DISUBSTITUTED PYRAZOLECOMPOUND

The present invention relates to novel ketohexokinase (KHK) inhibitor compounds, to pharmaceutical compositions comprising the compounds and to the use of the compounds for the treatment of certain conditions, such as type 2 diabetes mellitus (T2DM), heart failure, diabetic kidney disease and non-alcoholic steatohepatitis (NASH).

KHK, also referred to as fructokinase, is the rate-limiting enzyme involved in fructose metabolism. It catalyses the phosphorylation of fructose to fructose-1-phosphate (F1P), causing concomitant depletion of cellular ATP levels. In contrast to glucose, fructose metabolism lacks feedback inhibition and it triggers accumulation of downstream

intermediates involved in, for example, lipogenesis, gluconeogenesis and oxidative phosphorylation (Hannou, S.A., et al.; J. Clin. Invest., 128(2), 544-555, 2018). This has negative metabolic consequences which are associated with a number of serious metabolic disorders.

KHK exists in two alternatively spliced isoforms consisting of KHK-C and KHK-A differing in exon 3. KHK-C is expressed primarily in the liver, kidney and intestine, whereas KHK-A is more ubiquitous. Mice deficient in both isoforms are fully protected from fructose-induced metabolic syndrome. However, the adverse metabolic effects are exacerbated in mice lacking KHK-A only (Ishimoto T, et al.; Proc. Natl. Acad. Sci. USA, 109(11), 4320-4325, 2012).

Several epidemiologic and experimental studies have reported that increased consumption of fructose, and more precisely increased fructose metabolism, may play an important role in the development of certain disorders, including metabolic syndrome and in particular, in the development of T2DM (Softic et al.; J. Clin. Invest., 127(11), 4059-4074, 2017), heart failure (Mirtschink, P., et al.; Eur. Heart J., 39, 2497-2505, 2018), diabetic kidney disease (Cirillo, P., et al.; J. Am. Soc. Nephrol., 20, 545-553, 2009) and

NAFLD/NASH (Vos, M.B., et al.; Hepatology, 57, 2525-2531, 2013). Targeting inhibition of KHK is expected to limit fructose metabolism and provide effective treatment options for a number of metabolic disorders.

US 2017/0183328 A1 discloses substituted 3-azabicyclo[3.1.0]hexanes as KHK inhibitors. Recently published data shows that ketohexokinase inhibitor PF-06835919 administered for 6 weeks reduces whole liver fat as measured by magnetic resonance imaging-proton density fat fraction in subjects with non-alcoholic fatty liver disease (J. Hepatology. EASL International Liver Congress Abstracts, Supplement N°1S Vol.70, April 2019).

Compounds containing carboxylic functional groups carry a risk associated with the formation of acyl glucuronide metabolites (Vleet Van et al., Toxicology Letters, 272 (2017) 1-7). Acyl glucuronide metabolites are often unstable and may be chemically reactive leading to covalent bonding with macromolecules and toxicity.

There is a need for alternate treatments for metabolic syndrome and associated indications including T2DM, heart failure, diabetic kidney disease and NASH. In particular, there is a need for compounds which are potent inhibitors of KHK. There is a need for KHK inhibitor compounds having advantageous properties, for example, good oral bioavailability to support once daily dosing. Furthermore, there is a need for KHK inhibitor compounds which do not have a carboxylic acid moiety and lack the ability to form acyl glucuronides.

Accordingly, in one embodiment, the present invention provides a compound of the Formula I:

Formula I

wherein

X is N, or C substituted with CN;

R1 is selected from: H,

and ;

R2 and R3 are both H, or one is H and the other is OH;

R4, R5, R6, R7 and R9 are independently H or CH3;

R8 is H, CH3, CH2CH2OH, C(=O)CH2NH2, or C(=O)CH3; and R10 is OH or NH2;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, R1 is selected from: H,

,

,

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, there is provided a compound of Formula I wherein X is N or C substituted with CN;

R1 is selected from:

; and wherein

R2 is H and R3 is OH,

or R2 is OH and R3 is H,

or R2 and R3 are both H;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the compound is of Formula Ia:

Formula Ia;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the compound is of Formula Ic:

Formula Ic;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the compound is of Formula Ie:

Formula Ie;

or a pharmaceutically acceptable salt thereof.

