WO2015197550A1 - Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders - Google Patents

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

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Publication number
WO2015197550A1
WO2015197550A1 PCT/EP2015/063965 EP2015063965W WO2015197550A1 WO 2015197550 A1 WO2015197550 A1 WO 2015197550A1 EP 2015063965 W EP2015063965 W EP 2015063965W WO 2015197550 A1 WO2015197550 A1 WO 2015197550A1
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Prior art keywords
dihydro
pyrido
isoquinolin
ylmethoxy
dioxan
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PCT/EP2015/063965
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French (fr)
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Julien Georges Pierre-Olivier DOYON
Maxim Maria Paul DE WACHTER
Giovanni Alessandro TRICARICO
Pieter Isabelle Roger CLAES
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Galapagos Nv
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    • 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
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia 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) 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 et al. 2001).
  • RT-PCR primer reverse transcriptase-polymerase chain reaction
  • 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).
  • 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 1 1 ⁇ , respectively.
  • Three small molecules were also described to have some GPR84 agonist activity: 3,3 '-diindolylmethane (DIM) (Wang et al. 2006), embelin (Hakak et al. 2007) and 6-n-octylaminouracil (6-OAU) (Suzuki et al. 2013).
  • DIIM 3,3 '-diindolylmethane
  • 6-OAU 6-n-octylaminouracil
  • GPR84 has been shown to be expressed in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells and B cells (Hakak et al. 2007; Venkataraman & Kuo 2005; Wang et al. 2006; Yousefi et al. 2001). 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.
  • PMN polymorphonuclear leukocytes
  • neutrophils neutrophils
  • monocytes monocytes
  • T cells and B cells Heakak et al. 2007; Venkataraman & Kuo 2005; Wang et al. 2006; Yousefi et al. 2001.
  • Higher levels of GPR84 were measured in neutrophils and eosinophils
  • GPR84 knock-out mice are viable and indistinguishable from wild-type littermate controls (Venkataraman & Kuo 2005).
  • the proliferation of T and B cells in response to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman & Kuo 2005).
  • T helper 2 (T h 2) differentiated T cells from GPR84 KO secreted higher levels of IL4, IL5, IL13, the 3 major T h 2 cytokines, compared to wild-type littermate controls.
  • T h l cytokine, INFy was similar in T h l differentiated T cells from GPR84 KO and wild-type littermate (Venkataraman & Kuo 2005).
  • 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 (T h l) responses and inhibiting T helper 2 (T h 2) responses.
  • T helper 1 T helper 1
  • T h 2 T helper 2
  • Medium-chain FFAs through their direct actions on GPR84, may affect T h l/T h 2 balance.
  • Berry et al. identified a whole-blood 393-gene transcriptional signature for active tuberculosis (TB) (Berry et al. 2010). 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). 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
  • EAE experimental autoimmune encephalomyelitis
  • GPR84 would be up-regulated in CNS not only during endotoxemia and multiple sclerosis, but also in all neurological conditions in which TNFa or ILlb 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
  • 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/obesity, and therefore the inhibition of GPR84 activity might be beneficial for the treatment of endocrine and/or metabolic diseases.
  • GPR84 expression is also upregulated in microglia surrounding the neurons, after nerve injury (Gamo et al. 2008). Furthermore in GPR84 knock-out mice, hypersensitivity to mechanical stimuli were significantly reduced or completely absent in mouse models of inflammatory and neuropathic pain (Roman 2010). Molecules which block the activation of GPR84 may therefore have the potential to deliver broad-spectrum analgesia.
  • GPR84 expression is increased in human leukemic stem cells (LSC) from acute myeloid leukemia (AML) patients compared to hematopoietic stem cells from healthy donors.
  • LSC human leukemic stem cells
  • AML acute myeloid leukemia
  • GPR84 simultaneously augments ⁇ -catenin signaling and an oncogenic transcription program essential for establishment of mixed lineage leukemia (MLL)(Dietrich et al. 2014).
  • MLL mixed lineage leukemia
  • Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of stem cell-derived MLL leukemia, which represents a particularly aggressive and drug-resistant subtype of AML.
  • Targeting the oncogenic GPR84/p-catenin signaling axis may represent a novel therapeutic strategy for AML and possibly other leukemias.
  • GPR84 expression is increased 49.9 times in Ml type macrophages isolated from aortic artherosclerotic lesions of LDLR-/- mice fed a high western diet (Kadi et al. 2010). Therefore, molecules targeting GPR84 may have a potential benefit in treatment of artherosclerosis.
  • 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 (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))), neuromflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the present invention relates to novel dihydropyridoisoquinolinone compounds that antagonize GPR84, and that are potentially useful for the 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))), neuromflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
  • 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 (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))), neuromflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
  • 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)
  • COPD chronic obstructive pulmonary disease
  • R is H, CM alkyl, or cyclopropyl
  • L A is O or NH
  • A is phenyl or 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O and S;
  • each R 2A and R 2B are independently H or -CH 3 ;
  • R 3 is H, -OH or -OCH 3 ;
  • R 4 is -CN or -L 1 -W 1 -G 1 ,
  • L L is absent or O
  • Wi is absent, or is alkylene, C 2 - 4 alkenylene having one double bond or C 2 - 4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C alkoxy, o H,
  • o alkyl optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which heterocycloalkyl is optionally substituted with one or more independently selected R 7 groups),
  • phenyl optionally substituted with one or more independently selected R 7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O and S (which heteroaryl is optionally substituted with one or more independently selected R 7 groups),
  • each R 7 is:
  • CM alkyl C3.4 monocyclic cycloalkyl, or C1.4 alkoxy, each of which is optionally substituted with one or more independently selected halo;
  • R 5 is -CN or -L 2 -W 2 -G 2 ,
  • - L 2 is absent, O or S
  • W 2 is absent or C1.4 alkylene, optionally substituted with one or more independently selected halo,
  • R 6 is H, -OH or -OCH 3 .
  • the compounds of the invention have a surprisingly high chemical stability.
  • the compounds of the invention have a high chemical stability at acidic pH, more particularly between pH 1.0 and 6.0, and specifically at pH 1.2 and/or 5.0.
  • 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.
  • 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • inflammatory conditions e.g., inflammatory bowel diseases (IBD), rhe
  • 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
  • inflammatory conditions e.g., inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis
  • lung diseases e.g., chronic obstructive pulmonary disease (COPD) and lung inter
  • 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
  • inflammatory conditions e.g., inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis
  • lung diseases e.g., chronic obstructive pulmonary disease (COPD) and lung interstitial
  • 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.
  • alkyl groups are methyl (-CH 3 ), ethyl (-CH 2 -CH 3 ), n-propyl (-CH 2 -CH 2 -CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n- butyl (-CH 2 -CH 2 -CH 2 -CH 3 ), tert-butyl (-CH 2 -C(CH 3 ) 3 ), sec-butyl (-CH 2 -CH(CH 3 ) 2 ), n-pentyl (-CH 2 -CH 2 - CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), and 1 ,2-dimethylbutyl (-CHCH 3 )-C(CH 3 )H 2 - CH 2 -CH 3 ).
  • 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.
  • 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 o
  • 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 -O-C1-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.
  • '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.
  • 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.
  • 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.
  • piperidine
  • 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.
  • heterocycloalkyl groups are shown in the following illustrative exam les:
  • each W is selected from CH 2 , NH, O and S; and each Y is selected from NH, O, CO, SO 2 , and S.
  • Heterocycloalkenyl' means a 'heterocycloalkyl', which comprises at least one double bond.
  • Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:
  • '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. ⁇ ⁇
  • 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-toluenesulfonic acid
  • 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
  • the term refers to uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
  • neutrophilic dermatoses e.g., pyoderma gangrenosum, Sweet's syndrome
  • 'pain' refers to diseases or disorders characterized by unpleasant feeling often caused by intense or damaging stimuli, and include but is not limited to nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration) and neuropathic or dysfunctional pain (caused by damage to or abnormal function of the nervous system, and/or pain associated or caused by the conditions mentioned herein. Pain can be acute or chronic.
  • 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.
  • 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
  • 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.
  • a particular example of metabolic disorders is obesity.
  • 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 ⁇ ⁇
  • GBS Guillain-Barre syndrome
  • 'neurodegenerative conditions refers to diseases or disorders characterized by progressive loss of structure or function of neurons, including death of neurons, and includes but is not limited to conditions such as dementia, degenerative dementia, senile dementia, vascular dementia, dementia associated with intracranial space occupying lesions, mild cognitive impairment associated with ageing, age associated memory impairment, and /or peripheral neuropathies.
  • the term refers to retinopathies, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), motor neurone disease (MND), spinocerebellar ataxia (SCA), and/or spinal muscular atrophy (SMA).
  • ALS amyotrophic lateral sclerosis
  • MND motor neurone disease
  • SCA spinocerebellar ataxia
  • SMA spinal muscular atrophy
  • the term refers to retinopathies, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, and/or amyotrophic lateral sclerosis (ALS).
  • retinopathies glaucoma
  • macular degeneration stroke
  • cerebral ischemia traumatic brain injury
  • Alzheimer's disease Pick's disease
  • Huntington's chorea Huntington's chorea
  • Parkinson's disease Creutzfeldt-Jakob disease
  • ALS amyotrophic lateral sclerosis
  • cardiovascular disease refers to diseases affecting the heart or blood vessels or both.
  • cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue.
  • arrhythmia atrial or ventricular or both
  • atherosclerosis and its sequelae angina
  • cardiac rhythm disturbances myocardial ischemia
  • myocardial infarction myocardial infarction
  • leukemia refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
  • leukemia refers to acute myeloid leukemia (AML), mixed lineage leukemia (MLL) and acute lymphoblastic leukemia (ALL).
  • 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 Cg alkyl, and substituted or unsubstituted Ce-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.
  • 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' .
  • 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). 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. [0083] 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
  • 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 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, by administering a compound of the invention.
  • a compound of the invention is an inhibitor of GPR84.
  • R is H, CM alkyl, or cyclopropyl;
  • L A is O or NH;
  • A is phenyl or 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O and S;
  • each R 2a and R 2b are independently H or -CH 3 ;
  • R 3 is H, -OH or -OCH 3 ;
  • R 4 is -CN or -L 1 -W 1 -G 1 , wherein
  • Li is absent or O
  • Wi is absent, or is Ci_ 6 alkylene, C 2 - 4 alkenylene having one double bond or C 2 - 4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C 1 . 4 alkoxy, o H,
  • o alkyl optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which
  • heterocycloalkyl is optionally substituted with one or more independently selected R 7 groups
  • heterocycloalkenyl is optionally substituted with one or more independently selected R 7 groups
  • phenyl optionally substituted with one or more independently selected R 7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O and S (which heteroaryl is optionally substituted with one or more independently selected R 7 groups),
  • R 7 is:
  • CM alkyl C3. 4 monocyclic cycloalkyl, or C 1 . 4 alkoxy, each of which is optionally substituted with one or more independently selected halo;
  • R 5 is -CN or -L 2 -W 2 -G 2 , wherein
  • L 2 is absent, O or S,
  • W 2 is absent or C 1 . 4 alkylene, optionally substituted with one or more independently selected halo,
  • R 6 is H, -OH or -OCH 3 .
  • the compound of the invention is according to Formula I, wherein R 2a and R 2b are both -CH 3 .
  • the compound of the invention is according to Formula II:
  • R 1 , L A , G A , R 3 , R 4 , R 5 , and R 6 are as previously described.
  • the compound of the invention is according to Formula I or II, wherein R
  • the compound of the invention is according to Formula I or II, wherein R In one embodiment, the compound of the invention is according to Formula I or II, wherein R 6 In one embodiment, the compound of the invention is according to Formula I or II, wherein R 6 [0096] In one embodiment, the c to Formula III:
  • R 1 , L A , G A , R 4 , and R 5 are as previously described.
  • the compound of the invention is according to any one of Formulae I-III, wherein G A is Cy, and A is phenyl or 5-6 membered heteroaryl containing 1 or 2 independently selected N, O or S atoms.
  • G A is Cy
  • A is phenyl or 5-6 membered heteroaryl containing 1 or 2 independently selected N, O or S atoms.
  • Cy is:
  • the compound of the invention is according to any one of Formulae I-III, wherein G A is tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
  • the compound of the invention is according to any one of Formulae I-III, wherein G A is cyclobutyl, cyclopentyl, or cyclohexyl.
  • the compound of the invention is according to Formula IVa, IVb, IVc, or I
  • the compound of the invention is according to Formula IVe, IVf, IVg, or IV
  • R 1 , L A , R 4 , and R 5 are as previously described.
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -CN.
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 .
  • L 2 is absent.
  • L 2 is O.
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and G 2 are as previously described and W 2 is absent.
  • W 2 is CM alkylene.
  • W 2 is -CH 2 -, or -CH 2 -CH 2 -.
  • W 2 is -CH 2 -.
  • the compound of the invention is according to any one of Formulae I- IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and G 2 are as previously described and W 2 is CM alkylene substituted with one or more independently selected halo.
  • W 2 is -CH 2 -, or -CH 2 -CH 2 - substituted with one or more independently selected halo.
  • W 2 is C 1 . 4 alkylene substituted with one or more independently selected F or CI.
  • W 2 is -CH 2 -, or -CH 2 -CH 2 - substituted with one or more independently selected F or CI.
  • W 2 is -CF 2 -, or -CH 2 -CF 2 -.
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and W 2 are as previously described and G 2 is -CF 3 .
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and W 2 are as previously described and G 2 is C3. 7 cycloalkyl.
  • G 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the compound of the invention is according to any one of Formulae I- IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and W 2 are as previously described and G 2 is C 3 . 7 cycloalkyl substituted with one or more independently selected halo.
  • G 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with one or more independently selected halo.
  • G 2 is C 3 . 7 cycloalkyl substituted with one or more independently selected F or CI.
  • G 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with one or more independently selected F or CI.
  • G 2 is difluorocyclopropyl.
  • G 2 is:
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and W 2 are as previously described and G 2 is 5-6 membered heteroaryl containing one to three heteroatoms independently selected from O, N, and S.
  • G 2 is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl.
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and W 2 are as previously described and G 2 is phenyl.
  • the compound of the invention is according to any one of Formulae I-IVh, wherein R 5 is -L 2 -W 2 -G 2 , L 2 and W 2 are as previously described and G 2 is H.
  • the compound of the invention is according to Formula Va, Vb, Vc, or V
  • the compound of the invention is according to Formula Ve, Vf, Vg, or
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -CN. ⁇
  • the compound of the invention is according any one of Formulae I-Vh, wherein R 4 is -Li-Wi-Gi.
  • R 4 is -Li-Wi-Gi.
  • Li is absent.
  • Li is O.
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWpGi, Li and Gi are as previously described and Wi is absent.
  • Wi is Ci_6 alkylene.
  • Wi is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -LpWi-Gi, Li and Gi are as previously described and Wi is Ci_6 alkylene substituted with one or more independently selected halo, -CN, or C 1 .4 alkoxy.
  • Wi is - CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, each of which is substituted with one or more independently selected halo, -CN, or C 1 .4 alkoxy.
  • Wi is Ci_6 alkylene substituted with one or more independently selected F, CI, - OCH3, -OCH 2 -CH3, or -OCH(CH 3 ) 2 .
  • Wi is -CH 2 -, -CH 2 -CH 2 -, -CH 2 - CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, each of which is substituted with one or more independently selected F, CI, -OCH 3 , -OCH 2 -CH 3 , or -OCH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWpGi, Li and Gi are as previously described and Wi is C 2 -4 alkenylene having one double bond.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -L 1 -W 1 -G 1 , Li and Gi are as previously described and Wi is C 2 -4 alkenylene having one double bond, substituted with one or more independently selected halo, -CN, or C 1 .4 alkoxy.
  • Wi is C 2 -4 alkenylene having one double bond, substituted with one or more independently selected F, CI, - OCH 3 , -OCH 2 -CH 3 , or -OCH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWpGi, Li and Gi are as previously described and Wi is C 2 -4 alkynylene having one triple bond.
  • Wi is -C ⁇ C-, -CH 2 -C ⁇ C-, or -C ⁇ C-CH 2 -.
  • Wi is -C ⁇ C-.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -LpWpGi, Li and Gi are as previously described and Wi is C 2 -4 alkynylene having one triple bond, substituted with one or more independently selected halo, -CN, or C 1 .4 alkoxy.
  • Wi is -C ⁇ C-, -CH 2 -C ⁇ C-, or -C ⁇ C-CH 2 -, each of which is substituted with one or more independently selected halo, -CN, or C 1 .4 alkoxy.
  • Wi is C 2 -4 alkynylene ⁇ having one triple bond, substituted with one or more independently selected F, CI, -OCH 3 , -OCH 2 -CH 3 , or -OCH(CH 3 ) 2 .
  • Wi is -CH 2 -C ⁇ C-, or -C ⁇ C-CH 2 -, each of which is substituted with one or more independently selected F, CI, -OCH 3 , -OCH 2 -CH 3 , or -OCH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWi-Gi, Li and Wi are as previously described and Gi is -CF 3 .
  • the compound of the invention is according any one of Formulae I-Vh, wherein R 4 is -L r W r Gi, and Wi are as previously described and Gi is alkyl.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -L r W r Gi, and Wi are as previously described and Gi is alkyl, substituted with one or more independently selected halo.
  • Gi is alkyl, substituted with one or more independently selected F or CI.
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWpGi, Li and Wi are as previously described and Gi is 4-6 membered monocyclic heterocycloalkyl containing one or two O.
  • Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -L r W r Gi, and Wi are as previously described and Gi is 4-6 membered monocyclic heterocycloalkyl containing one or two O and substituted with one or more independently selected R 7 groups.
  • Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, substituted with one or more independently selected R 7 groups.
  • Gi is 4- 6 membered monocyclic heterocycloalkyl containing one or two O, substituted with one or more independently selected R 7 groups, wherein R 7 is halo, -OH, C alkyl, C 3 _4 monocyclic cycloalkyl, or C alkoxy.
  • Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, substituted with one or more independently selected R 7 groups, wherein R 7 is F, CI, -OH, -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -CH 3 , cyclopropyl, -OCH 3 , or -OCH 2 -CH 3 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWpGi, Li and Wi are as previously described and Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O.
  • Gi is dihydropyranyl or dihydrodioxinyl.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -LpWi-Gi, Li and Wi are as previously described and Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O, substituted with one or more independently selected R 7 groups.
  • Gi is dihydropyranyl or dihydrodioxinyl, substituted with one or more independently selected R 7 groups.
  • Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O, substituted with one or more independently selected R 7 groups, wherein R 7 is halo, -OH, C alkyl, C3.4 monocyclic cycloalkyl, or CM alkoxy.
  • Gi is dihydropyranyl or dihydrodioxinyl, substituted with one or more independently selected R 7 groups, wherein R 7 is F, CI, -OH, -CH 3 , -CH2-CH3, -CH2-CH2-CH3, cyclopropyl, -OCH 3 , or -OCH 2 -CH 3 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWpGi, Li and Wi are as previously described and Gi is C3.7 monocyclic cycloalkyl.
  • Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Gi is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -LpWi-Gi, Li and Wi are as previously described and Gi is C3.7 monocyclic cycloalkyl, substituted with one or more independently selected R 7 groups.
  • Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more independently selected R 7 groups.
  • Gi is C3.7 monocyclic cycloalkyl, substituted with one or more independently selected R 7 groups, wherein R 7 is halo, -OH, CM alkyl, C3.4 monocyclic cycloalkyl, or C alkoxy.
  • Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more independently selected R 7 groups, wherein R 7 is F, CI, -OH, -CH 3 , -CH2-CH3, -CH2-CH2-CH3, cyclopropyl, -OCH 3 , or -OCH 2 -CH 3 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWi-Gi, Li and Wi are as previously described and Gi is phenyl.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -LpWi-Gi, Li and Wi are as previously described and Gi is phenyl, substituted with one or more independently selected R 7 groups.
  • Gi is phenyl, substituted with one or more independently selected R 7 groups, wherein R 7 is halo, -OH, C alkyl, C alkyl substituted with one or more independently selected halo, C3.4 monocyclic cycloalkyl, CM alkoxy, or CM alkoxy substituted with one or more independently selected halo.
  • Gi is phenyl, substituted with one or more independently selected R 7 groups, wherein R 7 is F, CI, -OH, -CH 3 , -CH 2 - CH 3 , -CH2-CH2-CH3, -CF 3 , cyclopropyl, -OCH 3 , -OCH 2 -CH 3 , -O-CF3, or -0-CH 2 -CF 3 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWi-Gi, Li and Wi are as previously described and Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O.
  • Gi is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, ⁇ tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl.
  • Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl.
  • the compound of the invention is according to any one of Formulae I- Vh, wherein R 4 is -LpWpGi, Li and Wi are as previously described and Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R 7 groups.
  • Gi is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, substituted with one or more independently selected R 7 groups.
  • Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R 7 groups, wherein R 7 is halo, - OH, CM alkyl, CM alkyl substituted with one or more independently selected halo, C3.4 monocyclic cycloalkyl, C1.4 alkoxy, or C1.4 alkoxy substituted with one or more independently selected halo.
  • Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl, substituted with one or more independently selected R 7 groups, wherein R 7 is halo, -OH, C1.4 alkyl, CM alkyl substituted with one or more independently selected halo, C3.4 monocyclic cycloalkyl, CM alkoxy, or CM alkoxy substituted with one or more independently selected halo.
  • Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl, substituted with one or more independently selected R 7 groups, wherein R 7 is F, CI, -OH, -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -CH 3 , -CF 3 , cyclopropyl, - OCH 3 , -OCH 2 -CH 3 , -O-CF 3 , or -0-CH 2 -CF 3 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -0-CH 2 -cyclopropyl, substituted with one or more independently selected F or CI. In a more particular embodiment, R 4 is -0-CH 2 -cyclopropyl, substituted with one, two or three independently selected F or CI.
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 4 is -LpWi-Gi, Li and Wi are absent, and Gi is H.
  • the compound of the invention is according to any one of Formulae I-Vh, wherein R 1 is H, -CH 3 , -CH 2 -CH 3 , -CH(CH 3 ) 2 , or cyclopropyl.
  • R 1 is H.
  • R 1 is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-Vh, wherein L A is -NH-. In another embodiment, L A is -0-.
  • the compound of the invention is according to Formula Vie, Vlf, VIg, or Vlh:
  • the compound of the invention is according to any one of Formulae I- VIp wherein R 4 is -L 1 -W 1 -G 1 , Li is O, Wi is Ci_6 alkylene or Ci_6 alkylene substituted with one or more halo, and Gi is H or -CF 3 .
  • Wi is -CH 2 -, -CF 2 -, or -CH 2 -CF 2 -, and Gi is H or - CF 3 .
  • the compound of the invention is according to any one of Formulae I- VIp wherein R 4 is -L 1 -W 1 -G 1 , Li is O, Wi is -CH 2 -, and Gi is C3.7 monocyclic cycloalkyl or C3.7 monocyclic cycloalkyl substituted with one or more independently selected R 7 groups, wherein R 7 is halo, or C 1 .4 alkyl.
  • the compound of the invention is according to any one of Formulae I- VIp wherein R 4 is -L 1 -W 1 -G 1 , Li is O, Wi is absent, and Gi is alkyl.
