EA040948B1 - SELECTIVE JAK1 INHIBITORS AND THEIR USE - Google Patents

Description

Technical field

The invention relates to novel 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives, their pharmaceutically acceptable salts, their solvates, hydrates and polymorphs as selective Jak1-kinase inhibitors. The present invention also provides compositions comprising a compound of the present invention and the use of such compositions in methods of treating diseases and conditions associated with Jak1, the invention may be used in the treatment of disorders associated with Jak1 activity such as an autoimmune disease or disorder, an inflammatory disease or disorder, as well as a cancerous or neoplastic disease or disorder.

State of the art

Protein kinases are a large family of proteins that play a key role in regulating a wide range of cellular processes and maintaining cell function. Partially, but not limited to, the list of these kinases includes: non-receptor tyrosine kinases, such as the family of Janus kinases (Jak1, Jak2, Jak3 and Tyk2); receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGFR) kinase; and serine/threonine kinases such as b-RAF. Disruption of kinase activity has been observed in many disease states, including benign and malignant proliferative disorders, as well as diseases resulting from inappropriate activation of the immune and nervous systems. The compounds of the present invention selectively inhibit the activity of one or more protein kinases with respect to other related kinases, and accordingly, it is expected that they can be used in the treatment of diseases mediated by the selectively inhibited kinase(s) without the undesirable side effects associated with inhibition of the related kinase( kinase).

In particular, the Janus kinase family (Janus) includes 4 known members of the family: Jak1, 2, 3 and tyrosine kinase 2 (Tuk2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as conventional gamma chain receptors and glycoprotein 130 (gp 130) transmembrane proteins (Murray, J. Immunol. 178(5):2623-2629, 2007). Nearly 40 cytokine receptors signal through combinations of these 4 Jak family members and their 7 downstream substrates: transcription family member signal transduction activators (STAT) (Ghoreschi et al., Immunol Rev. 228(1):273-287, 2009). Binding of a cytokine to its receptor initiates Jak activation via trans and autophosphorylation. The Jak family kinases in turn phosphorylate cytokine receptor residues, creating binding sites for proteins containing the sarcoma homology domain 2 (SH2), such as STAT factors and other regulators, which are subsequently activated by Jak phosphorylation. Activated STATs enter the nucleus, initiating the expression of survival factors, cytokines, chemokines, and molecules that facilitate leukocyte cell migration (Schindler et al, J. Biol. Chem. 282(28):20059-20063, 2007). Jak activation also results in cell proliferation via phosphoinositide 3-kinase (PI3K) and protein kinase B mediated pathways.

Jak3 and Jak1 are components of common-gamma chain cytokine receptor complexes, and blockade of either inhibits inflammatory cytokine signaling: interleukins (IL)-2, 4, 7, 9, 15 and 21 (Ghoreschi et al., Immunol. Rev. 228(1):273-287, 2009). Other pathologically significant cytokines, such as IL-6, in contrast, are uniquely dependent on Jak1. Accordingly, blockade of Jak1 inhibits the signaling of many pro-inflammatory cytokines (Guschin et al., EMBO J. 14(7): 1421-1429, 1995). The IL-6 receptor neutralizing antibody, tocilizumab, has been observed to be clinically effective in rheumatoid arthritis (RA) (Maini et al., Arthritis Rheum. 54(9):2817-2829, 2006).

Deficiency of Jak1 and Jak2 in humans has not been described. Mice lacking Jak1 die perinatally (Schindler et al, J. Biol Chem. 282(28):20059-20063, 2007). Jak2 deficiency in mice is also lethal, and Jak2'/' embryos die between 12 and 13 days post conception due to a deficiency in erythropoiesis (Neubauer et al, Cell 93(3):397-409, 1998). In humans, Jak3 deficiency has been described, which is a severe combined immunodeficiency in the first few months of life with symptoms such as failure to thrive, severe and recurrent infections, candidiasis, and diarrhea. Jak3-deficient children lack circulating T and NK cells and have impaired B cell function. Tyk2 deficiency has been additionally described in humans, manifested by impaired antimicrobial responses, elevated serum IgE levels, and atopic dermatitis (Minegishi et al, Immunity 25(5):745-755, 2006).

Given the high degree of structural similarity between Jak1 and Jak2 (Williams et al, J. Mal. Biol. 387(l):219-232, 2009), the literature suggests that most Jak1 inhibitors also inhibit Jak2 (lncyte Corp. press release, 10 Nov. 2010; Changelian et al, Science 302(5646):875878, 2003).

Anticytokine therapy has become the standard of care in the treatment of rheumatoid arthritis (RA). A growing body of evidence suggests that for humans, Jak1 inhibition represents an effective therapy for the signs and symptoms of RA. Numerous clinical trials administering the Jak 1/3 inhibitor tofacitinib manufactured by Pfizer (Kremer et al, Arthritis Rheum. 60(7): 18951905, 2009; Riese et al. Best Pract. Res. Clin. Rheumatol. 24(4): 513-526, 2010), Jak1/2 inhibitor INCB28050/LY3009104 from Incyte/Lilly (lncyte Corp. press release, 10 Nov 2010) or Jak1 inhibitor GLP0634 from Galapagos (Galapagos NV press release, 22 Nov 2011) have demonstrated

- 1 040948 statistically significant efficacy in the specified disease.

Tofacitinib, a Jak1 and Jak3 inhibitor, has been approved in the United States and other countries around the world for adult patients with moderately or severely active RA who have a poor response to or intolerance to methotrexate (MTX), for use alone or in combination with MTX or other non-biological DMARDs (disease modifying anti-rheumatic drugs - disease-modifying antirheumatic drugs). Safety data from phase 2 and phase 3 studies (Fleischmann, Curr. Opin. Rheumatol. 24(3):335-341, 2012; Kremer et al, Arthritis Rheum. 64(4):970-981, 2012 ; Fleischmann et al, Arthritis Rheum 64(3):617-629, 2012) in RA patients compared to placebo showed that the most common serious adverse reactions were infections, including pneumonia, cellulitis, herpes zoster and urinary tract infection. In addition to this, tuberculosis (including cases of disseminated tuberculosis) and opportunistic infections such as other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, herpes zoster multidermatome, cytomegalovirus, and BK virus have been reported. Lymphoma and other malignancies have been observed in patients treated with tofacitinib. Renal transplant patients treated with tofacitinib and concomitant immunosuppressants had a higher incidence of post-transplant Epstein-Barr virus-associated lymphoproliferative disease. Gastrointestinal perforation has also been reported in patients receiving tofacitinib. In addition, laboratory abnormalities have been described, including dose-dependent decreases in absolute neutrophil counts as well as hemoglobin. In addition, slight increases in hepatic transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [ACT]) and serum creatinine have been reported, as well as elevated levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol.

The phase 2 study of VX-509 (a Jak3 inhibitor) also found an increased risk of infections and increased lipid levels in RA patients (Fleischmann et al., Arthritis Rheum. 63:LB3, 2011).

In a phase 2b, 52-week, open-label, long-term, long-term study 2b of baricitinib, an orally administered selective inhibitor of Jak1 and Jak2, no opportunistic infections, cases of tuberculosis, or lymphomas were found in 201 patients with active RA. Rarely, clinically significant laboratory abnormalities were observed (ALT increase, anemia, creatine kinase [CK] increase, pancytopenia, each deviation was noted in one subject); one subject discontinued the study due to laboratory abnormalities (increased ALT). There was one death that was associated with a suspected myocardial infarction (Keystone et al, Ann. Rheum. Dis. 71 (Suppl 3):152, 2012; Genovese et al, Arthritis Rheum. 64 (Suppl 10):2487, 2012; Taylor et al, Abstract OP0047, EULAR 2013, the Annual Congress of the European League Against Rheumatism, 2013 Jun 12-15, Madrid, Spain.

However, despite seemingly numerous treatment options, a large number of patients with RA do not experience a significant reduction in disease activity. Although earlier studies have shown that Jak blockade can be effective in treating disease and achieving remission, the potential of first-generation Jak inhibitors (such as tofacitinib and baricitinib) has not been fully explored, at least in part due to their tolerability and safety concerns. which limit the dose.

In particular, the first generation Jak inhibitors tofacitinib and baricitinib have been characterized as Jak1/Jak3 and Jak1/Jak2 inhibitors, respectively (Fridman et al., J. Immunol, 184:5298-5307, 2010; Meyer et al, J. Inflamm. (Lond .) 7:41, 2010; and Taylor et al, Rheumatology 52:i44-i55, 2013). Despite initial encouraging results, the potential of these first generation Jak inhibitors was not fully realized due to tolerability issues that limited the dose (Fleischmann et al, Curr. Opin. Rheumatol. 24:335-341, 2012; Riese et al, Best Pract. Res Clin Rheumatol 24:513-526, 2010). JAK kinases are known to play a role in regulating over forty cascades (Murray, J. Immunol. 178:2623-2629, 2007). However, despite the high selectivity of these two compounds for JAK kinases over other kinase families, these inhibitors may not be optimally selective for JAK family kinases. For example, the incidence of severe anemia has been reported to be a dosage limiting factor during phase II development of tofacitinib for RA (Pfizer, Investigators Brochure. In FDA Advisory Board (Bethesda MD), 2012; Riese et al, Best Pract. Res. Clin. Rheumatol 24:513-526, 2010). Moreover, an increase in herpesvirus infections, potentially secondary to a decrease in NK cells, has been reported in phase III trials of tofacitinib (O'Shea et al., Ann. Rheum. Dis. 72(Suppl 2):ii111-115 , 2013; Pfizer, Investigators Brochure. In FDA Advisory Board (Bethesda MD), 2012). It is hypothesized that these effects may be due to inhibition of EPO and IL-15 signaling via Jak2 and Jak3, respectively (Jost and Altfeld, Annu. Rev. Immunol. 31:163-194, 2013; Kennedy et al, J. Exp Med 191:771-780, 2000 and Richmond et al, Trends Cell Biol 15:146-155, 2005). Indeed, failure to intervene to treat anemia associated with RA may limit the chances of a fully successful response to treatment.

Thus, from a medical point of view, there is a need that is not satisfied by the existing

- 2 040948 current treatment options using Jak inhibitors. Efforts are ongoing to identify selective inhibitors of Jak1 (Zak et al. J. Med. Chem. 2013, 56, 4764-4785; Menet et al. Future Med. Chem. 2015, 7, 203-235; WO2013/007768). Jakl-selective compounds such as GLP0634, ABT-494 (WO 2015/061665), and a compound described in a recent patent publication from Incyte (WO 2015/168246) are currently known to be in development, but no selective inhibitor Jak1 is not approved yet.

This document describes novel 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives as selective Jak1 inhibitors. Said compounds and compositions containing a compound of the present invention may be used in the treatment of disorders associated with Jak1 activities, such as an autoimmune disease or disorder, or an inflammatory disease or disorder, and a cancerous or neoplastic disease or disorder.

Brief description of the invention

The present invention describes novel 1H-furo[3,2-b]imidazo[4,5-d]|pyridine derivatives, their pharmaceutically acceptable salts, their solvates, hydrates and polymorphs as selective Jak1 kinase inhibitors. The present invention also provides compositions containing a compound of the present invention and the use of said compositions in methods of treating diseases and conditions associated with Jak1.

In the present invention, the problems set forth above are solved by providing an isolated compound of formula I:

^R \ / ^Su

Y ^N \ ¹ or its pharmaceutically acceptable salt, where

R ¹ is H, halo or _C1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(=O )R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O) zR', S(O^R and S(O)2NRR';

R ² is H;

Cy is cyclohexyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of R ³ , oxo, halo, OH, CN, OR, NHR, NRR', N( R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N( R)S(O)2R', S(O^R and S(O) ₂ NRR', where R ³ is C1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo , OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(= O)R, C(=O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR';

R, R' are each independently H or _C1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH, and CN.

The compounds of the present invention and compositions containing them can be used to treat or reduce the severity of Jak1 modulated diseases, disorders or symptoms thereof.

In another aspect, the present invention relates to a method of treating a disease or symptom of a disease in a subject in need thereof, comprising administering to said subject an effective amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof (or a composition thereof). The disease and disease symptom may be any of those modulated by Jak1. The disease or disease symptom may be, for example, an autoimmune disease or disorder such as rheumatoid arthritis, or an inflammatory disease or disorder, and a cancerous or neoplastic proliferative disease or disorder (eg, including those described herein).

In another aspect, the present invention relates to a compound of formula A1-14:

suitable for use in the process for the preparation of compounds of formula I.

In another aspect, the present invention relates to a process for preparing a compound of formula I:

comprising bringing a compound of formula V:

- 3 040948 in contact with a compound of formula VI:

in the presence of (C1-6 alkyl)3-oxonium tetrafluoroborate at a sufficient temperature and for a sufficient time to obtain a compound of formula I:

where R ² represents H, and R 1 and Cy have the meanings defined above. (C _1-6 alkyl) 3-oxonium tetrafluoroborate may be triethyloxonium tetrafluoroborate.

