Polycyclic compounds and their uses

Abstract

The present application provides a compound of formula (I), or an optical isomer thereof, a pharmaceutically acceptable salt, a solvated form, or a prodrug. The compound may modulate NTCP function for the prevention and / or treatment of HBV / HDV and hepatitis virus-related diseases, bile acid-related cholestasis disorders, metabolic disorders, and / or liver diseases. Additionally, the present application relates to a pharmaceutical composition comprising such a compound and a method for modulating NTCP.

Description

Technology Field

[0001] The present invention generally relates to compounds and pharmaceutical compositions as modifiers of sodium taurocholate co-transport polypeptide (NTCP). Background Technology

[0003] Human sodium taurocholate co-transport polypeptide (hNTCP) is human SLC10A1 It is known as the hepatic bile acid transporter (LBAT), which belongs to the category of genes-encoded proteins (Hagenbuch et al. J Clin Invest. 1994, 93(3):1326-31.). Physiological substrates of NTCP include sulfated and unconjugated bile salts, as well as amidated (taurine, glycine) ones. Other substrates include sulfated steroids (estron-3-sulfate, DHEAS) and thyroid hormones. NTCP is located in the basolateral membrane domain (blood side) of human hepatocytes. Its primary role is to transport more than 80% of conjugated taurocholate and less than 50% of unconjugated cholate from the blood to the liver, which is important for maintaining the enterohepatic circulation of bile acids (Doring et al. Curr Top Membr, 2012. 70: p. 105-68.).

[0004] NTCP is a functional cell surface receptor required for the invasion of hepatitis B virus (HBV) / hepatitis D virus (HDV) (Yan et al. Elife, 2012.1: p. e00049.). The NTCP variant rs296651 has been reported to be inversely correlated with the progression of liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B and HBV infection (Reference). Therefore, inhibiting NTCP is an attractive therapeutic strategy for treating HBV and HBV / HDV infections.

[0005] Bile acids are major substrates of NTCP and are the primary active osmotic substances in bile; they possess various biological functions, such as promoting lipid digestion and absorption, preventing gallstone formation, and increasing bile secretion and excretion. Bile acids exist in the form of free acids and sodium salts and are primarily synthesized by hepatocytes. An imbalance in bile acid metabolism leads to a condition known as cholestasis, resulting in the accumulation of bile salts within hepatocytes and causing mitochondrial damage and hepatotoxicity (Sokol et al. J. Pediatr. Gastroenterol. Nutr., 2006, 43(Suppl 1), S4-S9). Therefore, regulating bile acid transport through NTCP blockade is a potential therapeutic option for cholestasis. Furthermore, NTCP inhibitors have been reported to provide potential benefits in diabetes, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and other related conditions (Donkers et al. Cell Mol Gastroenterol Hepatol). 2020;10:451-466).

[0006] The present invention relates to novel polycyclic compounds that regulate NTCP function for the prevention and / or treatment of HBV / HDV and hepatitis virus-related diseases, bile acid-related cholestasis disorders, metabolic disorders and / or liver diseases. Additionally, the present invention relates to pharmaceutical compositions comprising such compounds and methods for regulating NTCP.

[0007] In a major embodiment thereof, the present invention has a formula ( I Compound of )

[0008]

[0009] or provides an optical isomer thereof, a pharmaceutically acceptable salt, a solvated form, or a prodrug, wherein:

[0010] represents a single or double bond, and R if a single double bond is present. 5a or R 5b is absent and R4 is absent;

[0011] X is hydrogen, deuterium, halogen, OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , -OS(=O)2OR X , -OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X ) R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X ) N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and S(=O)2N(R X Selected from a group consisting of )2, where each R Xis independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, and a sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring together with intervening atoms; preferably, X is OH;

[0012] R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; preferably R 1 is selected from the group consisting of substituted or unsubstituted alkynoyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls, more preferably being a substituted or unsubstituted aryl;

[0013] A, B, C, D, and E are each independently -(CR R1 R R2 ) q -,-(CR R1 R R2 ) q -O-, -(CR R1 R R2 ) q -S-, and -(CR R1 R R2 ) q -(NR R3 Selected from a group consisting of )-, where R R1 , R R2 and R R3is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , -OS(=O)2OR X , -OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X ) N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and -S(=O)2N(R XSelected from a group consisting of )2, where each R X is independently selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or heteroalkenyl, substituted or unsubstituted alkynyl or heteroalkynyl, optionally substituted or unsubstituted cyclic ring or substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, sulfur protecting group when bonded to sulfur, or two Rs X The group forms a substituted or unsubstituted heterocyclic ring with intervening atoms; or R R1 and R R2 combines to form an oxo (=O) group; q is independently 0, 1, or 2;

[0014] R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , and R 9 Each is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(RX )2, -OC(=O)SR X , -OS(=O)2R X , -OS(=O)2OR X , -OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X ) N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and -S(=O)2N(R X Selected from a group consisting of )2, where each R X is independently selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclicle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring with intervening atoms; or R 2a and R 2b , R 5a and R5b , R 6a and R 6b , or R 8a and R 8b combines independently to form an oxo (=O) group;

[0015] R 10 -C(=O)OH, -C(=O)R 101 , -C(=O)NHR 101 , -C(=O)NHR 101 SO3H, -C(=O)NHSO2R 101 , -C(=O)NR 101 OH, -C(=O)NMeOH, -P(=O)OH, -P(=O)(OH)2, -SO2OH, -S(=O)OH, -SO2NHR 101 , -NHC(=O)NHSO2R 101 , NHC(=O)NHC(=O)R 101 , selected from the group consisting of tetrazolyl, thiazolidinyl, and oxazolidinedione groups, where R 101 It is selected from the group consisting of H, OH, alkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and natural or non-natural amino acid groups;

[0016] W is It is selected from a group consisting of , where K is R 9 Indicates the bonding site at the carbon conjugated with, and R W1 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when bonded to nitrogen; R W2 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when bonded to nitrogen; or R W1 and R W2It combines to form an oxo (=O) group.

[0017] Z is -(Z1) n -(Z2) m -(CR Y1 R Y2 ) o - and, where Z1 and Z2 each independently -CR Y3 R Y4 -, -NR Y5 -, O, S, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Y1 and R Y2 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R Y1 and R Y2 combines independently to form a double or triple bond with conjugated H; R Y3 and R Y4 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R Y3 or R Y4 combines independently to form a double or triple bond with an adjacent H; R Y5 is hydrogen, deuterium, hydroxyl, C1-C3 alkoxy, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n, m and o are each independently 0, 1 or 2.

[0018] Each of the above-mentioned desirable devices may be used individually, in combination with any one or all other desirable devices. Specific details for implementing the invention

[0021] The present invention is based on the chemical formula ( I Compound of )

[0022]

[0023] or provides an optical isomer, a pharmaceutically acceptable salt, a solvated form, or a prodrug, wherein:

[0024] represents a single or double bond, and R if a single double bond is present. 5a or R 5b is absent and R 4 is absent;

[0025] X is hydrogen, deuterium, halogen, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , - OS(=O)2OR X , - OS(=O)2N(R X )2, -N(R X )C(=O) R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X )N(R X )2, -N(R X )S(=O)2R X , -N(RX )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and -S(=O)2N(R X Selected from a group consisting of )2, where each R X is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, and a sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring together with intervening atoms; preferably, X is OH;

[0026] R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; preferably R 1 is selected from the group consisting of substituted or unsubstituted alkynoyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls, more preferably being a substituted or unsubstituted aryl;

[0027] A, B, C, D, and E independently (CR R1 R R2 ) q -,-(CR R1 R R2 )q -O-, -(CR R1 R R2 ) q -S-, and -(CR R1 R R2 ) q -(NR R3 Selected from a group consisting of )-, where R R1 , R R2 , and R R3 is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , - OS(=O)2OR X , - OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X )N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X)S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , or -S(=O)2N(R X Selected from a group consisting of )2, where each R X is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, or substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, and a sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring with intervening atoms; or R R1 and R R2 combines to form an oxo (=O) group; q is independently 0, 1, or 2;

[0028] R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 7 , R 8a , R 8b , and R 9 Each is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR X , -N(R X )2, -SRX , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , -OS(=O)2OR X , -OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X )N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , or -S(=O)2N(R X Selected from a group consisting of )2, where each R Xis independently selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclicle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, sulfur protecting group when bonded to sulfur, or two R X The group bonds with interposed atoms to form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , R 5a and R 5b , R 6a and R 6b , or R 8a and R 8b combines independently to form an oxo (=O) group;

[0029] R 10 -C(=O)OH, -C(=O)R 101 , -C(=O)NHR 101 , -C(=O)NHR 101 SO3H, -C(=O)NHSO2R 101 , -C(=O)NR 101 OH, -C(=O)NMeOH, -P(=O)OH, -P(=O)(OH)2, -SO2OH, -S(=O)OH, -SO2NHR 101 , -NHC(=O)NHSO2R 101 , -NHC(=O)NHC(=O)R 101 , selected from the group consisting of tetrazolyl, thiazolidinyl, and oxazolidinedione groups, where R 101 It is selected from the group consisting of H, OH, alkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and natural or non-natural amino acid groups;

[0030] W is , , , and It is selected from a group consisting of , where K is R 9 It represents the bonding site at the carbon conjugated with, and Rw1 is W1 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when bonded to nitrogen; R W2 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when bonded to nitrogen; or R W1 and R W2 It combines to form an oxo (=O) group.

[0031] Z is -(Z1) n -(Z2) m -(CR Y1 R Y2 ) o - and, where each Z1 and each Z2 is independently -CR Y3 R Y4 -, -NR Y5 -, O, S, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Y1 and R Y2 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R Y1 and Ry2 is Y2 combines independently to form a double or triple bond with conjugated H; R Y3 and R Y4is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R Y3 and R Y4 combines independently to form a double or triple bond with an adjacent H; R Y5 is hydrogen, deuterium, hydroxyl, C1-C3 alkoxy, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n, m and o are independently 0, 1 or 2.

[0032] In certain embodiments, R 1 It is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0033] In certain embodiments, R 1 The is selected from the group consisting of substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and more preferably is a substituted or unsubstituted aryl.

[0034] In certain embodiments, R 1 is a substituted or unsubstituted alkynyl.

[0035] In certain embodiments, R 1 is a substituted or unsubstituted C2-C8 alkynyl.

[0036] In certain embodiments, R 1is a substituted or unsubstituted alkynyl, a substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, e.g., C3-C6 cycloalkyl, a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted C6-C10 aryloxyl, or a substituted or unsubstituted C1-C10 heteroaryl.

[0037] In certain embodiments, one or more substituents from the mentioned substituted group are selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl.

[0038] Preferably, R 1 The following structure:

[0039] Selected from,

[0040] Here, R 11 is absent or is one or more substituents S, wherein S is selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl;

[0041] L is absent or selected from the group consisting of C1-C6 alkylenes and C1-C6 alkoxylenes. In certain embodiments, L is absent. In certain embodiments, L is a C1-C6 alkylene, e.g., -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, etc.

[0042] ;

[0043] Here, R 11 is absent or is one or more substituents S, wherein S is selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl;

[0044] L is absent or selected from the group consisting of C1-C6 alkylenes and C1-C6 alkoxylenes. In certain embodiments, L is absent. In certain embodiments, L is a C1-C6 alkylene, e.g., -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, etc.

[0046] More preferably, R 1 Eun Hagi Gi:

[0047] Selected from.

[0048] In certain embodiments, R 1 It is an unsubstituted or substituted C6-C10 aryl.

[0049] Preferably, R 1is a substituted phenyl having one or more substituents selected from the group consisting of deuterium, hydroxyl, halogen, CN, NO2, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, e.g., C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxyl, and substituted or unsubstituted C1-C10 heteroaryl.

[0050] Preferably, R 1 is a substituted phenyl having one or more substituents independently selected from the group consisting of fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, NO2, phenyl, and cyclopropyl.

[0051] Preferably, R 1 The following structure:

[0052] Selected from,

[0053] Here, R 11 is absent or is one or more substituents S, and S is selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C6-C10 aryloxyl (e.g., phenyloxyl), C7-C10 arylalkyl (e.g., benzyl), and C1-C10 heteroaryl.

[0054] More preferably, R 1 Eun Hagi Gi:

[0055] Selected from.

[0056] In certain embodiments, R 1is a substituted or unsubstituted C1-C20 heteroaryl.

[0057] In certain embodiments, R 1 is a substituted C1-C20 heteroaryl having one or more substituents selected from the group consisting of halogen, CN, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted C1-C10 heteroaryl.

[0058] Preferably, R 1 The following structure:

[0059] Selected from.

[0061] Preferably, R 1 The following structure:

[0064] Selected from.

[0065] In the above structure, R 11 is absent, or R 11 It represents one or more substituents selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C7-C10 arylalkyl (e.g., benzyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl.

[0066] More preferably, R 1 Eun Hagi Gi:

[0067] Selected from.

[0068] In certain embodiments, Z is -(Z1) n -(Z2) m(CR Y1 R Y2 ) o - and, where Z1 and Z2 are independently CR Y3 R Y4 , NR Y5 , O, S, selected from the group consisting of substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl and R Y1 and Ry2 is Y2 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R Y1 or R Y2 combines independently to form double or triple bonds with conjugated H; R Y3 and R Y4 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R Y3 or R Y4 combines independently to form a double or triple bond with an adjacent H; R Y5 is hydrogen, deuterium, hydroxyl, C1-C3 alkoxy, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when bonded to nitrogen; n, m and o are independently 0, 1 or 2.

[0069] Preferably, Z has the following structure:

[0070] Selected from;

[0071] In the above structure, 0-2 represents 0, 1, or 2.

[0072] In the above structure, Y is absent, or Y is NR Y5 , O, S, selected from the group consisting of substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0073] More preferably, Z is the following:

[0074] Selected from.

[0075] In certain embodiments, R 10 -(C=O)OH, -(C=O)R 101 , -(C=O)NHR 101 , -(C=O)NHR 101 SO3H, -(C=O)NHSO2R 101 , -(C=O)NR 101 OH, -(C=O)(NMe)OH, -(P=O)OH, -(P=O)(OH)2, -SO2OH, -(S=O)OH, -SO2NHR 101 , -NH(C=O)NHSO2R 101 , -NH(C=O)NH(C=O)R 101 , selected from the group consisting of tetrazolyl, thiazolidinyl, or oxazolidinedione groups, where R 101 It is selected from H, OH, alkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and natural or non-natural amino acid groups.

[0076] In certain embodiments, R 10 The next one:

[0077] Selected from.

[0078] In certain embodiments, R 10 It is a taurine-conjugated carboxylic acid group.

[0079] In certain embodiments, R 10is an amino acid-conjugated carboxylic acid group, where the amino acid is the following group:

[0080]

[0081] Selected from.

[0082] In certain embodiments, chemical formula ( I The above compound of ) is the chemical formula ( II ) or ( III ), or represented as a pharmaceutically acceptable salt thereof,

[0083]

[0085] Here, A, B, C, D, and E are each -(CR R1 R R2 Except for )-, it is as previously defined (chemical formula ( I As defined in ). Also X, W, Z, R 1 , R R1 , R R2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , R 10 is as previously defined (chemical formula ( I As defined in ).

[0086] In certain embodiments, chemical formula ( I The above compound of ) is the chemical formula ( IIa ), ( IIb ), ( IIc ), ( IId ), or ( IIe ), or represented as a pharmaceutically acceptable salt thereof,

[0087]

[0088] Here, A, B, C, D, and E are each -(CR R1 R R2 Except for )-, it is as previously defined (chemical formula ( I As defined in ). Also X, W, Z, R 1 , R R1 , R R2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 is as previously defined (chemical formula ( I As defined in ).

[0089] In certain embodiments, the compound of formula (I) is formula ( IIIa ) or ( IIIb ), chemical formula ( IIIa-A ), ( IIIb-B ), or represented as a pharmaceutically acceptable salt thereof,

[0090]

[0091]

[0092] Here, X, W, Z, R 1 , R R1 , R R2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 is as previously defined.

[0093] In certain embodiments, chemical formula ( I The above compound of ) chemical formula ( IIIa-1 ), ( IIIa-2 ), ( IIIa-3 ), ( IIIa-4 ), ( IIIa-1A ), ( IIIa-2A ), ( IIIa-3A ), or ( IIIa-4A ), or represented as a pharmaceutically acceptable salt thereof,

[0094]

[0096]

[0097] Here, X, Z, R 1 , R R1 , R R2 , R W1 , R W2 ,R 2a , R 2b , R 3 , R 5a , R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 is as previously defined.

[0098] In certain embodiments, chemical formula ( I The above compound of ) is the chemical formula ( IIIb-1 ), ( IIIb-2 ), ( IIIb-3 ), ( IIIb-4 ), ( IIIb-1B ), ( IIIb-2B ), ( IIIb-3B ), ( IIIb-4B It is represented as ),, or a pharmaceutically acceptable salt thereof, and

[0099]

[0100]

[0101] Here, X, Z, R 1 , R R1 , R R2 , RW1 , R W2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 is as previously defined.

[0102] In certain embodiments, chemical formula ( I The above compound of ) is the chemical formula ( IIIb-11 ), ( IIIb-12 ), ( IIIb-11A ), or ( IIIb-12B ), or represented as a pharmaceutically acceptable salt thereof,

[0103]

[0104]

[0105] Here, X, Z1, Z2, R 1 , R R1 , R R2 , R W1 , R W2 ,R Y1 , R Y2 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , R 10 , n, and m are as previously defined.

[0106] In a specific embodiment, the compound of formula (I) is of formula ( IVa ), ( IVb ), ( IVc ), ( IVd), ( IVe ), or ( IVf ), or represented as a pharmaceutically acceptable salt thereof,

[0108]

[0109]

[0111]

[0112] Here, X, Z1, Z2, R 1 , R R1 , R R2 , R W1 , R W2 ,R Y1 , R Y2 , R 2a , R 2b , R 5a , R 5b ,R 6a , R 6b , R 8a , R 8b , R 9 , R 10 , n, and m are as previously defined.

[0113] In certain embodiments, R 2a and / or R 2b is H. In certain embodiments, R 6a and / or R 6b is H. In certain embodiments, R 5a and / or R 5b is H. In certain embodiments, R 8a and / or R 8b is H.

[0114] In certain embodiments, R W1 is methyl. In certain embodiments, R 9 is H.

[0115] In certain embodiments, R R1 and R R2 is independently hydrogen, deuterium, halogen, -OR X , -C(=O)OR X , and -OC(=O)R XIt is selected from a group consisting of, where each R X It is independently selected from hydrogen, deuterium, substituted or unsubstituted alkyl (e.g., C1-C6 alkyl) and oxygen protecting group (e.g., TBS).

[0116] In certain embodiments, R R1 and R R2 is independently hydrogen, deuterium, halogen, -OR X , and -OC(=O)R X It is selected from a group consisting of, where each R X It is independently selected from hydrogen, deuterium, substituted or unsubstituted alkyl (e.g., C1-C6 alkyl) and oxygen protecting group (e.g., TBS).

[0117] In some embodiments, R R1 is H, and R R2 H, -OH, -OTBS, -OAc, Ph(C=O)O-, , , , , , F, Cl, or Br.

[0118] In some embodiments, R R2 is H, and R R1 H, -OH, -OTBS, -OAc, Ph(C=O)O-, , , , , , F, Cl, or Br.

[0119] In certain embodiments, R R1 and R R2 is the same.

[0120] In certain embodiments, R R1 and R R2 is different.

[0121] In certain embodiments, the compound of formula (I) is selected from the following compounds:

[0122] Examples structure Examples structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 20 23 24 25 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 122 123 124 125 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 170 171 172 173 174 175 176 177 178 181 182 183 184 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 236 239 240 241 242 243 244 245 246 247 248 249 250 252 253 254 255 256 257 258 259 260 261 262 263 264 265 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 378 379 380 381 382 383 384 385 386 387 388 389 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 412 413 414 415 416 417 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 487 488 489 492 493 494 495 496 497 498 499 500 501 502 503 504 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 525 526 527 528 529 530 531 532 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 651 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 729 730 731 732 733 734 735 737 738 739 740 741 742 744 745 746 747 748 749 750 751 752 753 754 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860

[0123] definition

[0124] For the interpretation of this application, the following definitions apply, where terms used in the singular include the plural where appropriate, and vice versa. It should be understood that the terms used herein are intended to describe only specific embodiments and are not intended to be restrictive.

[0125] Features, integers, properties, compounds, chemical residues, or groups described in connection with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to other aspects, embodiments, or examples described herein, except where incompatible. The present invention is not limited to details of any embodiments.

[0126] As used herein, the term "aryl" means a monocyclic or polycyclic carbocyclic ring system comprising at least one aromatic ring, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system comprising at least one aromatic ring. A polycyclic aryl may include a condensed ring, a ring connected by covalent bonds, or a combination thereof.

[0127] As used herein, the term "heteroaryl" means a monocyclic or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N, and the remaining ring atoms being carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and quinoxalinyl. Polycyclic heteroaryls may include condensed rings, rings connected by covalent bonds, or combinations thereof.

[0128] According to the present invention, aromatic groups may be substituted or unsubstituted.

[0129] The term "cyclic aryl" or "cyclic heteroaryl" refers to a ring system composed of two rings, wherein at least one ring is aromatic; and the two rings may be condensed or connected by covalent bonds.

[0130] As used herein, the term "alkyl" means a saturated straight-chain or branched-chain hydrocarbon radical. “C1-C3 alkyl,” “C1-C6 alkyl,” “C1-C 10 “alkyl,” “C2-C4alkyl,” or “C3-C6alkyl,” respectively refer to alkyl groups containing 1 to 3, 1 to 6, 1 to 10, 2 to 4, and 3 to 6 carbon atoms. Examples of C1-C8 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, tert - Includes butyl, neopentyl, n-hexyl, heptyl, and octyl radicals, but is not limited thereto.

[0131] As used herein, the term "alkenyl" means a straight-chain or branched-chain hydrocarbon radical having at least one carbon-carbon double bond by removing a single hydrogen atom. 10 “Alkenyl,” “C2-C8 alkenyl,” “C2-C4 alkenyl,” or “C3-C6 alkenyl,” each means an alkenyl group containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms. The alkenyl group includes, but is not limited to, examples such as ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.

[0132] As used herein, the term "alkynyl" means a straight-chain or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond by removing a single hydrogen atom. 10“Alkynyl,” “C2-C8 alkynyl,” “C2-C4 alkynyl,” or “C3-C6 alkynyl,” each means an alkynyl group containing 2 to 10, 2 to 8, 2 to 4, or 3 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethinyl, 1-propynyl, 1-butynyl, heptynyl, octinyl, etc.

[0133] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring, or a condensed, cross-linked, or spirocyclic dicyclic or tricyclic group, wherein the carbon atom may be optionally oxo-substituted or optionally substituted with an exocyclic olefin, iminic, or oxymic double bond. A preferred cycloalkyl group is a C3-C 12 It includes cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. C3-C 12 Examples of cycloalkyls 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.

[0134] As used herein, the term "cycloalkenyl" refers to a monocyclic or polycyclic carbocyclic ring having at least one carbon-carbon double bond, or a cyclic or tricyclic group of a condensation, crosslinking, or spiro system, wherein the carbon atom may be optionally oxo-substituted or optionally substituted with an exocyclic olefin, iminic, or oxymic double bond. Preferred cycloalkenyl groups include C3-C 12 It contains cycloalkenyl, C3-C8 cycloalkenyl, or C5-C7 cycloalkenyl groups. C3-C 12Examples 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.

[0135] As used herein, the term "arylalkyl" refers to a functional group in which an alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which an aryl group is substituted. Similarly, the term "heteroarylalkyl" refers to a functional group in which an alkylene chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which a heteroaryl group is substituted.

[0136] As used herein, the term “alkoxy” means an alkyl group having a specified number of carbon atoms connected to the rest of the molecule through an oxygen atom, when used alone or in combination with other terms, unless otherwise specified, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and their superordinate homologs and isomers. A preferred alkoxy is a (C1-C3) alkoxy.

[0137] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moiety described herein may also be an aliphatic group or an aliphatic ring group.

[0138] "Aliphatic" groups are non-aromatic moietyes composed of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, and optionally include one or more unsaturated units, e.g., double and / or triple bonds. Examples of aliphatic groups include alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(=O), S(=O)2, C(=O)O, C(=O)NH, OC(=O)O, OC(=O)NH, OC(=O)NH2, S(=O)2NH, S(=O)2NH2, NHC(=O)NH2, NHC(=O)C(=O)NH, NHS(=O)2NH, NHS(=O)2NH2, C(=O)NHS(=O) 2, There are functional groups such as C(=O)NHS(=O)2NH or C(=O)NHS(=O)2NH2, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by functional groups. Carbon atoms of the aliphatic group may optionally be oxo-substituted. The aliphatic group may be straight-chain, branched-chain, cyclic, or a combination thereof, preferably containing about 1 to about 24 carbon atoms, more typically about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, the aliphatic groups used herein explicitly include, for example, alkoxyalkyls, polyalkoxyalkyls, for example, polyalkylene glycols, polyamines, and polyimines. The aliphatic group may optionally be substituted.

[0139] The terms "heterocyclic" or "heterocycloalkyl" may be used interchangeably and refer to a condensation, crosslinking, or spiro system of a non-aromatic ring or a dicyclic or tricyclic group, wherein (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen; (ii) each ring system may be saturated or unsaturated; (iii) nitrogen and sulfur heteroatoms may be optionally oxidized; (iv) nitrogen heteroatoms may be optionally quaternized; (v) any one of the rings may be condensed to an aromatic ring; and (vi) the remaining ring atoms are carbon atoms, which may be optionally oxo-substituted or optionally substituted with an external olefin, imimic, or oxymic double bond. Representative heterocycloalkyl groups include 1,3-dioxolane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, Piperidinyl, piperazinyl, oxazolidinyl, iso-oxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonil, 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-oxo-oxephan-4-yl, and tetrahydrofuryl are included, but not limited to. These heterocyclic groups may be further substituted. The heteroaryl or heterocyclic group may be C-bonded or N-bonded (where possible).

[0140] It is understood that any alkyl, alkenyl, alkynyl, aliphatic ring, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc. described herein may be divalent or polyvalent groups that can be located on the same or different atoms(s) when used as linkers to connect two or more groups or substituents. A person skilled in the art can easily determine the valence of such groups from the context.

[0141] The term "substituted" means substituting one, two, three, or more hydrogen atoms independently with substituents, said substituents being -F, -Cl, -Br, -I, -OH, C1-C 12 -alkyl; C2-C 12 -Alkenyl, C2-C 12 -alkynyl, protected hydroxyl, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-C1-C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(=O)-C1-C 12 -alkyl, C(=O)-C2-C8-alkenyl, -C(=O)-C2-C8-alkynyl, -C(=O)-C3-C 12 -cycloalkyl, -C(=O)-aryl, -C(=O)-heteroaryl, -C(=O)-heterocycloalkyl, -C(=O)NH2, -C(=O)NH-C1-C 12 -alkyl, -C(=O)NH-C2-C8-alkenyl, -C(=O)NH-C2-C8-alkenyl, -C(=O)NH-C3-C 12 -cycloalkyl, -C(=O)NH-aryl, -C(=O)NH-heteroaryl, -C(=O)NH-heterocycloalkyl, -OC(=O)-O-C1-C 12 -alkyl, -OC(=O)-O-C2-C8-alkenyl, -OC(=O)-O-C2-C8-alkynyl, -OC(=O)-O-C3-C 12 -cycloalkyl, -OC(=O)-O-aryl, -OC(=O)-O-heteroaryl, -OC(=O)-O-heterocycloalkyl, -C(=O)-O-C1-C 12Alkyl, -C(=O)-O-C2-C8 alkenyl, -C(=O)-O-C2-C8 alkynyl, C(=O)-O-C3-C 12 -cycloalkyl, -C(=O)-O-aryl, C(=O)-O-heteroaryl, C(=O)-O-heterocycloalkyl, -OC(=O)NH2, -OC(=O)NH-C1-C 12 -alkyl, -OC(=O)NH-C2-C8-alkenyl, -OC(=O)NH-C2-C8-alkenyl, -OCONH-C3-C 12 -cycloalkyl, -OC(=O)NH-aryl, -OC(=O)NH-heteroaryl, -OC(=O)NH-heterocyclo-alkyl, -NHC(=O)H, -NHC(=O)-C1-C 12 -alkyl, -NHC(=O)-C2-C8-alkenyl, -NHC(=O)-C2-C8-alkenyl, -NHC(=O)-C3-C 12 -cycloalkyl, -NHC(=O)-aryl, -NHC(=O)-heteroaryl, -NHC(=O)-heterocyclo-alkyl, -NHC(=O)-O-C1-C 12 -alkyl, -NHC(=O)-O-C2-C8-alkenyl, -NHC(=O)-O-C2-C8-alkenyl, -NHC(=O)-O-C3-C 12 -cycloalkyl, -NHCO2-aryl, -NHC(=O)-O-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(=O)NH2, -NHC(=O)NH-C1-C 12 -alkyl, -NHC(=O)NH-C2-C8-alkenyl, -NHC(=O)NH-C2-C8-alkenyl, -NHC(=O)NH-C3-C 12 -cycloalkyl, -NHC(=O)NH-aryl, -NHC(=O)NH-heteroaryl, -NHC(=O)NH-heterocycloalkyl, NHC(=S)NH2, -NHC(=S)NH-C1-C 12 -alkyl, -NHC(=S)NH-C2-C8-alkenyl, -NHC(=S)NH-C2-C8-alkenyl, -NHC(=S)NH-C3-C 12-cycloalkyl, -NHC(=S)NH-aryl, -NHC(=S)NH-heteroaryl, -NHC(=S)NH-heterocycloalkyl, -NHC(=NH)NH2, -NHC(=NH)NH-C1-C 12 -alkyl, -NHC(=NH)NH-C2-C8-alkenyl, -NHC(=NH)NH-C2-C8-alkenyl, -NHC(=NH)NH-C3-C 12 -cycloalkyl, -NHC(=NH)NH-aryl, -NHC(=NH)NH-heteroaryl, -NHC(=NH)NH-heterocycloalkyl, -NHC(=NH)-C1-C 12 -alkyl, -NHC(=NH)-C2-C8-alkenyl, -NHC(=NH)-C2-C8-alkenyl, -NHC(=NH)-C3-C 12 -cycloalkyl, -NHC(=NH)-aryl, -NHC(=NH)-heteroaryl, -NHC(=NH)-heterocycloalkyl, -C(=NH)NH-C1-C 12 -alkyl, -C(=NH)NH-C2-C8-alkenyl, -C(=NH)NH-C2-C8-alkynyl, -C(=NH)NH-C3-C 12 -cycloalkyl, -C(=NH)NH-aryl, -C(=NH)NH-heteroaryl, -C(=NH)NH-heterocycloalkyl, -S(=O)-C1-C 12 -alkyl, -S(=O)-C2-C8-alkenyl, -S(=O)-C2-C8-alkynyl, -S(=O)-C3-C 12 -cycloalkyl, -S(=O)-aryl, -S(=O)-heteroaryl, -S(=O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1-C 12 -alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C3-C 12 -cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 -alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C3-C 12-cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12 -Cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl are included but not limited thereto. In certain embodiments, the substituents are independently selected from halo, preferably Cl and F; C1-C4-alkyl, preferably methyl and ethyl; C2-C4-alkenyl; halo-C1-C4-alkyl, e.g., fluoromethyl, difluoromethyl, and trifluoromethyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, e.g., cyclopropyl; -CN; -OH; NH2; C1-C4-alkylamino; di(C1-C4-alkyl)amino; and NO2. It is understood that substituents such as aryl, heteroaryl, alkyl, etc. are optionally additionally substituted. In some cases, each substituent in the substituted moiety is additionally optionally substituted with one or more groups, each group independently C1-C4-alkyl; CF3, C1-C4-alkoxy; selected from -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN and -NH2.

[0142] It is understood that aryl, heteroaryl, alkyl, cycloalkyl, etc., can be additionally substituted.

[0143] As used herein, the terms "halo" or "halogen" refer to a fluorine, chlorine, bromine, or iodine atom, either alone or as part of another substituent.

[0144] As used herein, the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, that is, the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) selected individually and independently from the group described herein.

[0145] The term "hydrogen" includes hydrogen, protons, and ionized hydrogen. The term "deuterium" includes deuterium and ionized deuterium. Additionally, references to atoms include other isotopes of those atoms to the extent that the resulting compound is pharmaceutically acceptable.

[0146] In certain embodiments, the compound of each formula of the present invention is defined as comprising an isotope-labeled compound. An “isotope-labeled compound” is a compound in which a specific isotope of a specified element is enriched at at least one atomic position to a level significantly higher than the natural abundance of that isotope. For example, one or more hydrogen atomic positions within the compound may be enriched with deuterium to a level significantly higher than the natural abundance of deuterium, for example, at least 1%, preferably at least 20%, or at least 50%. Such deuteridated compounds may be metabolized more slowly than, for example, non-deuteridated analogs and thus may exhibit a longer half-life when administered to a subject. Such compounds may be synthesized using methods known in the art, for example, using deuteridated starting materials. Unless otherwise noted, isotope-labeled compounds are pharmaceutically acceptable.

[0147] As used herein, the term "hydroxy-activating group" refers to an unstable chemical moiety known in the art as being activated to cause a hydroxyl group to be released during a synthesis process such as a substitution or elimination reaction. Examples of hydroxyl-activating groups include, but are not limited to, mesylates, tosylates, trilates, p-nitrobenzoates, phosphonates, etc.

[0148] The term "activated hydroxyl" as used herein refers to a hydroxyl group activated by a hydroxyl activating group as defined above, and includes, for example, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate group, etc.

[0149] As used herein, the term "hydroxy protecting group" refers to an unstable chemical moiety known in the art to protect a hydroxyl group from unwanted reactions during a synthesis process. After the synthesis process(s), the hydroxy protecting group described herein may be optionally removed. Hydroxyl protecting groups known in the art are generally THGreene and PGM Wuts, Protective Groups in Organic Synthesis This is described in the 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenylmethyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, etc.

[0150] The term "protected hydroxyl" as used herein means a hydroxyl group protected by a hydroxyl protecting group as defined above, and includes, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, etc.

[0151] As used herein, the term "hydroxy prodrug group" refers to a promoiety group known in the art to temporarily alter the physicochemical properties and consequently the biological properties of a parent drug by covering or masking a hydroxyl group. After the above synthesis process(s), the hydroxy prodrug group described herein In vivo It must be able to return to a hydroxyl group. Hydroxy prodrug groups known in the art are generally 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 SS Dhareshwar and VJ Stella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology:Pharmaceutical Aspects), edited by V. J. Stella, et al, Springer and AAPSPress, 2007, pp 31-99.

[0152] As used herein, the term "amino protecting group" refers to an unstable chemical moiety known in the art to protect an amino group from unwanted reactions during a synthesis process. After the synthesis process(s), the amino protecting group described herein may be optionally removed. Amino protecting groups known in the art are generally THGreene and PGMWuts, Protective Groups in Organic SynthesisIt is described in the 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, etc.

[0153] The term "protected amino" as used herein means an amino group protected by an amino protecting group as defined above.

[0154] The term "amino acid" means naturally occurring and synthesized α, β, γ, or d amino acids, including but not limited to amino acids found in proteins or intermediates of amino acid or protein metabolism, namely glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, citrulline, arginine, and histidine. In certain embodiments, the amino acid is in an L-configuration. In certain embodiments, the amino acid is in a D-configuration. In certain embodiments, the amino acid is provided as a substituent of the compound described herein, wherein the amino acid is alanyl, valine, leucinyl, isoleucinyl, prolinyl, phenylalanyl, tryptophanyl, methioninyl, glycinyl, serinyl, It is a residue selected from the group consisting of threonil, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, ricinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-cerinyl, β-threonil, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutarroyl, β-ricinyl, β-argininyl, and β-histidinyl.

