Amino Pyrimidine Compounds Useful As SSAO Inhibitors

This invention relates to amino pyrimidine compounds, pharmaceutically acceptable salts of the compounds, and therapeutic uses of the compounds and their salts.

Semicarbazide-sensitive amino oxidase/vascular adhesion protein-1 (SSAO/VAP-1) exists both as a membrane-bound isoform and a plasma soluble isoform. It is predominantly expressed from endothelial cell surfaces, vascular smooth muscle and adipose cells. SSAO/VAP-1 participates in many cellular processes including glucose disposition, inflammation responses and associated pain, and leukocyte recruitment. High activity levels of this enzyme are associated with diabetes, atherosclerosis, strokes, chronic kidney disease, and Alzheimer's disease, among other disorders. SSAO/VAP-1 has been implicated in the pathogenesis of liver diseases such as fatty liver disease.

(Weston C. J., et al, J. Neural. Transm., 2011, 118, 1055.) Fatty liver disease (FLD) encompasses a spectrum of disease states characterized by excessive accumulation of fat in the liver often accompanied with inflammation. FLD can lead to non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. If untreated NAFLD, can progress to a persistent inflammatory response or non-alcoholic

steatohepatitis (NASH), progressive liver fibrosis, and eventually to cirrhosis. Currently there is a need to provide alternative treatment therapies for liver diseases such as NAFLD and/or NASH.

It is thought that a SSAO/VAP-1 inhibitor will reduce liver inflammation and fibrosis and thereby provide a treatment for liver diseases, in particular, a treatment for NAFLD and/or NASH. In addition, since activation of SSAO/VAP-1 has been implicated in inflammation and associated pain, inhibition of SSAA/VAP-1 enzyme may be useful in treating pain, and in particular, pain associated with osteoarthritis. (Luis M. et al, J of Pharm and Experimental Therapeutics, 2005, 315, 553.)

US patent 8,426,587 discloses haloallylamine compounds useful as SSAO/VAPl inhibitors.

Currently, there is no approved drugs for the treatment for NASH; the standard of care for NASH consists of diet control and/or life style changes. In addition, the current standard of care for pain is dominated by nonsteroidal anti-inflammatory drugs

(NSAIDS) and opiates. Both classes of drugs are recommended for short term use only. It is desirable to have more treatment options to control pain, in particular chronic pain.

The present invention provides compounds that inhibit the SSAO/VAP-1 enzyme and which may address one or more of these needs.

The present invention provides a com ound of the Formula 1 below:

where Rl is selected from:

is selected from: H, -C(0) H2, -C(0) H(CH3), -C(0)N(CH3)2,

and ; ; RR33 i iss HH oorr CCHH33,, RR44 i iss HH oorr A " 0 ; R5 is selected from: H, -Ci-4alkyl, -C3-4 cycloalkyl, -CH2-C3 -4 cycloalkyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.

The bond to fluorine illustrated as indicates that the fluorine atom and the methoxypyrimidine group can be either Z (zusammen, together) or E (entgegen, opposite) relative to each other. (See Brecher, J., et al, "Graphical Representation of

Stereochemical Configuration", Pure and Appl. Chem, 2006, 78(10) 1897, at 1959.) The structure illustrated by Formula 1 includes compounds exhibiting the Z stereochemical configuration or the E stereochemical configuration about the double bond; or a mixture of compounds individually exhibiting the Z or E stereochemical configuration. Preferred compounds of the invention have the E stereochemical configuration about that double bond.

The present invention also provides a com ound of Formula 2:

where Rl is selected from:

and ; R2 is selected from: H, -C(0) H2, -C(0) H(CH3), -

C(0)N( ; R3 is H or CH3; R4 is

H or ; R5 is selected from: H, -Ci-4alkyl, -C3-4 cycloalkyl, and -CH2-C3-4 cycloalkyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a compound according to Formula

1 or 2 where Rl is selected from:

, and and where R2, R3, R4, R5, and n are as provided above; or a pharmaceutically acceptable salt thereof. In one preferred embodiment, Rl is

and R5, and n are as provided above. In another preferred

embodiment, Rl is and R5 is selected from: H, -CH3,

and ; more preferably, R5 is -CH3.

In another form, the present invention provides a compound according to Formula

1 or 2 where Rl is ; R2 is selected from: H -C(0) H2,

-C(0) H(CH3), -C(0)N(CH3)2,
; and

R3, and R4 are as provided above, or a pharmaceutically acceptable salt thereof. In one preferred embodiment, R3 is H and R4 is provided as above, or a pharmaceutically acceptable salt thereof. In another preferred embodiment, R3 is H and R4 is H.