In another aspect, the present invention relates to a process for the preparation of a compound of formula V comprising the reduction of a compound of formula VII:

in the presence of a hydrogenation catalyst and hydrogen gas at sufficient temperature, sufficient pressure and for sufficient time to obtain a compound of formula V, wherein Cy is as defined above. The hydrogenation catalyst may be palladium on carbon.

In another aspect, the present invention relates to a process for preparing a compound of formula VII, comprising bringing the compound of formula A1-14:

in contact with a compound of formula VIII:

Su—NH ₂

VIII in the presence of a base at a sufficient temperature and for a sufficient time to obtain a compound of formula VII wherein Cy is as defined above. The base may be N,N-diisopropylethylamine.

Detailed description of the invention

Definitions

The terms improve and treat are used interchangeably, and both mean reducing, suppressing, attenuating, reducing, delaying, or stabilizing the development or progression of a disease (eg, the disease or disorder noted herein).

The term disease means any condition or disorder that damages or impairs the normal function of a cell, tissue, or organ.

The term marker means any change associated with a disease or disorder. For example, any protein or polynucleotide having a change in expression level or activity that is associated with a disease or disorder.

As used herein, the terms contains, containing, consisting of, and having, and the like, may have the meanings assigned to them in US patent law, and may mean includes, including, and the like; essentially consisting of, or essentially consisting of, similarly have the meanings ascribed to them in US patent law, and the terms are open-ended, allowing for more than what is described, provided that the essential or new characteristics of what is being described are not altered by the presence of additional elements, but excludes implementations which are part of the prior art.

The term compound, as used herein, is also intended to include pharmaceutically acceptable salts, prodrugs, and prodrug salts of compounds of the formulas provided herein. The term also includes any solvates, hydrates and polymorphs of any of the above. The specific indication of the terms prodrug, prodrug salt, solvate, hydrate or polymorph in certain aspects of the present invention described in this application should not be interpreted as an intentional omission of these forms in other aspects of the present invention, where the term compound is used without listing these other forms.

The salt of the compound of the present invention is formed between an acid and a basic group of a compound, such as an amino functional group, or a base and an acidic group of a compound, such as a carboxyl functional group. According to another preferred embodiment, the compound is a pharmaceutically acceptable acid addition salt.

- 4 040948

As used herein, and unless otherwise indicated, the term prodrug means a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs may only become active upon such a reaction under biological conditions, or they may be active in their unreacted forms. Examples of prodrugs contemplated by the present invention include, but are not limited to, analogs or derivatives of compounds of any of the formulas disclosed herein, which include biohydrolysable moieties such as amides, esters, carbamates, carbonates, and phosphate analogs. Prodrugs can generally be prepared using well known methods such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed); see also Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, Biotransformation of Drugs.

As used herein, and unless otherwise indicated, the term biohydrolysable moiety means a functional group (e.g., amide, ester, carbamate, carbonate, or phosphate analog) that either: 1) does not destroy the biological activity of the compound and confers beneficial properties to said compound in vivo such as digestibility, duration of action, or onset of action; or 2) is not biologically active per se, but is converted in vivo to a biologically active compound.

A salt of a prodrug is a compound formed by an acid and a basic group of a prodrug, such as an amino functional group, or a base and an acidic group of a prodrug, such as a carboxyl functional group. In one embodiment, the salt of the prodrug is a pharmaceutically acceptable salt.

Particularly preferred prodrugs and salts of prodrugs are those which increase the bioavailability of the compounds of the present invention when such compounds are administered to a mammal (e.g., allowing easier absorption of an orally administered compound into the blood) or which improve delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) compared to the parent compounds. Preferred prodrug options include derivatives in which a group is attached to the structure of the formulas noted herein which increases water solubility or active transport across the intestinal membrane. See, for example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189-214.

The term pharmaceutically acceptable as used herein refers to an ingredient that is medically acceptable for use in contact with human and other mammalian tissues without undue toxicity, irritation, allergic response, or the like, and for which there is a reasonable benefit ratio. /risk.

A pharmaceutically acceptable salt means any non-toxic salt which, when administered to a recipient, is capable of providing, directly or indirectly, a compound or prodrug of a compound of the present invention.

Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen sulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids, as well as organic acids such as p-toluenesulfonic acid, salicylic, tartaric, divinic, ascorbic, maleic, benzenesulfonic acid, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, parabromophenylsulfonic, carbonic acid, succinic, citric, benzoic and acetic acids, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts. Preferred pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially salts formed with organic acids such as maleic acid.

Suitable bases for the formation of pharmaceutically acceptable salts with acid functions

- 5 040948 prodrug groups according to the present invention include, but are not limited to, hydroxides of alkali metals such as sodium, potassium and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines such as unsubstituted or hydroxy-substituted mono-, di- or trialkylamines; dicyclohexylamine; tributylamine; pyridine; K-methyl-K-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxy-lower alkylamines), such as mono-, bis- or tris-(2hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris-(hydroxymethyl)methylamine, N, Ν ,-di-lower alkyl-K-(hydroxy-lower alkyl)amines such as K,K-dimethyl-K-(2-hydroxyethyl)amine, or tri-(2hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine and the like.

In the context of the present description, the term hydrate means a compound that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

In the context of the present description, the term solvate means a compound that further includes a stoichiometric or non-stoichiometric amount of a solvent, such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.

In the context of the present description, the term polymorph means solid crystalline forms of the compound or its complex, which can be characterized by physical means, such as, for example, x-ray powder diffraction or infrared spectroscopy. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties. Various physical properties include, but are not limited to, stability (e.g., to heat, light, or humidity), compressibility and density (important in formulating and manufacturing a product), hygroscopicity, solubility, and dissolution rates (which can affect bioavailability). Differences in stability may result from changes in reactivity (for example, differential oxidation, so that the dosage form discolors faster when it is composed of one polymorph than when it is composed of another polymorph) or mechanical characteristics (for example, tablets break down on storage, so how a kinetically preferred polymorph is converted to a thermodynamically more stable polymorph), or the effects of both (e.g. tablets of one polymorph are more prone to disintegration at high humidity). Various physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be difficult to filter or wash out of impurities, compared to another polymorph, for example, due to shape or particle size distribution.

The term substantially free of other stereoisomers as used herein means that less than 25% of other stereoisomers are present, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers, and most preferably less than 2% of other stereoisomers, or less than X% of other stereoisomers. stereoisomers (where X is a number from 0 to 100 inclusive). Methods for preparing or synthesizing diastereomers are well known in the art and may be applied, as far as practicable, to the final compounds or to the starting material or intermediates. In other embodiments, the connection is a dedicated connection. The term at least X% enantiomerically enriched in the context of the present description means that at least X% of the compound is one enantiomeric form, where X is a number from 0 to 100 inclusive.

The term stable compounds, as used herein, refers to compounds that are stable enough for manufacture and that maintain compound integrity for a sufficient time to be usable for the purposes detailed herein (e.g., drug formulation, intermediate compounds for use in the manufacture of therapeutic compounds, isolated or well-storable intermediates, treatment of a disease or condition sensitive to therapeutic agents).

A stereoisomer refers to both enantiomers and diastereomers.

In the context of the present description, the term halo or halogen refers to any of the radicals of fluorine, chlorine, bromine or iodine.

The terms alk or alkyl refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression lower alkyl refers to alkyl groups with 1-4 carbon atoms (inclusive).

The term arylalkyl refers to refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group.

The term alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. In case the alkenyl group is bonded to the nitrogen atom, it is preferred that such a group is not bonded directly through the carbon bearing the double bond.

- 6 040948

The term alkoxy refers to an -O-alkyl radical. The term alkylenedioxo refers to divalent radicals of the -O-R-O- structure, in which R is alkylene.

The term alkynyl refers to straight or branched chain hydrocarbon groups of 210, preferably 2-4 carbon atoms, having at least one triple bond. In case the alkynyl group is bonded to a nitrogen atom, it is preferred that such a group is not bonded directly through the carbon bearing the triple bond.

The term alkylene refers to a straight chain divalent bridge of 1-5 carbon atoms linked by single bonds (eg -(CH ₂ ) _x - where x is 1-5) which may be substituted with 13 lower alkyl groups.

The term alkenylene refers to a straight chain bridge of 2-5 carbon atoms having one or two double bonds, which is connected by single bonds and may be substituted with 1-3 lower alkyl groups. Representative alkenylene groups are -CH=CH-CH=CH-, -CH2CH=CH-, -CH2-CH=CH-CH2-, -C(CH3) ₂ CH=CH- and -CH(C2H5)-CH= CH-.

The term alkynylene refers to a straight chain bridge of 2-5 carbon atoms that has a triple bond internally, is linked by single bonds, and may be substituted with 1-3 lower alkyl groups. Representative alkynylene groups are -OC-, -CH ₂ -C^C-, -CH(CH ₃ )C^C- and -C C-CH(C2H5)CH2-.

The terms cycloalkyl and cycloalkenyl as used herein include saturated and partially unsaturated cyclic, respectively, hydrocarbon groups having 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms.

The terms Ap or aryl refer to aromatic cyclic groups (eg, 6-membered monocyclic, 10-membered bicyclic, or 14-membered tricyclic ring systems) that contain from 6 to 14 carbon atoms. Typical aryl groups include phenyl, naphthyl, biphenyl and anthracene.

Heteroaryl refers to a monocyclic group or a group with fused rings (i.e. rings that share a pair of atoms) of 5-12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the rest of the ring atoms are C and, in addition, have a fully conjugated pi-electron system, where 0, 1, 2, 3 or 4 atoms of each ring can be replaced by a substituent. Non-limiting examples of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine, and carbazole.

The terms heterocycle, heterocyclic, or heterocyclo refer to fully saturated or partially unsaturated cyclic groups, e.g. one ring, where 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Each ring of a heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system.

The term heterocyclyl refers to fully saturated or partially unsaturated cyclic groups, for example, 3-7 membered monocyclic, 7-12 membered bicyclic, or 10-15 membered tricyclic ring systems that have at least one heteroatom in at least one ring, where 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Each ring of a heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system.

The term substituents refers to a group substituted by any functional group noted herein, for example, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic or heteroaryl group at any atom of the specified group. Suitable substituents include, without limitation, halogen, CN, NO ₂ , OR ¹⁵ , SR ¹⁵ , S(O)2OR ¹⁵ , NR ¹⁵ R ¹⁶ , Ci-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, 1,2-methylenedioxy, C( O)OR ¹⁵ , C(o)nR ¹⁵ R ¹⁶ , OC(O)NR ¹⁵ R ¹⁶ , NR ¹⁵ C(O)NR ¹⁵ R ¹⁶ , C(NR ¹⁶ )NR ¹⁵ R ¹⁶ , NR ¹⁵ C(NR ¹⁶ )NR ¹⁵ R ¹⁶ , S(O)2NR ¹⁵ R ¹⁶ , R ¹⁷ , C(O)R ¹⁷ , NR ¹⁵ C(O)R ¹⁷ , S(O)R ¹⁷ , S(O)2R ¹⁷ , R ¹⁶ , oxo, C(O)R ¹⁶ , C(O)(CH2) _n OH, (CH ₂ ) _n OR ¹⁵ , (CH2)nC(O)NR ¹⁵ R ¹⁶ , NR ¹⁵ S(O)2R ¹⁷ , where n is independently 0-6 inclusive. Each R ¹⁵ is independently H, C1-C4 alkyl, or C3-C6 cycloalkyl. Each R ¹⁶ is independently H, alkenyl, alkynyl, C3C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl, or C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl, or heteroaryl. Each R ¹⁷ is independently C3-C6

- 7 040948 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl or _C1 - _C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4 alkyl in each of R ¹⁵ , R ¹⁶ and R ¹⁷ may be optionally substituted with halo, CN, C1-C4 alkyl, OH, C1-C4 alkoxy, NH2, C1 -C4 alkylamino, C1-C4 dialkylamino, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or 1,2-methylenedioxy.

The term oxo refers to an oxygen atom that forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.

The term acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted with substituents.

The listing of a list of chemical groups in any definition of a variable herein includes definitions of the specified variable as any single group or combination of the listed groups. The statement of an implementation option for a variable herein includes the specified implementation option as any single implementation option or in combination with any other implementation options or parts thereof.

The compounds of the present invention may contain one or more asymmetric centers and thus exist as racemates and racemic mixtures, single enantiomers, single diastereomers and diastereomeric mixtures, as well as cis and trans geometric isomers. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of the present invention may also be present in multiple tautomeric forms, in which case the invention specifically includes all tautomeric forms of the compounds noted herein. All such isomeric forms of such compounds are specifically included in the present invention. All crystalline forms of the compounds noted herein are expressly included in the present invention.

