Antiviral heterocyclic compounds

Abstract

This invention discloses compounds of formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: inhibitors of human respiratory syncytial virus (HRSV) or human metapneumovirus (HMPV). The invention further relates to pharmaceutical compositions comprising the above-described compounds for administration to subjects suffering from HRSV or HMPV infection. The invention also relates to methods of treating HRSV or HMPV infection in subjects by administering a pharmaceutical composition comprising the compounds of the invention.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 910,712, filed October 4, 2019; U.S. Provisional Application No. 62 / 959,230, filed January 10, 2020; and U.S. Provisional Application No. 63 / 038,234, filed June 12, 2020. The entire teachings of these applications are incorporated herein by reference. Technical Field

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

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

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

[0006] HRSV infection can also affect healthy individuals, and recurrent HRSV infection can occur even after a two-month treatment course. Symptoms are similar to those of a cold in healthy individuals, but in more severe cases, fever, wheezing, shortness of breath and difficulty breathing, and cyanosis may occur.

[0007] Currently, treatment options for HRSV infection are very limited, and there is no vaccine due to unsuccessful attempts to date. Palizumab is a monoclonal antibody approved for prophylactic use, but its use is limited due to its high price. Palizumab is typically used only for high-risk infants, such as premature infants or those with cardiopulmonary / lung disease, but it is only 60% effective in reducing hospitalizations. Ribavirin is approved as an inhaled treatment option, but its effectiveness is limited, and there are associated safety concerns. Given the treatment options and the consistent seasonality of HRSV prevalence, the development of new therapeutic agents for treating HRSV is promising.

[0008] Several RSV fusion inhibitors have been disclosed in the following publications: WO2010 / 103306, WO2012 / 068622, WO2013 / 096681, WO2014 / 060411, WO2013 / 186995, WO2013 / 186334, WO2013 / 186332, WO 2012 080451, WO 2012 / 080450, WO2012 / 080449, WO 2012 / 080447, WO2012 / 080446, WO 2015 / 110446, WO Examples of other N-protein inhibitors for the treatment of HRSV have been disclosed in the following publications: WO 2004 / 026843, J.Med.Chem.2006,49,2311-2319, and J.Med.Chem.2007,50,1685-1692. Examples of L-protein inhibitors for HRSV have been disclosed in the following publications: WO 2011 / 005842, WO 2005 / 042530, Antiviral Res. 2005, 65, 125-131, and Bioorg. Med. Chem. Lett. 2013, 23, 6789-6793. Examples of nucleoside / polymerase inhibitors have been disclosed in the following publications: WO 2011 / 005842, WO 2013 / 242525, WO 2014 / 031784, WO 2015 / 026792, WO 2016 / 0055791, WO 2016 / 138158, and J. Med. Chem. 2015, 58, 1862-1878.

[0009] Similarly, human metapneumovirus (HMPV), a negative-sense single-stranded RNA enveloped virus belonging to the family Pneumoviridae and genus Metapneumovirus, discovered by van Den Hoogen in 2001, is also a common cause of acute lower respiratory tract infections (ALRTIs). While often mild, this virus can be severe and life-threatening in high-risk groups such as children under 5 years of age, adults over 65 years of age, and adults with underlying medical conditions such as chronic obstructive pulmonary disease (COPD), asthma, congestive heart failure, or diabetes. In healthy adults over 65 years of age, the annual incidence of HMPV infection is 1.2 / 1,000, accounting for 38% of diseases (such as COPD), and individuals are twice as likely to have symptomatic illness and require medical care. In immunocompromised individuals, HMPV accounts for 6% of all respiratory tract infections following lung transplantation and 3% of lower respiratory tract infections associated with stem cell transplantation. HMPV infection is also thought to be associated with acute graft rejection.

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

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

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

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

[0014]

[0015] in:

[0016] A. Choose from the following groups:

[0017] 1) Optionally substituted aryl groups; and

[0018] 2) Optionally substituted heteroaryl groups;

[0019] B is either O or S;

[0020] R1 and R2 are each independently selected from the following groups:

[0021] 1) Hydrogen;

[0022] 2) Fluorine; and

[0023] 3) Optionally substituted –C1-C6 alkyl groups;

[0024] Alternatively, R1 and R2 together with the carbon atoms to which they are attached form optionally substituted 3- to 6-membered rings;

[0025] Z can choose from the following groups:

[0026] 1) Hydrogen;

[0027] 2) Halogens;

[0028] 3) Hydroxyl group;

[0029] 4) Cyano group;

[0030] 5) Nitro;

[0031] 6) Optionally substituted –C1-C6 alkoxy groups; and

[0032] 7) Optionally substituted –C1-C6 alkyl groups;

[0033] W can choose from the following groups:

[0034] 1) Hydrogen;

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

[0036] 3) Optionally substituted –C1-C6 alkyl groups; and

[0037] 4) Optionally substituted –C3-C6 cycloalkyl groups;

[0038] G can choose from the following groups:

[0039] 1)–C(O)OR 12 ;

[0040] 2)–C(O)NR 11 R 12 ;

[0041] 3) Optionally substituted –C1-C6 alkyl-CN;

[0042] 4) Optionally substituted –C1-C6 alkyl-C(O)NR 11 R 12 ;

[0043] 5) Optionally substituted –C1-C6 alkyl-C(O)NR 11 S(O)2R 12 ;

[0044] 6) Optionally substituted –C1-C6 alkyl-OC(O)NR 11 R 12 ;

[0045] 7) Optionally substituted –C1-C6 alkyl-NHR 13 ;

[0046] 8) Optionally substituted –C1-C6 alkyl-NHC(O)R 13 ;

[0047] n is 1, 2, or 3; preferably n is 1 or 2;

[0048] Y is O, S, S(O)2, or NR 14 ;

[0049] E can choose from the following groups:

[0050] 1) Optionally substituted aryl groups;

[0051] 2) Optionally substituted heteroaryl groups;

[0052] 3) Optionally substituted 3- to 8-membered heterocycles, and

[0053] 4) Optionally substituted alkynyl groups;

[0054] R3 is a hydroxyl group or fluorine;

[0055] R4 can be selected from the following groups:

[0056] 1) Hydrogen;

[0057] 2) Optionally substituted –C1-C6 alkyl groups;

[0058] 3) Optionally substituted –C3-C8 cycloalkyl groups; and

[0059] 4) Optionally substituted 3- to 8-membered heterocycles;

[0060] R 11 Each time it appears, independently select from the following groups:

[0061] 1) Hydrogen;

[0062] 2) Optionally substituted –C1-C8 alkyl groups;

[0063] 3) Optionally substituted –C3-C8 cycloalkyl groups;

[0064] 4) Optionally substituted 4- to 8-membered heterocycles;

[0065] 5) Optionally substituted aryl groups;

[0066] 6) Optionally substituted aryl alkyl groups;

[0067] 7) Optionally substituted heteroaryl groups; and

[0068] 8) Optionally substituted heteroarylalkyl groups;

[0069] R 12 Each time it appears, independently select from the following groups:

[0070] 1) Hydrogen;

[0071] 2) Optionally substituted –C1-C8 alkyl groups;

[0072] 3) Optionally substituted –C3-C8 cycloalkyl groups;

[0073] 4) Optionally substituted 4- to 8-membered heterocycles;

[0074] 5) Optionally substituted aryl groups;

[0075] 6) Optionally substituted aryl alkyl groups;

[0076] 7) Optionally substituted heteroaryl groups; and

[0077] 8) Optionally substituted heteroarylalkyl groups;

[0078] Alternatively, R 11 and R 12 Together with the nitrogen atoms to which they are attached, they form 3- to 12-membered heterocycles, preferably, but not limited to, morpholino, piperidino, piperazino, pyrrolidinyl, and azacyclic butane;

[0079] R 13 Each time it appears, independently select from the following groups:

[0080] 1) Optionally substituted –C1-C8 alkyl;

[0081] 2) Optionally substituted –C3-C8 cycloalkyl groups;

[0082] 3) Optionally substituted 4- to 8-membered heterocycles;

[0083] 4) Optionally substituted aryl groups;

[0084] 5) Optionally substituted aryl alkyl groups;

[0085] 6) Optionally substituted heteroaryl groups; and

[0086] 7) Optionally substituted heteroarylalkyl groups; and

[0087] R 14 Selected from:

[0088] 1) Hydrogen;

[0089] 2) Optionally substituted –C1-C8 alkyl groups; and

[0090] 3) Optionally substituted –C3-C8 cycloalkyl groups;

[0091] Each of the above preferred groups can be combined with one, any, or all other preferred groups. Detailed Implementation

[0092] In one embodiment of the invention, it is a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments of the compound of formula (I), B is O.

[0094] In some embodiments of the compound of formula (I), Y is O.

[0095] In some embodiments of the compound of formula (I), B is O, Y is O, and n is 1 or 2.

[0096] In some embodiments of the compound of formula (I), R1 is hydrogen or F.

[0097] In some embodiments of the compound of formula (I), R2 is hydrogen or F.

[0098] In some embodiments of the compound of formula (I), Z is hydrogen, Cl or F.

[0099] In some embodiments of the compound of formula (I), R1 is hydrogen, R2 is hydrogen, and Z is hydrogen.

[0100] In some embodiments of the compounds of formula (I), W is an optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl.

[0101] In some embodiments of the compound of formula (I), W is -CH3 or -CF3.

[0102] In some embodiments of the compound of formula (I), R3 is -OH.

[0103] In some embodiments of the compound of formula (I), R4 is an optionally substituted methyl group.

[0104] In some embodiments of the compound of formula (I), R3 is OH and R4 is CF3.

[0105] In some embodiments of the compound of formula (I), R1 is hydrogen, R2 is hydrogen, R3 is OH and R4 is CF3.

[0106] In some embodiments of the compounds of formula (I), G is optionally substituted –C(O)NR 11 R 12 .

[0107] In some embodiments of the compound of formula (I), G is –CH2NHR 13 –CH2C(O)NR 11 R 12 –CH2NHC(O)R 13 –CH2OC(O)NR 11 R 12 –CH2CN or –CH2C(O)NR 11 S(O)2R 12 .

[0108] In some embodiments of the compound of formula (I), A is selected from the following by removing one of the hydrogen atoms:

[0109]

[0110] Each of these groups is optionally substituted.

[0111] In some embodiments of the compounds of formula (I), A is selected from the groups listed below.

[0112]

[0113]

[0114] Each of these groups is optionally substituted.

[0115] In some embodiments of the compound of formula (I), A is Where Ra represents hydrogen, halogen, -CN, -NO2, or -OR. 11 -NR 11 R 12 -NR 11 C(O)R 12 -NR 11 S(O)2R 12 -S(O)2R 12 -S(O)2NR 11 R 12 -NR 11 C(O)NR11 R 12 -C(O)R 11 -C(O)OR 11 -C(O)NR 11 R 12 Optionally substituted –C1-C6 alkyl, optionally substituted –C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl or optionally substituted heteroaryl; Rb and Rb' are each independently selected from hydrogen, halogen, -OR 11 -NR 11 R 12 Optionally substituted –C1-C6 alkyl, optionally substituted –C3-C8-cycloalkyl, optionally substituted 3- to 8-membered heterocycles, optionally substituted aryl and optionally substituted heteroaryl. Alternatively, Rb and Rb' together with the carbon atoms to which they are attached form 4- to 7-membered rings fused to the benzene ring.

[0116] In some embodiments of the compound of formula (I), E is an optionally substituted aryl group, preferably an optionally substituted phenyl group.

[0117] In some embodiments of the compound of formula (I), E is selected from the following by removing one of the hydrogen atoms:

[0118]

[0119] Each of these groups is optionally substituted.

[0120] In some embodiments of the compounds of formula (I), E is selected from the groups listed below.

[0121]

[0122] In one embodiment of the invention, the compound of formula (I) is represented by formula (Ia) or formula (Ib) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0123]

[0124] A, B, R1, R2, Z, W, G, n, Y, E, R3, and R4 are as previously defined.

[0125] In a preferred embodiment, the compound of formula (I) has the stereochemistry shown in formula (Ib).

[0126] In one embodiment of the invention, the compound of formula (I) is represented by formula (IIa) or formula (IIb) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0127]

[0128] A, R1, R2, W, G, n, Y, E, R3, and R4 are as previously defined.

[0129] In one embodiment of the invention, the compound of formula (I) is represented by formula (IIIa) or formula (IIIb) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0130]

[0131] A, W, G, n, Y, E, n, R3, and R4 are as previously defined.

[0132] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IVa) to (IVd) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0133]

[0134] A, W, G, Y, E, R3, and R4 are as previously defined.

[0135] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (Va) to (Vd) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0136]

[0137] Among them, A, W, G, E, R 14 R3 and R4 are as previously defined.

[0138] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VIa) to (VId) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0139]

[0140] Among them, A, W, G, E, R 14 R3 and R4 are as previously defined. Preferably, W is an optionally substituted methyl group; more preferably, W is -CH3 or -CF3.

[0141] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VII-1) to (VII-12) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0142]

[0143]

[0144] Among them, A, W, E, R 11 R12 R 13 R 14 R3 and R4 are as previously defined. Preferably, W is an optionally substituted methyl group; more preferably, W is -CH3 or -CF3.

[0145] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VII-1a) to (VII-12a) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0146]

[0147] Among them, A, W, E, R 11 R 12 R 13 R 14 R3 and R4 are as previously defined. Preferably, W is an optionally substituted methyl group; more preferably, W is -CH3 or -CF3.

[0148] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VIIIa) to (VIIId) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0149]

[0150] Each R 21 Independently, the methyl, halogen, CN, or -OR groups are optionally substituted. 11 or -NR 11 R 12 m is 0, 1, 2, 3, 4, or 5; A, W, G, R 11 R 12 R 14 R1, R2, and R3 are as previously defined. Preferably, each R1... 21 Independently, it is a halogen or optionally substituted methyl group, and m is 1 or 2. More preferably, each R 21 It is independently -F, -Cl, -CN, -CF3, -CH2F, or -CHF2, and m is 1 or 2.

[0151] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (VIIIe) to (VIIIh) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0152]

[0153] Where R 21 m, A, W, G, R 14 R1, R2, and R3 are as previously defined. Preferably, each R1... 21It is independently a halogen or optionally substituted methyl group, and m is 1 or 2.

[0154] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IXa) to (IXd) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0155]

[0156] Where R 21 m, R3, R4, A, W, R 11 R 12 and R 14 As previously defined. Preferably, each R 21 It is independently a halogen or optionally substituted methyl group, and m is 1 or 2.

[0157] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (IXe) to (IXh) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0158]

[0159] Where R 21 m, R3, R4, A, W, R 11 R 12 and R 14 As previously defined. Preferably, R 21 It is a halogenated or optionally substituted methyl group, and m is 1 or 2.

[0160] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (X-1) to (X-6) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0161]

[0162] Where m' is 0, 1, or 2; R 21 A, W, R 11 R 12 and R 13 As previously defined. Preferably, m' is 2.

[0163] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (X-1a) to (X-6a) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0164]

[0165] Where R 21 、m'、A、W、R 11 R 12 and R13 As previously defined. Preferably, m' is 2.

[0166] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XI-1) to (XI-12) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0167]

[0168]

[0169] Where R 21 m' A R 11 R 12 and R 13 As previously defined. Preferably, m' is 2.

[0170] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XI-1a) to (XI-12a) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0171]

[0172] Where R 21 m' A R 11 R 12 and R 13 As previously defined. Preferably, m' is 2.

[0173] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XIVa) to (XIVd) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0174]

[0175] Among them, W and R 21 、m'、R 11 and R 12 As previously defined.

[0176] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XIVe) to (XIVh) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0177]

[0178] Among them, W and R 21 、m'、R 11 and R 12 As previously defined.

[0179] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVa) to (XVd) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0180]

[0181] Each R 31 It is a halogen on its own; -CN; -NO2, -OR 11 ;-NR 11 R 12 ;-NR 11 C(O)R 12 ;-NR 11 S(O)2R 12 ;-S(O)2R 12 ;-S(O)2NR 11 R 12 -NR 11 C(O)NR 11 R 12 ;-C(O)R 11 -C(O)OR 11 ;-C(O)NR 11 R 12 ; optionally substituted –C1-C6 alkyl; optionally substituted –C3-C8-cycloalkyl; optionally substituted 3- to 8-membered heterocycle; optionally substituted aryl; or optionally substituted heteroaryl, and W, m', R3, R4, R 21 R 11 and R 12 As previously defined. In some implementations, two adjacent R 31 The groups together with the carbon atoms to which they are attached form a 4- to 12-membered carbon ring or heterocycle, and the 4- to 12-membered carbon ring or heterocycle is fused with a phenyl or quinolinyl group.

[0182] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVe) to (XVh) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0183]

[0184] Where W, m', R3, R4, R 21 R 31 R 11 and R 12 As previously defined. In some implementations, two adjacent R 31 The groups together with the carbon atoms to which they are attached form a 4- to 12-membered carbon ring or heterocycle, and the 4- to 12-membered carbon ring or heterocycle is fused with a phenyl or quinolinyl group.

[0185] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVa) to (XVh) or a pharmaceutically acceptable salt, ester or prodrug thereof, R3 is -OH and R4 is -CH3, -CF3 or cyclopropyl.

[0186] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (XVa-1) to (XVb-1), (XVc-1) to (XVc-4), (XVd-1) to (XVd-4), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0187]

[0188] Each R 32 Independently, it is halogen, -OR 11 ;-NR 11 R 12 Optionally substituted –C1-C6-alkyl; Optionally substituted –C3-C8-cycloalkyl; Optionally substituted 3- to 8-membered heterocycles; Optionally substituted aryl; or Optionally substituted heteroaryl; W, m', R3, R4, R 21 R 31 R 11 and R 12 As previously defined. In some implementations, two adjacent R 32 The groups together with the carbon atoms to which they are attached form a 4- to 12-membered carbon ring or heterocycle, and the 4- to 12-membered carbon ring or heterocycle is fused with a phenyl or quinolinyl group.

[0189] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVa-1) to (XVb-1), (XVc-1) to (XVc-4), (XVd-1) to (XVd-4) or a pharmaceutically acceptable salt, ester or prodrug thereof, where R3 is -OH and R4 is -CH3, -CF3 or cyclopropyl.

[0190] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulas (XVe-1)-(XVf-1), (XVg-1) to (XVg-4), (XVh-1) to (XVh-4), or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0191]

[0192] Where W, m', R3, R4, R 21 R 31 R 32 R 11 and R 12 As previously defined. In some implementations, two adjacent R32 The groups together with the carbon atoms to which they are attached form a 4- to 12-membered carbon ring or heterocycle, and the 4- to 12-membered carbon ring or heterocycle is fused with a phenyl or quinolinyl group.

[0193] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVe-1) to (XVf-1), (XVg-1) to (XVg-4), (XVh-1) to (XVh-4) or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R3 is -OH and R4 is -CH3, -CF3 or cyclopropyl.

[0194] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIa) to (XVIh) or a pharmaceutically acceptable salt, ester or prodrug thereof.

[0195]

[0196] Where R 22 It is hydrogen, halogen, -OR 11 ;-NR 11 R 12 Optionally substituted –C1-C6-alkyl; Optionally substituted –C3-C8-cycloalkyl; Optionally substituted 3- to 8-membered heterocycles; Optionally substituted aryl; or Optionally substituted heteroaryl; and W, R 31 R 21 、m'、R3、R4、R 11 and R 12 As previously defined.

[0197] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIa) to (XVIh) or a pharmaceutically acceptable salt, ester or prodrug thereof, R3 is -OH and R4 is -CH3, -CF3 or cyclopropyl.

[0198] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIIa) to (XVIIh) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0199]

[0200] Among them, W and R 21 R 22 R 31 、m'、R3、R4、R 11 and R 12 As previously defined.

[0201] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIIa) to (XVIIh) or a pharmaceutically acceptable salt, ester or prodrug thereof, R3 is -OH and R4 is -CH3, -CF3 or cyclopropyl.

[0202] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIIIa) to (XVIIId) or a pharmaceutically acceptable salt, ester, or prodrug thereof:

[0203]

[0204] Where R 23 It is hydrogen, optionally substituted –C1-C6-alkyl; optionally substituted –C3-C8-cycloalkyl; optionally substituted 3- to 8-membered heterocycle; optionally substituted aryl; or optionally substituted heteroaryl; R3, R4, A, W, R 11 R 12 and R 14 As previously defined.

[0205] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIIIe) to (XVIIIh) or a pharmaceutically acceptable salt, ester or prodrug thereof:

[0206]

[0207] Where R 23 R3, R4, A, W, R 11 R 12 and R 14 As previously defined.

[0208] In one embodiment of the invention, the compound of formula (I) is represented by one of formulas (XVIIIa) to (XVIIIh) or a pharmaceutically acceptable salt, ester or prodrug thereof, where R3 is -OH and R4 is -CH3, -CF3 or cyclopropyl.

[0209] It should be understood that the description of the invention herein should be interpreted as consistent 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.

[0210] The aim is to make the restriction of any substituent or variable (e.g., R1, R2, etc.) at a particular position in the molecule independent of its restriction elsewhere in the molecule.

[0211] It should also be understood that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomer, and optically active forms. It should still be understood that some compounds of the present invention may exist in different tautomer forms. All tautomers are considered to be within the scope of the present invention.

[0212] In some embodiments, the present invention provides methods for preventing or treating RSV activity in subjects with this need, and for treating RSV infection. The method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).

[0213] The present invention also provides the use of the compound of formula (I) for preparing a medicament for the prevention or treatment of RSV.

[0214] Therefore, in one embodiment, a 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, a compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a nonsteroidal anti-inflammatory compound, such as a leukotriene antagonist (e.g., Singulair (Merck) or Accolade (Astra Zeneca)), a phosphodiesterase 4 inhibitor (e.g., roflumilast (Altana)), a TNFα inhibitor (e.g., Enbrel (Amgen), Remicade (Centocor), Humira (Abbott), or CDP870 (Celltech)), or NSAIDs. In yet another embodiment, a compound of formula (I) is combined with an interleukin-8 or interleukin-9 inhibitor. Therefore, 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.

[0215] This invention also relates to combinations of compounds of formula (I) or pharmaceutically acceptable salts thereof with anti-influenza compounds, and the use of such combinations in the treatment of concomitant RSV and influenza infections. Therefore, this invention also relates to a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-influenza compound for simultaneous, separate, or sequential treatment of concomitant RSV and influenza infections. The compounds of this invention can be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, sugar lozenges, tablets, aqueous or oily suspensions, dispersible powders, or granules. The compounds of this invention can also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, percutaneously, or via infusion techniques. The compounds can also be administered as suppositories.

[0216] In embodiments, the compounds of the present invention are administered via intranasal or intrabronchial administration. The present invention also provides inhalers or nebulizers comprising a drug comprising (a) a derivative of formula (I) as defined above or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier or diluent.

[0217] The present invention also provides a pharmaceutical composition comprising such benzodiazepine Derivatives or their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers or diluents.

[0218] 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 a diluent, such as lactose, dextrose, sucrose, cellulose, corn starch, or potato starch, along with the active compound; a lubricant, such as silica, talc, stearic acid, magnesium stearate, or calcium stearate, and / or polyethylene glycol; a binder, such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; a disintegrant, such as starch, alginate, alginate, or sodium glycolate; an effervescent mixture; a dye; a sweetener; a humectant, such as lecithin, polysorbate, or lauryl sulfate; and, generally, a non-toxic and pharmacologically inactive substance used in pharmaceutical formulations. Such pharmaceutical formulations can be manufactured in known ways, for example, by mixing, granulation, tableting, sugar coating, or film coating processes.

[0219] Liquid dispersions for oral administration can be syrups, emulsions, and suspensions. Syrups may contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol as a carrier.

[0220] Suspensions and emulsions may contain carriers such as natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injection may contain a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycol (e.g., propylene glycol), and, if necessary, an appropriate amount of lidocaine hydrochloride.

[0221] Solutions intended for injection or infusion may contain, for example, sterile water as a carrier, or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

[0222] The present invention also relates to novel compounds as defined above; or pharmaceutically acceptable salts thereof, for use in methods of treating humans or animals. 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 the novel compounds as defined above. Pharmaceutically acceptable salts are defined above. The novel compounds of the present invention are generally administered in the manner defined above, and these compounds are generally formulated for administration in the manner defined above.

[0223] Preferably, the pharmaceutical composition comprises an optically active isomer of the novel compound of the present invention. Thus, for example, preferred novel compounds of the present invention comprising only one chiral center comprise substantially pure R enantiomers, substantially pure S enantiomers, and mixtures of enantiomers comprising excess R or excess S enantiomers. Particularly preferred is that the pharmaceutical composition comprises the compound of the present invention, which is a substantially pure optical isomer. For the avoidance of doubt, the novel compounds of the present invention may be used in solvate form if desired.

[0224] Another aspect of the invention is a method for producing any of the compounds described herein using any of the synthetic means described herein.

[0225] definition

[0226] The following are definitions of various terms used to describe the invention. These definitions apply to terms as used throughout the specification and claims, unless otherwise specified in the particular case, either individually or as part of a larger group.

[0227] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic system comprising at least one aromatic ring, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indenyl. A polycyclic aryl is a polycyclic system comprising at least one aromatic ring. Polycyclic aryl can include fused rings, covalently linked rings, or combinations thereof.

[0228] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic group having one or more ring atoms selected from S, O, and N; and the remaining ring atoms are carbon, wherein any N or S contained in the ring may optionally be oxidized. Heteroaryls include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and quinoxalinyl. Polycyclic heteroaryls may include fused rings, covalently linked rings, or combinations thereof.

[0229] According to the present invention, the aromatic groups may be substituted or unsubstituted.

[0230] 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 connected.

[0231] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group. "C1-C3 alkyl", "C1-C6 alkyl", "C1-C6 alkyl", "C1-C6 alkyl" are also used interchangeably. 10 "alkyl", "C2-C4 alkyl" or "C3-C6 alkyl" refers to an alkyl group containing one to three, one to six, one to ten, two to four, and three to six carbon atoms, respectively. Examples of C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl groups.

[0232] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond by removing a single hydrogen atom. "C2-C" 10 "Alkenyl", "C2-C8 alkenyl", "C2-C4 alkenyl" or "C3-C6 alkenyl" refer to alkenyl groups containing two to ten, two to eight, two to four, or three to six carbon atoms, respectively. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0233] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group that has at least one carbon-carbon triple bond by removing a single hydrogen atom. "C2-C" 10 "Alynyl", "C2-C8 alkynyl", "C2-C4 alkynyl", or "C3-C6 alkynyl" refer to alkynyl groups containing two to ten, two to eight, two to four, or three to six carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, and octyynyl.

[0234] As used herein, the term "cycloalkyl" refers to a system of fused, bridged, or spirocyclic monocyclic or polycyclic saturated carbocyclic or bicyclic or tricyclic groups, wherein the carbon atom may optionally be substituted with an oxine subunit or optionally with an exocyclic olefinic double bond, an imine double bond, or an oxime double bond. Preferred cycloalkyl groups include C3-C4 groups. 12 Cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. C3-C 12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonyl, etc.

[0235] As used herein, the term "cycloalkenyl" refers to a system of fused, bridged, or spirocyclic monocyclic or polycyclic carbocyclic or bicyclic or tricyclic groups having at least one carbon-carbon double bond, wherein the carbon atom may optionally be substituted with an oxoyl subunit or optionally with an exocyclic alkene double bond, an imine double bond, or an oxime double bond. Preferred cycloalkenyl groups include C3-C 12 Cycloalkenyl, C3-C8 cycloalkenyl, or C5-C7 cycloalkenyl groups. C3-C 12 Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, etc.

[0236] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is attached to an aryl group, such as -CH2CH2-phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which an aryl group is substituted. Similarly, the term "heteroarylalkyl" refers to a functional group in which an alkylene chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which a heteroaryl group is substituted.

[0237] As used herein, unless otherwise stated, the term "alkoxy" alone or in combination with other terms means an alkyl group having a specified number of carbon atoms attached via an oxygen atom to the remainder of a molecule, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologues and isomers. Preferred alkoxy groups are (C1-C3) alkoxy groups.

[0238] It should be understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moieties described herein may also be aliphatic or alicyclic groups.

[0239] An "aliphatic" group is a non-aromatic portion consisting of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, and optionally contains one or more unsaturated units, such as double and / or triple bonds. Examples of aliphatic groups are functional groups such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH, or C(O)NHS(O)2NH2, etc., including one or more functional groups, non-aromatic hydrocarbon (optionally substituted) groups, and groups in which one or more carbons of the non-aromatic hydrocarbon (optionally substituted) are replaced by functional groups. The carbon atoms of the aliphatic group may optionally be replaced by oxygen subunits. The aliphatic group may be straight-chain, branched, cyclic, or a combination thereof, and preferably contains about 1 to about 24 carbon atoms, more typically about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups as used herein, aliphatic groups explicitly include, for example, alkoxyalkyl, polyalkoxyalkyl, such as, for example, polyalkylene glycols, polyamines, and polyimides. The aliphatic group may optionally be substituted.

[0240] The term "carbocycle" or "carbocyclic" refers to a saturated, partially unsaturated, or aromatic cyclic group in which every atom within the ring is carbon. Examples of carbocycles include cycloalkyl, cycloalkenyl, and aryl groups.

[0241] The terms “heterocyclic” or “heterocyclic alkyl” are used interchangeably and refer to a system of non-aromatic or bi- or tricyclic groups that are fused, bridged, or spirocyclic, wherein (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen; (ii) each ring system may be saturated or unsaturated; (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized; (iv) the nitrogen heteroatom may optionally be quaternized; (v) any of the above rings may be fused to an aromatic ring; and (vi) the remaining ring atoms are carbon atoms that may optionally be substituted with oxy subunits or optionally with exocyclic alkene double bonds, imine double bonds, or oxime double bonds. Representative heterocyclic alkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolinyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolinyl, isoxazolinyl, morpholinyl, tetrahydrothiazolyl, isotetrahydrothiazolyl, quinoxolinyl, pyridazinonel, 2-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonyl, 7-oxomylideneoxetane-4-yl, and tetrahydrofuranyl. Such heterocyclic groups can be further substituted. Heteroaryl or heterocyclic groups can be C-linked or N-linked (where possible).

[0242] It should be understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc., described herein, when used as a linker for two or more groups or substituents (which may be on one or more identical or different atoms), may also be divalent or polyvalent. Those skilled in the art can readily determine the valence of any such group based on its environment of presence.

