Antiviral heterocyclic compounds

Abstract

The present invention discloses a compound of formula (I) or a pharmaceutically acceptable salt, ester, or prodrug thereof that inhibits human respiratory syncytial virus (HRSV) or human metapneumovirus (HMPV) infection. The present invention further relates to a pharmaceutical composition comprising the above-described compound for administration to a subject suffering from HRSV or HMPV infection. The present invention also relates to a method of treating HRSV or HMPV infection in a subject by administering a pharmaceutical composition comprising a compound of the present invention. [Formula 1] JPEG2022550436000592.jpg2460

Description

[Technical field]

[0001] Related Applications 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 the above applications are incorporated herein by reference.

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

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

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

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

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

[0007] There are several RSV fusion inhibitors disclosed in the following publications: WO 2010 / 103306, WO 2012 / 068622, WO 2013 / 096681, WO 2014 / 060411, WO 2013 / 186995, WO 2013 / 186334, WO 2013 / 186332, WO 2012 No. 080451, WO 2012 / 080450, WO 2012 / 080449, WO 2012 / 080447, WO 2012 / 080446, WO 2015 / 110446, WO 2017 / 009316, J. Med. Chem. 2015, 58, 1630-1643, Bioorg. Med. Chem. Lett., 2015, 25, 976-981, and Nat. Commun., 2017, 8, 167. Examples of other N protein inhibitors for the treatment of HRSV are disclosed in the following publications: 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 are 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 are 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.

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

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

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

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

[0012] The present invention provides compounds represented by formula (I), and pharma- ceutically acceptable salts, esters and prodrugs thereof, which can be used to treat or prevent a viral (particularly HRSV or HMPV) infection, [ka] During the ceremony, A is, 1) optionally substituted aryl, and 2) Optionally substituted heteroaryl is selected from the group consisting of B is O or S; R 1 and R 2 are each independently 1) Hydrogen, 2) Fluorine, and 3) optionally substituted -C 1 ~C 6 Alkyl is selected from the group consisting of Or, R 1 and R 2 form an optionally substituted 3- to 6-membered ring together with the carbon atom to which they are attached, Z is 1) Hydrogen, 2) Halogen, 3) Hydroxy, 4) Cyano, 5) Nitro, 6) Optionally substituted -C 1 ~C 6 Alkoxy, and 7) Optionally substituted -C 1 ~C 6 Alkyl is selected from the group consisting of W is 1) Hydrogen, 2) optionally substituted -C 1 ~C 6 Alkoxy, 3) optionally substituted -C 1 ~C 6 Alkyl, and 4) optionally substituted -C 3 ~C 6 Cycloalkyl is selected from the group consisting of G is 1)-C(O)OR 12 , 2) -C(O)NR 11 R 12 , 3) optionally substituted -C 1 ~C 6 Alkyl-CN, 4) optionally substituted -C 1 ~C 6 Alkyl-C(O)NR 11 R 12 , 5) Optionally substituted -C 1 ~C 6 Alkyl-C(O)NR 11 S(O) 2 R 12 , 6) Optionally substituted -C 1 ~C 6 Alkyl-OC(O)NR 11 R 12 , 7) Optionally substituted -C 1 ~C 6 Alkyl-NHR 13 , 8) Optionally substituted -C 1 ~C 6 Alkyl-NHC(O)R 13 is selected from the group consisting of n is 1, 2 or 3, preferably n is 1 or 2; Y is O, S, S(O) 2 or NR 14 and E is 1) optionally substituted aryl, 2) optionally substituted heteroaryl, 3) an optionally substituted 3- to 8-membered heterocycle, and 4) optionally substituted alkynyl is selected from the group consisting of R 3 is hydroxy or fluorine; R 4 teeth, 1) Hydrogen, 2) optionally substituted -C 1 ~C 6 Alkyl, 3) optionally substituted -C 3 ~C 8 Cycloalkyl, and 4) Optionally substituted 3- to 8-membered heterocycle is selected from the group consisting of R 11 independently for each occurrence, 1) Hydrogen, 2) optionally substituted -C 1 ~C 8 -alkyl, 3) optionally substituted -C 3 ~C 8 -cycloalkyl, 4) an optionally substituted 4- to 8-membered heterocycle, 5) optionally substituted aryl, 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl, and 8) optionally substituted heteroarylalkyl is selected from the group consisting of R 12 independently for each occurrence, 1) Hydrogen, 2) optionally substituted -C 1 ~C8 -alkyl, 3) optionally substituted -C 3 ~C 8 -cycloalkyl, 4) an optionally substituted 4- to 8-membered heterocycle, 5) optionally substituted aryl, 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl, and 8) optionally substituted heteroarylalkyl is selected from the group consisting of Or, R 11 and R 12 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle, preferably the 3- to 12-membered heterocycle including, but not limited to, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, and azetidine; R 13 independently for each occurrence, 1) optionally substituted -C 1 ~C 8 Alkyl, 2) optionally substituted -C 3 ~C 8 Cycloalkyl, 3) an optionally substituted 4- to 8-membered heterocycle, 4) optionally substituted aryl, 5) optionally substituted arylalkyl, 6) optionally substituted heteroaryl, and 7) Optionally substituted heteroaryl alkyl is selected from the group consisting of R 14 teeth, 1) Hydrogen, 2) optionally substituted -C 1 ~C 8 -alkyl, and 3) optionally substituted -C 3 ~C 8 -Cycloalkyl is selected from Each of the above preferred groups may be used in combination with one, any or all of the other preferred groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0014] In certain embodiments of compounds of Formula (I), B is O.

[0015] In certain embodiments of the compounds of Formula (I), Y is O.

[0016] In certain embodiments of compounds of Formula (I), B is O, Y is O and n is 1 or 2.

[0017] In certain embodiments of the compounds of formula (I), R 1 is hydrogen or F.

[0018] In certain embodiments of the compounds of formula (I), R 2 is hydrogen or F.

[0019] In certain embodiments of the compounds of Formula (I), Z is hydrogen, Cl or F.

[0020] In certain embodiments of the compounds of formula (I), R 1 is hydrogen and R 2 is hydrogen and Z is hydrogen.

[0021] In certain embodiments of compounds of Formula (I), W is optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl.

[0022] In certain embodiments of compounds of Formula (I), W is -CH 3 or -CF 3 It is.

[0023] In certain embodiments of the compounds of formula (I), R3 is -OH.

[0024] In certain embodiments of the compounds of formula (I), R 4 is optionally substituted methyl.

[0025] In certain embodiments of the compounds of formula (I), R 3 is OH and R 4 CF 3 It is.

[0026] In certain embodiments of the compounds of formula (I), R 1 is hydrogen, and R 2 is hydrogen, and R 3 is OH and R 4 CF 3 It is.

[0027] In certain embodiments of compounds of Formula (I), G is an optionally substituted -C(O)NR 11 R 12 It is.

[0028] In certain embodiments of compounds of Formula (I), G is -CH 2 NHR 13 , -CH 2 C(O)NR 11 R 12 , -CH 2 NHC(O)R 13 , -CH 2 OC(O)NR 11 R 12 , -CH 2 CN or -CH 2 C(O)NR 11 S(O) 2 R 12 It is.

[0029] In certain embodiments of compounds of formula (I), A is selected by removal of a hydrogen atom from one of the following: [ka] In the formula, each of these groups may be substituted.

[0030] In certain embodiments of compounds of Formula (I), A is selected from the groups shown below: [ka] [ka] In the formula, each of these groups may be substituted.

[0031] In certain embodiments of the compounds of formula (I), A is [ka] In the formula, Ra is hydrogen, halogen, -CN, -NO 2 , -OR 11 , -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 S(O) 2 R 12 , -S(O) 2 R 12 , -S(O) 2 NR 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 -C 1 ~C 6 Alkyl, optionally substituted -C 3 ~C 8 -cycloalkyl, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted aryl, or an optionally substituted heteroaryl; Rb and Rb' are each independently hydrogen, halogen, -OR 11 , -NR 11 R 12 , optionally substituted -C 1 ~C6 -alkyl, optionally substituted -C 3 ~C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, and optionally substituted heteroaryl. Alternatively, Rb and Rb' together with the carbon atom to which they are attached form a 4- to 7-membered ring fused to the phenyl ring.

[0032] In certain embodiments of compounds of formula (I), E is optionally substituted aryl, preferably optionally substituted phenyl.

[0033] In certain embodiments of compounds of formula (I), E is selected by removal of a hydrogen atom from one of the following: [ka] In the formula, each of these groups may be substituted.

[0034] In certain embodiments of compounds of Formula (I), E is selected from the groups shown below. [ka]

[0035] In one embodiment of the invention, the compound of formula (I) is represented by formula (Ia) or formula (Ib), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A, B, R 1 , R 2 , Z, W, G, n, Y, E, R 3 and R 4 is as defined above.

[0036] In a preferred embodiment, the compound of formula (I) has the stereochemistry shown in formula (Ib).

[0037] In one embodiment of the invention, the compound of formula (I) is represented by formula (IIa) or formula (IIb), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A, R 1 , R 2 ,W,G,n,Y,E,R 3 and R 4 is as defined above.

[0038] In one embodiment of the invention, the compound of formula (I) is represented by formula (IIIa) or formula (IIIb), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A, W, G, n, Y, E, n, R 3 and R 4 is as defined above.

[0039] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (IVa)-(IVd) or a pharma-ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, A, W, G, Y, E, R 3 and R 4 is as defined above.

[0040] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (Va)-(Vd) or a pharma-ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, A, W, G, E, R14 , R 3 and R 4 is as defined above.

[0041] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (VIa)-(VId) or a pharma-ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, A, W, G, E, R 14 , R 3 and R 4 is as defined above. Preferably, W is optionally substituted methyl, more preferably W is -CH 3 or -CF 3 It is.

[0042] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (VII-1) to (VII-12), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] [ka] In the formula, A, W, E, R 11 , R 12 , R 13 , R 14 , R 3 and R 4 is as defined above. Preferably, W is optionally substituted methyl, more preferably W is -CH 3 or -CF 3 It is.

[0043] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (VII-1a) to (VII-12a) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, A, W, E, R 11 , R 12 , R 13 , R 14 , R 3 and R 4 is as defined above. Preferably, W is optionally substituted methyl, more preferably W is -CH 3 or -CF 3 It is.

[0044] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (VIIIa)-(VIIId) or a pharma-ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, each R 21 are independently optionally substituted methyl, halo, -CN, -OR 11 or -NR 11 R 12 m is 0, 1, 2, 3, 4 or 5; A, W, G, R 11 , R 12 , R 14 , R 3 and R 4 is as defined above. Preferably, each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2. More preferably, each R 21 are independently -F, -Cl, -CN, -CF 3 , -CH 2 F or -CHF 2 and m is 1 or 2.

[0045] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (VIIIe)-(VIIIh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 21 ,m,A,W,G,R 14 , R 3 and R 4 is as defined above. Preferably, each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2.

[0046] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (IXa)-(IXd) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 21 , m, R 3 , R 4 , A, W, R 11 , R 12 and R 14 is as defined above. Preferably, each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2.

[0047] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (IXe)-(IXh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 21 , m, R 3 , R 4 , A, W, R 11 , R 12 and R 14 is as defined above. Preferably, R 21 is halo or optionally substituted methyl, and m is 1 or 2.

[0048] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (X-1) to (X-6), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, m′ is 0, 1 or 2; R 21 , A, W, R 11 , R 12 and R 13 is as defined above. Preferably, m' is 2.

[0049] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (X-1a) to (X-6a), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, R 21 , m', A, W, R 11 , R 12 and R 13 is as defined above. Preferably, m' is 2.

[0050] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XI-1) to (XI-12), or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] [ka] In the formula, R 21 , m', A, R 11 , R 12 and R 13 is as defined above. Preferably, m' is 2.

[0051] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XI-1a) to (XI-12a) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 21 , m', A, R 11 , R 12 and R 13 is as defined above. Preferably, m' is 2.

[0052] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (XIVa)-(XIVd) or a pharma-ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, W, R 21 , m', R 11 , and R 12 is as defined above.

[0053] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XIVe)-(XIVh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, W, R 21 , m', R 11 , and R 12 is as defined above.

[0054] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (XVa)-(XVd) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, each R 31 are independently halo, -CN, -NO 2 , -OR 11 , -NR 11 R 12 , -NR 11 C(O)R 12 , -NR 11 S(O) 2 R 12 , -S(O) 2 R 12 , -S(O) 2 NR 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 -C 1 ~C 6 Alkyl, optionally substituted -C 3 ~C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; W, m', R 3 , R 4 , R 21 , R 11 and R 12 is as defined above. In certain embodiments, two adjacent R 31 The groups, together with the carbon atom to which they are attached, form a 4- to 12-membered carbocyclic or heterocyclic ring which is fused to a phenyl or quinolinyl.

[0055] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVe)-(XVh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, W, m', R 3 , R 4 , R 21 , R31 , R 11 and R 12 is as defined above. In certain embodiments, two adjacent R 31 The groups, together with the carbon atom to which they are attached, form a 4- to 12-membered carbocyclic or heterocyclic ring, which is fused to a phenyl or quinolinyl.

[0056] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVa)-(XVh) or a pharma- ceutically acceptable salt, ester or prodrug thereof, wherein R 3 is -OH, and R 4 is -CH 3 , -CF 3 or cyclopropyl.

[0057] 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 pharma- ceutically acceptable salt, ester, or prodrug thereof; [ka] In the formula, each R 32 are independently halogen, -OR 11 , -NR 11 R 12 , optionally substituted -C 1 ~C 6 -alkyl, optionally substituted -C 3 ~C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; W, m', R 3 , R 4 , R 21 , R 31 , R 11 and R 12 is as defined above. In certain embodiments, two adjacent R 32The groups, together with the carbon atom to which they are attached, form a 4- to 12-membered carbocyclic or heterocyclic ring, which is fused to a phenyl or quinolinyl.

[0058] 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 pharma- ceutically acceptable salt, ester, or prodrug thereof; R 3 is -OH, and R 4 is -CH 3 , -CF 3 or cyclopropyl.

[0059] In one embodiment of the present 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 pharma- ceutically acceptable salt, ester, or prodrug thereof; [ka] In the formula, W, m', R 3 , R 4 , R 21 , R 31 , R 32 , R 11 and R 12 is as defined above. In certain embodiments, two adjacent R 32 The groups, together with the carbon atom to which they are attached, form a 4- to 12-membered carbocyclic or heterocyclic ring, which is fused to a phenyl or quinolinyl.

[0060] In one embodiment of the present 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 pharma- ceutically acceptable salt, ester, or prodrug thereof; R 3 is -OH, and R4 is -CH 3 , -CF 3 or cyclopropyl.

[0061] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (XVIa)-(XVIh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 22 is hydrogen, halogen, -OR 11 , -NR 11 R 12 , optionally substituted -C 1 ~C 6 -alkyl, optionally substituted -C 3 ~C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; W, R 31 , R 21 , m', R 3 , R 4 , R 11 and R 12 is as defined above.

[0062] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVIa)-(XVIh) or a pharma- ceutically acceptable salt, ester, or prodrug thereof, wherein R 3 is -OH, and R 4 is -CH 3 , -CF 3 or cyclopropyl.

[0063] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (XVIIa)-(XVIIh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, W, R 21 , R 22 , R 31 , m', R 3 , R 4 , R 11 and R 12 is as defined above.

[0064] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVIIa)-(XVIIh) or a pharma- ceutically acceptable salt, ester, or prodrug thereof, wherein R 3 is -OH, and R 4 is -CH 3 , -CF 3 or cyclopropyl.

[0065] In one embodiment of the invention, the compound of formula (I) is represented by one of formulae (XVIIIa)-(XVIIId) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 23 is hydrogen and may be substituted -C 1 ~C 6 -alkyl, optionally substituted -C 3 ~C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; R 3 , R 4 , A, W, R 11 , R 12 and R 14 is as defined above.

[0066] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVIIIe)-(XVIIIh) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, R 23 , R 3 , R 4 , A, W, R 11 , R 12 and R 14 is as defined above.

[0067] In one embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVIIIa)-(XVIIIh) or a pharma- ceutically acceptable salt, ester, or prodrug thereof, wherein R 3 is -OH, and R 4 is -CH 3 , -CF 3 or cyclopropyl.

[0068] It will be understood that the description of the invention herein is to be interpreted in accordance with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at any given position.

[0069] Any substituent or variable at a particular position in a molecule (e.g., R 1 , R 2 etc.) are intended to be independent of their definitions elsewhere in that molecule.

[0070] It will be further understood that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomeric and optically active forms.It will be further understood that certain compounds of the present invention may exist in different tautomeric forms.All tautomeric forms are considered to be within the scope of the present invention.

[0071] In certain embodiments, the present invention provides methods for the prevention or treatment of RSV activity, as well as methods for treating a RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[0072] The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of RSV.

[0073] Thus, in one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is combined with a steroidal anti-inflammatory compound, for example, budesonide or fluticasone. In a preferred embodiment, the steroid is administered at a low dose to minimize immunosuppressive effects. In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is combined with a non-steroidal anti-inflammatory compound, for example, a leukotriene antagonist, such as Singulair (Merck) or Accolate (Astra Zeneca), a phosphodiesterase 4 inhibitor, such as roflumilast (Altana), a TNF-alpha inhibitor, or an NSAID, such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech). In a further embodiment, the compound of formula (I) is combined with an interleukin-8 or interleukin-9 inhibitor. Thus, the present invention also relates to a product containing a compound of formula (I) or a pharma- ceutically acceptable salt thereof and an anti-inflammatory compound for simultaneous, separate or sequential use in the treatment of RSV.

[0074] The present invention also relates to the combination of the compound of formula (I) or its pharmaceutically acceptable salt with an anti-influenza compound, and the use of said combination in the treatment of concomitant RSV and influenza infections. Thus, the present invention also relates to a product containing the compound of formula (I) or its pharmaceutically acceptable salt with an anti-influenza compound for simultaneous, separate or sequential use in the treatment of concomitant RSV and influenza infections. The compounds of the present invention can be administered in various dosage forms. Thus, they can be administered orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the present invention can also be administered parenterally, or subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, or by injection techniques. The compounds can also be administered as suppositories.

[0075] In one embodiment, the compounds of the invention are administered by intranasal or intrabronchial administration.The invention also provides an inhaler or nebulizer containing a medicament comprising (a) a derivative of formula (I) or a pharma- ceutically acceptable salt thereof as defined above, and (b) a pharma- ceutically acceptable carrier or diluent.

[0076] The present invention also provides a pharmaceutical composition comprising such a benzodiazepine derivative, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

[0077] The compound of the present invention is typically formulated for administration with pharmaceutically acceptable carrier or diluent.For example, solid oral forms may contain diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch, lubricants such as silica, talc, stearic acid, magnesium stearate or calcium stearate, and / or polyethylene glycol, binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, disintegrants such as starch, alginic acid, alginate or sodium starch glycolate, effervescent mixtures, dyes, sweeteners, wetting agents such as lecithin, polysorbate, lauryl sulfate, and non-toxic and pharmacologically inactive substances generally used in pharmaceutical preparations.Such pharmaceutical preparations can be prepared in known manner, for example by mixing, granulating, tableting, sugar coating or film coating method.

[0078] Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and / or mannitol and / or sorbitol.

[0079] Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma- ceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol, and, if necessary, an appropriate amount of lidocaine hydrochloride.

[0080] The solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.

[0081] The present invention also relates to a novel compound as defined above or a pharma- ceutically acceptable salt thereof for use in a method for treating the human or animal body. The present invention also relates to a pharmaceutical composition comprising a novel compound as defined above and a pharma- ceutically acceptable diluent or carrier. Preferably, the pharmaceutical composition comprises a pharma- ceutically acceptable salt of the novel compound as defined above. The pharma- ceutically acceptable salt is as defined above. The novel compound of the present invention is typically administered in the manner defined above, and the compound is typically formulated for administration in the manner defined above.

[0082] Preferably, pharmaceutical compositions contain the optically active isomer of the novel compound of the present invention.Thus, for example, preferred novel compounds of the present invention that contain only one chiral center include substantially pure R enantiomer, substantially pure S enantiomer, and enantiomeric mixtures that contain excess R enantiomer or excess S enantiomer.It is particularly preferred that pharmaceuticals contain the compounds of the present invention that are substantially pure optical isomers.For the avoidance of doubt, novel compounds of the present invention can be used in the form of solvates, if necessary.

[0083] A further aspect of the invention is a method of making any of the compounds described herein, using any of the synthetic means described herein.

[0084] Definitions Listed below are definitions of various terms used to describe this invention. These definitions apply to those terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0085] The term "aryl" as used herein refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system containing at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. A polycyclic aryl can contain fused rings, covalently linked rings, or combinations thereof.

[0086] The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or polycyclic aromatic radical having one or more ring atoms selected from S, O and N, the remaining ring atoms being carbon, and any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. Polycyclic heteroaryls may contain fused rings, covalently linked rings, or combinations thereof.

[0087] According to the present invention, the aromatic group can be substituted or unsubstituted.

[0088] The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one of which is aromatic, and which may be fused or covalently linked.

[0089] The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon radical. 1 ~C 3 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 10 Alkyl, C 2 ~C 4 Alkyl" or "C 3 ~C 6 "Alkyl" refers to alkyl groups containing 1 to 3, 1 to 6, 1 to 10 carbon atoms, 2 to 4, and 3 to 6 carbon atoms, respectively. 1 ~C 8 Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl radicals.

[0090] The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond formed by the removal of a single hydrogen atom. 2 ~C 10 alkenyl", "C 2 ~C 8 alkenyl", "C 2 ~C 4 alkenyl" or "C 3 ~C 6 "Alkenyl" refers to an alkenyl group containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0091] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond formed by the removal of a single hydrogen atom. 2 ~C 10 alkynyl", "C 2 ~C 8 alkynyl", "C 2~C 4 alkynyl" or "C 3 ~C 6 "Alkynyl" refers to alkynyl groups containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0092] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic saturated carbocyclic ring, or a bicyclic or tricyclic fused, bridged, or spiro system, in which the carbon atoms may be oxo-substituted or substituted with exocyclic olefinic, imine, or oxime double bonds. Preferred cycloalkyl groups include: 3 ~C 12 Cycloalkyl, C 3 ~-C 6 Cycloalkyl, C 3 ~-C 8 Cycloalkyl and C 4 ~-C 7 Cycloalkyl is an example. 3 ~C 12 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.

[0093] The term "cycloalkenyl" as used herein refers to a monocyclic or polycyclic carbocyclic ring, or a bicyclic or tricyclic fused, bridged, or spiro system having at least one carbon-carbon double bond, where the carbon atoms may be oxo-substituted or substituted with an exocyclic olefin, imine, or oxime double bond. Preferred cycloalkenyl groups include those having C 3 ~C 12 Cycloalkenyl, C 3 ~C 8Cycloalkenyl or C 5 ~C 7 Cycloalkenyl groups are also included. 3 ~C 12 Examples of cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, and the like.

[0094] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which the aryl group is substituted. Similarly, the term "heteroarylalkyl" refers to a functional group in which an alkylene chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which the heteroaryl group is substituted.

[0095] As used herein, the term "alkoxy", used alone or in combination with other terms, unless otherwise specified, means an alkyl group having the specified number of carbon atoms attached to the remainder of the molecule through an oxygen atom, e.g., methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy are those represented by the formula (C 1 ~C 3 ) alkoxy.

[0096] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, and cycloalkenyl moiety described herein may also be an aliphatic or alicyclic group.

[0097] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon, hydrogen, halogen, oxygen, nitrogen, or other atoms, and optionally containing one or more units of unsaturation, e.g., double and / or triple bonds. Examples of aliphatic groups are alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 N.H., S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 , C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 and the like, groups containing one or more functional groups, non-aromatic hydrocarbons (which may be substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (which may be substituted) are replaced by a functional group. The carbon atoms of the aliphatic group may be optionally oxo-substituted. The aliphatic group may be linear, branched, cyclic, or a combination thereof, and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups as used herein, aliphatic groups expressly include, for example, alkoxyalkyl, polyalkoxyalkyl, such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group may be substituted.

[0098] The term "carbocycle" or "carbocyclic" refers to a saturated, partially unsaturated, or aromatic ring group in which each atom in the ring is carbon. Examples of carbocycles include cycloalkyl, cycloalkenyl, and aryl groups.

[0099] The terms "heterocyclic" or "heterocycloalkyl" may be used interchangeably and refer to a fused, bridged, or spiro system of non-aromatic rings or bicyclic or tricyclic groups, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are optionally oxo-substituted carbon atoms or carbon atoms substituted with exocyclic olefinic, iminic, or oximic double bonds. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxoxoxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups may be C-attached or N-attached (where possible).

[0100] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc. described herein, when used as a link to connect two or more groups or substituents, may be a divalent or polyvalent group, which may be on the same atom or different atoms. Those skilled in the art can easily determine the valency of any such group from the context in which it occurs.

