Antiviral heterocyclic compounds

Abstract

The present invention relates to a compound of formula (I): [Formula 1] JPEG2025511407000454.jpg3456 and pharma- ceutically acceptable salts, esters, or prodrugs thereof, which inhibit the activity of an inhibitor of human respiratory syncytial virus (HRSV) or human metapneumovirus (HMPV). The invention further relates to a pharmaceutical composition comprising the above-mentioned compound for administration to a subject suffering from a HRSV or HMPV infection. The invention also relates to a method of treating a HRSV or HMPV infection in a subject by administering a pharmaceutical composition comprising a compound of the invention.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 328,400, filed April 7, 2022, the entire teachings of which are incorporated herein by reference.

[0002] The present invention relates generally to compounds and pharmaceutical compositions useful as respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) inhibitors. [Background technology]

[0003] Human respiratory syncytial virus (HRSV) is a negative-sense virus that contains a nonsegmented, single-stranded, linear RNA genome. As a paramyxovirus of two serotypes in the genus Pneumoviridae, HRSV contains 10 genes encoding 11 proteins. The nucleocapsid protein (N), RNA polymerase protein (L), phosphorylation protein (P) and transcription antitermination factor (M2-1) together with the RNA genome constitute a ribonucleoprotein (RNP) complex. Several small molecule compounds have been shown to target the RNP complex. In addition, the fusion protein (F), which is most important for virus attachment to the host, has been extensively studied. Although high-resolution structures of the F protein interacting with inhibitors have been achieved, structural studies with the N protein are in the early stages of development. The F protein, L protein and N protein, which are direct results of HRSV protein research and studies, have been the primary focus of drug discovery efforts.

[0004] The growing efforts in HRSV drug discovery are due to HRSV being the leading cause of acute lower respiratory tract infections (ALRI) in patients of all ages. In addition to respiratory infections, high-risk patient populations during HRSV infection include the elderly, immunocompromised, children up to 2 years of age, and patients with chronic obstructive pulmonary disorder (COPD) or chronic heart failure (CHF). HRSV was found to cause 177,500 hospitalizations and 14,000 deaths in the elderly population in the United States over a 4-year period. It is well-known that almost all children are infected with HRSV during the first 3 years of life, and HRSV infection is more severe in premature infants. In fact, HRSV is the most common cause of bronchiolitis and pneumonia in infants under 1 year of age in the United States. It is estimated that approximately 3.2 million hospitalizations and 66,000 deaths worldwide in children under 5 years of age are due to HRSV. HRSV is associated with more deaths and more infant hospitalizations in infants under 1 year of age than influenza.

[0005] HRSV infection can also affect healthy individuals, with repeated HRSV infections occurring over periods of up to 2 months. Symptoms resemble the common cold in healthy individuals, but fever, wheezing, shortness and difficulty in breathing, and cyanosis occur in more severe cases.

[0006] Currently, treatment options for HRSV infection are very limited, and no vaccine exists, as previous attempts have been unsuccessful. Palivizumab is a monoclonal antibody approved for prophylactic use, but its use is limited due to its high price. Palivizumab is generally only used in high-risk infants, such as those born prematurely or with heart / lung disease, but was only 60% effective in reducing hospitalizations. Ribavirin is approved as an inhaled treatment option, but its efficacy is limited and there are safety concerns associated with it. Given the treatment options, and the consistent seasonality of HRSV epidemics, the development of new therapeutic agents for the treatment of HRSV is desirable.

[0007] There are several RSV fusion inhibitors disclosed in the following publications: WO 2010103306, WO 2012068622, WO 2013096681, WO 2014060411, WO 2013186995, WO 2013186334, WO 2013186332, WO 2012080451, WO 2012080450, WO 2012080 449, WO 2012080447, WO 2012080446, WO 2015110446, WO 2017009316, J.Med.Chem. 2015, 58, 1630-1643, Bioorg.Med.Chem.Lett., 2015, 25, 976-981 and Nat.Commun., 2017, 8, 167. Examples of other N protein inhibitors for the treatment of HRSV are disclosed in the following publications: WO 2004026843, J.Med.Chem. 2006, 49, 2311-2319, and J.Med.Chem. 2007, 50, 1685-1692. Examples of HRSV L protein inhibitors are disclosed in the following publications: WO2011005842, WO2005042530, Antiviral Res. 2005, 65, 125-131, and Bioorg.Med.Chem.Lett. 2013, 23, 6789-6793. Examples of nucleoside / polymerase inhibitors are disclosed in the following publications: WO2011005842, WO2013242525, WO2014031784, WO2015026792, WO20160055791, WO2016138158, and J.Med.Chem. 2015, 58, 1862-1878.

[0008] Similarly, human metapneumovirus (HMPV), a negative-sense single-stranded RNA enveloped virus belonging to the family Pneumoviridae and genus Metapneumovirus discovered by van Den Hoogen in 2001, is also a common cause of acute lower respiratory tract infections (ALRTIs). Although often mild, the virus can be severe and life-threatening in high-risk groups such as children under 5 years of age, older adults over 65 years of age, and adults with underlying medical conditions (e.g., chronic obstructive pulmonary disease (COPD), asthma, congestive heart failure, or diabetes). In healthy adults over 65 years of age, the annual incidence of HMPV infection is 1.2 / 1,000, but 38% of individuals have a disease (e.g., COPD), making them twice as likely to have symptomatic disease and in need of medical care. In immunocompromised individuals, HMPV is responsible for 6% of all respiratory infections in lung transplants and 3% of lower respiratory tract infections associated with stem cell transplants. HMPV infection is also thought to be associated with acute graft rejection.

[0009] Similar to HRSV, infection is thought to occur via attachment to target cells through glycoprotein (G) protein interactions followed by fusion via the F protein. The HMPV L protein sequence is homologous to the HRSV L protein.

[0010] HMPV infection is the second most common cause of lower respiratory tract infection in children (after HRSV) and is also a problem for the elderly population. There are four subtypes of HMPV found in clinical isolates (A1, A2, B1, and B2). Reinfection occurs throughout childhood after the initial infection. No treatment is currently available for HMPV infection.

[0011] Given the seasonal and predictable nature of HRSV and HMPV epidemics, the prevalence of HRSV in elderly care facilities, and the severity of infections in high-risk infants, the need for potent and effective treatments for HRSV and HMPV is evident. The present invention has identified compounds that are potent heterocyclic molecules against HRSV-A / B and HMPV. The present invention includes methods for preparing these molecules, methods for RSV cell-based assays, HMPV-TN / 94-49 A2 cell-based assays, and small molecules with the potential to treat HRSV / HMPV infections. Summary of the Invention

[0012] The present invention provides compounds represented by formula (I) and pharma- ceutically acceptable salts, esters and prodrugs thereof, which can be used to treat or prevent viral (particularly HRSV or HMPV) infections, [ka] or a pharma- ceutically acceptable salt, ester or prodrug thereof; A is, 1) optionally substituted aryl; and 2) optionally substituted heteroaryl; is selected from the group consisting of E is 1) optionally substituted aryl; and 2) optionally substituted heteroaryl is selected from the group consisting of R1 and R2 are each independently 1) Hydrogen; 2) optionally substituted C1-C8 alkyl; 3) optionally substituted C3-C8 cycloalkyl; 4) optionally substituted 3-8 membered heterocycloalkyl; 5) optionally substituted aryl; 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl; and 8) optionally substituted heteroarylalkyl is selected from the group consisting of or R1 and R2, together with the nitrogen atom to which they are attached, form an optionally substituted 3- to 8-membered heterocycle; R3 is hydroxy or fluorine, and R4 is, 1) Hydrogen; 2) optionally substituted -C1-C6 alkyl; 3) optionally substituted -C3-C8 cycloalkyl; 4) optionally substituted 3- to 8-membered heterocycles; 5) optionally substituted aryl; 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl; and 8) optionally substituted heteroarylalkyl is selected from the group consisting of Each of the above preferred groups may be incorporated for use in combination with one, any or all of the other preferred groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In one embodiment of the present invention is a compound of formula (I) above or a pharma- ceutically acceptable salt thereof.

[0014] In certain embodiments of the compounds of Formula (I), R 1 is hydrogen.

[0015] In certain embodiments of a compound of Formula (I), R 1 is hydrogen and R 2 is hydrogen.

[0016] In certain embodiments of compounds of Formula (I), R3 is -OH.

[0017] In certain embodiments of compounds of Formula (I), R4 is optionally substituted methyl or optionally substituted cyclopropyl.

[0018] In certain embodiments of compounds of formula (I), R4 is [ka] is selected from one of the following:

[0019] In certain embodiments of a compound of Formula (I), R3 is OH and R4 is CF3, CD3, or cyclopropyl.

[0020] In certain embodiments of a compound of Formula (I), R1 is hydrogen, R2 is hydrogen, R3 is OH, and R4 is CF3, CD3, or cyclopropyl.

[0021] In certain embodiments of compounds of Formula (I), A can be converted by removal of a hydrogen atom to the following: [ka] and each of these groups is optionally substituted.

[0022] In certain embodiments of compounds of Formula (I), A is selected from the groups shown below. [ka]

[0023] In certain embodiments of compounds of formula (I), E is optionally substituted aryl, preferably optionally substituted phenyl.

[0024] In certain embodiments of compounds of Formula (I), E is selected from the groups shown below. [ka]

[0025] In certain embodiments of compounds of Formula (I), R4 is an optionally substituted phenyl.

[0026] In certain embodiments of compounds of Formula (I), R4 is an optionally substituted heteroaryl.

[0027] In certain embodiments of compounds of formula (I), R4 is [ka] is selected from one of In the formula, R 31 is halogen, -CN, -OR 33 , -CO2R 33 , -SO2R 33 , -SO2NR 33 R 34 , -NR 33 R 34 , optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, or optionally substituted -C3-C8 cycloalkyl, n is 0, 1, or 2, R 33 and R 34 are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 31 is selected from halogen, optionally substituted methyl, and optionally substituted methoxyl. More preferably, R 31 is -F, -Cl, -CH3, -CHF2, -CF3 or -OCH3.

[0028] In certain embodiments of a compound of Formula (I), R3 is OH and R4 is an optionally substituted phenyl.

[0029] In certain embodiments of compounds of Formula (I), A can be converted by removal of a hydrogen atom to the following: [ka] and each of these groups is optionally substituted.

[0030] In certain embodiments of compounds of Formula (I), A is selected from the groups shown below. [ka]

[0031] In one embodiment of the invention, the compound of formula (I) is of formula (Ia) or (Ib) [ka] is represented by wherein A, E, R1, R2, R3 and R4 are as defined above. Preferably, the compound of formula (I) is represented by formula (Ia).

[0032] In one embodiment of the invention, the compound of formula (I) is represented by formula (II) [ka] is represented by wherein A, E, R3 and R4 are as defined above.

[0033] In one embodiment of the invention, the compound of formula (I) has the formula (IIa) [ka] is represented by wherein A, E, R3 and R4 are as defined above.

[0034] In one embodiment of the present invention, the compound of formula (I) is represented by the formulas (III-1) to (III-7): [ka] , wherein A, E, R1 and R2 are as defined above.

[0035] In one embodiment of the present invention, the compound of formula (I) is represented by the formulas (IV-1) to (IV-7): [ka] is represented by one of wherein A and E are as defined above.

[0036] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (IV-1) to (IV-7), wherein A is a group shown below: [ka] is selected from E is the group shown below. [ka] is selected from.

[0037] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (IV-1) to (IV-7), in which A is selected by removal of a hydrogen atom from one of the following, each of which is optionally substituted: [ka] E is the group shown below. [ka] is selected from.

[0038] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2): [ka] is represented by wherein E and R4 are as defined above; R 11 is selected from optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Preferably, R 11 is optionally substituted methyl or optionally substituted cyclopropyl. 11 is methyl or cyclopropyl.

[0039] R 12 is selected from hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Preferably, R 12 is optionally substituted methyl or optionally substituted cyclopropyl. More preferably, R 12 are -CH3, -CHF2, -CD3, cyclopropyl, [ka] or [ka] It is.

[0040] R 13 and R 14 are each independently hydrogen, halogen, or -OR 11, -NH2, optionally substituted -C1-C6-alkyl, optionally substituted -C3-C8-cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Alternatively, R 13 and R 14 together with the carbon atom to which they are attached form a 4- to 7-membered ring fused to the phenyl ring. 13 and R 14 are each independently selected from halogen, optionally substituted methyl, and optionally substituted methoxyl.

[0041] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), in which E is a substituted phenyl and R4 is [ka] is selected from one of the following:

[0042] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), wherein E is a group shown below. [ka] is selected from.

[0043] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), wherein E is a substituted phenyl and R 11 is optionally substituted methyl or optionally substituted cyclopropyl; R 12 is optionally substituted methyl or optionally substituted cyclopropyl; R 13 and R 14 are each independently selected from halogen, optionally substituted methyl, and optionally substituted methoxyl; R4 is [ka] is selected from one of the following:

[0044] In one embodiment of the present invention, the compound of formula (I) is represented by formula (VI-1) or formula (VI-2) [ka] is represented by In the formula, R4, R 11 , R 12 , R 13 and R 14 is as defined above, and R 21 , R 22 , R 23 , R 24 and R 25 are each independently selected from hydrogen, halogen, optionally substituted methyl, and optionally substituted methoxyl.

[0045] In one embodiment of the present invention, the compound of formula (I) is represented by the formulas (VII-1) to (VII-6): [ka] wherein R 11 , R 12 , R 13 , R 14 , R 21 , R 22 , R 23 , R 24 and R 25 is as defined above.

[0046] In one embodiment of the present invention, the compound of formula (I) is represented by the formulas (VIII-1) to (VIII-2): [ka] , In the formula, A, E, R1, R2, R31 and n is as defined above.

[0047] In one embodiment of the present invention, the compound of formula (I) is represented by the formulae (VIII-1a) to (VIII-2a): [ka] , In the formula, A, E, R1, R2, R 31 and n is as defined above.

[0048] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (VIII-1a) to (VIII-2a), in which A is selected by removal of a hydrogen atom from one of the following, each of which is optionally substituted: [ka] E is the group shown below. [ka] is selected from.

[0049] Preferably, R1 is hydrogen and R2 is hydrogen.

[0050] In one embodiment of the present invention, the compound of formula (I) is represented by the formulas (IX-1) to (IX-8): [ka] , In the formula, E, R 11 , R 12 , R 13 , R 14 , R 31 and n is as defined above.

[0051] In one embodiment of the present invention, the compound of formula (I) is represented by the formulae (IX-1a) to (IX-8a) [ka] , In the formula, E, R 11 , R 12 , R 13 , R 14 , R 31 and n is as defined above.

[0052] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (IX-1a) to (IX-8a), in which E is a group as shown below: [ka] is selected from.