[0155] The term “amino acid derivative” means a group derivable from naturally occurring or non-naturally occurring amino acids as described and illustrated herein. Amino acid derivatives are obvious to those skilled in the art and include, but are not limited to, esters, amino alcohols, amino aldehydes, amino lactones, and N-methyl derivatives of naturally occurring and non-naturally occurring amino acids. In one embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is -NR u -G(S c )-C(=O)-Q 1 and, Q 1 silver -SR v is, -NR v R v or is an alkoxyl, and R v is hydrogen or alkyl, and S c is a side chain of a naturally or non-naturally occurring amino acid, and G is C l -C2alkyl, and R u is hydrogen or; or R u and S c These are taken together with the atoms to which they are bonded to form a five-membered heterocyclic ring. In one embodiment, an amino acid derivative is provided as a substituent of the compound described herein, wherein the substituent is OC(=O)-G(S c )-NH-Q 2 and, Q 2 is hydrogen or an alkoxyl, and S c is a side chain of a naturally or non-naturally occurring amino acid, and G is a C1-C2 alkyl. In certain embodiments, Q 2 and S c is taken together with the atoms to which they are bonded to form a 5-membered heterocyclic ring. In certain embodiments, G is optionally substituted methylene, and S cis selected from the group consisting of hydrogen, deuterium, alkyl, arylalkyl, heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, and hydroxylarylalkyl. In one embodiment, an amino acid derivative is provided as a substituent of the compound described herein, wherein the amino acid derivative has a D-type structure. In one embodiment, an amino acid derivative is provided as a substituent of the compound described herein, wherein the amino acid derivative has an L-type structure.

[0156] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. Examples of typical leaving groups include chloro, bromo, and iodo groups; sulfonic acid ester groups such as mesylates, tosylates, brosylates, nosylates, etc.; and acyloxy groups such as acetoxy, trifluoroacetoxy, etc.

[0157] As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to proton activity, that is, does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene; halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, etc.; heterocyclic compounds such as, for example, tetrahydrofuran and N-methylpyrrolidinone; and ethers such as diethyl ether and bis-methoxymethyl ether. These compounds are well known to those skilled in the art, and it will be self-evident to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions depending on factors such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, for example, as follows: 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.

[0158] As used herein, the term "protogenic solvent" refers to a solvent that tends to donate a proton, such as alcohols like methanol, ethanol, propanol, isopropanol, butanol, and t-butanol. These solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions depending on factors such as the solubility of the reagent, the reactivity of the reagent, and the preferred temperature range. Further discussion of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, for example, as follows: 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.

[0159] The combinations of substituents and variables conceived by the present invention are limited only to those that result in the formation of a stable compound. As used herein, the term "stable" means a compound that has sufficient stability to allow for manufacture and maintains its integrity for a sufficient period to be useful for the purposes described in detail herein (e.g., therapeutic or prophylactic administration to a subject).

[0160] The synthesized compound can be separated from the reaction mixture and further purified through methods such as column chromatography, high-pressure liquid chromatography, or recrystallization. As will be understood by those skilled in the art, additional methods for synthesizing the compound of the above formula of the present invention will be obvious to those skilled in the art. Furthermore, various synthesis steps may be performed in an alternative order or sequence to obtain the desired compound. Synthetic chemical transformation and protecting methodologies (protection and deprotection) useful for synthesizing the compound described herein are known in the art and include, for example, those described in the following literature: 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 subsequent editions thereof.

[0161] As used herein, the term "object" means an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. The object also means, for example, a dog, cat, horse, cow, pig, guinea pig, fish, bird, etc.

[0162] The compound of the present invention may be modified by attaching appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and may include increased biological penetration into specific biological systems (e.g., blood, lymphatic system, central nervous system), increased oral availability, increased solubility for injection, altered metabolism, and altered excretion rate.

[0163] The compounds described herein contain one or more asymmetric centers and thus produce enantiomers, diastereomers, and other stereoisomer forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry, or (D)- or (L)- in the case of amino acids. The present invention is intended to include all such possible isomers as well as their racemic and optically pure forms. Optical isomers may be prepared from each optically active precursor according to the procedures described above, or may be prepared by splitting a racemic mixture. Such splitting may be performed in the presence of a resolving agent by chromatography, repeated crystallization, or a combination of these techniques known to those skilled in the art. Further details regarding splitting are provided by Jacques, et al ., Enantiomers, Racemates, and Resolutions (This can be verified in John Wiley & Sons, 1981). Where the compounds described herein contain olepinic double bonds, other unsaturated, or other geometrically asymmetric centers, unless specifically stated otherwise, said compounds E and Z It is intended to include both geometric isomers or cis- and trans- isomers. Likewise, it is intended to include all tautomeric forms. Tautomeric isomers may be cyclic or acyclic. Any arrangement of carbon-carbon double bonds appearing herein is chosen for convenience and is not intended to specify a particular arrangement unless otherwise stated in the text. Accordingly, any carbon-carbon double bond or carbon-heteroatom double bond arbitrarily designated as trans herein may be cis, trans, or a mixture of any proportion of both.

[0164] Specific compounds of the present invention may exist as different, stable conformational forms that are separable. For example, torsional asymmetry resulting from restricted rotation around an asymmetric single bond due to steric hindrance or ring deformation can enable the separation of different conformers. The present invention comprises each conformational isomer of these compounds and mixtures thereof.

[0165] As used herein, the term "pharmaceuticalally acceptable salt" means a salt that is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and that meets a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge, et al J. Pharmaceutical Sciences, 66:1-19 (1977) describes in detail pharmaceutically acceptable salts. The above salts are used in the final isolation and purification process of the compound of the present invention. in situIt may be manufactured in or separately prepared by reacting a free base functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of amino groups formed by inorganic acids such as hydrochloric acid, hydrobromide, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, Includes, but is not limited to, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include, where appropriate, halides, It includes non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfons, and aryl sulfons.

[0166] As used herein, the term “pharmaceuticalally acceptable ester” means an ester that is hydrolyzed in vivo and includes those that readily decompose in the human body to leave a parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, in particular, alkanes, alkenes, cycloalkanes, and alkanic acids in which each alkyl or alkenyl portion has 6 or fewer carbon atoms, which are advantageously derived. Examples of specific esters include, but are not limited to, esters of C1-C6-alkanes such as acetate, propionate, butyrate, and pivalate esters.

[0167] The terms "including," "containing," "having," and "included" should be interpreted as open-ended terms (i.e., meaning "including but not limited thereto") unless otherwise specified.

[0168] The term "pharmaceuticalally acceptable salt or prodrug" of a compound refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound.

[0169] The terms "subject" and "patient" are used interchangeably in this institution and refer to mammals, particularly humans.

[0171] Pharmaceutical composition

[0172] The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of the present invention formulated with one or more pharmaceutically acceptable carriers or excipients.

[0173] As used herein, the term “pharmaceuticalally acceptable carrier or excipient” means all types of non-toxic, inert solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or formulation aids. Some examples of substances that may be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanths; 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 such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-removing water; isotonic saline; Ringer’s solution; In addition to ethyl alcohol and phosphate buffer solution, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants may also be included in the composition at the discretion of the formulationr.

[0174] The pharmaceutical composition of the present invention may be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir, preferably by oral administration or by injection. The pharmaceutical composition of the present invention may include any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to improve the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0175] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may include inert diluents commonly used in the art, e.g., water or other solvents, solubilizers and emulsifiers, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition may include adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0176] Injectable preparations, e.g., sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, e.g., solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Additionally, sterile fixatives are typically used as solvents or suspension media. For this purpose, any neutral fixative containing synthetic mono- or diglycerides may be used. Additionally, fatty acids such as oleic acid are used in injectable preparations.

[0177] Injectable formulations may be sterilized, for example, by filtration through a bacteria-removing filter, or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0178] To prolong the effect of a drug, it is often desirable to slow down its absorption from subcutaneous or intramuscular injections. This can be achieved by using liquid suspensions of crystalline or amorphous materials with low water solubility. The rate of drug absorption depends on its dissolution rate, which in turn depends on crystal size and crystal form. Optionally, delayed absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oil vehicle. Injectable depot formulations are produced by forming a microcapsule matrix of the drug within a biodegradable polymer, such as polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of the drug to the polymer and the characteristics of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the drug within liposomes or microemulsions compatible with body tissues.

[0179] A composition for rectal or vaginal administration is preferably a suppository that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at room temperature but liquid at body temperature and melts in the rectal or vaginal cavity to release the active compound.

[0180] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound comprises at least one inert, pharmaceutically acceptable excipient or carrier, e.g., 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, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) release retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as, e.g., cetyl alcohol and glycerol monostearate; h) kaolin and It is mixed with an adsorbent such as bentonite clay, and i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may additionally contain a buffer.

[0181] Similar types of solid compositions can also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol, etc.

[0182] Solid dosage forms of tablets, coated tablets, capsules, pills, and granules may be formulated with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations. These may optionally contain opacifying agents and may also be compositions that release the active ingredient(s) only in specific parts of the intestinal tract or preferentially, selectively, and in a delayed manner. Examples of embedding compositions that may be used include polymeric materials and waxes.

[0183] Forms of administration for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any preservative or buffer. Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also considered to be included within the scope of the present invention.

[0184] In addition to the active compound of the present invention, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanths, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide, or mixtures thereof.

[0185] In addition to the compounds of the present invention, the powder and spray may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these materials. The spray may additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0186] Transdermal patches offer the additional advantage of being able to control the release of a compound into the body. This form of administration can be prepared by dissolving or dispersing the compound in a suitable medium. An absorption promoter may also be used to increase the flux of the compound passing through the skin. The rate can be controlled by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.

[0187] For pulmonary delivery, the therapeutic composition of the present invention is formulated in the form of solid or liquid particles and administered directly into the patient's respiratory system, for example, by inhalation. The solid or liquid particle form of the active compound prepared to carry out the present invention comprises particles of an inhalable size, that is, particles small enough to pass through the mouth and larynx upon inhalation and reach the bronchi and alveoli. The delivery of aerosolized therapeutic agents, in particular aerosolized antibiotics, is known in the art (e.g., US Pat. No. 5,767,068 to Van Devanter et al ., US Pat.No. 5,508,269 to Smith et al., and see WO 98 / 43650 by Montgomery, all of which are incorporated herein by reference).

[0188] antiviral activity

[0189] The inhibitory effective dose or dosage of the compound of the present invention may be in the range of about 0.01 mg / Kg to about 500 mg / Kg, optionally about 1 to about 50 mg / Kg. The inhibitory effective dose or dosage may also vary depending on the route of administration and the possibility of concomitant use with other agents.

[0190] According to the treatment method of the present invention, viral infections and diseases are treated or prevented by administering a compound of the present invention to a patient, such as a human or other animal, in a therapeutically effective amount for the amount and duration necessary to achieve the desired result.

[0191] The "therapeutic effective dose" of the compound of the present invention refers to the amount of the compound that imparts a therapeutic effect to a subject under a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by certain tests or markers) or subjective (i.e., the subject exhibits or feels the effect). The effective dose of the compound may be in the range of about 0.1 mg / kg to about 500 mg / kg, preferably about 1 to about 50 mg / kg. The effective dose may also vary depending on the route of administration and the possibility of concomitant use with other agents. However, it should be understood that the total daily use of the compound and composition of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutic effective dose level for a specific patient will depend on various factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health status, gender, and diet; the time of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known in the medical community.

[0192] When a compound of the present invention is administered to a human or other animal as a single dose or in divided doses, the total daily dose may be, for example, 0.01 to 50 mg per kg of body weight, or more typically, 0.1 to 25 mg per kg of body weight. A single dose composition may include these amounts or divided amounts thereof to constitute the daily dose. Generally, a therapeutic regimen according to the present invention comprises administering about 10 mg to about 1000 mg of the compound(s) of the present invention as a single or multiple doses daily to a patient requiring such treatment.

[0193] The compound of the present invention described herein is administered, for example, by injection, intravenous, arterial, subcutaneous, intraperitoneal, intramuscular, or subcutaneous administration; Alternatively, it may be administered orally, buccally, nasally, transmucosally, topically, as an ophthalmic preparation, or by inhalation, with a dosage range of about 0.1 to about 500 mg per kg of body weight, or optionally 1 mg to 1000 mg / dose, administered at intervals of 4 to 120 hours, or as required by the specific drug. The method of the present invention considers the administration of an effective amount of a compound or compound composition to achieve the desired or specified effect. Typically, the pharmaceutical composition of the present invention will be administered about 1 to about 6 times daily, or optionally by continuous infusion. Such administration may be used as chronic or acute therapy. The amount of active ingredient that can be combined with pharmaceutical excipients or carriers to form a single-dose form will vary depending on the target of treatment and the specific mode of administration. Typical formulations will contain about 5% to about 95% of the active compound (w / w). Optionally, such formulations will contain about 20% to about 80% of the active compound It is possible.

[0194] Lower or higher dosages than those mentioned above may be required. The specific dosage and treatment regimen for a particular patient will depend on various factors, namely the activity of the specific compound used, age, body weight, general health status, gender, diet, timing of administration, elimination rate, concomitant medications, severity and course of the disease, condition, or symptoms, the patient's disposition to the disease, condition, or symptoms, and the judgment of the attending physician.

[0195] As the patient's condition improves, a maintenance dose of the compound, composition, or combination of the present invention may be administered as needed. Subsequently, when symptoms have been alleviated to a desired level, the dosage, frequency of administration, or both may be reduced according to the symptoms to a level that maintains the improved condition. However, the patient may require long-term intermittent treatment if disease symptoms recur.

[0196] Where the composition of the present invention comprises a combination of a compound of the formula described herein and one or more additional therapeutic agents or prophylactic agents, said compound and additional agents should both be present at a dose level of about 1 to 100%, more preferably about 5 to 95%, of the dose typically administered in monotherapy. The additional agents may be administered separately from the compound of the present invention as part of a multi-dose regimen. Optionally, said agents may be mixed with the compound of the present invention into a single composition to form part of a single dose form.

[0197] The above “additional therapeutic agents or prophylactic agents” include, but are not limited to, immunotherapies (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytics, antimuscarinic agents, antileukotriene agents, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants and / or antimicrobial and antiviral agents (e.g., ribavirin and amantadine). The composition according to the present invention may also be used in combination with gene replacement therapy.

[0198] Combination and alternating therapy

[0199] It has been recognized that drug-resistant variants of HIV, HBV, and HCV may emerge after long-term treatment with antivirals. Drug resistance is most typically caused by mutations in genes encoding proteins, such as enzymes used for viral replication, and is most typically found in reverse transcriptase, protease, or DNA polymerase in HIV; DNA polymerase in HBV; and RNA polymerase, protease, or helicase in HCV. Recently, it has been demonstrated that the efficacy of a drug against HIV infection can be extended, enhanced, or restored by administering a second or third antiviral compound in combination or alternately, which induces mutations different from those caused by the primary drug. The aforementioned compounds may be used in combination and include HBV polymerase inhibitors, interferons, TLR modulators such as TLR-7 or TLR-9 agonists, therapeutic vaccines, immunoactivators of specific cytoviral RNA sensors, distinct viral entry inhibitors, viral maturation inhibitors, capsid assembly regulators, antiviral compounds with clear or unknown mechanisms of action, and It is selected from a group consisting of combinations of these. Optionally, pharmacokinetics, biodistribution, or other parameters may be altered by these combination therapies or alternating therapies. Generally, combination therapies are typically more preferable than alternating therapies because they induce multiple stresses on the virus simultaneously.

[0200] Compounds preferred for combination therapy or alternating therapy for HBV treatment include 3TC, FTC, L-FMAU, interferon, adefovir dipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3'-valinyl L-dC), bD-dioxolanyl-guanine (DXG), bD-dioxolanyl-2,6-diaminopurine (DAPD), and (3-D-dioxolanyl-6-chloropurine (ACP), famciclovir, penciclovir, lobucavir, ganciclovir, and ribavirin.

[0201] Although the present invention has been described with reference to various preferred embodiments, it is not limited thereto, and those skilled in the art will recognize that variations and modifications are possible within the spirit of the invention and the scope of the appended claims.

[0202] abbreviation

[0203] The abbreviations that may be used in the description of the scheme and examples below are as follows: Ac stands for acetyl; AcOH stands for acetic acid; Bz stands for benzoyl; Bn stands for benzyl; t-BuOK stands for potassium. tert -Butoxide; Bu₃SnH is tributyltin hydride; BOP is (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; Brine is aqueous sodium chloride solution; BSA is N,O-bis(trimethylsilyl)acetamide; CDI is carbonyldiimidazole; CH₂Cl₂ is dichloromethane; CH₃ is methyl; CH₃CN is acetonitrile; COMU is (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; Cs₂CO₃ is cesium carbonate; CuCl is copper(I) chloride; CuI is copper(I) iodide; dba is dibenzylideneacetone; dppb is diphenylphosphinobutane; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC is N,N'-dicyclohexylcarbodiimide; DEAD is diethylazodicarboxylate; DIAD is diisopropylazodicarboxylate; DIPEA or (i-Pr)₂EtN is N,N-diisopropylethylamine; Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP is 4-dimethylaminopyridine; DME is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; DMT is di( p-Methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA is diphenylphosphoryl azide; EDC is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; EDC HCl is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; EtOAc is ethyl acetate; EtOH is ethanol; Et₂O is diethyl ether; HATU is O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl is hydrogen chloride; HOBT is 1-hydroxybenzotriazole; hr is hour; K₂CO₃ is potassium carbonate; n-BuLi is n-butyl lithium; i -BuLi is i - Butyl lithium; t -BuLi is t-Lithium butyl; PhLi is phenyllithium; LDA is lithium diisopropylamide; LiTMP is lithium 2,2,6,6-tetramethylpiperidinate; MeOH is methanol; Mg is magnesium; min is min; MOM is methoxymethyl; Ms is mesyl or -SO₂-CH₃; Ms₂O is methanesulfonic anhydride or mesyl anhydride; MTBE is t-butylmethyl ether; NaCl is sodium chloride; NaH is sodium hydride; NaHCO₃ is sodium bicarbonate or sodium hydrogen carbonate; Na₂CO₃ is sodium carbonate; NaOH is sodium hydroxide; Na₂SO₄ is sodium sulfate; NaHSO₃ is sodium bisulfite or sodium hydrogen sulfite; Na₂S₂O₃ is sodium thiosulfate; NH₂NH₂ is hydrazine; NH₄HCO₃ is ammonium bicarbonate; NH₄Cl is ammonium chloride; OH is hydroxyl; o / n is overnight; PE is petroleum ether; PTSA is p-toluenesulfonic acid; PPTS is pyridinium p-toluenesulfonate; TBAF is tetrabutylammonium fluoride; TEA or Et₃N is triethylamine; TES is triethylsilyl; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TMEDA is N,N,N',N'-tetramethylethylenediamine; Ts is tosyl or -SO₂-C6H₄CH₃; Ts₂O is tolylsulfonic acid anhydride or tosyl anhydride; TsOH is p-tolylsulfonic acid; Pd is palladium; Ph is phenyl; PdOH is palladium hydroxide; Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium(O); Pd(PPh₃)₄ is tetrakis(triphenylphosphine)palladium(0); PdCl₂(PPh₃)₂ is trans-dichlorobis(triphenylphosphine)palladium(II); Pd(dppf)Cl₂ is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pt is platinum; Rh is rhodium; rt is room temperature; Ru is ruthenium; satd. is saturated; SFC is supercritical fluid chromatography; TBS is tert-Butyldimethylsilyl; TMS is trimethylsilyl; or TMSCl is trimethylsilyl chloride; Zn is zinc (powder); Zn(CN)2 is zinc cyanide; TLC is thin-layer chromatography; H2O is water; N2 is nitrogen; H2 is hydrogen; LiOH is lithium hydroxide; DAST is diethylaminosulfonate trifluoride; PCC is pyridinium chlorochromate.

[0204] Examples

[0205] The compounds and processes of the present invention will be better understood in connection with the following examples, which are merely illustrative and do not limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications may be made without departing from the spirit of the invention and the scope of the appended claims, including but not limited to those relating to chemical structures, substituents, derivatives, formulations and / or methods of the present invention.

[0206] Example 1

[0207]

[0208] Step 1a.Sulfuric acid (3 mL) was added to a methanol (80 mL) solution of rac-(4R)-4-[rac-(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoic acid (10 g, 25.47 mmol, free base) and stirred at 50 °C for 5 hours. After confirming that the reaction was complete via TLC monitoring, the solvent was concentrated under reduced pressure and water (50 mL) was added. The aqueous layer was extracted with EA (80 mL × 3), the combined organic layer was washed with brine (30 mL), and then with anhydrous Na2SO4 The residue was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography and eluted with 17% to 50% EtOAc in petroleum ether to obtain methyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (8.5 g, 20.91 mmol, 82.07% yield, free base) as a white powder.

[0209] Step 1b.In a 30 mL DCM solution of methyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (2.4 g, 5.90 mmol, free base) and trimethylsilyl (1E)-N-trimethylsilylethaneimidate (6.00 g, 29.51 mmol, 7.24 mL), 1-methylimidazole (2.42 g, 29.51 mmol, 2.35 mL) and trimethylsilyl chloride (3.85 g, 35.42 mmol (4.49 mL) was added. The mixture was stirred at 25 °C for 3 hours. Then, the reaction was concentrated. The residue was eluted in PE with 0 to 5% EA to obtain crude methyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-3,7-bis(trimethylsilyloxy)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (3.1 g, 5.63 mmol, 95.32% yield, free base) as a colorless viscous oil.

[0210] Step 1c. Stirred methyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]

[0211] Hydrochloric acid (1.17 mL, 1N) was added to a solution of phenanthrene-17-yl]pentanoate (300 mg, 472.35 μmol, free base) in THF (5 mL) and methanol (5 mL). The mixture was stirred at 25 °C for 3 hours. The reaction was then washed with saturated NaHCO₃ (5 mL), the aqueous layer was extracted with EA (20 mL × 3), the combined organic layer was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography and eluted with 0% to 10% EtOAc in petroleum ether to methyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (200 mg, 383.98 μmol, 81.29% yield, free base) was obtained as a white solid.

[0212] Step 1d.Des-martin periodinane (195.43 mg, 460.78 μmol) was added to a stirred DCM (5 mL) solution of methyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (80.00 mg, 153.59 μmol, free base). The mixture was stirred at 25 °C for 15 hours. TLC monitoring showed that the starting material disappeared and a new spot appeared. The mixture was filtered and concentrated, The residue was purified by silica gel column chromatography and eluted with 0% to 10% EtOAc in petroleum ether to obtain methyl (4R)-4-[(5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,

[0213] 14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoate (20 mg, 38.55 μmol, 25.10% yield, free base) was obtained as a white solid and confirmed by HNMR.

[0214] 1 H NMR (400 MHz, CDCl3) δ 3.68-3.62 (m, 4H), 2.60-2.49 (m, 1H), 2.38-2.14 (m, 5H), 2.03-1.98 (m, 2H), 1.88-1.76 (m, 4H), 1.64-1.56 (m, 3H),1.49-1.25(m, 8H),1.20-1.12(m, 2H), 1.08-1.02(m, 4H),0.93-0.84(m, 12H),0.69(s, 3H),0.05(s, 3H),0.03(s, 3H).

[0215] Step 1e.Lithium hydroxide (13.29 mg, 555.08 μmol) was added to a THF (2 mL) and water (2 mL) solution of methyl (4R)-4-[(5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (288 mg, 555.08 μmol, free base). The reaction mixture was stirred at 25 °C for 24 hours. It was diluted with EtOAc and acidified to pH 4 with 1 M HCl. The organic layer was washed with brine, and The crude product was dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain (4R)-4-[(5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,

[0216] 14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (230 mg, 455.61 μmol, 82.08% yield, free base) was obtained as a white solid. ESI-MS m / z = 1008.27 (MH) - .

[0217] Step 1f.To a 5 mL THF solution of (4R)-4-[(5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (200 mg, 396.18 μmol, free base), bromo(ethynyl)magnesium (153.61 mg, 1.19 mmol, free base) was added under N2 at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with a saturated NH4Cl solution and diluted with EtOAc. The organic layer was washed with brine and [treated with] (Na2SO4) The crude product was dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 4:1 to 3:1) to obtain (4R)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (166 mg, 297.07 μmol, 74.98% yield, 95% purity, free base) as a yellow oil and a chiral hydroxyl isomer at position 3.

[0218] 1 ¹H NMR (400 MHz, chloroform-d) δ3.60 (ddd, J = 11.2, 9.1, 4.7 Hz, 1H), 2.48 (s, 1H), 2.39 (ddd, J = 15.2, 10.1, 4.8 Hz, 1H), 2.26 (ddd, J = 15.7, 9.4, 6.4 Hz, 1H), 2.02 - 1.05 (m, 25H), 0.99 (s, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.88 (s, 9H), 0.65 (s, 3H), 0.04 (d, J = 2.8 Hz, 6H).

[0219] Example 2

[0221]

[0222] Step 2a. EDC (21.67 mg, 113.03 μmol) and DMAP (1.38 mg, 11.30 μmol) were added to a 1 mL DMF solution of (4R)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (30 mg, 56.51 μmol, free base) and benzenesulfonamide (17.77 mg, 113.03 μmol, free base). The reaction mixture was heated at 25 °C. The mixture was stirred for 16 hours. It was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain (4R)-N-(benzenesulfonyl)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanamide (10 mg, 14.92 μmol, 26.41% yield, free base) as a white solid, which was used in the next step.

[0223] Step 2b.A 4.0 M solution of hydrogen chloride in dioxane (10.30 mg, 282.56 μmol, 12.88 μL) was added to a 2 mL THF solution of (4R)-N-(benzenesulfonyl)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanamide (10 mg, 14.92 μmol, free base). The reaction mixture was stirred at 25°C for 24 hours. It was diluted with EtOAc and mixed with water. The organic layer was washed three times. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain (4R)-N-(benzenesulfonyl)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-3-ethynyl-3,7-dihydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanamide (3.6 mg, 6.15 μmol, 41.23% yield, 95% purity, free base) as a white solid.

[0224] 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.10 - 8.04 (m, 2H), 7.70 - 7.61 (m, 1H), 7.59 - 7.51 (m, 2H), 2.48 (s, 1H), 2.36 - 2.11 (m, 2H), 2.06 - 1.16 (m, 30H), 0.98 (s, 3H), 0.85 (d, J = 6.2 Hz, 3H), 0.61 (s, 3H).

[0225] Example 3

[0226]

[0227] (4R)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-7-[tert-butyl(dimethyl)silyl]oxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]

[0228] A 4.0 M solution of hydrogen chloride in dioxane (10.30 mg, 282.56 μmol, 12.88 μL) was added to a solution of pentasanic acid (30 mg, 56.51 μmol, free base) dissolved in THF (2.99 mL). The reaction mixture was stirred at 25°C for 24 hours. It was diluted with EtOAc and washed three times with water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography. (4R)-4-[(3R,5R,7S,8R,9S,10S,13R,14S,17R)-3-ethynyl-3,7-dihydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (19 mg, 43.33 μmol, yield 76.67%, purity 95%, free base) was obtained as a white solid. 1 1H NMR (400 MHz, Methanol- d 4 ) δ 2.82 (s, 1H), 2.36 - 2.14 (m, 2H), 2.04 (d, J = 12.5 Hz, 1H), 1.91 - 1.74 (m, 7H), 1.65 (d, J = 11.0 Hz, 2H), 1.58 - 1.40 (m, 7H), 1.37 - 1.21 (m, 7H), 0.99 (s, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.71 (s, 3H).

[0229] Intermediate 1

[0230]

[0231] Step intermediate 1a.To a methanol (120 mL) solution of (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoic acid (20 g, 50.95 mmol, free base), concentrated hydrochloric acid (12 mL) at 0 °C was added. The reaction mixture was stirred at 25 °C for 2 hours and evaporated. The residue was diluted with EA (300 mL) and washed with saturated NaHCO₃ (2 × 100 mL) and saturated NaCl (100 mL) solutions. The organic layer was dried with anhydrous Na₂SO₄, filtered, and concentrated to obtain methyl (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (20 g, 49.19 mmol, 96.55% yield, free base) as a white solid.

[0232] Step intermediate 1b. Methyl (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradeca

[0233] Imidazole (4.35 g, 63.95 mmol) and tert-butyl-chloro-dimethyl-silane (9.27 g, 61.49 mmol, 11.44 mL) were added to a DMF (200 mL) solution of hydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (20 g, 49.19 mmol, free base). The reaction was stirred at 25 °C for 15 hours. The mixture was diluted with water (500 mL) to induce precipitation from the solution, and the precipitate was collected by filtration and methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-[tert-butyl(dimethyl)silyl]oxy-7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,

[0234] 11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate (24.5 g, 47.04 mmol, 95.63% yield, free base) was obtained as a white powder.

[0235] Step intermediate 1c. Methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-[tert-butyl(dimethyl)silyl]oxy-7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,

[0236] Acetyl acetate (96.04 g, 940.76 mmol, 88.76 mL) and N,N-dimethylpyridine-4-amine (1.15 g, 9.41 mmol) were added to a solution of 11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (24.5 g, 47.04 mmol, free base) dissolved in pyridine (120 mL). The reaction was stirred at 25 °C for 15 hours and evaporated. The residue was diluted with water (400 mL) and extracted with EA (3 × 200 mL). The combined organic layer was washed with brine (200 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography and petroleum ether Methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-[tert-butyl(dimethyl)silyl]oxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (24 g, 42.64 mmol, 90.64% yield, free base) was obtained as a colorless oil by eluting with 0% to 10% EA.

[0237] Step intermediate 1d. Methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-[tert-butyl(dimethyl)silyl]oxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]

[0238] A 4.0 M hydrochloric acid solution in dioxane (40 mL) was added in portions to a stirred solution of phenanthrene-17-yl]pentanoate (24.00 g, 42.64 mmol, free base) dissolved in THF (100 mL) and water (20 mL). The mixture was stirred at 25 °C for 1 hour. Then, the reaction was extracted with EA (100 mL × 3), the combined organic layer was washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated to obtain methyl (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoate (15.5 g, 34.55 mmol, 81.03% yield, free base) was obtained as a white solid.

[0239] Step intermediate 1e. Methyl (4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenant

[0240] Des-martin periodinan (8.86 g, 20.90 mmol) was added to a solution of len-17-yl]pentanoate (7.5 g, 16.72 mmol, free base) dissolved in acetonitrile (100 mL). The reaction was stirred at 50 °C for 5 hours. Then, the reaction was diluted with water (100 mL), the aqueous layer was extracted with EA (100 mL × 3), the combined organic layer was washed with brine (100 mL), dried with anhydrous Na2SO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography and eluted with 0% to 20% EA in petroleum ether to obtain methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (6.8 g, 15.23 mmol, 91.08% yield, free base) as a white solid.

[0241] 1 H NMR (400 MHz, CDCl3) δ4.97-4.95 (m, 1H), 3.66 (s, 3H), 2.99 (t, J = 14.4 Hz, 1H), 2.43-1.06 (m, 28H), 1.03 (s, 3H), 0.93 (d, J = 6.4 Hz, 6H), 0.68 (s, 3H).

[0242] Examples 4 and 5

[0243]

[0244] Step 4a.Bromo(ethynyl)magnesium (99.83 mg, 772.47 μmol, free base) was added to a 5 mL THF solution of methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (230 mg, 514.98 μmol, free base) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours. This was quenched with an aqueous NH4Cl solution and extracted with EA. The organic layer was washed with brine, dried (Na2SO4), filtered, and The crude product was concentrated. The crude product was purified by silica gel column chromatography to obtain methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phe

[0245] phenylen-17-yl]pentanoate (172 mg, 363.90 μmol, 70.66% yield, free base) was obtained as a white solid (bottom pot), and methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenylen-17-yl]pentanoate (60 mg, 126.94 μmol, 24.65% yield) and a chiral hydroxy isomer at position 3 were obtained.

[0247] Step 4b.In a solution of methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (40 mg, 84.63 μmol, free base) dissolved in THF (5 mL), under N₂ protection, 4-iodo-1,1'-biphenyl (26.08 mg, 93.09 μmol), iodocopper (1.61 mg, 8.46 μmol, 2.87e-1 μL), dichloropalladium; triphenylphosphane (2.97 mg, 4.23 μmol), and N,N-diethylethanolamine (25.69 mg, 253.89 μmol, 35.39 μL) were added. The reaction mixture was stirred at 25°C for 24 hours. It was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-[2-(4-phenylphenyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (33.3 mg, 53.29 μmol, yield 62.97%, free base) was obtained as a white solid.

[0248] Step 4c. Methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-[2-(4-phenylphenyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]

[0249] Sodium hydroxide (19.20 mg, 480.12 μmol, 9.02 μL) was added to a solution of phenanthrene-17-yl]pentanoate (30 mg, 48.01 μmol, free base) dissolved in MeOH (1 mL) and water (1 mL). The reaction mixture was stirred at 80°C for 16 hours. It was diluted with EtOAc and acidified to pH 4 with 1 M HCl. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography, (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-3-[2-(4-phenylphenyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (9.7 mg, 16.20 μmol, 33.74% yield, 95% purity, free base) as a white solid, and (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-[2-(4-phenylphenyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradeca

[0250] Hydrocyclopenta[a]phenanthren-17-yl]pentanoic acid (12 mg, 18.66 μmol, 38.87% yield, 95% purity, free base) was obtained.

[0251] 1 H NMR (400 MHz, Chloroform-d) δ 7.60 - 7.53 (m, 4H), 7.52 -7.42 (m, 4H), 7.35 (t, J = 7.3 Hz, 1H), 3.87 (d, J = 2.9 Hz, 1H), 2.60 (t, J = 13.1 Hz, 1H), 2.34 (dddd, J = 56.2, 15.8, 9.8, 5.8 Hz, 4H), 2.07 - 1.11 (m, 30H), 0.98 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.67 (s, 3H).

[0252] 1 H NMR (400 MHz, Chloroform-d) δ 7.60 - 7.52 (m, 4H), 7.52 - 7.41 (m, 4H), 7.38 - 7.33 (m, 1H), 4.90 (d, J = 3.2 Hz, 1H), 2.48 - 2.22 (m, 3H), 2.10 (d, J = 0.6 Hz, 1H), 2.07 (d, J = 0.6 Hz, 3H), 2.06 - 1.97 (m, 2H), 1.91 - 1.07 (m, 28H), 0.99 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0253] Example 6

[0255]

[0256] Benzenesulfonamide (3.87 mg, 24.61 μmol, free base), EDC (4.72 mg, 24.61 μmol), and DMAP (1.50 mg, 12.31 μmol) were added to a solution of (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-3-[2-(4-phenylphenyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (7 mg, 12.31 μmol, free base) dissolved in DMF (2 mL). The reaction mixture was stirred at 25 °C for 16 hours. It was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain (4R)-N-(benzenesulfonyl)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-3-[2-(4-phenyl

[0257] phenyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanamide (5.4 mg, 7.25 μmol, 58.88% yield, 95% purity, free base) was obtained as a white solid.

[0258] 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.70 - 7.61 (m, 1H), 7.61 - 7.40 (m, 12H), 7.40 - 7.31 (m, 1H), 3.86 (s, 1H), 2.60 (t, J = 13.1 Hz, 1H), 2.42 - 2.23 (m, 2H), 2.22 - 2.12 (m, 1H), 2.09 - 1.05 (m, 40H), 0.97 (d, J = 1.0 Hz, 3H), 0.86 (d, J = 6.1 Hz, 3H), 0.61 (d, J = 1.6 Hz, 3H).

[0259] Example 7

[0260]

[0261] The title compound was prepared as a white solid (3 mg, 5.61 μmol, 10.26% yield, free base) from intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.35 (m, 2H), 7.34 - 7.29 (m, 3H), 2.39 - 2.29 (m, 2H), 2.25 - 2.16 (m, 1H), 2.06 (s, 3H), 1.92 - 1.85 (m, 3H), 1.82 - 1.76 (m, 3H), 1.73 - 1.09 (m, 20H), 1.02 (s, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.71 (s, 3H).

[0262] Example 8

[0263]

[0264] The title compound was prepared as a white solid (21 mg, 42.62 μmol, 77.97% yield, free base) according to a procedure similar to that of Example 5. 1 H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.36 (m, 2H), 7.31 (dt, J = 4.4, 2.8 Hz, 3H), 3.80 (d, J = 2.8 Hz, 1H), 2.69 - 2.55 (m, 1H), 2.33 (ddd, J = 15.1, 9.8, 5.2 Hz, 1H), 2.20 (ddd, J = 15.6, 9.4, 6.8 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.90 (dt, J = 15.9, 10.5 Hz, 3H), 1.82 - 1.71 (m, 5H), 1.70 - 1.63 (m, 1H), 1.58 - 1.43 (m, 6H), 1.39 - 1.27 (m, 4H), 1.25 - 1.08 (m, 3H), 0.99 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.70 (s, 3H).

