Antiviral heterocyclic compounds

Abstract

The present invention relates to formula (I): [Formula 1] JPEG2026513827000477.jpg3557 The present invention discloses compounds or pharmaceutically acceptable salts, esters, or prodrugs thereof that (I) inhibit inhibitors of human respiratory syncytial virus (HRSV) or human metapneumovirus (HMPV). The present invention further relates to a pharmaceutical composition comprising the above-mentioned compounds for administration to a subject suffering from HRSV or HMPV infection. The present invention also relates to a method for treating HRSV or HMPV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

[Technical Field]

[0001] Related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 457,546, filed on April 6, 2023, and U.S. Provisional Patent Application No. 63 / 541,923, filed on October 2, 2023. The entire teachings of the above applications are incorporated herein by reference.

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

[0003] Human respiratory syncytial virus (HRSV) is a negative sense virus containing an unsegmented single-stranded linear RNA genome. As a paramyxovirus of the genus Pneumoviridae with two serotypes, HRSV contains 10 genes encoding 11 proteins. The nucleocapsid protein (N), RNA polymerase protein (L), phosphorylated protein (P), and transcriptional 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), which is crucial for viral attachment to the host, has been widely studied. High-resolution structures of the F protein that interact with inhibitors have been achieved, but structural studies using the N protein are in the early stages of development. HRSV protein research and its direct results, the F, L, and N proteins, have been a major focus of drug discovery efforts.

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

[0005] HRSV infection can also affect healthy individuals, and recurrent HRSV infections can occur over a period of two months. Symptoms are similar to a common cold in healthy individuals, but fever, wheezing, rapid and difficult breathing, and cyanosis may occur in more severe cases.

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

[0007] Several RSV fusion inhibitors are disclosed in the following publications: International Publication No. 2010 / 103306, International Publication No. 2012 / 068622, International Publication No. 2013 / 096681, International Publication No. 2014 / 060411, International Publication No. 2013 / 186995, International Publication No. 2013 / 186334, International Publication No. 2013 / 186332, International Publication No. 2012 / 080451, and International Publication No. 2012 / 08045. Issue 0, International Publication No. 2012 / 080449, International Publication No. 2012 / 080447, International Publication No. 2012 / 080446, International Publication No. 2015 / 110446, International Publication No. 2017 / 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: International Publication 2004 / 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: International Publication 2011 / 005842, International Publication 2005 / 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: International Publication No. 2011 / 005842, International Publication No. 2013 / 242525, International Publication No. 2014 / 031784, International Publication No. 2015 / 026792, International Publication No. 2016 / 0055791, International Publication No. 2016 / 138158, and J.Med.Chem. 2015, 58, 1862-1878.

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

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

[0010] HMPV infection is the second most common cause of lower respiratory tract infections in children (after HRSV) and is also a concern in older populations. There are four subtypes of HMPV found in clinical isolates (A1, A2, B1, and B2). Reinfection can occur throughout childhood after the initial infection. There are currently no available treatments for HMPV infection.

[0011] Given the seasonality and predictability of HRSV and HMPV outbreaks, the prevalence of HRSV in elderly care facilities, and the severity of infections in high-risk infants, the need for potent and effective treatment of HRSV and HMPV is clear. This invention identifies compounds that are potent heterocyclic molecules against HRSV-A / B and HMPV. This invention includes methods for preparing these molecules, methods for RSV cell line assays, methods for HMPV-TN / 94-49A2 cell line assays, and small molecules with potential to treat HRSV / HMPV infections. [Overview of the project]

[0012] The present invention provides compounds represented by formula (I) and pharmaceutically acceptable salts, esters, and prodrugs thereof that can be used to treat or prevent viral infections (particularly HRSV or HMPV). [ka] During the ceremony, A is 1) Arbitrarily substituted aryl, and 2) A heteroaryl compound that has been arbitrarily substituted, E is 1) Arbitrarily substituted aryl, and 2) A heteroaryl compound that has been arbitrarily substituted, R1 and R2 are independent of each other. 1) Hydrogen, 2) Optionally substituted C1-C8 alkyl, 3) Optionally substituted C3-C8 cycloalkyl, 4) Optionally substituted 3- to 8-membered heterocycloalkyl groups, 5) Arbitrarily substituted aryl, 6) Arbitrarily substituted arylalkyls, 7) Optionally substituted heteroaryls, and 8) Selected from the group consisting of arbitrarily substituted heteroarylalkyls, Alternatively, R1 and R2, together with the nitrogen atom to which they are bonded, form an optionally substituted 3- to 8-membered heterocycle. R3 is either hydroxyl or fluorine. R4 is 1) Hydrogen, 2) Arbitrarily substituted -C1-C6 alkyl groups; 3) Arbitrarily substituted -C2-C6 alkynyl, 4) Optionally substituted C3-C8 cycloalkyl, 5) Arbitrarily substituted 3- to 8-membered complex rings, 6) Arbitrarily substituted aryl, 7) Arbitrarily substituted arylalkyls, 8) Optionally substituted heteroaryls, and 9) Optionally substituted heteroarylalkyl Selected from the group consisting of, Each of the above preferred groups can be used individually, in combination with any, or in combination with all other preferred groups. [Modes for carrying out the invention]

[0013] One embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments of the compound of formula (I), R1 is hydrogen.

[0015] In certain embodiments of the compound of formula (I), R1 is hydrogen and R2 is hydrogen.

[0016] In certain embodiments of the compound of formula (I), R3 is -OH.

[0017] In certain embodiments of the compound of formula (I), R4 is optionally substituted methyl or optionally substituted cyclopropyl.

[0018] In certain embodiments of the compound of formula (I), R4 is as follows: [ka] One of the following will be selected.

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

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

[0021] In certain embodiments of the compound of formula (I), A is obtained by removing a hydrogen atom as follows: [ka] One of these is selected, and each of these bases is optionally substituted.

[0022] In certain embodiments of the compound of formula (I), A is selected from the following groups: [ka]

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

[0024] In certain embodiments of the compound of formula (I), E is selected from the following groups: [ka]

[0025] In certain embodiments of the compound of formula (I), R4 is an optionally substituted phenyl compound.

[0026] In certain embodiments of the compound of formula (I), R4 is an optionally substituted heteroaryl.

[0027] In certain embodiments of the compound of formula (I), R4 is selected from one of the following

Chemical formula

[0029] ,

[0028] , , , is halogen, -CN, -OR 33 , -CO2R 33 , -SO2R 33 , -SO2NR 33 R 34 , -NR 33 R 34 is optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, or optionally substituted -C3-C8 cycloalkyl, and R 32 is hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 member heterocyclic ring, 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 are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C2-C6 alkenyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 member heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl). Preferably, R 31 is selected from halogen, optionally substituted methyl, and optionally substituted methoxyl. More preferably, R 31 [ is -F, -Cl, -CH3, -CHF2, -CF3 or -OCH3.

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

[0029] In certain embodiments of the compound of formula (I), E is an optionally substituted heteroaryl, preferably an optionally substituted condensed bicyclic heteroaryl.

[0030] In certain embodiments of the compound of formula (I), E is selected from the following groups: [ka] (In the formula, R 31 And n are as defined above, R 31 ' is hydrogen or R 31 (That is.)

[0031] In certain embodiments of the compound of formula (I), E is selected from the following groups: [ka]

[0032] In certain embodiments of the compound of formula (I), A is obtained by removing a hydrogen atom as follows: [ka] One of these is selected, and each of these bases is optionally substituted.

[0033] In certain embodiments of the compound of formula (I), A is selected from the following groups: [ka]

[0034] In one embodiment of the present invention, the compound of formula (I) is represented by formula (Ia) or formula (Ib), or is a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] (wherein A, E, R1, R2, R3, and R4 are as previously defined). Preferably, the compound of formula (I) is represented by formula (Ia).

[0035] In one embodiment of the present invention, the compound of formula (I) is represented by formula (II), or is a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] (In the formula, A, E, R3, and R4 are as defined above.)

[0036] In one embodiment of the present invention, the compound of formula (I) is represented by formula (IIa), or is a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] (In the formula, A, E, R3, and R4 are as defined above.)

[0037] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (III-1) to (III-7), or is a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] (In the formula, A, E, R1, and R2 are as defined above.)

[0038] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), or is a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] (In the formula, A and E are as defined above.)

[0039] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), where A is the group shown below. [ka] Selected from, E is based on the following basis [ka] Selected from.

[0040] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), where A is selected from one of the following by the removal of a hydrogen atom, and each of these groups is optionally substituted. [ka] E is based on the following basis [ka] Selected from (In the formula, R 31 , R 31 (And n are as defined above).

[0041] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-7), where A is selected from one of the following by the removal of a hydrogen atom, and each of these groups is optionally substituted. [ka] E is based on the following basis [ka] Selected from.

[0042] In one embodiment of the present 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. [ka] (In the formula, E and R4 are as defined above, R 11 (Selected from optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl). Preferably, R 11 is optionally substituted methyl or optionally substituted cyclopropyl. Preferably, R 11 It is methyl or cyclopropyl.

[0043] R 12 R is selected from hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Preferably, R 12 is optionally substituted methyl or optionally substituted cyclopropyl. More preferably, R 12 -CH3, -CHF2, -CD3, cyclopropyl, [ka] or [ka] That is the case.

[0044] R 13 and R 14These are, independently, hydrogen, halogen, and -OR. 11 Selected from -NH2, optionally substituted -C1-C6-alkyl, optionally substituted -C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl. Alternatively, R 13 and R 14 These, together with the carbon atoms to which they are bonded, form a 4- to 7-membered ring fused with a phenyl ring. Preferably, R 13 and R 14 Each of these is independently selected from halogens, optionally substituted methyl atoms, and optionally substituted methoxyls.

[0045] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), where E is a substituted phenyl and R4 is as follows: [ka] One of the following will be selected.

[0046] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), where E is the group shown below. [ka] Selected from.

[0047] In one embodiment of the present invention, the compound of formula (I) is represented by formula (V-1) or formula (V-2), where E is a substituted phenyl, and R 11 R is optionally substituted methyl or optionally substituted cyclopropyl, 12 R is optionally substituted methyl or optionally substituted cyclopropyl, 13 and R 14Each of these is independently selected from halogen, optionally substituted methyl, and optionally substituted methoxyl, and R4 is as follows: [ka] One of the following will be selected.

[0048] In one embodiment of the present 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. [ka] (In the formula, R4, R 11 , R 12 , R 13 and R 14 As defined earlier, R 21 , R 22 , R 23 , R 24 and R 25 Each of these is independently selected from hydrogen, halogen, optionally substituted methyl, and optionally substituted methoxyl.

[0049] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (VII-1) to (VII-6), or is a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] (In the formula, R 11 , R 12 , R 13 , R 14 , R 21 , R 22 , R 23 , R 24 and R 25 (This is as defined earlier.)

[0050] In one embodiment of the present 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: [ka] (In the formula, A, E, R1, R2, R 31 (and n are as defined above).

[0051] In one embodiment of the present 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: [ka] (In the formula, A, E, R1, R2, R 31 (and n are as defined above).

[0052] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (VIII-1a) to (VIII-2a), where A is selected from one of the following by the removal of a hydrogen atom, and each of these groups is optionally substituted. [ka] E is based on the following basis [ka] Selected from (In the formula, R1, R2, R 31 , R 31 (and n are as previously defined). Preferably, R1 is hydrogen and R2 is hydrogen.

[0053] In one embodiment of the present 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: [ka] (In the formula, E, R 11 , R 12 , R 13 , R 14 , R 31 (and n are as defined above).

[0054] In one embodiment of the present 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: [ka] (In the formula, E, R 11 , R 12 , R 13 , R 14 , R 31 (and n are as defined above).

[0055] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (IX-1a) to (IX-8a), and E is selected from the group shown below. [ka] (In the formula, R 11 , R 12 , R 13 , R 14 , R 31 , R 31 (And n are as defined above).

[0056] In one embodiment of the present 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. [ka] (In the formula, E, R 31 (and n are as defined above).

[0057] In one embodiment of the present invention, the compound of formula (I) is represented by one of the formulas (X-1) to (X-12), and E is selected from the group shown below. [ka] (In the formula, R 31 , R 31 (And n are as defined above).

[0058] It is understood that the description of the present 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 in order to accommodate a substituent at any given position.

[0059] The definition of any substituent or variable (e.g., R1, R2, etc.) at a specific location within a molecule is intended to be independent of its definition elsewhere within that molecule.

[0060] It is understood that the compounds of the present invention may contain one or more chiral carbon atoms and may exist in racemic, diastereoisomer, and optically active forms. It is further understood that certain compounds of the present invention may exist in different tautomeral forms. It is intended that all tautomers are within the scope of the present invention.

[0061] In certain embodiments, the present invention provides a method for the prevention or treatment of RSV activity and for treating RSV infection in subjects requiring such treatment. This method comprises administering a therapeutically effective amount of a compound of formula (I) to a subject.

[0062] The present invention also provides the use of compounds of formula (I) for preparing pharmaceuticals for the prevention or treatment of RSV.

[0063] Therefore, in one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a steroidal anti-inflammatory compound, such as 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 nonsteroidal anti-inflammatory compound, such as a leukotriene antagonist such as Singulair (Merck) or Accolate (Astra Zeneca), a phosphodiesterase 4 inhibitor such as roflumilast (Altana), a TNF-alpha inhibitor such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech), or an NSAID. In a further embodiment, the compound of formula (I) is combined with an interleukin 8 inhibitor or an interleukin 9 inhibitor. Accordingly, the present invention also relates to a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an anti-inflammatory compound for simultaneous, separate, or sequential use in the treatment of RSV.

[0064] The present invention also relates to combinations of the compound of formula (I) or a pharmaceutically acceptable salt thereof with an anti-influenza compound, and to the use of such combinations in the treatment of simultaneous RSV and influenza infections. Accordingly, the present invention also relates to products containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-influenza compound for simultaneous, separate, or sequential use in the treatment of simultaneous RSV and influenza infections. The compounds of the present invention can be administered in various dosage forms. Accordingly, they can be administered orally, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the present invention can also be administered parenterally, subcutaneously, intravenously, intramuscularly, intrasternally, percutaneously, or by infusion techniques. The compounds can also be administered as suppositories.

[0065] In one embodiment, the compounds of the present invention are administered by intranasal or intrabronchial administration. The present invention also provides an inhaler or nebulizer containing a pharmaceutical comprising (a) a derivative of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or diluent.

[0066] The present invention also provides a pharmaceutical composition containing such a benzodiazepine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0067] The compounds of the present invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, a solid oral form may contain, together with the active compound, a diluent, e.g., lactose, dextrose, saccharose, cellulose, corn starch, or potato starch; a lubricant, e.g., silica, talc, stearic acid, magnesium stearate, or calcium stearate, and / or polyethylene glycol; a binder, e.g., starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; a disaggregating agent, e.g., starch, alginic acid, alginate, or sodium starch glycolate; a foaming mixture; a dye; a sweetener; a wetting agent, e.g., lecithin, polysorbate, lauryl sulfate, and generally non-toxic and pharmacokinetically inert substances used in pharmaceutical formulations. Such pharmaceutical preparations may be produced by known methods, for example, by mixing, granulation, tableting, sugar coating, or film coating processes.

[0068] Liquid dispersions for oral administration may be syrups, emulsions, and suspensions. Syrups may contain, for example, saccharose or saccharose containing glycerin and / or mannitol and / or sorbitol as a carrier.

[0069] The suspensions and emulsions may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as a carrier. Suspensions or solutions for intramuscular injection may contain, along with the active compound, a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycol, such as propylene glycol, and optionally, an appropriate amount of lidocaine hydrochloride.

[0070] The solution for injection or infusion may contain, for example, sterile water as a carrier, or preferably in the form of sterile aqueous isotonic saline.

[0071] The present invention also relates to novel compounds as defined above, or pharmaceutically acceptable salts thereof, for use in methods of treating the body of a human or animal. The present invention also relates to pharmaceutical compositions comprising novel compounds as defined above and pharmaceutically acceptable diluents or carriers. Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a novel compound as defined above. A pharmaceutically acceptable salt is as defined above. The novel compounds of the present invention are typically administered in the manner defined above, and the compounds are formulated for administration in the manner defined above.

[0072] Preferably, the pharmaceutical composition contains optically active isomers of the novel compound of the present invention. Therefore, for example, a preferred novel compound of the present invention containing only one chiral center includes a substantially pure form of the R enantiomer, a substantially pure form of the S enantiomer, and an enantiomer mixture containing an excess of the R enantiomer or excess of the S enantiomer. It is particularly preferable that the pharmaceutical composition contains the compound of the present invention, which is a substantially pure optical isomer. To avoid misunderstanding, the novel compound of the present invention may be used in solvate form as needed.

[0073] Further aspects of the present invention are processes for producing any of the compounds described herein using any of the synthetic means described herein.

[0074] definition The following are definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout this specification and the claims, individually or as part of a larger group, unless specifically limited in particular cases.

[0075] As used herein, the term “aryl” refers to, but is not limited to, monocyclic, bicyclic, or polycyclic carbocyclic ring systems containing at least one aromatic ring, including phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. A polycyclic aryl may include fused rings, covalent rings, or combinations thereof.

[0076] As used herein, the term “heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N, the remaining ring atoms being carbon, and any N or S contained within the ring being optionally oxidizable. Heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and quinoxalinyl. Polycyclic heteroaryls may include fused rings, covalent rings, or combinations thereof.

[0077] According to the present invention, the aromatic group may be substituted or unsubstituted.

[0078] 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 bonded.

[0079] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbon radicals. Examples include "C1-C3 alkyl," "C1-C6 alkyl," and "C1-C 10 "Alkyl," "C2-C4 alkyl," or "C3-C6 alkyl" refers to alkyl groups containing 1-3, 1-6, 1-10, 2-4, and 3-6 carbon atoms, respectively. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals.

[0080] As used herein, the term “alkenyl” refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. 10 "Alkenyl," "C2-C8 alkenyl," "C2-C4 alkenyl," or "C3-C6 alkenyl" refers to an alkenyl group containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and octenyl.