In another form, the present invention provides a compound according to Formula

1 or 2 where Rl is ; R4 is , and R2 and R3 are as provided above, or a pharmaceutically acceptable salt thereof. More preferable, R2 and R3 are both H.

In another form, the present invention provides a compound according to Formula 3 below:

or a pharmaceutically acceptable salt thereof.

In yet another form, the present invention provides a compound of Formula 4 below:

or a pharmaceutically acceptable salt thereof. In one form, the compound of Formula 4 is provided as a free base.

In another form, the compound of Formula 4 is provided as a pharmaceutically acceptable salt. Preferably the compound of Formula 4 is provided as a mono or di hydrochloride addition salt.

In another form, the present invention provides a pharmaceutical composition comprising a compound according to any one of Formulae 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition can be used in the treatment of a patient suffering from a liver disorder.

In another form, the present invention provides a method of treating a patient in need there of for a liver disorder. The method comprises administering to the patient an effective amount of a compound according to Formulae 1 to 4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises treating a patient in need of treatment for a liver disorder where the liver disorder is selected from: liver fibrosis, alcohol induced fibrosis, alcoholic steatosis, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). In a particularly preferred embodiment, the method comprises treating a patient in need for treatment of NASH. Preferably the method comprises administering an effective amount of a compound of Formula 4, or a pharmaceutically acceptable salt thereof, for the treatment of NASH.

In another form, the present invention provides a compound according to any one of Formulae 1 to 4, or a pharmaceutically acceptable salt thereof, for use in therapy. In preferred embodiments, the present invention provides a compound according to any one of Formulae 1 to 4, or a pharmaceutically acceptable salt thereof, for the treatment of a liver disorder. The liver disorder may be selected from: liver fibrosis, alcohol induced fibrosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the therapy is for the treatment of liver fibrosis. In another embodiment, the therapy is for NAFLD. In still yet another embodiment, the therapy is for NASH.

In yet another form, the present invention provides for the use of a compound according to Formulae 1 to 4, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a liver disorder. In preferred embodiments, the liver disorder is selected from: liver fibrosis, alcohol induced fibrosis, alcoholic steatosis, NAFLD, and NASH.

The term "pharmaceutically-acceptable salt" as used herein refers a salt of a compound of the invention considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl, et al., 2nd Revised Edition, Wiley- VCH, 2011 and S.M. Berge, et al.,

"Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

The pharmaceutical compositions for the present invention may be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable additive(s)" as used herein for the pharmaceutical compositions, refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the compositions or formulations and not deleterious to the patient. Examples of

pharmaceutical compositions and processes for their preparation can be found in

"Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012.

As used herein, the term "effective amount" refers to an amount that is a dosage, which is effective in treating a disorder, such as a liver disease including liver

inflammation, fibrosis, and steatohepatitis. The attending physician, as one skilled in the art, can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of mammal; its size, age, and general health; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of

administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.

As used herein, the terms "treating", "to treat", or "treatment", includes slowing, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease, which can include treating liver disease, such as, liver

inflammation, fibrosis, and steatohepatitis.

As used herein, the term "patient" refers to a mammal, preferably the patient is a human or companion mammal, such as, a dog or cat.

A treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need.

Preferred pharmaceutical compositions can be formulated as a tablet or capsule for oral administration, a solution for oral administration or an injectable solution. The tablet, capsule, or solution can include a compound of the present invention in an amount effective for treating a patient in need of treatment.

The abbreviations used herein are defined according to Daub G.H., et al, "The Use of Acronyms in Organic Chemistry" Aldrichimica Acta, 1984, 17(1), 6-23. Other abbreviations are defined as follows: "Boc" refers to tert-butoxycarbonyl; "DBAD" refers to dibenzyl azodicarboxylate; "DCM" refers to dichloromethane; "DIPEA" refers to N,N-diisopropylethylamine; "DMF" refers to dimethylformamide; "DMSO" refers to dimethylsulfoxide; "EDTA" refers to ethylenediaminetetraacetic acid; "EGTA" refers to ethylene glycol tetraacetic acid; "ES/MS" refers to electrospray mass spectroscopy;

"EtOAc" refers to ethyl acetate; "EtOH" refers to ethanol or ethyl alcohol; "HATU" refers to (dimethylamino)-N,N-dimethyl(3H-[l,2,3]triazolo[4,5-^]pyridin-3-yloxy)methaniminium hexafluorophosphate; "HEPES" refers to 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid; "hr or hrs" refers to hour or hours; "IC50" refers to the concentration of an agent which produces 50 % of the maximal inhibitory response possible for that agent (relative IC50), or the concentration of an agent which produces 50 % inhibition of the target activity compared to placebo control (absolute IC50); "IU" refers to International units; LCMS" refers to liquid chromotrography mass spectrometry; "MAOa and MAOb" refers to monoamine oxidase a and b isoform, respectively;