[0265] Example 9

[0266]

[0267] The title compound was prepared as a white solid (10 mg, 15.83 μmol, 41.04% yield, free base) from the compound of Example 8 according to a procedure similar to that of Example 6. 1H NMR (400 MHz, Methanol-d4) δ 8.04 - 7.97 (m, 2H), 7.73 - 7.65 (m, 1H), 7.62 - 7.54 (m, 2H), 7.46 - 7.35 (m, 2H), 7.35 - 7.26 (m, 3H), 3.79 (d, J = 2.8 Hz, 1H), 2.68 - 2.52 (m, 1H), 2.26 (ddd, J = 14.2, 8.7, 5.2 Hz, 1H), 2.15 (dt, J = 15.2, 7.9 Hz, 1H), 2.06 - 1.91 (m, 2H), 1.92 - 1.59 (m, 10H), 1.58 - 1.40 (m, 6H), 1.36 - 1.00 (m, 9H), 0.98 (s, 3H), 0.87 (d, J = 6.4 Hz, 3H), 0.60 (s, 3H).

[0268] Example 10

[0269]

[0270] The title compound was prepared as a white solid (85 mg, 204.04 μmol, 87.67% yield, free base) from the compound of intermediate 1 according to a procedure similar to that of Example 5. 1 H NMR (400 MHz, Methanol-d4) δ3.78 (d, J = 2.8 Hz, 1H), 2.77 (s, 1H), 2.52 (t, J = 13.9 Hz, 1H), 2.33 (ddd, J = 15.2, 9.8, 5.3 Hz, 1H), 2.19 (ddd, J = 15.7, 9.5, 6.8 Hz, 1H), 2.06 - 1.95 (m, 2H), 1.94 - 1.73 (m, 5H), 1.70 - 1.60 (m, 3H), 1.56 - 1.42 (m, 7H), 1.40 - 1.08 (m, 8H), 0.95 (t, J = 3.3 Hz, 6H), 0.69 (s, 3H).

[0271] Example 11

[0272]

[0273] The title compound (67 mg, 125.07 μmol, 77.25% yield, free base) was prepared as a white solid from the compound of Intermediate 1 according to a procedure similar to that of Example 4. ESI-MS m / z = 534.51 [MH] - . 1 H NMR (400 MHz, CD3OD) δ8.49 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (dt, J = 7.8, 1.1 Hz, 1H), 7.39 (ddd, J = 7.7, 5.0, 1.2 Hz, 1H), 2.42 - 2.27 (m, 2H), 2.20 (ddd, J = 15.6, 9.3, 6.8 Hz, 1H), 2.14 - 2.07 (m, 1H), 2.06 (s, 3H), 2.02 (d, J = 8.3 Hz, 1H), 1.98 - 1.07 (m, 25H), 1.03 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.72 (s, 3H).

[0274] Example 12

[0275]

[0276] Step 12a. 3,3-dimethylbuty-1-yne (36.78 mg, 447.82 μmol) was dissolved in THF (5 mL), and n-butyllithium (14.34 mg, 223.91 μmol, 5.98 μL) was slowly added while stirring the solution at -78 °C, and the reaction mixture was stirred at -78 °C for 30 minutes. Methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]

[0277] Pentanoate (100 mg, 223.91 μmol) was dissolved in THF (0.5 mL) and added, and the reaction was stirred at -78 °C for 3 hours. The reaction was monitored by TLC; after confirming that the starting material was consumed, water was added and the mixture was extracted with EA. The EA layers were combined, washed, dried, and evaporated to obtain the crude product, which was purified by column chromatography to obtain methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-(3,3-dimethylbute-1-inyl)-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta

[0278] [a]phenanthrene-17-yl]pentanoate (60 mg, 113.47 μmol, yield 50.68%, free base) was obtained with yellow oil and a chiral hydroxy isomer at position 3.

[0279] Step 12b.Methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-(3,3-dimethylbut-1-inyl)-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (50.00 mg, 94.56 μmol) was dissolved in methanol (5 mL) and water (5 mL), LiOH (67.94 mg, 2.84 mmol) was added, and the mixture was stirred at 80 °C for 16 hours. The reaction was acidified with a diluted HCl solution and extracted with DCM. The DCM layers were combined, washed, dried, and evaporated to obtain a crude product, and the crude product was purified by column chromatography to obtain (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3-(3,3-dimethylbut-1-inyl)-3,7-dihydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (20 mg, 42.31 μmol, yield 44.74%, free base) as a white solid. 1 H NMR (400 MHz, Methanol-d4) δ= 3.78 (d,J=2.8, 1H), 2.47 (t,J=12.9, 1H), 2.38-2.25 (m, 1H), 2.25-2.07 (m, 1H), 2.03-1.03 (m, 33H), 1.00-0.89 (m,6H), 0.69 (s, 3H).LCMS (ESI) calcd for [MH] - 471.70, found 471.35

[0280] Example 13

[0281]

[0282] NaOH (1.49 mg, 37.33 μmol, 7.01 e-1 μL) was added to a solution of (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-[2-(2-pyridyl)ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (20 mg, 37.33 μmol, free base) dissolved in water (2 mL) and 1,4-dioxane (5 mL), and the resulting mixture was stirred at 100 °C for 16 hours, after which the reaction was neutralized with HCl at 0 °C. Volatile substances were removed by rotary evaporator, and the residue was purified by silica gel flash column chromatography. It was eluted with dichloromethane:methanol at a ratio of 10:1 to 100:1 to obtain (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-3-[2-(2-pyridyl)ethynyl]-1,2,4,5,6,7,8,9,11,

[0283] 12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (8 mg, 16.20 μmol, 43.41% yield, free base) was obtained as a white solid. ESI-MS m / z = 492.36[MH] - 1H NMR (400 MHz, CD3OD) δ8.48 (ddd, J = 5.0, 1.8, 1.0 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (dt, J = 7.9, 1.1 Hz, 1H), 7.38 (ddd, J = 7.7, 5.0, 1.2 Hz, 1H), 3.81 (d, J = 2.8 Hz, 1H), 2.65 (t, J = 13.2 Hz, 1H), 2.34 (ddd, J = 15.2, 9.8, 5.2 Hz, 1H), 2.20 (ddd, J = 15.6, 9.4, 6.8 Hz, 1H), 2.09 - 1.04 (m, 30H), 1.00 (s, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.71 (s, 3H).

[0284] Example 14

[0285]

[0286] The title compound was prepared as a white solid (19 mg, 45.61 μmol, 71.86% yield, free base) according to a procedure similar to that of Example 5. 1 H NMR (400 MHz, Chloroform-d) δ 3.86 (q, J = 3.0 Hz, 1H), 2.70 (t, J = 14.9 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.26 (ddd, J = 15.8, 9.6, 6.4 Hz, 1H), 2.03 - 1.09 (m, 24H), 0.94 (t, J = 3.2 Hz, 6H), 0.66 (s, 3H).

[0287] ¹H NMR (400 MHz, chloroform-d) δ 3.86 (q, J = 3.0 Hz, 1H), 2.70 (t, J = 14.9 Hz, 1H), 2.46 - 2.34 (m, 1H), 2.26 (ddd, J = 15.8, 9.6, 6.4 Hz, 1H), 2.03 - 1.09 (m, 24H), 0.94 (t, J = 3.2 Hz, 6H), 0.66 (s, 3H).

[0288]

[0289] The title compound was prepared as a white solid (8 mg, 17.44 μmol, 41.22% yield, free base) according to a procedure similar to that of Example 4. ESI-MS m / z = 457.30 (MH) + . 1H NMR (400 MHz, CD3OD) δ 4.86 - 4.80 (m, 1H), 2.81 (s, 1H), 2.22 (m, 4H), 2.07 - 2.00 (m, 5H), 1.84 - 1.33 (m, 17H), 1.27 - 1.07 (m, 5H), 0.97 - 0.82 (m, 6H), 0.70 (s, 3H).

[0290] Example 16

[0291]

[0292] Step 16a. BOP (66.17 mg, 149.61 μmol) was added to a solution of (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (40 mg, 74.80 μmol, free base) in DCM (10 mL) and stirred at 80 °C for 4 hours. Afterward, the solution was concentrated under reduced pressure at 40 °C and purified by FLASH (acetone:PE=0-100%, 1 hour) to obtain methyl 2-[[(4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoyl]amino]

[0293] Acetate (32 mg, 52.82 μmol, yield 70.61%, free base) was obtained as a white solid.

[0294] Step 16b.Methyl 2-[[(4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl] in methanol (10 mL) and water (10 mL)

[0295] Lithium hydroxide (6.33 mg, 264.11 μmol) was added to a solution of pentanoyl]amino]acetate (32 mg, 52.82 μmol, free base) and stirred at 25 °C for 16 hours. It was diluted with EtOAc and acidified to pH 4 with 1 M HCl. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography to obtain the title compound 2-[[(4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,

[0296] 11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoyl]amino]acetic acid (26 mg, 43.94 μmol, 83.18% yield, free base) was obtained as a white solid. ESI-MS m / z = 590.43 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.35 (m, 5H), 3.87 (s, 2H), 2.26 (m, 3H), 2.09 - 2.01 (m, 4H), 1.97 - 1.47 (m, 13H), 1.44 - 0.82 (m, 19H), 0.71 (s, 3H).

[0298] Example 17

[0299]

[0300] The title compound (15 mg, 28.37 μmol, 38.49% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 12. 1 H NMR (400 MHz, Methanol-d4) δ= 4.86-4.83 (m, 1H), 2.37-2.27 (m, 1H), 2.26-2.13 (m, 4H), 2.08-1.97 (m, 5H), 1.94-1.03 (m, 29H), 1.02-0.86 (m, 9H), 0.70 (s, 3H).

[0301] Example 18

[0302]

[0303] The title compound (15 mg, 27.74 μmol, 29.33% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 12. 1 H NMR (400 MHz, Methanol-d4) δ= 4.85 (t,J=3.0, 1H), 2.55-2.37 (m, 1H), 2.39-2.25 (m, 1H), 2.26-2.12 (m, 2H), 2.09-1.96 (m, 5H), 1.93-1.03 (m, 33H), 1.03-0.89 (m, 6H), 0.70 (d,J=2.5, 3H)LCMS (ESI) calcd for [MH] - 539.77, found 539.62

[0304] Example 20

[0305]

[0306] The compound of the title was prepared as a white solid (50 mg, 100.25 μmol, 61.80% yield, free base) according to a procedure similar to that of Example 13. 1HNMR (400 MHz, Methanol-d4) δ= 3.78 (d,J=2.8, 1H), 2.56-2.39 (m, 2H), 2.38-2.26 (m, 1H), 2.25-2.13 (m, 1H), 2.04-1.04 (m, 34H), 0.95 (t,J=3.3, 6H), 0.69 (s, 3H).LCMS (ESI) calcd for [MH] - 497.74, found 497.35.

[0307] Example 23

[0308]

[0309] The title compound was prepared as a white solid (8.3 mg, 13.56 μmol, 32.06% yield, free base) according to a procedure similar to that of Example 6. 1 H NMR (400 MHz, Methanol-d4) δ= 8.08-7.94 (m, 2H), 7.76-7.60 (m, 1H), 7.63-7.48 (m, 2H), 3.76 (d,J=2.8, 1H), 2.46 (t,J=12.8, 1H), 2.32-2.18 (m, 1H), 2.20-2.08 (m, 1H), 2.05-1.87 (m, 2H), 1.87-0.97 (m, 31H), 0.94 (s, 3H), 0.86 (d,J=6.3, 3H), 0.59 (s, 3H).LCMS (ESI) calcd for [MH] - 610.87, found 610.43

[0310] Example 24

[0311]

[0312] The title compound was prepared as a white solid (20 mg, 37.40 μmol, 31.58% yield, free base) according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Chloroform-d) δ 7.43 - 7.38 (m, 2H), 7.33 -7.28 (m, 3H), 4.89 (d, J = 3.1 Hz, 1H), 2.49 (t, J = 13.9 Hz, 1H), 2.40 (ddd, J = 15.5, 10.2, 5.1 Hz, 1H), 2.26 (ddd, J = 15.5, 9.6, 6.3 Hz, 1H), 2.07 (s, 3H), 2.00 (dd, J = 11.8, 6.5 Hz, 2H), 1.91 - 1.76 (m, 6H), 1.71 - 1.08 (m, 16H), 0.98 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0313] Example 25

[0314]

[0315] The title compound was prepared as a white solid (5 mg, 10.15 μmol, 8.57% yield, free base) according to a procedure similar to that of Example 5. 1 H NMR (400 MHz, Chloroform-d) δ 7.44 - 7.38 (m, 2H), 7.31 -7.27 (m, 3H), 3.88 (d, J = 3.0 Hz, 1H), 2.77 (t, J = 14.7 Hz, 1H), 2.40 (ddd, J = 15.4, 10.1, 5.1 Hz, 1H), 2.27 (ddd, J = 15.9, 9.6, 6.5 Hz, 1H), 2.10 - 1.73 (m, 9H), 1.68 - 1.60 (m, 2H), 1.54 - 1.12 (m, 16H), 0.97 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.68 (s, 3H).

[0316] Example 27

[0317]

[0318] Step 27a.Methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl] in THF (5 mL)

[0319] Phenylmagnesium bromide (60.90 mg, 335.86 μmol) was added to a solution of pentanoate (100 mg, 223.91 μmol, free base). The reaction mixture was stirred at 0 °C for 3 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EA (100 mL × 2), the combined organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by chromatography (silica, PE with 0-50% EA) to obtain methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-phenyl-1,2,4,5,6,7,8,9,11,12,14,15,

[0320] 16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoate (60 mg, 114.34 μmol, 51.07% yield) and a chiral hydroxy isomer at position 3 were obtained.

[0321] Step 27b.Lithium hydroxide monohydrate 98% (47.98 mg, 1.14 mmol, 31.78 μL) was added to a solution of methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-phenyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (60.00 mg, 114.34 μmol) dissolved in THF (3 mL) and water reagent (deionized water) (3 mL). The reaction mixture was stirred at 25 °C for 2 hours. It was diluted with EtOAc and the pH was adjusted with 1 M HCl. The organic layer was acidified to 4. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to obtain (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-phenyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (50 mg, 97.90 μmol, 85.62% yield) as a colorless gum.

[0322] 1 H NMR (400 MHz, CDCl3) δ 7.56 - 7.47 (m, 2H), 7.34 (dd, J = 8.4, 6.9 Hz, 2H), 7.29 - 7.19 (m, 1H), 4.83 (s, 1H), 3.95 - 3.85 (m, 1H), 2.58 - 2.42 (m, 1H), 2.41 - 2.13 (m, 4H), 2.11 (s, 3H), 2.09 - 1.98 (m, 4H), 1.98 - 1.87 (m, 3H), 1.87 - 1.72 (m, 5H), 1.72 - 1.53 (m, 4H), 1.53 - 1.23 (m, 12H), 1.23 - 1.03 (m, 4H), 0.97 (d, J = 6.5 Hz, 4H), 0.83 (s, 3H), 0.70 (s, 3H).

[0323] Example 28

[0324]

[0325] The title compound was prepared as a white solid (50 mg, 97.90 μmol, 85.62% yield) according to a procedure similar to that of Example 27. 1 HNMR (400 MHz, CDCl3) δ 7.56 - 7.47 (m, 2H), 7.34 (dd, J = 8.4, 6.9 Hz, 2H), 7.29 - 7.19 (m, 1H), 4.83 (s, 1H), 3.95 - 3.85 (m, 1H), 2.58 - 2.42 (m, 1H), 2.41 - 2.13 (m, 4H), 2.11 (s, 3H), 2.09 - 1.98 (m, 4H), 1.98 - 1.87 (m, 3H), 1.87 - 1.72 (m, 5H), 1.72 - 1.53 (m, 4H), 1.53 - 1.23 (m, 12H), 1.23 - 1.03 (m, 4H), 0.97 (d, J = 6.5 Hz, 4H), 0.83 (s, 3H), 0.70 (s, 3H).

[0326] Example 29

[0327]

[0328] The title compound was prepared as a white solid (6 mg, 12.80 μmol, 65.38% yield) from the compound of Example 27 according to a procedure similar to that of Example 13.

[0329] 1H NMR (400 MHz, CD3OD) δ 7.55 - 7.45 (m, 2H), 7.28 (dd, J = 8.4, 7.0 Hz, 2H), 7.17 (d, J = 7.3 Hz, 1H), 4.83 (s, 1H), 3.82 (d, J = 2.9 Hz, 1H), 2.91 - 2.73 (m, 1H), 2.34 (ddd, J = 15.2, 9.9, 5.2 Hz, 2H), 2.27 - 2.16 (m, 2H), 2.13 - 2.00 (m, 3H), 1.96 - 1.84 (m, 4H), 1.85 - 1.61 (m, 5H), 1.60 - 1.42 (m, 8H), 1.42 - 1.11 (m, 11H), 1.03 (s, 3H), 0.97 (dd, J = 7.0, 1.5 Hz, 3H), 0.72 (s, 3H).

[0330] Example 30

[0331]

[0332] The title compound was prepared as a white solid (40 mg, 70.45 μmol, 81.98% yield) from the compound of Example 27 according to a procedure similar to that of Example 16.

[0333] 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.43 (m, 2H), 7.38 - 7.25 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 5.45 (dd, J = 5.8, 2.1 Hz, 1H), 3.96 - 3.83 (m, 4H), 2.58 (t, J = 13.8 Hz, 1H), 2.40 - 2.12 (m, 3H), 2.12 - 1.93 (m, 6H), 1.91 (s, 5H), 1.86 - 1.63 (m, 7H), 1.63 - 1.08 (m, 16H), 1.06 (s, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.73 (s, 3H)

[0334] Example 31

[0335]

[0336] The title compound (45 mg, 92.45 μmol, yield 62.73%, free base) is a white solid and was prepared from the compound of Example 17 according to a procedure similar to that of Example 13. 1 H NMR (400 MHz, Methanol-d4) δ = 3.78 (d, J=2.8, 1H), 2.56 - 2.45 (m, 1H), 2.40 - 2.27 (m, 1H), 2.28 - 2.13 (m, 3H), 2.06 - 1.03 (m, 31H), 1.02 - 0.81 (m, 9H), 0.69 (s, 3H).LCMS (ESI) calcd for [MH] - 485.72, found 485.36.

[0337] Example 32

[0338]

[0339] The title compound (5 mg, 8.36 μmol, 34.12% yield, free base) is a white solid and was prepared from the compound of Example 18 according to a procedure similar to that of Example 16.

[0340] 1 H NMR (400 MHz, Methanol-d4) δ= 4.86-4.83 (m, 1H), 3.73 (s, 2H), 2.51-2.37 (m, 1H), 2.37-2.07 (m, 3H), 2.03 (s, 5H), 1.92-1.27 (m, 32H), 1.24-1.08 (m, 4H), 0.70 (s, 3H).LCMS (ESI) calcd for [MH] - 596.82, found 596.47.

[0341] Example 33

[0342]

[0343] The title compound (10 mg, 17.99 μmol, 34.17% yield, free base) is a white solid and was prepared from the compound of Example 32 according to a procedure similar to that of Example 13.

[0344] 1 H NMR (400 MHz, Methanol-d4) δ= 3.81-3.76 (m, 1H), 3.75 (s, 2H), 2.57-2.37 (m, 2H), 2.37-2.25 (m, 1H), 2.21-2.09 (m, 1H), 2.06-1.05 (m, 35H), 1.01-0.90 (m, 6H), 0.69 (s, 3H).

[0345] Example 34

[0346]

[0347] The title compound (6 mg, 11.03 μmol, 41.03% yield, free base) was prepared as a white solid from the compound of Example 31 according to a procedure similar to that of Example 16.

[0348] 1 H NMR (400 MHz, Methanol-d4) δ= 3.81-3.76 (m, 1H), 3.74 (s, 2H), 2.48 (t,J=12.5, 1H), 2.38-2.26 (m, 1H), 2.26-2.08 (m, 3H), 2.06-1.25 (m, 27H), 1.25-1.03 (m, 3H), 1.02-0.86 (m, 9H), 0.69 (s, 3H).LCMS (ESI) calcd for [MH] - 542.78, found 542.39.

[0349] Example 35

[0350]

[0351] The title compound (50 mg, 92.46 μmol, 64.12% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 12. 1H NMR (400 MHz, Methanol-d4) δ= 4.87-4.83 (m, 1H), 2.46-2.27 (m, 3H), 2.26-2.12 (m, 1H), 2.10-1.95 (m, 5H), 1.94-1.06 (m, 31H), 0.96 (d,J=6.2, 6H), 0.70 (s, 3H).

[0352] Example 36

[0353]

[0354] The title compound (3.4 mg, 6.18 μmol, 16.64% yield, free base) was prepared as a white solid from the compound of Example 16 according to a procedure similar to that of Example 13.

[0355] ESI-MS m / z = 548.38 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.62 - 7.05 (m, 5H), 3.80 (s, 2H), 3.25 (s, 1H), 2.61 (s, 1H), 2.18 (d,J= 7.9 Hz, 3H), 1.96 - 0.97 (m, 32H), 0.70 (s, 3H).

[0356] Example 37

[0357]

[0358] The title compound (92 mg, 163.47 μmol, 90.67% yield, free base) was prepared as a white solid from Intermediate 1 according to a procedure similar to that of Example 12. ESI-MS m / z = 561.15 [MH] - . 1H NMR (400 MHz, CD3OD) δ 7.30 - 7.20 (m, 4H), 7.20 -7.14 (m, 1H), 4.83 (d, J = 2.9 Hz, 1H), 2.79 (t, J = 7.0 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.33 (ddd, J = 15.1, 9.7, 5.3 Hz, 1H), 2.26 - 2.11 (m, 2H), 2.01 - 1.02 (m, 28H), 0.95 (d, J = 6.5 Hz, 3H), 0.88 (s, 3H), 0.69 (s, 3H).

[0359] Example 38

[0360]

[0361] The title compound (76 mg, 134.57 μmol, 79.48% yield, free base) was prepared as a white solid from Intermediate 1 according to a procedure similar to that of Example 12. ESI-MS m / z = 563.63 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.31 - 7.23 (m, 2H), 7.01 - 6.91 (m, 3H), 4.82 (d, J = 2.9 Hz, 1H), 4.78 (s, 2H), 2.32 (ddd, J = 15.1, 9.8, 5.2 Hz, 1H), 2.25 - 2.12 (m, 2H), 2.02 (s, 3H), 2.01 - 1.03 (m, 27H), 0.95 (d, J = 6.5 Hz, 3H), 0.85 (s, 3H), 0.69 (s, 3H).

[0362] Example 39

[0363]

[0364] The title compound (49 mg, 82.66 μmol, 61.93% yield, free base) was prepared as a white solid from the compound of Example 11 according to a procedure similar to that of Example 16.

[0365] 1 H NMR (400 MHz, CD3OD) δ 8.49 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 7.86 - 7.78 (m, 1H), 7.76 - 7.56 (m, 1H), 7.55 - 7.48 (m, 1H), 7.42 - 7.36 (m, 1H), 4.87 (s, 1H), 3.87 (s, 2H), 2.43 - 1.05 (m, 27H), 1.03 (s, 3H), 1.01 - 0.96 (m, 3H), 0.89 (d, J = 9.7 Hz, 1H), 0.72 (s, 3H).

[0366] Example 40

[0367]

[0368] The title compound (38 mg, 61.31 μmol, 74.73% yield, free base) was prepared as a white solid from the compound of Example 37 according to a procedure similar to that of Example 16.

[0369] ESI-MS m / z = 618.62[MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.31 - 7.21 (m, 4H), 7.20 - 7.12 (m, 1H), 4.85 -4.79 (m, 1H), 3.88 (s, 2H), 2.79 (t, J = 7.1 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.30 (ddd, J = 14.8, 10.1, 5.1 Hz, 1H), 2.22 - 2.11 (m, 2H), 2.09 - 1.02 (m, 26H), 0.97 (d, J = 6.5 Hz, 3H), 0.88 (s, 3H), 0.69 (s, 3H).

[0370] Example 41

[0371]

[0372] The title compound (31 mg, 49.86 μmol, 66.04% yield, free base) was prepared as a white solid from the compound of Example 38 according to a procedure similar to that of Example 16.

[0373] 1 H NMR (400 MHz, CD3OD) δ 7.31 - 7.21 (m, 4H), 7.20 - 7.12 (m, 1H), 4.85 -4.79 (m, 1H), 3.88 (s, 2H), 2.79 (t, J = 7.1 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.30 (ddd, J = 14.8, 10.1, 5.1 Hz, 1H), 2.22 - 2.11 (m, 2H), 2.09 - 1.02 (m, 26H), 0.97 (d, J = 6.5 Hz, 3H), 0.88 (s, 3H), 0.69 (s, 3H).

[0374] Example 42

[0375]

[0376] The title compound (109 mg, 173.89 μmol, 85.72% yield, free base) was prepared as a white solid from intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 7.41 - 7.30 (m, 4H), 7.13 (ddt, J = 7.4, 6.8, 1.2 Hz, 1H), 7.06 - 6.98 (m, 2H), 6.96 - 6.88 (m, 2H), 4.89 (d, J = 3.2 Hz, 1H), 2.48 - 2.20 (m, 3H), 2.06 (s, 3H), 1.89 - 1.74 (m, 7H), 1.72 - 1.27 (m, 14H), 1.22 - 1.02 (m, 3H), 0.98 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.65 (s, 3H).

[0377] Example 43

[0378]

[0379] The title compound (9 mg, 15.39 μmol, 64.31% yield, free base) was prepared as a white solid from the compound of Example 42 according to a procedure similar to that of Example 13.

[0380] 1 H NMR (400 MHz, Methanol-d4) δ 7.42 - 7.32 (m, 3H), 7.19 - 7.10 (m, 1H), 7.05 - 6.97 (m, 2H), 6.97 - 6.87 (m, 2H), 3.80 (d, J = 3.4 Hz, 1H), 2.62 (d, J = 13.1 Hz, 1H), 2.39 - 2.06 (m, 2H), 2.02 (dd, J = 9.3, 3.9 Hz, 2H), 1.95 - 1.68 (m, 10H), 1.58 - 1.08 (m, 17H), 0.98 (s, 3H), 0.98 - 0.95 (m, 3H).

[0381] Example 44

[0382]

[0383] The title compound (40 mg, 67.59 μmol, 74.45% yield, free base) was prepared as a white solid from the compound of Example 24 according to a procedure similar to that of Example 16.

[0384] 1 H NMR (400 MHz, Methanol-d4) δ 7.37 (ddd, J = 5.7, 3.1, 1.2 Hz, 2H), 7.33 - 7.28 (m, 3H), 3.87 (s, 2H), 2.81 (s, 1H), 2.48 (t, J = 13.9 Hz, 1H), 2.30 (ddd, J = 14.7, 10.0, 5.2 Hz, 1H), 2.21 - 2.10 (m, 1H), 2.03 (s, 3H), 1.95 - 1.29 (m, 20H), 1.05 - 0.94 (m, 6H), 0.71 (s, 3H).

[0385] Example 45

[0386]

[0387] The title compound (74 mg, 108.21 μmol, 94.40% yield, free base) was prepared as a white solid from the compound of Example 42 according to a procedure similar to that of Example 16.

[0388] 1 H NMR (400 MHz, Methanol-d4) δ 7.41 - 7.33 (m, 3H), 7.18 - 7.10 (m, 1H), 7.01 (dt, J = 7.8, 1.1 Hz, 2H), 6.95 - 6.88 (m, 2H), 3.81 (s, 2H), 2.05 (s, 3H), 1.01 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.71 (s, 3H).

[0389] Example 46

[0390]

[0391] The title compound (29 mg, 52.75 μmol, 62.44% yield, free base) was prepared as a white solid from the compound of Example 44 according to a procedure similar to that of Example 13.

[0392] 1H NMR (400 MHz, Methanol-d4) δ 7.37 - 7.33 (m, 2H), 7.29 (ddd, J = 6.3, 2.7, 0.6 Hz, 3H), 3.81 (d, J = 2.8 Hz, 1H), 3.77 (s, 2H), 2.87 - 2.70 (m, 1H), 2.31 (ddd, J = 15.0, 10.2, 4.6 Hz, 1H), 2.22 - 2.09 (m, 1H), 2.01 (dd, J = 15.7, 4.4 Hz, 2H), 1.95 - 1.68 (m, 9H), 1.65 - 1.42 (m, 8H), 1.38 - 1.17 (m, 8H), 0.98 (d, J = 6.1 Hz, 6H), 0.70 (s, 3H).

[0393] Example 47

[0394]

[0395] The title compound (2.5 mg, 4.80 μmol, 38.60% yield, free base) was prepared as a white solid from the compound of Example 37 according to a procedure similar to that of Example 13.

[0396] ESI-MS m / z = 519.57 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.31 -7.20 (m, 4H), 7.16 (td, J = 6.3, 2.7 Hz, 1H), 3.74 (d, J = 18.5 Hz, 1H), 2.78 (t, J = 7.0 Hz, 2H), 2.52 (t, J = 7.0 Hz, 2H), 2.43 (t, J = 13.2 Hz, 1H), 2.33 (ddd, J = 15.2, 9.8, 5.2 Hz, 1H), 2.19 (ddd, J = 15.6, 9.4, 6.7 Hz, 1H), 2.10 - 1.03 (m, 31H), 0.96 (t, J = 7.0 Hz, 4H), 0.86 (s, 4H), 0.68 (s, 3H).

[0397] Example 48

[0398]

[0399] The title compound (1.5 mg, 2.87 μmol, 23.15% yield, free base) was prepared as a white solid from the compound of Example 38 according to a procedure similar to that of Example 13.

[0400] ESI-MS m / z = 521.42 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.33 - 7.20 (m, 2H), 7.06 -6.89 (m, 3H), 4.78 (s, 2H), 3.76 (s, 1H), 2.48 (t, J = 13.3 Hz, 1H), 2.33 (ddd, J = 15.0, 9.8, 5.2 Hz, 1H), 2.19 (ddd, J = 15.7, 9.5, 6.8 Hz, 1H), 2.04 - 1.08 (m, 30H), 1.06 - 0.88 (m, 5H), 0.84 (s, 3H), 0.68 (s, 3H).

[0401] Example 49

[0402]

[0403] The title compound (1.5 mg, 2.87 μmol, 23.15% yield, free base) was prepared as a white solid from the compound of Intermediate 1 according to a procedure similar to that of Example 12. ESI-MS m / z = 561.26 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.30 - 7.22 (m, 4H), 7.21 - 7.15 (m, 1H), 4.85 (d, J = 3.1 Hz, 1H), 2.78 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.39 - 2.29 (m, 2H), 2.28 - 2.14 (m, 2H), 2.13 - 1.04 (m, 24H), 0.97 (d, J = 6.9 Hz, 7H), 0.71 (s, 3H).

[0404] Example 50

[0405]

[0406] The title compound (29 mg, 51.35 μmol, 72.49% yield, free base) was prepared as a white solid from the compound of Intermediate 1 according to a procedure similar to that of Example 12. ESI-MS m / z = 563.17 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.27 (dd, J = 8.8, 7.3 Hz, 2H), 7.02 - 6.86 (m, 3H), 4.93 (s, 1H), 4.75 (s, 2H), 3.09 (t, J = 14.4 Hz, 1H), 2.56 - 2.42 (m, 1H), 2.34 (ddd, J = 14.7, 9.1, 4.7 Hz, 4H), 2.27 - 1.11 (m, 17H), 1.07 (s, 3H), 0.97 (q, J = 3.7 Hz, 6H), 0.75 (s, 3H), 0.71 (d, J = 2.7 Hz, 3H).

[0407] Example 51

[0408]

[0409] The title compound (6 mg, 11.52 μmol, 64.84% yield, free base) was prepared as a white solid from the compound of Example 49 according to a procedure similar to that of Example 13.

[0410] ESI-MS m / z = 519.25 [MH] - . 1H NMR (400 MHz, CD3OD) δ 7.32 -7.21 (m, 4H), 7.18 (dd, J = 6.9, 2.4 Hz, 1H), 4.85 (s, 1H), 3.80 (d, J = 2.9 Hz, 1H), 2.78 (dt, J = 15.3, 7.4 Hz, 2H), 2.57 - 0.81 (m, 71H), 0.80 - 0.66 (m, 5H).

[0411] Example 52

[0412]

[0413] The title compound (5 mg, 9.57 μmol, 54.02% yield, free base) was prepared as a white solid from the compound of Example 50 according to a procedure similar to that of Example 13.

[0414] ESI-MS m / z = 521.42 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.34 - 7.21 (m, 2H), 6.99 - 6.91 (m, 3H), 4.71 (d, J = 2.4 Hz, 2H), 2.65 - 0.83 (m, 35H), 0.80 - 0.67 (m, 3H).

[0415] Example 53

[0416]

[0417] The title compound (4.5 mg, 7.53 μmol, 30.70% yield) was prepared as a white solid from the compound of Example 35 according to a procedure similar to that of Example 16. 1 HNMR (400 MHz, Methanol-d4) δ= 4.86-4.84 (m, 1H), 3.73 (d,J=1.2, 2H), 2.36 (s, 3H), 2.22-2.10 (m, 1H), 2.02 (s, 5H), 1.93-1.05 (m, 32H), 1.01-0.89 (m, 6H), 0.70 (s, 3H).1LCMS (ESI) calcd for [MH]- =596.82, found 596.47

[0418] Example 54

[0419]

[0420] The title compound (4.1 mg, 8.22 μmol, 45.61% yield, free base) was prepared as a white solid from the compound of Example 35 according to a procedure similar to that of Example 13.

[0421] 1 H NMR (400 MHz, Methanol-d4) δ= 3.79 (s, 1H), 2.71-2.58 (m,1H), 2.43-2.25 (m, 2H), 2.22-2.13 (m, 1H), 2.04-1.08 (m, 33H), 1.03-0.88 (m, 6H), 0.69 (s, 3H).LCMS (ESI) calcd for [MH] - =497.74, found 497.35

[0422] Example 55

[0423]

[0424] The title compound (15 mg, 29.14 μmol, 77.04% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 12. 1 H NMR (400 MHz, MeOD) δ 4.86-4.84 (m, 1H), 2.38-1.09 (m, 38H), 0.97-0.95 (m, 6H), 0.70 (s, 3H).

[0425] Example 56

[0426]

[0427] The title compound (29 mg, 52.75 μmol, 62.44% yield, free base) was prepared as a white solid from the compound of Example 35 according to a procedure similar to that of Example 6.

[0428] 1 H NMR (400 MHz, Methanol-d4) δ= 8.02-7.95 (m, 2H), 7.70-7.64 (m, 1H), 7.61-7.53 (m, 2H), 4.85-4.81 (m, 1H), 2.37 (d,J=14.2, 2H), 2.30-2.08 (m, 3H), 2.06-1.93 (m, 6H), 1.84-1.61 (m, 12H), 1.58-1.27 (m, 18H), 1.19 (s, 5H), 0.97 (d,J=7.5, 3H), 0.86 (d,J=6.3, 3H), 0.60 (s, 3H).

[0429] Example 57

[0430]

[0431] The title compound (4.2 mg, 6.58 μmol, 35.60% yield, free base) was prepared as a white solid from the compound of Example 20 according to a procedure similar to that of Example 6.

[0432] 1 H NMR (400 MHz, Methanol-d4) δ= 8.03-7.95 (m, 2H), 7.70-7.64 (m, 1H), 7.62-7.53 (m, 2H), 3.76 (d,J=2.8, 1H), 2.51-2.37 (m, 2H), 2.31-2.21 (m, 1H), 2.19-2.08 (m, 1H), 2.04-1.90 (m, 2H), 1.88-1.00 (m, 37H), 0.94 (s, 3H), 0.86 (d,J=6.4, 3H), 0.59 (s, 3H).

[0433] Example 58

[0434]

[0435] The title compound (100 mg, 194.27 μmol, 68.48% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 12. 1H NMR (400 MHz, Methanol-d4) δ= 4.86-4.83 (m, 1H), 2.40-2.26 (m, 1H), 2.26-2.12 (m, 2H), 2.11-1.94 (m, 5H), 1.95-1.73 (m, 4H), 1.73-1.25 (m, 14H), 1.26-1.07 (m, 12H), 1.02-0.87 (m, 6H), 0.70 (s, 3H).

[0436] Example 59

[0437]

[0438] The title compound (20 mg, 37.82 μmol, 78.96% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 12. 1 H NMR (400 MHz, MeOD) δ 4.86-4.84 (m, 1H), 2.38-1.09 (m, 37H), 0.97-0.90 (m, 9H), 0.70 (s, 3H).

