4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2h-imidazo[4,5-c]pyridin-2-one derivatives and salts thereof

Abstract

The present disclosure relates to 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one variants or derivatives and salts thereof for use as agonists and antagonists. The present disclosure further relates to compositions, methods of preparation, and methods of treatment.

Description

[0001] manual

[0002] This application claims priority to U.S. Provisional Application No. 63 / 130,010, filed December 23, 2020, and U.S. Provisional Application No. 63 / 245,288, filed September 17, 2021. Technical Field

[0003] This disclosure relates to 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one variants or derivatives thereof, used as agonists and antagonists. This disclosure further relates to pharmaceutical compositions, methods of preparation, and treatment methods. Background Technology

[0004] Small molecule drugs have been found to be effective for a wide range of diseases and conditions. Some act as antagonists by blocking or inhibiting biological responses. Some act as agonists by activating biological responses. Others can perform both functions.

[0005] While many small-molecule drugs are known, new and different treatments are still needed. For example, according to the National Center for Complementary and Integrative Health, approximately 2.5 million people worldwide, including about 400,000 in the United States, suffer from multiple sclerosis (“MS”). Although some drugs are available to treat MS, not everyone responds well to the available medications. Other examples of diseases or conditions for which a need exists include autoimmune disorders such as lupus, pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, granulomatous polyangiitis, or rheumatoid arthritis.

[0006] This disclosure provides compounds that are tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase (“BTK”) inhibitors, and are therefore useful for treating diseases such as cancer, autoimmune diseases, inflammatory diseases, and thromboembolic diseases. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided.

[0007] BTK, a member of the Tec family of non-receptor tyrosine kinases, is crucial for B cell signaling downstream of the B cell receptor. It is expressed on B cells and other hematopoietic cells such as monocytes, macrophages, and mast cells. It plays a role in various aspects of B cell function, maintaining the B cell repertoire (see Gauld SB et al., B cell antigen receptor signaling: roles in cell development and disease. Science, 296:1641-2. 2002). B cells are also involved in rheumatoid arthritis (see Perosa F. et al., CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med. 267:260-77. 2010 and...). T et al. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther. 125:464-75. 2010 and Honigberg, L. et al. The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mast cell-induced arthritis. Clin. Immunol. 127S1:S111. 2008) and in other autoimmune diseases such as systemic lupus erythematosus and cancer (see Shlomchik MJ et al. The role of B cells in lpr / lpr-induced autoimmunity. J. Exp Med. 180:1295–1306. 1994; Honigberg L.A. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is effective in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. 107:13075-80. 2010; and Mina-Osorio P et al., Suppression of glomerulonephritis in lupus-prone NZB x NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. Arthritis Rheum. 65:2380-91. 2013) play a role.

[0008] BTK inhibitors also have the potential to treat allergic diseases (see Honigberg, L. et al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen-induced arthritis. Clin. Immunol. 127S1:S111. 2008). Note that the irreversible inhibitor inhibits passive cutaneous anaphylaxis (PCA) induced by IgE antigen complexes in mice. These findings are consistent with those in BTK mutant mast cells and knockout mice, and suggest that BTK inhibitors could be used to treat asthma, an IgE-dependent airway allergic disease.

[0009] Therefore, compounds that inhibit BTK could be used to treat diseases such as autoimmune diseases, inflammatory diseases, and cancer.

[0010] Surprisingly, certain 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivatives have been found to act as agonists, antagonists, or both on a number of receptors involved in a wide range of diseases and disorders, including those listed above. Summary of the Invention

[0011] In some embodiments, 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivatives or salts thereof are described herein.

[0012] In one embodiment, a compound of formula I is disclosed herein:

[0013]

[0014] Or its salt.

[0015] In one embodiment, a compound of formula Ia is disclosed herein:

[0016]

[0017] Or its salts. In another embodiment, the compound of formula Ia or its salts is about 90% pure.

[0018] In another embodiment, a compound of formula Ib is disclosed herein:

[0019]

[0020] or its salts, wherein the compound or its salts are about 90% pure.

[0021] In a further embodiment, a compound of formula II is disclosed herein.

[0022]

[0023] or its salts, wherein the compound or its salts are about 99.6% pure.

[0024] In another embodiment, this document discloses a composition comprising a pharmaceutically acceptable excipient and at least one compound selected from:

[0025]

[0026] Or its salt.

[0027] In a further embodiment, this document discloses a method for preparing a compound of formula Ia or a salt thereof, the method comprising making a compound of formula VIa...

[0028] It reacts with acryloyl chloride.

[0029] In a further embodiment, this document discloses a method for preparing a compound of formula Ib or a salt thereof, the method comprising making a compound of formula VIb...

[0030] It reacts with acryloyl chloride.

[0031] Further objects and advantages will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice. These objects and advantages will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims.

[0032] It should be understood that both the above description of the invention and the following detailed embodiments are merely exemplary and explanatory, and are not restrictive in their application. Detailed Implementation

[0033] I. Definition

[0034] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0035] "Pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" means a carrier or excipient that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carriers or excipients acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutical acceptable carrier" or "pharmaceutical acceptable excipient" includes both one and more such excipients.

[0036] The treatment of a disease includes:

[0037] (1) Disease prevention, for example, preventing patients (e.g., human patients) who may have been exposed to or are susceptible to disease but have not yet experienced or shown symptoms of disease from developing clinical symptoms of disease;

[0038] (2) Suppress the disease, for example, prevent or reduce the development of the disease or its clinical symptoms; or

[0039] (3) To alleviate disease, for example, to cause the disease or its clinical symptoms to subside.

[0040] "Optional" or "optionally" means that the event or situation described below may occur but does not necessarily occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur.

[0041] "Therapeutic effective amount" means the amount of a 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivative or a salt thereof that, when administered to a patient (e.g., a human patient) to treat a disease, is sufficient to affect such treatment of the disease. "Therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient to be treated (e.g., a human patient).

[0042] "About X% pure" or "About X% purity" (where "X" is a number) means that the compound mentioned is present at about X%, as determined by the area of ​​the total peak area by HPLC (detected by UV@254nm).

[0043] Before describing the contents of this disclosure in detail, it should be understood that this disclosure is not limited to specific compositions or method steps, as these can vary. It should be noted that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “described” as used in this specification and the appended claims include plural indicators. Thus, for example, reference to “a conjugate” includes multiple conjugates, and reference to “a cell” includes multiple cells, and so on.

[0044] Numerical ranges include the numbers that define the range. Taking into account significant figures and measurement-related errors, measured and measurable values ​​should be understood as approximate values. Furthermore, the use of terms such as "comprise," "comprises," "comprising," "contain," "contains," and "include" is not intended to be limiting. It should be understood that the foregoing description and detailed embodiments are merely exemplary and illustrative and are not intended to limit the scope of this teaching.

[0045] Unless otherwise specified, embodiments described in the specification as “comprising” various components are also contemplated as “consisting of the described components” or “essentially composed of the described components”; embodiments described in the specification as “consisting of various components” are also contemplated as “comprising the described components” or “essentially composed of the described components”; and embodiments described in the specification as “essentially composed of various components” are also contemplated as “consisting of the described components” or “comprising the described components” (this interchangeability does not apply to the use of these terms in the claims).

[0046] Unless the context requires otherwise, "or" is used in an inclusive sense, that is, equivalent to "and / or".

[0047] II.Compounds

[0048] In one aspect, this document provides compounds that are 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivatives and their salts. In some embodiments, the compound is about 50% pure. In some embodiments, the compound is about 55% pure. In some embodiments, the compound is about 60% pure. In some embodiments, the compound is about 65% pure. In some embodiments, the compound is about 70% pure. In some embodiments, the compound is about 75% pure. In some embodiments, the compound is about 80% pure. In some embodiments, the compound is about 85% pure. In some embodiments, the compound is about 90% pure. In some embodiments, the compound is about 95% pure. In some embodiments, the compound is about 98% pure. In some embodiments, the compound is about 99% pure.

[0049] On one hand, this paper provides a compound of formula I:

[0050]

[0051] Or its salt.