[0243] The term "substituted" refers to substitution by independently replacing one, two, three, or more hydrogen atoms with substituents, including but not limited to: -F, -Cl, -Br, -I, -OH, -Cl-C. 12 -alkyl; -C2-C 12 -Alkenyl, -C2-C 12 -alkynyl group, -C3-C 12 -cycloalkyl, protected hydroxyl, -NO2, -N3, -CN, -NH2, protected amino, oxy subunit, thio, -NH-Cl-C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-ynyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Cl-C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-ynyl, -O-C3-C12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-ynyl, -C(O)-C3-C 12 -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-ynyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-ynyl, -OCO2-C3-C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 ynyl, CO2-C3-C 12 -cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12 -alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-ynyl, -OCONH-C3-C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclic-alkyl, -NHC(O)H, -NHC(O)-C1-C 12 -alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-ynyl, -NHC(O)-C3-C 12 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclic-alkyl, -NHCO2-C1-C 12 -alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-C 12 -cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C 12 -alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-ynyl, -NHC(O)NH-C3-C 12-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1-C 12 -alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-ynyl, -NHC(S)NH-C3-C 12 -cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 -alkyl, -NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C1-C 12 -alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-ynyl, -NHC(NH)-C3-C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-ynyl, -C(NH)NH-C3-C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1-C 12 -alkyl, -S(O)-C2-C8-alkenyl, -S(O)-C2-C8-ynyl, -S(O)-C3-C 12 -cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1-C 12 -alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -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-Cl-C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-ynyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. In some embodiments, the substituents are independently selected from halogenated groups, preferably Cl and F; C 1- C4-alkyl, preferably methyl and ethyl; halogenated-C 1- C4-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4 alkenyl; halo-C2-C4 alkenyl; C3-C6-cycloalkyl, such as cyclopropyl; C 1- C4-alkoxy groups, such as methoxy and ethoxy; halogenated-C 1- C4-alkoxy groups, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH; NH2; C 1- C4-alkylamino; di(C 1- C4-alkyl)amino; and NO2. It should be understood that aryl, heteroaryl, alkyl, etc., may be further substituted. In some cases, each substituent in the substituted portion is additionally optionally substituted by one or more groups (where possible), each group being independently selected from C1-C4-alkyl, -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2.

[0244] In some embodiments, the substituted alkyl, alkenyl, or alkoxy groups are substituted with one or more halogen atoms, preferably fluorine or chlorine atoms. Such substituted alkyl groups include fluoromethyl, difluoromethyl, and trifluoromethyl. Such substituted alkoxy groups include fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0245] As used herein, the term “halo” or “halogen” alone or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.

[0246] As used herein, the term "optionally substituted" means that the mentioned group may be substituted or unsubstituted. In one embodiment, the mentioned group is optionally substituted with zero substituents, i.e., the mentioned group is unsubstituted. In another embodiment, the mentioned group is optionally substituted with one or more additional groups selected individually and independently from the groups described herein.

[0247] The term "hydrogen" includes both hydrogen and deuterium. Additionally, detailed descriptions of atoms include other isotopes of that atom, provided the resulting compound is pharmaceutically acceptable.

[0248] In some embodiments, the compounds of each formula herein are defined as including isotopically labeled compounds. An "isotopically labeled compound" is a compound in which at least one atomic position is enriched with a specific isotope of a designated element to a level significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound may be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, for example, to a level of at least 1%, preferably at least 20%, or at least 50%. Such deuterated compounds may, for example, be metabolized more slowly than their non-deuterated analogues and thus exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example, by using deuterated starting materials. Unless otherwise stated, isotopically labeled compounds are pharmaceutically acceptable.

[0249] As used herein, the term "hydroxyl-activating group" refers to an unstable chemical moiety known in the art that activates a hydroxyl group to deactivate it in synthetic procedures such as substitution or elimination reactions. Examples of hydroxyl-activating groups include, but are not limited to, methanesulfonates, toluenesulfonates, trifluoromethanesulfonates, p-nitrobenzoates, phosphonates, etc.

[0250] As used herein, the term "activated hydroxyl group" refers to a hydroxyl group activated by a hydroxyl-activating group as defined above, including, for example, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, p-nitrobenzoate, and phosphonate groups.

[0251] As used herein, the term "hydroxyl protecting group" refers to an unstable chemical moiety known in the art for protecting a hydroxyl group from unwanted reactions during a synthetic procedure. Following one or more of the aforementioned synthetic procedures, the hydroxyl protecting group as described herein may be selectively removed. In THGreene and PGMWuts, Protective Groups in Organic SynthesisThe 3rd edition of John Wiley & Sons, New York (1999) generally describes hydroxyl protecting groups as known in the art. Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl (triphenylmethyl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, etc.

[0252] As used herein, the term "protected hydroxyl group" refers to a hydroxyl group protected by a hydroxyl protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, and methoxymethyl groups.

[0253] As used herein, the term "hydroxy prodrug group" refers to a promotive group known in the art to transiently alter the physicochemical properties and thus the biological properties of a parent drug by covering or masking a hydroxyl group. Following one or more of the aforementioned synthetic procedures, the hydroxy prodrug group, as described herein, must be able to revert to a hydroxyl group in vivo. In Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery , (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992) and "Prodrugs of Alcohols and Phenols" by SSDhareshwar and VJStella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects), edited by VJStella, et al, Springer and AAPSPress, 2007, pp 31-99, generally describes hydroxy prodrug groups as known in the art.

[0254] As used herein, the term "amino protecting group" refers to an unstable chemical moiety known in the art for protecting an amino group from unwanted reactions during the synthetic procedure. Following one or more of the aforementioned synthetic procedures, the amino protecting group as described herein may be selectively removed. In THGreene and PGMWuts, Protective Groups in Organic Synthesis The amino protecting groups as known in the art are generally described in the 3rd edition of John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, tert-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, etc.

[0255] As used herein, the term "protected amino" refers to an amino group protected by an amino protecting group as defined above.

[0256] The term "leaving group" refers to a functional group or atom that can be replaced by other functional groups or atoms in substitution reactions such as nucleophilic substitution. Representative leaving groups include chlorine, bromine, and iodine groups; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, and nosylates; and acyloxy groups, such as acetoxy and trifluoroacetoxy groups.

[0257] As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to proton reactivity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidone, and ethers such as diethyl ether and dimethoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions, depending on factors such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized works, for example: Organic Solvents Physical Properties and Methods of Purification ,4th ed.,edited by John A. Riddick etal.,Vol.II,in the Techniques of Chemistry Series John Wiley & Sons, NY, 1986.

[0258] As used herein, the term "proton solvent" refers to a solvent that tends to provide protons, such as alcohols, for example, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to them that for a particular compound and reaction conditions, individual solvents or mixtures thereof may be preferred, depending on factors such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range. Further discussion of proton solvents can be found in organic chemistry textbooks or specialized works, for example: Organic Solvents Physical Properties and Methods of Purification ,4th ed.,edited byJohn A. Riddick et al.,Vol.II,in the Techniques of Chemistry Series John Wiley & Sons, NY, 1986.

[0259] The combinations of substituents and variables contemplated in this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" means that a compound has sufficient stability to allow for preparation and that the integrity of the compound is maintained for a sufficient period of time to be used for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0260] The synthesized compounds can be isolated from the reaction mixture and further purified by methods such as column chromatography, high-performance liquid chromatography, or recrystallization. As will be appreciated by those skilled in the art, other methods for synthesizing the compounds of this formulation will be readily apparent to those of ordinary skill in the art. Furthermore, various synthetic steps can be performed in an alternating sequence or order to obtain the desired compound. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein are known in the art and include, for example, those described in: R. Larock, Comprehensive Organic Transformations ,2 nd Ed. Wiley-VCH (1999); TW Greene and P. GMWuts, Protective Groups in Organic Synthesis ,3rd Ed.,John Wiley and Sons(1999);L.Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis John Wiley and Sons (1995), and subsequent editions.

[0261] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subjects also refer to animals such as dogs, cats, horses, cattle, pigs, guinea pigs, fish, birds, etc.

[0262] The compounds of the present invention can be modified by adding appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those that increase biopermeability to a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism, and change excretion rates.

[0263] The compounds described herein contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers, which can be defined by absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This 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-described procedure or by resolving racemic mixtures. Resolution can be performed in the presence of a resolving agent by chromatography, by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution can be found in Jacques, et al., Enantiomers,Racemates,and Resolutions (Found in John Wiley & Sons, 1981). When the compounds described herein contain an alkene double bond, other unsaturation, or other geometrically asymmetric center, and unless otherwise stated, the compound is meant to include both E and Z geometric isomers or both cis and trans isomers. Likewise, all tautomers are intended to be included. Tautomers can be cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is chosen for convenience only and is not intended to specify a particular configuration unless stated herein; therefore, any carbon-carbon double bond or carbon-heteroatom double bond arbitrarily described herein as trans can be cis, trans, or a mixture of both in any proportion.

[0264] Some compounds of the present invention may also exist in different stable conformations, which can be separable. Torsional asymmetry caused by restricted rotation around asymmetric single bonds, for example due to steric hindrance or ring strain, can allow the separation of different conformational isomers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0265] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for use in contact with the tissues of humans and lower animals within the bounds of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, etc., and with a proportionately 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). These salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or separately prepared by reacting a free base functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-methyl, glycerol phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations, formed using anti-charge ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0266] 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 anti-charge ion is a cation. Suitable cations include ammonium and metal cations, such as alkali metal cations, including Li. + Na + K + and Cs + and alkaline earth metal cations, such as Mg 2+ and Ca 2+ .

[0267] As used herein, the term "pharmaceutically acceptable ester" refers to esters that are hydrolyzed in vivo and include those that readily decompose in the human body, leaving behind a parent compound or its salts. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly those derived from alkyl, olefinic, cycloalkyl, and alkyl diacids, wherein each alkyl or alkenyl moiety advantageously has no more than six carbon atoms. Examples of specific esters include, but are not limited to, esters of C1-C6-alkyl acids, such as acetates, propionates, butyrates, and neopentylates.

[0268] In some embodiments, the present invention provides pharmaceutically acceptable prodrugs of the compounds disclosed herein. As used herein, the term "pharmaceuticalally acceptable prodrug" refers to those prodrugs of compounds formed by the methods of the present invention that are suitable for use in contact with human and lower animal tissues within a reasonable medical judgment, have excessive toxicity, irritation, allergic reactions, etc., have a reasonably reasonable benefit / risk ratio, and are effective for their intended use, and, where possible, the zwitterionic form of the compounds of the present invention. As used herein, "prodrug" means a compound that can be converted in vivo by metabolic means (e.g., by hydrolysis) to provide any compound described by the formulas of the present invention. Various forms of prodrugs are known in the art, for example, as discussed in the following: Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

[0269] This also includes additional types of prodrugs. For example, the free carboxyl group can be derived into an amide or alkyl ester. The free hydroxyl group can be derivatized using groups including, but not limited to, hemisuccinates, ethyl succinates, phosphate esters, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Also included are urethane prodrugs with hydroxyl and amino groups, as well as carbonate prodrugs, sulfonates, and sulfates with hydroxyl groups. Also included are prodrugs derivatized with hydroxyl groups into (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem. 1996, 39, 10. Free amines can also be derived into amides, sulfonamides, or phosphoramides. All these prodrug moieties can be bound to groups including, but not limited to, ether, amine, and carboxylic acid functional groups. In some embodiments, the compounds of the present invention may be combined with two or more groups that are metabolically removed in vivo to produce an active parent compound.

[0270] As used herein, the term "treatment" means relief, reduction, elimination, regulation, or improvement, that is, causing the remission of a disease state or symptom. Treatment may also include suppression, that is, preventing the development of an existing disease state or symptom, and relief or improvement, that is, causing the remission of an existing disease state or symptom, for example when a disease state or symptom may have already existed.

[0271] As used herein, the term “prevention” means the complete or near-complete prevention of the occurrence of a disease state or condition in a patient or subject, especially when the patient or subject is susceptible to such a disease state or condition or is at risk of contracting such a disease state or condition.

[0272] Furthermore, the compounds of the present invention, such as salts of the compounds, may exist in hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0273] A solvate is a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcohol. Hydrates are formed by the combination of one or more water molecules with a substance, where water retains its molecular state as H₂O; such combinations can form one or more hydrates.

[0274] As used herein, the term "analogue" refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as by substituting an atom of a different element, or in the presence of a particular functional group, or by substituting one functional group for another). Thus, an analogue is a compound that is functionally similar to or equivalent to a reference compound.

[0275] The combinations of substituents and variables contemplated in this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" means that a compound has sufficient stability to allow for preparation and that the integrity of the compound is maintained for a sufficient period of time to be used for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0276] The synthesized compounds can be isolated from the reaction mixture and further purified by methods such as column chromatography, high-performance liquid chromatography, or recrystallization. Furthermore, various synthetic steps can be performed in an alternating sequence or order to obtain the desired compound. Additionally, the solvents, temperatures, reaction durations, etc., described herein are for illustrative purposes only, and variations in reaction conditions can produce the desired bridged macrocyclic products of the present invention. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein include, for example, those described below: R. Larock, Comprehensive Organic Transformations ,VCH Publishers(1989);TWGreene andP.GMWuts, Protective Groups in Organic Synthesis ,2d.Ed.,John Wiley and Sons(1991);L.Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis John Wiley and Sons (1995).

[0277] The compounds of the present invention can be modified by adding various functionalities through the synthetic methods described herein to enhance selective biological properties. Such modifications include those that increase biopermeability to a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral bioavailability, increase solubility to allow administration by injection, alter metabolism, and change excretion rates.

[0278] Pharmaceutical Composition

[0279] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of the compound of the present invention formulated with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions; and other non-toxic, compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, release agents, coating agents, sweeteners, flavorings and aromatizers, preservatives, and antioxidants may also be present in the composition at the formulator's discretion. The pharmaceutical compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment or drops), buccally, or as oral or nasal sprays.

[0280] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted container, preferably orally or by injection. The pharmaceutical compositions of the present invention may contain any conventional, non-toxic, pharmaceutically acceptable carrier, adjuvant, or mediator. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenterally includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0281] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycols and sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0282] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used in injectable formulations.

[0283] Injectable formulations can be sterilized by means of, for example, filtration through a bacterial retention filter, or by incorporation of a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0284] To prolong the action of a drug, it is often necessary to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil medium. Injectable reservoir forms are prepared by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolic acid. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0285] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository waxes, which are solid at ambient temperature but liquid at body temperature, and thus melt in the rectal or vaginal cavity and release the active compound.

[0286] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) humectants, such as, for example, cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0287] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0288] The active compound can also be in the form of microcapsules with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared 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 can be mixed with at least one inert diluent such as sucrose, lactose, or starch. According to conventional practice, such dosage forms may also include additional substances besides inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also include buffers. They may optionally contain light-blocking agents and may also be compositions that optionally release one or more active ingredients in a delayed manner, either only or preferably in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes.

[0289] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under aseptic conditions with any pharmaceutically acceptable carrier and any desired preservatives or buffers. Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also contemplated within the scope of the invention.

[0290] In addition to the active compounds of the present invention, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0291] In addition to the compounds of this invention, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Sprays may additionally contain conventional propellants such as chlorofluorocarbons (CFCs).

[0292] Transdermal patches offer the added advantage of controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of compounds across the skin. This rate can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0293] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly known to one of ordinary skill in the art. All publications, patents, published patent applications and other references mentioned herein are incorporated herein by reference in their entirety.

[0294] abbreviation

[0295] The abbreviations used in the following description of the schemes and embodiments are:

[0296] ACN, acetonitrile;

[0297] AD-mix-β, (9S)-(9″S)-9,9″-[1,4-phthalazinediylbis(oxy)]bis[10,11-dihydro-6'-methoxycinchonan];

[0298] Bn, benzyl

[0299] BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate;

[0300] BzCl, benzoyl chloride;

[0301] mCPBA, m-chloroperoxybenzoic acid;

[0302] Cbz, benzyloxycarbonyl;

[0303] CDI, carbonyl diimidazole;

[0304] DAST, diethylaminosulfuric acid

[0305] DBU, 1,8-diazabicycloundec-7-ene;

[0306] DCE, dichloroethane;

[0307] DCM, dichloromethane;

[0308] Dess-Martin periodinane, 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzyl-3-(1H)-one;

[0309] DIAD, diisopropyl azodicarbonate;

[0310] DIBAL-H, diisobutylaluminum hydride;

[0311] DMAP, N,N-dimethylaminopyridine;

[0312] DME, 1,2-dimethoxyethane;

[0313] DMF, N,N-dimethylformamide;

[0314] DMSO, dimethyl sulfoxide;

[0315] DPPA, diphenylphosphorylazidate;

[0316] dppf, 1,1'-bis(diphenylphosphino)ferrocene;

[0317] EDCI or EDC, 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0318] EtOAc, ethyl acetate;

[0319] Ghosez's reagent, 1-chloro-N,N,2-trimethyl-1-propenylamine;

[0320] HATU, O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate;

[0321] HCl, hydrochloric acid;

[0322] Hunig base, diisopropylethylamine;

[0323] PyBOP, (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate;

[0324] LDA, lithium diisopropylamine;

[0325] Pd-C, palladium on carbon;

[0326] Ph, phenyl;

[0327] RT, reverse transcription;

[0328] RT-PCR, reverse transcription polymerase chain reaction;

[0329] TBME, tert-butyl methyl ether;

[0330] TEA, triethylamine;

[0331] Tf2O, trifluoromethanesulfonic anhydride;

[0332] TFA, trifluoroacetic acid;

[0333] THF, tetrahydrofuran;

[0334] (TMS)2NH, hexamethyldisilazane;

[0335] TBS, tert-butyldimethylsilyl;

[0336] TBDPS, tert-butyldiphenylsilyl;

[0337] TMS, trimethylsilyl;

[0338] TPAP, Tetrapropylammonium perruthenate;

[0339] TPP or PPh3, triphenylphosphine;

[0340] Ts or toluenesulfonyl group, p-CH3C6H4SO2-;

[0341] tBOC or Boc, tert-butoxycarbonyl; and

[0342] Xantphos, 4,5-bis-diphenylphosphino-9,9-dimethyl-9H-xantphosphine.

[0343] Synthesis method

[0344] The compounds and methods of the present invention will be better understood in conjunction with the following synthetic schemes, which illustrate methods for preparing the compounds of the present invention and 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 can be made, including but not limited to those relating to the chemical structure, substituents, derivatives and / or methods of the present invention, without departing from the spirit of the invention and the scope of the appended claims.

[0345] Scheme 1 describes a method for preparing compound 11 from compounds 1 and 2, wherein n = 1, 2, or 3; P is a hydroxyl protecting group; Ar is E; and E is as previously defined. Hydroxypyridine 1 is alkylated with a hydroxy epoxide using Mitsunobu reaction conditions to give epoxide 4. Alternatively, the hydroxy epoxide is converted to 3 having leaving groups (such as, but not limited to, toluenesulfonyl and methanolsulfonyl), and then alkylated in the presence of a base (such as, but not limited to, K₂CO₃ and Cs₂CO₃) to give 4. Intramolecular ring-opening of the epoxide mediated by a base (such as, but not limited to, LDA) yields compound 5. The hydroxyl group of compound 5 is protected with a suitable protecting group (such as, but not limited to, TBDPS and TBS) to give compound 6. Trifluoromethyl ketone 7 is obtained by iodine-magnesium exchange of compound 6 followed by the addition of an ester (such as, but not limited to, ethyl 2,2,2-trifluoroacetate). Trifluoromethyl ketone 7 is cross-coupled with various metal coupling partners 8 (but not limited to boric acid, borate esters, organotin reagents, organozinc reagents, organomagnesium reagents, organosilicon reagents, etc.) via appropriate Pd, Ni, Cu or similar catalysts to give compound 9. Nitromethane is added to compound 9 in the presence of a base (such as, but not limited to, K₂CO₃ and Cs₂CO₃) to give compound 10. The nitro group is reduced with a reducing agent (such as, but not limited to, zinc and acetic acid) to produce the key intermediate 11.

[0346] Option 1

[0347]

[0348] As shown in Scheme 2, where Ar1 is A; Ar is E; R is R 11 n is 1, 2, or 3; and A, E, R 11 As previously defined, key intermediate 11 is coupled with various carboxylic acids to yield amide 14. Amide 14 is then reacted with various electrophiles to produce various ethers, esters, and carbamates of formula 15. Amide 14 is also oxidized to aldehyde 16 and then reductively amination to provide various amines 17. The -CH2OH hydroxyl group in amide 14 is activated and subsequently cyanidated to convert to cyanomethyl 18. In the presence of a catalyst (such as, but not limited to, Parkin catalyst), compound 14-1 is further converted to acetamide 19.

[0349] Option 2

[0350]

[0351] As shown in Scheme 3, where Ar1 is A; Ar is E; and R is R. 11 ;and A, E, R 11As previously defined, aldehyde 16 is converted to a benzyl-protected amine via reductive amination. Hydrogenolysis yields the free amine 20. Finally, substitution with various electrophiles yields the N-substituted compound 21.

[0352] Option 3

[0353]

[0354] As shown in Scheme 4, 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. After aldehyde 16 is oxidized to acid 22, it is further converted to amide 23 and sulfonamide 24 using common methods (such as, but not limited to, HATU and DIPEA). From there, diversification to various esters and amides is carried out.

[0355] Option 4

[0356]

[0357] Scheme 5 describes another method for preparing compounds of formula 11, wherein 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 compounds of formula 26 by olefination. Alternatively, 26 is obtained from: 1) crosslinking of 6 with a metal coupling partner 6-1 (which may be, but is not limited to, boric acid, borate ester, organotin reagent, organozinc reagent, organomagnesium reagent, organosilicon reagent, etc.) via a suitable Pd, Ni, Cu, or similar catalyst to obtain compound 25; 2) converting compound 25 to compound 26 as previously described in Scheme 1. Using 26 at hand, compounds of formula 27 are prepared by dihydroxylation followed by epoxide formation. Compound 27 is provided by epoxide ring-opening using amine equivalents (such as, but not limited to, NH4OH and NH3) to provide compounds of formula 11.

[0358] Option 5

[0359]

[0360] Scheme 6 describes another method for preparing compounds of formula 23, wherein Ar1 is A; Ar is E; R' is –C1-C6 alkyl, –C3-C6 cycloalkyl, aryl, or heteroaryl; n is 1, 2, or 3; and A and E are as previously defined. Amine 11 is protected with a protecting group (such as, but not limited to, Boc and Cbz). Following deprotection of the hydroxyl protecting group, subsequent oxidation provides acid 30. Compound 30 is coupled with various amines to provide amide 31. The amine protecting group is deprotected, followed by amide formation, to obtain compounds of formula 23.

[0361] Option 6

[0362]

[0363] Scheme 7 illustrates an alternative route for synthesizing the desired compound. This route differs in that it begins with oxidation and amide coupling to position amide 33 at the start of the synthesis. Sequential ethyleneation and arylation provide the bicoupled product 34. Asymmetric dihydroxylation followed by activation and substitution provides an amino alcohol precursor. Finally, the amide is coupled with its respective arylic acid to produce the desired compound described via compound 36.

[0364] Option 7

[0365]

[0366] Example

[0367] The compounds and methods of the present invention will be better understood in conjunction with the following examples, which 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 can be made, including but not limited to those relating to the chemical structure, substituents, derivatives, formulations, and / or methods of the present invention, without departing from the spirit of the invention and the scope of the appended claims.

[0368] Example 1

[0369]

[0370] Example 1, step a:

[0371]

[0372] Add 2-bromo-6-iodopyridin-3-ol (14.21 g, 47.4 mmol) and 2-pyridyldiphenylphosphine (13.3 g, 52.1 mmol) to a 500-mL round-bottom flask equipped with a stir bar. Purge the flask with nitrogen and dissolve the solids in THF (95 mL, 0.5 M). Slowly add (S)-(2-methylethyleneoxy-2-yl)methanol (4.176 g, 47.4 mmol) at 0 °C, followed by DIAD (10.14 mL, 52.1 mmol). Heat the flask to room temperature and monitor the reaction by LCMS (5 h). Dilute the reaction with EtOAc and quench with water. Perform EtOAc extraction, and pass the crude residue by automated column chromatography (silica gel, 50% ethyl acetate in hexane, R...). f =0.75) Purified and dried under high vacuum to give the title compound as a grayish-white, foamy solid (11.77 g, 67%). ESI-MS m / z: 370.0 / 372.0 [M+H] + .

[0373] Example 1, step b:

[0374]

[0375] Add the compound from step a (11.77 g, 31.8 mmol) to a 500-mL round-bottom flask equipped with a stir bar. Purge the flask with nitrogen and dissolve the solid in THF (80 mL, 0.3 M). Add the LDA solution (35.0 mmol, 17.5 mL 2.0 M LDA in 26 mL THF) slowly over 10 minutes at 0 °C (rapid, dropwise rate). The reaction is stirred at 0 °C and monitored by LCMS (5- and 6-membered rings have different retention times). If not complete, warm the flask to room temperature until complete. Dilute the reaction mixture with EtOAc at 0 °C and quench with water and saturated ammonium chloride. Perform EtOAc extraction and dry the residue under vacuum overnight to remove diisopropylamine to give the title compound, which is used unpurified for the next reaction. ESI-MS m / z: 370.0 / 372.0 [M+H] + .

[0376] Example 1, step c:

[0377]

[0378] Add a stir bar to a 500-mL round-bottom flask containing the compound from step b (11.77 g, 31.8 mmol, mixture). Dissolve the residue in DMF (64 mL, 0.5 M) and add imidazole (4.76 g, 70.0 mmol). Purge the flask with nitrogen and add tert-butylchlorodiphenylsilane (9.10 mL, 35.0 mmol) at 0 °C. Heat the flask to room temperature and monitor the reaction via LMCS (3 h). Dilute the reaction with EtOAc and quench with water. Perform EtOAc extraction, and pass the crude residue by automated column chromatography (silica gel, 25% ethyl acetate in hexane, R...). f =0.78) Purified and dried under high vacuum to give the title compound as a grayish-white, foamy solid (7.87 g, 57%, in two steps). ESI-MS m / z: 608.4 / 610.4 [M+H] + .

[0379] Example 1, step d:

[0380]

[0381] A stir bar was added to a 250-mL round-bottom flask containing the compound from step c (7.87 g, 12.94 mmol), and the flask was purged with nitrogen. The flask was cooled to -40 °C and ethyl trifluoroacetate (2.317 mL, 19.40 mmol) was added. Then, magnesium isopropyl chloride (7.76 mL, 15.52 mmol) was slowly added, and the reaction was stirred for 10 min. The flask was then heated to 0 °C and monitored by LCMS. (1 h: the reaction can be heated to room temperature). The reaction was diluted with EtOAc at 0 °C and quenched with water and saturated ammonium chloride. EtOAc extraction was performed, and the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate, in hexane, multiple peaks due to hydrate formation) and dried under high vacuum to give the title compound as a clear, viscous residue (7.27 g, 97%, a mixture of ketone and hydrate). ESI-MS m / z: 610.2 / 612.4 [M+H] + (MeOH adduct from LCMS in MeOH).

[0382] Example 1, step e:

[0383]

[0384] A stir bar was added to a 250-mL round-bottom flask containing the compound from step d (7.27 g, 12.57 mmol). The residue was dissolved in 1,4-dioxane (50 mL, 0.2 M), and potassium carbonate (3.91 g, 28.3 mmol) was added. PdCl2(dppf) (0.460 g, 0.628 mmol) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (3.35 g, 15.08 mmol) were added, and the flask was purged with nitrogen. Water (12 mL, purged with nitrogen for 15 min) was then added. The flask was then rapidly fitted with a condenser and heated to 90 °C under a nitrogen stream for 14 h. The reaction conversion was monitored by LCMS. The reaction was diluted with EtOAc and quenched with saturated ammonium chloride. EtOAc extraction was performed, and the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give a mixture of product and hydrate. The product was dissolved in 20 mL of toluene, and MgSO4 was added to form a suspension, which was then vigorously stirred for 1.5 h to dehydrate. Dehydration was monitored by aliquoting the sample by 1H NMR. The MgSO4 was filtered off, washed with DCM, and concentrated. The solid was ground with DCM to give the title compound as a white, foamy solid (6.33 g, 85%). ESI-MS m / z: 612.4 [M+H] + (Water adduct on LCMS).

[0385] Example 1, step f:

[0386]

[0387] Add a stir bar to a 250-mL round-bottom flask containing the compound from step e (6.33 g, 10.02 mmol). Add nitromethane (40 mL, 0.25 M), then potassium carbonate (4.16 g, 30.1 mmol). Stir the flask at room temperature and monitor the progress by LCMS (2.5 h). Dilute the reaction with EtOAc and quench with water and saturated ammonium chloride. Perform EtOAc extraction, and pass the crude residue by automated column chromatography (silica gel, 25% ethyl acetate in hexane, R...). f =0.70) Purified and dried under high vacuum to give the title compound as a white, foamy solid (6.02 g, 92%, a mixture of diastereomers). ESI-MS m / z: 655.4 [M+H] + .

[0388] Example 1, step g:

[0389]

[0390] Add a stir bar to a 250-mL round-bottom flask containing the compound from step f (6.02 g, 9.19 mmol). Dissolve the solid in AcOH (28 mL, 0.33 M) and cool the flask to 0 °C. Add zinc (6.01 g, 92 mmol), heat the reaction to room temperature and monitor by LCMS (2 h). Dilute the reaction mixture with EtOAc and remove zinc by filtration over a diatomaceous earth mat. Wash the diatomaceous earth with EtOAc and MeOH. Concentrate the combined organic matter under reduced pressure to remove most of the acetic acid. Dissolve the crude residue in EtOAc and add water. Adjust the pH to approximately 8-9 with saturated sodium bicarbonate and stirring. Extract the aqueous solution with EtOAc (4 times) and concentrate under reduced pressure. Purify the crude residue by automated column chromatography (silica gel, 0-25% methanol in dichloromethane) to give the title compound as a white, foamy solid (4.40 g, 77%, a mixture of diastereomers). ESI-MS m / z: 625.4 [M+H] + .

[0391] Example 2

[0392]

[0393] Example 2, step a:

[0394]

[0395] Method A

[0396] The compound from step g of Example 1 (1.00 g, 1.601 mmol) was added to a 40-mL flask equipped with a stir bar. The flask was purged with nitrogen, and the solid was dissolved in THF (5 mL, 0.33 M). TBAF (3.20 mL, 3.20 mmol) was slowly added at 0 °C. The reaction was stirred at room temperature and monitored by LCMS (3 h). After completion, the stir bar was removed, the reaction was concentrated, and the mixture was purified directly by automated column chromatography (silica gel, ethyl acetate in hexane to 25% methanol in dichloromethane). The residue was dissolved in EtOAc and washed three times with water to remove the ammonium salt, giving the title compound as a white, fluffy solid (489 mg, 79%, a mixture of diastereomers). ESI-MS m / z: 387.4 [M+H] + .