[0053] In one embodiment of the present invention, the compound of formula (I) is represented by the formulas (X-1) to (X-12): [ka] is represented by one of In the formula, E, R 31 and n is as defined above.

[0054] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (X-1) to (X-12), where E is a group as shown below: [ka] is selected from.

[0055] It will be understood that the description of the invention herein is to be interpreted in accordance with the rules and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at any given position.

[0056] It is intended that the definition of any substituent or variable (eg, R1, R2, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.

[0057] It will be further understood that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomeric and optically active forms.It will still be understood that certain compounds of the present invention may exist in different tautomeric forms.It is intended that all tautomers are within the scope of the present invention.

[0058] In certain embodiments, the present invention provides a method for preventing or treating RSV activity and treating RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0059] The invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of RSV.

[0060] Thus, in one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is combined with a steroidal anti-inflammatory compound, such as budesonide or fluticasone. In a preferred embodiment, the steroid is administered at a low dose to minimize immunosuppressive effects. In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is combined with a non-steroidal anti-inflammatory compound, such as a leukotriene antagonist, such as Singulair (Merck) or Accolate (Astra Zeneca), a phosphodiesterase 4 inhibitor, such as Roflumilast (Altana), a TNF-alpha inhibitor, such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech), or an NSAIDS. In a further embodiment, the compound of formula (I) is combined with an interleukin 8 inhibitor or an interleukin 9 inhibitor. Thus, the present invention also relates to a product containing a compound of formula (I) or a pharma- ceutically acceptable salt thereof and an anti-inflammatory compound for simultaneous, separate or sequential use in the treatment of RSV.

[0061] The present invention also relates to the combination of the compound of formula (I) or its pharmaceutically acceptable salt with an anti-influenza compound, and the use of such combination in the treatment of simultaneous RSV and influenza infections.Thus, the present invention also relates to a product containing the compound of formula (I) or its pharmaceutically acceptable salt with an anti-influenza compound for simultaneous, separate or sequential use in the treatment of simultaneous RSV and influenza infections.The compounds of the present invention can be administered in various dosage forms.Thus, they can be administered orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.The compounds of the present invention can also be administered parenterally, subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, or by injection techniques.The compounds can also be administered as suppositories.

[0062] In one embodiment, the compounds of the present invention are administered by intranasal or intrabronchial administration.The present invention also provides an inhaler or nebulizer containing a medicament comprising (a) a derivative of formula (I) as defined above or a pharma- ceutically acceptable salt thereof, and (b) a pharma- ceutically acceptable carrier or diluent.

[0063] The present invention also provides a pharmaceutical composition comprising such a benzodiazepine derivative or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or diluent.

[0064] The compound of the present invention is typically formulated for administration with pharmaceutically acceptable carrier or diluent.For example, solid oral forms can contain active compound together with diluent such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricant such as silica, talc, stearic acid, magnesium stearate or calcium stearate, and / or polyethylene glycol; binder such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agent such as starch, alginic acid, alginate or sodium starch glycolate; effervescent mixture; dye; sweetener; wetting agent such as lecithin, polysorbate, lauryl sulfate, and generally non-toxic and pharmacologically inactive substances used in pharmaceutical preparations.Such pharmaceutical preparations can be produced by known methods, for example, by mixing, granulating, tableting, sugar-coating or film-coating process.

[0065] The liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and / or mannitol and / or sorbitol.

[0066] Suspensions and emulsions may contain as a carrier, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma- ceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol, and, if necessary, an appropriate amount of lidocaine hydrochloride.

[0067] The solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.

[0068] The present invention also relates to the novel compound as defined above, or its pharmaceutically acceptable salt, for use in a method of treating the human or animal body.The present invention also relates to a pharmaceutical composition comprising the novel compound as defined above and a pharmaceutically acceptable diluent or carrier.Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the novel compound as defined above.The pharmaceutically acceptable salt is as defined above.The novel compound of the present invention is typically administered in the manner defined above, and the compound is typically formulated for administration in the manner defined above.

[0069] Preferably, pharmaceutical compositions contain the optically active isomer of the novel compound of the present invention.Thus, for example, preferred novel compounds of the present invention that contain only one chiral center include substantially pure form of R enantiomer, substantially pure form of S enantiomer, and enantiomeric mixtures that contain excess of R enantiomer or excess of S enantiomer.It is particularly preferred that pharmaceuticals contain the compounds of the present invention that are substantially pure optical isomers.For the avoidance of doubt, novel compounds of the present invention can be used in the form of solvates, if necessary.

[0070] Yet a further aspect of the invention is a process for making any of the compounds delineated herein using any of the synthetic means delineated herein.

[0071] definition Listed below are definitions of various terms used to describe this invention. These definitions apply to those terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0072] The term "aryl" as used herein refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system containing at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. A polycyclic aryl can include fused rings, covalently bonded rings, or combinations thereof.

[0073] The term "heteroaryl" as used herein refers to a monocyclic, bicyclic, or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N, with the remaining ring atoms being carbon, and any N or S contained within the ring may be optionally oxidized. Heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. Polycyclic heteroaryls may contain fused rings, covalently bonded rings, or combinations thereof.

[0074] In accordance with the present invention, aromatic groups can be substituted or unsubstituted.

[0075] The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one of which is aromatic, and which may be fused or covalently linked.

[0076] The term "alkyl" as used herein refers to a saturated, straight or branched chain hydrocarbon radical. 10 "Alkyl," "C2-C4 alkyl," or "C3-C6 alkyl" refer to alkyl groups containing 1 to 3, 1 to 6, 1 to 10 carbon atoms, 2 to 4, and 3 to 6 carbon atoms, respectively. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals.

[0077] The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond formed by the removal of a single hydrogen atom. 10 "Alkenyl," "C2-C8 alkenyl," "C2-C4 alkenyl," or "C3-C6 alkenyl" refers to an alkenyl group containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0078] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond formed by the removal of a single hydrogen atom. 10 "Alkynyl," "C2-C8 alkynyl," "C2-C4 alkynyl," or "C3-C6 alkynyl" refers to an alkynyl group containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0079] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic saturated carbocyclic ring, or a bicyclic or tricyclic fused, bridged, or spiro system, in which the carbon atoms may be oxo-substituted or optionally substituted with exocyclic olefinic, imine, or oxime double bonds. Preferred cycloalkyl groups include C3-C 12 Cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. 12 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.

[0080] The term "cycloalkenyl" as used herein refers to a monocyclic or polycyclic carbocyclic ring, or a bicyclic or tricyclic fused, bridged, or spiro system having at least one carbon-carbon double bond, in which the carbon atoms may be oxo-substituted or optionally substituted with an exocyclic olefin, imine, or oxime double bond. Preferred cycloalkenyl groups include C3-C 12 Cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups. 12 Examples of cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, and the like.

[0081] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which the aryl group is substituted. Similarly, the term "heteroarylalkyl" refers to a functional group in which an alkylene chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which the heteroaryl group is substituted.

[0082] As used herein, the term "alkoxy", used alone or in combination with other terms, unless otherwise specified, refers to an alkyl group having the specified number of carbon atoms attached to the remainder of the molecule through an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy is (C1-C3)alkoxy.

[0083] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic or alicyclic group.

[0084] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon, hydrogen, halogen, oxygen, nitrogen or other atoms, and may contain one or more units of unsaturation, e.g., double and / or triple bonds. Examples of aliphatic groups include alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH or C(O)NHS(O)2NH2, groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. The carbon atoms of an aliphatic group may be optionally oxo-substituted. The aliphatic group may be linear, branched, cyclic, or a combination thereof, and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group may be optionally substituted.

[0085] The term "carbocycle" or "carbocyclic" refers to a saturated, partially unsaturated, or aromatic ring group in which each atom in the ring is carbon. Examples of carbocycles include cycloalkyl groups, cycloalkenyl groups, and aryl groups.

[0086] The terms "heterocyclic" or "heterocycloalkyl" may be used interchangeably and refer to non-aromatic rings or bicyclic or tricyclic fused, bridged, or spiro systems, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or carbon atoms which may be optionally substituted with an exocyclic olefin, imine, or oxime double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinozalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxoxoxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups may be C-linked or N-linked (where possible).

[0087] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc. described herein may also be a divalent or polyvalent group when used as a bond to connect two or more groups or substituents that may be present on the same atom or different atoms. Those skilled in the art can easily determine the valency of any such group from the context in which it occurs.

[0088] The term "substituted" refers to one, two, or more of the hydrogen atoms being replaced with -F, -Cl, -Br, -I, -OH, -C1-C 12 -Alkyl, -C2-C 12-Alkenyl, -C2-C 12 -Alkynyl, -C3-C 12 -Cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-C1-C 12 -Alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12 -Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 -Alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -Alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C 12 -Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -Alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 -Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -Alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C 12 -Cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C 12 -cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12-Alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C 12 -Cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C1-C 12 -Alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclo-alkyl, -NHCO2-C1-C 12 -Alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-C 12 -Cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C 12 -Alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 -Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1-C 12 -Alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-alkynyl, -NHC(S)NH-C3-C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 -Alkyl, -NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-C 12 -Cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C1-C 12-Alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-C 12 -Cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -Alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-C 12 -Cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1-C 12 -Alkyl, -S(O)-C2-C8-alkenyl, -S(O)-C2-C8-alkynyl, -S(O)-C3-C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1-C 12 -Alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -SO2NH-C3-C 12 -Cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 -Alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkynyl, -NHSO2-C3-C 12 -Cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C 12 -Alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12- refers to substitution by being independently replaced with a substituent, including but not limited to, -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl or methylthiomethyl. In certain embodiments, the substituents are independently selected from halo, preferably Cl and F; C1-C4-alkyl, preferably methyl and ethyl; halo-C1-C4-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, such as cyclopropyl; C1-C4-alkoxy, such as methoxy and ethoxy; halo-C1-C4-alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH; NH2; C1-C4-alkylamino; di(C1-C4-alkyl)amino; and NO2. It is understood that aryl, heteroaryl, alkyl, etc. can be further substituted. In some cases, each substituent in the substituted moiety is optionally further substituted, if possible, with one or more groups, each group independently selected from C1-C4-alkyl, -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN and -NH2.

[0089] In certain embodiments, substituted alkyl, alkenyl or alkoxy groups are substituted with one or more halogen atoms, preferably fluorine or chlorine atoms.Such substituted alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.Such substituted alkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy.

[0090] The terms "halo" or "halogen," as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0091] The term "optionally substituted" as used herein means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with 0 substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional groups individually and independently selected from the groups described herein.

[0092] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharma- cetically acceptable.

[0093] In certain embodiments, the compounds of each formula herein are defined to include isotopically labeled compounds. An "isotopically labeled compound" is a compound in which at least one atomic position is enriched in a particular isotope of a specified element to a level significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, for example, to a level of at least 1%, preferably at least 20% or at least 50%. Such deuterated compounds can, for example, be metabolized more slowly than their non-deuterated analogues, and therefore can exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example, by using deuterated starting materials. Unless otherwise stated, isotopically labeled compounds can be pharma- ceutically acceptable.

[0094] As used herein, the term "hydroxy activating group" refers to a labile chemical moiety, which is known in the art to activate a hydroxyl group so that it is eliminated during a synthetic procedure, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, phosphonates, and the like.

[0095] The term "activated hydroxyl" as used herein refers to a hydroxy group that has been activated with a hydroxyl activating group as defined above, including, for example, a mesylate, tosylate, triflate, p-nitrobenzoate, or phosphonate group.

[0096] The term "hydroxy protecting group" as used herein refers to a labile chemical moiety, which is known in the art to protect hydroxyl groups from undesired reactions during synthetic procedures. After said synthetic procedures, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are generally described in TH Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0097] The term "protected hydroxy" as used herein refers to a hydroxy group protected with a hydroxy-protecting group, as defined above, which includes, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

[0098] The term "hydroxy prodrug group" as used herein refers to a promoiety group, which is known in the art to temporarily change the physicochemical and therefore biological properties of the parent drug by covering or masking the hydroxy group. After the synthesis procedure, the hydroxy prodrug group described herein must be able to revert back to the hydroxy group in vivo. Hydroxy prodrug groups known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992), and in Prodrugs Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects) by SSDhareshwar and VJ Stella, "Prodrugs of Alcohols and Phenols", VJ Stella et al., eds., Springer and AAPS Press, 2007, pp. 31-99.

[0099] The term "amino protecting group" as used herein refers to a labile chemical moiety, which is known in the art to protect amino groups from undesired reactions during synthetic procedures. After the synthetic procedures, the amino protecting groups described herein can be selectively removed. Amino protecting groups known in the art are generally described in TH Greene and PGM Huts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0100] The term "protected amino" as used herein refers to an amino group protected with an amino-protecting group as defined above.

[0101] The term "leaving group" means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo, and iodo groups; sulfonate ester groups, such as mesylate, tosylate, brosylate, nosylate; and acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like.

[0102] The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be clear to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th ed. (edited by John A. Riddick et al.), Vol. II in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0103] The term "protic solvent" as used herein refers to a solvent that tends to provide a proton, such as an alcohol, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th ed. (ed. John A. Riddick et al.), Vol. II, in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0104] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that has sufficient stability to permit its manufacture and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0105] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by those skilled in the art, further methods of synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Furthermore, various synthetic steps can be performed in an alternative order or sequence to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, 2001, Vol. 1, No. 1, pp. 111-115, 2001. ndEd. Wiley-VCH (1999); T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and successive editions thereof.

[0106] The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, etc.

[0107] The compounds of the present invention can be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and can include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to allow administration by injection, those that modify metabolism, and those that modify excretion rate.

[0108] The compounds described herein contain one or more asymmetric centers and therefore give rise to enantiomers, diastereomers, and other stereoisomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixture. Resolution may be carried out in the presence of a resolving agent, by chromatography, or by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution may be found in Jacques et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, it is intended that the compounds include both E and Z geometric isomers, or cis and trans isomers, unless otherwise specified. Likewise, all tautomeric forms are intended to be included. Tautomers may be cyclic or acyclic. Any carbon-carbon double bond configurations appearing herein are merely selected for convenience and are not intended to designate a particular configuration unless otherwise stated in the text. Thus, any carbon-carbon double bond or carbon-heteroatom double bond shown herein as trans may be cis, trans, or a mixture of the two in any ratio.

[0109] Certain compounds of the present invention may also exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation around a chiral single bond, for example due to steric hindrance or ring strain, may allow the separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0110] The term "pharmaceutically acceptable salts" as used herein refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. have described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts that are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobacillus acid salt, and the like. Representative salts include, but are not limited to, ionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, picrate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Further pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0111] Pharmaceutically acceptable salts can also be prepared by deprotonating the parent compound with a suitable base, thereby forming an anionic conjugate base of the parent compound. In such salts, the counterion is a cation. Suitable cations include ammonium and metal cations, such as alkali metal cations, e.g., Li + , Na + , K + and Cs + , as well as alkaline earth metal cations, such as Mg 2+ and Ca 2+ Examples include:

[0112] The term "pharmaceutical acceptable ester" as used herein refers to an ester that hydrolyzes in vivo, including those that decompose easily in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutical acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or less carbon atoms. Examples of specific esters include, but are not limited to, esters of C1-C6-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.