[0081] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. 10 "Alkynyl," "C2-C8 alkynyl," "C2-C4 alkynyl," or "C3-C6 alkynyl" refers to an alkynyl group containing 2-10, 2-8, 2-4, or 3-6 carbon atoms, respectively. Typical alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, and octinyl.

[0082] As used herein, the term "cycloalkyl" refers to monocyclic or polycyclic saturated carbocyclic rings, or bicyclic or tricyclic group condensations, crosslinks, or spiro systems, where the carbon atoms may be oxosubstituted or optionally substituted with extracyclic olefins, imines, or oxime double bonds. Preferred cycloalkyl groups include C3-C 12 Examples include cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. 12 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, and spiro[4.4]nonanyl.

[0083] As used herein, the term "cycloalkenyl" refers to a monocyclic or polycyclic carbocyclic ring having at least one carbon-carbon double bond, or a bicyclic or tricyclic group condensation, bridge, or spiro system, wherein the carbon atoms may be oxosubstituted or optionally substituted with extracyclic olefins, imines, or oxime double bonds. Preferred cycloalkenyl groups include C3-C 12 Examples include cycloalkenyl groups, C3-C8 cycloalkenyl groups, or C5-C7 cycloalkenyl groups. 12 Examples of cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hepta-2-enyl, bicyclo[3.1.0]hexa-2-enyl, spiro[2.5]octa-4-enyl, spiro[4.4]nona-1-enyl, and bicyclo[4.2.1]nona-3-en-9-yl.

[0084] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is bonded 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 bonded to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which a heteroaryl group is substituted.

[0085] As used herein, the term “alkoxy,” when used alone or in combination with other terms, means an alkyl group having a specified number of carbon atoms bonded to the rest of the molecule via an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and their higher congeners and isomers, unless otherwise specified. Preferred alkoxys are (C1-C3)alkoxys.

[0086] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moieties described herein may also be aliphatic or alicyclic groups.

[0087] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, optionally including one or more unsaturated units such as double and / or triple bonds. Examples of aliphatic groups are alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH or C(O)NHS(O)2NH2 and other functional groups, groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of non-aromatic hydrocarbons (optionally substituted) are replaced by functional groups. The carbon atoms of the aliphatic group may optionally be oxo-substituted. The aliphatic group may be linear, branched, cyclic or a combination thereof, preferably containing from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups explicitly include, for example, alkoxyalkyl, polyalkoxyalkyl such as polyalkylene glycol, polyamine and polyimine. The aliphatic group is optionally substituted.

[0088] The term "carbocyclic" or "carbocyclic ring" refers to a saturated, partially unsaturated or aromatic cyclic group in which each atom within the ring is carbon. Examples of carbocyclic rings include cycloalkyl groups, cycloalkenyl groups and aryl groups.

[0089] The terms "heterocyclic ring" or "heterocycloalkyl" can be used interchangeably and refer to a non-aromatic ring or a bicyclic or tricyclic group that is fused, bridged or spiro-linked, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated, (iii) nitrogen and sulfur heteroatoms can be optionally oxidized, (iv) nitrogen heteroatoms can be optionally quaternized, (v) any of the above rings can be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms that can be optionally oxo-substituted or carbon atoms that can be optionally substituted with exocyclic olefin, imine or oxime double bonds. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups can be further substituted. The heteroaryl or heterocyclic group can be a C-bond or an N-bond (where possible).

[0090] It is 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 when used as a bond to link two or more groups or substituents that can be present on the same atom or different atoms. One of ordinary skill in the art can readily determine the valence of any such group from the context in which it occurs.

[0091] The term "substituted" means that one, two, or three or more hydrogen atoms are replaced with, but not limited to, -F, -Cl, -Br, -I, -OH, C1-C 12 -alkyl; C2-C12 -alkenyl, C2-C 12 -alkynyl, -C3-C 12 -cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thio, -NH-C1-C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C 12 -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C 12 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C 12 -cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12-alkyl, -OCONH-C2~C8-alkenyl, -OCONH-C2~C8-alkynyl, -OCONH-C3~C 12 -Cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C1~C 12 -alkyl, -NHC(O)-C2~C8-alkenyl, -NHC(O)-C2~C8-alkynyl, -NHC(O)-C3~C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-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-alkynyl, -NHC(O)NH-C3~C 12 -Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1~C 12 -alkyl, -NHC(S)NH-C2~C8-alkenyl, -NHC(S)NH-C2~C8-alkynyl, -NHC(S)NH-C3~C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1~C 12 -alkyl, -NHC(NH)NH-C2~C8-alkenyl, -NHC(NH)NH-C2~C8-alkynyl, -NHC(NH)NH-C3~C 12 -Cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C1~C 12-alkyl, -NHC(NH)-C2~C8-alkenyl, -NHC(NH)-C2~C8-alkynyl, -NHC(NH)-C3~C 12 -Cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1~C 12 -alkyl, -C(NH)NH-C2~C8-alkenyl, -C(NH)NH-C2~C8-alkynyl, -C(NH)NH-C3~C 12 -Cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1~C 12 -alkyl, -S(O)-C2~C8-alkenyl, -S(O)-C2~C8-alkynyl, -S(O)-C3~C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1~C 12 -alkyl, -SO2NH-C2~C8-alkenyl, -SO2NH-C2~C8-alkynyl, -SO2NH-C3~C 12 -Cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1~C 12 -alkyl, -NHSO2-C2~C8-alkenyl, -NHSO2-C2~C8-alkynyl, -NHSO2-C3~C 12 -Cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3~C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1~C 12 -alkyl, -S-C2~C8-alkenyl, -S-C2~C8-alkynyl, -S-C3~C 12This refers to substitution by independently replacing with substituents including -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. In certain embodiments, substituents are independently selected from halo, preferably Cl and F; C1-C4-alkyl, preferably methyl and ethyl; halo-C1-C4-alkyl, e.g., fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, e.g., cyclopropyl; C1-C4-alkoxy, e.g., methoxy and ethoxy; halo-C1-C4-alkoxy, e.g., fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH; NH2; C1-C4-alkylamino; di(C1-C4-alkyl)amino; and NO2. It is understood that aryl, heteroaryl, alkyl, etc., may be further substituted. In some cases, each substituent in the substitution is optionally further substituted with one or more groups, where each group is C 1- It is independently selected from C4-alkyl, -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2.

[0092] In certain embodiments, the substituted alkyl, alkenyl, or alkoxy group is substituted with one or more halogen atoms, preferably fluorine or chlorine atoms. Examples of such substituted alkyl groups include fluoromethyl, difluoromethyl, and trifluoromethyl. Examples of such substituted alkoxy groups include fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0093] As used herein, the terms "halo" or "halogen" refer to a fluorine, chlorine, bromine, or iodine atom, either alone or as part of another substituent.

[0094] As used herein, the term “optionally substituted” means that the group referred to may be substituted or unsubstituted. In one embodiment, the group referred to is optionally substituted with zero substituents, i.e., the group referred to is unsubstituted. In another embodiment, the group referred to is optionally substituted with one or more further groups individually and independently selected from the groups described herein.

[0095] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the enumeration of atoms includes other isotopes of that atom, insofar as the resulting compound is pharmaceutically acceptable.

[0096] In certain embodiments, compounds of each formula herein are defined as including isotope-labeled compounds. An “isotope-labeled compound” is a compound in which at least one atomic position is enriched to a level significantly greater than the natural abundance of a particular isotope of a given element. For example, one or more hydrogen atomic positions in a compound can be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, for example, to at least 1%, preferably at least 20%, or at least 50%. Such deuterated compounds may be metabolized more slowly than their non-deuterated analogs, and therefore may exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example, by using deuterated starting materials. Unless otherwise stated, isotope-labeled compounds are pharmaceutically acceptable.

[0097] As used herein, the term “hydroxyl-activating group” refers to an unstable chemical moiety known in the art to activate a hydroxyl group to detach during synthetic procedures such as substitution or elimination reactions. Examples of hydroxyl-activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, and phosphonates.

[0098] As used herein, the term "activated hydroxyl" refers to a hydroxyl group activated by one of the hydroxyl activating groups defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, and phosphonate groups.

[0099] As used herein, the term “hydroxy protecting group” refers to an unstable chemical moiety known in the art to protect a hydroxyl group from undesirable reactions during a synthetic procedure. After the synthetic procedure, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are generally described in T. Greene and P. G. M. W. Tuts, Protective Groups in Organic Synthesis, 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, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0100] As used herein, the term "protected hydroxyl" refers to a hydroxyl group protected by a hydroxyl protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, and methoxymethyl groups.

[0101] As used herein, the term “hydroxyprodrug group” refers to a promoyety group known in the art to transiently alter the physicochemical and therefore biological properties of a parent drug by coating or masking a hydroxyl group. After the synthesis procedure, the hydroxyprodrug group described herein must be able to revert to a hydroxyl group in vivo. Hydroxyprodrug groups known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992), and in Prodrugs Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects) on pp. 31-99 of “Prodrugs of Alcohols and Phenols,” edited by SSDhareshwar and VJStella, Springer and AAPSPress, 2007.

[0102] As used herein, the term “amino protecting group” refers to an unstable chemical moiety known in the art to protect an amino group from undesirable reactions during a synthetic procedure. After the synthetic procedure, the amino protecting groups described herein can be selectively removed. Amino protecting groups known in the art are generally described in T. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, and benzyloxycarbonyl.

[0103] As used herein, the term "protected amino" refers to an amino group protected by the amino protecting group defined above.

[0104] The term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom in substitution reactions such as nucleophilic substitution reactions. Examples of typical leaving groups include chloro, bromo, and iodine groups, sulfonic acid ester groups such as mesylate, tosylate, brosylate, and nosylate, and acyloxy groups such as acetoxy and trifluoroacetoxy.

[0105] As used herein, the term “aprotic solvent” refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, and chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether and bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be apparent to those skilled in the art that, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature range, individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example, in *Organic Solvents: Physical Properties and Methods of Purification*, 4th ed., edited by John A. Riddick et al., Vol. II, in *Techniques of Chemistry Series*, John Wiley & Sons, NY, 1986.

[0106] As used herein, the term “protic solvent” refers to solvents that tend to provide protons, such as alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, and t-butanol. Such solvents are well known to those skilled in the art, and it will be apparent to them that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature range. Further discussion of proton-donating solvents can be found in organic chemistry textbooks or specialized monographs, for example, in *Organic Solvents: Physical Properties and Methods of Purification*, 4th ed., edited by John A. Riddick et al., Vol. II, in *Techniques of Chemistry Series*, John Wiley & Sons, NY, 1986.

[0107] The substituent and variable combinations envisioned in this invention are limited to those that result in the formation of stable compounds. As used herein, the term “stable” refers to a compound that is stable enough to enable production and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0108] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high-pressure liquid chromatography, or recrystallization. Further methods for synthesizing the compounds of the formulas herein will be obvious to those skilled in the art, as can be understood by those skilled in the art. Furthermore, various synthetic steps can be carried out in alternative order or sequence to obtain the desired compounds. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art, for example, R. Larock, Comprehensive Organic Transformations, 2 ndEd. Wiley-VCH (1999); T.W. Greene and P.G.M. 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 those described in L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), as well as subsequent editions thereof are included.

[0109] 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, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, etc.

[0110] The compounds of the present invention may be modified by adding suitable functional groups to enhance their selective biological properties. Such modifications are known in the art and may include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), enhance oral availability, increase solubility to enable administration by injection, alter metabolism, and alter the excretion rate.

[0111] The compounds described herein contain one or more chiral centers and thus give rise to other stereoisomeric forms that can be defined in terms of enantiomers, diastereomers, and absolute stereochemistry as (R)- or (S)- or (D)- or (L)- with respect to the amino acid. The present invention is intended 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 above procedure or by splitting racemic mixtures. Splitting can be carried out by chromatography in the presence of a splitting agent, by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding splitting can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Where the compounds described herein contain olefin double bonds, other unsaturated or other geometrically chiral centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers or cis and trans isomers. Similarly, all tautomers are intended to be included. Tautomers may be cyclic or acyclic. Any carbon-carbon double bond configurations appearing herein are selected for convenience only and are not intended to represent any particular configuration unless otherwise stated herein. Thus, any carbon-carbon double bond or carbon-heteroatom double bond optionally indicated as trans herein may be cis, trans, or a mixture of the two in any proportion.

[0112] Certain compounds of the present invention may also exist in different stable conformations that may be separable. Torsional asymmetry resulting from restricted rotation around an asymmetric single bond, for example, 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.

[0113] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free basic functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts, but not limited to these, include non-toxic acid addition salts of amino groups formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids, e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobio Examples of alkali or alkaline earth metal salts include, but are not limited to, sodium, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls, sulfonates, and arylsulfonates having 1 to 6 carbon atoms.

[0114] pharmaceutically acceptable salts can also be prepared by deprotonating the parent compound with a suitable base, thereby forming an anionic conjugate base of the parent compound. In such salts, the counterion is a cation. Suitable cations include ammonium and metal cations, such as alkali metal cations, such as Li. + kaNa + , K + and Cs + , as well as alkaline earth metal cations, such as Mg 2+ and Ca 2+ These are some examples.

[0115] As used herein, the term “pharmaceutically acceptable ester” refers to esters that hydrolyze in vivo and readily decompose in the human body, leaving a parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanes, alkenes, cycloalkanoates, and alkanediates, where each alkyl or alkenyl moiety has, advantageously, six or fewer carbon atoms. Examples of specific esters include, but are not limited to, esters of C1-C6-alkanoates, such as acetate esters, propionic acid esters, butyrate esters, and pivalate esters.

[0116] In certain embodiments, the present invention provides pharmaceutically acceptable prodrugs of compounds disclosed herein. As used herein, the term “pharmaceutically acceptable prodrug” refers to a prodrug of a compound formed by the process of the present invention that is suitable for use in contact with human and lower animal tissues with excessive toxicity, irritation, allergic reactions, etc., within the bounds of sound medical judgment, is commensurate with a reasonable benefit / risk ratio, and is effective for their intended use, as well as, if possible, a zwitterionic form of the compound of the present invention. As used herein, “prodrug” means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) and gives any compound described by the formula of the present invention. Various forms of prodrugs are known in the art, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder et al., (eds.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen et al., (eds.). This is discussed in "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 (1988); Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

[0117] Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinates, ethyl succinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs of hydroxyl groups, sulfonic acid esters, and sulfate esters. Derivatization of hydroxyl groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also included, where the acyl group may be an alkyl ester and optionally substituted with groups including, but not limited to, ethers, amines, and carboxylic acid functional groups, or where the acyl group is one of the above amino acid esters. This type of prodrug is described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides, or phosphonamides. All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups. In certain embodiments, the compounds of the present invention may incorporate two or more groups that are metabolically removed in vivo to produce the active parent compound.

[0118] As used herein, the term “treatment” means reducing, decreasing, mitigating, eliminating, regulating, or improving a disease state or symptom, i.e., causing a regression of the disease state or symptom. Treatment may also include, for example, inhibiting an existing disease state or symptom, i.e., stopping its onset, and alleviating or improving an existing disease state or condition, i.e., causing its regression, if such a disease state or symptom may already be present.

[0119] As used herein, the term “prevention” means completely or nearly completely stopping a disease condition or symptom from occurring in a patient or subject, especially when the patient or subject is susceptible to or at risk of developing such a disease condition or symptom.

[0120] Furthermore, the compounds of the present invention, such as salts of the compounds, can exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0121] A "solvate" refers to a solvation form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture a certain molar ratio of solvent molecules in their crystalline solid state, and thus form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more molecules of water and one of the substances in which water retains its molecular state as H2O, and such combinations can form one or more hydrates.

[0122] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but has a slightly different composition (e.g., by the substitution of one atom by an atom of a different element, or by the substitution of one functional group by another functional group). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance.

[0123] The substituent and variable combinations envisioned in this invention are limited to those that result in the formation of stable compounds. As used herein, the term “stable” refers to a compound that is stable enough to enable production and maintains the integrity of the compound over a sufficient period of time to serve the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0124] The synthesized compound can be separated from the reaction mixture and further purified by methods such as column chromatography, high-pressure liquid chromatography, or recrystallization. Furthermore, the desired compound can be obtained by carrying out various synthesis steps in an alternative order or sequence. In addition, the solvents, temperatures, reaction times, etc. described herein are for illustrative purposes only, and variations in reaction conditions can produce the desired crosslinked macrocyclic product of the present invention. Useful synthetic chemical transformations and protecting group methodologies (protection and deprotection) for synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and PG. MWuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

[0125] The compounds of the present invention may be modified by adding various functional groups via synthetic means described herein to enhance their selective biological properties. Such modifications may include increasing biopenetration into a given biological system (e.g., blood, lymphatic system, central nervous system), improving oral availability, increasing solubility to enable administration by injection, altering metabolism, and altering excretion rate.

[0126] Pharmaceutical composition The pharmaceutical composition of the present invention comprises 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 kind of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch, potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols, e.g., propylene glycol; esters, e.g., ethyl oleate, ethyl laurate; agar; buffers, e.g., magnesium hydroxide, aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; and ethyl alcohol. Phosphate buffers, as well as other non-toxic compatible lubricants, e.g., sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, flavoring agents, and fragrances, preservatives, and antioxidants may also be present in the composition at the discretion of the compounder. The pharmaceutical compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisional, vaginally, intraperitoneally, topically (as in powder, ointment, or drops), orally or as an oral or nasal spray.

[0127] The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir, preferably by oral or injectable administration. The pharmaceutical compositions of the present invention may contain any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-sacral, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques.

[0128] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, the oral composition may also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0129] Preparations for injection, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using appropriate dispersants or wetting and suspending agents. Sterile preparations for injection may also be sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Furthermore, sterile fixatives have been conventionally used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in preparations for injection.

[0130] Injectable formulations can be sterilized, for example, by filtration using a bacterial-retaining filter, 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 medium before use.