[0052] On one hand, this paper provides a compound of formula Ia:

[0053]

[0054] Or a salt thereof. In some embodiments, the compound of formula Ia or a salt thereof is about 90% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 95% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 98% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 99% pure.

[0055] On one hand, this paper provides a compound of formula Ib:

[0056]

[0057] Or a salt thereof, wherein the compound or salt thereof is about 90% pure. In some embodiments, the compound or salt thereof of formula Ib is about 95% pure. In some embodiments, the compound or salt thereof of formula Ib is about 98% pure. In some embodiments, the compound or salt thereof of formula Ib is about 99% pure.

[0058] On one hand, this article provides a compound of formula II:

[0059]

[0060] Or a salt thereof, wherein the compound or its salt is about 99.6% pure. In some embodiments, the compound is...

[0061]

[0062] Or a salt thereof, wherein the compound or its salt is about 90% pure. In some embodiments, the compound of formula IIa or its salt is about 95% pure. In some embodiments, the compound of formula IIa or its salt is about 98% pure. In some instances, the compound is...

[0063]

[0064] Or a salt thereof, wherein the compound or salt thereof is about 90% pure. In some embodiments, the compound of formula IIb or a salt thereof is about 95% pure. In some embodiments, the compound of formula IIb or a salt thereof is about 98% pure.

[0065] In one aspect, this disclosure relates to a compound selected from compounds of formulas III, IV and V.

[0066]

[0067]

[0068] Or its salt.

[0069] III. Composition

[0070] In one aspect, this document provides pharmaceutical compositions comprising pharmaceutically acceptable excipients and compounds that are variants or derivatives of 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one or salts thereof. The inventors of this invention have discovered that these compounds are in vivo metabolites of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0071] In one embodiment, this document provides a composition comprising a pharmaceutically acceptable excipient and at least one compound selected from:

[0072]

[0073]

[0074] Or its salts. In some embodiments, at least one compound or its salt is present in an effective amount.

[0075] In one embodiment, this document provides a composition comprising a pharmaceutically acceptable excipient and at least one compound selected from:

[0076]

[0077] Or its salt.

[0078] In some embodiments, at least one compound or a salt thereof is present in an effective amount. In one embodiment, a composition is provided herein comprising a pharmaceutically acceptable excipient and a compound of formula Ia or a salt thereof. In some embodiments, the compound of formula Ia or a salt thereof is at least about 98% pure.

[0079] In one embodiment, this document provides a composition comprising a pharmaceutically acceptable excipient and a compound of formula Ib or a salt thereof. In some embodiments, the compound of formula Ib or a salt thereof is at least about 99% pure.

[0080] The pharmaceutical compositions according to this disclosure may be in forms suitable for oral, buccal, parenteral, nasal, topical or rectal administration or in forms suitable for inhalation administration.

[0081] The compounds described herein can be used to prepare compositions, such as pharmaceutical compositions, by combining the compounds as active ingredients with pharmaceutically acceptable excipients. Some examples of materials that can be used as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; surfactants, such as polysorbate 80 (i.e., Tween 80); powdered astragalus gum; malt; gelatin; talc; suppository bases, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffer solutions; polyesters, polycarbonates, or polyanhydrides; and other non-toxic and compatible substances used in pharmaceutical compositions. Pharmaceutical compositions can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0082] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants may also be present in the composition.

[0083] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0084] The compositions of this disclosure suitable for oral administration may be in the following forms: capsules, flat capsules, pills, tablets, lozenges (using a flavored base, typically sucrose and gum arabic or astragalus gum), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pasteurees (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic), or mouthwashes, each containing a predetermined amount of the compound of this disclosure as an active ingredient. The compounds of this disclosure may also be administered as injections, syrups, or pastes.

[0085] In the solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) of this disclosure for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, or any of the following: fillers or enriching agents, such as starch, lactose, sucrose, glucose, mannitol, or silica; binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; humectants, such as glycerin; disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; solution blocking agents, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glyceryl monostearate, and nonionic surfactants; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft-shell and hard-shell gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0086] Tablets can be manufactured by compression or molding (optionally with one or more excipients). Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared in suitable machinery in which a mixture of powdered compounds is wetted with an inert liquid diluent.

[0087] The pharmaceutical compositions of this disclosure in tablet and other solid dosage forms (e.g., sugar-coated pills, capsules, pellets, and granules) may optionally be scribed or prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the field of pharmaceutical formulation). They may also be formulated, for example, using different proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, or microspheres to provide a desired release profile, to provide a slow or controlled release of the active ingredient therein. They may be formulated for rapid release, for example, by lyophilization. They may be sterilized, for example, by filtration through a filter that retains bacteria, or by incorporating a sterilizing agent into the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium just before use. These compositions may also optionally contain a light-blocking agent and may have a composition in which they release only one or more active ingredients, or in a portion of the gastrointestinal tract, preferably in a delayed manner. Examples of encapsulation compositions that may be used include polymeric substances and waxes. Where appropriate, the active ingredient may also be in the form of microencapsulated forms having one or more of the excipients described above.

[0088] Liquid dosage forms for oral administration of the compounds disclosed herein may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0089] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0090] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum and mixtures thereof.

[0091] IV. Treatment Methods

[0092] In one aspect, this article provides a treatment method comprising administering to a patient in need (e.g., a human patient) an effective amount of a 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivative or a salt thereof. In another aspect, this article provides a treatment method comprising administering to a patient in need (e.g., a human patient) a composition comprising a pharmaceutically acceptable excipient and an effective amount of a 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivative or a salt thereof.

[0093] In some embodiments, the method is a method for treating MS. In some embodiments, the method is a method for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0094] In one respect, this article provides a treatment method comprising administering an effective amount of a compound of formula Ia to a patient in need (e.g., a human patient):

[0095]

[0096] Or a salt thereof. In some embodiments, the compound of formula Ia or a salt thereof is about 90% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 95% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 98% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 99% pure.

[0097] In some embodiments, the treatment method comprising administering an effective amount of a compound of formula Ia or a salt thereof to a patient in need (e.g., a human patient) is a method for treating MS. In some embodiments, the treatment method comprising administering an effective amount of a compound of formula Ia or a salt thereof to a patient in need (e.g., a human patient) is a method for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0098] In one respect, this article provides a treatment method comprising administering an effective amount of a compound of formula Ib to a patient in need (e.g., a human patient):

[0099]

[0100] Or a salt thereof, wherein the compound or salt thereof is about 90% pure. In some embodiments, the compound or salt thereof of formula Ib is about 95% pure. In some embodiments, the compound or salt thereof of formula Ib is about 98% pure. In some embodiments, the compound or salt thereof of formula Ib is about 99% pure.

[0101] In some embodiments, the treatment method comprising administering an effective amount of a compound of formula Ib or a salt thereof to a patient in need (e.g., a human patient) is a method for treating MS. In some embodiments, the treatment method comprising administering an effective amount of a compound of formula Ia or a salt thereof to a patient in need (e.g., a human patient) is for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0102] In one respect, this article provides a treatment method comprising administering an effective amount of a compound of formula II to a patient in need (e.g., a human patient):

[0103]

[0104] or its salts, wherein the compound or its salts are about 99.6% pure.

[0105] In some embodiments, the treatment method comprising administering an effective amount of a compound of formula II or a salt thereof to a patient in need (e.g., a human patient) is a method for treating MS. In some embodiments, the treatment method comprising administering an effective amount of a compound of formula II or a salt thereof to a patient in need (e.g., a human patient) is for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0106] In some embodiments, the compound is

[0107]

[0108] Or a salt thereof, wherein the compound of formula IIa or a salt thereof is about 90% pure. In some embodiments, the compound of formula IIa or a salt thereof is about 95% pure. In some embodiments, the compound of formula IIa or a salt thereof is about 98% pure.