[0101] The term "substituted" refers to a group in which one, two, or more hydrogen atoms have been replaced with -F, -Cl, -Br, -I, -OH, -C, 1 ~C 12-Alkyl, -C 2 ~C 12 -alkenyl, -C 2 ~C 12 -Alkynyl, -C 3 ~C 12 -Cycloalkyl, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C 1 ~C 12 -Alkyl, -NH-C 2 ~C 8 -Alkenyl, -NH-C 2 ~C 8 -Alkynyl, -NH-C 3 ~C 12 -Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -OC 1 ~C 12 -Alkyl, -OC 2 ~C 8 -Alkenyl, -OC 2 ~C 8 -Alkynyl, -OC 3 ~C 12 -Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C 1 ~C 12 -Alkyl, -C(O)-C 2 ~C 8 -Alkenyl, -C(O)-C 2 ~C 8 -Alkynyl, -C(O)-C 3 ~C 12 -Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH 2 , -CONH-C 1 ~C 12 -Alkyl, -CONH-C 2 ~C 8 -Alkenyl, -CONH-C 2 ~C 8 -Alkynyl, -CONH-C 3 ~C12 -Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO 2 -C 1 ~C 12 -Alkyl, -OCO 2 -C 2 ~C 8 -Alkenyl, -OCO 2 -C 2 ~C 8 -Alkynyl, -OCO 2 -C 3 ~C 12 -Cycloalkyl, -OCO 2 -Aryl, -OCO 2 -heteroaryl, -OCO 2 -heterocycloalkyl, -CO 2 -C 1 ~C 12 Alkyl, -CO 2 -C 2 ~C 8 Alkenyl, -CO 2 -C 2 ~C 8 Alkynyl, CO 2 -C 3 ~C 12 -Cycloalkyl, -CO 2 -aryl, CO 2 -heteroaryl, CO 2 -heterocycloalkyl, -OCONH 2 , -OCONH-C 1 ~C 12 -Alkyl, -OCONH-C 2 ~C 8 -Alkenyl, -OCONH-C 2 ~C 8 -Alkynyl, -OCONH-C 3 ~C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C 1 ~C 12 -Alkyl, -NHC(O)-C 2 ~C 8 -Alkenyl, -NHC(O)-C 2 ~C8 -Alkynyl, -NHC(O)-C 3 ~C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO 2 -C 1 ~C 12 -Alkyl, -NHCO 2 -C 2 ~C 8 -Alkenyl, -NHCO 2 -C 2 ~C 8 -Alkynyl, -NHCO 2 -C 3 ~C 12 -Cycloalkyl, -NHCO 2 -Aryl, -NHCO 2 -Heteroaryl, -NHCO 2 -heterocycloalkyl, -NHC(O)NH 2 , -NHC(O)NH-C 1 ~C 12 -Alkyl, -NHC(O)NH-C 2 ~C 8 -Alkenyl, -NHC(O)NH-C 2 ~C 8 -Alkynyl, -NHC(O)NH-C 3 ~C 12 -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH 2 , -NHC(S)NH-C 1 ~C 12 -Alkyl, -NHC(S)NH-C 2 ~C 8 -Alkenyl, -NHC(S)NH-C 2 ~C 8 -Alkynyl, -NHC(S)NH-C 3 ~C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH 2 , -NHC(NH)NH-C 1 ~C 12-Alkyl, -NHC(NH)NH-C 2 ~C 8 -Alkenyl, -NHC(NH)NH-C 2 ~C 8 -Alkynyl, -NHC(NH)NH-C 3 ~C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C 1 ~C 12 -Alkyl, -NHC(NH)-C 2 ~C 8 -Alkenyl, -NHC(NH)-C 2 ~C 8 -Alkynyl, -NHC(NH)-C 3 ~C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C 1 ~C 12 -Alkyl, -C(NH)NH-C 2 ~C 8 -Alkenyl, -C(NH)NH-C 2 ~C 8 -Alkynyl, -C(NH)NH-C 3 ~C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C 1 ~C 12 -Alkyl, -S(O)-C 2 ~C 8 -Alkenyl, -S(O)-C 2 ~C 8 -Alkynyl, -S(O)-C 3 ~C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO 2 NH 2 , -SO 2 NH-C 1 ~C 12 -Alkyl, -SO 2 NH-C 2~C 8 -Alkenyl, -SO 2 NH-C 2 ~C 8 -Alkynyl, -SO 2 NH-C 3 ~C 12 -Cycloalkyl, -SO 2 NH-aryl, -SO 2 NH-heteroaryl, -SO 2 NH-Heterocycloalkyl, -NHSO 2 -C 1 ~C 12 -Alkyl, -NHSO 2 -C 2 ~C 8 -Alkenyl, -NHSO 2 -C 2 ~C 8 -Alkynyl, -NHSO 2 -C 3 ~C 12 -Cycloalkyl, -NHSO 2 -Aryl, -NHSO 2 -heteroaryl, -NHSO 2 -heterocycloalkyl, -CH 2 NH 2 , -CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C 3 ~C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -SC 1 ~C 12 -Alkyl, -SC 2 ~C 8 -Alkenyl, -SC 2 ~C 8 -Alkynyl, -SC 3 ~C 12In certain embodiments, the substituents are independently selected from halo, preferably Cl and F, C, C-C ... 1 ~C 4 -alkyl, preferably methyl and ethyl, halo-C 1 ~C 4 -alkyl, for example fluoromethyl, difluoromethyl and trifluoromethyl, C 2 ~C 4 -Alkenyl, halo-C 2 ~C 4 -Alkenyl, C 3 ~C 6 -Cycloalkyl, e.g. cyclopropyl, C 1 ~C 4 -alkoxy, such as methoxy and ethoxy, halo-C 1 ~C 4 -Alkoxy, for example, fluoromethoxy, difluoromethoxy and trifluoromethoxy, -CN, -OH, NH 2 , C 1 ~C 4 -Alkylamino, di(C 1 ~C 4 -alkyl)amino, and NO 2 It is understood that aryl, heteroaryl, alkyl, and the like can be further substituted. In some cases, each substituent of the substituted moiety is optionally further substituted, where possible, with one or more groups, each group being independently selected from C 1 ~C 4 -Alkyl, -CF 3 , -OCH 3 , -OCF 3 , -F, -Cl, -Br, -I, -OH, -NO 2 , -CN and -NH 2 is selected from.

[0102] In certain embodiments, substituted alkyl, alkenyl or alkoxy groups are substituted with one or more halogen atoms, preferably fluorine or chlorine atoms.Such substituted alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.Such substituted alkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy.

[0103] The terms "halo" or "halogen," as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0104] The term "optionally substituted" as used herein means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group may be substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group may be substituted with one or more additional groups individually and independently selected from the groups described herein.

[0105] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharma- cetically acceptable.

[0106] In certain embodiments, the compounds of each formula herein are defined to include isotopically labeled compounds. An "isotopically labeled compound" is a compound in which at least one atomic arrangement is enriched in a particular isotope of a specified element to a level significantly higher than the natural abundance of that isotope. For example, one or more hydrogen atomic arrangements in the compound can be enriched with deuterium to a level significantly higher than the natural abundance of deuterium, for example, to a level of at least 1%, preferably at least 20% or at least 50%. Such deuterated compounds can, for example, be metabolized slower than their non-deuterated analogs, and therefore can exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example, by using deuterated starting materials. Unless otherwise specified, isotopically labeled compounds are pharma- ceutically acceptable.

[0107] The term "hydroxy activating group" as used herein refers to a labile chemical moiety known in the art to activate hydroxyl groups for elimination during a synthetic procedure such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, phosphonates, and the like.

[0108] The term "activated hydroxyl" as used herein refers to a hydroxy group that has been activated with a hydroxyl activating group as defined above, including, for example, a mesylate, tosylate, triflate, p-nitrobenzoate, or phosphonate group.

[0109] The term "hydroxy protecting group" as used herein refers to a labile chemical moiety known in the art to protect a hydroxyl group from undesired reactions during synthetic procedures. After said synthetic procedures, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are described in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0110] The term "protected hydroxy" as used herein refers to a hydroxy group protected with a hydroxy-protecting group, as defined above, which includes, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

[0111] The term "hydroxy prodrug group" as used herein refers to a promoiety group known in the art to temporarily alter the physicochemical and therefore biological properties of the parent drug by covering or masking the hydroxy group. After the synthetic procedure, the hydroxy prodrug group described herein must be capable of reverting back to the hydroxy group in vivo. Hydroxy prodrug groups known in the art are described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery ,(Drugs and the Pharmaceutical Sciences;Volume 53), Marcel Dekker, Inc., New York(1992) and in ``Prodrugs of Alcohols and Phenols'' by SSDhareshwar and VJStella,in Prodrugs Challenges and Rewards Part-2(Biotechnology: Pharmaceutical Aspects), edited by VJ Stella, et al, Springer and AAPS Press, 2007, pp 31-99.

[0112] The term "amino-protecting group" as used herein refers to a labile chemical moiety known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedures, the amino-protecting groups described herein can be selectively removed. Amino-protecting groups known in the art are described in TH Greene and PG M Huts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons, New York (1999). Examples of amino-protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0113] The term "protected amino" as used herein refers to an amino group protected with an amino-protecting group as defined above.

[0114] The term "leaving group" means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo, and iodo groups, sulfonate ester groups, such as mesylate, tosylate, brosylate, nosylate, and acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like.

[0115] The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be 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, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, e.g., Organic Solvents Physical Properties and Methods of Purification ,4th ed.,edited by John A.Riddick et al.,Vol.II,in the Techniques of Chemistry Series , John Wiley & Sons, NY, 1986.

[0116] The term "protic solvent" as used herein refers to a solvent that tends to provide a proton, such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. Such solvents are well known to those of skill 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, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of protic solvents can be found in organic chemistry textbooks or specialized monographs, e.g., Organic Solvents Physical Properties and Methods of Purification ,4th ed.,edited by John A.Riddick et al.,Vol.II,in the Techniques of Chemistry Series , John Wiley & Sons, NY, 1986.

[0117] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and maintain their compound integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0118] The synthesized compounds may be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by one of ordinary skill in the art, additional methods of synthesizing the compounds of the formulae herein will be apparent to one of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations ,2 nd Ed. Wiley-VCH (1999), TWGreene and PGMWuts, 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 its successor editions.

[0119] The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, etc.

[0120] The compounds of the present invention can be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and can include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter excretion rate.

[0121] The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers that may be defined in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above or by resolving the racemic mixtures. Resolution may be carried out in the presence of a resolving agent, by chromatography, or by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution may be found in Jacques, et al., Enantiomers, Racemates, and Resolutions( John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers or cis and trans isomers. Likewise, all tautomeric forms are intended to be included. Tautomers may be cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein has been selected for convenience only and is not intended to designate a particular configuration unless so stated in the text, therefore, a carbon-carbon double bond or carbon-heteroatom double bond shown arbitrarily as trans herein may be cis, trans, or a mixture of the two in any ratio.

[0122] Certain compounds of the present invention may also exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation around an asymmetric single bond, for example due to steric hindrance or ring strain, may allow the separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0123] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts that are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or 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 pharma- ceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, valerate, and the like.Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and arylsulfonates.

[0124] Pharmaceutically acceptable salts can also be prepared by deprotonating the parent compound with a suitable base, thereby forming an anionic conjugate base of the parent compound. In such salts, the counterion is a cation. Suitable cations include Li + , Na + , K + and Cs + Alkali metal cations including Mg 2+ and Ca 2+ and alkaline earth metal cations such as ammonium and metal cations such as ammonium.

[0125] As used herein, the term "pharmaceutical acceptable ester" refers to an ester that hydrolyzes in vivo, including those that decompose easily in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or fewer carbon atoms. Examples of specific esters include, but are not limited to, C esters such as acetate, propionate, butyrate and pivalate. 1 ~C 6 -Esters of alkanoic acids.

[0126] In certain embodiments, the present invention provides pharma- ceutically acceptable prodrugs of the compounds disclosed herein. As used herein, the term "pharma- ceutically acceptable prodrugs" refers to prodrugs of the compounds formed by the methods of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals having excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, as well as zwitterionic forms of the compounds of the present invention, if possible. As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to provide any compound shown by the formulas of the present invention. Various forms of prodrugs are known in the art, see, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (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 This is explained in Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,' John Wiley and Sons, Ltd. (2002).

[0127] Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including but not limited to hemisuccinates, ethylsuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs of hydroxyl groups, sulfonate esters, and sulfate esters. Derivatization of hydroxyl groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also included, and the acyl group can be an alkyl ester, substituted with groups including but not limited to ether, amine, and carboxylic acid functional groups, or 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 derivatized as amides, sulfonamides, or phosphonamides. All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities. In certain embodiments, the compounds of the invention may incorporate two or more groups which are metabolically removed in vivo to yield the active parent compound.

[0128] The term "treat" as used herein means to alleviate, relieve, reduce, eliminate, modulate, or ameliorate, i.e., cause the regression of a disease state or condition. Treating can also include, for example, where a disease state or condition may already exist, inhibiting an existing disease state or condition, i.e., preventing its onset, and relieving or ameliorating an existing disease state or condition, i.e., causing its regression.

[0129] The term "prevent" as used herein means to stop a disease state or condition from occurring completely or nearly completely in a patient or subject, particularly if the patient or subject is susceptible to or at risk of contracting the disease state or condition.

[0130] Furthermore, the compounds of the present invention, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0131] "Solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds form solvates because they tend to trap a fixed molar ratio of solvent molecules in a crystalline solid. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is a compound formed by mixing one or more water molecules with water at a temperature of 100° C. or less. 2 O, and such combination can form one or more hydrates.

[0132] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound.

[0133] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and maintain their compound integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0134] The synthesized compounds may be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. Additionally, the various synthetic steps may be performed in an alternate sequence or order to obtain the desired compounds. Additionally, the solvents, temperatures, reaction times, and the like described herein are for illustrative purposes only, and variations in reaction conditions may produce the desired bridged macrocyclic products of the invention. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein include those described, for example, by R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989), T.W. Greene and P.G. M. Huts, 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).

[0135] The compounds of the invention can be modified by appending various functional groups via synthetic means described herein to enhance selective biological properties. Such modifications include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter excretion rate.

[0136] Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of the compounds of the present invention formulated together with one or more pharma- ceutically acceptable carriers. As used herein, the term "pharma-ceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating substance or formulation auxiliary. Some examples of substances which may function as pharma- ceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch, potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, esters such as propylene glycol, ethyl oleate, ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer; other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents and perfuming agents, preservatives and antioxidants may also be present in the composition according to the judgment of the formulator. The pharmaceutical compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powders, ointments or drops), buccally, or as an oral or nasal spray.

[0137] The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection.The pharmaceutical composition of the present invention can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle.Optionally, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form.The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0138] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0139] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0140] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium prior to use.

[0141] To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0142] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0143] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, f) absorption enhancers, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0144] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0145] The active compound may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient only, i.e. preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0146] The dosage form for topical or transdermal administration of the compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any necessary preservatives or buffers as required.Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also contemplated within the scope of the present invention.

[0147] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0148] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0149] Transdermal patch has the additional advantage of providing controlled compound delivery to the body.Such dosage forms can be made by dissolving or compounding the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0150] Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to those skilled in the art. All publications, patents, published patent applications, and other references mentioned herein are incorporated herein by reference in their entirety.

[0151] Abbreviations Abbreviations used in the description of the following schemes and examples are: ACN for acetonitrile, (9S)-(9''S)-9,9''-[1,4-phthalazinediylbis(oxy)]bis[10,11-dihydro-6'-methoxycinchonan] for AD-mix-β, Bn for benzyl, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate for BOP, BzCl for benzoyl chloride, mCPBA for meta-chloroperbenzoic acid; Cbz for benzyloxycarbonyl, CDI for carbonyldiimidazole, DAST for diethylaminosulfur trifluoride; DBU for 1,8-diazabicycloundec-7-ene, DCE for dichloroethane, DCM for dichloromethane, Dess-Martin periodinane for 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, DIAD for diisopropyl azodicarboxylate, DIBAL-H for diisobutylaluminum hydride, DMAP for N,N-dimethylaminopyridine, DME for 1,2-dimethoxyethane, DMF for N,N-dimethylformamide, DMSO for dimethyl sulfoxide, Diphenylphosphoryl azide or diphenylphosphoryl azidate to DPPA, dppf for 1,1'-bis(diphenylphosphino)ferrocene, 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride to EDCI or EDC, EtOAc for ethyl acetate, Ghosez reagent for 1-chloro-N,N,2-trimethyl-1-propenylamine, HATU for O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl for hydrochloric acid, Hunig's base for diisopropylethylamine, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate for PyBOP, Lithium diisopropylamine vs LDA, Palladium-C for palladium-carbon, Ph for phenyl, RT for reverse transcription; RT-PCR for reverse transcription polymerase chain reaction; TBME for tert-butyl methyl ether, TEA for triethylamine, Tf for trifluoromethanesulfonic anhydride 2 O. TFA for trifluoroacetic acid, THF for tetrahydrofuran, For hexamethyldisilazane (TMS) 2 N.H., TBS for tert-butyldimethylsilyl, TBDPS for tert-butyldiphenylsilyl, TMS for trimethylsilyl, TPAP for tetrapropylammonium perruthenate, TPP or PPh for triphenylphosphine 3 , p-CH 3 C 6 H 4 SO 2 -Ts or tosyl, tBOC or Boc for tert-butyloxycarbonyl, and Xantphos for 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene It is.

[0152] Synthesis Methods The compounds and methods of the present invention will be better understood with reference to the following synthetic schemes illustrating how the compounds of the present invention can be prepared, which are intended as examples only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, and / or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0153] Scheme 1 illustrates a method for preparing compounds of formula 11 from compounds 1 and 2, where n=1, 2, or 3, P is a hydroxy protecting group, Ar is E, and E is as defined above. Using Mitsunobu reaction conditions, hydroxypyridine 1 can be alkylated with a hydroxy epoxide to give epoxide 4. Alternatively, the hydroxy epoxide can be converted to 3 with a leaving group, such as, but not limited to, tosyl and methanesulfonyl, followed by reaction with a hydroxy epoxide, such as, but not limited to, K. 2 CO 3 and Cs 2 CO 3 Alkylation in the presence of a base such as, but not limited to, LDA, affords compound 4. Intramolecular epoxide ring opening mediated by a base such as, but not limited to, LDA, affords compound 5. Protection of the hydroxy group compound 5 with an appropriate protecting group such as, but not limited to, TBDPS and TBS affords compound 6. Trifluoromethyl ketone 7 can be obtained from iodine-magnesium exchange of compound 6 followed by addition of an ester such as, but not limited to, ethyl 2,2,2-trifluoroacetate. Cross-coupling of trifluoromethyl ketone 7 with various metal coupling partners 8 such as, but not limited to, boronic acids, boronic esters, organotin reagents, organozinc reagents, organomagnesium reagents, organosilicon reagents, catalyzed by an appropriate catalyst such as Pd, Ni, Cu, affords compound 9 ... 2 CO 3 and Cs 2 CO 3 Addition of nitromethane to compound 9 in the presence of a base such as affords compound 10. Reduction of the nitro group with a reducing agent such as, but not limited to, zinc and acetic acid produces the key intermediate 11. Scheme 1 [ka]

[0154] As seen in Scheme 2, Ar 1 is A, Ar is E, and R is R 11where n is 1, 2 or 3; A, E, R 11 is as defined above. The key intermediate 11 is coupled with various carboxylic acids to give amides 14. Amides 14 are then reacted with various electrophiles to generate various ethers, esters and carbamates of formula 15. Amides 14 are also oxidized to aldehydes 16, followed by reductive amination to give various amines 17. The -CH of amides 14 can be reacted with various electrophiles to give various ethers, esters and carbamates of formula 15. 2 The hydroxyl of OH is converted to cyanomethyl 18 by activation and subsequent cyanation. Compound 14-1 is further converted to acetamide 19 in the presence of a catalyst, such as, but not limited to, Perkin's catalyst. Scheme 2 [ka]

[0155] As seen in Scheme 3, Ar 1 is A, Ar is E, and R is R 11 A, E, R 11 is as defined above. Aldehydes 16 are converted to benzyl-protected amines by reductive amination. Hydrogenolysis affords the free amines 20. Finally, displacement with various electrophiles affords N-substituted compounds 21. Scheme 3 [ka]

[0156] As seen in Scheme 4, Ar 1 is A, Ar is E, and R' is -C 1 ~C 6 Alkyl, -C 3 ~C 6where n is cycloalkyl, aryl or heteroaryl, n is 1, 2 or 3, and A and E are as previously defined. Aldehyde 16 is oxidized to acid 22, which is then further transformed to amide 23 and sulfonamide 24 using common methods such as, but not limited to, HATU and DIPEA. From there, diversification to a variety of esters and amides can be carried out. Scheme 4 [ka]

[0157] Scheme 5 shows another method for preparing compounds of formula 11, where Ar is E, P is a hydroxy protecting group, n is 1, 2 or 3, and E is as defined above. Ketone 9 is converted to compounds of formula 26 by olefination. Alternatively, 26 can be prepared by 1) cross-coupling 6 with a metal coupling partner 6-1, such as, but not limited to, boronic acid, boronic ester, organotin reagent, organozinc reagent, organomagnesium reagent, organosilicon reagent, catalyzed by a suitable catalyst such as Pd, Ni, Cu, etc., to give compound 25, and 2) converting compound 25 to compound 26 as previously described in Scheme 1. With 26 in hand, compounds of formula 27 are prepared by dihydroxylation followed by epoxide formation. Examples of suitable methods include, but are not limited to, NH 4 OH and NH 3 Epoxide ring opening of compound 27 with an amine equivalent such as provides compounds of formula 11. Scheme 5 [ka]

[0158] Scheme 6 shows an alternative method for preparing compounds of formula 23, 1 is A, Ar is E, and R' is -C 1 ~C 6 Alkyl, -C 3 ~C 6where n is cycloalkyl, aryl or heteroaryl, n is 1, 2 or 3, and A and E are as defined above. Amine 11 is protected with a protecting group such as, but not limited to, Boc and Cbz. After deprotection of the hydroxy protecting group, subsequent oxidation provides acid 30. Compound 30 is coupled with various amines to provide amide 31. Deprotection of the amine protecting group followed by amide formation provides compounds of formula 23. Scheme 6 [ka]

[0159] Scheme 7 shows a further route to synthesize the desired compounds. The difference in this route is that it starts with oxidation and amide coupling to introduce amide 33 at the beginning of the synthesis. Sequential vinylation and arylation give the bis-coupled product 34. Asymmetric dihydroxylation followed by activation and substitution gives the amino alcohol precursor. Finally, amide coupling with the respective aryl acid produces the desired compound represented by compound 36. Scheme 7 [ka]

[0160] Examples The compounds and methods of the present invention will be better understood in connection with the following examples, which are intended as illustrations only and not as limitations on the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations and / or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0161] Example 1 [ka] Example 1 step a: [ka] To a 500 mL round bottom flask equipped with a stir bar was added 2-bromo-6-iodopyridin-3-ol (14.21 g, 47.4 mmol) and 2-pyridyldiphenylphosphine (13.3 g, 52.1 mmol). The flask was purged with nitrogen and the solid was dissolved in THF (95 mL, 0.5 M). At 0° C., (S)-(2-methyloxiran-2-yl)methanol (4.176 g, 47.4 mmol) was added, followed by the slow addition of DIAD (10.14 ml, 52.1 mmol). The flask was allowed to warm to room temperature and the reaction was monitored by LCMS (5 h). The reaction was diluted with EtOAc and quenched with water. EtOAc extraction was performed and the crude residue was purified by automated column chromatography (silica gel, 50% ethyl acetate in hexanes) for 1 h. f =0.75) and dried under high vacuum to give the title compound as an off-white foamy solid (11.77 g, 67%). ESI-MS m / z: 370.0 / 372.0 [M+H] + .

[0162] Example 1 step b: [ka] To a 500 mL round bottom flask equipped with a stir bar was added the compound from step a (11.77 g, 31.8 mmol). The flask was purged with nitrogen and the solid was dissolved in THF (80 mL, 0.3 M). At 0° C., LDA solution (35.0 mmol, 17.5 mL of 2.0 M LDA in 26 mL of THF) was added slowly (fast dropwise) over 10 min. The reaction was stirred at 0° C. and monitored by LCMS (5- and 6-membered rings have different retention times). If not complete, the flask was allowed to warm to room temperature until complete. The reaction mixture was diluted with EtOAc at 0° C. and quenched with water and saturated ammonium chloride. An EtOAc extraction was performed and the residue was dried in vacuum overnight to remove diisopropylamine to give the title compound, which was used in the next reaction without purification. ESI-MS m / z: 370.0 / 372.0 [M+H] + .

[0163] Example 1 step c: [ka] A 500 mL round bottom flask containing the compound from step b (11.77 g, 31.8 mmol, mixture) was fitted with a stir bar. The residue was dissolved in DMF (64 mL, 0.5 M) and imidazole (4.76 g, 70.0 mmol) was added. The flask was purged with nitrogen and tert-butylchlorodiphenylsilane (9.10 ml, 35.0 mmol) was added at 0° C. The flask was allowed to warm to room temperature and the reaction was monitored by LMCS (3 h). The reaction was diluted with EtOAc and quenched with water. EtOAc extraction was performed and the crude residue was purified by automated column chromatography (silica gel, 25% ethyl acetate in hexanes) to obtain a 1:1 ratio. f =0.78) and dried under high vacuum to give the title compound as an off-white foamy solid (7.87 g, 57%) over two steps. ESI-MS m / z: 608.4 / 610.4 [M+H] + .

[0164] Example 1 step d: [ka] A 250 mL round bottom flask containing the compound from step c (7.87 g, 12.94 mmol) was fitted with a stir bar 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. Isopropylmagnesium chloride (7.76 ml, 15.52 mmol) was then added slowly and the reaction was stirred for 10 min. The flask was then warmed to 0°C and monitored by LCMS. (1 h: reaction allowed to warm to room temperature). The reaction was diluted with EtOAc at 0°C and quenched with water and saturated ammonium chloride. An EtOAc extraction was performed and the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes, multiple peaks due to hydrate formation) and dried under high vacuum to give the title compound as a clear, sticky residue (7.27 g, 97%, mixture of ketone and hydrate). ESI-MS m / z: 610.2 / 612.4 [M+H] + (MeOH adduct from LCMS of MeOH).