[0397] Example 2, Step b:

[0398]

[0399] Add the compound from step a (489 mg, 1.266 mmol) and 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-methoxybenzoic acid (413 mg, 1.266 mmol) to a 20-mL vial equipped with a stir bar. Dissolve the solid in DMF (3.84 mL, 0.33 M) and add Hunig base (442 μl, 2.53 mmol). Add HATU (578 mg, 1.519 mmol) in one part, purge the vial with nitrogen, and stir the reaction at room temperature until complete (LCMS, 4 h). Dilute the mixture with EtOAc and quench with water and saturated ammonium chloride. Extract with EtOAc using a phase separator, and pass the crude residue by automated column chromatography (silica gel, ethyl acetate R). f Purification (=0.80) yielded the title compound as a white, foamy solid (625 mg, 71%, a mixture of diastereomers). ESI-MS m / z: 695.4 [M+H] + .

[0400] Example 2, step c:

[0401]

[0402] Method B

[0403] Add the compound from step b (575 mg, 0.828 mmol) to a 20-mL vial equipped with a stir bar. Dissolve the solid in DCM (2.5 mL, 0.33 M) and cool the vial to 0 °C. Add Dysmart reagent (386 mg, 0.91 mmol), purge the vial with nitrogen, and stir for 10 min. Heat the reaction to room temperature and monitor by LCMS (30 min–1 h). After completion, dilute the reaction with DCM and quench with a 1:1 solution of saturated sodium bicarbonate: saturated sodium thiosulfate. Stir the mixture vigorously for about 20 min until the solution becomes clear. Extract with DCM using a phase separator and purify the crude residue by automated column chromatography (silica gel, 0–100% ethyl acetate in hexane) to give the title compound as a white, foamy solid (518 mg, 90%, a mixture of diastereomers). ESI-MS m / z: 693.2 [M+H] + .

[0404] Example 2, step d:

[0405]

[0406] Method C

[0407] Add the compound from step c (40 mg, 0.058 mmol) to a 2-dram vial equipped with a stir bar. Dissolve the solid in DCE (0.2 mL, 0.33 M) and add cyclopropylamine (a solution of DCE, 3.3 mg, 0.058 mmol). Add sodium triacetoxyborohydride (18.36 mg, 0.087 mmol) in one part, purge the vial with nitrogen, and stir at room temperature. Monitor the reaction by LCMS (4 h), dilute with DCM, and quench with water. Adjust the aqueous solution to approximately pH 8-9 with saturated sodium bicarbonate. Perform DCM extraction using a phase separator cartridge to concentrate the residue. Proceed to the next step with the crude residue. Method D The TBS protection seen in the image is removed. ESI-MS m / z: 734.6 [M+H] + .

[0408] Example 3

[0409]

[0410] Method D

[0411] A stir bar was added to a 20-mL vial containing the compound from step d of Example 2 (42.4 mg, 0.058 mmol), and the solid was dissolved in DCM (0.39 mL, 0.15 M). HCl (4 M, 0.19 mL, 0.74 mmol) in dioxane was added, and the reaction was stirred at room temperature. After LCMS (2 h) was completed, the reaction was diluted with DCM and quenched with saturated sodium bicarbonate until pH approximately 8-9. The organic compound was extracted with DCM using a phase separator and concentrated. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (5.1 mg, 14%). ESI-MS m / z: 620.4 [M+H] + .

[0412] Example 4:

[0413]

[0414] Using 40 mg of the compound from step c of Example 2 and (S)-1-cyclopropylethylamine to react with Methods C and D The title compound was synthesized in a similar sequence. ESI-MS m / z: 762.4 [M+H] + (TBS alcohol). The mixture of diastereomers was not well separated by HPLC. The mixture was then subjected to automated column chromatography (silica gel, dichloromethane in 5% methanol R). f =0.65, purified in EtOAc / hexane and then in MeOH / DCM) and lyophilized to give the title compound as a white, fluffy solid (23 mg, 63%, a mixture of diastereomers). ESI-MS m / z: 648.4 [M+H] + .

[0415] Example 5:

[0416]

[0417] Using 40 mg of the compound from step c of Example 2 and aniline to... Methods C and D The title compound was synthesized in a similar sequence. ESI-MS m / z: 770.3 [M+H] + (TBS alcohol). The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (9 mg, 23%). ESI-MS m / z: 656.4 [M+H] + .

[0418] Example 6:

[0419]

[0420] The compound from step b of Example 2 (32.3 mg, 0.046 mmol) was added to a stirred 2-dallan vial. The vial was purged with nitrogen and the solid was dissolved in DCM (0.23 mL, 0.2 M). Hunig base (20.30 μl, 0.116 mmol) was added, followed by phenyl isocyanate (6.10 μl, 0.056 mmol). The reaction was monitored by LCMS (1 h). The reaction mixture was diluted with DCM and quenched with saturated sodium bicarbonate. DCM extraction was performed using a phase separator. ESI-MS m / z: 814.4 [M+H] + (TBS alcohol).

[0421] like Method D As explained in the paper, the crude residue was proceeded forward to TBS for deprotection. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (7 mg, 29%). ESI-MS m / z: 700.5 [M+H] + .

[0422] Example 7:

[0423]

[0424] The title compound was synthesized using 30 mg of the compound from step b of Example 2, but with cyclopropyl isocyanate (note, volatile), similar to the formation of phenyl carbamate described above (Example 6). ESI-MS m / z: 778.5 [M+H] + (TBS alcohol). For example... Method D The TBS group was deprotected as explained in the paper. The mixture of diastereomers was analyzed by HPLC to verify the separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (4 mg, 15%). ESI-MS m / z: 664.5 [M+H] + .

[0425] Example 8

[0426]

[0427] Example 8, Step a:

[0428]

[0429] according to Method C The title compound was synthesized using 137 mg of the compound from step c of Example 2, benzylamine (30.0 μl, 0.27 mmol, 1.7 equivalents), and 1.7 equivalents of sodium triacetoxyborohydride. The compound was subjected to automated column chromatography (silica gel, 50% ethyl acetate in hexane, R...). f Purification (=0.50) yielded the title compound as a white, foamy solid (112 mg, 72%, a mixture of diastereomers). ESI-MS m / z: 664.5 [M+H] + .

[0430] Example 8, step b:

[0431]

[0432] A stir bar was added to a 20-mL vial containing the compound from step a (100 mg, 0.128 mmol). The solid was dissolved in anhydrous MeOH (0.85 mL, 0.15 M) and Pd-C (33.9 mg, 0.032 mmol) was added. The vial was purged with an H2 balloon and the reaction was maintained under the H2 balloon. The reaction was monitored by LCMS (2 h). The balloon was removed and the mixture was filtered through an EtOAc filter on a diatomaceous earth mat. The organic matter was concentrated and milled with DCM to give the title compound as a white, foamy solid (75 mg, 84%, a mixture of diastereomers). ESI-MS m / z: 694.4 [M+H] + .

[0433] Example 8, step c:

[0434]

[0435] Method E

[0436] The compound from step b (28.65 mg, 0.041 mmol) was added to a 2-dallan vial equipped with a stir bar. The vial was purged with nitrogen, and the solid was dissolved in DCM (0.21 mL, 0.20 M). Hunig base (15.87 μl, 0.091 mmol) was added, followed by benzoyl chloride (5.75 μl, 0.050 mmol). The reaction was stirred at room temperature and monitored by LCMS (1 h). The reaction was diluted with DCM and quenched with saturated sodium bicarbonate. DCM extraction was performed using a phase separator. The crude residue was analyzed by ¹H NMR to observe the movement of the primary amine α-proton. ESI-MS m / z: 798.3 [M+H] + (TBS alcohol).

[0437] like Method DAs explained in the paper, the crude residue was proceeded forward to TBS for deprotection. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (4.9 mg, 16%). ESI-MS m / z: 684.4 [M+H] + .

[0438] Example 9:

[0439]

[0440] according to Method E The title compound was synthesized using 30 mg of the compound from step b of Example 8 and cyclopropaneformyl chloride. The crude residue was analyzed by ¹H NMR to observe the movement of the primary amine α-proton.

[0441] like Method D As described, the crude residue was proceeded forward to TBS for deprotection. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.1 mg, 19%). ESI-MS m / z: 648.4 [M+H] + .

[0442] Example 10

[0443]

[0444] Example 10, Step a:

[0445]

[0446] Method F

[0447] Add the compound (300 mg, 0.433 mmol) from step c of Example 2 to a 20-mL vial equipped with a stir bar. Dissolve the solid in tert-BuOH (5.8 mL, 0.05 M) and add 2-methyl-2-butene (1.0 M in THF, 6 mL, 12.0 mmol). Dissolve sodium chlorite (490 mg, 4.33 mmol) and sodium dihydrogen phosphate (520 mg, 4.33 mmol) in water (2.9 mL) and add the solution dropwise to the reaction vial. Purge the vial rapidly with nitrogen and monitor by LCMS (30 min). Remove the stir bar and concentrate the volatiles under reduced pressure. Dilute the mixture with EtOAc and water and check the pH to ensure it is acidic (approximately pH 4). Perform EtOAc extraction and pass the residue by automated column chromatography (silica gel, 5% methanol in dichloromethane, R).f Purification with 0.20 g yielded the title compound as a white, foamy solid (252 mg, 82%, a mixture of diastereomers). ESI-MS m / z: 709.4 [M+H] + .

[0448] Example 10, Step b:

[0449]

[0450] Method G

[0451] Add the compound from step a (52 mg, 0.073 mmol) to a 2-dallan vial equipped with a stir bar. Dissolve the solid in DMF (0.37 mL, 0.20 M) and add cyclopropylamine (7.76 μl, 0.110 mmol). Add Hunig base (32.0 μl, 0.183 mmol), followed by HATU (33.5 mg, 0.088 mmol) in a single volume. Purge the reaction with nitrogen and monitor by LCMS until complete (2.5 h). Dilute the reaction with EtOAc and quench with water. Extract with EtOAc using a phase separator. ESI-MS m / z: 748.3 [M+H] + (TBS alcohol).

[0452] like Method D As explained in the text, the coarse residue is carried forward to the TBS for protection.

[0453] The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (4 mg, 5%). ESI-MS m / z: 634.4 [M+H] + .

[0454] Example 11:

[0455]

[0456] according to Method G The title compound was synthesized using 50 mg of the compound from step a of Example 10, ammonium chloride (15 mg, 0.28 mmol, 4.0 equivalents), and 6.0 equivalents of Hunig base. ESI-MS m / z: 708.4 [M+H] + (TBS alcohol).

[0457] like Method DAs explained in the paper, the crude residue was proceeded forward to TBS for deprotection. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (4 mg, 10%). ESI-MS m / z: 594.1 [M+H] + .

[0458] Example 12:

[0459]

[0460] according to Method G The title compound was synthesized using 50 mg of the compound from step a of Example 10, cyclopropylsulfonamide (26 mg, 0.212 mmol, 3.0 equivalents), 3.0 equivalents of Hunig base, and 1.5 equivalents of HATU. ESI-MS m / z: 812.4 [M+H] + (TBS alcohol).

[0461] like Method D As explained in the paper, the crude residue was proceeded forward to TBS for deprotection. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6 mg, 12%, mixture of diastereomers). ESI-MS m / z: 698.1 [M+H] + .

[0462] Example 13:

[0463]

[0464] like Method D As explained herein, 44 mg of the compound from step a of Example 10 was proceeded to TBS for deprotection. The mixture of diastereomers was analyzed by HPLC to verify separation. The mixture was subjected to automated column chromatography (silica gel, dichloromethane in 10% methanol, R... f =0.20) purified and lyophilized overnight to give the title compound as a white, fluffy solid (23 mg, 62%, a mixture of diastereomers). ESI-MS m / z: 595.1 [M+H] + .

[0465] Example 14:

[0466]

[0467] Method H

[0468] Add 100 mg (0.480 mmol) of 4-cyclopropoxy-3-methoxybenzoic acid to a 40 mL vial equipped with a stir bar, and purge the vial with nitrogen. Add 3.20 mL (0.15 M) of DCM, followed by the slow addition of Ghosez's reagent (127 μl, 0.960 mmol). Stir the reaction at room temperature for 1.3 h.

[0469] Remove the stir bar and concentrate the reaction. Place under high vacuum for approximately 45 minutes to remove any Ghosez reagent. Add the stir bar to the acyl chloride, purge the vial with nitrogen, and add DCM (2 mL). Then add the amino alcohol (300 mg, 0.480 mmol) from step 1 of Example 1 as a solution of DCM (1.2 mL) and pyridine (252 μl, 3.12 mmol). Stir the reaction at room temperature and monitor by LCMS (1 h). Quench the reaction with MeOH and then with water. Dilute with DCM and add saturated sodium bicarbonate to pH approximately 9. Extract with DCM using a phase separator. Concentrate and then place under high vacuum to remove pyridine. Analyze the solid by automated column chromatography (silica gel, 20% ethyl acetate in hexane, R...). f Purification (=0.21) yielded the title compound as a white, foamy solid (343 mg, 88%, a mixture of diastereomers). ESI-MS m / z: 815.2 [M+H] + .

[0470] Example 15:

[0471]

[0472] according to Method A The title compound was synthesized using 343 mg of the compound from Example 14 and analyzed by automated column chromatography (silica gel, 50% ethyl acetate in hexane, R...). f Purification at concentrations of 0.2 and 0.30 yielded the title compound as a white, foamy solid (195 mg, 80%, a mixture of diastereomers). ESI-MS m / z: 577.4 [M+H] + .

[0473] Example 16:

[0474]

[0475] according to Method BThe title compound was synthesized using 195 mg of the compound from Example 15 and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a white, foamy solid (155 mg, 80%, a mixture of diastereomers). ESI-MS m / z: 593.4 [M+H] + (Water adduct on LCMS).

[0476] Example 17:

[0477]

[0478] according to Method C The title compound was synthesized using 50 mg of the compound from Example 16. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was subjected to automated column chromatography (silica gel, 40% ethyl acetate in hexane, R...). f =0.20) was purified and lyophilized to give the title compound as a white, fluffy solid (21.3 mg, 39%). ESI-MS m / z: 616.4 [M+H] + .

[0479] Example 18:

[0480]

[0481] according to Method C The title compound was synthesized using 50 mg of the compound from Example 16 and cyclopropylmethylamine. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (13 mg, 29%). ESI-MS m / z: 630.4 [M+H] + .

[0482] Example 19:

[0483]

[0484] according to Method C The title compound was synthesized using 50 mg of the compound from Example 16 and (S)-1-cyclopropylethylamine. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was subjected to automated column chromatography (silica gel, 75% ethyl acetate in hexane, R...). f =0.40) was purified and lyophilized to give the title compound as a white, fluffy solid (18 mg, 27%). ESI-MS m / z: 644.4 [M+H] + .

[0485] Example 20:

[0486]

[0487] according to Method H The title compound was synthesized using 500 mg of the compound from step g of Example 1 and 163 mg of the corresponding acid, and by automated column chromatography (silica gel, 70% ethyl acetate in hexane, R...). f Purification with 0.35 g / mL yielded the title compound as a white, foamy solid (428 mg, 66%, a mixture of diastereomers). ESI-MS m / z: 810.3 [M+H] + .

[0488] Example 21:

[0489]

[0490] according to Method A The title compound was synthesized using 428 mg of the compound from Example 20 and analyzed by automated column chromatography (silica gel, dichloromethane in 5% methanol, R). f =0.33) Purification yielded the title compound as a white, foamy solid (282 mg, 79%, a mixture of diastereomers). ESI-MS m / z: 572.2 [M+H] + .

[0491] Example 22:

[0492]

[0493] according to Method B The title compound was synthesized using 282 mg of the compound from Example 21 and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane, and 0-25% methanol in dichloromethane) to give the title compound as a white, foamy solid (260 mg, 93%, a mixture of diastereomers). ESI-MS m / z: 570.2 [M+H] + .

[0494] Example 23:

[0495]

[0496] according to Method CThe title compound was synthesized using 50 mg of the compound from Example 22. 1.50 equivalents of the amine and borohydride were used, and the reaction was stirred overnight. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (11.7 mg, 21%). ESI-MS m / z: 611.2 [M+H] + .

[0497] Example 24:

[0498]

[0499] according to Method C The title compound was synthesized using 50 mg of the compound from Example 22. 1.50 equivalents of (S)-1-cyclopropylethylamine and sodium triacetoxyborohydride were used, and the reaction was stirred overnight. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (40 mg, 72%, mixture of diastereomers). ESI-MS m / z: 639.6 [M+H] + .

[0500] Example 25:

[0501]

[0502] according to Method C The title compound was synthesized using 50 mg of the compound from Example 22. 1.50 equivalents of cyclopropylmethylamine and sodium triacetoxyborohydride were used, and the reaction was stirred overnight. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was purified by preparative HPLC (20–90%, 25 min, 0.01% TFA), washed with saturated sodium bicarbonate, and lyophilized to give a white, fluffy solid (31.4 mg, 64%, mixture of diastereomers). ESI-MS m / z: 625.2 [M+H] + .

[0503] Example 26:

[0504]

[0505] according to Method F The title compound was synthesized using 100 mg of the compound from Example 22, dried overnight under high vacuum, and the crude product was proceeded to the next step. White solid (100 mg, 97%).

[0506] Example 27:

[0507]

[0508] according to Method G The title compound was synthesized using 50 mg of the compound from Example 26. The mixture of diastereomers was analyzed by HPLC and TLC to verify separation. The mixture was purified by preparative HPLC (20–90%, 25 min, 0.01% TFA), washed with saturated sodium bicarbonate, and lyophilized to give the title compound as a white, fluffy solid (15 mg, 28%, mixture of diastereomers). ESI-MS m / z: 625.1 [M+H] + .

[0509] Example 28:

[0510]

[0511] according to Method G The title compound was synthesized using 56 mg of the compound from Example 26, ammonium chloride (20.46 mg, 0.383 mmol, 4.0 equivalents), 5.0 equivalents of Hunig base, and BOP (50.8 mg, 0.115 mmol, 1.2 equivalents) as a coupling agent. The mixture was subjected to automated column chromatography (silica gel, 5% methanol in dichloromethane, R...) f =0.31) Purified and lyophilized to give the title compound as a white, fluffy solid (7 mg, 13%). ESI-MS m / z: 585.2 [M+H] + .

[0512] Example 29, Step a:

[0513]

[0514] According to the procedure Method B The title compound was synthesized using 1.0 g of the compound from step b of Example 1, and analyzed by column chromatography (silica gel, 50% ethyl acetate in hexane, R...). f =0.52) Purification yielded the title compound as a white, foamy solid (501 mg, 50%). ESI-MS m / z: 384 / 385.8 [M+H] + .

[0515] Example 29, step b:

[0516]

[0517] according to Method CThe title compound was synthesized using 501 mg of the compound from step a of Example 29 and (S)-1-phenylethane-1-amine (176 μl, 1.362 mmol). The residue was subjected to column chromatography (silica gel, 25% ethyl acetate in hexane, R... f Purification with 0.25 g / mL yielded the title compound as a white solid, a single diastereomer (peak 1 = P1 at 172 mg, P2 at 184 mg, 55%). P1: ESI-MS m / z: 473.4 / 475.4 [M+H] + ;P2: ESI-MS m / z: 473.4 / 475.4[M+H] + .

[0518] Example 29, step c:

[0519]

[0520] according to Example 1, step d The procedure described in the text used 2.6 equivalents of Grignard reagent and step b of Example 29 (172 mg P1 and 184 mg P2 from step b, respectively) to synthesize the title compound. The residues were purified by column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a white solid, a single diastereomer. (P1: 132 mg, 82%; P2: 141 mg, 82%, respectively) P1: ESI-MS m / z: 443.0 / 445.0 [M+H] + ;P2: ESI-MSm / z: 443.2 / 445.4[M+H] + .

[0521] Example 29, step d:

[0522]

[0523] according to Example 1, step e The procedure described above uses the compounds from step c (P1: 132 mg and P2: 144 mg, respectively) to synthesize the title compound. The residues were purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give a viscous residue as a single diastereomer. The residues were dehydrated by azeotropic / milling three times with 2 mL of toluene (P1: 101 mg, 73%; P2: 141 mg, 80%, respectively). P1: ESI-MS m / z: 477.4 [M+H] + (Water adduct); P2: ESI-MS m / z: 477.2 [M+H] + (Water adduct)

[0524] Example 29, step e:

[0525]

[0526] according to Example 1, step f The procedure described uses compounds from step d (P1: 101 mg and P2: 141 mg, respectively) to synthesize the title compound. The crude residue was dried under high vacuum to give the title compound as a white solid (P1: 97 mg, 84%; P2: 113 mg, 85%). The crude material was proceeded to the next step without further purification. P1: ESI-MS m / z: 520.5 [M+H] + ;P2: ESI-MS m / z: 520.3[M+H] + .

[0527] Example 29, step f:

[0528]

[0529] according to Example 1, step g The procedure in this paper uses the compounds from step e (P1: 97 mg and P2: 113 mg, respectively) to synthesize the title compound. The crude residue was dried under high vacuum to give a white, foamy solid (P1: 90 mg, 98%; P2: 103 mg, 94%). The crude material was then proceeded to the next step. P1: ESI-MS m / z: 490.3 [M+H] + ;P2: ESI-MS m / z: 490.4[M+H] + .

[0530] Examples 30a and 30b

[0531]

[0532] according to Method G The title compound was synthesized using 90 mg of P1 from step f of Example 29 and 39 mg of the corresponding acid. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and preparative HPLC (20-90%, 25 min) to obtain pure samples of the two diastereomers (10 mg P1-A, 11 mg P1-B, 18%). P1-A: ESI-MS m / z: 684.5 [M+H] + ;P1-B: ESI-MS m / z: 684.4[M+H] + .

[0533] Example 31

[0534]

[0535] according to Method G The title compound was synthesized using 103 mg of P2 from step f of Example 29 and 45 mg of the corresponding acid. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and preparative HPLC (20-90%, 25 min) to obtain pure samples of the two diastereomers (18 mg P2-A, 14 mg P2-B, 22%). P2-A: ESI-MS m / z: 684.5 [M+H] + ;P2-B: ESI-MS m / z: 684.4[M+H] + .

[0536] Example 32, step a

[0537]

[0538] Add a stir bar to a 50 g round-bottom flask containing the compound from step g of Example 1 (2.164 g, 3.46 mmol). Purge the flask with nitrogen and add DCM (17 mL, 0.2 M). Add triethylamine (0.724 mL, 5.20 mmol), cool the flask to 0 °C, and add Boc-anhydride (3.81 mL, 3.81 mmol). Stir the reaction at room temperature and monitor by LCMS (5 h). Remove the stir bar and concentrate the mixture directly. Analyze the crude residue by automated column chromatography (silica gel, 20% ethyl acetate in hexane, R...). f =0.72) Purification yielded the title compound as a white, foamy solid (2.30 g, 93%). ESI-MS m / z: 724.9 [M+H] + .

[0539] Example 32, step b

[0540]

[0541] Add a stir bar to a 40 mL vial containing the compound from step a (2.515 g, 3.47 mmol). Purge the vial with nitrogen and add THF (17 mL, 0.2 M). Cool the vial to 0 °C and add TBAF (6.94 mL, 6.94 mmol). Stir the reaction for 10 min, heat to room temperature and monitor by LCMS (1.5 h, and then add 3.0 equivalents of TBAF after another 2 h). Remove the stir bar and concentrate the reaction directly. Analyze the crude residue by automated column chromatography (silica gel, 33% ethyl acetate in hexane, R...). f=0.29) Purification yielded the title compound as a white, foamy solid (525 mg nonpolar peak P1, 600 mg polar peak P2, 67%). P1: ESI-MS m / z: 487.2 [M+H] + ;P2: ESI-MS m / z: 487.2[M+H] + .

[0542] Example 33

[0543]

[0544] Example 33, Step a

[0545]

[0546] according to Method B The title compound was synthesized using 472 mg of the compound (P1) from step b of Example 32. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a white, foamy solid (387 mg, 82%, single diastereomer). ESI-MS m / z: 485.0 [M+H] + .

[0547] Example 33, step b

[0548]

[0549] according to Method C The title compound was synthesized using 200 mg of the compound from step a, but with 5.0 equivalents of cyclopropylmethylamine and 5.0 equivalents of its hydride over 14 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a white, foamy solid (163 mg, 73%). ESI-MS m / z: 540.2 [M+H] + .

[0550] Example 33 Step c

[0551]

[0552] Add a stir bar to a 20 mL scintillation vial containing the compound from step b (193 mg, 0.358 mmol). Add DCM (1.40 mL), then MeOH (0.35 mL). Cool the vial to 0 °C and add HCl (4.0 M, 894 μl, 3.58 mmol) in dioxane. Stir the reaction for 5 min, heat to room temperature, and monitor by LCMS (1.5 h). Dilute the reaction with EtOAc and quench with water. Adjust the pH to pH 8–9 with saturated sodium bicarbonate. Extract with ethyl acetate and lyophilize the viscous residue to give a clear, viscous solid (141 mg, 90%). ESI-MS m / z: 440.2 [M+H] + .

[0553] Example 33, step d

[0554]

[0555] according to Method G The title compound was synthesized over 2 hours using 15 mg of the compound from step c and 1.0 equivalent of the corresponding acid. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give the title compound as a white, fluffy solid (12.8 mg, 55%). ESI-MS m / z: 680.2 [M+H] + .

[0556] Example 34

[0557]

[0558] according to Method G The title compound was synthesized using 15 mg of the compound from step c and 1.0 equivalent of the corresponding acid over 2 hours. The crude residue was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give a white, fluffy solid (5 mg, 26%). ESI-MS m / z: 576.2 [M+H] + .

[0559] Example 35

[0560]

[0561] according to Method G The title compound was synthesized using 15 mg of the compound from step c and 1.0 equivalent of the corresponding acid over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (10.2 mg, 43%). ESI-MS m / z: 614.2 [M+H] + .

[0562] Example 36

[0563]

[0564] according to Method G The title compound was synthesized using 15 mg of the compound from step c, 1.0 equivalent of the corresponding acid, and PyBOP (21 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (9 mg, 42%). ESI-MS m / z: 581.2 [M+H] + .

[0565] Example 37

[0566]

[0567] according to Method G The title compound was synthesized using 15 mg of the compound from step c, 1.0 equivalent of the corresponding acid, and PyBOP (21 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (14.1 mg, 72%). ESI-MS m / z: 575.2 [M+H] + .

[0568] Example 38

[0569]

[0570] according to Method G The title compound was synthesized using 15 mg of the compound from step c, 1.0 equivalent of the corresponding acid, and PyBOP (21 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-50% ethyl acetate in hexane to 0-20% methanol in dichloromethane) and lyophilized to give a white, fluffy solid (16.2 mg, 79%). ESI-MS m / z: 601.2 [M+H] + .

[0571] Example 39

[0572]

[0573] according to Method GThe title compound was synthesized using 15 mg of the compound from step c, 1.0 equivalent of the corresponding acid, and PyBOP (21 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (8 mg, 37%). ESI-MS m / z: 619.1 [M+H] + .

[0574] Example 40

[0575]

[0576] according to Method G The title compound was synthesized using 15 mg of the compound from step c, 1.0 equivalent of the corresponding acid, and PyBOP (21 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-50% ethyl acetate in hexane to 0-20% methanol in dichloromethane) and lyophilized to give a white, fluffy solid (12 mg, 59%). ESI-MS m / z: 600.2 [M+H] + .

[0577] Example 41

[0578]

[0579] according to Method G The title compound was synthesized using 16 mg of step c of Example 33, 1.0 equivalent of the corresponding acid, and PyBOP (23 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (16.6 mg, 71%). ESI-MS m / z: 640.2 [M+H] + .

[0580] Example 42

[0581]

[0582] according to Method G The title compound was synthesized using 16 mg of step c of Example 33, 1.0 equivalent of the corresponding acid, and PyBOP (23 mg, 1.2 equivalent) as a coupling agent over 2 hours. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give a white, fluffy solid (7.6 mg, 33%). ESI-MS m / z: 626.2 [M+H] + .

[0583] Example 43:

[0584]

[0585] Example 43, Step a:

[0586]

[0587] In vials, the compound from step d of Example 1 (1 g, 1.644 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (438 mg, 1.972 mmol), Pd(dppf)Cl2·DCM (81 mg, 0.099 mmol), and K2CO3 (681 mg, 4.93 mmol) were dissolved in 1,4-dioxane (7.40 mL) and water (0.822 mL). The reaction was sprayed with N2 and sealed. The reaction was heated at 90 °C for 2 hours and cooled to room temperature with water added. The aqueous layer was washed with EtOAc. The combined organic layers were washed with water and brine, then dried over MgSO4 and concentrated under vacuum.

[0588] The residue was purified by silica gel column chromatography (0-20% hexane / ethyl acetate) to give the title compound (816 mg, 86%) as a clear, viscous liquid. ESI-MS: 576 / 578 m / z [M+H] + .

[0589] Example 43, step b:

[0590]

[0591] In a vial, the product from step a of Example 43 (686 mg, 1.190 mmol), (4-fluorophenyl)boronic acid (200 mg, 1.428 mmol), PdCl2 (dppf) (43.5 mg, 0.059 mmol), and K2CO3 (370 mg, 2.68 mmol) were dissolved in dioxane (4.76 mL) and water (1.190 mL). The reaction was sprayed with N2 and sealed. The vial was heated at 90 °C for 2 hours. The reaction was monitored by LCMS. The vial was cooled to room temperature and water was added. The aqueous layer was washed with EtOAc, and the combined organic layers were washed with water and brine, then dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (0-20% hexane / ethyl acetate) to give the title compound (584 mg, 83%) as a clear, viscous liquid. ESI-MS: 592.2 m / z [M+H] + .

[0592] Example 43, step c:

[0593]

[0594] In a vial, the compound from step b (400 mg, 0.676 mmol) was dissolved in tert-BuOH (3.38 mL), then in water (3.38 mL) (causing the olefin to begin to precipitate (crash out)). The solution was cooled to 0 °C. Methanesulfonamide (64.3 mg, 0.676 mmol) was added, followed by AD-mix-β (1053 mg, 1.352 mmol). The reaction was heated to room temperature and stirred overnight. The reaction was diluted with EtOAc and quenched with a saturated aqueous solution of sodium thiosulfate. The aqueous layer was washed with EtOAc, and the combined organic layers were dried over MgSO4 and concentrated. The residue was purified by column chromatography (0–30% hexane / EtOAc) to give the title compound (330 mg, 78%). ESI-MS: 626.34 m / z [M+H] + .

[0595] Example 43, step d:

[0596]

[0597] In a vial, the compound from step c (270 mg, 0.431 mmol) was dissolved in THF (4.31 mL). The vial was cooled to 0 °C and sodium hydride (43.1 mg, 1.079 mmol) was added. The reaction was stirred at 0 °C for at least 1 hour, and then toluenesulfonyl chloride (99 mg, 0.518 mmol) was added. The reaction was stirred for 1 hour, and then heated to room temperature. Water was added to quench the reaction, and the aqueous layer was washed with EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (0–40% hexane / EtOAc) to give the title compound (216 mg, 82%). ESI-MS: 608.38 m / z [M+H] + .

