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HK40068961B - Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors - Google Patents

Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors Download PDF

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Publication number
HK40068961B
HK40068961B HK62022058265.9A HK62022058265A HK40068961B HK 40068961 B HK40068961 B HK 40068961B HK 62022058265 A HK62022058265 A HK 62022058265A HK 40068961 B HK40068961 B HK 40068961B
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methyl
compound
phenylboronic acid
pharmaceutically acceptable
acceptable salt
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HK62022058265.9A
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German (de)
French (fr)
Chinese (zh)
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HK40068961A (en
Inventor
Ronald Hawley
Klaus Klumpp
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Riboscience Llc
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Description

The present disclosure provides certain bicyclic heteroaryl boronate compounds that inhibit ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) enzymatic activity and are therefore useful for the treatment of diseases treatable by inhibition of ENPP1. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
BACKGROUND
ENPP1 enzyme is present in a wide range of tissues and cell types, such as lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 hydrolyzes ATP and other nucleoside triphosphates and releases AMP or other nucleoside monophosphates as well as pyrophosphate (PPi) (Kato K et al. 2012 PNAS 109:16876-16881; Hessle L et al. 2002 PNAS 99:9445-9449). The enzyme can also hydrolyze other nucleoside monophosphate esters (Kato K et al. 2012 PNAS 109:16876-16881). ENPP1 has been identified as the dominant 2'-3'-cGAMP hydrolase in cultured cells, tissue extracts and blood (Li L et al. 2014 Nat Chem Biol 10:1043-1048). Tissues and blood from ENPP1 knockout mice lack 2'-3'-cGAMP hydrolase activity. Elevated levels of ENPP1 have been associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease, an inflammatory disease resulting from CPPD crystal deposits in the joint and surrounding tissues (Cote N et al. 2012 Eur J Pharmacol 689:139-146; Johnson K et al. 2001 Arthritis Rheum 44:1071). ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic and thyroid and breast cancers and has been associated with resistance to chemotherapy (see Lau WM et al. 2013 PLoS One 8:5; Bageritz J et al. 2014 Mol Cell Oncology 1:3; Bageritz J et al. 2014 Cell Death, Differentiation 21:929-940; Umar A et al. 2009 Mol Cell Proteomics 8:1278-1294). ENPP1 upregulation and variants of ENPP1 are also associated with insulin resistance and type 2 diabetes (Meyre D et al. 2005 Nat Genet 37:863-867; Maddux BA et al. 1995 Nature 373:448-451; Rey D et al. 2012 Mol Biol Rep 39:7687-7693) and enzyme activity of ENPP1 was reported to be required for the inhibition of insulin receptor signaling (Chin CN et al. 2009 Eur J Pharmacol 606:17-24).
Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA derived from viruses, bacteria, damaged mitochondria or cancer cells. The cGAMP molecule then binds to the stimulator of interferon genes (STING) protein, which initiates a signaling response that activates innate immunity and results in the production of type I interferon, antiviral and immune-stimulatory cytokines (Sun L et al. 2013 Science 339:786-791; Wu J et al. 2013 Science 339:826-830; Gao D et al. 2013 Science 341:903-906; Li X et al. 2013 Science 341:1390-1394; Schoggins JW et al. 2014 Nature 505:691-695; Wassermann R et al. 2015 Cell Host Microbe 17:799-810; Watson RO et al. 2015 Cell Host Microbe 17:811-819; Collins A et al. 2015 Cell Host Microbe 17:820-828; West A et al. 2015 Nature 520:533-557; Woo SR et al. 2014 Immunity 41:830-842; Deng L et al. 2014 Immunity 41:843-852; Chen Q et al. 2016 Nat Immunol 17:1142-1148). The cGAS enzyme, cGAMP messenger and STING are is also involved in host defense against RNA viruses and the immune control of tumor development (Aguirre S et al. 2012 PLoS Pathog 8: e1002934; Barber GN 2015 Nat Rev Immunol 15:760-770). ENPP1 has been identified as the enzyme that naturally hydrolyzes cGAMP and therefore counteracts the innate immune response against infectious agents, damaged cells and cancer cells (Li L et al. 2014 Nat Chem Biol 10:1043-1048). The efficacy of non-hydrolyzable cGAMP analogs in inducing functional immune responses is higher than that of natural, hydrolysable cGAMP (Li L et al. 2014 Nat Chem Biol 10:1043-1048; Corrales L et al. 2015 Cell Rep 11:1018-1030). Virus infection has been demonstrated to be facilitated by ENPP1 overexpression and is attenuated by silencing of ENPP1 (Wang J et al. 2018 Mol Immunol 95:56-63). WO 2018/119328 A1 disclsoes compounds and their use as inhibitors of ENPP1 for the treatment of a viral disease.
Inhibitors of cGAMP hydrolysis may therefore be used to increase the effectiveness of immune responses against cancer cells and tumors and against infections by RNA or DNA viruses or bacteria. Inhibitors of ENPP1 and of cGAMP or nucleoside triphosphate hydrolysis may also be used for the treatment of inflammatory diseases that are associated with elevated nucleotidase levels, reduced nucleoside triphosphate, reduced cGAMP or reduced nucleoside monophosphate ester levels or diseases associated with elevated nucleoside or nucleoside monophosphate levels. For these reasons, ENPP1 is an attractive therapeutic target for the treatment of diseases.
The present disclosure addresses these needs and provides related advantages as well.
 SUMMARY
In a first aspect, provided is a compound of the present disclosure selected from 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof, 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof, 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof, 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof, (4-((5-carbamoyl-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid or a pharmaceutically acceptable salt thereof, 4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid or a pharmaceutically acceptable salt thereof, 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof, 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof, 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid or a pharmaceutically acceptable salt thereof and 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt.
In a second aspect, provided is a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.
In a third aspect, also disclosed are methods of treating a disease or mediated by ENPP1 in a patient, preferably in a patient recognized as needing such a treatment, comprising administering to the patient a compound of the present disclosurein a therapeutically effective amount. In one embodiment, the disease is cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer. In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate dihydrate. In yet another embodiment the disease metabolic disease e.g., type 2 diabetes or a viral infection.
In a fourth aspect, provided is a compound of the present disclosure (or any embodiments thereof described herein), or a pharmaeceutical compositon of the present disclosure, for use in a method of treating a cancer, an inflammatory disease, a metabolic disease, or a viral disease. In one embodiment, the compound or composition is for use in the treatment of cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer. In another embodiment, the compound or composition is for use in the treatment of an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate dihydrate. In yet another embodiment, the compound or composition is for use in the treatment of a metabolic disease e.g., type 2 diabetes or a viral infection.
In any of the aforementioned aspects involving compounds or compositions for use in the treatment of cancer, are further embodiments wherein said treatment comprises administering said compound or composition, in combination with at least one additional anticancer. When combination therapy is used, the agents can be for administration simultaneously or sequentially.
 DETAILED DESCRIPTION
The present disclosure also includes polymorphic forms and deuterated forms of the compound of the present disclosure.
A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985
Certain compounds of the present disclosure can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. An example of tautomerism is shown below:
Furthermore, all hydrates of a compound of the present disclosure are within the scope of this disclosure.
The compounds of the present disclosure may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 1251, respectively. Isotopically-labeled compounds (e.g., those labeled with .sup.3H and .sup.14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1 below one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by 13C- or 14C-enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C, and 15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.
The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.
The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
The term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, and horses. Preferably, the patient is a human.
The terms "inhibiting" and "reducing," or any variation of these terms in relation of EPPI, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of EPPI activity compared to normal.