  • the compound of the invention is according to any one of Formulae I- VIp wherein R 4 is -L 1 -W 1 -G 1 , Li is absent, Wi is -C ⁇ C- and Gi is C3.7 monocyclic cycloalkyl. In a particular embodiment, Gi is cyclopropyl.
  • the compound of the invention is according to any one of Formulae I- VIp wherein R 4 is -L 1 -W 1 -G 1 , Li is absent, Wi is absent, and Gi is phenyl substituted with one or two independently selected R 7 groups.
  • Gi is phenyl substituted with one or two independently selected R 7 groups, wherein R 7 is C 1 .4 alkyl, C 1 .4 alkoxy, C 1 .4 alkyl substituted with one or more F, or C 1 .4 alkoxy substituted with one or more F.
  • R 7 is -CF 3 , or
  • the compound of the invention is according to any one of Formulae I- VIp wherein R 4 is -L 1 -W 1 -G 1 , Li is absent, Wi is absent, and Gi is pyridinyl substituted with one R 7 group.
  • Gi is pyridinyl substituted with one R 7 group, wherein R 7 is halo, -OH, C3.4 monocyclic cycloalkyl, C 1 .4 alkoxy, or C 1 .4 alkoxy substituted with one or more F.
  • R 7 is -CF 3 , or -OCF 3 .
  • the compound of the invention is selected from: 2o
  • 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.
  • 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.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci to Cg alkyl, C2-Cg 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.
  • Pv 1 is H, CM alkyl, or cyclopropyl
  • LA is O or NH
  • each R 2a and R 2b are independently H or -CH 3 ;
  • R 3 is H, -OH or -OCH 3 ;
  • R 4 is -CN or -Li-Wi-Gi, wherein
  • Li is absent or O
  • Wi is absent, or is Ci_ 6 alkylene, C 2 - 4 alkenylene having one double bond or C 2 - 4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C 1 . 4 alkoxy, o H,
  • o alkyl optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which
  • heterocycloalkyl is optionally substituted with one or more independently selected R 7 groups
  • heterocycloalkenyl is optionally substituted with one or more independently selected R 7 groups
  • phenyl optionally substituted with one or more independently selected R 7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O or S (which heteroaryl is optionally substituted with one or more independently selected R 7 groups),
  • R 7 is:
  • CM alkyl C 3 . 4 monocyclic cycloalkyl, or C 1 . 4 alkoxy, each of which is optionally substituted with one or more independently selected halo;
  • R 5 is -CN or -L 2 -W 2 -G 2 , wherein
  • L 2 is absent, O or S, W 2 is absent or C 1 . 4 alkylene, optionally substituted with one or more independently selected halo,
  • R 6 is H, -OH or -OCH 3 ;
  • R 1 , L A , G A , R 3 , R 4 , R 5 , and R 6 are as previously described.
  • R 3 is -OCH 3 .
  • R 3 is H
  • R 6 is -OCH 3 .
  • R 6 is H.
  • R 1 , L A , R 4 , and R 5 are as previously described.
  • W 2 is CM alkylene substituted with one or more independently selected halo.
  • W 2 is CM alkylene substituted with one or more independently selected F or CI.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-14 or 16- 24, wherein G 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37 or 39- 41, wherein Wi is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-CH 2 - or -CH 2 -CH 2 - CH 2 -CH 2 -CH 2 -.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37 or 39, wherein is absent, and Wi is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-CH 2 -, or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -.
  • Wi Ci_ 6 alkylene, C 2 - 4 alkenylene having one double bond, or C 2 - 4 alkynylene having one triple bond, each of which is substituted with one or more independently selected halo, -CN, or C alkoxy.
  • Wi is Ci_6 alkylene, C 2 _4 alkenylene having one double bond, or C 2 _4 alkynylene having one triple bond, each of which is substituted with one or more independently selected F, CI, -OCH 3 , - OCH 2 -CH 3 , or -OCH(CH 3 ) 2 .
  • R 7 is selected from CM alkyl and CM alkoxy, each of which is substituted with one or more F.
  • a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106, and a pharmaceutically acceptable carrier.
  • composition according to claim 107 comprising a further therapeutic agent.
  • 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 clauses 1-106, or a composition of clause 107 or 108.
  • a method for the treatment or prophylaxis of pain comprising administering a prophylactically or therapeutically effective amount of a compound according to any one of clauses 1-106, or a composition of clause 107 or 108.
  • 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.
  • 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 paraffmic 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.
  • 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 (1 1 :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/mL.
  • 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, in mammals including humans.
  • 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)
  • COPD chronic ob
  • 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))), 5Q 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, in mammals including humans, said method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • IBD inflammatory bowel diseases
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • 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, said method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • 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 in 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), idiopathic pulmonary fibrosis (IPF), uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • uveitis uveitis
  • periodontitis e.g., neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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), uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • uveitis uveitis
  • periodontitis e.g., neutrophilic dermatoses (e.g., pyoderma
  • 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).
  • 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, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • 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)
  • COPD chronic
  • 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), uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
  • 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 compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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
  • the present invention provides a 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 a compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the prophylaxis and/or treatment of infectious disease(s).
  • infectious disease(s) 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 a 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(s).
  • infectious disease(s) 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(s), which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
  • infectious disease 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 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 in 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, rickets, and obesity.
  • the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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, rickets, and obesity.
  • 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 ⁇ ⁇
  • ovarian dysfunction including polycystic ovary syndrome
  • cystic fibrosis including 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, rickets, and obesity.
  • 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 (
  • 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 DMAPvDS (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
  • DMAPvDS for example but without limitation methotrexate, leflunomide
  • 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 anthracyc lines, 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., I), anti-CD20, anti
  • 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 tinidazole. r r r
  • 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.,
  • 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
  • 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
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of pain, such as non-narcotic and narcotic analgesics; particular agents include but are not limited to: paracetamol, acetylsalicylic acid, NSAID's, codeine, dihydrocodeine, tramadol, pentazocine, pethidine, tilidine, buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, piritramide, tapentadol or combinations thereof.
  • another therapeutic agent for the treatment and/or prevention of pain such as non-narcotic and narcotic analgesics
  • agents include but are not limited to: paracetamol, acetylsalicylic acid, NSAID's, codeine, dihydrocodeine, tramadol, pentazocine, pethidine, tilidine, buprenorphine, f
  • Course of treatment for leukemia comprises chemotherapy, biological therapy, targeted therapy, radiation therapy, bone marrow transplantation and/or combinations thereof.
  • Examples of further therapeutic agents for Acute Lymphoblastic Leukemia comprise methotrexate, nelarabine, asparaginase Erwinia chrysanthemi, blinatumomab, daunorubicin, cyclophosphamide, clofarabine, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib, vincristine, mercaptopurine, pegaspargase, and/or prednisone.
  • ALL Acute Lymphoblastic Leukemia
  • Examples of further therapeutic agents for Acute Myeloid Leukemia comprise arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and/or vincristine.
  • Examples of further therapeutic agents for Chronic Lymphocytic Leukemia comprise alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, chlormethine, prednisone, vincristine, and/or rituximab.
  • Examples of further therapeutic agents for Chronic Myelogenous Leukemia comprise bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, chlormethine, nilotinib, and/or omacetaxine.
  • HCL Hairy Cell Leukemia
  • examples of further therapeutic agents for Hairy Cell Leukemia comprise electbine, pentostatin, and/or interferon alfa-2b.
  • 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.
  • 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.
  • the preparative HPLC purifications were performed with a mass-directed auto-purification system coupled with a ZQ single quadrapole mass spectrometer. All HPLC purifications were performed with a gradient of H 2 0 (different pHs)/MeCN.
  • Preparative HPLC separations under basic conditions were usually carried out using a BEH XBrigde CI 8 (5 ⁇ , 19 x 5 mm) precolumn and a BEH XBrigde CI 8 (5 ⁇ , 19 x 100 mm).
  • Separations under acidic conditions were usually carried out using CSH Select C18 (5 ⁇ , 19 x 5 mm) precolumn and a CSH Select CI 8 (5 ⁇ , 19 x 100 mm).
  • the focused gradient was from x% to x+25%) acetonitrile in water in 5 min with a cycle time of 10 min.
  • the column flow rate was 20 mL/min.
  • the injection volume ranged from 200 to 750 ⁇ .
  • a capillary splitter was used to divert flow after column separation to the mass spectrometer which was diluted by 1 mL/min of make-up flow.
  • the make-up flow is 0.1% formic acid in methanol. All samples were purified by a Waters mass directed fraction collection.
  • a solution of LiAlH 4 (2 M in THF, 2 eq.) is added dropwise to an ice cold solution of the nitrile (1 eq.) in THF. After stirring for 30 min at RT, the reaction mixture is heated to reflux until completion. Once cooled to RT, the resulting mixture is added to a suspension of Na 2 SO 4 .10 H 2 0 in EtOAc, stirred for 10 min, filtered and concentrated under vacuum. The residue is dissolved in DCM, dried (Na 2 S0 4 ), filtered and concentrated.
  • Dry dioxane is added to a mixture of chloro-pyridinone (1 eq.), the appropriate amine (1.2 eq.), Brettphos (0.01 eq.), Brettphos precatalyst (0.01 eq.) and sodium tert-butoxide (2 eq.) in a sealed vial under nitrogen atmosphere and the resulting mixture is heated to 100°C until completion of the reaction.
  • the reaction mixture is filtered over Celite, washed with a mixture of DCM:MeOH and concentrated under vacuum.
  • the residue is partitioned between DCM and water.
  • the organic layer is separated, dried (Na 2 S0 4 ), filtered and concentrated.
  • the residue is either used as such in the next step or purified by silica gel chromatography (7 N NH 3 in MeOH/DCM).
  • Pd/C (10% w/w, 0.1 eq.) is added to the benzyl-protected aryl alcohol (1 eq.) under nitrogen atmosphere.
  • EtOH is added and the resulting mixture put under hydrogen atmosphere and stirred at RT until completion of the reaction.
  • the mixture is filtered over Celite and the filtrate concentrated under vacuum.
  • NEt 3 (2-2.5 eq.) is added to a solution of the alcohol (1 eq.) and N- phenylbis(trifluoromethanesulfonimide) (1.2-2 eq.) in DCM and the reaction mixture is stirred at RT until completion. The resulting mixture is partitioned between DCM and aq. 0.2 M HC1. The organic layer is separated, dried (Na 2 S0 4 ) and concentrated. The residue is purified by silica gel chromatography (MeOH/EtOAc, MeOH/DCM or EtO Ac/petroleum ether).
  • the aryl triflate (1 eq.) is mixed with DMF, PdCl 2 (PPh 3 ) 4 (0.04 eq.), Cul (0.04 eq.), NEt 3 (4.5 eq.) and the appropriate alkyne (3 eq.) in a sealed vial under nitrogen atmosphere and the reaction mixture is heated to 80°C until completion of the reaction.
  • the resulting mixture is diluted with EtOAc, washed with aq. 5% NH 3 , water and brine.
  • the organic layer is dried (Na 2 S0 4 ), filtered and concentrated.
  • the residue is purified by silica gel chromatography (MeOH/DCM).
  • the aryl triflate (1 eq.) is mixed with Zn(CN) 2 (1.05 eq.) and Pd(PPh 3 ) 4 (0.1 eq.) in DMF and the reaction mixture is heated to 150°C in a microwave reactor for 5 min. The resulting mixture is diluted with EtOAc, washed with aq. sat. NaHCOs and brine. The organic layer is dried (Na 2 S0 4 ), filtered and concentrated. The residue is triturated with MeOH.
  • aryl triflate (1 eq.) is mixed with 3-mercaptopropionic acid-2-ethylhexyl ester (1.25 eq.), Pd 2 (dba) 3 (0.03 eq.), Xantphos (0.06 eq.) and DIPEA (2 eq.) in a sealed tube under nitrogen and the mixture is heated to 1 10°C. After completion of the reaction, the residue is filtered through a silica plug, washed with EtOAc and concentrated.
  • Pd/C (10% w/w, 0.1 eq.) is added to the aryl alkyne (1 eq.) under nitrogen atmosphere. MeOH is added and the resulting mixture put under hydrogen atmosphere and stirred at RT until completion of the reaction. The mixture is filtered through Celite and the filtrate concentrated under vacuum. The residue is purified by preparative HPLC.
  • the alkyl nitrile (1 eq.) is mixed with DMF, NaN 3 (5 eq.) and NH 4 C1 (5 eq.) in a sealed vial and the reaction mixture is heated to 100°C until completion of the reaction. Once cooled at RT, the mixture is diluted with water and acidified to pH 3 with aq. 2 M HCl and extracted with EtOAc. The organic layer is washed with water and brine, dried (Na 2 S0 4 ), filtered and concentrated.
  • Step ii 2 N-[2-(3-Benzyloxy-4-methoxy-phenyl)-ethylJ-propionamide
  • Step iv 9-Benzyloxy-2-hydroxy-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin-4-one
  • Step v 9-Benzyloxy-2-chloro-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, 1 -a] isoquinolin-4-one
  • POCl 3 (22 mL) is added to 9-benzyloxy-2-hydroxy-l 0-methoxy-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one (5.08 g, 14 mmol, 1 eq.) and the resulting solution is heated to 80°C. After 2 h, the mixture is poured on ice, basified to pH 8-9 using aq. sat. K 2 CO 3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na 2 S0 4 ), filtered and concentrated. The product is used as such without further purification.
  • Step vi 9-Benzyloxy-l 0-methoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino] -6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
  • the resulting mixture is degased and then heated to 100°C for 18 h.
  • the reaction mixture is filtered over Celite, washed with a mixture of DCM:MeOH (10:1 v/v) and concentrated under vacuum.
  • the residue is partitioned between DCM and aq. sat. NaHC0 3 .
  • the organic layer is separated, dried (Na 2 S0 4 ), filtered and concentrated. Purification by silica gel chromatography (7 N NH 3 in MeOH/DCM; 1 :99 to 2:98) affords the required compound.
  • Step vii 9-Hydroxy-l 0-methoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino] -6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
  • Pd/C (10% w/w, 132 mg, 0.12 mmol, 0.1 eq.) is added to 9-benzyloxy-l 0-methoxy-l -methyl- 2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one (552 mg, 1.23 mmol, 1 eq.) under nitrogen atmosphere.
  • EtOH 35 mL
  • the mixture is filtered over Celite and the filtrate concentrated under vacuum to afford the required compound that is used as such in the next step.
  • Step viii 10-Methoxy-l-methyl-2-f(tetrahydro ⁇ iran-2-ylmethyl)-aminoJ-9-(2,2,2-trifluoro-ethoxy)-6, 7- dihydro-pyrido[2, 1 -aJisoquinolin-4-one
  • Step i N-[2-(3,4-Dimethoxy-phenyl) -ethyl] -propionamide
  • Step ii l-Ethyl-6, 7-dimethoxy-3,4-dihydro-
  • POCl 3 (7.8 mL, 84 mmol, 4 eq.) is added dropwise to an ice cold solution of N-[2-(3,4- dimethoxy-phenyl)- ethyl] -propionamide (5.0 g, 21 mmol, 1 eq.) in DCM (6 mL) and the mixture is heated to reflux temperature for 24 h. The mixture is concentrated, the remaining residue is poured on ice and basified to pH 7-8 using aq. sat. K 2 CO 3 . The aqueous is extracted with DCM (3x), dried (Na 2 S0 4 ), filtered and concentrated. The product is used without further purification.
  • Step iv 2-Chloro-9, 10-dimethoxy-l -methyl-6, 7-dihydro-pyrido[2, l-a]isoquinolin-4-one
  • Step v 2-( (S)-l-[ 1, 4]Dioxan-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6, 7-dihydro-pyrido[2, 1- aJisoquinolin-4-one
  • Step vi 2-( (S)-l-[ 1, 4]Dioxan-2-ylmethoxy)-9-hydroxy-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, 1- aJisoquinolin-4-one
  • Step vii 9-(2, 2-Difluoro-ethoxy)-2-( (S)-l-[ 1 ,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
  • Step i 9-Benzyloxy-2-( (S)-l-[ 1, 4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, 1- aJisoquinolin-4-one
  • Step ii 2-((S)-l -[1 ,4]Dioxan-2-ylmethoxy)-9-hydroxy-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, l- aJisoquinolin-4-one
  • Pd/C (10% w/w, 360 mg, 0.34 mmol, 0.1 eq.) is added to 9-benzyloxy-2-((S)-l-[l,4]dioxan-2- ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (1.60 g, 3.41 mmol, 1 eq.) under nitrogen atmosphere.
  • EtOH 35 mL
  • the mixture is filtered over Celite and the filtrate concentrated under vacuum to afford the required compound.
  • Step Hi Trifluoro-methanesulfonic acid 2-((S)-l -[1,4] dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-4-oxo- 6, 7-dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester
  • NEt 3 (0.67 mL, 4.82 mmol, 2.0 eq.) is added to a solution of 2-((S)-l -[l,4]dioxan-2- ylmethoxy)-9-hydroxy- 10-methoxy- 1 -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one (900 mg, 2.41 mmol, 1 eq.) and N-phenylbis(trifluoromethanesulfonimide) (1.03 g, 2.90 mmol, 1.2 eq.) in DCM (19 mL) and the reaction mixture is stirred at RT overnight.
  • Step iv 2-( (S)-l-[ 1, 4]Dioxan-2-ylmethoxy)-l 0-methoxy- l-methyl-4-oxo-6, 7-dihydro-4H-pyrido [2, 1- aJisoquinoline-9-carbonitrile
  • Step iv 9-Benzyloxy-2-hydroxy-l-methyl-6, 7-dihydro-pyrido[2, l-a]isoquinolin-4-one
  • Step v 9-Benzyloxy-2-chloro-l-methyl- -dihydro-pyrido[2, 1 -aJisoquinolin-4-one
  • POCl 3 (14 mL) is added to 9-benzyloxy-2-hydroxy-l-methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one (3.04 g, 9.1 mmol, 1 eq.) and the resulting solution is heated to 80°C. After 1 h, the mixture is poured on ice, basified to pH 8-9 using aq. sat. K 2 CO 3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na 2 S0 4 ), filtered and concentrated. The product is used as such without further purification.
  • Step vi 9-Benzyloxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin- 4-one
  • Step vii 2-( (S)-l-[ 1 ,4]Dioxan-2-ylmethoxy)-9-hydroxy-l -methyl-6, 7-dihydro-pyrido[ 2, l-aJisoquinolin-4- one
  • Pd/C (10% w/w, 677 mg, 0.64 mmol, 0.1 eq.) is added to 9-benzyloxy-2-((S)-l-[l,4]dioxan-2- ylmethoxy)-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (2.76 g, 6.37 mmol, 1 eq.) under nitrogen atmosphere.
  • EtOH 160 mL
  • the mixture is filtered over Celite and the filtrate concentrated under vacuum. The residue is treated with THF and the resulting precipitate filtered to afford the required compound.
  • Step viii Trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-4-oxo-6, 7-dihydro- 4H-pyrido[2, l-aJisoquinolin-9-yl ester
  • NEt 3 (0.25 mL, 1.8 mmol, 1.8 eq.) is added to a solution of 2-((S)-l-[l,4]dioxan-2- ylmethoxy)-9-hydroxy-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (343 mg, 1 mmol, 1 eq.) and N-phenylbis(trifluoromethanesulfonimide) (393 mg, 1.1 mmol, 1.1 eq.) in DCM (10 mL) and the reaction mixture is stirred at RT overnight. The resulting mixture is washed with aq. sat. NaHCC>3 and brine. The organic layer is separated, dried (Na 2 S0 4 ) and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM; 1 :99 to 5:95).
  • Step ix 9-(3,5-Dimethyl-isoxazol-4-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
  • Step ii 2-(3-Benzyloxy-phenyl)-2-methy -propylamine
  • Step v 9-Benzyloxy-2-hydroxy-l , 7, 7-trimethyl-6, 7-dihydro-pyrido[2, 1 -aJisoquinolin-4-one
  • Step vi 9-Benzyloxy-2-chloro-l, 7, 7-trimethyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin-4-one
  • Step viii 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-9-hydroxy-l, 7, 7-trimethyl-6, 7-dihydro-pyrido[2,l- aJisoquinolin-4-one
  • Pd/C (10% w/w, 161 mg, 0.15 mmol, 0.1 eq.) is added to 9-benzyloxy-2-((S)-l-[l,4]dioxan-2- ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (700 mg, 1.52 mmol, 1 eq.) under nitrogen atmosphere. MeOH (6 mL) is added and the resulting mixture put under hydrogen atmosphere and stirred at RT for 2 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum.
  • Step ix 2-( (S)-l-[ l,4]Dioxan-2-ylmethoxy)-l, 7, 7-trimethyl-9-(oxazol-2-ylmethoxy)-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
  • the resulting mixture is diluted with DCM, washed with brine, dried (Na 2 S0 4 ), filtered and concentrated.
  • the resulting mixture is purified on an SCX column (equilibrated with 5% AcOH in MeOH, washed with MeOH and eluted with 2 N NH 3 in MeOH) to afford the required compound.
  • Step i 9-(3, 6-Dihydro-2H-pyran-4-yl)-2-((S)-l-[l,4Jdioxan-2-ylmethoxy)-l-methyl-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
  • Step ii 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-l-methyl-9-(tetrahydro-pyran-4-yl)-6, 7-dihydro-pyrido [2, 1 - aJisoquinolin-4-one
  • Pd/C (10% w/w, 5 mg, 0.005 mmol, 0.1 eq.) is added to 9-(3,6-dihydro-2H-pyran-4-yl)-2-((S)- l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (20 mg, 0.05 mmol, 1 eq.) under nitrogen atmosphere. MeOH (1.3 mL) is added and the resulting mixture put under hydrogen atmosphere and stirred at RT for 2 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum to give the required compound.
  • a mixture of trifluoro-methanesulfonic acid 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-10-methoxy- l-methyl-4-oxo-6,7-dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester (157 mg, 0.31 mmol, 1 eq.), K4(Fe(CN) 6 ).3H 2 0 (26 mg, 0.06 mmol, 0.2 eq.), Pd(OAc) 2 (3.5 mg, 0.02 mmol, 0.05 eq.), Pd(dppf)Cl 2 .DCM (24 mg, 0.03 mmol, 0.1 eq.) and Na 2 C0 3 (33 mg, 0.31 mmol, 1 eq.) in DMA (1.5 mL) under nitrogen atmosphere is heated at 140°C for 24 h. The resulting mixture is diluted with DCM,
  • Cell based assay GTp- S binding assay.
  • the following assay can be used for determination of GPR84 activation.
  • the [ 35 S]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 [ 35 S]GTPyS to Ga subunits.
  • 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 '-diindolylmethane at ECgo concentration (concentration which gives 80% of the activity of GPR84).
  • GPR84 agonists medium chain free fatty acids such as sodium decanoate and sodium undecanoate, 3,3'-diindolylmethane and embelin
  • GPR84 antagonists block GPR84 agonist-induced chemotaxis.
  • GPR84 antagonists do not inhibit IL8- or fMLP-induced human neutrophil chemotaxis, indicating that GPR84 is an essential player in the process of neutrophil trafficking and recruitment.
