Antiviral heterocyclic compounds

Abstract

Disclosed are compounds of Formula (I), or a pharmaceutically acceptable salt, ester, or prodrug thereof: which inhibit human respiratory syncytial virus (HRSV) or are inhibitors of human metapneumovirus (HMPV). The invention also relates to a pharmaceutical composition containing the compound, and the pharmaceutical composition is applied to a subject suffering from HRSV or HMPV infection. The invention also relates to methods of treating HRSV or HMPV infection in a subject by administering a pharmaceutical composition comprising a compound of the invention.

Description

[0001] Related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 457,546, filed April 6, 2023, and U.S. Provisional Application No. 63 / 541,923, filed October 2, 2023. The entire teaching of these applications is incorporated herein by reference. Technical Field

[0003] This invention generally relates to compounds and pharmaceutical compositions that can be used as inhibitors of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV). Background Technology

[0004] Human respiratory syncytial virus (HRSV) is a negative-sense virus containing a non-segmented, single-stranded linear RNA genome. As a member of two serotypes within the genus Paramyxovirus of the family Pneumoviridae, HRSV contains 10 genes encoding 11 proteins. The nucleocapsid protein (N), RNA polymerase protein (L), phosphoprotein (P), and transcription anti-termination factor (M2-1), together with the RNA genome, form the ribonucleoprotein (RNP) complex. Several small molecule compounds have been shown to target the RNP complex. Furthermore, the fusion protein (F) is crucial for viral attachment to the host and has been extensively studied. High-resolution structures of the F protein interacting with inhibitors have been obtained, while structural studies of the N protein are in their early stages. As a direct result of HRSV protein research, the F, L, and N proteins have become a major focus of drug discovery efforts.

[0005] Increased efforts in HRSV drug discovery are due to the fact that HRSV is a leading cause of acute lower respiratory infection (ALRI) in patients of all ages. In addition to respiratory infections, high-risk groups during HRSV infection include the elderly, immunocompromised individuals, children under two years of age, and patients with chronic obstructive pulmonary disease (COPD) or chronic heart failure (CHF). Studies have found that HRSV caused 177,500 hospitalizations and 14,000 deaths among the elderly in the United States over a four-year period. It is well known that almost all children will be infected with HRSV within the first three years of life, with premature infants experiencing more severe HRSV infections. In fact, HRSV is the most common cause of bronchiolitis and pneumonia in infants under one year of age in the United States. It is estimated that approximately 3.2 million hospitalizations and 66,000 deaths in children under five years of age worldwide are caused by HRSV. Compared to influenza, HRSV is associated with more infant deaths and more infant hospitalizations in infants under one year of age.

[0006] HRSV infection can also affect healthy individuals, and repeated HRSV infections can even occur within a two-month course of illness. Symptoms in healthy individuals are similar to those of a cold; however, in more severe cases, fever, wheezing, shortness of breath, and cyanosis may occur.

[0007] Currently, treatment options for HRSV infection are quite limited, and there is no vaccine due to the unsuccessful attempts to date. Palizumab is a monoclonal antibody approved for prophylactic use, but its use is limited due to its high price. Palizumab is usually only used for high-risk infants, such as premature infants or infants with heart / lung disease, but it has only a 60% efficacy rate in reducing hospitalizations. Ribavirin is approved as an inhaled treatment option, but its effectiveness is limited and there are associated safety concerns. Given the treatment options and the consistently seasonal nature of HRSV outbreaks, the development of new therapeutic agents for HRSV is promising.

[0008] The following publications disclose several RSV fusion inhibitors: WO2010 / 103306, WO2012 / 068622, WO2013 / 096681, WO2014 / 060411, WO2013 / 186995, WO2013 / 186334, WO2013 / 186332, WO2012080451, WO2012 / 080450, WO2012 / 080449, WO2012 / 080447, WO2012 / 080446, WO2015 / 110446, WO2017 / 009316, 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: WO2004 / 026843, J. Med. Chem. 2006, 49, 2311-2319 and J. Med. Chem. 2007, 50, 1685-1692. Examples of L protein inhibitors for HRSV are disclosed in the following publications: WO2011 / 005842, WO2005 / 042530, 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: WO2011 / 005842, WO2013 / 242525, WO2014 / 031784, WO2015 / 026792, WO2016 / 0055791, WO2016 / 138158 and J. Med. Chem. 2015, 58, 1862-1878.

[0009] 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). While often mild, this virus can be severe and life-threatening in high-risk groups, such as children under 5 years of age, adults over 65 years of age, and adults with underlying medical conditions such as chronic obstructive pulmonary disease (COPD), asthma, congestive heart failure, or diabetes. The annual incidence of HMPV infection is 1.2 / 1,000 in healthy adults over 65 years of age, compared to 38% in those with underlying conditions (such as COPD), and individuals with these conditions are twice as likely to develop symptomatic illness and require medical care. In immunocompromised individuals, HMPV accounts for 6% of all respiratory tract infections following lung transplantation and 3% of stem cell transplant-related ALRTIs. HMPV infection is also thought to be associated with acute graft rejection.

[0010] Similar to HRSV, infection is thought to occur through glycoprotein (G) interactions with target cells, followed by fusion via the F protein. The HMPV L protein sequence is homologous to the HRSV L protein.

[0011] HMPV infection is the second most common cause of lower respiratory tract infections in children (after HRSV) and is also a problem in the elderly. Four HMPV subtypes (A1, A2, B1, and B2) have been identified in clinical isolates. Reinfection can occur throughout childhood after the initial infection. Currently, there are no therapeutic drugs for HMPV infection.

[0012] Given the seasonality and predictability of HRSV and HMPV prevalence, the prevalence of HRSV in elderly care facilities, and the severity of infection in high-risk infants, there is a clear need for effective and potent treatments for HRSV and HMPV. This invention has identified heterocyclic molecular compounds effective against HRSV-A / B and HMPV. This invention includes methods for preparing these molecules, RSV cell-based assays, HMPV-TN / 94-49 A2 cell-based assays, and small molecules with potential therapeutic potential for HRSV / HMPV infection. Summary of the Invention

[0013] This invention provides compounds represented by formula (I), and pharmaceutically acceptable salts, esters, and prodrugs thereof, which can be used to treat or prevent viral (particularly HRSV or HMPV) infections:

[0014] ,

[0015] in:

[0016] A. Choose from the following groups:

[0017] 1) Optionally substituted aryl groups; and

[0018] 2) Optionally substituted heteroaryl groups;

[0019] E can choose from the following groups:

[0020] 1) Optionally substituted aryl groups; and

[0021] 2) Optionally substituted heteroaryl groups;

[0022] R1 and R2 are each independently selected from the following groups:

[0023] 1) Hydrogen;

[0024] 2) Optionally substituted -C1-C8 alkyl groups;

[0025] 3) Optionally substituted -C3-C8 cycloalkyl groups;

[0026] 4) Optionally substituted 3- to 8-membered heterocyclic alkyl groups;

[0027] 5) Optionally substituted aryl groups;

[0028] 6) Optionally substituted arylalkyl groups;

[0029] 7) Optionally substituted heteroaryl groups; and

[0030] 8) Optionally substituted heteroarylalkyl groups;

[0031] Alternatively, R1 and R2 together with the nitrogen atom to which they are attached form optionally substituted 3- to 8-membered heterocycles;

[0032] R3 is a hydroxyl group or fluorine; and

[0033] R4 can be selected from the following groups:

[0034] 1) Hydrogen;

[0035] 2) Optionally substituted -C1-C6 alkyl groups;

[0036] 3) Optionally substituted -C2-C6 ynyl group;

[0037] 4) Optionally substituted -C3-C8 cycloalkyl groups;

[0038] 5) Optionally substituted 3- to 8-membered heterocycles;

[0039] 6) Optionally substituted aryl groups;

[0040] 7) Optionally substituted aryl alkyl groups;

[0041] 8) Optionally substituted heteroaryl groups; and

[0042] 9) Optionally substituted heteroarylalkyl groups;

[0043] Each of the above preferred groups may be used in combination with one, any or all other preferred groups. Detailed Implementation

[0044] In one embodiment of the invention, it is a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments of the compound of formula (I), R1 is hydrogen.

[0046] In some embodiments of the compound of formula (I), R1 is hydrogen and R2 is hydrogen.

[0047] In some embodiments of the compound of formula (I), R3 is -OH.

[0048] In some embodiments of the compound of formula (I), R4 is an optionally substituted methyl or optionally substituted cyclopropyl.

[0049] In some embodiments of the compound of formula (I), R4 is selected from one of the following:

[0050] .

[0051] In some embodiments of the compound of formula (I), R3 is OH and R4 is CF3, CD3 or cyclopropyl.

[0052] In some embodiments of the compound of formula (I), R1 is hydrogen, R2 is hydrogen, R3 is OH, and R4 is CF3, CD3, or cyclopropyl.

[0053] In some embodiments of the compound of formula (I), A is selected from one of the following by removing a hydrogen atom:

[0054] Each of these groups is optionally substituted.

[0055] In some embodiments of the compound of formula (I), A is selected from the groups listed below:

[0056] .

[0057] In some embodiments of the compound of formula (I), E is an optionally substituted aryl group, preferably an optionally substituted phenyl group. In some embodiments of the compound of formula (I), E is selected from the groups listed below:

[0058] .

[0059] In some embodiments of the compound of formula (I), R4 is an optionally substituted phenyl group.

[0060] In some embodiments of the compound of formula (I), R4 is an optionally substituted heteroaryl group.

[0061] In some embodiments of the compound of formula (I), R4 is selected from one of the following:

[0062] ,

[0063] Among them, R 31 It 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; R 32 It is hydrogen, optionally substituted –C1-C6 alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; n is 0, 1 or 2; R 33 and R 34 Each is 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 heterocyclic alkyl, optionally substituted aryl, and optionally substituted heteroaryl. Preferably, R 31 Selected from halogens, optionally substituted methyl groups, and optionally substituted methoxy groups. More preferably, R 31 It can be -F, -Cl, -CH3, -CHF2, -CF3, or -OCH3.

[0064] In some embodiments of the compound of formula (I), R3 is OH and R4 is an optionally substituted phenyl group.

[0065] In some embodiments of the compound of formula (I), E is an optionally substituted heteroaryl group, preferably an optionally substituted fused bicyclic heteroaryl group.

[0066] In some embodiments of compounds of formula (I), E is selected from the groups listed below:

[0067] ,

[0068] Where R 31 And n is as defined before, and R 31'Is it hydrogen or R?' 31 .

[0069] In some embodiments of compounds of formula (I), E is selected from the groups listed below:

[0070] .

[0071] In some embodiments of the compound of formula (I), A is selected from one of the following by removing a hydrogen atom: Each of these groups is optionally substituted.

[0072] In some embodiments of the compound of formula (I), A is selected from the groups listed below:

[0073] .

[0074] In one embodiment of the invention, the compound of formula (I) is represented by formula (Ia) or formula (Ib), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0075] ,

[0076] Wherein A, E, R1, R2, R3 and R4 are as defined above. Preferably, the compound of formula (I) is represented by formula (Ia).

[0077] In one embodiment of the invention, the compound of formula (I) is represented by formula (II), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0078] ,

[0079] A, E, R3, and R4 are defined as previously.

[0080] In one embodiment of the invention, the compound of formula (I) is represented by formula (IIa), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0081] ,

[0082] A, E, R3, and R4 are defined as previously.

[0083] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (III-1) to (III-7), or by a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0084] ,

[0085] A, E, R1, and R2 are defined as previously.

[0086] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0087] ,

[0088] A and E are as defined above.

[0089] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), where A is selected from the groups listed below:

[0090] ;

[0091] And E is selected from the groups listed below:

[0092] .

[0093] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), where A is selected by removing a hydrogen atom from one of the following groups, and each of these groups is optionally substituted:

[0094] And E is selected from the groups listed below:

[0095] ,

[0096] Where R 31 R 31 ' and n are as defined above.

[0097] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), where A is selected by removing a hydrogen atom from one of the following groups, and each of these groups is optionally substituted:

[0098] And E is selected from the groups listed below:

[0099] .

[0100] In one embodiment of the invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0101] ,

[0102] Where E and R4 are as defined above, and

[0103] R 11The radical is selected from optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycles, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Preferably, R 11 It is an optionally substituted methyl or optionally substituted cyclopropyl group. Preferably, R 11 It is methyl or cyclopropyl.

[0104] R 12 The radical is selected from hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycles, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Preferably, R 12 It is an optionally substituted methyl or optionally substituted cyclopropyl. More preferably, R 12 It is -CH3, -CHF2, -CD3, cyclopropyl, or .

[0105] R 13 and R 14 Each is independently selected from hydrogen, halogen, and -OR 11 -NH2, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycles, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Alternatively, R 13 and R 14 Together with the carbon atoms attached thereto, it forms a 4- to 7-membered ring fused with the benzene ring. Preferably, R 13 and R 14 Each is independently selected from halogens, optionally substituted methyl groups, and optionally substituted methoxy groups.

[0106] In one embodiment of the invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), wherein E is a substituted phenyl group, and R4 is selected from one of the following:

[0107] .

[0108] In one embodiment of the invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), wherein E is selected from the groups listed below:

[0109] .

[0110] In one embodiment of the invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), wherein E is a substituted phenyl group; R 11 It is an optionally substituted methyl or optionally substituted cyclopropyl; R12 It is an optionally substituted methyl or optionally substituted cyclopropyl; R 13 and R 14 Each of the following is independently selected from halogens, optionally substituted methyl groups, and optionally substituted methoxy groups; and R4 is selected from one of the following:

[0111] .

[0112] In one embodiment of the invention, the compound of formula (I) is represented by formula (VI-1) or formula (VI-2), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0113] ,

[0114] Among them, R4, R 11 R 12 R 13 and R 14 As defined above, and each R 21 R 22 R 23 R 24 and R 25 It is independently selected from hydrogen, halogen, optionally substituted methyl and optionally substituted methoxy.

[0115] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VII-1) to (VII-6), or by a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0116] ,

[0117] Where R 11 R 12 R 13 R 14 R 21 R 22 R 23 R 24 and R 25 As defined above.

[0118] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VIII-1) to (VIII-2), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0119] ,

[0120] Where A, E, R1, R2, R 31 And n is as defined above.

[0121] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VIII-1a) to (VIII-2a), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0122] ,

[0123] Where A, E, R1, R2, R 31 And n is as defined above.

[0124] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VIII-1a) to (VIII-2a), where A is selected by removing a hydrogen atom from one of the following groups, and each of these groups is optionally substituted:

[0125] And E is selected from the groups listed below:

[0126] ,

[0127] Where R1, R2, R 31 R 31 ' and n are as defined above. Preferably, R1 is hydrogen and R2 is hydrogen.

[0128] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IX-1) to (IX-8), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0129] ,

[0130] Among them, E and R 11 R 12 R 13 R 14 R 31 And n is as defined above.

[0131] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IX-1a) to (IX-8a), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0132] ,

[0133] Among them, E and R 11 R 12 R 13 R 14 R 31 And n is as defined above.

[0134] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IX-1a) to (IX-8a), where E is selected from the groups listed below:

[0135] ,

[0136] Where R 11 R 12 R 13 R 14 R 31 R 31 ' and n are as defined above.

[0137] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (X-1) to (X-12), or is a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0138] E and R 31 And n is as defined above.

[0139] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (X-1) to (X-12), where E is selected from the groups listed below:

[0140] ,

[0141] Where R 31 R 31 ' and n are as defined above.

[0142] It should be understood that the description of the invention herein should be interpreted in accordance with the laws 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.

[0143] The aim is to make the definition of any substituent or variable (e.g., R1, R2, etc.) at a specific position in the molecule independent of its definition at other positions in the molecule.

[0144] It should be understood that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomer, and optically active forms. It should also be understood that some compounds of the present invention may exist in different tautomer forms. All tautomers are considered to be within the scope of the present invention.

[0145] In some embodiments, the present invention provides a method for preventing or treating RSV activity and for treating RSV infection in a subject in need. The method comprises administering a therapeutically effective amount of a compound of formula (I) to the subject.

[0146] The present invention also provides the use of the compound of formula (I) in the preparation of a medicament for the prevention or treatment of RSV.

[0147] Therefore, in one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a steroidal anti-inflammatory compound (e.g., budesonide or fluticasone). In a preferred embodiment, the steroid is administered in a low dose to minimize immunosuppressive effects. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a non-steroidal anti-inflammatory compound, such as a leukotriene antagonist, such as Singulair (Merck) or Accolade (Astra Zeneca); a phosphodiesterase 4 inhibitor, such as roflumilast (Altana); a TNF α inhibitor, such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott), or CDP870 (Celltech) or an NSAID. In another embodiment, the compound of formula (I) is combined with an interleukin-8 or interleukin-9 inhibitor. The present invention therefore also relates to a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-inflammatory compound for simultaneous, alone, or sequential use in the treatment of RSV.

[0148] This invention also relates to combinations of compounds of formula (I) or pharmaceutically acceptable salts thereof with anti-influenza compounds, and the use of such combinations in the treatment of coexisting RSV and influenza infections. This invention therefore also relates to a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-influenza compound for simultaneous, single, or sequential treatment of coexisting RSV and influenza infections. The compounds of this invention can be administered in a variety of dosage forms. Therefore, they can be administered orally, for example as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders, or granules. The compounds of this invention can also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, or via infusion techniques. These compounds can also be administered as suppositories.

[0149] In one embodiment, the compounds of the present invention are administered intranasally or intrabronchially. The present invention also provides an inhaler or nebulizer containing a drug comprising (a) a derivative of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or diluent.

[0150] The present invention also provides a pharmaceutical composition comprising such benzodiazepine derivatives or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent.

[0151] The compounds of the present invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral formulations may contain, along with the active compound, diluents such as lactose, glucose, sucrose, cellulose, corn starch, or potato starch; lubricants such as silica, talc, stearic acid, magnesium stearate, or calcium stearate, and / or polyethylene glycol; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrants such as starch, alginate, alginate, or sodium glycolate; effervescent mixtures; dyes; sweeteners; humectants such as lecithin, polysorbate, or lauryl sulfate; and non-toxic and pharmacologically inactive substances commonly used in pharmaceutical formulations. Such pharmaceutical formulations can be manufactured in known ways, for example, by mixing, granulation, tableting, sugar coating, or film coating processes.