[0109] In some embodiments, the treatment method comprising administering an effective amount of a compound of formula IIa or a salt thereof to a patient in need (e.g., a human patient) is a method for treating MS. In some embodiments, the treatment method comprising administering an effective amount of a compound of formula IIa or a salt thereof to a patient in need (e.g., a human patient) is for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0110] In some instances, the compound is

[0111]

[0112] Or a salt thereof, wherein the compound of formula IIb or a salt thereof is about 90% pure. In some embodiments, the compound of formula IIb or a salt thereof is about 95% pure. In some embodiments, the compound of formula IIb or a salt thereof is about 98% pure.

[0113] In some embodiments, the treatment method comprising administering an effective amount of a compound of formula IIb or a salt thereof to a patient in need (e.g., a human patient) is a method for treating MS. In some embodiments, the treatment method comprising administering an effective amount of a compound of formula IIb or a salt thereof to a patient in need (e.g., a human patient) is for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0114] In one respect, this article provides a treatment method comprising administering a composition to a patient in need (e.g., a human patient), the composition comprising a pharmaceutically acceptable excipient and an effective amount of at least one compound selected from:

[0115]

[0116] Or a salt thereof. In some embodiments, at least one compound or a salt thereof is present in an effective amount. In some embodiments, the compound or a salt thereof is about 90% pure. In some embodiments, the compound or a salt thereof is about 95% pure. In some embodiments, the compound or a salt thereof is about 98% pure. In some embodiments, the compound or a salt thereof is about 99% pure.

[0117] In some embodiments, the treatment method comprising administering the composition to a patient in need (e.g., a human patient) is a method of treating MS, the composition comprising a pharmaceutically acceptable excipient and an effective amount of at least one compound selected from the group consisting of formulas Ia, Ib, II, and III, or salts thereof. In some embodiments, the treatment method comprising administering the composition to a patient in need (e.g., a human patient) is a method of treating autoimmune disorders such as rheumatoid arthritis and lupus, the composition comprising a pharmaceutically acceptable excipient and an effective amount of at least one compound selected from the group consisting of formulas Ia, Ib, II, and III, or salts thereof.

[0118] In one aspect, this document provides compositions for use as medicaments in treating patients in need (e.g., human patients), said compositions comprising an effective amount of a 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivative or a salt thereof. In another aspect, this document provides compositions for use as medicaments in treating patients in need (e.g., human patients), said compositions comprising a pharmaceutically acceptable excipient and an effective amount of a 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivative or a salt thereof.

[0119] In some embodiments, the agent is used to treat MS. In some embodiments, the agent is used to treat autoimmune disorders such as rheumatoid arthritis and lupus.

[0120] In one respect, this article provides a composition for use as a medicament in treating patients in need (e.g., human patients), said composition comprising an effective amount of a compound of formula Ia:

[0121]

[0122] Or a salt thereof. In some embodiments, the compound of formula Ia or a salt thereof is about 90% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 95% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 98% pure. In some embodiments, the compound of formula Ia or a salt thereof is about 99% pure.

[0123] In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula Ia or a salt thereof for treating MS. In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula Ia or a salt thereof for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0124] In one respect, this article provides a composition for use as a medicament in treating patients in need (e.g., human patients), said composition comprising an effective amount of a compound of formula Ib:

[0125]

[0126] Or a salt thereof, wherein the compound or salt thereof is about 90% pure. In some embodiments, the compound or salt thereof of formula Ib is about 95% pure. In some embodiments, the compound or salt thereof of formula Ib is about 98% pure. In some embodiments, the compound or salt thereof of formula Ib is about 99% pure.

[0127] In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula Ia or a salt thereof for treating MS. In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula Ia or a salt thereof for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0128] In one aspect, this article provides a composition for use as a medicament in treating patients in need (e.g., human patients), said composition comprising an effective amount of a compound of formula II:

[0129]

[0130] or its salts, wherein the compound or its salts are about 99.6% pure.

[0131] In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula II or a salt thereof for treating MS. In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula II or a salt thereof for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0132] In some embodiments, the compound is

[0133]

[0134] Or a salt thereof, wherein the compound of formula IIa or a salt thereof is about 90% pure. In some embodiments, the compound of formula IIa or a salt thereof is about 95% pure. In some embodiments, the compound of formula IIa or a salt thereof is about 98% pure.

[0135] In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula IIa or a salt thereof for treating MS. In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula IIa or a salt thereof for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0136] In some instances, the compound is

[0137]

[0138] Or a salt thereof, wherein the compound of formula IIb or a salt thereof is about 90% pure. In some embodiments, the compound of formula IIb or a salt thereof is about 95% pure. In some embodiments, the compound of formula IIb or a salt thereof is about 98% pure.

[0139] In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula IIb or a salt thereof for treating MS. In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises an effective amount of a compound of formula IIb or a salt thereof for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0140] In one respect, this article provides a composition for use as a medicament in treating patients in need (e.g., human patients), said composition comprising a pharmaceutically acceptable excipient and an effective amount of at least one compound selected from:

[0141]

[0142]

[0143] Or a salt thereof. In some embodiments, at least one compound or a salt thereof is present in an effective amount. In some embodiments, the compound or a salt thereof is about 90% pure. In some embodiments, the compound or a salt thereof is about 95% pure. In some embodiments, the compound or a salt thereof is about 98% pure. In some embodiments, the compound or a salt thereof is about 99% pure.

[0144] In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) is for treating MS, the composition comprising a pharmaceutically acceptable excipient and an effective amount of at least one compound selected from formulas Ia, Ib, II, and III, or a salt thereof. In some embodiments, the composition used as a medicament for treating patients in need (e.g., human patients) comprises a pharmaceutically acceptable excipient and an effective amount of at least one compound selected from formulas Ia, Ib, II, and III and / or a salt thereof, for treating autoimmune disorders such as rheumatoid arthritis and lupus.

[0145] V. Synthesis Method

[0146] On the one hand, this article provides methods for synthesizing and preparing 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one or its salt derivatives.

[0147] In one embodiment, this document provides a method for preparing a compound of formula Ia or a salt thereof.

[0148]

[0149] The method includes using a compound of formula VIa.

[0150] It reacts with acryloyl chloride.

[0151] In some embodiments, the method further includes preparing a compound of formula VIa from a compound of formula IX by acid-based deprotection.

[0152]

[0153] In one embodiment, this document provides a method for preparing a compound of formula Ib or a salt thereof.

[0154]

[0155] The method includes using a compound of formula VIb.

[0156] It reacts with acryloyl chloride.

[0157] In some embodiments, the method further includes preparing compounds of formula VIb from compounds of formula VII by acid-based deprotection.

[0158]

[0159] In some embodiments, the method further comprises preparing a compound of formula VII from a compound of formula VIII by using a base for deprotection.

[0160]

[0161] In some embodiments, the method further comprises preparing a compound of formula VIII from a compound of formula IX with triphenylphosphine and an azodicarbonate.

[0162]

[0163] In some embodiments, the azodicarbonate ester is selected from diethyl azodicarbonate and diisopropyl azodicarbonate. In some embodiments, the azodicarbonate ester is diisopropyl azodicarbonate.

[0164] In one embodiment, this document provides a method for preparing a compound of formula IV or a salt thereof.

[0165] The method comprises reacting (4R)-5-amino-4-[4-amino-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]valeric acid with acryloyl chloride.

[0166] In some embodiments, the method further comprises preparing (4R)-5-amino-4-[4-amino-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(tert-butoxycarbonylamino)valeric acid or a salt thereof by acid deprotection of (4R)-4-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]valeric acid.

[0167] In some embodiments, the method further comprises preparing tert-butyl (4R)-4-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(tert-butoxycarbonylamino)valerate or a salt thereof by ring-opening in the presence of a base.

[0168] In some embodiments, the method further comprises preparing (5R)-5-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester or a salt thereof from (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylic acid tert-butyl ester by electrochemical reaction using a medium and an electrolyte. In some embodiments, the medium is a quinine ring. In a further embodiment, the electrolyte is tetramethylammonium tetrafluoroborate.

[0169] In one embodiment, this document provides a method for preparing a compound of formula V or a salt thereof.

[0170]

[0171] The method comprises reacting 4-amino-1-[(1R)-1-(aminomethyl)-4-hydroxy-butyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one with acryloyl chloride.