[0165] Example 1 step e: [ka] A 250 mL round-bottom flask containing the compound from step d (7.27 g, 12.57 mmol) was equipped with a stir bar. The residue was dissolved in 1,4-dioxane (50 mL, 0.2 M) and potassium carbonate (3.91 g, 28.3 mmol) was added. PdCl 2(dppf) (0.460 g, 0.628 mmol) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.35 g, 15.08 mmol) were added and the flask was purged with nitrogen. Water (12 mL, sparged with nitrogen for 15 min) was then added. The flask was then immediately fitted with a condenser and heated to 90 °C under a stream of nitrogen for 14 h. The reaction conversion was monitored by LCMS. The reaction was diluted with EtOAc and quenched with saturated ammonium chloride. An EtOAc extraction was performed and the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give a mixture of product and hydrate. The product was dissolved in 20 mL of toluene and diluted with MgSO 4 A suspension was formed and dehydrated with vigorous stirring for 1.5 h. Dehydration was monitored by HNMR aliquots. MgSO 4 The solid was triturated with DCM to give the title compound as a white foamy solid (6.33 g, 85%). ESI-MS m / z: 612.4 [M+H] + (LCMS water adduct). Example 1 step f:

[0166] [ka] A 250 mL round bottom flask containing the compound from step e (6.33 g, 10.02 mmol) was fitted with a stir bar. Nitromethane (40 mL, 0.25 M) was added followed by potassium carbonate (4.16 g, 30.1 mmol). The flask was stirred at room temperature and progress was monitored by LCMS (2.5 h). The reaction was diluted with EtOAc and quenched with water and saturated ammonium chloride. An EtOAc extraction was performed and the crude residue purified by automated column chromatography (silica gel, 25% ethyl acetate in hexanes) for 1 h. f =0.70) and dried under high vacuum to give the title compound as a white foamy solid (6.02 g, 92%, mixture of diastereomers). ESI-MS m / z: 655.4 [M+H] + .

[0167] Example 1 step g: [ka] A 250 mL round bottom flask containing the compound from step f (6.02 g, 9.19 mmol) was fitted with a stir bar. The solid was dissolved in AcOH (28 mL, 0.33 M) and the flask was cooled to 0° C. Zinc (6.01 g, 92 mmol) was added and the reaction was allowed to warm to room temperature and monitored by LCMS (2 h). The reaction was diluted with EtOAc and the zinc was removed by filtration through a celite pad. The celite was rinsed with EtOAc and MeOH. The combined organics were concentrated under reduced pressure to remove most of the acetic acid. The crude residue was dissolved in EtOAc and water was added. The pH was brought to 8-9 with saturated sodium bicarbonate and stirred. The aqueous was extracted with EtOAc (4×) and concentrated under reduced pressure. The crude residue was purified 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%, mixture of diastereomers). ESI-MS m / z:625.4 [M+H] + .

[0168] Example 2 [ka] Example 2 step a: [ka] Method A To a 40 mL flask equipped with a stir bar was added the compound from Example 1 step g (1.00 g, 1.601 mmol). The flask was purged with nitrogen and the solid was dissolved in THF (5 mL, 0.33 M). At 0° C., TBAF (3.20 ml, 3.20 mmol) was added slowly. The reaction was stirred at room temperature and monitored by LCMS (3 h). Upon completion, the stir bar was removed and the reaction was concentrated and directly purified 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 ammonium salts to give the title compound as a white fluffy solid (489 mg, 79%, mixture of diastereomers). ESI-MS m / z: 387.4 [M+H] + .

[0169] Example 2, step b: [ka] To a 20 mL vial equipped with a stir bar was added 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). The solid was dissolved in DMF (3.84 mL, 0.33 M) and Hunig's base (442 μl, 2.53 mmol) was added. HATU (578 mg, 1.519 mmol) was added in one portion, the vial was purged with nitrogen, and the reaction was stirred at room temperature until complete (LCMS 4 h). The mixture was diluted with EtOAc and quenched with water and saturated ammonium chloride. EtOAc extraction was performed using a phase separator cartridge and the crude residue was purified by automated column chromatography (silica gel, ethyl acetate in R). f =0.80) to give the title compound as a white foamy solid (625 mg, 71%, mixture of diastereomers). ESI-MS m / z: 695.4 [M+H] + .

[0170] Example 2 step c: [ka] Method B To a 20 mL vial equipped with a stir bar was added the compound from step b (575 mg, 0.828 mmol). The solid was dissolved in DCM (2.5 mL, 0.33 M) and the vial was cooled to 0 °C. Dess-Martin periodinane (386 mg, 0.91 mmol) was added, the vial was purged with nitrogen and stirred for 10 min. The reaction was allowed to warm to room temperature and monitored by LCMS (30 min to 1 h). Upon completion, the reaction was diluted with DCM and quenched with a 1:1 solution of saturated sodium bicarbonate:saturated sodium thiosulfate. The mixture was stirred vigorously for approximately 20 min until the solution was clear. DCM extraction was performed using a phase separator cartridge and the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound as a white foamy solid (518 mg, 90%, mixture of diastereomers). ESI-MS m / z:693.2 [M+H] + .

[0171] Example 2 step d: [ka] Method C To a 2-dram vial equipped with a stir bar was added the compound from step c (40 mg, 0.058 mmol). The solid was dissolved in DCE (0.2 mL, 0.33 M) and cyclopropylamine was added (solution in DCE, 3.3 mg, 0.058 mmol). Sodium triacetoxyborohydride (18.36 mg, 0.087 mmol) was added in one portion and the vial was purged with nitrogen and stirred at room temperature. The reaction was monitored by LCMS (4 h), diluted with DCM and quenched with water. The aqueous was brought to a pH of approximately 8-9 with saturated sodium bicarbonate. A DCM extraction was performed using a phase separator cartridge and the residue was concentrated. The crude residue was Method D The TBS deprotection was carried out as shown below. ESI-MS m / z: 734.6 [M+H] + .

[0172] Example 3 [ka] Method D A 20 mL vial containing the compound from Example 2 step d (42.4 mg, 0.058 mmol) was fitted with a stir bar and the solid was dissolved in DCM (0.39 mL, 0.15 M). HCl in dioxane (4 M, 0.19 mL, 0.74 mmol) was added and the reaction was stirred at room temperature. Once complete by LCMS (2 h), the reaction was diluted with DCM and quenched with saturated sodium bicarbonate until the pH was approximately 8-9. A DCM extraction was performed using a phase separator cartridge and the organics were concentrated. The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0173] Example 4 [ka] Using 40 mg of the compound from Example 2, step c, and (S)-1-cyclopropylethylamine, Methods C and D The title compound was synthesized in a similar sequence to that described above. ESI-MS m / z: 762.4 [M+H] + (TBS alcohol). The mixture of diastereomers did not separate well on HPLC. The mixture was purified by automated column chromatography (silica gel, 5% methanol in dichloromethane). f =0.65, EtOAc / Hexanes, then MeOH / DCM) and lyophilization afforded the title compound as a white fluffy solid (23 mg, 63%, mixture of diastereomers). ESI-MS m / z: 648.4 [M+H] + .

[0174] Example 5 [ka] Using 40 mg of the compound from Example 2, step c, and aniline, Methods C and D The title compound was synthesized in a similar sequence to that described above. ESI-MS m / z: 770.3 [M+H] + (TBS alcohol). The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0175] Example 6 [ka] To a 2-dram vial equipped with stirring was added the compound from Example 2, step b (32.3 mg, 0.046 mmol). The vial was purged with nitrogen and the solid was dissolved in DCM (0.23 mL, 0.2 M). Hunig's 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 cartridge. ESI-MS m / z: 814.4 [M+H] + (TBS Alcohol).

[0176] Method D The crude residue was carried forward for TBS deprotection as described in. The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0177] Example 7 [ka] The title compound was synthesized similarly to the phenyl carbamate formation above (Example 6) using 30 mg of the compound from Example 2 step b, but using cyclopropyl isocyanate (cAUTION, volatile). ESI-MS m / z: 778.5 [M+H] + (TBS Alcohol). Method D The TBS group was deprotected as described in. The mixture of diastereomers was analyzed by HPLC to confirm 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] + Obtained as.

[0178] Example 8 [ka] Example 8 step a: [ka] Using 137 mg of the compound from Example 2, step c, benzylamine (30.0 μl, 0.27 mmol, 1.7 eq.) and 1.7 eq. of sodium triacetoxyborohydride, Method C The title compound was synthesized according to the procedure described above. The compound was purified by automated column chromatography (silica gel, 50% ethyl acetate in hexane) using R f =0.50) to give the title compound as a white foamy solid (112 mg, 72%, mixture of diastereomers ESI-MS m / z: 664.5 [M+H] + .

[0179] Example 8 step b: [ka] A 20 mL vial containing the compound from step a (100 mg, 0.128 mmol) was equipped with a stir bar. 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 washed with H 2 The reaction was purged with a balloon of H 2 The reaction was monitored by LCMS (2 h). The balloon was removed and the mixture was filtered through a celite pad with EtOAc. The organics were concentrated and triturated with DCM to give the title compound as a white foamy solid (75 mg, 84%, mixture of diastereomers). ESI-MS m / z: 694.4 [M+H] + .

[0180] Example 8 step c: [ka] Method E To a 2-dram vial equipped with a stir bar was added the compound from step b (28.65 mg, 0.041 mmol). The vial was purged with nitrogen and the solid was dissolved in DCM (0.21 mL, 0.20 M). Hunig's 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. A DCM extraction was performed using a phase separator cartridge. The crude residue was analyzed by HNMR to observe a shift of the primary amine alpha-proton. ESI-MS m / z: 798.3 [M+H] + (TBS Alcohol).

[0181] Method D The crude residue was carried forward to TBS deprotection as described in. The mixture of diastereomers was analyzed by HPLC to confirm 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]+ .

[0182] Example 9 [ka] Using 30 mg of the compound from Example 8, step b, and cyclopropanecarbonyl chloride, Method E The title compound was synthesized according to: The crude residue was analyzed by HNMR to observe a shift of the primary amine alpha-proton.

[0183] The crude residue is Method D The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0184] Example 10 [ka] Example 10 step a: [ka] Method F To a 20 mL vial equipped with stirring was added the compound from Example 2, step c (300 mg, 0.433 mmol). The solid was dissolved in tert-BuOH (5.8 mL, 0.05 M) and 2-methyl-2-butene (1.0 M in THF, 6 mL, 12.0 mmol) was added. Sodium chlorite (490 mg, 4.33 mmol) and monobasic sodium phosphate (520 mg, 4.33 mmol) were dissolved in water (2.9 mL) and the solution was added dropwise to the reaction vial. The vial was quickly purged with nitrogen and monitored by LCMS (30 min). The stir bar was removed and the volatiles were concentrated under reduced pressure. The mixture was diluted with EtOAc and water and the pH was checked to ensure acidic (approximately pH=4). An EtOAc extraction was performed and the residue was purified by automated column chromatography (silica gel, 5% methanol in dichloromethane in R f =0.20) to give the title compound as a white foamy solid (252 mg, 82%, mixture of diastereomers). ESI-MS m / z: 709.4 [M+H] + .

[0185] Example 10 step b: [ka] Method G To a 2-dram vial equipped with a stir bar was added the compound from step a (52 mg, 0.073 mmol). The solid was dissolved in DMF (0.37 mL, 0.20 M) and cyclopropylamine (7.76 μl, 0.110 mmol) was added. Hunig's base (32.0 μl, 0.183 mmol) was added followed by HATU (33.5 mg, 0.088 mmol) in one portion. The reaction was purged with nitrogen and monitored by LCMS until complete (2.5 h). The reaction was diluted with EtOAc and quenched with water. Extracted with EtOAc using a phase separator cartridge. ESI-MS m / z: 748.3 [M+H] + (TBS Alcohol).

[0186] Method DThe crude residue was carried forward to TBS deprotection as described in. The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0187] Example 11 [ka] Using 50 mg of the compound of Example 10, step a, ammonium chloride (15 mg, 0.28 mmol, 4.0 equiv.) and 6.0 equiv. of Hunig's base, Method G The title compound was synthesized according to the method described in ESI-MS m / z: 708.4 [M+H]. + (TBS Alcohol).

[0188] Method D The crude residue was carried forward to TBS deprotection as described in. The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0189] Example 12 [ka] Using 50 mg of the compound of Example 10, step a, cyclopropylsulfonamide (26 mg, 0.212 mmol, 3.0 eq.), 3.0 eq. of Hunig's base and 1.5 eq. of HATU, Method G The title compound was synthesized according to the method described in ESI-MS m / z: 812.4 [M+H]. + (TBS Alcohol).

[0190] Method DThe crude residue was carried forward for TBS deprotection as described in. The mixture of diastereomers was analyzed by HPLC to confirm 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] + .

[0191] Example 13 [ka] 44 mg of the compound of Example 10, step a, Method D The mixture was analyzed by HPLC to confirm separation. The mixture was purified by automated column chromatography (silica gel, 10% methanol in dichloromethane) f =0.20) and lyophilized overnight to give the title compound as a white fluffy solid (23 mg, 62%, mixture of diastereomers). ESI-MS m / z: 595.1 [M+H] + .

[0192] Example 14 [ka] Method H To a 40 mL vial equipped with a stir bar was added 4-cyclopropoxy-3-methoxybenzoic acid (100 mg, 0.480 mmol) and the vial was purged with nitrogen. DCM (3.20 mL, 0.15 M) was added, followed by the slow addition of Ghosez's reagent (127 μl, 0.960 mmol). The reaction was stirred at room temperature for 1.3 h.

[0193] The stir bar was removed and the reaction was concentrated. Placed under high vacuum for approximately 45 minutes to remove any Ghosez reagent. A stir bar was added to the acid chloride, the vial was purged with nitrogen, and DCM (2 mL) was added. The amino alcohol from Example 1 step g (300 mg, 0.480 mmol) was then added as a solution in DCM (1.2 mL) and pyridine (252 μl, 3.12 mmol). The reaction was stirred at room temperature and monitored by LCMS (1 h). The reaction was quenched with MeOH, then water. Diluted with DCM and saturated sodium bicarbonate was added until pH approx. 9. Extracted with DCM using a phase separator cartridge. Concentrated and then placed on high vacuum to remove pyridine. The solid was purified by automated column chromatography (silica gel, 20% ethyl acetate in hexanes for R f =0.21) to give the title compound as a white foamy solid (343 mg, 88%, mixture of diastereomers). ESI-MS m / z: 815.2 [M+H] + .

[0194] Example 15 [ka] Using 343 mg of the compound of Example 14, Method A The title compound was synthesized according to the procedure described above and purified by automated column chromatography (silica gel, R f = 0.2, 0.30 with 50% ethyl acetate in hexanes) to give the title compound as a white foamy solid (195 mg, 80%, mixture of diastereomers). ESI-MS m / z: 577.4 [M+H] + .

[0195] Example 16 [ka] Using 195 mg of the compound of Example 15, Method BThe title compound was synthesized according to and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound as a white foamy solid (155 mg, 80%, mixture of diastereomers). ESI-MS m / z: 593.4 [M+H] + (LCMS water adduct).

[0196] Example 17 [ka] Using 50 mg of the compound of Example 16, Method C The title compound was synthesized according to the procedure described in . The mixture of diastereomers was analyzed by HPLC and TLC to confirm separation. The mixture was purified by automated column chromatography (silica gel, 40% ethyl acetate in hexane) R f =0.20) and lyophilized to give the title compound as a white fluffy solid (21.3 mg, 39%). ESI-MS m / z: 616.4 [M+H] + .

[0197] Example 18 [ka] Using 50 mg of the compound of Example 16 and cyclopropylmethylamine, Method C The title compound was synthesized according to the procedure described in Example 1. The mixture of diastereomers was analyzed by HPLC and TLC to confirm 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] + .

[0198] Example 19 [ka] Using 50 mg of the compound of Example 16 and (S)-1-cyclopropylethylamine, Method CThe title compound was synthesized according to the procedure described in . The mixture of diastereomers was analyzed by HPLC and TLC to confirm separation. The mixture was purified by automated column chromatography (silica gel, 75% ethyl acetate in hexane) R f =0.40) and lyophilized to give the title compound as a white fluffy solid (18 mg, 27%). ESI-MS m / z: 644.4 [M+H] + .

[0199] Example 20 [ka] Using 500 mg of the compound from Example 1, step g, and 163 mg of each acid, Method H The title compound was synthesized according to the procedure described above and purified by automated column chromatography (silica gel, 70% ethyl acetate in hexane) using R f =0.35) to give the title compound as a white foamy solid (428 mg, 66%, mixture of diastereomers). ESI-MS m / z: 810.3 [M+H] + .

[0200] Example 21 [ka] Using 428 mg of the compound of Example 20, Method A The title compound was synthesized according to the procedure described above and purified by automated column chromatography (silica gel, 5% methanol in dichloromethane) using R f =0.33) to give the title compound as a white foamy solid (282 mg, 79%, mixture of diastereomers). ESI-MS m / z: 572.2 [M+H] + .

[0201] Example 22 [ka] Using 282 mg of the compound of Example 21, Method BThe title compound was synthesized according to and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes, then 0-25% methanol in dichloromethane) to give the title compound as a white foamy solid (260 mg, 93%, mixture of diastereomers). ESI-MS m / z: 570.2 [M+H] + .

[0202] Example 23 [ka] Using 50 mg of the compound of Example 22 Method C The title compound was synthesized according to the procedure described in. 1.50 equivalents of each amine and borohydride were used and the reaction was stirred overnight. The mixture of diastereomers was analyzed by HPLC and TLC to confirm 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] + .

[0203] Example 24 [ka] Using 50 mg of the compound of Example 22, Method C The title compound was synthesized according to the procedure described in 1.50 equivalents each 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 confirm separation. The mixture was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a fluffy white solid (40 mg, 72%, mixture of diastereomers). ESI-MS m / z: 639.6 [M+H] + .

[0204] Example 25 [ka] Using 50 mg of the compound from Example 22, Method C The title compound was synthesized according to. 1.50 equivalents of each cyclopropylmethylamine and sodium triacetoxyborohydride were used and the reaction was stirred overnight. The mixture of diastereomers was analyzed by HPLC and TLC to confirm 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] + .

[0205] Example 26 [ka] Using 100 mg of the compound from Example 22, Method F The title compound was synthesized according to and dried under high vacuum overnight and carried on crude to the next step. White solid (100 mg, 97%).

[0206] Example 27 [ka] Using 50 mg of the compound of Example 26, Method G The title compound was synthesized according to the procedure described in Example 1. The mixture of diastereomers was analyzed by HPLC and TLC to confirm 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] + .

[0207] Example 28 [ka] Using 56 mg of the compound of Example 26, ammonium chloride (20.46 mg, 0.383 mmol, 4.0 equiv.), 5.0 equiv. of Hunig's base and BOP (50.8 mg, 0.115 mmol, 1.2 equiv.) as the coupling agent, Method G The title compound was synthesized according to the procedure described above. The mixture was purified by automated column chromatography (silica gel, 5% methanol in dichloromethane R f =0.31) and lyophilized to give the title compound as a white fluffy solid (7 mg, 13%). ESI-MS m / z: 585.2 [M+H] + .

[0208] Example 29 step a: [ka] Using 1.0 g of the compound from Example 1, step b, Method B The title compound was synthesized according to the procedure of and purified by column chromatography (silica gel, 50% ethyl acetate in hexane) f =0.52) to give the title compound as a white foamy solid (501 mg, 50%). ESI-MS m / z: 384 / 385.8 [M+H] + .

[0209] Example 29 step b: [ka] Using 501 mg of the compound from Example 29, step a and (S)-1-phenylethan-1-amine (176 μl, 1.362 mmol), Method C The title compound was synthesized according to the procedure described above. The residue was purified by column chromatography (silica gel, 25% ethyl acetate in hexane) R f =0.25) to give the title compound as a white solid as a single diastereomer (172 mg peak 1=P1, 184 mg P2, 55%). P1: ESI-MS m / z: 473.4 / 475.4 [M+H] +;P2:ESI-MS m / z:473.4 / 475.4 [M+H] + .

[0210] Example 29 step c: [ka] Using 2.6 equivalents of Grignard reagent and Example 29 step b (172 mg P1 and 184 mg P2 from step b, respectively), Example 1 Step d The title compound was synthesized according to the procedure of. The residue was purified by column chromatography (silica gel, 0-100% ethyl acetate in hexane) to give the title compound as a white solid as 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-MS m / z:443.2 / 445.4 [M+H] + .

[0211] Example 29 Step d: [ka] Using the compounds from step c (P1: 132 mg, P2: 144 mg, respectively), Example 1 Step e The title compound was synthesized according to the procedure of. The residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give a sticky residue as a single diastereomer. The residue was dehydrated by azeotroping / triturating 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).

[0212] Example 29 Step e: [ka] Using the compounds from step d (P1: 101 mg and P2: 141 mg, respectively), Example 1 Step f The title compound was synthesized according to the procedure of. 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 carried on 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] + .

[0213] Example 29 step f: [ka] Using the compounds from step e (P1: 97 mg and P2: 113 mg, respectively), Example 1 Step g The title compound was synthesized according to the procedure of. 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 carried on to the next step. P1: ESI-MS m / z: 490.3 [M+H] + ;P2: ESI-MS m / z: 490.4 [M+H] + .

[0214] Examples 30a and 30b [ka] Using 90 mg of P1 from Example 29, step f, and 39 mg of each acid, Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and preparative HPLC (20-90%, 25 min) to give pure samples of two diastereomers (10 mg of P1-A, 11 mg of P1-B, 18%). P1-A: ESI-MS m / z: 684.5 [M+H] + ;P1-B:ESI-MS m / z:684.4 [M+H] + .

[0215] Example 31 [ka] Using 103 mg of P2 from Example 29 step f and 45 mg of each acid, Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and preparative HPLC (20-90%, 25 min) to give pure samples of two diastereomers (18 mg of P2-A, 14 mg of P2-B, 22%). P2-A: ESI-MS m / z: 684.5 [M+H] + ;P2-B:ESI-MS m / z:684.4 [M+H] + .

[0216] Example 32 step a [ka] A No. 50 round bottom flask containing the compound from Example 1, step g (2.164 g, 3.46 mmol) was fitted with a stir bar. The flask was purged with nitrogen and DCM (17 mL, 0.2 M) was added. Triethylamine (0.724 ml, 5.20 mmol) was added, the flask was cooled to 0° C. and Boc anhydride (3.81 ml, 3.81 mmol) was added. The reaction was stirred at room temperature and monitored by LCMS (5 h). The stir bar was removed and the mixture was directly concentrated. The crude residue was purified by automated column chromatography (silica gel, 20% ethyl acetate in hexanes R f =0.72) to give the title compound as a white foamy solid (2.30 g, 93%). ESI-MS m / z: 724.9 [M+H] + .

[0217] Example 32 step b [ka] A 40 mL vial containing the compound from step a (2.515 g, 3.47 mmol) was fitted with a stir bar. The vial was purged with nitrogen and THF (17 mL, 0.2 M) was added. The vial was cooled to 0° C. and TBAF (6.94 ml, 6.94 mmol) was added. The reaction was stirred for 10 min, warmed to room temperature and monitored by LCMS (after 1.5 h, 3.0 eq. more TBAF was added over an additional 2 h). The stir bar was removed and the reaction was directly concentrated. The crude residue was purified by automated column chromatography (silica gel, 33% ethyl acetate in hexanes) to obtain a 1:1 ratio. f =0.29) to give the title compound as a white foamy solid (525 mg of non-polar peak P1, 600 mg of polar peak P2, 67%). P1: ESI-MS m / z: 487.2 [M+H] + ;P2: ESI-MS m / z: 487.2 [M+H] + .

[0218] Example 33 [ka] Example 33 Step a [ka] Using 472 mg of compound (P1) from Example 32, step b, Method B The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound as a white foamy solid (387 mg, 82%, single diastereomer). ESI-MS m / z: 485.0 [M+H] + .

[0219] Example 33 step b [ka] Using 200 mg of compound from step a, but with 5.0 equivalents of cyclopropylmethylamine and 5.0 equivalents of hydride, for 14 hours. Method CThe title compound was synthesized according to the procedure described in Example 1. The crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound as a white foamy solid (163 mg, 73%). ESI-MS m / z: 540.2 [M+H] + .

[0220] Example 33 step c [ka] A 20 mL scintillation vial containing the compound from step b (193 mg, 0.358 mmol) was fitted with a stir bar. DCM (1.40 mL) was added followed by MeOH (0.35 mL). The vial was cooled to 0° C. and HCl in dioxane (4.0 M, 894 μl, 3.58 mmol) was added. The reaction was stirred for 5 min, warmed to room temperature and monitored by LCMS (1.5 h). The reaction was diluted with EtOAc and quenched with water. The pH was brought to pH 8-9 with saturated sodium bicarbonate. An ethyl acetate extraction was performed and the sticky residue was lyophilized to give a clear sticky solid (141 mg, 90%). ESI-MS m / z: 440.2 [M+H] + .

[0221] Example 33 step d [ka] Using 15 mg of compound from step c and 1.0 equivalent of each acid for 2 hours, Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give the title compound as a white fluffy solid (12.8 mg, 55%). ESI-MS m / z: 680.2 [M+H] + .

[0222] Example 34 [ka] Using 15 mg of compound from step c and 1.0 equivalent of each acid for 2 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0223] Example 35 [ka] Using 15 mg of compound from step c and 1.0 equivalent of each acid for 2 hours, Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a fluffy white solid (10.2 mg, 43%). ESI-MS m / z: 614.2 [M+H] + .