[0152] Liquid dispersions for oral administration can be syrups, emulsions, and suspensions. Syrups may contain a carrier, such as sucrose or sucrose with glycerol and / or mannitol and / or sorbitol.

[0153] Suspensions and emulsions may contain carriers such as natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions intended for intramuscular injection may contain pharmaceutically acceptable carriers along with the active compound, such as sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol), and, if necessary, an appropriate amount of lidocaine hydrochloride.

[0154] Solutions intended for injection or infusion may contain a carrier, such as sterile water, or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

[0155] This invention also relates to novel compounds as defined above; or pharmaceutically acceptable salts thereof, for use in treating human or animal bodies. This invention also relates to a pharmaceutical composition comprising a 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. Pharmaceutically acceptable salts are defined above. The novel compounds of this invention are generally administered in the manner defined above, and these compounds are generally formulated for administration in the manner defined above.

[0156] Preferably, the pharmaceutical composition comprises an optically active isomer of the novel compound of the present invention. Thus, for example, preferred novel compounds of the present invention containing only one chiral center comprise substantially pure R enantiomers, substantially pure S enantiomers, and enantiomer mixtures containing excess R or excess S enantiomers. Particularly preferred pharmaceutical compositions comprise the compound of the present invention, which is a substantially pure optical isomer. For the avoidance of doubt, the novel compounds of the present invention may be used in solvate form if desired.

[0157] Another aspect of the invention is a method for preparing any of the compounds described herein, using any of the synthetic methods described herein.

[0158] Definitions

[0159] The following lists the definitions of various terms used to describe the invention. These definitions apply to terms used throughout this specification and claims, unless otherwise limited in specific circumstances, whether used alone or as part of a larger group.

[0160] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic system comprising at least one aromatic ring, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl, and indenyl. A polycyclic aryl is a polycyclic system comprising at least one aromatic ring. Polycyclic aryl groups may comprise fused rings, covalently linked rings, or combinations thereof.

[0161] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic group having one or more ring atoms selected from S, O, and N; and the remaining ring atoms are carbon, wherein any N or S contained in the ring may optionally be oxidized. Heteroaryls include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and quinoxalinyl. Polycyclic heteroaryls may comprise fused rings, covalently linked rings, or combinations thereof.

[0162] According to the present invention, the aromatic group may be substituted or unsubstituted.

[0163] The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one of which is aromatic; and the two rings may be fused or covalently linked.

[0164] As used in this article, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. "C1-C3 alkyl", "C1-C6 alkyl", "C1-C6 alkyl", "C1-C6 alkyl" are also used interchangeably. 10 "alkyl", "C2-C4 alkyl" and "C3-C6 alkyl" refer to alkyl groups containing one to three, one to six, one to ten, two to four, and three to six carbon atoms, respectively. Examples of C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl groups.

[0165] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group that has at least one carbon-carbon double bond by removing a single hydrogen atom. "C2-C" 10"Alkenyl", "C2-C8 alkenyl", "C2-C4 alkenyl" or "C3-C6 alkenyl" refer to alkenyl groups containing two to ten, two to eight, two to four or three to six carbon atoms, respectively. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0166] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group that has at least one carbon-carbon triple bond by removing a single hydrogen atom. "C2-C" 10 "Alynyl", "C2-C8 alynyl", "C2-C4 alynyl", or "C3-C6 alynyl" refer to alynyl groups containing two to ten, two to eight, two to four, or three to six carbon atoms, respectively. Representative alynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, and octyynyl.

[0167] As used herein, the term "cycloalkyl" refers to a fused, bridged, or spirocyclic system of monocyclic or polycyclic saturated carbocyclic, bicyclic, or tricyclic groups, wherein the carbon atom may optionally be substituted with an oxo group or optionally substituted with an exocyclic olefin, imine, or oxime double bond. Preferred cycloalkyl groups include C3-C64 groups. 12 Cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. C3-C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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]nonyl, etc.

[0168] As used herein, the term "cycloalkenyl" refers to a fused, bridged, or spirocyclic system of monocyclic or polycyclic carbocyclic, bicyclic, or tricyclic groups having at least one carbon-carbon double bond, wherein the carbon atom may optionally be substituted with an oxo or an exocyclic alkene, imine, or oxime double bond. Preferred cycloalkenyl groups include C3-C... 12 Cycloalkenyl, C3-C8 cycloalkenyl, or C5-C7 cycloalkenyl. C3-C 12 Examples of cycloalkenyl groups 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, etc.

[0169] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is attached to an aryl group, such as -CH2CH2-phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which an 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 a heteroaryl group is substituted.

[0170] As used herein, the term "alkoxy" alone or in combination with other terms, unless otherwise specified, refers to an alkyl group having a specified number of carbon atoms and connected to the remainder of the molecule by an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and more advanced homologues and isomers. Preferred alkoxy groups are (C1-C3) alkoxy groups.

[0171] It should be understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moieties described herein may also be aliphatic or alicyclic groups.

[0172] An "aliphatic" group is a non-aromatic moiety consisting of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, and optionally contains one or more unsaturated units, such as double and / or triple bonds. Examples of aliphatic groups are functional groups such as 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)2NH, etc., 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 substituted by functional groups. The carbon atoms of the aliphatic group may optionally be substituted with oxygen. The aliphatic group may be straight-chain, branched, cyclic, or a combination thereof, and preferably contains about 1 to about 24 carbon atoms, more typically about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, the aliphatic groups used herein explicitly include, for example, alkoxyalkyl, polyalkoxyalkyl (such as polyalkylene glycols), polyamines, and polyimides. The aliphatic group may optionally be substituted.

[0173] The term "carbocyclic" or "carbocyclic" refers to a cyclic group that is saturated, partially unsaturated, or aromatic, in which every atom within the ring is carbon. Examples of carbocyclic groups include cycloalkyl, cycloalkenyl, and aryl groups.

[0174] The terms “heterocyclic” or “heterocyclic alkyl” are used interchangeably to refer to a fused, bridged, or spirocyclic system of non-aromatic, bicyclic, or tricyclic groups, wherein (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 optionally be oxidized; (iv) the nitrogen heteroatom may optionally be quaternized; (v) any of the above rings may be fused with an aromatic ring; and (vi) the remaining ring atoms are carbon atoms, which may optionally be substituted with oxo or substituted with exocyclic olefins, imines, or oxime double bonds. Representative heterocyclic alkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolinyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolinyl, isoxazolinyl, morpholinyl, thiazolinyl, isothiazolinyl, quinoxolinyl, pyridazinoneyl, 2-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonyl, 7-oxooxepan-4-yl, and tetrahydrofuranyl. These heterocyclic groups can be further substituted. The heteroaryl or heterocyclic group can be C-linked or N-linked (if possible).

[0175] It should be understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc., described herein can also be a divalent or polyvalent group used as a bond connecting two or more groups or substituents, which may be on the same or different atoms. Those skilled in the art can readily determine the valence of any such group from the context in which it appears.

[0176] The term "substituted" refers to substitution achieved by independently replacing one, two, three, or more hydrogen atoms with a substituent, including but not limited to: -F, -Cl, -Br, -I, -OH, -Cl-C. 12 -alkyl; -C2-C 12 -Alkenyl, -C2-C 12 -alkynyl group, -C3-C 12 -cycloalkyl, protected hydroxyl, -NO2, -N3, -CN, -NH2, protected amino, oxo, thio, -NH-Cl-C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-ynyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Cl-C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-ynyl, -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-ynyl, -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-ynyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-ynyl, -OCO2-C3-C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 ynyl, CO2-C3-C 12 -cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12 -alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-ynyl, -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-ynyl, -NHC(O)-C3-C 12 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -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-ynyl, -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-ynyl, -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-ynyl, -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-ynyl, -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-ynyl, -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, -NHSO2-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-Cl-C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-ynyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. In some embodiments, the substituents are independently selected from halogens, 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 should be understood that aryl, heteroaryl, alkyl, etc., can be further substituted. In some cases, each substituent in the substituted moiety may optionally be additionally substituted by one or more groups, each group being independently selected from C1-C4-alkyl; -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN and -NH2.

[0177] In some embodiments, the substituted alkyl, alkenyl, or alkoxy group is 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.

[0178] The term “halogenated” or “halogen” as used in this article, whether used alone or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom.

[0179] As used herein, the term "optionally substituted" means that the mentioned group may be substituted or unsubstituted. In one embodiment, the mentioned group is optionally substituted with zero substituents, i.e., the mentioned group is unsubstituted. In another embodiment, the mentioned group is optionally substituted with one or more additional groups, which are individually and independently selected from the groups described herein.

[0180] The term "hydrogen" includes both hydrogen and deuterium. Furthermore, descriptions of atoms may include other isotopes of that atom, provided the resulting compound is pharmaceutically acceptable.

[0181] In some embodiments, compounds of the various forms herein are defined as compounds comprising isotope labeling. "Isotope-labeled compound" means a compound in which at least one atomic position is enriched with a specific isotope of a specified element to a level significantly higher than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound may be enriched with deuterium to a level significantly higher than the natural abundance of deuterium, for example, to at least 1%, preferably at least 20% or at least 50%. Such deuterated compounds may, for example, be metabolized more slowly than their non-deuterated analogues, and thus exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example by employing deuterated starting materials. Unless otherwise stated, isotope-labeled compounds are pharmaceutically acceptable.

[0182] As used herein, the term "hydroxyl-activating group" refers to an unstable chemical moiety of an activated hydroxyl group known in the art, such that it will leave during synthesis (e.g., in substitution or elimination reactions). Examples of hydroxyl-activating groups include, but are not limited to, methanesulfonates, toluenesulfonates, trifluoromethanesulfonates, p-nitrobenzoates, phosphonates, etc.

[0183] As used herein, the term "activated hydroxyl group" refers to a hydroxyl group activated by a hydroxyl-activating group as defined above (including, for example, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, p-nitrobenzoate, and phosphonate groups).

[0184] As used herein, the term "hydroxyl protecting group" refers to an unstable chemical moiety known in the art, used to protect hydroxyl groups from undesirable reactions during synthesis. Following the synthetic process, the hydroxyl protecting group, as described herein, can be selectively removed. Hydroxyl protecting groups known in the art are generally described in TH Greene and PGMUTS. Protective Groups in Organic Synthesis In the 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenylmethyl (triphenylmethyl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, etc.

[0185] As used herein, the term "protected hydroxyl group" refers to a hydroxyl group protected by a hydroxyl protecting group as defined above (including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl).

[0186] As used herein, the term "hydroxy prodrug group" refers to a precursor moiety known in the art that transiently alters the physicochemical properties of a parent drug by covering or masking a hydroxyl group, thereby changing its biological properties. Following the synthetic process, the hydroxy prodrug group, as described herein, must be able to revert to a hydroxyl group in vivo. Hydroxy prodrug groups known in the art are generally described in Kenneth B. Sloan's work. Prodrugs, Topical and Ocular Drug Delivery , (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992) and SS Dhareshwar and VJ Stella in Prodrugs Challenges and Rewards Part-2, In "Prodrugs of Alcohols and Phenols" in (Biotechnology: Pharmaceutical Aspects), edited by VJ Stella, et al, Springer and AAPSPress, 2007, pp 31-99.

[0187] As used herein, the term "amino protecting group" refers to an unstable chemical moiety known in the art, used to protect an amino group from undesirable reactions during synthesis. Following the synthetic process, the amino protecting group, as described herein, can be selectively removed. Amino protecting groups known in the art are generally described in TH Greene and PGMUTS. Protective Groups in Organic Synthesis In the 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, tert-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, etc.

[0188] As used in this article, the term "protected amino" refers to an amino group protected by an amino protecting group as defined above.

[0189] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom in a substitution reaction (such as a nucleophilic substitution reaction). Representative leaving groups include chlorine, bromine, and iodine groups; sulfonate groups, such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, etc.; and acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0190] As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to protons, 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 dichloromethane, dichloroethane, chloroform, etc.; heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidone; and ethers such as diethyl ether and dimethoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be apparent to them, for example, that for particular compounds and reaction conditions, depending on factors such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range, a single solvent or a mixture thereof may be preferred. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification , 4th ed., edited by John A. Riddick et al., Vol. II, included in Techniques of Chemistry Series , John Wiley & Sons, NY, 1986.

[0191] As used herein, the term "proton solvent" refers to a solvent that tends to provide protons, such as alcohols like methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to them, for example, that for a particular compound and reaction conditions, depending on factors such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range, a single solvent or a mixture thereof may be preferred. Further discussion of proton solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification , 4th ed., edited by John A. Riddick et al., Vol. II, included in Techniques of Chemistry Series , John Wiley & Sons, NY,1986.

[0192] The combinations of substituents and variables contemplated in this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" means a compound that possesses sufficient stability to allow its manufacture and to maintain its integrity for a period of time sufficient for its use for the purposes detailed herein (e.g., for therapeutic or prophylactic administration to a subject).

[0193] The synthesized compounds can be isolated from the reaction mixture and further purified by methods such as column chromatography, high-performance liquid chromatography, or recrystallization. Those skilled in the art will understand that other methods for synthesizing the compounds described herein will be readily apparent to those of ordinary skill in the art. Furthermore, various synthetic steps can be performed in an alternative sequence or order to obtain the desired compounds. Synthetic chemical transformations and protecting group methods (protection and deprotection) used to synthesize the compounds described herein are known in the art and include, for example, R. Larock, Comprehensive Organic Transformations , 2nd Ed. Wiley-VCH (1999); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd Ed., John Wiley and Sons (1999);L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis Those described in John Wiley and Sons (1995) and subsequent editions.

[0194] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subjects also refer to animals such as dogs, cats, horses, cattle, pigs, guinea pigs, fish, and poultry.

[0195] 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 may include modifications that increase biopermeability into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow for injection administration, alter metabolism, and change excretion rates.

[0196] The compounds described herein contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers, which can be defined according to absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This invention aims to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described above, or by resolving racemic mixtures. Resolution can be carried out in the presence of a resolving agent, by chromatography, by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution can be found in Jacques, et al. Enantiomers, Racemates, and Resolutions(Found in John Wiley & Sons, 1981). When the compounds described herein contain alkene double bonds, other degrees of unsaturation, or other geometrically asymmetric centers, it is intended that the compounds include E and Z geometric isomers or cis and trans isomers, unless otherwise stated. Similarly, all forms of tautomerism are intended to be included. Tautomers can be cyclic or acyclic. Any configuration of carbon-carbon double bonds appearing herein is chosen for convenience only and is not intended to specify a particular configuration unless otherwise stated in the text; therefore, any carbon-carbon double bond or carbon-heteroatom double bond arbitrarily depicted herein as trans can be cis, trans, or a mixture of both in any proportion.

[0197] Some compounds of the present invention may also exist in different stable conformations, which may be separable. Torsional asymmetry resulting from rotational restriction around asymmetric single bonds (e.g., due to steric hindrance or ring strain) may allow for the separation of different conformational isomers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0198] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. 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 a free base functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to: non-toxic acid addition salts formed by amino groups 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 salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enzyme, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, papoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0199] Pharmaceutically acceptable salts can also be prepared by deprotonating the parent compound with a suitable base, thereby forming the anionic conjugate base of the parent compound. In these salts, the counter ion is a cation. Suitable cations include ammonium and metal cations, such as alkali metal cations, including Li. + Na + K + and Cs + and alkaline earth metal cations, such as Mg 2+ and Ca 2+.

[0200] As used herein, the term "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo, including those that readily break down in the human body, leaving behind a parent compound or its salts. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly those of alkyl, olefinic, cycloalkyl, and alkyl diacids, wherein each alkyl or alkenyl moiety advantageously has no more than six carbon atoms. Examples of specific esters include, but are not limited to, esters of C1-C6-alkyl acids, such as acetates, propionates, butyrates, and pivalates.

[0201] In some embodiments, the present invention provides pharmaceutically acceptable prodrugs of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable prodrug" refers to those prodrugs of compounds formed by the methods of the present invention that, within reasonable medical judgment, are suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and are effective for their intended use; and the zwitterionic form of the compounds of the present invention (if possible). As used herein, "prodrug" refers to a compound that is converted in vivo by metabolic means (e.g., by hydrolysis) to provide any compound defined by the various forms of the present invention. Various forms of prodrugs are known in the art, for example in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.), 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 This is discussed in “Metabolism: Chemistry, Biochemistry and Enzymology,” John Wiley and Sons, Ltd. (2002).

[0202] Other types of prodrugs are also included. For example, the free carboxyl group can be derived into an amide or alkyl ester. The free hydroxyl group can be derivatized using groups including, but not limited to, hemisuccinates, ethylsuccinates, phosphate esters, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl groups, as described in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs with hydroxyl and amino groups are also included, as are carbonate prodrugs with hydroxyl groups, sulfonates, and sulfates. Hydroxyl derivatization into (acyloxy)methyl and (acyloxy)ethyl ethers is also included, wherein the acyl group can be an alkyl ester, optionally substituted with a group including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. Such prodrugs are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derived into amides, sulfonamides, or phosphoramides. All these prodrug moieties can contain groups including, but not limited to, ether, amine, and carboxylic acid functional groups. In some embodiments, the compounds of the present invention may contain two or more groups that are metabolically removed in vivo to produce an active parent compound.

[0203] As used in this article, the term "treatment" refers to relief, mitigation, reduction, elimination, regulation, or improvement, that is, causing the remission of a disease state or symptom. Treatment may also include suppression, that is, preventing the development of an existing disease state or symptom, and relief or improvement, that is, causing the remission of an existing disease state or symptom, for example, when a disease state or symptom is already present.

[0204] As used in this article, “prevention” means the complete or near-complete prevention of a disease state or condition from occurring in a patient or subject, particularly when the patient or subject is susceptible to such a disease or condition or at risk of contracting a disease state or condition.

[0205] Furthermore, the compounds of the present invention, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms, or as solvates of other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0206] A solvate is a solvent addition form containing stoichiometric or non-stoichiometric solvents. Some compounds tend to capture a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcohol. Hydrates are formed by the combination of one or more water molecules with a substance, where the water retains its molecular state as H₂O; this combination can form one or more hydrates.