"MeOH" refers to methyl alcohol or methanol; "min" or mins refers to minutes;

"MTBE" refers to methyl t-butyl ether; NASH" refers to Nonalcoholic steatohepatitis; "NMP" refers to N-m ethyl- pyrrolidone or 1 -methyl -2-pyrrolidinone; PE refers to petroleum ether; t(R> = retention time; "sat" refers to a saturated solution; "SS AO" refers to semicarbazide-sensitive amine oxidase; "hSSAO" refers to human SSAO; and "TG" refers to triglyceride; "THF" refers to tetrahydrofuran.

In the preparations described herein the hydroxyl and amino functionalities can be protected to facilitate the synthesis of the compounds described herein. Examples of protecting functionalities can be found in "Greene's Protective Groups in Organic Synthesis," Wuts, P.G.M., et al, Eds. 5th Ed., John Wiley and Sons, 2014. Other functional groups that can be readily converted to the hydroxyl group or the amino group can be used. Such functional groups, preparations, and transformations of these groups can be found in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Larock. R.C., Wiley VCH, 1999 and in "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure," Smith, M.B., Ed., 7th Ed., Wiley-Interscience, 2013.

The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures some of which are illustrated in the Schemes, Preparations, and Examples below. The products of each step in the Schemes below can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by methods such as selective

crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" ', John Wiley and Sons, Inc., 1981, and E.L Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). In the Schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.

Scheme 1

Step 1 Step 2

A B

PG is a protecting group

Scheme 1 depicts a generic synthesis of compounds of Formula 1, where "PG" is a protecting group for the hydroxyl group. Specifically in Step 1, substep 1, the chloro of compound A can be replaced with the nitrogen of an Rl substituted cyclic amine to give compound B. In Step 1, substep 2 deprotection of the hydroxyl group can be

accomplished by a variety of methods dependent upon the specific protecting group. In step 2, substep 1, the resulting hydroxyl of compound B can be alkylated with a suitably protected amine 2-bromo-3-fluoro-propyl-2-en-amine, to give compounds of Formula 1. The alkylation typically can be accomplished under basic conditions. The protected amine can be deprotected to give compounds of Formula 1.

Preparations and Examples

The following Preparations and Examples further illustrate the invention and represent typical synthesis of the compounds of the invention.

Preparation 1

tert-Butyl 4-(5-bromo-2- ridyl)-2-oxo-piperazine- 1 -carboxylate

Add triethylamine (2.4 mL, 17 mmol), DMAP (160 mg, 1.30 mmol) and tert-

butoxycarbonyl tert-butyl carbonate (1.87 g, 1.1 equiv., 8.59 mmol) to a solution of 4-(5-bromo-2-pyridyl)piperazin-2-one (2.00 g, 7.81 mmol) in DCM (45 mL). Stir the reaction mixture at 25 °C for 3 days to give a yellow suspension. Add DCM (50 mL) to the reaction and wash the mixture with brine (5 x 50 mL). Concentrate the organic layer to give the crude product as a yellow solid. Subject the material to silica gel

chromatography eluting with a gradient of 0 to 50% EtOAc in PE to give the title compound (1.57 g, 55%) as white solid.

Preparation 2

Jert-Butyl 2-oxo-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- pyridyl]piperazine-l-carboxylate

Add to a suspension of tert-butyl 4-(5-bromo-2-pyridyl)-2-oxo-piperazine-l-carboxylate (1.57 g, 4.41 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.23 g, 1.1 equiv., 4.85 mmol) and potassium acetate (1.29 g, 3.00 equiv., 13.2 mmol) in 1,4-dioxane (30 mL) Pd(dppf)Ch) (0.32 g, 0.1 equiv., 0.441 mmol) at 25 °C. Degas the reaction mixture while stirring at 100 °C under N2 for 1 hr. Filter the reaction mixture and concentrate the filtrate to give the crude product as a yellow oil. Subject the material to silica gel chromatograph eluting with a gradient of 0 to 50% EtOAc in PE to give the title compound (1.70 g, 96%) as pale yellow solid.