[0224] Example 36 [ka] Using 15 mg of compound from step c, 1.0 equivalent of each acid and PyBOP (21 mg, 1.2 equivalents) as coupling agent for 2 h. Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a fluffy white solid (9 mg, 42%). ESI-MS m / z: 581.2 [M+H] + .

[0225] Example 37 [ka] Using 15 mg of compound from step c, 1.0 equivalent of each acid and PyBOP (21 mg, 1.2 equivalents) as coupling agent for 2 h. Method GThe title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a fluffy white solid (14.1 mg, 72%). ESI-MS m / z: 575.2 [M+H] + .

[0226] Example 38 [ka] Using 15 mg of compound from step c, 1.0 equivalent of each acid and PyBOP (21 mg, 1.2 equivalents) as coupling agent for 2 h. Method G The title compound was synthesized according to the procedure described in Example 1. 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 fluffy white solid (16.2 mg, 79%). ESI-MS m / z: 601.2 [M+H] + .

[0227] Example 39 [ka] Using 15 mg of compound from step c, 1.0 equivalent of each acid and PyBOP (21 mg, 1.2 equivalents) as coupling agent for 2 h. Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a fluffy white solid (8 mg, 37%). ESI-MS m / z: 619.1 [M+H] + .

[0228] Example 40 [ka] Using 15 mg of compound from step c, 1.0 equivalent of each acid and PyBOP (21 mg, 1.2 equivalents) as coupling agent for 2 h.Method G The title compound was synthesized according to the procedure described in Example 1. 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 fluffy white solid (12 mg, 59%). ESI-MS m / z: 600.2 [M+H] + .

[0229] Example 41 [ka] Method G The title compound was synthesized according to the procedure described above using 16 mg of the compound from Example 33 step c, 1.0 equivalent of each acid, and PyBOP (23 mg, 1.2 equivalents) as the coupling agent for 2 h. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a white fluffy solid (16.6 mg, 71%). ESI-MS m / z: 640.2 [M+H] + .

[0230] Example 42 [ka] Method G The title compound was synthesized according to the procedure described above using 16 mg of the compound from Example 33 step c, 1.0 equivalent of each acid, and PyBOP (23 mg, 1.2 equivalents) as the coupling agent for 2 h. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give a fluffy white solid (7.6 mg, 33%). ESI-MS m / z: 626.2 [M+H] + .

[0231] Example 43 [ka] Example 43 step a: [ka] In a vial, add the compound of example 1, step d (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)Cl 2 DCM (81 mg, 0.099 mmol) and K 2 CO 3 (681 mg, 4.93 mmol) was dissolved in 1,4-dioxane (7.40 ml) and water (0.822 ml). 2 The mixture was sparged and sealed. The reaction was heated at 90° C. for 2 h, cooled to room temperature, and water was added. The aqueous layer was washed with EtOAc. The combined organic layers were washed with water and brine, then MgSO 4 It was dried over low heat and concentrated in vacuo.

[0232] The residue was purified by silica gel column (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] + .

[0233] Example 43 step b: [ka] In a vial, the product of Example 43, step a (686 mg, 1.190 mmol), (4-fluorophenyl)boronic acid (200 mg, 1.428 mmol), PdCl 2 (dppf) (43.5 mg, 0.059 mmol), and K 2 CO 3 (370 mg, 2.68 mmol) was dissolved in dioxane (4.76 ml) and water (1.190 ml). The reaction was diluted with N 2 The vial was sparged with ethyl acetate and sealed. The vial was heated at 90° C. for 2 h. 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, followed by MgSO4 The residue was purified by silica gel column, 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] + .

[0234] Example 43 step c: [ka] In a vial, the compound from step b (400 mg, 0.676 mmol) was dissolved in tert-BuOH (3.38 ml), followed by water (3.38 ml) (olefin begins to crash). 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 allowed to warm to room temperature and stirred overnight. The reaction was diluted with EtOAc and quenched with saturated aqueous sodium thiosulfate. The aqueous layer was washed with EtOAc and the combined organic layers were washed with MgSO 4 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] + .

[0235] Example 43 Step d: [ka] 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 h before tosyl chloride (99 mg, 0.518 mmol) was added. The reaction was stirred for 1 h and then allowed to warm to room temperature. It was quenched by the addition of water and the aqueous layer was washed with EtOAc. The combined organic layers were washed with MgSO 4The residue was purified by silica gel column (0-40% hexane / EtOAc) to give the title compound (216 mg, 82%). ESI-MS: 608.38 m / z [M+H] + .

[0236] Example 43 Step e: [ka] 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 was sealed and stirred overnight. Water was added and the aqueous layer was washed with DCM. The combined organic layers were diluted with H 2 Wash with O and MgSO 4 After drying at 40° C. and concentrating to give a foamy solid, the crude reaction was used in the next step without further purification. ESI-MS: 625.61 m / z [M+H] + .

[0237] Example 43 is a key chiral intermediate in the synthesis of compounds of formula (I), (Ia) or (Ib).

[0238] Example 44 [ka] Using 20 mg of the compound of Example 22 (as a single diastereomer), Method C The title compound was synthesized according to: 3.0 eq. amine HCl salt; 3.0 eq. borohydride, 4.0 eq. TEA was used and the reaction was stirred overnight. 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, 27%). ESI-MS m / z: 625.2 [M+H] + .

[0239] Example 45 [ka] Using 25 mg of the compound of Example 26 (as a single diastereomer), 4.0 equivalents of the amine HCl salt and 5.0 equivalents of DIPEA, Method G The title compound was synthesized according to the procedure described in Example 1. The crude reaction 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] + .

[0240] Example 46 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 12.0 equivalents of the amine and 5.0 equivalents of DIPEA for 48 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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 fluffy white solid (16.1 mg, 63%). ESI-MS m / z: 599.2 [M+H] + .

[0241] Example 47 [ka] Using 25 mg of the compound of Example 26 (as a single diastereomer), 14.0 equivalents of the amine and 4.0 equivalents of DIPEA, Method G The title compound was synthesized according to. 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] + .

[0242] Example 48 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 8.0 equivalents of the amine, 4.0 equivalents of DIPEA, after 2 hours 4.0 equivalents more of HATU was added, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0243] Example 49 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 10.0 equivalents of the amine and 4.0 equivalents of DIPEA for 14 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0244] Example 50 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 eq. of the amine, 4.0 eq. of DIPEA for 14 hours, then 10 eq. of the amine / DIPEA and 4.0 eq. of HATU for 3 hours. Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0245] Example 51 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 5.0 eq. of the amine HCl salt, 6.0 eq. of DIPEA for 3 hours, then 5 eq. of the amine / DIPEA and 4.0 eq. of HATU for 2 hours. Method G The title compound was synthesized according to. 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] + .

[0246] Example 52 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 eq. of the amine, 4.0 eq. of DIPEA for 4 hours, then 10 eq. of the amine / DIPEA and 4.0 eq. of HATU for 18 hours. Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0247] Example 53 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 eq. of the amine HCl salt, 5.0 eq. of DIPEA for 4 hours, then 10 eq. of the amine / DIPEA and 4.0 eq. of HATU for 18 hours. Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0248] Example 54 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of the amine HCl salt, 5.0 equivalents of DIPEA for 14 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0249] Example 55 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of the amine HCl salt, 5.0 equivalents of DIPEA for 14 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0250] Example 56 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 10.0 equivalents of the amine, and 5.0 equivalents of DIPEA for 14 hours, Method G The title compound was synthesized according to the procedure described in Example 1. The crude reaction was purified by automated column chromatography (0-10% methanol in dichloromethane) and lyophilized to give the title compound as a fluffy white solid (15.0 mg, 57%). ESI-MS m / z: 613.0 [M+H] + .

[0251] Example 57 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of the amine HCl salt, 5.0 equivalents of DIPEA for 14 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0252] Example 58 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 4.0 equivalents of the amine HCl salt, 5.0 equivalents of DIPEA for 14 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0253] Example 59 [ka] Example 59 Step a [ka] Using 380 mg of aldehyde (as a single diastereomer), Method F The title compound was synthesized according to the procedure described above. The crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound as a pale yellow solid (354 mg, 90%, ESI-MS m / z: 444.9 [M+H] + .

[0254] Example 59 Step b [ka] Using 354 mg of the acid from step a Method G The title compound was synthesized according to the procedure described in Example 1. The crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound as a pale yellow solid (266 mg, 57%). ESI-MS m / z: 443.9 [M+H] + .

[0255] Example 59 step c [ka] The title compound was synthesized following the deprotection procedure in Example 33, step c, using 120 mg of the amide from step b. The crude residue was triturated with dichloromethane / hexanes to give a pale yellow solid (95 mg, 99%). ESI-MS m / z: 400.0 [M+H] + .

[0256] Example 59 Step d [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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 fluffy white solid (6.7 mg, 24%). ESI-MS m / z: 621.1 [M+H] + .

[0257] Example 60 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0258] Example 61 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0259] Example 62 [ka] Using 23 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. The crude reaction was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give the title compound as a white fluffy solid (16.0 mg, 52%). ESI-MS m / z: 590.0 [M+H] + .

[0260] Example 63 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0261] Example 64 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described above. The crude reaction mixture was purified by preparative HPLC (20-90% MeCN / H 2 0, 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] + .

[0262] Example 65 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described above. The crude reaction mixture was purified by preparative HPLC (20-90% MeCN / H 2 0, 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] + .

[0263] Example 66 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described above. The crude reaction mixture was purified by preparative HPLC (20-90% MeCN / H 2 0, 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] + .

[0264] Example 67 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described above. The crude reaction mixture was purified by preparative HPLC (20-90% MeCN / H 2 0, 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] + .

[0265] Example 68 [ka] Using 25 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described above. The crude reaction mixture was purified by preparative HPLC (20-90% MeCN / H 2 0, 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] + .

[0266] Example 69 [ka] Using 25 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described above. The crude reaction mixture was purified by preparative HPLC (20-90% MeCN / H 2 0, 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] + .

[0267] Example 70 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0268] Example 71 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0269] Example 72 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0270] Example 73 [ka] Using 20 mg of the compound from Example 59, step c above (1.0 equivalent) and 1.0 equivalent of each acid for 1.5 hours, Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0271] Example 74 [ka] Example 74 step a [ka] A round flask was charged with Example 21 (as a single diastereomer) (200 mg, 0.35 mmol) in DMF (4 mL), followed by 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 h before it was 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] + .

[0272] Example 74 step b [ka] A solution of the compound from Example 74 step a (80 mg, 0.11 mmol) and sodium cyano (10.80 mg, 0.22 mmol) in DMSO (2 mL) was heated in a sealed vessel at 100° C. for 12 h. The reaction mixture was diluted with DCM (150 mL), washed with brine (50 mL×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] + .

[0273] Example 75 [ka] The compound from Example 74, step b (20 mg, 0.034 mmol) and Ghaffar-Parkins catalyst hydride (dimethylphosphinite-kP) [hydrogenbis(dimethylphosphinite-kP)]platinum(II) (2.95 mg, 6.89 μmol) in EtOH / H 2 A solution of 1:1 HO (4:1, 1.75 mL) was heated in a sealed vessel at 85 °C for 2 h. 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] + .

[0274] Example 76 [ka] Using 25 mg of the compound from Example 26 (as a single diastereomer), 8.0 equivalents of the amine HCl salt, 8.0 equivalents of DIPEA for 4 hours, then 10 equivalents of the amine HCl salt / DIPEA and 4.0 equivalents of HATU for 2 hours. Method G The title compound was synthesized according to the procedure described in Example 1. 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] + .

[0275] Example 77 [ka] Example 77 was prepared using a procedure similar to that used to prepare Example 59 from the corresponding acid in step d. ESI-MS m / z: 636.2 [M+H] + .

[0276] Example 78 [ka] Example 78 was prepared using a procedure similar to that used to prepare Example 59 from the corresponding acid in step d. ESI-MS m / z: 638.2 [M+H] + .

[0277] The following examples in Table 1 were made in a similar manner to Example 59 using the corresponding intermediates. [Table 1-1] [Table 1-2]

[0278] Method I [ka] Example 97 [ka] Example 97 Step a (Method I) [ka] 3-Bromo-4-hydroxybenzoate (16 g, 69.25 mmol), Cs 2 CO 3 A solution of bromocyclopropane (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 organics were dried and concentrated. The resulting solution was purified by reverse phase C18 column chromatography (CH 3 CN / H 2 0) 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.)

[0279] Example 97 Step b (Method I) [ka] Compound from step a (250 mg, 0.98 mmol), Pd(dppf)Cl 2 (142 mg, 0.19 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (425 mg, 1.94 mmol), H 2 O (0.1 mL) and Cs 2 CO 3 (950 mg, 2.91 mmol) in dioxane (3 mL) was dissolved in N 2 The mixture was stirred at 90° C. for 2 hours under atmospheric pressure. The resulting solution was purified by reverse phase C18 column chromatography (MeOH / H 2 0) to give the desired product as a white solid (180 mg, 68%). ESI-MS m / z: 270.15 [M+H] + .

[0280] Example 97 Step c (Method J) Method J [ka] To a 2-dram vial equipped with a stir bar was added the amine (30 mg, 0.075 mmol), acid (19.18 mg, 0.075 mmol) and the material was dissolved in DMF (0.2 M). Hunig's 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 and the reaction was stirred for 10 min, warmed to room temperature and monitored by LCMS (1 h). The reaction was diluted with EtOAc and quenched with water. The aqueous was extracted with EtOAc and DCM / MeOH using a phase separator cartridge 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] + .

[0281] Method K [ka] Example 98 Step a (Method K) [ka] Using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine and methyl 3-bromo-4-cyclopropoxybenzoate, Method I Engineering a The following example was carried out in a similar manner to that described above. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound. ESI-MS m / z: 338.10 [M+H] + .

[0282] Example 98 Step b (Method K) [ka] Compound from step a (crude), LiOH (300 mg, 12.52 mmol) and H 2 A solution of 1 mL of HO in 3 mL of MeOH was stirred at room temperature for 16 h. The resulting solution was purified by reverse phase C18 column chromatography (MeOH / 0.1% FA-containing H 2 Purification by HPLC (HPLC-MS / HPLC) afforded the desired product as a white solid (228 mg). ESI-MS m / z: 256.10 [M+H] + .

[0283] Method L [ka] Example 99 (Method L) [ka] A mixture of the bromide of the compound from Example 97, step a (250 mg, 0.98 mmol), 2-(tributylstannyl)pyridine (537 mg, 1.46 mmol) and Pd(PPh 3 ) 2 Cl 2 A solution of (68 mg, 0.09 mmol) in DMF (3 mL) was 2 The mixture was stirred at 90° C. for 2 hours under atmospheric pressure. The resulting solution was purified by reverse phase C18 column chromatography (MeOH / H 2 0) to give the desired product as a white solid (90.6 mg, 37%). ESI-MS m / z: 256.15 [M+H] + .

[0284] Method M [ka] Example 100 Steps a and b (Method M) [ka] Methyl 3-bromo-4-cyclopropoxybenzoate (300 mg, 1.11 mmol), 2-(tributylstannyl)pyrazine (615 mg, 1.66 mmol) and Pd(PPh 3 ) 2 Cl 2 A solution of (68 mg, 0.09 mmol) in DMF (3 mL) was 2 The mixture was stirred under atmosphere at 90° C. for 2 hours. The resulting solution was purified by silica gel column chromatography (hexane containing EtOAc) to give the desired product as a white solid. ESI-MS m / z: 271.00 [M+H]+.

[0285] Methyl ester Method K The crude solution was purified by reversed-phase C18 column chromatography (MeOH / 0.1% FA in H 2 0) to give the desired product as a white solid (100 mg, 35%). ESI-MS m / z: 257.05 [M+H] + .

[0286] Method N [ka] Example 101 Steps a and b (Method N) [ka] 3-Bromo-4-cyclopropoxybenzoic acid (1 g, 3.9 mmol), bis(pinacolato)diboron (2 g, 7.78 mmol), KOAc (1.2 g, 11.67 mmol) and Pd(dppf)Cl 2 A solution of (DCM) (635 mg, 0.78 mmol) in dioxane (6 mL) was stirred at 90° C. for 2 h. ESI-MS m / z: 223.05 [M+H] + .

[0287] Compound from step a (2 mL), 2-bromo-6-(trifluoromethyl)pyridine (611 mg, 2.70 mmol), Cs2 CO 3 (1.3g, 4.05mmol), H 2 O (0.1 mL) and Pd(dppf)Cl 2 (221 mg, 0.27 mmol) in dioxane (3 mL) was dissolved in N 2 The mixture was stirred at 90° C. for 2 hours under atmospheric pressure. The resulting solution was purified by reverse phase C18 column chromatography (MeOH / H 2 Purification by HPLC (HPLC-MS / HPLC) afforded the desired product as a white solid (130 mg). ESI-MS m / z: 256.10 [M+H] + .

[0288] Method O [ka] Example 102 Step a (Method O) [ka] Methyl 4-hydroxy-3-methoxybenzoate (3 g, 16.47 mmol), K 2 CO 3 A solution of (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 h. The resulting solution was quenched with water and extracted with EtOAc. The combined organics were dried, concentrated, and purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC) afforded the desired product as a pale yellow solid (3 g, 61%).

[0289] Example 102 Step b (Method O) [ka] Compound from step a (1 g, 3.64 mmol), morpholine (0.6 g, 6.88 mmol) and K 2 CO 3A solution of (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 organics were dried, concentrated and the crude product was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC) afforded the desired product (1 g, 93%). ESI-MS m / z: 296.05 [M+H] + .

[0290] Example 102 Step c (Method O) [ka] Compound from step b (1 g, 3.55 mmol) and LiOH (0.8 g, 33.76 mmol) in MeOH:H 2 The solution was stirred at room temperature for 2 h in 2:1 HO (60 mL). The pH of the resulting solution was adjusted to pH=6 with HCl (aq) and extracted with EtOAc. The combined organics were dried, concentrated and the crude product was purified by reverse phase C18 column chromatography (MeCN / H 2 0, 1% FA) to give the desired product as a white solid (1 g, 99%). ESI-MS m / z: 282.05 [M+H] + .

[0291] Using the corresponding acid intermediate, Method J The following examples in Table 2 were made in a similar manner to and the compounds were purified by preparative HPLC. The corresponding acid precursors were synthesized by methods previously described (Method I, Methods K-O). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0292] Example 196 [ka] Example 196 step a [ka] In a 40 mL vial, add methyl 4-bromo-3-cyclopropoxybenzoate (1 g, 3.69 mmol), tributyl(1-ethoxy-ethenyl)stannane (1.6 g, 4.426 mmol), Pd(dppf)Cl 2 DCM (0.6 g, 0.74 mmol) and DMF (15 mL) were added at room temperature. The resulting mixture was stirred at 110° C. under nitrogen atmosphere for 2 h and monitored by LCMS. 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] + .

[0293] Example 196 step b [ka] In a 100 mL round bottom flask, add the compound from step a (450 mg, 1.91 mmol), NBS (373 mg, 2.1 mmol), THF (10 mL) and H 2 HO (3 mL) was added at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h and monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel, 10-70%, 25 min, MeCN / H 2 0) to give the title compound (500 mg, 91%). ESI-MS m / z: 313.10 [M+H] + .

[0294] Example 196, steps c and d [ka] To a 20 mL vial was added the compound from step b (250 mg, 0.8 mmol), acetamide (236 mg, 4 mmol) and AcOH (5 mL) at room temperature. The resulting mixture was stirred at 120 °C for 16 h. The resulting mixture was concentrated under vacuum and purified by reverse phase chromatography (C18 silica gel, 10-70%, 25 min, MeCN / H 2 0) to give the title compound (45 mg, 20%). ESI-MS m / z: 274.10 [M+H] + .

[0295] Methyl ester Method O The material was hydrolyzed in a similar manner to that described above and purified by reverse phase chromatography (C18 silica gel, 10–70%, 25 min, MeCN / H 2 0) to give the title compound (45 mg, 99%). ESI-MS m / z: 260.08 [M+H] + .

[0296] Example 196 process e [ka] The title compound is Method JPrepared in a similar manner to that described above using the 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] + .

[0297] Example 197 [ka] The title compound was prepared in a similar manner to Example 196 above using the 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 (30.6 mg, 65%). ESI-MS m / z: 615.18 [M+H] + .

[0298] Example 198 [ka] Example 198 Steps a and b [ka] Bromide from Example 196 step b (187 mg, 0.60 mmol), HCONH 2 A solution of (158 mg, 3.5 mmol) and formic acid (5 mL) was stirred at 100 °C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo and purified by reverse phase chromatography (C18 silica gel, 10-70%, 25 min, MeCN / H 2 O) to give the title compound (60 mg, 33%). ESI-MS m / z: 260.08 [M+H] + .

[0299] Example 198 process c [ka] The title compound is Method JPrepared in a similar manner to that described above using the 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] + .

[0300] Example 199 [ka] The title compound was prepared using the amine (30 mg, 0.075 mmol) in a similar sequence to 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] + .

[0301] Example 200 [ka] Example 200 process a [ka] 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:H 2 A solution of O:TEA (4:4:1, 20 mL) was stirred at 100° C. under CO atmosphere for 6 h. The resulting solution was extracted with EtOAc, and the organic layer was dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC) afforded the desired product (1.8 g, 52%). ESI-MS m / z: 211.10 [M+H] + .

[0302] Example 200 steps b and c [ka] A solution of 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 h. The reaction was quenched with water, extracted with EtOAc and the combined organics were dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC (HPLC) gave the desired product (2.1 g, 80%). ESI-MS m / z 269.10 [M+H-56] + .

[0303] A solution of the compound from step b (2 g, 6.17 mmol) in 1,4-dioxane (30 mL) containing HCl was stirred at room temperature for 0.5 h. The resulting solution was concentrated and purified by reverse phase C18 column chromatography (MeCN / H 2 0) to give the desired product (1 g, 73%) as a yellow solid. ESI-MS m / z: 225.05 [M+H] + .

[0304] Example 200 steps d and e [ka] Compound from step c (250 mg, 1.11 mmol) and CH(OEt) 3 A solution of (355 mg, 3.34 mmol) in xylenes (10 mL) was stirred at 100° C. for 3 h. The reaction was quenched with water, extracted with EtOAc, and the combined organics were dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 0) to give the desired product (130 mg, 49%) as a white solid. ESI-MS m / z: 235.10 [M+H] + .

[0305] Methyl ester hydrolysis Method OThe resulting solution was purified by reverse phase C18 column chromatography (MeOH / 0.1% FA-containing H 2 0) to give the desired product (56 mg, 46%). ESI-MS m / z: 221.00 [M+H] + .

[0306] Example 200 process f [ka] The title compound is Method J Prepared in a similar manner to that described above using the 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] + .

[0307] Example 201 [ka] Example 201 process a [ka] A solution of Example 200 step b (above) (300 mg, 1.34 mmol) and formic acid (924 mg, 20.07 mmol) in toluene (5 mL) was stirred at 120° C. for 4 h. The reaction was quenched with water, extracted with EtOAc, and the combined organics were 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] + .

[0308] Example 201 steps b and c [ka] A solution of the compound from step a (80 mg, 0.32 mmol) and Lawesson'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 organics were 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] + .

[0309] Methyl ester hydrolysis Method O The resulting solution was purified by reverse phase C18 column chromatography (MeOH / 0.1% FA-containing H 2 0) to give the desired product (60 mg, 99%). ESI-MS m / z: 236.95 [M+H] + .

[0310] Example 201 process d [ka] The title compound is Method J Prepared in a similar manner to that described above using the 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] + .

[0311] Example 202 [ka] Example 202 process a [ka] 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 organics were dried and concentrated. The resulting solution was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC (HPLC) gave the desired product (80 mg, 13%). ESI-MS m / z 251.15 [M+H] + .

[0312] Example 202 steps b and c [ka] Compound from step a (70 mg, 0.28 mmol) and NH 2 OH HCl (97 mg, 1.40 mmol) in EtOH:H 2 The 2H2O (1:1, 30 mL) solution was stirred at 80° C. for 2 h. The reaction was quenched with water, extracted with EtOAc, and the combined organics were dried and concentrated. This material was purified by silica gel column chromatography (EtOAc:Hexanes) to give the desired product (60 mg, 76%). ESI-MS m / z 248.10 [M+H] + .

[0313] Methyl ester hydrolysis Method O The resulting solution was subjected to reverse phase C18 column chromatography (MeOH / 0.1% FA-containing H 2 0) to give the desired product (60 mg) as a white solid. ESI-MS m / z: 234.10 [M+H] + .

[0314] Example 202 process d [ka] The title compound is Method J Prepared in a similar manner to that described above using the 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] + .

[0315] Example 203 [ka] Example 203 process a [ka] In a vial, methyl (R)-3-bromo-4-(2-hydroxypropoxy)benzoate (100 mg, 0.346 mmol), PdCl 2 (dppf)(25.3mg, 0.035mmol), K 2 CO 3 (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 washed with MgSO 4 The crude reaction was purified by silica gel chromatography 0-100% EtOAc / Hexanes to give the title compound (54 mg, 54%). ESI-MS m / z: 289.10 [M+H] + .

[0316] Example 203 step b [ka] 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 aqueous HCl was added to pH 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] +

[0317] Example 203 process c [ka] The title compound is Method J Prepared in a similar manner to that described above using the 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] + .

[0318] Example 204 [ka] Using the above example 203 and the amine (30 mg, 0.075 mmol), Method J The title compound was prepared in a similar manner using 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] + .