[0207] As used herein, the term "analog" refers to a chemical compound that has a structure similar to another but differs slightly in composition (e.g., by replacing an atom with an atom of a different element, by the presence of a specific functional group, or by replacing one functional group with another). Therefore, an analog is a compound that is similar or equivalent to the reference compound in function and appearance.

[0208] The combinations of substituents and variables contemplated in this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" means a compound that possesses sufficient stability to allow its manufacture and to maintain its integrity for a period of time sufficient for its use for the purposes detailed herein (e.g., for therapeutic or prophylactic administration to a subject).

[0209] The synthesized compounds can be isolated from the reaction mixture and further purified by methods such as column chromatography, high-performance liquid chromatography, or recrystallization. Furthermore, the various synthetic steps can be performed in an alternative sequence or order to obtain the desired compounds. Additionally, the solvents, temperatures, reaction durations, etc., described herein are for illustrative purposes only; variations in reaction conditions can produce the bridging macrocyclic products desired in this invention. Synthetic chemical transformations and protecting group methods (protection and deprotection) used to synthesize the compounds described herein include, for example, R. Larock... Comprehensive Organic Transformations , VCHPublishers (1989); TW Greene and PGM Wuts, 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 Those described in John Wiley and Sons (1995).

[0210] The compounds of the present invention can be modified by adding various functional groups using the synthetic methods described herein to enhance their selective biological properties. Such modifications include those that increase biopermeability into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow for injection administration, alter metabolism, and change excretion rates.

[0211] Pharmaceutical Compositions

[0212] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of the compound of the present invention formulated with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulation material, or formulation adjuvant. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic, compatible lubricants such as sodium lauryl sulfate and magnesium stearate. Colorants, release agents, coating agents, sweeteners, flavorings, and fragrances, as well as preservatives and antioxidants, may also be present in the composition at the discretion of the formulator. The pharmaceutical compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, intravaginally, intraperitoneally, topically (e.g., powder, ointment or drops), buccally, or as oral or nasal sprays.

[0213] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implanted receptacle, preferably orally or by injection. The pharmaceutical compositions of the present invention may contain any conventional, non-toxic, pharmaceutically acceptable carrier, adjuvant, or excipient. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. The term parenterally as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0214] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof. Besides inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0215] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable excipients and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (such as oleic acid) are used in the preparation of injections.

[0216] Injectable formulations can be sterilized, for example, by filtering through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0217] To prolong the action of a drug, it is generally desirable to slow its absorption after subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms is achieved by dissolving or suspending the drug in an oily excipient. Injectable reservoir forms are prepared by forming a microcapsule matrix of the drug within a biodegradable polymer, such as polylactic acid-polyglycolic acid. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0218] Compositions for rectal or vaginal application are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers (such as cocoa butter, polyethylene glycol, or suppository waxes) that are solid at ambient temperature but liquid at body temperature, thus melting and releasing the active compound in the rectal or vaginal cavity.

[0219] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffers.

[0220] Similar solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0221] The active compound can also be present in the form of microcapsules, with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells (such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation). In these solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Such dosage forms may also conventionally contain substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain buffers. They may optionally contain light-blocking agents and may be compositions that release only or preferentially release the active ingredient, optionally in a delayed manner, in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes.

[0222] Dosage forms for topical or transdermal application of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers that may be necessary. Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of this invention.

[0223] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0224] In addition to the compounds of this invention, the powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The aerosols may also contain conventional propellants such as chlorofluorocarbons (CFCs).

[0225] Transdermal patches offer the added advantage of controlled delivery of compounds to the body. These dosage forms can be made by dissolving or dispersing 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-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0226] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are incorporated herein by reference in their entirety.

[0227] abbreviation

[0228] The abbreviations used in the description of the following schemes and embodiments are as follows:

[0229] ACN stands for acetonitrile;

[0230] AD-mix-β represents (9S)-(9''S)-9,9''-[1,4-phthalazinediylbis(oxy)]bis[10,11-dihydro-6'-methoxycinchonan] ((9S)-(9''S)-9,9''-[1,4-Phthalazinediylbis(oxy)]bis[10,11-dihydro-6'-methoxycinchonan]).

[0231] Bn represents benzyl;

[0232] BOP stands for (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate;

[0233] BzCl represents benzoyl chloride;

[0234] mCPBA represents m-chloroperoxybenzoic acid;

[0235] Cbz represents benzyloxycarbonyl;

[0236] CDI stands for carbonyl diimidazole;

[0237] DAST stands for diethylaminosulfur trifluoride;

[0238] DBU stands for 1,8-diazabicycloundec-7-ene;

[0239] DCE stands for dichloroethane;

[0240] DCM stands for dichloromethane;

[0241] Dess-Martin periodinane represents 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzoiodocyclopentan-3-(1H)-one;

[0242] DIAD stands for diisopropyl azodicarbonate;

[0243] DIBAL-H represents diisobutylaluminum hydride;

[0244] DMAP stands for N,N-dimethylaminopyridine;

[0245] DME stands for 1,2-dimethoxyethane;

[0246] DMF stands for N,N-dimethylformamide;

[0247] DMSO stands for dimethyl sulfoxide;

[0248] DPPA stands for diphenylphosphoazide or diphenylphosphoazide ester;

[0249] dppf represents 1,1'-bis(diphenylphosphine)ferrocene;

[0250] EDCI or EDC represents 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0251] EA or EtOAc represents ethyl acetate;

[0252] Ghosez's reagent represents 1-chloro-N,N,2-trimethyl-1-propenylamine;

[0253] HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate;

[0254] HCl represents hydrochloric acid;

[0255] Hunig's base represents diisopropylethylamine;

[0256] PyBOP represents (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate;

[0257] LDA stands for lithium diisopropylamine.

[0258] Pd-C indicates palladium on carbon;

[0259] PE stands for petroleum ether;

[0260] Ph represents phenyl;

[0261] RT stands for reverse transcription;

[0262] RT-PCR represents reverse transcription polymerase chain reaction;

[0263] TBME stands for tert-butyl methyl ether;

[0264] TEA stands for triethylamine;

[0265] TF2O represents trifluoromethanesulfonic anhydride;

[0266] TFA stands for trifluoroacetic acid;

[0267] THF stands for tetrahydrofuran;

[0268] (TMS)2NH represents hexamethyldisilazane;

[0269] TBS stands for tert-butyldimethylsilyl;

[0270] TBDPS stands for tert-butyldiphenylsilyl;

[0271] TMS stands for trimethylsilyl;

[0272] TPAP stands for tetrapropylammonium perruthenate;

[0273] TPP or PPh3 represents triphenylphosphine;

[0274] Ts or p-toluenesulfonyl group represents p-CH3C6H4SO2-;

[0275] tBOC or Boc represents tert-butoxycarbonyl; and

[0276] Xantphos represents 4,5-bis-diphenylphosphino-9,9-dimethyl-9H-oxanthracene.

[0277] Synthetic Methods

[0278] The compounds and processes of the present invention will be better understood in conjunction with the synthetic schemes described below for preparing the compounds of the present invention. These synthetic schemes are for illustrative purposes only and do not limit 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 can be made without departing from the spirit of the invention and the scope of the appended claims, including but not limited to those relating to the chemical structure, substituents, derivatives, and / or methods of the present invention.

[0279] Scheme 1 describes a method for preparing compound 11 from compounds 1 and 2, where n = 1, 2, or 3; P is a hydroxyl protecting group; Ar is E; and E is as previously defined. Using Mitsunobu reaction conditions, hydroxypyridine 1 is alkylated with a hydroxy epoxide to give epoxide 4. Alternatively, the hydroxy epoxide is converted to 3, which has leaving groups (e.g., but not limited to p-toluenesulfonyl and methanesulfonyl), followed by alkylation in the presence of a base (e.g., but not limited to K₂CO₃ and Cs₂CO₃) to provide 4. Intramolecular ring-opening of the epoxide mediated by a base (e.g., but not limited to LDA) yields compound 5. Protecting the hydroxyl group of compound 5 with a suitable protecting group (e.g., but not limited to TBDPS and TBS) gives compound 6. Trifluoromethyl ketone 7 is obtained by iodine-magnesium exchange of compound 6 followed by the addition of an ester (e.g., but not limited to ethyl 2,2,2-trifluoroacetate). Trifluoromethyl ketone 7 undergoes cross-coupling with various metal coupling partners 8 (including but not limited to boric acid, borate esters, organotin reagents, organozinc reagents, organomagnesium reagents, organosilicon reagents, etc.) under the catalysis of suitable Pd, Ni, Cu, or similar catalysts to yield compound 9. Nitromethane is added to compound 9 in the presence of a base (e.g., but not limited to K₂CO₃ and Cs₂CO₃) to yield compound 10. The nitro group is reduced with a reducing agent (e.g., but not limited to zincic acid and acetic acid) to produce the key intermediate 11.

[0280]

[0281] As shown in Scheme 2, where Ar1 is A; Ar is E; R is R 11 n is 1, 2, or 3; and A, E, R 11 As defined above. Key intermediate 11 is coupled with various carboxylic acids to yield amide 14. Amide 14 then reacts with various electrophilic agents to produce various ethers, esters, and carbamates of formula 15. Amide 14 is also oxidized to aldehyde 16, followed by reductive amination to provide various amines 17. The -CH2OH hydroxyl group in amide 14 is activated and subsequently cyanidated to convert to cyanomethyl 18. Compound 14-1 is further converted to acetamide 19 in the presence of a catalyst (e.g., but not limited to Parkin catalyst).

[0282]

[0283] As shown in Scheme 3, where Ar1 is A; Ar is E; and R is R. 11 ; and A, E, R 11 As defined above. Aldehyde 16 is converted to a benzyl-protected amine via reductive amination. Hydrogenolysis yields free amine 20. Finally, substitution with various electrophilic reagents yields N-substituted compound 21.

[0284]

[0285] As shown 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 defined above. After aldehyde 16 is oxidized to acid 22, it is further converted to amide 23 and sulfonamide 24 using common methods (e.g., but not limited to HATU and DIPEA). This diversification yields various esters and amides.

[0286]

[0287] Scheme 5 describes another method for preparing compound 11, where Ar is E; P is a hydroxyl protecting group; n is 1, 2, or 3; and E is as previously defined. Ketone 9 is converted to compound 26 via olefination. Alternatively, 26 is obtained by: 1) cross-coupling 6 with a metal coupling partner 6-1 (which may be, but is not limited to, boric acid, borate ester, organotin reagent, organozinc reagent, organomagnesium reagent, organosilicon reagent, etc.) under the catalysis of a suitable Pd, Ni, Cu, or similar catalyst to obtain compound 25; 2) converting compound 25 to compound 26 according to the method previously described in Scheme 1. After obtaining 26, compound 27 is prepared by dihydroxylation followed by the formation of an epoxide. The epoxide of compound 27 is ring-opened with an amine equivalent (e.g., but not limited to NH4OH and NH3) to provide compound 11.

[0288]

[0289] Scheme 6 describes another method for preparing compound 23, wherein 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. Amine 11 is protected with a protecting group (e.g., but not limited to Boc and Cbz). After the hydroxyl protecting group is deprotected, an oxidation reaction is subsequently carried out to provide acid 30. Compound 30 is coupled with various amines to provide amide 31. The amine protecting group is deprotected, and an amide is subsequently formed to provide compound 23.

[0290]

[0291] Scheme 7 illustrates an alternative route for synthesizing the desired compound. The difference lies in that it introduces amide 33 at the start of the synthesis via oxidation and amide coupling. Successive vinylation and arylation provide the bicoupled product 34. Asymmetric dihydroxylation, followed by activation and substitution, provides an amino alcohol precursor. Finally, amide coupling with the corresponding arylic acid yields the desired compound, represented by compound 36.

[0292] .

[0293] Examples

[0294] The compounds and processes of the present invention will be better understood in conjunction with the following examples, which are illustrative only and do not limit 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 can be made without departing from the spirit of the invention and the scope of the appended claims, including but not limited to those relating to the chemical structure, substituents, derivatives, formulations, and / or methods of the invention.

[0295] Certain synthetic procedures useful in the preparation of the compounds of this invention are disclosed in U.S. Patent Application No. 16 / 930,622, the contents of which are incorporated herein by reference in their entirety.

[0296] Intermediate 1

[0297]

[0298] Intermediate 1, steps a and b

[0299]

[0300] 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. ESI-MS m / z: 217.95 [M+H] + .

[0301] A solution of the compound from step a (10 g, 46.03 mmol) in MeOH (100 mL) was treated at 0 °C with SOCl2 (10 mL, 137.86 mmol). 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 mixture 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. ESI-MS m / z: 232.00 [M+H] + .

[0302] Intermediate 1, steps c and d

[0303]

[0304] The mixture of the methyl compound (3.9 g, 16.86 mmol) and m-CPBA (8.73 g, 50.59 mmol) from step b in DCM (20 mL) was stirred overnight at room temperature. The reaction was quenched with saturated sodium thiosulfate (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (15:1) to give the desired product (2.6 g, 62%) as a yellow solid. ESI-MS m / z: 248.05 [M+H] + .

[0305] A solution of the 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. ESI-MS m / z: 266.00 [M+H] + .

[0306] Intermediate 2

[0307]

[0308] Intermediate 2, steps a and b

[0309]

[0310] 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 at 100ºC for 1 hour under a nitrogen atmosphere. The resulting solution was concentrated to obtain the desired product (crude product), which was a brown solid. ESI-MS m / z: 282.00 [M+H] + .

[0311] The solution of the compound from step a (10 g, 35.45 mmol) and H₂SO₄ (10 mL) in MeOH (30 mL) was stirred at 80 °C for 2 hours. The mixture / residue was neutralized to pH 7–8 with NaHCO₃. The resulting mixture was extracted with EA (x3). 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. ESI-MS m / z: 296.00 [M+H] + .

[0312] Intermediate 2, steps c and d

[0313]

[0314] The 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 at 80 °C for 2 hours. 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. ESI-MS m / z: 346.00 [M+H] + .

[0315] The compound from step c (800 mg, 2.31 mmol) and LiOH (553 mg, 23.11 mmol) in a solution / mixture of MeOH (10 mL) and H₂O (10 mL) were stirred at room temperature for 6 hours under a N₂ atmosphere. The crude product was recrystallized from MeOH / H₂O to give the desired product (500 mg, 65%) as a yellow solid. ESI-MS m / z: 332.00 [M+H] + .

[0316] Intermediate 3

[0317]

[0318] Intermediate 3, Step a

[0319]

[0320] Add 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (500 mg, 2.153 mmol), toluene (4.98 ml), and MeOH (2.99 ml) to a 100 mL round-bottom flask (rbf), and then cool to 0 °C in an ice bath. Add TMS-diazomethane (2.8 mL, 5.60 mmol) dropwise manually over 10 minutes. Stir the mixture for 1 hour, then quench the diazo reagent by adding AcOH until the yellow color of the diazo reagent fades. Concentrate the mixture and use it directly for the next step. ESI-MS m / z: 247.213 [M+H] + .

[0321] Intermediate 3, Step b

[0322]

[0323] Methyl 2-cyclopropyl-7-hydroxy-2H-indazole-5-carboxylic acid (529 mg, 2.15 mmol), tetrabutylammonium iodide (1.032 g, 2.80 mmol), and CH₂Cl₂ (21.5 mL) were added to a 100 mL round-bottom flask equipped with a stir bar. The mixture was cooled to -78 °C, and boron trichloride (5.38 mL, 5.38 mmol) was added dropwise over 10 minutes. The mixture was stirred at -78 °C for 1 hour, then allowed to rise to 0 °C in an ice bath and stirred for 1 hour. The mixture was then diluted with water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The aqueous layer was washed with EtOAc (4 x 50 mL). The combined organic matter was washed with brine, dried over Na₂SO₄, 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). ESI-MS m / z: 233.201 [M+H] + .

[0324] Intermediate 3, Step c

[0325]

[0326] 2-Cyclopropyl-7-hydroxy-2H-indazole-5-carboxylic acid (0.499 g, 2.15 mmol), cesium carbonate (1.401 g, 4.30 mmol), and DMF (21.50 mL) were added to a 100 mL round-bottom flask, followed by sodium dichlorofluoroacetate (0.656 g, 4.30 mmol). The mixture was heated to 105 °C and held for 6 hours, 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). ESI-MS m / z: 283.160 [M+H] + .

[0327] Intermediate 3, Step d

[0328]

[0329] 2-Cyclopropyl-7-(difluoromethoxy)-2H-indazole-5-carboxylic acid methyl ester (174 mg, 0.616 mmol), dissolved in MeOH (2.055 ml), THF (2.055 ml), and water (2.055 ml), was added to a 20 mL vial. The mixture was freshly ground and lithium hydroxide (78 mg, 1.849 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was then carefully acidified by adding 1 M HCl. The mixture was diluted with water and EtOAc. The aqueous layer was washed with EtOAc (3 x 5 mL), and the combined organic layers were washed with brine. The mixture was then concentrated to give the desired product as a white solid (147.6 mg, 89% yield). ESI-MS m / z: 269.145 [M+H] + .

[0330] Intermediate 4

[0331]

[0332] Intermediate 4, Step a

[0333]

[0334] Add 20 mL of 3-chloro-8-methoxy-2-methylquinoline-6-carboxylic acid (200 mg, 0.795 mmol), toluene (1.84 mL), and MeOH (1.104 mL) to a 20 mL vial, then cool to 0 °C in an ice bath. Add TMS-diazomethane (1.0 mL, 2.07 mmol) dropwise manually over 10 minutes. Stir the mixture for 1 hour, then quench the diazo reagent by adding AcOH until the yellow color of the diazo reagent disappears. Concentrate the mixture to give the desired product (48 mg, 95%) as a yellow solid. ESI-MS m / z: 266.091 [M+H] + .

[0335] Intermediate 4, Step b

[0336]

[0337] 0.211 g (0.795 mmol) of methyl 3-chloro-8-methoxy-2-methylquinoline-6-carboxylate was added to an 8 mL vial, followed by the addition of D₂O (1.125 mmol). The mixture was heated to 100 °C and maintained for 18 hours. The mixture was then cooled to room temperature and diluted with EtOAc. The phases were separated, and the organic layer was washed with NaHCO₃ (3 x 1 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by combiflash to give the desired product as a yellow solid (10⁵ mg, 34% yield). ESI-MS m / z: 269.156 / 271.135 [M+H] + .