[0439] Example 60

[0440]

[0441] The title compound (72.3 mg, 118.37 μmol, 77.85% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Chloroform-d) δ 7.61 - 7.51 (m, 4H), 7.50 - 7.41 (m, 4H), 7.39 -7.32 (m, 1H), 4.90 (q, J = 3.0 Hz, 1H), 2.50 (t, J = 13.9 Hz, 1H), 2.39 (ddd, J = 15.5, 10.1, 5.1 Hz, 1H), 2.26 (ddd, J = 15.9, 9.7, 6.4 Hz, 1H), 2.08 (s, 3H), 2.05 - 1.95 (m, 2H), 1.93 - 1.76 (m, 6H), 1.73 - 1.05 (m, 19H), 0.98 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H).

[0442] Example 61

[0443]

[0444] The title compound (40 mg, 63.81 μmol, 58.42% yield) is a white solid and was prepared from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 7.41 - 7.31 (m, 4H), 7.18 - 7.09 (m, 1H), 7.05 - 6.97 (m, 2H), 6.97 -6.85 (m, 2H), 4.89 (q, J = 3.1 Hz, 1H), 2.47 (t, J = 13.9 Hz, 1H), 2.38 (ddt, J = 14.4, 9.2, 4.9 Hz, 1H), 2.25 (ddd, J = 15.9, 9.7, 6.4 Hz, 1H), 2.06 (s, 3H), 2.02 - 1.94 (m, 2H), 1.89 - 1.75 (m, 6H), 1.70 - 1.03 (m, 18H), 0.97 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H).

[0445] Example 62

[0446]

[0447] The title compound (4 mg, 6.23 μmol, 16.66% yield, free base) was prepared as a white solid from the compound of Example 7 according to a procedure similar to that of Example 6.

[0448] 1 H NMR (400 MHz, CD3OD) δ 7.45 - 7.25 (m, 5H), 3.57 (m, 3H), 2.95 (m, 3H), 2.17 (m, 9H), 1.83 - 1.38 (m, 14H), 1.25 - 1.12 (m, 4H), 1.03 - 0.85 (m, 7H), 0.71 (s, 3H).

[0449] Example 63

[0450]

[0451] The title compound (10 mg, 16.08 μmol, 41.39% yield, free base) was prepared as a white solid from the compound of Example 58 according to a procedure similar to that of Example 6.

[0452] 1 H NMR (400 MHz, Methanol-d4) δ= 4.86-4.83 (m, 1H), 3.57 (t,J=6.9, 2H), 2.94 (t,J=6.9, 2H), 2.32-2.15 (m, 2H), 2.03 (d,J= 0.6, 5H), 1.92-1.28 (m, 25H), 1.26-1.14 (m, 11H), 1.02-0.88 (m, 6H), 0.70 (s, 3H).LCMS (ESI) calcd for [MH]-620.87, found620.45

[0453] Example 64

[0454]

[0455] The title compound (10 mg, 17.71 μmol, 51.24% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.36-7.15 (m, 2H), 7.01-6.73 (m, 2H), 4.84-4.74 (m, 1H), 3.79 (s, 3H), 2.42-0.83 (m, 40H), 0.71 (s, 3H).LCMS (ESI) calcd for [MH] - =563.75, found563.43

[0456] Example 65

[0457]

[0458] The title compound (60 mg, 106.24 μmol, 61.49% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.38-7.16 (m, 2H), 6.95-6.76 (m, 2H), 3.79 (s, 3H), 2.37-2.26 (m, 2H), 2.25-2.14 (m, 1H), 2.05 (s, 5H), 1.95-1.09 (m, 22H), 1.01 (s, 3H), 0.96 (d, J=6.5, 3H), 0.71 (s, 3H).LCMS (ESI) calcd for [MH] - =563.75, found563.43

[0459] Example 66

[0460]

[0461] The title compound (6 mg, 11.22 μmol, 47.36% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Methanol-d4) δ= 7.51-7.37 (m, 2H), 7.39-7.20 (m, 3H), 4.81-4.66 (m, 1H), 2.38-2.02 (m, 4H), 2.01-1.94 (m, 3H), 1.91-1.16 (m, 24H), 1.12 (t,J=9.6, 1H), 1.08-0.92 (m, 6H), 0.71 (s, 3H).LCMS (ESI) calcd for [MH] - =533.72found533.62

[0462] Example 67

[0463]

[0464] The title compound (60 mg, 112.21 μmol, 61.57% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.44-7.33 (m, 2H), 7.35-7.25 (m, 3H), 4.81-4.63 (m, 1H), 2.41-2.12 (m, 2H), 2.12-1.91 (m, 5H), 1.92-1.14 (m, 24H), 1.07-0.91 (m, 7H), 0.73 (s, 3H).LCMS (ESI) calcd for [MH] - =533.72found533.62

[0465] Example 68

[0466]

[0467] The title compound (32.7 mg, 53.53 μmol, 90.41% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Chloroform-d) δ 7.61 - 7.56 (m, 4H), 7.53 - 7.49 (m, 4H), 7.46 -7.40 (m, 1H), 7.39 (q, J = 3.0 Hz, 1H), 7.32 (t, J = 13.9 Hz, 1H), 7.29 (ddd, J = 7.7, 6.0, 2.9 Hz, 1H), 4.86 (ddd, J = 15.9, 9.7, 6.4 Hz, 1H), 2.22 (s, 3H), 2.04 - 1.96 (m, 2H), 1.93 - 1.76 (m, 3H), 1.90 - 1.27 (m, 20H), 1.19 (s, 3H), 1.02 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H).

[0468] Example 69

[0469]

[0470] The title compound (75.6 mg, 123.77 μmol, 96.67% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 7.66 - 7.64 (m, 4H), 7.59 -7.52 (m, 4H), 7.44 (t, J = 1.2 Hz, 1H), 4.90 (d, J = 3.1 Hz, 1H), 2.50 (t, J = 13.9 Hz, 1H), 2.44 (dddd, J = 2.07, 15.8, 2.04, 5.8 Hz, 4H), 1.72 - 1.03 (m, 20H), 0.98 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H).

[0471] Example 70

[0472]

[0473] The title compound (40 mg, 66.37 μmol, 90.96% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 4.89 (q, J = 3.1 Hz, 1H), 2.48 (t, J = 13.9 Hz, 1H), 2.43 - 2.20 (m, 3H), 2.06 (s, 3H), 2.00 (ddd, J = 12.7, 6.9, 2.6 Hz, 2H), 1.93 - 1.75 (m, 6H), 1.72 - 1.05 (m, 20H), 0.98 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0474] Example 71

[0475]

[0476] The title compound (196 mg, 325.19 μmol, 87.20% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.89 (d, J = 3.1 Hz, 1H), 2.47 - 2.20 (m, 3H), 2.06 (s, 3H), 2.04 - 1.96 (m, 2H), 1.92 - 1.79 (m, 5H), 1.79 - 1.02 (m, 19H), 0.99 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0477] Example 72

[0478]

[0479] (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (20 mg, 37.40 μmol) was dissolved in 2-methylpropan-2-ol (9.98 mL) and 10 mL of water, to which 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholine-4-ium chloride (15.53 mg, 56.10 μmol) was added, and the reaction mixture was 25 It was stirred at ℃ for 16 hours. Then, it was purified with C18 FLASH (MeOH:water = 0-100% for 1 hour) to obtain 2-[[(4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11

[0480] ,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethylphosphonic acid (6 mg, 9.35 μmol, 25.00% yield, free base) was obtained as a white solid. ESI-MS m / z = 640.77 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.35 (m, 5H), 4.87 - 4.86 (m, 1H), 3.49 - 3.37 (m, 2H), 2.27 - 2.16 (m, 1H), 2.05 (m, 6H), 1.77 (m, 17H), 1.34 (m, 9H), 1.05 - 0.93 (m, 6H), 0.71 (s, 3H).

[0481] Example 73

[0482]

[0483] The title compound (6 mg, 11.10 μmol, 51.30% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 12. 1H NMR (400 MHz, CD3OD) δ 4.72 (m, 1H), 2.37 - 1.88 (m, 9H), 1.79 - 1.23 (m, 32H), 1.16 - 0.91 (m, 8H), 0.74 (s, 3H).

[0484] Example 74

[0485]

[0486] The title compound (62 mg, 114.65 μmol, 84.81% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 12. 1 H NMR (400 MHz, CD3OD) δ 4.71 (d, J= 5.2 Hz, 1H), 2.40 - 1.92 (m, 7H), 1.92 - 0.93 (m, 41H), 0.72 (s, 3H).

[0487] Example 75

[0488]

[0489] The title compound (16 mg, 32.08 μmol, 57.83% yield, free base) was prepared as a white solid from the compound of Example 74 according to a procedure similar to that of Example 13.

[0490] 1 H NMR (400 MHz, CD3OD) δ 3.41 (s, 1H), 2.55 - 2.14 (m, 3H), 2.04 - 0.96 (m, 38H), 0.71 (s, 3H).

[0491] Example 76

[0492]

[0493] 1H NMR (400 MHz, CD3OD) δ 8.03 (dt, J = 8.3, 1.1 Hz, 3H), 7.62 (ddd, J = 8.4, 6.5, 1.3 Hz, 2H), 7.54 - 7.47 (m, 3H), 7.46 - 7.39 (m, 1H), 5.21 (d, J = 3.0 Hz, 1H), 3.11 (t, J = 14.2 Hz, 1H), 2.59 (td, J = 15.3, 14.1, 5.4 Hz, 2H), 2.37 - 1.15 (m, 45H), 1.12 (d, J = 0.9 Hz, 4H), 1.07 - 0.81 (m, 8H), 0.78 (d, J = 2.0 Hz, 3H), 0.74 (d, J = 2.4 Hz, 1H).

[0494] Example 77

[0495]

[0496] The title compound (196 mg, 325.19 μmol, 87.20% yield, free base) was prepared as a white solid from the compound of Example 66 according to a procedure similar to that of Example 13.

[0497] 1 H NMR (400 MHz, Methanol-d4) δ= 7.43-7.36 (m,2H), 7.36-7.27 (m, 3H), 3.49-3.43 (m, 1H), 2.36-2.15 (m, 3H), 2.10-1.18 (m,32H), 1.03-0.92 (m, 6H), 0.72 (s, 3H).

[0498] LCMS (ESI) calcd for [MH] - =491.69, found 491.35

[0499] Example 78

[0500]

[0501] The title compound (10 mg, 20.30 μmol, 55.69% yield, free base) was prepared as a white solid from the compound of Example 67 according to a procedure similar to that of Example 13.

[0502] 1 H NMR (400 MHz, Methanol-d4) δ= 7.41-7.34 (m, 2H), 7.35-7.22 (m, 3H), 3.49-3.35 (m, 1H), 2.39-2.23 (m, 1H), 2.25-2.11 (m, 1H), 2.12-1.98 (m, 1H), 1.97-0.81 (m, 36H), 0.71 (s, 3H).LCMS (ESI) calcd for [MH] - =491.69, found 491.35

[0503] Example 79

[0504]

[0505] (4R)-4-[(3S,5R,7S,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,

[0506] 7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (10 mg, 18.70 μmol) was dissolved in DMF (2.01 mL), HATU (14.22 mg, 37.40 μmol) was added, TEA (3.78 mg, 37.40 μmol, 5.21 μL) was added, and the reaction was stirred for 30 minutes. 2-aminoethanesulfonic acid (4.68 mg, 37.40 μmol) was added, and the reaction was stirred at 25 °C for 16 hours. The crude product was then concentrated under reduced pressure, and the crude product was purified by flash chromatography to obtain 2-[[(4R)-4-[(3S,5R,7S,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclocyclo

[0507] Penta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonic acid (3 mg, 4.67 μmol, 24.99% yield, free base) was obtained as a white solid. 1 HNMR (400 MHz, Methanol-d4) δ= 7.44-7.36 (m, 2H), 7.36-7.26 (m, 3H), 4.79-4.72 (m, 1H), 3.57 (t,J=6.9, 2H), 2.94 (dd,J=7.3, 6.5, 2H), 2.29-2.01 (m, 6H), 1.97 (s, 3H), 1.93-1.05 (m, 34H), 1.02 (s, 3H), 0.96 (d,J=6.5, 3H), 0.72 (s, 3H).LCMS (ESI) calcd for [MH] - 640.86.69 found 640.54.

[0508] Example 80

[0509]

[0510] The title compound (16 mg, 22.29 μmol, 54.45% yield, free base) was prepared as a white solid from the compound of Example 60 according to a procedure similar to that of Example 79.

[0511] 1 H NMR (400 MHz, Methanol-d4) δ 7.62 - 7.54 (m, 4H), 7.51 - 7.38 (m, 4H), 7.37 - 7.29 (m, 1H), 3.58 (s, 2H), 2.96 (s, 2H), 2.50 (t, J = 13.8 Hz, 1H), 2.23 (d, J = 12.4 Hz, 1H), 2.04 (s, 3H), 1.93 - 1.61 (m, 10H), 1.59 - 1.49 (m, 3H), 1.49 - 1.06 (m, 12H), 1.00 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.70 (s, 3H).

[0512] Example 81

[0513]

[0514] The title compound (5 mg, 6.81 μmol, 17.08% yield, free base) was prepared as a white solid from the compound of Example 61 according to a procedure similar to that of Example 79.

[0515] 1H NMR (400 MHz, Methanol-d4) δ 7.46 - 7.32 (m, 4H), 7.18 - 7.10 (m, 1H), 7.01 - 6.96 (m, 2H), 6.94 - 6.84 (m, 2H), 3.59 (s, 2H), 2.96 (s, 2H), 2.47 (t, J = 13.8 Hz, 1H), 2.31 - 2.06 (m, 3H), 2.03 (s, 4H), 1.94 - 1.61 (m, 10H), 1.52 (dd, J = 14.7, 6.6 Hz, 3H), 1.47 - 1.14 (m, 15H), 0.99 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.71 (s, 3H).

[0516] Example 82

[0517]

[0518] Step 82a.2,2-dimethylpropane oil chloride (89.41 mg, 741.51 μmol, 90.77 μL) was added sequentially under a nitrogen atmosphere to a pyridine (4.91 mL) solution of methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (100 mg, 247.17 μmol, free base). The resulting mixture was stirred at 70 °C for 16 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, the mixture was quenched with water. The aqueous phase was extracted three times with DCM, and the organic phase was combined and washed with water and brine, respectively. The mixture was then dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted with dichloromethane:methanol = 100:1 to 10:1. Methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-(2,2-dimethylpropaneoiloxy)-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (98 mg, 200.53 μmol, 81.13% yield, free base) was obtained as a yellow solid.

[0519] Step 82b.Butyllithium (2.4 M, 167.11 μL) was added sequentially under a nitrogen atmosphere to a THF (4.74 mL) solution of methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-(2,2-dimethylpropaneoiloxy)-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (98 mg, 200.53 μmol, free base) and ethinylbenzene (81.92 mg, 802.13 μmol, 88.09 μL, free base). The resulting mixture was stirred at -20 °C for 2 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, the mixture was quenched with water. The aqueous phase was extracted three times with DCM, and the organic phases were combined, washed with water and brine respectively, dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted with dichloromethane:methanol = 100:1 to 10:1. Methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-(2,2-dimethylpropaneoiloxy)-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]

[0520] Phenanthrene-17-yl]pentanoate (105 mg, 177.72 μmol, 88.62% yield, free base) was obtained as a white solid.

[0521] Step 82c.Lithium hydroxide hydrate (5.33 mg, 126.94 μmol, 3.53 μL) was added sequentially under a nitrogen atmosphere to a solution of methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-(2,2-dimethylpropaneoiloxy)-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (15 mg, 25.39 μmol, free base) dissolved in water (2 mL) and 1,4-dioxane (5 mL). The resulting mixture was stirred at 25 °C for 4 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, the aqueous phase was quenched with 1M HCl at 0°C, extracted three times with DCM, and the organic phase was combined, washed with water and brine respectively, dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted with dichloromethane:methanol = 100:1 to 10:1. (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-(2,2-dimethylpropaneoiloxy)-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (2.5 mg, 3.79 μmol, 14.92% yield, free base) was obtained as a white solid. ESI-MS m / z = 575.63 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.41 - 7.26 (m, 5H), 4.85 - 4.75 (s, 1H), 3.87 - 3.72 (m, 1H), 3.69 - 3.52 (m, 2H), 2.69 - 2.45 (m, 3H), 2.42 - 0.84 (m, 35H), 0.73 (s, 3H).

[0522] Example 83

[0523]

[0524] The title compound (3.3 mg, 5.46 μmol, 21.50% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 82. ESI-MS m / z = 575.36 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.42 - 7.35 (m, 2H), 7.35 - 7.26 (m, 3H), 4.85 - 4.75 (s, 1H), 2.42 - 1.27 (m, 18H), 1.23 (d, J = 0.9 Hz, 11H), 1.20 - 1.06 (m, 3H), 1.05 - 0.99 (m, 4H), 0.99 - 0.94 (m, 4H), 0.90 (t, J = 6.4 Hz, 1H), 0.72 (s, 3H).

[0525] Example 84

[0526]

[0527] The title compound (59 mg, 100.55 μmol, 71.07% yield, free base) is a white solid and was prepared from the compound of intermediate 1 according to a procedure similar to that of Example 27. ESI-MS m / z = 585.37 [MH]-. 1 H NMR (400 MHz, CD3OD) δ 7.65 - 7.50 (m, 6H), 7.40 (dd, J = 8.4, 6.9 Hz, 2H), 7.33 -7.27 (m, 1H), 4.89 (q, J = 3.0 Hz, 1H), 2.62 (t, J = 13.8) Hz, 1H), 2.32 (ddd, J = 15.1, 9.8, 5.2 Hz, 1H), 2.19 (ddd, J = 15.6, 9.4, 6.8 Hz, 1H), 2.13 - 1.08 (m, 26H), 1.05 (s, 3H), 0.96 (d, J) = 6.5 Hz, 3H), 0.71 (s, 3H).

[0528] Example 85

[0529]

[0530] The title compound (25.9 mg, 44.14 μmol, 78.00% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 27. ESI-MS m / z = 585.71 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.68 - 7.52 (m, 6H), 7.42 (dd, J = 8.3, 6.9 Hz, 2H), 7.35 - 7.27 (m, 1H), 4.88 (s, 1H), 2.52 (t, J = 13.9 Hz, 1H), 2.40 - 2.26 (m, 2H), 2.26 - 1.01 (m, 25H), 0.97 (d, J = 6.5 Hz, 4H), 0.84 (s, 3H), 0.69 (s, 3H).

[0531] Example 86

[0532]

[0533] The title compound (25.9 mg, 44.14 μmol, 78.00% yield, free base) was prepared as a white solid from the compound of Example 73 according to a procedure similar to that of Example 13.

[0534] 1 H NMR (400 MHz, CD3OD) δ 3.74 - 3.31 (m, 1H), 2.42 - 1.63 (m, 17H), 1.43 - 0.85 (m, 31H), 0.72 (s, 3H).

[0535] Example 87

[0536]

[0537] Acetyl acetate (152.44 mg, 1.49 mmol, 140.89 μL) and N,N-dimethylpyridine-4-amine (6.08 mg, 49.77 μmol) were added to a solution of (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-10,13-dimethyl-3-[2-[4-(trifluoromethyl)phenyl]ethynyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (30 mg, 49.77 μmol, free base) dissolved in pyridine (1 mL). The reaction mixture was 25 It was stirred at °C for 16 hours. It was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-3,7-diacetoxy-10,13-dimethyl-3-[2-[4-(trifluoromethyl)phenyl]

[0538] Ethinyl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (3 mg, 4.65 μmol, 9.35% yield, free base) was obtained as a white solid.

[0539] 1 H NMR (400 MHz, Chloroform-d) δ 7.74 (t, J = 4.9 Hz, 4H), 5.09 (d, J = 3.3 Hz, 1H), 2.64 - 2.41 (m, 5H), 2.34 - 2.14 (m, 11H), 2.10 - 1.94 (m, 7H), 1.90 - 1.78 (m, 3H), 1.75 - 1.42 (m, 16H), 1.31 (dt, J = 22.0, 10.6 Hz, 3H), 1.18 (s, 3H), 1.13 (d, J = 6.3 Hz, 3H), 0.85 (s, 3H).

[0540] Example 88

[0541]

[0542] The title compound (10 mg, 13.33 μmol, 54.30% yield) was prepared as a white solid from the compound of Example 68 according to a procedure similar to that of Example 6. 1 H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H), 8.09 - 8.01 (m, 2H), 7.96 - 7.91 (m, 1H), 7.68 - 7.63 (m, 1H), 7.61 - 7.49 (m, 5H), 7.46 - 7.33 (m, 5H), 4.85 (d, J = 3.0 Hz, 1H), 2.36 - 2.24 (m, 2H), 2.22 - 2.11 (m, 1H), 1.97 (t, J = 3.7 Hz, 1H), 1.93 (s, 3H), 1.77 - 1.42 (m, 14H), 1.37 - 1.01 (m, 13H), 0.93 (s, 3H), 0.87 (d, J = 6.2 Hz, 3H), 0.59 (s, 3H).

[0543] Example 89

[0544]

[0545] The title compound (9 mg, 9.70 μmol, 39.00% yield, free base) was prepared as a white solid from the compound of Example 70 according to a procedure similar to that of Example 6.

[0546] 1H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.08 - 8.00 (m, 2H), 7.98 - 7.91 (m, 3H), 7.60 - 7.46 (m, 5H), 4.88 (d, J = 3.1 Hz, 1H), 2.46 (t, J = 13.9 Hz, 1H), 2.36 - 2.12 (m, 3H), 2.05 (s, 3H), 2.03 - 1.47 (m, 19H), 1.34 - 1.02 (m, 13H), 0.97 (s, 3H), 0.84 (d, J = 6.3 Hz, 3H), 0.59 (s, 3H).

[0547] Example 90

[0548]

[0549] The title compound (1.3 mg, 2.25 μmol, 22.19% yield, free base) is a white solid and was prepared from the compound of Intermediate 1 according to a procedure similar to that of Example 4. ESI-MS m / z = 575.41 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.69 - 7.53 (m, 1H), 7.34 (dt, J = 7.5, 1.1 Hz, 1H), 7.33 - 7.23 (m, 1H), 7.12 (ddd, J = 7.7, 5.7, 3.0 Hz, 1H), 4.86 (s, 1H), 2.51 (t, J = 13.8 Hz, 1H), 2.40 - 2.25 (m, 2H), 2.20 (q, J = 7.6 Hz, 2H), 2.11 - 1.97 (m, 6H), 1.94 - 1.04 (m, 22H), 1.01 (d, J = 5.7 Hz, 3H), 0.97 (dd, J = 7.0, 2.3 Hz, 4H), 0.90 (t, J = 6.8 Hz, 2H), 0.72 (s, 3H).

[0550] Example 91

[0551]

[0552] The title compound (4 mg, 5.87 μmol, 81.65% yield) was prepared as a white solid from the compound of Intermediate 1 according to a procedure similar to that of Example 4. ESI-MS m / z = 679.64,681.45 (MH) - . 1 H NMR (400 MHz, Methanol-d4) δ 7.97 - 7.89 (m, 1H), 7.69 - 7.59 (m, 2H), 5.42 - 5.27 (m, 1H), 2.67 - 2.47 (m, 2H), 2.45 - 0.79 (m, 30H), 0.71 (s, 3H).

[0553] Example 92

[0554]

[0555] The title compound (4.6 mg, 7.63 μmol, 33.62% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ 7.73 - 7.47 (m, 4H), 2.51 - 1.95 (m, 9H), 1.92 - 1.33 (m, 29H), 1.18 (m, 3H), 1.02 - 0.91 (m, 8H), 0.71 (s, 3H).

[0556] Example 93

[0557]

[0558] The title compound (4.9 mg, 9.10 μmol, 67.94% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ 7.59 (d, J= 83.8 Hz, 2H), 3.85 (s, 3H), 2.46 - 1.30 (m, 24H), 1.21 (m, 3H), 1.03 - 0.91 (m, 6H), 0.71 (s, 3H).

[0559] Example 94

[0560]

[0561] The title compound (6.7 mg, 11.46 μmol, 52.77% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 7.86 (s, 2H), 7.67 - 7.37 (m, 4H), 2.63 (t,J= 13.4 Hz, 1H), 2.38 - 1.43 (m, 27H), 1.20 - 0.88 (m, 9H), 0.72 (s, 3H).

[0562] Example 95

[0563]

[0564] 1 H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.37 (m, 2H), 7.32 -7.27 (m, 3H), 4.88 (q, J = 3.1 Hz, 1H), 3.65 (s, 3H), 2.47 (t, J = 13.9 Hz, 1H), 2.34 (ddd, J = 15.3, 10.3, 5.1 Hz, 1H), 2.21 (ddd, J = 15.5, 9.7, 6.5 Hz, 1H), 2.06 (s, 3H), 2.02 - 1.95 (m, 2H), 1.89 - 1.74 (m, 7H), 1.69 - 1.46 (m, 6H), 1.43 - 1.05 (m, 10H), 0.97 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.65 (s, 3H).

[0565] Example 96

[0566]

[0567] The title compound (11 mg, 16.47 μmol, 62.39% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 7.43-7.29 (m, J = 27.6 Hz, 5H), 7.26 - 7.18 (m, 4H), 4.89 (d, J = 3.1 Hz, 1H), 2.51 - 2.34 (m, 2H), 2.26 (m, J = 15.6, 9.6, 6.3 Hz, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 2.02 - 1.94 (m, 2H), 1.88 - 1.77 (m, 5H), 1.62 (dd, J = 21.3, 11.6 Hz, 4H), 1.56 - 1.43 (m, 3H), 1.39 - 1.06 (m, 10H), 0.97 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H).

[0568] Example 97

[0569]

[0570] The title compound (3.7 mg, 6.14 μmol, 45.07% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, CD3OD) δ 7.81 - 7.38 (m, 4H), 2.60 - 0.95 (m, 39H), 0.71 (s, 3H).

[0571] Example 98

[0572]

[0573] The title compound (20 mg, 32.59 μmol, 68.19% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Methanol-d4) δ= 7.57-7.41 (m, 2H), 7.37-7.22 (m, 2H), 2.40-2.13 (m, 3H), 2.05 (s, 5H), 1.95-1.06 (m, 26H), 1.04-0.83 (m, 6H), 0.71 (s, 3H).

[0574] Example 99

[0575]

[0576] The title compound (15 mg, 24.45 μmol, 51.14% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ = 7.57 - 7.36 (m, 2H), 7.36 - 7.14 (m, 2H), 4.83 (s, 1H), 2.56 - 2.40 (m, 1H), 2.39 - 2.13 (m, 4H), 2.13 - 1.99 (m, 5H), 1.96 - 1.39 (m, 15H), 1.25 - 1.07 (m, 4H), 1.07 - 0.83 (m, 8H), 0.71 (s, 3H).

[0577] Example 100

[0578]

[0579] The title compound (8 mg, 13.04 μmol, 40.91% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Methanol-d4) δ= 7.54 (t,J=1.7, 1H), 7.48 (ddd,J=8.0, 2.1, 1.1, 1H), 7.36 (dt,J=7.8, 1.3, 1H), 7.24 (t,J=7.9, 1H), 2.47 (t,J=13.8, 1H), 2.39-2.13 (m, 3H), 2.04 (s, 5H), 1.94-1.05 (m, 30H), 1.05-0.80 (m, 7H), 0.71 (s, 3H).

[0580] Example 101

[0581]

[0582] The title compound (20 mg, 32.59 μmol, 68.19% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.61 (dd,J=8.0, 1.2, 1H), 7.45 (dd,J=7.7, 1.7, 1H), 7.31 (td,J=7.6, 1.2, 1H), 7.26-7.09 (m, 1H), 2.54 (t,J=13.8, 1H), 2.40-2.14 (m, 3H), 2.03 (d,J=6.9, 5H), 1.94-1.11 (m, 26H), 1.13-0.83 (m, 7H), 0.73 (d,J=11.1, 3H).

[0583] Example 102

[0584]

[0585] The title compound (13.6 mg, 24.08 μmol, 81.99% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. ESI-MS m / z = 563.27.[MH] - . 1H NMR (400 MHz, CD3OD) δ 7.35 -7.23 (m, 2H), 6.97 (dd, J = 8.4, 1.0 Hz, 1H), 6.88 (td, J = 7.5, 1.0 Hz, 1H), 4.88 (d, J = 2.9 Hz, 1H), 3.83 (s, 3H), 2.51 (t, J = 13.8 Hz, 1H), 2.33 (ddd, J = 15.2, 9.8, 5.2 Hz, 1H), 2.20 (ddd, J = 15.5, 9.4, 6.8 Hz, 1H), 2.05 (d, J = 14.0 Hz, 6H), 1.97 - 1.03 (m, 19H), 1.00 (s, 3H), 0.97 (dd, J = 6.5, 3.0 Hz, 4H), 0.71 (s, 3H).

[0586] Example 103

[0587]

[0588] The title compound (2.1 mg, 3.82 μmol, 35.89% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 4. ESI-MS m / z = 560.47. [M+H] + . 1 H NMR (400 MHz, CD3OD) δ7.14 (dd, J = 7.7, 1.6 Hz, 1H), 7.05 (ddd, J = 8.9, 7.3, 1.6 Hz, 1H), 6.73 (dd, J = 8.2, 1.1 Hz, 1H), 6.59 (td, J = 7.5, 1.1 Hz, 1H),4.87(s, 1H)2.52 (t, J = 13.8 Hz, 1H), 2.33 (ddd, J = 15.2, 9.8, 5.2 Hz, 1H), 2.19 (ddd, J = 15.6, 9.3, 6.7 Hz, 1H), 2.12 - 1.97 (m, 6H), 1.96 - 1.04 (m, 19H), 1.01 (s, 3H), 0.97 (dd, J = 7.1, 2.7 Hz, 3H), 0.88 (d, J = 6.6 Hz, 1H), 0.72 (s, 3H).

[0589] Example 104

[0590]

[0591] The title compound (9 mg, 14.59 μmol, 61.36% yield) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ 7.55 - 7.48 (m, 2H), 7.45 - 7.38 (m, 1H), 2.49 (s, 3H), 2.38 - 2.13 (m, 3H), 2.02 (d, J = 8.7 Hz, 4H), 1.94 - 1.05 (m, 29H), 1.01 (s, 3H), 0.98 - 0.93 (m, 3H), 0.71 (s, 3H).

[0592] Example 105

[0593]

[0594] The title compound (4.7 mg, 7.94 μmol, 80.19% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. ESI-MS m / z = 590.18 [MH] - .1H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 8.2 Hz, 1H), 7.44 - 7.36 (m, 1H), 7.35 -7.27 (m, 1H), 7.12 (t, J = 7.7 Hz, 1H), 4.84 (s, 1H), 2.50 (t, J = 13.8 Hz, 1H), 2.32 (ddd, J = 15.2, 9.8, 5.3 Hz, 1H), 2.25 - 2.13 (m, 4H), 2.12 - 1.97 (m, 6H), 1.96 - 1.05 (m, 20H), 1.01 (s, 3H), 0.96 (dd, J = 5.5, 3.9 Hz,3H), 0.71 (s, 3H).

[0595] Example 106

[0596]

[0597] The title compound (0.8 mg, 1.38 μmol, 27.31% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. ESI-MS m / z = 576.49 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.31 (dd, J = 7.5, 1.7 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.02 - 6.95 (m, 1H), 6.87 (td, J = 7.5, 1.1 Hz, 1H), 4.87 (d, J = 4.7 Hz, 1H), 2.89 (s, 6H), 2.51 (t, J = 14.0 Hz, 1H), 2.39 - 2.24 (m, 3H), 2.23 - 2.13 (m, 2H), 2.02 (s, 5H), 1.98 - 1.05 (m, 16H), 1.00 (d, J = 4.9 Hz, 3H), 0.97 (dd, J = 7.0, 2.4 Hz, 3H), 0.93 - 0.83 (m, 3H), 0.72 (s, 3H).

[0598] Example 107

[0599]

[0600] The title compound (8.6 mg, 15.36 μmol, 44.04% yield) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 11H NMR (400 MHz, CD3OD) δ 7.69 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 2.48 (t, J = 13.8 Hz, 1H), 2.39 - 2.23 (m, 1H), 2.18 (dt, J = 16.2, 8.1 Hz, 1H), 2.03 (s, 5H), 1.85 (ddt, J = 26.5, 15.9, 5.5 Hz, 6H), 1.74 - 1.33 (m, 13H), 1.27 - 1.06 (m, 5H), 1.00 (s, 3H), 0.96 (dd, J = 7.0, 2.3 Hz) (4H), 0.71 (s, 3H).

[0601] Example 108

[0602]

[0603] (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-ethynyl-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (20 mg, 43.61 μmol) in a THF (4.98 mL) solution containing iodocopper (1.66 mg, 8.72 μmol, 2.96e-1 μL), dichloropalladium triphenylphosphine (3.06 mg, 4.36 μmol), and N,N-diethylethanolamine (13.24 mg, 130.82 μmol, 18.23 μL) was added. The reaction mixture was stirred at 25 °C for 12 hours. It was diluted with EtOAc and washed with 50 mL of saturated aqueous NaCl solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. It was purified by chromatography (silica, DCM:MeOH = 1:100-1:20) to obtain (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-3-[2-(4-methoxycarbonylphenyl)ethynyl]-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (4.6 mg, 7.76 μmol (17.80% yield) was obtained. 1 H NMR (400 MHz, CD3OD) δ 8.07 - 7.89 (m, 2H), 7.55 - 7.36 (m, 2H), 3.90 (s, 3H), 2.49 (t, J = 13.8 Hz, 1H), 2.41 - 2.14 (m, 3H), 2.04 (s, 5H), 1.97 - 1.73 (m, 6H), 1.73 - 1.61 (m, 3H), 1.54 (d, J = 14.9 Hz, 4H), 1.50 - 1.37 (m, 5H), 1.26 - 1.09 (m, 4H), 1.00 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.71 (s, 3H).

[0604] Example 109

[0605]

[0606] The title compound (2 mg, 3.46 μmol, 81.89% yield, free base) is a white solid and was prepared from the compound of Example 108 according to a procedure similar to Step 27b. 1H NMR (400 MHz, CDCl3) δ 8.08–7.98 (m, 2H), 7.54–7.43 (m, 2H), 4.90 (d, J = 2.9 Hz, 1H), 2.54–2.42 (m, 2H), 2.42–2.20 (m, 4H), 2.06 (s, 3H), 1.98 (dd, J = 17.4, 10.4 Hz, 3H), 1.84 (q, J = 14.7, 11.9 Hz, 7H), 1.77–1.28 (m, 21H), 1.11 (dq, J = 26.2, 14.2, 11.8 Hz, 4H), 0.98 (s, 3H), 0.95 (dd, J = 6.9, 3.2 Hz, 3H), 0.67 (s, 3H).

[0607] Example 110

[0608]

[0609] Step 96a.To a solution of methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (50 mg, 123.58 μmol, free base) dissolved in pyridine (5 mL), benzoyl chloride (26.06 mg, 185.38 μmol) and N,N-dimethylpyridine-4-amine (30.20 mg, 247.17 μmol) were added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 16 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, the aqueous phase was quenched with water, extracted three times with DCM, the organic phase was combined and washed with water and brine respectively, dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted from dichloromethane:methanol = 100:1 to 10:1. [(5R,7R,8R,9S,10S,13R,14S,17R)-17-[(1R)-4-methoxy-1-methyl-4-oxo-butyl]-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-7-yl]benzoate (51 mg, 100.26 μmol, 81.13% yield, free base) was obtained as a white solid.

[0610] Step 96b.Butyllithium (2.4 M, 230.99 μL) was added sequentially under a nitrogen atmosphere to a solution of [(5R,7R,8R,9S,10S,13R,14S,17R)-17-[(1R)-4-methoxy-1-methyl-4-oxo-butyl]-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-7-yl]benzoate (141 mg, 277.18 μmol, free base) and ethinylbenzene (113.24 mg, 1.11 mmol, 121.76 μL, free base) dissolved in THF (4.65 mL). The resulting mixture was stirred at -20 °C for 2 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, it was quenched with water. The aqueous phase was extracted three times with DCM, the organic phase was combined, washed with water and brine respectively, dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted from dichloromethane:methanol = 100:1 to 10:1. [(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-17-[(1R)-4-methoxy-1-methyl-4-oxo-butyl]-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-7-yl]benzoate (35 mg, 57.30 μmol, 20.67% yield, free base) was obtained as a white solid and a chiral hydroxy isomer at position 3.