In an embodiment, X is N.

In an embodiment, X is C substituted with CN.

In an embodiment, R1 is .

In an embodiment, the compound of Formula I is:

, or a pharmaceutically acceptable salt thereof.

In a particular embodiment, there is provided a succinate salt of

.

In a preferred embodiment, the succinate salt is the sesquisuccinate salt.

In an embodiment, the compound of Formula I is:

,

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is:

, or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is:

, or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is:

, or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is:
,

or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is:

,

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the compound is selected from:

2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]-1-piperazin-1-yl-ethanone;

[(2R)-1-[4-[1-(4-piperidyl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-2-yl]methanol;

[(2R)-1-[4-[1-(azetidin-3-yl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-2-yl]methanol;

(2S,3R)-1-[4-[1-(azetidin-3-yl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]-2-methyl-azetidin-3-ol;

2-[4-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]pyrazol-1-yl]-N-(2-hydroxyethyl)acetamide;

2-[(2R)-2-(hydroxymethyl)azetidin-1-yl]-6-[1-(4-piperidyl)pyrazol-4-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6-[1-(4-piperidyl)pyrazol-4-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S)-2-methylazetidin-1-yl]-6-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-[1-(2-hydroxyethyl)-4-piperidyl]pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S)-2-methylazetidin-1-yl]-6-[1-(4-piperidyl)pyrazol-4-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S)-2-methylazetidin-1-yl]-4-[1-(4-piperidyl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidine;

(2S,3R)-2-methyl-1-[4-[1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-ol;

(2S,3R)-2-methyl-1-[4-[1-[(3S)-pyrrolidin-3-yl]pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-ol;

[(2R)-1-[4-[1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-2-yl]methanol;

6-[1-(azetidin-3-yl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-[1-(2-aminoacetyl)-4-piperidyl]pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-(1-acetyl-4-piperidyl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S)-2-methylazetidin-1-yl]-6-[1-[2-(4-methylpiperazin-1-yl)-2-oxo-ethyl]pyrazol-4-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[4-[5-cyano-6-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)-2-pyridyl]pyrazol-1-yl]-N,N-bis(2-hydroxyethyl)acetamide;

6-[1-[2-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-[2-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-(2,3-dihydroxypropyl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S)-2-methylazetidin-1-yl]-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)pyridine-3-carbonitrile;

2-[(2S)-2-methylazetidin-1-yl]-6-(1-tetrahydropyran-4-ylpyrazol-4-yl)-4-(trifluoromethyl)pyridine-3-carbonitrile;

6-[1-(3-hydroxy-4-piperidyl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile;

N-(2-aminoethyl)-2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]acetamide;

2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]-1-[(3S)-3-methylpiperazin-1-yl]ethanone;

2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]-1-[(2S)-2-methylpiperazin-1-yl]ethanone;

1-(3,3-dimethylpiperazin-1-yl)-2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]ethanone;

1-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]ethanone;

4-[1-(azetidin-3-yl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidine;

2-[(2S)-2-methylazetidin-1-yl]-4-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidine;

(2S,3R)-2-methyl-1-[4-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-ol; or

[(2R)-1-[4-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-2-yl]methanol;

or a pharmaceutically acceptable salt thereof.

In a particular embodiment, the compound is 2-[4-[2-[(2S)-2-Methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl]pyrazol-1-yl]-1-piperazin-1-yl-ethanone sesquisuccinate, which is also known as ethanone, 2-[4-[2-[(2S)-2-methyl-1-azetidinyl]-6-(trifluoromethyl)-4-pyrimidinyl]-1H-pyrazol-1-yl]-1-(1-piperazinyl)-, butanedioate (1:1.5) or butanedioic acid-2-(4-{2-[(2S)-2- methylazetidin-1-yl]-6-( trifluoromethyl)pyrimidin-4-yl}-1H-pyrazol-1-yl)-1-(piperazin-1-yl)ethan-1-one (1.5/1).

Formula I encompasses Formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih and reference to Formula I below, for example in the methods of treatment and therapeutic uses, is also be read as a reference to each and all of these sub-formulae.

