 H, t)
(¾ CDCI3) δ ppm 8.56 - 8.45 (1 H, m), 8.38 (1 H, d), 7.83 (1 H, d), 7.63 (1 H,
24 dd), 7.54 (1 H, s), 7.42 (1 H, t), 6.45 (1 H, s), 4.54 - 4.36 (2 H, m), 4.31 - 4.23 (2 H, m), 4.05 - 3.96 (4 H, m), 3.93 - 3.62 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t)
(¾ CDCI3) δ ppm 8.17 (1 H, d), 8.01 (1 H, s), 7.78 (1 H, d), 7.72 - 7.60 (3 H, m),
25 7.57 (1 H, d), 6.42 (1 H, s), 4.52 - 4.38 (2 H, m), 4.32 - 4.24 (2 H, m), 4.01 (1 H, qd), 3.93 - 3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t)
(¾ CDCI3) δ ppm 7.74 (1 H, d), 7.57 (3 H, d), 7.48 (1 H, s), 7.01 (2 H, d), 6.40 (1
26 H, s), 4.51 - 4.36 (2 H, m), 4.25 (2 H, t), 3.99 (1 H, dd), 3.92 - 3.60 (8 H, m), 3.50 (1 H, t), 3.06 (2 H, t)
(¾ CDCI3) δ ppm 8.18 (1 H, s), 7.84 (3 H, d), 7.68 (1 H, dd), 7.64 - 7.55 (2 H,
27 m), 6.47 (1 H, s), 4.57 - 4.39 (2 H, m), 4.30 (2 H, t), 4.09 - 3.98 (1 H, m), 3.96 - 3.64 (5 H, m), 3.54 (1 H, dd), 3.13 (2 H, t)
(¾ CDCI3) δ ppm 8.45 (1 H, dd), 7.88 - 7.74 (2 H, m), 7.65 (1 H, d), 7.58 (1 H,
28 s), 7.36 - 7.25 (1 H, m), 6.46 (1 H, s), 4.57 - 4.40 (2 H, m), 4.29 (2 H, t), 4.03 (1 H, td), 3.96 - 3.64 (5 H, m), 3.60 - 3.46 (1 H, m), 3.12 (2 H, t)
(¾ CDCI3) δρρηι 7.99 (1 H, s), 7.80 (1 H, d), 7.64 (1 H, d), 7.56 (1 H, s), 7.50 -
29 7.32 (3 H, m), 6.45 (1 H, s), 4.56 - 4.40 (2 H, m), 4.29 (2 H, t), 4.11 - 3.97 (1 H, m), 3.95 - 3.64 (5 H, m), 3.60 - 3.46 (1 H, m), 3.11 (2 H, t), 2.26 (5 H, s)
(¾ CDCI3) δ ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.33 (1 H, s), 6.41 - 6.34 (1 H,
30 m), 4.53 - 4.39 (2 H, m), 4.29 - 4.18 (1 H, m), 4.06 - 3.97 (1 H, m), 3.93 - 3.64 (5 H, m), 3.52 (1 H, dd), 3.00 (2 H, t), 1.56 - 1.45 (1 H, m), 1.01 - 0.83 (4 H, m)
(¾ CDCI3) δ ppm 7.67 (1 H, d), 7.45 (1 H, dd), 7.39 (1 H, s), 6.40 (1 H, s), 4.53 -
31 4.38 (2 H, m), 4.31 - 4.17(2 H, m), 4.02 (1 H, dd), 3.94 - 3.64 (5 H, m), 3.52 (1 H, dd), 3.08 - 2.96 (2 H, m), 2.18 - 1.75 (7 H, m), 1.29 (1 H, s) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 9.32 (1 H, s), 9.04 (2 H, s), 7.90 (1 H, d), 7.66 (1 H, dd), 7.58
32 (1 H, s), 6.48 (1 H, s), 4.56 - 4.40 (2 H, m), 4.37 - 4.27 (2 H, m), 4.11 - 3.99 (1 H, m), 3.96 - 3.64 (5 H, m), 3.60 - 3.46 (1 H, m), 3.17 (2 H, t)
(¾ CDC13) δ ppm 7.67 (1 H, d), 7.42 (1 H, d), 7.32 (1 H, s), 6.39 (1 H, s), 6.31 (1
33 H, t), 4.54 - 4.38 (2 H, m), 4.25 (2 H, t), 4.02 (1 H, dd), 3.94 - 3.64 (5 H, m), 3.53 (1 H, t), 3.03 (2 H, t), 2.45 (2 H, d), 2.29 (2 H, dd), 1.91 - 1.58 (4 H, m)
(¾ DMSO-i/6) δ ppm 8.07 (1 H, d), 7.97 (1 H, s), 7.78 - 7.72 (2 H, m), 7.62 - 7.53 (2 H, m), 7.39 (1 H, d), 6.68 (1 H, s), 6.52 (1 H, d), 4.33 - 4.24 (2 H, m), 4.09
34
(2 H, t), 3.91 - 3.76 (5 H, m), 3.71 - 3.58 (2 H, m), 3.55 - 3.47 (1 H, m), 3.40 (1 H, m), 3.29 (1 H, s), 3.10 (2 H, t)
(¾ CDCI3) δ ppm 8.84 (1 H, d), 7.96 (1 H, d), 7.85 (1 H, d), 7.64 (1 H, dd), 7.56
35 (1 H, s), 7.40 (1 H, d), 6.47 (1 H, s), 4.55 - 4.40 (2 H, m), 4.37 - 4.23 (2 H, m), 4.04 (1 H, m), 3.95 - 3.65 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t), 2.74 (3 H, s)
(¾ CDCI3) δ ppm 8.69 (1 H, d), 7.78 - 7.72 (2 H, m), 7.65 - 7.57 (3 H, m), 7.33
36 (1 H, m), 6.43 (1 H, s), 4.54 - 4.39 (2 H, m), 4.27 (2 H, t), 4.05 (1 H, s), 3.95 - 3.64 (5 H, m), 3.53 (1 H, dd), 3.07 (2 H, t)
(¾ CDCI3) δ ppm 7.68 (1 H, d), 7.47 (1 H, dd), 7.42 (1 H, s), 6.40 (1 H, s), 4.53 -
37 4.41 (2 H, m), 4.38 (2 H, s), 4.24 (2 H, t), 4.07 - 3.96 (1 H, m), 3.93 - 3.63 (5 H, m), 3.55 - 3.33 (4 H, m), 3.03 (2 H, t)
(¾ CDCI3) δ ppm 7.67 (1 H, d), 7.44 (1 H, dd), 7.39 (1 H, s), 6.39 (1 H, s), 4.50 -
38 4.40 (2 H, m), 4.26 - 4.20 (2 H, m), 4.04 - 3.98 (1 H, m), 3.91 - 3.65 (5 H, m), 3.52 (1 H, dd), 3.02 (2 H, t), 2.90 - 2.83 (2 H, m), 2.75 - 2.68 (2 H, m)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.42 (1 H, dd), 7.37 (1 H, s), 6.38 (1 H, s), 4.51
39 (2 H, s), 4.48 - 4.378 (2 H, m), 4.19 (2 H, t), 4.03 - 3.96 (1 H, m), 3.89 - 3.64 (5 H, m), 3.51 (1 H, dd), 2.99 (2 H, t)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.50 - 7.44 (3 H, m), 7.41 (1 H, s), 6.94 - 6.84 (2 H, m), 6.35 (1 H, s), 4.45 - 4.36 (2 H, m), 4.19 (2 H, t), 4.04 - 3.91 (1 H, m), 3.87 -
40 3.62 (8 H, m), 3.48 (1 H, dd),7.81 (1 H, d), 7.59 - 7.48 (2 H, m), 7.43 (1 H, s), 7.41 - 7.33 (3 H, m), 6.47 (1 H, s), 4.54 - 4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 - 3.65 (5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t)
(¾ CDCI3) δ ppm 8.78 (1 H, d), 8.59 (1 H, dd), 7.83 (1 H, dt), 7.71 (1 H, d), 7.54 (1 H, dd), 7.49 (1 H, s), 7.39 - 7.25 (1 H, m), 6.40 (1 H, s), 4.51 - 4.33 (2 H, m),
41
4.30 - 4.16 (2 H, m), 4.07 - 3.93 (1 H, m), 3.90 - 3.59 (5 H, m), 3.49 (1 H, dd), 3.04 (2 H, t) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.93 (2 H, d), 7.78 (1 H, d), 7.72 - 7.59 (3 H, m), 7.54 (1 H, s),
42 6.42 (1 H, s), 4.49 - 4.35(2 H, m), 4.23 (2 H, t), 4.05 - 3.95 (1 H, m), 3.91 - 3.61 (5 H, m), 3.49 (1 H, t), 3.16 - 2.97 (5 H, m)
(¾ CDC13) δ ppm 7.81 (1 H, d), 7.64 (1 H, d), 7.55 (1 H, br. s.), 7.50 - 7.37 (1 H, m), 7.24 (1 H, d), 7.18 (1 H, br. s.), 7.00 (1 H, d), 6.46 (1 H, br. s.), 4.47 (2 H, d),
43
4.30 (2 H, br. s.), 4.04 (1 H, br. s.), 3.98 - 3.66 (7 H, m), 3.54 (1 H, t), 3.12 (2 H, br. s.), 1.83 (1 H, br. s.)
(¾ CDCI3) δ ppm 7.81 (1 H, d), 7.59 - 7.48 (2 H, m), 7.43 (1 H, s), 7.41 - 7.33 (3
44 H, m), 6.47 (1 H, s), 4.54 - 4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 - 3.65 (5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t)
(¾ CDCI3) δ ppm 7.62 (1 H, d), 7.39 (1 H, d), 7.34 (1 H, s), 6.36 (1 H, s), 4.51 -
45 4.34 (2 H, m), 4.19 (2 H, t), 3.99 (1 H, td), 3.91 - 3.59 (7 H, m), 3.50 (1 H, dd), 2.98 (2 H, t), 2.74 (2 H, t)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.02 (1 H, dd), 6.92 (1 H, d), 6.30 (1 H, s), 6.13
46 (1 H, s), 5.09 (2 H, s), 4.51 - 4.36 (2 H, m), 4.22 (2 H, t), 4.07 - 3.97 (1 H, m), 3.92 - 3.61 (8 H, m), 3.57 - 3.44 (1 H, m), 2.99 (2 H, t), 2.30 (3 H, s)
(¾ CDCI3) δρρηι 7.62 (1 H, d), 7.37 (1 H, d), 7.00 (1 H, dd), 6.90 (1 H, d), 6.33
47 (1 H, d), 6.27 (1 H, s), 5.12 (2 H, s), 4.47 - 4.34 (2 H, m), 4.23 - 4.143 (2 H, m), 4.02 - 3.89 (4 H, m), 3.88 - 3.59 (5 H, m), 3.48 (1 H, dd), 2.96 (2 H, t)
(¾ CDCI3) δ ppm 7.67 (1 H, d), 6.99 (1 H, dd), 6.90 (1 H, d), 6.29 (1 H, s), 5.33
48 (2 H, s), 4.47 - 4.35 (2 H, m), 4.20 (2 H, t), 4.03 - 3.93 (1 H, m), 3.89 - 3.60 (5 H, m), 3.48 (1 H, dd), 2.99 (2 H, t), 2.45 (3 H, s)
(¾ CDCI3) δ ppm 7.77 (1 H, d), 7.66 - 7.57 (3 H, m), 7.52 (1 H, d), 7.04 (2 H, d),
49 6.43 (1 H, s), 4.55 - 4.40 (2 H, m), 4.35 - 4.24 (2 H, m), 4.04 (1 H, dd), 3.97 - 3.66 (9 H, m), 3.54 (1 H, dd), 3.32 - 3.20 (4 H, m), 3.10 (2 H, s)
(¾ CDCI3) δ ppm 8.06 (1 H, dd), 7.92 - 7.78 (2 H, m), 7.63 (1 H, d), 7.56 (1 H,
50 s), 7.36 - 7.24 (1 H, m), 6.47 (1 H, s), 4.55 - 4.38 (2 H, m), 4.28 (2 H, t), 4.13 - 3.99 (1 H, m), 3.95 - 3.65 (5 H, m), 3.54 (1 H, t), 3.11 (2 H, t)
(¾ CDCI3) δ ppm 7.95 (1 H, t), 7.80 (1 H, d), 7.67 - 7.54 (3 H, m), 7.54 - 7.45 (1
51 H, m), 6.44 (1 H, s), 4.52 - 4.35 (2 H, m), 4.31 - 4.19 (2 H, m), 4.09 - 3.96 (1 H, m), 3.95 - 3.64 (5 H, m), 3.58 - 3.46 (1 H, m), 3.10 (2 H, t)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, d), 6.38 (1 H, s), 4.52 -
52 4.39 (2 H, m), 4.26 - 4.16 (2 H, m), 4.04 - 3.96 (1 H, m), 3.93 - 3.63 (5 H, m), 3.51 (1 H, dd), 3.00 (2 H, t), 1.36 (9 H, s) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 8.72 - 8.64 (2 H, m), 7.75 (1 H, d), 7.59 (1 H, dd), 7.54 (1 H,
53 s), 7.48 - 7.42 (2 H, m), 6.44 (1 H, s), 4.55 - 4.39 (2 H, m), 4.34 - 4.22 (2 H, m), 4.03 (1 H, dd), 3.95 - 3.64 (5 H, m), 3.53 (1 H, dd), 3.08 (2 H, t)
(¾ CDC13) δ ppm 7.68 (1 H, d), 6.98 (1 H, dd), 6.89 (1 H, d), 6.31 (1 H, s), 6.23
54 (1 H, s), 5.22 (2 H, s), 4.52 - 4.36 (2 H, m), 4.29 - 4.18 (2 H, m), 4.07 - 3.96 (1 H, m), 3.93 - 3.63 (5 H, m), 3.51 (1 H, dd), 3.06 - 2.96 (2 H, m), 2.35 (3 H, s)
(¾ CDCI3) δ ppm 7.60 (1 H, d), 7.39 - 7.35 (1 H, m), 7.32 (1 H, d), 6.33 (1 H, s),
55 4.45 - 4.35 (2 H, m), 4.17 (2 H, t), 3.97 (1 H, m), 3.87 - 3.60 (5 H, m), 3.47 (1 H, dd), 2.95 (2 H, t), 1.62 (6 H, s)
(¾ CDCI3) δ ppm 8.24 (1 H, dd), 7.78 (1 H, d), 7.67 (1 H, dd), 7.61 (1 H, dd),
56 7.54 (1 H, s), 7.04 (1 H, dd), 6.45 (1 H, s), 4.52 - 4.41 (2 H, m), 4.28 (2 H, t), 4.02 (4 H, s), 3.93 - 3.64 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t)
(¾ CDCI3) δ ppm 7.70 (1 H, d), 7.43 (1 H, dd), 7.33 (1 H, d), 6.39 (1 H, s), 6.31
58 (1 H, dt), 4.53 - 4.34 (4 H, m), 4.31 - 4.19 (2 H, m), 4.06 - 3.94 (3 H, m), 3.92 - 3.61 (5 H, m), 3.51 (1 H, dd), 3.04 (2 H, t), 2.62 - 2.50 (2 H, m)
(¾ CDCI3) δ ppm 9.02 (1 H, d), 8.09 (1 H, dd), 7.97 - 7.80 (2 H, m), 7.67 (1 H,
59 dd), 7.59 (1 H, d), 6.48 (1 H, s), 4.56 - 4.38 (2 H, m), 4.36 - 4.25 (2 H, m), 4.03 (1 H, m), 3.95 - 3.63 (5 H, m), 3.53 (1 H, dd), 3.16 (2 H, t)
(¾ CDCI3) δ ppm 8.43 (1 H, d), 7.86 - 7.74 (2 H, m), 7.56 (1 H, dd), 7.47 (1 H, d), 6.80 (1 H, d), 6.43 (1 H, s), 5.44 - 5.31 (1 H, m), 4.53 - 4.37 (2 H, m), 4.26 (2
60
H, t), 4.01 (1 H, m), 3.92 - 3.62 (5 H, m), 3.51 (1 H, dd), 3.09 (2 H, t), 1.40 (6 H, d)
(¾ CDCI3) δ ppm 8.44 (1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.57 (1 H, dd), 7.48
61 (1 H, d), 6.85 (1 H, d), 6.43 (1 H, s), 4.54 - 4.37 (4 H, m), 4.27 (2 H, t), 4.02 (1 H, m), 3.93 - 3.62 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t), 1.45 (3 H, t)
(¾ CDCI3) δ ppm 8.52 (1 H, d), 7.85 - 7.72 (2 H, m), 7.56 (1 H, dd), 7.47 (1 H,
62 d), 6.75 (1 H, d), 6.42 (1 H, s), 4.52 - 4.38 (2 H, m), 4.32 - 4.22 (2 H, m), 4.06 - 3.97 (1 H, m), 3.93 - 3.58 (13 H, m), 3.52 (1 H, dd), 3.09 (2 H, s)
(¾ CDCI3) δ ppm 7.77 (1 H, d), 7.60 (1 H, dd), 7.52 (1 H, d), 7.21 - 7.12 (1 H,
63 m), 6.99 (2 H, ddd), 6.45 (1 H, s), 4.53 - 4.40 (2 H, m), 4.28 (2 H, t), 4.06 - 3.98 (1 H, m), 3.95 (3 H, s), 3.92 - 3.63 (8 H, m), 3.52 (1 H, dd), 3.08 (2 H, t)
(¾ CDCI3) δ ppm 8.15 (1 H, d), 7.82 (1 H, d), 7.50 (1 H, dd), 7.45 - 7.40 (1 H,
64 m), 6.91 (1 H, d), 6.46 (1 H, s), 4.54 - 4.40 (2 H, m), 4.29 (2 H, t), 4.11 (2 H, s), 4.07 - 3.98 (1 H, m), 3.94 - 3.64 (4 H, m), 3.53 (1 H, dd), 3.11 (2 H, t) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 8.62 (1 H, d), 7.84 (1 H, d), 7.67 (1 H, dd), 7.59 (1 H, d), 7.42 (1 H, s), 7.36 (1 H, dd), 6.46 (1 H, s), 4.54 - 4.38 (2 H, m), 4.33 - 4.24 (2 H, m),
65
4.07 - 3.97 (1 H, m), 3.94 - 3.63 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t), 2.68 (3 H, s)
(¾ CDC13) δ ppm 8.88 (1 H, s), 8.82 (1 H, d), 7.88 (1 H, d), 7.68 (1 H, dd), 7.61
66 (1 H, dd), 7.53 (1 H, s), 6.45 (1 H, s), 4.49 - 4.38 (2 H, m), 4.27 (2 H, t), 4.00 (1 H, ddt), 3.90 - 3.61 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t)
(¾ CDCI3) δ ppm 7.76 (1 H, d), 7.58 (1 H, dd), 7.50 (1 H, s), 6.88 - 7.03 (3 H,
67 m), 6.44 (1 H, s), 4.54 - 4.39 (2 H, m), 4.28 (2 H, t), 4.03 (1 H, m), 3.95 - 3.63 (11 H, m), 3.53 (1 H, dd), 3.08 (2 H, t)
(¾ CDCI3) δ ppm 8.50 (1 H, d), 7.74 (2 H, td), 7.55 (1 H, dd), 7.45 (1 H, s), 6.75
68 (1 H, d), 6.40 (1 H, s), 4.56 - 4.38 (2 H, m), 4.26 (2 H, t), 4.01 (1 H, m), 3.94 - 3.58 (9 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.70 (6 H, br. s.)
(¾ CDCI3) δ ppm 8.21 (1 H, dd), 7.78 (1 H, d), 7.66 (2 H, ddd), 7.56 (1 H, s),
69 7.01 (1 H, dd), 6.45 (1 H, s), 4.54 - 4.39 (4 H, m), 4.28 (2 H, t), 4.03 (1 H, m), 3.94 - 3.64 (5 H, m), 3.53 (1 H, dd), 3.09 (2 H, t), 1.42 (3 H, t)
(¾ CDCI3) δ ppm 7.75 (1 H, d), 7.64 (1 H, d), 7.60 (1 H, dd), 7.52 (1 H, d), 6.47
70 (1 H, d), 6.43 (1 H, s), 4.53 - 4.39 (2 H, m), 4.33 - 4.23 (2 H, m), 4.03 (6 H, d), 3.94 - 3.64 (5 H, m), 3.59 - 3.48 (2 H, m), 3.08 (2 H, t)
(¾ CDCI3) δ ppm 9.00 (1 H, s), 8.87 (1 H, d), 7.87 (1 H, d), 7.63 (1 H, dd), 7.56
71 (1 H, s), 7.52 - 7.48 (1 H, m), 6.45 (1 H, s), 4.51 - 4.36 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, ddt), 3.90 - 3.60 (5 H, m), 3.54 - 3.44 (1 H, m), 3.12 (2 H, t)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.34 (1 H, d), 7.30 (1 H, s), 6.36 (1 H, s), 4.48 (2
72 H, s), 4.46 - 4.34 (2 H, m), 4.18 (2 H, t), 4.02 - 3.92 (1 H, m), 3.89 - 3.60 (5 H, m), 3.54 - 3.42 (1 H, m), 3.00 (2 H, t), 1.30 (9 H, s)
(¾ CDCI3) δ ppm 8.19 (1 H, dd), 7.69 (1 H, d), 7.38 (2 H, ddd), 7.29 (1 H, d), 6.72 (1 H, dd), 6.40 (1 H, s), 4.47 - 4.37 (2 H, m), 4.24 (2 H, t), 4.03 - 3.93 (1 H,
73
m), 3.89 - 3.59 (5 H, m), 3.49 (1 H, t), 3.18 - 3.08 (4 H, m), 3.04 (2 H, t), 1.82 - 1.72 (4 H, m)
(¾ CDCI3) δ ppm 8.51 (1 H, d), 7.75 (2 H, td), 7.56 (1 H, dd), 7.46 (1 H, s), 6.48