Preparation 3

tert-Butyl 4-(5-hydrox -2-pyridyl)-2-oxo-piperazine- 1 -carboxylate

Add sodium hydroxide (aq. 2 mL, 1 M) and hydrogen peroxide (aq. 2 mL, 30

mass%) to a suspension of tert-butyl 2-oxo-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-l-carboxylate (500 mg, 1.24 mmol) in THF (5 mL, 61.6 mmol) at 0 °C. Stir the reaction mixture at 25 °C for 2 hrs. Quench the reaction with saturated Na2S03 solution and adjust the pH to 6-7 with 1 M HC1. Extract the mixture with EtOAc (3 x 20 mL) and concentrate the combined organic extracts to give a crude product as a yellow oil. Subject the crude product to silica gel chromatography eluting with a gradient of 0 to 70 % of EtOAc in PE to give the title compound (120 mg, 33%) as yellow solid. LCMS (m/z): 294.0 [M+H]+.

Preparation 4

1 -Methyl -3-( -pyridyloxy)pyrrolidin-2-one

Dropwise add a solution of DBAD (3.06 g, 13.0 mmol) in THF (10 mL) to a solution of 3 -hydroxy- l-methyl-pyrrolidin-2-one (500 mg, 4.34 mmol), pyridin-4-ol (0.826 g, 8.69 mmol) and (n-butyl)3P (2.72 g, 13.0 mmol) in DCM (9 mL) and THF (15 mL) at 0 °C and stir the reaction mixture at room temperature for 4 hrs. Concentrate the reaction mixture under vacuum and purify the residue by silica gel flash chromatography eluting with a gradient of 0.5-10% MeOH in DCM to give the title compound (300 mg, 32% yield) as a light yellow oil. LCMS (m/z): 193.0 [M+H]+, ¾ MR (400 MHz, CDC13) δ 8.50 - 8.35 (m, 2H), 7.00 - 6.87 (m, 2H), 4.94 (dd, J = 6.0, 7.6 Hz, 1H), 3.56 -3.46 (m, 1H), 3.44-3.32 (m, 1H), 2.93 (s, 3H), 2.63-2.50 (m, 1H), 2.21-2.09 (m, 1H).

Preparation 5

3-(l-Benzylpyridin-l -ium-4-yl)oxy-l -methyl -pyrrolidin-2-one bromide

Add bromomethylbenzene (0.534 g, 3.12 mmol) to a mixture of l-methyl-3-(4-pyridyloxy)pyrrolidin-2-one (5, 300 mg, 1.56 mmol) in DMF (8.0 mL) and warm the reaction mixture to 55 °C for 16 hrs. Concentrate the reaction mixture under vacuum, dilute with water (20 mL) and extract with EtOAc (2 x 10 mL). Concentrate the aqueous layer under vacuum to give the title compound (450 mg, 71.4%) as a white solid. ¾

MR (400 MHz, d6-DMSO) δ 9.04 (d, J= 7.2 Hz, 2H), 7.75 (d, J= 7.6 Hz, 2H), 7.56 -7.48 (m, 2H), 7.47 - 7.33 (m, 3H), 5.72 (s, 2H), 5.61 (t, J= 8.0 Hz, 1H), 3.42 - 3.37 (m, 5H), 2.70-2.58 (m, 1H), 2.17 - 2.00 (m, 1H)

Preparation 6

3-[(l-Benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]-l -methyl -pyrrolidin

Add NaBH4 (212 mg, 5.58 mmol) to a solution of 3-(l-benzylpyridin-l-ium-4-yl)oxy-l -methyl -pyrrolidin-2-one bromide (450 mg, 1.12 mmol) in MeOH (8.0 mL) at 0 °C and stir the reaction mixture at 0 °C for 10 min. Dilute the reaction mixture with EtOAc (40 mL) and wash with NaHC03 (sat.aq.) (30 mL) and brine (30 mL). Dry the organic layer over anhydrous Na2S04, filter, and concentrate the filtrate under vacuum. Subject the crude product to silica gel flash chromatography eluting with a gradient of 0-1% MeOH in DCM to give the title compound (120 mg, 36%) as a colorless gum. LCMS (m/z): 287.1 [M+H]+, ¾ NMR (400 MHz, CDC13) δ 7.45-7.14 (m, 5H), 4.71 (t, J= 3.2 Hz, 1H), 4.62-4.50 (m, 1H), 3.74-3.50 (m, 2H), 3.50-3.40 (m, 1H), 3.40-3.25 (m, 1H),

3.18-3.06 (m, 1H), 3.05-2.95 (m, 1H), 2.89 (s, 3H), 2.75-2.65 (m, 1H), 2.55-2.47 (m, 1H), 2.43-2.30 (m, 1H), 2.25-2.15 (m, 2H), 2.06-1.94 (m, 1H)