In an embodiment, there is provided a method of treating T2DM in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In an embodiment, there is provided a method of treating heart failure in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In an embodiment, there is provided a method of treating diabetic kidney disease in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In an embodiment, there is provided a method of treating NASH in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In an embodiment, there is provided a method of treating a disease selected from the group consisting of metabolic syndrome, NAFLD, obesity, cardiovascular disease, coronary artery disease, chronic kidney disease, dyslipidemia and diabetic complications for example diabetic retinopathy, in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Furthermore, in an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating T2DM. In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating heart failure. In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating diabetic kidney disease. In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating NASH. In an embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating metabolic syndrome, NAFLD, obesity, cardiovascular disease, coronary artery disease, chronic kidney disease, dyslipidemia or diabetic complications for example diabetic retinopathy.

Furthermore, in an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating T2DM. In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating heart failure. In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating diabetic kidney disease. In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a

medicament for treating NASH. In an embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating metabolic syndrome, NAFLD, obesity, cardiovascular disease,

coronary artery disease, chronic kidney disease, dyslipidemia or diabetic complications for example diabetic retinopathy.

In an embodiment, there is provided a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients. In an embodiment, there is provided a process for preparing a pharmaceutical composition, comprising admixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.

As used herein, the terms“treating” or“to treat” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

As used herein, the term "patient" refers to a mammal. Preferably, the patient is human.

As used herein, the term“effective amount” refers to the amount or dose of compound of Formula I, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.

An effective amount can be determined by one skilled in the art by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. The compounds of Formula I are effective at a dosage per day that falls within the range of about 0.1 to about 15 mg/kg of body weight.

The compounds of Formula I are formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable. Preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes

for preparing same are well known in the art (See, e.g., Remington, J. P.,“Remington: The Science and Practice of Pharmacy”, L.V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012).

The compounds of Formula I and the pharmaceutically acceptable salts thereof may be used in the methods of treatment and therapeutic uses of the invention, with certain configurations being preferred. It will be understood that the following preferences are applicable both to the treatment methods, the therapeutic uses and to the compounds of the invention.

Compounds of the present invention include:

and pharmaceutically acceptable salts thereof.

Although the present invention contemplates all individual enantiomers and diasteromers, as well as mixtures of said compounds, including racemates, compounds of Formula Ia, Formula Ic and Formula Ie, and pharmaceutically acceptable salts thereof, are particularly preferred.

Individual enantiomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of Formula I, by methods such as selective crystallization techniques, 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), or supercritical fluid chromatography (SFC) (See for example, T. A. Berger;“Supercritical Fluid Chromatography Primer,” Agilent Technologies, July 2015).

A pharmaceutically acceptable salt of the compounds of Formula I can be formed, for example, by reaction of an appropriate free base of a compound of Formula I and an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art (See, for example, Bastin, R.J., et al.; Org. Process. Res. Dev., 4, 427-435, 2000 and Berge, S.M., et al.; J. Pharm. Sci., 66, 1-19, 1977). A preferred salt is a succinate salt. A particularly preferred salt is the sesquisuccinate salt. In the sesquisuccinate salt, the ratio of free base:succinate is 1:1.5. The succinate salt is also known as the butanedioate salt.

The compounds of Formula I, or salts thereof, may be prepared by a variety of procedures known to one of ordinary skill in the art, 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 well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. 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.

Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention. In addition, one of ordinary skill in the art appreciates that compounds of Formula I may be prepared by using starting material or intermediate with the corresponding desired stereochemical configuration which can be prepared by one of skill in the art.