[0598] Example 43, step e:

[0599]

[0600] In a vial, the compound from step d (216 mg, 0.355 mmol) was dissolved in DMF (7.11 mL). Ammonium hydroxide (138 μl, 3.55 mmol) was added, and the reaction mixture was sealed and stirred overnight. Water was added, and the aqueous layer was washed with DCM. The combined organic layers were washed with H₂O and dried over MgSO₄, then concentrated to give a foaming solid. The crude reaction mixture was used for the next step without further purification. ESI-MS: 625.61 m / z [M+H] + .

[0601] Example 43 is a key chiral intermediate in the synthesis of compounds of formula (I), (Ia) or (Ib).

[0602] Example 44

[0603]

[0604] according to Method C The title compound was synthesized using 20 mg of the compound from Example 22 (as a single diastereomer). 3.0 equivalents of amine HCl salt, 3.0 equivalents of borohydride, and 4.0 equivalents of TEA were used, and the reaction was stirred overnight. The crude reaction mixture was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.0 mg, 27%). ESI-MS m / z: 625.2 [M+H] + .

[0605] Example 45

[0606]

[0607] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of an amine HCl salt, and 5.0 equivalents of DIPEA. The crude reaction mixture was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (9.1 mg, 33%). ESI-MS m / z: 629.2 [M+H] + .

[0608] Example 46

[0609]

[0610] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 12.0 equivalents of amine, and 5.0 equivalents of DIPEA over a sustained period of 48 hours. The crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (16.1 mg, 63%). ESI-MS m / z: 599.2 [M+H] + .

[0611] Example 47

[0612]

[0613] according to Method GThe title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 14.0 equivalents of amine, and 4.0 equivalents of DIPEA. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (4.5 mg, 16%). ESI-MS m / z: 653.3 [M+H] + .

[0614] Example 48

[0615]

[0616] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 8.0 equivalents of amine, and 4.0 equivalents of DIPEA, followed by the addition of 4.0 equivalents of HATU after 2 hours. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (5.3 mg, 19%). ESI-MS m / z: 667.1 [M+H] + .

[0617] Example 49

[0618]

[0619] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 10.0 equivalents of amine, and 4.0 equivalents of DIPEA over a sustained period of 14 hours. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.0 mg, 22%). ESI-MS m / z: 629.2 [M+H] + .

[0620] Example 50

[0621]

[0622] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of amine, 4.0 equivalents of DIPEA for 14 h, followed by 10 equivalents of amine / DIPEA and 4.0 equivalents of HATU for 3 h. The crude reaction was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.0 mg, 22%). ESI-MS m / z: 639.2 [M+H]+ .

[0623] Example 51

[0624]

[0625] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 5.0 equivalents of an amine HCl salt, 6.0 equivalents of DIPEA for 3 h, followed by 5 equivalents of an amine / DIPEA and 4.0 equivalents of HATU for 2 h. The crude reaction was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (8.4 mg, 28%). ESI-MS m / z: 693.2 [M+H] + .

[0626] Example 52

[0627]

[0628] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of amine, 4.0 equivalents of DIPEA for 4 hours, followed by 10 equivalents of amine / DIPEA and 4.0 equivalents of HATU for 18 hours. The crude reaction was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (11.5 mg, 42%). ESI-MS m / z: 641.2 [M+H] + .

[0629] Example 53

[0630]

[0631] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of an amine HCl salt, and 5.0 equivalents of DIPEA for 4 hours, followed by 10 equivalents of an amine / DIPEA and 4.0 equivalents of HATU for 18 hours. The crude reaction was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (12.0 mg, 39%). ESI-MS m / z: 601.0 [M+H] + .

[0632] Example 54

[0633]

[0634] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of an amine HCl salt, and 5.0 equivalents of DIPEA over a sustained period of 14 hours. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (8.6 mg, 31%). ESI-MS m / z: 651.2 [M+H] + .

[0635] Example 55

[0636]

[0637] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of an amine HCl salt, and 5.0 equivalents of DIPEA over a sustained period of 14 hours. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (12.0 mg, 42%). ESI-MS m / z: 669.2 [M+H] + .

[0638] Example 56

[0639]

[0640] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 10.0 equivalents of amine, and 5.0 equivalents of DIPEA over a sustained period of 14 hours. The crude reaction was purified by automated column chromatography (0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (15.0 mg, 57%). ESI-MS m / z: 613.0 [M+H] + .

[0641] Example 57

[0642]

[0643] according to Method GThe title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of an amine HCl salt, and 5.0 equivalents of DIPEA over a sustained period of 14 hours. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (8.0 mg, 29%). ESI-MS m / z: 655.0 [M+H] + .

[0644] Example 58

[0645]

[0646] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of an amine HCl salt, and 5.0 equivalents of DIPEA over a sustained period of 14 hours. The crude reaction was purified by preparative HPLC (20–90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (10.9 mg, 37%). ESI-MS m / z: 689.0 [M+H] + .

[0647] Example 59

[0648]

[0649] Example 59, Step a

[0650]

[0651] according to Method F The title compound was synthesized using 380 mg of aldehyde (as a single diastereomer). The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a pale yellow solid (354 mg, 90%, ESI-MS m / z: 444.9 [M+H]). + .

[0652] Example 59, step b

[0653]

[0654] according to Method G The title compound was synthesized using 354 mg of acid from step a. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a pale yellow solid (266 mg, 57%). ESI-MS m / z: 443.9 [M+H] + .

[0655] Example 59, step c

[0656]

[0657] The title compound was synthesized using 120 mg of the amide from step b, following the deprotection procedure in step c of Example 33. The crude residue was ground with dichloromethane / hexane to give a pale yellow solid (95 mg, 99%), ESI-MS m / z: 400.0 [M+H]. + .

[0658] Example 59, step d

[0659]

[0660] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (6.7 mg, 24%). ESI-MS m / z: 621.1 [M+H] + .

[0661] Example 60

[0662]

[0663] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (19.6 mg, 72%). ESI-MS m / z: 603.1 [M+H] + .

[0664] Example 61

[0665]

[0666] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel, 0-20% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (20.9 mg, 76%). ESI-MS m / z: 611.1 [M+H] + .

[0667] Example 62

[0668]

[0669] according to Method G The title compound was synthesized using 23 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) and lyophilized to give the title compound as a white, fluffy solid (16.0 mg, 52%). ESI-MS m / z: 590.0 [M+H] + .

[0670] Example 63

[0671]

[0672] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (10.5 mg, 41%). ESI-MS m / z: 572.9 [M+H] + .

[0673] Example 64

[0674]

[0675] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid over 1.5 hours. The crude reaction was purified by preparative HPLC (20-90% MeCN / H2O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.3 mg, 22%). ESI-MS m / z: 622.9 [M+H] + .

[0676] Example 65

[0677]

[0678] according to Method GThe title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by preparative HPLC (20-90% MeCN / H2O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (10.9 mg, 38%). ESI-MS m / z: 640.0 [M+H] + .

[0679] Example 66

[0680]

[0681] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid over 1.5 hours. The crude reaction was purified by preparative HPLC (20-90% MeCN / H2O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (9.3 mg, 35%). ESI-MS m / z: 583.9 [M+H] + .

[0682] Example 67

[0683]

[0684] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid over 1.5 hours. The crude reaction was purified by preparative HPLC (20–90% MeCN / H₂O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (11.3 mg, 34%). ESI-MS m / z: 600.0 [M+H] + .

[0685] Example 68

[0686]

[0687] according to Method G The title compound was synthesized using 25 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid over 1.5 hours. The crude reaction was purified by preparative HPLC (20–90% MeCN / H₂O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (10.4 mg, 31%). ESI-MS m / z: 596.0 [M+H] + .

[0688] Example 69

[0689]

[0690] according to Method G The title compound was synthesized using 25 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by preparative HPLC (20-90% MeCN / H2O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (10.0 mg, 31%). ESI-MS m / z: 584.1 [M+H] + .

[0691] Example 70

[0692]

[0693] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel) and lyophilized to give the title compound as a white, fluffy solid (10.5 mg, 31%). ESI-MS m / z: 636.2 [M+H] + .

[0694] Example 71

[0695]

[0696] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel) and lyophilized to give the title compound as a white, fluffy solid (10.1 mg, 37%). ESI-MS m / z: 560.3 [M+H] + .

[0697] Example 72

[0698]

[0699] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid over 1.5 hours. The crude reaction was purified by automated column chromatography (silica gel) and lyophilized to give the title compound as a white, fluffy solid (9.8 mg, 29%). ESI-MS m / z: 578.3 [M+H] + .

[0700] Example 73

[0701]

[0702] according to Method G The title compound was synthesized using 20 mg (1.0 equivalent) of the compound from step c of Example 59 above and 1.0 equivalent of the corresponding acid for 1.5 hours. The crude reaction was purified by automated column chromatography and lyophilized to give the title compound as a white, fluffy solid (8.6 mg, 25%). ESI-MS m / z: 615.2 [M+H] + .

[0703] Example 74

[0704]

[0705] Example 74 Step a

[0706]

[0707] Example 21 (as a single diastereomer) (200 mg, 0.35 mmol) in DMF (4 mL) was loaded into a round flask, followed by the slow addition of 4-methylbenzenesulfonyl chloride (70.0 mg, 0.37 mmol), N,N-dimethylpyridin-4-amine (42.8 mg, 0.35 mmol), and triethylamine (0.15 mL, 1.05 mmol). The resulting mixture was stirred at room temperature for 20 hours and then diluted with DCM (50 mL). The mixture was washed with brine, dried, and purified by automated column chromatography (silica gel, 0–3% methanol in dichloromethane) to give the title compound (87 mg, 34%). ESI-MS m / z: 726.1 [M+H] + .

[0708] Example 74, step b

[0709]

[0710] A solution of the compound (80 mg, 0.11 mmol) from step a of Example 74 and sodium cyanocyanate (10.80 mg, 0.22 mmol) in DMSO (2 mL) was heated at 100 °C for 12 hours in a sealed container. The reaction mixture was diluted with DCM (150 mL), washed with brine (50 mL x 3), dried, and purified by automated column chromatography (silica gel, 0-2% methanol in dichloromethane) to give the title compound (24 mg, 37.5%). ESI-MS m / z: 581.0 [M+H] + .

[0711] Example 75

[0712]

[0713] A solution of the compound from step b of Example 74 (20 mg, 0.034 mmol) and Ghaffar-Parkins catalyst-hydrogenated (dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (2.95 mg, 6.89 μmol) in EtOH / H2O (4:1, 1.75 mL) was heated at 85 °C for 2 hours in a sealed container. After evaporation of the solvent, the residue was purified by automated column chromatography (silica gel, 0-4% methanol in dichloromethane) to give the title compound (11 mg, 53.3%). ESI-MS m / z: 599.0 [M+H] + .

[0714] Example 76

[0715]

[0716] according to Method G The title compound was synthesized using 25 mg of the compound from Example 26 (as a single diastereomer), 8.0 equivalents of amine HCl salt, 8.0 equivalents of DIPEA for 4 h, followed by 10 equivalents of amine HCl salt / DIPEA and 4.0 equivalents of HATU for 2 h. The crude reaction was purified by preparative HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.2 mg, 22%). ESI-MS m / z: 653.2 [M+H] + .

[0717] Example 77

[0718]

[0719] Example 77 was prepared from the corresponding acid in step d using a procedure similar to that used to prepare Example 59. ESI-MS m / z: 636.2 [M+H] + .

[0720] Example 78

[0721]

[0722] Example 78 was prepared from the corresponding acid in step d using a procedure similar to that used to prepare Example 59. ESI-MS m / z: 638.2 [M+H]+ .

[0723] The following examples in Table 1 are manufactured using the corresponding intermediates in a manner similar to that of Example 59.

[0724] Table 1

[0725]

[0726]

[0727]

[0728] Method I

[0729]

[0730] Example 97

[0731]

[0732] Example 97, Step a (Method I)

[0733]

[0734] A solution of 3-bromo-4-hydroxybenzoate (16 g, 69.25 mmol), Cs₂CO₃ (68 g, 207.75 mmol), KI (46 g, 277.00 mmol), and bromocyclopropane (21 g, 173.12 mmol) in NMP (30 mL) was stirred in a Parr reactor at 180 °C for 16 h. The resulting solution was diluted with water and extracted with EtOAC. The combined organic compounds were dried and concentrated. The resulting solution was purified by reversed-phase C18 column chromatography (CH₃CN / H₂O) to give the desired product as a yellow solid (3 g, 22%). ESI-MS m / z: 257.05 [M+H] + (The methyl ester product was also isolated and used.)

[0735] Example 97, step b (method I)

[0736]

[0737] A solution of the compound from step a (250 mg, 0.98 mmol), Pd(dppf)Cl2 (142 mg, 0.19 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (425 mg, 1.94 mmol), H2O (0.1 mL), and Cs2CO3 (950 mg, 2.91 mmol) in dioxane (3 mL) was stirred at 90 °C under a N2 atmosphere for 2 hours. The resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H2O) to give the desired product as a white solid (180 mg, 68%). ESI-MS m / z: 270.15 [M+H] + .

[0738] Example 97, step c (method J)

[0739] Method J

[0740]

[0741] An amine (30 mg, 0.075 mmol) and an acid (19.18 mg, 0.075 mmol) were added to a 2-dallan vial equipped with a stir bar, and the material was dissolved in DMF (0.2 M). Hunig base (0.053 mL, 0.30 mmol) was added, and the vial was cooled to 0 °C. HATU (43 mg, 0.113 mmol) was added, the reaction was stirred for 10 min, heated to room temperature, and monitored by LCMS (1 h). The reaction was diluted with EtOAc and quenched with water. The aqueous solution was extracted with EtOAc and DCM / MeOH using a phase separator and concentrated. The material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound as a white solid (23.6 mg, 48%). ESI-MS m / z: 651.25 [M+H] + .

[0742] Method K

[0743]

[0744] Example 98, step a (method K)

[0745]

[0746] With Method I Step aThe following examples were prepared in a similar manner using 3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-5-(trifluoromethyl)pyridine and methyl 3-bromo-4-cyclopropoxybenzoate. The materials were purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound. ESI-MS m / z: 338.10 [M+H] + .

[0747] Example 98, step b (method K)

[0748]

[0749] The solution of the compound from step a (crude product), LiOH (300 mg, 12.52 mmol), and H₂O (1 mL) in MeOH (3 mL) was stirred at room temperature for 16 hours. The resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H₂O) to give the desired product as a white solid (228 mg). ESI-MS m / z: 256.10 [M+H] + .

[0750] Method L

[0751]

[0752] Example 99 (Method L)

[0753]

[0754] A solution of the bromide (250 mg, 0.98 mmol), 2-(tributyltinyl)pyridine (537 mg, 1.46 mmol), and Pd(PPh3)2Cl2 (68 mg, 0.09 mmol) from step a of Example 97 was stirred at 90 °C for 2 hours under a nitrogen atmosphere in DMF (3 mL). The resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H2O) to give the desired product as a white solid (90.6 mg, 37%). ESI-MS m / z: 256.15 [M+H] + .

[0755] Method M

[0756]

[0757] Example 100, steps a and b (method M)

[0758]

[0759] A solution of methyl 3-bromo-4-cyclopropoxybenzoate (300 mg, 1.11 mmol), 2-(tributyltinyl)pyrazine (615 mg, 1.66 mmol), and Pd(PPh3)2Cl2 (68 mg, 0.09 mmol) in DMF (3 mL) was stirred at 90 °C for 2 hours under N2 atmosphere. The resulting solution was purified by silica gel column chromatography (EtOAc in hexane) to give the desired product as a white solid. ESI-MS m / z: 271.00 [M+H]+.

[0760] Methyl ester with Method K Hydrolysis was performed in a similar manner, and the crude solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA, in H2O) to obtain the desired product as a white solid (100 mg, 35%). ESI-MS m / z: 257.05 [M+H] + .

[0761] Method N

[0762]

[0763] Example 101 Steps a and b (Method N)

[0764]

[0765] A solution of 3-bromo-4-cyclopropoxybenzoic acid (1 g, 3.9 mmol), bis(pinacol)diboron (2 g, 7.78 mmol), KOAc (1.2 g, 11.67 mmol), and Pd(dppf)Cl2(DCM) (635 mg, 0.78 mmol) in dioxane (6 mL) was stirred at 90 °C for 2 hours. ESI-MS m / z: 223.05 [M+H] + .

[0766] A solution of the compound from step a (2 mL), 2-bromo-6-(trifluoromethyl)pyridine (611 mg, 2.70 mmol), Cs₂CO₃ (1.3 g, 4.05 mmol), H₂O (0.1 mL), and Pd(dppf)Cl₂ (221 mg, 0.27 mmol) in dioxane (3 mL) was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The resulting solution was purified by reversed-phase C₁₈ column chromatography (MeOH / 0.1% FA in H₂O) to give the desired product as a white solid (130 mg). ESI-MS m / z: 256.10 [M+H] + .

[0767] Method O

[0768]

[0769] Example 102, Step a (Method O)

[0770]

[0771] A solution of methyl 4-hydroxy-3-methoxybenzoate (3 g, 16.47 mmol), K₂CO₃ (6.8 g, 49.57 mmol), and 1,2-dibromoethane (15.5 g, 82.34 mmol) in DMF (30 mL) was stirred at 45 °C for 2 hours. The resulting solution was quenched with water and extracted with EtOAc. The combined organic compounds were dried, concentrated, and purified by reversed-phase C₁₈ column chromatography (MeCN / H₂O) to give the desired product as a pale yellow solid (3 g, 61%).

[0772] Example 102, step b (method O)

[0773]

[0774] A solution of the compound from step a (1 g, 3.64 mmol), morpholine (0.6 g, 6.88 mmol), and K₂CO₃ (1 g, 6.95 mmol) in DMF was stirred at 50 °C for 2 h. The reaction was quenched with water and extracted with EtOAc. The combined organic compounds were dried, concentrated, and the crude product was purified by reversed-phase C18 column chromatography (MeCN / H₂O) to give the desired product (1 g, 93%). ESI-MS m / z: 296.05 [M+H] + .

[0775] Example 102, step c (method O)

[0776]

[0777] A solution of the compound from step b (1 g, 3.55 mmol) and LiOH (0.8 g, 33.76 mmol) in MeOH:H₂O (2:1, 60 mL) was stirred at room temperature for 2 hours. The pH of the resulting solution was adjusted to pH 6 with HCl (aqueous solution) and extracted with EtOAc. The combined organic compounds were dried, concentrated, and the crude product was purified by reversed-phase C18 column chromatography (MeCN / H₂O, 1% FA) to give the desired product as a white solid (1 g, 99%). ESI-MS m / z: 282.05 [M+H] + .

[0778] With Method JThe following examples in Table 2 were prepared in a similar manner using the corresponding acid intermediates, and the compounds were purified by preparative HPLC. The corresponding acid precursors were synthesized by the methods previously described (Method I, Method KO).

[0779] Table 2

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787] Example 196

[0788]

[0789] Example 196, Step a

[0790]

[0791] 4-Bromo-3-cyclopropoxybenzoate (1 g, 3.69 mmol), tributyl(1-ethoxy-vinyl)stanane (1.6 g, 4.426 mmol), Pd(dppf)Cl2(DCM) (0.6 g, 0.74 mmol), and DMF (15 mL) were added to a 40-mL vial at room temperature. The resulting mixture was stirred at 110 °C for 2 hours under nitrogen atmosphere and monitored by LC-MS. The reaction was quenched with water, and the aqueous layer was extracted with DCM. The resulting mixture was concentrated and purified by automated column chromatography (0-25% EtOAc / hexane) to give the desired compound (450 mg, 47%). ESI-MS m / z: 263.12 [M+H] + .

[0792] Example 196, step b

[0793]

[0794] Add the compound from step a (450 mg, 1.91 mmol), NBS (373 mg, 2.1 mmol), THF (10 mL), and H₂O (3 mL) to a 100 mL round-bottom flask at room temperature. Stir the resulting mixture at room temperature under nitrogen atmosphere for 1 h, monitoring the reaction by LC-MS. Concentrate the mixture under reduced pressure. Purify the residue by reversed-phase rapid chromatography (C18 silica gel; 10-70%, 25 min. MeCN / H₂O) to give the title compound (500 mg, 91%). ESI-MS m / z: 313.10 [M+H] + .

[0795] Example 196, steps c and d

[0796]

[0797] The compound from step b (250 mg, 0.8 mmol), acetamide (236 mg, 4 mmol), and AcOH (5 mL) were added to a 20 mL vial at room temperature. The resulting mixture was stirred at 120 °C for 16 hours. The mixture was concentrated under vacuum and purified by reversed-phase chromatography (C18 silica gel; 10-70%, 25 min. MeCN / H2O) to give the title compound (45 mg, 20%). ESI-MS m / z: 274.10 [M+H] + .

[0798] Methyl ester with Method O Hydrolysis was performed in a similar manner, and the material was purified by reversed-phase chromatography (C18 silica gel; 10-70%, 25 min. MeCN / H2O) to give the title compound (45 mg, 99%). ESI-MS m / z: 260.08 [M+H] + .

[0799] Example 196, step e

[0800]

[0801] With Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (11 mg, 23%). ESI-MS m / z: 641.10 [M+H] + .

[0802] Example 197

[0803]

[0804] The title compound was prepared with an amine (30 mg, 0.075 mmol) in a manner similar to that described in Example 196 above, and the material was purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (30.6 mg, 65%). ESI-MS m / z: 615.18 [M+H] + .

[0805] Example 198

[0806]

[0807] Example 198 Steps a and b

[0808]

[0809] A solution of bromide (187 mg, 0.60 mmol), HCONH2 (158 mg, 3.5 mmol), and formic acid (5 mL) from step b of Example 196 was stirred at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and subjected to reversed-phase chromatography (C18 silica gel; 10-70%, 25 min. MeCN / H2O) to give the title compound (60 mg, 33%). ESI-MS m / z: 260.08 [M+H] + .

[0810] Example 198, step c

[0811]

[0812] With Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (36.7 mg, 74%). ESI-MS m / z: 627.25 [M+H] + .

[0813] Example 199

[0814]

[0815] The title compound was prepared with an amine (30 mg, 0.075 mmol) in a similar sequence to that in Example 198 above, and the material was purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (27.2 mg, 60%). ESI-MS m / z: 601.16 [M+H] + .

[0816] Example 200

[0817]

[0818] Example 200, Step a

[0819]

[0820] A solution of methyl 4-bromo-3-methoxybenzoate (4 g, 16.32 mmol), Pd(OAc)₂ (733 mg, 3.26 mmol), and dppp (1.3 g, 3.26 mmol) in DMF:H₂O:TEA (4:4:1, 20 mL) was stirred at 100 °C for 6 hours under a CO atmosphere. The resulting solution was extracted with EtOAc, and the organic layer was dried and concentrated. The crude material was purified by reversed-phase C18 column chromatography (MeCN / H₂O) to give the desired product (1.8 g, 52%). ESI-MS m / z: 211.10 [M+H] + .

[0821] Example 200, steps b and c

[0822]

[0823] A solution of the compound from step a (1.7 g, 8.08 mmol), HATU (4.6 g, 12.12 mmol), DIPEA (2 g, 16.17 mmol), and Boc-hydrazine (1.4 g, 12.12 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water, extracted with EtOAc, and the combined organic matter was dried and concentrated. The crude material was purified by reversed-phase C18 column chromatography (MeCN / H2O) to give the desired product (2.1 g, 80%). ESI-MS m / z 269.10 [M+H-56] + .

[0824] A solution of the compound from step b (2 g, 6.17 mmol) in HCl (30 mL) in 1,4-dioxane was stirred at room temperature for 0.5 h. The resulting solution was concentrated and purified by reversed-phase C18 column chromatography (MeCN / H2O) to give the desired product (1 g, 73%) as a yellow solid. ESI-MS m / z: 225.05 [M+H] + .

[0825] Example 200, steps d and e

[0826]

[0827] A solution of the compound from step c (250 mg, 1.11 mmol) and CH(OEt)3 (355 mg, 3.34 mmol) in xylene (10 mL) was stirred at 100 °C for 3 h. The reaction was quenched with water, extracted with EtOAc, and the combined organic matter was dried and concentrated. The crude material was purified by reversed-phase C18 column chromatography (MeCN / H2O) to give the desired product (130 mg, 49%) as a white solid. ESI-MS m / z: 235.10 [M+H] + .

[0828] With Method O The methyl ester was hydrolyzed in a similar manner, and the resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H2O) to give the desired product (56 mg, 46%). ESI-MS m / z: 221.00 [M+H] + .

[0829] Example 200 Step f

[0830]

[0831] With Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (36.5 mg, 74%). ESI-MS m / z: 602.05 [M+H] + .

[0832] Example 201

[0833]

[0834] Example 201, Step a

[0835]

[0836] A solution of step b (above) of Example 200 (300 mg, 1.34 mmol) and formic acid (924 mg, 20.07 mmol) in toluene (5 mL) was stirred at 120 °C for 4 hours. The reaction was quenched with water, extracted with EtOAc, and the combined organic matter was dried and concentrated. The crude material was purified by silica gel column chromatography to give the desired product (100 mg, 30%). ESI-MS m / z: 253.10 [M+H] + .

[0837] Example 201, steps b and c

[0838]

[0839] A solution of the compound from step a (80 mg, 0.32 mmol) and Lawrence's reagent (385 mg, 0.95 mmol) in toluene (5 mL) was stirred at 90 °C for 30 min. The reaction was quenched with water, extracted with EtOAc, and the combined organic matter was dried and concentrated. The crude material was purified by silica gel column chromatography to give the desired product (60 mg, 76%). ESI-MS m / z: 251.10 [M+H] + .

[0840] With Method O The methyl ester was hydrolyzed in a similar manner, and the resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H2O) to give the desired product (60 mg, 99%). ESI-MS m / z: 236.95 [M+H] + .

[0841] Example 201, step d

[0842]

[0843] With Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (24.9 mg, 53%). ESI-MS m / z: 618.05 [M+H] + .

[0844] Example 202

[0845]

[0846] Example 202 Step a

[0847]

[0848] LDA was added to acetone (691 mg, 11.89 mmol) in THF (10 mL) at -78 °C. The resulting solution was stirred at -78 °C for 0.5 h. A solution of 2-methoxy-4-(methoxycarbonyl)benzoic acid (500 mg, 2.38 mmol) and (1-chloro-2-methylprop-1-en-1-yl)dimethylamine (1.6 g, 12.03 mmol) in DCM (10 mL) was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under vacuum. The LDA reaction mixture was added and stirred at room temperature for 30 min. The reaction was quenched with water, extracted with EtOAc, and the combined organic matter was dried and concentrated. The resulting solution was purified by reversed-phase C18 column chromatography (MeCN / H2O) to give the desired product (80 mg, 13%). ESI-MS m / z 251.15 [M+H] + .

[0849] Example 202, steps b and c

[0850]

[0851] A solution of the compound from step a (70 mg, 0.28 mmol) and NH₂OH·HCl (97 mg, 1.40 mmol) in EtOH:H₂O (1:1, 30 mL) was stirred at 80 °C for 2 hours. The reaction was quenched with water, extracted with EtOAc, and the combined organic matter was dried and concentrated. The material was purified by silica gel column chromatography (EtOAc:hexane) to give the desired product (60 mg, 76%). ESI-MS m / z 248.10 [M+H] + .

[0852] With Method O The methyl ester was hydrolyzed in a similar manner, and the resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H2O) to give the desired product (60 mg) as a white solid. ESI-MS m / z: 234.10 [M+H] + .

[0853] Example 202, step d

[0854]

[0855] With Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (30.8 mg, 67%). ESI-MS m / z: 615.15 [M+H] + .

[0856] Example 203

[0857]

[0858] Example 203 Step a

[0859]

[0860] In a vial, methyl (R)-3-bromo-4-(2-hydroxypropoxy)benzoate (100 mg, 0.346 mmol), PdCl2 (dppf) (25.3 mg, 0.035 mmol), K2CO3 (120 mg, 0.865 mmol), and pyrimidin-5-ylboronic acid (64.3 mg, 0.519 mmol) were dissolved in dioxane (1.383 mL) and water (0.346 mL). The reaction was heated to 85 °C overnight. The reaction was cooled to room temperature and water was added. The aqueous layer was washed with EtOAc, and the combined organic layers were dried over MgSO4. The crude reaction was purified by silica gel chromatography (0-100% EtOAc / hexane) to give the title compound (54 mg, 54%). ESI-MS m / z: 289.10 [M+H] + .

[0861] Example 203 Step b

[0862]

[0863] In a vial, methyl(R)-4-(2-hydroxypropoxy)-3-(pyrimidin-5-yl)benzoate (54 mg, 0.187 mmol) and lithium hydroxide (22.43 mg, 0.937 mmol) were dissolved in THF (0.3 mL), MeOH (0.3 mL), and water (0.3 mL). The reaction was stirred overnight. Water was added, and 1 M HCl aqueous solution was added to adjust the pH to 2–3. The white precipitate was filtered and dried under vacuum to give (R)-4-(2-hydroxypropoxy)-3-(pyrimidin-5-yl)benzoic acid (38 mg, 74%) as a white solid. ESI-MS m / z: 275.02 [M+H] +

[0864] Example 203 Step c

[0865]

[0866] With Method JThe title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (35 mg, 66%). ESI-MS m / z: 656.24 [M+H] + .

[0867] Example 204

[0868]

[0869] Using the above embodiment 203 and Method J The title compound was prepared in a similar manner using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (1.2 mg, 3%). ESI-MS m / z: 655.18 [M+H] + .

[0870] Example 205

[0871]

[0872] Example 205, step a

[0873]

[0874] Add 3.80 g (10.27 mmol) of step b in Example 1 and 100 mL of acetone to a 100 mL round-bottom flask. Cool the solution to 0 °C, and then add Jones' reagent (1.9–2.2 M, 10 mL) dropwise (internal temperature monitoring). Heat the reaction to room temperature and monitor by LCMS (3 hours). Cool the reaction to 0 °C and use… i The reaction mixture was quenched with PrOH and stirred for 15 minutes. The reaction solution was diluted with EtOAc and water. The aqueous solution was extracted, and the combined organic matter was dried and concentrated under reduced pressure to give a crude product as a yellow solid (3.95 g, 99%). ESI-MS m / z: 383.80 [M+H] + .

[0875] Example 205, step b

[0876]

[0877] Add the compound from step a (3.95 g, 10.28 mmol), NH4Cl (1.10 g, 20.57 mmol), and the solid dissolved in DMF (20 mL) to a 100 mL round-bottom flask. Add Hunig base (5.27 mL, 30.84 mmol), cool the reaction to 0 °C, and add HATU (7.82 g, 20.56 mmol). Heat the reaction to room temperature and monitor by LCMS (1 h). Dilute the reaction with EtOAc and water. Extract the aqueous solution, dry the combined organic matter, and concentrate. Purify the material by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound (3 g, 76%). ESI-MS m / z: 382.95 [M+H] + .