Preparation 7

1 -Methyl -3-( -piperidyloxy)pyrrolidin-2-one

Add palladium on carbon (50% water, 10%w, 20.0 mg) to a solution of 3-[(l-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]-l-methyl-pyrrolidin-2-one (120 mg, 0.40 mmol) in EtOH (6.0 mL) and stir the reaction mixture at room temperature under a hydrogen atmosphere for 5 hrs. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate under vacuum to give the title compound (85.0 mg, 96.9%) as a colorless gum. ¾ MR (400 MHz, CDC13) δ 4.20-4.10 (m, 1H), 3.90-3.80 (m, 1H), 3.45-3.35 (m, 1H), 3.30-3.18 (m, 1H), 3.14-3.04 (m, 2H), 2.85 (s, 3H), 2.66-2.55 (m, 2H), 2.36-2.28 (m, 1H), 1.98-1.90 (m, 2H), 1.55-1.35 (m, 2H)

Preparation 8

tert-Butyl 2-cycloprop l-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Combine tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (161 mg, 0.60 mmol), copper(II) acetate (110 mg, 0.61 mmol) and cesium carbonate (98 mg, 0.30 mmol). Then add pyridine (145 mg, 1.83 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (203 mg, 1.21 mmol) and toluene (1.2 mL) via syringe. Heat the mixture to 110 °C for 64 hrs. Wash the mixture with EtOAc and filter through diatomaceous earth. Concentrate the filtrate and subject the residue to silica gel flash chromatography eluting with 50% EtOAc in hexanes to give the title compound as a light yellow oil. LCMS (m/z): 317.3 [M+Na]+

Preparation 9

2-Cyclopropyl-2,8-diazaspiro[4.5]decan-l-one hydrochloride

Dissolve tert-butyl 2-cyclopropyl-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (172 mg, 0.555 mmol) in HCI in MeOH (6.0 mL, 3 mmol, 0.5 mmol/mL) and heat to 80 °C for 50 min. Concentrate the mixture under vacuum to give the title compound as a pale brown oil which is used without further purification. LCMS (m/z): 195.3 [M+H]+

Preparation 10

01 -tert-Butyl 04-methyl 4-(2-bromoethyl)piperidine- 1 ,4-dicarboxylate

Add lithium diisopropylamide in hexanes (9.70 mL, 19.396 mmol, 2 mol/L) dropwise at -78 °C under N2 to a solution of Ol-tert-butyl 04-methyl piperidine-1,4-dicarboxylate (3.146 g, 12.93 mmol) in THF (45 mL). Stir the resulting mixture at -78 °C for 30 min and then add 1,2-dibromoethane (2.23 mL, 25.861 mmol). Allow the resultant mixture to warm to room temperature and stir for 1 hr. Quench the reaction with sat. H4CI aq. (20 mL), and extract with EtOAc (2 x 30 mL). Combine the organic extracts, dry over Na2S04, filter, and concentrate to dryness. Purify the crude material via silica gel flash chromatography eluting with 20% EtOAc in hexanes to give the title compound (0.698 g, 15%) as yellowish oil. LCMS (m/z): (79Br/81Br) 372.2/374.2 [M+Na]+

Preparation 11

tert-Butyl 2-/er/-butyl-l-oxo- -diazaspiro[4.5]decane-8-carboxylate

Dissolve Ol-tert-butyl 04-methyl 4-(2-bromoethyl)piperidine-l,4-dicarboxylate (698 mg, 1.89 mmol) in MeOH (5 mL) and add 2-methylpropan-2-amine (1.59 mL, 15.1 mmol). Heat the solution to 120 °C via microwave irradiation for 16 hrs. Concentrate the solution, then purify the residue via silica gel flash chromatography eluting with 25% EtOAc in hexanes to give the title compound (74 mg, 11%) as light yellow oil. LCMS (m/z): 333.3 [M+Na]+

Preparation 12

2-tert-Butyl-2,8-diazaspi can-l-one hydrochloride

Dissolve tert-butyl 2-tert-butyl-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (74 mg, 0.21 mmol) in HCI in MeOH (5 mL, 2.5 mmol, 0.50 mmol/mL) and heat to 80 °C via microwave irradiation for 5 min. Concentrate the solution to give the title compound (56 mg, 95%) as light yellow oil. LCMS (m/z): 211.2 [M+H]+

Preparation 13

2-Methyl -2, 8 -di azaspiro [4.5 ] decan- 1 -one hy drochl ori de

Cool tert-butyl 2-methyl-l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (45.2 g, 168 mmol) to 0 °C. Add HCI in MeOH (250 mL, 4.0 M) and stir the solution vigorously for 30 minutes. Warm the mixture to room temperature, stir for 5 hrs, and then concentrate to dryness to give the title compound (34.6 g, 98.4%) as a pale yellow solid. ES/MS (m/z) 169.2 (M+H).