[0131] To prolong the effects of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of a drug depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle. Depot formulations for injection are prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of the drug to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injection formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0132] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compound.

[0133] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is provided with at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) hydrating agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents. f) an absorption enhancer, such as a paraffin; g) a wetting agent, such as cetyl alcohol and glycerol monostearate; h) an absorbent, such as kaolin and bentonite clay; and i) a lubricant, 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 include a buffer.

[0134] Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0135] The active compound may also be in a microencapsulated form with one or more excipients, as described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets, and pills, the dosage form may also contain buffers. These may optionally contain opacifiers and may be compositions that release the active ingredient alone or preferentially, in a delayed manner, to a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0136] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions and, if necessary, with any required preservatives or buffers. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of the present invention.

[0137] The ointments, pastes, creams, and gels may contain, in addition to the active compound of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0138] The powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons.

[0139] Transdermal patches offer the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or aliquoting the compound in a suitable medium. Absorption enhancers can also be used to increase the flow 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.

[0140] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly known to those skilled in the art. All publications, patents, published patent applications, and other references referenced herein are incorporated herein by reference in their entirety.

[0141] Abbreviation The abbreviations used in the following explanations of schemes and examples are as follows: ACN: Acetonitrile AD-mix-β:(9S)-(9''S)-9,9''-[1,4-phthalazinediylbis(oxy)]bis[10,11-dihydro-6'-methoxycinconan] Bn: Benzyl BOP: (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BzCl: Benzoyl chloride mCPBA: Meth-chloroperbenzoic acid Cbz: Benzyloxycarbonyl CDI: Carbonyldiimidazole DAST: Diethylaminosulfur trifluoride DBU:1,8-diazabicycloundec-7-ene DCE: Dichloroethane DCM: Dichloromethane Dess-Martin periodinane:1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one DIAD: Diisopropyl azodicarboxylate DIBAL-H: Diisobutylaluminum hydride DMAP: N,N-dimethylaminopyridine DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DPPA: Diphenylphosphoryl azide or diphenylphosphoryl azidate dppf:1,1'-bis(diphenylphosphin)ferrocene EDCI or EDC: 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride EA or methoxy: ethyl acetate Ghosez Reagent: 1-Chloro-N,N,2-trimethyl-1-propenylamine HATU:O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl: Hydrochloric acid Hunig base: diisopropylethylamine PyBOP: (Benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate LDA: Lithium diisopropylamine Pd-C: Palladium Carbon PE: Petroleum ether Ph: Phenyl RT: Reverse transcription RT-PCR: Reverse transcription polymerase chain reaction TBME: tert-butylmethyl ether TEA: Triethylamine Tf2O: Trifluoromethanesulfonic anhydride TFA: Trifluoroacetic acid THF: Tetrahydrofuran (TMS)2NH:Hexamethyldisilazane TBS: tert-butyldimethylsilyl TBDPS: tert-butyldiphenylsilyl TMS: Trimethylsilyl TPAP: Tetrapropylammonium perlutenate TPP or PPh3: Triphenylphosphine Ts or Tosil: p-CH3C6H4SO2- tBOC or Boc:tert-butyloxycarbonyl Xantphos:4,5-bis(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen

[0142] Synthesis method The compounds and processes of the present invention will be better understood in connection with the following synthetic scheme illustrating a method by which the compounds of the present invention can be prepared, and these are intended 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, including but not limited to those relating to the chemical structure, substituents, derivatives and / or methods of the present invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0143] Scheme 1 shows a method for preparing the compound of formula 11 from compounds 1 and 2, where n=1, 2, or 3, P is a hydroxy protecting group, Ar is E, and E is as previously defined. Alkylation of hydroxypyridine 1 with a hydroxy epoxide using Mitsunobu reaction conditions yields epoxide 4. Alternatively, 4 is obtained by converting the hydroxy epoxide to 3 having a leaving group such as tosyl and methanesulfonyl (but not limited to), followed by alkylation in the presence of a base such as K2CO3 and Cs2CO3 (but not limited to). Intramolecular epoxide ring-opening mediated by a base such as LDA (but not limited to) yields compound 5. Protection of the hydroxyl group compound 5 with a suitable protecting group such as TBDPS and TBS (but not limited to) yields compound 6. Trifluoromethyl ketone 7 is obtained by iodine-magnesium exchange of compound 6 followed by the addition of an ester such as ethyl 2,2,2-trifluoroacetate (but not limited to). Compound 9 is obtained by cross-coupling trifluoromethyl ketone 7 with various metal coupling partners 8, such as boronic acids, boronic acid esters, organotin reagents, organozinc reagents, organomagnesium reagents, and organosilicon reagents, using a suitable catalyst such as Pd, Ni, or Cu. Compound 10 is obtained by nitromethane addition to compound 9 in the presence of bases such as K2CO3 and Cs2CO3. Reducing the nitro group with reducing reagents such as zinc and acetic acid generates an important intermediate 11. Scheme 1 [ka]

[0144] As seen in Scheme 2, Ar1 is A, Ar is E, and R is R 11 n is 1, 2, or 3, and A, E, R 11The definition is as previously described. The important intermediate 11 is coupled with various carboxylic acids to obtain amide 14. Then, amide 14 is reacted with various electrophiles to produce various ethers, esters, and carbamates of formula 15. Amide 14 is also oxidized to aldehyde 16, and then various amines 17 are obtained by reductive amination. The hydroxyl group of -CH2OH in amide 14 is converted to cyanomethyl 18 by activation and subsequent cyanation. Compound 14-1 is further converted to acetamide 19 in the presence of a catalyst, but not limited to a Perkin catalyst. Scheme 2 [ka]

[0145] As seen in Scheme 3, Ar1 is A, Ar is E, and R is R 11 A, E, R 11 This is as previously defined. Aldehyde 16 is converted to a benzyl-protected amine by reductive amination. Hydrolysis yields the free amine 20. Finally, substitution with various electrophiles yields the N-substituted compound 21. Scheme 3 [ka]

[0146] 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 previously defined. After oxidizing aldehyde 16 to acid 22, it is further converted to amide 23 and sulfonamide 24 using general methods such as HATU and DIPEA, but not limited to these. From there, diversification into various esters and amides is carried out. Scheme 4 [ka]

[0147] Scheme 5 illustrates another method for preparing the compound of formula 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 the compound of formula 26 via olefination. Alternatively, 26 can be obtained from: 1) a boronic acid, boronic ester, organotin reagent, organozinc reagent, organomagnesium reagent, organosilicon reagent, etc., which is catalyzed with a suitable catalyst such as Pd, Ni, or Cu to obtain compound 25 from 6 via cross-coupling with a metallic bonding partner 6-1; 2) compound 25 is converted to compound 26 as previously described in Scheme 1. With 26 prepared, the compound of formula 27 is prepared by dihydroxylation and subsequent epoxide formation. Epoxide ring-opening of compound 27 having amine equivalents such as but not limited to NH4OH and NH3 provides the compound of formula 11. Scheme 5 [ka]

[0148] Scheme 6 illustrates another method for preparing the compound of formula 23, where Ar1 is A, Ar is E, R' is -C1-C6 alkyl, -C3-C6 cycloalkyl, aryl, or heteroaryl, n is 1, 2, or 3, and A and E are as previously defined. Amine 11 is protected with protecting groups such as, but not limited to, Boc and Cbz. After deprotection of the hydroxyl protecting group, acid 30 is obtained by subsequent oxidation. Compound 30 is coupled with various amines to obtain amide 31. After deprotection of the amine protecting group and subsequent amide formation, the compound of formula 23 is obtained. Scheme 6 [ka]

[0149] Scheme 7 shows an additional route for synthesizing the desired compound. The difference in this route is that it begins with oxidation and amide coupling to introduce amide 33 at the start of the synthesis. Sequential vinylization and arylation yield the biscoupling product 34. Asymmetric dihydroxylation followed by activation and substitution yields the amino alcohol precursor. Finally, amide coupling with each aryl acid produces the desired compound represented by compound 36. Scheme 7 [ka]

[0150] example The compounds and methods of the present invention are intended to be illustrative only and will be better understood in relation to the following examples, which 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, including but not limited to those relating to the chemical structure, substituents, derivatives, formulations and / or methods of the present invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0151] A specific synthetic procedure useful for preparing the compounds of the present invention is disclosed in U.S. Patent Application No. 16 / 930,622, which is incorporated herein by reference in its entirety. Intermediate 1 [ka] Intermediate 1 Steps a and b [ka]

[0152] A solution of HCl (80 mL) containing methyl 4-amino-3-methoxybenzoate (10 g, 55.19 mmol) was treated with methacrolein (9.67 g, 137.97 mmol) at 100°C for 5 hours. The reaction was monitored by LC-MS. 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] + .

[0153] A 100 mL solution of MeOH containing the compound from step a (10 g, 46.03 mmol) was treated with SOCl2 (10 mL, 137.86 mmol) at 0°C. The final reaction mixture was reacted at 80°C for 40 minutes. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The reaction product was adjusted to pH=8 using 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 obtain the desired product (4.386 g, 41%) as a brown solid. ESI-MS m / z: 232.00 [M+H] + . Intermediate 1 Steps c and d [ka]

[0154] A mixture of methyl compound (3.9 g, 16.86 mmol) and m-CPBA (8.73 g, 50.59 mmol) from step b was stirred overnight at room temperature in a DCM (20 mL) solution. The reaction mixture was quenched at room temperature with saturated sodium hyposulfite (aqueous solution). The resulting mixture was extracted with CH2Cl2. The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (15:1) to obtain the desired product (2.6 g, 62%) as a yellow solid. ESI-MS m / z: 248.05 [M+H] + .

[0155] The 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 hour. The reaction was monitored by LC-MS. 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 obtain the desired product (1.5 g, 53%) as a yellow solid. ESI-MS m / z: 266.00 [M+H] + . Intermediate 2 [ka] Intermediate 2 steps a and b [ka]

[0156] A solution containing (2Z)-2-bromobuta-2-enal (5 g) and methyl 4-amino-3-hydroxybenzoate (10 g) in HCl (20 mL) and AcOH (30 mL) was stirred at 100°C for 1 hour under an N2 atmosphere. The resulting solution was concentrated to obtain the desired product (crude product) as a brown solid. ESI-MS m / z: 282.00 [M+H] + .

[0157] The compound from step a (10 g, 35.45 mmol) and a solution containing H2SO4 (10 mL) in MeOH (30 mL) were 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 (3 times). The combined organic layer was 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 obtain the desired product (1 g, 9.5%) as a yellow solid. ESI-MS m / z: 296.00 [M+H] + . Intermediate 2 steps c and d [ka]

[0158] A 10 mL solution of DMF containing 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) was stirred at 80°C for 2 hours. The residue was purified by silica gel column chromatography eluted with PE / EA to obtain the desired product (800 mg, 68%) as a yellow solid. ESI-MS m / z: 346.00 [M+H] + .

[0159] The compound from step c (800 mg, 2.31 mmol) and LiOH (553 mg, 23.11 mmol) were mixed in MeOH (10 mL) and H2O (10 mL) and stirred at room temperature under an N2 atmosphere for 6 hours. The crude product was recrystallized from MeOH / H2O to obtain the desired product (500 mg, 65%) as a yellow solid. ESI-MS m / z: 332.00 [M+H] + . Intermediate 3 [ka] Intermediate 3 step a [ka]

[0160] 100 mL of rbf was mixed with 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (500 mg, 2.153 mmol), toluene (4.98 ml), and MeOH (2.99 ml), and then cooled to 0°C in an ice bath. TMS-diazomethane (2.8 mL, 5.60 mmol) was added dropwise by hand over 10 minutes. The mixture was stirred for 1 hour, and then the diazo reagent was quenched by adding AcOH until the yellow color of the diazo reagent faded. The mixture was then concentrated and proceeded to the next step. ESI-MS m / z: 247.213 [M+H] + . Intermediate 3 Step b [ka]

[0161] 529 mg, 2.15 mmol methyl 2-cyclopropyl-7-hydroxy-2H-indazole-5-carboxylate, 1.032 g, 2.80 mmol tetrabutylammonium iodide, and 21.5 ml CH2Cl2 were added to a 100 mL rbf container equipped with a stirring bar. The mixture was cooled to -78°C, and trichloroborane (5.38 ml, 5.38 mmol) was added dropwise over 10 minutes. The mixture was stirred at -78°C for 1 hour, and then heated to 0°C in an ice bath for 1 hour with stirring. The mixture was then diluted with water (50 mL) and ethyl acetate (50 mL), the layers were separated, and the aqueous layer was washed with siRNA (4 × 50 mL). The combined organic layers were washed with brine and dried over Na2SO4. The mixture was filtered and concentrated to obtain a red oily substance, which was then purified by silica gel chromatography to obtain the desired product as a white solid (489 mg, 98% yield). ESI-MS m / z: 233.201 [M+H] + . Intermediate 3 Step c [ka]

[0162] In a 100 mL round-bottom flask, 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, followed by sodium chlorodifluoroacetate (0.656 g, 4.30 mmol). The mixture was heated at 105 °C for 6 hours, then cooled to room temperature, and purified by silica gel chromatography (cyclohexane containing 0 to 30% ethyl phosphate) to obtain the desired compound as a white solid (176.4 mg, yield 29%). ESI-MS m / z: 283.160 [M+H] + . Intermediate 3 Step d [ka]

[0163] Methyl 2-cyclopropyl-7-(difluoromethoxy)-2H-indazole-5-carboxylate (174 mg, 0.616 mmol) was added to a 20 mL vial and dissolved in MeOH (2.055 ml), THF (2.055 ml), and water (2.055 ml). Freshly pulverized 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 ethyl acetate. The aqueous layer was washed with ethyl acetate (3 × 5 mL), the combined organic layers were washed with brine, and then concentrated to obtain the desired product as a white solid (147.6 mg, yield 89%). ESI-MS m / z: 269.145 [M+H] + . Intermediate 4 [ka] Intermediate 4 Step a [ka]

[0164] 3-chloro-8-methoxy-2-methylquinoline-6-carboxylic acid (200 mg, 0.795 mmol), toluene (1.84 ml), and MeOH (1.104 ml) were added to a 20 mL vial. The mixture was then cooled to 0°C in an ice bath, and TMS-diazomethane (1.0 mL, 2.07 mmol) was added dropwise by hand over 10 minutes. The mixture was stirred for 1 hour, and then the diazo reagent was quenched by adding AcOH until the yellow color of the diazo reagent disappeared. The mixture was concentrated to obtain the desired product (48 mg, 95%) as a yellow solid. ESI-MS m / z: 266.091 [M+H] + . Intermediate 4 Step b [ka]

[0165] Methyl 3-chloro-8-methoxy-2-methylquinoline-6-carboxylate (0.211 g, 0.795 mmol) was added to an 8 mL vial, followed by the addition of D2O (1.125). The mixture was heated at 100°C for 18 hours. The mixture was then cooled to room temperature and diluted with siRNA. The phases were separated, and the organic layer was washed with 3 × 1 mL of NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by combiflush to obtain the desired product as a yellow solid (105 mg, 34% yield). ESI-MS m / z: 269.156 / 271.135 [M+H] + Intermediate 4 Step c [ka]

[0166] Methyl 3-chloro-8-methoxy-2-(methyl-d3)quinoline-6-carboxylate (100 mg, 0.372 mmol) was added to a 20 mL vial and dissolved in water (1.240 ml), THF (1.240 ml), and methanol (1.240 ml). Then, freshly pulverized lithium hydroxide (26.7 mg, 1.116 mmol) was added. The mixture was stirred for 1 hour, then diluted with DCM containing 10% MeOH, and carefully acidified by adding 1 M HCl to separate the phases. The aqueous layer was washed with DCM containing 10% MeOH. The combined organic phases were concentrated to obtain the desired product as a white solid (87 mg, 92% yield). ESI-MS m / z: 255.163 / 257.175 [M+H] + Intermediate 5 [ka]

[0167] 3-bromo-8-methoxy-2-methylquinoline-6-carboxylic acid was placed in an 8 mL vial, suspended in 0.7 mL of D2O, and then heated at 100°C for 18 hours. The crude product was freeze-dried and used as a (48 mg, 95%) yellow solid without further purification. ESI-MS m / z: 299.033 / 300.961 [M+H] + . Intermediate 6 [ka] Intermediate 6 Step a [ka]

[0168] In an oven-dried vial equipped with a stirring rod, methyl 2-chloro-8-methoxy-3-methylquinoline-6-carboxylate (250 mg, 0.941 mmol) was dissolved in DMF (1.9 mL), and anhydrous Me4NF (175 mg, 2.0 equivalents) was added. The vial was sealed and heated overnight at 80°C. The reaction mixture was then cooled to room temperature, diluted with DCM, and washed twice with water and once with brine. The organic phase was then dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by automated column chromatography (silica gel) to obtain a fluoride as a white solid, which contained some chloride starting material (48 mg, 20%). ESI-MS m / z: 250.134 [M+H] + . Intermediate 6 Step b [ka]

[0169] In a 1-drum vial, methyl-2-fluoro-8-methoxy-3-methylquinoline-6-carboxylate (48 mg, 0.18 mmol, 1.0 equivalent) 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 equivalents) was added, and the mixture was stirred for 15 minutes, after which the condenser was removed. After 2 hours at room temperature, the mixture was acidified to approximately pH 5 with AcOH, and the mixture was concentrated directly. The crude residue was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min) to obtain the product, carboxylic acid (13 mg, 31%). ESI-MS m / z: 236.16 [M+H] + . Intermediate 7 [ka] Intermediate 7 Step a [ka]

[0170] 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 DCM (5 mL) suspension containing methyl-3-bromo-2-chloro-8-methoxyquinoline-6-carboxylate (443 mg, 1.34 mmol, 1.0 equivalent), 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 equivalents) was then added, the vial was sealed, and the mixture was heated at 80°C for 3 hours. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was redissolved in DCM, the organic solution was sequentially washed 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 obtain iodide as a white solid (434 mg, 77%). ESI-MS m / z: 423.93 [M+H] + . Intermediate 7 Step b [ka]