[0878] Example 205, step c

[0879]

[0880] Add the compound from step b (3.00 g, 7.83 mmol), 3,3,3-trifluoroprop-1-en-2-ylboronic acid (2.19 g, 15.65 mmol), and Pd(dppf)Cl2 (1.15 g, 1.56 mmol) to a 100 mL round-bottom flask, and dissolve the material in dioxane (40 mL) and H2O (5 mL). Then add K2CO3 (3.25 g, 23.50 mmol) and stir the resulting mixture at 90 °C for 1 h under a nitrogen atmosphere. Cool the mixture to room temperature, pour it into water, extract with EtOAc, and concentrate the combined organic matter under reduced pressure. Purify the residue by column chromatography (silica gel, 0-100% EtOAc in hexane) to give the desired product as a brown oil (2.3 g, 83%). ESI-MS m / z: 350.90 [M+H] + .

[0881] Example 205, step d

[0882]

[0883] To the stirred solution of step c (5.00 g, 14.24 mmol) and 3-chloro-4-fluorophenylboronic acid (3.72 g, 21.33 mmol) in THF (80 mL), Na₂CO₃ (3.32 g, 31.33 mmol), H₂O (20 mL), and Pd(PPh₃)₂Cl₂ (1.00 g, 1.42 mmol) were added. The resulting mixture was stirred at 70 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by TLC and LCMS. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried, and concentrated under reduced pressure. The residue was purified by automated column chromatography (silica gel, 0-75% EtOAc in hexane) to give the title compound as a yellow solid (5.8 g, 99%). ESI-MS m / z: 401.05 [M+H] + .

[0884] Example 205 Step e

[0885]

[0886] Add AD-mix-β (33.82 g, 43.41 mmol) and methanesulfonamide (1.38 g, 14.47 mmol) to a 500 mL round-bottom flask equipped with a stir bar. Dissolve the solid in tBuOH (60 mL) and H₂O (100 mL), and cool the flask to 0 °C. Slowly add the compound from step d (5.80 g, 14.47 mmol) as a solution of tBuOH (40 mL). Allow the reaction to warm naturally to room temperature and stir for 16 hours. Quench the reaction by adding sodium sulfite (0.25 g / g AD-mix), and dilute with water and EtOAc. Separate the layers, and extract the aqueous layer with EtOAc. Wash the combined organic matter with brine, dry to Na₂SO₄, filter, concentrate, and purify by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound as a white solid (5.48 g, 87%). ESI-MS m / z: 435. [M+H] + .

[0887] Example 205 Step f

[0888]

[0889] The compound from step e (4.70 g, 10.81 mmol) and DCM (80 mL) were added to a 250 mL round-bottom flask at room temperature. The solution was cooled to 0 °C, and then DMAP (264 mg, 2.16 mmol), TEA (3.28 g, 32.43 mmol), and TsCl (2.47 g, 12.97 mmol) were added sequentially. The resulting mixture was stirred at 0 °C for 1 h. The mixture was acidified to pH 4 with 2 M HCl, and the aqueous solution was extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a crude product as a pale yellow solid (6.2 g, 97%). ESI-MS m / z: 589.15 [M+H] + .

[0890] Example 205 Step g

[0891]

[0892] NH3 in MeOH (35 mL) was added to a 100 mL round-bottom flask at room temperature, and the compound from step g (6.20 g, 10.52 mmol) was slowly added. The resulting mixture was stirred at room temperature and monitored by LCMS (5 h). The mixture was dissolved in EtOAc, washed three times with saturated sodium bicarbonate, washed with brine, dried, and concentrated to give the title compound (2.93 g, 64%). ESI-MS m / z: 434.05 [M+H] + .

[0893] Example 206

[0894]

[0895] Example 206 Step a

[0896]

[0897] A stir bar, N-methoxy-N-methylacetamide (1.43 mL, 13.4 mmol), and THF (45 mL) were added to a 100 mL round-bottom flask containing a compound derived from (R)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-2,3-dihydrofurano[2,3-c]pyridine. The flask was purged with nitrogen, cooled to -40 °C, and ethyl trifluoroacetate (2.317 mL, 19.40 mmol) was added. Then, magnesium isopropyl chloride (5.16 mL, 10.3 mmol) was slowly added, and the reaction was monitored by LCMS (stirring between -40 and -20 °C for 3 h). The reaction was quenched with 5 mL of MeOH and the temperature was raised to room temperature. The mixture was diluted with water and EtOAc, the phases were separated, and the aqueous layer was washed with EtOAc. The combined organic matter was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by automated silica gel chromatography (0-5% EtOAc / hexane) to give the title compound as a clear, viscous residue (3.00 g, 84%). ESI-MS m / z: 400.1 / 402.0 [M+H] + .

[0898] Example 206 Step b

[0899]

[0900] THF (42 mL) was added to a 250 mL round-bottom flask containing methyltriphenylphosphonium bromide (5.34 g, 15.0 mmol). The mixture was cooled to 0 °C, and potassium tert-butoxide (1.60 g, 14.2 mmol) was slowly added as a solution in THF (14 mL). The yellow suspension was stirred at 0 °C for 30 min, and then step a (4.327 g, 8.94 mmol) as a solution in THF (33 mL) was added. The reaction was allowed to rise to room temperature and monitored by LCMS until completion (6.5 h). The reaction was then quenched with 5 mL of MeOH and allowed to rise to room temperature. The mixture was diluted with water and EtOAc, the phases were separated, and the aqueous layer was washed with EtOAc. The combined organic matter was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by automated silica gel chromatography (0–5% EtOAc / hexane) to give the title compound as a clear, viscous residue (2.88 g, 94%). ESI-MS m / z: 398.2 / 400.1 [M+H] + .

[0901] Example 206 Step c

[0902]

[0903] The title compound was synthesized using 1.2 equivalents of (4-fluorophenyl)boric acid and the compound from step b (2.13 g 5.36 mmol) according to the procedure in step d of Example 205. The residue was purified by automated silica gel chromatography (0-5% EtOAc / hexane) to give the title compound as a colorless oil. (2.19 g, 99%) ESI-MS m / z: 414.8 [M+H] + .

[0904] Example 206, step d

[0905]

[0906] A suspension of AD-mix-β (8.26 g, 10.6 mmol) and methanesulfonamide (0.504 g, 5.30 mmol) in water (26.5 mL) and tBuOH (2 mL) was cooled to 0 °C, and then the compound from step c (2.19 g, 5.30 mmol) was added as a solution in tBuOH (24.5 mL). The reaction was heated to room temperature and stirred for 16 h, and then quenched by adding sodium sulfite (2.00 g, 15.9 mmol), and diluted with water and EtOAc. The layers were separated, and the aqueous layer was washed with EtOAc. The combined organic matter was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by automated silica gel chromatography to give the title compound (2.19 g, 89%) as a viscous colorless oil. ESI-MS m / z: 448.7 [M+H] + .

[0907] Example 206 Step e

[0908]

[0909] Triethylamine (2.1 mL, 15 mmol) and DMAP (627 mg, 5.13 mmol) were added to a solution of the compound from step d (2.30 g, 5.13 mmol). The mixture was cooled in an ice bath, and then TsCl (1.1 equivalents) was slowly added as a solid. The reaction was monitored by LCMS until completion (2 h). The reaction mixture was then concentrated and purified by automated silica gel chromatography (0–15% EtoAc / hexane) to give the title compound (2.97 g, 97%) as a white solid. ESI-MS m / z: 602.6 [M+H] + .

[0910] Example 206 Step f

[0911]

[0912] Ammonia (116 mL, 7 M, 812 mmol) in MeOH was added to a 250 mL flask equipped with a stir bar, along with the compound from step e (4.16 g, 6.92 mmol) as a solution in MeOH (10 mL). The reaction was monitored by LCMS until completion (62 h), and then concentrated, placed under vacuum for 1 h, and used directly for the next step. ESI-MS m / z: 447.6 [M+H] +

[0913] Example 206 Step g

[0914]

[0915] The title compound was synthesized using the compound from step f (3.09 g, 6.92 mmol) and 1.1 equivalents of Boc-anhydride according to the procedure in step a of Example 32. The reaction mixture was purified by automated silica gel chromatography (0–15% EtOAc / hexane) to give the title compound (3.39 g, 90% in both steps) as a yellow oil. ESI-MS m / z: 547.7 [M+H] + .

[0916] Example 206 Step h

[0917]

[0918] according to Method A The title compound was prepared using the compound from step g (3.39 g, 6.20 mmol) and 2.0 equivalents of TBAF. After aqueous post-treatment, the mixture was purified by automated silica gel chromatography (0–100% EtOAc / hexane) to give the title compound as a white solid as a single diastereomer (2.19 g, 82% peak 1 = P1, 192 mg, 7% peak 2 = P2). Product 2 was produced by imperfect selectivity in step d, but was not obvious or separated prior to this step. ESI-MS m / z: 433.5 [M+H] + =P1, ESI-MS m / z: 433.5[M+H] + =P2.

[0919] Example 206 Step i

[0920]

[0921] Potassium permanganate (281 mg, 0.778 mmol) was added dropwise to a suspension of P1 (220 mg, 0.508 mmol) from step h in an aqueous sodium hydroxide solution (1.2 mL, 5 wt%, 1.5 mmol), as a solution in water (5.6 mL). The reaction was monitored by LCMS until completion (42 h), and then cooled to 0 °C and quenched by dropwise addition of sodium sulfite (640 mg, 5.08 mmol) as a solution in water (6.4 mL). The mixture was then acidified to pH 1–3 by adding 1 M HCl. The solid was collected on glass frit and washed thoroughly with water to give the title compound (137 mg, 60%) as a white solid. ESI-MS m / z: 447.3 [M+H] + .

[0922] Example 206 Step j

[0923]

[0924] The title compound was synthesized according to step b of Example 205 using 137 mg of the compound from step i and 10 equivalents of NH4Cl. The compound was purified by automated silica gel chromatography (0-100% EtOAc / hexane) to give the title compound (86 mg, 63%) as a white solid. ESI-MS m / z: 446.4 [M+H] + 。

[0925] Example 206 Step k

[0926]

[0927] The suspension of the compound from step j (259 mg, 0.580 mmol) in DCM (7.3 mL) was cooled to 0 °C and HCl (1.5 mL, 4 N, 5.8 mmol) in water was added. The reaction was monitored by TLC and LCMS until completion (2 h), at which point diethyl ether (20 mL) was added, and the mixture was stirred for 1 h as a white solid precipitated. The solid was collected by filtration to give the title compound (184 mg, 83%) as a white solid. ESI-MS m / z: 346.3 [M+H] + .

[0928] Example 207

[0929]

[0930] This intermediate is used to synthesize a variety of analogs in a sequence similar to that of Examples 205 and 206.

[0931] This example was prepared in a similar sequence to Example 206, but using N-methoxy-N-methylcyclopropaneformamide. The residue was purified by silica gel column chromatography (10% EtOAc / hexane) to give the desired product as a yellow-green oil. ESI-MS m / z: 424.10 [M+H] + .

[0932] Example 208 Step a

[0933]

[0934] A solution of methyl 3-hydroxy-4-methoxybenzoate (20 g, 0.11 mol), vinyl acetate (19 g, 0.22 mol), [Ir(cod)Cl]₂ (62.4 mg, 0.11 mol), and NaHCO₃ (18.44 g, 0.22 mol) in toluene (500 mL) was stirred at 110 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (20% EtOAc in hexane, 30 min) to the desired compound as a yellow oil (10.4 g, 45%). ESI-MS m / z: 209.10 [M+H] + .

[0935] Example 208 Steps b and c

[0936]

[0937] CH₂I₂ (25.65 g, 95.69 mmol) and Et₂Zn (1 M, 96 mL, 96 mmol) were added fractionally to a stirred solution of compound a (10.4 g, 47.84 mmol) in a DCE (200 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding water-based DCM, and the combined organic matter was washed with brine, dried, and concentrated. The crude material was purified by reversed-phase C18 column chromatography (MeCN / H₂O) to give the desired compound as a yellow solid (7.8 g, 70%). ESI-MS m / z: 223.10 [M+H] + .

[0938] Under a nitrogen atmosphere at 0°C, BBr3 (22 g, 88 mmol) was added in portions to a stirred solution of the compound from step b (7.8 g, 35.13 mmol) in DCM (100 mL). The resulting mixture was stirred at 0°C for 3 h and the reaction was quenched by adding NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM, and the combined organic matter was washed with brine, dried, and concentrated. The crude material was purified by reversed-phase C18 column chromatography (MeCN / H2O) to give the desired compound as a yellow solid (4.6 g, 67%). ESI-MS m / z: 195.05 [M+H] + .

[0939] Example 208 Step d

[0940]

[0941] A solution of the compound from step c (4.6 g, 23.59 mmol) in MeOH (40 mL) and H₂O (3 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (20% EtOAc in hexane, 30 min) to give the desired compound as a yellow oil (4.7 g, 95.91%). ESI-MS m / z: 209.10 [M+H] + .

[0942] Example 208 Steps e and f

[0943]

[0944] K₂CO₃ (5.4 g, 40 mmol) was added to a stirred solution of methyl 3-cyclopropoxy-4-hydroxybenzoate (4.0 g, 20 mmol) and (+)-propylene oxide (3.43 g, 60 mmol) in DMF (50 mL), and the resulting mixture was stirred at 80 °C for 16 h. The reaction was quenched with water at 0 °C, and the resulting mixture was extracted with EtOAc. The combined organic compounds were washed with brine, dried, and concentrated. The crude material was purified by silica gel column chromatography (0-75% EtOAc in hexane) to give the product (3 g, 58%). ESI-MS m / z: 262.10 [M+H] + .

[0945] Methyl ester with Method O Hydrolysis was performed in a similar manner, and the material was purified by reversed-phase preparative HPLC (MeCN / H2O) to obtain the desired compound as a yellow solid (1.95 g, 68%). ESI-MS m / z: 253.10 [M+H] + .

[0946] Example 209

[0947]

[0948] A solution of 8-chloroquinoline-6-carboxylic acid (5 g, 29.14 mmol) and acrolein (3.27 g, 58.28 mmol) in AcOH:HCl (2:3, 20 mL) was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The resulting solution was concentrated, and the crude material was purified by reversed-phase C18 column chromatography (MeCN / H2O) to give the desired product (1.088 g, 18%) as a white solid. ESI-MS m / z: 208.20 [M+H] + .

[0949] Example 210

[0950]

[0951] A solution of 4-amino-3-hydroxybenzoic acid (600 mg, 3.91 mmol) and crotonaldehyde (824 mg, 11.75 mmol) in AcOH:HCl (2:3, 10 mL) was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The resulting solution was concentrated, and the crude material was purified by reversed-phase C18 column chromatography (MeCN / H2O) to obtain the desired product (600 mg, 75%). ESI-MS m / z: 203.95 [M+H] + .

[0952] Example 211

[0953] Method P

[0954]

[0955] But-3-en-2-one (4.88 mL, 60.5 mmol) was added to a suspension of 4-amino-3-hydroxybenzoic acid (4.6348 g, 30.3 mmol) in concentrated hydrochloric acid aqueous solution (50.4 mL). The reaction mixture was stirred at 100 °C for 4 h. The mixture was cooled to room temperature and the solid was collected by filtration to give the desired product, 8-hydroxy-4-methylquinoline-6-carboxylic acid (5.62 g, 91%), as a yellow solid. ESI-MS m / z: 203.9 [M+H] + .

[0956] Example 212

[0957]

[0958] according to Method PThe title compound was synthesized using 493 mg of 4-amino-3-hydroxybenzoic acid and 533 μl of methacrolein. The solid was collected by filtration to give the title compound (195 mg, 30%) as a yellow solid. ESI-MS m / z: 203.9 [M+H] + .

[0959] Example 213

[0960]

[0961] according to Method P The title compound was synthesized using 5.00 g of 4-amino-3-methoxybenzoic acid and 5.0 mL of methacrolein. The aqueous layer was washed with EtOAc (4 x 20 mL), and the solid subsequently precipitated in the aqueous layer. This was collected by filtration to give the title compound (1.23 g, 19%) as a yellow solid. ESI-MS m / z: 218.0 [M+H] + .

[0962] Example 214

[0963]

[0964] according to Method P The title compound was synthesized using 2.00 g of 4-amino-3-hydroxybenzoic acid and 1.82 g of 2-methylenebutyraldehyde. The aqueous layer was washed with EtOAc (4 x 5 mL), and the solid subsequently precipitated in the aqueous layer. This was collected by filtration to give the title compound (70 mg, 3%) as a yellow solid. ESI-MS m / z: 218.1 [M+H] + .

[0965] Example 215

[0966]

[0967] according to Method P The title compound was synthesized using 2.98 g of 4-amino-3-methoxybenzoic acid and 3.00 g of 2-methylenebutyral. The aqueous layer was washed with EtOAc (4 x 5 mL), and the solid subsequently precipitated in the aqueous layer. This was collected by filtration to give the title compound (811 mg, 20%) as a yellow solid. ESI-MS m / z: 232.1 [M+H] + .

[0968] Example 216 Step a

[0969]

[0970] Cs₂CO₃ (13.89 g, 42.6 mmol) and cyclopropanol (2.7 mL, 42.6 mmol) were added to a solution of methyl 3-fluoro-4-nitrobenzene (5.66 g, 28.4 mmol) in DMF (56 mL). The mixture was heated to 75 °C for 16 h, then cooled to room temperature, diluted with H₂O (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with water (2 × 5 mL) followed by saturated NaCl aqueous solution (5 mL) and dried over Na₂SO₄. The crude material was directly advanced to the next step. ESI-MS m / z: 237.7 [M+H] + .

[0971] Example 216 Steps b and c

[0972]

[0973] Iron (7.93 g, 142 mmol) and ammonium chloride (15.19 g, 284 mmol) were added to a solution of the compound from step a (6.74 g, 28.4 mmol) in EtOH (151 mL) and water (37.9 mL). The mixture was heated to 75 °C for 1 h, then cooled to room temperature and filtered through diatomaceous earth. The pH of the filtrate was adjusted to 9–11 using NaHCO3 and then diluted with EtOAc. The phases were separated, and the aqueous layer was washed with EtOAc (4 x 50 mL). The combined organic matter was washed with a saturated aqueous solution of NaCl (20 mL), dried over Na2SO4, filtered, concentrated, and purified by automated silica gel chromatography (0–20% EtOAc / hexane) to give the title compound as a yellow oil (4.25 g, 72.2% yield in two steps). ESI-MS m / z: 208.0 [M+H] + .

[0974] Add potassium trimethylsilanolide (3.96 g, 28.6 mmol) to a solution of the compound from step b (6.74 g, 28.4 mmol) in THF (15 mL). Quench the mixture with MeOH, then concentrate and use directly for the next step. ESI-MS m / z: 193.9 [M+H] + .

[0975] Example 216, step d

[0976]

[0977] pass Method PThis example was prepared using the compound from step c and methacrolein. After the reaction was complete, the aqueous layer was washed with EtOAc (3 x 15 mL), then concentrated to dryness. The resulting solid was washed with MeOH (3 mL) and collected to give the desired product as a yellow solid (160 mg, 14% in two steps). ESI-MS m / z: 244.0 [M+H] + .

[0978] Example 217 Steps a and b

[0979] Method R

[0980]

[0981] Methyl 8-hydroxyquinoline-6-carboxylate (500 mg, 2.461 mmol), 2-bromoacetamide (509 mg, 3.69 mmol), and potassium carbonate (850 mg, 6.15 mmol) were added to a 50 mL round-bottom flask equipped with a stir bar. The solid was dissolved in DMF (0.5 M), and the reaction was stirred at 40 °C and monitored by LCMS (3 h). The reaction was cooled to room temperature, diluted with EtOAc, and quenched with water. The solid was allowed to precipitate (quinoline products have solubility issues). DCM and hexane were added for further precipitation. The mixture was stirred vigorously. The mixture was filtered and washed several times with DCM to give the title compound as a light brown solid (620 mg, 97%). ESI-MS m / z: 244.0 [M+H] + .

[0982] Add a stir bar to a 20-mL vial containing step a (400 mg, 1.537 mmol). Dissolve the compound in THF and MeOH and water (1:2:1, 0.33 M). Then add lithium hydroxide hydrate (129 mg, 3.07 mmol), stir the reaction at room temperature and monitor by LCMS (30 min; if too much LiOH is present, acetamide will hydrolyze). Cool the reaction to 0 °C, acidify with 2 M HCl, and adjust the pH to approximately 4-5. Concentrate the organic compound and aqueous solution (the product is water-soluble). Place under high vacuum. Suspend the solid in minimal MeOH (white solid precipitate) and filter to remove LiCl salt. Wash the solid with minimal MeOH and dry under high vacuum overnight to give the title compound as a light brown / pink solid (240 mg, 63%). ESI-MS m / z: 246.994 [M+H] + .

[0983] Example 218

[0984]

[0985] Method 1:

[0986] Example 218, Method 1, Step a

[0987]

[0988] Vinyl ethers were synthesized using methyl 8-hydroxyquinoline-6-carboxylate (5 g, 24.6 mmol) in a manner similar to step a of Example 208. The material was purified by automated column chromatography to give the title compound (1.97 g, 35%). ESI-MS m / z: 230.10 [M+H] + .

[0989] Example 218 Method 1 Steps b and c

[0990]

[0991] Cyclopropanization was performed according to step b of Example 208 using step a. The material was purified by automated column chromatography to give the title compound (1.67 g, 80%). ESI-MS m / z: 243.08 [M+H] + .

[0992] Methyl ester with Method O Hydrolysis was performed in a similar manner, and the material was purified by reversed-phase preparative HPLC (MeCN / H2O) to obtain the desired compound as a white solid (1.50 g, 95%). ESI-MS m / z: 230.05 [M+H] + .

[0993] Method 2:

[0994] Example 218 Method 2 Steps a, b, c

[0995]

[0996] The cyclization precursor was synthesized in a manner similar to steps a, b, and c of Example 216 above. ESI-MS m / z: 194.0 [M+H] + .

[0997] Example 218 Method 2 Step d

[0998]

[0999] according to Method P The following examples were prepared using acrolein (1.5 equivalents) and step c to obtain the title compound as a light brown solid (5.2 g, 74%). ESI-MS m / z: 208.0 [M+H] + .

[1000] Method 3

[1001] Example 218, Method 3, Step a

[1002]

[1003] 6-Bromoquinoline-8-ol (10 g, 44.64 mmol) was added to a 250-mL vessel equipped with a stir bar. The solid was dissolved in NMP (100 mL), followed by the addition of bromocyclopropane (10.8 g, 89.28 mmol), Cs₂CO₃ (43.52 g, 133.92 mmol), and KI (29.64 g, 178.56 mmol). The vessel was sealed and stirred at 180 °C for 16 hours. The resulting mixture was diluted with water and extracted with EtOAc. The residue was purified by silica gel column chromatography (0–20% EtOAc / hexane) to give the desired product as a yellow oil (4.5 g, 38%). ESI-MS m / z: 263.90 [M+H] + .

[1004] Example 218 Method 3 Step b

[1005]

[1006] TEA (5.17 g, 51.11 mmol) and Pd(dppf)Cl2 (1.25 g, 1.70 mmol) were added to the stirred solution of step a (4.50 g, 17.03 mmol) in MeOH (50 mL). The resulting mixture was stirred at 100 °C for 4 hours under a CO atmosphere (10 atm). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc / hexane) to give the title compound (2.9 g, 70%) as a pale yellow solid. ESI-MS m / z: 244.05 [M+H] + .

[1007] Example 218 Method 3 Step c

[1008]

[1009] Methyl ester with Method O Hydrolysis was performed in a similar manner, and the material was purified by reversed-phase rapid chromatography (MeCN / H2O) to obtain the desired compound as a white solid (1.30 g, 48%). ESI-MS m / z: 230.15 [M+H] + .

[1010] Method 4

[1011] Example 218, Method 4, Step a

[1012]

[1013] according to Method P The following examples were prepared using acrolein (2.0 equivalents) to obtain the title compound as a yellow solid (9.0 g, 36%). ESI-MS m / z: 208.0 [M+H] + .

[1014] Example 218 Method 4 Step b

[1015]

[1016] The solution of step a (9.00 g, 47.57 mmol) in 98% H₂SO₄ (8 mL) and MeOH (100 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude material was diluted with EtOAc, washed with water and saturated NaHCO₃, and concentrated to give the title compound (8.9 g, 91%) as a yellow solid. ESI-MS m / z: 204.05 [M+H] + .

[1017] Example 218 Method 4 Steps c and d

[1018]

[1019] The alkylation of bromocyclopropane was carried out using step b in a manner similar to step a of method 3 in Example 218. The methyl ester was hydrolyzed in a manner similar to step c of method 3 in Example 218.

[1020] The following examples in Table 3 were prepared using the corresponding intermediates or derivatives from Examples 205-207. Method J The target compound was prepared using amines or amine HCl salts with PyBOP (and in some cases HATU). In most cases, the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). Aromatic acid coupling partners were prepared according to Examples 208-218, and unless otherwise specified, they were synthesized in a similar manner.

[1021] Table 3

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028] Table 4 below contains information based on... Method J Examples of preparations using commercially available arylic acid coupling couplers (PyBOP or HATU). Most compounds were purified by preparative HPLC using Gilson chromatography, and some were purified by automated column chromatography (silica gel).

[1029] Table 4

[1030]

[1031]

[1032]

[1033]

[1034] Method S

[1035]

[1036] Example 335, step a (method S)

[1037]

[1038] A suspension of methyl 8-hydroxyquinoline-6-carboxylate (3.00 g, 14.76 mmol) and Hunig base (5.16 mL, 29.5 mmol) in DCM (59.1 mL) was cooled to 0 °C and treated with trifluoromethanesulfonic anhydride (2.74 mL, 16.24 mmol). The suspension immediately became homogenized and was heated to room temperature and monitored by LC-MS. The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated. Purification by silica gel rapid column chromatography (0–100% EtOAc / hexane) gave the title compound (3.85 g, 78%). ESI-MS m / z: 336.1 [M+H] + .

[1039] Example 335, step b (method S)

[1040]

[1041] A mixture of pyridine-4-amine (0.047 g, 0.500 mmol), step a (0.168 g, 0.500 mmol), t-BuBrettPhosPd G3 (0.021 g, 0.025 mmol), and potassium carbonate (0.097 g, 0.700 mmol) in t-BuOH (2.0 mL) was heated to 90 °C. After stirring overnight, the reaction was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel rapid column chromatography, and the material was used directly for the next step (yield nd). ESI-MS m / z: 280.1 [M+H] + .

[1042] Note: For Method S Other effective amination conditions (X=I) include Pd(OAc)2 (catalyst), Xantphos (catalyst), Cs2CO3, toluene, 130℃, 2 hours.

[1043] Example 335, step c (method S)

[1044]

[1045] The solution of step b (0.140 g, 0.500 mmol) and potassium trimethylsilanolide (0.192 g, 1.500 mmol) in THF (5 mL) was stirred overnight at room temperature. The reaction was quenched with methanol, treated with silica gel, and concentrated. The resulting free-flowing mixture was directly purified by silica gel rapid column chromatography and used directly in the next step (19 mg, 14%). ESI-MS m / z: 265.9 [M+H] + .

[1046] use Method J The following examples in Table 5 were prepared using HATU, and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to obtain the title compound. Method S A similar procedure was used to prepare arylic acid coupling couplers.

[1047] Table 5

[1048]

[1049]

[1050] Example 350

[1051]

[1052] Example 350 Steps a and b

[1053]

[1054] A magnetic stir bar, pyridin-3-ylboronic acid (0.160 g, 1.300 mmol), step a (method S) of Example 335 (0.335 g, 1.00 mmol), and potassium carbonate (0.415 g, 3.00 mmol) were placed in a 20 mL vial. THF (8 mL) and water (2 mL) were added, and the reaction mixture was purged with nitrogen and treated with bis(triphenylphosphine)palladium(II) chloride (0.070 g, 0.100 mmol). The reaction was heated to 70 °C and monitored by LC-MS (1 h). The reaction was cooled to room temperature and poured into a separatory funnel containing EtOAc and brine. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. Purification by silica gel column chromatography yielded the title compound (260 mg, 98%) as a brown solid. ESI-MS m / z: 265.26 [M+H] + .

[1055] Methyl ester hydrolyzes to react with Method S The procedure was performed similarly, and the compound was purified by automated column chromatography (silica gel, 0-30% MeOH / DCM) to give the title compound (61 mg, 25%). ESI-MS m / z: 251.07 [M+H] + .

[1056] Example 350, step c

[1057]

[1058] according to Method J (HATU) The following examples were prepared using amine HCl salt (96 mg, 0.240 mmol). The crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (36 mg, 24%). ESI-MS m / z: 632.3 [M+H] + .

[1059] Example 351

[1060]

[1061] The following examples were prepared using amine HCl salt (35 mg, 0.08 mmol) in a manner similar to that of Example 350, and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (24 mg, 48%). ESI-MS m / z: 632.3 [M+H] + .

[1062] Example 352

[1063]

[1064] The following examples were prepared using amine HCl salt (33 mg, 0.075 mmol) in a manner similar to that of Example 350, and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (0.5 mg, 1%). ESI-MS m / z: 648.3 [M+H] + .

[1065] Example 353

[1066]

[1067] The following examples were prepared using amine (52 mg, 0.120 mmol) in a manner similar to that of Example 350, and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (6.4 mg, 9%). ESI-MS m / z: 632.2 [M+H] + .

[1068] Example 354

[1069]

[1070] The following examples were prepared using amine (78 mg, 0.179 mmol) in a manner similar to that of Example 350, and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (82 mg, 72%). ESI-MS m / z: 633.3 [M+H] + .

[1071] Example 355

[1072]

[1073] Example 355 Steps a and b

[1074]

[1075] A mixture of methyl 8-hydroxyquinoline-6-carboxylate (1.00 g, 4.92 mmol), tert-butyl (2-iodoethyl)carbamate (2.00 g, 7.38 mmol), and cesium carbonate (3.21 g, 9.84 mmol) in DMF (20 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into brine and extracted three times with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated. Purification by silica gel rapid column chromatography (0-100% EtOAc / hexane, then 0-30% MeOH / DCM) gave an orange / brown oil. The product contained a large amount of DMF but was otherwise pure. Overnight under high vacuum gave the pure title compound (1.36 g, 80%). ESI-MS m / z: 347.21 [M+H] + .

[1076] Methyl ester hydrolyzes to react with Method S The procedure was performed similarly, and the compound was purified by automated column chromatography (silica gel, 0-30% MeOH / DCM) to give the title compound (505 mg, 53%). ESI-MS m / z: 333.05 [M+H] + .