  • the activity of GPR84 agonists and antagonists can therefore be assayed in a human neutrophil migration assay.
  • the human neutrophil migration assay makes use of freshly isolated human neutrophils from buffy coats that are subsequently used in a functional chemotaxis assay setup. Freshly isolated human neutrophils from buffy coats obtained from healthy individuals are pre-treated with a compound for 30 minutes prior to the plating of neutrophils onto the upper chamber of the neutrophil chemotaxis assembly (Corning HTS 5- ⁇ Transwell 96 permeable support system) in the presence of embelin (GPR84 agonist) at ECgo concentration (concentration for which 80% of activity is measured) in the lower chamber. After 1 hour of incubation at 37°C and 5% CO 2 , the number of migrated neutrophils in the lower compartment can be quantified by measuring the ATP content using ATPliteTM Luminescence Assay System. ⁇ ⁇ ⁇
  • a human buffy coat suspension is diluted with an equal volume of ice cold DPBS. 20 mL of the diluted buffy coat suspension 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 a 6% dextran/0.9% NaCl solution (15 g dextran T2000 and 2.25 g NaCl dissolved in 250 mL H 2 0) is added to the mixture and the samples are inverted gently up to 20 times. The total volume is transferred to a new recipient and incubated at room temperature to allow sedimentation of red blood cells.
  • the yellowish upper fraction is then transferred to a clean centrifugation tube and centrifuged for 12 min 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 H 2 0 to perform a red blood cell lysis by osmotic burst. After 20 seconds, 4 mL of ice-cold 0.6 M KC1 is added to restore salt concentration. Samples are mixed carefully and centrifuged for 6 min at 1300 rpm and 4°C. The supernatant is discarded and the red blood cell lysis procedure is repeated one more time.
  • the cell pellet is resuspended in 4 mL of DPBS and layered over 5 mL of LymphoprepTM (Axis Shield, prod. No. 1114545) in a 15 mL centrifuge tube. After a gradient centrifugation step (30 min at 1500 rpm, 4°C and low brake), the supernatant is removed and the cell pellet, containing polymorphonuclear cells, is resuspended in 25 mL of chemotaxis buffer (RPMI 1640 medium, supplemented with 10 mM HEPES and 0.05% FFA-free BSA).
  • RPMI 1640 medium supplemented with 10 mM HEPES and 0.05% FFA-free BSA
  • a neutrophil cell suspension of 8.9 x 10 6 cells per mL is prepared in chemotaxis buffer and 180 ⁇ per well is plated in a 96-well V-bottom plate. 20 ⁇ of test compound solution in chemotaxis buffer is added to the 180 ⁇ cell suspension. The mixture is incubated at RT for 30 min with intermediate gentle resuspension of the cells after 15 min. Following this, 75 ⁇ of cell suspension is plated onto the upper compartment of a Transwell ® permeable support system (Corning HTS Transwell 96 permeable support system with 5.0 ⁇ pore size polycarbonate membrane, Corning, prod. No. 3387).
  • the lower compartment (receiver well) is then filled with 200 ⁇ chemotaxis buffer containing an equal concentration of test compound and a fixed concentration of chemotactic agent (embelin at EC80 concentration).
  • a fixed concentration of chemotactic agent embelin at EC80 concentration.
  • the upper plate of the Transwell ® system is gently removed.
  • the number of migrated cells in the lower chamber is quantified by addition of 200 ⁇ of ATPliteTM solution (ATPliteTM Luminescence Assay System, Perkin Elmer, Prod. No. 6016941) followed by incubation for 10 minutes in the dark with mild agitation.

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Abstract

A compound according to Formula I: wherein R1, LA, GA, R2a, R2b, R3, R4, R5, and R6 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia by administering a compound of the invention.

Description

NOVEL DIHYDROPYRIDOISOQUINOLINONES 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia 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) 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 et al. 2001).
[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). 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 1 1 μΜ, respectively. Three small molecules were also described to have some GPR84 agonist activity: 3,3 '-diindolylmethane (DIM) (Wang et al. 2006), embelin (Hakak et al. 2007) and 6-n-octylaminouracil (6-OAU) (Suzuki et al. 2013).
[0005] GPR84 has been shown to be expressed in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells and B cells (Hakak et al. 2007; Venkataraman & Kuo 2005; Wang et al. 2006; Yousefi et al. 2001). 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), 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).
[0008] GPR84 knock-out (KO) mice are viable and indistinguishable from wild-type littermate controls (Venkataraman & Kuo 2005). The proliferation of T and B cells in response to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman & Kuo 2005). 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 & Kuo 2005).
[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 Thl/Th2 balance.
[0010] Berry et al. identified a whole-blood 393-gene transcriptional signature for active tuberculosis (TB) (Berry et al. 2010). 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). 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 ILlb 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/obesity, and therefore the inhibition of GPR84 activity might be beneficial for the treatment of endocrine and/or metabolic diseases.
[0013] GPR84 expression is also upregulated in microglia surrounding the neurons, after nerve injury (Gamo et al. 2008). Furthermore in GPR84 knock-out mice, hypersensitivity to mechanical stimuli were significantly reduced or completely absent in mouse models of inflammatory and neuropathic pain (Roman 2010). Molecules which block the activation of GPR84 may therefore have the potential to deliver broad-spectrum analgesia.
[0014] GPR84 expression is increased in human leukemic stem cells (LSC) from acute myeloid leukemia (AML) patients compared to hematopoietic stem cells from healthy donors. GPR84 simultaneously augments β-catenin signaling and an oncogenic transcription program essential for establishment of mixed lineage leukemia (MLL)(Dietrich et al. 2014). Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of stem cell-derived MLL leukemia, which represents a particularly aggressive and drug-resistant subtype of AML. Targeting the oncogenic GPR84/p-catenin signaling axis may represent a novel therapeutic strategy for AML and possibly other leukemias.
[0015] GPR84 expression is increased 49.9 times in Ml type macrophages isolated from aortic artherosclerotic lesions of LDLR-/- mice fed a high western diet (Kadi et al. 2010). Therefore, molecules targeting GPR84 may have a potential benefit in treatment of artherosclerosis.
[0016] 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 (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))), neuromflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
SUMMARY OF THE INVENTION
[0017] The present invention relates to novel dihydropyridoisoquinolinone compounds that antagonize GPR84, and that are potentially useful for the 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))), neuromflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
[0018] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating 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))), neuromflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia. [0019] Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a Formula I:
Figure imgf000006_0001
wherein
R is H, CM alkyl, or cyclopropyl;
LA is O or NH;
4-6 membered monocyclic heterocycloalkyl containing one or two O,
C3.7 monocyclic cycloalkyl, or
a bicyclic group of formula Cy:
Figure imgf000006_0002
Cy
wherein A is phenyl or 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O and S;
each R2A and R2B are independently H or -CH3;
R3 is H, -OH or -OCH3;
R4 is -CN or -L1-W1-G1,
wherein
LL is absent or O,
Wi is absent, or is
Figure imgf000006_0003
alkylene, C2-4 alkenylene having one double bond or C2-4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C alkoxy, o H,
o -CF3,
o alkyl,
o
Figure imgf000006_0004
alkyl, optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which heterocycloalkyl is optionally substituted with one or more independently selected R7 groups),
o 6 membered monocyclic heterocycloalkenyl containing one or two O (which heterocycloalkenyl is optionally substituted with one or more independently selected R7 groups),
o C3.7 monocyclic cycloalkyl optionally substituted with one or more independently selected R7 groups,
o phenyl optionally substituted with one or more independently selected R7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O and S (which heteroaryl is optionally substituted with one or more independently selected R7 groups),
each R7 is:
halo,
- -OH,
CM alkyl, C3.4 monocyclic cycloalkyl, or C1.4 alkoxy, each of which is optionally substituted with one or more independently selected halo;
R5 is -CN or -L2-W2-G2,
wherein
- L2 is absent, O or S,
W2 is absent or C1.4 alkylene, optionally substituted with one or more independently selected halo,
G2 is
o H,
o -CF3,
o C3_7 monocyclic cycloalkyl (which cycloalkyl is optionally substituted with one or more independently selected halo),
o phenyl,
o or 5-6 membered heteroaryl containing one to three heteroatoms independently selected from N, O and S; and
R6 is H, -OH or -OCH3.
[0020] In a particular aspect, the compounds of the invention have a surprisingly high chemical stability. In a more particular aspect, the compounds of the invention have a high chemical stability at acidic pH, more particularly between pH 1.0 and 6.0, and specifically at pH 1.2 and/or 5.0.
[0021] 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 r
6
composition may additionally comprise further active ingredients suitable for use in combination with a compound of the invention.
[0022] In another aspect of the invention, this invention provides novel compounds of the invention for use in therapy.
[0023] 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, which method comprises administering a therapeutically effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[0024] 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
[0025] In additional aspects, this invention provides methods for synthesizing a compound of the invention, with representative synthetic protocols and pathways disclosed herein.
[0026] 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.
[0027] 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, that may be causally related to the activity and/or expression and/or distribution of GPR84.
[0028] 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 (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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
[0029] 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
[0030] 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.
[0031] 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.
[0032] 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.
[0033] '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 (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n- butyl (-CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2- CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1 ,2-dimethylbutyl (-CHCH3)-C(CH3)H2- CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.
[0034] '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.
[0035] '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 o
as -CH=CH-, -CH2-CH=CH-, -C(CH3)=CH-, -C(CH3)=CH-CH2-, -C(CH3)=C(CH3)-, and -CH2- C(CH3)=CH-.
[0036] '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-.
[0037] '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 -O-C1-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.
[0038] 'Amino' refers to the radical -NH2.
[0039] '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.
[0040] 'Carboxy' refers to the radical -C(0)OH.
[0041] '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.
[0042] 'Cyano' refers to the radical -CN.
[0043] 'Halo' or 'halogen' refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0044] '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.
[0045] '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.
[0046] Examples of
Figure imgf000011_0001
wherein each Y is selected from >C=0, NH, O and S.
[0047] 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 heterocycloalkyl groups are shown in the following illustrative exam les:
Figure imgf000012_0001
wherein each W is selected from CH2, NH, O and S; and each Y is selected from NH, O, CO, SO2, and S.
[0048] 'Heterocycloalkenyl' means a 'heterocycloalkyl', which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:
Figure imgf000012_0002
wherein each W is selected from CH2, NH, O and S; each Y is selected from NH, O, C(=0), SO2, and S; and each Z is selected from N or CH.
[0049] 'Hydroxy' refers to the radical -OH.
[0050] 'Nitro' refers to the radical -N02.
[0051] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
[0052] 'Thiol' refers to the group -SH. ^ ^
[0053] 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.
[0054] 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.
[0055] '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.
[0056] '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.
[0057] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[0058] '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.
[0059] '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.
[0060] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.
[0061] '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.
[0062] '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.
[0063] 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.
[0064] '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.
[0065] 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. In a further particular aspect, the term refers to uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
[0066] As used herein the term 'pain' refers to diseases or disorders characterized by unpleasant feeling often caused by intense or damaging stimuli, and include but is not limited to nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration) and neuropathic or dysfunctional pain (caused by damage to or abnormal function of the nervous system, and/or pain associated or caused by the conditions mentioned herein. Pain can be acute or chronic.
[0067] 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.
[0068] 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.
[0069] 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. A particular example of metabolic disorders is obesity.
[0070] 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.
[0071] As used herein the term 'neuroinflammatory conditions' refers to diseases or disorders characterized by abrupt neurologic deficits associated with inflammation, demyelination, and axonal Λ Λ
14
damage, and includes but is not limited to conditions such as Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.
[0072] As used herein the term 'neurodegenerative conditions' refers to diseases or disorders characterized by progressive loss of structure or function of neurons, including death of neurons, and includes but is not limited to conditions such as dementia, degenerative dementia, senile dementia, vascular dementia, dementia associated with intracranial space occupying lesions, mild cognitive impairment associated with ageing, age associated memory impairment, and /or peripheral neuropathies. In particular, the term refers to retinopathies, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), motor neurone disease (MND), spinocerebellar ataxia (SCA), and/or spinal muscular atrophy (SMA). More particularly, the term refers to retinopathies, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, and/or amyotrophic lateral sclerosis (ALS).
[0073] As used herein the term 'cardiovascular diseases' refers to diseases affecting the heart or blood vessels or both. In particular, cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue. Particularly, the term refers to atherosclerosis.
[0074] As used herein the term 'leukemia' refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukemia (AML), mixed lineage leukemia (MLL) and acute lymphoblastic leukemia (ALL).
[0075] '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.
[0076] 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.
[0077] 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 (Bundgaard 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 Cg alkyl, and substituted or unsubstituted Ce-io aryl esters of the compounds of the invention.
[0078] 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.
[0079] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
[0080] 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'.
[0081] 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'.
[0082] '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. [0083] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0084] 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.
[0085] 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.
[0086] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.
THE COMPOUNDS
[0087] The present invention relates to novel compounds that antagonize GPR84 and that may be useful for the 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
[0088] 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 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, by administering a compound of the invention. A compound of the invention is an inhibitor of GPR84.
[0089] Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a Formula I:
Figure imgf000018_0001
wherein
R is H, CM alkyl, or cyclopropyl; LA is O or NH;
4-6 membered monocyclic heterocycloalkyl containing one or two O,
C3.7 monocyclic cycloalkyl, or
a bicyclic group of formula Cy:
Figure imgf000019_0001
Cy
wherein A is phenyl or 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O and S;
each R2a and R2b are independently H or -CH3;
R3 is H, -OH or -OCH3;
R4 is -CN or -L1-W1-G1, wherein
Li is absent or O,
Wi is absent, or is Ci_6 alkylene, C2-4 alkenylene having one double bond or C2-4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C1.4 alkoxy, o H,
o -CF3,
o alkyl,
o
Figure imgf000019_0002
alkyl, optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which
heterocycloalkyl is optionally substituted with one or more independently selected R7 groups),
o 6 membered monocyclic heterocycloalkenyl containing one or two O (which
heterocycloalkenyl is optionally substituted with one or more independently selected R7 groups),
o C3.7 monocyclic cycloalkyl optionally substituted with one or more independently
selected R7 groups,
o phenyl optionally substituted with one or more independently selected R7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O and S (which heteroaryl is optionally substituted with one or more independently selected R7 groups),
R7 is:
halo,
- -OH, 1 o
CM alkyl, C3.4 monocyclic cycloalkyl, or C1.4 alkoxy, each of which is optionally substituted with one or more independently selected halo;
R5 is -CN or -L2-W2-G2, wherein
L2 is absent, O or S,
W2 is absent or C1.4 alkylene, optionally substituted with one or more independently selected halo,
G2 is
o H,
o -CF3,
o C3_7 monocyclic cycloalkyl (which cycloalkyl is optionally substituted with one or more independently selected halo),
o phenyl,
o or 5-6 membered heteroaryl containing one to three heteroatoms independently selected from N, O or S, and
R6 is H, -OH or -OCH3.
[0090] In one embodiment, the compound of the invention is according to Formula I, wherein R2a and R2b are both -CH3.
[0091] In one embodiment, the compound of the invention is according to Formula II:
Figure imgf000020_0001
I I
R1, LA, GA, R3, R4, R5, and R6 are as previously described.
In one embodiment, the compound of the invention is according to Formula I or II, wherein R
In one embodiment, the compound of the invention is according to Formula I or II, wherein R In one embodiment, the compound of the invention is according to Formula I or II, wherein R6 In one embodiment, the compound of the invention is according to Formula I or II, wherein R6 [0096] In one embodiment, the c to Formula III:
Figure imgf000021_0001
I I I
wherein R1, LA, GA, R4, and R5 are as previously described.
[0097] In one embodiment, the compound of the invention is according to any one of Formulae I-III, wherein GA is Cy, and A is phenyl or 5-6 membered heteroaryl containing 1 or 2 independently selected N, O or S atoms. In a particular embodiment, Cy is:
Figure imgf000021_0002
[0098] In one embodiment, the compound of the invention is according to any one of Formulae I-III, wherein GA is tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
[0099] In one embodiment, the compound of the invention is according to any one of Formulae I-III, wherein GA is cyclobutyl, cyclopentyl, or cyclohexyl.
[00100] In one embodiment, the compound of the invention is according to Formula IVa, IVb, IVc, or I
Figure imgf000021_0003
IVa IVb IVc
wherein R1, LA, R4, and R5 are as previously described. 2Q
[00101] In one embodiment, the compound of the invention is according to Formula IVe, IVf, IVg, or IV
Figure imgf000022_0001
IVe IVf
wherein R1, LA, R4, and R5 are as previously described.
[00102] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -CN.
[00103] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2. In a particular embodiment, L2 is absent. In another particular embodiment, L2 is O.
[00104] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2, L2 and G2 are as previously described and W2 is absent. In another embodiment, W2 is CM alkylene. In a particular embodiment, W2 is -CH2-, or -CH2-CH2-. In a more particular embodiment, W2 is -CH2-.
[00105] In another embodiment, the compound of the invention is according to any one of Formulae I- IVh, wherein R5 is -L2-W2-G2, L2 and G2 are as previously described and W2 is CM alkylene substituted with one or more independently selected halo. In a particular embodiment, W2 is -CH2-, or -CH2-CH2- substituted with one or more independently selected halo. In another particular embodiment, W2 is C1.4 alkylene substituted with one or more independently selected F or CI. In a more particular embodiment, W2 is -CH2-, or -CH2-CH2- substituted with one or more independently selected F or CI. In a most particular embodiment, W2 is -CF2-, or -CH2-CF2-.
[00106] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2, L2 and W2 are as previously described and G2 is -CF3.
[00107] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2, L2 and W2 are as previously described and G2 is C3.7 cycloalkyl. In a particular embodiment, G2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[00108] In another embodiment, the compound of the invention is according to any one of Formulae I- IVh, wherein R5 is -L2-W2-G2, L2 and W2 are as previously described and G2 is C3.7 cycloalkyl substituted with one or more independently selected halo. In a particular embodiment, G2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with one or more independently selected halo. In another particular embodiment, G2 is C3.7 cycloalkyl substituted with one or more independently selected F or CI. In a more particular embodiment, G2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with one or more independently selected F or CI. In a most particular embodiment, G2 is difluorocyclopropyl. In a further most particular embodiment, G2 is:
Figure imgf000023_0001
[00109] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2, L2 and W2 are as previously described and G2 is 5-6 membered heteroaryl containing one to three heteroatoms independently selected from O, N, and S. In a particular embodiment, G2 is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl.
[00110] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2, L2 and W2 are as previously described and G2 is phenyl.
[00111] In one embodiment, the compound of the invention is according to any one of Formulae I-IVh, wherein R5 is -L2-W2-G2, L2 and W2 are as previously described and G2 is H.
[00112] In one embodiment, the compound of the invention is according to Formula Va, Vb, Vc, or V
Figure imgf000023_0002
Va Vb Vc Vd wherein R1, LA, and R4 are as previously described.
[00113] In one embodiment, the compound of the invention is according to Formula Ve, Vf, Vg, or
Vh
Figure imgf000023_0003
Ve Vf Vg Vh wherein R1, LA, and R4 are as previously described.
[00114] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -CN. ^
[00115] In one embodiment, the compound of the invention is according any one of Formulae I-Vh, wherein R4 is -Li-Wi-Gi. In a particular embodiment, Li is absent. In another particular embodiment, Li is O.
[00116] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Gi are as previously described and Wi is absent. In another embodiment, Wi is Ci_6 alkylene. In a particular embodiment, Wi is -CH2-, -CH2-CH2-, -CH2-CH2-CH2- CH2-, -CH2-CH2-CH(CH3)-CH2- or -CH2-CH2-CH2-CH2-CH2-.
[00117] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LpWi-Gi, Li and Gi are as previously described and Wi is Ci_6 alkylene substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In a particular embodiment, Wi is - CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-CH2- or -CH2-CH2-CH2-CH2-CH2-, each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another particular embodiment, Wi is Ci_6 alkylene substituted with one or more independently selected F, CI, - OCH3, -OCH2-CH3, or -OCH(CH3)2. In a more particular embodiment, Wi is -CH2-, -CH2-CH2-, -CH2- CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-CH2- or -CH2-CH2-CH2-CH2-CH2-, each of which is substituted with one or more independently selected F, CI, -OCH3, -OCH2-CH3, or -OCH(CH3)2.
[00118] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Gi are as previously described and Wi is C2-4 alkenylene having one double bond. In a particular embodiment, Wi is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-. In a more particular embodiment, Wi is -CH=CH-.
[00119] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -L1-W1-G1, Li and Gi are as previously described and Wi is C2-4 alkenylene having one double bond, substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In a particular embodiment, Wi is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-, each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another particular embodiment, Wi is C2-4 alkenylene having one double bond, substituted with one or more independently selected F, CI, - OCH3, -OCH2-CH3, or -OCH(CH3)2. In a more particular embodiment, Wi is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-, each of which is substituted with one or more independently selected F, CI, -OCH3, - OCH2-CH3, or -OCH(CH3)2.
[00120] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Gi are as previously described and Wi is C2-4 alkynylene having one triple bond. In a particular embodiment, Wi is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-. In a more particular embodiment, Wi is -C≡C-.
[00121] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LpWpGi, Li and Gi are as previously described and Wi is C2-4 alkynylene having one triple bond, substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In a particular embodiment, Wi is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-, each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another particular embodiment, Wi is C2-4 alkynylene ^ having one triple bond, substituted with one or more independently selected F, CI, -OCH3, -OCH2-CH3, or -OCH(CH3)2. In a more particular embodiment, Wi is -CH2-C≡C-, or -C≡C-CH2-, each of which is substituted with one or more independently selected F, CI, -OCH3, -OCH2-CH3, or -OCH(CH3)2.
[00122] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWi-Gi, Li and Wi are as previously described and Gi is -CF3.
[00123] In one embodiment, the compound of the invention is according any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Wi are as previously described and Gi is -C(=0)-Ci_4 alkyl. In a particular embodiment, Gi is -C(=0)-CH3.
[00124] In one embodiment, the compound of the invention is according any one of Formulae I-Vh, wherein R4 is -LrWrGi, and Wi are as previously described and Gi is
Figure imgf000025_0001
alkyl. In a particular embodiment, Gi is -S(=0)2-CH3, or -S(=0)2-CH2-CH3. In a more particular embodiment, Gi is -S(=0)2-CH3.
[00125] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LrWrGi, and Wi are as previously described and Gi is
Figure imgf000025_0002
alkyl, substituted with one or more independently selected halo. In a particular embodiment, Gi is -S(=0)2-CH3 or -S(=0)2-CH2-CH3, each of which is substituted with one or more independently selected halo. In another particular embodiment, Gi is
Figure imgf000025_0003
alkyl, substituted with one or more independently selected F or CI. In a more particular embodiment, Gi is -S(=0)2-CH3 or -S(=0)2-CH2-CH3, each of which is substituted with one or more independently selected F or CI. In a most particular embodiment,
Figure imgf000025_0004
[00126] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Wi are as previously described and Gi is 4-6 membered monocyclic heterocycloalkyl containing one or two O. In a particular embodiment, Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
[00127] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LrWrGi, and Wi are as previously described and Gi is 4-6 membered monocyclic heterocycloalkyl containing one or two O and substituted with one or more independently selected R7 groups. In a particular embodiment, Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, substituted with one or more independently selected R7 groups. In another particular embodiment, Gi is 4- 6 membered monocyclic heterocycloalkyl containing one or two O, substituted with one or more independently selected R7 groups, wherein R7 is halo, -OH, C alkyl, C3_4 monocyclic cycloalkyl, or C alkoxy. In a more particular embodiment, Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, substituted with one or more independently selected R7 groups, wherein R7 is F, CI, -OH, -CH3, -CH2-CH3, -CH2-CH2-CH3, cyclopropyl, -OCH3, or -OCH2-CH3.