"Treating" or "treatment" of a disease includes:
  1. (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;
  2. (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or
  3. (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A "therapeutically effective amount" means the amount of a compound of the present disclosure that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
Representative compounds of the present disclosure are disclosed in Table 1 below:
4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt
4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
(4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid
4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid
4-((5-carbamoylimidazo[4, 5-b]pyridin-1-yl)methyl)phenylboronic acid
4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid
4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid
4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid
(4-((5-carbamoyl-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid
4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1 -yl)methyl)phenylboronic acid
Embodiments: GENERAL SYNTHETIC SCHEME
Compounds of this disclosure belong to Formula (I), as described below, or are pharmaceutically acceptable salts thereof. wherein:
  • a, b, d, and e are CH; or one or two of a, b, d, and e are N and remaining of a, b, d, and e are CH;
  • one of y and z is N and the other y and z is CR7; or both y and z are CR7 wherein each R7 is independently hydrogen, alkyl, hydroxy, or halo;
  • alk is alkylene optionally substituted with one, two, or three halo;
  • alk1 is alkylene wherein one carbon atom in the alkylene chain can be replaced by oxygen and the alkylene chain is optionally substituted with one, two, or three halo;
  • m and n are independently 0 or 1; provided that at least one of m and n is 1;
  • Ar is aryl or heteroaryl;
  • Rw and Rx are independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORc (where Rc is alkyl), -O-(alk2)ORd (where alk2 is alkylene and Rd is alkyl); or
  • Rw and Rx together with the boron atom to which they are attached can form -O(CRR')2O- or -O(CRR')3O- wherein each R and R' is independently hydrogen or methyl;
  • R2 and R3 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
  • R4 is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; and
  • R5 and R6 are independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with Rh, Rj, or Rk independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).
Compounds of Formula (I) are not claimed in general terms. Rather, the claims relate to certain compounds which belong to Formula (I), and pharmaceutically acceptable salts thereof, and the extent of protection of the present patent is determined by the claims in accordance with Article 69 EPC and the protocol on the interpretation of Article 69 EPC. Formula (I) is disclosed herein for reference, in particular to aid the the methods depicted in the reaction schemes shown below by which compounds of the present disclosure can be made.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.
Compounds of Formula (I) where Ar is aryl or heteroaryl, n is 1, m is 0, and other groups are as defined above can be prepared as illustrated and described in Scheme 1 below.
Arylation of a compound of formula 1 where a, b, d, e, y and z are as defined above and R4, R5, and R6 are as defined above or a precursor group thereof (e.g., hydroxy is a precursor group of alkoxy etc.), a boronic acid of the formula 2 where Ar is aryl or heteroaryl under Suzuki reaction (Suzuki, A Journal of Organometallic Chemistry. 576: 147-168, and references cited therein) conditions provides an alcohol compound of formula 3. The reaction is carried out under palladium or nickel catalyzed conditions using a base such as lithium, sodium, potassium or cesium carbonate; lithium, sodium or potassium tert-butoxide; lithium, sodium or potassium hydroxide; phosphate bases such as tripotassium phosphate; or any other organic or inorganic base, in solvents comprised of a mixture of water and organic solvents such as 1,4- dioxane, tetrahydrofuran (THF), diethyl ether, toluene, ethanol or methanol, dimethylformamide (DMF) and the like, either at room temperature or heating. Compounds of formula 1 such as 5,6-dimethoxy-1H-benzo[d]imidazole, 6-methoxy-1H-benzo[d]imidazole, 6-chloro-9H-purin-2-amine, 6-chloro-9H-purin, 5-methoxy-1H-indol, 5,6-dimethoxy-1H-indol , 9H-purin-6-amine, 1H-benzo[d]imidazole-5-carbonitrile, methyl 1H-benzo[d]imidazole-5-carboxylate, 1H-benzo[d]imidazole-5-carboxamide, 1H-benzo[d]imidazole-5-carboxylic acid, 1H-pyrrolo[3,2-c]pyridin-4-ol, 1H-imidazo[4,5-c]pyridine, are commercially available.
Conversion of the hydroxyl in a compound of formula 3 to a leaving group in compounds of formula 4 that is halide may be accomplished by means of the Appel reaction (Appel, R Angewandte Chemie International Edition in English. 14:801-811) by treatment of compound 3 with a halogenating agent such as N-bromosuccinimide, carbon tetrachloride, carbon tetrabromide, bromine, methyl iodide or iodine, in the presence of triphenylphosphine. The halo group in compounds of the formula 4 can be displaced by a variety of boronate or phosphite nucleophiles to provide a compound of Formula (I). For example, treatment of compound 4 with triethyl phosphite via heating in the absence or presence of aprotic organic solvents such as DMF or THF, followed by hydrolysis of the resulting triethylphosphonate provides a compound of Formula (I) where Q is -P(O)(OH)2. Triethylphosphonate may be hydrolyzed in the presence of bromo- or chloro-trimethylsilane in dichloromethane, or hydrogen chloride in water, or trimethylsilyl iodide in dichloromethane either at room temperature or with heating. Compounds of Formula (I) where Q is -B(OH)2 can be prepared by treatment of compound 4 with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane, followed by hydrolysis of resulting 4-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl group by methods well known in the art. Compounds of Formula (I) can be converted to other compounds of Formula (I) by method well known in the art. For example, diethyl (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonate is converted to (4-((5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid by treatment with bromotrimethylsilane in dichloromethane at room temperature.
Compounds of Formula (I) where Ar is aryl or heteroaryl, n is 1, m is 0, and other groups are as defined above can be prepared as illustrated and described in Scheme 2 below.
Treatment of a compound of formula 1 with a compound of formula 5 or 5' wherein Ar, alk are as defined above and R2 and R3 are as defined above or a precursor group thereof and LG is a suitable leaving group such as halo, in the presence of carbonate, hydroxide, or alkoxide (e.g. tert-butoxide) bases, either with heating or at room temperature, provides a compound of formula 6 or 7 respectively. Compound of formula 6 can be converted to compound 7 where LG is halo by methods well known in the art. Compounds of the formula 5 are either commercially available or may be prepared by methods well known in the art. Compounds of formula 7 can then be coverted to compounds of Formula (I) as described in Scheme 1 above.
Alternatively, compounds of the Formula (I) where Q is boronic acid may be prepared by displacement of the leaving group in compounds of the formula 8 by compounds of the formula 1. The reaction is carried out by treating a mixture of compounds of the formulas 1 and 8 with carbonate, hydroxide, or alkoxide (e.g. tert-butoxide) bases, or other organic or inorganic bases, in solvents such as acetonitrile, DMF, or THF and the like, either at room temperature or with heating. Compounds of the formula 8 are either commercially available or can be readily prepared by methods well known in the art. Compounds of formula 1 such as 5,6-dimethoxy-1H-benzo[d]imidazole, 6-methoxy-1H-bezno[d]imidazole, 6-chloro-9H-purin-2-amine, 6-chloro-9H-purin, 5-methoxy-1H-indol, 5,6-dimethoxy-1H-indol , 9H-purin-6-amine, 1H-benzo[d]imidazole-5-carbonitrile, methyl 1H-benzo[d]imidazole-5-carboxylate, 1H-benzo[d]imidazole-5-carboxamide, 1H-benzo[d]imidazole-5-carboxylic acid, 1H-pyrrolo[3,2-c]pyridin-4-ol, 1H-imidazo[4,5-c]pyridine, 5-methanesulfonyl-1H-1,3-benzodiazole are commercially available. Compounds of formula 8 such as (4-(bromomethyl)phenyl)boronic acid, are commercially available. Compounds of formula 5, such as 1-bromo-4-(bromomethyl)benzene, 5-Bromo-2-(bromomethyl)pyridine, are commercially available.