[0319] Example 205 [ka] Example 205 process a [ka] To a 100 mL round bottom flask was added Example 1 step b (3.80 g, 10.27 mmol), acetone (100 mL), the solution was cooled to 0° C., and then Jones reagent (1.9-2.2 M, 10 mL) was added dropwise (with internal temperature monitoring). The reaction was allowed to warm to room temperature and monitored by LCMS (3 h). The reaction was cooled to 0° C., i Quenched with PrOH and stirred for 15 min. The reaction was diluted with EtOAc and water. The aqueous was extracted and the combined organics were dried and concentrated under reduced pressure to give the crude product as a yellow solid (3.95 g, 99%). ESI-MS m / z: 383.80 [M+H] + .

[0320] Example 205 step b [ka] In a 100 mL round bottom flask, add the compound from step a (3.95 g, 10.28 mmol), NH 4 Cl (1.10 g, 20.57 mmol) and the solid dissolved in DMF (20 mL) were added. Hunig's base (5.27 mL, 30.84 mmol) was added, the reaction was cooled to 0° C., and HATU (7.82 g, 20.56 mmol) was added. The reaction was allowed to warm to room temperature and monitored by LCMS (1 h). The reaction was diluted with EtOAc and water. The aqueous was extracted and the combined organics were dried and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (3 g, 76%). ESI-MS m / z: 382.95 [M+H] + .

[0321] Example 205 process c [ka] In a 100 mL round bottom flask, 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), Pd(dppf)Cl 2 (1.15 g, 1.56 mmol), dioxane (40 mL) and H 2 The material dissolved in 20O (5 mL) was then added. 2 CO 3 (3.25 g, 23.50 mmol) was added and the resulting mixture was stirred at 90° C. for 1 h under nitrogen atmosphere. The mixture was cooled to room temperature, poured into water, extracted with EtOAc, and the combined organics were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the desired product as a brown oil (2.3 g, 83%). ESI-MS m / z: 350.90 [M+H] + .

[0322] Example 205 process d [ka] To a 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) was added Na 2 CO 3 (3.32g, 31.33mmol), H 2 O (20 mL) and Pd(PPh 3 ) 2 Cl 2 (1.00 g, 1.42 mmol) was added. The resulting mixture was stirred at 70° C. under nitrogen atmosphere for 1 h. 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] + .

[0323] Example 205 process e [ka] To a 500 mL round bottom flask equipped with a stir bar was added AD-mix-β (33.82 g, 43.41 mmol) and methanesulfonamide (1.38 g, 14.47 mmol). The solid was dissolved in tBuOH (60 mL) and H 2 The mixture was dissolved in 2H2O (100 mL), the flask was cooled to 0° C., and the compound from step d (5.80 g, 14.47 mmol) was added slowly as a solution in tBuOH (40 mL). The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by the addition of sodium sulfite (0.25 g per g of AD-mix) and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine and Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated and purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound as a white solid (5.48 g, 87%). ESI-MS m / z: 435. [M+H] + .

[0324] Example 205 process f [ka] To a 250 mL round bottom flask was added the compound from step e (4.70 g, 10.81 mmol) and DCM (80 mL) at room temperature. The solution was cooled to 0° C., 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 was extracted with DCM. The combined organic layers were washed with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude product as a pale yellow solid (6.2 g, 97%). ESI-MS m / z: 589.15 [M+H] + .

[0325] Example 205 process g [ka] In a 100 mL round-bottom flask, add NH 3 MeOH (35 mL) containing was added and the compound from step g (6.20 g, 10.52 mmol) was added slowly. 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, with brine, dried and concentrated to give the title compound (2.93 g, 64%). ESI-MS m / z: 434.05 [M+H] + .

[0326] Example 206 [ka] Example 206 process a [ka] To a 100 mL round bottom flask containing the compound from (R)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine (4.32 g, 8.94 mmol) was added a stir bar, N-methoxy-N-methylacetamide (1.43 mL, 13.4 mmol) and THF (45 mL). The flask was purged with nitrogen, cooled to -40 °C and ethyl trifluoroacetate (2.317 mL, 19.40 mmol) was added. Isopropylmagnesium chloride (5.16 mL, 10.3 mmol) was then added slowly and the reaction was monitored by LCMS (stirred at -40 to -20 °C for 3 h). The reaction was quenched with 5 mL of MeOH and warmed to room temperature. The mixture was diluted with water and EtOAc, the phases were separated, the aqueous layer was washed with EtOAc, the combined organics were washed with brine and sodium 2 SO 4The mixture was dried at 40° C., filtered, concentrated, and purified by automated silica gel chromatography (0-5% EtOAc / Hexanes) to give the title compound as a clear, sticky residue (3.00 g, 84%). ESI-MS m / z: 400.1 / 402.0 [M+H] + .

[0327] Example 206 process b [ka] To a 250 mL round bottom flask containing methyltriphenylphosphonium bromide (5.34 g, 15.0 mmol) was added THF (42 mL), the mixture was cooled to 0° C., and potassium tert-butoxide (1.60 g, 14.2 mmol) was added slowly as a solution in THF (14 mL). The yellow suspension was stirred at 0° C. for 30 min, then step a (4.327 g, 8.94 mmol) was added as a solution in THF (33 mL). The reaction was allowed to warm to room temperature and was monitored by LCMS until complete (6.5 h). The reaction was then quenched with 5 mL of MeOH and allowed to warm to room temperature. The mixture was diluted with water and EtOAc, the phases were separated, the aqueous layer was washed with EtOAc, the combined organics were washed with brine, and Na 2 SO 4 The mixture was dried at 4° C., filtered, concentrated, and purified by automated silica gel chromatography (0-5% EtOAc / Hexanes) to give the title compound as a clear, sticky residue (2.88 g, 94%). ESI-MS m / z: 398.2 / 400.1 [M+H] + .

[0328] Example 206 process c [ka] The title compound was synthesized according to the procedure of Example 205, step d, using 1.2 equivalents of (4-fluorophenyl)boronic acid and the compound from step b (2.13 g 5.36 mmol). The residue was purified by automated silica gel chromatography (0-5% EtOAc / Hexanes) to give the title compound as a colorless oil. (2.19 g, 99%) ESI-MS m / z: 414.8 [M+H] + .

[0329] Example 206 process d [ka] 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., 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 allowed to warm to room temperature with stirring for 16 hours, then quenched by the addition of 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 organics were washed with brine and Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated, and purified by automated silica gel chromatography to give the title compound (2.19 g, 89%) as a sticky colorless oil. ESI-MS m / z: 448.7 [M+H] + .

[0330] Example 206 process e [ka] To a solution of compound from step d (2.30 g, 5.13 mmol) was added triethylamine (2.1 mL, 15 mmol) and DMAP (627 mg, 5.13 mmol), the mixture was cooled in an ice bath, and then TsCl (1.1 equiv) was added slowly as a solid. The reaction was monitored by LCMS until complete (2 h), then the reaction mixture was concentrated and purified by automated silica gel chromatography (0-15% EtoAc / Hexanes) to give the title compound (2.97 g, 97%) as a white solid. ESI-MS m / z: 602.6 [M+H] + .

[0331] Example 206 process f [ka] To a 250 mL flask containing a stir bar was added ammonia in MeOH (116 mL, 7M, 812 mmol) and the compound from step e (4.16 g, 6.92 mmol) was added as a solution in MeOH (10 mL). The reaction was monitored by LCMS until complete (62 h), then concentrated and placed under vacuum for 1 h and used directly in the next step. ESI-MS m / z: 447.6 [M+H] +

[0332] Example 206 process g [ka] The title compound was synthesized according to the procedure of Example 32, step a, using the compound from step f (3.09 g, 6.92 mmol) and 1.1 equivalents of Boc anhydride. The reaction mixture was purified by automated silica gel chromatography (0-15% EtOAc / Hexanes) to give the title compound (3.39 g, 90% over two steps) as a yellow oil. ESI-MS m / z: 547.7 [M+H] + .

[0333] Example 206 process h [ka] The title compound was synthesized using the compound from step g (3.39 g, 6.20 mmol) and 2.0 equivalents of TBAF. Method A Prepared according to. After aqueous workup, the mixture was purified by automated silica gel chromatography (0-100% EtOAc / Hexanes) 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 arises from incomplete selectivity in step d, but was not evident or separable prior to this step. ESI-MS m / z: 433.5 [M+H] + = P1, ESI-MS m / z: 433.5 [M+H] + =P2.

[0334] Example 206 process i [ka] To a suspension of P1 from step h (220 mg, 0.508 mmol) in aqueous sodium hydroxide (1.2 mL, 5 wt%, 1.5 mmol) was added potassium permanganate (281 mg, 0.778 mmol) dropwise as an aqueous solution (5.6 mL). The reaction was monitored by LCMS until complete (42 h) and then cooled to 0° C. and quenched by the dropwise addition of sodium sulfite (640 mg, 5.08 mmol) as an aqueous solution (6.4 mL). The mixture was then acidified to pH 1-3 by the addition of 1M HCl. The solid was collected on a frit and washed extensively with water to give the title compound (137 mg, 60%) as a white solid. ESI-MS m / z: 447.3 [M+H] + .

[0335] Example 206 process j [ka] According to Example 205, step b, 137 mg of the compound from step i and 10 equivalents of NH 4The title compound was synthesized using Cl. The compound was purified by automated silica gel chromatography (0-100% EtOAc / Hexanes) to give the title compound (86 mg, 63%) as a white solid. ESI-MS m / z: 446.4 [M+H] + . .

[0336] Example 206 process k [ka] A suspension of the compound from step j (259 mg, 0.580 mmol) in DCM (7.3 mL) was cooled to 0° C. and aqueous HCl (1.5 mL, 4N, 5.8 mmol) was added. The reaction was monitored by TLC and LCMS until complete (2 h), at which point diethyl ether (20 mL) was added and the mixture was stirred for 1 h, resulting in the precipitation of a white solid. 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] + .

[0337] Example 207 [ka] This intermediate was used in the synthesis of a wide variety of analogs in sequences similar to Examples 205 and 206.

[0338] This example was prepared in a similar sequence to Example 206, using N-methoxy-N-methylcyclopropanecarboxamide instead. The residue was purified by silica gel column chromatography (10% EtOAc / Hexanes) to give the desired product as a yellow-green oil. ESI-MS m / z: 424.10 [M+H] + .

[0339] Example 208 process a [ka] 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 NaHCO 3 A solution of (18.44 g, 0.22 mol) in toluene (500 mL) was 2 The mixture was stirred at 110° C. under atmospheric pressure for 3 hours. 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 (10.4 g, 45%). ESI-MS m / z: 209.10 [M+H] + .

[0340] Example 208 Steps b and c [ka] To a stirred solution of compound step a (10.4 g, 47.84 mmol) in DCE (200 mL) was added CH 2 I 2 (25.65 g, 95.69 mmol) and Et 2 Zn (1M, 96 mL, 96 mmol) was added in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 16 h. The reaction was quenched by addition of water DCM and the combined organics were washed with brine, dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC) afforded the desired compound as a yellow solid (7.8 g, 70%). ESI-MS m / z: 223.10 [M+H] + .

[0341] A stirred solution of the compound from step b (7.8 g, 35.13 mmol) in DCM (100 mL) was treated with BBr 3 (22 g, 88 mmol) was added in portions. The resulting mixture was stirred at 0 °C for 3 h and then cooled to 0 °C. 3The reaction was quenched by the addition of (aqueous). The resulting mixture was extracted with DCM and the combined organics were washed with brine, dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC (HPLC-MS / HPLC) afforded the desired compound as a yellow solid (4.6 g, 67%). ESI-MS m / z: 195.05 [M+H] + .

[0342] Example 208 process d [ka] Compound from step c (4.6 g, 23.59 mmol) in MeOH (40 mL) and H 2 A solution of 2H2O (3 mL) was stirred at 80° C. under nitrogen atmosphere for 3 h. 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] + .

[0343] Example 208 Steps e and f [ka] 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) was added K 2 CO 3 (5.4 g, 40 mmol) was added 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 organics were washed with brine, dried and concentrated. The crude material was purified by silica gel column chromatography (0-75% EtOAc in hexanes) to give the product (3 g, 58%). ESI-MS m / z: 262.10 [M+H] + .

[0344] Methyl ester Method O The material was hydrolyzed in a similar manner to that described above and purified by reverse phase preparative HPLC (MeCN / H 2 0) to give the desired compound as a yellow solid (1.95 g, 68%). ESI-MS m / z: 253.10 [M+H] + .

[0345] Example 209 [ka] 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 diluted with N 2 The mixture was stirred at 100° C. for 1 hour under atmospheric pressure. The resulting solution was concentrated, and the crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 0) to give the desired product (1.088 g, 18%) as a white solid. ESI-MS m / z: 208.20 [M+H] + .

[0346] Example 210 [ka] 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 dissolved in N 2 The mixture was stirred at 100° C. for 1 hour under atmospheric pressure. The resulting solution was concentrated, and the crude material was purified by reverse phase C18 column chromatography (MeCN / H 2 Purification by HPLC) afforded the desired product (600 mg, 75%). ESI-MS m / z: 203.95 [M+H] + .

[0347] Example 211 Method P [ka] To a suspension of 4-amino-3-hydroxybenzoic acid (4.6348 g, 30.3 mmol) in concentrated aqueous hydrochloric acid (50.4 mL) was added but-3-en-2-one (4.88 ml, 60.5 mmol). 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] + .

[0348] Example 212 [ka] Using 493 mg of 4-amino-3-hydroxybenzoic acid and 533 μl of methacrolein, Method P The title compound was synthesized according to the procedure described above. 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] + .

[0349] Example 213 [ka] Using 5.00 g of 4-amino-3-methoxybenzoic acid and 5.0 ml of methacrolein, Method P The title compound was synthesized according to. The aqueous layer was washed with EtOAc (4×20 mL), then solids precipitated in the aqueous layer, which were collected by filtration to give the title compound (1.23 g, 19%) as a yellow solid. ESI-MS m / z: 218.0 [M+H] + .

[0350] Example 214 [ka] Using 2.00 g of 4-amino-3-hydroxybenzoic acid and 1.82 g of 2-methylenebutanal, Method P The title compound was synthesized according to. The aqueous layer was washed with EtOAc (4×5 mL), then solids precipitated in the aqueous layer, which were collected by filtration to give the title compound (70 mg, 3%) as a yellow solid. ESI-MS m / z: 218.1 [M+H] + .

[0351] Example 215 [ka] Using 2.98 g of 4-amino-3-methoxybenzoic acid and 3.00 g of 2-methylenebutanal, Method P The title compound was synthesized according to. The aqueous layer was washed with EtOAc (4×5 mL), then solids precipitated in the aqueous layer, which were collected by filtration to give the title compound (811 mg, 20%) as a yellow solid. ESI-MS m / z: 232.1 [M+H] + .

[0352] Example 216 Step a [ka] A solution of methyl 3-fluoro-4-nitrobenzoate (5.66 g, 28.4 mmol) in DMF (56 mL) was added to the 2 CO 3 (13.89 g, 42.6 mmol) and cyclopropanol (2.7 ml, 42.6 mmol) were added. The mixture was heated to 75° C. for 16 hours, then cooled to room temperature and H 2 The mixture was diluted with 2×O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with water (2×5 mL) and then with saturated aqueous NaCl (5 mL) and diluted with Na 2 SO 4 The crude material was carried on directly to the next step. ESI-MS m / z: 237.7 [M+H] + .

[0353] Example 216 steps b and c [ka] To a solution of the compound from step a (6.74 g, 28.4 mmol) in EtOH (151 ml) and water (37.9 ml) was added iron (7.93 g, 142 mmol) and ammonium chloride (15.19 g, 284 mmol). The mixture was heated to 75° C. for 1 h, then cooled to room temperature and filtered through celite. NaHCO 3 The pH of the filtrate was adjusted to 9-11 using ethyl acetate and then diluted with EtOAc. The phases were separated and the aqueous layer was washed with EtOAc (4×50 mL) and the combined organics were washed with saturated aqueous NaCl (20 mL) and Na 2 SO 4 The mixture was dried at 4° C., filtered, concentrated, and purified by automated silica gel chromatography (0-20% EtOAc / Hexanes) to give the title compound as a yellow oil (4.25 g, 72.2% yield over two steps). ESI-MS m / z: 208.0 [M+H] + .

[0354] To a solution of the compound from step b (6.74 g, 28.4 mmol) in THF (15 ml) was added potassium trimethylsilanolate (3.96 g, 28.6 mmol). The mixture was quenched with MeOH, then concentrated and used directly in the next step. ESI-MS m / z: 193.9 [M+H] + .

[0355] Example 216 process d [ka] This example uses the compound from step c and methacrolein Method P After the reaction was complete, the aqueous layer was washed with EtOAc (3×15 mL), then the aqueous layer was concentrated to dryness and the resulting solid was washed with MeOH (3 mL) and collected to give the desired product as a yellow solid (160 mg, 14% for two steps). ESI-MS m / z: 244.0 [M+H] +.

[0356] Example 217 steps a and b Method R [ka] To a 50 mL round bottom flask equipped with a stir bar was added 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). 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. A solid precipitated (the quinoline product has solubility issues). DCM and hexanes were added to further precipitate. Stir vigorously. Filtration and multiple washings with DCM gave the title compound as a light brown solid (620 mg, 97%). ESI-MS m / z: 244.0 [M+H] + .

[0357] A 20 mL vial containing step a (400 mg, 1.537 mmol) was fitted with a stir bar. The compound was dissolved in THF and MeOH, and water (1:2:1, 0.33 M). Lithium hydroxide hydrate (129 mg, 3.07 mmol) was then added and the reaction was stirred at room temperature and monitored by LCMS (30 min, too much LiOH can hydrolyze acetamide). The reaction was cooled to 0° C. and acidified with 2M HCl to pH approx. 4-5. Organics and aqueous were concentrated (aqueous soluble product). Placed on high vacuum. The solid was suspended in a minimum amount of MeOH (a white solid precipitated) and filtered to remove LiCl salts. The solid was rinsed with a minimum amount of MeOH and dried 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] + .

[0358] Example 218 [ka] Method 1: Example 218 Method 1 step a [ka] The vinyl ether was synthesized in a manner similar to Example 208, step a, utilizing methyl 8-hydroxyquinoline-6-carboxylate (5 g, 24.6 mmol). 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] + .

[0359] Example 218 Method 1, steps b and c [ka] Cyclopropanation was carried out according to Example 208, step b, 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] + .

[0360] Methyl ester Method O The material was hydrolyzed in a similar manner to that described above and purified by reverse phase preparative HPLC (MeCN / H 2 0) to give the desired compound as a white solid (1.50 g, 95%). ESI-MS m / z: 230.05 [M+H] + .

[0361] Method 2: Example 218 Method 2 steps a, b, c [ka] The cyclization precursor was synthesized in a manner similar to Example 216 steps a, b and c above. ESI-MS m / z: 194.0 [M+H] + .

[0362] Example 218 Method 2 step d [ka] The following example was performed using acrolein (1.5 equivalents) and step c Method P The title compound was obtained as a light brown solid (5.2 g, 74%). ESI-MS m / z: 208.0 [M+H] + .

[0363] Method 3 Example 218 Method 3 step a [ka] To a 250 mL tank equipped with a stir bar was added 6-bromoquinolin-8-ol (10 g, 44.64 mmol). The solid was dissolved in NMP (100 mL) and then bromocyclopropane (10.8 g, 89.28 mmol), Cs 2 CO 3 (43.52 g, 133.92 mmol) and KI (29.64 g, 178.56 mmol) were added. The sealed tank was stirred at 180° C. for 16 h. 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] + .

[0364] Example 218 Method 3 step b [ka] To a stirred solution of step a (4.50 g, 17.03 mmol) in MeOH (50 mL) was added TEA (5.17 g, 51.11 mmol) and Pd(dppf)Cl 2(1.25 g, 1.70 mmol) was added. The resulting mixture was stirred at 100° C. under CO atmosphere (10 atm) for 4 h. 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] + .

[0365] Example 218 Method 3 steps c [ka] Methyl ester Method O The material was purified by reversed-phase flash chromatography (MeCN / H 2 0) to give the desired compound as a white solid (1.30 g, 48%). ESI-MS m / z: 230.15 [M+H] + .

[0366] Method 4 Example 218 Method 4 Step a [ka] The following example is done using acrolein (2.0 equivalents): Method P to give the title compound as a yellow solid (9.0 g, 36%). ESI-MS m / z: 208.0 [M+H] + .

[0367] Example 218 Method 4 step b [ka] 98% H containing step a (9.00 g, 47.57 mmol) 2 SO 4 A solution of (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 and diluted 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] + .

[0368] Example 218 Method 4, steps c and d [ka] Bromocyclopropane alkylation was carried out in a manner similar to Example 218, method 3, step a using step b. Methyl ester hydrolysis was carried out in a manner similar to Example 218, method 3, step c.

[0369] The following examples in Table 3 were prepared using the corresponding intermediates of Examples 205-207 or their derivatives. Using either the amine or the amine HCl salt, PyBOP (and in some cases HATU) Method J The target compounds were made according to Example 208. In most cases, the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min). Aryl acid coupling partners were made according to Examples 208-218 and synthesized in a similar manner unless specifically listed. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0370] Table 4 below shows the coupling reactions using commercially available aryl acid coupling partners. Method J (PyBOP or HATU) are included. Most compounds were purified by Gilson prep-HPLC, some by automated column chromatography (silica gel). [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0371] Method S [ka] Example 335 Step a (Method S) [ka] A suspension of methyl 8-hydroxyquinoline-6-carboxylate (3.00 g, 14.76 mmol) and Hunig's 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 became homogeneous immediately, was allowed to warm to room temperature, and was monitored by LC-MS. The reaction was diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution of 1,000 ml of ethyl acetate and extracted three times with DCM. The combined organic extracts were washed with anhydrous MgSO 4The mixture was dried at 40° C., filtered and concentrated. Purification by flash column chromatography on silica gel (0-100% EtOAc / Hexanes) afforded the title compound (3.85 g, 78%). ESI-MS m / z: 336.1 [M+H] + .

[0372] Example 335 Step b (Method S) [ka] A mixture of pyridin-4-amine (0.047 g, 0.500 mmol), step a (0.168 g, 0.500 mmol), t-BuBrettPhos Pd 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 flash column chromatography on silica gel and the material was used directly in the next step (yield not detected). ESI-MS m / z: 280.1 [M+H] + .

[0373] Notes: Method S In the case of X = I, additional amination conditions that work well are Pd(OAc) 2 (catalyst), Xantphos (catalyst), Cs 2 CO 3 toluene, 130° C., 2 hours.

[0374] Example 335 Step c (Method S) [ka] A solution of step b (0.140 g, 0.500 mmol) and potassium trimethylsilanolate (0.192 g, 1.500 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction was quenched with methanol, loaded onto silica gel, and concentrated. The resulting mobile mixture was directly purified by flash column chromatography on silica gel and used directly in the next step (19 mg, 14%). ESI-MS m / z: 265.9 [M+H] + .

[0375] The following examples from Table 5 are for use with HATU: Method J and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound. The aryl acid coupling partner was Method S was prepared in the same manner as above. [Table 5-1] [Table 5-2]

[0376] Example 350 [ka] Example 350 steps a and b [ka] A 20 mL vial was charged with a magnetic stir bar, pyridin-3-ylboronic acid (0.160 g, 1.300 mmol), Example 335 step a (Method S) (0.335 g, 1.00 mmol) and potassium carbonate (0.415 g, 3.00 mmol). THF (8 mL) and water (2 mL) were added and the reaction mixture was sparged 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, poured into a separatory funnel and charged with EtOAc and brine. The organic phase was washed with anhydrous MgSO 4 It was dried at 40° C., filtered and concentrated. Purification by flash column chromatography on silica gel afforded the title compound (260 mg, 98%) as a tan solid. ESI-MS m / z: 265.26 [M+H] + .

[0377] Method S Methyl ester hydrolysis was carried out in a similar manner to that described above and 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] + .

[0378] Example 350 process c [ka] Method J The following example was prepared using the amine HCl salt (96 mg, 0.240 mmol) according to (HATU). The crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (36 mg, 24%). ESI-MS m / z: 632.3 [M+H] + .

[0379] Example 351 [ka] The following example was prepared in a similar manner to Example 350 using the amine HCl salt (35 mg, 0.08 mmol) and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (24 mg, 48%). ESI-MS m / z: 632.3 [M+H] + .

[0380] Example 352 [ka] The following example was prepared in a similar manner to Example 350 using the amine HCl salt (33 mg, 0.075 mmol) and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (0.5 mg, 1%). ESI-MS m / z: 648.3 [M+H] + .

[0381] Example 353 [ka] The following example was prepared in a similar manner to Example 350 using the amine (52 mg, 0.120 mmol) and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (6.4 mg, 9%). ESI-MS m / z: 632.2 [M+H] + .

[0382] Example 354 [ka] The following example was prepared in a similar manner to Example 350 using the amine (78 mg, 0.179 mmol) and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (82 mg, 72%). ESI-MS m / z: 633.3 [M+H] + .

[0383] Example 355 [ka] Example 355 steps a and b [ka] 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 h. The reaction mixture was poured into brine and extracted three times with EtOAc. The combined organic extracts were washed with anhydrous MgSO 4 Dry at 40° C., filter and concentrate. Purification by flash column chromatography on silica gel (0-100% EtOAc / Hexanes, then 0-30% MeOH / DCM) gave an orange / brown oil. The product contained a lot of DMF but was otherwise pure. High vacuum overnight gave the pure title compound (1.36 g, 80%). ESI-MS m / z: 347.21 [M+H] + .

[0384] Method S Methyl ester hydrolysis was carried out in a similar manner to that described above and 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] + .

[0385] Example 355 process c [ka] Using the amine HCl salt (204 mg, 0.511 mmol) Method J The following example was prepared according to (HATU) 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]+ .