[00128] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Wi are as previously described and Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O. In a particular embodiment, Gi is dihydropyranyl or dihydrodioxinyl. „„
24
[00129] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LpWi-Gi, Li and Wi are as previously described and Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O, substituted with one or more independently selected R7 groups. In a particular embodiment, Gi is dihydropyranyl or dihydrodioxinyl, substituted with one or more independently selected R7 groups. In another particular embodiment, Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O, substituted with one or more independently selected R7 groups, wherein R7 is halo, -OH, C alkyl, C3.4 monocyclic cycloalkyl, or CM alkoxy. In a more particular embodiment, Gi is dihydropyranyl or dihydrodioxinyl, substituted with one or more independently selected R7 groups, wherein R7 is F, CI, -OH, -CH3, -CH2-CH3, -CH2-CH2-CH3, cyclopropyl, -OCH3, or -OCH2-CH3.
[00130] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWpGi, Li and Wi are as previously described and Gi is C3.7 monocyclic cycloalkyl. In a particular embodiment, Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In a more particular embodiment, Gi is cyclopropyl or cyclobutyl.
[00131] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LpWi-Gi, Li and Wi are as previously described and Gi is C3.7 monocyclic cycloalkyl, substituted with one or more independently selected R7 groups. In a particular embodiment, Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more independently selected R7 groups. In another particular embodiment, Gi is C3.7 monocyclic cycloalkyl, substituted with one or more independently selected R7 groups, wherein R7 is halo, -OH, CM alkyl, C3.4 monocyclic cycloalkyl, or C alkoxy. In a more particular embodiment, Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more independently selected R7 groups, wherein R7 is F, CI, -OH, -CH3, -CH2-CH3, -CH2-CH2-CH3, cyclopropyl, -OCH3, or -OCH2-CH3.
[00132] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWi-Gi, Li and Wi are as previously described and Gi is phenyl.
[00133] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LpWi-Gi, Li and Wi are as previously described and Gi is phenyl, substituted with one or more independently selected R7 groups. In a particular embodiment, Gi is phenyl, substituted with one or more independently selected R7 groups, wherein R7 is halo, -OH, C alkyl, C alkyl substituted with one or more independently selected halo, C3.4 monocyclic cycloalkyl, CM alkoxy, or CM alkoxy substituted with one or more independently selected halo. In a more particular embodiment, Gi is phenyl, substituted with one or more independently selected R7 groups, wherein R7 is F, CI, -OH, -CH3, -CH2- CH3, -CH2-CH2-CH3, -CF3, cyclopropyl, -OCH3, -OCH2-CH3, -O-CF3, or -0-CH2-CF3.
[00134] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWi-Gi, Li and Wi are as previously described and Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O. In a particular embodiment, Gi is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, ^ tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl. In a more particular embodiment, Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl.
[00135] In another embodiment, the compound of the invention is according to any one of Formulae I- Vh, wherein R4 is -LpWpGi, Li and Wi are as previously described and Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R7 groups. In a particular embodiment, Gi is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, substituted with one or more independently selected R7 groups. In another particular embodiment, Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O, substituted with one or more independently selected R7 groups, wherein R7 is halo, - OH, CM alkyl, CM alkyl substituted with one or more independently selected halo, C3.4 monocyclic cycloalkyl, C1.4 alkoxy, or C1.4 alkoxy substituted with one or more independently selected halo. In a more particular embodiment, Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl, substituted with one or more independently selected R7 groups, wherein R7 is halo, -OH, C1.4 alkyl, CM alkyl substituted with one or more independently selected halo, C3.4 monocyclic cycloalkyl, CM alkoxy, or CM alkoxy substituted with one or more independently selected halo. In a most particular embodiment, Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl, substituted with one or more independently selected R7 groups, wherein R7 is F, CI, -OH, -CH3, -CH2-CH3, -CH2-CH2-CH3, -CF3, cyclopropyl, - OCH3, -OCH2-CH3, -O-CF3, or -0-CH2-CF3.
[00136] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -0-CH2-cyclopropyl, substituted with one or more independently selected F or CI. In a more particular embodiment, R4 is -0-CH2-cyclopropyl, substituted with one, two or three independently selected F or CI.
[00137] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R4 is -LpWi-Gi, Li and Wi are absent, and Gi is H.
[00138] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein R1 is H, -CH3, -CH2-CH3, -CH(CH3)2, or cyclopropyl. In a particular embodiment, R1 is H. In another particular embodiment, R1 is -CH3.
[00139] In one embodiment, the compound of the invention is according to any one of Formulae I-Vh, wherein LA is -NH-. In another embodiment, LA is -0-.
Figure imgf000028_0001
wherein R and G2 are as previously described.
[00141] In one embodiment, the compound of the invention is according to Formula Vie, Vlf, VIg, or Vlh:
Figure imgf000028_0002
VIi wherein R and G2 are as previously described.
Figure imgf000029_0001
Vim Vln Vlo VIp wherein R4 and G2 are as previously described.
[00144] In one embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is O, Wi is Ci_6 alkylene or Ci_6 alkylene substituted with one or more halo, and Gi is H or -CF3. In a particular embodiment, Wi is -CH2-, -CF2-, or -CH2-CF2-, and Gi is H or - CF3.
[00145] In one embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is O, Wi is -CH2-, and Gi is C3.7 monocyclic cycloalkyl or C3.7 monocyclic cycloalkyl substituted with one or more independently selected R7 groups, wherein R7 is halo, or C1.4 alkyl.
[00146] In one embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is O, Wi is absent, and Gi is
Figure imgf000029_0002
alkyl.
[00147] In another embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is O, Wi is absent, and Gi is
Figure imgf000029_0003
alkyl substituted with one or more F. In a particular embodiment, Gi is -S(=0)2CF3.
[00148] In another embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is absent, Wi is -C≡C- and Gi is C3.7 monocyclic cycloalkyl. In a particular embodiment, Gi is cyclopropyl.
[00149] In one embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is absent, Wi is absent, and Gi is phenyl substituted with one or two independently selected R7 groups. In a particular embodiment, Gi is phenyl substituted with one or two independently selected R7 groups, wherein R7 is C1.4 alkyl, C1.4 alkoxy, C1.4 alkyl substituted with one or more F, or C1.4 alkoxy substituted with one or more F. In a more particular embodiment, R7 is -CF3, or
[00150] In one embodiment, the compound of the invention is according to any one of Formulae I- VIp wherein R4 is -L1-W1-G1, Li is absent, Wi is absent, and Gi is pyridinyl substituted with one R7 group. In a particular embodiment, Gi is pyridinyl substituted with one R7 group, wherein R7 is halo, -OH, C3.4 monocyclic cycloalkyl, C1.4 alkoxy, or C1.4 alkoxy substituted with one or more F. In a more particular embodiment, R7 is -CF3, or -OCF3.
[00151] In one embodiment, the compound of the invention is selected from: 2o
9-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-10-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)- 1 - [ 1 ,4] dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-6,7-dihydro-pyrido [2, 1 - a]isoquinolin-4-one,
9- (2,2-difluoro-cyclopropylmethoxy)-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
10- (2,2-difluoro-ethoxy)-2-[([l,4]dioxan-2-ylmethyl)-amino]-9-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9- (2,2-difluoro-ethoxy)-10-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
10- methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9- (6-cyclopropyl-pyridin-3-yl)-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-(2,3-dihydro-thieno[3,4-b] [1 ,4]dioxin-2-ylmethoxy)-9, 10-dimethoxy-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-4-oxo-6,7- dihydro-4H-pyrido[2, 1 -a]isoquinolin-9-yl ester,
2-[([l,4]dioxan-2-ylmethyl)-amino]-9-methoxy- pyrido[2,l-a]isoquinolin-4-one,
10- (2,2-difluoro-ethoxy)-9-methoxy-l-methyl-2-[(tetrahydro^
pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl
dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(6-fluoro-pyridin-3-yl)-l 0-methoxy-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9,10-bis-(2,2-difluoro-cyclopropylmethoxy)-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihyd pyrido[2,l-a]isoquinolin-4-one,
9- (3,3-difluoro-cyclobutylmethoxy)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-9-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
10- difluoromethoxy-9-methoxy-l-methyl-2-[(tetrahydro-fe
pyrido[2,l-a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethyl)-amino] -6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-9-(6-oxo-l,6-dihydro-pyridin-3-yl)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one, -((S)-l-[l ,4] dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-9-(3 -methyl-oxetan-3 -ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
-methoxy-l-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-10-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
-(2,2-difluoro-ethoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
-[([l ,4]dioxan-2-ylmethyl)-amino]-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin- 4-one,
-(2,3-dihydro-benzo[l,4]dioxin-2-ylmethoxy)-9-hydroxy-10-methoxy-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
-difluoromethoxy-2-((S)- 1 - [1 ,4]dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
- cyclopropylmethoxy-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(4-ethoxy-3-trifluoromethyl-phenyl)-10-methoxy-l-methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
,10-dimethoxy-l -methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
.9- dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,.10- dimethoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin- 4-one,
0- difluoromethylsulfanyl-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-9-(4-trifluoromethoxy-phenyl)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
-(2,2-difluoro-cyclopropylmethoxy)-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
,9-dimethoxy-l-methyl-2-[(tenahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin-
4-one,
-(2,3-dihydro-benzo[l ,4]dioxin-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l , 10-dimethyl-6,7-dihydro-pyrido[2,l -a]isoquinolin-4- one,
,11 -dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 3Q
2-[([l ,4]dioxan-2-ylmethyl)-amino]-8, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 8,11 -dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-[(R)-l -(2,3-dihydro-[l ,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9, 10-dimethoxy-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-[([l,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-l-methyl-6,7-dihydro-pyrido[2,l-a]is
10-(2,2-difluoro-ethoxy)-9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
8,9-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-am^
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-[(S)-l-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9,l 0-dimethoxy-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-[([l,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 2-((S)- 1 -[1 ,4]dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 - a]isoquinoline-9-carbonitrile,
9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethoxy)- 10-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l ,7,7-trimethyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l ,7,7-trimethyl-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9, 11 -dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-(2,3-dihydro-benzo[l ,4]dioxin-2-ylmethoxy)-9, 10-dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-4-oxo-6,7-dihydro-4H- pyrido[2,l-a]isoquinolin-9-yl ester,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-9-pentyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l 0-methoxy- 1 -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-([l,4]dioxan-2-ylmethoxy)-9,10-dimethoxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
8,11 -dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, ^
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(5-ethyl-[l,2,4]oxadiazol-3-ylmethoxy)-l-methyl-6,7-dihydro- pyrido[2, 1 -a]isoquinolin-4-one,
2-[([l ,4]dioxan-2-ylmethyl)-amino]-9, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 8,9-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
2-(2,3-dihydro-benzo[l,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- 9-methoxy- 1 -methyl- 10-(pyridin-2-ylmethoxy)-2- [(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-(3,5-dimethyl-isoxazol-4-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-benzyloxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 9, 11 -dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)- 1 - [ 1 ,4] dioxan-2-ylmethoxy)-9-hydroxy- 10-methoxy- 1 -methyl-6,7-dihydro-pyrido [2,1- a]isoquinolin-4-one,
8.9- dimethoxy-l-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquino 4-one,
9-benzyloxy-l-cyclopropyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-8, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 9-(3,6-dihydro-2H-pyran-4-yl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-9-(oxazol-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9, 11 -dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(tetrahydro-pyran-4-yl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-benzyloxy-2-([l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, [2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -methyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 -a]isoquinolin-9-yloxy]- acetonitrile,
9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9.10- dimethoxy-l -methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(3-methyl-but-l-ynyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-(5,6-dihydro-[l ,4]dioxin-2-yl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-ethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(l-methyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one, ^
[2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-ethyl-4-oxo-6,7-dihydro-4H-pyrido[2,l-a]isoquinolin-9-yloxy]- acetonitrile,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(l-propyl-lH-tetrazol-5-ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 8,11 -dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9-[l ,4]dioxan-2-yl-2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)- 1 -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-8-hydroxy-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-( 1 -cyclopropyl- 1 H-tetrazol-5-ylmethoxy)-2-((S)- 1 - [ 1 ,4] dioxan-2-ylmethoxy)- 1 -methyl-6,7-dihydro- pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-4-oxo-9-(2,2,2-trifluoro-ethoxy)-6,7-dihydro-4H- pyrido [2, 1 -a] isoquinoline- 10-carbonitrile,
2,9-bis-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
8.9- dimethoxy-l-methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquino
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(3-methyl-oxetan-3-ylmethoxy)-6,7-dihydro-pyri a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l -ethyl-6,7-dihydro-pyrido[2,l-a]isoquinolm^ one,
9.10- dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(lH-tetrazol-5ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-cyclohexylmethoxy-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9, 10-dimethoxy- 1 -methyl-2- [(tetrahydro-pyran-3 -ylmethyl)-amino] -6,7-dihydro-pyrido [2,1- a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(l-methyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9,10-dimethoxy-l -methyl-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one 9-cyclopropylmethoxy-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
8,9-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methoxy-but-l -ynyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one, ^
8,9-dimethoxy-l-methyl-2-(tetrahydro-pyran-2-ylmethox
9-benzyloxy-l-cyclopropyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-ethyl-4-oxo-6,7-dihydro-4H- pyrido[2,l-a]isoquinolin-9-yl ester,
9-(2-cyclopropyl-ethyl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-
4-one,
9-cyclopropylmethoxy-2-([ 1 ,4] dioxan-2-ylmethoxy)- 1 -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2,l-a]isoquinoH one,
9, 11 -dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-l ,7,7-trimethyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l -methyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 - a]isoquinoline-10-carbonitrile,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-pentyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 9-benzyloxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -isopropyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methoxy-butyl)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
1 -cyclopropyl-9-(2-cyclopropyl-ethyl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
trifluoro-methanesulfonic acid l-cyclopropyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-4-oxo-6,7-dihydro-4H- pyrido[2,l-a]isoquinolin-9-yl ester,
trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-isopropyl-4-oxo-6,7-dihydro-4H- pyrido[2,l-a]isoquinolin-9-yl ester,
1- cyclopropyl-9-cyclopropylethynyl-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2- ((S)-l-[l,4]dioxan-2-ylmethoxy)-l -isopropyl-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2,l-a]isoquinolin-
4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-8-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one, ^
9-(2-cyclopropyl-ethyl)-2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l -isopropyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-methyl4)ut-l -ynyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-([l,4]dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-l -methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -isopropyl-9-(3-methyl4out-l-ynyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l -isopropyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-94 ydroxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, trifluoro-methanesulfonic acid 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l-methyl-4-oxo-6,7-dihydro-4H- pyrido[2,l-a]isoquinolin-9-yl ester,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-hydroxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 9-methoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 104 ydroxy-9-methoxy-l-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-arnino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-[([l ,4]dioxan-2-ylmethyl)-amino]-l 0-hydroxy-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
104iydroxy-9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one, and
104oenzyloxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one.
[00152] In one embodiment a compound of the invention is not an isotopic variant.
[00153] In one aspect a compound of the invention is present as the free base.
[00154] In one aspect a compound of the invention is a pharmaceutically acceptable salt.
[00155] In one aspect a compound of the invention is present as the free base or a pharmaceutically acceptable salt.
[00156] In one aspect a compound of the invention is a solvate.
[00157] In one aspect a compound of the invention is a solvate of a pharmaceutically acceptable salt of the compound.
[00158] 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.
[00159] 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 (Bundgaard 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 Cg alkyl, C2-Cg alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
[00160] 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.
[00161] 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.
[00162] 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
Figure imgf000037_0001
I
wherein
Pv1 is H, CM alkyl, or cyclopropyl;
LA is O or NH;
4-6 membered monocyclic heterocycloalkyl containing one or two O,
C3.7 monocyclic cycloalkyl, or a bicyclic group of formula Cy:
Figure imgf000038_0001
wherein A is phenyl or 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O and S;
each R2a and R2b are independently H or -CH3;
R3 is H, -OH or -OCH3;
R4 is -CN or -Li-Wi-Gi, wherein
Li is absent or O,
Wi is absent, or is Ci_6 alkylene, C2-4 alkenylene having one double bond or C2-4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C1.4 alkoxy, o H,
o -CF3,
o alkyl,
o
Figure imgf000038_0002
alkyl, optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which
heterocycloalkyl is optionally substituted with one or more independently selected R7 groups),
o 6 membered monocyclic heterocycloalkenyl containing one or two O (which
heterocycloalkenyl is optionally substituted with one or more independently selected R7 groups),
o C3.7 monocyclic cycloalkyl optionally substituted with one or more independently
selected R7 groups,
o phenyl optionally substituted with one or more independently selected R7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O or S (which heteroaryl is optionally substituted with one or more independently selected R7 groups),
R7 is:
halo,
- -OH,
CM alkyl, C3.4 monocyclic cycloalkyl, or C1.4 alkoxy, each of which is optionally substituted with one or more independently selected halo;
R5 is -CN or -L2-W2-G2, wherein
L2 is absent, O or S, W2 is absent or C1.4 alkylene, optionally substituted with one or more independently selected halo,
G2 is
o H,
o -CF3,
o C3_7 monocyclic cycloalkyl (which cycloalkyl is optionally substituted with one or more independently selected halo),
o phenyl,
o or 5-6 membered heteroaryl containing one to three heteroatoms independently selected from N, O or S,
R6 is H, -OH or -OCH3;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof; or a biologically active metabolite thereof.
A compound, or pharmaceutically acceptable salt thereof, according to clause 1 , wherein R2a and R21 are both -CH3.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 , wherein the compound is according to Formula II:
Figure imgf000039_0001
I I
wherein R1, LA, GA, R3, R4, R5, and R6 are as previously described.
4) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-3,
wherein R3 is -OCH3.
5) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-3,
wherein R3 is H.
6) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5,
wherein R6 is -OCH3.
7) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5,
wherein R6 is H. A compound or pharmaceutically acceptable salt thereof, according to clause 1 , wherein the compound is according to Formula III:
Figure imgf000040_0001
I I I wherein R1, LA, GA, R4, and R5 are as previously described.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein GA is Cy, and A is phenyl or 5-6 membered heteroaryl containing 1 or 2 independently selected N, O or S atoms.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein GA is Cy and Cy is:
Figure imgf000040_0002
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein GA is tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein GA is cyclobutyl, cyclopentyl, or cyclohexyl.
) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the
Figure imgf000040_0003
IVa IVb IVc IVd wherein R1, LA, R4, and R5 are as previously described.
) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula IVe, IVf, IVg, or IVh:
Figure imgf000041_0001
IVe IVf IVg IVh
wherein R1, LA, R4, and R5 are as previously described.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14, wherein R5 is -CN.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14, wherein R5 is -L2-W2-G2.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16, wherein L2 is absent.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16, wherein L2 is O.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 18, wherein W2 is absent.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 18, wherein W2 is CM alkylene.
A compound or pharmaceutically acceptable salt thereof, according to clauses 1-14 or 16-18, wherein W2 is -CH2- or -CH2-CH2-.
A compound or pharmaceutically acceptable salt thereof, according to clauses 1-14 or 16-18, wherein W2 is -CH2-
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16-
18, wherein W2 is CM alkylene substituted with one or more independently selected halo.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16-
18, wherein W2 is CM alkylene substituted with one or more independently selected F or CI.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16-
24, wherein G2 is -CF3.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is C3.7 cycloalkyl.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is C3.7 cycloalkyl substituted with one or more independently selected halo.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is C3.7 cycloalkyl substituted with one or more independently selected F or CI. 30) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is difluorocyclopropyl.
31) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is
Figure imgf000042_0001
32) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is 5-6 membered heteroaryl containing one to three heteroatoms independently selected from O, N, and S.
33) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl.
34) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein G2 is phenyl.
35) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-14 or 16- 24, wherein L2 and W2 are absent, and G2 is H.
36) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the
Figure imgf000042_0002
37) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the
c
Figure imgf000042_0003
Ve Vf Vg Vh
wherein R1, LA, and R4 are as previously described. „ Λ
41
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37, wherein R4 is -CN.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37, wherein R4 = -LrWi-Gi.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein Li is absent.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein Li is O.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is absent.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is Ci_6 alkylene.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-CH2- or -CH2-CH2- CH2-CH2-CH2-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is C2-4 alkenylene having one double bond.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is -CH=CH-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is C2-4 alkynylene having one triple bond.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 41, wherein Wi is -C≡C-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein is absent, and Wi is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-CH2-, or -CH2-CH2-CH2-CH2-CH2-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein is absent, and Wi is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein is absent, and Wi is -C≡C-, -CH2-C≡C-, or -C≡C-CH2-.
) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein Wi is Ci_6 alkylene, C2-4 alkenylene having one double bond, or C2-4 alkynylene having one triple bond, each of which is substituted with one or more independently selected halo, -CN, or C alkoxy. 55) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39, wherein Wi is Ci_6 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple bond, each of which is substituted with one or more independently selected F, CI, -OCH3, - OCH2-CH3, or -OCH(CH3)2.
56) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 55, wherein Gi is -CF3.
57) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 55, wherein Gi is
Figure imgf000044_0001
alkyl.
58) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39- 55, wherein Gi is -S(=0)2-CH3, or -S(=0)2-CH2-CH3.
59) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is -S(=0)2-CH3.
60) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is
Figure imgf000044_0002
alkyl, substituted with one or more independently selected halo. 61) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is
Figure imgf000044_0003
alkyl, substituted with one or more independently selected F or CI.
62) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is 4-6 membered monocyclic heterocycloalkyl containing one or two O.
63) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
64) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is 6 membered monocyclic heterocycloalkenyl containing one to two double bonds and one or two O.
65) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is dihydropyranyl or dihydrodioxinyl.
66) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is C3.7 monocyclic cycloalkyl.
67) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
68) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is cyclopropyl or cyclobutyl.
69) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is phenyl.
70) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-37 or 39-55, wherein Gi is 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, S, and O. 71 ) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -37 or 39-55, wherein Gi is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl.
72) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -37 or 39-55, wherein Gi is oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, or pyridinyl.
73) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -37 or 39-55, wherein Gi is 4-6 membered monocyclic heterocycloalkyl (containing one or two O), 6 membered monocyclic heterocycloalkenyl (containing one to two double bonds and one or two O), C3.7 monocyclic cycloalkyl, phenyl or 5-6 membered heteroaryl (containing one to four heteroatoms independently selected from N, S, and O), each of which is substituted with one or more independently selected R7 groups.
74) A compound or pharmaceutically acceptable salt thereof, according to clause 73, wherein R7 is halo, or -OH.
75) A compound or pharmaceutically acceptable salt thereof, according to clause 73, wherein R7 is F, CI, or -OH.