Compounds according to the invention

In one aspect, the present invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof; or its prodrug, or a pharmaceutically acceptable salt of its prodrug; or a hydrate, solvate, or polymorph thereof; Where

R ¹ is H, halo or C1.3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(=O )R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O) 2R', S(O)2R and S(O)2NRR';

R ² is H, halo or C1.3 alkyl;

Su is C ₃ . ₇ cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of R ³ , oxo, halogen, OH, CN, OR , NHR,

NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O) NRR', N(R)S(OhR', S(O)2R and S(O) ₂ NRR', where R ³ is _C1.3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group, consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(OhR', S(O)2R and S(O)2NRR';

R, R' are each independently H or C _1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH and CN.

In another aspect, Cy may be C _5-7 cycloalkyl or 5-7 membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R ³ , oxo, halogen, OH, CN, OR NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C( =O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR', where R ³ is C _b3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O) NRR', C(=O)R, C(=O)NRR', N(R)S(O)2R', S(O)2Rh S(O)2NRR'.

In another aspect, R ² may be H.

Typical compounds according to the present invention are presented in table. 1. In these examples, the stereochemistry at chiral carbons is independently RS, R, or S, unless otherwise noted. For compounds 4 and 7-11, according to the stereochemistry, only one of the trans or cis isomers is possible, and the structures of their respective isomers are not shown. The structures depicted in this document, including the structures of Table. 1 may contain certain -NH-, -NH2 (amino) and -OH (hydroxyl) groups, where the corresponding hydrogen atom(s) is not explicitly displayed; however, they should be read as -NH-, -NH2 or -OH as appropriate. In certain structures, the bond is shown as an elongated segment, which means a methyl group.

- 8 040948

Table 1

Exemplary compounds according to the present invention are listed below: cyclohexanecarbonitrile (1);

w/¥shs-4-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-c1]pyridin-1-yl]cyclohexanecarbonitrile (2);

2-[/w/?<twc-4-[2-[(/?)-I-hydroxyethyl ]furo[3,2-b]imidazo[4,5-c1]pyridin-1 yl]cyclohexyl]acetonitrile ( 3);

2-[(2L,55)-5-[2-[(L)-1-hydroxyethyl]furo[3,2-b]imidazo[4,5-b]pyridin-1-yl]tetrahydropyran-2- and l]acetonitrile (4);

3-[2-[(7?)-1-hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-b]pyridin-1-yl]-M-(2,2,2trifluoroethyl) pyrrolidine-1-carboxamide (5);

(L)-4-[2-(1-hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-0]pyridin-1-yl]-N-(2,2,2trifluoroethyl)piperidine -1-carboxamide (6);

2-[(2K,58)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-c1]pyridin-1yl]tetrahydropyran-2-yl]acetonitrile (7);

2-[(28.58)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-b]pyridin-1yl]tetrahydropyran-2-yl]acetonitrile (8),

2-[(2L,5V)-5-[2-ethylfuro[3,2-b]imidazo[4,5-0]pyridin-1-yl]tetrahydropyran-2yl]acetonitrile (9), 2-[(27 ?,55)-5-[2-furo[3,2-b]imidazo[4,5-c1]pyridin-1-yl]tetrahydropyran-2yl]acetonitrile (10),

2-[(2A,5V)-5-[2-methylfuro[3,2-b]imidazo[4,5-0]pyridin-1-yl]tetrahydropyran-2yl]acetonitrile (11).

The synthesis of the compounds of the formulas given herein can be easily carried out by synthetic chemists of ordinary skill. Appropriate methods and intermediates are disclosed, for example, in this document. The contents of each of the patents, patent applications, and publications published in conventional journals or available only via the Internet referred to in this document are incorporated herein by reference in their entirety.

Other approaches to the synthesis of compounds of the formulas given in this document can be easily adapted from the references cited in this document. Variations of these methods and their optimization are within the purview of the ordinary performer.

The specific methods and compounds presented above are not intended to be limiting. The chemical structures in the diagrams given in this document represent variables that are thus defined in accordance with the definitions of the chemical groups (fragments, atoms, etc.) of the corresponding position in the formulas of the compounds given in

- 9 040948 present document, whether they are identified with the same variable name (eg R ¹ , R ² , R, R', X, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound structure is known to one of ordinary skill in the art. Additional methods for the synthesis of compounds of the formulas provided herein, and their synthetic precursors, including methods not expressly indicated in the schemes provided herein, are available to chemists having ordinary skill in the art. Methods are known in the art for optimizing reaction conditions while minimizing competing by-products. The methods described herein may also further include steps either before or after the steps specifically noted herein to add or remove suitable protecting groups in order to ultimately allow the synthesis of the compounds described herein. In addition, the various steps of the synthesis can be performed in an alternative sequence or to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodology (protection and deprotection) used in the synthesis of suitable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, ^3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and their subsequent editions.

The methods outlined herein involve the conversion of compounds of one formula to compounds of another formula. The specified transformation method refers to one or more chemical transformations, which can be performed in situ or with isolation of intermediates. Transformations may involve reacting the parent compounds or intermediates with additional reagents using techniques and protocols known in the art, including those cited in the references cited herein. Intermediates may be used with or without purification (eg, filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography).

The combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds.

The present invention also provides compositions comprising an effective amount of a compound of any of the formulas herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or, if applicable, a prodrug of said compound; and acceptable carrier. Preferably, the composition according to the present invention is formulated for pharmaceutical use (pharmaceutical composition), where the carrier is a pharmaceutically acceptable carrier. The carrier(s) must be acceptable in the sense that it is compatible with the other ingredients of the medicinal product and, in the case of a pharmaceutically acceptable carrier, must not be harmful to its recipient in the amounts normally used in medicinal products.

Pharmaceutically acceptable carriers, adjuvants, and carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates , glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, substances on cellulose base, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat (lanolin, wool fat).

Pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In some embodiments, a compound of the formulas provided herein is administered transdermally (eg, using a transdermal patch). Other formulations may conveniently be presented in unit dosage form, for example, in sustained release tablets and capsules, and in liposomes, and may be prepared by any of the methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

Such preparative methods include the step of combining with a molecule to introduce ingredients, such as a carrier, which consists of one or more additional ingredients. In general, compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

- 10 040948

In some preferred embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as separate units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion, or packaged in liposomes and as a bolus, etc. As a content form for such suspensions, which can advantageously increase the rate of absorption of the compound, soft gelatin capsules may be suitable.

The tablet may be made by compression or moulding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable apparatus the active ingredient in free flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets can be made by molding in a suitable apparatus a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored tablets and may be formulated to provide slow or controlled release of the active ingredient. Methods for formulating such slow or controlled release compositions from pharmaceutically active ingredients such as those described herein and from other compounds known in the art are known in the art and are described in several published US patents, some of which include , but are not limited to, US patents No. 4369172 and 4842866, and references cited in these patents. Shells can be used to deliver compounds to the intestine (see, for example, US Pat. A suitable formulation for the compounds of the present invention is in the form of enteric granules wherein the enteric layer contains hydroxypropyl methylcellulose acetate succinate.

In the case of tablets for oral use, carriers commonly used include lactose and cornstarch. Lubricants such as magnesium stearate are also commonly added. Suitable diluents for oral administration in capsule form include lactose and dried corn starch. For oral administration of aqueous suspensions, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Formulations suitable for topical use include lozenges containing flavored ingredients, typically sucrose and acacia or tragacanth, and lozenges containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriosthetics, and solutes that render the composition isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Formulations may be presented in single or multiple dose containers, such as sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) forms requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Injectable solutions and suspensions for immediate administration may be prepared from sterile powders, granules and tablets.

Such injectable solutions may be, for example, a sterile injectable aqueous or oily suspension. Said suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or vehicle, such as a solution in 1,3-butanediol. Suitable carriers and solvents include mannitol, water, Ringer's solution and isotonic sodium chloride solution, among others. In addition, sterile fatty oils are commonly used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Both fatty acids, such as oleic acid and its glyceride derivatives, and natural pharmaceutically acceptable oils, such as olive oil or castor oil, can be used in the preparation of injectables, especially in their polyoxyethylated variants. Said oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant.

Pharmaceutical compositions according to the present invention may be administered in the form of suppositories for rectal administration. These compositions can be obtained by mixing

- 11 040948 compounds according to the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the active ingredients. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

The pharmaceutical compositions of the present invention may be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and/or other known solubilizing or dispersing agents. agents known in the art.

Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves areas or organs that are readily available for topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredients suspended or dissolved in a carrier. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene-polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention may also be applied topically in the lower intestinal tract via the form of a rectal suppository or suitable enema preparation. Topical transdermal patches and iontophoretic administration are also included in the present invention.

Particularly preferred derivatives and prodrugs are those which increase the bioavailability of the compounds of the present invention when such compounds are administered to a mammal (eg, by allowing easier blood absorption of an orally administered compound) or which accelerate delivery of the parent compound to a biological compartment (eg, the brain or central nervous system). nervous system) compared with the original forms. Preferred prodrugs include derivatives in which a group is attached to the structure of the formulas noted herein which increases water solubility or active transport across the intestinal membrane. See, for example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189214.

The use of the therapeutic agents in question may be local, allowing them to be administered at the site of interest. In order to ensure the delivery of the considered compositions to the site of interest, various methods can be used, such as injection, the use of catheters, trocars, bullets (projectiles), Pluronic gel, stents, polymers with prolonged release of the drug, or other device that provides ingestion .

According to another embodiment, the present invention provides a method for impregnating an implantable drug release device, comprising the step of contacting said drug release device with a compound or composition of the present invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules, and biodegradable polymer sheets.

According to another embodiment, the present invention provides an implantable medical device coated with a compound or composition containing a compound of the present invention, such that said compound is therapeutically active.

In another embodiment, the composition according to the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known to have or exhibit beneficial properties when administered alone or in combination with any of the formulas herein. Drugs that may be suitable for combination with these compounds include inhibitors of other kinases and/or other therapeutic agents for the treatment of diseases and disorders described above.

Such agents are described in detail in the art. The second therapeutic agent is preferably an agent suitable for use in the treatment or prevention of a disease.

- 12 040948 disease or condition selected from the group: a cancerous and neoplastic disease or disorder, or an autoimmune and inflammatory disease or disorder.

In another embodiment, the present invention provides separate dosage forms of a compound of the present invention and a second therapeutic agent that are associated with each other. The term related to each other in the context of the present description means that the individual dosage forms are packaged together or otherwise combined, so that it is clear that the individual dosage forms are intended to be sold and administered together (within less than 24 hours from each other, sequentially or simultaneously).

In the pharmaceutical compositions of the present invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered at the proper dosage regimen, is sufficient to reduce or lessen the severity, duration, or progression of the disorder being treated, prevent progression of the disorder being treated, cause regression of the disorder being treated, or aggravate or improves the prophylactic or therapeutic effect(s) of another therapy.

Dosage relationships for animals and humans (in terms of milligrams per square meter of body surface) are described in Freireich et al., (1966) Cancer Chemother Rep 50: 219. Body surface area can be approximately determined from the height and body weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. An effective amount of a compound of the present invention may be from about 0.001 to about 500 mg/kg, more preferably from 0.01 to about 50 mg/kg, more preferably 0.1 to about 2.5 mg/kg. Effective doses will also vary, as will be known to those skilled in the art, depending on the diseases being treated, the severity of the disease, the route of administration, the sex, age and general health of the patient, the use of the excipient, the possibility of co-administration with other therapeutic treatments such as as the use of other agents, and the decision of the attending physician.

For pharmaceutical compositions that contain a second therapeutic agent, the effective amount of the second therapeutic agent is from about 20% to 100% of the dose normally used in a monotherapy regimen in which only said agent is used. Preferably, the effective amount is from about 70% to 100% of the normal monotherapeutic dose. Normal monotherapeutic doses of these second therapeutic agents are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), where each of the references is fully incorporated into the present description by reference.

Some of the second therapeutic agents mentioned above are expected to act synergistically with the compounds of the present invention. If this effect is observed, it will allow to reduce the effective dosage of the second therapeutic agent and/or compound according to the present invention compared to that required in monotherapy. Dosage reduction has the advantage of minimizing the toxic side effects of any second therapeutic agent of the compound of the present invention, improves efficacy through synergy, simplifies administration or use, and/or reduces overall compound or formulation costs.

Methods of treatment

According to another embodiment, the present invention provides a method of treating a subject suffering from or susceptible to a disease or disorder or a symptom thereof (e.g., such as those described herein) comprising the step of administering to said subject an effective amount of a compound or composition of the present invention. invention. Such diseases are well known in the art and are also disclosed herein.

In one aspect, the method of treatment includes treating a disorder that is mediated by the Jak1 protein kinase.

In another aspect, the present invention provides a method of treating a disease in a subject, comprising administering to said subject a compound of any of the formulas provided herein.