[0386] Example 356 [ka] Example 355 step b and Method J The following example was prepared according to (HATU) using the amine HCl salt (17 mg, 0.511 mmol) and Boc acid (14 mg). The crude material was dissolved in approximately 1.5 mL of DCM and treated with 0.25 mL of TFA at room temperature. After 30 min, the reaction was concentrated and purified directly by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (2.8 mg, 11%). ESI-MS m / z: 614.1 [M+H] + .

[0387] Example 357 [ka] Example 357 step a [ka] A solution of Example 355, step a (1.00 g, 2.89 mmol) in DCM (9 mL) was treated with TFA (1.80 mL) at room temperature. Upon complete consumption of SM (14 h, LCMS), the reaction was concentrated and diluted with DCM / MeOH (9:1) and saturated NaHCO 3 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 used without further purification. ESI-MS m / z: 247.1 [M+H] + .

[0388] Example 357 steps b and c [ka] A 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 diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The crude material obtained was used without further purification. ESI-MS m / z: 289.9 [M+H] + .

[0389] Method S Methyl ester hydrolysis was carried out in a similar manner to that described above and 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] + .

[0390] Example 357 process d [ka] Using amine HCl salt (50 mg, 0.125 mmol) Method J The following example was prepared according to (HATU). The crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (52 mg, 63%). ESI-MS m / z: 656.2 [M+H] + .

[0391] Example 358 [ka] The aryl acid coupling partner was prepared in the same sequence using Example 357 step a (amine above) and mesyl chloride to give the title compound. ESI-MS m / z: 231.0 [M+H] + Using the amine HCl salt (27 mg, 0.068 mmol), Method JThe following example was prepared according to (HATU) and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (30 mg, 64%). ESI-MS m / z: 692.1 [M+H] + .

[0392] Example 359 [ka] The aryl acid coupling partner was prepared in the same sequence using Example 357 step a (amine above) and potassium cyanate to give the title compound (90 mg, 71%). ESI-MS m / z: 311.0 [M+H] + Using the amine HCl salt (50 mg, 0.125 mmol), Method J The following example was prepared according to (HATU) and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (0.5 mg, 6%). ESI-MS m / z: 657.1 [M+H] + .

[0393] Example 360 [ka] Example 360 ​​steps a and b [ka] 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 h. The reaction mixture was poured into brine and extracted three times with EtOAc. The combined organic extracts were washed with anhydrous MgSO 4It was dried at 40° C., filtered and concentrated. Repeated purification by flash column chromatography on silica gel (0-50% EtOAc / Hexanes) afforded the title compound (0.285 g, 16%) as a tan waxy solid.

[0394] Methyl ester hydrolysis Method S and 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] + .

[0395] Example 360 ​​steps c and d [ka] Using amine HCl salt (80 mg, 0.201 mmol) Method J The following example was prepared according to (HATU). 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 purified directly by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (20 mg, 16%). ESI-MS m / z: 615.3 [M+H] + .

[0396] Example 361 [ka] Example 361 steps a and b [ka] 6-Bromo-8-methoxyisoquinoline (400 mg, 1.7 mmol), TEA (510 mg, 5.0 mmol) and Pd(dppf)Cl 2A solution of (246 mg, 0.3 mmol) in MeOH (20 mL) was stirred under CO atmosphere (10 atm) at 100° C. for 3 h. The mixture was filtered, concentrated, and purified by silica gel column chromatography (EtOAc / Hexanes) to give the desired compound as a pale yellow solid (300 mg, 82%). ESI-MS m / z: 218.05 [M+H] + .

[0397] Methyl ester Method O The material was hydrolyzed in a similar manner to that described above and purified by reverse phase preparative HPLC (MeCN / H 2 0) to give the desired compound as a yellow solid (265 mg, 94%). ESI-MS m / z: 204.05 [M+H] + .

[0398] Example 361 process c [ka] Method J The title compound was prepared in a similar manner using the 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] + .

[0399] Example 362 [ka] Example 362 process a [ka] 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 at reflux overnight. The reaction was concentrated and water was added. The aqueous layer was acidified with 1M aqueous HCl and washed with EtOAc. The combined organics were washed with MgSO4 and concentrated to give 1-methoxyisoquinoline-6-carboxylic acid (85 mg, 87%). ESI-MS m / z: 203.93 [M+H] + .

[0400] Example 362 step b [ka] Method J The title compound was prepared in a similar manner using the 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] + .

[0401] Example 363 [ka] Using the corresponding acid and amine HCl salts (200 mg) coupling partners Method J The following example was prepared using the same procedure as for (PyBOP) and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give the title compound, 195 mg (68%). ESI-MS m / z: 571.1 [M+H] + .

[0402] Example 364 [ka] To a 2-dram vial containing a stir bar was added Example 363 (25 mg, 0.044 mmol), 2-bromoacetamide (7.25 mg, 0.053 mmol) and potassium carbonate (12.11 mg, 0.088 mmol). The solid was dissolved in DMF (0.15 M) and the reaction was stirred at room temperature and monitored by LCMS. Another equivalent of bromoacetamide was added after 2 h to drive conversion. The reaction was diluted with EtOAc and quenched with water. The aqueous was extracted with EtOAc using a phase separator cartridge and the combined organics were concentrated. The crude residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) and purified using ACN / H 2 Freeze-drying in O gave a white fluffy solid (10.3 mg, 36%). ESI-MS m / z: 628.2.

[0403] Example 365 [ka] 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 prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (8.1 mg, 23%). ESI-MS m / z: 664.1 [M+H] + .

[0404] Example 366 [ka] The starting material was prepared similarly to Example 363 using Example 212 to give the hydroxyquinoline precursor (53 mg, 61%). ESI-MS m / z: 585.2 [M+H] + .

[0405] Example 366 was prepared in a similar manner to Example 364 using 1.5 equivalents of 2-bromoacetamide after 3 hours (another 1.2 equivalents were added after 2 hours). The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (25.0 mg, 43%). ESI-MS m / z: 642.1 [M+H] + .

[0406] Example 367 [ka] The starting material was prepared similarly to Example 363 using Example 212 to give the hydroxyquinoline precursor (62 mg, 67%). ESI-MS m / z: 619.2 [M+H] + .

[0407] Example 367 was prepared in a similar manner to Example 364. The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (30.0 mg, 44%). ESI-MS m / z: 676.1 [M+H] + .

[0408] Example 368 [ka] The starting material was prepared in a similar manner to Example 363 using Example 214 to give the hydroxyquinoline precursor (58 mg, 65%). ESI-MS m / z: 599.1 [M+H] + .

[0409] Example 368 was prepared in a similar manner to Example 364 using 1.5 equivalents of 2-bromoacetamide after 3 hours (another 1.2 equivalents were added after 2 hours). The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (31.5 mg, 50%). ESI-MS m / z: 656.2 [M+H] + .

[0410] Example 369 [ka] The starting material was prepared in a similar manner to Example 363 using Example 214 to give the hydroxyquinoline precursor (63 mg, 66%). ESI-MS m / z: 635.3 [M+H] + .

[0411] Example 369 was prepared in a similar manner to Example 364. The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (33.0 mg, 48%). ESI-MS m / z: 690.1 [M+H] + .

[0412] Method T [ka] Example 370 [ka] Example 370 Step a (Method T) [ka] To a 50 mL round bottom flask equipped with a stir bar was added methyl 8-hydroxyquinoline-6-carboxylate (1.500 g, 7.38 mmol) and potassium carbonate (2.040 g, 14.76 mmol) and the solid was 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 was extracted with EtOAc and the combined organics were dried, filtered and concentrated. The residue was purified by automated column chromatography (silica gel, 50% ethyl acetate in hexanes) to obtain a 1:1 ratio. f=0.27) to give a white solid (1.93 g, 82%). ESI-MS m / z: 262.0 [M+H] + .

[0413] Example 370 Step b (Method T) [ka] A 100 mL round bottom flask containing step a (1.93 g, 6.08 mmol) was fitted with a stir bar and the solid was dissolved in DCM (0.5 M). The flask was cooled to 0° C. and TFA (4.69 ml, 60.8 mmol) was added. The reaction was stirred for 10 min, warmed to room temperature and monitored by LCMS (3 h total, 5.0 eq. more TFA added after 5.5 h). The mixture was quenched with water and diluted with DCM. A solid precipitates. Dilute further with DCM and stir vigorously for 10 min. The solid was collected by filtration, washed multiple times with DCM and dried under high vacuum to give a light brown fluffy solid (2.21 g, 97%). ESI-MS m / z: 262.0 [M+H] + .

[0414] Example 370 Step c (Method T) [ka] To a 40 mL vial fitted with a stir bar was added step b (125 mg, 0.333 mmol). The solid was dissolved in DMF and cooled to 0° C. DIPEA (407 μl, 2.332 mmol) was added followed by 1-methylcyclopropan-1-amine hydrochloride (124 mg, 1.148 mmol). PyBOP (260 mg, 0.500 mmol) was then added in one portion and the reaction was stirred for 10 min, warmed to room temperature and monitored by LCMS (1.5 h). The reaction was diluted with EtOAc and quenched with water. The aqueous layer was extracted with EtOAc using a phase separator cartridge and the combined organics were concentrated. The residue was purified by automated column chromatography (silica gel, 0-20% methanol in dichloromethane) to give the title compound (98 mg, 82%). ESI-MS m / z: 216.0 [M+H] + .

[0415] Example 370 Step d (Method T) [ka] General hydrolysis note: In some cases, the reaction was heated to 45° C. to bring the material into solution and facilitate hydrolysis. After hydrolysis, the product was isolated by precipitation. If no precipitate was present, the product was extracted or the aqueous was concentrated (the material was dried and used crude). Primary MS for all of these compounds was + m / z is CC fragmentation. ESI-MS m / z: 202.0 [M+H] + .

[0416] A 20 mL vial containing Example 370 step c (9 mg, 0.312 mmol) was fitted with a stir bar. 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 pH approx. 4-5 (1 M NaOH was used if too acidic). The product was extracted 3 times with 10% MeOH / DCM using a phase separator and concentrated. Drying under high vacuum gave the title compound (45 mg, 50%). ESI-MS m / z: 202.0 [M+H] + .

[0417] Example 370 process e [ka] Method J The following example was prepared using the same procedure as for (PyBOP) with the corresponding acid from step d and the amine HCl salt (25 mg) coupling partner. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (8 mg, 20%). ESI-MS m / z: 682.2

[0418] Example 371 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by extraction (32 mg, 50%). 20 mg of the amine HCl salt was used for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13 mg, 40%). ESI-MS m / z: 704.2 [M+H] + .

[0419] Example 372 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by extraction (14 mg, 40%), and 25 mg of the amine HCl salt was used for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15 mg, 41%). ESI-MS m / z: 642.2 [M+H] + .

[0420] Example 373 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by aqueous concentration (used crude) and 25 mg of the amine HCl salt was used in the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (4.3 mg, 11%). ESI-MS m / z: 656.2 [M+H] + .

[0421] Example 374 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by extraction (41 mg, 69%), and 25 mg of the amine HCl salt was used for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (18.8 mg, 49%). ESI-MS m / z: 670.3 [M+H] + .

[0422] Example 375 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by precipitation (42 mg, 70%) and 25 mg of the amine HCl salt was used for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13.4 mg, 35%). ESI-MS m / z: 686.3 [M+H] + .

[0423] Example 376 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by aqueous precipitation (used crude) and 25 mg of the amine HCl salt was used in the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13.0 mg, 34%). ESI-MS m / z: 668.2 [M+H] + .

[0424] Example 377 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method Tand isolated by Gilson HPLC purification (35 mg, 49%). 25 mg of the amine HCl salt was used for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (23.9 mg, 54%). ESI-MS m / z: 700.2 [M+H] + .

[0425] Example 378 [ka] Method J The following examples were prepared using a similar procedure to (PyBOP). Method T and isolated by aqueous concentration (used crude) and 25 mg of the amine HCl salt was used in the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (8.0 mg, 29%). ESI-MS m / z: 702.2 [M+H] + .

[0426] Example 379 [ka] Method J The following examples were prepared using a procedure similar to that described for (PyBOP): Method T and isolated by aqueous concentration (used crude) and 25 mg of the amine HCl salt was used in the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (6.0 mg, 15%). ESI-MS m / z: 702.2 [M+H] + .

[0427] Example 380 [ka] Example 380 steps a and b [ka] Method R Using the same procedure, 2.5 equiv. of K 2 CO 3 The methyl ester was prepared using 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 hexanes) followed by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (42.1 mg, 6%). ESI-MS m / z: 244.0 [M+H] + .

[0428] Acid precursor Method T and the material was isolated by aqueous concentration (used crude).

[0429] Example 380 process c [ka] Method J The following example was prepared according to (PyBOP) using 25 mg of the amine HCl salt and 1.2 equivalents of acid for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (17.6 mg, 46%). ESI-MS m / z: 656.2 [M+H] + .

[0430] Example 381 [ka] Example 381 step a [ka] Method T, Project a According to this, 2.5 equivalents of K 2CO 3 and 1.2 equivalents of tert-butyl 2,4-dibromobutanoate at 40° C. for 4 hours (1.0 equivalent more bromide was added after 3 hours). The material was purified by automated column chromatography (silica gel, 0-70% EtOAc in hexanes) to give the title compound (1.23 g, 59%). ESI-MS m / z: 370.1 [M+H] + .

[0431] Example 381 Step b [ka] To a 100 mL round bottom flask equipped with a stir bar was added step a (1.236 g, 2.91 mmol) as a solution in THF (0.1 M). The flask was cooled to 0° C. and potassium tert-butoxide (0.572 g, 5.10 mmol) was added in one portion. The flask was purged with nitrogen and stirred for 15 min, then warmed to room temperature and monitored by LCMS (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 was extracted with EtOAc and the combined organics were dried, filtered and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (82 mg, 8%). ESI-MS m / z: 344.2 [M+H] + .

[0432] Example 381 Steps c, d, e [ka] Deprotection of the t-Bu ester is carried out as follows: Method T, Engineering b (95 mg, 100%). ESI-MS m / z: 288.0 [M+H]. Method JPrimary amide formation was carried out with PyBOP (2 equiv.) and ammonium chloride (3 equiv.) according to and purified 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]. Methyl ester hydrolysis was Method T, Engineering d and isolated by precipitation (17 mg, 50%). ESI-MS m / z: 256.0 [M+H].

[0433] Example 381 process f [ka] Method J The following example was prepared according to (PyBOP) using 25 mg of the amine HCl salt and the residue was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (18 mg, 48%). ESI-MS m / z: 654.3 [M+H] + .

[0434] Example 382 [ka] Method R Using the acid precursor from Method J (PyBOP) and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12.4 mg, 41%). ESI-MS m / z: 662.1 [M+H] + .

[0435] Example 383 [ka] Method RThe methyl ester precursor was prepared in the same manner as above, using 1.5 equivalents of (±)-2-bromopropanamide at 40° C. for 16 hours. (109 mg, 32%). ESI-MS m / z: 230.0 [M+H] + . Method R Methyl ester hydrolysis was carried out in a similar manner to and isolated by precipitation (50 mg, 48%). ESI-MS m / z: 260.9 [M+H] + .

[0436] Method J Example 383 was prepared according to (PyBOP) using 60 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound as a mixture of diastereomers (34.3 mg, 38%). ESI-MS m / z: 642.1 [M+H] + .

[0437] Example 384 [ka] Using methyl-8-aminoquinoline 6-carboxylate (200 mg) and 4.0 equivalents of 2-bromoacetamide, Method R The methyl ester was prepared in a similar manner to that described above at 40° C. for 16 h (78 mg, 30%). ESI-MS m / z: 215.0 [M+H] + . Method T, Engineering d Methyl ester hydrolysis was carried out in a similar manner to and isolated by precipitation (38 mg, 52%). ESI-MS m / z: 246.0 [M+H] + .

[0438] Example 384 was prepared using 25 mg of the amine HCl salt and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (14.0 mg, 39%). ESI-MS m / z: 627.2 [M+H] + .

[0439] Example 385 [ka] Using methyl-8-aminoquinoline 6-carboxylate (300 mg) and 1.2 equivalents of iodomethane, Method R The methyl ester was prepared in a similar manner to that described above at room temperature for 48 hours (150 mg, 47%). ESI-MS m / z: 217.1 [M+H] + . Method T, Engineering d Methyl ester hydrolysis was carried out in a similar manner to and isolated by precipitation (75 mg, 65%). ESI-MS m / z: 203.0 [M+H] + .

[0440] Example 385 was prepared using 20 mg of the amine HCl salt and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (19.6 mg, 72%). ESI-MS m / z: 585.2 [M+H] + .

[0441] Example 386 [ka] Example 386 steps a and b [ka] To a 20 mL vial equipped with a stir bar and pressure relief septum was added methyl 8-hydroxyquinoline-6-carboxylate (116 mg, 0.570 mmol), picolinic acid (11.69 mg, 0.095 mmol), potassium phosphate tripotassium (202 mg, 0.949 mmol), and copper(I) iodide (9.04 mg, 0.047 mmol). The solid was dissolved in DMSO (0.33 M) and 2-bromopyridine (45.3 μl, 0.475 mmol) was added. The flask was then immersed in N 2The mixture was purged with ethyl acetate and heated to 90° C. overnight for 14 h. The reaction was diluted with EtOAc and quenched with water. The copper salts were filtered off through celite, the aqueous was extracted with 10% MeOH / DCM using a phase separator cartridge, and the combined organics were concentrated. The residue was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (11 mg, 8%). ESI-MS m / z: 281.1 [M+H] + . Method T, Engineering d Methyl ester hydrolysis was carried out according to and isolated by aqueous concentration (crude was used). ESI-MS m / z: 267.0 [M+H] + .

[0442] Example 386 process c [ka] Method J (This example was prepared according to PyBOP using 10 mg of the amine HCl salt precursor. The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (1.6 mg, 11%). ESI-MS m / z: 648.2 [M+H] + .

[0443] Example 387 [ka] This example was prepared in a similar sequence to Example 386. 2-Bromopyrazine Ullmann coupling (32 mg, 25%). ESI-MS m / z: 282.0 [M+H] + . Method T, Engineering d and isolated by aqueous extraction (15 mg, 50%). ESI-MS m / z: 268.0 [M+H] + .

[0444] Method JExample 387 was prepared according to (PyBOP) using 25 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (10.0 mg, 27%). ESI-MS m / z: 649.1 [M+H] + .

[0445] Example 388 [ka] Example 388 steps a and b [ka] To a 20 mL vial equipped with a stir bar was added 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). 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 was extracted with 10% MeOH / DCM using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes, then 0-20% MeOH in DCM) to give the title compound (10 mg, 7%). ESI-MS m / z: 281.0 [M+H] + .

[0446] Method T, Engineering d Methyl ester hydrolysis was carried out according to and isolated by aqueous concentration (used crude). ESI-MS m / z: 266.9 [M+H] + .

[0447] Example 388 process c [ka] Method J This example was prepared using 15 mg of the amine HCl salt precursor according to (PyBOP) and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (1.5 mg, 7%). ESI-MS m / z: 649.1 [M+H] + .

[0448] Example 389 [ka] This example was prepared in a similar sequence to Example 388. r was performed at 60 °C with 3 equivalents of 2-bromooxazole in DMF (0.33 M) without DIPEA (57 mg, 29%). ESI-MS m / z: 271.0 [M+H] + The acid precursor method T and isolated by precipitation (16 mg, 30%). ESI-MS m / z: 257.0 [M+H] + .

[0449] Method J Example 389 was prepared according to (PyBOP) using 20 mg of the amine HCl salt and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12 mg, 40%). ESI-MS m / z: 638.1 [M+H] + .

[0450] Example 390 [ka] Example 390, steps a and b [ka] To a 2-dram vial equipped with a stir bar was added oxazol-2-ylmethanol (58.5 mg, 0.591 mmol) and the oil was dissolved in THF. Methyl 8-hydroxyquinoline-6-carboxylate (100 mg, 0.492 mmol) and 2-pyridyldiphenylphosphine (155 mg, 0.591 mmol) were then added and the vial was cooled to 0° C. DIAD (115 μl, 0.591 mmol) was added and the reaction was stirred for 10 minutes, warmed to room temperature and monitored by LCMS (2 hours). 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 hexanes, then 0-20% MeOH / DCM) to give the title compound (140 mg, 99%). ESI-MS m / z: 285.0 [M+H] + Methyl ester hydrolysis Method T, Engineering d and purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (22 mg, 17%). ESI-MS m / z: 271.0 [M+H].

[0451] Example 390 process c [ka] Method J This example was prepared according to (PyBOP) using 25 mg of the amine HCl salt precursor. The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15.7 mg, 41%). ESI-MS m / z: 652.2 [M+H] + .

[0452] Example 391 [ka] This example was prepared in a similar sequence to Example 390. Mitsunobu reaction (162 mg, 110%, impure). ESI-MS m / z: 299.1 [M+H] +Ester hydrolysis is Method T, Engineering d and isolated by precipitation (17 mg, 12%). ESI-MS m / z: 285.0 [M+H] + .

[0453] Method J Example 391 was prepared according to (PyBOP) using 25 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13.8 mg, 36%). ESI-MS m / z: 666.2 [M+H] + .

[0454] Example 392 [ka] Example 392, steps a and b [ka] To a 40 mL vial equipped with a stir bar was added methyl 8-aminoquinoline-6-carboxylate (100 mg, 0.495 mmol). The solid was dissolved in DCM (0.2 M) and cooled to 0° C. DIPEA (216 μl, 1.236 mmol) was added followed by cyclopropanecarbonyl chloride (49.4 μl, 0.544 mmol). The reaction was allowed to warm 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 was extracted with 10% MeOH / DCM using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (120 mg, 89%). ESI-MS m / z: 271.2 [M+H] + Methyl ester hydrolysis is Method T, Engineering d and isolated by precipitation (73 mg, 64%). ESI-MS m / z: 257.0 [M+H] + .

[0455] Example 392 process c [ka] Method J This example was prepared according to (PyBOP) using 25 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (22.2 mg, 60%). ESI-MS m / z: 628.2 [M+H] + .

[0456] Example 393 [ka] This example was prepared in a similar sequence to Example 392. Aminoquinoline acylation (99 mg, 82%). ESI-MS m / z: 245.1 [M+H] + The acid precursor is heated to 55°C and hydrolyzed ( Method T, Engineering d ), isolated by precipitation (69 mg, 74%). ESI-MS m / z: 230.9 [M+H] + .

[0457] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as described in (PyBOP) to give the title compound (19 mg, 53%). ESI-MS m / z: 612.1 [M+H] + .

[0458] Example 394 [ka] This example was prepared in a similar sequence to Example 392. Aminoquinoline mesylation (98 mg, 71%). ESI-MS m / z: 281.2 [M+H] + The acid precursor Method T, Engineering d and isolated by precipitation (51 mg, 55%). ESI-MS m / z: 266.8 [M+H]+ .

[0459] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (25.2 mg, 67%). ESI-MS m / z: 648.1 [M+H] + .

[0460] Example 395 [ka] This example was prepared using a similar sequence to Example 392. The aminoquinoline sulfonylation required the addition of 10+ equivalents of sulfonyl chloride and 16 hours (36 mg, 24%). ESI-MS m / z: 307.3 [M+H] + The acid precursor Method T, Engineering d and isolated by precipitation (16 mg, 47%). ESI-MS m / z: 292.9 [M+H] + .

[0461] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as described in (PyBOP) to give the title compound (12.0 mg, 30%). ESI-MS m / z: 674.1 [M+H] + .

[0462] Method U [ka] Example 396 [ka] Example 396 Steps a and b (Method U) [ka] To a 20 mL vial fitted with a stir bar was added methyl 8-aminoquinoline-6-carboxylate (75 mg, 0.371 mmol), DIPEA (486 μl, 2.78 mmol) and the material was dissolved in DMF (0.2 M). 2,2-Difluoroacetic acid (46.7 μl, 0.742 mmol) was then added after buffering and the vial was cooled to 0° C. PyBOP (290 mg, 0.556 mmol) was then added and the reaction was stirred for 10 minutes, warmed to room temperature and monitored by LCMS (16 hours). The reaction was diluted with DCM and quenched with water and saturated sodium bicarbonate. The aqueous was extracted with 10% MeOH / DCM using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound (37 mg, 36%). ESI-MS m / z:263.0 [M+H] + .

[0463] Methyl ester hydrolysis is Method T, Engineering d The mixture was treated with 2.5 equivalents of LiOH (acetamide hydrolysis occurs) according to and isolated by precipitation (12 mg, 50%). ESI-MS m / z: 265.0 [MH] - .

[0464] Example 396 process c [ka] Method J This example was prepared according to (PyBOP) using 25 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (5.0 mg, 13%). ESI-MS m / z: 648.1 [M+H] + .

[0465] Example 397 [ka] Method U The acid precursor was prepared in a similar sequence to that described above. Aminoquinoline amide formation (19 mg, 17%). ESI-MS m / z: 312.0 [M+H] + . Method t, Engineering d The methyl ester was hydrolyzed as described above (heated to 45° C.) and isolated by aqueous concentration (used crude). ESI-MS m / z: 298.0 [M+H] + .

[0466] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 20 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (14.7 mg, 47%). ESI-MS m / z: 679.1 [M+H] + .