74 (1 H, d), 6.41 (1 H, s), 4.56 - 4.37 (2 H, m), 4.27 (2 H, t), 4.02 (1 H, dd), 3.95 - 3.63 (5 H, m), 3.61 - 3.45 (5 H, m), 3.09 (2 H, t), 2.14 - 1.99 (4 H, m)
(¾ CDCI3) δ ppm 7.70 - 7.57 (2 H, m), 7.47 - 7.20 (5 H, m), 7.05 (1 H, dd), 6.96
75 (1 H, d), 6.27 (1 H, s), 5.26 (2 H, s), 4.47 - 4.32 (2 H, m), 4.23 - 4.15 (2 H, m), 4.03 - 3.91 (1 H, m), 3.89 - 3.56 (5 H, m), 3.47 (1 H, dd), 2.97 (2 H, t) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.67 (1 H, d), 7.05 (1 H, dd), 6.96 (1 H, d), 6.75 (1 H, s), 6.31
76 (1 H, s), 5.18 (2 H, s), 4.53 - 4.34 (2 H, m), 4.22 (2 H, t), 4.00 (1 H, m), 3.92 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.00 (2 H, t), 1.32 (9 H, s)
(¾ CDC13) δ ppm 7.64 (1 H, d), 7.00 (1 H, dd), 6.91 (1 H, d), 6.27 (1 H, s), 5.17
77 (2 H, s), 4.47 - 4.32 (2 H, m), 4.23 - 4.14 (2 H, m), 3.96 (1 H, qd), 3.89 - 3.58 (5 H, m), 3.47 (1 H, dd), 2.97 (2 H, t), 2.29 - 2.17 (1 H, m), 1.30 - 1.24(4 H, m)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.92 (1 H, d), 6.27 (1 H, s), 5.22
78 (2 H, s), 4.47 - 4.30 (2 H, m), 4.24 - 4.13 (2 H, m), 3.96 (1 H, m), 3.90 - 3.580 (5 H, m), 3.47 (1 H, dd), 3.02 - 2.85 (4 H, m), 1.41 (3 H, t)
(¾ CDCI3) δ ppm 7.68 (1 H, d), 7.05 (1 H, dd), 6.95 (1 H, d), 6.32 (1 H, s), 5.26
79 (2 H, s), 4.52- 4.37 (2 H, m), 4.28 - 4.20 (2 H, m), 4.06 - 3.96 (1 H, m), 3.94 - 3.62 (5 H, m), 3.51 (1 H, dd), 3.02 (2 H, t), 2.67 (3 H, s)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.22
80 (2 H, s), 4.47 - 4.33 (2 H, m), 4.19 (2 H, t), 4.03 - 3.91 (1 H, m), 3.89 - 3.59 (5 H, m), 3.48 (1 H, dd), 3.26 (1 H, dt), 2.99 (2 H, t), 1.43 (6 H, d)
(¾ CDCI3) δ ppm 7.63 (1 H, d), 7.40 (1 H, dd), 7.34 (1 H, s), 6.38 (1 H, s), 4.53 - 4.37 (2 H, m), 4.27 - 4.17 (2 H, m), 4.05 - 3.96 (1 H, m), 3.93 - 3.63 (5 H, m), 3.58
81
- 3.46 (1 H, m), 3.00 (2 H, t), 2.88 (1 H, m), 2.13 - 1.97 (2 H, m), 1.90 - 1.56 (6 H, m)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.41 (1 H, d), 7.35 (1 H, s), 6.38 (1 H, s), 4.52 -
82 4.36 (2 H, m), 4.22 (2 H, t), 4.01 (1 H, m), 3.93 - 3.63 (5 H, m), 3.51 (1 H, t), 3.00 (2 H, t), 2.71 - 2.58 (1 H, m), 1.99 - 1.31 (10 H, m)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.49 -
83 4.40 (2 H, m), 4.22 (2 H, t), 4.05 - 3.97 (1 H, m), 3.91 - 3.65 (5 H, m), 3.51 (1 H, dd), 3.00 (2 H, t), 2.88 - 2.78 (1 H, m), 1.31 (6 H, d)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.51 -
84 4.38 (2 H, m), 4.26 - 4.18 (2 H, m), 4.07 - 3.97 (1 H, m), 3.93 - 3.64 (5 H, m), 3.52 (1 H, dd), 3.00 (2 H, t), 2.47 (2 H, t), 1.70 - 1.45 (4 H, m), 0.99 (3 H, t)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.45 (1 H, dd), 7.41 - 7.31 (5 H, m), 7.27 (1 H,
85 s), 6.37 (1 H, s), 4.49 - 4.34 (2 H, m), 4.24 - 4.17 (2 H, m), 4.02 - 3.94 (1 H, m), 3.90 - 3.60 (7 H, m), 3.54 (2 H, s), 3.52 - 3.45 (1 H, m), 3.00 (2 H, t), 2.42 (3 H, s)
(¾ CDCI3) δ ppm 7.63 (1 H, d), 7.42 (1 H, dd), 7.36 (1 H, s), 6.37 (1 H, s), 4.70 -
86 4.65 (1 H, m), 4.47 - 4.37 (2 H, m), 4.20 (2 H, t), 4.00-3.97 (1 H, m), 3.88 - 3.63 (5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.93 - 1.65 (4 H, m), 1.00 - 0.97 (6 H, m) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.63 (1 H, d), 7.42 (1 H, d), 7.36 (1 H, s), 6.37 (1 H, s), 4.80 -
87 4.77 (1 H, m), 4.46 - 4.37 (2 H, m), 4.20 (2 H, t), 4.01 -3.97 (1 H, m), 3.89 - 3.65 (5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.99 (1 H, d), 1.57 (3 H, d)
(¾ CDC13) δ ppm 7.60 (1 H, d), 7.07 (1 H, d), 6.99 (1 H, s), 6.35 (1 H, s), 4.49 -
88 4.38 (2 H, m), 4.21 (2 H, t), 4.01 (1 H, m), 3.94 - 3.62 (5 H, m), 3.51 (1 H, t), 2.99 (2 H, t), 2.07 - 1.86 (1 H, m), 1.15 - 1.06 (2 H, m), 0.85 - 0.78 (2 H, m)
(¾ DMSO-i½) δ ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H, s),
89 5.53 (1 H, d), 4.43 - 4.41 (1 H, m), 4.26 - 4.25 (2 H, m), 4.01 (2 H, t), 3.87 - 3.40 (7 H, m), 3.00 (2 H, t), 1.67 - 1.65 (2 H, m), 0.98 (3 H, t)
(¾ DMSO-i½) δ ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H, s),
90 5.53 (1 H, d), 4.28 - 4.25 (3 H, m), 4.01 (2 H, t), 3.85 - 3.38 (7 H, m), 3.00 (2 H, t), 1.85 - 1.80 (1 H, m), 0.98 (6 H, t)
(¾ DMSO-i½) δ ppm 8.00 (1 H, d), 7.44 (1 H, s), 7.38 (1 H, d), 6.68 (1 H, s), 5.27 (1 H, S), 4.26 - 4.25 (2 H, m), 4.01 (2 H, t), 3.86 - 3.74 (3 H, m), 3.67 - 3.60
91
(2 H, m) 3.52 - 3.46 (1 H, m), 3.37 - 3.35 (1 H, m), 3.00 (2 H, t), 1.66 - 1.62 (4 H, m), 0.99 (6 H, t)
(¾ CDCI3) δ ppm 7.71 (2 H, d), 7.66 (1 H, d), 7.47 (1 H, d), 7.43 - 7.32 (4 H, m),
92 6.38 (1 H, s), 4.47 - 4.37 (2 H, m), 4.20 (2 H, t), 4.00 - 3.98 (1 H, m), 3.97 - 3.68 (5 H, m), 3.49 (1 H, t), 3.00 (2 H, t), 2.53 (1 H, s), 1.88 (3 H, s)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.43 - 7.29 (7 H, m), 6.37 (1 H, s), 4.46 - 4.37 (2
93 H, m), 4.21 (2 H, t), 3.99 - 3.95 (3 H, m), 3.88 - 3.63 (7 H, m), 3.49 (1 H, t), 2.99 (2 H, t)
(¾ CDCI3) δ ppm 7.57 - 7.48 (1 H, d), 7.38 (1 H, s), 6.68 - 6.55 (1 H, d), 6.49 (1 H, s), 6.35 (1 H, s), 6.28 (1 H, s), 6.20 (1 H, s), 4.60 - 4.50 (1 H, m), 4.38 - 4.30 (4
94
H, m), 4.22 - 4.15 (2 H, m), 4.03 - 3.93 (1 H, m), 3.95 - 3.60 (5 H, m), 3.55 -3.40 (1 H, t), 2.98 - 2.85 (2 H, m)
(¾ CDCI3) δ ppm 7.86 (1 H, s), 7.77 (1 H, s), 7.70 (1 H, d), 7.51 (1 H, d), 7.42 (1
95 H, s), 6.39 (1 H, s), 4.51 - 4.37 (2 H, m), 4.330 - 4.20 (4 H, m), 4.05 - 3.96 (1 H, m), 3.87 (5 H, s), 3.51 (1 H, dd), 3.05 (2 H, t), 1.57 (4 H, t)
(¾ CDCI3) δ ppm 7.85 (1 H, s), 7.75 (1 H, s), 7.70 (1 H, d), 7.50 (1 H, dd), 7.42 (1 H, s), 6.39 (1 H, s), 4.50 - 4.39 (2 H, m), 4.27 - 4.18 (4 H, m), 4.05 - 3.97 (1 H,
96
m), 3.86 (5 H, m), 3.51 (1 H, dd), 3.05 (2 H, t), 1.88 - 1.79 (2 H, m), 1.69 - 1.59 (1 H, m), 1.00 (6 H, d) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 8.03 (1 H, d), 7.67 - 7.63 (2 H, m), 7.05 (1 H, d), 6.65 (1 H, s),
97 6.28 (1 H, dd), 4.30 - 4.23 (2 H, m), 4.04 (2 H, t), 3.89 - 3.75 (3 H, m), 3.63 (2 H, dd), 3.50 (1 H, d), 3.39 (1 H, dd), 3.04 (2 H, t), 2.37 (3 H, s)
(¾ CDC13) δ ppm 7.64 (1 H, d), 7.42 (1 H, d), 7.36 (1 H,s), 6.37 (1 H, s), 4.66 - 4.61 (1 H, m), 4.47 - 4.37 (2 H, t), 4.20 (2 H, t), 4.00 - 3.88 (1 H, m), 3.88 - 3.46
98
(5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.90 - 1.89 (1 H, m), 1.81 - 1.77 (2 H, m), 1.57 - 1.54 (2 H, m), 1.00 (3 H, t)
(¾ CDCI3) δ ppm 7.75 (1 H, d), 7.33 - 7.28 (1 H, m), 7.22 (1 H, s), 6.41 (1 H, s),
99 4.50 - 4.39 (2 H, m), 4.29 - 4.23 (2 H, m), 4.05 - 3.97 (1 H, m), 3.85 (5 H, m), 3.54 - 3.47 (1 H, m), 3.07 (2 H, d), 2.36 (6 H, s)
(¾ CDCI3) δ ppm 8.36 (1 H, br. s.), 8.07 (1 H, br. s.), 7.99 (1 H, d), 7.64 - 7.70 (2 H, m), 6.65 (1 H, s), 4.31 - 4.22 (2 H, m), 4.05 (2 H, t), 3.90 - 3.84 (1 H, m), 3.79
100
(2 H, td), 3.70 - 3.57 (2 H, m), 3.51 - 3.50 (1 H, m), 3.55 - 3.45 (1 H, m), 3.39 (1 H, dd), 3.01 (2 H, t)
(¾ CDCI3) δ ppm 7.85 (1 H, d), 7.74 (1 H, d), 7.70 (1 H, d), 7.50 (1 H, dd), 7.44 - 7.38 (1 H, m), 6.38 (1 H, s), 4.48 - 4.348 (2 H, m), 4.27 - 4.17 (2 H, m), 4.15 (2
101
H, t), 4.04 - 3.96 (1 H, m), 3.90 - 3.64 (5 H, m), 3.50 (1 H, dd), 3.04 (2 H, t), 2.02 - 1.90 (2 H, m), 0.97 (3 H, t)
(¾ CDCI3) δ ppm 7.91 - 7.80 (2 H, m), 7.71 (1 H, dd), 7.62 - 7.45 (4 H, m), 6.45
102 (1 H, s), 4.49 - 4.39 (2 H, m), 4.27 (2 H, t), 4.06 - 3.94 (1 H, m), 3.92 - 3.61 (5 H, m), 3.51 (1 H, dd), 3.11 (2 H, t)
(¾ CDCI3) δ ppm 7.80 - 7.90 (2 H, m), 7.79 - 7.69 (1 H, m), 7.66 - 7.51 (4 H, m),
103 6.47 (1 H, s), 4.57 - 4.41 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 - 3.64 (5 H, m), 3.53 (1 H, t), 3.14 (2 H, t)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.91 (1 H, d), 6.28 (1 H, s), 5.18 (2 H, s), 4.47 - 4.35 (2 H, m), 4.24 - 4.15 (2 H, m), 4.02 - 3.93 (1 H, m), 3.89 -
104
3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t), 2.29 - 2.18 (1 H, m), 1.33 - 1.20 (4 H, m)
(¾ CDCI3) δ ppm 7.65 (1 H, s), 7.51 - 7.46 (1 H, m), 7.45 - 7.41 (1 H, m), 6.37
105 (1 H, s), 4.49 - 4.36 (2 H, m), 4.21 (2 H, s), 4.04 - 3.94 (1 H, m), 3.90 - 3.610 (5 H, m), 3.53 - 3.44 (1 H, m), 3.25 (1 H, s), 3.00 (2 H, s)
(¾ CDCI3) δ ppm 9.18 (1 H, s), 8.88 (2 H, s), 7.72 (1 H, d), 7.60 - 7.53 (1 H, m),
106 7.51 (1 H, d), 6.40 (1 H, s), 4.49 - 4.36 (2 H, m), 4.23 (2 H, t), 4.02 - 3.95 (1 H, m), 3.89 - 3.58 (5 H, m), 3.49 (1 H, dd), 3.04 (2 H, t) Cpd# NMR data (δ)
(¾ CDC13) δ ppm: 7.54 (1 H, d), 7.37 (1 H, dd), 7.32 (1 H,s), 7.26 - 7.22 (2 H,
107 m), 6.81 (1 H, t), 6.75 (2 H, dd), 6.35 (1 H, s), 4.46 - 4.36 (2 H, m), 4.20 - 4.17 (4 H, m), 4.00 - 3.91 (1 H, m), 3.88 - 3.63 (5 H, m), 3.49 (1 H, t), 2.97 (2 H, t)
(¾ CDC13) δ ppm 8.36 (1 H, d), 7.89 - 7.65 (3 H, m), 7.62 - 7.55 (3 H, m), 6.44
108 (1 H, s), 4.51 - 4.38 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m), 3.91 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.22 - 3.14 (1 H, m), 3.09 (2 H, t), 1.40 (1 H, t)
(¾ CDCI3) δ ppm 7.70 - 7.60 (1 H, d), 7.50 - 7.42 (1 H, d), 7.39 (1 H, s), 6.37 (1 H, s), 4.50 - 4.35 (2 H, m), 4.25 - 4.15 (2 H, m), 4.05 - 3.95 (2 H, m), 3.92 - 3.60
110
(5 H, m), 3.56 - 3.45 (4 H, m), 3.05 - 3.95 (2 H, m), 2.15 - 1.95 (1 H, m), 1.15 - 1 (6 H, t)
(¾ CDCI3) δ ppm 7.58 (1 H, d), 7.33 (1 H, d), 7.27 (1 H, s), 6.32 (1 H, s), 4.45 -
111 4.34 (2 H, m), 4.17 (2 H, t), 3.96 (1 H, qd), 3.86 - 3.60 (5 H, m), 3.46 (1 H, dd), 2.94 (2 H, t), 1.46 (1 H, tt), 0.94 - 0.86 (2 H, m), 0.86 - 0.79 (2 H, m)
(¾ CDCI3) δ ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, s), 4.48 - 4.34 (2 H, m), 4.19 (2 H, t), 4.02 - 3.93 (1 H, m), 3.89 - 3.60 (5 H, m), 3.48 (1 H,
112
t), 3.43 - 3.35 (1 H, m), 2.98 (2 H, t), 2.95 - 2.85 (1 H, m), 2.76 - 2.64 (1 H, m), 1.84 - 1.62 (3 H, m), 0.92 (6 H, dd)
(¾ CDCI3) δ ppm 7.67 (1 H, d), 7.44 (1 H, d), 7.39 (1 H, s), 6.38 (1 H, s), 5.00 (2
113 H, s), 4.50 - 4.36 (2 H, m), 4.21 (2 H, t), 4.03 - 3.95 (1 H, m), 3.91 - 3.61 (5 H, m), 3.49 (1 H, dd), 3.01 (2 H, t)
(¾ CDCI3) δ ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.03 - 3.95 (1 H, m), 3.90 -
114
3.61 (5 H, m), 3.54 - 3.45(1 H, m), 3.02 - 2.95 (2 H, m), 2.81 - 2.72 (2 H, m), 1.59 - 1.49 (2 H, m), 0.77 - 0.64 (1 H, m), 0.49 - 0.42 (2 H, m), 0.10 - 0.02 (2 H, m)
(¾ CDCI3) δ ppm 7.66 (1 H, d), 7.33 (1 H, d), 7.29 (1 H, s), 6.36 (1 H, s), 4.50 (2
115 H, s), 4.47 - 4.35(2 H, m), 4.19 (2 H, t), 4.07 - 3.93 (2 H, m), 3.90 - 3.60 (5 H, m), 3.48 (1 H, t), 3.00 (2 H, t), 1.82 - 1.70 (6 H, m), 1.62 - 1.50 (2 H, m)
(¾ CDC13) 6 ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, s), 6.28 (1 H, s), 6.11 -
117 6.01 (1 H, m), 5.45 (1 H, dd), 5.34 (1 H, dd), 4.61 (2 H, dd), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.03 - 3.95 (1 H, m), 3.89 - 3.64 (5 H, m), 3.49 (1 H, t), 2.98 (2 H, t)
(¾ CDCI3) δ ppm 7.63 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, d), 6.28 (1 H, s), 6.11 - 6.01 (1 H, m), 5.44 (1 H, m), 5.34 (1 H, dd), 4.61 (2 H, dt), 4.47 - 4.37 (2 H, m),
118
4.21 (2 H, t), 4.03 - 3.95 (1 H, m), 3.89 - 3.63 (5 H, m), 3.49 (1 H, dd), 2.98 (2 H, t) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.68 (1 H, d), 7.36 (1 H, d), 7.31 (1 H, s), 6.41 - 6.38 (1 H, m), 4.61 (2 H, s), 4.47 - 4.37 (2 H, m), 4.25 - 4.17 (2 H, m), 3.99 (3 H, dt), 3.89 - 3.60
119
(6 H, m), 3.53 - 3.43 (3 H, m), 3.02 (2 H, t), 2.01 - 1.94 (2 H, m), 1.74 - 1.64 (2 H, m)
(¾ CDC13) δ ppm 8.62 (1 H, br. s.), 8.53 (1 H, br. s.), 7.73 (1 H, d), 7.64 (1 H, d),
120 7.41 (1 H, dd), 7.35 (1 H, s), 7.29 (1 H, d), 6.36 (1 H, s), 4.48 - 4.34 (2 H, m), 4.20 (2 H, t), 4.03 - 3.93 (3 H, m), 3.89 - 3.61 (7 H, m), 3.48 (1 H, dd), 2.99 (2 H, t)
(¾ CDCI3) δ ppm 7.60 (1 H, d), 7.19 (1 H, dd), 7.10 (1 H, s), 6.34 (1 H, s), 4.49 - 4.34 (2 H, m), 4.20 (2 H, t), 4.02 - 3.93 (1 H, m), 3.90 - 3.60 (5 H, m), 3.48 (1 H,
121
dd), 2.98 (2 H, t), 2.64 (2 H, t), 1.63 (2 H, m), 1.37 - 1.29 (4 H, m), 0.94 - 0.86 (3 H, m)
(¾, CDCI3) δ ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H, s), 4.50
122 - 4.39 (2 H, m), 4.20 (2 H, t), 4.02 - 3.98 (1 H, m), 3.89 - 3.66 (5 H, m), 3.49 (1 H, t), 2.96 (2 H, t), 1.59 - 1.48 (1 H, m), 0.98 - 0.81 (4 H, m)
(¾ CDCI3) δ ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H, m), 4.24 - 4.17 (2 H, m), 4.03 - 3.95 (1 H, m), 3.91 -
123
3.62 (5 H, m), 3.49 (1 H, dd), 3.03 - 2.95 (2 H, m), 2.81 - 2.73 (2 H, m), 1.59 - 1.50 (2 H, m), 0.71 (1 H, s), 0.49 - 0.42 (2 H, m), 0.09 - 0.03 (2 H, m)
(¾ CDCI3) δ ppm 7.69 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.82 -