[0172] In some embodiments, the method further comprises preparing 4-amino-1-[(1R)-1-[(tert-butoxycarbonylamino)methyl]-4-hydroxy-butyl]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-4-yl]carbamate tert-butyl ester by acid deprotection, or a salt thereof.

[0173] In some embodiments, the method further comprises preparing N-tert-butoxycarbonyl-N-[1-[(1R)-1-[(tert-butoxycarbonylamino)methyl]-4-hydroxy-butyl]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylic acid tert-butyl ester or a salt thereof by ring-opening in the presence of a base.

[0174] In some embodiments, the method further comprises preparing (5R)-5-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester or a salt thereof from (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylic acid tert-butyl ester by electrochemical reaction using a medium and an electrolyte. In some embodiments, the medium is a quinine ring. In a further embodiment, the electrolyte is tetramethylammonium tetrafluoroborate.

[0175] Table 1. Abbreviations and names used in the following embodiments and elsewhere herein include:

[0176] abbreviation definition AcOEt and EtOAc Ethyl acetate ATP Adenosine triphosphate Boc tert-butoxycarbonyl protecting group BTK Bruton's tyrosine kinase DCM dichloromethane DIAD Diisopropyl azodicarbonate DIEA N,N-Diisopropylethylamine DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMF DMA N,N-Dimethylformamide dimethylacetal DMSO Dimethyl sulfoxide HFIP 1,1,1,3,3,3-Hexafluoroprop-2-ol HPLC High performance liquid chromatography HOBt Hydroxybenzotriazole MeOH methanol MS Molecular sieve MTBE Methyl tert-butyl ether PMB p-Methoxybenzyl protecting group SGC Silica gel chromatography tBuOH tert-Butanol TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography

[0177] Example

[0178] Example 1. Synthesis of 4-amino-1-[(3R,5S)-5-hydroxy-1-prop-2-enoyl-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one and 4-amino-1-[(3R,5R)-5-hydroxy-1-prop-2-enoyl-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one

[0179]

[0180] The compounds of formula Ia and Ib were synthesized as shown in the above scheme (referred to as compounds 13 and 14, respectively) and are described in more detail below.

[0181] Step 1: Add DMF (21.5 mL) to a reactor under a nitrogen atmosphere. Add 2,4-dichloro-3-nitropyridine (SM1) (4.3 g, 22.28 mmol, 1.0 equivalent) at 20 °C ± 5 °C. After stirring for 5 minutes, add triethylamine (4.75 mL, 33.81 mmol, 1.5 equivalent) and cool the mixture to 0 °C ± 5 °C. After adding HOBt (301 mg, 2.23 mmol, 0.1 equivalent), add dropwise a solution of (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 22.28 mmol, 1.0 equivalent) in DMF (64.5 mL). Maintain the temperature between -10 °C and 0 °C during the reagent addition process. Stir the reaction mixture at 0 °C ± 5 °C for 2 hours, then at 20 °C ± 5 °C for 4 hours. HPLC analysis was performed to examine the formation of (3R,5S)-3-[[2-(benzotriazol-1-yloxy)-3-nitro-4-pyridyl]amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (110).

[0182] Step 2: Proceed immediately to the next step by adding triethylamine (4.75 mL, 33.81 mmol, 1.5 equivalents) and 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methylamine (5.7 g, 22.28 mmol, 1.0 equivalents) in a single pot. The reaction solution was warmed to 40-45°C and stirred at this temperature for 62 hours. HPLC analysis was performed to check for less than 1% of the remaining intermediates. After cooling to 10-20°C, EtOAc (129 mL) and water (129 mL) were added to the solution, and it was stirred at 10-20°C for 30 minutes. The organic phase was separated and washed with 5% CaCl2 aqueous solution (43 mL x 5). The organic phase was concentrated under vacuum at below 35°C to provide (3R,5S)-3-[[2-[bis[(4-methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (111) (94.3% purity) in EtOAc solution (brown solution), which was used directly in the next step.

[0183] Step 3: Dissolve (3R,5S)-3-[[2-[bis[(4-methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (111) (14.7 g, 24.76 mmol, 1 equivalent) (theoretical amount) in AcOEt (73.5 mL) and add it to the reactor. Inertize the reactor under vacuum and fill it with nitrogen five times. Add 10% wet Pd / C (2.64 g, 20 wt.%), inertize the reactor under vacuum and fill it with nitrogen five times, and then inert the reactor under vacuum and fill it with hydrogen three times. Maintain the reaction mixture under hydrogen pressure at 20 °C ± 5 °C and stir for 22 hours. Perform HPLC analysis to check for the disappearance of the starting material. Filter the suspension and wash the filter cake with acetonitrile (73.5 mL x 5). The filtrate was concentrated under vacuum to provide (3R,5S)-3-[[3-amino-2-[bis[(4-methoxyphenyl)methyl]amino]-4-pyridyl]amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (112) (12 g, yield = 87%, purity 91.1%) as a yellow foamy solid. This compound was used in the next step without any further purification.

[0184] Step 4: THF (60 mL), (3R,5S)-3-[[2-[bis[(4-methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (112) (12.0 g, 20.21 mmol, 1.0 equivalent), and triethylamine (4.4 mL, 40.42 mmol, 2.0 equivalent) were added to the reactor. The solution was stirred at 20 °C ± 5 °C for 10 min, then triphosgene (1.07 mL, 6.46 mmol, 0.32 equivalent) was added in three portions, and the resulting solution was stirred at 20 °C to 25 °C for 1.5 h. HPLC analysis was performed to check for residual intermediates less than 1%. The solution was concentrated to 24 mL, and CH2Cl2 (120 mL) and NaHCO3 aqueous solution (60 mL) were added. The mixture was stirred for 10 min. The organic phase was separated and concentrated under vacuum at below 40 °C to provide a crude product, which was purified by SGC (CH2Cl2 / MeOH = 30 / 1) to provide (3R,5S)-3-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-oxo-3H-imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (113) (10 g, yield = 74%, purity 97.1%) as a foamy solid.

[0185] Step 5: A solution of (3R,5S)-3-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-oxo-3H-imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (113) (10.0 g, 16.95 mmol, 1.0 equivalent) in CH2Cl2 (70 mL) was stirred at 20 °C ± 5 °C for 10 min, then cooled to 5 °C ± 5 °C; TFA (10 mL) was slowly added, thus maintaining the temperature at ≤10 °C. The reaction solution was stirred at 5 °C ± 5 °C for 30 min, warmed to 40 °C ± 5 °C, and then stirred for 14 h. HPLC analysis was performed to check for starting material ≤1.0%. The reaction mixture was cooled to 15 °C to 25 °C. The pH was adjusted to 9–10 with an aqueous solution of NaCO3. The aqueous phase containing 4-amino-1-[(3R,5S)-5-hydroxy-3-piperidinyl]-3H-imidazo[4,5-c]pyridin-2-one (117) was separated and held to proceed directly to the next step.

[0186] Step 6: Add CH2Cl2 (40 mL) to an aqueous solution containing 4-amino-1-[(3R,5S)-5-hydroxy-3-piperidinyl]-3H-imidazo[4,5-c]pyridin-2-one (117) cooled to 5 °C ± 5 °C, and add Boc2O (3.7 g, 16.95 mmol, 1.0 equivalent) dropwise in CH2Cl2 (10 mL) at 5 °C ± 5 °C. Warm the solution to 15 °C to 25 °C and stir at 20 °C to 25 °C for 42 hours. Perform HPLC analysis to check for starting material ≤ 3.0%. Separate the aqueous phase and extract with CH2Cl2 (100 mL x 3) and THF (100 mL x 2). The organic phases were combined and concentrated under vacuum at below 35°C to provide 5.4 g of (3R,5S)-3-(4-amino-2-oxo-3H-imidazo[4,5-c]pyridin-1-yl)-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (118) as solid, 92.2% purity (containing CH2Cl2 / THF).