76) A compound or pharmaceutically acceptable salt thereof, according to clause 73, wherein R7 is C alkyl, C3.4 monocyclic cycloalkyl, or C1.4 alkoxy.
77) A compound or pharmaceutically acceptable salt thereof, according to clause 73, wherein R7 is -CH3, -CH2-CH3, -CH2-CH2-CH3, cyclopropyl, -OCH3, or -OCH2-CH3.
78) A compound or pharmaceutically acceptable salt thereof, according to clause 73, wherein R7 is C alkyl, C3.4 monocyclic cycloalkyl or C1.4 alkoxy substituted with one or more halo.
79) A compound or pharmaceutically acceptable salt thereof, according to clause 73, wherein R7 is CM alkyl, C3.4 monocyclic cycloalkyl or C1.4 alkoxy substituted with one or more independently selected F or CI.
80) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -37, wherein R4 is -0-CH2-cyclopropyl substituted with one or more independently selected F or CI.
81 ) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -37 or 39, wherein Li and Wi are absent, and Gi is -H.
82) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -81 , wherein R1 is H, -CH3, -CH2-CH3, or -CH(CH3)2.
83) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -81 , wherein R1 is cyclopropyl.
84) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -81 , wherein R1 is H.
85) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -81 , wherein R1 is -CH3.
86) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -85, wherein LA is -NH-. „„
44
87) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-85, wherein LA is -0-.
88) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the com ound is according to Formula Via, VIb, Vic, or VId:
Figure imgf000046_0001
Via VIb Vic VId wherein R4 and G2 are as previously described.
89) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the com ound is according to Formula Vie, Vlf, VIg, or Vlh:
Figure imgf000046_0002
Vie Vlf VIg Vlh wherein R4 and G2 are as previously described.
90) A compound or pharmaceutically acceptable salt thereof, according to clause 1 , wherein the compound is according to Formula Vli, Vlj, VIk, or VII:
Figure imgf000046_0003
91) A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vim, VIn, VIo, or VIp:
Figure imgf000047_0001
Vim VIn VIo VIp wherein R and G2 are as previously described.
92) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is Ci_6 alkylene, and Gi is H.
93) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is Ci_6 alkylene, and Gi is -CF3.
94) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is Ci_6 alkylene substituted with one or more halo, and Gi is H.
95) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -O-CH3, -0-CHF2, -0-CH2-CF3, -0-CH2-CHF2.
96) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is -CH2-, and Gi is C3.7 monocyclic cycloalkyl.
97) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is -CH2-, and Gi is C3.7 monocyclic cycloalkyl substituted with one or more independently selected R7, wherein R7 is halo, or C1.4 alkyl.
98) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is absent, and Gi is
Figure imgf000047_0002
alkyl.
99) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is O, Wi is absent, and Gi is
Figure imgf000047_0003
alkyl substituted with one or more F.
100) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is absent, Wi is -C≡C- and Gi is C3.7 monocyclic cycloalkyl.
101) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -L1-W1-G1, Li is absent, Wi is absent, and Gi is phenyl substituted with one or two independently selected R7 groups.
102) A compound or pharmaceutically acceptable salt thereof, according to clause 101, wherein R7 is selected from CM alkyl and C1.4 alkoxy. „ r
46
103) A compound or pharmaceutically acceptable salt thereof, according to clause 101, wherein R7 is selected from CM alkyl and CM alkoxy, each of which is substituted with one or more F.
104) A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 88-91, wherein R4 is -Li-Wi-Gi, Li is absent, Wi is absent, and Gi is pyridinyl substituted with one R7 group.
105) A compound or pharmaceutically acceptable salt thereof, according to clause 104, wherein R7 is halo, -OH, C3.4 monocyclic cycloalkyl, or C1.4 alkoxy.
106) A compound or pharmaceutically acceptable salt thereof, according to clause 104, wherein R7 is Ci_ 4 alkoxy substituted with one or more F.
107) A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106, and a pharmaceutically acceptable carrier.
108) The pharmaceutical composition according to claim 107 comprising a further therapeutic agent.
109) A compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106, or the pharmaceutical composition according to clause 107 or 108, for use as a medicament.
110) The compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106, or the pharmaceutical composition according to clause 107 or 108, for use in the treatment and/or prophylaxis of inflammatory conditions.
111) 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 clauses 1-106, or a composition of clause 107 or 108.
112) The method according to clause 111, wherein a compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106 is administered in combination with a further therapeutic agent.
113) The use according to clause 110, or the method according to clause 111, wherein the inflammatory condition is rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, psoriasis, Crohn's disease, and/or ulcerative colitis.
114) The use according to clause 110, or the method according to clause 11 1, wherein the inflammatory condition is periodontitis, uveitis, pyoderma gangrenosum, and/or severe asthma.
115) The compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106, or the pharmaceutical composition according to clause 107 or 108, for use in the treatment and/or prophylaxis of pain.
116) A method for the treatment or prophylaxis of pain, comprising administering a prophylactically or therapeutically effective amount of a compound according to any one of clauses 1-106, or a composition of clause 107 or 108.
117) The method according to clause 116, wherein a compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106 is administered in combination with a further therapeutic agent. 118) The compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106, or the pharmaceutical composition according to clause 107 or 108, for use in the treatment and/or prophylaxis of leukemia.
119) A method for the treatment or prophylaxis of leukemia, comprising administering a prophylactically or therapeutically effective amount of a compound according to any one of clauses
1-106, or a composition of clause 107 or 108.
The method according to clause 119, wherein a compound, or pharmaceutically acceptable salt thereof, according to any one of clauses 1-106 is administered in combination with a further therapeutic agent.
PHARMACEUTICAL COMPOSITIONS
[00163] 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.
[00164] 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.
[00165] 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.
[00166] 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 Λ η
48
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.
[00167] 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.
[00168] 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 paraffmic 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.
[00169] 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.
[00170] 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 (Remington 1985).
[00171] 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.
[00172] 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
[00173] 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. Λ η
49
Formulation 2 - Capsules
[00174] 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
[00175] 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 (1 1 :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
[00176] 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
[00177] 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/mL.
Formulation 6 - Topical
[00178] 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
[00179] 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.
[00180] 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, in mammals including humans.
[00181] 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))), 5Q neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions, in mammals including humans.
[00182] 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.
[00183] 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.
[00184] 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, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia, in mammals including humans, said method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00185] 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, said method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00186] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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), idiopathic pulmonary fibrosis (IPF), uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
[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 in 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). ^
[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 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), uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
[00189] 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).
[00190] 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, which method comprises administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions herein described.
[00191] 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), uveitis, periodontitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and/or colon inflammation caused by oncology treatments aimed at activating the immune response.
[00192] 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).
[00193] In one aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the prophylaxis and/or treatment of ^ neuroinflammatory conditions, Guillain-Barre syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
[00194] In another aspect, the present invention provides a 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.
[00195] 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.
[00196] In one aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the prophylaxis and/or treatment of infectious disease(s). In a specific embodiment, the infectious disease(s) 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.
[00197] In another aspect, the present invention provides a 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(s). In a specific embodiment, the infectious disease(s) 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.
[00198] 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(s), 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 disease 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.
[00199] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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.
[00200] 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.
[00201] 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.
[00202] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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, rickets, and obesity.
[00203] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in 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.
[00204] 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, rickets, and obesity.
[00205] 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 Γ Λ
54
Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[00206] 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, rickets, and obesity.
[00207] 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.
[00208] 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.
[00209] 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.
[00210] 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.
[00211] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[00212] 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.
[00213] 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.
[00214] 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.
[00215] 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 DMAPvDS (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).
[00216] 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 anthracyc lines, 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.
[00217] 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 tinidazole. r r
56
[00218] 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)
[00219] 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.
[00220] 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).
[00221] 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.
[00222] 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).
[00223] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of pain, such as non-narcotic and narcotic analgesics; particular agents include but are not limited to: paracetamol, acetylsalicylic acid, NSAID's, codeine, dihydrocodeine, tramadol, pentazocine, pethidine, tilidine, buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, piritramide, tapentadol or combinations thereof. ^
[00224] Course of treatment for leukemia comprises chemotherapy, biological therapy, targeted therapy, radiation therapy, bone marrow transplantation and/or combinations thereof.
[00225] Examples of further therapeutic agents for Acute Lymphoblastic Leukemia (ALL) comprise methotrexate, nelarabine, asparaginase Erwinia chrysanthemi, blinatumomab, daunorubicin, cyclophosphamide, clofarabine, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib, vincristine, mercaptopurine, pegaspargase, and/or prednisone.
[00226] Examples of further therapeutic agents for Acute Myeloid Leukemia (AML) comprise arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and/or vincristine.
[00227] Examples of further therapeutic agents for Chronic Lymphocytic Leukemia (CLL) comprise alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, chlormethine, prednisone, vincristine, and/or rituximab.
[00228] Examples of further therapeutic agents for Chronic Myelogenous Leukemia (CML) comprise bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, chlormethine, nilotinib, and/or omacetaxine.
[00229] Examples of further therapeutic agents for Hairy Cell Leukemia (HCL) comprise cladiribine, pentostatin, and/or interferon alfa-2b.
[00230] 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
[00231] 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.
[00232] 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)(Wuts & Greene 2006), and references cited therein. 5o
[00233] The following methods are presented with details as to the preparation of representative 6,7- dihydro-pyrido[2,l-a]isoquinolin-4-one compounds 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.
[00234] 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). lH NMR spectra were recorded on a Broker DPX 400 NMR spectrometer (400 MHz) or a Broker 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 on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH CI 8 1.7 μητ, 2.1 mm ID x 50 mm L, Waters Acquity UPLC BEH CI 8 1.7 μιη, 2.1 mm ID x 30 mm L, or Waters Xterra MS 5 μιη C18, 100 x 4.6 mm. The methods are using either MeCN/H20 gradients (H20 contains either 0.1% TFA or 0.1% NH3) or MeOH /H20 gradients (H20 contains 0.05%> TFA). Microwave heating was performed with a Biotage Initiator.
[00235] The preparative HPLC purifications were performed with a mass-directed auto-purification system coupled with a ZQ single quadrapole mass spectrometer. All HPLC purifications were performed with a gradient of H20 (different pHs)/MeCN. Preparative HPLC separations under basic conditions were usually carried out using a BEH XBrigde CI 8 (5 μιη, 19 x 5 mm) precolumn and a BEH XBrigde CI 8 (5 μιη, 19 x 100 mm). Separations under acidic conditions were usually carried out using CSH Select C18 (5 μηι, 19 x 5 mm) precolumn and a CSH Select CI 8 (5 μηι, 19 x 100 mm). The focused gradient was from x% to x+25%) acetonitrile in water in 5 min with a cycle time of 10 min. The column flow rate was 20 mL/min. The injection volume ranged from 200 to 750 μΕ. A capillary splitter was used to divert flow after column separation to the mass spectrometer which was diluted by 1 mL/min of make-up flow. The make-up flow is 0.1% formic acid in methanol. All samples were purified by a Waters mass directed fraction collection.
Table I. List of abbreviations used in the experimental section:
μΕ microliter Aq. aqueous
AcOH Acetic acid ATP Adenosine 5 '-Triphosphate 2,2'-bis(diphenylphosphino)- 1,1'-
BINAP ι,ΐ '- binaphthyl DPPF Bis(diphenylphosphino)ferrocen e
Boc tert-Butyloxy-carbonyl
EtOAc Ethyl acetate
Boc20 Di-fert-butyl dicarbonate
Et20 Diethyl ether br s broad singlet
eq. equivalent
2-(Dicyclohexylphosphino)3,6-
BrettPhos dimethoxy-2 ' ,4 ' ,6 ' -triisopropyl- g gram
l,l '-biphenyl
guanosine 5'-0-[gamma-
Chloro[2- GTPyS
thio]triphosphate dicyclohexylphosphino)-3,6-
Brettphos
dimethoxy-2 ' ,4 ' ,6 ' -triisopropyl- precatalyst h hour
l,l '-biphenyl][2-(2- aminoethyl)phenyl]palladium(II)
High-performance liquid
HPLC
chromatography
Calcd calculated
iPrOH isopropanol
Cat. Catalytic amount
iPr20 Diisopropyl ether d doublet
KHMDS Potassium hexamethyldisilazane dd Doublet of doublet
Liquid Chromatography- Mass
LCMS
DCC Ν,Ν' -Dicyclohexylcarbodiimide Spectrometry
DCE 1 ,2-Dichloroethane L Liter
DCM Dichloromethane m multiplet
DIAD Diisopropyl azodicarboxylate MeOH Methanol
DIPEA N,N-diisopropylethylamine MeCN Acetonitrile
DMAP 4-Dimethylaminopyridine Mel Methyl iodide
DME Dimethoxyethane MEK Methyl ethyl ketone
DMF N,N-dimethylformamide MeOH Methanol
DMSO Dimethylsulfoxide mg milligram
Dulbecco's Phosphate-Buffered min minute
DPBS
Saline mL milliliter q quadruplet mmol millimole rpm revolutions per minute
MS mass spectrometry RT Room temperature
Mtd Method Rt retention time
MW Molecular weight 2-Dicyclohexylphosphino-2',6'-
RuPhos
di-i-propoxy- 1 , 1 '-biphenyl
MW (obs) Molecular weight observed
s singlet
MW (calc) Molecular weight calculated
sat. saturated
Nicotinamide adenine
NADP
dinucleotide phosphate SM Starting material
ND Not determined spA Scintillation proximity assay
NEAA Non-Essential Amino Acid SPE Solid phase extraction
NMP N-Methyl-2-pyrrolidone STAB sodiumtriacetoxyborohydride
NMR Nuclear Magnetic Resonance t triplet obsd observed TBAF Tetra-n-butylammonium fluoride
OTf Trifluoromethanesulfonate tBuOMe Methyl tert-butyl ether
Pd(OAc)2 Palladium(II) acetate TEA Triethylamine
Tetrakis(triphenylphosphine)pall
Pd(PPh3)4 TFA Trifluoroacetic acid
adium(O)
THF Tetrahydrofuran
Pd/C Palladium on Carbon 10 %
TLC Thin layer chromatography ppm part-per-million ^
61
SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION
Example 1. General Synthetic Methods for Preparation of the Compounds of Invention
Figure imgf000063_0001
Method U: Dimethylation of aryl acetonitrile
Figure imgf000063_0002
[00236] A solution of lithium bis(trimethylsilyl)amide (1 M in THF, 2 eq.) is added dropwise to an ice cold solution of the aryl acetonitrile (1 eq.) in THF. After stirring for 20 min, methyl iodide (5 eq.) is added and the resulting mixture is stirred at RT until completion. The mixture is quenched with water and concentrated under vacuum. The resulting aqueous is extracted with DCM, concentrated and the residue is purified by silica gel chromatography (EtO Ac/petroleum ether).
Method Al: Reduction of nitrite using Raney Ni
Figure imgf000063_0003
[00237] The nitrile (1 eq.) is dissolved in 7 M NH3 in MeOH and put under nitrogen atmosphere. Raney Ni (50% suspension in water, 1.2 eq.) is added dropwise, the resulting mixture put under hydrogen ^„
62
atmosphere and stirred at RT until completion of the reaction. The mixture is filtered over Celite and the filtrate concentrated under vacuum.
Method A2: Reduction of nitrite using LiAlH4
Figure imgf000064_0001
[00238] A solution of LiAlH4 (2 M in THF, 2 eq.) is added dropwise to an ice cold solution of the nitrile (1 eq.) in THF. After stirring for 30 min at RT, the reaction mixture is heated to reflux until completion. Once cooled to RT, the resulting mixture is added to a suspension of Na2SO4.10 H20 in EtOAc, stirred for 10 min, filtered and concentrated under vacuum. The residue is dissolved in DCM, dried (Na2S04), filtered and concentrated.
Method B: N-Acylation
Figure imgf000064_0002
[00239] Pyridine (2-3 eq.) is added to a solution of the amine (1 eq.) in DCM and the solution is cooled down to 0°C. The appropriate acyl chloride (1.5 eq.) is added dropwise, the reaction warmed to RT and stirred until completion. Water is added and the resulting mixture extracted with DCM (3x), dried (Na2S04), filtered and concentrated under vacuum. The residue is used as such or purified by silica gel chromatography (EtO Ac/petroleum ether).
Method C: Intramolecular cyclisation using POCI3
Figure imgf000064_0003
[00240] POCI3 (4 eq.) is added dropwise to an ice cold solution of the N-acylated amine (1 eq.) in DCM and the mixture is heated to reflux temperature until completion. The mixture is concentrated, the remaining residue is poured on ice and basified to pH 8 using aq. sat. K2C03. The aqueous is extracted with DCM (3x), dried (Na2S04), filtered and concentrated. Method D: Malonate condensation
Figure imgf000065_0001
[00241] Di-tertbutyl or di-benzyl malonate (4 eq.) is added to a solution of the dihydro-pyridine (1 eq.) in diglyme or NMP under nitrogen atmosphere and the resulting mixture is heated thermically or in a microwave reactor to 150°C until completion of the reaction. The resulting mixture is cooled to RT, diluted with tBuOMe, sonicated and filtered. The solid is washed with a mixture of MeCN/tBuOMe (1 : 1 v/v) and dried.
Method E: Chlorination
Figure imgf000065_0002
[00242] POCI3 (16 eq.) is added to the hydroxy-pyridinone (1 eq.) and the resulting solution is heated to 80°C. After 2 h, the mixture is poured on ice, basified to pH 8-9 using aq. sat. K2CO3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na2S04), filtered and concentrated.
Method Fl: SnAr with alcohol
Figure imgf000065_0003
X = CI, OTf [00243] The appropriate alcohol (1.05-2.2 eq.) is added to NaH (1.5-6 eq.) in THF or DMF and stirred for 10 min. The triflate- or chloro-pyridinone (1 eq.) is dissolved in DMF and added dropwise to the alkoxide mixture. The resulting mixture is heated to 70°C until completion. Aq. sat. NaHC03 is then added and the mixture is concentrated under vacuum. The residue is partitioned between DCM or EtOAc and brine and the aqueous layer is further extracted with the appropriate organic solvent. The combined organic layers is dried (Na2S04), filtered and concentrated. The residue is either used as such without further purification or purified by preparative HPLC. Method F2: SnAr with
Figure imgf000066_0001
[00244] The chloro-pyridinone (1 eq.) is mixed with the appropriate amine (10 eq.) in a sealed vial and the reaction mixture is heated to 140°C for 2 days. The resulting mixture is diluted with EtOAc, washed with aq. sat. NaHCOs, aq. 1 M NaOH (2x) and brine. The organic layer is dried (Na2S04), filtered and concentrated.
Method F3: Buchwald
Figure imgf000066_0002
[00245] Dry dioxane is added to a mixture of chloro-pyridinone (1 eq.), the appropriate amine (1.2 eq.), Brettphos (0.01 eq.), Brettphos precatalyst (0.01 eq.) and sodium tert-butoxide (2 eq.) in a sealed vial under nitrogen atmosphere and the resulting mixture is heated to 100°C until completion of the reaction. The reaction mixture is filtered over Celite, washed with a mixture of DCM:MeOH and concentrated under vacuum. The residue is partitioned between DCM and water. The organic layer is separated, dried (Na2S04), filtered and concentrated. The residue is either used as such in the next step or purified by silica gel chromatography (7 N NH3 in MeOH/DCM).
Method F4: O-alkylation
Figure imgf000066_0003
[00246] A mixture of the hydroxy-pyridinone (1 eq.), the appropriate alkylchloride (1 eq.), K2C03 (2 eq.) and KI (0.5 eq.) in dry DMF is heated to 60°C for 3 days. The resulting mixture is diluted with water and extracted with DCM (3x). The combined organic layers are dried (Na2S04), filtered and concentrated. The residue is purified by preparative HPLC.
Method Gl: deprotection of O-benzyl
¾o^ Ph . f oH
[00247] Pd/C (10% w/w, 0.1 eq.) is added to the benzyl-protected aryl alcohol (1 eq.) under nitrogen atmosphere. EtOH is added and the resulting mixture put under hydrogen atmosphere and stirred at RT until completion of the reaction. The mixture is filtered over Celite and the filtrate concentrated under vacuum.
Method G2: deprotection of O-methyl on aromatic
/
Ar-0 Ar- OH
[00248] Sodium thiomethoxide (2 eq.) is added to a solution of the methoxy-protected alcohol (1 eq.) in NMP and the reaction mixture heated to 140°C for 1 h. The resulting mixture is diluted with EtOAc and the formed precipitate filtered. The precipitate is partitioned between DCM and aq. 1 M HC1. The organic layer is separated, dried (Na2S04) and concentrated. The residue is either used as such in the next step or purified by preparative HPLC. Method H: O-Triflation of alcohol
-jrOH to
[00249] NEt3 (2-2.5 eq.) is added to a solution of the alcohol (1 eq.) and N- phenylbis(trifluoromethanesulfonimide) (1.2-2 eq.) in DCM and the reaction mixture is stirred at RT until completion. The resulting mixture is partitioned between DCM and aq. 0.2 M HC1. The organic layer is separated, dried (Na2S04) and concentrated. The residue is purified by silica gel chromatography (MeOH/EtOAc, MeOH/DCM or EtO Ac/petroleum ether).
Method II: Sonogashira on inflate
Figure imgf000067_0001
[00250] The aryl triflate (1 eq.) is mixed with DMF, PdCl2(PPh3)4 (0.04 eq.), Cul (0.04 eq.), NEt3 (4.5 eq.) and the appropriate alkyne (3 eq.) in a sealed vial under nitrogen atmosphere and the reaction mixture is heated to 80°C until completion of the reaction. The resulting mixture is diluted with EtOAc, washed with aq. 5% NH3, water and brine. The organic layer is dried (Na2S04), filtered and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM).
Method 12: Suzuki on tri ate
Figure imgf000067_0002
[00251] The aryl triflate (1 eq.) is mixed with the appropriate boronic acid/ester (1-3 eq.), Pd(dppf)Cl2.DCM (0.05 eq.) and DIPEA or Cs2C03 (3-4 eq.) in dioxane:water (2:1 v/v) and the reaction mixture is stirred to 100°C until completion of the reaction. The resulting mixture is partitioned between EtOAc and water. The organic layer is separated, dried (Na2S04), filtered and concentrated. The residue r r
66
is purified by silica gel chromatography (MeOH/EtOAc) or by preparative HPLC to afford the desired compound. In some cases, the reduced by-product (R"=H) was also isolated.
Method 13: CN insertion
Figure imgf000068_0001
[00252] The aryl triflate (1 eq.) is mixed with Zn(CN)2 (1.05 eq.) and Pd(PPh3)4 (0.1 eq.) in DMF and the reaction mixture is heated to 150°C in a microwave reactor for 5 min. The resulting mixture is diluted with EtOAc, washed with aq. sat. NaHCOs and brine. The organic layer is dried (Na2S04), filtered and concentrated. The residue is triturated with MeOH.
Method 14: Synthesis of thiol
Figure imgf000068_0002
Step i
[00253] The aryl triflate (1 eq.) is mixed with 3-mercaptopropionic acid-2-ethylhexyl ester (1.25 eq.), Pd2(dba)3 (0.03 eq.), Xantphos (0.06 eq.) and DIPEA (2 eq.) in a sealed tube under nitrogen and the mixture is heated to 1 10°C. After completion of the reaction, the residue is filtered through a silica plug, washed with EtOAc and concentrated.