124 4.75 (2 H, m), 4.72 - 4.64 (3 H, m), 4.49 (2 H, s), 4.48 - 4.37 (2 H, m), 4.21 (2 H, dd), 4.03 - 3.95 (1 H, m), 3.90 - 3.62 (5 H, m), 3.49 (1 H, dd), 3.02 (2 H, t)
(¾ CDCI3) δ ppm 7.69 (1 H, d), 7.35 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.62 (2
125 H, s), 4.54 (2 H, d), 4.48 - 4.36 (4 H, m), 4.21 (2 H, t), 3.99 (1 H, ddt), 3.90 - 3.61 (5 H, m), 3.58 (2 H, s), 3.49 (1 H, dd), 3.02 (2 H, t), 1.36 (3 H, s)
(¾ CDCI3) δ ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48 (1 H, s), 6.21 (1 H, s), 4.47 -
126 4.34 (2 H, m), 4.21 - 4.14 (2 H, m), 4.01 - 3.91 (1 H, m), 3.89 - 3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, s), 2.90 (2 H, t), 1.36 (2 H, dd), 0.96 (6 H, s), 0.87 (3 H, t)
(¾ CDCI3) δ ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, d), 4.46 - 4.34 (2 H, m), 4.19 (2 H, t), 3.97 (1 H, td), 3.89 - 3.60 (5 H, m), 3.48 (1 H, t), 3.42
127
- 3.35 (1 H, m), 2.97 (2 H, t), 2.93 - 2.85 (2 H, m), 2.70 (1 H, m), 1.84 - 1.63 (3 H, m), 0.92 (6 H, dd)
(¾ CDCI3) δ ppm 7.51 (1 H, d), 6.63 (1 H, d), 6.49 (1 H, br. s.), 6.21 (1 H, s), 4.46 - 4.356 (2 H, m), 4.21 - 4.11 (2 H, m), 3.97 (1 H, ddt), 3.88 - 3.62 (5 H, m),
128
3.48 (1 H, dd), 3.10 (2 H, d), 2.91 (2 H, t), 1.61 (1 H, m), 1.47 - 1.26 (8 H, m), 0.97 - 0.88 (6 H, m) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.63 (1 H, d), 6.93 (1 H, dd), 6.82 (1 H, d), 6.29 (1 H, s), 5.30
129 (1 H, s), 4.47 - 4.36 (2 H, m), 4.22 - 4.14 (4 H, m), 4.03 - 3.94 (1 H, m), 3.88 - 3.628 (7 H, m), 3.53 - 3.453 (4 H, m), 2.97 (2 H, t)
(¾ CDC13) δ ppm 7.64 - 7.58 (1 H, m), 6.90 (1 H, dd), 6.80 (1 H, d), 6.29 - 6.24
130 (1 H, m), 4.46 - 4.32 (2 H, m), 4.22 - 4.12 (4 H, m), 4.01 - 3.90 (1 H, m), 3.88 - 3.54 (9 H, m), 3.46 (1 H, dd), 2.95 (2 H, s), 1.23 (3 H, t)
(¾ CDCI3) δ ppm 7.60 - 7.67 (1 H, m), 6.93 - 6.86 (1 H, m), 6.78 (1 H, d), 6.29 (1 H, s), 4.50 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.94 (1 H, m), 3.91 -
131
3.61 (7 H, m), 3.53 - 3.44 (1 H, m), 3.01 - 2.93 (2 H, m), 1.37 - 1.227 (1 H, m), 0.73 - 0.65 (2 H, m), 0.42 - 0.34 (2 H, m)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 6.93 (1 H, s), 6.82 (1 H, d), 6.27 (1 H, s), 4.90 -
132 4.82 (1 H, m), 4.74 - 4.67 (1 H, m), 4.48 - 4.28 (3 H, m), 4.26 - 4.14 (3 H, m), 4.03 - 3.91 (1 H, m), 3.90 - 3.58 (5 H, m), 3.53 - 3.41 (1 H, m), 3.03 - 2.91 (2 H, m)
(¾ CDCI3) δ ppm 7.64 (1 H, s), 7.48 - 7.40 (1 H, m), 7.40 - 7.35 (1 H, m), 6.40 -
133 6.34 (1 H, m), 4.47 (4 H, s), 4.28 - 4.15 (1 H, m), 3.93 - 3.56 (10 H, m), 3.43 (5 H, s), 3.06 - 2.95 (2 H, m)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.47 - 7.41 (1 H, m), 7.38 (1 H, s), 6.37 (1 H, s),
134 4.37 - 4.49 (4 H, m), 4.26 - 4.17 (2 H, m), 3.99 (1 H, m), 3.93 - 3.44 (12 H, m), 3.05 - 2.94 (2 H, m), 1.25 (3 H, t)
(¾ CDCI3) δ ppm 7.66 (1 H, d), 7.47 - 7.42 (1 H, m), 7.40 (1 H, s), 6.37 (1 H, s),
135 4.73 - 4.67 (1 H, m), 4.62 - 4.54 (1 H, m), 4.49 (4 H, s), 4.26 - 4.16 (2 H, m), 4.04 - 3.95 (1 H, m), 3.94 - 3.60 (7 H, m), 3.56 - 3.43 (1 H, m), 3.05 - 2.96 (2 H, m)
(¾ CDCI3) δ ppm 7.68 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.57 (2
136 H, s), 4.50 - 4.36 (2 H, m), 4.27 - 4.17 (2 H, m), 4.06 - 3.92 (1 H, m), 3.92 - 3.60 (5 H, m), 3.57 - 3.44 (1 H, m), 3.17 (2 H, s), 3.09 - 2.96 (2 H, m), 0.97 (9 H, s)
(¾ CDCI3) δ ppm 7.70 - 7.64 (1 H, m), 7.40 - 7.33 (1 H, m), 7.31 (1 H, s), 6.37 (1 H, s), 4.59 (2 H, s), 4.50 - 4.35 (2 H, m), 4.27 - 4.16 (2 H, m), 4.07 - 3.94 (1 H,
137
m), 3.93- 3.59 (5 H, m), 3.57 - 3.44 (1 H, m), 3.45 - 3.34 (1 H, m), 3.08 - 2.96 (2 H, m), 2.05 - 1.90 (2 H, m), 1.82 - 1.71 (2 H, m), 1.48 - 1.18 (6 H, m)
(¾ CDCI3) δ ppm 7.68 (1 H, d), 7.37 (1 H, d), 7.32 (1 H, s), 6.38 (1 H, s), 4.58 (2 H, s), 4.51 - 4.36 (2 H, m), 4.26 - 4.176 (2 H, m), 4.05 - 3.94 (1 H, m), 3.92 - 3.61
138
(5 H, m), 3.54 - 3.44 (1 H, m), 3.38 (2 H, d), 3.07 - 2.98 (2 H, m), 1.20 - 1.05 (1 H, m), 0.63 - 0.54 (2 H, m), 0.29 - 0.20 (2 H, m) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.62 (1 H, s), 6.91 (1 H, m), 6.81 (1 H, m), 6.27 (1 H, s), 4.41
139 (2 H, s), 4.25 - 4.21 (2 H, m), 4.10 - 3.41 (12 H, m), 2.96 (2 H, t), 2.01 - 1.84 (1 H, m), 1.76 - 1.36 (5 H, m)
(¾ DMSO- ) δρρηι 7.91 (1 H, d), 7.28 - 7.18 (2 H, m), 6.60 (1 H, s), 4.32 - 4.17 (2 H, m), 4.07 - 3.96 (2 H, m), 3.92 - 3.71 (3 H, m), 3.70 - 3.43 (4 H, m), 3.38 (2
140
H, m), 3.03 - 2.91 (2 H, m), 2.78 - 2.58 (2 H, m), 1.68 - 1.58 (2 H, m), 1.08 (3 H, d)
(¾ CDC13) δ ppm 7.70 - 7.58 (1 H, d), 6.95 - 6.82 ( 1 H, d), 6.77 (1 H, s), 6.27 (1
H, s), 4.50 - 4.32 ( 2 H, m), 4.38- 4.15 (2 H, m), 4.05 - 3.92 (3 H, m), 3.92 - 3.60
141
(5 H, m), 3.55 - 3.42 (1 H, t), 3.05 - 2.92 (2 H, m), 1.85 - 1.70 (2 H, m), 1.40 -
I .30 (2 H, m), 0.92 (9 H, s)
(¾ CDCI3) δ ppm 7.61 (1 H, d), 7.21 (1 H, d), 7.13 (1 H, s) 6.35 (1 H, s), 4.46 - 4.40 (2 H, m), 4.20 (2 H, t), 3.99 - 3.97 (1 H, m), 3.87 - 3.65 (5 H, m), 3.49(1 H,
142
t), 3.39 (3 H, s), 3.00 - 2.93 (3 H, m), 2.83 - 2.82 (1 H, m), 2.66 - 2.64 (1 H, m), 1.95 - 1.91 (1 H, m), 1.75 - 1.73 (2 H, m), 0.90 (6 H, t)
(¾ CDCI3) δ ppm 7.66 - 7.60 (1 H, m), 6.91 - 6.86 (1 H, m), 6.80 - 6.76 (1 H, m), 6.28 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.17 (2 H, m), 4.11 - 4.04 (2 H, m), 4.02
143 - 3.95 (1 H, m), 3.91 - 3.61 (5 H, m), 3.54 - 3.45 (1 H, m), 3.03 - 2.94 (2 H, m), 1.98 - 1.88 (2 H, m), 1.45 - 1.36 (2 H, m), 0.78 - 0.66 (1 H, m), 0.50 - 0.43 (2 H, m), 0.09 - 0.03 (2 H, m)
(¾ CDCI3) δ ppm 7.47 (1 H, d), 6.55 - 6.48 (1 H, m), 6.40 - 6.34 (1 H, m), 6.18 (1 H, s), 4.47 - 4.33 (2 H, m), 4.22 - 4.12 (2 H, m), 4.02 - 3.92 (1 H, m), 3.83 (5 H,
145
dd), 3.53 - 3.43 (1 H, m), 3.40 - 3.28 (1 H, m), 2.89 (2 H, t), 2.13 - 1.98 (2 H, m), 1.86 - 1.73 (2 H, m), 1.73 - 1.63 (1 H, m), 1.50 - 1.11 (5 H, m)
(¾ DMSO- ) δ ppm 7.95 - 7.87 (1 H, m), 7.29 - 7.19 (2 H, m), 6.60 (1 H, s), 4.54 - 4.44 (1 H, m), 4.29 - 4.21 (2 H, m), 4.07 - 3.97 (2 H, m), 3.91 - 3.72 (3 H,
146 m), 3.70 - 3.54 (2 H, m), 3.54 - 3.43 (1 H, m), 3.43 - 3.34(1 H, m), 3.06 - 2.81 (4 H, m), 2.63 - 2.52 (1 H, m), 1.81 - 1.64 (1 H, m), 1.52 - 1.36 (1 H, m), 0.81 (9 H, s)
(¾ CDCI3) δ ppm 7.68 (1 H, d), 7.38 - 7.32 (1 H, m), 7.30 (1 H, s), 6.38 (1 H, s), 4.56 (2 H, s), 4.50 - 4.36 (2 H, m), 4.26 - 4.18 (2 H, m), 4.04 - 3.94 (1 H, m), 3.94
147
- 3.5994 (4 H, m), 3.55 - 3.44 (1 H, m), 3.40 (2 H, d), 3.07 - 2.98 (2 H, m), 2.30 - 2.16 (1 H, m), 1.86 - 1.72 (2 H, m), 1.66 - 1.51 (5 H, m), 1.35 - 1.20 (2 H, m)
(¾ CDCI3) δ ppm 7.61 (1 H, d), 7.18 (1 H, dd), 7.12 (1 H, d), 6.35 (1 H, s), 4.46 - 4.36 (2 H, m), 4.21 (2 H, t), 4.00 - 3.97 (1 H, m), 3.88 - 3.64 (5 H, m), 3.49 (1 H,
148
t), 3.34 - 3.30 (4 H, m), 2.98 (2 H, t), 2.81 - 2.60 (2 H, m), 1.89 - 1.676 (2 H, m), 1.18 (3 H, d) Cpd# NMR data (δ)
(¾ CDC13) δ ppm: 7.62 (1 H, d), 7.23 - 7.13 (4 H, m), 6.71 (1 H, t), 6.58 (2 H, d), 6.12 (1 H, s), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.08 - 3.98 (1 H, m), 3.88 - 3.63
149
(6 H, m), 3.49 (1 H, t), 3.17 (2 H, t), 2.98 (2 H, t), 2.79 (2 H, t), 2.01 - 1.94 (2 H, m)
(¾ CDC13) δ ppm 7.61 (1 H, d), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.01 - 3.97 (1 H, m), 3.88 - 3.63 (6 H, m), 3.49 (1 H,
150
t), 2.98 (2 H, t), 2.69 (2 H, t), 1.89 - 1.62 (2 H, m), 1.52 - 1.45 (2 H, m), 1.31 - 1.30 (1 H, m), 1.20 (3 H, d)
(¾ CDCI3) δ ppm 7.61 (1 H, d), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47 -
151 4.37 (2 H, m), 4.21 (2 H, t), 4.01 - 3.97 (1 H, m), 3.88 - 3.63 (7 H, m), 3.49 (1 H, t), 2.98 (2 H, t), 2.70 (2 H, t), 1.76 - 1.60 (4 H, m), 1.31 - 1.26 (1 H, m)
(¾ CDCI3) δ ppm 7.57 - 7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H, s), 4.513 - 4.33 (2 H, m), 4.26 - 4.14 (2 H, m), 4.06 - 3.93 (1 H, m), 3.92 - 3.56 (6
152
H, m), 3.56 - 3.41 (1 H, m), 3.00 - 2.90 (2 H, m), 2.88 (3 H, s), 2.04 - 1.63 (2 H, m), 1.60 - 1.31 (5 H, m), 1.28 - 1.08 (1 H, m)
(¾ CDCI3) δ ppm 7.52 - 7.46 (1 H, m), 6.55 - 6.50 (1 H, m), 6.40 - 6.36 (1 H, m), 6.19 (1 H, s), 4.48 - 4.33 (2 H, m), 4.23 - 4.13 (2 H, m), 4.04 - 3.92 (1 H, m), 3.85
153
(5 H, d), 3.56 - 3.42 (1 H, m), 3.06 - 2.99 (2 H, m), 2.93 - 2.84 (2 H, m), 1.92 - 1.50 (6 H, m), 1.36 - 1.12 (3 H, m), 1.08 - 0.91 (2 H, m)
(¾ CDCI3) δ ppm 7.50 (1 H, d), 6.59 - 6.49 (1 H, m), 6.44 - 6.35 (1 H, m), 6.20 (1 H, s), 4.49 - 4.33 (2 H, m), 4.24 - 4.13 (2 H, m), 4.05 - 3.93 (3 H, m), 3.92 -
154
3.59 (5 H, m), 3.56 - 3.32 (3 H, m), 3.16 - 3.07 (2 H, m), 2.96 - 2.84 (2 H, m), 1.98 - 1.80 (1 H, m), 1.79 - 1.64 (2 H, m), 1.428 - 1.28 (2 H, m)
(¾ CDCI3) δ ppm 7.54 - 7.46 (1 H, m), 7.14 - 7.08 (1 H, m), 7.04 (1 H, s), 6.23 (1 H, s), 4.35 - 4.21 (2 H, m), 4.13 - 3.99 (2 H, m), 3.91 - 3.80 (1 H, m), 3.79 -
155
3.45 (5 H, m), 3.41 - 3.30 (1 H, m), 2.86 (2 H, t), 2.64 - 2.54 (2 H, m), 1.67 - 1.58 (2 H, m), 1.45 (4 H, d), 0.80 (6 H, m)
(¾ CDCI3) δ ppm 7.60 (1 H, d), 7.23 - 7.19 (1 H, m), 7.13 (1 H, s), 6.34 (1 H, s),
156 4.45 - 4.35 (2 H, m), 4.18 (2 H, t), 4.02 - 3.92 (1 H, m), 3.82 (5 H, m), 3.48 (1 H, dd), 2.97 (2 H, br. t), 2.79 - 2.70 (2 H, m), 1.82 - 1.74 (2 H, m), 1.30 (6 H, s)
(¾ CDCI3) δ ppm 7.64 - 7.59 (1 H, m), 7.25 - 7.20 (1 H, m), 7.14 (1 H, s), 6.35 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.16 (2 H, m), 4.02 - 3.94 (1 H, m), 3.90 -
157
3.44 (7 H, m), 3.02 - 2.95 (2 H, m), 2.92 - 2.81 (1 H, m), 2.78 - 2.67 (1 H, m), 1.87 - 1.68 (2 H, m), 1.62 - 1.42 (2 H, m), 0.96 (3 H, s) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.70 - 7.56 (1 H, d), 6.95 - 6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1
158 H, s), 4.50 - 4.35 (2 H, m), 4.25 - 4.10 (2 H, m), 4.05 - 3.92 (1 H, m), 3.10 - 3.57 (8 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H, m), 1.05 (9H, s)
(¾ CDC13) δ ppm 7.63 (1 H, d), 6.88 (1 H, dd), 6.77 (1H, d), 6.28 (1 H, s), 4.46 - 4.36 (2 H, m), 4.20 (2 H, t), 4.05 - 3.96 (3 H, m), 3.88 - 3.65 (7 H, m), 3.51 - 3.43
159
(3 H, m), 2.97 (2 H, t), 2.12 - 2.01 (1 H, m), 1.78 - 1.75 (2 H, m), 1.59 - 1.42 (2 H, m)
(¾ CDCI3) δ ppm 7.63 (1 H, d), 7.35 - 7.18 (1 H, m), 7.12 (1H, s), 6.36 (1 H, s), 4.50 - 4.35 (2 H, m), 4.28 - 4.15 (2 H, m), 4.05 - 3.95 (1 H, m), 3.95 - 3.60 (5 H,
160
m), 3.55 - 3.42 (1 H, m), 3.05 - 2.90 (2 H, m), 2.75 - 2.60 (2 H, m), 1.80 - 1.65 (2 H, m), 1.55 - 1.48 (2 H, m), 1.22 (6 H, s)
(¾ CDCI3) δ ppm 7.68 (1 H, d), 7.34 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.55 (2 H, s), 4.48 - 4.38 (2 H, m), 4.22 (2 H, t), 4.02 - 3.96 (3 H, m), 3.91 - 3.61 (5 H,
161
m), 3.55 - 3.35 (5 H, m), 3.02 (2 H, t), 2.00 - 1.86 (1 H, m), 1.69 (2 H, dd), 1.38 (2 H, dd)
(¾ CDCI3) δ ppm 7.68 - 7.62 (1 H, m), 6.95 - 6.87 (1 H, m), 6.82 - 6.77 (1 H, m),
162 6.29 (1 H, s), 4.51 - 4.35 (2 H, m), 4.26 - 4.17 (2 H, m), 4.05 - 3.92 (1 H, m), 3.91 - 3.60 (8 H, m), 3.55 - 3.44 (1 H, m), 3.04 - 2.94 (2 H, m)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.81 (1 H, d), 6.29 (1H, s), 4.91
163 (2 H, t), 4.56 (2 H, t), 4.47 - 4.36 (2 H, m), 4.26 (2H, d), 4.21 (2 H, t), 4.00 - 3.96 (1 H, m), 3.88 - 3.63 (5 H, m), 3.51 - 3.45 (2 H, m), 2.98 (2H, t)
(¾ DMSO- ) δ ppm 7.93 (1 H, d), 6.97 - 6.92 (2 H, m),6.53 (1 H, s), 4.24 - 4.23 (2H, m), 4.08 (2 H, t), 4.00 (2 H, t), 3.98 - 3.74 (3 H, m), 3.68 - 3.57 (2 H, m),
164
3.51 - 3.48 (1 H, m), 3.37 (1 H, t), 2.96 (2 H, t), 1.84 - 1.80 (2 H, m), 1.36 - 1.30 (2 H, m), 0.81 - 0.63 (1 H, m), 0.42 - 0.39 (2 H, m), 0.04 - 0.02 (2 H, m)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 7.24 (1H, dd), 7.16 (1H, s), 6.38 (1 H, s), 4.49 -
165 4.40 (2 H, m), 4.24 (2 H, t), 4.02 - 4.00 (1 H, m), 3.89 - 3.66 (3 H, m), 3.52 (3 H, m), 3.43 (2 H, t), 3.38 (3 H, s), 3.02 (2H, t), 2.78 (2 H, t), 1.96 - 1.92 (2 H, m)
(¾ CDCI3) δ ppm 7.61 (1 H, d), 7.23 (1H, dd), 7.15 (1H, s), 6.35 (1 H, s), 4.46 - 4.36 (2 H, m), 4.20 (2 H, t), 4.01 - 3.95 (1 H, m), 3.88 - 3.62 (5 H, m), 3.49 (1 H,
166
t), 2.98 (2 H, t), 2.85 - 2.81 (2 H, m), 2.13 (1H, br s), 1.93 - 1.79 (4 H, m), 1.72 - 1.55 (6 H, m)
(¾ CDCI3) δ ppm 7.59 (1 H, d), 7.37 (1H, dd), 7.15 (1H, s), 6.34 (1 H, s), 4.44 -
167 4.35 (2 H, m), 4.17 (2 H, t), 4.01 - 3.92 (3 H, m), 3.88 - 3.60 (7 H, m), 3.47 (1 H, t), 2.94 (2 H, t), 2.07 - 2.02 (2 H, m), 1.95-1.88 (2H, m) Cpd# NMR data (δ)
(¾ CDC13) δ ppm 7.66 (1 H, d), 7.23 (1H, dd), 7.17 (1H, s), 6.39 (1 H, s), 4.51 -
168 4.40 (2 H, m), 4.24 (2 H, t), 4.09 - 3.96 (1 H, m), 3.93- 3.65 (5 H, m), 3.57-3.49 (1H, m), 3.44 (2 H, t), 3.40 (3H, s), 3.02 (2 H, t), 2.79 (2 H, t), 2.00-1.89 (2H, m)
(¾ CDC13) δ ppm 7.55 (1 H, d), 7.16 (1H, dd), 7.08 (1H, s), 6.29 (1 H, s), 4.41 -