[0113] In certain embodiments, the present invention provides pharma- ceutically acceptable prodrugs of the compounds disclosed herein. The term "pharma- ceutically acceptable prodrugs" as used herein refers to prodrugs of the compounds formed by the processes of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as, where possible, zwitterionic forms of the compounds of the present invention. As used herein, "prodrugs" refers to compounds that are convertible in vivo by metabolic means (e.g., by hydrolysis) to give any compound depicted by the formulas of the present invention. Various forms of prodrugs are known in the art, see, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (eds.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen et al. (eds.). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

[0114] Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including but not limited to hemisuccinate, ethyl succinate, phosphate ester, dimethylaminoacetate and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs of hydroxyl groups, sulfonate esters and sulfate esters. Derivatization of hydroxyl groups as (acyloxy)methyl and (acyloxy)ethyl ethers, where acyl groups may be alkyl esters, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functional groups, or where acyl groups are amino acid esters as described above, is also included. This type of prodrug is described in J.Med.Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities. In certain embodiments, the compounds of the invention may incorporate two or more groups which are metabolically removed in vivo to yield the active parent compound.

[0115] The term "treatment" as used herein means alleviating, reducing, reducing, eliminating, modulating or ameliorating a disease state or disease symptom, i.e., causing the regression of a disease state or disease symptom. Treating can also include, for example, where a disease state or symptom may already exist, inhibiting an existing disease state or symptom, i.e., arresting its development, and alleviating or ameliorating an existing disease state or condition, i.e., causing its regression.

[0116] The term "prevention" as used herein means completely or nearly completely stopping a disease state or condition from occurring in a patient or subject, particularly if the patient or subject is susceptible to or at risk of contracting such a disease state or condition.

[0117] Furthermore, the compounds of the present invention, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0118] "Solvate" refers to a solvent addition form that contains a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, and such a combination can form one or more hydrates.

[0119] The term "analog" as used herein refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound.

[0120] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that has sufficient stability to permit its manufacture and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0121] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. Additionally, the various synthetic steps can be performed in an alternate sequence or order to give the desired compounds. Additionally, the solvents, temperatures, reaction times, and the like depicted herein are for illustrative purposes only, and variations in the reaction conditions can produce the desired bridged macrocyclic products of the invention. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

[0122] The compounds of the invention can be modified by appending various functional groups via the synthetic means delineated herein to enhance selective biological properties. Such modifications can include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to allow administration by injection, those that alter metabolism, and those that alter excretion rate.

[0123] Pharmaceutical Compositions The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of the present invention formulated together with one or more pharma- ceutically acceptable carriers.As used herein, the term "pharma-ceutically acceptable carrier" refers to any type of non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary. Some examples of materials which may serve as pharma- ceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch, potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffers such as magnesium hydroxide, aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition according to the judgment of the formulator. The pharmaceutical compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally, or as an oral or nasal spray.

[0124] The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection.The pharmaceutical composition of the present invention can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle.In some cases, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form.The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0125] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0126] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0127] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0128] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0129] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0130] The solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders. In the case of capsules, tablets and pills, the dosage form may also include buffering agents.

[0131] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0132] The active compound may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient alone or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0133] The dosage form for topical or transdermal administration of the compound of the present invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, with any necessary preservative or buffer.Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

[0134] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0135] Powders and sprays can contain, in addition to the compounds of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0136] Transdermal patch has the additional advantage of controlling the delivery of compound to the body.Such a dosage form can be made by dissolving or dispensing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0137] Unless otherwise defined, all technical and scientific terms used herein are consistent with the meaning commonly known to those skilled in the art. All publications, patents, published patent applications, and other references mentioned herein are incorporated herein by reference in their entirety.

[0138] Abbreviation Abbreviations used in the description of the following schemes and examples are as follows: ACN: acetonitrile; AD-mix-β: (9S)-(9”S)-9,9”-[1,4-phthalazinediylbis(oxy)]bis[10,11 dihydro-6′-methoxycinchonan]; Bn: benzyl; BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; BzCl: benzoyl chloride; mCPBA: meta-chloroperbenzoic acid; Cbz: benzyloxycarbonyl; CDI: carbonyldiimidazole; DAST: diethylaminosulfur trifluoride; DBU: 1,8-diazabicycloundec-7ene; DCE: dichloroethane; DCM: dichloromethane; Dess-Martin Periodinane: 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one; DIAD: diisopropyl azodicarboxylate; DIBAL-H: diisobutylaluminum hydride; DMAP: N,N-dimethylaminopyridine; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; DPPA: diphenylphosphoryl azide or diphenylphosphoryl azidate; dppf: 1,1'-bis(diphenylphosphino)ferrocene; EDCI or EDC: 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EA or EtOAc: ethyl acetate; Ghosez's Reagent: 1-Chloro-N,N,2-trimethyl-1-propenylamine; HATU: O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl: Hydrochloric acid; Hunig's base: diisopropylethylamine; PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; LDA: lithium diisopropylamine; Pd-C: palladium on carbon; PE: petroleum ether; Ph: phenyl; RT: reverse transcription; RT-PCR: reverse transcription polymerase chain reaction; TBME: tert-butyl methyl ether; TEA: triethylamine; Tf2O: Trifluoromethanesulfonic anhydride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; (TMS)2NH;Hexamethyldisilazane; TBS: tert-butyldimethylsilyl; TBDPS: tert-butyldiphenylsilyl; TMS: trimethylsilyl; TPAP: tetrapropylammonium perruthenate; TPP or PPh3: Triphenylphosphine; Ts or Tosyl: p-CH3C6H4SO2-; tBOC or Boc: tert-butyloxycarbonyl; and Xantphos: 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.

[0139] Synthesis method The compounds and processes of the present invention are better understood in connection with the following synthetic schemes (intended as examples only and not as limiting the scope of the invention) illustrating how the compounds of the present invention may be prepared. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives and / or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0140] Scheme 1 shows a method for preparing compounds of formula 11 from compounds 1 and 2, where n=1, 2 or 3, P is a hydroxy protecting group, Ar is E, and E is as defined above. Alkylation of hydroxypyridine 1 with hydroxyepoxide using Mitsunobu reaction conditions gives epoxide 4. Alternatively, conversion of hydroxyepoxide to 3 with leaving groups such as, but not limited to, tosyl and methanesulfonyl, followed by alkylation in the presence of bases such as, but not limited to, K2CO3 and Cs2CO3 gives 4. Intramolecular epoxide ring opening mediated by a base such as, but not limited to, LDA produces compound 5. Protection of the hydroxy group compound 5 with an appropriate protecting group such as, but not limited to, TBDPS and TBS gives compound 6. Trifluoromethylketone 7 can be obtained from iodine-magnesium exchange of compound 6 followed by addition of an ester such as, but not limited to, ethyl 2,2,2-trifluoroacetate. Cross-coupling of trifluoromethyl ketone 7 with various metal coupling partners 8, such as but not limited to boronic acids, boronic esters, organotin reagents, organozinc reagents, organomagnesium reagents, organosilicon reagents, catalyzed by appropriate Pd, Ni, Cu, etc. catalysts, gives compound 9. Addition of nitromethane to compound 9 in the presence of bases, such as but not limited to K2CO3 and Cs2CO3, gives compound 10. Reduction of the nitro group with reducing reagents, such as but not limited to zinc and acetic acid, gives key intermediate 11. Scheme 1 [ka]

[0141] As seen in Scheme 2, Ar1 is A, Ar is E, and R is R 11 where n is 1, 2 or 3; A, E, R 11is as defined above. Key intermediate 11 is coupled with various carboxylic acids to give amide 14. Amide 14 is then reacted with various electrophiles to generate various ethers, esters and carbamates of formula 15. Amide 14 is also oxidized to aldehyde 16, which then undergoes reductive amination to give various amines 17. The hydroxyl of -CH2OH in amide 14 is converted to cyanomethyl 18 by activation and subsequent cyanation. Compound 14-1 is further converted to acetamide 19 in the presence of a catalyst, such as, but not limited to, Parkin's catalyst. Scheme 2 [ka]

[0142] As seen in Scheme 3, Ar1 is A, Ar is E, and R is R 11 A, E, R 11 is as defined above. Aldehydes 16 are converted to benzyl-protected amines by reductive amination. Hydrogenolysis affords the free amines 20. Finally, displacement with various electrophiles affords N-substituted compounds 21. Scheme 3 [ka]

[0143] As seen in Scheme 4, Ar1 is A, Ar is E, R' is -C1-C6 alkyl, -C3-C6 cycloalkyl, aryl or heteroaryl, n is 1, 2 or 3, and A and E are as previously defined. Aldehyde 16 is oxidized to acid 22, which is then further transformed to amide 23 and sulfonamide 24 using common methods such as, but not limited to, HATU and DIPEA. From there, diversification to a variety of esters and amides can be achieved. Scheme 4 [ka]

[0144] Scheme 5 illustrates another method for preparing a compound of formula 11, where Ar is E, P is a hydroxy protecting group, n is 1, 2 or 3, and E is as defined above. Ketone 9 is converted to a compound of formula 26 via olefination. Alternatively, 26 can be obtained from: 1) 6 via cross-coupling with a metal binding partner 6-1, which can be, but is not limited to, a boronic acid, a boronic ester, an organotin reagent, an organozinc reagent, an organomagnesium reagent, an organosilicon reagent, etc., catalyzed by a suitable catalyst such as Pd, Ni, Cu, etc., to obtain compound 25; 2) Compound 25 is converted to compound 26 as previously described in scheme 1. With 26 prepared, a compound of formula 27 is prepared by dihydroxylation followed by epoxide formation. Epoxide ring opening of compound 27 with an amine equivalent such as, but not limited to, NH4OH and NH3 provides a compound of formula 11. Scheme 5 [ka]

[0145] Scheme 6 illustrates another method for preparing compounds of formula 23, where Ar1 is A, Ar is E, R' is -C1-C6 alkyl, -C3-C6 cycloalkyl, aryl or heteroaryl, n is 1, 2 or 3, and A and E are as defined above. Amine 11 is protected with a protecting group such as, but not limited to, Boc and Cbz. After deprotection of the hydroxy protecting group, subsequent oxidation provides acid 30. Compound 30 is coupled with various amines to provide amide 31. Deprotection of the amine protecting group followed by amide formation provides compounds of formula 23. Scheme 6 [ka]

[0146] Scheme 7 shows an additional route to synthesize the desired compound. The difference in this route is that it starts with oxidation and amide coupling to introduce amide 33 at the beginning of the synthesis. Successive vinylation and arylation give the bis-coupled product 34. Asymmetric dihydroxylation followed by activation and substitution gives the amino alcohol precursor. Finally, amide coupling with the respective aryl acid produces the desired compound, shown by compound 36. Scheme 7 [ka] EXAMPLES

[0147] The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as illustrative only and not limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations and / or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0148] Certain synthetic procedures useful for preparing compounds of the invention are disclosed in US 2022 / 0356189, the contents of which are incorporated herein by reference in their entirety.

[0149] Intermediate 1 [ka] Intermediate 1 Steps a and b [ka] A solution of methyl 4-amino-3-methoxybenzoate (10 g, 55.19 mmol) in HCl (80 mL) was treated with methacrolein (9.67 g, 137.97 mmol) at 100° C. for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

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[0150] A solution of the compound from step a (10 g, 46.03 mmol) in MeOH (100 mL) was treated with SOCl2 (10 mL, 137.86 mmol) at 0° C. The final reaction mixture was reacted at 80° C. for 40 min. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was adjusted to pH=8 with NaHCO3 at room temperature. The resulting mixture was extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the desired product (4.386 g, 41%) as a brown solid.

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[0151] Intermediate 1 Steps c and d [ka] A mixture of the methyl compound from step b (3.9 g, 16.86 mmol) and m-CPBA (8.73 g, 50.59 mmol) in DCM (20 mL) was stirred at room temperature overnight. The reaction was quenched with saturated sodium hyposulfite (aq) at room temperature. The resulting mixture was extracted with CHCl. ​​The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (15:1) to give the desired product (2.6 g, 62%) as a yellow solid.

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[0152] A solution of compound from step c (2.6 g, 10.51 mmol) and POCl3 (20.96 g, 136.70 mmol) was stirred at 95 °C for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and quenched with water / ice. The aqueous layer was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the desired product (1.5 g, 53%) as a yellow solid.

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[0153] Intermediate 2 [ka] Intermediate 2 Steps a and b [ka] A solution of (2Z)-2-bromobut-2-enal (5 g) and methyl 4-amino-3-hydroxybenzoate (10 g) in HCl (20 mL) and AcOH (30 mL) was stirred under N2 atmosphere at 100° C. for 1 h. The resulting solution was concentrated to give the desired product (crude) as a brown solid.

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[0154] A solution of compound from step a (10 g, 35.45 mmol) and H2SO4 (10 mL) in MeOH (30 mL) was stirred at 80 °C for 2 h. The mixture / residue was neutralized with NaHCO3 to pH 7-8. The resulting mixture was extracted with EA (3 times). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (1 g, 9.5%) as a yellow solid.

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[0155] Intermediate 2 steps c and d [ka] A solution of the compound from step b (1 g, 3.38 mmol), sodium 2-chloro-2,2-difluoroacetate (1 g, 6.56 mmol) and Cs2CO3 (2.20 g, 6.75 mmol) in DMF (10 mL) was stirred for 2 h at 80° C. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (800 mg, 68%) as a yellow solid.

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[0156] A solution / mixture of compound from step c (800 mg, 2.31 mmol) and LiOH (553 mg, 23.11 mmol) in MeOH (10 mL) and HO (10 mL) was stirred at room temperature under N atmosphere for 6 h. The crude product was recrystallized from MeOH / HO to give the desired product (500 mg, 65%) as a yellow solid.

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[0157] Intermediate 3 [ka] Intermediate 3 step a [ka] A 100 mL rbf was charged with 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (500 mg, 2.153 mmol), toluene (4.98 ml) and MeOH (2.99 ml) and then cooled to 0° C. in an ice bath. TMS-diazomethane (2.8 mL, 5.60 mmol) was added dropwise by hand over 10 min. The mixture was stirred for 1 h and then the diazo reagent was quenched by the addition of AcOH until the yellow color of the diazo reagent had faded. The mixture was then concentrated and carried directly into the next step.