[1077] Example 355 Step c

[1078]

[1079] according to Method J (HATU) The following examples were prepared using amine HCl salt (204 mg, 0.511 mmol), and the crude material was purified by automated column chromatography to give the title compound (262 mg, 72%). ESI-MS m / z: 714.3 [M+H] + .

[1080] Example 356

[1081]

[1082] According to step b of Example 355 and Method J (HATU) was prepared in the following examples using an amine HCl salt (17 mg, 0.511 mmol) and a Boc-acid (14 mg). The crude material was dissolved in ~1.5 mL of DCM and treated with 0.25 mL of TFA at room temperature. After 30 min, the reaction was concentrated and directly purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (2.8 mg, 11%). ESI-MS m / z: 614.1 [M+H] + .

[1083] Example 357

[1084]

[1085] Example 357 Step a

[1086]

[1087] The solution of step a (1.00 g, 2.89 mmol) in DCM (9 mL) of Example 355 was treated with TFA (1.80 mL) at room temperature. After complete consumption of SM (14 h, LCMS), the reaction was concentrated and partitioned between DCM / MeOH (9:1) and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted three times with DCM / MeOH (9:1), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (0.7 g, 98%) as a light brown solid, which was ready for use without further purification. ESI-MS m / z: 247.1 [M+H] + .

[1088] Example 357 Steps b and c

[1089]

[1090] The solution of step a (0.100 g, 0.406 mmol) and triethylamine (0.170 mL, 1.218 mmol) in DCM (5 mL) was treated with acetyl chloride (0.029 mL, 0.406 mmol) at room temperature and stirred overnight. The reaction was quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude material was ready for use without further purification. ESI-MS m / z: 289.9 [M+H] + .

[1091] Methyl ester hydrolyzes to react with Method S The procedure was performed similarly, and the compound was purified by automated column chromatography (silica gel, 0-100% MeOH / DCM) to give the title compound (109 mg, 98%). ESI-MS m / z: 275.06 [M+H] + .

[1092] Example 357, step d

[1093]

[1094] according to Method J(HATU) The following examples were prepared using amine HCl salt (50 mg, 0.125 mmol). The crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (52 mg, 63%). ESI-MS m / z: 656.2 [M+H] + .

[1095] Example 358

[1096]

[1097] The title compound was prepared by using the amine and methanesulfonyl chloride in the same order as step a of Example 357 to form an arylic acid coupling coupler. ESI-MS m / z: 231.0 [M+H] + .according to Method J (HATU) The following examples were prepared using amine HCl salt (27 mg, 0.068 mmol), and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (30 mg, 64%). ESI-MS m / z: 692.1 [M+H] + .

[1098] Example 359

[1099]

[1100] The arylic acid coupling coupler was prepared in the same order using step a (above amine) and potassium cyanate in Example 357 to give the title compound (90 mg, 71%). ESI-MS m / z: 311.0 [M+H] + .according to Method J (HATU) The following examples were prepared using amine HCl salt (50 mg, 0.125 mmol), and the crude material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (0.5 mg, 6%). ESI-MS m / z: 657.1 [M+H] + .

[1101] Example 360

[1102]

[1103] Example 360 ​​Steps a and b

[1104]

[1105] A mixture of methyl 8-hydroxyquinoline-6-carboxylate (1.00 g, 4.92 mmol), tert-butyl(2-chloroethoxy)dimethylsilane (1.43 g, 7.38 mmol), and cesium carbonate (3.21 g, 9.84 mmol) in DMF (10 mL) was stirred at 50 °C for 24 hours. The reaction mixture was poured into brine and extracted three times with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated. Repeated purification by silica gel rapid column chromatography (0–50% EtOAc / hexane) yielded the title compound (0.285 g, 16%) as a brown waxy solid.

[1106] Methyl ester hydrolyzes to react with Method S The procedure was performed similarly, and the compound was purified by automated column chromatography (silica gel, 0-100% acetone / cyclohexane) to give the title compound (74 mg, 27%). ESI-MS m / z: 348.16 [M+H] + .

[1107] Example 360, steps c and d

[1108]

[1109] according to Method J (HATU) The following examples were prepared using amine HCl salt (80 mg, 0.201 mmol). The crude material was dissolved in THF (2 mL) and treated with TBAF (1 M in THF, 2.01 mL, 2.01 mmol). After complete conversion, the reaction was concentrated and directly purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (20 mg, 16%). ESI-MS m / z: 615.3 [M+H] + .

[1110] Example 361

[1111]

[1112] Example 361 Steps a and b

[1113]

[1114] A solution of 6-bromo-8-methoxyisoquinoline (400 mg, 1.7 mmol), TEA (510 mg, 5.0 mmol), and Pd(dppf)Cl2 (246 mg, 0.3 mmol) in MeOH (20 mL) was stirred at 100 °C for 3 h under a CO atmosphere (10 atm). The mixture was filtered, concentrated, and purified by silica gel column chromatography (EtOAc / hexane) to give the desired compound as a pale yellow solid (300 mg, 82%). ESI-MS m / z: 218.05 [M+H] + .

[1115] Methyl ester with Method O Hydrolysis was performed in a similar manner, and the material was purified by reversed-phase preparative HPLC (MeCN / H2O) to obtain the desired compound as a yellow solid (265 mg, 94%). ESI-MS m / z: 204.05 [M+H] + .

[1116] Example 361, step c

[1117]

[1118] To use Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (11 mg, 25%). ESI-MS m / z: 585.35 [M+H] + .

[1119] Example 362

[1120]

[1121] Example 362 Step a

[1122]

[1123] In a vial, 1-chloroisoquinoline-6-carboxylic acid (100 mg, 0.482 mmol) and sodium methoxide (771 μl, 3.37 mmol) (25% in MeOH) were stirred overnight under reflux. The reaction was concentrated, and water was added. The aqueous layer was acidified with 1 M HCl aqueous solution and washed with EtOAc. The combined organic matter was dried over MgSO4 and concentrated to give 1-methoxyisoquinoline-6-carboxylic acid (85 mg, 87%). ESI-MS m / z: 203.93 [M+H] + .

[1124] Example 362 Step b

[1125]

[1126] To use Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (13 mg, 30%). ESI-MS m / z: 585.10 [M+H] + .

[1127] Example 363

[1128]

[1129] Use and Method J (PyBOP) The following examples were prepared using the same procedure with the corresponding acid and amine HCl salt (200 mg) coupled with a partner, and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give 195 mg (68%) of the title compound. ESI-MS m / z: 571.1 [M+H] + .

[1130] Example 364

[1131]

[1132] Add Example 363 (25 mg, 0.044 mmol), 2-bromoacetamide (7.25 mg, 0.053 mmol), and potassium carbonate (12.11 mg, 0.088 mmol) to a 2-dallant vial containing a stir bar. Dissolve the solid in DMF (0.15 M), and stir the reaction at room temperature, monitoring the reaction by LCMS. After 2 hours, add another equivalent of bromoacetamide to drive the conversion. Dilute the reaction with EtOAc and quench with water. Extract the aqueous solution with EtOAc using a phase separator and concentrate the combined organic matter. Purify the crude residue by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) and lyophilize with ACN / H2O to give a white, fluffy solid (10.3 mg, 36%). ESI-MS m / z: 628.2.

[1133] Example 365

[1134]

[1135] This example was prepared in a similar manner to Example 364 using 4 equivalents of 2-bromo-2,2-difluoroacetamide at 60°C for 16 hours. The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (8.1 mg, 23%). ESI-MS m / z: 664.1 [M+H] + .

[1136] Example 366

[1137]

[1138] Similar to Example 363, starting materials were prepared using Example 212 to obtain the hydroxyquinoline precursor (53 mg, 61%). ESI-MS m / z: 585.2 [M+H] + .

[1139] Example 366 was prepared in a similar manner to Example 364 using 1.5 equivalents of 2-bromoacetamide for 3 hours (followed by adding 1.2 equivalents after 2 hours). The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (25.0 mg, 43%). ESI-MS m / z: 642.1 [M+H] + .

[1140] Example 367

[1141]

[1142] Similar to Example 363, starting materials were prepared using Example 212 to obtain the hydroxyquinoline precursor (62 mg, 67%). ESI-MS m / z: 619.2 [M+H] + .

[1143] Example 367 was prepared in a similar manner to Example 364. The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (30.0 mg, 44%). ESI-MS m / z: 676.1 [M+H] + .

[1144] Example 368

[1145]

[1146] Similar to Example 363, starting materials were prepared using Example 214 to obtain the hydroxyquinoline precursor (58 mg, 65%). ESI-MS m / z: 599.1 [M+H] + .

[1147] Example 368 was prepared in a similar manner to Example 364 using 1.5 equivalents of 2-bromoacetamide for 3 hours (followed by adding 1.2 equivalents after 2 hours). The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (31.5 mg, 50%). ESI-MS m / z: 656.2 [M+H] + .

[1148] Example 369

[1149]

[1150] Similar to Example 363, starting materials were prepared using Example 214 to obtain the hydroxyquinoline precursor (63 mg, 66%). ESI-MS m / z: 635.3 [M+H] + .

[1151] Example 369 was prepared in a similar manner to Example 364. The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (33.0 mg, 48%). ESI-MS m / z: 690.1 [M+H] + .

[1152] Method T

[1153]

[1154] Example 370

[1155]

[1156] Example 370, Step a (Method T)

[1157]

[1158] Methyl 8-hydroxyquinoline-6-carboxylate (1.500 g, 7.38 mmol) and potassium carbonate (2.040 g, 14.76 mmol) were added to a 50 mL round-bottom flask equipped with a stir bar, and the solids were dissolved in DMF (0.5 M). Then tert-butyl 2-bromoacetate (1.308 mL, 8.86 mmol) was added, and the reaction was stirred at 40 °C and monitored by LCMS (2 h). The reaction was cooled to room temperature, diluted with EtOAc, and quenched with water. The aqueous solution was extracted with EtOAc, and the combined organic matter was dried, filtered, and concentrated. The residue was subjected to automated column chromatography (silica gel, 50% ethyl acetate in hexane, R...). f=0.27) Purification yielded a white solid (1.93 g, 82%). ESI-MS m / z: 262.0 [M+H] + .

[1159] Example 370, step b (method T)

[1160]

[1161] Add a stir bar to a 100 mL round-bottom flask containing the product from step a (1.93 g, 6.08 mmol) and dissolve the solid in DCM (0.5 M). Cool the flask to 0 °C and add TFA (4.69 mL, 60.8 mmol). Stir the reaction for 10 min, then heat to room temperature and monitor by LCMS (add 5.0 equivalents of TFA after 3 hours, for a total of 5.5 hours). Quench the mixture with water and dilute with DCM. The solid precipitates. Further dilute with DCM and stir vigorously for 10 min. Collect the solid by filtration, wash several times with DCM, and dry under high vacuum to give a light brown, fluffy solid (2.21 g, 97%). ESI-MS m / z: 262.0 [M+H] + .

[1162] Example 370, step c (method T)

[1163]

[1164] Add step b (125 mg, 0.333 mmol) to a 40 mL vial equipped with a stir bar. Dissolve the solid in DMF and cool to 0 °C. Add DIPEA (407 μl, 2.332 mmol), followed by 1-methylcyclopropane-1-amine hydrochloride (124 mg, 1.148 mmol). Then add PyBOP (260 mg, 0.500 mmol) in a single-pass solution, stir the reaction for 10 min, heat to room temperature, and monitor by LCMS (1.5 h). Dilute the reaction with EtOAc and quench with water. Extract the aqueous layer with EtOAc using a phase separator and concentrate the combined organic compounds. Purify the residue by automated column chromatography (silica gel, 0-20% methanol in dichloromethane) to the title compound (98 mg, 82%). ESI-MS m / z: 216.0 [M+H] + .

[1165] Example 370, step d (method T)

[1166]

[1167] General precautions for hydrolysis: In some cases, the reaction is heated to 45°C to force the material into a solution and accelerate hydrolysis. After hydrolysis, the product is separated by precipitation. If no precipitate is formed, the product is extracted or the aqueous solution is concentrated (the material is dried and the crude product is used). Major MS of all these compounds... + m / z is for CC fragmentation: ESI-MS m / z: 202.0 [M+H] + .

[1168] A stir bar was added to a 20 mL vial containing the product from step c of Example 370 (9 mg, 0.312 mmol). The compound was dissolved in MeOH, THF, and water (0.2 M, 2:1:1). Lithium hydroxide hydrate (62 mg, 1.56 mmol) was added, and the reaction was stirred at room temperature and monitored by LCMS. The stir bar was removed, and the vial was cooled to 0 °C. The reaction was acidified with 2 M HCl to a pH of approximately 4–5 (or 1 M NaOH if the acidity was too strong). The product was extracted three times with 10% MeOH / DCM using a phase separator and concentrated. The product was dried under high vacuum to give the title compound (45 mg, 50%). ESI-MS m / z: 202.0 [M+H] + .

[1169] Example 370 Step e

[1170]

[1171] Use and Method J (PyBOP) Using the same procedure, the corresponding acid and amine HCl salt (25 mg) from step d were coupled with a partner to prepare the following examples. The residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (8 mg, 20%) ESI-MS m / z: 682.2

[1172] Example 371

[1173]

[1174] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and separated by extraction (32 mg, 50%). 20 mg of the amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (13 mg, 40%) ESI-MS m / z: 704.2 [M+H). + .

[1175] Example 372

[1176]

[1177] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and separated by extraction (14 mg, 40%), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (15 mg, 41%) ESI-MS m / z: 642.2 [M+H). + .

[1178] Example 373

[1179]

[1180] Use and Method J The following examples were prepared using a similar procedure (PyBOP). The acid precursor was prepared according to Method T and separated by concentration in aqueous solution (using the crude product), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (4.3 mg, 11%) ESI-MS m / z: 656.2 [M+H). + .

[1181] Example 374

[1182]

[1183] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and separated by extraction (41 mg, 69%), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (18.8 mg, 49%) ESI-MS m / z: 670.3 [M+H] + .

[1184] Example 375

[1185]

[1186] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method TThe acid precursor was prepared and precipitated by extraction (42 mg, 70%), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (13.4 mg, 35%) ESI-MS m / z: 686.3 [M+H] + .

[1187] Example 376

[1188]

[1189] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and separated by precipitation with aqueous solution (using the crude product), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13.0 mg, 34%) ESI-MS m / z: 668.2 [M+H] + .

[1190] Example 377

[1191]

[1192] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and purified by Gilson HPLC (35 mg, 49%). 25 mg of the amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (23.9 mg, 54%) ESI-MS m / z: 700.2 [M+H). + .

[1193] Example 378

[1194]

[1195] Use and Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and separated by concentration in aqueous solution (using crude product), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (8.0 mg, 29%) ESI-MS m / z: 702.2 [M+H]+ .

[1196] Example 379

[1197]

[1198] Use and basis Method J The following examples were prepared using a procedure similar to (PyBOP). Method T The acid precursor was prepared and separated by concentration in aqueous solution (using the crude product), and 25 mg of amine HCl salt was used for final amide coupling. The residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (6.0 mg, 15%) ESI-MS m / z: 702.2 [M+H]. + .

[1199] Example 380

[1200]

[1201] Example 380 Steps a and b

[1202]

[1203] Use and Method R A similar procedure was used to prepare the methyl ester using 2.5 equivalents of K₂CO₃ and 1.5 equivalents of 2-bromo-2-methylpropionamide at 80 °C for 16 h. The residue was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) followed by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (42.1 mg, 6%). ESI-MS m / z: 244.0 [M+H] + .

[1204] according to Method T An acid precursor was prepared, and the material was concentrated and separated by aqueous solution (using the crude product).

[1205] Example 380, step c

[1206]

[1207] according to Method J (PyBOP) was used to prepare the following examples, employing 25 mg of amine HCl salt and 1.2 equivalence acid for the final amide coupling. The residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (17.6 mg, 46%) ESI-MS m / z: 656.2 [M+H] + .

[1208] Example 381

[1209]

[1210] Example 381, Step a

[1211]

[1212] according to Method T, step a The following examples were prepared using 2.5 equivalents of K₂CO₃ and 1.2 equivalents of tert-butyl 2,4-dibromobutyrate at 40 °C for 4 hours (followed by the addition of 1.0 equivalent of bromide after 3 hours). The material was purified by automated column chromatography (silica gel, 0-70% EtOAc in hexane) to give the title compound (1.23 g, 59%). ESI-MS m / z: 370.1 [M+H] + .

[1213] Example 381, step b

[1214]

[1215] Step a (1.236 g, 2.91 mmol) of THF (0.1 M) solution was added to a 100 mL round-bottom flask equipped with a stir bar. The flask was cooled to 0 °C, and potassium tert-butoxide (0.572 g, 5.10 mmol) was added in partial fractions. The flask was purged with nitrogen, stirred for 15 min, and then heated to room temperature and monitored by LC-MS (3.5 h at room temperature, 1 h at 40 °C). The reaction was cooled to room temperature, diluted with EtOAc, and quenched with water. The aqueous solution was extracted with EtOAc, and the combined organic matter was dried, filtered, and concentrated. The material was purified by automated column chromatography (0-100% EtOAc in silica gel and hexane) to give the title compound (82 mg, 8%). ESI-MS m / z: 344.2 [M+H] + .

[1216] Example 381 Steps c, d, e

[1217]

[1218] Similar methods Step b Deprotection of tert-butyl ester was performed (95 mg, 100%). ESI-MS m / z: 288.0 [M+H]. According to... Method JPrimary amide formation was performed using PyBOP (2 equivalents) and ammonium chloride (3 equivalents), followed by purification by automated column chromatography (silica gel, 0-100% EtOAc / hex to 0-10% DCM / MeOH) to give the title compound (104 mg, 35% wt, 69%). ESI-MS m / z: 270.0 [M+H]. According to... Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (17 mg, 50%). ESI-MS m / z: 256.0 [M+H].

[1219] Example 381 Step f

[1220]

[1221] according to Method J (PyBOP) The following examples were prepared using 25 mg of amine HCl salt, and the residue was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (18 mg, 48%). ESI-MS m / z: 654.3 [M+H] + .

[1222] Example 382

[1223]

[1224] Use from Method R The acid precursor, and according to Method J (PyBOP) The title compound (12.4 mg, 41%) was obtained by using 20 mg of the amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 662.1 [M+H] + .

[1225] Example 383

[1226]

[1227] Similar to Method R The methyl ester precursor (109 mg, 32%) was prepared using 1.5 equivalents (±)-2-bromopropionamide at 40 °C for 16 hours. ESI-MS m / z: 230.0 [M+H] + Methyl ester hydrolyzes to react with... Method R The procedure was performed similarly, and separation was achieved by precipitation (50 mg, 48%). ESI-MS m / z: 260.9 [M+H] + .

[1228] according to Method JExample 383 was prepared using 60 mg of an amine HCl salt precursor (PyBOP). The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound, a mixture of diastereomers (34.3 mg, 38%). ESI-MS m / z: 642.1 [M+H] + .

[1229] Example 384

[1230]

[1231] With Method R Methyl ester (78 mg, 30%) was prepared similarly using methyl-8-aminoquinoline 6-carboxylate (200 mg) and 4.0 equivalents of 2-bromoacetamide at 40 °C for 16 hours. ESI-MS m / z: 215.0 [M+H] + Methyl ester hydrolyzes to react with... Method T steps sudden d The procedure was performed similarly, and separation was achieved via precipitation (38 mg, 52%). ESI-MS m / z: 246.0 [M+H] + .

[1232] Example 384 was prepared using 25 mg of amine HCl salt, and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (14.0 mg, 39%). ESI-MS m / z: 627.2 [M+H] + .

[1233] Example 385

[1234]

[1235] With Method R Methyl ester (150 mg, 47%) was prepared similarly using methyl-8-aminoquinoline 6-carboxylate (300 mg) and 1.2 equivalents of iodomethane at room temperature for 48 hours. ESI-MS m / z: 217.1 [M+H] + Methyl ester hydrolyzes to react with... Method T, Step d The procedure was performed similarly, and separation was achieved by precipitation (75 mg, 65%). ESI-MS m / z: 203.0 [M+H] + .

[1236] Example 385 was prepared using 20 mg of amine HCl salt, and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (19.6 mg, 72%). ESI-MS m / z: 585.2 [M+H]+ .

[1237] Example 386

[1238]

[1239] Example 386 Steps a and b

[1240]

[1241] Methyl 8-hydroxyquinoline-6-carboxylate (116 mg, 0.570 mmol), pyridinecarboxylic acid (11.69 mg, 0.095 mmol), tripotassium phosphate (202 mg, 0.949 mmol), and copper(I) iodide (9.04 mg, 0.047 mmol) were added to a 20 mL flask equipped with a stir bar and a pressure relief septa. The solids were dissolved in DMSO (0.33 M), and 2-bromopyridine (45.3 μl, 0.475 mmol) was added. The flask was purged with N2 and heated to 90 °C overnight for 14 hours. The reaction was diluted with EtOAc and quenched with water. The copper salts were filtered off with diatomaceous earth, and the aqueous solution was extracted with 10% MeOH / DCM using a phase separator. The combined organic compounds were then concentrated. The residue was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound (11 mg, 8%). ESI-MS m / z: 281.1 [M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and separated by concentration in aqueous solution (using the crude product). ESI-MS m / z: 267.0 [M+H] + .

[1242] Example 386 Step c

[1243]

[1244] according to Method J (PyBOP was used in this example to prepare the amine HCl salt precursor. The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (1.6 mg, 11%). ESI-MS m / z: 648.2 [M+H]) + .

[1245] Example 387

[1246]

[1247] This example was prepared in a similar order to Example 386. 2-Bromopyrazine was conjugated with Ullman (32 mg, 25%). ESI-MS m / z: 282.0 [M+H] + .according to Method T, Step d Acid hydrolysis and separation by aqueous extraction (15 mg, 50%). ESI-MS m / z: 268.0 [M+H] + .

[1248] according to Method J Example 387 was prepared using 25 mg of an amine HCl salt precursor (PyBOP), and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (10.0 mg, 27%). ESI-MS m / z: 649.1 [M+H] + .

[1249] Example 388

[1250]

[1251] Example 388 Steps a and b

[1252]

[1253] Methyl 8-hydroxyquinoline-6-carboxylate (100 mg, 0.492 mmol), cesium carbonate (481 mg, 1.476 mmol), and 4-fluoropyridine HCl (526 mg, 3.94 mmol) were added to a 20 mL vial equipped with a stir bar. The solid was dissolved in DMA (0.4 M), and DIPEA (688 μl, 3.94 mmol) was added. The reaction was stirred at room temperature for 30 min and heated to 100 °C for 22 h. The reaction was quenched with saturated ammonium chloride, and the aqueous solution was extracted and concentrated with 10% MeOH / DCM using a phase separator. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane, then 0-20% MeOH in DCM) to give the title compound (10 mg, 7%). ESI-MS m / z: 281.0 [M+H] + .

[1254] according to Method T, Step d The methyl ester was hydrolyzed and separated by concentration in aqueous solution (using the crude product). ESI-MS m / z: 266.9 [M+H] + .

[1255] Example 388 Step c

[1256]

[1257] according to Method J (PyBOP) This example was prepared using 15 mg of an amine HCl salt precursor and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (1.5 mg, 7%). ESI-MS m / z: 649.1 [M+H] + .

[1258] Example 389

[1259]

[1260] This example was prepared in a similar order to Example 388. SNA was performed at 60°C using 3 equivalents of 2-bromooxazole in DMF (0.33M) and without DIPEA. r (57 mg, 29%). ESI-MS m / z: 271.0[M+H] + .according to Method T The acid precursor was prepared and separated by precipitation (16 mg, 30%). ESI-MS m / z: 257.0 [M+H] + .

[1261] according to Method J Example 389 was prepared using 20 mg of amine HCl salt (PyBOP) and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12 mg, 40%). ESI-MS m / z: 638.1 [M+H] + .

[1262] Example 390

[1263]

[1264] Example 390 Steps a and b

[1265]

[1266] Oxazol-2-ylmethanol (58.5 mg, 0.591 mmol) was added to a 2-dallan vial equipped with a stir bar, and the oil was dissolved in THF. Then, methyl 8-hydroxyquinoline-6-carboxylate (100 mg, 0.492 mmol) and 2-pyridyldiphenylphosphine (155 mg, 0.591 mmol) were added, and the vial was cooled to 0 °C. DIAD (115 μl, 0.591 mmol) was added, the reaction was stirred for 10 min, heated to room temperature, and monitored by LCMS (2 h). The reaction was quenched with MeOH, the stir bar was removed, and the reaction was concentrated. The reaction was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane, then 0-20% MeOH / DCM) to give the title compound (140 mg, 99%). ESI-MS m / z: 285.0 [M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (22 mg, 17%). ESI-MS m / z: 271.0 [M+H].

[1267] Example 390, step c

[1268]

[1269] according to Method J (PyBOP) This example was prepared using 25 mg of an amine HCl salt precursor. The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15.7 mg, 41%). ESI-MS m / z: 652.2 [M+H] + .

[1270] Example 391

[1271]

[1272] This example was prepared in a similar order to Example 390. Photoelongation reaction (162 mg, 110%, impure). ESI-MS m / z: 299.1 [M+H] + .according to Method T, Step d The ester was prepared by hydrolysis and separation by precipitation (17 mg, 12%). ESI-MS m / z: 285.0

[1273] [M+H] + .

[1274] according to Method JExample 391 was prepared using 25 mg of an amine HCl salt precursor (PyBOP), and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13.8 mg, 36%). ESI-MS m / z: 666.2 [M+H] + .

[1275] Example 392

[1276]

[1277] Example 392 Steps a and b

[1278]

[1279] 100 mg (0.495 mmol) of methyl 8-aminoquinoline-6-carboxylate was added to a 40 mL vial equipped with a stir bar. The solid was dissolved in DCM (0.2 M) and cooled to 0 °C. DIPEA (216 μl, 1.236 mmol) was added, followed by cyclopropanecarbamate (49.4 μl, 0.544 mmol). The reaction was allowed to warm naturally to room temperature and monitored by LCMS (1 h). The reaction was diluted with DCM and quenched with water and saturated sodium bicarbonate. The aqueous solution was extracted with 10% MeOH / DCM using a phase separator and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound (120 mg, 89%). ESI-MS m / z: 271.2 [M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (73 mg, 64%). ESI-MS m / z: 257.0 [M+H] + .

[1280] Example 392 Step c

[1281]

[1282] according to Method J (PyBOP) This example was prepared using 25 mg of an amine HCl salt precursor and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (22.2 mg, 60%). ESI-MS m / z: 628.2 [M+H] + .

[1283] Example 393

[1284]

[1285] This example was prepared in a similar order to Example 392. Aminoquinoline acylation (99 mg, 82%). ESI-MS m / z: 245.1 [M+H] + The acid precursor was heated to 55°C for hydrolysis. Method T, Step d It was separated by precipitation (69 mg, 74%). ESI-MS m / z: 230.9 [M+H] + .

[1286] according to Method J (PyBOP) The title compound (19 mg, 53%) was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20–90%, MeCN / water, 25 min). ESI-MS m / z: 612.1 [M+H] + .

[1287] Example 394

[1288]

[1289] This example was prepared in a similar order to Example 392. Aminoquinoline methanesulfonation (98 mg, 71%). ESI-MS m / z: 281.2 [M+H] + .according to Method T, Step d The acid precursor was prepared and separated by precipitation (51 mg, 55%). ESI-MS m / z: 266.8 [M+H] + .

[1290] according to Method J (PyBOP) The title compound (25.2 mg, 67%) was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 648.1 [M+H] + .

[1291] Example 395

[1292]

[1293] This example was prepared in a similar sequence to Example 392. Aminoquinoline sulfonation required the addition of 10 equivalents of sulfonyl chloride and 16 hours (36 mg, 24%). ESI-MS m / z: 307.3 [M+H] + .according to Method T, Step d The acid precursor was prepared and separated by precipitation (16 mg, 47%). ESI-MS m / z: 292.9 [M+H] + .

[1294] according to Method J (PyBOP) The title compound (12.0 mg, 30%) was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 674.1 [M+H] + .

[1295] Method U

[1296]

[1297] Example 396

[1298]

[1299] Example 396 Steps a and b (Method U)

[1300]

[1301] Methyl 8-aminoquinoline-6-carboxylate (75 mg, 0.371 mmol) and DIPEA (486 μl, 2.78 mmol) were added to a 20 mL vial equipped with a stir bar, and the material was dissolved in DMF (0.2 M). After buffering, 2,2-difluoroacetic acid (46.7 μl, 0.742 mmol) was added, and the vial was cooled to 0 °C. PyBOP (290 mg, 0.556 mmol) was then added, the reaction was stirred for 10 min, heated to room temperature, and monitored by LCMS (16 h). The reaction was diluted with DCM and quenched with water and saturated sodium bicarbonate. The aqueous solution was extracted with 10% MeOH / DCM using a phase separator and concentrated. The material was purified by automated column chromatography (silica gel, 0-50% EtOAc in hexane) to give the title compound (37 mg, 36%). ESI-MS m / z: 263.0 [M+H] + .

[1302] according to Method T, Step d The methyl ester was hydrolyzed with 2.5 equivalents of LiOH (acetamide hydrolysis occurred) and separated by precipitation (12 mg, 50%). ESI-MS m / z: 265.0 [MH] - .

[1303] Example 396 Step c

[1304]

[1305] according to Method J(PyBOP) This example was prepared using 25 mg of an amine HCl salt precursor and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (5.0 mg, 13%). ESI-MS m / z: 648.1 [M+H] + .

[1306] Example 397

[1307]

[1308] With Method U The acid precursor was prepared in a similar sequence. Aminoquinoline amide was formed (19 mg, 17%). ESI-MS m / z: 312.0 [M+H] + Methyl ester according to Method t Step d Hydrolyze (heated to 45°C) and separate by concentration in aqueous solution (using crude product). ESI-MS m / z: 298.0 [M+H] + .

[1309] according to Method J (PyBOP) The title compound (14.7 mg, 47%) was obtained by using 20 mg of the amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 679.1 [M+H] + .

[1310] Method V

[1311]

[1312] Example 398

[1313]

[1314] Example 398 Steps a and b (Method V)

[1315]

[1316] Add oxazol-2-carboxylic acid (41.9 mg, 0.371 mmol) to a 20 mL vial containing a stir bar. Suspend the solid in DCM and cool the vial to 0 °C. Add 1-chloro-N,N,2-trimethylprop-1-en-1-amine (58.9 μL, 0.445 mmol), stir the reaction at 0 °C for 15 min, and then heat to room temperature (the solid will dissolve after 1.5 hours). Cool the reaction to 0 °C and add pyridine (225 μL, 2.78 mmol), followed by methyl 8-aminoquinoline-6-carboxylate (75 mg, 0.371 mmol) in a fraction. Allow the reaction to heat naturally to room temperature and monitor by LCMS (2 hours or longer). Dilute the reaction with DCM and quench with water and saturated sodium bicarbonate. Extract the aqueous solution with 10% MeOH / DCM using a phase separator and concentrate. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound (63 mg, 57%). ESI-MS m / z: 298.0 [M+H] + .