Preparation 14

tert-Butyl N-[(E)-2-[(2-chloropyrimidin-5-yl)oxymethyl]-3-fluoro-allyl]carbamate

Add potassium carbonate (1.126 g, 8.14 mmol) to a solution of 2-chloropyrimidin-5-ol (501 mg, 3.84 mmol) and fert-butyl N-[(E)-2-(bromomethyl)-3-fluoro-allyl]carbamate (507 mg, 1.89 mmol) in DMF (10 mL) and stir the resulting mixture at room temperature overnight. Quench the reaction by adding water and EtOAc and extract the aqueous phase with EtOAc (3 x 50 mL). Combine the organic extracts, dry the solution over Na2S04, filter, and concentrate the filtrate under vacuum. Subject the material to silica gel flash chromatography with EtOAc in hexanes to give the title compound as a white solid (658 mg, 87%). LCMS (ESI): m/s 340.2 [M+Na]+.

Preparation 15

8-(5-Benzyloxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-l-one

Add DIPEA (1.7 g, 13 mmol) and 5-benzyloxy-2-chloro-pyrimidine (0.61 g, 2.8 mmol) to a mixture of 2-methyl-2,8-diazaspiro[4.5]decan-l-one hydrochloride (0.50 g, 2.6 mmol) in MP (10 mL). Stir the reaction mixture at 100 °C for 20 hrs. Then dilute the reaction mixture with water (40 mL) and extract with EtOAc (2 x 20 mL). Combine the organic extracts; wash with brine (3 x 20 mL); dry over anhydrous Na2S04; filter; and concentrate the filtrate under vacuum to provide a residue. Subject the residue to flash chromatography on silica gel eluting with a gradient of 0-1% MeOH in DCM to give the title compound (0.39 g, 42%) as a light yellow solid. ¾ MR (400 MHz, CDCb) 5 8.11

(s, 2H), 7.45-7.30 (m, 5H), 5.79 (s, 1H), 5.02 (s, 2H), 4.55-4.45 (m, 2H), 3.38 (t, J = 6. Hz, 2H), 3.21-3.10 (m, 2H), 2.15 (t, J = 6.8 Hz, 2H), 1.98-1.85 (m, 2H), 1.55-1.43 (m, 2H).

Preparation 16

l-(5-Benzyloxypyrimidin-2-yl)piperidine-4-carboxamide

Stir a mixture of 5-benzyloxy-2-chloro-pyrimidine (400 mg, 1.81 mmol), piperidine-4-carboxamide (0.28 g, 1.2 equiv., 2.18 mmol) and DIPEA (2.0 equiv., 3.63 mmol) in DMF (6 mL) at 100 °C under N2 for 17 hrs. Pour the reaction mixture into water (60 mL) and filter. Wash the filter cake with EtOAc (30 mL) and stir the material for 0.5 hr. Filter the solution and dry the filter cake under reduced pressure to give the title compound (310 mg, 49%) as a pink solid. ¾ NMR: (400 MHz, CD3OD) δ 8.13 (s, 2H), 7.47-7.28 (m, 5H), 5.07 (s, 2H), 4.67-4.60 (m, 2H), 2.95-2.84 (m, 2H), 2.50-2.40 (r 1H), 1.85-1.75 (m, 2H), 1.68-1.60 (m, 2H).

Preparation 17

8- (5-Benzyloxypyrimidin-2- l c -2-chloro -diazaspiro l- [4.5] of

Add together 5-benzyloxy-2-chloro-pyrimidine (79 mg, 0.36 mmol) and potassium carbonate (164 mg, 1.19 mmol). Dissolve 2-cyclopropyl-2,8-diazaspiro[4.5]decan-l-one;hydrochloride (72 mg, 0.30 mmol) in EtOH (3.0 mL) and add to the reaction mixture. Heat the reaction to 110 °C via microwave irradiation for 62 hrs. Dilute the mixture with EtOAc and filter the slurry through diatomaceous earth.

Concentrate the filtrate and purify the crude mixture via silica gel flash chromatography eluting with 55% EtOAc in hexanes to give the title compound (40 mg, 35%) as white solid. LCMS (m/z): 379.2 [M+H]+.