In another aspect of the present invention, there is provided a method of treating a disease in a subject, comprising administering to said subject a composition comprising a compound of any of the formulas provided herein.

In some embodiments, the disease is mediated by Jak1 kinase. For example, said condition may be an inflammatory disease/disorder, an autoimmune disease/disorder such as, but not limited to, rheumatoid arthritis (RA), juvenile idiopathic arthritis, osteoarthritis, multiple sclerosis, allergic asthma, chronic obstructive pulmonary disease, bronchitis, experimental allergic encephalomyelitis, Crohn's disease,

- 13 040948 vasculitis, cardiomyopathy, ankylosing spondylitis (AS), glomerulonephritis, insulin dependent diabetes, psoriatic arthritis, psoriasis, plaque psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, peripheral neuropathy, uveitis, fibrosing alveolitis, type I diabetes , juvenile diabetes, Castleman's disease, neutropenia, endometriosis, autoimmune thyroid disease, sperm and testicular autoimmunity, scleroderma, axonal and neural neuropathies, allergic rhinitis, sinusitis, hemolytic anemia, Graves' disease, Hashimoto's thyroiditis, IgA nephropathy, amyloidosis, Behcet's disease, sarcoidosis, vesiculobullous dermatosis, myositis, dry eye syndrome, primary biliary cirrhosis, polymyalgia rheumatica, Reiter's syndrome, autoimmune immunodeficiency, Chagas disease, Kawasaki syndrome, celiac disease, myasthenia gravis, Sjögren's syndrome, alopecia areata, vitiligo, atopic dermatitis, POEMS syndrome, lupus, inflammatory bowel disease, ononic obstructive pulmonary disease (COPD), pemphigus vulgaris, bullous pemphigoid, chronic fatigue syndrome, organ transplant rejection (eg, allograft rejection and graft-versus-host disease), viral diseases such as Epstein-Barr virus, hepatitis C, HIV, HDTV- 1 (HTLV 1 - human T-lymphotropic virus 1 - human T-lymphotropic virus of the first type), varicella-zoster virus and human papillomavirus, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic degeneration, algodystrophy, Tietze's syndrome, costal atropopathy, Mseleni's disease, Handigod's disease, fibromyalgia, scleroderma, congenital cartilage malformations, and pulmonary arterial hypertension.

Additional JAK-associated diseases include inflammation and inflammatory diseases or disorders. Examples include sarcoidosis, inflammatory diseases of the eye (eg, iritis, uveitis, scleritis, conjunctivitis, blepharitis, or related diseases), inflammatory diseases of the respiratory tract (eg, upper respiratory tract, including nose and sinuses such as rhinitis or sinusitis or lower respiratory tract, including bronchitis, chronic obstructive pulmonary disease and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases.

In another embodiment, the disease is a cancerous, proliferative, or other neoplastic disease such as, but not limited to, breast cancer, Castleman's disease, colon and colorectal cancer, gastric cancer, gastrointestinal cancer, gastrointestinal cancer, glioblastoma, head and neck cancer, Kaposi's sarcoma, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, kidney cancer, rectal cancer, small intestine cancer, thyroid cancer, uterine leiomyosarcoma, lymphomas and leukemias such as acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonoid leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD). In some embodiments, the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (Post-ET MF) or post-polycythemia versus myelofibrosis (Post-PV MF),

Additionally, JAK-associated diseases include ischemia reperfusion injury or a disease or condition associated with an inflammatory ischemic event such as stroke or cardiac arrest, an endotoxin-induced condition (eg, bypass complications in chronic endotoxin conditions contributing to chronic heart failure), anorexia, sclerodermatitis, fibrosis, conditions associated with hypoxia or astrogliosis such as diabetic retinopathy, cancer or neurodegeneration, and other inflammatory diseases such as systemic inflammatory response syndrome and septic shock.

Other JAK-associated diseases include gout and prostate enlargement due to, for example, benign prostatic hypertrophy or benign prostatic hyperplasia, as well as bone resorption diseases such as osteoporosis or osteoarthritis, and bone resorption diseases associated with : hormonal imbalance and / or hormonal therapy, autoimmune disease (eg, bone sarcoidosis).

Other examples of JAK-associated diseases or conditions include amelioration of dermatological side effects of other drugs by administering a compound of the present invention. For example, numerous pharmaceutical agents lead to an undesirable allergic reaction, which can manifest itself as acne or dermatitis associated with said allergic reaction. Examples of pharmaceutical agents that have such undesirable side effects include anti-cancer drugs such as gefitinib, cetuximab, erlotinib, and the like. The compounds of the present invention may be administered systemically or topically (eg, localized in close proximity to dermatitis) in combination with a pharmaceutical agent having an undesirable dermatological side effect.

- 14 040948 effect. Accordingly, compositions of the present invention include topical formulations containing a compound of the invention and an additional pharmaceutical agent that may cause dermatitis, skin conditions, or associated side effects.

In one embodiment, the method of the present invention is used to treat a subject suffering from or susceptible to a disease or condition. Such diseases, disorders, or symptoms thereof include, for example, diseases modulated by Jak1 protein kinase. The disease or disease symptom may be, for example, rheumatoid arthritis, cancer, or a proliferative disease or disorder. The methods described herein include those in which the subject is identified as being in need of a particular claimed treatment. The identification of a subject in need of such treatment may be assessed by the subject or a healthcare professional and may be subjective (eg, opinion) or objective (eg, measured by a test or diagnostic method).

However, in another embodiment, the compounds of the formulas provided herein (and compositions thereof) may be used to treat subjects suffering from a disease or disorder that have been identified or have developed resistance to other therapeutic agents. In one aspect, the methods described herein include those in which the subject is resistant to treatment with methotrexate or anti-TNFa therapy (TNF - tumor necrosis factor).

In another embodiment, the present invention provides a method for modulating Jak1 protein kinase activity in a cell, comprising contacting the cell with one or more compounds of any of the formulas provided herein.

In another embodiment, the above method of treatment includes the additional step of co-administering one or more second therapeutic agents to said patient. The second therapeutic agent may be selected from any therapeutic agent known to be suitable for use in the indications described herein. One or more additional therapeutic agents may include chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, as well as inhibitors of kinases PI3Kdelta, mTOR, BCR-AB1, FLT3, RAF and FAK, and the like. Additional therapeutic agents include, but are not limited to, agents for the treatment of diseases, disorders, or symptoms thereof, including, for example, (1) agents that modulate the human immune system, or are anti-inflammatory agents selected from the group consisting of, but not ограничиваясь указанным, аспирина, ацетаминофена, аминосалицилата, антитимоимитного глобулина, ципрофлоксацина, кортикостероида, циклоспорина, дезоксиспергуалина, даклизумы, метронидазола, пробиотика, такролимуса, ибупрофена, напроксена, пироксикама, преднизолона, дексаметазона, противовоспалительного стероида, метотрексата, хлорохина, азатиоприна, гидроксихлорохина, микофенолата , muromonab-CD3, penicillamine, sulfasalazine, leflunomide, tacrolimus, tocilzumab, anakinra, abatacept, certolizumab, pegol, golimumab, rapamycin, vedolizumab, natalizumab, ustekinumab, rituximab, efalizumab, belimumab, etanercept, ra) for CD4+CD25+ regulatory T cells, NSAIDs, analgesics, other non-biological disease-modifying antirheumatic drugs (DMARDs) and/or in combination with anti-TNF-alphabiological agents such as TNA antagonists such as chimeric, humanized or human antibodies to TNF, adalimumab, infliximab, golimumab, CDP571 and soluble TNA receptors p55 or 175, derivatives thereof, etanercept or lenercept (2) anticancer and antineoplastic agents, antiproliferative agents, antineoplastic agents, antineoplastic agents, antimetabolite type antineoplastic agents/inhibitors thymidylate synthases, alkylating-type antineoplastic agents, antibiotic-type antineoplastic agents, or any other agent commonly administered as a primary or adjuvant agent in cancer treatment protocols (e.g., against nausea, against anemia, etc.), including, for example, vinblastine sulfate , vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5 -fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosourea, thiotephane, vincristine, taxol, taxotere, etoposide, teniposide , irinotecan, topotecan, epothilone, Iressa, Avastin, OSI-774, angiogenesis inhibitors, EGFR inhibitors, MEK inhibitors, VEGFR inhibitors, CDK inhibitors, Her1 and Her2 inhibitors, monoclonal antibodies, proteasome inhibitors such as bortezomib, thalidomide and revlimide; an apoptotic inducer such as ABT-737. Nucleic acid based therapies such as antisense therapy or RNA interference; nuclear receptor ligands (eg, agonists and/or antagonists, all-trans retinoic acid or boxarotene); epigenetic targeting agents such as histone deacetylase inhibitors (eg vorinostat), hypomethylating agents (eg decitabine), protein stability regulators such as HSP90 inhibitors, ubiquitin and/or ubiquitin-like conjugating or de

- 15 040948 conjugating molecules.

In some embodiments, the additional pharmaceutical agent is selected from immunomodulatory drugs (immunomodulators), an anti-IL-6 agent, an anti-TNF-alpha agent, a hypomethylating agent, and a biological response modifier (MBM). Typically, MBO is a substance from living organisms for the treatment of disease. Examples of MBOs include IL2, GM-CSF, CSF, monoclonal antibodies such as abciximab, etanercept, infliximab, rituximab, trastuzumab, and high dose ascorbate. The hypomethylating agent is a DNA methyltransferase inhibitor such as 5-azacytidine and decitabine. Examples of immunomodulators include thalidomide, lenalidomide, pomalidomide, CC-11006 and CC-10015.

In some embodiments, additional pharmaceutical agents include anti-thymocyte globulin, recombinant human granulocyte colony stimulating factor (GCSF), granulocyte-monocytic CSF (GM-CSF), an erythropoiesis-stimulating agent (ESA), and cyclosporine.

In some embodiments, the additional therapeutic agent is an additional JAK inhibitor. In some embodiments, the additional JAK inhibitor is tofacitinib, ruxolitinib, or baricitinib.

In some embodiments, one or more JAK inhibitors of the present invention may be used in combination with one or more other anti-cancer therapeutic agents in the treatment of a cancer, such as multiple myeloma, and may improve the efficacy of the treatment over that demonstrated by other anti-cancer therapeutic agents. without enhancing their toxic effects. Examples of additional pharmaceutical agents useful in the treatment of multiple myeloma may include, without limitation, melphalan, melphalan plus prednisone (MP), doxorubicin, dexamethasone, and bortezomib. Additional agents used in the treatment of multiple myeloma include inhibitors of BRC-ABL, FLT-3, RAF, MEK, PI3K, mTOR. When a JAK inhibitor of the present invention is combined with an additional agent, it is very important to detect additive or synergistic effects. In addition, in the treatment with the JAK inhibitor of the present invention, the resistance of multiple myeloma cells to agents such as dexamethasone or other agents can be reversible.

The agents may be combined with the compounds of the present disclosure in a single or continuous dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

In some embodiments, a corticosteroid, such as dexamethasone, is administered to a patient in combination with at least one JAK inhibitor of the present invention, wherein the dexamethasone is administered intermittently rather than continuously.

In some embodiments, combinations of one or more JAK inhibitors of the present invention with other therapeutic agents may be administered to a patient before, during, and/or after bone marrow transplantation or stem cell transplantation.

In some embodiments, the additional therapeutic agent is fluocinolone acetonide or remoxolone.

In some embodiments, the additional therapeutic agent is a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.

In some embodiments, the additional therapeutic agent includes dehydrex, civamide, sodium hyaluronate, cyclosporine, ARG101, AGR1012, sodium ecabet, gefarnate, 15-(s)hydroxyeicosatetraenoic acid, cevilamine doxycycline, minocycline, iDestrtin, cyclosporin A, oxytetracycline, voclosporin, ARG103, RX-10045, DYN15, Rivoglitazone, TB4, ORN-01, PCS101, REV131, Lacritin, Rebamipide, OT-551, PAI-2, Pilocarpine, Tacrolimus, Pimercrolimus, Loteprednol Etabonate, Rituximan, Diquafazole Tetrasodium, KLS-0611, Dehydroepiandrosterone, anakinra, efalizum, sodium mycophenolate, etanercept, hydroxychloroquine, NGX267, actemra, or L-asparaginase.

In some embodiments, the additional therapeutic agent is an antiangiogenic agent, a cholinergic agent, a TRP-1 receptor modulator, a calcium channel blocker, a mucin secretion stimulator, a MUC1 stimulator, a calcineurin inhibitor, a P2Y2 receptor agonist, a muscarinic receptor agonist, and a tetracycline derivative.

In some embodiments, additional therapeutic agents include soothing eye drops, which include, but are not limited to, compositions containing polyvinylchole, hydroxypropylmethylcellulose, glycerin, polyethylene glycol (eg, PEG400), or carboxymethylcellulose. In some embodiments, the additional therapeutic agent is a mucolytic drug, such as N-acetylcysteine, which can interact with mucoproteins and reduce tear film viscosity.