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[0158] Intermediate 3 Step b [ka] A 100 mL rbf equipped with a stir bar was charged with methyl 2-cyclopropyl-7-hydroxy-2H-indazole-5-carboxylate (529 mg, 2.15 mmol), tetrabutylammonium iodide (1.032 g, 2.80 mmol) and CHCl (21.5 ml). The mixture was cooled to −78° C. and trichloroborane (5.38 ml, 5.38 mmol) was added dropwise over 10 min. The mixture was stirred at −78° C. for 1 h and then warmed to 0° C. in an ice bath with stirring for 1 h. The mixture was then diluted with water (50 mL) and ethyl acetate (50 mL), the layers were separated and the aqueous layer was washed with EtOAc (4×50 mL). The combined organic layers were washed with brine, dried over NaSO, filtered and concentrated to give a red oil which was purified by silica gel chromatography to give the desired product as a white solid (489 mg, 98% yield).

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[0159] A 100 mL round bottom flask was charged with 2-cyclopropyl-7-hydroxy-2H-indazole-5-carboxylic acid (0.499 g, 2.15 mmol), cesium carbonate (1.401 g, 4.30 mmol), DMF (21.50 ml), followed by sodium chlorodifluoroacetate (0.656 g, 4.30 mmol). The mixture was heated to 105° C. for 6 h, then cooled to room temperature and purified by silica gel chromatography (0 to 30% EtOAc in cyclohexane) to give the desired compound as a white solid (176.4 mg, 29% yield).

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[0160] Intermediate 3 Step d [ka] A 20 mL vial was charged with methyl 2-cyclopropyl-7-(difluoromethoxy)-2H-indazole-5-carboxylate (174 mg, 0.616 mmol) which was dissolved in MeOH (2.055 ml), THF (2.055 ml) and water (2.055 ml). Lithium hydroxide (78 mg, 1.849 mmol) was freshly ground and added. The reaction mixture was stirred for 2 h. The reaction mixture was then carefully acidified by addition of 1 M HCl. The mixture was diluted with water and EtOAc. The aqueous layer was washed with EtOAc (3×5 mL) and the combined organic layers were washed with brine and then concentrated to give the desired product as a white solid (147.6 mg, 89% yield).

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[0161] Intermediate 4 [ka] Intermediate 4 Step a [ka] A 20 mL vial was charged with 3-chloro-8-methoxy-2-methylquinoline-6-carboxylic acid (200 mg, 0.795 mmol), toluene (1.84 ml), and MeOH (1.104 ml) and then cooled to 0° C. in an ice bath and TMS-diazomethane (1.0 mL, 2.07 mmol) was added dropwise by hand over 10 min. The mixture was stirred for 1 h, then the diazo reagent was quenched by the addition of AcOH until the yellow color of the diazo reagent disappeared and the mixture was concentrated to give the desired product (48 mg, 95%) as a yellow solid.

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[0162] An 8 mL vial was charged with methyl 3-chloro-8-methoxy-2-methylquinoline-6-carboxylate (0.211 g, 0.795 mmol), then DO (1.125 ml) was added and the mixture was heated to 100 °C for 18 h. The mixture was then cooled to room temperature and diluted with EtOAc. The phases were separated and the organic layer was washed with NaHCO 3 × 1 mL. The organic layer was dried over Na 2 SO 4 , filtered, concentrated and purified by Combi-Flash to give the desired product as a yellow solid (105 mg, 34% yield).

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[0163] Intermediate 4 Step c [ka] A 20 mL vial was charged with methyl 3-chloro-8-methoxy-2-(methyl-d3)quinoline-6-carboxylate (100 mg, 0.372 mmol) which was dissolved in water (1.240 ml), THF (1.240 ml), and methanol (1.240 ml) and then freshly ground lithium hydroxide (26.7 mg, 1.116 mmol) was added. The mixture was stirred for 1 h, then diluted with 10% MeOH in DCM and then carefully acidified by addition of 1 M HCl, the phases separated and the aqueous layer washed with 10% MeOH in DCM. The combined organic phases were concentrated to give the desired product as a white solid (87 mg, 92% yield).

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[0164] Intermediate 5 [ka] An 8 mL vial contained 3-bromo-8-methoxy-2-methylquinoline-6-carboxylic acid, which was suspended in 0.7 mL of DO and then heated for 18 h at 100° C. The crude material was lyophilized and used without further purification (48 mg, 95%) as a yellow solid.

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[0165] Intermediate 6 [ka] Intermediate 6 Step a [ka] In an oven-dried vial equipped with a stir bar, methyl 2-chloro-8-methoxy-3-methylquinoline-6-carboxylate (250 mg, 0.941 mmol) was dissolved in DMF (1.9 mL) and anhydrous Me4NF (175 mg, 2.0 equiv.) was added. The vial was sealed and heated to 80° C. overnight. The reaction mixture was then cooled to room temperature, diluted with DCM, and washed twice with water and once with brine. The organic phase was then dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by automated column chromatography (silica gel) to give the fluoride as a white solid, which was contaminated with some chloride starting material (48 mg, 20%).

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[0166] Intermediate 6 Step b [ka] In a 1-dram vial, methyl-2-fluoro-8-methoxy-3-methylquinoline-6-carboxylate (48 mg, 0.18 mmol, 1.0 equiv) was dissolved in THF (0.3 mL) and water (0.15 mL) and the mixture was cooled to 0 °C. LiOH (8.7 mg, 0.36 mmol, 2.0 equiv) was added and the mixture was stirred for 15 min, after which the cooling bath was removed. After 2 h at room temperature, the mixture was acidified to approximately pH 5 with AcOH and the mixture was directly concentrated. The crude residue was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min) to give the product carboxylic acid (13 mg, 31%).

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[0167] Intermediate 7 [ka] Intermediate 7 Step a [ka] The above compound was prepared from methyl-3-bromo-2-chloro-8-methoxyquinoline-6-carboxylate according to the following procedure: To a suspension of methyl-3-bromo-2-chloro-8-methoxyquinoline-6-carboxylate (443 mg, 1.34 mmol, 1.0 equiv) in DCM (5 mL) was added HCl (4 M in 1,4-dioxane, 0.34 mL, 1.34 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 5 min. The solvent was then removed in vacuo and the residue was suspended in MeCN (6.7 mL). NaI (1.0 g, 6.7 mmol, 5.0 equiv) was then added and the vial was sealed and heated to 80° C. for 3 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was redissolved in DCM and the organic solution was washed successively with 10% aqueous K2CO3 and water, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by automated column chromatography (silica gel) to give the iodide as a white solid (434 mg, 77%).

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[0168] Intermediate 7 Step b [ka] In an oven-dried vial equipped with a stir bar, methyl 3-bromo-2-iodo-8-methoxyquinoline-6-carboxylate (75 mg, 0.18 mmol, 1.0 equiv) was suspended in THF (0.5 mL) and Et2O (0.5 mL) and the mixture was cooled to 0 °C. Isopropylmagnesium chloride (0.11 mL, 0.22 mmol, 1.2 equiv) was added and the reaction mixture was stirred at that temperature for 1 h before being quenched by dropwise addition of CD3OD (0.6 mL, 14.8 mmol, 15 equiv). The mixture was stirred at room temperature for an additional 15 min before being poured into saturated aqueous ammonium chloride. The quenched reaction mixture was diluted with water and DCM, the layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by automated column chromatography (silica gel) to give the deuterated product methyl-3-bromo-8-methoxyquinoline-6-carboxylate-2-D as a white solid (9.0 mg, 17%).

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[0169] Intermediate 7 Step c [ka] Methyl-3-bromo-8-methoxyquinoline-6-carboxylate-2-D as a white solid (9.0 mg, 1.0 equiv, 0.032 mmol) was dissolved in THF (0.1 mL), MeOH (0.1 mL) and water (0.1 mL) in a 1-dram vial equipped with a stir bar. LiOH (7 mg, 0.30 mmol, 10 equiv) was added and the reaction mixture was stirred at room temperature overnight. The mixture was then acidified to approximately pH 2 with 2M HCl and concentrated directly to give the carboxylic acid, which was used without further purification (8.0 mg, 93%).

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[0170] Intermediate 8 [ka] The above compound was prepared from 8-methoxy-2-methyl-3-(methyl-d3)quinoline-6-carboxylic acid using a method similar to that of Example X, Step X to give the hexadeutero compound as an orange solid (27 mg, 96%).

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[0171] Intermediate 9 [ka] Intermediate 9 Step a [ka] A mixture of (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), 2-(1-(4-fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.57 g, 6.32 mmol), Pd(dppf)Cl2 (0.382 g, 0.52 mmol), K2CO3 (2.17 g, 15.67 mmol) in dioxane (21 mL) and H2O (5 mL) was stirred at 90 °C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 50% ethyl acetate in hexanes) to give the desired product (1.97 g, 75% by weight, 75%) as a red oil.

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[0172] Intermediate 9 Step b [ka] A mixture of compound from step a (1 g, 2.25 mmol), 2-(2,3-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.82 g, 2.82 mmol), Pd(dppf)Cl2 (0.165 g, 0.225 mmol), and K2CO3 (0.70 g, 5.07 mmol) in dioxane (9 mL) and H2O (2.25 mL) was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction was cooled to room temperature and the mixture was diluted with EtOAc and saturated ammonium chloride. The aqueous layers were extracted with EtOAc, combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by automated column chromatography (silica, 0-100% ethyl acetate in cyclohexane) to give the desired product (1.50 g, 80 wt%, 87%) as a red oil.

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[0173] Intermediate 9 Step c [ka] A solution of compound from step b (1.5 g, 3.38 mmol) in t-BuOH (17 mL) and HO (17 mL) was cooled to 0° C. Methanesulfonamide (0.64 g, 6.77 mmol) and AD-mix-β (13.18 g, 16.92 mmol) were added and the reaction was stirred at room temperature overnight and monitored by LCMS. The reaction was cooled to room temperature and the mixture was diluted with EtOAc and quenched with sodium sulfite. The aqueous layers were extracted with EtOAc, combined, dried over sodium sulfate, filtered and concentrated. The crude material was purified by automated column chromatography (silica, 0-100% ethyl acetate in cyclohexane) to give the desired product (1.0 g, 60%) as a yellow solid.

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[0174] Intermediate 9 Step d [ka] A solution of the compound from step c (1.0 g, 2.01 mmol) in DCM (11 mL) was cooled to 0 °C. TsCl (0.654 g, 3.43 mmol), TEA (0.84 mL, 6.06 mmol) and DMAP (0.24 g, 2.01 mmol) were added and the reaction was stirred at room temperature for 90 min. The crude reaction was concentrated and the material purified by automated column chromatography (silica, 0-100% ethyl acetate in cyclohexane) to give the desired product (1.6 g, 70 wt%, 85%) as a yellow solid.

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[0175] Intermediate 9 Step e [ka] To a 250 mL round bottom flask containing step d (1.6 g, 3.04 mmol), NH3 (55 mL in MeOH, 156 equiv, 7N) was added at room temperature. The resulting mixture was stirred at room temperature for 20 h and monitored by LCMS. The solvent was removed and the crude mixture was dissolved in EtOAc. The organics were washed three times with saturated sodium bicarbonate and the organics were concentrated. The crude material was triturated with DCM to give the desired product (425 mg, 35%) as an off-white solid.

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[0176] Intermediate 10 [ka] The above compound was prepared in a similar manner to Intermediate 9.

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[0177] Intermediate 11 [ka] The above compound was prepared in a similar manner to Intermediate 9.

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[0178] Intermediate 12 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol (133 mg, quantitative yield).

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[0179] Intermediate 13 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol (158 mg, quantitative yield).

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[0180] Intermediate 14 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (170 mg, quantitative yield).

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[0181] Example 1 [ka] To a 20 mL vial equipped with a stir bar was added (R)-5-((S)-2-amino-1-cyclopropyl-1-hydroxyethyl)-7-(5-chloro-2,4-difluorophenyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (15 mg, 0.035 mmol) and 8-methoxy-3-(trifluoromethyl)quinoline-6-carboxylic acid (10.56 mg, 0.039 mmol). The solid was dissolved in DMF (0.20 mL) and DIPEA (18.54 μl, 0.106 mmol) was added. The vial was cooled to 0° C. and PyBOP (22.10 mg, 0.042 mmol) was added. The reaction was stirred for 10 min, warmed to room temperature and monitored by LCMS (1 h). Upon completion, the reaction was diluted with EtOAc and quenched with saturated ammonium chloride. The aqueous phase was extracted with EtOAc, collected on a phase separator cartridge and concentrated. The crude material was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), the fractions were concentrated on a Biotage V10 evaporator and the material was lyophilized to give the desired product as a fluffy white solid (13 mg, 53%).

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[0182] Table 1 below includes examples prepared in a similar manner to Example 1. Most compounds were purified by preparative HPLC (ACN / HO, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). Aryl acid coupling partners were prepared according to intermediates 1-14 or by similar procedures with slight modifications, and also according to the procedures found in U.S. Patent Application Serial No. 17 / 679,746. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0183] Intermediate 15 [ka] Intermediate 15 Steps a and b [ka] To a 250 mL rbf flask was added 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.33 g, 32.6 mmol) and the oil was dissolved in 1,4-dioxane (104 mL). (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (10 g, 26.1 mmol) was added followed by PdCl2(dppf) (1.91 g, 2.61 mmol) and water (26.1 mL). Potassium carbonate (10.83 g, 78 mmol) was then added, the rbf was equipped with a condenser, the system was purged with N2, and the reaction was heated to 90 °C for 2 h. The reaction was cooled to room temperature and the mixture was diluted with EtOAc and saturated ammonium chloride. The aqueous layers were extracted with EtOAc, combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by automated column chromatography (silica, 0-100% ethyl acetate in cyclohexane) to give the desired product (10.38 g, 70% by weight, 86%) as a red oil.

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[0184] (R)-7-Bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (3.90 g, 12.07 mmol), K2OsO4.2H2O (0.19 g, 0.52 mmol) and NMO (3.96 g, 33.79 mmol) in THF (10 mL), H2O (10 mL) and acetone (10 mL) were stirred at room temperature overnight. The reaction was quenched by adding Na2S2O3 (20 mL) at room temperature. The aqueous layer was extracted with EA (3 x 200 mL). The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (2.60 g) as a yellow solid.

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[0185] Intermediate 15 steps c and d [ka] A solution of compound from step b (2.80 g, 7.84 mmol), TsCl (1.79 g, 9.41 mmol), DMAP (48 mg, 0.39 mmol) and TEA (2.38 g, 23.52 mmol) in DCM (50 mL) was stirred at 0 °C for 2 h. The mixture was acidified to pH 7-8 with HCl. The resulting mixture was extracted with EA (3 × 200 ml). The combined organic layers were washed with water (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (2 g, 50%) as a yellow solid.