Testing
The ENPP1 inhibitory activity of the compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples 1 and 2 below.
Administration and Pharmaceutical Composition
In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.
The compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of this disclosure or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred. However, the combination therapy may also include therapies in which the compound of this disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of the present disclosure.
The above combinations include combinations of a compound of this disclosure not only with one other drug, but also with two or more other active drugs. Likewise, a compound of this disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of this disclosure is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of this disclosure. The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of this disclosure in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol™, also referred to as "paclitaxel", which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™., such as Taxotere™. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein.
Further examples of anti-cancer agents for use in combination with a compound of this disclosure include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitor such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib, axitinib; EGFR inhibitor such as afatinib, brivanib, carbozatinib, erlotinib, gefitinib, neratinib, lapatinib; PI3K inhibitor such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946. BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, AZD8330; and proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib.
Other anti-cancer agents that can be employed in combination with a compound of this disclosure include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
Other anti-cancer agents that can be employed in combination with a compound of the disclosure used to determine the anti-tumor activity in HGS and RT4 tumor models (Example 4 below: In HGS model, vehicle dosed group reached tumor size 645dosing at day 42 after inoculation whereas for animals treated with 20/kg of compound, the tumor size was 55mm3 showing significant antitumor activity and induced tumor regression), include: 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+- 19 -iethylstilbe cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Yet other anticancer agents that can be employed in combination with a compound of this disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
Examples of natural products useful in combination with a compound of this disclosure include but are not limited to vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
Examples of alkylating agents that can be employed in combination a compound of this disclosure) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
Examples of hormones and antagonists useful in combination a compound of this disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).
Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irreversible Btk inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).
Further examples of anti-cancer agents for use in combination with a compound of this disclosure include immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologics) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).
In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383
 EXAMPLES
The following preparations of compounds are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. To the extent that the following examples relate to subject matter not defined in the claims, they are provided for reference purposes.
All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen.
1H spectra were recorded at 400 MHz or 300 MHz for proton on a Bruker 400 NMR Spectrometer equipped with a Bruker 400 BBO probe or Bruker BBFO ULTRASHIELD™300 AVANCE III, respectively. All deuterated solvents contained typically 0.03% to 0.05% v/v tetramethylsilane, which was used as the reference signal (set at δ 0.00 for both 1H and 13C).
LCMS analyses were performed on a SHIMADZU LCMS consisting of an LTFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 3.0 s.
HPLC analyses were performed on a SHIMADZU LTFLC with two LC20 AD pump and a SPD-M20A Photodiiode Array Detector. The column used was an XBridge C18, 3.5 µm, 4.6 × 100 mm. A linear gradient was applied, starting at 90 % A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) over 10 min with a total run time of 15 min. The column temperature was at 40 °C with the flow rate of 1.5 mL/min. The Diode Array Detector was scanned from 200-400 nm.
Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional visualization methods were also employed in some cases. In these cases the TLC plate was developed with iodine (generated by adding approximately 1 g of I2 to 10 g silica gel and thoroughly mixing), ninhydrin (available commercially from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (NH4)6Mo7O24.4H2O, 5 g (NH4)2Ce(IV)(NO3)6 in 450 mL water and 50 mL concentrated H2SO4) to visualize the compound. Flash chromatography was performed using 40-63 µm (230-400 mesh) silica gel from Silicycle following analogous techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents used for flash chromatography or thin layer chromatography were mixtures of chloroform/methanol, dichloromethane/methanol, ethyl acetate/methanol and hexanes/ethyl acetate.
Synthetic Examples Example 14
Synthesis of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14a), 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenylboronic acid trifluoroacetic acid salt (14b), 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetic acid salt (14c), 1-((4-(dihydroxy-boranyl)phenyl)methyl)-1,3-benzodiazole-6-carboxylic acid trifluoroacetic acid salt (14d), 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14e), and 4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt
Step 1: 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14a)and 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14b)
To a solution of methyl 1H-1,3-benzodiazole-5-carboxylate (500mg, 2.838 mmol, 1.00 equiv) in DMF (5 mL) was added sodium hydride (170 mg, 4.257 mmol, 1.50 equiv, 60% purity) at 0°C. After stirred for 20 minutes, 4-(bromomethyl)phenylboronic acid (732 mg, 3.406 mmol, 1.20 equiv) was added. The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 500 mg of a mixture of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14a) and 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)-phenylboronic acid trifluoroacetic acid salt (14b). 250 mg of the mixture was purified by prep-HPLC with the following conditions Column: XSelect CSH Prep C18 OBD Column, 19×250 mm, 5 um; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 12% B to 18% B in 17 min, 220 & 254 nm. The fractions containing the desired products were combined and lyophilized to give two fractions.
Fraction 1: Rt: 12.77 min. 70.3 mg (6% yield) of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14a) as a white solid. MS (ESI, pos. ion) m/z: 311.2 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 9.05-9.01 (m, 1H), 8.43-8.10 (m, 3H), 7.94-7.76 (m, 5H), 7.29 (d, J = 7.6 Hz, 2H), 5.71-5.69 (m, 2H), 3.86-3.82 (m, 3H).
Fraction 2: Rt: 14.7 min. 80.8 mg (6% yield) of 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt as a white solid (14b). MS (ESI, pos. ion) m/z: 311.2 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 9.05-9.01 (m, 1H), 8.34 (s, 1H), 7.96-7.85 (m, 2H), 7.77-7.50 (m, 5H), 7.36-7.32 (m, 2H), 5.60 (s, 2H), 3.87 (s, 3H).
Step 2: 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetic acid salt (14c), 1-((4-(dihydroxy-boranyl)phenyl)methyl)-1,3-benzodiazole-6-carboxylic acid trifluoroacetic acid salt (14d), 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14e) and 4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14f).
A mixture of 4-((6-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid) and 4-((5-(methoxycarbonyl)-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14a and 14b) (250 mg, 1 equiv) was dissolved in aqueous ammonia (10 mL). After stirring at 80°C for 12 h in a sealed tube, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions Column: XSelect CSH Prep C18 OBD Column, 19×250 mm, 5 um; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 5% B to 15% B in 14 min, 220 & 254 nm. The fractions containing the desired products were combined and lyophilized to give four fractions.
Fraction 1: Rt: 7.25 min. 16.8 mg (5% yield) of 3-((4-(dihydroxyboranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetic acid salt (14c) as a white solid. MS (ESI, pos. ion) m/z: 297.2 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 9.07 (s, 1H), 8.20 (s, 1H), 7.94-7.75 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 5.65 (s, 2H).
Fraction 2: Rt: 8.92 min. 20.6 mg (6% yield) of 1-((4-(dihydroxy-boranyl)phenyl)methyl)-1,3-benzodiazole-5-carboxylic acid trifluoroacetic acid salt (14d) as a white solid. MS (ESI, pos. ion) m/z: 297.3 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 12.81(brs, 1H), 8.68 (s, 1H), 8.26-7.85 (m, 4H), 7.76-7.61 (m, 3H), 7.35-7.28 (m, 2H), 5.57 (s, 2H).
Fraction 3: Rt: 10.22 min. 42.8 mg (13% yield) of 4-((6-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14e) as a white solid. MS (ESI, pos. ion) m/z: 296.2 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 9.27 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.97-7.73 (m, 5H), 7.50-7.20 (m, 5H), 5.68 (s, 2H).
Fraction 4: Rt: 11.84 min. 53.0 mg (16% yield) of 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt (14f) as a white solid. MS (ESI, pos. ion) m/z: 296.2 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 9.20 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.94-7.88 (m, 1H), 7.79-7.73 (m, 3H), 7.43 (s, 1H), 7.44-7.29 (m, 3H), 5.66 (s, 2H).