[0467] Method V [ka] Example 398 [ka] Example 398 Steps a and b (Method V) [ka] To a 20 ml vial containing a stir bar was added oxazole-2-carboxylic acid (41.9 mg, 0.371 mmol). The solid was suspended in DCM and the vial was cooled to 0° C. 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (58.9 μl, 0.445 mmol) was added and the reaction was stirred at 0° C. for 15 min and allowed to warm to room temperature (solid went into solution after 1.5 h). The reaction was cooled to 0° C. and pyridine (225 μL, 2.78 mmol) was added in one portion followed by methyl 8-aminoquinoline-6-carboxylate (75 mg, 0.371 mmol). The reaction was allowed to warm to room temperature and monitored by LCMS (2 h long). The reaction was diluted with DCM and quenched with water and saturated sodium bicarbonate. The aqueous was extracted with 10% MeOH / DCM using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (63 mg, 57%). ESI-MS m / z: 298.0 [M+H] + .

[0468] Methyl ester hydrolysis is Method T, Engineering d and isolated by precipitation (17 mg, 80% by weight, 23%). ESI-MS m / z: 214.8 [M+H] + .

[0469] Example 398 process c [ka] Method J This example was prepared according to (PyBOP) using 20 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12.0 mg, 35%). ESI-MS m / z: 665.1 [M+H] + .

[0470] Example 399 [ka] Example 399, steps a and b [ka] Method V The acid intermediate was prepared according to the procedure described above. The Ghosez coupling was carried out for 14 h (134 mg, 94%). ESI-MS m / z: 330.0 [M+H] + . Method T, Engineering d The compound was isolated by hydrolysis of the methyl ester with ethyl acetate and aqueous extraction (115 mg, 89%). ESI-MS m / z: 316.0 [M+H] + .

[0471] Example 399 steps c and d [ka] Step b and 40 mg of the amine HCl salt precursor Method J Amide formation was carried out according to (PyBOP). The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (65 mg, 94%). ESI-MS m / z: 753.2 [M+H] + .

[0472] A stir bar was placed in a 20 mL vial containing Example 399 step c (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, warmed 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 extracted with DCM / MeOH using a phase separator cartridge and concentrated. The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (13.0 mg, 23%). ESI-MS m / z: 653.2 [M+H] + .

[0473] Example 400 [ka] The following examples were prepared in a similar sequence to Example 399: Boc-azetidine Ghosez coupling, Method V (131 mg, 92%). ESI-MS m / z:330.0[M+H] + . Method T, Engineering d The compound was isolated by hydrolysis of the methyl ester with HCl and aqueous extraction (120 mg, 95%). ESI-MS m / z: 316.0 [M+H] + .

[0474] Method J Quinolinic acid amide formation (65 mg, 94%) using 40 mg of amine HCl salt precursor according to (PyBOP). ESI-MS m / z: 753.2 [M+H] + After TFA deprotection, the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (21.0 mg, 37%). ESI-MS m / z: 653.2 [M+H] + .

[0475] Example 401 [ka] The following examples were prepared in a similar sequence to Example 399: Boc-azetidine Ghosez coupling, Method V (119 mg, 83%). ESI-MS m / z:330.0[M+H] + . Method T, Engineering d The compound was isolated by hydrolysis of the methyl ester with HCl and aqueous extraction (80 mg, 70%). ESI-MS m / z: 316.0 [M+H] + 40 mg of the amine HCl salt precursor was used. Method J (PyBOP) amide formation and TFA deprotection were performed in one pot and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3.6 mg, 8%). ESI-MS m / z: 653.2 [M+H] + .

[0476] Example 402 [ka] Example 402 steps a and b [ka] To a 40 mL vial fitted with a stir bar was added ethyl 2-methyl-1H-imidazole-4-carboxylate (500 mg, 3.24 mmol) 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 portion. 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 added slowly. The reaction was allowed to warm to room temperature over 16 h. The reaction was diluted with EtOAc and quenched with water and saturated ammonium chloride. The aqueous was extracted with EtOAc using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (500 mg, 56 wt%, 35%). ESI-MS m / z: 285.1 [M+H] + Ethyl ester hydrolysis is Method T, Engineering d and isolated by precipitation (233 mg, 80%). ESI-MS m / z: 199.0 [M+H] + .

[0477] Example 402 steps c and d [ka] The following example Method V Prepared according to SEM-imidazole aminoquinoline Ghosez coupling (81 mg, 50%). ESI-MS m / z: 441.1 [M+H] + .

[0478] Method T, Engineering dThe methyl ester hydrolyzed by was isolated by precipitation (25 mg, 31%). ESI-MS m / z: 427.1 [M+H] + .

[0479] Example 402 steps e and f [ka] SEM-imidazole amide formation using 25 mg of the amine HCl salt precursor according to Method J (PyBOP) and purification by automated column chromatography (silica gel, 0-100% EtOAc / hexanes) afforded the title compound (50 mg, 100%). ESI-MS m / z: 808.2 [M+H] + .

[0480] TFA deprotection was performed using 60 equivalents of TFA (20 equivalents each for 3 h) and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15 mg, 35%). ESI-MS m / z: 678.1 [M+H] + .

[0481] Example 403 [ka] The following example was prepared in a similar sequence to Example 402: Ethyl imidazole carboxylate SEM-protected (872 mg, 90%). ESI-MS m / z: 199.0 [M+H] + SEM-Ethylimidazole carboxylate hydrolysis (Method T, step d) isolated by extraction (320 mg, 89%). ESI-MS m / z: 185.0 [M+H] + . Method U (158 mg, 60% by weight, 45%) of aminoquinoline and SEM-imidazole carboxylic acid amide. ESI-MS m / z: 427.0 [M+H] + . Method T, Engineering dThe mixture was isolated by hydrolysis of the quinoline methyl ester at 45° C. and precipitation (86 mg, 61%). ESI-MS m / z: 265.0 [M+H] + .

[0482] Use 30 mg of amine HCl salt precursor Method J The amide formation with (PyBOP) was purified by automated column chromatography (silica gel, 0-100% EtOAc / hexanes) to give the title compound (50 mg, 100%). ESI-MS m / z: 894.2 [M+H] + TFA deprotection was performed using 60 equivalents of TFA (20 equivalents each for 3 h): the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (17.4 mg, 37%). ESI-MS m / z: 664.1 [M+H] + .

[0483] Example 404 [ka] The following example was prepared in a similar sequence to Example 402: Ethyl triazole carboxylate SEM-protected (800 mg, 83%). ESI-MS m / z: 272.2 [M+H] + SEM-Ethyl triazole carboxylate hydrolysis (method T, step d) isolated by extraction (310 mg, 86%). ESI-MS m / z: 186.0 [M+H] + Aminoquinoline and SEM-triazole carboxylic acid amide formation Method U (150mg, 40% by weight, 28%). ESI-MS m / z:428.1[M+H] + It was isolated by extraction. Method T, Engineering d Methyl ester hydrolysis by (82 mg, 57%). ESI-MS m / z: 414.1 [M+H] + .

[0484] Use 40 mg of amine HCl salt precursor Method J(PyBOP) amide formation and purification by automated column chromatography (silica gel, 0-100% EtOAc / hexanes) afforded the title compound (64 mg, 88%). ESI-MS m / z: 795.2 [M+H] + TFA deprotection was performed using 40 equivalents of TFA (20 equivalents each for 2 h): the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (19.0 mg, 35%). ESI-MS m / z: 665.1 [M+H] + .

[0485] Example 405 [ka] Example 405 Steps a and b [ka] Add ethyl 8-cyclopropoxyquinoline-6-carboxylate (10.29 g, 40.0 mmol) to a 50 mL round-bottom flask equipped with a stir bar and dissolve the solid in CHCl 3 (0.33M). The flask was cooled to 0° C. and mCPBA (19.72 g, 80 mmol) was added portionwise over 5-10 min (internal temperature monitored at 3° C.). The reaction was stirred for 10 min and allowed to warm to room temperature over 20 min. The reaction was then warmed to 45° C. (internal temperature monitored) and monitored by LCMS (2 h).

[0486] The reaction was diluted with DCM and quenched with water and saturated sodium thiosulfate. The aqueous was extracted with DCM, dried, filtered and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc / Hexanes, then 0-20% MeOH / DCM) to give the title compound (4.14 g, 38%). ESI-MS m / z: 274.1 [M+H] + .

[0487] To a 50 mL vial containing a stir bar was added ethyl 2-chloro-8-cyclopropoxyquinoline-6-carboxylate (2.8 g, 9.60 mmol, 63%) and the solid was dissolved in DCM. 3 (2.83 ml, 30.3 mmol) was added, the flask was fitted with a condenser and the reaction was heated to 45° C. The reaction was monitored by LCMS and was complete after 2 hours. The reaction was cooled to 0° C., diluted with EtOAc and quenched slowly with water. Quenched for 30 minutes, additional water and saturated sodium bicarbonate were added slowly. The aqueous was extracted with DCM, dried, filtered and concentrated. The material was purified by automated column chromatography (silica gel, 0-50% EtOAc / Hexanes) to give the title compound (2.80 g, 63%). ESI-MS m / z: 292.0 [M+H] + .

[0488] Example 405 steps c and d [ka] To a 20 mL vial fitted with a stir bar was added (R)-2-((tert-butyldimethylsilyl)oxy)propan-1-ol (362 mg, 1.902 mmol) 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 allowed to warm to room temperature and stirred for 30 min. Ethyl 2-chloro-8-cyclopropoxyquinoline-6-carboxylate (111 mg, 0.380 mmol) was then added and the reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and quenched with water and 2M HCl. The aqueous was extracted with EtOAc using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (50 mg, 32%) ESI-MS m / z: 418.2 [M+H] +(Note: the methyl ester was hydrolyzed while quenching with HCl.) The TBS group was removed with TBAF for 1 h and purified by automated column chromatography (silica gel, 0-100% EtOAc / Hexanes, then 0-20% MeOH / DCM) to give the title compound (15 mg, 42%). ESI-MS m / z: 304.1 [M+H] + .

[0489] Example 405 process e [ka] Method J This example was prepared according to (PyBOP) using 20 mg of the amine HCl salt precursor and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (12.0 mg, 37%). ESI-MS m / z: 685.2 [M+H] + .

[0490] Example 406 [ka] Example 406 process a [ka] To a 50 mL round bottom flask equipped with a rod was added ethyl 2-chloro-8-cyclopropoxyquinoline-6-carboxylate (300 mg, 1.028 mmol) 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 (became cloudy 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 diluted with 5 mL of 10% K 2 CO 3The solution was quenched with 5 mL of saturated sodium thiosulfate. Using a phase separator cartridge, the aqueous was extracted with EtOAc, extracted twice with DCM / MeOH, and concentrated. The material was purified by automated column chromatography (silica gel, 0-30% EtOAc / hexanes) to give the title compound (341 mg, 78%). ESI-MS m / z: 384.1 [M+H] + .

[0491] Example 406 steps b, c, d [ka] Aldehyde intermediate: To a 20 mL vial equipped with a stir bar was added step a (100 mg, 0.261 mmol) and the solid was dissolved in THF (0.33 M). The vial was cooled to -15°C and isopropylmagnesium chloride (261 μl, 0.522 mmol) was added. The reaction was stirred for 30 min and then N,N-dimethylformamide (404 μl, 5.22 mmol) was added. The reaction was warmed to 0°C and further stirred for 1 h. The reaction was diluted with EtOAc and quenched with water and saturated ammonium chloride. The aqueous was extracted with EtOAc using a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (26 mg, 35%). ESI-MS m / z: 286.1 [M+H] + .

[0492] Alcohol: In a 20 mL vial containing ethyl 8-cyclopropoxy-2-formylquinoline-6-carboxylate, step b (26 mg, 0.091 mmol), a stir bar was placed and the solid was dissolved in EtOH (0.2 M). The reaction was cooled to 0 °C and NaBH 4 (5.17 mg, 0.137 mmol) was added. The reaction was kept at 0° C. for 1 h, diluted with EtOAc, and quenched with water and saturated ammonium chloride. The aqueous was extracted with EtOAc using a phase separator cartridge and concentrated (25 mg, 95%).

[0493] Method T, Engineering d The quinoline ethyl ester was isolated by hydrolysis of the quinoline ethyl ester with HCl and aqueous concentration (used crude). ESI-MS m / z: 260.0 [M+H] + .

[0494] Example 406 process e [ka] Method J This example was prepared according to (PyBOP) using step d and 30 mg of the amine HCl salt precursor, and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (15.0 mg, 33%). ESI-MS m / z: 641.2 [M+H] + .

[0495] Example 407 [ka] The following example was prepared similarly to Example 406 steps b and d (Grignard exchange and addition). Grignard quench was performed with acetone (20 eq.) and left for 16 h (14 mg, 11%). ESI-MS m / z: 316.1 [M+H] + .

[0496] Method T, Engineering d The quinoline ethyl ester hydrolysis by was isolated by aqueous concentration (used crude). ESI-MS m / z: 288.1 [M+H] + .

[0497] 20 mg of the amine HCl salt precursor was used. Method J (PyBOP) amide coupling was performed and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (3 mg, 61%). ESI-MS m / z: 669.2 [M+H] + .

[0498] Method W [ka] Example 408 [ka] Example 408 Steps a and b (Method W) [ka] To a 20 mL vial equipped with a stir bar was added methyl 8-aminoquinoline-6-carboxylate (300 mg, 1.484 mmol) and CDI (289 mg, 1.780 mmol). 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 precipitates). 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 precipitates). The vial was vortexed to induce precipitation and 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] + .

[0499] Method T, Engineering d Methyl ester hydrolysis was carried out according to the procedure described above for 1 h at 45° C. and isolated by precipitation (184 mg, 89%).

[0500] Example 408 process c [ka] Method J This example was prepared using 25 mg of the amine HCl salt precursor according to (PyBOP) and the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (21.8 mg, 61%). ESI-MS m / z: 613.1 [M+H] +.

[0501] Example 409 [ka] Preparing an acid precursor; Method W The following example was prepared according to. The methyl urea product was extracted and purified by automated column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (17 mg, 13%). ESI-MS m / z: 260.2. [M+H] + . Method T, Engineering d Methyl ester hydrolysis was carried out at 45° C. for 1 h according to and isolated by aqueous concentration (used crude). ESI-MS m / z: 245.9 [M+H] + .

[0502] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (12 mg, 33%). ESI-MS m / z: 627.2 [M+H] + .

[0503] Example 410 [ka] Preparing an acid precursor; Method W The following example was prepared according to the procedure described above. The urea formation was extracted and the crude product (91 mg, 100%) was used. ESI-MS m / z: 286.0. [M+H] + Methyl ester hydrolysis is Method T, Engineering d and isolated by precipitation (60 mg, 69%). ESI-MS m / z: 271.9 [M+H] + .

[0504] Method JThe material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 20 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (20.0 mg, 65%). ESI-MS m / z: 653.2 [M+H] + .

[0505] Example 411 [ka] Preparing an acid precursor; Method W The following example was prepared according to: Urea formation (40 mg, 36%). ESI-MS m / z: 258.1 [M+H] + Methyl ester hydrolysis occurs at 45°C. Method T, Engineering d and isolated by precipitation (23 mg, 60%). ESI-MS m / z: 189.0 [M+H] + .

[0506] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 20 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (15.7 mg, 50%). ESI-MS m / z: 667.2 [M+H] + .

[0507] Example 412 [ka] Preparing an acid precursor; Method W The following example was prepared according to: Urea formation (86 mg, 73%). ESI-MS m / z: 318.1 [M+H] + Methyl ester hydrolysis occurs at 45°C. Method T, Engineering d and isolated by precipitation (59 mg, 70%). ESI-MS m / z: 304.1 [M+H] + .

[0508] Method JThe material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as described in (PyBOP) to give the title compound (20.7 mg, 52%). ESI-MS m / z: 685.2 [M+H] + .

[0509] Example 413 [ka] Preparing an acid precursor; Method W The following example was prepared according to with final additional Boc deprotection. The urea formation was extracted and purified (127 mg, 86%). ESI-MS m / z: 401.1 [M+H] + Methyl ester hydrolysis, Method T, Engineering d at 45° C. and isolated by precipitation (97 mg, 79%). ESI-MS m / z: 331.1 [M+H] + .

[0510] 35 mg of amine HCl salt precursor Method J (PyBOP) and the material was purified by automated column chromatography (silica gel, 0-100% EtOAc / Hexanes) to give the title compound (60 mg, 97%). After Boc deprotection with TFA, the material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) to give the title compound (20.0 mg, 37%). ESI-MS m / z: 668.2 [M+H] + .

[0511] Example 414 [ka] Preparing an acid precursor; Method W The following example was prepared according to: Urea formation (56 mg, 50%). ESI-MS m / z: 302.0 [M+H] + Methyl ester hydrolysis, Method T, Engineering dat 45° C. and isolated by precipitation (26 mg, 50%). ESI-MS m / z: 288.0 [M+H] + .

[0512] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (15.0 mg, 38%). ESI-MS m / z: 669.2 [M+H] + .

[0513] Example 415 [ka] Preparing an acid precursor; Method W The following example was prepared according to the procedure described above. The urea formation was extracted and the crude product (106 mg, 100%) was used. ESI-MS m / z: 286.0 [M+H] + Methyl ester hydrolysis, Method T, Engineering d at 45° C. and isolated by precipitation (26 mg, 26%). ESI-MS m / z: 271.8 [M+H] + .

[0514] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (20.0 mg, 52%). ESI-MS m / z: 653.2 [M+H] + .

[0515] Example 416 [ka] Example 416 Step a [ka] A 50 mL round bottom flask was charged with 4-amino-3-nitrobenzoic acid (3.26 g, 17.90 mmol), followed by 30 mL of concentrated HCl, followed by methacrylaldehyde (2.95 ml, 35.8 mmol). The mixture was heated to 100° C. for 5 h and then cooled to room temperature. The mixture was filtered through celite. The aqueous layer was concentrated to give a brown mass, 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] + .

[0516] Example 416 steps b and c [ka] A stir bar was placed in 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 h. The reaction was diluted with EtOAC and quenched with water and saturated sodium ammonium chloride. The aqueous was extracted with EtOAc and DCM / MeOH using a phase separator cartridge and concentrated (168 mg, 42%). ESI-MS m / z: 261.0 [M+H] + .

[0517] The crude material from step b (168 mg, 0.646 mmol) was placed in 40 mL with 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 h. The reaction was cooled and diluted with EtOAc. The mixture was filtered through celite and rinsed with EtOAc and MeOH. The organics were concentrated. EtOAc was then added and the aqueous was basified 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]+ .

[0518] Example 416 steps d, e and f [ka] The acid precursor was prepared in a similar manner to Example 392 including step c above. The methylaminoquinoline acylation was extracted and used crude (39 mg, 100%). ESI-MS m / z: 299.1 [M+H] + Ethyl ester hydrolysis, Method T, Engineering d at 45° C. and isolated by precipitation (26 mg, 68%). ESI-MS m / z: 271.0 [M+H] + .

[0519] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (21.0 mg, 55%). ESI-MS m / z: 652.2 [M+H] + .

[0520] Example 417 [ka] The acid precursor was prepared using the 3-methylquinoline analog from Example 416, step c. Method W The following example was prepared according to the procedure described above. The urea formation was extracted and the crude product (54 mg, 99%) was used. ESI-MS m / z: 314.0 [M+H] + Ethyl ester hydrolysis, Method T, Engineering d at 45° C. and isolated by precipitation (26 mg, 53%). ESI-MS m / z: 285.8 [M+H] + .

[0521] Method JThe material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (15.0 mg, 38%). ESI-MS m / z: 667.2 [M+H] + .

[0522] Example 418 [ka] The following acid precursors were prepared using the 3-methylquinoline analogs from Example 416, step c: Method V The amide Ghosez coupling was purified by automated column chromatography (silica gel, 0-100% EtOAc / hexanes) to give the title compound (58 mg, 99%). ESI-MS m / z: 340.1 [M+H] + Ethyl ester hydrolysis, Method T, Engineering d at 45° C. and isolated by precipitation (25 mg, 47%). ESI-MS m / z: 312.2 [M+H] + .

[0523] Method J The material was purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min) using 25 mg of the amine HCl salt precursor as per (PyBOP) to give the title compound (10.0 mg, 24%). ESI-MS m / z: 693.2 [M+H] + .

[0524] Example 419 steps a and b [ka] In a vial, ethyl 2-chlorobenzo[d]thiazole-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 at room temperature overnight. The reaction was diluted with water and the aqueous layer was washed with EtOAc. The combined organic layers were washed with brine and then diluted with MgSO 4 The crude reaction mixture was purified by silica gel column chromatography (0-60% EtOAc / Hexanes) to give the title compound (250 mg, 97%).

[0525] In a vial, the compound from step a (250 mg, 0.999 mmol) and lithium hydroxide (239 mg, 10 equiv.) 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 h. The reaction was diluted with water and the pH was adjusted to 3-4 with 1M aqueous HCl. The aqueous layer was washed with DCM and 9:1 DCM / MeOH and the combined organics were washed with MgSO 4 It was dried over and concentrated under reduced pressure to give the title compound (220 mg, 99% yield). ESI-MS m / z: 223.16 [M+H] + .

[0526] Example 420 [ka] To a suspension of 4-amino-3-hydroxybenzoic acid (500 mg, 3.27 mmol) in acetic acid (6 ml, 105 mmol) was added potassium thiocyanate (1586 mg, 16.33 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 while maintaining the temperature below 10° C. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with water, boiled for 15 minutes and filtered while still hot. The filtrate was cooled in an ice bath and the crystallized 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 rinsed 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] + .

[0527] Example 421 steps a and b [ka] To a solution of methyl 4-amino-3-fluorobenzoate (45 g, 266 mmol) and sodium thiocyanate (86 g, 1064 mmol) in acetic acid (350 ml) at 0° C. was added bromine (13.57 ml, 263 mmol) in AcOH (100 ml) via an addition funnel over 1 h, the mixture was allowed to warm to room temperature and stirred for 2 days. The mixture was filtered and the precipitate was washed with water and dried under vacuum to the title compound, which was carried forward as a crude mixture.

[0528] A slurry of the product of 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., stirred for 4 h, cooled to room temperature, and then concentrated under reduced pressure. The pH was adjusted to 5 with 3M HCl and 3% citric acid. A pale yellow solid was precipitated, collected by filtration, washed with water, and dried. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with Na 2 SO 4and concentrated to give the title compound (250 mg, 33%) as a pale yellow solid.

[0529] Example 422 steps a and b [ka] In a vial, methyl 2-bromo-4-isopropoxybenzo[d]thiazole-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] + .

[0530] 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 at room temperature overnight. Water was added and the reaction was acidified to pH 2-3 with 1M aqueous HCl. The aqueous layer was extracted with EtOAc and the combined organics were washed with MgSO 4 and concentrated to give the title compound (90 mg, 95%). ESI-MS m / z: 267.92 [M+H] + .

[0531] Example 423 Step a [ka] In a vial, methyl 4-isopropoxy-2-methoxybenzo[d]thiazole-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 added slowly and the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the addition of 1N HCl. The aqueous layer was washed with DCM and the combined organic layers were washed with MgSO 4 The crude mixture was purified by silica gel column chromatography eluting with (0-50% EtOAc / Hexanes) to give the title compound (150 mg, 98%). ESI-MS m / z: 240.07 [M+H] + .

[0532] Example 423 steps b and c [ka] 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 added slowly and the reaction was allowed to warm to room temperature. After 4 h, trimethylsilyldiazomethane (940 μl, 1.881 mmol) was added and the reaction was stirred for an additional 12 h. Water was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with MgSO 4 The crude mixture was purified by silica gel column chromatography (0-50% EtOAc / Hexanes) to give the title compound (105 mg, 66%).

[0533] 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 h. Water was then added and the pH was adjusted to 2-3 by the addition of 4M aqueous HCl. The aqueous layer was washed with DCM and the combined organic layers were washed with MgSO 4and concentrated under reduced pressure to give the title compound (47 mg, 100%). ESI-MS m / z: 239.87 [M+H] + .

[0534] The following examples in Table 6 were prepared using the corresponding intermediates of Examples 205-207 and their derivatives. Method J Compounds were made according to. In most cases, compounds were purified by Gilson prep-HPLC (20-90%, MeCN / water, 25 min). Aryl acids, if not commercially available, were prepared according to Examples 419-423. If not specifically listed, acids were synthesized in a similar manner to the previous examples. [Table 6-1] [Table 6-2] [Table 6-3]

[0535] Example 449 [ka] Using the method described in Example 206 (CF 3 Using olefins and TBS-alcohols), Example 449 was prepared diastereomerically pure. Methods A, B and F The TBS-alcohol was converted to the acid according to (1.34g, 58%). ESI-MS m / z: 612.17 [M+H] + .

[0536] Table 7 below shows Example 449 (or the methoxy analogue) and Method J Compounds were purified by either automated column chromatography or Gilson prep-HPLC (20-90%, MeCN / water, 25 min). [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0537] Example 495 [ka] Example 495 step a [ka] The compound from Example 59 step a (400 mg, 0.80 mmol) and 1-amino-2-methylpropan-2-ol (142 mg, 1.60 mmol) were dissolved in DMF (2 mL) in a round bottom flask and cooled to 0° C., then Hunig's base (698 μl, 4.00 mmol) was added slowly. After 5 min, PyBOP (832 mg, 1.60 mmol) was added slowly. 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×2). The organic layer was washed with brine (50 mL×2) and Na 2 SO 4 The residue was purified by automated column chromatography (eluted with 0-70% EtOAc / hexanes) to give the desired compound (380 mg, 83% yield). ESI-MS m / z=572.20 [M+H] + .

[0538] Example 495 step b [ka] The compound from step a (360 mg, 0.63 mmol) was dissolved in DCM (2 mL) and then 4N HCl in 1,4-dioxane (2 mL) was added slowly. After stirring at room temperature for 2 h, the reaction was complete. After evaporating the solvent and drying in vacuum, the desired compound (310 mg, 97%) was obtained as the HCl salt. ESI-MS m / z=472.20 [M+H] + .