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[0186] To a stirred solution of NH3(g) in MeOH (200 mL) was added dropwise the compound from step c (3 g, 5.87 mmol) in MeOH (3 mL) at room temperature. The mixture was stirred at room temperature for 20 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, and concentrated to give the desired product (2 g, 96%) as a white solid.

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[0187] Intermediate 15 Step e [ka] A solution of the compound from step d (700 mg, 1.97 mmol) in DMF (5 mL) was treated with 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (391 mg, 1.68 mmol), PyBOP (877 mg, 1.69 mmol) and DIPEA (363 mg, 2.81 mmol) at room temperature for 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography to give the title compound (1 g, 86%) as a white solid.

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[0188] Intermediate 16 [ka] The above compound was prepared in a similar manner to Intermediate 15 and purified by automated column chromatography (silica gel) to give the pyridyl bromide as a white solid (812 mg, 85%).

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[0189] Example 47 [ka] To a 2-dram vial equipped with a stir bar was added Pd(PPh3)Cl2 (7.38 mg, 10.52 μmol), sodium carbonate (22.30 mg, 0.210 mmol), (5-chloro-2-fluoro-3-methylphenyl)boronic acid (19.82 mg, 0.105 mmol) and (3R)-7-bromo-5-(1-cyclopropyl-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamide)-1-hydroxyethyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (40 mg, 0.070 mmol). The vial was purged with N2 and the solid was dissolved in 1,4-dioxane (0.28 mL) and water (0.07 mL). The reaction was heated to 90 °C and monitored by LCMS (1 h). The reaction was cooled to room temperature, filtered through a pad of silica gel with EtOAc, and concentrated. The crude material was purified by preparative HPLC (ACN / HO, 20-90%, 25 min) to separate the diastereomers, the fractions were concentrated on a Biotage V10 evaporator, and the material was lyophilized to give a fluffy white solid (6 mg, 13%) as the desired product.

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[0190] Table 2 below contains examples prepared in a similar manner to Example 47 using intermediates 15-16 or their analogs. More palladium and boronic acid were added when necessary to promote conversion. Most compounds were purified and the diastereomers separated by preparative HPLC (ACN / HO, 20-90%, 25 min). When reported as a mixture of diastereomers, it is likely that they could not be separated by HPLC. [Table 2-1] [Table 2-2]

[0191] Intermediate 17 [ka] Intermediate 17 Step a [ka] A solution of 2,2-difluoro-1,3-benzodioxol-4-amine (5.00 g, 28.88 mmol) in CHCl3 (10 mL) was treated with NBS (5.66 g, 31.80 mmol) at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give the compound (5.66 g, 78%) as a yellow oil.

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[0192] Intermediate 17 Step b [ka] A solution of CuCl2 (3.20 g, 23.81 mmol) in MeCN (10 mL) was treated with t-BuNO2 (3.07 g, 29.76 mmol) under nitrogen atmosphere at 55 °C for 10 min, followed by dropwise addition of compound from step a (3 g, 11.90 mmol) at 55 °C. The final reaction mixture was heated at 55 °C for 30 min. The reaction was monitored by LCMS. The mixture was acidified to pH 3 with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 10:1) to give the title compound (396.6 mg, 7%) as a white oil.

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[0193] Intermediate 17 Step c [ka] A solution of the compound obtained from step b (2.87 g, 10.57 mmol) in THF (10 mL) was treated with iPrMgCl-LiCl (1.3 M in THF, 8 mL, 10.57 mmol) under nitrogen atmosphere at −20° C. for 30 min, followed by dropwise addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.36 g, 12.69 mmol) at −20° C. The final reaction mixture was reacted at room temperature for 1 h. The reaction was monitored by H-NMR. The resulting mixture was extracted with CHCl. ​​The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give the title compound (2.25 g, 67%) as a yellow oil.

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[0194] Intermediate 18 [ka] Intermediate 18 Steps a and b [ka] A solution of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (10 g, 40.00 mmol) in DMF (70 mL) was treated with Cs2CO3 (13.03 g, 40.00 mmol) and phenylmethanol (8.65 g, 80.00 mmol) at 70 °C overnight. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (9:1) to give the crude compound (15 g) as a yellow oil.

[0195] A solution of the compound from step a (15 g, 44.65 mmol) in EtOH (100 mL) was treated with NH4Cl (47.77 g, 893.08 mmol) in H2O (100 mL) and Fe (7.48 g, 133.96 mmol) at 80 °C for 30 min. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (9:1) to give the desired compound (8.9 g, 65%) as a brown oil.

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[0196] Intermediate 18 steps c and d [ka] A solution of compound from step b (6 g, 19.47 mmol) in THF (150 mL) was treated with Ac2O (4.97 g, 48.67 mmol) and Et3N (9.85 g, 97.35 mmol) from 0 °C to room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by trituration with PE to give the desired compound (6.24 g, 92%) as a white solid.

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[0197] A solution of the compound from step c (6.21 g, 17.73 mmol) in CH2Cl2 (200 mL) was treated with boron trichloride (88.66 mL, 88.66 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the desired compound (1.5 g, 33%) as a white solid.

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[0198] Intermediate 18 Steps e, f and g [ka] A solution of the compound from step d (1.5 g, 5.77 mmol) in CHCl3 (10 mL) was treated with POCl3 (1.33 g, 8.65 mmol) at 65° C. overnight. The reaction was monitored by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the desired compound (980 mg, 70%) as a white solid.

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[0199] To a solution of the compound from step e (1.25 g, 5.16 mmol) in DMF (6 mL), MeOH (6 mL) and TEA (1.5 mL) in a pressure tank was added DPPP (852 mg, 2.07 mmol), Pd(OAc)2 (232 mg, 1.03 mmol). The mixture was purged with carbon monoxide and then pressurized to 20 atm with carbon monoxide at 100° C. overnight. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give the title compound (730 mg, 64%) as a white solid.

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[0200] A solution of step f (400 mg, 1.81 mmol) in THF (8 mL) and MeOH (2 mL) was treated with a solution of LiOH (433 mg, 18.08 mmol) in HO (2 mL) at room temperature for 2 h. The reaction was monitored by LCMS. The product was precipitated by addition of HCl. The precipitated solid was collected by filtration and washed with water to give the title compound (249.8 mg, 66%) as a white solid.

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[0201] Intermediate 19 [ka] Intermediate 19 Step a [ka] A solution of the compound from step b of intermediate 18 (2.7 g, 8.76 mmol) in dioxane (20 mL) was treated with cyclopropanecarbonyl chloride (1.1 g, 10.52 mmol) at 100° C. for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether. The precipitated solid was collected by filtration and washed with diethyl ether to give the desired compound (2.78 g, 88%) as a white solid.

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[0202] Intermediate 19 steps b, c, d and e [ka] The following compound was prepared in a similar sequence to Intermediate 18 above and purified by reverse phase flash chromatography to afford the title compound (416.4 mg, 58%) as a white solid.

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[0203] Intermediate 20 [ka] Intermediate 20 Step a [ka] A solution of methyl 3,5-difluoro-4-nitrobenzoate (3 g, 13.82 mmol) in MeOH (50 mL) was treated with KOH (853 mg, 15.20 mmol) at 70° C. for 3 h. The reaction was monitored by TLC. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0204] Intermediate 20 Steps b and c [ka] To a flask containing compound from step a (2.50 g, 10.91 mmol) and 2-methanesulfonylethanol (1.42 g, 11.45 mmol) under N2 was added DMSO (50 mL) and t-BuOK (1.29 g, 11.45 mmol). The reaction was stirred at room temperature under N2 for 20 h. Additional 2-methanesulfonylethanol (1.42 g, 11.45 mmol) and t-BuOK (1.29 g, 11.45 mmol) were added and the reaction was stirred for an additional 3.5 h. The reaction was monitored by LCMS. The mixture / residue was acidified to pH<1 with concentrated HCl. The resulting mixture was extracted with EtOAc. The aqueous layer was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification.

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[0205] A solution of the compound from step b (400 mg, 1.88 mmol) in MeOH (10 mL) was treated with H2SO4 (1 mL) at 70° C. for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

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[0206] Intermediate 20 Step d [ka] A solution of the methyl compound from step c (1.4 g, 6.16 mmol) in EtOH (50 mL) was treated with NH4Cl (6.5 g, 123.26 mmol) in H2O (50 mL) and Fe (1.03 g, 18.49 mmol) at 80 °C for 30 min. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the title compound (428 mg, 35%) as a white solid.

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[0207] Intermediate 21 [ka] Intermediate 21 Steps a and b [ka] A solution of 5-bromo-1,3-difluoro-2-nitrobenzene (5 g, 21.00 mmol), cyclopropanol (1.22 g, 21.00 mmol) and Cs2CO3 (13.69 g, 42.00 mmol) in DMF (50 mL) was stirred overnight at 60° C. The resulting mixture was extracted, concentrated and purified by silica gel column chromatography to give the desired compound (4.4 g, 75%) as a yellow oil.

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[0208] A solution of the compound from step a (4 g, 14.50 mmol), 2-methanesulfonylethanol (1.89 g, 15.20 mmol) and t-BuOK (1.71 g, 15.20 mmol) in DMSO (40 mL) was stirred at room temperature overnight. 2-methanesulfonylethanol (1.89 g, 15.20 mmol) and t-BuOK (1.71 g, 15.20 mmol) were added and the mixture was stirred at room temperature for an additional 3 h. The mixture was acidified, extracted, concentrated and purified by silica gel column chromatography to give the desired compound (2.6 g, 65%) as a yellow solid.

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[0209] Intermediate 21 steps c and d [ka] A solution of the compound from step b (2.6 g, 9.50 mmol), NH4Cl (5.07 g, 95.00 mmol), Fe (5.30 g, 95.00 mmol), and HO (10 mL) in EtOH (20 mL) was stirred for 30 min at 80° C. The resulting mixture was filtered, concentrated, and purified by silica gel column chromatography to give the desired compound (2 g, 86%) as a brown solid.

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[0210] A solution of the compound from step c (1.5 g, 6.10 mmol), cyclopropanecarbonyl chloride (0.58 g, 5.50 mmol) and TEA (0.93 g, 9.20 mmol) in THF (20 mL) was stirred for 1 h at 0° C. The resulting mixture was extracted, concentrated and purified by silica gel column chromatography to give the desired compound (1.2 g, 62%) as a brown solid.

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[0211] Intermediate 21 Steps e and f [ka] A solution of the compound from step d (1.2 g, 3.80 mmol) and POCl3 (884 mg, 5.70 mmol) in CHCl3 (20 mL) was stirred for 24 h at 65° C. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to give the desired compound (1 g, 88%) as a yellow oil.

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[0212] A solution of the compound from step e (660 mg, 2.20 mmol), Ac2O (458 mg, 4.49 mmol), DIPEA (254 mg, 1.97 mmol), Xantphos (57 mg, 0.10 mmol), oxalic acid (404 mg, 4.49 mmol) and Pd(AcO)2 (50 mg, 0.22 mmol) in DMF (5 mL) was stirred under nitrogen atmosphere at 100° C. for 6 h. The resulting mixture was filtered and purified by reverse phase flash chromatography to give the desired compound (235.5 mg, 40%) as a white solid.

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[0213] Intermediate 22 [ka] Intermediate 22 Steps a and b [ka] A solution of 5-bromo-1-chloro-3-fluoro-2-nitrobenzene (4 g, 15.70 mmol), 2-methanesulfonylethanol (2.05 g, 16.50 mmol) and t-BuOK (1.85 g, 16.50 mmol) in DMSO (40 mL) was stirred overnight at room temperature under nitrogen atmosphere. 2-methanesulfonylethanol (2.05 g, 16.50 mmol) and t-BuOK (1.85 g, 16.50 mmol) were added and the resulting mixture was stirred at room temperature for an additional 3 h. The resulting mixture was extracted, concentrated and purified by silica gel column chromatography to give the desired compound (2.2 g, 55%) as a yellow solid.

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[0214] A solution of the compound from step a (2.2 g, 8.70 mmol), Fe (4.87 g, 87.10 mmol), NH4Cl (4.66 g, 87.10 mmol), and HO (10 mL) in EtOH (20 mL) was stirred for 30 min at 80° C. The resulting mixture was concentrated and purified by silica gel column chromatography to give the desired compound (1.2 g, 61%) as a brown solid.

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[0215] Intermediate 22 steps c, d and e [ka] A solution of the compound from step b (1.3 g, 5.80 mmol), cyclopropanecarbonyl chloride (0.61 g, 5.80 mmol) and TEA (0.89 g, 8.70 mmol) in THF (10 mL) was stirred for 1 h at 0° C. The resulting mixture was extracted, concentrated and purified by silica gel column chromatography to give the desired compound (1 g, 58%) as a yellow solid.

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[0216] A solution of the compound from step c (1 g, 3.44 mmol) and POCl (791 mg, 5.16 mmol) in CHCl (10 mL) was stirred overnight at 65° C. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to give the desired compound (800 mg, 85%) as a yellow oil.

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[0217] A solution of compound from step d (1 g, 3.67 mmol), Xantphos (212 mg, 0.36 mmol), Ac2O (749 mg, 7.34 mmol), DIPEA (948 mg, 7.34 mmol), oxalic acid (660 mg, 7.34 mmol) and Pd(AcO)2 (82 mg, 0.367 mmol) in DMF (20 mL) was stirred under nitrogen atmosphere at 100° C. for 6 h. The residue was purified by reverse-phase flash chromatography to give the desired compound (587.7 mg, 61%) as a white solid.

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[0218] Intermediate 23 [ka] Intermediate 23 Steps a and b [ka] A solution of 5-bromo-1,3-difluoro-2-nitrobenzene (2 g, 8.40 mmol), benzyl alcohol (4.54 g, 42.02 mmol) and Cs2CO3 (13.7 g, 42.02 mmol) in DMF (10 mL) was stirred overnight at 70 °C under N2 atmosphere. The aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were concentrated under reduced pressure to give the crude product directly for the next step.

[0219] A solution of the compound from step a (2 g, 4.83 mmol) and boron trichloride (20 mL) in CH2Cl2 (40 mL) was stirred at 0° C. for 2 h. The resulting mixture was extracted with EA. The combined organic layers were washed with water. The residual product was purified by reverse phase flash to give the desired product (1.5 g, 96%) as a yellow solid.

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[0220] Intermediate 23 steps c and d [ka] A solution of the compound from step b (1.5 g, 4.63 mmol), sodium 2-chloro-2,2-difluoroacetate (1.4 g, 9.26 mmol) and Cs2CO3 (3.02 g, 9.26 mmol) in DMF (15 mL) was stirred under N2 atmosphere at 80° C. for 2 h. The residue was purified by preparative TLC to give the desired product (1.2 g, 69%) as a yellow solid.