[0338] Intermediate 4, Step c

[0339]

[0340] 100 mg (0.372 mmol) of methyl 3-chloro-8-methoxy-2-(methyl-d3)quinoline-6-carboxylic acid was added to a 20 mL vial in water (1.240 mL), THF (1.240 mL), and methanol (1.240 mL). The mixture was then freshly ground and lithium hydroxide (26.7 mg, 1.116 mmol) was added. The mixture was stirred for 1 hour, diluted with 10% MeOH in DCM solution, and then carefully acidified by adding 1 M HCl. The phases were separated, and the aqueous layer was washed with 10% MeOH in DCM solution. The combined organic phases were concentrated to give the desired product as a white solid (87 mg, 92% yield). ESI-MS m / z: 255.163 / 257.175 [M+H] + .

[0341] Intermediate 5

[0342]

[0343] Add 3-bromo-8-methoxy-2-methylquinoline-6-carboxylic acid to an 8 mL vial, suspend it in 0.7 mL of D₂O, and then heat to 100 °C and maintain for 18 hours. The crude substance was lyophilized without further purification and used as a yellow solid (48 mg, 95%). ESI-MS m / z: 299.033 / 300.961 [M+H] + .

[0344] Intermediate 6

[0345]

[0346] Intermediate 6, Step a

[0347]

[0348] In a dry vial equipped with a stir bar, methyl 2-chloro-8-methoxy-3-methylquinoline-6-carboxylic acid (250 mg, 0.941 mmol) was dissolved in DMF (1.9 mL), and anhydrous Me4NF (175 mg, 2.0 equivalent) was added. The vial was sealed and heated to 80 °C overnight. The reaction mixture was then cooled to room temperature, diluted with DCM, 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, contaminated with some chloride starting material (48 mg, 20%). ESI-MS m / z: 250.134 [M+H] + .

[0349] Intermediate 6, Step b

[0350]

[0351] In a 1-dextrose vial, methyl 2-fluoro-8-methoxy-3-methylquinoline-6-carboxylic acid (48 mg, 0.18 mmol, 1.0 equivalence) 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 equivalence) was added, and the mixture was stirred for 15 min, then the cooling bath was removed. After 2 hours at room temperature, the mixture was acidified to pH approximately 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%). ESI-MS m / z: 236.16 [M+H]+ .

[0352] Intermediate 7

[0353]

[0354] Intermediate 7, Step a

[0355]

[0356] The above compound was prepared from methyl 3-bromo-2-chloro-8-methoxyquinoline-6-carboxylate according to the following procedure: HCl (4M, in 1,4-dioxane, 0.34 mL, 1.34 mmol, 1.0 equivalent) was added to a suspension of methyl 3-bromo-2-chloro-8-methoxyquinoline-6-carboxylate (443 mg, 1.34 mmol, 1.0 equivalent) in DCM (5 mL), and the mixture was stirred at room temperature for 5 minutes. The solvent was then removed under vacuum, and the residue was suspended in MeCN (6.7 mL). NaI (1.0 g, 6.7 mmol, 5.0 equivalent) was then added, the vial was sealed, and the mixture was heated to 80 °C and maintained for 3 hours. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was redissolved in DCM, and the organic solution was washed successively with 10% K2CO3 aqueous solution 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%). ESI-MS m / z: 423.93 [M+H] + .

[0357] Intermediate 7, Step b

[0358]

[0359] In a dry vial equipped with a stir bar, methyl 3-bromo-2-iodo-8-methoxyquinoline-6-carboxylic acid (75 mg, 0.18 mmol, 1.0 equivalent) was suspended in THF (0.5 mL) and Et₂O (0.5 mL), and the mixture was cooled to 0 °C. Magnesium isopropyl chloride (0.11 mL, 0.22 mmol, 1.2 equivalent) was added, and the reaction mixture was stirred at this temperature for 1 hour, then quenched dropwise by the addition of CD₃OD (0.6 mL, 14.8 mmol, 15 equivalent). The mixture was stirred again at room temperature for 15 minutes, then poured into a saturated aqueous solution of ammonium chloride. The quenched reaction mixture was diluted with water and DCM, and the layers were separated. The aqueous layer was extracted three times with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude substance was purified by automated column chromatography (silica gel) to give the deuterated product methyl 3-bromo-8-methoxyquinoline-6-carboxylic acid ester-2-D as a white solid (9.0 mg, 17%). ESI-MS m / z: 297.06 [M+H] + .

[0360] Intermediate 7, Step c

[0361]

[0362] In a 1-duralumin vial equipped with a stir bar, methyl 3-bromo-8-methoxyquinoline-6-carboxylic acid ester-2-D (white solid, 9.0 mg, 1.0 equivalent, 0.032 mmol) was dissolved in THF (0.1 mL), MeOH (0.1 mL), and water (0.1 mL). LiOH (7 mg, 0.30 mmol, 10 equivalent) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was then acidified to approximately pH 2 with 2 M HCl and concentrated directly to give the carboxylic acid, which was ready for use without further purification (8.0 mg, 93%). ESI-MS m / z: 283.05 [M+H] + .

[0363] Intermediate 8

[0364]

[0365] The above compound was prepared from 8-methoxy-2-methyl-3-(methyl-d3)quinoline-6-carboxylic acid using a method similar to step X in Example X, yielding a hexadeuterated compound as an orange solid (27 mg, 96%). ESI-MS m / z: 238.16 [M+H] + .

[0366] Intermediate 9

[0367]

[0368] Intermediate 9, Step a

[0369]

[0370] A mixture of (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), 2-(1-(4-fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (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 for 2 hours under nitrogen atmosphere. 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 (eluting with hexane solution of 50% ethyl acetate) to give the desired product (1.97 g, 75 wt%, 75%) as a red oil. ESI-MS m / z: 377.06 [M+H] + .

[0371] Intermediate 9, Step b

[0372]

[0373] The compound from step a (1 g, 2.25 mmol), 2-(2,3-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (0.82 g, 2.82 mmol), Pd(dppf)Cl2 (0.165 g, 0.225 mmol), and K2CO3 (0.70 g, 5.07 mmol) were stirred in dioxane (9 mL) and H2O (2.25 mL) under a nitrogen atmosphere at 90 °C for 2 hours. The reaction was cooled to room temperature, and the mixture was diluted with EtOAc and saturated ammonium chloride. The aqueous layer was extracted with EtOAc, combined, dried over sodium sulfate, filtered, and concentrated. The crude substance was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in cyclohexane solution) to give the desired product (1.50 g, 80% wt, 87%) as a red oil. ESI-MS m / z: 461.12 [M+H] + .

[0374] Intermediate 9, Step c

[0375]

[0376] The solution of the compound from step b (1.5 g, 3.38 mmol) in t-BuOH (17 mL) and H₂O (17 mL) was cooled to 0ºC. Methanesulfonamide (0.64 g, 6.77 mmol) and AD-mix-β (13.18 g, 16.92 mmol) were added, and the reaction was stirred overnight at room temperature and monitored by LCMS. The reaction was cooled to room temperature, the mixture was diluted with EtOAc and quenched with sodium sulfite. The aqueous layer was extracted with EtOAc, combined, dried over sodium sulfate, filtered, and concentrated. The crude substance was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in cyclohexane) to give the desired product (1.0 g, 60%) as a yellow solid. ESI-MS m / z: 495.09 [M+H] + .

[0377] Intermediate 9, Step d

[0378]

[0379] The compound from step c (1.0 g, 2.01 mmol) in DCM (11 mL) solution 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 product was concentrated and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in cyclohexane) to give the desired product (1.6 g, 70% wt, 85%) as a yellow solid. ESI-MS m / z: 649.10 [M+H] + .

[0380] Intermediate 9, Step e

[0381]

[0382] To a 250 mL round-bottom flask containing the product from step d (1.6 g, 3.04 mmol), NH3 (55 mL, 156 equivalents, 7N in MeOH) was added at room temperature. The resulting mixture was stirred at room temperature for 20 hours and monitored by LCMS. The solvent was removed, and the crude mixture was dissolved in EtOAc. The organic matter was washed three times with saturated sodium bicarbonate and concentrated. The crude matter was milled with DCM to give the desired product (425 mg, 35%) as a grayish-white solid. ESI-MS m / z: 494.11 [M+H] + .

[0383] Intermediate 10

[0384]

[0385] The above compound was prepared in a similar manner to intermediate 9. ESI-MS m / z: 478.17 [M+H] + .

[0386] Intermediate 11

[0387]

[0388] The above compound was prepared in a similar manner to intermediate 9. ESI-MS m / z: 470.17 [M+H] + .

[0389] Intermediate 12

[0390]

[0391] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (133 mg, quant. yield). ESI-MS m / z: 440.13 [M+H] + .

[0392] Intermediate 13

[0393]

[0394] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (158 mg, quantitative yield). ESI-MS m / z: 522.18 [M+H] + .

[0395] Intermediate 14

[0396]

[0397] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (170 mg, quantitative yield). ESI-MS m / z: 528.27 [M+H] + .

[0398] Example 1

[0399]

[0400] Add (R)-5-((S)-2-amino-1-cyclopropyl-1-hydroxyethyl)-7-(5-chloro-2,4-difluorophenyl)-3-methyl-2,3-dihydrofuran[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) to a 20 mL vial equipped with a stir bar. Dissolve the solid in DMF (0.20 mL) and add DIPEA (18.54 µl, 0.106 mmol). Cool the vial to 0ºC and add PyBOP (22.10 mg, 0.042 mmol). Stir the reaction for 10 min, heat to room temperature, and monitor by LCMS (1 h). After completion, dilute the reactants with EtOAc and quench with saturated ammonium chloride. The aqueous layer was extracted with EtOAc, collected and concentrated using a phase separation column. The crude material was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), the fraction was concentrated using a Biotage V10 evaporator, and the material was lyophilized to give a fluffy white solid (13 mg, 53%) as the desired product. ESI-MS m / z: 677.20 [M+H] + .

[0401] Table 1 below contains examples prepared using methods similar to those in Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel). Aromatic acid coupling couplers were prepared according to intermediates 1-14, or by similar procedures with slight modifications, also according to the procedure in U.S. Patent Application No. 17 / 679,746.

[0402] Table 1

[0403]

[0404]

[0405]

[0406]

[0407]

[0408] Intermediate 15

[0409]

[0410] Intermediate 15, steps a and b

[0411]

[0412] Add 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentane (6.33 g, 32.6 mmol), the oil dissolved in 1,4-dioxane (104 mL), to a 250 mL round-bottom flask. Add (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (10 g, 26.1 mmol), followed by PdCl2(dppf) (1.91 g, 2.61 mmol) and water (26.1 mL). Then add potassium carbonate (10.83 g, 78 mmol). The round-bottom flask is equipped with a condenser, the system is purged with N2, and the reaction is heated to 90ºC and maintained for 2 hours. Cool the reaction to room temperature, and dilute the mixture with EtOAc and saturated ammonium chloride. The aqueous layer was extracted with EtOAc, the extracts were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in cyclohexane solution) to obtain the desired product (10.38 g, 70% wt, 86%) as a red oil. ESI-MS m / z: 323.20 [M+H] + .

[0413] A mixture of (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (3.90 g, 12.07 mmol), K₂O₅sO₄·2H₂O (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) was stirred overnight at room temperature. The reaction was quenched by adding Na₂S₂O₃ (20 mL) at room temperature. The aqueous layer was extracted with EA (3 × 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. ESI-MS m / z: 356.90 [M+H] + .

[0414] Intermediate 15, steps c and d

[0415]

[0416] A solution of the 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 hours. The mixture was acidified to pH 7–8 with HCl. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with water (3 x 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. ESI-MS m / z: 510.90 [M+H] + .

[0417] A solution of the compound from step c (3 g, 5.87 mmol) in MeOH (3 mL) was added dropwise to a stirred solution of NH3 (g) in MeOH (200 mL) at room temperature. The mixture was stirred at room temperature for 20 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, and concentrated to give the desired product (2 g, 96%) as a white solid. ESI-MS m / z: 355.95 [M+H] + .

[0418] Intermediate 15 Step e

[0419]

[0420] The 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 reversed-phase rapid chromatography to the title compound (1 g, 86%) as a white solid. ESI-MS m / z: 570.30 [M+H] + .

[0421] Intermediate 16

[0422]

[0423] The above compound was prepared using a method similar to that used for intermediate 15 and purified by automated column chromatography (silica gel) to give pyridyl bromide as a white solid (812 mg, 85%). ESI-MS m / z: 610.02 [M+H] + .

[0424] Example 47

[0425]

[0426] 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-carboxamido)-1-hydroxyethyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (40 mg, 0.070 mmol) were added to a 2-darabin vial equipped with a stir bar. The vial was purged with N2, and the solids were dissolved in 1,4-dioxane (0.28 mL) and water (0.07 mL). The reaction was heated to 90ºC and monitored by LCMS (1 h). The reaction was cooled to room temperature, filtered through a silica gel pad using EtOAc, and concentrated. The crude substance was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min) to separate diastereomers. The fraction was concentrated using a Biotage V10 evaporator, and the substance was lyophilized to give a fluffy white solid (6 mg, 13%) as the desired product. ESI-MS m / z: 634.31 [M+H] + .

[0427] Table 2 below contains examples prepared using intermediates 15-16 or their analogues, using a method similar to that of Example 47. If necessary to promote conversion, more palladium and boric acid were added. Most compounds were purified and diastereomers separated by preparative HPLC (ACN / H2O, 20-90%, 25 min). If reported as a mixture of diastereomers, they may not be separable by HPLC.

[0428] Table 2

[0429]

[0430]

[0431]

[0432] Intermediate 17

[0433]

[0434] Intermediate 17 Step a

[0435]

[0436] A solution of 2,2-difluoro-1,3-benzodioxane-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. ESI-MS m / z: 253.80 [M+H] + .

[0437] Intermediate 17, Step b

[0438]

[0439] 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) at 55 °C for 10 min under a nitrogen atmosphere, followed by dropwise addition of the 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. 1 H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H).

[0440] Intermediate 17, Step c

[0441]

[0442] A solution of the compound 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) at -20 °C for 30 min under a nitrogen atmosphere, followed by dropwise addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (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 ¹H-NMR. The resulting mixture was extracted with CH₂Cl₂. The combined organic layers were 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 (4:1), to give the title compound (2.25 g, 67%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 1.36 (s, 12H), 6.96 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H).

[0443] Intermediate 18

[0444]

[0445] Intermediate 18, steps a and b

[0446]

[0447] A solution of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (10 g, 40.00 mmol) in DMF (70 mL) was treated overnight at 70 °C with Cs₂CO₃ (13.03 g, 40.00 mmol) and benzyl alcohol (8.65 g, 80.00 mmol). 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 crude compound (15 g) as a yellow oil.

[0448] The solution of the compound from step a (15 g, 44.65 mmol) in EtOH (100 mL) was treated with a solution of 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. ESI-MS m / z: 307.95 [M+H] + .

[0449] Intermediate 18, steps c and d

[0450]

[0451] The solution of the compound from step b (6 g, 19.47 mmol) in THF (150 mL) was treated overnight at 0 °C to room temperature with Ac₂O (4.97 g, 48.67 mmol) and Et₃N (9.85 g, 97.35 mmol). 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 milling with PE to give the desired compound (6.24 g, 92%) as a white solid. ESI-MS m / z: 350.05 [M+H] + .

[0452] 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 reversed-phase rapid chromatography to give the desired compound (1.5 g, 33%) as a white solid. ESI-MS m / z: 259.95 [M+H] + .

[0453] Intermediate 18 Steps e, f and g

[0454]

[0455] The solution of the compound from step d (1.5 g, 5.77 mmol) in CHCl3 (10 mL) was treated overnight at 65 °C with POCl3 (1.33 g, 8.65 mmol). 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. ESI-MS m / z: 241.95 [M+H] + .

[0456] 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), DPPP (852 mg, 2.07 mmol) and Pd(OAc)₂ (232 mg, 1.03 mmol) were added to a pressure vessel. The mixture was purged with carbon monoxide and then pressurized to 20 atm with carbon monoxide overnight at 100 °C. 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. ESI-MS m / z: 222.10 [M+H] + .

[0457] The solution of the compound from 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 H₂O (2 mL) at room temperature for 2 hours. The reaction was monitored by LCMS. The product was precipitated by adding HCl. The precipitate was collected by filtration and washed with water to give the title compound (249.8 mg, 66%) as a white solid. ESI-MS m / z: 208.10 [M+H] + .

[0458] Intermediate 19

[0459]

[0460] Intermediate 19, Step a

[0461]

[0462] A solution of the compound from intermediate 18b (2.7 g, 8.76 mmol) in dioxane (20 mL) was treated with cyclopropionyl 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 grinding with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether to give the desired compound (2.78 g, 88%) as a white solid. ESI-MS m / z: 376.05 [M+H] + .

[0463] Intermediate 19 Steps b, c, d, e

[0464]

[0465] The following compounds were prepared in a similar order to intermediate 18 described above and purified by reversed-phase rapid chromatography to give the title compound (416.4 mg, 58%) as a white solid. ESI-MS m / z: 234.10 [M+H] + .

[0466] Intermediate 20

[0467]

[0468] Intermediate 20, Step a

[0469]

[0470] 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 for the next step without further purification.

[0471] Intermediate 20, steps b and c

[0472]

[0473] To a flask containing the compound from step a (2.50 g, 10.91 mmol) and 2-methanesulfonylethanol (1.42 g, 11.45 mmol), DMSO (50 mL) and t-BuOK (1.29 g, 11.45 mmol) were added under N2. The reaction was stirred at room temperature under N2 for 20 h. Another portion of 2-methanesulfonylethanol (1.42 g, 11.45 mmol) and t-BuOK (1.29 g, 11.45 mmol) was added, and the reaction was stirred for another 3.5 h. The reaction was monitored by LCMS. The mixture / residue was acidified with concentrated HCl to pH <1. The resulting mixture was extracted with EtOAc. The aqueous layer was concentrated under reduced pressure. The resulting mixture was used directly for the next step without further purification. ESI-MS m / z: 211.95 [MH] - .