[0611] Step 96c. [(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-hydroxy-17-[(1R)-4-methoxy-1-methyl-4-oxo-butyl]-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]

[0612] Lithium hydroxide (3.53 mg, 147.34 μmol) was sequentially added under a nitrogen atmosphere to a solution of phenanthrene-7-yl]benzoate (30.00 mg, 49.11 μmol, free base) dissolved in THF (5 mL) and water (2 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, it was quenched with 1 M HCl at 0 °C. The aqueous phase was extracted three times with DCM. The organic phases were combined, washed with water and brine, dried with Na2SO4, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography and eluted from water to acetonitrile = 50:50 to 5:95. (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-benzoylyoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (7.9 mg, 13.24 μmol, 26.95% yield, free base) (retention Time: 6 min / 12 min) was obtained as a white solid. ESI-MS m / z = 595.35 [MH] - .1H NMR (400 MHz, CD3OD) δ 8.07 - 7.97 (m, 2H), 7.55 - 7.48 (m, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.34 - 7.25 (m, 3H), 7.25 - 7.17 (m, 2H), 5.17 (d, J = 3.1 Hz, 1H), 2.66 (t, J = 13.9 Hz, 1H), 2.35 - 2.24 (m, 1H), 2.22 - 2.14 (m, 2H), 2.07 (ddt, J = 11.6, 7.9, 4.8 Hz, 2H), 1.99 - 1.09 (m, 23H), 1.06 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.74 (s, 3H).

[0613] Example 111

[0614]

[0616] The title compound (9.7 mg, 16.82 μmol, 30.11% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 110. ESI-MS m / z = 575.62 [MH] - .1H NMR (400 MHz, CD3OD) δ7.37 (dtd, J = 5.4, 4.0, 2.3 Hz, 2H), 7.31 (dp, J = 5.3, 2.0 Hz, 3H), 4.91 (d, J = 3.2 Hz, 1H), 2.52 (t, J = 13.8) Hz, 1H), 2.32 (q, J = 7.7 Hz, 3H), 2.19 (ddd, J = 15.6, 9.5, 6.9 Hz, 1H), 2.11 - 2.01 (m, 2H), 1.95 - 1.06 (m, 25H), 1.01 (s, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.72 (s, 3H).

[0617] Example 112

[0618]

[0619] Step 112a. Methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-[2-(2-aminophenyl)ethynyl]-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]

[0620] N,N-dimethylpyridine-4-amine (1.30 mg, 10.64 μmol) was sequentially added under a nitrogen atmosphere to a solution of phenanthrene-17-yl]pentanoate (6 mg, 10.64 μmol, free base) and benzoyl chloride (4.49 mg, 31.93 μmol, free base) dissolved in THF (3 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction was monitored by HPLC-MS and TLC, and quenched with water after completion. The aqueous phase was extracted three times with DCM. The organic phases were combined, washed with water and brine, dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted with dichloromethane:methanol = 100:1 to 10:1. Methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-[2-(2-benzamidophenyl)ethynyl]-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (5.6 mg, 8.38 μmol, 78.78% yield, free base) was obtained as a white solid.

[0621] Step 112b. Methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-[2-(2-benzamidophenyl)ethynyl]-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta

[0622] Lithium hydroxide (602.41 μg, 25.15 μmol) was sequentially added under a nitrogen atmosphere to a solution of [a]phenanthrene-17-yl]pentanoate (5.6 mg, 8.38 μmol, free base) dissolved in THF (5 mL) and water (2 mL). The resulting mixture was stirred at 25 °C for 2 hours. The reaction was monitored by HPLC-MS and TLC, and after completion, it was quenched with 1 M HCl at 0 °C. The aqueous phase was extracted three times with DCM. The organic phases were combined, washed with water and brine, dried with Na2SO4, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography and eluted with dichloromethane:methanol = 100:1 to 10:1. (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-[2-(2-benzamidophenyl)ethynyl]-3-hydroxy-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta

[0623] [a]phenanthrene-17-yl]pentanoic acid (3.1 mg, 4.74 μmol, 56.54% yield, free base) was obtained as a white solid. ESI-MS m / z = 652.18. [MH] - .1H NMR (400 MHz, CD3OD) δ8.09 (s, 1H), 8.03 (s, 2H), 7.60 (d, J = 21.1 Hz, 3H), 7.48 (s, 1H), 7.40 (s, 1H), 7.19 (s, 1H), 4.87 (s, 1H), 2.46 (s, 1H), 2.33 (s, 1H), 2.21 (s, 1H), 2.13 - 1.05 (m, 25H), 1.00 (d, J = 5.9 Hz, 6H), 0.90 (s, 1H), 0.71 (s, 3H).

[0624] Example 113

[0625]

[0626] The title compound (1.8 mg, 2.84 μmol, yield 42.79%, free base) is a white solid and was prepared from the compound of intermediate 1 according to a procedure similar to that of Example 112. ESI-MS m / z = 632.58 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.84 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 7.7, 1.5 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 4.93 (s, 1H), 2.51 - 2.41 (m, 3H), 2.02 (s, 7H), 1.97 - 0.80 (m, 34H), 0.72 (s, 3H).

[0627] Example 114

[0628]

[0629] The title compound (4.7 mg, 7.86 μmol, yield 43.73%, free base) is a white solid and was prepared from the compound of Intermediate 1 according to a procedure similar to that of Example 110. ESI-MS m / z = 596.67 [MH] - . 1 H NMR (400 MHz, CD3OD) δ9.16 (dd, J = 2.2, 0.9 Hz, 1H), 8.68 (dd, J = 4.9, 1.7 Hz, 1H), 8.41 (dt, J = 8.0, 1.9 Hz, 1H), 7.43 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.32 - 7.26 (m, 3H), 7.25 - 7.20 (m, 2H), 5.20 (d, J = 3.1 Hz, 1H), 2.55 (t, J = 13.9 Hz, 1H), 2.29 (ddd, J = 15.1, 9.7, 5.3 Hz, 1H), 2.24 - 1.10 (m, 23H), 1.06 (s, 3H), 1.00 - 0.93 (m, 4H), 0.75 (s, 3H).

[0630] Example 115

[0631]

[0632] The title compound (2.1 mg, 3.51 μmol, 14.62% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 110. ESI-MS m / z = 596.27.[MH] - . 1 H NMR (400 MHz, CD3OD) δ 9.16 (dd, J = 2.2, 0.9 Hz, 1H), 8.77 (dd, J = 4.9, 1.7 Hz, 1H), 8.43 (dt, J = 7.9, 1.9 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.40 -7.33 (m, 2H), 7.30 (dt, J = 5.2, 1.7 Hz, 3H), 5.20 (d, J = 3.1 Hz, 1H), 2.34 (t, J = 13.1 Hz, 1H), 2.24 (d, J = 14.0 Hz, 2H), 2.19 - 1.11 (m, 22H), 1.08 (s, 3H), 0.97 (dd, J = 7.0, 2.0 Hz, 4H), 0.75 (s, 3H).

[0633] Example 116

[0634]

[0635] The title compound (16.6 mg, 27.82 μmol, 60.68% yield, free base) was prepared as a white solid according to a method similar to that of Example 110. ESI-MS m / z = 595.33. 1H NMR (400 MHz, CD3OD) δ 8.09 - 8.00 (m, 2H), 7.65 -7.58 (m, 1H), 7.51 (dd, J = 8.3, 7.0 Hz, 2H), 7.36 (ttd, J = 5.8, 3.9, 1.8 Hz, 2H), 7.30 (dp, J = 5.3, 2.0 Hz, 3H), 5.15 (q, J = 3.0 Hz, 1H), 2.41 (t, J = 13.2 Hz, 1H), 2.37 - 1.09 (m, 25H), 1.07 (s, 3H), 0.95 (d, J = 6.3 Hz, 3H), 0.73 (s, 3H).

[0636] Example 117

[0637]

[0638] The title compound (26.3 mg, 45.60 μmol, 72.81% yield, free base) was prepared as a white solid according to a method similar to that of Example 110. ESI-MS m / z = 575.82 [MH] - . 1 H NMR (400 MHz, CD3OD) δ 7.43 - 7.36 (m, 2H), 7.35 - 7.28 (m, 3H), 4.86 (d, J = 3.5 Hz, 1H), 2.46 - 1.07 (m, 31H), 1.02 (s, 3H), 0.99 - 0.91 (m, 7H), 0.70 (d, J = 6.4 Hz, 3H).

[0639] Example 118

[0640]

[0641] The title compound (8.5 mg, 14.49 μmol, 33.47% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 27. ESI-MS m / z = 585.65. 1H NMR (400 MHz, CD3OD) δ 7.76 (td, J = 1.9, 0.6 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.49 - 7.38 (m, 5H), 7.36 -7.30 (m, 1H), 4.91 (d, J = 3.0 Hz, 1H), 2.67 (t, J = 13.8 Hz, 1H), 2.34 (ddd, J = 15.1, 9.8, 5.3 Hz, 1H), 2.20 (ddd, J = 15.7, 9.4, 6.8 Hz, 1H), 2.15 - 1.10 (m, 26H), 1.07 (d, J = 2.8 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 3.6 Hz, 3H).

[0642] Example 119

[0643]

[0644] The title compound (10.4 mg, 17.72 μmol, 32.27% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 27. ESI-MS m / z = 585.62. 1 H NMR (400 MHz, CD3OD) δ 7.88 (dd, J = 8.1, 1.3 Hz, 1H), 7.49 -7.30 (m, 6H), 7.19 (td, J = 7.4, 1.3 Hz, 1H), 6.95 (dd, J = 7.5, 1.5 Hz, 1H), 4.84 (q, J = 3.3 Hz, 1H), 2.49 (t, J = 13.6 Hz, 1H), 2.38 (ddd, J = 15.0, 9.5, 5.2 Hz, 1H), 2.24 (ddd, J = 15.5, 9.2, 6.9 Hz, 1H), 2.07 (s, 3H), 2.04 - 1.02 (m, 23H), 0.99 (d, J = 6.4 Hz, 3H), 0.89 (s, 3H), 0.64 (s, 3H).

[0645] Example 120

[0646]

[0647] The title compound (5.6 mg, 9.54 μmol, 40.96% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 27. ESI-MS m / z = 585.325. 1 H NMR (400 MHz, CD3OD) δ 7.58 (dd, J = 8.0, 1.4 Hz, 1H), 7.42 -7.22 (m, 7H), 7.10 (dd, J = 7.4, 1.7 Hz, 1H), 4.71 (d, J = 3.1 Hz, 1H), 2.31 (ddd, J = 15.2, 9.8, 5.3 Hz, 1H), 2.17 (ddd, J = 15.8, 9.5, 7.0 Hz, 2H), 2.09 - 0.83 (m, 32H), 0.76 (s, 3H), 0.66 (s, 3H).

[0648] Example 122

[0649]

[0650] The title compound (4.7 mg, 7.93 μmol, 27.97% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 108. 1 H NMR (400 MHz, CD3OD) δ 7.61 - 7.49 (m, 3H), 7.46 - 7.36 (m, 1H), 3.90 (s, 3H), 2.62 - 1.56 (m, 24H), 1.24 - 0.89 (m, 12H), 0.71 (s, 3H).

[0651] Example 123

[0652]

[0653] Step 113a.Ethinylbenzene (24.29 mg, 237.79 μmol, 26.11 μL) was dissolved in THF (4 mL), and the reaction was stirred at -78 °C after dissolving in THF (4 mL). n-butyl lithium (2.4 M, 49.58 μL) was added, and the reaction was stirred at -78 °C for 30 minutes. Methyl (4R)-4-[(5R,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-diacetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (60 mg, 118.89 μmol) was added to the reaction, and the mixture was stirred at -78 °C for 5 hours. After the reaction was complete, an ammonium chloride solution was added to the reaction, and the mixture was extracted with DCM. The DCM layers were combined, washed, dried, and evaporated to obtain the crude product. The crude product was purified by column chromatography to obtain methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-diacetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]

[0654] Phenanthrene-17-yl]pentanoate (10 mg, 16.48 μmol, yield 13.86%, free base) methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-diacetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,

[0655] 6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoate (40 mg, 65.92 μmol, yield 55.45%, free base) was obtained as a white solid and a chiral hydroxy isomer at position 3 was obtained.

[0656] Step 113b.Methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-diacetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (10 mg, 16.48 μmol) was dissolved in methanol (3 mL) and water (3 mL), and sodium hydroxide (6.59 mg, 164.80 μmol, 3.09 μL) was added. The reaction was stirred at 25 °C for 3 hours, acidified with a diluted HCl solution, and then extracted with DCM. The DCM layers were combined, washed, dried, and evaporated to obtain a crude product. The crude product was purified by column chromatography to obtain (4R)-4-[(3S,5R,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-diacetoxy-3-hydroxy-10,13-dimethyl-3-(2-phenylethynyl)-1,2,4,5,

[0657] 6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid (3 mg, 5.06 μmol, 30.71% yield) was obtained. 1 H NMR (400 MHz, Methanol-d4) δ= 7.42-7.34 (m, 2H), 7.34-7.22 (m, 3H), 5.10 (s, 1H), 4.92 (s, 1H), 2.44 (d,J=13.6, 1H), 2.36-2.14 (m, 4H), 2.14-1.95 (m, 9H), 1.93-1.10 (m, 31H), 0.99 (s, 3H), 0.88-0.82 (m, 3H), 0.80 (s, 3H).

[0658] Example 124

[0659]

[0660] The title compound (20 mg, 33.74 μmol, 68.24% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 123.1 H NMR (400 MHz, Methanol-d4) δ= 7.41-7.34 (m, 2H), 7.31 (dt,J=5.0, 1.8, 3H), 5.10 (s, 1H), 4.92 (d,J=3.3, 1H), 2.30 (d,J=13.4, 5H), 2.09 (d,J=11.2, 7H), 2.04-1.84 (m, 3H), 1.84-1.09 (m, 24H), 1.01 (s, 3H), 0.84 (d,J=6.5, 3H), 0.80 (s, 3H).

[0661] Example 125

[0662]

[0663] The title compound (8 mg, 11.79 μmol, 40.83% yield) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.81 (d,J=8.0, 2H), 7.74 (d,J=8.3, 2H), 7.54 (dt,J=7.5, 1.1, 1H), 7.47-7.40 (m, 2H), 7.37 (ddd,J=7.6, 5.4, ​​3.4, 1H), 4.83 (d,J=3.0, 1H), 2.44-2.13 (m, 4H), 2.13-1.94 (m, 3H), 1.94-1.19 (m, 30H), 1.18-1.04 (m, 2H), 0.98 (d,J=6.6, 6H), 0.71 (s, 3H).

[0664] Example 127

[0665]

[0666] The title compound (10.4 mg, 17.72 μmol, 32.27% yield, free base) was prepared as a white solid from the compound of intermediate 1 according to a procedure similar to that of Example 27. ESI-MS m / z = 585.45. 1H NMR (400 MHz, CD3OD) δ 7.88 (dd, J = 8.1, 1.3 Hz, 1H), 7.49 -7.30 (m, 6H), 7.19 (td, J = 7.4, 1.3 Hz, 1H), 6.95 (dd, J = 7.5, 1.5 Hz, 1H), 4.84 (q, J = 3.3 Hz, 1H), 2.49 (t, J = 13.6 Hz, 1H), 2.38 (ddd, J = 15.0, 9.5, 5.2 Hz, 1H), 2.24 (ddd, J = 15.5, 9.2, 6.9 Hz, 1H), 2.07 (s, 3H), 2.04 - 1.02 (m, 23H), 0.99 (d, J = 6.4 Hz, 3H), 0.89 (s, 3H), 0.64 (s, 3H).

[0667] Example 128

[0668]

[0669] The title compound (10 mg, 18.74 μmol, 40.07% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, Chloroform-d) δ 7.40 (dd, J = 6.7, 3.1 Hz, 2H), 7.33 -7.28 (m, 3H), 5.73 (s, 2H), 4.89 (d, J = 3.1 Hz, 1H), 2.48 (t, J = 13.9 Hz, 1H), 2.31 (ddd, J = 12.6, 10.6, 5.0 Hz, 1H), 2.20 - 2.09 (m, 1H), 2.07 (s, 3H), 2.03 - 1.96 (m, 2H), 1.91 - 1.76 (m, 5H), 1.70 - 1.08 (m, 20H), 0.98 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0670] Example 129

[0671]

[0672] The title compound (15 mg, 21.74 μmol, 46.50% yield, free base) was prepared as a yellow solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, Methanol-d4) δ8.38 (s, 1H), 7.86 (d, J = 24.6 Hz, 2H), 7.50 (d, J = 23.0 Hz, 1H), 7.34 (d, J = 25.8 Hz, 5H), 2.51-2.26 (m, 4H), 2.03 (s, 4H), 1.97 - 1.25 (m, 30H), 1.01 (s, 6H), 0.72 (s, 3H).

[0673] Example 130

[0674]

[0675] The title compound (10 mg, 14.84 μmol, 39.67% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 - 8.02 (m, 2H), 7.67 - 7.59 (m, 1H), 7.57 - 7.48 (m, 2H), 7.42 -7.34 (m, 2H), 7.29 (dd, J = 5.0, 2.0 Hz, 3H), 4.87 (d, J = 3.1 Hz, 1H), 2.46 (t, J = 13.9 Hz, 1H), 2.29 (ddd, J = 15.1, 10.0, 4.9 Hz, 1H), 2.16 (ddd, J = 15.5, 9.3, 6.4 Hz, 1H), 2.04 (d, J = 2.8 Hz, 3H), 2.00 - 1.47 (m, 18H), 1.35 - 1.03 (m, 12H), 0.96 (s, 3H), 0.83 (d, J = 6.2 Hz, 3H), 0.58 (s, 3H).

[0676] Example 131

[0677]

[0678] The title compound (10 mg, 19.66 μmol, 77.68% yield, free base) is a white solid and was prepared from the compound of Example 124 according to a method similar to that of Example 13. 1 H NMR (400 MHz, MeOD) δ7.39-7.37 (m, 2H), 7.32-7.29 (m, 3H), 3.96 (s, 1H), 3.82-3.79 (m, 1H), 2.63 (t, J = 14.0 Hz, 1H), 2.38-1.10 (m, 23H), 1.02 (d, J = 6.4 Hz, 3H), 0.98 (m, 3H), 0.72 (s, 3H).

[0679] Example 132

[0680]

[0681] The title compound (3 mg, 5.90 μmol, 87.40% yield, free base) is a white solid and was prepared from the compound of Example 123 according to a method similar to that of Example 13. 1 H NMR (400 MHz, MeOD) δ7.35-7.32 (m, 2H), 7.30-7.28 (m, 3H), 3.97-3.96 (m, 1H), 3.83-3.81 (m, 1H), 2.82 (t, J = 15.2 Hz, 1H), 2.33-1.13 (m, 23H), 1.01 (d, J = 6.4 Hz, 3H), 0.96 (m, 3H), 0.72 (s, 3H).

[0682] Example 133

[0683]

[0684] Step 133a.Butyllithium (0.14 ml, 2.19 mmol) was added to a THF (10 mL) solution of 1-bromo-4-(4-methoxyphenyl)benzene (88.37 mg, 335.86 μmol) at -78 °C and stirred for 0.5 hours. Then, methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradeca

[0685] Hydrocyclopenta[a]phenanthrene-17-yl]pentanoate (100 mg, 223.91 μmol) was dissolved in THF (2 mL) and added under N2 protection. The reaction mixture was stirred under N2 protection from -78 °C to room temperature for 24 hours. This was diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography and methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-3-[4-(4-methoxyphenyl)phenyl]-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (24 mg, 38.04 μmol, 16.99% yield, free base) was obtained as a white solid. And methyl (4R)-4-[(3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-3-[4-(4-methoxyphenyl)phenyl]-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro

[0686] Cyclopenta[a]phenanthren-17-yl]pentanoate (6 mg, 9.51 μmol, 4.25% yield, free base) and a chiral hydroxy isomer at position 3 were obtained.

[0687] Step 133b.Methyl (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-3-[4-(4-methoxyphenyl)phenyl]-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]

[0688] Lithium hydroxide (4.56 mg, 190.22 μmol) was added to a 10 mL methanol solution of phenanthrene-17-yl]pentanoate (24 mg, 38.04 μmol, free base) and stirred at 25 °C for 16 hours. Then, after evaporating at 40 °C and adjusting the pH to 3, (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-3-hydroxy-3-[4-(4-methoxyphenyl)phenyl]-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradeca

[0689] Hydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (14 mg, 22.70 μmol, 59.66% yield, free base) was obtained as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.54 (m, 6H), 6.97 (m, 2H), 3.82 (s, 3H), 2.71 - 1.43 (m, 27H), 1.07 (s, 6H), 0.97 (m, 3H), 0.73 (s, 3H).

[0690] Example 134

[0691]

[0692] The title compound (4.5 mg, 7.21 μmol, 25.52% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 133. 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 8.11 (m, 1H), 7.71 - 7.56 (m, 4H), 7.52 (s, 1H), 2.64 (m, 1H), 2.40 - 1.69 (m, 17H), 1.46 (m, 15H), 1.11 - 0.94 (m, 6H), 0.74 (s, 3H).

[0693] Example 135

[0694]

[0695] The title compound (9.6 mg, 16.28 μmol, 46.80% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 501.61.1H NMR (400 MHz, CD3OD) δ 7.51 - 7.44 (m, 2H), 7.44 - 7.39 (m, 2H), 4.89 (d, J = 3.2 Hz, 1H), 2.53 (t, J = 13.9 Hz, 1H), 2.34 (ddd, J = 15.2, 9.8, 5.3 Hz, 1H), 2.21 (ddd, J = 15.7, 9.4, 6.9 Hz, 1H), 2.14 - 1.10 (m, 25H), 1.06 (d, J = 5.2 Hz, 3H), 0.97 (d, J = 6.5 Hz, 4H), 0.74 (d, J = 5.9 Hz, 3H).

[0696] Example 136

[0697]

[0698] The title compound (12 mg, 22.36 μmol, 61.57% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 12. 1H NMR (400 MHz, Methanol-d4) δ= 9.07 (s, 1H), 8.80 (s, 2H), 4.82 (s, 1H), 2.36 (s, 3H), 2.13-1.09 (m, 27H), 1.08-0.85 (m, 6H), 0.71 (s, 3H).

[0699] Example 137

[0700]

[0701] The title compound (10 mg, 17.01 μmol, 51.19% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, Methanol-d4) δ= 8.74 (dd,J=2.5, 0.8, 1H), 8.00 (dd,J=8.4, 2.4, 1H), 7.95-7.90 (m, 2H), 7.83 (dd,J=8.3, 0.8, 1H), 7.51-7.40 (m, 3H), 4.92 (s, 1H), 2.67-2.56 (m, 1H), 2.39-1.13 (m, 39H), 1.08 (s, 3H), 0.98 (d,J=6.5, 3H), 0.74 (s, 3H).

[0702] Example 138

[0703]

[0704] The title compound (40 mg, 67.36 μmol, 81.89% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. 1H NMR (400 MHz, Chloroform-d) δ 7.36 - 7.30 (m, 2H), 6.91 (s, 2H), 4.83 (q, J = 3.0 Hz, 1H), 2.41 - 2.19 (m, 3H), 2.07 - 1.91 (m, 5H), 1.82 (s, 3H), 1.78 - 1.69 (m, 5H), 1.62 - 1.10 (m, 20H), 1.02 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.66 (s, 3H).

[0705] Example 139

[0706]

[0707] The title compound (18 mg, 33.66 μmol, 52.25% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, DMSO-d6) δ 7.55 - 7.28 (m, 4H), 4.74 (s, 1H), 4.09 (s, 1H), 2.37 (t, J = 13.6 Hz, 1H), 2.25 - 2.02 (m, 2H), 2.02 - 1.89 (m, 2H), 1.85 (s, 5H), 1.78 - 1.48 (m, 6H), 1.39 - 1.24 (m, 6H), 1.21 - 0.98 (m, 6H), 0.95 (s, 3H), 0.87 (d, J = 6.4 Hz, 3H), 0.62 (s, 3H).

[0708] Example 140

[0709]

[0710] The title compound (5 mg, 8.29 μmol, 25.58% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. 1H NMR (400 MHz, Chloroform-d) δ 7.45 (dd, J = 9.2, 2.5 Hz, 2H), 7.33 (tt, J = 7.4, 2.1 Hz, 2H), 7.15 - 7.07 (m, 1H), 7.05 - 6.93 (m, 4H), 4.90 (t, J = 3.4 Hz, 1H), 2.56 (dd, J = 15.8, 11.9 Hz, 1H), 2.43 - 2.21 (m, 3H), 2.09 - 1.74 (m, 11H), 1.67 - 1.15 (m, 17H), 1.03 (s, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.67 (s, 3H).

[0711] Example 141

[0712]

[0713] The title compound (10 mg, 15.68 μmol, 41.92% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.48 - 7.36 (m, 2H), 7.32 -7.28 (m, 3H), 4.89 (d, J = 3.1 Hz, 1H), 2.94 (tt, J = 8.0, 4.8 Hz, 1H), 2.48 (t, J = 13.9 Hz, 1H), 2.37 (ddt, J = 14.5, 8.9, 4.7 Hz, 1H), 2.27 - 2.18 (m, 1H), 2.06 (s, 3H), 2.03 - 1.02 (m, 25H), 0.97 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H), 0.66 (s, 3H).

[0714] Example 142

[0715]

[0716] The title compound (10 mg, 17.07 μmol, 31.03% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, Chloroform-d) δ9.28 (s, 1H), 8.56 (s, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.94 (dt, J = 8.2, 1.1 Hz, 1H), 7.83 (dd, J = 7.3, 1.2 Hz, 1H), 7.56 (dd, J = 8.3, 7.2 Hz, 1H), 4.91 (q, J = 3.0 Hz, 1H), 2.60 (t, J = 13.7 Hz, 1H), 2.39 (ddt, J = 14.3, 8.8, 4.6 Hz, 1H), 2.26 (ddd, J = 15.9, 9.9, 6.4 Hz, 1H), 2.06 (s, 3H), 2.02 - 1.06 (m, 26H), 1.00 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.66 (s, 3H).

[0717] Example 143

[0718]

[0719] The title compound (2 mg, 3.39 μmol, 9.75% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, CD3OD) δ 7.85 (m, 2H), 7.49 (m, 4H), 3.91 (s, 3H), 2.35 - 1.30 (m, 32H), 1.10 - 0.94 (m, 6H), 0.73 (s, 3H).

[0720] Example 144

[0721]

[0722] The title compound (2.5 mg, 4.49 μmol, 19.72% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 12.1 H NMR (400 MHz, CD3OD) δ 2.70 (m, 2H), 2.44 - 1.03 (m, 35H), 1.02 - 0.92 (m, 6H), 0.70 (s, 3H).

[0723] Example 145

[0724]

[0725] The title compound (4.1 mg, 7.53 μmol, 22.08% yield, free base) was prepared from the compound of Example 84 according to a procedure similar to that of Example 13. ESI-MS m / z = 543.26. 1 H NMR (400 MHz, CD3OD) δ 7.63 - 7.51 (m, 6H), 7.45 - 7.38 (m, 2H), 7.34 - 7.27 (m, 1H), 3.84 (d, J = 2.9 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.35 (ddd, J = 15.1, 9.8, 5.2 Hz, 1H), 2.21 (ddd, J = 15.5, 9.3, 6.7 Hz, 1H), 2.12 - 1.07 (m, 23H), 1.05 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.73 (s, 3H).

[0726] Example 146

[0727]

[0728] The title compound (13 mg, 19.85 μmol, 49.18% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 653.62. 1H NMR (400 MHz, CD3OD) δ 7.63 - 7.52 (m, 7H), 7.46 - 7.38 (m, 2H), 7.34 - 7.28 (m, 1H), 3.85 (d, J = 2.9 Hz, 1H), 2.94 - 2.83 (m, 1H), 2.35 (ddd, J = 15.1, 9.8, 5.2 Hz, 1H), 2.21 (ddd, J = 15.5, 9.3, 6.7 Hz, 1H), 2.13 - 1.08 (m, 27H), 1.05 (s, 3H), 0.98 (d, J = 6.5 Hz, 4H), 0.73 (s, 3H).

[0729] Example 147

[0730]

[0731] The title compound (7.5 mg, 12.20 μmol, 59.01% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 4. ESI-MS m / z = 613.73. 1 H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.44 (dt, J = 7.7, 1.4 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.22 -7.12 (m, 1H), 4.87 (s, 1H), 3.96 (d, J = 1.2 Hz, 3H), 2.47 (t, J = 13.8 Hz, 1H), 2.33 (ddd, J = 15.2, 9.8, 5.4 Hz, 1H), 2.20 (ddd, J = 15.5, 9.2, 6.7 Hz, 1H), 2.05 (td, J = 10.0, 4.5 Hz, 2H), 1.96 - 1.05 (m, 24H), 1.02 (d, J = 1.2 Hz, 3H), 0.97 (dd, J = 6.5, 1.2 Hz, 3H), 0.72 (d, J = 1.2) Hz, 3H).

[0732] Example 148

[0733]

[0734] The title compound (20 mg, 36.32 μmol, 11.64% yield) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.42-7.34 (m, 2H), 7.31 (dq,J=4.4, 1.4, 3H), 3.99 (s, 1H), 2.48-2.14 (m, 5H), 2.07 (s, 4H), 1.96 (dd,J=12.1, 7.5, 1H), 1.91-1.25 (m, 21H), 1.15 (dd,J=16.2, 7.7, 2H), 1.07-0.93 (m, 6H), 0.73 (s, 3H).

[0735] Example 149

[0736]

[0737] The title compound (20 mg, 36.32 μmol, 11.64% yield) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Methanol-d4) δ= 7.42-7.34 (m, 2H), 7.31 (dq,J=4.4, 1.4, 3H), 3.99 (s, 1H), 2.48-2.14 (m, 5H), 2.07 (s, 4H), 1.96 (dd,J=12.1, 7.5, 1H), 1.91-1.25 (m, 21H), 1.15 (dd,J=16.2, 7.7, 2H), 1.07-0.93 (m, 6H), 0.73 (s, 3H).

[0738] Example 150

[0739]

[0740] The title compound (10 mg, 17.07 μmol, 56.89% yield) was prepared as a white solid according to a procedure similar to that of Example 4. 1H NMR (400 MHz, DMSO-d) δ9.30 (s, 1H), 8.58 (s, 1H), 8.17 (dd, J = 11.0, 8.3 Hz, 2H), 7.89 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.76 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 5.36 (s, 1H), 4.78 (s, 1H), 2.18 (s, 1H), 2.06 (d, J = 14.6 Hz, 1H), 1.98 (d, J = 10.2 Hz, 5H), 1.88 - 1.46 (m, 10H), 1.46 - 0.98 (m, 14H), 0.93 (s, 3H), 0.85 (d, J = 6.4 Hz, 4H), 0.61 (s, 3H).

[0741] Example 152

[0742]

[0743] The title compound (6 mg, 9.81 μmol, 34.10% yield) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 8.58 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.67 - 7.52 (m, 1H), 7.53 - 7.34 (m, 4H), 4.85 (s, 1H), 2.50 - 2.21 (m, 3H), 1.94 (d, J = 1.5 Hz, 3H), 1.86 - 1.03 (m, 23H), 0.93 (t, J = 2.0 Hz, 6H), 0.64 (d, J = 1.5 Hz, 3H).

[0744] Example 154

[0745]

[0746] The title compound (16.6 mg, 26.75 μmol, 14.68% yield) was prepared as a white solid according to a procedure similar to that of Example 133. 1H NMR (400 MHz, CD3OD) δ 7.65 (t, J = 1.8 Hz, 1H), 7.44 (dt, J = 7.5, 1.4 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.31 -7.18 (m, 1H), 2.56 (t, J = 13.8 Hz, 1H), 2.34 (ddd, J = 15.1, 9.7, 5.2 Hz, 1H), 2.20 (ddd, J = 15.5, 9.3, 6.8 Hz, 1H), 2.07 (ddd, J = 12.8, 8.8, 4.8 Hz, 2H), 1.95 (d, J = 1.1 Hz, 4H), 1.89 (d, J = 7.2 Hz, 2H), 1.85 - 1.62 (m, 5H), 1.62 - 1.28 (m, 12H), 1.05 (d, J = 1.3 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.73 (s, 3H).

[0747] Example 158

[0748]

[0749] The title compound (1.7 mg, 2.34 μmol, 6.87% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 7.72 (m, 14H), 2.61 (s, 1H), 1.98 (m, 23H), 1.06 (s, 4H), 0.89 (m, 7H), 0.64 (s, 3H).

[0750] Example 159

[0751]

[0752] The title compound (4.7 mg, 6.20 μmol, 16.58% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1H NMR (400 MHz, CD3OD) δ 8.09 (m, 2H), 7.62 - 7.24 (m, 7H), 2.53 - 1.49 (m, 24H), 1.22 - 0.79 (m, 12H), 0.62 (s, 3H).

[0753] Example 160

[0754]

[0755] The title compound (11.2 mg, 19.83 μmol, 63.77% yield) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 1.5 Hz, 1H), 7.29 (q, J = 1.4 Hz, 3H), 4.57 (s, 2H), 2.48 (t, J = 13.8 Hz, 1H), 2.41 - 2.12 (m, 3H), 2.04 (s, 5H), 1.94 - 1.83 (m, 3H), 1.83 - 1.73 (m, 3H), 1.73 - 1.29 (m, 15H), 1.24 - 1.07 (m, 3H), 1.00 (s, 3H), 0.96 (d, J = 6.5 Hz, 3H), 0.71 (s, 3H).

[0756] Example 163

[0757]

[0758] The title compound (2.5 mg, 4.08 μmol, 10.91% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 7.41 - 7.08 (m, 5H), 2.27 - 1.36 (m, 36H), 1.04 - 0.90 (m, 6H), 0.71 (s, 3H).

[0759] Example 164

[0760]

[0761] The title compound (6.5 mg, 8.76 μmol, 23.42% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 7.68 (m, 9H), 2.17 - 0.86 (m, 33H), 0.59 (s, 3H).

[0762] Example 165

[0763]

[0764] The title compound (6.3 mg, 8.37 μmol, 22.38% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 7.75 (d, 4H), 7.34 (s, 5H), 2.47 (s, 1H), 2.20 - 1.03 (m, 32H), 0.99 (s, 3H), 0.88 (d,J= 6.4 Hz, 3H), 0.61 (s, 3H).

[0765] Example 166

[0766]

[0767] The title compound (3.8 mg, 6.91 μmol, 24.36% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 82. ESI-MS m / z = 548.34. 1H NMR (400 MHz, CD3OD) δ 7.42 - 7.35 (m, 2H), 7.35 - 7.28 (m, 3H), 4.73 (s, 1H), 2.81-2.62 (m, 4H), 2.45 - 0.81 (m, 30H), 0.74 (s, 1H), 0.72 (s, 3H).

[0768] Example 167

[0769]

[0770] The title compound (6.2 mg, 11.28 μmol, 25.43% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 82. 1 H NMR (400 MHz, CD3OD) δ 7.38 (dtq, J = 4.0, 2.5, 1.3 Hz, 2H), 7.32 (dq, J = 4.4, 1.7, 1.2 Hz, 3H), 4.72 (s, 1H), 2.83-2.63 (m, 4H), 2.59 - 1.05 (m, 24H), 1.01 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 6.7 Hz, 1H), 0.71 (s, 3H).

[0771] Example 168

[0772]

[0773] The title compound (13 mg, 20.26 μmol, 36.11% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 72. 1 H NMR (400 MHz, Methanol-d4) δ 7.62 - 7.54 (m, 4H), 7.51 - 7.38 (m, 4H), 7.37 - 7.29 (m, 1H), 3.58 (s, 2H), 2.96 (s, 2H), 2.50 (t, J = 13.8 Hz, 1H), 2.23 (d, J = 12.4 Hz, 1H), 2.04 (s, 3H), 1.93 - 1.61 (m, 10H), 1.59 - 1.49 (m, 3H), 1.49 - 1.06 (m, 12H), 1.00 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.70 (s, 3H).