[1317] according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (17 mg, 80% wt, 23%). ESI-MS m / z: 214.8 [M+H] + .

[1318] Example 398 Step c

[1319]

[1320] according to Method J (PyBOP) This example was prepared using 20 mg of an amine HCl salt precursor and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12.0 mg, 35%). ESI-MS m / z: 665.1 [M+H] + .

[1321] Example 399

[1322]

[1323] Example 399 Steps a and b

[1324]

[1325] according to Method V Preparation of the acid intermediate. Ghosez coupling was performed for 14 hours (134 mg, 94%). ESI-MS m / z: 330.0 [M+H] + .according to Method T, Step dThe methyl ester was hydrolyzed and separated by aqueous extraction (115 mg, 89%). ESI-MS m / z: 316.0 [M+H] + .

[1326] Example 399 Steps c and d

[1327]

[1328] according to Method J (PyBOP) Amide formation was performed using step b and 40 mg of the amine HCl salt precursor. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound (65 mg, 94%). ESI-MS m / z: 753.2 [M+H] + .

[1329] A stir bar was added to a 20 mL vial containing step c of Example 399 (65 mg, 0.086 mmol), and the material was dissolved in DCM. The reaction was cooled to 0 °C, and TFA (66.5 μl, 0.864 mmol) was added. The reaction was stirred for 10 min, heated to room temperature, and monitored by LCMS (3 h). The reaction was diluted with DCM and quenched with water and saturated sodium bicarbonate. The pH was adjusted to approximately pH 9, and the mixture was extracted with DCM / MeOH using a phase separator and concentrated. The material was purified by Gilson preparative HPLC (20–90%, MeCN / water, 25 min) to give the title compound (13.0 mg, 23%). ESI-MS m / z: 653.2 [M+H] + .

[1330] Example 400

[1331]

[1332] The following examples were prepared in a similar order to Example 399. Boc-aziridine Ghosez coupling, Method V (131 mg, 92%). ESI-MS m / z: 330.0[M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and separated by aqueous extraction (120 mg, 95%). ESI-MS m / z: 316.0 [M+H] + .

[1333] according to Method J (PyBOP) Quinolinamide (65 mg, 94%) was formed from 40 mg of amine HCl salt precursor. ESI-MS m / z: 753.2 [M+H] +TFA was used to deprotect the compound, and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (21.0 mg, 37%). ESI-MS m / z: 653.2 [M+H] + .

[1334] Example 401

[1335]

[1336] The following examples were prepared in a similar order to Example 399. Boc-aziridine Ghosez coupling, Method V (119 mg, 83%). ESI-MS m / z: 330.0[M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and separated by aqueous extraction (80 mg, 70%). ESI-MS m / z: 316.0 [M+H] + .method J (PyBOP) amide formation was performed using 40 mg of the amine HCl salt precursor, followed by one-pot TFA deprotection. The material was then purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3.6 mg, 8%). ESI-MS m / z: 653.2 [M+H] + .

[1337] Example 402

[1338]

[1339] Example 402 Steps a and b

[1340]

[1341] Ethyl 2-methyl-1H-imidazolium-4-carboxylate (500 mg, 3.24 mmol) was added to a 40 mL vial equipped with a stir bar, and the material was dissolved in DMF. The vial was cooled to 0 °C, and NaH (136 mg, 5.68 mmol) was added in one part. The reaction was stirred at room temperature for 30 min. The vial was then cooled to 0 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (861 μl, 4.86 mmol) was slowly added. The reaction was allowed to warm naturally to room temperature for 16 h. The reaction was diluted with EtOAc and quenched with water and saturated ammonium chloride. The aqueous solution was extracted with EtOAc using a phase separator and concentrated. The material was purified by automated column chromatography (0-100% EtOAc in silica gel and hexane) to give the title compound (500 mg, 56% wt, 35%). ESI-MS m / z: 285.1 [M+H]+ .according to Method T, Step d Ethyl ester was hydrolyzed and separated by precipitation (233 mg, 80%). ESI-MS m / z: 199.0 [M+H] + .

[1342] Example 402 Steps c and d

[1343]

[1344] according to Method V The following example was prepared using SEM-conjugated imidazole aminoquinoline Ghosez (81 mg, 50%). ESI-MS m / z: 441.1 [M+H] + .

[1345] according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (25 mg, 31%). ESI-MS m / z: 427.1 [M+H] + .

[1346] Example 402 Steps e and f

[1347]

[1348] According to method J (PyBOP), SEM-formed imidazolium amide was prepared from a 25 mg amine HCl salt precursor, followed by purification by automated column chromatography (silica gel, 0-100% EtOAc / hexane) to obtain the title compound (50 mg, 100%). ESI-MS m / z: 808.2 [M+H] + .

[1349] TFA deprotection was performed using 60 TFA equivalents (20 equivalents each time, over 3 hours): The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15 mg, 35%). ESI-MS m / z: 678.1 [M+H] + .

[1350] Example 403

[1351]

[1352] The following examples were prepared in a similar order to Example 402. Ethylimidazolium carbamate was SEM protected (872 mg, 90%). ESI-MS m / z: 199.0 [M+H] + SEM-Ethylimidazolium carbamate hydrolysis (Method T, Step d) was separated by extraction (320 mg, 89%). ESI-MS m / z: 185.0 [M+H] + .according to Method U Aminoquinoline and SEM-imidazolium carboxamide (158 mg, 60% wt, 45%). ESI-MS m / z: 427.0 [M+H] + .according to Method T, Step d Quinoline methyl ester was hydrolyzed (at 45 °C) and separated by precipitation (86 mg, 61%). ESI-MS m / z: 265.0 [M+H] + .

[1353] according to Method J (PyBOP) was used to form an amide from a 30 mg amine HCl salt precursor, which was then purified by automated column chromatography (silica gel, 0-100% EtOAc / hexane) to give the title compound (50 mg, 100%). ESI-MS m / z: 894.2 [M+H] + Protection was performed with 60 TFA equivalents (20 equivalents each time, over 3 hours): The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (17.4 mg, 37%). ESI-MS m / z: 664.1 [M+H] + .

[1354] Example 404

[1355]

[1356] The following examples were prepared in a similar order to Example 402. Ethyltriazole carbamate was SEM protected (800 mg, 83%). ESI-MS m / z: 272.2 [M+H] + SEM-Ethyltriazole carbamate hydrolysis (Method T, Step d) was separated by extraction (310 mg, 86%). ESI-MS m / z: 186.0 [M+H] + Aminoquinoline and SEM-triazole carboxamide form Method U (150mg, 40%wt, 28%). ESI-MS m / z: 428.1[M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and separated by extraction (82 mg, 57%). ESI-MS m / z: 414.1 [M+H] + .

[1357] Method J (PyBOP) was used to form an amide from a 40 mg amine HCl salt precursor, which was then purified by automated column chromatography (silica gel, 0-100% EtOAc / hexane) to give the title compound (64 mg, 88%). ESI-MS m / z: 795.2 [M+H] +Protection was performed using 40 TFA equivalents (20 equivalents each time, over 2 hours): The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (19.0 mg, 35%). ESI-MS m / z: 665.1 [M+H] + .

[1358] Example 405

[1359]

[1360] Example 405 Steps a and b

[1361]

[1362] Ethyl 8-cyclopropoxyquinoline-6-carboxylate (10.29 g, 40.0 mmol) was added to a 50 mL round-bottom flask equipped with a stir bar, and the solid was dissolved in CHCl3 (0.33 M). The flask was cooled to 0 °C, and mCPBA (19.72 g, 80 mmol) was added in portions over 5–10 minutes (internal temperature monitored at 3 °C). The reaction was stirred for 10 minutes and then heated to room temperature over 20 minutes. The reaction was then heated to 45 °C (internal temperature monitored) and monitored by LCMS (2 hours).

[1363] The reaction was diluted with DCM and quenched with water and saturated sodium thiosulfate. The aqueous solution was extracted with DCM, dried, filtered, and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc / hexane, then 0-20% MeOH / DCM) to give the title compound (4.14 g, 38%). ESI-MS m / z: 274.1 [M+H] + .

[1364] Ethyl 2-chloro-8-cyclopropoxyquinoline-6-carboxylate (2.8 g, 9.60 mmol, 63%) was added to a 50 mL vial containing a stir bar, and the solid was dissolved in DCM. POCl3 (2.83 mL, 30.3 mmol) was added to the flask, which was equipped with a condenser, and the reaction was heated to 45 °C. The reaction was monitored by LCMS and completed after 2 hours. The reaction was cooled to 0 °C, diluted with EtOAc, and slowly quenched with water. After quenching for 30 minutes, more water and saturated sodium bicarbonate were slowly added. The aqueous solution was extracted with DCM, dried, filtered, and concentrated. The material was purified by automated column chromatography (silica gel, 0-50% EtOAc / hexane) to give the title compound (2.80 g, 63%). ESI-MS m / z: 292.0 [M+H] + .

[1365] Example 405 Steps c and d

[1366]

[1367] (R)-2-((tert-butyldimethylsilyl)oxy)prop-1-ol (362 mg, 1.902 mmol) was added to a 20 mL vial equipped with a stir bar, and the oil was dissolved in DMF. The vial was cooled to 0 °C, and NaH (116 mg, 2.66 mmol) was added. The reaction was heated to room temperature and stirred for 30 min. Then, ethyl 2-chloro-8-cyclopropoxyquinoline-6-carboxylate (111 mg, 0.380 mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and quenched with water and 2 M HCl. The aqueous solution was extracted with EtOAc using a phase separator and concentrated. The material was purified by automated column chromatography (0-100% EtOAc in silica gel and hexane) to give the title compound (50 mg, 32%) ESI-MS m / z: 418.2 [M+H] + (Note: Methyl ester was hydrolyzed and quenched with HCl.) The TBS group was removed with TBAF over 1 hour, and the compound was purified by automated column chromatography (silica gel, 0-100% EtOAc / hexane, then 0-20% MeOH / DCM) to give the title compound (15 mg, 42%). ESI-MS m / z: 304.1 [M+H] + .

[1368] Example 405 Step e

[1369]

[1370] according to Method J (PyBOP) This example was prepared using 20 mg of an amine HCl salt precursor and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12.0 mg, 37%). ESI-MS m / z: 685.2 [M+H] + .

[1371] Example 406

[1372]

[1373] Example 406 Step a

[1374]

[1375] Ethyl 2-chloro-8-cyclopropoxyquinoline-6-carboxylate (300 mg, 1.028 mmol) was added to a 50 mL round-bottom flask equipped with a rod, and the solid was dissolved in ACN (0.5 M). Sodium iodide (231 mg, 1.543 mmol) was added, followed by acetyl chloride (146 μl, 2.057 mmol). The reaction was stirred for 5 min (until it became turbid and orange), heated to 100 °C, and monitored by LCMS (4 h, 80% conversion). The flask was cooled to room temperature and diluted with EtOAc. The reaction was quenched with 5 mL of 10% K₂CO₃ solution and 5 mL of saturated sodium thiosulfate. The aqueous solution was extracted and concentrated with EtOAc and 2x DCM / MeOH using a phase separator. The material was purified by automated column chromatography (silica gel, 0–30% EtOAc / hexane) to give the title compound (341 mg, 78%). ESI-MS m / z: 384.1 [M+H] + .

[1376] Example 406 Steps b, c, d

[1377]

[1378] Aldehyde intermediate: The product from step a (100 mg, 0.261 mmol) was added to a 20 mL vial equipped with a stir bar, and the solid was dissolved in THF (0.33 M). The vial was cooled to -15 °C, and isopropyl magnesium chloride (261 μl, 0.522 mmol) was added. The reaction was stirred for 30 min, followed by the addition of N,N-dimethylformamide (404 μl, 5.22 mmol). The reaction was heated to 0 °C and stirred for another 1 h. The reaction was diluted with EtOAc and quenched with water and saturated ammonium chloride. The aqueous solution was extracted with EtOAc using a phase separator and concentrated. The material was purified by automated column chromatography (0-100% EtOAc in silica gel and hexane) to give the title compound (26 mg, 35%). ESI-MS m / z: 286.1 [M+H] + .

[1379] Alcohol: To a 20 mL vial containing ethyl 8-cyclopropoxy-2-formylquinoline-6-carboxylate (26 mg, 0.091 mmol) from step b, a stir bar was added, and the solid was dissolved in EtOH (0.2 M). The reaction was cooled to 0 °C, and NaBH4 (5.17 mg, 0.137 mmol) was added. The reaction was maintained at 0 °C for 1 hour, diluted with EtOAc, and quenched with water and saturated ammonium chloride. The aqueous solution was extracted with EtOAc using a phase separator and concentrated (25 mg, 95%).

[1380] according to Method T stepsd. Quinoline ethyl ester was hydrolyzed and separated by concentration in aqueous solution (using crude product). ESI-MS m / z: 260.0 [M+H] + .

[1381] Example 406 Step e

[1382]

[1383] according to Method J (PyBOP) This example was prepared using step d and 30 mg of the amine HCl salt precursor, and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15.0 mg, 33%). ESI-MS m / z: 641.2 [M+H] + .

[1384] Example 407

[1385]

[1386] The following examples were prepared similarly to steps b and d (Grignard exchange and addition) of Example 406. Grignard quenching was performed with acetone (20 equivalents) and carried out for 16 hours (14 mg, 11%). ESI-MS m / z: 316.1 [M+H] + .

[1387] according to Method T, Step d Quinoline ethyl ester was hydrolyzed and separated by concentration in aqueous solution (using crude product). ESI-MS m / z: 288.1 [M+H] + .

[1388] Using 20 mg of amine HCl salt precursor Method J (PyBOP) Amide Coupling: The material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3 mg, 61%). ESI-MS m / z: 669.2 [M+H] + .

[1389] Method W

[1390]

[1391] Example 408

[1392]

[1393] Example 408 Steps a and b (Method W)

[1394]

[1395] Methyl 8-aminoquinoline-6-carboxylate (300 mg, 1.484 mmol) and CDI (289 mg, 1.780 mmol) were added to a 20 mL vial equipped with a stir bar. The solid was dissolved in DCM (0.5 M), and DIPEA (518 μl, 2.97 mmol) was added. The reaction was stirred at room temperature for 1.5 h (CDI intermediate precipitated). Ammonia (1060 μl, 7.42 mmol) was added, and the reaction was monitored by LCMS (1.5 h). The reaction was quenched with water and further diluted with DCM (product precipitated). The vial was vortexed to induce precipitation, the solid was collected by vacuum filtration, and dried under high vacuum to give the desired product (220 mg, 61%). ESI-MS m / z: 245.9 [M+H] + .

[1396] according to Method T, Step d The methyl ester was hydrolyzed at 45°C for 1 hour and separated by precipitation (184 mg, 89%).

[1397] Example 408 Step c

[1398]

[1399] according to Method J (PyBOP) This example was prepared using 25 mg of an amine HCl salt precursor and purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (21.8 mg, 61%). ESI-MS m / z: 613.1 [M+H] + .

[1400] Example 409

[1401]

[1402] according to Method W The acid precursor was prepared according to the following examples. Methylurea was extracted to form the compound and purified by automated column chromatography (silica gel, 0-100% EtOAc in hexane) to give the title compound (17 mg, 13%). ESI-MS m / z: 260.2 [M+H] + .according to Method T, Step d The methyl ester was hydrolyzed at 45°C for 1 hour, and then concentrated and separated by aqueous solution (using the crude product). ESI-MS m / z: 245.9 [M+H] + .

[1403] according to Method J(PyBOP) The title compound (12 mg, 33%) was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 627.2 [M+H] + .

[1404] Example 410

[1405]

[1406] according to Method W The acid precursor was prepared according to the following examples. Urea was extracted to form and the crude product (91 mg, 100%) was used. ESI-MS m / z: 286.0 [M+H] + .according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (60 mg, 69%). ESI-MS m / z: 271.9 [M+H] + .

[1407] according to Method J (PyBOP) The title compound (20.0 mg, 65%) was obtained by using 20 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 653.2 [M+H] + .

[1408] Example 411

[1409]

[1410] according to Method W The acid precursor was prepared according to the following examples. Urea formation (40 mg, 36%). ESI-MS m / z: 258.1 [M+H] + At 45℃, according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (23 mg, 60%). ESI-MS m / z: 189.0 [M+H] + .

[1411] according to Method J (PyBOP) The title compound was obtained by using 20 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). (15.7 mg, 50%). ESI-MS m / z: 667.2 [M+H] + .

[1412] Example 412

[1413]

[1414] according to Method W The acid precursor was prepared in the following examples. Urea formation (86 mg, 73%). ESI-MS m / z: 318.1 [M+H] + At 45℃, according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (59 mg, 70%). ESI-MS m / z: 304.1 [M+H] + .

[1415] according to Method J (PyBOP) The title compound (20.7 mg, 52%) was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 685.2 [M+H] + .

[1416] Example 413

[1417]

[1418] according to Method W The acid precursor was prepared in the following examples, wherein an additional Boc- at the end was deprotected. Urea formation (127 mg, 86%) was extracted and purified. ESI-MS m / z: 401.1 [M+H] + At 45℃, according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (97 mg, 79%). ESI-MS m / z: 331.1 [M+H] + .

[1419] according to Method J (PyBOP) The title compound (60 mg, 97%) was obtained by automated column chromatography (silica gel, 0-100% EtOAc / hexane) using 35 mg of the amine HCl salt precursor. Boc deprotection was performed with TFA, and the material was purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min) to obtain the title compound (20.0 mg, 37%). ESI-MS m / z: 668.2 [M+H] + .

[1420] Example 414

[1421]

[1422] according to Method WThe acid precursor was prepared according to the following examples. Urea formation (56 mg, 50%). ESI-MS m / z: 302.0 [M+H] + At 45℃, according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (26 mg, 50%). ESI-MS m / z: 288.0 [M+H] + .

[1423] according to Method J (PyBOP) The title compound (15.0 mg, 38%) was obtained by using 25 mg of the amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 669.2 [M+H] + .

[1424] Example 415

[1425]

[1426] according to Method W The acid precursor was prepared according to the following examples. Urea was extracted to form and the crude product (106 mg, 100%) was used. ESI-MS m / z: 286.0 [M+H] + At 45℃, according to Method T, Step d The methyl ester was hydrolyzed and separated by precipitation (26 mg, 26%). ESI-MS m / z: 271.8 [M+H] + .

[1427] according to Method J (PyBOP) The title compound (20.0 mg, 52%) was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 653.2 [M+H] + .

[1428] Example 416

[1429]

[1430] Example 416 Step a

[1431]

[1432] 4-Amino-3-nitrobenzoic acid (3.26 g, 17.90 mmol) was added to a 50 mL round-bottom flask, followed by 30 mL of concentrated HCl, and then methacrolein (2.95 mL, 35.8 mmol). The mixture was heated to 100 °C for 5 h, then cooled to room temperature. The mixture was filtered through diatomaceous earth. The aqueous layer was concentrated to give a brown substance, which was stirred with MeOH for 1 h. The solid was collected by filtration and found to be mostly the desired product (349.4 mg, 8%). ESI-MS m / z: 233.1 [M+H] + .

[1433] Example 416 Steps b and c

[1434]

[1435] A stir bar was added to a 20 mL vial containing 3-methyl-8-nitroquinoline-6-carboxylic acid (357 mg, 1.538 mmol), and the solid was dissolved in DMF. Potassium carbonate (531 mg, 3.84 mmol) was added, followed by iodoethane (373 μl, 4.61 mmol). The reaction was stirred at room temperature for 14 hours. The reaction was diluted with EtOAC and quenched with water and saturated sodium ammonium chloride. The aqueous solution was extracted with EtOAc and DCM / MeOH using a phase separator and concentrated (168 mg, 42%). ESI-MS m / z: 261.0 [M+H] + .

[1436] The crude material from step b (168 mg, 0.646 mmol, in 40 mL) was added to a stir bar, and the solid was dissolved in EtOH and water (2:1, 0.15 M). Iron (180 mg, 3.23 mmol) and ammonium chloride (345 mg, 6.46 mmol) were added, and the reaction was heated to 80 °C for 2 hours. The reaction was cooled and diluted with EtOAc. The mixture was filtered through diatomaceous earth and washed with EtOAc and MeOH. The organic matter was concentrated. Then EtOAc was added, and the aqueous solution was alkalized with saturated sodium bicarbonate. The EtOAc and DCM / MeOH extracts were combined, dried, and concentrated (115 mg, 77%). ESI-MS m / z: 231.1 [M+H] + .

[1437] Example 416 Steps d, e and f

[1438]

[1439] The acid precursor was prepared using step c above in a manner similar to that of Example 392. Methylaminoquinoline acylation was performed by extraction, and the crude product (39 mg, 100%) was used. ESI-MS m / z: 299.1 [M+H] + At 45℃, according to Method T, Step d Ethyl ester was hydrolyzed and separated by precipitation (26 mg, 68%). ESI-MS m / z: 271.0 [M+H] + .

[1440] according to Method J (PyBOP) The title compound (21.0 mg, 55%) was obtained by using 25 mg of the amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 652.2 [M+H] + .

[1441] Example 417

[1442]

[1443] Preparation of acid precursors, according to Method W The following examples were prepared using a 3-methylquinoline analog from step c of Example 416. Urea was extracted to form and the crude product (54 mg, 99%) was used. ESI-MS m / z: 314.0 [M+H] + At 45℃, according to Method T Step d Ethyl ester was hydrolyzed and separated by precipitation (26 mg, 53%). ESI-MS m / z: 285.8 [M+H] + .

[1444] according to Method J (PyBOP) The title compound was obtained by using 25 mg of an amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). (15.0 mg, 38%). ESI-MS m / z: 667.2 [M+H] + .

[1445] Example 418

[1446]

[1447] according to Method VThe following acid precursor was prepared using a 3-methylquinoline analog from step c of Example 416. The amide Ghosez-coupled compound was purified by automated column chromatography (silica gel, 0-100% EtOAc / hexane) to give the title compound (58 mg, 99%). ESI-MS m / z: 340.1 [M+H] + At 45℃, according to Method T, Step d Ethyl ester was hydrolyzed and separated by precipitation (25 mg, 47%). ESI-MS m / z: 312.2 [M+H] + .

[1448] according to Method J (PyBOP) The title compound (10.0 mg, 24%) was obtained by using 25 mg of the amine HCl salt precursor and purifying the material by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). ESI-MS m / z: 693.2 [M+H] + .

[1449] Example 419 Steps a and b

[1450]

[1451] In a vial, ethyl 2-chlorobenzo[d]thiazolyl-6-carboxylate (250 mg, 1.034 mmol) and dimethylamine hydrochloride (101 mg, 1.241 mmol) were dissolved in DMF (2.96 mL). Triethylamine (721 μl, 5.17 mmol) was added and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with water, and the aqueous layer was washed with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography (0–60% EtOAc / hexane) to give the title compound (250 mg, 97%).

[1452] In a vial, the compound from step a (250 mg, 0.999 mmol) and lithium hydroxide (239 mg, 10 equivalents) were dissolved in THF (2.335 mL), MeOH (0.259 mL), and water (0.259 mL). The reaction was heated to 40 °C for 4 hours. The reaction mixture was diluted with water and the pH was adjusted to 3–4 with 1 M HCl aqueous solution. The aqueous layer was washed with DCM and 9:1 DCM / MeOH, and the combined organic matter was dried over MgSO4 and concentrated under reduced pressure to give the title compound (220 mg, 99% yield). ESI-MS m / z: 223.16 [M+H] + .

[1453] Example 420

[1454]

[1455] Potassium thiocyanate (1586 mg, 16.33 mmol) was added to a suspension of 4-amino-3-hydroxybenzoic acid (500 mg, 3.27 mmol) in acetic acid (6 mL, 105 mmol). The mixture was cooled and a solution of bromine (0.336 mL, 6.53 mmol) in acetic acid (6 mL, 3.27 mmol) was added dropwise, keeping the temperature below 10 °C. The mixture was heated to room temperature and stirred for 1 h. The reaction was quenched with water, boiled for 15 min, and filtered while hot. The filtrate was cooled in an ice bath and the crystalline solid was removed by filtration. The pH of the water was adjusted to 4 and the precipitated solid was collected by filtration. The solid was washed with water and dried under vacuum to give the title compound (125 mg, 0.595 mmol, 18%). ESI-MS m / z: 210.83 [M+H] + .

[1456] Example 421 Steps a and b

[1457]

[1458] At 0 °C, methyl 4-amino-3-fluorobenzoate (45 g, 266 mmol) and sodium thiocyanate (86 g, 1064 mmol) were added to bromine in AcOH (100 ml) for 1 h via an additional funnel. The mixture was then heated to room temperature and stirred for 2 days. The mixture was filtered, the precipitate was washed with water and dried under vacuum to obtain the title compound, which was used as the crude mixture.

[1459] A slurry of the product from step a (0.8 g, 3.54 mmol) in THF:EtOH (1:1, 12 mL) was mixed with a solution of potassium hydroxide (2.98 g, 53.0 mmol) in water (6 mL). The reaction mixture was heated to 60 °C and stirred for 4 hours, cooled to room temperature, and then concentrated under reduced pressure. The pH was adjusted to 5 with 3 M HCl and 3% citric acid. A pale yellow solid precipitated out and was collected by filtration, washed with water, and dried. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4 and concentrated to give the title compound (250 mg, 33%) as a pale yellow solid.

[1460] Example 422 Steps a and b

[1461]

[1462] In a vial, methyl 2-bromo-4-isopropoxybenzo[d]thiazolyl-6-carboxylate (500 mg, 1.514 mmol) was dissolved in MeOH (1.514 mL). Sodium methoxide (1039 μl, 4.54 mmol) (25%, in MeOH) was added and the reaction was heated to 65 °C. After 5 h, the reaction was cooled to room temperature and water was added. The precipitate was filtered and dried under vacuum to give the title compound (400 mg, 94%). ESI-MS m / z: 282.15 [M+H] + .

[1463] In a vial, the compound from step a (100 mg, 0.355 mmol) and lithium hydroxide (85 mg, 3.55 mmol) were dissolved in THF (2.91 mL), water (0.323 mL), and MeOH (0.323 mL). The reaction was stirred overnight at room temperature. Water was added and the reaction was acidified to pH 2–3 with 1 M HCl aqueous solution. The aqueous layer was extracted with EtOAc, and the combined organic matter was dried over MgSO4 and concentrated to give the title compound (90 mg, 95%). ESI-MS m / z: 267.92 [M+H] + .

[1464] Example 423 Step a

[1465]

[1466] In a vial, methyl 4-isopropoxy-2-methoxybenzo[d]thiazol-6-carboxylate (180 mg, 0.640 mmol) was dissolved in DCM (8 mL) and the solution was cooled to 0 °C. Boron trichloride (2559 μl, 2.56 mmol) was slowly added, and the reaction was heated to room temperature and stirred for 2 h. The reaction was quenched by adding 1 N HCl. The aqueous layer was washed with DCM, and the combined organic layers were dried over MgSO4 and concentrated. The crude mixture was purified by silica gel column chromatography, eluting with (0-50% EtOAc / hexane) to the title compound (150 mg, 98%). ESI-MS m / z: 240.07 [M+H] + .

[1467] Example 423 Steps b and c

[1468]

[1469] In a vial, step a (150 mg, 0.627 mmol) was dissolved in THF (4.18 mL) and MeOH (2.090 mL). The solution was cooled to 0 °C and trimethylsilyldiazomethane (940 μl, 1.881 mmol) was slowly added, and the reaction was heated to room temperature. After 4 hours, trimethylsilyldiazomethane (940 μl, 1.881 mmol) was added and the reaction was stirred for another 12 hours. Water was added, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The crude mixture was purified by silica gel column chromatography (0–50% EtOAc / hexane) to give the title compound (105 mg, 66%).

[1470] In a vial, the compound from step b (50 mg, 0.197 mmol) and lithium hydroxide (47.3 mg, 1.974 mmol) were dissolved in THF (1.615 mL), MeOH (0.179 mL), and water (0.179 mL). The reaction was stirred for 4 hours. Water was then added, and the pH was adjusted to 2–3 after the addition of 4 M HCl aqueous solution. The aqueous layer was washed with DCM, and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (47 mg, 100%). ESI-MS m / z: 239.87 [M+H] + .

[1471] The following examples in Table 6 were prepared using the corresponding intermediates and their derivatives from Examples 205-207. Method J Compounds were prepared using PyBOP and, in some cases, HATU. In most cases, the compounds were purified by Gilson preparative HPLC (20-90%, MeCN / water, 25 min). If not commercially available, arylic acids were prepared according to Examples 419-423. Unless otherwise specified, acids were synthesized in a manner similar to the examples described above.

[1472] Table 6

[1473]

[1474]

[1475] Example 449

[1476]

[1477] The diastereomer-pure form of Example 449 was prepared using the method described in Example 206 (using CF3 olefins and TBS-alcohols). Methods A, B, and FTBS-alcohol was converted to acid. (1.34 g, 58%). ESI-MS m / z: 612.17 [M+H] + .

[1478] Table 7 below contains examples synthesized using Example 449 (or methoxy analogs) and Method J (PyBOP). The compounds were purified by automated column chromatography or Gilson preparative HPLC (20-90%, MeCN / water, 25 min).

[1479] Table 7

[1480]

[1481]

[1482]

[1483]

[1484] Example 495

[1485]

[1486] Example 495, Step a

[1487]

[1488] In a round-bottom flask, the compound from step a of Example 59 (400 mg, 0.80 mmol) and 1-amino-2-methylpropane-2-ol (142 mg, 1.60 mmol) were dissolved in DMF (2 mL), cooled to 0 °C, and then Hunig base (698 μl, 4.00 mmol) was slowly added. After 5 min, PyBOP (832 mg, 1.60 mmol) was slowly added. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by adding water (10 mL), and extracted with ethyl acetate (50 mL x 2). The organic layer was washed with brine (50 mL x 2) and dried over Na2SO4. The residue was purified by automated column chromatography (eluting with 0-70% EtOAc / hexane) to give the desired compound (380 mg, 83% yield). ESI-MS m / z = 572.20 [M+H] + .

[1489] Example 495, step b

[1490]

[1491] The compound from step a (360 mg, 0.63 mmol) was dissolved in DCM (2 mL), followed by the slow addition of 4N HCl in 1,4-dioxane (2 mL). The reaction was completed after stirring at room temperature for 2 hours. Evaporation of the solvent and drying under vacuum gave the desired compound (310 mg, 97%) as an HCl salt. ESI-MS m / z = 472.20 [M+H] + .

[1492] Table 8 below contains examples of compounds synthesized according to Method J (PyBOP). Most compounds were purified by Gilson preparative HPLC, and some were purified by automated column chromatography (silica gel).