In some embodiments, the additional therapeutic agent includes antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents, including steroidal and non-steroidal anti-inflammatory agents, and antiallergic agents. Examples

- 16 040948 suitable drugs include aminoglycosides such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin, vanocomycin; tetracyclines; rifampin and its derivatives; cycloserine; beta lactams; cephalosporins; amphoterecins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; Suprofen; cromolyn; lodoxamide; levocabastine; naphazoline; antazolin; pheniramine; or an azalide antibiotic.

The term co-administration as used herein means that the second therapeutic agent may be co-administered with a compound of the present invention as part of the same dosage form (such as a composition of the present invention containing a compound of the present invention and a second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered before, sequentially or after the administration of the compound of the present invention. In such combination therapy, both the compounds of the present invention and the second therapeutic agent(s) are administered by conventional methods. Administering a composition of the present invention containing both a compound of the present invention and a second therapeutic agent to a subject does not preclude separate administration of the same therapeutic agent, any other second therapeutic agent, or any compound of the present invention to said subject at a different time during the course of treatment. .

Effective amounts of these second therapeutic agents are well known to those skilled in the art. Dosing guidance can be found in the patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and in other medical texts. However, one skilled in the art will be able to determine the optimal range of effective amounts of the second therapeutic agent.

In one embodiment of the present invention, if a second therapeutic agent is administered to a subject, the effective amount of a compound of the present invention is less than said effective amount would be if the second therapeutic agent were not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount in the absence of administration of the compound of the present invention. Thus, unwanted side effects associated with high doses of any agent can be minimized. Other potential benefits (including, without limitation, improved dosing regimens and/or reduced drug cost) will be apparent to those skilled in the art.

In another aspect, the present invention provides the use of a compound of any of the formulas herein, alone or together with one or more of the second therapeutic agents described above, in the preparation of a medicament, either as a single composition or as separate dosage forms, for the treatment or prophylaxis in a subject. disease, disorder or symptom as defined above. In another aspect, the present invention provides a compound of the formulas herein for use in the treatment or prevention in a subject of the disease, disorder, or symptom thereof noted herein.

In other aspects, the methods of the present disclosure include those that further include monitoring a subject's response to drug administration. Such monitoring may include periodic sampling of underlying tissue, fluids, samples, cells, proteins, chemical markers, genetic materials, etc. as markers or indicators of the treatment regimen. In other methods, the subject is prescreened or identified as in need of such treatment by evaluating an appropriate marker or indicator of suitability for such treatment.

In one embodiment, the present invention provides a method for monitoring treatment progress. The method includes the step of determining a level of a diagnostic marker (marker) (e.g., any target or cell type described herein, modulated by a compound as described herein) or a diagnostic measurement (e.g., screening, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof noted herein, wherein the subject is administered a therapeutic amount of a compound as described herein sufficient to treat the disease or symptoms thereof. In order to establish a subject's disease status, the level of the marker determined in the method can be compared to known levels of the marker, either in healthy normal subjects or in other diseased patients. In preferred embodiments, at a point in time later than the first level determination, a second marker level is determined in the subject and the two levels are compared to monitor the course of the disease or the effectiveness of therapy. In some preferred embodiments

- 17 040948 prior to treatment according to the present invention, the level of the marker is determined in the subject before treatment; to determine the effectiveness of treatment, the specified level of the marker before treatment can then be compared with the level of the marker in the subject after the start of treatment.

In some embodiments of the method, the level of the marker or marker activity in the subject is determined at least once. Comparison of marker levels, for example, with another measurement of marker level obtained previously or subsequently from the same patient, another patient, or a normal subject, may be useful in determining whether a therapy in accordance with the present invention has the desired effect, and thereby allows you to adjust dosage levels depending on the situation. Determination of marker levels can be performed using any suitable sample/expression analysis method known in the art or noted herein. Preferably, a tissue or fluid sample is first removed from the subject. Examples of suitable samples include blood, urine, tissue, oral or cheek cells, and hair samples containing roots. The person skilled in the art is aware of other suitable examples. Determination of protein levels and/or mRNA levels (e.g., marker levels) in said sample can be performed using any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA (enzyme-linked immunosorbent assay), techniques radioactive label/assay, blotting/chemiluminescence methods, real-time PCR, and the like.

The present invention also provides kits for use in the treatment of diseases, disorders, or symptoms thereof, including those described herein. These kits contain: a) a pharmaceutical composition containing a compound of any of the formulas herein or a pharmaceutically acceptable salt thereof; or a prodrug thereof or a pharmaceutically acceptable salt of a prodrug thereof; or a hydrate, solvate or polymorph thereof, wherein said pharmaceutical composition is in a container; and b) instructions describing the method of using the pharmaceutical composition for the treatment of a disease, disorder or symptoms thereof, including those described herein.

The container may be any vessel or other sealing or sealing device that can contain said pharmaceutical composition. Examples include vials, vials with split or multi-chamber holders in which each compartment or chamber contains one dose of said composition, a divided foil pack where each compartment contains one dose of said composition, or a dispenser that dispenses individual doses of said composition. The container may be of any conventional shape or form known in the art and made of a pharmaceutically acceptable material, such as a paper or cardboard box, a glass or plastic bottle or jar, a resealable pouch (for example, for refilling tablets to be placed in other container) or blister pack with individual doses to be squeezed out of the pack in accordance with the therapeutic schedule. The type of container used may depend on the particular dosage form, for example, a conventional carton box is usually not used to store a liquid suspension. For the sale of one dosage form, it is possible to use more than one container together in one package. For example, tablets may be contained in a vial, which in turn is contained in a box. Preferably the container is a blister pack.

The kit may further contain information and/or instructions for the physician, pharmacist or subject. Such memory aids include numbers printed on each chamber or compartment containing a dosage that corresponds to the days of the regimen on which the tablets or capsules so indicated are to be taken, or the days of the week printed on each chamber or compartment, or a card that contains information of the same type.

The compounds described herein can be evaluated for their biological activity using protocols known in the art, including, for example, those noted herein. Some of the compounds provided herein exhibit unexpectedly superior properties (eg, P450 inhibition, metabolic stability, pharmacokinetic properties, etc.), making them excellent candidates as potential therapeutic agents.

All references cited herein, whether in printed, electronic, computer-readable media or other forms, are expressly incorporated by reference in their entirety, including, but not limited to, invention abstracts, articles, journals, publications, texts, treatises , data sheets, internet sites, databases, patents, patent applications and patent publications.

Examples

Example 1 Synthesis of trans-4-[2-[(R)-1-hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexanecarbonitrile (1)

- 18 040948

Scheme 1

Step 1: A solution of trans-4-(Boc-amino)cyclohexanecarboxylic acid (A1-1) (62 g, 0.256 mol, 1.0 eq) in THF (1500 mL) was treated with N-methylmorpholine (NMM) (64.6 g , 0.64 mol, 2.5 eq) in a nitrogen atmosphere. The mixture was cooled to -78° C. and isobutyl chloroformate (33.6 g, 0.33 mol, 1.3 eq) was added dropwise. After stirring at -78°C for 1 hour, the NH ₃ (gas) mixture was bubbled through for about 20 minutes. After that, the reaction temperature was raised to -30°C, then stirred at -30°C for 1 hour. The resulting suspension was filtered, washed with water (3*200 ml) and dried in an oven to obtain compound A1-2 as a white powder ( 58 g, 93.5% yield. MS-ESI: [M+1]+: 243.1.

Ή NMR (300 MHz, d ₆ -DMSO): 7.192 (s, 1H), 6.688-6.728 (m, 2H), 3.122-3.147 (m, 1H), 1.92-1.959 (m, 1H), 1.696- 1.787 (m, 4H), 1.382 (s, 9H), 1.086-1.358 (m, 4H).

Step 2 A solution of compound A1-2 (74 g, 0.306 mol, 1.0 eq) in DCM (1000 ml) was treated with triethylamine (77.2 g, 0.64 mol, 2.5 eq). The mixture was cooled to 0° C. in an ice bath and TFUA (80.9 g, 0.383 mol, 1.25 eq) was added dropwise. After the addition, the ice bath was removed and the reaction temperature was raised to 20° C., then stirred at 20° C. for 2 h, water (300 ml) was added, and then the aqueous phase was subjected to extraction with DCM twice. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give Compound A1-3 as a white powder (46 g, 67.1% yield). MSIER: [M+1]+: 225.1.

Ή NMR (300 MHz, CDCl ₃ ): 4.397 (m, 1H), 3.467 (m, 1H), 2.381-2.418 (m, 1H), 2.079-2.147 (m, 4H), 1.613-1.757(m, 2H) , 1.454 (s, 9H), 1.114-1.232 (m, 2H).

Step 3 To a solution of compound A1-3 (10 g, 44.6 mmol, 1.0 eq) in DCM (50 ml) was added TFA (20 g). The reaction mixture was stirred for 2 h at room temperature until the reaction was complete, which was determined by TLC, then the mixture was concentrated under vacuum. Ice water (30 ml) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/l) until pH 10. The aqueous phase was then subjected to extraction six times with DCM/methanol (10/1). The combined extracts were dried over anhydrous sodium sulfate, concentrated to give compound A1-4 as an off-white solid (5.1 g, 91.9% yield). MS-ESI: [M+1]+: 125.1.

Ή NMR (300 MHz, CDCI3): 2.738-2.772 (m, 1H), 2.370-2.421 (m, 1H), 2.115-2.170 (m, 2H), 1.923-1.977 (m, 2H), 1.580-1.694 (m , 2H), 1.075-1.197 (m, 2H)

Step 4. To a solution of 2-bromo-3-hydroxypyridine (A1-5) (225 g, 1.293 mol, 1.0 eq), trimethylsilylacetylene (153.3 g, 1.592 mol, 1.23 eq) in 1.4- dioxane (2500 ml) was added CuI (25 g) and Pd(PPh ₃ ) ₂ Cl ₂ (45 g) under nitrogen atmosphere. The reaction mixture was stirred for 30 min at 25°C, then cooled

- 19 040948 to 10° C. and triethylamine (363 g, 3.594 mol, 2.78 eq) was added dropwise. After stirring for 4 hours at 60° C., the solution was cooled and concentrated in vacuo. Water (2000 ml) and methyl tert-butyl ether (MTBE) (200 ml) were added to the residue, stirred and filtered. The filtrate was subjected to extraction with MTBE (1000 ml*2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A1-6 as a light brown liquid (150 g, 60.7% yield). GC-MS: 191 (EI)

Step 5 To a solution of compound A1-6 (105 g, 0.55 mol, 1.0 eq) in DCM (1000 ml) was added m-chloroperoxybenzoic acid (85%, 230 g, 1.13 mol, 12.06 eq) at temperatures below 25°C. After stirring overnight at room temperature, saturated sodium bicarbonate solution was added to pH 7-8 in an ice bath. The resulting mixture was filtered, the filtrate was separated and extracted twice with DCM. The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, concentrated to give compound A1-7 as a brown liquid (115 g, 100% yield).

Step 6 A solution of compound A1-7 (115 g, 0.55 mol, 1.0 eq) in toluene (400 ml) was added to phosphorus oxychloride (400 ml) in an ice bath at a temperature below 30°C. The reaction mixture was stirred for 2 h at 90°C, cooled to room temperature and concentrated. A saturated sodium bicarbonate solution was slowly added to the residue to pH 7-8 at a temperature below 20°C, and the mixture was subjected to MTBE extraction twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A1-8 as a yellow liquid (73 g, 58.7% yield). GC-MS: 225 (EI)

Step 7 To a solution of compound A1-8 (73 g, 0.323 mol, 1.0 eq) in THF (400 ml) was added aqueous sodium hydroxide solution (300 ml, 4 mol/l). After stirring for 1 hour at 50° C., the reaction mixture was cooled to room temperature and 1000 ml of water was added. The mixture was subjected to MTBE extraction twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from ethyl acetate and petroleum ether to give Compound A1-9 as an off-white powder (30 g, 60.5% yield). GC-MS: 153 (EI) ¹ H NMR (300 MHz, CDCl3): 8.485 (d, 1H), 7.945 (d, 1H), 7.312 (d, 1H), 7.079 (d, 1H).

Step 8 Compound A1-9 (9.21 g, 60 mmol, 1.0 eq) was dissolved in methanol (150 ml), then water (150 ml) and sodium hydroxide (24 g, 10 eq) were added. After stirring for 1 hour at 50°C, the reaction mixture was cooled to 20°C and concentrated. The residue was extracted three times with DCM, then the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give compound A1-10 as a yellow liquid (5.5 g, 61.5% yield). MS-ER: [M+1]+: 150.