169 4.29 (2 H, m), 4.13 (2 H, t), 3.95 - 3.86 (1 H, m), 3.81 - 3.54 (5 H, m), 3.46-3.38 (lH, m), 2.91 (2 H, t), 2.78-2.72 (2H, m), 1.87-1.75 (4 H, m), 1.72-1.53 (6 H, m)
(¾ CDCI3) δ ppm 7.66 (1 H, d), 6.95 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50 -
170 4.39 (2 H, m), 4.25-4.21 (4 H, m), 4.05 - 3.98 (1 H, m), 3.91 - 3.65 (7 H, m), 3.55- 3.49 (3H, m), 3.00 (2 H, t), 1.71-1.62 (2 H, m), 0.96 (3 H, t)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 6.94 (1H, dd), 6.83 (1H, s), 6.31 (1 H, s), 4.50 -
171 4.39 (2 H, m), 4.25-4.18 (4 H, m), 4.04 - 3.97 (1 H, m), 3.91 - 3.65 (8 H, m), 3.51 (1H, t), 3.00 (2 H, t), 1.23 (6 H, d)
(¾ CDCI3) δ ppm 7.67 (1 H, d), 6.95 (1H, dd), 6.85 (1H, s), 6.31 (1 H, s), 4.50 -
172 4.40 (2 H, m), 4.25-4.21 (4 H, m), 4.05 - 3.98 (1 H, m), 3.91 - 3.65 (7 H, m), 3.55- 3.49 (3H, m), 3.00 (2 H, t), 1.72-1.62 (2 H, m), 0.97 (3 H, t)
(¾ CDCI3) δ ppm 7.65 (1 H, d), 6.94 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50 -
173 4.40 (2 H, m), 4.26-4.19 (4 H, m), 4.04 - 3.97 (1 H, m), 3.92- 3.65 (8 H, m), 3.52 (1H, t), 3.00 (2 H, t), 1.23 (6 H, d)
(¾ CDCI3) δ ppm 7.64 (1 H, d), 7.22 (1H, dd), 7.15 (1H, s), 6.38 (1 H, s), 4.51 - 4.41 (2 H, m), 4.23 (2 H, t), 4.06 - 4.00 (1 H, m), 3.92- 3.66 (5 H, m), 3.57-3.50
174
(lH, m), 3.43 (2 H, t), 3.37 (3H, s), 3.01 (2 H, t), 2.71 (2 H, t), 1.80-1.61 (2H, m), 1.69-1.62 (2H,m)
Biological Examples
1. In vitro assays
1.1. Cell based assay: GTp-γΞ binding assay.
[00458] The following assay can be used for determination of GPR84 activation. The [35S]GTPyS binding assay measures the level of G protein activation following agonist occupation of a GPCR, by determining the binding of the non-hydrolysable analog [35S]GTPyS to Ga subunits.
[00459] The assay is performed in a 96 well plate where the following reagents are added. First 50 compound is added into the assay plate, followed by addition of 20 3,3 ' di indolylmethane at EC80 concentration (concentration which gives 80% of the activity of GPR84). In a last step, 30 of a mixture consisting of membranes-GTPyS-SpA beads is added [mixture consists of 20 μg/well membranes derived from stable cell line over expressing GPR84 (membranes are pre -incubated with 0.1 μΜ GDP for 15 min at 4°C), 0.1 nM rS]GTPyS (Perkin Elmer, NEG030) and 0.5 mg/well PVT-WGA SpA beads (Perkin Elmer, RPNQ0001)]. All components are diluted in assay buffer containing 20mM HEPES pH 7.4; 5mM MgCl2; 250mM NaCl; 0.05% BSA; 75ug/mL saponin. Reactions are incubated for 90 min at room temperature followed by centrifugation at 2000 rpm during 15 min. Plates are read on a Topcount reader (Perkin Elmer) immediately after centrifugation (readout time, 1 min/well).
[00460] TABLE IV: GPR84 assay GTFyS IC^n (nM) of selected Compounds of the invention.
na: not active
*> 1001 nM
** 501-1000 nM
*** 101-500 nM
****0.01- 100 nM
Cpd# GPR84 Cpd# GPR84
1 63
3 ** 64
4 65 **
5 ** 66
6 67 ####
7 68 ####
8 69 ####
9 #### 70 ####
16 72 ####
20 #### 74 ####
28 ** 75 ####
30 #### 76 ####
36 #### 77 ####
41 78 ####
42 79
43 80 ####
45 ** 81 ####
50 82 ####
51 83 ####
52 #### 84 ####
53 85 ####
54 86 ####
55 * 87
56 89
57 90 ####
58 91
59 ** 93 ####
60 #### 94 ####
61 #### 95 **
62 #### 96 Cpd# GPR84 Cpd# GPR84
97 137 ####
98 #### 138 ####
101 139 ####
102 140
103 141
104 #### 142 ####
105 145
106 ** 146 ####
107 #### 147 ####
108 #### 148 ####
109 #### 149 ####
110 150
111 151
112 #### 152 **
113 153
114 #### 154 **
115 #### 155 ####
116 156
117 157
118 158
119 159 ####
120 160
121 #### 161
122 #### 162
123 #### 163 ####
124 164 ####
125 ** 165 ####
126 #### 166 ####
127 #### 167 **
128 168
129 169
130 170 ####
131 #### 171 ####
132 ** 172
133 173 **
134 174 ####
135
136 ####
2. Cellular assays
2J. Human neutrophil migration assay
[00461] We have established that GPR84 agonists (MCFA such as sodiumdecanoate, 3,3' di indolylmethane and Embelin induce neutrophil chemo taxis and that GPR84 antagonists could block GPR84 agonist-induced chemo taxis but not IL8-induced chemotaxis, indicating that G Protein-Coupled Receptor 84 (GPR84) is an essential player in the process of neutrophil recruitment.
[00462] The effect of agonists or antagonists for GPR84 can therefore be assayed in a neutrophil migration test. In the neutrophil migration assay, neutrophils, freshly isolated from buffy coats from human volunteers, are treated with a compound for 30 minutes. Subsequently, the neutrophils are transferred to the upper wells of a Corning HTS transwell 96 permeable support system, of which the lower wells are filled with a embelin solution at ECso (concentration which gives 80% of the activity of GPR84). After 1 h of incubation, migration of the neutrophils towards embelin in the lower compartment can be quantified by measuring the ATP-content of the lower wells using the ATPlite luminescence ATP detection assay system (Perkin Elmer, Cat. N° : 436110).
2.1.1 Isolation of neutrophils from human buffy coat
[00463] A human buffy coat is diluted with an equal volume of ice cold DPBS. 20 mL of the diluted buffy coat is gently mixed with 4 mL of ACD buffer (140 mM citric acid, 200 mM sodium citrate and 220 mM dextrose). Then, 12 mL of the 6% dextran/0.9% NaCl solution (15 g dextran T2000 and 2.25 g NaCl dissolved in 250 mL H20) is added to the mixture and the samples are inverted gently up to 20 times. The total volume was transferred to a new recipient and incubated at room temperature for 1 h for complete separation of the two phases to occur. The yellowish supernatant is then transferred to a clean centrifugation tube and centrifuged for 12 minutes at 1300 rpm and 4°C. After centrifugation, the supernatant is discarded and the remaining cell pellet is rapidly resuspended in 12 mL of ice-cold H20 for red blood cell lysis to occur. After 20 seconds, 4 mL of ice-cold 0.6 M KC1 is added. Samples are mixed carefully and centrifuged for 6 minutes at 1300 rpm, 4°C. The supernatant is discarded and the red blood cell lysis procedure is repeated one more time. Subsequently, the cell pellet is resuspended in 4 mL of DPBS and layered over 5 mL of Lymphoprep (Nycomed Pharma, Cat. N°.: 1114545) in a 15 mL centrifuge tube. After centrifugation for 12 min at 1300 rpm, 4°C, the supernatant is removed and the cell pellet, containing the neutrophils, is resuspended in 25 mL chemotaxis buffer (RPMI 1640 medium, supplemented with 10 mM HEPES; freshly made for each experiment)
2.1.2 Migration assay
[00464] A cell suspension of 8.9x106 cells per milliliter is prepared. 20 of compound solution in chemotaxis buffer is added to 180 cell suspension. The mixture is incubated at 37°C for 30 minutes with intermediate resuspension of the cells after 15 minutes. Following this, 70 cell suspension is transferred to the upper compartment of a Corning HTS transwell 96 permeable support system with 5.0 μιη pore size polycarbonate membrane (Corning, Cat.N0.: 3387). The receiver well of the transwell system is then filled with 200 chemotaxis buffer containing compound and chemotactic agent (embelin). After incubation at 37°C in 5% CO2 for 1 h, the upper plate of the transwell system is removed and the cell suspension in the receiver plate is transferred to a 96-well V-bottom plate.50 of DPBS is added to the receiver plate to prevent remaining cells from drying out. The V-bottom plate is centrifuged for 6 minutes at 1500 rpm. The supernatant is removed and the cells are resuspended in 50 DPBS. The cells are then transferred back to the receiver plate of the transwell system. After this, 100 ATPlite solution (Perkin Elmer, Cat. N°: 436110) was added to the cells. The plate is incubated for 10 minutes in the dark, while shaking. 170 of cell lysate is then transferred to a white 96-well plate and luminescence is measured. The detected luminescent signal is considered as linearely related to the number of cells having migrated from the upper well to the receiver well.
[00465] TABLE VII: human neutrophil migration inhibition
*> 1001 nM
** 501-1000 nM
*** 101-500 nM
**** 0.01-100 nM
Cpd# Neutrophils Cpd# Neutrophils
4 80 ####
7 83 ####
8 85 ####
9 #### 89 ####
16 90 ####
17 #### 92 ####
19 #### 98 ####
20 #### 107 ####
22 #### 109 ####
23 111 ####
30 #### 112 ####
34 #### 114 ####
35 115 ####
36 116 ####
41 #### 121
42 122 ####
52 #### 123 ####
56 126 ####
60 #### 133 ####
62 #### 139 ####
63 #### 140 ####
68 #### 147 ####
69 #### 149 ####
72 #### 150 ####
77 #### 158 #### Cpd# Neutrophils Cpd# Neutrophils
159 # # # # 169 ****
160 170 ****
161 # # # # 171 ****
168 **** 174 ****
2.2. Rat neutrophil migration assay
[00466] We have established that GPR84 agonists (MCFA such as sodiumdecanoate, 3,3 ' di indolylmethane and Embelin induce neutrophil chemotaxis and that GPR84 antagonists could block GPR84 agonist-induced chemotaxis but not IL8-induced chemotaxis, indicating that G Protein-Coupled Receptor 84 (GPR84) is an essential player in the process of neutrophil recruitment.
[00467] The effect of agonists or antagonists for GPR84 can therefore be assayed in a neutrophil migration test. In the rat neutrophil migration assay, neutrophils, freshly isolated from rat after intraperitoneal injection of glycogen (0.1 %, w/v), are treated with a compound for 30 minutes. Subsequently, the neutrophils are transferred to the upper wells of a Corning HTS transwell 96 permeable support system, of which the lower wells are filled with a embelin solution at EC80 (concentration which give 80% of the activity of the GPR84). After 1 h of incubation, migration of the neutrophils towards embelin in the lower compartment can be quantified by measuring the ATP-content of the lower wells using the Cell Titer Glow Substrate assay system (Promega, Cat.N0.: G755B).
2.2.1. Isolation of neutrophils from rats
[00468] 24 h after intraperitoneal injection of glycogen (0.1 %, w/v), cells are harvested by peritoneal lavage with 25mL HBSS then centrifuged for 12 minutes at 1300 rpm and 4°C. After centrifugation, the supernatant is discarded and the remaining cell pellet is rapidly resuspended in 12 mL of ice-cold H20 for red blood cell lysis to occur. After 20 seconds, 4 mL of ice-cold 0.6 M KCl is added. Samples are mixed carefully and centrifuged for 6 minutes at 1300 rpm, 4°C. The supernatant is discarded and the cell pellet is resuspended in 4 mL of DPBS and layered over 5 mL of Lymphoprep (Axis Shield, Cat. N°.: 1114544) in a 15 mL centrifuge tube. After centrifugation for 30 min at 1500 rpm, 4°C, the supernatant is removed and the cell pellet, containing the neutrophils, is resuspended in 5 mL chemotaxis buffer (RPMI 1640 medium, supplemented with 10 mM HEPES; freshly made for each experiment).
2.2.2. Migration assay
[00469] A cell suspension of 8.9x106 cells per milliliter is prepared. 10 of compound solution in chemotaxis buffer is added to 90 vL cell suspension. The mixture is incubated at 37°C for 30 minutes with intermediate resuspension of the cells after 15 minutes. Following this, 75 cell suspension is transferred to the upper compartment of a Corning HTS transwell 96 permeable support system with 5.0 μιη pore size polycarbonate membrane (Corning, Cat.N0.: 3387). The receiver well of the transwell system is then filled with 200 chemotaxis buffer containing compound and chemotactic agent (embelin). After incubation at 37°C in 5% C02 for 1 h, the upper plate of the transwell system is removed and 70 Cell Titer Glow Substrate (Promega, Cat.N0.: G755B) are added in the receiver plate. The receiver plate is incubated for 10 minutes in the dark, while shaking. 180 of cell lysate is then transferred to a white 96-well plate and luminescence is measured. The detected luminescent signal is considered as linearely related to the number of cells having migrated from the upper well to the receiver well.
3. ADME, PK and Safety Models
3.1 Aqueous Solubility
[00470] Starting from a lOmM stock in DMSO, a serial dilution of the compound is prepared in DMSO. The dilution series is transferred to a 96 NUNC Maxisorb plate F-bottom and 0.1M phosphate buffer pH 7.4 or 0.1 M citrate buffer pH3.0 at room temperature is added.