[1493] Table 8

[1494]

[1495] Example 508

[1496]

[1497] Example 508 Step a

[1498]

[1499] A solution of methyl 4-hydroxy-3-methoxybenzoate (2.0 g, 10.98 mmol), allyl bromide (1.58 g, 13.18 mmol), and K₂CO₃ (3.10 g, 22.50 mmol) in DMF (20 mL) was stirred at 40 °C for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by reversed-phase chromatography (MeCN / H₂O, 0% to 100%, 30 min) to give the desired compound as a yellow oil (2.3 g, 95%). ESI-MS m / z: 223.10 [M+H] + .

[1500] Example 508 Step b

[1501]

[1502] The compound from step a (2.3 g, 10.08 mmol) was stirred in NMP (10 mL) at 200 °C for 16 h. The crude product was purified by reversed-phase chromatography (MeCN / H₂O, 0% to 100%, 30 min) to give the desired compound as a yellow oil (2.0 g, 87%). ESI-MS m / z: 223.10 [M+H] + .

[1503] Example 508 Step c

[1504]

[1505] Under a nitrogen atmosphere at 0 °C, H₂O₂ (30%) (2.00 mL) and BH₃·THF (1N) (1.7 mL, 18 mmol) were added in portions to a stirred solution of compound b (2.0 g, 9 mmol) in THF (20 mL), and the reaction was stirred for 1 h. The reaction was quenched by adding NaOH (0.02 M) and the temperature was raised to room temperature. The resulting mixture was extracted with DCM, and the combined organic compounds were washed with brine, dried, and concentrated. The crude product mixture was used directly for the next step without further purification. ESI-MS m / z: 241.10 [M+H] + .

[1506] Example 508 Steps d and e

[1507]

[1508] DIAD (2.95 g, 15 mmol) was added fractionally to a stirred mixture of compound c (1.8 g, 7.3 mmol) and PPh3 (2.9 g, 11 mmol) in THF (30 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water / ice at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried, and concentrated under reduced pressure. The material was purified by reversed-phase column chromatography to give the desired product as a white solid (1.4 g, 86%). ESI-MS m / z: 223.09 [M+H] + .

[1509] Methyl ester with Method O Hydrolysis was performed in a similar manner, and the material was purified by reversed-phase preparative HPLC (MeCN / H2O) to give the title compound (720 mg, 55%) as a white solid. ESI-MS m / z: 248.25 [M+H] + .

[1510] Example 508 Step f

[1511]

[1512] With Method J The title compound was prepared similarly using an amine (30 mg, 0.075 mmol), and the material was purified by preparative HPLC (20-90%, 25 min) to give the title compound (23.4 mg, 53%). ESI-MS m / z: 590.40 [M+H] + .

[1513] Example 509

[1514]

[1515] Example 509 Step a

[1516]

[1517] This example was prepared using a similar procedure to Example 205, but with the use of a TBS-alcohol precursor. The material was prepared by cross-coupling of 3.05 g of (R)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-2,3-dihydrofurano[2,3-c]pyridine to give the title compound as a clear yellow oil (2.37 g, 83%). ESI-MS m / z: 452.0 / 454.0 [M+H] + .

[1518] Example 509, step b

[1519]

[1520] The solution of step a (4.75 g, 10.50 mmol) in acetone (105 mL) was cooled to 0 °C and treated with Jones' reagent (2 M, in aqueous H₂SO₄, 13.12 mL, 26.2 mmol). The reaction was slowly heated to room temperature and stirred overnight. After completion, the reaction was quenched with isopropanol and most of the acetone was removed by rotary evaporation. The remaining material was dissolved in water and extracted with EtOAc. The combined organic extracts were washed with brine, dried, filtered, and concentrated. Purification by rapid column chromatography (silica gel) gave the title compound (3.024 g, 82%) as a viscous syrup. ESI-MS m / z: 351.8 / 353.8 [M+H] + .

[1521] Example 509 Step c

[1522]

[1523] This embodiment follows the procedure of step b (new route) in Example 97, using step b (3.024 g) to prepare the material. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc) to obtain the title compound as a clear yellow oil (2.97 g, 98%). ESI-MS m / z: 352.8 [M+H] + .

[1524] Example 509, step d

[1525]

[1526] Add a magnetic stir bar, bis(triphenylphosphine)palladium(II) chloride (0.287 g, 0.409 mmol), and copper(I) iodide (0.078 g, 0.409 mmol) to a 500 mL round-bottom flask containing step c (2.87 g, 8.17 mmol). Evacuate the flask and backfill with nitrogen three times, then add dry diisopropylamine (40.9 mL) via a syringe. Treat the resulting mixture with ethynyltrimethylsilane (2.83 mL, 20.43 mmol) at room temperature. After 6 hours, concentrate the reaction under reduced pressure.

[1527] The crude material was dissolved in MeOH (50 mL) and treated with potassium carbonate (1.130 g, 8.17 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours, filtered through a silica gel septum, and concentrated. Purification by rapid silica gel column chromatography gave the title compound (1.3 g, 53%) as a light brown foam. ESI-MS m / z: 297.2 [M+H] + .

[1528] Example 509 Step e

[1529]

[1530] The above compound was prepared using step d (1.3 g) according to the procedure in step e of Example 205. The reaction was allowed to proceed for 53 hours, and the crude material was purified by automated column chromatography (silica gel, 0-100% EtOAc) to give the title compound (0.643 g, 44%). ESI-MS m / z: 331.0 [M+H] + .

[1531] Example 509 Step f

[1532]

[1533] The above compound was prepared using step e (0.643 g) according to the procedure in step f of Example 205. The reaction was allowed to proceed for 53 hours, and the crude material was purified by automated column chromatography (silica gel, 0-100% EtOAc) to give the title compound (0.712 g, 76%) as a white foam. ESI-MS m / z: 485.1 [M+H] + .

[1534] Example 509 Step g

[1535]

[1536] The above compound was prepared using step f (0.712 g) according to the procedure in step g of Example 205. The crude material was dissolved in EtOAc and washed three times with saturated sodium bicarbonate to obtain the title compound as a white foam, which could be used without further purification. ESI-MS m / z: 330.1 [M+H] + .

[1537] Example 509 Step h

[1538]

[1539] according to Method J Example 509 was prepared using step g (0.494 g) and HATU. The crude material was purified by automated column chromatography to give the title compound as a white solid (0.150 g, 19%). ESI-MS m / z: 520.3 [M+H] + .

[1540] Example 510

[1541]

[1542] A stir bar, 0.025 g (0.048 mmol) from step h of Example 509, 1-fluoro-4-iodobenzene (0.014 mL, 0.120 mmol), bis(triphenylphosphine)palladium(II) chloride (6.76 mg, 9.63 μmol), and copper(I) iodide (1.833 mg, 9.63 μmol) were added to a 1-dallan vial. The vial was purged with nitrogen and 1 mL of dry diisopropylamine was added. The yellow suspension was vigorously stirred at room temperature and monitored by LC-MS. The reaction was transferred to a 20 mL scintillation vial containing EtOAc and concentrated. The resulting crude material was directly purified by silica gel rapid column chromatography to give the title compound (20 mg, 67%) as a pale yellow solid. ESI-MS m / z: 614.2 [M+H] + .

[1543] Example 511

[1544]

[1545] Example 511 was prepared according to the procedure in Example 510. The crude material was purified by silica gel rapid column chromatography and further purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3 mg, 23%) as a white solid. ESI-MS m / z: 650.1 [M+H] + .

[1546] Example 512

[1547]

[1548] Example 512 was prepared according to the procedure in Example 510. The crude material was purified by silica gel rapid column chromatography and further purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3 mg, 10%) as a white solid. ESI-MS m / z: 648.2 [M+H] + .

[1549] Example 513

[1550]

[1551] Example 513 was prepared according to the procedure in Example 510. The crude material was purified by silica gel rapid column chromatography and further purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3 mg, 10%) as a white solid. ESI-MS m / z: 648.2 [M+H] + .

[1552] Example 514

[1553]

[1554] Example 514 was prepared according to the procedure in Example 510. The crude material was purified by silica gel rapid column chromatography and further purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3 mg, 10%) as a white solid. ESI-MS m / z: 648.2 [M+H] + .

[1555] Example 515

[1556]

[1557] Example 515 was prepared according to the procedure in Example 510. The crude material was purified by silica gel rapid column chromatography and further purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (6 mg, 21%) as a white solid. ESI-MS m / z: 596.2 [M+H] + .

[1558] Example 516

[1559]

[1560] Example 516 was prepared according to the procedure in Example 510. The crude material was purified by silica gel rapid column chromatography and further purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (2 mg, 7%) as a white solid. ESI-MS m / z: 613.5 [M+H] + .

[1561] Example 517

[1562]

[1563] The solution of Example 510 (0.050 g, 0.096 mmol) and 1-azido-4-fluorobenzene (0.193 mL, 0.096 mmol) in t-BuOH-H2O (1:1, 1 mL) was treated with sodium ascorbate (1.907 mg, 9.63 μmol) and copper(II) sulfate (0.154 mg, 0.963 μmol). The reaction was monitored by LC-MS; after 2 h, another portion of 1-azido-4-fluorobenzene (0.193 mL, 0.096 mmol) was added and the reaction was stirred overnight at room temperature. The organic solvent was removed under reduced pressure and 3 mL of DMF was added, which provided a slightly more homogeneous reaction mixture. The reaction was then heated to 50 °C for 4 days. The reaction mixture was poured into brine and extracted with EtOAc. The organic extract was dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by preparative HPLC (20-90%, MeCN / water, 25 min) to give the title compound (9 mg, 14%) as a white solid. ESI-MS m / z: 657.2 [M+H] + .

[1564] Table 9 below contains examples of synthesis using the methods previously described (see General Methods for Synthesis of Starting Materials following Table 9). The compounds were purified by automated column chromatography or Gilson preparative HPLC (20-90%, MeCN / water, 25 min). The synthesis of Examples 545 and 546 is described following Table 9.

[1565] Table 9

[1566]

[1567]

[1568]

[1569]

[1570] Example 545 (in the table)

[1571]

[1572] Example 545 Step a

[1573]

[1574] The title compound was prepared in a similar order to that in Example 205. The residue was concentrated under reduced pressure to give a crude product as a brown solid. ESI-MS m / z: 501.15 [M+H] + .

[1575] Example 545 step b

[1576]

[1577] The mixture of the compound from step a (1.30 g, 2.59 mmol) and LiBr (676 mg) in acetone (50 mL) was stirred at 60 °C for 3 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give the desired product (630 mg, 59%) as a brown solid. ESI-MS m / z: 409.00 [M+H] + .

[1578] Example 545 step c

[1579]

[1580] Add the compound from step b (620 mg, 1.51 mmol) and DCM (15 mL) to a 100 mL round-bottom flask at room temperature. Cool the mixture to 0 °C, add DAST (488 mg, 3.03 mmol), and stir the reaction at the same temperature for 30 min. Stir the reaction at room temperature for 5 min and quench with cold aqueous NaHCO3 solution. Extract the aqueous layer with CH2Cl2 and dry it over anhydrous Na2SO4. Filter and concentrate the filtrate under reduced pressure. Purify the residue by preparative TLC (EtOAc / hexane, 1:1) to give the crude product as a yellow solid. ESI-MS m / z: 411.10 [M+H] + .

[1581] Example 545 Step d

[1582]

[1583] A mixture of the compound from step c (545 mg, 1.32 mmol), NaN3 (1.39 g, 21.38 mmol), and TBAI (244 mg, 0.66 mmol) in DMSO (25 mL) was stirred at 100 °C for 4 h. The mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give a crude product (370 mg) as a yellow solid. ESI-MS m / z: 374.15 [M+H] + .

[1584] Example 545 Step e

[1585]

[1586] A mixture of the compound from step d (370 mg, 0.99 mmol), PPh3 (2.60 g, 9.91 mmol), THF (20 mL), and H2O (2 mL) was stirred at 70 °C for 1 h under a nitrogen atmosphere. The mixture was purified by preparative TLC (CH2Cl2 / 7N NH3, in MeOH, 15:1) to give the desired product (200 mg, 58%) as a white solid. ESI-MS m / z: 348.15 [M+H] + .

[1587] Example 545 Step f

[1588]

[1589] according to Method J Synthesized the title compound. The mixture was purified by preparative HPLC to give the desired product (32.5 mg, 80%) as a white solid. ESI-MS m / z: 559.30 [M+H] + .

[1590] Example 564

[1591]

[1592] The title compound was prepared from 2-bromopropenal in a manner similar to that in Example 210. 2-Bromopropenal was prepared according to literature (acrylaldehyde dibromination followed by TEA-promoted elimination). The crude compound was purified by reversed-phase rapid chromatography on C18 silica gel (MeOH / H2O) to give the title compound as a red solid (240 mg, 14%). ESI-MS m / z: 282.10 [M+H] + .

[1593] Example 565 Step a

[1594]

[1595] The solution of Example 564 (1.30 g, 4.61 mmol) in H₂SO₄ (2 mL) and MeOH (20 mL) was stirred at 80 °C for 2 hours. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the desired product (1.2 g, 88%) as a brown solid. ESI-MS m / z: 296.05 [M+H] + .

[1596] Example 565 step b

[1597]

[1598] A solution of the compound from step a (1.00 g, 3.38 mmol), Pd(PPh3)4 (585 mg, 0.51 mmol), and Sn2(nBu)6 (3.92 g, 6.76 mmol) in dioxane (20.00 mL) was stirred at 100 °C for 8 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with 20% ethyl acetate in hexane) to give the desired product (910 mg, 53%) as a yellow solid. ESI-MS m / z: 508.15 [M+H] + .

[1599] Example 565 Steps c and d

[1600]

[1601] A solution of the compound from step b (850 mg, 1.68 mmol), Ag₂O (155 mg, 0.67 mmol), F-TEDA-BF₄ (892 mg, 2.52 mmol), MeOH (269 mg, 8.40 mmol), and NaHCO₃ (282 mg, 3.36 mmol) in acetone (20 mL) was stirred at 65 °C for 48 h under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with 50% ethyl acetate in hexane) to give the desired product (110 mg, 28%) as a yellow solid. ESI-MS m / z: 236.06 [M+H] + .

[1602] Ester hydrolysis to react with Method T (Step d) A similar procedure was followed to obtain the desired acidic product. ESI-MS m / z: 222.05 [M+H] + .

[1603] Example 566 Steps a and b

[1604]

[1605] A solution of step a (300 mg, 1.01 mmol), cyclopropylboronic acid (261 mg, 3.04 mmol), PCy3 (284 mg, 1.01 mmol), tricyclohexylphosphine (9 mg, 0.03 mmol), and K3PO4 (645 mg, 3.04 mmol) in toluene / H2O (6 mL, 5:1) was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The resulting solution was diluted with water, extracted with EtOAc, and the organic layer was dried and concentrated. The resulting solution was purified by reversed-phase C18 column chromatography (CH3CN / H2O) to give the desired product as a yellow solid. ESI-MS m / z: 258.00 [M+H] + .

[1606] Ester hydrolysis to react with Method T (Step d) The procedure was similar. The resulting solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H2O) to give the desired product (120 mg) as a pale yellow solid. ESI-MS m / z: 244.05 [M+H] + .

[1607] Example 567

[1608]

[1609] The title compound was prepared from 2-chloropropenal in a manner similar to that of Example 210. 2-Chloropropenal was prepared in two steps from 2,3-dichloropropenyl according to the literature (Eur. J. Org. Chem. 2018, 45, 6256). The resulting solution was purified by reversed-phase C18 column chromatography (CH3CN / H2O) to give the desired product (300 mg, 23%) as a yellow solid. ESI-MS m / z: 238.15 [M+H] + .

[1610] Example 568

[1611]

[1612] The title compound was prepared in a manner similar to that in Example 567, yielding the desired product (350 mg, 27%) as a white solid. ESI-MS m / z: 264.00 [M+H] + .

[1613] Example 569 Steps a and b

[1614]

[1615] A solution of methyl 3-iodo-8-methoxyquinoline-6-carboxylate (400 mg, 1.16 mmol), CuI (444 mg, 2.33 mmol), KF (135 mg, 2.33 mmol), and methyl 2,2-difluoro-2-sulfoacetate (1.1 g, 5.83 mmol) in NMP (3 mL) was stirred at 120 °C for 4 hours under a nitrogen atmosphere. The resulting solution was diluted with water, extracted with EtOAc, and the organic layer was dried and concentrated. The resulting solution was purified by reversed-phase C18 column chromatography (CH3CN / H2O) to give the desired product (200 mg, 60%) as a pale yellow solid. ESI-MS m / z: 286.00 [M+H] + .

[1616] Ester hydrolysis to react with Method T (Step d) The procedure was performed in a similar manner. The resulting solution was purified by reversed-phase C18 column chromatography (CH3CN / H2O) to obtain the desired product (120 mg crude product), a pale yellow solid. ESI-MS m / z: 271.95 [M+H] + .

[1617] Example 570

[1618]

[1619] The title compound was prepared using 2-methyl-2-butenal (commercially available) in a manner similar to that used in Example 210 and Method P. ESI-MS m / z: 232.10 [M+H] + .

[1620] Example 571

[1621]

[1622] The title compound was prepared using methacrolein and methyl 4-amino-3-iodobenzoate in a manner similar to that used in Example 210 and Method P. The crude product was recrystallized from EA / H₂O to give the desired product (7 g, 62%) as a yellow solid. ESI-MS m / z: 313.85 [M+H] + .

[1623] Example 572 Step a

[1624]

[1625] A solution of the crude product from Example 571 above, benzyl bromide (6.56 g, 38.35 mmol), and DIEA (0.50 mg, 2.87 mmol) in DMSO (20 mL) was stirred at room temperature for 6 hours. The residue was purified by silica gel column chromatography (ethyl acetate in hexane) to give the desired product (20 g) as a yellow solid. ESI-MS m / z: 404.00 [M+H] + .

[1626] Example 572, steps b and c

[1627]

[1628] A solution of the compound from step a (9 g, 22.32 mmol), BocNH2 (3.66 g, 31.24 mmol), Pd(OAc)2 (100 mg, 0.45 mmol), BINAP (417 mg, 0.67 mmol), and Cs2CO3 (10 g, 31.24 mmol) in toluene was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The crude product was rapidly purified by reverse-phase chromatography to give the desired product (6 g, 68%) as a yellow solid. ESI-MS m / z: 393.05 [M+H] + .

[1629] The compound from step b (8 g, 20.39 mmol) was stirred in HCl (8 mL) and EtOAc (50 mL) for 2 hours at room temperature. The residue was purified by silica gel column chromatography to give the desired product (3 g, 50%) as a yellow solid. ESI-MS m / z: 293.05 [M+H] + .

[1630] Example 573

[1631]

[1632] The title compound was prepared in a manner similar to that in Examples 571 and 572. The residue was purified by reversed-phase rapid chromatography (10–50% MeOH / H₂O) to give the desired product as a grayish-white solid (1.62 g, 67%). ESI-MS m / z: 245.12 [M+H] + .

[1633] Example 574

[1634]

[1635] The title compound was prepared in a manner similar to that in Examples 571 and 572. The crude product was purified by reversed-phase rapid chromatography to give the desired product (1.2 g) as a yellow solid. ESI-MS m / z: 217.05 [M+H] + .

[1636] Example 575 Step a

[1637]

[1638] Under a nitrogen atmosphere, at 90 °C, BINAP (1.37 g, 2.2 mmol), Pd(OAc)₂ (495 mg, 2.2 mmol), and Cs₂CO₃ (10.79 g, 33.1 mmol) were added dropwise to a solution of methyl 4-amino-3-methoxybenzoate (2.00 g, 11.1 mmol) and 2-chlorocyclohexyl-1-encarbaldehyde (4.32 g, 0.1 mmol) in toluene for 3 hours. The resulting solution was extracted with EtOAc, and the organic layer was dried and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate in hexane) to give the desired product (2.6 g, 86%). ESI-MS m / z: 290.05 [M+H] + .

[1639] Example 575, steps b and c

[1640]

[1641] The solution of step a (2.6 g, 8.9 mmol) in TFA (10 mL) was stirred at 80 °C for 12 h under a nitrogen atmosphere. The resulting solution was extracted with EtOAc, and the organic layer was dried and concentrated to give the desired product (300 mg) as a yellow oil. ESI-MS m / z: 272.05 [M+H] + .

[1642] Ester hydrolysis to react with Method T (Step d) The procedure was performed similarly. The resulting solution was purified by reversed-phase C18 column chromatography (CH3CN / H2O) to give the desired product (106 mg, 40%) as a yellow solid. ESI-MS m / z: 258.05 [M+H] + .

[1643] Example 576 Step a

[1644]

[1645] Methyl 4-amino-3-hydroxybenzoate (5 g, 30 mmol), methyl 2-chloro-2,2-difluoroacetate (6.5 g, 45 mmol), K₂CO₃ (8.3 g, 60 mmol), and DMF (30 mL) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by TLC. The reaction mixture was diluted with water, and the aqueous layer was extracted with CH₂Cl₂. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-20% EtOAc in hexane) to give the desired compound (4.2 g, 65%) as a grayish-white solid. ESI-MS m / z: 248.05 [M+H] + .

[1646] Example 576 Step b

[1647]

[1648] Add the compound from step a (1.7 g, 6.9 mmol), Fe (3.07 g, 55.03 mmol), NH4Cl (2.94 g, 55.03 mmol), EtOH (30 mL), and H2O (30 mL) to a 250 mL round-bottom flask at room temperature. Stir the resulting mixture overnight at 80 °C under a nitrogen atmosphere. Filter the mixture, wash the filter cake with EtOH, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (0-33% EtOAc in hexane) to give the desired compound (1.2 g, 80%) as a grayish-white solid. ESI-MS m / z: 218.00 [M+H] + .

[1649] Example 576 Steps c and d

[1650]

[1651] The title compound was synthesized in a manner similar to that of Example 421. Ester hydrolysis was performed with... Method T (Step d) The procedure was similar. The residue was purified by reversed-phase rapid chromatography (0-50% MeOH / H2O, 25 min) to give the desired compound (105 mg, 55%). ESI-MS m / z: 260.95 [M+H] + .

[1652] Example 577 Step a

[1653]

[1654] 4-Amino-3-hydroxybenzoate (2 g, 11.96 mmol), 2-iodopropane (3.05 g, 17.95 mmol), Cs₂CO₃ (7.8 g, 23.93 mmol), and acetone (20 mL) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The aqueous layer was extracted with CH₂Cl₂ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–20% EtOAc in hexane) to give the desired compound (2.54 g, 100%). ESI-MS m / z: 210.15 [M+H] + .

[1655] Example 577, steps b and c

[1656]

[1657] The title compound was synthesized in a manner similar to that of Example 421. Ester hydrolysis was performed with... Method T (Step d) The procedure was similar. The residue was purified by reversed-phase rapid chromatography (0-50% MeOH / H2O, 25 min) to give the title compound (850 mg, 60%) as a grayish-white solid. ESI-MS m / z: 252.95 [M+H] + .

[1658] Example 578 Step a

[1659]

[1660] A solution of methyl 2-amino-4-methoxybenzo[d]thiazolyl-6-carboxylate (2 g), CuBr2 (3.7 g, 16.78 mmol), and t-BuNO2 (1.7 g, 16.77 mmol) in CH3CN was stirred at room temperature for 16 hours under a N2 atmosphere. The resulting solution was diluted with water, extracted with EtOAc, and the organic layer was dried and concentrated. The resulting solution was purified by silica gel column chromatography (EtOAc in hexane) to give the desired product (1.6 g, 63%) as an orange solid. ESI-MS m / z: 301.90 [M+H] + .

[1661] Example 578 Steps b and c

[1662]

[1663] A solution of the compound from step a (1.6 g), Pd(dppf)Cl2.CH2Cl2 (0.9 g, 1.06 mmol), Na2CO3 (1.7 g, 23.50 mmol), H2O (1 mL), and methylboric acid (0.48 g, 7.94 mmol) in dioxane (30 mL) was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting solution was diluted with water, extracted with EtOAc, and the organic layer was dried and concentrated. The resulting solution was purified by silica gel column chromatography (ethyl acetate in hexane) to give the desired product (700 mg, 56%) as an orange solid. ESI-MS m / z: 237.95 [M+H] + .

[1664] Ester hydrolysis to react with Method T (Step d) The procedure was similar. The residue was purified by reversed-phase rapid chromatography (MeCN / H2O) to give the title compound (350 mg) as a white solid. ESI-MS m / z: 223.90 [M+H] + .

[1665] Example 579 Steps a and b

[1666]

[1667] The title compound was synthesized using methyl 4-amino-3-(trifluoromethoxy)benzoate (1.50 g, 6.4 mmol) in a manner similar to that in Example 421. The ester was hydrolyzed to react with... Method T (Step d) The procedure was carried out in a similar manner. The title compound was separated by precipitation, and the solid was washed with MeCN to give the desired product (370 mg, 74.74%), which was white.

[1668] Solid. ESI-MS m / z: 279.05 [M+H] + .

[1669] Example 580 Steps a and b

[1670]

[1671] In a vial, methyl 2-aminobenzo[d]thiazolyl-6-carboxylate (350 mg, 1.681 mmol) was dissolved in DCM (8.40 mL). Cyclopropaneformyl chloride (183 μl, 2.017 mmol) was added, followed by pyridine (408 μl, 5.04 mmol). The reaction was stirred overnight. Water was added and the aqueous layer was washed with DCM. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel chromatography by elution with 0–60% EtOAc / hexane to give the title compound as a yellow solid (120 mg, 0.434 mmol, 25%). ESI-MS m / z: 276.81 [M+H] + .

[1672] Ester hydrolysis to react with Method T (Step d) The procedure was carried out in a similar manner. The title compound was isolated and concentrated by DCM extraction (65 mg, 0.248 mmol, 90%).

[1673] Example 581 Step a

[1674]

[1675] NaNO2 (0.7 g in 5 mL of water) was added dropwise to a stirred solution of methyl 4-amino-3-iodobenzoate (2.7 g, 10 mmol) in HCl (6 mL) at 5 °C for 1 hour. Piperidine (1 mL) was added dropwise to the mixture at 5 °C. The resulting mixture was stirred at room temperature for an additional hour. The resulting mixture was extracted with EA, and the combined organic layers were washed with water and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (EtOAc in hexane) to give the desired product (2.7 g) as a yellow solid. ESI-MS m / z: 374.00 [M+H] + .

[1676] Example 581, step b

[1677]

[1678] Magnesium bromo(propynyl-1-bromo)bromo (4.3 g, 29.94 mmol) was added to a dry, N2-washed 50 mL Schlenk tube equipped with a magnetic stirrer and septum. The solution was cooled to -30 °C and ZnBr2 (5.08 g, 22.56 mmol) was added dropwise to the reaction mixture. The reaction mixture was heated to room temperature for 30 min. The compound from step a (2 g, 5.36 mmol) was added, followed by (PPh3)4 (309 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with a saturated aqueous NH4Cl solution. The aqueous solution was extracted with EtOAc, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc in hexane) to give the desired product (2 g, 97%) as a yellow solid. ESI-MS m / z: 286.00 [M+H] + .

[1679] Example 581, step c

[1680]

[1681] A solution of the compound from step b (1.5 g, 5.26 mmol) and HBr in water (850 mg, 10.51 mmol) in acetone (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (EtOAc in hexane) to give the desired product (900 mg, 61%) as a yellow solid. ESI-MS m / z: 281.00 [M+H] + .

[1682] Example 581, step d

[1683]

[1684] The solution of the compound from step c (900 mg, 3.2 mmol) and Pd / C (681 mg, 6.40 mmol) in MeOH (20 mL) was stirred at room temperature for 2 hours under a H2 atmosphere. The resulting mi...

Claims

1. A compound represented by formula (VIIIa): Or its pharmaceutically acceptable salt, wherein: A. Choose from the following groups: W is CH3 or CF3; G is –C(O)NR 11 R 12 ; R3 is a hydroxyl group; R4 is methyl, trifluoromethyl, or cyclopropyl; R 11 Each time it appears, independently select from the following groups: 1) Hydrogen; 2) Optionally substituted –C1-C8 alkyl groups; 3) Optionally substituted –C3-C8 cycloalkyl groups; and 4) Optionally substituted 3- to 8-membered heterocycles; R 12 Each time it appears, independently select from the following groups: 1) Hydrogen; 2) Optionally substituted –C1-C8 alkyl groups; 3) Optionally substituted –C3-C8 cycloalkyl groups; and 4) Optionally substituted 3- to 8-membered heterocycles; Alternatively, R 11 and R 12 Together with the nitrogen atoms they are attached to, they form 3- to 12-membered heterocycles; Each R 21 Independently selected from the group consisting of: -F, -Cl, -CN, methyl, -CF3, -CH2F and -CHF2; Each R 31 It is a halogen on its own; -CN; -NO2, -OR 11 ;-NR 11 R 12 ;-NR 11 C(O)R 12 ;-NR 11 S(O)2R 12 ;-S(O)2R 12 ;-S(O)2NR 11 R 12 -NR 11 C(O)NR 11 R 12 ;-C(O)R 11 -C(O)OR 11 ;-C(O)NR 11 R 12 ; optionally substituted –C1-C6 alkyl; optionally substituted –C3-C8-cycloalkyl; optionally substituted 3- to 8-membered heterocycle; optionally substituted aryl; or optionally substituted heteroaryl; R 22 It is hydrogen, halogen, -OR 11 ;-NR 11 R 12 Optionally substituted –C1-C6-alkyl; Optionally substituted –C3-C8-cycloalkyl; Optionally substituted 3- to 8-membered heterocycles; Optionally substituted aryl; or Optionally substituted heteroaryl; and Each m' is independently 0, 1, or 2; and m is 0, 1, or 2; The term "substituted" refers to substitution achieved by independently replacing one, two, or three hydrogen atoms with substituents selected from halogens, C, and D. 1- C4-alkyl, halogenated-C 1- C4-alkyl, C2-C4-alkenyl, halogenated-C2-C4-alkenyl, C3-C6-cycloalkyl, C 1- C4-alkoxy, halogen generation-C 1- C4-alkoxy group, -CN, -OH, NH2, C 1- C4-alkylamino, di(C 1- C4-alkyl)amino and NO2.

2. The compound or pharmaceutically acceptable salt according to claim 1, wherein, The compound is represented by the following formula: Or its pharmaceutically acceptable salt.

3. The compound or pharmaceutically acceptable salt according to claim 1, wherein, G is -C(O)NHR 12 .

4. The compound or pharmaceutically acceptable salt according to claim 1, wherein, Choose from the following groups:

5. The compound or pharmaceutically acceptable salt according to claim 1, wherein, R4 is -CF3.

6. A compound, said compound being selected from the following: Or its pharmaceutically acceptable salt.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

8. Use of the compound according to any one of claims 1 to 6 in the manufacture of a medicament for treating or preventing RSV infection.

9. Use of the compound according to any one of claims 1 to 6 in the manufacture of a medicament for treating or preventing HMPV infection.

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