Certain abbreviations are defined as follows:“ACN” refers to acetonitrile;“BOC” refers to tert-butoxycarbonyl;“DCM” refers to methylene chloride or dichloromethane; “DIPEA” refers to N,N-diisopropylethylamine;“DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide;“ELSD” refers to Evaporative light scattering detector;“ES/MS” refers to Electrospray Mass Spectrometry;“EtOAc” refers to ethyl acetate;“EtOH” refers to ethanol or ethyl alcohol;“h” refers to hour or hours;“HATU” refers to 1-[Bis(dimethyl-amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;“HPLC” refers to high-performance liquid chromatography;“IPA” refers to isopropyl alcohol;“Me” refers to methyl;“MeOH” refers to methanol;“MTBE” refers to methyl-tert-butyl ether;“min” refers to minute or minutes;“m/z” refers to mass-to-charge ratio;“Ph” refers to phenyl;”RBF” refers to round bottom flask;“RT” refers to room temperature;“SCX” refers to selective cation exchange;“SEM” refers to standard error of

the mean;“SFC” refers to supercritical fluid chromatography;“TFA” refers to trifluoroacetic acid;“THF” refers to tetrahydrofuran.

Scheme 1 depicts the general preparation of the compounds of Formula I. R1a may be the same as R1 in the final compound of Fomula I or it may be a group requiring

transformation to reach R1 of Formula I. The routine synthetic transformations of R1a, such as BOC-deprotection, ester hydrolysis and amide coupling reactions may be performed either before or after Step B. In Step A, a Suzuki cross-coupling reaction between heteroaryl dichloride 1 and pyrazole boronate ester 2 yields substituted pyrazole compound 3. This reaction is performed using a base, for example 2 M aqeueous Na2CO3, in an organic solvent, for example 1,4-dioxane, in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) dichloride, at elevated temperature. In Step B, compound 3 is subjected to a nucleophilic aromatic substitution reaction with substituted azetidine 4 to give a compound of Formula I. This reaction is performed in the presence of an organic base, such as DIPEA, in an organic solvent, such as 1,4-dioxane, at elevated temperature.

Scheme 2 depicts the preparation of a subset of the compounds of Formula I wherein the pyrazole is substituted with a nitrogen-containing heterocycle (Formula I’). Pyrazole boronate ester 5 is substituted with a nitrogen containing heterocycle as depicted in Scheme 2, wherein“Y” and“Z” may each independently be -CH2- or -CH2-CH2-, and“PG” is a nitrogen protecting group such as BOC. In Step C, a Suzuki cross-coupling reaction between heteroaryl dichloride 1 and pyrazole boronate ester 5 yields substituted pyrazole compound 6. As described in Step A of Scheme 1, this reaction is performed using a base, for example 2 M aqeueous Na2CO3, in an organic solvent, for example 1,4-dioxane, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or

bis(triphenylphosphine)palladium(II) dichloride, at elevated temperature. Two different routes can be taken as depicted in Scheme 2, Route A and Route B.

In Route A, substituted pyrazole compound 6 undergoes deprotection in Step D to give compound 7. For example if“PG” is BOC, deprotection can be accomplished with TFA. In Step E, the heterocyclic nitrogen of compound 7 can undergo substitution reactions, for example reductive amination, acylation, or amide coupling to give compound 8. Such substitutions are depicted as“R” in this scheme. In Step F, compound 8 is subjected to a nucleophilic aromatic substitution reaction with substituted azetidine 4 to give compound of Formula I’. As described in Step B of Scheme 1, this reaction is performed in the presence of an organic base, such as DIPEA, in an organic solvent, such as 1,4-dioxane, at elevated temperature. This may be the final step or alternatively, the R group may be subjected to futher routine synthetic transformations such as protecting group removal.

In Route B, substituted pyrazole compound 6 undergoes nucleophilic aromatic substitution reaction in Step G with substituted azetidine 4 to give compound 9. This can be accomplished by nucleophilic aromatic substitution reaction with substituted azetidine 4 in the presence of an organic base, such as DIPEA, in an organic solvent, such as 1,4-dioxane at elevated temperature. Alternatively, Steps C and G can be accomplished in a one-pot procedure, wherein the Suzuki cross-coupling reaction of Step C is completed first, and then azetidine 4 is added to the reaction along with an organic base (e.g. DIPEA), and then Step G proceeds at elevated temperature. Protecting group“PG” is removed in Step H (e.g. with TFA if PG is BOC) to give compound 10. In Step I the nitrogen group of compound 10 can undergo substitution reactions, for example reductive amination, acylation, or amide coupling to give compound of Formula I’. This may be the final step or alternatively, the R group may be subjected to futher routine synthetic transformations such as protecting group removal.