[0474] The 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 for the next step without further purification. ESI-MS m / z: 225.95 [MH] - .

[0475] Intermediate 20, Step d

[0476]

[0477] The solution of the methyl compound (1.4 g, 6.16 mmol) from step c in EtOH (50 mL) was treated with a solution of 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. ESI-MS m / z: 198.10 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 3.79 (s, 3H), 7.00 (d, J = 1.8 Hz, 1H), 7.09 (dd, J= 1.8, 0.8 Hz, 1H), 9.45 (s, 1H).

[0478] Intermediate 21

[0479]

[0480] Intermediate 21, steps a and b

[0481]

[0482] 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. 1 H NMR (400 MHz, DMSO-d6) δ 0.70-0.94 (m, 4H), 4.17-4.26 (m, 1H), 7.60-7.65 (m, 1H), 7.68 (t, J = 1.8 Hz, 1H).

[0483] 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 overnight at room temperature. 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 another 3 hours. 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. ESI-MS m / z: 271.95 [MH] - .

[0484] Intermediate 21, steps c and d

[0485]

[0486] 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 H2O (10 mL) in EtOH (20 mL) was stirred at 80 °C for 30 minutes. The resulting mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain the desired compound (2 g, 86%) as a brown solid. ESI-MS m / z: 245.90 [M+H] + .

[0487] A solution of the compound from step c (1.5 g, 6.10 mmol), cyclopropionyl chloride (0.58 g, 5.50 mmol), and TEA (0.93 g, 9.20 mmol) in 20 mL of THF was stirred at 0 °C for 1 hour. 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. ESI-MS m / z: 313.90 [M+H] + .

[0488] Intermediate 21, steps e and f

[0489]

[0490] A solution of the compound from step d (1.2 g, 3.80 mmol) and POCl3 (884 mg, 5.70 mmol) in 20 mL of CHCl3 was stirred at 65 °C for 24 hours. 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. ESI-MS m / z: 293.90 [M+H] + .

[0491] 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 at 100 °C for 6 hours under a nitrogen atmosphere. The resulting mixture was filtered and purified by reversed-phase rapid chromatography to give the desired compound (235.5 mg, 40%) as a white solid. ESI-MS m / z: 260.10 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 0.72-0.79 (m, 2H), 0.79-0.91 (m,2H), 1.11-1.27 (m, 4H), 2.23-2.34 (m, 1H), 4.06-4.15 (m, 1H), 7.73 (d, J =1.3 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H), 13.12 (s, 1H).

[0492] Intermediate 22

[0493]

[0494] Intermediate 22, steps a and b

[0495]

[0496] 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 a nitrogen atmosphere. 2-Methanesulfonylethanol (2.05 g, 16.50 mmol) and t-BuOK (1.85 g, 16.50 mmol) were added, and the mixture was stirred for another 3 hours at room temperature. 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. ESI-MS m / z: 251.85 [MH] - .

[0497] 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 H2O (10 mL) in EtOH (20 mL) was stirred at 80 °C for 30 min. 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. ESI-MS m / z: 223.85 [M+H] + .

[0498] Intermediate 22, steps c, d, and e

[0499]

[0500] A solution of the compound from step b (1.3 g, 5.80 mmol), cyclopropionyl chloride (0.61 g, 5.80 mmol), and TEA (0.89 g, 8.70 mmol) in 10 mL of THF was stirred at 0 °C for 1 hour. 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. ESI-MS m / z: 291.85 [M+H] + .

[0501] The solution of the compound from step c (1 g, 3.44 mmol) and POCl3 (791 mg, 5.16 mmol) in CHCl3 (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. ESI-MS m / z: 273.85 [M+H] + .

[0502] A solution of the 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 at 100 °C for 6 hours under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to give the desired compound (587.7 mg, 61%) as a white solid. ESI-MS m / z: 238.05 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 1.16-1.35 (m, 4H), 2.31-2.42 (m, 1H), 7.91 (t,J = 1.6 Hz, 1H), 8.07-8.13 (m, 1H), 13.39 (s, 1H).

[0503] Intermediate 23

[0504]

[0505] Intermediate 23, steps a and b

[0506]

[0507] 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 a nitrogen atmosphere. The aqueous layer was extracted with EA (3 x 20 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product, which could be used directly in the next step.

[0508] The 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 hours. The resulting mixture was extracted with EA. The combined organic layers were washed with water. The residual product was purified by reversed-phase rapid chromatography to the desired product (1.5 g, 96%) as a yellow solid. ESI-MS m / z: 322.00 [MH] - .

[0509] Intermediate 23, steps c and d

[0510]

[0511] 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 at 80 °C for 2 hours under a nitrogen atmosphere. The residue was purified by preparative TLC to give the desired product (1.2 g, 69%) as a yellow solid.

[0512] A solution of the 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 for 2 hours under a nitrogen atmosphere. The resulting mixture was filtered. The mixture was extracted with EA. The combined organic layers were washed with water and concentrated under reduced pressure to give the desired product (1 g, 91%) as a yellow oil. ESI-MS m / z: 344.00 [M+H] + .

[0513] Intermediate 23, steps e and f

[0514]

[0515] A solution of the compound from step d (1 g, 2.91 mmol) and cyclopropionyl chloride (607 mg, 5.81 mmol) in dioxane (20 mL) was stirred at 100 °C for 2 hours under N2 atmosphere. The resulting mixture was extracted with EA (3 x 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. ESI-MS m / z: 412.00 [M+H] + .

[0516] The 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 hours. The resulting mixture was extracted with EA. The combined organic layers were washed with water. The residual product was purified by reversed-phase rapid chromatography to the desired product (600 mg, 85%) as a yellow oil. ESI-MS m / z: 322.00 [M+H] + .

[0517] Intermediate 23, steps g and h

[0518]

[0519] A solution of the compound from step f (600 mg, 1.86 mmol) and POCl3 (428 mg, 2.80 mmol) in 10 mL of CHCl3 was stirred overnight at 65 °C under a nitrogen 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. ESI-MS m / z: 304.00 [M+H] + .

[0520] A solution of the 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 a nitrogen atmosphere. The crude product was purified by reversed-phase rapid chromatography to obtain the desired product (200 mg, 56%) as a white solid. ESI-MS m / z: 270.00 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ1.15 – 1.31 (m, 4H), 2.34 (tdt, J = 13.4, 10.0, 5.0 Hz, 1H), 7.32 – 7.77 (m,2H), 8.01 (d, J = 3.0 Hz, 1H), 13.41 (s, 1H).

[0521] Intermediate 24

[0522]

[0523] Intermediate 24, Step a

[0524]

[0525] 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 at 0 °C for 2 hours. 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. ESI-MS m / z: 285.95 [M+H] + .

[0526] Intermediate 24, Step b

[0527]

[0528] The solution of the compound from step a (1.2 g, 4.19 mmol) and POCl3 (1.29 g, 8.38 mmol) in CHCl3 (5 mL) was stirred at 65 °C for 24 hours. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (1 g, 88%) as a brown solid. ESI-MS m / z: 267.90 [M+H] + .

[0529] Intermediate 24, Step c

[0530]

[0531] A solution of the 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 at 100 °C for 6 hours under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to give the desired compound (207.3 mg, 52%) as a white solid. ESI-MS m / z: 245.90 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 0.72-0.84 (m, 2H), 0.84-0.92 (m,2H), 2.62 (s, 3H), 4.10-4.20 (m, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.80 (d, J =1.3 Hz, 1H), 13.18 (s, 1H).

[0532] Intermediate 25

[0533]

[0534] Intermediate 25, Step a

[0535]

[0536] A mixture of nicotinic acid (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 hours. 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. ESI-MS m / z: 167.05 [M+H] + .

[0537] Intermediate 25, Step b

[0538]

[0539] (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[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 to a 250 mL three-necked round-bottom flask at room temperature. The mixture was cooled to 0 °C. iPrMgCl (1.07 g, 10.44 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) 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. ESI-MS m / z: 361.95 [M+H] + .

[0540] Intermediate 25, Step c

[0541]

[0542] The compound from step b (800 mg, 2.21 mmol), 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (606 mg, 2.21 mmol), K₂CO₃ (610 mg, 4.42 mmol), and Pd(dppf)Cl₂ (161 mg, 0.22 mmol) in dioxane (9 mL) and H₂O (1 mL) were stirred at 80 °C for 1 hour under a 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. ESI-MS m / z: 430.05 [M+H] + .

[0543] Intermediate 25, Step d

[0544]

[0545] Under a nitrogen atmosphere at 0°C, a solution of 1 M t-BuOK in THF (428 mg, 3.81 mmol) was added dropwise to a stirred solution of methyltriphenylphosphine bromide (1.70 g, 4.77 mmol) in THF (50 mL). The resulting mixture was stirred at 0°C for 30 min under a nitrogen atmosphere. A solution of the compound from step c (820 mg, 1.90 mmol) in THF was added, and the mixture was 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 a crude product (430 mg) as a yellow solid. ESI-MS m / z: 428.15 [M+H] + .

[0546] Intermediate 25 Step e

[0547]

[0548] The compound from step d (400 mg, 0.93 mmol), methanesulfonamide (89 mg, 0.93 mmol), and ADMIX-β (2.18 g, 2.80 mmol) were stirred overnight at room temperature in a mixture of t-BuOH (5 mL) and H₂O (5 mL). 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 a grayish-white solid. ESI-MS m / z: 462.10 [M+H] + .

[0549] Intermediate 25 Step f

[0550]

[0551] The mixture of the 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 hour. The mixture was acidified to pH 5 with HCl (2 M aqueous solution). The resulting mixture was extracted with CH2Cl2. 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. ESI-MS m / z: 616.15 [M+H] + .

[0552] Intermediate 25 Step g

[0553]

[0554] The solution of the compound from step f (30 mg, 0.05 mmol) and NH3 (g) in MeOH (5 mL) was stirred overnight at 40 °C. 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 a grayish-white solid. ESI-MS m / z: 461.25 [M+H] + .

[0555] Intermediate 26

[0556]

[0557] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (100 mg). ESI-MS m / z: 478.50 [M+H] + .

[0558] Intermediate 27

[0559]

[0560] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (60 mg, 53%). ESI-MS m / z: 478.20 [M+H] + .

[0561] Intermediate 28

[0562]

[0563] Intermediate 28 Step a

[0564]

[0565] A solution of (S)-(7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[2,3-c]pyridin-3-yl)methanol (3 g, 7.83 mmol), 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxoborane (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 H2O (4 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. 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. ESI-MS m / z: 346.05 [M+H] + .

[0566] Intermediate 28, Step b

[0567]

[0568] The compound from step a (2 g, 5.78 mmol), 1-(5-chloro-2,4-difluorophenyl)-3,3,4,4-tetramethylborane (1.6 g, 5.78 mmol), Pd(dppf)Cl2 (422 mg, 0.58 mmol), and K2CO3 (1.6 g, 11.55 mmol) were mixed in dioxane (20 mL) and H2O (2 mL) and stirred at 80 °C for 2 hours under a nitrogen 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. ESI-MS m / z: 414.20 [M+H] + .

[0569] Intermediate 28, steps c and d

[0570]

[0571] The compound from step b (1.6 g, 3.88 mmol), TBSCl (870 mg, 5.79 mmol), and imidazole (0.39 g, 5.80 mmol) were stirred in DCM (10 mL) for 2 hours at room temperature. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the desired product (1.9 g, 93%) as a white solid. ESI-MS m / z: 528.30 [M+H] + .

[0572] A solution of the 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 H₂O (10 mL) was stirred overnight at 0 °C. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with water (3 x 200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the desired product (1.5 g, 70%) as a white solid. ESI-MS m / z: 562.40 [M+H] + .

[0573] Intermediate 28, steps e and f

[0574]

[0575] A solution of the 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 hours. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with water (3 x 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. ESI-MS m / z: 716.50 [M+H] + .

[0576] 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 the mixture was 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. ESI-MS m / z: 561.40 [M+H] + .

[0577] Intermediate 28, steps g and h

[0578]

[0579] The solution of the 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 hours. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the desired product (600 mg, 56%) as a white solid. ESI-MS m / z: 661.20 [M+H] + .

[0580] The 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 hour. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with water (3 x 200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the desired product (430 mg, 57%) as a white solid. ESI-MS m / z: 547.15 [M+H] + .

[0581] Intermediate 28, steps i and j

[0582]

[0583] The 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 hours. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL). The organic layers were concentrated under reduced pressure to give the desired crude product as a white oil. ESI-MS m / z: 545.30 [M+H] + .

[0584] To a solution of the compound from step i (230 mg, 0.42 mmol), 2-methyl-2-butene (354 mg, 5.04 mmol), and NaClO2 (380 mg, 4.20 mmol) in water, and NaH2PO4 (504 mg, 4.20 mmol) were added dropwise at room temperature, and the mixture was stirred for 2 hours. 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 for the next step without further purification. ESI-MS m / z: 561.30 [M+H] +.

[0585] Intermediate 29

[0586]

[0587] Intermediate 29, Steps a and b

[0588]

[0589] The solution of intermediate 28 (120 mg, 0.21 mmol), deuterated methylamine (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 hours. The residue was purified by preparative TLC (PE / EA 1:1) to give the desired product (80 mg, 64%) as a white solid. ESI-MS m / z: 577.15 [M+H] + .

[0590] The compound from step a (120 mg, 2.66 mmol) was stirred in 2 mL of HCl in 1,4-dioxane at room temperature for 1 hour. The residue was purified by preparative TLC (DCM / NH3 in MeOH = 15 / 1) to give the desired product (36.8 mg, 54%) as a white solid. ESI-MS m / z: 477.15 [M+H] + .

[0591] Intermediate 30

[0592]

[0593] The above compound was prepared using a method similar to that used for intermediate 29, yielding an amino alcohol (23 mg). ESI-MS m / z: 474.15 [M+H] + .

[0594] Intermediate 31

[0595]

[0596] The above compound was prepared using a method similar to that used for intermediate 29 to obtain an amino alcohol.

[0597] Intermediate 32

[0598]

[0599] The above compound was prepared using a method similar to that used for intermediate 29 to obtain an amino alcohol.

[0600] Intermediate 33

[0601]

[0602] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (150 mg, 68%). ESI-MS m / z: 442.00 [M+H] + .

[0603] Intermediate 34

[0604]

[0605] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (46.1 mg, 19%). ESI-MS m / z: 476.25 [M+H] + .

[0606] Intermediate 35

[0607]

[0608] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (113.6 mg, 48%). ESI-MS m / z: 458.10 [M+H] + .

[0609] Intermediate 36

[0610]

[0611] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (89.5 mg, 60%). ESI-MS m / z: 476.00 [M+H] + .

[0612] Intermediate 37

[0613]

[0614] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol, which was a mixture of diastereomers. The diastereomers were isolated following subsequent amide coupling, and their stereochemistry was arbitrarily specified (370 mg, 78%). ESI-MS m / z: 460.05 [M+H] + .

[0615] Intermediate 38

[0616]

[0617] Intermediate 38, Step a

[0618]

[0619] (1-(6-fluoropyridin-2-yl)vinyl)diisobutylaluminum was prepared according to the literature procedure in 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-dihydrofuran[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 to 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 was performed by silica gel chromatography, 0–70% EtOAc / cHex, to give the title compound (603 mg, 55.5%). ESI-MS m / z: 378.00 / 380.00 [M+H] + .

[0620] Intermediate 38 Step be

[0621]

[0622] The above compound was prepared using a method similar to that used for intermediate 9, and the crude product was purified by preparative TLC (silica gel, MeOH in DCM containing NH3) to give the desired product (200 mg, 81%) as a white solid. ESI-MS m / z: 479.00 [M+H] + .

[0623] Intermediate 39

[0624]

[0625] The above compound was prepared using a method similar to that used for intermediate 38, yielding the desired product (13 mg, 62%) as a white solid. ESI-MS m / z: 495.09 [M+H] + .

[0626] Intermediate 40

[0627]

[0628] The above compound was prepared using a method similar to that used for intermediate 9, and the crude product was purified by preparative TLC (silica gel, MeOH in DCM containing NH3) to give the desired product (475 mg, 71%) as a white solid. ESI-MS m / z: 466.31 [M+H] + .

[0629] Intermediate 41

[0630]

[0631] Intermediate 41, Step a

[0632]

[0633] A solution of 4-acetylpyridine (2 g, 16.50 mmol) and p-toluenesulfonyl hydrazine (4.61 g, 24.70 mmol) in CH3OH (20 mL) was stirred at 70 °C for 2 hours. The mixture was filtered and washed to give the desired precipitate (2 g, 41%) as a white solid. ESI-MS m / z: 290.00 [M+H] + .

[0634] Intermediate 41, Step b

[0635]

[0636] The compound from step a (566 mg, 1.96 mmol), Pd(PPh3)2Cl2 (91 mg, 0.13 mmol), and LiO were added. t A solution of Bu (309 mg, 4.83 mmol) and (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (500 mg, 1.30 mmol) in dioxane (5 mL) was stirred overnight at 90 °C under nitrogen atmosphere. 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. ESI-MS m / z: 360.00 [M+H] + .

[0637] Intermediate 41 Steps c, d, e, f

[0638]

[0639] The amino alcohol was synthesized via four steps similar to those of intermediate 9 (cross-coupling, dihydroxylation, toluenesulfonation, and amination) to give the title compound (50 mg, 74%) as a white solid. ESI-MS m / z: 460.95 [M+H]+ .

[0640] The diastereomers were separated using preparative HPLC after subsequent amide coupling.

[0641] Intermediate 42

[0642]

[0643] Intermediate 42, Step a

[0644]

[0645] 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. ESI-MS m / z: 357.05 [M+H] + .

[0646] Intermediate 42, Step b

[0647]

[0648] At room temperature, 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 to a 40 mL vial. After degassing and purging with N₂, toluene (40 mL) was added to the vial. The reaction mixture was reacted overnight at 90 °C. 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. 1 H NMR (400 MHz, CDCl3) δ1.33 (s, 12H), 6.13 (s, 1H), 6.17 (d, J = 2.7 Hz, 1H), 7.57 (s, 4H).