[00471] The final concentrations range from 18.75 to 300 μΜ in 5 equal dilution steps. The final DMSO concentration does not exceed 3%.
[00472] 200μΜ Pyrene is added to the corner points of each 96 well plate and serves as a reference point for calibration of Z-axis on the microscope.
[00473] The assay plates are sealed and incubated for 1 h at 37°C while shaking at 230rpm. The plates are then scanned under a white light microscope, yielding individual pictures of the precipitate per concentration. The precipitate is analyzed and converted into a number by a custom-developed software tool. The first concentration at which the compound appears completely dissolved is the concentration reported, however the true concentration lies somewhere between this concentration and one dilution step higher.
[00474] Solubility values are reported in μΜ and in μg/mL. 3.2. Thermodynamic solubility
[00475] Two individual solutions of 2 mg/mL of compound are prepared in a 0.1 M phosphate buffer pH
7.4 or a 0.1 M citrate buffer pH 3.0 at room temperature in a 2mL glass vial.
[00476] After addition of a magnetic stir, the samples are stirred at room temperature for 24 h.
[00477] After 24 h, the vials are centrifuged 10 min at 1400 rpm. The supernatant of the sample is then transferred to a MultiscreenR Solubility Plate (Millipore, MSSLBPC50) and filtered (10-12" Hg) with the aid of a vacuum manifold into a clean Greiner polypropylene V-bottom 96 well plate. Per sample, two dilutions
(factor 10 and 100) are made in DMSO. Other dilutions can be made if the acquired peak area is not within the standard curve.
[00478] A lOmM DMSO stock, made from dry matter, is used to make a 200μg/mL working stock. The standard curve for the compound is prepared in DMSO starting from the 200μg/mL working stock. Eight concentrations and two quality control samples (QC) are made in 2mL tubes. The first 3 concentrations (50, 35 and 15μg/mL) and the first QC sample (20μg/mL) are made starting with the 200μg/mL working stock. The 4th concentration (5μg/mL) is made with the 50μg/mL solution and the 5th concentration (^g/mL) with the 15μg/mL. The last three concentrations (0.2, 0.1 and 0.05μg/mL) are made with the ^g/mL solution. The second QC sample (O^g/mL) is made with the first QC sample.
[00479] Of every step of the dilution series, quality control and sample dilutions, a volume is transferred to a 96-well Deepwell plate. The samples are injected on a LC-MS/MS system (API2000 from Applied Biosystems).
[00480] The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is 0.1 % Formic Acid in methanol. The sample is run under positive ion spray on a Pursuit 5 CI 8 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes and ranges from 10% B to 100% B.
[00481] The thermodynamic solubility samples are analyzed with the aid of QuanLynx software. For the standard curve a linear or quadratic curve can be used in the analysis. Samples of the standard curve that have more than 15% deviation are excluded; the lowest concentrations of the curve may vary up to 20%. Peak areas of the samples are plotted against the standard curve to obtain the solubility of the compound.
[00482] Solubility values are reported in μΜ or μg/mL.
3.3 Microsomal stability
[00483] A 10 niM stock solution of compound in DMSO is 1,668 fold diluted in a 105 niM phosphate buffer pH 7.4. Of this compound dilution, 50 μί is transferred in two 96 assay plates: one for time point 0 min (TO plate) and one for time point 30 min (T30 plate) and pre-warmed at 37°C.
[00484] In the time zero reference sample (TO plate), 100 μί MeOH (1 :1) is added to the wells. In each assay plate (TO and T30 min), 50 μί of microsomal mix is then added.
[00485] Final reaction concentrations are: 3 μΜ compound, 0.5 mg/mL microsomes, 0.4 U/mL GDPDH, 3.3 mM MgCl2, 3.3 mM glucose-6-phosphate and 1.3 niM NADP+.
[00486] The T30 plate is incubated at 37°C, 300 rpm and after 30 minutes of incubation the reaction is stopped with MeOH (1 : 1). The samples are mixed, centrifuged and the supernatant is harvested for analysis on LC-MS/MS (API2000 from Applied Biosystems).
[00487] The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is 0.1 % Formic Acid in methanol. The sample is run under positive ion spray on a Pursuit 5 CI 8 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes and ranges from 10%> B to 100%> B.Peak area from the parent compound at time 0 is considered to be 100%> remaining. The percentage remaining after 30 minutes incubation is calculated from time 0 The solubility of the compound in the final test concentration in buffer is inspected by microscope and results are also reported.
3.4 Hepatocyte stability.
[00488] Test compounds (1 μΜ initial concentration, n=2) are incubated in Williams' Medium E, containing 4 niM L-gutamine and 2 mM magnesium sulphate, with pooled cryopreserved hepatocytes (Celsis International) in suspension at cell densities of 0.25-0.5 million viable cells/mL. The incubations are performed at 37°C in a shaking water bath with 100
Figure imgf000186_0001
samples taken from the incubation at 0, 10, 20, 45 and 90 minutes, and reactions terminated by addition of 100
Figure imgf000186_0002
of acetonitrile containing carbamazepine as analytical internal standard. Samples are centrifuged and the supernatant fractions analysed by LC-MS/MS. The instrument responses {i.e. peak heights) are referenced to the zero time-point samples (as 100%) in order to determine the percentage of compound remaining. Ln plots of the %> remaining for each compound are used to determine the half-life for the hepatocyte incubations. Half-life values are calculated from the relationship: Ti 2 (min) = -0.693/λ, where λ is the slope of the Ln concentration vs time curve. Standard compounds testosterone, midazolam, and 4-methylumbelliferone are included in the assay design.
3.5 Plasma Protein Binding (Equilibrium Dialysis)
[00489] A l OmM stock solution of the compound in DMSO is diluted with a factor 10 in DMSO. This solution is further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation INC) with a final concentration of 5 μΜ and final DMSO concentration of 0.5%.
[00490] A Pierce Red Device plate with inserts (ThermoScientific) is prepared and filled with 450μί PBS in the buffer chamber and 300μΙ^ of the spiked plasma in the plasma chamber. The plate is incubated for 4 h at 37°C while shaking at l OOrpm. After incubation, 120μί of both chambers is transferred to 480μί methanol in a 96-well round bottom, PP deep-well plates (Nunc) and sealed with an aluminum foil lid. The samples are mixed and immediately centrifuged 30 min at 1400 rcf at 4°C and the supernatant is transferred to a 96 v-bottom PP plate (Greiner, 651201) for analysis on LC-MS/MS (API2000 from Applied Biosystems).
[00491] The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1% Formic Acid in water and solvent B is 0.1 % Formic Acid in methanol. The sample is run under positive ion spray on a Pursuit 5 CI 8 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes and ranges from 10% B to 100% B.
[00492] Peak area from the compound in the buffer chamber and the plasma chamber are considered to be 100%o compound. The percentage bound to plasma is derived from these results and is reported as percentage bound to plasma. [00493] The solubility of the compound in the final test concentration in PBS is inspected by microscope to indicate whether precipitation is observed or not.
3.6 Caco2 Permeability
[00494] Bi-directional Caco-2 assays are performed as described below. Caco-2 cells are obtained from European Collection of Cell Cultures (ECACC, cat 86010202) and used after a 21 day cell culture in 24-well Transwell plates (Corning, cell growth area: 0.33 cm2, Membrane pore size: 0.4 μΜ, membrane diameter: 6.5 mm)..
[00495] 2x105 cells/well are seeded in plating medium consisting of DMEM + GlutaMAX™-I + 1 % NEAA + 10% FBS (FetalClone II) + 1 % Pen/Strep. The medium is changed every 2 - 3 days.
[00496] Test and reference compounds (propranolol and rhodaminel23 or vinblastine, all purchased from Sigma) are prepared in Hanks' Balanced Salt Solution containing 25 niM HEPES (pH7.4) and added to either the apical (125μί) or basolateral (600μΕ) chambers of the Transwell plate assembly at a concentration of 10 μΜ with a final DMSO concentration of 0.25%.
[00497] 50μΜ Lucifer Yellow (Sigma) is added to the donor buffer in all wells to assess integrity of the cell layers by monitoring Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely permeate lipophilic barriers, a high degree of LY transport indicates poor integrity of the cell layer.
[00498] After a 1 h incubation at 37°C while shaking at an orbital shaker at 150rpm, ΊΟμΙ^ aliquots are taken from both apical (A) and basal (B) chambers and added to Ι ΟΟμί 50:50 acetonitrile: water solution containing analytical internal standard (0.5μΜ carbamazepine) in a 96 well plate.
[00499] Lucifer yellow is measured with a Spectramax Gemini XS (Ex 426nm and Em 538nm) in a clean 96 well plate containing 150μί of liquid from basolateral and apical side.
[00500] Concentrations of compound in the samples are measured by high performance liquid- chromatography/mass spectroscopy (LC-MS/MS).
[00501] Apparent permeability (Papp) values are calculated from the relationship:
P = [compound x V / ([compound]donor x Vdonor) / Tinc x Vdonor / surface area x 60 x 10"6 cm/s
V = chamber volume
Tinc = incubation time.
Surface area = 0.33cm2
[00502] The Efflux ratios, as an indication of active efflux from the apical cell surface, are calculated using the ratio of Papp B>A/ Papp A>B.
[00503] The following assay acceptance criteria are used:
Propranolol: Papp (A>B) value > 20(xl0"6 cm/s) Rhodamine 123 or Vinblastine: Papp (A>B) value < 5 (xlO 6 cm/s) with Efflux ratio >5. Lucifer yellow permeability: <100 nm/s
3.7 Liability for QT prolongation
[00504] Potential for QT prolongation is assessed in the hERG manual patch clamp assay.
3.7.1 Conventional whole-cell patch-clamp
[00505] Whole-cell patch-clamp recordings are performed using an EPC10 amplifier controlled by Pulse v8.77 software (HEKA). Series resistance is typically less than 10 ΜΩ and compensated by greater than 60%, recordings are not leak subtracted. Electrodes are manufactured from GC150TF pipette glass (Harvard).
[00506] The external bathing solution contains: 135 niM NaCl, 5 niM KC1, 1.8 niM CaCl2, 5 mM Glucose, 10 mM HEPES, pH 7.4.
[00507] The internal patch pipette solution contains: lOOmM Kgluconate, 20 mM KC1, lmM CaCl2, 1 mM MgCl2, 5mM Na2ATP, 2mM Glutathione, 1 1 mM EGTA, 10 mM HEPES, pH 7.2.
[00508] Drugs are perfused using a Biologic MEV-9/EVH-9 rapid perfusion system.
[00509] All recordings are performed on HEK293 cells stably expressing hERG channels. Cells are cultured on 12 mm round coverslips (German glass, Bellco) anchored in the recording chamber using two platinum rods (Goodfellow). hERG currents are evoked using an activating pulse to +40 mV for 1000 ms followed by a tail current pulse to -50 mV for 2000 ms, holding potential is -80 mV. Pulses are applied every 20s and all experiments are performed at room temperature.
3.7.2 Data Analysis
[00510] IC50 values are calculated for each compound tested. The fold difference between the IC50 in the manual hERG patch clamp and the unbound IC50 in the whole blood assay is calculated.
[00511] For the concentration response curves, peak tail current amplitude is measured during the voltage step to -50 mV. Curve-fitting of concentration-response data is performed using the equation:
y = a + [( b -a )/ ( 1+ 10A ( ( logc-x ) d )]
[00512] where a is minimum response, b is maximum response and d is Hill slope, this equation can be used to calculate both IC50 (where y = 50 and c is the IC50 value) and IC20 (where y = 20 and c is the IC20 value). GraphPad® Prism® (Graphpad® Software Inc.) software is used for all curve fitting. A difference of 100 fold or greater indicates a low potential for QT prolongation. 3.8 Pharmacokinetic study
3.8.1 Single dose pharmacokinetic study in rats