[0221] A solution of compound from step c (1.2 g, 3.21 mmol), Fe (1.79 g, 32.07 mmol) and NH4Cl (1.72 g, 32.07 mmol) in EtOH (20 mL) and H2O (10 mL) was stirred at 80 °C under N2 atmosphere for 2 h. The resulting mixture was filtered. The resulting mixture was extracted with EA. The combined organic layers were washed with water and the organic layer was concentrated under reduced pressure to give the desired product (1 g, 91%) as a yellow oil.

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[0222] Intermediate 23 Steps e and f [ka] A solution of compound from step d (1 g, 2.91 mmol) and cyclopropanecarbonyl chloride (607 mg, 5.81 mmol) in dioxane (20 mL) was stirred at 100° C. under N2 atmosphere for 2 h. The resulting mixture was extracted with EA (3×2 ml). The combined organic layers were washed with water and concentrated under reduced pressure to give the desired product (900 mg, 75%) as a yellow solid.

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[0223] A solution of the compound from step e (900 mg, 2.18 mmol) and boron trichloride (11.25 mL) in DCM (30 mL) was stirred at 0° C. for 2 h. The resulting mixture was extracted with EA. The combined organic layers were washed with water. The residual product was purified by reverse phase flash to give the desired product (600 mg, 85%) as a yellow oil.

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[0224] Intermediate 23 steps g and h [ka] A solution of the compound from step f (600 mg, 1.86 mmol) and POCl (428 mg, 2.80 mmol) in CHCl (10 mL) was stirred overnight at 65° C. under N atmosphere. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (400 mg, 71%) as a yellow oil.

number

[0225] A solution of compound from step g (400 mg, 1.32 mmol), Pd(OAc)2 (59 mg, 0.26 mmol), Ac2O (269 mg, 2.63 mmol), Xantphos (76 mg, 0.13 mmol) and DIEA (340 mg, 2.63 mmol) in DMF (10 mL) was stirred overnight at 100 °C under N2 atmosphere. The crude product was purified by reverse phase flash to give the desired product (200 mg, 56%) as a white solid.

number

[0226] Intermediate 24 [ka] Intermediate 24 Step a [ka] A solution of 2-amino-5-bromo-3-cyclopropoxyphenol (1 g, 4.09 mmol), acetyl chloride (289 mg, 3.68 mmol) and TEA (621 mg, 6.14 mmol) in THF (10 mL) was stirred for 2 h at 0° C. The resulting mixture was extracted, concentrated and purified by silica gel column chromatography to give the desired compound (600 mg, 51%) as a brown oil.

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[0227] Intermediate 24 Step b [ka] A solution of the compound from step a (1.2 g, 4.19 mmol), POCl3 (1.29 g, 8.38 mmol) in CHCl3 (5 mL) was stirred for 24 h at 65° C. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to give the desired compound (1 g, 88%) as a brown solid.

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[0228] Intermediate 24 Step c [ka] A solution of compound from step b (420 mg, 1.57 mmol), Pd(OAc)2 (35 mg, 0.157 mmol), Ac2O (319 mg, 3.13 mmol), Xantphos (90 mg, 0.157 mmol), oxalic acid (282 mg, 3.13 mmol) and DIPEA (404 mg, 3.13 mmol) in DMF (5 mL) was stirred under nitrogen atmosphere at 100° C. for 6 h. The residue was purified by reverse phase flash chromatography to give the desired compound (207.3 mg, 52%) as a white solid.

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[0229] Intermediate 25 [ka] Intermediate 25 Step a [ka] A mixture of niacin (5 g, 40.61 mmol), methoxy(methyl)amine hydrochloride (5.94 g, 60.92 mmol), HATU (15.44 g, 40.61 mmol) and DIEA (10.50 g, 81.23 mmol) in DCM (50 mL) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was washed with water. The aqueous layer was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the desired product (3.9 g, 57%) as a pale yellow liquid.

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[0230] Intermediate 25 Step b [ka] In a 250 mL three-necked round bottom flask, (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), the compound from step a (1.30 g, 7.83 mmol) and THF (15 mL) were added at room temperature. The mixture was cooled to 0° C. iPrMgCl (1.07 g, 10.44 mmol) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give the desired product (970 mg, 51%) as a yellow solid.

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[0231] Intermediate 25 Step c [ka] A mixture of compound from step b (800 mg, 2.21 mmol), 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (606 mg, 2.21 mmol), K2CO3 (610 mg, 4.42 mmol) and Pd(dppf)Cl2 (161 mg, 0.22 mmol) in dioxane (9 mL), H2O (1 mL) was stirred at 80 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the desired product (820 mg, 86%) as a yellow solid.

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[0232] Intermediate 25 Step d [ka] To a stirred solution of methyltriphenylphosphonium bromide (1.70 g, 4.77 mmol) in THF (50 mL) was added 1 M t-BuOK (428 mg, 3.81 mmol) in THF dropwise under nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 30 min under nitrogen atmosphere. Compound from step c (820 mg, 1.90 mmol) in THF was added and stirred at 50° C. for 2 h. The resulting mixture was poured into water and extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give the crude product (430 mg) as a yellow solid.

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[0233] Intermediate 25 Step e [ka] A mixture of compound from step d (400 mg, 0.93 mmol), methanesulfonamide (89 mg, 0.93 mmol) and ADMIX-β (2.18 g, 2.80 mmol) in t-BuOH (5 mL), H2O (5 mL) was stirred at room temperature overnight. The resulting mixture was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give the desired product (30 mg) as an off-white solid.

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[0234] Intermediate 25 Step f [ka] A mixture of compound from step e (30 mg, 0.06 mmol), TsCl (18 mg, 0.09 mmol), TEA (19 mg, 0.19 mmol) and DMAP (8 mg, 0.06 mmol) in DCM (2 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (2 M aq.). The resulting mixture was extracted with CHCl. ​​The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give the desired product (30 mg, 74%) as a yellow solid.

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[0235] Intermediate 25 Step g [ka] A solution of the compound from step f (30 mg, 0.05 mmol) and NH3(g) in MeOH (5 mL) was stirred at 40° C. overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH (7 M NH3) 10:1) to give the desired product (10 mg, 44%) as an off-white solid.

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[0236] Intermediate 26 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (100mg).

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[0237] Intermediate 27 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (60 mg, 53%).

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[0238] Intermediate 28 [ka] Intermediate 28 Step a [ka] A solution of (S)-(7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridin-3-yl)methanol (3 g, 7.83 mmol), 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (1.8 g, 7.83 mmol), Pd(dppf)Cl2 (573 mg, 0.78 mmol) and K2CO3 (2.1 g, 15.66 mmol) in dioxane (40 mL) and HO (4 mL) was stirred at 80 °C under N2 atmosphere for 2 h. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (2.8 g, 99 %) as a brown oil.

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[0239] Intermediate 28 Step b [ka] A mixture of compound from step a (2 g, 5.78 mmol), 1-(5-chloro-2,4-difluorophenyl)-3,3,4,4-tetramethylborolane (1.6 g, 5.78 mmol), Pd(dppf)Cl2 (422 mg, 0.58 mmol) and K2CO3 (1.6 g, 11.55 mmol) in dioxane (20 mL) and H2O (2 mL) was stirred at 80° C. for 2 h under N2 atmosphere. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (1.6 g, 66%) as a yellow solid.

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[0240] Intermediate 28 steps c and d [ka] A solution of compound from step b (1.6 g, 3.88 mmol), TBSCl (870 mg, 5.79 mmol) and imidazole (0.39 g, 5.80 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water (3×200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give the desired product (1.9 g, 93%) as a white solid.

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[0241] A solution of compound from step c (2 g, 3.78 mmol), ADMIX-β (8.85 g, 11.36 mmol) and methanesulfonamide (0.36 g, 3.78 mmol) in t-BuOH (10 mL) and HO (10 mL) was stirred at 0° C. overnight. The resulting mixture was extracted with EA (3×200 ml). The combined organic layers were washed with water (3×200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give the desired product (1.5 g, 70%) as a white solid.

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[0242] Intermediate 28 Steps e and f [ka] A solution of compound from step d (1.5 g, 2.66 mmol), TsCl (763 mg, 4.00 mmol), TEA (810 mg, 8.00 mmol) and DMAP (232 mg, 2.66 mmol) in DCM (20 mL) was stirred at 0° C. for 2 h. The resulting mixture was extracted with EA (3×200 ml). The combined organic layers were washed with water (3×200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (1.5 g, 78%) as a white solid.

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[0243] A solution of the compound from step e (1.5 g, 2.66 mmol) in MeOH (5 mL) was added to a solution of NH3(g) in MeOH (30 mL) and stirred overnight at 40° C. The residue was purified by preparative TLC (DCM / NH3 in MeOH=15 / 1) to give the desired product (1.1 g, 93%) as a white solid.

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[0244] Intermediate 28 steps g and h [ka] A solution of compound from step f (900 mg, 1.60 mmol), (Boc)2O (525 mg, 2.40 mmol) and TEA (486 mg, 4.81 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water (3×100 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give the desired product (600 mg, 56%) as a white solid.

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[0245] A solution of the compound from step g (900 mg, 1.36 mmol) and TBAF (355 mg, 1.36 mmol) in THF (10 mL) was stirred at room temperature for 1 h. The resulting mixture was extracted with EA (3×200 ml). The combined organic layers were washed with water (3×200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give the desired product (430 mg, 57%) as a white solid.

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[0246] Intermediate 28 Steps i and j [ka] A solution of the compound from step h (140 mg, 0.25 mmol) and DMP (271 mg, 0.64 mmol) in DCM (10 mL) was stirred at room temperature for 12 h. The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with water (3×20 mL). The organic layers were concentrated under reduced pressure to give the crude desired product as a white oil.

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[0247] To a solution of the compound from step i (230 mg, 0.42 mmol), 2-methyl-2-butene (354 mg, 5.04 mmol) in t-BuOH:H2O (2:1) was added dropwise at room temperature with water containing NaClO2 (380 mg, 4.20 mmol) and NaH2PO4 (504 mg, 4.20 mmol) and stirred for 2 h. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

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[0248] Intermediate 29 [ka] Intermediate 29 Steps a and b [ka] A solution of intermediate 28 (120 mg, 0.21 mmol) from above, deuteromethylamine (8 mg, 0.21 mmol), HATU (81 mg, 0.21 mmol) and DIEA (83 mg, 0.64 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. The residue was purified by preparative TLC (PE / EA 1:1) to give the desired product (80 mg, 64%) as a white solid.

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[0249] A solution of the compound from step a (120 mg, 2.66 mmol) in 1,4-dioxane, HCl (2 mL) was stirred at room temperature for 1 h. The residue was purified by preparative TLC (DCM / MeOH with NH3 = 15 / 1) to give the desired product (36.8 mg, 54%) as a white solid.

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[0250] Intermediate 30 [ka] The above compound was prepared in a similar manner to Intermediate 29 above to give the amino alcohol (23 mg).

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[0251] Intermediate 31 [ka] The above compound was prepared in a similar manner to intermediate 29 above to give the amino alcohol.

[0252] Intermediate 32 [ka] The above compound was prepared in a similar manner to intermediate 29 above to give the amino alcohol.

[0253] Intermediate 33 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (150 mg, 68%).

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[0254] Intermediate 34 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (46.1 mg, 19%).

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[0255] Intermediate 35 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (113.6 mg, 48%).

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[0256] Intermediate 36 [ka] The above compound was prepared in a similar manner to Intermediate 9 to give the amino alcohol. (89.5 mg, 60%).

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[0257] Intermediate 37 [ka] The above compound was prepared in a similar manner to intermediate 9 to give the amino alcohol as a mixture of diastereomers. The diastereomers were separated after subsequent amide coupling and the stereochemistry was arbitrarily assigned (370 mg, 78%).

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[0258] Intermediate 38 [ka] Intermediate 38 Step a [ka] (1-(6-fluoropyridin-2-yl)vinyl)diisobutylaluminum was prepared according to the literature procedure of Gao, F. et al., J. Am. Chem. Soc. 2010, 132, 32, 10961-10963. In a vial, (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (1.1 g, 2.87 mmol), Xantphos (0.332 g, 0.574 mmol) and palladium(II) chloride (0.051 g, 0.287 mmol) were dissolved in DCE (3.59 ml). (1-(6-fluoropyridin-2-yl)vinyl)diisobutylaluminum (5.22 ml, 5.74 mmol) was added as a solution in THF. The vial was heated to 80° C. and monitored by LCMS. Water was added and the aqueous layer was washed with EtOAc. The combined organic layers were dried over MgSO4 and concentrated. Purification by silica gel chromatography, 0-70% EtOAc / cHex afforded the title compound (603 mg, 55.5%).

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[0259] Intermediate 38 Steps b~e [ka] The above compound was prepared in a similar manner to Intermediate 9 and the crude material was purified by preparative TLC (silica gel, DCM with NH.sub.3 and MeOH) to give the desired product (200 mg, 81%) as a white solid.

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[0260] Intermediate 39 [ka] The above compound was prepared in a similar manner to Intermediate 38 to give the desired product (13 mg, 62%) as a white solid.

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[0261] Intermediate 40 [ka] The above compound was prepared in a similar manner to Intermediate 9 and the crude material was purified by preparative TLC (silica gel, DCM with NH.sub.3 and MeOH) to give the desired product (475 mg, 71%) as a white solid.

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[0262] Intermediate 41 [ka] Intermediate 41 Step a [ka] A solution of 4-acetylpyridine (2 g, 16.50 mmol) and 4-toluenesulfonylhydrazide (4.61 g, 24.70 mmol) in CHOH (20 mL) was stirred for 2 h at 70° C. The mixture was filtered and washed to give the desired precipitated solid (2 g, 41%) as a white solid.

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[0263] Intermediate 41 Step b [ka] Compound from step a (566 mg, 1.96 mmol), Pd(PPh3)2Cl2 (91 mg, 0.13 mmol), LiO t A solution of Bu (309 mg, 4.83 mmol) and (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (500 mg, 1.30 mmol) in dioxane (5 mL) was stirred overnight under nitrogen at 90° C. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to give the desired compound (450 mg crude) as a yellow solid.

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[0264] Intermediate 41 steps c, d, e and f [ka] The amino alcohol was synthesized in four steps (cross-coupling, dihydroxylation, tosylation, amination) analogous to intermediate 9 to give the title compound (50 mg, 74%) as a white solid.

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[0265] The diastereomers were subsequently separated after amide coupling using preparative HPLC.

[0266] Intermediate 42 [ka] Intermediate 42 Step a [ka] A mixture of p-(trifluoromethyl)acetophenone (1 g, 5.32 mmol) and TsNHNH2 (1.48 g, 8.00 mmol) in MeOH (18 mL) was stirred at 70° C. for 5 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the desired compound (1.75 g, 92%) as a white solid.