[0649] Intermediate 42, Step c

[0650]

[0651] The 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-dihydrofuran[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 for 1 h under a nitrogen atmosphere. 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 reversed-phase rapid chromatography to give the desired compound (443 mg, 79%) as a brown oil. ESI-MS m / z: 427.00 [M+H] + .

[0652] Intermediate 42, steps d, e, f, g

[0653]

[0654] The amino alcohol was synthesized via four steps similar to those of intermediate 9 (cross-coupling, racemic dihydroxylation, toluenesulfonation, and amination) to give the title compound (208 mg, 90%) as a white solid. ESI-MS m / z: 528.10 [M+H] + .

[0655] Following amide coupling, preparative TLC was used to separate the diastereomers.

[0656] Intermediate 43

[0657]

[0658] The amino alcohol was synthesized in a similar sequence to intermediate 42, and selectively dihydroxylated using ADMIX-β to give the title compound (181.4 mg, 66%) as a white solid. ESI-MS m / z: 528.10 [M+H] + .

[0659] Intermediate 44

[0660]

[0661] The amino alcohol was synthesized in a similar sequence to intermediate 42, and selectively dihydroxylated using ADMIX-β to give the title compound (10 mg, 23%) as a white solid. ESI-MS m / z: 464.30 [M+H] + .

[0662] Intermediate 45

[0663]

[0664] Intermediate 45, Step a

[0665]

[0666] (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (1.42 g, 4.39 mmol, 1.00 equivalent) was dissolved in 1,4-dioxane (22 mL), and sodium iodide (2.31 g, 15.4 mmol, 3.50 equivalent) was added. The suspension was purged with nitrogen, and copper iodide (I) (167 mg, 0.879 mmol, 0.2 equivalent) and N,N'-dimethylethylenediamine (0.208 mL, 1.93 mmol, 0.4 equivalent) were added. Purging continued for 5 minutes, then 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 hours, the reaction mixture was cooled to room temperature and diluted with a saturated aqueous solution of sodium bicarbonate, water, and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated into a crude oil. This crude substance was purified by automated rapid chromatography on silica gel (0-100% EtOAc, in cyclohexane) to give a pure iodide product as a yellow foam (1.03 g, 63%). ESI-MS m / z: 371.178 [M+H] + .

[0667] Intermediate 45, Step b

[0668]

[0669] 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. Isopropyl magnesium chloride (2 M in THF, 10.7 mL, 21.4 mmol, 1.1 equivalents) was added, and the resulting mixture was stirred at this temperature for 1 hour. Then, i-PrOB (pin) (4.76 mL, 23.3 mmol, 1.2 equivalents) was added. The reaction mixture was then heated to room temperature and stirred. During this time, some solids began to precipitate. After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (1 × 50 mL), dried over sodium sulfate, filtered, and concentrated to give crude borate ester as a crystalline white solid (5.65 g, 89%). The crude product contains approximately 8% pinacol by weight and can be used without further purification (no m / z of borate ester was detected).

[0670] Intermediate 45, Step c

[0671]

[0672] The compound from step a (1.04 g, 2.81 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (11.2 mL), and K₂CO₃ (1.17 g, 8.43 mmol, 3.0 equivalent), Pd(dppf)Cl₂ (123 mg, 0.169 mmol, 0.06 equivalent), and the borate ester from step b (1.10 g, 3.79 mmol, 1.35 equivalent) were added. Water (2.8 mL) was added, and the resulting biphasic suspension was purged with nitrogen for 5 min. The vial was sealed and heated to 90 °C with stirring for 1 hour, 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 × 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated into a crude oil. The crude substance was purified by automated rapid chromatography on silica gel (0-100% EtOAc, in cyclohexane) to give pure product 5 as a yellow foam (940 mg, 82%). ESI-MS m / z: 407.156 [M+H] + .

[0673] Intermediate 45, steps d, e, and f

[0674]

[0675] The above compound was prepared using a similar procedure to intermediate 9 to give the desired product (700 mg, 99%) as a white solid. ESI-MS m / z: 440.08 [M+H] + .

[0676] Intermediate 46

[0677]

[0678] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (138 mg, 90%) as a white solid. ESI-MS m / z: 504.14 [M+H] + .

[0679] Intermediate 47

[0680]

[0681] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (417 mg, 99%) as a white solid. ESI-MS m / z: 476.17 [M+H] + .

[0682] Intermediate 48

[0683]

[0684] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (222 mg, 93%) as a white solid. ESI-MS m / z: 458.22 [M+H] + .

[0685] Intermediate 49

[0686]

[0687] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (158 mg, 100%) as a white solid. ESI-MS m / z: 522.18 [M+H] + .

[0688] Intermediate 50

[0689]

[0690] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (291 mg, 76%) as a white solid. ESI-MS m / z: 494.24 [M+H] + .

[0691] Intermediate 51

[0692]

[0693] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (158 mg, 100%) as a white solid. ESI-MS m / z: 522.18 [M+H] + .

[0694] Intermediate 52

[0695]

[0696] The above compound was prepared using a method similar to that used for intermediate 45, yielding the desired product (800 mg, 96%) as a white solid. ESI-MS m / z: 476.17 [M+H] + .

[0697] Intermediate 53

[0698]

[0699] The above compound was prepared using a similar procedure to intermediate 9 to give the desired product (421 mg, 90%) as a white solid. ESI-MS m / z: 440.08 [M+H] + .

[0700] Intermediate 54

[0701]

[0702] The above compound was prepared using a similar procedure to intermediate 9 to give the desired product (608 mg, 97%) as a white solid. ESI-MS m / z: 440.08 [M+H] + .

[0703] Intermediate 55

[0704]

[0705] The above compound was prepared using a similar procedure to intermediate 9 to give the desired product (560 mg, 93%) as a white solid. ESI-MS m / z: 495.45 [M+H] + .

[0706] Intermediate 56

[0707]

[0708] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (689 mg, 94%). ESI-MS m / z: 459.44 [M+H] + .

[0709] Intermediate 57

[0710]

[0711] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (107 mg, 97%). ESI-MS m / z: 443.16 [M+H] + .

[0712] Intermediate 58

[0713]

[0714] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (293 mg, 100%). ESI-MS m / z: 441.34 [M+H] + .

[0715] Table 3 below contains examples prepared using methods similar to those in Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel). The arylboronic ester starting materials and aryl acid amide coupling couples were prepared according to intermediates 1-58, or by a similar procedure with slight modifications, also according to the procedure in U.S. Patent No. 11,572,367.

[0716] Table 3

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741] Table 4 below contains examples prepared using methods similar to those in Example 47. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel). Some examples could not be separated by preparative HPLC and were reported as mixtures of diastereomers.

[0742] Table 4

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751] Example 443

[0752]

[0753] Reference: Org. Lett. 2003, 5, 2453-2455

[0754] Add (3R)-7-bromo-5-(1-cyclopropyl-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamido)-1-hydroxyethyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (50 mg, 0.088 mmol, 1.0 equivalent), indole (26 mg, 0.22 mmol, 2.5 equivalent), K₂CO₃ (24 mg, 0.18 mmol, 2.0 equivalent), CuI (13 mg, 0.068 mmol, 0.78 equivalent), and N,N-dimethylglycine (13 mg, 0.13 mmol, 1.4 equivalent) to a dried vial. Dissolve the solids in DMSO (0.18 mL), seal the vial, and heat to 70°C with stirring. After stirring at this temperature for approximately 15 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc (approximately 5 mL). The organic phase was washed with water (3 × 1 mL), dried over sodium sulfate, filtered, and concentrated. The crude residue was first purified by reversed-phase HPLC, followed by automated rapid chromatography on silica gel (0–10% MeOH in DCM solution) to separate pure samples of diastereomer 1 (10 mg, 19%) and diastereomer 2 (8.0 mg, 15%), both as white solids.

[0755] Table 5 below contains examples prepared using methods similar to those in Example 443. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel).

[0756] Table 5

[0757]

[0758]

[0759] Table 6 below contains examples prepared using methods similar to those in Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel). The arylboronic ester starting materials and aryl acid amide coupling couples were prepared according to intermediates 1-58, or by a similar procedure with slight modifications, also according to the procedure in U.S. Patent No. 11,572,367.

[0760] Table 6

[0761]

[0762] Intermediate 59

[0763]

[0764] Intermediate 59, Step a

[0765]

[0766] A solution of CAN-7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), Pd(dppf)Cl2CH2Cl2 (0.43 g, 0.52 mmol), K2CO3 (1.44 g, 10.44 mmol), and N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)prop-2-en-1-yl]tert-butyl carbamate (1.48 g, 5.22 mmol) in dioxane (16 mL) and H2O (4 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (1.9 g, 88%) as a yellow oil. ESI-MS m / z: 413.90 [M+H] + .

[0767] Intermediate 59, Step b

[0768]

[0769] A solution of the compound from step a (1.9 g, 4.61 mmol), Pd(dppf)Cl2CH2Cl2 (375 mg, 0.46 mmol), K2CO3 (1.27 g, 9.22 mmol), and 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (1.90 g, 6.92 mmol) in dioxane (18 mL) and H2O (2 mL) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. 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. ESI-MS m / z: 480.10 [M+H] + .

[0770] Intermediate 59, Step c

[0771]

[0772] A solution of the compound from step b (2 g, 4.16 mmol), K₂O₅O₄∙2H₂O (0.06 g, 0.17 mmol), NMO (1.37 g, 11.67 mmol), and H₂O (20 mL) in acetone (20 mL) was stirred overnight at room temperature. 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 for another 4 hours at room temperature. 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. ESI-MS m / z: 482.00 [M+H] + .

[0773] Example 463

[0774]

[0775] Example 463 Step a

[0776]

[0777] A solution of 2-bromopyridine (373 mg, 2.36 mmol) and n-BuLi (151 mg, 2.36 mmol) in THF (3 mL) was stirred at -78 °C for 15 min under a nitrogen atmosphere. Intermediate 59 (190 mg, 0.39 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for another 30 min. The residue was quenched, extracted, concentrated, and purified by reversed-phase rapid chromatography to give the desired compound (100 mg, 45%) as a yellow crude solid. ESI-MS m / z: 561.05 [M+H] + .

[0778] Example 463 Step b

[0779]

[0780] The compound from step a (100 mg, 0.18 mmol), a solution of HCl in 1,4-dioxane (2 mL), and DCM (2 mL) were stirred at room temperature for 1 hour. The mixture was alkalized, extracted, concentrated, and purified by reversed-phase rapid chromatography to obtain the desired compound (50 mg, 60%) as a white solid. ESI-MS m / z: 460.95 [M+H] + .

[0781] Example 463 Step c

[0782]

[0783] A solution of the compound from step b (50 mg, 0.11 mmol), HATU (61 mg, 0.16 mmol), 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 hour. The resulting mixture was extracted, concentrated, and purified by preparative HPLC to give the desired compound (3.5 mg, 17%) as a white solid. ESI-MS m / z: 675.20 [M+H] + .

[0784] Intermediate 60

[0785]

[0786] The following intermediates were prepared in a similar order to step b of Example 463 to obtain the title compound (110 mg, 64%). ESI-MS m / z: 463.95 [M+H] + .

[0787] Intermediate 61

[0788]

[0789] The following intermediates were prepared in a similar order to step b of Example 463 to obtain the title compound (63 mg). ESI-MS m / z: 486.15 [M+H] + .

[0790] Table 7 below contains examples prepared using methods similar to those in Example 463. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel).

[0791] Table 7

[0792]

[0793]

[0794] Intermediate 62

[0795]

[0796] Intermediate 62 Step a

[0797]

[0798] Under a nitrogen atmosphere at 110 °C, Pd(dppf)Cl₂CH₂Cl₂ (851 mg, 1.04 mmol) was added dropwise to a stirred toluene solution of CAN-7-bromo-5-iodo-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (4 g, 10.44 mmol) and tributyl(1-ethoxyvinyl)stanane (3.96 g, 10.97 mmol) for 2 hours. 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. ESI-MS m / z: 327.00 [M+H] + .

[0799] Intermediate 62, Step b

[0800]

[0801] To a solution of compound a (4.7 g, 14.37 mmol) and 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (3.94 g, 14.37 mmol) in dioxane (40 mL), H₂O (10 mL), Pd(dppf)Cl₂CH₂Cl₂ (1.17 g, 1.44 mmol) and K₂CO₃ (3.97 g, 28.73 mmol) were added, along with Pd(dppf)Cl₂CH₂Cl₂. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. 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. ESI-MS m / z: 395.05 [M+H] + .

[0802] Intermediate 62, Step c

[0803]

[0804] Under a nitrogen atmosphere at 50 °C, the compound from step b (6 g, 16.36 mmol) and HCl (33 mL) were stirred in MeOH (20 mL) for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (1 x 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. ESI-MS m / z: 381.90 [M+H] + .

[0805] Intermediate 62, Step d

[0806]

[0807] 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 heated to room temperature and stirred at room temperature for 16 hours. 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. ESI-MS m / z: 514.00 [M+H] + .

[0808] Intermediate 63

[0809]

[0810] The following intermediates were prepared in a similar manner to intermediate 62 to give the desired compound (1.7 g, 65%). ESI-MS m / z: 512.00 [M+H] + .

[0811] Intermediate 64

[0812]

[0813] Intermediate 64, Step a

[0814]

[0815] K₂CO₃ (108 mg, 0.78 mmol) and Pd(dppf)Cl₂CH₂Cl₂ (32 mg, 0.04 mmol) were added to a solution of intermediate 62 (200 mg, 0.39 mmol) and 2-cyclopropylpyrimidin-5-ylboronic acid (64 mg, 0.39 mmol) in 1,4-dioxane / H₂O (9:1). The resulting mixture was stirred at 85 °C for 2 h under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to give the desired compound (130 mg, 69%) as a yellow oil. ESI-MS m / z: 484.30 [M+H] + .

[0816] Intermediate 64, Step b

[0817]

[0818] ADMIX-β (1.16 g, 1.49 mmol) was added to a solution of compound a (240 mg, 0.50 mmol) and methanesulfonamide (47 mg, 0.50 mmol) in t-BuOH / H2O, and the resulting mixture was stirred overnight at room temperature. The mixture was extracted with EtOAc (3 x 10 mL). The residue was purified by reversed-phase rapid chromatography to give the desired compound (115 mg, 45%) as a yellow oil. ESI-MS m / z: 518.15 [M+H] + .

[0819] Intermediate 64, steps c and d

[0820]

[0821] Under a nitrogen atmosphere at room temperature, TEA (67 mg, 0.67 mmol) and DMAP (27 mg, 0.22 mmol) were added to a stirred solution of compound b (100 mg, 0.20 mmol) and TsCl (64 mg, 0.33 mmol) in DCM, and the mixture was stirred for 2 hours. The resulting mixture was acidified to pH 3 with HCl (1 M aqueous solution), and extracted with DCM. 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. ESI-MS m / z: 672.25 [M+H] + .

[0822] The compound from step c (80 mg, 0.12 mmol) and a solution of NH3 (g) in MeOH (10 mL) were stirred overnight at 40 °C. 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 solution, 12:1) to give the methyl ester of the title compound (60 mg, 130%) as a yellow solid. ESI-MS m / z: 502.25 [M+H] + .

[0823] Intermediate 65

[0824]

[0825] The following intermediates were prepared in a similar sequence to intermediate 64 to give the title compound (110 mg, 64%). ESI-MS m / z: 444.00 [M+H] + .

[0826] Intermediate 66

[0827]

[0828] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound.

[0829] Intermediate 67

[0830]

[0831] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound.

[0832] Intermediate 68

[0833]

[0834] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound.

[0835] Intermediate 69

[0836]

[0837] The following intermediates were prepared in a similar order to intermediate 64 to give the title compound (50.2 mg, 41%) as a white solid. ESI-MS m / z: 538.15 [M+H] + .

[0838] Intermediate 70

[0839]

[0840] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound.

[0841] Intermediate 71

[0842]

[0843] The following intermediates were prepared in a similar order to intermediate 64 to give the title compound (70 mg, 75%), a white solid. ESI-MS m / z: 576.25 [M+H] + Following amide coupling, the final compound was obtained by Boc deprotection with a dioxane solution of HCl. See the table below.

[0844] Intermediate 72

[0845]

[0846] The following intermediates were prepared in a similar order to intermediate 64 to give the title compound (80 mg, 65%) as a white solid. ESI-MS m / z: 590.00 [M+H] + Following amide coupling, the final compound was obtained by Boc deprotection with a dioxane solution of HCl. See the table below.

[0847] Intermediate 73

[0848]

[0849] The following intermediates were prepared in a similar order to intermediate 64 to give the title compound (27 mg, 42%), a white solid. ESI-MS m / z: 474.95 [M+H] + .

[0850] Intermediate 74

[0851]

[0852] The following intermediates were prepared in a similar order to intermediate 64 to give the title compound (70 mg), a white solid. ESI-MS m / z: 639.00 [M+H] + Following amide coupling, the final compound was obtained by Boc deprotection with a dioxane solution of HCl. See the table below.

[0853] Intermediate 75

[0854]

[0855] The following intermediates were prepared in a similar sequence to intermediate 64 to give the title compound (70 mg, 71%) as a yellow solid. ESI-MS m / z: 484.95 [M+H] + .

[0856] Intermediate 76

[0857]

[0858] The following intermediates were prepared in a similar sequence to intermediate 64 to give the title compound (30 mg, 81%) as a yellow solid. ESI-MS m / z: 495.00 [M+H] + .

[0859] Intermediate 77

[0860]

[0861] The following intermediates were prepared in a similar sequence to intermediate 64 to give the title compound (22 mg), a yellow solid. ESI-MS m / z: 451.05 [M+H] + .

[0862] Intermediate 78

[0863]

[0864] The following intermediates were prepared in a similar sequence to intermediate 64 to give the title compound (59.4 mg, 69%) as a yellow solid. ESI-MS m / z: 509.10 [M+H] + .

[0865] Intermediate 79

[0866]

[0867] Intermediate 79 Step a

[0868]

[0869] 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 hours 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. ESI-MS m / z: 444.00 [M+H] + .

[0870] Intermediate 79, steps b, c, d, and e

[0871]

[0872] The following intermediates were prepared in a similar sequence to intermediate 64 to give the title compound (15 mg, 68%) as a yellow solid. ESI-MS m / z: 462.00 [M+H] + .