Scheme 3 depicts the preparation of a subset of the compounds of Formula I wherein the pyrazole is substituted with an acetamide group (Formula I’’). In Step J, a Suzuki cross- coupling reaction between heteroaryl dichloride 1 and pyrazole boronate ester 11 yields substituted pyrazole compound 12. As described in Schemes 1 and 2, this reaction is performed using a base, for example 2 M aqeueous Na2CO3, in an organic solvent, for example 1,4-dioxane, in the presence of a palladium catalyst, such as

tetrakis(triphenylphosphine)palladium(0) or bis(triphenylphosphine)palladium(II) dichloride, at elevated temperature. In Step K, heteroaryl chloride 12 undergoes nucleophilic aromatic substitution with azetidine 4 in the presence of an organic base, such as DIPEA, in an organic solvent, such as 1,4-dioxane, at elevated temperature to give compound 13. In Step L, ester hydrolysis using a base e.g. sodium hydroxide gives acid 14. In Step M, acid 14 undergoes amide coupling reaction with an amine of the formula HNR’R” to give amide compound of

Formula I’’. The amine HNR’R” can be cyclic (e.g. an optionally substituted piperazine). Step M may be the final step or there may be further routine synthetic transformations such as protecting group removal.

Preparations and Examples

The following Preparations and Examples further illustrate various embodiments of the invention and represent typical synthesis of the compounds of the invention. The reagents and starting materials are readily available or may be readily synthesized by one of ordinary skill in the art. It should be understood that the Preparations and Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.

LC-ES/MS is performed on an AGILENT® HP1200 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a Mass Selective Detector quadrupole mass spectrometer interfaced to an HPLC which may or may not have an ELSD. LC-MS conditions (low pH): column:

PHENOMENEX® GEMINI® NX C182.0 × 50 mm 3.0 ^m, 110 Å; gradient: 5-95% B in 1.5 min, then 95% B for 0.5 min column temperature: 50 °C +/-10 °C; flow rate: 1.2 mL/min; 1 ^L injection volume; Solvent A: deionized water with 0.1% HCOOH; Solvent B: ACN with 0.1% formic acid; wavelength 200-400 nm and 212-216 nm. If the HPLC is equipped with an ELSD the settings are 45 °C evaporator temperature, 40 °C nebulizer temperature, and 1.6 SLM gas flow rate. Alternate LC-MS conditions (high

pH): column: Waters xBridge® C18 column 2.1×50 mm, 3.5 ^m; gradient: 5-95% B in 1.5 min, then 95% B for 0.50 min; column temperature: 50 °C +/-10 °C; flow rate: 1.2 mL/min; 1mL injection volume; Solvent A: 10 mM NH4HCO3 pH 9; Solvent B: ACN ; wavelength: 200-400 nm and 212-216nm; if had ELSD: 45˚C evaporator temp, 40˚C nebulizer temp, and 1.60 SLM gas flow rate.

The XRPD patterns of crystalline solids are obtained on a Bruker D4 Endeavor X-ray powder diffractometer, equipped with a CuK ^ source and a Vantec detector, operating at 35 kV and 50 mA. The sample is scanned between 4 and 402q°, with a step size of 0.0082q° and a scan rate of 0.5 seconds/step, and using 1.0 mm divergence, 6.6 mm fixed anti-scatter, and 11.3 mm detector slits. The dry powder is packed on a quartz sample holder and a smooth surface is obtained using a glass slide. The crystal form diffraction patterns are collected at ambient temperature and relative humidity. Crystal peak positions are determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.7742q°. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National

Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ± 0.22q° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.