[0187] Step 7: CH2Cl2 (21.6 mL) and (3R,5S)-3-(4-amino-2-oxo-3H-imidazo[4,5-c]pyridin-1-yl)-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (118) (5.4 g, 15.45 mmol, 1.0 equivalent) were added to the reactor. The suspension was stirred for 10 minutes. After adding N,N-dimethylformamide dimethyl acetal (6.1 mL, 46.35 mmol, 3.0 equivalent) at 20 °C ± 5 °C, the solution became clear. After stirring at 20 °C ± 5 °C for 20 hours, a solid precipitate formed. HPLC analysis was performed to check for starting material ≤ 2.0%. MTBE (54 mL) was added and the reaction mixture was stirred at 20 °C ± 5 °C for 2 hours. The suspension was filtered. The filter cake was washed with MTBE (21.6 mL) and dried under vacuum at 35 °C ± 5 °C for 8 hours to provide (3R,5S)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3H-imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (7) (4.3 g, yield = 83%, purity 93.4%) as an off-white solid.

[0188] Step 8: Add CH2Cl2 (75 mL), Cu(OAc)2 (561.2 mg, 3.09 mmol, 0.5 equivalent), 2,2'-bipyridine (482 mg, 3.09 mmol, 0.5 equivalent), and Cs2CO3 (4.02 g, 12.36 mmol, 2.0 equivalent) to the reactor at 20℃±5℃. MS (2.5 g, 1.0 w / w) and (3R,5S)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3H-imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (7) (2.5 g, 6.18 mmol, 1.0 equivalent). Compressed air (21% oxygen and 79% nitrogen) was bubbled into the reaction mixture at 20 °C ± 5 °C for 30 min. 4-Phenoxyphenylboronic acid (1.98 g, 9.27 mmol, 1.5 equivalent) was added to the reaction mixture in four portions over 1.5 h at 15 °C to 25 °C. Compressed air (21% oxygen and 79% nitrogen) was bubbled into the reaction mixture over 5 h at 20 °C ± 5 °C. HPLC analysis was performed to check for starting material ≤5.0%. The suspension was filtered, and the filter cake was washed with CH2Cl2 (25 mL x 2). The filtrate was concentrated, and the crude product was purified by SGC (CH2Cl2 / MeOH = 50 / 1) to provide (3R,5S)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (a compound of formula IX, also referred to above as (8)) as solid, with a purity of 97.5% and a yield of 47.2%.

[0189] Step 9: Dissolve (3R,5S)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (8) (0.3 g, 0.52 mmol, 1.0 equivalent) in CH2Cl2 (1.5 mL). Add HCl aqueous solution (3N, 3 mL) dropwise to this solution at 20 °C ± 5 °C. Stir the solution at 30 °C to 35 °C for 2 h and then at 60 °C to 65 °C for 14 h. Perform HPLC analysis to check for starting material ≤1.0%. Add CH2Cl2 (15 mL) and water (45 mL) to the solution cooled to 20 °C to 25 °C. The solution was stirred for 10 minutes, then the aqueous phase was separated, extracted with CH2Cl2 (30 mL), and the pH of the aqueous phase was adjusted to 9-10 with an aqueous solution of Na2CO3. The aqueous phase turned pink. After stirring for 30 minutes, the organic phase was extracted and washed with brine (15 mL), dried over Na2SO4, and filtered to provide a solution of 4-amino-1-[(3R,5S)-5-hydroxy-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (a compound of formula VIa, also referred to above as (11A)) (81% purity) in CH2Cl2. It proceeds directly to step 10.

[0190] Step 10: Cool the previous solution of 4-amino-1-[(3R,5S)-5-hydroxy-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (11A) (164 mg, 0.39 mmol, 1 equivalent) in CH2Cl2 to 0 °C ± 5 °C. Add N,N-diisopropylethylamine (133 μL, 0.78 mmol, 2.0 equivalent) and trimethylsilyl chloride (50 μL, 0.39 mmol, 1.0 equivalent) to CH2Cl2 (2.5 mL). Stir the solution at 0 °C ± 5 °C for 30 minutes. After cooling the solution to -20 °C ± 5 °C, add acryloyl chloride (32 μL, 0.39 mmol, 1.0 equivalent) dropwise to CH2Cl2 (5 mL). The reaction was quenched with water (20 mL), and the organic phase was separated and concentrated under vacuum at below 35 °C to obtain a crude product. The crude product was purified by preparative TLC (CH2Cl2 / EtOH = 15 / 1), the fraction was concentrated, and CH2Cl2 was converted to EtOH. The solution was concentrated to 10 mL, and n-heptane (15 mL) was added. The solution was then concentrated to 10 mL, and a solid precipitate was formed. The precipitate was concentrated to provide 80 mg of 4-amino-1-[(3R,5S)-5-hydroxy-1-prop-2-enoyl-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (a compound of formula Ia, also referred to above as (13)) as a grayish-white solid, with a purity of 98.1% and a yield of 43%. 1 ¹H NMR spectra (500MHz, DMSO D6, δ, in ppm): 7.77 (d, 1H); 7.51–7.41 (m, 4H); 7.22 (t, 1H); 7.18–7.11 (m, 4H); 6.96 (br.m, 1H); 6.81 (m, 1H); 6.15 (d, 1H); 5.71 (dd, 1H); 5.28 (br.s, 1H); 4.83 (br.m, 2H); 4.58 (br.d, 0.5H); 4. 47(br.d,0.5H); 4.25(br.qd,1H); 4.15(br.d,0.5H); 4.1(br.d,0.5H); 3.69(br.t,0.5H); 3.60 (m,1H); 3.27(br.t,0.5H); 2.95(br.t,0.5H); 2.49(br.t,0.5H); 2.28(m,1H); 2.13(br.m,1H).

[0191] Step 9B: Add THF (12.5 mL), DIAD (683 μL, 3.48 mmol, 4.0 equivalents), and Ph3P (912 mg, 3.48 mmol, 4.0 equivalents) to a nitrogen-inert reactor. Cool the reactants to 0°C to 5°C, then add (3R,5S)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidin-1-carboxylic acid tert-butyl ester (8) (0.5 g, 0.87 mmol, 1.0 equivalents) to the reactor. Stir the reactants at 0°C to 5°C for 10 minutes, then add 4-nitrobenzoic acid (291 mg, 1.74 mmol, 2.0 equivalents) to the reactor and stir the reaction at 0°C to 5°C for another 2 hours. The reaction mixture was then stirred at 15°C to 20°C for 14 hours and concentrated under vacuum at below 35°C. The residue was purified by SGC (CH2Cl2 / MeOH = 50 / 1) to provide crude (3R,5R)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(4-nitrobenzoyl)oxy-piperidine-1-carboxylic acid tert-butyl ester (a compound of formula VIII, also referred to above as (9B)) (purity 87%), which contained Ph3PO. Ph3PO was difficult to isolate and this intermediate was not further purified.

[0192] Step 10B: MeOH (9 mL), (3R,5R)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(4-nitrobenzoyl)oxy-piperidine-1-carboxylic acid tert-butyl ester (9B) (0.45 g, 0.62 mmol, 1.0 equivalent) and K₂CO₃ (258 mg, 1.87 mmol, 3.0 equivalent) were added to a flask. The reaction mixture was stirred at 15°C to 20°C for 14 hours. HPLC analysis showed no residue of the starting material. The suspension was filtered, the filter cake was washed with MeOH (2.25 mL), and the filtrate was concentrated under vacuum at below 35°C to provide the crude product. The crude product was purified by SGC (CH2Cl2 / MeOH = 50 / 1) to provide (3R,5R)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (compound of formula VII, also referred to above as (10B)) as a powder solid (0.16 g, yield = 44%, purity 98.2%).