[0873] Example 477

[0874]

[0875] Example 477 Step a

[0876]

[0877] TBSOTf (7.86 g, 29.72 mmol) and TEA (1.91 g, 17.83 mmol) were added to a stirred solution of 2-methyl-3-butyn-2-ol (500 mg, 5.94 mmol) and DCM (10 mL). The reaction was monitored by TLC. The resulting mixture was extracted with EtOAc. 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 (10:1) to give the desired product (1 g, 85%) as a colorless crude oil. 1 H NMR (400 MHz, DMSO-d6) δ 0.00 (s, 6H), 0.69 (s, 9H), 1.27 (s, 6H), 3.27 (s, 1H).

[0878] Example 477 Step b

[0879]

[0880] To a solution of the product (400 mg, 0.78 mmol) from step a of Example 477 (216 mg, 1.09 mmol) in DMF (5 mL), TEA (315 mg, 3.11 mmol), Pd(dppf)Cl2CH2Cl2 (32 mg, 0.04 mmol), and CuI (7 mg, 0.04 mmol) were added. The resulting mixture was stirred at 60 °C for 2 hours under nitrogen atmosphere and 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 (9:1) to give the desired compound (330 mg, 75%) as a yellow oil. ESI-MS m / z: 562.15 [M+H] + .

[0881] Example 477 Step c

[0882]

[0883] The compound from step b (300 mg, 0.53 mmol) in t-BuOH (3 mL) and H₂O (3 mL) was treated at 0 °C with ADMIX-β (1.25 g, 1.60 mmol) and methanesulfonamide (51 mg, 0.53 mmol). The final reaction mixture was reacted overnight at room temperature. 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 preparative TLC (PE / EA 2:1) to give the desired compound (188 mg, 59%) as a pink oil. ESI-MS m / z: 596.20 [M+H] + .

[0884] Example 477 Step d

[0885]

[0886] A solution of the compound from step c (188 mg, 0.32 mmol) in DCM (3 mL) was treated at room temperature with TsCl (90 mg, 0.47 mmol), DMAP (39 mg, 0.32 mmol), and TEA (96 mg, 0.95 mmol) for 1.5 h. 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 concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 2:1) to give the desired compound (164 mg, 69%) as a white oil. ESI-MS m / z: 750.25 [M+H] + .

[0887] Example 477 Step e

[0888]

[0889] A solution of NH3(g) in MeOH (5 mL) was treated with the compound from step d (144 mg, 0.19 mmol) and stirred overnight at 40 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give the desired compound (100 mg) as a white oil. ESI-MS m / z: 580.20 [M+H] + .

[0890] Example 477 Step f

[0891]

[0892] The solution of the compound from step e (100 mg, 0.17 mmol) in DMF (3 mL) was treated with 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (40 mg, 0.17 mmol), HATU (66 mg, 0.17 mmol), and DIEA (45 mg, 0.34 mmol) at room temperature for 1 hour. The reaction was monitored by LCMS. The residue was purified by reversed-phase rapid chromatography to the desired compound (79 mg, 58%) as a white solid. ESI-MS m / z: 794.10 [M+H] + .

[0893] Example 477 Step g

[0894]

[0895] The solution of the compound from step f (70 mg, 0.09 mmol) in THF (4 mL) was treated with TBAF (0.9 mL, 0.88 mmol) at 60 °C for 1 h under a nitrogen atmosphere. 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 preparative TLC (CH2Cl2 / NH3(g) in MeOH solution, 13:1) to give the title compound (28.2 mg, 47%) as a white solid. ESI-MS m / z: 680.05 [M+H] + .

[0896] Intermediate 80

[0897]

[0898] The following intermediates were prepared in a similar order to those in Example 477 to give the title compound (4.5 mg, 90%) as a yellow solid. ESI-MS m / z: 528.11 [M+H] + .

[0899] Table 8 below contains examples prepared using methods similar to those in Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel). Amine starting materials were prepared according to intermediates 62-80, and aryl acid amide coupling couplers were prepared according to intermediates 1-58, or by a similar procedure with slight modifications according to the procedure in U.S. Patent No. 11,572,367.

[0900] Table 8

[0901]

[0902]

[0903]

[0904] Example 504

[0905]

[0906] Example 504 Step a

[0907]

[0908] To a solution of intermediate 62 (300 mg, 0.58 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyridin-2-one (129 mg, 0.58 mmol) in 1,4-dioxane / H2O, K2CO3 (161 mg, 1.17 mmol) and Pd(dppf)Cl2CH2Cl2 (47 mg, 0.06 mmol) were added, and the reaction was carried out under nitrogen atmosphere at 85 °C for 2 h. The residue was purified by reversed-phase rapid chromatography to give the desired product (105 mg, 39%) as a yellow solid. ESI-MS m / z: 459.00 [M+H] + .

[0909] Example 504, Step b

[0910]

[0911] The mixture of the methyl compound (100 mg, 0.22 mmol), methanesulfonamide (20 mg, 0.22 mmol), and ADMIX-β (509 mg, 0.65 mmol) from step a was stirred overnight at room temperature in tBuOH (3 mL) and H₂O (3 mL). 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 yellow-brown oil. ESI-MS m / z: 493.15 [M+H] + .

[0912] Example 504 Step c

[0913]

[0914] The mixture of the 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 hours. The reaction was monitored by LCMS. The mixture was acidified to pH 4 with HCl (1 M aqueous solution). 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. ESI-MS m / z: 800.95 [M+H] + .

[0915] Example 504, Step d

[0916]

[0917] The mixture of the compound from step c (60 mg, 0.07 mmol) and NH3 (g) in MeOH (3 mL) was stirred overnight at 40 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / 7M NH3 in MeOH solution) to give the desired product (20 mg, 42.3%) as a white solid. ESI-MS m / z: 631.15 [M+H] + .

[0918] Example 504 Step e

[0919]

[0920] The mixture of the 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 hour. The reaction was monitored by LCMS. The residue was purified by reversed-phase rapid chromatography to the desired product (20 mg, 59%) as a yellow solid. ESI-MS m / z: 845.05 [M+H] + .

[0921] Example 504 Step f

[0922]

[0923] At room temperature, a solution of LiOH (5 mg, 0.24 mmol) in H₂O (0.5 mL) was added dropwise to a stirred mixture of compound e (20 mg, 0.02 mmol) and MeOH (2 mL). The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH₂Cl₂ / 7 M NH₃ MeOH 10:1) to give the desired product (6.7 mg, 38%) as a white solid. ESI-MS m / z: 691.20 [M+H] + .

[0924] Example 505

[0925]

[0926] The following examples were prepared in a similar order to Example 504. The residue was purified by reversed-phase rapid chromatography to give the title compound (6.4 mg, 31%) as a white solid. ESI-MS m / z: 691.20 [M+H] + .

[0927] Table 9 below contains examples prepared using methods similar to those in Example 1 or the methods described above. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel).

[0928] Table 9

[0929]

[0930] Intermediate 81

[0931]

[0932] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (21.3 mg, 27%). ESI-MS m / z: 438.20 [M+H] + .

[0933] Intermediate 82

[0934]

[0935] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (197.5 mg, 72%). ESI-MS m / z: 485.10 [M+H] + .

[0936] Intermediate 83

[0937]

[0938] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (125.9 mg, 36%). ESI-MS m / z: 457.15 [M+H] + .

[0939] Intermediate 84

[0940]

[0941] Intermediate 84, Step a

[0942]

[0943] A mixture of 3-chloro-4-iodopyridine (4.3 g, 17.96 mmol), sodium difluoromethyl sulfinate (12.40 g, 89.79 mmol), and H₂O (52 mL) was stirred at room temperature. TFA was added to pH 7, followed by an additional TFA (3.07 g, 26.94 mmol). DCM (130 mL) was added, followed by dropwise addition of tert-butyl hydroperoxide (8.25 g, 91.59 mmol). The resulting mixture was stirred overnight at room temperature and monitored by LCMS. The mixture was neutralized to pH 8 with saturated NaHCO₃ (aqueous solution). 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 10:1) to the desired product (660 mg, 12%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 6.82 (t, J = 53.8 Hz, 1H), 7.88 (d, J = 5.0 Hz, 1H), 8.12 (d, J = 5.0 Hz, 1H).

[0944] Intermediate 84, Step b

[0945]

[0946] Under a nitrogen atmosphere at -78°C, in a 100-mL three-necked flask, n-BuLi (1.45 mL, 3.62 mmol) was added dropwise to a solution of the compound from step a (700 mg, 2.42 mmol) in THF (18 mL). The reaction mixture was stirred at -78°C for 15 minutes. Then, a solution of trimethyl borate (377 mg, 3.62 mmol) in 2 mL THF was added dropwise, and the mixture was stirred at room temperature for another 1 hour. The reaction was acidified to pH 3 with HCl (1 M aqueous solution). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (500 mg) as a brown solid. ESI-MS m / z: 208.10 [M+H] + .

[0947] Intermediate 85

[0948]

[0949] The above compound was prepared using intermediate 84 in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (103.5 mg, 51%). ESI-MS m / z: 439.15 [M+H] + .

[0950] Intermediate 86

[0951]

[0952] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (300 mg, 90%). ESI-MS m / z: 447.00 [M+H] + .

[0953] Intermediate 87

[0954]

[0955] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (100 mg, 71%). ESI-MS m / z: 467.05 [M+H] + .

[0956] Intermediate 88

[0957]

[0958] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (178 mg, 30%). ESI-MS m / z: 455.05 [M+H] + .

[0959] Intermediate 89

[0960]

[0961] The above compound was prepared in a similar manner to intermediate 9 to give the desired amino alcohol as a grayish-white solid (214.8 mg, 30%). ESI-MS m / z: 473.05 [M+H] + .

[0962] Intermediate 90

[0963]

[0964] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (293 mg, quantitative yield). ESI-MS m / z: 441.339 [M+H] + .

[0965] Intermediate 91

[0966]

[0967] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (107 mg, 97% yield). ESI-MS m / z: 443.157 [M+H] + .

[0968] Intermediate 92

[0969]

[0970] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (326 mg, 94% yield). ESI-MS m / z: 459.306 [M+H] + .

[0971] Intermediate 93

[0972]

[0973] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (326 mg, 98% yield). ESI-MS m / z: 403.068 [M+H] + .

[0974] Intermediate 94

[0975]

[0976] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (258 mg, quantitative yield). ESI-MS m / z: 426.378 [M+H] + .

[0977] Intermediate 95

[0978]

[0979] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (70 mg, 89% yield). ESI-MS m / z: 439.175 [M+H] + .

[0980] Intermediate 96

[0981]

[0982] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (475 mg, 98% yield). ESI-MS m / z: 473.240 [M+H] + .

[0983] Intermediate 97

[0984]

[0985] The above compound was prepared using a method similar to that used for intermediate 9, yielding an amino alcohol (135 mg, 65% yield). ESI-MS m / z: 439.26 [M+H] + .

[0986] Intermediate 98

[0987]

[0988] In a vial, (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (1 g, 3.09 mmol), 4-fluoro-1H-indazole (0.505 g, 3.71 mmol), and copper iodide (I) (0.059 g, 0.309 mmol) were suspended in toluene (20.63 ml). N,N-dimethylethane-1,2-diamine (0.067 ml, 0.619 mmol) was added, and the reaction was heated to 110 °C and maintained for 12 h. The reaction was cooled to room temperature and water was added. The aqueous layer was washed with EtOAc, and the combined organic layers were dried over MgSO4. The organic layers were concentrated under reduced pressure and purified by silica gel chromatography, eluting with 0–80% EtOAc / cHex, to give the title compound (540 mg, 46% yield). ESI-MS m / z: 379.00 [M+H] + .

[0989] Intermediate 99

[0990]

[0991] (R)-7-bromo-3-methyl-5-(3,3,3-trifluoroprop-1-en-2-yl)-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (675 mg, 1.92 mmol) was dissolved in toluene (9.61 ml), and K3PO4 (979 mg, 4.61 mmol) and 4-fluoro-1H-indole (338 mg, 2.50 mmol) were added. The suspension was initially purged with nitrogen, and N,N'-dimethylethylenediamine (62.1 µl, 0.577 mmol) and copper iodide (I) (54.9 mg, 0.288 mmol) were added sequentially. Purging was continued for 2 minutes, then the vial was sealed and heated to 110 °C with stirring and maintained for 2 hours. Subsequently, the reaction mixture was cooled to room temperature and diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by automated rapid chromatography on silica gel (0-100% EtOAc in cyclohexane solution) to give pure product 3 as a yellow oil (230 mg, 30%). ESI-MS m / z: 406.203.

[0992] Intermediate 100

[0993]

[0994] Intermediate 100, steps a and b

[0995]

[0996] Under N2, DMSO (200 mL) and t-BuOK (3.11 g, 27.72 mmol) were added to a flask containing 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (6.6 g, 26.40 mmol) and 2-methanesulfonylethanol (3.44 g, 27.72 mmol). The reaction was stirred at room temperature under N2 for 20 h. Another portion of 2-methanesulfonylethanol (3.44 g, 27.72 mmol) and t-BuOK (3.11 g, 27.72 mmol) was added, and the reaction was stirred for another 3.5 h. The reaction was monitored by LCMS. The resulting mixture was washed with water. The aqueous layer was acidified to pH 3 with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 5-Bromo-3-methoxy-2-nitrophenol (9.3 g) was obtained as a brown solid. ESI-MS m / z: 249.95 [MH] - .

[0997] The solution of the compound from step a (9.3 g, 37.49 mmol) in EtOH (100 mL) was treated with a solution of NH4Cl (20.06 g, 374.95 mmol) in H2O (50 mL) and Fe (10.47 g, 187.47 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 2-amino-5-bromo-3-methoxyphenol (4.5 g, 55%) as a brown solid. ESI-MS m / z: 218.15 [M+H] + .

[0998] Intermediate 100 Step c

[0999]

[1000] A solution of the compound from step b (1.35 g, 6.19 mmol) in THF (20 mL) was treated with 1-fluorocyclopropane-1-carboxylic acid (322 mg, 3.10 mmol), EDCI (1.19 g, 6.19 mmol), and HOBt (837 mg, 6.19 mmol) at room temperature 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 silica gel column chromatography, eluting with PE / EA (2:1) to give the desired compound (823 mg, 44%) as a white solid. ESI-MS m / z: 303.95 [M+H] + .

[1001] Intermediate 100, steps d and e

[1002]

[1003] A solution of the compound from step c (640 mg, 2.10 mmol) in POCl3 (5 mL, 53.65 mmol) was heated at 80 °C for 16 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 silica gel column chromatography, eluting with PE / EA (3:1) to give the desired compound (180 mg, 30%) as an orange solid. ESI-MS m / z: 285.90 [M+H] + .

[1004] The solution of the compound from step d (180 mg, 0.63 mmol) in DMF (3 mL) was treated with Pd(OAc)₂ (14 mg, 0.06 mmol), Xantphos (36 mg, 0.06 mmol), Ac₂O (128 mg, 1.26 mmol), DIEA (163 mg, 1.26 mmol), and oxalic acid (113 mg, 1.26 mmol) at 100 °C for 5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reversed-phase rapid chromatography to give the title compound (81.8 mg, 45%) as a white solid. ESI-MS m / z: 252.10 [M+H] + .

[1005] Intermediate 101

[1006]

[1007] Intermediate 101 Step a

[1008]

[1009] A solution of 2-amino-5-bromo-3-methoxyphenol (1.4 g, 6.42 mmol) in THF (15 mL) was treated with difluoroacetic acid (617 mg, 6.42 mmol), EDCI (2.46 g, 12.84 mmol), and HOBt (1.74 g, 12.84 mmol) at room temperature 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 silica gel column chromatography, eluting with PE / EA (1:1) to give the desired compound (1.4 g, 74%) as an orange solid. ESI-MS m / z: 295.85 [M+H] + .

[1010] Intermediate 101, Step b

[1011]

[1012] A solution of the compound from step a (1.36 g, 4.59 mmol) in CHCl3 (15 mL) was treated with POCl3 (1.06 g, 6.89 mmol) at 65 °C for 2 days. 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 (727 mg, 57%) as a white solid. ESI-MS m / z: 227.90 [M+H] + .

[1013] Intermediate 101, Step c

[1014]

[1015] The solution of the compound from step b (687 mg, 2.47 mmol) in DMF (10 mL) was treated with Pd(OAc)₂ (55 mg, 0.25 mmol), Xantphos (143 mg, 0.25 mmol), Ac₂O (504 mg, 4.94 mmol), DIEA (639 mg, 4.94 mmol), and oxalic acid (445 mg, 4.94 mmol) at 100 °C for 5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the title compound (585.1 mg, 89%) as a brown solid. ESI-MS m / z: 244.05 [M+H] + .

[1016] Intermediate 102

[1017]

[1018] Intermediate 102 Step a

[1019]

[1020] A solution of 3-chloro-2-(trifluoromethyl)pyridine (900 mg, 4.96 mmol) in THF (7 mL) was treated with LDA (2.5 mL, 4.96 mmol) at -78 °C for 1 h under nitrogen atmosphere, followed by the addition of I2 (1.26 g, 4.96 mmol) in THF (3 mL) in portions at -78 °C. The final reaction mixture was allowed to react at room temperature for 10 min. The reaction was monitored by LCMS. The reaction was quenched with Na2S2O3 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 (954 mg, 63%) as a yellow solid. ESI-MS m / z: 307.85 [M+H] + .

[1021] Intermediate 102, Step b

[1022]

[1023] A solution of the compound from step a (1.35 g, 4.39 mmol) in THF (10 mL) was treated with butyllithium (2.6 mL, 6.59 mmol) at -78 °C for 10 min under a nitrogen atmosphere, followed by the addition of trimethyl borate (684 mg, 6.59 mmol) in portions at -78 °C. The reaction was stirred for 1 h and monitored by LCMS. The mixture was acidified to pH 2 with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to give the desired compound (834 mg, crude) as a brown solid. ESI-MS m / z: 225.95 [M+H] + .

[1024] Table 10 below contains examples prepared using methods similar to those in Example 1 or the methods described above. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel).