[0539] Table 8 below contains examples that were synthesized according to Method J (PyBOP). Most compounds were purified by Gilson prep-HPLC and some by automated column chromatography (silica gel). [Table 8-1] [Table 8-2]

[0540] Example 508 [ka] Example 508 process a [ka] Methyl 4-hydroxy-3-methoxybenzoate (2.0 g, 10.98 mmol), allyl bromide (1.58 g, 13.18 mmol) and K 2 CO 3 A solution of (3.10 g, 22.50 mmol) in DMF (20 mL) was stirred at 40° C. for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by reverse phase chromatography (MeCN / H 20H2O, 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] + .

[0541] Example 508 process b [ka] A solution of the compound from step a (2.3 g, 10.08 mmol) in NMP (10 mL) was stirred at 200° C. for 16 h. The crude product was purified by reverse phase chromatography (MeCN / H 2 0H2O, 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] + .

[0542] Example 508 process c [ka] To a stirred solution of compound step b (2.0 g, 9 mmol) in THF (20 mL) was added H 2 O 2 (30%) (2.00 mL) and BH3·THF (1N) (1.7 mL, 18 mmol) were added in portions at 0 °C under nitrogen atmosphere and the reaction was stirred for 1 h. The reaction was quenched by the addition of NaOH (0.02 M) and allowed to warm to room temperature. The resulting mixture was extracted with DCM and the combined organics were washed with brine, dried and concentrated. The crude product mixture was used directly in the next step without further purification. ESI-MS m / z: 241.10 [M+H] + .

[0543] Example 508 Steps d and e [ka] Compound step c (1.8g, 7.3mmol) and PPh 3To a stirred mixture of (2.9 g, 11 mmol) in THF (30 mL) was added DIAD (2.95 g, 15 mmol) in portions 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 reverse phase column chromatography to give the desired product as a white solid (1.4 g, 86%). ESI-MS m / z: 223.09 [M+H] + .

[0544] Methyl ester Method O The material was hydrolyzed in a similar manner to that described above and purified by reverse phase preparative HPLC (MeCN / H 2 0) to give the title compound (720 mg, 55%) as a white solid. ESI-MS m / z: 248.25 [M+H] + .

[0545] Example 508 process f [ka] The title compound is Method J Prepared in a similar manner to that described above using the 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] + .

[0546] Example 509 [ka] Example 509 process a [ka] This example was prepared in a similar manner to Example 205, using the TBS-alcohol precursor instead. The material was prepared using 3.05 g of (R)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine for the cross-coupling to give the title compound as a clear yellow oil. (2.37 g, 83%). ESI-MS m / z: 452.0 / 454.0 [M+H] + .

[0547] Example 509 process b [ka] A solution of step a (4.75 g, 10.50 mmol) in acetone (105 ml) was cooled to 0° C. and Jones reagent (H 2 SO 4 The reaction was treated with 2M in water, 13.12 ml, 26.2 mmol). The reaction was allowed to warm gradually to room temperature and stirred overnight. Upon 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 flash column chromatography (silica gel) afforded the title compound (3.024 g, 82%) as a viscous syrup. ESI-MS m / z: 351.8 / 353.8 [M+H] + .

[0548] Example 509 process c [ka] This example was prepared according to the procedure of Example 97 step b (new route), using step b (3.024 g), and the material was purified by automated column chromatography (silica gel, 0-100% EtOAc) to give the title compound as a clear yellow oil (2.97 g, 98%). ESI-MS m / z: 352.8 [M+H] + .

[0549] Example 509 process d [ka] To a 500 mL round bottom flask containing step c (2.87 g, 8.17 mmol) was added 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). The flask was evacuated and filled with nitrogen three times and dry diisopropylamine (40.9 ml) was added via syringe. The resulting mixture was treated with ethynyltrimethylsilane (2.83 ml, 20.43 mmol) at room temperature. After 6 h, the reaction was concentrated under reduced pressure.

[0550] The resulting 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 h, filtered through a short pad of silica gel, and concentrated. Purification by flash column chromatography on silica gel afforded the title compound (1.3 g, 53%) as a light brown foam. ESI-MS m / z: 297.2 [M+H] + .

[0551] Example 509 process e [ka] The above compound was prepared following the procedure of Example 205 step e using step d (1.3 g). The reaction was left for 53 h 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] + .

[0552] Example 509 process f [ka] The above compound was prepared following the procedure of Example 205, step f, using step e (0.643 g). The reaction was left for 53 h 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] + .

[0553] Example 509 process g [ka] The above compound was prepared following the procedure of Example 205, step g, using step f (0.712 g). The crude material was dissolved in EtOAc and washed three times with saturated sodium bicarbonate to give the title compound as a white foam, which was used without further purification. ESI-MS m / z: 330.1 [M+H] + .

[0554] Example 509 process h [ka] Method J Example 509 was prepared according to 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] + .

[0555] Example 510 [ka] A 1-dram vial was charged with a stir bar, Example 509 step h (0.025 g, 0.048 mmol), 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). The vial was purged with nitrogen and 1 mL of dry diisopropylamine was added. The yellow suspension was stirred vigorously 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 flash column chromatography on silica gel to give the title compound (20 mg, 67%) as a pale yellow solid. ESI-MS m / z: 614.2 [M+H] + .

[0556] Example 511 [ka] Example 511 was prepared according to the procedure of Example 510. The crude material was purified by flash column chromatography on silica gel 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] + .

[0557] Example 512 [ka] Example 512 was prepared according to the procedure of Example 510. The crude material was purified by flash column chromatography on silica gel 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] + .

[0558] Example 513 [ka] Example 513 was prepared according to the procedure of Example 510. The crude material was purified by flash column chromatography on silica gel 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] + .

[0559] Example 514 [ka] Example 514 was prepared according to the procedure of Example 510. The crude material was purified by flash column chromatography on silica gel 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] + .

[0560] Example 515 [ka] Example 515 was prepared according to the procedure of Example 510. The crude material was purified by flash column chromatography on silica gel 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] + .

[0561] Example 516 [ka] Example 516 was prepared according to the procedure of Example 510. The crude material was purified by flash column chromatography on silica gel 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] + .

[0562] Example 517 [ka] Example 510 (0.050 g, 0.096 mmol) and 1-azido-4-fluorobenzene (0.193 ml, 0.096 mmol) in t-BuOH-H 2 A solution of 1:1O (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 and after 2 h, additional 1-azido-4-fluorobenzene (0.193 ml, 0.096 mmol) was added and the reaction was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and 3 mL of DMF was added to give a slightly more homogeneous reaction mixture. The reaction was then heated to 50° C. for 4 days. The reaction was poured into brine and extracted with EtOAc. The organic extracts were washed with anhydrous MgSO 4 The crude residue was purified by preparative HPLC 20-90%, MeCN / water, 25 min to give the title compound as a white solid (9 mg, 14%). ESI-MS m / z: 657.2 [M+H] + .

[0563] Table 9 below contains examples that were synthesized using the methods described above (see general method for synthesis of starting materials following Table 9). Compounds were purified by either automated column chromatography or Gilson prep-HPLC (20-90%, MeCN / water, 25 min). The synthesis of examples 545 and 546 is described following Table 9. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0564] Example 545 (in the table) [ka] Example 545 step a [ka] The title compound was prepared in a similar sequence to Example 205. The residue was concentrated under reduced pressure to give the crude product as a brown solid. ESI-MS m / z: 501.15 [M+H] + .

[0565] Example 545 step b [ka] A mixture of 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 reverse flash chromatography to give the desired product (630 mg, 59%) as a brown solid. ESI-MS m / z: 409.00 [M+H] + .

[0566] Example 545 process c [ka] In a 100 mL round bottom flask, the compound from step b (620 mg, 1.51 mmol) and DCM (15 mL) were added at room temperature. The mixture was cooled to 0° C., DAST (488 mg, 3.03 mmol) was added, and the reaction was stirred at the same temperature for 30 min. The reaction was stirred at room temperature for 5 min and cooled NaHCO 3 The aqueous layer was quenched with CH 2 Cl 2 Extract with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / Hexane, 1:1) to give the crude product as a yellow solid. ESI-MS m / z: 411.10 [M+H] + .

[0567] Example 545 process d [ka] Compound from step c (545 mg, 1.32 mmol), NaN 3 A mixture of TBAI (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 washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give the crude product (370 mg) as a yellow solid. ESI-MS m / z: 374.15 [M+H] + .

[0568] Example 545 process e [ka] Compound from step d (370 mg, 0.99 mmol), PPh 3 (2.60 g, 9.91 mmol), THF (20 mL) and H 2The mixture was stirred at 70 °C for 1 h under nitrogen atmosphere. The mixture was analyzed by preparative TLC (CH 2 Cl 2 / 7N NH 3 MeOH, 15:1) to give the desired product (200 mg, 58%) as a white solid. ESI-MS m / z: 348.15 [M+H] + .

[0569] Example 545 process f [ka] The title compound Method J 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] + .

[0570] Example 564 [ka] The title compound was prepared using 2-bromoacrolein in a manner similar to Example 210. 2-Bromoacrolein was prepared according to the literature (dibromination of acrolein followed by TEA-promoted elimination). Reverse flash chromatography on C18 silica gel (MeOH / H 2 The crude compound was purified by HPLC (HPLC-MS / MS) to give the title compound as a red solid (240 mg, 14%). ESI-MS m / z: 282.10 [M+H] + .

[0571] Example 565 process a [ka] Example 564 (1.30 g, 4.61 mmol) containing H 2 SO 4A solution of 1,2-dichloromethane (2 mL) and MeOH (20 mL) was stirred at 80° C. for 2 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., 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] + .

[0572] Example 565 step b [ka] Compound from step a (1.00 g, 3.38 mmol), Pd(PPh 3 ) 4 (585 mg, 0.51 mmol) and Sn 2 (nBu) 6 A solution of (3.92 g, 6.76 mmol) in dioxane (20.00 mL) was stirred at 100° C. under nitrogen atmosphere for 8 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted 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] + .

[0573] Example 565 steps c and d [ka] Compound from step b (850 mg, 1.68 mmol), Ag 2 O(155mg, 0.67mmol), F-TEDA-BF 4 (892 mg, 2.52 mmol), MeOH (269 mg, 8.40 mmol) and NaHCO 3A solution of (282 mg, 3.36 mmol) in acetone (20 mL) was stirred at 65° C. under nitrogen atmosphere for 48 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted 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] + .

[0574] Method T (engineering d) Ester hydrolysis was carried out in a similar manner to give the desired acid product. ESI-MS m / z: 222.05 [M+H] + .

[0575] Example 566 steps a and b [ka] Example 565 step a (300 mg, 1.01 mmol), cyclopropylboronic acid (261 mg, 3.04 mmol), PCy 3 (284 mg, 1.01 mmol), tricyclohexylphosphine (9 mg, 0.03 mmol) and K 3 PO 4 (645 mg, 3.04 mmol) in toluene / H 2 A solution of 2,4-dichlorophenyl ether (6 mL, 5:1) in 2,4-dichlorophenyl ether (1:1) and 1,2-dichlorophenyl ether (1:2) was stirred at 100° C. for 2 h under 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 reverse phase C18 column chromatography (CH 3 CN / H 2 O) to give the desired product as a yellow solid. ESI-MS m / z: 258.00 [M+H] + .

[0576] Ester hydrolysis is Method T (engineering d) The obtained solution was purified by reverse phase C18 column chromatography (MeOH / 0.1% FA-containing H 2 Purification by HPLC) afforded the desired product (120 mg) as a pale yellow solid. ESI-MS m / z: 244.05 [M+H]+ .

[0577] Example 567 [ka] The title compound was prepared using 2-chloroacrolein in a similar manner to Example 210. 2-Chloroacrolein was prepared in two steps from 2,3-dichloropropene according to the literature (Eur. J. Org. Chem. 2018, 45, 6256). The resulting solution was purified by reversed-phase C18 column chromatography (CH 3 CN / H 2 0) to give the desired product (300 mg, 23%) as a yellow solid. ESI-MS m / z: 238.15 [M+H] + .

[0578] Example 568 [ka] The title compound was prepared in a similar manner to Example 567 to give the desired product (350 mg, 27%) as a white solid. ESI-MS m / z: 264.00 [M+H] + .

[0579] Example 569, steps a and b [ka] 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 and extracted with EtOAc, and the organic layer was dried and concentrated. The resulting solution was purified by reverse phase C18 column chromatography (CH 3 CN / H 20) to give the desired product (200 mg, 60%) as a pale yellow solid. ESI-MS m / z: 286.00 [M+H] + .

[0580] Ester hydrolysis is Method T (engineering d) The resulting solution was purified by reversed-phase C18 column chromatography (CH 3 CN / H 2 0) to give the desired product (120 mg crude) as a pale yellow solid. ESI-MS m / z: 271.95 [M+H] + .

[0581] Example 570 [ka] The title compound was prepared in a manner similar to Example 210 and Method P using 2-methyl-2-butenal (commercially available). ESI-MS m / z: 232.10 [M+H] + .

[0582] Example 571 [ka] The title compound was prepared in a similar manner to Example 210 and Method P using methacrolein and methyl 4-amino-3-iodobenzoate. The crude product was purified by EA / H 2 Recrystallization from O gave the desired product (7 g, 62%) as a yellow solid. ESI-MS m / z: 313.85 [M+H] + .

[0583] Example 572 process a [ka] 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 h. 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] + .

[0584] Example 572 steps b and c [ka] Compound from step a (9 g, 22.32 mmol), BocNH 2 (3.66 g, 31.24 mmol), Pd(OAc) 2 (100 mg, 0.45 mmol), BINAP (417 mg, 0.67 mmol) and Cs 2 CO 3 (10 g, 31.24 mmol) in toluene 2 The mixture was stirred at 100° C. under atmospheric pressure for 2 hours. The crude product was purified by reverse phase flash to give the desired product (6 g, 68%) as a yellow solid. ESI-MS m / z: 393.05 [M+H] + .

[0585] A solution of the compound from step b (8 g, 20.39 mmol) in HCl (8 mL) and EtOAc (50 mL) was stirred at room temperature for 2 h. 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] + .

[0586] Example 573 [ka] The title compound was prepared in a similar manner to Examples 571 and 572. The residue was purified by reverse flash chromatography (10-50% MeOH / H 20) to give the desired product as an off-white solid (1.62 g, 67%). ESI-MS m / z: 245.12 [M+H] + .

[0587] Example 574 [ka] The title compound was prepared in a similar manner to Examples 571 and 572. The crude product was purified by reverse phase flash chromatography to give the desired product (1.2 g) as a yellow solid. ESI-MS m / z: 217.05 [M+H] + .

[0588] Example 575 step a [ka] A toluene solution containing methyl 4-amino-3-methoxybenzoate (2.00 g, 11.1 mmol) and 2-chlorocyclohex-1-enecarbaldehyde (4.32 g, 0.1 mmol) was added to BINAP (1.37 g, 2.2 mmol), Pd(OAc) 2 (495 mg, 2.2 mmol) and Cs 2 CO 3 (10.79 g, 33.1 mmol) was added dropwise under nitrogen atmosphere at 90° C. for 3 h. 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] + .

[0589] Example 575 steps b and c [ka] A solution of step a (2.6 g, 8.9 mmol) in TFA (10 mL) was 2The mixture was stirred at 80° C. under atmospheric pressure for 12 hours. 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] + .

[0590] Ester hydrolysis is Method T (engineering d) The resulting solution was purified by reversed-phase C18 column chromatography (CH 3 CN / H 2 0) to give the desired product (106 mg, 40%) as a yellow solid. ESI-MS m / z: 258.05 [M+H] + .

[0591] Example 576 process a [ka] In a 100 mL round-bottom flask, add methyl 4-amino-3-hydroxybenzoate (5 g, 30 mmol), methyl 2-chloro-2,2-difluoroacetate (6.5 g, 45 mmol), K 2 CO 3 (8.3 g, 60 mmol) and DMF (30 mL) were added at room temperature. The resulting mixture was stirred at 60° C. under nitrogen atmosphere for 2 h. The reaction was monitored by TLC. The reaction was diluted with water and the aqueous layer was extracted with CH 2 Cl 2 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 an off-white solid. ESI-MS m / z: 248.05 [M+H] + .

[0592] Example 576 Step b [ka] In a 250 mL round-bottom flask, add the compound from step a (1.7 g, 6.9 mmol), Fe (3.07 g, 55.03 mmol), NH4 Cl (2.94g, 55.03mmol), EtOH (30mL) and H 2 0 (30 mL) was added. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-33% EtOAc in hexanes) to give the desired compound (1.2 g, 80%) as an off-white solid. ESI-MS m / z: 218.00 [M+H] + .

[0593] Example 576 steps c and d [ka] The title compound was synthesized in a similar manner to Example 421. Ester hydrolysis was carried out by: Method T (engineering d) The residue was purified by reverse flash chromatography (0–50% MeOH / H 2 0, 25 min) to give the desired compound (105 mg, 55%). ESI-MS m / z: 260.95 [M+H] + .

[0594] Example 577 step a [ka] In a 100 mL round-bottom flask, add methyl 4-amino-3-hydroxybenzoate (2 g, 11.96 mmol), 2-iodopropane (3.05 g, 17.95 mmol), Cs 2 CO 3 (7.8 g, 23.93 mmol) and acetone (20 mL) were added at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 2 h. The aqueous layer was diluted with CH 2 Cl 2 The mixture was extracted with hexanes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc / Hexanes) to give the desired compound (2.54 g, 100%). ESI-MS m / z: 210.15 [M+H]+ .

[0595] Example 577 steps b and c [ka] The title compound was synthesized in a similar manner to Example 421. Ester hydrolysis was carried out by: Method T (engineering d) The residue was purified by reverse flash chromatography (0–50% MeOH / H 2 0, 25 min) to give the title compound (850 mg, 60%) as an off-white solid. ESI-MS m / z: 252.95 [M+H] + .

[0596] Example 578 process a [ka] Methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate (2g), CuBr 2 (3.7 g, 16.78 mmol) and t-BuNO 2 (1.7 g, 16.77 mmol) 3 CN solution, N 2 The mixture was stirred at room temperature under atmospheric pressure for 16 hours. 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 (hexane containing EtOAc) to give the desired product (1.6 g, 63%) as an orange solid. ESI-MS m / z: 301.90 [M+H] + .

[0597] Example 578 steps b and c [ka] Compound from step a (1.6 g), Pd(dppf)Cl 2 .CH 2 Cl 2 (0.9g, 1.06mmol), Na 2CO 3 (1.7g, 23.50mmol), H 2 A solution of 2H2O (1 mL) and methylboronic acid (0.48 g, 7.94 mmol) in dioxane (30 mL) was added to a 20 mL flask. 2 The mixture was stirred at 100° C. under atmospheric pressure for 3 hours. 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] + .

[0598] Ester hydrolysis is Method T (engineering d) The residue was purified by reverse flash chromatography (MeCN / H 2 0) to give the title compound (350 mg) as a white solid. ESI-MS m / z: 223.90 [M+H] + .

[0599] Example 579, steps a and b [ka] The title compound was synthesized in a similar manner to Example 421 using methyl 4-amino-3-(trifluoromethoxy)benzoate (1.50 g, 6.4 mmol). Ester hydrolysis was carried out by: Method T (engineering d) The title compound was isolated by precipitation and the solid was washed with MeCN to give the desired product (370 mg, 74.74%) as a white solid. ESI-MS m / z: 279.05 [M+H] + .

[0600] Example 580 steps a and b [ka] In a vial, methyl 2-aminobenzo[d]thiazole-6-carboxylate (350 mg, 1.681 mmol) was dissolved in DCM (8.40 ml). Cyclopropanecarbonyl 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 washed with MgSO 4 The crude reaction mixture was purified by silica gel chromatography eluting with 0-60% EtOAc / Hexanes to give the title compound as a yellow solid (120 mg, 0.434 mmol, 25%). ESI-MS m / z: 276.81 [M+H] + .

[0601] Ester hydrolysis is Method T (engineering d) The title compound was isolated by DCM extraction and enriched (65 mg, 0.248 mmol, 90%).

[0602] Example 581 Step a [ka] To a stirred solution of methyl 4-amino-3-iodobenzoate (2.7 g, 10 mmol) in HCl (6 mL), NaNO 2 (0.7 g in 5 mL water) was added dropwise at 5° C. for 1 h. To the above mixture, piperidine (1 mL) was added dropwise at 5° C. The resulting mixture was stirred at room temperature for another 1 h. The resulting mixture was extracted with EA, and the combined organic layer was washed with water and washed with anhydrous Na 2 SO 4 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] + .

[0603] Example 581 step b [ka] Equipped with a magnetic stirrer and a septum, 2 To a dry 50 mL Schlenk tube flushed with 100 mL of bromo(prop-1-yn-1-yl)magnesium (4.3 g, 29.94 mmol) was added. The solution was cooled to -30 °C and ZnBr 2 (5.08 g, 22.56 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature for 30 min. The compound from step a (2 g, 5.36 mmol) was added, followed by (PPh 3 ) 4 (309 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and saturated NH 4 Quenched with aqueous Cl. The aqueous 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] + .

[0604] Example 581 process c [ka] 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 h. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water and diluted with anhydrous Na 2 SO 4 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] + .

[0605] Example 581 process d [ka] A 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 2 The mixture was stirred at room temperature under atmospheric pressure for 2 hours. The resulting mixture was filtered, and the solution was concentrated and used directly in the next step. ESI-MS m / z: 205.00 [M+H] + .

[0606] Example 581 steps e and f [ka] Compound from step d and MnO 2 A solution of (1.5 g, 17.67 mmol) in THF (20 mL) was stirred at room temperature for 2 h. The crude product was purified by reverse phase flash to give the desired product (253 mg, 51%) as a yellow solid. ESI-MS m / z: 203.00 [M+H] + .

[0607] In a vial, the compound from step e (100 mg, 0.495 mmol) and lithium hydroxide (118 mg, 4.95 mmol) were dissolved in THF (2.2 ml), MeOH (2.2 ml) and water (0.55 ml). The reaction was stirred at room temperature for 4 h. The reaction was diluted with water and the pH was adjusted to 3-4 wit...

Claims

1. Formula (VIIIa): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof: During the ceremony, A is, 【Chemistry 2】 selected from the group consisting of: W is CH ３ Or CF ３ and G is -C(O)NR １１ R １２ and R ３ is hydroxy, R ４ is methyl, trifluoromethyl or cyclopropyl; R １１ independently for each occurrence, 1) Hydrogen; 2) optionally substituted -C １ ~C ８ - alkyl; 3) optionally substituted -C ３ ~C ８ -cycloalkyl; 4) an optionally substituted 3- to 8-membered heterocycle; 5) optionally substituted aryl; 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl; and 8) optionally substituted heteroarylalkyl; is selected from the group consisting of R １２ independently for each occurrence, 1) Hydrogen; 2) optionally substituted -C １ ~C ８ - alkyl; 3) optionally substituted -C ３ ~C ８ -cycloalkyl; 4) an optionally substituted 3- to 8-membered heterocycle; 5) optionally substituted aryl; 6) optionally substituted arylalkyl; 7) optionally substituted heteroaryl; and 8) optionally substituted heteroarylalkyl; is selected from the group consisting of Or, R １１ and R １２ together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycle; Each R ２１ are independently -F, -Cl, -CN, -CF ３ , -CH ２ F and -CHF ２ selected from the group consisting of: Each R ３１ are independently halo; -CN; -NO ２ , -OR １１ ;-NR １１ R １２ ;-NR １１ C(O)R １２ ;-NR １１ S (O) ２ R １２ -S(O) ２ R １２ -S(O) ２ N.R. 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 -C １ ~C ６ Alkyl, optionally substituted -C ３ ~C ８ -cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; R ２２ is hydrogen, halogen, -OR １１ ;-NR １１ R １２ , optionally substituted -C １ ~C ６ -alkyl; optionally substituted -C ３ ~C ８ -cycloalkyl; optionally substituted 3- to 8-membered heterocycle; optionally substituted aryl; or optionally substituted heteroaryl; and m' is independently 0, 1 or 2; and m is 0, 1 or 2; However, the term "substituted" means that one, two or three of the hydrogen atoms are replaced by halogen, C １－ C ４ -Alkyl, halo-C １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl; halo-C ２ ~C ４ -alkenyl; C ３ ~C ６ -Cycloalkyl, C １ ~C ４ -Alkoxy, halo-C １ ~C ４ -Alkoxy, -CN, -OH, NH ２ , C １ ~C ４ -Alkylamino, di(C １ ~C ４ -alkyl)amino and NO ２ "R" means substituted by independently replacing with a group selected from:

2. A compound represented by the following formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, which is:

3. G is -C(O)NHR １２ 3. The compound according to claim 1 or 2, which is: or a pharma- ceutically acceptable salt thereof. 【Request 4】 【Chemical 4】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is selected from the group consisting of: 【Chemistry 5】

5. R ４ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is -CF3.

6. 2. The compound according to claim 1, selected from the compounds listed below, or a pharma- ceutically acceptable salt thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 【Table 17】 【Table 18】 【Table 19】 【Table 20】 【Table 21】 【Table 22】 【Table 23】 【Table 24】 【Table 25】 【Table 26】 【Table 27】 【Table 28】 【Table 29】 【Table 30】 【Table 31】 【Table 32】 【Table 33】 【Table 34】 【Table 35】 【Table 36】 【Table 37】 【Table 38】

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

8. The pharmaceutical composition according to claim 7 for the treatment or prevention of RSV infection.

9. The pharmaceutical composition according to claim 7 for the treatment or prevention of HMPV infection.

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