Step 9 Compound A1-10 (5.5 g, 37 mmol, 1.0 eq) was added to 40% aqueous HBr (150 mL). The reaction mixture was heated at reflux for 18 h, cooled and concentrated. The residue was treated with saturated sodium bicarbonate solution (100 ml) to pH 7-8. After stirring for 20 minutes, the precipitate was filtered, washed with water and dried in an oven to give compound A1-11 as an off-white powder (3.1 g, 62% yield). MS-ER:[M+1]+: 136.

Step 10 A mixture of compound A1-11 (1.68 g, 12.4 mmol, 1.0 eq) in 120 ml DCM was cooled to -5° C. under nitrogen and tetrabutylammonium nitrate (5.17 g, 17 mmol, 1.36 eq) in DCM (30 ml) below 0° C., then all TFUA (5.17 g, 20 mmol, 1.6 eq) was added at once. After the addition, the reaction mixture was stirred at -5° C. for 1 h and then warmed to 25° C. and stirred for 15 h. The solvent was concentrated, ether (200 ml) was added to the residue, stirred and filtered. The filter cake was collected and saturated sodium bicarbonate solution (100 ml) was added. The mixture was extracted twice with ethyl acetate, then the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give compound A112 as a yellow powder (1.37 g, 61.4% yield). MS-ER:[M+1]+: 181.

Step 11 A mixture of compound A1-12 (1.37 g, 7.61 mmol, 1.0 eq) and propionic acid (50 ml) was heated to 110°C, then fuming nitric acid (0.65 ml) was added dropwise at a temperature of 110°C-120°C. After stirring for 30 min at 125° C. and cooling to room temperature, ether (100 ml) was added, the resulting solid was filtered off, washed with ether and dried under vacuum to give compound A1-13 as a yellow powder (1.2 g , yield 87.6%). MS-ER:[M+1]+: 181.

1H NMR (300 MHz, d6-DMSO): 13.149 (s, 1H), 9.024 (s, 1H), 8.234 (d, 1H), 6.966 (d, 1H).

Step 12 To a solution of compound A1-13 (1.2 g, 6.67 mmol, 1.0 eq) in 1,2-dichloroethane (50 ml) was added phosphorus oxychloride (15 ml) at a temperature below 20°C, then stirred for 2 h at 95° C. under nitrogen, cooled to 25° C. and concentrated. A saturated sodium bicarbonate solution was slowly added to the residue to pH 7-8 at a temperature below 20°C, and the mixture was subjected to MTBE extraction twice.

- 20 040948

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A1-14 as a light yellow powder (0.8 g, 60.4% yield),

1H NMR (300 MHz, CDCl ₃ ): 9.250 (s, 1H), 8.189 (d 1H), 7.191 (d, 1H).

Step 13 To a solution of A1-14 (280 mg, 1.41 mmol, 1.0 eq) in n-butanol (20 ml) was added compound A1-4 (290 mg, 2.34 mmol, 1.66 eq) and diisopropylethylamine (DIPEA) (403 mg, 3.12 mmol, 2.21 eq). The reaction mixture was stirred for 1 h at 135° C., concentrated and purified by silica gel column chromatography to give A1-15 as a yellow powder (320 mg, 79.4% yield). MS-ESI: [M+1] ⁺ : 287.1. ¹ H NMR (300 MHz, CDCl3): 9.268 (s, 1H), 8.653 (d, 1H), 7.952 (d, 1H), 7.034 (d, 1H), 4.423-4.511 (m, 1H), 2.629-2.723 (m, 1H), 2.241-2.355 (m, 4H), 1.864-1.902 (m, 2H), 1.5391.578 (m, 2H).

Step 14 To a solution of A1-15 (320 mg, 1.12 mmol, 1.0 eq) in methanol (15 mL) was added 10% Pd/C (0.3 g, 50 wt%). Hydrogenation was carried out at atmospheric pressure and room temperature until the absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrates were concentrated in vacuo to give A1-16 as a yellow oil (286 mg, 100% yield). MS-ESI: [M+1] ⁺ : 257.1

Step 15. Solution of (R)-(+)-lactamide (259 mg, 2.8 mmol, 5.0 eq) and Et ₃ O-BF ₄ (543 mg, 2.8 mmol, 5.0 eq) in THF (10 ml) was stirred for 30 min at room temperature under nitrogen. The above solution was then added to a mixture of Al-16 (143 mg, 0.56 mmol, 1.0 eq) in ethanol (10 ml). After stirring for 2 h at 85°C, the mixture was concentrated, water was added and extracted four times with ethyl acetate. The organic phase was discarded and the aqueous phase was treated with saturated sodium bicarbonate solution (100 ml) to pH 8, subjected to extraction twice with ethyl acetate. The second organic phases were dried over anhydrous sodium sulfate, concentrated to give the title compound as a light yellow powder (80 mg, 46% yield). MS-ESI: [M+1] ⁺ : 311.4.

1H NMR (300 MHz, CDCl ₃ ): 9.005 (s, 1H), 7.949 (s, 1H), 7.256 (s, 1H), 5.227-5.290 (m, 1H), 4.766-4.843 (m, 1H), 2.783 -2.864 (m, 1H), 2.438-2.527 (m, 4H), 2.068-2.192 (m, 2H), 1.913-2.003 (m, 2H), 1.767-1.846 (d, 3H).

Example 2 Synthesis of trans-4-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexanecarbonitrile (2)

Scheme 2

Example 2 was prepared using the same procedure as in example 1, except that (R)-(+)lactamide was replaced by 2-hydroxyacetamide in step 15): 40 mg of the title compound as a light yellow powder, MS-ESI: [M+1] ⁺ : 297.4.

1H NMR (300 MHz, CDCl ₃ ): 9.048 (s, 1H), 7.965 (s, 1H), 7.286 (s, 1H), 5.049 (s, 2H), 4.702-4.813 (m,

- 21 040948

1H), 2.753-2.873 (m, 1H), 2.376-2.527 (m, 4H), 2.087-2.226 (m, 2H), 1.872-2.053 (m, 2H).

Example 3 Synthesis of 2-[trans-4-[2-[(R)-1-hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexyl]acetonitrile (3 )

Scheme 3

Step 1. To a solution of trans-1,4-cyclohexane-dicarboxylic acid monomethyl ester (A3-1) (100 g, 0.538 mol, 1.0 eq) and triethylamine (57.4 g, 0.568 mol, 1.055 eq) in tert -butyl alcohol (1000 ml) was added dropwise diphenylphosphoryl azide (155 g, 0.563 mol, 1.047 eq) under nitrogen at room temperature. The mixture was heated at reflux for more than 16 hours. After completion of the reaction, which was determined by TLC, the mixture was cooled and concentrated. Water (1000 ml) was added and the mixture was subjected to MTBE extraction three times. The organic layer was then washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give Compound A3-2 as an off-white powder (53 g, 39.2% yield). MS-ESI: [M+1]+: 257.1.

Step 2: A suspension of LiAlH ₄ (9.0 g, 0.236 mol, 1.12 eq) in THF (500 ml) was cooled to 0° C. in an ice bath, and then a solution of compound A3-2 (54.3 g, 0.211 mol, 1.0 eq) in THF (200 ml), keeping the temperature below 10°C. The reaction mixture was stirred overnight at room temperature and then quenched with sodium sulfate decahydrate (27 g) at 15-25° C., filtered and the filtrate was concentrated to give compound A3-3 as a white powder (43 g, 89% yield). MSIER: [M+1]+: 229.1.

Step 3 To a mixture of compound A3-3 (11.5 g, 0.05 mol, 1.0 eq) and triethylamine (7.6 g, 0.075 mol, 1.5 eq) in DCM (200 ml) was added dropwise methylsufonyl chloride (6.9 g, 0.06 mol, 1.2 eq) below 10°C. After stirring for 2 hours at room temperature, water (300 ml) was added. The mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A3-4 as a yellow liquid (16.0 g, 100% yield). MS-IES: [M+1]+: 307.1.

Step 4 To a solution of compound A3-4 (16.0 g, 0.05 mol, 1.0 eq) in DMSO (150 ml) was added sodium cyanide (7.0 g, 0.143 mol, 2.86 eq) in portions at temperatures below 20°C. After stirring for 5 hours at 85° C., the mixture was cooled to room temperature, ice water (500 ml) was added. The mixture was subjected to MTBE extraction twice. The combined extracts were washed three times with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A3-5 as a white powder (9.3 g, 78% yield). MS-ESI: [M+1]+: 238.1.

¹ H NMR (300 MHz, CDCl ₃ ): 4.408 (m, 1H), 3.405 (m, 1H), 2.263-2.285 (d, 2H), 2.064-2.096 (m, 2H), 1.457 (s, 9H), 1.122-1.281 (m, 4H).

Step 5 To a solution of compound A3-5 (1.1 g, 4.6 mmol, 1.0 eq) in DCM (10 ml) was added TFA (6 g). The reaction mixture was stirred for 2 hours at room temperature, then concentrated in vacuo. Ice water (15 ml) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/l) to pH 10. The aqueous phase was then subjected to extraction five times with DCM/methanol (10/1). The combined extracts were dried over anhydrous sodium sulfate, concentrated to give

- 22 040948 compound A3-6 as a yellow oil (0.55 g, 87.7% yield). MS-ESI: [M+1]+: 138.1.

Steps 6-8 are the same as Steps 13-15 in Example 1 except that the amine A1-4 is replaced with A3-6 to give the title compound: 70 mg light yellow powder (yield: 0.565%). MS-ESI: [M+1] ⁺ : 325.5.

¹ H NMR (300 MHz, CDCl ₃ ): 9.003 (s, 1H), 7.965 (s, 1H), 7.270 (s, 1H), 5.255-5.298 (m, 1H), 4.713-4.795 (m, 1H), 2.439-2.611 (m, 4H), 2.068-2.512 (m, 5H), 1.808-1.829 (d, 3H), 1.452-1.576 (d, 2H).

Example 4 Synthesis of 2-[(2R,5S)-5-[2-[(R)-1-hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran -2-yl]acetonitrile (4)

Scheme 4

A4-1 A4-2 D4-3 A4-4

A4-5 _A4 _ ₆ A4-7 A4-8

Step 1. In a round bottom flask to a stirred solution of di-tert-butyl dicarbonate (162 g, 0.744 mol, 1.2 eq) and compound A4-1 (100 g, 0.62 mol, 1.0 eq) in water (500 ml ) and 1,4-dioceane (500 mL) triethylamine (188 g, 1.86 mol, 1.0 eq) was added dropwise. After stirring for 18 hours at room temperature, the solution was subjected to extraction with MTBE (500 ml*2), the aqueous phase was cooled on ice and carefully acidified to pH 3 by slowly adding 10% citric acid solution. The urethane was then extracted twice with ethyl acetate, the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give compound A4-2 as a clear viscous oil (180 g, 100% yield). MS-ESI: [M+1] ⁺ : 262.1.

Step 2 A solution of compound A4-2 (40 g, 0.153 mmol, 1.0 eq) in THF (600 ml) was treated with 4-methylmorpholine (17 g, 0.168, 1.1 eq) at room temperature. The resulting mixture was cooled to 0° C. followed by dropwise treatment with isobutyl chloroformate (22.7 g, 0.166 mmol, 1.08 eq). The resulting reaction mixture was stirred at 0°C for an additional 20 min, followed by filtration and washing with THF. Then the clear solution of the filtrate was cooled to 0°C, and treated with a solution of NaBH ₄ (11.2 g, 0.295 mol, 1.93 eq) in water (100 ml). The resulting mixture was stirred overnight at room temperature and then quenched dropwise with aqueous HCl (1.0 mol/l, 200 ml). The mixture was subjected to extraction with ethyl acetate, the combined extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated to give compound A4-3 as a yellow oil (25 g, 66% yield). MS-ESI: [M+1] ⁺ : 248.1.

Step 3 A solution of compound A4-3 (25 g, 0.1 mol, 1.0 eq) in toluene (300 ml) and acetic acid (150 ml) was heated at reflux for 5 h, then cooled and concentrated under vacuum . To the residue was added a saturated solution of sodium bicarbonate to pH 7-8 in an ice bath. The mixture was then extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from ethyl acetate and PE (petroleum ether) to give compound A4-4 as a white powder (8.0 g, yield 37 .2%). GC-MS: 215.

Step 4 A solution of tributylphosphine (72.9 g, 0.36 mol, 1.0 eq) in nitromethane (500 ml) was added dropwise to chloroacetonitrile (27.2 g, 0.36 mol, 1.0 eq) under atmospheric nitrogen. The resulting reaction mixture was stirred for 16 h at room temperature, then concentrated. The residual oil solidified with the addition of a small amount of ethyl acetate. The solid was recrystallized from ethyl acetate and DCM to give compound A4-5 as a white powder (95 g, 95% yield).