[0193] Step 11B: Add 1 mL of CH2Cl2, 0.16 g (0.28 mmol, 1 equivalent) of (3R,5R)-3-[4-[(Z)-dimethylaminomethyleneamino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10B), and 2 mL of HCl aqueous solution (3.0 M). Stir the solution at 25-30°C for 2 hours, then at 60-65°C for 14 hours. HPLC analysis showed no starting material remaining. Cool the reaction mixture to 15-20°C and add 15 mL of CH2Cl2 and 30 mL of H2O to the flask. Separate the organic phase. Add 30 mL of CH2Cl2 to the aqueous phase and adjust the pH of the aqueous phase to 9-10 with a saturated Na2CO3 aqueous solution. The organic phase was separated, and the aqueous phase was re-extracted with CH2Cl2 (30 mL x 2). The different organic phases were collected, washed with brine (10 mL), dried with Na2SO4, filtered, and concentrated under vacuum at below 35 °C to provide 0.11 g of crude material 4-amino-1-[(3R,5R)-5-hydroxy-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (a compound of formula VIb, also referred to above as (11B)), which was not further purified and proceeded directly to step 12B.

[0194] Step 12B: Add N,N-diisopropylethylamine (177 μL, 1.04 mmol, 4.0 equivalents) to a solution of 4-amino-1-[(3R,5R)-5-hydroxy-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (11B) (0.11 g, 0.26 mmol, 1 equivalent) in CH2Cl2 (44 mL). Cool the solution to -5°C to 0°C and add dropwise a solution of trimethylsilyl chloride (33 μL, 0.26 mmol, 1.0 equivalents) in CH2Cl2 (2.5 mL). Stir the solution at -5°C to 0°C for 30 minutes and cool to -25°C to -20°C. Add dropwise acryloyl chloride (27.5 μL, 0.34 mmol, 1.3 equivalents) in CH2Cl2 (2.5 mL). The reaction was stirred for 10 minutes, heated to 0°C to 5°C, and quenched with water (20 mL). The organic phase was separated, washed with brine (10 mL), and concentrated under vacuum at below 35°C to obtain a crude material. The crude product was purified by preparative TLC (CH2Cl2 / MeOH = 15 / 1) to give 4-amino-1-[(3R,5R)-5-hydroxy-1-prop-2-enoyl-3-piperidinyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (a compound of formula Ib, also referred to above as (14)) as a grayish-white powder (63 mg, yield = 51%, purity 99.1%). LC / HRMS: 472.1821 (M+H) + 470.1790 (MH) - . 1 ¹H NMR spectra (500 MHz, DMSO D6, δ, in ppm): 7.76 (d, 1H); 7.50–7.42 (m, 4H); 7.22 (t, 1H), 7.18–7.11 (m, 4H); 6.90 (d, 1H); 6.79 (dd, 1H); 6.13 (dd, 1H); 5.68 (dd, 1H); 5.05 (br.d, 0.75H); 4.96 (br.d, 0.25H); 4.81 (br.s, 2H); 4. 65(br.m,0.25H);4.59-4.46(m,1.75H);4.19(br.d,0.25H);4.07(br.s,1H);3.97(br.d,0.75H) ;3.72(t,0.25H);3.38(d,0.75H);3.32(m,0.75H);2.90(d,0.25H);2.53(m,1H);1.92(br.d,1H).

[0195] Example 2. Synthesis of 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(2,3-dihydroxypropionyl)-3-piperidinyl]imidazo[4,5-c]pyridin-2-one

[0196]

[0197] As shown in the above scheme, compounds of formulas IIa and IIb are prepared from 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidinyl]imidazo[4,5-c]pyridin-2-one using AD-Mix-α (i.e., (DHQ)2PHAL (hydroquinine 1,4-phthalazine dimethyl diether, Sigma Aldrich catalog number 392723) 0.0016 mol; potassium carbonate powder 0.4988 mol; potassium ferricyanide 0.4988 mol; potassium osmium dihydrate 0.0007 mol) or AD-Mix-β (i.e., (DHQD)2PHAL (Sigma Aldrich catalog number 392731) 0.0016 mol; potassium carbonate powder 0.4988 mol; potassium ferricyanide 0.4988 mol; potassium osmium dihydrate 0.0007 mol).

[0198] The starting material 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidinyl]imidazo[4,5-c]pyridin-2-one was prepared according to the procedure described in Example 3 of U.S. Patent No. 9,688,676.

[0199] To prepare compounds of formulas IIa and IIb, a suspension of AD-Mix-α (154 mg) or AD-Mix-β (154 mg) in water / tBuOH (1 / 1, 1 mL / 1 mL) was stirred for about 10 minutes until the solid dissolved. The starting material 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoyl-3-piperidinyl]imidazo[4,5-c]pyridin-2-one was added to a yellow solution under an argon atmosphere. Since the starting material was insoluble in the mixture, a yellow suspension was obtained. This suspension was stirred at room temperature for 20 hours. The progress of the reaction was monitored by TLC (AcOEt / MeOH 10 / 1). The reaction mixture was hydrolyzed with Na₂SO₃, stirred for 20 minutes, and extracted with CH₂Cl₂. The organic phase was separated, dried over MgSO₄, filtered, and concentrated under vacuum to provide a crude product. The crude product was purified by passing it through an SCX (strong cation exchange) column (MeOH, then NH3 3.5N in MeOH) to provide a clear oily mixture of two diastereomers, 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(2,3-dihydroxypropionyl)-3-piperidinyl]imidazo[4,5-c]pyridin-2-one, which was separated by chiral chromatography to provide compounds of formula IIa (98% purity) and IIb (98% purity). IIa: 1H NMR (500MHz, DMSO-d6) (50 / 50 of the two rotational isomers) δppm 1.45-1.65(m,1H),1.80-1.95(m,2H),2.45(m,1H),3.10(m,0.5H),3.25(m,0.5H) ,3.40-3.55(m,2H),3.67(m,0.5H),4.05-4.50(m,4.5H),4.62(t,J=4Hz,0.5H),4. 77(t,J=4Hz,0.5H),4.80(m,2H),4.95(d,J=4Hz,0.5H),5.01(d,J=4Hz,0.5H),6.9 0-6.96(m,1H),7.15(m,4H),7.22(t,J=7Hz,1H),7.45(m,4H),7.75(d,J=5Hz,1H).IIb:¹H NMR (500MHz, DMSO-d⁶) (50 / 50 50 rotational isomers) δppm 1.45-1.65(m,1H),1.80-1.95(m,2H),2.45(m,1H),3.10(m,0.5H),3.25(m ,0.5H),3.40-3.55(m,2H),3.67(m,0.5H),4.05-4.50(m,4.5H),4.65(t,J =4Hz,0.5H),4.76(t,J=4Hz,0.5H),4.80(m,2H),4.98(m,1H),6.90-6.96( m, 1H), 7.15 (m, 4H), 7.22 (t, J = 7Hz, 1H), 7.45 (m, 4H), 7.75 (d, J = 5Hz, 1H). LC / MS: 490(M+H). + .

[0200] Example 3. Synthesis of (R)-5-acrylamido-4-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)valeric acid

[0201]

[0202] The compound of formula IV (hereinafter referred to as compound (6)) was prepared as described in the above scheme and as described in more detail below. The starting material 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-3-piperidinyl]imidazo[4,5-c]pyridin-2-one (1) was prepared according to the procedure described in Example 2 of U.S. Patent No. 9,688,676. 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-3-piperidinyl]imidazo[4,5-c]pyridin-2-one (1) was then converted to oxalate by adding DCM to compound (1). The solution was converted to EtOH and the resulting solution was reacted with oxalic acid. After filtration, the crude solid was pulped in MTBE, filtered, and dried to provide the oxalate of compound (1).

[0203] Step 1: CH2Cl2 and oxalate of 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-3-piperidinyl]imidazo[4,5-c]pyridin-2-one (1.3 g, 2.66 mmol, 1 equivalent) were added to a flask under an argon atmosphere. DMAP (487 mg, 3.98 mmol, 1.5 equivalent), DIEA (1.35 mL, 7.97 mmol, 3 equivalent), and Boc2O (2.90 g, 13.28 mmol, 5 equivalent) were then added to the suspension. The starting material dissolved, and the reactants became clear. The solution was stirred at room temperature for 20 hours. The reactants were hydrolyzed with water and extracted with CH2Cl2. The organic phase was separated, dried over MgSO4, filtered, and concentrated under vacuum to provide a crude product. The crude product was purified by rapid chromatography (SiO2, Hep / AcOEt(1 / 1)) to give (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (2) (1.86 g, yield = 91.2%).