[1025] Table 10

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043] Intermediate 103

[1044]

[1045] Intermediate 103 Step a

[1046]

[1047] A solution of 4-bromo-3-chloropyridin-2-amine (1 g, 4.82 mmol) in 2-chloroacetaldehyde (10 mL) was heated at 100 °C for 16 h. The reaction was monitored by LCMS. The mixture was alkalized to pH 10 with saturated Na₂CO₃ (aqueous solution). The resulting mixture was extracted with CH₂Cl₂ / MeOH (10:1). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:2) to give the desired compound (890 mg, 80%) as a pale yellow solid. ESI-MS m / z: 230.85 [M+H] + .

[1048] Intermediate 103, Step b

[1049]

[1050] The solution of the compound from step a (500 mg, 2.16 mmol) in THF (7 mL) was treated with n-BuLi (1.3 mL, 3.24 mmol) at -78 °C for 5 min under a nitrogen atmosphere, followed by the fractional addition of Tin-San (1.05 g, 3.24 mmol) at -78 °C. The final reaction mixture was reacted at room temperature 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 resulting mixture was used directly for the next step without further purification. ESI-MS m / z: 443.05 [M+H] + .

[1051] Intermediate 104

[1052]

[1053] Intermediate 104 Step a

[1054]

[1055] Under a nitrogen atmosphere at -78°C, n-BuLi (216 mg, 3.37 mmol) was added dropwise to a stirred solution of 4-bromo-3-chloro-2-methoxypyridine (500 mg, 2.25 mmol) in 20 mL of THF. Trimethyl borate (350 mg, 3.37 mmol) was then added at -78°C. The reaction was monitored by LCMS. The reaction was quenched with NH4Cl solution at -78°C. The crude product was purified by reversed-phase rapid chromatography to give the desired product (300 mg, 71%) as a yellow solid. ESI-MS m / z: 188.00 [M+H] + .

[1056] Intermediate 104, Step b

[1057]

[1058] The solution of the compound from step a (300 mg, 1.6 mmol) and HCl (4 mL) in dioxane (15 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to give the desired product (70 mg, 25%) as a yellow solid. ESI-MS m / z: 174.00 [M+H] + .

[1059] Intermediate 105

[1060]

[1061] Intermediate 105 Step a

[1062]

[1063] A mixture of 5-bromo-6-chloropyridin-2-amine (1 g, 4.82 mmol), chloroacetaldehyde (563 mg, 7.23 mmol), and NaHCO3 (486 mg, 5.78 mmol) in EtOH (10 mL) and H2O (2.5 mL) was stirred at 80 °C for 4 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 reversed-phase rapid chromatography to give the desired product (380 mg, 34%) as a brown solid. ESI-MS m / z: 232.85 [M+H] + .

[1064] Intermediate 105, Step b

[1065]

[1066] Under a nitrogen atmosphere at -78°C, in a 50 mL round-bottom flask, n-BuLi (0.5 mL, 1.25 mmol) was added dropwise to a solution of the compound from step a (200 mg, 0.86 mmol) in THF (5 mL). The reaction mixture was stirred at -78°C for 10 min. Then, a solution of Tin-San (422 mg, 1.30 mmol) in THF (0.5 mL) was added dropwise, and the mixture was stirred for another 30 min. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly for the next step without further purification. ESI-MS m / z: 442.95 [M+H] + .

[1067] Intermediate 106

[1068]

[1069] Intermediate 106 Step a

[1070]

[1071] A solution of 4-bromo-3-chloropyridin-2-amine (500 mg, 2.41 mmol) and chloroacetone (446 mg, 4.82 mmol) in EtOH (10 mL) was stirred overnight at 80 °C under nitrogen atmosphere. The residue was purified by reversed-phase rapid chromatography to give the desired product (300 mg, 51%) as a yellow solid. ESI-MS m / z: 245.00 [M+H] + .

[1072] Intermediate 106, Step b

[1073]

[1074] A solution of the compound from step a (100 mg, 0.41 mmol), bis-pinacolborate (207 mg, 0.81 mmol), AcOK (80 mg, 0.81 mmol), and Pd(dppf)Cl2 (30 mg, 0.04 mmol) in dioxane (1 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The solution was filtered and used directly in the next step. ESI-MS m / z: 211.00 [M+H] + .

[1075] Intermediate 107

[1076]

[1077] Intermediate 107, steps a and b

[1078]

[1079] A solution of 2-bromopyridin-4-amine (5 g, 28.9 mmol) and NCS (3.86 g, 28.9 mmol) in ACN (100 mL) was stirred at 50 °C for 5 hours. The resulting mixture was concentrated and purified by silica gel column chromatography, eluting with PE / EA (3:1) to give the desired compound (4.5 g, 75%) as a yellow crude solid. ESI-MS m / z: 208.95 [M+H] + .

[1080] A solution of the compound from step a (3 g, 14.46 mmol) and cyclopropylboronic acid (1.24 g, 14.46 mmol), PCy3 (0.41 g, 1.45 mmol), Pd(OAc)2 (162.33 mg, 0.72 mmol), and K3PO4 (9.21 g, 43.38 mmol) in toluene (30 mL) and H2O (6 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give the desired compound (1 g, 41%) as a pale yellow oil. ESI-MS m / z: 169.10 [M+H] + .

[1081] Intermediate 107, steps c and d

[1082]

[1083] A solution of the compound from step b (790 mg, 4.68 mmol), 2-methyl-2-propyl nitrite (966 mg, 9.37 mmol), and CuBr2 (2092 mg, 9.37 mmol) in 10 mL of ACN was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography, eluting with PE / EA (3:1) to give the desired compound (550 mg, 50%) as a white solid. ESI-MS m / z: 233.85 [M+H] + .

[1084] A solution of the compound from step c (100 mg, 0.43 mmol), bis-pinacol boronic acid ester (164 mg, 0.65 mmol), Pd(dppf)Cl2CH2Cl2 (35 mg, 0.04 mmol), and KOAc (84 mg, 0.86 mmol) in dioxane (2 mL) was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered and used directly in the next step. The hydrolyzed pinacol ESI-MS m / z: 198.10 [M+H] + .

[1085] Table 11 below contains examples prepared using intermediates described above or previously as follows, in a manner similar to Example 47. If necessary to drive the conversion, additional palladium and boric acid were added. Most compounds were purified and diastereomers separated by preparative HPLC (ACN / H2O, 20-90%, 25 min). If reported as a mixture of diastereomers, they may not be separable by HPLC.

[1086] Table 11

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099] Example 884

[1100]

[1101] A solution of (R)-7-(5-chloro-2,4-difluorophenyl)-5-((S)-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamidyl)-1-hydroxy-1-(2-(methylamino)pyridin-4-yl)ethyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (20 mg, 0.03 mmol), HCHO (8.5 mg, 0.3 mmol), AcOH (3.4 mg, 0.06 mmol), and NaBH3CN (3.6 mg, 0.06 mmol) in MeOH (1 mL) was stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to obtain the desired product (6 mg, 29%) as a white solid. ESI-MS m / z: 718.25 [M+H] + .

[1102] Example 885

[1103]

[1104] A solution of (R)-7-bromo-5-((S)-1-cyclopropyl-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamido)-1-hydroxyethyl)-3-methyl-2,3-dihydrofuran[2,3-c]pyridine-3-carboxamide (20 mg, 0.03 mmol), 1H-indazole (4 mg, 0.03 mmol), K₂CO₃ (7 mg, 0.05 mmol), CuBr (2 mg, 0.02 mmol), and methyl[2-(methylamino)ethyl]amine (5 mg, 0.05 mmol) in dioxane (1 mL) was stirred at 105 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (15:1) to give the crude product. The crude product was purified by preparative HPLC to obtain the desired product (2.3 mg, 10.3%) as a white solid. ESI-MS m / z: 608.20 [M+H] + .

[1105] The compounds listed in Table 12 were prepared using the general methods described above.

[1106] Table 12

[1107]

[1108] Table 13 below contains compounds prepared using methods similar to those in Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), while some were purified by automated column chromatography (silica gel). Aromatic acid and amine coupling couplers were prepared as described above for intermediates or previously.

[1109] Table 13

[1110]

[1111]

[1112]

[1113] The compounds listed in Table 14 were prepared using the general methods described above.

[1114] Table 14

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123] Assays

[1124] RSV-A Measurement Method

[1125] Hep-2 cells (originally derived from tumors grown in irradiated and cortisone-treated weaned rats injected with laryngeal epidermoid carcinoma tissue from a 56-year-old male, but later found indistinguishable from HeLa cells by PCR DNA analysis) were used to culture the genotype A, "Long" strain RSV. Flasks were inoculated with RSV, and the viral stock was collected when the cytopathic effect (CPE) was greater than 90%. The viral stock in 25% sucrose medium was flash-frozen in liquid nitrogen to increase viral stability. The viral stock titer was determined by 50% tissue culture infectious dose (TCID). 50 Quantification was performed using 8,000 cells per well and a 3-fold virus dilution in a 96-well plate, incubated for 4 days. Virus stock titers were also quantified using a plaque-forming unit assay, as described elsewhere.

[1126] After extensive parameter testing, the final run was determined as follows: Hep-2 cells were seeded into 60 wells of a 96-well plate at a density of 8,000 cells per well, with a volume of 50 µL, using growth medium (phenol red-free DMEM, 1% L-Glut, 1% penicillin / streptomycin, 1% non-essential amino acids, 10% heat-inactivated FBS). Serial dilutions of control and test compounds were added in duplicate to the wells, for a total volume of 25 µL. Virus stock solution was then added to the wells at a multiplicity of infection (MOI) of 0.1, with a volume of 25 µL, bringing the total volume per well to 100 µL. MOI was calculated using PFU / mL, or TCID if unavailable. 50Each 96-well plate had a control column containing six wells with cells and virus but no compound (negative control, maximum CPE), one column with cells but no compound or virus (positive control, minimum CPE), and one column with no cells, virus, or compound (background / reagent control). The control wells with cells but no virus were additionally given 25 µL of growth medium containing an equal volume of sucrose, as were the wells receiving the viral stock solution, to maintain consistency in medium and volume conditions. The outer wells of the plate were filled with 125 µL of moat medium (DMEM, 1% penicillin / streptomycin) as a heat and evaporation moat around the test wells. After a 5-day incubation period, the plates were 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 were read using an Envision luminescence detector. These data were used to calculate the EC50 of each compound. 50 (Table 15). EC 50 The ranges are as follows: A < 0.2 μM; B > 0.2 μM.

[1127] Table 15 Summary of RSV-A activity

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140] HMPV antiviral assay method

[1141] Method 1:

[1142] The in vitro antiviral activity of HMPV was evaluated using the clinical isolate A2 strain TN 94-49 (obtained from Dr. John Williams of Vanderbilt University, Tennessee) and LLC-MK2 cells (ATCC#CCL-7, an immortalized renal epithelial cell line from macaques (Macaca mulatta).

[1143] The compound was resuspended in dimethyl sulfoxide (DMSO) at 10 mM, serially diluted, and added to 384-well source plates. Subsequently, the compound was diluted and transferred to 384-well assay plates using an Echo-650 automated liquid handling system (Beckman Coulter, Indiana). The test compound was evaluated in duplicate, with a maximum concentration of 2 µM, followed by 2.5-fold serial dilutions for a total of 10 concentration points. DMSO control wells were also included on the assay plates and were either infected or uninfected, serving as positive and negative controls, respectively.

[1144] A2 TN 94-49 virus infection was performed on LLC-MK2 cells in suspension. Cells were washed twice with PBS and removed from the cell culture flasks with 0.25% trypsin-EDTA (Thermo Fisher Scientific, MA). Trypsin-EDTA was inactivated by resuspending in 2% fetal bovine serum (FBS) containing 1% penicillin-streptomycin and OptiMEM (Thermo Fisher Scientific, MA). Cells were pelleted by centrifugation at 800 rpm for 5 min, the supernatant was removed, and the cells were resuspended and washed with PBS containing 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% penicillin-streptomycin (Thermo Fisher Scientific, MA), and 100 µg / mL CaCl2. Cells were counted and seeded at a density of 5,000 cells / well, 12.5 µL / well.

[1145] Viral infection was performed at a multiple of infection (MOI) of 0.005, with 12.5 µL added to each well. Infection was carried out in infection medium containing SF-OptiMEM, 100 µg / mL CaCl2, and 1% penicillin-streptomycin. The HMPV virus stock solution was suspended in infection medium + 5% glycerol; therefore, an equal volume of infection medium + 5% glycerol was added to uninfected wells to ensure a uniform final glycerol percentage across all wells in the assay plate. The final concentration of TPCK-trypsin was 2 µg / mL. The assay plate was incubated at 37°C with 5% CO2 for 7 days.

[1146] After 7 days of incubation, 12.5 µL of ATP-Lite (PerkinElmer, MA) was added to each well, and the raw luminescence value was measured using an Envision 2104 (PerkinElmer, MA). The average raw luminescence value of cell-only and virus-positive control wells was subtracted from all tested conditions, and the percentage of healthy cells was determined by dividing these values ​​by the average of cell-only negative control wells. EC was then calculated using a four-parameter curve logistic equation via nonlinear regression. 50 Value. The curve fitting model used is the XLFit Dose Response One Site Model 200:

[1147] y = (A+(B / (1+((x / C)^D)))), where A is the minimum y value, B is the maximum y value, and C is logEC. 50 The value, D, is the slope factor.

[1148] Method 2:

[1149] The in vitro antiviral activity of HMPV was evaluated using the clinical isolate A2 strain TN 94-49.

[1150] The in vitro antiviral activity of HMPV was evaluated using the clinical isolate A2 strain TN 94-49 (obtained from Dr. John Williams of Vanderbilt University, Tennessee) and LLC-MK2 cells (Millipore Sigma CB_85062804, an immortalized renal epithelial cell line from macaques (Macaca mulatta)).

[1151] The compound was resuspended in dimethyl sulfoxide (DMSO) at 10 mM, serially diluted, and added to 384-well source plates. Subsequently, the compound was diluted and transferred to 384-well assay plates using an Echo-650 automated liquid handling system (Beckman Coulter, Indiana). The test compound was evaluated in duplicate, with a maximum concentration of 200 nM, followed by 2.5-fold serial dilutions for a total of 10 concentration points. DMSO control wells were also included on the assay plates and were either infected or uninfected, serving as positive and negative controls, respectively.

[1152] A2 TN 94-49 virus infection was performed on LLC-MK2 cells in suspension. Cells were washed twice with PBS and removed from the cell culture flasks with 0.25% trypsin-EDTA (Thermo Fisher Scientific, MA). Trypsin-EDTA was inactivated by resuspending in 2% fetal bovine serum (FBS) containing 1% antibiotic-antifungal agent and OptiMEM (Thermo Fisher Scientific, MA). Cells were pelleted by centrifugation at 800 rpm for 5 min, the supernatant was removed, and the cells were resuspended and washed with PBS containing 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-antifungal agent (Thermo Fisher Scientific, MA), 100 µg / mL CaCl2, and 4 µM CP-100-356 (a P-glycoprotein inhibitor). Cells were counted and seeded at a density of 5,000 cells / well and 12.5 µL / well.

[1153] Viral infection was performed at a multiple of infection (MOI) of 0.16, with 12.5 µL added to each well. Infection was carried out in infection medium containing SF-OptiMEM, 100 µg / mL CaCl2, and 1% antibiotic-antifungal agent. The HMPV virus stock solution was suspended in infection medium + 5% glycerol; therefore, an equal volume of infection medium + 5% glycerol was added to uninfected wells to ensure a uniform final glycerol percentage 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 with 5% CO2 for 7 days.

[1154] After 7 days of incubation, 12.5 µL of ATP-Lite (PerkinElmer, MA) was added to each well, and the raw luminescence value was measured using an Envision 2104 (PerkinElmer, MA). The average raw luminescence value of cell-only and virus-positive control wells was subtracted from all tested conditions, and the percentage of healthy cells was determined by dividing these values ​​by the average of cell-only negative control wells. EC was then calculated using a four-parameter curve logistic equation via nonlinear regression. 50 Value. The curve fitting model used is the XLFit dose-response unit point model 200:

[1155] y = (A+(B / (1+((x / C)^D)))), where A is the minimum y value, B is the maximum y value, and C is logEC. 50 The value, D, is the slope factor.

[1156] These data are used to calculate the EC50 of each compound. 50 (Table 16).

[1157] Method 1 EC 50 The ranges are as follows: A < 0.5 μM; B > 0.5 μM. Method 2 EC 50 The ranges are as follows: A < 0.2 μM; B > 0.2 μM.

[1158] Table 16 Summary of hMPV A2 TN / 94-49 activity

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174] Although the invention has been particularly shown and described with reference to its preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the invention as covered by the appended claims.

Claims

1. A compound represented by any one of formulas (X-1) ~ (X-12): ， in: E is an optional substituted heteroaryl group; R 31 It 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; R 32 It is hydrogen, optionally substituted –C1-C6 alkyl, optionally substituted –C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic group, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; n is 0, 1 or 2; and R 33 and R 34 Each is 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 heterocyclic alkyl, optionally substituted aryl and optionally substituted heteroaryl.

2. The compound according to claim 1, wherein, E is selected from the following groups: ， Where R 31 'Is it hydrogen or R?' 31 And R 31 and n as defined in claim 1.

3. A compound selected from the plurality of compounds listed below, or a pharmaceutically acceptable salt thereof: 。 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

5. A method of treating or preventing RSV infection in a subject in need, 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. The method of claim 5, further comprising the step of administering an additional anti-RSV agent to the subject.

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

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

9. The method according to claim 6, wherein, The compound and the other anti-RSV agent were co-formulated.

10. The method according to claim 6, wherein, The compound and the other anti-RSV agent were co-administered.

11. The method according to claim 6, wherein, Compared to the separate administration of additional anti-RSV agents required to achieve similar results in prophylactic treatment of RSV infection in subjects in need, administration of the compound allows for the administration of the additional anti-RSV agents at a lower dose or frequency.

12. A method of treating or preventing HMPV infection in a subject in need, 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.

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

14. The method according to claim 13, wherein, The compound and the other anti-HMPV agent were co-formulated.

15. The method according to claim 13, wherein, The compound and the other anti-HMPV agent were co-administered.

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