[0171] Equipped with a stirring rod, in an oven-dried vial, methyl 3-bromo-2-iodo-8-methoxyquinoline-6-carboxylate (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. Isopropyl magnesium chloride (0.11 mL, 0.22 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at that temperature for 1 hour, after which it was quenched by the dropwise addition of CD3OD (0.6 mL, 14.8 mmol, 15 equivalents). The mixture was stirred further at room temperature for 15 minutes, and then poured into an aqueous saturated ammonium chloride solution. The quenched riasitol mixture was diluted with water and DCM, the layers were separated, and the aqueous layer was extracted three times with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude substance was purified by automated column chromatography (silica gel) to obtain the deuterated product methyl-3-bromo-8-methoxyquinoline-6-carboxylate-2-D as a white solid (9.0 mg, 17%). ESI-MS m / z: 297.06 [M+H] + . Intermediate 7 Step c [ka]

[0172] In a drum vial equipped with a stirring rod, methyl-3-bromo-8-methoxyquinoline-6-carboxylate-2-D was dissolved as a white solid (9.0 mg, 1.0 equivalent, 0.032 mmol) in THF (0.1 mL), MeOH (0.1 mL), and water (0.1 mL). LiOH (7 mg, 0.30 mmol, 10 equivalents) 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, concentrated to obtain the carboxylic acid, which was used without further purification (8.0 mg, 93%). ESI-MS m / z: 283.05 [M+H] + . Intermediate 8 [ka]

[0173] The above compound was prepared from 8-methoxy-2-methyl-3-(methyl-d3)quinoline-6-carboxylic acid using the same method as in step X of Example X, to obtain a hexadutero compound as an orange solid (27 mg, 96%). ESI-MS m / z: 238.16 [M+H] + . Intermediate 9 [ka] Intermediate 9 Step a [ka]

[0174] A mixture of dioxane (21 mL) containing (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), 2-(1-(4-fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.57 g, 6.32 mmol), Pd(dppf)Cl2 (0.382 g, 0.52 mmol), and K2CO3 (2.17 g, 15.67 mmol) and H2O (5 mL) was stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 50% ethyl acetate in hexane) to obtain the desired product (1.97 g, 75% by weight, 75%) as a red oily substance. ESI-MS m / z: 377.06 [M+H] + . Intermediate 9 Step b [ka]

[0175] The compound from step a (1 g, 2.25 mmol), 2-(2,3-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.82 g, 2.82 mmol), Pd(dppf)Cl2 (0.165 g, 0.225 mmol), and a mixture of dioxane (9 mL) and H2O (2.25 mL) containing K2CO3 (0.70 g, 5.07 mmol) were stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by automated column chromatography (silica, cyclohexane containing 0-100% ethyl acetate) to obtain the desired product (1.50 g, 80 wt%, 87%) as a red oil. ESI-MS m / z:461.12 [M+H] + . Intermediate 9 Step c [ka]

[0176] A solution of t-BuOH (17 mL) and H2O (17 mL) containing the compound from step b (1.5 g, 3.38 mmol) was cooled to 0°C. Methanesulfonamide (0.64 g, 6.77 mmol) and AD-MIX-β (13.18 g, 16.92 mmol) were added, and the reaction mixture was stirred overnight at room temperature and monitored by LC-MS. The reaction mixture was cooled to room temperature, diluted with SiO2, and quenched with sodium sulfite. The aqueous layer was extracted with SiO2, combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by automated column chromatography (silica, cyclohexane containing 0-100% ethyl acetate) to obtain the desired product (1.0 g, 60%) as a yellow solid. ESI-MS m / z: 495.09 [M+H] + . Intermediate 9 Step d [ka]

[0177] The compound (1.0 g, 2.01 mmol) from step c was cooled to 0°C in a DCM (11 mL) solution. 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 mixture was stirred at room temperature for 90 minutes. The crude reaction mixture was concentrated, and the material was purified by automated column chromatography (silica, cyclohexane containing 0-100% ethyl acetate) to obtain the desired product (1.6 g, 70 wt%, 85%) as a yellow solid. ESI-MS m / z: 649.10 [M+H] + . Intermediate 9 Step e [ka]

[0178] To a 250 mL round-bottom flask containing 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 LC-MS. The solvent was removed, and the crude mixture was dissolved in ethyl acetate. The organic matter was washed three times with saturated sodium bicarbonate, and the organic matter was concentrated. The crude substance was triturated with DCM to obtain the desired product (425 mg, 35%) as an off-white solid. ESI-MS m / z: 494.11 [M+H] + Intermediate 10 [ka]

[0179] The above compound was prepared in a manner similar to that of intermediate 9. ESI-MS m / z:478.17 [M+H] + . Intermediate 11 [ka]

[0180] The above compound was prepared in a manner similar to that of intermediate 9. ESI-MS m / z:470.17 [M+H]+ . Intermediate 12 [ka]

[0181] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (133 mg, quantitative yield). ESI-MS m / z: 440.13 [M+H] + . Intermediate 13 [ka]

[0182] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (158 mg, quantitative yield). ESI-MS m / z: 522.18 [M+H] + . Intermediate 14 [ka]

[0183] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (170 mg, quantitative yield). ESI-MS m / z: 528.27 [M+H] + . Example 1 [ka]

[0184] (R)-5-((S)-2-amino-1-cyclopropyl-1-hydroxyethyl)-7-(5-chloro-2,4-difluorophenyl)-3-methyl-2,3-dihydrofluoro[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) were added to a 20 mL vial equipped with a stirring bar. The solid was dissolved in DMF (0.20 mL) and DIPEA (18.54 μl, 0.106 mmol) was added. The vial was cooled to 0°C and PyBOP (22.10 mg, 0.042 mmol) was added. The reaction mixture was stirred for 10 minutes, warmed to room temperature, and monitored by LC-MS (1 hour). Upon completion, the reaction mixture was diluted with siRNA and quenched with saturated ammonium chloride. The aqueous phase was extracted with siRNA, collected in a phase separator cartridge, and concentrated. The crude product was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), the fraction was concentrated in a Biotage V10 evaporator, and the substance was freeze-dried to obtain the desired product: a fluffy white solid (13 mg, 53%). ESI-MS m / z: 677.20 [M+H] + .

[0185] Table 1 below includes examples prepared in a manner similar to that of Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20–90%, 25 min), and some by automated column chromatography (silica gel). Aryl acid coupling partners were prepared according to intermediates 1–14, or by similar procedures with slight modifications, and also according to the procedure found in U.S. Patent Application No. 17 / 679,746. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Intermediate 15 [ka] Intermediate 15 Steps a and b [ka]

[0186] In a 250 mL rbf flask, 6.33 g of 2-(1-cyclopropyl vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added, and the oil was dissolved in 1,4-dioxane (104 mL). (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (10 g of 26.1 mL) was added, followed by the addition of PdCl2 (dppf) (1.91 g of 2.61 mL) and water (26.1 mL). Next, potassium carbonate (10.83 g of 78 mL) was added, a condenser was placed in the rbf, the system was purged with N2, and the reaction mixture was heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was diluted with ELISA and saturated ammonium chloride. The aqueous layer was extracted with toluene, combined, dried over sodium sulfate, filtered, and concentrated. The crude substance was purified by automated column chromatography (silica, cyclohexane containing 0-100% ethyl acetate) to obtain the desired product (10.38 g, 70 wt%, 86%) as a red oil. ESI-MS m / z: 323.20 [M+H] + .

[0187] (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (3.90 g, 12.07 mmol), K2OsO4.2H2O (0.19 g, 0.52 mmol), and NMO (3.96 g, 33.79 mmol) were mixed in THF (10 mL), H2O (10 mL), and acetone (10 mL) and 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 eluted with PE / EA to obtain the desired product (2.60 g) as a yellow solid. ESI-MS m / z: 356.90 [M+H] + . Intermediate 15 steps c and d [ka]

[0188] A 50 mL solution of DCM containing 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) was stirred at 0°C for 2 hours. The mixture was acidified with HCl to pH 7-8. The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layer was washed with water (3 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA to obtain the desired product (2 g, 50%) as a yellow solid. ESI-MS m / z: 510.90 [M+H] + .

[0189] To a stirred solution of NH3(g) in MeOH(200mL), 3mL of MeOH containing the compound from step c (3g, 5.87 mmol) was added dropwise 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 RINKAN, washed with saturated NaHCO3 aqueous solution, and concentrated to obtain the desired product (2g, 96%) as a white solid. ESI-MS m / z: 355.95 [M+H] + . Intermediate 15 Step e [ka]

[0190] A solution of the compound from step d (700 mg, 1.97 mmol) in DMF (5 mL) was treated with 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid (391 mg, 1.68 mmol), PyBOP (877 mg, 1.69 mmol), and DIPEA (363 mg, 2.81 mmol) at room temperature for 1 hour. The reaction was monitored by LC-MS. The residue was purified by reverse-phase flash chromatography to obtain the title compound (1 g, 86%) as a white solid. ESI-MS m / z: 570.30 [M+H] + . Intermediate 16 [ka]

[0191] The above compound was prepared in the same manner as for intermediate 15 and purified by automated column chromatography (silica gel) to obtain pyridyl bromide as a white solid (812 mg, 85%). ESI-MS m / z: 610.02 [M+H] + . Example 47 [ka]

[0192] Pd(PPh3)Cl2 (7.38 mg, 10.52 μmol), sodium carbonate (22.30 mg, 0.210 mmol), (5-chloro-2-fluoro-3-methylphenyl)boronic acid (19.82 mg, 0.105 mmol), and (3R)-7-bromo-5-(1-cyclopropyl-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamide)-1-hydroxyethyl)-3-methyl-2,3-dihydrofluoro[2,3-c]pyridine-3-carboxamide (40 mg, 0.070 mmol) were added to a 2-drum vial equipped with a stirring rod. The vial was purged with N2, and the solid was dissolved in 1,4-dioxane (0.28 mL) and water (0.07 mL). The reaction mixture was heated to 90°C and monitored by LC-MS (1 hour). The reaction mixture was cooled to room temperature, filtered through a silica gel pad containing ethyl acetate, and concentrated. The crude product was purified by preparative HPLC (ACN / H2O, 20-90%, 25 min) to separate the diastereomers. The fraction was concentrated in a Biotage V10 evaporator, and the substance was freeze-dried to obtain the desired product: a fluffy white solid (6 mg, 13%). ESI-MS m / z: 634.31 [M+H] + .

[0193] Table 2 below includes examples prepared in a similar manner to Example 47 using intermediates 15-16 or their analogues. More palladium and boronic acid were added when it was necessary to accelerate conversion. Most compounds were purified, and the diastereomers were separated by preparative HPLC (ACN / H2O, 20-90%, 25 min). If a mixture of diastereomers was reported, it is likely that they could not be separated by HPLC. [Table 2-1] [Table 2-2] Intermediate 17 [ka] Intermediate 17 Step a [ka]

[0194] A solution of 2,2-difluoro-1,3-benzodioxol-4-amine (5.00 g, 28.88 mmol) in CHCl3 (10 mL) was treated with NBS (5.66 g, 31.80 mmol) at room temperature for 1 hour. The reaction was monitored by LC-MS. 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 eluted with PE / EA (2:1) to obtain the compound (5.66 g, 78%) as a yellow oil. ESI-MS m / z: 253.80 [M+H] + . Intermediate 17 Step b [ka]

[0195] A 10 mL solution of MeCN containing CuCl2 (3.20 g, 23.81 mmol) was treated with t-BuNO2 (3.07 g, 29.76 mmol) at 55°C for 10 minutes under a nitrogen atmosphere, and then the compound from step a (3 g, 11.90 mmol) was added dropwise at 55°C. The final reaction mixture was heated at 55°C for 30 minutes. The reaction was monitored by LC-MS. The mixture was acidified to pH 3 with concentrated HCl. The resulting mixture was extracted with toluene. 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 / EA10:1) to obtain 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). Intermediate 17 Step c [ka]

[0196] A THF (10 mL) solution containing the compound obtained from step b (2.87 g, 10.57 mmol) was treated with iPrMgCl-LiCl (1.3 M in THF, 8 mL, 10.57 mmol) under a nitrogen atmosphere at -20°C for 30 minutes, followed by the dropwise addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.36 g, 12.69 mmol) at -20°C. The final reaction mixture was allowed to react at room temperature for 1 hour. 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 obtain the title compound (2.25 g, 67%) as a yellow oily substance. 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). Intermediate 18 [ka] Intermediate 18 Steps a and b [ka]

[0197] A 70 mL solution of DMF containing 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (10 g, 40.00 mmol) was treated overnight at 70°C with Cs2CO3 (13.03 g, 40.00 mmol) and phenylmethanol (8.65 g, 80.00 mmol). The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filtrate was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. 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 obtain the crude compound (15 g) as a yellow oil.

[0198] A solution of EtOH (100 mL) containing the compound from step a (15 g, 44.65 mmol) was treated with H2O (100 mL) containing NH4Cl (47.77 g, 893.08 mmol) and Fe (7.48 g, 133.96 mmol) at 80°C for 30 minutes. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filtrate was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with ELISA. 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 obtain the desired compound (8.9 g, 65%) as a brown oily substance. ESI-MS m / z: 307.95 [M+H] + . Intermediate 18 steps c and d [ka]

[0199] A solution of the compound from step b (6 g, 19.47 mmol) in THF (150 mL) was treated overnight with Ac₂O (4.97 g, 48.67 mmol) and Et₃N (9.85 g, 97.35 mmol) from 0°C to room temperature. The reaction was monitored by LC-MS. The resulting mixture was extracted with SiO₂. The combined organic layers were concentrated under reduced pressure. The residue was purified by polishing with PE to obtain the desired compound (6.24 g, 92%) as a white solid. ESI-MS m / z: 350.05 [M+H]+ .

[0200] 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 hours. The reaction was monitored by LC-MS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired compound (1.5 g, 33%) as a white solid. ESI-MS m / z: 259.95 [M+H] + . Intermediate 18 steps e, f and g [ka]

[0201] A 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 LC-MS. The reaction product was quenched with water at room temperature. The resulting mixture was extracted with RINKAN. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain the desired compound (980 mg, 70%) as a white solid. ESI-MS m / z: 241.95 [M+H] + .

[0202] To a solution of DMF (6 mL), MeOH (6 mL), and TEA (1.5 mL) containing the compound from step e (1.25 g, 5.16 mmol), DPPP (852 mg, 2.07 mmol) and Pd(OAc)2 (232 mg, 1.03 mmol) were added in a pressure tank. The mixture was purged with carbon monoxide and then pressurized overnight at 100°C to 20 atm with carbon monoxide. The reaction was monitored by LC-MS. The resulting mixture was extracted with RINKAN. The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to obtain the title compound (730 mg, 64%) as a white solid. ESI-MS m / z: 222.10 [M+H] + .

[0203] A solution of THF (8 mL) and MeOH (2 mL) containing step f (400 mg, 1.81 mmol) 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 LC-MS. The product was precipitated by the addition of HCl. The precipitated solid was collected by filtration and washed with water to obtain the title compound (249.8 mg, 66%) as a white solid. ESI-MS m / z: 208.10 [M+H] + . Intermediate 19 [ka] Intermediate 19 Step a [ka]

[0204] A solution of the compound from step b of intermediate 18 (2.7 g, 8.76 mmol) in dioxane (20 mL) was treated with cyclopropane carbonyl chloride (1.1 g, 10.52 mmol) at 100°C for 5 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by scrubbing with diethyl ether. The precipitated solid was recovered by filtration and washed with diethyl ether to obtain the desired compound (2.78 g, 88%) as a white solid. ESI-MS m / z: 376.05 [M+H] + . Intermediate 19 Steps b, c, d and e [ka]

[0205] The following compounds were prepared in a similar order to intermediate 18 above and purified by reverse-phase flash chromatography to obtain the title compound (416.4 mg, 58%) as a white solid. ESI-MS m / z: 234.10 [M+H] + . Intermediate 20 [ka] Intermediate 20 Step a [ka]

[0206] 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 hours. The reaction was monitored by TLC. The resulting mixture was extracted with Âxa. The combined organic layers were concentrated under reduced pressure. The crude product was used directly in the next step without further purification. Intermediate 20 steps b and c [ka]

[0207] Under N2 conditions, DMSO (50 mL) and t-BuOK (1.29 g, 11.45 mmol) were added to a flask containing the compound from step a (2.50 g, 10.91 mmol) and 2-methanesulfonylethanol (1.42 g, 11.45 mmol). The reaction mixture was stirred under N2 conditions at room temperature for 20 hours. Further additions of 2-methanesulfonylethanol (1.42 g, 11.45 mmol) and t-BuOK (1.29 g, 11.45 mmol) were added, and the reaction mixture was stirred for a further 3.5 hours. The reaction was monitored by LC-MS. The mixture / residue was acidified to pH < 1 with concentrated HCl. The resulting mixture was extracted with ELISA. The aqueous layer was concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. ESI-MS m / z: 211.95 [MH] - .

[0208] A solution of the compound from step b (400 mg, 1.88 mmol) in MeOH (10 mL) was treated with H2SO4 (1 mL) at 70°C for 2 hours. The reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. ESI-MS m / z: 225.95 [MH] - . Intermediate 20 Step d [ka]

[0209] A solution of the compound from step c (1.4 g, 6.16 mmol) in methyl ethanol (50 mL) was treated with H2O (50 mL) containing NH4Cl (6.5 g, 123.26 mmol) and Fe (1.03 g, 18.49 mmol) at 80°C for 30 minutes. The reaction was monitored by LC-MS. 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 ethyl acetate. 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 obtain the title compound (428 mg, 35%) as a white solid. ESI-MS m / z: 198.10 [M+H] + . 1 H 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). Intermediate 21 [ka] Intermediate 21 Steps a and b [ka]

[0210] A 50 mL solution of DMF containing 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) was stirred overnight at 60°C. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain 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).