Step ii
[00254] Sodium ethoxide (21% w/w in EtOH, 2 eq.) is added to the protected-thiol (1 eq.) in EtOH and the reaction mixture is stirred at RT until completion. The resulting mixture is diluted with water, acidified with aq. 1 M HC1 and extracted with DCM. The organic layer is then dried (Na2S04) and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM).
Method Jl: O-alkylation
Figure imgf000068_0003
[00255] The appropriate alkyl halide or mesylate (1.5-2.5 eq.) is added to a mixture of the phenol (1 eq.) and K2CO3 (2-5 eq.) in DMF and the reaction mixture is heated to 60°C until completion of the reaction. The resulting mixture is diluted with EtOAc, washed with water, dried (Na2SO i), filtered and concentrated. The residue is purified by preparative HPLC or silica gel chromatography (MeOH/EtAc or MeOH/DCM). In some cases, when using the alkyl mesylate, the O-mesylated by-product (R = S02Me) was also observed and isolated. Method J2: Difluoromethylation
Figure imgf000069_0001
[00256] Bromodifluoromethyl diethylphosphonate (2 eq.) is added to a mixture of the aryl alcohol or aryl thiol (1 eq.) and KOH (20 eq.) in MeCN:water (1 : 1 w/w) at -30°C and the reaction mixture is stirred and left to warm to RT overnight. The resulting mixture is diluted with DCM, washed with water, dried (Na2S04), filtered and concentrated. The residue is purified by silica gel chromatography (MeOH/EtOAc).
Method J3: Mitsunobu reaction
Figure imgf000069_0002
[00257] The aryl alcohol (1 eq.) is mixed with THF, the appropriate alcohol (1.5 eq.) and PPh3 (2 eq.). DEAD (2 eq.) is added to this mixture and the reaction mixture is stirred at RT until completion of the reaction. The resulting mixture is then filtered, concentrated and purified by preparative HPLC.
Method K: O-Methylation
Figure imgf000069_0003
[00258] The alcohol (1 eq.) is mixed with THF, Mel (10 eq.) and potassium tertbutoxide (2 eq.) and the reaction mixture is stirred at RT overnight. The resulting mixture is dissolved with EtOAc, washed with aq. sat. NaHCOs and brine. The organic layer is dried (Na2S04), filtered and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM).
Method PI: Alkyne reduction
Figure imgf000069_0004
[00259] Pd/C (10% w/w, 0.1 eq.) is added to the aryl alkyne (1 eq.) under nitrogen atmosphere. MeOH is added and the resulting mixture put under hydrogen atmosphere and stirred at RT until completion of the reaction. The mixture is filtered through Celite and the filtrate concentrated under vacuum. The residue is purified by preparative HPLC.
Method P2: Tetrazole formation
H
N - N
= N
N N ^0
Do
[00260] The alkyl nitrile (1 eq.) is mixed with DMF, NaN3 (5 eq.) and NH4C1 (5 eq.) in a sealed vial and the reaction mixture is heated to 100°C until completion of the reaction. Once cooled at RT, the mixture is diluted with water and acidified to pH 3 with aq. 2 M HCl and extracted with EtOAc. The organic layer is washed with water and brine, dried (Na2S04), filtered and concentrated.
Method P3: Chloropyridine hydrolysis
Figure imgf000070_0001
[00261] The chloropyridine (1 eq.) is mixed with 4 M HCl in dioxane and the mixture is heated to 80°C. After consumption of the starting material, the resulting mixture is concentrated and purified by preparative HPLC.
Method P4: Alkene reduction
Figure imgf000070_0002
Y = CH2, O
[00262] Pd/C (10% w/w, 0.1 eq.) is added to the alkene (1 eq.) under nitrogen atmosphere. MeOH is added and the resulting mixture put under hydrogen atmosphere and stirred at RT until completion of the reaction. The mixture is filtered through Celite and the filtrate concentrated under vacuum. The residue is purified by preparative HPLC.
Example 2. Illustrative examples for the Preparation of the Compounds of Invention
Compound 6: 10-Methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(2,2,2-trifluoro- ethoxy)-6, 7-dihydro-pyrido[2, l-aJisoquinolin-4-one
Figure imgf000070_0003
Figure imgf000070_0004
Step i: 2-(3-Benzyloxy-4-methoxy-phenyl)-ethylamine
Figure imgf000071_0001
[00263] (3-Benzyloxy-4-methoxy-phenyl)-acetonitrile (5.0 g, 19.7 mmol, 1 eq.) is dissolved in 7 N NH3 in MeOH (100 mL) and put under nitrogen atmosphere. Raney Ni (50% suspension in water, 2.8 mL, 23.7 mmol, 1.2 eq.) is added dropwise, the resulting mixture put under hydrogen atmosphere and stirred at RT overnight. The mixture is filtered over Celite, washed thoroughly with MeOH and the filtrate concentrated under vacuum to give the required product.
Step ii: 2 N-[2-(3-Benzyloxy-4-methoxy-phenyl)-ethylJ-propionamide
Figure imgf000071_0002
[00264] Pyridine (3.3 mL, 41.4 mmol, 2.1 eq.) is added to a solution of the 2-(3-benzyloxy-4-methoxy- phenyl)-ethylamine (5.1 g, 19.7 mmol, 1 eq.) in DCM (40 mL) and the solution is cooled down to 0°C. Propionyl chloride (2.5 mL, 29.6 mmol, 1.5 eq.) is added dropwise, the reaction warmed to RT and stirred for 24 h. Water is added and the resulting mixture extracted with DCM (3x), dried (Na2S04), filtered and concentrated under vacuum to give the required compound.
Step Hi: 6-Benzyloxy-l-ethyl-7-methoxy-3 -dihydro-isoquinoline
Figure imgf000071_0003
[00265] POCI3 (7.3 mL, 78.8 mmol, 4 eq.) is added dropwise to an ice cold solution of 2 N-[2-(3- benzyloxy-4-methoxy-phenyl)-ethyl]-propionamide (6.1 g, 19.7 mmol, 1 eq.) in DCM (6 mL) and the mixture is heated to reflux temperature for 24 h. The mixture is concentrated, the remaining residue is poured on ice and basified to pH 7-8 using aq. sat. K2CO3. The aqueous is extracted with DCM (3x), dried (Na2S04), filtered and concentrated. The product is used without further purification.
Step iv: 9-Benzyloxy-2-hydroxy-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin-4-one
Figure imgf000071_0004
[00266] Di-tertbutyl malonate (1 1 mL, 78.8 mmol, 4 eq.) is added to a solution of 6-benzyloxy-l - ethyl-7-methoxy-3,4-dihydro-isoquinoline (5.8 g, 19.7 mmol, 1 eq.) in diglyme (10 mL) under nitrogen atmosphere and the resulting mixture is heated to 150°C for 5 min. The resulting mixture is cooled to RT, ^ diluted with tBuOMe, sonicated and filtered. The solid is washed with a mixture of MeCN/tBuOMe (1 : 1 v/v) and dried.
Step v: 9-Benzyloxy-2-chloro-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, 1 -a] isoquinolin-4-one
Figure imgf000072_0001
[00267] POCl3 (22 mL) is added to 9-benzyloxy-2-hydroxy-l 0-methoxy-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one (5.08 g, 14 mmol, 1 eq.) and the resulting solution is heated to 80°C. After 2 h, the mixture is poured on ice, basified to pH 8-9 using aq. sat. K2CO3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na2S04), filtered and concentrated. The product is used as such without further purification.
Step vi: 9-Benzyloxy-l 0-methoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino] -6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
Figure imgf000072_0002
[00268] Dry dioxane (10 mL) is added to a mixture of 9-benzyloxy-2-chloro-l 0-methoxy-l -methyl- 6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (1.0 g, 2.62 mmol, 1 eq.), tetrahydrofurfurylamine (0.32 g, 3.14 mmol, 1.2 eq.), Brettphos (13 mg, 0.026 mmol, 0.01 eq.), Brettphos precatalyst (20 mg, 0.026 mmol, 0.01 eq.) and sodium tert-butoxide (0.50 g, 5.24 mmol, 2 eq.) in a sealed vial under nitrogen atmosphere. The resulting mixture is degased and then heated to 100°C for 18 h. The reaction mixture is filtered over Celite, washed with a mixture of DCM:MeOH (10:1 v/v) and concentrated under vacuum. The residue is partitioned between DCM and aq. sat. NaHC03. The organic layer is separated, dried (Na2S04), filtered and concentrated. Purification by silica gel chromatography (7 N NH3 in MeOH/DCM; 1 :99 to 2:98) affords the required compound.
Step vii: 9-Hydroxy-l 0-methoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino] -6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
Figure imgf000072_0003
[00269] Pd/C (10% w/w, 132 mg, 0.12 mmol, 0.1 eq.) is added to 9-benzyloxy-l 0-methoxy-l -methyl- 2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one (552 mg, 1.23 mmol, 1 eq.) under nitrogen atmosphere. EtOH (35 mL) is added and the resulting mixture put under hydrogen atmosphere and stirred at RT for 1 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum to afford the required compound that is used as such in the next step.
Step viii: 10-Methoxy-l-methyl-2-f(tetrahydro^iran-2-ylmethyl)-aminoJ-9-(2,2,2-trifluoro-ethoxy)-6, 7- dihydro-pyrido[2, 1 -aJisoquinolin-4-one
Figure imgf000073_0001
[00270] 2-Iodo-l,l,l-trifluoroethane (42 μΕ, 0.43 mmol, 2.5 eq.) is added to a mixture of 9-hydroxy- 10-methoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one (60 mg, 0.17 mmol, 1 eq.) and K2CO3 (94 mg, 0.34 mmol, 4 eq.) in DMF (0.8 mL) and the reaction mixture is heated to 60°C for 24 h. The resulting mixture is diluted with DCM, washed with brine, dried (Na2S04), filtered and concentrated. The residue is purified by preparative HPLC to afford the required compound.
Compound 22: 9-(2,2-Difluoro-ethoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6, 7-
Figure imgf000073_0002
^
Step i: N-[2-(3,4-Dimethoxy-phenyl) -ethyl] -propionamide
Figure imgf000074_0001
[00271] Pyridine (33 mL, 414 mmol, 3.0 eq.) is added to a solution of 2-(3,4-dimethoxy-phenyl)- ethylamine (25 g, 138 mmol, 1 eq.) in DCM (40 mL) and the solution is cooled down to 0°C. Propionyl chloride (17 mL, 207 mmol, 1.5 eq.) is added dropwise, the reaction is warmed to RT and stirred for 24 h. Water is added and the resulting mixture extracted with DCM (3x), dried (Na2S04), filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (EtOAc/petroleum ether; 50:50 to 75:25) to afford the required compound.
Step ii: l-Ethyl-6, 7-dimethoxy-3,4-dihydro-
Figure imgf000074_0002
[00272] POCl3 (7.8 mL, 84 mmol, 4 eq.) is added dropwise to an ice cold solution of N-[2-(3,4- dimethoxy-phenyl)- ethyl] -propionamide (5.0 g, 21 mmol, 1 eq.) in DCM (6 mL) and the mixture is heated to reflux temperature for 24 h. The mixture is concentrated, the remaining residue is poured on ice and basified to pH 7-8 using aq. sat. K2CO3. The aqueous is extracted with DCM (3x), dried (Na2S04), filtered and concentrated. The product is used without further purification.
Step Hi: 2-Hydroxy-9, 10-dimethoxy-l -methyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin-4-one
Figure imgf000074_0003
[00273] Di-tertbutyl malonate (1 1.5 mL, 84 mmol, 4 eq.) is added to a solution of l -ethyl-6,7- dimethoxy-3,4-dihydro-isoquinoline (4.6 g, 21 mmol, 1 eq.) in diglyme (10 mL) under nitrogen atmosphere and the resulting mixture is heated to 150°C for 24 h. The mixture is cooled to RT, and the resulting precipitate filtered. The solid is washed with a mixture of sBuOH and petroleum ether and dried. The product is used as such without further purification.
Step iv: 2-Chloro-9, 10-dimethoxy-l -methyl-6, 7-dihydro-pyrido[2, l-a]isoquinolin-4-one
Figure imgf000074_0004
[00274] POCI3 (22 mL) is added to 2-hydroxy-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, l - a]isoquinolin-4-one (4.5 g, 16 mmol, 1 eq.) and the resulting solution is heated to 80°C. After 1 h, the ^ resulting mixture is concentrated. The residue is poured on ice, basified to pH 8-9 using aq. sat. K2CO3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na2S04), filtered and concentrated.
Step v: 2-( (S)-l-[ 1, 4]Dioxan-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6, 7-dihydro-pyrido[2, 1- aJisoquinolin-4-one
Figure imgf000075_0001
[00275] (R)-l-[l,4]Dioxan-2-yl-methanol (487 mg, 4.13 mmol, 1.05 eq.) is added to NaH (236 mg, 5.90 mmol, 1.5 eq.) in DMF (16 mL) 0°C. After 10 min, 2-chloro-9,l 0-dimethoxy-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one (1.20 g, 3.93 mmol, 1 eq.) in DMF (2 mL) is added and the reaction mixture heated to 70°C for 24 h. The resulting mixture is diluted with EtOAc and washed with water (3x). The organic layer is dried (Na2S04), filtered and concentrated. The residue is used as such without further purification.
Step vi: 2-( (S)-l-[ 1, 4]Dioxan-2-ylmethoxy)-9-hydroxy-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, 1- aJisoquinolin-4-one
Figure imgf000075_0002
[00276] Sodium thiomethoxide (470 mg, 6.72 mmol, 2 eq.) is added to a solution of 2-((S)-l- [1 ,4]dioxan-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one (1.30 g, 3.36 mmol, 1 eq.) in NMP (40 mL) and the reaction mixture heated to 140°C for 1 h. The resulting mixture is diluted with EtOAc and the formed precipitate filtered. The precipitate is partitioned between DCM and aq. 1 M HCl. The organic layer is separated, dried (Na2S04) and concentrated. The residue is used as such without further purification. „„
74
Step vii: 9-(2, 2-Difluoro-ethoxy)-2-( (S)-l-[ 1 ,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
Figure imgf000076_0001
[00277] l,l-Difluoro-2-iodo-ethane (54 mg, 0.28 mmol, 1.5 eq.) is added to a mixture 2-((S)-l - [l,4]dioxan-2-ylmethoxy)-9-hydroxy-l 0-methoxy-l -methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (70 mg, 0.19 mmol, 1 eq.) and K2CO3 (52 mg, 0.38 mmol, 2 eq.) in DMF (1 mL) and the reaction mixture is heated to 60°C for 24 h. The resulting mixture is diluted with DCM, washed with brine, dried (Na2S04), filtered and concentrated. The residue is purified by silica gel chromatography (MeOH/EtOAc; 5:95) to afford the required compound. Compound 50: 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-10-methoxy-l-methyl-4-oxo-6, 7-dihydro-4H- pyrido[2,l-a]isoquinoUne-9-carbonitrile
Figure imgf000076_0002
^
Step i: 9-Benzyloxy-2-( (S)-l-[ 1, 4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, 1- aJisoquinolin-4-one
Figure imgf000077_0001
[00278] (R)-l-[l,4]Dioxan-2-yl-methanol (423 mg, 3.58 mmol, 1.05 eq.) is added to NaH (205 mg, 5.12 mmol, 1.5 eq.) in DMF (5 mL) 0°C. After 10 min, 9-benzyloxy-2-chloro-l 0-methoxy-l -methyl-6,7- dihydro-pyrido[2,l-a]isoquinolin-4-one (1.30 g, 3.41 mmol, 1 eq.) in DMF (9 mL) is added and the reaction mixture heated to 70°C for 24 h. The resulting mixture is diluted with EtOAc and washed with water, aq. sat. NaHCOs, aq. 1 M HC1 and brine. The organic layer is dried (Na2S04), filtered and concentrated. The residue is used as such without further purification. Step ii: 2-((S)-l -[1 ,4]Dioxan-2-ylmethoxy)-9-hydroxy-l 0-methoxy-l -methyl-6, 7-dihydro-pyrido[2, l- aJisoquinolin-4-one
Figure imgf000077_0002
[00279] Pd/C (10% w/w, 360 mg, 0.34 mmol, 0.1 eq.) is added to 9-benzyloxy-2-((S)-l-[l,4]dioxan-2- ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (1.60 g, 3.41 mmol, 1 eq.) under nitrogen atmosphere. EtOH (35 mL) is added and the resulting mixture put under hydrogen atmosphere and stirred at RT for 2 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum to afford the required compound.
Step Hi: Trifluoro-methanesulfonic acid 2-((S)-l -[1,4] dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-4-oxo- 6, 7-dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester
Figure imgf000077_0003
^
[00280] NEt3 (0.67 mL, 4.82 mmol, 2.0 eq.) is added to a solution of 2-((S)-l -[l,4]dioxan-2- ylmethoxy)-9-hydroxy- 10-methoxy- 1 -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one (900 mg, 2.41 mmol, 1 eq.) and N-phenylbis(trifluoromethanesulfonimide) (1.03 g, 2.90 mmol, 1.2 eq.) in DCM (19 mL) and the reaction mixture is stirred at RT overnight. The resulting mixture is partitioned between DCM and aq. 1 M HC1. The organic layer is separated, dried (Na2S04) and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM; 5:95).
Step iv: 2-( (S)-l-[ 1, 4]Dioxan-2-ylmethoxy)-l 0-methoxy- l-methyl-4-oxo-6, 7-dihydro-4H-pyrido [2, 1- aJisoquinoline-9-carbonitrile
Figure imgf000078_0001
[00281] Trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l -methyl-4- oxo-6,7-dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester (100 mg, 0.20 mmol, 1 eq.) is mixed with Zn(CN)2 (24 mg, 0.21 mmol, 1.05 eq.) and Pd(PPh3)4 (23 mg, 0.02 mmol, 0.1 eq.) in DMF (1 mL) and the reaction mixture is heated to 150°C in a microwave reactor for 5 min. The resulting mixture is diluted with EtOAc, washed with aq. sat. NaHCOs and brine. The organic layer is dried (Na2S04), filtered and concentrated. The residue is triturated with MeOH to afford the required compound.
Compound 3: 9-(3,5-Dimethyl soxazol-4-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6 -dihydm pyrido[2,l-a]isoquinolin-4-one
Figure imgf000078_0002
Step i: 2-(3-Benzyloxy-phenyl)-ethylami
Figure imgf000079_0001
[00282] (3-Benzyloxy-phenyl)-acetonitrile (3.35 g, 15 mmol, 1 eq.) is dissolved in 7 N NH3 in MeOH (75 mL) and put under nitrogen atmosphere. Raney Ni (50% suspension in water, 2.1 mL, 18 mmol, 1.2 eq.) is added dropwise, the resulting mixture put under hydrogen atmosphere and stirred at RT overnight. The mixture is filtered over Celite, washed thoroughly with MeOH and the filtrate concentrated under vacuum to give the required product.
Step ii: N-[2-(3-Benzyloxy-phenyl)-ethylJ-propionamide
Figure imgf000079_0002
[00283] Pyridine (2.7 mL, 33.9 mmol, 2.1 eq.) is added to a solution of the 2-(3-benzyloxy-phenyl)- ethylamine (3.67 g, 16.1 mmol, 1 eq.) in DCM (32 mL) and the solution is cooled down to 0°C. Propionyl chloride (1.48 mL, 16.9 mmol, 1.5 eq.) is added dropwise, the reaction is warmed to RT and stirred for 24 h. Water is added and the resulting mixture extracted with DCM (3x), dried (Na2SO i), filtered and concentrated under vacuum. Step Hi: 6-Benzyloxy-l-ethyl-3, 4-dihydro-
Figure imgf000079_0003
[00284] POCI3 (6 mL, 64 mmol, 4 eq.) is added dropwise to an ice cold solution of N-[2-(3-benzyloxy- phenyl)-ethyl]-propionamide (4.75 g, 16 mmol, 1 eq.) in DCM (5 mL) and the mixture is heated to reflux temperature for 6 h. The mixture is concentrated, the remaining residue is poured on ice and basified to pH 7-8 using aq. sat. K2CO3. The aqueous is extracted with DCM (3x), dried (Na2SO i), filtered and concentrated.
Step iv: 9-Benzyloxy-2-hydroxy-l-methyl-6, 7-dihydro-pyrido[2, l-a]isoquinolin-4-one
Figure imgf000079_0004
[00285] Di-tertbutyl malonate (14 mL, 64 mmol, 4 eq.) is added to a solution of 6-benzyloxy-l -ethyl- 3,4-dihydro-isoquinoline (4.43 g, 16 mmol, 1 eq.) in diglyme (7 mL) under nitrogen atmosphere and the resulting mixture is heated to 150°C for 5 min. The resulting mixture is cooled to RT, diluted with tBuOMe, sonicated and filtered. The solid is washed with a mixture of MeCN/tBuOMe (1 : 1 v/v) and dried. ^
Step v: 9-Benzyloxy-2-chloro-l-methyl- -dihydro-pyrido[2, 1 -aJisoquinolin-4-one
Figure imgf000080_0001
[00286] POCl3 (14 mL) is added to 9-benzyloxy-2-hydroxy-l-methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one (3.04 g, 9.1 mmol, 1 eq.) and the resulting solution is heated to 80°C. After 1 h, the mixture is poured on ice, basified to pH 8-9 using aq. sat. K2CO3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na2S04), filtered and concentrated. The product is used as such without further purification.
Step vi: 9-Benzyloxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin- 4-one
Figure imgf000080_0002
[00287] (R)-l-[l,4]Dioxan-2-yl-methanol (868 mg, 7.35 mmol, 1.05 eq.) is added to NaH (420 mg, 10.5 mmol, 1.5 eq.) in THF (14 mL) 0°C. After 10 min, 9-benzyloxy-2-chloro-l -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one (2.46 g, 7.00 mmol, 1 eq.) in DMF (14 mL) is added and the reaction mixture heated to 70°C for 24 h. The resulting mixture is treated with aq. sat. NaHCOs and concentrated under vacuum. The residue is diluted with water, sonicated and filtered. The solid is washed with water, petroleum ether and dried to afford the required compound.
Step vii: 2-( (S)-l-[ 1 ,4]Dioxan-2-ylmethoxy)-9-hydroxy-l -methyl-6, 7-dihydro-pyrido[ 2, l-aJisoquinolin-4- one
Figure imgf000080_0003
[00288] Pd/C (10% w/w, 677 mg, 0.64 mmol, 0.1 eq.) is added to 9-benzyloxy-2-((S)-l-[l,4]dioxan-2- ylmethoxy)-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (2.76 g, 6.37 mmol, 1 eq.) under nitrogen atmosphere. EtOH (160 mL) is added and the resulting mixture put under hydrogen atmosphere ^ and stirred at RT for 1 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum. The residue is treated with THF and the resulting precipitate filtered to afford the required compound.