[0774] Example 169

[0775]

[0776] The title compound (30 mg, 38.51 μmol, 41.18% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.28 (m, 10H), 6.99 (d, J = 7.3 Hz, 1H), 6.08 (s, 1H), 5.29 - 5.06 (m, 2H), 4.89 (d, J = 3.2 Hz, 1H), 4.72 - 4.49 (m, 1H), 2.48 (t, J = 13.9 Hz, 1H), 2.30 - 2.09 (m, 2H), 2.05 (s, 3H), 2.02 - 1.94 (m, 2H), 1.81 (q, J = 12.5 Hz, 6H), 1.70 - 1.47 (m, 9H), 1.44 - 1.01 (m, 17H), 0.97 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.65 (s, 3H).

[0777] Example 170

[0778]

[0779] The title compound (12 mg, 19.49 μmol, 29.77% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1H NMR (400 MHz, Methanol-d4) δ7.37 (dtd, J = 5.1, 2.4, 1.6 Hz, 2H), 7.31 (ddt, J = 5.4, 3.1, 1.5 Hz, 3H), 4.63 (s, 2H), 2.48 (t, J = 13.8 Hz, 1H), 2.32 (ddd, J = 14.7, 10.4, 5.1 Hz, 1H), 2.17 (ddd, J = 14.4, 9.5, 6.1 Hz, 1H), 2.03 (s, 5H), 1.92 - 1.75 (m, 6H), 1.67 (dd, J = 26.9, 3.2 Hz, 3H), 1.53 (dd, J = 14.8, 7.1 Hz, 3H), 1.48 - 1.06 (m, 11H), 1.00 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.69 (s, 3H).

[0780] Example 171

[0781]

[0782] The title compound (6.3 mg, 8.51 μmol, 18.21% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 8.41 (d,J= 2.6 Hz, 1H), 8.15 - 7.97 (m, 4H), 7.78 (d,J= 1.5 Hz, 1H), 7.34 (s, 5H), 6.59 (dd,J= 2.6, 1.8 Hz, 1H), 2.46 - 1.39 (m, 25H), 1.25 - 0.80 (m, 16H), 0.46 (s, 3H).

[0783] Example 176

[0784]

[0785] The title compound (1.5 mg, 2.67 μmol, 7.69% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 4. 1H NMR (400 MHz, Methanol-d4) δ = 7.45 - 7.36 (m, 2H), 7.36 -7.23 (m, 2H), 5.12 (s, 1H), 2.21 (dt, J=19.4, 7.6, 5H), 2.06 (s, 5H), 1.68 (dd, J=100.6, 20.7, 18H), 1.30 (d, J=15.4, 27H), 1.24 - 1.08 (m, 6H), 1.05 - 0.86 (m, 12H), 0.71 (s, 3H).

[0786] Example 181

[0787]

[0788] The title compound (9 mg, 13.54 μmol, 70.69% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 4. 1 H NMR (400 MHz, MeOD) δ9.20(s, 1H),8.59(s, 1H),8.43(d, J = 1.6 Hz, 1H),8.08(d, J = 8.4 Hz, 1H),7.87(dd, J = 8.8 Hz, 2.0 Hz, 1H),4.93-4.89 (m, 1H),2.63(t, J = 13.6 Hz,1H),2.36-2.15(m, 2H),2.11-1.11 (m, 26H),1.04(m, 3H),0.96(d, J = 6.4 Hz, 3H),0.72(s, 3H).

[0789] Example 182

[0790]

[0791] The title compound (1.3 mg, 2.07 μmol, 5.54% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1H NMR (400 MHz, CD3OD) δ 7.45 - 7.25 (m, 5H), 2.61 (s, 1H), 2.16 - 1.36 (m, 49H), 1.04 - 0.91 (m, 7H), 0.71 (s, 3H).

[0792] Example 183

[0793]

[0794] The title compound (1.3 mg, 2.03 μmol, 5.42% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1H NMR (400 MHz, CD3OD) δ 7.52–7.16 (m, 5H), 2.88 (s, 6H), 2.53–1.42 (m, 23H), 1.08–0.95 (m, 5H), 0.72 (s, 3H).

[0795] Example 184

[0796]

[0797] The title compound (15 mg, 24.40 μmol, 51.14% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, Methanol-d4) δ= 7.59 (d, J=12.7, 6H), 7.41 (s, 2H), 7.31 (s, 1H), 5.15 (s, 1H), 2.51-2.09 (m, 4H), 2.09-1.67 (m, 13H), 1.66-1.03 (m, 21H), 0.95 (d,J=17.6, 7H), 0.73 (s, 3H)

[0798] Example 187

[0799]

[0800] Step 187a.Methyl (4R)-4-[(5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate

[0801] BLAH pyridin-1-ium (71.61 mg, 223.91 μmol) was added to a 99.9% (3 mL) solution of tetrahydrofuran (100 mg, 223.91 μmol). The reaction mixture was stirred at 25 °C for 3 hours. It was diluted with EtOAc and a saturated sodium bicarbonate solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography to obtain the title compound, methyl (4R)-4-[(2R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-2-bromo-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17

[0802] -Tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoate (105 mg, 199.80 μmol, yield 89.24%) was obtained as a colorless oil.

[0803] Step 187b.Bromo-(4-phenylphenyl)magnesium (0.5 M, 285.43 μL) was added to a 3 mL solution of tetrahydrofuran containing methyl (4R)-4-[(2R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-2-bromo-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoate (50 mg, 95.14 μmol). The reaction mixture was stirred at 0 °C for 1 hour. This was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was [obtained by] chromatography Purified to the title compound methyl (4R)-4-[(2R,3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-2-bromo-3-hydroxy-10,13-dimethyl-3-(4-phenylphenyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta

[0804] [a]phenanthrene-17-yl]pentanoate (22 mg, 32.37 μmol, yield 34.02%) was obtained as a white solid.

[0805] Step 187c. Methyl (4R)-4-[(2R,3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-2-bromo-3-hydroxy-10,13-dimethyl-3-(4-phenylphenyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro

[0806] Lithium hydroxide (775.12 μg, 32.37 μmol) was added to a solution of cyclopenta[a]phenanthrene-17-yl]pentanoate (22 mg, 32.37 μmol) dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (1 mL). The reaction mixture was stirred at 23°C for 3 hours. It was diluted with EtOAc and acidified to pH 4 with 1 M HCl. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography to obtain the title compound, (4R)-4-[(2R,3S,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetoxy-2-bromo-3-hydroxy-10,13-dimethyl-3-(4-phenylphenyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (13 mg, 19.53 μmol, yield 60.34%) was obtained as a white solid. ESI-MS m / z = 663.83,665.86 (MH)-. 1 H NMR (400 MHz, Methanol-d4) δ 7.69 - 7.58 (m, 4H), 7.54 - 7.48 (m, 2H), 7.47 - 7.37 (m, 2H), 7.36 - 7.26 (m, 1H), 5.34 (d, J = 11.9 Hz, 1H), 4.97 (d, J = 3.2 Hz, 1H), 2.55 - 2.44 (m, 1H), 2.40 - 1.10 (m, 49H), 0.97 (d, J = 6.5 Hz, 3H), 0.92 - 0.85 (m, 2H), 0.74 (s, 3H).

[0807] Example 190

[0808]

[0809] The title compound (3 mg, 4.35 μmol, 11.64% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.22 (m, 10H), 4.89 (s, 1H), 2.47 - 1.29 (m, 38H), 0.97 (s, 3H), 0.85 (d,J= 6.5 Hz, 3H), 0.63 (s, 3H).

[0810] Example 191

[0811]

[0812] The title compound (6 mg, 8.85 μmol, 27.84% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, Chloroform-d) δ= 7.60 (dd,J=8.6, 1.4, 5H), 7.44 (dd,J=8.4, 6.9, 2H), 7.35 (d,J=7.4, 1H), 5.14 (s, 1H), 2.42 (d,J=11.6, 2H), 2.27 (s, 1H), 2.02 (s, 4H), 1.93-0.99 (m, 41H), 0.97-0.80 (m, 10H), 0.68 (s, 3H)

[0813] Example 192

[0814]

[0815] The title compound (29 mg, 53.23 μmol, 55.15% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, CD3OD) δ 7.85 - 7.04 (m, 9H), 4.12 (d, J= 12.1 Hz, 1H), 2.32 - 1.11 (m, 27H), 1.08 - 0.92 (m, 6H), 0.72 (s, 3H).

[0816] Example 194

[0817]

[0818] (4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-3-(4-phenylphenyl)-1,2,4,5,6,7,8,9,11

[0819] ,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (30 mg, 55.07 μmol) was dissolved in DCM (4 mL), and (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl)acetate (35.04 mg, 82.60 μmol) was added, and the reaction was stirred at 25 °C for 4 hours. 1 mL of water was added to the reaction, the mixture was filtered, the filtrate was extracted with DCM, and the DCM layers were combined, washed, dried, and evaporated to obtain the crude product. The crude product was purified by column chromatography to obtain (4R)-4-[(3S,5S,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-7-oxo-3-(4-phenylphenyl)-2,4,5,6,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]

[0820] Phenanthrene-17-yl]pentanoic acid (13 mg, 23.95 μmol, 43.49% yield, free base) was obtained as a white solid. 1 H NMR (400 MHz, Methanol-d4) δ= 7.67-7.52 (m, 4H), 7.53-7.45 (m, 2H), 7.41 (ddd,J=8.0, 6.9, 1.1, 2H), 7.34-7.24 (m, 1H), 3.07 (dd,J=12.8, 6.2, 1H), 2.61 (t,J=11.3, 1H), 2.49-2.25 (m, 2H), 2.24-1.99 (m, 3H), 1.98-1.09 (m, 21H), 1.08-0.85 (m, 4H), 0.73 (d,J=2.0, 3H)

[0821] Example 195

[0822]

[0823] The title compound (5.5 mg, 7.93 μmol, 23.25% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 7.71 - 7.18 (m, 9H), 3.59 (t,J= 6.7 Hz, 2H), 2.97 (t,J= 6.7 Hz, 2H), 2.62 (t,J= 13.8 Hz, 1H), 2.32 - 1.14 (m, 31H), 1.11 - 0.93 (m, 6H), 0.73 (s, 3H).

[0824] Example 196

[0825]

[0826] Ac₂O (74.96 mg, 734.27 μmol, 69.28 μL) and N,N-dimethylpyridine-4-amine (1.35 mg, 11.01 μmol) were added to a solution of (4R)-4-[(3S,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-3-(4-phenylphenyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (20 mg, 36.71 μmol, free base) dissolved in pyridine (10 mL). The reaction was stirred at 25 °C for 16 hours and then evaporated. Then 10 mL of EA and water were added and separated. The organic layer was evaporated and purified with FLASH to obtain (4R)-4-[(3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-(4-phenylphenyl)-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-17-yl]pentanoic acid (4.7 mg, 8.01 μmol, 21.82% yield, free base) as a white solid.

[0827] 1H NMR (400 MHz, CDCl3) δ 7.62 - 7.52 (m, 6H), 7.45 (dd,J= 10.3, 4.8 Hz, 2H), 7.36 (dt,J= 9.3, 4.3 Hz, 1H), 5.28 (dd,J= 11.2, 6.2 Hz, 1H), 2.37 - 1.38 (m, 30H), 1.24 - 1.04 (m, 8H), 0.95 (d,J= 6.5 Hz, 3H), 0.68 (s, 3H).

[0828] Example 197

[0829]

[0830] The title compound (5.5 mg, 8.57 μmol, 22.91% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 79. 1 H NMR (400 MHz, CD3OD) δ 7.44 - 7.14 (m, 5H), 3.66 - 3.51 (m, 2H), 2.96 (t,J= 6.8 Hz, 2H), 2.48 (t,J= 13.8 Hz, 1H), 2.10 - 1.10 (m, 28H), 1.02 - 0.90 (m, 6H), 0.71 (s, 3H).

[0831] Example 201

[0832]

[0833] The title compound (4.3 mg, 7.70 μmol, 33.91% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 557.58. 1H NMR (400 MHz, CD3OD) δ 7.64 - 7.50 (m, 7H), 7.41 (dd, J = 8.5, 7.0 Hz, 2H), 7.33 - 7.27 (m, 1H), 3.25 (q, J = 1.7 Hz, 1H), 3.22 (s, 3H), 2.78 (t, J = 13.8 Hz, 1H), 2.40 - 2.26 (m, 1H), 2.25 - 2.15 (m, 1H), 2.09 - 1.07 (m, 16H), 1.04 (s, 3H), 0.97 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 6.9 Hz, 1H), 0.72 (s, 3H).

[0834] Example 204

[0835]

[0836] The title compound (7.6 mg, 12.20 μmol, 59.78% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, Chloroform-d) δ 7.69 - 7.53 (m, 2H), 7.47 (dt, J = 8.4, 1.5 Hz, 2H), 7.32 - 7.26 (m, 1H), 7.06 - 6.91 (m, 2H), 5.00 - 4.87 (m, 1H), 2.48 - 2.17 (m, 3H), 2.10 - 0.80 (m, 32H), 0.68 (s, 3H).

[0837] Example 209

[0838]

[0839] The title compound (4.1 mg, 7.16 μmol, 62.87% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 27. ESI-MS m / z = 571.97 (MH) - , 1 H NMR (400 MHz, Chloroform-d) δ 7.62 - 7.52 (m, 5H), 7.49 - 7.40 (m, 3H), 7.36 - 7.30 (m, 1H), 3.77 - 3.74 (m, 1H), 2.59 - 2.47 (m, 1H), 2.46 - 2.18 (m, 4H), 2.03 - 0.83 (m, 31H), 0.69 (s, 3H).

[0840] Example 210

[0841]

[0842] The title compound (7.3 mg, 12.74 μmol, 48.97% yield) was obtained as a white solid and was prepared according to a procedure similar to that of Example 27. ESI-MS m / z = 571.90 (MH) - . 1 H NMR (400 MHz, Chloroform-d) δ 7.65 - 7.52 (m, 6H), 7.44 (m, 2H), 7.37 - 7.31 (m, 1H), 3.75 (s, 1H), 2.38 (dt, J = 20.2, 6.3 Hz, 3H), 2.33 - 2.18 (m, 2H), 2.14 -0.77 (m, 31H), 0.67 (s, 3H).

[0843] Example 216

[0844]

[0845] The title compound (50 mg, 85.21 μmol, 63.99% yield, free base) was prepared as a white solid according to a similar procedure to Example 27. 1H NMR (400 MHz, CDCl3) δ7.60-7.53 (m, 6H), 7.46-7.42 (m, 2H), 7.37-7.32 (m, 1H), 5.14-5.13 (m, 1H), 2.43-2.36 (m, 1H), 2.29-2.22 (m, 2H), 2.11 (s, 3H), 1.98-1.05 (m, 23H), 1.02 (m, 3H), 0.84 (d, J = 6.4 Hz, 3H), 0.76 (s, 3H).

[0846] Example 217

[0847]

[0848] The title compound (20 mg, 34.08 μmol, 58.51% yield, free base) was prepared as a white solid according to a similar procedure to Example 27. 1 H NMR (400 MHz, CDCl3) δ 7.61-7.56 (m, 6H),7.46-7.42 (m, 2H),7.37-7.33 (m, 1H),5.10-5.09 (m, 1H),2.44-2.19 (m, 4H),2.14(s, 3H),2.09-0.88 (m, 22H),0.84-0.82(m, 6H),0.73(s, 3H).

[0849] Example 221

[0850]

[0851] The title compound (20 mg, 36.71 μmol, 53.86% yield, free base) was prepared as a white solid from the compound of Example 217 according to a similar procedure of Example 13. 1 H NMR (400 MHz, CDCl3) δ 7.60-7.53 (m, 6H), 7.46-7.42 (m, 2H), 7.36-7.31 (m, 1H), 4.04-4.03 (m, 1H), 2.45-2.38 (m, 1H), 2.31-2.24 (m, 2H),2.05-1.07 (m, 23H),1.03-0.99(m, 6H),0.71(s, 3H).

[0852] Example 224

[0853]

[0854] The title compound (8 mg, 14.74 μmol, 44.61% yield, free base) was prepared as a white solid from the compound of Example 221 according to a similar procedure of Example 194. 1 H NMR (400 MHz, CDCl3) δ 7.60-7.53 (m, 6H), 7.46-7.42 (m, 2H), 7.36-7.32 (m, 1H), 2.60-2.53 (m, 1H), 2.49-2.41 (m, 1H), 2.34-2.26 (m, 1H),2.15-1.25 (m, 23H), 1.13(s, 3H),1.05(s, 3H),0.88(d, J = 6.4 Hz, 3H).

[0855] Example 225

[0856]

[0857] The title compound (37 mg, 63.05 μmol, 78.93% yield, free base) was prepared as a white solid according to a similar procedure to Example 27. 1 H NMR (400 MHz, Chloroform-d) δ 7.63 - 7.52 (m, 6H), 7.45 (dd, J = 8.4, 6.9 Hz, 2H), 7.38 -7.32 (m, 1H), 4.77 (td, J = 10.9, 5.3 Hz, 1H), 2.39 (ddt, J = 14.4, 9.3, 4.8 Hz, 1H), 2.26 (ddd, J = 15.8, 9.5, 6.5 Hz, 1H), 2.20 - 2.00 (m, 3H), 1.98 (s, 3H), 1.92 - 1.20 (m, 20H), 1.08 (s, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.71 (s, 3H).

[0858] Example 226

[0859]

[0860] Step 226a. To a 300 mL solution of methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (27.0 g, 66.7 mmol) in methanol, a 50 mL solution of hydroxylamine hydrochloride (9.3 g, 133.4 mmol) and sodium acetate (16.4 g, 200.1 mmol) was added under a nitrogen atmosphere at 25 °C. The mixture was stirred at 70 °C for 4 hours. The hot reaction mixture was filtered and concentrated until the volume was reduced by half, then poured into 70 mL of acidified pH 2 brine. The resulting precipitate was filtered. The residue was ethyl It was dissolved in acetate (200 mL) and washed with brine (100 mL). The organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (120 g silica gel column, DCM / MeOH, MeOH 0% to 5% for 20 min) to obtain methyl (R)-4-((3R,5R,8R,9S,10S,13R,14S,17R,Z)-3-hydroxy-7-(hydroxyimino)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (crude product, 32.6 g) as a white solid. ESI-MS m / z = 420.3 [M+H] + .

[0861] Step 226b.PtO2 (1.6 g, 7.1 mmol) was added to a solution of methyl (R)-4-((3R,5R,8R,9S,10S,13R,14S,17R,Z)-3-hydroxy-7-(hydroxyimino)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (10 g, 23.8 mmol) dissolved in CH3COOH (10 mL) at 25 °C under an H2 atmosphere. The mixture was stirred at 25 °C for 18 hours. The resulting mixture was filtered. The filter cake was washed with EtOAc (10 mL × 2). The filtrate was concentrated under reduced pressure. The mixture was alkalized to pH=9 with sodium hydroxide (2.0 mol / L in H2O). The resulting mixture Extraction was performed with EtOAc (150 mL × 2). The combined organic layer was washed with brine (100 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel column, DCM / MeOH, MeOH 0% to 5% for 20 min) to obtain methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-amino-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (8.6 g, 80% yield) as a white solid. ESI-MS m / z = 406.3 [M+H] + .

[0862] Step 226c.Ac2O (528 mg, 5.2 mmol) was added to a stirred mixture of methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-amino-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (700 mg, 1.7 mmol), pyridine (682 mg, 8.6 mmol), and DMAP (21 mg, 0.2 mmol) dissolved in DCE (15 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 24 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL). The resulting mixture was dissolved in saturated NaHCO3 (50 mL, aqueous solution) and brine (50 The organic layer was washed with mL). The organic layer was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g silica gel column, DCM / EtOAc, EtOAc gradient from 10% to 50% for 15 minutes) to obtain methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetamido-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (650 mg, 75% yield) as a white solid. ESI-MS m / z = 490.3 [M+H] + .

[0863] Step 226d.Sodium methylate (5.4 mol / L in MeOH) (0.7 mL, 3.7 mmol) was added to a stirred mixture of methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetamido-3-acetoxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (600 mg, 1.2 mmol) dissolved in MeOH (30 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was quenched at 0 °C with HCl (1.0 mol / L in H2O) (3.0 mL) and H₂O (50 mL). The resulting mixture was then added to EtOAc (100 mL). Extraction was performed. The organic layer was washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, DCM / MeOH, MeOH 0% to 6% for 15 min) to obtain methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetamido-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (450 mg, 81% yield) as a white solid. ESI-MS m / z = 448.3 [M+H] + .

[0864] Step 226e.PCC (385 mg, 1.8 mmol) was added to a stirred mixture in which methyl (R)-4-((3R,5R,7R,8R,9S,10S,13R,14S,17R)-7-acetamido-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (400 mg, 0.9 mmol) was dissolved in DCM (10 mL) at 25 °C under an air atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was quenched with a 20% aqueous NaHSO₃ solution at 25 °C. The resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate The residue was concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g silica gel column, DCM / EtOAc, EtOAc from 10% to 50% for 20 minutes) to obtain methyl (R)-4-((5R,7R,8R,9S,10S,13R,14S,17R)-7-acetamido-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (350 mg, 87% yield) as a white solid. ESI-MS m / z = 446.3 [M+H] + .

[0865] Step 226f.[1,1'-biphenyl]-4-yl magnesium bromide (0.5 mol / L in THF) (2.8 mL, 1.4 mmol) was added to a mixture of methyl (R)-4-((5R,7R,8R,9S,10S,13R,14S,17R)-7-acetamido-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (300 mg, 0.7 mmol) in THF (12 mL) under a nitrogen atmosphere at -20 °C. The resulting mixture was stirred at -20 °C for 2 hours. The reaction was quenched with saturated NH4Cl (20 mL, aq.) at 0 °C. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, DCM / EtOAc, EtOAc concentration from 0% to 30% for 20 minutes) to obtain methyl (R)-4-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7-acetamido-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (130 mg (32% yield) was obtained as a white solid and a 3rd-position chiral hydroxy isomer.

[0866] Step 226g.Lithium hydroxide (14 mg, 0.6 mmol) was added to a stirred mixture of methyl (R)-4-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7-acetamido-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (120 mg, 0.2 mmol) dissolved in THF (6 mL) and H2O (1 mL) under an air atmosphere at 25 °C. The resulting mixture was stirred at 25 °C for 16 hours. The mixture was acidified to pH=5 with hydrochloric acid (1.0 mol / L, in H2O). The resulting mixture was extracted with EtOAc (60 mL). The organic layer Washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g silica gel column, DCM / MeOH, MeOH 0% to 10% for 20 min) to obtain (R)-4-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7-acetamido-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)

[0867] Pentanoic acid (70 mg, 59% yield) was obtained as a white solid. ESI-MS m / z = 586.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.74 -7.63 (m, 5H), 7.58 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 4.60 (s, 1H), 3.71 (s, 1H), 2.42 - 2.41 (m, 1H), 2.28 - 1.10 (m, 28H), 0.97 (s, 3H), 0.90 (d, J = 8.0 Hz, 3H), 0.65 (s, 3H).

[0868] Examples 227 and 246

[0869]

[0870] Step 227a. Methyl (4 R )-4-((3 R ,5 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-7-amino-3-hydroxy-10,13-dimethylhexadecahydro-1 H -Cyclopenta[ a Paraformaldehyde (296 mg, 9861.5 μmol) was added to a 10 mL MeOH solution of phenanthrene-17-yl)pentanoate (800 mg, 1972.3 μmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. Sodium cyanoborohydride (868 mg, 13.8 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 15.5 hours. The reaction mixture was quenched with saturated NH₄Cl (aqueous solution) (60 mL). The resulting mixture was extracted with DCM (40 mL × 3). The combined organic layer was dried with anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by flash column chromatography (25 g silica gel column, DCM / MeOH, MeOH 0% to 20%). Purified with methyl (4) (16 min) R )-4-((3 R ,5 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1 H -Cyclopenta[ a ]Phenanthrene-17-yl)pentanoate (400 mg, 42% yield) was obtained as a colorless oil. ESI-MS m / z = 434.3 [M+H] + .

[0871] Step 227b. Methyl (4 R )-4-((3 R ,5 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1 H -Cyclopenta[ a PCC (398 mg, 1844.8 μmol) was added to a stirred mixture of phenanthrene-17-yl)pentanoate (400 mg, 922.4 μmol) in DCM (8 mL) at 25 °C under an air atmosphere. The resulting mixture was stirred at 25 °C for 4 hours. The reaction was quenched with a saturated aqueous Na₂S₂O₃ solution at 25 °C. The resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic layer was washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g silica gel column, DCM / MeOH, MeOH 0% to 20% for 16 min) to obtain methyl (4 R )-4-((5 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-7-(dimethylamino)-10,13-dimethyl-3-oxohexadecahydro-1 H -Cyclopenta[ a ]Phenanthren-17-yl)pentanoate (300 mg, yield 60%) was obtained as a yellow oil. ESI-MS m / z = 432.3 [M+H] + .

[0872] Step 227c. Methyl (4 R )-4-((5 R ,8 R ,9 S ,10 S ,13 R ,14S ,17 R )-7-(dimethylamino)-10,13-dimethyl-3-oxohexadecahydro-1 H -Cyclopenta[ a [1,1'-biphenyl]-4-yl magnesium bromide (2.8 mL, 1390 μmol) (0.5 mol / L in THF) was added at -15 °C to a solution of ]phenanthrene-17-yl)pentanoate (300 mg, 695 μmol) dissolved in THF (8 mL). The reaction mixture was stirred at -15 °C for 2 hours. The reaction mixture was diluted with H2O (10 mL). The resulting mixture was extracted with EtOAc (10 mL × 3). The combined organic layer was dried with anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, DCM / EtOAc, EtOAc 0% to 100% for 20 min) to obtain methyl ( R )-4-((3 S ,5 R ,7 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-3-([1,1'-biphenyl]-4-yl)-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1 H -Cyclopenta[ a ]phenanthrene-17-yl)pentanoate (20 mg, yield 4%) as a white solid, and methyl ( R )-4-((3 R ,5 R ,7 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-3-([1,1'-biphenyl]-4-yl)-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1 H -Cyclopenta[ a]Phenanthrene-17-yl)pentanoate (20 mg, yield 4%) was obtained as a white solid. ESI-MS m / z = 586.3 [M+H] + .

[0873] Step 227d. LiOH·H2O (5 mg, 102.3 μmol) was added to a solution of methyl (R)-4-((3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (20 mg, 34.1 μmol) dissolved in THF (2 mL) and H2O (0.4 mL). The resulting mixture was stirred at 25 °C for 16 hours. The mixture was adjusted to pH=5 using an aqueous HCl (1.0 M) solution and extracted with EtOAc (5 mL × 2). The organic layers were combined, dried with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Chromatography column: Welch- 18 C 250 × 21.2 mm, 10 μm; mobile phase: CH3CN / H2O (0.1% NH3); gradient: 30% to 50% within 9 minutes ( R )-4-((3 S ,5 R ,7 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-3-([1,1'-biphenyl]-4-yl)-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1 H -Cyclopenta[ a ]Phenanthrene-17-yl)pentanoic acid (4.7 mg, 24% yield) was obtained as a white solid. ESI-MS m / z = 572.3 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ7.65 (d, J = 8.0 Hz, 2H), 7.60 - 7.53 (m, 4H), 7.45 (m, 2H), 7.35 (m, 1H), 4.65 (s, 1H), 2.27 (s, 6H), 2.20 - 2.15 (m, 3H), 1.90 - 1.73 (m, 7H), 1.67 - 1.15 (m, 17H), 1.00 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.61 (s, 3H).

[0874] Step 227e. methyl ( R )-4-((3 R ,5 R ,7 R ,8 R ,9 S ,10 S ,13 R ,14 S ,17 R )-3-([1,1'-biphenyl]-4-yl)-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1 H LiOH·H2O (5 mg, 102.3 μmol) was added to a solution of cyclopenta[a]phenanthrene-17-yl)pentanoate (20 mg, 34.1 μmol) dissolved in THF (2 mL) and H2O (0.4 mL). The resulting mixture was stirred at 25 °C for 16 hours. The pH of the mixture was adjusted to 5 using an aqueous solution of HCl (1.0 M), and then extracted with EtOAc (5 mL × 2). The organic layers were combined, dried with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Chromatography column: Welch- 18 C 250 × 21.2 mm, 10 μm; mobile phase: CH3CN / H2O (0.1% NH3); gradient: 30% to 50% within 9 minutes ( R )-4-((3 R ,5 R ,7 R ,8 R ,9 S ,10 S ,13R ,14 S ,17 R )-3-([1,1'-biphenyl]-4-yl)-7-(dimethylamino)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (2.9 mg, 14% yield) was obtained as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.65 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.60 - 7.55(m, 4H), 7.45 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 4.59 (s, 1H), 2.25 (s, 6H), 2.20 - 2.14 (m, 3H), 1.95 - 1.68 (m, 7H), 1.60 - 1.02 (m, 17H), 0.95 (s, 3H), 0.91 (d, J = 8.0 Hz, 3H), 0.62 (s, 3H).ESI-MS m / z = 572.3 [M+H] + .

[0875] Example 252

[0876]

[0877] Step 252a.Under a nitrogen atmosphere, Ac2O (5047 mg, 49.4 mmol) was added at 25 °C to a stirred mixture in DCM (100 mL) of methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (10.0 g, 24.7 mmol), pyridine (7.8 g, 98.9 mmol), and 4-dimethylaminopyridine (302 mg, 2.5 mmol). The resulting mixture was stirred at 25 °C for 3 hours. The mixture was diluted with a 1N HCl aqueous solution (50 mL) and extracted with DCM (50 mL × 2). The combined organic layer was washed with brine (20 mL). The organic phase was dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (11.2 g, 91% yield) was obtained as a white solid.

[0878] Step 252b.A mixture of methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-acetoxy-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (1500 mg, 3.4 mmol) in DAST (5 mL) was stirred at 80 °C under N2 for 12 hours. The reaction mixture was quenched by adding 40 mL of saturated aqueous NaHCO3 solution at 0 °C, followed by extraction with EtOAc (30 mL × 2). The combined organic phase was dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash column chromatography (12 g silica gel column, EtOAc / petroleum ether, EtOAc 0% for 20 minutes). Methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-acetoxy-7,7-difluoro-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (900 mg, 49% yield) was obtained as a yellow solid by purification to (up to 20%). ESI-MS m / z = 491.3 [M+Na] + .

[0879] Step 252c.Sodium methylate (115 mg, 2.1 mol) was added at 25 °C to a stirred mixture in which methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-acetoxy-7,7-difluoro-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (200 mg, 0.4 mol) was dissolved in MeOH (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 1 hour. The reaction was quenched with HCl (1.0 mol / L in H2O, 20 mL) and H2O (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine (30 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, EtOAc / petroleum ether, EtOAc concentration from 0% to 60% for 20 min) to obtain methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-7,7-difluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (230 mg, The crude product was obtained as a colorless oil. ESI-MS m / z = 449.3 [M+Na] + .

[0880] Step 252d.DMP (274 mg, 0.6 mmol) was added to a solution of methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-7,7-difluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (230 mg, 0.5 mmol) dissolved in CH3CN (5 mL). The mixture was stirred at 25 °C for 2 hours. A new spot was detected on TLC (PE:EtOAc = 4:1). The reaction was quenched with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (20 mL) and dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue Methyl (R)-4-((5S,8R,9S,10S,13R,14S,17R)-7,7-difluoro-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (150 mg, 52% yield) was obtained as a white solid by purification by flash column chromatography (12 g silica gel column, EtOAc / petroleum ether, EtOAc 0–20% gradient for 20 min). ESI-MS m / z = 447.2 [M+Na] + .

[0881] Step 252e.Bromo(4-phenylphenyl)magnesium (0.5 mol / L in THF, 0.7 mL, 0.4 mmol) was added to a stirred mixture of methyl (R)-4-((5S,8R,9S,10S,13R,14S,17R)-7,7-difluoro-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (100 mg, 0.2 mmol) in THF (5 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was quenched with an aqueous solution of saturated NH4Cl (20 mL, aq.) at 25 °C. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (10 mL) and anhydrous sodium sulfate It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc / petroleum ether = 1 / 10) to obtain a mixed product. The residue was purified by Pre-HPLC (chromatography column: Welch Xtimate-18C 250 × 21.2 mm, 10 μm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 85% to 95% for 9 min) to obtain methyl (R)-4-((3S,5S,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7,7-difluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (18 mg, 12% yield) was obtained as a white solid. ESI-MS m / z = 561.3 [M-H2O+H] + .

[0882] Methyl (R)-4-((3R,5S,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7,7-difluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (20 mg, 14% yield) was obtained as a white solid. ESI-MS m / z = 561.3 [M-H2O+H] + .

[0883] Step 252f. Lithium hydroxide (0.2 mL, 0.2 mmol, 2 M, in H2O) was added at 25°C to a stirred mixture in which methyl (R)-4-((3S,5S,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7,7-difluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (18 mg, 0.03 mmol) was dissolved in THF (5 mL), CH3OH (1 mL), and H2O (1 mL). The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 0°C by adding an aqueous HCl solution (0.2 mL, 2 M in H2O). Then, it was diluted with water (20 mL) and Extraction was performed with EtOAc (20 mL × 2). The combined organic phase was dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH = 10 / 1) to obtain (R)-4-((3S,5S,8R,9S,10S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7,7-difluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (5.9 mg, 31% yield) as a white solid. ESI-MS m / z = 547.2 [M-H2O+H] + .1H NMR (400 MHz, DMSO-d6) δ 7.65 - 7.61 (m, 4H), 7.55 - 7.53 (m, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 4.79 (s, 1H), 2.23 - 1.92 (m, 9H), 1.82 - 1.57 (m, 9H), 1.39-1.26 (m, 8H), 0.98 (s, 3H), 0.85 (d, J = 8.0 Hz, 3H), 0.63 (s, 3H).19F NMR (400 MHz, DMSO-d6) δ -81.93, -82.56, -99.10, -99.73.

[0884] Example 271

[0885]

[0886] The title compound (3.6 mg, 6.44 μmol, 8.58% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1H NMR (400 MHz, CDCl3) δ 7.65 - 7.30 (m, 8H), 3.64 (d, J= 11.8 Hz, 1H), 2.40 - 1.33 (m, 34H), 1.23 - 1.06 (m, 2H), 1.04 - 0.90 (m, 6H), 0.67 (s, 3H).

[0887] Example 272

[0888]

[0889] The title compound (3.6 mg, 6.44 μmol, 8.58% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.30 (m, 8H), 3.64 (d,J= 11.8 Hz, 1H), 2.40 - 1.33 (m, 34H), 1.23 - 1.06 (m, 2H), 1.04 - 0.90 (m, 6H), 0.67 (s, 3H). 1 H NMR (400 MHz, cdcl3) δ 7.83 - 7.31 (m, 8H), 3.48 (d, J= 12.0 Hz, 1H), 2.51 - 1.03 (m, 27H), 0.97 - 0.74 (m, 6H), 0.65 (s, 3H).

[0890] Example 281

[0891]

[0892] The title compound (18 mg, 36% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 623.4 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ11.93 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.60 (s, 4H), 7.46 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 5.21 (s, 1H), 4.28 (m, 1H), 4.18 (m, 1H), 2.30 - 2.18 (m, 1H), 2.16 - 2.05 (m, 1H), 1.98 (m, 2H), 1.89 - 1.78(m, 1H), 1.75 - 1.55 (m, 5H), 1.53 - 1.42 (m, 7H), 1.43 - 1.34 (m,, 3H), 1.33 - 1.19 (m, 7H), 1.16 - 1.05 (m, 3H), 0.94 (s, 3H), 0.90 (d, J = 8.0 Hz,, 3H), 0.65 (s, 3H).

[0893] Example 301

[0894]

[0895] The title compound (8.3 mg, 28% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 567.3 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.65 - 7.55 (m, 6H), 7.46 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 4.69 (s, 1H), 4.22 (s, 1H), 3.81 (s, 1H), 2.14 - 2.12 (m, 2H), 1.98 - 1.75 (m, 7H), 1.67 - 1.34 (m, 11H), 1.28 - 1.09 (m, 6H), 0.94 (s, 3H), 0.92 (d, J = 4.0 Hz, 3H), 0.62 (s, 3H).