[0211] A DMSO (40 mL) solution containing 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) 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 for a further 3 hours at room temperature. The mixture was acidified, extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (2.6 g, 65%) as a yellow solid. ESI-MS m / z: 271.95 [MH] - . Intermediate 21 steps c and d [ka]

[0212] A solution containing 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] + .

[0213] A solution of THF (20 mL) containing the compound from step c (1.5 g, 6.10 mmol), cyclopropane carbonyl chloride (0.58 g, 5.50 mmol), and TEA (0.93 g, 9.20 mmol) was stirred at 0°C for 1 hour. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (1.2 g, 62%) as a brown solid. ESI-MS m / z: 313.90 [M+H] + . Intermediate 21 Steps e and f [ka]

[0214] The compound (1.2 g, 3.80 mmol) from step d and POCl3 (884 mg, 5.70 mmol) were mixed in CHCl3 (20 mL) and 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 yellow oil. ESI-MS m / z: 293.90 [M+H] + .

[0215] A 5 mL solution of DMF containing the compound from step e (660 mg, 2.20 mmol), Ac2O (458 mg, 4.49 mmol), DIPEA (254 mg, 1.97 mmol), xanthophos (57 mg, 0.10 mmol), oxalic acid (404 mg, 4.49 mmol), and Pd(AcO)2 (50 mg, 0.22 mmol) was stirred at 100°C for 6 hours under a nitrogen atmosphere. The resulting mixture was filtered and purified by reverse-phase flash chromatography to obtain the desired compound (235.5 mg, 40%) as a white solid. ESI-MS m / z: 260.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ0.72-0.79 (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). Intermediate 22 [ka] Intermediate 22 Steps a and b [ka]

[0216] A DMSO (40 mL) solution containing 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) 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 resulting mixture was stirred for a further 3 hours at room temperature. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (2.2 g, 55%) as a yellow solid. ESI-MS m / z: 251.85 [MH] - .

[0217] A solution containing 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 minutes. The resulting mixture was concentrated and purified by silica gel column chromatography to obtain the desired compound (1.2 g, 61%) as a brown solid. ESI-MS m / z: 223.85 [M+H] + . Intermediate 22 steps c, d and e [ka]

[0218] The compound from step b (1.3 g, 5.80 mmol), cyclopropane carbonyl chloride (0.61 g, 5.80 mmol), and TEA (0.89 g, 8.70 mmol) were mixed in a THF (10 mL) solution and stirred at 0°C for 1 hour. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (1 g, 58%) as a yellow solid. ESI-MS m / z: 291.85 [M+H] + .

[0219] The compound (1 g, 3.44 mmol) from step c and POCl3 (791 mg, 5.16 mmol) were dissolved in CHCl3 (10 mL) and stirred overnight at 65°C. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (800 mg, 85%) as a yellow oil. ESI-MS m / z: 273.85 [M+H] + .

[0220] A 20 mL solution of DMF containing the compound from step d (1 g, 3.67 mmol), xanthophos (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) was stirred at 100°C for 6 hours under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography to obtain 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) δ1.16-1.35 (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). Intermediate 23 [ka] Intermediate 23 Steps a and b [ka]

[0221] A 10 mL solution of DMF containing 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) was stirred overnight at 70°C under an N2 atmosphere. The aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were concentrated under reduced pressure to directly obtain the crude product for the next step.

[0222] The compound from step a (2 g, 4.83 mmol) and a solution containing boron trichloride (20 mL) in CH2Cl2 (40 mL) were stirred at 0°C for 2 hours. The resulting mixture was extracted with EA. The combined organic layer was washed with water. The residue product was purified by reverse-phase flash to obtain the desired product (1.5 g, 96%) as a yellow solid. ESI-MS m / z: 322.00 [MH] - . Intermediate 23 steps c and d [ka]

[0223] A 15 mL solution of DMF containing 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) was stirred at 80°C for 2 hours under an N2 atmosphere. The residue was purified by preparative TLC to obtain the desired product (1.2 g, 69%) as a yellow solid.

[0224] A solution containing 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 an N2 atmosphere. The resulting mixture was filtered. The resulting mixture was extracted with EA. The combined organic layers were washed with water, and the organic layers were concentrated under reduced pressure to obtain the desired product (1 g, 91%) as a yellow oil. ESI-MS m / z: 344.00 [M+H] + . Intermediate 23 steps e and f [ka]

[0225] A solution of dioxane (20 mL) containing the compound from step d (1 g, 2.91 mmol) and cyclopropane carbonyl chloride (607 mg, 5.81 mmol) was stirred at 100°C for 2 hours under an N2 atmosphere. The resulting mixture was extracted with EA (3 × 2 mL). The combined organic layer was washed with water and concentrated under reduced pressure to obtain the desired product (900 mg, 75%) as a yellow solid. ESI-MS m / z: 412.00 [M+H] + .

[0226] A solution of the compound from step e (900 mg, 2.18 mmol) and boron trichloride (11.25 mL) in DCM (30 mL) was stirred at 0°C for 2 hours. The resulting mixture was extracted with EA. The combined organic layer was washed with water. The residue product was purified by reverse-phase flash to obtain the desired product (600 mg, 85%) as a yellow oil. ESI-MS m / z: 322.00 [M+H] + . Intermediate 23 steps g and h [ka]

[0227] A solution of the compound from step f (600 mg, 1.86 mmol) and POCl3 (428 mg, 2.80 mmol) in CHCl3 (10 mL) was stirred overnight at 65°C under an N2 atmosphere. The residue was purified by silica gel column chromatography eluted with PE / EA to obtain the desired product (400 mg, 71%) as a yellow oily substance. ESI-MS m / z: 304.00 [M+H] + .

[0228] A 10 mL solution of DMF containing the compound from step g (400 mg, 1.32 mmol), Pd(OAc)2 (59 mg, 0.26 mmol), Ac2O (269 mg, 2.63 mmol), xanthophos (76 mg, 0.13 mmol), and DIEA (340 mg, 2.63 mmol) was stirred overnight at 100°C under an N2 atmosphere. The crude product was purified by reverse-phase flash to obtain the desired product (200 mg, 56%) as a white solid. ESI-MS m / z: 270.00 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.15 - 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). Intermediate 24 [ka] Intermediate 24 Step a [ka]

[0229] A 10 mL solution of THF containing 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) was stirred at 0°C for 2 hours. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (600 mg, 51%) as a brown oily substance. ESI-MS m / z: 285.95 [M+H] + . Intermediate 24 Step b [ka]

[0230] A solution containing 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] + . Intermediate 24 Step c [ka]

[0231] A 5 mL solution of DMF containing the compound from step b (420 mg, 1.57 mmol), Pd(OAc)2 (35 mg, 0.157 mmol), Ac2O (319 mg, 3.13 mmol), xanthophos (90 mg, 0.157 mmol), oxalic acid (282 mg, 3.13 mmol), and DIPEA (404 mg, 3.13 mmol) was stirred at 100°C for 6 hours under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography to obtain 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) δ0.72-0.84 (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). Intermediate 25 [ka] Intermediate 25 Step a [ka]

[0232] A mixture of niacin (5 g, 40.61 mmol), methoxy(methyl)amine hydrochloride (5.94 g, 60.92 mmol), HATU (15.44 g, 40.61 mmol), and DIEA (10.50 g, 81.23 mmol) in DCM (50 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. 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 obtain the desired product (3.9 g, 57%) as a pale yellow liquid. ESI-MS m / z: 167.05 [M+H] + . Intermediate 25 Step b [ka]

[0233] In a 250 mL three-necked round-bottom flask, (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (2 g, 5.22 mmol), the compound from step a (1.30 g, 7.83 mmol), and THF (15 mL) were added at room temperature. The mixture was cooled to 0°C. iPrMgCl (1.07 g, 10.44 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction product 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 obtain the desired product (970 mg, 51%) as a yellow solid. ESI-MS m / z: 361.95 [M+H] + . Intermediate 25 Step c [ka]

[0234] The compound from step b (800 mg, 2.21 mmol), 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (606 mg, 2.21 mmol), K2CO3 (610 mg, 4.42 mmol), and dioxane (9 mL) containing Pd(dppf)Cl2 (161 mg, 0.22 mmol), along with 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 obtain the desired product (820 mg, 86%) as a yellow solid. ESI-MS m / z: 430.05 [M+H] + . Intermediate 25 Step d [ka]

[0235] To a stirred solution of methyltriphenylphosphonium bromide (1.70 g, 4.77 mmol) in THF (50 mL), THF containing 1 M t-BuOK (428 mg, 3.81 mmol) was added dropwise under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at 0°C for 30 minutes. THF containing the compound from step c (820 mg, 1.90 mmol) was added, and the mixture was stirred at 50°C for 2 hours. 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 and eluted with EA to obtain the crude product (430 mg) as a yellow solid. ESI-MS m / z: 428.15 [M+H] + . Intermediate 25 Step e [ka]

[0236] 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 mixed in t-BuOH (5 mL) and H2O (5 mL) and stirred overnight at room temperature. The resulting mixture was extracted with EA. The combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH10:1) to obtain the desired product (30 mg) as an off-white solid. ESI-MS m / z: 462.10 [M+H] + . Intermediate 25 Step f [ka]

[0237] A 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 layer was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to obtain the desired product (30 mg, 74%) as a yellow solid. ESI-MS m / z: 616.15 [M+H] + . Intermediate 25 Step g [ka]

[0238] A solution of the compound (30 mg, 0.05 mmol) from step f and MeOH (5 mL) containing NH3 (g) was stirred overnight at 40°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH(7M NH3) 10:1) to obtain the desired product (10 mg, 44%) as an off-white solid. ESI-MS m / z: 461.25 [M+H] + . Intermediate 26 [ka]

[0239] The above compound was prepared in the same manner as intermediate 9 to obtain an amino alcohol (100 mg). ESI-MS m / z: 478.50 [M+H] + . Intermediate 27 [ka]

[0240] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (60 mg, 53%). ESI-MS m / z: 478.20 [M+H] + . Intermediate 28 [ka] Intermediate 28 Step a [ka]

[0241] A solution of dioxane (40 mL) containing (S)-(7-bromo-5-iodo-3-methyl-2,3-dihydrofluoro[2,3-c]pyridine-3-yl)methanol (3 g, 7.83 mmol), 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (1.8 g, 7.83 mmol), Pd(dppf)Cl2 (573 mg, 0.78 mmol), and K2CO3 (2.1 g, 15.66 mmol) and H2O (4 mL) was stirred at 80°C for 2 hours under an N2 atmosphere. The residue was purified by silica gel column chromatography eluted with PE / EA to obtain the desired product (2.8 g, 99%) as a brown oily substance. ESI-MS m / z: 346.05 [M+H] + . Intermediate 28 Step b [ka]

[0242] The compound from step a (2 g, 5.78 mmol), 1-(5-chloro-2,4-difluorophenyl)-3,3,4,4-tetramethylbororane (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) under an N2 atmosphere at 80°C for 2 hours. The residue was purified by silica gel column chromatography eluted with PE / EA to obtain the desired product (1.6 g, 66%) as a yellow solid. ESI-MS m / z: 414.20 [M+H] + . Intermediate 28 steps c and d [ka]

[0243] A solution of 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) in DCM (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layer was washed with water (3 × 200 mL). The organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired product (1.9 g, 93%) as a white solid. ESI-MS m / z: 528.30 [M+H] + .

[0244] A solution containing 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 × 200 mL). The combined organic layer was washed with water (3 × 200 mL). The organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired product (1.5 g, 70%) as a white solid. ESI-MS m / z: 562.40 [M+H] + . Intermediate 28 steps e and f [ka]

[0245] The compound (1.5 g, 2.66 mmol) from step d, TsCl (763 mg, 4.00 mmol), TEA (810 mg, 8.00 mmol), and DMAP (232 mg, 2.66 mmol) were mixed in a DCM (20 mL) solution and stirred at 0°C for 2 hours. The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layer was washed with water (3 × 200 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA to obtain the desired product (1.5 g, 78%) as a white solid. ESI-MS m / z: 716.50 [M+H] + .

[0246] A 5 mL solution of MeOH containing the compound from step e (1.5 g, 2.66 mmol) was added to a 30 mL solution of MeOH containing NH3 (g), and the mixture was stirred overnight at 40°C. The residue was purified by preparative TLC (DCM / MeOH containing NH3 = 15 / 1) to obtain the desired product (1.1 g, 93%) as a white solid. ESI-MS m / z: 561.40 [M+H] + . Intermediate 28 steps g and h [ka]

[0247] A solution of DCM (10 mL) containing the compound from step f (900 mg, 1.60 mmol), (Boc)2O (525 mg, 2.40 mmol), and TEA (486 mg, 4.81 mmol) was stirred at room temperature for 2 hours. The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layer was washed with water (3 × 100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired product (600 mg, 56%) as a white solid. ESI-MS m / z: 661.20 [M+H] + .

[0248] A solution of THF (10 mL) containing the compound from step g (900 mg, 1.36 mmol) and TBAF (355 mg, 1.36 mmol) was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with water (3 × 200 mL). The organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired product (430 mg, 57%) as a white solid. ESI-MS m / z: 547.15 [M+H] + . Intermediate 28 steps i and j [ka]

[0249] A solution of the compound from step h (140 mg, 0.25 mmol) and DMP (271 mg, 0.64 mmol) in DCM (10 mL) was stirred at room temperature for 12 hours. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layer was washed with water (3 × 20 mL). The organic layer was concentrated under reduced pressure to obtain the desired crude product as a white oil. ESI-MS m / z: 545.30 [M+H] + .

[0250] To a t-BuOH:H2O (2:1) solution containing the compound from step i (230 mg, 0.42 mmol) and 2-methyl-2-butene (354 mg, 5.04 mmol), water containing NaClO2 (380 mg, 4.20 mmol) and NaH2PO4 (504 mg, 4.20 mmol) was added dropwise at room temperature and the mixture was stirred for 2 hours. The aqueous layer was extracted with ELISA (3 × 10 mL), and 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: 561.30 [M+H] + . Intermediate 29 [ka] Intermediate 29 Steps a and b [ka]

[0251] A solution of DMF (1 mL) containing the above intermediate 28 (120 mg, 0.21 mmol), deuterium methylamine (8 mg, 0.21 mmol), HATU (81 mg, 0.21 mmol), and DIEA (83 mg, 0.64 mmol) was stirred at room temperature for 2 hours. The residue was purified by preparative TLC (PE / EA 1:1) to obtain the desired product (80 mg, 64%) as a white solid. ESI-MS m / z: 577.15 [M+H] + .

[0252] A solution of HCl in 1,4-dioxane (2 mL) containing the compound from step a (120 mg, 2.66 mmol) was stirred at room temperature for 1 hour. The residue was purified by preparative TLC (MeOH = 15 / 1 with DCM / NH3) to obtain the desired product (36.8 mg, 54%) as a white solid. ESI-MS m / z: 477.15 [M+H] + . Intermediate 30 [ka]

[0253] The above compound was prepared in the same manner as intermediate 29 to obtain an amino alcohol (23 mg). ESI-MS m / z: 474.15 [M+H] + . Intermediate 31 [ka]

[0254] The above compound was prepared in the same manner as intermediate 29 to obtain an amino alcohol. Intermediate 32 [ka]

[0255] The above compound was prepared in the same manner as intermediate 29 to obtain an amino alcohol. Intermediate 33 [ka]

[0256] The above compound was prepared in the same manner as intermediate 9 to obtain an amino alcohol (150 mg, 68%). ESI-MS m / z: 442.00 [M+H] + . Intermediate 34 [ka]

[0257] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (46.1 mg, 19%). ESI-MS m / z: 476.25 [M+H] + . Intermediate 35 [ka]

[0258] The above compound was prepared in the same manner as intermediate 9 to obtain an amino alcohol (113.6 mg, 48%). ESI-MS m / z: 458.10 [M+H] + . Intermediate 36 [ka]

[0259] The above compound was prepared in the same manner as intermediate 9 to obtain an amino alcohol (89.5 mg, 60%). ESI-MS m / z: 476.00 [M+H] + . Intermediate 37 [ka]

[0260] The above compound was prepared in the same manner as intermediate 9 to obtain an amino alcohol as a mixture of diastereomers. After subsequent amide coupling, the diastereomers were separated and their stereochemistry was arbitrarily assigned (370 mg, 78%). ESI-MS m / z: 460.05 [M+H] + . Intermediate 38 [ka] Intermediate 38 Step a [ka]

[0261] (1-(6-fluoropyridine-2-yl)vinyl)diisobutylaluminum was prepared according to the procedure described 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-dihydrofluoro[2,3-c]pyridine-3-carboxamide (1.1 g, 2.87 mmol), xanthophos (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-fluoropyridine-2-yl)vinyl)diisobutylaluminum (5.22 ml, 5.74 mmol) was added as a THF solution. The vial was heated to 80°C and monitored by LCMS. Water was added, and the aqueous layer was washed with toluene. The combined organic layers were dried over MgSO4 and concentrated. Purification by silica gel chromatography, 0-70% toluene / cHex, yielded the title compound (603 mg, 55.5%). ESI-MS m / z: 378.00 / 380.00 [M+H] + . Intermediate 38 Steps b~e [ka]

[0262] The above compound was prepared in the same manner as for intermediate 9, and the crude product was purified by preparative TLC (silica gel, DCM containing NH3 and MeOH) to obtain the desired product (200 mg, 81%) as a white solid. ESI-MS m / z: 479.00 [M+H] + . Intermediate 39 [ka]

[0263] The above compound was prepared in the same manner as for intermediate 38 to obtain the desired product (13 mg, 62%) as a white solid. ESI-MS m / z: 495.09 [M+H] + . Intermediate 40 [ka]

[0264] The above compound was prepared in the same manner as for intermediate 9, and the crude product was purified by preparative TLC (silica gel, DCM containing NH3 and MeOH) to obtain the desired product (475 mg, 71%) as a white solid. ESI-MS m / z: 466.31 [M+H] + . Intermediate 41 [ka] Intermediate 41 Step a [ka]

[0265] A CH3OH (20 mL) solution containing 4-acetylpyridine (2 g, 16.50 mmol) and 4-toluenesulfonyl hydrazide (4.61 g, 24.70 mmol) was stirred at 70°C for 2 hours. The mixture was filtered and washed to obtain the desired precipitated solid (2 g, 41%) as a white solid. ESI-MS m / z: 290.00 [M+H] + . Intermediate 41 Step b [ka]

[0266] Compound from step a (566 mg, 1.96 mmol), Pd(PPh3)2Cl2 (91 mg, 0.13 mmol), LiO tA 5 mL solution of dioxane containing Bu (309 mg, 4.83 mmol) and (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (500 mg, 1.30 mmol) was stirred overnight at 90°C under a nitrogen atmosphere. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (450 mg crude product) as a yellow solid. ESI-MS m / z: 360.00 [M+H] + . Intermediate 41 steps c, d, e and f [ka]

[0267] The amino alcohol was synthesized using four steps similar to intermediate 9 (cross-coupling, dihydroxylation, tosylation, and amination) to obtain the title compound (50 mg, 74%) as a white solid. ESI-MS m / z: 460.95 [M+H] + .