[0204] Step 2: Add NaIO4 (1.22 g, 5.7 mmol, 4 equivalents) and RuCl3·xH2O (32 mg, 142 μmol, 0.1 equivalents) to a solution of (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (2) (1 g, 1.42 mmol, 1 equivalent) in MeCN / H2O / CCl4 (15 mL / 20 mL / 15 mL), in this order. The reaction is a light brown mixture. After stirring at room temperature for 1 hour, add some more NaIO4 (152 mg, 0.7 mmol, 0.25 equivalents). Stir the reaction mixture at room temperature for 24 hours, and it is dark brown. After hydrolysis with Na2S2O5 aqueous solution and stirring for 30 minutes, the solution turns light yellow. Extract it with AcOEt. The organic phase was separated, dried over MgSO4, filtered, and concentrated under vacuum to provide a crude product. The crude product was purified by rapid chromatography (SiO2, Hep / AcOEt(1 / 1)) to provide (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester (starting material) (450 mg, yield = 45%) and (5R)-5-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylic acid tert-butyl ester (desired product) (3) (200 mg, yield = 20%).

[0205] Step 2: Electrochemical Process - Using an Electrasyn 2.0 (IKA) and a 20 mL vial apparatus, quinine rings were added as a medium (2 equivalents, 0.86 mmol, 95 mg), 1,1,1,3,3,3-hexafluoroprop-2-ol (“HFIP”) (11 equivalents, 4.70 mmol, 790 mg), and tetramethylammonium tetrafluoroborate as an electrolyte (2.05 equivalents, 0.88 mmol, 141 mg) to a solution of (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidin-1-carboxylic acid tert-butyl ester (2) (300 mg, 0.43 mmol, 1 equivalent) in MeCN (12 mL), 1,1,1,3,3,3-hexafluoroprop-2-ol (“HFIP”) (11 equivalents, 4.70 mmol, 790 mg), and tetramethylammonium tetrafluoroborate as an electrolyte (2.05 equivalents, 0.88 mmol, 141 mg). Vial cap assembly: (Working electrode) RVC-mesh glassy carbon foam as the anode and Ni nickel foam as the cathode. The electrochemical reaction was carried out in constant current mode; a constant current of 8 mA with no polarity switch. The total load was 16 farads / mol at room temperature. The reaction was monitored by LC / MS. The reaction was poured into ice water and then 1 M sodium thiosulfate solution was added. The aqueous phase was washed with ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under vacuum to provide a crude product. The expected product, tert-butyl 5-(5R)-5-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylate (3) (150 mg, yield = 49%), was given by rapid chromatography on silica gel (elution mixture of ethyl acetate / pentane (70 / 30)).

[0206] Step 3: Add LiOH (471 mg, 19.4 mmol, 17 equivalents) to a solution of (5R)-5-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylic acid tert-butyl ester (3) (820 mg, 1.15 mmol, 1 equivalent) in THF / H2O (30 mL / 30 mL). Stir the solution at room temperature for 3 hours. Hydrolyze the reaction mixture with 1N HCl aqueous solution until pH = 1-2, and then extract with AcOEt. The organic phase was separated, dried over MgSO4, filtered, and concentrated under vacuum to provide the desired compound: (4R)-4-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(tert-butoxycarbonylamino)valerate (4) (780 mg, yield = 92.8%).

[0207] Step 4: CH2Cl2 (5 mL), (4R)-4-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(tert-butoxycarbonylamino)valeric acid (720 mg, 0.98 mmol, 1 equivalent) (4), and TFA (2 mL) were added to a flask under an argon atmosphere. The mixture was stirred at room temperature for 6 hours. After evaporating CH2Cl2 and TFA and drying under high vacuum for 10 hours, (4R)-5-amino-4-[4-amino-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]valeric acid (5) (410 mg, 96%) was obtained. It was not further purified and the next step was performed as is.

[0208] Step 5: Add DMF (0.5 mL) to a suspension of 4R)-5-amino-4-[4-amino-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]valeric acid (5) (425 mg, 0.98 mmol, 1 equivalent) and CH2Cl2 (6 mL) to dissolve the starting material. Then, cool the reaction solution to 0 °C, add DIEA (343 μL, 1.96 mmol, 2 equivalents), and add dropwise a solution of acryloyl chloride (41 μL, 0.49 mmol, 0.5 equivalents) in CH2Cl2 (2 mL). Allow the solution to warm to room temperature and stir for 2 hours. The reactants were concentrated under vacuum and purified directly by preparative HPLC, and then purified by supercritical HPLC to obtain (4R)-4-[4-amino-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-(prop-2-enoylamino)valerate (a compound of formula IV, also referred to above as (6)) (180 mg, yield = 38%, 98% purity). 1H NMR(500MHz,DMSO-d6)δppm 2.02(m,1H),2.17(m,2H),2.28(m,1H),3.65(m,2H),4.36(m,1H),4.78(s,2H),5.53(dd,J=8,2Hz,1H),6.02(dd,J=17,2Hz,1H),6.09(dd,J =17,8Hz,1H),6.65(m,1H),7.15(d,J=8Hz,4H),7.21(t,J=7Hz,1H),7.45(m,4H),7.71(d,J=5Hz,1H),8.28(t,J=6Hz,1H)LC / MS:488.2(M+H) + / 486.1 (MH) - .

[0209] Example 4. Synthesis of (R)-N-(2-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-5-hydroxypentyl)acrylamide

[0210]

[0211] The compound of formula V (hereinafter referred to as compound (6)) was prepared as shown in the above scheme and as discussed in more detail below.

[0212] Steps 1 and 2 were performed as described in steps 1 and 2 of Example 3. Step 3: (5R)-5-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-2-oxo-piperidin-1-carboxylic acid tert-butyl ester (3) (280 mg, 0.39 mmol, 1 equivalent), MeOH (8 mL), and NaBH4 (148 mg, 3.9 mmol, 10 equivalent) were added to a flask under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then hydrolyzed with H2O. The organic phase was separated, dried over MgSO4, filtered, and concentrated under vacuum to provide the desired compound (3R)-3-[4-[bis(tert-butoxycarbonyl)amino]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (4) (281 mg, yield = 77%). It was not further purified and proceeded directly to the next step.

[0213] Step 4: HCl (15 mL) in dioxane was added to the starting material N-tert-butoxycarbonyl-N-[1-[(1R)-1-[(tert-butoxycarbonylamino)methyl]-4-hydroxy-butyl]-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-4-yl]carbamate (4) (216 mg, 0.30 mmol, 1 equivalent). The solution was stirred at room temperature for 2 hours. The solvent was evaporated, and the crude product 4-amino-1-[(1R)-1-(aminomethyl)-4-hydroxy-butyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (5) (126 mg, yield = 95.3%) was used for the next step.

[0214] Step 5: Add 4-amino-1-[(1R)-1-(aminomethyl)-4-hydroxy-butyl]-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-2-one (125 mg, 0.29 mmol, 1 equivalent) and CH2Cl2 (2 mL) to a flask under an argon atmosphere. Then, cool the reaction solution to 0 °C, add DIEA (104 μL, 0.59 mmol, 2 equivalents), and then add dropwise a solution of acryloyl chloride (12.5 μL, 0.15 mmol, 0.5 equivalents) in CH2Cl2 (1 mL). Maintain the solution at 0 °C and stir for 1 hour. Hydrolyze the reaction mixture with H2O and extract with AcOEt. The organic phase was separated, dried over MgSO4, filtered, and concentrated under vacuum to provide a crude compound, which was purified by preparative HPLC to give N-[(2R)-2-[4-amino-2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-1-yl]-5-hydroxy-pentyl]prop-2-enamide (a compound of formula V, referred to above as (6)) (38 mg, yield = 27%, purity >95%). ¹H NMR (500 MHz, DMSO-d6) δppm 1.25-1.40(m,2H),1.83(m,1H),2.08(m,1H),3.35(m,2H),3.50-3.70(m,2H),4.35(m, 1H),4.43(m,1H),4.80(s,2H),5.53(dd,J=8,2Hz,1H),6.03(dd,J=17,2Hz,1H),6.11( dd,J=17,8Hz,1H),6.70(m,1H),7.15(d,J=8Hz,4H),7.22(t,J=7Hz,1H),7.43(d,J=7H z,2H),7.48(t,J=7Hz,2H),7.74(d,J=5Hz,1H),8.29(t,J=6Hz,1H)LC / MS:474.1(M+H) + .