[00513] Compounds are formulated in PEG200/physiological saline mixtures for the intravenous route and in PEG400/0.5% methylcellulose (10/90 v/v) for the oral route. Test compounds are orally dosed as a single esophageal gavage at 5-10 mg/kg and intravenously dosed as a bolus via the caudal vein at 1 mg/kg to male Sprague-Dawley rats. Each group consists of 3 rats. Blood samples are collected either via the jugular vein using cannulated rats or at the retro-orbital sinus with lithium heparin as anti-coagulant at the time points in the following range: 0.05 to 8 h (intravenous route), and 0.25 to 6 or 24 h (oral route). Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending analysis.
3.8.2 Multiple dose pharmacokinetic study in rats
[00514] Compounds are formulated in PEG400/0.5% methylcellulose (10/90 v/v) for the oral route. Test compounds are orally dosed as an esophageal daily gavage at 30 or 300 mg/kg to male Sprague-Dawley rats for 14 days. Each group consists of 3 rats. Blood samples are collected via the tail vein with lithium heparin as anti-coagulant at the following time points on day 1, 7 and 14: 0.25, 1, 4, 8 and 24 h. In addition, on day 2 blood samples are taken at 0.25, 1 and 4 h and at day 4 and 11 at 0.25 h. Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending analysis.
3.8.3 Quantification of compound levels in plasma
[00515] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode.
3.8.4 Determination of pharmacokinetic parameters
[00516] Pharmacokinetic parameters are calculated using Winnonlin® (Pharsight®, US).
3.9 7-Day rat toxicity study
[00517] A 7-day oral toxicity study with test compounds is performed in Sprague-Dawley male rats to assess their toxic potential and toxicokinetics, at daily doses of 100, 300 and 1000 mg/kg/day, by gavage, at the constant dosage-volume of 10 mL/kg/day.
[00518] The test compounds are formulated in PEG400/0.5% methylcellulose (10/90, v/v). Each group includes 6 principal male rats as well as 3 satellite animals for toxicokinetics. A fourth group is given PEG400/0.5% methylcellulose (10/90, v/v) only, at the same frequency, dosage volume and by the same route of administration, and acts as the vehicle control group.
[00519] The goal of the study is to determine the lowest dose that results in no adverse events being identified (no observable adverse effect level - NOAEL). 3.10 Cytochrome P450 inhibition
[00520] Reversible CYP inhibition and time-dependent CYP3A4 inhibition is determined in human liver microsomes and specific probe substrates.
3.10.1 P450 inhibition in human liver microsomes, reversible inhibition
[00521] The inhibitory potential of a test compound is assessed for human cytochrome P450 isoenzymes CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4.
[00522] A 10 niM stock solution of the test compound is prepared in DMSO, serially diluted in Tris buffer (100 mM pH 7.4) and added to hepatic microsomes (Xenotech LLC) and NADPH at 37°C in a shaking water bath. Seven different test compounds concentrations (0.05 to 100 μΜ), 1% DMSO and 1 mM NADPH are obtained to react.
[00523] After 15 or 30 minutes reactions are terminated by addition of 100
Figure imgf000190_0001
of acetonitrile containing carbamazepine as analytical internal standard. Samples are centrifuged and the supernatant fractions analysed by LC-MS/MS. For each isoform, the instrument responses (peak heights) are referenced to those for DMSO controls (considered as 100%) in order to determine the percentage reduction in probe metabolism, using midazolam and testosterone as probe substrate. Percentage inhibition of probe metabolism and Log [test compound concentration] are plotted using Graphpad Prism software. The sigmoidal dose response model is fitted to the data in order to determine the IC50.
[00524] Inhibition of CYP3A4 using nifedipine and atorvastatin as probe substrate is carried out as follows.
[00525] A 1.67 mM stock solution of test compound is prepared in methanol, serially diluted 1 :3 in 50 mM potassium phosphate buffer pH7.4 and added to human hepatic microsomes (BD Gentest) and probe substrate. Seven different test compounds concentrations (0.045 - 33.3 μΜ), 2% methanol, 0.1 mg/mL microsomes, 10 μΜ atorvastatin or 5 μΜ nifedipine. After pre-warming 5 minutes at 37°C, the reaction was started by adding cofactor mix (7.65 mg/mL glucose-6-phosphate, 1.7 mg/mL NADP, 6U/mL of glucoses- phosphate dehydrogenase).
[00526] After 5 min (nifedipine) or 10 min (atorvastatin) at 37°C, the reaction (50
Figure imgf000190_0002
is terminated with 150 acetonitrile:methanol (2: 1) solution with internal standard (Warfarin). Samples are centrifuged and the supernatant fractions analyzed by LC-MS/MS. The instrument responses (ratio of test compound/internal standard peak areas) are referenced to those for solvent controls (assumed as 100%) in order to determine the percentage reduction in probe metabolism. Percent of control activity vs concentration plots are generated and fitted using GraphPad Prism software to generate IC50. 3.10.2 CYP3A4 inhibition in human liver microsomes, time-dependent
[00527] The time-dependent inhibitory potential of a test compound is assessed for human cytochrome P450 isoenzyme 3A4. The compound is pre-incubated with the human liver microsomes before addition of the probe substrates. The result is compared to the condition where the compound is not pre-incubated with the human liver microsomes to see if there was a shift in IC50, indicating time-dependent inhibition.
[00528] A 10 mM stock solution of test compound is prepared in DMSO and diluted 1 :20 with Tris buffer (100 mM pH 7.4) and further serially diluted in Tris buffer/5% DMSO.
[00529] The cofactor, NADPH, and each test compound dilution is mixed in two separate plates for 0 and 30 min pre-incubation. Human hepatic microsomes (Xenotech LLC) are added only to the "30 minute preincubation" plate and both plates are then incubated for 30 minutes at 37°C in a shaking water bath. Following the pre-incubation, microsomes are added to the "0 minute" plate and appropriate probe substrates (in 0.5% DMSO) are added to both plates. Plates are then returned to the water bath for a further incubation.
[00530] In total, six different test compound concentrations (1.6 to 50 μΜ) are assessed. Reactions are terminated with 100
Figure imgf000191_0001
of acetonitrile containing carbamazepine as analytical internal standard. Samples are centrifuged and the supernatant fractions analysed by LC- MS/MS. For each isoform, the instrument responses (peak height ratio with internal standard) are referenced to those for DMSO controls (considered as 100%>) in order to determine the percentage reduction in probe metabolism. Percentage inhibition of probe metabolism and Log [Test Compound concentration] are plotted using Graphpad Prism software. The sigmoidal dose response model is fitted to the data in order to determine the IC50.
4. In-vivo studies
[00531] The in-vivo activity of the compounds of the invention may be demonstrated in the following in vivo efficacy inflammation models.
4.1 Inflammatory bowel disease (mice).
[00532] The mouse chronic DSS-induced inflammatory bowel disease model (IBD) is a well validated disease model for inflammatory bowel disease (Wirtz S. et al, 2007 Nature Protocols 2, 541-546; Sina C. et al, 2009 J. Immunol. 183 7514-7522).
[00533] To induce a chronic colitis, female BALB/c mice are fed with 4% dextran sodium sulfate (DSS) dissolved in drinking water for 4 days, followed by 3 days of regular drinking water. This cycle is repeated three times. This protocol allows inducing a strong colitis while avoiding high mortality rates. Animals are divided into several groups:
a. intact water; vehicle alone, n=l 0),
b. diseased (DSS; vehicle alone, n=10), c. sulfazalazine used as reference (DSS; 20 mg/kg/day, >.o., n=10) and
d. the tested compound (DSS; 1 , 3, 10, 30 mg/kg/day, >.o., n=10).
[00534] Clinical parameters are measured every other day. The disease activity index (DAI) is a composite measure combining of the individual scores for weight loss, stool consistency and rectal bleeding. Mice are sacrificed at day 20 of the experiment according to the protocol introduced by Sina et /.(2009). At sacrifice time, the complete colon is removed and rinsed with sterile PBS. Segments of the distal colon are dissected for histological analysis, gene expression and protein level measurement. 4.2 Collagen-induced arthritis (mice).
[00535] The mouse collagen-induced arthritis (CIA) is the gold standard rheumatoid arthritis model (Brand, et al., 2007 Nature Protocols 2, 1269- 1275, Lin et al, 2007 Br J Pharmacol 1, 829-831). DBA1//J male mice are injected with a collagen II solution (Completed Freund's adjuvant). Immune reaction is boosted by a second injection (incomplete Freund's adjuvant) 21 days later. At day 31 , arthritis is scored according to the method of Khachigian et al. (Khachigian et al., 2006 Nature Protocols 1, 2512-2516) and animals are randomized to reach an average clinical score of 2 per group. Animals are divided into several groups: intact (no treatment, n=5), diseased (vehicle alone, n=10), Enbrel® as reference (10 mg/kg, 3x week., i.p., n=10), and the tested compound (3, 10 or 30 mg/kg/day, p.o., n=10). Therapeutic dosing lasted from day 31 to day 46 and the arthritis is scored every day. Mice are sacrificed at day 46, X-ray photos are taken of the hind paws of each individual animal and the severity of bone erosion is ranked with the radiological Larsen's score (Salvemini et al, 2001 Arthritis Rheum 44, 2909-2921).
4.3 Tabacco smoke model (mice)
[00536] Daily exposures of female inbred C57BL/6J mice to tobacco smoke (TS) for 11 consecutive days result in pulmonary inflammation, as indicated by an increase in the total number of cells recovered in the bronchoalveolar lavage (BAL), when compared with a similarly treated air-exposed group, 24 h after the final exposure. The exposure period to TS is increased initially from 25 minutes at the start of the study (day 1) to a maximum of 45 minutes on day 3 until day 11. Animals are divided into several groups: intact (no treatment, n=5), diseased (vehicle alone, n=10), Roflumilast as reference (5 mg/kg/day p.o., n=10), and the tested compounds (10 or 30 mg/kg/bid, p.o., n=10). At the end of 11 days, the numbers of macrophages, epithelial cells, neutrophils and lymphocytes are counted in the BAL. BAL is further analysed for gene expression and protein level. Lung tissue is dissected for histological analysis, gene expression and protein level measurement. [00537] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognise apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.
[00538] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
[00539] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.
[00540] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
[00541] Chemical structures shown herein were prepared using either ChemDraw® or ISIS® /DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.
[00542] REFERENCES
Wittenberger et al, 2001 J Mol Biol, 307, 799-813
Yousefi S et al, 2001 J Leukoc Biol, 69, 1045-52
Wang et al, 2006 The Journal of Biological Chemistry, 281 , 45, 34457-34464
Venkataraman et al, 2005, Immunology Letters, 101, 144-153
WO2007/027661 A2
Berry et al, 2010, Nature, 466, 973-979
Bouchard et al, 2007, Glia, 55:790-800
Bundgard, H., 1985 Design of Prodrugs, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985
Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania
T. W. Greene and P. G. M. Wuts, 2006 Protecting Groups in Organic Synthesis, Wiley-Blackwell; 4th Revised edition
Young Kim et al, 2007 Bioorganic & Medicinal Chemistry 15, 2667-2679 Le Pouls et al., 2003, The Journal of Biological Chemistry, 278, 28, 25481 -25489
Brown et al, 2003, The Journal of Biological Chemistry, 278, 13, 11312-11319
Stoddart et al, 2008, Pharmacological Reviews, 60, 405-417
Wirtz S. et al, 2007 Nature Protocols 2, 541-546
Sina C. et al, 2009 J. Immunol. 183 7514-7522
Brand, et al, 2007 Nature Protocols 2, 1269- 1275
Lin et al, 2007 Br J Pharmacol 1, 862-872
Khachigian et al, 2006 Nature Protocols 1, 2512-2516
Salvemini et al, 2001 Arthritis Rheum 44, 2909-2921
Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129
Nagasaki et.al, 2012, FEBS Letters, 586, 368-372