Preparation 18

8-(5-Benzyloxypyrimidin-2-yl)-2-/er/-butyl-2,8-diazaspiro[4.5]di

Add MP (1 mL) to 2-/er/-butyl-2,8-diazaspiro[4.5]decan-l-one;hydrochloride (56 mg, 0.20 mmol), 5-benzyloxy-2-chloro-pyrimidine (54 mg, 0.25 mmol) and potassium carbonate (113 mg, 0.82 mmol). Heat the mixture to 120 °C via microwave irradiation for 16 hrs. Dilute the mixture with EtOAc and filtrate it through diatomaceous earth. Concentrate the filtrate to provide a residue and subject the residue to silica gel flash chromatography eluting with 25% EtOAc in hexanes to give the title compound (16 mg, 19% yield) as a white solid. LCMS (m/z): 395.3 [M+H]+

Preparation 19

9-(5-Benzyloxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-l-one

Dissolve tert-butyl l-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (1.907 g, 6.96 mmol) in DCM (50 mL) and add trifluoroacetic acid (10 mL) at room temperature with stirring. Stir the resultant solution for 4 hrs. Concentrate the solution to give an intermediate 2,9-diazaspiro[5.5]undecan-l-one;2,2,2-trifluoroacetic acid (2.096 g, 6.683 mmol) as a light yellow oil. Add to the crude mixture 5-benzyloxy-2-chloro-pyrimidine (880 mg, 3.99 mmol), cuprous iodide (158 mg, 0.830 mmol), N,N'-bis(2-phenoxyphenyl)oxamide (220 mg, 0.804 mmol) and potassium phosphate tribasic (2.612 g, 12.06 mmol) with DMF (10 mL). Stir the resultant mixture under N2 and heat to 100 °C for 6 hrs. Dilute the mixture with EtOAc and filter through diatomaceous earth.

Concentrate the filtrate and subject the resulting crude material to silica gel flash chromatography eluting with 7% MeOH in DCM to give the title compound (869 mg, 61%) as a yellow solid. LCMS (m/z): 353.2 [M+H]+

Preparation 20

8-(5-Benzyloxypyrimidin-2-yl)-2-methyl-2,8-diazaspiro[4.5]di

Add sodium hydride in mineral oil (60 mass%, 66 mg, 1.6 mmol) to a solution of 8-(5-benzyloxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-l-one (0.39 g, 1.1 mmol) in DMF (8.0 mL); stir the mixture at 0 °C for 20 min. Add iodomethane (0.31 g, 2.2 mmol) to the cold (0 °C) mixture. Allow the mixture to warm to ambient temperature and stir the mixture for 1 hr. Quench the reaction with water (30 mL). Extract the resulting mixture with EtOAc (2 x 15 mL). Combine the organic extracts and wash with brine (2 x 20 mL); dry over anhydrous Na2S04; filter; and concentrate the filtrate under vacuum to give the title compound (0.42 g, 98%) as a yellow solid, which can be used without further purification. ¾ NMR (400 MHz, CDCb) δ 8.04 (s, 2H), 7.38-7.24 (m, 5H), 4.95 (s, 2H),

4.42 (dt, J = 4.0, 13.6 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 3.15-3.02 (m, 2H), 2.79 (s, 1.96 (t, J = 6.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.42-1.34 (m, 2H).

Alternate Preparation 20

8-(5-Benzyloxypyrimidin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-l-one Combine 5-benzyloxy-2-chloro-pyrimidine (24.824 g, 112.50 mmol), 2-methyl- 2,8-diazaspiro[4.5]decan-l-one hydrochloride (29.736 g, 145.27 mmol) and potassium carbonate (46.643 g, 337.50 mmol) in MP. Add MP (170 mL) and triethylamine (23.5 mL, 168.75 mmol) and heat the mixture to 130 °C for 30 hrs. Cool the mixture, filter to collect the solid, then wash the solid with EtOAc. Concentrate the filtrate and pour the concentrated solution into crushed ice (about 1.2 L). A light brown solid precipitates immediately. Stir the mixture for 30 min and then allow the mixture to stand at room temperature overnight. Filter the mixture to collect the solid and wash the solid with MTBE (400 mL). Dry the solid under vacuum at 50 °C for 1.5 days to give the title compound (36.924 g, 88.48%) as a pale brown solid, which can be used without further purification. ES/MS (m/z) 353.3 (M+H).