Step viii: Trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-4-oxo-6, 7-dihydro- 4H-pyrido[2, l-aJisoquinolin-9-yl ester
Figure imgf000081_0001
[00289] NEt3 (0.25 mL, 1.8 mmol, 1.8 eq.) is added to a solution of 2-((S)-l-[l,4]dioxan-2- ylmethoxy)-9-hydroxy-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (343 mg, 1 mmol, 1 eq.) and N-phenylbis(trifluoromethanesulfonimide) (393 mg, 1.1 mmol, 1.1 eq.) in DCM (10 mL) and the reaction mixture is stirred at RT overnight. The resulting mixture is washed with aq. sat. NaHCC>3 and brine. The organic layer is separated, dried (Na2S04) and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM; 1 :99 to 5:95).
Step ix: 9-(3,5-Dimethyl-isoxazol-4-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
Figure imgf000081_0002
[00290] Trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-4-oxo-6,7- dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester (24 mg, 0.05 mmol, 1 eq.) is mixed with 3,5-dimethyl-4- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-isoxazole (33 mg, 0.15 mmol, 3 eq.), Pd(dppf)Cl2.DCM (2 mg, 0.003 mmol, 0.05 eq.) and Cs2C03 (57 mg, 0.175 mmol, 3.5 eq.) in dioxane (0.5 mL) and water (0.05 mL) and the reaction mixture is stirred to 80°C until completion of the reaction. The resulting mixture is partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried (Na2S04), filtered and concentrated. The residue is purified by preparative HPLC to afford the required compound. Compound 77: 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-l, 7, 7-trimethyl-9-(oxazol-2-ylmethoxy)-6, 7-dihydro-
Figure imgf000082_0001
Step i: 2-(3-Benzyloxy-phenyl)-2-m
Figure imgf000082_0002
[00291] A solution of lithium bis(trimethylsilyl)amide (1 M in THF, 53 mL, 53 mmol, 2 eq.) is added dropwise to an ice cold solution of (3-benzyloxy-phenyl)-acetonitrile (5.9 g, 26 mmol, 1 eq.) in THF (110 mL). After stirring for 20 min, methyl iodide (8.3 mL, 132 mmol, 5 eq.) is added and the resulting mixture is stirred at RT for 1 h. The mixture is quenched with water and concentrated under vacuum. The resulting aqueous is extracted with DCM, concentrated and the residue is purified by silica gel chromatography (EtO Ac/petroleum ether; 10:90).
Step ii: 2-(3-Benzyloxy-phenyl)-2-methy -propylamine
Figure imgf000082_0003
[00292] A solution of LiAlH4 (2 M in THF, 25 mL, 49 mmol, 2 eq.) is added dropwise to an ice cold solution of 2-(3-benzyloxy-phenyl)-2-methyl-propionitrile (6.2 g, 25 mmol, 1 eq.) in THF (25 mL). After stirring for 30 min at RT, the reaction mixture is heated to reflux temperature overnight. Once cooled to RT, the resulting mixture is added to a suspension of Na2SO4.10H2O in EtO Ac, stirred for 10 min, filtered and concentrated under vacuum. The residue is dissolved in DCM, dried (Na2SO i), filtered and concentrated. The compound is used as such without further purification. .' N-[2-(3-Benzyloxy-phenyl)-2-methyl-propyl]-propionamide
Figure imgf000083_0001
[00293] Pyridine (4.5 mL, 56 mmol, 3.0 eq.) is added to a solution of the 2-(3-benzyloxy-phenyl)-2- methyl-propylamine (4.8 g, 19 mmol, 1 eq.) in DCM (6 mL) and the solution is cooled down to 0°C. Propionyl chloride (2.4 mL, 28 mmol, 1.5 eq.) is added dropwise, the reaction warmed to RT and stirred for 2 h. Water is added and the resulting mixture extracted with DCM (3x), dried (Na2S04), filtered and concentrated under vacuum. Purification by silica gel chromatography (EtOAc/petroleum ether; 60:40) affords the required compound.
Step iv: 6-Benzyloxy-l -ethyl-4, 4-dimethyl- -dihydro-isoquinoline
Figure imgf000083_0002
[00294] POCI3 (7 mL, 76 mmol, 4 eq.) is added dropwise to an ice cold solution of N-[2-(3-benzyloxy- phenyl)-2-methyl-propyl]-propionamide (5.9 g, 19 mmol, 1 eq.) in DCM (6 mL) and the mixture is heated to reflux temperature for 5 h. The mixture is concentrated, the remaining residue is poured on ice and basified to pH 7-8 using aq. sat. K2CO3. The aqueous is extracted with DCM (3x), dried (Na2S04), filtered and concentrated. The product is used without further purification.
Step v: 9-Benzyloxy-2-hydroxy-l , 7, 7-trimethyl-6, 7-dihydro-pyrido[2, 1 -aJisoquinolin-4-one
Figure imgf000083_0003
[00295] Di-tertbutyl malonate (2.8 mL, 20 mmol, 5 eq.) is added to a solution of 6-benzyloxy-l-ethyl- 4,4-dimethyl-3,4-dihydro-isoquinoline (1.2 g, 4.1 mmol, 1 eq.) in NMP (8 mL) under nitrogen atmosphere and the resulting mixture is heated to 180°C for 25 min in a microwave reactor. The resulting mixture is purified on an SCX column (equilibrated with 5% AcOH in MeOH, washed with MeOH and eluted with 2 N NH3 in MeOH).
Step vi: 9-Benzyloxy-2-chloro-l, 7, 7-trimethyl-6, 7-dihydro-pyrido [2, 1 -a] isoquinolin-4-one
Figure imgf000083_0004
o2
[00296] POCI3 (6.6 mL) is added to 9-benzyloxy-2-hydroxy-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one (2.0 g, 4.43 mmol, 1 eq.) and the resulting solution is heated to 80°C. After 2 h, the mixture is poured on ice, basified to pH 8-9 using aq. sat. K2CO3 and stirred at RT for 1 h. The aqueous is extracted with DCM, dried (Na2S04), filtered and concentrated. The product is used as such without further purification.
9-Benzyloxy-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l, 7, 7-trimethyl-6, 7-dihydro-pyrido[2, 1 -
Figure imgf000084_0001
[00297] (R)-l-[l,4]Dioxan-2-yl-methanol (794 mg, 6.73 mmol, 1.5 eq.) is added to NaH (1.07 g, 27.0 mmol, 6.0 eq.) in DMF (9 mL) 0°C. After 10 min, 9-benzyloxy-2-chloro-l,7,7-trimethyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one (1.70 g, 4.48 mmol, 1 eq.) in DMF (9 mL) is added and the reaction mixture heated to 70°C for 24 h. The resulting mixture is treated with water and extracted with EtOAc. The residue is purified by silica gel chromatography (MeOH/EtOAc; 4:96).
Step viii: 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-9-hydroxy-l, 7, 7-trimethyl-6, 7-dihydro-pyrido[2,l- aJisoquinolin-4-one
Figure imgf000084_0002
[00298] Pd/C (10% w/w, 161 mg, 0.15 mmol, 0.1 eq.) is added to 9-benzyloxy-2-((S)-l-[l,4]dioxan-2- ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (700 mg, 1.52 mmol, 1 eq.) under nitrogen atmosphere. MeOH (6 mL) is added and the resulting mixture put under hydrogen atmosphere and stirred at RT for 2 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum. The residue is triturated with sBuOH and the resulting precipitate filtered to afford the required compound. Step ix: 2-( (S)-l-[ l,4]Dioxan-2-ylmethoxy)-l, 7, 7-trimethyl-9-(oxazol-2-ylmethoxy)-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
Figure imgf000085_0001
[00299] 2-Chloromethyl-oxazole (35 mg, 0.30 mmol, 1.5 eq.) is added to a mixture 2-((S)-l- [1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-l ,7,7-trimethyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one (73 mg, 0.20 mmol, 1 eq.), potassium iodide (7 mg, 0.04 mmol, 0.2 eq) and K2CO3 (54 mg, 0.39 mmol, 2 eq.) in DMF (1 mL) and the reaction mixture is heated to 60°C for 4 h. The resulting mixture is diluted with DCM, washed with brine, dried (Na2S04), filtered and concentrated. The resulting mixture is purified on an SCX column (equilibrated with 5% AcOH in MeOH, washed with MeOH and eluted with 2 N NH3 in MeOH) to afford the required compound.
Compound 79: 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-l-methyl-9-(tetrahydro-pyran-4-yl)-6, 7-dihydro- pyrido[2,l-a]isoquinolin-4-one
Figure imgf000085_0002
Step i: 9-(3, 6-Dihydro-2H-pyran-4-yl)-2-((S)-l-[l,4Jdioxan-2-ylmethoxy)-l-methyl-6, 7-dihydro- pyrido[2, l-a]isoquinolin-4-one
Figure imgf000085_0003
[00300] Trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-4-oxo-6,7- dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester (24 mg, 0.05 mmol, 1 eq.) is mixed with 4-(4 ,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (32 mg, 0.15 mmol, 3 eq.), n„
84
Pd(dppf)Cl2.DCM (2 mg, 0.003 mmol, 0.05 eq.) and Cs2C03 (57 mg, 0.175 mmol, 3.5 eq.) in dioxane (0.5 mL) and water (0.05 niL) and the reaction mixture is stirred to 80°C until completion of the reaction. The resulting mixture is partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried (Na2S04), filtered and concentrated. The residue is purified by silica gel chromatography (MeOH/DCM; 1 :99 to 10:90).
Step ii: 2-((S)-l-[l,4]Dioxan-2-ylmethoxy)-l-methyl-9-(tetrahydro-pyran-4-yl)-6, 7-dihydro-pyrido [2, 1 - aJisoquinolin-4-one
Figure imgf000086_0001
[00301] Pd/C (10% w/w, 5 mg, 0.005 mmol, 0.1 eq.) is added to 9-(3,6-dihydro-2H-pyran-4-yl)-2-((S)- l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one (20 mg, 0.05 mmol, 1 eq.) under nitrogen atmosphere. MeOH (1.3 mL) is added and the resulting mixture put under hydrogen atmosphere and stirred at RT for 2 h. The mixture is filtered over Celite and the filtrate concentrated under vacuum to give the required compound.
Compound 146: Acetic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-4-oxo-6, 7- dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester
Figure imgf000086_0002
[00302] A mixture of trifluoro-methanesulfonic acid 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-10-methoxy- l-methyl-4-oxo-6,7-dihydro-4H-pyrido[2,l-a]isoquinolin-9-yl ester (157 mg, 0.31 mmol, 1 eq.), K4(Fe(CN)6).3H20 (26 mg, 0.06 mmol, 0.2 eq.), Pd(OAc)2 (3.5 mg, 0.02 mmol, 0.05 eq.), Pd(dppf)Cl2.DCM (24 mg, 0.03 mmol, 0.1 eq.) and Na2C03 (33 mg, 0.31 mmol, 1 eq.) in DMA (1.5 mL) under nitrogen atmosphere is heated at 140°C for 24 h. The resulting mixture is diluted with DCM, washed with water, dried (Na2S04), filtered and concentrated. The compound is obtained by purification by preparative HPLC. „
Table II. List of precursors
Figure imgf000087_0002
Table III. Mass Spectral Data of Reprentative Compounds of the Invention
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
ester
Table IV. NMR Data of Representative Compounds of the Invention
Cpd NMR data (δ)
'H NMR δ (ppm)(DMSO-d6) 7.20 (IH, s), 7.12 (IH, s), 5.85 (IH, m), 5.37 (IH, s), 4.79 (2H,
6 q), 4.12 (IH, m), 3.82 (5H, m), 3.64 (IH, dd), 3.15 (3H, m), 2.70 (2H, t), 2.17 (3H, s), 1.98 (IH, m), 1.84 (2H, m), 1.61 (IH, m)
'H NMR δ (ppm)(CDCl3) 7.14 (IH, s), 6.81 (IH, s), 6.16 (IH, dt), 5.94 (IH, s), 4.29 (2H,
22 dt), 4.12 (2H, br), 4.10 (2H, m), 3.92 (2H, m), 3.87 (3H, s), 3.84 (IH, m) 3.78 (2H, m), 3.67 (IH, m), 3.57 (IH, m), 2.78 (2H, t), 2.27 (3H, s) Cpd NMR data (δ)
Ή ΝΜΡν δ (ppm)(CDCl3) 7.48 (1H, s), 7.18 (1H, s), 6.08 (1H, s), 4.12 (2H, t), 4.02 (2H, m),
50 3.95 (3H, s), 3.92 (2H, m), 3.82 (2H, m), 3.75 (1H, d), 3.65 (1H, m), 3.56 (1H, m), 2.82 (2H, t), 2.30 (3H, s)
Ή ΝΜΡν δ (ppm)(DMSO-d6) 7.76 (1H, d), 7.45 (1H, d), 7.40 (1H, dd), 5.93 (1H, s), 4.00
69 (3H, m), 3.95-3.75 (3H, m), 3.73-3.60 (2H, m), 3.55-3.40 (3H, m), 2.89 (2H, m), 2.47 (3H, s), 2.29 (3H, s), 2.21 (3H, s)
Ή ΝΜΡν δ (ppm)(CDCl3) 7.72 (1H, d), 7.52 (1H, d), 7.18 (1H, d), 7.04 (1H, d), 6.94 (1H,
77 dd), 6.00 (1H, s), 5.23 (2H, s), 4.02 (2H, m), 3.95 (1H, d), 3.92 (2H, m), 3.86 (1H, m), 3.82 (2H, m), 3.77 (1H, m), 3.67 (1H, m), 3.58 (1H, m), 2.24 (3H, s), 1.20 (6H, s)
Ή ΝΜΡν δ (ppm)(DMSO-d6) 7.61 (1H, d), 7.27 (2H, m), 5.89 (1H, s), 3.99 (2H, m), 3.99-
79
3.75 (6H, m), 3.75-3.60 (2H, m), 3.55-3.35 (6H, m), 2.81 (2H, m), 2.16 (3H, s), 1.71 (4H, m)
Biological Examples
1. In vitro assays
1.1. Cell based assay: GTp- S binding assay.
[00303] 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.
[00304] The assay is performed in a 96 well plate where the following reagents are added. First 50 μΐ. compound is added into the assay plate, followed by addition of 20 μΐ. 3,3 '-diindolylmethane at ECgo concentration (concentration which gives 80% of the activity of GPR84). Then, 30 μL· 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 [35S]GTPyS (Perkin Elmer, NEG030) and 0.5 mg/well PVT-WGA SpA beads (Perkin Elmer, RPNQ0001)] . All components are diluted in assay buffer containing 20 mM Tris pH 7.5; 5 mM MgCl2; 250 mM NaCl; 0.05%> BSA; 75 μg/mL saponin. After an incubation of 90 min at room temperature, 20 μΕ CsC¾ 0.8 M (MP Biomedicals, 02150589) is added, followed by centrifugation at 2000 rpm during 20 min. Plates are read on a Topcount reader (Perkin Elmer) immediately after centrifugation (readout time, 1 min/well). Table V. GPR84 GTPyS assay IC50 of selected compounds of the invention.
> 1000 nM
>500- 1000 nM
> 100- 500 nM
0.01 - 100 nM
Figure imgf000111_0001
Figure imgf000112_0001
2. Cellular assays
2.1. Human neutrophil migration assay
[00305] We have established that GPR84 agonists (medium chain free fatty acids such as sodium decanoate and sodium undecanoate, 3,3'-diindolylmethane and embelin) induce neutrophil chemotaxis and that GPR84 antagonists block GPR84 agonist-induced chemotaxis. GPR84 antagonists do not inhibit IL8- or fMLP-induced human neutrophil chemotaxis, indicating that GPR84 is an essential player in the process of neutrophil trafficking and recruitment.
[00306] The activity of GPR84 agonists and antagonists can therefore be assayed in a human neutrophil migration assay. The human neutrophil migration assay makes use of freshly isolated human neutrophils from buffy coats that are subsequently used in a functional chemotaxis assay setup. Freshly isolated human neutrophils from buffy coats obtained from healthy individuals are pre-treated with a compound for 30 minutes prior to the plating of neutrophils onto the upper chamber of the neutrophil chemotaxis assembly (Corning HTS 5-μιη Transwell 96 permeable support system) in the presence of embelin (GPR84 agonist) at ECgo concentration (concentration for which 80% of activity is measured) in the lower chamber. After 1 hour of incubation at 37°C and 5% CO2, the number of migrated neutrophils in the lower compartment can be quantified by measuring the ATP content using ATPlite™ Luminescence Assay System. ^ ^ ^
2.1.1 Isolation of neutrophils from human buffy coat
[00307] A human buffy coat suspension is diluted with an equal volume of ice cold DPBS. 20 mL of the diluted buffy coat suspension 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 a 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 is transferred to a new recipient and incubated at room temperature to allow sedimentation of red blood cells. The yellowish upper fraction is then transferred to a clean centrifugation tube and centrifuged for 12 min 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 to perform a red blood cell lysis by osmotic burst. After 20 seconds, 4 mL of ice-cold 0.6 M KC1 is added to restore salt concentration. Samples are mixed carefully and centrifuged for 6 min at 1300 rpm and 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™ (Axis Shield, prod. No. 1114545) in a 15 mL centrifuge tube. After a gradient centrifugation step (30 min at 1500 rpm, 4°C and low brake), the supernatant is removed and the cell pellet, containing polymorphonuclear cells, is resuspended in 25 mL of chemotaxis buffer (RPMI 1640 medium, supplemented with 10 mM HEPES and 0.05% FFA-free BSA).
2.1.2 Migration assay
[00308] A neutrophil cell suspension of 8.9 x 106 cells per mL is prepared in chemotaxis buffer and 180 μΕ per well is plated in a 96-well V-bottom plate. 20 μΕ of test compound solution in chemotaxis buffer is added to the 180 μΕ cell suspension. The mixture is incubated at RT for 30 min with intermediate gentle resuspension of the cells after 15 min. Following this, 75 μΕ of cell suspension is plated onto the upper compartment of a Transwell® permeable support system (Corning HTS Transwell 96 permeable support system with 5.0 μιη pore size polycarbonate membrane, Corning, prod. No. 3387). The lower compartment (receiver well) is then filled with 200 μΕ chemotaxis buffer containing an equal concentration of test compound and a fixed concentration of chemotactic agent (embelin at EC80 concentration). After 1 h at 37°C, 5% CO2 in a humidified incubator, the upper plate of the Transwell® system is gently removed. The number of migrated cells in the lower chamber is quantified by addition of 200 μΕ of ATPlite™ solution (ATPlite™ Luminescence Assay System, Perkin Elmer, Prod. No. 6016941) followed by incubation for 10 minutes in the dark with mild agitation. After incubation, 270 μΕ of cell lysate is then transferred onto a white 96-well plate for quantification by a luminescence plate reader. The relative luminescent signal measured is considered linearly related to the number of cells having migrated from the upper compartment into the receiver well. Table VI. Human neutrophil migration IC5o of selected compounds of the invention.
* > 1000 nM
** > 500 - 1000 nM
*** > 100 - 500 nM
**** 0.01 - 100 nM
Cpd Neutrophils Cpd Neutrophils
1 **** 50 ***
2 **** 51 ***
3 **** 52 ***
4 **** 53 ***
5 **** 54 ***
7 **** 55 ***
8 **** 56 ****
9 **** 57 ***
10 **** 58 ****
11 **** 59 **
12 **** 60 ***
13 **** 61 **
14 **** 62 ***
15 **** 63 ***
16 **** 64 ***
17 **** 66 ***
19 *** 67 ***
20 **** 68 ***
22 *** 73 ***
23 *** 74 ***
24 *** 75 ***
25 *** 79 *
26 *** 80 ***
27 **** 81 **
28 **** 82 ***
29 *** 83 **
30 **** 84 ***
31 **** 85 ***
33 *** 86 **
34 **** 90 **
35 *** 96 *
36 *** 97 **
37 **** 98 *
38 *** 99 *
39 *** 100 ***
40 *** 102 *
41 *** 105 **
42 **** 108 *
43 *** 109 ***
44 *** 117 **
45 **** 120 *
46 ** 121 *
47 *** 130 *
48 ** 135 **
49 **** 137 * 2.2. Rat neutrophil migration assay
[00309] We have established that GPR84 agonists (medium chain free fatty acids such as sodium decanoate and sodium undecanoate, 3,3'-diindolylmethane 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.
[00310] 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 min. 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 ECgo (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.N°.: G755B).
2.2.1. Isolation of neutrophils from rats
[00311] 24 h after intraperitoneal injection of glycogen (0.1 %, w/v), cells are harvested by peritoneal lavage with 25 mL HBSS then centrifuged for 12 min 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 min 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
[00312] A cell suspension of 8.9x 106 cells per milliliter is prepared. 10 μΕ of compound solution in chemotaxis buffer is added to 90 μΕ cell suspension. The mixture is incubated at 37°C for 30 min with intermediate resuspension of the cells after 15 min. Following this, 75 μΕ 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 μΕ 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 μΕ Cell Titer Glow Substrate (Promega, Cat.N°.: G755B) are added in the receiver plate. The receiver plate is incubated for 10 min in the dark, while shaking. 180 μΕ 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. Λ Λ Λ
1 14
3. ADME, ΡΚ and Safety Models
3.1 Aqueous Solubility
[00313] Starting from a lO mM 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 0.1M citrate buffer pH3.0 at room temperature is added.
[00314] The final concentrations range from 18.75 to 300 μΜ in 5 equal dilution steps. The final DMSO concentration does not exceed 3%.
[00315] 200 μΜ 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.
[00316] The assay plates are sealed and incubated for 1 h at 37°C while shaking at 230 rpm. 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.
[00317] Solubility values are reported in μΜ and in μg/mL.
3.2. Thermodynamic solubility
[00318] Thermodynamic solubility of a compound is determined in water, phosphate or citrate buffer with pH of choice or biologically relevant gastrointestinal media (FaSSIF, FeSSIF, SGF). Dry matter of the compound is added to the medium of choice and incubated for 24 hours at room temperature. The concentration of compound in the supernatant is analyzed by LC/MS-MS and the signal is plotted against the linear standard curve of that compound.
[00319] 2.5-3 mg dry matter of test compound is dissolved in water, phosphate or citrate buffer with pH of choice or biologically relevant gastrointestinal media (FaSSIF, FeSSIF, SGF) in a glass vial. After addition of a magnetic stirrer, the samples are stirred for 24 hours at room temperature. The vials are then centrifuged shortly and the supernatant is filtered. Each sample is diluted by a factor of 100 and a 10 in
DMSO. A final 100 fold dilution in 70/30 water/acetonitrile is used for LCMS-MS analysis.
[00320] A standard curve is made starting from a 10 mM stock in DMSO, freshly prepared from dry matter. From this 10 mM DMSO stock solution, intermediate working solutions of 200, 50 and 10 μg/mL in DMSO are made and used to prepare 40, 20, 10, 5, 1, 0.2, 0.1 and 0.04 μg/mL solutions in DMSO.
Two quality control samples are made: one of 15 μg/mL and one of 0.5 μg/mL in DMSO, also starting from the DMSO working stock solutions.
[00321] The standard curve and quality controls are diluted by a factor of 100 in 70/30 water/acetonitrile and analyzed on LC/MS-MS. The peak areas of the standard curve are plotted in a graph and a linear or polynomial of the second order equation is used to calculate the unknown concentrations of the test compound.