Claims

WHAT IS CLAIMED:
1. A compound according to Formu
Figure imgf000195_0001
la
wherein
R1 is H, Me, or halo;
Li is absent or is -0-, -S-, or -NR4a-;
G is
R2,
-W-L2-R2, or
W is Ci_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alk nylene having one triple bond;
L2 is absent or is -0-;
R2 is
- H,
Ci_8 alkyl, optionally substituted with one to three groups independently selected from o OH,
o halo,
o CN,
o Ci_6 alkoxy,
o C3-7 cycloalkyl,
o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O,
o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and
o phenyl,
C4.7 cycloalkenyl comprising one double bond, 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from N, O, and S,
C3.7 cycloalkyl optionally substituted with one or more independently selected R5 groups,
4- 10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, optionally substituted with one to three independently selected R5 groups,
5- 10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O optionally substituted with one to three independently selected R6 groups, or
C6-io aryl optionally substituted with one or more independently selected R6 groups;
L3 is -NR4b-;
R3 is
Ci_4 alkyl substituted with
o C6-io aryl optionally substituted with one or more independently selected R7 groups, or o 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more R independently selected R7 groups,
5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected R7 group, or
C6-io aryl optionally substituted with one or more independently selected R7 groups;
Each R4a and R4b is independently selected from H, C1 alkyl, and C3.7 cycloalkyl;
R5 is oxo or R6;
R6 is
- OH,
halo,
Ci_6 alkyl optionally substituted with one to three groups independently selected from halo, and OH,
Ci_6 alkoxy optionally substituted with one to three groups independently selected from halo, and OH,
C3.7 cycloalkyl,
- -C(=0)OR8,
- -C(=0)NR9R10,
-
Figure imgf000196_0001
alkyl,
- -CN,
phenyl, -O-phenyl,
4- 7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or
5- 6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S, optionally substituted with one or more indepentently selected Cw alkyl, CM alkoxy, CN, halo, and -C(=0)ORu;
R7 is Ci_4 alkyl, or halo; and
each of R8, R9, R10 and R11 is independently selected from H and C1.4 alkyl,
or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable salt.
2. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein R1 is H.
3. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula Ila or Ilia:
Figure imgf000197_0001
Ma wherein Li, W, L2, and R are as described in claim 1.
4. A compound or pharmaceutically acceptable salt thereof, according to claim 3, wherein the compound is according to Formula Ila, and Li is absent.
5. A compound or pharmaceutically acceptable salt thereof, according to claim 3, wherein the compound is according to Formula Ilia, and Li is absent or is -0-; W is Ci_4 alkylene, or C2_4 alkenylene having one double bond.
6. A compound or pharmaceutically acceptable salt thereof, according to claim 3, wherein the compound is according to Formula Ilia, and Li is absent; W is C2_4 alkynylene having one triple bond; and L2, and R2 are as described in claim 1.
7. A compound or pharmaceutically acceptable salt thereof, according to claim 5 or 6, wherein L2 is absent.
8. A compound or pharmaceutically acceptable salt thereof, according to claim 3, wherein the compound is according to Formula Ilia, wherein Li and L2 are absent, W is -CH2-CH2-, -CH=CH-, or C≡C-, and R2 is as described in claim 1.
9. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 3-8, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, optionally substituted with one to three independently selected R6 groups.
10. A compound or pharmaceutically acceptable salt thereof, according to claim 9, wherein R6 is selected from OH, halo, Ci_6 alkyl, Ci_6 alkyl substituted with one or more halo, Ci_6 alkoxy, -CN, C3.7 cycloalk l , 4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, and phenyl.
1 1. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 3 -8 wherein R2 is Ci_8 alkyl optionally substituted with one to three groups independently selected from OH, halo, CN, Ci_ 6 alkoxy, C3.7 cycloalkyl, 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O, 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, and phenyl
12. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 3-8, wherein R2 is C3.7 cycloalkyl.
13. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is selected from:
9-Allyloxy-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-3-yl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-4-yl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-[2-([l ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l -a]isoquinolin-9-yl]-benzonitrile, 3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzonitrile, 4-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzonitrile, [2-([l ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l -a]isoquinolin-9-yloxy]-acetonitrile, 2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -(oxazol-2 -ylm^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm
9-(3,5-Dichloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinoH
9-Benzofuran-2-yl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -indole- 1 -carboxylic acid tert-butyl ester,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-indol-2-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-methoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]isoquino
2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -(6-trifluoromethy
one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-3H-imidazol-4-ylethynyl)-6,7-diliydro-pyrimido[6,l- a]isoquinolin-4-one,
9-(5-tert-Butyl-[l ,2,4]oxadiazol-3-ylmethoxy)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimi^ a]isoquinolin-4-one,
5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -pyridine-2- carboxylic acid methylamide,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pent-l -ynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-pyridin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-pyrazin-2-yl-ethyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-indol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-methoxy-pyridm^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-indazol-5-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -benzamide, 5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -2-fluoro- benzamide,
N-{3-[2-([l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-phenyl}- acetamide,
9-Cyclopropylethynyl-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(l-hydroxy-cyclopentylethynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm one,
2 -( [ 1 ,4 ]Dioxan-2 -ylmethoxy)-9 -pyrimidin^
9-Cyclohex- 1 -enyl-2-([ 1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6, 1 -a]isoquinolin-4-one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(l-methyl H n^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-methyl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l -a]isoqum
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-2-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-on
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-pro^
5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -pent-4-ynenitrile,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-prop-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4
2-([l ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-3-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolm^
4-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -N-methyl- benzamide,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
9-(2-Chloro-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one
2-([l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
9-(l,5-Dimethyl-lH-pyrazol-3-ylmethoxy)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one, 2-([ 1 ,4]Dioxan-2-ylmethoxy)-9 -( 1 -methyl- 1 H-pyrazol-3 -ylmethoxy)-6,7 -dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-[l,2,4]oxadra^
a]isoquinolin-4-one,
2- ([l ,4]Dioxan-2-ylmethoxy)-9-(4-moφholin-4-yl-phenyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
3 - [2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -4-fluoro- benzamide,
3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -5 -fluoro- benzamide,
9 -(3 ,3 -Dimethyl-but- 1 -ynyl)-2-([ 1 ,4]dioxan-2-ylmethoxy)-6,7 -dihydro-pyrimido [6, 1 -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyridin-4-ylethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-isoxazol-5-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-but-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoqum^ one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-pyridm^
2-([l ,4]Dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
9-(3,6-Dihydro-2H-pyran-4-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-
5 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -pyridine-2- carbonitrile,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-isopropoxy-pyridin^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-ethoxy-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-moφholin-4-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l -a]isoqu^ one,
9-(2,3-Dimethoxy-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin 9-(3-Chloro-2-methoxy-pyridin-4-yl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6J 4 -one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-methyl-pyridin-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-on
3 -[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -isonicotinonitrile,
9-(2,5-Dimethoxy-phenyl)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3,4,5,6-tetrahydro-2H-[l ,^^
a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-pyridm 9-(2,6-Dimethoxy-pyridin-3-yl)-2-([l ,4]dioxan-2-yM
4-[2-([ 1 ,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6, 1 -a]isoquinolin-9-yl] -nicotinonitrile,
9-tert-Butoxymethyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(2-pyrrolidin-l-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]^^ one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(6-pyrrolidin-l-yl-pyridin-3-yl)-6,7-dihydro-pyrimido[6,l-a]i^ one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-phenyl-oxazol-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4- one,
9-(5-tert-Butyl-oxazol-2-ylmethoxy)-2-([l,4]dioxan-2-ylm^
one,
9-(5-Cyclopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-ethyl-[l,2,4]oxadiazol-3-ylmetlioxy)-6,7-diliydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-methyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-isopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one, 9-Cyclopentylethynyl-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-Cyclohexylethynyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([ 1 ,4]Dioxan-2-ylmethoxy)-9 -(3 -methyl-but- 1 -ynyl)-6,7 -dihydro-pyrimido [6, 1 -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-hex-l-ynyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-[3-(Benzyl-methyl-amino)-prop-l-ynyl]-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimid
a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-5-methyl-hex-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4 one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-but-l -ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
9-Cyclopropyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4-methyl-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinoto 4 -one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydroxy-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-phenyl-b^
one,
9-(3-Benzylamino-prop-l -ynyl)-2-([l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquino^^
2-([l ,4]Dioxan-2-ylmethoxy)-9-[(foran-2-ylmethyl)-amino]-6,7-dihydro-pyrimido[6,l-a]isoquinolm
2-([l ,4]Dioxan-2-ylmethoxy)-9-(l-ethyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm
2-([l ,4]Dioxan-2-ylmethoxy)-9-[l-(3-methyl-butyl)-lH-pyrazol-4-yl]-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(5-methyl-furan-2-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-hex-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-
9-(3,5-Dimethyl-lH-pyrazol-4-yl)-2-([l ,4]dioxan-2^
one, 2-([l ,4]Dioxan-2-ylmethoxy)-9-(lH-pyrazol-4-yl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin 2-([l ,4]Dioxan-2-ylmethoxy)-9-(l -propyl-1 H-pyra^ 2-[2-((R)-l -[l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H^
2-[2-((S)-l -[l,4]Dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,l-a]isoquinolin-9-yl]-benzonte^
9-(5-Cyclopropyl-[l,2,4]oxadiazol-3-ylmethoxy)-2-((R)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro- pyrimido [6,1 -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-ethynyl-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-pyrimidin-2-ylethynyl-6,7-dihydro-pyrimido[6,l-a]isoquinoto
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-prop-l -ynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-([l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pent-l-ynyl)-6,7-dihydro-pyrimido[6,l-a]i
4 -one,
9-Cyclopropylethynyl-2-((R)-l-[l,4]dioxan-2-ylmet^^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoqum
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-imidazol-l -yl-prop-1 -ynyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4- one,
9-(2-Cyclopropyl-ethyl)-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolm 9-Cyclopentyloxymethyl-2-((R)-l-[l,4]dioxan-2-ylme^
2-([l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-pyridin-3-yl-propyl)-6,7-dihydro-pyrimido[6,l-a]isoq 4 -one,
9-Allyloxy-2-((R)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 9-Allyloxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one, 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyra^
a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-{3-[(pyridin-3-ylme&^
a]isoquinolin-4-one,
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^
9-(2-Cyclopropyl-ethyl)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-yloxymethyl)-6,7-dihydro-pyrimido[6,l -a]isoquin
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methyl-oxetan-3-ylmethoxymethyl)-6,7-dihydro-pyrim a]isoquinolin-4-one,
9-(2,2-Dimethyl-butylamino)-2-((S)-l-[l,4]dioxan^
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy
4 -one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-ethyl-hexylamino)-6,7-dihydro-pyrimido[6,l-a]isoqum^ 2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-ethoxy-ethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-4-o^
9-Cyclopropylmethoxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-fluoro-etho^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[3-(2-methoxy-ethoxy)-prop-l-ynyl]-6,7-dihydro-pyrimido[6,l ^ a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[3-(2-ethoxy-ethoxy)-prop-l-ynyl]-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[3-(2-fluoro-ethoxy)-prop-l -ynyl]-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one, 9-(2,2-Dimethyl-propoxymethyl)-2-((S)-l ^
a]isoquinolin-4-one,
9 -Cyclohexyloxymethyl-2-((S)- 1 - [ 1 ,4]dioxan-2-ylmethoxy)-6,7 -dihydro-pyrimido [6, 1 -a]isoquinolin-4-one,
9-Cyclopropylmethoxymethyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoqum one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydro
9-(4,4-Dimethyl-pentyloxy)-2-((S)-l-[l ,4]dioxan-2-yl^
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,l-a]i^ 4 -one,
9-(3-Cyclopropyl-propoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4- one,
9-Cyclohexylamino-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-o
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
9-Cyclopentylmethoxymethyl-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolm one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-butyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-phenylamino
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-pen
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-butyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolm
9-(Cyclohexyl-methyl-amino)-2-((S)-l-[l ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,l-a]isoqum^ one, 9-(Cyclohexylmethyl-amino)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[(tetrahydro-pyran-4-ylmethyl)-amino]-6,7-dihydro-pyrim^ a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-ethyl-3-hydro^
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-3-methyl-butyl)-6,7-dihydro-pyrimido[6,l -a]iso one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-hydroxy-pentyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm^ 9-(2,2-Dimethyl-propoxy)-2-((S)-l-[l,4]dioxan-2-ylmet^^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-4-methyl-pentyl)-6,7-dihydro-pyrimido[6,l-a]isoq 4 -one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(tetrahydro-pyran-4-ylmethoxymethyl)-6,7-dihydro-pyrimido[6,l- a]isoquinolin-4-one,
2-([l ,4]Dioxan-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrimido[6,l-a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(oxetan-3-ylm
9-(3-Cyclopropyl-propoxy)-2-((R)-l-[l ,4]dioxan-2-ylmeth^
one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-propyl)-6,7-dihydro-pyrimido[6,l -a]isoquinolin-^
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[2-(l-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-6,7-dihydro-pyrimido[6,l - a]isoquinolin-4-one,
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(3-methoxy-prop 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-[2-(l -hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimid^ a]isoquinolin-4-one,
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-pro
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinolin 2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,l -a]isoquinolm
2-((R)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,l-a]isoquinoH and
2-((S)-l-[l ,4]Dioxan-2-ylmethoxy)-9-(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,l-a]isoquinolm
14. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof, according to any of claims 1-13, and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition according to claim 14 comprising a further therapeutic agent.
16. A compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-13, or the pharmaceutical composition according to claim 14 or 15, for use as a medicament.
17. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1 -13, or the pharmaceutical composition according to claim 14 or 15, for use in the treatment or prophylaxis of inflammatory conditions.
18. A method for the treatment or prophylaxis of inflammatory conditions, comprising administering a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 -13, or a composition of claim 14 or 15.
19. The method according to claim 18, wherein a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-13 is administered in combination with a further therapeutic agent.
20. The use according to claim 17, or the method according to claim 18, wherein the inflammatory condition is rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, psoriasis, Crohn's disease, and/or ulcerative colitis.
PCT/EP2012/076275 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders WO2013092791A1 (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
ES12812237.1T ES2643379T3 (en) 2011-12-22 2012-12-20 New dihydropyrimidinoisoquinolinones and their pharmaceutical compositions for the treatment of inflammatory disorders
EP17184834.4A EP3378862B1 (en) 2011-12-22 2012-12-20 Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of multiple sclerosis
EP22155038.7A EP4019519A1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
LTEP12812237.1T LT2794604T (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
KR1020147020306A KR102012268B1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
PL12812237T PL2794604T3 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
AU2012357067A AU2012357067B2 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
UAA201408294A UA111767C2 (en) 2011-12-22 2012-12-20 DIGIDROPIRIMIDINIZOHINOLINONS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM FOR THE TREATMENT OF INFLAMMATORY DISORDERS
IN1033MUN2014 IN2014MN01033A (en) 2011-12-22 2012-12-20
BR112014015142-3A BR112014015142B1 (en) 2011-12-22 2012-12-20 Dihydropyrimidineisoquinolinones, their uses, and pharmaceutical composition
PL17184834T PL3378862T3 (en) 2011-12-22 2012-12-20 Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of multiple sclerosis
EA201491245A EA023826B1 (en) 2011-12-22 2012-12-20 Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
SI201231087T SI2794604T1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
NZ626473A NZ626473B2 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
DK12812237.1T DK2794604T3 (en) 2011-12-22 2012-12-20 UNKNOWN DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
EP12812237.1A EP2794604B1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
SG11201403169PA SG11201403169PA (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
CA2859578A CA2859578C (en) 2011-12-22 2012-12-20 Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders.
CN201280061536.3A CN103998448B (en) 2011-12-22 2012-12-20 Be used for the treatment of the dihydro-pyrimidin of inflammatory diseases and isoquinolinone compound and medicinal compositions thereof
MX2014007363A MX351681B (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders.
JP2014547997A JP6062453B2 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
PH12014501178A PH12014501178B1 (en) 2011-12-22 2014-05-26 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
IL233212A IL233212B (en) 2011-12-22 2014-06-18 2-[(1,4-dioxan-2-yl)methoxy]-6,7-dihydro-pyrimido[6,1-a] isoquinolin-4-one derivatives and pharmaceutical compositions comprising them
ZA2014/04607A ZA201404607B (en) 2011-12-22 2014-06-23 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
HK15102096.2A HK1201528A1 (en) 2011-12-22 2015-03-02 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
HRP20171404TT HRP20171404T1 (en) 2011-12-22 2017-09-18 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
CY20171101053T CY1119434T1 (en) 2011-12-22 2017-10-11 NEW DIHYDROPYRIMIDINOINKINOLINONES AND THEIR PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF INFLAMMATORY DISORDERS
IL257581A IL257581A (en) 2011-12-22 2018-02-18 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161578979P 2011-12-22 2011-12-22
US61/578,979 2011-12-22