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[0267] Intermediate 42 Step b [ka] In a 40 mL vial, the compound from step a (1.29 g, 3.62 mmol,), TMBQ (1.63 g, 10.86 mmol), bis(pinacolato)diboron (1.38 g, 5.43 mmol), Pd(OAc)2 (41 mg, 0.18 mmol), PPh3 (95 mg, 0.36 mmol) and NaH (261 mg, 10.86 mmol) were added at room temperature. After degassing and filling with N2, toluene (40 mL) was added to the vial. The reaction mixture was reacted at 90 °C overnight. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the desired compound (2.4 g) as a brown solid.

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[0268] Intermediate 42 Step c [ka] A solution of the compound from step b (778 mg, 2.61 mmol) in dioxane (8 mL) and H2O (2 mL) was treated with (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (500 mg, 1.31 mmol), K2CO3 (361 mg, 2.61 mmol) and Pd(dppf)Cl2CH2Cl2 (106 mg, 0.13 mmol) at 80 °C under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give the desired compound (443 mg, 79%) as a brown oil.

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[0269] Intermediate 42 Steps d, e, f and g [ka] The amino alcohol was synthesized in four steps (cross-coupling, racemic dihydroxylation, tosylation, amination) analogous to intermediate 9 to give the title compound (208 mg, 90%) as a white solid.

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[0270] Intermediate 43 [ka] The amino alcohol was synthesized in a sequence similar to intermediate 42 using ADMIX-β for selective dihydroxylation to afford the title compound (181.4 mg, 66%) as a white solid.

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[0271] Intermediate 44 [ka] The amino alcohol was synthesized in a similar sequence to intermediate 42 using ADMIX-β for selective dihydroxylation to give the title compound (10 mg, 23%) as a white solid.

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[0272] Intermediate 45 [ka] Intermediate 45 Step a [ka] (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (1.42 g, 4.39 mmol, 1.00 equiv.) dissolved in 1,4-dioxane (22 mL) and sodium iodide (2.31 g, 15.4 mmol, 3.50 equiv.) was added. Sparging of nitrogen gas into the suspension was started and copper(I) iodide (167 mg, 0.879 mmol, 0.2 equiv.) and N,N'-dimethylethylenediamine (0.208 mL, 1.93 mmol, 0.4 equiv.) were added. Sparging was continued for an additional 5 min, after which a reflux condenser was attached to the flask and the mixture was heated to 100 °C with stirring. After stirring at this temperature for 2 h, the reaction mixture was cooled to room temperature and diluted with saturated aqueous sodium bicarbonate, water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated to a crude oil. This crude material was purified by automated flash chromatography on silica gel (0-100% EtOAc in cyclohexane) to give the pure iodide product as a yellow foam (1.03 g, 63%).

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[0273] Intermediate 45 Step b [ka] 1-Bromo-2,3-dichloro-4-fluorobenzene (4.74 g, 19.4 mmol) was dissolved in THF (97 ml) and the solution was cooled to -40 °C in a dry ice / acetone bath. Isopropylmagnesium chloride (2 M in THF, 10.7 ml, 21.4 mmol, 1.1 equiv) was added and the resulting mixture was stirred at that temperature for 1 h. Then, i-PrOB(pin) (4.76 ml, 23.3 mmol, 1.2 equiv) was added. The reaction mixture was then warmed to room temperature and stirred. During this time, some solid began to precipitate. After 1 h, the reaction was quenched with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (1 x 50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude boronic ester as a crystalline white solid (5.65 g, 89%). The crude product contained approximately 8% pinacol by weight and was used without further purification (no m / z for the boronic ester was detected).

[0274] Intermediate 45 Step c [ka] The compound from step a (1.04 g, 2.81 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (11.2 mL) and K2CO3 (1.17 g, 8.43 mmol, 3.0 equiv), Pd(dppf)Cl2 (123 mg, 0.169 mmol, 0.06 equiv) and the boronic ester from step b (1.10 g, 3.79 mmol, 1.35 equiv) were added. Water (2.8 mL) was added and the resulting biphasic suspension was sparged with nitrogen for 5 min. The vial was sealed and heated to 90 °C with stirring for 1 h, then cooled to room temperature. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated to a crude oil. The crude material was purified by automated flash chromatography on silica gel (0-100% EtOAc in cyclohexane) to give the pure product 5 as a yellow foam (940 mg, 82%).

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[0275] Intermediate 45 steps d, e and f [ka] The above compound was prepared using a similar procedure to Intermediate 9 to give the desired product (700 mg, 99%) as a white solid.

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[0276] Intermediate 46 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (138 mg, 90%) as a white solid.

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[0277] Intermediate 47 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (417 mg, 99%) as a white solid.

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[0278] Intermediate 48 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (222 mg, 93%) as a white solid.

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[0279] Intermediate 49 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (158 mg, 100%) as a white solid.

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[0280] Intermediate 50 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (291 mg, 76%) as a white solid.

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[0281] Intermediate 51 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (158 mg, 100%) as a white solid.

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[0282] Intermediate 52 [ka] The above compound was prepared in a similar manner to Intermediate 45 to give the desired product (800 mg, 96%) as a white solid.

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[0283] Intermediate 53 [ka] The above compound was prepared using a similar procedure to Intermediate 9 to give the desired product (421 mg, 90%) as a white solid.

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[0284] Intermediate 54 [ka] The above compound was prepared using a similar procedure to Intermediate 9 to give the desired product (608 mg, 97%) as a white solid.

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[0285] Intermediate 55 [ka] The above compound was prepared using a similar procedure to Intermediate 9 to give the desired product (560 mg, 93%) as a white solid.

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[0286] Intermediate 56 [ka] The above compound was prepared in a similar manner to Intermediate 9 to afford the desired amino alcohol as an off-white solid (689 mg, 94%).

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[0287] Intermediate 58 [ka] The above compound was prepared in a similar manner to Intermediate 9 to afford the desired amino alcohol as an off-white solid (293 mg, 100%).

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[0288] Table 3 below includes examples prepared in a similar manner to Example 1. Most compounds were purified by preparative HPLC (ACN / HO, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). Aryl boronic ester starting materials and aryl acid amide coupling partners were prepared according to intermediates 1-58 or by similar procedures with minor modifications, and also according to the procedures found in U.S. Pat. No. 11,572,367. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17]

[0289] Table 4 below contains examples prepared using methods similar to Example 47. Most compounds were purified by preparative HPLC (ACN / HO, 20-90%, 25 min), some by automated column chromatography (silica gel). Some examples were not separable by preparative HPLC and were reported as mixtures of diastereomers. [Table 4-1] [Table 4-2]

[0290] Intermediate 59 [ka] Intermediate 59 Step a [ka] A solution of CAN-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), Pd(dppf)Cl2CH2Cl2 (0.43 g, 0.52 mmol), and K2CO3 (1.44 g, 10.44 mmol) and tert-butyl N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (1.48 g, 5.22 mmol) in dioxane (16 mL), HO (4 mL) was stirred at 80° C. for 2 h under nitrogen atmosphere. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to give the desired compound (1.9 g, 88%) as a yellow oil.

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[0291] Intermediate 59 Step b [ka] A solution of the compound from step a (1.9 g, 4.61 mmol), Pd(dppf)Cl2CH2Cl2 (375 mg, 0.46 mmol), and K2CO3 (1.27 g, 9.22 mmol) and 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.90 g, 6.92 mmol) in dioxane (18 mL) and HO (2 mL) was stirred under nitrogen atmosphere at 80° C. for 2 h. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to give the desired compound (1.8 g, 81%) as a yellow solid.

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[0292] Intermediate 59 Step c [ka] A solution of the compound from step b (2 g, 4.16 mmol), K2OsO4.2H2O (0.06 g, 0.17 mmol), NMO (1.37 g, 11.67 mmol) and H2O (20 mL) in acetone (20 mL) was stirred at room temperature overnight. The resulting mixture was extracted, concentrated and dissolved in H2O (20 mL) and acetone (20 mL). NaIO4 (4.01 g, 18.75 mmol) was added. The resulting mixture was stirred at room temperature for an additional 4 h. The resulting mixture was extracted, concentrated and purified by silica gel column chromatography to give the desired compound (1.7 g, 84%) as a yellow solid.

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[0293] Example 463 [ka] Example 463 Process a [ka] A solution of 2-bromopyridine (373 mg, 2.36 mmol), n-BuLi (151 mg, 2.36 mmol) in THF (3 mL) was stirred at −78° C. for 15 min under nitrogen atmosphere. Intermediate 59 (190 mg, 0.39 mmol) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for an additional 30 min. The residue was quenched, extracted, concentrated, and purified by reverse phase flash chromatography to give the desired compound (100 mg, 45%) as a crude yellow solid.

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[0294] Example 463 Process b [ka] A solution of the compound from step a (100 mg, 0.18 mmol), HCl in 1,4-dioxane (2 mL) and DCM (2 mL) was stirred at room temperature for 1 h. The mixture was basified, extracted, concentrated and purified by reverse-phase flash chromatography to give the desired compound (50 mg, 60%) as a white solid.

number

[0295] Example 463 Process c [ka] A solution of the compound from step b (50 mg, 0.11 mmol), HATU (61 mg, 0.16 mmol), and DIPEA (42 mg, 0.32 mmol) and 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (25 mg, 0.11 mmol) in DMF (1 mL) was stirred at room temperature for 1 h. The resulting mixture was extracted, concentrated, and purified by preparative HPLC to give the desired compound (3.5 mg, 17%) as a white solid.

number

[0296] Intermediate 60 [ka] The following intermediates were prepared in a similar sequence to Example 463, step b, to afford the title compound (110 mg, 64%).

number

[0297] Intermediate 61 [ka] The following intermediates were prepared in a similar sequence to Example 463, step b, to afford the title compound (63 mg).

number

[0298] Table 7 below contains examples that were prepared in a similar manner to Example 463. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). [Table 5]

[0299] Intermediate 62 [ka] Intermediate 62 Step a [ka] To a stirred solution of CAN-7-bromo-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine-3-carboxamide (4 g, 10.44 mmol) and tributyl(1-ethoxyethenyl)stannane (3.96 g, 10.97 mmol) in toluene was added Pd(dppf)Cl2CH2Cl2 (851 mg, 1.04 mmol) dropwise under nitrogen atmosphere at 110 °C for 2 h. The resulting mixture was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the desired compound (2.1 g, 67%) as a brown solid.

number

[0300] Intermediate 62 Step b [ka] To a stirred solution of compound from step a (4.7 g, 14.37 mmol) and 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.94 g, 14.37 mmol) in dioxane (40 mL) was added Pd(dppf)Cl2CH2Cl2 (1.17 g, 1.44 mmol) and K2CO3 (3.97 g, 28.73 mmol). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the desired compound (4 g, 71%) as a yellow oil.

number

[0301] Intermediate 62 Step c [ka] A stirred solution of compound from step b (6 g, 16.36 mmol) and HCl (33 mL) in MeOH (20 mL) was added under nitrogen atmosphere at 50° C. for 2 h. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 7 with saturated NaHCO3 (aq). The resulting mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the desired compound (4 g, 64%) as a yellow oil.

number

[0302] Intermediate 62 Step d [ka] The compound from step c (4 g, 10.48 mmol) was dissolved in DCM (50 mL) at 0° C. 2,6-Di-tert-butyl-4-methylpyridine (2.58 g, 12.57 mmol) and Tf2O (4.43 g, 15.72 mmol) were added. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the title compound (4 g, 74%) as a yellow oil.

number

[0303] Intermediate 63 [ka] The following intermediates were prepared in a similar manner to Intermediate 62 to give the desired compound (1.7 g, 65%).

number

[0304] Intermediate 64 [ka] Intermediate 64 Step a [ka] To a stirred solution of intermediate 62 (200 mg, 0.39 mmol) and 2-cyclopropylpyrimidin-5-ylboronic acid (64 mg, 0.39 mmol) in 1,4-dioxane / HO (9:1) was added KCO (108 mg, 0.78 mmol) and Pd(dppf)ClCHCl (32 mg, 0.04 mmol), and the resulting mixture was stirred at 85° C. under nitrogen atmosphere for 2 h. The residue was purified by reverse-phase flash chromatography to give the desired compound (130 mg, 69%) as a yellow oil.

number

[0305] Intermediate 64 Step b [ka] To a stirred solution of the compound from step a (240 mg, 0.50 mmol) and methanesulfonamide (47 mg, 0.50 mmol) in t-BuOH / H2O was added ADMIX-β (1.16 g, 1.49 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was extracted with EtOAc (3×10 mL). The residue was purified by reverse-phase flash chromatography to give the desired compound (115 mg, 45%) as a yellow oil.

number

[0306] Intermediate 64 steps c and d [ka] To a stirred solution of compound from step b (100 mg, 0.20 mmol) and TsCl (64 mg, 0.33 mmol) in DCM was added TEA (67 mg, 0.67 mmol) and DMAP (27 mg, 0.22 mmol) at room temperature under nitrogen atmosphere and stirred for 2 h. The resulting mixture was acidified to pH 3 with HCl (1 M aqueous solution), the resulting mixture was extracted with DCM, and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give the desired compound (80 mg, 62%) as a yellow solid.

number

[0307] A solution of the compound from step c (80 mg, 0.12 mmol) and NH3(g) in MeOH (10 mL) was stirred at 40° C. overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / NH3 in MeOH 12:1) to give the methyl title compound (60 mg, 130%) as a yellow solid.

number

[0308] Intermediate 65 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (110 mg, 64%).

number

[0309] Intermediate 66 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compounds.

[0310] Intermediate 67 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compounds.

[0311] Intermediate 68 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compounds.

[0312] Intermediate 69 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (50.2 mg, 41%) as a white solid.

number

[0313] Intermediate 70 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compounds.