[0896] Example 318

[0897]

[0898] Step 318a. Under a nitrogen atmosphere at 25 °C, bromo(ethenyl)magnesium (2.0 mL, 2.0 mmol, 1.0 mol / L, in THF) was added to a THF (20 mL) solution of methyl (R)-4-((5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (600 mg, 1.3 mmol). The resulting mixture was stirred at 25 °C for 12 hours. The reaction was quenched at 0 °C with an aqueous solution of saturated NH4Cl (30 mL, aq.). The resulting mixture was extracted with EtOAc (60 mL). The organic layer was washed with brine (20 mL) and anhydrous sodium sulfate It was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, petroleum ether / EtOAc, EtOAc gradient from 0% to 40% for 25 minutes) to obtain methyl (R)-4-((3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-vinylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate and methyl A mixture of (R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-vinylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (400 mg, crude product) was obtained as a colorless oil and a chiral hydroxy isomer at the 3rd position was obtained.

[0899] ESI-MS m / z = 497.3 [M+Na] + .

[0900] Step 318b.A mixture of methyl (R)-4-((3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-vinylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate and methyl (R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-vinylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (200 mg, 0.4 mmol) in a stirred solution dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), Iodobenzene (172 mg, 0.8 mmol), dicyclohexylamine (153 mg, 0.8 mmol), and palladium diacetate (38 mg, 0.2 mmol) were added at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (10 mL). The organic phase was dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Pre-HPLC (chromatography column: Welch Xtimate-18C 250 × 21.2 mm, 10 μm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 85% to 95% for 10 minutes) to methyl (R)-4-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-((E)-styryl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (60 mg, 25% yield) was obtained as a white solid. ESI-MS m / z = 573.3 [M+Na] + .

[0901] Methyl (R)-4-((3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-((E)-styryl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (55 mg, 19% yield) was obtained as a white solid. ESI-MS m / z = 573.3 [M+Na] + .

[0902] Step 318c. Lithium hydroxide (0.2 mL, 0.4 mmol, 2 M in H₂O) was added to a stirred mixture of methyl (R)-4-((3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-((E)-styryl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (45 mg, 0.08 mmol) dissolved in THF (5 mL), CH₃OH (1 mL), and H₂O (1 mL) at 25°C. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched at 0°C by adding an aqueous HCl solution (0.3 mL, 2 M in H₂O). It was then diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phase was dried with Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Pre-HPLC (chromatography column: Welch Xtimate-18C 250 × 21.2 mm, 10 μm; mobile phase: CH₃CN / H₂O (0.1% FA); gradient: 85% to 95% for 10 minutes). (R)-4-((3S,5R,6S,8S,9S,10R,13R,14S,17R)-6-acetoxy-3-hydroxy-10,13-dimethyl-3-((E)-styryl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (1.2 mg, 2.7% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ11.96 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 5.11-5.08 (m, 1H), 4.43 (s, 1H), 2.27 - 2.00 (m, 4H), 1.95 (s, 3H), 1.78-1.66 (m, 4H), 1.53 - 1.35 (m, 9H), 1.27-1.08 (m, 9H), 0.95 (s, 3H), 0.88 (d, J = 4.0 Hz, 3H), 0.63 (s, 3H).

[0903] Example 326

[0904]

[0905] The title compound (70 mg, 79% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 525.3 [M-36+H] + . 1 H NMR (400 MHz, DMSO-d6) δ11.96 (s, 1H), 7.68 - 7.54 (m, 6H), 7.46 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 1H), 4.72 (s, 1H), 4.39 (s, 1H), 4.05 (s, 1H), 3.60 (m, 2H), 2.27 - 2.18 (m, 1H), 2.15 - 2.01 (m, 2H), 1.95 - 1.93 (m, 1H), 1.87 - 1.58 (m, 6H), 1.54 - 1.08 (m, 14H), 0.90 (d, J = 8.0 Hz, 3H), 0.74 (s, 3H), 0.61 (s, 3H).

[0906] Example 328

[0907]

[0908] The title compound (70 mg, 79% yield) was prepared as a white solid according to a procedure similar to that of Example 318. ESI-MS m / z = 517.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ7.41 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H) 16.0 Hz, 1H), 4.34 (s, 1H), 4.10 (s, 1H), 3.79 (s, 1H), 2.24 - 1.69 (m, 9H), 1.58 (m, 4H), 1.51 - 1.28 (m, 6H), 1.30 - 1.04 (m, 7H), 1.06 - 0.82 (m, 6H), 0.61 (s, 3H).

[0909] Example 330

[0910]

[0911] The title compound (9.3 mg, 7% yield) was prepared as a white solid according to a procedure similar to that of Example 79. ESI-MS m / z = 720.2 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.51 (s, 1H), 7.65 - 7.56 (m, 6H), 7.46 (t, J = 8.0 Hz, 2H), 7.39 - 7.28 (m, 4H), 7.28 - 7.22 (m, 2H), 4.69 (s, 1H), 4.43 (s, 2H), 4.23 (d, J = 4.0 Hz, 1H), 3.82 (m, 1H), 2.20 - 2.04 (m, 2H), 1.95 - 1.78 (m, 7H), 1.66 - 1.38 (m, 10H), 1.27 - 1.01 (m, 7H), 0.95 (s, 3H), 0.91 (d,J = 8.0 Hz, 3H), 0.64 (s, 3H).

[0912] Example 337

[0913]

[0914] N,N-dimethylpyridine-4-amine (2 mg, 10.7 μmol) and acetic anhydride (327 mg, 3.2 mmol) were added to a DCM (4 mL) mixture of (R)-4-((3S,5R,6R,7S,8S,9S,10R,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-3,6,7-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (60 mg, 107.0 μmol) and pyridine (423 mg, 5.4 mmol) maintained at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 48 hours. The reaction was carried out at 25 °C in an aqueous HCl solution (2.0 mL, It was quenched with 1.0 mol / L of H2O and brine (20 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (30 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, DCM / MeOH, MeOH 0% to 7% for 15 min) and then subjected to Prep-HPLC (chromatography column: Xtimate-18C 250 × 21.2 mm, 10 μm; mobile phase: CH3CN / H2O (0.1% NH3); gradient: 30% to 50% for 9 min) (R)-4-((3S,5R,6R,7S,8S,9S,10R,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-6,7-diacetoxy-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (15 mg, 21% yield) was obtained as a white solid. ESI-MS m / z = 667.3 [M+Na] +.1H NMR (400 MHz, DMSO-d6) δ 7.68 - 7.63 (m, 4H), 7.50 - 7.44 (m, 4H), 7.35 (t, J = 8.0 Hz, 1H), 5.11 (s, 1H), 4.97 (s, 2H), 2.42 - 2.41 (m, 1H), 2.30 - 2.08 (m, 6H), 2.07 - 1.85 (m, 6H), 1.80 - 1.48 (m, 7H), 1.38 - 1.01 (m, 10H), 0.88 (d, J = 8.0 Hz, 3H), 0.83 (s, 3H), 0.63 (s, 3H).

[0915] Example 340

[0916]

[0917] The title compound (1.6 mg, 68% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 567.2 [M+Na] + . 1 ¹H NMR (400 MHz, MeOD- d ) δ 7.63 - 7.61 (m, 6H), 7.42 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 3.41 - 3.39 (m, 1H), 2.37 - 2.20 (m, 4H), 2.12 - 2.08 (d, 1H), 1.94 - 1.81 (m, 4H), 1.77 - 1.69 (m, 3H), 1.65 - 1.56 (m, 2H), 1.51 - 1.48 (m, 2H), 1.44 - 1.38(m, 2H), 1.33 - 1.28 (m, 8H), 1.03 (d, J = 4.0 Hz, 3H), 0.86 (s, 3H), 0.72 (s, 3H).

[0918] Example 354

[0919]

[0920] The title compound (9.4 mg, 23% yield) was prepared as a white solid according to a procedure similar to that of Example 318. 1 H NMR (400 MHz, DMSO-d6) δ11.96 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 6.51 (d, J = 16.0 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.29 (s, 1H), 4.18 (d, J = 4.0 Hz, 1H), 3.94 - 3.85 (m, 1H), 2.26 - 2.18 (m, 1H), 2.14-2.06 (m, 1H), 1.94 - 1.63 (m, 5H), 1.49 - 1.08 (m, 19H), 0.89 (s, 3H), 0.87 (d, J = 4.0 Hz, 3H), (m, 6H), 0.61 (s, 3H).

[0921] Example 355

[0922]

[0923] The title compound (2.6 mg, 3% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 623.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ11.99 (d, J = 8.0 Hz, 1H), 8.26 (t, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H) 8.0 Hz, 1H), 5.01 (s, 1H), 4.65 (s, 1H), 2.25 (s, 1H), 2.11 - 2.02 (m, 2H), 1.93 (m, 11H), 1.42 - 1.08 (m, 6H), 0.99 - 1.04 (m, 3H), 0.91 - 0.84 (m, 6H), 0.64 (s, 3H).

[0924] Example 370

[0925]

[0926] The title compound (4.1 mg, 4% yield) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, DMSO-d6) δ12.00 (s, 1H), 7.67-7.62 (m, 4H), 7.52 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.36-7.33 (m, 1H), 4.73 (s, 1H), 4.19 (d, J = 4.0 Hz, 1H), 3.54 (s, 1H), 2.32 - 2.07 (m, 6H), 1.96 - 1.59 (m, 10H), 1.44 - 1.12 (m, 11H), 0.93 - 0.79 (m, 6H), 0.74 (s, 3H), 0.61 (s, 3H).

[0927] Example 373

[0928]

[0929] Step 373a. A solution of 1,4-dibromobenzene (528 mg, 2.2 mmol) in THF (5 mL) was added to a stirred mixture of Mg (54 mg, 2.2 mmol) and I2 (6 mg, 22.3 μmol) in THF (5 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 hours (this mixture was designated as Part A). Under a nitrogen atmosphere, methyl (R)-4-((5R,8R,9S,10S,12S,13R,14S,17R)-12-acetoxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]

[0930] Part A (10 mL) was added to a THF (5 mL) solution of phenanthrene-17-yl)pentanoate (500 mg, 1.1 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with an aqueous solution of saturated NH4Cl (30 mL, aq.) at 0 °C. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (40 g silica gel column, petroleum ether / EtOAc, EtOAc 5% to 20% for 17 min) to methyl (R)-4-((3S,5R,8R,9S,10S,12S,13R,14S,17R)-12-acetoxy-3-(4-bromophenyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (350 mg, 39% yield) as a white solid and a 3rd-position chiral hydroxy isomer were obtained.

[0931] ESI-MS m / z = 625.2, 627.2 [M+Na] + .

[0932] Step 373b.Under a nitrogen atmosphere, potassium (2,6-difluorophenyl)trifluoroborate (146 mg, 662 μmol), K2CO3 (91 mg, 662 μmol), and Pd(dppf)Cl2·DCM (27 mg, 33 μmol) were added at 25 °C to a mixture of 1,4-dioxane (10 mL) and H2O (2 mL) of methyl (R)-4-((3S,5R,8R,9S,10S,12S,13R,14S,17R)-12-acetoxy-3-(4-bromophenyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (200 mg, 331 μmol) at 25 °C. The resulting mixture was heated at 100 °C The mixture was stirred for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g silica gel column, petroleum ether / EtOAc, EtOAc 5% to 20% for 15 minutes) to obtain methyl (R)-4-((3S,5R,8R,9S,10S,12S,13R,14S,17R)-12-acetoxy-3-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (100 mg, yield 33%) as a pale yellow solid. ESI-MS m / z = 659.3 [M+Na] + .

[0933] Step 373c.Sodium methoxide (5.4 mol / L, 0.9 mL, 4.7 mmol in CH3OH, 3OH) was added to a stirred mixture in which methyl (R)-4-((3S,5R,8R,9S,10S,12S,13R,14S,17R)-12-acetoxy-3-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (100 mg, 157 μmol) was dissolved in MeOH (2 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 hours. The mixture was adjusted to pH-5 with hydrochloric acid (1.0 mol / L, in H2O). It was acidified. The resulting mixture was extracted with EtOAc (60 mL). The organic layer was washed with brine (50 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g silica gel column, DCM / MeOH, MeOH 0% to 10% for 15 min), and then subjected to Prep-HPLC (chromatography column: Xtimate-18C 150 × 19 mm, 5 μm; mobile phase: CH3CN / H2O (0.1% FA); gradient: 55% to 85% for 9 min) (R)-4-((3S,5R,8R,9S,10S,12S,13R,14S,17R)-3-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)-3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (25 mg, 12% yield) was obtained as a white solid. ESI-MS m / z = 603.3 [M+Na] + . 1H NMR (400 MHz, DMSO-d6 ) δ 11.94 (s, 1H), 7.64 - 7.55 (m, 2H), 7.51 - 7.32 (m, 3H), 7.24 - 7.20 (m, 2H), 4.75 (s, 1H), 4.22 (s, 1H), 3.81 (s, 1H), 2.28 - 2.04 (m, 3H), 1.96 - 1.72 (m, 6H), 1.70 - 1.59 (m, 2H), 1.58 - 1.05 (m, 15H), 0.95 (s, 3H), 0.92 (d, J = 4.0 Hz, 3H), 0.63 (s, 3H).19F NMR (400 MHz, DMSO-d6) -114.83.

[0934] Example 382

[0935]

[0936] Step 382a.(Diisopropylamino)lithium (2 M, 18.81 mL) was added to THF (50 mL) at -78 °C under a nitrogen atmosphere, and the resulting mixture was stirred for 15 minutes. Chloro(trimethyl)silane (5.11 g, 47.02 mmol, 5.97 mL) was added to the above solution at -78 °C, and the resulting mixture was stirred for 1 hour. To the above solution, a solution of methyl (R)-4-((5R,8R,9S,10S,12S,13R,14S,17R)-12-acetoxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (2.1 g, 4.70 mmol, free base) dissolved in 2 mL THF and N,N-diethylethanolamine (8.56 g, 84.64 mmol (11.80 mL) was added sequentially under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 15 hours. The reaction was monitored by TLC, and after completion, the reaction was quenched with water. The aqueous phase was extracted with EA (10 mL × 3), the organic phases were combined and washed with water and brine, respectively, dried with Na2SO4, and filtered and concentrated. The residue was dissolved in acetonitrile (50 mL), and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborate (8.33 g, 23.51 mmol) was added at 25°C, followed by stirring for 12 hours at the same temperature. The reaction was monitored by TLC, and after completion, the reaction was quenched with 10 mL of 6 N HCl. The aqueous phase was extracted with EA (30 mL × 3). The organic phases were washed with water and brine, respectively, dried with Na2SO4, and filtered and concentrated. The crude product was purified by silica gel flash column chromatography, and petroleum ether : ethyl acetate = methyl (4R)-4-((5S,8R,9S,10R,12S,13R,14S,17R)-12-acetoxy-4-fluoro-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (260 mg, 559.61 μmol, yield 11) by elution from 15:1 to 5:1.90% (free base) was obtained as a white solid.

[0937] 1 H NMR (400 MHz, CDCl3) δ5.23-5.08 (m, 2H), 3.65 (s, 3H), 2.38-2.15 (m, 4H), 2.06 (s, 3H), 2.01-1.08 (m, 20H), 1.03 (s, 3H), 0.79 (d, J = 6.4 Hz, 3H), 0.75 (s, 3H).

[0938] Step 382b. Bromo-(4-phenylphenyl)magnesium (0.5 M, 387.42 μL, free base) was added to a THF (3 mL) solution of methyl (4R)-4-((5S,8R,9S,10R,12S,13R,14S,17R)-12-acetoxy-4-fluoro-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (60 mg, 129.14 μmol, free base) at 0°C. The reaction was stirred at 0°C for 2 hours. The residue was diluted with water (10 mL), the aqueous layer was washed with EA (3 x 10 mL), the combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, and then filtered and concentrated. The residue was purified by flash silica gel column chromatography and eluted with 10% to 25% EA in PE to obtain methyl (4R)-4-((3R,5S,8R,9S,10R,12S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-12-acetoxy-4-fluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (12 mg, 19.39 μmol, yield 15.02%, free base) was obtained as a white solid and a chiral hydroxy isomer at position 3 was obtained.

[0939] 1H NMR (400 MHz, CDCl3) δ7.66-7.65 (m, 4H), 7.61-7.59 (m, 2H), 7.53-7.49 (m, 2H), 7.43-7.39 (m, 1H), 5.29 (dd, J = 57.2 Hz, 10.4Hz, 1H), 5.18 (s, 1H), 3.74 (s, 3H), 2.51-1.21 (m, 27H), 1.12 (s, 3H), 0.89-0.84 (m, 6H).

[0940] Step 382c. LiOH (33.09 mg, 1.38 mmol) and water (1 mL) were added to a methanol (2 mL) solution of methyl (4R)-4-((3R,5S,7R,8S,9S,10R,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7-acetoxy-4-fluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoate (57 mg, 92.11 μmol, free base). The reaction was stirred at 25 °C for 2 hours. The basic aqueous solution was neutralized with 6 N HCl. Then, the reaction was evaporated, the residue was purified by silica gel column chromatography, and eluted in 0% to 60% EA in petroleum ether to obtain (4R)-4-((3R,5S,8R,9S,10R,12S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-12-acetoxy-4-fluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (48 mg, 79.37 μmol, 86.16% yield, free base) as a white solid.

[0941] 1H NMR (400 MHz, CDCl3) δ7.61-7.58 (m, 4H), 7.54-7.52 (m, 2H), 7.46-7.42 (m, 2H), 7.37-7.33 (m, 1H), 5.26 (dd, J = 46.8 Hz, 10.8Hz, 1H), 5.12 (s, 1H), 2.44-2.36 (m, 1H), 2.30-2.22 (m, 1H), 2.07 (s, 3H), 2.02-1.11 (m, 22H), 1.06 (m, 3H), 0.85 (d, J = 12.0 Hz,3H), 0.77 (s, 3H).

[0942] Step 382d. Sodium hydroxide (39.68 mg, 992.08 μmol, 18.63 μL) and water (1 mL) were added to a methanol (1 mL) solution of (4R)-4-((3R,5S,7R,8S,9S,10R,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-7-acetoxy-4-fluoro-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (30 mg, 49.60 μmol, free base). The reaction mixture was refluxed for 6 hours while stirring. The basic aqueous solution was neutralized with 6 N HCl. Then, the reaction was evaporated, the residue was purified by silica gel column chromatography, and eluted in 0% to 70% EA in petroleum ether to obtain (4R)-4-((3R,5S,8R,9S,10R,12S,13R,14S,17R)-3-([1,1'-biphenyl]-4-yl)-4-fluoro-3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid (20 mg, 35.54 μmol, 71.65% yield, free base) as a white solid.

[0943] 1H NMR (400 MHz, CDCl3) δ7.68-7.65 (m, 2H), 7.62-7.58 (m, 4H), 7.43-7.39 (m, 2H), 7.33-7.29 (m, 1H), 5.17 (dd, J = 46.8 Hz, 10.8Hz, 1H), 3.99 (s, 1H), 2.39-2.31 (m, 1H), 2.25-2.17 (m, 1H), 2.09-1.12 (m, 22H), 1.08 (m, 3H), 1.02 (d, J = 6.4 Hz,3H), 0.74 (s, 3H).

[0944] Example 383

[0945]

[0946] The title compound (3.4 mg, 7% yield) was prepared as a white solid according to a procedure similar to that of Example 27. 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.65–7.58 (m, 4H), 7.52–7.43 (m, 4H), 7.34 (t, J = 8.0 Hz, 1H), 4.51 (s, 1H), 4.02 (d, J = 4.0 Hz, 1H), 3.52 (s, 1H), 2.38–2.34 (m, 1H), 2.28–2.20 (m, 1H), 2.11–2.07 (m, 1H), 1.95–1.93 (m, 1H), 1.85–1.18 (m, 23H), 0.93 (s, 3H), 0.90 (d, J = 4.0 Hz, 3H), 0.83 (t, J = 8.0 Hz, 3H), 0.64 (s, 3H).

[0947] Example 387

[0948]

[0949] The title compound (3.8 mg, 6% yield) was prepared as a white solid from the compound of Example 204 according to a procedure similar to that of Example 13. ESI-MS m / z = 603.3 [M+Na] + . 1¹H NMR (400 MHz, DMSO- d 6 ) δ 11.93 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.50 - 7.42 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0 Hz, 2H), 4.62 (s, 1H), 4.09 (m, 1H), 3.65 (s, 1H), 2.78 - 2.71 (m, 1H), 2.23 - 2.20 (m, 1H), 2.13 - 2.08 (m, 1H), 1.91 - 1.79 (m, 5H), 1.71 - 1.56 (m, 4H), 1.49 - 1.11 (m, 14H), 0.94 (s, 3H), 0.89 (d, J = 4.0 Hz, 3H), 0.63 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ -114.82.

[0950] Example 388

[0951]

[0952] The title compound (3.8 mg, 6% yield) was prepared as a white solid from the compound of Example 204 according to a procedure similar to that of Example 79. ESI-MS m / z = 702.3 [M+Na] +.1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.10 (t, J = 4.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 - 7.35 (m, 3H), 7.23 - 7.18 (m, 2H), 4.78 (s, 1H), 4.75 (s, 1H), 3.70 (d, J = 8.0 Hz, 2H), 2.19 - 2.09 (m, 1H), 2.08 - 1.98 (m, 2H), 1.97 - 1.84 (m, 6H), 1.82 - 1.02 (m, 20H), 0.99 (s, 3H), 0.90 (d, J = 8.0 Hz, 3H), 0.64 (s, 3H).19F NMR (400 MHz, DMSO-d6) -114.85.

[0953] Example 389

[0954]

[0955] The title compound (20 mg, 31% yield) was prepared as a white solid from the compound of Example 204 according to a procedure similar to that of Example 79. ESI-MS m / z = 798.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.50 - 7.38 (m, 6H), 7.32 - 7.26 (m, 2H), 7.21 (t, J = 7.9 Hz, 2H), 4.79 (s, 1H), 4.75 (s, 1H), 4.66 (s, 2H), 2.28 - 2.19 (m, 1H), 2.18 - 2.09 (m, 1H), 2.06 - 1.58 (m, 13H), 1.53 - 1.02 (m, 14H), 0.99 (s, 3H), 0.87 (d, J = 4.0 Hz, 3H), 0.66 (s, 3H).19F NMR (400 MHz, DMSO-d6) -114.85.

[0956] Example 392

[0957]

[0958] The title compound (18.8 mg, 23.81% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 645.4 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 12.00 (s, 1H), 7.72 (d, J = 8.0 Hz,2H), 7.55 (d, J = 8.0 Hz,2H), 7.45 (d, J = 8.0 Hz,2H), 7.21 (t, J = 8.0 Hz,1H), 4.78 (s, 1H), 4.75(s, 1H), 2.28-1.96 (m, 4H), 1.91 (s, 3H), 1.88-1.50 (m, 9H), 1.40-1.04 (m, 13H), 0.98 (s, 3H), 0.90 (d, J = 4.0 Hz, 3H), 0.65 (s, 3H). 19 F NMR (376 MHz, DMSO- d 6 ) δ -109.58.

[0959] Example 393

[0960]

[0961] The title compound (39.9 mg, 40% yield) was prepared as a white solid from the compound of Example 217 according to a procedure similar to that of Example 13. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.94 (s, 1H), 7.67 - 7.61 (m, 4H), 7.55 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.35 (t,J = 8.0 Hz, 1H), 4.89 (s, 1H), 4.30 (d, J = 4.0 Hz, 1H), 3.82 (s, 1H), 2.24 - 2.18 (m, 1H), 2.17 - 2.05 (m, 3H), 1.97 - 1.94 (m, 2H), 1.82 - 1.57 (m, 8H), 1.47 - 1.08 (m, 12H), 0.93 (d, J = 8.0 Hz, 3H), 0.76 (s, 3H), 0.61 (s, 3H).

[0962] Example 394

[0963]

[0964] The title compound (20 mg, 35.54 μmol, 71.65% yield, free base) was prepared as a white solid from the compound of Example 382 according to a procedure similar to that of Example 13. 1 H NMR (400 MHz, CDCl3) δ7.68-7.65 (m, 2H), 7.62-7.58 (m, 4H), 7.43-7.39 (m, 2H), 7.33-7.29 (m, 1H), 5.17 (dd, J = 46.8 Hz, 10.8Hz, 1H), 3.99 (s, 1H), 2.39-2.31 (m, 1H), 2.25-2.17 (m, 1H), 2.09-1.12 (m, 22H), 1.08 (m, 3H), 1.02 (d, J = 6.4 Hz,3H), 0.74 (s, 3H).

[0965] Example 401

[0966]

[0967] The title compound (13.4 mg, 25% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 645.1 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.50 - 7.38 (m, 3H), 7.22 (t, J = 8.0 Hz, 2H), 5.14 - 5.11 (m, 1H), 4.82 (s, 1H), 2.28 - 1.96 (m, 4H), 1.93 (s, 3H), 1.85 - 1.79 (m, 2H), 1.73 - 1.64 (m, 2H), 1.60 - 1.49 (m, 6H), 1.46 - 1.36 (m, 3H), 1.33 - 1.04 (m, 9H), 0.99 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.65 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -114.87.

[0968] Example 403

[0969]

[0970] The title compound (20.4 mg, 23% yield) was prepared as a white solid according to a procedure similar to that of Example 373. LCMS:ESI-MS m / z = 637.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.14 - 7.06 (m, 5H), 4.77 (s, 1H), 4.67 (s, 1H), 2.26 - 2.20 (m, 1H), 2.15 - 2.08 (m, 1H), 2.03 - 1.98 (m, 1H), 1.95 (s, 6H), 1.92 - 1.87 (m, 2H), 1.86 (s, 3H), 1.82 - 1.70 (m, 2H), 1.68 - 1.60 (m, 4H), 1.58 - 1.38 (m, 5H), 1.32 - 1.16 (m, 8H), 1.15 - 1.03 (m, 2H), 0.98 (s, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.64 (s, 3H).

[0971] Example 404

[0972]

[0973] The title compound (5 mg, 17% yield) was prepared as a white solid according to a procedure similar to that of Example 373. LCMS:(ESI) m / z [M+Na] + =669.4. 1 H NMR (400 MHz, DMSO-d6) δ7.42 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.40 Hz, 2H), 4.79 (s, 1H), 4.63 (s, 1H), 3.64 (s, 6H), 2.26 - 2.17 (m, 1H), 2.12 - 2.00 (m, 2H), 1.93 (s, 3H), 1.88 - 1.86 (m, 2H), 1.79 - 1.60 (m,6H), 1.51 - 1.05 (m, 15H), 0.98 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.65 (s, 3H).

[0974] Example 405

[0975]

[0976] The title compound (30 mg, 47% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 559.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.54 (m, 4H), 4.89 (s, 1H), 4.22 (s, 1H), 3.80 (s, 1H), 2.25 - 2.04 (m, 3H), 1.94 - 1.06 (m, 23H), 0.97 - 0.89 (m, 6H), 0.62 (s, 3H).19F NMR (400 MHz, DMSO-d6) -60.60.

[0977] Example 406

[0978]

[0979] The title compound (8.7 mg, 11% yield) was prepared as a white solid according to a procedure similar to that of Example 318. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.22 -7.19 (m, 1H), 6.56 (s, 2H), 4.70 (s, 1H), 4.23 (d, J = 4.0 Hz, 1H), 3.81 (s, 1H), 2.24-2.19 (m, 1H), 2.07-1.98 (m, 3H), 1.80 - 1.47 (m, 10H), 1.40 - 1.03 (m, 12H), 0.92 (d, J = 8.0 Hz, 3H), 0.89 (s, 3H), 0.61 (s, 3H).

[0980] Example 407

[0981]

[0982] The title compound (15 mg, 37% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 645.3 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.57 (d, J = 8.0 Hz, 2H), 7.49 - 7.44 (m, 1H), 7.41 - 7.39 (m, 2H), 7.22 (t, J= 8.0 Hz, 2H), 4.91 (s, 1H), 4.77 (s, 1H), 2.39 - 2.36 (m, 1H), 2.23 - 2.21 (m, 1H), 2.15 - 2.10 (m, 2H), 2.05 (s, 3H), 2.02 - 1.86 (m, 4H), 1.71 - 1.49 (m, 7H), 1.42 - 1.05 (m, 11H), 0.89 (d, J = 4.0 Hz, 3H), 0.80 (s, 3H), 0.63 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ -114.77.

[0983] Example 408

[0984]

[0985] The title compound (14.6 mg, 17% yield) was prepared as a white solid from the compound of Example 407 according to a procedure similar to that of Example 13. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.61 - 7.55 (m, 2H), 7.50 - 7.44 (m, 1H), 7.45 - 7.40 (m, 2H), 7.22 (t, J = 8.0 Hz, 2H), 4.82 (s, 1H), 4.24 (s, 1H), 3.67 (s, 1H), 2.71 - 2.67(m, 1H), 2.22 - 2.18 (m, 1H), 2.07 (d, J = 12.0 Hz, 2H), 1.95 - 1.93 (m, 2H), 1.81 - 1.66 (m, 5H), 1.48 - 1.14 (m, 15H), 0.89 (d, J = 4.0 Hz, 3H), 0.76 (s, 3H), 0.62 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ-114.76.

[0986] Example 410

[0987]

[0988] The title compound (25 mg, 51% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 601.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 5.00 (s, 2H), 2.26 - 2.02 (m, 6H), 1.89 - 1.05 (m, 23H), 0.95 (s, 3H), 0.76 (d, J = 8.0 Hz, 3H), 0.72 (s, 3H).19F NMR (400 MHz, DMSO-d6) -60.63.

[0989] Example 412

[0990]

[0991] The title compound (4 mg, 6.66 μmol, 27.29% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 599.37 [MH] -.1H NMR (400 MHz, CD3OD) δ 8.05 - 7.95 (m, 2H), 7.73 (d, J = 1.5 Hz, 1H), 7.60 -7.54 (m, 2H), 7.47 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.35 (td, J = 7.5, 1.0 Hz, 1H), 2.59 (t, J = 13.9 Hz, 1H), 2.35 (ddd, J = 15.1, 9.5, 4.9 Hz, 2H), 2.27 - 2.16 (m, 2H), 2.14 (s, 3H), 2.13 - 1.00 (m, 26H), 0.98 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H), 0.71 (s, 3H).

[0992] Example 413

[0993]

[0994] The title compound (6.6 mg, 10.24 μmol, 9.63% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, Methanol-d4) δ = 7.72 - 7.49 (m, 6H), 7.41 (dd, J=8.5, 6.8, 2H), 7.31 (d, J=7.3, 1H), 4.03 (s, 1H), 2.67 (s, 1H), 2.50 - 1.26 (m, 33H), 1.17 (s, 1H), 1.10 - 0.97 (m, 6H), 0.90 (d, J=6.5, 1H), 0.87 (d, J=6.5, 2H), 0.76 (s, 3H).

[0995] Example 414

[0996]

[0997] The title compound (2.9 mg, 4.81 μmol, 4.53% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1H NMR (400 MHz, Methanol-d4) δ = 7.67 - 7.58 (m, 3H), 7.56 - 7.48 (m, 2H), 7.41 (dd, J=8.4, 6.9, 2H), 7.32 (d, J=7.2, 1H), 5.14 (s, 1H), 4.94 (s, 1H), 2.64 (s, 1H), 2.40 - 2.16 (m, 3H), 2.13 (s, 3H), 2.12 - 2.01 (m, 2H), 1.97 (s, 3H), 1.96 - 1.17 (m, 18H), 1.06 (s, 3H), 0.87 (d, J=6.5, 3H), 0.82 (s, 3H).

[0998] Example 415

[0999]

[1000] The title compound (6.6 mg, 10.24 μmol, 9.63% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, Methanol-d4) δ = 7.68 - 7.47 (m, 6H), 7.40 (t, J=7.7, 2H), 7.35 - 7.10 (m, 1H), 3.99 (s, 1H), 3.83 (d, J=3.5, 1H), 2.88 (s, 1H), 2.58 - 2.33 (m, 2H), 2.21 (dt, J=16.2, 7.8, 1H), 2.15 - 1.24 (m, 20H), 1.25 - 1.10 (m, 1H), 1.03 (d, J=5.7, 6H), 0.75 (d, J=3.4, 3H).

[1001] Example 416

[1002]

[1003] The title compound (20.6 mg, 21% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 573.3 [M+Na] + . 1¹H NMR (400 MHz, DMSO- d 6 ) δ 11.94 (s, 1H), 7.30 (d, J = 12.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 4.76 (s, 1H), 4.52 (s, 1H), 2.44 - 2.37 (m, 1H), 2.27 - 2.19 (m, 1H), 2.14 - 2.07 (m, 1H), 2.04 - 1.91 (m, 2H), 1.89 (s, 3H), 1.87 - 1.81 (m, 3H), 1.71 - 1.54 (m, 5H), 1.47 (s, 1H), 1.44 - 0.99 (m, 13H), 0.96 (s, 3H), 0.93 - 0.90 (m, 2H), 0.89 (d, J = 4.0 Hz, 3H), 0.64 (s, 3H), 0.63 - 0.60 (m, 2H).

[1004] Example 417

[1005]

[1006] The title compound (18.9 mg, 14% yield) was prepared as a white solid from the compound of Example 204 according to a procedure similar to that of Example 79. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.67 - 7.64 (m, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.50 - 7.43 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.21 (t, J= 8.0 Hz, 2H), 6.77 (s, 1H), 4.79 (s, 1H), 4.72 (s, 1H), 3.28 - 3.26 (m, 2H), 2.05 - 1.95 (m, 5H), 1.91 (s, 3H), 1.89 - 1.02 (m, 23H), 0.99 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.64 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ -114.82.

[1007] Example 419

[1008]

[1009] The title compound (46.4 mg, 51.38% yield) was prepared as a white solid according to a procedure similar to that of Example 27. LCMS:(ESI) m / z [M+Na] + =541.3. 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.96 (s, 1H), 7.90 - 7.84 (m, 3H), 7.65 (d, J = 8.0 Hz, 1H), 7.48 - 7.45 (m, 2H), 4.77 (s, 1H), 4.23 (s, 1H), 3.82 (s, 1H), 2.26 - 2.20 (m, 2H), 2.12 - 2.07 (m, 1H), 1.93 - 1.78 (m, 5H), 1.66 - 1.61 (m, 3H), 1.54 - 1.51 (m, 3H), 1.45 - 1.28 (m, 8H), 1.15 - 1.12 (m, 4H), 0.96 (s, 3H), 0.93 (d, J = 8.0 Hz, 3H), 0.63 (s, 3H).

[1010] Example 420

[1011]

[1012] The title compound (13.5 mg, 19% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 541.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.95 - 7.84 (m, 4H), 7.67 (d, J = 8.0 Hz, 1H), 7.48 - 7.46 (m, 2H), 4.95 (s, 1H), 4.29 (s, 1H), 3.83 (s, 1H), 2.27 - 2.01 (m, 6H), 1.88 - 1.55 (m, 8H), 1.47 - 1.29 (m, 7H), 1.25 - 1.15 (m, 3H), 1.06 - 0.98 (m, 1H), 0.93 (d, J = 8.0 Hz, 3H), 0.83 - 0.76 (m, 1H), 0.73 (s, 3H), 0.61 (s, 3H).

[1013] Example 421

[1014]

[1015] The title compound (35 mg, 54% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 559.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 7.68 (s, 4H), 5.09 (s, 1H), 4.28 (s, 1H), 3.81 (s, 1H), 2.29 - 1.89 (m, 6H), 1.86 - 1.48 (m, 8H), 1.46 - 0.98 (m, 11H), 0.93 (d, J = 4.0 Hz, 3H), 0.75 (s, 3H), 0.73 - 0.65 (m, 1H), 0.60 (s, 3H).19F NMR (400 MHz, DMSO-d6) -60.80.

[1016] Example 422

[1017]

[1018] The title compound (39 mg, 40% yield) was prepared as a white solid according to a procedure similar to that of Example 133. LCMS:(ESI) m / z [M+Na] + =583.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.94 (s, 1H), 7.90 - 7.83 (m, 3H), 7.58 - 7.55 (m, 1H), 7.49 - 7.46 (m, 2H), 5.02 (s, 1H), 4.86 (s, 1H), 2.22 - 2.21 (m, 2H), 2.09 (s, 3H), 2.07 - 2.08 (m, 1H), 1.89 - 1.81 (m, 4H), 1.72 - 1.56 (m, 7H), 1.51 - 1.38 (m, 5H), 1.36 - 1.08 (m, 7H), 0.97 (s, 3H), 0.77 (d, J = 8.0 Hz, 3H), 0.73 (s, 3H).