Step 5 To a solution of dry compound A4-5 (8.3 g, 30 mmol, 3.0 eq) in N,N-dimethylacetamide (30 ml) was added portionwise solid potassium tert-butoxide (3.1 g, 28 mmol, 2.8 eq) in a nitrogen atmosphere at 0°C. The resulting mixture was gradually heated to 30°C and stirred for 2 hours. The resulting ylide solution was then treated with compound A4-4 (2.15 g, 10 mmol, 1.0 eq) and stirred for

- 23 040948 nights at 70°C. After cooling to room temperature, the resulting suspension was poured into a mixture of ice water (100 ml) and saturated sodium bicarbonate solution (100 ml). The mixture was extracted twice with ethyl acetate, the combined extracts were washed three times with brine, dried over anhydrous sodium sulfate, concentrated to give compound A4-6 as a yellow oil without purification (7.5 g, 100% yield). MS-ESI: [M+1]+: 239.1.

Step 6 To a solution of compound A4-6 (7.5 g, 10 mmol, 1.0 eq) in methanol (200 ml) was added 10% Pd/C (0.5 g, 50 wt %). Hydrogenation was carried out at atmospheric pressure at room temperature until the absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrates were concentrated in vacuo and purified by silica gel column chromatography to give compound A4-7 as an off-white powder (1.6 g, 66.7% yield). MS-ESI: [M+1]+: 241.1.

Step 7 To a solution of compound A4-7 (1.6 g, 6.67 mmol, 1.0 eq) in DCM (20 ml) was added TFA (10 g, 88.5 mmol, 13.2 eq). The reaction mixture was stirred for 2 h at room temperature until the reaction was complete, which was determined by TLC, then concentrated under vacuum. Water (20 ml) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/l) to pH 10. The aqueous phase was then subjected to extraction six times with a mixture of DCM/methanol (10/1). The combined extracts were dried over anhydrous sodium sulfate, concentrated to give compound A4-8 as a light brown oil (950 mg, 100% yield). MS-ESI: [M+1]+: 141.1.

Step 8 To a solution of compound A1-14 (obtained by the same procedure as in steps 4-12 in example 1) (600 mg, 3.0 mmol, 1.0 eq) in n-butanol (15 ml) was added the compound A4-8 (950 mg, 6.7 mmol, 2.26 eq) and DIPEA (1.36 g, 10.5 mmol, 3.5 eq). The reaction mixture was stirred for 1 hour at 135° C., concentrated and purified by silica gel column chromatography to give compound A4-9 (2R, 5S) as a light yellow powder (254 mg, 28.0% yield). -ESI: [M+1] ⁺ : 303.1.

1H NMR (300 MHz, d ₆ -DMSO): 9.063 (s, 1H), 8.503 (d, 1H), 9.326 (d, 1H), 7.176 (d, 1H), 4.431-4.513 (m, 1H), 4.128 -4.156 (m, 1H), 3.633-3.659 (m, 1H), 3.448-3.518 (m, 1H), 2.775-2.841 (m, 2H), 2.205-2.312 (m, 1H), 1.829-1.859 (m, 2H), 1.501-1.521 (m, 1H).

Step 9 To a solution of compound A4-9 (254 g, 0.84 mmol, 1.0 eq) in methanol (20 ml) was added 10% Pd/C (0.15 g, 50 wt %). Hydrogenation was carried out at atmospheric pressure at room temperature until the absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrates were concentrated in vacuo to give compound A4-10 as a yellow oil (230 mg, 100% yield). MS-ESI: [M+1]+: 273.1.

Step 10 Solution of D-lactamide (388 mg, 4.2 mmol, 5.0 eq) and Et ₃ O-BF ₄ (1.3 g, 6.72 mmol, 8.0 eq) in THF (10 ml) stirred for 30 min at room temperature under nitrogen. The above solution was then added to a mixture of compound A4-10 (230 mg, 0.84 mmol, 1.0 eq) in ethanol (10 ml). After stirring for 3 hours at 85° C. until completion of the reaction, which was determined by HPLC, the mixture was concentrated, water was added and subjected to extraction four times with ethyl acetate. The organic phases were discarded and the aqueous phase was treated with saturated sodium bicarbonate to pH 8, extracted twice with ethyl acetate. The second organic phases were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as a light yellow powder (120 mg, 43.8% yield). MS-ESI: [M+1]+: 327.6.

1H NMR (300 MHz, CDCl ₃ ): 9.039 (s, 1H), 7.939 (d, 1H), 7.196 (d, 1H), 5.235-5.336 (m, 1H), 4.806-4.973 (m, 1H), 4.403 -4.483 (t, 1H), 4.096-6.116 (m, 2H), 2.700-2.807 (m, 4H), 2.105-2.312 (m, 2H), 1.830-1.852 (d, 3H).

Example 5 Synthesis of 3-[2-[(R)-1-hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2 ,2trifluoroethyl)pyrrolidine-1-carboxamide (5)

- 24 040948

Scheme 5

Step 1 To a solution of compound A1-14 (obtained by the same procedure as steps 4-12 in example 1) (820 mg, 4.13 mmol, 1.0 eq) in n-butanol (15 ml) was added compound A5-3 (1.0 g, 5.37 mmol, 1.3 eq) and DIPEA (1.6 g, 12.4 mmol, 3.0 eq). The reaction mixture was stirred for 1 hour at 135° C., concentrated and purified by silica gel column chromatography to give Compound A5-4 as a yellow powder (1.32 g, 91.8% yield). MS-ESI: [M+1]+: 349.1.

Step 2 To a solution of compound A5-4 (1.32 g, 3.8 mmol, 1.0 eq) in DCM (15 ml) was added a solution of HCl in ethanol (30% w/w) (15 ml). The reaction mixture was stirred for 2 h at room temperature until completion of the reaction, which was confirmed by TLC, then concentrated under vacuum. Ice water (20 ml) was added and the solution was treated with aqueous sodium hydroxide solution (4 mol/l) to pH 10. The aqueous phase was then subjected to extraction with DCM three times. The combined extracts were dried over anhydrous sodium sulfate, concentrated to give compound A5-5 as a yellow powder (950 mg, 100% yield). MS-ESI: [M+1]+: 249.1.

Step 3: Mixture of 2,2,2-trifluoroethylamine (A5-1) (1.21 g, 12.2 mmol, 1.0 eq) and pyridine (2.4 g, 30.5 mmol, 2.5 eq) in DCM (50 ml) was cooled to 0°C, and treated dropwise with a solution of triphosgene (1.34 g, 4.52 mmol, 0.37 eq) in DCM (50 ml) at a temperature below 5°C. After this solution was added, the reaction mixture was stirred at 35°C for 1 hour and then at 25°C for 2 hours. The isocyanate solution (A5-2) was used in the next step without purification.

Step 4 A mixture of compound A5-5 (0.95 g, 3.8 mmol, 1.0 eq) and pyridine (0.45 g, 5.7 mmol, 1.5 eq) in DCM (60 ml) was cooled to 10° C. and treated dropwise with a solution of isocyanate (A5-2) (12.2 mmol, 3.2 eq). The reaction mixture was heated at reflux for 3 hours and then cooled. Saturated sodium bicarbonate solution (200 ml) was added and the mixture was extracted twice with DCM. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A5-6 as a yellow powder (850 mg, 60% yield). MS-ESI: [M+1]+: 374.3.

'll NMR (300 MHz, d6-DMSO): 9.282 (s, 1H), 8.718 (d, 1H), 7.962 (d, 1H), 7.024 (d, 1H), 5.165-5.186 (m, 1H), 4.642 (m, 1H), 3.926-4.008 (m, 3H), 3.517-3.675 (m, 3H), 2.502-2.568 (m, 1H), 2.206-2.267 (m, 2H).

Step 5 To a solution of compound A5-6 (850 mg, 2.28 mmol, 1.0 eq) in methanol (80 ml) was added 10% Pd/C (0.45 g, 50% wt). Hydrogenation was carried out at atmospheric pressure and room temperature until the absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo to give compound A5-7 as a brown oil (800 mg, 100% yield). MS-ESI: [M+1]+: 344.3.

Step 6: Solution of D-lactamide (1.27 g, 13.68 mmol, 6.0 eq) and Et ₃ O-BF ₄ (3.53 g, 18.24 mmol, 8.0 eq) in THF (20 ml) was stirred for 30 min at room temperature under nitrogen. The above solution was then added to a mixture of compound A5-7 (800 mg, 2.28 mmol, 1.0 eq) in ethanol (20 ml). After stirring for 5 hours at 85° C. until completion of the reaction, which was determined by HPLC, the mixture was concentrated, HCl (1 mol/l, 30 ml) was added and subjected to extraction four times with ethyl acetate. The organic phases were discarded and the aqueous phase was treated with saturated sodium bicarbonate to pH 8 and extracted three times with ethyl acetate. The second organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as a light yellow powder (530 mg, 58.5% yield). MS-ER: [M-1] ^- : 396.5.

1H NMR (300 MHz, d ₆ -DMSO): 8.931 (s, 1H), 8.338 (d, 1H), 7.276 (d, 1H), 7.007 (m, 1H), 5.889-5.910 (m, 1H), 5.661 -5.683 (m, 1H), 5.251-5.273 (m, 2H), 3.652-3.970 (m, 5H), 3.435-3.505 (m, 1H), 2.455-2.712 (m,

- 25 040948

2H), 1.672 (d, 3H).

Example 6 Synthesis of (R)-4-[2-(1-hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2 ,2trifluoroethyl)piperidine-1-carboxamide (6)

Scheme 6

Preparation procedure similar to that described in Example 5 to obtain the title compound as an off-white powder (21 mg, yield: 6.7%), MS-ESI: [M-1] ^- : 410.6.

¹ H NMR (300 MHz, CD ₃ OD): 8.862 (s, 1H), 8.046 (d, 1H), 7.150 (d, 1H), 5.152-5.383 (m, 2H), 4.3254.386 (m, 2H), 3.990-4.022 (m, 2H), 3.110-3.192 (m, 2H), 2.423-2.653 (m, 2H), 1.984-2.117 (m, 2H), 1.7931.915 (d, 3H).

Example 7 Synthesis of 2-[(2R,5S)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (7)

Step 1. To a solution of compound A1-14 (500 mg, 2.0 mmol, 1.0 eq) in butyl alcohol (8 ml) was added compound A4-8 (350 mg, 2.5 mmol, 1.0 eq) and DIPEA (403 mg, 8.25 mmol, 3.3 eq) under nitrogen atmosphere. The reaction mixture was stirred 2 h at 135° C., then concentrated and purified by silica gel column chromatography to give compound A4-9 as a yellow solid (194 mg, 25.6% yield). MS-ESI: [M+1]+: 302.3.

Step 2 To a solution of compound A4-9 (97 mg, 1.0 mmol) in methanol (15 ml) was added 10% Pd/C (50 mg, 50 wt%). Hydrogenation was carried out at atmospheric pressure and room temperature until the absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrate was concentrated to give compound A4-10 as a yellow oil (535 mg, yield: 100%). MS-ESI: [M+1] ⁺ : 272.5.

Stage 3. A solution of glycolamide (126 mg, 1.6 mmol, 5.0 eq) and Et ₃ O-BF ₄ (310 mg, 1.6 mmol, 5.0 eq) in THF (10 ml) was stirred for 30 min at room temperature under a nitrogen atmosphere. The above solution was then added to a mixture of compound A4-10 (88 mg, 0.32 mmol, 1.0 eq) in ethanol (10 ml). After stirring for 12 hours at 85° C., the mixture was concentrated, water was added and extracted three times with ethyl acetate. The organic phases were discarded and the aqueous phase was treated with saturated sodium bicarbonate solution (100 ml) to pH: 8, then the mixture was extracted twice with ethyl acetate. The second organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound in

- 26 040948 as an off-white powder (70 mg, yield: 70%). MS-ESI: [M+1]+: 313.5.

1H NMR (300 MHz, CDCl3): 9.00 (s, 1H), 7.95(d, 1H), 7.26 (d, 1H), 5.27-5.29 (m, 1H), 4 .76-4.84 (m, 1H), 2.78-2.86 (m, 1H), 2.43-2.52 (m, 4H), 2.06-2.19 (m, 2H) , 1.91-2.00 (m, 2H), 1.76-1.84 (d, 3H).

Example 8 Synthesis of 2-[(2S,5S)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (8)

Step 1. To a solution of compound A1-14 (500 mg, 2.0 mmol, 1.0 eq) in butyl alcohol (8 ml) was added compound A4-8 (350 mg, 2.5 mmol, 1.0 eq) and DIPEA (403 mg, 8.25 mmol, 3.3 eq) under nitrogen atmosphere. The reaction mixture was stirred 2 h at 135° C., then concentrated and purified by silica gel column chromatography to give compound A8-1 as a yellow solid (67 mg, 8.84% yield). MS-ESI: [M+1] ⁺ : 302.3.