Example 20 Synthesis of (4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (20a) 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (20b)
Step 1: methyl 2-ethyl-1H-1,3-benzodiazole-5-carboxylate
To a solution of methyl 3,4-diaminobenzoate (500 mg, 3.01 mmol, 1.00 equiv.) in N,N-dimethyl- propenamide (5 mL) was added 1H-imidazole hydrochloride (63 mg, 0.60 mmol, 0.20 equiv.) at room temperature. After stirring for 24 hours at 140 °C, the reaction mixture was cooled to room temperature, diluted with ethyl acetateand washed water. The combined organic layers were dried with over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ ethyl acetate = 7:3) to give 0.36 g (51%) of methyl 2-ethyl-1H-1,3-benzodiazole-5-carboxylate as a brown solid. 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 12.79-12.33 (brs, 1H), 8.08 (s, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 2.87 (q, J = 8.0 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H).
Step 2: 2-ethyl-1H-1,3-benzodiazole-5-carboxylic acid
To a solution of methyl 2-ethyl-1H-1,3-benzodiazole-5-carboxylate (300 mg, 1.47 mmol, 1.00 equiv.) in methanol (5 mL) were added sodium hydroxide (176 mg, 4.41 mmol, 3.00 equiv.) and water (2 mL) at room temperature. After stirring for 1 hour at room temperature, the mixture was adjusted to pH = 3 with 2 N hydrogen chloride (3 mL) and a white precipitate was formed. The solid was collected by filtration, washed with water and dried under reduced pressure to give 0.25 g (89%) of 2-ethyl-1H-1,3-benzodiazole-5-carboxylic acid as an off-white solid.
Step 3: 2-ethyl-1H-1,3-benzodiazole-5-carboxamide
2-Ethyl-1H-1,3-benzodiazole-5-carboxylic acid (250 mg, 1.31 mmol, 1.00 equiv.) was added to thionyl chloride (15 mL), resulting in a suspension, which was stirred for 1 hour at 80 °C. The mixture was evaporated under reduced pressure to give the intermediate acid chloride as a brown solid, which was suspended in dichloromethane and slowly added into a stirred solution of ammonia in methanol (10 mL, 7 M, 70 mmol, 53.26 equiv.) at room temperature. The resulting mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 0.23 g (92%) of 2-ethyl-1H-1,3-benzodiazole-5-carboxamide as a yellow solid.
Step 4: (4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (20a) and 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (20b)
To a suspension of sodium hydride (44 mg, 1.82 mmol, 1.50 equiv.) in N, N-dimethylformamide (5 mL) was added a solution of 2-ethyl-1H-1,3-benzodiazole-5-carboxamide (230 mg, 1.22 mmol, 1.00 equiv.) in N, N-dimethylformamide (5 mL) at 0°C. After stirring for 30 minutes at 0 °C, a solution of 4-(bromomethyl)phenylboronic acid (313 mg, 1.46 mmol, 1.20 equiv.) in N, N-dimethylformamide (2 mL) was added at the same temperature. The resulting mixture was further stirred for 2 hours at room temperature. The reaction mixture was quenched with 2 N hydrogen chloride (5 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC with following conditions Column: XBridge C18 OBD column, 100 Å, 19×250, 5 um; Mobile Phase A: Water (0.05% FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 7% B to 14% B in 7 min; 220 & 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.
Fraction 1: Rt = 5.35 min. 23.4 mg (5% yield) of (4-((6-carbamoyl-2-ethyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (20a) as a white solid. MS (ESI, pos. ion) m/z: 323.8 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 8.04 (d, J = 1.6 Hz, 1H), 8.01 (s, 2H), 7.90 (s, 1H), 7.78-7.70 (m, 3H), 7.62 (d, J= 8.4 Hz, 1H), 7.26 (s, 1H), 7.04 (d, J= 7.9 Hz, 2H), 5.52 (s, 2H), 2.86 (q, J= 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).
Fraction 2: Rt = 7.13 min. 17.5 mg (4% yield) of 4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (20b) as a white solid. MS (ESI, pos. ion) m/z: 324.4 (M+1). 1H-NMR: (400 MHz, DMSO-d6 , ppm) δ 12.69 (s, 0.7 HCOOH), 8.16 (d, J = 1.6 Hz, 1H), 8.13 (s, 0.7HCOOH), 8.02 (s, 2H), 7.92 (s, 1H), 7.76-7.70 (m, 3H), 7.50 (d, J= 8.4 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J = 8.1 Hz, 2H), 5.52 (s, 2H), 2.86 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).
Example 22 Synthesis of (4-((6-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (22a) and (4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (22b)
Step 1: methyl 2-methyl-1H-1,3-benzodiazole-5-carboxylate
To a stirred solution of methyl 3,4-diaminobenzoate (1.00 g, 6.02 mmol, 1.00 equiv) in dimethylacetamide (15 mL) was added imidazole hydrochloride (307 mg, 3.01 mmol, 0.50 equiv) at room temperature. After stirring for 8 h at 150 °C, the mixture was poured into water. The aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: PE/EA 4: 1) to give 0.95 g (71% yield) of methyl 2-methyl-1H-1,3-benzodiazole-5-carboxylate as a brown solid.
Step 2: 2-Methyl-1H-1,3-benzodiazole-5-carboxylic acid
To a stirred solution of methyl 2-methyl-1H-1,3-benzodiazole-5-carboxylate (500 mg, 2.63 mmol, 1.00 equiv, 86%) in MeOH (5.00 mL) and H2O (5.00 mL) was added NaOH (210 mg, 5.23 mmol, 2 equiv) at room temperature. After stirring for 2 h at room temperature, the mixture was acidified to pH 4~5 with concentrated hydrochloric acid at 0 °C. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 300 mg (74% yield) 2-methyl-1H-1,3-benzodiazole-5-carboxylic acid.
Step 3: 2-methyl-1H-1,3-benzodiazole-5-carboxamide
A suspension of 2-Methyl-1H-1,3-benzodiazole-5-carboxylic acid (300 mg, 1.70 mmol, 1.00 equiv) in thionyl chloride (10 mL) was stirred for 1 hour at 80 °C. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was suspended in dichloromethane (10 mL) and added into a stirring solution of ammonia in methanol (10 mL, 7 M, 70 mmol, 41.11 equiv.) at room temperature slowly. The resulting mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure to give 180 mg (60% yield) of 2-methyl-1H-1,3-benzodiazole-5-carboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 176.25 (M+1).
Step 4: (4-((6-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-boronic acid (22a) and and (4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-phenyl)boronic acid (22b)
To a suspension of sodium hydride (43 mg, 1.78 mmol, 2.0 equiv.) in N, N-dimethylformamide (8 mL) was added 1H-1,3-benzodiazole-5-carboxamide (180 mg, 0.89 mmol, 1.00 equiv, 80%) at 0°C. After stirring for 30 minutes at 0 °C, 4-(bromomethyl)phenylboronic acid (230 mg, 1.07 mmol, 1.20 equiv) was added at this temperature and the mixture was further stirred for 2 hours at room temperature. The mixture was quenched with 2 N hydrogen chloride and concentrated under reduced pressure. The residue was purified by prep-HPLC with Column: Sunfire prep C18 column, 30*150, 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:2 B to 9 B in 10 min; 254/220 nm; RT1:7.62;9.32; RT2:; Injection Volumn: ml; Number Of Runs:;. The fractions containing the desired product were combined and lyophilized to give two fractions.