[0268] Next, after amide coupling, the diastereomers were separated using preparative HPLC. Intermediate 42 [ka] Intermediate 42 Step a [ka]

[0269] 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 hours. 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 obtain the desired compound (1.75 g, 92%) as a white solid. ESI-MS m / z: 357.05 [M+H] + . Intermediate 42 Step b [ka]

[0270] In a 40 mL vial, the compound from step a (1.29 g, 3.62 mmol), TMBQ (1.63 g, 10.86 mmol), bis(pinacolate)diborone (1.38 g, 5.43 mmol), Pd(OAc)2 (41 mg, 0.18 mmol), PPh3 (95 mg, 0.36 mmol), and NaH (261 mg, 10.86 mmol) were added at room temperature. After degassing and packing with N2, toluene (40 mL) was added to the vial. The reaction mixture was allowed to react overnight at 90 °C. The reaction was monitored by LC-MS. 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 obtain the desired compound (2.4 g) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 1.33 (s, 12H), 6.13 (s, 1H), 6.17 (d, J = 2.7 Hz, 1H), 7.57 (s, 4H). Intermediate 42 Step c [ka]

[0271] A solution of dioxane (8 mL) and H2O (2 mL) containing the compound from step b (778 mg, 2.61 mmol) was treated with (R)-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[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) under a nitrogen atmosphere at 80°C for 1 hour. The reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired compound (443 mg, 79%) as a brown oily substance. ESI-MS m / z: 427.00 [M+H] + . Intermediate 42 steps d, e, f and g [ka]

[0272] The amino alcohol was synthesized using four steps similar to those used in intermediate 9 (cross-coupling, racemic dihydroxylation, tosylation, and amination) to obtain the title compound (208 mg, 90%) as a white solid. ESI-MS m / z: 528.10 [M+H] + .

[0273] Next, after amide coupling, the diastereomers were separated using preparative TLC. Intermediate 43 [ka]

[0274] The amino alcohol was synthesized using ADMIX-β for selective dihydroxylation with a sequence similar to intermediate 42 to obtain the title compound (181.4 mg, 66%) as a white solid. ESI-MS m / z: 528.10 [M+H] + . Intermediate 44 [ka]

[0275] The amino alcohol was synthesized using ADMIX-β for selective dihydroxylation with a sequence similar to intermediate 42 to obtain the title compound (10 mg, 23%) as a white solid. ESI-MS m / z: 464.30 [M+H] + . Intermediate 45 [ka] Intermediate 45 Step a [ka]

[0276] (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofl[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 equivalents) was added. Nitrogen gas was started to sparge the suspension, and copper(I) iodide (167 mg, 0.879 mmol, 0.2 equivalents) and N,N'-dimethylethylenediamine (0.208 mL, 1.93 mmol, 0.4 equivalents) were added. After continuing sparging for another 5 minutes, a reflux condenser was attached to the flask, and the mixture was heated to 100°C while stirring. After stirring at this temperature for 2 hours, the reaction mixture was cooled to room temperature and diluted with saturated sodium bicarbonate aqueous solution, water, and ethyl acetate. The layers were separated, and the aqueous layer was extracted with toluene (3 × 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated into crude oil. This crude substance was purified by automated flash chromatography on silica gel (cyclohexane containing 0-100% toluene) to obtain a pure iodide product as a yellow foam (1.03 g, 63%). ESI-MS m / z: 371.178 [M+H] + . Intermediate 45 Step b [ka]

[0277] 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 that temperature for 1 hour. Then, i-PrOB(pin) (4.76 ml, 23.3 mmol, 1.2 equivalents) was added. Next, the reaction mixture was warmed to room temperature and stirred. During this time, some solid began to precipitate. After 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. The layers were separated, and the aqueous layer was extracted with RINKAN (3 × 50 mL). The combined organic extract was washed with brine (1 × 50 mL), dried over sodium sulfate, filtered, and concentrated to obtain crude boronic acid ester as a crystalline white solid (5.65 g, 89%). The crude product contained approximately 8% pinacol by weight and was used without further purification (no m / z of boronic acid esters was detected). Intermediate 45 Step c [ka]

[0278] 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 boronic acid ester from step b (1.10 g, 3.79 mmol, 1.35 equivalent) were added. Water (2.8 mL) was added, and the resulting two-phase suspension was sparged with nitrogen for 5 minutes. 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 phenylethylamine. The layers were separated, and the aqueous layer was extracted with phenylethylamine (3 × 50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated into crude oil. This crude substance was purified by automated flash chromatography of silica gel (cyclohexane containing 0-100% methoxy) to obtain pure product 5 as a yellow foam (940 mg, 82%). ESI-MS m / z: 407.156 [M+H] + . Intermediate 45 steps d, e and f [ka]

[0279] The above compound was prepared using the same procedure as for intermediate 9 to obtain the desired product (700 mg, 99%) as a white solid. ESI-MS m / z: 440.08 [M+H] + . Intermediate 46 [ka]

[0280] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (138 mg, 90%) as a white solid. ESI-MS m / z: 504.14 [M+H] + . Intermediate 47 [ka]

[0281] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (417 mg, 99%) as a white solid. ESI-MS m / z: 476.17 [M+H] + . Intermediate 48 [ka]

[0282] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (222 mg, 93%) as a white solid. ESI-MS m / z: 458.22 [M+H] + . Intermediate 49 [ka]

[0283] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (158 mg, 100%) as a white solid. ESI-MS m / z: 522.18 [M+H] + . Intermediate 50 [ka]

[0284] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (291 mg, 76%) as a white solid. ESI-MS m / z: 494.24 [M+H] + . Intermediate 51 [ka]

[0285] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (158 mg, 100%) as a white solid. ESI-MS m / z: 522.18 [M+H] + . Intermediate 52 [ka]

[0286] The above compound was prepared in the same manner as for intermediate 45 to obtain the desired product (800 mg, 96%) as a white solid. ESI-MS m / z: 476.17 [M+H] + . Intermediate 53 [ka]

[0287] The above compound was prepared using the same procedure as for intermediate 9 to obtain the desired product (421 mg, 90%) as a white solid. ESI-MS m / z: 440.08 [M+H] + . Intermediate 54 [ka]

[0288] The above compound was prepared using the same procedure as for intermediate 9 to obtain the desired product (608 mg, 97%) as a white solid. ESI-MS m / z: 440.08 [M+H] + . Intermediate 55 [ka]

[0289] The above compound was prepared using the same procedure as for intermediate 9 to obtain the desired product (560 mg, 93%) as a white solid. ESI-MS m / z: 495.45 [M+H] + . Intermediate 56 [ka]

[0290] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (689 mg, 94%). ESI-MS m / z: 459.44 [M+H] + . Intermediate 57 [ka]

[0291] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (107 mg, 97%). ESI-MS m / z: 443.16 [M+H] + . Intermediate 58 [ka]

[0292] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (293 mg, 100%). ESI-MS m / z: 441.34 [M+H] + .

[0293] Table 3 below includes examples prepared in a manner similar to that of Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20–90%, 25 min), and some by automated column chromatography (silica gel). The arylboronic acid ester starting materials and aryl amide coupling partners were prepared according to intermediates 1–58, or by similar procedures with minor modifications, and also by the procedure found in U.S. Patent No. 11,572,367. [Table 3-1] [Table 3-2] [Table 3-3] Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29

[0294] Table 4 below includes examples prepared in a similar manner to Example 47. Most compounds were purified by preparative HPLC (ACN / H2O, 20–90%, 25 min), and some by automated column chromatography (silica gel). Some examples were inseparable by preparative HPLC and reported as a mixture of diastereomers. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] Example 443 [ka] Reference:Org.Lett.2003,5,2453-2455

[0295] (3R)-7-bromo-5-(1-cyclopropyl-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamide)-1-hydroxyethyl)-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (50 mg, 0.088 mmol, 1.0 equivalent), indole (26 mg, 0.22 mmol, 2.5 equivalents), K2CO3 (24 mg, 0.18 mmol, 2.0 equivalents), CuI (13 mg, 0.068 mmol, 0.78 equivalents), and N,N-dimethylglycine (13 mg, 0.13 mmol, 1.4 equivalents) were added to a vial dried in a drying oven. The solid was dissolved in DMSO (0.18 mL), the vial was sealed, and heated to 70°C with stirring. After stirring at that temperature for approximately 15 hours, the reaction mixture was cooled to room temperature and diluted with dimethyl (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 reverse-phase HPLC, and then by automated flash chromatography on silica gel (0–10% MeOH in DCM) to isolate pure samples of both diastereomer 1 (10 mg, 19%) and diastereomer 2 (8.0 mg, 15%) as white solids.

[0296] Table 5 below includes examples prepared in a similar manner to Example 443. Most of the compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). [Table 5-1] [Table 5-2]

[0297] Table 6 below includes examples prepared in a manner similar to that of Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20–90%, 25 min), and some by automated column chromatography (silica gel). The arylboronic acid ester starting materials and aryl amide coupling partners were prepared according to intermediates 1–58, or by similar procedures with minor modifications, and also by the procedure found in U.S. Patent No. 11,572,367. [Table 6] Intermediate 59 [ka] Intermediate 59 Step a [ka]

[0298] A solution of dioxane (16 mL) containing CAN-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[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 tert-butyl N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (1.48 g, 5.22 mmol), along with 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] + . Intermediate 59 Step b [ka]

[0299] 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-dioxaborolane (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 obtain the desired compound (1.8 g, 81%) as a yellow solid. ESI-MS m / z: 480.10 [M+H] + . Intermediate 59 Step c [ka]

[0300] Compound from step b (2g, 4.16 mmol), K2OsO4 . A solution of 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 further at room temperature for 4 hours. The resulting mixture was extracted, concentrated, and purified by silica gel column chromatography to obtain the desired compound (1.7 g, 84%) as a yellow solid. ESI-MS m / z: 482.00 [M+H] + . Example 463 [ka] Example 463 Process a [ka]

[0301] A THF (3 mL) solution containing 2-bromopyridine (373 mg, 2.36 mmol) and n-BuLi (151 mg, 2.36 mmol) was stirred at -78°C for 15 minutes under a nitrogen atmosphere. Intermediate 59 (190 mg, 0.39 mmol) was added dropwise at -78°C. The resulting mixture was stirred for a further 30 minutes at -78°C. The residue was quenched, extracted, concentrated, and purified by reverse-phase flash chromatography to obtain the desired compound (100 mg, 45%) as a crude yellow solid. ESI-MS m / z: 561.05 [M+H] + . Example 463 Process b [ka]

[0302] The compound from step a (100 mg, 0.18 mmol), 1,4-dioxane (2 mL) containing HCl, and DCM (2 mL) were mixed in a solution and stirred at room temperature for 1 hour. The mixture was basicized, extracted, concentrated, and purified by reverse-phase flash chromatography to obtain the desired compound (50 mg, 60%) as a white solid. ESI-MS m / z: 460.95 [M+H] + . Example 463 Process c [ka]

[0303] A solution of DMF (1 mL) containing 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) was stirred at room temperature for 1 hour. The resulting mixture was extracted, concentrated, and purified by preparative HPLC to obtain the desired compound (3.5 mg, 17%) as a white solid. ESI-MS m / z: 675.20 [M+H] + . Intermediate 60 [ka]

[0304] The following intermediate was 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] + . Intermediate 61 [ka]

[0305] 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] + .

[0306] Table 7 below includes examples prepared in a similar manner to Example 463. Most of the compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). [Table 7-1] [Table 7-2] Intermediate 62 [ka] Intermediate 62 Step a [ka]

[0307] To a toluene-stirred solution containing CAN-7-bromo-5-iodo-3-methyl-2,3-dihydrofl[2,3-c]pyridine-3-carboxamide (4 g, 10.44 mmol) and tributyl(1-ethoxyethenyl) stannane (3.96 g, 10.97 mmol), Pd(dppf)Cl2CH2Cl2 (851 mg, 1.04 mmol) was added dropwise at 110°C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with EA. The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to obtain the desired compound (2.1 g, 67%) as a brown solid. ESI-MS m / z: 327.00 [M+H] + . Intermediate 62 Step b [ka]

[0308] A stirring solution of dioxane (40 mL) containing the compound from step a (4.7 g, 14.37 mmol) and 2-(5-chloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.94 g, 14.37 mmol), and H2O (10 mL) is prepared, to which Pd(dppf)Cl2CH2Cl2 (1.17 g, 1.44 mmol) and K2CO2 are added. -3 (3.97 g, 28.73 mmol) was added. The resulting mixture was stirred at 80°C for 2 hours 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 obtain the desired compound (4 g, 71%) as a yellow oil. ESI-MS m / z: 395.05 [M+H] + . Intermediate 62 Step c [ka]

[0309] Under a nitrogen atmosphere, the compound from step b (6 g, 16.36 mmol) and HCl (33 mL) were stirred in MeOH (20 mL) solution at 50°C 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 × 30 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to obtain the desired compound (4 g, 64%) as a yellow oil. ESI-MS m / z: 381.90 [M+H] + . Intermediate 62 Step d [ka]

[0310] 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 LC-MS. The resulting mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain the title compound (4 g, 74%) as a yellow oil. ESI-MS m / z: 514.00 [M+H] + . Intermediate 63 [ka]

[0311] The following intermediate was prepared in a manner similar to that of intermediate 62 to obtain the desired compound (1.7 g, 65%). ESI-MS m / z: 512.00 [M+H] + . Intermediate 64 [ka] Intermediate 64 Step a [ka]

[0312] To a 1,4-dioxane / H2O (9:1) stirred solution containing intermediate 62 (200 mg, 0.39 mmol) and 2-cyclopropylpyrimidine-5-ylboronic acid (64 mg, 0.39 mmol), K2CO3 (108 mg, 0.78 mmol) and Pd(dppf)Cl2CH2Cl2 (32 mg, 0.04 mmol) were added, and the resulting mixture was stirred at 85°C under a nitrogen atmosphere for 2 hours. The residue was purified by reverse-phase flash chromatography to obtain the desired compound (130 mg, 69%) as a yellow oil. ESI-MS m / z: 484.30 [M+H] + . Intermediate 64 Step b [ka]

[0313] ADMIX-β (1.16 g, 1.49 mmol) was added to a t-BuOH / H2O stirred solution containing the compound from step a (240 mg, 0.50 mmol) and methanesulfonamide (47 mg, 0.50 mmol), and the resulting mixture was stirred overnight at room temperature. The mixture was extracted with RINKAN (3 × 10 mL). The residue was purified by reverse-phase flash chromatography to obtain the desired compound (115 mg, 45%) as a yellow oil. ESI-MS m / z: 518.15 [M+H] + . Intermediate 64 steps c and d [ka]

[0314] To a DCM-stirred solution containing the compound from step b (100 mg, 0.20 mmol) and TsCl (64 mg, 0.33 mmol), TEA (67 mg, 0.67 mmol) and DMAP (27 mg, 0.22 mmol) were added under a nitrogen atmosphere at room temperature and the mixture was stirred for 2 hours. The resulting mixture was acidified to pH 3 with HCl (1 M aqueous solution), extracted using DCM, and the combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA1:1) to obtain the desired compound (80 mg, 62%) as a yellow solid. ESI-MS m / z: 672.25 [M+H] + .