[1019] Example 423

[1020]

[1021] The title compound (47 mg, 57% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 583.3 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.85 (m, 4H), 7.66 (d, J = 8.0 Hz, 1H), 7.52 - 7.42 (m, 2H), 4.99 (s, 2H), 2.30 - 2.15 (m, 3H), 2.11 (s, 3H), 2.07 - 2.05 (m, 1H), 1.90 - 1.75 (m, 3H), 1.72 - 1.56 (m, 6H), 1.56 - 1.29 (m, 8H), 1.29 - 1.01 (m, 4H), 0.87 - 0.79 (m, 1H), 0.74 (d, J = 4.0 Hz, 3H), 0.76 (s, 2H), 0.70 (s, 3H).

[1022] Example 424

[1023]

[1024] The title compound (20 mg, 41% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 601.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 4H), 5.08 (s, 1H), 4.97 (s, 1H), 2.28 - 2.15 (m, 1H), 2.14 - 2.03 (m, 5H), 1.98 - 1.03 (m, 22H), 0.86 - 0.64 (m, 10H). 19 F NMR (400 MHz, DMSO-d6) -60.83.

[1025] Example 426

[1026]

[1027] The title compound (7.6 mg, 19% yield) was prepared as a white solid according to a procedure similar to that of Example 318. ESI-MS m / z = 559.3 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 6.62 - 6.51 (m, 2H), 4.97 (s, 1H), 4.71 (s, 1H), 2.28-2.16 (m, 1H), 2.14-2.08 (m, 1H), 2.07 (s, 3H), 2.01-1.94 (m, 1H), 1.80 - 1.09 (m, 23H), 0.90 (s, 3H), 0.75 (d, J = 4.0 Hz, 3H), 0.70 (s, 3H).

[1028] Example 429

[1029]

[1030] The title compound (2.8 mg, 4.34 μmol, 19.07% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 27. 1 H NMR (400 MHz, Methanol-d4) δ = 7.66 -7.51 (m, 6H), 7.42 (t, J=7.6, 2H), 7.32 (d, J=7.4, 1H), 5.11 (s, 1H), 4.93 (s, 1H), 2.51 (s, 2H), 2.31 (s, 3H), 2.19 (t, J=7.6, 3H), 2.15 (d, J=3.0, 7H), 2.03 (d, J=4.5, 3H), 1.95 - 1.66 (m, 9H), 1.58 (s, 2H), 1.53 - 1.25 (m, 12H), 0.99 (s, 2H), 0.92 - 0.83 (m, 7H), 0.79 (s, 3H).

[1031] Example 430

[1032]

[1033] The title compound (5.9 mg, 9.82 μmol, 30.19% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 599.72 [MH] - . 1 H NMR (400 MHz, CD3OD) δ7.98 (dd, J = 7.6, 2.6 Hz, 2H), 7.73 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 8.2, 1.6 Hz, 1H), 7.45 (ddd, J = 8.4, 7.3, 1.4 Hz, 1H), 7.34 (td, J = 7.5, 1.0 Hz, 1H), 4.92 (d, J = 9.0 Hz, 1H), 2.69 (t, J = 13.8 Hz, 1H), 2.34 (ddd, J = 15.1, 9.7, 5.2 Hz, 1H), 2.28 - 2.16 (m, 1H), 2.05 (dtd, J = 32.5, 13.8, 11.4, 5.1 Hz, 5H), 1.94 (s, 3H), 1.92 - 1.11 (m, 26H), 1.08 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.74 (s, 3H).

[1034] Example 433

[1035]

[1036] The title compound (35 mg, 57.87 μmol, 74.61% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 382. 1 H NMR (400 MHz, MeOD) δ7.63-7.57 (m, 6H), 7.44-7.40 (m, 2H), 7.33-7.29 (m, 1H), 5.50 (dd, J = 45.6 Hz, 11.2 Hz, 1H), 4.96-4.95 (m, 1H), 2.37-1.14 (m, 27H), 1.10 (m, 3H), 0.97 (d, J = 6.4 Hz,3H), 0.77 (s, 3H).

[1037] Example 434

[1038]

[1039] The title compound (12 mg, 21.32 μmol, 67.88% yield, free base) is a white solid and was prepared from the compound of Example 433 according to a method similar to that of Example 13. 1 H NMR (400 MHz, MeOD) δ7.61-7.56 (m, 6H), 7.43-7.39 (m, 2H), 7.32-7.29 (m, 1H), 5.80 (dd, J = 44.8 Hz, 10.8 Hz, 1H), 3.88 (s, 1H), 2.38-1.11 (m, 24H), 1.08 (m, 3H), 0.97 (d, J = 6.0 Hz, 3H), 0.73 (s, 3H).

[1040] Example 435

[1041]

[1042] The title compound (22.4 mg, 28% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 601.3 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.94 (s, 1H), 7.71 - 7.63 (m, 4H), 4.89 (s, 1H), 4.78 (d, J = 4.0 Hz, 1H), 2.42 - 2.41 (m, 2H), 2.27 - 2.20 (m, 1H), 2.12 - 1.93 (m, 3H), 1.89 (s, 3H), 1.86 - 1.71 (m, 3H), 1.69 - 1.56 (m, 4H), 1.49 (s, 1H), 1.39 - 1.06 (m, 12H), 0.98 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.64 (s, 3H).19 F NMR (400 MHz, DMSO- d 6 ) δ -60.58.

[1043] Example 436

[1044]

[1045] The title compound (4.7 mg, 19% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 567.2, 569.1 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.45 (d, J = 8.0 Hz,2H), 7.35 (d, J = 8.0 Hz,2H), 4.76 (s, 2H), 2.41-2.33 (m, 1H), 2.22-1.93 (m, 4H), 1.88 (s, 3H), 1.85-1.82 (m, 2H), 1.70-1.48 (m, 6H), 1.73-1.20 (m, 10H), 1.17-1.02 (m, 3H), 0.97 (s, 3H), 0.89(d, J = 4.0 Hz, 3H), 0.64 (s, 3H).

[1046] Example 437

[1047]

[1048] The title compound (20 mg, 51% yield) was prepared as a white solid according to a procedure similar to that of Example 373. LCMS:(ESI) m / z [M+Na] + =745.2. 1H NMR (400 MHz, DMSO-d6) δ11.90 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.84 (m, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.75 (s, 2H), 2.35 - 2.00 (m, 4H), 1.96 - 1.84 (m, 4H), 1.78 (s, 3H), 1.64 (m, 4H), 1.56 - 1.33 (m, 6H), 1.30 - 1.09 (m, 8H), 0.98 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.64 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -56.21.

[1049] Example 438

[1050]

[1051] The title compound (30 mg, 32% yield) was prepared as a white solid according to a procedure similar to that of Example 133. LCMS:(ESI) m / z [M+Na] + = 521.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 4.50 (s, 1H), 4.19 (s, 1H), 3.80 (s, 1H), 3.72 (s, 3H), 2.24 - 2.18 (m, 1H), 2.12 - 2.06 (m, 2H), 1.93 - 1.70 (m, 7H), 1.64 - 1.60 (m, 2H), 1.52 - 1.44 (m, 4H), 1.38 - 1.29 (m, 4H), 1.23 - 1.16 (m, 3H), 1.10 - 0.97 (m, 3H), 0.93 (s, 3H), 0.92(d, J = 4.0 Hz, 3H), 0.62 (s, 3H).

[1052] Example 439

[1053]

[1054] The title compound (17.1 mg, 7% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 531.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 4.51 (s, 1H), 4.20 (s, 1H), 3.80 (s, 1H), 2.26-2.18 (m, 1H), 2.13 - 2.01 (m, 2H), 1.93 - 1.72 (m, 7H), 1.63 - 1.01 (m, 17H), 0.95 - 0.86 (m, 8H), 0.67-0.56(m, 5H).

[1055] Example 440

[1056]

[1057] The title compound (7.5 mg, 15% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 563.7 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.32 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 4.99 (s, 1H), 4.59 (s, 1H), 3.72 (s, 3H), 2.25 - 2.18 (m, 1H), 2.12 - 2.07 (m, 1H), 2.05 (s, 3H), 2.00 (s, 1H), 1.90 - 1.71 (m, 4H), 1.65 - 1.51 (m, 6H), 1.48 - 1.03 (m, 13H), 0.93 (s, 3H), 0.76 (d, J = 4.0 Hz, 3H), 0.71 (s, 3H).

[1058] Example 441

[1059]

[1060] The title compound (5.6 mg, 3% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 573.3 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 4.99 (s, 1H), 4.60 (s, 1H), 2.22-2.18 (m, 1H), 2.14-2.07 (m, 1H), 2.05 (s, 3H), 1.92-1.72 (m, 5H), 1.64-1.03 (m, 20H), 0.93 (s, 3H), 0.92 - 0.87 (m, 2H), 0.76 (d, J = 8.0 Hz, 3H), 0.71 (s, 3H), 0.64-0.60 (m, 2H).

[1061] Example 442

[1062]

[1063] The title compound (20 mg, 11% yield) was prepared as a white solid according to a procedure similar to that of Example 27. ESI-MS m / z = 583.3 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.91 - 7.84 (m, 3H), 7.62 (d, J = 8.6 Hz, 1H), 7.52 - 7.41 (m, 2H), 4.79 (s, 2H), 2.61 - 2.53 (m, 1H), 2.21 - 2.12 (m, 1H), 2.08 - 1.98 (m, 2H), 1.97 - 1.74 (m, 8H), 1.72 - 1.58 (m, 4H), 1.55 - 1.08 (m, 13H), 0.99 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.65 (s, 3H).

[1064] Example 443

[1065]

[1066] The title compound (9.6 mg, 13% yield) was prepared as a white solid according to a procedure similar to that of Example 133. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.36 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 4.67 (s, 1H), 4.26 (s, 1H), 3.81 (s, 1H), 3.73 (s, 3H), 2.25 - 2.17 (m, 1H), 2.13 - 2.06 (m, 2H), 2.01 - 1.86 (m, 3H), 1.81 - 1.51 (m, 8H), 1.42 - 0.98 (m, 12H), 0.92 (d, J = 8.0 Hz, 3H), 0.73 (s, 3H), 0.60 (s, 3H).

[1067] Example 444

[1068]

[1069] The title compound (7.9 mg, 10% yield) was prepared as a white solid according to a procedure similar to that of Example 133. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.35 (d, J = 12.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 4.97 (s, 1H), 4.68 (s, 1H), 3.73 (s, 3H), 2.23 - 2.17 (m, 1H), 2.11 (s, 1H), 2.08 (s, 3H), 2.03 (d, J = 16.0 Hz, 2H), 1.90 (d, J= 16.0 Hz, 1H), 1.85 - 1.70 (m, 3H), 1.68 - 1.52 (m, 5H), 1.52 - 0.84 (m, 13H), 0.75 (d, J = 4.0 Hz, 6H), 0.69 (s, 3H).

[1070] Example 445

[1071]

[1072] The title compound (1.4 mg, 2.36 μmol, 5.73% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 373. 1 H NMR (400 MHz, CD3OD) δ 6.60 (dd,J= 18.6, 8.1 Hz, 4H), 5.33 (s, 1H), 3.45 (s, 2H), 3.08 (t,J= 5.5 Hz, 2H), 1.53 - 0.37 (m, 30H), 0.22 (s, 3H), 0.14 (d,J= 6.4 Hz, 3H), -0.10 (s, 3H).

[1073] Example 447

[1074]

[1075] The title compound (5.4 mg, 9.08 μmol, 9.82% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, CD3OD) δ 7.29 (dd,J= 68.6, 8.3 Hz, 4H), 5.11 (s, 1H), 4.03 (dd,J= 10.3, 2.8 Hz, 2H), 3.55 (s, 2H), 2.77 (td,J= 11.0, 5.1 Hz, 1H), 2.32 - 1.07 (m, 38H), 1.02 (s, 3H), 0.87 - 0.78 (m, 6H).

[1076] Example 448

[1077]

[1078] The title compound (15 mg, 37% yield) was prepared as a white solid according to a procedure similar to that of Example 226. ESI-MS m / z = 586.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.66 -7.63 (m, 4H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 4.70 (s, 1H), 4.10 (d, J = 8.0 Hz, 1H), 2.26 - 2.14 (m, 2H), 2.12 - 2.00 (m, 1H), 1.89 (s, 3H), 1.86 - 1.49 (m, 10H), 1.44 - 1.29 (m, 6H), 1.27 - 1.20 (m, 3H), 1.17 - 1.05 (m, 3H), 0.94 (s, 3H), 0.87 - 0.74 (m, 7H).

[1079] Example 449

[1080]

[1081] The title compound (13 mg, 14% yield) was prepared as a white solid according to a procedure similar to that of Example 373. LCMS:(ESI) m / z [M+Na] + = 677.1. 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.60 - 7.50 (m, 4H), 7.44 - 7.40 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 4.78 (s, 1H), 4.73 (s, 1H), 2.46 - 2.17 (m, 2H), 2.15 - 1.97 (m, 3H), 1.87 (s, 3H), 1.83 - 1.73 (m, 2H), 1.70 - 1.58 (m, 4H), 1.57 - 1.41 (m, 3H), 1.38 - 1.37 (m, 2H), 1.35 - 1.01 (m, 10H), 0.98 (s, 3H), 0.89 (d, J = 8.0 Hz, 3H), 0.65 (s, 3H).

[1082] Example 450

[1083]

[1084] The title compound (22.5 mg, 38% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 588.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.33 - 7.30 (m, 1H), 4.76 (s, 1H), 2.49-2.41 (m, 1H), 2.12 - 1.92 (m, 4H), 1.88 (s, 3H), 1.81-1.72 (m, 2H), 1.71 - 1.06 (m, 19H), 0.97 (s, 3H), 0.87 (d, J = 6.3 Hz, 3H), 0.63 (s, 3H).

[1085] Example 451

[1086]

[1087] The title compound (4.1 mg, 3% yield) was prepared as a white solid according to a procedure similar to that of Example 373. 1 H NMR (400 MHz, DMSO-d6) δ11.96 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 4.69 (s, 1H), 4.26 (s, 1H), 3.81 (s, 1H), 2.22-2.18 (m, 1H), 2.12-2.05 (m, 2H), 1.98-1.94 (m, 2H), 1.89-1.83 (m, 2H), 1.81 - 1.49 (m, 8H), 1.47 - 0.97 (m, 12H), 0.93-0.85 (m, 5H), 0.72 (s, 3H), 0.67 - 0.56 (m, 5H).

[1088] Example 452

[1089]

[1090] The title compound (7.3 mg, 7% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 573.3 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 4.97 (s, 1H), 4.71 (s, 1H), 2.26 - 2.18 (m, 1H), 2.08 (s, 3H), 2.06-2.02 (m, 2H), 1.94 - 1.72 (m, 5H), 1.71 - 0.98 (m, 19H), 0.94 - 0.89 (m, 2H), 0.78-0.71 (m, 6H), 0.69 (s, 3H), 0.65 - 0.60 (m, 2H).

[1091] Example 453

[1092]

[1093] The title compound (6.1 mg, 15% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 615.2 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.94 (s, 1H), 7.60 (d, J = 4.0 Hz,2H), 7.39 (t, J = 4.0 Hz,2H), 7.32 (d, J = 4.0 Hz,1H), 7.26 (t, J = 8.0 Hz,2H), 5.17 (s, 1H), 4.78(s, 1H), 2.45-2.42 (m, 1H), 2.26-2.19 (m, 1H), 2.14-2.03 (m, 1H), 1.96 (s, 3H), 1.83-1.48 (m, 11H), 1.42-1.03 (m, 12H), 0.96 (s, 3H), 0.89 (d, J = 4.0 Hz, 3H), 0.64 (s, 3H).

[1094] Example 454

[1095]

[1096] The title compound (61.2 mg, 60.7% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 563.2 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.96 (s, 1H), 7.36 (d, J = 8.0 Hz,2H), 6.86(d, J= 8.0 Hz,2H), 4.77 (s, 1H), 4.51(s, 1H), 3.72 (s, 2H), 2.42-2.36 (m, 1H), 2.23-1.95 (m, 4H), 1.84-1.81 (m, 2H), 1.66-1.47 (m, 6H), 1.37-1.06 (m, 13H), 0.96 (s, 3H), 0.89 (d, J = 4.0 Hz, 3H), 0.64 (s, 3H).

[1097] Example 455

[1098]

[1099] The title compound (6.1 mg, 10.35 μmol, 31.23% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 133. 1 H NMR (400 MHz, CD3OD) δ 7.61 - 7.21 (m, 4H), 5.11 (s, 1H), 2.37 - 1.25 (m, 30H), 1.20 - 1.09 (m, 2H), 1.02 (s, 3H), 0.85 (d,J= 6.5 Hz, 3H), 0.79 (s, 3H).

[1100] Example 456

[1101]

[1102] The title compound (5.4 mg, 9.11 μmol, 15.35% yield, free base) was prepared as a white solid according to a procedure similar to that of Example 373. 1 H NMR (400 MHz, CD3OD) δ 7.57 - 7.27 (m, 4H), 6.30 - 6.03 (m, 1H), 5.12 (s, 1H), 4.28 (q,J= 2.8 Hz, 2H), 3.91 (t,J= 5.5 Hz, 2H), 2.59 - 2.48 (m, 2H), 2.45 - 1.23 (m, 33H), 1.02 (s, 3H), 0.85 (d,J= 6.5 Hz, 3H), 0.80 (s, 3H).

[1103] Example 457

[1104]

[1105] The title compound (5.1 mg, 7.95 μmol, 14.68% yield) was prepared as a white solid according to a procedure similar to that of Example 373. 1 H NMR (400 MHz, CD3OD) δ 7.34 (d,J= 8.8 Hz, 2H), 6.94 (d,J= 8.8 Hz, 2H), 5.11 (s, 0H), 3.90 - 3.71 (m, 4H), 3.18 - 3.06 (m, 4H), 2.29 - 1.14 (m, 27H), 1.01 (s, 3H), 0.90 - 0.68 (m, 6H).

[1106] Example 458

[1107]

[1108] The title compound (22.1 mg, 28% yield) was prepared as a white solid according to a procedure similar to that of Example 133. ESI-MS m / z = 589.1 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.99 (s, 1H), 7.37 - 7.31 (m, 4H), 4.78 (s, 1H), 4.52 (s, 1H), 2.45 - 2.42 (m, 2H), 2.23 - 2.20 (m, 1H), 2.12 - 2.10 (m, 1H), 2.06 - 1.93 (m, 2H), 1.92 (s, 3H), 1.88 - 1.76 (m, 3H), 1.70 - 1.54 (m, 5H), 1.49 - 1.30 (m, 6H), 1.26 (s, 9H), 1.24 - 1.01 (m, 6H), 0.97 (s, 3H), 0.88 (d, J = 4.0 Hz, 3H), 0.64 (s, 3H).

[1109] Example 460

[1110]

[1111] The title compound (14.4 mg, 22% yield) was prepared as a white solid according to a procedure similar to that of Example 79. ESI-MS m / z = 699.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ11.59 (s, 1H), 8.52 (d, J = 4.1 Hz, 1H), 8.44 (s, 1H), 7.70-7.63 (m, 3H), 7.62-7.56 (m, 4H), 7.46 (t, J = 7.6) Hz, 2H), 7.40-7.33 (m, 2H), 4.69 (s, 1H), 4.58 (s, 2H), 4.23 (d, J = 4.7 Hz, 1H), 3.82 (s, 1H), 2.18-2.11 (m, 2H), 2.06 - 1.73 (m, 8H), 1.63 - 1.12 (m, 16H), 0.95 (s, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.64 (s, 3H).

[1112] Example 461

[1113]

[1114] The title compound (25 mg, 40% yield) was prepared as a white solid according to a procedure similar to that of Example 79. ESI-MS m / z = 761.9 [M+Na] + . 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 7.66 - 7.61 (m, 4H), 7.52 - 7.44 (m, 4H), 7.40 - 7.38 (m, 3H), 7.37 - 7.33 (m, 1H), 7.31 - 7.27 (m, 2H), 5.02 (s, 1H), 4.77 (s, 1H), 4.67 (s, 2H), 2.27 - 2.19 (m, 1H), 2.18 - 2.10 (m, 2H), 2.08 (s, 3H), 1.92 - 1.76 (m, 4H), 1.70 - 1.56 (m, 7H), 1.51 - 1.38 (m, 5H), 1.32 - 1.18 (m, 4H), 1.17 - 1.07 (m, 3H), 0.96 (s, 3H), 0.75 (d, J = 4.0 Hz, 3H), 0.74 (s, 1H).

[1115] Example 462

[1116]

[1117] The title compound (21.8 mg, 25% yield) was prepared as a white solid according to a procedure similar to that of Example 79. ESI-MS m / z = 777.0 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.57 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 2H), 7.48 - 7.39 (m, 4H), 7.23 - 7.19 (m, 2H), 4.79 (s, 1H), 4.74 (s, 1H), 4.70 (s, 2H), 2.47 - 2.42 (m, 2H), 2.23 -2.19 (m, 1H), 2.17 - 1.93 (m, 4H), 1.91 (s, 3H), 1.80 - 1.78 (m, 2H), 1.72 - 1.61 (m, 4H), 1.54 - 1.50 (m, 1H), 1.44 - 1.24 (m, 10H), 1.11 - 1.07 (m, 2H), 0.99 (s, 3H), 0.87 (d, J = 8.0 Hz, 3H), 0.66 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ -114.83.

[1118] Example 463

[1119]

[1120] The title compound (25.4 mg, 32% yield) was prepared as a white solid according to a procedure similar to that of Example 79. ESI-MS m / z = 751.9 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.57 (d, J = 8.0 Hz, 2H), 7.50 - 7.44 (m, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0 Hz, 2H), 4.79 (s, 1H), 4.73 (s, 1H), 3.71 (t, J= 8.0 Hz, 2H), 3.42 - 3.40 (m, 2H), 2.47 - 2.43 (m, 2H), 2.26 - 2.18 (m, 1H), 2.14 - 1.94 (m, 3H), 1.91 (s, 3H), 1.80 - 1.75 (m, 2H), 1.69 - 1.58 (m, 4H), 1.53 - 1.50 (m, 1H), 1.44 - 1.08 (m, 13H), 0.99 (s, 3H), 0.88 (d, J = 8.0 Hz, 3H), 0.65 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ -114.83.

[1121] Example 464

[1122]

[1123] The title compound (6.1 mg, 41% yield) was prepared as a white solid according to a procedure similar to that of Example 373. ESI-MS m / z = 627.1 [M+Na] + . 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.73 (s, 1H), 7.56-7.49 (m, 5H), 7.41 -7.38 (m, 1H), 7.7.32-7.27 (m, 2H), 4.78 (s, 1H), 4.72 (s, 1H), 2.45 (m, 1H), 2.22-1.96 (m,4H), 1.91 (s, 3H), 1.79-1.62 (m, 6H), 1.50-1.30 (m, 10H), 1.21-1.03 (m, 5H), 0.99 (s, 3H), 0.90 (d, J = 8.0 Hz,3H), 0.85-0.84 (m, 1H), 0.65 (s, 3H). 19 F NMR (400 MHz, DMSO- d 6 ) δ -118.44.

[1124] Example 465

[1125]

[1126] The title compound (9.5 mg, 13% yield) was prepared as a white solid according to a procedure similar to that of Example 110. ESI-MS m / z = 671.0 [M+Na] + . 1 ¹H NMR (400 MHz, MeOD- d 4 ) δ 8.15 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 5.39 (s, ...

Claims

Claim 1 As a compound having the following general formula (I), an optical isomer thereof, a pharmaceutically acceptable salt or a prodrug: Here: represents a single or double bond, and R if a single double bond is present. 5a or R 5b is absent and R 4 is absent; X is hydrogen, deuterium, halogen, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , -OS(=O)2OR X , -OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)N(R X )2, -N(R X )C(=NR X )N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and -S(=O)2N(R X Selected from a group consisting of )2, where each R X is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, and a sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring together with intervening atoms; preferably, X is OH; and R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; preferably R 1 is selected from the group consisting of substituted or unsubstituted alkynoyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls, more preferably being a substituted or unsubstituted aryl; A, B, C, D, and E are independently (CR R1 R R2 ) q -,-(CR R1 R R2 ) q -O-, -(CR R1 R R2 ) q -S-, and -(CR R1 R R2 ) q -(NR R3 Selected from a group consisting of )-, where R R1 , R R2 , and R R3 is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , -OS(=O)2OR X , -OS(=O)2N(R X )2, -N(R X )C(=O)R X , -N(R X )C(=NR X )R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X )N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and -S(=O)2N(R X Selected from a group consisting of )2, where each R X is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, or substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, and a sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring with intervening atoms; or R R1 and R R2 combines to form an oxo (=O) group; q is independently 0, 1, or 2; R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , and R 9 Each is independently hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR X , -N(R X )2, -SR X , -C(=O)R X , -C(=O)OR X , -C(=O)SR X , -C(=O)N(R X )2, -OC(=O)R X , -OC(=O)OR X , -OC(=O)N(R X )2, -OC(=O)SR X , -OS(=O)2R X , - OS(=O)2OR X , - OS(=O)2N(R X )2, -N(R X )C(=O) R X , -N(R X )C(=NR X ) R X , -N(R X )C(=O)OR X , -N(R X )C(=O)NR X )2, -N(R X )C(=NR X ) N(R X )2, -N(R X )S(=O)2R X , -N(R X )S(=O)2OR X , -N(R X )S(=O)2N(R X )2,-SC(=O)R X , -SC(=O)OR X , -SC(=O)SR X , -SC(=O)N(R X )2, -S(=O)2R X , -S(=O)2OR X , and -S(=O)2N(R X Selected from a group consisting of )2, where each R X is independently selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbociclel, substituted or unsubstituted heterocyclile, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, and a sulfur protecting group when bonded to sulfur, or two R X The group forms a substituted or unsubstituted heterocyclic ring with intervening atoms; or R 2a and R 2b , R 5a and R 5b , R 6a and R 6b , or R 8a and R 8b combines independently to form an oxo (=O) group; R 10 -C(=O)OH, -C(=O)R 101 , -C(=O)NHR 101 , -C(=O)NHR 101 SO3H, -C(=O)NHSO2R 101 , -C(=O)NR 101 OH, -C(=O)NMeOH, -P(=O)OH, -P(=O)(OH)2, -SO2OH, -S(=O)OH, -SO2NHR 101 , -NHC(=O)NHSO2R 101 , -NHC(=O)NHCOR 101 , selected from the group consisting of tetrazolyl, thiazolidinyl, or oxazolidinedione groups, where R 101 is selected from H, OH, alkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or natural or non-natural amino acid groups; W is , , , and It is selected from a group consisting of , where K is R 9 Indicates the bonding site at the carbon conjugated with, and R W1 and R W2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and nitrogen protecting group when bonded to nitrogen; or R W1 and R W2 combines to form an oxo (=O) group; Z is -(Z1) n -(Z2) m -(CR Y1 R Y2 ) o - and, where Z1 and Z2 are independently -CR Y3 R Y4 -, -NR Y5 -, O, S, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Y1 and R Y2 is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or R Y1 or R Y2 is independently combined to form a double or triple bond with conjugated H; R Y3 and R Y4 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R Y3 or R Y4 combines independently to form a double or triple bond with an adjacent H; R Y5 A compound characterized in that is hydrogen, deuterium, hydroxyl, C1-C3 alkoxy, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and n, m and o are independently 0, 1 or 2. Claim 2 In paragraph 1, the chemical formula ( I The above compound of ) chemical formula ( II ), or ( III Displayed as ), Here, A, B, C, D, and E are each independently -(CR R1 R R2 Except for )-, it is as previously defined (chemical formula ( I As defined in ); and X, W, Z, R 1 , R R1 , R R2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 is as previously defined (chemical formula ( I A compound characterized by being as defined in ). Claim 3 In paragraph 1, the chemical formula ( I The above compound of ) chemical formula ( IIa ), ( IIb ), ( IIc ), ( IId ) or ( IIe Displayed as ), Here, A, B, C, D, and E are each -(CR R1 R R2 Except for )-, as defined in Paragraph 1, and X, W, Z, R 1 , R R1 , R R2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 A compound characterized by being as defined in paragraph 1. Claim 4 In paragraph 1, the chemical formula ( I The above compound of ) chemical formula ( IIIa ) or ( IIIb Displayed as ), Here, X, W, Z, R 1 , R R1 , R R2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , and R 10 A compound characterized by being as defined in paragraph 1. Claim 5 In paragraph 1, the chemical formula ( I The above compound of ) chemical formula ( IIIa ), ( IIIb ), ( IIIa-A ) or ( IIIb-B Displayed as ), Here, X, W, Z, R 1 , R R1 , R R2 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , R 10 A compound characterized by being as defined in paragraph 1. Claim 6 In paragraph 1, the chemical formula ( I The above compound of ) chemical formula ( IIIa-1 ), ( IIIa-2 ), ( IIIa-3 ), ( IIIa-4 ), ( IIIa-1A ), ( IIIa-2A ), ( IIIa-3A ), or ( IIIa-4A Displayed as ), Here, X, Z, R 1 , R R1 , R R2 , R W1 , R W2 ,R 2a , R 2b , R 3 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , R 10 is as defined in paragraph 1; or chemical formula ( I The above compound of ) chemical formula ( IIIb-1 ), ( IIIb-2 ), ( IIIb-3 ), ( IIIb-4 ), ( IIIb-1B ), ( IIIb-2B ), ( IIIb-3B ), or ( IIIb-4B Displayed as ), Here, X, Z, R 1 , R R1 , R R2 , R W1 , R W2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , R 10 A compound characterized by being as defined in paragraph 1. Claim 7 In claim 1, the compound of formula (I) is formula ( IIIb-11 ), ( IIIb-12 ), ( IIIb-11A ), or (IIIb-12B Displayed as ), Here, X, Z1, Z2, R 1 , R R1 , R R2 , R W1 , R W2 ,R 2a , R 2b , R 3 , R 4 , R 5a , R 5b ,R 6a , R 6b , R 7 , R 8a , R 8b , R 9 , R 10 A compound characterized in that , n, and m are as defined in claim 1. Claim 8 In claim 1, the compound of formula (I) is formula ( IVa ), ( IVb ), ( IVc ), ( IVd ), ( IVe ), or ( IVf Displayed as ), Here, X, Z1, Z2, R 1 , R R1 , R R2 , R W1 , R W2 ,R Y1 , R Y2 , R 2a , R 2b ,R 5a , R 5b ,R 6a , R 6b , R 8a , R 8b , R 9 , R 10 A compound characterized in that , n, and m are as defined in claim 1. Claim 9 In any one of paragraphs 1 through 8, R 1 is a substituted or unsubstituted alkynyl; preferably, R 1 is a substituted or unsubstituted C2-C8 alkynyl; preferably, R 1 The alkynyl is substituted with one or more substituents selected from the group consisting of deuterium, hydroxyl, halogen, CN, NO2, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, e.g., C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, optionally substituted or unsubstituted C6-C10 aryloxyl, substituted or unsubstituted C7-C10 arylalkyl, substituted or unsubstituted C2-C10 heterocyclyl, and substituted or unsubstituted C1-C10 heteroaryl, wherein one or more substituents from the aforementioned substituted groups are deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, Selected from the group consisting of halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C7-C10 arylalkyl (e.g., benzyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl; preferably, R 1 The following structure: Selected from, R 11 is absent, or R 11 is one or more substituents selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C7-C10 aryl (e.g., benzyl), C6-C10 aryloxyl (e.g., phenyloxyl), C2-C10 heterocyclyl, and C1-C10 heteroaryl; L is absent or selected from C1-C6 alkyl or C1-C6 alkoxy; more preferably, R 1 Eun Hagi Gi: ; A compound characterized by being selected from. Claim 10 In any one of paragraphs 1 through 8, R 1 is an unsubstituted or substituted C6-C10 aryl; preferably, R 1 is a phenyl substituted with one or more substituents independently selected from deuterium, hydroxyl, halogen, CN, NO2, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl, optionally substituted or unsubstituted C3-C10 cycloalkyl, e.g., C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxyl, and optionally substituted or unsubstituted C1-C10 heteroaryl; preferably, R 1 is a phenyl substituted with one or more substituents independently selected from fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, NO2, phenyl, and cyclopropyl; preferably, R 1 The following structure: Selected from, R 11 is absent, or is one or more substituents selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl; more preferably, R 1 Eun Hagi Gi: A compound characterized by being selected from. Claim 11 In any one of paragraphs 1 through 8, R 1 is a substituted or unsubstituted C1-C20 heteroaryl; preferably, R 1 is a C1-C20 heteroaryl substituted with one or more substituents independently selected from halogen, CN, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted C1-C10 heteroaryl; preferably, R 1 The following structure: Selected from, R 11 is absent, or is one or more substituents selected from the group consisting of deuterium, hydroxyl, halogen (e.g., fluoro, chloro, bromo, or iodo), CN, NO2, C1-C6 alkoxy, e.g., CH3O-, C1-C6 alkyl, halogenated C1-C6 alkyl (e.g., CF3), C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C10 aryl (e.g., phenyl), C6-C10 aryloxyl (e.g., phenyloxyl), and C1-C10 heteroaryl; more preferably, R 1 Eun Hagi Gi: A compound characterized by being selected from. Claim 12 In any one of paragraphs 1 through 11, Z is -(Z1) n -(Z2) m -(CR Y1 R Y2 ) o - and, where Z1 and Z2 are each independently CR Y3 R Y4 , NR Y5 , O, S, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R Y1 and R Y2 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R Y1 or R Y2 is independently combined to form a double or triple bond with conjugated H; R Y3 and R Y4 is independently hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkoxy, CN, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or R Y3 or R Y4 combines independently to form a double or triple bond with an adjacent H; R Y5 is hydrogen, deuterium, hydroxyl, C1-C3 alkoxy, substituted or unsubstituted -C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when bonded to nitrogen; n, m, and o are independently 0, 1, or 2; preferably, Z is the following structure: Selected from, where 0-2 represents 0, 1, or 2; Y is absent or NR Y5 , O, S, selected from the group consisting of substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; more preferably, Z is the following: A compound characterized by being selected from. Claim 13 In any one of paragraphs 1 through 12, R 10 -C(=O)OH, -C(=O)R 101 , -C(=O)NHR 101 , -C(=O)NHR 101 SO3H, -C(=O)NHSO2R 101 , -C(=O)NR 101 OH, -C(=O)(NMe)OH, -P(=O)OH, -P(=O)(OH)2, -SO2OH, -S(=O)OH, -SO2NHR 101 , -NHC=ONHSO2R 101 , -NHC(=O)NHCOR 101 , selected from the group consisting of tetrazolyl, thiazolidinyl, and oxazolidinedione groups, where R 101 It is selected from the group consisting of H, OH, alkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or natural or non-natural amino acid groups; preferably R 10 The next one: Selected from; preferably R 10 is a taurine-conjugated carboxylic acid group; or R 10 is an amino acid-conjugated carboxylic acid group, where the said amino acid is the following group: A compound characterized by being selected from. Claim 14 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound presented below: A compound characterized by being selected from. Claim 15 A pharmaceutical composition characterized by comprising, wherein the compound or optical isomer according to any one of claims 1 to 14, the solvated form, the prodrug, or the pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient. Claim 16 A method for treating or preventing diseases associated with HBV infection or HDV infection, or for regulating NTCP function, comprising the step of administering to a subject a therapeutically effective amount of the compound or the optical isomer according to any one of claims 1 to 14, the solvated form, the prodrug, or the pharmaceutically acceptable salt, or a combination of the compound and / or the optical isomer, the solvated form, the prodrug, or the pharmaceutically acceptable salt according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15. Claim 17 A method according to claim 16, further comprising the step of administering to a subject at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, an immunomodulator, an interferon, a separate viral entry inhibitor, a viral maturation inhibitor, a capsid assembly regulator, a core protein inhibitor or regulator, a reverse transcriptase inhibitor, a TLR regulator, an immunoactivator of a cell viral RNA sensor, a therapeutic vaccine, an antisense oligonucleotide (ASO), RNA interference (RNAi), small interfering RNA (siRNA), and combinations thereof. Claim 18 A method according to any one of claims 16 to 17, characterized in that the compound and / or the optical isomer, the solvated form, the prodrug, or the pharmaceutically acceptable salt and the at least one additional therapeutic agent are co-formulated. Claim 19 Use of the compound or combination of the compounds according to any one of claims 1 to 16 and / or the optical isomer, the solvated form, the prodrug, or the pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 15 in the manufacture of a drug for treating or preventing HBV infection or HDV infection-related disease or for regulating NTCP function. Claim 20 Use of the compound or combination of the compounds according to any one of claims 1 to 14 and / or the optical isomer, the solvated form, the prodrug, or the pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 15 as an NTCP inhibitor.

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