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP22155038.7A Previously-Filed-Application EP4019519A1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Publications (1)

Publication Number Publication Date
WO2013092791A1 true WO2013092791A1 (en) 2013-06-27

Family

ID=47520068

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/076275 WO2013092791A1 (en) 2011-12-22 2012-12-20 Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Country Status (35)

Country Link
US (5) US8927543B2 (en)
EP (3) EP2794604B1 (en)
JP (1) JP6062453B2 (en)
KR (1) KR102012268B1 (en)
CN (1) CN103998448B (en)
AR (1) AR089284A1 (en)
AU (1) AU2012357067B2 (en)
BR (1) BR112014015142B1 (en)
CA (1) CA2859578C (en)
CL (1) CL2014001664A1 (en)
CO (1) CO7010835A2 (en)
CR (1) CR20140305A (en)
CY (1) CY1119434T1 (en)
DK (2) DK2794604T3 (en)
EA (1) EA023826B1 (en)
ES (2) ES2643379T3 (en)
HK (1) HK1201528A1 (en)
HR (2) HRP20220456T1 (en)
HU (1) HUE12812237T4 (en)
IL (2) IL233212B (en)
IN (1) IN2014MN01033A (en)
LT (2) LT2794604T (en)
MX (1) MX351681B (en)
NI (1) NI201400060A (en)
PE (1) PE20141685A1 (en)
PH (1) PH12014501178B1 (en)
PL (2) PL3378862T3 (en)
PT (2) PT3378862T (en)
SG (1) SG11201403169PA (en)
SI (2) SI2794604T1 (en)
TW (1) TWI567073B (en)
UA (1) UA111767C2 (en)
UY (1) UY34545A (en)
WO (1) WO2013092791A1 (en)
ZA (1) ZA201404607B (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014095798A1 (en) * 2012-12-20 2014-06-26 Galapagos Nv Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists)
WO2015197550A1 (en) * 2014-06-25 2015-12-30 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
CN106061926A (en) * 2013-11-07 2016-10-26 Eth苏黎世公司 Cyclopropanation
US10047083B2 (en) 2011-12-22 2018-08-14 Galapagos Nv Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2018161831A1 (en) 2017-03-06 2018-09-13 中国科学院上海药物研究所 Gpr84 receptor antagonist and use thereof
WO2019096944A1 (en) 2017-11-15 2019-05-23 Galapagos Nv Compounds and pharmaceutical compositions thereof for use in the treatment of fibrotic diseases
US10464965B2 (en) 2011-12-22 2019-11-05 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10485815B2 (en) 2012-03-21 2019-11-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
WO2021123394A1 (en) 2019-12-20 2021-06-24 University Of Copenhagen G protein-coupled receptor modulators and a pharmaceutical composition
WO2021122415A1 (en) 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Furoindazole derivatives
WO2022112186A1 (en) 2020-11-24 2022-06-02 Galapagos Nv Compound for use in and methods of treatment of fibrotic diseases
WO2022179940A1 (en) 2021-02-23 2022-09-01 Bayer Aktiengesellschaft Furoindazole derivatives as gpr84 antagonists
WO2022229061A1 (en) 2021-04-29 2022-11-03 Bayer Aktiengesellschaft Furoindazole derivatives as antagonists or inhibitors of gpr84
WO2022263676A1 (en) 2021-06-18 2022-12-22 University Of Copenhagen Polysubstituted 4-hydroxypyridine and 4-hydroxyquinoline derivatives as gpr84 antagonists
WO2022268088A1 (en) 2021-06-21 2022-12-29 武汉人福创新药物研发中心有限公司 Tricyclic compound used as gpr84 antagonist
WO2023284794A1 (en) 2021-07-15 2023-01-19 中国科学院上海药物研究所 Asymmetric gpr84 antagonist and use thereof
WO2024083705A1 (en) 2022-10-18 2024-04-25 Bayer Aktiengesellschaft Furoindazole derivatives for the treatment of pain

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201506894D0 (en) * 2015-04-23 2015-06-10 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
EP3403649A1 (en) 2017-05-16 2018-11-21 Bayer Pharma Aktiengesellschaft Inhibitors and antagonists of gpr84 for the treatment of endometriosis
WO2022194267A1 (en) * 2021-03-18 2022-09-22 武汉人福创新药物研发中心有限公司 Gpr84 antagonist, and preparation method therefor and use thereof
WO2022218372A1 (en) * 2021-04-14 2022-10-20 武汉人福创新药物研发中心有限公司 Dihydropyrimidoisoquinolinone derivative and use thereof
WO2023076668A1 (en) * 2021-10-29 2023-05-04 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions and methods for treatment of cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007027661A2 (en) 2005-09-02 2007-03-08 Arena Pharmaceuticals, Inc. Human g protein-coupled receptor and modulators thereof for the treatment of atherosclerosis and atherosclerotic disease and for the treatment of conditions related to mcp-1 expression
JP2011088847A (en) * 2009-10-21 2011-05-06 Takeda Chem Ind Ltd Tricyclic compound and application thereof

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2720085A1 (en) 1977-05-05 1978-11-16 Hoechst Ag PYRIMIDO (6.1-A) ISOCHINOLIN-2-ON DERIVATIVES
AU744986B2 (en) * 1997-07-12 2002-03-07 Cancer Research Technology Limited Cyclin dependent kinase inhibiting purine derivatives
AU3974700A (en) * 1999-03-31 2000-10-16 Vernalis Limited Derivatives of pyrimido(6,1-a)isoquinolin-4-one
JP2007525475A (en) * 2003-07-08 2007-09-06 スミスクライン・ビーチャム・コーポレイション New chemical compounds
WO2005050225A2 (en) 2003-10-31 2005-06-02 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with g protein-coupled receptor 84 (gpr84)
US7989461B2 (en) 2005-12-23 2011-08-02 Amgen Inc. Substituted quinazolinamine compounds for the treatment of cancer
US8217177B2 (en) * 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
AU2009276339B2 (en) 2008-07-31 2012-06-07 Genentech, Inc. Pyrimidine compounds, compositions and methods of use
AR089284A1 (en) 2011-12-22 2014-08-13 Galapagos Nv DIHYDROPIRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS OF THE SAME FOR THE TREATMENT OF INFLAMMATORY DISORDERS
SG11201403266RA (en) 2011-12-22 2014-07-30 Connexios Life Sciences Pvt Ltd Derivatives of aza adamantane and uses thereof
WO2013128465A1 (en) 2011-12-22 2013-09-06 Connexios Life Sciences Pvt. Ltd. Cyclic amide derivatives as inhibitors of 11 - beta - hydroxysteroid dehydrogenase and uses thereof
CR20200286A (en) 2011-12-22 2020-09-23 Novartis Ag Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives
EP2935262B1 (en) 2012-12-20 2017-03-15 Galapagos NV Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007027661A2 (en) 2005-09-02 2007-03-08 Arena Pharmaceuticals, Inc. Human g protein-coupled receptor and modulators thereof for the treatment of atherosclerosis and atherosclerotic disease and for the treatment of conditions related to mcp-1 expression
JP2011088847A (en) * 2009-10-21 2011-05-06 Takeda Chem Ind Ltd Tricyclic compound and application thereof

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
BERRY ET AL., NATURE, vol. 466, 2010, pages 973 - 979
BOUCHARD ET AL., GLIA, vol. 55, 2007, pages 790 - 800
BRAND ET AL., NATURE PROTOCOLS, vol. 2, 2007, pages 1269 - 1275
BROWN ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 13, 2003, pages 11312 - 11319
BUNDGARD, H.: "Design of Prodrugs", 1985, ELSEVIER, pages: 7 - 9,21-24
DU BOIS, NAT REV, DRUG DISCOVERY, vol. 9, 2010, pages 129
KHACHIGIAN ET AL., NATURE PROTOCOLS, vol. 1, 2006, pages 2512 - 2516
LE POULS ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 28, 2003, pages 25481 - 25489
LIN ET AL., BR J PHARMACOL, vol. 1, 2007, pages 829 - 831
LIN ET AL., BR J PHARMACOL, vol. 1, 2007, pages 862 - 872
NAGASAKI, FEBS LETTERS, vol. 586, 2012, pages 368 - 372
SALVEMINI ET AL., ARTHRITIS RHEUM, vol. 44, 2001, pages 2909 - 2921
SINA C. ET AL., J. IMMUNOL., vol. 183, 2009, pages 7514 - 7522
STODDART ET AL., PHARMACOLOGICAL REVIEWS, vol. 60, 2008, pages 405 - 417
T. W. GREENE; P. G. M. WUTS: "Protecting Groups in Organic Synthesis", 2006, WILEY-BLACKWELL
T. W. GREENE; P. G. M. WUTS: "Protecting Groups in Organic Synthesis", WILEY-BLACKWELL
VENKATARAMAN ET AL., IMMUNOLOGY LETTERS, vol. 101, 2005, pages 144 - 153
VENKATARAMAN; KUO, IMMUNOLOGY LETTERS, vol. 101, 2005, pages 144 - 153
WANG ET AL., J. BIOL. CHEM., vol. 281, 2006, pages 3457 - 64
WANG ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 281, no. 45, 2006, pages 34457 - 34464
WANG ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 281, no. 45, 2006, pages 3457 - 3464
WIRTZ S. ET AL., NATURE PROTOCOLS, vol. 2, 2007, pages 541 - 546
WITTENBERGER ET AL., J MOL BIOL, vol. 307, 2001, pages 799 - 813
YOUNG KIM ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 15, 2007, pages 2667 - 2679
YOUSEFI ET AL., JOURNAL OF LEUKOCYTE BIOLOGY, vol. 69, 2001, pages 1045 - 1052
YOUSEFI S ET AL., J LEUKOC BIOL, vol. 69, 2001, pages 1045 - 52

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10047083B2 (en) 2011-12-22 2018-08-14 Galapagos Nv Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
US11220499B2 (en) 2011-12-22 2022-01-11 Galapagos Nv Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
US10464965B2 (en) 2011-12-22 2019-11-05 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US11021509B2 (en) 2011-12-22 2021-06-01 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10485815B2 (en) 2012-03-21 2019-11-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9708312B2 (en) 2012-12-20 2017-07-18 Galapagos Nv Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (GPR84 antagonists)
WO2014095798A1 (en) * 2012-12-20 2014-06-26 Galapagos Nv Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists)
CN106061926A (en) * 2013-11-07 2016-10-26 Eth苏黎世公司 Cyclopropanation
CN106061926B (en) * 2013-11-07 2018-03-16 Eth苏黎世公司 It is Cyclopropanated
WO2015197550A1 (en) * 2014-06-25 2015-12-30 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2018161831A1 (en) 2017-03-06 2018-09-13 中国科学院上海药物研究所 Gpr84 receptor antagonist and use thereof
US11098071B2 (en) 2017-03-06 2021-08-24 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences GPR84 receptor antagonist and use thereof
EP4186507A1 (en) 2017-11-15 2023-05-31 Galapagos N.V. Compounds and pharmaceutical compositions thereof for use in the treatment of fibrotic diseases
WO2019096944A1 (en) 2017-11-15 2019-05-23 Galapagos Nv Compounds and pharmaceutical compositions thereof for use in the treatment of fibrotic diseases
CN111343986A (en) * 2017-11-15 2020-06-26 加拉帕戈斯股份有限公司 Compounds and pharmaceutical compositions thereof for the treatment of fibrotic diseases
WO2021122415A1 (en) 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Furoindazole derivatives
WO2021123394A1 (en) 2019-12-20 2021-06-24 University Of Copenhagen G protein-coupled receptor modulators and a pharmaceutical composition
WO2022112186A1 (en) 2020-11-24 2022-06-02 Galapagos Nv Compound for use in and methods of treatment of fibrotic diseases
WO2022179940A1 (en) 2021-02-23 2022-09-01 Bayer Aktiengesellschaft Furoindazole derivatives as gpr84 antagonists
WO2022229061A1 (en) 2021-04-29 2022-11-03 Bayer Aktiengesellschaft Furoindazole derivatives as antagonists or inhibitors of gpr84
WO2022263676A1 (en) 2021-06-18 2022-12-22 University Of Copenhagen Polysubstituted 4-hydroxypyridine and 4-hydroxyquinoline derivatives as gpr84 antagonists
WO2022268088A1 (en) 2021-06-21 2022-12-29 武汉人福创新药物研发中心有限公司 Tricyclic compound used as gpr84 antagonist
WO2023284794A1 (en) 2021-07-15 2023-01-19 中国科学院上海药物研究所 Asymmetric gpr84 antagonist and use thereof
WO2024083705A1 (en) 2022-10-18 2024-04-25 Bayer Aktiengesellschaft Furoindazole derivatives for the treatment of pain

Also Published As

Publication number Publication date
CN103998448A (en) 2014-08-20
EP2794604A1 (en) 2014-10-29
IN2014MN01033A (en) 2015-05-01
CR20140305A (en) 2014-07-23
BR112014015142B1 (en) 2022-03-29
KR20140117427A (en) 2014-10-07
TWI567073B (en) 2017-01-21
US8927543B2 (en) 2015-01-06
ES2911449T3 (en) 2022-05-19
UY34545A (en) 2013-07-31
PT2794604T (en) 2017-10-23
BR112014015142A2 (en) 2017-06-13
KR102012268B1 (en) 2019-08-21
ZA201404607B (en) 2020-02-26
EP4019519A1 (en) 2022-06-29
IL233212A0 (en) 2014-08-31
HRP20171404T1 (en) 2017-11-17
DK2794604T3 (en) 2017-11-06
JP2015500861A (en) 2015-01-08
IL257581A (en) 2018-04-30
NI201400060A (en) 2015-04-27
HK1201528A1 (en) 2015-09-04
HUE12812237T4 (en) 2017-12-28
EP3378862A1 (en) 2018-09-26
CA2859578A1 (en) 2013-06-27
NZ626473A (en) 2016-03-31
US11220499B2 (en) 2022-01-11
US9255095B2 (en) 2016-02-09
AR089284A1 (en) 2014-08-13
SG11201403169PA (en) 2014-07-30
LT2794604T (en) 2017-10-25
HRP20220456T1 (en) 2022-05-27
US20190002458A1 (en) 2019-01-03
CN103998448B (en) 2016-04-20
DK3378862T3 (en) 2022-04-11
US20140121204A1 (en) 2014-05-01
US20220227751A1 (en) 2022-07-21
SI3378862T1 (en) 2022-05-31
CY1119434T1 (en) 2018-03-07
US20130165437A1 (en) 2013-06-27
ES2643379T9 (en) 2018-01-05
PE20141685A1 (en) 2014-11-25
US10047083B2 (en) 2018-08-14
IL233212B (en) 2018-03-29
PL2794604T3 (en) 2017-12-29
MX351681B (en) 2017-10-25
CA2859578C (en) 2020-03-10
AU2012357067A1 (en) 2014-07-10
AU2012357067B2 (en) 2017-01-05
PL3378862T3 (en) 2022-05-16
PH12014501178A1 (en) 2014-10-20
CO7010835A2 (en) 2014-07-31
UA111767C2 (en) 2016-06-10
EA023826B1 (en) 2016-07-29
EP2794604B1 (en) 2017-09-13
CL2014001664A1 (en) 2014-10-03
EA201491245A1 (en) 2014-10-30
TW201331201A (en) 2013-08-01
LT3378862T (en) 2022-04-25
SI2794604T1 (en) 2017-12-29
EP3378862B1 (en) 2022-03-16
ES2643379T3 (en) 2017-11-22
JP6062453B2 (en) 2017-01-18
US20160244442A1 (en) 2016-08-25
MX2014007363A (en) 2014-08-01
PH12014501178B1 (en) 2014-10-20
PT3378862T (en) 2022-04-11

Similar Documents

Publication Publication Date Title
US11220499B2 (en) Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
EP2935262B1 (en) Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists)
EP3286191B1 (en) Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2015197550A1 (en) Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
CA2824460A1 (en) Azetidine derivatives useful for the treatment of metabolic and inflammatory diseases
CA3130154A1 (en) Pyrazolopyridine derivatives as inhibitors of pask
NZ626473B2 (en) Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201280061536.3

Country of ref document: CN

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

Ref document number: 12812237

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 12014501178

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 2859578

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 233212

Country of ref document: IL

Ref document number: 000988-2014

Country of ref document: PE

Ref document number: MX/A/2014/007363

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2014547997

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2014001664

Country of ref document: CL

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: CR2014-000305

Country of ref document: CR

ENP Entry into the national phase

Ref document number: 2012357067

Country of ref document: AU

Date of ref document: 20121220

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2012812237

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2012812237

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20147020306

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201491245

Country of ref document: EA

Ref document number: A201408294

Country of ref document: UA

WWE Wipo information: entry into national phase

Ref document number: 14158655

Country of ref document: CO

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014015142

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112014015142

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20140620