Fraction 1: Rt: 7.62 min. 84 mg (29% yieid) 4-((6-carbamoyl-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (22a) as a white solid. MS (ESI, pos. ion) m/z: 310.3 (M+1). 1H NMR (300 MHz, DMSO-d 6) δ 12.95 - 12.63(s, 0.3 HCOOH), δ 8.20 - 7.91 (m, 4H), 7.73 (d, J = 7.8 Hz, 3H), 7.50 (d, J= 8.5 Hz, 1H), 7.24 (s, 1H), 7.07 (d, J= 7.9 Hz, 2H), 5.51 (s, 2H), 2.53 (s, 3H).
Fraction 2: Rt: 9.32min. 110 mg (37% yieid) 4-((5-carbamoyl-2-methyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (22b) as a white solid. MS (ESI, pos. ion) m/z: 310.3 (M+1). 1H NMR (300 MHz, DMSO-d 6) δ 8.14 (s, 1H), 8.05 (s, 2H), 7.92 (s, 1H), 7.74 (d, J= 7.7 Hz, 3H), 7.58 (d, J= 8.4 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J= 7.7 Hz, 2H), 5.51 (s, 2H), 2.54 (d, J = 2.2 Hz, 3H).
Example 23
Synthesis of 4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23a) and 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23b)
Step 1: methyl 2-isopropyl-1H-1,3-benzodiazole-5-carboxylate
The title compound was synthesized by the method described in step 1 of Example 22 except N,N-dimethylisobutyramide (5 mL) was used in place of dimethylacetamide.
Step 2 : 2-isopropyl-1H-1,3-benzodiazole-5-carboxylic acid
The title compound was synthesized by the method described in step 2 of Example 22 except methyl 2-isopropyl-1H-1,3-benzodiazole-5-carboxylate (220 mg) and sodium hydroxide (121 mg, 3.02 mmol 3.00 equiv.) were used.
Step 3 : 2-isopropyl-1H-1,3-benzodiazole-5-carboxamide
The title compound was synthesized by the method described in step 3 of example 22 except 2-isopropyl-1H-1,3-benzodiazole-5-carboxylic acid (180 mg) was used.
Step 4 : 4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23a) and 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23b)
The title compound was synthesized by the method described in step 4 of example 22 except 2-isopropyl-1H-1,3-benzodiazole-5-carboxamide (160 mg) was used. The crude product was purified by prep-HPLC with following conditions Column XBridge C18 OBD column, 100 Å, 19×250, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL/min; Gradient: 7% B to 15% B in 7 min; 220 & 254 nm. The fractions containing the desired product were combined and lyophilized to give two fractions.
Fraction 1: Rt = 5.55 min. 43.4 mg (16% yield) of 4-((6-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23a) as a white solid. MS (ESI, pos. ion) m/z: 338.3 (M+1). 1H-NMR (400 MHz, DMSO-d6 , ppm) δ 8.06-8.01 (m, 3H), 7.90 (s, 1H), 7.76-7.67 (m, 3H), 7.62 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 5.56 (s, 2H), 3.31-3.22 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H).
Fraction 2: Rt = 7.22 min. 37.6 mg (13% yield) of 4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid (23b) as a white solid. MS (ESI, pos. ion) m/z: 338.4 (M+1). 1H-NMR (400 MHz, DMSO-d6 , ppm) δ 8.16 (s, 1H), 8.03 (s, 2H), 7.91 (s, 1H), 7.74-7.70 (m, 3H), 7.46 (d, J= 8.4 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J= 8.0 Hz, 2H), 5.55 (s, 2H), 3.31-3.22 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H)
Example 34 Synthesis of 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (34a) and 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (34b)
Step 1: 1H-imidazo[4,5-b]pyridine-5-carbonitrile
A solution of 1H-imidazo[4,5-b]pyridine-5-carboxamide (150 mg, 0.93 mmol) in POCl3 (8.00 mL) was stirred for 3 hour at 110 °C in an oil bath. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: EA / MEOH 85:15) to get130 mg (91.0% yield) of 1H-imidazo[4,5-b]pyridine-5-carbonitrile as an off-white solid.
Step 2: 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (34a) and 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (34b)
The title compounds were synthesized by the method described in step 4 of Example 22 except 1H-imidazo[4,5-b]pyridine-5-carbonitrile (150 mg, 1.04 mmol) was used. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30∗150, 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:5 B to 30 B in 10 min; 254/220 nm; RT1:8.82 min; RT2: 9.12 min) to give two fractions:
Fraction 1: Rt: 8.82 min. 20.7 mg (7.07% yield) of 4-((5-cyanoimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (34b) as a white solid. MS (ESI, pos. ion) m/z: 278.85 (M+1). 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.98 (s, 1H), 8.23 (d, J= 8.2 Hz, 1H), 8.07 (s, 2H), 7.89 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 5.61 (s, 2H).
Fraction 2: Rt: 9.12 min. 16.4 mg (5.42% yield) of 4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (34a) as a white solid. MS (ESI, pos. ion) m/z: 279.20 (M+1). 1H-NMR (400 MHz, DMSO-d6 , ppm) δ 8.94 (s, 1H), 8.36 (d, J= 8.2 Hz, 1H), 8.07 (s, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.29 (d, J= 7.7 Hz, 2H), 5.56 (s, 2H).
Example 37 (For Reference) Synthesis of 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (37a )and 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (37b)
Step 1: 4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine
To a stirred solution of 2-methoxypyridine-3,4-diamine (300 mg, 2.156 mmol, 1.00 equiv) in MeOH (5.00 mL) were added Pd/C (210 mg, 1.078 mmol, 0.5 equiv) and acetaldehyde (95 mg, 1.617 mmol, 1.50 equiv). After stirring for 12 hours at 120 °C in an oil bath, the mixture was concentrated under reduced pressure. After stirring for 24 h, the resulting mixture was filtered through a Celite and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / petroleum ether 3:2) to give 4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine (300 mg, 56.3% yield) as a white solid.
Step 2: 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (37a) and 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (37b)
NaH (101 mg, 4.204 mmol, 2 equiv) was placed into a three-neck flask which was purged with nitrogen at room temperature. A solution of 4-methoxy-2-methyl-1H-imidazo[4,5-c]pyridine (343 mg, 2.10 mmol, 1.00 equiv) in DMF (6.00 mL) was added at 0 °C. After stirring for 30 min, 4-(bromomethyl)phenylboronic acid (542 mg, 2.522 mmol, 1.20 equiv) was added at 0 °C. The mixture was stirred for additional 1 h at room temperature, thenquenched with hydrochloric acid (3 N, 5.0 mL) and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge C18 OBD Prep Column, 100Å, 5 µm, 19 mm X 250 mm; Mobile Phase A:Water (0.05%FA), Mobile Phase B:ACN; Flow rate:25 mL/min; Gradient:5 B to 12 B in 7 min; 254/220 nm; RT1:7.13 min; RT2: 8.42 min) to afford two fractions:
Fraction 1: Rt: 7.13 min. 32.7 mg (5.3% yield) of 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (37b). MS (ESI, pos. ion) m/z: 284.25 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.27 (d, J = 5.8 Hz, 1H), 8.06 (s, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.09 (dd, J= 11.1, 7.1 Hz, 3H), 6.51 (d, J = 7.0 Hz, 1H), 5.73 (s, 2H), 2.35 (s, 3H).
Fraction 2: Rt: 8.42 min. 3.7 mg (0.6% yield) of 4-((4-hydroxy-2-methylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (37a) as a white solid. MS (ESI, pos. ion) m/z: 284.25(M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.12 (s, 1H), 8.45 (s, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 7.6 Hz, 3H), 6.52 (d, J = 7.0 Hz, 1H), 5.38 (s, 2H), 2.39 (s, 3H).