Preparation 1

(2S)-1-Benzhydryl-2-methyl-azetidine [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1- yl]methanesulfonic acid salt

Assemble a 2000 mL 3-neck RBF with an addition funnel, nitrogen inlet and a thermometer adapter. Purge the vessel with nitrogen and add (3R)-butane-1,3-diol (25 g, 277 mmol), DIPEA (127 mL, 731 mmol) and ACN (556 mL). Cool the mixture to -30 °C. Add trifluoromethanesulfonic anhydride (101 mL, 601 mmol) dropwise over 3 h such that the internal temperature is maintained between -35 and -30 °C. After the completion of the addition, stir for 10 min at -35 to -30 °C. Add trifluoromethanesulfonic anhydride (1.9 mL, 11 mmol) dropwise over 5 min such that the internal temperature is maintained between -35 and -30 °C. After the completion of the addition, stir for 10 min at -35 to -30 °C. Add DIPEA (127 mL, 731 mmol) dropwise over 15 min such that the internal temperature is maintained between -35 and -30 °C. After the completion of the addition, stir for 10 min at -35 to -30 °C. In a separate flask under nitrogen, dissolve aminodiphenylmethane (48.0 mL, 270 mmol) in ACN (49 mL) and transfer the resulting solution to the addition funnel. Add the amine solution to the cold triflate dropwise over 40 min such that the internal temperature is maintained between -20 to -35 °C. After the completion of the addition, stir for 30 min at -35 to -30 °C. Transfer the reaction to a water bath and allow it to slowly warm over 30 min. Remove the bath and allow the reaction to warm to RT over 30 min. Transfer the vessel to a heating mantle and warm the reaction to 45 °C for 30 min, then cool to RT. Pour the resulting mixture into 1200 mL of water and extract with toluene (400 mL × 3). Combine the extracts and wash with water and saturated aqueous NaCl solution. Dry the organics over anhydrous Na2SO4, filter and concentrate in vacuo. Dry the residue under vacuum overnight, then dissolve it in DCM (400 mL). Prepare a silica gel pad on a fritted funnel and equilibrate it with 1:1 heptane/EtOAc. Load the product solution onto the silica gel pad and wash with 1600 mL of 1:1 heptane/EtOAc. Concentrate the filtrate to give a red oil. Dissolve the oil in MeOH (250 mL) and place the flask in a water bath (~10 °C). Add L(-)-camphorsulfonic acid (61.6 g, 265 mmol) portion-wise keeping the internal temperature below 20 °C. Stir the resulting mixture for 15 min and then concentrate in vacuo to give a brown foam. Dry the foam on a vacuum pump for 2 h. Dissolve the foam in DCM (130 mL), then slowly add EtOAc (1100 mL) to the stirring solution via addition funnel. Transfer the resulting mixture to a 4000 mL beaker and stir open to the atmosphere overnight. Cool the beaker in an ice bath for 10 min. Collect the precipitate in a fritted funnel by vacuum filtration washing with a minimal amount of ice-cold EtOAc. Dry the solid on the frit for 2 h. Dissolve the resulting white solid in a minimal amount of DCM, transfer to a 2000 mL beaker and then dilute slowly with EtOAc until the clear solution starts to become cloudy. Stir the suspension for 4 h while open to the atmosphere. Collect the solids by vacuum filtration using a fritted funnel and dry on the frit overnight to give the title compound (111.8 g, 238.06 mmol, 86% Yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) d 10.54-10.47 (m, 1H), 7.61 (d, J= 7.3 Hz, 5H), 7.47-7.37 (m, 7H), 5.85 (d, J= 10.3 Hz, 1H), 4.68-4.61 (m, 1H), 3.91-3.83 (m, 2H), 3.37 (s, 8H), 2.99 (d, J= 14.6 Hz, 1H), 2.77-2.68 (m, 1H), 2.51-2.44 (m, 4H), 2.30-2.16 (m, 2H), 1.91-1.81 (m, 2H), 1.42-1.28 (m, 3H), 1.08 (s, 3H), 1.01 (d, J= 6.6 Hz, 3H), 0.77 (s, 4H); >98% ee [HPLC: Chiralcel® OJ (10 cm × 4.6 mm, 5 ^m), 5 mL/min, 40 ^C isocratic 10% EtOH (0.2% iPrNH2)/CO2].