[00322] Solubility values are reported in μΜ or μg/mL. 3.3 Microsomal stability
[00323] A 10 mM stock solution of compound in DMSO is 1,668 fold diluted in a 105 mM phosphate buffer pH 7.4. Of this compound dilution, 50 μΐ^ 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.
[00324] In the time zero reference sample (TO plate), 100 μΐ. MeOH (1 : 1) is added to the wells. In each assay plate (TO and T30 min), 50 μΐ^ of microsomal mix is then added.
[00325] 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 mM NADP+.
[00326] The T30 plate is incubated at 37°C, 300 rpm and after 30 min 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).
[00327] The samples are analyzed on LC-MS/MS with a flow rate of 0.5 mL/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 2.0 mm column (Varian). The solvent gradient has a total run time of 1.4 min 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 min 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.
[00328] Test compounds (1 μΜ initial concentration, n=2) are incubated in Williams' Medium E, containing 4 mM L-glutamine 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 \L samples taken from the incubation at 0, 10, 20, 45 and 90 min, and reactions terminated by addition of 100 \L 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: Ύυ2 (min) = -0.693/λ, where λ is the slope of the Ln concentration time curve. Standard compounds testosterone, midazolam, and 4-methylumbelliferone are included in the assay design.
3.5 Plasma Protein Binding (Equilibrium Dialysis)
[00329] A 10 mM 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%>. Λ Λ r
1 16
[00330] A Pierce Red Device plate with inserts (ThermoScientific) is prepared and filled with 450 μΐ. PBS in the buffer chamber and 300 \\L of the spiked plasma in the plasma chamber. The plate is incubated for 4 h at 37°C while shaking at 100 rpm. After incubation, 120 \\L of both chambers is transferred to 480 \\L 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).
[00331] The samples are analyzed on LC-MS/MS with a flow rate of 0.5 mL/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 2.0 mm column (Varian). The solvent gradient has a total run time of 1.4 min and ranges from 10%> B to 100%) B.
[00332] Peak area from the compound in the buffer chamber and the plasma chamber are considered to be 100%) compound. The percentage bound to plasma is derived from these results and is reported as percentage bound to plasma.
[00333] 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
[00334] 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).
[00335] 2x l05 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.
[00336] Test and reference compounds (propranolol and rhodaminel23 or vinblastine, all purchased from Sigma) are prepared in Hanks' Balanced Salt Solution containing 25 mM HEPES (pH7.4) and added to either the apical (125 μΕ) or basolateral (600 μΕ) chambers of the Transwell plate assembly at a concentration of 10 μΜ with a final DMSO concentration of 0.25%.
[00337] 50 μΜ 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.
[00338] After a 1 h incubation at 37°C while shaking at an orbital shaker at 150 rpm, 70 μΕ aliquots are taken from both apical (A) and basal (B) chambers and added to 100 μΕ 50:50 acetonitrile:water solution containing analytical internal standard (0.5 μΜ carbamazepine) in a 96 well plate.
[00339] Lucifer yellow is measured with a Spectramax Gemini XS (Ex 426 nm and Em 538 nm) in a clean 96 well plate containing 150 μΕ of liquid from basolateral and apical side.
[00340] Concentrations of compound in the samples are measured by high performance liquid- chromatography/mass spectroscopy (LC-MS/MS). [00341] Apparent permeability (Papp) values are calculated from the relationship:
Papp = [compound] acceptor fmd x Vacceptor / ([compound]donor initial x Vdonor) / Tinc x Vdonor / surface area X 60 X
10"6 cm/s
V = chamber volume
Tinc = incubation time.
Surface area = 0.33 cm2
[00342] 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.
[00343] The following assay acceptance criteria are used:
Propranolol: Papp (A>B) value > 20(x 10"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
[00344] Potential for QT prolongation is assessed in the hERG manual patch clamp assay.
3.7.1 Conventional whole-cell patch-clamp
[00345] 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).
[00346] The external bathing solution contains: 135 mM NaCl, 5 mM KC1, 1.8 mM CaCl2, 5 mM Glucose, 10 mM HEPES, pH 7.4.
[00347] The internal patch pipette solution contains: 100 mM Kgluconate, 20 mM KC1, 1 mM CaCl2, 1 mM MgCl2, 5 mM Na2ATP, 2 mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
[00348] Drugs are perfused using a Biologic MEV-9/EVH-9 rapid perfusion system.
[00349] 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 20 s and all experiments are performed at room temperature.
3.7.2 Data Analysis
[00350] IC5o values are calculated for each compound tested. The fold difference between the IC5o in the manual hERG patch clamp and the unbound IC50 in the whole blood assay is calculated.
[00351] 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+ 10Λ ( ( logc-x ) d )]
[00352] where a is minimum response, b is maximum response and d is Hill slope, this equation can be used to calculate both IC5o (where y = 50 and c is the IC5o value) and IC2o (where y = 20 and c is the IC2o 1 1 o
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
[00353] 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
[00354] 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
[00355] 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
[00356] Pharmacokinetic parameters are calculated using Winnonlin® (Pharsight®, US).
3.9 7-Day rat toxicity study
[00357] 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.
[00358] 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.
[00359] 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
[00360] 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
[00361] The inhibitory potential of a test compound is assessed for human cytochrome P450 isoenzymes CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4.
[00362] A 10 mM 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.
[00363] After 15 or 30 min reactions are terminated by addition of 100 μL 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 IC5o.
[00364] Inhibition of CYP3A4 using nifedipine and atorvastatin as probe substrate is carried out as follows.
[00365] 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 min 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 glucose- 6-phosphate dehydrogenase).
[00366] After 5 min (nifedipine) or 10 min (atorvastatin) at 37°C, the reaction (50 μL) is terminated with 150 μL 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 IC5o.
3.10.2 CYP3A4 inhibition in human liver microsomes, time-dependent
[00367] 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 IC5o, indicating time-dependent inhibition.
[00368] 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, [00369] 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 min pre- incubation" plate and both plates are then incubated for 30 min at 37°C in a shaking water bath. Following the pre-incubation, microsomes are added to the "0 min" 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.
[00370] In total, six different test compound concentrations (1.6 to 50 μΜ) are assessed. Reactions are terminated with 100 μL 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 IC5o.
3.11 Chemical Stability
3.11.1 Protocol
[00371] This in vitro model is aimed at assessing the stability of a test compound in aqueous solutions with different pH. The decrease in parent compound is assessed by measuring the percentage parent remaining after 2 and 24 hours incubation at 37°C.
[00372] A 2 mM DMSO stock is made for each test compound starting from dry matter. Then a 80 μΜ working solution of compound in DMSO is made by diluting the 2 mM DMSO.
[00373] The 80 μΜ working solution is diluted to a final concentration of 2 μΜ - 2.5% DMSO in buffer with the desired pH (pH 1.2: hydrochloric acid buffer, pH 5.0: acetate buffer, pH 7.4: phosphate buffer, pH 9.0: Tris buffer) in 96-well plates with glass inserts (Cat no. 548-0201/548-0202, VWR- Thermo Scientific). Two replicates are run for each buffer solution and each time point.
[00374] One set of vials is incubated for 24 hours at 200 rpm and another for 2 hours at 200 rpm. To stop the reaction after the respective incubation times, 4 volumes of acetonitrile containing the internal standard (stop solution) are added to the reaction solution and the vials are vortexed briefly.
[00375] For the 0 hour incubation, the stop solution with internal standard is first added to the buffer solution in glass vials and then the working solution of test compound (final concentration: 2 μΜ - 2.5% DMSO) is added.
[00376] Propranolol is used as internal standard, but if the mass difference is too low with the test compound(s), another product is selected as internal standard. The concentration of the internal standard is chosen to obtain a peak area half of the average peak area of the test compounds and control at time point 0.
[00377] Analysis is performed on an LCMS-MS system (API2000 or API4000). The average of the peak areas of the two replicates from the parent compound at time 0 divided by the peak area of the internal standard is considered to be 100% remaining. The percentage remaining after 2 and 24 hours of incubation is calculated for all other peaks and the percentage remaining after 2 and 24 hours is reported. Table VII. Chemical Stability Percentage remaining after 2 and 24 hours incubation.
Figure imgf000123_0001
3.11.2 Conclusion
[00378] As shown in Table VII above, the compounds of the invention, when tested in this protocol surprisingly exhibit a high chemical stability, in particular at acidic pH, more particularly between pH 1.0 and 6.0, and specifically at pH 1.2 and/or 5.0. Such property is particularly desirable for compounds administered orally, which need to transit through the acidic stomach environment.
4. In vivo studies
[00379] 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).
[00380] The mouse chronic DSS-induced inflammatory bowel disease model (IBD) is a well validated disease model for inflammatory bowel disease (Sina et al. 2009; Wirtz et al. 2007).
[00381] 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=10),
b. diseased (DSS; vehicle alone, n=10),
c. sulfazalazine used as reference (DSS; 20 mg/kg/day, /j.o., n=10) and
d. the tested compound (DSS; 1, 3, 10, 30 mg/kg/day, /j.o., n=10).
[00382] 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 al. (Sina et al. 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).
[00383] The mouse collagen-induced arthritis (CIA) is the gold standard rheumatoid arthritis model (Brand et al. 2007; Lin et al. 2007). 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 2006) 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).
4.3 Tobacco smoke model (mice)
[00384] 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 min at the start of the study (day 1) to a maximum of 45 min 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.
[00385] 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.
[00386] 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.
[00387] 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. [00388] 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.
[00389] 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.
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Claims

WHAT IS CLAIMED:
1 A compound according to Formul
Figure imgf000127_0001
wherein
R is H, CM alkyl, or cyclopropyl;
LA is O or NH;
4-6 membered monocyclic heterocycloalkyl containing one or two O,
C3.7 monocyclic cycloalkyl, or
a bicyclic group of formula Cy:
Figure imgf000127_0002
Cy
wherein A is phenyl or 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O and S;
each R2a and R2b are independently H or -CH3;
R3 is H, -OH or -OCH3;
R4 is -CN or -L1-W1-G1,
wherein
Li is absent or O,
Wi is absent, or is Ci_6 alkylene, C2-4 alkenylene having one double bond or C2-4 alkynylene having one triple bond, each of which is optionally substituted with one or more independently selected halo, -CN or C1.4 alkoxy, o H,
o -CF3,
o
Figure imgf000127_0003
alkyl, o
Figure imgf000128_0001
alkyl, optionally substituted with one or more independently selected halo, o 4-6 membered monocyclic heterocycloalkyl containing one or two O (which heterocycloalkyl is optionally substituted with one or more independently selected R7 groups),
o 6 membered monocyclic heterocycloalkenyl containing one or two O (which heterocycloalkenyl is optionally substituted with one or more independently selected R7 groups),
o C3.7 monocyclic cycloalkyl optionally substituted with one or more independently selected R7 groups,
o phenyl optionally substituted with one or more independently selected R7 groups, o or 5-6 membered heteroaryl containing one to four heteroatoms independently selected from N, O or S (which heteroaryl is optionally substituted with one or more independently selected R7 groups),
R7 is:
halo,
- -OH,
CM alkyl, C3.4 monocyclic cycloalkyl, or CM alkoxy, each of which is optionally substituted with one or more independently selected halo;
R5 is -CN or -L2-W2-G2,
wherein
L2 is absent, O or S,
W2 is absent or CM alkylene, optionally substituted with one or more independently selected halo,
G2 is
o H,
o -CF3,
o C3_7 monocyclic cycloalkyl (which cycloalkyl is optionally substituted with one or more independently selected halo),
o phenyl,
o or 5-6 membered heteroaryl containing one to three heteroatoms independently selected from N, O or S,
R6 is H, -OH or -OCH3;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof; or a biologically active metabolite thereof.
A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula IVe, IVf, IVg, or IVh:
Figure imgf000129_0001
wherein R1, LA, R4, and R5 are as previously described.
3. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-2, wherein L2 is O.
4. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein W2 is -CH2-.
5. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein G2 is C3.7 cycloalkyl substituted with one or more independently selected F or CI.
6. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein Li is absent.
7. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein Li is O.
8. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein Wi is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-CH2- or -CH2-CH2-CH2-CH2-CH2-.
9. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein Wi is -OC-, -CH2-C≡C-, or -C≡C-CH2-.
10. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein Gi is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
11. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein Gi is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
12. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-11, wherein R1 is H, -CH3, -CH2-CH3, or -CH(CH3)2.
13. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-12, wherein LA is -0-.
14. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from:
9-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-10-(2,2,2-trifluoro-ethoxy)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 12ο
9-cyclopropylethynyl-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9- (2,2-difluoro-cyclopropylmethoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l -methyl- 6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
10- (2,2-difluoro-ethoxy)-2-[([l,4]dioxan-2-ylmethyl)-amino]-9-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9- (2,2-difluoro-ethoxy)-10-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
10- methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-9-(2,2,2-trifluoro-ethoxy)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9- (6-cyclopropyl-pyridin-3-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-(2,3-dihydro-thieno[3,4-b] [1 ,4]dioxin-2-ylmethoxy)-9, 10-dimethoxy-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
trifluoro-methanesulfonic acid 2-((S)-l-[l ,4] dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-4-oxo- 6,7-dihydro-4H-pyrido[2, 1 -a]isoquinolin-9-yl ester,
2-[([l,4]dioxan-2-ylmethyl)-amino]-9-methoxy-l-methyl-10-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
10- (2,2-difluoro-ethoxy)-9-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-9-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3- yl]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(6-fluoro-pyridin-3-yl)-10-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9,10-bis-(2,2-difluoro-cyclopropylmethoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9- (3,3-difluoro-cyclobutylmethoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-9-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
10- difluoromethoxy-9-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethyl)-amino] -6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-9-(6-oxo-l,6-dihydro-pyridin-3-yl)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l ,4] dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-9-(3 -methyl-oxetan-3 -ylmethoxy)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 9-methoxy-l-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-10-(2,2,2-trifluoro-ethoxy)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9-(2,2-difluoro-ethoxy)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-[([l ,4]dioxan-2-ylmethyl)-amino]-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-(2,3-dihydro-benzo[l,4]dioxin-2-ylmethoxy)-9-hydroxy-10-methoxy-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-difluoromethoxy-2-((S)- 1 - [1 ,4]dioxan-2-ylmethoxy)- 10-methoxy- 1 -methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9- cyclopropylmethoxy-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)- 1 -[ 1 ,4] dioxan-2-ylmethoxy)-9-(4-ethoxy-3 -trifluoromethyl-phenyl)- 10-methoxy- 1 -methyl- 6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9,10-dimethoxy-l -methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
8.9- dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
9.10- dimethoxy-l -methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
10- difluoromethylsulfanyl-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-methoxy-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-methoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-10-methoxy-l-methyl-9-(4-trifluoromethoxy-phenyl)-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9-(2,2-difluoro-cyclopropylmethoxy)-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
8,9-dimethoxy-l-methyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-(2,3-dihydro-benzo[l ,4]dioxin-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l , 10-dimethyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
8,11 -dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one, 2-[([l ,4]dioxan-2-ylmethyl)-amino]-8, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 8,11 -dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-[(R)-l -(2,3-dihydro-[l ,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9, 10-dimethoxy-l -methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-[([l,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-l-methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
10-(2,2-difluoro-ethoxy)-9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
8,9-dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-armno]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4- one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-[(S)-l-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methoxy]-9,l 0-dimethoxy-l -methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-[([l,4]dioxan-2-ylmethyl)-amino]-8,9-dimethoxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 - a]isoquinoline-9-carbonitrile,
9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethoxy)- 10-(2,2,2-trifluoro-ethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-9-(pyridin-2-ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9, 11 -dimethoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-(2,3-dihydro-benzo[l ,4]dioxin-2-ylmethoxy)-9, 10-dimethoxy-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido [2, 1 - a]isoquinolin-4-one,
methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-4-oxo-6,7-dihydro- 4H-pyrido[2,l-a]isoquinolin-9-yl ester,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l ,7,7-trimethyl-9-pentyl-6,7-dihydro-pyrido[2, 1 -ajisoquinolin- 4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l 0-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4 one,
2-([l,4]dioxan-2-ylmethoxy)-9,10-dimethoxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 8,11 -dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-9-(5-ethyl-[l,2,4]oxadiazol-3-ylmethoxy)-l-methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-[([l ,4]dioxan-2-ylmethyl)-amino]-9, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one 8,9-dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 2-(2,3-dihydro-benzo[l,4]dioxin-2-ylmethoxy)-9-methoxy-6,7-dihydro-pyrido[2,l-a]isoquinolin- one,
9-methoxy- 1 -methyl- 10-(pyridin-2-ylmethoxy)-2- [(tetrahydro-furan-2-ylmethyl)-amino]-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9-(3,5-dimethyl-isoxazol-4-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-benzyloxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin- one,
9, 11 -dimethoxy-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-< one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-l 0-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
8,9-dimethoxy-l-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-benzyloxy-l-cyclopropyl-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-8, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
9-(3,6-dihydro-2H-pyran-4-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-9-(oxazol-2-ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9, 11 -dimethoxy-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(tetrahydro-pyran-4-yl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-benzyloxy-2-([l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l-a]isoquinolin- one,
[2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -methyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 -a]isoquinolin-9- yloxy] -acetonitrile, 9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9, 10-dimethoxy-l -methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin- 4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(3-methyl-but-l-ynyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-(5,6-dihydro-[l,4]dioxin-2-yl)-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-methyl-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-ethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(l-methyl-lH-pyrazol-4-yl)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
[2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 -a]isoquinolin-9- yloxy] -acetonitrile,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(l-propyl-lH-tetrazol-5-ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-8,9-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -ajisoquinolin- 4-one,
8,11 -dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 9-[l ,4]dioxan-2-yl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)- 1 -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-8-hydroxy-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-( 1 -cyclopropyl- 1 H-tetrazol-5-ylmethoxy)-2-((S)- 1 - [ 1 ,4] dioxan-2-ylmethoxy)- 1 -methyl-6,7- dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-4-oxo-9-(2,2,2-trifluoro-ethoxy)-6,7-dihydro-4H- pyrido [2, 1 -a] isoquinoline- 10-carbonitrile,
2,9-bis-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9, 11 -dimethoxy-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one,
8.9- dimethoxy-l-methyl-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquino 4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -methyl-9-(3-methyl-oxetan-3-ylmethoxy)-6,7-dihydro- pyrido[2,l-a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l -ethyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9.10- dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(pyridin-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(lH-tetrazol-5ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-cyclohexylmethoxy-9, 10-dimethoxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 9, 10-dimethoxy- 1 -methyl-2- [(tetrahydro-pyran-3 -ylmethyl)-amino] -6,7-dihydro-pyrido [2,1- a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(l-methyl-lH-pyrazol-4-yl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9,10-dimethoxy-l -methyl-2-(tetrahydro-pyran-4-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin 4-one,
9-cyclopropylmethoxy-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l,7,7-trimethyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
8,9-dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methoxy-but-l -ynyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
8,9-dimethoxy-l-methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2,l-a]isoquinolin- 4-one,
9-benzyloxy-l-cyclopropyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-ethyl-4-oxo-6,7-dihydro-4H pyrido[2,l-a]isoquinolin-9-yl ester,
9-(2-cyclopropyl-ethyl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -ethyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-cyclopropylmethoxy-2-([ 1 ,4] dioxan-2-ylmethoxy)- 1 -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9, 11 -dimethoxy-2-(tetrahydro-furan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4-one, 2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-l ,7,7-trimethyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l -methyl-4-oxo-6,7-dihydro-4H-pyrido[2, 1 - a]isoquinoline-10-carbonitrile,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-pentyl-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one, 1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-pentyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4 one, 9-benzyloxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-l -isopropyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin- 4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-(3-methoxy-butyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
1 -cyclopropyl-9-(2-cyclopropyl-ethyl)-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
trifluoro-methanesulfonic acid 1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-4-oxo-6,7 dihydro-4H-pyrido[2, 1 -a]isoquinolin-9-yl ester,
trifluoro-methanesulfonic acid 2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l-isopropyl-4-oxo-6,7-dihydro 4H-pyrido[2,l-a]isoquinolin-9-yl ester,
1- cyclopropyl-9-cyclopropylethynyl-2-((S)-l-[l,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2- ((S)-l-[l,4]dioxan-2-ylmethoxy)-l -isopropyl-9-(3-methyl-butyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-8-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
9-(2-cyclopropyl-ethyl)-2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-l -isopropyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one,
1 -cyclopropyl-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-(3-methyl-but-l -ynyl)-6,7-dihydro-pyrido[2, 1■ a]isoquinolin-4-one,
2-([l,4]dioxan-2-ylmethoxy)-9-(2-methoxy-ethoxy)-l -methyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -isopropyl-9-(3-methyl-but-l-ynyl)-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
9-cyclopropylethynyl-2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l -isopropyl-6,7-dihydro-pyrido[2,l- a]isoquinolin-4-one,
2-((S)-l - [1 ,4]dioxan-2-ylmethoxy)-9-hydroxy-l -methyl-6,7-dihydro-pyrido[2, 1 -a]isoquinolin-4- one,
trifluoro-methanesulfonic acid 2-((S)-l -[l,4]dioxan-2-ylmethoxy)-l-methyl-4-oxo-6,7-dihydro-4H pyrido[2,l-a]isoquinolin-9-yl ester,
2-((S)-l-[l,4]dioxan-2-ylmethoxy)-l -ethyl-9-hydroxy-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
9- methoxy-2-[(tetrahydro-furan-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l-a]isoquinolin-4-one,
10- hydroxy-9-methoxy-l-methyl-2-[(tetrahydro-pyran-2-ylmethyl)-amino]-6,7-dihydro-pyrido[2,l a]isoquinolin-4-one,
2-[([l ,4]dioxan-2-ylmethyl)-amino]-l 0-hydroxy-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one, 10-hydroxy-9-methoxy- 1 -methyl-2-(tetrahydro-pyran-2-ylmethoxy)-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one, and
10-benzyloxy-2-((S)-l -[1 ,4]dioxan-2-ylmethoxy)-9-methoxy-l -methyl-6,7-dihydro-pyrido[2, 1 - a]isoquinolin-4-one.
15. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof, according to any of claims 1-14, and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition according to claim 15 comprising a further therapeutic agent.
17. A compound, or pharmaceutically acceptable salt thereof, according to any of claims 1-14, or the pharmaceutical composition according to claim 15 or 16, for use as a medicament.
18. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-14, or the pharmaceutical composition according to claim 15 or 16, for use in the treatment and/or prophylaxis of inflammatory conditions, neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
19. The use according to claim 18, wherein the inflammatory condition is rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, periodontitis, and/or pyoderma gangrenosum.
20. The use according to claim 18, wherein a compound, or pharmaceutically acceptable salt thereof, according to claim 1 -14 is administered in combination with a further therapeutic agent.
21. The use according to claim 18, wherein the further therapeutic agent is an agent for the treatment and/or prophylaxis of inflammatory conditions, neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, diseases involving impairment of immune cell functions, pain, neurodegenerative conditions, cardiovascular diseases, and/or leukemia.
PCT/EP2015/063965 2014-06-25 2015-06-22 Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders WO2015197550A1 (en)

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