Example 38 Synthesis of 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (38a) and 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (38b)
Step 1: 2-ethyl-4-methoxy-1H-imidazo[4,5-c]pyridine
The compound was synthesized by the at step 1 of Example 37 except 2-methoxypyridine-3,4-diamine (500 mg, 3.59 mmol) and propionaldehyde (208 mg, 3.59 mmol) were used. Yield: 200 mg (30.8%).
Step 2: 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (38a) and 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (38b)
The title compounds were synthesized by the in step 2 of Example 37 except 2-ethyl-4-methoxy-1H-imidazo[4,5-c]pyridine (350 mg, 1.975 mmol) was used. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30* 150, 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:8 B to 25 B in 10 min; 254/220 nm; RT1:5.08 min; RT2: 6.10 min) to afford two fractions:
Fraction 1: Rt: 5.08 min. 12.7 mg (2.1% yield) of 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (38b). MS (ESI, pos. ion) m/z: 298.25 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.27 (d, J = 5.7 Hz, 1H), 8.15 (d, J= 39.2 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.13 - 7.03 (m, 3H), 6.55 (d, J= 6.9 Hz, 1H), 5.75 (s, 2H), 2.67 (q, J= 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).
Fraction 2: Rt: 6.10 min. 13.8 mg (2.3% yield) of 4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (38a) as a white solid. MS (ESI, pos. ion) m/z: 298.20 (M+1). 1H-NMR (400 MHz, DMSO-d6 , ppm) δ 11.11 (d, J = 5.5 Hz, 1H), 8.10 (s, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.06 (dd, J = 29.5, 7.0 Hz, 3H), 6.52 (d, J = 7.0 Hz, 1H), 5.39 (s, 2H), 2.71 (q, J= 7.5 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H).
Example 39 Synthesis of 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) and 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid with formic acid (39a)
Step 1: 2-isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridine
The title compounds were synthesized by the method described in step 1 of Example 37 except 2-methoxypyridine-3,4-diamine (500 mg, 3.59 mmol) and isobutyraldehyde (285 mg, 3.952 mmol) were used. Yield: 370 mg (46.2%). MS (ESI, pos. ion) m/z: 192.25 (M+1).
Step 2: 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) and 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (39b)
The compounds were synthesized by the in step 4 in Example 22 except 2-isopropyl-4-methoxy-1H-imidazo[4,5-c]pyridine (370 mg, 1.935 mmol) was used and the residue was dissolved in methanol (5 mL) and filtered. The filtrate was concentrated under reduced pressure to give 420 mg (58.6% yield) of a mixture of 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid and 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (ratio=1:1) as a brown solid. MS (ESI, pos. ion) m/z: 325.90 (M+1).
Step 3: 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic (39a) and 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid formate (39a)
To a solution of a mixture of 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid and 4-((2-isopropyl-4-methoxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid) (420 mg, 1.033 mmol, 1.00 equiv, 80%) in ACN (10.00 mL) was added TMSI (1.29 g, 6.458 mmol, 5 equiv) at room temperature. The resulting mixture was stirred for 2 hours at 90 °C. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: Sunfire prep C18 column, 30∗150, 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:9 B to 20 B in 10 min; 254/220 nm; RT1: 8.12 min; RT2: 8.90 min) to give two fractions:
Fraction 1: Rt: 8.12 min. 74.2 mg (19.5% yield) of 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (39b) as a formate salt (light yellow solid). MS (ESI, pos. ion) m/z: 312.25 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ11.27 (d, J= 5.8 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 2H), 7.73 (d, J = 7.9 Hz, 2H), 7.09 (dd, J = 16.9, 7.1 Hz, 3H), 6.56 (d, J = 6.9 Hz, 1H), 5.80 (s, 2H), 3.10 (m, 1H), 1.12 (d, J= 6.7 Hz, 6H).
Fraction 2: Rt: 8.90 min. 108.3 mg (33.0% yield) 4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (39a) as an off-white solid. MS (ESI, pos. ion) m/z: 312.30 (M+1). 1H-NMR (400 MHz, DMSO-d6 , ppm) 811.11 (d, J = 5.9 Hz, 1H), 8.05 (s, 2H), 7.74 (d, J = 7.8 Hz, 2H), 7.10 (t, J = 6.5 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.57 - 6.44 (m, 1H), 5.44 (s, 2H), 3.19 - 3.09 (m, 1H), 1.18 (d, J= 6.8 Hz, 6H).
Example 55 (For Reference) Synthesis of 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a), and 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55b)
Step 1: 4-methoxy-1H-pyrazolo[4,3-c]pyridine
To a solution of 30% NaOMe in MeOH (10.00 mL) was added 4-chloro-1H-pyrazolo[4,3-c]pyridine (500.00 mg, 1 equiv). The resulting mixture was stirred for 2 h at 140 °C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-methoxy-1H-pyrazolo[4,3-c]pyridine (300 mg, 60.54% yield) as a yellow solid
Step 2: 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a)
To a solution of 4-methoxy-1H-pyrazolo[4,3-c]pyridine (280 mg, 1.840 mmol, 1.00 equiv, 98%) in DMF (10.00 mL) were added 4-(bromomethyl)phenylboronic acid (474 mg, 2.21 mmol, 1.2 eq) and cesium carbonate (1.20 g, 3.68 mmol, 2 eq). After stirring for 2 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by Column: Sunfire prep C18 column, 30∗150, 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:20 B to 30 B in 10 min; 254/220 nm; RT1: 5.02 min; RT2: 9.17 min) to give 100 mg (18.4% yield) of 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a) as a white solid. MS (ESI, pos. ion) m/z: 284.25 (M+1). 1H NMR (300 MHz, DMSO-d 6, ppm) δ 8.18 (s, 1H), 8.02 (s, 2H), 7.90 (d, J = 6.1 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.32 (d, J= 6.1 Hz, 1H), 7.16 (d, J= 7.5 Hz, 2H), 5.64 (s, 2H), 4.00 (s, 3H).
Step 3: 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid
Into a solution of 4-((4-methoxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55a, 85.00 mg, 0.300 mmol, 1.00 equiv) in ACN (5 mL) was added TMSI (1.0 mL.. After stirring for 1 h at 90 °C, the reaction mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column,, 19*250mm,5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:20 mL/min; Gradient: 10 B to 71 B in 7 min; 254/220 nm; RT: 5.83 min) to afford 4-((4-hydroxypyrazolo[4,3-c]pyridin-1-yl)methyl)phenylboronic acid (55c, 57.0 mg, 67.8% yield) as a white solid. MS (ESI, pos. ion) m/z: 270.20 (M+1). 1H-NMR (400 MHz, DMSO-d6, ppm) 1H NMR (300 MHz, DMSO-d 6) δ 11.05 (d, J = 5.7 Hz, 1H), 8.06 (d, J = 0.8 Hz, 2H), 7.82 - 7.69 (m, 2H), 7.25 - 7.12 (m, 3H), 6.70 - 6.61 (m, 1H), 5.54 (s, 2H)
Example 58 (For Reference) Synthesis of 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) and 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b)
Step 1: 3H-imidazo[4,5-c]pyridine-6-carboxamide
Methyl 3H-imidazo[4,5-c]pyridine-6-carboxylate (200 mg, 1.13 mmol) was dissolved in NH3-H2O (10 mL) in a sealed tube. The resulting mixture was stirred for 2 hours at 80 °C. The reaction mixture was cooled to room temperature and evaporated to dryness to give 3H-imidazo[4,5-c]pyridine-6-carboxamide (180 mg, 98.3% yield) as a light yellow solid.