Step 2 To a solution of compound A8-1 (67 mg, 1.0 mmol) in methanol (10 ml) was added 10% Pd/C (30 mg, 50 wt%). Hydrogenation was carried out at atmospheric pressure and room temperature until the absorption of hydrogen ceased. The catalyst was filtered off and washed with methanol. The filtrate was concentrated to give compound A8-2 as a yellow oil (60 mg, yield: 100%). MS-ESI: [M+1] ⁺ : 272.5.

Stage 3. A solution of glycolamide (105 mg, 1.33 mmol, 6.0 eq) and Et ₃ O-BF4 (258 mg, 1.33 mmol, 6.0 eq) in THF (10 ml) was stirred for 30 min at room temperature temperature in a nitrogen atmosphere. The above solution was then added to a mixture of compound A8-2 (60 mg, 0.221 mmol, 1.0 eq) in ethanol (10 ml). After stirring for 12 hours at 85° C., the mixture was concentrated, water was added and extracted three times with ethyl acetate.

The organic phases were discarded and the aqueous phase was treated with saturated sodium bicarbonate solution (100 ml) to pH: 8, then the mixture was extracted twice with ethyl acetate. The second organic phases were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as an off-white powder (21 mg, yield: 30.5%). MS-ESI: [M+1] ⁺ : 313.5.

1H NMR (300 MHz, CD3OD): 8.85 (s, 1H), 8.29 (d, 1H), 7.18 (d, 1H), 4.98 (d, 3H), 4.35-4 .42 (m, 2H), 3.95-3.99 (m, 1H), 3.48-3.65 (m, 1H), 3.04-3.11 (m, 1H), 2.67 -2.76 (m, 1H), 1.97-2.31 (m, 3H).

Example 9 Synthesis of 2-[(2R, 5S)-5-[2-ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2yl]acetonitrile (9)

A solution of compound A4-10 (1.1 g, 4.04 mmol, 1.0 eq) and trimethylorthopropionate (2.2 ml) in 1,2dichloroethane (50 ml) was refluxed under nitrogen and then pyridine hydrochloride ( 200 mg). The reaction mixture was stirred for 2 hours at 80°C, concentrated and treated with saturated sodium bicarbonate solution to pH: 8. The mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as a yellow solid (800 mg, yield: 63.8%). MS-ESI: [M+1] ⁺ : 311.0.

1H NMR (300 MHz, CDCl ₃ ): 9.01 (s, 1H), 7.91 (d, 1H), 7.17 (d, 1H), 4.54-4.59 (m, 1H), 4.33-4.38 (t, 1H), 4.05-4.09 (m, 2H), 3.01-3.06 (m, 2H), 2.70-2.83 (m, 3H ), 2.15-2.19 (m, 2H), 1.85-1.92 (m, 1H), 1.49-1.54 (t, 3H).

Example 10 Synthesis of 2-[(2R,5S)-5-[2-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10)

- 27 040948

To a solution of compound A4-10 (136 mg, 0.5 mmol, 1.0 eq) in trimethyl orthoformate (5.0 ml) was added formic acid (1.0 ml) under nitrogen atmosphere. The reaction mixture was stirred 1 h at 80°C, concentrated and treated with saturated sodium bicarbonate solution (100 ml) to pH 8. The mixture was subjected to extraction twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as a yellow solid (400 mg, yield: 28.4%). MS-ESI: [M+1]+: 282.9.

¹ H NMR (300 MHz, CDCl ₃ ): 9.10 (s, 1H), 7.94 (s, 1H), 7.92 (d, 1H), 7.19 (d, 1H), 4.76 -4.79 (m, 1H), 4.324.37 (m, 1H), 3.92-4.03 (m, 2H), 2.71-2.73 (d, 2H), 2.46-2 .51 (m, 2H), 2.17-2.21 (m, 1H), 1.89-1.91 (m, 1H).

Example 11 Synthesis of 2-[(2R, 5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran2-yl]acetonitrile (11)

A solution of compound A4-10 (1.0 g, 3.67 mmol, 1.0 eq) and trimethylorthoacetate (2.0 ml) in 1,2dichloroethane (30 ml) was refluxed under nitrogen and then pyridine hydrochloride ( 200 mg). The reaction mixture was stirred for 2 hours at 80°C, concentrated and treated with saturated sodium bicarbonate solution to pH: 8. The mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give the title compound as a yellow solid (500 mg, yield: 46.0%). MS-ESI: [M+1] ⁺ : 296.9.

¹ H NMR (300 MHz, CDCl ₃ ): 8.98 (s, 1H), 7.91 (d, 1H), 7.16 (d, 1H), 4.54-4.59 (m, 1H) , 4.31-4.38(t, 1H), 4.02-4.09(m, 2H), 2.71-2.82(m, 6H), 2.15-2.22(m, 2H), 1.85-1.92 (m, 1H).

Biological test example B1. Biological studies with Jak1, 2, 3, Tyk2.

The studies were performed by Reaction Biology Corp, Malvern, PA. The methodology is briefly described below.

Reagent.

Basic reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA (tetraacetic acid ethylene glycol), 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT (dithiothreitol), 1% DMSO. The necessary cofactors were added individually to each kinase reaction.

Reaction procedure.

1. Prepare the indicated substrate in freshly prepared base reaction buffer.

2. Add any necessary cofactors to the above substrate solution.

3. Add the indicated kinase to the substrate solution and mix gently.

4. Add compounds in DMSO to the kinase reaction mixture using acoustic dosing and distribution technology (Echo550; nanoliter range) for 20 minutes at room temperature.

5. Add ³³ P-ATP (specific activity 10 μCi/μl) to the reaction mixture to initiate the reaction.

6. Incubate the kinase reaction for 2 hours at room temperature.

7. Reactions are applied to P81 ion exchange paper.

8. Determine the kinase activity by the method of binding to the filter.

The activities of the compounds are given below depending on the IC50 range: +: >1 μM; ++: 0.1-1 μM; +++: 10 - 100 nM; ++++: <10 nM; NT: not tested. Compounds according to examples 3, 6 and 7 are potent and selective inhibitors of Jak1.

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Claims (23)

Example B2. p-STAT3 study of human whole blood. Materials and reagents. 1. Whole blood samples from donors. 2. IL-6 (R&D systems; Cat#206-IL). 3. Thrombopoietin (TPO; R&D systems; Cat# 288-TP). 4. RBC lysis buffer (Qiagen, Cat#79217). 5. ELISA kit for pSTAT3 (Invitrogen; Cat# KHO0481). Devices. 1. Centrifuge. 2 Envision; absorption at 450 nm. Measurement technique. 1. 150 µl heparinized blood sample/tube. 2. Compounds are added to the blood at various concentrations, incubated for 10 minutes at room temperature (10 doses, 2 repetitions for each compound). 3. IL-6 (final concentration: 100 ng/ml) or TPO (final concentration: 50 ng/ml) is added to the blood over 15 minutes. 4. After stimulation, add 0.6 ml of erythrocyte lysis buffer (Qiagen 79217) and mix and shake for 1-2 minutes at room temperature, followed by centrifugation to remove lysed erythrocytes. This step may be repeated once if the erythrocytes are not completely lysed. Separate leukocytes. 5. Add 200 µl of cell lysis buffer, freeze for 30 min. 6. Centrifuge at 16,000 g, 10 min, 4°C. 7. Transfer the supernatant to a new tube as a cell lysate. 8. Perform the ELISA procedure in accordance with the instructions for the ELISA kit. These studies show that the compounds of Examples 3, 4 and 7 selectively inhibit IL-6-induced STAT3 phosphorylation but not TPO-induced STAT3 phosphorylation as shown below based on the IC50 range: +: >100 μM; ++: 20-100 μM; +++: 5-20 µM; ++++: <5 µM. Example 11 also shows some activity in a TPO-induced STAT3 phosphorylation assay. CLAIM 1. A compound that is a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, halogen or C _1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, OH, CN, OR, NHR, NRR', N(R)C(= O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O )2R', S(O)2R and S(ObNRR'; R ² is H; Cy is cyclohexyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of R ³ , oxo, halo, OH, CN, OR, NHR, NRR', N( R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N( R)S(O)2R', S(O)2R and S(O)2NRR', where R ³ is C1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O )R, C(=O)NRR', N(R)S(O)2R', S(O)2R and S(O)2NRR'; R, R' are each independently H or C _1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, OH, and CN. 2. The compound of claim 1 wherein Cy is substituted with 1, 2 or 3 substituents independently selected from the group consisting of R ³ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(= O)R', N(R)C(=O)(O)R', OC(=O)NRR', C(=O)R, C(=O)NRR', N(R)S(O )2R S(O)2R and S(ObNRR', where R ³ is C1.3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of - 29 040948 soup from halogen, OH, CN, OR, NHR, NRR', N(R)C(=O)R', N(R)C(=O)(O)R', OC(=O) NRR', C(=O)R, C(=O)NRR', N(R)S(O)iR', S(O)2R and S(O)2NRR'. 3. The compound of claim 1, wherein said compound is selected from the group consisting of 3-[2-[(R)-1-hydroxyethyl]-N-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl )pyrrolidine-1-carboxamide (5) and (R)-4-[2-(1-hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]- N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide (6); or a pharmaceutically acceptable salt thereof. 4. A compound selected from the group consisting of trans-4-[2-[(R)-1-hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl ]cyclohexanecarbonitrile (1), trans-4-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexanecarbonitrile (2), 2-[trans-4- [2-[(R)-1-hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexyl]acetonitrile (3), 2-[(2R,5S)-5-[2-[(R)-1-hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl ]acetonitrile (4), 2-[(2R,5S)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (7), 2-[(2S,5S)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (8); or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 4, wherein said compound is 2-[(2R,5S)-5-[2-[(R)-1hydroxyethyl] furo[3,2-b]imidazo[4,5-d] pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (4). 6. The compound of claim 4, wherein said compound is a pharmaceutically acceptable salt of 2-[(2R,5S)-5-[2-[(R)-1-hydroxyethyl]furo[3,2-b]imidazo[4 ,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (4). 7. A compound according to claim 4, wherein said compound is 2-[(2R,5S)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridine-1- yl]tetrahydropyran-2-yl]acetonitrile (7). 8. The compound of claim 4, wherein said compound is a pharmaceutically acceptable salt of 2-[(2R,5S)-5-[2-(hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridine -1-yl]tetrahydropyran-2-yl]acetonitrile (7). 9. A compound selected from the group consisting of 2-[(2R,5S)-5-[2-ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9), 2-[(2R,5S)-5-[2-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10) and 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11); or a pharmaceutically acceptable salt thereof 10. A compound according to claim 9, wherein said compound is 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran -2-yl]acetonitrile (11). 11. A compound according to claim 9, wherein said compound is a pharmaceutically acceptable salt of 2-[(2R,5S)-5-[2-methylfuro[3,2-b]imidazo[4,5-d]pyridine-1- yl]tetrahydropyran-2-yl]acetonitrile (11). 12. The use of a compound according to any one of claims 1-11 for the treatment of a disease, wherein the disease is selected from the group consisting of an autoimmune disease or disorder, an inflammatory disease or disorder, a cancerous and neoplastic disease or disorder. 13. Use according to claim 12, wherein said disease is rheumatoid arthritis. 14. A composition for the treatment of a disease selected from the group consisting of an autoimmune disease or disorder, an inflammatory disease or disorder, a cancerous disease or disorder, and a neoplastic disease or disorder, said composition comprising an effective amount of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier. 15. The composition according to claim 14, characterized in that the disease is rheumatoid arthritis. 16. Intermediate compound of formula A1-14 17. A method for obtaining a compound of formula I according to claim 1, including bringing the compound of formula V: - 30 040948 in interaction with a compound of formula VI: o r ^1X ^NH ₂ VI in the presence of tetrafluoroborate (C^ alkyl) ₃ -oxonium at a sufficient temperature and for a sufficient time to obtain a compound of formula I: where R ² represents H, and R ¹ and Cy have the meanings defined in π. 1. 18. The method of claim 17, wherein said reagent tetrafluoroborate (Ci. ₆ alkyl) ₃ -oxonium is triethyloxonium tetrafluoroborate. 19. The method of claim 17, wherein said compound of formula V is prepared by a process comprising reducing a compound of formula VII: in the presence of a hydrogenation catalyst and hydrogen gas at sufficient temperature, sufficient pressure and for sufficient time to obtain a compound of formula V, where Cy is defined in π. 1. 20. The method of claim 19, wherein said hydrogenation catalyst is palladium on carbon. 21. The method according to claim 19, where the specified compound of formula VII is obtained by a method comprising bringing the compound of formula A1-14: About CI in interaction with a compound of formula VIII: Su—nh ₂ VIII in the presence of a base at a sufficient temperature and for a sufficient time to obtain a compound of formula VII wherein Cy is as defined in π. 1; wherein the base is preferably N,N-diisopropylethylamine. 22. The method according to any one of paragraphs. 17-21, where Su has the meanings defined in paragraph 2. 23. The method according to any one of paragraphs. 17-21, where the compound of formula I or a pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt according to any one of claims 3-11. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2