[0215] Example 5. BTK(h) Study

[0216] As described herein, compounds of formulas Ib, II, and III were tested for BTK(h). All tested compounds were prepared into working stock solutions at a final determination concentration of 50x in 100% DMSO. Where appropriate, more concentrated stock solutions were manually diluted to 50x using 100% DMSO. Compounds in powder form were reconstituted into 10 mM stock solutions in 100% DMSO, and then further diluted to 50x.

[0217] Measurement ProcedureAdd the required volume of 50x test compound stock solution to the assay well, followed by the reaction mixture containing the enzyme and substrate. Initiate the reaction by adding the selected concentration of ATP. Do not pre-incubate the compound with the enzyme / substrate mixture before adding ATP.

[0218] Data Analysis The result is expressed as the remaining kinase activity as a percentage of the DMSO control. This is calculated using the following formula:

[0219]

[0220] For IC 50 Determined, data analysis was performed using XLFit version 5.3 (ID Business Solutions). A nonlinear regression analysis was used to fit an S-shaped dose-response (variable slope) curve based on the average result for each test concentration. If the top and / or bottom of the curve fall outside 100 and 0 by >10%, respectively, one or both of these limits can be set to 100 and 0, provided that R0 is satisfied. 2 QC standards.

[0221] The results are shown in Table 2.

[0222] Table 2

[0223] compound <![CDATA[IC 50 (nM)]]> Formula Ib 34 Formula II 279 Formula III 1375

[0224] Example 6. In vitro studies

[0225] Compounds of formulas Ia, Ib, III, IV, and V were tested in various in vitro assays. Compound binding was calculated as the percentage inhibition of binding to the target-specific radiolabeled ligand. Compound enzyme inhibition was calculated as the percentage inhibition of control enzyme activity. Some compounds exhibited significant activity, defined in this case as inhibition or stimulation exceeding 50% in certain assays.

[0226] BZD binding assay The general procedure is as follows. See Le Fur, G. et al. (1983), Life Sci., 33:449-457. Kd is the affinity of the radioligand for the receptor. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0227]

[0228] Compounds of formula Ia showed significant activity in this assay, exhibiting 52.2% inhibition.

[0229] Dopamine binding assayThe general procedure is as follows. See Pristupa, ZB et al. (1994), Mol. Pharmacol., 45:125-135. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0230]

[0231] Compounds of Formula Ia showed significant activity in this assay, exhibiting 65% inhibition. Compounds of Formula III also showed significant activity, exhibiting 96.2% inhibition.

[0232] D1(h) binding assay The general procedure is as follows. See Zhou, QY et al. (1990), Nature, 347:76-80. The experimental protocols described below may be slightly modified during testing, but if so, they will not affect the quality of the results obtained.

[0233]

[0234] The compounds of Formula III showed significant activity in this assay, exhibiting 80% inhibition.

[0235] H2(h) binding determination The general procedure is as follows. See Leurs, R. et al. (1994), Brit. J. Pharmacol., 112:847-854. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0236]

[0237] The compound of formula III showed significant activity in this assay, exhibiting 56.7% inhibition.

[0238] δ(DOP)(h) binding determination The general procedure is as follows. See Simonin, F. et al. (1994), Mol. Pharmacol., 46:1015-1021. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0239]

[0240] The compound of formula III showed significant activity in this assay, exhibiting 56.7% inhibition.

[0241] κ(h)(KOP) binding assayThe general procedure is as follows. See Simonin, F. et al. (1995), Proc. Natl. Acad. Sci. USA, 92:7006-7010. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0242]

[0243] The compound of formula III showed significant activity in this assay, exhibiting 54.6% inhibition.

[0244] 5-HT 5a (h) combined with determination The general procedure is as follows. See Rees, S. et al. (1994), FEBS Lett., 355:242-246. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0245]

[0246] The compound of formula III showed significant activity in this assay, exhibiting 56.1% inhibition.

[0247] Norepinephrine transporter (h) binding assay The general procedure is as follows. See Pacholczyk, T. et al. (1991), Nature, 350:350-354. The experimental protocols described below may be subject to minor variations during testing, but if so, they will not affect the quality of the results obtained.

[0248]

[0249] The compound of formula III showed significant activity in this assay, exhibiting 66.7% inhibition.

[0250] Equivalent form

[0251] The foregoing written description is considered sufficient to enable those skilled in the art to implement these embodiments. The foregoing description and examples detail certain embodiments and describe the best mode envisioned by the inventors. However, it should be understood that, regardless of the detail shown above, the embodiments can be implemented in many ways and should be interpreted in accordance with the appended claims and any equivalents.

[0252] As used herein, whether explicitly indicated or not, the term "about" refers to a numerical value, including, for example, integers, fractions, and percentages. The term "about" generally refers to a range of numerical values ​​(e.g., + / - 5% to 10% of the range) that a person skilled in the art would consider equivalent to the stated value (e.g., having the same function or result). When terms such as "at least" and "about" precede a list of numerical values ​​or ranges, the term modifies all values ​​or ranges provided in the list. In some cases, the term "about" may include numerical values ​​rounded to the nearest significant digit.

Claims

1. A compound of formula Ib: Or its salt.

2. A compound of formula II Or its salt.

3. The compound according to claim 2, wherein the compound of formula II is a compound of formula IIa. Or its salt.

4. The compound according to claim 2, wherein the compound of formula II is a compound of formula IIb. Or its salt.

5. A composition comprising a pharmaceutically acceptable excipient and at least one compound selected from: and Or its salt.

6. The composition according to claim 5, wherein at least one compound or a salt thereof is present in an effective amount.

7. The composition according to claim 5, wherein at least one compound is a compound of formula Ib or a salt thereof.

8. The composition according to claim 7, wherein the compound of formula Ib or a salt thereof is at least about 99% pure.

9. The composition according to any one of claims 5-8, wherein the composition is in the form of capsules, tablets or pills.

10. A method for preparing a compound of formula Ib or a salt thereof, The method includes using a compound of formula VIb. It reacts with acryloyl chloride.

11. The method of claim 10, wherein the method further comprises preparing a compound of formula VIb from a compound of formula VII by acid-based deprotection. 。 12. The method of claim 11, wherein the method further comprises preparing a compound of formula VII from a compound of formula VIII by deprotection with a base. 。 13. The method of claim 12, wherein the method further comprises preparing a compound of formula VIII from a compound of formula IX with triphenylphosphine and an azodicarbonate. 。 14. The method of claim 13, wherein the azodicarbonate is selected from diethyl azodicarbonate and diisopropyl azodicarbonate.

15. The method of claim 14, wherein the azodicarbonate is diisopropyl azodicarbonate.

16. Use of a compound in the preparation of a medicament for treating autoimmune disorders, wherein said compound is selected from compounds of formula Ib and II. and Or its salt.

17. The use according to claim 16, wherein the autoimmune disorder is selected from lupus, pemphigus vulgaris, myasthenia gravis, Schogren's syndrome, dry eye syndrome, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, granulomatous polyangiitis, and rheumatoid arthritis.

18. The use according to claim 16, wherein the autoimmune disorder is lupus or rheumatoid arthritis.

19. A composition for use as a medicament in treating a patient in need, said composition comprising an effective amount of at least one compound selected from: and Or its salts, used to treat autoimmune disorders.

20. The composition of claim 19, wherein the autoimmune disorder is selected from lupus, pemphigus vulgaris, myasthenia gravis, Schoenberg syndrome, dry eye syndrome, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, granulomatous polyangiitis, and rheumatoid arthritis.

21. The composition of claim 19, wherein the autoimmune disorder is lupus or rheumatoid arthritis.

22. The composition of claim 19, wherein the autoimmune disorder is multiple sclerosis.

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