Step 2: 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) and 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b)
The title compounds were synthesized by the method described in step 2 of Example 55 except 3H-imidazo[4,5-c]pyridine-6-carboxamide (80 mg, 0.493 mmol). Two fractions were obtained:
Fraction 1: Rt: 13.05 min. 28.9 mg (18.9% yield) of 4-((6-carbamoylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid (58b) as a white solid. MS (ESI, pos. ion) m/z: 297.30 (M+1). 1H NMR (300 MHz, DMSO-d6 , ppm) δ 8.98 (d, J= 1.0 Hz, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.08 (d, J = 4.4 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.60 (d, J= 3.1 Hz, 1H), 7.26 (d, J= 7.7 Hz, 2H), 5.66 (s, 2H).
Fraction 2: Rt: 14.0 min. 21.2 mg (13.9% yield) 4-((6-carbamoylimidazo[4,5-c]pyridin-3-yl)methyl)phenylboronic acid (58a) as a white solid. MS (ESI, pos. ion) m/z: 297.30 (M+1). 1H NMR (300 MHz, DMSO-d6 , ppm) δ 8.88 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 8.11 - 8.03 (m, 3H), 7.76 (d, J = 7.8 Hz, 2H), 7.56 (s, 1H), 7.35 (d, J = 7.7 Hz, 2H), 5.67 (s, 2H).
Example 61 Synthesis of 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (61a) and 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b)
Step 1: 1H-imidazo[4,5-b]pyridine-5-carboxamide
The title compound was synthesized by the method described in step 1 of Example 58 except methyl 1H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg, 2.26 mmol) was used. Yield: 350 mg (83.1%) as a light yellow solid.
Step 2: 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (61a) and 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b)
The title compounds were synthesized by the method described in step 2 of Example 55 except 1H-imidazo[4,5-b]pyridine-5-carboxamide (100 mg, 0.62 mmol) was used. Two fractions were obtained:
Fraction 1: Rt: 13.05 min. 40.4 mg (21.3% yield) of 4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (61a) as a white solid. MS (ESI, pos. ion) m/z: 297.25 (M+1). 1H NMR (300 MHz, DMSO-d 6, ppm) ) δ 8.83 (s, 1H), 8.17 - 8.05 (m, 4H), 7.98 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 7.8 Hz, 2H), 7.56 - 7.49 (m, 1H), 7.30 (d, J= 7.7 Hz, 2H), 5.58 (s, 2H).
Fraction 2: Rt: 14.0 min. 44.8 mg (23.6% yield) of 4-((5-carbamoylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (61b) as a white solid. MS (ESI, pos. ion) m/z: 297.30 (M+1). 1H NMR (300 MHz, DMSO-d6 , ppm) δ 8.78 (s, 1H), 8.26 - 8.18 (m, 2H), 8.09 (d, J= 4.0 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 7.7 Hz, 2H), 7.66 (d, J = 2.8 Hz, 1H), 7.42 (d, J= 7.7 Hz, 2H), 5.60 (s, 2H).
Example 96 Synthesis of 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (96a) and 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (96b)
Step 1: 5-chloro-2-isopropyl-1H-imidazo[4,5-b]pyridine
A solution of 6-chloropyridine-2,3-diamine (1.0 g, 6.96 mmol) in acetic acid (20 mL) was stirried for 12 hours at 135 °C in an oil-bath. After cooling to room temperature, the precipitate was collected by filtration, washed with MeOH and dried in vacuo to give 5-chloro-2-isopropyl-1H-imidazo[4,5-b]pyridine (1.1 g, 77%) as a brown solid.
Step 2: 2-isopropyl-1H-imidazo[4,5-b]pyridine-5-carboxamide
To a stirred solution of NH3 (g) (80.00 mL, 7 M) in MeOH were added 5-chloro-2-isopropyl-1H-imidazo[4,5-b]pyridine (1.10 g, 5.6 mmol, 1.00equiv) and Pd(dppf)Cl2 (523 mg, 0.716 mmol, 0.10 equiv) at room temperature. After stirring for 12 hours at 120 °C in the 20 atm high pressure reactor filled with carbon monoxide, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: DCM / MEOH 95:5) to give 2-isopropyl-1H-imidazo[4,5-b]pyridine-5-carboxamide (769 mg, 55% yield) as a brown solid.
Step 3: 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (96a) and 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (96b)
The title compounds were synthesized by the method described in step 2 of Example 61 except 2-isopropyl-1H-imidazo[4,5-b]pyridine-5-carboxamide (150 mg, 0.734 mmol) was used. The crude product was purified by prep-HPLC under following conditions (Column: C18 column, 30*150, 5um; Mobile Phase A: Water (10 mmoL/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate:45 mL/min; Gradient:15 B to 35 B in 7 min; 254,220 nm; RT1:3.2 min; RT2: 4.5 min;). The fractions containing the desired product were combined and lyophilized to give two fractions:
Fraction 1: Rt: 3.2 min. 87.2 mg (34.8% yield) of 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-3-yl)methyl)phenylboronic acid (96a) as a white solid. MS (ESI, pos. ion) m/z: 339.25 (M+1). 1H NMR (300 MHz, DMSO-d6/D2O, ppm) δ 8.11 (d, J = 8.3 Hz, 1H), 7.98 (d, J= 8.2 Hz, 1H), 7.70 (d, J= 7.9 Hz, 2H), 7.12 (d, J= 7.8 Hz, 2H), 5.66 (s, 2H), 3.22 (p, J = 6.8 Hz, 1H), 1.17 (d, J = 6.7 Hz, 6H).
Fraction 2: Rt: 4.5 min. 78.1 mg (31.4% yield) of 4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid (96b) as a white solid. MS (ESI, pos. ion) m/z: 339.25 (M+1). 1H NMR (300 MHz, DMSO-d6/D2O, ppm) 1H NMR (300 MHz, DMSO-d 6) δ 7.95 (q, J= 8.4 Hz, 2H), 7.69 (d, J= 7.7 Hz, 2H), 7.03 (d, J= 7.7 Hz, 2H), 5.56 (s, 2H), 3.30 (p, J= 6.8 Hz, 1H), 1.23 (d, J = 6.7 Hz, 6H).
Biological Examples Example 1 Measurement of pNP-TMP hydrolysis by ENPP1
p-Nitrophenyl thymidine 5'-monophosphate (pNP-TMP) is a synthesized substrate for ENPP1. The ENPP1 enzyme activity assay with pNP-TMP substrate was conducted as follows:
First, in a 60 µl reaction, 7.5 ng purified ENPP1 was mixed with compounds of the present disclosure (test compound) ranging from 13.7 pM to 10 µM. Incubation of ENPP1 with compounds was set at 25 °C for 10 min. Reactions with DMSO only (with ENPP1 but no compound) gave the fastest reaction (MAX Activity). For each compound dilution, wells with assay buffer (50 mM Tris-HCl, pH8.8, 250mM NaCl, 0.1mg/ml BSA, 1% DMSO) only but no ENPP1 were included as controls for subtraction of test compound derived absorbance at 405 nm.
Second, after the 10 minutes ENPP1 and test compound incubation the assay was initiated by transferring 50 µl of the above mentioned ENPP1/test compound reaction into 50 µl of 1mM pNP-TMP in assay buffer results in a 100 µl total reaction in clear bottom 96 well plates. Absorbance at 405 nm was recorded immediately in kinetic mode by PerkinElmer 2300 Enspire multimode plate reader.
For each inhibitor, the specific ENPP1 activity was calculated using the following equation: ENPP1 activity (pmol/min/µg) = Adjusted Vmax (OD405nm/min) X conversion factor (pmol/OD405nm)/amount of enzyme (µg)
Adjusted Vmax = V0 X (Km + (S))/(S). In this assay, Km = 232 µM, (S) = 500 µM. Adjusted Vmax = 1.464 X V0.