[0315] A solution of the compound (80 mg, 0.12 mmol) from step c and MeOH (10 mL) containing NH3 (g) was stirred overnight at 40°C. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH 12:1 containing CH2Cl2 / NH3) to obtain methyl methyl of the title compound (60 mg, 130%) as a yellow solid. ESI-MS m / z: 502.25 [M+H] + . Intermediate 65 [ka]

[0316] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (110 mg, 64%). ESI-MS m / z: 444.00 [M+H] + . Intermediate 66 [ka]

[0317] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound. Intermediate 67 [ka]

[0318] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound. Intermediate 68 [ka]

[0319] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound. Intermediate 69 [ka]

[0320] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (50.2 mg, 41%) as a white solid. ESI-MS m / z: 538.15 [M+H] + . Intermediate 70 [ka]

[0321] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound. Intermediate 71 [ka]

[0322] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (70 mg, 75%) as a white solid. ESI-MS m / z: 576.25 [M+H] + After subsequent amide coupling, the final compound was isolated after Boc deprotection with dioxane containing HCl. See the table below. Intermediate 72 [ka]

[0323] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (80 mg, 65%) as a white solid. ESI-MS m / z: 590.00 [M+H] + After subsequent amide coupling, the final compound was isolated after Boc deprotection with dioxane containing HCl. See the table below. Intermediate 73 [ka]

[0324] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (27 mg, 42%) as a white solid. ESI-MS m / z: 474.95 [M+H] + . Intermediate 74 [ka]

[0325] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (70 mg) as a white solid. SI-MS m / z: 639.00 [M+H] + After subsequent amide coupling, the final compound was isolated after Boc deprotection with dioxane containing HCl. See the table below. Intermediate 75 [ka]

[0326] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (70 mg, 71%) as a yellow solid. ESI-MS m / z: 484.95 [M+H] + . Intermediate 76 [ka]

[0327] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (30 mg, 81%) as a yellow solid. ESI-MS m / z: 495.00 [M+H] + . Intermediate 77 [ka]

[0328] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (22 mg) as a yellow solid. ESI-MS m / z: 451.05 [M+H] + . Intermediate 78 [ka]

[0329] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (59.4 mg, 69%) as a yellow solid. ESI-MS m / z: 509.10 [M+H] + . Intermediate 79 [ka] Intermediate 79 Step a [ka]

[0330] A 10 mL solution of DMF containing 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) was stirred at 90°C for 2 hours under an N2 atmosphere. The residue was purified by silica gel column chromatography eluted with PE / EA to obtain the desired product (70 mg, 29%) as a yellow oily substance. ESI-MS m / z: 444.00 [M+H] + . Intermediate 79 steps b, c, d and e [ka]

[0331] The following intermediates were prepared in a similar order to intermediate 64 to obtain the title compound (15 mg, 68%) as a yellow solid. ESI-MS m / z: 462.00 [M+H] + . Example 477 [ka] Example 477 Process a [ka]

[0332] To a stirred solution of 2-methyl-3-buty-2-ol (500 mg, 5.94 mmol) and DCM (10 mL), TBSOTf (7.86 g, 29.72 mmol) and TEA (1.91 g, 17.83 mmol) were added. The reaction was monitored by TLC. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium 2SO4. 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 obtain 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). Example 477 Process b [ka]

[0333] To a stirred solution in DMF (5 mL) containing step a (400 mg, 0.78 mmol) from Example 477 and the compound from step a (216 mg, 1.09 mmol), 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 a nitrogen atmosphere and monitored by LC-MS. The resulting mixture was extracted with Â. The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (9:1) to obtain the desired compound (330 mg, 75%) as a yellow oil. ESI-MS m / z: 562.15 [M+H] + . Example 477 Process c [ka]

[0334] A solution of t-BuOH (3 mL) and H2O (3 mL) containing the compound from step b (300 mg, 0.53 mmol) was treated with ADMIX-β (1.25 g, 1.60 mmol) and methanesulfonamide (51 mg, 0.53 mmol) at 0°C. The final reaction mixture was allowed to react overnight at room temperature. The reaction was monitored by LC-MS. The resulting mixture was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA2:1) to obtain the desired compound (188 mg, 59%) as a pink oil. ESI-MS m / z: 596.20 [M+H] + . Example 477 Process d [ka]

[0335] A 3 mL solution of DCM containing the compound from step c (188 mg, 0.32 mmol) was treated with TsCl (90 mg, 0.47 mmol), DMAP (39 mg, 0.32 mmol), and TEA (96 mg, 0.95 mmol) at room temperature for 1.5 hours. The reaction was monitored by LC-MS. The mixture was acidified to pH 3 with concentrated HCl. The resulting mixture was extracted with Â. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA2:1) to obtain the desired compound (164 mg, 69%) as a white oil. ESI-MS m / z: 750.25 [M+H] + . Example 477 Process e [ka]

[0336] 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 LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA1:1) to obtain the desired compound (100 mg) as a white oil. ESI-MS m / z: 580.20 [M+H] + . Example 477 Process f [ka]

[0337] A 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 LC-MS. The residue was purified by reverse-phase flash chromatography to obtain the desired compound (79 mg, 58%) as a white solid. ESI-MS m / z: 794.10 [M+H] + . Example 477 Process g [ka]

[0338] A THF (4 mL) solution containing the compound from step f (70 mg, 0.09 mmol) was treated with TBAF (0.9 mL, 0.88 mmol) at 60°C for 1 hour under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was extracted with Âx. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH 13:1 containing CH2Cl2 / NH3(g)) to obtain the title compound (28.2 mg, 47%) as a white solid. ESI-MS m / z: 680.05 [M+H] + . Intermediate 80 [ka]

[0339] The following intermediates were prepared in a similar order to Example 477 to obtain the title compound (4.5 mg, 90%) as a yellow solid. ESI-MS m / z: 528.11 [M+H] + .

[0340] Table 8 below includes examples prepared in a manner similar to that of Example 1. Most compounds were purified by preparative HPLC (ACN / H2O, 20–90%, 25 min), and some by automated column chromatography (silica gel). Amine starting materials were prepared according to intermediates 62–80, and aryl amide coupling partners were prepared according to intermediates 1–58, or by similar procedures with minor modifications following the procedure found in U.S. Patent No. 11,572,367. [Table 8-1] [Table 8-2] [Table 8-3] Example 504 [ka] Example 504 Process a [ka]

[0341] To a 1,4-dioxane / H2O stirring solution containing intermediate 62 (300 mg, 0.58 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine-2-one (129 mg, 0.58 mmol), K2CO3 (161 mg, 1.17 mmol) and Pd(dppf)Cl2CH2Cl2 (47 mg, 0.06 mmol) were added, and the reaction was stirred at 85°C under a nitrogen atmosphere for 2 hours. The residue was purified by reverse-phase flash chromatography to obtain the desired product (105 mg, 39%) as a yellow solid. ESI-MS m / z: 459.00 [M+H] + . Example 504 Process b [ka]

[0342] A mixture of tBuOH (3 mL) and H2O (3 mL) containing methyl (100 mg, 0.22 mmol), methanesulfonamide (20 mg, 0.22 mmol), and ADMIX-β (509 mg, 0.65 mmol) of the compound from step a was stirred overnight at room temperature. The reaction was monitored by LC-MS. The resulting mixture was extracted with EA. The combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to obtain the desired product (70 mg, 65%) as a yellowish-brown oil. ESI-MS m / z: 493.15 [M+H] + . Example 504 Process c [ka]

[0343] A 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 LC-MS. The mixture was acidified to pH 4 with HCl (1 M aqueous solution). The resulting mixture was extracted with CH2Cl2. The combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA1:1) to obtain the desired product (60 mg, 52.73%) as a yellow solid. ESI-MS m / z: 800.95 [M+H] + . Example 504 Process d [ka]

[0344] The mixture of the compound from step c (60 mg, 0.07 mmol) and MeOH (3 mL) containing NH3 (g) was stirred overnight at 40°C. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH containing CH2Cl2 / 7M NH3) to obtain the desired product (20 mg, 42.3%) as a white solid. ESI-MS m / z: 631.15 [M+H] + . Example 504 Process e [ka]

[0345] A 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 LC-MS. The residue was purified by reverse-phase flash chromatography to obtain the desired product (20 mg, 59%) as a yellow solid. ESI-MS m / z: 845.05 [M+H] + . Example 504 Process f [ka]

[0346] To a stirred mixture of the compound from step e (20 mg, 0.02 mmol) and MeOH (2 mL), H2O (0.5 mL) containing LiOH (5 mg, 0.24 mmol) was added dropwise at room temperature. The reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH2Cl2 / 7M NH3MeOH10:1) to obtain the desired product (6.7 mg, 38%) as a white solid. ESI-MS m / z: 691.20 [M+H] + . Example 505 [ka]

[0347] The following example was prepared in a similar order to Example 504. The residue was purified by reverse-phase flash chromatography to obtain the title compound (6.4 mg, 31%) as a white solid. ESI-MS m / z: 691.20 [M+H] + .

[0348] Table 9 below includes examples prepared using the same method as in Example 1 or the method described above. Most of the compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). [Table 9] Intermediate 81 [ka]

[0349] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (21.3 mg, 27%). ESI-MS m / z: 438.20 [M+H] + . Intermediate 82 [ka]

[0350] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (197.5 mg, 72%). ESI-MS m / z: 485.10 [M+H] + . Intermediate 83 [ka]

[0351] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (125.9 mg, 36%). ESI-MS m / z: 457.15 [M+H] + . Intermediate 84 [ka] Intermediate 84 Step a [ka]

[0352] A mixture of 3-chloro-4-iodopyridine (4.3 g, 17.96 mmol), sodium difluoromethanesulfinate (12.40 g, 89.79 mmol), and H2O (52 mL) was stirred at room temperature. TFA was added to bring the pH to 7, and an additional TFA (3.07 g, 26.94 mmol) was added. After adding DCM (130 mL), tert-butyl hydroperoxide (8.25 g, 91.59 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature and monitored by LC-MS. The mixture was neutralized with saturated NaHCO3 (aqueous solution) to bring the pH to 8. The resulting mixture was extracted with CH2Cl2. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA10:1) to obtain the desired product (660 mg, 12%) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d): δ 6.82 (t, J=53.8Hz, 1H), 7.88 (d, J=5.0Hz, 1H), 8.12 (d, J=5.0Hz, 1H). Intermediate 84 Step b [ka]

[0353] In a 100 mL three-necked flask, n-BuLi (1.45 mL, 3.62 mmol) was added dropwise to a solution of THF (18 mL) containing the compound from step a (700 mg, 2.42 mmol) under an N2 atmosphere at -78°C. The reaction mixture was stirred at -78°C for 15 minutes. Then, a solution of THF containing trimethyl borate (377 mg, 3.62 mmol) was added dropwise, and the mixture was stirred at room temperature for a further 1 hour. The reaction product was acidified to pH 3 with HCl (1 M aqueous solution). The resulting mixture was extracted with Âr (3 × 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 obtain the crude product (500 mg) as a brown solid. ESI-MS m / z: 208.10 [M+H] + . Intermediate 85 [ka]

[0354] The above compound was prepared using intermediate 84 in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid. (103.5 mg, 51%) ESI-MS m / z: 439.15 [M+H] + . Intermediate 86 [ka]

[0355] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (300 mg, 90%). ESI-MS m / z: 447.00 [M+H] + . Intermediate 87 [ka]

[0356] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (100 mg, 71%). ESI-MS m / z: 467.05 [M+H] + . Intermediate 88 [ka]

[0357] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (178 mg, 30%). ESI-MS m / z: 455.05 [M+H] + . Intermediate 89 [ka]

[0358] The above compound was prepared in a manner similar to that of intermediate 9 to obtain the desired amino alcohol as an off-white solid (214.8 mg, 30%). ESI-MS m / z: 473.05 [M+H] + . Intermediate 90 [ka]

[0359] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (293 mg, quantitative yield). ESI-MS m / z: 441.339 [M+H] + .' Intermediate 91 [ka]

[0360] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (107 mg, 97% yield). ESI-MS m / z: 443.157 [M+H] + . Intermediate 92 [ka]

[0361] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (326 mg, 94% yield). ESI-MS m / z: 459.306 [M+H] + . Intermediate 93 [ka]

[0362] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (326 mg, 98% yield). ESI-MS m / z: 403.068 [M+H] + . Intermediate 94 [ka]

[0363] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (258 mg, quantitative yield). ESI-MS m / z: 426.378 [M+H] + . Intermediate 95 [ka]

[0364] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (70 mg, 89% yield). ESI-MS m / z: 439.175 [M+H] + . Intermediate 96 [ka]

[0365] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (475 mg, 98% yield). ESI-MS m / z: 473.240 [M+H] + . Intermediate 97 [ka]

[0366] The above compound was prepared in the same manner as for intermediate 9 to obtain an amino alcohol (135 mg, 65% yield). ESI-MS m / z: 439.26 [M+H] + . Intermediate 98 [ka]

[0367] In a vial, (R)-7-bromo-5-(1-cyclopropylvinyl)-3-methyl-2,3-dihydrofluoro[2,3-c]pyridine-3-carboxamide (1 g, 3.09 mmol), 4-fluoro-1H-indazole (0.505 g, 3.71 mmol), and copper(I) iodide (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 mixture was heated at 110°C for 12 hours. The reaction mixture was cooled to room temperature, and water was added. The aqueous layer was washed with ethyl acetate, 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% ethyl acetate / cHex to obtain the title compound (540 mg, yield 46%). ESI-MS m / z:379.00 [M+H] + . Intermediate 99 [ka]

[0368] (R)-7-bromo-3-methyl-5-(3,3,3-trifluoropropane-1-en-2-yl)-2,3-dihydrofluoro[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) was added, followed by 4-fluoro-1H-indole (338 mg, 2.50 mmol). Nitrogen gas was started to sparge the suspension, and N,N'-dimethylethylenediamine (62.1 μL, 0.577 mmol) and copper(I) iodide (54.9 mg, 0.288 mmol) were added sequentially. Sparging was continued for another 2 minutes, then the vial was sealed and heated to 110°C with stirring for 2 hours. After this time, the reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with toluene (3 × 15 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by automated flash chromatography on silica gel (0-100% toluene in cyclohexane) to obtain pure HCl as a yellow oil (230 mg, 30%). ESI-MS m / z: 406.203. Intermediate 100 [ka] Intermediate 100 Steps a and b [ka]

[0369] Under N2 conditions, 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 mixture was stirred under N2 conditions at room temperature for 20 hours. Further addition of 2-methanesulfonylethanol (3.44 g, 27.72 mmol) and t-BuOK (3.11 g, 27.72 mmol) was added, and the reaction mixture was stirred for a further 3.5 hours. The reaction was monitored by LC-MS. The resulting mixture was washed with water. The aqueous layer was acidified to pH 3 with concentrated HCl. The resulting mixture was extracted with ELISA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 5-bromo-3-methoxy-2-nitrophenol (9.3g) as a brown solid. ESI-MS m / z: 249.95 [MH] - .

[0370] A solution of the compound from step a (9.3 g, 37.49 mmol) in EtOH (100 mL) was treated with H2O (50 mL) containing NH4Cl (20.06 g, 374.95 mmol) and Fe (10.47 g, 187.47 mmol) at 80°C for 30 minutes. The reaction was monitored by LC-MS. 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 ethyl acetate. 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 obtain 2-amino-5-bromo-3-methoxyphenol (4.5 g, 55%) as a brown solid. ESI-MS m / z: 218.15 [M+H] + . Intermediate 100 Step c [ka]

[0371] A THF (20 mL) solution containing the compound from step b (1.35 g, 6.19 mmol) 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 hour. The reaction was monitored by LC-MS. The resulting mixture was extracted with phenylethylamine. 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 obtain the desired compound (823 mg, 44%) as a white solid. ESI-MS m / z: 303.95 [M+H] + . Intermediate 100 steps d and e [ka]

[0372] A solution of POCl3 (5 mL, 53.65 mmol) containing the compound from step c (640 mg, 2.10 mmol) was heated at 80°C for 16 hours. The reaction was monitored by LC-MS. The reaction product was quenched with water at room temperature. The resulting mixture was extracted with RINKAN. 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 obtain the desired compound (180 mg, 30%) as an orange solid. ESI-MS m / z: 285.90 [M+H] + .

[0373] A 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), xanthophos (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) under a nitrogen atmosphere at 100°C for 5 hours. The reaction was monitored by LC-MS. The residue was purified by reverse-phase flash chromatography to obtain the title compound (81.8 mg, 45%) as a white solid. ESI-MS m / z: 252.10 [M+H]+ . Intermediate 101 [ka] Intermediate 101 Step a [ka]

[0374] 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 hour. The reaction was monitored by LC-MS. The resulting mixture was extracted with SiO2. 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 obtain the desired compound (1.4 g, 74%) as an orange solid. ESI-MS m / z: 295.85 [M+H] + . Intermediate 101 Step b [ka]

[0375] A CHCl3 (15 mL) solution containing the compound from step a (1.36 g, 4.59 mmol) was treated with POCl3 (1.06 g, 6.89 mmol) at 65°C for 2 days. The reaction was monitored by LC-MS. The reaction product was quenched with water at room temperature. The resulting mixture was extracted with RINKAN. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain the desired compound (727 mg, 57%) as a white solid. ESI-MS m / z: 227.90 [M+H] + . Intermediate 101 Step c [ka]

[0376] A 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), xanthophos (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) under a nitrogen atmosphere at 100°C for 5 hours. The reaction was monitored by LC-MS. The resulting mixture was filtered, and the filtrate was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the title compound (585.1 mg, 89%) as a brown solid. ESI-MS m / z: 244.05 [M+H] + . Intermediate 102 [ka] Intermediate 102 Step a [ka]

[0377] 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) under a nitrogen atmosphere at -78°C for 1 hour. Subsequently, a solution of I2 (1.26 g, 4.96 mmol) in THF (3 mL) was added in divided portions at -78°C. The final reaction mixture was allowed to react at room temperature for 10 minutes. The reaction was monitored by LC-MS. The reaction products were quenched with Na2S2O3 at room temperature. The resulting mixture was extracted with RINKAN. 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 obtain the desired compound (954 mg, 63%) as a yellow solid. ESI-MS m / z: 307.85 [M+H] + . Intermediate 102 Step b [ka]

[0378] A solution of THF (10 mL) containing the compound from step a (1.35 g, 4.39 mmol) was treated with butyllithium (2.6 mL, 6.59 mmol) under a nitrogen atmosphere at -78°C for 10 minutes, followed by the addition of trimethyl borate (684 mg, 6.59 mmol) in fractional amounts at -78°C. The reaction mixture was stirred for 1 hour and monitored by LC-MS. The mixture was acidified to pH 2 with concentrated HCl. The resulting mixture was extracted with toluene. The combined organic layers were concentrated under reduced pressure to obtain the desired compound (834 mg, crude) as a brown solid. ESI-MS m / z: 225.95 [M+H] + .