Preparation 2

[(1R,4S)-7,7-Dimethyl-2-oxo-norbornan-1-yl]methanesulfonate (2S)-2-methylazetidin-1-ium salt

To a 2250 mL Parr vessel add 20 wt% Pd(OH)2 on carbon (6.62 g). Purge the bottle with nitrogen and add MeOH (250 mL). To the resulting suspension, slowly add (2S)-1-benzhydryl-2-methyl-azetidine [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid salt (111 g, 236 mmol) dissolved in MeOH (250 mL). Seal the vessel. Purge with nitrogen followed by hydrogen and pressurize to 60 PSI. Vigorously shake the reaction vessel in a Parr Shaker apparatus for 15 h at RT. Purge the vessel with nitrogen and then filter the reaction mixture through a pad of Celite®, washing with MeOH. Concentrate the filtrate to give a white solid and dry under vacuum. Suspend the solid in 780 mL of 1:1 MTBE/EtOAc and heat the mixture to 65 ^C for 20 h then cool to RT and stir overnight. Collect the solids by filtration. Suspend the solids in 380 mL of MTBE and stir at RT for 24 h. Collect the white solid by filtration to give the title compound (41.5 g, 137 mmol, 58% Yield). 1H NMR (400 MHz, DMSO-d6) d 8.68-8.55 (m, 1H), 4.51-4.42 (m, 1H), 3.91-3.75 (m, 1H), 3.36 (s, 3H), 2.91 (d, J= 14.6 Hz, 1H), 2.69-2.61 (m, 1H), 2.52-2.46 (m, 2H), 2.28-2.22 (m, 1H), 2.17-2.10 (m, 1H), 1.96 (t, J= 4.5 Hz, 1H), 1.89-1.79 (m, 1H), 1.43 (d, J= 6.7 Hz, 2H), 1.36-1.26 (m, 1H), 1.05 (s, 2H), 0.75 (s, 2H).

Preparation 3

(R)-2-Azetidinemethanol hydrochloride

To a 2-neck RBF, equipped with a nitrogen inlet, add: (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (30 g, 146 mmol), THF (300 mL), and 4-methylmorpholine (17.7 mL, 161 mmol). Cool the mixture to -10 ºC and add isobutyl chloroformate (21 mL, 161 mmol) dropwise. Stir the mixture for 30 min and then warm to RT. Remove the resulting solid by filtration. Cool the filtrate to 0 ºC and add a solution of sodium borohydride (11.1 g, 292 mmol) in water (90 mL) dropwise (caution: gas evolution). After the addition, warm the mixture to RT and stir for 30 min. Dilute the mixture with MTBE (300 mL) and water (100 mL). Wash the mixture with saturated aqueous NaHCO3 (200 mL) and then saturated aqueous NaCl (200 mL). Dry the organic phase over MgSO4, filter, and concentrate to dryness to give an oil (27 g). Carefully add HCl (4.0 M) in 1,4-dioxane (110 mL) [Caution: Gas evolution] and stir the resulting mixture for 3 h at RT. Evaporate the solvent in vacuo to give the title compound as an oil (16 g, 89 %). Use this material directly in preparations 9, 11, 16 and 36.

CLAIMS

1. A compound of the formula:

wherein

X is N, or C substituted with CN;

R1 is selected from: H,

R2 and R3 are both H, or one is H and the other is OH;

R4, R5, R6, R7 and R9 are independently H or CH3;

R8 is H, CH3, CH2CH2OH, C(=O)CH2NH2, or C(=O)CH3; and R10 is OH or NH2;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R1 is selected from:

; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, wherein the compound is:

,

or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of the claims 1 to 3, wherein X is N, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 3, wherein X is C

substituted with CN, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 4, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

7. The compound, or pharmaceutically acceptable salt thereof, according to claim 6, which is a succinate salt.

8. A method of treating type 2 diabetes mellitus in a patient, comprising

administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. A method of treating heart failure in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

10. A method of treating diabetic kidney disease in a patient, comprising

administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

11. A method of treating non-alcoholic steatohepatitis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

12. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 for use in therapy.

13. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 for use in treating type 2 diabetes mellitus.

14. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 for use in treating heart failure.

15. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 for use in treating diabetic kidney disease.

16. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 for use in treating non-alcoholic steatohepatitis.

17. A pharmaceutical composition, comprising a compound, or a

pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 with one or more pharmaceutically acceptable carriers, diluents, or excipients.

18. A process for preparing a pharmaceutical composition, comprising admixing a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 with one or more pharmaceutically acceptable carriers, diluents, or excipients.