Preparation 21

8-(5-Benzyloxypyrimidi -2-yl)-2-(cyclopropylmethyl)-2,8-diazaspiro[4.5]decan-l-one

Add sodium hydride in mineral oil (22 mg, 0.55 mmol, 60 mass%) to a stirred solution of 8-(5-benzyloxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decan-l-one (60 mg, 0.18 mmol) in DMF (5.0 mL) at 0 °C. Allow the mixture to warm to room temperature and stir for 5 min. Add (bromomethyl)cyclopropane (100 mg, 0.71 mmol) and stir the resulting mixture at room temperature for 16 hrs. Evaporate the solvent under reduced pressure to give the crude product. Subject the material to silica gel flash chromatography eluting with 40% EtOAc in hexanes to give the title product (40 mg, 55%) as a white solid. LCMS (m/z): 392.2 [M+H]+

Preparation 22

9-(5-Benzyloxypyrimidin-2- l -2-meth l-2 9-diazas iro[5.5]undecan- 1 -one

Dissolve 9-(5-benzyloxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-l-one (183 mg, 0.51 mmol) in THF (8 mL) and cool the solution to 0 °C. Add sodium hydride (41 mg, 1.018 mmol, 60 mass%) in one portion. Stir the solution at 0 ° for 15 min. Add iodomethane (0.064 mL, 1.02 mmol) at 0 °, warm the mixture to room temperature and stir for 30 min. Cool the mixture to 0 ° add further sodium hydride (20 mg, 0.51 mmol) and stir for 15 min. Add iodomethane (0.032 mL, 0.51 mmol), warm the mixture to room temperature, and stir for 30 min. Add saturated H4CI (aq) to quench the reaction and dilute with EtOAc. Separate the organic phase and extract the aqueous phase with EtOAc (2x). Combine the organic extracts, dry over Na2S04, filter, concentrate the filtrate to ptovide a residue. Subject the residue to silica gel flash chromatography eluting with 75% EtOAc in hexanes to give the title compound (158 mg, 83%). LCMS (m/z): 367.2 [M+H]+

Preparation 23

8-(5-Hydroxypyrimidin-2- l)-2-methyl-2,8-diazaspiro[4.5]di

Add palladium on carbon (50% in water, 10% w, 42 mg) to a solution of 8-(5-benzyloxypyrimidin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-l-one (0.42 g, 1.1 mmol) in MeOH (40 mL). Stir the mixture at room temperature under a hydrogen atmosphere for 4 hrs and then at 40 °C for 6 hrs. Filter the mixture through a pad of diatomaceous earth. Concentrate the filtrate under vacuum to give the title compound (0.34 g, 97%) as a light yellow solid, which can be used without further purification. ¾ MR (400 MHz, CDCb) δ 8.05 (s, 2H), 4.54-4.44 (m, 2H), 3.37 (t, J = 7.2 Hz, 2H), 3.15-3.05 (m, 2H), 2.88 (s, 3H), 2.07 (t, J = 7.2 Hz, 2H), 1.96-1.88 (m, 2H), 1.45-1.40 (m, 2H), ES/MS (m/z) 262.9 (M+H).

What is claimed

1. A com ound of the formula below:

R2 is selected from: H, -C(0) H2, -C(0) H(CH3), -C(0)N(CH3)2,

R3 is H or CH3,

R5 is selected from: H, -Ci-4alkyl, -C3-4 cycloalkyl, -CH2-C3-4 cycloalkyl; and n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, which is:

where Rl is selected from:

R2 is selected from: H, -C(0) H2, -C(0) H(CH3), -C(0)N(CH3)2,

R3 is H or CH3;

R5 is selected from: H, -Ci-4alkyl, -C3-4 cycloalkyl, and -CH2-C3-4 cycloalkyl; and

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2 wherein Rl is selected

; or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3 wherein Rl

; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 wherein R5 is selected from:

-CH3, K , and ; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 or 2 wherein Rl is

)NH2, -C(0) H(CH3), -C(0)N(CH3)2,

, and ; or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6 wherein R3 is H.

8. A compound according to claim 6 wherein R4 is ; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, which is:

or a pharmaceutically acceptable salt thereof.

10. A com ound according to claim 1 or 2, which is:

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 which is provided as a mono or di hydrochloride addition salt.

12. A com ound according to claim 10 which is:

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier, diluent or excipient.

14. A method of treating a patient in need of treatment for nonalcoholic steatohepatitis wherein the method comprises administering to the patient an effective amount of a pharmaceutical composition according to claim 13.

15. A method of treating a patient in need of treatment for nonalcoholic steatohepatitis wherein the method comprises administering to the patient an effective amount of a compound according to any one of claims 1 to 12.

16. A compound according to any one of claims 1 to 12 for use in therapy.

17. A compound according to any one of claims 1 to 12 for use in the treatment of a non-alcoholic steatohepatitis.

18. Use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament to treat a non-alcoholic steatohepatitis.