[0314] Intermediate 71 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (70 mg, 75%) as a white solid.

number

[0315] Intermediate 72 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (80 mg, 65%) as a white solid.

number

[0316] Intermediate 73 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (27 mg, 42%) as a white solid.

number

[0317] Intermediate 74 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (70 mg) as a white solid.

number

[0318] Intermediate 75 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (70 mg, 71%) as a yellow solid.

number

[0319] Intermediate 76 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (30 mg, 81%) as a yellow solid.

number

[0320] Intermediate 77 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (22 mg) as a yellow solid.

number

[0321] Intermediate 78 [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (59.4 mg, 69%) as a yellow solid.

number

[0322] Intermediate 79 [ka] Intermediate 79 Step a [ka] A solution of compound A3-1036 (280 mg, 0.55 mmol), Pd(dppf)Cl2 (40 mg, 0.06 mmol), CuCl (54 mg, 0.55 mmol) and Cs2CO3 (355 mg, 1.09 mmol) in DMF (10 mL) was stirred at 90 °C for 2 h under N2 atmosphere. The residue was purified by silica gel column chromatography eluting with PE / EA to give the desired product (70 mg, 29%) as a yellow oil.

number

[0323] Intermediate 79 steps b, c, d and e [ka] The following intermediates were prepared in a similar sequence to Intermediate 64 to afford the title compound (15 mg, 68%) as a yellow solid.

number

[0324] Table 8 below includes examples prepared in a similar manner to Example 1. Most compounds were purified by preparative HPLC (ACN / HO, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). Amine starting materials were prepared according to intermediates 62-80, and aryl acid amide coupling partners were prepared according to intermediates 1-58 or by analogous procedures with minor modifications according to the procedures found in U.S. Pat. No. 11,572,367. [Table 6-1] [Table 6-2] [Table 6-3]

[0325] Example 504 [ka] Example 504 Process a [ka] To a stirred solution of intermediate 62 (300 mg, 0.58 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (129 mg, 0.58 mmol) in 1,4-dioxane / HO was added KCO (161 mg, 1.17 mmol) and Pd(dppf)ClCHCl (47 mg, 0.06 mmol) and the reaction was stirred at 85° C. under nitrogen for 2 h. The residue was purified by reverse phase flash chromatography to give the desired product (105 mg, 39%) as a yellow solid.

number

[0326] Example 504 Process b [ka] A mixture of the methyl compound from step a (100 mg, 0.22 mmol), methanesulfonamide (20 mg, 0.22 mmol) and ADMIX-β (509 mg, 0.65 mmol) in tBuOH (3 mL), HO (3 mL) was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was extracted with EA. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give the desired product (70 mg, 65%) as a tan oil.

number

[0327] Example 504 Process c [ka] A mixture of compound from step b (70 mg, 0.14 mmol), TsCl (40 mg, 0.21 mmol), DMAP (17 mg, 0.14 mmol) and TEA (43 mg, 0.43 mmol) in DCM (3 mL) was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 4 with HCl (1 M aq.). The resulting mixture was extracted with CH2Cl2. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give the desired product (60 mg, 52.73%) as a yellow solid.

number

[0328] Example 504 Process d [ka] A mixture of compound from step c (60 mg, 0.07 mmol) and NH3(g) in MeOH (3 mL) was stirred at 40° C. overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / 7 M NH3 in MeOH) to give the desired product (20 mg, 42.3%) as a white solid.

number

[0329] Example 504 Process e [ka] A mixture of compound from step d (25 mg, 0.04 mmol), 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (9 mg, 0.04 mmol), HATU (15 mg, 0.04 mmol) and DIEA (10 mg, 0.08 mmol) in DMF (1 mL) was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash chromatography to give the desired product (20 mg, 59%) as a yellow solid.

number

[0330] Example 504 Process f [ka] To a stirred mixture of compound from step e (20 mg, 0.02 mmol) and MeOH (2 mL), LiOH (5 mg, 0.24 mmol) in H2O (0.5 mL) was added dropwise at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / 7 M NH3MeOH 10:1) to give the desired product (6.7 mg, 38%) as a white solid.

number

[0331] Example 505 [ka] The following example was prepared in a similar sequence to Example 504. The residue was purified by reverse phase flash chromatography to give the title compound (6.4 mg, 31%) as a white solid.

number

[0332] Assay Methods for RSV-A Assay Hep-2 cells (originally derived from a tumor grown in irradiated, cortisone-treated weanling rats injected with epidermoid carcinoma tissue from the larynx of a 56-year-old male, but later found to be indistinguishable from HeLa cells by PCR DNA analysis) were used to culture genotype A, "long" strain RSV. Flasks were inoculated with RSV and virus stocks were harvested when cytopathic effect (CPE) exceeded 90%. Viral stocks in 25% sucrose medium were flash frozen using liquid nitrogen to enhance virus stability. Viral stock titers were determined using 8,000 cells / well and 3-fold virus dilutions across 96-well plates to determine tissue culture infectious dose 50% (TCID 50 ) and cultured for 4 days. Viral stock titers were also quantified by plaque-forming unit assay as described elsewhere.

[0333] After extensive parameter testing, the final assay is performed as follows: Hep-2 cells are seeded into the inner 60 wells of a 96-well plate at 8,000 cells / well in a volume of 50 μL with growth medium (DMEM without phenol red, 1% L-Glut, 1% Penn / Strep, 1% non-essential amino acids, 10% heat-inactivated FBS). Two-fold serial dilutions of control and test compounds are added to the wells in duplicate in a total volume of 25 μL. Virus stocks are then added to the wells in a volume of 25 μL at a multiplicity of infection (MOI) of 0.1, bringing the total volume of each well to 100 μL. MOI is expressed in PFU / mL, or, if unavailable, TCID 50 Each 96-well plate has a 6-well control column containing cells and virus but no compound (negative control, maximum CPE), a column containing cells but no compound or virus (positive control, minimum CPE), and a column containing no cells, virus, or compound (background plate / reagent control). Control wells containing cells but no virus receive an additional 25 μL of growth medium containing an equal amount of sucrose as the wells receiving the virus stock to keep media and volume conditions constant. The outer wells of the plate are filled with 125 μL of moat media (DMEM, 1% Penn / Strep) to act as a thermal and evaporation barrier (moat) around the test wells. After a 5-day incubation period, the plates are read using ATPlite (50 μL added per well), which quantifies the amount of ATP present in each well (a measure of cell health). The assay plates are read using an Envision luminometer. These data are used to calculate the EC 50 Calculate (Table 10). EC 50 The ranges are as follows: A<0.2 μM; B>0.2 μM. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0334] Methods for HMPV antiviral assay Method 1: In vitro HMPV antiviral activity was assessed using the clinical isolate A2 strain TN 94-49 (obtained from Dr. John Williams, Vanderbilt University, TN) and LLC-MK2 cells (ATCC#CCL-7), an immortalized renal epithelial cell line derived from Macaca mulatta.

[0335] Compounds were resuspended in 10 mM dimethyl sulfoxide (DMSO), serially diluted, and added to a 384-well source plate. Compounds were then diluted and transferred to a 384-well assay plate using an Echo-650 automated liquid handling system (Beckman Coulter, Indiana). Test compounds were evaluated in duplicate at a top concentration of 2 μM, followed by 2.5-fold serial dilutions to obtain a total of 10 concentration points. DMSO control wells were also included in the assay plate, either infected or uninfected, to act as positive and negative controls.

[0336] A2 TN 94-49 virus infection was performed in suspension with LLC-MK2 cells. Cells were washed twice with PBS and removed from cell culture flasks with 0.25% trypsin-EDTA (Thermo Fisher Scientific, MA). Trypsin-EDTA was inactivated by resuspending in OptiMEM (ThermoFisher Scientific, MA) containing 2% fetal bovine serum (FBS) and 1% penicillin-streptomycin. Cells were pelleted by centrifugation at 800 rpm for 5 min, the supernatant was removed, and cells were resuspended in PBS + 100 μg / mL CaCl2 and washed. This step was performed twice. Cells were then resuspended in serum-free (SF)-OptiMEM containing 4 μg / mL TPCK-trypsin (Sigma Aldrich, MO), 1% penicillin-streptomycin (ThermoFisher Scientific, MA) and 100 μg / mL CaCl2. Cells were counted and plated at a density of 5,000 cells / well, 12.5 μL / well.

[0337] Viral infection was performed at a multiplicity of infection (MOI) of 0.005 by adding 12.5 μL per well. Viral infection was performed in infection medium containing SF-OptiMEM, 100 μg / mL CaCl2 and 1% penicillin-streptomycin. HMPV viral stocks were suspended in infection medium + 5% glycerol, and therefore an equal volume of infection medium + 5% glycerol was added to non-infected wells to equalize the final % glycerol across all wells of the assay plate. The final concentration of TPCK-trypsin was 2 μg / mL. Assay plates were incubated at 37°C, 5% CO2 for 7 days.

[0338] After 7 days of incubation, 12.5 μL of ATP-Lite (PerkinElmer, MA) was added to each well and raw luminescence values ​​were determined using an Envision 2104 (Perkin Elmer, MA). The average raw luminescence values ​​of the cells and virus only positive control wells were subtracted from all conditions tested and the percentage of cell health was determined by dividing these values ​​by the average of the cells only negative control wells. EC 50 Values ​​were calculated by non-linear regression using a four parameter curve logistic equation. The curve fitting model used was the XLFit dose-response One Site Model 200: y=(A+(B / (1+((x / C)^D)))) where A is the minimum y value, B is the maximum y value, and C is the logEC 50 value and D is the slope coefficient).

[0339] Method 2: In vitro HMPV antiviral activity was evaluated using the clinical isolate A2 strain TN 94-49. In vitro HMPV antiviral activity was assessed using the clinical isolate A2 strain TN 94-49 (obtained from Dr. John Williams, Vanderbilt University, TN) and LLC-MK2 cells (Millipore Sigma CB_85062804), an immortalized renal epithelial cell line derived from Macaca mulatta.

[0340] Compounds were resuspended in 10 mM dimethyl sulfoxide (DMSO), serially diluted, and added to a 384-well source plate. Compounds were then diluted and transferred to a 384-well assay plate using an Echo-650 automated liquid handling system (Beckman Coulter, Indiana). Test compounds were evaluated in duplicate at a top concentration of 200 nM, followed by 2.5-fold serial dilutions to obtain a total of 10 concentration points. DMSO control wells were also included in the assay plate, either infected or uninfected, to act as positive and negative controls.

[0341] A2 TN 94-49 virus infection was performed in suspension with LLC-MK2 cells. Cells were washed twice with PBS and removed from cell culture flasks with 0.25% trypsin-EDTA (Thermo Fisher Scientific, MA). Trypsin-EDTA was inactivated by resuspending in OptiMEM (ThermoFisher Scientific, MA) containing 2% fetal bovine serum (FBS) and 1% antibiotic-antimycotic. Cells were pelleted by centrifugation at 800 rpm for 5 min, the supernatant was removed, and cells were resuspended and washed in PBS + 100 μg / mL CaCl2. This step was performed twice. Cells were then resuspended in serum-free (SF)-OptiMEM containing 4 μg / mL TPCK-trypsin (Sigma Aldrich, MO), 1% antibiotic-antimycotic (ThermoFisher Scientific, MA), 100 μg / mL CaCl2, and 4 μM P-glycoprotein inhibitor CP-100-356. Cells were counted and plated at a density of 5,000 cells / well, 12.5 μL / well.

[0342] Viral infection was performed at a multiplicity of infection (MOI) of 0.16 by adding 12.5 μL per well. Viral infection was performed in infection medium containing SF-OptiMEM, 100 μg / mL CaCl2 and 1% antibiotic-antimycotic. HMPV viral stock was suspended in infection medium + 5% glycerol, therefore an equal volume of infection medium + 5% glycerol was added to non-infected wells to equalize the final % glycerol across all wells of the assay plate. The final concentration of TPCK-trypsin was 2 μg / mL. The final concentration of CP-100-356 was 2 μM. The assay plate was incubated at 37°C, 5% CO2 for 7 days.

[0343] After 7 days of incubation, 12.5 μL of ATP-Lite (PerkinElmer, MA) was added to each well and raw luminescence values ​​were determined using an Envision 2104 (Perkin Elmer, MA). The average raw luminescence values ​​of the cells and virus only positive control wells were subtracted from all conditions tested and the percentage of cell health was determined by dividing these values ​​by the average of the cells only negative control wells. EC 50 Values ​​were calculated by non-linear regression using a four parameter curve logistic equation. The curve fitting model used was the XLFit dose-response One Site Model 200: y=(A+(B / (1+((x / C)^D)))) where A is the minimum y value, B is the maximum y value, and C is the logEC 50 value and D is the slope coefficient).

[0344] These data were used to determine the EC 50 Calculate (Table 11).

[0345] Method 1 EC 50 The ranges of A and B are as follows: A<0.5 μM; B>0.5 μM. EC 50 The ranges are as follows: A<0.2 μM; B>0.2 μM. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0346] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Formula (I): 【Chemistry 1】 wherein: A, 1) optionally substituted aryl; and 2) optionally substituted heteroaryl is selected from the group consisting of E. 1) optionally substituted aryl; and 2) optionally substituted heteroaryl is selected from the group consisting of R １ and R ２ However, each independently, 1) Hydrogen; 2) optionally substituted C １ -C ８ Alkyl; 3) optionally substituted C ３ -C ８ Cycloalkyl; 4) optionally substituted 3-8 membered heterocycloalkyl; 5) optionally substituted aryl; 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl; and 8) optionally substituted heteroarylalkyl is selected from the group consisting of Or, R １ and R ２ together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocycle; R ３ is hydroxy or fluorine, and R ４ but, 1) optionally substituted aryl; 2) optionally substituted arylalkyl; 3) optionally substituted heteroaryl; and 4) optionally substituted heteroarylalkyl 1. A compound selected from the group consisting of:

2. R ４ is a group shown below: 【Chemistry 2】 is selected from In the formula, R ３１ is halogen, -CN, -OR ３３ , -CO ２ R ３３ , -SO ２ R ３３ , -SO ２ N.R. ３３ R ３４ , -NR ３３ R ３４ , optionally substituted -C １ -C ６ Alkyl, optionally substituted -C ２ -C ６ alkenyl, or optionally substituted -C ３ -C ８ cycloalkyl, n is 0, 1 or 2, R ３３ and R ３４ each independently represents hydrogen, an optionally substituted —C １ -C ６ Alkyl, optionally substituted -C ２ -C ６ Alkenyl, optionally substituted -C ３ -C ８ 2. The compound of claim 1, wherein the aryl is selected from the group consisting of cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

3. A compound selected from the compounds shown below, or a pharma- ceutically acceptable salt thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent or excipient.

5. A method of treating or preventing an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or combination of compounds according to any one of claims 1 to 3.

6. 6. The method of claim 5, further comprising administering to the subject an additional anti-RSV agent.

7. 6. The method of claim 5, further comprising administering to the subject a steroidal anti-inflammatory compound.

8. 10. A method of treating RSV infection and influenza in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-3 and a therapeutically effective amount of an anti-influenza agent.

9. 7. The method of claim 6, wherein the compound and the additional anti-RSV agent are combined.

10. 7. The method of claim 6, wherein the compound and the additional anti-RSV agent are administered simultaneously.

11. The method of claim 6, wherein administration of the compound allows for administration of the additional anti-RSV agent at a lower dose or frequency in a subject in need of prophylactic treatment of an RSV infection compared to administration of the additional anti-RSV agent alone required to achieve a similar result in the prophylactic treatment.

12. A method of treating or preventing an HMPV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or combination of compounds described in any one of claims 1 to 3.

13. 13. The method of claim 12, further comprising administering to the subject an additional anti-HMPV agent.

14. The method of claim 13 , wherein the compound and the additional anti-HMPV agent are combined.

15. The method of claim 13 , wherein the compound and the additional anti-HMPV agent are administered simultaneously.

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