[0379] Table 10 below includes examples prepared in the same manner as in Example 1 or by the method described above. Most of the compounds were purified by preparative HPLC (ACN / H2O, 20-90%, 25 min), and some were purified by automated column chromatography (silica gel). [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] Table 10-8 Table 10-9 Table 10-10 Table 10-11 Table 10-12 Table 10-13 Table 10-14 Table 10-15 Table 10-16 Table 10-17 Table 10-18 Table 10-19 Table 10-20 Intermediate 103 [ka] Intermediate 103 Step a [ka]

[0380] A solution of 2-chloroacetaldehyde (10 mL) containing 4-bromo-3-chloropyridine-2-amine (1 g, 4.82 mmol) was heated at 100°C for 16 hours. The reaction was monitored by LC-MS. The mixture was basicized 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 eluted with PE / EA (1:2) to obtain the desired compound (890 mg, 80%) as a pale yellow solid. ESI-MS m / z: 230.85 [M+H] + . Intermediate 103 Step b [ka]

[0381] A 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) under a nitrogen atmosphere at -78°C for 5 minutes, followed by the addition of Tin-San (1.05 g, 3.24 mmol) in fractional amounts at -78°C. The final reaction mixture was allowed to react at room temperature for 1 hour. The reaction was monitored by LC-MS. The resulting mixture was extracted with RINKAN. The combined organic layers were concentrated under reduced pressure. The resulting mixture was used directly in the next step without further purification. ESI-MS m / z: 443.05 [M+H] + . Intermediate 104 [ka] Intermediate 104 Step a [ka]

[0382] To a stirred solution of 4-bromo-3-chloro-2-methoxypyridine (500 mg, 2.25 mmol) in THF (20 mL), n-BuLi (216 mg, 3.37 mmol) was added dropwise at -78°C under an N2 atmosphere. Then, trimethyl borate (350 mg, 3.37 mmol) was added at -78°C. The reaction was monitored by LC-MS. The reaction products were quenched with NH4Cl solution at -78°C. The crude product was purified by reverse-phase flushing to obtain the desired product (300 mg, 71%) as a yellow solid. ESI-MS m / z: 188.00 [M+H] + . Intermediate 104 Step b [ka]

[0383] A solution of the compound from step a (300 mg, 1.6 mmol) and dioxane (15 mL) containing HCl (4 mL) was stirred overnight at 90°C under an N2 atmosphere. The residue was purified by reverse-phase flushing to obtain the desired product (70 mg, 25%) as a yellow solid. ESI-MS m / z: 174.00 [M+H] + . Intermediate 105 [ka] Intermediate 105 Step a [ka]

[0384] A mixture of 5-bromo-6-chloropyridine-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 hours. The reaction was monitored by LC-MS. The resulting mixture was extracted with RINKAN. The combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the desired product (380 mg, 34%) as a brown solid. ESI-MS m / z: 232.85 [M+H] + . Intermediate 105 Step b [ka]

[0385] In a 50 mL round-bottom flask, n-BuLi (0.5 mL, 1.25 mmol) was added dropwise to a solution of THF (5 mL) containing the compound from step a (200 mg, 0.86 mmol) under an N2 atmosphere at -78°C. The reaction mixture was stirred at -78°C for 10 minutes. Then, a solution of THF (0.5 mL) containing Tin-San (422 mg, 1.30 mmol) was added dropwise, and the mixture was stirred for a further 30 minutes. The reaction product was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with Â. 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 in the next step without further purification. ESI-MS m / z: 442.95 [M+H] + . Intermediate 106 [ka] Intermediate 106 Step a [ka]

[0386] A solution of 4-bromo-3-chloropyridine-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 an N2 atmosphere. The residue was purified by reverse-phase flushing to obtain the desired product (300 mg, 51%) as a yellow solid. ESI-MS m / z: 245.00 [M+H] + . Intermediate 106 Step b [ka]

[0387] A solution of dioxane (1 mL) containing the compound from step a (100 mg, 0.41 mmol), bis(pinacolate)diborone (207 mg, 0.81 mmol), AcOK (80 mg, 0.81 mmol), and Pd(dppf)Cl2 (30 mg, 0.04 mmol) was stirred overnight at 100°C under an N2 atmosphere. The solution was filtered and used directly in the next step. ESI-MS m / z: 211.00 [M+H] + . Intermediate 107 [ka] Intermediate 107 Steps a and b [ka]

[0388] A solution of 2-bromopyridine-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, purified by silica gel column chromatography, and eluted with PE / EA (3:1) to obtain the desired compound (4.5 g, 75%) as a crude yellow solid. ESI-MS m / z: 208.95 [M+H] + .

[0389] The compound from step a (3 g, 14.46 mmol) and a solution of toluene (30 mL) and H2O (6 mL) containing 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) were 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 obtain the desired compound (1 g, 41%) as a pale yellow oil. ESI-MS m / z: 169.10 [M+H] + . Intermediate 107 steps c and d [ka]

[0390] 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 ACN (10 mL) was stirred at 90°C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted, concentrated, purified by silica gel column chromatography, and eluted with PE / EA (3:1) to obtain the desired compound (550 mg, 50%) as a white solid. ESI-MS m / z: 233.85 [M+H] + .

[0391] A solution of dioxane (2 mL) containing the compound from step c (100 mg, 0.43 mmol), bis(pinacolate)diborone (164 mg, 0.65 mmol), Pd(dppf)Cl2CH2Cl2 (35 mg, 0.04 mmol), and KOAc (84 mg, 0.86 mmol) was stirred at 90°C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered and used directly in the next step. Pinacol hydrolysis ESI-MS m / z: 198.10 [M+H] + .

[0392] Table 11 below includes examples prepared in a manner similar to Example 47 using the above or previously mentioned intermediates. More palladium and boronic acid were added when it was necessary to accelerate conversion. Most of the compounds were purified, and the diastereomers were separated by preparative HPLC (ACN / H2O, 20–90%, 25 min). If a mixture of diastereomers was reported, it is likely that they could not be separated by HPLC. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12] [Table 11-13] Example 884 [ka]

[0393] A solution of a compound derived from (R)-7-(5-chloro-2,4-difluorophenyl)-5-((S)-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamide)-1-hydroxy-1-(2-(methylamino)pyridine-4-yl)ethyl)-3-methyl-2,3-dihydrofluoro[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] + . Example 885 [ka]

[0394] A solution of dioxane (1 mL) containing (R)-7-bromo-5-((S)-1-cyclopropyl-2-(2-cyclopropyl-7-methoxy-2H-indazole-5-carboxamide)-1-hydroxyethyl)-3-methyl-2,3-dihydrofl[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) was stirred at 105°C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted, concentrated, purified by silica gel column chromatography, and eluted with CH2Cl2 / MeOH (15:1) to obtain 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] + .

[0395] The compounds shown in Table 12 were prepared using the general methods described. [Table 12]

[0396] Table 13 below contains compounds prepared using the same method as in Example 1. Most of these compounds were purified by preparative HPLC (ACN / H2O, 20–90%, 25 min), and some by automated column chromatography (silica gel). Aryl acids and amine coupling partners were prepared as described for the intermediates described above or previously. [Table 13-1] [Table 13-2] [Table 13-3]

[0397] The compounds shown in Table 14 are prepared using the general methods described above. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8]

[0398] Assay Method for RSV-A assay Hep-2 cells (originally derived from tumors that grew in irradiated, cortisone-treated, weaned rats injected with epidermal carcinoid tissue from the larynx of a 56-year-old male, but later found to be indistinguishable from HeLa cells by PCR DNA analysis) were used to culture genotype A, "long" strain RSV. RSV was inoculated into flasks, and the virus stock was collected when the cytopathic effect (CPE) exceeded 90%. The virus stock in 25% sucrose medium was rapidly frozen using liquid nitrogen to enhance viral stability. The virus stock titer was measured using 3-fold virus dilutions across 8,000 cells / well and 96-well plates to achieve a tissue culture infectious dose of 50% (TCID). 50 The titer was quantified by ) and cultured for 4 days. The viral stock titer was also quantified by the plaque-forming unit assay, as described elsewhere.

[0399] After extensive parameter testing, the final assay is performed as follows: Hep-2 cells are seeded in 60 inner wells of a 96-well plate at 8,000 cells / well in 50 μL of growth medium (phenol red-free DMEM, 1% L-Glut, 1% Penn / Strep, 1% non-essential amino acids, 10% thermo-inactivated FBS). Twofold serial dilutions of the control and test compounds are added to the wells in double series in total volumes of 25 μL. Then, the virus stock is added to the wells in 25 μL volumes at an infection multiplicity (MOI) of 0.1, bringing the total volume of each well to 100 μL. MOI is PFU / mL, or TCID if PFU / mL is unavailable. 50The calculation is performed using the following method. Each 96-well plate has six control columns containing cells and viruses but no compounds (negative control, maximum CPE), six columns containing cells but no compounds or viruses (positive control, minimum CPE), and six columns containing neither cells, viruses, nor compounds (background plate / reagent control). The control wells containing cells but no viruses are given an additional 25 μL of growth medium containing the same amount of sucrose as the wells receiving the virus stock to maintain constant medium and volume conditions. The outer wells of the plate are filled with 125 μL of moat media (DMEM, 1% Penn / Strep) to act as a thermal and evaporation barrier (moat) around the test wells. After a 5-day incubation period, the plates are read using ATPlite (50 μL added per well) to quantify the amount of ATP present in each well (a measure of cell health). The assay plates are read using an Envision luminometer. These data are used to calculate the EC of each compound. 50 Calculate (Table 15). EC 50 The range is as follows: A < 0.2 μM; B > 0.2 μM. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8] [Table 15-9] [Table 15-10] [Table 15-11]

[0400] Method for HMPV antiviral assay Method 1: In vitro HMPV antiviral activity was evaluated using clinical isolate A2 strain TN 94-49 (obtained from Dr. John Williams, Vanderbilt University, Tennessee) and LLC-MK2 cells (ATCC#CCL-7), an immortalized renal epithelial cell line derived from Macaca mulatta.

[0401] The compound was resuspended in 10 mM dimethyl sulfoxide (DMSO), serially diluted, and added to a 384-well source plate. Subsequently, the compound was diluted and transferred to a 384-well assay plate using an Echo-650 automated liquid processing system (Beckman Coulter, Indiana). The test compound was evaluated in two consecutive wells at the highest concentration of 2 μM, followed by 2.5-fold serial dilutions to obtain a total of 10 concentration points. A DMSO control well was also included in the assay plate, representing either infection or non-infection, and served as both a positive and negative control.

[0402] A2TN94-49 virus infection was performed by suspension with LLC-MK2 cells. The cells were washed twice with PBS and removed from the cell culture flask using 0.25% trypsin-EDTA (Thermo Fisher Scientific, Massachusetts). The trypsin-EDTA was inactivated by resuspending in OptiMEM (Thermo Fisher Scientific, Massachusetts) containing 2% fetal bovine serum (FBS) and 1% penicillin-streptomycin. The cells were pelleted by centrifugation at 800 rpm for 5 minutes, the supernatant was removed, and the cells were resuspended in PBS + 100 μg / mL CaCl2 and washed. This process was repeated twice. The cells were then resuspended in serum-free (SF)-OptiMEM containing 4 μg / mL TPCK-trypsin (Sigma Aldrich, Missouri), 1% penicillin-streptomycin (Thermo Fisher Scientific, Massachusetts), and 100 μg / mL CaCl2. The cells were counted and seeded at a density of 5,000 cells / well and 12.5 μL / well.

[0403] Viral infection was performed with 12.5 μL added per well, resulting in a multiple of infection (MOI) of 0.005. Viral infection was carried out using infection medium containing SF-OptiMEM, 100 μg / mL CaCl2, and 1% penicillin-streptomycin. HMPV virus stock was suspended in infection medium + 5% glycerol, and therefore an equal volume of infection medium + 5% glycerol was added to the uninfected wells to equalize the final % glycerol across all wells of the assay plate. The final concentration of TPCK-trypsin was 2 μg / mL. The assay plate was incubated at 37°C and 5% CO2 for 7 days.

[0404] After 7 days of incubation, 12.5 μL of ATP-Lite (Perkin Elmer, Massachusetts) was added to each well, and the raw luminescence values ​​were determined using Envision 2104 (Perkin Elmer, Massachusetts). The average raw luminescence values ​​of the cell- and virus-only positive control wells were subtracted from all conditions tested, and the percentage of healthy cells was determined by dividing these values ​​by the average of the cell-only negative control wells. Subsequently, EC 50 The values ​​were calculated by nonlinear regression using a four-parameter curve rheological equation. The curve-fitted model used was the XLFit Dose-Response One Site Model 200: y = (A + (B / (1 + ((x / C)^D)))) (where A is the minimum y value, B is the maximum y value, and C is log EC) 50 (This is a value, and D is the gradient coefficient.)

[0405] Method 2: In vitro HMPV antiviral activity was evaluated using clinical isolate A2 strain TN94-49. In vitro HMPV antiviral activity was evaluated using clinical isolate A2 strain TN94-49 (obtained from Dr. John Williams, Vanderbilt University, Tennessee) and LLC-MK2 cells (Millipore Sigma CB_85062804), an immortalized renal epithelial cell line derived from Macaca mulatta.

[0406] The compound was resuspended in 10 mM dimethyl sulfoxide (DMSO), serially diluted, and added to a 384-well source plate. Subsequently, the compound was diluted and transferred to a 384-well assay plate using an Echo-650 automated liquid processing system (Beckman Coulter, Indiana). The test compound was evaluated in two series at the highest concentration of 200 nM, followed by 2.5-fold serial dilution to obtain a total of 10 concentration points. DMSO control wells were also included in the assay plate, representing either infection or non-infection, and served as positive and negative controls.

[0407] A2TN94-49 virus infection was performed by suspension with LLC-MK2 cells. The cells were washed twice with PBS and removed from the cell culture flask using 0.25% trypsin-EDTA (Thermo Fisher Scientific, Massachusetts). The trypsin-EDTA was inactivated by resuspending in OptiMEM (Thermo Fisher Scientific, Massachusetts) containing 2% fetal bovine serum (FBS) and 1% antibiotic-antifungal agent. The cells were pelleted by centrifugation at 800 rpm for 5 minutes, the supernatant was removed, and the cells were resuspended in PBS + 100 μg / mL CaCl2 and washed. This process was repeated twice. The cells were then resuspended in serum-free (SF)-OptiMEM containing 4 μg / mL TPCK-trypsin (Sigma Aldrich, Missouri), 1% antibiotic-antifungal agent (ThermoFisher Scientific, Massachusetts), 100 μg / mL CaCl2, and 4 μM P-glycoprotein inhibitor CP-100-356. The cells were counted and seeded at a density of 5,000 cells / well and 12.5 μL / well.

[0408] Viral infection was performed with 12.5 μL added per well, resulting in a multiple of infection (MOI) of 0.16. Viral infection was carried out using infection medium containing SF-OptiMEM, 100 μg / mL CaCl2, and 1% antibiotic-antifungal agent. HMPV virus stock was suspended in infection medium + 5% glycerol, and therefore an equal volume of infection medium + 5% glycerol was added to the uninfected wells to equalize the final % glycerol across all wells of the assay plate. The final concentration of TPCK-trypsin was 2 μg / mL. The final concentration of CP-100-356 was 2 μM. The assay plate was incubated at 37°C and 5% CO2 for 7 days.

[0409] After 7 days of incubation, 12.5 μL of ATP-Lite (Perkin Elmer, Massachusetts) was added to each well, and the raw luminescence values ​​were determined using Envision 2104 (Perkin Elmer, Massachusetts). The average raw luminescence values ​​of the cell- and virus-only positive control wells were subtracted from all conditions tested, and the percentage of healthy cells was determined by dividing these values ​​by the average of the cell-only negative control wells. Subsequently, EC 50 The values ​​were calculated by nonlinear regression using a four-parameter curve rheological equation. The curve-fitted model used was the XLFit Dose-Response One Site Model 200: y = (A + (B / (1 + ((x / C)^D)))) (where A is the minimum y value, B is the maximum y value, and C is log EC) 50 (This is a value, and D is the gradient coefficient.)

[0410] Using this data, the EC of each compound 50 Calculate (Table 16).

[0411] Method 1 EC 50 The range is as follows: A < 0.5 μM; B > 0.5 μM. EC of Method 2 50 The range is as follows: A < 0.2 μM; B > 0.2 μM. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9] [Table 16-10] [Table 16-11] [Table 16-12] [Table 16-13]

[0412] While the present invention has been specifically illustrated and described with reference to its preferred embodiments, it will be understood by those skilled in the art that various modifications in form and detail can be made without departing from the scope of the invention as encompassed in the appended claims.

Claims

1. Compounds represented by one of the formulas (X-1) to (X-12) 【Chemistry 1】 (In the formula, E is an arbitrarily substituted heteroaryl, R ３１ is halogen, -CN, -OR ３３ , -CO ２ R ３３ , -SO ２ R ３３ , -SO ２ , -SONR ３３ R ３４ , -NR ３３ R ３４ , optionally substituted -C １ ~C ６ alkyl, optionally substituted -C ２ ~C ６ alkenyl, or optionally substituted -C ３ ~C ８ cycloalkyl, and R ３２ is hydrogen, optionally substituted -C １ ~C ６ alkyl, optionally substituted -C ３ ~C ８ cycloalkyl, an optionally substituted 3- to 8-membered heterocyclic ring, an optionally substituted aryl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, or an optionally substituted heteroarylalkyl, n is 0, 1 or 2, and R ３３ and R ３４ are each independently hydrogen, optionally substituted -C １ ~C ６ alkyl, optionally substituted -C ２ ~C ６ alkenyl, optionally substituted -C ３ ~C ８ cycloalkyl, an optionally substituted 3- to 8-membered heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl, selected from the group consisting of).

2. The compound according to claim 1, wherein E is selected from the group shown below: 【Chemistry 2】 (In the formula, R ３１ ' is hydrogen or R ３１ And R ３１ (and n are as defined in claim 1).

3. A compound selected from the compounds listed below, or a pharmaceutically acceptable salt thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 【Table 1-67】

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 for treating or preventing RSV infection in a subject requiring treatment or prevention of RSV infection, comprising administering to the subject a therapeutically effective amount of a compound or combination of compounds described in any one of claims 1 to 3.

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

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

8. A method for treating RSV infection and influenza in a subject requiring treatment for RSV infection and influenza, comprising administering to the subject a therapeutically effective amount of a 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 additional anti-RSV agent are co-formulated.

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

11. The method according to claim 6, wherein, in subjects requiring prophylactic treatment for RSV infection, administering the compound allows for the administration of the additional anti-RSV agent at a lower dose or frequency compared to the administration of the additional anti-RSV agent alone required to obtain similar results in the prophylactic treatment.

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

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

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

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

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