V0 = (OD405nm with ENPP1 - OD405 nm ENPP1 blank)/minutes. OD405 nm was plotted, with blank subtracted, against time (minutes), the initial linear rate is V0. blank subtracted, against time (minutes), the initial linear rate is V0.
The conversion factor (pmol/OD405nm), was determined by plotting the amount of standard, 4-Nitrophenol (Sigma-Aldrich, Catalog # 241326), against absorbance at 405nm. The slope is the conversion factor. The percent ENPP1 activity for each sample was calculated using the following equation:
To determine the IC50 for each compound, compound concentration values and percent enzyme activity values were inserted into GraphPad Prism (GraphPad Prism version 7.0 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com), and Prism's Transform analysis was used to convert the x-axis values (compound concentration) to logarithms. A sigmoidal variable slope nonlinear regression analysis was performed using the following equation: Y = Bottom + (Top-Bottom)/(1+10^((LogIC50 -X)∗HillSlope)).
Ki values for each compound were calculated from the observed IC50 from GraphPad analysis using the Cheng-Prusoff equation: Ki = IC50/(1+(S)/KM). (S) here is 500 µM and KM is determined to be 232 µM.
Ki for representative compounds in Compound Table 1 above is provided in Table 2 below: Table 2
Ki (pNP-TMP)
Group A (< 10 nM) Group B (< 100 nM)
Cpd. 17, 36, 37, 59, 70, 144, 146 Cpd. 73, 75,
Example 2 Measurement of 2'3'-cGAMP hydrolysis by ENPP1
ENPP1 catalyzes the hydrolysis of 2'3'-cGAMP into 5'-AMP and 5'-GMP, and hence the ENPP1 enzyme activity with 2'3'-cGAMP as substrate is monitored by measurement of the product 5'-AMP. The AMP-Glo assay kit from Promega (catalog number V5012) is used for measurement of 5'-AMP production.
First, an ENPP1 and test compound incubation is set up in assay buffer (50mM Tris-HCl, pH8.8, 250mMNaCl, 0.1mg/ml BSA, 1% DMSO) with following conditions: ENPP1 concentration: 1.25nM; test compound concentration ranging from 68 pM to 20 µM. This incubation is carried out at 25°C for 10 min.
Second, after the 10 minute ENPP1 and test compound incubation, prepare on a separate plate, 15 µl of the substrate 2'3'-cGAMP at 200 µM in assay buffer. Then, 15 µl of the ENPP1/Compound incubation is transferred to the 200 µM 2'3'-cGAMP solution to initiate the reaction. The 30 µl mixture is incubated for 30 min at 25°C. In all these assays a DMSO control without compound is included which gave the maximum 5'-AMP production (MAX RLU). After 30 min the reaction is stopped by heating at 90 °C for 3 min.
Third, the Promega AMP-Glo kit is used to detect 5'-AMP production as a measurement of ENPP1 enzyme activity. To do this 10 µl of the above mentioned 30 µl total reaction per sample is transferred into 384 well white solid assay plate for measurement of 5'-AMP production. For each well, 10 µl of AMP-Glo Reagent I is added, mixed well, and incubated for 1 hour at 25°C. At this time AMP detection solution is prepared and 20 µl is added per well, and the resulting solution is incubated for 1 hr at 25°C. Duplicates are run for each inhibitor concentration. Luminescence signal (relative luminescence units, RLU) is recorded using a PerkinElmer 2300 Enspire multimode plate reader.
The % inhibition is calculated using the following equation: % inhibition = (MAX RLU - sample RLU)/MAX RLU X 100%.
IC50 values of compounds are determined by loading compound concentration data and percent inhibition values into GraphPad Prism (GraphPad Prism version 7.0 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com) and conducted a Sigmoidal variable slope nonlinear regression fitting.
Ki values for each compound are calculated from the observed IC50 from GraphPad analysis using the Cheng-Prusoff equation: Ki = IC50/(1+(S)/KM). (S) here is 100 µM and KM is 32 µM.
Formulation Examples
The following are representative pharmaceutical formulations containing a compound of the present disclosure.
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet mg
compound of this disclosure 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per capsule mg
compound of this disclosure 200
lactose spray dried 148
magnesium stearate 2
Injectable Formulation
Compound of the disclosure in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL.
Inhalation Composition
To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
Topical Gel Composition
To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
Ophthalmic Solution Composition
To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
Nasal spray solution
To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims (17)

  1. A compound selected from:
    4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    (4-((5-carbamoyl-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof; and
    4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt
  2. The compound of claim 1, selected from:
    4-((5-carbamoyl-2-ethyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid according to the following structure: and
    4-((2-ethyl-4-hydroxyimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or
    a pharmaceutically acceptable salt thereof.
  3. The compound of claim 1, selected from:
    4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid according to the following structure:
    4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: and
    4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure:or
    a pharmaceutically acceptable salt thereof.
  4. The compound of claim 1, selected from:
    (4-((5-carbamoyl-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)boronic acid according to the following structure: and
    4-((5-carbamoyl-2-methyl-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid according to the following structure: or
    a pharmaceutically acceptable salt thereof.
  5. The compound of claim 1, selected from:
    4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof;
    4-((5-cyanoimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure:or a pharmaceutically acceptable salt thereof; and
    4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt
  6. The compound of claim 1 or 3, selected from:
    4-((5-carbamoyl-2-isopropyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid according to the following structure: or
    4-((5-carbamoyl-2-isopropylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or a pharmaceutically acceptable salt thereof.
  7. The compound of claim 1 or 3, selected from:
    4-((4-hydroxy-2-isopropylimidazo[4,5-c]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or
    a pharmaceutically acceptable salt thereof.
  8. The compound of claim 1 or 5, selected from: 4-((5-carbamoyl-1,3-benzodiazol-1-yl)methyl)phenylboronic acid trifluoroacetic acid salt
  9. The compound of claim 1 or 5, selected from:
    4-((5-carbamoylimidazo[4,5-b]pyridin-1-yl)methyl)phenylboronic acid according to the following structure: or
    a pharmaceutically acceptable salt thereof.
  10. A pharmaceutical composition comprising a compound any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  11. A compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 9, or a pharmaceutical composition of claim 10, for use in a method of treating a cancer, an inflammatory disease, a metabolic disease, or a viral disease.
  12. The compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition for use according to claim 11 wherein the method is for treating a cancer.
  13. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition for use of claim 12 wherein the cancer is hepatocellular carcinoma, glioblastoma, melanoma, testicular, pancreatic, thyroid or breast cancer.
  14. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for use of claim 12, or 13, wherein the compound or pharmaceutically acceptable salt thereof or pharmaceutical composition is for administration with at least one additional anticancer agent.
  15. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for use of claim 14, wherein the at least one additional anticancer agent is an immune checkpoint inhibitor.
  16. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for use of claim 15, wherein the immune checkpoint inhibitor is an anti-PD-1 monoclonal antibody or an anti-PDL1 monoclonal antibody.
  17. The compound or pharmaceutically acceptable salt thereof or pharmaceutical composition for use of claim 16, wherein the anti-PD-1 monoclonal antibody or an anti-PDL1 monoclonal antibody is nivolumab, pembrolizumab, pidilizumab, atezolizumab or durvalumab.
HK62022058265.9A 2019-04-12 2020-04-10 Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors HK40068961B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62/833,455 2019-04-12
US62/881,111 2019-07-31

Publications (2)

Publication Number Publication Date
HK40068961A HK40068961A (en) 2022-09-30
HK40068961B true HK40068961B (en) 2023-11-24

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